Heterocyclic compounds as TRK inhibitors
阅读说明：本技术 作为trk抑制剂的杂环化合物 (Heterocyclic compounds as TRK inhibitors ) 是由 孔祥龙 周超 郑之祥 于 2018-06-25 设计创作，主要内容包括：本发明涉及化合物、含有其的药物组合物、以及它们的制备方法,和其作为TRK抑制剂的用途。所述化合物为式I所示的化合物,或其药学上可接受的盐、前药、溶剂化合物、多晶型体、异构体、稳定同位素衍生物。本发明还涉及所述化合物用于治疗或预防由TRK介导的相关疾病例如肿瘤的用途以及应用其治疗所述疾病的方法。<Image he="125" wi="187" file="830136DEST_PATH_IMAGE001.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention relates to compounds, pharmaceutical compositions containing them, as well as processes for their preparation, and their use as TRK inhibitors. The compound is a compound shown in a formula I, or pharmaceutically acceptable salt, prodrug, solvate, polymorph, isomer and stable isotope derivative thereof. The invention also relates to the use of said compounds for the treatment or prevention of related diseases mediated by TRK, such as tumours, and to methods of using them to treat said diseases.)
1. A compound of formula I, isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts thereof:
I
wherein:
L1is selected from-NR6C(O)-、-NR6CON(R7)-、-NR6S(O)m-and-NR6S(O)mN(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage, preferably, L1Is selected from-NR6C (O) -and-NR6CON(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage; l is1Most preferably selected from NR6CON(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage;
L2selected from the group consisting of C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkynylene and C3-C8 cycloalkylene, wherein said alkylene, alkenylene, alkynylene, cycloalkylene may optionally be substituted with one or more G1, L2Preferably selected from C1-C6 alkylene and C2-C6 alkenylene, optionally substituted with one or more G1, L2More preferably selected from C1-C4 alkylene optionally substituted by one or more G1;
L3selected from the group consisting of single chemical bonds, -O-and-N (R)x)-，L3Preferably selected from the group consisting of single chemical bonds and-O-, L3Most preferably selected from-O-;
R1、R2、R3each independently selected from hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cyclyl, 3-8 member heterocyclyl, aryl, heteroaryl, aldehyde, -NR8R9、-C(O)R10Carboxy, alkenyl, alkynyl, -OR10、-OC(O)NR8R9、-C(O)OR10、-C(O)NR8R9、-NR11C(O)R10、-NR11C(O)NR8R9、-S(O)mR10、-NR11S(O)mR10、-SR10、-S(O)mNR8R9and-NR11S(O)mNR8R9Wherein said alkyl, cyclyl, heterocyclyl, aryl OR heteroaryl is optionally substituted with one OR more substituents selected from halogen, cyano, C1-C8 alkyl, C3-C8 cyclyl, 3-8 membered heterocyclyl, -OR12、-NR13R14、-OC(O)NR13R14、-C(O)OR12、-C(O)R12、-C(O)NR13R14、-NR15C(O)R12、-NR15C(O)NR13R14、-S(O)mR12、-NR15S(O)mR12、-SR12、-S(O)mNR13R14and-NR15S(O)mNR13R14Is preferably R2、R3Are all hydrogen; more preferably R1、R2、R3Are all hydrogen;
R4selected from hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cyclyl, 3-8 membered heterocyclyl, aryl, heteroaryl, aldehyde, -C (O) R10Carboxy, alkenyl, alkynyl, -OR10、-NR8R9 -OC(O)NR8R9、-C(O)OR10、-C(O)NR8R9、-NR8C(O)R10、-NR10C(O)NR8R9、-S(O)mR10、-NR8S(O)mR10、-SR10、-S(O)mNR8R9and-NR10S(O)mNR8R9Preferably R4Selected from hydrogen, halogen, more preferably R4Is hydrogen or fluorine;
R5selected from hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cyclyl, 3-8 membered heterocyclyl, aryl, heteroaryl, aldehyde, -C (O) R10Carboxy, alkenyl, alkynyl, -OR10、-NR8R9 -OC(O)NR8R9、-C(O)OR10、-C(O)NR8R9、-NR8C(O)R10、-NR10C(O)NR8R9、-S(O)mR10、-NR8S(O)mR10、-SR10、-S(O)mNR8R9and-NR10S(O)mNR8R9Preferably R5Selected from hydrogen, halogen, C1-C6 alkyl and C3-C6 cyclyl, more preferably R5Selected from hydrogen, halogen, C1-C4 alkyl and C3-C6 cyclyl, further preferably R5Selected from hydrogen and halogen, most preferably R5Selected from fluorine;
R6、R7、Rxeach independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, heteroalkyl, C3-C8 cyclyl, 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl, monocyclic aryl, alkenyl, and alkynyl, preferably R6、R7、RxEach independently selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl, further preferably R6、R7、RxEach independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl, with R being even more preferred6、R7、RxEach independently selected from hydrogen and C1-C4 alkyl;
g1 is selected from halogen, cyano, C1-C8 alkyl, C3-C8 cyclyl, 3-8 member heterocyclyl, aryl, heteroaryl, aldehyde, -NR8R9、-C(O)R10Carboxy, alkenyl, alkynyl, -OR10、-OC(O)NR8R9、-C(O)OR10、-C(O)NR8R9、-NR11C(O)R10、-NR11C(O)NR8R9、-S(O)mR10、-NR11S(O)mR10、-SR10、-S(O)mNR8R9and-NR11S(O)mNR8R9Preferably G1 is selected from halogen, C1-C6 alkyl, -OR10、-NR8R9More preferably G1 is selected from halogen, C1-C4 alkyl, -OR10、-NR8R9Wherein said alkyl is optionally substituted by one OR more groups selected from halogen, -OR16、-NR13R14Substituted with the substituent(s); when two G1 s are located on the same carbon atom or on adjacent carbon atoms, the two G1 s optionally together with the carbon atom to which they are attached form a 3-8 membered cyclic group, preferably a 3-6 membered cyclic alkyl groupCycloalkyl radicals optionally substituted by one OR more radicals selected from halogen, OR16、-NR13R14Substituted with the substituent(s);
R8、R9、R10、R11、R12、R13、R14、R15、R16each independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, heteroalkyl, C3-C8 cyclyl, 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl, monocyclic aryl, alkenyl, and alkynyl; r8And R9、R13And R14A 3-to 7-membered heterocyclic group may be formed;
and m is 1 or 2;
wherein the compounds do not include the following compounds (1) to (7):
。
2. a compound according to claim 1, an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof,
wherein:
L1is selected from-NR6C(O)-、-NR6CON(R7)-、-NR6S(O)m-and-NR6S(O)mN(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage;
L2selected from the group consisting of C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, and C3-C6 cycloalkylene, wherein said alkylene, alkenylene, alkynylene, and cycloalkylene groups may be optionally substituted with one or more G1 groups;
L3selected from the group consisting of a single chemical bond and-O-;
R1、R2、R3each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cyclyl, 3-6 membered heterocyclyl, aryl and heteroaryl, wherein said alkyl, cyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, and heteroarylC1-C6 alkyl, C3-C6 cyclyl, and 3-6 member heterocyclyl;
R4selected from hydrogen, halogen, -NR8R9、-OR10；
R5Selected from hydrogen, halogen, C1-C6 alkyl, and C3-C6 cyclyl;
R6、R7each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;
g1 is selected from halogen, C1-C6 alkyl, -NR8R9、-OR10Wherein said alkyl is optionally substituted by one or more substituents selected from halogen, -NR11R12、-OR16Substituted with the substituent(s);
R8、R9、R10、R11、R12and R16Each independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
and m is 1 or 2;
wherein the compounds do not include the following compounds (1) to (7):
。
3. a compound according to claim 1, an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof,
wherein:
L1is selected from-NR6C (O) -and-NR6CON(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage;
L2selected from the group consisting of C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, and C3-C6 cycloalkylene, wherein said alkylene, alkenylene, alkynylene, and cycloalkylene groups may be optionally substituted with one or more G1 groups;
L3selected from the group consisting of a single chemical bond and-O-;
R1、R2、R3each independently of the otherSelected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C4-C6 cyclyl, and 4-6 membered heterocyclyl, wherein said alkyl, cyclyl, and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen;
R4selected from hydrogen, halogen, -NR8R9、-OR10；
R5Selected from hydrogen, halogen, C1-C6 alkyl, and C3-C6 cyclyl;
R6、R7each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;
g1 is selected from halogen, C1-C6 alkyl, -NR8R9、-OR10Wherein said alkyl is optionally substituted by one or more substituents selected from halogen, -NR11R12、-OR16Substituted with the substituent(s);
R8、R9、R10、R11、R12and R16Each independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
wherein the compounds do not include the following compounds (1) to (7):
。
4. a compound according to claim 1, an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof,
wherein:
L1is selected from-NR6CON(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage;
L2selected from the group consisting of C1-C4 alkylene, C2-C4 alkenylene, C2-C4 alkynylene, and C3-C4 cycloalkylene, wherein said alkylene, alkenylene, alkynylene, and cycloalkylene groups may be optionally substituted with one or more G1 groups;
L3selected from the group consisting of a single chemical bond and-O-;
R1、R2、R3each independently selected from hydrogen, halogen, and C1-C4 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from halogen;
R4selected from hydrogen, halogen, -NR8R9、-OR10；
R5Selected from hydrogen, halogen, C1-C6 alkyl, and C3-C6 cyclyl;
R6、R7each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;
g1 is selected from halogen, C1-C6 alkyl, -NR8R9、-OR10Wherein said alkyl is optionally substituted by one or more substituents selected from halogen, -NR11R12、-OR16Substituted with the substituent(s);
R8、R9、R10、R11、R12and R16Each independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
wherein the compounds do not include the following compounds (1) to (5):
。
5. a compound according to claim 1, an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof,
wherein:
L1is selected from-NR6CON(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage;
L2selected from C1-C4 alkylene and C2-C4 alkenylene, wherein said alkylene and alkenylene may be optionally substituted with one or more G1;
L3selected from the group consisting of a single chemical bond and-O-;
R1、R2、R3each independently selected from hydrogen, halogen and C1-C4 alkyl, wherein the alkyl is optionallySubstituted with one or more substituents selected from halogen;
R4selected from hydrogen, halogen, -NR8R9、-OR10；
R5Selected from hydrogen, halogen, C1-C4 alkyl, and C3-C6 cyclyl;
R6、R7each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl;
g1 is selected from halogen, C1-C4 alkyl, -NR8R9、-OR10Wherein said alkyl is optionally substituted by one or more substituents selected from halogen, -NR11R12、-OR16Substituted with the substituent(s);
R8、R9、R10、R11、R12and R16Each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl;
wherein the compounds do not include the following compounds (1) to (5):
。
6. a compound according to claim 1, an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof,
wherein:
L1is selected from-NR6CON(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage;
L2is selected from C1-C4 alkylene, wherein the alkylene may be optionally substituted by one or more G1;
L3is selected from-O-;
R1、R2、R3each independently selected from hydrogen, halogen, and C1-C4 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from halogen;
R4selected from hydrogen, halogen, -NR8R9、-OR10；；
R5Selected from hydrogen, halogen and C1-C4 alkyl;
R6、R7each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl;
g1 is selected from halogen, C1-C4 alkyl, -NR8R9、-OR10Wherein said alkyl is optionally substituted by one or more substituents selected from halogen, -NR11R12、-OR16Substituted with the substituent(s);
R8、R9、R10、R11、R12and R16Each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl;
wherein the compounds do not include the following compounds (1) to (4):
。
7. the compound according to claim 1, an isomer, a prodrug, a solvate, a stable isotopic derivative thereof or a pharmaceutically acceptable salt thereof,
wherein:
L1is selected from-NR6CON(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage;
L2is selected from C1-C4 alkylene, wherein the alkylene may be optionally substituted by one or more G1;
L3is selected from-O-;
R1、R2、R3each independently selected from hydrogen and halogen;
R4selected from hydrogen and halogen;
R5selected from hydrogen, halogen and C1-C4 alkyl, located at L3The alignment of (3);
R6、R7each independently selected from hydrogen and C1-C4 alkyl;
g1 is selected from halogen, C1-C4 alkyl, wherein the alkyl is optionally substituted with one or more groups selected from halogen, -NR11R12、-OR16Substituted with the substituent(s);
R11、R12and R16Each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl;
wherein the compounds do not include the following compounds (1) to (4):
。
8. the compound, its isomer, prodrug, solvate, stable isotopic derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein said compound is selected from the group consisting of:
。
9. a pharmaceutical composition comprising a compound according to any one of claims 1-8, or an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient.
10. Use of a compound according to any one of claims 1-8 or an isomer, prodrug, solvate, stable isotopic derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the treatment or prevention of a TRK-mediated disease, such as cancer, in particular hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma.
Technical Field
The present invention relates to compounds, pharmaceutical compositions containing them and their use as TRK inhibitors. More particularly, the present invention provides novel compounds that are inhibitors of TRK, pharmaceutical compositions containing such compounds, and methods of using such compounds to treat or prevent related disorders mediated by TRK, such as tumors. The invention also relates to a process for the preparation of the compounds described below.
Background
TRK (Tropomyosin receptor kinase) is a tyrosine kinase of neurotrophic receptors present in a variety of tissues and activates a variety of downstream processes during cell proliferation and survival. There are three members of the TRK proto-oncogene family: TRK a, B and C, encoded by NTRK1, NTRK2, NTRK3, respectively. Binding of neurotrophic factors to TRK proteins results in receptor dimerization, phosphorylation and activation of downstream signaling pathways, including the Ras/MAPK, PI3K/AKT and PLC γ pathways, thereby modulating cell proliferation, differentiation, metabolism, apoptosis (Brodeur g. m., Minturn j. e., Ho R,et al. Clinical Cancer Research, 2009, 15, 3244-50). Genomic analysis of kinase fusions confirmed that NTRK gene fusions occur in a variety of cancers: such as glioma, hepatobiliary tract, papillary thyroid carcinoma, colon carcinoma, non-small cell lung carcinoma, head and neck squamous cell carcinoma, pancreatic carcinoma, sarcoma and melanoma (Khotskaya, y. B).et al.Pharmacology & Therapeutics, 2017, 173, 58-66). The TRK inhibitor can be used for treating various tumors of NTRK fusion protein by research and development, and has huge potential and wide market prospect. The disease was objectively alleviated in 38 (76%) patients treated with the TRK inhibitor, larotretinib (LOXO-101), in an early clinical trial. Of these 6 (12%) patients had complete remission and no tumor was detected by the current means. Of these patients, 30 patients had remission times of more than one year (2017 annual meeting of the american society for clinical oncology). However, the development of target mutations by continuous administration renders tumors resistant. Clinically, mutations in NTRK have been observed, such as mutations in NTRK 1G 595R and G667C (Russo, M. et al Cancer Discovery, 2016, 6(1), 36-44). Therefore, it is necessary to develop a TRK inhibitor that has high activity, little side effects, and is effective for TRK mutation.
Disclosure of Invention
The invention aims to provide a compound shown as a formula I, an isomer, a prodrug, a solvate, a stable isotope derivative or a pharmaceutically acceptable salt thereof, which can be used as a TRK inhibitor:
wherein:
L1is selected from-NR6C(O)-、-NR6CON(R7)-、-NR6S(O)m-and-NR6S(O)mN(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage, preferably, L1Is selected from-NR6C (O) -and-NR6CON(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage; l is1Most preferably selected from NR6CON(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage;
L2selected from the group consisting of C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkynylene and C3-C8 cycloalkylene, wherein said alkylene, alkenylene, alkynylene, cycloalkylene may optionally be substituted with one or more G1, L2Preferably selected from C1-C6 alkylene and C2-C6 alkenylene, optionally substituted with one or more G1, L2More preferably selected from C1-C4 alkylene optionally substituted by one or more G1;
L3selected from the group consisting of single chemical bonds, -O-and-N (R)x)-，L3Preferably selected from the group consisting of single chemical bonds and-O-, L3Most preferably selected from-O-;
R1、R2、R3each independently selected from hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cyclyl, 3-8 member heterocyclyl, aryl, heteroaryl, aldehyde, -NR8R9、-C(O)R10Carboxy, alkenyl, alkynyl, -OR10、-OC(O)NR8R9、-C(O)OR10、-C(O)NR8R9、-NR11C(O)R10、-NR11C(O)NR8R9、-S(O)mR10、-NR11S(O)mR10、-SR10、-S(O)mNR8R9and-NR11S(O)mNR8R9Wherein said alkyl, cyclyl, heterocyclyl, aryl OR heteroaryl is optionally substituted with one OR more substituents selected from halogen, cyano, C1-C8 alkyl, C3-C8 cyclyl, 3-8 membered heterocyclyl, -OR12、-NR13R14、-OC(O)NR13R14、-C(O)OR12、-C(O)R12、-C(O)NR13R14、-NR15C(O)R12、-NR15C(O)NR13R14、-S(O)mR12、-NR15S(O)mR12、-SR12、-S(O)mNR13R14and-NR15S(O)mNR13R14Is preferably R2、R3Are all hydrogen; more preferably R1、R2、R3Are all hydrogen;
R4selected from hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cyclyl, 3-8 membered heterocyclyl, aryl, heteroaryl, aldehyde, -C (O) R10Carboxy, alkenyl, alkynyl, -OR10、-NR8R9 -OC(O)NR8R9、-C(O)OR10、-C(O)NR8R9、-NR8C(O)R10、-NR10C(O)NR8R9、-S(O)mR10、-NR8S(O)mR10、-SR10、-S(O)mNR8R9and-NR10S(O)mNR8R9Preferably R4Selected from hydrogen, halogen, more preferably R4Is hydrogen or fluorine;
R5selected from hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cyclyl, 3-8 membered heterocyclyl, aryl, heteroaryl, aldehyde, -C (O) R10Carboxy, alkenyl, alkynyl, -OR10、-NR8R9 -OC(O)NR8R9、-C(O)OR10、-C(O)NR8R9、-NR8C(O)R10、-NR10C(O)NR8R9、-S(O)mR10、-NR8S(O)mR10、-SR10、-S(O)mNR8R9and-NR10S(O)mNR8R9Preferably R5Selected from hydrogen, halogen, C1-C6 alkyl and C3-C6 cyclyl, more preferably R5Selected from hydrogen, halogen, C1-C4 alkyl and C3-C6 cyclyl, further preferably R5Selected from hydrogen and halogen; most preferred is R5Selected from fluorine;
R6、R7、Rxeach independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, heteroalkyl, C3-C8 cyclyl, 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl, monocyclic aryl, alkenyl, and alkynyl, preferably R6、R7、RxEach independently selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl, further preferably R6、R7、RxEach independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; further preferred is R6、R7、RxEach independently selected from hydrogen and C1-C4 alkyl;
g1 is selected from halogen, cyano, C1-C8 alkyl, C3-C8 cyclyl, 3-8 member heterocyclyl, aryl, heteroaryl, aldehyde, -NR8R9、-C(O)R10Carboxy, alkenyl, alkynyl, -OR10、-OC(O)NR8R9、-C(O)OR10、-C(O)NR8R9、-NR11C(O)R10、-NR11C(O)NR8R9、-S(O)mR10、-NR11S(O)mR10、-SR10、-S(O)mNR8R9and-NR11S(O)mNR8R9Preferably G1 is selected from halogen, C1-C6 alkyl, -OR10、-NR8R9(ii) a More preferably G1 is selected from halogen, C1-C4 alkyl, -OR10、-NR8R9(ii) a Wherein said alkyl is optionally substituted by one OR more groups selected from halogen, -OR16、-NR13R14Substituted with the substituent(s); when two G1 are on the same carbon atom OR on adjacent carbon atoms, these two G1 optionally together with the carbon atom to which they are attached form a 3-8 membered cyclic group, preferably a 3-6 membered cyclic alkyl group, the cycloalkyl group formed optionally being substituted by one OR more groups selected from halogen, OR16、-NR13R14Substituted with the substituent(s);
R8、R9、R10、R11、R12、R13、R14、R15、R16each independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, heteroalkyl, C3-C8 cyclyl, 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl, monocyclic aryl, alkenyl, and alkynyl; r8And R9、R13And R14A 3-to 7-membered heterocyclic group may be formed;
and m is 1 or 2;
wherein the compounds do not include the following compounds (1) to (7):
。
in a preferred embodiment of the present invention, there is provided a compound represented by the general formula I, an isomer, a prodrug, a solvate, a stable isotopic derivative thereof or a pharmaceutically acceptable salt thereof, wherein:
L1is selected from-NR6C(O)-、-NR6CON(R7)-、-NR6S(O)m-and-NR6S(O)mN(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage;
L2selected from the group consisting of C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, and C3-C6 cycloalkylene, wherein said alkylene, alkenylene, alkynylene, and cycloalkylene groups may be optionally substituted with one or more G1 groups;
L3selected from the group consisting of a single chemical bond and-O-;
R1、R2、R3each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cyclyl, 3-6 membered heterocyclyl, aryl and heteroaryl, wherein said alkyl, cyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, C1-C6 alkyl, C3-C6 cyclyl and 3-6 membered heterocyclyl;
R4selected from hydrogen, halogen, -NR8R9、-OR10；
R5Selected from hydrogen, halogen, C1-C6 alkyl, and C3-C6 cyclyl;
R6、R7each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;
g1 is selected from halogen, C1-C6 alkyl, -NR8R9、-OR10Wherein said alkyl is optionally substituted by one or more substituents selected from halogen, -NR11R12、-OR16Substituted with the substituent(s);
R8、R9、R10、R11、R12and R16Each independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
and m is 1 or 2;
wherein the compounds do not include the following compounds (1) to (7):
。
in another preferred embodiment of the present invention, there is provided a compound represented by the general formula I, an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof; wherein:
L1is selected from-NR6C (O) -and-NR6CON(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage;
L2selected from the group consisting of C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, and C3-C6 cycloalkylene, wherein said alkylene, alkenylene, alkynylene, and cycloalkylene groups may be optionally substituted with one or more G1 groups;
L3selected from the group consisting of a single chemical bond and-O-;
R1、R2、R3each independently selected from hydrogen, halogen, C1-C4 alkyl, C4-C6 cyclyl, and 4-6 membered heterocyclyl, wherein said alkyl, cyclyl, and heterocyclyl are optionally substituted with one or more substituents selected from halogen;
R4selected from hydrogenHalogen, -NR8R9、-OR10；
R5Selected from hydrogen, halogen, C1-C6 alkyl, and C3-C6 cyclyl;
R6、R7each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;
g1 is selected from halogen, C1-C6 alkyl, -NR8R9、-OR10Wherein said alkyl is optionally substituted by one or more substituents selected from halogen, -NR11R12、-OR16Substituted with the substituent(s);
R8、R9、R10、R11、R12and R16Each independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
wherein the compounds do not include the following compounds (1) to (7):
。
in another preferred embodiment of the present invention, there is provided a compound represented by the general formula I, an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof; wherein:
L1is selected from-NR6CON(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage;
L2selected from the group consisting of C1-C4 alkylene, C2-C4 alkenylene, C2-C4 alkynylene, and C3-C4 cycloalkylene, wherein said alkylene, alkenylene, alkynylene, and cycloalkylene groups may be optionally substituted with one or more G1 groups;
L3selected from the group consisting of a single chemical bond and-O-;
R1、R2、R3each independently selected from hydrogen, halogen, and C1-C4 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from halogen;
R4selected from hydrogen, halogen, -NR8R9、-OR10；
R5Selected from hydrogen, halogen, C1-C6 alkyl, and C3-C6 cyclyl;
R6、R7each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;
g1 is selected from halogen, C1-C6 alkyl, -NR8R9、-OR10Wherein said alkyl is optionally substituted by one or more substituents selected from halogen, -NR11R12、-OR16Substituted with the substituent(s);
R8、R9、R10、R11、R12and R16Each independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
wherein the compounds do not include the following compounds (1) to (5):
。
in another preferred embodiment of the present invention, there is provided a compound represented by the general formula I, an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof; wherein:
L1is selected from-NR6CON(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage;
L2selected from C1-C4 alkylene and C2-C4 alkenylene, wherein said alkylene and alkenylene may be optionally substituted with one or more G1;
L3selected from the group consisting of a single chemical bond and-O-;
R1、R2、R3each independently selected from hydrogen, halogen, and C1-C4 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from halogen;
R4selected from hydrogen, halogen, -NR8R9、-OR10；
R5Selected from hydrogen, halogen, C1-C4 alkyl, and C3-C6 cyclyl;
R6、R7each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl;
g1 is selected from halogen, C1-C4 alkyl, -NR8R9、-OR10Wherein said alkyl is optionally substituted by one or more substituents selected from halogen, -NR11R12、-OR16Substituted with the substituent(s);
R8、R9、R10、R11、R12and R16Each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl;
wherein the compounds do not include the following compounds (1) to (5):
。
in another preferred embodiment of the present invention, there is provided a compound represented by the general formula I, an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof; wherein:
L1is selected from-NR6CON(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage;
L2is selected from C1-C4 alkylene, wherein the alkylene may be optionally substituted by one or more G1;
L3is selected from-O-;
R1、R2、R3each independently selected from hydrogen, halogen, and C1-C4 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from halogen;
R4selected from hydrogen, halogen, -NR8R9、-OR10；；
R5Selected from hydrogen, halogen and C1-C4 alkyl;
R6、R7each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl;
g1 selectionFrom halogen, C1-C4 alkyl, -NR8R9、-OR10Wherein said alkyl is optionally substituted by one or more substituents selected from halogen, -NR11R12、-OR16Substituted with the substituent(s);
R8、R9、R10、R11、R12and R16Each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl;
wherein the compounds do not include the following compounds (1) to (4):
。
in another preferred embodiment of the present invention, there is provided a compound represented by the general formula I, an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof; wherein:
L1is selected from-NR6CON(R7) -, where NR6And the said quilt R1、R2、R3A substituted nitrogen-containing heteroaryl linkage;
L2is selected from C1-C4 alkylene, wherein the alkylene may be optionally substituted by one or more G1;
L3is selected from-O-;
R1、R2、R3each independently selected from hydrogen and halogen;
R4selected from hydrogen and halogen;
R5selected from hydrogen, halogen and C1-C4 alkyl, located at L3The alignment of (3);
R6、R7each independently selected from hydrogen and C1-C4 alkyl;
g1 is selected from halogen, C1-C4 alkyl, wherein the alkyl is optionally substituted with one or more groups selected from halogen, -NR11R12、-OR16Substituted with the substituent(s);
R11、R12and R16Each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl;
wherein the compounds do not include the following compounds (1) to (4):
。
in another preferred embodiment of the present invention, there is provided a compound represented by the general formula I, an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof; characterized in that said compound is selected from:
。
the present invention further relates to a pharmaceutical composition comprising a compound as described in any of the previous embodiments or an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.
The present invention also relates to the use of a compound according to any one of the embodiments of the present invention or its isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention for the manufacture of a medicament for the treatment or prevention of a TRK-mediated disease, such as cancer, in particular hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma.
The present invention also relates to a method for treating or preventing TRK-mediated diseases (e.g., tumors, particularly hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of the embodiments of the present invention or an isomer, prodrug, solvate, stable isotopic derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.
Another aspect of the present invention relates to a compound represented by the general formula (I), or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof according to any one of the embodiments of the present invention, for use in treating or preventing TRK-mediated diseases, such as tumors, particularly hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma.
Another aspect of the present invention relates to a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of the embodiments of the present invention, which is useful for the treatment and/or prevention of diseases such as tumor.
Typical compounds of the invention include, but are not limited to:
and isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts thereof.
The compound shown in the general formula (I) is a TRK inhibitor, so that the compound shown in the general formula (I) can be used for treating or preventing TRK mediated diseases, such as tumors, particularly malignant hematological diseases, lung cancer, breast cancer, ovarian cancer, prostatic cancer, pancreatic cancer and brain glioma.
The invention further relates to a pharmaceutical composition, which comprises the compound shown in the general formula (I) or an isomer, a prodrug, a solvate, a stable isotope derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, a diluent or an excipient.
Another aspect of the present invention relates to a use of a compound represented by the general formula (I) or an isomer, a prodrug, a solvate, a stable isotope derivative or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof for the preparation of a medicament for treating or preventing a TRK-mediated disease, such as a tumor, in particular, a hematological malignancy, a lung cancer, a breast cancer, an ovarian cancer, a prostate cancer, a pancreatic cancer, a brain glioma.
Another aspect of the present invention relates to the use of a compound of formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment and/or prevention of tumors.
According to the present invention, the drug may be in any pharmaceutical dosage form including, but not limited to, tablets, capsules, solutions, lyophilized formulations, injections.
The pharmaceutical preparations of the present invention may be administered in dosage units containing a predetermined amount of the active ingredient per dosage unit. Such units may contain, for example, from 0.5 mg to 1 g, preferably from 1 mg to 700 mg, particularly preferably from 5 mg to 300 mg, of a compound of the invention, depending on the condition to be treated, the method of administration and the age, weight and condition of the patient, or the pharmaceutical preparations may be administered in dosage units containing a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing a daily dose or sub-dose, or corresponding fraction thereof, of the active ingredient as indicated above. In addition, pharmaceutical formulations of this type may be prepared using methods well known in the pharmaceutical art.
The pharmaceutical formulations of the invention may be adapted for administration by any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared, for example, by combining the active ingredient with one or more excipients or one or more adjuvants using all methods known in the pharmaceutical art.
The present invention also relates to a method for treating or preventing TRK-mediated diseases (e.g., tumors, particularly hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or an isomer, prodrug, solvate, stable isotopic derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.
Another aspect of the present invention relates to a compound represented by the general formula (I), or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition for treating or preventing a TRK-mediated disease, such as a tumor, particularly, hematological malignancy, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma.
Another aspect of the present invention relates to a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament for treating and/or preventing diseases such as tumor.
Preparation process
The invention also provides a method for preparing the compound.
Scheme 1
Accordingly, the substituents are defined as follows:
R1、R2、R3each independently selected from hydrogen, halogen and C1-C4 alkyl;
R4selected from hydrogen, halogen, -NR8R9、-OR10；
R5Selected from hydrogen, halogen, C1-C4 alkyl, and C3-C6 cyclyl;
R17selected from hydrogen, C1-C4 alkyl;
L2independently selected from C1-C4 alkylene, wherein said alkylene optionally may be substituted by one OR more halogens, C1-C4 alkyl, -OR10、-NR8R9Wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -NR11R12、-OR16Substituted with the substituent(s);
R8、R9、R10、R11、R12and R16Each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl;
the first step is as follows:
the substitution reaction is carried out in n-butanol orN,N-dimethylacetamide and the like, and addingN,NDiisopropylethylamine or 1, 8-diazabicycloundecen-7-ene (DBU), etc., at 60-80 deg.C-Heating in microwave or oil bath; reacting to obtain a compound (II);
the second step is that:
LG1halogen such as Cl, Br, I and the like or leaving groups such as OTf, OTs, OMs and the like, performing substitution reaction in solvents such as acetonitrile and the like, adding alkali such as cesium carbonate and the like, and performing the substitution reaction under the heating condition of microwave or oil bath at 50-100 ℃; reacting to obtain a compound (III);
the third step:
LG2is halogen such as Cl, Br, I and the like or leaving groups such as OTf, OTs, OMs and the like, and the substitution reaction is carried outN, NDimethylformamide and the like, and simultaneously adding alkali such as sodium hydride and the like, and carrying out the reaction at the temperature of 0-25 ℃; reacting to obtain a compound (IV);
the fourth step:
the reduction reaction of the nitro uses zinc powder as a reducing agent; adding saturated ammonium chloride solution, reacting in solvent such as dichloromethane and the like at 0-25 ℃; reacting to obtain a compound (V);
the fifth step:
deprotection of the tert-butoxycarbonyl group using trifluoroacetic acid as the acid; in solvents such as dichloromethane and the like, the reaction is carried out at the temperature of 0-25 ℃; reacting to obtain a compound (VI);
and a sixth step:
use of diamines (VI) to form ureasN,N'-carbonyldiimidazole orN,N'Carbonyl bis (1,2, 4-triazole), optionally with a base such as triethylamine, and reacting inN,NDimethylformamide and the like at the room temperature of 20-50 ℃ or under the oil bath heating condition; the reaction gives the compound (VII).
Detailed Description
Definition of
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
As used herein, the expression "Cx-Cy" denotes a range of numbers of carbon atoms, wherein x and y are both integers, e.g., C3-C8 cyclic group denotes a cyclic group having 3-8 carbon atoms, C0-C2 alkyl group denotes an alkyl group having 0-2 carbon atoms, wherein C0 alkyl group refers to a single chemical bond.
As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms, such as straight and branched chain groups that may be 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, and the various branched chain isomers thereof, and the like. Alkyl groups may be optionally substituted or unsubstituted.
As used herein, the term "alkenyl" refers to straight and branched chain hydrocarbon groups containing at least 1 carbon-carbon double bond, which may include from 2 to 20 carbon atoms, for example straight and branched chain groups that may be 2 to 18 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Wherein 1-3 carbon-carbon double bonds, preferably 1 carbon-carbon double bond, may be present. The term "C2-4 alkenyl" refers to alkenyl groups having 2-4 carbon atoms. Including ethenyl, propenyl, butenyl, buten-2-yl, 2-methylbutenyl. The alkenyl group may be substituted.
As used herein, the term "alkynyl" refers to straight and branched chain hydrocarbon radicals containing at least 1 carbon-carbon triple bond, which may include from 2 to 20 carbon atoms, for example straight and branched chain radicals which may be 2 to 18 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Wherein 1-3 carbon-carbon triple bonds, preferably 1 carbon-carbon triple bond, may be present. The term "C2-4 alkynyl" refers to alkynyl groups having 2-4 carbon atoms. Non-limiting examples include ethynyl, propynyl, butynyl, and butyn-2-yl, 3-methylbutynyl.
As used herein, the terms "alkylene," "alkenylene," "alkynylene" refer to substituted or unsubstituted alkyl, alkenyl, and alkynyl groups, respectively, having a core of two terminal monovalent radicals resulting from the removal of one hydrogen atom from each of the two terminal carbon atoms; the "alkylene", "alkenylene" and "alkynylene" usually have 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms. Non-limiting examples of "alkylene" include substituted or unsubstituted methylene, ethylene, propylene, butylene, and the like; non-limiting examples of "alkenylene" include substituted or unsubstituted vinylene, propenylene, butenylene, and the like; non-limiting examples of "alkynylene" include substituted or unsubstituted ethynylene, propynyl, butynyl, and the like;
as used herein, the term "cyclyl" refers to an all-carbon saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group comprising 3 to 12 ring atoms, which may be, for example, 3 to 12, 3 to 10, 3 to 8, or 3 to 6 ring atoms, or may be a 3, 4, 5, 6 membered ring. Non-limiting examples of monocyclic radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like. The cyclic group may be substituted or unsubstituted.
As used herein, the term "cyclyl" refers to a substituted or unsubstituted cyclyl having a core of two terminal monovalent groups, the cyclyl having the definition set forth above. Non-limiting examples of "cyclylene" include cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cyclohexadienylene, cycloheptylene, cycloheptatrienylene, cyclooctenylene, and the like. The cycloalkylene group may be substituted or unsubstituted.
In this context, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon radical comprising 3 to 20 ring atoms, which may be, for example, 3 to 16, 3 to 12, 3 to 10, 3 to 8 or 3 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or a heteroatom of S (O) m (wherein m is an integer from 0 to 2), but not including the ring portion of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms of which 1 to 4 are heteroatoms, more preferably a heterocyclyl ring comprising 3 to 10 ring atoms, more preferably 3 to 8 ring atoms, even more preferably 3 to 6 ring atoms, most preferably a 5-or 6-membered ring of which 1 to 4 are heteroatoms, more preferably 1 to 3 are heteroatoms, most preferably 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Bicyclic and polycyclic heterocyclic groups include heterocyclic groups that are spiro, fused, and bridged.
"spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group which shares a single atom (referred to as the spiro atom) between single rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or a heteroatom of S (O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro groups are classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi spiro heterocyclic group according to the number of spiro atoms shared between rings, and preferably, the single spiro cyclic group and the double spiro cyclic group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclic group. Non-limiting examples of spiro ring groups include
。
"fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, in which one or more ring atoms are selected from nitrogen, oxygen or heteroatoms of S (O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include
。
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
and the like. The heterocyclic group may be optionally substituted or unsubstituted.
As used herein, the term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group containing 6 to 14 carbon ring atoms, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system. Aryl groups can be monocyclic or polycyclic (i.e., can contain more than one ring). In the case of polycyclic aromatic rings, only one ring of the polycyclic ring system is required to be aromatic, while the remaining rings may be saturated, partially saturated, or unsaturated. Aryl is preferably 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cyclyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
the aryl group may be substituted or unsubstituted.
As used herein, the term "arylene" refers to substituted or unsubstituted aryl groups each having a core of two monovalent radicals, the aryl groups being as defined above. Non-limiting examples of arylene groups are phenylene, naphthylene, and the like. The arylene group can be optionally substituted or unsubstituted.
As used herein, the term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 membered. More preferably 5-or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, and the like, which heteroaryl ring may be fused to an aryl, heterocyclyl, or cyclyl ring, wherein the ring linked together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
heteroaryl groups may be optionally substituted or unsubstituted.
As used herein, the term "heteroarylene" refers to a substituted or unsubstituted heteroaryl group having two monovalent radical cores, respectively, as defined above. Non-limiting examples of heteroarylenes are furanylene, thiophenylene, pyridinylene, pyrrolylene, N-alkylpyrrolylene, pyrimidinylene, pyrazinylene, imidazolyl, tetrazolylene, oxazolylene, isoxazolylene, and the like. The heteroarylene group may be optionally substituted or unsubstituted.
"halogen" means fluorine, chlorine, bromine or iodine.
"haloalkyl" means an alkyl substituent wherein at least one hydrogen is replaced by a halogen group. Typical halogen groups include chlorine, fluorine, bromine and iodine. Examples of the haloalkyl group include a fluoromethyl group, a fluoroethyl group, a chloromethyl group, a chloroethyl group, a 1-bromoethyl group, a difluoromethyl group, a trifluoromethyl group and a1, 1, 1-trifluoroethyl group. It will be appreciated that if a substituent is substituted with more than one halo group, those halo groups may be the same or different (unless otherwise specified).
"aldehyde" means-CHO.
"carboxyl" means-COOH.
"cyano" means-CN.
"Heteroalkyl" means a stable straight or branched chain hydrocarbon radical consisting of the indicated number of carbon atoms and at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, wherein the nitrogen and sulfur atoms may optionally be oxidized, the nitrogen atom may optionally be quaternized, the heteroatom oxygen, nitrogen, and sulfur may be located at any internal position of the heteroalkyl radical, or at a position where the alkyl radical is attached to the remainder of the molecule, and two or more heteroatoms may be independent or continuous.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
Such substituents include, but are not limited to, each of the substituents described previously.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
The "room temperature" of the invention means 15-30 ℃.
The compounds of the present invention may also exist as isomers, prodrugs, solvates or stable isotopic derivatives thereof. It will be appreciated by those skilled in the art that such isomers, prodrugs, solvates or stable isotopic derivatives generally have similar activity to the compounds of the present invention or a pharmaceutically acceptable salt thereof and are therefore encompassed within the scope of the present invention.
As used herein, "stable isotopic derivatives" include: an isotopically substituted derivative in which any hydrogen atom in formula I is substituted with 1 to 5 deuterium atoms, an isotopically substituted derivative in which any carbon atom in formula I is substituted with 1 to 3 carbon 14 atoms, or an isotopically substituted derivative in which any oxygen atom in formula I is substituted with 1 to 3 oxygen 18 atoms.
The "Pharmaceutically acceptable salts" of the present invention are described in Berge, et al, "Pharmaceutically acceptable salts",J. Pharm. Sci.,66, 1-19(1977), which is discussed and is apparent to the pharmaceutical chemist, is substantially non-toxic and provides desirable pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, etc.
The pharmaceutically acceptable salts of the present invention can be synthesized by a general chemical method.
In general, salts can be prepared by reacting the free base or acid with an equivalent stoichiometric amount or an excess of the acid (inorganic or organic) or base in a suitable solvent or solvent composition.
By "prodrug" as used herein is meant a compound that is metabolized in vivo to the original active compound. Prodrugs are typically inactive substances or less active than the active parent compound, but may provide convenient handling, administration, or improved metabolic properties.
The term "isomers" as used herein means that the compounds of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and individual diastereomers, and all such isomers, including stereoisomers and geometric isomers, are encompassed by the present invention. The geometric isomers include cis-trans isomers.
The present invention includes any polymorph as well as any hydrate or other solvate of the compound or salt thereof.
As used herein, the term "tumor" includes both benign tumors and malignant tumors, such as cancers.
Herein, the term "cancer" includes TRK-mediated tumors of various types, including, but not limited to, hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma.
As used herein, the term "therapeutically effective amount" is meant to include an amount of a compound of the present invention that is effective to treat or prevent the associated disorder mediated by TRK.
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