CN112110918B - Spiro substituted pyrimido cyclic compounds, process for their preparation and their use in medicine - Google Patents

Spiro substituted pyrimido cyclic compounds, process for their preparation and their use in medicine Download PDF

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CN112110918B
CN112110918B CN202010563517.7A CN202010563517A CN112110918B CN 112110918 B CN112110918 B CN 112110918B CN 202010563517 A CN202010563517 A CN 202010563517A CN 112110918 B CN112110918 B CN 112110918B
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substituted
diazaspiro
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CN112110918A (en
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周福生
蒋涛
彭灵
赵金柱
何宛
兰炯
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Genfleet Therapeutics Shanghai Inc
Zhejiang Genfleet Therapeutics Co Ltd
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Zhejiang Genfleet Therapeutics Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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Abstract

The invention discloses a spiro-substituted pyrimido-ring compound with selective inhibition effect on KRAS gene mutation, and pharmaceutically acceptable salts, stereoisomers, solvent compounds or prodrugs thereof, which are shown as a formula (I), wherein the definition of each group or symbol in the formula is shown in the specification in detail. In addition, the invention also discloses a pharmaceutical composition containing the compound and application thereof in preparing cancer drugs.

Description

Spiro substituted pyrimido cyclic compounds, process for their preparation and their use in medicine
Technical Field
The invention relates to the technical field of medicines, in particular to a spiro-substituted pyrimido-cyclic compound, application thereof as a selective inhibitor of KRAS gene mutation and a pharmaceutical composition prepared from the spiro-substituted pyrimido-cyclic compound.
Background
Lung cancer is the highest incidence of cancer worldwide, the first of all cancers in chinese lung cancer incidence, and also the highest incidence and mortality in chinese, and according to published data by the american cancer society in 2016, approximately 180 ten thousand people in the world suffer from lung cancer, of which nearly 80% are non-small cell lung cancers (NSCLC).
RAS is a closely related monomeric globular protein (21 kDa molecular weight) of 188-189 amino acids that binds to guanosine diphosphate GDP or guanosine triphosphate GTP. RAS subfamily members include HRAS, KRAS, and NRAS. The RAS functions as a molecular switch that is in a dormant or off position and "inactive" when the RAS contains bound GDP. When cells are exposed to certain somatotrophic stimuli, the RAS is induced to convert its bound GDP to GTP, and when bound to GTP, the RAS "turns on" and is able to interact with other downstream target proteins and activate these proteins. The RAS protein itself has very low inherent ability to hydrolyze GTP and restore it to GDP (thereby switching itself to the off state). Exogenous protein GTPase Activating Proteins (GAPs) are required to return to the off state, and the interaction of GAPs with RAS greatly accelerates the conversion of GTP to GDP.
Any mutation in the RAS that would affect the interaction of the RAS with GAP, and the ability of GTP to convert to GDP, would result in an extension of the protein activation time, and thus in an extension of cell signaling, which in turn would result in continued cell growth and division. Since this signaling causes cell growth and division, overactivated RAS signaling can ultimately lead to cancer.
In lung cancer, mutations in the RAS gene are confirmed in about 32% of lung cancers, and any one of the three major subtypes of the RAS (HRAS, NRAS, or KRAS) gene may lead to the occurrence of human tumors. The highest frequency of mutation among the RAS genes was reported to be the KRAS gene, with KRAS mutations detected in 25-30% of tumors. In contrast, the rate of oncogenic mutations in NRAS and HRAS family members is much lower (8% and 3%, respectively). The most common KRAS mutations are found at residues G12 and G13 and at residue Q61 in the P loop. G12C mutation is a frequent mutation of the KRAS gene (glycine-12 mutation to cysteine). This mutation has been found in about 13% of cancers, about 43% of lung cancers and almost 100% of MYH-related polyposis (familial colon cancer syndrome).
Therefore, the development of an inhibitor for selectively inhibiting KRAS mutation is a better direction, and in order to improve the inhibition activity on KRAS mutation and reduce the inhibition activity on wild KRAS, the development of a novel RAS mutant selective inhibitor with higher activity, better selectivity and lower toxicity has important significance.
Disclosure of Invention
The invention provides a spiro-substituted pyrimido ring compound which is used as a selective inhibitor of KRAS mutation and has the advantages of high activity, good selectivity, low toxic and side effects and the like.
In one aspect, the invention provides a spiro-substituted pyrimido cyclic compound, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein the structure of the compound is shown as formula (I):
in the method, in the process of the invention,
x is N-C (O) -CR X3 ＝CR X1 R X2 Or N-C (O) -CCR X4 ；
Wherein R is X1 、R X2 Each independently is hydrogen, halogen, cyano, NR a R b 、C 1-3 Alkyl, halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 alkyl-C 1-3 Alkoxy, -C 1-3 alkyl-NR a R b 、-C 1-3 Alkyl-3To 6 membered heterocycloalkyl, -C 1-3 Alkyl-5 or 6 membered monocyclic heteroaryl;
R X3 is hydrogen, halogen, -O-C 1-3 Alkyl, -O-halo C 1-3 Alkyl, -O-C 3-6 Cycloalkyl or-O-halo C 3-6 Cycloalkyl;
R X4 is hydrogen or halogenated C 1-3 Alkyl, -C 1-3 Alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 alkyl-C 1-3 An alkoxy group;
wherein R is a 、R b Each independently is hydrogen or C 1-3 An alkyl group;
m, n are each independently 1, 2 or 3; and m and n are not 1 at the same time;
R 1 is halogen, -O-R 11 、-NH-R 11 or-N (R) 11 )R 12 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 11 、R 12 Each independently is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-or 6-membered monocyclic heteroaryl, or substituted or unsubstituted 8-to 10-membered bicyclic heteroaryl; or R is 11 、R 12 Together with the attached nitrogen atom form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl; and when m=n=2, R 1 Is not halogen; wherein the 3-to 6-membered heterocycloalkyl, 5-or 6-membered monocyclic heteroaryl, 8-to 10-membered bicyclic heteroaryl each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;
l is a bond, -CR L1 R L2 -、-O-(CR L1 R L2 ) t1 -or-NH- (CR) L3 R L4 ) t2 -; wherein R is L1 、R L2 、R L3 、R L4 The same or different, each independently hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, C 1-3 Alkyl or oxo; t1, t2 are each independently 0, 1, 2, 3 or 4;
R 2 is halogen, hydroxy, -SO 2 C 1-6 Alkyl, substituted or unsubstituted 3 to20 membered heterocycloalkyl, substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted 5-or 6-membered monocyclic heteroaryl or NR 21 R 22 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 21 、R 22 Each independently is hydrogen, substituted or unsubstituted C 1-6 Alkyl, -SO 2 C 1-6 Alkyl, -SO 2 C 3-6 Cycloalkyl, -C (O) C 1-6 Alkyl or-C (O) halo C 1-6 An alkyl group; or R is 21 And R is 22 Together with the attached nitrogen atom form a substituted or unsubstituted 3 to 20 membered heterocycloalkyl; wherein the 3-to 20-membered heterocycloalkyl, 5-or 6-membered monocyclic heteroaryl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;
z is N or CR 3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 Is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 Alkynyl or substituted or unsubstituted C 3-20 Cycloalkyl;
e is CR 4 Or N; wherein R is 4 Is hydrogen, halogen, cyano, hydroxy, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted C 3-20 Cycloalkoxy, -NH- (C) 1-4 Alkyl) or-N (C) 1-4 Alkyl group 2 ；
By "substituted" is meant that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S;
the S group substituents are selected from: hydroxy, halogen, nitro, oxo, C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, benzyl, - (CH) 2 ) u -cyano, - (CH) 2 ) u -C 1-6 Alkoxy, - (CH) 2 ) u Halogenated C 1-6 Alkoxy, - (CH) 2 ) u Halogenated C 1-6 Alkyl, - (CH) 2 ) u -3 to 6 membered heterocycloalkyl, - (CH) 2 ) u -5-or 6-membered monocyclic heteroaryl, - (CH) 2 ) u -C 3-8 Cycloalkyl, - (CH) 2 ) u -O-(CH 2 ) v -C 3-8 Cycloalkyl, - (CH) 2 ) u -O-(CH 2 ) v -C 1-6 Alkoxy, - (CH) 2 ) u -O-(CH 2 ) v OH、-(CH 2 ) u -SO 2 C 1-6 Alkyl, - (CH) 2 ) u -NR a0 R b0 、-(CH 2 ) u -C(O)NR a0 R b0 、-(CH 2 ) u -C(O)C 1-6 Alkyl, -C (O) OC 1-6 Alkyl, NR a0 C(O)-(CH 2 ) u -NR a0 R b0 、NR a0 C(O)-(CH 2 ) u OH、NR a0 C (O) -halo C 1-6 An alkyl group; wherein the 3-to 6-membered heterocycloalkyl, 5-or 6-membered monocyclic heteroaryl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3-to 6-membered heterocycloalkyl, 5-or 6-membered monocyclic heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Substituents of cycloalkyl groups; u, v are each independently 0, 1, 2, 3 or 4; r is R a0 、R b0 Each independently is hydrogen or C 1-3 An alkyl group;
b is C 6-10 Aryl, 5-or 6-membered monocyclic heteroaryl or 8-to 10-membered bicyclic heteroaryl; wherein the 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C is 6-10 Aryl, 5-or 6-membered monocyclic heteroaryl, 8-to 10-membered bicyclic heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from R s1 Is substituted by a group of (2); or alternatively
B is a structure shown in formula (B):
wherein, the B1 ring is benzene ring or 5 or 6 membered monocyclic heteroaryl ring; the B2 ring is a 5-or 6-membered heterocycloalkyl ring fused with the B1 ring or a 5-or 6-membered cycloalkyl ring fused with the B1 ring; wherein the 5-or 6-membered monocyclic heteroaryl ring, 5-or 6-membered heterocycloalkyl ring each independently have 1, 2, or 3 heteroatoms selected from N, O and S as ring atoms;
(R s1 ) p represents hydrogen on the B1 ring being bound by p R s1 Substituted, p is 0, 1, 2 or 3, each R s1 The same or different;
(R s2 ) q represents hydrogen on the B2 ring being bound by q R s2 Substituted, q is 0, 1, 2 or 3, each R s2 The same or different;
R s1 、R s2 each independently is hydroxy, halogen, nitro, oxo, C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, benzyl, - (CH) 2 ) u1 -cyano, - (CH) 2 ) u1 -C 1-6 Alkoxy, - (CH) 2 ) u1 Halogenated C 1-6 Alkoxy, - (CH) 2 ) u1 Halogenated C 1-6 Alkyl, - (CH) 2 ) u1 -3 to 6 membered heterocycloalkyl, - (CH) 2 ) u1 -5-or 6-membered monocyclic heteroaryl, - (CH) 2 ) u1 -C 3-8 Cycloalkyl, - (CH) 2 ) u1 -O-(CH 2 ) v1 -C 3-8 Cycloalkyl, - (CH) 2 ) u1 -O-(CH 2 ) v1 -C 1-6 Alkoxy, - (CH) 2 ) u1 -O-(CH 2 ) v1 OH、-(CH 2 ) u1 -SO 2 C 1-6 Alkyl, - (CH) 2 ) u1 -NR a0 R b0 、-(CH 2 ) u1 -C(O)NR a0 R b0 、-(CH 2 ) u1 -C(O)C 1-6 Alkyl, -C (O) OC 1-6 Alkyl, NR a0 C(O)-(CH 2 ) u1 -NR a0 R b0 、NR a0 C(O)-(CH 2 ) u1 OH、NR a0 C (O) -halo C 1-6 An alkyl group; wherein the 3-to 6-membered heterocycloalkyl, 5-or 6-membered monocyclic heteroaryl each independently has 1,2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3-to 6-membered heterocycloalkyl, 5-or 6-membered monocyclic heteroaryl is optionally substituted with 1,2 or 3 groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Substituents of cycloalkyl groups; u1, v1 are each independently 0, 1,2, 3 or 4; r is R a0 、R b0 Each independently is hydrogen or C 1-3 An alkyl group.
In one embodiment of the invention, X is N-C (O) -CR X3 ＝CR X1 R X2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is X1 、R X2 Each independently is hydrogen, halogen, cyano, amino, NHCH 3 、N(CH 3 ) 2 Methyl, ethyl, n-propyl, isopropyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -CH 2 -hydroxy, -CH 2 -cyano, -CH 2 -methoxy, -CH 2 -ethoxy, -CH 2 -propoxy, -CH 2 -isopropoxy, -CH 2 -NH 2 、-CH 2 -NHCH 3 、-CH 2 -N(CH 3 ) 2 、-CH 2 -3-to 6-membered heterocycloalkyl, -CH 2 -5 or 6 membered monocyclic heteroaryl; the 3-to 6-membered heterocycloalkyl is selected from: aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran; the 5-or 6-membered monocyclic heteroaryl is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine; the 3-to 6-membered heterocycloalkyl, 5-or 6-membered monocyclic heteroaryl is optionally substituted with 1 or 2 halogen or C 1-3 Alkyl substitution; r is R X3 Is hydrogen, halogen, methoxy, ethoxy, propoxy or isopropoxy.
In one embodiment of the invention, X is N-C (O) -CCR X4 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is X4 Is hydrogen, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoro Methyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -CH 2 -hydroxy, -CH 2 -cyano, -CH 2 -methoxy, -CH 2 -ethoxy, -CH 2 -propoxy, -CH 2 -isopropoxy.
In one embodiment of the invention, R 1 Is halogen, -O-R 11 、-NH-R 11 or-N (R) 11 )R 12 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 11 、R 12 Each independently is a substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5 or 6 membered monocyclic heteroaryl, or substituted or unsubstituted 8 to 10 membered bicyclic heteroaryl; or R is 11 、R 12 Together with the attached nitrogen atom form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl; and when m=n=2, R 1 Is not halogen; wherein the 3-to 6-membered heterocycloalkyl, 5-or 6-membered monocyclic heteroaryl, 8-to 10-membered bicyclic heteroaryl each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; by "substituted" is meant that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S.
In one embodiment of the invention, R 1 Is halogen, -O-R 11 、-NH-R 11 or-N (R) 11 )R 12 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 11 、R 12 Each independently is a substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 or 6 membered monocyclic heteroaryl; or R is 11 、R 12 Together with the attached nitrogen atom form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl; and when m=n=2, R 1 Is not halogen; by "substituted" is meant that 1,2,3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S; the C is 3-6 Cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the 3-to 6-membered heterocycloalkyl is selected from: aziridine ring, ringOxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran; the 5-or 6-membered monocyclic heteroaryl is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.
In one embodiment of the invention, R 2 Is halogen, hydroxy, -SO 2 C 1-3 Alkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 5-or 6-membered monocyclic heteroaryl, or NR 21 R 22 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 21 、R 22 Each independently is hydrogen, substituted or unsubstituted C 1-3 Alkyl, -SO 2 C 1-3 Alkyl, -SO 2 C 3-6 Cycloalkyl, -C (O) C 1-3 Alkyl or-C (O) halo C 1-3 An alkyl group; or R is 21 And R is 22 Together with the attached nitrogen atom form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl; wherein 3 to 6 membered heterocycloalkyl, 5 or 6 membered monocyclic heteroaryl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; by "substituted" is meant that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S.
In one embodiment of the invention, R 2 Is halogen, hydroxy, -SO 2 C 1-3 Alkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 5-or 6-membered monocyclic heteroaryl, or NR 21 R 22 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 21 、R 22 Each independently is hydrogen, substituted or unsubstituted C 1-3 Alkyl, -SO 2 C 1-3 Alkyl, -SO 2 C 3-6 Cycloalkyl, -C (O) C 1-3 Alkyl or-C (O) halo C 1-3 An alkyl group; or R is 21 And R is 22 Together with the attached nitrogen atom form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl; by "substituted" is meant that 1,2,3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S; the C is 3-6 Cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the 3-to 6-membered heterocycloalkyl is selected from: aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran; the 5-or 6-membered monocyclic heteroaryl is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.
In one embodiment of the invention, Z is N or CR 3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 Is hydrogen, halogen, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4 Alkynyl or substituted or unsubstituted C 3-6 Cycloalkyl; by "substituted" is meant that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S.
In one embodiment of the invention, Z is N or CR 3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 Is hydrogen, halogen, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4 Alkynyl or substituted or unsubstituted C 3-6 Cycloalkyl; by "substituted" is meant that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S; the C is 3-6 Cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
In one embodiment of the invention E is CR 4 Or N; wherein R is 4 Is hydrogen, halogen or cyanoHydroxy, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cycloalkoxy, -NH- (C) 1-3 Alkyl) or-N (C) 1-3 Alkyl group 2 The method comprises the steps of carrying out a first treatment on the surface of the By "substituted" is meant that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S.
In one embodiment of the invention E is CR 4 Or N; wherein R is 4 Is hydrogen, halogen, cyano, hydroxy, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cycloalkoxy, -NH- (C) 1-3 Alkyl) or-N (C) 1-3 Alkyl group 2 The method comprises the steps of carrying out a first treatment on the surface of the By "substituted" is meant that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S; the C is 3-6 Cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the C is 3-6 The cycloalkoxy group is selected from: cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
In one embodiment of the invention, the S group of substituents is selected from: hydroxy, halogen, nitro, oxo, C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, benzyl, - (CH) 2 ) u -cyano, - (CH) 2 ) u -C 1-3 Alkoxy, - (CH) 2 ) u Halogenated C 1-3 Alkoxy, - (CH) 2 ) u Halogenated C 1-3 Alkyl, - (CH) 2 ) u -3 to 6 membered heterocycloalkyl, - (CH) 2 ) u -5-or 6-membered monocyclic heteroaryl, - (CH) 2 ) u -C 3-6 Cycloalkyl, - (CH) 2 ) u -O-(CH 2 ) v -C 3-6 Cycloalkyl, - (CH) 2 ) u -O-(CH 2 ) v -C 1-3 Alkoxy, - (CH) 2 ) u -O-(CH 2 ) v OH、-(CH 2 ) u -SO 2 C 1-3 Alkyl, - (CH) 2 ) u -NR a0 R b0 、-(CH 2 ) u -C(O)NR a0 R b0 、-(CH 2 ) u -C(O)C 1-3 Alkyl, -C (O) OC 1-3 Alkyl, NR a0 C(O)-(CH 2 ) u -NR a0 R b0 、NR a0 C(O)-(CH 2 ) u OH、NR a0 C (O) -halo C 1-3 An alkyl group; wherein the 3-to 6-membered heterocycloalkyl, 5-or 6-membered monocyclic heteroaryl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3-to 6-membered heterocycloalkyl, 5-or 6-membered monocyclic heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Substituents of cycloalkyl groups; u, v are each independently 0, 1, 2, 3 or 4; r is R a0 、R b0 Each independently is hydrogen or C 1-3 An alkyl group.
In one embodiment of the invention, the S group of substituents is halogen.
In one embodiment of the invention, the S group of substituents is selected from: c (C) 1-3 Alkyl, - (CH) 2 ) u -3 to 6 membered heterocycloalkyl, - (CH) 2 ) u -SO 2 C 1-3 Alkyl, - (CH) 2 ) u -NR a0 R b0 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the 3-to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3-to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Substituents of cycloalkyl groups; u is 0, 1, 2, 3 or 4; r is R a0 、R b0 Each independently is hydrogen or C 1-3 An alkyl group.
In one embodiment of the invention, in the S group of substituents, the 3-to 6-membered heterocycloalkyl is selected from: aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran.
In one embodiment of the invention, the substituents of group S are the same as those of group C 3-6 NaphtheneThe radicals are selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
In one embodiment of the invention, the 5-or 6-membered monocyclic heteroaryl group in group S substituents is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.
In one embodiment of the invention, the R s1 、R s2 Each independently selected from: hydroxy, halogen, nitro, oxo, C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, benzyl, - (CH) 2 ) u1 -cyano, - (CH) 2 ) u1 -C 1-3 Alkoxy, - (CH) 2 ) u1 Halogenated C 1-3 Alkoxy, - (CH) 2 ) u1 Halogenated C 1-3 Alkyl, - (CH) 2 ) u1 -3 to 6 membered heterocycloalkyl, - (CH) 2 ) u1 -5-or 6-membered monocyclic heteroaryl, - (CH) 2 ) u1 -C 3-6 Cycloalkyl, - (CH) 2 ) u1 -O-(CH 2 ) v1 -C 3-6 Cycloalkyl, - (CH) 2 ) u1 -O-(CH 2 ) v1 -C 1-3 Alkoxy, - (CH) 2 ) u1 -O-(CH 2 ) v1 OH、-(CH 2 ) u1 -SO 2 C 1-3 Alkyl, - (CH) 2 ) u1 -NR a0 R b0 、-(CH 2 ) u1 -C(O)NR a0 R b0 、-(CH 2 ) u1 -C(O)C 1-3 Alkyl, -C (O) OC 1-3 Alkyl, NR a0 C(O)-(CH 2 ) u1 -NR a0 R b0 、NR a0 C(O)-(CH 2 ) u1 OH、NR a0 C (O) -halo C 1-3 An alkyl group; wherein the 3-to 6-membered heterocycloalkyl, 5-or 6-membered monocyclic heteroaryl each independently has 1,2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3-to 6-membered heterocycloalkyl, 5-or 6-membered monocyclic heteroaryl is optionally substituted1. 2 or 3 are selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Substituents of cycloalkyl groups; u1, v1 are each independently 0, 1, 2, 3 or 4; r is R a0 、R b0 Each independently is hydrogen or C 1-3 An alkyl group.
In one embodiment of the invention, the R s1 、R s2 Each independently is halogen.
In one embodiment of the invention, the R s1 、R s2 Each independently selected from: c (C) 1-3 Alkyl, - (CH) 2 ) u1 -3 to 6 membered heterocycloalkyl, - (CH) 2 ) u1 -SO 2 C 1-3 Alkyl, - (CH) 2 ) u1 -NR a0 R b0 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the 3-to 6-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3-to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Substituents of cycloalkyl groups; u1 is 0, 1, 2, 3 or 4; r is R a0 、R b0 Each independently is hydrogen or C 1-3 An alkyl group.
In one embodiment of the invention, R s1 、R s2 Wherein said 3-to 6-membered heterocycloalkyl is selected from the group consisting of: aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran.
In one embodiment of the invention, R s1 、R s2 In (C) 3-6 Cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
In one embodiment of the invention, R s1 、R s2 Wherein said 5-or 6-membered monocyclic heteroaryl is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, and,Thiadiazoles, pyridines, pyridazines, pyrimidines, pyrazines.
In one embodiment of the invention, m is 2 and n is 1.
In one embodiment of the invention, m is 1 and n is 2.
In one embodiment of the invention, m is 2; n is 2.
In one embodiment of the present invention, the compound of formula (I) is a compound of formula (II) or a compound of formula (III):
in the formulae, R 1 、R 2 X, B, E, Z, L are as defined above.
In one embodiment of the invention, R 1 Is halogen or-O-R 11 。
In one embodiment of the present invention, in formula (III), R 1 is-O-R 11 。
In one embodiment of the present invention, in formula (II), R 1 Is halogen.
In one embodiment of the invention, R 1 Is chlorine or fluorine.
In one embodiment of the invention, R 11 Is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-or 6-membered monocyclic heteroaryl, or substituted or unsubstituted 8-to 10-membered bicyclic heteroaryl; wherein 3 to 6 membered heterocycloalkyl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl each independently have 1,2 or 3 heteroatoms selected from N, O and S as ring atoms; by "substituted" is meant that 1,2,3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S.
In one embodiment of the invention, R 11 Is substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstitutedSubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-or 6-membered monocyclic heteroaryl; by "substituted" is meant that 1,2,3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S; the C is 3-6 Cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the 3-to 6-membered heterocycloalkyl is selected from: aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran; the 5-or 6-membered monocyclic heteroaryl is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.
In one embodiment of the invention E is CR 4 。
In one embodiment of the invention, R 4 Is hydrogen.
In one embodiment of the invention, E is N.
In one embodiment of the invention, Z is CR 3 。
In one embodiment of the invention, R 3 Is hydrogen or halogen.
In one embodiment of the invention, R 3 Is hydrogen or fluorine.
In one embodiment of the invention, Z is N.
In one embodiment of the invention, L is a bond; r is R 2 Is NR (NR) 21 R 22 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 21 And R is 22 Together with the attached nitrogen atom form a substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted 6-to 10-membered fused heterocycloalkyl, or substituted or unsubstituted 7-to 11-membered spiroheterocycloalkyl; wherein the 3-to 6-membered heterocycloalkyl, 6-to 10-membered fused heterocycloalkyl, 7-to 11-membered spiroheterocycloalkyl each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said'By substituted "is meant that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S.
In one embodiment of the invention, L is-CR L1 R L2 -、-O-(CR L1 R L2 ) t1 -or-NH- (CR) L3 R L4 ) t2 -；R 2 Is halogen, hydroxy, -SO 2 C 1-6 Alkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted 6-to 10-membered fused heterocycloalkyl, substituted or unsubstituted 7-to 11-membered spiroheterocycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 5-or 6-membered monocyclic heteroaryl, or NR 21 R 22 ；
Wherein R is L1 、R L2 、R L3 、R L4 The same or different, each independently hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, C 1-3 Alkyl or oxo; t1, t2 are each independently 0, 1, 2, 3 or 4;
R 21 、R 22 each independently is hydrogen, substituted or unsubstituted C 1-6 Alkyl, -SO 2 C 1-6 Alkyl, -SO 2 C 3-6 Cycloalkyl, -C (O) C 1-6 Alkyl, -C (O) halo C 1-6 An alkyl group; or R is 21 And R is 22 Together with the attached nitrogen atom form a substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted 6-to 10-membered fused heterocycloalkyl, or substituted or unsubstituted 7-to 11-membered spiroheterocycloalkyl;
wherein the 3-to 6-membered heterocycloalkyl, 6-to 10-membered fused heterocycloalkyl, 7-to 11-membered spiroheterocycloalkyl each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; by "substituted" is meant that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S.
In one embodiment of the invention, R 1 In B, C is as follows 6-10 Aryl groups are each independently phenyl or naphthyl.
In one embodiment of the present invention, the said C 6-10 When aryl is phenyl, B is selected from the following structures:
wherein R is s1 、R s2 The definition is the same as before.
In one embodiment of the invention, R 1 、R 2 In B, each of said 5-or 6-membered monocyclic heteroaryl groups is independently selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.
In one embodiment of the invention, R 1 In B, each 8-to 10-membered bicyclic heteroaryl is independently a 9-to 10-membered bicyclic heteroaryl formed by fusing a benzene ring with a 5-or 6-membered monocyclic heteroaryl ring, or an 8-to 10-membered bicyclic heteroaryl formed by fusing a 5-or 6-membered monocyclic heteroaryl ring with a 5-or 6-membered monocyclic heteroaryl ring; wherein the 9 to 10 membered bicyclic heteroaryl groups formed by the condensation of the benzene ring with a 5 or 6 membered monocyclic heteroaryl ring, the 8 to 10 membered bicyclic heteroaryl groups formed by the condensation of a 5 or 6 membered monocyclic heteroaryl ring with a 5 or 6 membered monocyclic heteroaryl ring each independently have 1,2 or 3 heteroatoms selected from N, O and S as ring atoms.
In one embodiment of the invention, the 5-or 6-membered monocyclic heteroaryl ring forming the bicyclic heteroaryl is selected from: thiophene ring, furan ring, thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2, 3-triazole ring, 1,2, 4-triazole ring, 1,2, 5-triazole ring, 1,3, 4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2, 3-oxadiazole ring, 1,2, 4-oxadiazole ring, 1,2, 5-oxadiazole ring, 1,3, 4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, or pyrazine ring.
In one embodiment of the invention, the 5-or 6-membered monocyclic heteroaryl ring forming the bicyclic heteroaryl is selected from the following structures: wherein->Representative of two ring atoms attached are adjacent pairs of atoms that are shared when fused with other rings.
In one embodiment of the invention, R 1 In B, each of the 8-to 10-membered bicyclic heteroaryl groups is independently selected from: benzoxazole, benzisoxazole, benzimidazole, benzothiazole, benzisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyridopyrimidine, naphthyridine.
In one embodiment of the invention, in the B1 ring, the 5 or 6 membered monocyclic heteroaryl ring is selected from: thiophene ring, furan ring, thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2, 3-triazole ring, 1,2, 4-triazole ring, 1,2, 5-triazole ring, 1,3, 4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2, 3-oxadiazole ring, 1,2, 4-oxadiazole ring, 1,2, 5-oxadiazole ring, 1,3, 4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, or pyrazine ring.
In one embodiment of the invention, in the B1 ring, the 5-or 6-membered monocyclic heteroaryl ring is selected from the following structures: Wherein->The two ring atoms to which they are attached being shared when condensed with other ringsAdjacent pairs of atoms.
In one embodiment of the invention, in the B2 ring, the 5-or 6-membered cycloalkyl ring fused to the B1 ring is selected from: cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring, cyclopentanone, cyclopentane-1, 3-dione, cyclohexanone, cyclohexane-1, 3-dione.
In one embodiment of the invention, in the B2 ring, the 5-or 6-membered heterocycloalkyl ring fused with the B1 ring is selected from: oxazolidines, pyrrolidin-2-ones, pyrrolidine-2, 5-diones, 1, 3-dioxolanes, dihydrofuran-2 (3H) -ones, dihydrofuran-2, 5-diones, piperidin-2-ones, piperidine-2, 6-diones, tetrahydro-2H-pyran-2-ones, imidazolidines, tetrahydrofuran, tetrahydrothiophenes, tetrahydropyrroles, 1, 3-dioxolan-2-ones, oxazolidin-2-ones, imidazolidin-2-ones, piperidines, piperazines, piperazin-2-ones, morpholines, morpholin-3-ones, morpholin-2-ones, thiomorpholin-3-ones 1, 1-dioxides, thiomorpholines, thiomorpholin-1, 1-dioxides tetrahydropyran, 1, 2-dihydroazetidine, 2, 5-dihydro-1H-pyrrole, 2, 5-dihydrofuran, 2, 3-dihydro-1H-pyrrole, 3, 4-dihydro-2H-pyran, 1,2,3, 4-tetrahydropyridine, 3, 6-dihydro-2H-pyran, 1,2,3, 6-tetrahydropyridine, 1, 3-oxazinane, hexahydropyrimidine, 1, 4-dioxane, tetrahydropyrimidin-2 (1H) -one, 1, 4-dioxan-2-one, 5, 6-dihydro-2H-pyran-2-one, 5, 6-dihydropyrimidin-4 (3H) -one, 3, 4-dihydropyridin-2 (1H) -one, 5, 6-dihydropyridin-2 (1H) -one, 5, 6-dihydropyrimidin-4 (1H) -one, pyrimidin-4 (3H) -one, pyrimidin-4 (1H) -one, 4, 5-dihydro-1H-imidazole, 2, 3-dihydro-oxazole, 1, 3-dioxole, 2, 3-dihydrothiophene, 2, 5-dihydrothiophene, 3, 4-dihydro-2H-1, 4-oxazine, 3, 4-dihydro-2H-1, 4-thiazine 1, 1-dioxide, 1,2,3, 4-tetrahydropyrazin, 1, 3-dihydro-2H-pyrrole-2-one, 1, 5-dihydro-2H-pyrrole-2-one 1H-pyrrole-2, 5-dione, furan-2 (3H) -one, furan-2 (5H) -one, 1, 3-dioxol-2-one, oxazol-2 (3H) -one, 1, 3-dihydro-2H-imidazol-2-one, furan-2, 5-dione, 3, 6-dihydropyridin-2 (1H) -one, pyridine-2, 6- (1H, 3H) -dione, 5, 6-dihydro-2H-pyran-2-one, 3, 4-dihydro-2H-1, 3-oxazine, 3, 6-dihydro-2H-1, 3-oxazine, 1,2,3, 4-tetrahydropyrimidine.
In one embodiment of the invention, B is selected from the following structures:
wherein Z is 1e Is NR (NR) 1e O or S; z is Z 1f Is N or CR 1f ；Z 1g Is N or CR 1g ；Z 1h Is N or CR 1h ；Z 1i Is N or CR 1i ；
Z 2e Is N or CR 2e ；Z 2f Is N or CR 2f ；Z 2h Is N or CR 2h ；Z 2i Is N or CR 2i ；
R 1e 、R 1f 、R 1g 、R 1h 、R 1i 、R 1j 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 2j Each independently is hydrogen, halogen, C 1-3 Alkyl, -CONH 2 、-CONHC 1-3 Alkyl, -CON (C) 1-3 Alkyl group 2 Cyano, nitro, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxy, acetyl, hydroxymethyl, hydroxyethyl, carboxyl, NH 2 、NHC 1-3 Alkyl, N (C) 1-3 Alkyl group 2 Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkoxy radicals C 2-4 Alkenyl, C 2-4 Alkynyl, -C (O) OC 1-3 Alkyl, -CHO, -OC (O) C 1-3 Alkyl, -SO 2 C 1-3 Alkyl, -SO 2 -phenyl or-CO-phenyl.
In one embodiment of the invention, R 1 In B, the 8-to 10-membered bicyclic heteroaryl is selected from the structures:
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in one embodiment of the invention, R 1 In B, the 8-to 10-membered bicyclic heteroaryl is selected from the structures:
in one embodiment of the invention, R 1 In B, the 8-to 10-membered bicyclic heteroaryl is selected from the structures:
in one embodiment of the present invention, B is a structure represented by formula (B), wherein,selected from the following structures:
in one embodiment of the present invention, B is a structure of formula (B) selected from the following structures:
In one embodiment of the invention, B is selected from the following structures:
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in one embodiment of the present invention, the group-L-R in formula (I) 2 Selected from the following structures:
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/>
/>
/>
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in one embodiment of the invention, R 2 Wherein said 5-or 6-membered monocyclic heteroaryl is selected from:
in one embodiment of the invention, R 2 Wherein the 3-to 20-membered heterocycloalkyl is a 3-to 6-membered heterocycloalkylA 6 to 10 membered fused heterocycloalkyl, a 7 to 11 membered spiroheterocycloalkyl, or a 7 to 10 membered bridged heterocycloalkyl.
In one embodiment of the invention, R 2 In (C) 3-20 Cycloalkyl radicals are C 3-8 Cycloalkyl group selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclobutanone, cyclobutane-1, 2-dione, cyclopentanone-1, 3-dione, cyclohexanone, cyclohexane-1, 3-dione; the above C 3-8 Cycloalkyl is unsubstituted or substituted with 1,2, 3 or 4 substituents each independently selected from group S.
In one embodiment of the invention, R 21 And R is 22 The 3-to 20-membered heterocycloalkyl group formed together with the nitrogen atom to which it is attached is a 3-to 6-membered nitrogen-containing heterocycloalkyl group, a 6-to 10-membered nitrogen-containing thick heterocycloalkyl group, or a 7-to 11-membered nitrogen-containing spiroheterocycloalkyl group.
In one embodiment of the application, the R 21 And R is 22 The 3-to 6-membered nitrogen-containing heterocycloalkyl group formed together with the nitrogen atom to which it is attached is selected from the structures:the above 3-to 6-membered nitrogen-containing heterocycloalkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents each independently selected from group S.
In one embodiment of the application, the X, n, m, R 1 、B、E、Z、L、R 2 Each independently is the corresponding group in each particular compound in the examples.
In one embodiment of the application, the compounds of formula (I) are selected from the specific compounds noted in the examples.
In one embodiment of the application, the compounds of formula (II) or (II) are selected from the compounds prepared in the examples according to the application.
In one embodiment of the application, the compound of formula (I) is selected from the group consisting of:
in another aspect, the present application provides a pharmaceutical composition comprising a compound of the foregoing, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and a pharmaceutically acceptable carrier.
As used herein, the term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that is capable of delivering an effective amount of the active agents of the present application, does not interfere with the biological activity of the active agents, and is free of toxic side effects to the host or subject, and is a non-toxic, inert, solid, semi-solid material or liquid filling machine, diluent, encapsulating material or co-formulation or any type of adjuvant. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. Such matrices include suspending agents, viscosity enhancers, transdermal enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts.
In embodiments of the invention, the pharmaceutical composition may be administered in any of the following ways: oral, spray inhalation, rectal, nasal, buccal, topical, parenteral, e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or by means of an explanted reservoir. When administered orally, the compounds of the present invention may be formulated in any orally acceptable formulation, including, but not limited to, tablets, capsules, aqueous solutions or suspensions. The carriers used in tablets generally include lactose and corn starch and, optionally, lubricants such as magnesium stearate. Diluents used in capsule formulations generally include lactose and dried corn starch. Aqueous suspension formulations are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweetener, flavoring agent or coloring agent may be added to the above oral preparation. When topically applied, particularly in the treatment of conditions of the affected area or organ, such as the eye, skin or lower intestinal tract, where topical application is readily available, the compounds of the invention may be formulated in various topical formulations depending on the affected area or organ, and when topically applied to the eye, the compounds of the invention may be formulated in the form of a micronized suspension or solution in which an isotonic sterile saline solution of a certain pH is used as a carrier, with or without the addition of a preservative such as benzyl chloride alkoxide. For ophthalmic use, the compounds may also be formulated as ointments, such as petrolatum. When topically applied to the skin, the compounds of the present invention may be formulated in the form of suitable ointments, lotions or creams, where the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used for ointment formulations include, but are not limited to: mineral oil, liquid vaseline, white vaseline, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water. The compounds of the invention may also be administered in sterile injectable preparations, including sterile injectable aqueous or oleaginous suspensions or sterile injectable solutions. Carriers and solvents that can be used include water, ringer's solution, and isotonic sodium chloride solution. In addition, the sterilized fixed oils may also be used as solvents or suspending media, such as mono-or diglycerides.
In another aspect, the present invention provides the use of a compound of the foregoing, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition of the foregoing, for the preparation of a medicament for the prevention and/or treatment of cancer.
In one embodiment of the invention, the cancer is pancreatic ductal carcinoma, colorectal carcinoma, multiple myeloma, lung carcinoma, cutaneous melanoma, endometrial carcinoma, uterine sarcoma, thyroid carcinoma, acute myelogenous leukemia, bladder urothelial carcinoma, gastric carcinoma, cervical carcinoma, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal carcinoma, chronic lymphocytic leukemia, lung squamous cell carcinoma, small-cell lung carcinoma, renal papillary cell carcinoma, adenoid cystic carcinoma, chromophobe renal cell carcinoma, liver carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, ovarian serous adenocarcinoma, adrenal cortical carcinoma, prostate carcinoma, neuroblastoma, brain low-grade glioma, glioblastoma, medulloblastoma, esophageal squamous cell carcinoma, renal clear cell carcinoma, osteosarcoma, ovarian small cell carcinoma, rhabdoid tumor, sarcoma, small intestine neuroendocrine tumor, T cell juvenile lymphocytic leukemia.
In one embodiment of the invention, the cancer is lung cancer, preferably non-small cell lung cancer.
In another aspect, the invention provides the use of a compound of the foregoing, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition of the foregoing, for the preparation of a KRAS mutation inhibitor, (preferably the KRAS mutation is a KRAS G12C mutation).
As used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds of the invention that are pharmaceutically acceptable and are capable of retaining the biological effectiveness of the free base without other side effects. Such salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with organic acids; such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, trifluoroacetic acid, formic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when acidic protons present on the parent compound are replaced with metal ions, for example alkali metal ions or alkaline earth metal ions, such as sodium, potassium, calcium and magnesium salts and the like. Or with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
As used herein, the terms "solvent compound" and "solvate" refer to a substance formed by the combination of a compound of the invention with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include water, ethanol, acetic acid, and the like. The solvent compound includes a stoichiometric amount of the solvent compound and a non-stoichiometric amount of the solvent compound, preferably a hydrate. Certain compounds of the invention may exist in unsolvated forms or solvated forms, including hydrated forms. In general, solvated forms, which are equivalent to unsolvated forms, are intended to be encompassed within the scope of the present invention.
As used herein, "stereoisomers" include conformational isomers and configurational isomers, wherein configurational isomers include predominantly cis-trans isomers and optical isomers. The compounds of the present invention may exist as stereoisomers and thus encompass all possible stereoisomeric forms, including but not limited to cis, trans, tautomers, enantiomers, diastereomers, atropisomers and the like, as well as any combination or mixture of any of the aforementioned stereoisomers, for example, meso, racemates, equal amounts of the atropisomers and the like. For example, a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compounds of the present invention contain olefinic double bonds, they include cis-isomers and trans-isomers, as well as any combination thereof, unless specified otherwise.
As used herein, the term "heteroatom" is selected from nitrogen, oxygen or sulfur. Wherein nitrogen is optionally substituted; sulfur is also optionally substituted, e.g. oxo, i.e. to form S (O) t3 (wherein t3 is an integer from 0 to 2).
As used herein, the term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbyl group containing from 1 to 20 carbon atoms. The term "C 1-10 Alkyl "means a straight or branched alkyl group having 1 to 10 carbon atoms, more preferably a straight or branched alkyl group having 1,2, 3, 4, 5 or 6 carbon atoms, i.e. C 1-6 Alkyl, more preferably C 1-4 Alkyl, most preferably C 1-3 An alkyl group. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and various branched isomers thereof, and the like.
As used herein, the term "alkoxy" refers to a group having the structure of an-O-alkyl, wherein alkyl is as defined above. The term "C 1-10 Alkoxy "means an alkoxy group having 1 to 10 carbon atoms, preferably C 1-6 Alkoxy, more preferably C 1-4 Alkoxy, more preferably C 1-3 An alkoxy group. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy, n-pentoxy, and the like.
As used herein, the term "alkenyl" refers to an alkyl group as defined above having one or more carbon-carbon double bonds at any position of the chain, the term "C 2-8 Alkenyl "means alkenyl having 2 to 8 carbon atoms and at least one carbon-carbon double bond, preferably alkenyl having 2 to 6 carbon atoms and 1 to 2 carbon-carbon double bonds, i.e. C 2-6 Alkenyl groups. More preferably alkenyl having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds, i.e. C 2-4 Alkenyl groups. Specific examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, pentenyl, hexenyl, butadienyl and the like.
As used herein, the term "alkynyl" refers to an alkyl group as defined above having one or more carbon-carbon triple bonds at any position of the chain, the term "C 2-8 Alkynyl "refers to alkynyl having 2 to 8 carbon atoms and at least one carbon-carbon triple bond, preferably alkynyl having 2 to 6 carbon atoms and 1 to 2 carbon-carbon triple bonds, i.e. C 2-6 Alkynyl groups. More preferred are alkynyl groups having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds, i.e. C 2-4 Alkynyl groups. Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine.
As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (e.g., 1,2, 3, 4, or 5) halogens, wherein the alkyl group is defined above. The term "halogenated C 1-10 Alkyl "refers to haloalkyl groups having 1 to 10 carbon atoms. Preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-4 Alkyl, more preferably halogenated C 1-3 An alkyl group. Specific examples include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.
As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more (e.g., 1,2, 3, 4, or 5) halogens, wherein the alkoxy group is defined as above. The term "halogenated C 1-10 Alkoxy "refers to haloalkoxy groups having 1 to 10 carbon atoms. Preferably halogenated C 1-6 Alkoxy, more preferably halo C 1-4 Alkoxy, more preferably halo C 1-3 An alkoxy group. Specific examples include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
As used herein, the terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably to refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group. The term "cycloalkyl"May be cycloalkyl (C) containing 3 to 20 carbon atoms 3-20 Cycloalkyl), preferably cycloalkyl (C) containing 3 to 12 carbon atoms 3-12 Cycloalkyl), more preferably cycloalkyl (C) containing 3 to 10 carbon atoms 3-10 Cycloalkyl), more preferably cycloalkyl (C) containing 3 to 6 carbon atoms 3-6 Cycloalkyl). The ring carbon atoms of the cycloalkyl groups may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone structure. When a monocyclic cycloalkyl group, it is preferred to contain 3 to 8 ring carbon atoms (i.e., 3 to 8 members or C 3-8 ) Is a monocyclic cycloalkyl group of the formula, "C" herein 3-8 Monocyclic cycloalkyl AND C 3-8 Cycloalkyl "is used interchangeably and more preferably contains 3 to 6 ring carbon atoms (i.e., 3 to 6 members or C 3-6 ) Monocyclic cycloalkyl, monocyclic cycloalkyl (or C) 3-6 Monocyclic cycloalkyl) includes cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclobutanone, cyclobutane-1, 2-dione, cyclopentanone, cyclopentane-1, 3-dione, cyclohexanone, cyclohexane-1, 3-dione, and the like. Cycloalkyl groups (C) typically containing 3 to 6 carbon atoms 3-6 Cycloalkyl) is monocyclic cycloalkyl (C) 3-6 Monocyclic cycloalkyl). As used herein, "3 to 6 membered monocyclic", "3 to 6 membered monocyclic cycloalkyl", "C 3-6 Monocyclic cycloalkyl AND C 3-6 Cycloalkyl "is used interchangeably and refers to a saturated or partially unsaturated all-carbon monocyclic ring containing 3 to 6 ring atoms. The monocyclic ring carbon atoms may be optionally substituted with 1,2 or 3 oxo groups to form a cyclic ketone structure. Examples of 3-to 6-membered monocyclic rings include (but are not limited to): cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring, cyclobutanone, cyclobutane-1, 2-dione, cyclopentanone, cyclopentane-1, 3-dione, cyclohexanone, cyclohexane-1, 3-dione, etc.
When polycyclic cycloalkyl, polycyclic cycloalkyl includes spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl. The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl ring, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the groups described herein.
As used herein, the terms "heterocycloalkyl" and "heterocycloalkyl ring" are used interchangeably to refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group in which one or more (preferably 1 to 4 or 1 to 3 or 1 to 2) ring atoms are selected from nitrogen, oxygen or S (O) t3 (wherein t3 is an integer from 0 to 2), but does not include-O-; a ring moiety of O-S-or-S-S-, the remaining ring atoms are carbon. The term "heterocycloalkyl" may be a heterocycloalkyl containing 3 to 20 ring atoms (i.e., 3 to 20 members); preferably 3 to 12 membered heterocycloalkyl; more preferably 3 to 10 membered heterocycloalkyl, still more preferably 3 to 6 membered heterocycloalkyl; wherein one or more, preferably 1 to 4, ring atoms are selected from nitrogen, oxygen or S (O) t3 (wherein t3 is an integer from 0 to 2), but does not include-O-; a ring moiety of O-S-or-S-S-, the remaining ring atoms are carbon. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, R being hydrogen or any of the substituents already defined herein). The ring carbon atoms of the heterocycloalkyl group may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.
In some embodiments of the invention, "heterocycloalkyl" refers to a monocyclic heterocycloalkyl group that is saturated or partially unsaturated, preferably a monocyclic heterocycloalkyl group containing 3 to 8 ring atoms (i.e., 3 to 8 members), 1, 2, or 3 of which are heteroatoms. More preferably 3 to 6 ring atoms (i.e., 3 to 6 members), 1, 2 or 3 of which are heteroatomic monocyclic heterocycloalkyl. Most preferably, a monocyclic heterocycloalkyl group containing 5 or 6 ring atoms (i.e., 5 or 6 members), 1, 2 or 3 of which are heteroatoms. As used herein, the term "3-to 6-membered heterocycloalkyl" is used interchangeably with "3-to 6-membered monocyclic heterocycloalkyl", and the term "5-or 6-membered heterocycloalkyl" is used interchangeably with "5-or 6-membered monocyclic heterocycloalkyl". When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, R being hydrogen or other substituents as already defined herein). When the heteroatom is a sulfur atom, the sulfur atom may be any Optionally oxidized (i.e. S (O) t3 T3 is an integer from 0 to 2). The ring carbon atoms of the monocyclic heterocycloalkyl group may be optionally substituted with 1,2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure. Non-limiting examples of monocyclic heterocycloalkyl groups include: aziridine, oxirane, azetidine, azetidin-2-one, oxetane, oxetan-2-one, oxazolidine, pyrrolidin-2-one, pyrrolidine-2, 5-dione, 1, 3-dioxolane, dihydrofuran-2 (3H) -one, dihydrofuran-2, 5-dione, piperidin-2-one, piperidine-2, 6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1, 3-dioxolan-2-one, oxazolidine-2-one, imidazolidin-2-one, piperidine, piperazine-2-one, morpholine, morpholin-3-one morpholin-2-one, thiomorpholin-3-one 1, 1-dioxide, thiomorpholin-1, 1-dioxide, tetrahydropyran, 1, 2-dihydroazetidine, 2, 5-dihydro-1H-pyrrole, 2, 5-dihydrofuran, 2, 3-dihydro-1H-pyrrole, 3, 4-dihydro-2H-pyran, 1,2,3, 4-tetrahydropyridine, 3, 6-dihydro-2H-pyran, 1,2,3, 6-tetrahydropyridine, 1, 3-oxazinane, hexahydropyrimidine, 1, 4-dioxane, tetrahydropyrimidin-2 (1H) -one, 1, 4-dioxane-2-one, 5, 6-dihydro-2H-pyran-2-one, 5, 6-dihydropyrimidin-4 (3H) -one, 3, 4-dihydropyridin-2 (1H) -one, 5, 6-dihydropyrimidin-4 (1H) -one, pyrimidin-4 (3H) -one, pyrimidine-4 (1H) -one, 4, 5-dihydro-1H-imidazole, 2, 3-dihydro-oxazole, 1, 3-dioxole, 2, 3-dihydrothiophene, 2, 5-dihydrothiophene, 3, 4-dihydro-2H-1, 4-oxazine, 3, 4-dihydro-2H-1, 4-thiazine 1, 1-dioxide 1,2,3, 4-tetrahydropyrazine, 1, 3-dihydro-2H-pyrrol-2-one, 1, 5-dihydro-2H-pyrrol-2-one, 1H-pyrrol-2, 5-dione, furan-2 (3H) -one, furan-2 (5H) -one, 1, 3-dioxol-2-one, oxazol-2 (3H) -one, 1, 3-dihydro-2H-imidazol-2-one, furan-2, 5-dione, 3, 6-dihydropyridin-2 (1H) -one, pyridine-2, 6- (1H, 3H) -dione, 5, 6-dihydro-2H-pyran-2-one, 3, 6-dihydro-2H-pyran-2-one, 3, 4-dihydro-2H-1, 3-oxazine, 3, 6-dihydro-2H-1, 3-oxazine, 1,2,3, 4-tetrahydropyrimidine, and the like.
Typically 3 to 6 membered heterocycloalkyl is a 3 to 6 membered monocyclic ringA heterocycloalkyl group. As used herein, "3 to 6 membered mono-heterocycle" or "3 to 6 membered monocyclic heterocycloalkyl" are used interchangeably and refer to a 3 to 6 membered saturated or partially unsaturated monocyclic ring wherein 1,2 or 3 carbon atoms are selected from nitrogen, oxygen or S (O) t5 (wherein t5 is an integer from 0 to 2) but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon; preferably 4 to 6 membered, more preferably 5 to 6 membered. The ring carbon atoms of the mono-heterocycle may be optionally substituted with 1,2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure. Examples of 3-to 6-membered mono-heterocycles include, but are not limited to, aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran, 1, 2-dihydroazetidine, 2, 5-dihydro-1H-pyrrole, 2, 5-dihydrofuran, 2, 3-dihydro-1H-pyrrole, 3, 4-dihydro-2H-pyran, 1,2,3, 4-tetrahydropyridine, 3, 6-dihydro-2H-pyran, 1,2,3, 6-tetrahydropyridine, and the like.
The 2 ring atoms attached to the above monocyclic heterocycloalkyl group, including C-C, N-C, may be optionally fused to a cycloalkyl group such as a monocyclic cycloalkyl ring, a monocyclic heterocycloalkyl ring, a monoaryl ring, a 5-or 6-membered monocyclic heteroaryl ring, etc., heterocycloalkyl, aryl or heteroaryl groups to form a fused polycyclic ring, and the 2 ring atoms attached to the monocyclic heterocycloalkyl groups forming fused rings with other rings are preferably C-C.
In some embodiments of the invention, "heterocycloalkyl" refers to a polycyclic heterocycloalkyl group including spiroheterocycloalkyl, fused heterocycloalkyl, and bridged heterocycloalkyl groups.
As used herein, the term "spiroheterocycloalkyl" refers to a saturated or partially unsaturated polycyclic heterocycloalkyl group in which one atom (referred to as the spiro atom) is shared between the monocyclic rings in the system, wherein one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms are selected from nitrogen, oxygen, or S (O) t4 (wherein t4 is an integer from 0 to 2) and the remaining ring atoms are carbon. The term "saturated spiroheterocycloalkyl" means that there is no unsaturation in the spiroheterocycloalkyl systemAnd a key. The term "partially unsaturated spiroheterocycloalkyl" means that one or more rings in the spiroheterocycloalkyl system may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. The term "spiroheterocycloalkyl" may be a spiroheterocycloalkyl group containing 5 to 20 ring atoms (i.e., 5 to 20 members), wherein 3 to 8 member (i.e., containing 3 to 8 ring atoms) single rings share one atom (called a spiro atom), preferably a 6 to 14 member spiroheterocycloalkyl group, more preferably a 7 to 11 member spiroheterocycloalkyl group; wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) t4 (wherein t4 is an integer from 0 to 2) and the remaining ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, R being hydrogen or other substituents as already defined herein). Each single ring may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. The spiroheterocycloalkyl group is classified into a mono-spiroheterocycloalkyl group, a di-spiroheterocycloalkyl group or a multi-spiroheterocycloalkyl group according to the number of common spiro atoms between rings, and is preferably a mono-spiroheterocycloalkyl group or a di-spiroheterocycloalkyl group. More preferably 7-membered (4-membered monocyclic/4-membered monocyclic), 8-membered (4-membered monocyclic/5-membered monocyclic), 9-membered (4-membered monocyclic/6-membered monocyclic, 5-membered monocyclic/5-membered monocyclic), 10-membered (5-membered monocyclic/6-membered monocyclic), or 11-membered (6-membered monocyclic/6-membered monocyclic) single spiroheterocycloalkyl. Non-limiting examples of spiroheterocycloalkyl groups include:
as used herein, the term "fused heterocycloalkyl" refers to a saturated or partially unsaturated polycyclic heterocycloalkyl, each ring in the system sharing an adjacent pair of atoms with the other rings in the system, and one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms in the system being selected from nitrogen, oxygen, or S (O) t4 (wherein t4 is an integer from 0 to 2) and the remaining ring atoms are carbon. The term "saturated fused heterocycloalkyl" means that the fused heterocycloalkyl system does not have any unsaturation. The term "partially unsaturated fused heterocycloalkanes By "group" is meant that one or more of the rings in the fused heterocycloalkyl system may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system. The term "fused heterocycloalkyl" may be a fused heterocycloalkyl group containing 5 to 20 ring atoms (i.e., 5 to 20 members), preferably a 6 to 14 member fused heterocycloalkyl group, more preferably a 6 to 10 member fused heterocycloalkyl group, and more preferably an 8 to 10 member fused heterocycloalkyl group; one or more ring atoms in the system being selected from nitrogen, oxygen or S (O) t4 (wherein t4 is an integer from 0 to 2) and the remaining ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, R being hydrogen or other substituents as already defined herein). The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl group, preferably a bicyclic or tricyclic, more preferably an 8-membered (5-membered monocyclic fused with 5-membered monocyclic fused), a 9-membered (5-membered monocyclic fused with 6-membered monocyclic fused) or a 10-membered (6-membered monocyclic fused with 6-membered monocyclic) bicyclic fused heterocycloalkyl group. Non-limiting examples of fused heterocycloalkyl groups include:
as used herein, the term "bridged heterocycloalkyl" refers to a saturated or partially unsaturated polycyclic heterocycloalkyl group in which any two rings in the system share two atoms that are not directly connected, wherein one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms are selected from nitrogen, oxygen, or S (O) t3 Wherein t3 is an integer from 0 to 2) of heteroatoms, the remaining ring atoms being carbon. The term "saturated bridged heterocycloalkyl" means that the bridged heterocycloalkyl system does not have any unsaturation. The term "partially unsaturated bridged heterocycloalkyl" means that one or more of the rings in the bridged heterocycloalkyl system may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. The term "bridged heterocycloalkyl" may be a bridged heterocycloalkyl containing 5 to 20 ring atoms (i.e., 5 to 20 members), preferably a 6 to 14 member bridged heterocycloalkyl, more preferably a 7 to 10 member bridged heterocycloalkyl; wherein one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms are selected from nitrogen, oxygen or S (O) t3 Wherein t3 is an integer from 0 to 2) of heteroatoms, the remaining ring atoms being carbon. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocycloalkyl groups include:
in the present application, the above-mentioned various heterocycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the groups described in the present application.
As used herein, the terms "aryl", "aryl ring" and "aromatic ring" are used interchangeably to refer to a fully unsaturated aliphatic hydrocarbon group. It may be a ring containing 6 to 14 ring atoms (i.e. 6 to 14 members or C 6-14 ) All-carbon polycyclic (rings are covalently linked to rings, are not fused) or all-carbon fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) groups, at least one of the rings being aromatic, i.e., having a conjugated pi-electron system. Preferably containing 6 to 10 ring atoms (i.e. 6 to 10 members or C 6-10 ) Aryl groups of (a). Each ring in the ring system contains 5 or 6 ring atoms.
In some embodiments of the invention, "aryl" refers to a monoaryl or polyaryl ring, non-limiting examples of which include: phenyl, biphenyl, and the like.
In some embodiments of the invention, "aryl" refers to an aromatic fused polycyclic ring that is a polycyclic group having a monoaryl ring fused to one or more monoaryl rings, non-limiting examples of which include: naphthyl, anthracenyl, and the like.
In some embodiments of the invention, aryl rings (e.g., monoaryl rings, preferably phenyl) described herein may be fused with one or more non-aromatic rings to form a polycyclic group wherein the rings attached to the parent structure are aromatic or non-aromatic rings including, but not limited to: 3 to 6 membered monocyclic heterocycloalkyl ring, preferably 5 or 6 membered monocyclic heterocycloalkyl ring A ring (the ring carbon atoms of the monocyclic heterocycloalkyl ring may be substituted with 1 to 2 oxo groups to form a lactam or a lactone structure), a 3 to 6-membered monocyclic cycloalkyl ring, preferably a 5-or 6-membered monocyclic cycloalkyl ring (the ring carbon atoms of the monocyclic cycloalkyl ring may be substituted with 1 or 2 oxo groups to form a cyclic ketone structure), and the like. The above Shan Fangji ring and one or more non-aromatic ring fused polycyclic groups may be attached to other groups or to the parent structure through a nitrogen or carbon atom, and the ring attached to the parent structure is a monoaryl ring or a non-aromatic ring. Non-limiting examples of which include:
in the present application, the above-mentioned various aryl groups may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the groups described in the present application.
As used herein, the terms "heteroaryl", "heteroaryl ring" and "heteroaryl ring" are used interchangeably to refer to a fully unsaturated aliphatic hydrocarbon group containing heteroatoms. It may be a monocyclic or fused polycyclic (i.e. rings sharing adjacent carbon atoms or heteroatom pairs) group having from 5 to 14 ring atoms (i.e. 5 to 14 members), preferably from 5 to 10 ring atoms (i.e. 5 to 10 members), more preferably 5, 6, 8, 9 or 10 ring atoms, containing from 1 to 4 heteroatoms as ring atoms, selected from oxygen, sulfur and nitrogen. Wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The heteroaryl group preferably has a shared 6, 10 or 14 pi electrons in the ring system. At least one ring in the ring system is aromatic.
In some embodiments of the invention, "heteroaryl" refers to a monocyclic heteroaryl ring (preferably a 5 or 6 membered monocyclic heteroaryl ring), non-limiting examples of monocyclic heteroaryl groups include: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like.
In some embodiments of the invention, "heteroaryl" refers to a fused polyheteroaryl ring (preferably an 8-to 10-membered bicyclic heteroaryl ring). The fused polyheteroaryl ring includes both polycyclic groups (preferably 9 or 10 membered bicyclic heteroaryl rings) fused to a monoaryl ring (preferably phenyl) and a monocyclic heteroaryl ring (preferably 5 or 6 membered monocyclic heteroaryl ring) and polycyclic groups (preferably 8 to 10 membered bicyclic heteroaryl rings) fused to a monocyclic heteroaryl (preferably 5 or 6 membered monocyclic heteroaryl) and a monocyclic heteroaryl (preferably 5 or 6 membered monocyclic heteroaryl).
Any of the 2 ring atoms attached to the monocyclic heteroaryl ring, including C-C, N-C, N-N, may be fused to a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, such as a monocyclic cycloalkyl ring, a monocyclic heterocycloalkyl ring, a monoaryl ring, a 5-or 6-membered monocyclic heteroaryl ring, as defined herein, to form a fused polycyclic ring. The 2 ring atoms attached to the monocyclic heteroaryl ring forming a fused ring with the other ring are preferably C-C, including without limitation the following forms:
Non-limiting examples of fused polyheteroaryl rings include: benzo [ d ] isoxazoles, 1H-indoles, isoindoles, 1H-benzo [ d ] imidazoles, benzo [ d ] isothiazoles, 1H-benzo [ d ] [1,2,3] triazoles, benzo [ d ] oxazoles, benzo [ d ] thiazoles, indazoles, benzofurans, benzo [ b ] thiophenes, quinolines, isoquinolines, quinazolines, quinoxalines, cinnolines, pyrido [3,2-d ] pyrimidines, pyrido [2,3-d ] pyrimidines, pyrido [3,4-d ] pyrimidines, pyrido [4,3-d ] pyrimidines, 1, 8-naphthyridines, 1, 7-naphthyridines, 1, 6-naphthyridines, 1, 5-naphthyridines, pyrazolo [1,5-a ] pyrimidines, imidazo [1,2-b ] pyridazines, and the like.
The monocyclic heteroaryl, or the polycyclic group in which the monoaryl ring is fused to the monocyclic heteroaryl ring, or the polycyclic group in which the monocyclic heteroaryl ring is fused to the monocyclic heteroaryl ring, may be linked to other groups or parent structures through a nitrogen atom or a carbon atom. In the case of a polycyclic group, the ring attached to the parent structure is a heteroaryl ring, an aryl ring, a monocyclic cycloalkyl ring, or a monocyclic heterocycloalkyl ring, non-limiting examples of which include:
in some embodiments of the invention, heteroaryl rings described herein (e.g., monocyclic heteroaryl rings, preferably 5 or 6 membered monocyclic heteroaryl rings) may be fused to one or more non-aromatic rings to form a polycyclic group, wherein the ring attached to the parent structure is a heteroaryl ring or a non-aromatic ring, including but not limited to: 3 to 6 membered (preferably 5 or 6 membered) monocyclic heterocycloalkyl ring (the ring carbon atoms of which may be substituted with 1 to 2 oxo groups to form a lactam or lactone structure), 3 to 6 membered (preferably 5 or 6 membered) monocyclic cycloalkyl ring (the ring carbon atoms of which may be substituted with 1 or 2 oxo groups to form a cyclic ketone structure), and the like.
The polycyclic group in which the monocyclic heteroaryl ring is fused to one or more non-aromatic rings may be attached to other groups or to the parent structure through a nitrogen or carbon atom, and the ring attached to the parent structure is a heteroaryl ring or a non-aromatic ring. Non-limiting examples of which include:
in the present application, each of the above heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the groups described in the present application.
As used herein, the term "hydroxy" refers to an-OH group.
The term "hydroxymethyl" as used herein refers to the-CH 2 OH, "hydroxyethyl" means-CH 2 CH 2 OH or-CHOHCH 3 。
The term "cyanomethyl" as used herein refers to the-CH 2 CN, "cyanoethyl" means-CH 2 CH 2 CN or-CHCNCH 3 。
The term "amino" as used herein refers to-NH 2 。
As used herein, the term "cyano" refers to-CN.
The term "nitro" as used herein refers to-NO 2 。
The term "benzyl" as used herein refers to the-CH 2 -benzene.
As used herein, the term "oxo" refers to = O.
As used herein, the term "carboxy" refers to-C (O) OH.
As used herein, the term "carboxylate group" refers to either-C (O) O (alkyl) or-C (O) O (cycloalkyl).
The term "acetyl" as used herein refers to-COCH 3 。
As used herein, the term "substituted" means that any one or more hydrogen atoms on a particular atom are substituted with substituents, and may include heavy hydrogens and variants of hydrogens, provided that the valence 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 substituted. Oxo substitution does not occur on the aryl group. The term "optionally substituted" or "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.
When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.
Herein, C 1-10 May be preferably C 1-6 The method comprises the steps of carrying out a first treatment on the surface of the More preferably C 1-4 The method comprises the steps of carrying out a first treatment on the surface of the More preferably C 1-3 . For example, C 1-10 Alkyl groups may preferably be C 1-6 An alkyl group; more preferably C 1-4 An alkyl group; more preferably C 1-3 An alkyl group. For example, C 1-10 Alkoxy groups may preferably be C 1-6 An alkoxy group; more preferably C 1-4 An alkoxy group; more preferably C 1-3 An alkoxy group.
Herein, C 3-20 May be preferably C 3-10 The method comprises the steps of carrying out a first treatment on the surface of the More preferably C 3-8 The method comprises the steps of carrying out a first treatment on the surface of the More preferably C 3-6 The method comprises the steps of carrying out a first treatment on the surface of the More preferably C 3-5 . For example, C 3-20 Cycloalkyl groups may preferably be C 3-8 Cycloalkyl; more preferably C 3-6 Cycloalkyl; more preferably C 3-6 Cycloalkyl groups.
In one embodiment of the invention, in any of the groups, the 3 to 20 membered heterocycloalkyl is a 3 to 6 membered heterocycloalkyl, a 6 to 10 membered fused heterocycloalkyl, a 7 to 11 membered spiroheterocycloalkyl, or a 7 to 10 membered bridged heterocycloalkyl; wherein the 3-to 6-membered heterocycloalkyl, 6-to 10-membered fused heterocycloalkyl, 7-to 11-membered spiroheterocycloalkyl, 7-to 10-membered bridged heterocycloalkyl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms.
In one embodiment of the invention, in any of the groups, the C 3-6 Cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
In one embodiment of the invention, in any of the groups, the 3 to 6 membered heterocycloalkyl is selected from: aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran.
In one embodiment of the invention, in any of the groups, the 5 or 6 membered monocyclic heteroaryl is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.
In one embodiment of the invention, in any of the groups, the 8-to 10-membered bicyclic heteroaryl is selected from: benzoxazole, benzisoxazole, benzimidazole, benzothiazole, benzisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyridopyrimidine, naphthyridine.
Detailed Description
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
As used herein, room temperature refers to about 20-25 ℃.
Example 1: preparation of Z1
Step one: 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline (298 mg,0.9 mmol) was dissolved in dichloromethane/acetonitrile (3 mL/3 mL) and cooled to 0deg.C. Triethylamine (136 mg,1.35 mmol) and tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate (200 mg,0.94 mmol) were added thereto, and stirred at room temperature for 3 hours. Dichloromethane (30 x 2 ml), washing the organic phase with water, washing with brine, drying over anhydrous sodium sulfate, and spin-evaporating to remove the solvent to give tert-butyl 6- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (yellow solid, 620mg, Y: crude). ES-API: [ m+h ] +=506.
Step two: 6- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (620 mg,1.2 mmol) was dissolved in N, N-dimethylformamide (10 mL), to which was added cesium carbonate (1.17 g,3.6 mmol), triethylenediamine (20 mg,0.18 mmol) and 1-methylpiperidin-4-ol (423 mg,3.6 mmol). The reaction mixture was reacted at 80℃for 16 hours. Ethyl acetate (50 ml x 2) was extracted, the organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and spin-distilled over a column (dichloromethane/methanol=20/1-10/1) to give tert-butyl 6- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (yellow solid, 360mg, y: 50%). ES-API: [ m+h ] += 584.9.
Step three: 6- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (360 mg,0.62 mmol) was dissolved in 1, 4-dioxane/water (8 mL/2 mL), and (5-methyl-1H-indazol-4-yl) boronic acid (217 mg,1.23 mmol), tris (dibenzyl-acetone) dipalladium (55 mg,0.06 mmol), 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (50 mg,0.12 mmol) and potassium phosphate (261 mg,1.23 mmol) were added. The reaction solution was stirred for 16 hours at 100℃under nitrogen. Ethyl acetate (30 ml x 3) was extracted, the organic phases were combined, dried over anhydrous magnesium sulfate, and spin-dried over column (dichloromethane/methanol=10/1-5/1) to give tert-butyl 6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (yellow solid, 278mg, yield: 71%). ES-API: [ m+h ] +=636.
Step four: 6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (278 mg,0.437 mmol) was dissolved in dichloromethane (6 mL), triethylamine (2 mL) was added, the reaction mixture was stirred at room temperature for 1 hour, and spin-distilled off to give 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) oxy) -4- (2, 6-diazaspiro [3.4] oct-6-yl) quinazoline (brown solid, 234mg, Y: crude product) which was used directly for the next reaction without purification. ES-API: [ m+h ] +=536.
Step five: 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) oxy) -4- (2, 6-diazaspiro [ 3.4)]Octyl-6-yl) quinazoline (234 mg,0.437 mmol) was dissolved in dichloromethane (6 mL), the reaction mixture was cooled to 0deg.C, triethylamine (133 mg,1.3 mmol) and acrylic anhydride (49.6 mg,0.39 mmol) were added, the reaction mixture was reacted at 0deg.C for 1 hour, desolventized, and the prepared liquid phase was separated to give 1- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4]]Oct-2-yl) prop-2-en-1-one (Z1, white solid, 35mg, y: 19%). ES-API [ M+H ]]+＝590。 1 H NMR(400MHz，CDCl 3 )δ12.95(s，1H)，8.06(s，1H)，7.59-7.50(m，2H)，7.39(d，J＝8.6Hz，1H)，6.40(d，J＝17.0Hz，1H)，6.22(dd，J＝16.9，10.3Hz，1H)，5.74(d，J＝10.3Hz，1H)，5.52(s，1H)，4.33-4.10(m，10H)，3.43-3.25(m，4H)，2.80(d，J＝3.9Hz，4H)，2.48-2.31(m，4H)，2.27(s，3H)。
Example 2: preparation of Z2
Step one: tert-butyl 6- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2, 6-diazaspiro [3.4 ]]Octane-2-carboxylate (200 mg, 0.015 mmol), (S) - (1-methylpyrrolidin-2-yl) methanol (140 mg,1.185 mmol), cesium carbonate (687 mg,0.185 mmol) and 1, 4-diazabicyclo [ 2.2.2.2 ]]Octane (10 mg,0.079 mmol) was added to dry tetrahydrofuran (5.0 mL) and N, N-dimethylformamide (5.0 mL), and the argon was replaced three to five times. The reaction solution was stirred at 60℃for 16 hoursCooled to room temperature and poured into ice water. Three times (10 ml x 3) with ethyl acetate and the organic phases were combined. The organic phase was washed successively with water, saturated brine and then dried over anhydrous sodium sulfate. Concentration under vacuum gives the crude (S) -tert-butyl 6- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4 ] as a yellow solid]Octane-2-carboxylate (231 mg, yield: 100%). ES-API [ M+H ]] + ＝586.3。
Step two: (S) -tert-butyl 6- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Octane-2-carboxylate (231 mg,0.396mmol, crude), (5-methyl-1H-indazol-4-yl) boronic acid (105 mg,0.594 mmol), sodium carbonate (84 mg,0.792 mmol), tris (dibenzylideneacetone) dipalladium (20 mg,0.0198 mmol) and 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (17 mg,0.0396 mmol) were added to dioxane (2.0 mL) and water (2.0 mL), and argon was displaced three to five times. The reaction solution was heated to 100℃in a microwave and stirred for 90 minutes. The reaction was cooled to room temperature, filtered, the filtrate extracted three times with ethyl acetate (10 ml x 3) and the organic phases combined. The organic phase was washed successively with water, saturated brine and then dried over anhydrous sodium sulfate. Purification of the crude product obtained gives 6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4 ] as a white solid ]Octane-2-carboxylate (75 mg, Y: 30%). ES-API [ M+H ]] + ＝636.3。
Step three: 6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Octane-2-carboxylate (75 mg,0.11 mmol) and dioxane hydrochloride (5.0 mL) were added to methanol (5 mL), and the reaction mixture was reacted at 25℃for 2 hours; the reaction solution is concentrated to obtain white solid which is 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 6-diazaspiro [3.4 ]]Oct-6-yl) quinazoline hydrochloride (59 mg, yield: 90%). ES-API [ M+H ]] + ＝536.5。
Step four: 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 6-diazaspiro [ 3.4)]Oct-6-yl) quinazolinesOxazoline (59 mg,0.109 mmol) was added to dichloromethane (5.0 mL), then N, N-diisopropylethylamine was added until the reaction was slightly basic (ph=6-7), then a solution of acryloyl chloride (10.0 mg,0.109 mmol) in dichloromethane was slowly added at-70 ℃. The reaction mixture was stirred at-70℃for 30 minutes, and quenched by the addition of methanol. The reaction solution was then warmed to 25℃and concentrated. The obtained product is used for preparing white solid which is 1- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-4-yl) -2, 6-diazaspiro [3.4 ] ]Oct-2-yl) prop-2-en-1-one (Z2, 30mg, yield: 40%). ES-API [ M+H ]] + ＝590.6。 1 H NMR(400MHz,DMSO-d 6 )δ9.88(br,1H),δ8.28(s,1H),δ7.60(d,J＝8.0Hz,1H),δ7.57(s,1H),δ7.40(d,J＝8.0Hz,1H),δ6.36(m,2H),δ6.15(m,2H),δ5.71(m,1H),δ4.73(m,1H),δ4.61(d,J＝8.0Hz,1H),δ4.35(m,1H),δ4.23(d,J＝8.0Hz,3H),δ4.06(d,J＝8.0Hz,3H),δ3.94(d,J＝8.0Hz,2H),δ3.83(m,1H),δ3.60(m,1H),δ3.14(m,1H),δ2.96(m,2H),δ2.26(m,3H),δ2.07(m,1H),δ1.95(m,3H).
Example 3: preparation of Z3
Step one: tert-butyl 6- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (200 mg, 0.015 mmol), methylpiperazine (119 mg,1.185 mmol), cesium carbonate (687 mg,0.185 mmol) and 1, 4-diazabicyclo [2.2.2] octane (10 mg,0.079 mmol) were added to dry tetrahydrofuran (5.0 mL) and N, N-dimethylformamide (5.0 mL), and the argon substitution was performed three to five times. After stirring the reaction solution at 60 ℃ for 16 hours, it was cooled to room temperature and poured into ice water, and extracted three times with ethyl acetate (10.0 ml x 3). The organic phases were combined, the organic phase was washed successively with water, saturated brine and then dried over anhydrous sodium sulfate. Then concentrated in vacuo to give the crude product 6- (7-bromo-6-chloro-8-fluoro-2- (4-methylpiperazin-1-yl) quinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (225 mg, yield: 100%) as a yellow solid. ES-API: [ m+h ] += 586.3.
Step two: 6- (7-bromo-6-chloro-8-fluoro-2- (4-methylpiperazin-1-yl) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Tert-butyl octane-2-carboxylate (225 mg,0.396mmol, crude), (5-methyl-1H-indazol-4-yl) boronic acid (105 mg,0.594 mmol), sodium carbonate (84 mg,0.792 mmol), tris (dibenzylideneacetone) dipalladium (20 mg,0.0198 mmol) and 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (17 mg,0.0396 mmol) were added to dioxane (2.0 mL) and water (2.0 mL), and argon was displaced three to five times. The reaction mixture was then heated to 100deg.C in a microwave, stirred for 90 minutes, cooled to room temperature, filtered, and the filtrate extracted three times with ethyl acetate (10.0 mL. Times.3). The organic phases were combined, the organic phase was washed successively with water, saturated brine and then dried over anhydrous sodium sulfate. Purification of the crude product obtained gives 6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- (4-methylpiperazin-1-yl) quinazolin-4-yl) -2, 6-diazaspiro [3.4] as a white solid ]Tert-butyl octane-2-carboxylate (70 mg, Y: 28%). ES-API [ M+H ]] + ＝621.2。
Step three: 6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- (4-methylpiperazin-1-yl) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Tert-butyl octane-2-carboxylate (70 mg,0.11 mmol) and dioxane hydrochloride (5.0 mL) were added to methanol (5 mL), and the reaction mixture was reacted at 25℃for 2 hours. The reaction solution is concentrated to obtain yellow solid which is 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- (4-methylpiperazine-1-yl) -4- (2, 6-diazaspiro [3.4 ]]Oct-6-yl) quinazoline (60 mg, yield: 90%). ES-API [ M+H ]] + ＝521.3。
Step four: 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- (4-methylpiperazin-1-yl) -4- (2, 6-diazaspiro [ 3.4)]Oct-6-yl) quinazoline (60 mg,0.115 mmol) was added to dichloromethane (5.0 mL), followed by N, N-diisopropylethylamine until the reaction was slightly basic (ph=6-7). Then a solution of acryloyl chloride (11.0 mg,0.115 mmol) in methylene chloride was slowly added at-70 ℃. The reaction mixture was stirred at-70℃for 30 minutes, and then quenched by addition of methanol. Then, the reaction mixture was warmed to 25℃and concentrated. The obtained product is used for preparing white solid 1- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- (4-methylpiperazin-1-yl) quinazoline-4-yl) -2, 6-diazaspiro [3.4 ] ]Oct-2-yl) prop-2-en-1-one (Z3, 10mg, yield: 14％)。ES-API:[M+H] + ＝575.6。 1 H NMR(400MHz,DMSO-d 6 )δ9.65(br,1H),δ8.12(s,1H),δ7.58(d,J＝8.0Hz,1H),δ7.49(s,1H),δ7.39(d,J＝8.0Hz,1H),δ6.36(m,1H),δ6.14(m,1H),δ4.83(m,2H),δ4.33(d,J＝8.0Hz,1H),δ4.31(m,3H),δ4.04(d,J＝8.0Hz,2H),δ3.95(m,3H),δ3.24(m,3H),δ3.05(s,3H),δ2.84(s,3H),δ2.25(m,2H),δ2.15(s,3H).
Example 4: preparation of Z4
Step one: 7- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (200 mg,0.4 mmol) was dissolved in N, N-dimethylformamide/tetrahydrofuran (4/0.4 mL), and (S) - (1-methylpyrrolidin-2-yl) methanol (140 mg,0.2 mmol), triethylenediamine (10 mg,0.08 mmol) and cesium carbonate (400 mg,1.2 mmol) were added to the reaction solution, and the reaction solution was reacted at 25℃for 16 hours; then, the reaction solution was poured into water (20 mL), and extracted with a mixture of methylene chloride and methanol (20/1) (20 mL. Times.3). The organic phases were combined, washed with water (20 ml x 3), dried and concentrated and passed through a silica gel column (dichloromethane/methanol=30/1 to 20/1,0.3% aqueous ammonia) to give 6- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4 ] as a yellow solid]]Octane-2-carboxylic acid methyl ester (120 mg, Y: 50%). ES-API [ M+H ]] + ＝584.1。
Step two: 6- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4]]Octane-2-carboxylic acid methyl ester (120 mg,0.2 mmol), 2-fluoro-6-hydroxyphenylboronic acid (310 mg,2 mmol), tetrakis (triphenylphosphine) palladium (23 mg,0.02 mmol), sodium carbonate (400 mg,3 mmol) and dioxane/water (4/1, 2.5 mL) were added to a 5mL microwave reaction tube, the tube was sealed after blowing argon for 1 minute, the reaction was subjected to microwave reaction at 110℃for 3 hours, water (10 mL) was added after cooling, and the mixture (10 mL. Times.3) was extracted with a mixture (20/1) of methylene chloride and methanol. The combined organic phases were washed with water (10 mL. Times.3), dried and concentrated and purified using prep. plates (200X 200 mL) to give 6- (6-chloro-2- (cyclopentylmethoxy) -8-fluoro-7- (2-fluoro-6-hydroxyphenyl) as a yellow solid Quinazolin-4-yl) -2, 6-diazaspiro [3.4]Octane-2-t-butyl carboxylic acid (100 mg, yield: 79%). ES-API [ M+H ]] + ＝616.2。
Step three: 6- (6-chloro-2- (cyclopentylmethoxy) -8-fluoro-7- (2-fluoro-6-hydroxyphenyl) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Octane-2-t-butyl carboxylic acid (100 mg,0.16 mmol) was added to a mixture of hydrochloric acid/dioxane (4M, 2 mL) and methanol (2 mL), stirred at room temperature for 1 hour and concentrated in vacuo to give 2- (6-chloro-2- (cyclopentylmethoxy) -8-fluoro-4- (2, 6-diazaspiro [ 3.4) as a yellow solid]Oct-6-yl) quinazolin-7-yl) -3-fluorophenol hydrochloride crude (100 mg, y: 100%) was used directly in the next reaction. ES-API [ M+H ]] + ＝516.2。
Step four: 2- (6-chloro-2- (cyclopentylmethoxy) -8-fluoro-4- (2, 6-diazaspiro [ 3.4)]The crude hydrochloride salt of oct-6-yl) quinazolin-7-yl) -3-fluorophenol (100 mg,0.16 mmol) was dissolved in an anhydrous dichloromethane solution (5 mL) of triethylamine (500 mg,5 mmol), stirred under argon for half an hour, cooled to about-70℃in a dry ice ethanol bath, and acryloyl chloride (50 mg,0.5 mmol) was added dropwise. Stirring for 20 min, adding methanol (1 mL) dropwise, returning to room temperature, and vacuum concentrating to obtain yellow solid 2- (4- (2-acryl-2, 6-diazaspiro [3.4 ])]Oct-6-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -3-fluorophenylacrylate crude (100 mg, y: 100%) was used directly in the next reaction. ES-API [ M+H ] ] + ＝624.6。
Step five: 2- (4- (2-propenoyl-2, 6-diazaspiro [ 3.4)]Crude oct-6-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -3-fluorophenylacrylate (100 mg,0.16 mmol) was dissolved in a mixture of saturated aqueous LiOH (3 mL) and methanol (6 mL), stirred at room temperature for 20 minutes, and then saturated aqueous ammonium chloride (20 mL) was added. Extraction with dichloromethane/methanol (20/1) (20 mL. Times.3), washing the combined organic phases with water (20 mL. Times.1), concentration, prep. purification by pre-HPLC (0.1% TFA) gives a preparation, which is most of the acetonitrile is spun off and lyophilized to give 1- (6- (6-chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [ 3.4)]Oct-2-yl) prop-2-en-1-one (Z4, 5.1mg, yield: 5%). ES-API:[M+H] + ＝569.2。 1 H NMR(400MHz,DMSO-d 6 )：δ10.30(s,1H),9.82-9.80(b,1H),8.18(s,1H),7.35(q,J＝8,1H),6.86-6.80(m,2H),6.35-6.28(m,1H),6.12(dd,J 1 ＝2,J 2 ＝16.8,1H),5.69(dd,J 1 ＝1.6,J 2 ＝10,1H),4.75-4.72(m,1H),4.60-4.54(m,1H),4.32(d,J＝9.6),4.03-3.78(m,1H),4.32(d,J＝9.6),4.20(d,J＝8.4,3H),4.03-3.78(m,4H),3.53-3.47(m,4H),2.95(s,3H),2.09-2.01(m,1H),1.95-1.90(m,2H).
example 5: preparation of Z5
Step one: 4-bromo-5-fluoro-2-nitrobenzoic acid (6.0 g,22.7 mmol) was dissolved in methanol (80 mL) and sodium methoxide (3.7 g,68.2 mmol) was added at room temperature. Heated to 60℃and reacted for 18 hours. Cool to room temperature and add 3M HCl until ph=2. Extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and spin-drying of the filtrate gave 4-bromo-5-methoxy-2-nitrobenzoic acid (6.0 g, yield: 50%) as a pale yellow solid. ES-API [ M-H ] ] - ＝276.1
Step two: 4-bromo-5-methoxy-2-nitrobenzoic acid (5.0 g,18.1 mmol) was dissolved in ethanol (200 mL) and glacial acetic acid (10.9 g,181 mmol), iron powder (5.1 g,90.5 mmol) was added at room temperature. Heated to 70℃and reacted for 18 hours. Filtration and spin-drying of the filtrate gave 2-amino-4-bromo-5-methoxybenzoic acid as a red solid (3.0 g. Yield: 68%). ES-API [ M-H ]] - ＝244.1。
Step three: a mixture of 2-amino-4-bromo-5-methoxybenzoic acid (2.9 g,11.8 mmol) and urea (60.0 g,1000 mmol) was heated to 200℃and stirred for 3 hours. Cooled to room temperature, water (500 mL) was added and extracted with ethyl acetate (200 mL. Want.3). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 7-bromo-6-methoxyquinoline-2, 4 (1H, 3H) -dione (3.0 g, yield: 90%) ES-API as a yellow solid: [ M+H)] + ＝273.0。
Step four: 7-bromo-6-methoxyquinoline-2, 4 (1H, 3H) -dione (1.9 g,7.0 mmol) was dissolved in phosphorus oxychloride (20 mL). Heated to 80℃and reacted for 3 hours. Cooled to room temperature, the reaction was poured into cold water and extracted with ethyl acetate (50 ml x 2). The extracts were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 7-bromo-2, 4-dichloro-6-methoxyquinoline as a yellow solid (2.0 g, yield: 60%).
Step five: 7-bromo-2, 4-dichloro-6-methoxyquinoline (1.9 g,6.2 mmol) was dissolved in dioxane (30 mL), and triethylamine (3.1 g,31.0 mmol) was added sequentially at room temperature to 2, 7-diazaspiro [3.5 ] ]Nonane-2-carboxylic acid tert-butyl ester (2.1 g,9.3 mmol). Heated to 50℃and reacted for 3 hours. The mixture is directly purified by column with methylene dichloride as eluent to obtain yellow solid 7- (7-bromo-2-chloro-6-methoxyquinazolin-4-yl) -2, 7-diazaspiro [3.5 ]]Nonane-2-carboxylic acid tert-butyl ester (500 mg, yield: 16%). ES-API [ M+H ]] + ＝497.1。
Step six: 7- (7-bromo-2-chloro-6-methoxyquinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (450 mg,0.9 mmol) was dissolved in N, N-dimethylformamide (10 mL) and 1-methylpiperidin-4-ol (125 mg,1.1 mmol) and 1, 4-diazabicyclo [ 2.2.2.2 were added sequentially at room temperature]Octane (202 mg,1.8 mmol), cesium carbonate (586 mg,1.8 mmol) was added to the reaction solution. Heated to 60 ℃ for reaction for 3 hours, cooled to room temperature. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL. Times.3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and spun-dried to give the crude product. Purification by column with dichloromethane: methanol=100/1 to 20/1 as eluent to give 7- (7-bromo-6-methoxy-2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ] as a pale yellow solid]Nonane-2-carboxylic acid tert-butyl ester (80 mg, yield: 15%). ES-API [ M+H ] ] + ＝578.2。
Step seven: 7- (7-bromo-6-methoxy-2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (70 mg,0.12 mmol) was dissolved in dioxane/water=10/1 (2 mL), and (5-methyl-1H-indazol-4-yl) boronic acid (26 mg,0.15 mmol), 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (20 mg,0.048 mmol), potassium phosphate (76 mg,0.36 mmol), tris (dibenzylidene-BASE acetone) dipalladium (22 mg,0.024 mmol) were added sequentially at room temperature. The argon gas is changed for three times,the reaction was carried out at 100℃for 1.5 hours with microwaves and cooled to room temperature. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL. Times.3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and spun-dried to give the crude product. Purification by column with dichloromethane: methanol=100/1 to 20/1 as eluent to give 7- (6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ] as a pale yellow solid]Nonane-2-carboxylic acid tert-butyl ester (40 mg, yield: 55%). ES-API [ M+H ]] + ＝628.3。
Step eight: 7- (6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ]Nonane-2-carboxylic acid tert-butyl ester (40 mg,0.06 mmol) was dissolved in methanol (1 mL), and hydrochloric acid/dioxane (1 mL, 4M) was slowly added dropwise to the reaction solution at room temperature, followed by stirring at room temperature for 1 hour. Concentrating and spin drying to obtain light yellow solid 6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) oxy) -4- (2, 7-diazaspiro [ 3.5)]Non-7-yl) quinazoline (40 mg, y: 99%). ES-API [ M+H ]] + ＝528.3。
Step nine: 6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) oxy) -4- (2, 7-diazaspiro [ 3.5)]Non-7-yl) quinazoline (40 mg,0.06 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (30 mg,0.3 mmol) and acryloyl chloride (8 mg,0.09 mmol) were added to the reaction liquid at-70 ℃. The reaction was carried out at-70℃for 0.5 hours. Methanol (1 mL) is added dropwise for quenching reaction, the reaction solution is dried by spin-drying, and high performance liquid chromatography is used for preparing and purifying to obtain yellow solid 1- (7- (6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) oxy) quinazoline-4-yl) -2, 7-diazaspiro [3.5 ]]Non-2-yl) prop-2-en-1-one (Z5, 3.7mg, y: 10%). ES-API [ M+H ]] + ＝582.3。 1 H NMR(400MHz,DMSO-d 6 )δ13.2(s,1H),9.48(s,1H),7.52-7.30(m,5H),6.39-5.36(m,4H),4.10-3.94(m,12H),3.22-1.98(m,17H).
Example 6: preparation of Z6
Step one: tert-butyl 6- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (300 mg,0.59 mmol), 1- (methylsulfonyl) piperidin-4-ol (159 mg,0.89 mmol), cesium carbonate (481 mg,1.475 mmol) and 1, 4-diazabicyclo [2.2.2] octane (13 mg,0.12 mmol) were added to dry tetrahydrofuran (5.0 mL) and N, N-dimethylformamide (5.0 mL) and argon was replaced three to five times. After stirring the reaction at room temperature for 24 hours, it was cooled to room temperature and poured into ice water, and extracted three times with ethyl acetate (50 ml×3). The organic phases were combined, the organic phase was washed successively with water, saturated brine and then dried over anhydrous sodium sulfate. Then concentrated in vacuo to give the crude 6- (7-bromo-6-chloro-8-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (400 mg, yield: 100%) as a yellow oil. ES-API: [ m+h ] += 647.9.
Step two: 6- (7-bromo-6-chloro-8-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Tert-butyl octane-2-carboxylate (400 mg,0.59mmol, crude), (5-methyl-1H-indazol-4-yl) boronic acid (156 mg,0.885 mmol), sodium carbonate (125 mg,1.18 mmol), tris (dibenzylideneacetone) dipalladium (26 mg,0.028 mmol) and 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (24 mg,0.059 mmol) were added to dioxane (5 mL) and water (0.5 mL) and argon was displaced three to five times. The reaction mixture was then heated to 100deg.C in the microwave, stirred for 60 minutes, cooled to room temperature, filtered, and water (30 mL) was added to the filtrate and extracted three times with ethyl acetate (50 mL. Times.3). The organic phases were combined, and the organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. The crude product obtained is purified by means of a silica gel column (petroleum ether: acetone equal to 3:2) to give a yellow oil, 6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1- (methylsulfonyl) piperidin-4-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Tert-butyl octane-2-carboxylate (280 mg, 68% yield). ES-API [ M+H ]] + ＝700.2。
Step three: 6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1- (methylsulfonyl) piperidin-4-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4 ]Tert-butyl octane-2-carboxylate (280 mg,0.40 mmol) and dioxane hydrochloride (4 mol)Mol/l, 2 mL) was added to methanol (2 mL), and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1- (methylsulfonyl) piperidin-4-yl) oxy) -4- (2, 6-diazaspiro [3.4 ] as a yellow solid]Octane-6-yl) quinazoline hydrochloride (254 mg, 100% yield). ES-API [ M+H ]] + ＝600.1。
Step four: 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1- (methylsulfonyl) piperidin-4-yl) oxy) -4- (2, 6-diazaspiro [ 3.4)]Octane-6-yl) quinazoline hydrochloride (254 mg,0.40 mmol) was added to dichloromethane (5 mL) followed by N, N-diisopropylethylamine (413 mg,3.2 mmol). Then a solution of acryloyl chloride (36 mg,0.40 mmol) in dichloromethane (1 mL) was slowly added at-70 ℃. The reaction mixture was stirred at-70℃for 30 minutes, and then quenched by addition of methanol. Then, the reaction mixture was warmed to 25℃and concentrated under reduced pressure. The yellow oil was prepared by reverse phase liquid chromatography to give 1- (6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1- (methylsulfonyl) piperidin-4-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4 ] as a white solid]Oct-2-yl) prop-2-en-1-one (Z6, 37mg, 14% yield). ES-API [ M+H ] ] + ＝654.1。 1 H NMR(400MHz,DMSO-d 6 )δ8.25(s,1H),7.59(d,J＝8.8Hz,1H),7.52(s,1H),7.39(d,J＝8.8Hz,1H),6.29-6.36(m,1H),6.12(dd,J＝17.2,2.4Hz,1H),5.69(dd,J＝10.4,2.0Hz,1H),5.24-5.26(m,2H),4.33-4.35(m,2H),4.20-4.22(m,2H),3.99-4.07(m,4H),3.92-3.94(m,2H),3.35-3.40(m,2H),3.12-3.18(m,2H),2.25-2.28(m,2H),2.09-2.16(m,5H),1.84-1.87(m,2H).
Example 7: preparation of Z7
Step one: tert-butyl 6- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (300 mg, 0.292 mmol), 1-methylpyrrolidin-3-ol (90 mg,0.889 mmol), cesium carbonate (580 mg,1.779 mmol) and 1, 4-diazabicyclo [2.2.2] octane (15 mg,0.118 mmol) were added to dry tetrahydrofuran (5.0 mL) and N, N-dimethylformamide (5.0 mL) and argon was replaced three to five times. After stirring the reaction solution at 60 ℃ for 2 hours, it was cooled to room temperature and poured into ice water, and extracted three times with ethyl acetate (10.0 ml x 3). The organic phases were combined, the organic phase was washed successively with water, saturated brine and then dried over anhydrous sodium sulfate. Then concentrated in vacuo to give the crude product tert-butyl 6- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpyrrolidin-3-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (339 mg, yield: 100%) as a yellow solid. ES-API: [ m+h ] += 572.3.
Step two: tert-butyl 6- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpyrrolidin-3-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Octane-2-carboxylate (399 mg,0.594mmol, crude), (5-methyl-1H-indazol-4-yl) boronic acid (160 mg,0.891 mmol), sodium carbonate (130 mg,1.188 mmol), tris (dibenzylideneacetone) dipalladium (30 mg,0.0297 mmol) and 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (25 mg,0.0594 mmol) were added to dioxane (5.0 mL) and water (2.0 mL), and argon was displaced three to five times. The reaction mixture was then heated to 100deg.C in a microwave, stirred for 90 minutes, cooled to room temperature, filtered, and the filtrate extracted three times with ethyl acetate (10.0 mL. Times.3). The organic phases were combined, the organic phase was washed successively with water, saturated brine and then dried over anhydrous sodium sulfate. Purification of the crude product obtained gives tert-butyl 6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpyrrolidin-3-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4] as a white solid ]Octane-2-carboxylate (80 mg, Y: 20%). ES-API [ M+H ]] + ＝622.6。
Step three: 6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpyrrolidin-3-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Tert-butyl octane-2-carboxylate (60 mg,0.096 mmol) and dioxane hydrochloride (5.0 mL) were added to methanol (5 mL), and the reaction mixture was reacted at 25℃for 2 hours. The reaction solution is concentrated to obtain yellow solid which is 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpyrrolidin-3-yl) oxy) -4- (2, 6-diazaspiro [3.4 ]]Oct-6-yl) quinazoline (49 mg, yield: 90%). ES-API [ M+H ]] + ＝522.4。
Step four: 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpyrrolidin-3-yl) oxy) -4- (2, 6-diazaspiro[3.4]Oct-6-yl) quinazoline (49 mg,0.094 mmol) was added to dichloromethane (5.0 mL), followed by N, N-diisopropylethylamine until the reaction solution appeared slightly basic (ph=6 to 7). Then a solution of acryloyl chloride (10.0 mg,0.094 mmol) in methylene chloride was slowly added at-70 ℃. The reaction mixture was stirred at-70℃for 30 minutes, and then quenched by addition of methanol. Then, the reaction mixture was warmed to 25℃and concentrated. The obtained product is used for preparing white solid which is 1- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpyrrolidin-3-yl) oxy) quinazoline-4-yl) -2, 6-diazaspiro [3.4 ] ]Oct-2-yl) prop-2-en-1-one (Z7, 30mg, yield: 50%). ES-API [ M+H ]] + ＝576.2。 1 H NMR(400MHz,DMSO-d 6 )δ10.28(br,1H),δ8.26(s,1H),δ7.60(d,J＝8.0Hz,1H),δ7.49(s,1H),δ7.40(d,J＝8.0Hz,1H),δ6.35(m,1H),δ6.14(m,1H),δ5.70(m,2H),δ4.34(m,1H),δ4.22(d,J＝8.0Hz,2H),δ4.06(m,2H),δ3.98(m,2H),δ3.94(d,J＝8.0Hz,2H),δ3.84(m,2H),δ2.92(s,1H),δ2.86(m,2H),δ2.32(s,1H),δ2.26(s,3H),δ2.15(s,4H).
Example 8: preparation of Z8
Step one: tert-butyl 6- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (200 mg, 0.399mmol), N, N-dimethylazacyclo-3-amine (80 mg,0.800 mmol), cesium carbonate (399mg, 1.2 mmol) and 1, 4-diazabicyclo [2.2.2] octane (10 mg,0.079 mmol) were added to anhydrous dry tetrahydrofuran (1.0 mL) and N, N-dimethylformamide (5.0 mL), and argon was replaced three to five times. After stirring the reaction at room temperature for 16 hours, it was diluted with water (30 mL) and extracted three times with ethyl acetate (10.0 mL. Times.3). The organic phases were combined, washed with water (10 ml x 3) and dried over anhydrous sodium sulfate. Then concentrated in vacuo and applied to a silica gel column (DCM/meoh=30/1) to give 6- (7-bromo-6-chloro-2- (3- (dimethylamino) azetidin-1-yl) -8-fluoroquinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-tert-butyl carboxylic acid (100 mg, yield: 45%) as a yellow solid. ES-API: [ m+h ] += 569.1.
Step two: 6- (7-bromo-6-chloro-2- (3- (dimethylamino) azetidin-1-yl) -8-fluoroquinazolin-4-yl) -2, 6-diazaspiro [3.4]]Octane-2-t-butyl carboxylic acid (100 mg,0.175 mmol), (5-methyl-1H-indazol-4-yl) boronic acid (105 mg,0.594 mmol), sodium carbonate (84 mg,0.792 mmol), tris (dibenzylideneacetone) dipalladium (20 mg,0.0198 mmol) and 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (17 mg,0.0396 mmol) were added to dioxane (4.0 mL) and water (1.0 mL) and argon was displaced three to five times. The reaction solution was then heated to 100deg.C in a microwave, stirred for 90 minutes, cooled to room temperature, filtered, and the filtrate was extracted three times with ethyl acetate (10.0 mL. Times.3). The organic phases were combined, the organic phase was washed successively with water, saturated brine and then dried over anhydrous sodium sulfate. The crude product obtained was purified by prep. plate (DCM/meoh=13/1) to give 6- (6-chloro-2- (3- (dimethylamino) azetidin-1-yl) -8-fluoro-7- (5-methyl-1H-indazol-4-yl) quinazolin-4-yl) tert-butyl) -2, 6-diazaspiro [3.4] as a white solid ]Octane-2-carboxylic acid methyl ester (80 mg, yield: 80%). ES-API [ M+H ]] + ＝621.3。
Step three: 6- (6-chloro-2- (3- (dimethylamino) azetidin-1-yl) -8-fluoro-7- (5-methyl-1H-indazol-4-yl) quinazolin-4-yl) tert-butyl) -2, 6-diazaspiro [3.4]Octane-2-carboxylic acid methyl ester (80 mg,0.129 mmol) and dioxane hydrochloride (5.0 mL) were added to methanol (5 mL), stirred at room temperature for 1 hour and concentrated to give 1- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -4- (2, 6-diazaspiro [ 3.4) as a yellow solid]Oct-6-yl) quinazolin-2-yl) -N, N-dimethylazacyclo-3-amine (100 mg crude, yield: 100%). ES-API [ M+H ]] + ＝521.2。
Step four: 1- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -4- (2, 6-diazaspiro [ 3.4)]Oct-6-yl) quinazolin-2-yl) -N, N-dimethylazacyclo-3-amine (100 mg crude, 0.129 mmol) was added to dichloromethane (5.0 mL), and triethylamine (1 mL) was added thereto and stirred at room temperature for 1 hour. Then acryloyl chloride (33.0 mg,0.36 mmol) was added slowly at-70 ℃. After stirring the reaction solution at-70℃for 30 minutes, it was quenched by addition of methanol (1 mL), warmed to room temperature, and concentrated. The crude product was prepared in reverse phase to give 1- (6- (6-chloro-2- (3- (dimethylamino) azetidin-1-yl) -8-fluoro-7- (5-methyl-1H-indazol-4-yl) quinazolin-4-yl) -2, 6-diazaspiro [3 ] as a white solid. 4]Oct-2-yl) prop-2-en-1-one (Z8, 15.5mg, yield: 21%). ES-API [ M+H ]] + ＝575.2。 1 H NMR(400MHz,DMSO-d 6 )δ13.25(br,1H),10.49(br,1H),8.14(s,1H),7.58(d,J＝8.4Hz,1H),7.49(s,1H),7.38(d,J＝8.4Hz,1H),6.36-6.32(m,1H),6.15-6.10(m,1H),5.71-5.68(m,1H),4.36-4.18(m,13H),4.10-3.92(m,6H),2.25(t,J＝6.4,2H),2.15(s,3H).
Example 8-1: preparation of Z8-1 and Z8-2
The compound Z8 (500 mg) obtained in example 8 was isolated by chiral resolution (Co-Solvent: 30% EtOH 1% MA); column: OJ 250mm 4.6mm 5 um); flow rate: 1.0ml/min; column temperature: 40.3 ℃ C.) to give compound Z8-1 (retention time: 1.014 min), which compound was arbitrarily designated as (S) -1- (6- (6-chloro-2- (3- (dimethylamino) azetidin-1-yl) -8-fluoro-7- (5-methyl-1H-indazol-4-yl) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Oct-2-yl) prop-2-en-1-one (270 mg, p:100%, ee value: 100%). ES-API [ M+H ]] + = 575.1. Compound Z8-2 (retention time: 1.707 min), arbitrarily designated as (R) -1- (6- (6-chloro-2- (3- (dimethylamino) azetidin-1-yl) -8-fluoro-7- (5-methyl-1H-indazol-4-yl) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Oct-2-yl) prop-2-en-1-one (200 mg, p:100%, ee value: 100%). ES-API [ M+H ]] + ＝575.1。
Example 9: preparation of Z9
Step one: 4-bromo-5-fluoro-2-nitrobenzoic acid (5.0 g,18.9 mmol) was dissolved in tetrahydrofuran (50 mL) and Raney nickel (1.0 g,17.0 mmol) was added at room temperature. The reaction was carried out at room temperature for 18 hours under the protection of a hydrogen balloon. Filtration and spin-drying of the filtrate gave 2-amino-4-bromo-5-fluorobenzoic acid (2.8 g, yield: 64%) as a yellow solid. ES-API [ M+H ] ] +- ＝236.1。
Step two: 2-AmmoniaA mixture of base-4-bromo-5-fluorobenzoic acid (2.3 g,9.8 mmol) and urea (50.0 g,84.9 mmol) was heated to 200℃and stirred for 3 hours. Cooled to room temperature, water (500 mL) was added and extracted with ethyl acetate (200 mL. Want.3). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 7-bromo-6-fluoroquinoline-2, 4 (1H, 3H) -dione (2.5 g, yield: 90%) as a yellow solid. ES-API [ M-H ]] - ＝259.0.
Step three: 7-bromo-6-fluoroquinoline-2, 4 (1H, 3H) -dione (2.5 g,9.7 mmol) was dissolved in phosphorus oxychloride (30 mL). Heated to 80℃and reacted for 3 hours. Cooled to room temperature, the reaction was poured into cold water and extracted with ethyl acetate (50 ml x 2). The extracts were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 7-bromo-2, 4-dichloro-6-fluoroquinoline as a yellow solid (1.3 g, yield: 50%).
Step four: 7-bromo-2, 4-dichloro-6-fluoroquinoline (1.4 g,4.7 mmol) was dissolved in dioxane (20 mL), and triethylamine (1.4 g,14.1 mmol) was added at room temperature, 2, 6-diazaspiro [3.4 ]]Tert-butyl octane-2-carboxylate (1.0 g,4.7 mmol). Heated to 50℃and reacted for 1 hour. The reaction was quenched by the addition of water (50 mL). Extracted with ethyl acetate (50 ml x 3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and spun-dried to give the crude product. Purification by column with dichloromethane: methanol=100/1 to 20/1 as eluent to give 6- (7-bromo-2-chloro-6-fluoroquinazolin-4-yl) -2, 6-diazaspiro [3.4 ] as a pale yellow solid ]Tert-butyl octane-2-carboxylate (600 mg, yield: 27%). ES-API [ M+H ]] + ＝471.1。
Step five: 6- (7-bromo-2-chloro-6-fluoroquinazolin-4-yl) -2, 6-diazaspiro [3.4]Tert-butyl octane-2-carboxylate (500 mg,1.1 mmol) was dissolved in N, N-dimethylformamide (10 mL), and (S) - (1-methylpyrrolidin-2-yl) methanol (150 mg,1.3 mmol), 1, 4-diazabicyclo [ 2.2.2.2 were added sequentially at room temperature]Octane (246 mg,2.2 mmol), cesium carbonate (7197 mg,2.2 mmol) was added to the reaction solution. Heated to 60 ℃ for reaction for 3 hours, cooled to room temperature. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL. Times.3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and spun-dried to give the crude product. Purification by column with dichloromethane: methanol=100/1 to 20/1 as eluent to obtain yellowish solidIn the form of (S) -6- (7-bromo-6-fluoro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4 ]]Octane-2-carboxylic acid tert-butyl ester (450 mg, yield: 75%). ES-API [ M+H ]] + ＝550.2。
Step six: (S) -6- (7-bromo-6-fluoro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Tert-butyl octane-2-carboxylate (350 mg,0.64 mmol) was dissolved in dioxane/water=10/1 (5 mL), and (5-methyl-1H-indazol-4-yl) boronic acid (120 mg,0.76 mmol), potassium phosphate (410 mg,1.92 mmol), chloro (2-dicyclohexylphosphino-2 ',6' -dimethoxy-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II) (95 mg,0.13 mmol) was added sequentially at room temperature. Argon is changed three times, the reaction is carried out for 1.5 hours at the temperature of 100 ℃ by microwaves, and the reaction product is cooled to the room temperature. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL. Times.3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and spun-dried to give the crude product. Purification by column with dichloromethane: methanol=100/1 to 20/1 as eluent to give 6- (6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4 ] as a pale yellow solid ]Tert-butyl octane-2-carboxylate (150 mg, yield: 40%). ES-API [ M+H ]] + ＝582.3。
Step seven: 6- (6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Tert-butyl octane-2-carboxylate (150 mg,0.26 mmol) was dissolved in methanol (1 mL), and hydrochloric acid/dioxane (1 mL, 4M) was slowly added dropwise to the reaction solution at room temperature, followed by stirring at room temperature for 1 hour. Concentrating and spin drying to obtain light yellow solid 3-fluoro-2- (6-fluoro-2- (((S) -1-methylpyrrolidine-2-yl) methoxy) -4- (2, 6-diazaspiro [ 3.4)]Oct-6-yl) quinazolin-7-yl-phenol (150 mg, yield: 99%). ES-API [ M+H ]] + ＝482.2。
Step eight: 3-fluoro-2- (6-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 6-diazaspiro [ 3.4)]Oct-6-yl) quinazolin-7-yl) phenol (150 mg,0.26 mmol) was dissolved in dichloromethane (5 mL). To the reaction solution was added triethylamine (130 mg,1.3 mmol) and acryloyl chloride (46 mg,0.39 mmol) successively at-70 ℃. The reaction was carried out at-70℃for 0.5 hours. Quenching reaction by dropwise adding methanol (1 mL), and spinning the reaction solutionCrude 2- (4- (2-propenoyl-2, 6-diazaspiro [ 3.4) as a dry yellow solid]Oct-6-yl) -6-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -3-fluorophenyl acrylate (300 mg, yield: 99%). ES-API [ M+H ] ] + ＝590.3。
Step nine: 2- (4- (2-propenoyl-2, 6-diazaspiro [ 3.4)]Oct-6-yl) -6-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -3-fluorophenyl acrylate (300 mg,0.26 mmol) was dissolved in tetrahydrofuran/water=4/1 (10 mL) and lithium hydroxide (25 mg,1.04 mmol) was added at room temperature. Heated to 50℃and reacted for 3 hours. The reaction solution is dried by spin and purified by high performance liquid chromatography to obtain yellow solid 1- (6- (6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4]]Oct-2-yl) prop-2-en-1-one (Z9, 10.5mg, yield: 7%). ES-API [ M+H ]] + ＝536.2。 1 H NMR(400MHz,DMSO-d 6 )δ10.32(s,1H),9.93(s,1H),8.13-5.67(m,8H),4.77-3.61(m,12H),3.17-2.82(m,4H),3.30-1.84(m,8H).
Example 10: preparation of Z10
Step one: tert-butyl 6- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (300 mg,0.59 mmol), (1-methylpiperidin-4-yl) methanol (115 mg,0.89 mmol), cesium carbonate (481 mg,1.475 mmol) and 1, 4-diazabicyclo [2.2.2] octane (13 mg,0.12 mmol) were added to dry tetrahydrofuran (5.0 mL) and N, N-dimethylformamide (5.0 mL) and the argon substitution was performed three to five times. After stirring the reaction at room temperature for 24 hours, it was cooled to room temperature and poured into ice water, and extracted three times with ethyl acetate (50 ml×3). The organic phases were combined, the organic phase was washed successively with water, saturated brine and then dried over anhydrous sodium sulfate. Then concentrated in vacuo to give the crude product 6- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpiperidin-4-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (350 mg, 99% yield) as a yellow oil. ES-API: [ m+h ] += 598.0.
Step two: 6- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpiperidin-4-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Tert-butyl octane-2-carboxylate (350 mg,0.59mmol, crude), (5-methyl-1H-indazol-4-yl) boronic acid (156 mg,0.885 mmol), sodium carbonate (125 mg,1.18 mmol), tris (dibenzylideneacetone) dipalladium (26 mg,0.028 mmol) and 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (24 mg,0.059 mmol) were added to dioxane (5 mL) and water (0.5 mL) and argon was displaced three to five times. The reaction mixture was then heated to 100deg.C in the microwave, stirred for 60 minutes, cooled to room temperature, filtered, and water (30 mL) was added to the filtrate and extracted three times with ethyl acetate (50 mL. Times.3). The organic phases were combined, and the organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. The crude product obtained was purified by column chromatography on silica gel (dichloromethane: methanol 10 to 1) to give 6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4 ] as a yellow oil]Tert-butyl octane-2-carboxylate (140 mg, yield 36%). ES-API [ M+H ]] + ＝650.2。
Step three: 6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4 ]Tert-butyl octane-2-carboxylate (140 mg,0.22 mmol) and dioxane hydrochloride (4 mol/l, 1 mL) were added to methanol (1 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure to obtain yellow solid which is 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) methoxy) -4- (2, 6-diazaspiro [ 3.4)]Octane-6-yl) quinazoline hydrochloride (129 mg, yield 100%). ES-API [ M+H ]] + ＝550.1。
Step four: 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) methoxy) -4- (2, 6-diazaspiro [ 3.4)]Octane-6-yl) quinazoline hydrochloride (129 mg,0.22 mmol) was added to dichloromethane (3 mL) followed by N, N-diisopropylethylamine (284 mg,2.2 mmol). Then a solution of acryloyl chloride (20 mg,0.22 mmol) in dichloromethane (1 mL) was slowly added at-70 ℃. The reaction mixture was stirred at-70℃for 30 minutes, and then quenched by addition of methanol. Then, the reaction mixture was warmed to 25℃and concentrated under reduced pressure. The yellow oil was prepared by reversed phase liquid chromatography to give a white solid 1- (6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Trifluoroacetate salt of oct-2-yl) prop-2-en-1-one (Z10, 14mg, 9% yield). ES-API [ M+H ] ] + ＝604.2。 1 H NMR(400MHz,DMSO-d 6 )δ8.24(s,1H),7.59(d,J＝8.4Hz,1H),7.50(s,1H),7.39(d,J＝8.4Hz,1H),6.29-6.36(m,1H),6.12(dd,J＝17.2,2.4Hz,1H),5.69(m,1H),3.40-4.30(m,10H),2.92-3.01(m,2H),2.76(m,3H),2.53-2.57(m,3H),2.25(m,2H),2.16(s,3H),1.95-1.99(m,3H),1.49-1.53(m,2H).
Example 11: preparation of Z11
Step one: 6- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (800 mg,1.58 mmol), N-methylpiperidin-4-amine (360 mg,3.16 mmol), cesium carbonate (1.54 g,4.74 mmol) and 1, 4-diazabicyclo [2.2.2] octane (40 mg,0.32 mmol) were added to dry tetrahydrofuran (4.0 mL) and N, N-dimethylformamide (20.0 mL) and the argon substitution was performed three to five times. After stirring the reaction at room temperature for 16 hours, it was diluted with water (50 mL) and extracted three times with ethyl acetate (20.0 mL. Times.3). The organic phases were combined, washed with water (50 ml x 2) and dried over anhydrous sodium sulfate. Then concentrated in vacuo and applied to a silica gel column (DCM/meoh=30/1) to give the yellow solid product tert-butyl 6- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpiperidin-4-yl) amino) quinazolin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (500 mg, yield: 53.9%). ES-API: [ m+h ] += 583.1.
Step two: 6- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpiperidin-4-yl) amino) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Tert-butyl octane-2-carboxylate (400 mg,0.69 mmol), 5-methyl-1H-indazole-4-boronic acid (182 mg,1.04 mmol), sodium carbonate (146 mg,1.38 mmol), tris (dibenzylideneacetone) dipalladium (31 mg,0.035 mmol) and 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (28 mg,0.069 mmol) were added to dioxane (10.0 mL) and water (1.0 mL), and the argon gas was displaced three to five times. Then the reaction solution was heated to 100℃in a microwave and stirred for 90 minutes After cooling to room temperature, filtration was performed, and the filtrate was extracted three times with ethyl acetate (10.0 ml x 3). The organic phases were combined, the organic phase was washed successively with water, saturated brine and then dried over anhydrous sodium sulfate. The crude product obtained was purified by prep. plate (DCM/meoh=10/1) to give 6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) amino) quinazolin-4-yl) -2, 6-diazaspiro [3.4 ] as a white solid]Tert-butyl octane-2-carboxylate (120 mg, yield: 27.6%). ES-API [ M+H ]] + ＝635.2。
Step three: 6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) amino) quinazolin-4-yl) -2, 6-diazaspiro [3.4]Tert-butyl octane-2-carboxylate (120 mg,0.189 mmol) and dioxane hydrochloride (10 mL) were added to methanol (5 mL), stirred at room temperature for 1 hour and concentrated to give 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -N- (1-methylpiperidin-4-yl) -4- (2, 6-diazaspiro [ 3.4) as a yellow solid]Oct-6-yl) quinazolin-2-amine hydrochloride (100 mg crude, yield: 92.6%). ES-API [ M+H ]] + ＝535.1。
Step four: 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -N- (1-methylpiperidin-4-yl) -4- (2, 6-diazaspiro [ 3.4)]Oct-6-yl) quinazolin-2-amine hydrochloride (100 mg crude, 0.175 mmol) was added to dichloromethane (10 mL), and triethylamine (1 mL) was added and stirred at room temperature for 1 hour. Then acryloyl chloride (19 mg,0.21 mmol) was added slowly at-70 ℃. After stirring the reaction solution at-70℃for 30 minutes, it was quenched by addition of methanol (5 mL), warmed to room temperature, and concentrated. The crude product is prepared by reverse phase to obtain white solid which is 1- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) amino) quinazolin-4-yl) -2, 6-diazaspiro [3.4 ] ]Oct-2-yl) prop-2-en-1-one (Z11, 8.5mg, yield: 8.3%). ES-API [ M+H ]] + ＝589.5。 1 H NMR(400MHz,CDCl 3 )δ10.79(s,1H),7.89(s,1H),7.60(s,1H),7.49-7.47(d,J＝8.8Hz,1H),7.36-7.34(d,J＝8.4Hz,1H),6.41-6.37(m,1H),6.25-6.18(m,1H),5.74-5.71(m,1H),4.30-3.95(m,10H),2.78(m,2H),2.33-2.30(m,5H),2.24-2.20(m,5H),2.10-2.01(m,2H),1.62-1.54(m,2H).
Example 12: preparation of Z13
Step one: 7- (7-bromo-2-chloro-6-methoxyquinazolin-4-yl) -2, 7-diazaspiro [3.5]A mixture of tert-butyl nonane-2-carboxylate (10 g,20.1 mmol), (S) - (1-methylpyrrolidin-2-yl) methanol (34.7 g,301 mmol) and cesium carbonate (19.6 g,60.3 mmol) was stirred at 120℃for 1 hour. After the completion of the reaction, the reaction solution was poured into 500mL of ethyl acetate and washed three times with 200mL of water. The obtained organic phase was dried over anhydrous sodium sulfate, and concentrated by filtration to obtain a residue. The residue was purified by column chromatography (DCM: meOH (1% Et) 3 N), 0-5%) to give (R) -7- (7-bromo-6-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ] as a pale yellow solid]Nonane-2-carboxylate (9.5 g). ES-API [ M+H ]] + ＝576.1。
Step two: (R) -7- (7-bromo-6-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylate (4.5 g,7.81 mmol), (5-methyl-1H-indazol-4-yl) boronic acid (2.06 g,11.71 mmol), tris (dibenzylideneacetone) dipalladium (714 mg,0.78 mmol), SPhos (320 mg,0.78 mmol) and potassium phosphate (4.97 g,23.43 mmol) were dissolved in 80mL of 1, 4-dioxane and 20mL of water, the mixture was replaced three times with nitrogen and reacted at 120℃for 1 hour under nitrogen protection. The reaction solution was dissolved in 300mL of ethyl acetate and washed three times with 100mL of saturated brine, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by flash silica gel column (methanol/dichloromethane, 0-10%) to give tert-butyl 7- (6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) as a yellow solid ]) -2, 7-diazaspiro [3.5 ]]Nonane-2-carboxylate (4.5 g). ES-API [ M+H ]] + ＝628.2。
Step three: tert-butyl 7- (6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl)]) -2, 7-diazaspiro [3.5 ]]A solution of nonane-2-carboxylate (1.2 g,1.91 mmol) in dichloromethane (12 mL) was cooled to 0deg.C and trifluoroacetic acid (3 mL) was slowly added. After the addition was completed, the reaction mixture was returned to room temperature and stirred for 2 hours. After the reaction, the reaction solution was depressurizedConcentration gave 6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [ 3.5) as a yellow viscous material]]Nonyl-7-yl) quinazoline (1.01 g). ES-API [ M+H ]] + ＝508.2。
Step four: to 6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [ 3.5) under ice bath conditions]]To a mixture of nonyl-7-yl) quinazoline (1.01 g,1.91 mmol) and methylene chloride (20 mL) was slowly added triethylamine (1 mL) and acrylic anhydride (229 mg,1.82 mmol) and reacted for 5 minutes. The reaction solution was quenched with water (10 mL), extracted with dichloromethane (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified by preparative HPLC to give 1- (7- (6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) as a white solid ]) -2, 7-diazaspiro [3.5 ]]Nonyl-2-yl) prop-2-en-1-one (Z13, 580mg, P:99.37%, yield: 45%). 1 H NMR(500MHz,DMSO)δ13.04(s,1H),7.51-7.46(m,2H),7.42(s,1H),7.33-7.29(m,2H),6.36(dd,J＝17.0,10.3Hz,1H),6.13(dd,J＝17.0,2.2Hz,1H),5.69(dd,J＝10.3,2.2Hz,1H),4.42-4.35(m,1H),4.19(s,1H),4.05(s,2H),3.79(s,3H),3.77(s,2H),3.69(s,4H),3.03(s,1H),2.67(d,J＝25.9Hz,1H),2.43(s,3H),2.29(s,1H),2.17(s,3H),2.02-1.89(m,5H),1.79-1.61(m,3H).ES-API:[M+H] + ＝582.2。
EXAMPLE 13 preparation of Z14
Step one: (S) -7-bromo-6-methoxy-2- (((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (3.8G, 6.59 mmoL), (2-fluoro-6-hydroxyphenyl) boronic acid (2.04G, 13.18 mmoL), SPhos Pd G2 (356 mg,0.494 mmoL), SPhos (203 mg,0.494 mmoL) and K 3 PO 4 (4.2 g,19.77 mmoL) was added to a mixture of 1, 4-dioxane (120 mL) and water (12 mL), nitrogen was replaced 3 times, heated to 120℃and stirred for 1.5 hours, cooled to room temperature after the reaction was completed, filtered, concentrated, and 100mL of ethyl acetate was addedThe ester was washed with water (3X 50 ml) and then with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed (methanol/dichloromethane: 0-10%) to give (S) -7- (2-fluoro-6-hydroxyphenyl) -6-methoxy-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [ 3.5)]Nonane-2-carboxylic acid tert-butyl ester (3.08 g, Y77%). ES-API [ M+H ]] + ＝608.2。
Step two: (S) -7- (2-fluoro-6-hydroxyphenyl) -6-methoxy-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2,7 diazaspiro [3.5 ]Nonane-2-carboxylic acid tert-butyl ester (3.08 g,5.07 mmoL) was dissolved in 20ml of methylene chloride, 7ml of trifluoroacetic acid was slowly added dropwise at room temperature, after 2 hours of reaction, 10ml of methylene chloride was added, and the mixture was concentrated under reduced pressure to give 3-fluoro-2- (6-methoxy-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [3.5 ])]Azenan-7-yl) quinazolin-7-yl-phenol (2.57 g, crude) was used directly in the next step. ES-API [ M+H ]] + ＝508.1
Step three: 3-fluoro-2- (6-methoxy-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [ 3.5)]Non-nan-7-yl) quinazolin-7-yl phenol (2.57 g,5.07 mmol) was dissolved in methylene chloride, and triethylamine (1.53 g,15.21 mmol) and acrylic anhydride (511 mg,4.06 mmol) were added dropwise under ice-water bath conditions and stirred under ice-water bath conditions for 10 minutes. After the reaction was completed, 100ml of DCM was added, washed with water (50 ml) and saturated brine in this order, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give (1- (7- (7- (2-fluoro-6-hydroxyphenyl) -6-methoxy-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [ 3.5)]Nonyl-2-yl) propen-2-one (Z14, 950mg, yield: 35%) ES-API [ M+H] + ＝562.1。 1 H NMR(400MHz,DMSO-d 6 )δ9.85(s,1H),7.38(s,1H),7.30-7.16(m,2H),6.86-6.64(m,2H),6.34(dd,J＝17.0,10.3Hz,1H),6.12(dd,J＝17.0,2.3Hz,1H),5.68(dd,J＝10.3,2.3Hz,1H),4.34(m,1H),4.12(m,1H),4.02(s,2H),3.80(s,3H),3.74(s,2H),3.65(m,4H),2.96(m,1H),2.58(s,1H),2.37(s,3H),2.18(m,1H),1.95(m,5H),1.74-1.56(m,3H).
EXAMPLE 14 preparation of Z15
Step one: 2-amino-4-bromo-5-methoxybenzoic acid methyl ester (50.0 g,192.2 mmol) and urea (200 g,3300.3 mmol) were added to a 1L reaction flask. The reaction was stirred at 200℃for 1 hour. The reaction system was cooled to room temperature, 1L of water was added, followed by stirring at 100℃under reflux for 1 hour, filtration, and the cake was dried under vacuum and reduced pressure to give the objective 7-bromo-6-methoxyquinazoline-2, 4 (1H, 3H) -dione (51 g, yield: 82.3%) as an off-white solid. ES-API [ M+H ]] + ＝270.09
Step two: 7-bromo-6-methoxyquinazoline-2, 4 (1H, 3H) -dione (1.0 g,3.68 mmol) was dissolved in toluene (5 mL), phosphorus oxychloride (5.66 g,36.91 mmol) was added, and N, N-diisopropylethylamine (1.41 g,10.91 mmol) was slowly added dropwise. The reaction was stirred at 105℃for 0.5 h. The reaction solution was concentrated under reduced pressure and evaporated to dryness, quenched with 50ml of ice water, extracted three times with ethyl acetate (15 ml x 3), and dried under vacuum under reduced pressure to give the target product 7-bromo-2, 4-dichloro-6-methoxyquinazoline (1.0 g, yield: 88%) as a yellow solid. ES-API [ M+H ]] + ＝306，308
Step three: 7-bromo-2, 4-dichloro-6-methoxyquinazoline (340 mg,1.1 mmol) was dissolved in 5ml of 1, 4-dioxane solution, and 2, 6-diazaspiro [3.4 ] was added sequentially]Tert-butyl octane-2-carboxylate (200 mg,0.94 mmol), N, N-diisopropylethylamine (340 mg,2.634 mmol). The reaction was stirred at 50℃for 1 hour. Adding 30ml of ammonium chloride solution into the reaction solution, extracting twice with 50ml of ethyl acetate, drying, concentrating, and purifying the crude product by using a rapid silica gel column (ethyl acetate/petroleum ether: 0-20%) to obtain a target product 6- (7-bromo-2-chloro-6-methoxyquinazolin-4-yl) -2, 6-diazaspiro [3.4 ] ]Tert-butyl octane-2-carboxylate (250 mg, yield: 46.8%) as an off-white solid. ES-API [ M+H ]] + ＝482，484
Step four: 6- (7-bromo-2-chloro-6-methoxyquinazolin-4-yl) -2, 6-diazaspiro [3.4]Tert-butyl octane-2-carboxylate (200 mg,0.413 mmol) was dissolved in 1-methylpiperidin-4-ol (3 g,26.04 mmol), and cesium carbonate (400 mg,1.22 mmol) was added. After heating to 120 ℃, stirring and reacting for 3-4 hours. To the reaction mixture was added 30ml of an ammonium chloride solution, followed by extraction with 50ml of ethyl acetateTwice, drying and concentrating, purifying the crude product with a rapid silica gel column (ethyl acetate/petroleum ether: 0-30%) to obtain the target product 6- (7-bromo-6-methoxy-2- (((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4 ]]Tert-butyl octane-2-carboxylate (180 mg, yield: 77.4%) as an off-white solid. ES-API [ M+H ]] + ＝562
Step five: 6- (7-bromo-6-methoxy-2- (((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 6-diazaspiro [ 3.4)]Tert-butyl octane-2-carboxylate (180 mg,0.32 mmol) was dissolved in 5ml of 1, 4-dioxane and 1ml of water, and (5-methyl-1H-indazol-4-yl) boric acid (57.58 mg,0.384 mmol), 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl (20 mg,0.048 mmol), chloro (2-dicyclohexylphosphino-2 ',6' -dimethoxy-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II) (20 mg,0.024 mmol) and potassium phosphate (203.52 mg,0.96 mmol) were added sequentially. The system was replaced three times with nitrogen and then blanketed with nitrogen spheres. The reaction was stirred at 120℃for 1 hour. The reaction mixture was washed 3 times with 100mL of saturated brine, dried and concentrated, and the crude product was purified by flash column chromatography (ethyl acetate/petroleum ether: 0-20%) to give tert-butyl 6- (6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2,6 diazaspiro [3.4 ] as the target product ]Octane-2-carboxylate (80 mg, yield: 50%) as an off-white solid. ES-API [ M+H ]] + ＝614.
Step six: tert-butyl 6- (6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2,6 diazaspiro [3.4]Octane-2-carboxylate (80 mg,0.130 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was added. Stirring for 2 hours at room temperature, concentrating the reaction liquid to obtain a target product of 6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) oxy) -4- (2, 6-diazaspiro [ 3.4)]The octan-6-yl) quinazoline (90 mg, crude) was used directly in the next reaction. ES-API [ M+H ]] + ＝514。
Step seven: 6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) oxy) -4- (2, 6-diazaspiro [ 3.4)]The octan-6-yl) quinazoline (66 mg,0.130 mmol) was dissolved in dichloromethane (5 mL) and N, N-diisopropylethylamine (20.16 mg,0.156 mm) was addedAnd (3) an ol). The reaction was cooled to 0℃and acrylic anhydride (19.67 mg,0.156 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0℃for 15 minutes. 80mL of methylene chloride is added into the reaction solution, 100mL of saturated NaHCO3 aqueous solution and 80mL of saturated saline solution are used for washing, the mixture is dried and concentrated, and the crude product is purified by a rapid silica gel column (ethyl acetate/petroleum ether: 0-60%) to obtain the target product 1- (6- (6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((1-methylpiperidin-4-yl) oxy) quinazoline-4-yl) -2, 6-diazaspiro [3.4 ] ]-2-propenoyl-1 ketone (15 mg, yield: 20%) as an off-white solid. ES-API [ M+H ]] + ＝569.2。 1 H NMR(500MHz,CDCl 3 )δ7.62(d,J＝1.1Hz,1H),7.59(s,1H),7.52(s,1H),7.45(d,J＝8.5Hz,1H),7.34(d,J＝8.6Hz,1H),6.39(dd,J＝17.0,1.8Hz,1H),6.22(dd,J＝16.9,10.3Hz,1H),5.74(dd,J＝10.4,1.7Hz,1H),5.41(s,1H),4.31(d,J＝6.4Hz,1H),4.24(d,J＝8.5Hz,1H),4.15(d,J＝14.9Hz,6H),3.79(s,3H),3.26(s,3H),2.74(s,3H),2.43(s,2H),2.35(t,J＝6.4Hz,2H),2.24(s,6H).
The following compounds were prepared according to a similar method as described above (except for the replacement of the different starting materials) or according to conventional synthetic methods.
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EXAMPLE 15 preparation of Z30
Step one: the compound (R) -7- (7-bromo-6-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acidThe acid salt (570 mg,0.99 mmol), 2-fluoro-5-hydroxyphenylboronic acid (230 mg,1.48 mmol), SPos Pd G2 (143 mg,0.20 mmol), SPos (81 mg,0.20 mmol) and potassium phosphate (630 mg,2.97 mmol) were dissolved in 8mL of 1, 4-dioxane and 1.6mL of water and reacted under nitrogen at 120℃for 1 hour. The reaction solution was dissolved in 30mL of ethyl acetate and washed three times with 10mL of water, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by flash column on silica gel (methanol/dichloromethane, 0-10%) to give tert-butyl (S) -7- (7- (2-fluoro-5-hydroxyphenyl) -6-methoxy-2- (((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2,7 diazaspiro [3.5 ] as a yellow solid]Nonane-2-carboxylate (600 mg). ES-API [ M+H ]] + ＝608.2。
Step two: the compound tert-butyl (S) -7- (7- (2-fluoro-5-hydroxyphenyl) -6-methoxy-2- (((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2,7 diazaspiro [3.5 ]A solution of nonane-2-carboxylate (600 mg,0.98 mmol) in dichloromethane (5 mL) was cooled to 0deg.C and trifluoroacetic acid (2.5 mL) was slowly added. After the addition was completed, the reaction mixture was returned to room temperature and stirred for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to give (S) -4-fluoro-3- (6-methoxy-2- (((1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [ 3.5) as a yellow viscous material]Non-nan-7-yl) quinazolin-7-yl) phenol trifluoroacetate (580 mg). ES-API [ M+H ]] + ＝508.2。
Step four: under ice bath conditions, to (S) -4-fluoro-3- (6-methoxy-2- (((1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [ 3.5)]Triethylamine (500 mg,4.95 mmol) and acrylic anhydride (100 mg,0.79 mmol) were slowly added to a mixture of nonanan-7-yl) quinazolin-7-yl) phenol trifluoroacetate (580 mg,0.96 mmol) in dichloromethane (10 mL) and reacted for 30 min. The reaction mixture was quenched with water (10 mL), extracted with dichloromethane (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified by preparative HPLC to give (S) -1- (7- (7- (2-fluoro-5-hydroxyphenyl) -6-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ] as a white solid]Nonyl-2-yl) prop-2-en-1-one (260 mg). ES-API [ M+H ] ] + ＝562.2。
EXAMPLE 16 preparation of Z31
Step one: 4-bromo-3, 5-dimethoxybenzoic acid (30 g,115.4 mmol), acetic anhydride (31.8 g,311.5 mmol), concentrated sulfuric acid (560 mg,5.77 mmol) were added to dichloromethane (300 mL), the reaction solution was cooled to 0℃and then 70% concentrated nitric acid (10.9 g,121.2 mmol) was slowly added and reacted at 15℃for 4 hours, the reaction solution was poured into ice water to quench, extracted with ethyl acetate, the organic phase was dried and concentrated under reduced pressure to give crude 4-bromo-3, 5-dimethoxy-2-nitrobenzoic acid (36 g, yield 100%). ES-API [ M-1 ]] - ＝304.0
Step two: 4-bromo-3, 5-dimethoxy-2-nitrobenzoic acid (36 g,118 mmol) was dissolved in methanol (400 mL), stannous chloride (213 g,944 mmol), reacted at 60℃for 16 hours, and the reaction mixture was concentrated under reduced pressure to dryness the solvent to give crude 2-amino-4-bromo-3, 5-dimethoxy benzoic acid (200 g, yield 100%). ES-API [ M-1 ]] - ＝274.0
Step three: 2-amino-4-bromo-3, 5-dimethoxybenzoic acid (30.0 g,0.11 mmol) was dissolved in water (450 mL), acetic acid (9.9 g,0.165 mmol) was added, then potassium cyanate was slowly added dropwise in water, the reaction was carried out for 1 hour at 40℃and cooled, sodium hydroxide solid (88 g,2.2 mmol) was added, the reaction was carried out for 1 hour at 90℃and cooled with ice water, the solid was precipitated, and the solution was filtered and dried to give 7-bromo-6, 8-dimethoxyquinazoline-2, 4-diol (3.1 g, yield: 9.5%). ES-API [ M+1 ] ] + ＝301.1。
Step four: 7-bromo-6, 8-dimethoxyquinazoline-2, 4-diol (3.7 g,12.3 mmol) was dissolved in phosphorus oxychloride (30 mL), heated to 115℃for 16 hours, cooled, concentrated under reduced pressure to remove most of the solvent, dissolved in dichloromethane, slowly poured into ice water for quenching, the organic phase was brine washed, dried over anhydrous sodium sulfate, and dried under reduced pressure to give 7-bromo-2, 4-dichloro-6, 8-dimethoxyquinazoline (3.2 g, yield 77.5%). ES-API [ M+1 ]] + ＝337.1。
Step five: 7-bromo-2, 4-dichloro-6, 8-dimethoxyquinazoline (2 g,5.95 mmol), 2, 7-diazaspiro [3.5 ]]Nonane-2-carboxylic acid tert-butyl ester (1.35 g,5.95 mmol) was dissolved in dichloromethane (20 mL), iceTriethylamine (1.2 g,11.9 mmol) is added under water cooling, the reaction is carried out for 1 hour at room temperature, the reaction liquid is quenched by water, the organic phase is washed with brine, dried by anhydrous sodium sulfate and dried by decompression and spin-drying to obtain crude 7- (7-bromo-2-chloro-6, 8-dimethoxy quinazoline-4-yl) -2, 7-diazaspiro [3.5 ]]Nonane-2-carboxylic acid tert-butyl ester (3.2 g, yield 100%). ES-API [ M+1 ]] + ＝527.1。
Step six: 7- (7-bromo-2-chloro-6, 8-dimethoxyquinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (3.2 g,5.95 mmol) was added to (S) - (1-methylpyrrolidin-2-yl) methanol (20 mL), then potassium fluoride (3.45 g,59.5 mmol) was added, heated to 100℃for 16 h, LCMS detection showed complete reaction, 200mL water was added, extraction with ethyl acetate (100 mL. Times.3) was performed after the reaction was cooled to room temperature, the organic phase was dried and spun-dried to give crude product, and the crude product was purified by column purification (petroleum ether/ethyl acetate=30-100%) to give (S) -tert-butyl 7- (7-bromo-6, 8-dimethoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ] ]Nonane-2-carboxylate (2.0 g, yield: 55.6%). ES-API [ M+1 ]] + ＝606.2。
Step seven: (S) -tert-butyl 7- (7-bromo-6, 8-dimethoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylate (2 g,3.31 mmol), (5-methyl-1H-indazol-4-yl) boronic acid (1.164 g,6.62 mmol), potassium carbonate (1.4 g,6.62 mmol), 2-dicyclohexylphosphine-2 6 dimethoxy-1, 1-biphenyl (271 mg,0.662 mmol), tris (dibenzylideneacetone) dipalladium (303 mg,0.331 mmol) were added sequentially to dioxane (20 mL) water (4 mL), and after three nitrogen substitutions, the reaction was warmed to 100℃for 16 hours. After cooling to room temperature, ethyl acetate (30 mL) was poured, washed once with brine, dried over anhydrous sodium sulfate, dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol=0-10%) to give tert-butyl 7- (6, 8-dimethoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ]]Nonane-2-carboxylate (1.6 g, yield 73.7%). ES-API [ M+1 ]] + ＝658.4。
Step eight: tert-butyl 7- (6, 8-dimethoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [ 3.5)]Nonane-2-carboxylate (1.6 g,2.44 mmol) was dissolved in dichloromethane (8 mL) and trifluoroacetic acid (8 mL) was added for 0.5H at room temperature, and the mixture was dried by spin to give crude 6, 8-dimethoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [ 3.5) ]Azenan-7-yl) quinazoline (2 g, 100% yield). ES-API [ M+1 ]] + ＝558.4。
Step nine: 6, 8-dimethoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [ 3.5)]Azenan-7-yl) quinazoline (2 g, crude, 2.44 mmol) was dissolved in dichloromethane (20 mL), triethylamine (5 mL) was added with ice water cooling, then acrylic anhydride (246 mg,1.95 mmol) was added dropwise, and the reaction was incubated at 0℃for 0.5 h. The reaction solution was extracted with 20mL of water and DCM (20 mL x 3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, and dried under reduced pressure, and purified (column information: ultimate XB-C18,50 x 250mm,10um, mobile phase system: a: purified water B: pure acetonitrile, flow rate: 80mL/min, gradient: within 40 min, B% = 20% -100%, wavelength: 214nm, column temperature: room temperature) was prepared to give the product 1- (7- (6, 8-dimethoxy-7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-4- (2, 7-diazaspiro [ 3.5)]Azenan-7-yl) quinazoline (160 mg, yield 10.7%). ES-API [ M+1 ]] + ＝612.3。 1 H NMR(400MHz,CDCl 3 )δ7.57(s,1H),7.44(d,J＝8.4Hz,1H),7.35(d,J＝8.6Hz,1H),6.99(s,1H),6.38(d,J＝17.1Hz,1H),6.23(dd,J＝17.0,10.2Hz,1H),5.70(d,J＝10.2Hz,1H),4.60(s,1H),4.36(d,J＝9.1Hz,1H),4.01(s,2H),3.91(s,2H),3.80-3.58(m,10H),3.16(s,1H),2.83(s,1H),2.54(s,3H),2.38-2.31(m,1H),2.20(s,3H),2.05(t,J＝5.2Hz,6H),1.86(s,2H).
Example 16-1: preparation of Z31-1 and Z31-2
The compound Z31 prepared in example 16 was resolved chiral (Co-Solvent:: ACN-IPA-DEA=90-10-0.2); column: IC 250mm 4.6mm 5 um); flow rate: 1.0ml/min; column temperature: 30.0 ℃) to give the compound Z31-1 (retention time: 14.696 min): the compound structure is arbitrarily designated as 1- (7- ((R) -6, 8-dimethoxy-7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [ 3.5)]Non-2-yl) prop-2-en-1-one (40 mg, p:99.1%, ee value: 99.5%). ES-API [ M+H ]] + = 612.3. Compound Z31-2 (retention time: 21.400 min): the compound structure is arbitrarily designated as 1- (7- ((S) -6, 8-dimethoxy-7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [ 3.5)]Non-2-yl) prop-2-en-1-one (40 mg, p:98.5%, ee value: 98.9%). ES-API [ M+H ]] + ＝612.3。
EXAMPLE 17 preparation of Z32
Step one: 3- (trifluoromethoxy) benzoic acid (50 g,0.24 mol) was dissolved in concentrated sulfuric acid (500 mL), and potassium nitrate (31.9 g,0.32 mol) was added in portions under an ice bath, and reacted at room temperature for one hour after the addition was completed. TLC starting material was reacted completely, the reaction solution was poured into ice water (3L), extracted with ethyl acetate (1.5L. Times.2), the combined organic phases were washed with water (1L. Times.3), brine (1L), dried over anhydrous sodium sulfate, filtered and spun-dried to give 2-nitro-5- (trifluoromethoxy) benzoic acid (65 g, yield 100%) as a white solid.
Step two: 2-Nitro-5- (trifluoromethoxy) benzoic acid (25.1 g,0.1 mol) was dissolved in concentrated sulfuric acid (100 mL), N-bromosuccinimide (17.8 g,0.1 mol) was added next time at 80℃temperature, the reaction was allowed to proceed for 2 hours after the completion of the incubation, N-bromosuccinimide (8.9 g,0.05 mol) was added, and the reaction was allowed to proceed for 2 hours after the completion of the incubation. The TLC starting material was reacted about 60% (two batches in parallel), the reaction solution was cooled and poured into ice water (1L), extracted with ethyl acetate (1L x 2), the combined organic phases were washed with water (1L x 2), brine (1L), dried over anhydrous sodium sulfate, and filtered and spun-dried to give crude 4-bromo-2-nitro-5- (trifluoromethoxy) benzoic acid (52 g, 100% yield) as a brown oil.
Step three: 4-bromo-2-nitro-5- (trifluoromethoxy) benzoic acid (50 g,0.15 mol) was added to isopropanol (300 mL) and saturated ammonium chloride solution (200 mL), and after 50℃temperature increase, the mixture was separatedZinc powder (98.5 g,1.5 mol) was added in portions and the reaction was allowed to stand for 1 hour. The reaction solution was cooled and poured into a mixed solvent of ethyl acetate (1L) and water (1L), the mixture was filtered, the ethyl acetate extract (1 L×2) was carried out in the aqueous phase, the organic phase was washed with water (1 L×2), washed with brine (1L), dried over anhydrous sodium sulfate, and filtered and dried to give crude 2-amino-4-bromo-5- (trifluoromethoxy) benzoic acid (45 g, yield 100%) as a brown oily substance. ES-API [ M+1 ]] + ＝300.0 302.0。
Step four: urea (270 g,4.5 mol) was dissolved at 190 degrees and 2-amino-4-bromo-5- (trifluoromethoxy) benzoic acid (45 g,0.15 mol) was added with stirring and the reaction was incubated until the reactants solidified for about 3 hours. Cooled to 100 ℃, water (1L) is added, and the mixture is stirred for one hour with heat preservation. The crude solid after filtration was added to ethanol (0.5L) and stirred for one hour, and the mother liquor after filtration was dried by spin, and methyl tert-butyl ether (0.2L) was slurried to give 7-bromo-6- (trifluoromethoxy) quinazoline-2, 4-diol (5.6 g, yield 11%). ES-API [ M+1 ]] + ＝325.0 327.0。
Step five: 7-bromo-6- (trifluoromethoxy) quinazoline-2, 4-diol (5.6 g,0.017 mol) was added to phosphorus oxychloride (60 mL), and reacted at 100℃for 16 hours. The reaction solution was cooled and poured into ice water (200 mL), extracted with ethyl acetate (100 mL x 2), washed with brine, dried and dried, and purified by column chromatography (petroleum ether: ethyl acetate=0 to 5:1) to give 7-bromo-2, 4-dichloro-6- (trifluoromethoxy) quinazoline (1.3 g, yield 21%) as a yellow solid. ES-API [ M+1 ] ] + ＝362.8。
Step six: 7-bromo-2, 4-dichloro-6- (trifluoromethoxy) quinazoline (1.3 g,3.6 mmol), N, N-diisopropylethylamine (929 mg,7.2 mmol), dissolved in dichloromethane (20 mL), cooled in an ice bath and then added with 2, 7-diazaspiro [3.5 ]]Nonane-2-carboxylic acid tert-butyl ester (813 mg,3.6 mmol) was added and the reaction was continued for one hour. The reaction solution is dried by spin and pulped (methyl tertiary butyl ether: petroleum ether=1:10:20 mL), filtered and dried to obtain 7- (7-bromo-2-chloro-6- (trifluoromethoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ]]Nonane-2-carboxylic acid tert-butyl ester (2.1 g, yield 100%). ES-API [ M+1 ]] + ＝552.8。 1 H NMR(400MHz CDCl 3 )δ8.09(s,1H),7.69(s,1H),3.73(s,8H),1.96(s,4H),1.44(s,9H).
Step seven: (S) - (1-methylpyrrolidin-2-yl) methanol(1.1 g,9.24 mmol) in tetrahydrofuran (50 mL), sodium hydrogen (185 mg,4.62 mmol) was added at 0℃and stirred at constant temperature for 0.5 h, 7- (7-bromo-2-chloro-6- (trifluoromethoxy) quinazolin-4-yl) -2, 7-diazaspiro [ 3.5)]Nonane-2-carboxylic acid tert-butyl ester (1.7 g,3.08 mmol) was added to the reaction solution and reacted at a constant temperature for 1 hour. The reaction was poured into ethyl acetate (100 mL), the organic phase was washed with water (20 mL. Times.2), brine (20 mL), dried over anhydrous sodium sulfate, and filtered and spun-dried to give (S) -7- (7-bromo-2- ((1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 as a yellow oil ]Nonylbutyl-2-carboxylic acid (3 g, 100% yield). ES-API [ M+1 ]] + ＝630.1632.1。
Step eight: (S) -7- (7-bromo-2- ((1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonylbutyl-2-carboxylic acid (3 g,4.76 mmol), (5-methyl-1H-indazol-4-yl) boronic acid (1.7 g,9.52 mmol), tripotassium phosphate (2 g,9.52 mmol), tris (dibenzylideneandentacetone) dipalladium (300 mg), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (300 mg) were added sequentially to dioxane (60 mL) water (10 mL), and after three nitrogen substitutions, the temperature was raised to 105℃for 2 hours. After cooling to room temperature, ethyl acetate (100 mL) was poured, washed once with brine and purified by column chromatography over silica gel (methanol: dichloromethane=0 to 1:10) to give 7- (7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethoxy) quinazolin-4-tert-butylyl) -2, 7-diazaspiro [ 3.5) as a yellow, foamed solid]Nonane-2-carboxylic acid methyl ester (1.3 g, 40% yield). ES-API [ M+1 ]] + ＝682.1。
Step nine: 7- (7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethoxy) quinazolin-4-tert-butyl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid methyl ester (1150 mg,1.68 mmol), dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added and reacted at room temperature for 1 hour, followed by spin-drying to give crude 7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [ 3.5) as a yellow oil ]Crude non-7-yl) -6- (trifluoromethoxy) quinazoline (1 g, 100% yield). ES-API [ M+1 ]] + ＝582.1
Step ten: 7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methyl)Pyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [3.5]Non-7-yl) -6- (trifluoromethoxy) quinazoline (1 g,1.68 mmol), and triethylamine (521 mg,5.15 mmol) were dissolved in dichloromethane (10 mL), and after cooling to 0℃acrylic anhydride (325 mg,2.58 mmol) was added and the reaction was continued for 1 hour at 0 ℃. The reaction solution was dried by spin-drying and then purified by a rapid column (dichloromethane: methanol: ammonia=95:4:1) to give the product 1- (7- (7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Non-2-yl) prop-2-en-1-one (700 mg, 56% yield). ES-API [ M+1 ]] + ＝318.7 636.3。 1 H NMR(400MHz,CDCl 3 )δ10.72(s,1H),7.79(s,1H),7.70(s,1H),7.62(s,1H),7.48(d,J＝8.5Hz,1H),7.32(d,J＝8.5Hz,1H),6.38(d,J＝16.9Hz,1H),6.23(dd,J＝16.8,10.3Hz,1H),5.71(d,J＝10.3Hz,1H),4.67(s,1H),4.42(s,1H),4.02(s,2H),3.92(s,2H),3.74(d,J＝20.7Hz,4H),3.31(s,1H),3.07(dt,J＝29.6,14.8Hz,2H),2.65(s,3H),2.48(s,1H),2.24(s,3H),2.14(s,1H),2.04(s,4H),1.89(d,J＝19.7Hz,2H),1.33(t,J＝7.2Hz,1H).
Example 17-1 preparation of Z32-1 and Z32-2
The compound Z32 (41 mg) prepared in example 17 was isolated by chiral resolution (Co-Solvent: hex: etOH: AMMN=40:60:0.2); column: IC 250mm 4.6mm 5 um); flow rate: 1.0ml/min; column temperature: 30.0 ℃) to obtain: compound Z32-1 (retention time: 9.296 min): the compound structure is arbitrarily designated as 1- (7- ((R) -7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethoxy) quinazolin-4-yl) -2, 7-diazaspiro [ 3.5) ]Non-2-yl) prop-2-en-1-one (16 mg, p:94.35%, ee value: 95%). ES-API [ M+H ]] + =636.2. Compound Z32-2 (retention time: 13.960 min): the compound structure is arbitrarily designated as 1- (7- ((S) -7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Non-2-yl) prop-2-en-1-one (14 mg, p:96.52%, ee value: 94%). ES-API [ M+H ]] + ＝636.2。
EXAMPLE 18 preparation of Z33
Step one: methyl 4-bromo-5-fluoro-2-nitrobenzoate (14 g,50.4 mmol) and cesium carbonate (29.6 g,90.72 mmol) were added to 40mL of N, N-dimethylformamide followed by addition of cyclopropyl alcohol (4.38 g,75.6 mmol) at room temperature and stirring overnight. After completion of the TLC, the reaction solution was poured into a large amount of water and stirred, followed by filtration to give methyl 4-bromo-5-cyclopropyloxy-2-nitrobenzoate (yellow solid, 18g, yield: crude).
Step two: methyl 4-bromo-5-cyclopropyloxy-2-nitrobenzoate (6.0 g,19.05 mmol) was added to methanol/water (40 mL/10 mL), followed by addition of ammonium chloride (3.56 g,66.68 mmol) and iron powder (3.7 g,66.68 mmol) at room temperature and stirring at 80℃for 2 hours. Concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase concentrated to give methyl 2-amino-4-bromo-5-cyclopropoxybenzoate (yellow solid, 2.2g, yield: 40%). ES-API [ M+H ] ] + ＝288.0。
Step three: methyl 2-amino-4-bromo-5-cyclopropoxybenzoate (2.2 g,7.7 mmol) was dissolved in 20mL of methanol and 4mL of water, lithium hydroxide (970 mg,23.1 mmol) was added at room temperature, and stirred overnight at 40 ℃. Cooling to room temperature, removing methanol by rotary evaporation, extracting with ethyl acetate and water, regulating the pH of the water phase to be between 6 and 7 by using 2M dilute hydrochloric acid, and filtering to obtain the product 2-amino-4-bromo-5-cyclopropyloxy benzoic acid (yellow solid, 2.2g, yield: crude product). ES-API [ M+H ]] + ＝274.0。
Step four: 2-amino-4-bromo-5-cyclopropoxybenzoic acid (1.5 g,5.5 mmol) and urea (6.6 g,110 mmol) were stirred at 200℃for 2 hours. The reaction was then cooled to 100deg.C and 100mL of water was added and stirred for 20min, and the reaction solution was filtered to give 7-bromo-6-cyclopropyloxy) quinazoline-2, 4-diol (yellow solid, 1.2g, yield: 74%). ES-API [ M+H ]] + ＝297.0。
Step five: 7-bromo-6-cyclopropyloxy) quinazoline-2, 4-diol (1.2 g,4.05 mmol) was dissolved in phosphorus oxychloride (15 mL) and DIEA (2.6 g,20.25 mmo) was added dropwise at room temperaturel) the reaction was stirred at 120℃overnight. Cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, diluted with ethyl acetate (50 mL), poured into 50mL ice water, and extracted by separation. The organic phase was concentrated and spin-dried to give 7-bromo-2, 4-dichloro-6-cyclopropyloxy quinazoline (yellow solid, 2.0g, yield: crude). ES-API [ M+H ] ] + ＝334.9。
Step six: 7-bromo-2, 4-dichloro-6-cyclopropyloxy quinazoline (2.0 g,6.02 mmol) and triethylamine (1.82 g,18.06 mmol) were added to DCM (20 mL) and 2, 7-diazaspiro [3.5 ] was added to an ice-water bath]Nonane-2-carboxylic acid tert-butyl ester (2.04 g,9.03 mmol). The reaction was then stirred at room temperature overnight. Then the reaction solution is concentrated and purified by a forward silica gel column to obtain 7- (7-bromo-2-chloro-6- (cyclopropyloxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ]]Nonane-2-carboxylic acid tert-butyl ester (yellow solid, 1.4g, yield: 83%). ES-API [ M+H ]] + ＝525.0。
Step seven: (S) - (1-methylpyrrolidin-2-yl) methanol (661.3 mg,5.75 mmol) and sodium hydride (230 mg,5.75 mmol) were dissolved in THF (5 mL), the reaction solution was stirred in an ice-water bath for 30min, then 7- (7-bromo-2-chloro-6- (cyclopropyloxy) quinazolin-4-yl) -2, 7-diazaspiro [ 3.5)]Nonane-2-carboxylic acid tert-butyl ester (600 mg,1.15 mmol) was added to the reaction system and reacted at room temperature for 2 hours. After the reaction is finished, the mixture is quenched by ice water, extracted by ethyl acetate, and the organic phase is separated and concentrated to obtain (S) -7- (7-bromo-6-cyclopropoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazoline-4-yl) -2, 7-diazaspiro [3.5 ]]Nonane-2-carboxylic acid tert-butyl ester (yellow liquid, 1.4g, yield: crude). ES-API [ M+H ] ] + ＝602.3。
Step eight: (S) -7- (7-bromo-6-cyclopropyloxy-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (300 mg, crude), (5-methyl-1H-indazol-4-yl) boronic acid (116.2 mg,0.66 mmol), potassium phosphate (140 mg,0.66 mmol), x-phos (40 mg), pd 2 (dba) 3 (40 mg) was dissolved in 1, 4-dioxane (5 mL) and water (1 mL), and the reaction was stirred at 110℃for 2 hours, which was detected by TLC. The reaction solution is extracted by ethyl acetate and water, the organic phase is concentrated, and the mixture is passed through a forward silica gel column to obtain 7- (6-cyclopropoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-4-yl)]) -2, 7-dinitrogenHeterospiro [3.5]]Nonane-2-carboxylic acid tert-butyl ester (yellow solid, 170mg, yield: 80%).
Step nine: 7- (6-Cyclopropoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester (170 mg,0.26 mmol) was dissolved in DCM/TFA (3 mL/1 mL), stirred in an ice-water bath for 20min, and the TLC spot plate was checked for reaction after which it was concentrated to give 6-Cyclopropoxy-7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [3.5] ] nonyl-7-yl) quinazoline (yellow solid, 144mg, crude).
Step ten: 6-Cyclopropoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [ 3.5)]]Nonyl-7-yl) quinazoline (144 mg,0.26 mmol) was dissolved in 3mL of methylene chloride, and triethylamine (131.3 mg,1.3 mmol) and acrylic anhydride (90.72 mg,0.72 mmol) were added under ice-water bath. The reaction was stirred at room temperature for 30min, after which time it was purified by a silica gel column to give Z33 (yellow solid, 9.1mg, yield: 6%). ES-API [ M+H ]] + ＝608.3。 1 H NMR(400MHz,CDCl 3 )δ7.64(s,1H),7.57(s,1H),7.22(d,J＝8.4Hz,1H),7.31(d,J＝8.8Hz,1H),6.37(d,J＝16.8Hz,1H),6.26-6.23(m,1H),5.71(d,J＝10.4Hz,1H),5.20(s,1H),4.74(s,1H),4.41(s,1H),4.03(s,2H),3.92(s,2H),3.80-3.71(m,4H),3.06(s,3H),2.89(m,1H),2.35(s,2H),2.19(s,3H),2.07(s,4H),1.25(s,4H),0.91-0.66(m,4H).
EXAMPLE 19 preparation of Z34
Step one: 5-bromo-6-methoxy-pyridine acid (2.5 g,10.7 mmol) was dissolved in concentrated sulfuric acid (20.8 g,212 mmol), stirred and cooled in an ice bath, 65% nitric acid (5.22 g,53.8 mmol) was slowly added dropwise, after which the resulting reaction mixture was heated to 50℃and stirred overnight (about 22 hours) at this temperature, cooled to room temperature, slowly poured into ice water (200 g), 25% aqueous ammonia (32 g,470 mmol) was then added dropwise, extracted three times with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, and spun dry to give the crude product, which was passed through a silica gel column, rinsed with dichloromethane/methanol (100:1 to 100:15) to give the product 5-bromo-6-methoxy-3-nitropyridine acid (pale yellow solid, 1.45g, yield: 49%).
Step two: 5-bromo-6-methoxy-3-nitropyridine acid (1.45 g,5.2 mmol) was dissolved in methanol (15 mL), 5 drops of concentrated sulfuric acid were added with stirring using a disposable plastic dropper, and the resulting reaction solution was refluxed under stirring in an oil bath at 70℃over the weekend (about 68 hours). Concentrating under reduced pressure to dryness, adding dropwise sodium bicarbonate solution, adjusting pH to 8-9, extracting with ethyl acetate, and concentrating the organic phase to obtain 5-bromo-6-methoxy-3-nitropicolinic acid methyl ester (pale yellow solid, 1.45g, yield: 95%). ES-API [ M+H ] ] + ＝291.0。 1 H NMR(400MHz,CDCl 3 )：δ8.58(s,1H),4.14(s,3H),4.01(s,3H).
Step three: methyl 5-bromo-6-methoxy-3-nitropicolinate (1.84 g,6.3 mmol) and stannous chloride dihydrate (3.06 g,18.9 mmol) are dissolved in 50mL of ethanol and 10mL of 0.5N diluted hydrochloric acid are added and the resulting mixture stirred at 60℃for 3 hours. TLC was followed completely, cooled to room temperature, ethanol was removed by rotary evaporation, the residue was dissolved in ethyl acetate, sodium bicarbonate saturated aqueous solution was added, stirring was sufficient, filtration, separation was carried out, the organic phase was rotary dried to give crude product, which was passed through a silica gel column, and eluted with petroleum ether/ethyl acetate (5:1 to 3:15) to give methyl 5-bromo-6-methoxy-3-aminopicolinate (pale yellow solid, 0.48g, yield: 29%). ES-API [ M+H ]] + ＝261.0。
Step four: methyl 3-amino-5-bromo-6-methoxypicolinate (1.5 g,5.5 mmol) was dissolved in methanol (10 mL) and lithium chloride (10 mL, 2M) and stirred at room temperature for 1 hour. TLC monitored reaction was complete. Methanol was distilled off, the residue was acidified with dilute hydrochloric acid, and the product was extracted with ethyl acetate (3×50 ml), dried over anhydrous sodium sulfate, and concentrated to give a crude product. Purification by silica gel column (PE/ea=3:1) gave 3-amino-5-bromo-6-methoxypicolinic acid (yellow solid 2.1g, yield: 58.5%). ES-API [ M+H ]] + ＝248，250。
Step five: 3-amino-5-bromo-6-methoxypicolinic acid (1.1 g,4.45 mmol) ammonium chloride (1.19 g,22.25 mmol) and sodium bicarbonate (1.87 g,22.25 m) were each reacted with mol) in DMF (30 mL) and then HATU (2.54 g,6.68 mmoles) were added in portions and reacted for 2 hours at room temperature. The product was extracted with ethyl acetate (3×80 mL), and the organic phase was washed with saturated brine (3×50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Purification by silica gel column (PE/ea=2:1) gave 3-amino-5-bromo-6-methoxypyridine carboxamide (white solid 2.1g, yield: 100%). ES-API [ M+H ]] + ＝247，249。
Step six: 3-amino-5-bromo-6-methoxypyridine carboxamide (1.1 g,4.47 mmol) was dissolved in dioxane (15 mL), BTC (664mg,2.24mmol,5mL of dioxane) was added dropwise at 0deg.C, and after the addition was allowed to react at 110deg.C for 0.5h. Cooling to room temperature, and evaporating the solvent to obtain a crude product. Purification by silica gel column (PE/ea=1:1) gives 7-bromo-6-methoxypyridine [3,2-d]Pyrimidine-2, 4-diol (white solid, 1.21g, yield: 99.5%). ES-API [ M+H ]] + ＝273，275。
Step seven: 7-bromo-6-methoxypyridine [3,2-d ]]Pyrimidine-2, 4-diol (1.21 g,4.45 mmol) was dissolved in phosphine oxide (10 mL), DIEA (1 mL) was added dropwise at 0deg.C, and the mixture was reacted at 120deg.C for 16h. Cooling to room temperature, evaporating to remove solvent to obtain residual liquid, adding toluene (10 mL), spin drying, repeating the above steps twice to obtain 7-bromo-2, 4-dichloro-6-methoxypyridine [3,2-d ] ]Pyrimidine (black oil 1.51g, crude). ES-API [ M+H ]] + ＝308，310。
Step eight: 7-bromo-2, 4-dichloro-6-methoxypyridine [3,2-d ]]Pyrimidine (1.37 g,4.45 mmol) was dissolved in DCM (20 mL) and DIEA (2.87 g,22.25 mmol) was added at 0deg.C, stirred for 2min at 0deg.C, then 2, 7-diazaspiro [3.5 ] was added in portions]Nonane-2-carboxylic acid tert-butyl ester (1.51 g, 6.6755 mmol). The reaction was then stirred at room temperature overnight. The product was washed with DCM (3X 80 mL) and the organic phase was washed with saturated brine (2X 60 mL) and dried over anhydrous sodium sulfate and concentrated to give the crude product. Purification by silica gel column (DCM/meoh=10:1) afforded 7- (7-bromo-2-chloro-6-methoxypyridine [3, 2-d)]Pyrimidin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (yellow solid 1.45g, yield: 65.3%). ES-API [ M+H ]] + ＝498，500。
Step nine: (S) - (1-methylpyrrolidin-2-yl) methanol (1.035 g,9.0 mmol) was dissolved in THF (15 mL) and placed at 0deg.CNext, after adding sodium hydride (360 mg,9.0 mmol) in portions, the reaction was continued at 0℃for 30 minutes, and then 7- (7-bromo-2-chloro-6-methoxypyridine [3, 2-d) was added in portions]Pyrimidin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (900 m g,1.8 mmol) was reacted at 0℃to room temperature overnight. After the completion of the reaction, the mixture was left at 0℃and diluted with ethyl acetate (60 mL), ice water was added thereto, the product was extracted with ethyl acetate (3X 30 mL), washed with saturated brine (2X 20 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. Purifying by silica gel column to obtain (S) -7- (7-bromo-6-methoxy-2- ((1-methylpyrrolidine-2-yl) methoxy) pyridine [3,2-d ]Pyrimidin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (off-white solid 700mg, yield: 67.45). ES-API [ M+H ]] + ＝577，579。
Step ten: (S) -7- (7-bromo-6-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) pyridine [3,2-d]Pyrimidin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (300 mg,0.52 mmol), potassium phosphate (331 mg,1.56 mmol), (5-methyl-1H-indazol-3-yl) boronic acid (110 mg,0.624 mmol), xan-phos (25 mg, 0.052), pd 2 (dba) 3 (48 mg,0.052 mmol) was dissolved in 1, 4-dioxane (5 mL) and water (1 mL) and the reaction stirred at 110℃for 2 hours for TLC detection. The product was extracted with ethyl acetate (3×30 mL), washed with saturated brine (2×20 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. Purifying by silica gel column to obtain 7- (6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [3, 2-d)]Pyrimidin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (yellow solid, 360mg, yield: 100%). ES-API [ M+H ]] + ＝629，631。
Step eleven: 7- (6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [3, 2-d)]Pyrimidin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (330 mg,0.525 mmol). Dissolved in DCM (3.0 mL) and TFA (1 mL) was added at 0deg.C. The reaction was carried out at room temperature for 1 hour. The reaction solution is concentrated to obtain 6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [ 3.5) ]Nonan-7-yl) pyridine [3,2-d]Pyrimidine (brown solid 300mg, crude). ES-API:[M+H] + ＝529，3631。
Step twelve: 6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [ 3.5)]Nonan-7-yl) pyridine [3,2-d]Pyrimidine (300 mg, 0.618 mmol) was dissolved in DCM (6 mL) and triethylamine (172 mg,1.707 mmol) was added at 0deg.C. After stirring for 2min, acrylic anhydride (71.6mg,0.568mmol,1.0mL DCM) was added dropwise. After the completion of the dropping, the reaction was carried out at 0℃for 1 hour. Saturated sodium bicarbonate (10 mL) was added to the reaction, the product was extracted with DCM (3X 30 mL), and the reaction was washed with saturated sodium bicarbonate (2X 20 mL) and saturated brine (2X 20 mL) and the solvent was concentrated to give the crude product. Purification of the product by silica gel column (DCM/meoh=10:1) and TLC (DCM/meoh=20:1) gave 1- (7- (6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [3, 2-d)]Pyrimidin-4-yl) -2, 7-diazaspiro [3.5]Nonan-2-yl) prop-2-en-1-one (white solid, 50.8mg, yield: 16.3%). ES-API [ M+H ]] + ＝583。 1 H NMR(400MHz,DMSO-d 6 )δ1.77-1.92(m,8H),2.16(s,3H),2.76-2.88(m,4H),3.4-3.5(m,2H),3.73-4.01(m,9H),4.32-4.57(m,6H),5.66(d,J＝10.3Hz,1H),6.10(d,J＝16.9Hz,1H),6.32(dd,J＝16.9,10.4Hz,1H),7.29(d,J＝8.5Hz,1H),7.49-7.56(m,2H),7.76(s,1H),13.14(s,1H).
EXAMPLE 20 preparation of Z35
Step one: 7- (7-bromo-2-chloro-6-methoxyquinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (3 g,6.05 mmol) was dissolved in DCM (30 mL), the reaction solution was cooled to 0℃and then boron tribromide (7.56 g,30.25 mmol) was slowly added and stirred for 1 hour, LCMS was sent to check that the reaction was complete, the reaction was quenched with water+tetrahydrofuran and the reaction solution was directly added to the next step. ES-API [ M+1 ] ] + ＝383.0。
Step two: the reaction solution in the previous step was adjusted to pH 8-9 with sodium carbonate, and di-tert-butyl dicarbonate (1.32 g,6.05 mmol) was added thereto and reacted at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with brine,drying with sodium sulfate, and spin-drying to obtain crude 7- (7-bromo-2-chloro-6-hydroxyquinazolin-4-yl) -2, 7-diazaspiro [3.5 ]]Nonane-2-carboxylic acid tert-butyl ester (4.0 g, yield 100%). ES-API [ M+1 ]] + ＝583.0。
Step three: 7- (7-bromo-2-chloro-6-hydroxyquinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (4.0 g,6.05 mmol), sodium difluorochloroformate (2.31 g,15.13 mmol), cesium carbonate (3.94 g,12.1 mmol), dissolved in N, N-dimethylformamide/water (49/7 mL), stirred at room temperature for 15 min, heated to 100℃again for 2 hours, cooled to room temperature, added with 30mL of water, extracted with ethyl acetate, the organic phase dried, spun-dried, and purified by column chromatography (ethyl acetate/petroleum ether/=0-30%) to give 7- (7-bromo-2-chloro-6- (difluoromethoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ]]Nonane-2-carboxylic acid tert-butyl ester (1.4 g, yield: 43.5%). ES-API [ M+1 ]] + ＝533.1。
Step four: 7- (7-bromo-2-chloro-6- (difluoromethoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (1.4 g,2.63 mmol), added to (S) - (1-methylpyrrolidin-2-yl) methanol (15 mL), then KF (458 mg,7.89 mmol) was added, heated to 100℃for two hours, LCMS was taken to check that the reaction was complete, the reaction solution was cooled to room temperature, 30mL of water was added, extracted with ethyl acetate, the organic phase was dried and spun-dried to give crude (S) -tert-butyl 7- (7-bromo-6- (difluoromethoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [ 3.5) ]Nonane-2-carboxylate (1.8 g, yield: 100%). ES-API [ M+1 ]] + ＝612.2
Step five: (S) -tert-butyl 7- (7-bromo-6- (difluoromethoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylate (1.7 g,2.78 mmol), (5-methyl-1H-indazol-4-yl) boronic acid (480 mg,5.56 mmol), potassium phosphate (1.18 mg,5.56 mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (260 mg, 0.5538 mmol), tris (dibenzylideneacetone) dipalladium (255 mg,0.278 mmol), were added sequentially to dioxane (30 mL) water (5 mL), and after three nitrogen substitutions, the reaction was warmed to 100℃for 16 hours. Cooling to room temperature, pouring into ethyl acetate and water, washing with brine, drying with anhydrous sodium sulfate, drying under reduced pressure, and purifying with column (ethyl acetate/petroleum ether)V=30-100%) to give tert-butyl 7- (6- (difluoromethoxy) -7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [ 3.5)]Nonane-2-carboxylate (1.1 g, yield 59.8%). ES-API [ M+1 ]] + ＝664.3。
Step six: tert-butyl 7- (6- (difluoromethoxy) -7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [ 3.5) ]Nonane-2-carboxylate (1.1 g 1.66 mmol), dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was added for 0.5H at room temperature to give crude 6- (difluoromethoxy) -7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [ 3.5) as a crude product by spin-drying]Azenan-7-yl) quinazoline (1.2 g, 100% yield). ES-API [ M+1 ]] + ＝564.3。
Step seven: 6- (difluoromethoxy) -7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [ 3.5)]Non-7-yl) quinazoline (1.2 g,1.66 mmol), and triethylamine (3 mL) were dissolved in dichloromethane (10 mL), and after cooling to 0℃acrylic anhydride (167 mg,1.33 mmol) was added and the reaction was continued for 0.5 hours at 0 ℃. The reaction solution is added with 20mL of water and dichloromethane (20 mL) for extraction, the organic phase is washed by saline solution, dried by anhydrous sodium sulfate and dried by spin drying under reduced pressure, and purified (chromatographic column information: ultimate XB-C18,50 x 250mm,10um, mobile phase system: A: purified water; B: pure acetonitrile, flow rate: 80mL/min, gradient: within 40 minutes, B% = 20% -100%, wavelength: 214nm, column temperature: room temperature) is prepared to obtain the product 1- (7- (6- (difluoromethoxy) -7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [3.5 ]) -3.5) ]Azenan-7-yl) quinazoline (212 mg, 20.7% yield). ES-API [ M+1 ]] + ＝618.3。 1 HNMR(400MHz,CDCl 3 )δ7.73(s,1H),7.69(s,1H),7.64(s,1H),7.47(d,J＝8.6Hz,1H),7.32(s,1H),6.41-6.33(m,1H),6.23(dd,J＝17.0,10.3Hz,1H),6.15(s,1H),5.71(d,J＝10.4Hz,1H),4.55(dt,J＝8.8,4.3Hz,1H),4.37-4.26(m,1H),4.02(s,2H),3.91(s,2H),3.73(q,J＝14.7,13.5Hz,4H),3.13(d,J＝8.7Hz,1H),2.78(s,1H),2.52(s,3H),2.32(q,J＝9.6,8.8Hz,1H),2.25(s,3H),2.11-1.99(m,6H),1.91-1.80(m,3H).
EXAMPLE 21 preparation of Z36
Step one: 7- (7-bromo-8-fluoro-6-iodo-2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (350 mg,0.51 mmol), dissolved in tetrahydrofuran (5 mL), added with sodium ethoxide (7 mg,1.02 mmol), reacted for 48 hours at 65℃after addition, cooled to room temperature, poured into water (100 mL), extracted with ethyl acetate (50 mL. Times.2), and column chromatographed (dichloromethane: methanol=10:1) to give 7- (7-bromo-6-iodo-8-ethoxy-2- (((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [ 3.5)]Nonane-2-carboxylic acid tert-butyl ester (0.3 g, yield 58%). ES-API [ M-55 ]] + ＝660.1 662.1。
Step two: 7- (7-bromo-6-iodo-8-ethoxy-2- (((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [ 3.5)]Nonane-2-carboxylic acid tert-butyl ester (280 mg,0.39 mmol), cyclopropylboronic acid (37 mg,0.43 mmol), sodium carbonate (83 mg,0.78 mmol), 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (30 mg) was sequentially added to a mixed solvent of dioxane (3 mL) and water (0.5 mL), and reacted at 90℃for 1 hour. The reaction solution was cooled and extracted with ethyl acetate (50 mL), washed with brine, dried and purified by column chromatography (methanol: dichloromethane=0 to 1:10) to give 7- (7-bromo-6-cyclopropyl-8-ethoxy-2- (((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ] as a yellow oil ]Nonane-2-carboxylic acid tert-butyl ester (130 mg, yield 54%). ES-API [ M-55 ]] + ＝574.2 576.2
Step three: 7- (7-bromo-6-cyclopropyl-8-ethoxy-2- (((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [ 3.5)]Nonane-2-carboxylic acid tert-butyl ester (50 mg,0.079 mmol), (2-fluoro-6-hydroxyphenyl) boric acid (19 mg,0.12 mmol), tripotassium phosphate (50 mg,0.24 mmol), spos-Pd-G2 (5 mg), S-Phos (10 mg) were added successively to dioxane (0.5 mL) water (0.1 mL), and after three nitrogen substitutions, the reaction was carried out at 120℃for 0.5 hours under microwave irradiation. After cooling to room temperature, ethyl acetate (20 mL) was poured, and after washing with brine once, plate purification (methanol: dichloromethane=0 to 1:10) was prepared to give yellow colorFoamy solid 7- (6-cyclopropyl-8-ethoxy-7- (2-fluoro-6-hydroxyphenyl) -2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (15 mg, yield 28%). ES-API [ M-55 ]] + ＝606.3
Step four: 7- (6-cyclopropyl-8-ethoxy-7- (2-fluoro-6-hydroxyphenyl) -2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester (15 mg,0.023 mmol), dissolved in dichloromethane (0.5 mL), was added trifluoroacetic acid (0.5 mL) and reacted at room temperature for 1 hour, dried by spinning to give crude 2- (6-cyclopropyl-8-ethoxy-2- ((1-methylpiperidin-4-yl) oxy) -4- (2, 7-diazaspiro [3.5] non-7-yl) quinazolin-7-yl) -3 fluorophenol as a yellow oil (13 mg, yield 100%) which was used directly in the next step.
Step five: 2- (6-cyclopropyl-8-ethoxy-2- ((1-methylpiperidin-4-yl) oxy) -4- (2, 7-diazaspiro [ 3.5)]Non-7-yl) quinazolin-7-yl) -3-fluorophenol (13 mg,0.023 mmol) and triethylamine (7 mg,0.069 mmol) were dissolved in dichloromethane (0.5 mL), and after cooling to 0℃acrylic anhydride (3 mg,0.025 mmol) was added and the reaction was continued at 0℃for 1 hour. The reaction solution is dried by spin to prepare purified (chromatographic column information: ultimate XB-C18,50 x 250mm,10um, mobile phase system: A: purified water B: pure acetonitrile, flow rate: 80ml/min, gradient: B/A=20% -90% in 50 minutes, wavelength: 214nm, column temperature: room temperature) to obtain the product 1- (7- (6-cyclopropyl-8-ethoxy-7- (2-fluoro-6-hydroxyphenyl) -2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ]]Non-2-yl) prop-2-en-1-one (Z36, 1.5mg, yield 9.5%). ES-API [ M/2+1 ]] + ＝308.8。 1 H NMR(400MHz,CDCl 3 )δ12.10(s,1H),6.93(s,1H),6.77(s,1H),6.38(d,J＝16.7Hz,1H),6.23(s,1H),5.72(s,1H),5.34(s,2H),3.96(d,J＝39.6Hz,4H),3.34(s,3H),3.10(s,8H),2.80(s,3H),2.65(s,1H),2.21(s,2H),2.02(s,6H),1.11(s,3H),0.56(d,J＝45.1Hz,4H).
EXAMPLE 22 preparation of Z37
Step one: 7-bromo-2, 4, 6-triose8-fluoroquinazoline (1 g,3 mmol) was dissolved in dichloromethane (8 mL) and acetonitrile (8 mL), cooled to 0deg.C with stirring, triethylamine (0.9 g,9 mmol) and 2, 7-diazaspiro [3.5 ] were added dropwise]A solution of tert-butyl nonane-2-carboxylate (0.68 g,3 mmol) in methylene chloride (4 mL) was reacted at this temperature for 1 hour. Pouring the reaction solution into water, extracting with dichloromethane three times (30 mL. Times.3), and spin-drying the extracted organic phase to obtain crude product 7- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2, 7-diazaspiro [3.5 ] ]Nonane-2-carboxylic acid tert-butyl ester (1.5 g, yield: 96%) was used in the next reaction without purification. ES-API [ M+1 ]] + ＝521.0。
Step two: 1-methyl-4-piperidinol (180 mg,1.5 mmol), cesium carbonate (0.96 mg,3 mmol) and triethylenediamine (20 mg,0.2 mmol) were dissolved in dry N, N-dimethylformamide (10 mL), and 7- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2, 7-diazaspiro [3.5 ] was added]The reaction mixture was stirred overnight at room temperature for about 18 hours, was submitted to a liquid chromatography-mass spectrometry detection to show complete reaction, 20 ml of ethyl acetate and 50ml of 0.5N diluted hydrochloric acid were added, stirred for 1 minute, then washed with ethyl acetate (50 ml x 2), the resulting organic phase was washed, the aqueous phase was adjusted to PH 8-9 with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate (50 ml x 3), the organic phase was dried over sodium sulfate and spin-evaporated to dryness to give the product 7- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ]]Nonane-2-carboxylic acid tert-butyl ester (0.55 g, yield: 91%). ES-API [ M+1 ]] + ＝600.0(M-56+H) +
Step three: 7- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (0.55 g,0.91 mmol) was dissolved in dry tetrahydrofuran (10 mL), anhydrous sodium ethoxide solid (93 mg,1.37 mmol) was added, the reaction solution was stirred at 65℃for 2 hours, the reaction solution was stirred with silica gel powder and dried by spin-drying over a flash silica gel column (20 g column, methanol/methanol+dichloromethane=5% -20%) to give the product 7- (7-bromo-6-chloro-8-ethoxy-2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ] ]Nonane-2-carboxylic acid tert-butyl ester (240 mg, yield: 42%). ES-API [ M+1 ]] + ＝570.0/626.0。
Step four: 7- (7-bromo-6-chloro-8-ethoxy-2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (240 mg,0.38 mmol), (2-fluoro-6-hydroxyphenyl) boric acid (126 mg,0.76 mmol), tripotassium phosphate (244 mg,1.15 mmol), chloro (2-dicyclohexylphosphino-2 ',6' -dimethoxy-1, 1 '-biphenyl) (2' -amino-1, 1 '-biphenyl-2-yl) palladium (II) (60 mg,0.076 mmol), 2-dicyclohexylphosphine-2', 4',6' -triisopropylbiphenyl (36 mg,0.076 mmol), and after three nitrogen substitutions, dioxane (8 mL) water (2 mL) was added and the mixture was heated to 100℃under argon for 4 hours. Cooling to room temperature, adding water (50 mL), extracting with ethyl acetate (30 mL), drying the extracted organic phase, evaporating to obtain crude product, subjecting the crude product to silica gel column [10% methanol ethyl acetate solution/(petroleum ether+10% methanol ethyl acetate solution) =20% to 50%]To obtain the product 7- (-6-chloro-8-ethoxy-7- (2-fluoro-6-hydroxyphenyl) -2- ((1-methylpiperidinyl-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ]]Solid of nonane-2-carboxylic acid tert-butyl ester (306 mg, yield 42%). ES-API [ M+1 ] ] + ＝300.6/600.2/656.2。
Step five: 7- (-6-chloro-8-ethoxy-7- (2-fluoro-6-hydroxyphenyl) -2- ((1-methylpiperidin-4-yl) oxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (120 mg,0.18 mmol), dissolved in dichloromethane (6 mL), added trifluoroacetic acid (2 mL) and reacted for 1 hour at room temperature, and LCMS detection was carried out to show complete reaction, which was spin-evaporated to dryness to give crude 2- (6-chloro-8-ethoxy-2- ((1-methylpiperidin-4-yl) oxy) -4- (2, 7-diazaspiro [ 3.5) as a yellow viscous oil]Nonan-7-yl) -quinazolin-7-yl) -3-fluorophenol (200 mg, yield 100%). ES-API [ M+1 ]] + ＝278.5/556.1。
Step six: 2- (6-chloro-8-ethoxy-2- ((1-methylpiperidin-4-yl) oxy) -4- (2, 7-diazaspiro [ 3.5)]Nonan-7-yl) -quinazolin-7-yl) -3-fluorophenol (200 mg,0.18 mmol) and triethylamine (92 mg) were dissolved in dichloromethane (6 mL), after cooling to 0℃the solution of acrylic anhydride diluted in dichloromethane (18 mg,0.14 mmol) was added dropwise, the reaction was continued for 20 min at 0℃and was followed by completion of the LC-MS reaction. 30 ml of methylene chloride was added to the reaction solution, followed by washing with waterThree times (20 ml x 3), the organic phase was dried and spin evaporated to dryness to give 150 mg of crude product, which was passed through a silica gel column (20 g silica gel, methanol/dichloromethane=1/20 to 3.5/20) to give the product 1- (7- (6-chloro-8-ethoxy-7- (2-fluoro-6-hydroxyphenyl) -2- ((1-methylpiperidin-4-yl) oxy) -4- (2, 7-diazaspiro [ 3.5) ]Nonan-7-yl) prop-2-enamide (20 mg, 18% yield). ES-API [ M+1 ]] + ＝610.1。 1 H NMR(400MHz,CDCl 3 )δ7.68(s,1H),7.36-7.28(m,1H),6.83(d,J＝32.0Hz,2H),6.37(d,J＝16.8Hz,1H),6.23(s,1H),5.70(d,J＝10.6Hz,1H),5.14(s,1H),4.39(s,1H),4.11(s,1H),3.95(d,J＝42.7Hz,4H),3.68(s,4H),2.89(s,2H),2.37(s,3H),2.20(s,2H),2.02(s,6H),1.59(s,2H),1.25(s,2H),1.14(s,3H).
EXAMPLE 24 preparation of Z39
Step one: 4-bromo-5-fluoro-2-nitrobenzoic acid (5 g,19 mmol), dimethylamine hydrochloride (2.43 g,30 mmol), sodium carbonate (6.36 g,60 mmol) were added to DMF (80 mL), heated and stirred under sealed condition at 70℃under argon for 2 hours, cooled and diluted with water (300 mL), EA extract (100 mL. Times.3), and the combined organic phases were washed with water (100 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-bromo-5- (dimethylamino) -2-nitrobenzoic acid (yellow solid, 5.5g, yield: 100%). ES-API [ M+H ]] + ＝289。
Step two: 4-bromo-5- (dimethylamino) -2-nitrobenzoic acid (19 mmol,5.5 g), raney Ni (catalytic amount, one scoop) and ammonia (3 mL) were added to a solution of methanol (60 mL), stirred overnight at room temperature under hydrogen atmosphere (air bag pressure), and then filtered through celite. The filtrate was dried by spinning to give 2-amino-4-bromo-5- (dimethylamino) benzoic acid (yellow solid, 5g, yield: 99%). ES-API [ M+H ]] + ＝259。
Step three: 2-amino-4-bromo-5- (dimethylamino) benzoic acid (5 g,17.7 mmol) and urea (10.6 g,177 mmol) were mixed and heated to 200℃with stirring for 3 hours, cooled, filtered with water, and the solid was filtered off and dried to give 7-bromo-6- (dimethylamino) quinazoline-2, 4 (1H, 3H) -dione (yellow solid, crude 3.3g, yield: 60%). ES-API [ M+H ] ] + ＝284,286。
Step four: 7-bromo-6- (dimethylamino) quinazoline-2, 4 (1H, 3H) -dione (3.53 mmol,1 g), phosphorus oxychloride (36 mmol,5.51 g) and DIEA (11 mmol,1.3 g) were added to toluene (20 mL), heated under argon at 110℃overnight, cooled and concentrated (whole argon without exposure to air) to give 7-bromo-2, 4-dichloro-N, N-dimethylquinazolin-6-amine (crude yellow solid 2g, yield: 100%).
Step five: 7-bromo-2, 4-dichloro-N, N-dimethylquinazolin-6-amine (crude 2g,3.53 mmol), 2, 7-diazaspiro [3.5 ]]Nonane-2-carboxylic acid tert-butyl ester (0.96 g,4.24 mmol) and TEA (1 g,10 mmol) were added to anhydrous DMF (15 mL) and stirred at room temperature for 2 hours before being dissolved in EA (50 mL) and washed with water (20 mL. Times.3). The organic phases were combined and dried over anhydrous sodium sulfate and passed through a silica gel column to give 7- (7-bromo-2-chloro-6- (dimethylamino) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ]]Nonane-2-carboxylic acid tert-butyl ester (yellow solid, 590mg, yield: 33%). ES-API [ M+H ]] + ＝510。
Step six: 7- (7-bromo-2-chloro-6- (dimethylamino) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (300 mg,0.6 mmol), (S) - (1-methylpyrrolidin-2-yl) methanol (210 mg,1.8 mmol), DABCO (13 mg,0.12 mmol) and cesium carbonate (600 mg,1.8 mmol) were added to anhydrous DMF (5 mL) and stirred overnight at 60℃under argon. After cooling, EA (50 mL) was added and the mixture was washed with water (20 mL. Times.3). Drying over anhydrous sodium sulfate, filtering and concentrating to obtain (S) -7- (7-bromo-6- (dimethylamino) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinazoline-4-yl) -2, 7-diazaspiro [3.5 ]Tert-butyl nonane-2-carboxylate (yellow solid, 400mg, yield: 94%). ES-API [ M+H ]] + ＝589。
Step seven: (S) -7- (7-bromo-6- (dimethylamino) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Tert-butyl nonylalkyl-2-carboxylate (435 mg,0.74 mmol), (5-methyl-1H-indazol-4-yl) boronic acid (399mg, 2.22 mmol), pd 2 (dba) 3 (68 mg,0.074 mmol), sphos (62 mg,0.15 mmol) and sodium carbonate (400 mg,3.8 mmol) were added to dioxane/water (4/1, 5 mL), stirred for 6 hours at 110℃under argon, cooled and purified to give 7- (6- (dimethylamino) -7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidine) by plate purification-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (yellow solid 100mg, yield: 25%).
Step eight: 7- (6- (dimethylamino) -7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester (100 mg,0.16 mmol) was dissolved in a mixture of dioxane hydrochloride (4M) and methanol (2/2 mL) and stirred at room temperature for 1 hour before spin-drying to give N, N-dimethyl-7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [3.5] non-7-yl) quinazolin-6-amine (110 mg as white hydrochloride solid, yield: 100%).
Step nine: n, N-dimethyl-7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (2, 7-diazaspiro [ 3.5)]Non-7-yl) quinazolin-6-amine (100 mg,0.16 mmol) was dissolved in TEA (160 mg,1.6 mmol) in DCM (2 mL) and stirred at room temperature for 30 min, then cooled to-70℃and acryloyl chloride (28 mg,0.32 mmol) was added dropwise, followed by stirring for 30 min and then methanol (2 mL) was added to return to temperature, dried by spinning, the plate was prepared and purified to give a white solid, which was purified by pre-HPLC to give 1- (7- (6- (dimethylamino) -7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [ 3.5)]Non-2-yl) prop-2-en-1-one (Z39, cyan solid 2.8mg, y: 4%). ES-API [ M+H ]] + ＝595。 1 H NMR(400MHz,DMSO-d 6 )δ.13.11(br,1H),9.96(br,1H),7.58-7.32(m,5H),6.39-6.32(m,1H),6.13(d,J＝17.2,1H),5.69(d,J＝11.6,1H),4.79-4.76(m,1H),4.62-4.58(m,1H),4.07(s,1H),3.90-3.73(m,8H),3.30-3.24(m,1H),2.97(s,3H),2.47(s,6H),2.29-2.22(m,4H),2.05-1.88(m,7H).
EXAMPLE 25 preparation of Z40
Step one: 4-bromo-3, 5-difluorobenzoic acid (20 g,0.084 mol) was added to concentrated sulfuric acid (100 mL), potassium nitrate (8.5 g,0.084 mol) was added, and the mixture was stirred well and heated at 80℃for 3 hours. The reaction mixture was cooled and poured into water (500 mL), followed by extraction with ethyl acetate (300)mL x 3), washed with brine, dried and spin-dried to give the yellow solid product 4-bromo-3, 5-difluoro-2-nitrobenzoic acid (18 g, 75% yield). 1 H NMR(400MHz,DMSO-d 6 )δ7.84(d,J＝8.1Hz,1H).
Step two: cyclopropyl alcohol (2.68 g,0.046 mol) was added to tetrahydrofuran (400 mL), sodium hydrogen (5.5 g,0.14 mol) was added at 0℃and after stirring well 4-bromo-3, 5-difluoro-2-nitrobenzoic acid (13 g,0.046 mol) was added and the reaction was completed at room temperature overnight. The reaction solution was quenched with water (20 mL), most of the tetrahydrofuran was removed by swirling, the pH was adjusted to 4 to 5 with dilute hydrochloric acid, extracted with ethyl acetate (100 mL. Times.3), washed with brine, dried and dried to give 4-bromo-3-cyclopropyloxy-5-fluoro-2-nitrobenzoic acid (13 g, yield 80%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) 6 )δ7.65(s,1H),4.47-4.38(m,1H),0.69(d,J＝12.1Hz,2H),0.65-0.57(m,2H).
Step three: 4-bromo-3-cyclopropyloxy-5-fluoro-2-nitrobenzoic acid (13 g,0.04 mol) was dissolved in methanol (80 mL), and a methanol solution (16 mL, 5M) of sodium methoxide was added thereto, and the mixture was heated to 50℃to react for 2 hours. The reaction mixture was quenched with water (10 mL), most of the methanol was removed by swirling, the pH was adjusted to 4-5 with dilute hydrochloric acid, extracted with ethyl acetate (100 mL. Times.3), washed with brine, dried and dried to give 4-bromo-3-cyclopropyloxy-5-methoxy-2-nitrobenzoic acid (10 g, yield 75%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) 6 )δ7.34(s,1H),4.40-4.35(m,1H),3.98(s,3H),0.72-0.67(m,2H),0.59(d,J＝6.8Hz,2H).
Step four: 4-bromo-3-cyclopropyloxy-5-methoxy-2-nitrobenzoic acid (9.6 g,28.91 mmol) was added to thionyl chloride (100 mL), reacted for 3 hours with heating at 80℃until the crude product was dried directly for the next step.
Step five: 4-bromo-3-cyclopropyloxy-5-methoxy-2-nitrobenzoyl chloride (10.1 g,28.91 mmol) was dissolved in ultra-dry tetrahydrofuran (100 mL), and added dropwise to 0℃aqueous ammonia (100 mL), and reacted at room temperature for 3 hours after the addition. Ethyl acetate extraction (100 ml x 3), water washing with brine, drying and spin-drying to obtain the product 4-bromo-3-cyclopropyloxy-5-methoxy-2-nitrobenzamide (9 g, yield 90%). ES-API [ M+H ]] + ＝334
Step six: 4-bromo-3-cyclopropyloxy-5-methoxy-2-nitrobenzamide (8.9 g,0.027 mol) was added to acetic acid (140 mL) and water (70 mL) Iron powder (15.1 g,0.27 mol) was added to the mixed solvent in portions at 60℃and the reaction was continued for 2 hours at the end of the addition. After the reaction mixture was cooled, ethyl acetate (500 mL) was added, and the mixture was filtered and dried by spin-drying to give a crude product, which was slurried (10% ethyl acetate/petroleum ether 50 mL) to give 2-amino-4-bromo-3-cyclopropyloxy-5-methoxybenzamide (4 g, yield 49%) as a white solid. ES-API [ M+H ]] + ＝302
Step seven: 2-amino-4-bromo-3-cyclopropyloxy-5-methoxybenzamide (4 g,0.013 mol) was dissolved in tetrahydrofuran (65 ml), sodium hydrogen (2.7 g,0.066 mol) was added thereto after cooling to 0℃and after stirring for 0.5 hours, carbonyldiimidazole (3.2 g,0.02 mol) was slowly added thereto, and the reaction was completed at room temperature for 1 hour. Quenching reaction by dropping water (5 mL) at a temperature of 0 ℃, spin-drying most tetrahydrofuran (10% ethyl acetate/petroleum ether 50 mL), pulping, and drying to obtain 7-bromo-8-cyclopropyloxy-6-methoxyquinazoline-2, 4-diol (3.5 g, yield 82%). 1 H NMR(400MHz,DMSO-d 6 )δ11.42(s,1H),10.58(s,1H),7.25(s,1H),4.40-4.33(m,1H),3.87(s,3H),0.99(p,J＝5.2Hz,2H),0.55-0.46(m,2H).ES-API:[M+H] + ＝329
Step eight: 7-bromo-8-cyclopropyloxy-6-methoxyquinazoline-2, 4-diol (2 g,6.1 mol) is added to phosphorus oxychloride (30 ml), heated to 100 ℃, N-diisopropylethylamine is slowly added to the solution of the reaction liquid to be clear (3 ml), heated to 130 ℃ for 2 hours, the reaction liquid is cooled, most of phosphorus oxychloride is removed by screwing, then poured into water (100 ml), washed with brine, dried and dried to obtain 7-bromo-2, 4-dichloro-8-cyclopropyloxy-6-methoxyquinazoline crude product (2.2 g, yield 95%).
Step nine: the compound 7-bromo-2, 4-dichloro-8-cyclopropyloxy-6-methoxyquinazoline (2 g,5.49 mol) was dissolved in tetrahydrofuran (50 ml), and (S) 3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.2 g,6.04 mol), triethylamine (1.7 g,16.48 mol) was added. Heating to 60 ℃ for reaction for 5 hours, cooling the reaction liquid, adding ethyl acetate (100 ml), washing with water, washing with ammonium chloride solution, washing with brine, drying, spin-drying, and purifying by column (petroleum ether: ethyl acetate=3:1) to obtain yellow foaming solid (S) 4- (7-bromo-2-chloro-8-cyclopropyloxy-6-methoxyquinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (3 g, yield 100%). ES-API: [ M+H)] + ＝529。
Step ten: (S) - (1-methylpyridine)Sodium hydrogen (318 mg,7.96 mmol) was added to pyrrolidin-2-yl) methanol (20 mL) at reduced temperature of 0℃and (S) 4- (7-bromo-2-chloro-8-cyclopropyloxy-6-methoxyquinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.4 g,2.65 mmol) was added and stirred well before heating to 110℃for 1 hour. The reaction solution was cooled and poured into water (100 mL), extracted with ethyl acetate (100 mL x 3), and purified by column (methanol: dichloromethane=0 to 1:10) to give (S) -tert-butyl 4- (7-bromo-8-cyclopropyloxy-6-methoxy-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid as a yellow foamy solid (1/2 m+h) (1 g, yield 58%). ES-API: [1/2m+h ] + ＝303.6。
Step eleven: (S) -tert-butyl 4- (7-bromo-8-cyclopropyloxy-6-methoxy-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid (1 g,1.65 mmol), (5-methyl-1H-indazol-4-yl) boronic acid (435 mg,2.47 mmol), tripotassium phosphate (1.05 g,4.95 mmol), tris (dibenzylideneacetone) dipalladium (100 mg), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (200 mg), sequentially added to dioxane (2 mL), after three substitutions of nitrogen, the mixture was warmed up to 110℃for 16 hours, cooled to room temperature and poured into ethyl acetate (50 mL), washed once with brine and purified by a column of silica gel (methanol: dichloromethane=0 to 1:10) to obtain yellow foamed solid (3S) tert-butyl 4- (8-cyclopropyloxy-6-methoxy-7- (5-methyl-1H-indazol) -2-methyl) -2- ((-methyl) 2-azolyl) 1-quinazolin-1-carboxylic acid (550 mg), yield 50%). ES-API [1/2M+H ]] + ＝329.6
Step twelve: (3S) tert-butyl 4- (8-cyclopropoxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- (((((S) -1-methylpyrrolidin-2-yl)) methoxy) quinazolin-4-yl) -3-methylpiperazine-1-carboxylate (550 mg,0.84 mmol) dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) added and allowed to react at room temperature for 1 hour, and dried by spinning to give crude 8-cyclopropoxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -4- ((S) -2-methylpiperazin-1-yl) -2- (((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline (468 mg, 100% yield) as a yellow oil
Step thirteen: 8-cyclopropoxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -4- ((S) -2-methylpiperazin-1-yl) -2- ((((S) -1-methylpyrrolidine-2)-methoxy) quinazoline (4638 mg,0.84 mmol) and triethylamine (255 mg,2.52 mmol) dissolved in dichloromethane (4 mL), cooled to 0℃and then added with acrylic anhydride (95 mg,0.76 mmol) and incubated at 0℃for 1 hour. The reaction was extracted with water (10 mL), dichloromethane (10 mL x 3), dried and spun-dried to give 1- ((3S) -4- (8-cyclopropoxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl)) methoxy) quinazolin-4-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one (Z40, 60mg, yield 11%) as a white solid. ES-API [ M+H ]] + ＝515.3。 1 H NMR(400MHz,cdcl3)δ10.16(s,1H),7.59(s,1H),7.43(d,J＝8.6Hz,1H),7.33(d,J＝8.6Hz,1H),6.97(s,1H),6.61(dd,J＝30.7,11.0Hz,1H),6.38(d,J＝16.4Hz,1H),5.77(d,J＝10.9Hz,1H),4.75-4.33(m,5H),4.11(s,1H),3.70(d,J＝25.7Hz,5H),3.28(d,J＝13.7Hz,1H),3.11(s,1H),2.75(s,1H),2.50(s,3H),2.28(s,1H),2.21(s,3H),2.07(s,1H),1.79(d,J＝21.6Hz,4H),1.43(d,J＝6.7Hz,3H),0.26-0.10(m,4H).
Example 25-1 preparation of Z40-1 and Z40-2
The compound Z40 (55 mg) produced in example 25 was isolated by chiral resolution (Co-Solvent: HEX: ETOH: DEA=40:60:02); column: IG 250mm 4.6mm 5 um); flow rate: 1.0ml/min; column temperature: 30.0 ℃) to obtain: compound Z40-1 (retention time: 6.171 min) arbitrarily designated as 1- ((S) -4- ((R) -8-cyclopropoxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidinone-pyridin-2-yl) methoxy) quinazolin-4-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one (19 mg, P:99.5%, ee value: 99.3%). ES-API: [ M+H ] + = 612.3; compound Z40-2 (retention time: 7.600 min) was arbitrarily designated as 1- ((S) -4- ((S) -8-cyclopropoxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidinone-pyridin-2-yl) methoxy) quinazolin-4-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one (23 mg, P:98%, ee value: 99%). ES-API: [ M+H)] + ＝612.3。
EXAMPLE 23 preparation of Z38
Step one: 7-bromo-2, 4-dichloro-8-cyclopropyloxy-6-methoxyquinazoline (2.1 g,5.78 mol) was dissolved in tetrahydrofuran (50 ml), and piperazine-1-carboxylic acid tert-butyl ester (1.6 g,8.68 mol) and triethylamine (1.75 g,17.34 mol) were added. Heating to 60 ℃ for reaction for 5 hours, cooling the reaction liquid, adding ethyl acetate (100 ml), washing with water, washing with ammonium chloride solution, washing with brine, drying, spin-drying, and purifying by column (petroleum ether: ethyl acetate=3:1) to obtain yellow foaming solid 4- (7-bromo-2-chloro-8-cyclopropyloxy-6-methoxyquinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (1.1 g, yield 50%). ES-API: [ M+H] + ＝513.1。
Step two: sodium hydrogen (390 mg,9.73 mmol) was added to (S) - (1-methylpyrrolidin-2-yl) methanol (15 mL) at reduced temperature of 0℃and tert-butyl 4- (7-bromo-2-chloro-8-cyclopropyloxy-6-methoxyquinazolin-4-yl) piperazine-1-carboxylate (1 g,1.95 mmol) was added, followed by stirring and heating at 110℃for 1 hour. The reaction solution was cooled and poured into water (100 mL), extracted with ethyl acetate (100 mL x 3), and purified by column chromatography (methanol: dichloromethane=0 to 1:10) to give tert-butyl ((S) -4- (7-bromo-8-cyclopropyloxy-6-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (750 mg, yield 68%) as a yellow foamy solid: [ m+h ] + ＝592.2。
Step three: ((S) -4- (7-bromo-8-cyclopropyloxy-6-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (750 mg,1.26 mmol), (5-methyl-1H-indazol-4-yl) boronic acid (450 mg,2.52 mmol), tripotassium phosphate (850 mg,3.78 mmol), tris (dibenzylideneacetone) dipalladium (100 mg), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (60 mg) were added in sequence to dioxane (8 mL) water (2 mL), after three nitrogen substitutions were reacted at 110℃for 16 hours, after cooling to room temperature, ethyl acetate (50 mL) was poured, and after one washing with brine, silica gel was purified by column chromatography (methanol: dichloromethane=0 to 1:10) to give tert-butyl 4- (8-cyclopropyloxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- (((S-methylpyrrolidin-2-yl) as a yellow foamy solid) Quinazolin-4-yl) piperazine-1-carboxylate crude (200 mg, yield 30%). ES-API [ M+H ]] + ＝644.3。
Step four: tert-butyl 4- (8-cyclopropoxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (200 mg,0.3 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added and reacted at room temperature for 1 hour, and the mixture was dried by spinning to give crude 8-cyclopropoxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) quinazoline (169 mg, yield 100%) ES-API: [ M+H ] + ＝544.3
Step five: 8-Cyclopropoxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) quinazoline (169 mg,0.3 mmol) was dissolved in dichloromethane (4 mL), triethylamine (2 mL) was added after cooling down to 0 degree, acrylic anhydride (32 mg,0.25 mmol), the reaction solution was incubated at 0 degree for 1 hour with water (10 mL), dichloromethane (10 mL x 3) was extracted, dried and spun dry, and chromatographed to give the purified (column: ultimate XB-C18, 50X 250mm,10um; mobile phase: acetonitrile/water=10/90-90/10, 40 min) as a white solid product 1- (4- (8-cyclopropoxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazin-1-2-yl) 2-one in a yield of [ 8.5H-1-8+ API-1-8:8:] + ＝598.3。 1 H NMR(400MHz,CDCl 3 )δ12.57(s,1H),7.55(s,1H),7.46(d,J＝8.5Hz,1H),7.32(d,J＝8.5Hz,1H),7.01(s,1H),6.63(dd,J＝16.8,10.5Hz,1H),6.37(d,J＝16.7Hz,1H),5.78(d,J＝10.5Hz,1H),5.20(s,1H),4.85(d,J＝12.4Hz,1H),4.15(d,J＝15.5Hz,2H),3.90(d,J＝29.1Hz,9H),3.74(d,J＝2.6Hz,3H),3.07(s,3H),3.01-2.81(m,2H),2.34(s,2H),2.20(s,3H),2.09(s,1H),0.15(d,J＝14.5Hz,4H).
EXAMPLE 26 preparation of Z41
Step one: the compound 7-bromo-2, 4-dichloro-8-cyclopropyloxy-6-methoxyquinazoline (2.1 g,5.78 mol) was dissolved in tetrahydrofuran (50 ml), and (S) -2- (piperazin-2-yl) acetonitrile (3.2 g,16.5 mol), triethylamine (3.3 g,33 mol) was added. After heating to 60℃for 2 hours, ethyl acetate (100 ml) was added to the reaction mixture after cooling, followed by washing with water, ammonium chloride solution, brine, and drying and spin-drying to give (S) -2- (4- (7-bromo-2-chloro-8-cyclopropyloxy-6-methoxypquinazolin-4-yl) piperazin-2-yl) acetonitrile (2.7 g, yield 55%) as a yellow solid. ES-API: [ m+1] += 452.0
Step two: the compound (S) -2- (4- (7-bromo-2-chloro-8-cyclopropyloxy-6-methoxyquinazolin-4-yl) piperazin-2-yl) acetonitrile (3.7 g,8.2 mol) was dissolved in tetrahydrofuran and water (40/20 ml), then sodium hydroxide solid (984 mg,24.6 mmol) and di-tert-butyl dicarbonate (9 g,41 mmol) were added, the reaction was stirred at room temperature for 16 hours, the reaction was monitored to completion, ethyl acetate (100 ml) was added after cooling the reaction solution, washed with water, ammonium chloride solution, brine, and the organic phase was dried and spun dry and purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give (S) -4- (7-bromo-2-chloro-8-cyclopropyloxy-6-methoxyquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (2.78 g, yield 62%). ES-API: [ m+1] +=552.1
Step three: (S) -4- (7-bromo-2-chloro-8-cyclopropyloxy-6-methoxyquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (2.5 g,4.5 mmol) was dissolved in (S) - (1-methylpyrrolidin-2-yl) methanol (20 mL), followed by addition of potassium fluoride (1.3 g,22.7 mmol), stirring well and heating at 110℃for 2 hours. The reaction solution was cooled and poured into water (100 mL), extracted with ethyl acetate (100 mL x 3), and purified by column (methanol: dichloromethane=0 to 1:10) to give tert-butyl (S) -4- (7-bromo-8-cyclopropyloxy-6-methoxy-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethylpiperazine-1-carboxylate (2 g, yield 71%). ES-API: [ m+1] += 631.2) as a yellow foamy solid
Step four: tert-butyl (S) -4- (7-bromo-8-cyclopropyloxy-6-methoxy-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethylpiperazin-1-carboxylate (2 g,3.17 mmol), (5-methyl-1H-indazol-4-yl) boronic acid (1.13 g,6.35 mmol), tripotassium phosphate (2 g,9.51 mmol), tris (dibenzylideneacetone) dipalladium (290 mg), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (150 mg) were added sequentially to dioxane (16 mL) water (4 mL), after three substitutions of nitrogen, the reaction was warmed to 110℃for 16 hours, ethyl acetate (100 mL) was poured after cooling to room temperature, and after one washing with brine, a column purification (methanol: dichloromethane=0 to 1:10) to give yellow foamy solid (2S) -2- (cyanomethyl) -4- (8-cyclopropyloxy-6-methoxy-7- (5-methyl-indazol-4-yl) 1- ((-tert-butyl) 2-methoxy) quinazolin-1-carboxylate, yield 43%). ES-API: [ m+1] += 683.2
Step five: (2S) -2- (cyanomethyl) -4- (8-cyclopropoxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- (((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-ylpiperazin-1-carboxylic acid tert-butyl ester (910 mg,1.33 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added and reacted at room temperature for 1 hour, and the mixture was dried to give crude 2- ((2S) -4- (8-cyclopropoxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- (((((S) -1-methylpyrrolidin-2-yl)) methoxy) quinazolin-4-ylpiperazin-2-yl acetonitrile (770 mg, yield 100%). ES-API + = 583.1 as a yellow oil
Step six: 2- ((2S) -4- (8-Cyclopropoxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl)) methoxy) quinazolin-4-yl-piperazin-2-yl-acetonitrile (770 mg,1.33 mmol) was dissolved in dichloromethane (5 mL), triethylamine (3 mL) was added after cooling down to 0 degree, acrylic anhydride (150 mg,1.2 mmol), the reaction was incubated at 0 degree for 1 hour, water (10 mL) was added to the reaction solution, dichloromethane (30 mL. Times.3) was extracted, and dried and spun dry to give the product 2- ((2S) -1-propenoyl-4- (8-cyclopropoxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- (((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazin-2-yl) acetonitrile (8.2 mg, yield 10%) ES-API: [ M+1:1:1.3 ]]+＝636.2。 1 H NMR(400MHz,CDCl 3 )δ7.58(d,J＝3.8Hz,1H),7.44(d,J＝8.5Hz,1H),7.33(d,J＝8.5Hz,1H),7.02(d,J＝17.0Hz,1H),6.63(s,1H),6.42(d,J＝16.6Hz,1H),5.84(d,J＝10.5Hz,1H),4.69(s,1H),4.45(s,1H),4.31(d,J＝11.7Hz,3H),3.75(s,3H),3.73(s,1H),3.61(d,J＝12.4Hz,1H),3.32(d,J＝39.7Hz,2H),3.07-2.75(m,3H),2.62(s,3H),2.45(s,1H),2.21(d,J＝3.3Hz,4H),2.14(s,1H),1.87(s,4H),0.23-0.10(m,4H).
Example 26-1 preparation of Z41-1 and Z42-2
Compound Z41 (42 mg) prepared in example 26 was isolated by chiral resolution (Co-Solvent:: CAN: IPA: DEA=90:10:0.2); IC 254 nm @4.8 nm); flow rate: 1.0ml/min; column temperature: 30.0 ℃) to obtain: compound Z41-1 (retention time: 4.966 min): the compound structure was arbitrarily designated as 2- ((S) -1-propenoyl-4- ((R) -8-cyclopropyloxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S-1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-ylpiperazin-2-yl) acetonitrile (23 mg, P:94.58%, ee value: 99.6%). ES-API: [ M+H) ] + = 637.3; compound Z41-2 (retention time: 6.381 min): the compound structure was arbitrarily designated as 2- ((S) -1-propenoyl-4- ((S) -8-cyclopropyloxy-6-methoxy-7- (5-methyl-1H-indazol-4-yl) -2- ((((S-1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-ylpiperazin-2-yl) acetonitrile (19 mg, P:93.55%, ee value: 100%). ES-API: [ M+H)] + ＝637.3。
Test example 1 cell proliferation inhibition experiment
NCI-H358 is a human non-small cell lung cancer cell strain mutated by Kras G12C, and is cultured in 10% FBS RPMI-1640 culture medium; a549 is a Kras G12S mutated human lung adenocarcinoma cell line cultured in 10% fbs F-12K medium. Taking cells in logarithmic growth phase, pancreatin EDTA-digested cells were collected and counted and H358 was adjusted to 1.8E4 cells/ml using 2% fbs RPMI-1640 medium, a549 was adjusted to 8.9E3 cells/ml using 2% fbs F-12K medium; 800 (45. Mu.l) H358 or 400 (45. Mu.l) A549 cells were inoculated into 384 Kong Qiuti plates, respectively, and cultured overnight to establish a 3D cell model. Compound 3.16-fold gradient stock solution of 1000X was prepared using DMSO, 100-fold to 10X compound stock solution was diluted using 2% fbs medium, and 5 μl of 10X compound stock solution was added per cell culture well the next day after cell inoculation at a final concentration of 1X and DMSO content of 0.1%. DMSO was used as experimental control (control), 2% fbs medium as blank control (blank). After 5 days of culture with the addition of the compound, 25. Mu.l CellTiter-Glo working solution was added to each well Mixing at 400rpm, incubating for 30 min, standing at room temperature for 30 min, transferring 40 μl of the mixture to a white bottom-penetrating 384-well plate, reading the chemiluminescence value of luminences, calculating the cell proliferation inhibition ratio IR (%) = (RLU control-RLU compound)/(RLU control-RLU blank) ×100%, fitting the compound gradient dilution concentration and the corresponding cell proliferation inhibition ratio by Prism 6 four-parameter method, and calculating IC 50 Values, found: the compound of the application has higher inhibitory activity on NCI-H358 cells with Kras G12C mutation, and IC thereof 50 Less than 1000nM; even below 500nM, even below 300nM or below 200nM, more some compounds IC 50 Less than 100nM, even less than 50nM; while the inhibition activity on A549 cells is lower, and the IC thereof 50 Over 1000nM, even over 5000nM, more some compound ICs 50 Over 10000nM, even over 15000nM or 20000nM. The results of the example compounds are shown in table 1 below.
Inhibitory Activity of the Compounds of Table 1 on H358 and A549 cells
As can be seen from Table 1, the exemplary compounds of the present application have higher inhibitory activity against Kras G12C mutated NCI-H358 cells, while having lower inhibitory activity against A549 cells, with significant selective inhibitory activity.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (17)

1. A spiro-substituted pyrimido-cyclic compound, or a pharmaceutically acceptable salt thereof, which has a structure as shown in formula (I):
in the method, in the process of the invention,
x is N-C (O) -CR X3 ＝CR X1 R X2 ；
Wherein R is X1 、R X2 Is hydrogen or-C 1-3 alkyl-NR a R b ；R X3 Is hydrogen or-O-C 1-3 An alkyl group;
wherein R is a 、R b Each independently is hydrogen or C 1-3 An alkyl group; m, n are each independently 1, 2 or 3; and m and n are not 1 at the same time;
R 1 is halogen, -O-R 11 、-NH-R 11 or-N (R) 11 )R 12 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 11 、R 12 Each independently is a substituted or unsubstituted C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-to 6-membered heterocycloalkyl or R 11 、R 12 Together with the attached nitrogen atom form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl; and when m=n=2, R 1 Is not halogen; wherein the 3-to 6-membered heterocycloalkyl has 1O heteroatom as a ring atom;
l is a bond, -O- (CR) L1 R L2 ) t1 or-NH- (CR) L3 R L4 ) t2 -; wherein R is L1 、R L2 、R L3 、R L4 The same or different, each independently hydrogen or C 1-3 An alkyl group; t1, t2 are each independently 0, 1, 2, 3 or 4;
R 2 is a substituted or unsubstituted 3 to 20 membered heterocycloalkyl or NR 21 R 22 ；R 21 And R is 22 Together with the attached nitrogen atom form a substituted or unsubstituted 3 to 20 membered heterocycloalkyl; wherein the 3-to 20-membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;
z is CR 3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 Is hydrogen, halogen or substituted or unsubstituted C 1-6 An alkoxy group;
e is CR 4 Or N; wherein R is 4 Is hydrogen;
by "substituted" is meant that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S;
the S group substituents are selected from: hydroxy, halogen, nitro, oxo, C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, benzyl, - (CH) 2 ) u -cyano, - (CH) 2 ) u -C 1-6 Alkoxy, - (CH) 2 ) u Halogenated C 1-6 Alkoxy, - (CH) 2 ) u Halogenated C 1-6 Alkyl, - (CH) 2 ) u -3 to 6 membered heterocycloalkyl, - (CH) 2 ) u -5-or 6-membered monocyclic heteroaryl, - (CH) 2 ) u -C 3-8 Cycloalkyl, - (CH) 2 ) u -O-(CH 2 ) v -C 3-8 Cycloalkyl, - (CH) 2 ) u -O-(CH 2 ) v -C 1-6 Alkoxy, - (CH) 2 ) u -O-(CH 2 ) v OH、-(CH 2 ) u -SO 2 C 1-6 Alkyl, - (CH) 2 ) u -NR a0 R b0 、-(CH 2 ) u -C(O)NR a0 R b0 、-(CH 2 ) u -C(O)C 1-6 Alkyl, -C (O) OC 1-6 Alkyl, NR a0 C(O)-(CH 2 ) u -NR a0 R b0 、NR a0 C(O)-(CH 2 ) u OH、NR a0 C (O) -halo C 1-6 An alkyl group; wherein the 3-to 6-membered heterocycloalkyl, 5-or 6-membered monocyclic heteroaryl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3-to 6-membered heterocycloalkyl, 5-or 6-membered monocyclic heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Substituents of cycloalkyl groups; u, v are each independently 0, 1, 2, 3 or 4; r is R a0 、R b0 Each independently is hydrogen or C 1-3 An alkyl group;
b is C 6-10 Aryl or 8 to 10 membered bicyclic heteroaryl; wherein the C 6-10
Aryl is unsubstituted or substituted with 1, 2, 3 or 4 members independently selected from R s1 Is substituted by a group of (2); said 8 to 10The meta bicyclic heteroaryl is selected from the following structures:；
R s1 is hydroxy or halogen;
with the proviso that the compound of formula (I) is not 1- (6- (6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4] oct-2-yl) prop-2-en-1-one, 1- (6- (6-chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 6-diazaspiro [3.4] oct-2-yl) prop-2-en-1-one, 1- (6- (6-chloro-8-fluoro-7- (3-hydroxynaphtalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-2-yl) -2, 6-diazaspiro [3.4] oct-2-yl) prop-2-en-1-one, 1- (6- (6-chloro-2- (3- (dimethylamino) azetidin-1-yl) -8-fluoro-7- (5-methyl-1H-indazol-4-yl) quinazolin-4-yl) -2, 6-diazaspiro [3.4] oct-2-yl) prop-2-en-1-one, 1- (6- (6-chloro-2- (3- (dimethylamino) azetidin-1-yl) -8-fluoro-7- (2-fluoro-6-hydroxyphenyl) -quinazolin-4-yl) -2, 6-diazaspiro [3.4] oct-2-yl) prop-2-en-1-one, 1- (6- (6-chloro-2- (3- (dimethylamino) azetidin-1-yl) -8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-4-yl) -2, 6-diazaspiro [3.4] oct-2-yl) prop-2-en-1-one, or 1- (6- (6-chloro-7- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8- (2, 2-trifluoroethoxy) quinazolin-5-yl) -2, 6-diazaspiro [3.4] oct-2-yl) prop-2-en-1-one.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (II) or a compound of formula (III):
in the formulae, R 1 、R 2 X, B, E, Z, L are as defined above.
3. A compound according to claim 1 or 2, or a pharmaceutical thereofThe above acceptable salt is characterized in that C in B 6-10 Aryl is phenyl.
4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein B is selected from the structures:wherein R is s1 、R s2 Each independently is a hydroxyl group or a halogen.
5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein B is selected from the structures:
。
6. the compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein B is。
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Is halogen or-O-R 11 。
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a bond; r is R 2 Is NR (NR) 21 R 22 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 21 And R is 22 Together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted 6-to 10-membered fused heterocycloalkyl, or substituted or unsubstituted 7-to 11-membered spiroheterocycle An alkyl group; wherein the 3-to 6-membered heterocycloalkyl, 6-to 10-membered fused heterocycloalkyl, 7-to 11-membered spiroheterocycloalkyl each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; by "substituted" is meant that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S.
9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is-O- (CR L1 R L2 ) t1 -or-NH- (CR) L3 R L4 ) t2 -；R 2 Is halogen, hydroxy, -SO 2 C 1-6 Alkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted 6-to 10-membered fused heterocycloalkyl, substituted or unsubstituted 7-to 11-membered spiroheterocycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 5-or 6-membered monocyclic heteroaryl or NR 21 R 22 ；
Wherein R is L1 、R L2 、R L3 、R L4 The same or different, each independently hydrogen or C 1-3 An alkyl group; t1, t2 are each independently 0, 1, 2, 3 or 4;
R 21 、R 22 each independently is hydrogen, substituted or unsubstituted C 1-6 Alkyl, -SO 2 C 1-6 Alkyl, -SO 2 C 3-6 Cycloalkyl, -C (O) C 1-6 Alkyl or-C (O) halo C 1-6 An alkyl group; or R is 21 And R is 22 Together with the attached nitrogen atom form a substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted 6-to 10-membered fused heterocycloalkyl, or substituted or unsubstituted 7-to 11-membered spiroheterocycloalkyl;
Wherein the 3-to 6-membered heterocycloalkyl, 6-to 10-membered fused heterocycloalkyl, 7-to 11-membered spiroheterocycloalkyl each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; by "substituted" is meant that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from group S.
10. A compound of the structure:
。
11. a pharmaceutical composition comprising a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
12. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the manufacture of a medicament for the prevention and/or treatment of cancer.
13. The use of claim 12, wherein the cancer is pancreatic ductal carcinoma, colorectal carcinoma, multiple myeloma, lung carcinoma, cutaneous melanoma, endometrial carcinoma, uterine sarcoma, thyroid carcinoma, acute myelogenous leukemia, bladder urothelial carcinoma, gastric carcinoma, cervical carcinoma, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal carcinoma, chronic lymphocytic leukemia, lung squamous cell carcinoma, small-cell lung carcinoma, renal papillary cell carcinoma, adenoid cystic carcinoma, chromophobe renal cell carcinoma, liver carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, ovarian serous adenocarcinoma, adrenal cortical carcinoma, prostate carcinoma, neuroblastoma, brain low-grade glioma, glioblastoma, medulloblastoma, esophageal squamous cell carcinoma, renal clear cell carcinoma, osteosarcoma, ovarian small cell carcinoma, rhabdoid tumor, sarcoma, small intestine neuroendocrine tumor, or T cell prolymphocytic leukemia.
14. The use according to claim 12, wherein the cancer is lung cancer, pancreatic ductal cancer or colorectal cancer.
15. The use of claim 12, wherein the cancer is non-small cell lung cancer.
16. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the preparation of a KRAS mutation inhibitor.
17. The use of claim 16, wherein the KRAS mutation is a KRAS G12C mutation.
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