Urea substituted aromatic ring-linked dioxane quinazoline or quinoline compound, composition and application thereof
阅读说明：本技术 脲取代的芳环连二噁烷并喹唑啉或喹啉类化合物、组合物及其应用 (Urea substituted aromatic ring-linked dioxane quinazoline or quinoline compound, composition and application thereof ) 是由 张强 于善楠 孙月明 郑南桥 杨磊夫 于 2019-08-20 设计创作，主要内容包括：本发明涉及作为VEGFR-2及CSF1R抑制剂的一类新化合物、组合物及其应用。具体地,本发明提供了一类具有强力抑制VEGFR-2及CSF1R活性的化合物(如式(1)所示)或其异构体、溶剂化物、水合物、在药学上可接受的盐、前药,及包含所述化合物的药物组合物。本发明还公开了本发明化合物或药物组合物在制备药物中的应用,该药物用于治疗自身免疫疾病、肿瘤以及阿尔兹海默病等疾病。<Image he="537" wi="700" file="DDA0002172926260000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to a novel compound serving as VEGFR-2 and CSF1R inhibitor, a composition and application thereof. Specifically, the invention provides a compound (shown as a formula (1)) with strong VEGFR-2 and CSF1R inhibiting activity, or an isomer, a solvate, a hydrate, a pharmaceutically acceptable salt and a prodrug thereof, and a pharmaceutical composition containing the compound. The invention also discloses application of the compound or the pharmaceutical composition in preparing medicaments for treating diseases such as autoimmune diseases, tumors, Alzheimer's disease and the like.)
1. A compound of structural formula (I), isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof:
wherein the content of the first and second substances,
q is N or CH;
g is O or NH;
R1is-H, or from 1 to 3 are selected from C1-C6Alkoxy group of (C)1-C6Alkylthio of, C1-C3Acyl, hydroxy, halogen, trifluoromethyl, cyano, -CONH2Oxo (═ O) or-NRaRbC substituted or unsubstituted by the substituent in (1)3-C8Or from 1 to 3 cycloalkyl groups selected from C1-C6Alkoxy group of (C)1-C6Alkylthio of, C1-C3Acyl, hydroxy, halogen, trifluoromethyl, cyano, -CONH2、C3-C7Cycloalkyl or-NRaRbC substituted or unsubstituted by a substituent of (A)1-C10Alkyl, or- (CH)2)n-R6Said R is6Is a substituted or unsubstituted 4-8-membered heteroalicyclic group, said 4-8-membered heteroalicyclic group being a 4-8-membered heteroalicyclic group containing 1-2 atoms selected from N, O, S as ring atoms, and said substituted 4-8-membered heteroalicyclic group being substituted with 1 to 3 atoms selected from halogen, C1-C3Alkyl of (C)1-C3Alkoxy group of (C)1-C3Alkylthio, hydroxy, -NRaRb、C1-C3Substitution in acyl, oxoSubstituted by a group, n is 0 to 10,
Raand RbEach independently is-H, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy-substituted C1-C6Alkyl radical, C1-C3Alkylthio substituted C1-C6Alkyl or mono-or di-C1-C3Alkyl-substituted or unsubstituted amino-substituted C1-C6An alkyl group;
R2、R3each independently is-H, -CF3Halogen, C1-C3Alkyl of (C)1-C3Alkoxy group of (a);
R4is-H, C1-C3An alkyl group;
R5is- (CH)2)mR7Wherein m is an integer of 0 to 3, said R7Is aryl or heteroaryl, substituted or unsubstituted by one to two substituents-A, each independently C1-C3Alkyl of (C)1-C3Alkoxy group of (C)1-C3Alkylthio, halogen, trifluoromethyl or methylsulfonyl,
the heteroaryl group is a monocyclic or bicyclic heteroaryl group having 1 to 3 heteroatoms selected from N, O, S as ring atoms and having 5 to 10 ring atoms.
2. The compound, isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein R is1is-H, or unsubstituted C3-C8Or from 1 to 3 cycloalkyl groups selected from C1-C6Alkoxy group of (C)1-C6Alkylthio of, C1-C3Acyl, hydroxy, -F, trifluoromethyl, cyano, -CONH2、C3-C6Cycloalkyl or-NRaRbC substituted or unsubstituted by a substituent of (A)1-C8An alkyl group, a carboxyl group,
or- (CH)2)n-R6Said R is6Is a substituted or unsubstituted 4-8-membered heteroalicyclic group, the 4-8-membered heteroalicyclic group is a 4-8-membered heteroalicyclic group containing 1-2 atoms selected from N, O, S as ring atoms, and the substituted 4-8-membered heteroalicyclic group is substituted with 1 to 3 atoms selected from-F, C1-C3Alkyl of (C)1-C3Alkoxy, hydroxy, -NRaRb、C1-C3Acyl and oxo, n is 0 to 8,
Raand RbEach independently is-H, C1-C6Alkyl radical, C3-C6Cycloalkyl, or C1-C3Alkoxy-substituted C1-C6An alkyl group.
3. The compound, isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 2, wherein R is1is-H, unsubstituted C3-C6From 1 to 3 cycloalkyl groups selected from C1-C3Alkoxy group of (C)1-C3Alkylthio of, C1-C3Acyl, hydroxy, -F, trifluoromethyl, cyano, -CONH2、C3-C5Cycloalkyl or-NRaRbC substituted or unsubstituted by a substituent of (A)1-C8An alkyl group, a carboxyl group,
or- (CH)2)n-R6Said R is6Is a substituted or unsubstituted 4-6-membered heteroalicyclic group, the 4-6-membered heteroalicyclic group is a 4-6-membered heteroalicyclic group containing 1-2 atoms selected from N, O, S as ring atoms, and the substituted 4-6-membered heteroalicyclic group is substituted with 1 to 3 atoms selected from-F, C1-C3Alkyl of (C)1-C3Alkoxy, hydroxy, -NRaRb、C1-C3Acyl and oxo, n is 0 to 6,
Raand RbEach independently is-H, C1-C3Alkyl radical, C3-C6Cycloalkyl, or C1-C3Alkoxy-substituted C1-C3An alkyl group.
4. The compound, isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 3, wherein R is1is-H, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or is substituted by 1 to 3 substituents selected from methoxy, ethoxy, methylthio, ethylthio, formyl, acetyl, hydroxy, -F, trifluoromethyl, cyano, -CONH2Cyclopropyl, cyclobutyl, cyclopentyl, -NRaRbC substituted or unsubstituted by a substituent of (A)1-C6Alkyl, or- (CH)2)n-R6Said R is6Is a substituted or unsubstituted 4-6-membered heteroalicyclic group, the 4-6-membered heteroalicyclic group being a 4-6-membered heteroalicyclic group containing 1-2 atoms selected from N, O, S as ring atoms, and the substituted 4-6-membered heteroalicyclic group being substituted with 1 to 3 substituents selected from-F, methyl, ethyl, hydroxy, amino, acetyl, formyl, trifluoromethyl, cyano, oxo, n is 0 to 6,
the 4-6 membered heteroalicyclic group is selected from 4-6 membered oxacycloalkyl, or 4-6 membered azacycloalkyl, or 4-6 membered thiacycloalkyl, or the following groups:
Raand RbEach independently is-H, methyl, ethyl, methoxymethyl, methoxyethyl, methoxypropyl, cyclopropyl, or cyclobutyl.
5. The compound, isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein R is2、R3Each independently is-H, -CF3-F, -Cl, methyl, ethyl, methoxy or ethoxy.
6. The compound of claim 1, an isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, which isIn, R4Is H, methyl or ethyl.
7. The compound, isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein R is5Is- (CH)2)mR7Wherein m is an integer of 0 to 3, said R7Is aryl or heteroaryl, substituted or unsubstituted by one to two substituents-A, each independently C1-C3Alkyl of (C)1-C3Alkoxy group of (C)1-C3Alkylthio, -F, -Cl, trifluoromethyl or methylsulfonyl,
the aryl is phenyl, naphthyl, phenanthryl, the heteroaryl is pyrrolyl, furyl, pyridyl, thienyl, imidazolyl, thiazolyl, isothiazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 1, 5-naphthyridinyl, 1, 6-naphthyridinonyl, oxadiazolyl, oxazolyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazolyl, pyrazolo [3,4-d ] pyrimidinyl, pyridinyl, pyrido [3,2-d ] pyrimidinyl, pyrido [3,4-d ] pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl.
8. The compound, isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any one of claims 1 to 7, wherein the compound is selected from:
9. use of a compound of any one of claims 1 to 7, or an isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof for the manufacture of a medicament for treating a disease associated with VEGFR-2 and/or CSF1R, wherein the disease associated with VEGFR-2 and/or CSF1R includes alzheimer's disease, ocular fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, crohn's disease, atheroma, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, melanoma, pancreatic cancer, melanoma, prostate cancer, bladder cancer, liver cancer, kidney cancer, liver cancer, lung cancer, kidney cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, multiple myeloma, biliary tract carcinosarcoma, cholangiocarcinoma.
10. A pharmaceutical composition comprising a compound of any one of claims 1 to 7, an isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients.
11. The pharmaceutical composition of claim 10, further comprising one or more additional therapeutic agents.
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a urea-substituted aromatic ring-linked dioxanoquinazoline or quinoline compound, an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, a pharmaceutical composition thereof, and application of the urea-substituted aromatic ring-linked dioxanoquinazoline or quinoline compound and the pharmaceutical composition thereof in preparation of drugs for treating autoimmune diseases, tumors and Alzheimer's disease related to vascular endothelial growth factor receptor 2(VEGFR-2) and/or colony stimulating factor 1 receptor (CSF 1R).
Background
Protein Kinases (PKs) are enzymes that catalyze the process of protein phosphorylation. To date, more than about 400 protein kinases have been discovered. As a subfamily of protein kinases, tyrosine kinases (RTKs) play an important role in cell signal transduction and are involved in tumorigenic processes including cell proliferation, survival, angiogenesis, invasion and metastasis.
VEGFR (vascular endothelial growth factor) is one of receptor tyrosine kinase families, and a series of biochemical and physiological processes are generated by combining with VEGF (vascular endothelial growth factor) serving as a ligand of VEGFR, so that new blood vessels are finally formed. The generation of tumor vessels and their permeability is mainly regulated by Vascular Endothelial Growth Factor (VEGF), which acts via at least two different receptors (VEGFR-1, VEGFR-2). Studies according to Jakeman, Kolch, Connolly et al show that: VEGF is an important stimulator of normal and pathological angiogenesis and vascular permeability (Jakeman et al, 1993, Endocrinology 133: 848-859; Kolch et al, 1995, Breast Cancer Research and Treatment, 36: 139-155; Connolly et al, 1989, J.biol.chem.264: 20017-20024). Vascular endothelial cell growth factor induces the angiogenic phenotype by inducing endothelial cell proliferation, protease expression and migration and subsequent formation of capillary cellular tissue. Thus, antagonism of VEGF by chelation of VEGF by antibodies can lead to inhibition of tumor growth (Kim et al, 1993, Nature 362: 841-844).
Since VEGFR-2 is mainly distributed in vascular endothelial cells, it can bind to VEGF-A, VEGF-C, VEGF-D, VEGF-E. The effects of VEGF in stimulating endothelial cell proliferation, increasing vascular permeability and neovascularization are primarily achieved by binding to and activating VEGFR-2. If the activity of VEGFR-2 is blocked, the growth and metastasis of tumor can be inhibited through direct and indirect ways, and further the ideal anti-tumor effect is achieved. Therefore, the search for small molecule inhibitors with high activity and selectivity for VEGFR-2 is a promising strategy for tumor therapy.
Colony stimulating factor 1 receptors (hereinafter CSF1R, also referred to in the art as FMS, FIM2, C-FMS, MCSF receptor and CD115) are single transmembrane receptors possessing tyrosine kinase activity with an N-terminal extracellular domain (ECD) and a C-terminal intracellular domain and are a member of the CSF1/PDGF receptor tyrosine kinase family. Binding of CSF1 or interleukin 34 ligand (also known as IL-34) to the ligand of CSF1R results in receptor dimerization and autophosphorylation and activation of downstream signal transduction pathways including PI3K/Akt and the mitogen-activated protein kinase MAPK pathway. Activation of CSF1R by CSF1 or IL-34 results in proliferation, survival, motility and differentiation of cells of the monocyte (e.g., osteoclasts, dendritic cells and microglia)/macrophage lineage, and thus plays an important role in general tissue development and immune defense. The existing research finds that CSF1R is involved in diseases including inflammatory diseases, tumor diseases, bone diseases and nervous system related diseases, therefore, CSF1R inhibitor is expected to be used for treating inflammatory diseases, tumor diseases, bone diseases and nervous system related diseases.
Higher expression or activation of CSF1R and/or its ligands has been found to be associated with a poor prognosis of certain cancers in patients with acute myeloid leukemia, prostate Cancer, breast Cancer, ovarian Cancer, endometrial Cancer, colorectal Cancer, pancreatic Cancer, as well as a variety of other cancers (see Muller-Tidow et al Clincancer Res,2004,10: 1241. 1249, Bauknecht et al Cancer Detect. Prev. 1994,18: 231. sup. 239; Baiocchi G et al Cancer1991,67: 990. sup. 996; Kirma et al Cancer Res.2007; Sapi et al Exp.biol.146. Med. 2004,229: 1-11; Kluger et al Clin. Cancer. Res. 173. sup. 200410: M. sup. 177; Mroczko et al chem. Lab. 200134. mu. 134. mu. and Mckom. 380. sup. 380. mu. K. 2007). This data suggests that CSF1R may be an effective therapeutic target for these solid tumors.
Meanwhile, Claudina Balduci et al found that activated microglia played an important role in the evolution of Alzheimer's disease (pharmaceutical research.2018; 130: 402-; murphy GM et al found that microglial expression of M-CSF1R was detected in the brains of Alzheimer-like mice (American Journal of Pathology, Vol.157, No.3, September 2000); the study by Dagher et al found that CSF1R inhibitors reduced the number of microglia and inhibited cytokine expression in the brains of mice like Alzheimer (Journal of neuroinfilformation (2015)12: 139). Therefore, the CSF1R inhibitor is expected to be applied to the treatment of Alzheimer's disease.
Currently, there are some ongoing studies on CSF1R inhibitors, but there are no drugs that are successfully marketed. There is a great need for further research and development of CSF1R inhibitor-based drugs.
The application provides a class of urea-substituted aromatic ring-linked dioxane quinazoline or quinoline compounds, which show good CSF1R inhibitory activity and VEGFR-2 inhibitory activity and are expected to be used as CSF1R and/or VEGFR-2 inhibitors to be applied to preparation of drugs for treating autoimmune diseases, tumors or Alzheimer's disease.
Disclosure of Invention
In view of the above discussion, the present invention aims to provide a urea-substituted aryl-linked dioxanoquinazoline or quinoline compound, an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutical composition thereof, and an application thereof in preparing a medicament for treating diseases such as autoimmune diseases, tumors or alzheimer's disease related to VEGFR-2 and/or CSF 1R.
One aspect of the present invention provides a urea substituted arylfused dioxanoquinazoline or quinoline compound, an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, having the structural formula (I):
wherein the content of the first and second substances,
q is N or CH;
g is O or NH;
R1is-H, or from 1 to 3 are selected from C1-C6Alkoxy group of (C)1-C6Alkylthio of, C1-C3Acyl, hydroxy, halogen, trifluoromethyl, cyano, -CONH2Oxo (═ O) or-NRaRbC substituted or unsubstituted by the substituent in (1)3-C8Or from 1 to 3 cycloalkyl groups selected from C1-C6Alkoxy group of (C)1-C6Alkylthio of, C1-C3Acyl, hydroxy, halogen, trifluoromethyl, cyano, -CONH2、C3-C7Cycloalkyl or-NRaRbC substituted or unsubstituted by a substituent of (A)1-C10Alkyl, or- (CH)2)n-R6Said R is6Is a substituted or unsubstituted 4-8-membered heteroalicyclic group, said 4-8-membered heteroalicyclic group being a 4-8-membered heteroalicyclic group containing 1-2 atoms selected from N, O, S as ring atoms, and said substituted 4-8-membered heteroalicyclic group being substituted with 1 to 3 atoms selected from halogen, C1-C3Alkyl of (C)1-C3Alkoxy group of (C)1-C3Alkylthio, hydroxy, -NRaRb、C1-C3Acyl and oxo, n is 0 to 10,
Raand RbEach independently is-H, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy-substituted C1-C6Alkyl radical, C1-C3Alkylthio substituted C1-C6Alkyl or mono-or di-C1-C3Alkyl-substituted or unsubstituted amino-substituted C1-C6An alkyl group;
R2、R3each independently is-H, -CF3Halogen, C1-C3Alkyl of (C)1-C3Alkoxy of the formula (I), R2、R3Represent only a double substitution, and do not limit the substitution position on the benzene ring;
R4is-H, C1-C3An alkyl group;
R5is- (CH)2)mR7Wherein m is an integer of 0 to 3, said R7Is aryl or heteroaryl, substituted or unsubstituted by one to two substituents-A, each independently C1-C3Alkyl of (C)1-C3Alkoxy group of (C)1-C3Alkylthio, halogen, trifluoromethyl or methylsulfonyl,
the heteroaryl group is a monocyclic or bicyclic heteroaryl group having 1 to 3 heteroatoms selected from N, O, S as ring atoms and having 5 to 10 ring atoms.
According to some preferred embodiments of the present application, G is O.
According to some preferred embodiments of the present application, R1is-H, or unsubstituted C3-C8Or from 1 to 3 cycloalkyl groups selected from C1-C6Alkoxy group of (C)1-C6Alkylthio of, C1-C3Acyl, hydroxy, -F, trifluoromethyl, cyano, -CONH2、C3-C6Cycloalkyl or-NRaRbC substituted or unsubstituted by a substituent of (A)1-C8An alkyl group, a carboxyl group,
or- (CH)2)n-R6Said R is6Is a substituted or unsubstituted 4-8-membered heteroalicyclic group, the 4-8-membered heteroalicyclic group is a 4-8-membered heteroalicyclic group containing 1-2 atoms selected from N, O, S as ring atoms, and the substituted 4-8-membered heteroalicyclic group is substituted with 1 to 3 atoms selected from-F, C1-C3Alkyl of (C)1-C3Alkoxy, hydroxy, -NRaRb、C1-C3Acyl and oxo, n is 0 to 8,
Raand RbEach independently is-H, C1-C6Alkyl radical, C3-C6Cycloalkyl, or C1-C3Alkoxy-substituted C1-C6An alkyl group.
More preferably, R1is-H, unsubstituted C3-C6From 1 to 3 cycloalkyl groups selected from C1-C3Alkoxy group of (C)1-C3Alkylthio of, C1-C3Acyl, hydroxy, -F, trifluoromethyl, cyano, -CONH2、C3-C5Cycloalkyl or-NRaRbC substituted or unsubstituted by a substituent of (A)1-C8An alkyl group, a carboxyl group,
or- (CH)2)n-R6Said R is6Is a substituted or unsubstituted 4-6-membered heteroalicyclic group, the 4-6-membered heteroalicyclic group is a 4-6-membered heteroalicyclic group containing 1-2 atoms selected from N, O, S as ring atoms, and the substituted 4-6-membered heteroalicyclic group is substituted with 1 to 3 atoms selected from-F, C1-C3Alkyl of (C)1-C3Alkoxy, hydroxy, -NRaRb、C1-C3Acyl and oxo, n is 0 to 6,
Raand RbEach independently is-H, C1-C3Alkyl radical, C3-C6Cycloalkyl, or C1-C3Alkoxy-substituted C1-C3An alkyl group.
More preferably, R1is-H, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or is substituted by 1 to 3 substituents selected from methoxy, ethoxy, methylthio, ethylthio, formyl, acetyl, hydroxy, -F, trifluoromethyl, cyano, -CONH2Cyclopropyl, cyclobutyl, cyclopentyl, -NRaRbC substituted or unsubstituted by a substituent of (A)1-C6Alkyl, or- (CH)2)n-R6Said R is6Is a substituted or unsubstituted 4-6-membered heteroalicyclic group, the 4-6-membered heteroalicyclic group being a 4-6-membered heteroalicyclic group containing 1-2 atoms selected from N, O, S as ring atoms, and the substituted 4-6-membered heteroalicyclic group being substituted with 1 to 3 substituents selected from-F, methyl, ethyl, hydroxy, amino, acetyl, formyl, trifluoromethyl, cyano, oxo, n is 0 to 6,
the 4-6 membered heteroalicyclic group is selected from 4-6 membered oxacycloalkyl, or 4-6 membered azacycloalkyl, or 4-6 membered thiacycloalkyl, or the following groups:
Raand RbEach independently is-H, methyl, ethyl, methoxymethyl, methoxyethyl, methoxypropyl, cyclopropyl, or cyclobutyl. In particular, when n is 0, R6Can be 4-6 membered oxacycloalkyl, or 4-6 membered azacycloalkyl, or 4-6 membered thiacycloalkyl, and when n is 1-6, R6May be substituted or unsubstituted 4-6 membered heterocycloaliphatic.
In the present application, the oxacycloalkyl group, azacycloalkyl group, and thiacycloalkyl group refer to alicyclic groups in which one oxygen atom, nitrogen atom, or sulfur atom is doped in the ring of the alicyclic group.
Most preferably, R1Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, methylthiopropyl, ethylthiopropyl, cyanomethyl, cyanoethyl, cyanopropyl, cyclopropylmethyl, cyclopropylethyl, -CH2CONH2、-CH2CF32-methyl-2-hydroxypropyl,
According to some preferred embodiments of the present application, R2、R3Each independently is-H, -CF3-F, -Cl, methyl, ethyl, methoxy or ethoxy.
According to some preferred embodiments of the present application, R4Is H, methyl or ethyl.
According to some preferred embodiments of the present application, R5In, R5Is- (CH)2)mR7Wherein m is an integer of 0 to 3, said R7Is aryl or heteroaryl, substituted or unsubstituted by one to two substituents-A, each independently being C1-C3Alkyl of (C)1-C3Alkoxy group of (C)1-C3Alkylthio, -F, -Cl, trifluoromethyl or methylsulfonyl, wherein the aryl is phenyl, naphthyl, phenanthryl and the heteroaryl is pyrrolyl, furyl, pyridyl, thienyl, imidazolyl, thiazolyl, isothiazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, 1, 5-naphthyridinyl, 1, 6-naphthyridonyl, oxadiazolyl, oxazolyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazolyl, pyrazolo [3,4-d ] phenyl, indolinyl, isoindolyl, indolinyl, 1, 5-naphthyridinyl, 1, 6-naphthyridonyl, oxadiazolyl, oxazolyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl]Pyrimidinyl, pyridinyl, pyrido [3,2-d ]]Pyrimidinyl, pyrido [3,4-d ]]Pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl.
More preferably, wherein said aryl is phenyl and said heteroaryl is thiazolyl.
Most preferably, R5Is phenyl or thiazolyl substituted or not substituted by one or more of methyl, ethyl, methoxy, ethoxy, F, Cl and trifluoromethyl, or methyl or ethyl substituted by one or more of methyl, ethyl, methoxy, ethoxy, F, Cl and trifluoromethyl.
According to some embodiments of the present application, the pharmaceutically acceptable salt of the urea-substituted arylvicinal dioxanoquinazoline or quinoline compound is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, tartrate, malate, citrate, fumarate, gluconate, benzoate, mandelate, methanesulfonate, isethionate, benzenesulfonate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclamate, salicylate, hexonate, trifluoroacetate, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, salts of benzoic acid, salts of benzoic, One or more of a sodium salt and a zinc salt.
Another aspect of the invention relates to the use of the urea-substituted aryl-linked-dioxane quinazoline or quinoline compound, or an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof in the preparation of a medicament for treating diseases related to VEGFR-2 and/or CSF1R, wherein the diseases related to VEGFR-2 and/or CSF1R comprise Alzheimer's disease, fundus diseases, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atheroma, pulmonary fibrosis, hepatic fibrosis, myelofibrosis, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, Bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, multiple myeloma, biliary tract carcinosarcoma, cholangiocarcinoma.
In a further aspect of the invention there is provided a pharmaceutical composition comprising a urea-substituted aryl-fused dioxanoquinazoline or quinoline compound of the present application, an isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients.
According to some embodiments of the present application, the pharmaceutical composition may further comprise one or more additional therapeutic agents.
Advantageous effects
The urea-substituted aromatic ring-linked dioxanoquinazoline or quinoline compound shows strong inhibitory activity on VEGFR-2 and CSF1R, and the urea-substituted aromatic ring-linked dioxanoquinazoline or quinoline compound, isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof and pharmaceutical compositions thereof are expected to be used for preparing drugs for treating diseases such as autoimmune diseases, tumors and Alzheimer's disease related to VEGFR-2 and/or CSF 1R.
Drawings
The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which,
FIG. 1 shows a liquid chromatogram of a mixture of compounds prepared in example 127 and example 171 of the present application;
FIG. 2 shows a liquid chromatogram of a compound prepared in example 127 of the present application;
FIG. 3 shows a liquid chromatogram of a compound prepared in example 171 of the present application;
FIG. 4 is a graph showing the inhibition of M-CSFR (cFMS) phosphorylation in RAW264.7 cells by protein labeling of a compound prepared in example 41 of the present application;
FIG. 5 shows the inhibition of M-CSFR (cFMS) phosphorylation in RAW264.7 cells at various concentrations of the compound prepared in example 41 of the present application;
FIG. 6 is a graph showing the inhibition of M-CSFR (cFMS) phosphorylation in RAW264.7 cells by protein labeling of a compound prepared in example 100 of the present application;
FIG. 7 shows the inhibition rate of M-CSFR (cFMS) phosphorylation in RAW264.7 cells at various concentrations of the compound prepared in example 100 of the present application.
Detailed Description
Unless otherwise indicated, the following terms used in the present application (including the specification and claims) have the definitions given below. In this application, the use of "or" and "means" and/or "unless stated otherwise. Furthermore, the use of the terms "including" and other forms, such as "including", "comprising", and "having", are not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
"alkyl" refers to aliphatic hydrocarbon groups. The alkyl group is saturated or unsaturated. The alkyl moiety, whether saturated or unsaturated, may be branched or straight chain. The "alkyl group" may have 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms. In one aspect, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, allyl, vinyl, acetylene, but-2-enyl, but-3-enyl and the like.
The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic non-aromatic group in which each atom (i.e., a backbone atom) that makes up the ring is a carbon atom. Cycloalkyl groups may be saturated or partially unsaturated. The cycloalkyl group may be fused to the aromatic ring and the point of attachment is on a carbon other than a carbon atom of the aromatic ring. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may be substituted or unsubstituted. In one aspect, cycloalkyl is C3-C8A cycloalkyl group.
"alkoxy" refers to a (alkyl) -O-group, and "alkylthio" refers to a (alkyl) -S-group, wherein alkyl is as defined herein. Preferably, the alkoxy group is C1-C6Alkoxy, more preferably C1-C3An alkoxy group. Preferably, said alkylthio group is C1-C6Alkylthio, more preferably C1-C3An alkylthio group.
The term "heterocycloaliphatic" means a heterocycloalkyl ring containing one or more heteroatoms in the ring, wherein each heteroatom in the ring is selected from O, S and N, specifically, may contain 1 to 2 atoms selected from N, O, S as ring atoms, and each heterocyclic group may contain 4 to 8 atoms, preferably 4 to 6 atoms, in its ring system. And the heteroalicyclic group may be unsubstituted or substituted.
More specifically, the heteroalicyclic in the heteroalicyclic group containing 1 to 2 heteroatoms selected from N, O, S may be any one selected from the following ring structures:
where substitutions may be made in the ring structure, the substituents may be as hereinbefore described.
The term "isomer" in this application is a different compound having the same molecular formula and may include various isomeric forms such as stereoisomers, tautomers and the like. "stereoisomers" are isomers that differ only in the arrangement of the atoms in space. Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms which can be defined as (R) -or (S) -in terms of absolute stereochemistry. The chemical entities, pharmaceutical compositions and methods of the present invention are intended to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R) -and (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of the compounds can be analyzed by any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other can be determined.
When a compound described herein contains an olefinic double bond, it is meant that the compound includes various cis-trans isomers, unless otherwise specified.
"tautomers" are structurally different isomers that can be interconverted by tautomerization. "tautomerization" is a form of isomerization and includes proton shift or proton shift tautomerization, which can be considered a subset of acid-base chemistry. "proton shift tautomerization" or "proton shift tautomerization" involves the migration of protons with a shift in the bond order, often an interchange of a single bond with an adjacent double bond. When tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomers can be reached. One example of tautomerization is keto-enol tautomerization.
In the present application, the compounds of structural formula (I), isomers, crystals or prodrugs and pharmaceutically acceptable salts thereof may exist in solvated as well as unsolvated forms. For example, the solvated form may be water soluble. The present invention includes all such solvated and unsolvated forms.
The invention also provides a method for preparing the corresponding compound, which can be prepared by the following route. Three representative synthetic routes are shown below:
synthetic route (I)
Synthetic route (II)
Synthetic route (III)
In the above reaction formula, R1、R2、R3、R4、R5The definition of (A) is as described above.
The above synthetic routes are provided for illustrative purposes only, and the synthetic methods of the compounds of the present application are not limited to the above routes, and the specific conditions in the above schemes are also provided for illustrative purposes only, and it will be understood by those skilled in the art that the above specific conditions are not limited thereto.
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to specific embodiments and accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
In the following description, it will be understood by those skilled in the art that benzylamine and benzyl represent the same meanings, while, for example, 4-amino-2-methylphenol and 2-methyl-4-aminophenol, only written differences, represent the same compounds. Part of the compound nomenclature of this application is translated into Chinese using the nomenclature chemdraw.
Sources of partial chemical reagents
The reaction solvent is provided by Chinese medicine reagent
Common reaction chemistry is provided by the companies of Yinakai, Annaiji, Mecline, Bailingwei, Yashi, etc
Thin layer chromatography silica gel plate (thickness 0.5mm,1mm, 200X200mm) is provided by Nicotiana Summinck chemical Co., Ltd
Silica gel (200-mesh 300-mesh) is provided by China national drug reagent company
Chemical abbreviation
DMF: n' N-dimethylformamide
DIEA: n' N-diisopropylethylamine
NMP: n-methyl pyrrolidone
Pd(OAc)2: palladium acetate
Pd2(dba)3: tris (dibenzylideneacetone) dipalladium
Xantphos: 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene
The method comprises the following steps of (1) Binap: 1,1 '-binaphthyl-2, 2' -bis (diphenylphosphines)
(Boc)2O: di-tert-butyl dicarbonate
Synthesis of intermediates
Intermediate 1 intermediate 2
Synthesis of intermediates 1 and 2 is described in patent application WO 2016112847
And (3) preparing an intermediate 3.
Step 1) A solution of 3-methoxybenzenediol (25.3g,180mmol), potassium carbonate (104.5g,756mmol), and 1, 2-dibromoethane (74.4g,396mmol) in DMF (100mL) was reacted in a nitrogen system at 60 ℃ and heated for 6 hours, quenched with water and extracted with ethyl acetate; the organic phase was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated to a dark grey oil: 5-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxane (25.4g,153mmol, 85% yield);
step 2) adding AlCl into the mixture under the condition of nitrogen atmosphere in ice-water bath3Acetyl chloride (5.57mL,78mmol) was slowly added dropwise to (12.0g,90mmol) nitromethane (200mL), followed by 5-methoxy-2, 3-dihydrobenzo [ b ] b][1,4]Dioxane (10.0g,60mmol) in nitromethane (100mL) is stirred at room temperature for 5 hours, quenched by the addition of 1N hydrogen chloride solution, the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, concentrated, heated under reflux in isopropanol (25mL), cooled, allowed to stand, filtered to give the product as a gray solid: 5-acetyl-2, 3-dihydro-8-methoxy-1, 4-benzodioxan (10.1g,49mmol, 81%);
step 3) adding concentrated nitric acid (62%, 20mL) dropwise into a solution of 5-acetyl-2, 3-dihydro-8-methoxy-1, 4-benzodioxole (10.1g,49mmol) in acetic acid (60mL) under the condition of ice-water bath, stirring for 3 hours at room temperature, adding water for pulping, filtering and drying to obtain a yellow solid product: 1- (8-methoxy-6-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-5-yl) ethyl-1-one 10.5g, 85% yield;
step 4) adding 1- (8-methoxy-6-nitro-2, 3-dihydrobenzo [ b)][1,4]Dioxacyclohex-5-yl) ethyl-1-one (10.1g,40mmol) in methanol(100mL) solution was added wet palladium on carbon (10%, 0.5g), replaced with hydrogen and stirred for 10 hours, filtered and concentrated to give a purple oil: 1- (6-amino-8-methoxy-2, 3-dihydrobenzo [ b ]][1,4]Dioxacyclohex-5-yl) ethyl-1-one (8.8g, 95% yield), MS:224[ M + H]+
Step 5) to 1- (6-amino-8-methoxy-2, 3-dihydrobenzo [ b ]][1,4]Dioxane-5-yl) ethyl-1-one (4.5g,20mmol) in dioxane (80mL) was added sodium tert-butoxide (4.4g,46mmol), stirred at room temperature for half an hour, a solution of methyl formate (10.8mL,132mmol) in dioxane (10mL) was added, stirred at room temperature for 15 hours, added to ice water and slurried after adjusting the pH to 7 with 2N dilute hydrochloric acid, filtered and dried to give the product as a gray solid: 5-methoxy-2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]Quinoline-10-ol 3.8 g, yield 82%, MS 234[ M + H ]]+
Step 6) adding 5-methoxy-2, 3-dihydro- [1,4] under the condition of ice-water bath]Dioxane [2,3-f ]]Adding triethylamine (3mL) into a quinoline-10-alcohol (2.4g,10mmol) solution of phosphorus oxychloride (30mL), heating under reflux for 5 hours for reaction, cooling, concentrating, adding water for dissolution, adjusting the pH value to 9 with potassium bicarbonate, pulping, filtering and drying to obtain an earthy yellow solid product 2.2 g: 10-chloro-5-methoxy-2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]Quinoline, 88% yield, MS:252[ M + H ]]+
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