CN111269233A - Preparation and application of imidazo aromatic ring compounds - Google Patents

Preparation and application of imidazo aromatic ring compounds Download PDF

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CN111269233A
CN111269233A CN201811481061.9A CN201811481061A CN111269233A CN 111269233 A CN111269233 A CN 111269233A CN 201811481061 A CN201811481061 A CN 201811481061A CN 111269233 A CN111269233 A CN 111269233A
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diseases
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江磊
冯志勇
尚珂
寿建勇
吴淡宜
徐圆
张淑芸
张毅
张宇星
郑明伟
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Shanghai Ennovabio Pharmaceuticals Co Ltd
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Priority to CN201980081131.8A priority patent/CN113166162A/en
Priority to PCT/CN2019/123407 priority patent/WO2020114465A1/en
Publication of CN111269233A publication Critical patent/CN111269233A/en
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Abstract

The invention provides preparation and application of aromatic amide compounds, and particularly provides a compound shown as a formula I, wherein the definition of each group is described in the specification. The compound has TRK kinase inhibitory activity and can be used as a pharmaceutical composition for treating TRK dysfunction related diseases.

Description

Preparation and application of imidazo aromatic ring compounds
Technical Field
The invention relates to the field of small molecule drugs, in particular to a TRK kinase inhibitor and preparation and application thereof.
Background
Tropomyosin-receptor kinase (TRK) is a nerve growth factor receptor, belongs to a receptor tyrosine kinase family, mainly comprises three highly homologous members of TRKA, TRKB and TRKC, and is respectively encoded by three genes of NTRK1, NTRK2 and NTRK 3. These receptor tyrosine kinases are mainly expressed in nervous tissues and play an important role in development and physiological functions of the nervous system through activation of neurotrophic factors nts (neurotropins). TRK function as tyrosine kinase receptors, each TRK having a signaling pathway that binds to and activates its downstream ligand. NGF (nerve growth factor) specifically binds to and activates TRKA; the TRKB ligand comprises BDGF (broad-derived growth factor) and NT-4/5 (neurotropin-4/5); NT-3 specifically binds to and activates TRKC. All three TRK receptors contain an extracellular domain for ligand binding, a transmembrane domain, and an intracellular domain with kinase activity.
When a specific ligand is combined with the extracellular domain of a corresponding receptor, oligomerization of the receptor and phosphorylation of specific tyrosine residues in the cytoplasmic kinase domain are initiated, thereby causing activation of downstream signaling pathways such as Ras/MAPK, PLC γ/PKC and PI3K/AKT signaling pathways, and further regulating a series of physiological processes such as proliferation, differentiation and survival of nerve cells (Bergman, et al 1999). The TRK signaling pathway is usually precisely regulated, while its aberrant activation is closely associated with tumorigenesis (Amatu, et al.2016). Research results show that there are many mechanisms causing abnormal activation of TRK pathway, including gene fusion, protein overexpression and single nucleotide mutation, and these abnormalities are closely related to the pathogenesis of tumor, especially NTRK gene fusion has been proved to be an important factor causing multiple tumorigenesis, and is independent of the tissue source and type of tumor. Under the rapid development of current second-generation sequencing technologies and precision medicine, more and more NTRK fusion genes are found, such as ETV6-NTRK3, MPRIP-NTRK 1, CD 74-NTRK 1 and the like. The results of recent clinical trials show that these fusion genes are very effective anticancer targets, and the tumors containing the NTRK fusion gene have very significant response rate to TRK inhibitors (Drilon, et al.2018). Therefore, more and more TRK target inhibitors are reported, e.g. (WO2010048314, WO2011146336, WO 2017004342). Meanwhile, in the clinical trial stage, it has been found that some patients receiving treatment have drug resistance phenomenon and proved to be caused by partial base mutation of enzyme activity region, such as NTRK1G595R or G667C mutation, G623R or G696A mutation of NTRK3, and the development of new generation TRK kinase inhibitor is expected to solve these problems.
In view of the above, there is an urgent need in the art to develop a new generation of TRK kinase inhibitors.
Disclosure of Invention
The invention aims to provide a novel TRK kinase inhibitor.
In a first aspect of the present invention, there is provided a compound of formula I:
Figure BDA0001893386950000021
wherein the content of the first and second substances,
r has the formula-L1-RAThe structure of (1);
L1selected from the group consisting of: substituted or unsubstituted 5-to 10-membered heterocyclylene having 1 to 3 heteroatoms selected from N, S and O, or substituted or unsubstituted- (X)y-wherein each of said xs is independently selected from the group consisting of: substituted or unsubstituted C1-C8Alkylene, -O-, -C (═ O) -, -CONH-, -NHCO-, -S (═ O)2-、-NH-；
y is selected from the group consisting of: 1.2 or 3;
RAselected from the group consisting of: substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O;
Y1、Y2、Y3、Y4、Y5、Y6、Y7each independently selected from the group consisting of: CR1Or N; z1、Z2Each independently selected from the group consisting of: c or N;
and is
Figure BDA0001893386950000022
Is an aromatic ring;
R1each independently selected from the group consisting of: H. d, OH, Cl, F and NH2；
Ring a is selected from the group consisting of: substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 5-10 membered heteroaryl (including monocyclic, fused cyclic) having 1-3 heteroatoms selected from N, S and O;
l is selected from the group consisting of: none, -NR7-，-O-；
R7Selected from: h, substituted C1-C6 alkyl; wherein said substitution means that one or more H atoms on the group are substituted with a substituent selected from the group consisting of: halogen, hydroxy;
ring C is selected from the group consisting of: substituted or unsubstituted 3-12 membered cycloalkyl (including monocyclic, fused, spiro or bridged ring), substituted or unsubstituted 4-12 membered heterocyclyl (including monocyclic, fused, spiro or bridged ring) having 1-3 heteroatoms selected from N, S and O;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C8 cycloalkyl, methylsulfonyl, -S (═ O)2NH2Oxo (═ O), -CN, hydroxy, -NH2Carboxy, C1-C6 amido (-C (═ O) -N (Rc)2or-NH-C (═ O) (Rc), Rc being H or C1-C5 alkyl), C1-C6 alkyl- (C1-C6 amido),
Figure BDA0001893386950000031
Or a substituted or unsubstituted group selected from: C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 amino, C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, 5-12 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O, - (CH) 6 alkyl2) -C6-C10 aryl, - (CH)2) - (5-to 10-membered heteroaryl having 1 to 3 heteroatoms selected from N, S and O), and the substituents are selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, oxo, -CN, -NH2OH, -OH, C6-C10 aryl, C1-C6 amino, C1-C6 amido, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O;
Figure BDA0001893386950000036
is the attachment site of the group;
with the proviso that the compounds of formula I are chemically stable structures.
In another preferred embodiment, L is1Selected from the group consisting of:
Figure BDA0001893386950000032
n is selected from the group consisting of: 0.1, 2 or 3;
R2、R2aand R2bEach independently selected from the group consisting of: H. OH, halogen, substituted or unsubstituted C1-C8An alkyl group;
X5selected from the group consisting of: NH, O, -CONH-, -NHCO-, S, -S (═ O)2-、-NHS(＝O)-、-NHS(＝O)2-；
RAIs composed of
Figure BDA0001893386950000033
Wherein, the
Figure BDA0001893386950000034
Means RAAnd L1The attachment site of (a); x4Is CH or N;
R3selected from the group consisting of: H. halogen, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy.
In another preferred embodiment, the ring C has the following structure:
Figure BDA0001893386950000035
wherein k1, k2, k3 are each independently selected from the group consisting of: 0.1, 2 or 3;
X1、X2each independently is C (R)4)R5、NR6Or O;
wherein R is4，R5，R11Each independently selected from: h, OH, Me, halogen, oxo，CF3，CN，NH2，-OMe，COOH，CONH2；R6Selected from: none, H, Me, CONH2。
In another preferred embodiment, the ring C has the following structure:
Figure BDA0001893386950000041
wherein m, p are each independently selected from the group consisting of: 0.1, 2 or 3;
X3is C (R)9)R10；
Wherein R is8，R9，R10Each independently selected from: h, OH, Me, halogen, CF3，CN，NH2，-OMe，COOH，CONH2；
In another preferred embodiment, said ring C is linked to L via an N atom.
In another preferred embodiment, the compound has the structure shown in formula II below:
Figure BDA0001893386950000042
in another preferred embodiment, the compound has the structure shown in formula III below:
Figure BDA0001893386950000043
in another preferred embodiment, the compound has a structure selected from the group consisting of:
Figure BDA0001893386950000044
Figure BDA0001893386950000051
Figure BDA0001893386950000061
in a second aspect of the invention, there is provided a pharmaceutical composition comprising (1) a compound according to the first aspect of the invention or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof; (2) a pharmaceutically acceptable carrier.
In another preferred embodiment, the disease is selected from the group consisting of: cancer, proliferative diseases, pain, skin diseases or conditions, metabolic diseases, muscular diseases, neurological diseases, autoimmune diseases, dermatitis-induced pruritus, inflammation-related diseases, bone-related diseases.
In a third aspect of the present invention, there is provided a use of the compound according to the first aspect of the present invention or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition according to the second aspect of the present invention, for the preparation of a pharmaceutical composition for the prevention and/or treatment of a disease associated with abnormal TRK function (abnormal TRK activation due to amplification, or overexpression, or mutation, or gene fusion).
In another preferred embodiment, the disease is selected from the group consisting of: the disease is selected from the group consisting of: cancer, proliferative diseases, pain, skin diseases or conditions, metabolic diseases, muscular diseases, neurological diseases, autoimmune diseases, dermatitis-induced pruritus.
In a fourth aspect of the invention, there is provided a TRK inhibitor comprising a compound of the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
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 this invention belongs.
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
Definition of
As used herein, the term "alkyl" includes straight or branched chain alkyl groups. E.g. C1-C8Alkyl represents a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.
As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups. E.g. C2-C6Alkenyl means a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.
As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. E.g. C2-C6Alkynyl means straight or branched chain alkynyl having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
As used herein, the term "C3-C8Cycloalkyl "refers to cycloalkyl groups having 3 to 8 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. It may also be in the form of a double ring, for example a bridged or spiro ring.
As used herein, the term "C1-C8Alkoxy "means a straight or branched chain alkoxy group having 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxyAnd tert-butoxy, and the like.
As used herein, the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a saturated or partially saturated cyclic group having 3-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be monocyclic or may be in the form of a double ring, for example a bridged or spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.
As used herein, the term "C6-C10Aryl "means an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.
As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a cyclic aromatic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a single ring or a condensed ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl and (1,2,4) -triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
Unless otherwise specified, the groups of the present invention may be substituted with a substituent selected from the group consisting of: halogen, nitrile group, nitro group, hydroxyl group, amino group, C1-C6Alkyl-amino, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy, halo C1-C6Alkyl, halo C2-C6Alkenyl, halo C2-C6Alkynyl, halo C1-C6Alkoxy, allyl, benzyl, C6-C12Aryl radical, C1-C6alkoxy-C1-C6Alkyl radical, C1-C6Alkoxy-carbonyl, phenoxycarbonyl, C2-C6Alkynyl-carbonyl, C2-C6Alkenyl-carbonyl, C3-C6Cycloalkyl-carbonyl, C1-C6Alkyl-sulfonyl, and the like.
As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "halogenated" means substituted with an atom selected from F, Cl, Br, and I.
Unless otherwise specified, the structural formulae depicted herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.
As used herein, the term "tautomer" means that structural isomers having different energies may exceed the low energy barrier, thereby converting with each other. For example, proton tautomers (i.e., proton transmutations) include interconversion by proton shift, such as 1H-indazoles and 2H-indazoles. Valence tautomers include interconversion by recombination of some of the bonding electrons.
As used herein, the term "solvate" refers to a complex of a compound of the present invention coordinated to solvent molecules in a specific ratio.
A compound of formula I
The invention provides a compound shown as the following formula I:
Figure BDA0001893386950000081
wherein the content of the first and second substances,
r has the formula-L1-RAThe structure of (1);
L1selected from the group consisting of: substituted or unsubstituted 5-to 10-membered heterocyclylene having 1 to 3 heteroatoms selected from N, S and O, or substituted or unsubstituted- (X)y-wherein each of said xs is independently selected from the group consisting of: substituted or unsubstituted C1-C8Alkylene, -O-, -C (═ O) -, -CONH-, -NHCO-、-S-、-S(＝O)-、-S(＝O)2-、-NH-；
y is selected from the group consisting of: 1.2 or 3;
RAselected from the group consisting of: substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O;
Y1、Y2、Y3、Y4、Y5、Y6、Y7each independently selected from the group consisting of: CR1Or N; z1、Z2Each independently selected from the group consisting of: c or N; and is
Figure BDA0001893386950000082
Is an aromatic ring;
R1each independently selected from the group consisting of: H. d, OH, Cl, F and NH2；
Ring a is selected from the group consisting of: substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 5-10 membered heteroaryl (including monocyclic, fused, spiro or bridged) having 1-3 heteroatoms selected from N, S and O;
l is selected from the group consisting of: none, -NR7-，-O-；
R7Selected from: H. substituted C1-C6 alkyl; wherein said substitution means that one or more H atoms on the group are substituted with a substituent selected from the group consisting of: halogen, hydroxy;
ring C is selected from the group consisting of: substituted or unsubstituted 3-12 membered cycloalkyl (including monocyclic, fused, spiro or bridged ring), substituted or unsubstituted 4-12 membered heterocyclyl (including monocyclic, fused, spiro or bridged ring) having 1-3 heteroatoms selected from N, S and O;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C8 cycloalkyl, methylsulfonyl, -S (═ O)2NH2Oxo (═ O), -CN, hydroxy, -NH2Carboxy, C1-C6 amido (-C (═ O) -N (Rc)2or-NH-C (═ O) (Rc), Rc being H or C1-C5 alkyl), C1-C6 alkyl- (C1-C6 amido),
Figure BDA0001893386950000091
Or a substituted or unsubstituted group selected from: C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 amino, C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, 5-12 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O, - (CH) 6 alkyl2) -C6-C10 aryl, - (CH)2) - (5-to 10-membered heteroaryl having 1 to 3 heteroatoms selected from N, S and O), and the substituents are selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, oxo, -CN, -NH2OH, -OH, C6-C10 aryl, C1-C6 amino, C1-C6 amido, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O;
Figure BDA0001893386950000092
is the attachment site of the group;
with the proviso that the compounds of formula I are chemically stable structures.
In another preferred embodiment, the compounds of formula I of the present invention are the compounds prepared in the examples.
Preparation of Compounds of formula I
The compounds of formula I of the present invention may be prepared by the following process:
Figure BDA0001893386950000093
pharmaceutical compositions and methods of administration
Since the compound of the present invention has excellent inhibitory activity of TRK kinase, the compound of the present invention and various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates, or solvates thereof, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient may be used for the prevention and/or treatment of diseases (e.g., cancer) associated with TRK kinase activity or expression level.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
Figure BDA0001893386950000101
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When administered in combination, the pharmaceutical composition further comprises one or more other pharmaceutically acceptable compounds. One or more of the other pharmaceutically acceptable compounds may be administered simultaneously, separately or sequentially with a compound of the invention.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 20 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Synthesis of intermediate A
Figure BDA0001893386950000111
(R, E) -N- (2, 5-difluorobenzylidene) -2-methylpropane-2-sulfinamide
Figure BDA0001893386950000112
2, 5-Difluorobenzaldehyde (5g,35.2mmol) and (R) -2-methylpropane-2-sulfinamide (4.47g,36.9mmol) were dissolved in dichloromethane (50mL), cesium carbonate (8.0g,24.6mmol) was added at room temperature, and then the reaction was warmed to 50 ℃ for 3 hours, TLC showed the reaction was complete, filtration was carried out, the filter cake was washed with dichloromethane, the filtrate was washed with brine, dried over anhydrous sodium sulfate, and spin-dried to give a yellow oily liquid (9 g).
(R) -N- ((R) -1- (2, 5-difluorophenyl) -3- (1, 3-dioxan-2-yl) propyl) -2-methylpropane-2-sulfinamide
Figure BDA0001893386950000113
Magnesium turnings (2g,83.3mmol) were dissolved in tetrahydrofuran (72mL), nitrogen blanketed, a solution of diisobutylaluminum hydride in tetrahydrofuran (0.1mL,1.5M,0.15mmol) was added dropwise to the system at 40 ℃ for 0.5h at 40 ℃, then a solution of 2- (2-bromoethyl) -1, 3-dioxane (14.3g,73.47mmol) in tetrahydrofuran (40mL) was slowly added dropwise to the system and the temperature was controlled at 40-50 ℃, and after dropping, stirring was maintained at 40 ℃ for 1 h. The heating was removed, the reaction was cooled to-30 ℃ and then (R, E) -N- (2, 5-difluorobenzylidene) -2-methylpropane-2-sulfinamide (9g,36.73mmol) in tetrahydrofuran (40mL) was added dropwise to the system, the temperature was controlled at-30 ℃ to 20 ℃, after completion of the addition, the mixture was stirred at-30 ℃ for 2h, TLC showed completion of the reaction, quenched with 10% aqueous citric acid and controlled at 10 ℃, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and spin-dried to give a colorless oily liquid (15.8 g).
(R) -2- (2, 5-difluorophenyl) pyrrolidine
Figure BDA0001893386950000121
(R) -N- ((R) -1- (2, 5-difluorophenyl) -3- (1, 3-dioxan-2-yl) propyl) -2-methylpropane-2-sulfinamide (15.8g,43.76mmol) was added to a mixed solution of trifluoroacetic acid (32mL) and water (8mL) at room temperature, stirred at room temperature for 1h, then trifluoroacetic acid (60mL) was added to the system, triethylsilane (15.2g,131.1mmol) was added dropwise to the system, the reaction was allowed to stand overnight at room temperature, LCMS monitored for completion of the reaction, most of the trifluoroacetic acid was spun off, the residue was dissolved in hydrochloric acid (1N,100mL) and stirred for 0.5h, extracted with methyl tert-butyl ether, the organic phase was washed with hydrochloric acid (1N,50mL), the aqueous phases were combined, the pH of the aqueous phase was adjusted to 11 with 40% aqueous sodium hydroxide solution and then extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and spin-dried to give an oily liquid (6.7 g).
Synthesis of intermediate B
Figure BDA0001893386950000122
(S) -N- ((S) -1- (2, 5-difluorophenyl) but-3-en-1-yl) -2-methylpropane-2-sulfinamide
Figure BDA0001893386950000123
(R) -N- (2, 5-difluorobenzylidene) -2-methylpropane-2-sulfinamide (30 g, 122.45mmol) was added to an aqueous solution of saturated sodium bromide (480 ml) at room temperature, In (42 g, 367.35 mmol) was added, then allylmagnesium bromide (42 ml, 489.8 mmol) was added, the reaction was carried out at room temperature for 6 hours, TLC was monitored for completion, the reaction was quenched with saturated sodium bicarbonate solution, filtered, the filtrate was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to give (S) -N- ((S) -1- (2, 5-difluorophenyl) but-3-en-1-yl) -2-methylpropane-2-sulfinamide as a yellow solid (35 g).
(S) -N- ((1S) -1- (2, 5-difluorophenyl) -2- (oxiran-2-yl) ethyl) -2-methylpropane-2-sulfinamide
Figure BDA0001893386950000131
(S) -N- ((S) -1- (2, 5-difluorophenyl) but-3-en-1-yl) -2-methylpropane-2-sulfinamide (35 g, 121.95 mmol) is dissolved in dichloromethane (800 ml), m-chloroperoxybenzoic acid (80 g, 365.85 mmol) is added in portions at room temperature, the mixture is stirred at room temperature overnight, TLC is used for monitoring the completion of the reaction, the reaction solution is washed by saturated sodium bicarbonate and saturated sodium thiosulfate solution, the saturated saline is washed, anhydrous sodium sulfate is dried, and the (S) -N- ((S) -1- (2, 5-difluorophenyl) but-3-en-1-yl) -2-methylpropane-2-sulfinamide is obtained by spin-drying, yellow solid (31 g, yield: 79%).
(3R, 5R) -1- (tert-butylsulfonyl) -5- (2, 5-difluorophenyl) pyrrolidin-3-ol
Figure BDA0001893386950000132
(S) -N- ((S) -1- (2, 5-difluorophenyl) but-3-en-1-yl) -2-methylpropane-2-sulfinamide (31 g, 97.18 mmol) is dissolved in N, N-dimethylformamide (300 ml), potassium carbonate (40 g, 291.53 mmol), potassium iodide (16 g, 97.18 mmol) are added at room temperature, the mixture is heated to 1000C for 1 hour, TLC monitors the completion of the reaction, the reaction mixture is cooled to room temperature, filtered, the filtrate is poured into water, extracted with ethyl acetate, the organic phases are combined, the saturated brine is washed, dried over anhydrous sodium sulfate, and spin-dried column purification (PE/EA 10/1-5/1) is carried out to obtain the compound (3R, 5R) -1- (tert-butylsulfonyl) -5- (2, 5-difluorophenyl) pyrrolidin-3-ol (7.5 g).
(2R,4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidine
Figure BDA0001893386950000133
(3R, 5R) -1- (tert-butylsulfonyl) -5- (2, 5-difluorophenyl) pyrrolidin-3-ol (2.0g,6.27mmol) was dissolved in dichloromethane (50ml), cooled to-60 ℃ and DAST (2ml) was added dropwise to the system, then it was naturally warmed to room temperature and stirred overnight, the reaction was monitored by lcms for completion, the reaction was diluted with dichloromethane, slowly poured into ice water, separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by spin-column chromatography (PE/EA: 10/1) to give (2R,4S) -1- (tert-butylsulfonyl) -2- (2, 5-difluorophenyl) -4-fluoro as a yellow solid (1.2 g, yield: 60%).
(2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidine
Figure BDA0001893386950000141
To a dichloromethane solution (20 ml) of (2R,4S) -1- (tert-butylsulfonyl) -2- (2, 5-difluorophenyl) -4-fluoro (500 mg, 1.55 mmol) was added trifluoromethanesulfonic acid (0.7 ml), reacted for 2 hours, the solvent was dried, washed with 2 mol sodium hydroxide solution, extracted with ethyl acetate, separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by spin-column chromatography (petroleum ether/ethyl acetate: 4/1) to give (2R,4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidine as a yellow solid (305 mg, yield: 99%).
Synthesis of intermediate C
Figure BDA0001893386950000142
(R) -6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) -3-nitroimidazo [1,2-b ] pyridazine
Figure BDA0001893386950000143
Dimethyl sulfoxide (30 ml) was added to a three-necked flask (100 ml) at room temperature, the compounds 6-chloro-3-nitroimidazo [1,2-b ] pyridazine (1.0 g, 5.0 mmol), (R) -2- (2, 5-difluorophenyl) pyrrolidine (1.0 g, 5.5 mmol) and N, N-diisopropylethylamine (2.0g, 15.1 mmol) were added, stirred overnight at 110 ℃, poured into ice water, extracted with ethyl acetate (100 ml × 3), the organic phase was spin-dried, and purified with a silica gel column (petroleum ether: ethyl acetate ═ 2:1) to give a yellow solid (650 mg, yield 37.6%).
(R) -6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-amine
Figure BDA0001893386950000144
Ethanol (30 ml) was added to a three-necked flask (100 ml) at room temperature, the compound (R) -6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) -3-nitroimidazo [1,2-b ] pyridazine (650 mg, 1.9 mmol), iron powder (516.4 mg, 9.2 mmol) and ammonium chloride (985.5 mg, 18.5 mmol) were added, stirred at 80 ℃ for 3 hours, cooled to room temperature, filtered, the filtrate was concentrated and extracted with ethyl acetate (50ml × 3), the organic phase was spin-dried and purified with a silica gel column (dichloromethane: methanol: 50:1) to give a green solid (200 mg, yield 33.7%).
1H NMR(400MHz,CDCl3):δ(ppm)7.52-7.50(m,1H),7.08-7.00(m,1H),6.98(s,1H),6.92-6.87(m,1H),6.83-6.78(m,1H),6.27(s,1H),5.30-5.27(m,1H),3.92-3.87(m,1H),3.70-3.63(m,1H),2.49-2.44(m,1H),2.10-2.01(m,5H).
Synthesis of intermediate D
Figure BDA0001893386950000151
6- ((2R,4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -3-nitroimidazo [1,2-b ] pyridazine
Figure BDA0001893386950000152
To a solution of (2R,4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidine (150 mg, 0.75 mmol), 6-chloro-3-nitroimidazo [1,2-b ] pyridazine (222 mg, 1.12 mmol) in dimethyl sulfoxide (2ml) was added triethylamine (151 mg, 1.5 mmol), and the reaction was stirred at 100 degrees for 16 hours. LCMS showed most of the starting material disappeared. The reaction was purified by preparative high performance liquid chromatography to give a yellow solid (150 mg, 55%) as a yellow solid.
MS(ESI):m/z＝363.9[M+H]+.
6- ((2R,4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-amine
Figure BDA0001893386950000153
To a solution of 6- ((2R,4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -3-nitroimidazo [1,2-b ] pyridazine (60 mg, 0.16 mmol) in methanol (20 ml) was added palladium on carbon (15 mg), and the reaction solution was replaced three times with a hydrogen balloon by a water pump and stirred at room temperature for 8 hours. LCMS showed most of the starting material disappeared. The reaction was filtered through celite and rinsed with dichloromethane (20 ml). The filtrate was concentrated and purified by preparative high performance liquid chromatography to give a yellow solid (30 mg, 57%).
MS(ESI):m/z＝333.9[M+H]+.
Synthesis of intermediate E
Figure BDA0001893386950000154
6- (3-hydroxypyrrolidin-1-yl) nicotinic acid
Figure BDA0001893386950000155
Anhydrous N-butanol (10 mL) was added to a microwave tube (20 mL), compound 6-chloronicotinic acid (1.576 g, 10.0 mmol), compound pyrrolidin-3-ol (1.05 g, 12.0 mmol) and N, N-diisopropylethylamine (3.87 g, 30.0 mmol) were added. The reaction was stirred at 150 ℃ for 16 hours. The reaction was concentrated on a silica gel column and purified (dichloromethane: methanol ═ 4:1) to obtain a white solid (1.1 g, yield 52%).
1H NMR(400MHz,CDCl3):δ(ppm)12.29(s,1H),8.61(d,J＝2.0Hz,1H),7.90-7.87(m,1H),6.46(d,J＝8.8Hz,1H),5.0(s,1H),4.39(s,1H),3.53-2.43(m,3H),2.0-1.2(m,2H),1.19(s,1H).
Example 1:
n- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazin-3-yl) -6- (3-hydroxy-substituted aryl radicals Pyrrolidin-1-yl) nicotinamide
Figure BDA0001893386950000161
To a solution of (R) -6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-amine (25 mg, 0.08 mmol), N-diisopropylethylamine (30 mg, 0.24 mmol), 6- (3-hydroxypyrrolidin-1-yl) nicotinic acid (50 mg, 0.24 mmol) in dichloromethane (6 ml) was added 2- (7-oxabenzotriazol-oxide) -N, N' -tetramethyluronium hexafluorophosphate (130 mg, 0.24 mmol). The reaction solution was stirred at room temperature for 3 days. Concentrating, and purifying the residue by preparative high performance liquid chromatography to obtain white solid.
MS(ESI):m/z＝506.2[M+H]+.
1H NMR(400MHz,CD3OD)δ(ppm)8.63(s,1H),7.95(dd,J＝9.0,2.3Hz,1H),7.65(d,J＝9.9Hz,1H),7.51(s,1H),6.97-6.82(m,3H),6.79(d,J＝10.0Hz,1H),6.58(d,J＝9.0Hz,1H),5.32(d,J＝5.6Hz,1H),4.61–4.52(m,1H),3.98–3.87(m,1H),3.72–3.49(m,5H),2.51-2.42(m,1H),2.26–2.14(m,1H),2.11-2.08(m,3H),1.99–1.87(m,1H).
Example 2:
n- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazin-3-yl) -6- ((S) - 3-hydroxypyrrolidin-1-yl) nicotinamide
Figure BDA0001893386950000162
(R) -N- (6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazin-3-yl) -6-fluoroni Ketame
Figure BDA0001893386950000163
To a solution of (R) -6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-amine (150 mg, 0.476 mmol), N-diisopropylethylamine (307 mg, 2.18 mmol), 6-fluoronicotinic acid (134 mg, 0.951 mmol) in dichloromethane (12 ml) was added 2- (7-oxabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate (362 mg, 0.951 mmol). The reaction solution was stirred at room temperature for 3 days. Liquid quality monitoring showed product formation. Concentration and purification on column (ethyl acetate/dichloromethane ═ 5/1) gave a brown oil (197 mg, 94.4%).
MS(ESI):m/z＝439.1[M+H]+.
N- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazin-3-yl) -6- ((S) - 3-hydroxypyrrolidin-1-yl) nicotinamide
Figure BDA0001893386950000171
To a solution of (R) -N- (6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -6-fluoronicotinamide (55 mg, 0.125 mmol), N-diisopropylethylamine (129 mg, 1.004 mmol) in N, N-dimethylformamide (2ml) was added (S) -3-hydroxypyrrolidine hydrochloride (47 mg, 0.374 mmol). The temperature is raised to 90 ℃ and the mixture is stirred for 5 hours. Liquid quality monitoring showed product formation. Concentrating, and purifying the residue by preparative high performance liquid chromatography to obtain yellow solid. MS (ESI) M/z 506.2[ M + H ] +.
1H NMR(400MHz,CD3OD)δ(ppm)8.61(d,J＝1.7Hz,1H),7.94(dd,J＝8.8,2.1Hz,1H),7.64(d,J＝9.8Hz,1H),7.51(s,1H),6.98–6.81(m,3H),6.78(d,J＝9.7Hz,1H),6.57(d,J＝9.0Hz,1H),5.31(dd,J＝8.2,2.7Hz,1H),4.56(s,3H),3.97–3.87(m,1H),3.72–3.50(m,4H),2.54–2.38(m,1H),2.23-2.13(m,1H),2.11–2.03(m,2H),1.98–1.86(m,1H).
Example 3:
n- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazin-3-yl) -6- ((R) - 3-hydroxypyrrolidin-1-yl) nicotinamide
Figure BDA0001893386950000172
The title compound was prepared from intermediate C and (R) -3-hydroxypyrrolidine hydrochloride under conditions analogous to example 2.
MS(ESI):m/z＝506.5[M+H]+.
1H NMR(400MHz,CD3OD)δ(ppm)8.62(s,1H),7.94(d,J＝7.2Hz,1H),7.64(d,J＝9.9Hz,1H),7.52(s,1H),6.95-6.85(m,3H),6.77(d,J＝9.7Hz,1H),6.56(d,J＝9.0Hz,1H),5.32(d,J＝5.9Hz,1H),4.57(s,2H),3.97–3.88(m,1H),3.73–3.51(m,5H),2.52-2.42(m,1H),2.20-2.16(m,1H),2.13-2.02(m,3H),1.98-1.90(m,1H).
Example 4:
n- (6- ((2R,4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) imidazo [1,2-b]Pyridazine-3- 6- ((S) -3-hydroxypyrrolidin-1-yl) nicotinamide
Figure BDA0001893386950000181
The title compound was prepared from intermediate D and (S) -3-hydroxypyrrolidine hydrochloride under conditions analogous to example 2.
MS(ESI):m/z＝523.9[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm)9.62(s,1H),8.66(s,1H),8.00–7.92(m,1H),7.78(d,J＝9.8Hz,1H),7.46(s,1H),7.16–7.09(m,1H),7.06–6.89(m,2H),6.78–6.69(m,1H),6.52(d,J＝9.0Hz,1H),5.53(s,0.5H),5.40(s,0.5H),5.30(m,1H),5.03–4.98(m,1H),4.40(s,1H),4.13–3.98(m,2H),3.60–3.49(m,2H),3.05–2.86(m,1H),2.79–2.67(m,1H),2.24–1.86(m,4H).
Example 5:
(R) -N- (6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -6- ((2-hydroxyethyl) amino) nicotinamide
Figure BDA0001893386950000182
The title compound was prepared from intermediate C and 2-aminoethan-1-ol under conditions analogous to example 2.
MS(ESI):m/z＝480.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm)9.53(s,1H),8.51(s,1H),7.76(d,J＝9.8Hz,2H),7.43(s,1H),7.26-7.19(m,1H),7.02(m,2H),6.92–6.84(m,1H),6.68(d,J＝9.8Hz,1H),6.54(d,J＝8.9Hz,1H),5.24(d,J＝6.0Hz,1H),4.75(m,1H),3.93–3.83(m,1H),3.61–3.48(m,3H),3.39(dd,J＝11.6,5.8Hz,2H),2.43–2.30(m,1H),2.03-1.88(m,2H),1.85-1.72(m,1H).
Example 6:
n- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -6- ((3-hydroxycyclopentyl) amino) nicotinamide
Figure BDA0001893386950000183
The title compound was prepared from intermediate C and 3-aminocyclopentane-1-ol hydrochloride under conditions analogous to example 2.
MS(ESI):m/z＝519.9[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm)9.51(s,1H),8.50(s,1H),7.77-7.74(m,2H),7.43(s,1H),7.21(d,J＝7.4Hz,1H),7.08–6.96(m,2H),6.91–6.85(m,1H),6.68(d,J＝9.6Hz,1H),6.50(d,J＝8.9Hz,1H),5.25(d,J＝5.9Hz,1H),4.64(d,J＝3.9Hz,1H),4.26–4.07(m,2H),3.92-3.83(m,1H),3.55(dd,J＝17.3,8.1Hz,1H),2.42–2.19(m,2H),2.05–1.88(m,3H),1.86-1.76(m,1H),1.75–1.52(m,3H),1.45–1.33(m,1H).
Example 7:
(R) -N- (6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -6- (dimethylamino) nicotinamide
Figure BDA0001893386950000191
The title compound was prepared from intermediate C and 3-aminocyclopentane-1-ol hydrochloride under conditions analogous to example 2.
MS(ESI):m/z＝464.0[M+H]+.
1H NMR(400MHz,dmso)δ(ppm)9.61(s,1H),8.61(s,1H),7.90(d,J＝8.0Hz,1H),7.76(d,J＝9.8Hz,1H),7.44(s,1H),7.08-6.98(m,2H),6.92-6.86(m,1H),6.69(d,J＝8.8Hz,2H),5.24(d,J＝6.5Hz,1H),3.95-3.85(m,1H),3.55(dd,J＝17.4,7.8Hz,1H),3.27(s,1H),3.11(s,5H),2.42-2.29(m,1H),2.03-1.90(m,2H),1.85-1.76(m,1H).
Example 8:
n- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -2- ((S) -3-hydroxypyrrolidin-1-yl) pyrimidine-5-carboxamide
Figure BDA0001893386950000192
The title compound was prepared from intermediate C and 2-chloropyrimidine-5-carboxylic acid under conditions analogous to example 2.
MS(ESI):m/z＝506.9[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm)9.81(s,1H),8.75(s,1H),7.77(d,J＝10.0Hz,2H),7.43(s,1H),7.01–6.83(m,3H),6.73–6.49(m,1H),5.21–5.19(m,1H),5.01(d,J＝3.2Hz,1H),4.39(s,1H),3.88–3.86(m,2H),3.69-3.52(m,5H),2.39–2.29(m,2H),2.04–1.78(m,6H).
Example 9:
n- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -2- ((S) -3-hydroxypyrrolidin-1-yl) thiazole-5-carboxamide
Figure BDA0001893386950000201
Methyl (S) -2- (3-hydroxypyrrolidin-1-yl) thiazole-5-carboxylic acid ester
Figure BDA0001893386950000202
To a solution of methyl 2-bromothiazole-5-carboxylate (500 mg, 2.27 mmol) in 1, 4-dioxane (10 ml) was added (S) -3-hydroxypyrrolidine hydrochloride (234 mg, 2.72 mmol) and 1, 8-diazabicycloundec-7-ene (690 mg, 4.54 mmol). The reaction was stirred at 85 ℃ for 16 hours. The reaction was concentrated on a silica gel column (eluent ethyl acetate) to give a white solid (465 mg, yield 90%).
MS(ESI):m/z＝228.8[M+H]+.
(S) -2- (3-hydroxypyrrolidin-1-yl) thiazole-5-carboxylic acid
Figure BDA0001893386950000203
Methyl (S) -2- (3-hydroxypyrrolidin-1-yl) thiazole-5-carboxylate (465 mg, 2.04 mmol), lithium hydroxide monohydrate (257 mg, 6.11 mmol) were sequentially added to a mixed solution of tetrahydrofuran/water (10 ml/4 ml). Stirred at room temperature for 3 hours. LCMS showed reaction complete. The reaction solution was evaporated to remove tetrahydrofuran, 3 ml of water was added, and the solution was adjusted to pH 4 with 1N hydrochloric acid. The precipitated solid was filtered and washed four times with water. A solid was obtained as the title compound (400 mg, yield 91%).
N- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -2- ((S) -3-hydroxypyrrolidin-1-yl) thiazole-5-carboxamide
Figure BDA0001893386950000204
The title compound was prepared from intermediate C and (S) -2- (3-hydroxypyrrolidin-1-yl) thiazole-5-carboxylic acid under conditions analogous to example 1.
MS(ESI):m/z＝511.9[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm)9.61(s,1H),7.92(s,1H),7.74(d,J＝9.6Hz,2H),7.38(s,1H),7.03–7.02(m,2H),6.89–6.86(m,1H),6.68–6.66(m,1H),5.25–5.22(m,1H),5.12(d,J＝3.6Hz,1H),4.40(s,1H),3.88–3.84(m,2H),3.55-3.47(m,4H),2.39–2.28(m,2H),2.12–1.79(m,6H).
Example 10:
3-cyano-N- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -4- ((S) -3-hydroxypyrrolidin-1-yl) benzamide
Figure BDA0001893386950000211
The title compound was prepared from intermediate C and 3-cyano-4-fluorobenzoic acid under conditions analogous to example 2.
MS(ESI):m/z＝529.9[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm)9.76(s,1H),8.02(s,1H),7.84(d,J＝8.0Hz,1H),7.77(d,J＝9.2Hz,1H),7.41(s,1H),7.02–6.98(m,2H),6.89–6.85(m,1H),6.83(d,J＝9.2Hz,1H),6.73–6.71(m,1H),5.22–5.21(m,1H),5.10(d,J＝3.6Hz,1H),4.40(s,1H),3.89–3.85(m,1H),3.81-3.64(m,3H),3.56-3.48(m,2H),2.38–2.33(m,1H),2.03–1.90(m,5H),1.81–1.78(m,1H).
Example 11:
(R) -N- (6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -6- (pyrrolidin-1-yl) nicotinamide
Figure BDA0001893386950000212
The title compound was prepared from intermediate C and pyrrolidine under conditions analogous to example 2.
MS(ESI):m/z＝489.9[M+H]+.
1H NMR(400MHz,CD3OD)δ(ppm)8.61(s,1H),7.92(d,J＝7.0Hz,1H),7.64(d,J＝9.9Hz,1H),7.52(s,1H),6.95-6.85(m,3H),6.77(d,J＝9.7Hz,1H),6.55(d,J＝9.0Hz,1H),5.32(d,J＝5.4Hz,1H),3.96–3.88(m,1H),3.65(dd,J＝17.5,8.0Hz,1H),3.60-3.50(m,4H),2.49-2.44(m,1H),2.12–2.00(m,6H),2.00–1.90(m,1H).
Example 12:
n- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -6- ((S) -3-hydroxypyrrolidin-1-yl) pyridazine-3-carboxamide
Figure BDA0001893386950000213
Methyl (S) -6- (3-hydroxypyrrolidin-1-yl) pyridazine-3-carboxylic acid ester
Figure BDA0001893386950000214
To a solution of methyl 6-chloropyridazine-3-carboxylate (1.0 g, 5.8 mmol) in tetrahydrofuran (20 ml) were added (S) -3-hydroxypyrrolidine hydrochloride (610 mg, 7.0 mmol), potassium carbonate (1.2 g, 0.58 mmol), and tetrabutylammonium iodide (210 mg, 0.58 mmol). The reaction was stirred at 70 ℃ for 16 hours. The reaction was quenched with water, extracted with dichloromethane and isopropanol (3:1), and the organic phase was concentrated to a silica gel column (dichloromethane/methanol-95/5) to give a white solid (1 g, 76% yield).
MS(ESI):m/z＝224.3[M+H]+.
(S) -6- (3-hydroxypyrrolidin-1-yl) pyridazine-3-carboxylic acid
Figure BDA0001893386950000221
Methyl (S) -6- (3-hydroxypyrrolidin-1-yl) pyridazine-3-carboxylate (300 mg, 1.3 mmol), lithium hydroxide monohydrate (170 mg, 3.0 mmol) were sequentially added to a mixed solution of tetrahydrofuran/water (13 ml/5 ml). Stirred at room temperature for 2 hours. LCMS showed reaction complete. The reaction solution was evaporated to remove tetrahydrofuran, 3 ml of water was added, and the solution was adjusted to pH 4 with 1N hydrochloric acid. The precipitated solid was filtered and washed four times with water. A solid was obtained as the title compound (470 mg, yield 97%).
MS(ESI):m/z＝209.9[M+H]+.
N- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -6- ((S) -3-hydroxypyrrolidin-1-yl) pyridazine-3-carboxamide
Figure BDA0001893386950000222
The title compound was prepared from intermediate C and (S) -6- (3-hydroxypyrrolidin-1-yl) pyridazine-3-carboxylic acid under conditions analogous to example 1.
MS(ESI):m/z＝507.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm)10.22(s,1H),7.88(d,J＝9.4Hz,1H),7.76(d,J＝9.9Hz,1H),7.64(s,1H),7.31–7.22(m,1H),7.08–6.93(m,3H),6.67–6.57(m,1H),5.25(d,J＝5.5Hz,1H),5.09(s,1H),4.46(s,1H),3.93(s,1H),3.84–3.44(m,5H),2.45–2.36(m,1H),2.14–1.93(m,4H),1.91–1.81(m,1H).
Example 13:
n- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -5- ((S) -3-hydroxypyrrolidin-1-yl) pyrazine-2-carboxamide
Figure BDA0001893386950000223
The title compound was prepared from intermediate C and methyl 5-chloropyrazine-2-carboxylate under conditions analogous to example 12.
MS(ESI):m/z＝507.3[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm)9.84(s,1H),8.68(d,J＝1.1Hz,1H),7.95(s,1H),7.77(d,J＝9.8Hz,1H),7.64(s,1H),7.24(td,J＝9.3,4.5Hz,1H),7.07–6.96(m,2H),6.73–6.64(m,1H),5.29(d,J＝5.6Hz,1H),5.09(s,1H),4.44(s,1H),3.99–3.89(m,1H),3.72–3.43(m,5H),2.45–2.35(m,1H),2.16–1.81(m,5H).
Example 14:
n- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -5- ((S) -3-hydroxypyrrolidin-1-yl) pyrimidine-2-carboxamide
Figure BDA0001893386950000231
The title compound was prepared from intermediate C and 5-bromopyrimidine-2-carboxylic acid under conditions analogous to example 12.
MS(ESI):m/z＝501.8[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm)10.17(s,1H),8.19(s,2H),7.77(d,J＝9.8Hz,1H),7.67(s,1H),7.28–7.19(m,1H),7.07–6.97(m,2H),6.74–6.61(m,1H),5.34–5.28(m,1H),5.11(d,J＝3.8Hz,1H),4.46(s,1H),3.99–3.91(m,1H),3.65–3.43(m,4H),2.14–1.81(m,5H).
Example 15:
n- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b]Pyridazin-3-yl) -1- (3-hydroxy-substituted aryl radicals Cyclopentyl) -1H-pyrazole-3-carboxamide (cis or tran)
Figure BDA0001893386950000232
Methyl 1- (3-carbonyl cyclopentyl) -1H-pyrazole-3-carboxylate
Figure BDA0001893386950000233
To a mixture of methyl 1H-pyrazole-3-carboxylate (1 g, 7.9 mmol) and cyclopent-2-en-1-one (1.3 g, 16.0 mmol) was added p-toluenesulfonic acid monohydrate (100 mg, 0.53 mmol). The reaction was stirred at 60 ℃ for 16 hours and then purified by flash column (dichloromethane to dichloromethane: methanol 9: 1). The crude product was purified by high performance liquid chromatography to give a pale yellow oil (1.1 g, 67% yield).
MS(ESI):m/z＝208.9[M+H]+.
Methyl 1- (3-Hydroxycyclopentyl) -1H-pyrazole-3-carboxylate and example 492C methyl 1- (3-Hydroxycyclopentyl) -1H-pyrazole-3-carboxylate
Figure BDA0001893386950000241
Will be provided withMethyl 1- (3-carbonyl cyclopentyl) -1H-pyrazole-3-carboxylateA solution of (500 mg, 2.4 mmol) in methanol (20 ml) was cooled to 0 ℃. To the reaction was added sodium borohydride (500 mg, 13.0 mmol), the reaction was stirred at 0 ℃ for 1.5 hours and poured into a mixture of ice and water, extracted three times with ethyl acetate, dichloromethane: isopropanol-3: 1 was extracted three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash separation (dichloromethane/methanol ═ 9/1) to give the target compounds as colorless oils 15A-2-1(300 mg, 59%) and 15A-2-2(100 mg, yield 22%).
MS(ESI):m/z＝210.9[M+H]+。
N- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -1- (3-hydroxycyclopentyl) -1H-pyrazole-3-carboxamide
Figure BDA0001893386950000242
To a solution of 15A-2-1(84 mg, 0.4 mmol) in tetrahydrofuran (3 ml) and water (3 ml) was added lithium hydroxide (50 mg, 1.2 mmol). after stirring the reaction at room temperature for 3 hours, it was acidified with concentrated hydrochloric acid, concentrated and lyophilized. The resulting oil was dissolved in isopropanol and concentrated to give a white solid. A mixture of the resulting white solid and (R) -6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-amine (50 mg, 0.16 mmol), 2- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol), N, N-diisopropylethylamine (62 mg, 0.48 mmol) and anhydrous N, N-dimethylformamide (1 ml) was stirred at 40 ℃ for 16 hours. The reaction solution was purified by preparative high performance liquid chromatography to obtain compound 15A (33 mg, yield 42%) as a white solid.
MS(ESI):m/z＝494.4[M+H]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)9.36(s,1H),8.00(d,J＝2.3Hz,1H),7.77(d,J＝9.7Hz,1H),7.56(s,1H),7.21–7.09(m,1H),7.09–7.01(m,1H),7.01–6.91(m,1H),6.75(d,J＝2.2Hz,1H),6.66(d,J＝9.2Hz,1H),5.30(d,J＝6.7Hz,1H),4.93–4.75(m,2H),4.24(s,1H),3.97–3.89(m,1H),3.63–3.54(m,1H),2.46–2.36(m,2H),2.27–1.68(m,8H).
Figure BDA0001893386950000251
Lithium hydroxide (50 mg, 1.2 mmol) was added to a solution of 15A-2-2(84 mg, 0.4 mmol) in tetrahydrofuran (3 ml) and water (3 ml) and the reaction was stirred at room temperature for 3 hours, acidified with concentrated hydrochloric acid, concentrated and lyophilized. The resulting oil was dissolved in isopropanol and concentrated to give a white solid. A mixture of the resulting white solid and (R) -6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-amine (50 mg, 0.16 mmol), 2- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol), N, N-diisopropylethylamine (62 mg, 0.48 mmol) and anhydrous N, N-dimethylformamide (1 ml) was stirred at 40 ℃ for 16 hours. The reaction was purified by preparative high performance liquid chromatography to give 15B (34 mg, yield 43%) as a white solid.
MS(ESI):m/z＝494.4[M+H]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)9.56(s,1H),8.00(s,1H),7.94(d,J＝10.0Hz,1H),7.87(s,1H),7.20–6.89(m,4H),6.75(d,J＝1.4Hz,1H),5.33(d,J＝7.8Hz,1H),5.08–4.94(m,1H),4.73(brs,1H),4.39(s,1H),4.01–3.91(m,1H),3.66–3.55(m,1H),2.46–2.37(m,1H),2.36–2.25(m,1H),2.22–1.79(m,7H),1.69–1.56(m,1H).
Example 16:
n- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -1- (3-hydroxycyclopentyl) -1H-imidazole-4-carboxamide
Figure BDA0001893386950000252
The title compound was prepared from intermediate C and methyl 1H-imidazole-4-carboxylate under conditions analogous to example 15.
16A：MS(ESI):m/z＝494.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)9.50(s,1H),7.96(d,J＝3.8Hz,2H),7.76(d,J＝9.9Hz,1H),7.60(s,1H),7.30–7.20(m,1H),7.08–7.01(m,1H),7.00–6.92(m,1H),6.71–6.61(m,1H),5.31–5.24(m,1H),4.87–4.77(m,1H),4.76–4.70(m,1H),4.35–4.27(m,1H),3.97–3.88(m,1H),3.63–3.54(m,1H),2.44–2.38(m,1H),2.34–2.23(m,1H),2.14–1.93(m,5H),1.91–1.82(m,1H),1.82–1.69(m,1H),1.57(s,1H).
16B：MS(ESI):m/z＝494.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)9.69(s,1H),8.07–7.89(m,4H),7.29–7.17(m,1H),7.17–6.92(m,3H),5.31(d,J＝6.5Hz,1H),4.76–4.64(m,1H),4.27–4.17(m,1H),4.03–3.94(m,1H),3.68–3.59(m,1H),2.46–2.35(m,2H),2.26–2.16(m,1H),2.08–1.83(m,4H),1.78–1.69(m,3H).
Example 17:
n- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -5- ((S) -3-hydroxypyrrolidin-1-yl) picolinamide
Figure BDA0001893386950000261
The title compound was prepared from intermediate C and 5-fluoro-o-picolinic acid under conditions analogous to example 2.
MS(ESI):m/z＝505.9[M+H]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)10.16(s,1H),7.95(d,J＝2.7Hz,1H),7.88(d,J＝8.8Hz,1H),7.77(d,J＝9.8Hz,1H),7.65(s,1H),7.28–7.20(m,1H),7.08–6.97(m,3H),6.75–6.65(m,1H),5.35–5.29(m,1H),5.07(d,J＝3.7Hz,1H),4.45(s,1H),4.00–3.91(m,1H),3.65–3.44(m,4H),3.28–3.22(m,1H),2.17–1.83(m,6H).
Example 18:
(R) -N- (6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -6- (oxetan-3-ylamino) nicotinamide
Figure BDA0001893386950000262
The target compound was prepared from intermediate C and oxetan-3-amine under conditions similar to example 2.
MS(ESI):m/z＝492.4[M+H]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)9.59(s,1H),8.32(s,1H),8.24(d,J＝12.0Hz,1H),7.76(d,J＝9.5Hz,1H),7.52(t,J＝9.0Hz,1H),7.38(s,1H),7.13-7.00(m,2H),6.93–6.82(m,1H),6.75-6.67(m,1H),6.46(dd,J＝9.5,4.0Hz,1H),5.22(d,J＝8.1Hz,1H),4.29(t,J＝10.5Hz,1H),4.25–4.15(m,1H),4.13-4.05(m,1H),3.92-3.83(m,1H),3.57-3.48(m,2H),3.45-3.40(m,1H),2.45-2.32(m,1H),2.00-1.90(m,2H),1.85-1.75(m,1H).
Example 19:
n- (6- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -6- ((S) -3-methoxypyrrolidin-1-yl) nicotinamide
Figure BDA0001893386950000263
The title compound was prepared from intermediate C and (S) -3-methoxypyrrolidine under conditions analogous to example 2.
MS(ESI):m/z＝520.0[M+H]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)9.61(s,1H),8.61(s,1H),7.90(d,J＝8.1Hz,1H),7.76(d,J＝9.8Hz,1H),7.44(s,1H),7.10-7.00(m,2H),6.93-6.85(m,1H),6.68(d,J＝9.0Hz,1H),6.52(d,J＝8.9Hz,1H),5.24(d,J＝6.2Hz,1H),4.12-4.06(m,1H),3.93-3.85(m,1H),3.65–3.48(m,4H),3.46-3.38(m,1H),3.26(s,3H),2.43–2.30(m,1H),2.15–2.02(m,2H),2.00-1.90(m,2H),1.85-1.77(m,1H).
Example 20:
n- (6- ((2R,4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -5- ((S) -3-hydroxypyrrolidin-1-yl) pyrazine-2-carboxamide
Figure BDA0001893386950000271
The title compound was prepared from intermediate D and methyl 5-chloropyrazine-2-carboxylate under conditions analogous to example 13.
MS(ESI):m/z＝524.9[M+H]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)9.81(s,1H),8.69(s,1H),8.04(s,1H),7.81(d,J＝9.8Hz,1H),7.65(s,1H),7.29–7.23(m,1H),7.21–7.13(m,1H),7.02(mf,1H),6.77(d,J＝9.6Hz,1H),5.52(d,J＝52.3Hz,1H),5.38–5.32(m,1H),5.09(s,1H),4.45(s,1H),4.23–3.98(m,2H),3.73–3.46(m,4H),2.84–2.71(m,1H),2.31–1.91(m,3H).
Example 21:
n- (6- ((2R,4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -5- ((S) -3-hydroxypyrrolidin-1-yl) pyrimidine-2-carboxamide
Figure BDA0001893386950000272
The title compound was prepared from intermediate D and 5-bromopyrimidine-2-carboxylic acid under conditions analogous to example 14.
MS(ESI):m/z＝524.9[M+H]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)10.13(s,1H),8.31–8.18(m,2H),7.82(d,J＝9.8Hz,1H),7.67(s,1H),7.36–7.25(m,1H),7.21–7.11(m,1H),7.06–6.96(m,1H),6.77(d,J＝9.8Hz,1H),5.52(d,J＝52.5Hz,1H),5.42–5.30(m,1H),5.12(s,1H),4.46(s,1H),4.23–3.98(m,2H),3.60–3.48(m,3H),3.31(d,J＝10.3Hz,1H),2.87–2.73(m,1H),2.31–2.12(m,1H),2.11–2.01(m,1H),2.00–1.92(m,1H).
Biological test example 1TRKA, TRKB, TRKC kinase in vitro Activity test
Experimental Material
Recombinant human TRKA, TRKB, TRKC proteins were purchased from Carna Biosciences. HTRF kinEASE TKkit was purchased from CisbioBioassays. The BioTek microplate reader Synergy Neo 2 plate was used.
Experimental methods
Test compounds were diluted in 3-fold concentration gradient to a final concentration of 1 μ M to 0.05nM 10 concentrations, two replicate wells per concentration; the content of DMSO in the assay reaction was 1%.
TRKA enzyme reaction:
0.2 ng/. mu.l TRKA protein kinase, 1. mu.M TK Substrate-biotin polypeptide Substrate, 14.68. mu.M ATP, 1 × enzymetic buffer, 5mM MgCl21mM DTT. The detection plate is White Proxiplate384-Plusplate (PerkinElmer), and the reaction system is 10 mu l at room temperature for 40 minutes.
TRKB enzyme reaction:
0.037 ng/. mu.l TRKB protein kinase, 1. mu.M TK Substrate-biotin polypeptide Substrate, 4.77. mu.M ATP, 1 × enzymetic buffer, 5mM MgCl2，1mMMnCl21mM DTT. The assay plate was a White Proxiplate384-Plus plate (PerkinElmer) and reacted at room temperature for 50 minutes in a 10. mu.l reaction system.
TRKC enzyme reaction:
0.037 ng/. mu.l TRKC protein kinase, 1. mu.M TK Substrate-biotin polypeptide Substrate, 25.64. mu.M ATP, 1 × enzymatic buffer, 5mM MgCl21mM DTT. The detection plate is White Proxiplate384-Plus plate (PerkinElmer), the reaction is carried out for 40 minutes at room temperature, and the reaction system is 10 mu l.
Reaction detection:
add 10. mu.l of assay reagent to the reaction plate, containing SA-XL665 at a final concentration of 0.125. mu.M and 1 XTK-Antibody 5. mu.l, incubated overnight at room temperature, Synergy Neo 2 read plate.
Data analysis
The 665/620Ratio value was converted into an inhibition Ratio (%) (1-Ratio) by the following equationtest/Ratiomax)×100％。RatiomaxRatio as a positive control without test CompoundtestThe values were measured for each concentration of different compounds. IC50(nM) data were obtained by 4-parameter curve fitting, as shown in Table 1.
TABLE 1
Figure BDA0001893386950000281
Figure BDA0001893386950000291
Bioassay example 2 detection of cytological level of TRK kinase Activity by the Elisa method
NIH-3T3 cell line stably expressing normal TRKA or TRKB or TRKC was constructed by plasmid transfection.
Cells were seeded on the first day in 96-well cell culture plates at 10000 cells/well in normal medium (DMEM + 10% FBS). The next day, the medium containing 0.5% FBS was starved overnight. On the third day, cells were treated with different concentrations of test compound for 1 hour and then stimulated with 100ng/ul growth factor for 10 minutes (NGF for TRKA, BDNF for TRKB, NT-3 for TRKC). Placing the cell culture plate on ice; the supernatant was removed and rinsed once with pre-cooled PBS. The lysis buffer (cellsingailing Technology) attached to the elisa kit was diluted with double distilled water and protease and phosphatase inhibitors were added. The prepared cell lysate was added to the well plate and allowed to stand on ice for 20 minutes. The cell lysate was blown several times by the rifle and transferred to antibody pre-coated strips, capped and incubated 4 degrees overnight. The remaining steps are performed with reference to the methods provided in the elisa kit (e.g. as described in Cellsignaling Technology # 7212C).
The results show that the compound of the invention can effectively inhibit the phosphorylation levels of TRKA, TRKB and TRKC at a cytological level.
Bioassay example 3 KM12-LUC cell proliferation assay
A human colon cancer cell line KM12-LUC (LUC, stably expressing Luciferace) containing TPM3-NTRK1 fusion gene is used as a model for evaluating the pharmacodynamics of a test compound at a cytological level. The TRK fusion gene in KM12-LUC cells makes the cells independent of stimulation of extracellular growth factors, and can continuously and spontaneously activate downstream signaling pathways MAPK-ERK, PI3K-AKT and other signaling pathways closely related to cell proliferation. Therefore, inhibition of TRK activity in KM12-LUC cells significantly inhibited cell proliferation. The method comprises the following steps: the first day, cells were seeded in 384-well plates, 2000 cells/well; adding the compounds to be detected with different concentrations on the next day; on the fifth day, cell activity was measured by adding CellTiter-glo (Promega), and the cell proliferation inhibition rate was calculated for 72 hours. Statistical analysis with prism5 and IC of test compound50The value is obtained.
The results show that the compound of the invention can effectively inhibit the proliferation of KM12-LUC cells.
Biological test example 4 in vivo efficacy test of the Small molecule inhibitor of the present invention in treating tumor
Subcutaneous transplanted tumors were modeled by immunodeficient mice (nude mice) to examine the in vivo inhibitory effect of these compounds on tumor growth. The method comprises the following steps:
KM12-LUC cells (5X 10)6) Subcutaneously injected into the dorsal zone of nude mice. Tumor growth and changes in body weight were monitored throughout the experiment. Tumor volume was monitored by measuring the diameter with a caliper and calculated by the following formula: length x (width 2)/2. Mice were randomly selected to receive either diluent, 60mg/kg dose or 200mg/kg dose of test compound when the tumor size was between 150 and 200mm 2. The test compound is administered by oral administration once a day for about 10-14 days. After the last administration, the mice were weighed, and tumor tissues and blood were collected 2 hours after the administration. Calculating tumor inhibition rate, detecting the concentration of the compound to be detected in the tumor and blood samples, and detecting TRKA phosphorylation level and downstream signal molecules such as ERK or AKT phosphorylation level in the tumor samples.
The results show that the compound can effectively inhibit the growth of tumors in a nude mouse subcutaneous transplantation tumor model.
Bioassay example 5 mutant TRKA (G595R), TRKA (G667C) and TRKC (G623R) kinase in vitro Activity assay
Experimental Material
Recombinant human TRKA (G595R), TRKA (G667C), and TRKC (G623R) proteins were purchased from SignalChem. HTRFkinease TKkit was purchased from CisbioBioassays. The BioTek microplate reader Synergy Neo 2 plate was used.
Experimental methods
Test compounds were diluted in 4-fold concentration gradient to a final concentration of 10 concentrations from 1 μ M to 0.004nM, two duplicate wells per concentration; the content of DMSO in the assay reaction was 1%.
TRKA (G595R) enzyme reaction:
0.12 ng/. mu.l TRKA (G595R) protein kinase, 1. mu.M TK Substrate-biotin polypeptide Substrate, 4.5. mu.MATP, 1 × enzymic buffer, 5mM MgCl21mM DTT. The detection plate is White Proxiplate384-Plusplate (PerkinElmer), and the reaction system is 10 mu l at room temperature for 30 minutes.
TRKA (G667C) enzyme reaction:
0.026 ng/. mu.l TRKA (G667C) protein kinase, 1. mu.M TK Substrate-biotin polypeptide Substrate, 5.5. mu.MATP, 1 × enzymic buffer, 5mM MgCl21mM DTT. The detection plate is White Proxiplate384-Plusplate (PerkinElmer), and the reaction system is 10 mu l at room temperature for 30 minutes.
TRKC (G623R) enzymatic reaction:
1.0 ng/. mu.l TRKC (G623R) protein kinase, 1. mu.M TK Substrate-biotin polypeptide Substrate, 62.9. mu.MATP, 1 × enzymic buffer, 5mM MgCl21mM DTT. The detection plate is White Proxiplate384-Plusplate (PerkinElmer), and the reaction is carried out for 50 minutes at room temperature, and the reaction system is 10 mu l.
Reaction detection:
add 10. mu.l of assay reagent to the reaction plate, containing SA-XL665 at a final concentration of 0.125. mu.M and 1 XTK-Antibody 5. mu.l, incubated overnight at room temperature, Synergy Neo 2 read plate.
Data analysis
The value of 665/620Ratio minus the value of the enzyme-free negative control well was converted to the percent inhibition (%) (1-Ratio) by the following equationtest/Ratiomax)×100％。RatiomaxRatio as a positive control without test CompoundtestThe values were measured for each concentration of different compounds. IC50(nM) data were obtained by 4-parameter curve fitting, as shown in Table 2.
Figure BDA0001893386950000311
Biological test example 6: pharmacokinetic experiment of small molecule inhibitor mouse in the invention
The test compounds were administered to ICR mice in a single Intravenous (IV) and oral (PO) administration, respectively, blood samples were collected at different time points, and LC-MS/MS was used to determine the concentration of the test substance in the plasma of the mice and to calculate the relevant parameters. The method comprises the following specific steps: dissolving the required amount of test sample in 5% DMSO + 10% Solutol + 85% water for injection to obtain solution with required concentration for intravenous administration or oral administration. Animals were aged about 6-8 weeks at the start of the dosing experiment. Blood sampling time of vein: 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration. The blood sampling time is as follows: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after administration. Establishing a biological sample analysis method and a sample detection method. Collecting the data of blood concentration at different time points, and calculating pharmacokinetic parameters such as AUC (0-T), AUC (0- ∞), T1/2, Cmax, Tmax and MRT by using Phoenix WinNonlin 7.0 software.
The results show that the compounds of the invention have excellent pharmacokinetic properties.
Biological test example 7: pharmacokinetic experiment of small molecule inhibitor rat in the invention
Test compounds were administered to SD rats in a single Intravenous (IV) and oral (PO) administration, respectively, blood samples were collected at different time points, and the concentration of the test substance in rat plasma was determined by LC-MS/MS and the relevant parameters were calculated. The method comprises the following specific steps: dissolving the required amount of test sample in 5% DMSO + 10% Solutol + 85% water for injection to obtain solution with required concentration for intravenous administration or oral administration. Animals were aged about 6-8 weeks at the start of the dosing experiment. Vein samplingBlood time: 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration. The blood sampling time is as follows: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after administration. Establishing a biological sample analysis method and a sample detection method. Calculating pharmacokinetic parameters, such as AUC, of blood concentration data at different time points by using Phoenix WinNonlin 7.0 software(0-t)，AUC(0-∞)，T1/2，Cmax，TmaxAnd MRT, etc.
The results show that the compounds of the invention have excellent pharmacokinetic properties.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A compound of formula I:
Figure FDA0001893386940000011
wherein the content of the first and second substances,
r has the formula-L1-RAThe structure of (1);
L1selected from the group consisting of: substituted or unsubstituted 5-to 10-membered heterocyclylene having 1 to 3 heteroatoms selected from N, S and O, or substituted or unsubstituted- (X)y-wherein each of said xs is independently selected from the group consisting of: substituted or unsubstituted C1-C8Alkylene, -O-, -C (═ O) -, -CONH-, -NHCO-, -S (═ O)2-、-NH-；
y is selected from the group consisting of: 1.2 or 3;
RAselected from the group consisting of: substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O;
Y1、Y2、Y3、Y4、Y5、Y6、Y7each independently selected from the group consisting of: CR1Or N; z1、Z2Each independently selected from the group consisting of: c or N;
and is
Figure FDA0001893386940000012
Is an aromatic ring;
R1each independently selected from the group consisting of: H. d, OH, Cl, F and NH2；
Ring a is selected from the group consisting of: substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 5-10 membered heteroaryl (including monocyclic, fused cyclic) having 1-3 heteroatoms selected from N, S and O;
l is selected from the group consisting of: none, -NR7-，-O-；
R7Selected from: h, substituted C1-C6 alkyl; wherein said substitution means that one or more H atoms on the group are substituted with a substituent selected from the group consisting of: halogen, hydroxy;
ring C is selected from the group consisting of: substituted or unsubstituted 3-12 membered cycloalkyl (including monocyclic, fused, spiro or bridged ring), substituted or unsubstituted 4-12 membered heterocyclyl (including monocyclic, fused, spiro or bridged ring) having 1-3 heteroatoms selected from N, S and O;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C8 cycloalkyl, methylsulfonyl, -S (═ O)2NH2Oxo (═ O), -CN, hydroxy, -NH2Carboxy, C1-C6 amido (-C (═ O) -N (Rc)2or-NH-C (═ O) (Rc), Rc being H or C1-C5 alkyl), C1-C6 alkyl- (C1-C6 amido),
Figure FDA0001893386940000021
Or a substituted or unsubstituted group selected from: C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 amino, C6-C10 aryl, having 1-3 substituents selected from N, S and5-10 membered heteroaryl of a heteroatom of O, 5-12 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O, - (CH)2) -C6-C10 aryl, - (CH)2) - (5-to 10-membered heteroaryl having 1 to 3 heteroatoms selected from N, S and O), and the substituents are selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, oxo, -CN, -NH2OH, -OH, C6-C10 aryl, C1-C6 amino, C1-C6 amido, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O;
Figure FDA0001893386940000022
is the attachment site of the group;
with the proviso that the compounds of formula I are chemically stable structures.
2. The compound of claim 1, wherein L is1Selected from the group consisting of:
Figure FDA0001893386940000023
n is selected from the group consisting of: 0.1, 2 or 3;
R2、R2aand R2bEach independently selected from the group consisting of: H. OH, halogen, substituted or unsubstituted C1-C8An alkyl group;
X5selected from the group consisting of: NH, O, -CONH-, -NHCO-, S, -S (═ O)2-、-NHS(＝O)-、-NHS(＝O)2-；
RAIs composed of
Figure FDA0001893386940000024
Wherein, the
Figure FDA0001893386940000025
Means RAAnd L1The attachment site of (a); x4Is CH or N;
R3selected from the group consisting of: H. halogen, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenatedC1-C6 alkoxy.
3. The compound of claim 1, wherein said compound has the structure shown in formula II:
Figure FDA0001893386940000026
4. the compound of claim 1, wherein the compound has the structure shown in formula III below:
Figure FDA0001893386940000027
5. the compound of claim 1, wherein said compound has a structure selected from the group consisting of:
Figure FDA0001893386940000031
Figure FDA0001893386940000041
6. a pharmaceutical composition comprising (1) a compound of claim 1 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; (2) a pharmaceutically acceptable carrier.
7. The use according to claim 6, wherein the disease is selected from the group consisting of: cancer, proliferative diseases, pain, skin diseases or conditions, metabolic diseases, muscular diseases, neurological diseases, autoimmune diseases, dermatitis-induced pruritus, inflammation-related diseases, bone-related diseases.
8. Use of a compound according to claim 1 or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 6, for the preparation of a pharmaceutical composition for the prophylaxis and/or treatment of a disease associated with an abnormal TRK function (abnormal TRK activation due to amplification, or overexpression, or mutation, or gene fusion).
9. The use according to claim 8, wherein the disease is selected from the group consisting of: the disease is selected from the group consisting of: cancer, proliferative diseases, pain, skin diseases or conditions, metabolic diseases, muscular diseases, neurological diseases, autoimmune diseases, dermatitis-induced pruritus.
10. A TRK inhibitor, wherein said inhibitor comprises a compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
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