CN111773225A - KRAS and its mutant expression inhibitor - Google Patents

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a Chinese medicinal compositionAnd a compound shown as a formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof and new application of a crystal form thereof, R¹、R²、R³、R⁴、R⁵、R⁶L, n are as defined in the specification; the invention particularly relates to application of the compounds, pharmaceutical preparations containing the compounds and pharmaceutical compositions in preparing medicines for treating tumor patients mediated by KRAS and/or mutant expression thereof.

Description

KRAS and its mutant expression inhibitor

1. Field of the invention

The invention belongs to the field of medicines, and particularly relates to a quinazoline derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof and an application of a crystal form thereof in preparing a medicine for treating a tumor patient mediated by KRAS and/or mutant expression thereof.

2. Background of the invention

KRAS is a murine sarcoma virus oncogene, and there are three genes of the ras gene family associated with human tumors-H-ras, K-ras and N-ras, which are located on chromosomes 11, 12 and 1, respectively. The K-ras gene is like a switch in vivo, plays an important role in regulating and controlling signal transduction pathways in the processes of tumor cell growth, angiogenesis and the like, and can control and control the cell growth path when the K-ras is normal; when abnormality occurs, the cells are caused to grow continuously and are prevented from self-destruction. When K-ras gene is mutated, the gene is activated permanently, so that the cell growth is stimulated continuously, the signal transduction in the cell is disturbed, and the cell proliferation is out of control and cancerated.

KRAS is the most common cancer mutant gene in humans, with approximately 30% of all cancers associated with activation of KRAS mutations, with the highest incidence, particularly in colon, lung and pancreatic cancers. KRAS gene mutant cancers are associated with poor prognosis. Although the role of KRAS is widespread in several types of cancer, there is currently no targeted drug on the KRAS gene on the market, KRAS is considered to be a "druggable" target, for these cancer patients, once a mutation carrying KRAS is detected it means a poor prognosis, and there is no therapeutic drug. Most of the research and development ideas of the drugs are to attack MEK targets at the downstream of the gene, but the effect is not ideal. Therefore, it is of great significance to find and find efficient KRAS and its mutation inhibitors.

WO2012/027960A1 discloses a series of quinazoline derivatives tyrosine kinase inhibitors irreversibly inhibited by Pan-HER, and researches show that the irreversible inhibitors for Pan-HER tyrosine kinase have an inhibiting effect on HER2/4 besides effectively inhibiting EGFR. In the process of researching the patent compounds, the inventor unexpectedly finds that the compounds have good inhibition and treatment effects on KRAS mutation-related tumors/cancers.

3. Summary of the invention

The invention provides an application of a compound shown in a formula (I), a stereoisomer, a pharmaceutically acceptable salt or a crystal form thereof in preparing a medicament for treating tumors mediated by KRAS and/or a mutant thereof,

wherein the content of the first and second substances,

R¹selected from unsubstituted or substituted by 1 to 2 substituents Q₁Substituted of the following groups: 6-to 10-membered fused ring C_0-6Alkyl, 7-10 membered spirocyclic C_0-6Alkyl or 7-to 10-membered bridged ring C_0-6Alkyl, wherein 1 to 3 carbon atoms in the fused, spiro or bridged ring may be the same or different by 1 to 3 atoms selected from O, S (O)_m、N(H)_m、NCH₃And C (O) but wherein O and C (O) are not adjacent to each other in the ring after the substitution,

Q₁selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, C_1-6Alkyl carbonyloxy, C_1-6Alkylamido radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl radical, C_1-6Alkylsulfonamide group and C_3-8A cycloalkyl group;

R²selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q₂Substituted C_1-6Alkyl or C_1-6Alkoxy radicals, substituted radicals Q₂Substituted formyl or N (H)_m，

Q₂Selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, C_1-6Alkyl carbonyloxy, C_1-6Alkylamido radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl radical, C_1-6Alkylsulfonamido radical, C_3-8Cycloalkyl, unsaturated C_5-7Cycloalkyl and a saturated or unsaturated 3-to 8-membered heterocyclic group, wherein said C_3-8Cycloalkyl, unsaturated C_5-7The cycloalkyl group and the saturated or unsaturated 3-8 membered heterocyclic group may be further substituted by 1 to 2 substituents Q₃The substitution is carried out by the following steps,

Q₃selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, C_1-6Alkyl carbonyloxy, C_1-6Alkylamido radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl radical, C_1-6Alkylsulfonamido and halogen substituted C_1-6An alkoxy group;

R³selected from hydrogen, halogen, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_1-6Alkoxy, halogen substituted C_1-6Alkyl or C_1-6Alkoxy radical, C_1-6Alkyl carbonyloxy, C_1-6Alkylamido radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl or C_1-6An alkylsulfonamide group;

R⁴、R⁵and R⁶Each independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, halogen substituted C_1-6Alkyl or C_1-6Alkoxy radical, C_1-6Alkylamino or di (C)_1-6Alkyl) amino;

l is selected from the group consisting of a covalent bond, O, S (O)_m，N(H)_m，NCH₃Or C (O);

n is selected from 1,2 or 3; and

m is independently selected from 0, 1 or 2.

In some of the preferred embodiments, the first and second,

R¹selected from unsubstituted or substituted by 1 to 2 substituents Q₁Substituted of the following groups: 6-10 membered saturated fused ring C_0-4Alkyl, 7-10 membered saturated spirocyclic ring C_0-4Alkyl or 7-10 membered saturated bridged ring C_0-4Alkyl, wherein 1 to 3 carbon atoms in the fused, spiro or bridged ring may be the same or different by 1 to 3 atoms selected from O, S (O)_m、N(H)_m、NCH₃And C (O) but wherein O and C (O) are not adjacent to each other in the ring after the substitution,

Q₁selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C_1-4An alkyl group, a carboxyl group,C_1-4alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, C_1-4Alkyl carbonyloxy, C_1-4Alkylamido radical, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfinyl radical, C_1-4Alkylsulfonamide group and C_3-6A cycloalkyl group;

R²selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q₂Substituted C_1-4Alkyl or C_1-4Alkoxy radicals, substituted radicals Q₂Substituted formyl or N (H)_m，

Q₂Selected from the group consisting of: halogen, hydroxy, amino, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, C_1-4Alkyl carbonyloxy, C_1-4Alkylamido radical, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfinyl radical, C_1-4Alkylsulfonamido radical, C_3-6Cycloalkyl, unsaturated C_5-7Cycloalkyl and a saturated or unsaturated 5-to 8-membered heterocyclic group, wherein said C_3-6Cycloalkyl, unsaturated C_5-7The cycloalkyl group and the saturated or unsaturated 5-8 membered heterocyclic group may be further substituted by 1 to 2 substituents Q₃The substitution is carried out by the following steps,

Q₃selected from the group consisting of: halogen, hydroxy, amino, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, C_1-4Alkyl carbonyloxy, C_1-4Alkylamido radical, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfinyl radical, C_1-4Alkylsulfonamido and halogen substituted C_1-4An alkoxy group;

R³selected from halogen, cyano, nitro, C_1-4Alkyl radical, C_1-4Alkoxy, halogen substituted C_1-4Alkyl or C_1-4Alkoxy radical, C_1-4Alkyl carbonyloxy, C_1-4Alkylamido radical, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfinyl or C_1-4An alkylsulfonamide group;

R⁴、R⁵and R⁶Each independently selected from hydrogen, halogen, C_1-4Alkyl radical, C_1-4Alkoxy, halogen substituted C_1-4Alkyl or C_1-4Alkoxy radical, C_1-4Alkylamino or di (C)_1-4Alkyl) amino;

l is selected from the group consisting of a covalent bond, O, S (O)_mOr N (H)_m；

n is selected from 1,2 or 3; and

m is independently selected from 0, 1 or 2.

In some of the preferred embodiments, the first and second,

R¹selected from unsubstituted or substituted by 1 to 2 substituents Q₁Substituted of the following groups:

wherein 1 to 3 carbon atoms in the ring may be the same or different by 1 to 3 atoms selected from O, S (O)_m、N(H)_m、NCH₃And C (O), but O and C (O) are not adjacent to each other in the ring after the replacement, p is selected from 0, 1 or 2,

Q₁selected from the group consisting of: halogen, hydroxy, amino, carboxyl, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino and C_3-6A cycloalkyl group;

R²selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q₂Substituted C_1-4Alkyl radicals, substituted radicals Q₂Substituted formyl or N (H)_m，

Q₂Selected from the group consisting of: halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, C_1-4Alkyl carbo groupOxy radical, C_1-4Alkylamido radical, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfonamido radical, C_3-5Cycloalkyl and saturated or unsaturated 5-8 membered heterocyclyl, wherein said C_3-5The cycloalkyl group, saturated or unsaturated 5-8 membered heterocyclic group may be further substituted by 1 to 2 substituents Q₃The substitution is carried out by the following steps,

Q₃selected from the group consisting of: halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, C_1-4Alkyl carbonyloxy, C_1-4Alkylamido radical, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfonamido and halogen substituted C_1-4An alkoxy group;

R³selected from fluorine, chlorine, bromine, C_1-4Alkyl or C_1-4An alkoxy group;

R⁴、R⁵and R⁶Each independently selected from hydrogen, fluorine or chlorine;

l is selected from the group consisting of a covalent bond, O, S (O)_mOr N (H)_m；

n is selected from 1,2 or 3; and

m is selected from 0, 1 or 2.

In some of the preferred embodiments, the first and second,

R¹selected from unsubstituted or substituted by 1 to 2 substituents Q₁Substituted of the following groups:

p is selected from the group consisting of 0, 1 or 2,

Q₁selected from the group consisting of: halogen, amino, C_1-4Alkyl radical, C_1-4Alkylamino and di (C)_1-4Alkyl) amino;

R²selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q₂Substituted methyl or ethyl radicals, by substituents Q₂Substituted formyl or N (H)_m，

Q₂Selected from the group consisting of:

(1) halogen, hydroxy, amino, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, acetoxy, acetamido, methylsulfonyl and methylsulfonylamino,

(2) cyclopropyl, cyclopentyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyrazinyl and pyrimidinyl, said Q₂The radicals may be further substituted by 1 to 2 substituents Q₃The substitution is carried out by the following steps,

Q₃selected from the group consisting of: halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, halogen-substituted C_1-4Alkoxy, acetoxy, acetamido, methylsulfonyl, and methylsulfonylamino;

R³selected from fluorine or chlorine;

R⁴、R⁵and R⁶Is hydrogen;

l is selected from a covalent bond or O;

n is 2; and

m is independently selected from 0, 1 or 2.

In some of the preferred embodiments, the first and second,

R¹selected from:

R²selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q₂A substituted methyl group or an ethyl group,

Q₂selected from the group consisting of:

(1) methoxy and di (C)_1-4Alkyl) amino groups, in the presence of a nitrogen atom,

(2) piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, furanyl, cyclopropylalkyl, cyclopentylalkyl, pyrrolyl, pyridinyl, pyrimidinyl and thiazolyl, said Q₂The radicals may be further substituted by 1 to 2 substituents Q₃The substitution is carried out by the following steps,

Q₃selected from the group consisting of: halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino and halogen substituted C_1-4An alkoxy group;

R³selected from fluorine or chlorine;

R⁴、R⁵and R⁶Is hydrogen;

l is selected from a covalent bond or O; and

n is 2.

In some of the preferred embodiments, the first and second,

R¹selected from:

R²selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q₂A substituted methyl group or an ethyl group,

Q₂selected from the group consisting of: methoxy, dimethylamino, diethylamino, piperidinyl, piperazinyl and morpholinyl;

R³selected from fluorine or chlorine;

R⁴、R⁵and R⁶Is hydrogen;

l is selected from a covalent bond or O; and

n is 2.

In some of the preferred embodiments, the first and second,

R¹selected from:

preferably R¹Selected from:

in some of the preferred embodiments, the first and second,

R²selected from hydrogen;

R³independently selected from fluorine or chlorine;

l is selected from O; and

n is selected from 2.

In some preferred embodiments, wherein said compound of formula (I) is selected from:

in some preferred embodiments, the KRAS mutant is selected from a mutation at position G12, G13, K117 or Q61.

In some preferred embodiments, the KRAS mutant is selected from the group consisting of mutations at G12, K117.

In some preferred embodiments, the KRAS mutant is selected from the Q61 mutation.

In some preferred embodiments, the KRAS mutant is selected from the G12 mutation.

In some preferred embodiments, the mutation at position KRAS G12 is selected from one or more of G12A, G12D, G12F, G12K, G12N, G12S, G12V, G12Y, G12C, G12E, G12I, G12L, G12R, G12T and G12W.

In some preferred embodiments, the mutation at position KRAS G12 is selected from one or more of G12A, G12D, G12S, G12V, G12C, and G12R.

In some preferred embodiments, the mutation at position KRAS G13 is selected from one or more of G13D, G13C, G13S, G13R, G13A, and G13V.

In some preferred embodiments, the mutation at position KRAS Q61 is selected from one or more of Q61H, Q61K, Q61R, Q61L, Q61P, and Q61E.

In some preferred embodiments, the KRAS K117 mutation is selected from K117N.

In some preferred embodiments, wherein said crystalline form is selected from an isolated crystalline form of the compound of formula (I), a crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), a solvate crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), or a co-crystal of the compound of formula (I).

In some preferred embodiments, the crystalline form of the pharmaceutically acceptable salt of the compound of formula (I) is selected from the hydrochloride, phosphate, mesylate, triflate, malate, fumarate, succinate, tartrate, benzoate or maleate form of the compound of formula (I), preferably the hydrochloride, maleate, succinate or benzoate form;

the solvate crystal form of the compound of formula (I) is selected from a hydrate crystal form, a methoxide crystal form, an ethoxide crystal form, an etherate crystal form and an acetonide crystal form, preferably a hydrate crystal form;

the solvate of a pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of a hydrochloride hydrate crystal form, a hydrochloride methoxide crystal form, a hydrochloride etherate crystal form, a benzoate hydrate crystal form, a benzoate methoxide crystal form, a benzoate etherate crystal form, a maleate hydrate crystal form, a maleate methoxide crystal form, or a maleate etherate crystal form, preferably a hydrochloride hydrate crystal form, more preferably a dihydrochloride monohydrate crystal form;

the co-crystal of the compound of formula (I) is selected from co-crystal of the compound of formula (I) and one or more of proline, gallic acid, oxalic acid, maleic acid, tartaric acid and saccharin, preferably co-crystal of proline, tartaric acid or saccharin.

In some preferred embodiments, the tumor is selected from one or more of pancreatic cancer, colorectal cancer, lung cancer, multiple myeloma, melanoma, brain cancer, head and neck cancer, thyroid cancer, oral cancer, esophageal adenocarcinoma, gastric cancer, liver cancer, bile duct cancer, kidney cancer, peritoneal cancer, gallbladder cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, epidermal carcinoma, non-hodgkin's lymphoma, glioma, and glioblastoma.

In some preferred embodiments, the tumor is selected from non-small cell lung cancer. In some preferred embodiments, the tumor is selected from the group consisting of lung adenocarcinoma, lung squamous carcinoma and large cell carcinoma, colorectal cancer, gastric cancer, and the like.

The invention also provides application of a pharmaceutical preparation of a compound shown as a formula (I), a stereoisomer, a pharmaceutically acceptable salt or a crystal form of the compound in preparing a medicament for treating tumors mediated by KRAS and/or a mutant thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R⁶L and n are as defined in the preceding schemes.

The invention also provides application of the composition of the compound shown in the formula (I), the stereoisomer, the pharmaceutically acceptable salt or the crystal form thereof and one or more other anti-tumor medicaments in preparing medicaments for treating tumors mediated by KRAS and/or mutants thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R⁶L and n are as defined in the preceding schemes.

The invention also provides a method for treating a patient with tumor mediated by KRAS and/or its mutant by using the compound shown in formula (I), its stereoisomer, its pharmaceutically acceptable salt or its crystal form, which comprises administering therapeutically effective amount of the compound shown in formula (I), its stereoisomer, its pharmaceutically acceptable salt or its crystal form to the patient in need of the treatment,

wherein R is¹、R²、R³、R⁴、R⁵、R⁶L and n are as defined in the preceding schemes.

In the specification and claims of this application, compounds are named according to chemical structural formula, and if the name of a compound does not match the chemical structural formula when the same compound is represented, the chemical structural formula or chemical reaction formula is the standard.

Detailed Description

The KRAS G12 site mutation refers to the mutation at the site 12 for compiling glycine on KRAS, wherein G is an amino acid abbreviation, and is specifically glycine; the number "12" is the specific site for coding amino acids, and the G12 mutation includes but is not limited to point mutation and insertion mutation. Examples of mutations at other sites of KRAS are defined as the mutation at position G12 of KRAS.

The KRAS G12C mutation refers to point mutation at the site 12 on KRAS, and the amino acid compiled by the point mutation is changed from glycine to cysteine. The letter "G" means as described above, and the letter "C" is an abbreviated form of cysteine. Other examples of the KRAS12 mutation are defined as the G12C mutation.

The KRAS G13D mutation refers to that amino acid compiled at site 13 of KRAS is mutated from glycine to aspartic acid, the letter "G" is as described above, and the letter "D" is in the abbreviation form of aspartic acid. Other examples of KRAS 13 mutations are defined as the G13D mutation.

The KRAS Q61H mutation refers to that amino acid compiled at the 61 th site of KRAS is mutated from glutamine into histidine, and letters Q and H are short-hand forms of glutamine and histidine respectively. Other examples of KRAS 61 mutations are defined as Q61H mutations.

In the present invention, "halo" means substituted by "halogen" and the term "halogen" means fluorine, chlorine, bromine or iodine.

In the present invention, the term "C_1-6Alkyl "refers to a straight or branched alkyl group having 1 to 6 carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2-methylpropyl, and the like. "C" according to the invention_1-4Alkyl "means C_1-6Specific examples of the alkyl group having 1 to 4 carbon atoms.

In the present invention, the term "C_1-6Alkoxy "means" C_1-6alkyl-O- "group, wherein C_1-6Alkyl is as previously defined; examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy, and the like. "C" according to the invention_1-4Alkoxy "means C_1-6Specific examples of the alkoxy group having 1 to 4 carbon atoms.

In the present invention, the term "C_3-8Cycloalkyl "refers to a monocyclic saturated carbocyclic group containing 3 to 8, e.g., 3,4, 5,6, 7, or 8 carbon atoms, preferably 3 to 6 or 3 to 5 carbon atoms, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, 1-methylcyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

In the present invention, the term "C_1-6Alkylamino "refers to" C_1-6alkyl-NH- "group, wherein C_1-6Alkyl is as previously defined; examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, sec-butylamino, pentylamino, neopentylamino, hexylamino and the like.

In the present invention, the term "di (C)_1-6Alkyl) amino "refers to" (C)_1-6Alkyl radical)₂-N- "group, two of which are C_1-6The alkyl groups may be the same or different and are each as defined above; examples include, but are not limited to, dimethylamino, diethylamino, dipropylamino, dibutylamino and the like.

In the present invention, the term "C_1-6Alkylcarbonyloxy group and C_1-6Alkylamide group "," C_1-6Alkylsulfonyl group "," C_1-6Alkylsulfonamido "and" C_1-6Alkylsulfinyl "means respectively" C_1-6alkyl-C (O) O- "," C_1-6alkyl-C (O) NH-, "C_1-6alkyl-SO₂-”、“C_1-6alkyl-SO₂NH- "and" C_1-6alkyl-SO- "group, wherein C_1-6Alkyl is as defined above.

In the present invention, the term "6-to 10-membered fused ring" means a saturated or unsaturated fused ring system containing 6 to 10 carbon atoms, wherein the ring carbon atoms may be substituted by 1 to 3 same or different atoms selected from O, S (O), which is formed by connecting at least two cyclic structures sharing two adjacent atoms_m、N(H)_m、NCH₃And C (O), but O and C (O) are not adjacent to each other in the ring after the replacement. Examples include, but are not limited to, 5, 6-dihydroimidazole [1.2-a ]]Pyrazin-7 (8H) -yl, 5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl, 5H-pyrrolo [3.4-b ]]Pyridin-6 (7H) -yl, 7, 8-dihydropyridine [4.3-d ]]Pyrimidin-6 (5H) -yl, 2,3,6, 7-tetrahydro-1H-pyrazolo [4.3-c]Pyridin-5 (4H) -yl, 6, 7-dihydrothiazole [5.4-c]Pyridin-5 (4H) -yl, 3-methyl-6, 7-dihydro-3H-pyrazolo [4.5-c]Pyridin-5 (4H) -yl, 2-methylhexahydropenta [ c ]]Pyrrol-5-yl and the like.

In the present invention, the term "7-to 10-membered spirocyclic ring" means a ring composed of at least twoThe rings share an atom with each other to form a fused ring system containing 7 to 10 carbon atoms, which may be substituted by 1 to 3 identical or different atoms selected from O, S (O)_m、N(H)_m、NCH₃And C (O), but O and C (O) are not adjacent to each other in the ring after the replacement. Examples include, but are not limited to, 6-azaspiro [2.5]]Octane-6-yl, 7-azaspiro [3.5]]Nonan-7-yl, 8-azaspiro [4.5]]Decan-8-yl, 1-methyl-1, 7-diazaspiro [4.4 ]]Nonan-7-yl, 2-methyl-2, 6-diazaspiro [3.4 ]]Octane-6-yl, 6-azaspiro [3.4 ]]Octane-6-yl, 2-oxa-7-azaspiro [4.5]]Decan-7-yl, 2-oxa-8-azaspiro [4.5]]Decan-8-yl, 2-methyl-2, 7-diazaspiro [4.5]]Decane, etc.

In the present invention, the term "7-to 10-membered bridged ring" means a saturated or unsaturated fused ring system containing 7 to 10 carbon atoms, wherein any two rings share two atoms which are not directly bonded, and wherein the ring carbon atoms may be substituted by 1 to 3 same or different atoms selected from the group consisting of O, S (O)_m、N(H)_m、NCH₃And C (O), but O and C (O) are not adjacent to each other in the ring after the replacement. Examples include, but are not limited to, (1S,4S) -2-methyl-2-azabicyclo [2.2.1]Hexane, 2-azabicyclo [2.2.1]]Heptane, 8-methylbicyclo [3.2.1]]Octane, 3-oxa-8-azabicyclo [3.2.1]Octane, 2-azabicyclo [2.2.2]Octane, 7-azabicyclo [2.2.1]Heptane, 3-azabicyclo [3.2.1]Octane, 3-azabicyclo [3.3.2 ]]Decane, 7-oxabicyclo [2.2.1]Heptane, 8-oxabicyclo [3.2.1]]Octane, and the like.

In the present invention, the term "unsaturated C_5-7Cycloalkyl "refers to a monocyclic unsaturated carbocyclic group containing 5 to 7, e.g., 5,6, or 7, carbon atoms, examples of which include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, and the like.

In the present invention, the term "3-8 membered heterocyclic group" means a cyclic system composed of 3 to 8, for example, 3,4, 5,6, 7 or 8, preferably 5 to 8 carbon atoms and 1 to 4 (preferably 1 to 3, more preferably 1 to 2) heteroatoms selected from nitrogen, oxygen and sulfur, examples of which include, but are not limited to, the following ring-forming groups: aziridine, 2H-aziridine, diazirine, 3H-diazirine, azetidine, 1, 2-diazetidine, azetidine, 1, 2-diazacyclobutene, pyrrole, dihydropyrrole, pyrrolidine, imidazole, 4, 5-dihydroimidazole, imidazolidine, pyrazole, 4, 5-dihydropyrazole, pyrazolidine, 1,2, 3-triazole, 1,2, 4-triazole, tetrazole, pyridine, 2-pyridone, 4-pyridone, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, 1,2, 3-triazine, 1,2, 4-triazine, 1,3, 5-triazine, 1,2,4, 5-tetrazine, azepane, 1, 2-diazepatriene, 1, 3-diazepatriene, 1, 4-diazacyclotriene, azacyclooctatetraene, 1, 4-dihydro-1, 4-diazacyclooctatriene, ethylene oxide, dioxirane, thietane, oxetane, 1, 2-dioxetane, thietane, 1, 2-dithiocyclobutene, furan, tetrahydrofuran, thiophene, 2, 5-dihydrothiophene, tetrahydrothiophene, 1, 3-dioxolane, 1, 3-dioxol-2-one, 1, 2-dithiole, 1, 3-dithiolane, 2H-pyran-2-one, 3, 4-dihydro-2H-pyran, 4H-pyran, tetrahydropyran, 4H-pyran-4-one, 1, 4-dihydro-1, 4-dithiacyclooctatriene, thiolane, 2H-pyran-2-one, 3, 4-dihydro-, 1, 4-dioxane, 1, 4-dithiine, 1, 4-oxathiadiene, 1, 4-dioxanone, 1, 3-dioxane, 1, 3-oxathiahexane, oxepitriene, thiepin, 1, 4-dioxacyclooctatriene, oxaziridine, oxazole, 4, 5-dihydrooxazole, isoxazole, 4, 5-dihydroisoxazole, 2, 3-dihydroisoxazole, 1,2, 3-oxadiazole, 1,2, 5-oxadiazole, thiazole, 4, 5-dihydrothiazole, isothiazole, 1,2, 3-thiadiazole, 1,2, 4-thiadiazole, 1,3, 4-thiadiazole, 2H-1, 2-oxazine, 4H-1, 2-oxazine, 6H-1, 2-oxazine, 2H-1, 3-oxazine, 4H-1, 3-oxazine, 5, 6-dihydro-4H-1, 3-oxazine, 6H-1, 3-oxazine, 2H-1, 4-oxazine, 4H-1, 4-oxazine, 2H-1, 3-thiazine, 4H-1, 3-thiazine, 5, 6-dihydro-4H-1, 3-thiazine, 6H-1, 3-thiazine, 2H-1, 4-thiazine, 4H-1, 4-thiazine, morpholine and the like.

"C" according to the invention_0-6Alkyl "refers to a straight or branched chain alkyl group containing 0 to 6 carbon atoms, when the alkyl group contains 0 carbon atoms it means that the alkyl group is absent, when the alkyl group contains 1 to 6 carbon atoms it is as previously defined for" C_1-6Alkyl groups "as described.

The "halo C" of the present invention_1-6Alkyl "means one or more halogen atoms substituted for C_1-6Radicals derived from one or more hydrogen atoms of the alkyl radical, the said "halogens" and "C_1-6Alkyl "is as defined above.

The "halo C" of the present invention_1-6Alkoxy "means one or more halogen atoms substituted for C_1-6Radicals derived from one or more hydrogen atoms of alkoxy radicals, said "halogen" and "C_1-6Alkoxy "is as defined above.

The stereoisomers of the compounds of formula (I) according to the invention include all possible optical isomers and diastereoisomeric mixtures and pure or partially pure compounds. Optical isomers are meant when the compounds of the present invention contain one or more asymmetric centers and thus may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.

The compounds of formula (I) according to the invention contain olefinic double bonds, and unless otherwise specified, the stereoisomers according to the invention include cis-and trans-isomers thereof.

The compounds of formula (I) according to the invention may exist in tautomeric forms, the individual tautomers as well as mixtures thereof being included within the scope of the invention.

The crystal form of the compound shown in the formula (I) comprises free crystal form of the compound shown in the formula (I), pharmaceutically acceptable salt crystal form of the compound shown in the formula (I), solvate crystal form of the compound shown in the formula (I), pharmaceutically acceptable salt solvate crystal form of the compound shown in the formula (I), co-crystal of the compound shown in the formula (I) and the like. The "solvent" in the "solvate" includes one or more of water, methanol, ethanol, isopropanol, diethyl ether, acetone, ethyl acetate, tetrahydrofuran, dichloromethane, N' -dimethylformamide, dimethyl sulfoxide, and the like.

The "solvate crystal form of the compound of formula (I)" and "solvate crystal form of a pharmaceutically acceptable salt of the compound of formula (I)" described in the present invention have any molecular ratio of the compound of formula (I) to the solvent, preferably 10:1 to 1:10, more preferably 3:1 to 1:3, and examples thereof include, but are not limited to, 10:1, 8:1, 7:1, 5:1, 3:1, 2:1, 1.5:1, 1:2, 1:3, 1:5, and the like.

The 'co-crystal of the compound of the formula (I)' described in the invention includes a co-crystal system formed by combining the compound of the formula (I) and one or more of amino acid, carboxylic acid compound, saccharide, mineral, vitamin, pharmaceutical excipient and the like through non-covalent bonds.

The pharmaceutically acceptable salts of the compounds of formula (I) described in the present invention include alkali metal salts, such as sodium salt, potassium salt, lithium salt, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; other metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.; inorganic base salts such as ammonium salts; organic base salts such as t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylamine salt, tris (hydroxymethyl) aminomethane salt, and the like; inorganic acid salts such as hydrohalic acid salts, e.g., hydrofluoride salts, hydrochloride salts, dihydrochloride salts, hydrobromide salts, hydroiodide salts, etc., nitrate salts, perchlorate salts, sulfate salts, phosphate salts, etc.; organic acid salts, for example, lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate and the like, arylsulfonate such as benzenesulfonate, p-toluenesulfonate and the like, carboxylates such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, maleate, benzoate and the like, amino acid salts such as glycinate, trimethylglycinate, arginate, ornithine, glutamate, aspartate and the like.

In the "pharmaceutically acceptable salt of the compound of formula (I)" and "solvate crystal form of the pharmaceutically acceptable salt of the compound of formula (I)" of the present invention, the molecular ratio of the compound of formula (I) to the corresponding alkali metal, other metal, organic base, inorganic acid, organic acid may be any value, preferably 10:1 to 1:10, more preferably 3:1 to 1:3, and examples thereof include, but are not limited to, 10:1, 8:1, 7:1, 5:1, 3:1, 2:1, 1.5:1, 1:2, 1:3, 1:5, and the like.

The "pharmaceutical preparation" of the present invention is any pharmaceutically acceptable dosage form, and is administered to a patient in need thereof by oral, parenteral, rectal or pulmonary administration. For oral administration, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, it can be made into injection, including injection solution, sterile powder for injection and concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine. For rectal administration, it can be made into suppository, etc. For pulmonary administration, it can be made into inhalant or spray.

The present invention also provides a method of treating a patient having a tumor mediated by KRAS and/or mutations thereof comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I), which may be administered by any conventional and acceptable means known in the art, the therapeutically effective amount being adjusted according to the race, sex, age, weight, medical condition, type of disease, severity of disease, route of administration and associated health condition of the patient and other factors known to those skilled in the art.

The invention also provides a combination of a compound of formula (I) and one or more other anti-tumour agents, which agents may be administered simultaneously or sequentially with a compound of formula (I), for the treatment of a patient suffering from a tumour mediated by KRAS and/or mutations thereof.

The composition may further comprise any pharmaceutically acceptable carrier, wherein the carrier includes but is not limited to: fillers, diluents, binders, wetting agents, disintegrants, lubricants, surfactants, preservatives, colorants, flavors, fragrances, effervescent agents, emulsifiers, flocculants, deflocculants, bacteriostats, and solubilizers.

The "other antitumor drug" according to the present invention is selected from antimetabolites, growth factor inhibitors, antibodies, mitotic inhibitors, antitumor hormones, alkylating agents, metal platins, topoisomerase inhibitors, and immunosuppressive drugs.

The tumor, cancer or carcinoma of the present invention also includes metastases in the primary organ, tissue and/or any other location, regardless of the location of the tumor metastasis.

4. Detailed description of the preferred embodiments

The above-mentioned contents of the present invention will be described in further detail with reference to experimental examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following experimental examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

The following abbreviations represent the following definitions:

DMSO, DMSO: dimethyl sulfoxide

1000 × wherein "x": multiple times

Experimental example 1 in vitro cytological Activity experiment

And (3) testing the sample: form I of compound 18-2, self-made, the chemical name, XRPD pattern and method of preparation refer to the preparation examples of international patent application WO2017107985a 1.

Method of producing a composite material

The effect of compounds on cell proliferation of NCIH460(KrasQ61H) and NCIH358(KrasG12C) was examined using the CTG kit.

Compound preparation

393. mu.l DMSO was added to an EP tube containing 2.45mg Compound 18-2 form I, shaken well (10 mM);

1000 × compound stock solution preparation:

compounds were diluted 3.16-fold with DMSO from 10mM down to: 10000. mu.M, 3164.5. mu.M, 1001.4. mu.M, 316.9. mu.M, 100.3. mu.M, 31.7. mu.M, 10. mu.M, 3.18. mu.M, 1. mu.M.

10 XCompound 2. mu.l of 1000 Xtest compound were added to 198. mu.l of medium, and mixed by shaking.

Addition of the Compounds

The prepared 10X compound was added to the cells (10. mu.l) according to the compound profile using a lining gun to a final concentration of 10000nM,3164.5nM,1001.4nM,316.9nM,100.3nM,31.7nM,10nM,3.18nM,1nM.

The cell culture method comprises the following steps: using RPMI1640+ 10% FBS medium at 37 ℃, 5% CO₂The cells are cultured.

Cell plating

1) Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion to ensure cell viability above 90%.

2) Adjusting the cell concentration; each 90 μ L of cell suspension was added to a 96-well plate and the culture medium control wells were supplemented with 90 μ L of medium.

3) Cells in 96-well plates were incubated at 37 ℃ with 5% CO₂And cultured overnight under 95% humidity conditions.

Drug treatment

1) In 96-well plates seeded with cells, 10. mu.L of 10 Xcompound solution was added per well, 10. mu.L of medium was added to each of the media control and cell control wells, three replicates per drug concentration were set, and the final DMSO concentration was 0.1%.

2) The cells in the dosed 96-well plate were placed at 37 ℃ in 5% CO₂And further cultured under 95% humidity conditions for 72 hours, after which CTG analysis was performed.

Data processing

Data were analyzed using GraphPad Prism 5.0 software, fitted to the data using non-linear sigmoidal regression to derive a dose-effect curve, and IC was calculated therefrom₅₀The value is obtained.

The cell survival rate (%) × (Lum test drug-Lum culture solution control)/(Lum cell control-Lum culture solution control) × 100%.

Results of the experiment

TABLE 1 inhibitory Effect of the Compounds of the present invention on cells

Conclusion of the experiment

The compound has good tumor cell inhibition effect, and particularly has obvious inhibition effect on tumor cells containing KRAS mutation.

EXAMPLE 2 esophageal squamous carcinoma PDX model E7(Kras G12D)

Materials and methods

And (3) testing the sample: compound 18-2 form I, prepared according to the methods of prior art WO2017107985a 1.

Method of producing a composite material

Collecting tumor tissue from human xenograft esophageal squamous carcinoma model E7 tumor-bearing mouse, and cutting into [2-4mm ]]Tumor masses of diameter were inoculated in the right anterior scapular region of BALB/c nude mice. When the average tumor volume reaches 100mm³The mice are randomly divided into 5 groups according to the tumor volume, and the dividing date is the 1 st day of the experiment. Administration was started on the day of the group, oral gavage once daily for 21 consecutive days. Tumor Volume (TV) was measured with a vernier caliper. The evaluation of the therapeutic effect was carried out based on the relative tumor inhibition ratio (TGI).

Results

The mean tumor volume of the vehicle control group reached 1.31cm at the end of the experiment³The tumor volume of the administration group is 0.38cm³。

Experimental observation indexes and calculation:

tumor volume TV-0.5 a × b². Where a is the major diameter of the tumor and b is the minor diameter of the tumor.

Relative tumor inhibition ratio TGI (%) (1-T/C) × 100%. T and C are the Relative Tumor Volumes (RTV) at a particular time point for the treated and control groups, respectively.

T/C% is the relative tumor proliferation rate, i.e. the percentage value of the relative tumor volume in the treated and control groups at a certain time point. The calculation formula is as follows: T/C%_RTV/C_RTV×100％(T_RTV: treatment group mean RTV; c_RTV: vehicle control mean RTV; RTV ═ V_t/V₀，V₀Is the tumor volume of the animal in the group, V_tTumor volume in the animal after treatment).

Results of the experiment

TABLE 2 TGI, T/C values for groups of compounds of the invention in the E7 human esophageal cancer model

Remark, a, mean ± sem;

d. tumor volume at day 22 compared to vehicle control, P <0.001 compared to vehicle control.

Conclusion of the experiment

The compound 18-2 of the invention shows better tumor growth inhibition under the administration scheme of oral administration once a day at 20 mg/kg. After 21 days of continuous administration, the mean tumor volume reached 0.38cm³The TGI value was 52.3%, which is significantly different from the control group (P)<0.001)。

EXAMPLE 3 gastric carcinoma PDX model GA0318(KrasG12D)

Materials and methods

And (3) testing the sample: compound 18-2 form I, prepared according to the methods of prior art WO2017107985a 1.

Control drug: neratinib, purchased or prepared according to prior art methods, has the structural formula shown below.

Method of producing a composite material

From

Collecting tumor tissue from GA0318 tumor-bearing mouse, cutting into 2-4mm]The tumor mass of diameter was inoculated subcutaneously in the right anterior aspect of the mouse. When the average tumor volume reaches 100-150 mm³The time is randomly grouped, and the grouping date is Day 0. Mice were randomly assigned to 3 experimental groups based on tumor volume. Each group had 5. Dosing began on day0 post-group, oral gavage once daily for 28 consecutive days. Tumor Volume (TV) was measured with a vernier caliper. The evaluation of the therapeutic effect was carried out based on the relative tumor inhibition ratio (TGI).

Experimental observation indexes and calculation methods are the same as those in Experimental example 2

Results

TABLE 3 treatment with compounds of the invention

Inhibition of allograft model GA0318

Note a. mean. + -. standard error.

Conclusion of the experiment

The compound has obvious tumor growth inhibition effect on a KRAS mutation-containing human allograft model GA 0318.

Claims (17)

1. Use of a compound of formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a crystal form thereof in the preparation of a medicament for treating tumors mediated by KRAS and/or mutants thereof,

wherein the content of the first and second substances,

R¹selected from unsubstituted or substituted by 1 to 2 substituents Q₁Substituted of the following groups: 6-to 10-membered fused ring C_0-6Alkyl, 7-10 membered spirocyclic C_0-6Alkyl or 7-to 10-membered bridged ring C_0-6Alkyl, wherein 1 to 3 carbon atoms in the fused, spiro or bridged ring may be the same or different by 1 to 3 atoms selected from O, S (O)_m、N(H)_m、NCH₃And C (O) but wherein O and C (O) are not adjacent to each other in the ring after the substitution,

Q₁selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, C_1-6Alkyl carbonyloxy, C_1-6Alkylamido radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl radical, C_1-6Alkylsulfonamide group and C_3-8A cycloalkyl group;

R²selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q₂Substituted C_1-6Alkyl or C_1-6Alkoxy radicals, substituted radicals Q₂Substituted formyl or N (H)_m，

Q₂Selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, C_1-6Alkyl carbonyloxy, C_1-6Alkylamido radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl radical, C_1-6Alkylsulfonamido radical, C_3-8Cycloalkyl, unsaturated C_5-7Cycloalkyl and a saturated or unsaturated 3-to 8-membered heterocyclic group, wherein said C_3-8Cycloalkyl, unsaturated C_5-7The cycloalkyl group and the saturated or unsaturated 3-8 membered heterocyclic group may be further substituted by 1 to 2 substituents Q₃The substitution is carried out by the following steps,

Q₃selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, C_1-6Alkyl carbonyloxy, C_1-6Alkylamido radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl radical, C_1-6Alkylsulfonamido and halogen substituted C_1-6An alkoxy group;

R³selected from hydrogen, halogen, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_1-6Alkoxy, halogen substituted C_1-6Alkyl or C_1-6Alkoxy radical, C_1-6Alkyl carbonyloxy, C_1-6Alkylamido radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl or C_1-6An alkylsulfonamide group;

R⁴、R⁵and R⁶Each independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, halogen substituted C_1-6Alkyl or C_1-6Alkoxy radical, C_1-6Alkylamino or di (C)_1-6Alkyl) amino;

l is selected from the group consisting of a covalent bond, O, S (O)_m，N(H)_m，NCH₃Or C (O);

n is selected from 1,2 or 3; and

m is independently selected from 0, 1 or 2.

2. The use according to claim 1, wherein,

R¹selected from unsubstituted or substituted by 1 to 2 substituents Q₁Substituted of the following groups: 6-10 membered saturated fused ring C_0-4Alkyl, 7-10 membered saturated spirocyclic ring C_0-4Alkyl or 7-10 membered saturated bridged ring C_0-4Alkyl, wherein 1 to 3 carbon atoms in the fused, spiro or bridged ring may be the same or different by 1 to 3 atoms selected from O, S (O)_m、N(H)_m、NCH₃And C (O) but wherein O and C (O) are not adjacent to each other in the ring after the substitution,

Q₁selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, C_1-4Alkyl carbonyloxy, C_1-4Alkylamido radical, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfinyl radical, C_1-4Alkylsulfonamide group and C_3-6A cycloalkyl group;

R²selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q₂Substituted C_1-4Alkyl or C_1-4Alkoxy radicals, substituted radicals Q₂Substituted formyl or N (H)_m，

Q₂Selected from the group consisting of: halogen, hydroxy, amino, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, C_1-4Alkyl carbonyloxy, C_1-4Alkylamido radical, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfinyl radical, C_1-4Alkylsulfonamido radical, C_3-6Cycloalkyl, unsaturated C_5-7Cycloalkyl and a saturated or unsaturated 5-to 8-membered heterocyclic group, whereinSaid C is_3-6Cycloalkyl, unsaturated C_5-7The cycloalkyl group and the saturated or unsaturated 5-8 membered heterocyclic group may be further substituted by 1 to 2 substituents Q₃The substitution is carried out by the following steps,

Q₃selected from the group consisting of: halogen, hydroxy, amino, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, C_1-4Alkyl carbonyloxy, C_1-4Alkylamido radical, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfinyl radical, C_1-4Alkylsulfonamido and halogen substituted C_1-4An alkoxy group;

R³selected from halogen, cyano, nitro, C_1-4Alkyl radical, C_1-4Alkoxy, halogen substituted C_1-4Alkyl or C_1-4Alkoxy radical, C_1-4Alkyl carbonyloxy, C_1-4Alkylamido radical, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfinyl or C_1-4An alkylsulfonamide group;

R⁴、R⁵and R⁶Each independently selected from hydrogen, halogen, C_1-4Alkyl radical, C_1-4Alkoxy, halogen substituted C_1-4Alkyl or C_1-4Alkoxy radical, C_1-4Alkylamino or di (C)_1-4Alkyl) amino;

l is selected from the group consisting of a covalent bond, O, S (O)_mOr N (H)_m；

n is selected from 1,2 or 3; and

m is independently selected from 0, 1 or 2.

3. The use according to any one of claims 1 to 2, wherein,

R¹selected from unsubstituted or substituted by 1 to 2 substituents Q₁Substituted of the following groups:

wherein 1 to 3 carbon atoms in the ring may be the same or different by 1 to 3 atoms selected from O, S (O)_m、N(H)_m、NCH₃And C (O), but O and C (O) are not adjacent to each other in the ring after the replacement, p is selected from 0, 1 or 2,

Q₁selected from the group consisting of: halogen, hydroxy, amino, carboxyl, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino and C_3-6A cycloalkyl group;

R²selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q₂Substituted C_1-4Alkyl radicals, substituted radicals Q₂Substituted formyl or N (H)_m，

Q₂Selected from the group consisting of: halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, C_1-4Alkyl carbonyloxy, C_1-4Alkylamido radical, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfonamido radical, C_3-5Cycloalkyl and saturated or unsaturated 5-8 membered heterocyclyl, wherein said C_3-5The cycloalkyl group, saturated or unsaturated 5-8 membered heterocyclic group may be further substituted by 1 to 2 substituents Q₃The substitution is carried out by the following steps,

Q₃selected from the group consisting of: halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, C_1-4Alkyl carbonyloxy, C_1-4Alkylamido radical, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfonamido and halogen substituted C_1-4An alkoxy group;

R³selected from fluorine, chlorine, bromine, C_1-4Alkyl or C_1-4An alkoxy group;

R⁴、R⁵and R⁶Each independently selected from hydrogen, fluorine or chlorine;

l is selectedSelf-covalent bond, O, S (O)_mOr N (H)_m；

n is selected from 1,2 or 3; and

m is selected from 0, 1 or 2.

4. The use according to any one of claims 1 to 3, wherein,

R¹selected from unsubstituted or substituted by 1 to 2 substituents Q₁Substituted of the following groups:

p is selected from the group consisting of 0, 1 or 2,

Q₁selected from the group consisting of: halogen, amino, C_1-4Alkyl radical, C_1-4Alkylamino and di (C)_1-4Alkyl) amino;

R²selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q₂Substituted methyl or ethyl radicals, by substituents Q₂Substituted formyl or N (H)_m，

Q₂Selected from the group consisting of:

(1) halogen, hydroxy, amino, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, acetoxy, acetamido, methylsulfonyl and methylsulfonylamino,

(2) cyclopropyl, cyclopentyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyrazinyl and pyrimidinyl, said Q₂The radicals may be further substituted by 1 to 2 substituents Q₃The substitution is carried out by the following steps,

Q₃selected from the group consisting of: halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino, halogen-substituted C_1-4Alkoxy, acetoxyAcetamido, methylsulfonyl and methylsulfonylamino;

R³selected from fluorine or chlorine;

R⁴、R⁵and R⁶Is hydrogen;

l is selected from a covalent bond or O;

n is 2; and

m is independently selected from 0, 1 or 2.

5. The use according to any one of claims 1 to 4,

R¹selected from:

R²selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q₂A substituted methyl group or an ethyl group,

Q₂selected from the group consisting of:

(1) methoxy and di (C)_1-4Alkyl) amino groups, in the presence of a nitrogen atom,

(2) piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, furanyl, cyclopropylalkyl, cyclopentylalkyl, pyrrolyl, pyridinyl, pyrimidinyl and thiazolyl, said Q₂The radicals may be further substituted by 1 to 2 substituents Q₃The substitution is carried out by the following steps,

Q₃selected from the group consisting of: halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di (C)_1-4Alkyl) amino and halogen substituted C_1-4An alkoxy group;

R³selected from fluorine or chlorine;

R⁴、R⁵and R⁶Is hydrogen;

l is selected from a covalent bond or O; and

n is 2.

6. The use according to any one of claims 1 to 5, wherein,

R¹selected from:

R²selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q₂A substituted methyl group or an ethyl group,

Q₂selected from the group consisting of: methoxy, dimethylamino, diethylamino, piperidinyl, piperazinyl and morpholinyl;

R³selected from fluorine or chlorine;

R⁴、R⁵and R⁶Is hydrogen;

l is selected from a covalent bond or O; and

n is 2.

7. The use according to claim 1, wherein the compound of formula (I) is selected from:

(E) -N- [7- (8-oxabicyclo [3.2.1] octan-3-yloxy) -4- (3-chloro-4-fluoroanilino) quinazolin-6-yl ] -4- (piperidin-1-yl) -2-butenamide,

(E) -N- [7- (7-oxabicyclo [2.2.1] heptan-2-yloxy) -4- (3-chloro-4-fluoroanilino) quinazolin-6-yl ] -4- (piperidin-1-yl) -2-butenamide,

(E) -N- [4- (3-chloro-4-fluoroanilino) -7- (2-methyl-2, 7-diazaspiro [4.5] decan-7-yl) quinazolin-6-yl ] -4- (piperidin-1-yl) -2-butenamide,

n- [4- (3-chloro-4-fluoroanilino) -7- (8-methyl-8-azabicyclo [3.2.1] octan-3-yloxy) quinazolin-6-yl ] -acrylamide,

n- [4- (3-chloro-4-fluoroanilino) -7- (8-methyl-1-oxa-8-azaspiro [4.5] decan-3-yloxy) quinazolin-6-yl ] -acrylamide,

n- [4- (3-chloro-4-fluoroanilino) -7- ((8-methyl-1-oxa-8-azaspiro [4,5] decan-3-yl) methoxy) quinazolin-6-yl ] -acrylamide,

n- [4- (3-chloro-4-fluoroanilino) -7- (8-methyl-1-oxa-8-azaspiro [4,5] decan-2-ylmethoxy) quinazolin-6-yl ] -acrylamide,

n- [4- (3-chloro-4-fluoroanilino) -7- (2- ((1R,5S,6S) -3-methyl-3-azabicyclo [3.1.0] hex-6-ylethoxy) quinazolin-6-yl ] -acrylamide,

n- [4- (3-chloro-4-fluoroanilino) -7- ((2-methyloctahydrocyclopenta [ c ] pyrrol-4-yl) methoxy) quinazolin-6-yl ] -acrylamide,

n- [4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azabicyclo [2.2.1] heptan-2-yl) methoxy) quinazolin-6-yl ] -acrylamide,

n- [4- (3-chloro-4-fluoroanilino) -7- (2- (3-methyl-3-azabicyclo [3.2.1] octan-8-yl) ethoxy) quinazolin-6-yl ] -acrylamide,

n- [4- (3-chloro-4-fluoroanilino) -7- ((5-methyl-5-azaspiro [2.4] heptan-1-yl) methoxy) quinazolin-6-yl ] -acrylamide,

n- [4- (3-chloro-4-fluoroanilino) -7- ((6-methyl-6-azaspiro [2.5] octan-1-yl) methoxy) quinazolin-6-yl ] -acrylamide,

n- [4- (3-chloro-4-fluoroanilino) -7- (2- (6-methyl-6-azaspiro [2.5] octan-1-yl) ethoxy) quinazolin-6-yl ] -acrylamide,

(E) -N- [4- (3-chloro-4-fluoroanilino) -7- (2- ((1R,5S,6S) -3-methyl-3-azabicyclo [3.1.0] hex-6-yl) ethoxy) quinazolin-6-yl ] -2-butenamide,

(E) -N- [4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azaspiro [3.5] nonan-2-yl) methoxy) quinazolin-6-yl ] -2-butenamide,

(E) -N- [4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azaspiro [3.5] nonan-2-yl) methoxy) quinazolin-6-yl ] -2-pentenamide,

n- [4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azaspiro [3.5] nonan-2-yl) methoxy) quinazolin-6-yl ] -acrylamide,

n- [4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azaspiro [3.5] nonan-2-yl) methoxy) quinazolin-6-yl ] -acrylamide dihydrochloride,

n- [4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azaspiro [3.5] nonan-2-yl) methoxy) quinazolin-6-yl ] -acrylamide dihydrochloride monohydrate,

n- [4- (3-chloro-4-fluoroanilino) -7- (2- (7-methyl-7-azaspiro [3.5] nonan-2-yl) ethoxy) quinazolin-6-yl ] -acrylamide,

(E) -N- (4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azaspiro [3.5] nonan-2-yl) methoxy) quinazolin-6-yl) -4-dimethylamino-2-butenamide,

(E) -N- [4- (3-chloro-4-fluoroanilino) -7- ((2- (3-methyl-3-aza-bicyclo [3.1.0] -6-hexyl) -ethoxy) quinazolin-6-yl) -4-dimethylamino ] -crotonamide,

(E) -N- [4- (3-chloro-4-fluoroanilino) -7- (((spiro [3.5] octan-2-yl) methoxy) quinazolin-6-yl) -4-dimethylamino ] -crotonamide, and

(E) -N- (7- (bicyclo [3.1.0] hex-6-ylmethoxy) -4- (3-chloro-4-fluoroanilino) quinazolin-6-yl) -4- (dimethylamino) butyl-2-enamide.

8. The use of any one of claims 1 to 7, wherein the KRAS mutant is selected from mutations at positions G12, G13, K117 or Q61, preferably at position G12.

9. The use of claim 8, wherein the mutation at position KRAS G12 is selected from one or more of G12A, G12D, G12F, G12K, G12N, G12S, G12V, G12Y, G12C, G12E, G12I, G12L, G12R, G12T and G12W, preferably from one or more of G12A, G12D, G12S, G12V, G12C and G12R.

10. The use of any one of claims 1-7, wherein the crystalline form is selected from an isolated crystalline form of the compound of formula (I), a crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), a crystalline form of a solvate of a pharmaceutically acceptable salt of the compound of formula (I), or a co-crystal of the compound of formula (I) with other compound molecules.

11. The use according to claim 10, wherein,

the crystal form of the pharmaceutically acceptable salt of the compound of formula (I) is selected from a hydrochloride crystal form, a phosphate crystal form, a mesylate crystal form, a triflate crystal form, a malate crystal form, a fumarate crystal form, a succinate crystal form, a tartrate crystal form, a benzoate crystal form or a maleate crystal form of the compound of formula (I);

the solvate crystal form of the compound shown in the formula (I) is selected from a hydrate crystal form, a methoxide crystal form, an ethoxide crystal form, an ether crystal form and an acetonide crystal form of the compound shown in the formula (I);

the solvate crystalline form of the pharmaceutically acceptable salt of the compound of formula (I) is selected from the hydrochloride hydrate crystalline form, the hydrochloride methoxide crystalline form, the hydrochloride etherate crystalline form, the benzoate hydrate crystalline form, the benzoate methoxide crystalline form, the benzoate etherate crystalline form, the maleate hydrate crystalline form, the maleate methoxide crystalline form, or the maleate etherate crystalline form of the compound of formula (I);

the co-crystal of the compound of the formula (I) is selected from co-crystals formed by the compound of the formula (I) and one or more of proline, gallic acid, oxalic acid, maleic acid, tartaric acid and saccharin.

12. Use of a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a crystalline form thereof, optionally together with one or more other anti-neoplastic agents, in the manufacture of a medicament for the treatment of a tumour mediated by KRAS and/or mutants thereof.

13. Use according to claim 12, wherein the further antineoplastic agent is selected from the group consisting of antimetabolites, growth factor inhibitors, antibodies, mitotic inhibitors, antineoplastic hormones, alkylating agents, metalloplatins, topoisomerase inhibitors, immunosuppressions.

14. The use of any one of claims 1-13, wherein the tumor is selected from one or more of pancreatic cancer, colorectal cancer, lung cancer, multiple myeloma, melanoma, brain cancer, head and neck cancer, thyroid cancer, oral cancer, esophageal adenocarcinoma, gastric cancer, liver cancer, bile duct cancer, kidney cancer, peritoneal cancer, gall bladder cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, epidermal cancer, non-hodgkin's lymphoma, glioma, glioblastoma.

15. Use according to any one of claims 1 to 13, wherein the tumour is selected from non-small cell lung cancer, preferably wherein the non-small cell lung cancer is selected from one or more of large cell lung cancer, lung adenocarcinoma or lung squamous carcinoma.

16. Use of a pharmaceutical preparation of a compound of formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a crystal form thereof in the preparation of a medicament for treating a patient with a tumor mediated by KRAS and/or a mutant thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R⁶L and n are as defined in claim 1.

17. Use of a combination of a compound of formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a crystal form thereof and one or more other anti-tumor drugs in the preparation of a medicament for treating a patient with a tumor mediated by KRAS and/or a mutant thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R⁶L and n are as defined in claim 1.