CN111592541B - Macrocyclic kinase inhibitors and uses thereof - Google Patents

Macrocyclic kinase inhibitors and uses thereof Download PDF

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CN111592541B
CN111592541B CN201910131148.1A CN201910131148A CN111592541B CN 111592541 B CN111592541 B CN 111592541B CN 201910131148 A CN201910131148 A CN 201910131148A CN 111592541 B CN111592541 B CN 111592541B
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CN111592541A (en
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刘斌
陈博
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Shandong Xuanzhu Pharma Co Ltd
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a macrocyclic tyrosine kinase inhibitor compound, a pharmaceutically acceptable salt, an ester and a stereoisomer thereof, more specifically, the tyrosine kinase is one or more of TRK, ALK and ROS1, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salt, the ester and the stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt, the ester and the stereoisomer thereof, and application of the compound, the pharmaceutically acceptable salt, the ester and the stereoisomer thereof.

Description

Macrocyclic kinase inhibitors and uses thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a macrocyclic tyrosine kinase inhibitor compound, a pharmaceutically acceptable salt, an ester and a stereoisomer thereof, more specifically, the tyrosine kinase is one or more of TRK, ALK and ROS1, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salt, the ester and the stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt, the ester and the stereoisomer thereof, and application of the compound, the pharmaceutically acceptable salt, the ester and the stereoisomer thereof.
Background
Molecular targeted therapy is a major breakthrough in cancer therapy in recent years. Compared with traditional treatment means such as surgery, radiotherapy and chemotherapy, the molecular targeted therapy opens up a new place for treating cancers by high specificity and relatively low toxic and side effects, and gradually becomes a standard treatment scheme for patients at later stage. Protein kinases are a large area of targeted therapy and key regulators of cell growth, proliferation and survival, and both genetic and epigenetic changes may contribute to the development of cancer.
ALK, known as anaplastic lymphoma kinase, the anaplastic lymphoma kinase, was named for the first time as found in anaplastic large cell lymphoma AMS3 cell line. EML4 belongs to echinoderm microtubule-associated protein family, and is composed of three parts, namely an N-terminal base, a hydrophobic echinoderm microtubule-associated protein region and a WD repetitive region, and the literature reports prove that the EML4-ALK fusion gene is related to the formation of tumors, wherein the function of the N-terminal base region is most important. In 2007, Soda et al report EML4-ALK gene fusion in NSCLC for the first time, the fusion is caused by inversion of the short arm of chromosome 2, EML4 at the N-terminal end is fused to the ALK kinase region in cells, the EML4-ALK fusion sites are diverse, and at least 8 EML4-ALK mutants are formed. ALK mutations have been found in a variety of cancers, including ALCL, non-small cell lung cancer, inflammatory myofibroblast tumors, colorectal cancer, breast cancer, and several others.
ROS1 is also a tyrosine kinase receptor currently of great interest. ROS1 is located in the 6q21 region, and the full-length cDNA contains 44 exons, encodes 2347 amino acids, and has a molecular weight of 259 kDa. The basic structure consists of the extramembranous region (amino acids 1-1861), the transmembrane region (amino acids 1862 and 1882), and the intramembranous tyrosine kinase-active region (amino acids 1883 and 2347). The first proto-oncogene fusion site of ROS1 (FIG-ROS1) is found in glioblastoma, and an intermediate deletion of 240 bases at 6q21 results in the expression of FIG-ROS1 fusion protein, which activates tyrosine kinase activity. ROS1 mutations have also been found in a variety of cancers, including glioblastoma, non-small cell lung cancer, colorectal cancer, breast cancer, and the like.
Trk is a nerve growth factor activated tyrosine kinase family, comprising 3 subtypes of TrkA, TrkB and TrkC, and is respectively encoded by NTRK1 (neuroreceptor tyrosine kinase 1), NTRK2 and NTRK3 genes. After the Trk kinase is phosphorylated, the Trk kinase can activate downstream signal molecules, thereby playing roles in regulating cell proliferation, differentiation, metabolism, apoptosis and the like. The NTRK gene can be fused with other genes, so that the high expression of Trk kinase or the continuous increase of the Trk kinase activity is caused, and finally, the cancer can be caused. NTRK gene fusion occurs in a variety of adult and childhood solid tumors, including breast cancer, colorectal cancer, non-small cell lung cancer, and various sarcomas.
The three tyrosine kinases have strong homology, namely the ROS1 gene and the ALK gene have 49 percent of homology in the tyrosine kinase region sequence, the ATP binding site in the kinase catalytic region has 77 percent of homology, the TRKA/B/C kinase region sequence has more than 80 percent of homology, and the TRKA gene, the ROS1 gene and the ALK gene have about 40 percent of homology in the tyrosine kinase region sequence. The marketed ALK inhibitor crizotinib has the kinase activity of ROS1 and TRK, and the TRK inhibitor entletinib also has the activity of ALK and ROS 1.
Currently, the marketed ALK/ROS1 inhibitors and the marketed NTRK inhibitors declared in 2017 have corresponding drug resistance phenomena in the long-term medication process, mainly because gene mutation causes the change of amino acid sequences in kinase proteins, for example, mutation sites common in ALK kinases include L1196M, L1152R, G1202R, G1269A, 1151Tins, S1206Y, C1156Y, F1174L, etc., mutation sites common in ROS1 kinases include G2032R, D3N, S1986F, L2026M, L1951R, etc., and mutation sites common in ntkinase include G595R, G623R, G667C, G623E, L203M, etc. Therefore, the method has very important clinical value and significance for developing an anti-tumor drug which has strong drug effect and low toxicity and can solve the problem of drug resistance.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a compound with a novel structure and a tyrosine kinase receptor inhibition effect, further, the tyrosine kinase receptor is one or more of TRK, ALK and ROS1, and further, the compound has good inhibition activity on TrkA and/or TrkB and/or TrkC kinase, and has high exposure and bioavailability in organisms.
The technical problem underlying the present invention also consists in the fact that the compounds of the invention are useful for the treatment of cancer diseases mediated by one or more tyrosine kinase receptors of TRK, ALK and ROS1, and further in that said cancer diseases are resistant to one or more therapeutically active agents already present, and further in that said resistance is caused by a mutation in the gene coding for the target.
The technical scheme of the invention is as follows:
in one aspect, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof,
Figure BDA0001974801310000031
wherein,
X1、X2、X3、X4、X5each independently is selected from CH or N;
M1、M2、M3each independently selected from-C (R)2)(R3)-、-N(R4) -, -O-, -S-, -S (O) -or-S (O)2-；
Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl;
each R1、R2、R3、R4Each independently selected from hydrogen, halogen, nitro, cyano, -ORa、-SRa、-NRaRb、-C(O)Ra、-C(O)ORa、-OC(O)Ra、-OC(O)ORa、-OC(O)NRaRb、-C(O)NRaRb、-NRaC(O)Rb、-NRaC(O)ORb、-NRaC(O)NRaRb、-S(O)Ra、-S(O)ORa、-OS(O)Ra、-OS(O)ORa、-OS(O)NRaRb、-S(O)NRaRb、-NRaS(O)Rb、-NRaS(O)ORb、-NRaS(O)NRaRb、-S(O)2Ra、-S(O)2ORa、-OS(O)2Ra、-OS(O)2ORa、-OS(O)2NRaRb、-S(O)2NRaRb、-NRaS(O)2Rb、-NRaS(O)2ORb、-NRaS(O)2NRaRbC unsubstituted or substituted by one or more Q11-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkoxy, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocyclyl, 6-to 10-membered aryl or 5-to 10-membered heteroaryl;
each Q1 is independently selected from hydroxy, amino, halogen, nitro, cyano, -ORa、-SRa、-NRaRb、-C(O)Ra、-C(O)ORa、-OC(O)Ra、-OC(O)ORa、-OC(O)NRaRb、-C(O)NRaRb、-NRaC(O)Rb、-NRaC(O)ORb、-NRaC(O)NRaRb、-S(O)Ra、-S(O)ORa、-OS(O)Ra、-OS(O)ORa、-OS(O)NRaRb、-S(O)NRaRb、-NRaS(O)Rb、-NRaS(O)ORb、-NRaS(O)NRaRb、-S(O)2Ra、-S(O)2ORa、-OS(O)2Ra、-OS(O)2ORa、-OS(O)2NRaRb、-S(O)2NRaRb、-NRaS(O)2Rb、-NRaS(O)2ORb、-NRaS(O)2NRaRb3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
L1、L2each independently selected from C1-6Alkylene radical, C2-6Alkenylene radical, C2-6An alkynylene group;
or L2And M3Together form a 3-10 membered cycloalkyl, 3-10 membered heterocycle unsubstituted or substituted by one or more Q2Or 5-6 membered monoheteroaryl; each Q2 is independently selected from amino, hydroxy, halogen, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkoxy, -ORa、-SRa、-NRaRb、-C(O)Ra、-C(O)ORa、-OC(O)Ra、-OC(O)ORa、-OC(O)NRaRb、-C(O)NRaRb、-NRaC(O)Rb、-NRaC(O)ORb、-NRaC(O)NRaRb、-S(O)Ra、-S(O)ORa、-OS(O)Ra、-OS(O)ORa、-OS(O)NRaRb、-S(O)NRaRb、-NRaS(O)Rb、-NRaS(O)ORb、-NRaS(O)NRaRb、-S(O)2Ra、-S(O)2ORa、-OS(O)2Ra、-OS(O)2ORa、-OS(O)2NRaRb、-S(O)2NRaRb、-NRaS(O)2Rb、-NRaS(O)2ORbor-NRaS(O)2NRaRb；
Each Ra、RbEach independently selected from hydrogen and C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkoxy, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocyclyl, 6-to 10-membered aryl or 5-to 10-membered heteroaryl;
p is selected from 0, 1,2,3,4, 5.
In certain preferred embodiments, wherein,
ring A is selected from 3-8 membered monocyclic cycloalkyl, 8-10 membered fused ring cycloalkyl, 3-8 membered heteromonocyclic group, 8-10 membered fused heterocyclic group, 6-8 membered monocyclic aryl, 8-10 membered fused ring aryl, 5-8 membered monocyclic heteroaryl, 8-10 membered fused heteroaryl;
L1、L2each independently selected from C1-6Alkylene radical, C2-6Alkenylene radical, C2-6An alkynylene group;
or L2And M3Together form a 3-8 membered monocyclic cycloalkyl, 8-10 membered fused ring cycloalkyl, 3-8 membered heteromonocyclic group, 8-10 membered fused ring heterocyclyl or 5-8 membered monoheteroaryl unsubstituted or substituted with one or more Q2; each Q2 is independently selected from amino, hydroxy, halogen, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkoxy, -ORa、-SRa、-NRaRb、-C(O)Ra、-C(O)ORa、-OC(O)Ra、-OC(O)ORa、-OC(O)NRaRb、-C(O)NRaRb、-NRaC(O)Rb、-NRaC(O)ORb、-NRaC(O)NRaRb、-S(O)Ra、-S(O)ORa、-OS(O)Ra、-OS(O)ORa、-OS(O)NRaRb、-S(O)NRaRb、-NRaS(O)Rb、-NRaS(O)ORb、-NRaS(O)NRaRb、-S(O)2Ra、-S(O)2ORa、-OS(O)2Ra、-OS(O)2ORa、-OS(O)2NRaRb、-S(O)2NRaRb、-NRaS(O)2Rb、-NRaS(O)2ORbor-NRaS(O)2NRaRb；
Each Ra、RbEach independently selected from hydrogen and C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkoxy, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocyclyl, 6-to 10-membered aryl or 5-to 10-membered heteroaryl.
In certain preferred embodiments, wherein X is1、X3Are all CH; x2、X4、X5Are all N.
In certain preferred embodiments, ring a is selected from 5-6 membered monoheteroaryl.
In certain preferred embodiments, ring a is selected from 6-membered nitrogen-containing monoheteroaryl.
In certain preferred embodiments, L2And M3Together form a 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, which is unsubstituted or substituted with one or more Q2; the substituent Q2 is as described hereinbefore.
In certain preferred embodiments, L2And M3Together form an unsubstituted 5-6 membered monocyclic cycloalkyl or 5-6 membered monocyclic heterocyclyl.
In certain preferred embodiments, L2And M3Together form an unsubstituted 5-6 membered monocyclic saturated cycloalkyl group or a 5-6 membered saturated nitrogen-containing heteromonocyclic group.
In certain embodiments, the compound, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, further has a structure represented by formula (II),
Figure BDA0001974801310000051
wherein, X5Selected from CH or N;
M1、M2、M3each independently selected from-C (R)2)(R3)-、-N(R4) -, -O-, -S-, -S (O) -or-S (O)2-；
Ring A is selected from 3-6 membered monocyclic heterocyclic group, 8-10 membered fused heterocyclic group, phenyl group, naphthyl group, 5-6 membered monocyclic heteroaryl group, 8-10 membered fused heteroaryl group;
each R1、R2、R3、R4Each independently selected from hydrogen, halogen, nitro, cyano, unsubstituted C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkoxy, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocyclyl, 6-to 10-membered aryl or 5-to 10-membered heteroaryl;
L1is selected from C1-6Alkylene radical, C2-6Alkenylene radical, C2-6An alkynylene group;
L2and M3Together form a 3-6 membered saturated monocyclic cycloalkyl, 3-6 membered saturated monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, which is unsubstituted or substituted with one or more Q2; each Q2 is independently selected from amino, hydroxy, halogen, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl or halo C1-6An alkoxy group;
p is selected from 0, 1,2,3,4, 5.
In certain preferred embodiments, the compound, pharmaceutically acceptable salt thereof, ester thereof or stereoisomer thereof, as described hereinbefore, wherein ring a is selected from 5-6 membered mono heterocyclic group, 8-10 membered oxygen containing fused heterocyclic group, phenyl, naphthyl or 5-6 membered mono heteroaryl.
In certain preferred embodiments, ring A is selected from 5-6 membered mono heterocyclyl, phenyl, or 5-6 membered mono heteroaryl.
In certain preferred embodiments, ring A is selected from a 5-6 membered nitrogen containing monoheterocyclyl, phenyl, or a 5-6 membered nitrogen containing monoheteroaryl.
In certain preferred embodiments, ring a is selected from a 6-membered nitrogen-containing monoheterocyclyl or a 6-membered nitrogen-containing monoheteroaryl.
In certain preferred embodiments, L1Is selected from C1-4An alkylene group;
L2and M3Group in commonTo a 5-6 membered saturated monocyclic cycloalkyl, 5-6 membered nitrogen containing saturated monocyclic heterocyclyl unsubstituted or substituted with one or more Q2; each Q2 is independently selected from amino, hydroxy, halogen, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl or halo C1-6An alkoxy group.
In certain preferred embodiments, L1Is selected from C1-4An alkylene group;
L2and M3Together form an unsubstituted 5-6 membered saturated monocyclic cycloalkyl group, a 5-6 membered nitrogen containing saturated monocyclic heterocyclyl group.
In certain preferred embodiments, the compound, pharmaceutically acceptable salt thereof, ester thereof, or stereoisomer thereof, as described hereinbefore, wherein,
X5is N;
M1、M2、M3each independently selected from-C (R)2)(R3)-、-N(R4) -or-O-;
ring A is selected from a 5-6 membered nitrogen containing mono-heterocyclyl, phenyl or a 5-6 membered nitrogen containing mono-heteroaryl;
each R1Each independently selected from hydrogen, halogen, nitro, cyano, and unsubstituted C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, halo C1-4Alkyl, hydroxy C1-4Alkyl, amino C1-4Alkyl or halo C1-4An alkoxy group;
R2、R3、R4each independently selected from hydrogen, halogen, unsubstituted C1-4Alkyl or halo C1-4An alkyl group;
L1is selected from C1-4An alkylene group;
L2and M3Together form a 5-6 membered saturated monocyclic cycloalkyl or 5-6 membered nitrogen containing saturated monocyclic heterocyclyl unsubstituted or substituted with one or more Q2; each Q2 is independently selected from amino and hydroxyHalogen, nitro, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, halo C1-4Alkyl, hydroxy C1-4Alkyl, amino C1-4Alkyl or halo C1-4An alkoxy group;
p is selected from 1,2 or 3.
In certain preferred embodiments, the compound, pharmaceutically acceptable salt thereof, ester thereof, or stereoisomer thereof, as described hereinbefore, wherein,
X5is N;
M1、M2、M3each independently selected from-C (R)2)(R3)-、-N(R4) -or-O-;
ring a is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, hexahydropyridazinyl, hexahydropyrazinyl, hexahydropyrimidinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl;
each R1Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, ethylamino, diethylamino, trifluoromethyl, trifluoromethoxy, hydroxymethyl, hydroxyethyl, aminomethyl or aminoethyl;
R2、R3、R4each independently selected from hydrogen, fluoro, chloro, bromo, iodo, unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl or trifluoroethyl;
L1is selected from-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH(CH2)CH2-、-CH2CH(CH2)-、-CH2CH2CH2CH2-、-CH(CH2)CH2CH2-、-CH2CH(CH2)CH2-、-CH2CH2CH(CH2)-、-CH(CH2CH2)CH2-、-CH2CH(CH2CH2) -or-CH (CH)2)CH(CH2)-；
L2And M3Together form cyclopentyl, cyclohexyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, hexahydropyridazinyl, hexahydropyrazinyl, or hexahydropyrimidinyl which are unsubstituted or substituted with one or more Q2; each Q2 is independently selected from amino, hydroxy, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, ethylamino, diethylamino, trifluoromethyl, trifluoromethoxy, hydroxymethyl, hydroxyethyl, aminomethyl, or aminoethyl;
p is selected from 1,2 or 3.
In certain preferred embodiments, the compound, pharmaceutically acceptable salt thereof, ester thereof, or stereoisomer thereof, as described hereinbefore, wherein,
L1is selected from-CH2CH2-、-CH2CH2CH2-、-CH(CH2)CH2-、-CH2CH(CH2)-、-CH2CH2CH2CH2-、-CH(CH2)CH2CH2-、-CH2CH(CH2)CH2-、-CH2CH2CH(CH2) -or-CH (CH)2)CH(CH2)-；
L2And M3Together form cyclopentyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, or piperidinyl groups.
In certain preferred embodiments, L1Is selected from-CH2CH2CH2-、-CH(CH2)CH2-or-CH2CH(CH2)-。
In certain preferred embodiments, L2And M3Together form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, or piperidinyl groups.
In certain preferred embodiments, the compound, pharmaceutically acceptable salt thereof, ester thereof, or stereoisomer thereof, as described hereinbefore, wherein,
ring a is selected from pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl.
In certain preferred embodiments, each R is1Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy;
p is selected from 1 or 2.
In certain preferred embodiments, p is 1.
In certain preferred embodiments, M1、M3is-N (R)4)-；M2Is selected from-C (R)2)(R3)-、-N(R4) -or-O-;
R2、R3each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, unsubstituted methyl, ethyl, propyl, isopropyl or trifluoromethyl;
R4selected from hydrogen, unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
Any substituent and any optional group thereof in the technical schemes in the application can be combined with each other to form a new and complete technical scheme, and the formed new technical scheme is included in the scope of the invention.
In certain embodiments, the compound of formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, is selected from the group consisting of:
Figure BDA0001974801310000081
Figure BDA0001974801310000091
in another aspect, the present application further provides a pharmaceutical preparation, which contains the compound of the aforementioned general formula (I), (II), its pharmaceutically acceptable salt, its ester or its stereoisomer, and one or more pharmaceutically acceptable excipients, and the pharmaceutical preparation can be in any pharmaceutically acceptable dosage form. Pharmaceutically acceptable excipients are substances which are non-toxic, compatible with the active ingredient and otherwise biologically suitable for use in the organism. The choice of a particular excipient will depend on the mode of administration or disease type and state used to treat a particular patient. Examples of the pharmaceutically acceptable excipient include, but are not limited to, solvents, diluents, dispersing agents, suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, binders, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, antioxidants, and the like, which are conventional in the pharmaceutical field. If necessary, a flavor, a preservative, a sweetener and the like may be further added to the pharmaceutical composition.
In certain embodiments, the pharmaceutical formulations described above may be administered to a patient or subject in need of such treatment by oral, parenteral, rectal, or pulmonary administration, among others. For oral administration, the pharmaceutical composition can be prepared into oral preparations, for example, conventional oral solid preparations such as tablets, capsules, pills, granules and the like; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, the pharmaceutical preparations can also be prepared into injections, including injections, sterile powders for injection, and concentrated solutions for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding suitable additives according to the properties of the medicine. For rectal administration, the pharmaceutical composition may be formulated as a suppository or the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalation formulation, aerosol, powder spray, or the like.
In another aspect, the present application also provides a pharmaceutical composition comprising a compound of the aforementioned general formula (I), (II), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, and one or more second therapeutically active agents which can be used in combination with the tyrosine kinase inhibitor compounds of the present application for the treatment and/or prevention of related diseases mediated thereby, such as pain, cancer, inflammation, neurodegenerative diseases, autoimmune diseases, infectious diseases, and the like.
The pain disease refers to pain of any origin or etiology. Therapeutically active agents suitable for use in combination treatment of painful conditions include, but are not limited to: nav1.7 channel modulators, opioid analgesics, nonsteroidal anti-inflammatory drugs, sedatives, selective/nonselective cyclooxygenase inhibitors, antiepileptics, antidepressants, local anesthetics, 5-HT receptor blockers, 5-HT receptor agonists, ergot alkaloids, beta body receptor blockers, M receptor blockers, nitrates, vitamin K, and the like.
Second therapeutically active agents suitable for use in the combination treatment of cancer include, but are not limited to: mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal drugs, angiogenesis inhibitors, cytostatic agents, targeting antibodies, HMG-CoA reductase inhibitors, prenyl protein transferase inhibitors, and the like.
Therapeutically active agents suitable for use in combination treatment of painful conditions include, but are not limited to: steroidal drugs and non-steroidal drugs.
Therapeutically active agents suitable for use in combination treatment of painful conditions include, but are not limited to: dopamine-mimetic agents, dopamine receptor agonists, agents affecting dopamine metabolism, NMDA receptor antagonists, adenosine A2AReceptor inhibitors, influencing DA ReleaseAnd reuptake drugs, central anticholinergic drugs, cholinesterase inhibitors, 5-HT agonists, alpha 2 adrenergic receptor antagonists, antidepressants, cholinergic receptor agonists, beta-gamma secretase inhibitors, H3 receptor antagonists, antioxidant drugs, etc
The autoimmune disease includes, but is not limited to, one or more of rheumatoid arthritis, sjogren's syndrome, type I diabetes, and lupus erythematosus. Therapeutically active agents suitable for use in combination treatment of painful conditions include, but are not limited to: antirheumatic, nonsteroidal anti-inflammatory drug, glucocorticoid drug, TNF antagonist, NSAIDs drug, cyclophosphamide, mycophenolate mofetil, cyclosporine, etc. for improving disease condition.
In certain embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients, as described above.
In certain embodiments, the compound of formula (I), (II), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof and the second therapeutically active agent may be present in the same formulation, i.e., in a combined formulation, or may be present in separate formulations for simultaneous or sequential administration to a subject.
In another aspect, the present application also relates to the use of the compound of the aforementioned general formula (I), (II), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, for the preparation of a medicament for the treatment and/or prevention of a related disease mediated by one or more tyrosine kinases of TRK, ALK and ROS 1.
In certain embodiments, the related diseases mediated by one or more tyrosine kinases of TRK, ALK, and ROS1 include, but are not limited to, pain, cancer, inflammation, neurodegenerative disease, autoimmune disease, infectious disease, and the like.
In certain embodiments, the cancer mediated by one or more tyrosine kinases of TRK, ALK, and ROS1 comprises a cancer that is at least partially resistant to one or more existing target therapeutically active agents.
In certain embodiments, the cancer resistance is caused by one or more mutations in the genes encoding the TRK, ALK, and ROS1 kinase proteins.
In certain embodiments, the cancer contains one or more of a TRK mutation, an ALK mutation, and a ROS1 mutation.
In certain preferred embodiments, the TRK mutation is selected from one or more of G595R and G623R; the ROS1 mutation is selected from G2032R.
In certain embodiments, the compounds of the present application are also useful for treating tyrosine kinase mediated disorders associated with the group consisting of JAK2, SRC, FYN, LYN, YES, FGR, FAK, ARK5, or any combination thereof, preferably cancer.
In another aspect, the present application also provides a method for treating a related disease mediated by one or more tyrosine kinases of TRK, ALK and ROS1, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or (II) as described above, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, a pharmaceutical preparation as described above, or a pharmaceutical composition as described above; the tyrosine kinase mediated related disease of one or more of TRK, ALK and ROS1 is as described above.
In certain embodiments, the TRK, ALK, and ROS1 include wild-type and mutant versions thereof.
By "effective amount" is meant a dosage of a drug that reduces, delays, inhibits or cures a condition in a subject. The size of the administered dose is determined by the administration mode of the drug, the pharmacokinetics of the medicament, the severity of the disease, the individual physical signs (sex, weight, height, age) of the subject, and the like.
In another aspect, the present application also provides a process for the preparation of compounds of general formula (I), including, but not limited to, the following steps:
Figure BDA0001974801310000121
(1) under the action of a solvent and/or a catalytic reagent, carrying out multi-step substitution reaction on the intermediate 1 and the intermediate 2 at a proper temperature to obtain an intermediate 3;
(2) carrying out substitution reaction on the intermediate 3 and the intermediate 4 under the action of an organic solvent and a catalyst to obtain an intermediate 5;
(3) the intermediate 5 is subjected to ester hydrolysis reaction under acidic or alkaline conditions, deprotection reaction under acidic conditions, and cyclization reaction under the action of a catalytic reagent or an activating agent to obtain a compound shown in the formula (I);
the substituent groups in the above formula are as defined above; x is selected from halogen, hydroxyl or amino; the protecting group is selected from benzyloxycarbonyl, tert-butoxycarbonyl, benzyl, p-methoxyphenyl, acetyl, methoxymethyl ether, 2-methoxyethoxymethyl ether or p-methoxybenzyl ether; the solvent is selected from a single organic solvent, a single inorganic solvent or a mixed solvent. The organic solvent includes common reaction solvents known to those skilled in the art, including polar solvents and non-polar solvents, such as halogenated hydrocarbons, alcohols, ketones, nitriles, esters, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, N-dimethylformamide dimethyl acetal, N-methylpyrrolidone, and the like.
The inorganic solvent includes water and the like.
The mixed solvent is a mixture of two or more mutually soluble different solvents, and includes an organic solvent mixed solvent, an organic solvent/inorganic solvent mixed solvent, an inorganic solvent mixed solvent, and the like, wherein the organic solvent and the inorganic solvent are defined as above.
The catalytic reagent comprises a palladium catalyst, a dehydration catalyst, a base catalyst and an acid catalyst; the palladium catalyst comprises palladium acetate, palladium tetratriphenylphosphine, palladium dichlorotriphenylphosphine and Pd (dppf) Cl2Etc.; such as diethyl azodicarboxylate, azobispiperidine azodicarboxylate, tri-n-butylphosphine, etc.; the base catalyst includes organic bases and inorganic bases, preferably organic bases, more preferably organic amine bases such as triethylamine, pyridine, 4-dimethylaminopyridine, N-diisopropylethylamine, DIEA, etc.; all acid catalysts include organic and inorganic acids, preferably hydrochloric acid, trifluoroacetic acid and the like.
The activating agent refers to a reagent that activates a reactant to facilitate a chemical reaction, such as a carboxyl activating agent, including, but not limited to, 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC), N, N ' -Carbonyldiimidazole (CDI), N, N ' -Dicyclohexylcarbodiimide (DCC), N-hydroxysuccinimide (NHS), O-benzotriazole-tetramethyluronium Hexafluorophosphate (HBTU), 2- (7-oxybenzotriazole) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), 1-hydroxybenzotriazole (HOBt), or N, N ' -disuccinimidyl carbonate (DSC), and the like.
The substitution reaction may be, for example, a reaction of forming an ester between an acid and an alcohol, dehydration between alcohols to an ether, dehydration between carboxylic acids to an acid anhydride, or the like
The deprotection reaction is a reaction for removing a protecting group of a hydroxyl group or an amino group, and the protecting group is as described above.
The cyclization reaction refers to a cyclization reaction, and can be a reaction for generating lactam by amide condensation, or a reaction for generating lactone by an acylation reagent or acid and hydroxyl.
The intermediates described in the preparation process of the present application are commercially or self-prepared, and can be obtained by a person skilled in the art according to known conventional chemical reaction preparation methods, and the preparation method is also within the protection scope of the present application.
In the specification and claims of this application, compounds are named according to chemical structure, and if the name and chemical structure of a compound do not match when referring to the same compound, the chemical structure controls.
In the present application, unless otherwise defined, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art, however, in order to better understand the present invention, definitions of some terms are provided below. Where a definition of a term provided herein does not correspond to a meaning commonly understood by one of ordinary skill in the art, the definition and interpretation of the term provided herein shall control.
The "halogen" as referred to herein means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
Described in the invention "C1-6Alkyl "denotes straight or branched alkyl having 1 to 6 carbon atoms, including for example" C1-5Alkyl group "," C1-4Alkyl group "," C1-3Alkyl group "," C1-2Alkyl group "," C2-6Alkyl group "," C2-5Alkyl group "," C2-4Alkyl group "," C2-3Alkyl group "," C3-6Alkyl group "," C3-5Alkyl group "," C3-4Alkyl group "," C4-6Alkyl group "," C4-5Alkyl group "," C5-6Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" according to the invention1-4Alkyl "means C1-6Specific examples of the alkyl group having 1 to 4 carbon atoms.
"C" according to the invention1-6Alkylene "refers to a straight or branched chain alkane containing 1 to 6 carbon atoms derived from the removal of two hydrogens not on the same carbon atom, and includes" C1-5Alkylene group "," C1-4Alkylene group "," C1-3Alkylene group "," C1-2Alkylene ", specific examples include, but are not limited to: -CH2-、-CH2CH2-、-CH2CH2CH2-、-CH(CH2)CH2-、-CH2CH2CH2CH2-、-CH(CH2)CH2CH2-、-CH(CH2CH2)CH2-、-C(CH2)(CH2)CH2-、-CH2CH2CH2CH2CH2-and the like.
"C" according to the invention1-6Alkoxy "means" C1-6alkyl-O- ", said" C1-6Alkyl "is as defined above."C" according to the invention1-4Alkoxy "means" C1-4alkyl-O- ", said" C1-4Alkyl "is as defined above.
"C" according to the invention2-6The "alkenyl group" means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms and containing at least one double bond, and includes, for example, "C2-5Alkenyl group "," C2-4Alkenyl group "," C2-3Alkenyl group "," C3-6Alkenyl group "," C3-5Alkenyl group "," C3-4Alkenyl group "," C4-6Alkenyl group "," C4-5Alkenyl group "," C5-6Alkenyl groups "and the like. Examples include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1, 3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1, 3-pentadienyl, 1, 4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1, 4-hexadienyl and the like.
"C" according to the invention2-6Alkenylene refers to a group derived from a straight or branched chain alkene containing at least one double bond and having 2 to 6 carbon atoms by removing two hydrogens not on the same carbon atom, and includes "C2-5Alkenylene group and C2-4Alkenylene group and C2-3Alkenylene ", specific examples include, but are not limited to: -CH ═ CH-, -CH ═ CHCH2-、-C(CH2)＝CH-、-CH＝CHCH2CH2-、-CH2CH＝CHCH2-、-C(CH2)＝C(CH2) -and the like.
"C" according to the invention2-6Alkynyl "refers to a straight or branched chain alkynyl group containing at least one triple bond and having 2 to 6 carbon atoms, including, for example," C2-5Alkynyl group "," C2-4Alkynyl group "," C2-3Alkynyl group "," C3-6Alkynyl group "," C3-5Alkynyl group "," C3-4Alkynyl group "," C4-6Alkynyl "and the like. Examples include, but are not limited to: ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1, 3-butadiynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexenyl and the like.
"C" according to the invention2-6Alkynylene "refers to a straight or branched chain alkyne having at least one triple bond and 2-6 carbon atoms, derived from the removal of two hydrogens not located on the same carbon atom, and includes" C2-5Alkynylene group and C2-4Alkynylene group and C2-3Alkynylene ", specific examples include, but are not limited to:
Figure BDA0001974801310000141
and the like.
The "hydroxy group C" of the present invention1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl "means C1-6The hydrogen in the alkyl group is substituted with one or more of hydroxyl, amino or halogen, respectively. C1-6Alkyl is as previously defined
The "halo C" of the present invention1-6Alkoxy "means" C1-6The hydrogen in alkoxy "is substituted with one or more halogens.
"C" according to the invention1-6Alkylamino radical, di (C)1-6Alkyl) amino "means independently C1-6alkyl-NH-, (C)1-6Alkyl radical)2N-。
The "3-to 10-membered cycloalkyl" described in the present invention includes "3-to 8-membered monocyclic cycloalkyl" and "8-to 10-membered fused ring cycloalkyl".
The "3-8 membered monocyclic cycloalkyl" as used herein means a saturated or partially saturated monocyclic cyclic alkyl group having 3 to 8 carbon atoms and having no aromaticity, and includes "3-8 membered saturated monocyclic cycloalkyl" and "3-8 membered partially saturated monocyclic cycloalkyl"; preferred are "3-4 membered monocyclic cycloalkyl", "3-5 membered monocyclic cycloalkyl", "3-6 membered monocyclic cycloalkyl", "4-6 membered monocyclic cycloalkyl", "5-6 membered monocyclic cycloalkyl", "3-6 membered saturated monocyclic cycloalkyl", "5-7 membered saturated monocyclic cycloalkyl", "5-6 membered saturated monocyclic cycloalkyl" and the like. Specific examples of said "3-to 8-membered saturated cycloalkyl" include, but are not limited to: a cyclopropane group (cyclopropyl), a cyclobutane group (cyclobutyl), a cyclopentyl group (cyclopentyl), a cyclohexane group (cyclohexyl), a cycloheptyl group (cycloheptyl), a cyclooctyl group (cyclooctyl), etc.; specific examples of the "3-to 8-membered partially saturated cycloalkyl group" include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexa-1, 3-diene, cyclohexa-1, 4-diene, cycloheptenyl, cyclohepta-1, 3-dienyl, cyclohepta-1, 4-dienyl, cyclohepta-1, 3, 5-trienyl, cyclooctenyl, cycloocta-1, 3-dienyl, cycloocta-1, 4-dienyl, cycloocta-1, 5-dienyl, cycloocta-1, 3, 5-trienyl, cyclooctatetraenyl and the like.
The 8-10 membered fused ring alkyl group refers to a saturated or partially saturated non-aromatic cyclic group containing 8-10 ring atoms, which is formed by two or more cyclic structures sharing two adjacent carbon atoms, wherein one ring in the fused ring can be an aromatic ring, but the fused ring does not have aromaticity; including "8-9-membered fused ring group", "9-10-membered fused ring group", etc., the fusion mode may be: 5-6 membered monocyclic cycloalkyl and 5-6 membered monocyclic cycloalkyl, benzo 5-6 membered monocyclic cycloalkyl, and the like. Examples include, but are not limited to: bicyclo [3.1.0] hexanyl, bicyclo [4.1.0] heptanyl, bicyclo [2.2.0] hexanyl, bicyclo [3.2.0] heptanyl, bicyclo [4.2.0] octanyl, octahydropentanyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthryl, bicyclo [3.1.0] hex-2-enyl, bicyclo [4.1.0] hept-3-enyl, bicyclo [3.2.0] hept-3-enyl, bicyclo [4.2.0] oct-3-enyl, 1,2,3,3 a-tetrahydropentanyl, 2,3,3a,4,7,7 a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8 a-octahydronaphthyl, 1,2,4a,5,6,8 a-hexahydronaphthyl, 1,2,3,4,5, 8 a-hexahydronaphthyl, 10-decahydrophenanthryl, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl, and the like.
The "3-to 10-membered heterocyclic group" described in the present invention includes "3-to 8-membered heteromonocyclic group" and "8-to 10-membered fused heterocyclic group".
The "3-to 8-membered heteromonocyclic group" according to the present invention means a saturated or partially saturated and non-aromatic monocyclic cyclic group containing at least one hetero atom (e.g., 1,2,3,4 or 5) which is a nitrogen atom, an oxygen atom and/or a sulfur atom and has 3 to 8 ring atoms, and optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo. The "3-to 8-membered heteromonocyclic group" described in the present invention includes "3-to 8-membered saturated heterocyclic group" and "3-to 8-membered partially saturated heterocyclic group". Preferably, the "3-8 membered heteromonocyclic group" described herein contains 1-3 heteroatoms; preferably, the "3-to 8-membered heteromonocyclic group" of the present invention contains 1 to 2 hetero atoms selected from nitrogen atom and/or oxygen atom; preferably, the "3-to 8-membered heteromonocyclic group" described herein contains 1 nitrogen atom. The "3-to 8-membered heterocyclic group" is preferably "3-to 6-membered heterocyclic group", "4-to 6-membered heterocyclic group", "6-to 8-membered heterocyclic group", "5-to 7-membered heterocyclic group", "5-to 6-membered heterocyclic group", "3-to 6-membered saturated heterocyclic group", "5-to 6-membered saturated heterocyclic group", "3-to 6-membered nitrogen-containing heterocyclic group", "3-to 6-membered saturated nitrogen-containing heterocyclic group", "5-to 6-membered saturated nitrogen-containing heterocyclic group", etc. For example, containing only 1 or 2 nitrogen atoms, or, alternatively, containing one nitrogen atom and 1 or 2 other heteroatoms (e.g., oxygen and/or sulfur atoms). Specific examples of "3-8 membered heteromonocyclic group" include, but are not limited to: aziridinyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuryl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidonyl, dihydropiperidonyl, piperazinyl, morpholinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, oxazolidinyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl and the like.
The "8-to 10-membered fused heterocyclic group" as used herein means a saturated or partially saturated, nonaromatic cyclic group containing 8 to 10 ring atoms, at least one of which may be an aromatic ring but the whole fused ring may not have aromaticity, which is formed by two or more cyclic structures sharing two adjacent atoms with each other, and at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo, and includes, but is not limited to, "8-to 9-membered fused heterocyclic group", "9-to 10-membered fused heterocyclic group" and the like, which may be fused in such a manner as 5-to 6-membered heteromonocyclic group, 5-to 6-membered monocyclic cycloalkyl group, Benzo 5-6 membered heteromonocyclic group, 5-6 membered monoheteroaryl and 5-6 membered heteromonocyclic group; 5-6 membered mono heteroaryl is as defined below; specific examples of the "8-to 10-membered fused heterocyclic group" include, but are not limited to: pyrrolidinyl cyclopropyl, cyclopenta-cyclopropyl, pyrrolidinyl cyclobutyl, pyrrolidinyl, pyrrolidinyl piperidinyl, pyrrolidinyl piperazinyl, pyrrolidinyl morpholinyl, piperidinyl morpholinyl, pyrrolidinyl, tetrahydroimidazo [4,5-c ] pyridinyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, benzo [ d ] [1,3] dioxolyl, 1, 3-dihydroisobenzofuranyl, 2H-chromenyl, 2H-chromen-2-one, 4H-chromenyl, 4H-chromen-4-one, chromanyl, 4H-1, 3-benzoxazinyl, 4, 6-dihydro-1H-furo [3,4-d ] imidazolyl, pyrrolidinyl cyclopropyl, piperidinyl, morpholinyl, pyrrolidinyl, piperidinyl, pyrrolidinyl, 1, 3-dihydroquinazolinyl, 2H-chromenyl, 4-one, 4H-1, 3-d, 4-d, and the like, 3a,4,6,6 a-tetrahydro-1H-furo [3,4-d ] imidazolyl, 4, 6-dihydro-1H-thieno [3,4-d ] imidazolyl, 4, 6-dihydro-1H-pyrrolo [3,4-d ] imidazolyl, benzimidazolyl, octahydro-benzo [ d ] imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuroimidazolyl, 4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazolyl, octahydrocyclopenta [ c ] pyrrolyl, indolinyl, dihydroisoindolyl, benzoxazolinyl, benzothiazolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2,3, 4-tetrahydroquinolinyl, 4H-1, 3-benzoxazinyl, and the like.
The "6-to 10-membered aryl" as referred to in the present invention includes "6-to 8-membered monocyclic aryl" and "8-to 10-membered fused ring aryl".
The "6-to 8-membered monocyclic aryl" as referred to herein means a monocyclic aryl group containing 6 to 8 ring carbon atoms, examples of which include, but are not limited to: phenyl, cyclooctatetraenyl, and the like; phenyl is preferred.
The "8-to 10-membered fused ring aryl" as referred to herein means an unsaturated aromatic cyclic group having 8 to 10 ring carbon atoms, formed by two or more cyclic structures sharing two adjacent atoms with each other, and is preferably a "9-to 10-membered fused ring aryl", and specific examples thereof are naphthyl and the like.
The "5-to 10-membered heteroaryl" as referred to herein includes "5-to 8-membered monoheteroaryl" and "8-to 10-membered fused heteroaryl".
The "5-to 8-membered monoheteroaryl group" according to the present invention means a monocyclic cyclic group having aromaticity, which contains 5 to 8 ring atoms, at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. The "5-to 8-membered monoheteroaryl group" includes, for example, "5-to 7-membered monoheteroaryl group", "5-to 6-membered nitrogen-containing monoheteroaryl group", "6-membered nitrogen-containing monoheteroaryl group", and the like, in which the hetero atom contains at least one nitrogen atom, for example, contains only 1 or 2 nitrogen atoms, or contains one nitrogen atom and the other 1 or 2 hetero atoms (for example, oxygen atom and/or sulfur atom), or contains 2 nitrogen atoms and the other 1 or 2 hetero atoms (for example, oxygen atom and/or sulfur atom). Specific examples of "5-to 8-membered monocyclic heteroaryl" include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepinyl, 1, 3-diazacycloheptenyl, azepinyl, and the like. The "5-6 membered monoheteroaryl" refers to a specific example containing 5 to 6 ring atoms in the 5-8 membered heteroaryl.
The "8-to 10-membered fused heteroaryl group" as used herein refers to an unsaturated aromatic cyclic structure having 8 to 10 ring atoms (at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom) formed by two or more cyclic structures sharing two adjacent atoms with each other. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. Including "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", etc., which can be fused in a manner of benzo 5-6 membered monoheteroaryl, 5-6 membered monoheteroaryl and 5-6 membered monoheteroaryl, etc.; specific examples include, but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furothiophene, pyrazoloxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, and the like.
In the structural formula of the compound, when the chemical bond connected with the chiral carbon atom is a direct bond' -, the compound is racemic, namely, the compound contains each single isomer generated by the chiral carbon atom.
The expression "carbon atom, nitrogen atom or sulfur atom is oxo" as used herein means that C-O, N-O, S-O or SO is formed2The structure of (1).
The term "optionally substituted" in the present invention includes both "substituted" and "unsubstituted".
"pharmaceutically acceptable salt" as used herein refers to an acidic functional group (e.g., -COOH, -OH, -SO) present in a compound3H, etc.) with a suitable inorganic or organic cation (base), including salts with alkali or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and salts of basic functional groups present in the compounds (e.g., -NH2, etc.) with suitable inorganic or organic anions (acids), including salts with inorganic or organic acids (e.g., carboxylic acids, etc.).
"stereoisomers" as used herein refers to compounds of the invention when they contain one or more asymmetric centers and thus may be present as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention may have asymmetric centers that each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. The compounds of the present invention, if they contain an olefinic double bond, include cis-isomers and trans-isomers, unless otherwise specified. The compounds of the invention may exist in tautomeric (one of the functional group isomers) forms having different points of attachment of hydrogen through one or more double bond shifts, e.g., a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included within the scope of the present invention. All enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of the compounds are included within the scope of the present invention.
The "dosage form" of the present invention refers to a form prepared from the drug suitable for clinical use, including, but not limited to, powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injections, sterile powders for injections and concentrated solutions for injections), sprays, aerosols, powders, lotions, liniments, ointments, plasters, pastes, patches, gargles or suppositories, more preferably powders, tablets, granules, capsules, solutions, injections, ointments, gargles or suppositories.
The technical solutions cited in the references cited in this application are included in the disclosure of the present invention, and can be used to explain the contents of the present invention.
Advantageous effects of the invention
1. The compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof has excellent tyrosine kinase inhibition activity of one or more of TRK, ALK and ROS1, has good pharmacokinetic property in vivo, has lasting effect, high exposure and high bioavailability, and can treat and/or prevent diseases mediated by one or more tyrosine kinases of TRK, ALK and ROS1 and related diseases.
2. The compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof have better therapeutic effect on cancerous diseases mediated by one or more tyrosine kinases of TRK, ALK and ROS1, and particularly on cancerous diseases with drug resistance of existing anticancer active agents.
3. The compound has good in vivo kinase activity and antitumor activity of animals, and has high in vivo and in vitro stability.
4. The compound of the invention has simple preparation process, high medicine purity, stable quality and easy large-scale industrial production.
Detailed description of the preferred embodiments
The technical solutions of the present invention will be described below with reference to specific embodiments, and the above-mentioned contents of the present invention will be further described in detail, which should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
The carbon atom marked with the "+" sign in the compound structure represents a chiral carbon atom with a single configuration, such as an R configuration or an S configuration.
Abbreviations:
ADDP, azodicarbonyl dipiperidine; DIEA: n, N' -diisopropylethylamine; DIPEA is N, N' -diisopropylethylamine; DMF: n, N-dimethylformamide; DMAP N, N-dimethyl-4-pyridylamine; EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; FDPP: pentafluorophenyl diphenyl phosphate; NBS: n-bromosuccinimide; NMP: n-methyl pyrrolidone; TMSCl is trimethylchlorosilane; XPhos 2-dicyclohexylphosphonium-2 ',4',6' -triisopropylbiphenyl.
Example 1 (2)2S,6R)-35-fluoro-6-methyl-7-aza-1 (6,3) -imidazo [1,2-b]Preparation of pyridazin-3 (3,2) -pyridinyl-2- (1,2) -pyrrolidino-cyclooctan-8-one
1. Preparation of ethyl 6-chloroimidazo [1,2-b ] pyridazine-3-carboxylate
Figure BDA0001974801310000191
Ethyl (E) -3-ethoxyacrylate (1.0g,6.94mmol), dissolved in H2NBS (1.36g,7.63mmol) is added into a mixed solvent of O (4mL) and 1, 4-dioxane (4mL) at the temperature of minus 10 ℃, after the addition is finished, the temperature is raised to 25 ℃, stirring is carried out for 1h, then 6-chloro-3-aminopyridazine (0.9g,6.94mmol) is added, after the addition is finished, the temperature is raised to 80 ℃, reaction is carried out for 1h, and TLC detection reaction is finished. The temperature was reduced to 25 ℃, diluted with water (20mL), extracted with EA (20mL × 3), the organic phases were combined, dried, concentrated, and purified by silica gel column chromatography (PE: EA ═ 1:1) to give the title compound (1.1g, yield 63.2%).
2. Preparation of ethyl 6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylate
Figure BDA0001974801310000192
5-fluoro-2-methoxy-3- (pyrrolidin-2-yl) pyridine (2.0g,10.2mmol) and ethyl 6-chloroimidazo [1,2-b ]]Pyridazine-3-carboxylate (2.5g,11.25mmol) was dissolved in NMP (10mL), DIEA (2.6g,20.4mmol) was added, and the reaction was carried out at 200 ℃ for 1.5 h. After the reaction, the reaction solution was purified by C18 column chromatography (MeCN: H)2O ═ 0% to 100%) to give the title compound (2.0g, yield 51.0%).
3. Preparation of ethyl 6- (2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylate
Figure BDA0001974801310000201
Ethyl 6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazine-3-carboxylate (2.0g,5.2mmol) was dissolved in 6M HCl/EtOH (30mL) and reacted at 80 ℃ for 12 h. Concentrating the solvent, and purifying the concentrate by C18 column chromatography (MeOH: H)2O ═ 0% to 100%) to give the title compound (1.5g, yield 77.7%).
4. Preparation of Ethyl 6- (2- (5-fluoro-2- (((trifluoromethyl) sulfonyl) oxy) pyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylate
Figure BDA0001974801310000202
Ethyl 6- (2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylate (1.5g,4.0mmol) was dissolved in DCM (20mL) and TEA (809.6mg,8.0mmol) was added. N-phenylbis (trifluoromethanesulfonyl) imide (2.1g,6.0mmol) was added at 0 ℃ and the reaction was completed at 25 ℃ for 12 h. The concentrated solvent was purified by silica gel column (PE: EA ═ 1:1) to obtain the objective compound (1.6g, yield 78.8%).
5. Preparation of Ethyl 6- (2- (2- ((R) -3- (1, 3-dioxoisoindolin-2-yl) but-1-yn-1-yl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylate
Figure BDA0001974801310000203
Ethyl 6- (2- (5-fluoro-2- (((trifluoromethyl) sulfonyl) oxy) pyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazine-3-carboxylate (503.0mg,1.0mmol) was dissolved in toluene (20mL), and Pd (PPh) was added3)2Cl2(70.2mg,0.1mmol), CuI (38.1mg,0.2mmol), DIEA (258.6mg,2.0mmol), pyridine N2Reacting at 60 ℃ for 1h under protection, adding (R) -2- (butyl-3-alkyne-2-yl) isoindoline-1, 3-diketone (299.0mg,1.5mmol), and reacting at 60 ℃ for 3 h. After completion of the reaction, the reaction mixture was quenched with water (20mL), extracted with EA (50mL × 3), combined and dried, and purified by silica gel column chromatography (PE: EA 1:1) to obtain the objective compound (230mg, yield 41.7%).
Preparation of 6- (2- (2- ((R) -3-aminobut-1-yn-1-yl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carbohydrazide
Figure BDA0001974801310000211
Ethyl 6- (2- (2- ((R) -3- (1, 3-dioxoisoindolin-2-yl) but-1-yn-1-yl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylate (230mg,0.42mmol) was dissolved in ethanol (10mL), hydrazine hydrate (80%) (1mL) was added, reaction was completed at 25 ℃ for 3h, solvent was concentrated, the solid was washed with DCM, filtered, and the filtrate was concentrated to afford the title compound (150mg, 88.1% yield).
Preparation of 6- (2- (2- ((R) -3-aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carbohydrazide
Figure BDA0001974801310000212
6- (2- (2- ((R) -3-aminobut-1-yn-1-yl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carbohydrazide (150mg,0.37mmol) was dissolved in MeOH (10mL), Pd/C (30mg) was added, after the addition was completed, reaction was carried out with a hydrogenation balloon at 25 ℃ for 2h, the reaction was filtered through celite, and the filtrate was concentrated to give the title compound (130mg, yield 87.5%).
Preparation of 6- (2- (2- ((R) -3-aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylic acid
Figure BDA0001974801310000213
Mixing 6- (2- (2- ((R) -3-aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazine-3-carbohydrazide (130mg,0.32mmol) was dissolved in 4M aqueous NaOH (25mL) and reacted at 100 ℃ for 12 h. Adjusting pH to 7 with concentrated HCl at 0 deg.C, concentrating the solvent, soaking the solid in mixed solution (DCM: MeOH 10:1), filtering, drying the filtrate, concentrating, and purifying by C18 column chromatography (MeOH: H)2O ═ 0-50%) to give the title compound (110mg, yield 88.0%).
9.(22S,6R)-35-fluoro-6-methyl-7-aza-1 (6,3) -imidazo [1,2-b]Preparation of pyridazin-3 (3,2) -pyridinyl-2- (1,2) -pyrrolidino-cyclooctan-8-one
Figure BDA0001974801310000221
6- (2- (2- ((R) -3-Aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylic acid (110mg,0.28mmol) was dissolved in DCM (8mL) and DMF (2mL), DIEA (72.4mg, 0.56mmol) and FDPP (118.3mg, 0.31mmol) were added and the reaction was completed at 25 ℃ for 10 h. The solvent was concentrated and purified by HPLC (high pressure preparative separation conditions: C18 column: 30X 250 mm; flow rate 43 mL/min; injection volume 2 mL; detection wavelength: 214nm,254nm, acetonitrile: 0-50% water) to give the title compound (8.0mg, yield 7.6%).
HPLC retention time: 6.793 min.
Molecular formula C20H21FN6O molecular weight 380.4LC-MS (M/e):381.0(M + H)+)
1H-NMR(400MHz,CDCl3)δ:8.38(d,J＝2.4Hz,1H),8.34(d,J＝7.2Hz,1H),8.16(s,1H),7.86(d,J＝9.6Hz,1H),6.84(d,J＝10Hz,1H),5.43(d,J＝6.4Hz,1H),4.47(m,1H),4.02-4.04(m,1H),3.74-3.76(m,1H),3.53(m,1H),3.12(m,1H),2.52-2.62(m,4H),2.35-2.37(m,1H),1.84-1.86(m,1H),1.24(d,J＝6.8Hz,3H).
Example 2 (2)2R,6R)-35-fluoro-6-methyl-7-aza-1 (6,3) -imidazo [1,2-b]Preparation of pyridazin-3 (3,2) -pyridinyl-2- (1,2) -pyrrolidino-cyclooctan-8-one
1. Preparation of ethyl (R) -6- (2- (5-fluoro-2- (((trifluoromethyl) sulfonyl) oxy) pyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylate
Figure BDA0001974801310000222
Ethyl (R) -6- (2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylate (400mg,1.1mmol) was dissolved in DCM (20mL), TEA (222.2mg,2.2mmol) and N-phenylbis (trifluoromethanesulfonyl) imide (583.5g,1.6mmol) were added, and the reaction was completed at 25 ℃ for 5 h. The concentrated solvent was purified by silica gel column chromatography (PE: EA ═ 1:2) to give the target compound (450mg, yield 83.0%).
2. Preparation of Ethyl 6- ((R) -2- (2- ((R) -3- (1, 3-dioxoisoindolin-2-yl) but-1-yn-1-yl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylate
Figure BDA0001974801310000231
Ethyl (R) -6- (2- (5-fluoro-2- (((trifluoromethyl) sulfonyl) oxy) pyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazine-3-carboxylate (850mg,1.7mmol) was dissolved in toluene (20mL), and Pd (PPh) was added3)2Cl2(233.6mg,0.34mmol), CuI (64.6mg,0.34mmol), DIEA (439.6mg,3.4mmol), pyridine N2The reaction is carried out for 1h at 60 ℃ under protection, and (R) -2- (butyl-3-alkyne-2-yl) isoindoline-1, 3-dione (504.7mg,2.5mmol) is added, and the reaction is carried out for 12h at 60 ℃. After completion of the reaction, the reaction mixture was quenched with water (20mL), extracted with EA (30mL × 3), combined and dried, and purified by silica gel column chromatography (DCM: MeOH ═ 30:1) to obtain the objective compound (800mg, yield 85.8%).
Preparation of 6- ((R) -2- (2- ((R) -3-aminobut-1-yn-1-yl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carbohydrazide
Figure BDA0001974801310000232
Ethyl 6- ((R) -2- (2- ((R) -3- (1, 3-dioxoisoindolin-2-yl) but-1-yn-1-yl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylate (800mg,1.45mmol) was dissolved in ethanol (50mL), hydrazine hydrate (85%) was added (10mL), reaction was completed at 25 ℃ for 4h, solvent was concentrated, solid was washed with DCM, filtered and the filtrate was concentrated to afford the title compound (600mg, crude) which was used directly in the next step.
Preparation of 6- ((R) -2- (2- ((R) -3-aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carbohydrazide
Figure BDA0001974801310000233
6- ((R) -2- (2- ((R) -3-Aminobut-1-yn-1-yl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carbohydrazide (600mg,1.45mmol) is dissolved in MeOH (30mL), Pd/C (200mg) is added, hydrogenation is completed at 25 ℃ for 24h, celite is filtered, and the filtrate is concentrated to give the title compound (350mg, yield 57.8%).
Preparation of 6- ((R) -2- (2- ((R) -3-aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylic acid
Figure BDA0001974801310000241
Mixing 6- ((R) -2- (2- ((R) -3-aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazine-3-carbohydrazide (350mg,0.85mmol) was dissolved in 4M aqueous NaOH (15mL) and reacted at 100 ℃ for 15 h. After the reaction is finished, cooling to 25 ℃, adjusting the pH value to 7 by using concentrated HCl at 0 ℃, concentrating the solvent, dissolving the solid by using methanol, filtering, drying and concentrating the filtrate, and purifying by using C18 column chromatography (MeOH: H)2O ═ 0-50%) to give the title compound (140mg, yield 41.4%).
6.(22R,6R)-35-fluoro-6-methyl-7-aza-1 (6,3) -imidazo [1,2-b]Preparation of pyridazin-3 (3,2) -pyridinyl-2- (1,2) -pyrrolidino-cyclooctan-8-one
Figure BDA0001974801310000242
Mixing 6- ((R) -2- (2- ((R) -3-aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazine-3-carboxylic acid (140mg,0.35mmol) was dissolved in DCM (8mL) and DMF (2mL), DIEA (135.7mg,1.05mmol) and FDPP (161.4mg,0.42mmol) were added, and the reaction was completed at 25 ℃ for 3 h. The solvent was concentrated and purified by HPLC (MeCN: H)2O ═ 0-50%) to give the title compound (11.0mg, yield 8.2%).
HPLC high pressure preparative separation conditions: c18 column: 30 x 250 mm; the flow rate is 43 mL/min; the sample introduction volume is 2 mL; detection wavelength: 214nm,254 nm; HPLC retention time 5.829min.
Molecular formula C20H21FN6O molecular weight 380.4LC-MS (M/e):381.0(M + H)+)
1H-NMR(400MHz,CDCl3)δ:8.38(d,J＝2.4Hz,1H),8.34(d,J＝7.2Hz,1H),8.16(s,1H),7.86(d,J＝9.6Hz,1H),6.84(d,J＝10Hz,1H),5.43(d,J＝6.4Hz,1H),4.47(m,1H),4.02-4.04(m,1H),3.74-3.76(m,1H),3.53(m,1H),3.12(m,1H),2.52-2.62(m,4H),2.35-2.37(m,1H),1.84-1.86(m,1H),1.24(d,J＝6.8Hz,3H).
Example 3 (2)2R,6R)-35-fluoro-6-methyl-4-oxa-7-aza-1 (6,3) -imidazo [1,2-b]Preparation of pyridazin-3 (3,2) -pyridinyl-2 (1,2) -pyrrolidino-cyclooctan-8-one
1. Preparation of ethyl (R) -6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylate
Figure BDA0001974801310000251
Mixing (R) -5-fluoro-2-methoxy-3- (pyrrolidin-2-yl) pyridine (1.0g,5.1mmol) and ethyl 6-chloroimidazo [1,2-b ]]Pyridazine-3-carboxylate (1.26g,5.6mmol) was dissolved in NMP (8mL), DIEA (1.3g,10.3mmol) was added, and the reaction was completed under microwave at 200 ℃ for 2 hours. TLC detection of the reaction completion, the reaction solution was purified by C18 column chromatography (MeOH: H)2O ═ 0% to 100%) to give the title compound (1.0g, yield 51.0%).
2. Preparation of ethyl (R) -6- (2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylate
Figure BDA0001974801310000252
Ethyl (R) -6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazine-3-carboxylate (1.0g,2.6mmol) was dissolved in 6M HCl/EtOH (30mL) and the reaction was completed at 80 ℃ for 10 h. After concentration of the solvent, C18 column chromatography purification (MeOH: H)2O ═ 0% to 100%) to give the title compound (600mg, yield 62.2%).
3. Preparation of Ethyl 6- ((R) -2- (2- ((R) -2- ((tert-butoxycarbonyl) amino) propoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylate
Figure BDA0001974801310000253
Ethyl (R) -6- (2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazine-3-carboxylate (400mg,1.1mmol), (R) -N-Boc-alaninol (377.6mg,2.2mmol), ADDP (554.4mg,2.2mmol) in THF (10mL), N2Tri-n-butylphosphine (444.4mg,2.2mmol) was added under protection, and the reaction was carried out at 25 ℃ for 3 hours. DCM was dissolved and purified by silica gel column chromatography (PE: EA ═ 1:1) to give the title compound (300mg, yield 52.9%).
Preparation of 6- ((R) -2- (2- ((R) -2- ((tert-butoxycarbonyl) amino) propoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2b ] pyridazine-3-carboxylic acid
Figure BDA0001974801310000261
Ethyl 6- ((R) -2- (2- ((R) -2- ((tert-butoxycarbonyl) amino) propoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazine-3-carboxylate (300mg,0.57mmol) was dissolved in a mixed solvent THF/MeOH/H2To O ═ 3:1:1(10mL), lioh was added2O (119.3mg,2.8mmol), after addition, was reacted at 25 ℃ for 5 h. After the reaction was complete, it was diluted with water, adjusted to pH 3 with 1M HCl, concentrated to remove THF and MeOH, extracted with DCM, the organic phases were combined, dried and concentrated to afford the title compound (270mg, 95.1% yield).
Preparation of 6- ((R) -2- (2- ((R) -2-aminopropoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylic acid
Figure BDA0001974801310000262
Reacting 6- ((R) -2- (2- ((R) -2- ((tert-butoxycarbonyl) amino) propoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2b]Pyridazine-3-carboxylic acid (270mg,0.54mmol) was dissolved in DCM (15mL), TFA (5mL) was added, reaction was performed at 25 ℃ for 5H, the solvent was concentrated, TEA was adjusted to pH7, C18 column chromatography purification (MeOH: H)2O ═ 0% to 50%) to give the title compound (170mg, yield 78.7%).
6.(22R,6R)-35-fluoro-6-methyl-4-oxa-7-aza-1 (6,3) -imidazo [1,2-b]Preparation of pyridazin-3 (3,2) -pyridinyl-2 (1,2) -pyrrolidino-cyclooctan-8-one
Figure BDA0001974801310000263
EDCI (165.1mg,0.86mmol) and DMAP (105.7mg,0.86mmol) were dissolved in DCM (20mL) and 6- ((R) -2- (2- ((R) -2-aminopropoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b was added]Pyridazine-3-carboxylic acid (170mg,0.43mmol) was reacted at 25 ℃ for 24 hours after the addition was completed. Purification by column chromatography on silica gel (DCM: MeOH ═ 30:1) followed by HPLC purification (MeCN: H)2O ═ 10% to 60%) to give the title compound (65mg, yield 40.0%).
HPLC high pressure preparative separation conditions: c18 column: 30 x 250 mm; the flow rate is 43 mL/min; the sample introduction volume is 2 mL; detection wavelength: 214nm,254 nm; HPLC (Small polarity) retention time 7.427min
Molecular formula C19H19FN6O2Molecular weight 382.4 LC-MS (M/e):383.4(M + H)+)
1H-NMR(400MHz,CDCl3)δ:9.91(d,J＝2.4Hz,1H),8.17(s,1H),7.84(d,J＝10Hz,1H),7.33(dd,J＝2.8Hz,1H),6.80(d,J＝9.6Hz,1H),5.57-5.60(m,1H),5.09-5.13(m,1H),4.57-4.60(m,1H),4.18-4.22(m,1H),4.02-4.08(m,1H),3.69-3.75(m,1H),2.42-2.49(m,1H),2.28-2.31(m,1H),2.00-2.07(m,1H),1.55(d,J＝6.8Hz,3H).
Example 4 (2)2R,6R)-35-fluoro-6-methyl-11H-7-aza-1 (5,3) -pyrrolo [3,2-b]Preparation of pyridine-3 (3,2) -pyridine-2 (1,2) -pyrrolidine cyclooctan-8-one
1. Preparation of diethyl 2- (6-methoxy-3-nitropyridin-2-yl) malonate
Figure BDA0001974801310000271
Sodium hydride (15.9g,397.6mmol) was dissolved in tetrahydrofuran (400mL),diethyl malonate (63.7g,397.6mmol) is added dropwise, and 2-chloro-6-methoxy-3-nitropyridine (50g,265.1mmol), N, are added after the dropwise addition2Stirring for 1 hour at 25 ℃, then heating to 80 ℃, continuing stirring for 16 hours, concentrating the reaction solution after the reaction is finished, adjusting the pH value to 6 by using 2M hydrochloric acid, washing with water, extracting by using ethyl acetate, and concentrating to obtain a crude product which is directly used for the next reaction.
2. Preparation of ethyl 2- (6-methoxy-3-nitropyridin-2-yl) acetate
Figure BDA0001974801310000272
Diethyl 2- (6-methoxy-3-nitropyridin-2-yl) malonate (crude) was added to DMSO (200mL) and H2Lithium chloride (22.5g,530.2mmol) was added to a mixed solvent of O (20mL), reacted at 120 ℃ for 48 hours, and concentrated to give a crude product which was used directly in the next reaction.
3. Preparation of ethyl 3- (dimethylamino) -2- (6-methoxy-3-nitropyridin-2-yl) acrylate
Figure BDA0001974801310000273
Adding ethyl 2- (6-methoxy-3-nitropyridin-2-yl) acetate (crude product) into DMF (500mL), adding DMF DMA (63g,530.2mmol) to react at 80 ℃ for 16 hours, concentrating, washing with water, washing with saturated salt water, drying to obtain the crude product, and directly using the crude product in the next reaction.
4. Preparation of ethyl 5-methoxy-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate
Figure BDA0001974801310000281
Ethyl 3- (dimethylamino) -2- (6-methoxy-3-nitropyridin-2-yl) acrylate (crude) was added to acetic acid (200mL), zinc powder (86g,1325mmol) was added, stirred at 60 ℃ for 16 hours, concentrated, filtered, washed with ethyl acetate, and purified by column chromatography (EA/PE 10% to 55%) to give the title product (15g, 26% over four steps).
5. Preparation of ethyl 5-hydroxy-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate
Figure BDA0001974801310000282
Ethyl 5-methoxy-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate (11g,50mmol) was dissolved in acetonitrile (120mL), TMSCl (27g,250mmol) and sodium iodide (37g,250mmol) were added, reacted at 70 ℃ for 2 hours, concentrated to give the crude product, which was used directly in the next reaction.
6. Preparation of ethyl 5-chloro-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate
Figure BDA0001974801310000283
Ethyl 5-hydroxy-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate (crude product), dissolved in phosphorus oxychloride (200mL) at 110 ℃ for 24 hours, concentrated, diluted with ethyl acetate, filtered, concentrated, and purified by column chromatography (ethyl acetate/petroleum ether ═ 0% to 75%) to give the title product (1.7g, 15% total yield over two steps).
7. Preparation of ethyl 5-chloro-1-tosyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate
Figure BDA0001974801310000284
Ethyl 5-chloro-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate (700mg,3.12mmol) was dissolved in dichloromethane (10mL), TsCl (894mg,4.68mmol) and triethylamine (631mg,6.24mmol) were added, the reaction was carried out at 25 ℃ for 16H, concentrated, and purified by column chromatography (ethyl acetate/petroleum ether ═ 0% to 85%) to give the title product (1g, yield 85%).
8. Preparation of ethyl (R) -5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -1-tosyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate
Figure BDA0001974801310000291
Ethyl 5-chloro-1-tosyl-1H-pyrrolo [3,2-b ]]Pyridine-3-carboxylate (0.4g,1.06mmol), (R) -5-fluoro-2-methoxy-3- (pyrrolidin-2-yl) pyridine (0.3g,1.53mmol), Pd (OAc)2(40mg,0.18mmol), XPhos (200mg,0.42mmol), cesium carbonate (0.55g, 1.69mmol) was added to 1, 4-dioxane (30mL), N2Stirring at 80 ℃ for 16 hours under the protection condition, concentrating, and purifying by column chromatography (EA/PE is 0% -30%) to obtain the product (400mg, yield 70.3%).
9. Preparation of ethyl (R) -5- (2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) -1-tosyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate
Figure BDA0001974801310000292
Ethyl (R) -5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -1-tosyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate (400mg,0.74mmol) was added to 6M HCl-EtOH (20mL) and reacted at 90 ℃ for 3 hours and concentrated to give the crude which was used directly in the next reaction.
10. Preparation of ethyl (R) -5- (2- (5-fluoro-2- (((trifluoromethyl) sulfonyl) oxy) pyridin-3-yl) pyrrolidin-1-yl) -1-tosyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate
Figure BDA0001974801310000293
Ethyl (R) -5- (2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) -1-tosyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate (crude) was added to DCM (20mL), phenylbis (trifluoromethanesulfonyl) imide (530mg,1.48mmol) and TEA (400mg,3.7mmol) were added, reacted at 25 ℃ for 16 hours, concentrated, purified by column chromatography (EA/PE ═ 0% to 20%) and purified by reverse phase column chromatography (acetonitrile/water ═ 30% to 90%) to give the product (380mg, 78.4% yield over two steps)
11. Preparation of ethyl 5- ((R) -2- (2- ((R) -3- (((benzyloxy) carbonyl) amino) but-1-yn-1-yl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) -1-tosyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate
Figure BDA0001974801310000301
Ethyl (R) -5- (2- (5-fluoro-2- (((trifluoromethyl) sulfonyl) oxy) pyridin-3-yl) pyrrolidin-1-yl) -1-tosyl-1H-pyrrolo [3, 2-b)]Pyridine-3-carboxylate (0.38g,0.58mmol), Pd (PPh)3)2Cl2(85mg,0.12mmol), CuI (24mg,0.13mmol), DIPEA (0.23g, 1.78mmol) were added to toluene (30mL), N2Stirring at 60 ℃ for 0.5 hour under the protection condition, adding benzyl (R) -but-3-yn-2-ylcarbamate (0.15g,0.74mmol), stirring at 60 ℃ for 16 hours, concentrating, and purifying by column chromatography (EA/PE 10% -50%) to obtain the product (250mg, yield 60.9%).
12. Preparation of Ethyl 5- ((R) -2- (2- ((R) -3-aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) -1-tosyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate
Figure BDA0001974801310000302
Ethyl 5- ((R) -2- (2- ((R) -3- (((benzyloxy) carbonyl) amino) but-1-yn-1-yl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) -1-tosyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate (200mg,2.8mmol), Pd/C (150mg, 10%) was added to methanol (50mL) and reacted under hydrogen at 25 ℃ for 16 hours, concentrated to give crude which was used directly in the next reaction.
13. Preparation of ethyl 5- ((R) -2- (2- ((R) -3-aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) -1H-pyrrolo [3,2-b ] pyridine-3-carboxylate
Figure BDA0001974801310000303
Ethyl 5- ((R) -2- (2- ((R) -3-aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) -1-tosyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate (crude), NaOH (1mL,10mmol,10M) in water was added to isopropanol (100mL) and reacted at 80 ℃ for 3 hours, NaOH (1mL,10mmol,10M) was added and the reaction was continued for 2 hours, after completion of the reaction, pH was adjusted to 3 with concentrated hydrochloric acid, concentrated and purified by reverse phase column chromatography (methanol/water 0% to 30%) to obtain crude (50mg) which was used directly in the next reaction.
Preparation of 5- ((R) -2- (2- ((R) -3-aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) -1H-pyrrolo [3,2-b ] pyridine-3-carboxylic acid
Figure BDA0001974801310000311
Ethyl 5- ((R) -2- (2- ((R) -3-aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) -1H-pyrrolo [3,2-b ] pyridine-3-carboxylate (crude) and lithium hydroxide monohydrate (50mg,1.2mmol) were dissolved in tetrahydrofuran (2mL), methanol (2mL) and water (2mL) and reacted at 25 ℃ for 16H, hydrochloric acid adjusted to pH 3, concentrated, and purified by reverse phase column chromatography (methanol/water 0% to 30%) to give crude (50mg) which was used directly in the next reaction.
15.(22R,6R)-35-fluoro-6-methyl-11H-7-aza-1 (5,3) -pyrrolo [3,2-b]Preparation of pyridine-3 (3,2) -pyridine-2 (1,2) -pyrrolidine cyclooctan-8-one
Figure BDA0001974801310000312
5- ((R) -2- (2- ((R) -3-aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) -1H-pyrrolo [3,2-b ] pyridine-3-carboxylic acid (50mg, crude), EDCI (50mg,0.25mmol), DMAP (100mg,0.82mmol) were added to DMF (6mL) and DCM (20mL) and reacted at 25 ℃ for 16H, concentrated and preparative HPLC separation (HPLC separation conditions: C18 column: 30X 250 mm; flow rate: 43 mL/min; sample volume 2 mL; detection wavelength: 214nm,254 nm; mobile phase acetonitrile: water ═ 10% to 50%) gave the product (3mg, 0.3% four step yield).
HPLC retention time: 8.100min.
Molecular formula C21H22FN5O molecular weight 379.4 LC-MS (M/e):380.2(M + H)+)
1H-NMR(400MHz,DMSO)δ:11.36(s,1H),9.24(d,J＝8.8Hz,1H),8.31(s,1H),7.64-7.69(m,2H),7.36(dd,J＝3.2Hz,J＝10.4Hz,1H),6.55(d,J＝8.8Hz,1H),5.50(m,1H),4.10-4.20(m,1H),3.50-3.60(m,2H),2.70-2.80(m,2H),2.20-2.30(m,1H),2.00-2.10(m,1H),1.90-2.00(m,1H),1.70-1.75(m,1H),1.2(d,J＝7.6Hz,3H)
Example 5 (2)2S,6S)-35-fluoro-6-methyl-4-oxa-7-aza-1 (6,3) -imidazo [1,2-b]Preparation of pyridazin-3 (3,2) -azaphen-2 (1,2) -pyrrolidino-cyclooctan-8-one
1. Preparation of Ethyl 6- (2- (2- ((S) -2- ((tert-butoxycarbonyl) amino) propoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylate
Figure BDA0001974801310000321
Ethyl 6- (2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazine-3-carboxylate (200mg,0.54mmol), (S) -N-Boc-alaninol (188.3mg,1.08mmol), ADDP (272.4mg,1.08mmol) in THF (5mL), N2Tri-n-butylphosphine (218.5mg,1.08mmol) was added under protection, and the reaction was carried out at 25 ℃ for 3 h. DCM was dissolved and purified by silica gel column chromatography (PE: EA ═ 1:2) to give the title compound (200mg, yield 70.7%).
Preparation of 6- (2- (2- ((S) -2- ((tert-butoxycarbonyl) amino) propoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2b ] pyridazine-3-carboxylic acid
Figure BDA0001974801310000322
Reacting ethyl 6- (2- (2- ((S) -2- ((tert-butoxycarbonyl) amino) propoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazine-3-carboxylate (200mg,0.38mmol) was dissolved in a mixed solvent THF/MeOH/H2To O ═ 3:1:1(10mL), lioh was added2O (63.6mg,1.5mmol), after addition, was reacted at 25 ℃ for 15 h.Dilute with water (10mL), adjust pH to 3 with 1M HCl, concentrate to remove THF and MeOH, extract with DCM, combine the organic phases and dry concentrate to give the title compound (180mg, 95.1% yield).
Preparation of 6- (2- (2- ((S) -2-aminopropoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylic acid
Figure BDA0001974801310000323
6- (2- (2- ((S) -2- ((tert-butoxycarbonyl) amino) propoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylic acid (180mg,0.36mmol) was dissolved in DCM (15mL), TFA (5mL) was added and reaction was completed at 25 ℃ for 2h, and the solvent was concentrated to give the title compound (140mg) which was used directly in the next step.
4.(22S,6S)-35-fluoro-6-methyl-4-oxa-7-aza-1 (6,3) -imidazo [1,2-b]Preparation of pyridazin-3 (3,2) -azaphen-2 (1,2) -pyrrolidino-cyclooctan-8-one
Figure BDA0001974801310000331
6- (2- (2- ((S) -2-Aminopropoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylic acid (140mg,0.35mmol) was dissolved in DCM (4mL) and DMF (2mL), DIEA (135.7mg,1.05mmol) and FDPP (161.4mg,0.42mmol) were added and the reaction was completed at 25 ℃ for 12 h. After the reaction was completed, the reaction was quenched with methanol (2mL), and purified by HPLC using a concentrated solvent (preparative high pressure separation conditions: C18 column: 30X 250 mm; flow rate 43 mL/min; sample volume 2 mL; detection wavelength: 214nm,254 nm; MeCN: H2O ═ 0% to 60%) to obtain the title compound (13mg, yield 9.7%).
Molecular formula C19H19FN6O2Molecular weight 382.4 LC-MS (M/e):383.4(M + H)+)
HPLC (polar large) retention time: 7.873min
1H-NMR(400MHz,CDCl3)δ:9.75(s,1H),8.16-8.32(m,1H),7.93(s,1H),7.30-7.37(m,1H),7.02-7.17(m,1H),5.60(s,1H),5.11-5.15(m,1H),4.59(s,1H),4.18(d,J＝10.8Hz,1H),4.09(s,1H),3.69-3.17(m,1H),2.07-2.75(m,4H),1.55(d,J＝6.4Hz,3H).
Example 6 (2)2R,6S)-35-fluoro-6-methyl-4-oxa-7-aza-1 (6,3) -imidazo [1,2-b]Preparation of pyridazin-3 (3,2) -azaphen-2 (1,2) -pyrrolidino-cyclooctan-8-one
1. Preparation of Ethyl 6- ((R) -2- (2- ((S) -2- ((tert-butoxycarbonyl) amino) propoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylate
Figure BDA0001974801310000332
Ethyl (R) -6- (2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazine-3-carboxylate (200mg,0.54mmol), (S) -N-Boc-alaninol (188.3mg,1.08mmol), ADDP (272.4mg,1.08mmol) in THF (5mL), N2Tri-n-butylphosphine (218.5mg,1.08mmol) was added under protection, and the reaction was carried out at 25 ℃ for 3 h. DCM was dissolved and purified by silica gel column chromatography (PE: EA ═ 1:2) to give the title compound (200mg, yield 70.7%).
Preparation of 6- ((R) -2- (2- ((S) -2- ((tert-butoxycarbonyl) amino) propoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2b ] pyridazine-3-carboxylic acid
Figure BDA0001974801310000341
Ethyl 6- ((R) -2- (2- ((S) -2- ((tert-butoxycarbonyl) amino) propoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazine-3-carboxylate (200mg,0.38mmol) was dissolved in a mixed solvent THF/MeOH/H2To O ═ 3:1:1(10mL), lioh was added2O (63.6mg,1.5mmol), after addition, was reacted at 25 ℃ for 4 h. Dilution with water, pH 3 with 1M HCl, concentration to remove THF and MeOH, extraction with DCM, organic phase combination and dry concentration afforded the title compound (170mg, 89.8% yield).
Preparation of 6- ((R) -2- (2- ((S) -2-aminopropoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine-3-carboxylic acid
Figure BDA0001974801310000342
Reacting 6- ((R) -2- (2- ((S) -2- ((tert-butoxycarbonyl) amino) propoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2b]Pyridazine-3-carboxylic acid (170mg,0.34mmol) was dissolved in DCM (8mL), TFA (2mL) was added, reaction was completed at 25 ℃ for 3H, the solvent was concentrated, TEA adjusted to pH7, C18 column chromatography purification (MeOH/H)2O ═ 0% to 60%) to give the title compound (100mg, yield 73.5%).
4.(22R,6S)-35-fluoro-6-methyl-4-oxa-7-aza-1 (6,3) -imidazo [1,2-b]Preparation of pyridazin-3 (3,2) -azaphen-2 (1,2) -pyrrolidino-cyclooctan-8-one
Figure BDA0001974801310000343
EDCI (52.8mg,0.0.28mmol) and DMAP (61.1mg,0.0.5mmol) were dissolved in DCM (10mL) and 6- ((R) -2- (2- ((S) -2-aminopropoxy) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazine-3-carboxylic acid (100mg,0.25mmo) was reacted at 25 ℃ for 14 hours after the addition. Purification by column chromatography on silica gel (DCM: MeOH: 30:1) followed by HPLC purification (preparative high pressure separation conditions: C18 column: 30X 250 mm; flow rate 43 mL/min; injection volume 2 mL; detection wavelength: 214nm,254 nm; MeCN: H)2O ═ 10% to 60%) to give the title compound (25mg, yield 26.2%).
Molecular formula C19H19FN6O2Molecular weight 382.4 LC-MS (M/e):383.4(M + H)+) HPLC (Small polarity) retention time 8.719min
1H-NMR(400MHz,CDCl3)δ:9.39(s,1H),8.18(s,1H),7.93(d,J＝2.8Hz,1H),7.84(d,J＝10Hz,1H),7.37(dd,J＝2.8Hz,1H),6.80(d,J＝10Hz,1H),5.67-5.69(m,1H),5.11-5.16(m,1H),4.33-4.36(m,1H),4.01-4.06(m,1H),3.64-3.70(m,1H),2.42-2.55(m,2H),2.23-2.28(m,1H),1.96-2.01(m,1H),1.59(d,J＝6.8Hz,3H)
Experimental protocol
An exemplary experimental scheme of a portion of the compounds of the invention is provided below to show the advantageous activity and advantageous technical effects of the compounds of the invention. It should be understood, however, that the following experimental protocols are only illustrative of the present disclosure and are not intended to limit the scope of the present disclosure.
Experimental example 1 in vitro cytological inhibitory Activity of Compounds of the invention
Test article: the chemical names and structures of some compounds of the invention are shown in the preparation examples.
Comparison products: TPX-0005, purchased or prepared according to the method disclosed in prior art WO 2015112806.
The cell lines used in the following experiments represent the following:
Ba/F3LMNA-NTRK1-G595R Cell Line:
Ba/F3 cells are transfected with a stable expression cell strain of LMNA-NTRK1G 595R;
Ba/F3ETV6-NTRK3-G623R Cell Line：
Ba/F3 cells were transfected with a stably expressing cell line of ETV6-NTRK 3-G623R;
Ba/F3SLC34A2-ROS1-G2032R Cell Line：
Ba/F3 cells were transfected with a stably expressing cell line of SLC34A2-ROS 1-G2032R;
experimental method (CelltiterGlo assay)
1. Preparation of cells
1.1 cell culture:
all cells were suspension cells, the medium was RPMI-1640+ 10% FBS, and the cells were tested in logarithmic growth phase.
1.2 cell suspension preparation:
cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion to ensure cell viability above 90%. Adjusted to the appropriate concentration, 90 μ L of cell suspension was added to 96-well plates, respectively.
TABLE 1 cell seeding number
Figure BDA0001974801310000361
2. Formulating test compounds
2.1 test compound DMSO stock solutions were prepared at concentrations given in Table 2.
TABLE 2 stock solution concentration (mM) of test compound
Figure BDA0001974801310000362
2.2 preparation of working stock solutions of test Compounds
Test compound stock was diluted to 1mM at 10mM and then diluted with DMSO in 3-fold serial gradients for a total of 9 concentrations. Then, 2. mu.L of each DMSO-diluted compound was added to 98. mu.L of the culture solution as a working stock solution of the test compound (10-fold concentration of the compound, 1% concentration of DMSO, and 10. mu.M concentration at the highest concentration)
The maximum is DMSO solvent control, blank wells are media only, and cells are not inoculated.
2.3 treatment of Compounds
mu.L of compound working stock (10-fold dilution, final DMSO concentration of 0.1%) was added to each well of a 96-well plate seeded with cells.
The final concentrations of test compounds were: 1000nM, 333.33nM, 111.11nM, 37.04nM, 12.35nM, 4.12nM, 1.37nM, 0.46nM, 0.15 nM.
5％CO2The cells were cultured in a cell incubator for 72 hours.
3. Detection of
The CTG reagent (Celltiter Glo assay kit) was thawed and the cell plates were equilibrated to room temperature for 30 minutes, 60 μ L of CTG reagent was added to each well, shaken for 2min with a shaker (protected from light), and incubated at room temperature for 10 minutes (protected from light). And reading the light signal value by a multifunctional microplate reader.
4. Data processing
1) Inhibition (%) × (DMSO solvent control well reading-test well reading)/(DMSO solvent control well reading-blank control well reading) × 100%;
2) input GraphPad Prism 5.0 mappingObtaining a curve and IC50。
Results of the experiment
TABLE 3 in vitro cytological Activity (IC) of Compounds of the invention50,nM)
Figure BDA0001974801310000371
And (4) experimental conclusion:
as shown in Table 3, the compound can effectively inhibit the proliferation of cells such as Ba/F3LMNA-NTRK1-G595R, Ba/F3ETV6-NTRK3-G623R, Ba/F3SLC34A2-ROS1-G2032R and the like, and the compound has the clinical application potential of treating drug-resistant cancerous diseases caused by NTRK gene mutation.
Experimental example 2 pharmacokinetic experiment of the Compound of the present invention
And (3) testing the sample: see the examples in the specification for compound 3, compound 4 and compound 11, for their preparation.
Comparison products: compound TPX-0005, purchased or prepared according to the method disclosed in prior art WO2015112806, has the structure shown below:
Figure BDA0001974801310000372
experimental animals: female mice (9 mice/group).
Preparation of test solution
1. Preparation of Compound 3 solution
(1) Oral administration (po): compound 3(4.79mg) was placed in a tissue grinder, 4.565mL of solvent (2% HPC + 0.1% Tween 80) was added, and the mixture was ground uniformly at 1000rpm to obtain a 1mg/mL homogeneous suspension.
2. Preparation of Compound 4 solution
(1) Oral administration (po): putting the compound 4(4.88mg) in a centrifuge tube, adding 4.621mL of the solvent, performing ultrasonic treatment, performing vortex until the solid is fully dispersed, transferring to a tissue grinder, uniformly grinding at 1000rpm, and performing vortex mixing to obtain a uniform suspension with the concentration of 1 mg/mL.
3. Preparation of Compound 11 solution
(1) Oral administration (po): taking compound 11(5.01mg), placing in a tissue grinder, adding 4.795mL of the above solvent, grinding uniformly at the rotation speed of 1000rpm, and vortex mixing uniformly to obtain a uniform suspension with the concentration of 1 mg/mL.
4. Preparation of control TPX-0005 solution
(1) Oral administration (po): compound TPX-0005(4.55mg) was placed in a tissue grinder, 4.505mL of the above solvent was added, and the mixture was ground uniformly at 1000rpm to obtain a uniform suspension with a final concentration of 1 mg/mL.
Experimental methods
Administration of drugs
Oral administration (po) was carried out at a dose of 10mg/kg and a volume of 10 mL/kg.
Blood sampling
Collecting tail vein blood at 0.083, 0.25, 0.5, 1,2,3,4, 6,8, and 24 hr after administration, collecting whole blood of about 100 μ L at each time point, centrifuging at 8000rpm in high speed centrifuge for 6min to separate plasma, and freezing at-80 deg.C.
Plasma sample analysis
Adopting a protein precipitation method: putting 20 mu L of plasma into a 96-hole deep-hole plate, adding 200 mu L of internal standard solution, vortexing for 10min, then centrifuging for 20min at 4000 rpm, taking 100 mu L of supernatant, adding 100 mu L of water, and vortexing for 3 min; LC-MS/MS analysis.
Results of the experiment
Table 4 mouse PK evaluation results (po) for compounds of the invention
Figure BDA0001974801310000381
Wherein, T1/2Represents the half-life; cmaxRepresents the maximum blood concentration value; AUClastArea under curve 0 → t when drug is represented; MRT stands for mean residence time.
Conclusion of the experiment
Experimental data show that the compound has higher exposure and appropriate half-life in organisms, shows good pharmacokinetic properties and has good clinical application prospect.
Experimental example 3 human Mixed liver microsome metabolic stability experiment of the Compound of the present invention
And (3) testing the sample: see the examples in the specification for compound 4, its preparation.
Comparison products: compound LOXO-195, purchased or prepared according to the method disclosed in prior art WO2011146336a1, has the structure shown below:
Figure BDA0001974801310000391
experimental materials:
human mixed liver microsomes were purchased from Corning-1。
The experiment initiation factor beta-NADPH is purchased from Roche of America; phosphate Buffered Saline (PBS) pH7.4 was prepared by the laboratory.
Preparing a test solution:
a proper amount of test powder is precisely weighed, a proper amount of dimethyl sulfoxide (DMSO) is added to dissolve the test powder to 1mM, and the test powder is diluted by 20 times to 50 mu M of working solution by using methanol.
The experimental method comprises the following steps:
TABLE 5 liver microsome metabolic stability experiment incubation system composition
Figure BDA0001974801310000392
The experimental operation steps are as follows:
(1) according to the above Table 5 "constitution of the Experimental incubation System", 100mM PBS (5.85mL), 20mM MgCl were used for each compound2Solution (0.585mL) and H2O (3.57mL), and a mixed solution 1 (containing no microsome, sample and. beta. -NADPH) was prepared as an incubation system.
(2) Liver microsomes (20mg protein/mL) were removed from the-80 ℃ freezer and placed on a 37 ℃ water bath constant temperature shaker for pre-incubation for 3 min.
(3) For each compound, 1.9mL of mixed solution 1 of incubation system was taken for each species, and 56. mu.L of microsomes of different species was added to prepare mixed solution 2 of incubation system (containing no test substance and. beta. -NADPH).
(4) Sample set (microsome and β -NADPH containing): and adding 14 mu L of the test sample working solution with the concentration of 50 mu M into 616 mu L of the mixed solution 2 of the incubation system, and adding 70 mu L of 10mM beta-NADPH working solution. Mix well and duplicate (two samples). The sampling time points are 0min, 5min, 10min, 20min, 30min and 60 min.
(5) Control group (microsome-containing, no β -NADPH, water instead of β -NADPH): 264 mu L of the mixed solution 2 of the incubation system is taken, 6 mu L of the working solution of the test article with the concentration of 50 mu M is added, and 30 mu L of water is added. Mixing, and repeating the steps. Sampling time points were 0min and 60 min.
(6) At each predetermined time point, 50 μ L of sample was taken from the incubation sample tube, added to a stop sample tube (containing 300 μ L of cold stop reagent, containing 50ng/mL acetonitrile as internal standard of tolbutamide), vortexed, and the reaction was stopped.
(7) After vortexing for 10min, centrifuge for 5min (12000 rpm).
(8) Taking 100 mu L of supernatant, adding 100 mu L of water, mixing uniformly by vortex, and carrying out LC-MS/MS sample injection analysis.
And (3) data analysis:
the percent residual was converted by the ratio of peak area of control to internal standard in the following equation.
Figure BDA0001974801310000401
The experimental results are as follows:
TABLE 6 hepatic microsome stability results for compounds of the invention
Figure BDA0001974801310000402
And (4) experimental conclusion:
the compounds of the invention all have better metabolic stability of liver microsomes, and the metabolic stability is obviously superior to that of a contrast medicament.

Claims (12)

1. A compound shown in a general formula (I), pharmaceutically acceptable salt thereof or a stereoisomer thereof,
Figure FDA0003195388020000011
wherein,
X2、X4is N;
X1、X3is CH;
X5is N;
M1is-N (R)4)-；
M2is-O-;
M3is-N (R)4)-；
Ring A is selected from pyridyl;
each R1Each independently selected from hydrogen, halogen, unsubstituted C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl or halo C1-4An alkoxy group;
each R4Each independently selected from hydrogen, unsubstituted C1-4Alkyl or halo C1-4An alkyl group;
L1is selected from C1-4An alkylene group;
and L is2And M3Together form a pyrrolidinyl group that is unsubstituted or substituted with one or more Q2;
each Q2 is independently selected from amino, hydroxy, halogen, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl or halo C1-4An alkoxy group;
p is selected from 1,2 or 3.
2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
each R1Are respectively provided withIndependently selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, methoxy, trifluoromethyl or trifluoromethoxy;
R4each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or trifluoromethyl
Each Q2 is independently selected from amino, hydroxy, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, methoxy, trifluoromethyl, or trifluoromethoxy;
p is selected from 1 or 2.
3. The compound of claim 1 or 2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein L1Is selected from-CH2CH2-、-CH2CH2CH2-、-CH(CH3)CH2-、-CH2CH(CH3)-。
4. A compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as shown below:
Figure FDA0003195388020000021
。
5. pharmaceutical formulation comprising a compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, characterized in that it comprises one or more pharmaceutically acceptable carriers and/or diluents.
6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, characterized by comprising one or more second therapeutically active agents selected from:
a drug for the treatment of cancer selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal drugs, angiogenesis inhibitors, cell growth inhibitors, targeting antibodies, HMG-CoA reductase inhibitors, prenyl protein transferase inhibitors, and the like;
the drug for treating neurodegenerative disorder is selected from dopamine-like drugs, dopamine receptor agonists, drugs affecting dopamine metabolism, NMDA receptor antagonists, adenosine A2AReceptor inhibitors, drugs that affect DA release and reuptake, central anticholinergics, cholinesterase inhibitors, 5-HT agonists, alpha 2 adrenergic receptor antagonists, antidepressants, cholinergic receptor agonists, beta/gamma secretase inhibitors, H3 receptor antagonists, or anti-oxidant drugs;
the medicine for treating autoimmune diseases is selected from antirheumatic, nonsteroidal anti-inflammatory, glucocorticoid medicine, TNF antagonist, cyclophosphamide, mycophenolate mofetil, and cyclosporine for improving disease condition;
the drug for treating inflammatory diseases is selected from steroidal anti-inflammatory drugs and non-steroidal anti-inflammatory drugs.
7. Use of a compound of any one of claims 1-4, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for the manufacture of a medicament for the treatment and/or prevention of a related disease mediated by one or more tyrosine kinases of TRK, ALK, and ROS1, said related disease selected from one or more of pain, cancer, inflammation, neurodegenerative disease, autoimmune disease.
8. The use of claim 7, wherein the cancer is a cancer that has developed at least partial resistance to a TRK, ALK and/or ROS1 therapeutic active.
9. The use of claim 7 or 8, wherein the cancer contains one or more of a TRK mutation, an ALK mutation, and a ROS1 mutation.
10. The use according to claim 7 or 8, wherein the TRK, ALK and ROS1 comprise wild-type and mutant forms thereof.
11. The use of claim 10, wherein the mutant form of TRK kinase is selected from one or more of G595R and G623R, and the mutant form of ROS1 kinase is selected from G2032R.
12. A process for preparing a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, comprising the steps of:
Figure FDA0003195388020000031
(1) under the action of a solvent and/or a catalytic reagent, carrying out multi-step substitution reaction on the intermediate 1 and the intermediate 2 at a proper temperature to obtain an intermediate 3;
(2) carrying out substitution reaction on the intermediate 3 and the intermediate 4 under the action of an organic solvent and a catalyst to obtain an intermediate 5;
(3) the intermediate 5 is subjected to ester hydrolysis reaction under acidic or alkaline conditions, deprotection reaction under acidic conditions, and cyclization reaction under the action of a catalytic reagent or an activating agent to obtain a compound shown in the formula (I);
the substituent groups in the above structural formula are as defined in any one of claims 1 to 4;
x is selected from halogen, hydroxyl or amino;
the protecting group is selected from benzyloxycarbonyl, tert-butoxycarbonyl, benzyl, p-methoxyphenyl, acetyl, methoxymethyl ether, 2-methoxyethoxymethyl ether or p-methoxybenzyl ether;
the solvent is selected from a single organic solvent, a single inorganic solvent or a mixed solvent.
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