WO2018095353A1

WO2018095353A1 - Salts of aminoquinazoline derivative and uses thereof

Info

Publication number: WO2018095353A1
Application number: PCT/CN2017/112553
Authority: WO
Inventors: Bing Liu; Liang Chen; Weihong Zhang; Yingjun Zhang
Original assignee: Sunshine Lake Pharma Co., Ltd.
Priority date: 2016-11-25
Filing date: 2017-11-23
Publication date: 2018-05-31
Also published as: CN108148071B; TW201818941A; CN108148071A

Abstract

Provided are salts of aminoquinazoline derivative, pharmaceutical compositions containing the salts or a combination thereof, and uses of the salts or the pharmaceutical compositions in the manufacture of a medicament for the treatment and prevention of proliferative diseases.

Description

SALTS OF AMINOQUINAZOLINE DERIVATIVE AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority and benefits of Chinese Patent Application No. 201611050237.6, filed with State Intellectual Property Office on 25 November 2016, the entire content of which is incorporated herein by reference.

FIELD

The invention belongs to the field of medicine, and relates to salts of aminoquinazoline derivative and uses thereof, particularly relates to a salt of (E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4aR, 7aS) -tetra hydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide and uses thereof, and further relates pharmaceutical compositions containing the salt. The salt or the pharmaceutical compositions can be used as a tyrosine kinase inhibitor for the treatment and prevention of proliferative diseases.

BACKGROUND

Protein kinases (PKs) represent a large class of proteins which play important roles in the control of cell function and the regulation of various cell diseases, and can be divided into two categories: protein tyrosine kinases (PTKs) and serine threonine kinases (STKs) . Protein tyrosine kinase is a kind of enzyme that can catalyze and transfer a phosphate group from ATP to a tyrosine residue of a protein substrate, which plays a role in normal cell growth. Many growth factor receptor proteins act through tyrosine kinases, which influence signals transduction, and then regulate cell growth. However, under certain conditions, these receptors mutate or overexpress, and become abnormal, which cause cell proliferation to be uncontrolled, lead to tumor growth, eventually lead to well-known disease-cancer. Growth factor receptor protein tyrosine kinase inhibitors play a role in the treatment of cancer and other disorders characterized by uncontrolled or abnormal cell growth by inhibiting the above phosphorylation process.

An epidermal growth factor receptor (EGFR) is a receptor type tyrosine kinase that is widely distributed on the cell membranes of human body tissues, and is an oncogene analog of avian erythroblastic leukemia viral (v-erb-b) . EGFR/HER1/ErbB-1 and HER2 (human epidermal growth factor receptor-2) /ErbB-2/Teu/p185, HER3/ErbB-3, HER4/ErbB-4 and the like are grouped into the HER/ErbB family, and belong to protein tyrosine kinases (PTKs) . They are each a single polypeptide chain, and respectively encoded by genes located on different chromosomes. EGFR and the like overexpress in the epithelia-derived tumors such as squamous cell carcinoma of head and neck, mammary cancer, rectal cancer, ovarian cancer, prostate carcinoma, non-small cell lung cancer, and the like. Their expression is related to cancer cell proliferation and metastasis. Pan-HER tyrosine kinase inhibitors inhibit the activation of the HER-2 family by competitively with ATP binding to the intracellular kinase catalytic site, blocking the autophosphorylation of intracellular tyrosine and blocking tyrosine kinase activation, thereby play a therapeutic role by inhibiting cell cycle progression and accelerating apoptosis .

An EGFR binds to a ligand, forms a dimer with the HER family subtype, and then binds to ATP to activate EGFR's own tyrosine kinase activity, causes autophosphorylation of several tyrosine sites in the intracellular kinase domain. Pan-HER tyrosine kinase inhibitors play an important role in inhibiting tumor growth by simultaneously acting on EGFR and HER2/4 and inhibiting the HER family activation.

Studies have shown that Pan-HER tyrosine kinase irreversible inhibitors, in addition to an effective inhibition on EGFR, have an inhibition effect on HER2/4. These drugs that have irreversible inhibitory effects on the HER/ErbB family can improve drug activity, also reduce the generation of drug resistance, and have a significant inhibitory effect on Erlotinib-resistant H1975 cell line.

The mutations of the EGFR gene often occurred in the Tyrosin kinase coding region (TK, 18-21 exon) , which are mainly drug-sensitive 19 exon deletion mutations and 21 exon point mutations, as well as a few 18 exon point mutations and 20 exon insertion mutations. T790M mutation is a point mutation in EGFR 20 exon, which is one of the more recognized drug resistance mechanisms. The main mechanism is that secondary mutation of threonine residue 790 region, the threonine residue converts into methionine (T790M) . The mutation leads to changes in EGFR structure, hinders the binding of EGFR to its inhibitors or greatly increases the affinity of EGFR and ATP, and the ATP affinity is restored to the EGFR wild level, which leads to resistance. Further studies have shown that pre-treatment EGFR mutant tumor samples also contain T790M mutation, which indicates that T790M mutation is not only related to drug resistance, but may also have carcinogenic potential.

Irreversible inhibitors can covalently bind to EGFR tyrosine kinases, so that the drugs can act on the entire process of the epidermal growth factor signal transduction pathway and increase the blocking efficiency of the drugs. Many clinical studies have shown that the current development of irreversible inhibitors can against T790M mutation, which can overcome the resistance caused by T790M.

Patent applications WO 2014/177038 and CN 104119350 discloses aminoquinazoline tyrosine kinase inhibitors with irreversible inhibition effect on Pan-HER, wherein the compound (E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4aR, 7aS) -tetra hydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide (i.e. compound (I) ) has an excellent antitumor effect. It can reduce the generation of drug resistance and also have good tolerance.

Drug polymorphism is a common phenomenon in drug development, which is an important factor affecting the quality of drugs. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and may have different effects on the stability, bioavailability and efficacy of the drug. Therefore, the drug polymorphism should be fully considered in drug research and development.

Amorphism is a form of polymorphism occurred in substance, which is a non-crystal state. The various physical and chemical properties and clinical efficacy characteristics of amorphous drugs are often different from the general crystalline drugs. Therefore, the in-depth study of amorphous substances also has great significance in the solid drug polymorphic study.

SUMMARY

(E) -N- (4- (3-Chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4a R, 7aS) -tetrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide (compound (I) ) is a brown solid, in order to improve the stability and bioavailability of the compound, the present invention has studied the salt of compound (I) and the crystalline form thereof. Furthermore, a pharmaceutically acceptable acid addition salt of compound (I) and a composition thereof are provided herein, which have good biological activity, less toxic side effects and better stability, and thus have a more excellent druggability.

To be more specific, the present invention relates to acid addition salts of compound (I) and pharmaceutical compositions thereof, and use of salts or pharmaceutical compositions in the manufacture of a medicament for the treatment or prevention of a proliferative disease. The acid addition salts disclosed herein may be crystalline form, partially crystalline form, polymorphism or amorphous forms; in another aspect, the acid addition salts disclosed herein may also be in the form of solvates, such as hydrate forms.

In one aspect, the present invention provides a pharmaceutically acceptable acid addition salt of compound (I) ,

In some embodiments, the acid addition salt disclosed herein is an addition salt formed by a reaction of compound (I) with an inorganic acid.

In other embodiments, the inorganic acid disclosed herein is hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, carbonic acid, sulfurous acid, pyrosulfuric acid, phosphoric acid, perchloric acid, peroxosulfuric acid, thiocyanic acid, pyrophosphoric acid, metaphosphoric acid or a combination thereof.

In some embodiments, the acid addition salt disclosed herein is an addition salt formed by a reaction of compound (I) with an organic acid.

In other embodiments, the organic acid disclosed herein is formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, malonic acid, succinic acid, pyruvic acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, citric acid, 4-nitrobenzoic acid, benzenesulfonic acid, p-toluenesulfonic acid, malic acid, L-malic acid, propiolic acid, 2-tetrolic acid, vinylacetic acid, tartaric acid, L-tartaric acid, fumaric acid, hydroxyethyl-sulfonic acid, maleic acid, lactic acid, lactobionic acid, pamoic acid, salicylic acid, galactaric acid, glucoheptonic acid, mandelic acid, 1, 2-ethanedisulfonic acid, naphthalene sulfonic acid, oxalic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, adipic acid, octanedioic acid, sebacic acid, butyne-1, 4-dioic acid, hexyne-1, 6-dioic acid, glycolic acid, alginic acid, ascorbic acid, isoascorbic acid, aspartic acid, L-aspartic acid, glutamic acid, L-glutamic acid, 2-phenoxybenzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, acetoacetic acid, boric acid, chlorinated benzoic acid, camphanic acid, itaconic acid, camphor sulfonic acid, L-camphor sulfonic acid, methyl benzoic acid, dinitrobenzoic acid, sulfamic acid, galacturonic acid acid, cyclopentyl propionic acid, dodecyl sulfuric acid, acrylic acid, cyclopentane propionic acid, glycerophosphoric acid, methoxybenzoic acid, glucose diacid, gluconic acid, heptanoic acid, caproic acid, trimethylacetic acid, glucuronic acid, lauric acid, phthalic acid, phenylacetic acid, lauryl sulfuric acid, 2-acetoxylbenzoic acid, nicotinic acid, cinnamic acid, oleic acid, palmitic acid, pectic acid, phthalic acid, glutaric acid, hydroxyl maleic acid, hydroxybenzoic acid, 3-hydroxy-2-naphthoic acid, 3-phenylpropionic acid, isobutyric acid, neopentanoic acid, picric acid, stearic acid, 2, 2-dichloroacetic acid, acylated amino acid, alginic acid, 4-acetyl aminobenzene sulfonic acid, canoic acid, cholic acid, octanoic acid, nonanoic acid, cyclamic acid, phthalic acid, cysteine hydrochloride, sorbic acid, palmoxiric acid, glycine, naphthalene disulfonic acid, xylenesulfonic acid, cystine dihydrochloride, undecanoic acid, polyethylenesulphonate, sulfosalicylic acid, phenylbutyric acid, 4-hydroxybutyric acid, polyvinyl sulfuric acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, valeric acid or a combination thereof.

In some embodiments, the acid addition salt disclosed herein, wherein the salt is mesylate obtained by reacting compound (I) with methanesulfonic acid. In some embodiments, the acid addition salt of disclosed herein is mesylate of compound (I) , wherein a molar ratio of compound (I) to methanesulfonic acid of the salt is 1: 2. In other embodiments, the acid addition salt disclosed herein is dimesylate of compound (I) having a structure as shown in formula (II) .

In some embodiments, the acid addition salt disclosed herein is dimesylate having crystalline form A of compound (I) exhibiting the characteristic X-ray powder diffraction peaks expressed as 2θ at 18.76±0.2°, 18.99±0.2°, 19.17±0.2°, 23.33±0.2°, 26.56±0.2°.

In some embodiments, the acid addition salts disclosed herein is dimesylate having crystalline form A of compound (I) exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 16.52± 0.2°, 18.10± 0.2°, 18.76 ± 0.2°, 18.99 ± 0.2°, 19.17 ± 0.2°, 19.91 ±0.2°, 20.41 ± 0.2°, 23.33 ± 0.2°, 23.81 ± 0.2°, 26.56 ± 0.2°, 28.22 ± 0.2°.

In some embodiments, the acid addition salts disclosed herein is dimesylate having crystalline form A of compound (I) exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 5.51 ± 0.2°, 6.60 ± 0.2°, 7.64 ± 0.2°, 9.45 ± 0.2°, 11.60 ± 0.2°, 12.01 ± 0.2°, 13.18 ± 0.2°, 14.02 ± 0.2°, 14.87 ± 0.2°, 15.36 ± 0.2°, 16.52 ± 0.2°, 17.50 ± 0.2°, 17.68 ± 0.2°, 18.10 ± 0.2°, 18.76 ± 0.2°, 18.99 ± 0.2°, 19.17 ± 0.2°, 19.91 ± 0.2°, 20.41 ± 0.2°, 21.86 ± 0.2°, 22.16 ± 0.2°, 22.37 ± 0.2°, 22.64 ± 0.2°, 23.33 ± 0.2°, 23.81 ± 0.2°, 24.64 ± 0.2°, 24.88 ± 0.2°, 25.68 ± 0.2°, 26.56 ± 0.2°, 27.06 ± 0.2°, 27.66 ± 0.2°, 28.22 ± 0.2°, 29.91 ± 0.2°, 30.58 ± 0.2°, 30.99 ± 0.2°, 31.81 ± 0.2°, 32.89 ± 0.2°, 33.46 ± 0.2°, 34.20 ± 0.2°, 34.97 ± 0.2°, 35.46 ± 0.2°, 36.79 ± 0.2°, 37.61 ± 0.2°, 38.47 ± 0.2°, 39.63 ± 0.2°.

In some embodiments, the acid addition salts disclosed herein is dimesylate having crystalline form A of compound (I) having a differential scanning calorimetry thermogram comprising endothermic peak at 151.30 ℃ ± 3 ℃.

In some embodiments, the acid addition salts disclosed herein is dimesylate having crystalline form A of compound (I) having an X-ray powder diffraction pattern substantially as shown in figure 1.

In some embodiments, the acid addition salts disclosed herein is dimesylate having crystalline form A of compound (I) having a differential scanning calorimetry thermogram substantially as shown in figure 2.

In some embodiments, the acid addition salts disclosed herein is dimesylate having crystalline form B of compound (I) exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 6.63 ± 0.2°, 17.80 ± 0.2°, 18.15 ± 0.2°, 19.26 ± 0.2°, 23.41 ± 0.2°.

In some embodiments, the acid addition salts disclosed herein is dimesylate having crystalline form B of compound (I) exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 6.43± 0.2°, 6.63± 0.2°, 17.50 ± 0.2°, 17.80 ± 0.2°, 18.15 ± 0.2°, 18.45 ± 0.2°, 19.26 ± 0.2°, 19.55 ± 0.2°, 20.81 ± 0.2°, 23.41 ± 0.2°, 26.69 ± 0.2°.

In some embodiments, the acid addition salts disclosed herein is dimesylate having crystalline form B of compound (I) exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 5.64 ± 0.2°, 5.93 ± 0.2°, 6.43 ± 0.2°, 6.63 ± 0.2°, 7.22 ± 0.2°, 7.67 ± 0.2°, 10.80 ± 0.2°, 11.29 ± 0.2°, 11.62 ± 0.2°, 12.02 ± 0.2°, 12.80 ± 0.2°, 13.21 ± 0.2°, 14.09 ± 0.2°, 14.56 ± 0.2°, 16.15 ± 0.2°, 16.55 ± 0.2°, 16.96 ± 0.2°, 17.50 ± 0.2°, 17.80 ± 0.2°, 18.15 ± 0.2°, 18.45 ± 0.2°, 18.77 ± 0.2°, 19.26 ± 0.2°, 19.55 ± 0.2°, 19.95 ± 0.2°, 20.43 ± 0.2°, 20.81 ± 0.2°, 21.40 ± 0.2°, 21.89 ± 0.2°, 22.76 ± 0.2°, 23.41 ± 0.2°, 24.35 ± 0.2°, 25.09 ± 0.2°, 25.68 ± 0.2°, 26.69 ± 0.2°, 28.34 ± 0.2°, 29.55 ± 0.2°, 30.07 ± 0.2°, 31.68 ± 0.2°, 32.63 ± 0.2°.

In some embodiments, the acid addition salts disclosed herein is dimesylate having crystalline form B of compound (I) having a differential scanning calorimetry thermogram comprising endothermic peaks at 138.86 ℃ ± 3 ℃ and 185.77 ℃ ± 3 ℃.

In some embodiments, the acid addition salts disclosed herein is dimesylate having crystalline form B of compound (I) having an X-ray powder diffraction pattern substantially as shown in figure 3.

In some embodiments, the acid addition salts disclosed herein is dimesylate having crystalline form B of compound (I) having a differential scanning calorimetry thermogram substantially as shown in figure 4.

In some embodiments, the acid addition salt disclosed herein is maleate obtained by reacting compound (I) with maleic acid. In some embodiments, the acid addition salt disclosed herein is maleate of compound (I) , wherein the molar ratio of compound (I) to maleic acid is 1: 2. In other embodiments, the acid addition salt disclosed herein is a dimaleate of compound (I) having a structure as shown in formula (III) .

In some embodiments, the acid addition salts disclosed herein is dimaleate having crystalline form A of compound (I) exhibiting the characteristic X-ray powder diffraction peaks expressed as 2θ at 20.62 ± 0.2°, 21.59 ± 0.2°, 21.98 ± 0.2°, 23.26 ± 0.2°, 25.86 ± 0.2°, 28.04 ± 0.2°.

In some embodiments, the acid addition salts disclosed herein is dimaleate having crystalline form A of compound (I) exhibiting the characteristic X-ray powder diffraction peaks expressed as 2θ at 19.67 ± 0.2°, 20.18 ± 0.2°, 20.62 ± 0.2°, 21.59 ± 0.2°, 21.98 ± 0.2°, 22.84 ±0.2°, 23.26 ± 0.2°, 24.07 ± 0.2°, 25.86 ± 0.2°, 28.04 ± 0.2°.

In some embodiments, the acid addition salts disclosed herein is dimaleate having crystalline form A of compound (I) exhibiting the characteristic X-ray powder diffraction peaks expressed as 2θ at 7.13 ± 0.2°, 8.97 ± 0.2°, 10.73 ± 0.2°, 12.38 ± 0.2°, 14.14 ± 0.2°, 14.35 ± 0.2°, 14.80 ± 0.2°, 15.33 ± 0.2°, 15.59 ± 0.2°, 16.29 ± 0.2°, 16.48 ± 0.2°, 16.74 ± 0.2°, 17.83 ± 0.2°, 18.05 ± 0.2°, 18.65 ± 0.2°, 19.03 ± 0.2°, 19.67 ± 0.2°, 20.18 ± 0.2°, 20.62 ± 0.2°, 21.00 ± 0.2°, 21.59 ± 0.2°, 21.98 ± 0.2°, 22.84 ± 0.2°, 23.26 ± 0.2°, 23.53 ± 0.2°, 24.07 ± 0.2°, 24.53 ± 0.2°, 24.88 ± 0.2°, 25.50 ± 0.2°, 25.86 ± 0.2°, 26.29 ± 0.2°, 26.71 ± 0.2°, 27.21 ± 0.2°, 28.04 ± 0.2°, 28.49 ± 0.2°, 28.86 ± 0.2°, 29.40 ± 0.2°, 30.18 ± 0.2°, 31.32 ± 0.2°, 31.62 ± 0.2°, 32.53 ± 0.2°, 33.43 ± 0.2°, 34.36 ± 0.2°, 34.74 ± 0.2°, 35.14 ± 0.2°, 36.21 ± 0.2°, 36.80 ± 0.2°, 37.76 ± 0.2°.

In some embodiments, the acid addition salts disclosed herein is dimaleate having crystalline form A of compound (I) having a differential scanning calorimetry thermogram comprising an endothermic peak at 192.25 ℃ ± 3 ℃.

In some embodiments, the acid addition salts disclosed herein is dimaleate having crystalline form A having an X-ray powder diffraction pattern substantially as shown in figure 5.

In some embodiments, the acid addition salts disclosed herein is dimaleate having crystalline form A having a differential scanning calorimetry thermogram substantially as shown in figure 6.

In some embodiments, the acid addition salts disclosed herein is dimaleate having crystalline form A, wherein TGA test shows its weight loss is about 0.48%. In some embodiments, the acid addition salts disclosed herein is dimaleate having crystalline form A having a thermogravimetric analysis (TGA) pattern substantially as shown in figure 10.

In some embodiments, the acid addition salts disclosed herein is dimaleate having crystalline form B exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 16.29 ± 0.2°, 26.06 ± 0.2°, 27.65 ± 0.2°, 28.35 ± 0.2°.

In some embodiments, the acid addition salts disclosed herein is dimaleate having crystalline form B exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 8.10 ± 0.2°, 12.58 ± 0.2°, 16.29 ± 0.2°, 18.65 ± 0.2°, 19.07 ± 0.2°, 22.46 ± 0.2°, 26.06 ± 0.2°, 27.65 ± 0.2°, 28.35 ± 0.2°.

In some embodiments, the acid addition salts disclosed herein is dimaleate having crystalline form B exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 5.58 ± 0.2°, 8.10 ± 0.2°, 10.47 ± 0.2°, 11.82 ± 0.2°, 12.58 ± 0.2°, 13.07 ± 0.2°, 13.96 ± 0.2°, 15.01 ± 0.2°, 15.41 ± 0.2°, 16.29 ± 0.2°, 16.96 ± 0.2°, 17.76 ± 0.2°, 18.65 ± 0.2°, 19.07 ± 0.2°, 20.32 ± 0.2°, 21.60 ± 0.2°, 22.46 ± 0.2°, 23.82 ± 0.2°, 24.46 ± 0.2°, 25.57 ± 0.2°, 26.06 ± 0.2°, 27.65 ± 0.2°, 28.35 ± 0.2°, 29.26 ± 0.2°, 30.30 ± 0.2°, 31.87 ± 0.2°, 33.25 ± 0.2°, 34.30 ± 0.2°, 37.47 ± 0.2°, 38.40 ± 0.2°, 39.44 ± 0.2°.

In some embodiments, the acid addition salts disclosed herein is dimaleate having crystalline form B of compound (I) having a differential scanning calorimetry thermogram comprising an endothermic peak at 157.96 ℃ ± 3 ℃.

In some embodiments, the acid addition salts disclosed herein is dimaleate having crystalline form B having an X-ray powder diffraction pattern substantially as shown in figure 7.

In some embodiments, the acid addition salts disclosed herein is dimaleate having crystalline form B having a differential scanning calorimetry thermogram substantially as shown in figure 8.

In some embodiments, the acid addition salts disclosed herein is dimaleate amorphism having an X-ray powder diffraction pattern as shown in figure 9.

In one aspect, the present invention also provides a pharmaceutical composition comprising an acid addition salt of compound (I) or a combination thereof; the pharmaceutical composition further comprising a pharmaceutically acceptable carrier, an excipient, diluent, adjuvant, or a combination thereof. In some embodiments, the acid addition salts in the pharmaceutical compositions disclosed herein may be in any of the crystalline forms of the salts, and specifically, may be any crystalline form, amorphism or a combination thereof. In some embodiments, the pharmaceutical compositions disclosed herein comprise any of the acid addition salts of compound (I) , or any of the crystalline forms or amorphous forms of the invention, or a combination thereof.

In some embodiments, the pharmaceutical composition disclosed herein further comprises an additional therapeutic agent.

In other embodiments, the additional therapeutic agent disclosed herein is a chemotherapeutic agent, an antiproliferative agent, a medicament for the treatment of non-small cell lung cancer, a medicament for the treatment of epidermal cancer, or a combination thereof.

In other embodiments, the additional therapeutic agent disclosed herein is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatinum, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbozine, methotrexate, fluorouracil, cytosine arabinoside, gemcitabine, purinethol, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogue, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon α, calcium folinate, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab or a combination thereof.

In another aspect, the invention also relates to the use of the acid addition salt of compound (I) or a combination thereof or the pharmaceutical compositions disclosed herein in the manufacture of a medicament preventing, treating or alleviating a proliferative disease, atherosclerosis or pulmonary fibrosis in a patient. The use comprises administering to a human or animal a therapeutically effective amount of the acid addition salt of the invention or the pharmaceutical compositions disclosed herein.

In some embodiments, the proliferative disease comprises metastatic carcinoma, colon cancer, gastric adenocarcinoma, bladder carcinoma, breast carcinoma, renal carcinoma, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostatic cancer, pancreatic cancer, central nervous system cancer, spongioblastoma or myeloproliferative diseases.

In one aspect, the present invention relates to the use of an acid addition salt of compound (I) or a combination thereof or the pharmaceutical compositions disclosed herein in the manufacture of a medicament for modulating protein kinase activity. In some embodiments, the salt or pharmaceutical compositions disclosed herein can be used to inhibit the activity of protein kinase.

In some embodiments, the protein kinase of the invention is a receptor tyrosine kinase.

In other embodiments, the receptor tyrosine kinase of the invention is EGFR, EGFR T790M, HER-2, or a combination thereof.

In one aspect, the acid addition salt of compound (I) or the pharmaceutical compositions disclosed herein can be used for preventing, treating or alleviating a proliferative disease, atherosclerosis or pulmonary fibrosis in a patient. In some embodiments, the proliferative disease is metastatic carcinoma, colon cancer, gastric adenocarcinoma, bladder carcinoma, breast carcinoma, renal carcinoma, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostatic cancer, pancreatic cancer, central nervous system cancer, spongioblastoma or myeloproliferative diseases.

In another aspect, the acid addition salt of compound (I) or the pharmaceutical compositions disclosed herein can be used to modulate protein kinase activity. In some embodiments, the salt or pharmaceutical compositions disclosed herein can be used to prevent, treat or alleviate a disease associated with a protein kinase in a patient. In some embodiments, the protein kinase of the invention is a receptor tyrosine kinase. In other embodiments, the receptor tyrosine kinase of the invention is EGFR, EGFR T790M, HER-2, or any combination thereof.

In another aspect, the invention also relates to a pharmaceutical combination comprising any of the acid addition salts or a combination thereof, and an additional therapeutic agent.

In some embodiments, the additional therapeutic agent disclosed herein is a chemotherapeutic agent, an antiproliferative agent, a medicament for the treatment of non-small cell lung cancer, a medicament for the treatment of epidermal cancer, or a combination thereof.

In some embodiments, the additional therapeutic agent disclosed herein is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cis-platinum, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbozine, methotrexate, fluorouracil, cytosine arabinoside, gemcitabine, purinethol, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogue, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon α, calcium folinate, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab or a combination thereof.

In one aspect, the present invention relates to a method of preventing, treating or ameliorating proliferative disease in a patient, comprising administering to the patient a pharmaceutically acceptable effective amount of the acid addition salt or the pharmaceutical compositions disclosed herein. In some embodiments, the proliferative disease is metastatic carcinoma, colon cancer, gastric adenocarcinoma, bladder carcinoma, breast carcinoma, renal carcinoma, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostatic cancer, pancreatic cancer, central nervous system cancer, spongioblastoma or a myeloproliferative disease.

In another aspect, the present invention relates to a method of modulating protein kinase activity using an acid addition salt of compound (I) or the pharmaceutical compositions disclosed herein. In some embodiments, the present invention relates to a method of inhibiting the activity of a protein kinase using an acid addition salt of compound (I) or the pharmaceutical compositions disclosed herein.

In another aspect, the present invention also relates to the preparation method of acid addition salts of compound (I) and crystalline form or amorphism thereof.

The amorphism of the invention can be prepared by spray drying. The amorphous yield of the spray drying according to the invention is affected by the factors such as the temperature of the air inlet of the instrument, the temperature of the air outlet of the instrument, the pressure of the system during the spraying process, and the like, which are related to the type of the instrument, the solvent used, and other factors.

The solvent used in the preparation method of the invention is not particularly restricted, and any solvent which can dissolve the starting material to a degree and does not affect the properties of the starting material is included in the present invention. Additionally, many similar modifications in the art, equivalent replacements, or solvent, solvent combination and the solvent combination with different proportions which are equivalent to those described in the invention, all are deemed to be included in the present invention. The present invention gives the preferred solvent for each reaction step.

The preparation of the salt disclosed herein will be described in detail in the examples section. Meanwhile, the present invention provides a pharmacological activity test (e.g., a pharmacokinetic test) of the salt, a solubility test, a stability test (including high temperature, a high humidity and light test) , and a hygroscopic test. From the test results, it can be seen that the salt of the invention has good biological activity (e.g., better pharmacokinetic properties) , good solubility and high stability, and is suitable for pharmaceutical use.

In the hygroscopic test of the salt disclosed herein, the description of the hygroscopicity feature and the definition of the hygroscopicity gain (Chinese Pharmacopoeia 2015 edition, Appendix 9103 Drug hygroscopic test guidelines, experimental conditions: 25℃ ± 1 ℃, 80%± 2%relative humidity) are as described in the table below.

The description of the hygroscopicity feature and the definition of the hygroscopicity gain

The salt of the invention is not susceptible to high humidity to cause deliquescence, and it is convenient for the long-term storage of the medicine.

DEFINITIONS AND GENERAL TERMINOLOGY

Unless otherwise indicated, all technical and scientific terminology used in the present invention have the same meaning as commonly understood by those of ordinary skill in the art to which this invention pertains. All patents and publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or identical to those described herein may be used in the practice or testing of the invention, but the methods, apparatus and materials described in the invention are preferred.

"Pharmaceutically acceptable acid addition salt" is a salt formed by compound (I) with a pharmaceutically acceptable non-toxic acid, including but not limited to the salt formed by compound (I) with any of various organic or inorganic acids.

"An acid addition salt of compound (I) " means a salt formed by reacting compound (the free base) (I) with any of various suitable organic or inorganic acids, including, but not limited to, hydrochloride, hydrobromide, sulfate, maleate, benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate, oxalate, methanesulfonate and the like. Wherein, the "acid addition salt of compound (I) ” includes an amorphous or a crystalline form of the salt, including its solvate form (e.g., a hydrate form) , and also including its polymorphism. For example, dimesylates of compound (I) include its amorphous forms, various crystalline forms, various solvates, various hydrates, and also include polymorphic forms of such salts.

"Crystal form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, a mono-or multi-component crystal, and/or a polymorphism of compound, a solvate, a hydrate, a clathrate, a eutectic, a salt, a solvate of salt, a hydrate of salt. The crystalline form of the material can be obtained by a number of methods known in the art. Such methods include, but not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in defined space, for example, in nanopores or capillaries, on a surface or template, for example, on a polymer, in the presence of additives such as co-crystallization counterions, removing solvent, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reaction crystallization, anti-solvent addition, grinding and solvent drop milling.

"Amorphism" or "amorphous form" refers to a substance formed by particle (such as molecule, atom, ion) of a substance arranged in a non-periodic manner in three-dimensional space, which is characterized by an X-ray powder diffraction pattern with no sharp peaks. Amorphism is a special physical form of solid substance, and its ordered structural characteristics in a part of amorphous substance imply that there are innumerable links between amorphous substance and crystal substance. The amorphous form of a substance can be obtained by a number of methods known in the art. Such methods include, but not limited to, quenching, anti-solvent flocculation, ball milling, spray drying, freeze drying, wet granulation and solid dispersion techniques.

"Solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid) . Solvents for use in the practice of this invention include, but not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N, N-dimethylacetamide, N, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, or a combination thereof, and the like.

"Anti-solvent" refers to a fluid that promotes the precipitation of a product (or product precursor) from a solvent. The anti-solvent comprise a cold gas, or a fluid that promotes the precipitation by chemical reaction or reduces the solubility of the product in the solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a liquid different from the solvent.

"Solvate" refers to a compound having a solvent on a surface, in a lattice or on a surface and in a lattice of the compound. The solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N, N-dimethylacetamide, N, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, or a combination thereof, and the like. A specific example of the solvate is a hydrate in which the solvent on the surface, in the lattice or on the surface and in the lattice is water. On the surface, in the lattice or on the surface and in the lattic of the substance, the hydrate may or may not have any solvent other than water.

The stoichiometric solvate has a fixed ratio of the solvent molecule to the compound molecule. This is typically due to the bonding interaction between the solvent and the compound molecules. In non-stoichiometric solvates, the solvent does not exist at a fixed ratio to the compound molecule and its content can often vary. In non-stoichiometric solvates, the solvent often exists in the void space or channel within the lattice. The stoichiometric hydrate has a fixed ratio of the water molecule to the compound molecule. This is typically due to the bonding interaction between the water and the compound molecules. In non-stoichiometric hydrate, the water does not exist at a fixed ratio to the compound molecule and its content can often vary. In non-stoichiometric hydrate, the water is often present in the void space or channel within the lattice.

The acid addition salts disclosed herein or their crystalline or amorphous forms are preferably present in a separate and substantially pure form.

The present invention also relates to physical properties of the acid addition salts disclosed herein or their crystalline or amorphous in a solid state. These properties can be influenced by controlling the condition of obtaining salt or crystalline or amorphous in solid form. The physical properties of the solid state include, for example, the flowability of the solid that has been ground. The mobility affects the complexity in the process of handling of the substance into drug. When the powdered particles do not flow easily, the preparation specialist has to consider the fact that it is necessary to use a glidant such as colloidal silica, talc, starch or trivalent calcium phosphate in the development of tablets or capsules.

Another important solid state property of the pharmaceutical compound is its dissolution rate in aqueous liquid or the bioavailability of the drug. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream.

For example, in the case of dissolution rate and bioavailability, different crystalline forms or amorphous forms of the same drug may vary widely in such important pharmaceutical properties. Likewise, different crystalline or amorphous forms may have different processing properties, such as hygroscopicity, fluidity, etc., which may affect their suitability as an active drug for commercial preparation.

In the preparation of syrups, elixirs and other liquid medicaments, the rate of dissolution should also be taken into account. The solid state of the compound can also affect its behavior against compression and storage stability.

These physical properties are influenced by molecular conformation and orientation in the unit cell, and the conformation and orientation of the molecules in the unit cell determine the specific polymorphism of the substance.

Crystal form or amorphism can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD) , infrared absorption spectroscopy (IR) , melting point method, differential scanning calorimetry (DSC) , thermogravimetric analysis (TGA) , Nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscopy (SEM) , quantitative analysis, solubility and dissolution rate.

X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, crystal state and other information, which is a common mean for identifying crystalline form. The peak position of the XRPD pattern primarily depends on the structure of the crystalline form and is relatively insensitive to the experimental details, and its relative peak height depends on many factors associated with sample preparation and instrument geometry. Thus, in some embodiments, the crystalline form disclosed herein is characterized by an XRPD pattern having certain peak positions, which is substantially as shown in the XRPD pattern provided in the drawings disclosed herein. At the same time, the 2θ of the XRPD pattern measured may exist an experimental error. The measurement of 2θ of the XRPD pattern may be slightly different because of the different instruments and the different samples. Therefore, the value of 2θ could not be regarded as absolute. According to the condition of the instrument used in this test, the diffraction peak has an error margin of ± 0.2°.

Differential Scanning Calorimetry (DSC) is a technique of measuring the energy difference between a sample and an inert reference (commonly used α-Al₂O₃) which varies with temperature by continuously heating or cooling under program control. The endothermic peak height of the DSC thermogram depends on many factors associated with sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline form disclosed herein is characterized by a DCS thermogram having certain characteristic peak positions, which is substantially as shown in the DCS thermogram provided in the drawings disclosed herein. At the same time, the DCS thermogram measured may be existed an experimental error. The peak position and peak value of DCS thermogram may be slightly different because of the different instruments and the different samples. Therefore, the peak position or the peak value of the DSC endothermic peak could not be regarded as absolute. According to the condition of the instrument used in this test, the melting peak has an error margin of ± 3℃.

Differential scanning calorimetry (DSC) can also be used to detect and analyse whether there is a crystal transformation or mixed grain phenomenon in crystalline form.

Thermogravimetric analysis (TGA) is a technique for measuring the quality of a substance which varies with temperature under the control of a program. It is suitable for examining the process of the solvent loss or the samples sublimation and decomposition. It can be presumed that the crystal contains crystal water or crystallization solvent. The quality changes shown on the TGA curve depend on a number of factors, such as the sample preparation and the instrument, and the like. The quality changes obtained from TGA test may be slightly different between the different instruments and between the different samples. The dimaleate having crystalline form A disclosed herein is characterized by the weight loss of the TGA test is about 0.48%and the TGA pattern is substantially as shown in figure 10. According to the condition of the instrument used in this test, there exists a ± 0.1%error margin of the quality change.

In the context of the present invention, the 2θ values in the X-ray powder diffraction pattern are in degrees (°) .

The terminology "substantially as shown in the figure" refers to at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 80%, or At least 90%, or at least 95%, or at least 99%of the peaks are shown in the X-ray powder diffraction pattern or DSC pattern or Raman spectra pattern or infrared spectra pattern.

The "peak" refers to a feature that a person skilled in the art can recognize as not attributable to background noise when referring to a spectrum or/and data that appears in the figure.

The invention relates to all kinds of new crystalline forms of the acid addition salts of (E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4aR, 7aS) -tetrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide, which exist in a substantially pure crystalline form.

The invention also refers to all kinds of amorphism of the acid addition salt of (E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4aR, 7aS) -tetra hydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide. The amorphism can be prepared by spray drying.

"Substantially pure" means that a crystalline form is substantially free of another or more crystalline forms, that means the purity of the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or crystalline form containing other crystalline form. The percentage of the other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

"Substantially free" means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

"Relative strength" (or "relative peak height" ) means the ratio of the intensity of the other peak to the intensity of the first strong peak when the intensity of the first strong peak in all the diffraction peaks of the X-ray powder diffraction pattern (XRD) is 100%.

In the context of the present invention, when used or whether or not used the word, such as "about" , it means that within a given value or range of 10%or less, appropriately within 5%, especially within 1%. Or, for those of ordinary skilled in the art, the terminology "about" means within an acceptable standard error range of the mean value. When a number with an N value is disclosed, any number within N +/-1%, N +/-2%, N +/-3%, N +/-5%, N +/-7%, N +/-8%, or N +/-10%will be disclosed clearly, wherein "+/-" means plus or minus.

Unless otherwise stated, the organic acids depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, geometric (or conformational) ) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric isomers, diastereomeric isomers, or geometric isomers (or conformational isomers) mixtures of the organic acids in the present invention are within the scope disclosed herein.

Unless otherwise stated, all tautomeric forms of the organic acid disclosed herein are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include organic acid that differ only in the presence of one or more isotopically enriched atoms.

The use of stereochemical definitions and conventions in the present invention is generally referred to the following: S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds" , John Wiley&Sons, Inc., New York, 1994. The organic acid disclosed herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the organic acid disclosed herein, including, but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center (s) . The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terminology "racemic mixture" or "racemate" refers to an equimolar mixture of two enantiomeric species, devoid of optical activity.

In the present invention, "room temperature" means that the temperature is from about 10℃ to about 40℃. In some embodiments, "room temperature" refers to a temperature of from about 20℃ to about 30℃; in other embodiments, "room temperature" refers to 20℃, 22.5℃, 25℃, 27.5℃, and the like.

PHARMACEUTICAL COMPOSITIONS OF THE ACID ADDITION SALT OF THE INVENTION, FORMULATION AND ADMINISTRATION

In one aspect, the pharmaceutical compositions disclosed herein comprise any acid addition salts of compound (I) , and a pharmaceutically acceptable carrier, an adjuvant, or a excipient. The amount of acid addition salt in the composition disclosed herein is the effectively and detectably inhibit protein kinases in a biological specimen or a patient.

As described above, the pharmaceutical compositions disclosed herein further comprise a pharmaceutically acceptable carrier, an adjuvant, or a vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. As described in the following: In Remington: Troy et al., Remington: The Science and Practice of Pharmacy, 21st ed., 2005, Lippincott Williams &Wilkins, Philadelphia, and Swarbrick et al., Encyclopedia of Pharmaceutical Technology, eds. 1988-1999, Marcel Dekker, New York, both of which are herein incorporated by reference in their entireties, disclose various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium incompatible with the compounds or acid addition salts thereof disclosed herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other components of the pharmaceutical compositions, its use is contemplated to be within the scope of this invention.

Substances that may be pharmaceutically acceptable carriers, including, but not limited to, ion exchangers; aluminium; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; wool fat; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants.

The pharmaceutical compositions disclosed herein can be administered by the following route: orally, parenteral, inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The terminology “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection and infusion techniques. The preferred compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions disclosed herein include aqueous and oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, non-volatile oil can be conventionally employed as a solvent or suspending medium.

For this purpose, any bland non-volatile oil includes synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, which are useful in the preparation of injectables, can be used as natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions disclosed herein may be administered orally in any acceptable oral dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. With regard to the oral use of tablets, carriers generally include lactose and corn starch. Lubricants, such as magnesium stearate, are typically added. For oral administration of capsules, suitable diluents include lactose and dry corn starch. When the oral administration of water is an aqueous suspension, the active ingredient is consisted by the emulsifier and suspending agent. If these dosage forms are desired, certain sweeteners, flavoring or coloring agents may also be added.

In addition, the pharmaceutical compositions disclosed herein may be administered rectally in the form of suppositories. These can be prepared by mixing the reagent with a suitable non-perfused adjuvant. This kind of adjuvant is solid at room temperature, but is liquid at the temperature of the rectum, and melt and release the drug in the rectum. Such substances include cocoa butter, beeswax, and polyethylene glycols. The pharmaceutical compositions disclosed herein may be administered by topical. Especially when topical administration, the treatment goals of areas or organs involved are easy to achieve, such as eye, skin or lower intestinal disease. Suitable topical formulations can be prepared and applied to these fields or organs.

Rectal suppositories (see above) or suitable enema agents can be applied to topical administration of the lower intestine. Local skin spots can also be treated like this. For topical administration, the pharmaceutical compositions may be prepared into a suitable ointment according to the formulation method. The ointment comprises an active ingredient suspended or dissolved in one or more carriers. Carrier compounds for topical administration disclosed herein include, but not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes and water. In addition, the pharmaceutical compositions may be prepared into a suitable lotion or emulsion. The lotion or emulsion comprises an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but not limited to, mineral oil, pan-60 (sorbitan monostearate) , Tween 60 (polysorbate 60) , cetyl ester wax, palmityl alcohol, 2-Octyl dodecanol, benzyl alcohol and water.

The ophthalmic pharmaceutical compositions may be formulated into a formulation, such as isotonic micronized suspensions, pH-adjusted sterile saline or other aqueous solutions, preferably, isotonic solutions and pH-adjusted sterile saline or other aqueous solutions can be added with preservative preservatives such as benzalkonium chloride. In addition, pharmaceutical compositions for ophthalmic preparations may be formulated as ointments such as vaseline oil in a formulation. The pharmaceutical compositions disclosed herein may be administered by a nasal air solvent or an inhalation agent. Such compositions may be prepared according to the well-known techniques of formulation or may be prepared as salt solutions. The use of benzyl alcohol or other suitable preservatives, absorption enhancers, fluorocarbons or other conventional solubilizing or dispersing agents can enhance bioavailability.

Liquid dosage forms for oral administration include, but not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain a known general inert diluent such as water or other solvent, solubilizing agent and emulsifier such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butanediol, dimethylformamide, grease (especially cottonseed, peanut, corn, microbe, olive, castor and sesame oil) , glycerol, 2-tetrahydrofuran methanol, polyethylene glycol, sorbitan fatty acid esters, and a mixture thereof. In addition to the inert diluent, the oral compositions may also contain adjuvants such as wetting agents, emulsifying or suspending agents, sweetening agents, flavoring agents and fragrances.

Injections, such as sterile injectable or oily suspensions, may be formulated according to techniques known in the art and formulation using suitable dispersing or wetting agents and suspending agents. The sterile injectable agent may be a non-toxic sterile injectable solution, suspension or emulsion made by injection of an acceptable diluent or solvent, for example, a 1, 3-butanediol solution. The acceptable vehicles and solvents include water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, non-volatile oil can be conventionally employed as a solvent or suspending medium. For this purpose, any bland non-volatile oil includes synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be used in injections.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In order to prolong the effect of the acid addition salt of compound (I) , it is generally necessary to slow down the absorption of the compound by subcutaneous injection or intramuscular injection. This can be achieved by using a liquid suspension to solve the problem of poor water solubility of the crystal or non-crystal material. The absorbance of the compound or its salt depends on its dissolution, which in turn depends on the grain size and the crystal shape. In addition, the delayed absorption of the compound injection can be accomplished by dissolving or dispersing the compound or a salt thereof in an oil excipient.

Some of these embodiments are pharmaceutical preparations for rectal or vaginal administration as suppositories which can be prepared by mixing the acid addition salts of the compounds disclosed herein with suitable non-perfused excipients or carriers, such as cocoa butter, polyethylene glycol, or suppository waxes, which are solid at room temperature but are liquid at body temperature, so that the active compound is melted and released in the vagina or in the sheath cavity.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these dosage forms, the acid addition salts of the compounds disclosed herein are mixed with at least one pharmaceutically acceptable inert excipient or carrier such as sodium citrate or calcium phosphate or a filler or, a) fillers such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) blocker solutions such as paraffin, f) absorption enhancers such as quaternary amines, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite, i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. As for capsules, tablets and pills, these dosage forms may contain buffering agents.

A similar type of solid composition may be a filler that filled in soft or hard capsules using lactose and macromolecule of polyethylene glycol and the like. Solid dosage forms, such as tablets, lozenges, capsules, pills and granules can be prepared by coating, capsules such as enteric coatings and other pharmaceutical formulations known in the coating process. They may optionally contain a sunscreen agent, or preferably, release the only active ingredient in the composition in a delayed manner in a portion of the intestinal tract, optionally, in a delayed manner. For example, the implanted composition may comprise multimeric substances and waxs.

The acid addition salts disclosed herein may form microcapsule formulations together with one or more excipients described herein. Solid dosage forms, such as tablets, lozenges, capsules, pills and granules can be prepared by coating or capsules, such as enteric coatings, controlled release coatings and other well-known pharmaceutical formulation methods. In these solid dosage forms, the active compound or salt thereof may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms, as a general application, may also include addition substances other than inert diluents, such as tabletting lubricants and other tablet auxiliaries, such as magnesium stearate and microcrystalline cellulose. As for capsules, tablets and pills, these dosage forms may contain buffering agents. They may optionally contain sedative, or preferably, release the only active ingredient in the composition in a delayed manner in a portion of the intestinal tract, optionally, in a delayed manner. Applicable implant compositions may include, but not limited to, multimer substancesand waxes.

Dosage forms of the acid addition salts disclosed herein by topical or transdermal administration include ointments, pastes, emulsions, lotions, gels, powders, solutions, sprays, inhalants, patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or the necessary buffers. Ophthalmic pharmaceutical formulation, ear drops and eye drops are considered by the present invention.

The acid addition salts of the compound disclosed herein are preferably formulated in dosage form according to the formulation to reduce the dose and dose uniformity. The terminology "dosage unit type" herein refers to a physically dispersed unit in which a patient obtains the appropriate treatment. However, it should be understood that the daily general use of the acid addition salt or pharmaceutical compositions disclosed herein will be determined by the attending physician on the basis of a reliable medical range judgment. The specific effective dose level for any particular patient or organism will depend on a number of factors including the severity of the disease and condition being treated, the activity of the particular compound or salt thereof, the particular composition used, the age, weight, health, sex and eating habits of the patient, time of administration, route of administration and excretion rate of the particular compound used, duration of treatment, drug use in combination or in combination with a specific compound, and other well-known factors in the field of pharmacy.

The amount of acid addition salt of the compounds disclosed herein that can bind to the carrier material to produce a single dosage form composition depending on the attending and the particular mode of administration. Some of these embodiments are that the composition can be prepared as an active ingredient in an amount of from 0.01 to 200 mg/kg body weight per day by formulation, administered by the amount of the patient receiving the composition.

The acid addition salts of the compound disclosed herein may be administered with the only pharmaceutically acceptable agent or in combination with one or more additional therapeutics (pharmaceutically acceptable) agents, wherein the combination of drugs causes acceptable adverse reactions, which is of special significance for the treatment of hyperplastic disease such as cancer. In this case, the salt of the compound disclosed herein may be used in combination with known cytotoxic agent, individual transduction inhibitor or other anti-cancer agent, as well as a mixture or a combination thereof. As used herein, use of additional therapeutics to treat a particular disease by normal administration is known as "the proper treatment of the disease" . “Additional therapeutic agent” used in the present invention includes a chemotherapeutic agent or other anti-proliferative drug that can treat a proliferative disease or cancer in combination with a compound of the invention. The additional therapeutic agent disclosed herein also includes an anti-inflammatory drug, a drug for the treatment of non-small cell lung cancer, a drug for the treatment of epidermal cancer, or a combination thereof.

Chemotherapeutic agents or other anti-proliferative drugs include histone deacetylase (HDAC) inhibitors, and include, but not limited to, SAHA, MS-275, MGO103, and those described in the following patents: WO 2006/010264, WO 03/024448, WO 2004/069823, US 2006/0058298, US 2005/0288282, WO 00/71703, WO 01/38322, WO 01/70675, WO 03/006652, WO 2004/035525, WO2005/030705, WO 2005/092899, and demethylating agents include, but not limited to, 5-aza-2'-deoxycytidine (5-aza-dC) , azacitidine (Vidaza) , decitabine and the compounds described in the following documents: US 6,268137, US 5,578,716, US5,919,772, US 6,054,439, US 6,184,211, US 6,020,318, US 6,066,625, US 6,506,735, US 6,221,849, US 6,953,783, US 11/393,380.

In other embodiments, chemotherapeutic agent or other anti-proliferative drug may be used in combination with the salt of the compound disclosed herein for the treatment of proliferative diseases and cancers. The known chemotherapeutic drugs include, but not limited to, other therapies or anticancer agents that may be used in combination with the anticancer agents disclosed herein, including surgery, radiotherapy (a few examples such as gamma radiation, neutron beam radiation therapy, electron beam radiation Therapy, proton therapy, brachytherapy and systemic radioisotope therapy) , endocrine therapy, taxane (paclitaxel, docetaxel, etc. ) , platinum derivatives, biological response modifiers (interferon, interleukin, tumor necrosis factor (TNF) , TRAIL receptor targeting and vehicle) , overheating and cryotherapy, dilution of any adverse reactions of reagents (such as antiemetic) , and other approved chemotherapeutic drugs, including but not limited to, alkylated drugs (nitrogen mustard, chlorambucil, cyclophosphamide, phenylalanine mustard, ifosfamide) , antimetabolites (methotrexate, pemetrexed, etc. ) , purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabile, Gemcitabine) , spindle inhibitors (vinblastine, vincristine, vinorelbine, paclitaxel) , podophyllotoxin (etoposide, Irinotecan, Topotecan) , antibiotics (doxorubicin, bleomycin, mitomycin) , nitrosourea (carmustine, lomustine) , inorganic ions (cisplatin, carboplatin) , cell division cycle inhibitors (KSP by mitotic kinesin inhibitors, CENP-E and CDK inhibitors) , enzymes (asparaginase) , hormones (tamoxifen, leuprolide, flutamide, megestrol) , gleevec, adriamycin, dexamethasone, and cyclophosphamide. antiangiogenic factors (avastin and others) , kinase inhibitors (imatinib, sutent, nexavar, erbitux, herceptin, tarceva, iressa and others) . The cancer pathways that drugs can inhibit or activate include mTOR, HIF (hypoxia-inducible factor) pathways and others. A wide range of cancer treatment forums see http: //www. nci. nih. gov/, FAD-approved list of oncology drugs see http: //www. fda. gov/cder/cancer/druglist-rame. htm, and Merck Manuals, the eighteenth edition . 2006, all the contents are combined with the reference.

In other embodiments, the salt of the compound disclosed herein may in combination with cytotoxic anti-cancer agent. Such anticancer agent can be found in the thirteenth edition of the Merck Index (2001) . These anti-cancer agents include, but not limited to, asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cycles phosphoric acid, cytarabine, dacarbazine, dactinomycin, daunorubicin, adriamycin (doxorubicin) , epirubicin, etoposide, 5-fluorouracil, hexamethyl melamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, cyclohexanimidazole, nitrogen mustard, 6-mercaptopurine, mesna, methotrexate, mitomycin c, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, vindesine.

Other suitable cytotoxic drugs for use in combination with the salt of the compound disclosed herein include, but not limited to, those compounds which are commonly used in the treatment of neoplastic diseases, as described in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill. ) ; These anti-cancer agents include, but not limited to, aminoglutethimide, l-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2', 2'-difluorodeoxychiocholine, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, floxuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphate-L-aspartic acid (PALA) , plicamycin, semustine, teniposide, testosterone propionate, Thiotepa, trimethyl melamine, uridine and vinorelbine.

Other suitable cytotoxic anti-cancer agents for use in combination with salts of the compound disclosed herein include newly discovered cytotoxic substances, including, but not limited to, oxaliplatin, gemcitabine, capecitabine, macrolide antineoplastic agents and their natural or synthetic derivatives, temozolomide (Quinn et al., J. Clin. Oncology, 2003, 21 (4) , 646-651) , bexxar, trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3181) , and the driving protein spindle protein inhibitor Eg5 (Wood et al., Curr. Opin. Pharmacol. 2001, 1, 370-377) .

In other embodiments, the salts of the compound disclosed herein may in combination with signal transduction inhibitors. It is interesting to note that the signal transduction inhibitor targets the EGFR family, such as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000, 60 (Suppl. l) , 15-23; Harari et al. Oncogene, 2000, 19 (53) , 6102-6114) and their respective ligands. Such agents include, but not limited to, antibody therapies such as herceptin (trastuzumab) , trbitux and pertuzumab. Such treatments also include, but not limited to, small molecule kinase inhibitors such as gefitinib, erlotinib, tykerb (lapatinib) , canertinib (CI1033) , AEE788 (Traxler et al., Cancer Research , 2004, 64, 4931-4941) .

In other embodiments, the acid addition salts disclosed herein may in combination with other signal transduction inhibitors to target receptor kinases of split kinase domain family (VEGFR, FGFR, PDGFR, flt-3, c-kit, c -fins, etc. ) , and their respective ligands. Such agents include, but not limited to, antibodies such as bevacizumab (avastin) . Such agents include, but not limited to, small molecule inhibitors such as gleevec/imanitib, sprycel (dasatinib) , tasigna/nilotinib, nexavar (vandetanib) , vatalanib (PTK787/ZK222584) (Wood et al., Cancer Res. 2000, 60 (8) , 2178-2189) , telatinib/BAY-57-9352, BMS-690514, BMS-540215, axitinib/AG-013736, motesanib/AMG706, sutent/sunitinib/SU-11248, ZD-6474 (Hennequin et al., 92nd AACR Meeting, New Orleans, Mar. 24-28, 2001, abstract 3152) , KRN-951 (Taguchi et al., 95th AACR Meeting, Orlando, FIa, 2004, abstract 2575) , CP-547, 632 (Beebe et al., Cancer Res. 2003, 63, 7301-7309) , CP-673, 451 (Roberts et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract 3989) , CHIR-258 (Lee et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract 2130) , MLN-518 (Shen et al., Blood, 2003, 102, 11, abstract 476) .

In other embodiments, the acid addition salts disclosed hereinmay in combination with histone deacetylase inhibitors. Such agents include, but not limited to, octadecanilide hydroxamic acids (SAHA) , LAQ-824 (Ottmann et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3024) , LBH-589 (Beck et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3025) , MS-275 (Ryan et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract 2452) , FR-901228 (Piekarz et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3028) and MGCDOI 03 (US 6,897,220) .

In other embodiments, the acid addition salts disclosed herein may in combination with other anti-cancer agents, such as proteasome inhibitors and m-TOR inhibitors. These include, but not limited to, bortezomib (Mackay et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, Abstract 3109) , and CCI-779 (Wu et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract 3849) . The acid addition salts disclosed herein may also bind to other anti-cancer agents such as topoisomerase inhibitors, including but not limited to camptothecin.

Those additional therapeutic agents can be administered separately from the pharmaceutical compositions comprising the acid addition salts disclosed herein, and as a part of the multi-administration regimen. Alternatively, those therapeutic agents may be part of a single dosage form, mixed with the acid addition salt disclosed herein to form a single composition. If the administration is a part of the multi-dosing regimen, the two active agents can be delivered simultaneously or continuously for a period of time to obtain the target reagent activity.

The amount of both the compound and the additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Normally, the amount of the therapeutic agent added to the pharmaceutical compositions disclosed herein will not exceed the amount of normal administration of the pharmaceutical compositions comprising the therapeutic agent as the sole active agent. On the other hand, the amount of the additional therapeutic agent in the disclosed pharmaceutical compositions is in the range of about 50%to 100%of the normal amount of the conventional composition, and the contained agent is used as the sole active therapeutic agent. In the pharmaceutical compositions containing additional therapeutic agents, additional therapeutic agents will act synergistically with the compounds disclosed herein.

USE OF THE COMPOUNDS AND COMPOSITIONS

The pharmaceutical composition disclosed herein is characterized by including an acid addition salt of compound (I) . The acid addition salt disclosed herein or a pharmaceutical compositions comprising the salt disclosed herein can be used effectively in the preparation of a medicament for preventing, managing or treating a proliferative disorder in a patient and lessening the its severity; The drug obtained can also be used for protecting, managing or treating atherosclerosis or pulmonary fibrosis. The amount of compound in the above-mentioned drug can effectively and detectably inhibit protein kinases such as EGFR activity. The acid addition salt of the compound disclosed herein will be used for treating or reducing the deleterious effects of EGFR as antineoplastic agents.

The acid addition salts of the compounds disclosed herein would be useful for, but not limited to, preventing or treating proliferative disease by administering to the patient the acid addition salt of the compound or a pharmaceutical composition disclosed herein in an effective amount. Such diseases include cancer, especially metastatic cancer, non-small cell lung cancer and epidermal cancer.

The acid addition salts of the compound disclosed herein will be applied to the treatment of tumors including cancer and metastatic cancer, and further include, but not limited to, cancer such as epidermal cancer, bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (non-small cell lung cancer) , esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer (including squamous cell carcinoma) ; lymphoid system hematopoietic tumors (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell leukemia and Burkitt's lymphoma) ; Bone marrow hematopoietic tumors (including acute and chronic myeloid leukemia, myelodysplastic syndrome, and myeloid leukemia) ; tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, such as soft tissue and cartilage; tumors of central peripheral nervous system (including astrocytoma, neuroblastoma, neuroglioma and schwannomas) ; and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular tumor and Kaposi's sarcoma.

The acid addition salts of the compound disclosed herein are also useful for the treatment of ophthalmic disorders such as corneal transplant rejection, neovascularization of the eye, retinal neovascularization including neovascularization after injury or infection, diabetic retinopathy, posterior lens fibrous tissue hyperplasia, neovascular glaucoma, retinal ischemia, vitreous hemorrhage, etc. ; ulcerative diseases such as gastric ulcers; pathologic but nonmalignant conditions such as hemangiomas, including infant vascular endothelial cell tumors, nasopharynx and hemangiofibroma without vascular osteonecrosis; female reproductive system disorders such as endometriosis. These compounds are also used to treat edema and the condition of increased vascular permeability.

The acid addition salts of the compound disclosed herein can be used to treat diabetes-related conditions such as diabetic retinopathy and microvascular disease. The acid addition salts of the compound disclosed herein are also used in the case of reduced blood flow in cancer patients. The acid addition salts of the compound disclosed herein also have beneficial effects on decrease of tumor metastasis in patients.

Besides being useful for human treatment, the acid addition salts of the compound are also useful for veterinary treatment of animals such as companion animals, exotic animals and farm animals, including mammals, rodents, and the like. In other embodiments, the animals disclosed herein include horses, dogs, and cats. As used herein, the acid addition salts of the compound disclosed herein include the pharmaceutically acceptable derivatives thereof.

The method of administering an acid addition salt or a pharmaceutical composition comprising a compound disclosed herein further comprises administering to a patient an additional therapeutic agent (combination therapy) , wherein the additional therapeutic agent is selected from the group consisting of a chemotherapeutic agent, an anti-proliferative agent or an antiinflammatory agent, wherein the additional therapeutic agent is suitable for the treatment of the disease, and the additional therapeutic agent may be administered in combination with an acid addition salt or a pharmaceutical composition of the compound disclosed herein, the acid addition salt or pharmaceutical compositions of the compound disclosed herein as a single dosage form, or a separate salt or pharmaceutical compositions as part of the multiple dosage forms. The additional therapeutic agent may be administered concurrently with or without administration of the acid addition salt of the compound disclosed herein.

The present invention also encompasses a method of inhibiting cell growth in expression of EGFR, which comprises contacting an acid addition salt or a pharmaceutical composition of the compound disclosed herein with a cell, thereby inhibiting cell growth. The cells that can be inhibited growth include: epidermal cancer cells, breast cancer cells, colorectal cancer cells, lung cancer cells, papillary carcinoma cells, prostate cancer cells, lymphoma cells, colon cancer cells, pancreatic cancer cells, ovarian cancer cells, Cervical cancer cells, central nervous system cancer cells, osteogenic sarcoma cells, kidney cancer cells, hepatocellular carcinoma cells, bladder cancer cells, gastric cancer cells, head or neck squamous cell carcinoma cells, melanoma cells and leukemia cells.

The present invention provides a method for inhibiting EGFR kinase activity in a biological sample, which comprises contacting an acid addition salt or a pharmaceutical composition of the compound disclosed herein with a biological specimen. The terminology "biological specimen" as used herein refers to a specimen that is outside the living body, including, but not limited to, cell culture or cell extraction; biopsy substances obtained from mammals or their extracts; blood, saliva, urine, feces, semen, tears, or other living tissue liquid substances and their extracts. Inhibition of kinase activity in the biological specimen, in particular EGFR kinase activity, can be used for a variety of uses known to those skilled in the art. Such uses include, but not limited to, blood transfusion, organ transplantation, biological specimen storage and bioassay.

An “effective amount” or “effective dose” of the acid addition salts of the compound or pharmaceutically acceptable composition is an amount that is effective in treating or lessening the severity of one or more of the aforementioned disorders. The acid addition salt of the compound and pharmaceutical compositions, according to the method disclosed herein, may be administered using any amount and any route of administration which is effective for treating or lessening the severity of the disorder or disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The acid addition salts or pharmaceutical compositions can also be administered with one or more other therapeutic agents as discussed above.

The acid addition salts or pharmaceutical compositions thereof disclosed herein can be applied to coatings of implantable medical devices such as prostheses, prosthetic valves, artificial blood vessels, stems and catheters. For example, vasculature stems have been used to overcome restenosis (retraction of the vessel wall after injury) . However, the use of stems or other implantable devices will have a risk of clot formation or platelet activation. These adverse effects can be prevented or mitigated by using a pharmaceutical composition pre-coating device comprising the acid addition salt disclosed herein.

Suitable preparation methods of suitable coatings and coating of implantable devices are described in documents US 6,099,562; US 5,886,026; and US 5,304,121. The coating is a representative biocompatible multimeric material such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene-vinyl acetate, and mixtures thereof. The coating may optionally be further covered by a suitable coating, such as fluorosilicone oil, polysaccharase, polyethylene glycol, phospholipids, or a combination thereof, to characterize the controlled release of the pharmaceutical compositions. Another aspect disclosed herein includes an implantable device that is coated with an acid addition salt disclosed herein. The acid addition salts disclosed herein may also be coated on a medical device which can be implanted in body, such as a bead, or mixed with a polymer or other molecule to provide "drug storage" , thus, compared with the drug aqueous solution, allowing the drug to release a longer period of time.

DESCRIPTION OF DRAWINGS

Figure 1 is an X-ray powder diffraction (XRPD) pattern of the dimesylate having crystalline form A prepared according to the method of Example 1 disclosed herein.

Figure 2 is a Differential Scanning Calorimetry (DSC) thermogram of the dimesylate having crystalline form A prepared according to the method of Example 1 disclosed herein.

Figure 3 is an X-ray powder diffraction (XRPD) pattern of the dimesylate having crystalline form B prepared according to the method of Example 2 disclosed herein.

Figure 4 is a Differential Scanning Calorimetry (DSC) thermogram of the dimesylate having crystalline form B prepared according to the method of Example 2 disclosed herein

Figure 5 is an X-ray powder diffraction (XRPD) pattern of the dimaleate having crystalline form A prepared according to the method of Example 3 disclosed herein.

Figure 6 is a Differential Scanning Calorimetry (DSC) thermogram of the dimaleate having crystalline form A prepared according to the method of Example 3 disclosed herein.

Figure 7 is an X-ray powder diffraction (XRPD) pattern of the dimaleate having crystalline form B prepared according to the method of Example 4 disclosed herein.

Figure 8 is a Differential Scanning Calorimetry (DSC) thermogram of the dimaleate having crystalline form B prepared according to the method of Example 4 disclosed herein.

Figure 9 is an X-ray powder diffraction (XRPD) pattern of the dimaleate amorphism prepared according to the method of Example 5 disclosed herein.

Figure 10 is a Thermogravimetric analysis (TGA) pattern of the dimaleate having crystalline form A prepared according to the method of Example 3 disclosed herein.

Figure 11 is a Dynamic water adsorption (DVS) pattern of the dimaleate having crystalline form A prepared according to the method of Example 3 disclosed herein.

Figure 12 is a Nuclear magnetic resonance hydrogen spectrogram of the dimesylate having crystalline form A prepared according to the method of Example 1 disclosed herein.

Figure 13 is a Nuclear magnetic resonance hydrogen spectrogram of the dimesylate having crystalline form B prepared according to the method of Example 2 disclosed herein.

Figure 14 is a Nuclear magnetic resonance hydrogen spectrogram of the dimaleate having crystalline form A prepared according to the method of Example 3 disclosed herein.

Figure 15 is a Nuclear magnetic resonance hydrogen spectrogram of the dimaleate having crystalline form B prepared according to the method of Example 4 disclosed herein.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention will now be further illustrated by the following examples. However, these examples should not be used to limit the scope disclosed herein.

In the examples described below, unless otherwise indicated, all temperatures are set forth in degrees Celsius. Unless otherwise specified, the agents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, which were used directly without further purification. Common solvents were purchased from commercial suppliers such as Shantou XiLong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd., Qingdao Tenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory.

The X-ray powder diffraction analysis in the present invention was recorded on an Empyrean diffractometer using Cu-Kα radiation (45 KV, 40 mA) to give an X-ray powder diffraction pattern. The powdery sample was prepared as a thin layer on a monocrystalline silicon sample holder and placed on a specimen rotating holder, analyzed with step size of 0.0167 °in the scan range of 3 °-40 °. The data were collected using Data Collector software, processed using HighScore Plus software and read using Data Viewer software.

The differential scanning calorimetry (DSC) analysis was recorded on a TA Q2000 module equipped with a thermal analysis controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1-5 mg of the sample was accurately weighed into a specially crafted aluminum crucible with a lid and analyzed from room temperature to about 300 ℃ using a linear heating device at 10 ℃/min. During use, the DSC chamber was purged with dry nitrogen.

The hygroscopicity disclosed herein is detected on a DVS INT-Std dynamic vapor and gas absorption analyzer (England Surface Measurement Systems Company) under the humidity ranged from 0%to 95%, the airflow rate is 200 mL/min, the temperature is 25 ℃, and one test point is provided per rising 5%humidity.

The compound used in the stability test or accelerated test is measured by Aglient 1200 high performance liquid chromatography with VWD detector. The chromatographic column model is ZORBAX Extend-C18 (4.6 × 150 mm, 5 μm) , the detection wavelength is 250 nm, the flow rate is 1.0 mL/min, the column temperature is 40 ℃, and the mobile phase is 10 mM KH₂PO₄ (pH = 7.5) -acetonitrile (v/v = 55/45) .

Thermogravimetric Analysis (TGA) : Thermogravimetric curve is recorded on a TA Q500 instrument with a thermoanalysis controller. The data are collected and analyzed by TA Instruments Thermal Solutions software. About 10 mg sample is weighed accurately in platinum sample pans, then heated from ambient temperature to 350 ℃ using a linear heating device at a scan rate of 10 ℃ /minute for sample analysis. During the period of sample analysis, TGA furnace chamber is purged by dry nitrogen.

¹H NMR spectra were recorded by a Bruker Avance 400 MHz spectrometer or Bruker Avance III HD 600 spectrometer, using CDCl₃, DMSO-d₆, CD₃OD or acetone-d₆ (reported in ppm) as solvent, and using TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet) , d (doublet) , t (triplet) , m (multiplet) , q (quartet) , br (broadened) , dd (doublet of doublets) , dt (doublet of triplets) , ddd (doublet of doublet of doublets) , ddt (doublet of doublet of triplets) , dddd (doublet of doublet of doublet of doublets) . Coupling constants, when given, were reported in Hertz (Hz) .

EXPERIMENTAL PART

The specific synthetic method for compound (I) (E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4aR, 7aS) -tetra hydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide refers to Example 20 of Patent CN 104119350 A (Application Publication No. ) .

EXAMPLES

Example 1

(E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4aR, 7aS) -t etrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide dimesylate having crystalline form A

1. Preparation of dimesylatesulfonate having crystalline form A

(E) -N- (4- (3-Chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4a R, 7aS) -tetrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide (1.032 g, 2.0 mmol) was added to acetone (80 mL) , the mixture was heated to reflux for 30 minutes and filtered. The filtrate was refluxed, and mesylate (0.481 g, 5.0 mmol) was added. The resulting mixture was refluxed overnight. A part of solvent was evaporated under reduced pressure, then the temperature of the residue was gradually cooled to room temperature and maintained at this temperature overnight. The resulting mixture was filtered with suction. The filter cake was washed with acetone and dried at 50 ℃ for 8 hours in vacuo to give a white solid (1.15 g, 81.3%) .

2. Identification of dimesylatesulfonate having crystalline form A

(1) Determination by hydrogen nuclear magnetic resonance spectroscopy, the nuclear magnetic resonance hydrogen spectrogram of the dimesylate having crystalline form A prepared according to the method here is shown in Figure 12; wherein the molar ratio of compound (I) to methanesulfonic acid is 1: 2 in the salt.

(2) Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation, the dimesylate having crystalline form A has the following characteristic peaks expressed as 2θ at 5.51°, 6.60°, 7.64°, 9.45°, 11.60°, 12.01°, 13.18°, 14.02°, 14.87°, 15.36°, 16.52°, 17.50°, 17.68°, 18.10°, 18.76°, 18.99°, 19.17°, 19.91°, 20.41°, 21.86°, 22.16°, 22.37°, 22.64°, 23.33°, 23.81°, 24.64°, 24.88°, 25.68°, 26.56°, 27.06°, 27.66°, 28.22°, 29.91°, 30.58°, 30.99°, 31.81°, 32.89°, 33.46°, 34.20°, 34.97°, 35.46°, 36.79°, 37.61°, 38.47° and 39.63°. There is an error margin of ± 0.2 °. The X-ray powder diffraction (XRPD) pattern of the dimesylate having crystalline form A prepared according to the method here is shown in Figure 1.

(3) Analysis and identification by TA Q2000 Differential Scanning Calorimetry (DSC) : the scanning speed was 10 ℃/min. The dimesylate having crystalline form A has an endothermic peak at 151.30 ℃ in the DSC curve. There is an error margin of ± 3 ℃. The differential Scanning Calorimetry (DSC) thermogram of the dimesylate having crystalline form A prepared according to the method here is shown in Figure 2.

Example 2

(E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4aR, 7aS) -t etrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide dimethylsulfonate having crystalline form B

1. Preparation of dimesylate having crystalline form B

(E) -N- (4- (3-Chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4a R, 7aS) -tetrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide (0.517 g, 1.00 mmol) was dissolved in ethanol (3.0 mL) . To the solution was added dropwise a solution of methanesulfonic acid (0.233 g, 2.05 mmol) in ethanol (3.0 mL) at 70 ℃. After the addition, the mixture was cooled slowly to 0 ℃ and stirred overnight. The mixture was filtered with suction, and the filter cake was washed with ethanol (2.0 mL) and dried in vacuum at 50 ℃ for 12 hours to give an off-white solid (0.61 g, 86.1%) .

2. Identification of dimesylate having crystalline form B

(1) Determination hydrogen nuclear magnetic resonance spectroscopy, the nuclear magnetic resonance hydrogen spectrogram of the dimesylate having crystalline form B prepared according to the method here is shown in Figure 13; wherein the molar ratio of compound (I) to methanesulfonic acid is 1: 2 in the salt.

(2) Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation, the dimesylate having crystalline form B has the followingcharacteristic peaks expressed as 2θ at 5.64°, 5.93°, 6.43°, 6.63°, 7.22°, 7.67°, 10.80°, 11.29°, 11.62°, 12.02°, 12.80°, 13.21°, 14.09°, 14.56°, 16.15°, 16.55°, 16.96°, 17.50°, 17.80°, 18.15°, 18.45°, 18.77°, 19.26°, 19.55°, 19.95°, 20.43°, 20.81°, 21.40°, 21.89°, 22.76°, 23.41°, 24.35°, 25.09°, 25.68°, 26.69°, 28.34°, 29.55°, 30.07°, 31.68° and 32.63°. There is an error margin of ± 0.2 °. The X-ray powder diffraction (XRPD) pattern of the dimesylate having crystalline form B prepared according to the method here is shown in Figure 3.

(3) Analysis and identification by TA Q2000 Differential Scanning Calorimetry (DSC) : the scanning speed was 10 ℃/min. The dimesylate having crystalline form B has endothermic peaks at 138.86 ℃ and 185.77 ℃ in the DSC curve. There is an error margin of ± 3 ℃. The differential Scanning Calorimetry (DSC) thermogram of the dimesylate having crystalline form A prepared according to the method here is shown in Figure 4.

Example 3

(E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4aR, 7aS) -t etrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide dimaleate having crystalline form A

1. Preparation of dimaleate having crystalline form A

(E) -N- (4- (3-Chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4a R, 7aS) -tetrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide (0.128 g, 0.2476 mmol was added to methyl acetate (12 mL) , the mixture was heated to 60 ℃. Maleic acid (0.063 g, 0.54 mmol) was added and the mixture was held at 60 ℃ for 4 hours, then the heating was stopped. The reaction mixture was cooled to room temperature and stirred overnight. The mixture was filtered with suction, then the filter cake was dried in vacuo to give a white solid (0.153 g, 82.5%) .

2. Identification of dimaleate having crystalline form A

(1) Determination by hydrogen nuclear magnetic resonance spectroscopy, the nuclear magnetic resonance hydrogen spectrogram of the dimaleate having crystalline form A prepared according to the method here is shown in Figure 14; wherein the molar ratio of compound (I) to maleic acid is 1: 2 in the salt.

(2) Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation, the dimaleate having crystalline form A has the following characteristic peaks expressed as 2θ at 7.13°, 8.97°, 10.73°, 12.38°, 14.14°, 14.35°, 14.80°, 15.33°, 15.59°, 16.29°, 16.48°, 16.74°, 17.83°, 18.05°, 18.65°, 19.03°, 19.67°, 20.18°, 20.62°, 21.00°, 21.59°, 21.98°, 22.84°, 23.26°, 23.53°, 24.07°, 24.53°, 24.88°, 25.50°, 25.86°, 26.29°, 26.71°, 27.21°, 28.04°, 28.49°, 28.86°, 29.40°, 30.18°, 31.32°, 31.62°, 32.53°, 33.43°, 34.36°, 34.74°, 35.14°, 36.21°, 36.80° and 37.76°. There is an error margin of ± 0.2 °. The X-ray powder diffraction (XRPD) pattern of the dimaleate having crystalline form A prepared according to the method here is shown in Figure 5.

(3) Analysis and identification by TA Q2000 Differential Scanning Calorimetry (DSC) : the scanning speed was 10 ℃/min. The dimaleate having crystalline form A has an endothermic peak at 192.25 ℃ in the DSC curve. There is an error margin of ± 3 ℃. The differential Scanning Calorimetry (DSC) thermogram of the dimaleate having crystalline form A prepared according to the method here is shown in Figure 6.

(4) The TGA curve was analyzed and identified by using TA Q500 thermal gracity analysis (TGA) with a scan rate of 10 ℃/minute at a temperature range of 25 ℃ ～ 150 ℃, the weight loss ratio is 0.4837%. The error margin in the weight loss ratio is ±0.1%. the thermogravimetric analysis (TGA) pattern of the dimaleate having crystalline form A prepared according to the method here is shown in Figure 10.

Example 4

(E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4aR, 7aS) -t etrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide dimaleate having crystalline form B

1. Preparation of dimaleate having crystalline form B

(E) -N- (4- (3-Chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4a R, 7aS) -tetrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide (0.261 g, 0.50 mmol) and isopropanol (2.0 mL) were added to a single-neck flask. Then a solution of maleic acid (0.128 g, 1.10 mmol) in isopropanol (3.0 mL) was added. The reaction was carried out at room temperature for 90 minutes. The mixture was filtered with suction, then the filter cake was washed with isopropanol (3.0 mL x 2) and dried in vacuo at room temperature to give a white solid (0.286 g, 75.6%) .

2. Identification of dimaleate having crystalline form B

(1) Determination by hydrogen nuclear magnetic resonance spectroscopy, the nuclear magnetic resonance hydrogen spectrogram of the dimaleate having crystalline form B prepared according to the method here is shown in Figure 15; wherein the molar ratio of compound (I) to methanesulfonic acid is 1: 2 in the salt.

(2) Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation, the dimaleate having crystalline form B has the following characteristic peaks expressed as 2θ at 5.58°, 8.10°, 10.47°, 11.82°, 12.58°, 13.07°, 13.96°, 15.01°, 15.41°, 16.29°, 16.96°, 17.76°, 18.65°, 19.07°, 20.32°, 21.60°, 22.46°, 23.82°, 24.46°, 25.57°, 26.06°, 27.65°, 28.35°, 29.26°, 30.30°, 31.87°, 33.25°, 34.30°, 37.47°, 38.40° and 39.44°. There is an error margin of ± 0.2 °. The X-ray powder diffraction (XRPD) pattern of the dimaleate having crystalline form B prepared according to the method here is shown in Figure 7.

(2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry (DSC) : the scanning speed was 10 ℃/min. The dimaleate having crystalline form B has an endothermic peak of 157.96 ℃. There is an error tolerance of ± 3 ℃. The differential Scanning Calorimetry (DSC) thermogram of the dimaleate having crystalline form B prepared according to the method here is shown in Figure 8.

Example 5

(E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4aR, 7aS) -t etrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide bismaleate amorphism

1. Preparation of dimaleate amorphism

(E) -N- (4- (3-Chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4a R, 7aS) -tetrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide (0.131 g, 0.25 mmol) was added to n-propanol (8.0 mL) and the mixture was heated to 70 ℃ to dissolve the solid. Maleic acid (0.064 g, 0.55 mmol) was added, and the resulting mixture was held at 70 ℃ for 2 hours, then the heating was stopped. The reaction mixture was cooled naturally to room temperature, and the resulting mixture was stirred overnight. The mixture was filtered with suction, and the filter cake was dried in vacuo at room temperature to get an off-white solid (0.04 g, 21.1%) .

2. Identification of dimaleate amorphism

Dimaleate amorphism identified by Empyrean X-ray powder diffraction (XRPD) analysis, and its X-ray powder diffraction pattern was substantially the same as shown in figure 9.

Example 6

Pharmacokinetics experiments of the salts of the present invention

(E) -N- (4- (3-Chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4a R, 7aS) -tetrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide (compound (I) ) , crystalline forms of different salts thereof were prepared respectively into capsules forms for oral administration.

6-10 kg male Beagle dogs were randomly divided into groups and each group had 3 dogs. One group was administered with compound (I) at a dose of 5 mg/kg by oral. The other groups were administered with different salts at a dose of 5 mg/kg by oral (based on the amount of compound (I) ) . Blood samples were taken at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24 h time points after administration and centrifuged at 3,000 rpm for 10 minutes. Plasma solutions were collected and stored at -20 ℃. Standard curve was plotted based on concentrations of the samples in a suitable range, and the concentration of the test sample in the plasma sample was measured and quantified by Agilent 6430 LC-MS /MS in MRM mode. Pharmacokinetic parameters were calculated according to drug concentration time curve using a noncompartmental method by WinNonLin 6.3 software. Results were as shown in table 1.

Table 1 Pharmacokinetic data of the salts of the present invention

Conclusion:

As can be seen from Table 1, the salts of compound (I) disclosed herein have higher exposure level in the Beagle dog than (E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D₃) -quinazolin-6-yl) -4- ( (4aR, 7aS) -tetra hydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide (compound (I) ) in free state. Among them, the salt in Example 3 (dimaleate having crystalline form A) has relatively high exposure level and fast absorption.

Example 7

Stability test of the salts of the present invention

(1) High-temperature test: taking appropriate amount of the test sample into the flat weighing bottle in the form of a thin layer of ≤ 5 mm under a temperature of 60 ℃ for 10 days. Color variances of the samples were observed and purity of the samples was detected using HPLC respectively at the 5 th and 10 th day by sampling. The experimental results were shown in Table 2.

Table 2 High temperature experiments of the salts of the present invention

(2) High-humidity test: taking a batch of the test sample into the flat weighing bottle in the form of a thin layer of ≤ 5 mm under the conditions of 25 ℃ and RH for 90%± 5%for 10 days. Color variances of the samples were observed and purity of the samples was detected using HPLC respectively at the 5 th and 10 th day by sampling. The experimental results were shown in Table 3.

Table 3 High humidity experiments of the salts of the present invention

Conclusion:

From the results shown in Table 2 and Table 3, it was found that the salts disclosed herein, particularly salt of Example 1 (dimesylate having crystalline form A) and salt of Example 3 (dimaleate having crystalline form A) , did not show any obvious changes in appearances and purities under the conditions of high temperature (60 ℃) and high humidity (25 ℃, RH 90%± 5%) . The salts disclosed herein have good stability and suitable for pharmaceutical use.

Example 8

Hygroscopic test of the salts of the present invention

Taking an appropriate amount of the test sample, hygroscopicity was tested by a dynamic moisture adsorption device. The results of the hygroscopicity test of the dimaleate having crystalline form A prepared in Example 3 of the present invention are shown in Table 4, and the DVS pattern thereof is basically as shown in Figure 11.

Table 4 Hygroscopicity test of the dimaleate having crystalline form A of the present invention

The results demonstrate that the dimaleate having crystalline form A of compound (I) disclosed herein has 0.717%of weigh increase under relative humidity (RH) 80%, which belongs to Slight hygroscopicity according to the definition standard of hygroscopic weight gain; i.e., the dimaleate having crystalline form A disclosed herein is not easy to deliquesce under high humidity conditions.

The foregoing description is merely a basic illustration disclosed herein and any equivalent transformation made in accordance with the technical solution disclosed herein is intended to be within the scope disclosed herein.

Reference throughout this specification to "an embodiment, " "some embodiments, " "one embodiment" , "another example, " "an example, " "a specific example, " or "some examples, " means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. Thus, the appearances of the phrases such as "in some embodiments, " "in one embodiment" , "in an embodiment" , "in another example, "in an example, " "in a specific example, " or "in some examples, " in various places throughout this specification are not necessarily referring to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can integrate and combine different embodiments, examples or the features of them as long as they are not contradictory to one another.

Although explanatory embodiments have been shown and described, it would be appreciated by those skilled in the art that the above embodiments cannot be construed to limit the present disclosure, and changes, alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure.

Claims

A pharmaceutically acceptable acid addition salt of compound (I) ,

wherein the salt is formed by a reaction of compound (I) with an inorganic acid, an organic salt or a combination thereof;

wherein the inorganic acid is hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, carbonic acid, sulfurous acid, pyrosulfuric acid, phosphoric acid, perchloric acid, peroxosulfuric acid, thiocyanic acid, pyrophosphoric acid, metaphosphoric acid or a combination thereof; and

wherein the organic acid is formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, malonic acid, succinic acid, pyruvic acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, citric acid, 4-nitrobenzoic acid, benzenesulfonic acid, p-toluenesulfonic acid, malic acid, L-malic acid, propiolic acid, 2-tetrolic acid, vinylacetic acid, tartaric acid, L-tartaric acid, fumaric acid, hydroxyethyl-sulfonic acid, maleic acid, lactic acid, lactobionic acid, pamoic acid, salicylic acid, galactaric acid, glucoheptonic acid, mandelic acid, 1,2-ethanedisulfonic acid, naphthalene sulfonic acid, oxalic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, adipic acid, octanedioic acid, sebacic acid, butyne-1, 4-dioic acid, hexyne-1, 6-dioic acid, glycolic acid, alginic acid, ascorbic acid, isoascorbic acid, aspartic acid, L-aspartic acid, glutamic acid, L-glutamic acid, 2-phenoxybenzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, acetoacetic acid, boric acid, chlorinated benzoic acid, camphanic acid, itaconic acid, camphor sulfonic acid, L-camphor sulfonic acid, methyl benzoic acid, dinitrobenzoic acid, sulfamic acid, galacturonic acid, cyclopentyl propionic acid, dodecyl sulfuric acid, acrylic acid, cyclopentane propionic acid, glycerophosphoric acid, methoxybenzoic acid, glucose diacid, gluconic acid, heptanoic acid, caproic acid, trimethylacetic acid, glucuronic acid, lauric acid, phthalic acid, phenylacetic acid, lauryl sulfuric acid, 2-acetoxylbenzoic acid, nicotinic acid, cinnamic acid, oleic acid, palmitic acid, pectic acid, phthalic acid, glutaric acid, hydroxyl maleic acid, hydroxybenzoic acid, 3-hydroxy-2-naphthoic acid, 3-phenylpropionic acid, isobutyric acid, neopentanoic acid, picric acid, stearic acid, 2, 2-dichloroacetic acid, acylated amino acid, alginic acid, 4-acetyl aminobenzene sulfonic acid, canoic acid, cholic acid, octanoic acid, nonanoic acid, cyclamic acid, phthalic acid, cysteine hydrochloride, sorbic acid, palmoxiric acid, glycine, naphthalene disulfonic acid, xylenesulfonic acid, cystine dihydrochloride, undecanoic acid, polyethylenesulphonate, sulfosalicylic acid, phenylbutyric acid, 4-hydroxybutyric acid, polyvinyl sulfuric acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, valeric acid or a combination thereof.
The acid addition salt of claim 1, wherein the salt is dimesylate or dimaleate.
The acid addition salt of claim 1 or 2, wherein the salt is dimesylate having crystalline form A exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 18.76±0.2°, 18.99±0.2°, 19.17±0.2°, 23.33±0.2°, and 26.56±0.2°.
The acid addition salt of claim 1 or 2, wherein the salt is dimesylate having crystalline form A having a differential scanning calorimetry thermogram comprising an endothermic peak at 151.30 ° C ± 3 ° C.
The acid addition salt of claim 1 or 2, wherein the salt is dimesylate having crystalline form A exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 16.52± 0.2°, 18.10± 0.2°, 18.76 ± 0.2°, 18.99 ± 0.2°, 19.17 ± 0.2°, 19.91 ± 0.2°, 20.41 ± 0.2°, 23.33 ± 0.2°, 23.81 ± 0.2°, 26.56 ± 0.2°, and 28.22 ± 0.2°.
The acid addition salt of claim 1 or 2, wherein the salt is dimesylate having crystalline form A exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 5.51 ± 0.2°, 6.60 ± 0.2°, 7.64 ± 0.2°, 9.45 ± 0.2°, 11.60 ± 0.2°, 12.01 ± 0.2°, 13.18 ± 0.2°, 14.02 ± 0.2°, 14.87 ± 0.2°, 15.36 ± 0.2°, 16.52 ± 0.2°, 17.50 ± 0.2°, 17.68 ± 0.2°, 18.10 ± 0.2°, 18.76 ± 0.2°, 18.99 ±0.2°, 19.17 ± 0.2°, 19.91 ± 0.2°, 20.41 ± 0.2°, 21.86 ± 0.2°, 22.16 ± 0.2°, 22.37 ± 0.2°, 22.64 ±0.2°, 23.33 ± 0.2°, 23.81 ± 0.2°, 24.64 ± 0.2°, 24.88 ± 0.2°, 25.68 ± 0.2°, 26.56 ± 0.2°, 27.06 ±0.2°, 27.66 ± 0.2°, 28.22 ± 0.2°, 29.91 ± 0.2°, 30.58 ± 0.2°, 30.99 ± 0.2°, 31.81 ± 0.2°, 32.89 ±0.2°, 33.46 ± 0.2°, 34.20 ± 0.2°, 34.97 ± 0.2°, 35.46 ± 0.2°, 36.79 ± 0.2°, 37.61 ± 0.2°, 38.47 ±0.2°, and 39.63 ± 0.2°.
The acid addition salt of claim 1 or 2, wherein the salt is dimesylate having crystalline form A having an X-ray powder diffraction pattern as shown in figure 1.
The acid addition salt of claim 1 or 2, wherein the salt is dimesylate having crystalline form A having a differential scanning calorimetry thermogram as shown in figure 2.
The acid addition salt of claim 1 or 2, wherein the salt is dimesylate having crystalline form B exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 6.63 ± 0.2°, 17.80 ± 0.2°, 18.15 ± 0.2°, 19.26 ± 0.2°, and 23.41 ± 0.2°.
The acid addition salt of claim 1 or 2, wherein the salt is dimesylate having crystalline form B having a differential scanning calorimetry thermogram comprising endothermic peaks at 138.86℃ ± 3℃ and 185.77℃ ± 3℃.
The acid addition salt of claim 1 or 2, wherein the salt is dimesylate having crystalline form B exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 6.43 ± 0.2°, 6.63 ± 0.2°, 17.50 ± 0.2°, 17.80 ± 0.2°, 18.15 ± 0.2°, 18.45 ± 0.2°, 19.26 ± 0.2°, 19.55 ± 0.2°, 20.81 ± 0.2°, 23.41 ± 0.2°, and 26.69 ± 0.2°.
The acid addition salt of claim 1 or 2, wherein the salt is dimesylate having crystalline form B exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 5.64 ± 0.2°, 5.93 ± 0.2°, 6.43 ± 0.2°, 6.63 ± 0.2°, 7.22 ± 0.2°, 7.67 ± 0.2°, 10.80 ± 0.2°, 11.29 ± 0.2°, 11.62 ±0.2°, 12.02 ± 0.2°, 12.80 ± 0.2°, 13.21 ± 0.2°, 14.09 ± 0.2°, 14.56 ± 0.2°, 16.15 ± 0.2°, 16.55 ±0.2°, 16.96 ± 0.2°, 17.50 ± 0.2°, 17.80 ± 0.2°, 18.15 ± 0.2°, 18.45 ± 0.2°, 18.77 ± 0.2°, 19.26 ±0.2°, 19.55 ± 0.2°, 19.95 ± 0.2°, 20.43 ± 0.2°, 20.81 ± 0.2°, 21.40 ± 0.2°, 21.89 ± 0.2°, 22.76 ±0.2°, 23.41 ± 0.2°, 24.35 ± 0.2°, 25.09 ± 0.2°, 25.68 ± 0.2°, 26.69 ± 0.2°, 28.34 ± 0.2°, 29.55 ±0.2°, 30.07 ± 0.2°, 31.68 ± 0.2°, and 32.63 ± 0.2°.
The acid addition salt of claim 1 or 2, wherein the salt is dimesylate having crystalline form B having an X-ray powder diffraction pattern as shown in figure 3.
The acid addition salt of claim 1 or 2, wherein the salt is dimesylate having crystalline form B having a differential scanning calorimetry thermogram as shown in figure 4.
The acid addition salt of claim 1 or 2, wherein the salt is dimaleate having crystalline form A exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 20.62 ± 0.2°, 21.59 ± 0.2°, 21.98 ± 0.2°, 23.26 ± 0.2°, 25.86 ± 0.2°, and 28.04 ± 0.2°.
The acid addition salt of claim 1 or 2, wherein the salt is dimaleate having crystalline form A having a differential scanning calorimetry thermogram comprising an endothermic peak at 192.25℃ ± 3℃.
The acid addition salt of claim 1 or 2, wherein the salt is dimaleate having crystalline form A exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 19.67 ± 0.2°, 20.18 ± 0.2°, 20.62 ± 0.2°, 21.59 ± 0.2°, 21.98 ± 0.2°, 22.84 ± 0.2°, 23.26 ± 0.2°, 24.07 ± 0.2°, 25.86 ± 0.2°, and 28.04 ± 0.2°.
The acid addition salt of claim 1 or 2, wherein the salt is dimaleate having crystalline form A exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 7.13 ± 0.2°, 8.97 ± 0.2°, 10.73 ± 0.2°, 12.38 ± 0.2°, 14.14 ± 0.2°, 14.35 ± 0.2°, 14.80 ± 0.2°, 15.33 ± 0.2°, 15.59 ± 0.2°, 16.29 ± 0.2°, 16.48 ± 0.2°, 16.74 ± 0.2°, 17.83 ± 0.2°, 18.05 ± 0.2°, 18.65 ± 0.2°, 19.03 ± 0.2°, 19.67 ± 0.2°, 20.18 ± 0.2°, 20.62 ± 0.2°, 21.00 ± 0.2°, 21.59 ± 0.2°, 21.98 ± 0.2°, 22.84 ± 0.2°, 23.26 ± 0.2°, 23.53 ± 0.2°, 24.07 ± 0.2°, 24.53 ± 0.2°, 24.88 ± 0.2°, 25.50 ± 0.2°, 25.86 ± 0.2°, 26.29 ± 0.2°, 26.71 ± 0.2°, 27.21 ± 0.2°, 28.04 ± 0.2°, 28.49 ± 0.2°, 28.86 ± 0.2°, 29.40 ± 0.2°, 30.18 ± 0.2°, 31.32 ± 0.2°, 31.62 ± 0.2°, 32.53 ± 0.2°, 33.43 ± 0.2°, 34.36 ± 0.2°, 34.74 ± 0.2°, 35.14 ± 0.2°, 36.21 ± 0.2°, 36.80 ± 0.2°, and 37.76 ± 0.2°.
The acid addition salt of claim 1 or 2, wherein the salt is dimaleate having crystalline form A having an X-ray powder diffraction pattern as shown in figure 5.
The acid addition salt of claim 1 or 2, wherein the salt is dimaleate having crystalline form A having a differential scanning calorimetry thermogram as shown in figure 6.
The acid addition salt of claim 1 or 2, wherein the salt is dimaleate having crystalline form B exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 16.29 ± 0.2°, 26.06 ± 0.2°, 27.65 ± 0.2°, and 28.35 ± 0.2°.
The acid addition salt of claim 1 or 2, wherein the salt is dimaleate having crystalline form B having a differential scanning calorimetry thermogram comprising an endothermic peak at 157.96℃ ± 3℃.
The acid addition salt of claim 1 or 2, wherein the salt is dimaleate having crystalline form B exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 8.10 ± 0.2°, 12.58 ± 0.2°, 16.29 ± 0.2°, 18.65 ± 0.2°, 19.07 ± 0.2°, 22.46 ± 0.2°, 26.06 ± 0.2°, 27.65 ± 0.2°, and 28.35 ± 0.2°.
The acid addition salt of claim 1 or 2, wherein the salt is dimaleate having crystalline form B exhibiting characteristic X-ray powder diffraction peaks expressed as 2θ at 5.58 ± 0.2°, 8.10 ± 0.2°, 10.47 ± 0.2°, 11.82 ± 0.2°, 12.58 ± 0.2°, 13.07 ± 0.2°, 13.96 ± 0.2°, 15.01 ± 0.2°, 15.41 ± 0.2°, 16.29 ± 0.2°, 16.96 ± 0.2°, 17.76 ± 0.2°, 18.65 ± 0.2°, 19.07 ± 0.2°, 20.32 ± 0.2°, 21.60 ± 0.2°, 22.46 ± 0.2°, 23.82 ± 0.2°, 24.46 ± 0.2°, 25.57 ± 0.2°, 26.06 ± 0.2°, 27.65 ± 0.2°, 28.35 ± 0.2°, 29.26 ± 0.2°, 30.30 ± 0.2°, 31.87 ± 0.2°, 33.25 ± 0.2°, 34.30 ± 0.2°, 37.47 ± 0.2°, 38.40 ± 0.2°, and 39.44 ± 0.2°.
The acid addition salt of claim 1 or 2, wherein the salt is dimaleate having crystalline form B having an X-ray powder diffraction pattern as shown in figure 7.
The acid addition salt of claim 1 or 2, wherein the salt is dimaleate having crystalline form B having a differential scanning calorimetry thermogram as shown in figure 8.
The acid addition salt of claim 1 or 2, wherein the salt is dimaleate amorphism having an X-ray powder diffraction pattern as shown in figure 9.
A pharmaceutical composition comprising the acid addition salt of any one of claims 1 to 27, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof.
The pharmaceutical composition of claim 28 further comprising an additional therapeutic agent.
The pharmaceutical composition of claim 29, wherein the additional therapeutic agent is a chemotherapeutic agent, an antiproliferative agent, a medicament for the treatment of non-small cell lung cancer, a medicament for the treatment of epidermal cancer or a combination thereof; or

wherein the additional therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatinum, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbozine, methotrexate, fluorouracil, cytosine arabinoside, gemcitabine, purinethol, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogue, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon α, calcium folinate, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab or a combination thereof.
Use of the acid addition salt of any one of claims 1 to 27 or the pharmaceutical composition of any one of claims 28 to 30 in the manufacture of a medicament for preventing, treating or alleviating a proliferative disease, atherosclerosis, or pulmonary fibrosis in a patient.
The use of claim 31, wherein the proliferative disease is metastatic carcinoma, colon cancer, gastric adenocarcinoma, bladder carcinoma, breast carcinoma, renal carcinoma, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostatic cancer, pancreatic cancer, central nervous system cancer, spongioblastoma or a myeloproliferative disease.
Use of the acid addition salt of any one of claims 1 to 27 thereof or the pharmaceutical composition of any one of claims 28 to 30 in the manufacture of a medicament for modulating protein kinase activity.
The use of claim 33, wherein the protein kinase is a receptor tyrosine kinase.
The use of claim 34, wherein the receptor tyrosine kinase is EGFR, EGFR T790M, HER-2, or a combination thereof.
A pharmaceutical combination comprising the acid addition salt of any one of claims 1 to 27 and an additional therapeutic agent.
The pharmaceutical combination of claim 36, wherein the additional therapeutic agent is a chemotherapeutic agent, an antiproliferative agent, a medicament for the treatment of non-small cell lung cancer, a medicament for the treatment of epidermal cancer or a combination thereof; or

wherein the additional therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cis-platinum, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbozine, methotrexate, fluorouracil, cytosine arabinoside, gemcitabine, purinethol, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogue, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon α, calcium folinate, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab or a combination thereof.
The acid addition salt of any one of claims 1 to 27 or the pharmaceutical composition of any one of claims 28 to 30 for use in preventing, treating or alleviating a proliferative disease, atherosclerosis, or pulmonary fibrosis in a patient.
The acid addition salt or the pharmaceutical composition of claim 38, wherein the proliferative disease is metastatic carcinoma, colon cancer, gastric adenocarcinoma, bladder carcinoma, breast carcinoma, renal carcinoma, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostatic cancer, pancreatic cancer, central nervous system cancer, spongioblastoma or a myeloproliferative disease.
The acid addition salt of any one of claims 1 to 27 or the pharmaceutical composition of any one of claims 28 to 30 for use in modulating protein kinase activity.
The acid addition salt or a combination thereof or the pharmaceutical composition of claim 40, wherein the protein kinase is a receptor tyrosine kinase.
The acid addition salt or a combination thereof or the pharmaceutical composition of claim 41, wherein the receptor tyrosine kinase is EGFR, EGFR T790M, HER-2, or a combination thereof.
A method of preventing, treating or alleviating a proliferative disease, atherosclerosis, or pulmonary fibrosis, comprising administering to a patient in need of such treatment a therapeutically effective amount of the acid addition salt of any one of claims 1 to 27 or the pharmaceutical composition of any one of claims 28 to 30.
The method of claim 43, wherein the proliferative disease is metastatic carcinoma, colon cancer, gastric adenocarcinoma, bladder carcinoma, breast carcinoma, renal carcinoma, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostatic cancer, pancreatic cancer, central nervous system cancer, spongioblastoma or a myeloproliferative disease.
A method of modulating protein kinase activity, comprising administering to a subject a therapeutically effective amount of the acid addition salt of any one of claims 1 to 27 or the pharmaceutical composition of any one of claims 28 to 30.
The method of claim 45, wherein the protein kinase is a receptor tyrosine kinase.
The method of claim 46, wherein the receptor tyrosine kinase is EGFR, EGFR T790M, HER-2, or a combination thereof.