Fourth-generation egfr inhibitors

Abstract

The present invention provides a compound as a fourth-generation EGFR inhibitor, which is a compound or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. The present invention also provides a pharmaceutical composition comprising the compound, and use thereof in the treatment of cancer.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to an EGFR inhibitor. BACKGROUND

[0002] Lung cancer is one of the most common malignant tumors, with about 1.6 million new cases of lung cancer worldwide each year, which is divided into small cell lung cancer and non-small cell lung cancer (NSCLC). Among them, non-small cell lung cancer accounts for about 85% of the total number of lung cancer (Nature Reviews Disease Primers, 2015, 1, 15009). Epidermal growth factor receptor (EGFR) is the most common driver gene of non-small cell lung cancer, with a positive rate of 17% in all non-small cell lung cancers, close to 30%-40% in domestic patients, and as high as about 60% in lung adenocarcinoma.

[0003] EGFR is a transmembrane glycoprotein belonging to the ErbB family of tyrosine kinase receptors. EGFR is abnormally activated by various mechanisms, such as receptor overexpression, mutation, ligand-dependent receptor dimerization, and ligand-independent activation, and the continuous activation of its kinase activity initiates downstream signaling of cell proliferation, differentiation, and survival. Small molecule inhibitors of EGFR kinase can inhibit the activation of tyrosine kinase, inhibit the proliferation of tumor cells, promote the apoptosis of tumor cells, and other biological effects, which is a hot field of lung cancer development.

[0004] Osimertinib is a drug developed for EGFR (del19 or L858R) with T790M mutation, which shows very significant efficacy in clinical practice. However, as the treatment continues, patients will also develop drug resistance. In 2015 (Nature Medicine, 2015, 21, 560-562), 15 cases of drug resistance data of patients taking Osimertinib were first reported, among which EGFR C797S mutation is one of the main mechanisms leading to drug resistance of Osimertinib, accounting for about 40%. In addition, the latest literature reports show that among the patients with drug resistance after Osimertinib second-line treatment, 22-25% of them have C797S mutation (Nature Cancer, 2021, 377-391). Therefore, developing new small molecule inhibitors targeting C797S mutation to provide safer and more effective fourth-generation EGFR inhibitors for patients has an urgent clinical need. SUMMARY

[0005] In this invention, we used major clinically observed mutation types such as del19 and del19 / T790M / C797S to conduct cellular-level evaluations and validate them on constructed Ba / F3 cells. Ultimately, we discovered a series of novel chemical entities with strong biological activity. Furthermore, they exhibited weak inhibition against wild-type, demonstrating high selectivity and safety.

[0006] In one aspect, the present invention provides compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof:

[0007]

[0008]

[0009]

[0010] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and optionally a pharmaceutically acceptable excipient.

[0011] In another aspect, the present invention provides pharmaceutical compositions comprising the compounds of the present invention and pharmaceutically acceptable excipients, and further comprising other therapeutic agents.

[0012] In another aspect, the present invention provides the use of the compounds of the present invention in the preparation of medicaments for treating and / or preventing EGFR kinase-mediated diseases.

[0013] In another aspect, the present invention provides a method for treating and / or preventing EGFR kinase-mediated diseases in a subject, comprising administering the subject a compound or composition of the present invention.

[0014] In another aspect, the present invention provides compounds or compositions thereof for the treatment and / or prevention of EGFR kinase-mediated diseases.

[0015] In a specific implementation, the diseases treated by the present invention include cancers selected from the following: lung cancer (including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), lung adenocarcinoma, and lung squamous cell carcinoma).

[0016] Other objects and advantages of the invention will become apparent to those skilled in the art from the following detailed embodiments, examples and claims.

[0017] definition

[0018] Chemical definition

[0019] The definitions of specific functional groups and chemical terms are described in more detail below.

[0020] When a numerical range is listed, it is intended to include each value and sub-range within the range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl groups.

[0021] "C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl and C 1-2 alkyl groups are preferred. Examples of C 1-6 alkyl groups include: methyl (Ci), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), t-butyl (C4), sec-butyl (C4), i-butyl (C4), n-pentyl (C5), 3-pentyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), t-amyl (C5), and n-hexyl (C6). The term "C 1-6 alkyl" also includes heteroalkyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkyl groups can be optionally substituted with one or more substituents, e.g., with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0022] "C 1-6 "Alkylene" refers to a divalent radical, formed by removing two hydrogen atoms from a C 1-6 alkyl group, and can be substituted or unsubstituted. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-3Alkylene is preferred. Unsubstituted alkylene groups include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylene groups, e.g., alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like. 2-

[0023] "Halo" or "halogen" refers to fluoro (F), chloro (CI), bromo (Br), and iodo (I).

[0024] Thus, "C 1-6 Haloalkyl" refers to the above "C 1-6 alkyl" groups substituted with one or more halogen groups. In some embodiments, C 1-4 haloalkyl groups are particularly preferred, more preferably C 1-2 haloalkyl groups. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CC13, -CH2CI, -CHC12, 2,2,2-trifluoro-l,l-dimethyl-ethyl, and the like. Haloalkyl groups can be substituted at any available attachment point, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0025] "C 3-10 Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 4-10 cycloalkyl groups, C 3-7 cycloalkyl groups, C 3-6 cycloalkyl groups, and C 3-5 cycloalkyl groups are particularly preferred, more preferably C 5-6 ​Cycloalkyl. Cycloalkyl also includes ring systems in which the above cycloalkyl ring is fused with one or more aryl or heteroaryl rings, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons refers to the number of carbons in the cycloalkyl ring. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like. Cycloalkyl groups can be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0026] "3-10 membered heterocyclyl" refers to a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. In some embodiments, 4-9 membered heterocyclyl groups are preferred, which are 4- to 9-membered non-aromatic ring systems having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5-8 membered heterocyclyl groups are preferred, which are 5- to 8-membered non-aromatic ring systems having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3-8 membered heterocyclyl groups are preferred, which are 3- to 8-membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms; 3-7 membered heterocyclyl groups are preferred, which are 3- to 7-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; 4-7 membered heterocyclyl groups are preferred, which are 4- to 7-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; 4-6 membered heterocyclyl groups are preferred, which are 4- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; and 5-6 membered heterocyclyl groups are preferred, which are 5- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the above heterocyclyl ring is fused with one or more cycloalkyl rings, wherein the point of attachment is on the cycloalkyl ring, or with one or more aryl or heteroaryl rings, wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: hexahydrotriazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azepanyl, oxepanyl, and thiepanyl.Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl groups) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Heterocyclyl groups can be optionally substituted with one or more substituents, for example, with one to five substituents, one to three substituents, or one substituent.

[0027] "C 6-10 Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 p electrons shared in a cyclic array) having from 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C10aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl rings, with the point of attachment at the aryl ring, in which case the number of carbon atoms designates the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with one to five substituents, one to three substituents, or one substituent. 10 Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 p electrons shared in a cyclic array) having from 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C10aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl rings, with the point of attachment at the aryl ring, in which case the number of carbon atoms designates the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with one to five substituents, one to three substituents, or one substituent.

[0028] "5-10 membered heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems wherein an above-described heteroaryl ring is fused with one or more cycloalkyl or heterocyclyl rings, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms indicates the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-9 membered heteroaryl is preferred, which is a 5-9 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Heteroaryl groups can be optionally substituted with one or more substituents, e.g., with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0029] Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, and the like, as defined herein, are optionally substituted groups.

[0030] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa)3, -OSi(R aa )3, -C(=S)N(R bb )2, -C(=O)SR aa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0031] or two geminal hydrogens on a carbon atom are replaced with a group =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc ;

[0032] R aa each independently is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0033] R bb each independently is selected from: hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R bb groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0034] R cc each independently is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0035] R ddeach independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff )OR ee , -OC(=NR ff )R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2Ree , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents can be combined to form =O or =S;

[0036] each R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

[0037] each R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ff groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

[0038] each R gg is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6alkyl), -OC(=O)(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 alkyl, -SO2OC 1-6 alkyl, -OSO2C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 alkyl, -SC(=S)SC 1-6 alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6alkyl)2, -OP(=0)(OR 1-6 alkyl)2, -OP(=0)(OR 1-6 alkyl)2, -OP(=0)(OR 1-6 alkyl)2, -OP(=0)(OR 10 alkyl)2, -OP(=0)(OR 10 alkyl)2, -OP(=0)(OR gg alkyl)2, -OP(=0)(OR - alkyl)2, -OP(=0)(OR

[0039] alkyl)2, -OP(=0)(OR aa alkyl)2, -OP(=0)(OR cc alkyl)2, -OP(=0)(OR aa alkyl)2, -OP(=0)(OR cc alkyl)2, -OP(=0)(OR aa alkyl)2, -OP(=0)(OR aa alkyl)2, -OP(=0)(OR bb alkyl)2, -OP(=0)(OR aa alkyl)2, -OP(=0)(OR cc alkyl)2, -OP(=0)(OR aa alkyl)2, -OP(=0)(OR cc alkyl)2, -OP(=0)(OR cc alkyl)2, -OP(=0)(OR cc alkyl)2, -OP(=0)(OR cc alkyl)2, -OP(=0)(OR cc alkyl)2, -OP(=0)(OR aa alkyl)2, -OP(=0)(OR cc alkyl)2, -OP(=0)(OR cc alkyl)2, -OP(=0)(OR cc alkyl)2, -OP(=0)(OR aa alkyl)2, -OP(=0)(OR aa alkyl)2, -OP(=0)(OR cc alkyl)2, -OP(=0)(OR cc alkyl)2, -OP(=0)(OR cc alkyl)2, -OP(=0)(OR dd alkyl)2, -OP(=0)(OR aa alkyl)2, -OP(=0)(OR bb alkyl)2, -OP(=0)(OR cc alkyl)2, -OP(=0)(OR dd alkyl)2, -OP(=0)(OR

[0040] alkyl)2, -OP(=0)(OR

[0041] The term "pharmaceutically acceptable salt" as used herein means those carboxylic acid salts, amino acid addition salts of the compounds of the present application which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without an undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, effective for their intended use, including, where appropriate, the zwitterionic forms of the compounds of the present application.

[0042] A "subject" for administration includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)) and / or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a bovine, a porcine, an equine, an ovine, a caprine, a rodent, a feline, and / or a canine. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0043] "Disease," "disorder," and "condition" are used interchangeably herein.

[0044] In general, an "effective amount" of a compound refers to an amount that is sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the present application can vary depending on, e.g., the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both therapeutically effective and prophylactically effective amounts.

[0045] "Combination" and related terms refer to the administration of a compound of the present application and another therapeutic agent simultaneously or sequentially. For example, a compound of the present application can be administered simultaneously or sequentially in separate unit dosage forms, or concurrently in a single unit dosage form, with another therapeutic agent.

[0046] Example 1

[0047] Preparation of key intermediates

[0048] Commonly used abbreviations notes:

[0049] Abbreviations: PE = petroleum ether; EA = ethyl acetate; MeOH = methanol; DCM = dichloromethane; DCE = dichloroethane; CH3CN = acetonitrile; 1,4-dioxane = 1,4-dioxane; DMSO = dimethyl sulfoxide; HFIP = hexafluoroisopropanol; DMF = N,N-dimethylformamide; Hex = n-hexane; IPA = isopropanol; NMP = N-methylpyrrolidone; NMO = N-methylmorpholine-N-oxide; TEA = triethylamine; DIEA = diisopropylethylamine; CuI = copper iodide; CuCN = copper cyanide; triphosgene = triphosgene; p-TsOH = p-toluenesulfonic acid; T3P = 1-propylphosphonic anhydride; TsN3 = p-toluenesulfonyl azide; PPA = polyphosphoric acid; BINAP = 1,1'-binaphthalene-2,2'-bisphosphine.

[0050] Synthesis of intermediates a1-a2, a7-a10

[0051]

[0052] Step 1: Ice bath, dissolve raw material 2-amino-3-fluoro-5-iodobenzoic acid methyl ester a1-1 (3.0 g, 10.2 mmol) and copper bromide (225 mg, 1.02 mmol) in 50 mL of acetonitrile, slowly add nitrous acid (1.05 g, 10.2 mmol), after dropping, react at room temperature for 4 hours, stop the reaction. Add 200 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography to obtain white solid a1-2 (2.1 g), yield: 58%, LCMS: ESI-MS (m / z): 358.8 [M+H] + .

[0053] Step 2: Under nitrogen protection, -10°C, dissolve the intermediate a1-2 (2.1 g, 5.85 mmol) in 18 mL of anhydrous THF, slowly add diisobutylaluminum hydride DIBAL-H (17.5 mL, 1M), drop to the end, and then warm to room temperature for 12 hours, stop the reaction. Add 1M concentration of dilute hydrochloric acid (20 mL) to the system, filter, extract with ethyl acetate, and evaporate the solvent under reduced pressure to obtain oily intermediate a1-3 (1.8 g), LCMS: ESI-MS (m / z): 330.9 [M+H] + .

[0054] Step 3: The crude product a1-3 (1.8 g) and triethylamine (1.74 g, 17.2 mmol) from the previous step were dissolved in 20 mL of dichloromethane, and methanesulfonic anhydride (1.5 g, 8.61 mmol) was slowly added. The reaction was allowed to proceed at room temperature for 1 h, and then the reaction was stopped. The reaction was placed in an ice bath, and 40 mL of ice water was added to the system. The mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate a1-4 (2.0 g), which was used directly in the next step. LCMS: ESI-MS (m / z): 408.8 [M+H] + .

[0055] Step 4: The starting material 2,2-diethoxyacetamide a1-5 (1.44 g, 9.78 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran in an ice bath, and NaH (390 mg, 9.78 mmol) was slowly added. After stirring for 15 min, intermediate a1-4 (1.8 g) from the previous step was added, and the reaction was allowed to proceed at 50 °C for 2 h. The reaction was stopped, and 60 mL of ice water was added to the system. The mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by flash column chromatography to give intermediate a1-6 (1.2 g) in a three-step yield of 45%. LCMS: ESI-MS (m / z): 459.9 [M+H] + .

[0056] Step 5: The intermediate a1-6 (1.2 g, 2.61 mmol) from the previous step, potassium carbonate (1.08 g, 7.83 mmol), and the starting material isopropenylboronic acid pinacol ester a1-7 (460 mg, 2.74 mmol) were dissolved in 11 mL of a mixture of 1,4-dioxane and water (v / v, 10 / 1) under nitrogen protection. A catalyst Pd(dppf)Cl2 (95 mg, 0.13 mmol) was added, and the reaction was allowed to proceed at 80 °C for 5 h. The reaction was stopped, and 60 mL of ice water was added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by flash column chromatography to give intermediate a1-8 (900 mg) in a yield of 92%. LCMS: ESI-MS (m / z): 374.1 [M+H] + .

[0057] Step 6: The intermediate a1-8 (1.0 g, 2.67 mmol) from the previous step and palladium on carbon (100 mg) were dissolved in 11 mL of ethanol under a hydrogen atmosphere (1 atm). The reaction was allowed to proceed at room temperature for 12 h, and then the reaction was stopped and filtered. The solvent was evaporated under reduced pressure to give intermediate a1-9 (900 mg) in a yield of 90%. LCMS: ESI-MS (m / z): 376.1 [M+H] + .

[0058] Step 7: Intermediate a1-9 (900 mg, 2.39 mmol) from previous step was dissolved in 5 mL of concentrated sulfuric acid, after stirring for 5 minutes, the reaction was heated to 50 °C for 2 hours, the reaction was stopped. The reaction was slowly poured into 50 mL of ice water, dichloromethane was extracted, dried over anhydrous sodium sulfate, filtered, concentrated to give intermediate a1-10 (300 mg), yield: 44%, LCMS: ESI-MS (m / z): 284.0 [M+H] + .

[0059] Step 8: Intermediate a1-9 (250 mg, 0.88 mmol) from previous step was dissolved in 5 mL of dichloromethane, diisopropylethylamine DIEA (340 mg, 2.64 mmol) was added slowly, triflic anhydride (320 mg, 1.14 mmol) was added slowly, the reaction was stirred to room temperature for 1 hour, the reaction was stopped. 30 mL of ice water was added to the system, dichloromethane was extracted, saturated brine was washed, dried over anhydrous sodium sulfate, filtered, concentrated, the crude product was separated by flash column chromatography to give intermediate a1 (200 mg), yield: 55%, LCMS: ESI-MS (m / z): 415.9 [M+H] + .

[0060] Referring to the synthesis route of compound a1, using similar raw materials / skeleton structures, the following intermediates were synthesized.

[0061]

[0062] Synthesis of intermediates a3-a5

[0063]

[0064] Step 1: The starting material 1H-4-pyrazole boronic acid pinacol ester a3-1 (25.0 g, 130 mmol) was dissolved in 300 mL of anhydrous DMF, NaH (7.7 g, 190 mmol) was added slowly, after stirring for 5 minutes, cyclopropylsulfonyl chloride (19.9 g, 140 mmol) was added, the reaction was stirred at room temperature for 12 hours, the reaction was stopped. 1 L of ice water was added to the system, ethyl acetate was extracted, saturated brine was washed, dried over anhydrous sodium sulfate, filtered, concentrated to give intermediate a3-2 (35.0 g), yield: 91%, LCMS: ESI-MS (m / z): 299.2 [M+H] + .

[0065] Step 5: Under nitrogen protection, the intermediate a3-2 (27.5 g, 92.2 mmol), cesium carbonate (90.2 g, 280 mmol) and raw material 2-chloro-4-aminopyrimidine a3-3 (11.9 g, 92.2 mmol) were dissolved in a mixed solution of 250 mL of 1,4-dioxane and water (v / v, 5 / 1), a catalyst Pd(dppf)Cl2(3.4 g, 4.6 mmol) was added, stirred for 5 minutes, then heated to 90°C for 10 hours, the reaction was stopped, filtered. To the mixture, 1 L of ice water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash column chromatography to obtain intermediate a3 (8.7 g), yield: 36%, LCMS: ESI-MS (m / z): 266.3 [M+H] + .

[0066] Referring to the synthesis route of compound a3, using similar raw materials / skeleton structures, the following intermediates were synthesized.

[0067]

[0068] Synthesis of intermediate a6

[0069]

[0070] Step 1: Under nitrogen protection, raw material 3-bromothiophene a6-1 (2.0 g, 12.3 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (870 mg, 6.13 mmol), potassium iodide (1.02 g, 6.13 mmol) and raw material sodium cyclopropane sulfite a6-2 (3.14 g, 24.5 mmol) were added to a 35 mL microwave reactor, a catalyst [Cu(OTf)]2-toluene (1.27 g, 2.45 mmol) was added, stirred for 5 minutes, then heated to 100°C for 2 hours under microwave, the reaction was stopped, filtered. To the mixture, 100 mL of ice water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash column chromatography to obtain intermediate a6-3 (2.2 g), yield: 95%, LCMS: ESI-MS (m / z): 189.0 [M+H] + .

[0071] Step 2: The intermediate a6-3 (1.8 g, 9.56 mmol) and aluminium trichloride (1.53 g, 11.5 mmol) from the previous step were dissolved in 20 mL of dichloromethane under nitrogen protection, and bromine (1.68 g, 10.5 mmol) was added dropwise slowly. The reaction was allowed to warm to room temperature for 2 hours, and then stopped. 50 mL of saturated aqueous sodium thiosulfate solution was added to the reaction solution, which was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by flash column chromatography to obtain intermediate a6-4 (1.6 g), with a yield of 63%, LCMS: ESI-MS (m / z): 266.9 [M+H] + .

[0072] Step 3: The intermediate a6-4 (1.0 g, 3.74 mmol) from the previous step, potassium acetate (730 mg, 7.48 mmol), and bis(pinacolato)diboron (1.42 g, 5.61 mmol) were dissolved in 10 mL of toluene under nitrogen protection. A catalyst Pd(dppf)Cl2 (310 mg, 0.37 mmol) was added, and the mixture was stirred for 5 minutes before being heated to 80°C for 10 hours. The reaction was stopped, and the mixture was filtered. The solvent was removed by evaporation under reduced pressure, and the crude product was separated by flash column chromatography to obtain intermediate a6 (900 mg) with a yield of 77%, LCMS: ESI-MS (m / z): 315.1 [M+H] + .

[0073] Synthesis of intermediate b1

[0074]

[0075] Step 1: The starting material b1-1 (7.0 g, 27.7 mmol) and triethylamine (4.2 g, 41.5 mmol) were dissolved in 40 mL of dichloromethane under nitrogen protection. Methylsulfonyl chloride (3.21 g, 28.0 mmol) was added, and the reaction was allowed to proceed at room temperature for 4 hours. The reaction was stopped, and the solvent was removed by evaporation under reduced pressure to obtain the crude product b1-2 (10.8 g).

[0076] Step 2: The crude product b1-2 (10.8 g) from the previous step and the starting material b1-3 (4.21 g, 27.7 mmol) were dissolved in 30 mL of DMF. NaH (1.11 g, 27.7 mmol) was added, and the reaction was allowed to proceed at 80°C for 12 hours. The reaction was monitored by LC-MS. The reaction was quenched by adding 100 mL of saturated brine solution, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product b1-4 (15 g). LC-MS: ESI-MS (m / z): 388.3 [M+H] + .

[0077] Step 3: The crude product b1-4 (15 g) and LiCl (2.52 g, 60.0 mmol) from the previous step were dissolved in 40 mL of N,N-dimethylacetamide (DMA) and heated to 150 °C for 2 h. The reaction was stopped. 100 mL of ice water was added to the reaction mixture, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting yellow solid b1-5 (6.42 g) was separated by flash column chromatography. The total yield of three steps was 71%, and LC-MS: ESI-MS (m / z): 330.1 [M+H] + .

[0078] Step 4: The intermediate b1-5 (6.42 g, 19.5 mmol) from the previous step was mixed with Pd / C (1.28 g, 20%) under a hydrogen atmosphere (2 atm) in 40 mL of methanol. 2 mL of trifluoroacetic acid was added, and the reaction was allowed to proceed at room temperature for 16 h. The reaction was stopped, filtered, and concentrated to give a yellow oil b1 (4.5 g), which was used directly in the next step. LC-MS: ESI-MS (m / z): 164.2 [M+H] + .

[0079] Synthesis of intermediates b2-b5

[0080]

[0081] Step 1: Intermediate b1-2 (70.0 g, 210 mmol) was added to a 500 mL reaction flask, and a solution of methylamine in isopropanol (200 mL, 28% concentration) was slowly added. The reaction was heated to 70 °C for 4 h, and the reaction was monitored by LC-MS. The solvent was evaporated under reduced pressure, and the crude product was separated by flash column chromatography to give an oil intermediate b2-1 (39.0 g) with a yield of 69%, LCMS: ESI-MS (m / z): 267.4 [M+H] + .

[0082] Step 2: Intermediate b2-1 (39.0 g, 150 mmol) and triethylamine (44.5 g, 440 mmol) from the previous step were dissolved in 400 mL of dichloromethane, and methanesulfonic anhydride (30.6 g, 180 mmol) was slowly added. The reaction was allowed to proceed at room temperature for 1 h, and the reaction was stopped. The reaction mixture was placed in an ice bath, and 1 L of ice water was added to the system. The reaction mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate b2-2 (40 g), which was used directly in the next step. LCMS: ESI-MS (m / z): 345.5 [M+H] + .

[0083] Step 4: The intermediate b2-2 (40 g, 120 mmol) and trifluoroacetic acid (53.0 g, 460 mmol) were dissolved in 200 mL of methanol, and palladium on carbon (4.0 g) was added slowly under hydrogen atmosphere (1 atm), and the reaction was carried out at room temperature for 12 h. The reaction was stopped, filtered, and the solvent was removed under reduced pressure. 100 mL of water was added to the mixture, and the impurities were removed by dichloromethane extraction. The aqueous phase was freeze-dried to obtain intermediate b3 (27.0 g), yield: 84%, LCMS: ESI-MS (m / z): 179.1 [M+H] + .

[0084] Referring to the synthesis route of compound b2, using similar raw materials / skeleton structures, the following intermediates were synthesized.

[0085]

[0086] Synthesis of intermediate c1

[0087]

[0088] Step 1: Intermediate a2 (3.25 g, 8.15 mmol), cesium carbonate (5.31 g, 16.3 mmol), and intermediate a4 (2.0 g, 8.15 mmol) were dissolved in 25 mL of 1,4-dioxane under nitrogen protection, and a catalyst Xantphos Pd-G3 (420 mg, 0.41 mmol) was added. After stirring for 5 min, the reaction was carried out at 80°C for 2 h. The reaction was stopped, and the mixture was filtered. 100 mL of water was added to the mixture, and the impurities were removed by ethyl acetate extraction, saturated brine washing, anhydrous sodium sulfate drying, filtration, concentration, and flash column chromatography separation of the crude product to obtain intermediate c1-1 (2.7 g), yield: 67%, LCMS: ESI-MS (m / z): 493 [M+H] + .

[0089] Step 2: The intermediate c1-1 (2.7 g, 5.47 mmol) from the previous step was dissolved in 60 mL of hydrogen chloride in 1,4-dioxane solution (2M concentration) in an ice bath, and the reaction was carried out at room temperature for 1 h. The reaction was stopped, and 100 mL of saturated aqueous sodium bicarbonate solution was added to the system to adjust the pH to about 9. The impurities were removed by ethyl acetate extraction, saturated brine washing, anhydrous sodium sulfate drying, filtration, and concentration to obtain intermediate c1 (2.2 g), which was directly used in the next step, LCMS: ESI-MS (m / z): 409 [M+H] + .

[0090] Synthesis of intermediates c2-c7

[0091]

[0092] Step 1: Under nitrogen protection, intermediate a8 (2.0 g, 3.96 mmol), sodium tert-butoxide (1.14 g, 11.9 mmol) and raw material c2-1 (784 mg, 7.92 mmol) were dissolved in 20 mL of toluene, catalyst Pd2dba3 (733 mg, 0.8 mmol) and ligand BINAP (498 mg, 0.8 mmol) were added, stirred for 5 minutes, then heated to 110°C for 12 hours, the reaction was stopped, filtered. 100 mL of water was added to the mixture, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash column chromatography (PE / EA, 4 / 1) to obtain intermediate c2-2 (830 mg), yield: 44%, LCMS: ESI-MS (m / z): 479 [M+H] + .

[0093] Step 2: Under nitrogen protection, intermediate c2-2 (600 mg, 1.26 mmol), cesium carbonate (1.44 g, 4.41 mmol) and intermediate b2 (640 mg, 2.3 mmol) were dissolved in 6 mL of 1,4-dioxane, catalyst XantPhosPd G3 (120 mg, 0.13 mmol) was added, stirred for 5 minutes, then heated to 110°C for 4 hours, the reaction was stopped, filtered. 100 mL of water was added to the mixture, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash column chromatography (PE / EA, 2 / 1) to obtain intermediate c2 (150 mg), yield: 21%, LCMS: ESI-MS (m / z): 575 [M+H] + .

[0094] Step 3: Intermediate c2 (150 mg, 0.26 mmol) from the previous step was dissolved in 6 mL of tetrahydrofuran, TBAF (120 mg, 0.34 mmol) was added, and the reaction was stirred at room temperature for 1.5 hours, then the reaction was stopped and filtered. 100 mL of water was added to the mixture, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate c3 (100 mg), LCMS: ESI-MS (m / z): 419 [M+H] + .

[0095] Referring to the synthesis route of compound c2 / c3, using similar raw materials / skeleton structures, the following intermediates were synthesized.

[0096]

[0097]

[0098] Example 2

[0099] Preparation of target molecules P1-P5, P13-P14

[0100]

[0101] Step 1: Intermediate c1 (500 mg, 1.22 mmol) and raw material P1-1 (350 mg, 1.22 mmol) were dissolved in 5 mL of anhydrous DMF under nitrogen protection, NaH (78 mg, 1.95 mmol) was added, and after stirring for 5 min, the reaction was heated to 80°C for 2 h. The reaction was stopped, and the mixture was filtered. 30 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash column chromatography to obtain compound P1-2 (270 mg) with a yield of 39%, LCMS: ESI-MS (m / z): 564 [M+H] + .

[0102] Step 2: The intermediate P1-2 (270 mg, 0.48 mmol) from the previous step was dissolved in 6 mL of dichloromethane in an ice bath, and 2 mL of trifluoroacetic acid was added. The reaction was allowed to proceed at room temperature for 2 h, and the reaction was stopped. Saturated aqueous sodium bicarbonate solution was added to the system to adjust the pH to about 9, and the mixture was extracted with ethyl acetate and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound P1-3 (150 mg), which was directly used in the next step. LCMS: ESI-MS (m / z): 464 [M+H] + .

[0103] Step 3: The intermediate P1-3 (150 mg, 0.32 mmol) from the previous step and formaldehyde aqueous solution (0.6 mL) were dissolved in 12 mL of a mixed solution of dichloromethane and tetrahydrofuran (v / v, 1 / 1), and sodium triacetyl borohydride (750 mg, 3.54 mmol) was added. The reaction was allowed to proceed at room temperature for 2 h, and the reaction was stopped. 50 mL of water was added to the system, and the mixture was extracted with dichloromethane and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by flash column chromatography to obtain compound P1-4 (26 mg) with a yield of 17%, LCMS: ESI-MS (m / z): 478 [M+H] + .

[0104] Step 4: Under nitrogen protection, the compound P1-4 (26 mg, 0.054 mmol), cesium carbonate (53 mg, 0.16 mmol) and intermediate b2 (24 mg, 0.086 mmol) were dissolved in 2 mL of 1,4-dioxane, and a catalyst Xantphos Pd-G3 (8.4 mg, 0.008 mmol) was added. After stirring for 5 minutes, the reaction was heated to 110 °C for 4 hours. The reaction was stopped, and filtered. The solvent was removed by evaporation under reduced pressure. The crude product was separated by flash column chromatography to obtain the target molecule P1 (7.0 mg), yield: 22%, LCMS: ESI-MS (m / z): 576 [M+H] + .

[0105] 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.15 (s, 1H), 8.76 (s, 1H), 8.47 (s, 1H), 8.39 (d, J = 1.5 Hz, 1H), 8.16 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 5.1 Hz, 1H), 6.71 (d, J = 7.7 Hz, 1H), 5.07 (t, J = 7.1 Hz, 1H), 4.69 (t, J = 7.8 Hz, 1H), 4.51 - 4.46 (m, 1H), 4.25 (t, J = 6.6 Hz, 1H), 3.86 (t, J = 7.2 Hz, 1H), 3.76 (t, J = 6.6 Hz, 2H), 3.63 (t, J = 6.5 Hz, 1H), 2.98 (s, 3H), 2.89 - 2.83 (m, 6H), 2.38 (s, 3H), 1.44 (d, J = 6.0 Hz, 3H), 1.39 (dd, J = 8.3, 7.0 Hz, 6H).

[0106] Referring to the synthesis route of compound P1, the following target molecules were synthesized using similar backbone structures.

[0107]

[0108]

[0109] Example 3

[0110] Preparation of target molecule P6

[0111]

[0112] Step 1: Intermediate cl (400 mg, 0.98 mmol) and raw material P4-1 (300 mg, 1.1 mmol) were dissolved in 5 mL of anhydrous DMF under nitrogen protection, NaH (51 mg, 1.3 mmol) was added, and after stirring for 5 min, the reaction was heated to 80°C for 8 h. The reaction was stopped, and the mixture was filtered. 30 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash column chromatography to obtain compound P6-1 (400 mg), yield: 69%, LCMS: ESI-MS (m / z): 592 [M+H] + .

[0113] Step 4: The compound P6-1 (400 mg, 0.68 mmol) obtained in the previous step, cesium carbonate (774 mg, 2.37 mmol), and intermediate b2 (281 mg, 1.36 mmol) were dissolved in 3 mL of 1,4-dioxane under nitrogen protection, and a catalyst Xantphos Pd-G3 (76 mg, 0.068 mmol) was added. After stirring for 5 min, the reaction was heated to 110°C for 8 h. The reaction was stopped, and the mixture was filtered. The solvent was removed by evaporation under reduced pressure, and the crude product was separated by flash column chromatography to obtain compound P6-2 (200 mg), yield: 73%, LCMS: ESI-MS (m / z): 690 [M+H] + .

[0114] Step 2: The compound P6-2 (200 mg, 0.29 mmol) obtained in the previous step was dissolved in 3 mL of dichloromethane in an ice bath, and 2 mL of trifluoroacetic acid was added. The reaction was stopped after 2 h at room temperature. The pH of the system was adjusted to about 9 by adding saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by HPLC preparative chromatography to obtain the target molecule P6 (100 mg), yield: 59%, LCMS: ESI-MS (m / z): 590 [M+H] + .

[0115] 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.12 (s, 1H), 8.77 (s, 1H), 8.34 (d, J = 5.8 Hz, 1H), 8.29 (s, 1H), 8.09 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 5.6 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 4.66 (t, J = 7.4 Hz, 1H), 4.45 (t, J = 6.0 Hz, 1H), 4.32 - 4.18 (m, 2H), 3.83 (t, J = 7.1 Hz, 1H), 3.62 (dd, J = 13.5, 6.6 Hz, 1H), 3.11 - 3.05 (m, 2H), 2.95 (s, 3H), 2.83 (s, 3H), 2.60 (t, J = 11.6 Hz, 2H), 2.08 - 1.95 (m, 3H), 1.89 - 1.78 (m, 2H), 1.45 - 1.32 (m, 9H).

[0116] Example 4

[0117] Preparation of target molecules P7, P15-P17

[0118]

[0119] Step 1: Under nitrogen protection, intermediate a1 (200 mg, 0.48 mmol), cesium carbonate (470 mg, 1.44 mmol) and intermediate a3 (130 mg, 0.48 mmol) were dissolved in 5 mL of 1,4-dioxane, and a catalyst XantphosPd-G3 (50 mg, 0.048 mmol) was added. After stirring for 5 min, the temperature was raised to 80 °C, and the reaction was carried out for 5 h. The reaction was stopped, and filtered. The solvent was removed by evaporation under reduced pressure. The crude product was separated by flash column chromatography to obtain compound P7-1 (200 mg), yield: 78%, LCMS: ESI-MS (m / z): 531.1 [M+H] + .

[0120] Step 4: Under nitrogen protection, compound P7-1 (240 mg, 0.45 mmol) from the previous step, cesium carbonate (440 mg, 1.35 mmol) and intermediate b2 (170 mg, 0.63 mmol) were dissolved in 3 mL of 1,4-dioxane, and a catalyst XantphosPd-G3 (46 mg, 0.045 mmol) was added. After stirring for 5 min, the temperature was raised to 110 °C, and the reaction was carried out for 5 h. The reaction was stopped, and filtered. The solvent was removed by evaporation under reduced pressure. The crude product was separated by flash column chromatography to obtain target molecule P7 (110 mg), yield: 39%, LCMS: ESI-MS (m / z): 629.2 [M+H]+ .

[0121] 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.25 (s, 1H), 8.80 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.44 (d, J = 5.9 Hz, 1H), 7.40 (d, J = 15.5 Hz, 1H), 7.22 (d, J = 5.3 Hz, 1H), 4.86 - 4.77 (m, 1H), 4.56 (t, J = 7.1 Hz, 1H), 4.14 (q, J = 6.8 Hz, 1H), 4.04 (t, J = 7.1 Hz, 1H), 3.69 - 3.58 (m, 1H), 2.95 (s, 3H), 2.86 (s, 3H), 1.47 - 1.39 (m, 10H), 1.38 - 1.24 (m, 4H).

[0122] Referring to the synthesis route of compound P7, using similar backbone structure, the following target molecules were synthesized.

[0123]

[0124] Example 5

[0125] Preparation of target molecules P8-P9

[0126]

[0127] Step 1: Under nitrogen protection, intermediate a2 (100 mg, 0.25 mmol), cesium carbonate (165 mg, 0.5 mmol) and intermediate a5 (59 mg, 0.25 mmol) were dissolved in 3 mL of 1,4-dioxane, and a catalyst Xantphos Pd-G3 (3 mg, 0.003 mmol) was added. After stirring for 5 minutes, the reaction was heated to 80°C for 4 hours. The reaction was stopped, filtered, and the solvent was removed under reduced pressure. The crude product was separated by flash column chromatography to obtain compound P8-1 (40 mg), yield: 33%, LCMS: ESI-MS (m / z): 482.0 [M+H] + .

[0128] Step 2: The compound P8-1 (40 mg, 0.08 mmol), cesium carbonate (81 mg, 0.25 mmol) and intermediate b2 (32 mg, 0.11 mmol) were dissolved in 2 mL of 1,4-dioxane under nitrogen protection, and a catalyst Xantphos Pd-G3 (8.5 mg, 0.008 mmol) was added. After stirring for 5 minutes, the reaction was heated to 110 °C for 12 hours. The reaction was stopped and filtered. The solvent was removed by evaporation under reduced pressure. The crude product was separated by flash column chromatography to obtain the target molecule P8 (14.7 mg), yield: 31%, LCMS: ESI-MS (m / z): 579.6 [M+H] + .

[0129] 1 H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.56 (s, 1H), 8.39 (d, J = 5.9 Hz, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.83 (brs, 1H), 7.46 (d, J = 7.9 Hz, 1H), 6.95 (d, J = 5.8 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 4.60 (t, J = 7.4 Hz, 1H), 4.41 (p, J = 6.1 Hz, 1H), 4.30 (dd, J = 13.5, 6.9 Hz, 1H), 4.15 (s, 2H), 3.85 (t, J = 7.2 Hz, 1H), 3.65 (dt, J = 13.6, 6.8 Hz, 1H), 2.93 (s, 3H), 2.86 (s, 3H), 1.51 (d, J = 6.1 Hz, 3H), 1.45 - 1.40 (m, 6H), 1.23 (s, 6H).

[0130] Referring to the synthesis route of compound P8, the following target molecules were synthesized using similar backbone structures.

[0131]

[0132] Example 6

[0133] Preparation of target molecules P10-P12

[0134]

[0135] Step 1: Intermediate c3 (100 mg, 0.24 mmol) and triethylamine (102 mg, 1.0 mmol) were dissolved in 3 mL of dry dichloromethane under ice bath and nitrogen protection, triflic anhydride (102 mg, 0.36 mmol) was added, stirred for 5 minutes, then warmed to room temperature for 2 hours, 30 mL of water was added to quench the reaction. Dichloromethane extraction, anhydrous sodium sulfate drying, concentration, and flash column chromatography separation (DCM / MeOH, 20 / 1) of the crude product to obtain compound P10-1 (100 mg), yield: 76%, LCMS: ESI-MS (m / z): 551.1 [M+H] + .

[0136] Step 4: The compound P10-1 (100 mg, 0.18 mmol) of the above step, cesium carbonate (117 mg, 0.36 mmol) and intermediate a3 (54 mg, 0.20 mmol) were dissolved in 3 mL of 1,4-dioxane under nitrogen protection, catalyst Xantphos Pd-G3 (19 mg, 0.02 mmol) was added, stirred for 5 minutes, then warmed to 110°C for 4 hours, the reaction was stopped and filtered. The solvent was removed under reduced pressure, and the crude product was separated by flash column chromatography (DCM / MeOH, 20 / 1) to obtain the target molecule P10 (50 mg), yield: 42%, LCMS: ESI-MS (m / z): 666.2 [M+H] + .

[0137] 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.10 (s, 1H), 8.66 (s, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.44 (d, J = 5.9 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 4.58 (t, J = 7.3 Hz, 1H), 4.53 (s, 1H), 4.39 (dd, J = 11.5, 5.7 Hz, 1H), 4.20 (s, 1H), 4.19 - 4.13 (m, 1H), 3.98 (d, J = 7.5 Hz, 1H), 3.70 (dd, J = 14.5, 7.4 Hz, 2H), 3.55 - 3.40 (m, 1H), 3.39 - 3.35 (m, 1H), 3.30 - 3.22 (m, 1H), 2.95 (s, 3H), 2.83 (s, 3H), 2.00 - 1.92 (m, 1H), 1.82 - 1.72 (m, 1H), 1.38 (d, J = 6.0 Hz, 3H), 1.36 - 1.31 (m, 2H), 1.27 - 1.22 (m, 2H).

[0138] Following the synthetic route of compound P10, the following target molecules were synthesized using similar backbone structures.

[0139]

[0140] Example 7

[0141] The effect of small molecule inhibitors on the proliferation of 4 Ba / F3 cell lines (Ba / F3-EGFR-del19, Ba / F3-FL-EGFR, Ba / F3-EGFR-del19-T790M-C797S and Ba / F3-EGFR-L858R-C797S) was determined using Promega CellTiter-Glo reagent.

[0142] (Ba / F3-EGFR-del19, Ba / F3-EGFR-del19-T790M-C797S and Ba / F3-EGFR-L858R-C797S) culture medium: 1640 medium, 10% FBS, Glutamax and penicillin streptomycin.

[0143] (Ba / F3-FL-EGFR) culture medium: 1640 medium, 10% FBS, Glutamax, 100 ng / mL EGF and penicillin streptomycin.

[0144] The cell lines were cultured in an incubator at 37°C, 5% CO2. Cells were passaged regularly and cells in the logarithmic growth phase were used for plating. 95 μL of cell suspension was added to each well of the cell plate, and culture medium without cells (containing 0.1% DMSO) was added to the Min control wells. Compound test cell plates were dosed: 5 μL of 20x compound working solution was added to the cell culture plate. In the Max control, 5 μL of DMSO-cell culture medium mixture was added, and the final concentration of DMSO was 0.1%. In the Max control, 5 μL of DMSO-cell culture medium mixture was added. The final concentration of DMSO was 0.1%.

[0145] The culture plates were incubated in a 37°C, 5% CO2 incubator for 72 hours. CellTiter-Glo luminescence method for cell activity detection. Data analysis:

[0146] The cell proliferation inhibition rate (Inhibition Rate) data was processed using the following formula:

[0147] Inhibition Rate (Inh%) = 100 - (RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100%.

[0148] RLU Drug RLU Min RLU Max RLU

[0149] The inhibition rate of different concentrations of compounds was calculated in EXCEL, and then the inhibition rate curve was drawn and the related parameters were calculated by using GraphPad Prism software. The parameters included the maximum and minimum inhibition rates of cells, IC 50 values.

[0150] Table 1: Anti-proliferation inhibition effect of representative compounds on BaF3 cells transfected with wild-type EGFR (wt), mutant EGFR (del19) and mutant EGFR (del19 / T790M / C797S and Ba / F3-EGFR-L858R-C797S)

[0151]

[0152]

[0153] N.D. = not tested

[0154] The above results show that the molecules of the present application have good anti-proliferation effect on the cell strain resistant to Osimertinib (containing C797S mutation), which embodies the effect of the present application on solving Osimertinib-resistant tumors. The molecules also have good inhibition effect on the primary cell strain of EGFR mutant (EGFR del19), and weak inhibition effect on the wild type, which embodies the high selectivity of the molecules of the present application.

Claims

1. A compound, or a tautomer, a stereoisomer, a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. A pharmaceutical composition comprising a compound of claim 1, or a tautomer, a stereoisomer, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

3. The pharmaceutical composition of claim 2, comprising a compound of claim 1, or a tautomer, a stereoisomer, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and another therapeutic agent.

4. Use of a compound of claim 1, or a tautomer, a stereoisomer, a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of a disease mediated by EGFR kinase.

5. The disease mediated by EGFR kinase according to claim 4 is cancer.

6. The cancer according to claim 5 is lung cancer.

7. The cancer according to claim 6 is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma.

8. The cancer according to claim 7 is non-small cell lung cancer.

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