CN109942544B - Novel indazole derivative kinase inhibitor - Google Patents

Novel indazole derivative kinase inhibitor Download PDF

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CN109942544B
CN109942544B CN201711394182.5A CN201711394182A CN109942544B CN 109942544 B CN109942544 B CN 109942544B CN 201711394182 A CN201711394182 A CN 201711394182A CN 109942544 B CN109942544 B CN 109942544B
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indazol
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CN109942544A (en
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刘静
刘青松
刘学松
王蓓蕾
蒋宗儒
余凯琳
陈程
邹凤鸣
刘青旺
刘晓川
王伟
汪文亮
胡晨
王文超
王俊杰
王黎
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Hefei Institutes of Physical Science of CAS
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Abstract

The present invention relates to a kinase inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof. The invention also relates to pharmaceutical compositions comprising the kinase inhibitors, and uses and methods of using these compounds and compositions to inhibit tyrosine kinase activity of one or more cells or subjects selected from cKIT, BCR/ABL, pdgfra, pdgfrp, and VEGFR2, and to prevent or treat kinase-associated disorders in subjects.

Description

Novel indazole derivative kinase inhibitor
Technical Field
The present invention relates to novel kinase inhibitor compounds, pharmaceutical compositions comprising the compounds, and uses of the compounds or compositions to reduce or inhibit cKIT (particularly mutant cKIT/T670I), BCR/ABL (particularly mutant BCR-ABL/T315I), pdgfra, pdgfrp, and/or VEGFR2 activity in a cell or subject, and to the use and methods of preventing or treating kinase-associated disorders in a subject.
Background
Tyrosine kinase is a kinase which catalyzes gamma-phosphate on ATP to transfer to protein tyrosine residue, can catalyze phosphorylation of various substrate protein tyrosine residues, and has important functions in cell growth, proliferation and differentiation. Abnormal kinase function is of great significance in cancer, immune, neurological, metabolic and infectious diseases. There are currently approximately 30 different kinase-targeted drugs, the vast majority of which are used to treat cancer. Most of the protein tyrosine kinases discovered to date are oncogene products belonging to oncogenic RNA viruses, and can also be produced from vertebrate proto-oncogenes.
Tyrosine kinase inhibitors can be used as competitive inhibitors of the combination of Adenosine Triphosphate (ATP) and tyrosine kinase, and can also be used as tyrosine analogues to block the activity of tyrosine kinase and inhibit cell proliferation, and a plurality of antitumor drugs have been developed.
There are 518 kinases encoded in the human genome, and almost every signaling process requires communication through the phosphate conversion cascade (cascade): suggesting that inhibition of kinase activity may actually abolish the physiological response of the cell. For example, the oncogene BCR (BreakPoint Cluster region) -ABL fusion protein is a key factor causing the occurrence of chronic myelogenous leukemia, and the tyrosine activity of the fusion protein has obvious therapeutic significance. Although ATP binding sites are highly conserved, small molecules can be developed that are significantly selective in pharmacological profile. Normal cells are normally resistant to inhibition by kinases, thus providing a therapeutic window for selective killing of tumor cells. For example, Dasatinib, which inhibits nearly 9 kinases of the SRC family (and many other tyrosine kinases) for treating Imatinib-resistant chronic myelogenous leukemia CML, is also easily tolerated as a side effect compared to traditional cellular chemotherapy. Therefore, the development of new kinase inhibitors has important clinical significance.
Disclosure of Invention
The present invention provides a novel kinase inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
Figure BDA0001518077870000021
wherein X is selected from
Figure BDA0001518077870000022
Figure BDA0001518077870000023
Y is selected from phenyl, thiophen-2-yl, isoxazol-3-yl, pyridin-4-yl, 2-pyrrolidin-5-yl, N-methyl-2 (1H) -pyridon-5-yl, and furan-2-yl;
R1selected from hydrogen, C1-6Alkyl, 2- (pyridin-2-yl) vinyl, optionally substituted with R3Pyridin-3-yl substituted by a radical, optionally R3Phenyl substituted by a group, and optionally R3Radical-substituted pyrazol-4-yl;
(R2)nrepresents optionally n independent R2Substituted by substituents, wherein n is an integer from 0 to 5, R2Independently selected from hydroxy, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, C2-6Amido, C1-6Alkylamino, 4-methyl-imidazol-1-yl,
Figure BDA0001518077870000024
Figure BDA0001518077870000025
R3Selected from halogen, aminoacyl, C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0001518077870000026
R4Is selected from C1-6An alkyl group;
R5selected from hydrogen and C1-6An alkylamino group.
In a preferred embodiment, the kinase inhibitor of the present invention comprises a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
Figure BDA0001518077870000027
wherein R is1Selected from hydrogen, C1-6Alkyl, 2- (pyridin-2-yl) vinyl, optionally substituted with R3Pyridin-3-yl substituted with a group, and optionally R3Phenyl substituted with a group;
(R2)nrepresenting optionally n independent R in ortho-, meta-and para-positions of the phenyl ring2Substituted by substituents, wherein n is an integer from 0 to 5, R2Independently selected from halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Alkylamino, 4-methyl-imidazol-1-yl,
Figure BDA0001518077870000031
R3Selected from halogen, aminoacyl, C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0001518077870000032
R4Is selected from C1-6An alkyl group;
R5is selected from C1-6An alkylamino group.
In another preferred embodiment, the kinase inhibitor of the present invention comprises a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
Figure BDA0001518077870000033
wherein R is1Selected from hydrogen, C1-6Alkyl, 2- (pyridin-2-yl) vinyl, optionally substituted with R3Pyridin-3-yl substituted by a radical, optionally R3Phenyl substituted by a group, and optionally R3Radical-substituted pyrazol-4-yl;
(R2)nrepresenting optionally n independent R in ortho-, meta-and para-positions of the phenyl ring2Substituted by substituents, wherein n is an integer from 0 to 5, R2Independently selected from halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, C2-6Amido, C1-6Alkylamino, 4-methyl-imidazol-1-yl,
Figure BDA0001518077870000034
Figure BDA0001518077870000035
R3Is selected from C1-6Alkyl radicals and
Figure BDA0001518077870000036
R4is selected from C1-6An alkyl group;
R5selected from hydrogen and C1-6An alkylamino group.
The invention is also directed to pharmaceutical compositions comprising the above compounds and to methods and uses of the compounds or pharmaceutical compositions in the prevention or treatment of diseases, disorders, or conditions modulated by or affected by tyrosine kinase activity or in which tyrosine kinase activity is implicated.
Drawings
FIGS. 1a to 1c show the tumor suppressive effect of Compound 4 in a TEL-cKIT/T670I-BaF3 cell tumor-transplanted mouse model.
FIGS. 2a to 2c show the tumor suppressive effect of compound 142 in a P210/T315I-BaF3 cell tumor-transplanted mouse model.
Detailed Description
Term(s) for
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.
The present invention employs, unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. Unless a specific definition is provided, nomenclature and laboratory procedures and techniques related to the chemistry described herein, such as analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry, are known to those skilled in the art. In general, the foregoing techniques and procedures may be practiced by conventional methods well known in the art and described in various general and more specific documents that are cited and discussed in this specification.
The term "alkyl" refers to an aliphatic hydrocarbon group, which may be a branched or straight chain alkyl group. Depending on the structure, the alkyl group may be a monovalent group or a divalent group (i.e., alkylene). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a "lower alkyl group" having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like. It is to be understood that reference herein to "alkyl" includes reference to that alkyl in all configurations and conformations that may exist, for example reference herein to "propyl" includes n-propyl and isopropyl, "butyl" includes n-butyl, isobutyl and tert-butyl, "pentyl" includes n-pentyl, isopropyl, neopentyl, tert-pentyl, and pent-3-yl, and the like.
The term "alkoxy" refers to an-O-alkyl group, wherein alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like.
The term "alkoxyalkyl" means an alkyl group, as defined herein, substituted with an alkoxy group, as defined herein.
The term "aryl" refers to a planar ring having a delocalized pi-electron system and containing 4n +2 pi electrons, where n is an integer. An aryl ring may be composed of five, six, seven, eight, nine or more than nine atoms. The aryl group may be optionally substituted. The term "aryl" includes carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "heteroaryl") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.
The term "aryl" as used herein means that each of the ring-forming atoms in the aromatic ring is a carbon atom. The aryl ring may be composed of five, six, seven, eight, nine or more than nine atoms. The aryl group may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracyl, fluorenyl, and indenyl. Depending on the structure, the aryl group can be a monovalent group or a divalent group (i.e., arylene).
The term "aryloxy" refers to-O-aryl, wherein aryl is as defined herein.
The term "heteroaryl" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing "heteroaryl" moiety means that at least one of the backbone atoms in the ring in the aryl group is a nitrogen atom. Depending on the structure, heteroaryl groups may be monovalent or divalent (i.e., heteroarylene). Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, and furopyridyl, and the like.
The term "alkyl (aryl)" or "aralkyl" means that an alkyl group, as defined herein, is substituted with an aryl group, as defined herein. Non-limiting alkyl (aryl) groups include benzyl, phenethyl, and the like.
The term "alkyl (heteroaryl)" or "heteroarylalkyl" means that an alkyl group, as defined herein, is substituted with a heteroaryl group, as defined herein.
The term "heteroalkyl," as used herein, means that one or more backbone chain atoms in an alkyl group, as defined herein, is a heteroatom, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof. The heteroatom(s) may be located anywhere within the heteroalkyl group or at the position where the heteroalkyl group is attached to the remainder of the molecule.
The term "heterocycloalkyl" or "heterocyclyl" as used herein means that one or more of the ring-forming atoms in the non-aromatic ring is a heteroatom selected from nitrogen, oxygen and sulfur. A heterocycloalkyl ring can be composed of three, four, five, six, seven, eight, nine, or more than nine atoms. The heterocycloalkyl ring may be optionally substituted. Examples of heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimines, cyclic carbamates, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1, 3-dioxins, 1, 3-dioxanes, 1, 4-dioxins, 1, 4-dioxanes, piperazines, 1, 3-oxathianes, 1, 4-oxathianes, tetrahydro-1, 4-thiazines, 2H-1, 2-oxazines, maleimides, succinimides, barbituric acid, thiobarbituric acid, dioxopiperazines, hydantoins, dihydrouracils, morpholines, trioxanes, hexahydro-1, 3, 5-triazines, tetrahydrothiophenes, tetrahydrofurans, pyrrolines, pyrrolidines, imidazolidines, pyrrolidones, 4-oxazides, 4-dioxanes, 1, 4-dioxanes, piperazines, Pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1, 3-dioxole, 1, 3-dioxolane, 1, 3-dithiole, 1, 3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1, 3-oxathiolane. Depending on the structure, heterocycloalkyl groups can be monovalent or divalent (i.e., heterocycloalkylene).
The term "alkyl (heterocycloalkyl)" or "heterocycloalkylalkyl" means that an alkyl group, as defined herein, is substituted with a heterocycloalkyl group, as defined herein.
The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
The terms "haloalkyl", "haloalkoxy" and "haloheteroalkyl" include alkyl, alkoxy, or heteroalkyl groups in which at least one hydrogen is replaced with a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced with a halogen atom, the halogen atoms are the same or different from each other.
The term "hydroxy" refers to a group of the formula-OH.
The term "cyano" refers to a group of formula-CN.
The term "ester group" refers to a chemical moiety having the formula-COOR, wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon), and heterocyclyl (attached through a ring carbon).
The term "amino" refers to the group-NH2。
The term "aminoacyl" refers to-CO-NH2。
The term "amido" or "amido" refers to the group-NR-CO-R ', wherein R and R' are each independently hydrogen or alkyl.
The term "alkylamino" refers to an amino substituent further substituted by one or two alkyl groups, in particular to the group-NRR ', wherein R and R ' are each independently selected from hydrogen or lower alkyl, with the proviso that-NRR ' is not-NH2. "alkylamino" includes the group-NH-thereof2The nitrogen of (a) is linked to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like. "dialkylamino" includes wherein-NH2The nitrogen of (a) is linked to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.
The term "acyl" refers to the monovalent radical remaining after removal of the hydroxyl group by an organic or inorganic oxoacid, and has the general formula R-M (O) -where M is typically C.
The term "carbonyl" is an organic functional group consisting of two atoms, carbon and oxygen, connected by a double bond (C ═ O).
The term "alkanoyl" or "alkylcarbonyl" refers to a carbonyl group further substituted with an alkyl group. Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, and the like.
The term "arylcarbonyl" means a carbonyl group, as defined herein, substituted with an aryl group, as defined herein.
The term "optionally" means that one or more of the subsequently described events may or may not occur, and includes both occurring events and non-occurring events. The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional groups each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, cyano, halo, amido, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, amino protecting groups, and the like. Among them, the amino-protecting group is preferably selected from pivaloyl, t-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trifluoroacetyl and the like.
The term "Tyrosine Protein Kinase (TPK)" as used herein is a class of kinases that catalyze the transfer of gamma-phosphate from ATP to protein tyrosine residues, which catalyze the phosphorylation of tyrosine residues of various substrate proteins, and play an important role in cell growth, proliferation, and differentiation.
The term "inhibition", "inhibitory" or "inhibitor" of a kinase, as used herein, means that phosphotransferase activity is inhibited.
A "metabolite" of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized" as used herein, refers to the sum of processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes, e.g., oxidation reactions) by which a particular substance is altered by an organism. Thus, enzymes can produce specific structural transformations into compounds. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while phosphoglucose glycyltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Further information on metabolism can be obtained from The Pharmacological Basis of Therapeutics, ninth edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified by administering the compounds to a host and analyzing a tissue sample from the host, or by incubating the compounds with hepatocytes in vitro and analyzing the resulting compounds. Both methods are known in the art. In some embodiments, the metabolite of the compound is formed by an oxidation process and corresponds to the corresponding hydroxyl-containing compound. In some embodiments, the compound is metabolized to a pharmaceutically active metabolite. The term "modulate," as used herein, refers to interacting, directly or indirectly, with a target to alter the activity of the target, including by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.
The term "target protein" as used herein refers to a protein molecule or portion of a protein that can be bound by a selective binding compound. In certain embodiments, the target protein is tyrosine kinase KIT (wild-type or various mutations or combinations thereof), ABL (wild-type or various mutations or combinations thereof), EGFR (wild-type or various mutations or combinations thereof), FLT3 (wild-type or various mutations or combinations thereof), VEGFR2 (wild-type or various mutations or combinations thereof), RET (wild-type or various mutations or combinations thereof), pdgfra (wild-type or various mutations or combinations thereof), PDGFR β (wild-type or various mutations or combinations thereof), BCR/ABL (wild-type or various mutations or combinations thereof), FGFR1 (wild-type or various mutations or combinations thereof), FGFR2 (wild-type or various mutations or combinations thereof), FGFR3 (wild-type or various mutations or combinations thereof), FGFR4 (wild-type or various mutations or combinations thereof).
IC as used herein50Refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximal effect in an assay that measures such effect.
EC as used herein50Refers to a dose, concentration, or amount of a test compound that elicits a dose-dependent response that is 50% of the maximal expression of a particular response that a particular test compound induces, stimulates, or potentiates.
GI as used herein50Is meant to refer to the concentration of drug required to inhibit 50% of the cell growth, i.e., the concentration of drug at which 50% of the cell (e.g., cancer cell) growth is inhibited or controlled by the drug.
The novel kinase inhibitors of the present invention
The present invention provides a novel kinase inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
Figure BDA0001518077870000071
wherein X is selected from
Figure BDA0001518077870000072
Figure BDA0001518077870000073
Y is selected from phenyl, thiophen-2-yl, isoxazol-3-yl, pyridin-4-yl, 2-pyrrolidin-5-yl, N-methyl-2 (1H) -pyridon-5-yl, and furan-2-yl;
R1selected from hydrogen, C1-6Alkyl, 2- (pyridin-2-yl) vinyl, optionally substituted with R3Pyridin-3-yl substituted by a radical, optionally R3Phenyl substituted by a group, and optionally R3Radical-substituted pyrazol-4-yl;
(R2)nrepresents optionally n independent R2Substituted by substituents, wherein n is an integer from 0 to 5, R2Independently selected from hydroxy, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, C2-6Amido, C1-6Alkylamino, 4-methyl-imidazol-1-yl,
Figure BDA0001518077870000081
Figure BDA0001518077870000082
R3Selected from halogen, aminoacyl, C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0001518077870000083
R4Is selected from C1-6An alkyl group;
R5selected from hydrogen and C1-6An alkylamino group.
In a preferred embodiment, the kinase inhibitor of the present invention comprises a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
Figure BDA0001518077870000084
wherein R is1Selected from hydrogen, C1-6Alkyl, 2- (pyridin-2-yl) vinyl, optionally substituted with R3Pyridin-3-yl substituted with a group, and optionally R3Phenyl substituted with a group;
(R2)nrepresenting optionally n independent R in ortho-, meta-and para-positions of the phenyl ring2Substituted by substituents, wherein n is an integer from 0 to 5, R2Independently selected from halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Alkylamino, 4-methyl-imidazol-1-yl,
Figure BDA0001518077870000085
R3Selected from halogen, aminoacyl, C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0001518077870000086
R4Is selected from C1-6An alkyl group;
R5is selected from C1-6An alkylamino group.
In another preferred embodiment, the kinase inhibitor of the present invention comprises a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
Figure BDA0001518077870000087
wherein R is1Selected from hydrogen, C1-6Alkyl, 2- (pyridine)-2-yl) vinyl, optionally substituted with R3Pyridin-3-yl substituted by a radical, optionally R3Phenyl substituted by a group, and optionally R3Radical-substituted pyrazol-4-yl;
(R2)nrepresenting optionally n independent R in ortho-, meta-and para-positions of the phenyl ring2Substituted by substituents, wherein n is an integer from 0 to 5, R2Independently selected from halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, C2-6Amido, C1-6Alkylamino, 4-methyl-imidazol-1-yl,
Figure BDA0001518077870000091
Figure BDA0001518077870000092
R3Is selected from C1-6Alkyl radicals and
Figure BDA0001518077870000093
R4is selected from C1-6An alkyl group;
R5selected from hydrogen and C1-6An alkylamino group.
In the present invention, substituent C1-6Alkyl is more preferably methyl, ethyl, isopropyl or tert-butyl, halogen is more preferably fluorine or chlorine, C1-6Alkoxy is more preferably methoxy, C1-6Haloalkoxy is more preferably trifluoromethoxy, C1-6Haloalkyl is more preferably trifluoromethyl, C1-6More preferably alkylamino is dimethylamino, C2-6More preferably, the amido group is acetyl.
For each variable, any combination of the above groups is also contemplated herein. It can be understood that: substituents and substitution patterns on the compounds provided herein can be selected by one of skill in the art to provide compounds that are chemically stable and can be synthesized using techniques known in the art as well as those set forth herein.
Described herein are novel kinase inhibitors. Pharmaceutically acceptable salts, solvates, esters, acids, pharmaceutically active metabolites and prodrugs of this compound are also described herein.
In additional or further embodiments, the compounds described herein are metabolized in vivo upon administration to an organism in need thereof to produce a metabolite, which is then used to produce a desired effect, including a desired therapeutic effect.
The compounds described herein may be formulated and/or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, 2-naphthalenesulfonic acid, tert-butylacetic acid, glucoheptonic acid, 4' -methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, or mixtures thereof, Dodecyl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthoic acid, stearic acid, muconic acid, and the like; (2) base addition salts, which are formed when an acidic proton in the parent compound is replaced by a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), alkaline earth metal ion (e.g., magnesium or calcium), or aluminum ion; or coordinated with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
The corresponding counterion of the pharmaceutically acceptable salt can be analyzed and identified using a variety of methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.
Recovering the salt using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or in the case of aqueous solutions, lyophilization.
Screening and characterization of pharmaceutically acceptable salts, polymorphs, and/or solvates can be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, microscopy, elemental analysis. Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state). Various microscopy techniques include, but are not limited to, IR microscopy and Raman (Raman) microscopy.
Pharmaceutical compositions of the invention
The present application also provides pharmaceutical compositions comprising at least one compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt, solvate, ester, acid, pharmaceutically active metabolite, or prodrug of said compound, and a pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.
During the course of treatment, the agent may be used alone or in combination with one or more other therapeutic agents, as the case may be. A medicament comprising a compound of the invention may be administered to a patient by at least one of injection, oral, inhalation, rectal and transdermal administration. The additional therapeutic agent may be selected from the following: immunosuppressants (e.g., tacrolimus, cyclosporin, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate mofetil, or FTY720), glucocorticoids (e.g., prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, prednisolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal anti-inflammatory drugs (e.g., salicylates, aryl alkanoic acids, 2-aryl propionic acids, N-aryl anthranilic acids, oxicams, coxibs or thioacetanilides), allergy vaccines, antihistamines, anti-leukotrienes, beta-agonists, theophylline, anti-alkaloidsCholine drugs or other selective kinase inhibitors (e.g., mTOR inhibitors, c-Met inhibitors) or her2 antibody-drugs. In addition, other therapeutic agents mentioned may also be Rapamycin (Rapamycin), Crizotinib (Crizotinib), tamoxifen, raloxifene, anastrozole, exemestane, letrozole, herceptinTM(trastuzumab) GlibcTM(imatinib), paclitaxelTM(paclitaxel), cyclophosphamide, lovastatin, minocycline (Minosine), cytarabine, 5-fluorouracil (5-FU), Methotrexate (MTX), taxotereTM(docetaxel), norradTM(goserelin), vincristine, vinblastine, nocodazole, teniposide, etoposide, and jiaojianTM(gemcitabine), Epothilone (Epothilone), norben, camptothecin, daunorubicin (daunonibiin), dactinomycin, mitoxantrone, amsacrine, doxorubicin (doxorubicin), epirubicin or idarubicin. Alternatively, the other therapeutic agent may also be a cytokine such as G-CSF (granulocyte colony stimulating factor). Alternatively, the other therapeutic agent may also be, for example, but not limited to, CMF (cyclophosphamide, methotrexate, and 5-fluorouracil), CAF (cyclophosphamide, doxorubicin, and 5-fluorouracil), AC (doxorubicin and cyclophosphamide), FEC (5-fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC (doxorubicin, cyclophosphamide, and paclitaxel), or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone).
In embodiments of the invention, where a patient is treated according to the invention, the amount of a given drug will depend on factors such as the particular dosing regimen, the type of disease or disorder and its severity, the uniqueness (e.g., body weight) of the subject or host in need of treatment, however, the dosage administered may be routinely determined by methods known in the art depending on the particular circumstances, including, for example, the particular drug that has been employed, the route of administration, the disorder being treated, and the subject or host being treated. In general, for dosages used for adult human therapy, dosages administered will typically range from 0.02 to 5000 mg/day, for example from about 1 to 1500 mg/day. The desired dose may conveniently be presented as a single dose, or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example two, three, four or more divided doses per day. It will be appreciated by those skilled in the art that, notwithstanding the dosage ranges set forth above, the specific effective amounts may be adjusted as appropriate to the circumstances of the patient and in conjunction with the diagnosis by the physician.
Use of the medicament of the invention
Compounds of formulae (I), (Ia), and (Ib) or pharmaceutically acceptable salts, solvates, esters, acids, metabolites, or prodrugs thereof, or pharmaceutical compositions comprising compounds of formulae (I), (Ia), and (Ib) are useful for inhibiting tyrosine kinase KIT (wild-type or various mutations or combinations thereof), ABL (wild-type or various mutations or combinations thereof), EGFR (wild-type or various mutations or combinations thereof), FLT3 (wild-type or various mutations or combinations thereof), VEGFR2 (wild-type or various mutations or combinations thereof), RET (wild-type or various mutations or combinations thereof), PDGFR α (wild-type or various mutations or combinations thereof), PDGFR β (wild-type or various mutations or combinations thereof), BCR/ABL (wild-type or various mutations or combinations thereof), FGFR1 (wild-type or various mutations or combinations thereof), FGFR2 (wild-type or various mutations or combinations thereof), FGFR3 (wild type or various mutations or combinations thereof), and/or FGFR4 (wild type or various mutations or combinations thereof).
Preferably, the compounds and pharmaceutical compositions of the invention are capable of inhibiting tyrosine kinase KIT (particularly mutant cKIT/T670I), BCR/ABL (particularly mutant BCR-ABL/T315I), PDGFR α, PDGFR β, and/or VEGFR2 activity. Thus, the compounds and pharmaceutical compositions of the invention can be used to treat or prevent KIT (particularly mutant cKIT/T670I), BCR/ABL (particularly mutant BCR-ABL/T315I), PDGFR α, PDGFR β, and/or VEGFR2 related diseases.
In particular, the compounds of the present invention, or pharmaceutically acceptable salts, solvates, esters, acids, metabolites or prodrugs thereof, and the pharmaceutical compositions thereof, are useful for treating or preventing one or more diseases selected from the group consisting of: solid Tumors (including benign and malignant types), in particular sarcomas, Gastrointestinal Stromal Tumors (GIST), Acute Myeloid Leukemia (AML), chronic myelogenous Leukemia (AML)Myeloid Leukemia (CML), mesothelioma, thyroid cancer (thyroid cancer), systemic mastocytosis, hypereosinophilic syndrome (HES), fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft-versus-host disease (GVHD), neurofibroma, pulmonary hypertension, Alzheimer's disease, seminoma, psoriasis, dysgerminoma, mast cell tumor, lung cancer, bronchial carcinoma, dysgerminoma, intratesticular neoplasia, melanoma, breast cancer, neuroblastoma, thyroid cancer of the papillary/follicular type, malignant lymphoma, non-Hodgkin's lymphoma, multiple endocrine neoplasia type 2, pheochromocytoma, thyroid cancer, parathyroid hyperplasia/adenoma, colon cancer, rectal adenoma, ovarian cancer, colon cancer, rectal adenoma, and colon cancer, Prostate cancer, glioblastoma, brain tumors, malignant gliomas, pancreatic cancers, malignant pleural mesothelioma, hemangioblastoma, hemangioma, kidney cancers, liver cancers, adrenal cancers, bladder cancers, stomach cancers, rectal cancers, vaginal cancers, cervical cancers, endometrial cancers, multiple myeloma, neck and head tumors, arthritis, rheumatoid arthritis, osteoarthritis, lupus, rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, alder's thyroiditis, Graves' disease, rheumatoid arthritis syndrome (rheumatoid arthritis syndrome)
Figure BDA0001518077870000121
syndrome), multiple sclerosis, infectious neuronitis (Guillain-Barr é syndrome), acute disseminated encephalomyelitis, Addison's disease, optic twins-myotwins syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Retter's syndrome, Gao ' an-Ampere's syndromeArteritis (Takayasu's arteritis), temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, systemic alopecia, Behcet's disease, chronic fatigue, familial autonomic dysfunction, endometriosis, interstitial cystitis, neuromuscular stiffness, scleroderma, vulvodynia, or a combination thereof. Particularly preferred is the treatment of gastrointestinal stromal tumors, acute myeloid leukemia, chronic myeloid leukemia, thyroid cancer, or combinations thereof.
Preparation of the Compounds
The compounds of formula (I), (Ia) and (Ib) may be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. In addition, the solvents, temperatures, and other reaction conditions set forth herein may be varied according to the skill in the art. As a further guide, the following synthesis method may be used.
The reactions may be used sequentially to provide the compounds described herein; or they may be used to synthesize fragments that are subsequently added by the methods described herein and/or known in the art.
In certain embodiments, provided herein are methods of making and methods of using the tyrosine kinase inhibitor compounds described herein. In certain embodiments, the compounds described herein can be synthesized using the following synthetic schemes. The compounds can be synthesized using procedures analogous to those described below, by using appropriate alternative starting materials.
The starting materials for synthesizing the compounds described herein may be synthesized or may be obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using techniques and starting materials known to those skilled in the art. General methods of preparing the compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to incorporate various moieties in the molecules provided herein.
If desired, the reaction product may be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. These products can be characterized using conventional methods, including physical constants and profile data.
The compounds disclosed herein are obtained in good yield and purity using the synthetic methods described herein. The compounds prepared according to the methods disclosed herein are purified by conventional methods known in the art, such as filtration, recrystallization, chromatography, distillation, and combinations thereof.
At sites on the aromatic ring portion of the compounds of formula (I), (Ia) and (Ib), various metabolic reactions may readily occur, and so appropriate substituents are introduced to the aromatic ring structure, for example, by way of example only, halogens can reduce, reduce or eliminate this metabolic pathway.
Examples
The following specific non-limiting examples are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present disclosure to its fullest extent.
Example 1: (E) synthesis of (E) -N1- (3- (2- (2-pyridyl) vinyl) -1H-indazol-6-yl) -N3- (3-tolyl) malonamide
Figure BDA0001518077870000131
(E) -3-oxo-3- (3- (2- (2-pyridyl) vinyl) -1- (tetrahydro-2H-pyran-2-yl ] -1H-indazol-6-yl) amino) -propionic acid methyl ester (1 b): after (E) -3- (2- (pyridin-2-yl) vinyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-amine (10.0 g) was added to a round-bottom flask, anhydrous dichloromethane (100 ml) and triethylamine (6.8 ml) were added, and then the system was cooled to 0 ℃ with an ice-water bath. Methyl malonate monoacyl chloride (3.9 ml) was then added slowly. The reaction system is reacted for 14 hours at room temperature under the protection of argon. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resultant was diluted with water and extracted with dichloromethane. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Filtering the organic phase, and evaporating to dryness under reduced pressure to obtain a crude compound 1 b. LC/MS: m + H421.18. 1H NMR (400MHz, DMSO-d6) δ 10.49(s,1H),8.62(s,1H),8.22(s,1H),8.15(d, J ═ 8.5Hz,1H),7.86(dd, J ═ 24.7,13.4Hz,2H),7.69(d, J ═ 7.3Hz,1H),7.58(d, J ═ 16.4Hz,1H),7.31(d, J ═ 8.5Hz,2H),5.76(s,1H),3.92(d, J ═ 10.0Hz,1H),3.69(s,4H),3.56(s,2H),2.43(d, J ═ 11.1Hz,1H),2.03(s,2H),1.80(s,1H),1.61(s, 2H).
(E) -3-oxo-3- (3- (2- (2-pyridyl) vinyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) amino) propanoic acid (1 c): to a round bottom flask was added (E) -3-oxo-3- (3- (2- (2-pyridyl) vinyl) -1- (tetrahydro-2H-pyran-2-yl ] -1H-indazol-6-yl) amino) -propionic acid methyl ester (8 g), followed by tetrahydrofuran (40 ml), water (40 ml), and lithium hydroxide (2.5 g). The reaction system is reacted for 4 hours at room temperature under the protection of argon. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained product was neutralized with 1 mol/l dilute hydrochloric acid until the pH was 3 to 5, and a solid was precipitated. And filtering the water phase to obtain a precipitated solid, and drying the solid to obtain a crude compound 1 c. LC/MS: m + H407.17. 1H NMR (400MHz, DMSO-d6) δ 10.46(s,1H),8.62(s,1H),8.24(s,1H),8.14(d, J ═ 8.5Hz,1H), 8.00-7.79 (m,2H),7.71(d, J ═ 7.2Hz,1H),7.59(d, J ═ 16.3Hz,1H),7.33(d, J ═ 9.3Hz,2H),5.77(d, J ═ 8.6Hz,1H),3.92(d, J ═ 9.7Hz,1H),3.73(s,1H),3.63(s,2H),2.44(d, J ═ 10.5Hz,1H),2.03(s,2H),1.79(s,1H),1.60(s, 2H).
(E) -N1- (3- (2- (2-pyridyl) vinyl) -1H-indazol-6-yl) -N3- (3-tolyl) malonamide (1): to a round bottom flask was added (E) -3-oxo-3- (3- (2- (2-pyridyl) vinyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) amino) propionic acid (100 mg), followed by N, N-dimethylformamide (5 ml), m-toluidine (27 mg), 2- (7-oxybenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate (120 mg), and triethylamine (0.05 ml). The reaction was stirred at room temperature for 14 hours under argon. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered, evaporated to dryness under reduced pressure to give the crude product which was dissolved in anhydrous dichloromethane (5 ml) and trifluoroacetic acid (1 ml) was added. The reaction was stirred at room temperature for 14 hours under argon. After the reaction was complete, the solvent was evaporated under reduced pressure and the resulting material was diluted with water and neutralized with saturated sodium bicarbonate solution to pH > 10. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, and then dried over anhydrous sodium sulfate. Filtering the organic phase, and evaporating to dryness under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel under pressure to give example Compound 1. LC/MS: m + H412.16. 1H NMR (400MHz, DMSO-d6) δ 13.15(s,1H),10.43(s,1H),10.16(s,1H),8.62(s,1H),8.18(d, J ═ 24.7Hz,2H),7.86(d, J ═ 33.3Hz,2H),7.68(s,1H),7.48(s,3H),7.23(s,3H),6.92(s,1H),3.54(s,2H),2.30(s, 3H).
Example 2: (E) -N1- (4-fluorophenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000141
The synthesis of the compound of example 2 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 416.14.
Example 3: (E) -N1-phenyl-N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000151
The synthesis of the compound of example 3 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 398.15.
Example 4: (E) -N1- (3-fluorophenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000152
The synthesis of the compound of example 4 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 416.14.
Example 5: (E) -N1- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -N3- (3- (2- (2-pyridinyl) vinyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000153
The synthesis of the compound of example 5 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 510.25.
Example 6: (E) -N1- (4-chlorophenyl) -N3- (3- (2- (2-pyridyl) vinyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000154
The synthesis of the compound of example 6 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 432.11.
Example 7: (E) -N1- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) -N3- (thiophen-2-ylmethyl) malonamide
Figure BDA0001518077870000155
The synthesis of the compound of example 7 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 418.12.
Example 8: (E) -N1- (3-bromophenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000161
The synthesis of the compound of example 8 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 476.06.
Example 9: (E) -N1- (3-chlorophenyl) -N3- (3- (2- (2-pyridyl) vinyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000162
The synthesis of the compound of example 9 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 432.11.
Example 10: (E) -N1- (3 (4-methylpiperazin-1-yl) phenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000163
The synthesis of the compound of example 10 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 496.23.
Example 11: (E) -N1- (3-chloro-4-fluorophenyl) -N3- (3- (2- (2-pyridyl) vinyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000164
The synthesis of the compound of example 11 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 450.10.
Example 12: (E) -N1- (3- (dimethylamino) phenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000165
The synthesis of the compound of example 12 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 441.19.
Example 13: (E) -N1- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) -N3- (3,4, 5-trimethoxyphenyl) malonamide
Figure BDA0001518077870000171
The synthesis of the compound of example 13 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 488.18.
Example 14: (E) -N1- (3-methoxyphenyl) -N3- (3- (2- (2-pyridyl) vinyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000172
The synthesis of the compound of example 14 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 428.16.
Example 15: (E) -N1- (4- ((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -N3- (3- (2- (2-pyridinyl) vinyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000173
The synthesis of the compound of example 15 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 592.25.
Example 16: (E) -N1- (4- ((4-isopropylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -N3- (3- (2- (2-pyridinyl) vinyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000174
The synthesis of the compound of example 16 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 606.27.
Example 17: (R, E) -N1- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -N3- (3- (2- (2-pyridyl) vinyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000175
The synthesis of the compound of example 17 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 692.26.
Example 18: (E) -N1- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) -N3- (3-trifluoromethylphenyl) malonamide
Figure BDA0001518077870000181
The synthesis of the compound of example 18 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 466.14.
Example 19: (E) -N1- (2-fluoro-3- (trifluoromethyl) phenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000182
The synthesis of the compound of example 19 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 484.13.
Example 20: (E) -N1- (2-fluoro-5- (trifluoromethyl) phenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000183
The synthesis of the compound of example 20 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 484.13.
Example 21: (E) -N1- (2-chloro-5- (trifluoromethyl) phenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000184
The synthesis of the compound of example 21 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 500.10.
Example 22: (E) -N1- (3-fluoro-5- (trifluoromethyl) phenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000185
The synthesis of the compound of example 22 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 484.13.
Example 23: (E) -N1- (2, 3-difluorophenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000191
The synthesis of the compound of example 23 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 434.13.
Example 24: (E) -N1- (2-chlorophenyl) -N3- (3- (2- (2-pyridyl) vinyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000192
The synthesis of the compound of example 24 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 432.11.
Example 25: (E) -N1- (2,3, 4-trifluorophenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000193
The synthesis of the compound of example 25 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 452.12.
Example 26: (E) -N1- (3, 5-difluorophenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000194
The synthesis of the compound of example 26 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 434.13.
Example 27: (E) -N1- (3, 4-difluorophenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000201
The synthesis of the compound of example 27 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 434.13.
Example 28: (E) -N1- (2,3,4,5, 6-pentafluorophenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000202
The synthesis of the compound of example 28 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 488.10.
Example 29: (E) -N1- (2-fluoro-4- (trifluoromethyl) phenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000203
The synthesis of the compound of example 29 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 484.13.
Example 30: (E) -N1- (2, 4-difluorophenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000204
The synthesis of the compound of example 30 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 434.13.
Example 31: (E) -N1- (2-chloro-3- (trifluoromethyl) phenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000205
The synthesis of the compound of example 31 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 500.10.
Example 32: (E) -N1- (2, 5-difluorophenyl) -N3- (3- (2- (2-pyridyl) ethenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000211
The synthesis of the compound of example 32 was accomplished using procedures analogous to those described in example 1. MS (ESI) M/z (M +1) +: 434.13.
Example 33: synthesis of N1- (3-chlorophenyl) -N3- (1H-indazol-6-yl) malonamide
Figure BDA0001518077870000212
6-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (2 b): after 6-nitro-1H-indazole (1.5 g) was added to a round bottom flask, tetrahydrofuran (40 ml), 3, 4-dihydro-2H-pyran (80 g) and methanesulfonic acid (89 μ l) were added. The reaction was heated to reflux under argon for 14 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. And filtering the organic phase, and evaporating to dryness under reduced pressure to obtain a crude product 2 b. LC/MS: m + H248.09.
6-amino-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (2 c): to methanol was added the compound 6-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (1.5 g), and palladium on carbon (64 mg) was added, followed by stirring at room temperature for 4 hours under a hydrogen atmosphere. Filtering with diatomite, and evaporating the filtrate under reduced pressure to obtain a crude product 2 c. LC/MS: m + H218.12.
3-oxo-3- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) amino) propionic acid methyl ester (2 d): after 6-amino-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (1 g) was added to a round-bottom flask, anhydrous dichloromethane (30 ml) and triethylamine (1 ml) were added, and then the system was cooled to 0 ℃ with an ice-water bath. Methyl malonate monoacyl chloride (0.6 ml) was then added slowly. The reaction system is reacted for 14 hours at room temperature under the protection of argon. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resultant was diluted with water and extracted with dichloromethane. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase is filtered, decompressed and evaporated to dryness to obtain a crude product 2 d. LC/MS: m + H318.13.
3-oxo-3- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) amino) propionic acid (2 e): methyl 3-oxo-3- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) amino) propanoate (1 g) was added to tetrahydrofuran (10 ml) and water (10 ml), followed by lithium hydroxide (0.7 g). The reaction system is reacted for 4 hours at room temperature under the protection of argon. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained product was neutralized with 1 mol/l dilute hydrochloric acid until a solid precipitated at pH 3 to 5. Filtering the water phase to obtain a precipitated solid, and drying the solid to obtain a crude product 2 e. LC/MS: m + H304.12.
N1- (3-chlorophenyl) -N3- (1H-indazol-6-yl) malonamide (33): to a round bottom flask was added 3-oxo-3- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) amino) propionic acid (50 mg), followed by N, N-dimethylformamide (5 ml), m-chloroaniline (25 mg), 2- (7-oxybenzotriazole) -N, N' -tetramethylurea hexafluorophosphate (94 mg), and triethylamine (0.05 ml). The reaction was stirred at room temperature for 14 hours under argon. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered, evaporated to dryness under reduced pressure to give the crude product which was dissolved in anhydrous dichloromethane (5 ml) and trifluoroacetic acid (1 ml) was added. The reaction was stirred at room temperature for 14 hours under argon. After the reaction was complete, the solvent was evaporated under reduced pressure and the resulting material was diluted with water and neutralized with saturated sodium bicarbonate solution to pH > 10. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, and then dried over anhydrous sodium sulfate. Filtering the organic phase, and evaporating to dryness under reduced pressure to obtain a crude product. Purifying the crude product by pressurized silica gel column chromatography to obtain a pure compound 33. LC/MS: 329.07.
example 34: n1- (4- ((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -N3- (1H-indazol-6-yl) malonamide
Figure BDA0001518077870000221
The synthesis of the compound of example 34 was accomplished using procedures analogous to those described in example 33. MS (ESI) M/z (M +1) +: 489.21.
Example 35: n1- (1H-indazol-6-yl) -N3-phenylmalonamide
Figure BDA0001518077870000222
The synthesis of the compound of example 35 was accomplished using procedures analogous to those described in example 33. MS (ESI) M/z (M +1) +: 294.11.
Example 36: n1- (3-fluorophenyl) -N3- (1H-indazol-6-yl) malonamide
Figure BDA0001518077870000223
The synthesis of the compound of example 36 was accomplished using procedures analogous to those described in example 33. MS (ESI) M/z (M +1) +: 313.10.
Example 37: n1- (1H-indazol-6-yl) -N3- (3- (4-methylpiperazin-1-yl) phenyl) malonamide
Figure BDA0001518077870000224
The synthesis of the compound of example 37 was accomplished using procedures analogous to those described in example 33.
MS(ESI)m/z(M+1)+:393.19。
Example 38: n1- (1H-indazol-6-yl) -N3- (3,4, 5-trimethoxyphenyl) malonamide
Figure BDA0001518077870000231
The synthesis of the compound of example 38 was accomplished using procedures analogous to those described in example 33. MS (ESI) M/z (M +1) +: 385.14.
Example 39: n1- (3-chloro-4-fluorophenyl) -N3- (1H-indazol-6-yl) malonamide
Figure BDA0001518077870000232
The synthesis of the compound of example 39 was accomplished by using procedures analogous to those described in example 33. MS (ESI) M/z (M +1) +: 347.06.
Example 40: n1- (3- (dimethylamino) phenyl) -N3- (1H-indazol-6-yl) malonamide
Figure BDA0001518077870000233
The synthesis of the compound of example 40 was accomplished using procedures analogous to those described in example 33. MS (ESI) M/z (M +1) +: 338.15.
Example 41: n1- (1H-indazol-6-yl) -N3- (3-methoxyphenyl) malonamide
Figure BDA0001518077870000234
The synthesis of the compound of example 41 was accomplished by using procedures analogous to those described in example 33. MS (ESI) M/z (M +1) +: 325.12.
Example 42: n1- (4-chlorophenyl) -N3- (3-methyl-1H-indazol-6-yl) malonamide
Figure BDA0001518077870000235
The synthesis of the compound of example 42 was accomplished using procedures analogous to those described in example 33. MS (ESI) M/z (M +1) +: 343.08.
Example 43: n1- (3-fluorophenyl) -N3- (3-methyl-1H-indazol-6-yl) malonamide
Figure BDA0001518077870000236
The synthesis of the compound of example 43 was accomplished using procedures analogous to those described in example 33. MS (ESI) M/z (M +1) +: 327.11.
Example 44: n1- (3-methyl-1H-indazol-6-yl) -N3- (3- (trifluoromethyl) phenyl) malonamide
Figure BDA0001518077870000241
The synthesis of the compound of example 44 was accomplished using procedures analogous to those described in example 33. MS (ESI) M/z (M +1) +: 377.11.
Example 45: n1- (4-chloro-3- (trifluoromethyl) phenyl) -N3- (3-methyl-1H-indazol-6-yl) malonamide
Figure BDA0001518077870000242
The synthesis of the compound of example 45 was accomplished using procedures analogous to those described in example 33. MS (ESI) M/z (M +1) +: 411.07.
Example 46: synthesis of N1-phenyl-N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000243
6-nitro-3- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (3 b): to a round bottom flask was added 3-iodo-6-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (5 g) followed by 1, 4-dioxane (100 ml), water (20ml), 3-pyridineboronic acid (2.7 g), Pd (Ph)3P)4(0.7 g) and potassium carbonate (5.5 g). The reaction system is heated to 80 ℃ under the protection of argon and reacted for 14 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Filtering the organic phase, and evaporating to dryness under reduced pressure to obtain a crude product. Purifying the crude product by pressurized silica gel column chromatography to obtain a pure product 3 b. LC/MS: m + H325.12.
6-amino-3- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (3 c): the compound 6-nitro-3- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (3 g), palladium on carbon (97 mg) was added to methanol, and stirred at room temperature for 4 hours under a hydrogen atmosphere. Filtering with diatomite, and evaporating the filtrate under reduced pressure to obtain a crude product 3 c. LC/MS: m + H295.15.
3-oxo-3- ((pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) amino) propionic acid methyl ester (3 d): after 6-amino-3- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (1 g) was added to a round bottom flask, anhydrous dichloromethane (30 ml) and triethylamine (0.7 ml) were added, and the system was cooled to 0 ℃ with an ice water bath. Methyl malonate monoacyl chloride (0.4 ml) was then added slowly. The reaction system is reacted for 14 hours at room temperature under the protection of argon. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resultant was diluted with water and extracted with dichloromethane. The organic phase was washed with water and saturated brine, respectively, and then dried over anhydrous sodium sulfate. And filtering the organic phase, and evaporating to dryness under reduced pressure to obtain a crude product 3 d. LC/MS: m + H395.16.
3-oxo-3- ((pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) amino) propionic acid (3 e): methyl 3-oxo-3- ((pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) amino) propanoate (1 g) was added to tetrahydrofuran (10 ml) and water (10 ml), followed by lithium hydroxide (0.6 g). The reaction system is reacted for 4 hours at room temperature under the protection of argon. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained product was neutralized with 1 mol/l dilute hydrochloric acid until a solid precipitated at pH 3 to 5. Filtering the water phase to obtain a precipitated solid, and drying the solid to obtain a crude product 3 e. LC/MS: m + H381.14.
N1-phenyl-N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide (46): after 3-oxo-3- ((pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) amino) propionic acid (50 mg) was added to a round bottom flask, N-dimethylformamide (5 ml), aniline (16 mg), 2- (7-oxybenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate (75 mg) and triethylamine (0.05 ml) were added. The reaction was stirred at room temperature for 14 hours under argon. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered, evaporated to dryness under reduced pressure to give the crude product which was dissolved in anhydrous dichloromethane (5 ml) and trifluoroacetic acid (1 ml) was added. The reaction was stirred at room temperature for 14 hours under argon. After the reaction was complete, the solvent was evaporated under reduced pressure and the resulting material was diluted with water and neutralized with saturated sodium bicarbonate solution to pH > 10. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, and then dried over anhydrous sodium sulfate. Filtering the organic phase, and evaporating to dryness under reduced pressure to obtain a crude product. Purifying the crude product by pressurized silica gel column chromatography to obtain a pure compound 46. LC/MS: 372.13.
example 47: n1- (3-fluorophenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000251
The synthesis of the compound of example 47 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 390.39.
Example 48: n1- (4-chloro-3- (trifluoromethyl) phenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000252
The synthesis of the compound of example 48 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 474.84.
Example 49: n1- (5- (tert-butyl) isoxazol-3-yl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000253
The synthesis of the compound of example 49 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 419.45.
Example 50: n1- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000261
The synthesis of the compound of example 50 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 520.48.
Example 51: n1- (3- (pyridin-3-yl) -1H-indazol-6-yl) -N3- (3- (trifluoromethyl) phenyl) malonamide
Figure BDA0001518077870000262
The synthesis of the compound of example 51 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 540.39.
Example 52: n1- (2-fluorophenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide.
Figure BDA0001518077870000263
The synthesis of the compound of example 52 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 390.39.
Example 53: n1- (3-chloro-4-fluorophenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000264
The synthesis of the compound of example 53 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 424.83.
Example 54: n1- (4-methoxy-3- (trifluoromethyl) phenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000265
The synthesis of the compound of example 54 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 470.42.
Example 55: n1- (2, 6-difluorophenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000271
The synthesis of the compound of example 55 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 408.38.
Example 56: n1- (2-fluoro-5- (trifluoromethyl) phenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000272
The synthesis of the compound of example 56 was accomplished by using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 458.11.
Example 57: n1- (3-fluoro-5- (trifluoromethyl) phenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000273
The synthesis of the compound of example 57 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 458.11.
Example 58: n1- (2,3, 4-trifluorophenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000274
The synthesis of compound 58 was accomplished by using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 426.11.
Example 59: n1- (2, 3-difluorophenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000275
The synthesis of the compound of example 59 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 408.12.
Example 60: n1- (3, 5-difluorophenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000276
The synthesis of the compound of example 60 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 408.12.
Example 61: n1- (3-fluoro-5- (trifluoromethyl) phenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000281
The synthesis of the compound of example 61 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 458.11.
Example 62: n1- (2-chloro-5- (trifluoromethyl) phenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000282
The synthesis of the compound of example 62 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 474.09.
Example 63: n1- (4-fluoro-3- (trifluoromethyl) phenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000283
The synthesis of the compound of example 63 was accomplished by using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 458.11.
Example 64: n1- (4-chlorophenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000284
The synthesis of the compound of example 64 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 406.10.
Example 65: n1- (2-fluoro-3- (trifluoromethyl) phenyl) -N3- (3- (pyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000285
The synthesis of the compound of example 65 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 458.12.
Example 66: n1- (3-chloro-4-fluorophenyl) -N3- (3- (3-fluorophenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000286
The synthesis of the compound of example 66 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 441.06.
Example 67: n1- (4-chloro-3- (trifluoromethyl) phenyl) -N3- (3- (3-fluorophenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000291
The synthesis of the compound of example 67 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 491.08.
Example 68: n1- (4-chlorophenyl) -N3- (3- (3-fluorophenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000292
The synthesis of the compound of example 68 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 423.09.
Example 69: n1- (3-fluorophenyl) -N3- (3- (3-fluorophenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000293
The synthesis of the compound of example 69 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 407.12.
Example 70: n1- (3- (3-fluorophenyl) -1H-indazol-6-yl) -N3- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) malonamide
Figure BDA0001518077870000294
The synthesis of the compound of example 70 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 537.15.
Example 71: n1- (3- (3-fluorophenyl) -1H-indazol-6-yl) -N3- (m-tolyl) malonamide
Figure BDA0001518077870000295
The synthesis of the compound of example 71 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 403.14.
Example 72: n1- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -N3- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000301
The synthesis of the compound of example 72 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 617.61.
Example 73: n1- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) -N3- (3- (trifluoromethyl) phenyl) malonamide
Figure BDA0001518077870000302
The synthesis of the compound of example 73 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 537.55.
Example 74: n1- (2-fluorophenyl) -N3- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000303
The synthesis of the compound of example 74 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 487.55.
Example 75: n1- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) -N3- (m-tolyl) malonamide
Figure BDA0001518077870000304
The synthesis of the compound of example 75 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 483.58.
Example 76: n1- (3-fluorophenyl) -N3- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000311
The synthesis of the compound of example 76 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 487.55.
Example 77: n1- (2-fluoro-3- (trifluoromethyl) phenyl) -N3- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000312
The synthesis of the compound of example 77 was accomplished by using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 555.54.
Example 78: n1- (2-chloro-5- (trifluoromethyl) phenyl) -N3- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000313
The synthesis of the compound of example 78 was accomplished by using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 572.00.
Example 79: n1- (4-fluoro-3- (trifluoromethyl) phenyl) -N3- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000314
The synthesis of the compound of example 79 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 555.55.
Example 80: n1- (2, 6-difluorophenyl) -N3- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000321
The synthesis of the compound of example 80 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 505.54.
Example 81: n1- (2-fluoro-5- (trifluoromethyl) phenyl) -N3- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000322
The synthesis of the compound of example 81 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 555.55.
Example 82: n1- (3-chloro-4-fluorophenyl) -N3- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000323
The synthesis of the compound of example 82 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 521.99.
Example 83: n1- (3-chloro-5- (trifluoromethyl) phenyl) -N3- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000324
The synthesis of the compound of example 83 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 571.17.
Example 84: n1- (2,3, 4-trifluorophenyl) -N3- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000331
The synthesis of the compound of example 84 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 523.20.
Example 85: n1- (2, 3-difluorophenyl) -N3- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000332
The synthesis of the compound of example 85 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 505.54.
Example 86: n1- (3, 5-difluorophenyl) -N3- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000333
The synthesis of the compound of example 86 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 505.54.
Example 87: n1- (3, 4-difluorophenyl) -N3- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000334
The synthesis of the compound of example 87 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 505.54.
Example 88: n1- (3-fluoro-5- (trifluoromethyl) phenyl) -N3- (3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000341
The synthesis of the compound of example 88 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 555.55.
Example 89: n1- (3-fluoro-5- (trifluoromethyl) phenyl) -N3- (3- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000342
The synthesis of the compound of example 89 was accomplished by using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 567.22.
Example 90: n1- (4-chloro-3- (trifluoromethyl) phenyl) -N3- (3- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000343
The synthesis of the compound of example 90 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 585.19.
Example 91: n1- (2, 3-difluorophenyl) -N3- (3- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000344
The synthesis of the compound of example 91 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 519.22.
Example 92: n1- (3- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazol-6-yl) -N3- (m-tolyl) malonamide
Figure BDA0001518077870000351
The synthesis of the compound of example 92 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 497.25.
Example 93: n1- (2-fluorophenyl) -N3- (3- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000352
The synthesis of the compound of example 93 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 501.23.
Example 94: n1- (3-fluorophenyl) -N3- (3- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000353
The synthesis of the compound of example 94 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 501.23.
Example 95: n1- (4-fluoro-3- (trifluoromethyl) phenyl) -N3- (3- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000354
The synthesis of the compound of example 95 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 569.22.
Example 96: n1- (2-fluoro-5- (trifluoromethyl) phenyl) -N3- (3- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000361
The synthesis of the compound of example 96 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 569.22.
Example 97: n1- (3-chloro-5- (trifluoromethyl) phenyl) -N3- (3- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000362
The synthesis of the compound of example 97 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 585.19.
Example 98: n1- (3- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazol-6-yl) -N3-phenylmalonamide
Figure BDA0001518077870000363
The synthesis of the compound of example 98 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 483.24.
Example 99: n1- (3- (3-carbamoyl) phenyl-1H-indazol-6-yl) -N3- (3-chloro-5- (trifluoromethyl) phenyl) malonamide
Figure BDA0001518077870000364
The synthesis of the compound of example 99 was accomplished by using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 516.09.
Example 100: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (4-chloro-3- (trifluoromethyl) phenyl) malonamide
Figure BDA0001518077870000371
The synthesis of the compound of example 100 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 516.09.
Example 101: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (m-tolyl) malonamide
Figure BDA0001518077870000372
The synthesis of the compound of example 101 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 428.16.
Example 102: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (2-fluorophenyl) malonamide
Figure BDA0001518077870000373
The synthesis of the compound of example 102 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 432.13.
Example 103: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (4-fluoro-3- (trifluoromethyl) phenyl) malonamide
Figure BDA0001518077870000374
The synthesis of the compound of example 103 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 500.12.
Example 104: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (3-fluoro-5- (trifluoromethyl) phenyl) malonamide
Figure BDA0001518077870000375
The synthesis of the compound of example 104 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 500.12.
Example 105: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (2, 3-difluorophenyl) malonamide
Figure BDA0001518077870000381
The synthesis of compound 105 was accomplished by using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 450.13.
Example 106: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (2-fluoro-5- (trifluoromethyl) phenyl) malonamide
Figure BDA0001518077870000382
The synthesis of the compound of example 106 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 500.13.
Example 107: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (2,3, 4-trifluorophenyl) malonamide
Figure BDA0001518077870000383
The synthesis of the compound of example 107 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 468.12.
Example 108: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (3, 5-difluorophenyl) malonamide
Figure BDA0001518077870000384
The synthesis of the compound of example 108 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 450.13.
Example 109: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (3-fluorophenyl) malonamide
Figure BDA0001518077870000385
The synthesis of the compound of example 109 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 432.14.
Example 110: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (3- (trifluoromethyl) phenyl) malonamide
Figure BDA0001518077870000391
The synthesis of the compound of example 110 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 482.13.
Example 111: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (2-chloro-5- (trifluoromethyl) phenyl) malonamide
Figure BDA0001518077870000392
The synthesis of the compound of example 111 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 516.10.
Example 112: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (3-chloro-4-fluorophenyl) malonamide
Figure BDA0001518077870000393
The synthesis of the compound of example 112 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 466.10.
Example 113: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (4-methoxy-3- (trifluoromethyl) phenyl) malonamide
Figure BDA0001518077870000394
The synthesis of the compound of example 113 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 512.14.
Example 114: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) malonamide
Figure BDA0001518077870000395
The synthesis of the compound of example 114 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 562.17.
Example 115: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (2, 6-difluorophenyl) malonamide
Figure BDA0001518077870000401
The synthesis of the compound of example 115 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 550.13.
Example 116: n1- (5- (tert-butyl) isoxazol-3-yl) -N3- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) malonamide
Figure BDA0001518077870000402
The synthesis of the compound of example 116 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 461.18.
Example 117: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (4-chlorophenyl) malonamide
Figure BDA0001518077870000403
The synthesis of the compound of example 117 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 448.10.
Example 118: n1- (3- (3-aminoacyl) phenyl-1H-indazol-6-yl) -N3- (2-fluoro-3- (trifluoromethyl) phenyl) malonamide
Figure BDA0001518077870000404
The synthesis of the compound of example 118 was accomplished by using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 500.13.
Example 119: n1- (3-fluorophenyl) -N3- (3- (6-methylpyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000405
The synthesis of the compound of example 119 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 404.14.
Example 120: n1- (4-methoxy-3- (trifluoromethyl) phenyl) -N3- (3- (6-methylpyridin-3-yl) -1H-indazol-6-yl) malonamide
Figure BDA0001518077870000411
The synthesis of the compound of example 120 was accomplished using procedures analogous to those described in example 46. MS (ESI) M/z (M +1) +: 484.15.
Example 121: (E) synthesis of (E) -N- (2- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) ethyl) nicotinamide
Figure BDA0001518077870000412
(E) -2- ((3- (2- (pyridin-2-yl) vinyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) thio) ethyl-1-amine (4 c): adding (E) -6-iodo-3- [2- (pyridin-2-yl) ethenyl in a round bottom flask]-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (5 g) and N, N-dimethylacetamide (20ml), 2-aminoethanethiol (1.1 g), Pd (OAc)2(0.3 g) and 9, 9-dimethyl-4, 5-bisdiphenylphosphinoxaanthracene (0.8 g), N-diisopropylethylamine (6.5 ml). The reaction system is heated to 150 ℃ under the protection of argon and reacted for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Filtering the organic phase, and evaporating to dryness under reduced pressure to obtain a crude product. Purifying the crude product by pressurized silica gel column chromatography to obtain a pure product 4 c. LC/MS: m + H381.16.
(E) -N- (2- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) ethyl) nicotinamide (121): to a round bottom flask was added (E) -2- ((3- (2- (pyridin-2-yl) vinyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) thio) ethyl-1-amine (50 mg) followed by N, N-dimethylformamide (5 ml), nicotinic acid (19 mg), 2- (7-oxybenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate (75 mg) and triethylamine (0.04 ml). The reaction was stirred at room temperature for 14 hours under argon. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered, evaporated to dryness under reduced pressure to give the crude product which was dissolved in anhydrous dichloromethane (5 ml) and trifluoroacetic acid (1 ml) was added. The reaction was stirred at room temperature for 14 hours under argon. After the reaction was complete, the solvent was evaporated under reduced pressure and the resulting material was diluted with water and neutralized with saturated sodium bicarbonate solution to pH > 10. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, and then dried over anhydrous sodium sulfate. Filtering the organic phase, and evaporating to dryness under reduced pressure to obtain a crude product. The crude product is purified by pressurized silica gel column chromatography to obtain a pure compound 121. LC/MS: m + H402.13.
Example 122: (E) -5-oxo-N- (2- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) ethyl) pyrrolidine-2-carboxamide
Figure BDA0001518077870000421
The synthesis of the compound of example 122 was accomplished using procedures analogous to those described in example 121. MS (ESI) M/z (M +1) +: 408.14.
Example 123: (E) -1-methyl-2-oxo-N- (2- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) ethyl) -1, 2-dihydropyridine-3-carboxamide
Figure BDA0001518077870000422
The synthesis of compound 123 was accomplished by using procedures analogous to those described in example 121. MS (ESI) M/z (M +1) +: 432.14.
Example 124: (E) synthesis of (E) -1- (3, 4-difluorophenyl) -3- (2- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) ethyl) urea
Figure BDA0001518077870000423
To a round bottom flask was added (E) -2- ((3- (2- (pyridin-2-yl) vinyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) thio) ethyl-1-amine (50 mg) followed by dichloromethane (5 ml), 3, 4-difluorophenylisocyanate (23 mg). The reaction was stirred at room temperature for 14 hours under argon atmosphere and then trifluoroacetic acid (1 ml) was added. The reaction was stirred at room temperature for a further 14 hours under argon. After the reaction was complete, the solvent was evaporated under reduced pressure and the resulting material was diluted with water and neutralized with saturated sodium bicarbonate solution to pH > 10. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, and then dried over anhydrous sodium sulfate. Filtering the organic phase, and evaporating to dryness under reduced pressure to obtain a crude product. Purifying the crude product by pressurized silica gel column chromatography to obtain a pure compound 124. LC/MS: m + H452.12.
Example 125: (E) -1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (2- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) ethyl) urea
Figure BDA0001518077870000424
The synthesis of the compound of example 125 was accomplished using procedures analogous to those described in example 124. MS (ESI) M/z (M +1) +: 518.09.
Example 126: (E) -1- (2- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) ethyl) -3- (3- (trifluoromethyl) phenyl) urea
Figure BDA0001518077870000431
The synthesis of the compound of example 126 was accomplished using procedures analogous to those described in example 124. MS (ESI) M/z (M +1) +: 484.13.
Example 127: (E) -4- ((4-methylpiperazin-1-yl) methyl) -N- (3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propyl) -3- (trifluoromethyl) benzamide
Figure BDA0001518077870000432
The synthesis of compound 127 was accomplished using procedures analogous to those described in example 121. MS (ESI) M/z (M +1) +: 595.23.
Example 128: (E) -N- (3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propyl) furan-2-carboxamide
Figure BDA0001518077870000433
The synthesis of the compound of example 128 was accomplished using procedures analogous to those described in example 121. MS (ESI) M/z (M +1) +: 405.48.
Example 129: (E) -N- (3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propyl) benzamide
Figure BDA0001518077870000434
The synthesis of the compound of example 129 was accomplished using procedures analogous to those described in example 121. MS (ESI) M/z (M +1) +: 401.13.
Example 130: (E) -2-hydroxy-N- (3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propyl) isonicotinamide
Figure BDA0001518077870000441
The synthesis of the compound of example 130 was accomplished using procedures analogous to those described in example 121. MS (ESI) M/z (M +1) +: 432.51.
Example 131: (E) -4-chloro-N- (3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propyl) -3- (trifluoromethyl) benzamide
Figure BDA0001518077870000442
The synthesis of the compound of example 131 was accomplished using procedures analogous to those described in example 121. MS (ESI) M/z (M +1) +: 517.96.
Example 132: (E) -4- ((4-methylpiperazin-1-yl) methyl) -N- (3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propyl) benzamide
Figure BDA0001518077870000443
The synthesis of the compound of example 132 was accomplished using procedures analogous to those described in example 121. MS (ESI) M/z (M +1) +: 527.25.
Example 133: (E) -N- (3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propyl) thiophene-2-carboxamide
Figure BDA0001518077870000444
The synthesis of the compound of example 133 was accomplished using procedures analogous to those described in example 121. MS (ESI) M/z (M +1) +: 421.11.
Example 134: (E) synthesis of (E) -N (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000451
(E) Methyl- (3- (3- (2- (2-pyridyl) vinyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) thio) propanoate (5 b): adding (E) -6-iodo-3- [2- (pyridin-2-yl) ethenyl in a round bottom flask]-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (5 g) and N, N-dimethylacetamide (20ml), methyl 3-mercaptopropionate (1.7 g), Pd (OAc)2(0.3 g) and 9, 9-dimethyl-4, 5-bisdiphenylphosphinoxaanthracene (0.8 g), N-diisopropylethylamine (6.5 ml). The reaction system is heated to 150 ℃ under the protection of argon and reacted for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Filtering the organic phase, and evaporating to dryness under reduced pressure to obtain a crude product. Purifying the crude product by pressurized silica gel column chromatography to obtain a pure product 5 b. LC/MS: m + H424.16.
(E) - (3- (3- (2- (2-pyridyl) vinyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) thio) propionic acid (5 c): methyl (E) - (3- (3- (2- (2-pyridyl) vinyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) thio) propanoate (1 g) was added to tetrahydrofuran (20ml) and water (20ml), followed by lithium hydroxide (1.7 g). The reaction system is reacted for 4 hours at room temperature under the protection of argon. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained product was neutralized with 1 mol/l dilute hydrochloric acid until a solid precipitated at pH 3 to 5. The water phase is filtered to obtain solid, and the solid is dried to obtain crude product 5 c. LC/MS: m + H410.14.
(E) -N (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide (134): after (E) - (3- (3- (2- (2-pyridyl) vinyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) thio) propanoic acid (50 mg) was added to a round bottom flask, N-dimethylformamide (5 ml), 4- ((4-methylpiperazin-1-yl) methyl) aniline (28 mg), 2- (7-oxybenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate (70 mg) and triethylamine (0.05 ml) were added. The reaction was stirred at room temperature for 14 hours under argon. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered, evaporated to dryness under reduced pressure to give the crude product which was dissolved in anhydrous dichloromethane (5 ml) and trifluoroacetic acid (1 ml) was added. The reaction was stirred at room temperature for 14 hours under argon. After the reaction was complete, the solvent was evaporated under reduced pressure and the resulting material was diluted with water and neutralized with saturated sodium bicarbonate solution to pH > 10. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, and then dried over anhydrous sodium sulfate. Filtering the organic phase, and evaporating to dryness under reduced pressure to obtain a crude product. Purifying the crude product by pressurized silica gel column chromatography to obtain a pure compound 134. LC/MS: m + H513.23.
Example 135: (E) -N- (3-fluorophenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000461
The synthesis of the compound of example 135 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 419.26.
Example 136: (E) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) -N- (3,4, 5-trimethoxyphenyl) propanamide
Figure BDA0001518077870000462
The synthesis of the compound of example 136 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 491.16.
Example 137: (E) -N- (3-chlorophenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000463
The synthesis of the compound of example 137 was accomplished by using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 435.09.
Example 138: (E) -N- (4-chloro-3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000464
The synthesis of the compound of example 138 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 503.08.
Example 139: (E) -N- (3-methoxyphenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000465
The synthesis of the compound of example 139 was accomplished by using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 431.01.
Example 140: (E) -N- (3- (dimethylamino) phenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000471
The synthesis of the compound of example 140 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 444.17.
Example 141: (E) -N- (3- (4-methylpiperazin-1-yl) phenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000472
The synthesis of the compound of example 141 was accomplished by using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 499.22.
Example 142: (E) -N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) -phenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000473
The synthesis of the compound of example 142 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 581.22.
Example 143: (E) -N- (3-fluoro-4-methylphenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000474
The synthesis of the compound of example 143 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 433.14.
Example 144: (E) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) -N- (4- (trifluoromethoxy) phenyl) propanamide
Figure BDA0001518077870000475
The synthesis of the compound of example 144 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 485.11.
Example 145: (E) -N-benzyl-3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000481
The synthesis of the compound of example 145 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 415.15.
Example 146: (E) -N- (4-acetylphenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000482
The synthesis of the compound of example 146 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 443.14.
Example 147: (E) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) -N- (m-tolyl) propionamide
Figure BDA0001518077870000483
The synthesis of the compound of example 147 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 415.15.
Example 148: (E) -N- (3, 4-dimethylphenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000484
The synthesis of the compound of example 148 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 429.16.
Example 149: (E) -N- (4-methoxybenzyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000485
The synthesis of the compound of example 149 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 445.16.
Example 150: (E) -N- (4- (tert-butyl) phenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000491
The synthesis of the compound of example 150 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 457.18.
Example 151: (E) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) -N- (p-tolyl) propionamide
Figure BDA0001518077870000492
The synthesis of the compound of example 151 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 415.15.
Example 152: (E) -N- (4-methoxy-3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000493
The synthesis of the compound of example 152 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 499.13.
Example 153: (E) -N- (3-fluoro-4-methylphenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000494
The synthesis of the compound of example 153 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 433.14.
Example 154: (E) -N- (4-methyl-3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000501
The synthesis of the compound of example 154 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 483.14.
Example 155: (E) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) -N- (3- (trifluoromethyl) benzyl) propionamide
Figure BDA0001518077870000502
The synthesis of the compound of example 155 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 483.14.
Example 156: (E) -N-phenyl-3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000503
The synthesis of the compound of example 156 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 401.14.
Example 157: (E) -N- (4-fluoro-3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000504
The synthesis of the compound of example 157 was accomplished by using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 487.11.
Example 158: (E) -N- (4- ((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000505
The synthesis of the compound of example 158 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 595.24.
Example 159: (E) -N- ((4- (((2-dimethylamino) ethyl) (methyl) amino) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridin-2-yl) ethenyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000511
The synthesis of the compound of example 159 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 583.24.
Example 160: (E) -N- (4- ((3- (dimethylamino) pyrrol-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000512
The synthesis of the compound of example 160 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 595.24.
Example 161: (E) -N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000513
The synthesis of the compound of example 161 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 549.16.
Example 162: (E) -N- (4- ((4-methylpiperidin-1-yl) methyl) -3- (trifluoromethyl) -phenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000514
The synthesis of the compound of example 162 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 580.23.
Example 163: (E) -N- (4- (morpholinomethyl) -3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000515
The synthesis of the compound of example 163 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 568.19.
Example 164: (E) -3- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) -N- (4- (pyrrol-1-ylmethyl) -3- (trifluoromethyl) phenyl) propanamide
Figure BDA0001518077870000521
The synthesis of the compound of example 164 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 552.20.
Example 165: 3- ((1H-indazol-6-yl) thio) -N- (4-methyl-3- (trifluoromethyl) phenyl) propanamide
Figure BDA0001518077870000522
The synthesis of the compound of example 165 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 380.10.
Example 166: 3- ((1H-indazol-6-yl) thio) -N- (4- ((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) propanamide
Figure BDA0001518077870000523
The synthesis of the compound of example 166 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 492.20.
Example 167: 3- ((1H-indazol-6-yl) thio) -N- (4-chloro-3- (trifluoromethyl) phenyl) propanamide
Figure BDA0001518077870000524
The synthesis of the compound of example 167 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 400.04.
Example 168: 3- ((1H-indazol-6-yl) thio) -N- (4-fluorophenyl) propanamide
Figure BDA0001518077870000525
The synthesis of the compound of example 168 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 316.08.
Example 169: 3- ((1H-indazol-6-yl) thio) -N- (thiophene-2-methyl) propanamide
Figure BDA0001518077870000526
The synthesis of the compound of example 169 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 318.07.
Example 170: 3- ((1H-indazol-6-yl) thio) -N- (3- (trifluoromethyl) phenyl) propanamide
Figure BDA0001518077870000531
The synthesis of the compound of example 170 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 366.08.
Example 171: 3- ((1H-indazol-6-yl) thio) -N- (3-fluorophenyl) propanamide
Figure BDA0001518077870000532
The synthesis of the compound of example 171 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 316.08.
Example 172: 3- ((1H-indazol-6-yl) thio) -N- (2, 3-difluorophenyl) propanamide
Figure BDA0001518077870000533
The synthesis of the compound of example 172 was accomplished using procedures analogous to those described in example 134. MS (ESI) M/z (M +1) +: 334.07.
Example 173: synthesis of N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (pyridin-3-yl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000534
6-iodo-3- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (6 a): 6-amino-3- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (5 g) was added to a round bottom flask followed by acetic acid (20ml) and the system was cooled to 0 ℃ with an ice water bath. 3 mol/l sulfuric acid (11 ml) was added, sodium nitrite (1.8 g) was added, and after stirring the reaction system at 0 ℃ for 4 hours under argon protection, 3 mol/l potassium iodide (17 ml) was added. The reaction was stirred at 0 ℃ for 3 hours under argon. After completion of the reaction, the solid obtained by filtering the reaction solution was dissolved in ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate and saturated brine, respectively, and then dried over anhydrous sodium sulfate. The organic phase is filtered, decompressed and evaporated to dryness to obtain a crude product 6 a. LC/MS: m + H406.03.
Methyl 3- ((3- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) thio) propanoate (6 b): after 6-iodo-3- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (2 g) was added to a round bottom flask, N-dimethylacetamide (10 ml), methyl 3-mercaptopropionate (0.7 g), palladium acetate (0.1 g), and 9, 9-dimethyl-4, 5-bis diphenylphosphinoxaanthracene (0.3 g), N-diisopropylethylamine (2.7 ml) were added. The reaction system is heated to 150 ℃ under the protection of argon and reacted for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Filtering the organic phase, and evaporating to dryness under reduced pressure to obtain a crude product. Purifying the crude product by pressurized silica gel column chromatography to obtain a pure product 6 b. LC/MS: m + H398.14.
3- ((3- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) thio) propionic acid (6 c): to a round bottom flask was added methyl 3- ((3- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) thio) propanoate (1 g), followed by tetrahydrofuran (20ml) and water (20ml), and then lithium hydroxide (0.6 g). The reaction system is reacted for 4 hours at room temperature under the protection of argon. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained product was neutralized with 1 mol/l dilute hydrochloric acid until a solid precipitated at pH 3 to 5. The water phase is filtered to obtain solid, and the solid is dried to obtain crude product 6 c. LC/MS: m + H384.13.
N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (pyridin-3-yl) -1H-indazol-6-yl) thio) propionamide (173): adding 50mg of (3- ((3- (pyridine-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-6-yl) sulfur) propionic acid into a round-bottom flask, adding 5 ml of N, N-dimethylformamide, 42 mg of 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline, 74 mg of 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate and 0.05 ml of triethylamine, stirring the reaction system for 14 hours at room temperature under the protection of argon, evaporating the solvent in the reaction system under reduced pressure after the reaction is finished, diluting the obtained substance with water, extracting with ethyl acetate, extracting the organic phase with water, extracting with ethyl acetate, extracting with water, extracting with ethyl acetate, and performing condensation reaction by using a solvent extraction method, The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered, evaporated to dryness under reduced pressure to give the crude product which was dissolved in anhydrous dichloromethane (5 ml) and trifluoroacetic acid (1 ml) was added. The reaction was stirred at room temperature for 14 hours under argon. After the reaction was complete, the solvent was evaporated under reduced pressure and the resulting material was diluted with water and neutralized with saturated sodium bicarbonate solution to pH > 10. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, and then dried over anhydrous sodium sulfate. Filtering the organic phase, and evaporating to dryness under reduced pressure to obtain a crude product. The crude product is purified by pressurized silica gel column chromatography to obtain a pure compound 173. LC/MS: m + H555.20.
Example 174: n- (3-fluorophenyl) -3- ((3- (pyridin-3-yl) -1H-indazol-6-yl) thio) propanamide
Figure BDA0001518077870000541
The synthesis of the compound of example 174 was accomplished by using procedures analogous to those described in example 173. MS (ESI) M/z (M +1) +: 393.11.
Example 175: n- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (6-methylpyridin-3-yl) -1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000542
The synthesis of the compound of example 175 was accomplished by using procedures analogous to those described in example 173. MS (ESI) M/z (M +1) +: 568.22.
Example 176: 3- ((3-methyl-1H-indazol-6-yl) thio) -N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) propanamide
Figure BDA0001518077870000551
The synthesis of the compound of example 176 was accomplished using procedures analogous to those described in example 173. MS (ESI) M/z (M +1) +: 492.20.
Example 177: 3- ((3- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-6-yl) thio) -N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) propanamide
Figure BDA0001518077870000552
The synthesis of the compound of example 177 was accomplished using procedures analogous to those described in example 173. MS (ESI) M/z (M +1) +: 558.22.
Example 178: n- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (phenyl-1H-indazol-6-yl) thio) propionamide
Figure BDA0001518077870000553
The synthesis of the compound of example 178 was accomplished by using procedures analogous to those described in example 173. MS (ESI) M/z (M +1) +: 554.21.
Example 179: effect on cancer cell proliferation
The inhibitory effect of the compounds herein on cancer cell proliferation, and their selectivity for inhibiting cancer cell proliferation, were further evaluated by testing the effect of the compounds of the present invention on cancer cell growth (table 2). Human gastrointestinal stromal tumor cell line cell GIST-T1 (expressing wild-type C-KIT gene) (purchased from Cosmo Bio Co., Ltd. (Japan)), and murine primary B cell BaF3 (purchased from ATCC) were selected for use in this example. In addition, the examples also selected mouse P210/BaF3 (stably expressing P210Bcr-Abl mutant gene), mouse P210/T315I-BaF3 (stably expressing mutant P210Bcr-Abl/T315I kinase), mouse Tel-cKit-BaF3 (stably expressing C-KIT wild-type kinase), mouse Tel-cKit/V559D-BaF3 (stably expressing C-KIT V559D mutant kinase), mouse Tel-cKit/V559D/T670 638-BaF 3 (stably expressing C-KIT V559D/T670I mutant kinase), mouse Tel-cKit/T670I-BaF3 (stably expressing C-KIT 670I mutant kinase), mouse Tel-PDGFR alpha-BaF 3 (stably expressing mouse Tel-BaF 46beta kinase), and mouse Tel-VEGFR 4684 (stably expressing BaF 4642) and mouse Tel-VEGFR 3727 (stably expressing mouse PDGF 2) kinase, Mouse Tel-RET-BaF3 (stably expressing RET kinase), mouse Tel-FLT3-BaF3 (stably expressing FLT3 kinase), mouse Tel-FGFR1-BaF3 (stably expressing FGFR1 kinase), mouse Tel-FGFR2-BaF3 (stably expressing FGFR2 kinase), mouse Tel-FGFR3-BaF3 (stably expressing FGFR3 kinase), and mouse Tel-FGFR4-BaF3 (stably expressing FGFR4 kinase). The cell lines are constructed in the laboratory, and the construction method comprises the following steps: human P210Bcr-Abl, P210Bcr-Abl/T315I, C-KIT V559D, C-KIT V559/T670I, C-KIT T670I, PDGFR alpha, PDGFR beta, VEGFR2, RET, FLT3, FGFR1, FGFR2, FGFR3 and FGFR 29 kinase domain sequences are respectively amplified by PCR and inserted into MSCV-Puro vectors (purchased from Clontech) with N-terminal TEL fragments and/or NPM fragments and/or TPR fragments, and are stably transferred into mouse BaF3 cells by a retrovirus method, and IL-3 growth factors are withdrawn, finally, the P210Bcr-Abl, P210Bcr-Abl/T315, C-KIT 3946, C-KIT/V559 469, C-KIT 55D/V I, KIT 6348, KIT 670-1, FGFR 598 and FGFR1 are transferred into the cell line.
In the examples, test compounds at various concentrations (0.000508. mu.M, 0.00152. mu.M, 0.00457. mu.M, 0.0137. mu.M, 0.0411. mu.M, 0.123. mu.M, 0.370. mu.M, 1.11. mu.M, 3.33. mu.M, 10. mu.M in DMSO) were added to the above cells, respectively, and incubated for 72 hours, and the number of living cells was determined by quantitative determination of the reduced dehydrogenase in the living cells using CCK8 (Beeber, China) cell viability assay kit. Determining the GI of a Compound of the invention for each test cell50Values (units), experimental results are shown in table 2.
TABLE 2
Figure BDA0001518077870000561
Figure BDA0001518077870000571
Figure BDA0001518077870000581
Figure BDA0001518077870000591
Table 2 (continuation)
Figure BDA0001518077870000592
Figure BDA0001518077870000601
Figure BDA0001518077870000611
Figure BDA0001518077870000621
Figure BDA0001518077870000631
Table 2 (continuation)
Figure BDA0001518077870000632
Figure BDA0001518077870000641
Figure BDA0001518077870000651
Figure BDA0001518077870000661
The main targets of the compounds of the invention were found by testing to be CKIT, CKIT/T670I, BCR-ABL/T315I, PDGFR α, PDGFR β, and VEGFR 2. The compounds of the invention have obvious inhibition effects on TEL-CKIT/T670I-BaF3 and gastrointestinal stromal tumor GIST-T1, which can prove that the compounds can be used for treating gastrointestinal stromal tumors and are particularly effective on gastrointestinal stromal tumors with drug resistance caused by T670I point mutation. In addition, some preferred compounds of the invention further have an effect on P210/T315I-BaF3 cells. P210/T315I-BaF3 is a BCR-ABL/T315I mutant cell line, BCR-ABL/T315I is a common drug-resistant mutation in chronic myelogenous leukemia clinic, and no particularly good small molecule inhibitor can treat the mutant chronic myelogenous leukemia at present.
Based on the above findings, the inventors of the present application further selected the preferred compound 142 of the present invention for testing and determined the GI of human chronic myelogenous leukemia cell K562 (expressing P210Bcr-Abl mutant gene), human chronic myelogenous leukemia cell MEG-01 (expressing P210Bcr-Abl mutant gene), and human chronic myelogenous leukemia cell Ku812 (expressing P210Bcr-Abl mutant gene) (all of which were purchased from ATCC (USA)) for GI assay50Values (units), experimental results are shown in table 3.
TABLE 3
GI50/μM Compound 142
K562 0.0012
KU812 0.005
MEG01 0.0014
As shown in the table above, some preferred compounds of the invention have strong inhibition effect on P210/T315I-BaF3 cells, and the compounds also have obvious inhibition effect on the proliferation of three chronic myelogenous leukemia cell lines K562, MEG-01 and KU812 expressing BCR-ABL fusion genes, and GI50Are all less than 0.01 mu M. This demonstrates that the preferred compounds of the present invention have a better therapeutic effect on chronic myelogenous leukemia and also have a certain therapeutic effect on drug-resistant chronic myelogenous leukemia caused by the point mutation T315I.
Example 180: animal experiments
In this example, compound 4 and compound 142 were tested for experimental results in a mouse model of TEL-cKIT/T670I-BaF3 and P210/T315I-BaF3, respectively.
The experimental procedure was as follows:
(1) the method comprises the steps of purchasing and breeding Balb/c female mice of 4-6 weeks old from Beijing Wintonlifa laboratory animal Limited liability company, breeding in an SPF-grade laboratory, sterilizing and aseptically treating drinking water and padding, and performing all operations on the mice under aseptic conditions;
(2) on day 0, all mice were injected subcutaneously into the left dorsal part of the body at approximately 5X 10 times6TEL-cKIT/T670I-BaF3 or 5X 106P210/T315I-BaF3 cells;
(3) for the mouse model of TEL-cKIT/T670I-BaF3, starting on day 6, the corresponding mice were orally administered methyl cellulose (HKI) vehicle (5 mice) daily; compound 4 at a dose of 25mg/kg mouse weight (5 mice); imatinib (purchased from MedChem Express, China) at a dose of 100mg/kg mouse weight (5 mice). For the mouse model of P210/T315I-BaF3, starting on day 6, the corresponding mice were orally administered methylcellulose (HKI) vehicle (5 mice) daily; compound 142 at a dose of 25mg/kg mouse weight (5 mice); compound 142 at a dose of 50mg/kg mouse weight (5 mice); compound 142 at a dose of 100mg/kg mouse weight (5 mice);
(4) from day 6 onwards, the length/width of the subcutaneous tumors was measured daily with a vernier caliper and the body weight of the mice was recorded daily, determining the effect of compound 4 and compound 142 on the body weight of the mice, respectively;
(5) mice were sacrificed on day 18, subcutaneous tumors were removed and tumors were weighed for comparison;
(6) counting the growth trend of the tumor under endothelium, and calculating the tumor volume: length, width and width 2mm3。
The results of the experiments are shown in FIGS. 1a-c and 2 a-c. In a mouse tumor model of TEL-cKIT/T670I-BaF3, the compound 4 already shows a certain effect of inhibiting mouse tumors when the administration dose is 25mg/kg, and the inhibition effect of the compound 4 on the mouse tumors is more obvious along with the increase of the administration days, and the tumor inhibition rate is as high as 49.6%. Compound 4 was not only effective in inhibiting tumor growth in mice, but also had essentially no effect on mouse body weight, indicating that compound 4 could be suitable for animal administration. This also demonstrates that the CKIT/T670I inhibitor compound 4 of the present invention can be used to treat T670I mutant gastrointestinal stromal tumors. In a P210/T315I-BaF3 mouse model, the compound 142 already shows a certain effect of inhibiting mouse tumors when the dosage is 25mg/kg, and the inhibition effect of the compound 142 on the mouse tumors is more obvious along with the increase of the dosage and the administration days, and the tumor inhibition rate is up to 69% when the dosage is 100 mg/kg. Compound 142 is not only effective in inhibiting tumor growth in mice, but also has substantially no effect on body weight in mice, indicating that compound 142 may be suitable for administration to animals. This also demonstrates that the BCR-ABL/T315I inhibitor compound 142 of the invention can be used to treat chronic myelogenous leukemia with a T315I mutation.
Industrial applicability
The present invention provides novel kinase inhibitor compounds that may be used to reduce or inhibit cKIT (particularly mutant cKIT/T670I), BCR/ABL (particularly mutant BCR-ABL/T315I), pdgfra, pdgfrp, and/or VEGFR2 kinase activity in a cell or subject, and/or to prevent or treat disorders related to cKIT (particularly mutant cKIT/T670I), BCR/ABL (particularly mutant BCR-ABL/T315I), pdgfra, pdgfrp, and/or VEGFR2 activity in a subject. Therefore, the compound can be prepared into corresponding medicaments and is suitable for industrial application.
Although the present invention has been described in detail herein, the present invention is not limited thereto, and modifications can be made by those skilled in the art based on the principle of the present invention, and thus, it is to be understood that various modifications made in accordance with the principle of the present invention are within the scope of the present invention.

Claims (11)

1. A kinase inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0003040758450000011
wherein X is selected from
Figure FDA0003040758450000012
Figure FDA0003040758450000013
Y is selected from phenyl, thiophen-2-yl, isoxazol-3-yl, pyridin-4-yl, 2-pyrrolidin-5-yl, N-methyl-2 (1H) -pyridon-5-yl, and furan-2-yl;
R1selected from hydrogen, C1-6Alkyl, 2- (pyridin-2-yl) vinyl, optionally substituted with R3Pyridin-3-yl substituted by a radical, optionally R3Phenyl substituted by a group, and optionally R3Radical-substituted pyrazol-4-yl;
(R2)nrepresents optionally n independent R2Substituted by substituents, wherein n is an integer from 0 to 5, R2Independently selected from hydroxy, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, C2-6Amido, C1-6Alkylamino, 4-methyl-imidazol-1-yl,
Figure FDA0003040758450000014
Figure FDA0003040758450000015
R3Selected from halogen, aminoacyl, C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure FDA0003040758450000016
R4Is selected from C1-6An alkyl group;
R5selected from hydrogen and C1-6An alkylamino group.
2. The kinase inhibitor of claim 1, comprising a compound of (Ia):
Figure FDA0003040758450000017
wherein R is1Selected from hydrogen, C1-6Alkyl, 2- (pyridin-2-yl) vinyl, optionally substituted with R3Pyridin-3-yl substituted with a group, and optionally R3Phenyl substituted with a group;
(R2)nrepresenting optionally n independent R in ortho-, meta-and para-positions of the phenyl ring2Substituted by substituents, wherein n is an integer from 0 to 5, R2Independently selected from halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Alkylamino, 4-methyl-imidazol-1-yl,
Figure FDA0003040758450000021
R3Selected from halogen, aminoacyl, C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure FDA0003040758450000022
R4Is selected from C1-6An alkyl group;
R5is selected from C1-6An alkylamino group.
3. The kinase inhibitor of claim 1, comprising a compound of (Ib):
Figure FDA0003040758450000023
wherein R is1Selected from hydrogen, C1-6Alkyl, 2- (pyridin-2-yl) vinyl, optionally substituted with R3Pyridin-3-yl substituted by a radical, optionally R3Phenyl substituted by a group, and optionally R3Radical-substituted pyrazol-4-yl;
(R2)nrepresenting optionally n independent R in ortho-, meta-and para-positions of the phenyl ring2Substituted by substituents, wherein n is an integer from 0 to 5, R2Independently selected from halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, C2-6Amido, C1-6Alkylamino, 4-methyl-imidazol-1-yl,
Figure FDA0003040758450000024
Figure FDA0003040758450000025
R3Is selected from C1-6Alkyl radicals and
Figure FDA0003040758450000026
R4is selected from C1-6An alkyl group;
R5selected from hydrogen and C1-6An alkylamino group.
4. The kinase inhibitor of claim 1, comprising the following compound, or a pharmaceutically acceptable salt thereof:
Figure FDA0003040758450000031
Figure FDA0003040758450000041
Figure FDA0003040758450000051
Figure FDA0003040758450000061
Figure FDA0003040758450000071
Figure FDA0003040758450000081
Figure FDA0003040758450000091
Figure FDA0003040758450000101
Figure FDA0003040758450000111
5. a pharmaceutical composition comprising a compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, and optionally an additional therapeutic agent.
6. Use of a kinase inhibitor according to any one of claims 1-4 in the manufacture of a medicament for inhibiting tyrosine kinase activity of one or more selected from cKIT, BCR/ABL, pdgfra, pdgfrp, and VEGFR 2.
7. The use of claim 6, wherein the kinase inhibitor is for inhibiting tyrosine kinase activity of one or more selected from mutant cKIT/T670I and mutant BCR-ABL/T315I.
8. Use of a kinase inhibitor according to any one of claims 1-4 in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition modulated by or affected by tyrosine kinase activity selected from one or more of cKIT, BCR/ABL, pdgfra, pdgfrp, and VEGFR 2.
9. The use of claim 8, wherein the disease, disorder or condition is modulated by or affected by one or more tyrosine kinase activities selected from mutant cKIT/T670I and mutant BCR-ABL/T315I.
10. The use of claim 8 or 9, wherein the disease, disorder or condition is selected from: sarcoma, gastrointestinal stromal tumor, acute myeloid leukemia, chronic myeloid leukemia, mesothelioma, thyroid cancer, systemic mastocytosis, hypereosinophilic syndrome, fibrosis, scleroderma, lupus erythematosus, graft versus host disease, neurofibroma, pulmonary hypertension, alzheimer's disease, seminoma, psoriasis, dysgerminoma, mast cell tumor, lung cancer, bronchial cancer, intraepithelial neoplasia of the testis, melanoma, breast cancer, neuroblastoma, malignant lymphoma, non-hodgkin's lymphoma, multiple endocrine neoplasia type 2, pheochromocytoma, parathyroid hyperplasia/adenoma, colon cancer, colorectal adenoma, ovarian cancer, prostate cancer, glioblastoma, brain tumor, malignant glioma, pancreatic cancer, malignant pleural mesothelioma, hemangioblastoma, renal carcinoma, multiple sclerosis, neuroblastoma, melanoma, neuroblastoma, melanoma, and other cancers, Liver cancer, adrenal cancer, bladder cancer, stomach cancer, rectal cancer, vaginal cancer, cervical cancer, endometrial cancer, multiple myeloma, neck and head tumors, arthritis, lupus, inflammatory bowel disease, still's disease, diabetes, myasthenia gravis, hashimoto's thyroiditis, alder's thyroiditis, graves ' disease, multiple sclerosis, infectious neuronitis, acute disseminated encephalomyelitis, addison's disease, optic twin-myofascial syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, primary biliary cirrhosis, reiter's syndrome, takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, wegener's granulomatosis, systemic alopecia, behcet's disease, cervical cancer, endometrial cancer, multiple myeloma, cervical and head tumor, arthritis, lupus, inflammatory bowel disease, still's, Chronic fatigue, familial autonomic dysfunction, endometriosis, interstitial cystitis, neuromuscular stiffness, vulvodynia, or a combination thereof.
11. The use of claim 8 or 9, wherein the disease, disorder or condition is selected from: gastrointestinal stromal tumors, acute myeloid leukemia, chronic myeloid leukemia, thyroid cancer, or combinations thereof.
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