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CN-121991073-A - N-substituted aromatic ring-aza-bicyclo amine derivative and medical application thereof

CN121991073ACN 121991073 ACN121991073 ACN 121991073ACN-121991073-A

Abstract

The invention discloses a compound shown in a formula (I) and medical application thereof, including optical isomers and pharmaceutically acceptable salts thereof. The compound has FLT3 and IRAK4 kinase inhibition activity, has proliferation inhibition activity on FLT3-ITD positive leukemia cell strains MV4-11 and MOLM13 and proliferation inhibition activity on IRAK4 positive leukemia cell strain TF-1, can overcome the adaptive drug resistance of clinical FLT3 inhibitors, and can be applied to the preparation of antitumor drugs.

Inventors

  • LIU TAO
  • LI JIA
  • ZHOU YUBO
  • YUAN HAIBIN
  • WANG PEIPEI
  • GAO YUE

Assignees

  • 浙江大学
  • 中国科学院上海药物研究所

Dates

Publication Date
20260508
Application Date
20241101

Claims (10)

  1. 1. A compound having a structure represented by the general formula (I): Or an optical isomer thereof or a pharmaceutically acceptable salt thereof; Wherein the ring A is selected from benzene ring or 5-6 membered heteroaromatic ring, the heteroatom in the heteroaromatic ring is 1-4N atoms, and the benzene ring or heteroaromatic ring can be further substituted by 1-3R 4 ; x is selected from CH or N; Y is selected from N, CR X ;R X selected from H, deuterium, halogen, C 1-3 alkyl, C 1-3 alkyloxy, halogen substituted C 1-3 alkyl, CN, NO 2 ; R 1 is selected from H, deuterium, halogen, C 1-3 alkyl, halogen substituted C 1-3 alkyl, C 1-3 alkyloxy, -NR a R b 、-C(＝O)-NR a R b 、-S(＝O) 2 -NR a R b ; R 2 、R 3 is each independently selected from H, deuterium, halogen, C 1-3 alkyl, halogen substituted C 1-3 alkyl, C 1-3 alkyloxy 、CN、NO 2 、-C(＝O)-NR aa R bb 、-S(＝O) 2 -NR aa R bb 、-L 1 -NR aa R bb 、-L 1 -R 5 ; L 1 is a bond, -O (CH 2 ) o -、-NR 7 (CH 2 ) p -; R a 、R b 、R aa 、R bb are each independently selected from H, deuterium, OH, alkyl of C 1-3 , cycloalkyl of C 3-5 , - (c=o) - (alkyl of C 1-3 ), -CHO, -S (=o) 2 -(C 1-3 alkyl; o, p are independently selected from 0, 1,2, 3, 4, 5, 6, 7, 8; R 4 is selected from H, C 1-5 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocycloalkyl, -C (=O) - (C 1-3 alkyl), -CHO, -S (=O) 2 -(C 1-3 alkyl), phenyl, and 5-8 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, and heteroaryl may be independently substituted with 0,1, or 2R 8 , and when substituted with multiple R 8 , the multiple R 8 may be the same or different; R 5 is selected from H, OH, CN, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 4-8 cycloalkyl, 4-8 membered heterocycloalkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl may be further substituted with 0, 1 or 2R 6 ; R 6 is selected from H, NH 2 、-NH-C 1-3 alkyl, -N- (C 1-3 alkyl) 2 、C 1-5 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocycloalkyl, -C (=O) - (C 1-3 alkyl), -CHO, -S (=O) 2 -(C 1-3 alkyl, said alkyl cycloalkyl being further substituted with 0, 1 or 2 hydroxy groups; r 7 is H, C 1-3 alkyl; r 8 is H, deuterium, halogen, OH, alkyl of NH 2 、CF 3 、OCH 3 、CN、NO 2 、C 1-5 , -C (=o) NH-L 2 -R 9 , said alkyl being optionally further substituted with 0, 1 or 2 hydroxy or amino groups; L 2 is a bond, an alkylene group of C 1-8 , S and t are respectively and independently selected from 1,2 and 3; R 9 is H, OH, NH 2 .
  2. 2. A compound according to claim 1 wherein, A is selected from: Wherein the method comprises the steps of Represents a substituent connection, and R 4 is defined as in claim 1.
  3. 3. The compound of claim 2, having a structure of formula (II): Said R 1 、R 2 、R 3 、R 4 is as defined in claim 1.
  4. 4. The compound of claim 1 or 3, wherein R 1 is H, -NR a R b ;R 2 is-NH (CH 2 ) p -NR aa R bb 、-NR 7 (CH 2 ) p -R 5 ; R a 、R b 、R aa 、R bb are each independently selected from H, Deuterium, methyl, ethyl, p is selected from 0, 1, 2, 3, 4,5, R 3 is H, deuterium, halogen, R 4 is H, C 1-5 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, -S (=O 2 -(C 1-3 alkyl), phenyl, 5-8 membered heteroaryl, which alkyl, cycloalkyl, phenyl, heteroaryl may be independently substituted with 0,1 or 2R 8 , R 5 is 4-8 membered heterocycloalkyl, R 5 is, C 4-8 cycloalkyl, R 6 is H, NH 2 , methylamino, dimethylamino, methylsulfonyl, C 1-4 alkyl, The alkyl can be further substituted by 0 or 1 hydroxyl group, R 7 is H, CH 3 ;R 8 which is H, deuterium, halogen, OH and CF 3 、OCH 3 、C 1-5 , and the alkyl can be further substituted by 0 or 1 hydroxyl group.
  5. 5. The compound of claim 1, wherein the compound has the structure: Wherein R 2 is-NH (CH 2 ) p -NR aa R bb ), R aa 、R bb is independently selected from H, deuterium and CH 3 , m, n and p are independently selected from 1, 2, 3, 4 and 5, R 6 is H, methylsulfonyl, C 1-4 alkyl and 3-6 membered heterocycloalkyl, wherein the alkyl can be further substituted by hydroxy.
  6. 6. A compound according to any one of claims 1.3.5, wherein a is selected from: R 4 is selected from H, ethyl, methyl, propyl, cyclopropyl, isopropyl, cyclohexyl, oxetanyl, hydroxy tert-butyl, methylsulfonyl, phenyl, pyridyl, methylimidazole, one or two halogen substituted phenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, hydroxyisopropyl substituted phenyl, carbamoylphenyl, hydroxy and methyl substituted butylcarbamoylphenyl; R 1 is selected from H, deuterium, halogen, ethylamino, Y is selected from N, CH, R 3 is selected from H, F; R 2 is selected from:
  7. 7. a compound according to claim 1, selected from the group consisting of: and optical isomers or pharmaceutically acceptable salts thereof.
  8. 8. The compound of claim 1, wherein the pharmaceutically acceptable salt comprises an acid addition salt of a compound of formula (I) with formic acid, acetic acid, propionic acid, pyruvic acid, glycolic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, mandelic acid, citric acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, L-malic acid, D-malic acid, lactic acid, camphorsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, salicylic acid, benzoic acid, tartaric acid, L-tartaric acid, D-tartaric acid, oxalic acid, succinic acid, maleic acid, ascorbic acid, amino acids, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, hydroiodic acid or perchloric acid.
  9. 9. The use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, alone or in combination with other agents selected from one or more of IDH1 inhibitors, IDH2 inhibitors, bcL-2 inhibitors, hypomethylants, antimetabolites, for the manufacture of a medicament for the treatment of an antitumor or an immune disorder.
  10. 10. The use according to claim 9, wherein the tumor is bladder cancer, breast cancer, colon cancer, kidney cancer, epidermoid cancer, liver cancer, lung cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer or skin cancer, hematopoietic tumors of lymphoid lineage such as acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, burkett's lymphoma, hematopoietic tumors of myeloid lineage, acute and chronic myelogenous leukemia, myelodysplastic syndrome, promyelocytic leukemia, thyroid follicular cancer, tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma, tumors of the central or peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, colored stem skin disease, keratoxanthoma, kaposi's sarcoma; The immune disease is selected from the group consisting of arthritis, lupus, inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, still's disease, juvenile arthritis, diabetes, myasthenia gravis, hashimoto's thyroiditis, aldthyroiditis, graves 'disease, rheumatoid arthritis syndrome, multiple sclerosis, infectious neuronal inflammation, acute disseminated encephalomyelitis, addison's disease, aplastic anemia, autoimmune hepatitis, optic neuritis, psoriasis, graft versus host disease, transplantation, transfusion allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, atopic dermatitis.

Description

N-substituted aromatic ring-aza-bicyclo amine derivative and medical application thereof Technical Field The invention relates to the field of medicines, in particular to an N-substituted aromatic ring-aza-bicyclo amine derivative, medical application, optical isomer, salt and a preparation method thereof, and application of the N-substituted aromatic ring-aza-bicyclo amine derivative serving as an Fms-like tyrosine kinase 3 (FLT 3), interleukin-1 receptor related kinase 4 (IRAK 4) or dual-targeting FLT3/IRAK4 inhibitor in an anti-tumor medicine. Background FLT3 (FMS-like tyrosine kinase 3) is a transmembrane receptor tyrosine kinase protein that is normally expressed by hematopoietic stem cells and plays an important role in cell development by promoting cell survival, growth and differentiation through various signaling pathways. FLT3 gene mutation drives oncogenic signals, one of the most common genetic abnormalities in AML, with about 30% of AML patients undergoing FLT3 gene mutation. It was found that activated FLT3 promotes proliferation and differentiation of AML cells through PI3K, RAS and STAT5 signaling pathways. There are mainly two types of FLT3 mutations, namely internal tandem repeat mutations of the membrane paradomains (FLT 3-ITD) and point mutations (FLT 3-TKD) or deletions of the tyrosine kinase domain, both of which mutant FLT3 molecules can be activated by ligand-independent dimerization and trans-phosphorylation. Of these FLT3-ITD is the most common FLT3 mutation affecting about 25% of AML patients. Compared to AML patients without FLT3-ITD mutations, FLT3-ITD AML patients have worse overall prognosis, including increased recurrence rate, increased risk of death after recurrence, and higher likelihood of recurrence after hematopoietic stem cell transplantation. FLT3 targeted therapies have become a research hotspot based on the important role of FLT3 mutations in the development of AML. Currently, several FLT3 inhibitors (FLT 3 i) have been marketed, of which Midostaurin, gilteritinib and Quizaritinib have been approved for the treatment of AML patients with FLT3 mutations. Although these drugs have shown excellent initial clinical responses in AML patients in monotherapy or combination therapy, mutations in the FLT 3-kinase domain (acquired resistance) and activation of the alternative pathway (adaptive resistance) result in short response periods and susceptibility to relapse remain major problems faced in current AML patient treatment procedures. It is necessary to develop therapeutic methods that can overcome the availability and adaptive drug resistance. Tumor immunotherapy is one of the hot areas of current medical research, and it utilizes the regulatory mechanism of the immune system to identify and kill tumor cells, and is considered as an important direction for future tumor therapy. Interleukin-1 receptor-associated kinase 4 (IRAK 4) is a key signaling node for the transduction of signals of the interleukin-1 receptor and the T lymphocyte-like receptor family. Studies have shown that IRAK4-L is highly expressed in 50% of MDS and AML patients and highly correlated with poor prognosis, that TLRs expression on FLT3-ITD AML cells is increased following FLT3i treatment, that the innate immune pathway (IRAK 1/4) is competitively activated, and that Ras/MAPK and NF-kB can be restored further, ultimately leading to cell survival, i.e. the generation of adaptive drug resistance. Thus, FLT3/IRAK4 dual-target inhibitors can overcome AML treatment adaptive resistance by targeting the immune stress response pathway. The development of novel framework small molecule inhibitors with excellent FLT3/IRAK4 kinase inhibition activity has important significance for the treatment of hematologic malignancies. Disclosure of Invention The invention aims to provide N-substituted aromatic ring-aza-bicyclo amine derivatives with FLT3 and IRAK4 inhibiting activities and anti-tumor effects and medical application, the compounds have excellent biological activity, and meanwhile, the molecular diversity and novelty of the compounds are improved, and the invention also aims to provide a preparation method and application of the N-substituted aromatic ring-aza-bicyclo amine derivatives and medical application. The technical scheme of the invention is as follows: A compound of the general formula (I): or an optical isomer thereof or a pharmaceutically acceptable salt thereof. Wherein A is selected from benzene ring or 5-6 membered heteroaromatic ring, heteroatom in the heteroaromatic ring is 1-4N atoms, the benzene ring or heteroaromatic ring can be further substituted by 1-3R 4; x is selected from CH or N; Y is selected from N, CR X;RX selected from H, deuterium, halogen, C 1-3 alkyl, C 1-3 alkyloxy, halogen substituted C 1-3 alkyl, CN, NO 2; R 1 is selected from H, deuterium, halogen, C 1-3 alkyl, halogen substituted C 1-3 alkyl, C 1-3 alkyloxy, -NR aRb、-C(＝O)-NRaRb、-S(＝O)2-NRaRb; R 2、R3 is each independent