CN113061132B - Condensed ring lactam compound, preparation method and application - Google Patents

Condensed ring lactam compound, preparation method and application Download PDF

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CN113061132B
CN113061132B CN202011448242.9A CN202011448242A CN113061132B CN 113061132 B CN113061132 B CN 113061132B CN 202011448242 A CN202011448242 A CN 202011448242A CN 113061132 B CN113061132 B CN 113061132B
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substituted
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CN113061132A (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 thereof. The condensed ring lactam compound is shown as a general formula I. The compound provided by the invention has the function of inhibiting the activity of Ras mutant protein, and has a good application prospect.

Description

Condensed ring lactam compound, preparation method and application
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a condensed ring lactam compound, a compound for inhibiting activity of Ras mutein, a preparation method and application thereof.
Background
RAS is the first oncogene identified in human tumors, and was first discovered in two murine sarcoma viruses. The RAS gene family has three members, hras, kras, nras respectively. In human tumors, kras mutations are most common, accounting for about 85%. Previous studies have shown that Kras mutations are oncogenic because of missense mutation at codon 12, altering the structure of the Kras protein and allowing it to remain active. Ras plays a major role in signaling pathway in activating kinases that control gene transcription, thereby regulating cell differentiation and proliferation, and is intimately involved in tumor cell survival, proliferation, migration, metastasis, and angiogenesis. It is counted that there are Kras G12C mutations in 11% -16% of cases of lung adenocarcinoma, and that some of pancreatic cancer, colorectal cancer, ovarian cancer and cholangiocarcinoma are caused by Kras mutations. However, since the first discovery of Kras oncogenes has been over thirty years, targeting drugs for common proto-oncogenes such as EGFR, BCL, etc. have been used for several generations, and targeting drugs for Kras have not been successfully developed all the time. Targeting drugs against KRas pathway mutant tumors have been mainly focused on farnesyl transferase inhibitors and Raf-MEK pathway inhibitors, but have had little effect. In recent years, inhibitors against KRas specific gene mutation have been developed as hot spots, and part of the inhibitors gradually move from preclinical hatching to clinical researches, such as KRas G12C inhibitor AMG510, MRTX1257, and the like, and show a certain curative effect in early clinical experiments. The first clinical data of the global first-line KRASG12C inhibitor AMG510 was formally published by the american clinical oncology institute held at month 6 of 2019, in which the advanced drug AMG510 was shown to be able to prevent tumor growth in most non-small cell lung and colorectal cancer patients with KRas mutations. Therefore, finding and searching for targeted drugs with high specificity and excellent pharmaceutical properties for KRAS specific mutant genes becomes a great hotspot in the industry.
Disclosure of Invention
The invention aims to overcome the defect of few KRAS G12C inhibitor types, and provides a condensed ring lactam compound, a preparation method and application thereof, wherein the condensed ring lactam compound is a KRAS G12C inhibitor with a brand new structure and has good inhibition activity on tumor cells.
The invention solves the technical problems through the following technical proposal.
The invention provides a condensed ring lactam compound shown in a general formula I, pharmaceutically acceptable salts thereof, enantiomers thereof, diastereomers thereof, tautomers thereof, torsional isomers thereof, solvates thereof, polymorphs thereof or prodrugs thereof,
wherein:
r1 is independently hydrogen, deuterium, halogen, cyano, nitro, C 1 -C 6 Alkyl, C 1 -C 6 alkyl-SO 2 -、C 1 -C 6 alkyl-SO-, or C 1 -C 6 A haloalkyl group;
r2 and R3 are independently hydrogen, deuterium, halogen, cyano, nitro, C 1 -C 6 Alkyl, C 1 -C 6 alkyl-SO 2 -、C 1 -C 6 alkyl-SO-, N (R) 2a )(R 2b )-(CH 2 ) X-; wherein R is 2a And R is 2b Each independently is hydrogen or C 1 -C 6 Alkyl, x is selected from any integer from 0 to 5;
r4 is independently substituted or unsubstituted C 1 -C 12 Substituted or unsubstituted 3-to 12-membered cycloalkyl or heterocycloalkyl, substituted or unsubstituted 5-to 10-membered aryl or heteroaryl A base;
r5 is independently one or more of hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, 3-6 membered cycloalkyl or heterocycloalkyl, vinyl or cyano; m is independently selected from 0 to 6;
m is CH, C-D or N; m1 is N or CR6;
r6 is independently H, deuterium, halogen, cyano, hydroxy, ether, thioether, sulfoxide, sulfone, amide, sulfonamide, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl;
ra, rb, rc, rd, re, rf, rg and Rh are each independently hydrogen, deuterium, C 1 -C 6 Alkyl, 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;
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 condensed ring, a 5-12 membered aromatic heterocyclic ring or aromatic condensed ring; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C 1 -C 6 Alkyl, alkoxy, 3-8 membered cycloalkyl or heterocycloalkyl, C 1 -C 6 Haloalkoxy, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, substituted or unsubstituted amino, amido, sulfonamide, or hydroxy;
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, C 1 -C 8 Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, C 1 -C 8 Alkoxy, C 1 -C 8 Alkylamino, alkenyl, alkynyl, acyl or sulfonyl, urea or sulfonylurea, 5-to 8-membered aryl or heteroaryl, or substituted with 1 or more C 1 -C 6 Alkyl substituted 3-8 membered heterocycloalkyl;
wherein the heteroaryl group comprises 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said ring system comprising spiro, bridged, fused, and ring saturated or partially unsaturated ring systems.
In a preferred embodiment of the present invention,
r1 is independently hydrogen, halogen, cyano or C 1 -C 6 An alkyl group;
r2 and R3 are hydrogen;
r4 is independently substituted C 1 -C 12 An alkyl or substituted 5-10 membered heteroaryl group;
said substituted C 1 -C 12 The substituents in the alkyl groups of (a) are independently 3-8 membered heterocycloalkyl, or are substituted with 1 or more C 1 -C 6 Alkyl substituted 3-8 membered heterocycloalkyl;
the substituents in the substituted 5-10 membered heteroaryl are independently C 1 -C 6 An 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 together with R6 form a 3-8 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 CR6;
ra, rb, rc, rd, re, rf, rg and Rh are each independently hydrogen or C 1 -C 6 An alkyl group; when Ra, rb, rc, rd, re, rf, rg and Rh are independently C 1 -C 6 Alkyl, and C as described 1 -C 6 When one or more hydrogen atoms on the alkyl group are substituted with a substituent, the substituent is independently cyano;
or Rg and R6 together form a 3-8 membered saturated or partially unsaturated ring system (R6 is a substituent on the lactam);
ar is independently a 5-12 membered aromatic ring or an aromatic condensed ring5-12 membered aromatic or aromatic fused heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C 1 -C 6 Alkyl, unsubstituted amino or hydroxy.
In a preferred embodiment of the present invention,
r1 is independently hydrogen, halogen or C 1 -C 6 An alkyl group;
r2 and R3 are hydrogen;
r4 is independently substituted C 1 -C 12 An alkyl or substituted 5-10 membered heteroaryl group;
said substituted C 1 -C 12 The substituents in the alkyl groups of (a) are independently 3-8 membered heterocycloalkyl, or are substituted with 1 or more C 1 -C 6 Alkyl substituted 3-8 membered heterocycloalkyl;
the substituents in the substituted 5-10 membered heteroaryl are independently C 1 -C 6 An alkyl group;
r5 is independently hydrogen, halogen, 3-6 membered cycloalkyl or vinyl;
R6 is independently H, halo, cyano or haloalkoxy;
m is CH or N;
m1 is N or CR6;
ra, rb, rc, rd, re, rf, rg and Rh are each independently hydrogen or C 1 -C 6 An alkyl group; when Ra, rb, rc, rd, re, rf, rg and Rh are independently C 1 -C 6 Alkyl, and C as described 1 -C 6 When one or more hydrogen atoms on the alkyl group are substituted with a substituent, the substituent is independently cyano;
or Rg and R6 together form a 3-8 membered saturated or partially unsaturated ring system (R6 is a substituent on the lactam);
ar is independently a 5-12 membered aromatic ring or aromatic condensed ring, a 5-12 membered aromatic heterocyclic ring or aromatic condensed ring; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C 1 -C 6 Alkyl, 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 C 1 -C 12 An alkyl or substituted 5-10 membered heteroaryl group;
said substituted C 1 -C 12 The substituents in the alkyl groups of (a) are independently 3-8 membered heterocycloalkyl, or are substituted with 1 or more C 1 -C 6 Alkyl substituted 3-8 membered heterocycloalkyl;
the substituents in the substituted 5-10 membered heteroaryl are independently C 1 -C 6 An alkyl group;
r5 is independently hydrogen, halogen or 3-6 membered cycloalkyl;
R6 is independently H, halo, cyano or haloalkoxy;
m is CH or N;
m1 is N or CR6;
ra, rb, rc, rd, re and Rf are independently hydrogen or C 1 -C 6 An alkyl group; when Ra, rb, rc, rd, re and Rf are independently C 1 -C 6 Alkyl, and C as described 1 -C 6 When one or more hydrogen atoms on the alkyl group are substituted with a substituent, the substituent is independently cyano;
rg and Rh are hydrogen;
ar is independently a 5-12 membered aromatic ring or aromatic condensed ring, a 5-12 membered aromatic heterocyclic ring or aromatic condensed ring; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C 1 -C 6 Alkyl, 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 C 1 -C 12 An alkyl or substituted 5-10 membered heteroaryl group;
said substituted C 1 -C 12 Substituents in the alkyl groups of (2) are independentWith ground being covered by 1 or more C' s 1 -C 6 Alkyl substituted 3-8 membered heterocycloalkyl;
the substituents in the substituted 5-10 membered heteroaryl are independently C 1 -C 6 An alkyl group;
r5 is independently hydrogen or halogen;
r6 is independently H, halogen or cyano;
m is CH or N;
M1 is N or CR6;
ra, rb, rc, rd, re and Rf are independently hydrogen or C 1 -C 6 An alkyl group;
when Ra, rb, rc, rd, re, rf is independently C 1 -C 6 Alkyl, and C as described 1 -C 6 When one or more hydrogens on the alkyl are substituted with a substituent, the substituent is cyano;
rg and Rh are hydrogen;
ar is independently a 5-12 membered aromatic ring or aromatic condensed ring, a 5-12 membered aromatic heterocyclic ring or aromatic condensed ring; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C 1 -C 6 Alkyl, 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, rb are independently C 1 -C 6 Alkyl, and C as described 1 -C 6 When one or more hydrogens on the alkyl are substituted with substituents, R1 is halogen; ar is
In a preferred embodiment of the present invention,
r1 is independently hydrogen or halogen;
r2 and R3 are independently hydrogen;
r4 is independently substituted C 1 -C 12 An alkyl or substituted 5-10 membered heteroaryl group;
the saidSubstituted C of (2) 1 -C 12 Substituents in the alkyl groups of (2) are independently C1 or more 1 -C 6 Alkyl substituted 3-8 membered heterocycloalkyl;
The substituents in the substituted 5-10 membered heteroaryl are independently C 1 -C 6 An 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 CR6;
ra, rb, rc, rd, re and Rf are independently hydrogen or C 1 -C 6 An alkyl group; when Ra, rb, rc, rd, re, rf, rg and Rh are independently C 1 -C 6 Alkyl, and C as described 1 -C 6 When one or more hydrogen atoms on the alkyl group are substituted with a substituent, the substituent is independently cyano;
rg and Rh are hydrogen;
ar is independently a 5-12 membered aromatic ring or aromatic condensed ring, a 5-12 membered aromatic heterocyclic ring or aromatic condensed ring; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C 1 -C 6 Alkyl, 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 C 1 -C 12 An alkyl or substituted 5-10 membered heteroaryl group;
said substituted C 1 -C 12 Substituents in the alkyl groups of (2) are independently C1 or more 1 -C 6 Alkyl substituted 3-8 membered heterocycloalkyl;
the substituents in the substituted 5-10 membered heteroaryl are independently C 1 -C 6 An alkyl group;
r5 is independently hydrogen or halogen;
r6 is independently H, halogen or cyano;
m is CH or N;
m1 is N or CR6; when M1 is CR6, R6 is H or halogen;
ra, rb, rc, rd, re, rf, rg and Rh are independently hydrogen or C 1 -C 6 An alkyl group;
ar is a 5-12 membered aromatic ring or aromatic condensed ring, a 5-12 membered aromatic heterocyclic ring or aromatic condensed ring; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C 1 -C 6 Alkyl, unsubstituted amino or hydroxy.
In a preferred embodiment of the present invention, the condensed ring lactam compound represented by formula I is represented by formula (IIA), (IIB), (IIC), (IID), (IIE), (IIF), (IIG), (IIH), (IIM), (IIN), (IIO) or (IIP):
wherein, the carbon marked in the general formula (IIG) refers to R configuration chiral carbon;
the carbon noted in formula (IIH) refers to the chiral carbon of S configuration;
the carbon noted in formula (IIM) refers to the chiral carbon of R configuration;
the carbon noted in formula (IIN) refers to the chiral carbon of S configuration;
the carbon noted in formula (IIO) refers to the chiral carbon of S configuration;
the carbon noted in formula (IIP) refers to the chiral carbon of S configuration;
M, M1, 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, said halogen is F, cl, br or I, preferably F.
In a preferred embodiment of the invention, when R1 is independentlyThe ground is C 1 -C 6 In the case of alkyl, said C 1 -C 6 Alkyl is C 1 -C 3 Alkyl (e.g., methyl, ethyl, n-propyl or isopropyl), more preferably methyl.
In a preferred embodiment of the invention, when R4 is independently substituted or unsubstituted C 1 -C 12 When alkyl is said C 1 -C 12 Is C as alkyl 1 -C 6 Alkyl of (C) is preferred 1 -C 3 The alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl) is more preferably methyl.
In a preferred embodiment of the invention, when R4 is independently substituted C 1 -C 12 Said substituents are independently 3-8 membered heterocycloalkyl, or are substituted with 1 or more C 1 -C 6 Alkyl substituted 3-8 membered heterocycloalkyl.
Wherein, when the substituents are independently 3-8 membered heterocycloalkyl, or are substituted with 1 or more C 1 -C 6 In the case of an alkyl-substituted 3-8 membered heterocycloalkyl group, the hetero atom in the 3-8 membered heterocycloalkyl group is independently preferably N, and the number is preferably 1.
Wherein, when the substituents are independently 3-8 membered heterocycloalkyl, or are substituted with 1 or more C 1 -C 6 In the case of an alkyl-substituted 3-8 membered heterocycloalkyl group, the 3-8 membered heterocycloalkyl group is preferably a 3-5 membered heterocycloalkyl group, and more preferably a tetrahydropyrrolyl group.
Wherein, when the substituents are independently at least 1C 1 -C 6 In the case of alkyl-substituted 3-8 membered heterocycloalkyl, the substitution site of the substituent is independently preferably on a heteroatom in the 3-5 membered heterocycloalkyl.
Wherein, when the substituents are independently at least 1C 1 -C 6 In the case of alkyl-substituted 3-8 membered heterocycloalkyl, said C 1 -C 6 Alkyl is preferably C 1 -C 4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl), more preferably methyl.
Wherein, when the substituents are independently at least 1C 1 -C 6 In the case of alkyl-substituted 3-8 membered heterocycloalkyl, said alkyl is substituted by 1 or more C 1 -C 6 The 3-8 membered heterocycloalkyl of alkyl is preferably
In a preferred embodiment of the invention, when R4 is independently substituted C 1 -C 12 Said substituted C 1 -C 12 Is an alkyl group of (2)Further is->
In a preferred embodiment of the present invention, when R4 is independently a substituted or unsubstituted 5-10 membered aryl or heteroaryl, the heteroatoms in the 5-10 membered heteroaryl are N, 1 in number.
In a preferred embodiment of the invention, when R4 is independently a substituted or unsubstituted 5-10 membered aryl or heteroaryl, the 5-10 membered heteroaryl is a 6 membered heteroaryl, further is pyridinyl.
In a preferred embodiment of the invention, when R4 is independently a substituted 5-10 heteroaryl, the number of substituents is 2.
In a preferred embodiment of the invention, when R4 is independently substituted 5-10 heteroaryl, the substituents are independently C 1 -C 6 An alkyl group.
Wherein, when the substituents are independently C 1 -C 6 In the case of alkyl, said C 1 -C 6 Alkyl is preferably C 1 -C 4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl), more preferably methyl or isopropyl.
In a preferred embodiment of the invention, when R4 is independently a substituted 5-10 membered heteroaryl, the 5-10 membered heteroaryl is
In a preferred embodiment of the invention, R4 is
In a preferred embodiment of the invention, when R5 is independently halogen, said halogen is F, cl, br or I, preferably F or Cl.
In a preferred embodiment of the present invention, when R5 is independently 3-6 membered cycloalkyl, said 3-6 membered cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.
In a preferred embodiment of the invention, the substitution position of R5 is located in the ortho-position with respect to Ar.
In a preferred embodiment of the invention, when R6 is haloalkoxy, said haloalkoxy is haloC 1 -C 4 Alkoxy is more preferably trifluoromethoxy.
In a preferred embodiment of the present invention, when R6 is a 3-8 membered cycloalkyl group, the 3-8 membered cycloalkyl group is a 3-6 membered cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), and further preferably cyclopropyl.
In a preferred embodiment of the invention, when R6 is a substituent on the lactam ring in formula I, said Rg together with R6 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
In a preferred embodiment of the invention, when Ra, rb, rc, rd, re and Rf are each independently C 1 -C 6 In the case of alkyl, said C 1 -C 6 Alkyl is C 1 -C 3 Alkyl (e.g., methyl, ethyl, n-propyl or isopropyl), more preferably methyl.
In a preferred embodiment of the invention, when Ra, rb, rc, rd, re and Rf are each independently C 1 -C 6 Alkyl, and C as described 1 -C 6 When one or more hydrogen atoms on the alkyl group are substituted with a substituent, the substituent is independently cyano.
In a preferred embodiment of the invention, when Ra, rb, rc, rd, re and Rf are each independently C 1 -C 6 Alkyl, and C as described 1 -C 6 When one or more hydrogen atoms on the alkyl group are substituted by substituents, said C 1 -C 6 Alkyl is
In a preferred embodiment of the invention, when Rg and Rh are each independently C 1 -C 6 In the case of alkyl, said C 1 -C 6 Alkyl is C 1 -C 3 Alkyl (e.g., methyl, ethyl, n-propyl or isopropyl), more preferably methyl.
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 further preferably phenyl.
In a preferred embodiment of the present invention, when Ar is independently a 5-12 membered aromatic fused ring, the 5-12 membered aromatic fused ring is a 6-10 membered aromatic fused ring, further preferably a naphthyl group (e.g.)。
In a preferred embodiment of the present invention, when Ar is independently a 5-12 membered aromatic fused heterocycle, the heteroatoms in the 5-12 membered aromatic fused heterocycle are N and/or S, and the number is 1 or 2.
In a preferred embodiment of the present invention, when Ar is independently a 5-12 membered aromatic fused heterocycle, the 5-12 membered aromatic fused heterocycle is a 9-membered aromatic fused heterocycle, further
In a preferred embodiment of the invention, when the Ar ring is substituted with one or more groups, and the groups are halogen, the halogen is F, cl, br or I, preferably F, cl.
In a preferred embodiment of the invention, when the Ar ring is substituted with one or more groups, and said groups are C 1 -C 6 In the case of alkyl, said C 1 -C 6 Alkyl is C 1 -C 3 Alkyl (e.g., methyl, ethyl, n-propyl or isopropyl), more preferably methyl.
In a preferred embodiment of the invention, when the Ar ring is substituted with one or more groups, and the groups are alkoxy groups, the alkoxy groups are C 1 -C 6 An alkoxy group.
In a preferred embodiment of the invention, when Ar is substituted with one or more groups, the number of substitutions is 1, 2, 3 or 4.
In a preferred embodiment of the 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
In a preferred embodiment of the invention, when Ar is independently a 5-12 membered aromatic fused ring, and Ar is substituted with one or more groups, the 5-12 membered aromatic fused ring is
In a preferred embodiment of the invention, when Ar is independently a 5-12 membered aromatic fused heterocycle, and Ar is substituted with one or more groups, the 5-12 membered aromatic fused heterocycle is
In a preferred embodiment of the invention Ar is independently
In a preferred embodiment of the invention, the cycloalkyl is a non-aromatic saturated monocyclic ring.
In a preferred embodiment of the invention, the heterocyclic group is a saturated or unsaturated monocyclic ring system.
In a preferred embodiment of the invention, the heterocyclic group is one in which the nitrogen, carbon or sulfur atom is not oxidized; the nitrogen atom is not quaternized.
In a preferred embodiment of the invention, R1 is independently hydrogen, halogen, cyano or C 1 -C 6 Alkyl, 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 C 1 -C 12 Or a substituted 5-10 membered heteroaryl group.
In a preferred embodiment of the invention, when R4 is independently substituted C 1 -C 12 Said substituted C 1 -C 12 The substituents in the alkyl groups of (a) are independently 3-8 membered heterocycloalkyl, or are substituted with 1 or more C 1 -C 6 Alkyl substituted 3-8 membered heterocycloalkyl.
In a preferred embodiment of the invention, when R4 is independently a substituted 5-10 membered heteroaryl, the substituents in said substituted 5-10 membered heteroaryl are independently C 1 -C 6 An 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 C 1 -C 6 An alkyl group;
in a preferred embodiment of the invention, when Ra and Rb are independently C 1 -C 6 Alkyl, and C as described 1 -C 6 When one or more hydrogen atoms on the alkyl group are substituted with a substituent,the substituents are 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 C 1 -C 6 An alkyl group.
In a preferred embodiment of the 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 with one or more of the following groups, the groups are hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkoxy, unsubstituted amino or hydroxy.
In a preferred embodiment of the present invention,is that
In a preferred embodiment of the present invention,is->
In a preferred embodiment of the present invention,is->
In a preferred embodiment of the present invention,is that/>
In a preferred embodiment of the present invention,is-> />
In a preferred embodiment of the present invention, the fused ring lactam compound represented by the general formula I and/or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, stereoisomer, solvate, polymorph or prodrug thereof,
wherein:
r1 is independently selected from hydrogen, halogen, cyano, nitro, C 1 -C 6 Alkyl, C 1 -C 6 alkyl-SO 2 -、C 1 -C 6 alkyl-SO-, or C 1 -C 6 A haloalkyl group;
r2, R3 are independently selected from hydrogen, halogen, cyano, nitro, C 1 -C 6 Alkyl, C 1 -C 6 alkyl-SO 2 -、C 1 -C 6 alkyl-SO-, N (R) 2a )(R 2b )-(CH 2 ) X-; wherein R is 2a And R is 2b Each independently selected from hydrogen or C 1 -C 6 Alkyl, x is selected from any integer from 0 to 5;
r4 is independently selected from substituted or unsubstituted C 1 -C 12 Substituted or unsubstituted 3-to 12-membered cycloalkyl or heterocycloalkyl;
r5 is independently selected from one or more of hydrogen, halogen, C 1 -C 6 Alkyl, 3-6 membered cycloalkyl or heterocycloalkyl, vinyl, cyano, and the like; m is independently selected from 0 to 6;
M is independently selected from CH or N; m1 is independently selected from N or CR6;
r6 is independently selected from H, halogen, cyano, hydroxy, ether, thioether, sulfoxide, sulfone, amide, sulfonamide, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, and the like;
ra, rb, rc, rd, re, rf, rg, rh are respectively and independently selected from hydrogen, C1-C6 alkyl, alkoxy, halogenated alkyl, carboxyl and the like, or Ra, rb, rc, rd, re, rf, rg, rh form a 3-8 membered saturated or partially unsaturated ring system between two; or Rg and R6 form a 3-8 membered saturated or partially unsaturated ring system;
ar is independently selected from 5-12 membered aromatic rings or aromatic condensed rings, 5-12 membered aromatic heterocyclic rings or aromatic condensed rings; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C 1 -C 6 Alkyl, alkoxy, 3-8 membered cycloalkyl or heterocycloalkyl, C 1 -C 6 Haloalkoxy, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, substituted or unsubstituted amino, amido, sulfonamide, 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, C 1 -C 8 Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, C 1 -C 8 Alkoxy, C 1 -C 8 Alkylamino, alkenyl, alkynyl, acyl or sulfonyl, urea or sulfonylurea, 5-8 membered aryl or heteroaryl; wherein the heteroaryl group comprises 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said ring system comprising a spiro, bridged, fused, or other saturated or partially unsaturated ring system.
In a further embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, is preferably a compound of formula (IIA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, torsional isomer tautomer, solvate, polymorph or prodrug thereof:
wherein M1 is selected from N or CR6; r1, R2, R3, R4, R5, R6, ra, rb, rc, rd, re, rf, rg, rh, ar, m are as defined hereinabove.
In a still further preferred embodiment, a compound of formula (1), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, is characterized in that:
R1, R2, R3 are each independently preferably selected from hydrogen, fluoro, methyl, cyano, and the like;
ra, rb, rc, rd, re, rf, rg, rh are each independently preferably selected from hydrogen, fluoro, methyl, hydroxymethyl, cyanomethylene, and the like;
m1 is independently preferably selected from N or CH, C-F, C-Cl, C-Me, C-CN, C-OMe, C-OCF 3 、C-OCH 2 CF 3 Etc.;
m is preferably from 0,1,2;
r4 is independently preferably selected from C 4 -C 12 Alkyl or cycloalkyl or heterocycloalkyl, 3-to 8-membered cycloalkyl or heterocycloalkyl substituted alkylene, and the like;
r5 is independently selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, 3-to 5-membered cycloalkyl, vinyl, cyano, etc.;
r6 is independently selected from H, halogen, cyano, nitro, methyl, ether linkage, thioether linkage, and the like;
ar is independently preferably selected from a monocyclic aromatic group such as a substituted or unsubstituted phenyl group and a pyridyl group, or a bicyclic aromatic group such as a substituted or unsubstituted naphthyl group, naphthyridinyl group, indazolyl group, benzimidazolyl group, benzothiazolyl group, etc.; the one or more substituents are preferably selected from the group consisting of: hydrogen, halogen, C 1 -C 4 Alkyl, hydroxy, amino, cyano, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Haloalkoxy, and the like;
in a preferred embodiment of the present invention, the 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 torsional isomer thereof, a solvate thereof, a polymorph thereof or a prodrug thereof is any one of the following compounds:
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The invention also provides a preparation method of the condensed ring lactam compound shown in the general formula I, pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, which 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 a compound of formula (B) with a piperazine derivative to produce a compound of formula (C);
c) Removing the protecting group from the compound (C) to obtain a compound D;
d) Reacting the general formula compound (D) with acrylic acid/acrylic acid chloride/chloropropionyl chloride and the like to generate a general formula compound (I);
e) Converting the compound of the general formula (E) into a compound of the general formula (F) through various functional group conversion reactions;
f) Reacting a compound of formula (F) with a piperazine derivative to produce a compound of formula (G);
g) Converting the general formula compound G and arylboronic acid or arylboronic acid ester or arylmetal reagent into the general formula compound (C) through transition metal catalytic coupling reaction;
/>
wherein Cy isThe definition of each group shown is as above.
Preferably, the steps a), b), c), d), e), f), g) are each performed in a solvent, and the solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 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, dichloro-bis (triphenylphosphine) palladium, trifluoroacetic acidPalladium, triphenylphosphine palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, bis (triphenylphosphine) 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 a combination 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) carbodiimide hydrochloride (EDCI), 1-hydroxy-7-azabenzotriazol (HOAt), 1-hydroxybenzotriazol (HOBt), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytris (pyrrolidinyl) phosphonium hexafluorophosphate (PyBOP), 2- (7-azabenzotriazol) -N, N, N ', N ' -tetramethylurea Hexafluorophosphate (HATU), O-benzotriazol-N, N, N ', N ' -tetramethylurea 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 t-butoxide, sodium t-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or a combination 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 combinations 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.
It is another object of the present invention to provide a medicament for treating or preventing tumors and a composition thereof. The technical scheme for achieving the purpose is as follows:
the invention also provides a pharmaceutical composition comprising an effective amount of the condensed 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.
It is a further object of the present invention to provide the use of the above compound or pharmaceutical composition. The technical scheme for achieving the purpose is as follows:
the invention also provides application of the condensed 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, prodrugs thereof or pharmaceutical compositions thereof in preparing Ras mutant protein inhibitors.
In the application, the Ras mutant protein is preferably KRAS G12C; the Ras mutein inhibitors are useful in mammalian organisms; it is also useful in vitro, mainly as an experimental use, for example: provides comparison as a standard sample or a control sample, or is prepared into a kit according to a conventional method in the field, and provides rapid detection for the inhibition effect of Ras mutant protein.
The invention also provides application of the condensed 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, prodrugs thereof or pharmaceutical compositions thereof in preparing medicaments, wherein the medicaments are medicaments for treating diseases related to activity or expression quantity of Ras mutant proteins.
The disease related to activity or expression level of Ras mutant protein is preferably tumor. The tumor is independently 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, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal carcinoma and pancreatic cancer, preferably non-small cell lung cancer, small cell lung cancer or pancreatic cancer.
The invention also provides application of the condensed 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, prodrugs thereof or pharmaceutical compositions thereof in preparing medicaments, wherein the medicaments are tumor therapeutic medicaments.
The tumor is independently 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, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal carcinoma and pancreatic cancer, preferably non-small cell lung cancer, small cell lung cancer or pancreatic cancer.
Another aspect of the invention relates to a method for preventing and/or treating a disease associated with activity or expression of a Ras mutein comprising administering to a patient a therapeutically effective amount of a fused ring lactam compound as described above, 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 as described above, as described above.
The Ras mutant protein activity or expression 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 dose of the above-described fused ring lactam compound as shown in the general formula I, 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 tumors are as described above.
The invention relates to a compound with the structural characteristics of a general formula (I), which can inhibit various tumor cells, especially can efficiently kill tumors related to abnormal KRAS G12C mutant protein signal paths, and is a therapeutic drug with a brand-new action mechanism.
Terminology
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 hereby 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 inventive subject matter. In the present application, the singular is used to include 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" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.
The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY TH ED." vols. A (2000) and B (2001), plenum Press, new York). Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may 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 manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present application. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.
When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH 2 O-is equivalent to-OCH 2 -。
The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this disclosure, 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 simplified symbol to indicate the total number of carbon atoms present in the group. For example, C 1-6 Alkyl 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 reduced notation does not include carbon that may be present in a substituent of the group.
In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below, unless otherwise specified.
In the present application, the term "halogen" refers to fluorine, chlorine, bromine or iodine; "hydroxy" refers to an-OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted with a hydroxy (-OH); "carbonyl" refers to a-C (=o) -group; "nitro" means-NO 2 The method comprises the steps of carrying out a first treatment on the surface of the "cyano" refers to-CN; "amino" means-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the "substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., mono-, di-, alkylamido, aralkylamino, heteroaralkylamino; "carboxy" refers to-COOH.
In the present application, as part of a group or other groups (e.g., as used in halogen-substituted alkyl groups and the like), the term "alkyl" means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and linked to the rest of the molecule by a single bond. 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 part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon 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 linked to the rest of the molecule by a single bond, such as, but not limited to, ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.
In the present application, the term "alkynyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon atoms 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 linked 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, as part of a group or other group, the term "cycloalkyl" means a stable, non-aromatic, mono-or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, which may include fused ring systems, bridged ring systems, or spiro ring systems, having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the remainder 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 optionally be oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexanyl, 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 [ 2.2.2.2 ] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, bicyclo [ 2.1.1 ] octadienyl, adamantylene, and the like.
In the present application, as part of a group or other group, the term "heterocyclyl" 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 specifically indicated otherwise in the present specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include fused, bridged or spiro ring systems; aromatic condensed rings in heterocyclic groups thereof; and the heterocyclyl may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclyl 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 remainder of the molecule is a non-aromatic ring atom. For the purposes of the present application, heterocyclyl groups are preferably stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 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, dioxacyclopentyl, tetrahydroisoquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.
In the present application, the term "aryl" as part of a group or other 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 application, aryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that the aryl groups are linked to the remainder of the molecule by single bonds via atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, 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 the present application, the term "heteroaryl" as part of a group or other group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 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 present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that heteroaryl groups are attached to the remainder of the molecule via an atom on an aromatic ring by a single bond. The nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of the present application, heteroaryl groups are preferably stable 5-to 12-membered aromatic groups comprising 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-to 10-membered aromatic groups comprising 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or 5-to 6-membered aromatic groups comprising 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, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthyridinyl, [1,2,4] triazolo [4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [1, 4] triazolo [1, 4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [ 2,4] a ] 1, 4-imidazo [ 2, 4-a ] 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 the present 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 aryl groups and unsubstituted aryl groups.
The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a particular fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded or attached to a molecule.
"stereoisomers" refer to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present application is intended to cover various stereoisomers and mixtures thereof.
When an olefinic double bond is contained in the compounds of the present application, the compounds of the present application 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 application are also intended to be included within the scope of the application.
The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and thus may be produced in 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 racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography, see, for example, gerald gabiz and Martin g.schmid (eds.), chiral Separations, methods and Protocols, methods in Molecular Biology, vol.243,2004; m.stalcup, chiral Separations, annu.rev.animal.chem.3:341-63, 2010; fumigs et al (EDs.), VOGEL' S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY.sup.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 salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains 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, formate, acetate, 2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, and the like. These salts can be prepared by methods known in the art.
By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability 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 natural 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.
"polymorphs" refer to the 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 crystal form, and the present invention is intended to include various crystal forms and mixtures thereof.
In general, crystallization will produce solvates of the compounds of the present invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of a compound of the 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 monohydrate, dihydrate, hemihydrate, sesquihydrate, 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 may also retain only adventitious water or a mixture of water plus a portion of the 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 present invention are also included within the scope of the present invention.
The application also includes prodrugs of the above compounds. In the present application, the term "prodrug" means a compound that can be converted into the biologically active compound of the present application under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the application. Prodrugs may not be active when administered to an individual in need thereof, but are converted in vivo to the active compounds of the present application. Prodrugs are typically rapidly converted in vivo to the parent compounds of the present application, 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 of prodrug preparation can be found in saunnier, m.g., et al, biorg. Med. Chem. Lett.1994,4,1985-1990; greenwald, r.b., et al, j.med.chem.2000,43,475.
In the present application, "pharmaceutical composition" refers to a formulation of a compound of the present application with a medium commonly 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 promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
In the present application, "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, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.
The "tumor", "cell proliferation abnormality related disease", and the like of the present application include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, lung squamous carcinoma, 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 "prevent", "preventing" and "preventing" as used herein include reducing the likelihood of a patient from developing or worsening a disease or condition.
The term "treatment" and other similar synonyms as used herein include the following meanings:
(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;
(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;
(iii) Alleviating a disease or condition, i.e., causing the state of the disease or condition to subside; or alternatively
(iv) Alleviating symptoms caused by the disease or condition.
The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers 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 of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.
The terms "administering," "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, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Application techniques useful in the compounds and methods described herein are well known to those skilled in the art, for example, at Goodman and Gilman, the Pharmacological Basis of Therapeutics, current ed.; pergamon; and Remington's, pharmaceutical Sciences (current edition), mack Publishing co., easton, pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The terms "pharmaceutical combination", "co-administration", "administration of other treatments", "administration of other therapeutic agents" and the like as used herein refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, which includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or single dosage form. The term "ambulatory combination" refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation as separate entities to a patient at variable intervals. These also apply to cocktail therapies, for example, administration of three or more active ingredients.
It will also be appreciated by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino groups include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto-protecting groups include-C (O) -R "(wherein 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. The protecting group may also be a polymeric resin.
The above preferred conditions can be arbitrarily combined to obtain the preferred examples of the present invention without departing from the common sense in the art.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the condensed ring lactam compound can be used as KRAS G12C An inhibitor; has good anti-tumor effect.
Detailed Description
The inventor has studied deeply for a long time to prepare a compound with a novel structure shown in a formula I, and found that the compound has better KRAS G12C protein inhibition activity, and the compound has specific inhibition effect on KRAS G12C protein at a very low concentration (which can be as low as less than 100 nM), and quite excellent cell proliferation inhibition activity related to KRAS G12C, and the compound has stronger killing effect on KRAS G12C positive tumor cells at a very low concentration (which can be as low as less than 10 nM), so that the compound can be used for treating related diseases such as tumors caused by KRAS G12C mutation or abnormal expression quantity. Based on the above findings, the inventors have completed the present invention.
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Intermediate preparation
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
The first step: methyl 2, 6-dichloro-5-fluoronicotinate (20 g,89.7 mmol), 2-fluoro-6-methoxyphenylboronic acid (19.4 g,114.1 mmol) and potassium phosphate (K) 3 PO 4 ) (24.3 g,114.3 mmol) in 1, 4-dioxane/H 2 To O (200 mL/20 mL) was added a three-generation palladium catalyst (Pd-Xphos-G3) (3.75G, 4.4 mmol) and 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (Ru-phos) (4.44G, 9.5 mmol) and reacted at 60℃overnight under nitrogen. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, followed by purification by column chromatography to give methyl 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinate (8.9 g, yellow oily substance). LC-MS ESI [ M+H ]] + ＝314.3； 1 H-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)。
And a second step of: methyl 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinate (8.9 g,28.4 mmol) was dissolved in (tetrahydrofuran/water) THF/H 2 O (90 mL/45 mL) mixed solvent, lithium hydroxide monohydrate (LiOH. H) 2 O) (3.6 g,85.7 mmol) was 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 to 4, dichloromethane (DCM) was added to extract, and the organic phase was washed with saturated brine, dried and concentrated under reduced pressure to give 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid (8.3 g, yellow solid). LC-MS ESI [ M+H ] ] + ＝300.0。
And a third step of: 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid (8.3 g,27.8 mmol) was dissolved in N-methylpyrrolidinone (NMP) (25 mL), and (S) - (1-methylpyrrolidin-2-yl) methylamine (9.5 g,83.4 mmol) and N, N-Diisopropylethylamine (DIEA) were added) (10.8 g,83.4 mmol) was reacted at 180℃for 16 hours under nitrogen. The reaction solution was cooled to room temperature, and saturated ammonium chloride (NH) was slowly poured into the reaction solution 4 Cl) aqueous solution, filtering, dissolving the filter cake by methanol, drying, concentrating under reduced pressure, and purifying by column chromatography to obtain 5-fluoro-6- (2-fluoro-6-methoxyphenyl) -2- ((((S) -1-methylpyrrolin-2-yl) methyl) amino) nicotinic acid (tan oil). LC-MS ESI [ M+H ]] + ＝378.2。
Fourth step: 5-fluoro-6- (2-fluoro-6-methoxyphenyl) -2- ((((S) -1-methylpyrrolidin-2-yl) methyl) amino) nicotinic acid (2.0 g,5.3 mmol) and DIEA (4.1 g,31.8 mmol) were dissolved in THF (30 mL), triphosgene (3.1 g,10.6 mmol) was added dropwise at 0℃and reacted overnight at room temperature, and LC-MS detection showed the reaction to be complete. The reaction solution is concentrated under reduced pressure, and is purified by column chromatography to obtain 6-fluoro-7- (2-fluoro-6-methoxyphenyl) -1- (((S) -1-methylpyrroline-2-yl) methyl) -2H-pyrido [2, 3-d)][1,3]Oxazine-2, 4 (1H) -dione (640 mg, yellow solid). LC-MS ESI [ M+H ]] + ＝404.1。
Fifth step: 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 (640 mg,1.6 mmol) and ethyl cyanoacetate (200 mg,1.8 mmol) were dissolved in DMF (10 mL) and sodium hydride (NaH) (60% in mineral oil, 141mg,3.5 mmol) was added at 0℃and reacted at room temperature for 3 hours and LCMS detection showed complete reaction. Pouring into water, extracting with ethyl acetate, combining the 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 (282 mg, yellow solid). LC-MS ESI [ M+H ]] + ＝427.2。
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 (200 mg,0.47 mmol) was dissolved in phosphorus oxychloride (POCl) 3 ) To (10 mL) was added dropwise N, N-Dimethylformamide (DMF) (1 drop), and the mixture was stirred at 80℃for 2 hours. Concentrating under reduced pressure, dissolving the residue in ethyl acetate, sequentially adding 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
The first step: cyanoacetic acid (1.5 g,17.5 mmol) was dissolved in DMF (20 mL), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (8.0 g,21 mmol) and Triethylamine (TEA) (2.6 g,25.7 mmol) were added and stirred for 5 min and (S) - (1-methylpyrrolidin-2-yl) methylamine (2.0 g,17.5 mmol) was added and reacted at room temperature for 2 h. Ethyl acetate, saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give (S) -2-cyano-N- ((1-methylpyrrolidin-2-yl) methyl) acetamide (2.8 g, white solid). LC-MS ESI [ M+H ]] + ＝182.1。
And a second step of: (S) -2-cyano-N- ((1-methylpyrrolidin-2-yl) methyl) acetamide (2.8 g,15.5 mmol) was dissolved in THF (30 mL), naH (60% in mineral oil, 1.86g,46.5 mmol) was added and stirred at room temperature for 15 min, and a solution of 2, 6-dichloro-5-fluoronicotinoyl chloride (3.52 g,15.5 mmol) in THF (20 mL) was added dropwise. After the completion of the dropwise addition, the temperature was raised to 80℃and 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 (1.6 g, yellow solid). LC-MS ESI [ M+H ] ] + ＝337.1。
And a third step of: (S) -7-chloro-6-fluoro-4-hydroxy-1- ((1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (500 mg,1.49 mmol) was dissolved in POCl 3 DMF (1 drop) was added dropwise to (10 mL) and stirred at 80℃for 2 hours. Concentrating under reduced pressure, dissolving the residue in ethyl acetate, sequentially using saturated NaHCO 3 The aqueous solution was washed with water, 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
The first step: 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (1.4 g,5.3 mmol) and DIEA (4.1 g,31.8 mmol) were dissolved in THF (30 mL), triphosgene (3.1 g,10.6 mmol) was added dropwise at 0℃and reacted overnight at room temperature, and LCMS detection showed complete reaction. Concentrating the reaction solution under reduced pressure, and purifying by column chromatography to obtain 7-bromo-6-chloro-8-fluoro-2H-benzo [ d ]][1,3]Oxazine-2, 4 (1H) -dione (410 mg, yellow solid). LC-MS ESI [ M+H ]] + ＝294.3。
And a second step of: 7-bromo-6-chloro-8-fluoro-2H-benzo [ d ]][1,3]Oxazine-2, 4 (1H) -dione (410 mg,1.4 mmol) and (S) - (1-methylpyrrolidin-2-yl) methyl methanesulfonate (300 mg,1.6 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate (290 mg,2.1 mmol) was added and reacted overnight at room temperature. The reaction solution is filtered, the filtrate is concentrated under reduced pressure, and the (S) -7-bromo-6-chloro-8-fluoro-1- ((1-methylpyrroline-2-yl) methyl) -2H-benzo [ d ] is obtained by column chromatography purification ][1,3]Oxazine-2, 4 (1H) -dione (120 mg, yellow solid). LC-MS ESI [ M+H ]] + ＝391.3。
And a third step of: (S) -7-bromo-6-chloro-8-fluoro-1- ((1-methylpyrrolidin-2-yl) methyl) -2H-benzo [ d ]][1,3]Oxazine-2, 4 (1H) -dione (120 mg,0.31 mmol) and ethyl cyanoacetate (40 mg,0.35 mmol) were dissolved in DMF (5 mL), naH (60% in mineral oil, 27mg,0.68 mmol) was added at 0℃and reacted at room temperature for 3 hours, and LCMS detection showed complete reaction. Pouring into water, extracting with ethyl acetate, combining the organic phases, drying, concentrating under reduced pressure, and purifying 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 (82 mg, yellow solid). LC-MS ESI [ M+H ]] + ＝414.2。
Fourth step: (S) -7-bromo-6-chloro-8-fluoro-4-hydroxy-1- ((1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile (82 mg,0.20 mmol) was dissolved in POCl 3 To (5 mL) was added DMF (1 drop) dropwise and the mixture was stirred at 80℃for 2 hours. Concentrating under reduced pressure, dissolving the residue in ethyl acetate, sequentially using saturated NaHCO 3 The aqueous solution was washed with water, 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
The first step: 7-bromo-6-chloro-8-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2H-benzo [ d ]][1,3]Oxazine-2, 4 (1H) -dione (426 mg,1 mmol) and ethyl cyanoacetate (125 mg,1.1 mmol) were dissolved in DMF (10 mL) and NaH (60% in mineral oil, 80mg,2 mmol) was added at 0℃and reacted at room temperature to 60℃for 5 hours, and LC-MS detection showed complete reaction. Pouring into water, extracting with ethyl acetate, combining the organic phases, drying, concentrating under reduced pressure, and purifying by column chromatography to obtain 7-bromo-6-chloro-8-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile (182 mg, yellow solid). LC-MS ESI [ M+H ]] + ＝450.2/452.2。
And a second step of: the yellow solid from the previous step (90 mg,0.20 mmol) was dissolved in POCl 3 To (5 mL) was added DMF (1 drop) dropwise and the mixture was stirred at 80℃for 2 hours. Concentrating under reduced pressure, dissolving the residue in ethyl acetate, sequentially using saturated NaHCO 3 The aqueous solution and water were washed, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give intermediate 4 (yellow solid, 52 mg) 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-fluorobenzo [ 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
The first step: methyl 2, 6-dichloro-5-fluoronicotinate (20 g,89.7 mmol), (2- ((tert-butoxycarbonyl) amino) -7-fluorobenzo [ d) ]Thiazol-4-yl) boronic acid (35.6 g,114.1 mmol) and K 3 PO 4 (24.3 g,114.3 mmol) in 1, 4-dioxane/water (dioxane/H) 2 O) (200 mL/20 mL) was added Pd-Xphos-G3 (3.75G, 4.4 mmol) and Ru-phos (4.44G, 9.5 mmol) and reacted at 60℃overnight under nitrogen. The reaction solution is filtered, the filtrate is concentrated under reduced pressure, and the methyl 6- (2- ((tert-butoxycarbonyl) amino) -7-fluorobenzo [ d ] is obtained by column chromatography purification]Thiazol-4-yl) -2-chloro-5-fluoro nicotinic acid ester (10.3 g, yellow solid). LC-MS ESI [ M+H ]] + ＝456.3/458.2；
And a second step of: the yellow solid from the previous step (8.9 g,28.4 mmol) was dissolved in THF/H 2 O (90 mL/45 mL) mixed solvent, lithium hydroxide monohydrate (LiOH. H) 2 O) (3.6 g,85.7 mmol) was 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, drying, concentrating under reduced pressure to obtain 6- (2- ((tert-butoxycarbonyl) amino) -7-fluorobenzo [ d ]]Thiazol-4-yl) -2-chloro-5-fluoro-nicotinic acid (7.6 g, yellow solid). LC-MS ESI [ M+H ]] + ＝442.1/444.1。
And a third step of: the yellow solid (7.5 g,17 mmol) from the previous step was dissolved in NMP (25 mL) and 2-isopropyl-4-methylpyridin-3-amine (5.1 g,34 mmol) and DIEA (10.8 g,83.4 mmol) were added and reacted for 2 hours under a 180℃microwave under nitrogen. The reaction solution is cooled to room temperature, and saturated NH is slowly poured in 4 In Cl water solution, filtering, dissolving filter cake by methanol, drying, decompressing and concentrating, purifying by column chromatography to obtain 5-fluoro-6- (2-fluoro-6-methoxyphenyl) -2- ((((S) -1-methylpyrrolin-2-yl) methyl) amino) nicotinic acid (tan oil). LC-MS ESI [ M+H ]] + ＝378.2。
Fourth step: the yellow solid from the previous step (2.9 g,5.3 mmol) and DIEA (4.1 g,31.8 mmol) were dissolved in THF (30 mL) and triphosgene (3.1 g,10.6 mmol) was added dropwise at 0℃and reacted overnight at room temperature and the reaction was complete as detected by LC-MS. 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 (640 mg, yellow solid). LC-MS ESI [ M+H ]] + ＝582.1。
Fifth step: the above yellow solid (930 mg,1.6 mmol) and cyano group were reactedEthyl acetate (200 mg,1.8 mmol) was dissolved in DMF (10 mL) and NaH (60% suspended in mineral oil, 141mg,3.5 mmol) was added at 0℃and reacted at room temperature to 80℃for 3 hours, and LC-MS detection showed completion of the reaction. Pouring into water, extracting with ethyl acetate, mixing the organic phases, drying, 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-fluorobenzo [ d) ]Thiazol-2-yl) formate (282 mg, yellow solid). LC-MS ESI [ M+H ]] + ＝605.2。
Sixth step: the yellow solid from the previous step (284 mg,0.47 mmol) was dissolved in POCl 3 DMF (1 drop) was added dropwise to (10 mL) and stirred at 80℃for 2 hours. Concentrating under reduced pressure, dissolving the residue in ethyl acetate, sequentially using saturated NaHCO 3 The aqueous solution and water were washed, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give intermediate 5 (yellow solid, 92 mg), which was used in the next reaction without further purification. LC-MS ESI [ M+H ]] + ＝523.2/525.2。
Example preparation
Example 1:4- (4-propenoylpiperazin-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
The first step: 2, 6-dichloro-5-fluoronicotinic acid (100 g,478.5 mmol) was dissolved in methanol (1.0L) and thionyl chloride (SOCl) was added dropwise at 0 ℃ 2 ) (69 mL,949.8 mmol) was refluxed for 4 hours under nitrogen. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was taken up in Dichloromethane (DCM) and taken up in sodium bicarbonate (NaHCO) 3 ) The saturated solution was washed twice with saturated brine, dried and concentrated under reduced pressure to give methyl 2, 6-dichloro-5-fluoronicotinate (106 g, yellow oil). LC-MS ESI [ M+H ]] + ＝224.0； 1 H NMR(400MHz,CDCl 3 ):δ8.01(d,J＝7.6MHz,1H),3.98(s,3H)。
And a second step of: methyl 2, 6-dichloro-5-fluoronicotinic acid (20 g,89.7 mmol), (2-fluoro-6-methoxyphenyl) borate (19.4 g,114.1 mmol) and potassium phosphate (K) 3 PO 4 ) (24.3 g,114.6 mmol) in 1, 4-dioxane/H 2 To O (200 mL/20 mL) was added methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (Pd-Xphos-G3) (3.75G, 4.76 mmol) and 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl (Ru-phos) (4.44G, 9.52 mmol), and the mixture was reacted overnight at 60℃under nitrogen. The reaction solution 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 (8.92 g, yellow oil). LC-MS ESI [ M+H ]] + ＝314.3； 1 H 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)。
And a third step of: methyl 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinate (8.92 g,28.5 mmol) was dissolved in tetrahydrofuran/water (THF/H) 2 O) (90 mL/45 mL) to LiOH.H 2 O (3.58 g,85.2 mmol) was 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, extracted with DCM, and the organic phases were combined, washed with saturated brine, dried, and concentrated under reduced pressure to give 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid (8.33 g, yellow solid). LC-MS ESI [ M+H ]] + ＝300.0。
Fourth step: 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid (8.33 g,27.9 mmol) was dissolved in N-methylpyrrolidone (NMP) (25 mL) and p-methoxybenzylamine (PMB-NH) was added 2 ) (11.44 g,83.5 mmol) and N, N-Diisopropylethylamine (DIPEA) (10.77 g,83.5 mmol) were reacted at 180℃for 16 hours under nitrogen. The reaction solution was cooled to room temperature, and saturated ammonium chloride (NH) was slowly poured into the reaction solution 4 Cl) aqueous solution, filtering, dissolving the filter cake with 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 (13.6 g, tan oil, crude product). LC-MS ESI [ M+H ]] + ＝401.1。
Fifth step: 5-fluoro-6- (2-fluoro-6-methoxyphenyl-2- ((4-methoxybenzyl) amino) nicotinic acid (9.6 g, crude) was dissolved in methanol (MeOH) (100 mL) and trimethylsilylated diazomethane (TMSCHN) was added 2 ) (2.0M in n-hexane, 18mL,36 mmol) was 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 (5.4 g, yellow oily substance). LC-MS: ESI [ M+H)] + ＝415.4。
Sixth step: methyl 5-fluoro-6- (2-fluoro-6-methoxyphenyl-2- ((4-methoxybenzyl) amino) nicotinic acid (5.4 g,13.0 mmol) was dissolved in trifluoroacetic acid (TFA) (14 mL) and DCM (30 mL), heated to 40℃for 3 hours, and the reaction mixture was concentrated under reduced pressure and then dissolved in 100mL ethyl acetate, and concentrated under reduced pressure with saturated sodium carbonate (Na 2 CO 3 ) 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 (3.7 g, yellow solid). LC-MS ESI [ M+H ]] + ＝295.3。
Seventh step: na (2.7 g,117.4 mmol) was slowly added to absolute ethanol (EtOH) (50 mL), stirred at room temperature until sodium particles completely disappeared, methyl 2-amino-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinate (3.7 g,12.6 mmol) and diethyl malonate (4.0 g,25.0 mmol) were added and the reaction was heated to 120℃in a stirred tank 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 (1.1 g, yellow solid). LC-MS ESI [ M+H ]] + ＝377.4。
Eighth step: 6-fluoro-7- (2-fluoro-6-methoxyphenyl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxylic acid ethyl ester (700 mg,1.9 mmol) was dissolved in EtOH (70 mL) and concentrated ammonia (3.5 mL) and the pot was heated to 120℃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 (680 mg, pale yellow solid, crude product). LC-MS ESI [ M+H ]] + ＝348.6。
Ninth step: 6-fluoro-7- (2-fluoro-6-methoxyphenyl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide (680 mg, crude) was dissolved in phosphorus oxychloride (POCl) 3 ) (10 mL) was heated to 110℃and reacted for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and then dissolved in 10mL of ethyl acetate, and saturated NaHCO was used 3 The aqueous solution is adjusted to be alkaline, and is separatedThe organic layer was dried and concentrated under reduced pressure to give 2, 4-dichloro-6-fluoro-7- (2-fluoro-6-methoxyphenyl) -1, 8-naphthyridine-3-carbonitrile (670 mg, red solid). LC-MS ESI [ M+H ]] + ＝366.3。
Tenth step: 2, 4-dichloro-6-fluoro-7- (2-fluoro-6-methoxyphenyl) -1, 8-naphthyridine-3-carbonitrile (670 mg,1.8 mmol), 1-benzyloxycarbonyl-piperazine (306 mg,1.4 mmol) and DIPEA (1.2 g,9.3 mmol) were dissolved in 1.4-dioxane (20 mL) and reacted overnight at room temperature. 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-methoxyphenyl) -1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (605 mg, red solid). LC-MS ESI [ M+H ]] + ＝550.6。
Eleventh step: benzyl 4- (2-chloro-3-cyano-6-fluoro-7- (2-fluoro-6-methoxyphenyl) -1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (605 mg,1.1 mmol) was dissolved in TFA (2.5 mL) and water (0.5 mL) and heated to 120 degrees overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and ethyl acetate was added to the residue, which was 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 (690 mg, red solid, crude product). LC-MS ESI [ M+H ] ] + ＝398.5。
Twelfth step: 6-fluoro-7- (2-fluoro-6-methoxyphenyl) -2-oxo-4- (piperazin-1-yl) -1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (690 mg, crude) was dissolved in DCM (20 mL), TEA (1.9 g,19 mmol) and (Boc) were added 2 O (8238 mg,3.8 mmol) was 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 (280 mg, yellow solid). LC-MS ESI [ M+H ]] + ＝498.5。
Thirteenth step: 4- (3-cyano-6-fluoro-7- (2-fluoro-6-methoxyphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (280 mg,0.56 mmol) and (S) -2- (chloromethyl) -1-methylpyrrolidine hydrochloride (137 mg,0.81 mmol) were dissolved in DMF (6 mL) and potassium carbonate (K) was added 2 CO 3 ) (308 mg,2.23 mmol) was reacted at room temperature for 3 hours. The reaction mixture was diluted with 50mL of ethyl acetate, washed twice with water, dried, and concentrated under reduced pressureTo 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 (332 mg, red solid, crude). LC-MS ESI [ M+H ]] + ＝595.7。
Fourteenth step: 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-carboxylic acid tert-butyl ester (24 mg,0.04 mmol) was dissolved in DCM (1 mL) and boron tribromide (BBr) was added dropwise at-78 degrees 3 ) (1.0M in DCM,1.4mL) slowly warmed to room temperature and reacted overnight. Methanol (MeOH) (5 mL) was added to the reaction mixture to quench the reaction, followed by Na addition 2 CO 3 The solid was neutralized, filtered, and the filtrate 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 (35 mg, yellow solid, crude). LC-MS ESI [ M+H ]] + ＝481.6。
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 (35 mg, crude) and TEA (0.3 mL) were dissolved in DCM (1 mL), and acryloyl chloride (1 drop) was added at room temperature and reacted for 2 hours at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 2- (5- (4-propenoylpiperazin-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 (40 mg, yellow solid, crude product). LC-MS ESI [ M+H ]] + ＝589.7。
Sixteenth step: 2- (5- (4-propenoylpiperazin-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 (40 mg, crude) was dissolved in THF (2 mL), 10% aqueous sodium hydroxide (NaOH) solution (1 mL) was added at room temperature, and the reaction was carried out at room temperature for 3 hours. The reaction mixture 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 title compound (yellow solid). LC-MS ESI [ M+H ] ] + ＝535.2； 1 H-NMR(CD 3 OD,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-propenoyl-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
The title compound was prepared by the synthetic method of reference example 1, substituting (S) -2-methyl-4-Boc piperazine for N-Boc piperazine. LC-MS [ M+H ]] + :m/z 549.2。 1 H NMR(400MHz,DMSO-d 6 )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-propenoyl-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
The first step: intermediate 2 (814 mg,2.3 mmol) was dissolved in 1, 4-dioxane (10 mL) and DIPEA (0.58 g,4.6 mmol) and tert-butyl (S) -3-methylpiperazine-1-carboxylate (0.51 g,2.5 mmol) were added. Heating to 50deg.C under stirring overnight, concentrating under reduced pressure, and purifying the residue by column chromatography to give (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 (710 mg, yellow solid). LC-MS ESI [ M+H ]] + ＝519.2。
And a second step of: (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 (710 mg,1.4 mmol) and 5-methyl-1H-indazole-4-boronic acid (271mg, 1.5 mmol) were dissolved in 1, 4-di- Oxaline (10 mL), water (1 mL), sodium carbonate (445 mg,4.2 mmol) and Pd (PPh) 3 ) 4 (81 mg,0.07 mmol), nitrogen displacement, heating to 90 degrees and reacting overnight, LCMS detection showed complete reaction. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by column chromatography to give (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-carboxylic acid tert-butyl ester (420 mg, yellow solid). LC-MS ESI [ M+H ]] + ＝615.3。
And a third step of: (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-carboxylic acid tert-butyl ester (420 mg,0.68 mmol) was dissolved in DCM (4 mL), TFA (2 mL) was added and stirred at room temperature for 4 hours. Concentration under reduced pressure afforded 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 (510 mg, crude, yellow solid). LC-MS ESI [ M+H ]] + ＝515.3。
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 (120 mg, crude) was dissolved in dichloromethane (10 mL), DIPEA (70 mg,0.54 mmol) and acryloyl chloride (17 mg,0.19 mmol) were added sequentially at 0℃and stirred at room temperature for 2 hours. The reaction solution 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-propenoyl-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
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The first step: intermediate 3 (991 mg,2.3 mmol) was dissolved in 1, 4-dioxane (10 mL),DIPEA (0.58 g,4.6 mmol) and (R) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (0.51 g,2.5 mmol) were added. Heating to 50deg.C under stirring overnight, concentrating under reduced pressure, and purifying the residue by column chromatography to give tert-butyl (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-carboxylate (774 mg, yellow solid). LC-MS ESI [ M+H ]] + ＝596.2。
And a second step of: (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 (774 mg,1.3 mmol) and 5-methyl-1H-indazole-4-boronic acid (271mg, 1.5 mmol) were dissolved in 1, 4-dioxane (10 mL), water (1 mL), sodium carbonate (445 mg,4.2 mmol) and Pd (PPh) were added 3 ) 4 (81 mg,0.07 mmol), nitrogen displacement, heating to 90 degrees and reacting overnight, LCMS detection showed complete reaction. 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 (440 mg, yellow solid). LC-MS ESI [ M+H ] ] + ＝648.3。
And a third step of: (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-dihydro-quinolin-4-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (440 mg,0.68 mmol) was dissolved in DCM (4 mL), trifluoroacetic acid (TFA) (2 mL) was added and stirred at room temperature for 4 hours. Concentration under reduced pressure afforded 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 (530 mg, crude, yellow solid). LC-MS ESI [ M+H ]] + ＝548.3。
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 (150 mg, crude) was dissolved in dichloromethane (10 mL), DIPEA (70 mg,0.54 mmol) and acryloyl chloride (17 mg,0.19 mmol) 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 brineDrying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the residue by preparative chromatography to give the target compound (yellow solid). LC-MS ESI [ M+H ]] + ＝602.2。
Example 5:4- ((S) -4-propenoyl-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
The synthesis of example 4 gave the target compound, LC-MS: ESI [ M+H ]] + ＝582.2。 1 H 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-propenoyl-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
The first step: sodium (Na) pellets (3.2 g,139.1 mmol) were added to EtOH (250 mL) in portions and stirred at room temperature until the Na pellets completely disappeared, ethyl 5-amino-1-benzyl-1, 2,3, 6-tetrahydropyridine-4-carboxylate (18.0 g,69.2 mmol) and ethyl cyanoacetate (15.7 g,138.9 mmol) were added and the pot heated to 120℃for three days. After cooling, the mixture was filtered and the filter cake EtOH was purified by beating to give 7-benzyl-2, 4-dihydroxy-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-3-carbonitrile (15.4 g, yellow solid). LC-MS ESI [ M+H ]] + ＝282.3。
And a second step of: 7-benzyl-2, 4-dihydroxy-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-3-carbonitrile (5.0 g,17.8 mmol), trifluoromethanesulfonic anhydride (15.0 g,53.4 mmol) and TEA (7.2 g,71.3 mmol) were dissolved in DCM (50 mL) and stirred at room temperature overnight. Concentrating under reduced pressure, and purifying the residue by column chromatography to obtain 7-benzyl-3-cyano-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-2, 4-diylbis (trifluoromethanesulfonic acid)Ester) (3.1 g, yellow solid). LC-MS ESI [ M+H ]] + ＝546.1。
And a third step of: 7-benzyl-3-cyano-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-2, 4-diylbis (trifluoromethanesulfonate) (3.1 g,5.7 mmol) was dissolved in 1, 4-dioxane (30 mL), and DIPEA (2.9 g,22.8 mmol) and (S) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.16 g,5.7 mmol) were added. Heating to 60 ℃ and stirring overnight, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain (S) -4- (7-benzyl-3-cyano-2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.7 g, yellow solid). LC-MS ESI [ M+H ] ] + ＝464.2。
Fourth step: (S) -4- (7-benzyl-3-cyano-2-oxo-1, 2,5,6,7, 8-hexahydro-1, 7-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.7 g,3.7 mmol) and (S) - (1-methylpyrrolidin-2-yl) methanesulfonate (0.77 g,4.1 mmol) were dissolved in acetonitrile (20 mL), and potassium carbonate (0.77 g,5.6 mmol) was added and reacted overnight at room temperature. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to give (S) -tert-butyl 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 (1.4 g, yellow solid). LC-MS ESI [ M+H ]] + ＝561.3。
Fifth step: (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-carboxylic acid tert-butyl ester (1.4 g,2.5 mmol) was dissolved in MeOH (30 mL), 10% Pd/C (140 mg) was added and reacted overnight at room temperature and LC-MS detection showed complete reaction. Filtration and concentration of the filtrate under reduced pressure gave (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 (0.93 g, yellow solid) which was used directly in the next reaction. LC-MS ESI [ M+H ]] + ＝471.3。
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 (0.93 g,2.0 mmol) and 4-bromo-5-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole (1.02 g,3.0 mmol) were dissolved in 1, 4-dioxane (20 mL) and carbon was added under argon protection, respectively Cesium acid (Cs) 2 CO 3 ) (1.63G, 5.0 mmol), ru-phos (187 mg,0.40 mmol) and Pd-Ruphos-G3 (84 mg,0.10 mmol) were replaced three times with argon after the addition and heated to 110℃overnight, and LC-MS showed complete reaction. 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 (0.46 g, yellow solid). LC-MS ESI [ M+H ]] + ＝731.4。
Seventh step: (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-carboxylic acid tert-butyl ester (460 mg,0.63 mmol) was dissolved in DCM (4 mL), TFA (2 mL) was added and stirred at room temperature for 4 hours. Concentrating under reduced pressure to give 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 (510 mg, crude, yellow solid). LC-MS: ESI [ M+H)] + ＝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 (120 mg, crude product) was dissolved in dichloromethane (10 mL), DIPEA (70 mg,0.54 mmol) and acryloyl chloride (17 mg,0.19 mmol) were added sequentially at 0deg.C, and stirred at room temperature for 2 hours, the reaction solution was washed with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative chromatography to give the title compound (yellow solid). LC-MS: ESI [ M+H) ] + ＝555.3。 1 H NMR(400MHz,CD 3 OD):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
The synthesis of example 6 gave the target compound, LC-MS: ESI [ M+H ]] + ＝628.3/630.2。 1 H-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-propenoyl-3- (2-fluoro-6-hydroxyphenyl) -5- (((S) -1-methylpyrrolidin-2-yl) methyl) -1,3,4,5, 8a,9,10,11, 12-decahydropyrazine [1',2':4,5] [1,4] oxazine [2,3-c ] [1,7] naphthyridin-6 (2H) -one
The first step: sodium (Na) beads (3.2 g,139.1 mmol) were added to EtOH (250 mL) in portions and stirred at room temperature until the Na beads completely disappeared, ethyl 5-amino-1-benzyl-1, 2,3, 6-tetrahydropyridine-4-carboxylate (18.0 g,69.2 mmol) and diethyl malonate (22.2 g,138.8 mmol) were added and the pot was heated to 120℃for four days. After cooling, the mixture was filtered and the filter cake EtOH was purified by beating to give ethyl 7-benzyl-2, 4-dihydroxy-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-3-carboxylate (22.3 g, yellow solid). LC-MS ESI [ M+H ]] + ＝329.4。
And a second step of: 7-benzyl-2, 4-dihydroxy-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-3-carboxylic acid ethyl ester (22.3 g,68.0 mmol) was added to a 3M aqueous HCl solution (200 mL) and reacted at 100℃for 16 hours. Concentrated under reduced pressure to give 7-benzyl-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-2, 4-diphenol hydrochloride (17.5 g, yellow solid) which was used directly in the next reaction. LC-MS ESI [ M+H ] ] + ＝256.9。
And a third step of: 7-benzyl-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-2, 4-diphenol hydrochloride (4.0 g,13.7 mmol) was dissolved in MeOH (100 mL), 10% Pd/C (400 mg) was added and reacted for 2 days at room temperature, and LC-MS detection showed complete reactionAll of them. Filtration and concentration of the filtrate under reduced pressure gave 5,6,7, 8-tetrahydro-1, 7-naphthyridine-2, 4-diphenol hydrochloride (2.8 g, white solid) which was used directly in the next reaction. LC-MS ESI [ M+H ]] + ＝167.1。
Fourth step: 5,6,7, 8-tetrahydro-1, 7-naphthyridine-2, 4-diphenol hydrochloride (7.9 g,39.1 mmol), trifluoroacetic anhydride (8.2 g,39.1 mmol) and TEA (11.8 g,117.3 mmol) were dissolved in DCM (80 mL) and stirred at room temperature overnight. Concentrating under reduced pressure, and purifying the residue by column chromatography to obtain 1- (2, 4-dihydroxy-5, 8-dihydro-1, 7-naphthyridin-7 (6H) -yl) -2, 2-trifluoroethyl-1-one (3.0 g, white solid). LC-MS ESI [ M+H ]] + ＝263.0； 1 H-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)。
Fifth step: 1- (2, 4-dihydroxy-5, 8-dihydro-1, 7-naphthyridin-7 (6H) -yl) -2, 2-trifluoroethyl-1-one (2.1 g,8.0 mmol) was dissolved in concentrated sulfuric acid (60 mL) and 70% nitric acid (HNO) was added dropwise at 0 degree 3 ) (6 mL), and reacted at room temperature for 1 hour. Pouring into an ice-water mixture, filtering out yellow solid, concentrating the water phase after extracting with DCM, combining and pulping with water to obtain 1- (2, 4-dihydroxyl-3-nitro-5, 8-dihydro-1, 7-naphthyridin-7 (6H) -yl) -2, 2-trifluoroethyl-1-ketone (1.6 g, yellow solid). LC-MS ESI [ M+H ] ] + ＝308.0； 1 H-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)。
Sixth step: 1- (2, 4-dihydroxy-3-nitro-5, 8-dihydro-1, 7-naphthyridin-7 (6H) -yl) -2, 2-trifluoroethyl-1-one (69mg, 2.25 mmol) was dissolved in POCl 3 DMF (2 drops) was added dropwise to (10 mL) and stirred at 80℃for 3 hours. Concentrating under reduced pressure, dissolving the residue in ethyl acetate, sequentially using saturated NaHCO 3 Washing the aqueous solution with water, drying over anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain 1- (2, 4-dichloro-3-nitro-5, 8-dihydro-1, 7-naphthyridin-7 (6H) -yl) -2, 2-trifluoroethyl-1-one (yellow solid). LC-MS ESI [ M+H ]] + ＝344.2/346.2； 1 H-NMR(DMSO_d6,400MHz)：4.84-4.86(m,2H),3.94(brs,2H),2.95-3.01(m,2H)。
Seventh step: 1- (2, 4-dichloro-3-nitro-5, 8-dihydro-1, 7-naphthyridin-7 (6H) -yl) -2, 2-trifluoroethyl-1-one (2.0 g,5.7 mmol) was dissolved in 1, 4-dioxane (30 mL) and DIPEA (2) was added.9g,22.8 mmol) and tert-butyl (R) -3- (hydroxymethyl) piperazine-1-carboxylate (1.23 g,5.7 mmol). Heating to 60 ℃ and stirring overnight, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain (R) -4- (2-chloro-3-nitro-7- (2, 2-trifluoroacetyl) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (1.6 g, yellow solid). LC-MS ESI [ M+H ]] + ＝524.2。
Eighth step: (R) -4- (2-chloro-3-nitro-7- (2, 2-trifluoroacetyl) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (1.6 g,3.1 mmol) was dissolved in 1, 4-dioxane (30 mL), 2N sodium hydroxide solution (16 mL,32 mmol) was added and the reaction was carried out overnight at room temperature. The pH was adjusted to 7 with 2N hydrochloric acid, concentrated under reduced pressure, extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered, 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 (1.2 g, yellow solid) which was used directly in the next reaction. LC-MS ESI [ M+H ] ] + ＝410.2。
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 (0.82 g,2.0 mmol) and 2-bromo-1-fluoro-3-methoxybenzene (0.61 g,3.0 mmol) were dissolved in 1, 4-dioxane (20 mL) and Cs were added under argon protection, respectively 2 CO 3 (1.63G, 5.0 mmol), ru-phos (187 mg,0.40 mmol) and Pd-Ruphos-G3 (84 mg,0.10 mmol) were replaced three times with argon after the addition, heated to 110℃overnight, and LCMS showed complete reaction. Cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to give (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-carboxylic acid tert-butyl ester (0.44 g, yellow solid). LC-MS ESI [ M+H ]] + ＝534.3。
Tenth step: (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-carboxylic acid tert-butyl ester (0.44 g,0.83 mmol) and (S) - (1-methylpyrrolidin-2-yl) methyl methanesulfonate (0.17 g,0.91 mmol) were dissolved in acetonitrile (20 mL) and potassium carbonate (0.17 g,1.2 mmol) was added and reacted overnight at room temperature. The reaction solution is filtered, the filtrate is concentrated under reduced pressure, and the (R) -4- (7- (2-fluoro-6-methoxyphenyl) -1- ((. About.m.) is obtained by column chromatography purificationS) -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-carboxylic acid tert-butyl ester (0.4 g, yellow solid). LC-MS ESI [ M+H ] ] + ＝631.3。
Eleventh step: (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-carboxylic acid tert-butyl ester (0.4 g,0.63 mmol) was dissolved in NMP (5 mL), liHMDS (1M, 0.63mL,0.63 mmol) was added and heated to 100℃under nitrogen and stirred for 8 hours. Cooling the reaction liquid to room temperature, pouring the reaction liquid into a saturated ammonium chloride aqueous solution, extracting with dichloromethane, drying, decompressing and concentrating, and purifying by column chromatography to obtain (R) -3- (2-fluoro-6-methoxyphenyl) -5- (((S) -1-methylpyrroline-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。
Twelfth step: (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 (95 mg,0.16 mmol) was dissolved in dichloromethane (10 mL), cooled to-78 degrees, boron tribromide (1M, 1.6mL,1.6 mmol) was added dropwise, and the mixture was allowed to warm to room temperature naturally and stirred overnight. Quenching with methanol, concentrating under reduced pressure, dissolving the residue in dichloromethane, and extracting with saturated NaHCO 3 The aqueous solution was washed twice, the organic phase was dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by column chromatography to give (R) -3- (2-fluoro-6-hydroxyphenyl) -5- (((S) -1-methylpyrrolidin-2-yl) methyl) -1,3,4,5, 8a,9,10,11, 12-decahydropyrazine [1',2':4, 5)][1,4]Oxazines [2,3-c][1,7]Naphthyridin-6 (2H) -one (45 mg, yellow solid). LC-MS ESI [ M+H ]] + ＝470.1。
Thirteenth step: (R) -3- (2-fluoro-6-hydroxyphenyl) -5- (((S) -1-methylpyrrolidin-2-yl) methyl) -1,3,4,5, 8a,9,10,11, 12-decahydropyrazine [1',2':4,5] [1,4] oxazine [2,3-c ] [1,7] naphthyridin-6 (2H) -one
(45 mg,0.10 mmol) was dissolved in dichloromethane (5 mL), DIPEA (40 mg,0.30 mmol) and acryloyl chloride (10 mg,0.11 mmol) were added sequentially at 0℃and stirred at room temperature for 2 hours. Reverse-rotationThe reaction solution 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 title compound (yellow solid, 5.2 mg). LC-MS ESI [ M+H ]] + ＝524.2。
Example 9: (8 aR, 11R) -10-propenoyl-3- (2-fluoro-6-hydroxyphenyl) -11-methyl-5- (((S) -1-methylpyrrolidin-2-yl) methyl) -1,3,4,5, 8a,9,10,11, 12-decahydropyrazine [1',2':4,5] [1,4] oxazine [2,3-c ] [1,7] naphthyridin-6 (2H) -one
The title compound (yellow solid, 3.5 mg), LC-MS: ESI [ M+H ] was prepared by the synthesis method of example 8 ] + ＝538.2。
Example 10:4- ((R) -3- (cyanomethylene) -4- (2-fluoropropenoyl) 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
The title compound (white solid, 12 mg), LC-MS: ESI [ M+H ] was prepared by the synthesis method of example 6] + ＝608.1。 1 H NMR(400MHz,MeOD-d 4 ):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-propenoyl-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
The title compound (white solid, 18 mg), LC-MS: ESI [ M+H ] was prepared by the synthesis method of example 6] + ＝610.1/612.2。 1 H NMR(400MHz,CD 3 OD):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
The title compound (white solid, 4.3 mg), LC-MS: ESI [ M+H ] was prepared by the synthesis method of example 6] + ＝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-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile
The first step: (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 (480 mg,0.75 mmol), cyclopropylboronic acid (130 mg,1.5 mmol) was dissolved in 1, 4-dioxane (10 mL), water (1 mL), sodium carbonate (445 mg,4.2 mmol) and Pd (PPh) were added 3 ) 4 (81 mg,0.07 mmol), nitrogen displacement, heating to 90 degrees and reacting overnight, LCMS detection showed complete reaction. 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-methylpiperazine-1-carboxylate (105 mg, yellow solid), LC-MS: ESI [ M+H ]] + ＝654.2。
Second, three steps: the title compound (25 mg, yellow solid) was obtained by the same procedures as in the third and fourth steps of example 4, 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-carbonitrile
The same procedures as in example 13 were employed to prepare the title compound (5 mg, yellow solid), LC-MS: ESI [ M+H ]] + ＝694.2。
Example 15;4- ((R) -4-propenoyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-8-fluoro-1- (((S) -1-methyl pyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile
The title compound (yellow solid, 8 mg), LC-MS: ESI [ M+H ] was prepared by the synthesis method of example 4 ] + ＝649.2/651.2。
EXAMPLE 16 4- (4-Acrylpiperazin-1-yl) -7- (2-amino-7-fluorobenzo [ d ] thiazol-4-yl) -6-chloro-8-fluoro-1- (((S) -1-methyl-pyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-quinoline-3-carbonitrile
The title compound (yellow solid, 12 mg), LC-MS: ESI [ M+H ] was prepared by the synthesis method of example 4] + ＝624.1/626.1。 1 H-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-propenoyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-fluoro-1- (((S) -1-methyl pyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
The title compound (off-white solid, 9 mg), LC-MS: ESI [ M+H ] was prepared by the method of synthesis according to example 4] + ＝616.3/618.3。
Example 18: (S) -4- (4-Acrylpiperazin-1-yl) -7- (2-amino-7-fluoro-benzo [ d ] thiazol-4-yl) -6-fluoro-1- ((1-methyl-pyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
The title compound (yellow solid, 10 mg), LC-MS: ESI [ M+H ] was prepared by the synthesis method of example 4] + ＝591.0/593.1。
Example 19:4- (4-propenoylpiperazin-1-yl) -7- (2-amino-7-fluoro-benzo [ d ] thiazol-4-yl) -8-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile
The first step: intermediate 4 (1.1 g,2.3 mmol) was dissolved in 1, 4-dioxane (10 mL) and DIPEA (0.58 g,4.6 mmol) and tert-butyl piperazine-1-carboxylate (460 mg,2.5 mmol) were added. Heating to 50deg.C under stirring overnight, concentrating under reduced pressure, and purifying the residue 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 (650 mg, yellow solid). LC-MS ESI [ M+H ] ] + ＝618.2/620.2。
And a second step of: the solid obtained in the previous step (803 mg,1.3 mmol) and (2- ((tert-butoxycarbonyl) amino) -7-fluorobenzo [ d ]]Thiazol-4-yl) boronic acid (470 mg,1.5 mmol) was dissolved in 1, 4-dioxane (10 mL), water (1 mL), sodium carbonate (445 mg,4.2 mmol) and tetrakis (triphenylene) were addedPhosphine) palladium (Pd (PPh) 3 ) 4 ) (81 mg,0.07 mmol), nitrogen displacement, heating to 90 degrees and reacting overnight, LCMS detection showed complete reaction. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by column chromatography to give tert-butyl 4- (7- (2- ((tert-butoxycarbonyl) amino) -7-fluorobenzo [ d)]Thiazole-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 (435 mg, yellow solid). LC-MS ESI [ M+H ]] + ＝806.3/808.3。
And a third step of: the yellow solid (480 mg,0.68 mmol) obtained in the previous step was dissolved in DCM (4 mL), TFA (2 mL) 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 (410 mg, crude, yellow solid). LC-MS ESI [ M+H ]] + ＝706.1/708.1。
Fourth step: the product (150 mg, crude) obtained in the above step was dissolved in methylene chloride (10 mL), DIPEA (70 mg,0.54 mmol) and acryloyl chloride (17 mg,0.19 mmol) were added sequentially at 0℃and stirred at room temperature for 2 hours. The reaction solution 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 title compound (yellow solid, 40 mg). MS ESI [ M+H ] ] + ＝660.2/662.2。 1 H NMR(400MHz,MeOD-d 4 ):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-propenoyl-3-methylpiperazin-1-yl) -7- (2-amino-7-fluorobenzo [ d ] thiazol-4-yl) -8-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile
The same procedures used in example 19 were repeated except for using intermediate 4 and tert-butyl (R) -2-methylpiperazine-1-carboxylate as raw materials to give the example20 (yellow solid, 23 mg). LC-MS ESI [ M+H ]] + ＝674.2/676.2。/>
Example 21:4- ((R) -4-propenoyl-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
Example 21 (yellow solid, 19 mg) was prepared in the same manner as in example 19 using intermediate 4 and tert-butyl (R) -2-methylpiperazine-1-carboxylate as starting materials. LC-MS ESI [ M+H ]] + ＝685.2/687.2。
Example 22:4- (4-propenoylpiperazin-1-yl) -7- (2-amino-7-fluoro-benzo [ d ] thiazol-4-yl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
Example 22 (yellow solid, 13 mg) was prepared in the same manner as in example 19 using intermediate 5 and tert-butylmethylpiperazine-1-carboxylate as starting materials. LC-MS ESI [ M+H ]] + ＝627.3/629.3。 1 H NMR(400MHz,MeOD-d 4 ):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-propenoyl-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
Example 22 (yellow solid, 18 mg) was prepared in the same manner as in example 19 using intermediate 5 and tert-butyl (R) -2-methylpiperazine-1-carboxylate as starting materials. LC-MS ESI [ M+H ]] + ＝638.2/640.2。
Test example 1 Kras G12C Functional analysis
Test method 1: all enzyme and substrate solutions were buffered with reaction buffer (20 mM HEPES (pH 7.5), 5mM MgCl 2 150mM NaCl and 0.01% tween 20). The experimental procedure was as follows: biotinylated KRAS loaded with GDP was formulated with 10nM using reaction buffer G12C And 37.5ng/ml of streptavidin europium cryptate, 5. Mu.L of the above protein reaction solution was added to each well of a 384-well HiBase micro polystyrene microplate, while a test sample or control compound prepared from DMSO was added and incubated for 4 hours. In addition, 20nM GST-Raf Ras binding domain (GST-Raf RBD) and 4. Mu.g/mL anti-GST XL665 antibody (Cisbio) were mixed separately, formulated in reaction buffer (50 mM potassium fluoride and 0.05mg/mL BSA), and after equilibration for 4 hours 0.6. Mu.M GTPγS (Sigma) and 0.08. Mu.M SOS were added. mu.L of GST-RAF RBD mix was added to each well of the microplate. The addition of the mixed solution in this step initiates the nucleotide exchange reaction, which promotes KRAS of the non-activated supported GDP G12C Conversion to activated GTPγS KRAS G12C . Activated GTPγS KRAS G12C Specific binding to GST-RAF RBD pulls in europium and XL665 distance to enhance FRET signal, which is detected using Pherastar (BMG) reader equipped with HTRF filter module. Any compound that inhibited nucleotide exchange or activated KRAS binding to RAF RBD resulted in a decrease in FRET signal was curve fitted to FRET dose-response data using Genedata Screener and IC was calculated 50 .
Test method 2: KRAS using CisBio G12C SOS1 kit for testing compound inhibition SOS1 and KRAS by using Binding assay method G12C Efficacy of protein-protein interactions between them, as a result of IC 50 The value represents.
The testing method comprises the following steps: (1) Test compounds were tested at 1000nM, 100% DMSO solution diluted to 200-fold final concentration in 384well plates 3-fold diluted compound, 10 concentrations. 50nL of compound at 200-fold final concentration was transferred to the 384well plate of interest using a dispenser Echo 550. 50nL of 100% DMSO is added to each of the negative control well and the positive control well; (2) Preparing Tag1 SOS1 solution with 4 times of final concentration by using a reagent buffer; (3) In 384 wells2.5. Mu.L of a 4-fold final concentration of Tag1 SOS1 solution was added to the plates; (4) Tag2 KRAS was formulated at 4-fold final concentration with a Diluent buffer G12C A solution; (5) Tag2 KRAS was added at a final concentration of 4-fold of 2.5. Mu.L to each of the compound well and positive control well G12C A solution; 2.5. Mu.L of a reagent buffer was added to the negative control well; (6) Centrifuging the 384-well plate at 1000rpm for 30 seconds, shaking and uniformly mixing, and incubating for 15 minutes at room temperature; (7) Preparing an Anti Tag1Tb3+ solution with a 1-time final concentration and an Anti Tag2XL665 solution with a 1-time final concentration by using a Detection buffer, uniformly mixing the two solutions, and adding 5 mu L of mixed solution into each hole; (8) Centrifuging the 384-well plate at 1000rpm for 30 seconds, shaking and uniformly mixing, and incubating for 120 minutes at room temperature; (9) reading Em665/620 with an Envision microplate reader; (10) Data analysis, calculation formulaWherein Min signal negative control Kong Junzhi Max signal positive control Kong Junzhi. The log value of concentration is taken as an X-axis of the fit-up dose-response curve, the percentage inhibition rate is taken as a Y-axis, and log (inhibitor) vs. response Variable slope fit-up dose-response curve of analysis software GraphPad Prism 5 is adopted, so that the IC of each compound on enzyme activity is obtained 50 Values. The fitting formula is: y=bottom+ (Top Bottom)/(1+10 ((log ic) 50 X)*HillSlope))。
Results: most of the compounds of the present invention are directed to KRAS G12C SOS1 interaction has obvious inhibition and inhibition activity IC 50 Less than 1000nM, IC of some examples 50 Less than 200nM as in examples 1,4, 11, 13, 16, 18, 19, 22, 23; some of these examples have an IC50 of less than 50nM, as in examples 16, 19, superior to AMG510 The IC50 is between 50nM and 100 nM).
Test example 2: KRAS G12C Mass spectrometry addition analysis
All enzyme and substrate solutions were formulated with reaction buffer (20 mM HEPES (pH 7.5), 5mM MgCl2,150mM NaCl and 0.01% tween 20). 50. Mu.L of 4. Mu.M GDP-loaded biotinylated KRAS configured from reaction buffer was added to each well of a 96-well polypropylene microplate G12C 0.5. Mu.L of 1mM test compound (final concentration 10. Mu.M) was reacted for 4 hours, and then the reaction was terminated by adding 50. Mu.L of 1% formic acid. Plates were read for Xex G2 QTOF (Waters) and Acquity LC system (Waters) after sealing of the plates. 10 μl of sample was injected into Xbridge BEH300; c4;3.5 μm; gradient analysis was performed for 3 minutes on a 2.1x 50mm column (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 Apo-protein KRAS G12C (APO) and kras+ relative compound mass (addition), the calculation of the percentage addition was performed using the following formula: percent sum = 100x (sum peak area/sum of APO and sum peak).
Test example 3: test of the Effect of the Compounds of the invention on NCI-H358, miaPaca-2 cell proliferation and downstream Signal ERK phosphorylation Capacity
Test method one (2D) NCI-H358 (lung cancer) and MiaPaca-2 cells (pancreatic cancer) cells (100. Mu.L/well, 20000 cells/mL) were inoculated in 96-well culture plates and supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin sulfate, respectively. Cells were treated with a 10. Mu.M solution of the test compound diluted three times in an eight-gradient with 0.5% dimethyl sulfoxide as a blank and incubated in a 5% CO2 incubator for a certain period of time (5-7 days). At the end of incubation, 10. Mu.L of MTT stock solution (5 mg/mL) was added to each well. The plates were incubated at 37℃for 4 hours, after which the medium was removed. Dimethyl sulfoxide (100 μl) was added to each well, followed by shaking well. The absorbance of the formazan product was measured at 570nm on a Thermo Scientific Varioskan Flash multimode reader. IC was obtained by fitting dose response data to a three-parameter nonlinear regression model using GraphPad Prism 6.0 software 50 Values.
Results: the invention provides example compounds having proliferation inhibiting activity on NCI-H358 and MiaPaca-2 cells, IC 50 Values are less than 5000nM; in particular as in examples 1,4,7, 16, 17, 18, 19, 20, 22 have a cell proliferation inhibitory activity on NCI-H358 and MiaPaca-2 of less than 500nM; some examples have cell proliferation inhibiting activity on NCI-H358 and MiaPaca-2 even less than 100nM, as in examples 16, 17, 19 20, 22; some of the examples have cell proliferation inhibiting activity on NCI-H358 and MiaPaca-2 even less than 10nM, as in example 16, which is significantly better than AMG510 (IC 50 at 20-50 nM) on NCI-H358 and MiaPaca-2.
Test method two (3D): tumor cells in the logarithmic growth phase were diluted to a certain concentration with a culture medium of 80. Mu.L/well and inoculated to a 96-well plate with an ultra-low adhesion surface. Cells were incubated overnight at 37℃in a humidity chamber. Serial dilutions of test compounds (10 concentrations, 3-fold dilution) were added to the next day plate, 20 μl/well, and the incubator incubated for 96h. The plate is taken out and placed at room temperature, and then added with an equal volumeIncubation of 3D reagent for 1h, en Vision TM The board reader detects the signal. The signal is converted to percent suppression using the following formula: % inhibition = 100- [ (test compound signal-median minimum signal)/(median maximum signal-median minimum signal) x 100]. The maximum signal is the signal value of the inhibitor-free wells, the minimum signal is the signal value of the wells containing a reference inhibitor sufficient to completely inhibit cell proliferation, a four-parameter nonlinear regression fit was performed on the percent inhibition of each concentration of compound and IC was calculated 50 。
Results: the invention provides example compounds having proliferation inhibiting activity on NCI-H358 and MiaPaca-2 cells, IC 50 Less than 1000nM, and some examples 1, 4, 7, 10, 11, 14, 16, 17, 18, 19, 20, 22, etc. have cell proliferation inhibiting activity IC on NCI-H358 and MiaPaca-2 50 Less than 200nM.
Test method three (ERK phosphorylation): inoculating Miapaca-2 or H358 cells into a 96-well plate according to a certain concentration, placing at 37 ℃ and 5% CO 2 The cells were cultured overnight, serial dilutions of test compounds (5 concentrations, 3-fold dilution) were added to the second plate and allowed to act for 24H (miappa-2) or 3H (H358), then the lysate containing protease and phosphatase inhibitors was added to lyse the cells to extract protein, and the level of p-ERK was detected by the western blot method.
Results: most of the example compounds provided by the present inventionFor example, 1, 4, 7, 10, 11, 14, 16, 17, 18, 19, 20, 22 have remarkable effect on inhibiting the phosphorylated ERK levels of NCI-H358 and MiaPaca-2, and IC 50 Less than 500nM.
And a testing method IV:
1. NCI-H358 cells were maintained in RPMI with 10% FBS medium. To quantitatively measure the cytotoxic activity of compounds by ATP, NCI-H358 cells were plated at 5000 cells/well/100 μl in RPMI medium in 96-well polystyrene clear black tissue culture plates in the presence or absence of a range of concentrations of test compounds. After 3 days, 100uL of Cell Titer-GLO luminescent Cell culture was added to each well for 10 minutes at room temperature to stabilize the luminescent signal. The number of living cells in the medium was thus determined based on the quantification of the presence of ATP, which indicates the presence of metabolically active cells. Luminescence was measured with Top Count 384. The inhibition (%) of the compound against tumor cell growth was calculated using the following formula = (OD negative control well-OD dosing well)/OD negative control well x 100%. The IC50 value is obtained by adopting a random software of an enzyme label instrument through regression by a four-parameter method.
2. Results: the invention provides part of examples 2-6 of the proliferation-inhibiting Activity on NCI-H358 cells, IC 50 The values were less than 500nM, and the inhibitory activity IC of some of the compounds of the examples 50 Values even less than 10nM show strong cell proliferation inhibitory activity.
Test example 4: ADMET test of example Compounds
(1) Metabolic stability test: metabolic stability incubation was performed with 150 μl of liver microsomes (final concentration 0.5 mg/mL) containing NADPH (final concentration 1 mM), 1 μΜ test compound and positive control midazolam or negative control atenolol, and the reaction was stopped with tinidazole-containing acetonitrile at 0min, 5min, 10min and 30min, vortexed for 10min, centrifuged at 15000rmp for 10min, and 50 μl of supernatant was sampled in 96-well plates. The metabolic stability of the compounds was calculated by measuring the relative decrease in the drug substance.
(2) Direct inhibition assay (DI assay): direct inhibition incubation was performed with 100. Mu.L of human liver microsomes (final concentration 0.2 mg/mL) containing NADPH (final concentration 1 mM), 10. Mu.M compound, positive inhibitor cocktail (ketoconazole 10. Mu.M, quinidine 10. Mu.M, sulfanilide 100. Mu.M, alpha-naphthaleneflavone 10. Mu.M, tranylcypromine 1000. Mu.M), negative control (BPS of 0.1% DMSO) and mixed probe substrates (midazolam 10. Mu.M, testosterone 100. Mu.M, dextromethorphan 10. Mu.M, diclofenac 20. Mu.M, phenacetin 100. Mu.M), and the reaction was stopped after incubation for 20 min. The relative enzyme activity was calculated by measuring the relative production of metabolites.
(3) hERG inhibition assay: diluting 20mM compound mother liquor with DMSO, adding 10 mu L of 20mM compound mother liquor into 20 mu L of DMSO solution, and continuously diluting 3 times to 6 DMSO concentrations; respectively taking 4 mu L of 6 DMSO concentration compounds, adding the compounds into 396 mu L of extracellular fluid, diluting the extracellular fluid to 6 intermediate concentrations by 100 times, respectively taking 80 mu L of 6 intermediate concentration compounds, adding the compounds into 320 mu L of extracellular fluid, and diluting the compounds to the final concentration required to be tested by 5 times; the highest test concentration is 40 mu M, and the highest test concentration is respectively 40 mu M and 13.3,4.4,1.48,0.494,0.165 mu M, and the total concentration is 6; DMSO content in the final test concentration was no more than 0.2%, this concentration of DMSO had no effect on hERG potassium channel; the compound was ready for the whole dilution process by a Bravo instrument; the current and time-course plots of compounds versus hERG potassium channels were read and the fitted curves were made to compound inhibition curves versus hERG.
Results: some embodiments of the invention are compounds 1,4,7, 16, 18, 19, 20, 22 with high stability to mouse, rat, human, canine liver microsomes and half-life greater than 20 minutes; has no obvious inhibition to each CYP enzyme, IC 50 Greater than 10uM; has no obvious inhibition to hERG, IC 50 Greater than 10uM.
Test example 5: in vivo pharmacokinetic parameter testing of example Compounds in rats, mice
The 6 male SPF-class SD rats (Shanghai Sipulel-BiKai experimental animals) were divided into two groups, and the test compounds were formulated as appropriate solutions or suspensions; one group is administered by intravenous injection and one group is administered orally. Blood was collected via jugular vein puncture, each sample was collected at about 0.2 mL/time point, heparin sodium was anticoagulated, and the blood collection time points were as follows: 5, 15 and 30min,1, 2, 4, 6, 8 and 24h before and after administration; blood samples were collected and placed on ice, and plasma was centrifuged (centrifugation conditions: 8000 rpm, 6 min, 2-8 ℃) and stored at-80℃prior to analysis of the collected plasma. Plasma samples were analyzed by LC-MS/MS.
According to the blood concentration data of the medicine, respectively calculating the pharmacokinetic parameters AUC of the test sample by using a pharmacokinetic calculation software WinNonlin5.2 non-atrioventricular model 0-t 、AUC 0-∞ 、MRT 0-∞ 、C max 、T max 、T 1/2 And V d Isoparametric parameters, mean and standard deviation. In addition, the bioavailability (F) will be calculated by the following formula.
Test example 6: test of Compounds of examples for MiaPaca-2, NCI-H358 tumor cell nude mice transplantation tumor growth inhibition
Cutting tumor tissue in vigorous growth period into 1.5mm 3 Left and right, under aseptic conditions, the mice were inoculated subcutaneously in the right armpit. The diameter of the transplanted tumor is measured by a vernier caliper for subcutaneous transplantation of the nude mice, and the average tumor volume is up to 130mm 3 Animals were randomly grouped left and right. The compound of the examples (prepared with 1% tween80 in water for injection to the desired concentration for use) was orally administered daily at given doses for three consecutive weeks, and the solvent control group was given an equivalent amount of solvent. Throughout the experiment, the diameter of the transplanted tumor was measured 2 times per week while weighing the mice. The calculation formula of Tumor Volume (TV) is: tv=1/2×a×b 2 Wherein a and b respectively represent length and width. Based on the measured results, the relative tumor volume (relative tumor volume, RTV) is calculated as: rtv=vt/V0. Where V0 is the tumor volume measured at the time of divided cage administration (i.e., d 0), 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 RTV; 2) Tumor volume increase inhibition rate GI), the calculation formula is as follows: GI% = [1- (TVt-TV 0)/(CVt-CT 0)]×100％，TVt the tumor volume measured each time in the treatment group; TV0 is the tumor volume obtained when therapeutic component is administered in the cage; CVt is the tumor volume measured each time in the control group; CV0 is the tumor volume obtained when the control component is administered in a cage; 3) Tumor weight inhibition rate was calculated as follows: tumor weight inhibition% = (Wc-WT)/wc×100%, wc: tumor weight of control group, WT: treating the tumor weight of the group.
Results: the compounds of some examples of the application, such as examples 4, 8, 19, 22, etc., are orally administered once daily at doses of 30mg/kg and 100mg/kg for 14-21 days continuously, and have remarkable inhibition effect on the transplanted tumor growth of MiaPaca-2 and NCI-H358 tumor cell nude mice, and the tumor inhibition rate is more than 70%.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (55)

1. A condensed ring lactam compound shown as a general formula I-1, pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, torsional isomer or polymorph thereof,
wherein:
r1 is independently hydrogen, halogen or C 1 -C 6 An alkyl group;
r2 and R3 are hydrogen;
r4 is independently substituted C 1 -C 12 Alkyl of (a);
said substituted C 1 -C 12 The substituents in the alkyl groups of (a) are independently 3-8 membered heterocycloalkyl, or are substituted with 1 or more C 1 -C 6 Alkyl substituted 3-8 membered heterocycloalkyl; the heterocycloalkyl group comprises 1 to 3 hetero atoms selected from the group consisting of An atom: n, O, P or S;
r5 is independently hydrogen, halogen, 3-6 membered cycloalkyl or vinyl; m is independently selected from 0 to 6;
r6 is independently H, halogen, cyano or C1-C6 alkoxy, one or more hydrogen atoms on the C1-C6 alkoxy being substituted by halogen;
m is CH or N;
ra, rb, rc, rd, re, rf, rg and Rh are each independently hydrogen or C 1 -C 6 An alkyl group; when Ra, rb, rc, rd, re, rf, rg and Rh are independently C 1 -C 6 Alkyl, and C as described 1 -C 6 When one or more hydrogen atoms on the alkyl group are substituted with a substituent, the substituent is independently cyano;
or Rg and R6 together form a 6 membered monocyclic heterocycloalkyl wherein the heteroatoms are O and N and the number is 2;
ar is independently a 5-12 membered aromatic ring or aromatic condensed ring, a 5-12 membered aromatic heterocyclic ring or aromatic condensed ring; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C 1 -C 6 Alkyl, unsubstituted amino or hydroxy;
wherein the heteroaryl group comprises 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S.
2. The fused ring lactam compound of claim 1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof, or a polymorph thereof, according to formula I-1, wherein:
R1 is independently hydrogen;
r2 and R3 are independently hydrogen;
r4 is independently substituted C 1 -C 12 Alkyl of (a);
said substituted C 1 -C 12 The substituents in the alkyl groups of (a) are independently 3-8 membered heterocycloalkyl, or are substituted with 1 or more C 1 -C 6 Alkyl substituted 3-8 membered heterocycloalkyl;
r5 is independently hydrogen, halogen or 3-6 membered cycloalkyl;
r6 is independently H, halogen, cyano or C1-C6 alkoxy, one or more hydrogen atoms on the C1-C6 alkoxy being substituted by halogen;
m is CH or N;
ra, rb, rc, rd, re and Rf are independently hydrogen or C 1 -C 6 An alkyl group; when Ra, rb, rc, rd, re and Rf are independently C 1 -C 6 Alkyl, and C as described 1 -C 6 When one or more hydrogen atoms on the alkyl group are substituted with a substituent, the substituent is independently cyano;
rg and Rh are hydrogen;
ar is independently a 5-12 membered aromatic ring or aromatic condensed ring, a 5-12 membered aromatic heterocyclic ring or aromatic condensed ring; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C 1 -C 6 Alkyl, unsubstituted amino or hydroxy.
3. The fused ring lactam compound of claim 1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof, or a polymorph thereof, according to formula I-1, wherein:
R1 is independently hydrogen or halogen;
r2 and R3 are independently hydrogen;
r4 is independently substituted C 1 -C 12 Alkyl of (a);
said substituted C 1 -C 12 Substituents in the alkyl groups of (2) are independently C1 or more 1 -C 6 Alkyl substituted 3-8 membered heterocycloalkyl;
r5 is independently hydrogen or halogen;
r6 is independently H, halogen or cyano;
m is CH or N;
ra, rb, rc, rd, re and Rf are independently hydrogen or C 1 -C 6 An alkyl group;
when Ra, rb, rc, rd, re, rf is independently C 1 -C 6 Alkyl, and C as described 1 -C 6 One or more hydrogens on the alkyl group being substituted by substituentsWhen the substituent is cyano;
rg and Rh are hydrogen;
ar is independently a 5-12 membered aromatic ring or aromatic condensed ring, a 5-12 membered aromatic heterocyclic ring or aromatic condensed ring; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C 1 -C 6 Alkyl, unsubstituted amino or hydroxy;
and when Ra, rb are independently C 1 -C 6 Alkyl, and C as described 1 -C 6 When one or more hydrogens on the alkyl are substituted with substituents, R1 is halogen; ar is
4. The fused ring lactam compound of claim 1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof, or a polymorph thereof, according to formula I-1, wherein:
R1 is independently hydrogen or halogen;
r2 and R3 are independently hydrogen;
r4 is independently substituted C 1 -C 12 Alkyl of (a);
said substituted C 1 -C 12 Substituents in the alkyl groups of (2) are independently C1 or more 1 -C 6 Alkyl substituted 3-8 membered heterocycloalkyl;
r5 is independently hydrogen, halogen or vinyl;
r6 is independently H, halogen or cyano;
m is CH or N;
ra, rb, rc, rd, re and Rf are independently hydrogen or C 1 -C 6 An alkyl group; when Ra, rb, rc, rd, re, rf, rg and Rh are independently C 1 -C 6 Alkyl, and C as described 1 -C 6 When one or more hydrogen atoms on the alkyl group are substituted with a substituent, the substituent is independently cyano;
rg and Rh are hydrogen;
ar is independently a 5-12 membered aromatic ring or aromatic condensed ring, a 5-12 membered aromatic heterocyclic ring or aromatic condensed ring; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C 1 -C 6 Alkyl, unsubstituted amino or hydroxy.
5. The fused ring lactam compound of claim 1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof, or a polymorph thereof, according to formula I-1, wherein:
r1 is independently hydrogen;
r2 and R3 are independently hydrogen;
R4 is independently substituted C 1 -C 12 Alkyl of (a);
said substituted C 1 -C 12 Substituents in the alkyl groups of (2) are independently C1 or more 1 -C 6 Alkyl substituted 3-8 membered heterocycloalkyl;
r5 is independently hydrogen or halogen;
r6 is independently H, halogen or cyano;
m is CH or N;
ra, rb, rc, rd, re, rf, rg and Rh are independently hydrogen or C 1 -C 6 An alkyl group;
ar is a 5-12 membered aromatic ring or aromatic condensed ring, a 5-12 membered aromatic heterocyclic ring or aromatic condensed ring; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C 1 -C 6 Alkyl, unsubstituted amino or hydroxy.
6. The condensed ring lactam compound according to claim 1, which is represented by the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof or a polymorph thereof,
the condensed ring lactam compound shown in the general formula I-1 is shown in the general formulas (IIA) and (IIB):
wherein M, R, R2, R3, R4, R5, R6, ra, rb, rc, rd, re, rf, rg, rh, ar and m are as defined in claim 1.
7. The condensed ring lactam compound according to claim 1, which is represented by the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof or a polymorph thereof,
The condensed ring lactam compound shown in the general formula I-1 is shown in the general formula (IIG):
wherein, the carbon marked in the general formula (IIG) refers to R configuration chiral carbon;
m, R1, R2, R3, R4, R5, R6, ra, rb, rc, rd, re, rf, rg, rh, ar and m are as defined in claim 1.
8. The condensed ring lactam compound according to claim 1, which is represented by the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof or a polymorph thereof,
the condensed ring lactam compound shown in the general formula I-1 is shown in the general formula (IIH):
wherein, the carbon marked in the general formula (IIH) refers to S configuration chiral carbon;
r6 is independently H, halogen, cyano or C1-C6 alkoxy, one or more hydrogen atoms on the C1-C6 alkoxy being substituted by halogen;
rg is independently hydrogen or C 1 -C 6 An alkyl group; when Ra isRb, rc, rd, re, rf, rg and Rh are independently C 1 -C 6 Alkyl, and C as described 1 -C 6 When one or more hydrogen atoms on the alkyl group are substituted with a substituent, the substituent is independently cyano;
m, R1, R2, R3, R4, R5, ra, rb, rc, rd, re, rf, rh, ar and m are as defined in claim 1.
9. The condensed ring lactam compound according to claim 1, which is represented by the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof or a polymorph thereof,
the condensed ring lactam compound shown in the general formula I-1 is shown in the general formula (IIF):
wherein M, R, R2, R3, R4, R5, ra, rb, rc, rd, re, rf, rh, ar and m are as defined in claim 1.
10. The fused ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof or polymorph thereof according to claim 1, wherein R1 is independently F, cl, br, I or C 1 -C 3 An alkyl group.
11. The fused ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof or polymorph thereof according to claim 1, wherein R4 is independently substituted C 1 -C 6 Is a hydrocarbon group.
12. The fused ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof, or polymorph thereof according to claim 1, wherein R5 is independently halogen, and wherein the halogen is F, cl, br or I;
And/or R5 is independently 3-6 membered cycloalkyl, said 3-6 membered cycloalkyl being cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
13. The fused ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof or polymorph thereof according to claim 1, wherein Ra, rb, rc, rd, re and Rf are each independently C 1 -C 3 An alkyl group.
14. The condensed ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof or polymorph thereof according to claim 1, wherein Rg and Rh are each independently C 1 -C 3 An alkyl group.
15. The fused ring lactam compound of the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof, or a polymorph thereof according to claim 1, wherein Ar is independently a 6-10 membered aromatic ring, a 6-10 membered aromatic fused ring, or a 9-membered aromatic fused ring.
16. The condensed ring lactam compound according to claim 1, which is represented by the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof or a polymorph thereof,
Said quilt is 1 or more C 1 -C 6 C in alkyl-substituted 3-8 membered heterocycloalkyl 1 -C 6 Alkyl is C 1 -C 4 An alkyl group.
17. The fused ring lactam compound of formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof, or polymorph thereof according to claim 1, wherein Ar ring is substituted with one or more halogen, wherein said halogen is F, cl, br or I.
18. The fused ring lactam compound of the general formula I-1, the pharmaceutically acceptable salt thereof, the enantiomer thereof, the diastereomer thereof, the tautomer thereof, the torsional isomer thereof or the polymorph thereof according to claim 1, wherein Ar ring is substituted with one or more C 1 -C 6 Substituted by alkyl groups, said C 1 -C 6 Alkyl is C 1 -C 3 An alkyl group.
19. The fused ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof or polymorph thereof according to claim 1, wherein R1 is independently F or methyl.
20. The fused ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof or polymorph thereof according to claim 1, wherein R4 is independently substituted C 1 -C 3 Is a hydrocarbon group.
21. The fused ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof or polymorph thereof according to claim 1, wherein R5 is independently F, cl or cyclopropyl.
22. The fused ring lactam compound of claim 1, the pharmaceutically acceptable salt thereof, the enantiomer thereof, the diastereomer thereof, the tautomer thereof, the torsional isomer thereof, or the polymorph thereof, according to formula I-1, wherein Ra, rb, rc, rd, re and Rf are each independently methyl.
23. The fused ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof or polymorph thereof according to claim 1, wherein Rg and Rh are each independently methyl.
24. The fused ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof or polymorph thereof according to claim 1, wherein Ar is independently phenyl, naphthyl or polymorph thereof
25. The fused ring lactam compound of the general formula I-1, the pharmaceutically acceptable salt thereof, the enantiomer thereof, the diastereomer thereof, the tautomer thereof, the torsional isomer thereof or the polymorph thereof according to claim 1, wherein the hetero atoms in the 3-8 membered heterocycloalkyl are independently N and the number is 1.
26. The fused ring lactam compound of the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof, or a polymorph thereof according to claim 1, wherein the 3-8 membered heterocycloalkyl is a 3-5 membered heterocycloalkyl.
27. The fused ring lactam of claim 26, represented by formula I-1An amine compound, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof, or a polymorph thereof, characterized in that said compound is represented by 1 or more C 1 -C 6 The substitution sites of substituents in the alkyl-substituted 3-8 membered heterocycloalkyl are independently on heteroatoms in the 3-5 membered heterocycloalkyl.
28. The fused ring lactam compound of the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof, or a polymorph thereof according to claim 1, wherein the 3-8 membered heterocycloalkyl is tetrahydropyrrolyl.
29. The fused ring lactam compound of formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof, or polymorph thereof according to claim 1, wherein the substitution position of R5 is ortho to Ar.
30. The fused ring lactam compound of the general formula I-1, the pharmaceutically acceptable salt thereof, the enantiomer thereof, the diastereomer thereof, the tautomer thereof, the torsional isomer thereof or the polymorph thereof according to claim 1, wherein the hetero atoms in the 5-12 membered aromatic fused heterocycle are N and/or S, and the number is 1 or 2.
31. The fused ring lactam compound of the general formula I-1, the pharmaceutically acceptable salt thereof, the enantiomer thereof, the diastereomer thereof, the tautomer thereof, the torsional isomer thereof, or the polymorph thereof according to claim 1, wherein Ar is substituted with one or more groups, and the number of the substitutions is 1, 2, 3, or 4.
32. The condensed ring lactam compound according to claim 1, which is represented by the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof or a polymorph thereof,
Said quilt is 1 or more C 1 -C 6 C in alkyl-substituted 3-8 membered heterocycloalkyl 1 -C 6 Alkyl is methyl.
33. The fused ring lactam compound of formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof, or polymorph thereof according to claim 1, wherein Ar ring is substituted with one or more groups, said groups being F, cl or methyl.
34. The fused ring lactam compound of the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof, or a polymorph thereof according to claim 1, wherein the nitrogen, carbon, or sulfur atom of the heterocycloalkyl is not oxidized; the nitrogen atom is not quaternized.
35. The fused ring lactam compound of formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof, or polymorph thereof according to claim 1, wherein R4 is independently substituted C1-C12 alkyl, and wherein said C1-C12 alkyl is methyl.
36. The condensed ring lactam compound according to claim 1, which is represented by the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof or a polymorph thereof,
rg and R6 together form
37. The condensed ring lactam compound according to claim 1, which is represented by the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof or a polymorph thereof,
ar is independently
38. The condensed ring lactam compound according to claim 1, which is represented by the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof or a polymorph thereof,
r4 is independently
39. The condensed ring lactam compound according to claim 1, which is represented by the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof or a polymorph thereof,
r4 is independently
40. The fused ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof or polymorph thereof according to claim 1, wherein Ra, rb, rc, rd, re and Rf are each independently
41. The fused ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof or polymorph thereof according to claim 1, wherein Ar is independently
42. The fused ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof, or polymorph thereof according to claim 1, wherein R1 is independently hydrogen or halogen.
43. The fused ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof, or polymorph thereof according to claim 1, wherein R5 is independently hydrogen, halogen or vinyl.
44. The fused ring lactam compound of formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof, or polymorph thereof according to claim 1, wherein Rc, rd, re and Rf are independently hydrogen.
45. The fused ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof, or polymorph thereof according to claim 1, wherein R6 is independently hydrogen or cyano.
46. The fused ring lactam compound of the general formula I-1, pharmaceutically acceptable salt thereof, enantiomer thereof, diastereomer thereof, tautomer thereof, torsional isomer thereof or polymorph thereof according to claim 1, wherein m is independently 0 or 1.
47. The condensed ring lactam compound according to claim 1, which is represented by the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof or a polymorph thereof,
is->
48. The condensed ring lactam compound according to claim 1, which is represented by the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof or a polymorph thereof,
49. the condensed ring lactam compound according to claim 1, which is represented by the general formula I-1, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof or a polymorph thereof,
Is->
50. A condensed ring lactam compound shown as a general formula I-2, pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, torsional isomer or polymorph thereof,
wherein:
r1 is independently hydrogen, halogen or C 1 -C 6 An alkyl group;
r2 and R3 are hydrogen;
r4 is independently substituted C 1 -C 12 Alkyl of (a);
said substituted C 1 -C 12 The substituents in the alkyl groups of (a) are independently 3-8 membered heterocycloalkyl;
r5 is independently hydrogen, halogen, 3-6 membered cycloalkyl or vinyl; m is independently selected from 0, 1 or 2;
r6 is independently H, halogen, cyano or C1-C6 alkoxy, one or more hydrogen atoms on the C1-C6 alkoxy being substituted by halogen;
m1 is CR6; in CR6, R6 is hydrogen or halogen;
ra, rb, rc, rd, re, rf, rg and Rh are each independently hydrogen or C 1 -C 6 An alkyl group; when Ra, rb, rc, rd, re, rf, rg and Rh are independently C 1 -C 6 Alkyl, and C as described 1 -C 6 When one or more hydrogen atoms on the alkyl group are substituted with a substituent, the substituent is independently cyano;
ar is independently a 5-12 membered aromatic ring or aromatic condensed ring, a 5-12 membered aromatic heterocyclic ring or aromatic condensed ring; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C 1 -C 6 Alkyl, unsubstituted amino or hydroxy;
wherein the heteroaryl group comprises 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S.
51. A fused ring lactam compound, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof, or a polymorph thereof, characterized by being any one of the following compounds:
/>
52. a pharmaceutical composition comprising an effective amount of the fused ring lactam compound of any one of claims 1-51, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof, or a polymorph thereof, and a pharmaceutically acceptable carrier.
53. Use of a fused ring lactam compound of any one of claims 1-51, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a torsional isomer thereof, or a polymorph thereof, or a pharmaceutical composition of claim 52, in the preparation of a Ras mutein inhibitor or medicament for treating a disease associated with activity or expression of a Ras mutein.
54. The use of claim 53, wherein the Ras mutein is KRAS G12C.
55. The use of claim 53, wherein the disease is non-small cell lung cancer, small cell lung cancer or pancreatic cancer.
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