Tricyclic heteroaryl-containing compounds
阅读说明：本技术 一类含有三环杂芳基的化合物 (Tricyclic heteroaryl-containing compounds ) 是由 张汉承 刘世峰 叶向阳 于 2017-12-12 设计创作，主要内容包括：本发明提供了一类含有三环杂芳基化合物。具体地,本发明提供了如下式(I)所示结构的化合物(各基团定义如说明书中所述)、含有式(I)化合物的药物组合物及所述化合物,以及这些化合物的同位素衍生物,手性异构体,变构体,不同的盐,前药,制剂等等。其能够有效抑制蛋白激酶(例如EGFR,FAK,SYK,FLT-3,Axl,CDK,JAK等),从而起到治疗各种肿瘤,非酒精性肝病(NASH),肺纤微化(IPF)等相关多种疾病的作用。<Image he="348" wi="247" file="DDA0002292317220000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention provides a tricyclic heteroaryl-containing compound. Specifically, the invention provides a compound with a structure shown as the following formula (I) (each group is defined as the specification), a pharmaceutical composition containing the compound of the formula (I), the compound, and isotopic derivatives, chiral isomers, variants, different salts, prodrugs, preparations and the like of the compound. It can effectively inhibit protein kinases (such as EGFR, FAK, SYK, FLT-3, Axl, CDK, JAK, etc.), thereby treating various tumorsTumor, nonalcoholic liver disease (NASH), pulmonary fibrosis (IPF) and other related diseases.)
1. A compound having a structure represented by the following formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof:
wherein M is a group represented by the following formula (II):
in formula (I) and formula (II):
"+" indicates a chiral center;
a is selected from aryl or heteroaryl;
b is
U is NRdO or S;
x is hydrogen, halogen, C1-4Alkyl radical, C1-4Haloalkyl, C3-6Cycloalkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, 3-to 10-membered heterocyclyl, ORe、SRe、NReRe、CN、C(O)Re、C(O)ORe，C(O)NReRe、OC(O)Re、NReC(O)ReOr S (O)2Re；
J and G are each independently NRf、O、S、S(O)、S(O)2Or CRgRg；
R1And R2Each independently selected from the group consisting of: hydrogen, halogen, C1-4Alkyl radical, C3-6Cycloalkyl, 3-to 8-membered heterocyclyl, or C (O) NReRe(ii) a Wherein said alkyl, cycloalkyl, heterocyclyl may optionally be substituted with one or more RcSubstitution;
each R is3Each independently of the other being hydrogen, or C1-4An alkyl group; when two R are3When both R are attached to the same carbon atom3The carbon atoms to which they are attached may optionally be taken together to form a carbonyl group (C ═ O);
n is 0,1, 2, or 3;
Rais hydrogen, C1-4Alkyl radical, C3-6Cycloalkyl, or 3-to 12-membered heterocyclyl; wherein the alkyl, cycloalkyl and heterocyclyl groups may be optionally and independently substituted by one OR more halogen, ORe、CN、SO2NReReSubstitution, provided that the chemical formula formed is stable and meaningful;
Rbis aryl, heteroaryl, C1-4Alkyl radical, C3-8Cycloalkyl, 3-to 12-membered heterocyclyl, C (O)ReOr C (O) NReRe(ii) a Wherein said aryl, heteroaryl, alkyl, cycloalkyl, heterocyclyl may optionally be substituted with one or more RcSubstitution;
each R iscEach independently of the other being halogen, C1-4Alkyl radical, C3-8Cycloalkyl, 3-to 8-membered heterocyclyl, C (O) NReRe、NReC(O)Re、OReCN, or SO2NReRe；
RdIs hydrogen or C1-4An alkyl group;
each R iseEach independently selected from the group consisting of: hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, C2-4Alkenyl radical, C2-4Alkynyl, C3-8Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl; or two ReTogether with the nitrogen atom to which they are attached form a 3-to 8-membered heterocyclic group containing 1 or 2N atoms and 0 or 1 heteroatom selected from O, S;
Rfis hydrogen, C1-8Alkyl radical, C1-8Haloalkyl, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, C (O) Re、C(O)ORe、C(O)NReRe、S(O)2ReOr S (O)2NRhRh；
Each R isgEach independently selected from the group consisting of: hydrogen, halogen, or C1-4An alkyl group; or two RgTogether with the carbon atom to which they are attached form a carbonyl group (C ═ O); or two RgTogether with the same carbon atom to which it is attached, form a 3-to 8-membered cyclic structure optionally containing 0,1 or 2 heteroatoms selected from N, O, S;
each R ishEach independently of the other being hydrogen, or C1-4An alkyl group; or two RhTogether with the nitrogen atom to which they are attached form a 3-to-membered cyclic structure
Wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cyclic structure, aryl and heteroaryl is optionally substitutedAnd each independently substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, C1-4Alkyl radical, C1-4Haloalkyl, C2-4Alkenyl radical, C2-4Alkynyl, C3-8Cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, CN, NO2、ORe、SRe、NReRe、C(O)Re、C(O)ORe、C(O)NReRe、NReC(O)ReOr S (O)2ReProvided that the chemical structure formed is stable and meaningful;
the above-mentioned aryl group is an aromatic group having 6 to 12 carbon atoms unless otherwise specified; heteroaryl is a 5-to 15-membered heteroaromatic group; a cyclic group whose cyclic structure is saturated or unsaturated, containing or not containing a heteroatom;
with the proviso that A is not selected from the group consisting of:
wherein ". x" indicates a connection to U; "x" indicates a connection to B;
and said compound of formula (I) is not
2. The compound of claim 1, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, wherein M is a group of formula (IIa):
x, R therein3G, and n are as defined in claim 1.
3. The compound of any one of claims 1-2, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, wherein M is selected from the group consisting of formula (IIb), formula (IIc), or formula (IId):
wherein R isfIs as defined in claim 1.
4. The compound of any one of claims 1-3, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, wherein each A in formula (I) is independently selected from the group consisting of:
wherein ". x" indicates a connection to U; "x" indicates a connection to B;
u is NRd。
5. The compound of claim 1, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, of formula (I):
x is hydrogen, halogen, C1-4Alkyl radical, C1-4Haloalkyl, C3-6Cycloalkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, 3-to 10-membered heterocyclyl, ORe、SRe、NReRe、CN、C(O)Re、C(O)ORe，C(O)NReRe、OC(O)Re、NReC(O)ReOr S (O)2Re；
G is NRf、O、S、S(O)、S(O)2Or CRgRg；
R1Selected from the group consisting of: hydrogen, halogen, C1-4Alkyl radical, C3-6Cycloalkyl, 3-to 8-membered heterocyclyl, or C (O) NReRe(ii) a Wherein said alkyl, cycloalkyl, heterocyclyl may optionally be substituted with one or more RcSubstitution;
each R is3Each independently of the other being hydrogen, or C1-4An alkyl group; when two R are3When both R are attached to the same carbon atom3The carbon atoms to which they are attached may optionally be taken together to form a carbonyl group (C ═ O);
n is 0,1, 2, or 3;
each R iscEach independently of the other being halogen, C1-4Alkyl radical, C3-8Cycloalkyl, 3-to 8-membered heterocyclyl, C (O) NReRe、NReC(O)Re、OReCN, or SO2NReRe；
Each R iseEach independently selected from the group consisting of: hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, C2-4Alkenyl radical, C2-4Alkynyl, C3-8Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl; or two ReTogether with the nitrogen atom to which they are attached form a 3-to 8-membered heterocyclic group containing 1 or 2N atoms and 0 or 1 heteroatom selected from O, S;
Rfis hydrogen, C1-8Alkyl radical, C1-8Haloalkyl, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, C (O) Re、C(O)ORe、C(O)NReRe、S(O)2ReOr S (O)2NRhRh；
Each R isgEach independently selected from the group consisting of: hydrogen, halogen, or C1-4An alkyl group; or two RgTogether with the carbon atom to which they are attached form a carbonyl group (C ═ O); or two RgTogether with the same carbon atom to which they are attached form a 3-to 8-membered cyclic structureStructure optionally contains 0,1 or 2 heteroatoms selected from N, O, S;
each R ishEach independently of the other being hydrogen, or C1-4An alkyl group; or two RhTogether with the nitrogen atom to which they are attached form a 3-to-membered cyclic structure;
wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cyclic structure, aryl and heteroaryl is optionally and independently substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, C1-4Alkyl radical, C1-4Haloalkyl, C2-4Alkenyl radical, C2-4Alkynyl, C3-8Cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, CN, NO2、ORe、SRe、NReRe、C(O)Re、C(O)ORe、C(O)NReRe、NReC(O)ReOr S (O)2ReProvided that the chemical structure formed is stable and meaningful;
the above-mentioned aryl group is an aromatic group having 6 to 12 carbon atoms unless otherwise specified; heteroaryl is a 5-to 15-membered heteroaromatic group; the cyclic structure is a saturated or unsaturated, heteroatom-containing or heteroatom-free cyclic group.
6. The compound of claim 5, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof,
wherein R isfIs as defined in claim 5.
7. The compound of claim 5, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof,
x is H;
g is NRfOr O; wherein R isfAs defined in claim 5;
R1selected from hydrogen, halogen, or C1-4An alkyl group;
each R is3Each independently is hydrogen, or two R3Taken together at the same carbon atom to form a carbonyl group (C ═ O);
n is 0,1, or 2.
8. The compound of any one of claims 5-7, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, formula (I) is:
wherein R isfComprises the following steps: methyl, methyl,
9. The compound of claim 1, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, wherein the compound is selected from the group consisting of:
10. use of a compound of formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, as claimed in any one of claims 1 to 9, for:
(a) preparing a medicament for treating diseases related to the activity or expression amount of protein kinase;
(b) preparing a protein kinase targeted inhibitor; and/or
(c) Non-therapeutically inhibiting the activity of a protein kinase in vitro;
wherein the protein kinase is CDK.
11. The use of a compound according to any one of claims 1 to 9, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, as a CDK inhibitor or in the treatment of a disorder associated with high CDK expression.
12. A pharmaceutical composition, comprising: (i) an effective amount of a compound of any one of claims 1-9, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof; and (ii) a pharmaceutically acceptable carrier.
13. A process for the preparation of a compound as claimed in claim 1, which process comprises the steps of:
reacting Ia compound with Ib in an inert solvent to obtain a compound shown in the formula I;
preferably said compound of formula Ia is prepared by:
(i) reacting a compound of formula (Va) with a compound of formula (Vb) under alkaline conditions to obtain compounds of formula (Vc-1) and (Vc-2);
optionally (ii) reacting the compounds of formulae (Vc-1) and (Vc-2) respectively under acidic conditions, thereby deprotecting;
(iii) respectively reacting the compounds of the formulas (Vc-1) and (Vc-2) with the protecting groups removed to respectively obtain compounds of the formulas (Vd-1) and (Vd-2);
and optionally (iv) reducing the compounds of formulae (Vd-1) and (Vd-2), respectively, to give compounds of formulae (V-1) and (V-2), respectively.
Technical Field
The present invention relates to the field of pharmaceutical chemistry; in particular, the invention relates to a novel derivative containing tricyclic heteroaryl, a synthesis method thereof and application of the derivative as one or more protein kinase inhibitors in preparing medicaments for treating tumors, nonalcoholic steatohepatitis (NASH), Idiopathic Pulmonary Fibrosis (IPF) and other related diseases.
Background
Cancer, also known as malignant tumor, is one of the diseases with the highest morbidity and mortality in the world and is characterized by abnormal proliferation and metastasis of cells, spreading and metastasizing within a short time or relatively short time after the onset of disease. Conventional treatment regimens include resection (if resection conditions are met), radiation therapy, and chemotherapy. The target therapy developed in recent years has the advantages of reducing toxicity and side effects on patients, improving survival rate and the like. However, the target drug will develop drug resistance for a period of time, and then the growth spread of cancer cells will be abnormally rapid. Common cancers are: blood cancer, lung cancer, liver cancer, bladder cancer, rectal cancer, stomach cancer, and the like.
Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, fibrotic, interstitial lung disease with lesions confined to the lungs, well-developed in the elderly population, characterized by common interstitial pneumonia (UIP) and unclear etiology by pulmonary histology and/or high-resolution ct (hrct) in the chest. As a chronic interstitial lung disease, IPF is hidden and gradually worsened, or is manifested as acute exacerbation. The mean survival after IPF diagnosis is only 2.8 years, with mortality higher than most tumors, IPF is known as a "tumor-like disease".
Non-alcoholic fatty liver disease (NASH) refers to the clinical pathological syndrome characterized mainly by excessive fat deposition in liver cells due to the exclusion of alcohol and other definite liver damage factors, and acquired metabolic stress liver injury closely related to insulin resistance and genetic susceptibility. With the global epidemic trend of obesity and related metabolic syndrome, the nonalcoholic fatty liver disease becomes an important cause of chronic liver disease in developed countries such as Europe and America and affluent areas of China, the prevalence rate of NAFLD of common adults is 10% -30%, wherein 10% -20% of NASH is NASH, and the incidence rate of cirrhosis of liver in 10 years of NASH is up to 25%. Non-alcoholic fatty liver disease can directly cause decompensated liver cirrhosis, hepatocellular carcinoma and relapse of transplanted liver, can affect the progress of other chronic liver diseases, and is involved in the onset of type 2 diabetes and atherosclerosis. Malignant tumors related to metabolic syndrome, arteriosclerotic cardiovascular and cerebrovascular diseases and liver cirrhosis are important factors influencing the quality of life and the life expectancy of non-alcoholic fatty liver patients. For this reason, non-alcoholic fatty liver disease is a new challenge in the contemporary medical field, and the harm of non-alcoholic fatty liver disease to human health will continue to increase in the near future.
With the progress of the research on the molecular biology of tumors, people increasingly know the molecular mechanisms of tumor development and different pathogenic targets. Among the many information transduction and pathways involved in inducing cancer, protein kinases are a class of biologically active entities that catalyze the transfer of the gamma phosphate group of ATP to the residues of many important proteins, phosphorylate them, and transmit signals, thus participating in a series of cellular activities, and being closely related to cell growth, differentiation, and proliferation. The development of selective protein kinase inhibitors to block or modulate diseases caused by these abnormal signaling pathways has been considered as an effective research strategy for the development of antitumor drugs. Have been validated in clinical trials and several protein kinase inhibitors have been approved for marketing.
Epidermal growth factor receptor tyrosine kinase (EGFR) is a transmembrane glycoprotein composed of 1186 amino acids and having a coded molecular weight of 170-kDa. EGFR is capable of mediating multiple signal transduction pathways to transmit extracellular signals into cells, and plays an important regulatory role in the proliferation, differentiation and apoptosis of normal and tumor cells (Cell,2000,100, 113-127). EGFR is a constitutively expressed component of many normal epithelial tissues (e.g., skin and hair follicles), while in most solid tumors, EGFR is either overexpressed or highly expressed. For example, in lung cancer, the expression rate of EGFR reaches 40-80%. Therefore, EGFR is selectively inhibited, the signal transduction path mediated by EGFR is interfered, the aim of treating lung cancer can be achieved, and a feasible way is opened for targeted treatment of lung cancer. In clinical treatment, EGFR targeting drugs such as gefitinib are combined with traditional radiotherapy and chemotherapy
The spleen tyrosine kinase (SYK) gene was first cloned from pig spleen cDNA in 1991 and encodes an unresponsive protein tyrosine kinase. Human SYK gene is located in chromosome 9 q22 region, SYK protein contains 635 amino acids, and plays an important role in autoimmune diseases and hematological malignancies, for example, SYK gene can inhibit proliferation and metastasis of malignant tumor cells such as breast cancer, melanoma and liver cancer. Currently, SYK inhibitors have been used in phase II/III clinical trials in rheumatoid arthritis, chronic lymphocytic leukemia, and the like. Recent studies have shown that the use of SYK inhibitors or interfering with the expression of the SYK gene can effectively slow down the progression of liver fibrosis/cirrhosis, with a good therapeutic effect (see CN 105664178A).
Focal Adhesion Kinase (FAK) is an unresponsive tyrosine protein Kinase identified in 1992 as a highly phosphorylated protein associated with the oncogene v-src, located in the integrin-rich Focal Adhesion region of normal cells. FAK is an important framework protein in cells and a key molecule of various signal pathways, and plays an important role in cell survival, proliferation and migration and invasion. Multiple scientific studies indicate that FAK inhibitors may be effective antitumor drugs. Recent scientific studies have also shown that FAK inhibitors may also be effective in the treatment of pulmonary fibrosis.
AXL is an important tyrosine receptor kinase, and is known as AXL receptor tyrosine kinase. AXL is also known as UFO/ARK/Tyro, and its ligand is vitamin K-dependent growth promoting factor GAS 6. AXL was first discovered as a transforming gene in Chronic Myelogenous Leukemia (CML). AXL is overexpressed in metastatic colon cancer, thyroid cancer, breast cancer, prostate cancer, and melanoma. Inhibition of AXL activity may serve the purpose of inhibiting tumor growth, spread and metastasis.
FLT-3(Fms-related tyrosine kinase 3) belongs to a family member of type III receptor tyrosine kinases, and is a signaling molecule. FLT-3 is expressed in various tissues such as liver, spleen, lymph, brain, placenta and gonad, and also expressed in normal bone marrow cells and lymphoid cell precursors, and is expressed in a plurality of hematopoietic malignant diseases, and the signal conduction pathway of the FLT-3 is related to a plurality of tumor conduction pathways, so that the FLT-3 becomes an ideal anti-tumor drug action target.
The regulation of the cell cycle is mainly affected by a series of serine/threonine kinases, also called Cyclin-dependent kinases (CDKs), which, by binding to their corresponding regulatory subunits, cyclins, facilitate the progression of the cell cycle, the transcription of genetic information and the normal division and proliferation of cells. CDK4/6 is a key regulator of the cell cycle and is capable of triggering a transition of the cell cycle from the growth phase (Gl phase) to the DNA replication phase (SI phase). During cell proliferation, the complex formed by cyclin d (cyclin d) and CDK4/6 can phosphorylate retinoblastoma protein (Rb). Once the tumor suppressor protein Rb-is phosphorylated, releasing its transcription factor E2F, which is tightly bound in an unphosphorylated state, E2F activates further transcription driving the cell cycle through a restriction site (R site) and progressing from Gl phase to S phase, into the cycle of cell proliferation. Therefore, the inhibition of CDK4/6 to make it unable to form CyclinD-CDK4/6 complex can block the progress of cell cycle from Gl phase to S phase, thereby achieving the purpose of inhibiting tumor proliferation.
Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signals from membrane receptors to STAT transcription factors. Scientific research shows that JAK inhibition can become a promising target of anticancer drugs.
In view of the above, the development of novel protein kinase inhibitors is of great significance.
Disclosure of Invention
The invention aims to provide a novel protein kinase inhibitor.
In a first aspect of the present invention, there is provided a compound having a structure represented by the following formula (I):
wherein M is a group represented by the following formula (II):
in formula (I) and formula (II):
"+" indicates a chiral center;
a is selected from aryl or heteroaryl;
b is aryl, heteroaryl, C3-8Cycloalkyl, 3-to 12-membered heterocyclyl, NRaRb、ORb、SRbOr SO2RbWherein said aryl, heteroaryl, cycloalkyl, heterocyclyl may be independently substituted with one or more RcSubstitution;
u is NRdO or S;
x is hydrogen, halogen, C1-4Alkyl radical, C1-4Haloalkyl, C3-6Cycloalkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, 3-to 10-membered heterocyclyl, ORe、SRe、NReRe、CN、C(O)Re、C(O)ORe，C(O)NReRe、OC(O)Re、NReC(O)ReOr S (O)2Re；
J and G are each independently NRf、O、S、S(O)、S(O)2Or CRgRg；
R1And R2Each independently selected from the group consisting of: hydrogen, halogen, C1-4Alkyl radical, C3-6Cycloalkyl, 3-to 8-membered heterocyclyl, or C (O) NReRe(ii) a Wherein said alkyl, cycloalkyl, heterocyclyl may optionally be substituted with one or more RcSubstitution;
each R is3Each independently of the other being hydrogen, or C1-4An alkyl group; when two R are3When both R are attached to the same carbon atom3The carbon atoms to which they are attached may optionally be taken together to form a carbonyl group (C ═ O);
n is 0,1, 2, or 3;
Rais hydrogen, C1-4Alkyl radical, C3-6Cycloalkyl, or 3-to 12-membered heterocyclyl; wherein the alkyl, cycloalkyl and heterocyclyl groups may be optionally and independently substituted by one OR more halogen, ORe、CN、SO2NReReSubstitution, provided that the chemical formula formed is stable and meaningful;
Rbis aryl, heteroaryl, C1-4Alkyl radical, C3-8Cycloalkyl, 3-to 12-membered heterocyclyl, C (O) ReOr C (O) NReRe(ii) a Wherein said aryl, heteroaryl, alkyl, cycloalkyl, heterocyclyl may optionally be substituted with one or more RcSubstitution;
each R iscEach independently of the other being halogen, C1-4Alkyl radical, C3-8Cycloalkyl, 3-to 8-membered heterocyclyl, C (O) NReRe、NReC(O)Re、OReCN, or SO2NReRe；
RdIs hydrogen or C1-4An alkyl group;
each R iseEach independently selected from the group consisting of: hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, C2-4Alkenyl radical, C2-4Alkynyl, C3-8Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl; or two ReTogether with the nitrogen atom to which they are attached form a 3-to 8-membered heterocyclic group containing 1 or 2N atoms and 0 or 1 heteroatom selected from O, S;
Rfis hydrogen, C1-8Alkyl radical, C1-8Haloalkyl, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, C (O) Re、C(O)ORe、C(O)NReRe、S(O)2ReOr S (O)2NRhRh；
Each R isgEach independently selected from the group consisting of: hydrogen, halogen, or C1-4An alkyl group; or two RgTogether with the carbon atom to which they are attached form a carbonyl group: (C ═ O); or two RgTogether with the same carbon atom to which it is attached, form a 3-to 8-membered cyclic structure optionally containing 0,1 or 2 heteroatoms selected from N, O, S;
each R ishEach independently of the other being hydrogen, or C1-4An alkyl group; or two RhTogether with the nitrogen atom to which they are attached form a 3-to-membered cyclic structure
Wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cyclic structure, aryl and heteroaryl is optionally and independently substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, C1-4Alkyl radical, C1-4Haloalkyl, C2-4Alkenyl radical, C2-4Alkynyl, C3-8Cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, CN, NO2、ORe、SRe、NReRe、C(O)Re、C(O)ORe、C(O)NReRe、NReC(O)ReOr S (O)2ReProvided that the chemical structure formed is stable and meaningful;
the above-mentioned aryl group is an aromatic group having 6 to 12 carbon atoms unless otherwise specified; heteroaryl is a 5-to 15-membered heteroaromatic group; a cyclic group whose cyclic structure is saturated or unsaturated, containing or not containing a heteroatom;
with the proviso that A is not selected from the group consisting of:
wherein ". x" indicates a connection to U; "x" indicates a connection to B;
and said compound of formula (I) is not
In another preferred embodiment, M is a group represented by the following formula (IIa):
x, R therein3G, and n are as defined above.
In another preferred embodiment, M is selected from the group consisting of formula (IIb), formula (IIc), or formula (IId):
wherein R isfIs as defined above.
In another preferred embodiment, a in formula (I) is each independently selected from the following groups:
wherein ". x" indicates a connection to U; "x" indicates a connection to B;
u is NRd。
In another preferred embodiment, in formula (I), B is selected from the group consisting of: -NH-aryl, -NH-C3-8Cycloalkyl, -NH- (3-to 12-membered heterocyclyl), heteroaryl, C3-8Cycloalkyl, 3-to 12-membered heterocyclyl, wherein any of the above aryl, heteroaryl, cycloalkyl, heterocyclyl (alone or together with other groups forming substituents) may be independently substituted with one or more RcAnd (4) substitution.
In another preferred embodiment, in formula (I), B is selected from the group consisting of:
in another preferred embodiment, R1、R2A, U, M, B are the corresponding groups for each of the specific compounds of formula (I) prepared in the examples.
In another preferred embodiment, formula (I) is:
x is H;
g is NRfOr O; wherein R isfAs defined above;
R1selected from hydrogen, halogen, or C1-4Alkyl, wherein said alkyl may be optionally substituted with one or more halogens;
each R is3Each independently is hydrogen, or two R3Taken together at the same carbon atom to form a carbonyl group (C ═ O);
n is 0,1, or 2.
In another preferred embodiment, formula (I) is:
x is H;
g is NRfOr O; wherein R isfIs as defined above;
R1selected from hydrogen, halogen, or C1-4An alkyl group;
each R is3Each independently is hydrogen, or two R3Taken together at the same carbon atom to form a carbonyl group (C ═ O);
n is 0,1, or 2.
In another preferred embodiment, formula (I) is:
x is H;
g is NRfOr O; wherein R isfIs as defined in the first aspect of the invention;
R1selected from hydrogen, halogen, or CONH2；
Each R is3Each independently is hydrogen, or two R3Taken together at the same carbon atom to form a carbonyl group (C ═ O);
n is 0,1, or 2.
In another preferred embodiment, formula (I) is:
x is H;
g is NRfOr O; wherein R isfThe definition of (1) is as above;
R1selected from hydrogen, or C1-4An alkyl group; r2Is CONH2；
Each R is3Each independently is hydrogen, or two R3Taken together at the same carbon atom to form a carbonyl group (C ═ O);
n is 0,1, or 2.
In another preferred embodiment, formula (I) is:
x is H;
g is NRfOr O; wherein R isfThe definition of (1) is as above;
R1selected from hydrogen, halogen, or C1-4Alkyl, wherein said alkyl may be optionally substituted with one or more halogens;
each R is3Each independently is hydrogen, or two R3Taken together at the same carbon atom to form a carbonyl group (C ═ O);
n is 0,1, or 2.
In another preferred embodiment, the compound is selected from one of the following groups:
in a second aspect of the present invention, there is provided a use of a compound according to the first aspect of the present invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, for:
(a) preparing a medicament for treating diseases related to the activity or expression amount of protein kinase;
(b) preparing a protein kinase targeted inhibitor; and/or
(c) Non-therapeutically inhibiting the activity of a protein kinase in vitro;
wherein the protein kinase is selected from the group consisting of but not limited to: EGFR, CDK, SYK, JAK, Flt-3, Axl, FAK, or combinations thereof.
In a third aspect of the present invention, there is provided a use of the compound according to the first aspect of the present invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, as an EGFR inhibitor, or for treating a disease associated with high expression of EGFR.
In a fourth aspect of the invention, there is provided a use of a compound according to the first aspect of the invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, as a CDK inhibitor, or for the treatment of a disorder associated with high CDK expression.
In a fifth aspect of the present invention, there is provided a use of the compound according to the first aspect of the present invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, as an inhibitor of SYK and JAK, or for treating a disease associated with high expression of SYK and JAK.
In a sixth aspect of the invention, there is provided the use of a compound according to the first aspect of the invention, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, as an Flt-3 and Axl inhibitor, or for the treatment of a disease associated with high expression of Flt-3 and Axl.
In a seventh aspect of the present invention, there is provided a use of the compound according to the first aspect of the present invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, as a FAK inhibitor, or for treating a disease associated with FAK overexpression.
In an eighth aspect of the present invention, there is provided a pharmaceutical composition, comprising: (i) an effective amount of a compound of formula I as described in the first aspect of the invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof; and (ii) a pharmaceutically acceptable carrier.
In a ninth aspect of the invention, there is provided a method of inhibiting protein kinase activity, the method comprising the steps of: administering to a subject an inhibitory effective amount of a compound of formula I as described in the first aspect of the invention, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, or administering to a subject an inhibitory effective amount of a pharmaceutical composition as described in the eighth aspect of the invention; wherein the protein kinase is selected from the group consisting of: EGFR, FAK, SYK, FLT-3, Axl, CDK, JAK, or combinations thereof.
In a tenth aspect of the present invention, there is provided a process for the preparation of a compound according to the first aspect of the present invention, which process comprises the steps of:
reacting Ia compound with Ib in an inert solvent to obtain a compound shown in the formula I;
preferably said compound of formula Ia is prepared by:
(i) reacting a compound of formula (Va) with a compound of formula (Vb) under alkaline conditions to obtain compounds of formula (Vc-1) and (Vc-2);
optionally (ii) reacting the compounds of formulae (Vc-1) and (Vc-2) respectively under acidic conditions, thereby deprotecting;
(iii) respectively reacting the compounds of the formulas (Vc-1) and (Vc-2) with the protecting groups removed to respectively obtain compounds of the formulas (Vd-1) and (Vd-2);
and optionally (iv) reducing the compounds of formulae (Vd-1) and (Vd-2), respectively, to give compounds of formulae (V-1) and (V-2), respectively.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventors have long and intensive research and unexpectedly found a protein kinase inhibitor containing tricyclic aryl compounds with a novel structure, and a preparation method and application thereof. The protein kinase inhibitor can inhibit various protein kinases including EGFR, FAK, SYK, FLT-3, Axl, CDK, JAK and the like. The compounds of the invention may be used in the treatment of various diseases associated with the activity of said kinases. Based on the above findings, the inventors have completed the present invention.
Term(s) for
Unless otherwise indicated, reference to "or" herein has the same meaning as "and/or" (meaning "or" and ").
Unless otherwise specified, each chiral carbon atom (chiral center) in all compounds of the invention may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
As used herein, the term "alkyl", alone or as part of another substituent, refers to a straight-chain (i.e., unbranched) or branched-chain saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched-chain groups. When the alkyl group is preceded by a carbon atom number limitation (e.g. C)1-10) When used, it means that the alkyl group contains 1 to 10 carbon atoms. E.g. C1-8Alkyl refers to an alkyl group having 1 to 8 carbon atoms, and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
As used herein, the term "alkenyl", alone or as part of another substituent, refers to a straight or branched chain carbon chain radical having at least one carbon-carbon double bond. Alkenyl groups may be substituted or unsubstituted. When the alkenyl radical is preceded by a carbon atom number limitation (e.g. C)2-8) When used, it means that the alkenyl group has 2 to 8 carbon atoms. E.g. C2-8Alkenyl means alkenyl having 2 to 8 carbon atoms and includes ethenyl, propenyl, 1, 2-butenyl, 2, 3-butenyl, butadienyl, or the like.
As used herein, the term "alkynyl", alone or as part of another substituent, refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group can be linear or branched, or a combination thereof. When alkynyl is preceded by a carbon atom number limitation (e.g. C)2-8Alkynyl) means that the alkynyl group contains 2 to 8 carbon atoms. For example, the term "C2-8Alkynyl "refers to straight or branched chain alkynyl groups having 2 to 8 carbon atoms and includes ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or the like.
As used herein, the term "cycloalkyl", alone or as part of another substituent, refers to a monocyclic, bicyclic, or polycyclic (fused, bridged, or spiro) ring system group having a saturated or partially saturated unit ring. When a cycloalkyl group is preceded by a carbon atom number limitation (e.g. C)3-10) When used, means that the cycloalkyl group contains 3 to 10 carbon atoms. In some preferred embodiments, the term "C3-8Cycloalkyl "refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or the like. "spirocycloalkyl" refers to a bicyclic or polycyclic group having a single ring with a common carbon atom (called the spiro atom) between them, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. ' ThickCycloalkyl "refers to an all-carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. "bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly connected, and these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. The cycloalkyl groups contain all carbon atoms. Some examples of cycloalkyl groups are given below, and the present invention is not limited to only the cycloalkyl groups described below.
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings. "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings) but must not contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be at a carbon atom on the ring which has a conjugated pi-electron system. The aryl group may be substituted or unsubstituted. Some examples of aryl groups are given below, and the present invention is not limited to only the aryl groups described below.
"heteroaryl" refers to a heteroaromatic group containing one to more heteroatoms. The hetero atoms referred to herein include oxygen, sulfur and nitrogen. Such as furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted. Some examples of heteroaryl groups are given below, to which the present invention is not limited. Of these, the last three heteroaryls are tricyclic heteroaryls, which are the focus of the present invention.
"Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl. Polycyclic heterocyclic groups refer to heterocyclic groups including spiro rings, fused rings, and bridged rings. "Spirocyclic heterocyclyl" refers to polycyclic heterocyclic groups in which each ring in the system shares one atom (referred to as a spiro atom) with other rings in the system, where one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "fused ring heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and in which one or more of the ring atoms is selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. "bridged heterocyclyl" means a polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system, and in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. If both saturated and aromatic rings are present in the heterocyclyl (e.g., the saturated and aromatic rings are fused together), the point of attachment to the parent moiety must be at the saturated ring. Note: when the point of attachment to the parent is on the aromatic ring, it is referred to as heteroaryl and not as heterocyclyl. The following are some examples of heterocyclic groups, and the present invention is not limited to only the heterocyclic groups described below.
As used herein, the term "halogen", alone or as part of another substituent, refers to F, Cl, Br, and I.
As used herein, the term "substituted" (with or without "optionally" modifying) means that one or more hydrogen atoms on a particular group is replaced with a particular substituent. Particular substituents are those described correspondingly in the foregoing, or as appearing in the examples. Unless otherwise specified, an optionally substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position. A cyclic substituent, such as a heterocyclic group, may be attached to another ring, such as a cycloalkyl group, to form a spiro bicyclic ring system, i.e., the two rings have a common carbon atom. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such substituents are for example (but not limited to): c1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, halogen, hydroxy, carboxy (-COOH), C1-8Aldehyde group, C2-10Acyl radical, C2-10Ester group and amino group.
For convenience and in accordance with conventional understanding, the terms "optionally substituted" or "optionally substituted" are only applicable to sites which can be substituted by substituents, and do not include those substitutions which are not chemically achievable.
As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of a subject (e.g., a human) without undue side effects. In some embodiments, pharmaceutically acceptable salts of a certain compound of the invention include salts of a compound of the invention having an acidic group (e.g., potassium, sodium, magnesium, calcium) or a basic group (e.g., sulfate, hydrochloride, phosphate, nitrate, carbonate).
The application is as follows:
the invention provides the use of a class of compounds of formula (I) or formula (II), or deuterated derivatives thereof, salts thereof, isomers (enantiomers or diastereomers, if present), hydrates, pharmaceutically acceptable carriers or excipients, for inhibiting protein kinases. Protein kinases referred to herein include, but are not limited to, EGFR, CDK, SYK, JAK, Flt-3, Axl, and FAK.
The compounds of the invention may be useful as inhibitors of one or more kinases, for example in some embodiments certain classes of compounds of the invention may be useful as inhibitors of EGFR kinases; in some embodiments, certain compounds of the invention are useful as CDK kinase inhibitors; in some embodiments, certain compounds of the present invention are useful as SYK kinase inhibitors; in some embodiments, certain compounds of the invention are useful as FAK kinase inhibitors; in some embodiments, certain classes of compounds of the invention are useful as dual inhibitors of SYK kinase and JAK kinase; in other embodiments, certain compounds of the invention are useful as dual inhibitors of Flt-3 kinase and Axl kinase.
In cancer patients, the expression or activity of the above-mentioned protein kinases is significantly increased. These overexpressed and/or abnormal levels of protein kinase activity are directly linked to the development of tumors. The compounds of the present invention are single and/or dual inhibitors of these protein kinases. Diseases are prevented, alleviated or cured by modulating the activity of these protein kinases. The diseases include allergic asthma, myelofibrosis, rheumatoid arthritis, B cell lymphoma, monocytic leukemia, splenomegaly, hypereosinophilic syndrome, primary thrombocytopenia, systemic giant cell disease, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, lung adenocarcinoma, squamous lung cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell cancer, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, stomach cancer, multiple myeloma and solid tumors, and the like.
In some respects, dual protein kinase inhibitors interfere with two different kinases simultaneously, and the resulting antitumor effects tend to be additive, thus having the potential to more effectively treat a variety of cancers.
The compounds of the invention can be used with biological agents such as PD-1 inhibitors
The compounds of the present invention and deuterated derivatives thereof, as well as pharmaceutically acceptable salts or isomers thereof (if present) or hydrates thereof and/or compositions thereof, may be formulated with pharmaceutically acceptable excipients or carriers for in vivo administration to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases the resulting compositions may be in the form of tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injectable solutions, sterile powders, and the like.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments.
General synthetic method of compound
The compound of formula I of the invention can be prepared by the following method:
reacting (Ia) with (Ib) in an inert solvent to obtain a compound (I);
in the above formulae, the groups are as defined above. Reagents and conditions for each step may be selected from those conventional in the art for carrying out such preparation methods, and such selection may be made by those skilled in the art after the structure of the compound of the present invention is disclosed, according to the knowledge in the art.
More specifically, the compound represented by the general formula I of the present invention can be prepared by the following method, however, the conditions of the method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to the following explanation. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
In the preparation method of the present invention, each reaction is usually carried out in an inert solvent at a reaction temperature of usually-20 to 150 ℃ (preferably 0 to 120 ℃). The reaction time in each step is usually 0.5 to 48 hours, preferably 2 to 12 hours.
Equation 1 describes the general synthetic methods for compounds 1-A7 and 1-A8:
reaction formula 1:
equation 2 describes a general synthetic approach for compounds 2-B4 and 2-B5:
reaction formula 2:
equation 3 describes a general synthetic method for compound 3-C8:
reaction formula 3:
equation 4 describes a general synthetic method for compound 4-D2:
reaction formula 4:
equation 5 describes the general synthetic method for compound 5-E2:
reaction formula 5:
equation 6 describes the general synthetic method for compound 6-F4:
reaction formula 6:
equation 7 describes a general synthetic method for compounds 7-G3:
reaction formula 7:
equation 8 describes a general synthetic method for compound 8-H3:
reaction formula 8:
equation 9 describes a general synthetic method for compounds 9-I2:
reaction formula 9:
equation 10 describes a general synthetic method for compound 10-J2:
reaction formula 10:
pharmaceutical compositions and methods of administration
Because the compound has excellent inhibitory activity on a series of protein kinases, the compound and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound as a main active ingredient can be used for treating, preventing and relieving diseases related to the activity or expression quantity of EGFR, FAK, SYK, FLT-3, Axl, CDK and JAK.
The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 5-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g.cellulose and its derivatives)Sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 5 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The main advantages of the invention include:
1. provides a compound shown as a formula I.
2. Provides an activity inhibitor of protein kinases such as EGFR, FAK, SYK, FLT-3, Axl, CDK, JAK and the like with novel structure, and preparation and application thereof, wherein the activity of the protein kinases can be inhibited by the inhibitor under extremely low concentration.
3. Provides a pharmaceutical composition for treating diseases related to the activity of protein kinases such as EGFR, FAK, SYK, FLT-3, Axl, CDK, JAK and the like.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.