CN106279176A - Deuterated 3-[(6-quinolyl) difluoromethyl]-6-[(1-methyl)-4-pyrazolyl] [1,2,4] triazol [4,3-b] pyridazine and application thereof - Google Patents

Abstract

The present invention relates to deuterated 3-[(6-quinolyl) difluoromethyl]-6-[(1-methyl)-4-pyrazolyl] [1,2,4] triazol [4,3-b] pyridazine (formula I) or its crystal formation, pharmaceutically acceptable salt and comprise the pharmaceutical composition of described compound or its crystal formation or its pharmaceutically acceptable salt in preparation for prevention or treatment by protein tyrosine kinase, the application in the medicine of the disease of especially c-Met kinase signal mediation.

Description

Deuterated 3-[(6-quinolyl)difluoromethyl]-6-[(1-methyl)-4-pyrazolyl][1,2,4]triazolo[4,3- b] pyridazine and its application

technical field

The present invention relates to the fields of medicinal chemistry and drug therapeutics, in particular to deuterated 3-[(6-quinolyl)difluoromethyl]-6-[(1-methyl)-4-pyrazolyl][1 ,2,4]triazolo[4,3-b]pyridazine, or its crystal form, pharmaceutically acceptable salt, and a pharmaceutical combination comprising said compound or its crystal form, or its pharmaceutically acceptable salt Application of the substance in the preparation of medicines for preventing or treating diseases mediated by protein tyrosine kinase, especially c-Met kinase signal.

Background technique

Known [1,2,4]triazolo[4,3-b]pyridazines are selective c-Met inhibitors, which have been disclosed in patents WO2007075567A1 and WO2008155378A1 for the treatment of tyrosine kinases including Neoplastic diseases caused by dysregulation of c-Met kinase.

Protein tyrosine kinases (PTKs) are a group of enzymes that regulate a variety of important biological functions, including cell growth, differentiation, organ formation, neovascularization, tissue repair and regeneration, and so on. Protein tyrosine kinases exert their biological effects by catalyzing the phosphorylation of protein tyrosine residues, which then regulate the biological activity of substrate proteins. The dysregulation of a class of protein tyrosine kinases may lead to tumor formation and growth, and further play an important role in the survival and development of tumors (Blume J P, Hunter T. Oncogenic kinase signaling [J]. Nature, 2001, 411 (6835) :355-365). Thus, tumor-associated protein tyrosine kinases represent the most important class of protein targets relevant to cancer therapy and drug development.

c-Met is hepatocyte growth factor receptor (HGFR), encoded by the MET proto-oncogene. c-Met is highly expressed in most cancers and some sarcomas and is closely related to poor prognosis, such as lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, neuroglial cancer tumors, melanoma, etc. c-Met interacts with its ligand HGF/SF or activates the tyrosine kinase in the intracellular region through other pathways, induces cell proliferation, invasion, migration, inhibits cell apoptosis, and promotes angiogenesis. play an important role.

In summary, there is an urgent need in this field to develop new drugs with protein tyrosine kinase inhibitory activity, especially c-Met inhibitory activity.

Contents of the invention

The purpose of the present invention is to provide a new drug with protein tyrosine kinase inhibitory activity, especially with c-Met inhibitory activity.

The first aspect of the present invention provides a compound represented by the following formula (I):

In the formula:

D represents a deuterium atom;

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , and R ₉ are each independently a hydrogen atom or a deuterium atom;

R ₁₀ is selected from the group consisting of CH ₃ , CH ₂ D, CHD ₂ , or CD ₃ .

In another preferred example, the deuterium isotope content of deuterium at the deuterium substitution position is at least greater than the natural deuterium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably Preferably greater than 95%, more preferably greater than 99%.

In another preferred example, all or substantially (>99wt%) of the other elements (such as N, C, F, etc.) except H in the compound of formula (I) are the naturally occurring elements with the highest abundance, for example ^14N , ^12C and ^19F .

In another preferred example, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , and R ₉ are all hydrogen atoms;

R ₁₀ is CH ₃ .

In another preferred example, the compound of formula I is the following compound II.

The second aspect of the present invention provides a method for preparing a pharmaceutical composition, the method comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound as described in the first aspect of the present invention, or its crystal form, pharmaceutically acceptable salts, hydrates or solvates are mixed to form a pharmaceutical composition.

The third aspect of the present invention provides a pharmaceutical composition comprising: a therapeutically effective amount of the compound of formula I as described in the first aspect of the present invention, or its crystal form, pharmaceutically acceptable salt , hydrate or solvate; and a pharmaceutically acceptable carrier.

In another preference, the pharmaceutical composition includes a therapeutically effective amount of the compound of formula II, namely 3-[(2-deuterium-6-quinolyl)difluoromethyl]-6-[(1-methyl base)-4-pyrazolyl][1,2,4]triazolo[4,3-b]pyridazine, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate:

and a pharmaceutically acceptable carrier.

In another preferred example, the pharmaceutical composition further includes a therapeutically effective amount of other active ingredients, and the other active ingredients include one or more active ingredients selected from the group consisting of cytotoxic agents, signal transduction Inhibitors, and other antineoplastic substances.

In another preferred example, the pharmaceutical composition is used for treating or preventing diseases related to the activity or expression of tyrosine kinases, preferably diseases related to the activity or expression of c-Met.

In another preferred example, the disease is selected from the group consisting of papilloma, budding glioma, melanoma, lung cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer , neck cancer, bladder cancer, breast cancer, colorectal cancer, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, hemangioma, keloid, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, Urethral cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and its distant metastases, lymphoma, sarcoma, colon cancer, bone cancer, kidney cancer, testicular cancer, skin cancer, renal cell carcinoma , Non-small cell lung cancer.

In another preferred example, the pharmaceutical composition is a formulation selected from the group consisting of tablets, capsules, pills, powders, granules or injections; preferably tablets, capsules, or intravenous injections.

In another preferred example, when the pharmaceutical composition is a tablet, the pharmaceutical composition includes a carrier selected from the group consisting of colloidal silicon dioxide, magnesium stearate, modified starch, microcrystalline fiber vegan, lactose, or a combination thereof.

In another preferred example, when the pharmaceutical composition is a capsule, the pharmaceutical composition includes a carrier selected from the group consisting of starch, microcrystalline cellulose, or a combination thereof.

In another preferred example, when the pharmaceutical composition is an intravenous injection, the pharmaceutical composition includes a carrier selected from the group consisting of sterile water for injection.

In another preferred example, the pharmaceutical composition is a long-acting preparation.

The fourth aspect of the present invention provides a compound of formula (I) as described in the first aspect of the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate for the preparation of tyrosine Use of a pharmaceutical composition for diseases mediated by acid kinases, especially c-Met.

In another preferred example, the disease is selected from the group consisting of papilloma, budding glioma, melanoma, lung cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer , neck cancer, bladder cancer, breast cancer, colorectal cancer, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, hemangioma, keloid, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, Urethral cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and its distant metastases, lymphoma, sarcoma, colon cancer, bone cancer, kidney cancer, testicular cancer, skin cancer, renal cell carcinoma , Non-small cell lung cancer.

The fifth aspect of the present invention provides a method for preparing the formula II compound 3-[(2-deuterium-6-quinolyl)difluoromethyl]-6-[(1- Methyl)-4-pyrazolyl][1,2,4]triazolo[4,3-b]pyridazine,

It is characterized in that, comprising steps:

In an organic solvent, the compound of the formula (VII) and the compound of the formula (VIII) are used for ring-closing reaction to obtain the compound of the formula (II).

In another preferred example, the ring-closing reaction is carried out in the presence of dioxane and methanesulfonic acid.

In another preferred example, the organic solvent is a solvent selected from the group consisting of dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, acetone, N,N-dimethylformaldehyde Amide, N,N-dimethylacetamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or combinations thereof.

In another preferred example, the reaction is carried out at 60-130°C.

In another preferred example, the reaction time is 8-16 hours.

In another preference, the compound of formula (VII) is prepared by the following method:

In an organic solvent, the compound of formula (VI) is reacted with ethyl difluorobromoacetate and hydrazine hydrate to obtain the compound of formula (VII).

In another preferred example, the reaction is carried out in the presence of copper powder; preferably, compound (VI) is condensed with ethyl difluorobromoacetate in the presence of copper powder, and then reacted with hydrazine hydrate to obtain the compound of formula (VII) .

In another preferred example, the organic solvent is a solvent selected from the group consisting of dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, acetone, N,N-dimethylformaldehyde Amide, N,N-dimethylacetamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or combinations thereof.

In another preferred example, the reaction is carried out at 60-100°C.

In another preferred example, the reaction time is 18-30 hours.

In another preference, the compound of formula (VI) is prepared by the following method:

In an organic solvent, the compound of formula (V) is reacted with an iodinating reagent to obtain a compound of formula (VI); preferably, the iodinating reagent is sodium iodide, cuprous iodide and N,N-dimethyl Ethylenediamine.

In another preferred example, the organic solvent is a solvent selected from the group consisting of dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, acetone, N,N-dimethylformaldehyde Amide, N,N-dimethylacetamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or combinations thereof.

In another preferred example, the reaction is carried out at 80-140°C.

In another preferred example, the reaction time is 8-16 hours.

In another preference, the compound of formula (V) is prepared by the following method:

In an organic solvent, carry out a reduction reaction with a compound of the formula (IV) and a reducing agent to obtain a compound of the formula (V); preferably, the reducing agent is iron powder; more preferably, the reducing reaction is carried out in the presence of glacial acetic acid next.

In another preferred example, the organic solvent is a solvent selected from the group consisting of dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, acetone, N,N-dimethylformaldehyde Amide, N,N-dimethylacetamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or combinations thereof.

In another preferred example, the reaction is carried out at 80-140°C.

In another preferred example, the reaction time is 1-5 hours.

In another preference, the compound of formula (IV) is prepared by the following method:

In an organic solvent, the compound of formula (III) is used for deuteration reaction to obtain the compound of formula (IV); preferably, the deuteration reaction is carried out in the presence of heavy water and/or sodium tert-butoxide.

In another preferred example, the organic solvent is a solvent selected from the group consisting of dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, acetone, N,N-dimethylformaldehyde Amide, N,N-dimethylacetamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or combinations thereof.

In another preferred example, the reaction is carried out at 70-130°C.

In another preferred example, the reaction time is 8-16 hours.

In another preference, the compound of formula (III) is prepared by the following method:

In an organic solvent, carry out oxidation reaction with 6-bromoquinoline to obtain compound (III); preferably, the oxidation reaction uses m-chloroperoxybenzoic acid as an oxidizing agent.

In another preferred example, the organic solvent is a solvent selected from the group consisting of dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, acetone, N,N-dimethylformaldehyde Amide, N,N-dimethylacetamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or combinations thereof.

In another preferred example, the reaction is carried out at 10-40°C.

In another preferred example, the reaction time is 8-16 hours.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.

Description of drawings

Figure 1 The plasma concentration-time curves of cynomolgus monkeys after oral administration of 10 mg/kg compound II and JNJ38877605 respectively;

Fig. 2 The inhibitory effect of compound Ⅱ and JNJ38877605 on the growth of human lung cancer EBC-1 transplanted tumor in nude mice.

detailed description

After long-term and in-depth research, the inventors unexpectedly found that deuterated [1,2,4]triazolo[4,3-b]pyridazine compounds have good protein tyrosine kinase inhibitory activity At the same time, there is a significant improvement in pharmacokinetics, and the exposure in animals after administration can be higher, so it has better therapeutic effect. Based on the above findings, the inventors have accomplished the present invention.

the term

Unless otherwise specified, in the present invention, the deuterium isotope content of deuterium at the deuterium substitution position is at least greater than the natural deuterium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, More preferably greater than 95%, more preferably greater than 99%.

Deuterated 3-[(6-quinolyl)difluoromethyl]-6-[(1-methyl)-4-pyrazolyl][1,2,4]triazolo[4,3- b] Pyridazine

The present invention provides a new type of compound with c-Met inhibitory activity and better pharmacodynamic properties and its use, namely the deuterated 3-[(6-quinolyl)difluoro compound represented by formula (I) Methyl]-6-[(1-methyl)-4-pyrazolyl][1,2,4]triazolo[4,3-b]pyridazine, its crystal form, pharmaceutically acceptable salt , hydrate or solvate:

In the formula:

D represents a deuterium atom;

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , and R ₉ are each independently a hydrogen atom or a deuterium atom;

R ₁₀ is CH ₃ , CH ₂ D, CHD ₂ , or CD ₃ ;

Preferably, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ are all hydrogen atoms, R ₁₀ is CH ₃ , and the compound is the following compound II:

Deuterated 3-[(6-quinolyl)difluoromethyl]-6-[(1-methyl)-4-pyrazolyl][1,2,4]triazolo[4,3- b] Preparation of pyridazine

Deuterated 3-[(6-quinolyl)difluoromethyl]-6-[(1-methyl)-4-pyrazolyl][1,2,4]triazolo [4,3-b]pyridazine can be prepared by a method commonly used in the art for preparing deuterated compounds, for example, in a preferred embodiment of the present invention, the method for preparing the compound II includes the following steps: from 6- Starting from bromoquinoline, the intermediate (VII) is obtained through oxidation, deuteration, reduction, iodine substitution, coupling and hydrazinolation, and then ring-closing with the compound (VIII) to obtain the target product.

Specifically, the preparation method includes:

Starting from 6-bromoquinoline, the compound (Ⅲ) is obtained through the oxidation of m-chloroperoxybenzoic acid;

Compound (Ⅲ) reacts with heavy water and sodium tert-butoxide to obtain deuterated compound (Ⅳ);

Compound (Ⅳ) is reduced to compound (Ⅴ) by iron powder in the presence of glacial acetic acid;

Compound (V) is converted into compound (VI) in the presence of sodium iodide, cuprous iodide and N,N-dimethylethylenediamine;

Compound (VI) is condensed with ethyl difluorobromoacetate in the presence of copper powder, and then reacted with hydrazine hydrate to obtain intermediate (VII);

Intermediate (VII) and intermediate (VIII) are ring-closed in the presence of methanesulfonic acid to obtain compound (II).

active ingredient

As used herein, the term "compound of the present invention" refers to a compound represented by formula (I). The term also includes the various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I).

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or a base which is suitable for use as a medicine. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are the salts of the compounds of the invention with acids. Acids suitable for salt formation include but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, malonic acid, etc. Organic acids such as toric acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenemethanesulfonic acid, benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

Pharmacokinetic and pharmacodynamic evaluation of compound Ⅱ (compared with the prototype drug JNJ38877605)

JNJ38877605 is a c-Met inhibitor developed by Johnson&Johnson. On this basis, the compound II prepared by the inventors through deuteration has significantly better pharmacokinetic and/or pharmacodynamic properties than compound JNJ38877605. Therefore It is more suitable as a compound for inhibiting c-Met kinase, and thus more suitable for preparing medicines for treating cancer and related diseases.

The pharmacokinetic results showed that the peak plasma concentration C _max and exposure AUC _0-t of compound II in cynomolgus monkeys at the same dose were 1.56 times and 2.29 times that of JNJ38877605; The pharmacodynamic results of the mouse transplantation model showed that compound Ⅱ had a tumor growth inhibition rate (TGI) of 90.4% at a dose of 5 mg/kg twice a day for 21 consecutive days, which was significantly better than that at the same dose. Inhibition of tumor growth by JNJ38877605 (TGI 83.8%).

The above results show that compound Ⅱ has significantly better pharmacokinetic and pharmacodynamic properties than JNJ38877605, and has potential value in the development of antitumor drugs accepted by humans.

Instructions

The present invention provides compounds capable of regulating signal transduction pathways mediated by protein tyrosine kinases, especially c-Met kinase. c-Met is an important signaling molecule involved in the regulation of many important cellular processes including cell growth, cell survival and invasion. The HGF/c-Met signaling pathway exists in most tumor cells. Dysregulation of the c-Met signaling pathway is the most prevalent in human cancers. Disruption of c-Met signaling has been demonstrated in many solid and hematological tumors. The strongest evidence linking c-Met and cancer is the initial discovery that almost all patients with hereditary renal papilloma (PRCC) have overexpression of c-Met. Trisomy 7 carrying HGF and c-Met genes is common in PRCC patients. It has also been reported that c-Met mutation occurs in many cancers, such as gastric cancer, brain tumor, liver cancer, ovarian cancer, non-small cell lung cancer and thyroid cancer. The oncogenic potential of multiple c-Met mutants has been confirmed in preclinical models. The compounds described herein can be used to inhibit their activity.

The term "modulate" refers to altering the functional activity of the pathway (or a component thereof) as compared to the normal activity in the absence of the compound. This action includes modulation of any number or degree, including enhancing, stimulating, activating, enhancing, increasing, facilitating, decreasing, decreasing, diminishing, hindering, inhibiting, antagonizing, and the like.

Compounds of the invention may also modulate one or more of the following processes including, but not limited to, for example, cell growth (including, for example, differentiation, cell survival and/or proliferation), tumor cell growth (including, for example, differentiation, cell survival and/or proliferation), tumor regression, etc.

While not wishing to be bound by any mechanism or mechanism of action, the compounds of the present invention have been found to possess the ability to modulate kinase activity. However, the methods described herein are not limited to any particular mechanism or how the compounds achieve their therapeutic effect. The term "kinase activity" refers to catalytic activity in which a gamma phosphate is transferred from adenosine triphosphate (ATP) to an amino acid residue (eg, serine, threonine, or tyrosine) in a protein substrate. Compounds can regulate kinase activity, for example inhibiting its activity by directly competing with ATP for the ATP binding site of the kinase, affecting its activity by producing conformational changes in the structure of the enzyme (for example by destroying the three-dimensional structure with biological activity) and the like.

The compound of the present invention can be used for treating and/or preventing any disease or disease caused by abnormality of cell signal transduction pathway mediated by protein tyrosine kinase, especially c-Met kinase. The term "treatment" is used in its conventional sense, eg, treating or caring for a patient for the purpose of combating, alleviating, reducing, resolving, ameliorating the symptoms of a disease or disorder, and the like. Said compounds may also be described for use in the prevention and/or treatment of diseases and/or disorders mediated by said signaling molecules. The term "mediated" means, for example, that the signaling molecule is part of a pathway that is abnormal or dysfunctional in the disease and/or disorder.

Diseases and conditions that may be treated include any of the diseases mentioned above and below as well as related diseases caused by c-Met abnormalities including, for example, cell proliferation disorders, cancer, tumors, and the like. The diseases include papilloma, budding glioma, Kaposi's sarcoma, melanoma, lung cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer , breast cancer, colorectal cancer, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, hemangioma, keloid.

The methods of the invention include modulating tumor cell proliferation, which includes inhibiting cell proliferation. The latter means that the growth and/or differentiation of tumor cells is reduced, diminished, impaired, slowed, etc. The term "proliferation" includes any process involving cell growth and division, and includes differentiation and apoptosis. As mentioned above, c-Met kinase plays an important role in the activation of cytoplasmic signaling cascades involved in cell proliferation, differentiation and apoptosis.

Included in the method of the present invention is the use of the above-mentioned compounds (compounds described in formula (I)) including or their crystal forms, pharmaceutically acceptable salts, hydrates or solvates, and compositions thereof to treat mammals A method for a hyperproliferative disease comprising administering to a mammal, including a human in need thereof, an amount of a compound of the present invention, its crystal form, a pharmaceutically acceptable salt, a hydrate, or solvates. Hyperproliferative diseases include, but are not limited to, solid tumors such as breast cancer, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and distant metastases. These diseases also include lymphomas, sarcomas, and leukemias.

Any tumor may be treated, including, but not limited to, tumors having one or more mutations in c-Met and any upstream or downstream members of the signaling pathways in which it participates. As previously stated, tumors can be treated with the compounds of the present invention irrespective of the underlying mechanism. Tumors of any organ may be treated, including but not limited to, for example, colon cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer, kidney cancer, lung cancer, testicular cancer, breast cancer, skin cancer, stomach cancer, colorectal cancer, renal cell carcinoma, hepatocellular carcinoma, melanoma, etc.

Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are not limited to, small cell and non-small cell lung cancers, as well as bronchial adenomas and pleuropulmonary blastomas.

Examples of brain cancers include, but are not limited to, brainstem and pituitary gliomas, medulloblastomas, cerebellar and cerebral astrocytomas, atriotympanomas, and neuroectodermal and pinealomas.

Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer. Tumors of the female reproductive organs include, but are not limited to, ovarian, endometrial, cervical, vaginal, and vulvar cancers, and uterine sarcomas.

Gastrointestinal tumors include, but are not limited to, cancers of the anus, colon, colorectum, esophagus, gallbladder, rectum, stomach, small intestine, and salivary glands.

Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without a fibrolamellar form), cholangiocarcinoma, and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, Kaposi's sarcoma, squamous cell tumor, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head and neck cancers include, but are not limited to, cancers of the larynx, hypopharynx, nasopharynx, and/or oropharynx, as well as cancers of the lips and mouth.

Lymphomas include, but are not limited to, non-Hodgkin's lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and central nervous system lymphoma.

Sarcomas include, but are not limited to, chondrosarcoma, histiosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

Leukemias include, but are not limited to, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, and villous cell leukemia.

In addition to inhibiting tumor cell proliferation, the compounds of the invention can also cause tumor regression, eg, a decrease in tumor size or a decrease in the extent of tumor distribution in the body.

Pharmaceutical compositions based on the compounds of the present invention

The present invention also relates to a pharmaceutical composition containing the compound of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, and a pharmaceutically acceptable salt thereof. These compositions can be administered to a patient in need thereof to achieve the desired pharmacological effect. It is the purpose of the present invention that the patient is a mammal including a human being in need of treatment for a specific symptom or disease. Accordingly, the present invention includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the compound of the present invention or a salt thereof. A pharmaceutically acceptable carrier is any carrier that is relatively non-toxic and harmless to patients at a concentration that matches the effective activity of the active ingredient so that any side effects caused by the carrier do not impair the beneficial effects of the active ingredient. A pharmaceutically effective amount of a compound is that amount that produces or exerts an effect on the particular condition being treated. The compounds of the present invention can be administered orally, parenterally, topically, ophthalmically, in any effective conventional dosage unit form using pharmaceutically acceptable carriers well known in the art, including immediate release formulations, sustained release formulations, and timed release formulations. It can be administered through the mouth, eyeball, nose, sublingual, rectal, vaginal, etc.

For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, powders, melts, solutions, emulsions or suspensions, and can be formulated according to established methods in the art. Prepared by known methods for the manufacture of pharmaceutical compositions. Solid unit dosage forms can be ordinary soft- or hard-shell gelatin-type capsules containing, for example, surfactants, lubricants, and inert fillers such as sucrose, lactose, corn starch, and calcium phosphate.

In another embodiment, the compounds of the present invention can be prepared with conventional tablet bases such as lactose, sucrose and cornstarch with binders such as gum arabic, gelatin or cornstarch; such as potato starch, cornstarch, alginic acid, And guar gum, gum arabic, tragacanth, etc. are used to help the tablet split and dissolve after administration; such as talc, stearic acid or magnesium stearate, calcium or zinc, etc. are used to improve the tablet granulation flow. Lubricants that prevent tablet raw materials from sticking to tablet molds and tablet presses; dyes, colorants, and flavorings such as wintergreen oil, peppermint oil, or cherry flavorings that improve the appearance of tablets and make them more acceptable to patients Flavor combinations are prepared into tablets. Suitable excipients for oral solid dosage forms include dicalcium phosphate and pharmaceutically acceptable surfactants, suspending agents or emulsifying agents such as water and alcohols (e.g. ethanol, benzyl alcohol and polyethylene glycol) with or without pharmaceutically acceptable surfactants, suspending agents or emulsifying agents. Thinner for solvents. Various other materials may be present to sugar-coat or to otherwise modify the physical form of the dosage form. For example, tablets, pills or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for preparation of aqueous suspensions. They provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable wetting or dispersing agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as those above-mentioned sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifiers may be (1) natural phospholipids such as soybean lecithin and lecithin, (2) natural gums such as acacia and tragacanth, (3) condensation products of said partial esters with ethylene oxide, such as poly Oxyethylene sorbitan monooleate, (4) ester or partial ester derivatives of fatty acids and hexitol anhydrides such as sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as olive oil, arachis oil, coconut oil or sesame oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, hard paraffin, beeswax or cetyl alcohol. The suspension may also include one or more preservatives such as n-propyl p-hydroxybenzoate or ethyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and a or more sweeteners such as saccharin or sucrose.

Syrups or elixirs may be formulated with sweetening agents such as, for example, propylene glycol, glycerol, sucrose or sorbitol. Such formulations may also contain a demulcent and a preservative, such as propyl and methylparaben, as well as flavoring and coloring agents.

The compounds of the present invention can also be administered parenterally, i.e., subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, in a physiologically acceptable diluent in an injectable dose of the compound. or intraperitoneal administration, the diluent containing may be such as water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol or cetyl alcohol, glycols such as propylene glycol or polyethylene glycol, such as Glycerol ketals of 2,2-methyl-1,1-oxolane-4-methanol, ethers such as polyethylene glycol 400, oils, fatty acids, fatty acid esters or fatty acid glycerides, or acetylated fatty acid glycerol Pharmaceutical carrier for sterile liquids or liquid mixtures of esters with or without pharmaceutically acceptable surfactants such as fatty acid salts or detergents, such as carbomer, pectin, methylcellulose, carboxymethyl Suspending agent of base cellulose or hydroxypropyl methylcellulose, or emulsifying agent and other pharmaceutical adjuvants.

Examples of oils which may be used in the parenteral dosage forms of the invention are petroleum, oils of synthetic origin, animal or vegetable oils, such as soft paraffin, mineral oil, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil and olive oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, isopropyl myristate and ethyl oleate. Suitable fatty acid salts include fatty acid alkali metal, fatty acid ammonium and fatty acid triethylamine, and suitable surfactants include cationic surfactants such as alkylpyridine halides and alkylamine acetates, dimethyldialkylammonium halides ; anionic surfactants such as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates and sulfosuccinates; nonionic surfactants such as fatty amine oxides, Alkanolamide fatty acids, and poly(oxyethylene-oxypropyl) or oxyethylene or oxypropylene copolymers; and amphoteric surfactants such as 2-alkylimidazoline quaternary ammonium salts and alkyl-β-alanine salt, and mixtures thereof.

The parenteral compositions of the invention will generally contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers are also conveniently used. To minimize or eliminate irritation at the injection site, such compositions may contain a nonionic surfactant having a hydrophilic-lipophilic balance constant (HLB) of between about 12 and about 17. The level of surfactant in such dosage forms is between about 5% and about 15% by weight. The surfactant can be a single component with the above HLB or can be a mixture of two or more components with the desired HLB.

Examples of surfactants used in such parenteral dosage forms are polyethylene sorbitan fatty acid ester surfactants such as sorbitan monooleate and oxyethylene with a hydrophobic base formed by condensation of propylene glycol with propylene peroxide high molecular weight adducts.

The pharmaceutical composition may be in the form of a sterile injectable aqueous suspension. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and agents such as, for example, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, sodium alginate, polyethylene glycol, Suspending agents of pyrrolidone, tragacanth and gum arabic; dispersing or wetting agents may be natural phospholipids such as lecithin, condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, such as heptadecylethylene oxide Condensation products of oxyethylenes of hexaols with long-chain fatty alcohols, condensation products of oxyethylenes such as polyoxyethylene sorbitan monooleate with partial esters derived from fatty acids and hexitols, or, for example, polyoxyethylene sorbitan Condensation product of ethylene oxide of monooleate with partial esters derived from fatty acids and hexitol anhydrides.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents or solvents that can be used are, for example, water, Ringer's solution, isobaric dextrose solution and isobaric sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compositions of the present invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycols.

Another dosage form used in the methods of the invention employs a transdermal delivery device ("ointment"). Such transdermal ointments may be used to provide continuous or intermittent infusions of controlled amounts of the compounds described herein. The construction and use of transdermal ointments for drug delivery is well known in the art (see, eg, US Patent No. 5,023,252, issued June 11, 1991, which is incorporated herein by reference). Such ointments can be constructed for continuous, pulsatile, or on-demand drug delivery.

It may be desirable or desirable to administer the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for drug delivery is well known in the art. Direct drug delivery techniques, such as drug delivery directly to the brain, typically involve placing a drug delivery catheter in the patient's ventricular system to bypass the blood-brain barrier. One such implanted drug delivery system for delivering substances to specific anatomical regions of the body is described in US Patent No. 5,011,472, issued April 30, 1991.

Controlled-release formulations for parenteral administration include liposomes, polymer microparticles and polymer colloid formulations known in the art.

The compositions of the present invention may also contain conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, where necessary or desired. Conventional techniques for preparing such compositions in appropriate dosage forms may be employed. Such ingredients and processes include those described in the following references incorporated herein by reference: Powell, M.F. et al. Compendium of Excipients for Parenteral Formulations, PDA Journal of Pharmaceutical Science&Technology 1998,52(5),238-311; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999) - Part-l), PDA Journal of Pharmaceutical Science&Technology 1999, 53(6), 324-349; and Nenia, S. et al. "Excipients and Their Use in Injectable Products" (Excipients and Their Use in Injectable Products), PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients for which the route of administration is designed to match the dosage form of the composition include:

Acidulants (examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);

Alkalizing agents (examples include, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, ethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine);

Adsorbents (examples include, but are not limited to, powdered cellulose and activated carbon);

Aerosol propellants (examples include, but are not limited to, carbon _dioxide , CCl2F2, _{F2ClC - CClF2} , and _CClF3 );

An air displacer (examples include, but are not limited to, nitrogen and argon);

Antioxidants (examples include, but are not limited to, ascorbic acid, ascorbyl palmitate, hypophosphorous acid, thioglycerol, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallic acid, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, meta sodium bisulfite);

Antifungal preservatives (examples include, but are not limited to, benzoic acid, butylparaben, methylparaben, propylparaben, ethylparaben, sodium benzoate);

Antimicrobial preservatives (examples include, but are not limited to, benzalkonium chloride, benzethonium chloride, chlorobutanol, benzyl alcohol, phenylethyl alcohol, cetylpyridinium chloride, phenol, phenylmercuric nitrate, and thimerosal );

Buffers (examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, sodium citrate anhydrous, sodium citrate dihydrate);

Adhesive materials (examples include, but are not limited to, block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes, and styrene-butadiene copolymers);

Carriers (examples include, but are not limited to, gum arabic syrup, aroma syrup, aroma elixir, cherry syrup, orange syrup, molasses syrup, cocoa syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection, and antibacterial water for bacterial injection);

Chelating agents (examples include, but are not limited to, edetate and edetate disodium);

Colorants (examples include but are not limited to FD&C Red No.3, FD&C Red No.20, FD&C Yellow No.6, FD&C Blue No.2, D&C Green No.5, D&C Orange No.5, D&C Red No.8 , caramel and iron oxide red);

Clarifying agents (examples include, but are not limited to, gum arabic, polyethylene glycol, cetyl alcohol, glyceryl monostearate, lecithin, polysorbate monooleate, polyoxyethylene 50 monostearate );

● Capsules (examples include but are not limited to gelatin and cellulose acetate);

Flavors (examples include, but are not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil, and vanillin);

Humectants (examples include, but are not limited to, glycerin, propylene glycol, and sorbitol);

Abrasives (examples include, but are not limited to, mineral oil and glycerin);

Ointment bases (examples include, but are not limited to, lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, butter ointment, and rose-red water ointment);

Oils (examples include, but are not limited to, peanut oil, mineral oil, olive oil, peanut oil, sesame oil, and vegetable oil);

Penetration enhancers (transdermal drug delivery) (examples include but are not limited to monohydric or polyhydric alcohols, monovalent or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids , essential oils, phosphatidyl derivatives, cephalins, terpenes, amides, ethers, ketones and ureas);

Solvents (examples include, but are not limited to, ethanol, corn oil, cottonseed oil, glycerin, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, and sterile water for infusion);

- Plasticizers (examples include, but are not limited to, diethyl phthalate and glycerin);

Hardeners (examples include, but are not limited to, cetyl alcohol, cetyl esters, waxes, microcrystalline waxes, paraffin waxes, stearyl alcohol, white wax, and yellow wax);

Suppository bases (examples include, but are not limited to, cocoa butter and polyethylene glycol (mixtures));

Surfactants (examples include, but are not limited to, benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate, and sorbitan monopalmitate);

Suspending agents (examples include but are not limited to agar, bentonite, carbomer, sodium carboxyethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, kaolin, methylcellulose , tragacanth and veegum);

Sweeteners (examples include, but are not limited to, aspartame, dextrose, glycerin, mannitol, propylene glycol, sodium saccharin, sorbitol, and sucrose);

- Tablet binders (examples include, but are not limited to, gum arabic, alginic acid, sodium carboxymethylcellulose, compressible sucrose, ethylcellulose, gelatin, liquid dextrose, methylcellulose, and gelatinized starch);

- Tablet detackifiers (examples include, but are not limited to, magnesium stearate and talc);

Tablet and capsule diluents (examples include but are not limited to dicalcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol, and starch);

Tablet coatings (examples include, but are not limited to, liquid dextrose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetate, and insecticide glue);

Tablet direct compression excipients (examples include but are not limited to dicalcium phosphate);

Tablet disintegrating agents (examples include, but are not limited to, alginic acid, carmellose calcium, microcrystalline cellulose, polacrillin potassium, sodium alginate, sodium glycolate starch, and starch);

- Tablet lubricants (examples include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate);

- Tablet slip agents (examples include, but are not limited to, colloidal silicon, cornstarch, and talc);

- Tablet polishes (examples include, but are not limited to, carnauba wax and white wax);

- Tablet/capsule opacifiers (examples include but are not limited to titanium dioxide);

Thickeners (examples include, but are not limited to, beeswax, cetyl alcohol, and paraffin);

Viscosity enhancers (examples include, but are not limited to, alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, sodium alginate, and tragacanth);

Tonicity agents (examples include, but are not limited to, dextrose and sodium chloride);

- Moisturizing agents (examples include, but are not limited to, heptadecanyl ethylene cetyl alcohol, lecithin, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and polyoxyethylene stearate).

Dosage of the pharmaceutical composition of the present invention

On the basis of known routine laboratory techniques for evaluating compounds useful in the treatment of any of the above diseases, by routine toxicity testing and by routine pharmacological assays for determining efficacy in mammals for the above symptoms, and by applying Comparison of these results with those of known drugs used in the treatment of these conditions allows for the convenient determination of therapeutically effective doses of the compounds of the invention for the treatment of each desired indication. The amount of the active ingredient administered in the treatment of one of these conditions can vary widely, depending on such factors as the particular compound and dosage unit employed, the mode of administration, the duration of treatment, the age and Factors such as gender and the nature and extent of the condition being treated.

The total amount of active ingredient administered may be between about 0.01 mg/kg to about 50 mg/kg, and preferably between about 0.1 mg to about 10 mg per kilogram of body weight per day. A unit dose may preferably contain from about 1 milligram to about 300 milligrams of active ingredient and may be administered one or more times per day. The daily dosage for oral administration should preferably be between 0.1 and 5 mg per kg body weight. The daily dosage for administration by injection (including intravenous, subcutaneous, intramuscular and parenteral injection) and administration using infusion techniques should preferably be in the range of 0.1 to 5 mg per kg body weight. The daily rectal regimen should preferably be between 0.1 and 15 mg per kg body weight. The daily topical dosing regimen should preferably range from 0.1 to 5 mg/kg administered 1 to 4 times daily. The transdermal concentration should preferably be maintained at a daily dose of 0.1 to 3 mg/kg. The daily inhalation regimen should preferably be 0.1 to 5 mg per kg body weight. Other doses and quantities can be selected routinely.

The specific initial and continued dosage regimen will vary for each patient, depending on the character and severity of the condition as determined by the attending physician, the activity of the specific compound being used, the age and physical condition of the patient, the time of administration, the route, drug excretion rate, drug combination, etc. The required mode of treatment and the number of doses of the compounds of this invention, or pharmaceutically acceptable salts or compositions thereof, can be determined by those skilled in the art using routine therapeutic testing.

Combination with other active ingredients

The compounds of the present invention may be administered as a single agent or in combination with one or more other agents, wherein said combination does not cause unacceptable deleterious effects. This may be especially useful for treating hyperproliferative diseases such as cancer. In this case, the compounds according to the invention can be used in combination with known cytotoxic agents, signal transduction inhibitors, or with other antineoplastic substances and mixtures and compositions thereof.

In one embodiment, the compounds according to the invention may be used in combination with cytotoxic antineoplastic substances. Examples of such substances can be found in the 11th edition of the Merck Index (1996). These substances include, but are not limited to, asparaginase, L-asparaginase, bleomycin, carboplatin, cisplatin, nitrogen mustard, carmustine, chlorambucil, cyclophosphamide, cytarabine, Dacarbazine, actinomycin D, daunorubicin, epirubicin, doxorubicin, etoposide, 6-mercaptopurine, methotrexate, 5-fluorouracil, hexamethylmelamine, hydroxyurea, heterocyclic Phosphoramide, leucovorin, lomustine, mesna, mitomycin C, mitoxantrone hydrochloride, procarbazine, raloxifene, streptozotocin, tamoxifen, sulfur Guanine, topotecan, irinotecan, prednisolone, prednisone, vinblastine, vincristine, vindesine.

Other cytotoxic drugs suitable for use in combination with the compounds of the present invention include, but are not limited to, those described in The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill) by Goodman and Oilman. Those compounds recognized as above for the treatment of neoplastic diseases. These substances include, but are not limited to, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine Glycoside, plicamycin, docetaxel, erythroxynonyl adenine, estriol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, fluoride Hetamide, hydroxyprogesterone caproate, paclitaxel, daunorubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, N-phosphoacetyl-L - Aspartate (PALA), pentostatin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uracil, and vinorelbine.

Other cytotoxic antineoplastic substances suitable for use in combination with the compounds of the present invention also include newly discovered cytotoxic agents such as gemcitabine, capecitabine, epothilone, oxaliplatin and their natural and synthetic derivatives , temozolomide, tositumomab (Bexxar), trabedectin, and inhibitors of the kinesin spindle protein Eg5.

In another embodiment, the compounds of the invention may be used in combination with other signal transduction inhibitors. Of particular interest are signal transduction inhibitors directed against the EGFR family (such as EGFR, HER-2 and HER-4) and their respective ligands. Examples of such substances include, but are not limited to, antibody drugs such as Herceptin (trastuzumab), Erbitux (cetuximab), and pertuzumab. Examples of such drugs also include, but are not limited to, small molecule kinase inhibitors such as ZD-1839/Iressa, CM033, OSI-774/Tarceva, CP-724,714, EKB-569, and GW-2016.

The compounds of the present invention have a series of advantages over compounds known in the prior art which do not carry deuterium. The main advantages of the present invention include:

(1) The compounds of the present invention have excellent inhibitory activity against tyrosine kinases such as c-Met.

(2) Compared with non-deuterated compounds, the compounds of the present invention are less likely to be metabolized in animals, which leads to a reduction in the first-pass effect, so the dosage can be changed and a long-acting preparation can be formed, which can also be long-acting The form of the formulation improves applicability.

(3) The pharmacokinetic effect is also changed by deuteration, so that the distribution of the compound of the present invention in the living body is obviously different from that of the non-deuterated compound.

(4) The compound of the present invention has a higher drug concentration in the animal body, thereby improving the drug effect.

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.

Example 1 3-[(2-Deuterium-6-quinolyl)difluoromethyl]-6-[(1-methyl)-4-pyrazolyl][1,2,4]triazolo[ Preparation of 4,3-b]pyridazine(Ⅱ)

Step 1: 6-Bromoquinoline-1-oxo(III)

Dissolve 20 grams of 6-bromoquinoline in 200 milliliters of dichloromethane, add dropwise a solution of 21.5 grams of m-chloroperoxybenzoic acid in 200 milliliters of dichloromethane under stirring in an ice bath, and stir overnight at room temperature after the addition is complete. The reaction solution was washed with saturated sodium thiosulfate solution, and the organic phase was concentrated to dryness to obtain 19.4 g of a light brown solid with a yield of 90%. ¹ H-NMR (300Hz, DMSO-d ₆ ) δ: 8.63 (d, J=6.3Hz, 1H), 8.42-8.47 (m, 2H), 7.89-7.96 (m, 2H), 7.51-7.56 (m, 1H).

Step 2: 2-Deuterium-6-bromoquinoline-1-oxo(IV)

A mixture of 10 g of 6-bromoquinoline-1-oxo, 10.7 g of sodium tert-butoxide and 33 ml of deuterium water was heated in an oil bath at 100°C for 12 hours. The reaction solution was cooled to room temperature, extracted with dichloromethane, and the organic layer was concentrated to dryness to obtain 6.7 g of light yellow solid, with a yield of 67%. ¹ H-NMR (300Hz, DMSO-d ₆ ) δ: 7.55 (d, J=8.4Hz, 1H), 7.89-7.97 (m, 2H), 8.42-8.47 (m, 2H). LRMS (ESI) m/ z[M+H] ⁺ :225.3.

Step 3: 2-Deuterium-6-bromoquinoline (Ⅴ)

Dissolve 4 g of 2-deuterium-6-bromoquinoline-1-oxygen in 70 ml of glacial acetic acid, add 8 g of iron powder in batches, and heat to reflux for 3 hours. The reaction solution was concentrated to dryness, the residue was dissolved in water, adjusted to pH = 8 with solid sodium carbonate, extracted with dichloromethane, and the organic layer was concentrated to dryness to obtain 2.5 g of a light brown oil, with a yield of 67%. ¹ H-NMR (300Hz, CDCl ₃ ) δ: 8.10(d, J=8.1Hz, 1H), 7.97-8.00(m, 2H), 7.81(dd, J=2.4, 9.0Hz, 1H), 7.45(d ,J＝8.7Hz,1H).

Step 4: 2-Deuterium-6-iodoquinoline (VI)

1 g of 2-deuterium-6-bromoquinoline, 182 mg of cuprous iodide, 1.43 g of sodium iodide, 0.22 ml of N,N-dimethylethylenediamine, and 10 ml of 1,4-dioxane The mixture was refluxed overnight. The reaction liquid was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate, and the filtrate was concentrated to dryness to obtain 1.1 g of light yellow solid with a yield of 90%. ¹ H-NMR (300Hz, CDCl ₃ ) δ: 8.23(s, 1H), 8.07(d, J=8.1Hz, 1H), 7.97(dd, J=1.2, 8.7Hz, 1H), 7.86(d, J ＝8.7Hz, 1H), 7.44(d, J＝8.4Hz, 1H).

Step 5: 2-(2-Deuterium-6-quinolyl)-2,2-difluoroacetylhydrazide (VII)

3 g of 2-deuterium-6-iodoquinoline, 3 ml of ethyl difluorobromoacetate, 2.08 g of nano-copper powder, and 30 ml of dimethyl sulfoxide were heated and stirred at 80° C. overnight. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, and the organic layer was concentrated to dryness to obtain a brown oil.

The brown oil obtained above was dissolved in 30 ml of methanol, 0.7 ml of hydrazine hydrate (85%) was added, and reacted at 80° C. for 1 hour, the reaction solution was concentrated to dryness, and the residue was subjected to column chromatography to obtain 1.1 g of a light yellow solid. Yield 39.4%. ¹ H-NMR (300Hz, DMSO-d ₆ )δ: 10.39(br s, 1H), 8.57(d, J=8.4Hz, 1H), 8.28(s, 1H), 8.18(d, J=8.7Hz, 1H), 7.92(dd, J=1.8, 8.7Hz, 1H), 7.66(d, J=8.4Hz, 1H), 4.73(br s, 2H)

Step 6: 3-[(2-Deuterium-6-quinolinyl)difluoromethyl]-6-[(1-methyl)-4-pyrazolyl][1,2,4]triazolo[ 4,3-b]pyridazine(Ⅱ)

3 grams of 2-(2-deuterium-6-quinolinyl)-2,2-difluoroacetylhydrazide, 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine 1.64 gram, 1.5 grams of methanesulfonic acid, and 33 milliliters of n-butanol were placed in a sealed tube, heated and stirred at 90°C overnight. The reaction solution was concentrated to dryness, dissolved in water, adjusted to pH=8 with ammonia water, extracted with dichloromethane, the organic layer was concentrated to dryness, and the residue was subjected to column chromatography to obtain 2.5 g of a yellow solid with a yield of 79%. ¹ H-NMR (300Hz, CDCl ₃ ) δ: 8.24-8.28(m, 3H), 8.16(d, J=10.0Hz, 1H), 8.09(dd, J=2.0, 8.8Hz, 1H), 7.98(d ,J=9.6Hz,2H),7.51(d,J=8.4Hz,1H),7.42(d,J=9.6Hz,1H),4.01(s,3H).LRMS(EI)m/z[M] ⁺ :378.

Example 2 Metabolism of compound II in monkey liver S9

The total volume of each in vitro incubation system is 200 μL, the medium is 100 mM phosphate buffer (PBS, pH 7.4), including JNJ38877605 or compound II and 2 mM NADPH at a final concentration of 3 μM, and incubated in a 37°C water bath. After 3 minutes of pre-incubation, monkey liver S9 protein was added to the buffer-substrate-cofactor mixture to initiate the reaction, and after 60 minutes of reaction, the same volume of ice-cold acetonitrile was added to terminate the reaction. The experimental conditions of the control group were the same as above, but NADPH was replaced by PBS; in addition, in the blank control group, the S9 protein was inactivated by high temperature. All incubation samples were double samples.

Take 200 μL of each of the two samples and combine them, add 400 μL of acetonitrile, vortex for 1 min, centrifuge for 5 min (14000 rpm), take out all the supernatant, transfer it to a 10 mL plastic tube, dry it under nitrogen flow at 40 °C, and wash the residue with 80 μL of acetonitrile-water ( 10:90, v/v) was dissolved, and 10 μL was taken for UPLC-UV/Q-TOF MS analysis.

The possible metabolites of JNJ38877605 and compound Ⅱ monkey liver S9 incubation system were identified by UPLC-UV/Q-TOF MS, and the results showed that the proportion of the prototype drug of compound Ⅱ was 31.8% higher than that of JNJ38877605. It shows that the pharmacokinetic properties of compound Ⅱ are obviously better than JNJ38877605.

Example 3 Compound II Pharmacokinetics Test in Cynomolgus Monkeys After Oral Administration

Four cynomolgus monkeys were given the test compound by intragastric administration, and the specific arrangements were as follows:

Before administration (0h) and after administration at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12 and 24h, 0.8mL of venous blood was taken from the veins of the extremities, placed in an EDTA anticoagulant test tube, centrifuged at 3500rpm for 10min, and the plasma was separated at -70 ℃ refrigerator for storage until testing.

The concentration in plasma was determined by LC/MS/MS method, and the possible metabolites in plasma and urine were identified by UPLC-Q/TOF-MS method.

The non-compartmental model of WinNonlin 6.3 software (Pharsight, USA) was used to calculate the pharmacokinetic parameters after administration.

Figure 1 shows the plasma concentration-time curves of cynomolgus monkeys administered 10 mg/kg compound II and JNJ38877605 respectively.

After intragastric administration, the exposure C _max and AUC _0-t of compound II in cynomolgus monkeys were 1.56 times and 2.29 times that of JNJ38877605, respectively.

It can be seen from the above results that the compound of the present invention has better pharmacokinetics in animals, and thus will have better pharmacodynamics and therapeutic effects.

Example 4 The growth inhibitory effect of compound II on human lung cancer EBC-1 subcutaneously transplanted tumor in nude mice

BALB/cA nude mice. Number of animals in each group: 6 in the negative control group and 6 in the treatment group.

The human lung cancer EBC-1 cell line was inoculated subcutaneously in the right armpit of nude mice, and the cell inoculation amount was 5×10 ⁶ /mouse. After forming transplanted tumors, they were passed in nude mice for one generation before use.

The tumor tissue in the vigorous growth stage was cut into about 1.5 mm ³ , and inoculated subcutaneously in the right armpit of nude mice under sterile conditions. The diameter of the subcutaneous transplanted tumor in nude mice was measured with a vernier caliper, and the animals were randomly divided into groups after the average volume of the tumor grew to about 176 mm ³ . Compound II and JNJ38877605 were administered at a dose of 5 mg/kg orally twice a day for 21 consecutive days. The solvent control group was given the same amount of solvent. During the whole experiment, the diameter of the transplanted tumor was measured twice a week, and the body weight of the mice was weighed at the same time. The formula for calculating tumor volume (TV) is: TV=1/2×a×b ² , where a and b represent length and width, respectively. The relative tumor volume (RTV) was calculated according to the measurement results, and the calculation formula was: RTV=V _t /V ₀ . Wherein, V ₀ is the tumor volume measured during administration in separate cages (ie, d ₀ ), and V _t is the tumor volume at each measurement.

The evaluation index of antitumor activity is:

1) Relative tumor proliferation rate T/C (%), the calculation formula is as follows: T/C (%)=(T _RTV /C _RTV )×100%, T _RTV : treatment group RTV; C _RTV : negative control group RTV;

2) Tumor volume growth inhibition rate GI%, the calculation formula is as follows: TGI%=[1-(TV _t -TV ₀ )/(CV _t -CV ₀ )]×100%, TV _t is the tumor volume measured each time in the treatment group Volume; TV ₀ is the tumor volume obtained when the treatment component is administered in cages; CV _t is the tumor volume measured each time in the control group; CV ₀ is the tumor volume obtained when the control group is administered in cages;

3) Tumor weight inhibition rate, the calculation formula is as follows: tumor weight inhibition rate %=(W _C -W _T )/W _C ×100%, W _C : tumor weight in the control group, W _T : tumor weight in the treatment group.

The experimental results are shown in Figure 2. Compound Ⅱ and JNJ38877605 at a dose of 5 mg/kg, orally administered twice a day for 21 consecutive days, had extremely significant inhibitory effects on the growth of human lung cancer EBC-1 subcutaneously transplanted tumors in nude mice. Among them, the T/C percentage obtained by compound II on the 21st day was 9.98%, and the tumor growth inhibition rate (TGI) was 90.4%, while the T/C percentage obtained by JNJ38877605 on the 21st day was 21.56%, and the tumor growth inhibition rate (TGI) was 83.8%. . During the experimental treatment, the mice in each administration group were in good condition.

Embodiment 5 pharmaceutical composition

pill

The above-mentioned substances were mixed uniformly, and 1000 tablets were prepared by conventional techniques. Appropriate aqueous or non-aqueous coatings may be used to enhance palatability, improve appearance and stability or delay absorption.

capsule

Compound II (Example 1) 30g

Starch 140g

Microcrystalline Cellulose 60g

According to the conventional method, the above-mentioned substances were mixed evenly, and packed into ordinary gelatin capsules to prepare 1000 capsules.

sterile IV the solution

Compound II (Example 1) 0.2g

Sterile Water for Injection 50mL

Compound II was prepared into a 4 mg/ml solution with sterile water for injection and the pH was adjusted as necessary. Dilute with 5% sterile dextrose to 1.5-2.0 mg/ml for intravenous infusion.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (10)

1. A compound shown in the following formula (I): In the formula: D represents a deuterium atom; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , and R ₉ are each independently a hydrogen atom or a deuterium atom; R ₁₀ is selected from the group consisting of CH ₃ , CH ₂ D, CHD ₂ , or CD ₃ . 2. The compound of claim 1, wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , and R ₉ are all hydrogen atoms; R ₁₀ is CH ₃ . 3. A method for preparing a pharmaceutical composition, characterized in that it comprises the step of: mixing a pharmaceutically acceptable carrier with the compound according to claim 1 or 2, or its crystal form, pharmaceutically acceptable salt, or hydrate or solvates are mixed to form a pharmaceutical composition. 4. A pharmaceutical composition, characterized in that it comprises: a therapeutically effective amount of the compound of formula I according to claim 1 or 2, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate; and pharmaceutically acceptable carrier. 5. pharmaceutical composition as claimed in claim 4, is characterized in that, comprises the compound of formula II of therapeutically effective dose i.e. 3-[(2-deuterium-6-quinolyl) difluoromethyl]-6-[( 1-methyl)-4-pyrazolyl][1,2,4]triazolo[4,3-b]pyridazine, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate : and a pharmaceutically acceptable carrier. 6. The pharmaceutical composition according to claim 4 or 5, characterized in that, the pharmaceutical composition also includes other active ingredients in a therapeutically effective amount, and the other active ingredients include one selected from the following group or multiple active ingredients: cytotoxic agents, signal transduction inhibitors, and other antineoplastic substances. 7. A compound of formula (I) as claimed in claim 1, or the use of its crystal form, pharmaceutically acceptable salt, hydrate or solvate, characterized in that it is used for the preparation of therapeutic tyrosine kinase , especially pharmaceutical compositions for c-Met mediated diseases. 8. The use according to claim 7, wherein the disease is selected from the group consisting of papilloma, budding glioma, melanoma, lung cancer, ovarian cancer, prostate cancer, squamous cell Carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer, breast cancer, colorectal cancer, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, hemangioma, keloid, respiratory tract cancer, brain cancer, Reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and its distant metastases, lymphoma, sarcoma, colon cancer, bone cancer, kidney cancer, testicular cancer cancer, skin cancer, renal cell carcinoma, non-small cell lung cancer. 9. A preparation of formula II compound 3-[(2-deuterium-6-quinolyl) difluoromethyl]-6-[(1-methyl)-4-pyrazolyl] according to claim 2 [1,2,4]triazolo[4,3-b]pyridazine method, It is characterized in that, comprising steps: In an organic solvent, the compound of the formula (VII) and the compound of the formula (VIII) are used for ring-closing reaction to obtain the compound of the formula (II). 10. The method of claim 9, wherein the compound of formula (VII) is prepared by the following method: In an organic solvent, the compound of formula (VI) is reacted with ethyl difluorobromoacetate and hydrazine hydrate to obtain the compound of formula (VII).