CN113061132A - Condensed ring lactam compound, preparation method and application - Google Patents

Condensed ring lactam compound, preparation method and application Download PDF

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CN113061132A
CN113061132A CN202011448242.9A CN202011448242A CN113061132A CN 113061132 A CN113061132 A CN 113061132A CN 202011448242 A CN202011448242 A CN 202011448242A CN 113061132 A CN113061132 A CN 113061132A
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CN113061132B (en
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万惠新
查传涛
马金贵
沈竞康
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Shanghai Lingji Biotechnology Co Ltd
Shanghai Lingda Biomedical Co Ltd
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Shanghai Lingda Biomedical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Abstract

The invention discloses a condensed ring lactam compound, a preparation method and application. Fused ring lactams of the invention, e.g.Shown in a general formula I. The compound of the invention has the activity of inhibiting Ras mutein and has better application prospect.

Description

Condensed ring lactam compound, preparation method and application
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a fused ring lactam compound, a compound with Ras mutein inhibition activity, a preparation method and application.
Background
RAS is the first oncogene identified in human tumors and was first found in two murine sarcoma viruses. There are three members of the RAS gene family, Hras, Kras, Nras. In human tumors, Kras mutations are most common, accounting for approximately 85%. Previous studies have shown that Kras mutations are carcinogenic because codon 12 is missense mutated, altering the structure of the Kras protein and keeping it activated at all times. Ras plays a major role in signal pathway transmission, mainly activating kinases controlling gene transcription, thereby regulating cell differentiation and proliferation, and is closely related to survival, proliferation, migration, metastasis and angiogenesis of tumor cells. According to statistics, Kras G12C mutation exists in 11% -16% of lung adenocarcinoma cases, and part of pancreatic cancer, colorectal cancer, ovarian cancer and bile duct cancer is caused by Kras mutation. However, over thirty years ago since the first discovery of Kras oncogene, the targeting drugs for EGFR, BCL and other common protooncogenes have been developed for several generations, and the targeting drugs for Kras have not been successfully developed. Historically, targeted drugs against KRas pathway mutant tumors have focused primarily on farnesyl transferase inhibitors and Raf-MEK pathway inhibitors, but with little success. In recent years, inhibitors aiming at KRas specific gene mutation are developed into hot spots, and part of inhibitors gradually go from preclinical hatching to clinical research, such as KRas G12C inhibitors AMG510, MRTX1257 and the like, and show certain curative effect in early clinical experiments. The first clinical data of the first global KRASG12C inhibitor AMG510 was finally promulgated by the american clinical oncology institute held in 6 months 2019, in which clinical studies the installed drug AMG510 was shown to prevent tumor growth in most non-small cell lung and colorectal cancer patients with KRas mutations. Therefore, finding and searching for a target drug against KRas specific mutant gene with high specificity and excellent drug availability is a major hotspot in the industry.
Disclosure of Invention
The invention aims to overcome the defect of few types of KRAS G12C inhibitors, and provides a condensed cyclic lactam compound, a preparation method and application thereof.
The present invention solves the above-mentioned problems by the following technical means.
The invention provides a fused ring lactam compound shown as a general formula I, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, twisted isomer thereof, solvate thereof, polymorph thereof or prodrug thereof,
Figure BDA0002825639160000021
in the formula:
r1 is independently hydrogen, deuterium, halogen, cyano, nitro, C1-C6Alkyl radical, C1-C6alkyl-SO2-、C1-C6alkyl-SO-, or C1-C6A haloalkyl group;
r2 and R3 are independently hydrogen, deuterium, halogen, cyano, nitro, C1-C6Alkyl radical, C1-C6alkyl-SO2-、C1-C6alkyl-SO-, N (R)2a)(R2b)-(CH2) x-; wherein R is2aAnd R2bEach independently is hydrogen or C1-C6Alkyl, x is selected from any integer of 0-5;
r4 is independently substituted or unsubstituted C1-C12Substituted or unsubstituted cycloalkyl or heterocycloalkyl of 3 to 12 members, substituted or unsubstituted aryl or heteroaryl of 5 to 10 members;
r5 is independently one or more of hydrogen, deuterium, halogen, C1-C6Alkyl, 3-6 membered cycloalkyl or heterocycloalkyl, vinyl or cyano; m is independently selected from 0-6;
m is CH, C-D or N; m1 is N or CR 6;
r6 is independently H, deuterium, halogen, cyano, hydroxy, ether, thioether, sulfoxide, sulfone, amide, sulfonamide, C1-C6Alkyl radical, C1-C6Alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl;
ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are each independently hydrogen, deuterium, C1-C6Alkyl, alkoxy, haloalkyl or carboxyl;
or Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh form a 3-8-membered saturated or partially unsaturated ring system between each two;
or Rg and R6 form a 3-8 membered saturated or partially unsaturated ring system;
ar is independently a 5-12 membered aromatic ring or aromatic fused ring, a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, alkoxy, 3-to 8-membered cycloalkyl or heterocycloalkyl, C1-C6Haloalkoxy, C2-C6Alkenyl radical, C2-C6An alkynyl group, a substituted or unsubstituted amino group, an amido group, a sulfonamide group, or a hydroxyl group;
one or more hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of: including but not limited to deuterium, halogen, hydroxy, amino or cyclic amino, cyano, nitro, sulfone or sulfoxide, C1-C8Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, C1-C8Alkoxy radical, C1-C8Alkylamino, alkenyl, alkynyl, acyl or sulfonyl, urea or sulfonylurea, 5-to 8-membered aryl or heteroaryl, or substituted with 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl;
wherein said heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, the heterocycloalkyl group containing 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said ring system comprising spiro, bridged, fused, or partially unsaturated ring systems.
In a preferred embodiment of the present invention,
r1 is independently hydrogen, halogen, cyano or C1-C6An alkyl group;
r2 and R3 are hydrogen;
r4 is independently substituted C1-C12Alkyl or substituted 5-10 membered heteroaryl of (a);
said substituted C1-C12The substituents in the alkyl group of (a) are independently a 3-to 8-membered heterocycloalkyl group, or substituted with 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl;
of said substituted 5-to 10-membered heteroarylThe substituents are independently C1-C6An alkyl group;
r5 is independently hydrogen, halogen, 3-6 membered cycloalkyl or vinyl;
r6 is independently H, halogen, cyano or haloalkoxy (e.g. when R6 is a substituent on the lactam ring in formula I, R6 is independently hydrogen or cyano, or Rg and R6 together form a 3-to 8-membered saturated or partially unsaturated ring system; when M1 is independently CR6, R6 is H, halogen or haloalkoxy);
m is CH or N;
m1 is N or CR 6;
ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are each independently hydrogen or C1-C6An alkyl group; when Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are independently C1-C6Alkyl, and said C1-C6When one or more hydrogen atoms on the alkyl group are substituted with a substituent, said substituent is independently cyano;
or Rg and R6 together form a 3-8 membered saturated or partially unsaturated ring system (said R6 is a substituent on the cyclic lactam);
ar is independently a 5-12 membered aromatic ring or aromatic fused ring, a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, unsubstituted amino or hydroxy.
In a preferred embodiment of the present invention,
r1 is independently hydrogen, halogen or C1-C6An alkyl group;
r2 and R3 are hydrogen;
r4 is independently substituted C1-C12Alkyl or substituted 5-10 membered heteroaryl of (a);
said substituted C1-C12The substituents in the alkyl group of (a) are independently a 3-to 8-membered heterocycloalkyl group, or substituted with 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl;
the substituents in said substituted 5-10 membered heteroaryl are independently C1-C6An alkyl group;
r5 is independently hydrogen, halogen, 3-6 membered cycloalkyl or vinyl;
r6 is independently H, halogen, cyano, or haloalkoxy;
m is CH or N;
m1 is N or CR 6;
ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are each independently hydrogen or C1-C6An alkyl group; when Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are independently C1-C6Alkyl, and said C1-C6When one or more hydrogen atoms on the alkyl group are substituted with a substituent, said substituent is independently cyano;
or Rg and R6 together form a 3-8 membered saturated or partially unsaturated ring system (said R6 is a substituent on the cyclic lactam);
ar is independently a 5-12 membered aromatic ring or aromatic fused ring, a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, unsubstituted amino or hydroxy.
In a preferred embodiment of the present invention,
r1 is independently hydrogen;
r2 and R3 are independently hydrogen;
r4 is independently substituted C1-C12Alkyl or substituted 5-10 membered heteroaryl of (a);
said substituted C1-C12The substituents in the alkyl group of (a) are independently a 3-to 8-membered heterocycloalkyl group, or substituted with 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl;
the substituents in said substituted 5-10 membered heteroaryl are independently C1-C6An alkyl group;
r5 is independently hydrogen, halogen, or 3-6 membered cycloalkyl;
r6 is independently H, halogen, cyano, or haloalkoxy;
m is CH or N;
m1 is N or CR 6;
Rarb, Rc, Rd, Re and Rf are independently hydrogen or C1-C6An alkyl group; when Ra, Rb, Rc, Rd, Re and Rf are independently C1-C6Alkyl, and said C1-C6When one or more hydrogen atoms on the alkyl group are substituted with a substituent, said substituent is independently cyano;
rg and Rh are hydrogen;
ar is independently a 5-12 membered aromatic ring or aromatic fused ring, a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, unsubstituted amino or hydroxy;
when M1 is CR6, Ar is independently a 5-12 membered aromatic heterocycle or aromatic fused heterocycle.
In a preferred embodiment of the present invention,
r1 is independently hydrogen or halogen;
r2 and R3 are independently hydrogen;
r4 is independently substituted C1-C12Alkyl or substituted 5-10 membered heteroaryl of (a);
said substituted C1-C12The substituents in the alkyl group of (a) are independently substituted by 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl;
the substituents in said substituted 5-10 membered heteroaryl are independently C1-C6An alkyl group;
r5 is independently hydrogen or halogen;
r6 is independently H, halogen or cyano;
m is CH or N;
m1 is N or CR 6;
ra, Rb, Rc, Rd, Re and Rf are independently hydrogen or C1-C6An alkyl group;
when Ra, Rb, Rc, Rd, Re and Rf are independently C1-C6Alkyl, and said C1-C6When one or more hydrogens on the alkyl group is substituted with a substituent, said substituent is cyano;
rg and Rh are hydrogen;
ar is independently a 5-12 membered aromatic ring or aromatic fused ring, a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, unsubstituted amino or hydroxy;
and when M1 is CR6, Ar is independently a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, unsubstituted amino or hydroxy;
and when Ra and Rb are independently C1-C6Alkyl, and said C1-C6R1 is halogen when one or more hydrogens on the alkyl group is substituted with a substituent; ar is
Figure BDA0002825639160000051
In a preferred embodiment of the present invention,
r1 is independently hydrogen or halogen;
r2 and R3 are independently hydrogen;
r4 is independently substituted C1-C12Alkyl or substituted 5-10 membered heteroaryl of (a);
said substituted C1-C12The substituents in the alkyl group of (a) are independently substituted by 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl;
the substituents in said substituted 5-10 membered heteroaryl are independently C1-C6An alkyl group;
r5 is independently hydrogen, halogen, or vinyl;
r6 is independently H, halogen or cyano;
m is CH or N;
m1 is N or CR 6;
ra, Rb, Rc, Rd, Re and Rf are independently hydrogen or C1-C6An alkyl group; when Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are independently C1-C6Alkyl, and said C1-C6When one or more hydrogen atoms of the alkyl group are substituted with the substituent(s), the substituents are independentlyIs cyano;
rg and Rh are hydrogen;
ar is independently a 5-12 membered aromatic ring or aromatic fused ring, a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, unsubstituted amino or hydroxy;
when M1 is CR6, Ar is independently a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, unsubstituted amino or hydroxy.
In a preferred embodiment of the present invention,
r1 is independently hydrogen;
r2 and R3 are independently hydrogen;
r4 is substituted C1-C12Alkyl or substituted 5-10 membered heteroaryl of (a);
said substituted C1-C12The substituents in the alkyl group of (a) are independently substituted by 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl;
the substituents in said substituted 5-10 membered heteroaryl are independently C1-C6An alkyl group;
r5 is independently hydrogen or halogen;
r6 is independently H, halogen or cyano;
m is CH or N;
m1 is N or CR 6; when M1 is CR6, R6 is H or halogen;
ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are independently hydrogen or C1-C6An alkyl group;
ar is a 5-12-membered aromatic ring or aromatic condensed ring, a 5-12-membered aromatic heterocycle or aromatic condensed heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, unsubstituted amino or hydroxy.
In a preferred embodiment of the present invention, the condensed ring lactam compound shown in formula I is shown in formula (IIA), (IIB), (IIC), (IID), (IIE), (IIF), (IIG), (IIH), (IIM), (IIN), (IIO) or (IIP):
Figure BDA0002825639160000061
wherein, the carbon marked by the symbol in the general formula (IIG) refers to R configuration chiral carbon;
the carbon marked with x in the general formula (IIH) refers to S configuration chiral carbon;
the carbon marked with x in the general formula (IIM) refers to an R configuration chiral carbon;
the carbon marked with x in the general formula (IIN) refers to an S configuration chiral carbon;
the carbon marked with ×, in the general formula (IIO), refers to an S configuration chiral carbon;
the carbon marked with x in the general formula (IIP) refers to S configuration chiral carbon;
m, M1, R1, R2, R3, R4, R5, R6, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ar and m are as defined in any of the above schemes.
In a preferred embodiment of the invention, when R1 is independently halogen, the halogen is F, Cl, Br or I, preferably F.
In a preferred embodiment of the invention when R1 is independently C1-C6When alkyl, said C1-C6Alkyl is C1-C3The alkyl group (for example, methyl, ethyl, n-propyl, or isopropyl) is more preferably a methyl group.
In a preferred embodiment of the invention when R4 is independently substituted or unsubstituted C1-C12When there is an alkyl group, said C1-C12Alkyl of (A) is C1-C6Is preferably C1-C3The alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl) of (b) is more preferably methyl.
In a preferred embodiment of the invention when R4 is independently substituted C1-C12When said substituent is independently a 3-to 8-membered heterocycloalkyl group, or substituted with 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl.
Wherein, when the substituents are independently 3-8 membered heterocycloalkyl, or substituted with 1 or more C1-C6In the case of an alkyl-substituted 3-to 8-membered heterocycloalkyl group, the heteroatoms in the 3-to 8-membered heterocycloalkyl group are independently preferably N, and the number thereof is preferably 1.
Wherein, when the substituents are independently 3-8 membered heterocycloalkyl, or substituted with 1 or more C1-C6In the case of an alkyl-substituted 3-to 8-membered heterocycloalkyl group, the 3-to 8-membered heterocycloalkyl group is preferably a 3-to 5-membered heterocycloalkyl group, and more preferably a tetrahydropyrrolyl group.
Wherein, when the substituents are independently substituted by 1 or more C1-C6In the case of an alkyl-substituted 3-to 8-membered heterocycloalkyl group, the substituent is preferably independently at a heteroatom in the 3-to 5-membered heterocycloalkyl group.
Wherein, when the substituents are independently substituted by 1 or more C1-C6When the alkyl group is substituted with a 3-to 8-membered heterocycloalkyl group, said C1-C6Alkyl is preferably C1-C4The alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl) is more preferably a methyl group.
Wherein, when the substituents are independently substituted by 1 or more C1-C6When the 3-to 8-membered heterocycloalkyl group is substituted with an alkyl group, said group is substituted with 1 or more C1-C63-to 8-membered heterocycloalkyl of alkyl is preferred
Figure BDA0002825639160000071
In a preferred embodiment of the invention when R4 is independently substituted C1-C12Alkyl of (2), said substituted C1-C12Alkyl of (A) is
Figure BDA0002825639160000072
Further comprises
Figure BDA0002825639160000073
In a preferred embodiment of the present invention, when R4 is independently a substituted or unsubstituted 5-10 membered aryl or heteroaryl group, the heteroatom in said 5-10 membered heteroaryl group is N, and the number is 1.
In a preferred embodiment of the present invention, when R4 is independently substituted or unsubstituted 5-10 membered aryl or heteroaryl, said 5-10 membered heteroaryl is 6 membered heteroaryl, further pyridinyl.
In a preferred embodiment of the present invention, when R4 is independently substituted 5-10 heteroaryl, the number of substituents is 2.
In a preferred embodiment of the present invention, when R4 is independently substituted 5-10 heteroaryl, the substituents are independently C1-C6An alkyl group.
Wherein, when the substituent is independently C1-C6When alkyl, said C1-C6The alkyl group is preferably C1-C4The alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl) is more preferably methyl or isopropyl.
In a preferred embodiment of the present invention, when R4 is independently substituted 5-10 membered heteroaryl, said 5-10 membered heteroaryl is
Figure BDA0002825639160000081
In a preferred embodiment of the invention, R4 is
Figure BDA0002825639160000082
In a preferred embodiment of the invention, when R5 is independently halogen, the halogen is F, Cl, Br or I, preferably F or Cl.
In a preferred embodiment of the invention, when R5 is independently a 3-6 membered cycloalkyl group, said 3-6 membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.
In a preferred embodiment of the invention, the substitution position of R5 is ortho to Ar as defined above.
In a preferred embodiment of the present invention, when R6 is haloalkoxy, said haloalkoxy is halo C1-C4Alkoxy, more preferably trifluoromethoxy.
In a preferred embodiment of the present invention, when R6 is a 3-to 8-membered cycloalkyl group, the 3-to 8-membered cycloalkyl group is a 3-to 6-membered cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), and further preferably cyclopropyl.
In a preferred embodiment of the present invention, when R6 is a substituent on the lactam ring in formula I and Rg and R6 together form a 3-8 membered saturated or partially unsaturated ring system, said 3-8 membered saturated or partially unsaturated ring system is a 3-8 membered monocyclic heterocycloalkyl, more preferably a 6 membered monocyclic heterocycloalkyl, the heteroatoms are O and/or N, the number is 2, even more preferably 2
Figure BDA0002825639160000083
In a preferred embodiment of the invention, when Ra, Rb, Rc, Rd, Re and Rf are each independently C1-C6When alkyl, said C1-C6Alkyl is C1-C3The alkyl group (for example, methyl, ethyl, n-propyl, or isopropyl) is more preferably a methyl group.
In a preferred embodiment of the invention, when Ra, Rb, Rc, Rd, Re and Rf are each independently C1-C6Alkyl, and said C1-C6When one or more hydrogen atoms on the alkyl group are substituted with a substituent, said substituent is independently cyano.
In a preferred embodiment of the invention, when Ra, Rb, Rc, Rd, Re and Rf are each independently C1-C6Alkyl, and said C1-C6When one or more hydrogen atoms of the alkyl group are substituted by the substituent(s), said C1-C6Alkyl is
Figure BDA0002825639160000084
In a preferred embodiment of the present invention, when Rg and Rh are each independently C1-C6When alkyl, said C1-C6Alkyl is C1-C3The alkyl group (for example, methyl, ethyl, n-propyl, or isopropyl) is more preferably a methyl group.
In a preferred embodiment of the present invention, when Ar is independently a 5-12 membered aromatic ring, the 5-12 membered aromatic ring is a 6-10 membered aromatic ring, and is more preferably a phenyl group.
In a preferred embodiment of the present invention, when Ar is independently a 5-12 membered aromatic condensed ring, the 5-12 membered aromatic condensed ring is a 6-10 membered aromatic condensed ring, and further preferably a naphthyl group (for example
Figure BDA0002825639160000091
)。
In a preferred embodiment of the present invention, when Ar is independently a 5-12 membered fused aromatic heterocyclic ring, the number of heteroatoms in the 5-12 membered fused aromatic heterocyclic ring is 1 or 2, and N and/or S.
In a preferred embodiment of the present invention, when Ar is independently a 5-12 membered fused aromatic heterocyclic ring, the 5-12 membered fused aromatic heterocyclic ring is a 9 membered fused aromatic heterocyclic ring, further
Figure BDA0002825639160000092
In a preferred embodiment of the invention, when the Ar ring is substituted with one or more groups and said groups are halogens, said halogens are F, Cl, Br or I, preferably F, Cl.
In a preferred embodiment of the invention, when the Ar ring is substituted by one or more groups C1-C6When alkyl, said C1-C6Alkyl is C1-C3The alkyl group (for example, methyl, ethyl, n-propyl, or isopropyl) is more preferably a methyl group.
In a preferred embodiment of the present invention, when the Ar ring is substituted with one or more groups and said group is an alkoxy group, said alkoxy group is C1-C6An alkoxy group.
In a preferred embodiment of the invention, when Ar is substituted by one or more groups, the number of said substitutions is 1,2,3 or 4.
In a preferred embodiment of the present invention, when Ar is independently a 5-12 membered aromatic ring, and Ar is substituted with one or more groups, the 5-12 membered aromatic ring is
Figure BDA0002825639160000093
In a preferred embodiment of the present invention, when Ar is independently a 5-12 membered aromatic fused ring and Ar is substituted with one or more groups, said 5-12 membered aromatic fused ring is
Figure BDA0002825639160000094
In a preferred embodiment of the present invention, when Ar is independently a 5-12 membered fused aromatic heterocycle, and Ar is substituted with one or more groups, the 5-12 membered fused aromatic heterocycle is
Figure BDA0002825639160000095
In a preferred embodiment of the invention, Ar is independently
Figure BDA0002825639160000101
Figure BDA0002825639160000102
In a preferred embodiment of the invention, the cycloalkyl is a non-aromatic saturated monocyclic ring.
In a preferred embodiment of the invention, the heterocyclyl is a saturated or unsaturated monocyclic ring system.
In a preferred embodiment of the present invention, the heterocyclic group is a heterocyclic group in which the nitrogen, carbon or sulfur atom is not oxidized; the nitrogen atoms are not quaternized.
In a preferred embodiment of the invention, R1 is independently hydrogen, halogenCyano or C1-C6Alkyl, preferably hydrogen or halogen.
In a preferred embodiment of the invention, R2 and R3 are hydrogen.
In a preferred embodiment of the invention, R4 is independently substituted C1-C12Or a substituted 5-10 membered heteroaryl.
In a preferred embodiment of the invention when R4 is independently substituted C1-C12Alkyl of (2), said substituted C1-C12The substituents in the alkyl group of (a) are independently a 3-to 8-membered heterocycloalkyl group, or substituted with 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl.
In a preferred embodiment of the present invention, when R4 is independently substituted 5-10 membered heteroaryl, the substituent in said substituted 5-10 membered heteroaryl is independently C1-C6An alkyl group.
In a preferred embodiment of the invention, R5 is independently hydrogen, halogen, 3-6 membered cycloalkyl or vinyl, preferably hydrogen, halogen or vinyl.
In a preferred embodiment of the invention, Ra and Rb are independently hydrogen or C1-C6An alkyl group;
in a preferred embodiment of the invention, when Ra and Rb are independently C1-C6Alkyl, and said C1-C6When one or more hydrogen atoms on the alkyl group are substituted with a substituent, said substituent is independently cyano.
In a preferred embodiment of the invention, Rc, Rd, Re and Rf are independently hydrogen.
In a preferred embodiment of the invention, Rg and Rh are hydrogen or C1-C6An alkyl group.
In a preferred embodiment of the present invention, when R6 is a substituent on the lactam ring in formula I, said R6 is independently hydrogen or cyano;
or Rg and R6 together form a 3-8 membered saturated or partially unsaturated ring system.
In a preferred embodiment of the invention, when M1 is independently CR6, R6 is H, halogen or haloalkoxy.
In a preferred embodiment of the invention, m is independently 0 or 1.
In a preferred embodiment of the invention, when the Ar ring is substituted by one or more of the following groups, said groups are hydrogen, halogen, C1-C6Alkyl radical, C1-C6Haloalkoxy, unsubstituted amino or hydroxy.
In a preferred embodiment of the present invention,
Figure BDA0002825639160000111
is composed of
Figure BDA0002825639160000112
In a preferred embodiment of the present invention,
Figure BDA0002825639160000113
is composed of
Figure BDA0002825639160000114
Figure BDA0002825639160000115
In a preferred embodiment of the present invention,
Figure BDA0002825639160000116
is composed of
Figure BDA0002825639160000117
Figure BDA0002825639160000118
In a preferred embodiment of the present invention,
Figure BDA0002825639160000121
is composed of
Figure BDA0002825639160000122
Figure BDA0002825639160000123
In a preferred embodiment of the present invention,
Figure BDA0002825639160000124
is composed of
Figure BDA0002825639160000125
Figure BDA0002825639160000126
Figure BDA0002825639160000131
In a preferred embodiment of the invention, the condensed ring lactam compound shown in the general formula I and/or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, twisted isomer, solvate, polymorph or prodrug thereof,
Figure BDA0002825639160000141
in the formula:
r1 is independently selected from hydrogen, halogen, cyano, nitro, C1-C6Alkyl radical, C1-C6alkyl-SO2-、C1-C6alkyl-SO-, or C1-C6A haloalkyl group;
r2 and R3 are independently selected from hydrogen, halogen, cyano, nitro and C1-C6Alkyl radical, C1-C6alkyl-SO2-、C1-C6alkyl-SO-, N (R)2a)(R2b)-(CH2) x-; wherein R is2aAnd R2bEach independently selected from hydrogen or C1-C6Alkyl, x is selected from any integer of 0-5;
r4 is independently selected from substituted or unsubstituted C1-C12Substituted or unsubstituted 3-12 membered cycloalkyl or heterocycloalkyl;
r5 is independently selected from one or more of hydrogen, halogen, C1-C6Alkyl, 3-6 membered cycloalkyl or heterocycloalkyl, vinyl, cyano, and the like; m is independently selected from 0-6;
m is independently selected from CH or N; m1 is independently selected from N or CR 6;
r6 is independently selected from H, halogen, cyano, hydroxy, ether, thioether, sulfoxide, sulfone, amide, sulfonamide, C1-C6Alkyl radical, C1-C6Alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, 3-to 8-membered cycloalkyl or heterocycloalkyl, and the like;
ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are respectively and independently selected from hydrogen, C1-C6 alkyl, alkoxy, haloalkyl, carboxyl and the like, or Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh form a 3-8-membered saturated or partially unsaturated ring system between every two of them; or Rg and R6 form a 3-8 membered saturated or partially unsaturated ring system;
ar is independently selected from a 5-12 membered aromatic ring or aromatic condensed ring, a 5-12 membered aromatic heterocycle or aromatic condensed heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, alkoxy, 3-to 8-membered cycloalkyl or heterocycloalkyl, C1-C6Haloalkoxy, C2-C6Alkenyl radical, C2-C6Alkynyl groups, substituted or unsubstituted amino groups, amide groups, sulfonamide groups, and the like;
one or more hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of: including but not limited to deuterium, halogen, hydroxy, amino or cyclic amino, cyano, nitro, sulfone or sulfoxide, C1-C8Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, C1-C8Alkoxy radical, C1-C8Alkylamino, alkenyl, alkynyl, acyl or sulfonyl, urea or sulfonylurea, 5-to 8-membered aryl or heteroaryl; wherein said heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, the heterocycloalkyl group containing 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said ring systemIncluding saturated or partially unsaturated ring systems such as spiro, bridged, fused, and fused rings.
In a further embodiment, the compound having the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsionmer, solvate, polymorph or prodrug thereof, is preferably a compound represented by the general formulae (IIA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, torsionmer, tautomer, solvate, polymorph or prodrug thereof:
Figure BDA0002825639160000151
wherein M1 is selected from N or CR 6; r1, R2, R3, R4, R5, R6, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ar, m are as defined above.
In a further preferred form, the compound of formula (1), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsiomer, solvate, polymorph or prodrug thereof, characterized in that:
r1, R2, R3 are each independently preferably selected from hydrogen, fluoro, methyl, cyano, etc.;
ra, Rb, Rc, Rd, Re, Rf, Rg, Rh are each independently preferably selected from hydrogen, fluorine, methyl, hydroxymethyl, cyanomethylene, etc.;
m1 is preferably independently selected from N or CH, C-F, C-Cl, C-Me, C-CN, C-OMe, C-OCF3、C-OCH2CF3Etc.;
m is preferably selected from 0,1, 2;
r4 is independently preferably selected from C4-C12Alkyl or cycloalkyl or heterocycloalkyl group of (a), 3-to 8-membered cycloalkyl or heterocycloalkyl substituted alkylene group, etc.;
r5 is independently selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy, 3-5 membered cycloalkyl, vinyl, cyano, and the like;
r6 is independently selected from H, halogen, cyano, nitro, methyl, ether linkages, thioether linkages, and the like;
ar is independently preferably a monocyclic aromatic group such as a substituted or unsubstituted phenyl group or pyridyl group, or a substituted or unsubstituted bicyclic aromatic group such as a naphthyl group, a naphthyridinyl group, an indazolyl group, a benzimidazolyl group, or a benzothiazolyl group; said one or more substituents are preferably selected from the group consisting of: hydrogen, halogen, C1-C4Alkyl, hydroxy, amino, cyano, C1-C4Alkoxy radical, C1-C4Haloalkyl, C1-C4Haloalkoxy and the like;
in a preferred embodiment of the present invention, the fused ring lactam compound shown in formula I, its pharmaceutically acceptable salt, its enantiomer, its diastereomer, its tautomer, its twisted isomer, its solvate, its polymorph or its prodrug is any one of the following compounds:
Figure BDA0002825639160000152
Figure BDA0002825639160000161
Figure BDA0002825639160000171
the invention also provides a preparation method of the fused ring lactam compound shown as the general formula I, pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, twisted isomer, solvate, polymorph or prodrug thereof, wherein the preparation method comprises the following steps: a → g
a) Converting the compound of the general formula (A) into a compound of the general formula (B) through various functional group conversion reactions;
b) reacting the compound of the general formula (B) with a piperazine derivative to produce a compound of the general formula (C);
c) removing the protecting group of the compound (C) to obtain a compound D;
d) reacting the compound (D) with acrylic acid/acryloyl chloride/chloropropionyl chloride and the like to generate a compound (I) with a general formula;
e) converting the compound of formula (E) to a compound of formula (F) by various functional group transformations;
f) reacting the compound (F) with a piperazine derivative to produce a compound (G);
g) converting compound G of formula (la) with an arylboronic acid or arylboronic ester or arylmetal reagent by a transition metal catalysed coupling reaction to compound (C);
Figure BDA0002825639160000181
wherein Cy is
Figure BDA0002825639160000182
The definition of each group is as described above.
Preferably, said steps a), b), c), d), e), f), g) are each carried out in a solvent, and said solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methyl pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.
Preferably, the transition metal catalyst is selected from the group consisting of: 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]Palladium dichloride, bis (tri-o-phenylphosphino) palladium dichloride, 1, 2-bis (diphenylphosphino) ethane palladium dichloride, or a combination thereof; the catalyst ligand is selected from the group consisting of: tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine,Tri-p-benzylphosphine, tricyclohexylphosphine, tri-o-benzylphosphine, or combinations thereof.
Preferably, the condensing agent is selected from the group consisting of: n, N '-Dicyclohexylcarbodiimide (DCC), N, N' -Diisopropylcarbodiimide (DIC), N, N '-Carbonyldiimidazole (CDI), 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride (EDCI), 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytris (pyrrolidinyl) phosphonium hexafluorophosphate (PyBOP), 2- (7-azabenzotriazole) -N, N, N', N '-tetramethyluronium Hexafluorophosphate (HATU), O-benzotriazol-N, N, N', n' -tetramethyluronium tetrafluoroborate (TBTU), and the like, or combinations thereof.
Preferably, the inorganic base is selected from the group consisting 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, sodium bicarbonate, or combinations thereof; the organic base is selected from the group consisting of: pyridine, triethylamine, N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or a combination thereof.
Preferably, the acid is selected from the group consisting of: hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, trifluoromethanesulfonic acid, or combinations thereof.
The invention also aims to provide a medicament for treating or preventing tumors and a composition thereof. The technical scheme for realizing the purpose is as follows:
the invention also provides a pharmaceutical composition, which comprises an effective amount of the fused ring lactam compound shown in the general formula I, pharmaceutically acceptable salts thereof, enantiomers thereof, diastereomers thereof, tautomers thereof, torsional isomers thereof, solvates thereof, polymorphs thereof or prodrugs thereof, and a pharmaceutically acceptable carrier.
Another object of the present invention is to provide a use of the above compound or pharmaceutical composition. The technical scheme for realizing the purpose is as follows:
the invention also provides application of the fused ring lactam compound shown as the general formula I, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, twisted isomers, solvates, polymorphs, prodrugs or pharmaceutical compositions of the fused ring lactam compound and the pharmaceutically acceptable salts in preparation of Ras mutein inhibitors.
In the application, the Ras mutein is preferably KRAS G12C; the Ras mutein inhibitors are useful in mammalian organisms; also useful in vitro, primarily for experimental purposes, for example: provide comparison as a standard sample or a control sample, or prepare a kit according to the conventional method in the field, and provide rapid detection for the inhibition effect of the Ras mutein.
The invention also provides application of the fused ring lactam compound shown as the general formula I, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, twisted isomers, solvates, polymorphs, prodrugs or pharmaceutical compositions of the fused ring lactam compound and the pharmaceutically acceptable salts thereof in preparation of drugs for treating diseases related to Ras mutein activity or expression.
The disease related to the activity or expression amount of Ras mutein is preferably tumor. The tumor is independently one or more of non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostatic cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymph cancer, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer and pancreatic cancer, preferably non-small cell lung cancer, small cell lung cancer or pancreatic cancer.
The invention also provides application of the fused ring lactam compound shown as the general formula I, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, twisted isomers, solvates, polymorphs, prodrugs or the pharmaceutical composition in preparation of drugs, wherein the drugs are tumor treatment drugs.
The tumor is independently one or more of non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostatic cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymph cancer, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer and pancreatic cancer, preferably non-small cell lung cancer, small cell lung cancer or pancreatic cancer.
Another aspect of the present invention relates to a method for preventing and/or treating diseases associated with Ras mutein activity or expression level, comprising administering to a patient a therapeutically effective dose of a fused ring lactam compound represented by the above general formula Ia or Ib, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof, a solvate thereof, a polymorph thereof, a prodrug thereof or a pharmaceutical composition thereof.
The Ras mutant protein activity or expression of the related diseases as described above.
Another aspect of the present invention relates to a method for preventing and/or treating tumors, which comprises administering to a patient a therapeutically effective amount of the above-mentioned fused ring lactam compound represented by the general formula I, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a twisted isomer thereof, a solvate thereof, a polymorph thereof, a prodrug thereof, or the above-mentioned pharmaceutical composition.
The tumor is as described above.
The invention relates to a compound with the structural characteristics of a general formula (I), which can inhibit various tumor cells, particularly can efficiently kill tumors related to abnormal KRas G12C mutant protein signal pathways, and is a treatment medicament with a brand-new action mechanism.
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 sector can be found in the literature references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." 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, IR and UV/VIS 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, -CH2O-is equivalent to-OCH2-。
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; aromatic condensed rings in the heterocyclic group thereof; 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 the preparation/separation of 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, as described, for example, in Gerald Gubitz and Martin G.Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol.243, 2004; m. Stalcup, Chiral Separations, Annu. Rev. anal. chem.3:341-63, 2010; fumiss et al (eds.), VOGEL' S ENCYCOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5. TH ED., Longman Scientific and Technical Ltd., Essex,1991, 809-816; heller, acc, chem, res, 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 condition, i.e., causing regression of the state of the disease or condition; 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 pharmaceutical 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.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the field.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the condensed ring lactam compound can be used as KRASG12CAn inhibitor; has good effect of inhibiting and resisting tumor.
Detailed Description
The inventor has made a long-term and intensive study to prepare a compound with a novel structure shown in formula I, and finds that the compound has a better inhibitory activity for inhibiting the KRas G12C protein, the compound has a specific inhibitory effect on the KRas G12C protein at a very low concentration (which can be as low as less than 100nM), the inhibitory activity on the KRas G12C-related cell proliferation is quite excellent, and the compound has a stronger killing effect on KRas G12C-positive tumor cells at a very low concentration (which can be as low as less than 10nM), so that the compound can be used for treating related diseases such as tumors caused by KRas G12C mutation or abnormal expression. Based on the above findings, the inventors have completed the present invention.
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Preparation of intermediates
Intermediate 1: 4-chloro-6-fluoro-7- (2-fluoro-6-methoxyphenyl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
Figure BDA0002825639160000261
The first step is as follows: methyl 2, 6-dichloro-5-fluoronicotinate (20g, 89.7mmol), 2-fluoro-6-methoxyphenylboronic acid (19.4g, 114.1mmol) and potassium phosphate (K)3PO4) (24.3g, 114.3mmol) was dissolved in 1, 4-dioxane/H2To O (200mL/20mL) was added a tertiary palladium catalyst (Pd-Xphos-G3) (3.75G,4.4mmol) and 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (Ru-phos) (4.44G,9.5mmol), and the mixture was reacted overnight at 60 ℃ under nitrogen. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give methyl 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinate (8.9g, yellow oil). LC-MS ESI [ M + H ]]+＝314.3；1H-NMR(DMSO_d6,400MHz)：8.39(d,J＝8.4MHz,1H),7.57-7.59(m,1H),7.07(d,J＝8.4MHz,1H),7.01(t,J＝8.4MHz,1H),3.93(s,3H),3.79(s,3H)。
The second step is that: methyl 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinate (8.9g, 28.4mmol) was dissolved in (tetrahydrofuran/water) THF/H2O (90mL/45mL) mixed solvent, and lithium hydroxide monohydrate (LiOH. H) is added2O) (3.6g,85.7mmol), and stirred at room temperature for 5 hours. The reaction solution was concentrated to remove the organic solvent, 3N hydrochloric acid was added to adjust the pH to 3-4, Dichloromethane (DCM) was added for extraction, and the organic phase was washed with saturated brine, dried, and concentrated under reduced pressure to obtain 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid (8.3g, yellow solid). LC-MS ESI [ M + H ]]+＝300.0。
The third step: 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid (8.3g, 27.8mmol) was dissolved in N-methylpyrrolidone (NMP) (25mL), and (S) - (1-methylpyrrolidin-2-yl) methylamine (9.5g, 83.4mmol) and N, N-Diisopropylethylamine (DIEA) (10.8g,83.4mmol) were added and reacted for 16 hours at 180 degrees under nitrogen. The reaction solution was cooled to room temperature, and saturated ammonium chloride (NH) was slowly poured in4Cl) aqueous solution, filtering, dissolving filter cakes by methanol, drying, decompressing, concentrating, and purifying by column chromatography to obtain 5-fluoro-6- (2-fluoro-6-methoxyphenyl) -2- ((((S) -1-methylpyrrolidin-2-yl) methylYl) amino) nicotinic acid (tan oil). LC-MS ESI [ M + H ]]+＝378.2。
The fourth step: 5-fluoro-6- (2-fluoro-6-methoxyphenyl) -2- ((((S) -1-methylpyrrolidin-2-yl) methyl) amino) nicotinic acid (2.0g,5.3mmol) and DIEA (4.1g,31.8mmol) were dissolved in THF (30mL) and triphosgene (3.1g,10.6mmol) was added dropwise at 0 deg.C and reacted overnight at room temperature with LC-MS detection indicating complete reaction. The reaction liquid is decompressed and concentrated, and is purified by column chromatography to obtain 6-fluoro-7- (2-fluoro-6-methoxyphenyl) -1- (((S) -1-methylpyrrolin-2-yl) methyl) -2H-pyrido [2,3-d][1,3]Oxazine-2, 4(1H) -dione (640mg, yellow solid). LC-MS ESI [ M + H ]]+＝404.1。
The fifth step: reacting 6-fluoro-7- (2-fluoro-6-methoxyphenyl) -1- (((S) -71-methylpyrrolidin-2-yl) methyl) -2H-pyrido [2,3-d][1,3]Oxazine-2, 4(1H) -dione (640mg,1.6mmol) and ethyl cyanoacetate (200mg,1.8mmol) were dissolved in DMF (10mL), sodium hydride (NaH) (60% in mineral oil, 141mg,3.5mmol) was added at 0 deg.C and the reaction was complete by LCMS after 3H at RT. Pouring into water, extracting with ethyl acetate, combining organic phases, drying, concentrating under reduced pressure, and purifying by column chromatography to obtain 6-fluoro-7- (2-fluoro-6-methoxyphenyl) -4-hydroxy-1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (282mg, yellow solid). LC-MS ESI [ M + H ]]+＝427.2。
And a sixth step: 6-fluoro-7- (2-fluoro-6-methoxyphenyl) -4-hydroxy-1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (200mg,0.47mmol) was dissolved in phosphorus oxychloride (POCl)3) To the mixture (10mL) was added dropwise N, N-Dimethylformamide (DMF) (1 drop) and the mixture was stirred at 80 ℃ for 2 hours. Concentrated under reduced pressure, the residue was dissolved in ethyl acetate and washed successively with saturated sodium bicarbonate (NaHCO)3) The aqueous solution and water were washed, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give intermediate 1 (yellow solid). LC-MS ESI [ M + H ]]+＝445.2。
Intermediate 2: 4-chloro-6-fluoro-7- (2-fluoro-6-methoxyphenyl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
Figure BDA0002825639160000271
The first step is as follows: cyanoacetic acid (1.5g, 17.5mmol) was dissolved in DMF (20mL), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (8.0g, 21mmol) and Triethylamine (TEA) (2.6g, 25.7mmol) were added, stirred for 5 minutes, (S) - (1-methylpyrrolidin-2-yl) methylamine (2.0g, 17.5mmol) was added and reacted at room temperature for 2 hours. Diluting with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain (S) -2-cyano-N- ((1-methylpyrrolidin-2-yl) methyl) acetamide (2.8g, white solid). LC-MS ESI [ M + H ]]+＝182.1。
The second step is that: (S) -2-cyano-N- ((1-methylpyrrolidin-2-yl) methyl) acetamide (2.8g, 15.5mmol) was dissolved in THF (30mL), NaH (60% in mineral oil, 1.86g,46.5mmol) was added, stirring was carried out at room temperature for 15 minutes, and a solution of 2, 6-dichloro-5-fluoronicotinoyl chloride (3.52g, 15.5mmol) in THF (20mL) was added dropwise. After the dropwise addition, the temperature was raised to 80 ℃ and the mixture was stirred for 6 hours. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried, concentrated under reduced pressure, and purified by column chromatography to give (S) -7-chloro-6-fluoro-4-hydroxy-1- ((1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (1.6g, yellow solid). LC-MS ESI [ M + H ]]+＝337.1。
The third step: (S) -7-chloro-6-fluoro-4-hydroxy-1- ((1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (500mg,1.49mmol) was dissolved in POCl3DMF (1 drop) was added dropwise to the mixture (10mL), and the mixture was stirred at 80 ℃ for 2 hours. Concentrated under reduced pressure, the residue was dissolved in ethyl acetate and successively saturated NaHCO3The aqueous solution and water were washed, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give intermediate 2 (yellow solid). LC-MS ESI [ M + H ]]+＝355.2。
Intermediate 3: (S) -7-bromo-4, 6-dichloro-8-fluoro-1- ((1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile
Figure BDA0002825639160000272
The first step is as follows: 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (1.4g,5.3mmol) and DIEA (4.1g,31.8mmol) were dissolved in THF (30mL), triphosgene (3.1g,10.6mmol) was added dropwise at 0 deg.C, and the reaction was complete as determined by LCMS. The reaction liquid is decompressed, concentrated and purified by column chromatography to obtain 7-bromo-6-chloro-8-fluoro-2H-benzo [ d][1,3]Oxazine-2, 4(1H) -dione (410mg, yellow solid). LC-MS ESI [ M + H ]]+＝294.3。
The second step is that: reacting 7-bromo-6-chloro-8-fluoro-2H-benzo [ d][1,3]Oxazine-2, 4(1H) -dione (410mg,1.4mmol) and (S) - (1-methylpyrrolidin-2-yl) methyl methanesulfonate (300mg,1.6mmol) were dissolved in acetonitrile (10mL), and potassium carbonate (290mg,2.1mmol) was added to react at room temperature overnight. Filtering the reaction solution, concentrating the filtrate under reduced pressure, and purifying by column chromatography to obtain (S) -7-bromo-6-chloro-8-fluoro-1- ((1-methylpyrrolidin-2-yl) methyl) -2H-benzo [ d][1,3]Oxazine-2, 4(1H) -dione (120mg, yellow solid). LC-MS ESI [ M + H ]]+＝391.3。
The third step: reacting (S) -7-bromo-6-chloro-8-fluoro-1- ((1-methylpyrrolidin-2-yl) methyl) -2H-benzo [ d][1,3]Oxazine-2, 4(1H) -dione (120mg,0.31mmol) and ethyl cyanoacetate (40mg,0.35mmol) were dissolved in DMF (5mL), NaH (60% in mineral oil, 27mg,0.68mmol) was added at 0 deg.C and the reaction was complete at room temperature for 3H, as determined by LCMS. Poured into water, extracted with ethyl acetate, the organic phases were combined, dried, concentrated under reduced pressure, and purified by column chromatography to give (S) -7-bromo-6-chloro-8-fluoro-4-hydroxy-1- ((1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile (82mg, yellow solid). LC-MS ESI [ M + H ]]+＝414.2。
The fourth step: (S) -7-bromo-6-chloro-8-fluoro-4-hydroxy-1- ((1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile (82mg,0.20mmol) was dissolved in POCl3To the mixture (5mL), DMF (1 drop) was added dropwise and the mixture was stirred at 80 ℃ for 2 hours. Concentrated under reduced pressure, the residue was dissolved in ethyl acetate and successively saturated NaHCO3The aqueous solution and water were washed, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give intermediate 3 (yellow solid). LC-MS ESI [ M + H ]]+＝432.2。
Intermediate 4: 7-bromo-4, 6-dichloro-8-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile
Figure BDA0002825639160000281
The first step is as follows: reacting 7-bromo-6-chloro-8-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2H-benzo [ d][1,3]Oxazine-2, 4(1H) -dione (426mg,1mmol) and ethyl cyanoacetate (125mg,1.1mmol) were dissolved in DMF (10mL), NaH (60% in mineral oil, 80mg,2mmol) was added at 0 deg.C, the reaction was allowed to react for 5 hours at room temperature to 60 deg.C and LC-MS detection indicated completion of the reaction. Poured into water, extracted with ethyl acetate, the organic phases were combined, dried, concentrated under reduced pressure, and purified by column chromatography to give 7-bromo-6-chloro-8-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile (182mg, yellow solid). LC-MS ESI [ M + H ]]+＝450.2/452.2。
The second step is that: the yellow solid obtained above (90mg,0.20mmol) was dissolved in POCl3To the mixture (5mL), DMF (1 drop) was added dropwise and the mixture was stirred at 80 ℃ for 2 hours. Concentrated under reduced pressure, the residue was dissolved in ethyl acetate and successively saturated NaHCO3The aqueous solution and water were washed, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give intermediate 4 (yellow solid, 52mg) which was used in the next reaction without further purification. LC-MS ESI [ M + H ]]+＝468.1/470.1。
Intermediate 5: 7- (2-amino-7-fluoropheno [ d ] thiazol-4-yl) -4-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
Figure BDA0002825639160000282
The first step is as follows: methyl 2, 6-dichloro-5-fluoronicotinate (20g, 89.7mmol), (2- ((tert-butoxycarbonyl) amino) -7-fluoropheno [ d [ -d ]]Thiazol-4-yl) boronic acid (35.6g, 114.1mmol) and K3PO4(24.3g, 114.3mmol) was dissolved in 1, 4-dioxane/water (dioxane/H)2O) (200mL/20mL), Pd-Xphos-G3(3.75G,4.4mmol) and Ru-phos (4.44G,9.5mmol) were added and reacted overnight at 60 ℃ under nitrogen. Filtering the reaction solutionConcentrating the filtrate under reduced pressure, and purifying by column chromatography to obtain methyl 6- (2- ((tert-butoxycarbonyl) amino) -7-fluorobenzo [ d]Thiazol-4-yl) -2-chloro-5-fluoronicotinate (10.3g, yellow solid). LC-MS ESI [ M + H ]]+＝456.3/458.2；
The second step is that: the yellow solid from the previous step (8.9g, 28.4mmol) was dissolved in THF/H2O (90mL/45mL) mixed solvent, and lithium hydroxide monohydrate (LiOH. H) is added2O) (3.6g,85.7mmol), and stirred at room temperature for 5 hours. Concentrating the reaction solution to remove the organic solvent, adding 3N hydrogen chloride (HCl) aqueous solution to adjust the pH to 3-4, adding DCM for extraction, washing the organic phase with saturated saline water, drying, and concentrating under reduced pressure to obtain 6- (2- ((tert-butoxycarbonyl) amino) -7-fluorobenzo [ d]Thiazol-4-yl) -2-chloro-5-fluoronicotinic acid (7.6g, yellow solid). LC-MS ESI [ M + H ]]+＝442.1/444.1。
The third step: the yellow solid (7.5g, 17mmol) obtained above was dissolved in NMP (25mL), and 2-isopropyl-4-methylpyridin-3-amine (5.1g, 34mmol) and DIEA (10.8g,83.4mmol) were added and reacted with a microwave at 180 ℃ for 2 hours under nitrogen. The reaction solution is cooled to room temperature, and saturated NH is slowly poured into the reaction solution4And (3) filtering the solution in the Cl aqueous solution, dissolving a filter cake in methanol, drying, concentrating under reduced pressure, and purifying by column chromatography to obtain 5-fluoro-6- (2-fluoro-6-methoxyphenyl) -2- ((((S) -1-methylpyrrolidin-2-yl) methyl) amino) nicotinic acid (tan oily substance). LC-MS ESI [ M + H ]]+＝378.2。
The fourth step: the yellow solid from the previous step (2.9g,5.3mmol) and DIEA (4.1g,31.8mmol) were dissolved in THF (30mL), triphosgene (3.1g,10.6mmol) was added dropwise at 0 deg.C and reacted overnight at room temperature, and LC-MS detection indicated complete reaction. Concentrating the reaction solution under reduced pressure, and purifying by column chromatography to obtain tert-butyl (7-fluoro-4- (6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2, 4-dioxo-1, 4-dihydro-2H-pyrido [2,3-d ]][1,3]Oxazin-7-yl) benzo [ d]Thiazol-2-yl) formate (640mg, yellow solid). LC-MS ESI [ M + H ]]+＝582.1。
The fifth step: the yellow solid from the previous step (930mg,1.6mmol) and ethyl cyanoacetate (200mg,1.8mmol) were dissolved in DMF (10mL), NaH (60% suspended in mineral oil, 141mg,3.5mmol) was added at 0 deg.C, the reaction was allowed to react at room temperature to 80 deg.C for 3 hours, and LC-MS detection indicated completion of the reaction. Pouring into water, extracting with ethyl acetate, and mixing the organic phasesDrying, concentrating under reduced pressure, and purifying by column chromatography to obtain tert-butyl (4- (6-cyano-3-fluoro-5-hydroxy-8- (2-isopropyl-4-methylpyridin-3-yl) -7-oxo-7, 8-dihydro-1, 8-naphthyridin-2-yl) -7-fluoro-benzo [ d]Thiazol-2-yl) formate (282mg, yellow solid). LC-MS ESI [ M + H ]]+＝605.2。
And a sixth step: the yellow solid from the previous step (285mg,0.47mmol) was dissolved in POCl3DMF (1 drop) was added dropwise to the mixture (10mL), and the mixture was stirred at 80 ℃ for 2 hours. Concentrated under reduced pressure, the residue was dissolved in ethyl acetate and successively saturated NaHCO3The aqueous solution and water were washed, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give intermediate 5 (yellow solid, 92mg) which was used in the next reaction without further purification. LC-MS ESI [ M + H ]]+＝523.2/525.2。
Examples preparation
Example 1: 4- (4-acryloylpiperazin-1-yl) -6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
Figure BDA0002825639160000301
The first step is as follows: 2, 6-dichloro-5-fluoronicotinic acid (100g, 478.5mmol) was dissolved in methanol (1.0L) and thionyl chloride (SOCl) was added dropwise at 0 deg.C2) (69mL,949.8mmol) was refluxed for 4 hours under nitrogen. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in Dichloromethane (DCM) and washed with sodium bicarbonate (NaHCO)3) The saturated solution was washed twice with water and once with saturated brine, dried and concentrated under reduced pressure to give methyl 2, 6-dichloro-5-fluoronicotinate (106g, yellow oil). LC-MS ESI [ M + H ]]+＝224.0；1H NMR(400MHz,CDCl3):δ8.01(d,J＝7.6MHz,1H),3.98(s,3H)。
The second step is that: methyl 2, 6-dichloro-5-fluoronicotinate (20g, 89.7mmol), (2-fluoro-6-methoxyphenyl) boronic acid (19.4g, 114.1mmol) and potassium phosphate (K)3PO4) (24.3g, 114.6mmol) was dissolved in 1, 4-dioxane/H2To O (200mL/20mL) was added methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl)Group) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (Pd-Xphos-G3) (3.75G,4.76mmol) and 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (Ru-phos) (4.44G, 9.52mmol) were reacted overnight at 60 ℃ under nitrogen. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give methyl 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinate (8.92g, yellow oil). LC-MS ESI [ M + H ]]+＝314.3；1H NMR(400MHz,DMSO-d6):δ8.39(d,J＝8.4MHz,1H),7.57-7.59(m,1H),6.99-7.08(m,2H),3.93(s,3H),3.79(s,3H)。
The third step: methyl 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinate (8.92g, 28.5mmol) was dissolved in tetrahydrofuran/water (THF/H)2O) (90mL/45mL), LiOH. H was added2O (3.58g,85.2mmol), and reacted at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to remove most of the organic solvent, the pH was adjusted to 3-4 with 3N HCl, and extraction was performed with DCM, and the organic phases were combined, washed with saturated brine, dried, and concentrated under reduced pressure to obtain 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid (8.33g, yellow solid). LC-MS ESI [ M + H ]]+＝300.0。
The fourth step: 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid (8.33g, 27.9mmol) was dissolved in N-methylpyrrolidone (NMP) (25mL), and p-methoxybenzylamine (PMB-NH) was added2) (11.44g, 83.5mmol) and N, N-Diisopropylethylamine (DIPEA) (10.77g,83.5mmol), under nitrogen at 180 ℃ for 16 h. The reaction solution was cooled to room temperature, and saturated ammonium chloride (NH) was slowly poured in4Cl) aqueous solution, filtering, dissolving a filter cake by methanol, drying, concentrating under reduced pressure, and purifying by column chromatography to obtain 5-fluoro-6- (2-fluoro-6-methoxyphenyl-2- ((4-methoxybenzyl) amino) nicotinic acid (13.6g, tan oily substance, crude product). LC-MS ESI [ M + H ]]+＝401.1。
The fifth step: 5-fluoro-6- (2-fluoro-6-methoxyphenyl-2- ((4-methoxybenzyl) amino) nicotinic acid (9.6g, crude) was dissolved in methanol (MeOH) (100mL) and trimethylsilylated diazomethane (TMSCHN) was added2) (2.0M n-hexane solution, 18mL, 36mmol), and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give methyl 5-fluoro-6- (2-fluoro-6-methoxyphenyl-2- ((4-methoxybenzyl) amino) nicotinate (5.4g, as a yellow oil)Substance (d). LC-MS ESI [ M + H ]]+＝415.4。
And a sixth step: methyl 5-fluoro-6- (2-fluoro-6-methoxyphenyl-2- ((4-methoxybenzyl) amino) nicotinate (5.4g,13.0mmol) was dissolved in trifluoroacetic acid (TFA) (14mL) and DCM (30mL), heated to 40 ℃ and reacted for 3 hours, the reaction was concentrated under reduced pressure and dissolved in 100mL of ethyl acetate, followed by addition of saturated sodium carbonate (Na)2CO3) The aqueous solution was washed twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 2-amino-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinate (3.7g, yellow solid). LC-MS ESI [ M + H ]]+＝295.3。
The seventh step: na (2.7g,117.4mmol) was slowly added to absolute ethanol (EtOH) (50mL), stirred at room temperature until the sodium particles disappeared completely, added were methyl 2-amino-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinate (3.7g,12.6mmol) and diethyl malonate (4.0g,25.0mmol), and heated in a jar to 120 ℃ for three days. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to give ethyl 6-fluoro-7- (2-fluoro-6-methoxyphenyl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (1.1g, yellow solid). LC-MS ESI [ M + H ]]+＝377.4。
Eighth step: ethyl 6-fluoro-7- (2-fluoro-6-methoxyphenyl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (700mg, 1.9mmol) was dissolved in EtOH (70mL) and concentrated ammonia (3.5mL), and the mixture was heated to 120 ℃ in a jar closed to react for three days. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to give 6-fluoro-7- (2-fluoro-6-methoxyphenyl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide (680mg, pale yellow solid, crude product). LC-MS ESI [ M + H ]]+＝348.6。
The ninth step: 6-fluoro-7- (2-fluoro-6-methoxyphenyl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide (680mg, crude) was dissolved in phosphorus oxychloride (POCl)3) (10mL), the mixture was heated to 110 ℃ and reacted for 3 hours. The reaction solution is cooled to room temperature, concentrated under reduced pressure and dissolved in 10mL ethyl acetate, saturated NaHCO is used3The aqueous solution was made alkaline, the organic layer was separated, dried, and concentrated under reduced pressure to give 2, 4-dichloro-6-fluoro-7- (2-fluoro-6-methoxyphenyl) -1, 8-naphthyridine-3-carbonitrile (670mg, red solid). LC-MS ESI [ M + H ]]+＝366.3。
Tenth itemThe method comprises the following steps: 2, 4-dichloro-6-fluoro-7- (2-fluoro-6-methoxyphenyl) -1, 8-naphthyridine-3-carbonitrile (670mg,1.8mmol), 1-benzyloxycarbonyl-piperazine (306mg, 1.4mmol), and DIPEA (1.2g, 9.3mmol) were dissolved in 1.4-dioxane (20mL) and reacted at room temperature overnight. The reaction solution was diluted with 100mL of ethyl acetate, washed twice with water, dried, and concentrated under reduced pressure to give benzyl 4- (2-chloro-3-cyano-6-fluoro-7- (2-fluoro-6-6-methoxyphenyl) -1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (605mg, red solid). LC-MS ESI [ M + H ]]+＝550.6。
The eleventh step: benzyl 4- (2-chloro-3-cyano-6-fluoro-7- (2-fluoro-6-6-methoxyphenyl) -1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (605mg, 1.1mmol) was dissolved in TFA (2.5mL) and water (0.5mL) and heated to 120 degrees for reaction overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was added to ethyl acetate and concentrated under reduced pressure twice to give 6-fluoro-7- (2-fluoro-6-methoxyphenyl) -2-oxo-4- (piperazin-1-yl) -1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (690mg, red solid, crude product). LC-MS ESI [ M + H ]]+＝398.5。
The twelfth step: 6-fluoro-7- (2-fluoro-6-methoxyphenyl) -2-oxo-4- (piperazin-1-yl) -1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (690mg, crude) was dissolved in DCM (20mL), and TEA (1.9g, 19mmol) and (Boc) were added2O (828mg, 3.8mmol), and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give tert-butyl 4- (3-cyano-6-fluoro-7- (2-fluoro-6-methoxyphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (280mg, yellow solid). LC-MS ESI [ M + H ]]+＝498.5。
The thirteenth step: tert-butyl 4- (3-cyano-6-fluoro-7- (2-fluoro-6-methoxyphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (280mg,0.56mmol) and (S) -2- (chloromethyl) -1-methylpyrrolidine hydrochloride (137mg,0.81mmol) were dissolved in DMF (6mL), and potassium carbonate (K) was added2CO3) (308mg,2.23mmol), and reacted at room temperature for 3 hours. The reaction solution was diluted with 50mL of ethyl acetate, washed twice with water, dried, and concentrated under reduced pressure to give tert-butyl 4- (3-cyano-6-fluoro-7- (2-fluoro-6-methoxyphenyl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (332mg, red solid, crude product). LC-MS ESI [ M + H ]]+＝595.7。
The fourteenth step is that: dissolving tert-butyl 4- (3-cyano-6-fluoro-7- (2-fluoro-6-methoxyphenyl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (24mg, 0.04mmol) in DCM (1mL), boron tribromide (BBr) was added dropwise at-78 degrees3) (1.0M in DCM, 1.4mL) and allowed to slowly warm to room temperature overnight. The reaction was quenched by addition of methanol (MeOH) (5mL) and Na was added2CO3The solids were neutralized, filtered, and the filtrate was concentrated under reduced pressure to give 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-4- (piperazin-1-yl) -1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (35mg, yellow solid, crude). LC-MS ESI [ M + H ]]+＝481.6。
The fifteenth step: 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-4- (piperazin-1-yl) -1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (35mg, crude) and TEA (0.3mL) were dissolved in DCM (1mL), and acryloyl chloride (1 drop) was added at room temperature and reacted at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 2- (5- (4-acryloylpiperazin-1-yl) -6-cyano-3-fluoro-8- (((S) -1-methylpyrrolidin-2-yl) methyl) -7-oxo-7, 8-dihydro-1, 8-naphthyridin-2-yl) -3-fluorophenylacryloyl ester (40mg, yellow solid, crude). LC-MS ESI [ M + H ]]+＝589.7。
Sixteenth, step: 2- (5- (4-acryloylpiperazin-1-yl) -6-cyano-3-fluoro-8- (((S) -1-methylpyrrolidin-2-yl) methyl) -7-oxo-7, 8-dihydro-1, 8-naphthyridin-2-yl) -3-fluorophenylacryloyl ester (40mg, crude) was dissolved in THF (2mL), and 10% aqueous sodium hydroxide (NaOH) solution (1mL) was added at room temperature to react at room temperature for 3 hours. The reaction solution was diluted with 10mL of ethyl acetate, washed twice with water, dried, filtered, concentrated under reduced pressure, and the residue was purified by preparative chromatography to give the objective compound (yellow solid). LC-MS ESI [ M + H ]]+＝535.2；1H-NMR(CD3OD,400MHz)：8.14(d,J＝9.6Hz,1H),7.31-7.33(m,1H),6.68-6.88(m,3H),6.28(d,J＝17.6Hz,1H),5.81(d,J＝10.4Hz,1H),3.96(brs,4H),3.79(brs,4H),2.94-3.15(m,3H),2.66(brs,2H),2.45(s,3H),1.80-2.19(m,4H)。
Example 2: 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
Figure BDA0002825639160000321
The target compound was prepared according to the synthesis method of example 1, substituting (S) -2-methyl-4-Boc piperazine for N-Boc piperazine. LC-MS [ M + H ]]+:m/z 549.2。1H NMR(400MHz,DMSO-d6)δ8.23(d,1H),7.37(dd,1H),7.03-6.65(m,3H),6.21(d,1H),5.76(d,1H),4.45-3.95(m,6H),3.95-3.65(m,3H),3.41-3.51(m,1H),2.89-2.92(m,1H),2.90-2.93(m,1H),2.25(s,3H),2.09(d,1H),1.75-1.58(m,4H),1.12(s,3H)。
Example 3: 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -6-fluoro-7- (5-methyl-1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
Figure BDA0002825639160000331
The first step is as follows: intermediate 2(814mg,2.3mmol) was dissolved in 1, 4-dioxane (10mL) and DIPEA (0.58g, 4.6mmol) and tert-butyl (S) -3-methylpiperazine-1-carboxylate (0.51g,2.5mmol) were added. The mixture was heated to 50 ℃ and stirred overnight, concentrated under reduced pressure, and the residue was purified by column chromatography to give tert-butyl (S) -4- (7-chloro-3-cyano-6-fluoro-1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylate (710mg, yellow solid). LC-MS ESI [ M + H ]]+＝519.2。
The second step is that: (S) -4- (7-chloro-3-cyano-6-fluoro-1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (710mg, 1.4mmol) and 5-methyl-1H-indazole-4-boronic acid (271mg, 1.5mmol) were dissolved in 1, 4-dioxane (10mL), water (1mL), sodium carbonate (445mg, 4.2mmol) and Pd (PPh) were added3)4(81mg, 0.07mmol), nitrogen substitution, heating to 90 degrees reaction overnight, LCMS detection showsIndicating complete reaction. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by column chromatography to give tert-butyl (3S) -4- (3-cyano-6-fluoro-7- (5-methyl-1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylate (420mg, yellow solid). LC-MS ESI [ M + H ]]+＝615.3。
The third step: tert-butyl (3S) -4- (3-cyano-6-fluoro-7- (5-methyl-1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylate (420mg, 0.68mmol) was dissolved in DCM (4mL), TFA (2mL) was added, and stirred at room temperature for 4 hours. Concentration under reduced pressure gave 6-fluoro-7- (5-methyl-1H-indazol-4-yl) -4- ((S) -2-methylpiperazin-1-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (510mg, crude, yellow solid). LC-MS ESI [ M + H ]]+＝515.3。
The fourth step: 6-fluoro-7- (5-methyl-1H-indazol-4-yl) -4- ((S) -2-methylpiperazin-1-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (120mg, crude) was dissolved in dichloromethane (10mL), DIPEA (70mg, 0.54mmol) and acryloyl chloride (17mg, 0.19mmol) were added sequentially at 0 ℃ and stirred at room temperature for 2 hours. The reaction mixture was washed with a saturated ammonium chloride solution and a saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative chromatography to give the objective compound (yellow solid). LC-MS ESI [ M + H ]]+＝569.2。
Example 4: 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile
Figure BDA0002825639160000332
The first step is as follows: intermediate 3(991mg,2.3mmol) was dissolved in 1, 4-dioxane (10mL) and DIPEA (0.58g, 4.6mmol) and (R) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (0.51g,2.5mmol) were added. Heating to 50 deg.C, stirring overnight, concentrating under reduced pressure, and purifying with column chromatography to obtain the final productTo (R) -4- (7-bromo-6-chloro-3-cyano-8-fluoro-1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinolin-4-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (774mg, yellow solid). LC-MS ESI [ M + H ]]+＝596.2。
The second step is that: (R) -4- (7-bromo-6-chloro-3-cyano-8-fluoro-1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinolin-4-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (774mg, 1.3mmol) and 5-methyl-1H-indazole-4-boronic acid (271mg, 1.5mmol) were dissolved in 1, 4-dioxane (10mL), water (1mL), sodium carbonate (445mg, 4.2mmol) and Pd (PPh) were added3)4(81mg, 0.07mmol), nitrogen displacement, heating to 90 degrees reaction overnight, LCMS detection showed reaction complete. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by column chromatography to give tert-butyl (2R) -4- (6-chloro-3-cyano-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinolin-4-yl) -2-methylpiperazine-1-carboxylate (440mg, yellow solid). LC-MS ESI [ M + H ]]+＝648.3。
The third step: tert-butyl (2R) -4- (6-chloro-3-cyano-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinolin-4-yl) -2-methylpiperazine-1-carboxylate (440mg, 0.68mmol) was dissolved in DCM (4mL), trifluoroacetic acid (TFA) (2mL) was added, and the mixture was stirred at room temperature for 4 hours. Concentration under reduced pressure gave 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -4- ((R) -3-methylpiperazin-1-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile (530mg, crude, yellow solid). LC-MS ESI [ M + H ]]+＝548.3。
The fourth step: 6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -4- ((R) -3-methylpiperazin-1-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile (150mg, crude) was dissolved in dichloromethane (10mL), DIPEA (70mg, 0.54mmol) and acryloyl chloride (17mg, 0.19mmol) were added successively at 0 ℃ and stirred at room temperature for 2 hours. The reaction mixture was washed with a saturated ammonium chloride solution and a saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative chromatography to give the objective compound (yellow solid). LC-MS ESI [ M + H ]]+＝602.2。
Example 5: 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -6-chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile
Figure BDA0002825639160000341
The title compound was prepared according to the synthetic method of example 4, LC-MS: ESI [ M + H ]]+＝582.2。1H NMR(400MHz,DMSO-d6):δ8.15-8.19(m,1H),6.91-7.02(m,2H),6.19-6.40(m,3H),5.75(d,1H),4.35-4.42(m,2H),4.06-4.20(m,3H),3.75-3.85(m,3H),2.94-2.98(m,1.5H),2.64-2.68(m,1.5H),2.41(s,3H),2.18-2.26(m,1H),1.96-2.00(m,1H),1.61-1.75(m,4H),1.08(s,3H)。
Example 6:4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (5-methyl-1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridine-3-carbonitrile
Figure BDA0002825639160000351
The first step is as follows: sodium (Na) particles (3.2g,139.1mmol) were added in portions slowly to EtOH (250mL), stirred at room temperature until the Na particles completely disappeared, added with ethyl 5-amino-1-benzyl-1, 2,3, 6-tetrahydropyridine-4-carboxylate (18.0g,69.2mmol) and ethyl cyanoacetate (15.7g,138.9mmol), and heated to 120 ℃ in a jar for three days. After cooling, filtration and cake EtOH pulping purification 7-benzyl-2, 4-dihydroxy-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-3-carbonitrile (15.4g, yellow solid) was obtained. LC-MS ESI [ M + H ]]+＝282.3。
The second step is that: 7-benzyl-2, 4-dihydroxy-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-3-carbonitrile (5.0g,17.8mmol), trifluoromethanesulfonic anhydride (15.0g,53.4mmol) and TEA (7.2g,71.3mmol) were dissolved in DCM (50mL) and stirred at RT overnight. Concentrated under reduced pressure, and the residue was purified by column chromatography to give 7-benzyl-3-cyano-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-2, 4-diylbis (trifluoromethanesulfonate) (3.1g, yellow solid). LC-MS ESI [ M + H ]]+＝546.1。
The third step: reacting 7-benzyl-3-cyano-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-2, 4-diylbis (trifluoromethanesulfonate) (3.1g,5.7mmol) was dissolved in 1, 4-dioxane (30mL), DIPEA (2.9g, 22.8mmol) and (S) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.16g,5.7mmol) were added. The mixture was heated to 60 ℃ and stirred overnight, concentrated under reduced pressure, and the residue was purified by column chromatography to give tert-butyl (S) -4- (7-benzyl-3-cyano-2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylate (1.7g, yellow solid). LC-MS ESI [ M + H ]]+＝464.2。
The fourth step: tert-butyl (S) -4- (7-benzyl-3-cyano-2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylate (1.7g,3.7mmol) and (S) - (1-methylpyrrolidin-2-yl) methyl methanesulfonate (0.77g,4.1mmol) were dissolved in acetonitrile (20mL), potassium carbonate (0.77g,5.6mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give tert-butyl (S) -4- (7-benzyl-3-cyano-1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylate (1.4g, yellow solid). LC-MS ESI [ M + H ]]+＝561.3。
The fifth step: tert-butyl (S) -4- (7-benzyl-3-cyano-1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylate (1.4g,2.5mmol) was dissolved in MeOH (30mL), 10% Pd/C (140mg) was added and the reaction was allowed to react overnight at room temperature, and LC-MS detection indicated completion of the reaction. Filtration and concentration of the filtrate under reduced pressure gave (S) -tert-butyl 4- (3-cyano-1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylate (0.93g, yellow solid) which was used directly in the next reaction. LC-MS ESI [ M + H ]]+＝471.3。
And a sixth step: (S) -4- (3-cyano-1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.93g, 2.0mmol) and 4-bromo-5-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole (1.02g,3.0mmol) were dissolved in 1, 4-dioxane (20mL) and cesium carbonate (Cs) was added under argon protection2CO3) (1.63G,5.0mmol), Ru-phos (187mg,0.40mmol) and Pd-Ruphos-G3(84mg,0.10mmol), after addition of argonThe displacement was carried out three times, the reaction was heated to 110 ℃ overnight, and LC-MS showed the reaction to be complete. Cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to give tert-butyl (S) -4- (3-cyano-7- (5-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylate (0.46g, yellow solid). LC-MS ESI [ M + H ]]+＝731.4。
The seventh step: tert-butyl (S) -4- (3-cyano-7- (5-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylate (460mg, 0.63mmol) was dissolved in DCM (4mL), TFA (2mL) was added, and stirring was carried out at room temperature for 4 hours. Concentrating under reduced pressure to obtain 7- (5-methyl-1H-indazol-4-yl-4- ((S) -2-methylpiperazin-1-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridine-3-carbonitrile (510mg, crude product, yellow solid), LC-MS: ESI [ M + H ] S]+＝501.3。
Eighth step: 7- (5-methyl-1H-indazol-4-yl-4- ((S) -2-methylpiperazin-1-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridine-3-carbonitrile (120mg, crude) was dissolved in dichloromethane (10mL), DIPEA (70mg, 0.54mmol) and acryloyl chloride (17mg, 0.19mmol) were added sequentially at 0 ℃, stirred at room temperature for 2 hours the reaction was washed with a saturated ammonium chloride solution and a saturated saline solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative chromatography to give the target compound (yellow solid). ESI [ M + H.]+＝555.3。1H NMR(400MHz,CD3OD):δ8.07(s,1H),7.23-7.28(m,2H),6.78-6.85(m,1H),6.25(dd,J＝16.8,2.0Hz,1H),5.78(dd,J＝10.8,2.0Hz,1H),4.43-4.47(m,1H),4.24-4.31(m,3H),3.82(brs,4H),3.52-3.55(m,2H),3.48(brs,4H),3.06-3.10(m,2H),2.87-2.89(m,2H),2.76-2.80(m,1H),2.54(s,3H),2.34-2.41(m,4H),2.06-2.11(m,1H),1.78-1.84(m,2H),1.65-1.70(m,4H)。
Example 7: 7- (8-chloronaphthalen-1-yl) -4- ((R) -3- (cyanomethyl) -4- (2-fluoroacryloyl) piperazin-1-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridine-3-carbonitrile
Figure BDA0002825639160000361
The title compound was prepared according to the synthetic method of example 6, LC-MS: ESI [ M + H ]]+＝628.3/630.2。1H-NMR(400MHz,MeOD-d4):δ7.62-7.71(m,2H),7.30-7.45(m,3H),7.23(d,1H),5.27-5.39(m,2H),4.72-4.82(m,1H),4.36-4.48(m,1H),4.15-4.29(m,2H),3.83-4.02(m,2H),3.41-3.77(m,6H),3.19-3.30(m,4H),2.84-3.02(m,6H),1.92-2.43(m,4H)。
Example 8: (R) -10-acryloyl-3- (2-fluoro-6-hydroxyphenyl) -5- (((S) -1-methylpyrrolin-2-yl) methyl) -1,3,4,5,8,8a,9,10,11, 12-decahydropyrazine [1',2':4,5] [1,4] oxazine [2,3-c ] [1,7] naphthyridin-6 (2H) -one
Figure BDA0002825639160000371
The first step is as follows: sodium (Na) particles (3.2g,139.1mmol) are added in portions slowly to EtOH (250mL), stirred at room temperature until Na particles completely disappear, added with ethyl 5-amino-1-benzyl-1, 2,3, 6-tetrahydropyridine-4-carboxylate (18.0g,69.2mmol) and diethyl malonate (22.2g,138.8mmol), and heated to 120 ℃ in a sealed tank for four days. After cooling, filtration and cake EtOH pulping purification 7-benzyl-2, 4-dihydroxy-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-3-carboxylic acid ethyl ester (22.3g, yellow solid) was obtained. LC-MS ESI [ M + H ]]+＝329.4。
The second step is that: ethyl 7-benzyl-2, 4-dihydroxy-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-3-carboxylate (22.3g,68.0mmol) was added to 3M aqueous HCl (200mL) and reacted at 100 ℃ for 16 hours. Concentration under reduced pressure gave 7-benzyl-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-2, 4-diol hydrochloride (17.5g, yellow solid) which was used directly in the next reaction. LC-MS ESI [ M + H ]]+＝256.9。
The third step: 7-benzyl-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-2, 4-diol hydrochloride (4.0g,13.7mmol) was dissolved in MeOH (100mL), 10% Pd/C (400mg) was added and the reaction was allowed to proceed for 2 days at room temperature and complete by LC-MS. Filtration and concentration of the filtrate under reduced pressure gave 5,6,7, 8-tetrahydro-1, 7-naphthyridine-2, 4-diol hydrochloride (2.8g,white solid) was used directly in the next reaction. LC-MS ESI [ M + H ]]+＝167.1。
The fourth step: 5,6,7, 8-tetrahydro-1, 7-naphthyridine-2, 4-diol hydrochloride (7.9g,39.1mmol), trifluoroacetic anhydride (8.2g,39.1mmol) and TEA (11.8g,117.3mmol) were dissolved in DCM (80mL) and stirred at room temperature overnight. Concentrated under reduced pressure, and the residue was purified by column chromatography to give 1- (2, 4-dihydroxy-5, 8-dihydro-1, 7-naphthyridin-7 (6H) -yl) -2,2, 2-trifluoroethyl-1-one (3.0g, white solid). LC-MS ESI [ M + H ]]+＝263.0；1H-NMR(DMSO_d6,400MHz):10.93(brs,2H),5.51(s,1H),4.45(s,2H),3.73-3.80(m,2H),2.41-2.51(m,2H)。
The fifth step: 1- (2, 4-dihydroxy-5, 8-dihydro-1, 7-naphthyridin-7 (6H) -yl) -2,2, 2-trifluoroethyl-1-one (2.1g,8.0mmol) was dissolved in concentrated sulfuric acid (60mL) and 70% nitric acid (HNO) was added dropwise at 0 ℃3) (6mL) and reacted at room temperature for 1 hour. Pouring into an ice-water mixture, filtering off a yellow solid, extracting the aqueous phase with DCM, concentrating, combining, and purifying by beating with water to obtain 1- (2, 4-dihydroxy-3-nitro-5, 8-dihydro-1, 7-naphthyridin-7 (6H) -yl) -2,2, 2-trifluoroethyl-1-one (1.6g, yellow solid). LC-MS ESI [ M + H ]]+＝308.0；1H-NMR(DMSO_d6,400MHz)：12.01(brs,2H),4.48-4.57(m,2H),3.76-3.82(m,2H),2.50-2.57(m,2H)。
And a sixth step: 1- (2, 4-dihydroxy-3-nitro-5, 8-dihydro-1, 7-naphthyridin-7 (6H) -yl) -2,2, 2-trifluoroethyl-1-one (690mg,2.25mmol) was dissolved in POCl3To the mixture (10mL), DMF (2 drops) was added dropwise and the mixture was stirred at 80 ℃ for 3 hours. Concentrated under reduced pressure, the residue was dissolved in ethyl acetate and successively saturated NaHCO3The aqueous solution and water are washed, dried by anhydrous sodium sulfate, concentrated and purified by column chromatography to obtain the 1- (2, 4-dichloro-3-nitro-5, 8-dihydro-1, 7-naphthyridin-7 (6H) -yl) -2,2, 2-trifluoroethyl-1-ketone (yellow solid). LC-MS ESI [ M + H ]]+＝344.2/346.2；1H-NMR(DMSO_d6,400MHz)：4.84-4.86(m,2H),3.94(brs,2H),2.95-3.01(m,2H)。
The seventh step: 1- (2, 4-dichloro-3-nitro-5, 8-dihydro-1, 7-naphthyridin-7 (6H) -yl) -2,2, 2-trifluoroethyl-1-one (2.0g,5.7mmol) was dissolved in 1, 4-dioxane (30mL), DIPEA (2.9g, 22.8mmol) and (R) -tert-butyl 3- (hydroxymethyl) piperazine-1-carboxylate (1.23g,5.7mmol) were added. Heating to 60 ℃ and stirringStirred overnight, concentrated under reduced pressure, and the residue was purified by column chromatography to give tert-butyl (R) -4- (2-chloro-3-nitro-7- (2,2, 2-trifluoroacetyl) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -3- (hydroxymethyl) piperazine-1-carboxylate (1.6g, yellow solid). LC-MS ESI [ M + H ]]+＝524.2。
Eighth step: tert-butyl (R) -4- (2-chloro-3-nitro-7- (2,2, 2-trifluoroacetyl) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -3- (hydroxymethyl) piperazine-1-carboxylate (1.6g,3.1mmol) was dissolved in 1, 4-dioxane (30mL), and 2N sodium hydroxide solution (16mL, 32mmol) was added and reacted at room temperature overnight. The pH was adjusted to 7 with 2N hydrochloric acid, concentrated under reduced pressure, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (R) -3- (hydroxymethyl) -4- (3-nitro-2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) piperazine-1-carboxylate (1.2g, yellow solid) which was used directly in the next reaction. LC-MS ESI [ M + H ]]+＝410.2。
The ninth step: (R) -3- (hydroxymethyl) -4- (3-nitro-2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (0.82g, 2.0mmol) and 2-bromo-1-fluoro-3-methoxybenzene (0.61g,3.0mmol) were dissolved in 1, 4-dioxane (20mL) and Cs was added under argon protection2CO3(1.63G,5.0mmol), Ru-phos (187mg,0.40mmol) and Pd-Ruphos-G3(84mg,0.10mmol), after addition was done, replaced with argon three times, heated to 110 deg.C for overnight reaction, and LCMS indicated completion of the reaction. Cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to give tert-butyl (R) -4- (7- (2-fluoro-6-methoxyphenyl) -3-nitro-2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) -3- (hydroxymethyl) piperazine-1-carboxylate (0.44g, yellow solid). LC-MS ESI [ M + H ]]+＝534.3。
The tenth step: tert-butyl (R) -4- (7- (2-fluoro-6-methoxyphenyl) -3-nitro-2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) -3- (hydroxymethyl) piperazine-1-carboxylate (0.44g,0.83mmol) and (S) - (1-methylpyrrolidin-2-yl) methylmethanesulfonate (0.17g,0.91mmol) were dissolved in acetonitrile (20mL), potassium carbonate (0.17g,1.2mmol) was added, and the reaction was allowed to proceed overnight at room temperature. Filtering the reaction solution, concentrating the filtrate under reduced pressure, and purifying by column chromatography to obtain (R) -4- (7- (2-fluoro-6-methoxyphenyl) -1- (((S) -1-methylpyrrolin-2-yl) methyl) -3-nitro-2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) -3- (R) -4- (2-fluoro-6-methoxyphenyl) methyl) -3-nitro-2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-Hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (0.4g, yellow solid). LC-MS ESI [ M + H ]]+＝631.3。
The eleventh step: tert-butyl (R) -4- (7- (2-fluoro-6-methoxyphenyl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -3-nitro-2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) -3- (hydroxymethyl) piperazine-1-carboxylate (0.4g,0.63mmol) was dissolved in NMP (5mL), LiHMDS (1M,0.63mL,0.63mmol) was added, and heated to 100 ℃ under nitrogen blanket and stirred for 8 hours. Cooling the reaction solution to room temperature, pouring the reaction solution into saturated ammonium chloride aqueous solution, extracting by dichloromethane, drying, decompressing and concentrating, and purifying by column chromatography to obtain (R) -3- (2-fluoro-6-methoxyphenyl) -5- (((S) -1-methylpyrrolidin-2-yl) methyl) -6-oxo-1, 2,3,4,5,6,8a,9,11, 12-decahydropyrazine [1',2':4, 5)][1,4]Oxazines [2,3-c ]][1,7]Naphthyridine-10 (8H) -carboxylic acid tert-butyl ester 95mg, yellow solid). LC-MS ESI [ M + H ]]+＝584.3。
The twelfth step: mixing (R) -3- (2-fluoro-6-methoxyphenyl) -5- (((S) -1-methylpyrrolin-2-yl) methyl) -6-oxo-1, 2,3,4,5,6,8a,9,11, 12-decahydropyrazine [1',2':4,5][1,4]Oxazines [2,3-c ]][1,7]Naphthyridine-10 (8H) -carboxylic acid tert-butyl ester (95mg, 0.16mmol) was dissolved in dichloromethane (10mL), cooled to-78 deg.C, boron tribromide (1M,1.6mL,1.6mmol) was added dropwise, and the mixture was allowed to warm to room temperature naturally and stirred overnight. Quenched with methanol, concentrated under reduced pressure, and the residue dissolved in dichloromethane and washed with saturated NaHCO3Washing the aqueous solution twice, drying the organic phase by anhydrous MgSO4, concentrating under reduced pressure, and purifying by column chromatography to obtain (R) -3- (2-fluoro-6-hydroxyphenyl) -5- (((S) -1-methylpyrrolidin-2-yl) methyl) -1,3,4,5,8,8a,9,10,11, 12-decahydropyrazine [1',2':4,5][1,4]Oxazines [2,3-c ]][1,7]Naphthyridin-6 (2H) -one (45mg, yellow solid). LC-MS ESI [ M + H ]]+＝470.1。
The thirteenth step: mixing (R) -3- (2-fluoro-6-hydroxyphenyl) -5- (((S) -1-methylpyrrolin-2-yl) methyl) -1,3,4,5,8,8a,9,10,11, 12-decahydropyrazine [1',2':4,5] [1,4] oxazine [2,3-c ] [1,7] naphthyridin-6 (2H) -one
(45mg, 0.10mmol) was dissolved in dichloromethane (5mL), DIPEA (40mg, 0.30mmol) and acryloyl chloride (10mg, 0.11mmol) were added sequentially at 0 deg.C, and the mixture was stirred at room temperature for 2 hours. Washing the reaction solution with saturated ammonium chloride solution and saturated brine, drying over anhydrous sodium sulfate, filtering, and reducingConcentration under reduced pressure and preparative chromatography of the residue afforded the title compound (yellow solid, 5.2 mg). LC-MS ESI [ M + H ]]+＝524.2。
Example 9: (8aR,11R) -10-acryloyl-3- (2-fluoro-6-hydroxyphenyl) -11-methyl-5- (((S) -1-methylpyrrolin-2-yl) methyl) -1,3,4,5,8,8a,9,10,11, 12-decahydropyrazine [1',2':4,5] [1,4] oxazine [2,3-c ] [1,7] naphthyridin-6 (2H) -one
Figure BDA0002825639160000391
Preparation of the title compound (yellow solid, 3.5mg) by the synthetic method of reference example 8 LC-MS: ESI [ M + H ]]+＝538.2。
Example 10: 4- ((R) -3- (cyanomethylene) -4- (2-Fluoroacryloyl) piperazin-1-yl) -7- (8-methylnaphthalen-1-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridine-3-carbonitrile
Figure BDA0002825639160000392
Preparation of the title compound (white solid, 12mg) by the synthetic method of reference example 6 LC-MS: ESI [ M + H ]]+＝608.1。1H NMR(400MHz,MeOD-d4):δ7.62-7.71(m,2H),7.30-7.45(m,3H),7.23(d,1H),5.27-5.39(m,2H),4.72-4.82(m,1H),4.36-4.48(m,1H),4.15-4.29(m,2H),3.83-4.02(m,2H),3.41-3.77(m,6H),3.19-3.30(m,4H),3.13(d,3H),2.84-3.02(m,6H),1.92-2.43(m,4H).
Example 11: 4- ((R) -4-acryloyl-3- (cyanomethylene) piperazin-1-yl) -7- (8-chloronaphthalen-1-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridine-3-carbonitrile
Figure BDA0002825639160000393
Preparation of the title compound (white solid, 18mg) by the synthetic method of reference example 6 LC-MS: ESI [ M + H ]]+＝610.1/612.2。1H NMR(400MHz,CD3OD):δ8.22-8.19(m，1H)，7.87-7.85(m，1H)，7.62-7.60(d，J＝8.0Hz，1H)，7.51-7.49(m，2H)，7.45-7.43(m，1H)，7.15-7.13(m，1H)，6.60(bs，1H)，6.42-6.38(m，1H)，5.84-5.82(m，1H)，5.08(m，1H)，4.78-4.53(m，2H)，4.42-4.40(m，1H)，4.27(bs，2H)，4.21-4.18(m，1H)，4.12-3.78(m，2H)，3.68-3.07(m，7H)，3.05-2.84(m，3H)，2.77(s，3H)，2.71-2.64(m，1H)，2.26-2.17(m，1H)，2.11-2.03(m，1H)，2.02-1.88(m，2H)。
Example 12: 7- (8-chloronaphthalen-1-yl) -4- ((R) -3- (cyanomethylene) -4-methacryloylpiperazin-1-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridine-3-carbonitrile
Figure BDA0002825639160000401
Preparation of the title compound (white solid, 4.3mg) by the synthetic method of reference example 6 LC-MS: ESI [ M + H ]]+＝624.2/626.2。
Example 13: 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -6-cyclopropyl-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -1- (((S) -1-methylpyrrolin-2-yl) methyl) -2-oxo-1, 2-dihydroquinoline-3-methylcyano
Figure BDA0002825639160000402
The first step is as follows: (2R) -4- (6-chloro-3-cyano-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinolin-4-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (485mg,0.75mmol), cyclopropylboronic acid (130mg, 1.5mmol) dissolved in 1, 4-dioxane (10mL), water (1mL), sodium carbonate (445mg, 4.2mmol) and Pd (PPh)3)4(81mg, 0.07mmol), nitrogen displacement, heating to 90 degrees reaction overnight, LCMS detection showed reaction complete. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by column chromatography to give tert-butyl (2R) -4- (3-cyano-6-cyclopropyl-8-fluoro-7- (5-methyl-1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinolin-4-yl) -2-methylpiperazin-1-carboxylate (105mg, yellow solid), LC-MS: ESI [ M + H ] ESI]+＝654.2。
The second step and the third step: the title compound (25mg, yellow solid) was prepared by the same procedure as in the third and fourth steps of example 4 using LC-MS: ESI [ M + H ]]+＝608.2。
Example 14: 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -8-fluoro-7- (5-methyl-1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-6-vinyl-1, 2-dihydroquinoline-3-methylcyano
Figure BDA0002825639160000403
The same procedures used in example 13 were repeated except for using potassium vinylborate instead of cyclopropylboronic acid to give the title compound (5mg, yellow solid), LC-MS: ESI [ M + H ] as a reaction product]+＝694.2。
Example 15; 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-8-fluoro-1- (((S) -1-methylmethylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile
Figure BDA0002825639160000411
Preparation of the title compound (yellow solid, 8mg) by the synthetic method of reference example 4 LC-MS: ESI [ M + H ]]+＝649.2/651.2。
Example 16- (4-Acryloylpiperazin-1-yl) -7- (2-amino-7-fluorofluoro-benzo [ d ] thiazol-4-yl) -6-chloro-8-fluoro-1- (((S) -1-methylmethylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinoline-3-ca-rbocyanamide
Figure BDA0002825639160000412
Preparation of the title compound (yellow solid, 12mg) by the synthetic method of reference example 4 LC-MS: ESI [ M + H ]]+＝624.1/626.1。1H-NMR(400MHz,MeOD-d4):δ7.95(s,1H),7.31-7.16(m,1H),6.99(t,1H),6.82(dd,1H),6.28(d,1H),5.81(d,1H),4.56-4.38(m,2H),4.01-3.95(m,8H),3.10(s,1H),2.81(s,1H),2.53(s,3H),2.37(d,1H),2.25-1.64(m,4H)。
Example 17: 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-fluoro-1- (((S) -1-methylmethylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
Figure BDA0002825639160000413
Preparation of the title compound (off-white solid, 9mg) by the synthetic method of reference example 4 LC-MS: ESI [ M + H ]]+＝616.3/618.3。
Example 18: (S) -4- (4-acryloylpiperazin-1-yl) -7- (2-amino-7-fluorofluoro [ d ] thiazol-4-yl) -6-fluoro-1- ((1-methylmethylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
Figure BDA0002825639160000414
Preparation of the title compound (yellow solid, 10mg) by the synthetic method of reference example 4 LC-MS: ESI [ M + H ]]+＝591.0/593.1。
Example 19: 4- (4-acryloylpiperazin-1-yl) -7- (2-amino-7-fluoropheno [ d ] thiazol-4-yl) -8-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile
Figure BDA0002825639160000421
The first step is as follows: intermediate 4(1.1g,2.3mmol) was dissolved in 1, 4-dioxane (10mL) and DIPEA (0.58g, 4.6mmol) and tert-butyl piperazine-1-carboxylate (465mg,2.5mmol) were added. The mixture was heated to 50 ℃ and stirred overnight, concentrated under reduced pressure, and the residue was purified by column chromatography to give tert-butyl 4- (7-bromo-8-chloro-3-cyano-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinolin-4-yl) piperazine-1-carboxylate (650mg, yellow solid). LC-MS ESI [ M + H ]]+＝618.2/620.2。
The second step is that: the solid obtained in the above step (802mg, 1.3mmol) and (2- ((tert-butoxycarbonyl) amino) -7-fluorophenylo [ d)]Thiazol-4-yl) boronic acid (470mg, 1.5mmol) was dissolved in1, 4-dioxane (10mL), Water (1mL), sodium carbonate (445mg, 4.2mmol) and tetrakis (triphenylphosphine) palladium (Pd (PPh)3)4) (81mg, 0.07mmol), nitrogen displacement, heating to 90 degrees reaction overnight, LCMS detection showed reaction complete. Cooling the reaction solution to room temperature, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain tert-butyl 4- (7- (2- ((tert-butoxycarbonyl) amino) -7-fluorobenzo [ d)]Thiazol-4-yl) -8-chloro-3-cyano-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinolin-4-yl) piperazine-1-carboxylate (435mg, yellow solid). LC-MS ESI [ M + H ]]+＝806.3/808.3。
The third step: the yellow solid (480mg, 0.68mmol) from the above step was dissolved in DCM (4mL), and TFA (2mL) was added and stirred at room temperature for 4 hours. Concentrating under reduced pressure to obtain tert-butyl (4- (8-chloro-3-cyano-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-4- (piperazin-1-yl) -1, 2-dihydroquinolin-7-yl) -7-fluorobenzo [ d]Thiazol-2-yl) carboxylate (410mg, crude, yellow solid). LC-MS ESI [ M + H ]]+＝706.1/708.1。
The fourth step: the product (150mg, crude) obtained in the above step was dissolved in methylene chloride (10mL), DIPEA (70mg, 0.54mmol) and acryloyl chloride (17mg, 0.19mmol) were added sequentially at 0 ℃ and stirred at room temperature for 2 hours. The reaction mixture was washed with a saturated ammonium chloride solution and a saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative chromatography to give the objective compound (yellow solid, 40 mg). MS: ESI [ M + H ]]+＝660.2/662.2。1H NMR(400MHz,MeOD-d4):δ8.79(s,1H),8.51(d,J＝5.0Hz,1H),8.11(d,1H),7.26-7.28(m,2H),7.12-6.92(m,1H),6.87(dd,1H),6.30(dd,1H),5.83(dd,1H),4.09-3.92(m,4H),3.86(s,4H)，2.82-2.92(m,1H)，2.04(s,3H),1.08(d,J＝6.6Hz,3H)，1.01(d,J＝6.6Hz,3H)。
Example 20: 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-7-fluoropheno [ d ] thiazol-4-yl) -8-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile
Figure BDA0002825639160000431
With intermediate 4 and tertButyl (R) -2-methylpiperazine-1-carboxylic acid ester was used as a starting material, and example 20 (yellow solid, 23mg) was prepared by the same method as in example 19. LC-MS ESI [ M + H ]]+＝674.2/676.2。
Example 21: 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -8-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile
Figure BDA0002825639160000432
Example 21 (yellow solid, 19mg) was prepared in the same manner as in example 19, starting from intermediate 4 and tert-butyl (R) -2-methylpiperazine-1-carboxylate. LC-MS ESI [ M + H ]]+＝685.2/687.2。
Example 22: 4- (4-acryloylpiperazin-1-yl) -7- (2-amino-7-fluoropheno [ d ] thiazol-4-yl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
Figure BDA0002825639160000433
Example 22 (yellow solid, 13mg) was prepared in the same manner as in example 19, starting from intermediate 5 and tert-butylmethylpiperazine-1-carboxylic acid ester. LC-MS ESI [ M + H ]]+＝627.3/629.3。1H NMR(400MHz,MeOD-d4):δ8.82(s,1H),8.48-8.52(m,2H),8.13(d,1H),7.29(d,J＝4.8Hz,1H),7.12-6.92(m,1H),6.83～6.85(m,1H),6.27～6.30(m,1H),5.79～5.83(m,1H),4.09-3.92(m,4H),3.86(s,4H)，2.82-2.92(m,1H)，1.99～2.06(m,3H),1.08(d,J＝6.6Hz,3H)，1.01(d,J＝6.6Hz,3H)。
Example 23: 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -8-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (5-methyl-1H-indazol-7-yl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile
Figure BDA0002825639160000434
Taking intermediate 5 and tert-butyl (R) -2-methylpiperazine-1-carboxylic ester as raw materials, adoptingExample 22 (yellow solid, 18mg) was prepared by the same procedure as in example 19. LC-MS ESI [ M + H ]]+＝638.2/640.2。
Test example 1 KrasG12CFunctional analysis
Test method 1: all enzyme and substrate solutions were treated with reaction buffer (20mM HEPES (pH7.5), 5mM MgCl2150mM NaCl and 0.01% tween 20). The experimental procedure was as follows: use of reaction buffer configuration of 10nM of GDP-loaded biotinylated KRASG12CAnd 37.5ng/ml of streptavidin europium cryptate, 384well HiBase micro polystyrene microwell plates in each well with 5. mu.L of the above protein reaction solution, while adding test sample or control compound formulated with DMSO and incubating for 4 hours. Separately, 20nM GST-Raf Ras binding domain (GST-Raf RBD) and 4. mu.g/mL anti-GST XL665 antibody (Cisbio) in reaction buffer (50mM potassium fluoride and 0.05mg/mL BSA) were mixed, and after 4 hours of equilibration, 0.6. mu.M GTP. gamma.S (Sigma) and 0.08. mu.M SOS were added. And 5 mu L of GST-RAF RBD mixed solution is added into each hole of the microplate. This addition of the mixture initiates the nucleotide exchange reaction, promoting KRas that are not activated to load GDPG12CConversion to activated GTP γ S KRasG12C. Activated GTP γ S KRasG12CSpecific binding to GST-RAF RBD draws the europium and XL665 closer together to enhance the FRET signal, which is detected using a Pheastar (BMG) plate reader equipped with an HTRF filter module. The FRET signal is attenuated by any compound that inhibits nucleotide exchange or inhibits activated KRAS from binding to RAF RBD, and the FRET dose-response data is curve-fitted using Genetida Screener and IC is calculated50.
The test method 2: KRAS Using CisBioG12CSOS1 kit for testing compound inhibition SOS1 and KRAS by using Binding assay methodG12CThe efficacy of protein-protein interactions between, the results are in IC50The values are represented.
The test method comprises the following steps: (1) test compounds were tested at 1000nM concentration, compounds were diluted 3-fold in a 384-well plate in 100% DMSO at 200-fold final concentration, 10 concentrations. Transfer of 50nL 200-fold final concentration to the destination plate 384well plate using the knockout Echo 550A compound (I) is provided. Respectively adding 50nL of 100% DMSO into the negative control well and the positive control well; (2) preparing a Tag1 SOS1 solution with 4 times of final concentration by using a Diluent buffer; (3) add 2.5. mu.L of a 4-fold final concentration solution of Tag1 SOS1 to a 384-well plate; (4) 4-fold final concentration of Tag2 KRAS was made up using Diluent bufferG12CA solution; (5) add 2.5. mu.L of Tag2 KRAS at 4-fold final concentration to the compound wells and positive control wells, respectivelyG12CA solution; add 2.5. mu.L of differential buffer to the negative control wells; (6) centrifuging a 384-hole plate at 1000rpm for 30 seconds, shaking and uniformly mixing, and incubating at room temperature for 15 min; (7) preparing a solution of Anti Tag1 TB3+ with the final concentration of 1 time and a solution of Anti Tag2 XL665 with the final concentration of 1 time by using a Detection buffer, mixing the two solutions uniformly, and adding 5 mu L of mixed solution into each hole; (8) centrifuging a 384-well plate at 1000rpm for 30 seconds, shaking and uniformly mixing, and incubating for 120 minutes at room temperature; (9) reading Em665/620 by an Envision microplate reader; (10) data analysis, calculation formula
Figure BDA0002825639160000441
Wherein Min signal negative control well mean Max signal positive control well mean. The fitted dose-effect curve was fitted with the log value of the concentration as the X-axis and the percent inhibition as the Y-axis, using the analysis software GraphPad Prism 5 log (inhibitor) vs. again Variable slope, to obtain the IC of each compound for the enzyme activity50The value is obtained. The fitting formula is: y ═ Bottom + (Top Bottom)/(1+10^ ((LogIC)50X)*HillSlope))。
As a result: most of the compounds of the present invention are para KRASG12Cthe/SOS 1 interaction has obvious inhibition and inhibitory activity IC50Less than 1000nM, IC of some embodiments50Less than 200nM, as in examples 1,4, 11, 13, 16, 18, 19, 22, 23; some of the examples had IC50 values less than 50nM, as in examples 16 and 19, and better than AMG510
Figure BDA0002825639160000451
The binding activity of (IC50 between 50nM and 100 nM).
Test example 2: KRASG12CMass spectrometry summation analysis
All enzyme and substrate solutions were treated with reaction buffer (20mM HEPE)S (pH7.5), 5mM MgCl2,150mM NaCl and 0.01% tween 20). Add 50. mu.L of 4. mu.M GDP-loaded biotinylated KRAS in each well of a 96-well polypropylene microplate in a reaction bufferG12C0.5. mu.L of 1mM test compound (final concentration: 10. mu.M), and after 4 hours of the reaction, the reaction was terminated by adding 50. mu.L of 1% formic acid. The plates were sealed and then read by Xevo G2 QTOF (Waters) and Acquity LC system (Waters). 10 μ L of the sample was injected into Xbridge BEH 300; c4; 3.5 μm; gradient analysis was performed for 3 min on 2.1X 50mm columns (Waters). A blank sample needs to be run between each test sample. Data analysis was performed using Mass Lynx Software (Waters) using total ion number (TIC) and combining the eluted protein peak data. Testing of Apo-protein KRASG12C(APO) and KRAS + relative to the compound mass (sum), the percentage of sum being calculated using the following formula: sum percentage is 100x (sum of sum peak area/APO and sum peak).
Test example 3: test of Effect of Compounds of the present invention on the cell proliferation of NCI-H358, MiaPaca-2 and phosphorylation of downstream Signal ERK
Test method one (2D) NCI-H358 (lung cancer) and MiaPaca-2 cells (pancreatic cancer) cells (100. mu.L/well, 20000 cells/mL) were seeded into 96-well culture plates and supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin sulfate, respectively. Cells were treated with a 0.5% dimethyl sulfoxide blank, diluted with an initial 10 μ M solution of test compound diluted three times with an eight gradient, and incubated in a 5% CO2 incubator for a defined period of time (5-7 days). At the end of the incubation, 10. mu.L of MTT stock solution (5mg/mL) was added to each well. The plates were incubated at 37 ℃ for 4 hours and then the medium was removed. Dimethylsulfoxide (100 μ L) was added to each well, followed by sufficient shaking. The absorbance of the formazan product was measured at 570nm on a Thermo Scientific Varioskan Flash multimodal reader. IC was obtained by fitting dose-response data to a three-parameter nonlinear regression model using GraphPad Prism 6.0 software50The value is obtained.
As a result: the example compounds provided herein have proliferation-inhibiting activity, IC, on NCI-H358 and MiaPaca-2 cells50The values are all less than 5000 nM; in particular examples 1,4, 7, 16, 17, 18, 19, 2022 cell proliferation inhibitory activity against NCI-H358 and MiaPaca-2 of less than 500 nM; some of the examples had cell proliferation inhibitory activity against NCI-H358 and MiaPaca-2 of even less than 100nM, as described in examples 16, 17, 19, 20, 22; some of the examples showed cell proliferation inhibitory activity against NCI-H358 and MiaPaca-2 of even less than 10nM, as in example 16, which was significantly better than that of AMG510 against NCI-H358 and MiaPaca-2 (IC50 at 20-50 nM).
Test method two (3D): tumor cells in logarithmic growth phase were diluted to a certain concentration with culture medium and inoculated in 96-well plate with ultra-low attachment surface, culture medium was 80 μ L/well. Cells were incubated overnight at 37 ℃ in a humidity chamber. The next day the plate was added serial dilutions of test compound (10 concentrations, 3-fold dilution), 20 μ L/well and incubated in incubator for 96 h. Taking out the plate, standing at room temperature, and adding the same volume
Figure BDA0002825639160000452
Incubation with 3D reagent for 1h, En VisionTMThe plate reader detects the signal. The signal was converted to percent inhibition using the following equation: % inhibition 100- [ (test compound signal-median minimum signal)/(median maximum signal-median minimum signal) x 100]. Maximum signal is the signal value from wells without inhibitor and minimum signal is the signal value from wells containing a reference inhibitor sufficient to completely inhibit cell proliferation, a four-parameter non-linear regression fit curve is performed on the percent inhibition for each concentration of compound and the IC is calculated50。
As a result: the example compounds provided herein have proliferation-inhibiting activity, IC, on NCI-H358 and MiaPaca-2 cells50Are all less than 1000nM, some examples being examples 1,4, 7, 10,11, 14, 16, 17, 18, 19, 20, 22, etc., IC's for cell proliferation inhibitory activity on NCI-H358 and MiaPaca-250Less than 200 nM.
Test method three (ERK phosphorylation): miapaca-2 or H358 cells were seeded at a certain concentration in 96-well plates and placed at 37 ℃ in 5% CO2The next day the plate was incubated overnight with serial dilutions of test compound (5 concentrations, 3-fold dilution) for 24H (Miapaca-2) or 3H (H358), followed by protein-containing solutionsThe lysate of enzyme and phosphatase inhibitor is used for cracking cells to extract protein, and the western blot method is used for detecting the level of p-ERK.
As a result: most of the compounds of the examples provided by the invention, such as 1,4, 7, 10,11, 14, 16, 17, 18, 19, 20 and 22, have obvious effects on inhibiting the level of phosphorylated ERK of NCI-H358 and MiaPaca-2, and IC50Less than 500 nM.
The test method four comprises the following steps:
1. NCI-H358 cells were maintained in RPMI with 10% FBS medium. To measure the cytotoxic activity of compounds quantitatively by ATP, NCI-H358 cells were plated at 5000 cells/well/100 μ L in RPMI medium in 96-well polystyrene clear black tissue culture plates in the presence or absence of a range of concentrations of test compound. After 3 days, 100uL of Cell Titer-GLO luminogenic Cell culture medium was added to each well for 10 minutes at room temperature to stabilize the luminescence signal. The number of viable cells in the culture medium is thus determined on the basis of the quantification of the presence of ATP, which indicates the presence of metabolically active cells. Luminescence was measured with a Top Count 384. 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%. The IC50 value was determined by four parameter regression using microplate reader random accessory software.
2. As a result: some examples provided by the invention are, for example, examples 2-6, proliferation inhibitory Activity on NCI-H358 cells, IC50Values were all less than 500nM, IC for inhibitory activity of some of the example compounds50Values even less than 10nM show strong cell proliferation inhibitory activity.
Test example 4: ADMET testing of the example Compounds
(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): the incubation was directly inhibited with 100. mu.L of human liver microsomes (final concentration 0.2mg/mL), which contained NADPH (final concentration 1mM), 10. mu.M of compound, cococktail (ketoconazole 10. mu.M, quinidine 10. mu.M, sulfaphenazole 100. mu.M, alpha-naphthoflavone 10. mu.M, tranylcypromine 1000. mu.M), negative control (BPS with 0.1% DMSO), and 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. The relative activity of the enzyme was calculated by measuring the relative production of the metabolite.
(3) hERG inhibition assay: compound stock solution of 20mM was diluted with DMSO, 10 μ L of 20mM compound stock solution was added to 20 μ L DMSO solution, and 3-fold serial dilutions were made to 6 DMSO concentrations; respectively taking 4 mu L of compounds with 6 DMSO concentrations, adding the compounds into 396 mu L of extracellular fluid, diluting the compounds to 6 intermediate concentrations by 100 times, then respectively taking 80 mu L of compounds with 6 intermediate concentrations, adding the compounds into 320 mu L of extracellular fluid, and diluting the compounds to a final concentration to be tested by 5 times; the highest test concentration is 40 mu M, and the highest test concentration is respectively 40, 13.3, 4.4, 1.48, 0.494 and 0.165 mu M for 6 concentrations; the DMSO content in the final assay concentration did not exceed 0.2%, and DMSO at this concentration had no effect on the hERG potassium channel; compounds were prepared for the entire dilution process by Bravo instrument; the current and time course of compound to hERG potassium channel were read and the inhibition curve of compound to hERG was made by fitting the curve.
As a result: in some embodiments of the invention, the compounds 1,4, 7, 16, 18, 19, 20, 22 have high stability to mouse, rat, human, and canine liver microsomes, and have a half-life of greater than 20 min; has no obvious inhibition to each CYP enzyme, IC50Greater than 10 uM; no significant inhibition of hERG, IC50Greater than 10 uM.
Test example 5: examples in vivo pharmacokinetic parameter testing of Compounds in rats and mice
6 male SPF-grade SD rats (Shanghai Spill-Bikea laboratory animals) were divided into two groups, and the test compounds were formulated into appropriate solutions or suspensions; one group was administered intravenously and one group was administered orally. 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 calculation software WinNonlin5.2 non-atrioventricular model is used for respectively calculating the pharmacokinetic parameters AUC of the test sample0-t、AUC0-∞、MRT0-∞、Cmax、Tmax、T1/2And VdIsoparametric and their mean and standard deviation. In addition, the bioavailability (F) will be calculated by the following formula.
Figure BDA0002825639160000471
Zero value calculation, when reaching CmaxSamples from later sampling points should be calculated as not quantifiable (BLQ).
Test example 6: EXAMPLES test of the Compounds for growth inhibition of MiaPaca-2, NCI-H358 tumor cells in nude mice transplanted tumors
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. The compound of the example (prepared to the required concentration with water for injection containing 1% Tween 80) was administered orally at the given dose daily 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. Wherein V0 is administered in separate cages (i.e. d 0)) The resulting tumor volumes were measured, 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.
As a result: the compounds of some examples of the invention, such as examples 4, 8, 19, 22, are orally administered once a day at a dose of 30mg/kg and 100mg/kg for 14-21 days continuously, and have significant inhibitory effect on the growth of MiaPaca-2, NCI-H358 tumor cell nude mouse transplanted tumor, and the tumor inhibition rate is more than 70%.
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 fused ring lactam compound shown as a general formula I, pharmaceutically acceptable salts thereof, enantiomers thereof, diastereomers thereof, tautomers thereof, twisted isomers thereof, solvates thereof, polymorphs thereof or prodrugs thereof,
Figure FDA0002825639150000011
in the formula:
r1 is independently hydrogen, deuterium, halogen, cyano, nitro, C1-C6Alkyl radical, C1-C6alkyl-SO2-、C1-C6alkyl-SO-, or C1-C6A haloalkyl group;
r2 and R3 are independently hydrogen, deuterium, halogen, cyano, nitro, C1-C6Alkyl radical, C1-C6alkyl-SO2-、C1-C6alkyl-SO-, N (R)2a)(R2b)-(CH2) x-; wherein R is2aAnd R2bEach independently is hydrogen or C1-C6Alkyl, x is selected from any integer of 0-5;
r4 is independently substituted or unsubstituted C1-C12Substituted or unsubstituted cycloalkyl or heterocycloalkyl of 3 to 12 members, substituted or unsubstituted aryl or heteroaryl of 5 to 10 members;
r5 is independently one or more of hydrogen, deuterium, halogen, C1-C6Alkyl, 3-6 membered cycloalkyl or heterocycloalkyl, vinyl or cyano; m is independently selected from 0-6;
m is CH, C-D or N; m1 is N or CR 6;
r6 is independently H, deuterium, halogen, cyano, hydroxy, ether, thioether, sulfoxide, sulfone, amide, sulfonamide, C1-C6Alkyl radical, C1-C6Alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl;
ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are each independently hydrogen, deuterium, C1-C6Alkyl, alkoxy, haloalkyl or carboxyl;
or Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh form a 3-8-membered saturated or partially unsaturated ring system between each two;
or Rg and R6 form a 3-8 membered saturated or partially unsaturated ring system;
ar is independently a 5-12 membered aromatic ring or aromatic fused ring, a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, alkoxy, 3-to 8-membered cycloalkyl or heterocycloalkyl, C1-C6Haloalkoxy, C2-C6Alkenyl radical, C2-C6An alkynyl group, a substituted or unsubstituted amino group, an amido group, a sulfonamide group, or a hydroxyl group;
one or more hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of: including but not limited to deuterium, halogen, hydroxy, amino or cyclic amino, cyano, nitro, sulfone or sulfoxide, C1-C8Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, C1-C8Alkoxy radical, C1-C8Alkylamino, alkenyl, alkynyl, acyl or sulfonyl, urea or sulfonylurea, 5-to 8-membered aryl or heteroaryl, or substituted with 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl;
wherein said heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, the heterocycloalkyl group containing 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said ring system comprising spiro, bridged, fused, or partially unsaturated ring systems.
2. The fused ring lactam compound of formula I, pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, twisted isomer, solvate, polymorph or prodrug thereof according to claim 1, wherein said fused ring lactam compound of formula I is according to any one of the following schemes:
scheme 1:
r1 is independently hydrogen, halogen, cyano or C1-C6An alkyl group;
r2 and R3 are hydrogen;
r4 is independently substituted C1-C12Alkyl or substituted 5-10 membered heteroaryl of (a);
said substituted C1-C12The substituents in the alkyl group of (a) are independently a 3-to 8-membered heterocycloalkyl group, or substituted with 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl;
the substituents in said substituted 5-10 membered heteroaryl are independently C1-C6Alkyl radical；
R5 is independently hydrogen, halogen, 3-6 membered cycloalkyl or vinyl;
r6 is independently H, halogen, cyano, or haloalkoxy;
m is CH or N;
m1 is N or CR 6;
ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are each independently hydrogen or C1-C6An alkyl group; when Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are independently C1-C6Alkyl, and said C1-C6When one or more hydrogen atoms on the alkyl group are substituted with a substituent, said substituent is independently cyano;
or Rg and R6 together form a 3-8 membered saturated or partially unsaturated ring system;
ar is independently a 5-12 membered aromatic ring or aromatic fused ring, a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, unsubstituted amino or hydroxy;
scheme 2:
r1 is independently hydrogen, halogen or C1-C6An alkyl group;
r2 and R3 are hydrogen;
r4 is independently substituted C1-C12Alkyl or substituted 5-10 membered heteroaryl of (a);
said substituted C1-C12The substituents in the alkyl group of (a) are independently a 3-to 8-membered heterocycloalkyl group, or substituted with 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl;
the substituents in said substituted 5-10 membered heteroaryl are independently C1-C6An alkyl group;
r5 is independently hydrogen, halogen, 3-6 membered cycloalkyl or vinyl;
r6 is independently H, halogen, cyano, or haloalkoxy;
m is CH or N;
m1 is N or CR 6;
ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are each independently hydrogen or C1-C6An alkyl group; when Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are independently C1-C6Alkyl, and said C1-C6When one or more hydrogen atoms on the alkyl group are substituted with a substituent, said substituent is independently cyano;
or Rg and R6 together form a 3-8 membered saturated or partially unsaturated ring system;
ar is independently a 5-12 membered aromatic ring or aromatic fused ring, a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, unsubstituted amino or hydroxy;
scheme 3:
r1 is independently hydrogen;
r2 and R3 are independently hydrogen;
r4 is independently substituted C1-C12Alkyl or substituted 5-10 membered heteroaryl of (a);
said substituted C1-C12The substituents in the alkyl group of (a) are independently a 3-to 8-membered heterocycloalkyl group, or substituted with 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl;
the substituents in said substituted 5-10 membered heteroaryl are independently C1-C6An alkyl group;
r5 is independently hydrogen, halogen, or 3-6 membered cycloalkyl;
r6 is independently H, halogen, cyano, or haloalkoxy;
m is CH or N;
m1 is N or CR 6;
ra, Rb, Rc, Rd, Re and Rf are independently hydrogen or C1-C6An alkyl group; when Ra, Rb, Rc, Rd, Re and Rf are independently C1-C6Alkyl, and said C1-C6When one or more hydrogen atoms on the alkyl group are substituted with a substituent, said substituent is independently cyano;
rg and Rh are hydrogen;
ar is independently a 5-12 membered aromatic ring or aromatic fused ring, a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted by oneSubstituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, unsubstituted amino or hydroxy;
when M1 is CR6, Ar is independently a 5-12 membered aromatic heterocycle or aromatic fused heterocycle;
scheme 4:
r1 is independently hydrogen or halogen;
r2 and R3 are independently hydrogen;
r4 is independently substituted C1-C12Alkyl or substituted 5-10 membered heteroaryl of (a);
said substituted C1-C12The substituents in the alkyl group of (a) are independently substituted by 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl;
the substituents in said substituted 5-10 membered heteroaryl are independently C1-C6An alkyl group;
r5 is independently hydrogen or halogen;
r6 is independently H, halogen or cyano;
m is CH or N;
m1 is N or CR 6;
ra, Rb, Rc, Rd, Re and Rf are independently hydrogen or C1-C6An alkyl group;
when Ra, Rb, Rc, Rd, Re and Rf are independently C1-C6Alkyl, and said C1-C6When one or more hydrogens on the alkyl group is substituted with a substituent, said substituent is cyano;
rg and Rh are hydrogen;
ar is independently a 5-12 membered aromatic ring or aromatic fused ring, a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, unsubstituted amino or hydroxy;
and when M1 is CR6, Ar is independently a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, unsubstituted amino or hydroxy;
and when Ra and Rb are independently C1-C6An alkyl group, a carboxyl group,and said C1-C6R1 is halogen when one or more hydrogens on the alkyl group is substituted with a substituent; ar is
Figure FDA0002825639150000041
Scheme 5:
r1 is independently hydrogen or halogen;
r2 and R3 are independently hydrogen;
r4 is independently substituted C1-C12Alkyl or substituted 5-10 membered heteroaryl of (a);
said substituted C1-C12The substituents in the alkyl group of (a) are independently substituted by 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl;
the substituents in said substituted 5-10 membered heteroaryl are independently C1-C6An alkyl group;
r5 is independently hydrogen, halogen, or vinyl;
r6 is independently H, halogen or cyano;
m is CH or N;
m1 is N or CR 6;
ra, Rb, Rc, Rd, Re and Rf are independently hydrogen or C1-C6An alkyl group; when Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are independently C1-C6Alkyl, and said C1-C6When one or more hydrogen atoms on the alkyl group are substituted with a substituent, said substituent is independently cyano;
rg and Rh are hydrogen;
ar is independently a 5-12 membered aromatic ring or aromatic fused ring, a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, unsubstituted amino or hydroxy;
when M1 is CR6, Ar is independently a 5-12 membered aromatic heterocycle or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, unsubstituted amino or hydroxy;
scheme 6:
r1 is independently hydrogen;
r2 and R3 are independently hydrogen;
r4 is substituted C1-C12Alkyl or substituted 5-10 membered heteroaryl of (a);
said substituted C1-C12The substituents in the alkyl group of (a) are independently substituted by 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl;
the substituents in said substituted 5-10 membered heteroaryl are independently C1-C6An alkyl group;
r5 is independently hydrogen or halogen;
r6 is independently H, halogen or cyano;
m is CH or N;
m1 is N or CR 6; when M1 is CR6, R6 is H or halogen;
ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are independently hydrogen or C1-C6An alkyl group;
ar is a 5-12-membered aromatic ring or aromatic condensed ring, a 5-12-membered aromatic heterocycle or aromatic condensed heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, unsubstituted amino or hydroxy;
scheme 7:
the condensed ring lactam compound shown in the general formula I is shown in general formula (IIA), (IIB), (IIC), (IID), (IIE), (IIF), (IIG), (IIH), (IIM), (IIN), (IIO) or (IIP):
Figure FDA0002825639150000051
wherein, the carbon marked by the symbol in the general formula (IIG) refers to R configuration chiral carbon;
the carbon marked with x in the general formula (IIH) refers to S configuration chiral carbon;
the carbon marked with x in the general formula (IIM) refers to an R configuration chiral carbon;
the carbon marked with x in the general formula (IIN) refers to an S configuration chiral carbon;
the carbon marked with ×, in the general formula (IIO), refers to an S configuration chiral carbon;
the carbon marked with x in the general formula (IIP) refers to S configuration chiral carbon;
m, M1, R1, R2, R3, R4, R5, R6, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ar and m are as defined in claim 1.
3. The fused ring lactam compound of formula I, pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, twisted isomer, solvate, polymorph or prodrug thereof according to claim 1, wherein when R1 is independently halogen, said halogen is F, Cl, Br or I, preferably F;
and/or, when R1 is independently C1-C6When alkyl, said C1-C6Alkyl is C1-C3Alkyl, more preferably methyl;
and/or, when R4 is independently substituted or unsubstituted C1-C12When there is an alkyl group, said C1-C12Alkyl of (A) is C1-C6Is preferably C1-C3Further preferably a methyl group;
and/or, when R4 is independently substituted C1-C12The substituents are independently 3-8 membered heterocycloalkyl, or substituted with 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl; the heteroatoms in the 3-8 membered heterocyclic alkyl are independently and preferably N, and the number of the heteroatoms is preferably 1;
and/or, when R4 is independently substituted C1-C12The substituents are independently 3-8 membered heterocycloalkyl, or substituted with 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl; the 3-8 membered heterocycloalkyl group is preferably a 3-5 membered heterocycloalkyl group, and is more preferably a tetrahydropyrrolyl group;
and/or, when R4 is independently substituted C1-C12Said substituents being independentlyBy 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl; the substituent position of the substituent group is independently on a heteroatom in the 3-5 membered heterocycloalkyl;
and/or, when R4 is independently substituted C1-C12Said substituents being independently substituted by 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl; said C1-C6Alkyl is C1-C4Alkyl, more preferably methyl;
and/or, when R4 is independently a substituted or unsubstituted 5-10 membered aryl or heteroaryl, the heteroatom in said 5-10 membered heteroaryl is N, the number is 1;
and/or, when R4 is independently a substituted or unsubstituted 5-10 membered aryl or heteroaryl, said 5-10 membered heteroaryl is a 6 membered heteroaryl, further is a pyridyl;
and/or, when R4 is independently substituted 5-10 heteroaryl, the number of substituents is 2;
and/or, when R4 is independently substituted 5-10 heteroaryl, said substituent is independently C1-C6When alkyl, said C1-C6Alkyl is C1-C4An alkyl group, more preferably a methyl group or an isopropyl group;
and/or, when R5 is independently halogen, said halogen is F, Cl, Br or I, preferably F or Cl;
and/or, when R5 is independently a 3-6 membered cycloalkyl group, said 3-6 membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl;
and/or the substitution position of R5 is positioned at the ortho-position of Ar;
and/or, when R6 is haloalkoxy, the haloalkoxy is halo C1-C4Alkoxy, more preferably trifluoromethoxy;
and/or, when R6 is a 3-8 membered cycloalkyl group, said 3-8 membered cycloalkyl group is a 3-6 membered cycloalkyl group, further preferably cyclopropyl;
and/or, when R6 is on the lactam ring in formula IWhen said Rg and R6 together form a 3-8 membered saturated or partially unsaturated ring system, said 3-8 membered saturated or partially unsaturated ring system is a 3-8 membered monocyclic heterocycloalkyl, more preferably a 6 membered monocyclic heterocycloalkyl, and the heteroatoms are O and/or N, the number is 2, more preferably 2
Figure FDA0002825639150000071
And/or, when Ra, Rb, Rc, Rd, Re and Rf are each independently C1-C6When alkyl, said C1-C6Alkyl is C1-C3Alkyl, more preferably methyl;
and/or, when Ra, Rb, Rc, Rd, Re and Rf are each independently C1-C6Alkyl, and said C1-C6When one or more hydrogen atoms on the alkyl group are substituted with a substituent, said substituent is independently cyano;
and/or, when Rg and Rh are respectively and independently C1-C6When alkyl, said C1-C6Alkyl is C1-C3Alkyl, more preferably methyl;
and/or, when Ar is independently a 5-12 membered aromatic ring, the 5-12 membered aromatic ring is a 6-10 membered aromatic ring, and is further preferably a phenyl group;
and/or, when Ar is independently a 5-12 membered aromatic condensed ring, said 5-12 membered aromatic condensed ring is a 6-10 membered aromatic condensed ring, more preferably a naphthyl group, for example
Figure FDA0002825639150000072
And/or, when Ar is independently a 5-12 membered fused aromatic heterocycle, the heteroatoms in the 5-12 membered fused aromatic heterocycle are N and/or S, and the number is 1 or 2;
and/or, when Ar is independently a 5-12 membered fused aromatic heterocycle, the 5-12 membered fused aromatic heterocycle is a 9 membered fused aromatic heterocycle, further is
Figure FDA0002825639150000073
And/or, when the Ar ring is substituted with one or more groups that are halogen, said halogen is F, Cl, Br or I, preferably F, Cl;
and/or, when the Ar ring is substituted by one or more groups C1-C6When alkyl, said C1-C6Alkyl is C1-C3Alkyl, more preferably methyl;
and/or, when the Ar ring is substituted by one or more groups, and the group is alkoxy, the alkoxy is C1-C6An alkoxy group;
and/or, when Ar is substituted with one or more groups, the number of said substitutions is 1,2,3 or 4;
and/or, said cycloalkyl is a non-aromatic saturated monocyclic ring;
and/or, said heterocyclyl is a saturated or unsaturated monocyclic ring system;
and/or, the heterocyclic group is one in which the nitrogen, carbon or sulfur atom is not oxidized; the nitrogen atoms are not quaternized.
4. The fused ring lactam compound of formula I, pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, twisted isomer, solvate, polymorph or prodrug thereof, according to claim 3, wherein when R4 is independently substituted 5-10 membered heteroaryl, said 5-10 membered heteroaryl is
Figure FDA0002825639150000081
And/or, when R4 is independently substituted C1-C12Alkyl of (2), said substituted C1-C12Alkyl of (A) is
Figure FDA0002825639150000082
Further comprises
Figure FDA0002825639150000083
And/or, when R4 is independently substituted 5-10 membered heteroaryl, said 5-10 membered heteroaryl is
Figure FDA0002825639150000084
And/or, when Ra, Rb, Rc, Rd, Re and Rf are each independently C1-C6Alkyl, and said C1-C6When one or more hydrogen atoms of the alkyl group are substituted by the substituent(s), said C1-C6Alkyl is
Figure FDA0002825639150000085
And/or, when Ar is independently a 5-12 membered aromatic ring, and Ar is substituted with one or more groups, the 5-12 membered aromatic ring is
Figure FDA0002825639150000086
And/or, when Ar is independently a 5-12 membered aromatic fused ring and Ar is substituted with one or more groups, said 5-12 membered aromatic fused ring is
Figure FDA0002825639150000087
And/or, when Ar is independently a 5-12 membered fused aromatic heterocycle and Ar is substituted with one or more groups, said 5-12 membered fused aromatic heterocycle is
Figure FDA0002825639150000088
5. The fused ring lactam compound of formula I, pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof according to claim 1A medicine, characterized in that R1 is independently hydrogen, halogen, cyano or C1-C6Alkyl, preferably hydrogen or halogen;
and/or, R2 and R3 are hydrogen;
and/or, R4 is independently substituted C1-C12Alkyl or substituted 5-10 membered heteroaryl of (a);
and/or, when R4 is independently substituted C1-C12Alkyl of (2), said substituted C1-C12The substituents in the alkyl group of (a) are independently a 3-to 8-membered heterocycloalkyl group, or substituted with 1 or more C1-C6Alkyl-substituted 3-8 membered heterocycloalkyl;
and/or, when R4 is independently substituted 5-10 membered heteroaryl, the substituent in said substituted 5-10 membered heteroaryl is independently C1-C6An alkyl group;
and/or, R5 is independently hydrogen, halogen, 3-6 membered cycloalkyl or vinyl, preferably hydrogen, halogen or vinyl;
and/or Ra and Rb are independently hydrogen or C1-C6An alkyl group;
and/or, when Ra and Rb are independently C1-C6Alkyl, and said C1-C6When one or more hydrogen atoms on the alkyl group are substituted with a substituent, said substituent is independently cyano;
and/or, Rc, Rd, Re and Rf are independently hydrogen;
and/or Rg and Rh are hydrogen or C1-C6An alkyl group;
and/or, when R6 is a substituent on the lactam ring in formula I, said R6 is independently hydrogen or cyano;
or Rg and R6 together form a 3-8 membered saturated or partially unsaturated ring system;
and/or, when M1 is independently CR6, said R6 is H, halogen, or haloalkoxy;
and/or, m is independently 0 or 1;
and/or the presence of a gas in the gas,
Figure FDA0002825639150000091
is composed of
Figure FDA0002825639150000092
And/or the presence of a gas in the gas,
Figure FDA0002825639150000093
is composed of
Figure FDA0002825639150000094
Figure FDA0002825639150000095
And/or the presence of a gas in the gas,
Figure FDA0002825639150000101
is composed of
Figure FDA0002825639150000102
Figure FDA0002825639150000103
And/or the presence of a gas in the gas,
Figure FDA0002825639150000104
is composed of
Figure FDA0002825639150000105
Figure FDA0002825639150000106
And/or the presence of a gas in the gas,
Figure FDA0002825639150000107
is composed of
Figure FDA0002825639150000108
Figure FDA0002825639150000111
Figure FDA0002825639150000121
6. The fused ring lactam compound of formula I, pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, twist isomer, solvate, polymorph or prodrug thereof according to claim 1, wherein R1 is independently selected from hydrogen, halogen, cyano, nitro, C1-C6Alkyl radical, C1-C6alkyl-SO2-、C1-C6alkyl-SO-, or C1-C6A haloalkyl group;
r2 and R3 are independently selected from hydrogen, halogen, cyano, nitro and C1-C6Alkyl radical, C1-C6alkyl-SO2-、C1-C6alkyl-SO-, N (R)2a)(R2b)-(CH2) x-; wherein R is2aAnd R2bEach independently selected from hydrogen or C1-C6Alkyl, x is selected from any integer of 0-5;
r4 is independently selected from substituted or unsubstituted C1-C12Substituted or unsubstituted 3-12 membered cycloalkyl or heterocycloalkyl;
r5 is independently selected from one or more of hydrogen, halogen, C1-C6Alkyl, 3-6 membered cycloalkyl or heterocycloalkyl, vinyl, cyano, and the like; m is independently selected from 0-6;
m is independently selected from CH or N; m1 is independently selected from N or CR 6;
r6 is independently selected from H, halogen, cyano, hydroxy, ether, thioether, sulfoxide, sulfone, amide, sulfonamide, C1-C6Alkyl radical, C1-C6Alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, 3-to 8-membered cycloalkyl or heterocycloalkyl, and the like;
ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are respectively and independently selected from hydrogen, C1-C6 alkyl, alkoxy, haloalkyl, carboxyl and the like, or Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh form a 3-8-membered saturated or partially unsaturated ring system between every two of them; or Rg and R6 form a 3-8 membered saturated or partially unsaturated ring system;
ar is independently selected from a 5-12 membered aromatic ring or aromatic condensed ring, a 5-12 membered aromatic heterocycle or aromatic condensed heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6Alkyl, alkoxy, 3-to 8-membered cycloalkyl or heterocycloalkyl, C1-C6Haloalkoxy, C2-C6Alkenyl radical, C2-C6Alkynyl groups, substituted or unsubstituted amino groups, amide groups, sulfonamide groups, and the like;
one or more hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of: including but not limited to deuterium, halogen, hydroxy, amino or cyclic amino, cyano, nitro, sulfone or sulfoxide, C1-C8Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, C1-C8Alkoxy radical, C1-C8Alkylamino, alkenyl, alkynyl, acyl or sulfonyl, urea or sulfonylurea, 5-to 8-membered aryl or heteroaryl; wherein said heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, the heterocycloalkyl group containing 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said ring system including spiro, bridged, fused, etc. saturated or partially unsaturated ring systems.
7. The fused ring lactam compound of formula I, pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, twisted isomer, solvate, polymorph or prodrug thereof according to claim 1, wherein fused ring lactam compound of formula I, pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, twisted isomer, solvate, polymorph or prodrug thereof is any one of the following compounds:
Figure FDA0002825639150000131
Figure FDA0002825639150000141
8. a pharmaceutical composition comprising an effective amount of a fused ring lactam compound of general formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, twist isomer, solvate, polymorph or prodrug thereof, according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier.
9. Use of a fused ring lactam compound of formula I, as defined in any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a twisted isomer thereof, a solvate thereof, a polymorph thereof, a prodrug thereof, or a pharmaceutical composition of claim 8, for the preparation of a Ras mutein inhibitor or medicament,
the Ras mutein is preferably KRAS G12C;
the drug is used for treating diseases related to the activity or expression amount of the Ras mutein;
the disease related to the activity or expression amount of Ras mutein is preferably tumor;
the tumor is preferably one or more of non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, stomach cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymph cancer, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer and pancreatic cancer, more preferably non-small cell lung cancer, small cell lung cancer or pancreatic cancer.
10. Use of a fused ring lactam compound according to any one of claims 1 to 7, of the general formula I, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a twisted isomer thereof, a solvate thereof, a polymorph thereof, a prodrug thereof, or a pharmaceutical composition according to claim 8, for the preparation of a medicament for the treatment of tumors;
the tumor is preferably one or more of non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, stomach cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymph cancer, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer and pancreatic cancer, more preferably non-small cell lung cancer, small cell lung cancer or pancreatic cancer.
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WO2022053022A1 (en) * 2020-09-12 2022-03-17 赛诺哈勃药业（成都）有限公司 Methionine adenosyltransferase inhibitor, preparation method therefor, and application thereof
WO2022111513A1 (en) * 2020-11-24 2022-06-02 杭州多域生物技术有限公司 Aromatic compound, and preparation method therefor and use thereof
WO2022135591A1 (en) * 2020-12-25 2022-06-30 苏州泽璟生物制药股份有限公司 Aryl or heteroaryl pyridone or pyrimidone derivative and preparation method therefor and application thereof
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