CN116554150A - Fourth generation EGFR inhibitors - Google Patents

Fourth generation EGFR inhibitors Download PDF

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CN116554150A
CN116554150A CN202310502540.9A CN202310502540A CN116554150A CN 116554150 A CN116554150 A CN 116554150A CN 202310502540 A CN202310502540 A CN 202310502540A CN 116554150 A CN116554150 A CN 116554150A
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刘彬
赵卉
高峰
郭永起
吴勇勇
景连栋
原帅
张鹏志
彭星哲
吴卓
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Suzhou Puhe Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

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Abstract

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

Description

Fourth generation EGFR inhibitors
Technical Field
The invention belongs to the field of medicines, and particularly relates to an EGFR inhibitor.
Background
Lung cancer is one of the most common malignant tumors, and the number of new lung cancer cases worldwide is about 160 ten thousand, and is divided into two types, small cell lung cancer and non-small cell lung cancer (NSCLC), with non-small cell lung cancer accounting for about 85% of the total lung cancer (Nature Reviews Disease Primers,2015,1,15009). The Epidermal Growth Factor Receptor (EGFR) is the most common driving gene of non-small cell lung cancer, the positive rate in all non-small cell lung cancer reaches 17%, the positive rate in domestic patients is close to 30% -40%, and the positive rate in lung adenocarcinoma is more high than about 60%.
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, ligand-independent activation, and continued activation of kinase activity initiates downstream signaling of cell proliferation, differentiation and survival. The small molecule inhibitor of EGFR kinase can inhibit the activation of tyrosine kinase, inhibit the proliferation of tumor cells, promote the biological effects of apoptosis and the like of the tumor cells, and is a hot spot field of lung cancer development.
Ornitinib (Osimertinib) is a drug developed against the primary drug resistant mutant EGFR (del 19 or L858R) along with the T790M mutation, and clinically shows very remarkable curative effects, but patients also develop drug resistance with the duration of treatment. The first data reported in 2015 (Nature Medicine,2015,21,560-562) on drug resistance of 15 patients taking octenib, in which the EGFR C797S mutation is one of the main mechanisms leading to drug resistance of the drug octenib, accounting for about 40%. In addition, recent literature reports indicate that 22-25% of patients with post-second line treatment resistance to octenib have a C797S mutation (Nature Cancer,2021, 377-391). Therefore, there is an urgent clinical need to develop new small molecule inhibitors against the C797S mutation, providing safer and more effective fourth generation EGFR inhibitors for patients.
Disclosure of Invention
In the invention, the main mutation types of del19, del19/T790M/C797S and the like which appear clinically are used for carrying out cell level evaluation and verification on the constructed Ba/F3 cell level, and finally a series of novel chemical entities with stronger biological activity are discovered. And the inhibition to wild type is weaker, thus showing higher selectivity and safety.
In one aspect, the invention provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
in another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient.
In another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient, which also contains an additional therapeutic agent.
In another aspect, the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of EGFR kinase mediated diseases.
In another aspect, the invention provides a method of treating and/or preventing an EGFR kinase mediated disease in a subject comprising administering to the subject a compound of the invention or a composition of the invention.
In another aspect, the invention provides a compound of the invention or a composition of the invention for use in the treatment and/or prevention of EGFR kinase mediated diseases.
In particular embodiments, the disease treated by the present invention includes a cancer selected from the group consisting of: lung cancer (including non-small cell lung cancer NSCLC, small Cell Lung Cancer (SCLC), lung adenocarcinoma, lung squamous carcinoma).
Other objects and advantages of the present invention will be apparent to those skilled in the art from the detailed description, examples, and claims that follow.
Definition of the definition
Chemical definition
The definition of specific functional groups and chemical terms is described in more detail below.
When numerical ranges are listed, it is intended to include each and every value and subrange within the range. For example "C 1-6 Alkyl "includes C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、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 An alkyl group.
“C 1-6 Alkyl "refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl and C 1-2 Alkyl groups are preferred. C (C) 1-6 Examples of alkyl groups include: methyl (C) 1 ) Ethyl (C) 2 ) N-propyl (C) 3 ) Isopropyl (C) 3 ) N-butyl group(C 4 ) Tert-butyl (C) 4 ) Sec-butyl (C) 4 ) Isobutyl (C) 4 ) N-pentyl (C) 5 ) 3-pentyl (C) 5 ) Amyl (C) 5 ) Neopentyl (C) 5 ) 3-methyl-2-butyl (C) 5 ) Tert-amyl (C) 5 ) And n-hexyl (C) 6 ). The term "C 1-6 Alkyl "also includes heteroalkyl groups in which one or more (e.g., 1,2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: me (-CH) 3 )、Et(-CH 2 CH 3 )、iPr(-CH(CH 3 ) 2 )、nPr(-CH 2 CH 2 CH 3 )、n-Bu(-CH 2 CH 2 CH 2 CH 3 ) Or i-Bu (-CH) 2 CH(CH 3 ) 2 )。
“C 1-6 Alkylene "means removal of C 1-6 The other hydrogen of the alkyl group forms a divalent group and may be substituted or unsubstituted. In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylene groups are preferred. Unsubstituted alkylene groups include, but are not limited to: methylene (-CH) 2 (-), ethylene (-CH) 2 CH 2 (-), propylene (-CH) 2 CH 2 CH 2 -) and butylene (-CH) 2 CH 2 CH 2 CH 2 -) pentylene (-CH) 2 CH 2 CH 2 CH 2 CH 2 (-), hexylene (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 2 (-), etc. Exemplary substituted alkylene groups, for example, alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH (CH) 3 )-、-C(CH 3 ) 2 (-), substituted ethylene (-CH (CH) 3 )CH 2 -、-CH 2 CH(CH 3 )-、-C(CH 3 ) 2 CH 2 -、-CH 2 C(CH 3 ) 2- ) Substituted propyleneRadical (-CH (CH) 3 )CH 2 CH 2 -、-CH 2 CH(CH 3 )CH 2 -、-CH 2 CH 2 CH(CH 3 )-、-C(CH 3 ) 2 CH 2 CH 2 -、-CH 2 C(CH 3 ) 2 CH 2 -、-CH 2 CH 2 C(CH 3 ) 2 (-), etc.
"halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
Thus, "C 1-6 Haloalkyl "means" C "as described above 1-6 Alkyl ", substituted with one or more halo groups. In some embodiments, C 1-4 Haloalkyl is particularly preferred, more preferably C 1-2 A haloalkyl group. Exemplary such haloalkyl groups include, but are not limited to: -CF 3 、-CH 2 F、-CHF 2 、-CHFCH 2 F、-CH 2 CHF 2 、-CF 2 CF 3 、-CCl 3 、-CH 2 Cl、-CHCl 2 2, 2-trifluoro-1, 1-dimethyl-ethyl, and the like. The haloalkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 3-10 Cycloalkyl "refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 4-10 Cycloalkyl, C 3-7 Cycloalkyl, C 3-6 Cycloalkyl and C 3-5 Cycloalkyl is particularly preferred, more preferably C 5-6 Cycloalkyl groups. Cycloalkyl also includes ring systems in which the cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary such cycloalkyl groups include, but are not limited to: cyclopropyl (C) 3 ) Cyclopropenyl (C) 3 ) Cyclobutyl (C) 4 ) Cyclobutenyl (C) 4 ) Cyclopentyl (C) 5 ) Cyclopentenyl (C) 5 ) Cyclohexyl (C) 6 ) Cyclohexenyl (C) 6 ) Cyclohexadienyl (C) 6 ) Cycloheptyl (C) 7 ) Cycloheptenyl (C) 7 ) Cycloheptadienyl (C) 7 ) Cycloheptatrienyl (C) 7 ) And so on. Cycloalkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
"3-10 membered heterocyclyl" refers to a group of a 3-10 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 a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as the valence permits. In some embodiments, a 4-9 membered heterocyclic group is preferred, which is a 4-9 membered non-aromatic ring system having a ring carbon atom and 1 to 5 ring heteroatoms; in some embodiments, a 5-8 membered heterocyclic group is preferred, which is a 5-8 membered non-aromatic ring system having a ring carbon atom and 1 to 5 ring heteroatoms; in some embodiments, 3-8 membered heterocyclyl is preferred, which is a 3-to 8-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms; preferably a 3-7 membered heterocyclic group which is a3 to 7 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; preferably a 4-7 membered heterocyclic group which is a 4-7 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; preferably a 4-6 membered heterocyclic group which is a 4-to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; more preferably a 5-6 membered heterocyclic group which is a 5-to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms. Heterocyclyl further includes ring systems in which the above heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or ring systems in which the above heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridinyl, oxetanyl, thietanyl (thio). Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited toIn the following steps: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxathiolanyl (oxathiolanyl), dithiolanyl (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 (thianyl). Exemplary 6 membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiocyclohexenyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepanyl, oxepinyl, and thiepanyl. Exemplary AND C 6 Aryl ring fused 5-membered heterocyclyl groups (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 AND C 6 Aryl ring fused 6 membered heterocyclyl (also referred to herein as 6, 6-bicyclic heterocyclyl) groups include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 6-10 Aryl "refers to a group of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) having 6 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C 6 Aryl "; for example, phenyl). In some embodiments, aryl groups have ten ring carbon atoms ("C 10 Aryl "; for example, naphthyl groups, such as 1-naphthyl and 2-naphthyl). Aryl also includes wherein the aryl ring is substituted with one or more cycloalkyl groups orA heterocyclic ring system is fused and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
"5-10 membered heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as the valency permits. The heteroaryl bicyclic ring system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, a 5-9 membered heteroaryl group 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 groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems 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 thienyl. 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: a pyridyl group. 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. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azetidinyl, oxepinyl, and thiepinyl. Exemplary 5, 6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazole, benzothienyl, isobenzothienyl, benzofuranyl, benzisotofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl 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 may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like as defined herein are optionally substituted groups.
Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO 2 、-N 3 、-SO 2 H、-SO 3 H、-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 、-CO 2 H、-CHO、-C(OR cc ) 2 、-CO 2 R aa 、-OC(＝O)R aa 、-OCO 2 R aa 、-C(＝O)N(R bb ) 2 、-OC(＝O)N(R bb ) 2 、-NR bb C(＝O)R aa 、-NR bb CO 2 R 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 SO 2 R aa 、-NR bb SO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R 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) 2 R aa 、-OP(＝O) 2 R aa 、-P(＝O)(R aa ) 2 、-OP(＝O)(R aa ) 2 、-OP(＝O)(OR cc ) 2 、-P(＝O) 2 N(R bb ) 2 、-OP(＝O) 2 N(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 5R dd Group substitution;
or two geminal hydrogen-cover groups on carbon atom=o, =s, =nn (R bb ) 2 、＝NNR bb C(＝O)R aa 、＝NNR bb C(＝O)OR aa 、＝NNR bb S(＝O) 2 R aa 、＝NR bb Or=nor cc Substitution;
R aa independently selected from the group consisting of alkyl, haloalkyl, alkenyl,Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The 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 5R dd Group substitution;
R bb independently selected from: hydrogen, -OH, -OR aa 、-N(R cc ) 2 、-CN、-C(＝O)R aa 、-C(＝O)N(R cc ) 2 、-CO 2 R aa 、-SO 2 R aa 、-C(＝NR cc )OR aa 、-C(＝NR cc )N(R cc ) 2 、-SO 2 N(R cc ) 2 、-SO 2 R cc 、-SO 2 OR cc 、-SOR aa 、-C(＝S)N(R cc ) 2 、-C(＝O)SR cc 、-C(＝S)SR cc 、-P(＝O) 2 R aa 、-P(＝O)(R aa ) 2 、-P(＝O) 2 N(R cc ) 2 、-P(＝O)(NR cc ) 2 Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The 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 5R dd Group substitution;
R cc independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc The 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 5R dd Group substitution;
R dd independently selected from: halogen, -CN, -NO 2 、-N 3 、-SO 2 H、-SO 3 H、-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 、-CO 2 H、-CO 2 R ee 、-OC(＝O)R ee 、-OCO 2 R ee 、-C(＝O)N(R ff ) 2 、-OC(＝O)N(R ff ) 2 、-NR ff C(＝O)R ee 、-NR ff CO 2 R 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 SO 2 R ee 、-SO 2 N(R ff ) 2 、-SO 2 R ee 、-SO 2 OR ee 、-OSO 2 R 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) 2 R ee 、-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 5R gg Substituted by a group, or by two gem R dd Substituents may combine to form =o or =s;
R ee independently selected from the group consisting of 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 5R gg Group substitution;
R ff each of (a) is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, and ringAlkyl, heterocyclyl, aryl and heteroaryl, or two R ff The 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 5R gg Group substitution;
R gg independently is: halogen, -CN, -NO 2 、-N 3 、-SO 2 H、-SO 3 H、-OH、-OC 1-6 Alkyl, -ON (C) 1-6 Alkyl group 2 、-N(C 1-6 Alkyl group 2 、-N(C 1-6 Alkyl group 3 + X - 、-NH(C 1-6 Alkyl group 2 + X - 、-NH 2 (C 1-6 Alkyl group + X - 、-NH 3 + 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 1-6 Alkyl) -CO 2 H、-CO 2 (C 1-6 Alkyl), -OC (=o) (C 1-6 Alkyl), -OCO 2 (C 1-6 Alkyl), -C (=O) NH 2 、-C(＝O)N(C 1-6 Alkyl group 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), -NHCO 2 (C 1-6 Alkyl), -NHC (=o) N (C) 1-6 Alkyl group 2 、-NHC(＝O)NH(C 1-6 Alkyl), -NHC (=o) NH 2 、-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 group 2 、-C(＝NH)NH(C 1-6 Alkyl), -C (=nh) NH 2 、-OC(＝NH)N(C 1-6 Alkyl group 2 、-OC(NH)NH(C 1-6 Alkyl), -OC (NH) NH 2 、-NHC(NH)N(C 1-6 Alkyl group 2 、-NHC(＝NH)NH 2 、-NHSO 2 (C 1-6 Alkyl), -SO 2 N(C 1-6 Alkyl group 2 、-SO 2 NH(C 1-6 Alkyl), -SO 2 NH 2 、-SO 2 C 1-6 Alkyl, -SO 2 OC 1-6 Alkyl, -OSO 2 C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si (C) 1-6 Alkyl group 3 、-OSi(C 1-6 Alkyl group 3 、-C(＝S)N(C 1-6 Alkyl group 2 、C(＝S)NH(C 1-6 Alkyl), C (=S) NH 2 、-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 group 2 、-OP(＝O)(C 1-6 Alkyl group 2 、-OP(＝O)(OC 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, C 6 -C 10 Aryl, C 3 -C 7 Heterocyclyl, C 5 -C 10 Heteroaryl; or two gem R gg Substituents may combine to form =o or =s; wherein X is - Is a counter ion.
Exemplary substituents on nitrogen atoms include, but are not limited to: hydrogen, -OH, -OR aa 、-N(R cc ) 2 、-CN、-C(＝O)R aa 、-C(＝O)N(R cc ) 2 、-CO 2 R aa 、-SO 2 R aa 、-C(＝NR bb )R aa 、-C(＝NR cc )OR aa 、-C(＝NR cc )N(R cc ) 2 、-SO 2 N(R cc ) 2 、-SO 2 R cc 、-SO 2 OR cc 、-SOR aa 、-C(＝S)N(R cc ) 2 、-C(＝O)SR cc 、-C(＝S)SR cc 、-P(＝O) 2 R aa 、-P(＝O)(R aa ) 2 、-P(＝O) 2 N(R cc ) 2 、-P(＝O)(NR cc ) 2 Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R's attached to a nitrogen atom cc The groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,Heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1,2, 3, 4, or 5R dd Substituted with radicals, and wherein R aa 、R bb 、R cc And R is dd As described above.
Other definitions
The term "pharmaceutically acceptable salts" as used herein means those carboxylate salts, amino acid addition salts of the compounds of the invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, and effective for their intended use, including (if possible) zwitterionic forms of the compounds of the invention.
The "subject" to be administered includes, but is not limited to: a human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle aged adults, or senior adults)) and/or a non-human animal, e.g., a mammal, e.g., a primate (e.g., cynomolgus monkey, rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and/or dog. 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.
"disease," "disorder," and "condition" are used interchangeably herein.
In general, an "effective amount" of a compound refers to an amount sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of the compounds of the present invention may vary depending on the following factors: for example, biological targets, pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age health and symptoms of the subject. The effective amount includes a therapeutically effective amount and a prophylactically effective amount.
"combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, the compounds of the invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form.
Example 1
Preparation of key intermediates
Commonly used abbreviation notes:
abbreviations: PE = petroleum ether; EA = ethyl acetate; meoh=methanol; DCM = dichloromethane; DCE = dichloroethane; CH (CH) 3 Cn=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 = cuprous iodide; cuCN = cuprous cyanide; triphosgene = triphosgene; p-TsOH = p-toluenesulfonic acid; t (T) 3 P=1-propylphosphoric acid cyclic anhydride; tsN 3 P-toluenesulfonyl azide; PPA = polyphosphoric acid; binap=1, 1 '-binaphthyl-2, 2' -bisdiphenylphosphine.
Synthesis of intermediates a1-a2, a7-a10
Step 1: the starting material, methyl 2-amino-3-fluoro-5-iodobenzoate a1-1 (3.0 g,10.2 mmol) and copper bromide (225 mg,1.02 mmol), were dissolved in 50mL of acetonitrile in an ice bath, and nitrous acid (1.05 g,10.2 mmol) was slowly added thereto, and the reaction was stopped after the dropwise addition at room temperature for 4 hours. 200mL of ice water was added to the reaction solution, extraction was performed with ethyl acetate, drying was performed with anhydrous sodium sulfate, concentration was performed, and the crude product was separated by flash column chromatography to obtain white solid a1-2 (2.1 g), yield: 58%, LCMS: ESI-MS (m/z): 358.8[ M+H ]] + 。
Step 2: under the protection of nitrogen, the intermediate a1-2 (2.1 g,5.85 mmol) in the previous step is dissolved in 18mL of anhydrous THF at-10 ℃, diisobutylaluminum hydride DIBAL-H (17.5 mL, 1M) is slowly added to the solution after dropwise addition, the temperature is raised to room temperature for reaction for 12 hours, and the reaction is stopped. To the system was added 1M dilute hydrochloric acid (20 mL), filtered, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to give intermediate a1-3 (1.8 g) as an oil, LCMS: ESI-MS (m/z): 330.9[ M+H ]] + 。
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 20mL of methylene chloride, and methanesulfonic anhydride (1.5 g,8.61 mmol) was slowly added and reacted at room temperature for 1 hour to stop the reaction. The reaction solution was placed in an ice bath, 40mL of ice water was added to the system, 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 directly used for the next reaction, LCMS: ESI-MS (m/z): 408.8[ M+H ]] + 。
Step 4: raw material 2, 2-diethoxyacetamide a1-5 (1.44 g,9.78 mmol) was dissolved in 20mL of anhydrous tetrahydrofuran in an ice bath, naH (390 mg,9.78 mmol) was slowly added thereto, and after stirring for 15 minutes, the intermediate a1-4 (1.8 g) of the above step was added thereto, and the reaction was stopped by heating to 50℃for 2 hours. 60mL of ice water is added into the system, dichloromethane extraction, saturated saline water washing, anhydrous sodium sulfate drying, filtration and concentration are carried out, and crude products are separated by flash column chromatography to obtain an intermediate a1-6 (1.2 g), and three-step yield: 45%, LCMS: ESI-MS (m/z): 459.9[ M+H ]] + 。
Step 5: under the protection of nitrogen, the intermediates a1-6 (1.2 g,2.61 mmol), potassium carbonate (1.08 g,7.83 mmol) and the raw material isopropenylboronic acid pinacol ester a1-7 (460 mg,2.74 mmol) are dissolved in a mixed solution of 11ml of 1,4-dioxane and water (v/v, 10/1), and the catalyst Pd (dppf) Cl is added 2 (95 mg,0.13 mmol) and stirred for 5 minutes, the temperature was raised to 80℃and the reaction was stopped for 5 hours. To the mixture was added 60mL of ice water, 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 give intermediate a1-8 (900 mg), yield: 92%, LCMS: ESI-MS (m/z): 374.1[ M+H ]] + 。
Step 6: under a hydrogen atmosphere (1 atm), the intermediates a1-8 (1.0 g,2.67 mmol) and palladium on carbon (100 mg) in the above step were dissolved in 11mL of ethanol, reacted at room temperature for 12 hours, the reaction was stopped, and filtered. The solvent was distilled off under reduced pressure to give intermediate a1-9 (900 mg), yield: 90%, LCMS: ESI-MS (m/z): 376.1[ M+H ]] + 。
Step 7: the intermediates a1-9 (900 mg,2.39 mmol) of the above step were dissolved in 5mL of concentrated sulfuric acid and stirred for 5 minutesAfter that, the reaction was stopped by heating to 50℃for 2 hours. The reaction solution was slowly poured into 50mL of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate a1-10 (300 mg), yield: 44%, LCMS: ESI-MS (m/z): 284.0[ M+H ]] + 。
Step 8: ice bath, intermediate a1-9 (250 mg,0.88 mmol) and diisopropylethylamine DIEA (340 mg,2.64 mmol) were dissolved in 5mL dichloromethane, and trifluoromethanesulfonic anhydride (320 mg,1.14 mmol) was slowly added, and the reaction was stopped after stirring and warming to room temperature for 1 hour. 30mL of ice water was added to the system, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and 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 ]] + 。
Referring to the synthetic route for compound a1, the following intermediates were synthesized using similar starting materials/framework structures.
Synthesis of intermediates a3-a5
Step 1: raw material 1H-4-pyrazoloboronic acid pinacol ester a3-1 (25.0 g,130 mmol) was dissolved in 300mL of anhydrous DMF in an ice bath, naH (7.7 g,190 mmol) was slowly added, and after stirring for 5 minutes, cyclopropylsulfonyl chloride (19.9 g,140 mmol) was added and reacted at room temperature for 12 hours, the reaction was stopped. To the system was added 1L of ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate a3-2 (35.0 g), yield: 91%, LCMS: ESI-MS (m/z): 299.2[ M+H ]] + 。
Step 5: under the protection of nitrogen, the intermediate a3-2 (27.5 g,92.2 mmol), cesium carbonate (90.2 g,280 mmol) and the starting material 2-chloro-4-aminopyrimidine a3-3 (11.9 g,92.2 mmol) were dissolved in 250mL of a mixed solution of 1,4-dioxane and water (v/v, 5-1) Adding catalyst Pd (dppf) Cl 2 (3.4 g,4.6 mmol) was stirred for 5 minutes, then the reaction was stopped by heating to 90℃for 10 hours, and filtration was performed. To the mixture was added 1L of ice water, 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 give intermediate a3 (8.7 g), yield: 36%, LCMS: ESI-MS (m/z): 266.3[ M+H ]] + 。
Referring to the synthetic route for compound a3, the following intermediates were synthesized using similar starting materials/framework structures.
Synthesis of intermediate a6
Step 1: under nitrogen protection, 3-bromothiophene a6-1 (2.0 g,12.3 mmol), N' -dimethyl-1, 2-cyclohexanediamine (870 mg,6.13 mmol), potassium iodide (1.02 g,6.13 mmol) and sodium cyclopropane sulfite a6-2 (3.14 g,24.5 mmol) were added to a 35mL microwave reactor, and catalyst [ Cu (OTf)] 2 Tolene (1.27 g,2.45 mmol), after stirring for 5 min, the reaction was stopped by heating with microwaves to 100℃for 2 hours, and filtered. To the mixture was added 100mL of ice water, 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 give intermediate a6-3 (2.2 g), yield: 95%, LCMS: ESI-MS (m/z): 189.0[ M+H ]] + 。
Step 2: ice bath, under nitrogen protection, the intermediate a6-3 (1.8 g,9.56 mmol) and aluminum trichloride (1.53 g,11.5 mmol) in the previous step are dissolved in 20mL of dichloromethane, bromine (1.68 g,10.5 mmol) is slowly added dropwise, the temperature is raised to room temperature for reaction for 2 hours, and the reaction is stopped. 50mL of saturated aqueous sodium thiosulfate solution was added to the reaction solution, the mixture was extracted with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash column chromatography to give intermediate a6-4 (1.6)g) Yield: 63%, LCMS: ESI-MS (m/z): 266.9[ M+H ]] + 。
Step 3: under the protection of nitrogen, the intermediate a6-4 (1.0 g,3.74 mmol), potassium acetate (730 mg,7.48 mmol) and pinacol bisborate (1.42 g,5.61 mmol) of the above step are dissolved in 10mL of toluene, and the catalyst Pd (dppf) Cl is added 2 (310 mg,0.37 mmol) was stirred for 5 minutes, then the temperature was raised to 80℃and the reaction was stopped for 10 hours, followed by filtration. The solvent was distilled off under reduced pressure, and the crude product was separated by flash column chromatography to give intermediate a6 (900 mg), yield: 77%, LCMS: ESI-MS (m/z): 315.1[ M+H ]] + 。
Synthesis of intermediate b1
Step 1: under nitrogen, starting material b1-1 (7.0 g,27.7 mmol) and triethylamine (4.2 g,41.5 mmol) were dissolved in 40mL of dichloromethane, and methanesulfonyl chloride (3.21 g,28.0 mmol) was added thereto and reacted at room temperature for 4 hours. The reaction was stopped, and the solvent was removed by pressure reduction to give crude b1-2 (10.8 g).
Step 2: the crude product b1-2 (10.8 g) and starting material b1-3 (4.21 g,27.7 mmol) from the previous step were dissolved in 30mL DMF and NaH (1.11 g,27.7 mmol) was added and the reaction was slowly warmed to 80℃for 12 hours and monitored by LC-MS for completion. The reaction was quenched by adding 100mL of a saturated aqueous solution of sodium chloride, extracted with methylene chloride, the organic phases were combined, washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude b1-4 (15 g). LC-MS: ESI-MS (m/z): 388.3[ M+H ]] + 。
Step 3: the crude product b1-4 (15 g) and LiCl (2.52 g,60.0 mmol) from the previous step were dissolved in 40mL of N, N-dimethylacetamide DMA and the reaction was stopped after heating to 150℃for 2 hours. To the reaction solution was added 100mL of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on flash column to give b1-5 (6.42 g) as a yellow solid, three-step total yield: 71%, LC-MS: ESI-MS (m/z): 330.1[ M+H ]] + 。
Step 4: under hydrogen atmosphere (2 atm), the intermediates b1-5 (6.42 g,19.5 mmol) and Pd/C (1.28 g,20%) Mix in 40mL of methanol, add 2mL of trifluoroacetic acid, react for 16 hours at room temperature, stop the reaction. Filtration and concentration gave b1 (4.5 g) as a yellow oil which was used directly in the next reaction. LC-MS: ESI-MS (m/z): 164.2[ M+H ]] + 。
Synthesis of intermediates b2-b5
Step 1: intermediate b1-2 (70.0 g,210 mmol) was added to a 500mL reaction flask, and a solution of methylamine in isopropanol (200 mL, 28% strength) was slowly added, and the reaction was warmed to 70℃for 4 hours, and the completion of the reaction was monitored by LC-MS. The solvent was distilled off under reduced pressure, and the crude product was separated by flash column chromatography to give oily intermediate b2-1 (39.0 g), yield: 69%, LCMS: ESI-MS (m/z): 267.4[ M+H ]] + 。
Step 2: intermediate b2-1 (39.0 g,150 mmol) and triethylamine (44.5 g,440 mmol) from the previous step were dissolved in 400mL of methylene chloride, and methanesulfonic anhydride (30.6 g,180 mmol) was slowly added and reacted at room temperature for 1 hour to stop the reaction. The reaction solution was placed in an ice bath, 1L of ice water was added to the system, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate b2-2 (40 g), which was directly used for the next reaction, LCMS: ESI-MS (m/z): 345.5[ M+H ]] + 。
Step 4: under hydrogen atmosphere (1 atm), the intermediate b2-2 (40 g,120 mmol) and trifluoroacetic acid (53.0 g,460 mmol) in the above step were dissolved in 200mL of methanol, palladium on carbon (4.0 g) was slowly added, the reaction was stopped at room temperature for 12 hours, and the solvent was distilled off under reduced pressure after filtration. To the mixture was added 100mL of water, the impurities were removed by extraction with dichloromethane, and the aqueous phase was lyophilized by a lyophilizer to give intermediate b3 (27.0 g), yield: 84%, LCMS: ESI-MS (m/z): 179.1[ M+H ]] + 。
Referring to the synthetic route for compound b2, the following intermediates were synthesized using similar starting materials/framework structures.
Synthesis of intermediate c1
Step 1: under nitrogen, intermediate a2 (3.25G, 8.15 mmol), cesium carbonate (5.31G, 16.3 mmol) and intermediate a4 (2.0G, 8.15 mmol) were dissolved in 25mL 1,4-dioxane and the catalyst XantphosPd-G was added 3 (420 mg,0.41 mmol), stirred for 5 minutes, then heated to 80℃for 2 hours, the reaction was stopped, and filtered. To the mixture was added 100mL of water, 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 give intermediate c1-1 (2.7 g), yield: 67%, LCMS: ESI-MS (m/z): 493[ M+H ]] + 。
Step 2: in an ice bath, the intermediate c1-1 (2.7 g,5.47 mmol) obtained in the above step was dissolved in 60mL of a1, 4-dioxane solution of hydrogen chloride (2M concentration), and the reaction was stopped at room temperature for 1 hour. To the system was added 100mL of saturated aqueous sodium bicarbonate to adjust the pH to about 9, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate c1 (2.2 g), which was used directly in the next reaction, LCMS: ESI-MS (m/z): 409[ M+H ]] + 。
Synthesis of intermediates c2-c7
Step 1: under nitrogen, intermediate a8 (2.0 g,3.96 mmol), sodium tert-butoxide (1.14 g,11.9 mmol) and starting material c2-1 (784 mg,7.92 mmol) were dissolved in 20mL toluene and catalyst Pd was added 2 dba 3 (733 mg,0.8 mmol) and ligand BINAP (498 mg,0.8 mmol), after stirring for 5 minutes, the reaction was stopped by heating to 110℃for 12 hours, and filtration was performed. 100mL of water was added to the mixture, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and concentration were performed, 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 ]] + 。
Step 2: under nitrogen, the intermediate c2-2 (600 mg,1.26 mmol), cesium carbonate (1.44 g,4.41 mmol) and intermediate b2 (640 mg,2.3 mmol) of the above procedure were dissolved in 6mL of 1,4-dioxane, and the catalyst XantPhospdG was added 3 (120 mg,0.13 mmol) was stirred for 5 minutes, then the temperature was raised to 110℃for 4 hours, the reaction was stopped, and the mixture was filtered. To the mixture was added 100mL of water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was separated by flash column chromatography (PE/EA, 2/1) to give intermediate c2 (150 mg), yield: 21%, LCMS: ESI-MS (m/z): 575[ M+H ]] + 。
Step 3: intermediate c2 (150 mg,0.26 mmol) from the previous step was dissolved in 6mL tetrahydrofuran, TBAF (120 mg,0.34 mmol) was added, the reaction was stopped at room temperature for 1.5 hours, and the reaction was filtered. To the mixture was added 100mL of water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate c3 (100 mg), LCMS: ESI-MS (m/z): 419[ M+H ]] + 。
Referring to the synthetic route for compound c2/c3, the following intermediates were synthesized using similar starting materials/framework structures.
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Example 2
Preparation of target molecules P1-P5, P13-P14
Step 1: under nitrogen protection, intermediate c1 (500 mg,1.22 mmol) and raw material P1-1 (350 mg,1.22 mmol) were dissolved in 5mL anhydrous DMF, naH (78 mg,1.95 mmol) was added, and after stirring for 5 minutes, the temperature was raised toThe reaction was stopped at 80℃for 2 hours, and filtered. To the mixture was added 30mL of water, 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 give compound P1-2 (270 mg), yield: 39%, LCMS: ESI-MS (m/z): 564[ M+H ]] + 。
Step 2: ice bath, the intermediate P1-2 (270 mg,0.48 mmol) from the previous step was dissolved in 6mL of methylene chloride, 2mL of trifluoroacetic acid was added, and the reaction was stopped at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the system to adjust the pH to about 9, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound P1-3 (150 mg), which was used directly in the next reaction, LCMS: ESI-MS (m/z): 464[ M+H ]] + 。
Step 3: the intermediate P1-3 (150 mg,0.32 mmol) obtained in the above step and an aqueous formaldehyde solution (0.6 mL) were dissolved in a mixed solution (v/v, 1/1) of 12mL of methylene chloride and tetrahydrofuran, and sodium triacetylborohydride (750 mg,3.54 mmol) was added thereto to react at room temperature for 2 hours, whereby the reaction was stopped. 50mL of water was added to the system, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by flash column chromatography to give Compound P1-4 (26 mg), yield: 17%, LCMS: ESI-MS (m/z): 478[ M+H ]] + 。
Step 4: under the protection of nitrogen, the compound P1-4 (26 mg,0.054 mmol), cesium carbonate (53 mg,0.16 mmol) and intermediate b2 (24 mg,0.086 mmol) of the above-mentioned compound are dissolved in 2mL of 1,4-dioxane, and the catalyst XantphosPd-G is added 3 (8.4 mg,0.008 mmol) and stirred for 5 minutes, then the reaction was stopped by heating to 110℃for 4 hours, and filtered. The solvent was distilled off under reduced pressure, and the crude product was separated by flash column chromatography to give the target molecule P1 (7.0 mg), yield: 22%, LCMS: ESI-MS (m/z): 576[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ10.25(s,1H),9.15(s,1H),8.76(s,1H),8.47(s,1H),8.39(d,J＝1.5Hz,1H),8.16(s,1H),7.50(d,J＝7.8Hz,1H),7.21(d,J＝5.1Hz,1H),6.71(d,J＝7.7Hz,1H),5.07(t,J＝7.1Hz,1H),4.69(t,J＝7.8Hz,1H),4.51–4.46(m,1H),4.25(t,J＝6.6Hz,1H),3.86(t,J＝7.2Hz,1H),3.76(t,J＝6.6Hz,2H),3.63(t,J＝6.5Hz,1H),2.98(s,3H),2.89–2.83(m,6H),2.38(s,3H),1.44(d,J＝6.0Hz,3H),1.39(dd,J＝8.3,7.0Hz,6H).
Referring to the synthetic route of compound P1, the following target molecule was synthesized using a similar backbone structure.
Example 3
Preparation of target molecule P6
Step 1: intermediate c1 (400 mg,0.98 mmol) and starting material P4-1 (300 mg,1.1 mmol) were dissolved in 5mL anhydrous DMF under nitrogen, naH (51 mg,1.3 mmol) was added, stirred for 5 minutes, then heated to 80℃for 8 hours, the reaction was stopped, and filtration was performed. To the mixture was added 30mL of water, 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 give compound P6-1 (400 mg), yield: 69%, LCMS: ESI-MS (m/z): 592[ M+H ]] + 。
Step 4: under the protection of nitrogen, the compound P6-1 (400 mg,0.68 mmol), cesium carbonate (774 mg,2.37 mmol) and intermediate b2 (281mg, 1.36 mmol) of the above-mentioned compound are dissolved in 3mL of 1,4-dioxane, and the catalyst XantphosPd-G is added 3 (76 mg,0.068 mmol), stirred for 5 minutes, then heated to 110℃and reacted for 8 hours, the reaction was stopped, and filtered. The solvent was distilled off under reduced pressure, and the crude product was separated by flash column chromatography to give Compound P6-2 (200 mg), yield: 73%, LCMS: ESI-MS (m/z): 690[ M+H ]] + 。
Step 2: ice bath, dissolving the compound P6-2 (200 mg,0.29 mmol) in 3mL dichloromethane, adding 2mL trifluoroacetic acid, reacting at room temperature for 2 hours, stoppingStopping the reaction. Saturated aqueous sodium bicarbonate was added to the system to adjust the pH to about 9, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by HPLC preparative chromatography to give the target molecule P6 (100 mg), yield: 59%, LCMS: ESI-MS (m/z): 590[ M+H ]] + 。
1H NMR(400MHz,DMSO-d 6 )δ10.19(s,1H),9.12(s,1H),8.77(s,1H),8.34(d,J＝5.8Hz,1H),8.29(s,1H),8.09(s,1H),7.47(d,J＝8.0Hz,1H),7.12(d,J＝5.6Hz,1H),6.68(d,J＝8.0Hz,1H),4.66(t,J＝7.4Hz,1H),4.45(t,J＝6.0Hz,1H),4.32–4.18(m,2H),3.83(t,J＝7.1Hz,1H),3.62(dd,J＝13.5,6.6Hz,1H),3.11–3.05(m,2H),2.95(s,3H),2.83(s,3H),2.60(t,J＝11.6Hz,2H),2.08–1.95(m,3H),1.89–1.78(m,2H),1.45–1.32(m,9H).
Example 4
Preparation of target molecules P7, P15-P17
Step 1: under nitrogen, 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 5mL of 1,4-dioxane and the catalyst XantphosPd-G was added 3 (50 mg,0.048 mmol), stirred for 5 minutes, then heated to 80℃for 5 hours, the reaction was stopped, and filtered. The solvent was distilled off under reduced pressure, and the crude product was separated by flash column chromatography to give Compound P7-1 (200 mg), yield: 78%, LCMS: ESI-MS (m/z): 531.1[ M+H ]] + 。
Step 4: under nitrogen, the above compound P7-1 (240 mg,0.45 mmol), cesium carbonate (440 mg,1.35 mmol) and intermediate b2 (170 mg,0.63 mmol) were dissolved in 3mL 1,4-dioxane and the catalyst XantphosPd-G was added 3 (46 mg,0.045 mmol), stirred for 5 minutes, then heated to 110℃and reacted for 5 hours, the reaction was stopped, and filtered. The solvent was distilled off under reduced pressure, and the crude product was separated by flash column chromatography to give the target molecule P7 (110 mg), yield: 39%, LCMS: ESI-MS (m/z): 629.2[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ10.42(s,1H),9.25(s,1H),8.80(s,1H),8.69(s,1H),8.50(s,1H),8.44(d,J＝5.9Hz,1H),7.40(d,J＝15.5Hz,1H),7.22(d,J＝5.3Hz,1H),4.86–4.77(m,1H),4.56(t,J＝7.1Hz,1H),4.14(q,J＝6.8Hz,1H),4.04(t,J＝7.1Hz,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).
Referring to the synthetic route of compound P7, the following target molecule was synthesized using a similar backbone structure.
Example 5
Preparation of target molecules P8-P9
Step 1: under nitrogen, 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 3mL 1,4-dioxane and the catalyst XantphosPd-G was added 3 (3 mg, 0.003mmol), stirred for 5 minutes, then heated to 80℃for 4 hours, the reaction was stopped, and filtered. The solvent was distilled off under reduced pressure, and the crude product was separated by flash column chromatography to give Compound P8-1 (40 mg), yield: 33%, LCMS: ESI-MS (m/z): 482.0[ M+H ]] + 。
Step 2: under the protection of nitrogen, the compound P8-1 (40 mg,0.08 mmol), cesium carbonate (81 mg,0.25 mmol) and intermediate b2 (32 mg,0.11 mmol) of the above-mentioned compound are dissolved in 2mL of 1,4-dioxane, and the catalyst XantphosPd-G is added 3 (8.5 mg,0.008 mmol) and stirred for 5 minutes, then the reaction was stopped by heating to 110℃for 12 hours, and filtered. The solvent was distilled off under reduced pressure, and the crude product was separated by flash column chromatography to give the target molecule P8 (14.7 mg), yield: 31%, LCMS: ESI-MS (m/z): 579.6[ M+H ]] + 。
1 H NMR(400MHz,CDCl 3 )δ9.13(s,1H),8.56(s,1H),8.39(d,J＝5.9Hz,1H),8.30(s,1H),8.22(s,1H),7.83(brs,1H),7.46(d,J＝7.9Hz,1H),6.95(d,J＝5.8Hz,1H),6.62(d,J＝8.0Hz,1H),4.60(t,J＝7.4Hz,1H),4.41(p,J＝6.1Hz,1H),4.30(dd,J＝13.5,6.9Hz,1H),4.15(s,2H),3.85(t,J＝7.2Hz,1H),3.65(dt,J＝13.6,6.8Hz,1H),2.93(s,3H),2.86(s,3H),1.51(d,J＝6.1Hz,3H),1.45–1.40(m,6H),1.23(s,6H).
Referring to the synthetic route of compound P8, the following target molecule was synthesized using a similar backbone structure.
Example 6
Preparation of target molecule P10-P12
Step 1: intermediate c3 (100 mg,0.24 mmol) and triethylamine (102 mg,1.0 mmol) were dissolved in 3mL of anhydrous dichloromethane under nitrogen protection, and trifluoromethanesulfonic anhydride (102 mg,0.36 mmol) was added thereto, followed by stirring for 5 minutes, heating to room temperature and reacting for 2 hours, and then 30mL of water was added to the reaction mixture to quench the reaction. Dichloromethane extraction, drying over anhydrous sodium sulfate, concentration, and flash column chromatography (DCM/MeOH, 20/1) of the crude product gave compound P10-1 (100 mg), yield: 76%, LCMS: ESI-MS (m/z): 551.1[ M+H ]] + 。
Step 4: under the protection of nitrogen, the compound P10-1 (100 mg,0.18 mmol), cesium carbonate (117 mg,0.36 mmol) and intermediate a3 (54 mg,0.20 mmol) of the above-mentioned compound are dissolved in 3mL of 1,4-dioxane, and the catalyst XantphosPd-G is added 3 (19 mg,0.02 mmol), stirred for 5 minutes, then heated to 110℃for 4 hours, the reaction was stopped, and filtered. The solvent was evaporated under reduced pressure and the crude product was separated by flash column chromatography (DCM/MeOH, 20/1) to give the target molecule P10 (50 mg), yield: 42%, LCMS: ESI-MS (m/z): 666.2[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ10.39(s,1H),9.10(s,1H),8.66(s,1H),8.60(s,1H),8.49(s,1H),8.44(d,J＝5.9Hz,1H),7.16(d,J＝8.3Hz,1H),6.65(d,J＝8.4Hz,1H),4.58(t,J＝7.3Hz,1H),4.53(s,1H),4.39(dd,J＝11.5,5.7Hz,1H),4.20(s,1H),4.19–4.13(m,1H),3.98(d,J＝7.5Hz,1H),3.70(dd,J＝14.5,7.4Hz,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＝6.0Hz,3H),1.36–1.31(m,2H),1.27–1.22(m,2H).
According to the synthetic route of the compound P10, the following target molecules are synthesized by adopting similar framework structures.
Example 7
The effect of small molecule inhibitors on proliferation of 4 strains of Ba/F3 cell lines (Ba/F3-EGFR-del 19, ba/F3-FL-EGFR, ba/F3-EGFR-del19-T790M-C797S and Ba/F3-EGFR-L858R-C797S) was examined using a Promega CellTiter-Glo reagent.
(Ba/F3-EGFR-del 19, ba/F3-EGFR-del19-T790M-C797S and Ba/F3-EGFR-L858R-C797S) culture solution: 1640m medium,10% FBS, glutamax and Green streptomycin.
(Ba/F3-FL-EGFR) culture solution: 1640 media, 10%FBS,Glutamax,100 ng/mL EGF and penicillin.
The cell line was cultured at 37℃under 5% CO 2 Is cultured in an incubator of (a). Cells in the logarithmic growth phase were taken for plating at regular passages. mu.L of cell suspension was added to each well of the cell plate, and cell-free (0.1% DMSO) culture medium was added to the Min control wells. Compound detection cell plate dosing: mu.L of 20 XCompound working solution was added to the cell culture plate. 5. Mu.L of DMSO-cell culture medium mixture was added to the Max control, and the final DMSO concentration was 0.1%. Add 5. Mu.L of DMSO-cell culture medium mixture to Max control. The final DMSO concentration was 0.1%.
The plates were incubated at 37℃with 5% CO 2 Culturing in an incubator for 72 hours. Cell activity assay by CellTiter-Glo luminescence. Data analysis:
cell proliferation Inhibition Rate (Inhibition Rate) data were processed using the following formula:
Inhibition Rate(Inh％)＝100-(RLU Drug -RLU Min )/(RLU Max -RLU Min )*100％。
wherein: RLU (radio link Unit) Drug Indicating relative luminescence units of cells to which the drug was added, RLU Min Indicating the luminescence unit of the culture solution, RLU Max The relative luminescence units of cells added with DMSO are shown.
Calculating inhibition rates corresponding to different concentrations of the compounds in EXCEL, using GraphPad Prism software as inhibition rate curve graph, and calculating related parameters including maximum and minimum inhibition rate of cell, IC 50 Values.
Table 1: representative Compounds antiproliferative inhibitory effects on BaF3 cell transfected kinase wild-type EGFR (wt), mutant EGFR (del 19) and mutant EGFR (del 19/T790M/C797S and Ba/F3-EGFR-L858R-C797S)
N.d. =untested
The results show that the molecule of the invention has good antiproliferative effect on the cell strain (containing C797S mutation) resistant to the Ornitinib, and shows the effect of the invention on solving the Ornitinib resistant tumor. The novel EGFR mutant type cell line (EGFR del 19) has good inhibition effect, and has weak inhibition on wild type, thus the novel EGFR mutant type cell line shows high selectivity.

Claims (6)

1. A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is selected from the group consisting of:
2. a pharmaceutical composition comprising a compound of any one of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, or isotopic variant thereof, and a pharmaceutically acceptable excipient; preferably, it also contains other therapeutic agents.
3. Use of a compound according to any one of claims 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of EGFR kinase mediated diseases.
4. According to claim 3, the EGFR kinase mediated disease is cancer.
5. The cancer of claim 4 being lung cancer, further selected from the group consisting of: non-small cell lung cancer (NSCLC), small Cell Lung Cancer (SCLC), lung adenocarcinoma, and lung squamous carcinoma.
6. According to claim 5, the lung cancer is selected from: non-small cell lung cancer NSCLC.
CN202310502540.9A 2022-12-30 2023-05-06 Fourth generation EGFR inhibitors Pending CN116554150A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024008048A1 (en) * 2022-07-04 2024-01-11 杭州德睿智药科技有限公司 Novel pyrimidine or triazine-substituted pyridoheterocyclic compound

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024008048A1 (en) * 2022-07-04 2024-01-11 杭州德睿智药科技有限公司 Novel pyrimidine or triazine-substituted pyridoheterocyclic compound

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