CN112824410A - Aza-heptacyclic inhibitor and preparation method and application thereof - Google Patents
Aza-heptacyclic inhibitor and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to an aza-heptacyclic inhibitor and a preparation method and application thereof. Specifically, the compound has a structure shown in a formula (I), and the invention also discloses a preparation method of the compound and application of the compound as KRASG12CUse of inhibitors of KRASG12CHas good selective inhibition effect, better pharmacodynamics and pharmacokinetic performance and lower toxic and side effect.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to an aza-heptacyclic inhibitor, and a preparation method and application thereof.
Background
Lung cancer is one of the leading causes of death in human cancers. Lung cancer can be divided into Small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, with NSCLC accounting for 85% of all lung cancer patients. The global NSCLC market was statistically estimated to be $ 209 billion in 2016, with the U.S. market taking up half, followed by Japan, Germany, and China. From the current trend, the market for non-small cell lung cancer is continuing to grow, and the global market is expected to reach $ 540 billion in 2023 (Nature, 2018; 553(7689):446- > 454).
At present, the main therapeutic drugs for NSCLC include chemotherapeutic drugs, molecular targeted drugs, tumor immunotherapy and the like. The chemotherapy drugs mainly comprise gemcitabine, paclitaxel, platinum drugs and the like, but the drugs generally have poor selectivity and high toxicity, so that relatively strong toxic and side effects are caused. In recent years, molecular targeted drugs have become research hotspots due to the obvious advantages of high selectivity, relatively small toxic and side effects, accurate treatment and the like. Existing NSCLC molecular targeted drugs include EGFR inhibitors (e.g., afatinib, gefitinib, erlotinib, lapatinib, dacatinib, icotinib, pyrroltinib, rolatinib, ocitinib, etc.), ALK inhibitors (e.g., ceritinib, erlotinib, bugatitinib, loratinib, ocatinib, etc.), and VEGFR inhibitors (sorafenib, regoratinib, cabozitinib, sunitinib, doranib, etc.) (Current Medicinal Chemistry,2019,26, 1-39).
In lung cancer patients, KRAS mutations are often detected, accounting for approximately 32% of all oncogene mutations. Wherein KRASG12CMutations account for 44% of all oncogene mutations within NSCLC. To date, the market has not been targeted to KRASG12CMutated drugs are approved for marketing.
Due to KRASG12CThe target proteins are pathologically associated with a variety of diseases, and there is therefore a need for novel KRASG12CThe inhibitor is used for clinical treatment. KRAS with high selectivity and high activityG12CThe inhibitor may be on KRASG12CThe mutation-induced diseases such as cancer are more effectively treated, and the off-target effect potential is reduced, so that the clinical requirement is more urgent.
Disclosure of Invention
In a first aspect of the present invention, there is provided an aza-heptacyclic compound having a structure of general formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof:
in the formula:
A. b are the same or different and are each independently selected from: CH. CR5Or N;
C. d, E, F are the same or different and are each independently selected from the group consisting of: o, S, SO2、CO、CH、CR3aR3b、N、NH、NR3a(ii) a C. D, E, N, F and the adjacent two on the pyrimidine ring to which they are attachedCarbon forms a seven-membered ring; wherein R is3aAnd R3bEach independently selected from the group consisting of: hydrogen, deuterium, oxygen, halogen, hydroxy, cyano, C1-C6Alkyl radical, C1-C6An alkoxy group; or R3aAnd R3bAnd the carbon atoms bound to form C3-C6Cycloalkyl or 4-6 membered heterocyclyl; wherein the seven membered ring may be further substituted;
x is independently selected from the group consisting of: 4-14 membered saturated or unsaturated nitrogen heterocycle or heterocyclyl, C6-C14Aryl or 5-14 membered heteroaryl, wherein said saturated or unsaturated nitrogen heterocycle or heterocyclyl, aryl or heteroaryl may optionally be substituted with one or more R8Substituted; r8Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C18Alkyl, deuterated C1-C18Alkyl, halo C1-C18Alkyl radical, C3-C20Cycloalkyl radical, C1-C18Alkoxy, deuterated C1-C18Alkoxy, halo C1-C18Alkoxy, amino, hydroxy, 4-20 membered heterocyclic group, C6-C14Aryl, 5-14 membered heteroaryl;
y is independently selected from the group consisting of: bond, O, S, NH, NR5、CR5R6、CONH、CONR5、SO2NH、SO2NR5、NHCO、NR5CO、NHSO2、NR5SO2；
Z is independently selected from the group consisting of: key, C1-C18Alkylene, deuterated C1-C18Alkylene, halogeno C1-C18Alkylene radical, C3-C20Cycloalkylene, 4-20 membered heterocyclylene, C1-C18Alkyleneoxy, deuterated C1-C18Alkyleneoxy, halogeno C1-C18An alkyleneoxy group;
w is independently selected from the group consisting of: bond, O, NH, NR5、CONH、CONR5、SO2NH、SO2NR5、NHCO、NHSO2、NHCONH、NR5CONH、NHCONR5、NR5CONR6、NHSO2NH、NR5SO2NH、NHSO2NR5、NR5SO2NR6；
When B is N, R1Independently selected from:
or
Wherein the content of the first and second substances,
represents a double or triple bond;
when B is selected from CH or CR5，R1Independently selected from:
or
Wherein the content of the first and second substances,
represents a double or triple bond;
RAis absent or is independently selected from the group consisting of: hydrogen, deuterium, fluoro, cyano, or C1-C3An alkyl group; rBIndependently selected from the group consisting of: hydrogen, deuterium, cyano, or C1-C3An alkyl group; wherein, the C1-C3The alkyl group may be substituted with one or more substituents selected from the group consisting of: deuterium, halogen, cyano, amino, C3-C7Cycloalkyl, 4-7 membered heterocyclyl, NHR9Or NR9R10；R9、R10Each independently is C1-C3An alkyl group;
R2independently selected from the group consisting of: - (CH)2)nR7、-(CH2)nO(CH2)qR7、-(CH2)nSR7、-(CH2)nCOR7、-(CH2)nC(O)OR7、-(CH2)nS(O)qR7、-(CH2)nNR5R7、-(CH2)nC(O)NR5R7、-(CH2)nNR5C(O)R7、-(CH2)nNR5C(O)NR5R7、-(CH2)nS(O)qNR5R7、-(CH2)nNR5S(O)qR7Or- (CH)2)nNR5S(O)qNR5R7In which CH2H in (a) may be substituted; r7Selected from the group consisting of: substituted or unsubstituted C1-C18Alkyl, substituted or unsubstituted C3-C20Cycloalkyl, or a substituted or unsubstituted 4-20 membered heterocyclyl;
l is selected from the group consisting of: a bond, -C (O) -, C1-C3An alkylene group;
R4independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C18Alkyl, deuterated C1-C18Alkyl, halo C1-C18Alkyl radical, C3-C20Cycloalkyl radical, C1-C18Alkoxy, deuterated C1-C18Alkoxy, halo C1-C18Alkoxy, amino, hydroxy, 4-20 membered heterocyclic group, C6-C14Aryl, 5-14 membered heteroaryl;
R5and R6The same or different, and each is independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C18Alkyl, deuterated C1-C18Alkyl, halo C1-C18Alkyl radical, C3-C20Cycloalkyl radical, C1-C18Alkoxy, deuterated C1-C18Alkoxy, halo C1-C18Alkoxy, halogen, amino, hydroxy, cyano, amino, 4-20 membered heterocyclyl, C6-C14Aryl, 5-14 membered heteroaryl;
wherein said substitution is by one or more groups selected from the group consisting of: hydrogen, deuterium, C1-C18Alkyl, deuterated C1-C18Alkyl, halo C1-C18Alkyl radical, C3-C20Cycloalkyl radical, C1-C18Alkoxy, deuterated C1-C18Alkoxy, halo C1-C18Alkoxy radical, C6-C14Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;
n is an integer of 0, 1, 2,3, 4 or 5;
p is an integer of 1 or 2;
q is an integer of 0, 1, 2,3, 4 or 5.
In another preferred embodiment, C, D, E, F are the same or different and are each independently selected from the group consisting of: o, S, SO2、CO、CH、CR3aR3b、N、NH、NR3a(ii) a C. D, E, N, F and the two adjacent carbons on the pyrimidine ring to which they are attached form a 7-membered heterocyclic group; wherein R is3aAnd R3bEach independently selected from the group consisting of: hydrogen, deuterium, oxygen, halogen, hydroxy, cyano, C1-C6Alkyl radical, C1-C6An alkoxy group; or R3aAnd R3bAnd the carbon atoms bound to form C3-C6Cycloalkyl or C3-C6A heterocyclic group of (a); wherein said 7 membered heterocyclyl may be further substituted; wherein said substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C1-C6Alkyl, deuterated C1-C6Alkyl, halo C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, deuterated C1-C6Alkoxy, halo C1-C6Alkoxy radical, C6-C10Aryl, 5-to 10-membered heteroaryl, 4-to 6-membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amino, amido,Sulfonamide or ureido.
In another preferred embodiment, E is SO2。
In another preferred embodiment, D is SO2。
In another preferred embodiment, E is CO.
In another preferred embodiment, C is CR3aR3bAnd R is3aAnd R3bAnd the carbon atoms bound to form C3-C6Cycloalkyl or C4-C6The heterocyclic group of (1).
In another preferred embodiment, L is a bond.
In another preferred embodiment, Y is O.
In another preferred embodiment, X is independently a 4-14 membered saturated or unsaturated nitrogen heterocycle, wherein said saturated or unsaturated nitrogen heterocycle may optionally be substituted with one or more R8Substituted, R8Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C6Alkyl, deuterated C1-C6Alkyl, halo C1-C6Alkyl radical, C1-C6Alkoxy, deuterated C1-C6Alkoxy, halo C1-C6Alkoxy, amino, hydroxy, 4-7 membered heterocyclic group, C6-C14Aryl, 5-14 membered heteroaryl; the substitutions are selected from the group consisting of: halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea groups.
In another preferred embodiment, R8Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C6Alkyl, deuterated C1-C6Alkyl, halo C1-C6Alkyl radical, C1-C6Alkoxy, deuterated C1-C6Alkoxy, halo C1-C6Alkoxy, amino, hydroxy, 4-7 membered heterocyclic group, C6-C14Aryl, 5-14 membered heteroaryl; the substitutions are selected from the group consisting of: halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea groups.
In another preferred embodiment, R8Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C3Alkyl, deuterated C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy, deuterated C1-C3Alkoxy, halo C1-C3Alkoxy, amino, hydroxy, 4-7 membered heterocyclyl, phenyl, pyrimidinyl, pyridyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl; the substitutions are selected from the group consisting of: halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea groups.
In another preferred embodiment, Y is independently selected from the group consisting of: bond, O, S, NH, NR5、CR5R6、CONH、CONR5、SO2NH、SO2NR5、NHCO、NR5CO、NHSO2、NR5SO2；R5Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C6Alkyl, deuterated C1-C6Alkyl, halo C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, deuterated C1-C6Alkoxy, halo C1-C6Alkoxy, amino, hydroxy, C3-C6Cycloalkyl, 4-7 membered heterocyclyl, C6-C14Aryl, 5-14 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: hydrogen, deuterium, C1-C6Alkyl, deuterated C1-C6Alkyl, halo C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, deuterated C1-C6Alkoxy, halo C1-C6Alkoxy radical, C6-C10Aryl, 5-14 membered heteroaryl, 4-7 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido.
In another preferred embodiment, Z is independently selected from the group consisting of: key, C1-C6Alkylene, deuteriumGeneration C1-C6Alkylene, halogeno C1-C6Alkylene radical, C3-C6Azacycloalkylene, 4-7 membered heterocyclylene, C1-C6Alkyleneoxy, deuterated C1-C6Alkyleneoxy, halogeno C1-C6An alkylene oxide group.
In another preferred embodiment, W is independently selected from the group consisting of: bond, O, NH, NR5、CONH、CONR5、SO2NH、SO2NR5、NHCO、NHSO2、NHCONH、NR5CONH、NHCONR5、NR5CONR6、NHSO2NH、NR5SO2NH、NHSO2NR5、NR5SO2NR6；R5And R6The same or different, and each is independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C6Alkyl, deuterated C1-C6Alkyl, halo C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, deuterated C1-C6Alkoxy, halo C1-C6Alkoxy, amino, hydroxy, C3-C6Cycloalkyl, 4-7 membered heterocyclyl, C6-C14Aryl, 5-14 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: hydrogen, deuterium, C1-C6Alkyl, deuterated C1-C6Alkyl, halo C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, deuterated C1-C6Alkoxy, halo C1-C6Alkoxy radical, C6-C14Aryl, 5-14 membered heteroaryl, 4-7 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido.
In another preferred embodiment, R4Independently selected from the group consisting of substituted or unsubstituted: c1-C6Alkyl, deuterated C1-C6Alkyl, halo C1-C6Alkyl, aryl, heteroaryl, and heteroaryl,C3-C12Cycloalkyl radical, C1-C6Alkoxy, deuterated C1-C6Alkoxy, halo C1-C6Alkoxy, amino, hydroxy, 4-12 membered heterocyclic group, C6-C14Aryl, 5-14 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: hydrogen, deuterium, C1-C6Alkyl, deuterated C1-C6Alkyl, halo C1-C6Alkyl radical, C3-C12Cycloalkyl radical, C1-C6Alkoxy, deuterated C1-C6Alkoxy, halo C1-C6Alkoxy, phenyl, pyrimidinyl, pyridyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 4-12 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amino, amide, sulfonamide, or ureido.
In another preferred embodiment, R2Independently selected from the group consisting of: - (CH)2)nR7、-(CH2)nO(CH2)qR7、-(CH2)nSR7、-(CH2)nCOR7、-(CH2)nC(O)OR7、-(CH2)nS(O)qR7、-(CH2)nNR5R7、-(CH2)nC(O)NR5R7、-(CH2)nNR5C(O)R7、-(CH2)nNR5C(O)NR5R7、-(CH2)nS(O)qNR5R7、-(CH2)nNR5S(O)qR7Or- (CH)2)nNR5S(O)qNR5R7In which CH2H in (a) may be substituted; and R is7Selected from: substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6Cycloalkyl or a substituted or unsubstituted 4-7 membered heterocyclyl; wherein, CH2H in (1) may be substituted；R7Selected from the group consisting of: substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6Cycloalkyl, or a substituted or unsubstituted 4-7 membered heterocyclyl; r5Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C6Alkyl, deuterated C1-C6Alkyl, halo C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, deuterated C1-C6Alkoxy, halo C1-C6Alkoxy, amino, hydroxy, C3-C6Cycloalkyl, 4-7 membered heterocyclyl, C6-C14Aryl, 5-14 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: hydrogen, deuterium, C1-C6Alkyl, deuterated C1-C6 alkyl, halo C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, deuterated C1-C6Alkoxy, halo C1-C6Alkoxy radical, C6-C14Aryl, 5-14 membered heteroaryl, 4-7 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido; n is an integer of 0, 1, 2,3, 4 or 5; q is an integer of 0, 1, 2,3, 4 or 5.
In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has a structure shown in a general formula (II-A) or (II-B):
in the formula:
R1、R2、R4A, B, X, Y, Z, L, W, C, D, E, F are as defined above.
In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has a structure shown in the general formula (III):
R1、R2、R4x, Y, Z, L, W, C, D, E, F are as defined above.
In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has a structure shown in a general formula (IV-a):
R1、R2、R3a、R3b、R4x, Y, Z, L, W are as defined above.
In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has a structure shown in a general formula (IV-B):
R1、R2、R4x, Y, Z, L, W are as defined above.
In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has a structure shown in a general formula (V):
R1、R2、R4x, Z, W, C, D, E, F are as defined above.
In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has the structure shown in the general formula (VI):
in the formula:
R1、R2、R4、R8y, Z, L, W, C, D, E, F are as defined above.
In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has a structure shown in a general formula (VII):
in the formula:
R1、R2、R4、R8y, Z, W, C, D, E, F are as defined above.
In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has a structure shown in a general formula (VIII):
in the formula:
R1、R2、R4、R8z, W, C, D, E, F are as defined above.
In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has the structure shown in the general formula (XII):
wherein R is1、R2、R4、R8C, D, E, F are as defined above.
In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has a structure shown in a general formula (IX-a) or (IX-B):
in the formula:
R1、R2、R4、R5、R8Z, C, D, E, F are as defined above.
In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is selected from the group consisting of:
in a second aspect of the present invention, there is provided a process for preparing an aza heptacyclic compound having a structure of formula (IV-B), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, comprising the steps of:
(i) under the action of a first alkali, reacting the compound of the formula X-1 with one amino group in a molecule of a diamine compound, and then reacting with an amino protective agent to generate a compound of the formula X-2;
(ii) reacting the compound of formula X-2 with a second base to produce a compound of formula X-3;
(iii) under the action of a deprotection agent, the compound shown in the formula X-3 is subjected to deprotection to generate a compound shown in the formula X-4;
(iv) the compound of the formula X-4 is subjected to coupling, substitution or acylation reaction to obtain a compound of a formula X-5;
(v) under the action of acid, deprotecting the compound of formula X-5 to produce a compound of formula X-6;
(vii) the compound shown in the formula (IV-B) is obtained by the substitution or acylation reaction of the formula X-6;
in the formula (I), the compound is shown in the specification,
rs and Rs' are protecting groups for amino groups selected from: boc, Bn, Cbz or Fmoc;
the deprotection agent is selected from: (Boc)2O, benzyl chloroformate, di-tert-butyl dicarbonate, phthaloyl chloride, benzyl chloride, triphenylchloromethane, 9-fluorenylmethyl chloroformate and allyl chloroformate.
R1、R2、R4L, X, Y, Z, W are as defined above.
In another preferred embodiment, in step (i), the first base is TEA or DIPEA.
In another preferred embodiment, in step (ii), the second base is sodium alkoxide, potassium alkoxide, NaH or LiHNMDS, preferably sodium tert-butoxide or potassium tert-butoxide.
In another preferred embodiment, in step (v), the acid is TFA.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising one or more compounds of the structure of formula (I) according to the first aspect, stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof; and a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the group consisting of:
PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemipimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009, or the like biologically similar to the above drugs), PD-L1 inhibitors (e.g., Duvalimab, alemtuzumab, Avelumab (avelumab), CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR, MSB2311, or the like biologically similar to the above drugs), CD20 antibodies (e.g., rituximab, otuzumab, ofatumumab, ovuzumab, vetutumumab, tositumumab, 131I-tositumomab, ibritumomab, 90-Ititutentitiu 90, Iitumomab, In-90, and In-5956, or the like), and the like, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01, ALK inhibitors (e.g., Ceritinib, Aleptinib, Bugatinib, Laratinib, Ocatinib), PI3K inhibitors (e.g., Idiranib, Duvelisib, Dactlisib, Taselisib, Bimiralisib, Omipalisib, Bupalisib, etc.), BTK inhibitors (e.g., Ibrutinib, Tirabutinib, Acatinib, Zabritinib, Vebrutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, erlotinib, Lapatinib, Darkatinib, Icotinib, Netinib, Sapatinib, Napatinib, pyrroltinib, Hirtitinib, HDAC, erlotinib, Galatinib, e, Galatinib, e, vorinostat, fimepinastat, drosrinostat, entinostat, daciclast, Quisinostat, tacrine, etc.), CDK inhibitors (e.g., palbociclib, ribbociclib, Abemaciclib, micciib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (e.g., semetinib (AZD6244), trametinib (GSK1120212), PD0325901, seru 0126, pimatiib (AS-703026), PD184352(CI-1040), etc.), mTOR inhibitors (e.g., vistuertib, etc.), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, etc.), or combinations thereof.
In another preferred embodiment, there is provided a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of the general formula (I), a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug of the invention, thereby forming the pharmaceutical composition.
In a fourth aspect of the invention, there is provided an aza compound of the first aspect having the structure of formula (I)Use of a heptacyclic compound, a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, or a pharmaceutical composition according to the third aspect, for the preparation of a medicament for the prophylaxis and/or treatment of KRASG12COr an expression level of the compound (b).
In another preferred embodiment, the disease is a tumor or a dysregulated disease.
In another preferred embodiment, the disease is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, leukemia, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, and skin cancer.
In a fifth aspect of the invention, an in vitro inhibitor for KRAS is providedG12CThe method comprises the following steps: contacting a compound of the first aspect, a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, or a composition of the third aspect, with a somatic cell.
In another preferred embodiment, the somatic cells are from a primate (e.g., human).
In a sixth aspect of the invention, there is provided a method of preventing and/or treating KRASG12CA disease associated with the activity or expression level of (a), which comprises the steps of: administering to a patient in need thereof an effective amount of a compound of general formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, as described above, or administering a pharmaceutical composition as described above.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The present inventors have made extensive and intensive studies and have unexpectedly prepared a novel class of KRASG12CSelective inhibition and/orCompounds with good pharmacodynamic properties. On this basis, the inventors have completed the present invention.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Term(s) for
In the present invention, unless otherwise specified, the terms used have the ordinary meanings well known to those skilled in the art.
The term "alkyl" refers to straight or branched chain or cyclic alkyl groups, such as methyl, ethyl, propyl, isopropyl
N-butyl, t-butyl, isobutyl (e.g. butyl, isobutyl)
N-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl. "substituted alkyl" means an alkyl group which is substituted at one or more positions, especially 1 to 4 substituents, and may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalo substituents, the latter such as trifluoromethyl or containing Cl3Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe,P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe、NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)RaOr NRbP(＝O)2ReWherein R is present thereinaMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, Rb、RcAnd RdMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or RbAnd RcTogether with the N atom may form a heterocyclic ring; reMay independently represent hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted.
The term "alkylene" refers to a group formed by removing a hydrogen atom from an "alkyl" group, such as methylene, ethylene, propylene, isopropylene (e.g.
Butylene (e.g. of
Pentylene radicals (e.g. ethylene glycol)
Hexamethylene (e.g. hexamethylene)
Heptylene (e.g. heptylene)
) And the like.
The term "cycloalkyl" refers to a fully saturated or partially saturated cyclic hydrocarbon group, comprising 1 to 4 rings, each ring containing 3 to 8 carbon atoms. Cycloalkyl radical is excellentC3-20 cycloalkyl is selected, more preferably C3-12 cycloalkyl, more preferably C3-8 cycloalkyl, more preferably C5-6 cycloalkyl. "substituted cycloalkyl" means that one or more positions in the cycloalkyl group are substituted, especially 1 to 4 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalo substituents, the latter such as trifluoromethyl or containing Cl3Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe、P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe,NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)RaOr NRbP(＝O)2ReWherein R is present thereinaMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, Rb、RcAnd RdMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or RbAnd RcTogether with the N atom may form a heterocyclic ring; reMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include spiro, bridged or fused ring substituents, especially spirocycloalkyl, spiroalkenyl, spiroheterocycle (excluding heteroaryl rings), bridged cycloalkyl, fused,A bridged alkenyl group, a bridged heterocyclic ring (excluding the heteroaromatic ring), a fused ring alkyl group, a fused ring alkenyl group, a fused ring heterocyclic group, or a fused ring aromatic ring group, and the above cycloalkyl group, cycloalkenyl group, heterocyclic group, and heterocyclic aryl group may be optionally substituted.
The term "cycloalkylene" refers to a group formed by a cycloalkyl group minus two hydrogen atoms, such as:
and the like.
The term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, e.g., a 3-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic ring system) in which at least one heteroatom is present in the ring having at least one carbon atom. Each heteroatom-containing heterocyclic ring may carry 1, 2,3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, wherein the nitrogen or sulfur atoms may be oxidized and the nitrogen atoms may also be quaternized. The heterocyclic group may be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule. The heterocyclic group is preferably a 3-20-membered heterocyclic group, more preferably a 3-12-membered heterocyclic group, more preferably a 3-8-membered heterocyclic group, more preferably a 5-6-membered heterocyclic group. Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidyl, tetrahydropyranyl, morphinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxanyl, and tetrahydro-1, 1-dioxythiophene, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or are further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms on the rings; the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate.
The term "seven-membered ring" includes seven-membered cycloalkyl, seven-membered heterocyclyl, wherein cycloalkyl, heterocyclyl are as defined above.
The term "heterocyclylene" refers to a group formed by a heterocyclyl group with two hydrogen atoms removed, such as:
and the like.
The term "aryl" refers to aromatic cyclic hydrocarbon groups having 1 to 5 rings, especially monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. Where the aromatic ring contains two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be linked by a single bond (e.g., biphenyl), or fused (e.g., naphthalene, anthracene, etc.). "substituted aryl" means that one or more positions in the aryl group are substituted, especially 1 to 3 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalo substituents, the latter such as trifluoromethyl or containing Cl3Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe、P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe,NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)RaOr NRbP(＝O)2ReWherein R is present thereinaMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, Rb、RcAnd RdMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or RbAnd RcTogether with the N atom may form a heterocyclic ring; reMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclyl or fused ring aromatic ring groups, which cycloalkyl, cycloalkenyl, heterocyclyl and heterocyclylaryl groups may be optionally substituted.
The term "heteroaryl" refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. The heteroaryl group is preferably a 5-to 10-membered ring, more preferably a 5-or 6-membered ring, for example, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl and the like. "heteroaryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate.
The term "alkoxy" refers to straight or branched chain or cyclic alkoxy groups, preferably C1-C8 alkoxy groups, more preferably C1-C6 alkoxy groups, more preferably C1-C3 alkyleneoxy groups, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. .
The term "alkyleneoxy" refers to a group resulting from the removal of one hydrogen atom from an "alkoxy" group. Preferably C1-C6 alkyleneoxy groups, more preferably C1-C3 alkyleneoxy groups.
The term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.
The term "halo" means substituted with halogen.
The term "deuterated" refers to a substitution by deuterium.
The term "hydroxy" refers to a group with the structure OH.
The term "nitro" refers to a group with the structure NO2A group of (1).
The term "cyano" refers to a group with the structure CN.
The term "ester group" refers to a group with the structure-COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic.
The term "amine" refers to a group having the structure-NRR ', where R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' may be the same or different in the dialkylamine fragment.
The term "amido" refers to a group with the structure-CONRR ', where R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle as defined above. R and R' may be the same or different in the dialkylamine fragment.
The term "sulfonamide" refers to a sulfonamide group having the structure-SO2NRR 'wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic as hereinbefore defined. R and R' may be the same or different in the dialkylamine fragment.
The term "ureido" refers to a group having the structure — NRCONR 'R ", where R, R' and R" may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R, R' and R "may be the same or different in the dialkylamine fragment.
The term "plurality" means two or more.
In the present invention, the term "substituted" means that one or more hydrogen atoms on a specified group are replaced with a specified substituent. Particular substituents are those described correspondingly in the foregoing, or as appearing in the examples. Unless otherwise specified, a certain substituted group may have one substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 member heterocyclyl, C6-C10 aryl, 5-14 member heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, C1-C6 ureido, and the like.
Unless otherwise stated, it is assumed that any heteroatom that is not in a valence state has sufficient hydrogen to replenish its valence state.
When the substituent is a non-terminal substituent, it is a subunit of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl corresponds to heterocyclylene, alkoxy corresponds to alkyleneoxy, and the like.
The salts which the compounds of the invention may form are also within the scope of the invention. Unless otherwise indicated, the compounds of the present invention are understood to include salts thereof. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in either an acidic or basic form. Furthermore, when a compound of the present invention contains a basic moiety, including but not limited to pyridine or imidazole, and an acidic moiety, including but not limited to carboxylic acid, zwitterions ("inner salts") that may form are included within the scope of the term "salt(s)". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps during manufacture. The compounds of the invention may form salts, for example, by reacting compound I with an amount of acid or base, e.g. an equivalent amount, and salting out in a medium, or lyophilizing in an aqueous solution.
The compounds of the invention may contain basic moieties, including but not limited to amine or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids which may form salts include acetates (e.g. with acetic acid or trihaloacetic acid such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, diglycolates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptonates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g. 2-hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g. 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g. 3-phenylpropionates), phosphates, propionates, citrates, and the like, Picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates, e.g., p-toluenesulfonate, dodecanoate, and the like
Acidic moieties that certain compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases. Typical salts with bases include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts with organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydrabamine (salt with N, N-bis (dehydroabietyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, and salts with amino acids such as arginine, lysine, and the like. The basic nitrogen-containing groups may be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenyl bromides), and the like.
Prodrugs and solvates of the compounds of the invention are also contemplated. The term "prodrug" as used herein refers to a compound that undergoes chemical conversion by metabolic or chemical processes to yield a compound, salt, or solvate of the present invention when used in the treatment of a related disease. The compounds of the present invention include solvates, such as hydrates.
The compounds, salts or solvates of the invention may exist in tautomeric forms (e.g. amides and imino ethers). All of these tautomers are part of the present invention.
All stereoisomers of the compounds (e.g., those asymmetric carbon atoms that may exist due to various substitutions), including enantiomeric and diastereomeric forms thereof, are contemplated within the invention. The individual stereoisomers of the compounds of the invention may not be present in combination with the other isomers (e.g. as a pure or substantially pure optical isomer having a particular activity), or may be present as a mixture, e.g. as a racemate, or as a mixture with all or a portion of the other stereoisomers. The chiral center of the invention has two S or R configurations, and is defined by the International Union of theory and applied chemistry (IUPAC) proposed in 1974. The racemic forms can be resolved by physical methods such as fractional crystallization, or by separation of the crystals by derivatization into diastereomers, or by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including, but not limited to, conventional methods such as salt formation with an optically active acid followed by crystallization.
The compounds of the present invention, obtained by preparing, isolating and purifying the compound in sequence, have a weight content of 90% or more, for example, 95% or more, 99% or more ("very pure" compounds), as set forth in the text. Such "very pure" compounds of the invention are also part of the invention herein.
All configurational isomers of the compounds of the invention are within the scope of the invention, whether in mixture, pure or very pure form. The definition of compounds in the present invention encompasses both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.
Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
Specific functional groups and definitions of chemical terms are detailed below. For purposes of the present invention, the chemical Elements are compatible with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics,75thD. as defined in. The definition of a particular functional group is also described herein. In addition, the basic principles of Organic Chemistry, as well as specific functional groups and reactivities are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, which is incorporated by reference in its entirety.
Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomer, (L) isomer, racemic mixtures and other mixtures thereof. Further the asymmetric carbon atom may represent a substituent such as an alkyl group. All isomers, as well as mixtures thereof, are encompassed by the present invention.
According to the present invention, the mixture of isomers may contain a variety of isomer ratios. For example, in a mixture of only two isomers, the following combinations are possible: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, all ratios of isomers are within the scope of the invention. Similar ratios, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention, as would be readily understood by one of ordinary skill in the art.
The invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as the original compound. In practice, however, it will often occur that one or more atoms are replaced by an atom having a different atomic weight or mass number. Examples of isotopes that can be listed as compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F and36and (4) Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, wherein isotopes or other isotopic atoms containing such compounds are within the scope of the present invention. Certain isotopically-labelled compounds of the invention, e.g.3H and14among these, the radioactive isotope of C is useful in tissue distribution experiments of drugs and substrates. Tritium, i.e.3H and carbon-14, i.e.14C, their preparation and detection are relatively easy. Is the first choice among isotopes. In addition, heavier isotopes such as deuterium, i.e.2H, due to its good metabolic stability, may be advantageous in certain therapies, such as increased half-life in vivo or reduced dose, and therefore, may be preferred in certain circumstances. Isotopically labeled compounds can be prepared by conventional methods by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent using the protocols disclosed in the examples.
If it is desired to design the synthesis of a particular enantiomer of a compound of the invention, it may be prepared by asymmetric synthesis or by derivatization with chiral auxiliary agents, separation of the resulting diastereomeric mixture and removal of the chiral auxiliary agent to give the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed therewith with an appropriate optically active acid or base, and the isolated enantiomers can be obtained in pure form by conventional means such as fractional crystallization or chromatography.
As described herein, the compounds of the present invention can be extended in their inclusion range with any number of substituents or functional groups. In general, the term "substituted", whether occurring before or after the term "optional", in the formula of the present invention including substituents, means that the hydrogen radical is replaced with a substituent of the indicated structure. When a plurality of the specified structures are substituted at a position with a plurality of the specified substituents, each position of the substituents may be the same or different. The term "substituted" as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any permissible organic compound described hereinabove to supplement its valence state. Furthermore, the present invention is not intended to be limited in any way as to the permissible substitution of organic compounds. The present invention recognizes that the combination of substituents and variable groups is excellent in the treatment of diseases, such as infectious diseases or proliferative diseases, in the form of stable compounds. The term "stable" as used herein refers to compounds that are stable enough to maintain the structural integrity of the compound when tested for a sufficient period of time, and preferably are effective for a sufficient period of time, and are used herein for the purposes described above.
Metabolites of the compounds and pharmaceutically acceptable salts thereof to which this application relates, and prodrugs that can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof to which this application relates, are also included in the claims of this application.
Preparation method
The process for the preparation of the compounds of formula (VI) according to the invention is described in more detail below, but these particular processes do not constitute any limitation to the invention. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
Typically, the process for the preparation of the compounds of the present invention is as follows, wherein the starting materials and reagents used are commercially available without specific reference.
The compound of the general formula (X-1) is reacted with a base (such as TEA or DIPEA) to generate an intermediate general formula (X-2); then obtaining an intermediate (X-3) through a substitution reaction; deprotection of the protecting group Rs produces intermediate (X-4); the compound (X-4) is coupled or substituted or acylated to obtain an intermediate (X-5); deprotection of the group Rs' yields intermediate (X-6); then obtaining a target product general formula (IV-B) through substitution or acylation reaction; wherein R is1、R2、R4Y, Z, W, X and L are as defined above, and Rs' are amino protecting groups (e.g., Boc, Bn, Cbz or Fmoc).
Pharmaceutical compositions and methods of administration
The pharmaceutical composition of the invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immunological disease, and metabolic disease.
The compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the mode of administration and dosage of the original drug may be maintained unchanged while the compound of formula I is administered simultaneously or subsequently. When the compound of formula I is administered simultaneously with one or more other drugs, it may be preferable to use a pharmaceutical composition containing both one or more known drugs and the compound of formula I. The pharmaceutical combination also includes administration of the compound of formula I in an overlapping time period with one or more other known drugs. When a compound of formula I is administered in a pharmaceutical combination with one or more other drugs, the dose of the compound of formula I or the known drug may be lower than the dose at which they are administered alone.
Drugs or active ingredients that may be used in combination with the compounds of formula (I) include, but are not limited to: PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemipimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009, or the like biologically similar to the above drugs), PD-L1 inhibitors (e.g., Duvalimab, alemtuzumab, Avelumab (avelumab), CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR, MSB2311, or the like biologically similar to the above drugs), CD20 antibodies (e.g., rituximab, otuzumab, ofatumumab, ovuzumab, vetutumumab, tositumumab, 131I-tositumomab, ibritumomab, 90-Ititutentitiu 90, Iitumomab, In-90, and In-5956, or the like), and the like, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01, ALK inhibitors (e.g., Ceritinib, Aleptinib, Bugatinib, Laratinib, Ocatinib), PI3K inhibitors (e.g., Idiranib, Duvelisib, Dactlisib, Taselisib, Bimiralisib, Omipalisib, Bupalisib, etc.), BTK inhibitors (e.g., Ibrutinib, Tirabutinib, Acatinib, Zabritinib, Vebrutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, erlotinib, Lapatinib, Darkatinib, Icotinib, Netinib, Sapatinib, Napatinib, pyrroltinib, Hirtitinib, HDAC, erlotinib, Galatinib, e, Galatinib, e, vorinostat, fimepinastat, drosrinostat, entinostat, daciclast, Quisinostat, tacrine, etc.), CDK inhibitors (e.g., palbociclib, ribbociclib, Abemaciclib, micciib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (e.g., semetinib (AZD6244), trametinib (GSK1120212), PD0325901, seru 0126, pimatiib (AS-703026), PD184352(CI-1040), etc.), mTOR inhibitors (e.g., vistuertib, etc.), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, etc.), or combinations thereof.
Dosage forms of the pharmaceutical compositions of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, pellicle, dripping pill, topical liniment, controlled release type or delayed release type or nanometer preparation.
The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-1000mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The treatment methods of the present invention can be administered alone or in combination with other therapeutic means or agents.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 50 to 1000 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: mixing a pharmaceutically acceptable carrier with the compound of the general formula (I) or a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof to form the pharmaceutical composition.
The present invention also provides a method of treatment comprising the steps of: administering to a subject in need thereof a compound of formula (I) as described herein, or a crystalline form, a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as described herein, for selectively inhibiting KRASG12C。
Compared with the prior art, the invention has the following main advantages:
(1) the compound is right to KRASG12CHas good selective inhibition effect;
(2) the compound has better pharmacodynamics and pharmacokinetic performance and lower toxic and side effects.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are by weight.
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. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) and liquid mass chromatography (LC-MS).
NMR was detected using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the assay solvent contained deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated acetone (CD)3COCD3) Deuterated chloroform (CDCl)3) And deuterated methanol (CD)3OD), and internal standards are Tetramethylsilane (TMS), chemical shifts are measured in parts per million (ppm).
Liquid chromatography-mass spectrometry (LC-MS) was detected using a Waters SQD2 mass spectrometer. HPLC measurements were performed using an Agilent 1100 high pressure chromatograph (Microsorb 5micron C18100 x 3.0.0 mm column).
Thin layer chromatography silica gel plate is blue island GF254 silica gel plate, TLC is 0.15-0.20mm, and preparative thin layer chromatography is 0.4-0.5 mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available or may be used or synthesized according to literature reports in the art.
All reactions of the present invention are carried out under continuous magnetic stirring under the protection of a dry inert gas (e.g., nitrogen or argon) except for the specific indications, and the reaction temperatures are all in degrees centigrade.
Examples
Preparation of intermediate 12-cyanomethyl-4- [2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidinyl [4,5-c ] azepin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester
First step preparation of 5- (benzyl-ethoxycarbonylmethyl-amino) -pentanoic acid ethyl ester
Ethyl benzylaminoacetate (50g, 259mmol), ethyl 5-bromopentanoate (65g, 311mmol) and potassium carbonate (79g, 570mmol) were added to 600 ml acetonitrile. The reaction solution was refluxed at 85 ℃ for 16 hours, and then potassium carbonate was removed by suction filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate: 100/1 to 20/1) to obtain the objective product (65g, yield: 78%).
LC-MS：m/z 322(M+H)+.1H NMR(300MHz,CDCl3)δ7.40-7.20(m,5H),4.22-4.11(m,4H),3.80(s,2H),3.32(s,2H),2.68(t,J＝7.2Hz,2H),2.31(t,J＝7.2Hz,2H),1.72-1.52(m,4H),1.32-1.25(m,6H).
Second step preparation of 1-benzyl-3-oxo-azepane-4-carboxylic acid ethyl ester
5- (benzyl-ethoxycarbonylmethyl-amino) -pentanoic acid ethyl ester (65g, 202mmol) was dissolved in 650 ml of anhydrous tetrahydrofuran and then sodium hydrogen (60% wt, 16g, 404mmol) was added in portions under ice bath and nitrogen flow. The resulting reaction was refluxed at 70 ℃ for 16 hours, and then the reaction was placed in an ice bath and quenched with 500 ml of saturated ammonium chloride. The resulting mixture was extracted 3 times with 500 ml of ethyl acetate. The ethyl acetate layers were combined, washed with 500 ml of brine, dried over anhydrous sulfuric acid, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate: 100/1 to 40/1) to obtain the objective product (20.8g, yield: 37%).
LC-MS：m/z 276(M+H)+.1H NMR(300MHz,CDCl3)δ7.44-7.32(m,5H),4.32-4.20(m,2H),3.93(t,J＝6.6Hz,1H),3.79-3.67(m,2H),3.45-3.27(m,2H),2.70-2.60(m,2H),2.22-2.10(m,1H),2.09-1.95(m,1H),1.90-1.80(m,1H),1.80-1.70(m,1H),1.28(t,J＝7.2Hz,3H).
The third step is the preparation of 8-benzyl-6, 7,8, 9-tetrahydro-5H-pyrimidine [4,5-c ] azepine-2, 4-diol
1-benzyl-3-oxo-azepane-4-carboxylic acid ethyl ester (20.8g, 75.6mmol) was dissolved in 310 ml ethanol, followed by addition of urea (22.7g, 378.2mmol) and sodium methoxide (10.2g, 189.1 mmol). The reaction was refluxed at 90 ℃ for 16 hours, and then concentrated under reduced pressure. The residue is dissolved in 400 ml of water and the insoluble viscous mass is filtered off with suction. And adjusting the pH of the filtrate to 5-6 by using 6M hydrochloric acid, separating out white solids, continuously stirring for 1 hour, and performing suction filtration. The obtained solid was washed with 30 ml of water and then lyophilized to obtain the objective product (9.5g, yield: 46%).
LC-MS：m/z 272(M+H)+.1H NMR(300MHz,DMSO-d6)δ10.98(s,1H),10.58(s,1H),7.35-7.24(m,5H),5.40(brs,2H),3.67(s,2H),3.63(s,2H),2.81(t,J＝5.1Hz,2H),2.50(overlap,2H),1.52-1.50(m,2H).
The fourth step is the preparation of 8-benzyl-2, 4-dichloro-6, 7,8, 9-tetrahydro-5H-pyrimidine [4,5-c ] azepine
8-benzyl-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepine-2, 4-diol (1g, 3.7mmol) was added to 12 ml of phosphorus oxychloride followed by careful addition of 6 ml of N, N-diisopropylethylamine. The resulting reaction solution was heated at 110 ℃ and stirred for 16 hours, and then concentrated under reduced pressure to remove excess solvent. The residue was slowly added dropwise to 100 ml of water and the pH was then adjusted to above 8 with 6M sodium hydroxide solution. The resulting mixture was extracted 3 times with 80 ml of ethyl acetate. The ethyl acetate layers were combined and washed with 50 ml of brine, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate: 50/1 to 20/1) to give the objective product (420mg, yield: 37%).
LC-MS：m/z 308(M+H)+.1H NMR(400MHz,CDCl3)δ7.33-7.23(m,5H),4.02(s,2H),3.67(s,2H),3.07(t,J＝5.6Hz,2H),2.96(t,J＝5.6Hz,2H),1.86-1.79(m,2H).
The fifth step is the preparation of 2- (4- (8-benzyl-2-chloro-6, 7,8, 9-tetrahydro-5H-pyrimidine [4,5-c ] azepin-4-yl) piper-azine-2-yl) acetonitrile
8-benzyl-2, 4-dichloro-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepine (385mg, 1.25mmol), piperazin-2-ylacetonitrile hydrochloride (260mg, 1.32mmol) and N, N-diisopropylethylamine (1mL, 6.27mmol) were added to 5mL of DMF. The resulting reaction solution was stirred at room temperature for 16 hours, then 25 ml of water was added, followed by 3-time extraction with 20 ml of ethyl acetate. The ethyl acetate layers were combined and washed 3 times with 15 ml brine, then dried and concentrated under reduced pressure to give the desired product. The reaction mixture was used in the next reaction without further purification.
LC-MS：m/z 397(M+H)+.
The sixth step is the preparation of 4- (8-benzyl-2-chloro-6, 7,8, 9-tetrahydro-5H-pyrimidine [4,5-c ] azepin-4-yl) -2-cyanomethyl-piperazine-1-carboxylic acid tert-butyl ester
The 2- (4- (8-benzyl-2-chloro-6, 7,8, 9-tetrahydro-5H-pyrimidine [4,5-c ] azepin-4-yl) piper-pera-piperazin-2-yl) acetonitrile obtained in the previous step was dissolved in 2.7g di-tert-butyl dicarbonate. The resulting reaction solution was stirred at room temperature for 2 hours, and then purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate: 10/1 to 2/1) to obtain the objective product (490mg, two-step yield: 79%).
LC-MS：m/z 497(M+H)+.1H NMR(400MHz,CDCl3)δ7.40-7.20(m,5H),4.61(brs,1H),4.10-4.00(m,1H),3.95-3.80(m,3H),3.79-3.60(m,3H),3.30-3.10(m,2H),3.05-2.96(m,1H),2.95-2.60(m,6H),1.90-1.70(m,2H),1.51(s,9H).
Seventh step preparation of tert-butyl 4- (8-benzyl-2- (((S) -1-methyl-pyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidinyl [4,5-c ] azepin-4-yl) -2-cyanomethylpiperazine-1-carboxylate
(S) - (1-methyl-pyrrolidin-2-yl) methanol (288mg, 2.5mmol) was dissolved in 5ml of anhydrous tetrahydrofuran and sodium hydrogen (60% wt, 80mg, 2.0mmol) was added over ice. The resulting reaction was stirred under nitrogen for an additional 30 minutes, then a solution of 4- (8-benzyl-2-chloro-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2-cyanomethyl-piperazine-1-carboxylic acid tert-butyl ester (490mg, 1.0mmol) in 5ml of anhydrous tetrahydrofuran was added dropwise to the mixture. The resulting reaction was refluxed at 70 ℃ for 16 hours, then quenched with 20 ml of saturated ammonium chloride, and extracted 3 times with 20 ml of ethyl acetate. The ethyl acetate layers were combined, dried and concentrated under reduced pressure. The residue was purified by silica gel column (eluent: dichloromethane/methanol 30/1 to 10/1) to obtain the objective product (350mg, yield: 60%).
LC-MS：m/z 576(M+H)+.1H NMR(400MHz,CDCl3)δ7.30-7.20(m,5H),4.60(brs,1H),4.39(dd,J＝10.8Hz,4.8Hz,1H),4.17-4.11(m,1H),4.04(brs,1H),3.88(s,2H),3.73(d,J＝14.4Hz,1H),3.68(s,2H),3.58(d,J＝12.8Hz,1H),3.20-3.11(m,3H),2.95-2.85(m,3H),2.80-2.65(m,5H),2.49(s,3H),2.35-2.27(m,1H),2.10-2.00(m,2H),1.90-1.80(m,4H),1.51(s,9H).
Eighth step preparation of tert-butyl 2-cyanomethyl-4- [2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidinyl [4,5-c ] azepin-4-yl ] -piperazine-1-carboxylate
Tert-butyl 4- (8-benzyl-2- (((S) -1-methyl-pyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidinyl [4,5-C ] azepin-4-yl) -2-cyanomethylpiperazine-1-carboxylate (340mg, 0.6mmol) was dissolved in 15 ml of a 7M solution of ammonia-methanol followed by addition of 10% Pd/C (100 mg). The obtained reaction solution was replaced with hydrogen gas 3 times, and then heated and stirred at 40 ℃ for 16 hours. The resulting mixture was filtered off with suction to remove the catalyst and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol/═ 5/1, 1.5% ammonia water as an additive) to obtain the objective product (230mg, yield: 80%).
LC-MS：m/z 486(M+H)+.1H NMR(400MHz,CDCl3)δ4.59(brs,1H),4.45(dd,J＝10.8Hz,4.8Hz,1H),4.19(dd,J＝10.4Hz,6.4Hz,1H),4.02(brs,1H),3.96(s,2H),3.71(d,J＝13.2Hz,1H),3.56(d,J＝12.8Hz,1H),3.23-3.10(m,5H),2.95-2.65(m,6H),2.54(s,3H),2.40-2.35(m,1H),2.10-1.90(m,7H),1.50(s,9H).
Example 12 preparation of (1-acryloyl-4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidi-no [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
Preparation of tert-butyl 2- (cyanomethyl) -4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidi-No. 4,5-c ] azepin-4-yl) piperazine-1-carboxylate
2-cyanomethyl-4- [2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidinyl [4,5-c ] azepin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester (50mg, 0.10mmol), 1-bromo-8-methylnaphthalene (55mg, 0.25mmol), cesium carbonate (98mg, 0.30mmol) and dioxane (2mL) were added to a reaction flask, and Ruphos G3 pd (25mg, 0.03mmol) was added after three nitrogen replacements. The obtained reaction solution was replaced with nitrogen three times, heated to 72 ℃ and stirred for 16 hours. After completion of the reaction, acetonitrile (1mL) was also added to the reaction, followed by filtration. The filtrate was purified by preparative chromatography (acetonitrile: 0.05% TFA in water 0% to 50%) to give the objective product (18 mg).
LC-MS：m/z 626(M+H)+.
Second step preparation of 2- (4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidi-no 4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
Tert-butyl 2- (cyanomethyl) -4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidine [4,5-c ] azepin-4-yl) piperazine-1-carboxylate (12mg) was dissolved in dichloromethane (1mL) followed by trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for 0.5h, then concentrated to dryness under reduced pressure to give the objective product (18 mg). The product is used in the next reaction without purification.
LC-MS：m/z 526(M+H)+.
The third step is the preparation of 2- (1-acryloyl-4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidi-no [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
Adding dichloromethane (1.5mL) and N, N-diisopropylethylamine (20mg, 0.144mmol) to 2- (4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (18mg, 0.024mmol) obtained in the above step, and cooling to-40 ℃ under nitrogen; acryloyl chloride (5mg, 0.048mmol) was then added dropwise. After the addition was complete, the reaction was warmed to room temperature and stirred for 1h, then quenched by the addition of 1mL of methanol. The resulting mixture was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (acetonitrile/0.05% aqueous ammonium bicarbonate 5% to 85%, 10v) to give the objective product (4.5 mg).
LC-MS：m/z 580(M+H)+.1H NMR(400MHz,CDCl3)δ7.55(m,2H),7.28(m,2H),7.13(m,2H),6.52(m,1H),6.34(d,J＝16.8Hz,1H),5.77(d,J＝10.4Hz,1H),5.04(brs,0.5H),4.53(brs,0.5H),4.33(m,2H),4.23(m,1H)，4.10(m,1H)，3.79(m,3H),3.08(m,14H),2.42(s,3H),2.28(m,1H),1.95(m,3H),1.69(m,3H)。
The compound is obtained by manual preparation and separation
2- ((S) -1-acryloyl-4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidine [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (A) and 2- ((R) -1-acryloyl-4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidine [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (B)
Example 1A 2- ((S) -1-acryloyl-4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidine [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
LC-MS：m/z 580(M+H)+.
Example 1B 2- ((R) -1-acryloyl-4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidine [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
LC-MS：m/z 580(M+H)+.
Following the procedure of example 1, the following compounds were synthesized from different starting materials:
example 22 preparation of (1-acryloyl-4- (2- (2- (cyclobutyl (methyl) amino) ethoxy) -8- (8-methylnaphthalen-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimidi-no [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
LC-MS：m/z 594(M+H)+.
Example preparation of 32- (1-acryloyl-4- (2- (2- ((cyclopropylmethyl) (methyl) amino) ethoxy) -8- (8-methylnaphthalen-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimidi-n [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
LC-MS：m/z 594(M+H)+.
Example 42- (1-acryloyl-4- (8- (2-methyl-3-fluorophenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidi-n [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
LC-MS：m/z 548(M+H)+.1H NMR(400MHz,CDCl3)δ7.19–7.06(m,1H),6.84(d,J＝8.0Hz,1H),6.76(t,J＝8.6Hz,1H),6.61(brs,1H),6.40(d,J＝16.7Hz,1H),5.84(d,J＝10.5Hz,1H),5.31(m,1H),5.08(brs,0.5H),4.72–4.47(m,1.5H),4.37–3.50(m,7H),3.47–3.21(m,3H),3.20–2.66(m,9H),2.45–2.27(m,2H),2.26–1.98(m,8H).
Example 52- (1-acryloyl-4- (8- (2-fluoro-3-methylphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidi-n [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
LC-MS：m/z 548(M+H)+.
Example 62- (1-acryloyl-4- (8- (2-fluorophenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidi-n [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
LC-MS：m/z 534(M+H)+.
Example 72- (1-acryloyl-4- (8- (2, 3-dimethylphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
LC-MS：m/z 544(M+H)+.1H NMR(400MHz,CDCl3)δ7.06(t,J＝7.7Hz,1H),6.94(d,J＝7.8Hz,1H),6.89(d,J＝7.4Hz,1H),6.59(brs,1H),6.38(d,J＝16.7Hz,1H),5.82(d,J＝10.6Hz,1H),5.09(brs,0.5H),4.68(brs,1.5H),4.31(brs,1H),4.23–4.07(m,2H),4.05–3.67(m,3H),3.64–3.15(m,5H),3.15–2.90(m,3H),2.76(m,6H),2.25(s,3H),2.20–1.80(m,10H).
Example 82- (1-acryloyl-4- (8- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidi-n [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
LC-MS：m/z 550(M+H)+.
Example 92- (1-acryloyl-4- (8- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidi-no [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
LC-MS：m/z 570(M+H)+.
Example 102- (1-acryloyl-4- (8- (5, 6-dimethyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidi-no [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
LC-MS：m/z 584(M+H)+.
Example 112- (1-acryloyl-4- (8-benzyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimidi-n [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
LC-MS：m/z 530(M+H)+.
Example 12 evaluation of biological assay
The following biological test examples further illustrate the present invention, but these examples are not meant to limit the scope of the present invention.
Compound Pair NCI-H358 (KRAS)G12CMutant) cells and a549 (KRAS)G12SMutation) cell experiment of antiproliferative activity of cells.
Experimental procedure
To the peripheral wells of 384 microwell plates 40. mu.L of phosphate buffer was added, followed by 40. mu.L of the test cell suspension to the other wells, and the microwell plates were then placed in a carbon dioxide incubator overnight.
The test compounds were diluted in a gradient of 10 concentrations (from 50. mu.M to 0.003. mu.M) and 100nL of each was added to the corresponding well of the microplate. After dosing, 40. mu.L of phosphate buffer was added to each well at line A, P and columns 1 and 24, and the plates were incubated for 5 days in a carbon dioxide incubator.
mu.L of Promega CellTiter-Glo reagent was added to each well of the plate, followed by shaking at room temperature for 10min to stabilize the luminescence signal, which was then read using a Pekinelmer Envision multi-label analyzer.
Finally, IC of the compound was calculated using GraphPad Prism software50And (5) obtaining values, and drawing a fitting curve.
Compound couple NCI-H358 (KRAS) as an example of the present inventionG12CMutant) cells and a549 (KRAS)G12SMutant) cell antiproliferative activity is shown in table 1.
TABLE 1 antiproliferative activity of the compounds of the examples of the invention
| IC50 | NCI-H358(μM) | A549(μM) |
| Example 1 | 0.36 | / |
| Example 4 | 0.28 | 8.2 |
As can be seen from table 1:
example Compounds of the invention for KRASG12CThe mutant NCI-H358 cells showed very good cell antiproliferative activity and also for KRASG12SThe mutant A549 cells have weak antiproliferative activity and show high selectivity.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. An aza-heptacyclic compound having the structure of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof:
in the formula:
A. b are the same or different and are each independently selected from: CH. CR5Or N;
C. d, E, F are the same or different and are each independently selected from the group consisting of: o, S, SO2、CO、CH、CR3aR3b、N、NH、NR3a(ii) a C. D, E, N, F and the two adjacent carbons on the pyrimidine ring to which they are attached form a seven-membered ring; wherein R is3aAnd R3bEach independently selected from the group consisting of: hydrogen, deuterium, oxygen, halogen, hydroxy, cyano, C1-C6Alkyl radical, C1-C6An alkoxy group; or R3aAnd R3bAnd the carbon atoms bound to form C3-C6Cycloalkyl or 4-6 membered heterocyclyl; wherein the seven membered ring may be further substituted;
x is independently selected from the group consisting of: 4-14 membered saturated or unsaturated nitrogen heterocycle or heterocyclyl, C6-C14Aryl or 5-14 membered heteroaryl, wherein said saturated or unsaturated nitrogen heterocycle or heterocyclyl, aryl or heteroaryl may optionally be substituted with one or more R8Substituted; r8Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C18Alkyl, deuterated C1-C18Alkyl, halo C1-C18Alkyl radical, C3-C20Cycloalkyl radical, C1-C18Alkoxy, deuterated C1-C18Alkoxy, halo C1-C18Alkoxy, amino, hydroxy, 4-20 membered heterocyclic group, C6-C14Aryl, 5-14 membered heteroaryl;
y is independently selected from the group consisting of: bond, O, S, NH, NR5、CR5R6、CONH、CONR5、SO2NH、SO2NR5、NHCO、NR5CO、NHSO2、NR5SO2；
Z is independently selected from the group consisting of: key, C1-C18Alkylene, deuterated C1-C18Alkylene, halogeno C1-C18Alkylene radical, C3-C20Cycloalkylene, 4-20 membered heterocyclylene, C1-C18Alkyleneoxy, deuterated C1-C18Alkyleneoxy, halogeno C1-C18An alkyleneoxy group;
w is independently selected from the group consisting of: bond, O, NH, NR5、CONH、CONR5、SO2NH、SO2NR5、NHCO、NHSO2、NHCONH、NR5CONH、NHCONR5、NR5CONR6、NHSO2NH、NR5SO2NH、NHSO2NR5、NR5SO2NR6；
When B is N, R1Independently selected from:
wherein the content of the first and second substances,
represents a double or triple bond;
when B is selected from CH or CR5，R1Independently selected from:
wherein the content of the first and second substances,
represents a double or triple bond;
RAis absent or is independently selected from the group consisting of: hydrogen, deuterium, fluoro, cyano, or C1-C3An alkyl group; rBIndependently selected from the group consisting of: hydrogen, deuterium, cyano, or C1-C3An alkyl group; wherein, the C1-C3The alkyl group may be substituted with one or more substituents selected from the group consisting of: deuterium, halogen, cyano, amino, C3-C7Cycloalkyl, 4-7 membered heterocyclyl, NHR9Or NR9R10；R9、R10Each independently is C1-C3An alkyl group;
R2independently selected from the group consisting of: - (CH)2)nR7、-(CH2)nO(CH2)qR7、-(CH2)nSR7、-(CH2)nCOR7、-(CH2)nC(O)OR7、-(CH2)nS(O)qR7、-(CH2)nNR5R7、-(CH2)nC(O)NR5R7、-(CH2)nNR5C(O)R7、-(CH2)nNR5C(O)NR5R7、-(CH2)nS(O)qNR5R7、-(CH2)nNR5S(O)qR7Or- (CH)2)nNR5S(O)qNR5R7In which CH2H in (a) may be substituted; r7Selected from the group consisting of: substituted or unsubstituted C1-C18Alkyl, substituted or unsubstituted C3-C20Cycloalkyl, or a substituted or unsubstituted 4-20 membered heterocyclyl;
l is selected from the group consisting of: a bond, -C (O) -, C1-C3An alkylene group;
R4independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C18Alkyl, deuterated C1-C18Alkyl, halo C1-C18Alkyl radical, C3-C20Cycloalkyl radical, C1-C18Alkoxy, deuterated C1-C18Alkoxy, halo C1-C18Alkoxy, amino, hydroxy, 4-20 membered heterocyclic group, C6-C14Aryl, 5-14 membered heteroaryl;
R5and R6The same or different, and each is independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C18Alkyl, deuterated C1-C18Alkyl, halo C1-C18Alkyl radical, C3-C20Cycloalkyl radical, C1-C18Alkoxy, deuterated C1-C18Alkoxy, halo C1-C18Alkoxy, halogen, amino, hydroxy, cyano, amino, 4-20 membered heterocyclyl, C6-C14Aryl, 5-14 membered heteroaryl;
wherein said substitution is by one or more groups selected from the group consisting of: hydrogen, deuterium, C1-C18Alkyl, deuterated C1-C18Alkyl, halo C1-C18Alkyl radical, C3-C20Cycloalkyl radical, C1-C18Alkoxy, deuterated C1-C18Alkoxy, halo C1-C18Alkoxy radical, C6-C14Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;
n is an integer of 0, 1, 2,3, 4 or 5;
p is an integer of 1 or 2;
q is an integer of 0, 1, 2,3, 4 or 5.
2. The compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug of claim 1, having the structure of formula (V):
R1、R2、R4x, Z, W, C, D, E, F are as defined in claim 1.
3. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to claim 1, characterized in that it has the structure according to general formula (VI):
in the formula:
R1、R2、R4、R8y, Z, L, W, C, D, E, F are as defined in claim 1.
4. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof according to claim 1, having the structure of formula (VII):
in the formula:
R1、R2、R4、R8y, Z, W, C, D, E, F are as defined inThe method is described in 1.
5. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to claim 1, characterized in that it has the structure according to general formula (VIII):
in the formula:
R1、R2、R4、R8z, W, C, D, E, F are as defined in claim 1.
6. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to claim 1, characterized in that it has the structure according to general formula (IX-a) or (IX-B):
in the formula:
R1、R2、R4、R5、R8z, C, D, E, F are as defined in claim 1.
7. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof according to claim 1, wherein said compound is selected from the group consisting of:
8. a pharmaceutical composition comprising one or more compounds of formula (I) according to claim 1, stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof; and a pharmaceutically acceptable carrier.
9. Use of an aza-heptacyclic compound having the structure of general formula (I), or a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to claim 1, or a pharmaceutical composition according to claim 8, for the preparation of a medicament for the prophylaxis and/or treatment of KRASG12COr an expression level of the compound (b).
10. KRAS inhibition in vitroG12CThe method of (2), comprising the steps of: contacting a compound of claim 1, a stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a composition of claim 8, with a somatic cell.
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| EP4051678A1 (en) | 2019-10-28 | 2022-09-07 | Merck Sharp & Dohme Corp. | Small molecule inhibitors of kras g12c mutant |
| US20230107642A1 (en) | 2020-12-18 | 2023-04-06 | Erasca, Inc. | Tricyclic pyridones and pyrimidones |
| WO2022266206A1 (en) | 2021-06-16 | 2022-12-22 | Erasca, Inc. | Kras inhibitor conjugates |
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| WO2019099524A1 (en) * | 2017-11-15 | 2019-05-23 | Mirati Therapeutics, Inc. | Kras g12c inhibitors |
| CN109843856A (en) * | 2016-05-18 | 2019-06-04 | 米拉蒂治疗股份有限公司 | KRAS G12C inhibitor |
| WO2019141250A1 (en) * | 2018-01-19 | 2019-07-25 | 南京明德新药研发股份有限公司 | Pyridone-pyrimidine derivative acting as krasg12c mutein inhibitor |
| CN112430234A (en) * | 2019-08-26 | 2021-03-02 | 信达生物制药(苏州)有限公司 | Novel KRAS G12C protein inhibitor and preparation method and application thereof |
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| EP3844151B1 (en) * | 2018-08-31 | 2023-08-23 | Mirati Therapeutics, Inc. | Kras g12c inhibitors |
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| CN109843856A (en) * | 2016-05-18 | 2019-06-04 | 米拉蒂治疗股份有限公司 | KRAS G12C inhibitor |
| WO2019099524A1 (en) * | 2017-11-15 | 2019-05-23 | Mirati Therapeutics, Inc. | Kras g12c inhibitors |
| WO2019141250A1 (en) * | 2018-01-19 | 2019-07-25 | 南京明德新药研发股份有限公司 | Pyridone-pyrimidine derivative acting as krasg12c mutein inhibitor |
| CN112430234A (en) * | 2019-08-26 | 2021-03-02 | 信达生物制药(苏州)有限公司 | Novel KRAS G12C protein inhibitor and preparation method and application thereof |
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| WO2024002373A1 (en) * | 2022-07-01 | 2024-01-04 | 苏州泽璟生物制药股份有限公司 | Substituted pyrimidine-fused ring inhibitor, method for preparing same, and use thereof |
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