CN110950876A - Furanolactam compounds, preparation method and application - Google Patents

Furanolactam compounds, preparation method and application Download PDF

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CN110950876A
CN110950876A CN201911260477.2A CN201911260477A CN110950876A CN 110950876 A CN110950876 A CN 110950876A CN 201911260477 A CN201911260477 A CN 201911260477A CN 110950876 A CN110950876 A CN 110950876A
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CN110950876B (en
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万惠新
潘建峰
马金贵
沈竞康
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Rudong Lingda Biomedical Technology Co ltd
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    • 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
    • C07D491/04—Ortho-condensed systems
    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/02—Antineoplastic agents specific for leukemia

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Abstract

The invention discloses a furolactam compound, a preparation method and application. The invention particularly discloses a furolactam compound shown as a formula (I), or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, solvate, polymorph or prodrug thereof, a preparation method and pharmaceutical application thereof.

Description

Furanolactam compounds, preparation method and application
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a furolactam compound, a preparation method and application thereof.
Background
Extracellular signal-regulated kinases (ERKs) are a class of serine/threonine protein kinases found in the 90's of the 20 th century, and are one of the important subfamilies of the mitogen-activated protein kinase MAPKs family. Activated ERK can transmit extracellular signals to the nucleus, promote phosphorylation of cytoplasmic target proteins or regulate the activity of other protein kinases, thereby regulating gene expression. Ras-Raf-MEK-ERK signaling is central to the signaling network involved in regulating cell growth, development and differentiation, and therefore ERK has a variety of biological effects in regulating cell proliferation, differentiation, migration, invasion and apoptosis.
The Ras/Raf/MEK/ERK pathway is a main signal pathway related to the ERK function, is a hot spot for the development of cancer-targeted drugs, and a plurality of drugs developed aiming at node proteins on the signal pathway are successfully marketed in recent years. For example, specific B-Raf inhibitors Vemurafenib and dabrafenib, which are used for treating B-RafV600E mutant non-small cell lung cancer, were marketed in 2011 and 2013, respectively, for the treatment of melanoma, which received FDA-breakthrough drug eligibility. The MEK1/2 inhibitor trametinib was also marketed in 2013 for the treatment of melanoma. However, inhibition of these upstream pathway nodes has its limitations, tumors can rapidly develop resistance to B-Raf and MEK inhibitors, and Ras protein mutations are also found in numerous tumors, such as colorectal, pancreatic, lung, etc. The above mechanisms of drug resistance generation include point mutations, changes in protein multimeric forms, changes in protein peptide chain length, and the like, which are extremely challenging for the development of therapeutic drugs for next generation Ras-Raf-MEK resistance. However, the ERK is used as a downstream key node of the pathway, so that the occurrence of drug-resistant mutation is not discovered at present, and the ERK targeting drug can greatly improve the treatment of patients with drug resistance to upstream target inhibitors, so that the ERK targeting drug is a promising anti-cancer drug research and development field. Although a number of ERK inhibitors have been introduced into clinical studies in the early days, such as GDC0994, SCH772984, etc., these compounds have either been too toxic or poorly druggable to terminate clinical studies. Therefore, the discovery and search of novel ERK inhibitor compounds with high selectivity, high activity and high druggability become a major hot spot at present.
Disclosure of Invention
The invention aims to overcome the defects of single structure, low activity, easy drug resistance and the like of the conventional ERK inhibitor, and provides a furolactam compound, a preparation method and application thereof. The furolactam compound has a novel structure, has good inhibitory activity on ERK kinase, can inhibit the proliferation of tumor cells, and has anti-tumor activity.
The present invention solves the above-described problems by the following means.
The invention provides a compound shown as a formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a solvate, a polymorph or a prodrug thereof,
Figure BDA0002311469940000021
in the formula (I), the compound is shown in the specification,
R2selected from hydrogen, halogen, cyano, hydroxy, acyl, sulfonyl, sulfone, sulfoxide, sulfinyl, amino, substituted amino, C1-C10Alkyl radical, C1-C10Alkoxy radical, C1-C10Alkylamino, cycloalkyl or heterocycloalkyl of 3 to 10 members, aryl or heteroaryl of 5 to 10 members;
R3a、R3b、R4a、R4bindependently selected from hydrogen, halogen, hydroxy, alkoxy, amino, cyclic amino, C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl;
or, the above R3a、R3b、R4aAnd R4bAny two groups in between may form a 3-8 membered saturated or partially unsaturated carbocyclic or heterocyclic ring;
R6、R7、R8and R9Independently selected from hydrogen, halogen, hydroxyl, amino, C1-C8Alkyl, 3-to 8-membered cycloalkyl or heterocycloalkyl, 5-to 10-membered aryl or heteroaryl; or, the above R6、R7、R8And R9Any two groups in between may form a 3-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring;
l is selected from O, NR1、S(O)pAcyl, sulfonyl, amide, urea, sulfonylurea, sulfinyl, alkenyl, alkynyl, 3-to 8-membered cycloalkyl or heterocycloalkyl5-10 membered aryl or heteroaryl, wherein p is selected from 0-2;
R1independently selected from hydrogen, C1-C8Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl;
m is selected from N or CR5；R5Independently selected from hydrogen, halogen, cyano, nitro, C1-C6Alkyl, or 3-8 membered cycloalkyl; m, n and q are independently selected from 0-3;
one or more hydrogen atoms on any of the above groups are substituted with a substituent selected from the group consisting of: deuterium, halogen, hydroxy, amino, substituted amino, cyano, sulphonyl or sulphoxy, urea, sulphonyl urea, C1-C8Alkyl radical, R2-1Substituted C1-C8Alkyl, 3-8 membered cycloalkyl, C1-C8Alkoxy radical, C1-C8Alkylamino or cycloalkylamino, alkenyl, alkynyl, acyl or sulfonyl or sulfinyl, 5-8 membered aryl or heteroaryl, 4-8 membered cycloalkyl or heterocycloalkyl; wherein the substituent of the substituted amino is C1-C8An alkyl group; r2-1Selected from halogen, hydroxy, cyano, C1-C8Alkoxy, or C1-C8Alkylamino radical, R2-1The number of (A) is 1 or more;
wherein said heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of: n, O, P and S, said heterocycloalkyl group containing 1 to 3 heteroatoms selected from the group consisting of: n, O, P and S; each ring system is independently a saturated, partially unsaturated or unsaturated monocyclic, fused, bridged or spiro ring.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is1Is C1-C8When alkyl, said C1-C8Alkyl is preferably C1-C4An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably an isopropyl group.
In some preferred aspects of the inventionIn embodiments, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is1Is C1-C8When alkyl, said C1-C8Alkyl is optionally substituted with 1-3 halogens or hydroxy, preferably fluorine.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is1In the case of a 3-to 8-membered heterocycloalkyl group, the 3-to 8-membered heterocycloalkyl group is preferably a 5-to 6-membered heterocycloalkyl group having "one or more hetero atoms selected from N, O and S and a number of hetero atoms of 1 to 3", and more preferably a tetrahydropyranyl group.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is1In the case of a 5-to 10-membered heteroaryl group, the 5-to 10-membered heteroaryl group is preferably a 5-to 6-membered heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 to 3", more preferably a pyrazolyl group (for example, a pyrazolyl group)
Figure BDA0002311469940000041
) Or pyridyl (e.g. of
Figure BDA0002311469940000042
)。
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is1In the case of a 5-10 membered heteroaryl group, said 5-10 membered heteroaryl group is optionally substituted with 1 to 3C1-C8Alkyl is substituted, said C1-C8Alkyl is preferably C1-C4An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably a methyl group.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes):when R is2In the case of a 3-to 10-membered cycloalkyl group, the 3-to 10-membered cycloalkyl group is preferably a 5-to 6-membered cycloalkyl group, and more preferably a cyclohexyl group.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is2In the case of a 5-to 10-membered aryl group, the 5-to 10-membered aryl group is preferably a 6-to 10-membered aryl group or an 8-to 10-membered bicyclic aryl group, the 6-to 10-membered aryl group is preferably a phenyl group, and the 8-to 10-membered bicyclic aryl group is preferably a dihydroindenyl group (for example
Figure BDA0002311469940000043
)。
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is2In the case of a 5-10 membered aryl group, said 5-10 membered aryl group is optionally substituted with 1-3 halogens, preferably fluorine or chlorine.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is2In the case of a 5-10 membered aryl group, said 5-10 membered aryl group is optionally substituted with C1-C8Alkyl or R2-1Substituted C1-C8Alkyl substitution, said C1-C8Alkyl is preferably C1-C4An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably methyl or isopropyl.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is2When 5-10 membered aryl, said 5-10 membered aryl is optionally substituted with R2-1Substituted C1-C8Alkyl substitution, said R2-1The number of (a) is 1,2 or 3.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined below (undefined groups such asAs described in any of the previous schemes): when R is2When 5-10 membered aryl, said 5-10 membered aryl is optionally substituted with R2-1Substituted C1-C8Alkyl substitution, R2-1Is halogen, preferably fluorine.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is2In the case of a 5-to 10-membered aryl group, the 5-to 10-membered aryl group is substituted with a 5-to 8-membered heteroaryl group, and the 5-to 8-membered heteroaryl group is preferably a 5-to 6-membered heteroaryl group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", more preferably an oxazolyl group (for example, oxazolyl group
Figure BDA0002311469940000051
)。
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is2In the case of a 5-to 10-membered heteroaryl group, the 5-to 10-membered heteroaryl group is preferably an 8-to 9-membered bicyclic heteroaryl group in which "one or more heteroatoms selected from N, O and S and the number of heteroatoms is 1 to 3", or a 5-to 6-membered monocyclic heteroaryl group in which "one or more heteroatoms selected from N, O and S and the number of heteroatoms is 1 to 3", and the 5-to 6-membered monocyclic heteroaryl group is preferably a pyridyl group (for example, a pyridyl group)
Figure BDA0002311469940000052
) Said 8-9 membered bicyclic heteroaryl is preferably imidazopyridyl (e.g. imidazole-pyridyl)
Figure BDA0002311469940000053
)。
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is2In the case of a 5-10 membered heteroaryl group, said 5-10 membered heteroaryl group is optionally substituted with C1-C8Alkyl substitution, said C1-C8Alkyl is preferably C1-C4Alkyl (e.g., methyl, ethyl, propyl, isopropyl,propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably methyl.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is2In the case of a 5-10 membered heteroaryl group, said 5-10 membered heteroaryl group is optionally substituted with C1-C8Alkylamino substitution, said C1-C8Alkylamino is preferably C1-C4Alkylamino, more preferably alkylamino
Figure BDA0002311469940000054
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is3a、R3b、R4a、R4bIndependently is C1-C8When alkyl, said C1-C8Alkyl is preferably C1-C4An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably a methyl group.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is3a、R3b、R4a、R4bIndependently is C1-C8When alkyl, said C1-C8Alkyl is optionally substituted by 1-3C1-C8Alkoxy substitution of said C1-C8Alkoxy is preferably C1-C4An alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), more preferably a methoxy group.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is5When halogen is used, the halogen is preferably fluorine or chlorine.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is5Is C1-C6When alkyl, said C1-C6Alkyl is preferably C1-C4An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably a methyl group.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is5Is C1-C6When alkyl, said C1-C6Alkyl is optionally substituted with 1-3 halogens, preferably fluorine.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is6、R7、R8And R9Independently is C1-C8When there is an alkyl group, said C1-C8Alkyl is preferably C1-C4An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably a methyl group or an ethyl group.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is6、R7、R8And R9Independently is C1-C8When there is an alkyl group, said C1-C8Is optionally substituted with 1-3 halogens, preferably fluorine.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is6、R7、R8And R9Independently is C1-C8When there is an alkyl group, said C1-C8Optionally substituted by 1-3C1-C8Alkoxy substitution of said C1-C8Alkoxy is preferably C1-C4An alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), more preferably a methoxy group.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is6、R7、R8And R9Independently is C1-C8When there is an alkyl group, said C1-C8Optionally substituted by 1-3C1-C8Alkylamino substitution, said C1-C8Alkylamino is preferably C1-C4Alkylamino, more preferably alkylamino
Figure BDA0002311469940000071
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when L is an amide, said amide is preferably-C (═ O) NH-; wherein, C terminal is connected with
Figure BDA0002311469940000072
Are connected, N terminal to
Figure BDA0002311469940000073
Are connected.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r1Is selected from C1-C8Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; said C1-C8Alkyl is optionally substituted with 1-3 halogens or hydroxy; said 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with 1-3C1-C8Alkyl groups are substituted.
In some preferred embodiments of the inventionIn this case, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as defined in any of the preceding schemes): r1Is selected from C1-C8Alkyl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl; said C1-C8Alkyl is optionally substituted with 1-3 halogens or hydroxy; said 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with 1-3C1-C8Alkyl groups are substituted.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r1Selected from 5-10 membered heteroaryl; said 5-10 membered heteroaryl group optionally substituted with 1-3C1-C8Alkyl groups are substituted.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r2Selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; said 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with 1-3 halogens, C1-C8Alkyl radical, R2-1Substituted C1-C8Alkyl radical, C1-C8Alkoxy radical, C1-C8Alkylamino, or 5-8 membered heteroaryl; r2-1Selected from halogen or hydroxyl.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r2Is 6-10 membered aryl or 5-10 membered heteroaryl; said 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted by 1-3 halogen, C1-C8Alkyl or C1-C8Alkylamino.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r2Is a 6-to 10-membered aryl group; said 6-to 10-membered aryl being optionally substituted by 1-3 halogens, C1-C8Alkyl or C1-C8Alkylamino.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r2Is a 6-to 10-membered aryl group; said 6-to 10-membered aryl is optionally substituted with 1-3 halogens.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r3a、R3b、R4aAnd R4bIndependently selected from hydrogen, or C1-C8An alkyl group; said C1-C8Alkyl is optionally substituted by 1-3C1-C8Alkoxy substitution.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r3a、R3b、R4aAnd R4bIs hydrogen.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r5Independently selected from hydrogen, halogen, cyano, or C1-C6An alkyl group; said C1-C6Alkyl is optionally substituted with 1-3 halogens.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r6、R7、R8And R9Independently selected from hydrogen, or C1-C8Alkyl groups of (a); said C1-C8Optionally substituted by 1-3 halogens, hydroxy, C1-C8Alkoxy, or C1-C8And (4) alkyl amino substitution.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r6、R7、R8And R9Independently selected from hydrogen, or C1-C8Alkyl groups of (a); said C1-C8Is optionally substituted with 1-3 hydroxyl groups.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r6、R7、R8And R9Independently selected from hydrogen, or C1-C8Alkyl groups of (a); said C1-C8Is optionally substituted with 1-3 hydroxyl groups; r6And R7Is different from R6And R7The attached C atom is in the R configuration.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r6And R7Independently selected from hydrogen, or C1-C8Alkyl group of (1).
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r8Is hydrogen, R9Is C1-C8Or R is8Is C1-C8Alkyl of R9Is hydrogen; said C1-C8Is substituted with 1 hydroxyl group.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): l is an amide.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m is selected from N or CR5。
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m is selected from N or CH.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m is CH.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m, n and q are independently selected from 0, 1,2 or 3.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m and n are 1.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): q is selected from 0 or 1.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): q is 0.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r1Is composed of
Figure BDA0002311469940000101
Preference is given to
Figure BDA0002311469940000102
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r2Is composed of
Figure BDA0002311469940000103
Figure BDA0002311469940000104
Figure BDA0002311469940000105
Preference is given to
Figure BDA0002311469940000106
Figure BDA0002311469940000107
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r3aAnd R3bIndependently hydrogen or methyl.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r4aAnd R4bIndependently is hydrogen, methyl or
Figure BDA0002311469940000108
Hydrogen is preferred.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r5Is hydrogen, fluorine, chlorine, cyano, methyl or trifluoromethyl.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r6And R7Independently is hydrogen, methyl, ethyl or-CH2F, preferably hydrogen or methyl.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r8And R9Independently hydrogen, methyl, -CH2OH、
Figure BDA0002311469940000111
Preferably hydrogen or-CH2OH。
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): l is-C (═ O) NH-; wherein, C terminal is connected with
Figure BDA0002311469940000112
Are connected, N terminal to
Figure BDA0002311469940000113
Are connected.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m is N or CH.
In certain preferred embodiments of the present invention, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, wherein the compound of formula (I) may be any one of the following compounds:
Figure BDA0002311469940000114
Figure BDA0002311469940000121
Figure BDA0002311469940000131
the invention also provides a preparation method of the compound shown in the formula (I), which comprises the following steps of a-d:
a) subjecting the compound of the general formula (A) to multi-step functional group conversion reaction to obtain a compound of the general formula (B1); and
b) reacting a compound of the general formula (B1) with a compound of the general formula (C1) R1-NH under basic conditions2Reacting to prepare a compound shown in the general formula (I); and
c) in the presence of a transition metal catalyst, carrying out cross-coupling reaction of a compound of a general formula (A) and a compound of a general formula (B2 or B3) as shown in the specification to prepare a compound of a general formula (I) or a compound of a general formula (C); and
d) in the presence of acid, alkali or transition metal, carrying out catalytic coupling or substitution reaction on the compound shown in the general formula (C) and the compound shown in the general formula (C1) to prepare a compound shown in the general formula (I);
Figure BDA0002311469940000141
wherein Mc is boric acid, borate, organotin, or organozinc, X is hydrogen, halogen, or sulfonate, and each of the other groups is as defined in any one of the preceding embodiments.
Preferably, each of the steps a), b), c), d) is carried out in a solvent, and the solvent is selected from one or more of water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, and dioxane.
Preferably, the transition metal catalyst is selected from iridium catalysts [ such as bis (1, 5-cyclooctadiene) bis- μ -methoxydiidium, Ir (acac) (COD), [ Ir (COD) ((PPP))]Trivalent iridium catalyst such as (OTf)]Tris (dibenzylideneacetone) dipalladium (Pd)2(dba)3) Tetrakis (triphenylphosphine) palladium (Pd (PPh)3)4) Palladium acetate, palladium chloride, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene]One or more of palladium dichloride, bis (tri-o-phenylphosphino) palladium dichloride, and 1, 2-bis (diphenylphosphino) ethane palladium dichloride; the catalyst ligand is selected from one or more of tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-benzylphosphine, tricyclohexylphosphine, and tri-o-benzylphosphine.
Preferably, the inorganic base is selected from one or more of sodium hydride, potassium hydroxide, sodium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate; the organic base is selected from one or more of pyridine, triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, and lutidine.
Preferably, the acid is selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid.
The invention also provides a pharmaceutical composition, which comprises the compound shown in the formula (I) or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, solvate, polymorph or prodrug thereof and a pharmaceutically acceptable carrier. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof, can be in a therapeutically effective amount.
The pharmaceutical composition is preferably a pharmaceutical composition for preventing and/or treating tumors, and consists of a compound shown as a formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a solvate, a polymorph or a prodrug thereof, and a pharmaceutically acceptable carrier; wherein the tumor includes but is not limited to non-small cell lung cancer, melanoma, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, pancreatic cancer, skin cancer, stomach cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymph cancer or nasopharyngeal cancer.
The invention also provides the application of the compound shown as the formula (I) or the pharmaceutically acceptable salt thereof, or the enantiomer, the diastereomer, the tautomer, the solvate, the polymorph or the prodrug thereof, or the pharmaceutical composition in preparing medicines. The medicament is preferably a medicament for preventing and/or treating tumors or a medicament for treating diseases related to ERK kinase. Wherein, the tumor includes but is not limited to non-small cell lung cancer, melanoma, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, pancreatic cancer, skin cancer, stomach cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymph cancer or nasopharyngeal carcinoma; the ERK kinase is preferably ERK1 and/or ERK2, more preferably ERK 2.
The invention also provides application of the compound shown as the formula (I) or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, solvate, polymorph or prodrug thereof, or the pharmaceutical composition in preparing ERK kinase inhibitors. The ERK kinase is preferably ERK1 and/or ERK2, more preferably ERK 2.
The compound shown in the formula (I) can inhibit various tumor cells, particularly can efficiently kill tumors related to Ras-Raf-MEK-ERK signal channel abnormity, has the characteristics of high cell activity, difficult drug resistance and the like compared with compounds such as BVD523, and is a treatment drug with a brand new action mechanism.
The present invention also provides a method for preventing and/or treating tumors, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, or a pharmaceutical composition thereof; wherein the tumor includes but is not limited to non-small cell lung cancer, melanoma, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, pancreatic cancer, skin cancer, stomach cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymph cancer or nasopharyngeal cancer.
In the present invention, the tumor can be Ras-Raf-MEK-ERK positive tumor, including but not limited to Ras-Raf-MEK-ERK positive non-small cell lung cancer, melanoma, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, pancreatic cancer, skin cancer, stomach cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymph cancer or nasopharyngeal cancer.
Term(s) for
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are not limiting.
Definitions for the terms of the standardization industry can be found in the literature references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4. THED." vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, (I) R and UV/V (I) S spectroscopy, and pharmacological methods. Unless a specific definition is set forth, the terms used herein in the pertinent description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.
When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, -CH 2O-is equivalent to-OCH 2-.
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. E.g. C1-6Alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the shorthand notation excludes carbons that may be present in a substituent of the group.
In addition to the foregoing, the following terms, when used in the specification and claims of this application, have the meanings indicated below, unless otherwise specifically indicated.
In the present application, the term "halogen" means fluorine, chlorine, bromine or iodine; "hydroxy" means an-OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted with a hydroxyl (-OH) group; "carbonyl" refers to a-C (═ O) -group; "nitro" means-NO2(ii) a "cyano" means-CN; "amino" means-NH2(ii) a "substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., monoalkylamino, dialkylamino, alkylamido, aralkylamino, heteroaralkylamino; "carboxyl" means-COOH.
In the present application, the term "alkyl", as a group or as part of another group (e.g. as used in groups such as halogen-substituted alkyl), means a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing no unsaturated bonds, having, for example, from 1 to 12 (preferably from 1 to 8, more preferably from 1 to 6) carbon atoms and being attached to the rest of the molecule by single bonds. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, and the like.
In the present application, the term "alkenyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, and being connected to the rest of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.
In the present application, the term "alkynyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being connected to the rest of the molecule by single bonds, such as but not limited to ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl and the like.
In the present application, the term "cycloalkyl" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon atoms and hydrogen atoms, which may include fused, bridged or spiro ring systems, having 3 to 15 carbon atoms, preferably having 3 to 10 carbon atoms, more preferably having 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the rest of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the specification, carbon atoms in cycloalkyl groups may be optionally oxidized. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2, 3-indanyl, 1,2,3, 4-tetrahydro-naphthyl, 5,6,7, 8-tetrahydro-naphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 7-dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [2.2.2] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, Bicyclo [3.2.1] octenyl, adamantyl, octahydro-4, 7-methylene-1H-indenyl, octahydro-2, 5-methylene-pentalenyl and the like.
In this application, the term "heterocyclyl" as a group or part of another group means a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise specifically indicated in the specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or higher ring system, which may include fused ring systems, bridged ring systems or spiro ring systems; wherein the nitrogen, carbon or sulfur atom in the heterocyclic group may be optionally oxidized; the nitrogen atoms may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclic groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl is preferably a stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2, 7-diaza-spiro [3.5] nonan-7-yl, 2-oxa-6-aza-spiro [3.3] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.
In this application, the term "aryl" as a group or as part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group may be a monocyclic, bicyclic, tricyclic or higher polycyclic ring system and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is attached to the remainder of the molecule by a single bond via an atom on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.
In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.
In this application, the term "heteroaryl" as a group or part of another group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or higher ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is attached to the rest of the molecule by a single bond via an atom on the aromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atoms may optionally be quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5-to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5-to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or a 5-to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindolyl, purinyl, quinolyl, isoquinolyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, orthophenanthrolidinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthopyridyl, pyridinyl, and the like, [1,2,4] triazolo [4,3-b ] pyridazine, [1,2,4] triazolo [4,3-a ] pyrazine, [1,2,4] triazolo [4,3-c ] pyrimidine, [1,2,4] triazolo [4,3-a ] pyridine, imidazo [1,2-b ] pyridazine, imidazo [1,2-a ] pyrazine and the like.
In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.
In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.
The terms "moiety," "structural moiety," "chemical moiety," "group," "chemical group" as used herein refer to a specific fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded in or attached to a molecule.
"stereoisomers" refers to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present invention is intended to cover various stereoisomers and mixtures thereof.
When the compounds of the present invention contain olefinic double bonds, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.
"tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention.
The compounds of the present invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting as starting materials or intermediates racemates, diastereomers or enantiomers. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, e.g., crystallization and chiral chromatography.
Conventional techniques for preparing/isolating individual isomers include Chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, Chiral high performance liquid chromatography, see, for example, GeraldG ü b (I) tz and Martin G.Schmid (Eds.), Chiral separators, Methods and Protocols, Methods in Molecular Biology, Vol.243,2004, A.M.Stalcup, Chiral separators, Annu.Rev.Anal.Chem.3: 341. 63,2010, Fumis et al (Eds.), VOGEL' S ENCYCLOPOPA OFICA ORGANIC CHEMISTRY 5. TH, Longman Scientific and Technical Ltd., Essex,1991,809, 1990. 23,128.
In the present application, the term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
"pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids which retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formates, acetates, 2-dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, caprates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartates, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbates, salicylates, 4-aminosalicylates, napadisylates, and the like. These salts can be prepared by methods known in the art.
"pharmaceutically acceptable base addition salts" refers to salts with inorganic or organic bases which maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.
"polymorph" refers to different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystalline form and the present invention is intended to include the various crystalline forms and mixtures thereof.
Typically, crystallization will result in solvates of the compounds of the invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrate, hemihydrate, sesquihydrates, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases it is also possible to retain only adventitious water or a mixture of water plus a portion of adventitious solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
The invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" denotes a compound that can be converted under physiological conditions or by solvolysis to the biologically active compound of the invention. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs may not be active when administered to a subject in need thereof, but are converted in vivo to the active compounds of the invention. Prodrugs are generally rapidly converted in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. Prodrug compounds generally provide solubility, histocompatibility, or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups. Specific methods for preparing prodrugs can be found in Saulnier, M.G., et al, bioorg.Med.chem.Lett.1994,4, 1985-1990; greenwald, r.b., et al, j.med.chem.2000,43,475.
In the present application, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of active ingredients and exert biological activity.
The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.
As used herein, a "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that is approved by the relevant governmental regulatory agency for human or livestock use.
The "tumor" and "diseases related to abnormal cell proliferation" include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, squamous cell lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.
The terms "preventing," "prevention," and "prevention" as used herein include reducing the likelihood of occurrence or worsening of a disease or disorder in a patient.
As used herein, the term "treatment" and other similar synonyms include the following meanings:
(I) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;
(II) inhibiting the disease or disorder, i.e., arresting its development;
(III) alleviating the disease or disorder, i.e., causing regression of the state of the disease or disorder; or
(Iv) alleviating the symptoms caused by the disease or disorder.
The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.
The terms "administering," "administration," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, the pharmacological Basis of Therapeutics, current ed.; pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The terms "drug combination", "administering other treatment", "administering other therapeutic agent" and the like as used herein refer to a drug treatment obtained by mixing or combining more than one active ingredient, including fixed and unfixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one co-agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration, concomitant administration, or sequential administration at variable intervals of at least one compound described herein and at least one synergistic formulation to a patient as separate entities. These also apply to cocktail therapy, for example the administration of three or more active ingredients.
It will also be appreciated by those skilled in the art that in the processes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butyloxycarbonyl, benzyloxycarbonyl and the like. Suitable thiol protecting groups include-C (O) -R (where "R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
Protecting groups may be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting Groups is described in detail in Greene, T.W. and P.G.M.Wuts, Protective Groups in organic Synthesis, (1999),4th Ed., Wiley. The protecting group may also be a polymeric resin.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. The space is not described herein in a repeated fashion.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the compound prepared by the invention has a novel structure and better ERK kinase inhibitory activity, and the compound has a specific inhibitory action on ERK kinase, particularly ERK2, at an extremely low concentration (which can be as low as less than or equal to 10nmol/L), has quite excellent cell proliferation inhibitory activity on Ras-Raf-MEK-ERK, and can be used for treating related diseases such as tumors caused by Ras-Raf-MEK-ERK kinase mutation or abnormal expression amount.
Detailed Description
The invention will be further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
The first preparation method of the intermediate comprises the following steps: preparation of furohexa-lactam
Intermediate a 1: (R) -tert-butyl 2- (2-bromo-4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionate
Figure BDA0002311469940000261
The first step is as follows: ethyl 2- (2-hydroxyethyl) furan-3-carboxylate (1.9g, 0.01mol) was dissolved in methanol (10mL), 2M sodium hydroxide NaOH (10.3mL) was added, the reaction was allowed to proceed overnight at room temperature, 2M hydrochloric acid solution was added to adjust pH to 2-3, ethyl acetate was extracted 4 times, dried over anhydrous magnesium sulfate, and concentrated to give 2- (2-hydroxyethyl) furan-3-carboxylic acid (1.6g, white solid). LC-MS ESI [ M + H ]]+＝155.2。
The second step is that: dissolving 2- (2-hydroxyethyl) furan-3-carboxylic acid (1.6g, 10.3mmol) in N, N-dimethylformamide DMF (20mL), adding D-alanine tert-butyl ester (2.8g, 15.4mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate HATU (5.9g, 15.4mmol) and N, N-diisopropylethylamine DIEA (5.3g, 41.2mmol), stirring at room temperature for 5.5h, adding saturated ammonium chloride NH4The Cl solution was extracted with ethyl acetate, dried, concentrated under reduced pressure, and purified by column chromatography to give the compound tert-butyl 2- (2-hydroxyethyl) furan-3-carbonyl) -D-alanine (2.5g, white solid). LC-MS ESI [ M + H ]]+＝284.2。
The third step: tert-butyl 2- (2-hydroxyethyl) furan-3-carbonyl) -D-alanine (2.5g, 8.8mmol) was dissolved in dichloromethane (20ml), protected with nitrogen, triethylamine TEA (2.7g, 26.4mmol) and methanesulfonyl chloride Ms-Cl (1.2g, 10.4mmol) were added, reacted at room temperature for 40 minutes, washed twice with water and dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in DMF (20ml), protected with nitrogen, sodium hydrogen NaH (0.32g,13.2mmol) was added in portions under ice salt bath, reacted overnight at room temperature, saturated NH was added4Extracting with ethyl acetate, drying, concentrating under reduced pressure, and purifying by column chromatography to obtain compound (R) -2- (4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid tert-butyl ester (0.64g, white solid). LC-MS ESI [ M + H ]]+＝266.2。
The fourth step: mixing (R) -2- (4-oxo-6, 7-dihydrofuran [3, 2-c)]Tert-butyl pyridin-5 (4H) -yl) propionate (2g, 7.5mmol) was dissolved in DMF (20mL), 2mL of acetic acid was added dropwise, NBS (1.3g, 7.5mmol) was added, and the reaction was stirred at room temperature overnight. Adding saturated NH4Cl solution, acetic acid ethyl esterExtracting with ester, drying, concentrating under reduced pressure, and purifying by column chromatography to obtain compound (R) -2- (2-bromo-4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid tert-butyl ester (0.6g, white solid). LC-MS ESI [ M + H ]]+＝344.1。1H-NMR(400MHz,CD3OD)δ6.64(s,1H),4.92-4.98(q,1H),3.68-3.74(m,2H),2.95-3.06(m,2H),1.45(s,9H),1.43(d,3H)。
Intermediate a 2: 5- (3-chlorobenzyl) -6, 7-dihydrofuran [3,2-c]Pyridin-4 (5H) -ones
Figure BDA0002311469940000271
Intermediate a2 was prepared using the same synthetic route and procedure as intermediate a 1. LC-MS ESI [ M + H ]]+＝262.1；1H-NMR(400MHz,DMSO-d6)δ7.70(d,J＝1.2Hz,1H),7.25-7.37(m,4H),6.70(d,J＝1.6Hz,1H),4.61(s,2H),3.57(t,J＝7.2Hz,2H),2.98(t,J＝7.2Hz,2H)。
And a second intermediate preparation method comprises the following steps: synthesis of 2-aminopyridines
Intermediate B1: (4-chloro-5-methylpyridin-2-yl) (1-methyl-1H-pyrazol-5-yl) carbamic acid tert-butyl ester
Figure BDA0002311469940000272
The first step is as follows: 2, 4-dichloro-5-methylpyridine (50g, 0.31mol) and 1-methyl-1H-pyrazol-5-amine (30g, 0.31mol) were dissolved in DMF (500mL), and cesium carbonate Cs was added under nitrogen protection2CO3(202g, 0.62mol), palladium Pd on tris (dibenzylideneacetone)2(dba)3(28g, 0.031mol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene xanthophos (36g, 0.062mol), and the reaction was carried out at 100 ℃ for 2 days. The reaction solution was cooled to room temperature, and saturated NH was added4The Cl solution was extracted with ethyl acetate, dried, concentrated under reduced pressure, and purified by column chromatography to give 4-chloro-5-methyl-N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine (23.4g, white solid). LC-MS ESI [ M + H ]]+＝223.2。
The second step is that: 4-chloro-5-methyl-N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine (23.4g, 0.11mol) was dissolved in dichloromethane DCM (200mL) and di-tert-butyl dicarbonate, Boc, was added2O (25.3g, 0.12mol), DMAP (1.3g, 11mmol) and TEA (16.7g, 0.16mol) were stirred at room temperature overnight and saturated NH was added4The resulting Cl solution was extracted with dichloromethane, dried, concentrated under reduced pressure, and purified by column chromatography to give tert-butyl (4-chloro-5-methylpyridin-2-yl) (1-methyl-1H-pyrazol-5-yl) carbamate (29.6g, white solid). LC-MS ESI [ M + H ]]+＝323.4/325.4。1H-NMR(DMSO-d6,400MHz)8.12(s,1H),7.75(s,1H),7.47(d,J＝2Hz,1H),6.08(d,J＝2Hz,1H),3.73(s,3H),2.30(s,3H),1.45(s,9H)。
Intermediate B2: (4-Chloropyridin-2-yl) (1-methyl-1H-pyrazol-5-yl) carbamic acid tert-butyl ester
Figure BDA0002311469940000281
Intermediate B2 was prepared using the same synthetic route and procedure as intermediate B1. LC-MS ESI [ M + H ]]+＝309.1/311.1。
Examples
Example 1: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000282
The first step is as follows: tert-butyl (4-chloro-5-methylpyridin-2-yl) (1-methyl-1H-pyrazol-5-yl) carbamate (5G, 15.5mmol), pinacol borate (15.8G, 62.1mmol) were dissolved in dimethylsulfoxide DMSO (50mL), Pd-XPhos-G2(1.2G, 1.5mmol), 2-dicyclohexylphosphonium-2 ', 4', 6 ' -triisopropylbiphenyl XPhos (1.4G, 3.0mmol) and potassium acetate (3G, 31mmol) were added under nitrogen protection, and the mixture was heated to 75 ℃ for overnight reaction. The reaction solution was cooled to room temperature, filtered, and the residue was purified by column chromatography to give (2- ((tert-butoxycarbonyl) (1-methyl-1H-pyrazol-5-yl) amino) -5-methylpyridin-4-yl) boronic acid pinacol ester (2g, white solid). LC-MS ESI [ M + H ]]+＝415.3。
The second step is that: (2- ((tert-Butoxycarbonyl) (1-methyl-1H-pyrazol-5-yl) amino) -5-methylpyridin-4-yl) boronic acid pinacol ester (724mg, 1.75mmol) and (R) -2- (2-bromo-4-oxo)6, 7-dihydrofuran [3,2-c ]]Pyridin-5 (4H) -yl) propionic acid tert-butyl ester (600mg, 1.75mmol) was dissolved in Dioxane/H2O (20mL/4mL), tetrakis (triphenylphosphine) palladium (0) Pd (PPh) was added3)4(92.4mg, 0.08mmol) and Cs2CO3(1.15g, 3.5mmol), heated to 90 ℃ and reacted for 18 hours. Cooling the reaction solution to room temperature, filtering, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain (R) -2- (2- (2- ((tert-butoxycarbonyl) (1-methyl-1H-pyrazol-5-yl) amino) -5-methylpyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid tert-butyl ester (530mg, white solid). LC-MS ESI [ M + H ]]+＝552.3。
The third step: reacting (R) -2- (2- (2- ((tert-butoxycarbonyl) (1-methyl-1H-pyrazol-5-yl) amino) -5-methylpyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ]]Tert-butyl pyridin-5 (4H) -yl) propionate (530mg, 0.96mmol) was dissolved in dichloromethane (40mL), trifluoroacetic acid (10mL) was added, and the reaction was carried out at room temperature for 18H. Concentrating under reduced pressure, and purifying the residue by column chromatography to obtain (R) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridine-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid (white solid). LC-MS ESI [ M + H ]]+＝396.2。
The fourth step: mixing (R) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridine-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid (50mg, 0.12mmol) and (S) -2-amino-2- (3-chlorophenyl) ethyl-1-ol (23mg, 0.13mmol) were dissolved in DMF (20mL), HATU (136.8mg, 0.36mmol) and DIEA (31mg, 0.24mmol) were added and reacted at room temperature for 18H. Concentrating under reduced pressure, and purifying the residue by column chromatography to obtain (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridine-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionamide (5.2mg, white solid). LC-MS: ESI (M + H) 549.5.1H-NMR(CD3OD,400MHz)7.85(s,1H),7.33(d,J＝2.0Hz,1H),7.29(s,1H),7.14-7.23(m,3H),7.00(s,1H),6.92(s,1H),6.11(d,J＝2.0Hz,1H),5.17-5.23(m,1H),4.86-4.89(m,1H),3.61-3.70(m,7H),3.06-3.12(m,1H),2.91-2.97(m,1H),2.26(s,1H),1.32(d,J＝7.2Hz,3H)。
Example 2: (R) -N- ((6- (dimethylamino) pyridin-2-yl) methyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000291
Synthesized by the same method as in example 1, LC-MS: ESI (M + H) 529.4.1H-NMR(DMSO-d6,400MHz)8.76(s,1H),8.33-8.37(m,1H),8.04(s,1H),7.44(t,J＝7.6Hz,1H),7.31(d,J＝5.6Hz,1H),7.13(s,1H),7.07(s,1H),6.46(t,J＝8.4Hz,2H),6.24(s,1H),5.14-5.19(m,1H),4.21(d,J＝6.0Hz,2H),3.63-3.70(m,5H),3.00-3.10(m,2H),2.98(s,6H),2.38(s,3H),1.37(d,J＝7.2Hz,3H)。
Example 3: (R) -N- ((6- (dimethylamino) pyridin-2-yl) methyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000301
Synthesized by the same method as in example 1, LC-MS: ESI (M + H) 515.5.1H-NMR(DMSO-d6,400MHz)9.52(br s,1H),8.63(t,J＝5.6Hz,1H),8.12(d,J＝6.0Hz,1H),7.82(t,J＝8.0Hz,1H),7.61(s,1H),7.47(d,J＝2.0Hz,1H),7.29(d,J＝5.6Hz,1H),7.13(s,1H),6.98(d,J＝8.4Hz,1H),6.67(d,J＝7.2Hz,1H),6.34(d,J＝2.0Hz,1H),5.07-5.09(m,1H),4.38-4.40(m,2H),3.68-3.71(m,5H),3.18(s,6H),3.12(t,J＝7.2Hz,2H),1.38(d,J＝7.2Hz,3H)。
Example 4: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000302
Synthesized by the same method as in example 1, LC-MS: ESI (M + H) 535.5.1H-NMR(CD3OD,400MHz)8.06-8.09(m,1H),7.46(s,1H),7.24-7.37(m,5H),7.10(d,J＝6.8Hz,1H),6.99(s,1H),6.24(d,J＝1.6Hz,1H),5.26-5.28(m,1H),4.92-4.97(m,1H),3.69-3.80(m,7H),3.04-3.21(m,2H),1.43(d,J＝7.2Hz,3H)。
Example 5: (S) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000303
Synthesized by the same method as in example 1, LC-MS: ESI (M + H) 535.5.1H-NMR(CD3OD,400MHz)8.06-8.09(m,1H),7.42-7.46(m,1H),7.22-7.33(m,5H),7.10(d,J＝7.2Hz,1H),6.99(s,1H),6.24(d,J＝2.0Hz,1H),5.26-5.31(m,1H),4.92-4.97(m,1H),3.58-3.79(m,7H),2.94-3.13(m,2H),1.45(d,J＝7.2Hz,3H)。
Example 6: (S) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000311
Synthesized by the same method as in example 1, LC-MS: ESI (M + H) 549.3.1H-NMR(CD3OD,400MHz)：7.95(s,1H),7.44(d,J＝2.0Hz,1H),7.23-7.32(m,4H),7.14(s,1H),7.07(s,1H),6.21(d,J＝1.6Hz,1H),5.29-5.32(m,1H),4.94-4.99(m,1H),3.58-3.80(m,8H),2.98-3.04(m,1H),2.39(s,3H),1.45(d,J＝6.8Hz,3H)。
Example 7: (R) -N- ((S) -2-hydroxy-1- (m-tolyl) ethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000312
Synthesized by the same method as in example 1, LC-MS: ESI (M + H) 529.4;1H-NMR(CD3OD,400MHz)：8.76(s,1H),8.30(d,J＝8.0Hz,1H),8.05(s,1H),7.33(s,1H),7.03-7.21(m,6H),6.25(s,1H),5.17-5.19(m,1H),4.82-4.85(m,2H),3.55-3.72(m,7H),3.05-3.18(m,2H),2.35(s,3H),2.29(s,3H),1.29(d,J＝6.8Hz,3H)。
example 8: (R) -N- ((S) -1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000313
Synthesized by the same method as in example 1, LC-MS: ESI (M + H) 567.4;1H-NMR(CD3OD,400MHz)：7.98(s,1H),7.43-7.49(m,2H),7.23-7.26(m,1H),7.20(t,J＝8.8Hz,1H),7.13(s,1H),7.07(s,1H),6.21(d,J＝1.6Hz,1H),5.22-5.28(m,1H),4.92-4.97(m,1H),3.72-3.78(m,7H),3.02-3.22(m,2H),2.40(s,3H),1.43(d,J＝7.2Hz,3H)。
example 9: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (4-oxo-2- (2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanamide
Figure BDA0002311469940000321
The first step is as follows: mixing (R) -2- (2-bromo-4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid tert-butyl ester (1.0g, 3.3mmol) and tributyl (1-ethoxyvinyl) stannane (1.4g, 4.0mmol) were dissolved in DMF (20mL) and bis (triphenylphosphine) palladium (II) chloride Pd (PPh) was added3)2Cl2(230mg, 0.3mmol), nitrogen substitution, heating to 115 ℃ for 4 hours, cooling to room temperature, pouring into aqueous potassium fluoride KF, extracting with ethyl acetate, concentrating under reduced pressure, dissolving the residue in tetrahydrofuran, adding 2M dilute hydrochloric acid, and stirring at room temperature for 1 hour. Concentrating under reduced pressure, and purifying the residue by column chromatography to obtain compound (R) -2- (2-acetyl-4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid (0.59g, white solid). LC-MS ESI [ M + H ]]+＝252.1。
The second step is that: mixing (R) -2- (2-acetyl-4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid (0.59g, 2.4mmol) was dissolved in DMF (5mL), HATU (1.8g, 4.8mmol) and DIEA (0.93g, 7.2mmol) were added, stirred at room temperature for 5min, and then(S) -2-amino-2- (3-chlorophenyl) ethyl-1-ol (0.48g, 2.8mmol) was added, and the reaction was allowed to proceed at room temperature for 1 hour. Diluting with ethyl acetate, washing with saturated saline, drying, concentrating, and purifying by column chromatography to obtain compound (R) -2- (2-acetyl-4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide (0.85g, white solid). LC-MS ESI [ M + H ]]+＝405.1。
The third step: mixing (R) -2- (2-acetyl-4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide (670mg, 1.7mmol) was dissolved in N, N-dimethylformamide dimethyl acetal DMF-DMA (5mL), heated to 100 ℃ for 2 hours, concentrated under reduced pressure, and the residue was purified by column chromatography to give the compound (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (3- (dimethylamino) acryloyl) -4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) propionamide (380mg, yellow solid). LC-MS ESI [ M + H ]]+＝460.3。
The fourth step: mixing (R) -N- ((S) -1- (3-chlorphenyl) -2-hydroxyethyl) -2- (2- (3- (dimethylamino) acryloyl) -4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) propionamide (30mg, 0.07mmol) and 1- (tetrahydro-2H-pyran-4-yl) guanidine (11.2mg, 0.08mmol) were dissolved in DMF (3mL) and K was added2CO3(18mg, 0.13mmol), nitrogen substitution, heating to 90 ℃ for reaction overnight, cooling to room temperature, filtering, concentrating under reduced pressure, and column chromatography purification of the residue to give the compound (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (4-oxo-2- (2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -6, 7-dihydrofuran [3,2-c]Pyridin-5 (4H) -yl) propionamide (5mg, yellow solid). LC-MS: ESI (M + H) 540.5.1H-NMR(CDCl3,400MHz)8.28(d,J＝5.2Hz,1H),7.42(br s,1H),7.19-7.31(m,5H),6.81(d,J＝5.2Hz,1H),5.29-5.34(m,1H),5.02-5.07(m,1H),4.00-4.10(m,3H),3.72-3.90(m,4H),3.54-3.60(m,2H),3.03-3.18(m,2H),2.02-2.07(m,2H),1.57-1.72(m,2H),1.44(d,J＝7.2Hz,3H)。
Example 10: (R) -2- (2- (5-chloro-2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide
Figure BDA0002311469940000331
The first step is as follows: mixing (R) -N- ((S) -1- (3-chlorphenyl) -2-hydroxyethyl) -2- (2- (3- (dimethylamino) acryloyl) -4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) propionamide (300mg, 0.65mmol) was dissolved in DCM (5mL), N-chlorosuccinimide NCS (87mg, 0.65mmol) was added and reacted overnight at room temperature with LC-MS detection showing completion of the reaction. Concentrating the reaction solution under reduced pressure, and separating by column chromatography to obtain (R) -2- (2- (2-chloro 3- (dimethylamino) acryloyl) -4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide (220mg, yellow solid). LC-MS ESI [ M + H ]]+＝494.0。
The second step is that: reacting (R) -2- (2- (2-chloro-3- (dimethylamino) acryloyl) -4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide (9mg, 0.02mmol) and 1- (tetrahydro-2H-pyran-4-yl) guanidine (4mg, 0.03mmol) were dissolved in DMF (2mL) and K was added2CO3(5mg, 0.04mmol), nitrogen substitution, heating to 90 ℃ for reaction overnight, cooling to room temperature, filtering, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain the compound (R) -2- (2- (5-chloro-2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide (2mg, yellow solid). LC-MS: ESI (M + H) 574.4.1H-NMR(CD3OD,400MHz)8.29(s,1H),7.74(s,1H),7.35-7.38(m,4H),5.27-5.32(m,1H),4.95-4.98(m,1H),3.96-4.06(m,3H),3.70-3.81(m,4H),3.52-3.57(m,2H),3.07-3.30(m,2H),1.98-2.01(m,2H),1.55-1.68(m,2H),1.43(d,J＝7.2Hz,3H)。
Example 11: (R) -2- (2- (5-chloro-2- (isopropylamino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide
Figure BDA0002311469940000341
The first step is as follows: mixing (R) -2- (2- (2-chloro 3- (dimethylamino)Acryloyl) -4-oxo-6, 7-dihydrofuro [3,2-c]Pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide (390mg, 0.8mmol) and methylthioguanidine hydrochloride (330mg, 2.6mmol) were dissolved in DMF (5mL) and K was added2CO3(660mg, 4.8mmol), nitrogen substitution, heating to 90 ℃ for reaction overnight, cooling to room temperature, filtering, concentrating under reduced pressure, and column chromatography purification of the residue to give compound (R) -2- (2- (5-chloro-2- (methylthio) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide (310mg, yellow solid). LC-MS: ESI (M + H) 521.1.
The second step is that: mixing (R) -2- (2- (5-chloro-2- (methylthio) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide (253mg, 0.49mmol) was dissolved in DCM (5mL), m-CPBA (192mg,1.1mmol) m-chloroperoxybenzoic acid was added, the reaction was carried out at room temperature for 1 hour, diluted with ethyl acetate, saturated Na2CO3Washing with water solution twice, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain compound (R) -2- (2- (5-chloro-2- (methylsulfonyl) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide (160mg, yellow solid). LC-MS ESI (M-H) 551.1.
The third step: mixing (R) -2- (2- (5-chloro-2- (methylsulfonyl) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide (20mg, 0.036mmol) and TEA (4mg, 0.04mmol) were dissolved in acetonitrile (3mL), isopropylamine (42mg, 0.72mmol) was added, reaction was carried out at room temperature for 2 days, concentration was carried out under reduced pressure, and the residue was purified by column chromatography to give the compound (R) -2- (2- (5-chloro-2- (isopropylamino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ]]Pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide (4.6mg, white solid). LC-MS: ESI (M + H) 532.4.1H-NMR(CD3OD,400MHz)：8.27(s,1H),7.74(s,1H),7.25-7.38(m,4H),5.27-5.32(m,1H),4.88-4.98(m,1H),4.11-4.14(m,1H),3.70-3.81(m,4H),3.07-3.26(m,2H),1.43(d,J＝7.2Hz,3H),1.23(d,J＝6.4Hz,6H)。
Example 12: (R) -2- (2- (5-chloro-2- ((1, 3-dihydroxypropyl-2-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide
Figure BDA0002311469940000351
Synthesized by the same method as in example 11, LC-MS: ESI (M + H) 564.4;1H-NMR(CD3OD,400MHz)：8.30(s,1H),7.75(s,1H),7.24-7.39(m,4H),5.27-5.34(m,1H),4.96-4.99(m,1H),4.09-4.14(m,1H),3.71-3.81(m,8H),3.05-3.31(m,2H),1.42(d,J＝7.2Hz,3H)。
example 13: (2R) -2- (2- (5-chloro-2- ((1-hydroxypropyl-2-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide
Figure BDA0002311469940000352
Synthesized by the same method as in example 11, LC-MS: ESI (M + H) 548.4;1H-NMR(CD3OD,400MHz)：8.25(s,1H),7.70(d,J＝2.8Hz,1H),7.40(s,1H),7.24-7.33(m,3H),5.28-5.34(m,1H),4.96-5.00(m,1H),4.09-4.11(m,1H),3.72-3.80(m,4H),3.55-3.64(m,2H),3.03-3.31(m,2H),1.41(d,J＝7.2Hz,3H),1.24(d,J＝6.8Hz,3H)。
example 14: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanamide
Figure BDA0002311469940000361
The first step is as follows: mixing (R) -2- (4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid tert-butyl ester (1g,3.8mmol), bis-valeryldiboron (pinacol bisborate) B2pin2(531mg,2.1mmol), 4,4' -di-tert-butylbipyridine dtbpy (20mg,0.076mmol) and (1, 5-cyclopentadiene) (methoxy) iridium (I) dimer [ Ir (cod) OMe](25mg,0.038mmol) was dissolved in THF (20mL), purged with nitrogen for 10 minutes, heated to 80 ℃ under nitrogen and reactedAnd (4) at night. Cooling the reaction solution to room temperature, filtering, and concentrating under reduced pressure to obtain (R) -2- (4-oxo-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxan-2-yl) -6, 7-dihydrofuran [3, 2-c)]Tert-butyl pyridin-5 (4H) -yl) propionate (1.5g, red oil) was used directly in the next reaction. LC-MS ESI [ M + H ]]+＝392.2。
The second step is that: mixing (R) -2- (4-oxo-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxan-2-yl) -6, 7-dihydrofuran [3,2-c ]]Tert-butyl pyridin-5 (4H) -yl) propionate (750mg, crude) and 2, 4-dichloropyrimidine (425mg,2.9mmol) were dissolved in 1,4-dioxane (10mL), water (1mL), sodium carbonate (604mg, 5.7mmol) and Pd (PPh3)4(110mg,0.1mmol) were added, the mixture was replaced with nitrogen, heated to 90 ℃ and reacted for 4 hours, and the reaction was complete as determined by LCMS. Cooling the reaction solution to room temperature, filtering, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain (R) -2- (2- (2-chloropyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid tert-butyl ester (225mg, white solid). LC-MS ESI [ M + H ]]+＝378.4。
The third step: mixing (R) -2- (2- (2-chloropyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid tert-butyl ester (195mg,0.52mmol), 1-methyl-1H-pyrazol-5-amine (55mg,0.57mmol), Cs2CO3(254mg,0.78mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene Xantphos (60mg,0.1mmol) and Pd2(dba)3(48mg,0.05mmol) was dissolved in 1,4-dioxane (6mL), purged with nitrogen for 10 minutes, and heated to 100 ℃ under nitrogen for overnight reaction. Cooling the reaction solution to room temperature, filtering, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain (R) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidine-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid tert-butyl ester (93mg, red oil). LC-MS: ESI (M + H) 439.0.
The fourth step: tert-butyl (R) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanoate (93mg,0.21mmol) was dissolved in anhydrous dichloromethane (2mL), trifluoroacetic acid TFA (1mL) was added dropwise, reaction was carried out at room temperature for 1 hour, and concentration under reduced pressure was carried out to give (R) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanoic acid as a yellow solid, directly used for the next reaction. LC-MS ESI (M + H) 383.0.
The fifth step: reacting (R) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid (105mg, crude) was dissolved in DMF (1mL), HATU (160mg,0.42mmol) and TEA (85mg,0.84mmol) were added, stirred at room temperature for 5 minutes, and (S) -2-amino-2- (3-chlorophenyl) ethyl-1-ol (44mg,0.25mmol) was added and reacted at room temperature for 1 hour. Concentrating under reduced pressure, and purifying the residue to obtain (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionamide (29.7mg, white solid). LC-MS ESI (M + H) 536.3;1H-NMR(CD3OD,400MHz)：8.42(d,J＝5.2Hz,1H),7.43-7.44(m,2H),7.38(s,1H),7.25-7.34(m,3H),7.13(d,J＝5.6Hz,1H),6.35(d,J＝2.0Hz,1H),5.26-5.32(m,1H),4.95-4.99(m,1H),3.70-3.81(m,7H),3.03-3.26(m,2H),1.42(d,J＝7.2Hz,3H)。
example 15: (R) -2- (2- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide
Figure BDA0002311469940000371
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 569.9;1H-NMR(CD3OD,400MHz)：8.38(s,1H),7.75(m,1H),7.54(d,J＝2.4Hz,1H),7.43(s,1H),7.25-7.32(m,3H),6.58(d,J＝2.0Hz,1H),5.32-5.35(m,1H),4.95-5.01(m,1H),3.74-3.82(m,7H),3.30-3.36(m,1H),3.02-3.07(m,1H),1.40(d,J＝7.2Hz,3H)。
example 16: (R) -2- (2- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) -N- ((S) -2-hydroxy-1- (m-methylphenyl) ethyl) propionamide
Figure BDA0002311469940000381
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 550.4.
Example 17: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanamide
Figure BDA0002311469940000382
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 550.4;1H-NMR(CD3OD,400MHz)：8.34(s,1H),7.77(s,1H),7.48(s,1H),7.39(s,1H),7.25-7.34(m,3H),6.78(s,1H),5.28-5.33(m,1H),4.86-5.00(m,1H),3.88(s,3H),3.72-3.83(m,4H),3.21-3.31(m,1H),3.07-3.12(m,1H),2.44(s,3H),1.43(d,J＝7.2Hz,3H)。
example 18: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanamide
Figure BDA0002311469940000383
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 554.0;1H-NMR(CD3OD,400MHz)：8.42(d,J＝3.2Hz,1H),7.58(d,J＝2.4Hz,1H),7.49(d,J＝2.4Hz,1H),7.40(s,1H),7.25-7.32(m,3H),6.59(d,J＝2.4Hz,1H),5.30-5.32(m,1H),4.96-5.00(m,1H),3.72-3.83(m,7H),3.06-3.31(m,2H),1.42(d,J＝7.2Hz,3H)。
example 19: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-cyano-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanamide
Figure BDA0002311469940000384
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 561.2.
Example 20: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000391
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 604.2.
Example 21: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (3-fluoro-2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c]Pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000392
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 554.4.
Example 22: (R) -2- (2- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) -N- ((S) -1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl) propionamide
Figure BDA0002311469940000393
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 588.3.
Example 23: (R) -N- ((S) -1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c]Pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000394
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 554.2.
Example 24: (R) -N- ((S) -2-hydroxy-1- (m-toluene) ethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000395
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 516.2.
Example 25: (R) -N- ((S) -2-hydroxy-1- (m-toluene) ethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c]Pyridin-5 (4H) -yl) propanesAmides of carboxylic acids
Figure BDA0002311469940000401
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 530.2.
Example 26: (R) -N- ((S) -1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c]Pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000402
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 568.1.
Example 27: (R) -N- ((S) -1- (3, 5-difluorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c]Pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000403
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 552.2.
Example 28: (R) -N- ((S) -1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl) -2- (2- (5-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c]Pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000404
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 572.2.1H-NMR(CD3OD,400MHz)：8.42(d,J＝3.2Hz,1H),7.58(d,J＝2.4Hz,1H),7.49(d,J＝2.4Hz,1H),7.43(d,J＝2.0Hz,1H),7.18-7.32(m,2H),6.59(d,J＝2.4Hz,1H),5.30-5.32(m,1H),4.96-5.00(m,1H),3.72-3.83(m,7H),3.06-3.31(m,2H),1.42(d,J＝7.2Hz,3H)。
Example 29: (R) -2- (2- (5-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) -N- ((S) -2-hydroxy-1- (m-methylphenyl) ethyl) propanamide
Figure BDA0002311469940000411
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 534.2.1H-NMR(CD3OD,400MHz)：8.42(d,J＝3.2Hz,1H),7.58(d,J＝2.4Hz,1H),7.49(d,J＝2.4Hz,1H),7.03-7.21(m,4H),6.59(d,J＝2.4Hz,1H),5.30-5.32(m,1H),4.96-5.00(m,1H),3.72-3.83(m,7H),3.06-3.31(m,2H),2.31(s,3H),1.42(d,J＝7.2Hz,3H)。
Example 30: (R) -N- ((S) -1- (3, 5-difluorophenyl) -2-hydroxyethyl) -2- (2- (5-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c]Pyridin-5 (4H) -yl) propionamide
Figure BDA0002311469940000412
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 556.2.1H-NMR(CD3OD,400MHz)：8.42(d,J＝3.2Hz,1H),7.58(d,J＝2.4Hz,1H),7.49(d,J＝2.4Hz,1H),6.65-6.74(m,3H),6.59(d,J＝2.4Hz,1H),5.30-5.32(m,1H),4.96-5.00(m,1H),3.72-3.83(m,7H),3.06-3.31(m,2H),1.42(d,J＝7.2Hz,3H)。
Example 31: 5- (3-chlorobenzyl) -2- (2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -6, 7-dihydrofuran [3,2-c ] pyridin-4 (5H) -one
Figure BDA0002311469940000413
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 439.0.1H-NMR(CDCl3,400MHz)：8.31(d,J＝5.2Hz,1H),7.47(s,1H),7.20-7.31(m,4H),6.84(d,J＝5.2Hz,1H),5.19-5.21(m,1H),4.69(s,2H),4.99-4.11(m,3H),3.54-3.62(m,4H),3.06(t,J＝7.2Hz,2H),2.01-2.08(m,2H),1.52-1.62(m,2H)。
Example 32: 5- (3-chlorobenzyl) -2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -6, 7-dihydrofuran [3,2-c ] pyridin-4 (5H) -one
Figure BDA0002311469940000421
Synthesized by the same method as in example 14, LC-MS: ESI (M + H) 448.0.1H-NMR(CDCl3,400MHz)：8.24(s,1H),7.57(d,J＝2.0Hz,1H),7.18-7.29(m,4H),6.65(s,1H),6.17(d,J＝1.6Hz,1H),5.53(s,1H),4.67(s,2H),3.74(s,3H),3.55(t,J＝7.2Hz,2H),3.01(t,J＝7.2Hz,2H),2.30(s,3H)。
Comparative compound 1: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (6- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -1-oxoisoindolin-2-yl) propionamide
Figure BDA0002311469940000422
The title compound was prepared by reference to the procedures and reaction conditions of the examples of WO2017068412A1, LC-MS: ESI (M + H) 531.3.1H-NMR(CD3OD,400MHz)8.16(d,J＝8.0Hz,1H),8.06(d,J＝1.2Hz,1H),7.93(dd,J＝1.6,8.0Hz,1H),7.71(d,J＝8.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.26-7.39(m,4H),7.14(dd,J＝1.6,5.6Hz,1H),7.02(d,J＝1.2Hz,1H),6.27(d,J＝2.0Hz,1H),5.07-5.09(m,1H),4.95(t,J＝6.4Hz,1H),4.81(d,J＝17.6Hz,1H),4.66(d,J＝17.6Hz,1H),3.72-3.75(m,5H),1.58(d,J＝7.6Hz,3H)。
Test example 1 determination of the inhibitory Activity of the Compounds of the present invention against ERK2 kinase
The test method comprises the following steps: (1) 1 XKinase buffer was prepared according to the instructions of ERK2 enzyme from Carna company; (2) preparation of compound concentration gradient: test compounds were tested at 1000nM, diluted to 100-fold final concentration in 100% DMSO solutions in 384source plates, and compounds were diluted 3-fold with Precision, 10 concentrations. Using the dispenser Echo 550 to the target plate OptiPlate-384F transfer 250nL 100 times the final concentration of compounds; (3) preparing a Kinase solution with 2.5 times of final concentration by using 1 XKinase buffer; (4) add 10. mu.L of 2.5 fold final concentration kinase solution to the compound well and positive control well, respectively; add 10. mu.L of 1 XKinase buffer to the negative control wells; (5) centrifuging at 1000rpm for 30 s, oscillating and mixing the reaction plate, and incubating at room temperature for 10 min; (6) preparing a mixed solution of ATP and Kinase substrate8 (GL) at 5/3 times final concentration by using 1 XKinase buffer; (7) adding 15 μ L of a mixed solution of ATP and substrate at 5/3 times final concentration to initiate the reaction; (8) centrifuging a 384-hole plate at 1000rpm for 30 seconds, shaking and uniformly mixing, and incubating at room temperature for 40 min; (9) adding 30 mu L of termination detection solution to stop kinase reaction, centrifuging at 1000rpm for 30 seconds, and uniformly mixing by oscillation; (10) the conversion rate is read by a Caliper EZ Reader, the log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and a dose-effect curve is fitted by using the log (inhibitor) vs. the response-Variable slope of the GraphPad Prism 5 analysis software, so as to obtain the IC50 value of each compound to the enzyme activity.
2. As a result, the present invention provides examples 1 to 32, which have IC of inhibitory activity against ERK250All values are less than 500nM, and the inhibitory activity IC of most of the examples50Less than 10nM, even less than 2nM, show strong inhibitory activity. The specific data are shown in table one.
Table one: example Compounds Activity against ERK2 kinase inhibition
Figure BDA0002311469940000431
Test example 2: test of Effect of Compounds of the present invention on Ras-Raf-MEK-ERK-mediated proliferation Capacity of tumor cells
1. The test method comprises the following steps: colo-205 cells (ATCC) in logarithmic growth phase were inoculated into 96-well culture plates at an appropriate density, 90. mu.L per well, incubated overnight, and then a solvent control group (negative control) was set by adding compounds at different concentrations for 72 hr. After the compound acts on cells for 72 hours, the influence of the compound on cell proliferation is detected by a CCK-8 cell counting kit (Dojindo), 10 mu L of CCK-8 reagent is added into each hole, the hole is placed in an incubator at 37 ℃ for 2 to 4 hours, then a SpectraMax 190 reading is carried out by a full-wavelength microplate reader, and the measurement wavelength is 450 nm. The inhibition rate (%) of the compound on the growth of tumor cells was calculated by the following formula (OD negative control well-OD administration well)/OD negative control well × 100%. IC (integrated circuit)50The values were determined by regression with a four parameter method using a microplate reader random plus software.
2. As a result, the present invention provides proliferation inhibitory activity, IC, of Colo-205 cells by most of the compounds of examples 1-3250Values were all less than 500nM, IC for inhibitory activity of some of the example compounds50Values even less than 50nM show strong cell proliferation inhibitory activity. Specific data as tableAnd II, showing.
Table two: the compounds of the examples have inhibitory activity on Colo-205 cell proliferation.
Figure BDA0002311469940000441
Meanwhile, as shown in table three, compared with the comparative compound and the positive compound, the compound of some examples of the invention has obvious advantages on the proliferation inhibition activity of ERK2 kinase and Colo-205 cells due to the fact that the 1-oxoisoindoline mother nucleus in the comparative compound and the pyrrole mother nucleus, pyridone mother nucleus and 5, 6-dihydro-4H-thiophene [2,3-c ] pyrrole-4-ketone mother nucleus in the positive compound are replaced by the 4-oxo-6, 7-dihydrofuran [3,2-c ] pyridine mother nucleus structure, and the compound of the examples of the invention has the obvious advantages on the proliferation inhibition activity of ERK2 kinase and Colo-205 cells.
TABLE III, some examples and comparative compounds inhibit the activity of ERK2 kinase and Colo-205 cell proliferation
Figure BDA0002311469940000442
Figure BDA0002311469940000451
Test example 3: EXAMPLES testing of the different kinase inhibitory Activity of the Compounds
The compounds of the embodiments of the invention have also been tested for their inhibitory activity against different kinases such as EGFR, VEGFR, RAF, MEK, PDGFR, FGFR, RET, MET, Src, Lyn, Syk, MEK, CDK, RAF, ROS, etc., and some of the compounds of the embodiments such as examples 1, 7, 10, 15, 18, etc. show better ERK kinase selectivity, which is greater than 100-fold.
Test example 4: examples proliferation inhibitory Activity of Compounds of examples on different tumor cells
The SRB staining method or CCK8 method or CTG method is used for testing proliferation inhibition of various tumor cells, such as Colo-205, NCI-H1666, HT29, MOLM-3, MIAPACA-2, A375, HCT116. Proliferation inhibition activity of CAPAN-2, Calu6, NCI-H358, NCI-H508, HuH-7, JHH-7, SNU-16, KG1, UM-UC-14, NCI-H716, MCF-7, RT-112, OPM-2, NCI-H460, SNU-869, NCI-H2122, NCI-H1299, MG63, Kappars-299, SK-OV-3, U87MG, BT474, LNCAP, A498, KYSE140, HUCC-T1, PANC-1, etc., cells positive for Ras-Raf-MEK pathway (e.g., Colo-205, A375, HCT116, Calu-6, etc.) some example compounds such as examples 1, 7, 10, 15, 18, etc., showed strong inhibitory activity, and IC thereof showed strong inhibitory activity50Are all less than 1000nM, even all less than 500nM, showing better antitumor activity.
Test example 5: ADME testing of the Compounds of the examples
(1) Metabolic stability test: the system is 150 mu L liver microsome (final concentration is 0.5mg/mL) for metabolic stability incubation, the system contains NADPH (final concentration is 1mM), 1 mu M test compound and positive control midazolam or negative control atenolol, the reaction is stopped by acetonitrile containing tinidazole at 0min, 5min, 10min and 30min respectively, vortex for 10min, centrifuge for 10min at 15000rmp, and 50 mu L supernatant is taken to be injected into a 96-well plate. The metabolic stability of the compounds was calculated by determining the relative decrease of the bulk drug.
(2) Direct inhibition assay (DI assay) incubation was performed with direct inhibition using 100. mu.L of human liver microsomes (final concentration 0.2mg/mL) containing NADPH (final concentration 1mM), 10. mu.M of a compound, the positive inhibitor cocktail (ketoconazole 10. mu.M, quinidine 10. mu.M, sulfaphenazole 100. mu.M, α -naflavone 10. mu.M, tranylcypromine 1000. mu.M), the negative control (BPS in 0.1% DMSO), and the mixed probe substrate (midazolam 10. mu.M, testosterone 100. mu.M, dextromethorphan 10. mu.M, diclofenac 20. mu.M, phenacetin 100. mu.M, and mefenton 100. mu.M), and the reaction was terminated after incubation for 20 min.
Some of the compounds of examples, e.g., examples 1, 7, 18, etc., have high microsomal metabolic stability in rats and dogs and T1/2All above 30min, has no direct inhibition effect on main metabolic enzyme, and IC50All are larger than 20uM, showing better drug property.
Test example 6: examples in vivo pharmacokinetic parameter testing of Compounds in rats and mice
6 male SPF-level SD rats or Balb-c mice (Shanghai Sphere-BiKai experimental animals) are respectively divided into two groups, and a tested compound is prepared into a proper solution or suspension; one group was administered intravenously (1mg/kg dose) and one group was administered orally (5mg/kg dose). Blood is collected by jugular venipuncture, about 0.2 mL/time point of each sample is collected, heparin sodium is anticoagulated, and the blood collection time points are as follows: pre-and post-dose 5, 15 and 30min, 1,2,4, 6, 8 and 24 h; blood samples were collected and placed on ice, plasma was centrifuged (centrifugation conditions: 8000 rpm, 6 min, 2-8 ℃) and collected plasma was stored at-80 ℃ before analysis. Plasma samples were analyzed by LC-MS/MS.
According to the data of the blood concentration of the drug, pharmacokinetic parameters of the test sample, such as AUC0-T, AUC0- ∞, MRT0- ∞, Cmax, Tmax, T1/2 and Vd, and the average value and standard deviation thereof are respectively calculated by using a pharmacokinetic calculation software WinNonlin5.2 non-atrioventricular model. Furthermore, the bioavailability (F) will be calculated by the following formula:
Figure BDA0002311469940000471
for samples with concentrations below the lower limit of quantitation, in performing pharmacokinetic parameter calculations, samples taken before Cmax was reached should be calculated as zero values and samples taken at points after Cmax was reached should be calculated as non-quantifiable (BLQ).
Some of the compounds of the examples, e.g., examples 1, 7, 18, showed better potency when administered intragastrically to mice with a Cmax of greater than 2000nM, an AUC of greater than 4000hr nM, and an F% of greater than 20%.
Test example 7: test of Compounds for growth inhibition of Colo-205 transplanted tumors in nude mice
Cutting tumor tissue in vigorous growth stage into 1.5mm3And left and right, under aseptic conditions, inoculated subcutaneously in the right axilla of nude mice. Measuring the diameter of the transplanted tumor by using a vernier caliper in the nude mouse subcutaneous transplanted tumor until the average tumor volume reaches 130mm3Animals were randomized into groups. Example Compounds (with 1% Tween 8)0 water for injection is prepared to the desired concentration for use) is orally administered at a given dose every day for three weeks with the solvent control group given an equal amount of solvent. Throughout the experiment, the diameter of the transplanted tumor was measured 2 times per week, while the body weight of the mice was weighed. The formula for Tumor Volume (TV) is: TV 1/2 × a × b2Wherein a and b represent length and width, respectively. Calculating Relative Tumor Volume (RTV) according to the measurement result, wherein the calculation formula is as follows: RTV is Vt/V0. Where V0 is the tumor volume measured at the time of caged administration (i.e., d0) and Vt is the tumor volume at each measurement. The evaluation index of the antitumor activity is 1) the relative tumor proliferation rate T/C (%), and the calculation formula is as follows: T/C (%) (TRTV/CRTV) × 100%, TRTV: treatment group RTV; CRTV: negative control group RTV; 2) the tumor volume increase inhibition rate GI% is calculated according to the following formula: GI% ([ 1- (TVt-TV0)/(CVt-CT 0))]X 100%, TVt is the tumor volume measured for each treatment group; TV0 is the tumor volume obtained when therapeutic components were administered in cages; CVt is the tumor volume measured in each time in the control group; CV0 is the tumor volume obtained when the control component was administered in cages; 3) the tumor weight inhibition rate is calculated according to the following formula: tumor weight inhibition ratio (% Wc-WT)/Wc × 100%, Wc: tumor weight of control group, WT: the treated group had heavy tumor.
Some of the compounds of the examples of the present invention showed good tumor growth inhibition, as shown in examples 1, 7, 18, etc. at a dose of 100mg/kg/day, for 21 days with a T/C of less than 40% after continuous oral administration.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof,
Figure FDA0002311469930000011
in the formula, R2Selected from hydrogen, halogen, cyano, hydroxy, acyl, sulfonyl, sulfone, sulfoxide, sulfinyl, amino, substituted amino, C1-C10Alkyl radical, C1-C10Alkoxy radical, C1-C10Alkylamino, cycloalkyl or heterocycloalkyl of 3 to 10 members, aryl or heteroaryl of 5 to 10 members;
R3a、R3b、R4a、R4bindependently selected from hydrogen, halogen, hydroxy, alkoxy, amino, cyclic amino, C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl;
or, the above R3a、R3b、R4aAnd R4bAny two groups in between form a 3-8 membered saturated or partially unsaturated carbocyclic or heterocyclic ring;
R6、R7、R8and R9Independently selected from hydrogen, halogen, hydroxyl, amino, C1-C8Alkyl, 3-to 8-membered cycloalkyl or heterocycloalkyl, 5-to 10-membered aryl or heteroaryl; or, the above R6、R7、R8And R9Any two groups in between form a 3-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring;
l is selected from O, NR1、S(O)pAcyl, sulfonyl, amide, urea, sulfonylurea, sulfinyl, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl, wherein p is selected from 0-2;
R1independently selected from hydrogen, C1-C8Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl; m is selected from N or CR5；R5Independently selected from hydrogen, halogen, cyano, nitro, C1-C6Alkyl, or 3-8 membered cycloalkyl; m, n and q are independently selected from 0-3;
one or more hydrogen atoms on any of the above groups are substituted with a substituent selected from the group consisting of: deuterium, halogen, hydroxy, amino, substituted amino, cyano, sulphonyl or sulphoxy, urea, sulphonyl urea, C1-C8Alkyl radical, R2-1Substituted C1-C8Alkyl, 3-8 membered cycloalkyl, C1-C8Alkoxy radical, C1-C8Alkylamino or cycloalkylamino, alkenyl, alkynyl, acyl or sulfonyl or sulfinyl, 5-8 membered aryl or heteroaryl, 4-8 membered cycloalkyl or heterocycloalkyl; wherein the substituent of the substituted amino is C1-C8An alkyl group; r2-1Selected from halogen, hydroxy, cyano, C1-C8Alkoxy, or C1-C8Alkylamino radical, R2-1The number of (A) is 1 or more;
wherein said heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of: n, O, P and S, said heterocycloalkyl group containing 1 to 3 heteroatoms selected from the group consisting of: n, O, P and S; each ring system is independently a saturated, partially unsaturated or unsaturated monocyclic, fused, bridged or spiro ring.
2. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, as claimed in claim 1, wherein when R is1Is C1-C8When alkyl, said C1-C8Alkyl is C1-C4Alkyl, preferably isopropyl;
and/or when R1Is C1-C8When alkyl, said C1-C8Alkyl is optionally substituted with 1-3 halogens or hydroxy, preferably fluorine;
and/or when R1When the heterocyclic group is a 3-8 membered heterocyclic group, the 3-8 membered heterocyclic group is a 5-6 membered heterocyclic group in which "one or more hetero atoms are selected from N, O and S, and the number of hetero atoms is 1-3", preferably a tetrahydropyranyl group;
and/or when R1In the case of 5-10 membered heteroaryl, the 5-10 membered heteroaryl is a 5-6 membered heteroaryl having "one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1-3", preferably pyrazolyl or pyridyl;
and/or when R1In the case of a 5-10 membered heteroaryl group, said 5-10 membered heteroaryl group is optionally substituted with 1 to 3C1-C8Alkyl is substituted, said C1-C8Alkyl is preferably C1-C4Alkyl, more preferably methyl;
and/or when R2When the alkyl group is a 3-to 10-membered cycloalkyl group, the 3-to 10-membered cycloalkyl group is a 5-to 6-membered cycloalkyl group, preferably a cyclohexyl group;
and/or when R2When 5-10 membered aryl, said 5-10 membered aryl is 6-10 membered aryl, or 8-10 membered bicyclic aryl, said 6-10 membered aryl is preferably phenyl, said 8-10 membered bicyclic aryl is preferably indanyl;
and/or when R2When 5-10 membered aryl, said 5-10 membered aryl is optionally substituted with 1-3 halogens, preferably fluorine or chlorine;
and/or when R2In the case of a 5-10 membered aryl group, said 5-10 membered aryl group is optionally substituted with C1-C8Alkyl or R2-1Substituted C1-C8Alkyl substitution, said C1-C8Alkyl is preferably C1-C4Alkyl, more preferably methyl or isopropyl;
and/or when R2When 5-10 membered aryl, said 5-10 membered aryl is optionally substituted with R2-1Substituted C1-C8Alkyl substitution, said R2-1The number of (a) is 1,2 or 3;
and/or when R2When 5-10 membered aryl, said 5-10 membered aryl is optionally substituted with R2-1Substituted C1-C8Alkyl substitution, R2-1Is halogen, preferably fluorine;
and/or when R2In the case of a 5-to 10-membered aryl group, the 5-to 10-membered aryl group is substituted with a 5-to 8-membered heteroaryl group, and the 5-to 8-membered heteroaryl group is preferably a group of one or more "hetero atoms selected from N, O and SA 5-6 membered heteroaryl group of a number of 1-3 ", more preferably an oxazolyl group;
and/or when R2In the case of a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is an 8-9 membered bicyclic heteroaryl group having "one or more heteroatoms selected from N, O and S, a 5-6 membered monocyclic heteroaryl group having" 1 to 3 heteroatoms ", or" one or more heteroatoms selected from N, O and S, a 1-3 heteroatom, the 5-6 membered monocyclic heteroaryl group is preferably a pyridyl group, the 8-9 membered bicyclic heteroaryl group is preferably an imidazopyridinyl group;
and/or when R2In the case of a 5-10 membered heteroaryl group, said 5-10 membered heteroaryl group is optionally substituted with C1-C8Alkyl substitution, said C1-C8Alkyl is preferably C1-C4Alkyl, more preferably methyl;
and/or when R2In the case of a 5-10 membered heteroaryl group, said 5-10 membered heteroaryl group is optionally substituted with C1-C8Alkylamino substitution, said C1-C8Alkylamino is preferably C1-C4Alkylamino, more preferably alkylamino
Figure FDA0002311469930000031
And/or when R3a、R3b、R4aAnd R4bIndependently is C1-C8When alkyl, said C1-C8Alkyl is C1-C4Alkyl, preferably methyl;
and/or when R3a、R3b、R4aAnd R4bIndependently is C1-C8When alkyl, said C1-C8Alkyl is optionally substituted by 1-3C1-C8Alkoxy substitution of said C1-C8Alkoxy is preferably C1-C4Alkoxy, more preferably methoxy;
and/or when R5When the halogen is fluorine or chlorine;
and/or when R5Is C1-C6When alkyl, said C1-C6Alkyl is C1-C4Alkyl, preferably methyl;
and/or when R5Is C1-C6When alkyl, said C1-C6Alkyl is optionally substituted with 1-3 halogens, preferably fluorine;
and/or when R6、R7、R8And R9Independently is C1-C8When there is an alkyl group, said C1-C8Alkyl is C1-C4Alkyl, preferably methyl or ethyl;
and/or when R6、R7、R8And R9Independently is C1-C8When there is an alkyl group, said C1-C8Is optionally substituted with 1-3 halogens, preferably fluorine;
and/or when R6、R7、R8And R9Independently is C1-C8When there is an alkyl group, said C1-C8Optionally substituted by 1-3C1-C8Alkoxy substitution of said C1-C8Alkoxy is preferably C1-C4Alkoxy, more preferably methoxy;
and/or when R6、R7、R8And R9Independently is C1-C8When there is an alkyl group, said C1-C8Optionally substituted by 1-3C1-C8Alkylamino substitution, said C1-C8Alkylamino is preferably C1-C4Alkylamino, more preferably alkylamino
Figure FDA0002311469930000041
And/or, when L is an amide, said amide is-C (═ O) NH-; wherein, C terminal is connected with
Figure FDA0002311469930000042
Are connected, N terminal to
Figure FDA0002311469930000043
Are connected.
3. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, as claimed in claim 1, wherein R is1Is selected from C1-C8Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; said C1-C8Alkyl is optionally substituted with 1-3 halogens or hydroxy; said 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with 1-3C1-C8Alkyl substituted;
and/or, R2Selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; said 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with 1-3 halogens, C1-C8Alkyl radical, R2-1Substituted C1-C8Alkyl radical, C1-C8Alkoxy radical, C1-C8Alkylamino, or 5-8 membered heteroaryl; r2-1Selected from halogen or hydroxy;
and/or, R3a、R3b、R4aAnd R4bIndependently selected from hydrogen, or C1-C8An alkyl group; said C1-C8Alkyl is optionally substituted by 1-3C1-C8Alkoxy substitution;
and/or, R5Independently selected from hydrogen, halogen, cyano, or C1-C6An alkyl group; said C1-C6Alkyl is optionally substituted with 1-3 halogens;
and/or, R6、R7、R8And R9Independently selected from hydrogen, or C1-C8Alkyl groups of (a); said C1-C8Optionally substituted by 1-3 halogens, hydroxy, C1-C8Alkoxy, or C1-C8Alkyl amino substitution;
and/or, L is an amide; and/or, M is selected from N or CR5(ii) a And/or, m, n and q are independently selected from 0, 1,2 or 3.
4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, as claimed in claim 1, wherein R is1Is selected from C1-C8Alkyl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl; said C1-C8Alkyl is optionally substituted with 1-3 halogens or hydroxy; said 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with 1-3C1-C8Alkyl substituted;
and/or, R2Is 6-10 membered aryl or 5-10 membered heteroaryl; said 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted by 1-3 halogen, C1-C8Alkyl or C1-C8Alkyl amino substituted;
and/or, R3a、R3b、R4aAnd R4bIs hydrogen; and/or, R6、R7、R8And R9Independently selected from hydrogen, or C1-C8Alkyl groups of (a); said C1-C8Is optionally substituted with 1-3 hydroxyl groups; and/or, M is selected from N or CH; and/or, m and n are 1; and/or q is selected from 0 or 1.
5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, as claimed in claim 1, wherein R is1Selected from 5-10 membered heteroaryl; said 5-10 membered heteroaryl group optionally substituted with 1-3C1-C8Alkyl substituted;
and/or, R2Is a 6-to 10-membered aryl group; said 6-to 10-membered aryl being optionally substituted by 1-3 halogens, C1-C8Alkyl or C1-C8Alkyl amino substituted; preferably R2Is 6-A 10-membered aryl group; said 6-10 membered aryl is optionally substituted with 1-3 halogens;
and/or, R6、R7、R8And R9Independently selected from hydrogen, or C1-C8Alkyl groups of (a); said C1-C8Is optionally substituted with 1-3 hydroxyl groups; r6And R7Is different from R6And R7The attached C atom is in the R configuration; preferably R6And R7Independently selected from hydrogen, or C1-C8Alkyl groups of (a); preferably R8Is hydrogen, R9Is C1-C8Or R is8Is C1-C8Alkyl of R9Is hydrogen; said C1-C8Is substituted with 1 hydroxyl group; and/or, M is CH; and/or q is 0.
6. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, as claimed in claim 1, wherein R is1Is composed of
Figure FDA0002311469930000067
Figure FDA0002311469930000061
Preferably,
Figure FDA0002311469930000062
And/or, R2Is composed of
Figure FDA0002311469930000063
Figure FDA0002311469930000064
Figure FDA0002311469930000065
Preference is given to
Figure FDA0002311469930000068
Figure FDA0002311469930000066
And/or, R3aAnd R3bIndependently hydrogen or methyl;
and/or, R4aAnd R4bIndependently is hydrogen, methyl or
Figure FDA0002311469930000069
Preferably hydrogen;
and/or, R5Is hydrogen, fluoro, chloro, cyano, methyl or trifluoromethyl;
and/or, R6And R7Independently is hydrogen, methyl, ethyl or-CH2F, preferably hydrogen or methyl;
and/or, R8And R9Independently hydrogen, methyl, -CH2OH、
Figure FDA00023114699300000610
Preferably hydrogen or-CH2OH；
And/or, L is-C (═ O) NH-; wherein, C terminal is connected with
Figure FDA00023114699300000611
Are connected, N terminal to
Figure FDA00023114699300000612
Connecting;
and/or, M is N or CH.
7. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, according to any one of claims 1 to 6, wherein the compound of formula (I) is any one of the following:
Figure FDA0002311469930000071
Figure FDA0002311469930000081
Figure FDA0002311469930000091
8. a pharmaceutical composition, comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, according to any one of claims 1 to 7, together with a pharmaceutically acceptable carrier; the pharmaceutical composition is preferably a pharmaceutical composition for preventing and/or treating tumors; the tumor is preferably non-small cell lung cancer, melanoma, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostatic cancer, liver cancer, pancreatic cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymph cancer or nasopharyngeal carcinoma.
9. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, as defined in any one of claims 1 to 8, or a pharmaceutical composition as defined in claim 8, for the manufacture of a medicament; the medicine is preferably a medicine for preventing and/or treating tumors or a medicine for treating diseases related to ERK kinase; the tumor is preferably non-small cell lung cancer, melanoma, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostatic cancer, liver cancer, pancreatic cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymph cancer or nasopharyngeal carcinoma; the ERK kinase is preferably ERK1 and/or ERK2, more preferably ERK 2.
10. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, as defined in any one of claims 1 to 9, or a pharmaceutical composition as defined in claim 8, for the preparation of an ERK kinase inhibitor; the ERK kinase is preferably ERK1 and/or ERK2, more preferably ERK 2.
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CN107108648A (en) * 2014-12-22 2017-08-29 伊莱利利公司 It is used as the ketone derivatives of thieno [2,3 c] pyrroles 4 of ERK inhibitor
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CN112457326A (en) * 2019-09-06 2021-03-09 上海凌达生物医药有限公司 Aromatic heterocyclic lactam compound, preparation method and application
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