CN115872979A

CN115872979A - Pyrimidine derivatives and their use in medicine

Info

Publication number: CN115872979A
Application number: CN202211197506.7A
Authority: CN
Inventors: 李敏雄; 李晓波; 席云龙; 廖敏; 唐林
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2021-09-29
Filing date: 2022-09-29
Publication date: 2023-03-31

Abstract

The invention belongs to the field of medicines, discloses a pyrimidine derivative and application thereof in medicines, and particularly relates to a novel pyrimidine derivative and a pharmaceutical composition containing the compound. The invention also relates to methods for preparing said compounds and pharmaceutical compositions, and to the use thereof for the preparation of a medicament for the treatment of diseases mediated by KRAS G12C, in particular for the treatment of cancer.

Description

Pyrimidine derivatives and their use in medicine

Technical Field

The invention belongs to the field of medicines, and particularly relates to a novel compound serving as a KRAS inhibitor, a preparation method of the novel compound, a pharmaceutical composition containing the novel compound, and application of the novel compound and the pharmaceutical composition in treatment of various diseases. More specifically, the compounds of the present invention are useful as KRAS G12C inhibitors.

Background

KRAS is a murine sarcoma virus gene, and RAS gene family has three genes related to human tumor-HRAS, KRAS and NRAS, which are located on chromosome 11, 12 and 1, respectively. KRAS is also known as the p21 gene because it encodes a 21kD RAS protein. Among the RAS genes, KRAS has the greatest effect on human cancer, accounting for 86% of all RAS mutations, as if the molecular switch: when normal, the cell growth regulation path can be controlled; when abnormality occurs, the cells are caused to grow continuously and are prevented from self-destruction. It is involved in intracellular signal transmission, and when KRAS gene is mutated, the KRAS gene is permanently activated and can not produce normal RAS protein, so that intracellular signal transmission is disturbed, and cell proliferation is out of control and cancerated.

The G12C mutation is a common subtype of KRAS gene mutation, and refers to the mutation of No. 12 glycine into cysteine. The KRAS G12C mutation is most common in lung cancer, and as can be seen from data reported in the literature (Nat Rev Drug Discov 2014 13, 828-851), KRAS G12C mutations account for around 10% of all lung cancer patients. For decades, efforts have been made to develop small molecule inhibitors targeting the RAS, yet no related drugs have been marketed so far. Scientists have long desired to develop competitive inhibitors of GTP that act directly on the RAS protein. But have not been successful because of the strong affinity between GTP and RAS (pmol/L scale), the high concentration of GTP in cells (0.5 mM), and the lack of a pocket in the RAS protein structure that facilitates small molecule binding.

In recent years, some progress has been made in drug development using the allosteric site of KRAS G12C mutant. In 2013, a research group reported the discovery of KRAS G12C small molecule inhibitors (Nature, 2013,503, 548-551). They identified a novel binding pocket from the KRAS G12C mutant located below the region of molecular switch II to which these inhibitors bind and form covalent bonds with nearby Cys12, thereby selectively inhibiting KRAS G12C activation. Other researchers have reported KRAS inhibitors with cellular activity (Science, 2016,351, 604-608). Since the KRAS G12C target protein is pathologically associated with a variety of diseases, there is also a need for novel KRAS G12C inhibitors for clinical therapy. The KRAS G12C inhibitor with high selectivity and high activity can effectively treat diseases such as cancers caused by KRAS G12C mutation, and has the potential of reducing off-target effects, so that the KRAS G12C inhibitor has more urgent clinical requirements.

Disclosure of Invention

The present invention provides a compound, or a pharmaceutical composition thereof, which is useful as an inhibitor of KRAS. The invention further relates to the use of said compounds or pharmaceutical compositions thereof for the preparation of a medicament for the treatment of diseases and/or conditions by inhibition of KRAS activity by said compounds. The invention further describes a synthetic method of the compound. The compounds of the present invention exhibit excellent biological activity and pharmacokinetic properties.

Specifically, the method comprises the following steps:

in one aspect, the invention relates to a compound, which is a compound shown as formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown as formula (I),

wherein:

x is-L-X ¹ -, wherein L is a bond or-NH-, X ¹ Is a 4-12 membered saturated or partially unsaturated monocyclic, fused, spiro or bridged ring containing nitrogen atoms, each of which is independently optionally substituted by p R ^x Substitution;

y is N or CR ^y ；

R ¹ is-C (= O) -CR ^a ＝CR ^b -R ^c 、-C(＝O)-C≡C-R ^c 、-S(＝O) ₂ -CR ^a ＝CR ^b -R ^c or-S (= O) ₂ -C≡C-R ^c ；

R ^a And R ^b Each independently is H, D, F, cl, br, I, C _1-3 Alkyl radical, C _1-3 Haloalkyl or C _1-3 Alkoxy, wherein said C _1-3 Alkyl radical, C _1-3 Haloalkyl and C _1-3 Each alkoxy is independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 Substituted by the radical hydroxyalkoxy;

R ^c is H, D, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino, 5-6 membered heteroaryl, C _3-6 Carbocyclyl or 3-6 membered heterocyclyl, wherein said C is _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino, 5-6 membered heteroaryl, C _3-6 Carbocyclyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _1-3 Hydroxyalkoxy and 3-6 membered heterocyclyl;

w is-O- (CR) ^m R ⁿ ) _q -、-S-(CR ^m R ⁿ ) _q -or-NR ^d -(CR ^m R ⁿ ) _q -；

R ^d Is H, D, C _1-3 Alkyl or C _1-3 Haloalkyl, wherein said C _1-3 Alkyl and C _1-3 Haloalkyl is each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 Substituted by the radical hydroxyalkoxy;

R ² is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-12 membered heteroaryl or-CR ^e R ^f -NR ^g R ^h Wherein said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-12 membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy and C _1-6 Substituted by the radical hydroxyalkoxy;

R ^m 、R ⁿ 、R ^e and R ^f Each independently is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-3 Alkyl radical, C _1-3 Haloalkyl or C _1-3 Alkoxy, wherein said C _1-3 Alkyl radical, C _1-3 Haloalkyl and C _1-3 Each alkoxy is independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 Substituted by the radical hydroxyalkoxy;

R ^g and R ^h Each independently is H, D, C _1-3 Alkyl or C _1-3 Haloalkyl, wherein said C _1-3 Alkyl and C _1-3 Haloalkyl is independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 Substituted by the radical hydroxyalkoxy;

or R ^f 、R ^g And the atoms to which they are attached form a 3-6 membered heterocyclic ring, wherein said 3-6 membered heterocyclic ring is independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 Substituted by the radical hydroxyalkoxy;

R ³ is C _6-10 Aryl or 5-12 membered heteroaryl, wherein, said C _6-10 Aryl and 5-12 membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5R ^3a Substitution;

each R ^3a Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-12 membered heteroaryl; wherein said-OH, -NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-12 membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _1-3 Hydroxyalkoxy, -C (= O) C _1-3 Alkyl, -C (= O) C _2-3 Alkenyl and-C (= O) C _2-3 Alkynyl group;

R ⁴ is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino or C _3-8 A cycloalkyl group.

Each R ^x Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino radical, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl; wherein said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino radical, C _3-8 Cycloalkyl and 3-8 membered heterocyclyl are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 Substituted by the radical hydroxyalkoxy;

R ^y is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino radical, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl;

p is 0, 1,2,3, 4,5, 6, 7 or 8;

q is 0, 1,2,3, 4,5 or 6.

In some embodiments, the compounds of the present invention have the structure shown in formula (II):

wherein each of Y and R ¹ 、R ^3a 、R ^x And p have the meanings described in the present invention.

In some embodiments, the compounds of the present invention have the structure shown in formula (III):

wherein each R is ¹ 、R ^x And p have the meanings described in the present invention.

In some embodiments, X is

In some embodiments, R ^a And R ^b Each independently is H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH is substituted by a group;

R ^c is H, D, methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazole, etcAn oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl group; wherein said methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH ₂ OH、-OCH ₂ CH ₂ OH, isopropoxy, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, and morpholinyl;

R ^d is H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH is substituted by a group;

R ^m 、R ⁿ 、R ^e and R ^f Each independently of the other is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethylOxy or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are each independently optionally substituted by 1,2,3, 4 or 5 groups selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH is substituted by a group;

R ^g and R ^h Each independently is H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ Methoxy, ethoxy, isopropoxy, -OCF ₃ 、-OCH ₂ OH and-OCH ₂ CH ₂ OH is substituted by the group;

or R ^f 、R ^g And the atoms to which they are attached form an azetidine, pyrrolidine, piperidine ring, piperazine ring, or morpholine ring, wherein said azetidine, pyrrolidine, piperidine ring, piperazine ring, and morpholine ring are each independently optionally substituted with 1,2,3, 4, or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ Methoxy, ethoxy, isopropoxy, -OCF ₃ 、-OCH ₂ OH and-OCH ₂ CH ₂ OH groups.

In some embodiments, R ² Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-4 Alkylamino radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroarylRadical or-CR ^e R ^f -NR ^g R ^h Wherein said C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-4 Alkylamino radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-10 Aryl and 5-to 10-membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 The group of hydroxyalkoxy.

In some embodiments, R ² Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or-CR ^e R ^f -NR ^g R ^h Wherein said methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino,Ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently optionally substituted with 1,2,3, 4, or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH groups.

In some embodiments, R ³ Is C _6-10 Aryl or 5-to 10-membered heteroaryl, wherein, said C _6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5R ^3a And (4) substitution.

In some embodiments, R ³ Is composed of

Wherein said>

Each independently optionally substituted by 1,2,3, 4 or 5R ^3a Substitution;

each R ^3a Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _3-6 Cycloalkyl radicals3-6 membered heterocyclic group, C _6-10 Aryl or 5-10 membered heteroaryl; wherein said-OH, -NH ₂ 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-10 Aryl and 5-to 10-membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _1-3 Hydroxyalkoxy, -C (= O) C _1-3 Alkyl, -C (= O) C _2-3 Alkenyl and-C (= O) C _2-3 Alkynyl groups.

In some embodiments, each R is ^x Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-4 Alkylamino radical, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl; wherein said C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-4 Alkylamino radical, C _3-6 Cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 Substituted by the radical hydroxyalkoxy;

R ^y is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-4 Alkylamino radical, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl.

In some implementationsIn the scheme, each R ^x Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein said methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl are each independently optionally substituted with 1,2,3, 4, or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH is substituted by a group;

R ^y is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, or morpholinyl.

In some embodiments, each R is ^3a Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein said-OH, -NH ₂ Methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCH ₂ OH、-OCH ₂ CH ₂ OH、-C(＝O)CH ₃ 、-C(＝O)CH ₂ CH ₃ and-C (= O) CH = CH ₂ Substituted with a group of (a);

R ⁴ is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the pharmaceutical compositions of the present invention further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

In one aspect, the present invention relates to the use of a compound as described above, or a pharmaceutical composition thereof, for the manufacture of a medicament for preventing, treating or ameliorating a KRAS G12C mediated disease in a patient.

In some embodiments, the KRAS G12C-mediated disease described herein is cancer.

In some embodiments, the cancer of the invention is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, and melanoma.

In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I), formula (II) or formula (III).

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable combination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", thomas Sorrell, university Science Books, sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, john Wiley & Sons, new York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.

"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, enantiomers, racemes and solutions (Wiley Interscience, new York, 1981); principles of Asymmetric Synthesis (2) ^nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds.

The term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. The term "optionally substituted with (8230) \ 8230; may be used interchangeably with the term" unsubstituted or substituted with (8230; i.e., the structure is unsubstituted or substituted with one or more substituents described herein; when the number of said substituents is more than 1, said substituents may be the same or different from each other. For example, the term "optionally substituted with 1,2,3, 4 or 5 groups selected from the group consisting of 8230 \8230;" when the number of said substituents is greater than 1 ", said substituents may be the same or different.

Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein said substituent may be, but is not limited to, deuterium, oxo, halogen, cyano, nitro, hydroxy, mercapto, amino, alkylamino, arylamino, aminoalkyl, alkyl, alkenyl, alkynyl, alkylthio, hydroxyalkyl, hydroxyalkoxy, haloalkyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkanoyl, arylacyl, heteroarylacyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, alkanoyloxy, carboxy, alkoxyacyl, aryloxoyl, heteroaryloxyacyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkoxysulfonyl, aminoacyl, alkylaminoacyl, aminosulfonyl, alkylaminosulfonyl, and the like.

In addition, unless otherwise explicitly indicated, the description of "each of the methods 8230, independently" and "\8230"; independently "and" \8230, independently "and" \8230 "; independently" are used interchangeably in the present invention and are to be understood broadly, and they may mean that specific items expressed between the same symbols in different groups do not affect each other, or that specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C _1-6 Alkyl "means in particular independently disclosed methyl, ethyl, C ₃ Alkyl radical, C ₄ Alkyl radical, C ₅ Alkyl and C ₆ An alkyl group.

In various parts of this specification, the term "C" or "C" refers to _m-n "number of carbon atoms used to describe the groups mentioned in the present invention, e.g." C _1-6 Alkyl "represents an alkyl group containing 1 to 6 carbon atoms; "C _3-6 Cycloalkyl "denotes a packageCycloalkyl groups having 3 to 6 carbon atoms; "C _3-6 Carbocyclyl "means carbocyclyl containing 3 to 6 carbon atoms wherein said alkyl, cycloalkyl and carbocyclyl have the definitions as described herein.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, the alkyl group contains 1 to 20 carbon atoms and is represented by C _1-20 An alkyl group. In some embodiments, the alkyl group contains 1 to 12 carbon atoms and is represented by C _1-12 An alkyl group; in other embodiments, the alkyl group contains 1 to 6 carbon atoms and is represented by C _1-6 An alkyl group; in still other embodiments, the alkyl group contains 1 to 4 carbon atoms and is represented by C _1-4 An alkyl group; in still other embodiments, the alkyl group contains 1 to 3 carbon atoms and is represented by C _1-3 An alkyl group.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH) ₃ ) Ethyl group (Et, -CH) ₂ CH ₃ ) N-propyl (n-Pr, -CH) ₂ CH ₂ CH ₃ ) Isopropyl group (i-Pr, -CH (CH) ₃ ) ₂ ) N-butyl (n-Bu, -CH) ₂ CH ₂ CH ₂ CH ₃ ) Isobutyl (i-Bu, -CH) ₂ CH(CH ₃ ) ₂ ) Sec-butyl (s-Bu, -CH (CH) ₃ )CH ₂ CH ₃ ) Tert-butyl (t-Bu, -C (CH) ₃ ) ₃ ) N-pentyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-pentyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₃ ) 3-pentyl (-CH (CH) ₂ CH ₃ ) ₂ ) 2-methyl-2-butyl (-C (CH) ₃ ) ₂ CH ₂ CH ₃ ) 3-methyl-2-butyl (-CH (CH) ₃ )CH(CH ₃ ) ₂ ) 3-methyl-1-butyl (-CH) ₂ CH ₂ CH(CH ₃ ) ₂ ) 2-methyl-1-butyl (-CH) ₂ CH(CH ₃ )CH ₂ CH ₃ ) N-hexyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-hexyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ) 3-hexyl (-CH (CH) ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ ) 2-methyl-2-pentyl (-C (CH)) ₃ ) ₂ CH ₂ CH ₂ CH ₃ ) 3-methyl-2-pentyl (-CH (CH) ₃ )CH(CH ₃ )CH ₂ CH ₃ ) 4-methyl-2-pentyl (-CH (CH) ₃ )CH ₂ CH(CH ₃ ) ₂ ) 3-methyl-3-pentyl (-C (CH) ₃ )(CH ₂ CH ₃ ) ₂ ) 2-methyl-3-pentyl (-CH (CH) ₂ CH ₃ )CH(CH ₃ ) ₂ ) 2, 3-dimethyl-2-butyl (-C (CH) ₃ ) ₂ CH(CH ₃ ) ₂ ) 3, 3-dimethyl-2-butyl (-CH (CH) ₃ )C(CH ₃ ) ₃ ) N-heptyl, n-octyl, and the like.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp ² A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms and is represented by C _2-8 An alkenyl group; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms and is represented by C _2-6 An alkenyl group; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms and is represented by C _2-4 An alkenyl group. Examples of alkenyl groups include, but are not limited to, vinyl (-CH = CH) ₂ ) Allyl (-CH) ₂ CH＝CH ₂ ) 1-propenyl (propenyl, -CH = CH-CH) ₃ ) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp triple bond, wherein the alkynyl radical may optionally be substituted with one or more substituents as described herein. In some embodiments, alkynyl groups contain 2-8 carbon atoms, represented as C _2-8 An alkynyl group; in other embodiments, alkynyl groups contain 2-6 carbon atoms and are represented by C _2-6 An alkynyl group; in still other embodiments, alkynyl groups contain 2-4 carbon atoms and are represented by C _2-4 Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C ≡ CH), propargyl (-CH) ₂ C.ident.CH), 1-propynyl (propynyl, -C.ident.C-CH) ₃ ) And so on.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms and is represented by C _1-12 An alkoxy group. In some embodiments, the alkoxy group contains 1 to 6 carbon atoms and is represented as C _1-6 An alkoxy group; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms and is represented by C _1-4 An alkoxy group; in still other embodiments, the alkoxy group contains 1 to 3 carbon atoms and is represented as C _1-3 An alkoxy group. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) ₃ ) Ethoxy (EtO, -OCH) ₂ CH ₃ ) 1-propoxy (n-PrO, n-propoxy, -OCH) ₂ CH ₂ CH ₃ ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) ₃ ) ₂ ) 1-butoxy (n-BuO, n-butoxy, -OCH) ₂ CH ₂ CH ₂ CH ₃ ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) ₂ CH(CH ₃ ) ₂ ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) ₃ )CH ₂ CH ₃ ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) ₃ ) ₃ ) 1-pentyloxy (n-pentyloxy, -OCH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-pentyloxy (-OCH (CH)) ₃ )CH ₂ CH ₂ CH ₃ ) 3-pentyloxy (-OCH (CH)) ₂ CH ₃ ) ₂ ) 2-methyl-2-butoxy (-OC (CH)) ₃ ) ₂ CH ₂ CH ₃ ) 3-methyl-2-butoxy (-OCH (CH) ₃ )CH(CH ₃ ) ₂ ) 3-methyl-l-butoxy (-OCH) ₂ CH ₂ CH(CH ₃ ) ₂ ) 2-methyl-l-butoxy (-OCH) ₂ CH(CH ₃ )CH ₂ CH ₃ ) And so on.

The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, wherein alkyl and alkoxy have the definitions as set forth herein, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.

The term "hydroxyalkoxy" means an alkoxy group substituted with one or more hydroxy groups, wherein alkoxy has the definition as set forth herein, examples of which include, but are not limited to, -OCH ₂ OH、-OCH ₂ CH ₂ OH and the like.

The term "carbocyclyl" or "carbocycle" denotes a monovalent or multivalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbocyclic, fused carbobicyclic, and bridged carbobicyclic groups, and suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent, non-aromatic, saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. In some embodiments, cycloalkyl groups contain 3 to 12 carbon atoms; in other embodiments, cycloalkyl groups contain 3 to 8 carbon atoms; in still other embodiments, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.

The terms "heterocycle", "heterocyclyl" or "heterocyclic" are used interchangeably herein and refer to a mono-or polyvalent mono-, bi-or tricyclic ring system containing 3 to 14 ring atoms, wherein one or more of the atoms in the ring is independently a heteroatom having the meaning described herein, which ring may be fully saturated or contain one or more unsaturations, but not one aromatic ring. In some embodiments, a "heterocycle", "heterocyclyl" or "heterocyclic" group is a 3-8 membered ring monocyclic (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give a ring system like SO, SO ₂ A group of PO), or a 7-to 12-membered bicyclic ring (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give a compound like SO, SO ₂ The group of PO). In other embodiments, a "heterocycle", "heterocyclyl", or "heterocyclic" group is a 3-6 membered ring monocyclic (2-4 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give a ring system like SO, SO ₂ The group of PO). The heterocyclyl group is optionally substituted with one or more substituents described herein.

The heterocyclic group may be a carbon-based or heteroatom group; wherein, is cyclic-CH ₂ The group can optionally be replaced by-C (= O) -the sulphur atom of the ring can optionally be oxidized to S-oxide and the nitrogen atom of the ring can optionally be oxidized to N-oxygen compound. Examples of heterocyclic groups include, but are not limited to, ethylene oxideA group, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thianyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl

Radical, diaza

Based on the sulfur and nitrogen impurity->

Radical, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic radicals-CH ₂ Examples of-group replacement by-C (= O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1, 1-dioxide, and the like. The heterocyclyl group is optionally substituted with one or more substituents described herein.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group is optionally substituted with one or more substituents described herein.

The term "heteroaryl" or "heteroaromatic ring" means a mono-, bi-or tricyclic ring system containing 5 to 14 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, of mono-or polyvalent, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms. The heteroaryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, a heteroaryl group of 5 to 10 ring atoms contains 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, the heteroaryl group of 5 to 6 ring atoms is a monocyclic ring system and contains 1,2,3, or 4 heteroatoms independently selected from O, S, and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1, 3-thiadiazolyl, 1,2, 5-thiadiazolyl, 1, 5-triazinyl; the following bicyclic rings are also included, but by no means limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.

The term "nitrogen atom-containing monocyclic ring" refers to a monocyclic ring of 4 to 8 ring atoms containing nitrogen atoms in the ring atoms, which ring may be fully saturated or contain one or more degrees of saturation, but is not aromatic. Examples of nitrogen atom-containing monocyclic rings include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, and the like. The nitrogen atom-containing monocyclic ring is optionally substituted with one or more substituents described herein.

The terms "fused bicyclic ring", "fused bicyclic group" and "fused ring group" are used interchangeably herein and all refer to monovalent or polyvalent saturated or partially unsaturated fused ring systems containing from 4 to 12 ring atoms, said fused ring systems referring to non-aromatic bicyclic ring systems consisting of two rings sharing two adjacent ring atoms. Such systems may contain independent or conjugated unsaturated systems, but the core structure does not contain aromatic or heteroaromatic rings (although aromatic groups may be substituted thereon). The term "fused ring containing nitrogen atoms" means a fused ring containing 1 or 2 nitrogen atoms, and examples of the fused ring containing nitrogen atoms include, but are not limited to, octahydropyrrolo [3,4-c ] pyrrole and the like. The fused rings are optionally substituted with one or more substituents described herein.

The terms "spirocyclic", "spiro", "spirobicyclic" or "spirobicyclic" are used interchangeably herein and refer to a monovalent or polyvalent saturated or partially unsaturated ring system containing 5 to 12 ring atoms, one of which is derived from a specific ring carbon atom on the other ring. As shown in formula (a), ring a and ring B share one carbon atom in two saturated ring systems, referred to as "spirocyclic" or "spirobicyclic", while ring B and ring B' are referred to as "fused bicyclic". Each ring in the spirobicyclic group may be a carbocyclic or heterocyclic group. The term "nitrogen atom-containing spiro ring" refers to a spiro ring containing 1 or 2 nitrogen atoms in the ring atoms, and examples of the nitrogen atom-containing spiro ring include, but are not limited to, 2, 7-diazaspiro [3.5] nonane, 2, 6-diazaspiro [3.3] heptane, and the like. Said spiro ring being optionally substituted with one or more substituents as described herein.

The term "bridged ring" or "bridged ring group" denotes a saturated or partially unsaturated bridged ring system, wherein the bridged ring system refers to a ring system formed by two rings sharing an alkane or heteroalkyl chain, wherein said alkane or heteroalkyl chain comprises at least 3 chain atoms, and relates to a non-aromatic bicyclic ring system, such as that represented by formula (b), i.e., ring A1 shares an alkane or a heteroalkyl chain with ring A2, wherein each X on said alkane or heteroalkyl chain ³ Independently optionally a carbon atom or a heteroatom, j is 1,2,3 or 4. Such systems contain 5 to 12 ring atoms and may contain independent or conjugated unsaturation, but the core structure does not contain aromatic rings or aromatic rings (although aromatics may be substituents thereon). Wherein each ring, such as A1 or A2, contains 4 to 7 atoms, the term "nitrogen atom-containing bridged ring" refers to a bridged ring containing 1 or 2 nitrogen atoms in the ring atoms, and examples of such nitrogen atom-containing bridged rings include, but are not limited to, (1R, 5S) -3, 8-diazabicyclo [3.2.1]Octane, and the like. The bridged ring is optionally substituted with one or more substituents described herein.

The term "k atoms make up" or "k-member", where k is an integer, typically describes the number of atoms making up a ring in a molecule in which the number of atoms making up a ring is k. For example, piperidinyl is a 6 atom heterocycle or 6-membered heterocycle, while pyridinyl is a 6 atom heteroaryl or 6-membered heteroaryl.

The term "unsaturated" as used herein means that the group contains one or more unsaturations.

The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state form of N, S and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl, R being a substituent on N, representing a substituent according to the present invention).

The term "halogen" or "halogen atom" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C _1-6 Alkyl groups are attached to nitrogen atoms to form alkylamino groups. In other embodiments, the alkylamino group is substituted with one or two C _1-3 An alkyl-substituted amino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N-dimethylamino (dimethylamino), N-diethylamino (diethylamino), and the like.

The term "aminoalkyl" includes C substituted with one or more amino groups _1-10 A straight or branched alkyl group. In some of these embodiments, aminoalkyl is C substituted with one or more amino groups _1-6 Aminoalkyl groups, examples of which include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.

As described herein, the substituent (R) ^x ) _p The ring system formed by a ring bound to the center represents p substituents R ^x Substitutions may be made at any substitutable position or at any reasonable position on the ring in which it is placed. For example, formula c represents a G ring which may be substituted by p R ^x Substituted, when p is greater than 1, each R ^x May be independently selected from the same or different substituent groups.

The attachment point may be attached to the rest of the molecule at any attachable position on the loop as described herein. For example, formula D represents the point of attachment at any possible point on the C-ring or D-ring to which it may be attached.

As described herein, the group X has a substructure with two attachment sites that can be connected to the rest of the molecule, and the attachment of the two attachment sites can be interchanged. For example, when X is

When the general formula (I) of the present invention represents that nn connecting end on X is connected with R ¹ The other mm connecting end is connected with the rest part of the general formula (I) as shown in the formula f; or mm in X connecting end connection R ¹ And the other nn connecting end is connected with the rest part of the general formula (I) as shown in a formula g.

The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: gre Wene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastrointestinal upset, dizziness and the like, when administered to a human.

The term "carrier" refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, particularly injectable solutions. Suitable Pharmaceutical carriers are described in e.w. martin "Remington's Pharmaceutical Sciences".

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I), formula (II) or formula (III). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C) _1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, pro-drugs as Novel Delivery Systems, vol.1 of the A.C.S.Symphosis Series, edward B.Roche, ed., bioreversible Carriers in Drug designs, american Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, prodrugs in Design and Clinical Applications, nature Review Delivery, 2008,7,255-270, and S.J.Herer et al, prodrugs of pharmaceuticals and Phosphates, journal of therapeuticsal Chemistry,2008,51,2328-2345。

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compounds via oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refers to both organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the descriptive pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences,1977, 66. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, etc., or obtained by other methods described in the literature above such as ion exchange. Pharmaceutically acceptable base addition salts include, but are not limited to, inorganic base salts such as ammonium salts and metal salts of groups I through XII of the periodic table, and organic base salts such as salts with primary, secondary and tertiary amines.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

The term "therapeutically effective amount" means an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" may vary with the compound, the disease and the severity, as well as the condition, age, weight, sex, etc., of the subject to be treated.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., na, ca, mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In the fields of, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, selection and application (Handbook of Pharmaceutical Salts: properties, selection, and Use) ", stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002), may find a list of additional suitable Salts.

In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ² H， ³ H， ¹¹ C， ¹³ C， ¹⁴ C， ¹⁵ N， ¹⁷ O， ¹⁸ O， ³² P， ³⁵ S， ¹⁸ F， ³⁶ Cl and ¹²⁵ I. isotopically enriched compounds of the present invention can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described herein using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.

The term "cancer" as used herein refers to or describes a physiological condition in a patient that is typically characterized by uncontrolled cell growth. A "tumor" comprises one or more cancer cells. Examples of cancers include, but are not limited to, carcinomas (carcinoma), lymphomas, blastomas, sarcomas and leukemias, or lymphoproliferative disorders (lymphoids). More specific examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer (including small-cell lung cancer, non-small cell lung cancer (NSCLC)), esophageal cancer, peritoneal cancer, gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer (liver cancer), bladder cancer, breast cancer, colon cancer, rectal cancer, appendiceal cancer, small intestine cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer (kidney or renal cancer), prostate cancer, vulval cancer, thyroid cancer, anal cancer, penile cancer, and head and neck cancer.

The term "KRAS G12C inhibitor" as used herein refers to a substance that binds to KRAS G12C and inhibits its activity.

Description of the Compounds of the invention

The invention provides a compound or a pharmaceutical composition thereof, which can be used as an inhibitor of KRAS G12C. The invention further relates to the use of said compounds or pharmaceutical compositions thereof for the preparation of a medicament for the treatment of diseases and/or conditions by inhibiting KRAS G12C activity with said compounds. The invention further describes methods for synthesizing the compounds. The compounds of the invention show improved biological activity and pharmacokinetic properties.

wherein each R is ¹ 、R ² 、R ³ 、R ⁴ X, Y and W all have the meanings described in the invention.

In some embodiments, X is-L-X ¹ -, wherein L is a bond or-NH-, X ¹ Is a 4-12 membered saturated or partially unsaturated monocyclic, fused, spiro or bridged ring containing a nitrogen atom, each of which is independently optionally substituted with p R ^x Substitution; wherein p and R ^x Have the meaning as described in the present invention.

In other embodiments, X is

Wherein p and R ^x Have the meaning as described in the present invention.

In some embodiments, R ¹ is-C (= O) -CR ^a ＝CR ^b -R ^c 、-C(＝O)-C≡C-R ^c 、-S(＝O) ₂ -CR ^a ＝CR ^b -R ^c or-S (= O) ₂ -C≡C-R ^c (ii) a Wherein R is ^a 、R ^b And R ^c Have the meaning as described in the present invention.

In some embodiments, R ^a Is H, D, F, cl, br, I, C _1-3 Alkyl radical, C _1-3 Haloalkyl or C _1-3 Alkoxy, wherein said C _1-3 Alkyl radical, C _1-3 Haloalkyl and C _1-3 Each alkoxy is independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 The group of hydroxyalkoxy.

In other embodiments, R ^a Is H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups are each independently optionally substituted by 1,2,3, 4 or 5 groups selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH groups.

In some embodiments, R ^b Is H, D, F, cl, br, I, C _1-3 Alkyl radical, C _1-3 Haloalkyl or C _1-3 Alkoxy, wherein said C _1-3 Alkyl radical, C _1-3 Haloalkyl and C _1-3 Each alkoxy is independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 The group of hydroxyalkoxy.

In other embodiments, R ^b Is H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups are each independently optionally substituted by 1,2,3, 4 or 5 groups selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH groups.

In some embodiments, R ^c Is H, D, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino, 5-6 membered heteroaryl, C _3-6 Carbocyclyl or 3-6 membered heterocyclyl, wherein said C is _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino, 5-6 membered heteroaryl, C _3-6 Carbocyclyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _1-3 Hydroxyalkoxy and 3-6 membered heterocyclyl.

In other embodiments, R ^c Is H, D, methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein said methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furalPyranyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH ₂ OH、-OCH ₂ CH ₂ OH, isopropoxy, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl and morpholinyl.

In some embodiments, W is-O- (CR) ^m R ⁿ ) _q -、-S-(CR ^m R ⁿ ) _q -or-NR ^d -(CR ^m R ⁿ ) _q -, wherein q, R ^d 、R ^m And R ⁿ Have the meaning as described in the present invention.

In some embodiments, R ^d Is H, D, C _1-3 Alkyl or C _1-3 Haloalkyl, wherein said C _1-3 Alkyl and C _1-3 Haloalkyl is each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 The group of hydroxyalkoxy.

In other embodiments, R ^d Is H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH groups.

In some embodiments, R ² Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-12 membered heteroaryl or-CR ^e R ^f -NR ^g R ^h Wherein said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-12 membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy and C _1-6 Substituted by the radical hydroxyalkoxy; wherein R is ^e 、R ^f 、R ^g And R ^h Have the meaning described in the present invention.

In other embodiments, R ² Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-4 Alkylamino radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl or-CR ^e R ^f -NR ^g R ^h Wherein said C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-4 Alkylamino radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-10 Aryl and 5-to 10-membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 Substituted with a hydroxyalkoxy group; wherein R is ^e 、R ^f 、R ^g And R ^h Have the meaning as described in the present invention.

In other embodiments, R ² Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or-CR ^e R ^f -NR ^g R ^h Wherein said methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, each independently optionally substituted with 1,2,3, 4, or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methylEthyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH is substituted by a group; wherein R is ^e 、R ^f 、R ^g And R ^h Have the meaning described in the present invention.

In some embodiments, R ^m Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-3 Alkyl radical, C _1-3 Haloalkyl or C _1-3 Alkoxy, wherein said C _1-3 Alkyl radical, C _1-3 Haloalkyl and C _1-3 Each alkoxy is independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 The group of hydroxyalkoxy.

In other embodiments, R ^m Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH groups are substituted.

In some embodiments, R ⁿ Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-3 Alkyl radical, C _1-3 Haloalkyl or C _1-3 Alkoxy, wherein said C _1-3 Alkyl radical, C _1-3 Haloalkyl and C _1-3 Each alkoxy is independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 The group of hydroxyalkoxy.

In other embodiments, R ⁿ Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH groups.

In some embodiments, R ^e Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-3 Alkyl radical, C _1-3 Haloalkyl or C _1-3 Alkoxy, wherein said C _1-3 Alkyl radical, C _1-3 Haloalkyl and C _1-3 Each alkoxy is independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 The group of hydroxyalkoxy.

In other embodiments, R ^e Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl,N-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH groups.

In some embodiments, R ^f Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-3 Alkyl radical, C _1-3 Haloalkyl or C _1-3 Alkoxy, wherein said C _1-3 Alkyl radical, C _1-3 Haloalkyl and C _1-3 Each alkoxy is independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 The group of hydroxyalkoxy.

In other embodiments, R ^f Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH groups.

In some embodiments, R ^g Is H, D, C _1-3 Alkyl or C _1-3 Haloalkyl, wherein said C _1-3 Alkyl and C _1-3 Haloalkyl is independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 The group of hydroxyalkoxy.

In other embodiments, R ^g Is H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ Methoxy, ethoxy, isopropoxy, -OCF ₃ 、-OCH ₂ OH and-OCH ₂ CH ₂ OH groups.

In some embodiments, R ^h Is H, D, C _1-3 Alkyl or C _1-3 Haloalkyl, wherein said C _1-3 Alkyl and C _1-3 Haloalkyl is independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 The group of hydroxyalkoxy.

In other embodiments, R ^h Is H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ Methoxy, ethoxy, isopropoxy, -OCF ₃ 、-OCH ₂ OH and-OCH ₂ CH ₂ OH groups.

In some embodiments, R ^f 、R ^g And the atoms to which they are attached together form a 3-6 membered heterocyclic ring, wherein the 3-6 membered heterocyclic ring is independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 Of hydroxyalkoxyl groupsSubstituted by a group.

In other embodiments, R ^f 、R ^g And the atoms to which they are attached form an azetidine, pyrrolidine, piperidine ring, piperazine ring, or morpholine ring, wherein said azetidine, pyrrolidine, piperidine ring, piperazine ring, and morpholine ring are each independently optionally substituted with 1,2,3, 4, or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ Methoxy, ethoxy, isopropoxy, -OCF ₃ 、-OCH ₂ OH and-OCH ₂ CH ₂ OH groups.

In some embodiments, R ³ Is C _6-10 Aryl or 5-12 membered heteroaryl, wherein, said C _6-10 Aryl and 5-12 membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5R ^3a Substitution; wherein R is ^3a Have the meaning described in the present invention.

In other embodiments, R ³ Is C _6-10 Aryl or 5-to 10-membered heteroaryl, wherein, said C _6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5R ^3a Substitution; wherein R is ^3a Have the meaning as described in the present invention.

In other embodiments, R ³ Is composed of

Wherein said->

Each independently optionally substituted by 1,2,3, 4 or 5R ^3a Substitution; wherein R is ^3a Have the meaning as described in the present invention.

In some embodiments, R ^3a Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-12 membered heteroaryl; wherein said-OH, -NH ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-12 membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _1-3 Hydroxyalkoxy, -C (= O) C _1-3 Alkyl group, -C (= O) C _2-3 Alkenyl and-C (= O) C _2-3 Alkynyl groups.

In other embodiments, R ^3a Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl; wherein said-OH, -NH ₂ 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-10 Aryl and 5-to 10-membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 HaloalkoxyBase, C _1-3 Hydroxyalkoxy, -C (= O) C _1-3 Alkyl, -C (= O) C _2-3 Alkenyl and-C (= O) C _2-3 Alkynyl groups.

In other embodiments, R ^3a Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein said-OH, -NH ₂ Methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCH ₂ OH、-OCH ₂ CH ₂ OH、-C(＝O)CH ₃ 、-C(＝O)CH ₂ CH ₃ and-C (= O) CH = CH ₂ Substituted with a group of (a).

In some embodiments, R ⁴ Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino or C _3-8 A cycloalkyl group.

In some embodiments, R ⁴ Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, each R is ^x Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino radical, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl; wherein said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino radical, C _3-8 Cycloalkyl and 3-8 membered heterocyclyl are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 The group of hydroxyalkoxy.

In other embodiments, each R is ^x Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-4 Alkylamino radical, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl; wherein said C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-4 Alkylamino radical, C _3-6 Cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 The group of hydroxyalkoxy.

In other embodiments, each R is ^x Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein said methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy,-OCHF ₂ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl are each independently optionally substituted with 1,2,3, 4, or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH groups.

In some embodiments, R ^y Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino radical, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl.

In other embodiments, R ^y Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-4 Alkylamino radical, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl.

In other embodiments, R ^y Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,Azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl.

In some embodiments, p is 0, 1,2,3, 4,5, 6, 7, or 8.

In some embodiments, q is 0, 1,2,3, 4,5, or 6.

In another aspect, the present invention relates to a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a solvate, a hydrate, a metabolite, an ester, a pharmaceutically acceptable salt, or a prodrug thereof, of a compound of one of the following, but is in no way limited to:

in another aspect, the present invention relates to a pharmaceutical composition comprising a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound described above.

In some embodiments, the pharmaceutical compositions of the present invention further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or any combination thereof.

In another aspect, the present invention relates to the use of a compound as described above or a pharmaceutical composition thereof in the manufacture of a medicament for preventing, treating or ameliorating a KRAS G12C mediated disease in a patient.

In some embodiments, the KRAS G12C-mediated disease described herein is cancer.

In another aspect, the invention relates to methods of preparation, isolation and purification of compounds encompassed by formula (I), formula (II) or formula (III).

Pharmaceutical compositions, formulations, administration and uses of the compounds of the invention

The pharmaceutical compositions of the invention are characterized by comprising a compound of formula (I), formula (II) or formula (III), a compound listed herein, or a compound of the examples, and a pharmaceutically acceptable carrier. The amount of compound in the pharmaceutical composition of the invention is effective to treat or ameliorate KRAS G12C mediated diseases in a subject.

The compounds of the invention exist in free form or, where appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adduct or derivative that can be administered directly or indirectly in accordance with the needs of the patient, compounds described in other aspects of the invention, metabolites thereof, or residues thereof.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in: in Remington, the Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, lippincott Williams and Wilkins, philadelphia, and Encyclopedia of Pharmaceutical technology, eds.J.Swarbrick and J.C.Boylan,1988-1999, marcel Dekker, new York, taken together with The disclosure of this document, indicate that different carriers can be used In The formulation of pharmaceutically acceptable compositions and their well known methods of preparation. Except insofar as any conventional carrier vehicle is incompatible with the compounds of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, its use is contemplated by the present invention.

Substances which may serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins, such as human serum protein, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol, phosphate buffered solutions, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating materials, sweetening, flavoring and perfuming agents, preservatives and antioxidants.

Preferably, the compounds are administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (referred to herein as pharmaceutical carriers) selected with regard to the mode of administration and conventional pharmaceutical practice, which may be oral tablets, capsules, elixirs, syrups, and the like.

For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier, such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral pharmaceutical composition can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, and the like. Moreover, suitable binders, lubricants, disintegrating agents, and coloring agents can also be added to the mixture, as desired or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrating agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention may be administered in the form of oral dosage forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously, or intramuscularly, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They may be administered separately, but will generally be administered together with a pharmaceutical carrier selected based on the mode of administration selected and standard pharmaceutical practice.

The compounds of the invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or by the transdermal route using transdermal patches. When administered in the form of a transdermal delivery system, the dosage administered throughout the administration period is continuous rather than intermittent.

The compounds of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

The compounds of the invention are also conjugated to soluble polymers that serve as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers for controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.

The dosage regimen for a compound of the invention will vary depending upon a variety of factors known, such as the pharmacokinetic characteristics of the particular agent and its mode and route of administration; race, age, sex, health condition, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the desired effect. A physician or veterinarian can make a decision and prescribe the effective amount of the drug to prevent, counter or arrest the progress of the cancer.

In accordance with general guidelines, the daily oral dosage of each active ingredient used is in the range of about 0.001 to 1000mg/kg body weight, preferably about 0.01 to 100mg/kg body weight, in order to achieve the indicated effect. And, most preferably, between about 1.0 and 20mg/kg body weight/day. For intravenous administration, the most preferred dosage range during infusion at conventional rates is from about 1 to about 10mg/kg body weight/minute. The compounds of the invention may be administered once daily, or may be administered in divided doses of two, three or four times daily.

Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain from about 1mg to about 100mg of the active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally be from about 0.5% to about 95% of the total weight of the composition.

When the compounds of the present invention are administered with other therapeutic agents, generally, the amount of each component in a typical daily dose and a typical dosage form may be reduced relative to the usual dose when administered alone, taking into account the additive or synergistic effect of the therapeutic agents when administered in combination.

The compound or the medicinal salt or the hydrate thereof can be effectively used for preventing, treating or relieving the KRAS G12C mediated diseases of patients, and particularly can be effectively used for treating lung cancer, lymphoma, esophagus cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, melanoma and the like.

General synthetic procedure

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the invention may be prepared by the methods described herein, unless otherwise indicated, wherein the substituents are as defined herein. The following synthetic schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents other than those described herein, or by some routine modification of the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, arco Chemical Company and Alfa Chemical Company and were used without further purification. Unless otherwise indicated, general reagents were purchased from Shantou Wen Long chemical plant, guangdong Guanghua chemical plant, guangzhou chemical plant, tianjin Haoyu Chemicals Co., ltd, tianjin Shuchen chemical plant, wuhan Xin Hua Yuan science and technology development Co., ltd, qingdao Tenglong chemical plant Co., ltd, and Qingdao maritime chemical plant.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. Glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao oceanic plants.

¹ H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer. ¹ H NMR spectrum CDC1 ₃ 、DMSO-d ₆ 、CD ₃ OD or acetone-d ₆ TMS (0 ppm) or chloroform (7.26 ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singlets), d (doublets), t (triplets), q (quatets), m (multiplets), br (broadpeds), br (broadpedsinglets), dd (doublets of doublets), dt (doublets of triplets). Coupling constant J, expressed in Hertz (Hz).

The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-MS (column model: zorbax SB-C18,2.1x30mm,3.5 micron, 6min, flow rate 0.6mL/min. Mobile phase 5% -95% (CH with 0.1% formic acid) ₃ CN) in (H containing 0.1% formic acid) ₂ O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.

Pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC).

The following acronyms are used throughout the invention:

the following synthetic schemes describe the procedures for preparing the compounds of the present invention. Wherein each R is, unless otherwise specified ^x 、R ^a 、R ³ P and Y have the meanings given in the description, R ^B Is D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy or C _1-3 A hydroxyalkoxy group; v is 0, 1,2,3, 4 or 5.

Synthesis scheme 1

Formula (A), (B) and17) The compounds shown can be prepared by synthesis scheme 1. Formula (A), (B) and1) A compound of the formula2) The compound shown in the formula (I) is reacted to obtain3) The compounds shown. Formula (A), (B) and3) A compound of the formula (I) and4) Reacting the compound shown in the formula (A) to obtain a compound shown in the formula (B)5) The compounds shown. Formula (A), (B) and5) A compound of the formula6) The compound is reacted under alkaline condition to obtain the formula (I)7) The compounds shown. Formula (A), (B) and7) A compound represented by the formula (I) and8) The compound is reacted under the action of sodium hydride to obtain a compound shown as a formula (I)9) The compounds shown. Formula (A), (B) and9) A compound represented by the formula (I) and10) The compound is reacted under the action of bis (tri-tert-butylphosphine) palladium to obtain a compound shown in a formula (I)11) The compounds shown. Formula (A), (B) and11) A compound of the formula12) A compound of the formula (A)13) The compound is reacted under the action of a palladium catalyst and potassium acetate (or cesium carbonate) to obtain a compound shown in a formula (I)14) The compounds shown. A compound represented by the formula (14)Can react under the action of trifluoroacetic acid to obtain a compound of formula (A)15) The compounds shown. Formula (A), (B) and15) A compound of the formula16) The compound can react under the action of triethylamine to obtain a compound shown in a formula (I)17) The compounds shown.

Synthesis scheme 2

Formula (A), (B) and17) The compounds shown can be prepared by synthesis scheme 2: formula (A), (B) and11) The compound is reacted under the action of trifluoroacetic acid to obtain a compound shown in a formula (I)18) The compounds shown. Formula (A), (B) and18) A compound of the formula16) The compound reacts under the action of triethylamine to obtain a compound shown in a formula (I)19) The compounds shown. Formula (A), (B) and19) A compound of the formula12) A compound of the formula (A)13) The compound is reacted under the action of a palladium catalyst and potassium acetate (or cesium carbonate) to obtain a compound shown in a formula (I), (II)17) The compounds shown.

The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.

Examples

Example 1- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-fluoro-5-methylphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

First step synthesis of 6-bromo-7-chloroquinazoline-2, 4 (1H, 3H) -dione

To the reaction flask were added 2-amino-5-bromo-4-chlorobenzoic acid (5.0g, 19.6 mmol), urea (11.9 g, 196mmol), potassium acetate (0.19g, 1.8mmol) and dioxane (6.0 mL). The reaction system is heated to 160 ℃ for reaction for 3h. After the reaction was complete, the reaction mixture was cooled to 100 ℃ and water (40 mL) was added and stirred for 5min, then 1M aqueous sodium hydroxide solution (40 mL) was added and stirred for 5min. The system is cooled to room temperature and the pH of the system is adjusted with 1N hydrochloric acid=2, stir at room temperature for 0.5h, filter. The filter cake was dried in vacuo at 70 ℃ to give the title compound as a yellow solid (5.51 g, 100% yield). MS (ESI, pos.ion) m/z 275.0[ m ] +H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.07(s,1H),7.32(s,1H).

Second step synthesis of 6-bromo-2, 4, 7-trichloroquinazoline

6-bromo-7-chloroquinazoline-2, 4 (1H, 3H) -dione (5.58g, 20.3mmol), phosphorus oxychloride (50.4g, 0.32mol) and N, N-diisopropylethylamine (6.7g, 50.6 mmol) were added to the reaction flask. The reaction system is heated to 100 ℃ for reaction for 5h. And (5) after the reaction is completed, carrying out decompression and spin-drying. The residue was diluted with dichloromethane (20 mL) and poured into ice water (200 mL). The aqueous phase was extracted with dichloromethane (400 mL) and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 20/1) to give the title compound as a yellow solid (4.98 g, yield 79%).

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.55(s,1H),8.12(s,1H).

Step three, synthesizing (S) -4- (6-bromo-2, 7-dichloroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester

To a reaction flask were added 6-bromo-2, 4, 7-trichloroquinazoline (1.80g, 5.8mmol), (S) -2-cyanomethylpiperazine-1-carboxylic acid tert-butyl ester (1.39g, 6.1mmol) and N, N-diisopropylethylamine (0.98g, 7.5mmol). The reaction system was reacted at room temperature for 3 hours, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 6/1) to give the title compound as a yellow solid (2.8 g, yield 97%).

MS(ESI,pos.ion)m/z:500.0[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.16(s,1H),7.95(s,1H),4.74-4.57(m,1H),4.33(d,J＝14.7Hz,1H),4.24(d,J＝12.5Hz,1H),4.12(dd,J＝14.3,7.1Hz,1H),3.76(dd,J＝13.9,4.1Hz,1H),3.59(td,J＝12.0,3.5Hz,1H),3.51-3.25(m,1H),2.85(dd,J＝16.9,6.1Hz,1H),2.72(dd,J＝16.9,6.2Hz,1H),1.51(s,9H).

The fourth step Synthesis of tert-butyl (S) -4- (6-bromo-7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

To the reaction flask were added (S) - (1-methylpyrrolidin-2-yl) methanol (2.03g, 16.8mmol) and tetrahydrofuran (20 mL). The reaction system was cooled to 0 ℃ and 60% sodium hydride (0.67g, 16.8mmol) was added thereto. The system was transferred to room temperature and stirred for 0.5h. To another reaction flask was added tert-butyl (S) -4- (6-bromo-2, 7-dichloroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (2.8g, 5.6 mmol), cooled to 0 deg.C, and the above mixture was added dropwise, followed by transferring to room temperature and stirring for 4 hours. After the reaction was complete, ethyl acetate (400 mL) was added and washed with water (40 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100/1) to give the title compound as a yellow oil (3.5 g, yield 100%).

MS(ESI,pos.ion)m/z:579.1[M+H] ⁺ .

The fifth step Synthesis of tert-butyl (S) -4- (7-chloro-6-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

To a reaction flask were added (S) -4- (6-bromo-7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (2.37g, 4.1mmol), zinc cyanide (0.25g, 2.0mmol), bis (tri-tert-butylphosphine) palladium (0.43g, 0.82mmol), anhydrous N, N-dimethylformamide (12 mL). The reaction was heated to 70 ℃ and reacted overnight. The heating was stopped, the mixture was cooled to room temperature, diluted with ethyl acetate (400 mL), and washed with water (25 mL. Times.4) and saturated brine (25 mL) in this order. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 200/1) to give the title compound as a yellow solid (0.65 g, yield 30%).

MS(ESI,pos.ion)m/z:526.5[M+H] ⁺ .

Sixth step Synthesis of tert-butyl (S) -4- (6-cyano-7- (2-fluoro-5-methylphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

To a reaction flask was added tert-butyl (S) -4- (7-chloro-6-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (0.51g, 0.97mmol), (2-fluoro-5-methylphenyl) boronic acid (0.45g, 2.90mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (0.12g, 0.15mmol), bis (tri-tert-butylphosphino) palladium (76mg, 0.15mmol), potassium acetate (0.50g, 4.90mmol) and 1, 4-dioxane (10 mL). Under the protection of nitrogen, the temperature of the reaction system is raised to 90 ℃ for reaction for 5 hours. After the raw materials react completely, cooling to room temperature, and concentrating under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 200/1) to give the title compound as a yellow solid (0.27 g, yield 46%).

MS(ESI,pos.ion)m/z:600.5[M+H] ⁺ .

Seventh step Synthesis of 4- ((S) -3- (cyanomethyl) piperazin-1-yl) -7- (2-fluoro-5-methylphenyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To the reaction flask were added (S) -4- (6-cyano-7- (2-fluoro-5-methylphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (0.27g, 0.45mmol), trifluoroacetic acid (3.0 mL) and dichloromethane (6.0 mL). The reaction was stirred at room temperature for 1.5h. After the reaction of the starting materials was completed, the solvent was removed by concentration under reduced pressure, and the obtained residue was used directly in the next reaction.

MS(ESI,pos.ion)m/z:500.4[M+H] ⁺ .

Eighth step Synthesis of 4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-fluoro-5-methylphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To a reaction flask were charged 4- ((S) -3- (cyanomethyl) piperazin-1-yl) -7- (2-fluoro-5-methylphenyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile (0.22g, 0.45mmol), triethylamine (0.18g, 1.78mmol), and dichloromethane (6.0 mL). The system was cooled to 0 ℃, acryloyl chloride (50mg, 0.54mmol) was slowly added dropwise thereto, stirred at room temperature for 2.5h, after completion of the reaction, the reaction solution was diluted with dichloromethane (200 mL), washed with water (40 mL × 2), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/1.1M ammonia in methanol (v/v) = 500/1) to give the title compound as a yellow solid (78 mg, 31% yield).

MS(ESI,pos.ion)m/z:554.1[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.28(s,1H),7.76(s,1H),7.31-7.21(m,2H),7.13(t,J＝9.1Hz,1H),6.70-6.51(m,1H),6.41(d,J＝16.4Hz,1H),5.85(d,J＝10.7Hz,1H),5.17-4.95(m,1H),4.97-4.81(m,1H),4.56(dd,J＝11.7,4.5Hz,1H),4.45(dd,J＝14.2,3.4Hz,1H),4.37(d,J＝11.2Hz,1H),4.00-3.87(m,1H),3.79-3.61(m,2H),3.60-3.44(m,1H),3.37-3.15(m,2H),3.02(dd,J＝16.9,7.8Hz,1H),2.80(s,3H),2.74-2.61(m,2H),2.40(s,3H),2.31-2.18(m,1H),2.17-2.06(m,1H),2.05-1.90(m,2H).

Example 2N- (3- (4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -4- (trifluoromethyl) phenyl) acrylamide

Synthesis of (S) -4- (7- (5-amino-2- (trifluoromethyl) phenyl) -6-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester in the first step

To a reaction flask was added tert-butyl (S) -4- (7-chloro-6-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (0.63g, 1.19mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- (trifluoromethyl) aniline (520mg, 1.81mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (0.10g, 0.12mmol), bis (tri-tert-butylphosphino) palladium (520mg, 0.21mmol), potassium acetate (0.61g, 6.22mmol), and 1, 4-dioxane (6.0 mL). Heating the reaction system to 90 ℃ for reaction for 7h under the protection of nitrogen. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 200/1) to obtain the title compound as a yellow solid (0.29 g, yield 37%).

MS(ESI,pos.ion)m/z:651.2[M+H] ⁺ .

Second step Synthesis of 7- (5-amino-2- (trifluoromethyl) phenyl) -4- ((S) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To the reaction flask was added (S) -tert-butyl 4- (7- (5-amino-2- (trifluoromethyl) phenyl) -6-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (0.29g, 0.45mmol), trifluoroacetic acid (3.0 mL) and dichloromethane (6.0 mL). The reaction was allowed to react at room temperature for 1 hour, and then the solvent was removed by concentration under reduced pressure, and the obtained residue was used directly in the next reaction.

MS(ESI,pos.ion)m/z:551.2[M+H] ⁺ .

Third step Synthesis of N- (3- (4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -4-trifluoromethyl) phenyl) acrylamide

To the reaction flask was added 7- (5-amino-2- (trifluoromethyl) phenyl) -4- ((S) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile (0.25g, 0.45mmol), triethylamine (0.23g, 2.27mmol), dichloromethane (4.0 mL). The reaction was cooled to 0 ℃ and acryloyl chloride (42mg, 0.45mmol) was slowly added dropwise thereto. After the dropwise addition, the reaction mixture was transferred to room temperature for reaction for 3.5 hours. After the reaction was complete, the system was diluted with dichloromethane (200 mL), washed with water (40 mL. Times.2), and the layers were separated to give an organic phase. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/1.1M ammonia in methanol (v/v) = 500/1) to give the title compound as a yellow solid (67 mg, yield 23%).

MS(ESI,pos.ion)m/z:659.2[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)10.70(s,1H),8.66(s,1H),8.03-7.83(m,2H),7.57(s,1H),7.01-6.76(m,1H),6.47(dd,J＝16.9,10.1Hz,1H),6.31(d,J＝16.7Hz,1H),6.21(d,J＝16.2Hz,1H),5.84(d,J＝10.3Hz,1H),5.80(d,J＝10.9Hz,1H),5.05-4.75(m,2H),4.54-4.16(m,4H),4.14-3.96(m,1H),3.96-3.75(m,1H),3.73-3.60(m,1H),3.14-2.87(m,4H),2.79-2.59(m,1H),2.41(s,3H),2.31-2.18(m,1H),2.04-1.86(m,1H),1.74-1.51(m,2H).

Example 3- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (5-amino-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

First step Synthesis of 7-chloro-4- ((S) -3- (cyanomethyl) piperazin-1-yl) -2- (((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To a reaction flask was added tert-butyl (S) -4- (7-chloro-6-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (1.14g, 2.2mmol), trifluoroacetic acid (5 mL) and dichloromethane (10 mL). The reaction was allowed to react at room temperature for 1 hour, then concentrated under reduced pressure, and the obtained residue was used directly in the next reaction.

MS(ESI,pos.ion)m/z:426.2[M+H] ⁺ .

Second step Synthesis of 4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To the reaction flask was added 7-chloro-4- ((S) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile (0.92g, 2.2mmol), triethylamine (1.1g, 10.8mmol), dichloromethane (6.0 mL). The reaction was cooled to 0 deg.C and acryloyl chloride (0.40g, 4.3mmol) was slowly added dropwise. After the dropwise addition, the system was transferred to room temperature for reaction for 3.5h. After the reaction was complete, dichloromethane (200 mL) was added and the reaction mixture was washed with water (40 mL. Times.2). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/1.1M ammonia in methanol (v/v) = 500/1) to give the title compound as a yellow solid (85 mg, yield 8%).

MS(ESI,pos.ion)m/z:480.4[M+H] ⁺ .

Third step Synthesis of 4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (5-amino-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To a reaction flask was added 4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile (80mg, 0.17mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- (trifluoromethyl) aniline (0.10g, 0.34mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloromethane complex (14mg, 0.017mmol), bis (tri-t-butylphosphino) palladium (9mg, 0.017mmol), potassium acetate (88mg, 0.85mmol), and 1, 4-dioxane (4.0 mL). Heating the reaction system to 90 ℃ for reaction for 7h under the protection of nitrogen. Cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/1.1M ammonia in methanol (v/v) = 500/1) to give the title compound as a yellow solid (36 mg, yield 35%).

MS(ESI,pos.ion)m/z:605.1[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.22(s,1H),7.68(s,1H),7.56(d,J＝8.7Hz,1H),6.78(d,J＝8.2Hz,1H),6.66-6.57(m,1H),6.55(s,1H),6.42(d,J＝16.3Hz,1H),5.86(d,J＝10.1Hz,1H),4.60-4.47(m,1H),4.41-4.24(m,4H),4.20-4.07(m,2H),3.94-3.77(m,1H),3.69-3.47(m,1H),3.22-3.06(m,1H),3.05-2.87(m,1H),2.86-2.64(m,3H),2.50(s,3H),2.38-2.24(m,1H),2.12-1.98(m,1H),1.93-1.81(m,2H).

Example 4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (5-amino-2-fluorophenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To a reaction flask was added 4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile (100mg, 0.21mmol), (5-amino-2-fluorophenyl) boronic acid (67mg, 0.42mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (17mg, 0.021mmol), bis (tri-tert-butylphosphino) palladium (11mg, 0.021mmol), potassium acetate (110mg, 1.05mmol) and 1, 4-dioxane (4 mL). Heating the reaction system to 90 ℃ under the protection of nitrogen, and reacting for 4h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated to remove the solvent. The concentrate was purified by silica gel column chromatography (DCM/1.1M ammonia in methanol (v/v) = 500/1) to give the title compound as a yellow solid (29 mg, yield 25%).

MS(ESI,pos.ion)m/z:555.5[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.26(s,1H),7.75(s,1H),7.03(t,J＝9.1Hz,1H),6.79-6.68(m,2H),6.62-6.53(m,1H),6.41(d,J＝16.0Hz,1H),5.85(d,J＝10.4Hz,1H),4.58-4.49(m,1H),4.43-4.29(m,4H),3.94-3.54(m,4H),3.17-3.08(m,1H),3.03-2.90(m,1H),2.79-2.63(m,3H),2.50(s,3H),2.36-2.25(m,1H),2.10-2.02(m,1H),1.84-1.70(m,2H).

Example 5- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (5-amino-2-methylphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

First step Synthesis of 4-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline

To a reaction flask were added 3-bromo-4-methylaniline (3.00g, 15.8mmol), pinacol diboron (6.14g, 23.7mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (1.32g, 1.58mmol), potassium carbonate (4.46g, 31.6 mmol) and dimethyl sulfoxide (30 mL). Heating the reaction system to 80 ℃ for reaction for 7h under the protection of nitrogen. After the reaction was complete, it was cooled to room temperature and diluted with ethyl acetate (400 mL). The system was washed with tap water (60 mL. Times.4) and saturated brine (60 mL) in this order, and the organic phase was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as a yellow oil (3.20 g, yield 87%).

MS(ESI,pos.ion)m/z:234.4[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.11(d,J＝2.5Hz,1H),6.96(d,J＝8.0Hz,1H),6.68(dd,J＝8.0,2.6Hz,1H),2.94(br,2H),2.42(s,3H),1.33(s,12H).

Second step Synthesis of 4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (5-amino-2-methylphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile (100mg, 0.21mmol), 4-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (49mg, 0.21mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloromethane complex (17mg, 0.021mmol), bis (tri-tert-butylphosphine) palladium (11mg, 0.021mmol), potassium acetate (110mg, 1.05mmol) and 1, 4-dioxane (5 mL) were added to a reaction flask and heated to 90 ℃ for 4.5h under nitrogen protection. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane/1.1M ammonia in methanol (v/v) = 500/1) to give the title compound as a yellow solid (49 mg, yield 42%).

MS(ESI,pos.ion)m/z:551.2[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ ) δ (ppm) 8.60 (S, 1H), 7.42 (S, 1H), 7.01 (d, J =8.1hz, 1h), 6.94-6.83 (m, 1H), 6.61 (dd, J =8.2,2.0hz, 1h), 6.46 (S, 1H), 6.21 (d, J =16.1hz, 1h), 5.80 (d, J =10.3hz, 1h), 5.07 (S, 2H), 4.46-4.35 (m, 2H), 4.35-4.25 (m, 2H), 4.26-4.15 (m, 2H), 4.12-3.97 (m, 1H), 3.94-3.79 (m, 1H), 3.76-3.59 (m, 1H), 3.58-3.43 (m, 2H), 3.13-2.88 (m, 3H), 2.36 (S, 3H), 2.26-2.10 (m, 2H), 1.99 (S, 3H), 1.99-1.86 (m, 2H). Example 6- ((2S, 5R) -4-acryloyl-2, 5-dimethylpiperazin-1-yl) -7- (5-amino-2- (trifluoromethyl) phenyl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

First step Synthesis of tert-butyl (2R, 5S) -4- (6-bromo-2, 7-dichloroquinazolin-4-yl) -2, 5-dimethylpiperazine-1-carboxylate

6-bromo-2, 4, 7-trichloroquinazoline (0.63g, 2.02mmol), ethyl acetate (30 mL), DIPEA (1.30g, 10.10 mmol), (2R, 5S) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.39g, 3.06mmol) were added to the reaction flask. The reaction system is reacted for 3 hours at room temperature. After the reaction was complete, the system was washed with water (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 12/1) to give the title compound as a yellow solid (0.63 g, yield 63.9%).

MS(ESI,pos.ion)m/z:489.1[M+H] ⁺ ；

Second step Synthesis of (2R, 5S) -4- (6-bromo-7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester

To a reaction flask was added (2R, 5S) -4- (6-bromo-2, 7-dichloroquinazolin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.63g, 1.29mmol), anhydrous tetrahydrofuran (20 mL). The system was cooled to 0 ℃ and sodium hydride (0.15g, 3.87mmol, 60%) was slowly added with stirring, and after completion of the addition, the mixture was transferred to room temperature to react for 0.5h, and then (S) - (1-methylpyrrolidin-2-yl) methanol (0.45g, 3.87mmol) was added thereto. The system was reacted at room temperature for 5h. After the reaction is finished, the system is decompressed and dried by spinning. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a yellow solid (0.71 g, yield 96.7%).

MS(ESI,pos.ion)m/z:568.3[M+H] ⁺ ；

Step three Synthesis of (2R, 5S) -4- (7-chloro-6-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester

To a reaction flask was added (2R, 5S) -4- (6-bromo-7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.71g, 1.25mmol), zinc cyanide (0.07g, 0.63mmol), pd (TTBP) ₂ (0.13g, 0.25mmol) and DMF (10 mL). Heating the reaction system to 65 ℃ for reaction for 5h under the protection of nitrogen. Cooling to room temperature, filtering, and spin-drying the mother liquor under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a yellow solid (0.30 g, yield 47.5%).

MS(ESI,pos.ion)m/z:515.1[M+H] ⁺ ；

The fourth step Synthesis of 4- ((2S, 5R) -4-acryloyl-2, 5-dimethylpiperazin-1-yl) -7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To the reaction flask were added (2r, 5s) -4- (7-chloro-6-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.31g, 0.59mmol), dichloromethane (15 mL). Trifluoroacetic acid (0.88mL, 11.80mmol) was added dropwise at room temperature, and the mixture was reacted at room temperature for 3 hours, followed by spin-drying under reduced pressure. Methylene chloride (15 mL) and DIPEA (0.15g, 1.16mmol) were added to the residue, the system was cooled to 0 ℃ and acryloyl chloride (0.05g, 0.58mmol) was added dropwise, and after the addition, the system was reacted at room temperature for 1.5h. After the reaction was complete, the system was washed with water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and dried by spinning under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a yellow solid (0.22 g, yield 79.0%).

MS(ESI,pos.ion)m/z:469.4[M+H] ⁺ ；

Fifth step Synthesis of 4- ((2S, 5R) -4-acryloyl-2, 5-dimethylpiperazin-1-yl) -7- (5-amino-2- (trifluoromethyl) phenyl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To a reaction flask was added 4- ((2S, 5R) -4-acryloyl-2, 5-dimethylpiperazin-1-yl) -7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile (0.22g, 0.46mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- (trifluoromethyl) aniline (0.2g, 0.69mmol), pd (dppf) Cl ₂ (0.07g,0.09mmol)，Pd(TTBP) ₂ (0.05g, 0.09mmol), 1, 4-dioxane (20 mL) and water (0.5 mL). Heating the reaction system to 90 ℃ for reaction for 5h under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with methylene chloride (20 mL. Times.3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a grey solid (0.03 g, yield 9.2%).

MS(ESI,pos.ion)m/z:594.1[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.17(s,1H),7.66(s,1H),7.57(d,J＝8.6Hz,1H),6.79(d,J＝8.3Hz,1H),6.59–6.51(m,1H),6.40(t,J＝15.6Hz,1H),5.85–5.74(m,1H),5.08–4.86(m,1H),4.74(d,J＝5.0Hz,1H),4.60–4.46(m,1H),4.44–4.30(m,1H),4.25–4.12(m,2H),3.94–3.83(m,1H),3.78–3.62(m,1H),3.41(s,1H),3.12(s,1H),2.71(s,2H),2.59(s,2H),2.26–2.15(m,1H),1.99–1.86(m,2H),1.48–1.39(m,3H),1.31–1.17(m,5H).

Example 7- ((2R, 6S) -4-acryloyl-2, 6-dimethylpiperazin-1-yl) -7- (5-amino-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

Synthesis of (3R, 5S) -4- (6-bromo-2, 7-dichloroquinazolin-4-yl) -3, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester in the first step

To a reaction flask was added 6-bromo-2, 4, 7-trichloroquinazoline (1.24g, 3.97mmol), ethyl acetate (30 mL), DIPEA (2.57g, 19.85mmol), (3R, 5S) -3, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.85g, 3.97mmol). The reaction system is reacted for 3 hours at room temperature. After the reaction was complete, the system was washed with water (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and dried by spinning under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a yellow solid (0.25 g, yield 12.8%).

MS(ESI,pos.ion)m/z:489.0[M+H] ⁺ ；

Second step Synthesis of (3R, 5S) -4- (6-bromo-7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester

To the reaction flask was added (3R, 5S) -4- (6-bromo-2, 7-dichloroquinazolin-4-yl) -3, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.25g, 0.51mmol), anhydrous tetrahydrofuran (20 mL). The system was cooled to 0 ℃ and sodium hydride (0.06g, 1.53mmol, 60%) was slowly added with stirring, and after completion of the addition, the reaction mixture was transferred to room temperature for 0.5h, and then (S) - (1-methylpyrrolidin-2-yl) methanol (0.18g, 1.53mmol) was added thereto. The system was reacted at room temperature for 5h. After the reaction is finished, the system is decompressed and dried by spinning. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a yellow solid (0.29 g, yield 99.9%).

MS(ESI,pos.ion)m/z:568.0[M+H] ⁺ ；

Third step Synthesis of tert-butyl (3R, 5S) -4- (7-chloro-6-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 5-dimethylpiperazine-1-carboxylate

To a reaction flask was added (3R, 5S) -4- (6-bromo-7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.29g, 0.51mmol), zinc cyanide (0.03g, 0.26mmol), pd (TTBP) ₂ (0.21g, 0.41mmol), DMF (10 mL). Heating the reaction system to 65 ℃ for reaction for 5h under the protection of nitrogen. Cooling to room temperature, filtering, and spin-drying the mother liquor under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a yellow solid (0.10 g, yield 38.1%).

MS(ESI,pos.ion)m/z:515.5[M+H] ⁺ ；

Fourthly synthesis of 4- ((2R, 6S) -4-acryloyl-2, 6-dimethylpiperazin-1-yl) -7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To the reaction flask were added (3R, 5S) -4- (7-chloro-6-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.10g, 0.19mmol), dichloromethane (10 mL). Trifluoroacetic acid (0.28mL, 3.80mmol) was added dropwise at room temperature, reacted at room temperature for 3 hours, and then dried by spinning under reduced pressure. Methylene chloride (10 mL) and DIPEA (0.05g, 0.38mmol) were added to the residue, the system was cooled to 0 ℃ and acryloyl chloride (0.02g, 0.19mmol) was added dropwise thereto, after the addition, the system was reacted at room temperature for 1.5 hours. After the reaction was complete, the system was washed with water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and dried by spinning under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a yellow solid (0.08 g, yield 85.3%).

MS(ESI,pos.ion)m/z:469.4[M+H] ⁺ ；

The fifth step of synthesis of 4- ((2R, 6S) -4-acryloyl-2, 6-dimethylpiperazin-1-yl) -7- (5-amino-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To a reaction flask was added 4- ((2R, 6S) -4-acryloyl-2, 6-dimethylpiperazin-1-yl) -7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile (0.08g, 0.16mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- (trifluoromethyl) aniline (0.07g, 0.24mmol), pd (dppf) Cl ₂ (0.02g,0.03mmol)，Pd(TTBP) ₂ (0.02g, 0.03mmol), 1, 4-dioxane (15 mL) and water (0.5 mL). Heating the reaction system to 90 ℃ for reaction for 5h under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with methylene chloride (20 mL. Times.3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a grey solid (0.01 g, yield 7.8%).

MS(ESI,pos.ion)m/z:594.2[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.38(s,1H),7.54–7.44(m,2H),6.87(dd,J＝16.5,10.5Hz,1H),6.75(d,J＝8.5Hz,1H),6.50(s,1H),6.24(d,J＝16.4Hz,1H),6.09(s,2H),5.78(d,J＝10.5Hz,1H),4.87(s,2H),4.45–4.37(m,1H),4.29–4.17(m,2H),3.99(d,J＝13.1Hz,1H),3.65–3.55(m,2H),3.51(s,1H),3.00(s,1H),2.77–2.63(m,1H),2.41(s,3H),2.32–2.21(m,1H),2.02–1.93(m,1H),1.74–1.64(m,2H),1.47–1.36(m,6H).

Example 8- ((2R, 6S) -4-acryloyl-2, 6-dimethylpiperazin-1-yl) -7- (5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

Synthesis of 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- (trifluoromethyl) phenol in the first step

To a reaction flask was added 3-bromo-4- (trifluoromethyl) phenol (2.00g, 8.13mmol), pinacol diboron (3.16g, 12.2mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (1.32g, 1.58mmol), potassium carbonate (0.68g, 0.81mmol) and dimethyl sulfoxide (16 mL). Heating the reaction system to 80 ℃ for reaction for 6h under the protection of nitrogen. After the reaction was complete, it was cooled to room temperature and diluted with ethyl acetate (400 mL). The system was washed with tap water (60 mL. Times.4) and saturated brine (60 mL) in this order, and the organic phase was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as a yellow oil (1.08 g, yield 46%).

MS(ESI,neg.ion)m/z:287.1[M-H] ^- ；

Second step Synthesis of 4- ((2R, 6S) -4-acryloyl-2, 6-dimethylpiperazin-1-yl) -7- (5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To a reaction flask was added 4- ((2r, 6s) -4-acryloyl-2, 6-dimethylpiperazin-1-yl) -7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile (100mg, 0.21mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- (trifluoromethyl) phenol (91mg, 0.32mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (17mg, 0.021mmol), bis (tri-tert-butylphosphino) palladium (1mg, 0.021mmol), potassium acetate (110mg, 1.05mmol) and 1, 4-dioxane (5 mL). The reaction system is heated to 90 ℃ for reaction for 7.5h under the protection of nitrogen. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane/1.1M ammonia in methanol (v/v) = 500/1) to give the title compound as a yellow solid (64 mg, yield 51%).

MS(ESI,pos.ion)m/z:595.3[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.43(s,1H),7.68(s,1H),7.38(s,1H),7.30(s,1H),7.21(s,1H),6.88(dd,J＝16.6,10.4Hz,1H),6.24(dd,J＝16.7,1.9Hz,1H),5.79(dd,J＝10.5,2.0Hz,1H),4.93–4.75(m,2H),4.45–4.33(m,1H),4.28–4.14(m,2H),4.06–3.92(m,1H),3.67–3.56(m,1H),3.28–3.16(m,2H),3.01–2.90(m,1H),2.63–2.54(m,1H),2.36(s,3H),2.25–2.13(m,1H),2.03–1.89(m,1H),1.74–1.63(m,2H),1.42(s,3H),1.40(s,3H).

Example 9- (5-amino-2- (trifluoromethyl) phenyl) -4- ((2R, 6S) -4- (2-Fluoroacryloyl) -2, 6-dimethylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

First step Synthesis of 7-chloro-4- ((2R, 6S) -4- (2-fluoroacryloyl) -2, 6-dimethylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To a reaction flask were added (3R, 5S) -4- (7-chloro-6-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.65g, 3.20mmol), dichloromethane (16 mL), and trifluoroacetic acid (12.24g, 0.11mol) at room temperature. The system was reacted at room temperature for 3.5h. After the reaction is finished, the reaction product is dried by spinning under reduced pressure. Triethylamine (1.64g, 16.5 mmol) and methylene chloride (15 mL) were added to the residue. The mixture was cooled to 0 deg.C and then 2-fluoroacryloyl chloride (0.55g, 4.81mmol) was slowly added dropwise. After the dropwise addition, the system was reacted at room temperature for 2.5 hours. After completion of the reaction, the system was diluted by adding dichloromethane (200 mL), adjusted to pH =8 of the aqueous phase with saturated aqueous sodium bicarbonate solution, and washed with water (40 mL × 2). The organic phase was spin dried under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/1.1M ammonia in methanol (v/v) = 500/1) to give the title compound as a yellow solid (917 mg, yield 59%).

MS(ESI,pos.ion)m/z:487.5[M+H] ⁺ ；

Second step Synthesis of 7- (5-amino-2- (trifluoromethyl) phenyl) -4- ((2R, 6S) -4- (2-Fluoroacryloyl) -2, 6-dimethylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To a reaction flask was added 7-chloro-4- ((2r, 6s) -4- (2-fluoroacryloyl) -2, 6-dimethylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile (108mg, 0.22mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- (trifluoromethyl) aniline (77mg, 0.26mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (18mg, 0.022mmol), bis (tri-tert-butylphosphino) palladium (11mg, 0.022mmol), potassium acetate (110mg, 1.1mmol), and 1, 4-dioxane (5 mL). Heating the reaction system to 90 ℃ for reaction for 7h under the protection of nitrogen. Cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/1.1M ammonia in methanol (v/v) = 500/1) to give the title compound as a yellow solid (59 mg, yield 44%).

MS(ESI,pos.ion)m/z:612.3[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.38(s,1H),7.59–7.41(m,2H),6.76(d,J＝8.7Hz,1H),6.49(s,1H),6.08(s,2H),5.40(s,1H),5.37–5.24(m,1H),4.96–4.80(m,2H),4.45–4.33(m,1H),4.26–4.16(m,1H),4.13–3.95(m,1H),3.94–3.78(m,1H),3.77–3.59(m,1H),3.56–3.44(m,2H),3.03–2.88(m,1H),2.66–2.56(m,1H),2.37(s,3H),2.27–2.12(m,1H),2.04–1.87(m,1H),1.74–1.55(m,2H),1.44(d,J＝5.8Hz,3H),1.40(s,3H).

Example 10 (S) -4- (4-Acrylpiperazin-1-yl) -7- (5-amino-2- (trifluoromethyl) phenyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

First step Synthesis of tert-butyl 4- (6-bromo-2, 7-dichloroquinazolin-4-yl) piperazine-1-carboxylate

6-bromo-2, 4, 7-trichloroquinazoline (1.00g, 3.20mmol), ethyl acetate (30 mL), DIPEA (2.07g, 16.00mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.60g, 3.20mmol) were charged into a reaction flask. The reaction system is reacted for 2 hours at room temperature. After the reaction was complete, the system was washed with water (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and dried by spinning under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as a yellow solid (1.48 g, yield 100%).

MS(ESI,pos.ion)m/z:461.0[M+H] ⁺ ；

Second step Synthesis of tert-butyl (S) -4- (6-bromo-7-chloro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate

To a reaction flask was added tert-butyl 4- (6-bromo-2, 7-dichloroquinazolin-4-yl) piperazine-1-carboxylate (1.48g, 3.20mmol), anhydrous tetrahydrofuran (20 mL). The system was cooled to 0 ℃ and sodium hydride (0.26g, 6.40mmol, 60%) was slowly added with stirring, and after completion of the addition, the reaction was transferred to room temperature for 0.5h, and then (S) - (1-methylpyrrolidin-2-yl) methanol (1.11g, 9.60mmol) was added thereto. The system was reacted at room temperature for 2h. After the reaction is finished, the system is decompressed and dried by spinning. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a yellow solid (1.26 g, yield 72.8%).

MS(ESI,pos.ion)m/z:540.1[M+H] ⁺ ；

Step three, synthesizing (S) -4- (7-chloro-6-cyano-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

To a reaction flask was added (S) -4- (6-bromo-7-chloro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (1.26g, 2.33mmol), zinc cyanide (0.14g, 1.17mmol), pd (TTBP) ₂ (0.24g, 0.47mmol) and DMF (10 mL). Heating the reaction system to 65 ℃ for reaction for 5h under the protection of nitrogen. Cooling to room temperature, filtering, and spin-drying the mother liquor under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a yellow solid (0.87 g, yield 76.4%).

MS(ESI,pos.ion)m/z:487.5[M+H] ⁺ ；

The fourth step (S) -4- (4-acryloylpiperazin-1-yl) -7-chloro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile synthesis

To the reaction flask was added tert-butyl (S) -4- (7-chloro-6-cyano-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (0.50g, 1.03mmol), dichloromethane (20 mL). Trifluoroacetic acid (1.54mL, 20.60mmol) was added dropwise at room temperature, and the system was reacted at room temperature for 3 hours, followed by spin-drying under reduced pressure. Methylene chloride (20 mL) and DIPEA (0.27g, 2.06mmol) were added to the residue, the system was cooled to 0 ℃ and acryloyl chloride (0.09g, 1.03mmol) was added dropwise, and after the addition, the system was allowed to react at room temperature for 2 hours. After the reaction was complete, the system was washed with water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and dried by spinning under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a yellow solid (0.15 g, yield 33.0%).

MS(ESI,pos.ion)m/z:441.4[M+H] ⁺ ；

Fifth step Synthesis of (S) -4- (4-acryloylpiperazin-1-yl) -7- (5-amino-2- (trifluoromethyl) phenyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To the reaction flask was added (S) -4- (4-acryloylpiperazin-1-yl) -7-chloro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile (0.15g, 0.34mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- (trifluoromethyl) aniline (0.15g, 0.51mmol), pd (dppf) Cl ₂ (0.05g,0.07mmol)，Pd(TTBP) ₂ (0.03g, 0.07mmol), 1, 4-dioxane (20 mL) and water (0.5 mL). Heating the reaction system to 90 ℃ under the protection of nitrogen, and reacting for 5h. After completion of the reaction, the reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with methylene chloride (20 mL. Times.3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a grey solid (0.04 g, yield 18.2%).

MS(ESI,pos.ion)m/z:566.4[M+H] ⁺ ；

¹ H NMR(400MHz,CD ₃ OD)δ(ppm)8.62(s,1H),7.62(s,1H),7.54(d,J＝8.6Hz,1H),6.89–6.78(m,2H),6.67–6.58(m,1H),6.40–6.28(m,1H),5.85(d,J＝10.2Hz,1H),4.32–4.19(m,4H),4.02–3.93(m,4H),3.33(s,2H),3.11(s,3H),2.98(s,1H),2.51–2.36(m,1H),2.25–2.01(m,5H).

Example 11- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (5-amino-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

First step Synthesis of tert-butyl (S) -4- (6-bromo-2, 7-dichloroquinazolin-4-yl) -3-methylpiperazine-1-carboxylate

To a reaction flask were added 6-bromo-2, 4, 7-trichloroquinazoline (1.00g, 3.20mmol), ethyl acetate (30 mL), DIPEA (2.07g, 16.00mmol) and (S) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.64g, 3.20mmol). The reaction system is reacted for 2 hours at room temperature. After the reaction was complete, the system was washed with water (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and dried by spinning under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as a yellow solid (1.52 g, yield 100%).

MS(ESI,pos.ion)m/z:475.0[M+H] ⁺ ；

Second step Synthesis of tert-butyl (S) -4- (6-bromo-7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3-methylpiperazine-1-carboxylate

To a reaction flask were added (S) -4- (6-bromo-2, 7-dichloroquinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.52g, 3.20mmol), anhydrous tetrahydrofuran (20 mL). The system was cooled to 0 ℃ and sodium hydride (0.26g, 6.40mmol, 60%) was slowly added with stirring, and after completion of the addition, the reaction mixture was transferred to room temperature for 0.5h, and then (S) - (1-methylpyrrolidin-2-yl) methanol (1.10g, 9.60mmol) was added thereto. The system was reacted at room temperature for 2h. After the reaction is finished, the system is decompressed and dried by spinning. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a yellow solid (1.77 g, yield 100%).

MS(ESI,pos.ion)m/z:554.4[M+H] ⁺ ；

Step three, synthesizing (S) -4- (7-chloro-6-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxyl) quinazoline-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester

To a reaction flask was added (S) -4- (6-bromo-7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.60g, 2.88mmol), zinc cyanide (0.17g, 144mmol), pd (TTBP) ₂ (0.29g, 0.58mmol) and DMF (15 mL). Heating the reaction system to 65 ℃ under the protection of nitrogen, and reacting for 5h. Cooling to room temperature, filtering, and spin-drying the mother liquor under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a yellow solid (0.97 g, yield 6)7.3％)。

MS(ESI,pos.ion)m/z:501.3[M+H] ⁺ ；

The fourth step Synthesis of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To the reaction flask was added (S) -4- (7-chloro-6-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.97g, 1.94mmol), dichloromethane (20 mL). Trifluoroacetic acid (2.89mL, 38.90mmol) was added dropwise at room temperature, and the system was reacted at room temperature for 3 hours, followed by spin-drying under reduced pressure. To the residue were added dichloromethane (20 mL), DIPEA (0.50g, 3.90mmol). The system was cooled to 0 ℃ and acryloyl chloride (0.18g, 1.95mmol) was added dropwise and the system reacted at room temperature for 2h after addition. After the reaction was complete, the system was washed with water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and dried by spinning under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a yellow solid (0.20 g, yield 22.5%).

MS(ESI,pos.ion)m/z:455.2[M+H] ⁺ ；

The fifth step Synthesis of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (5-amino-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile

To a reaction flask was added 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-6-carbonitrile (0.20g, 0.44mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- (trifluoromethyl) aniline (0.19g, 0.66mmol), pd (dppf) Cl ₂ (0.06g,0.09mmol)，Pd(TTBP) ₂ (0.04g, 0.09mmol), 1, 4-dioxane (20 mL) and water (0.5 mL). Heating the reaction system to 90 ℃ for reaction for 5h under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with methylene chloride (20 mL. Times.3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as a grey solid (0.04 g, yield 16.7%).

MS(ESI,pos.ion)m/z:580.4[M+H] ⁺ ；

¹ H NMR(400MHz,CD ₃ OD)δ(ppm)8.55(s,1H),7.63(s,1H),7.55(d,J＝8.7Hz,1H),6.92–6.78(m,2H),6.64(s,1H),6.34(d,J＝16.7Hz,1H),5.86(d,J＝11.0Hz,1H),4.64–4.55(m,1H),4.50–4.42(m,1H),4.17–3.87(m,4H),3.86–3.60(m,4H),3.11(s,3H),2.98(s,1H),2.52–2.40(m,1H),2.26–2.08(m,4H),1.53(d,J＝6.2Hz,3H).

Biological assay

The LC/MS/MS system used for the analysis was a Waters Xevo G2-XS Qtof time-of-flight mass spectrometer. Mass spectrometry conditions are shown in table a:

TABLE A

Item	Condition
		Capillary voltage (kV)	4
Taper hole voltage (V)	60
		Ion Source temperature e (. Degree. C.)	120
Taper hole air flow (L/h)	50
		Flow rate of drying gas (L/h)	1000
Scanning mode	ES source, positive ion mode
		Analysis mode	Sensitivity of the probe
Scanning Range (m/z)	500-2000

Analysis A Waters Acquity I Class Sepax Bio-C4, 2.1X 50mm,3 μ M column was used to inject 10 μ L of sample. Analysis conditions were as follows: the mobile phases were water (containing 0.1% formic acid) (a) and acetonitrile (containing 0.1% formic acid) (B). The flow rate was 0.6mL/min. The column temperature was 65 ℃. Mobile phase gradients are shown in table B:

TABLE B

Time	Gradient of mobile phase A	Gradient of mobile phase B
			0min	95％	5％
0.75min	95％	5％
			1.0min	75％	25％
6.0min	50％	50％
			6.25min	0％	100％
7.5min	0％	100％
			7.75min	95％	5％
9min	95％	5％

Example A stability in human and mouse liver microsomes

Human or mouse liver microsomes were incubated in duplicate wells in polypropylene tubes. A typical incubation mixture comprises human or mouse liver microsomes (0.5 mg protein/mL), the compound of interest (1. Mu.M) and a total volume of 15. Mu.L of NADPH (2.0 mM) potassium phosphate buffer (PBS, 100mM, pH 7.4), and the test compound is dissolved in DMSO and diluted with PBS to give a final DMSO solution concentration of 0.05%. And incubated in a water bath at 37 ℃ in communication with the air, and after pre-incubation for 3min, protein was added to the mixture and the reaction started. At different time points (0, NCF,20 and 60 min), the reaction was stopped by the addition of the same volume of ice-cold acetonitrile. The samples were stored at-80 ℃ until LC/MS/MS analysis.

The concentration of compound in the human or mouse liver microsome incubation mixture was determined by the method of LC/MS.

Parallel incubation experiments were performed using denatured microsomes as negative controls, incubated at 37 ℃ and the reactions stopped at different time points (0, NCF,20 and 60 min).

Verapamil (1 μm) was used as a positive control, incubated at 37 ℃ and the reaction was stopped at different time points (0, ncf,20 and 60 min).

Data analysis

For each reaction, the concentration of compound in human or mouse liver microsome incubations (expressed as a percentage) was plotted as a percentage relative to the zero time point to infer intrinsic liver clearance CLint in vivo (reference: naritomi Y, terashita S, kimura S, suzuki a, kagayama a, sugiyama y.prediction of human hepatic clearance from human biological tissue and human biological tissue with liver microorganisms and tissue displacement, 29, 1316-1324). Results see table 1, table 1 for experimental results of the stability of the compounds provided in the examples of the present invention in human and mouse liver microparticles.

Table 1 experimental results of the stability of the compounds provided in the examples of the present invention in human and mouse liver microparticles

As can be seen from Table 1, the compounds of the present invention showed better stability when incubated in human and mouse liver microsomes. EXAMPLE B inhibitory Activity of Compounds of the invention on cell proliferation

The experimental method comprises the following steps: the CTG method measures the inhibitory activity of a compound on cell proliferation.

The cell assay conditions are shown in table C:

watch C

Cell name	Cell/well	Incubation time (h)	Complete culture medium
				H358	1000	72	RPMI1640+10％FBS

1) Cell culture

The cells are cultured by adopting a proper culture medium and are placed in a 5% carbon dioxide incubator at 37 ℃. Cells were observed 1 time daily using an inverted microscope and the medium was changed every 2-4 days. The collected cells were centrifuged at 1,200rpm for 5min, and the supernatant was discarded and transferred to a new sterile petri dish at a ratio of 1.

2) Cell plating

Cells in the exponential growth phase were collected and counted using a cell counter. The cells were resuspended in the respective medium and adjusted to the appropriate concentration. 90 μ L of cell suspension was added to each well in a 96-well cell culture plate. The cells were cultured overnight in a 5% carbon dioxide incubator at 37 ℃.

3) Compound preparation and dosing treatment

a, preparing a mother solution: test compounds were dissolved in DMSO to prepare a 10mM stock.

b, diluting the compound by 3 times by DMSO to obtain 9 concentration gradients of the compound, diluting the gradient diluted compound by 20 times by complete culture medium, and uniformly mixing to obtain 10 multiplied by concentration of a drug working solution.

c, adding medicine: the cell culture plate was removed, 10. Mu.L/well of the above 10 Xconcentration drug working solution was added to the corresponding well of the cell culture plate, and incubated for 72 hours in an incubator at 37 ℃.

4) Plate reading detection

and (a) after the compound is treated for 72 hours, the cell morphology is observed under an inverted microscope, the cell growth state in the DMSO control hole is normal, no pollution phenomenon is seen, and whether the compound is separated out from each hole or not is judged.

b, the prepared CTG solution is placed at room temperature for balancing for 10-20min.

c adding 50 mu L/hole of CTG solution according to the CTG operation instructions, and placing on a shaking table to shake for 20min in the dark.

d, measuring the fluorescence signal value by using a microplate reader.

5) Data analysis

Growth inhibition% = (V) _{Negative group} -V _{Experimental group} )/(V _{Negative group} -V _{Blank group} ) X 100% where V _{Negative group} Average value of solvent control group, V _{Experimental group} Reading for drug treatment group, V _{Blank group} The readings were from the cell-free drug-free treatment group. Data were analyzed and IC counted using GraphPad Prism 5.0 software ₅₀ The value is obtained.

Experiments prove that the compound has higher inhibitory activity on KRAS G12C mutant NCI-H358 cells. Specifically, the inhibitory activity of the compounds of the invention on KRAS G12C mutated NCI-H358 cells was less than 1000nM, with the majority of compounds having IC ₅₀ IC of less than 100nM, preferably, of partial compounds ₅₀ Less than 10nM. The results of inhibition tests of some of the example compounds are shown in table 2.

TABLE 2 results of experiments for inhibiting cell proliferation of compounds provided in some of the examples of the present invention

The compound AMG510 has the following specific structure:

EXAMPLE C binding of Compounds of the invention to KRAS4B-G12C protein

The experimental method comprises the following steps: and detecting the binding of the compound and the KRAS4B-G12C protein by an LC-MS method.

The experimental steps are as follows:

1) Experimental buffer preparation is shown in Table D

Watch D

2) Loading of GDP into KRAS-4B-G12C protein

2 times of KRAS-4B-G12C protein is diluted to 103 mu M, 2mL of protein is taken and added with 1mL of 2 XGDP loading buffer solution, the mixture is mixed evenly and gently, after the mixture is incubated for 1.5h at room temperature, the mixture is subpackaged into 100 mu L/tube, and the mixture is frozen rapidly in liquid nitrogen and stored in a refrigerator at minus 80 ℃.

3) KRAS-4B-G12C assay

Mixing the reagents of Table E below

TABLE E

Reagent	Amount of the composition
		KRAS-4B-G12C loaded with GDP (20 uM)	5uL
Compound (10% DMSO solution)	5uL
		10 × incubation buffer	5uL
Ultrapure water	35uL
		In total	50uL

4) Incubating respectively at room temperature for 30min and 3h

5) The reaction was stopped by adding 5. Mu.L of 5% formic acid

6) LC-MS detection

A total of 55. Mu.L of the reaction mixture was centrifuged at 15,000rpm for 10min before loading on the machine.

7) Calculating the KRAS (G12C) binding Rate%

KRAS (G12C) binding% = complex peak height/[ complex peak height + peak height not bound to KRAS G12C ] × 100

Experimental results see table 3, table 3 for protein binding 5min and 1h experimental results for compounds provided in some examples of the invention.

TABLE 3 protein binding 5min and 1h test results for compounds provided in some of the examples of the invention

Experimental results show that the compound has high binding rate with KRAS4B-G12C protein.

In the description of the specification, reference to the description of "one embodiment," "some embodiments," "an example," "a specific example," or "some examples" or the like means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

1. A compound which is a compound represented by formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

wherein:

y is N or CR ^y ；

R ^d Is H, D, C _1-3 Alkyl or C _1-3 Haloalkyl, wherein said C _1-3 Alkyl and C _1-3 Haloalkyl is independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 Substituted by the radical hydroxyalkoxy;

R ² is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-12 membered heteroaryl or-CR ^e R ^f -NR ^g R ^h Wherein said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-12 membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy and C _1-6 Substituted with a hydroxyalkoxy group;

R ^m 、R ⁿ 、R ^e and R ^f Each independently is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-3 Alkyl radical, C _1-3 Haloalkyl or C _1-3 Alkoxy, wherein said C _1-3 Alkyl radical, C _1-3 Haloalkyl and C _1-3 Each alkoxy is independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 Substituted with a hydroxyalkoxy group;

R ^g and R ^h Each independently is H, D, C _1-3 Alkyl or C _1-3 Haloalkyl, wherein said C _1-3 Alkyl and C _1-3 Haloalkyl is independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 Substituted with a hydroxyalkoxy group;

or R ^f 、R ^g And the atoms to which they are attached form a 3-6 membered heterocyclic ring, wherein the 3-6 membered heterocyclic ring is independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 Substituted by the radical hydroxyalkoxy;

R ³ is C _6-10 Aryl or 5-12-membered heteroaryl, wherein, said C _6-10 Aryl and 5-12 membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5R ^3a Substitution;

R ⁴ is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino or C _3-8 A cycloalkyl group;

each R ^x Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino radical, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl; wherein said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkylamino radical, C _3-8 CycloalkanesEach of which is independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 Substituted by the radical hydroxyalkoxy;

p is 0, 1,2,3, 4,5, 6, 7 or 8;

q is 0, 1,2,3, 4,5 or 6.

2. The compound of claim 1, wherein X is

3. The compound of claim 1 or 2, wherein R ^a And R ^b Each independently is H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH is substituted by a group;

R ^c is HD, methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein said methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH ₂ OH、-OCH ₂ CH ₂ OH, isopropoxy, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, and morpholinyl;

R ^d is H, D, methyl, ethyl, n-propyl, isopropylTrifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH is substituted by a group;

R ^m 、R ⁿ 、R ^e and R ^f Each independently of the other is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH is substituted by a group;

R ^g and R ^h Each independently is H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ Methoxy, ethoxy, isopropoxy, -OCF ₃ 、-OCH ₂ OH and-OCH ₂ CH ₂ OH is substituted by a group;

or R ^f 、R ^g And the atoms to which they are attached form an azetidine, pyrrolidine, piperidine ring, piperazine ring, or morpholine ring, wherein the azetidine, pyrrolidine, piperidine ring, piperazine ring and morpholine ring are each independently optionally substituted with 1,2,3, 4 or 5 substituents selected from D, F, cl, br,I、-NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ Methoxy, ethoxy, isopropoxy, -OCF ₃ 、-OCH ₂ OH and-OCH ₂ CH ₂ OH groups are substituted.

4. The compound of claim 1, wherein R ² Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-4 Alkylamino radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl or-CR ^e R ^f -NR ^g R ^h Wherein said C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-4 Alkylamino radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-10 Aryl and 5-to 10-membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 The group of hydroxyalkoxy.

5. The compound of claim 1, wherein R ² Is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ A methylamino group,Dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or-CR ^e R ^f -NR ^g R ^h Wherein said methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, each independently optionally substituted with 1,2,3, 4, or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH groups.

6. The compound of claim 1, wherein R ³ Is composed of

Wherein said

Each independently optionally substituted by 1,2,3, 4 or 5R ^3a Substitution;

each R ^3a Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl; wherein said-OH, -NH ₂ 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-10 Aryl and 5-to 10-membered heteroaryl are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _1-3 Hydroxyalkoxy, -C (= O) C _1-3 Alkyl, -C (= O) C _2-3 Alkenyl and-C (= O) C _2-3 Alkynyl groups.

7. The compound of claim 1, wherein each R ^x Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-4 Alkylamino radical, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl; wherein said C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-4 Alkylamino radical, C _3-6 Cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy and C _1-3 Substituted by the radical hydroxyalkoxy;

8. The compound of claim 1, wherein each R ^x Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein said methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentylCyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH ₂ OH and-OCH ₂ CH ₂ OH is substituted by a group;

R ^y is H, D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl.

9. The compound of claim 1, wherein each R ^3a Independently D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyrazoylPyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; wherein said-OH, -NH ₂ Methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, each independently optionally substituted by 1,2,3, 4 or 5 substituents selected from D, F, cl, br, I, -NO ₂ 、-CN、-OH、-NH ₂ Oxo, methyl, ethyl, n-propyl, isopropyl, -CHF ₂ 、-CF ₃ Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF ₂ 、-OCF ₃ 、-OCH ₂ OH、-OCH ₂ CH ₂ OH、-C(＝O)CH ₃ 、-C(＝O)CH ₂ CH ₃ and-C (= O) CH = CH ₂ Substituted with a group of (a);

10. The compound of claim 1, which is a compound having one of the following structures or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof of a compound having one of the following structures:

11. a pharmaceutical composition comprising a compound of any one of claims 1-10; and

the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

12. Use of a compound of any one of claims 1-10 or a pharmaceutical composition of claim 11 in the manufacture of a medicament for preventing, treating or ameliorating a KRAS G12C mediated disease in a patient.

13. The use of claim 12, wherein the KRAS G12C-mediated disease is cancer;

wherein the cancer is lung cancer, lymph cancer, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia or melanoma.