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CN112292374A - Novel phosphoinositide 3-kinase inhibitor and preparation method and application thereof - Google Patents

Novel phosphoinositide 3-kinase inhibitor and preparation method and application thereof Download PDF

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CN112292374A
CN112292374A CN201980036339.8A CN201980036339A CN112292374A CN 112292374 A CN112292374 A CN 112292374A CN 201980036339 A CN201980036339 A CN 201980036339A CN 112292374 A CN112292374 A CN 112292374A
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张龙
宋国伟
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Innovent Biologics Suzhou Co Ltd
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Abstract

The invention belongs to the field of pharmaceutical chemistry, and discloses a novel phosphoinositide 3-kinase inhibitor, and a preparation method and application thereof. The phosphoinositide 3-kinase (PI3K) inhibitor has a structure shown in formula I, and has various pharmacological activities such as anti-tumor, anti-neurodegenerative disease, anti-inflammation and the like.

Description

Novel phosphoinositide 3-kinase inhibitor and preparation method and application thereof Technical Field
The invention belongs to the field of medicinal chemistry, and relates to a potent phosphoinositide 3-kinase (PI3K) inhibitor, a preparation method thereof, a pharmaceutical composition containing the same, and a medical application thereof, in particular to an application in preparing a medicament for preventing and/or treating diseases at least partially mediated by PI 3K.
Background
Phosphoinositide 3-kinases (PI3K) are a large class of enzymes whose primary function is phosphorylation of the inositol ring of phosphoinositides. Based on structural similarity, the type of regulatory subunit and the specificity of various phosphoinositide substrates, PI3K is divided into three classes (I, II and III) (Marone R, et al, Biochim. Biophys. acta, 2008; 1784: 159. sub.185), with the most extensive studies on class I PI 3K. All members of this class are composed of a catalytic subunit and an associated regulatory component for the catalytic phosphorylation of phosphatidylinositol 4, 5-bisphosphate (PIP2) to produce the signal molecule phosphatidylinositol 3, 4, 5-trisphosphate (PIP 3). In addition, there is some evidence that this type can act as a protein kinase, although the exact nature and physiological significance of the substrate is still being explored (Backer JM., et al, nat. cell. biol., 2005; 7: 773. su. 774). This type is further divided into two subgroups (IA and IB). Three subtypes, the group IA members PI3K α, PI3K β, and PI3K γ, are activated by cellular signaling events involving tyrosine phosphorylation. PI3K α and PI3K β are widely expressed and play a role in cell growth, division and survival (Thomas M, et al, Curr. Opin. Pharmacol., 2008; 8: 267-274). The role of these two kinases in many biological functions is enhanced by embryonic lethality observed in mice lacking PI3K α or PI3K β. Due to their role in homeostasis, clinical evaluation of PI3K α and PI3K β is limited to the field of oncology, and some compounds are also in different stages of clinical development. The PI3K δ subtype, which differs in its behavior, appears to be expressed primarily in hematopoietic cells and may play an important role in the inflammatory response. As such, the recently emerging PI3K δ selective compounds have attracted more attention.
The PI3K γ subtype is expressed in immune cells and has limited expression in normal or malignant epithelial and connective tissue cells. The results of studies in PI3K γ knockout mice indicate that PI3K γ is important for cell activation and migration of some chemokines (Sasaki T., et al, Science, 2000; 287: 1040-. PI3K γ signaling is particularly important for myeloid cell function, downstream of G protein-coupled receptors (GPCRs), such as chemokine receptors, and RAS. In addition, in these cells, PI3K γ can be activated in response to tissue hypoxia. PI3K γ plays a key role in unique myeloid cells, which form a key component of the immunosuppressive tumor microenvironment, as demonstrated in PI3K γ deletion and kinase death knock-in studies. For example, mouse syngeneic tumors grow slowly when transplanted into immunocompetent mice with inactivated PI3K γ gene (Schmid M.C., et al, Cancer Cell, 2011; 19: 715-. This growth delay is due to the elimination of tumor-associated bone marrow, and the immunosuppressive tumor microenvironment in which these cells promote tumor growth is well known (Gunderson A.J., et al., Cancer Discovery, 2016; 6: 270-285). Furthermore, tumor-associated bone marrow cells are hypothesized to support tumor regeneration following radiation or chemotherapy and to be able to metastasize to spread (De Palma m., et al., j.med.chem., 2012; 55: 8559-8581). These preclinical studies highlight a key role for PI3K γ in myeloid cell biology and suggest that PI3K γ inhibition in tumor-associated myeloid cells may be effective in preventing tumor growth in a variety of settings.
Although PI3K γ inhibitors have been reported in the last decade, there are still few reports of highly selective PI3K γ inhibitors in vivo (WO2017214269, WO2016054491, CN106456628, WO 2015051241). Therefore, from the existing data analysis, the development of the high-selectivity PI3K gamma inhibitor has huge theoretical and clinical values.
Disclosure of Invention
Problems to be solved by the invention
The invention aims to provide a series of novel compounds with a regulating or inhibiting effect on the activity of PI3K, a preparation method of the series of compounds, a pharmaceutical composition containing the series of compounds and medical application of the series of compounds.
Means for solving the problems
In a first aspect, the present invention provides a compound having the structure of formula I:
Figure PCTCN2019089027-APPB-000001
or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion thereof, wherein:
R 1、R 3、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 3、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 0is-CH2-、-C(＝R 2)-、-S(＝R 2) n-or-P (═ R)2)(R 0)-；
X 1、X 2、X 3、X 5、X 6、X 7、X 9、X 10、X 11、X 12、X 13And X14Each independently is CH, CR7Or N;
X 4and X8Each independently is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
Or X4And X5Form a double bond therebetween, wherein: x5Is C, X4Is CH, CR7Or N;
R 0is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and when R is0When not hydrogen, R0Hydrogen in (a) is optionally substituted with deuterium or halogen;
R 2and R5Each independently is NH, NR7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In a second aspect, the present invention provides a compound having the structure of formula I as described above, comprising:
(1) 2-amino-N- (1- (8- (dimethylphosphoryl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(2) (R) -2-amino-N- (1- (8- (dimethylphosphoryl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(3) (S) -2-amino-N- (1- (8- (dimethylphosphoryl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(4) 2-amino-N- (1- (1-oxo-8- (pentafluoro-lambda)6-sulfanyl) -2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a]Pyrimidine-3-carboxamides;
(5) (R) -2-amino-N- (1- (1-oxo-8- (pentafluoro-lambda)6-sulfanyl) -2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a]Pyrimidine-3-carboxamides;
(6) (S) -2-amino-N- (1- (1-oxo-8- (pentafluoro-lambda)6-sulfanyl) -2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a]Pyrimidine-3-carboxamides;
(7) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 1-dioxo-2-phenyl-2H-benzo [ e ] [1, 2] thiazin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(8) (R) -2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 1-dioxo-2-phenyl-2H-benzo [ e ] [1, 2] thiazin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(9) (S) -2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 1-dioxo-2-phenyl-2H-benzo [ e ] [1, 2] thiazin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(10) 2-amino-N- (1- (8- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(11) (R) -2-amino-N- (1- (8- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(12) (S) -2-amino-N- (1- (8- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(13) 2-amino-N- (1- (8- (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(14) (R) -2-amino-N- (1- (8- (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(15) (S) -2-amino-N- (1- (8- (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(16) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydro-2, 6-naphthyridin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(17) (R) -2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydro-2, 6-naphthyridin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(18) (S) -2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydro-2, 6-naphthyridin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(19) 2-amino-N- (1- (4- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -5-oxo-6-phenyl-5, 6-dihydro-1, 6-naphthyridin-7-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(20) (R) -2-amino-N- (1- (4- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -5-oxo-6-phenyl-5, 6-dihydro-1, 6-naphthyridin-7-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(21) (S) -2-amino-N- (1- (4- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -5-oxo-6-phenyl-5, 6-dihydro-1, 6-naphthyridin-7-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(22) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(23) (R) -2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(24) (S) -2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(25) 2-amino-N- (1- (2- (1-adamantyl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(26) (R) -2-amino-N- (1- (2- (1-adamantyl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(27) (S) -2-amino-N- (1- (2- (1-adamantyl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(28)3- (4- (2-aminopyrazolo [1, 5-a ] pyrimidin-3-yl) -4-oxobutan-2-yl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenylisoquinolin-1 (2H) -one;
(29) (S) -3- (4- (2-aminopyrazolo [1, 5-a ] pyrimidin-3-yl) -4-oxobutan-2-yl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenylisoquinolin-1 (2H) -one;
(30) (R) -3- (4- (2-aminopyrazolo [1, 5-a ] pyrimidin-3-yl) -4-oxobutan-2-yl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenylisoquinolin-1 (2H) -one;
(31) 2-amino-N- (2- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) propan-2-yl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(32) 2-amino-N '-methyl-N' - (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) pyrazolo [1, 5-a ] pyrimidine-3-carboxylic acid hydrazide;
(33) 2-amino-N' -hydroxy-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamidine;
(34) (R) -2-amino-N' -hydroxy-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamidine;
(35) (S) -2-amino-N' -hydroxy-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamidine;
(36)3- (3-amino-4- (2-aminopyrazolo [1, 5-a ] pyrimidin-3-yl) -4-oxobutan-2-yl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenylisoquinolin-1 (2H) -one;
(37) (S) -3- (3-amino-4- (2-aminopyrazolo [1, 5-a ] pyrimidin-3-yl) -4-oxobutan-2-yl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenylisoquinolin-1 (2H) -one;
(38) (R) -3- (3-amino-4- (2-aminopyrazolo [1, 5-a ] pyrimidin-3-yl) -4-oxobutan-2-yl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenylisoquinolin-1 (2H) -one;
(39) 2-amino-N- (1- (5- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-3-phenyl-3, 4-dihydrophthalazin-2 (1H) -yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(40) (S) -2-amino-N- (1- (5- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-3-phenyl-3, 4-dihydrophthalazin-2 (1H) -yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(41) (R) -2-amino-N- (1- (5- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-3-phenyl-3, 4-dihydrophthalazin-2 (1H) -yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(42) 2-amino-N- (1- (5- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 4-dioxo-3-phenyl-3, 4-dihydrophthalazin-2 (1H) -yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(43) (S) -2-amino-N- (1- (5- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 4-dioxo-3-phenyl-3, 4-dihydrophthalazin-2 (1H) -yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(44) (R) -2-amino-N- (1- (5- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 4-dioxo-3-phenyl-3, 4-dihydrophthalazin-2 (1H) -yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(45) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 4-dioxo-2-phenyl-1, 2, 3, 4-tetrahydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(46) 2-amino-N- ((1R) -1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 4-dioxo-2-phenyl-1, 2, 3, 4-tetrahydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(47) 2-amino-N- ((1S) -1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 4-dioxo-2-phenyl-1, 2, 3, 4-tetrahydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(48) n- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (sulfamoylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(49) (R) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (aminosulfonylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(50) (S) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (aminosulfonylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(51) 2-amino-N- (1- (1- (hydroxyimino) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-2-phenyl-1, 2, 3, 4-tetrahydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(52) (R) -2-amino-N- (1- (1- (hydroxyimino) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-2-phenyl-1, 2, 3, 4-tetrahydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(53) (S) -2-amino-N- (1- (1- (hydroxyimino) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-2-phenyl-1, 2, 3, 4-tetrahydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(54) 2-amino-N- (1- (1-imino-8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-2H-benzo [ e ] [1, 2] thiazin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(55) 2-amino-N- (1- (1-ethylimino-8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-2H-benzo [ e ] [1, 2] thiazin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(56) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-imino-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(57) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-ethylimino-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(58) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamidine;
(59) 2-amino-N' -ethyl-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamidine;
(60) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-methyl-1-oxo-2-phenyl-1, 2-dihydrobenzo [ c ] [1, 2] azaphenanthroline-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(61) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2- (2- (dimethylphosphoryl) phenyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(62) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2- (4- (pentafluoro- λ)6-sulfanyl) phenyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a]Pyrimidine-3-carboxamides;
(63) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carbothioamide;
(64) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 1-dioxo-2-phenyl-2H-benzo [ e ] [1, 2, 4] thiadiazin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(65) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-1-methyl-2-phenyl-1, 2-dihydrobenzo [ c ] [1, 5, 2] diazaphosphaphenazine-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(66) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-thioxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(67) 2-amino-N' -hydroxy-N- (1- (1-oxo-2-phenyl-8- (phenylethynyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamidine;
(68) 2-amino-N- (1- (1- (hydroxyimino) -2-phenyl-8- (phenylethynyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(69) 2-amino-N' -methyl-N- (1- (1-oxo-2-phenyl-8- (phenylethynyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamidine;
(70) 2-amino-N- (1-deuterated-1- (4-deuterated-8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(71) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) cyclopropyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(72) 2-amino-N-methyl-N- (2- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) propan-2-yl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(73) n- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 1-dioxo-2-phenyl-2H-benzo [ e ] [1, 2] thiazin-3-yl) ethyl) -2- (sulfamoylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(74) (S) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 1-dioxo-2-phenyl-2H-benzo [ e ] [1, 2] thiazin-3-yl) ethyl) -2- (sulfamoylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(75) (R) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 1-dioxo-2-phenyl-2H-benzo [ e ] [1, 2] thiazin-3-yl) ethyl) -2- (sulfamoylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(76) n- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- ((N-methylsulfamoyl) amino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(77) n- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- ((N-ethylsulfamoyl) amino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(78) n- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- ((N-isopropylaminosulfonyl) amino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(79) (S) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- ((N-methylsulfamoyl) amino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(80) (S) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- ((N-ethylsulfamoyl) amino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(81) (S) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- ((N-isopropylaminosulfonyl) amino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(82) (R) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- ((N-methylsulfamoyl) amino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(83) (R) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- ((N-ethylsulfamoyl) amino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(84) (R) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- ((N-isopropylaminosulfonyl) amino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(85)2- ((N-cyclopropylsulfamoyl) amino) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(86) (S) -2- ((N-cyclopropylsulfamoyl) amino) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(87) (R) -2- ((N-cyclopropylsulfamoyl) amino) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(88) n- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- ((N-phenylsulfamoyl) amino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(89) (S) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- ((N-phenylsulfamoyl) amino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(90) (R) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- ((N-phenylsulfamoyl) amino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(91)2- ((N, N-dimethylaminosulfonyl) amino) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(92) (S) -2- ((N, N-dimethylaminosulfonyl) amino) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(93) (R) -2- ((N, N-dimethylaminosulfonyl) amino) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(94) n- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (pyrrolidin-1-ylsulfonylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(95) (S) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (pyrrolidin-1-ylsulfonylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(96) (R) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (pyrrolidin-1-ylsulfonylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(97) n- (1- (1-oxo-2-phenyl-8- ((1- (2, 2, 2-trifluoroethyl) -1H-pyrazol-4-yl) ethynyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (sulfamoylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(98) (S) -N- (1- (1-oxo-2-phenyl-8- ((1- (2, 2, 2-trifluoroethyl) -1H-pyrazol-4-yl) ethynyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (sulfamoylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(99) (R) -N- (1- (1-oxo-2-phenyl-8- ((1- (2, 2, 2-trifluoroethyl) -1H-pyrazol-4-yl) ethynyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (sulfamoylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(100) n- (1- (1-oxo-2-phenyl-8- ((1- (2, 2, 2-trifluoroethyl) -1H-pyrazol-4-yl) ethynyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) -2- ((N-cyclopropylsulfamoyl) amino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(101) (S) -N- (1- (1-oxo-2-phenyl-8- ((1- (2, 2, 2-trifluoroethyl) -1H-pyrazol-4-yl) ethynyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) -2- ((N-cyclopropylsulfamoyl) amino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(102) (R) -N- (1- (1-oxo-2-phenyl-8- ((1- (2, 2, 2-trifluoroethyl) -1H-pyrazol-4-yl) ethynyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) -2- ((N-cyclopropylsulfamoyl) amino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(103) n- (1- (8-ethynyl-1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (sulfamoylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(104) (S) -N- (1- (8-ethynyl-1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (sulfamoylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(105) (R) -N- (1- (8-ethynyl-1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (sulfamoylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(106)2- ((N-cyclopropylsulfamoyl) amino) -N- (1- (8-ethynyl-1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(107) (S) -2- ((N-cyclopropylsulfamoyl) amino) -N- (1- (8-ethynyl-1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(108) (R) -2- ((N-cyclopropylsulfamoyl) amino) -N- (1- (8-ethynyl-1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(109) n- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenyl-1-thioxo-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (sulfamoylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(110) (S) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenyl-1-thioxo-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (sulfamoylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(111) (R) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenyl-1-thioxo-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (sulfamoylamino) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(112)2- ((N-cyclopropylsulfamoyl) amino) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenyl-1-thioxo-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(113) (S) -2- ((N-cyclopropylsulfamoyl) amino) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenyl-1-thioxo-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(114) (R) -2- ((N-cyclopropylsulfamoyl) amino) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenyl-1-thioxo-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(115) (S) -2-amino-N- (1- (8- (7-methyl-1-oxo-2, 7-diazaspiro [3.5] nonan-2-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(116) 2-amino-N- (1- (8- (7-methyl-1-oxo-2, 7-diazaspiro [3.5] non-2-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(117) (R) -2-amino-N- (1- (8- (7-methyl-1-oxo-2, 7-diazaspiro [3.5] nonan-2-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(118) (S) -2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-thioxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide;
(119) (R) -2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-thioxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1, 5-a ] pyrimidine-3-carboxamide.
In a third aspect, the present invention provides a process for the preparation of a compound having the structure of formula I as described above, comprising:
1) a method for preparing a compound having the structure of formula IA comprises the following steps:
Figure PCTCN2019089027-APPB-000002
s1: replacement of X in Compound IA-1-1 with R3To obtain compound IA-1-2;
s2: reacting compound IA-1-2 with compound IA-a to obtain compound IA-1-3;
s3: reacting compound IA-1-3 with compound IA-b to obtain compound IA-1-4;
s4: reacting compound IA-1-4 with compound IA-c to obtain a compound having the structure of formula IA;
wherein:x is chlorine, bromine or iodine; x4Is CH or CR7；X 1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 2、R 3、R 4、R 5、R 6And R7As defined in the following compounds of formula IA; or
The specific steps are as follows:
Figure PCTCN2019089027-APPB-000003
s1: by replacing X in compound IA-2-1 with R3To obtain compound IA-2-2;
s2: reacting the compound 1A-2-2 with a compound IA-a to obtain a compound IA-2-3;
s3: reacting the compound IA-2-3 with the compound IA-d to obtain a compound IA-2-4;
s4: performing ring closing reaction on the compound IA-2-4 under the nitro reduction condition to obtain a compound IA-2-5;
s5: reacting compound IA-2-5 with compound IA-c to obtain a compound having the structure of formula IA;
wherein: x is chlorine, bromine or iodine; x1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 2、R 3、R 4、R 5And R6As defined in the following compounds of formula IA;
2) the preparation method of the compound with the structure of the formula IB comprises the following specific steps:
Figure PCTCN2019089027-APPB-000004
s1: replacement of X in Compound IB-1-1 by R3To obtain a compound IB-1-2;
s2: reacting the compound IB-1-2 with the compound IB-a to obtain a compound IB-1-3;
s3: reacting the compound IB-1-3 with the compound IB-b to obtain a compound IB-1-4;
s4: reacting the compound IB-1-4 with a compound IB-c to obtain a compound with a structure of a formula IB;
wherein: x is chlorine, bromine or iodine; x4Is CH or CR7；X 1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 2、R 3、R 4、R 5、R 6And R7As defined in compounds of formula IB below; or
The specific steps are as follows:
Figure PCTCN2019089027-APPB-000005
s1: replacement of X in Compound IB-2-1 with R3To obtain a compound IB-2-2;
s2: reacting the compound 1B-2-2 with a compound IB-a to obtain a compound IB-2-3;
s3: reacting the compound IB-2-3 with a compound IB-d to obtain a compound IB-2-4;
s4: performing ring closing reaction on the compound IB-2-4 under the nitro reduction condition to obtain a compound IB-2-5;
s5: reacting the compound IB-2-5 with a compound IB-c to obtain a compound with a structure of a formula IB;
wherein: x is chlorine, bromine or iodine; x1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 2、R 3、R 4、R 5And R6As defined in compounds of formula IB below;
3) the preparation method of the compound with the structure of formula IC comprises the following steps:
Figure PCTCN2019089027-APPB-000006
s1: replacement of X in Compound IC-1-1 by R3To obtain a compound IC-1-2;
s2: reacting the compound IC-1-2 with the compound IC-a to obtain a compound IC-1-3;
s3: reacting the compound IC-1-3 with the compound IC-b to obtain a compound IC-1-4;
s4: reacting the compound IC-1-4 with a compound IC-c to obtain a compound with a formula IC structure;
wherein: x is chlorine, bromine or iodine; x4Is CH or CR7；X 1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 5、R 6And R7As defined in the following formula IC compounds; or
The specific steps are as follows:
Figure PCTCN2019089027-APPB-000007
s1: replacement of X in Compound IC-2-1 by R3To obtain a compound IC-2-2;
s2: reacting the compound 1C-2-2 with a compound IC-a to obtain a compound IC-2-3;
s3: reacting the compound IC-2-3 with the compound IC-d to obtain a compound IC-2-4;
s4: performing ring closing reaction on the compound IC-2-4 under the nitro reduction condition to obtain a compound IC-2-5;
s5: reacting the compound IC-2-5 with a compound IC-c to obtain a compound with a formula IC structure;
wherein: x is chlorine, bromine or iodine; x1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 5And R6As defined in the following formula IC compounds; or
The specific steps are as follows:
Figure PCTCN2019089027-APPB-000008
s1: replacement of X in Compound IC-3-1 by R3To obtain a compound IC-3-2;
s2: reacting the compound 1C-3-2 with a compound IC-a to obtain a compound IC-3-3;
s3: reacting the compound IC-3-3 with the compound IC-b to obtain a compound IC-3-4;
s4: reacting the compound IC-3-4 with the compound IC-c to obtain a compound IC-3-5;
s5: replacement of one of the hydrogen atoms of the amino group of Compound IC-3-5 by S (O)nR 7To obtain a compound with a structure of formula IC;
wherein: x is chlorine, bromine or iodine; x4Is CH or N; r6Is NH2；X 1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 5And R7As defined in the following formula IC compounds; each n is independently 0, 1 or 2;
4) the preparation method of the compound with the structure shown in the formula ID comprises the following specific steps:
Figure PCTCN2019089027-APPB-000009
s1: replacement of X in Compound ID-1-1 by R3To obtain compound ID-1-2;
s2: under the action of the compound ID-a, the compound ID-1-2 undergoes a ring closure reaction to obtain a compound ID-1-3;
s3: introduction of R into Compound ID-1-31To obtain compound ID-1-4;
s4: reacting the compound ID-1-4 with the compound ID-b to obtain a compound ID-1-5;
s5: reacting the compound ID-1-5 with the compound ID-c to obtain a compound ID-1-6;
s6: reacting the compound ID-1-6 with the compound ID-d to obtain a compound ID;
wherein: x is chlorine, bromine or iodine; x1、X 2、X 3、X 4、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 6And R7As defined in the following formula ID compounds; or
The specific steps are as follows:
Figure PCTCN2019089027-APPB-000010
s1: replacement of X in Compound ID-2-1 by R3To obtain compound ID-2-2;
s2: reacting the compound ID-2-2 with the compound ID-e to obtain a compound ID-2-3;
s3: reacting the compound ID-2-3 with the compound ID-f to obtain a compound ID-2-4;
s4: reacting the compound ID-2-4 with a Lawson reagent and a compound ID-g to obtain a compound ID-2-5;
s5: reacting the compound ID-2-5 with the compound ID-c to obtain a compound with a structure shown in a formula ID;
wherein: x is chlorine, bromine or iodine; r is H, OH or R7；X 4Is CH or CR7；X 1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 6And R7As defined in the following formula ID compounds;
5) the preparation method of the compound with the structure of the formula IE comprises the following specific steps:
Figure PCTCN2019089027-APPB-000011
s1: the compound IE-1-1 reacts with the compound IE-a to obtain a compound IE-1-2;
s2: the compound IE-1-2 reacts with the compound IE-b to obtain a compound IE-1-3;
s3: the compound IE-1-3 reacts with the compound IE-c to obtain a compound IE-1-4;
s4: carrying out ammonolysis reaction on the compound IE-1-4 to obtain a compound IE-1-5;
s5: replacement of X in Compound IE-1-5 by R3To obtain a compound IE-1-6;
s6: reacting the compound IE-1-6 with the compound IE-d to obtain a compound IE;
wherein: x is chlorine, bromine or iodine; r is alkyl; x1、X 2、X 3、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 5And R6As defined in the following formula IE compound;
6) the preparation method of the compound with the structure of the formula IF comprises the following specific steps:
Figure PCTCN2019089027-APPB-000012
s1: reacting the compound IF-1-1 with the compound IF-a to obtain a compound IF-1-2;
s2: reacting the compound IF-1-2 with the compound IF-b to obtain a compound IF-1-3;
s3: reacting the compound IF-1-3 with the compound IF-c to obtain a compound IF-1-4;
s4: replacement of X in Compound IF-1-4 by R3To obtain a compound IE-1-5;
s5: carrying out amino reaction on the compound IF-1-5 to obtain a compound IF-1-6;
s6: reacting compound IF-1-6 with compound IF-d to obtain compound IF;
wherein: x is chlorine, bromine or iodine; r is alkyl; x1、X 2、X 3、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 5And R6As defined in the following compounds of formula IF.
In a fourth aspect, the present invention provides a pharmaceutical composition comprising a compound having the structure of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or mixture thereof, in any proportion.
In a fifth aspect, the present invention provides a compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any ratio, or a pharmaceutical composition as described above, for use as a PI3K inhibitor.
In a sixth aspect, the present invention provides the use of a compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any proportion, or a pharmaceutical composition thereof, as described above, as an inhibitor of PI 3K.
In a seventh aspect, the present application provides a use of the above compound having a structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any ratio, or the above pharmaceutical composition, in the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by PI 3K.
In an eighth aspect, the present invention provides a method for preventing and/or treating a disease mediated at least in part by PI3K, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion, or a pharmaceutical composition as described above.
In a ninth aspect, the present invention provides a pharmaceutical combination comprising a compound having the structure of formula I as described above or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any proportion, or a pharmaceutical composition as described above, and at least one additional cancer therapeutic agent.
In a tenth aspect, the present invention provides a method for preventing and/or treating cancer, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or a mixture thereof in any proportion, or a pharmaceutical composition as described above, and at least one additional cancer therapeutic.
ADVANTAGEOUS EFFECTS OF INVENTION
The invention provides a compound of formula I with a novel structure, which can be used as a high-efficiency PI3K inhibitor and has various pharmacological activities of resisting tumors, neurodegenerative diseases (such as Alzheimer disease), inflammation, infection and the like. The synthesis method is mild, simple and easy to operate, easy to derivatize and suitable for industrial mass production.
Drawings
FIG. 1 is a compound of the present invention having the structure of formula I.
FIG. 2 is a synthetic route for Compound 1 of the present invention.
FIG. 3 is a scheme for the synthesis of compound 7 of the present invention.
FIG. 4 is a scheme for the synthesis of compound 10 of the present invention.
FIG. 5 is a scheme for the synthesis of compound 32 of the present invention.
FIG. 6 is a scheme showing the synthesis of compound 42 of the present invention.
FIG. 7 is a scheme for the synthesis of compound 51 of the present invention.
Detailed Description
Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
[ definition of terms ]
Unless otherwise indicated, the following terms have the following meanings.
"pharmaceutically acceptable salt" refers to salts of compounds having the structure of formula I that are substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting a compound of the invention with a pharmaceutically acceptable inorganic/organic acid or inorganic/organic base, such salts also being referred to as acid addition salts or base addition salts. Common inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like, common organic acids include, but are not limited to, trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, oxalic acid, formic acid, acetic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, common inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, and the like, and common organic bases include, but are not limited to, diethylamine, triethylamine, ethambutol, and the like.
The term "solvate" refers to a substance formed by the binding of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to at least one solvent molecule by non-covalent intermolecular forces. The term "solvate" includes "hydrate". Common solvates include, but are not limited to, hydrates, ethanolates, acetonates, and the like.
The term "hydrate" refers to a substance formed by the non-covalent intermolecular binding of a compound of the present invention or a pharmaceutically acceptable salt thereof with water. Common hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, and the like.
The term "isomers" refers to compounds having the same number and type of atoms and thus the same molecular weight, but differing in the spatial arrangement or configuration of the atoms.
The term "stereoisomer" refers to isomers resulting from the different arrangement of atoms in a molecule, and includes both "configurational isomers" and "conformational isomers". The term "configurational isomers" refers to isomers resulting from different spatial arrangements of atoms in a molecule, and includes both "cis-trans isomers" and "optical isomers". The term "cis-trans isomer" refers to isomers in which the atoms (or groups) on both sides of a double bond or ring system are in different positions relative to a reference plane, in the cis isomer the atoms (or groups) are on the same side of the double bond or ring system, and in the trans isomer the atoms (or groups) are on the opposite side of the double bond or ring system, wherein "double bond" refers generally to a carbon-carbon double bond and also includes a carbon-nitrogen double bond and a nitrogen-nitrogen double bond. The term "optical isomer" refers to a stable isomer having a perpendicular asymmetric plane due to having at least one chiral factor (including a chiral center, a chiral axis, a chiral plane, etc.) so that plane polarized light can be rotated. Because of the presence of asymmetric centers and other chemical structures in the compounds of the present invention that may lead to stereoisomers, the present invention also includes such stereoisomers and mixtures thereof. Since the compounds of the present invention and their salts comprise asymmetric carbon atoms, they can exist in the form of single stereoisomers, racemates, mixtures of enantiomers and diastereomers. Generally, these compounds can be prepared in the form of a racemic mixture. However, if desired, such compounds may be prepared or isolated to give pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in single stereoisomers (purity. gtoreq.98%,. gtoreq.95%,. gtoreq.93%,. gtoreq.90%,. gtoreq.88%,. gtoreq.85% or. gtoreq.80%). As described hereinafter, individual stereoisomers of compounds are prepared synthetically from optically active starting materials containing the desired chiral center, or by preparation of mixtures of enantiomeric products followed by separation or resolution, e.g., conversion to mixtures of diastereomers followed by separation or recrystallization, chromatography, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. The starting compounds of a particular stereochemistry are either commercially available or may be prepared according to the methods described hereinafter and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that have non-superimposable mirror images of each other. The term "diastereomer" or "diastereomer" refers to optical isomers that do not form mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of the two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.
The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The term "isotopic label" refers to a compound formed by replacing a particular atom in a structure with its isotopic atom. Unless otherwise indicated, compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as2H(D)、 3H(T)、 13C、 14C、 15N、 17O、 18O、 18F、 31p、 32p、 35S、 36S and37Cl。
the term "prodrug" refers to a derivatized compound that, upon application to a patient, is capable of providing, directly or indirectly, a compound of the invention. Particularly preferred derivative compounds or prodrugs are those which, when administered to a patient, increase the bioavailability of the compounds of the invention (e.g., are more readily absorbed into the blood), or facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are well known in the art.
The term "independently of each other" means that at least two groups (or ring systems) present in the structure in the same or similar range of values may have the same or different meaning in a particular case. For example, X and Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, and when X is hydrogen, Y is either hydrogen or halogen, hydroxy, cyano, alkyl or aryl; similarly, when Y is hydrogen, X may be hydrogen, or may be halogen, hydroxy, cyano, alkyl or aryl.
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) located in main group VII of the periodic Table of the elements.
The term "hypophosphoryl" refers to a monovalent group formed by hypophosphorous acid upon loss of the hydroxyl group and attached to the parent (-P (═ O) H) by a single bond to the phosphorus atom2). The phosphoryl group can be attached in unsubstituted form to the structural parent nucleus of the compounds of the formula I according to the invention, or the hydrogen atom can be replaced by other substituents. Common substituted phosphoryl groups include, but are not limited to, dialkylphosphoryl (-P (═ O) (Alk)2E.g. dimethylphosphoryl), diarylphosphoryl (- ═ O) (Ar)2E.g. diphenylphosphinyl), alkylarylphosphinylphosphinyl (-P (═ O) (Alk) (Ar), e.g. methylphenylphosphinyl), dialkoxyphosphinyl (-P (═ O) (OAlk)2Such as dimethoxyphosphoryl) and the like.
The term "phosphoryl" refers to a monovalent group formed by the loss of a hydroxyl group from a phosphoric acid and attached to the parent (-P (═ O) (OH) by a single bond to the phosphorus atom2)。
The term "alkyl" refers to a monovalent straight or branched chain alkane group consisting of carbon and hydrogen atoms, containing no unsaturation, and attached to the parent nucleus by a single bond, preferably C1-C 6Alkyl, more preferably C1-C 4An alkyl group; common alkyl groups include, but are not limited to, methyl (-CH)3) Ethyl (-CH)2CH 3) N-propyl (-CH)2CH 2CH 3) Isopropyl (-CH (CH)3) 2) N-butyl (-CH)2CH 2CH 2CH 3) Sec-butyl (-CH (CH)3)CH 2CH 3) Isobutyl (-CH)2CH(CH 3) 2) T-butyl (-C (CH))3) 3) N-pentyl (-CH)2CH 2CH 2CH 2CH 3) Neopentyl (-CH)2C(CH 3) 3) And the like.
The term "alkenyl" refers to a monovalent straight or branched chain alkene group consisting of only carbon and hydrogen atoms, containing at least one double bond, and connected to the parent nucleus by a single bond, preferably C2-C 6An alkenyl group; common alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)2) 1-propen-1-yl (-CH ═ CH-CH)3) 1-buten-1-yl (-CH ═ CH-CH)2-CH 3) 1-penten-1-yl (-CH ═ CH-CH)2-CH 2-CH 3)1, 3-butadien-1-yl (-CH ═ CH)2)1, 4-pentadien-1-yl (-CH ═ CH-CH)2-CH＝CH 2) And the like.
The term "alkynyl" refers to a monovalent straight or branched chain alkyne group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, and connected to the parent nucleus by a single bond, preferably C2-C 6An alkynyl group; common alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), 1-propyn-1-yl (i.e., propynyl) (-C.ident.C-CH)3) 1-butyn-1-yl (i.e. butynyl)
Figure PCTCN2019089027-APPB-000013
Pentyn-1-yl
Figure PCTCN2019089027-APPB-000014
1, 3-diacetylene-1-yl (-C.ident.C-C.ident.CH), 1, 4-pentadiyne-1-yl
Figure PCTCN2019089027-APPB-000015
And the like.
The term "alkoxy" refers to a monovalent straight or branched chain radical consisting solely of carbon, hydrogen and oxygen atoms, which may contain unsaturation, and which is attached to the parent nucleus by a single bond to the oxygen atom, preferably C1-C 4An alkoxy group; common alkoxy groups include, but are not limited to, methoxy (-OCH)3) Ethoxy (-OCH)2CH 3) N-propoxy group (-OCH)2CH 2CH 3) I-propoxy (-OCH (CH)3) 2) N-butoxy (-OCH)2CH 2CH 2CH 3) Sec-butoxy (-OCH (CH)3)CH 2CH 3) Isobutoxy (-OCH)2CH(CH 3) 2) T-butoxy (-OC (CH))3) 3) N-pentyloxy (-OCH)2CH 2CH 2CH 2CH 3) Neopentyloxy (-OCH)2C(CH 3) 3) And the like.
The term "alkanoyl" refers to a monovalent straight or branched chain radical consisting only of carbon, hydrogen and oxygen atoms, containing no unsaturation other than the carbonyl group in its structure, and attached to the parent nucleus by a single bond to the carbonyl group, preferably C1-C 4An alkyl acyl group; common alkanoyl groups include, but are not limited to, formyl (-C (═ O) H), acetyl (-C (═ O) CH3) N-propionyl (-C (═ O) CH2CH 3) N-butyryl (-C (═ O) CH2CH 2CH 3) Isobutyryl group (-C (═ O) CH (CH)3) 2) N-pentanoyl (-C (═ O) CH2CH 2CH 2CH 3) Pivaloyl (-C (═ O) C (CH)3) 3) And the like.
The term "alkylamido" refers to a monovalent straight or branched chain radical consisting of only carbon, hydrogen, oxygen and nitrogen atoms, containing no unsaturation other than the carbonyl group in its structure, and attached to the parent nucleus by a single bond to the nitrogen atom, preferably C1-C 4An alkylamido group; common alkylamido groups include, but are not limited to, formylamino (-NHC (═ O) H), acetamido (-NHC (═ O) CH3) N-propionylamino (-NHC (═ O) CH2CH 3) N-butylamido (-NHC (═ O) CH2CH 2CH 3) Isobutyramido (-NHC (═ O) CH (CH)3) 2) N-pentanoylamino (-NHC (═ O) CH2CH 2CH 2CH 3) Pivaloylamino (-NHC (═ O) C (CH)3) 3) And the like.
The term "alkanoyloxy" refers to a monovalent straight or branched chain radical consisting of only carbon, hydrogen and oxygen atoms, containing no unsaturation other than the carbonyl group in its structure, and attached to the parent nucleus by a single bond to the oxygen atom, preferably C1-C 4An alkyl acyloxy group; common alkanoyloxy groups include, but are not limited to, formyloxy (-OC (═ O) H), acetyloxy (-OC (═ O) CH3) N-propionyloxy (-OC (═ O) CH2CH 3) N-butyryloxy (-OC (═ O) CH2CH 2CH 3) Isobutyroyloxy (-OC (═ O) CH (CH)3) 2) N-valeryloxy (-OC (═ O) CH2CH 2CH 2CH 3) Pivaloyloxy (-OC (═ O) C (CH)3) 3) And the like.
The term "alkoxycarbonyl" refers to a monovalent radical of a straight chainA chain or branched group consisting of carbon, hydrogen and oxygen atoms only, containing no unsaturation other than the carbonyl group in its structure, and linked to the parent nucleus by a single bond to the carbonyl group, preferably C1-C 4An alkoxycarbonyl group; common alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl (-C (═ O) OCH3) Ethoxycarbonyl (-C (═ O) OCH2CH 3) N-propoxycarbonyl (-O) OCH2CH 2CH 3) Iso-propoxycarbonyl (-C (═ O) OCH (CH)3) 2) N-butoxycarbonyl (-C (═ O) OCH2CH 2CH 2CH 3) T-butyloxycarbonyl (-C (═ O) OC (CH)3) 3) And the like.
The term "cycloalkyl" refers to a monovalent monocyclic, non-aromatic ring system consisting only of carbon and hydrogen atoms, containing no unsaturation, and connected to the parent nucleus by a single bond; common cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "heterocyclyl" refers to a monovalent monocyclic non-aromatic ring system consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing no unsaturation, and being connected to the parent nucleus by a single bond; common heterocyclyl groups include, but are not limited to, oxiranyl, oxetan-3-yl, azetidin-3-yl, tetrahydrofuran-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, tetrahydro-2H-pyran-4-yl, piperidin-2-yl, piperidin-4-yl, and the like.
The term "spirocyclic group" refers to a monovalent non-aromatic ring system in which two single rings share a carbon atom, which consists only of carbon and hydrogen atoms, contains no unsaturation, and is connected to the parent nucleus by a single bond; according to the number of spiro atoms, they can be classified into mono-spiro compounds, di-spiro compounds, tri-spiro compounds, etc.; common spirocyclic groups include, but are not limited to, spiro [2.4] heptan-1-yl, spiro [3.5] nonan-2-yl, spiro [4.5] decan-2-yl, dispiro [5.2.5.2] hexadecan-3-yl, and the like.
The term "heterospirocyclic" refers to a monovalent non-aromatic ring system of two monocyclic rings sharing a single carbon atom, consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing no unsaturation, and being linked to the parent nucleus by a single bond; common heterospirocyclic groups include, but are not limited to, 6-oxaspiro [3.3] heptan-2-yl, 7-methyl-7-azaspiro [3.5] nonan-2-yl, 7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl, 9-methyl-9-phosphaspiro [5.5] undecan-3-yl, and the like.
The term "bridged cyclic group" refers to a monovalent non-aromatic ring system in which any two monocyclic rings share two carbon atoms that are not directly connected, are composed of only carbon and hydrogen atoms, contain no unsaturation, and are connected to the parent nucleus by a single bond; according to the number of constituent rings, they can be classified into bicyclic compounds, tricyclic compounds, tetracyclic compounds, etc.; common bridging groups include, but are not limited to, decahydronaphthalen-1-yl, bicyclo [ 3.2.1%]Octane-1-yl, tricyclo [2.2.1.02.6]Heptane-1-yl, 1-adamantyl, and the like.
The term "heterobridged cyclic group" refers to a monovalent non-aromatic ring system in which any two monocyclic rings share two carbon atoms not directly connected, are composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, contain no unsaturation, and are connected to the parent nucleus by a single bond; common heterobridged cyclic groups include, but are not limited to, 1, 4-diazabicyclo [2.2.2] octan-2-yl, 2, 8-diazabicyclo [4.3.0] nonan-8-yl, and the like.
The term "aryl" refers to a monovalent monocyclic or polycyclic (including fused forms) aromatic ring system consisting of only carbon and hydrogen atoms and being linked to the parent nucleus by a single bond; common aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like.
The term "arylalkyl" refers to a monovalent straight or branched chain alkyl radical consisting solely of carbon and hydrogen atoms, containing at least one aryl group, and connected to the parent nucleus by a single bond, preferably C6-C 10aryl-C1-C 6Alkyl, more preferably C6-C 10aryl-C1-C 4An alkyl group; common arylalkyl groups include, but are not limited to, benzyl, β -phenylethyl, α -phenylethyl, naphthylmethyl, and the like.
The term "arylalkenyl" refers to a monovalent straight or branched chain alkene group consisting of only carbon and hydrogen atoms, containing at least one double bond and at least one aryl group, and being connected to the parent nucleus by a single bond, preferably C6-C 10aryl-C2-C 6An alkenyl group; common arylalkenyl groups include, but are not limited to, 1-styryl (-CPh ═ CH)2) 2-styryl (-CH ═ CHPh), 3-phenyl-1-propen-1-yl (-CH ═ CH-CH)2Ph), 2-phenyl-1-propen-1-yl (-CH ═ CPh-CH)3) 4-phenyl-1, 3-butadien-1-yl (-CH ═ CHPh), 4-diphenyl-1, 3-butadien-1-yl (-CH ═ CH-CH ═ CPh)2) And the like.
The term "arylalkynyl" refers to a monovalent straight or branched chain alkyne group consisting of only carbon and hydrogen atoms, containing at least one triple bond and at least one aryl group, and connected to the parent nucleus by a single bond, preferably C6-C 10aryl-C2-C 6An alkynyl group; common arylalkynyl groups include, but are not limited to, phenylethynyl (-C ≡ CPh), 3-phenyl-1-propyn-1-yl (-C ≡ C-CH)2Ph), 3-diphenyl-1-propyn-1-yl (-C.ident.C-CHPh)2) And 4-phenyl-1, 3-diacetylene-1-yl (-C.ident.C-C.ident.CPh).
The term "heteroaryl" refers to a monovalent monocyclic or polycyclic (including fused forms) aromatic ring system composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, and connected to the parent nucleus by a single bond; common heterocyclyl groups include, but are not limited to, benzopyrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, acridinyl, carbazolyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, indazolyl, indolizinyl, indolyl, quinolinyl, isoquinolinyl, phenazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, purinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridyl, triazolyl, tetrazolyl, and the like.
The term "heteroarylalkyl" refers to a monovalent straight or branched chain alkane group consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing at least one heteroaryl group, and connected to the parent nucleus by a single bond, preferably a 5-to 10-membered heteroaryl-C1-C 6Alkyl, more preferably 5-10 membered heteroaryl-C1-C 4An alkyl group; common heteroarylalkyl groups include, but are not limited to, pyrrol-2-ylmethyl, furan-2-ylmethyl, thiophen-2-ylmethyl, 1H-pyrazol-3-ylmethyl, quinolin-4-ylmethyl, and the like.
The term "heteroarylalkenyl" refers to a monovalent straight or branched chain alkene group consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing at least one double bond and at least one heteroaryl group, and connected to the parent nucleus by a single bond, preferably a 5-to 10-membered heteroaryl-C2-C 6An alkenyl group; common heteroarylalkenyl groups include, but are not limited to, 2- (pyrrol-2-yl) vinyl, 2- (furan-2-yl) vinyl, 2- (thiophen-2-yl) vinyl, 4- (1H-pyrazol-3-yl) -1, 3-butan-1-yl, and the like.
The term "heteroarylalkynyl" refers to a monovalent straight or branched chain alkyne group consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing at least one triple bond and at least one heteroaryl group, and connected to the parent nucleus by a single bond, preferably a 5-to 10-membered heteroaryl-C2-C 6An alkynyl group; common heteroarylalkynyls include, but are not limited to, (pyrrol-2-yl) ethynyl, (furan-2-yl) ethynyl, (thiophen-2-yl) ethynyl, (1H-pyrazol-3-yl) ethynyl, (1H-pyrazol-4-yl) ethynyl, (1-methyl-1H-pyrazol-4-yl) ethynyl, and the like.
The term "ureido" refers to a monovalent group formed from urea after one hydrogen atom has been lost and which is attached to the parent (-NHC (═ O) NH via a single bond2). The term "alkylureido" refers to a monovalent radical which has an alkyl group substituted for a hydrogen atom (the substitution site) in the ureido groupA dot is usually on the nitrogen atom in the other amino group) and is linked to the parent nucleus (-NHC (═ O) NHAlk or-NHC (═ O) NAlk by a single bond2)。
The term "pentafluoro- λ6-thioalkyl "(also known as" sulfur pentafluoride ") means a monovalent group consisting of only a sulfur atom and a fluorine atom, and is bonded to the parent nucleus (-SF) by a single bond5)。
[ Compound of the general formula ]
The present invention provides a compound of formula I:
Figure PCTCN2019089027-APPB-000016
or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion thereof, wherein:
R 1、R 3、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 3、R 4And R6The hydrogen in (1) can optionally be replaced by 0 to more than oneR 7Substitution;
X 0is-CH2-、-C(＝R 2)-、-S(＝R 2) n-or-P (═ R)2)(R 0)-；
X 1、X 2、X 3、X 5、X 6、X 7、X 9、X 10、X 11、X 12、X 13And X14Each independently is CH, CR7Or N;
X 4and X8Each independently is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
Or X4And X5Form a double bond therebetween, wherein: x5Is C, X4Is CH, CR7Or N;
R 0is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and when R is0When not hydrogen, R0Hydrogen in (a) is optionally substituted with deuterium or halogen;
R 2and R5Each independently is NH, NR7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In some preferred embodiments of the invention, the compound of formula I above is a compound of formula IA:
Figure PCTCN2019089027-APPB-000017
wherein:
R 1、R 3、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、 -OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 3、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 1、X 2、X 3、X 4、X 6、X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N;
X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
R 2And R5Each independently is NH, NR7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In some preferred embodiments of the invention, the compound of formula I above is a compound of formula IB:
Figure PCTCN2019089027-APPB-000018
wherein:
R 0is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and when R is0When not hydrogen, R0Hydrogen in (a) is optionally substituted with deuterium or halogen;
R 1、R 3、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 3、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 1、X 2、X 3、X 4、X 6、X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N;
X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
R 2And R5Each independently is NH, NR7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylAlkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In some preferred embodiments of the invention, the compound of formula I above is a compound of formula IC:
Figure PCTCN2019089027-APPB-000019
wherein:
R 1、R 3、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 3、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 1、X 2、X 3、X 4、X 6、X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N;
X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
R 2Is NH, NR7NOH, S or O;
R 5NH, NR, NOH or S;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In some preferred embodiments of the invention, the compound of formula I above is a compound of formula ID:
Figure PCTCN2019089027-APPB-000020
wherein:
R 3is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Phosphoryl or substituted or unsubstituted phosphoryl hypo; and R is3Optionally substituted with at least one R7Substitution;
R 1、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 1、X 2、X 3、X 4、X 6、X 7、X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N; or X7And R4May form a 3-6 membered ring;
X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
R 2Optionally independently is NH、NR 7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2;
if and only if X6Is N, X7Is CH, X8is-NH-or-NR7-, and R2When is O, R1And R3At least one group selected from spiro ring group, hetero-spiro ring group, bridged ring group, hetero-bridged ring group, - (CH)2) nSF 5Substituted or unsubstituted phosphoryl, SF5Substituted aryl or heteroaryl, substituted or unsubstituted phosphoryl-substituted aryl or heteroaryl.
In some preferred embodiments of the invention, the compound of formula I above is a compound of formula IE:
Figure PCTCN2019089027-APPB-000021
wherein:
R 1、R 3、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro-ring, heterospiro-ring, bridged-ring, heterobridged-ring, aryl, arylalkyl,Arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 3、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 0is-CH2-、-C(＝R 2)-、-S(＝R 2) n-or-P (═ R)2)(R 0)-；
X 1、X 2、X 3、X 5、X 6、X 9、X 10、X 11、X 12、X 13And X14Each independently is CH, CR7Or N;
X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
R 0Is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and when R is0When not hydrogen, R0Hydrogen in (a) is optionally substituted with deuterium or halogen;
R 2and R5Each independently is NH, NR7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In some preferred embodiments of the invention, the compound of formula I above is a compound of formula IF:
Figure PCTCN2019089027-APPB-000022
wherein:
R 1、R 3、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 3、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 1、X 2、X 3、X 5、X 6、X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N;
X 4and X8Each independently is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
R 2And R5Each independently is NH, NR7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In some more preferred embodiments of the present invention, in the compounds of formula I or formula IA above:
R 1is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, heteroaryl, or,Heteroarylalkyl, alkoxy or heterocyclyloxy, preferably hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, heteroaryl or heteroarylalkyl, more preferably aryl or heteroaryl;
R 3is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, preferably hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged cyclic, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, more preferably alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged cyclic, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, phosphoryl or substituted or unsubstituted hypophosphoryl;
R 4is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;
R 6is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR7Amino, -NHS (═ O) R7Spiro-, hetero-spiro-, bridged-or heterobridged-ring groups, more preferably amino or-NHS (═ O) R7；
And R is1、R 3、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 1、X 2、X 3and X4Each independently is CH, CR7Or N, preferably CH or CR7More preferably CH;
X 6is N;
X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N, preferably X9、X 13、X 14Is N, more preferably X9、X 13And X14And is N at the same time;
X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-, preferably-NH-or-NR7-；
R 2And R5Each independently is NH, NR7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In some more preferred embodiments of the invention, in the above compound of formula I or formula IB:
R 0is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, heteroaryl or heteroarylalkyl, and when R is0When not hydrogen, R0Hydrogen in (a) is optionally substituted with deuterium or halogen; preferably hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; more preferably hydrogen, alkyl, cycloalkyl or heterocyclyl;
R 1is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclyl, bridged cyclic, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, or heterocyclyloxy, preferably hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclyl, bridged cyclic, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, more preferably aryl or heteroaryl;
R 3is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, preferably hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged cyclic, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, more preferably alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged cyclic, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, phosphoryl or substituted or unsubstituted hypophosphoryl;
R 4is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;
R 6is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR7Amino, -NHS (═ O) R7Spiro-, hetero-spiro-, bridged-or heterobridged-ring groups, more preferably amino or-NHS (═ O) R7；
And R is1、R 3、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 1、X 2、X 3and X4Each independently is CH, CR7Or N, preferably CH or CR7More preferably CH;
X 6is N;
X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N, preferably X9、X 13、X 14Is N, more preferably X9、X 13And X14And is N at the same time;
X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-, preferably-NH-or-NR7-；
R 2And R5Each independently is NH, NR7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In some more preferred embodiments of the invention, in the compounds of formula I or formula IC above:
R 1is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclyl, bridged cyclic, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, or heterocyclyloxy, preferably hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclyl, bridged cyclic, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, more preferably aryl or heteroaryl;
R 3is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, or a pharmaceutically acceptable salt thereof,Heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、- (CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, preferably hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged cyclic, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, more preferably alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged cyclic, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, phosphoryl or substituted or unsubstituted hypophosphoryl;
R 4is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;
R 6is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR7Amino, -NHS (═ O) R7Spiro-, hetero-spiro-, bridged-or heterobridged-ring groups, more preferably amino or-NHS (═ O) R7；
And R is1、R 3、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 1、X 2、X 3and X4Each independently is CH, CR7Or N, preferably CH or CR7More preferably CH;
X 6is N;
X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N, preferably X9、X 13、X 14Is N, more preferably X9、X 13And X14And is N at the same time;
X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-, preferably-NH-or-NR7-；
R 2Is NH, NR7NOH, S or O;
R 5is NH, NR7NOH or S;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In some more preferred embodiments of the invention, in the compounds of formula I or formula ID above:
R 3is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, or- (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Phosphoryl or substituted or unsubstituted phosphoryl hypo;
R 1is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclyl, bridged cyclic, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, or heterocyclyloxy, preferably hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclyl, bridged cyclic, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, more preferably aryl or heteroaryl;
R 4is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;
R 6is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR7Amino, -NHS (═ O) R7Spiro-, hetero-spiro-, bridged-or hetero-bridged ring groups, more preferably hydrogen, alkyl, -NHCOR7Amino or-NHS (═ O) R7；
And R is1、R 3、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 1、X 2、X 3and X4Each independently is CH, CR7Or N, preferably CH or CR7More preferably CH;
X 6is N;
X 7is CH, CR7Or N; or X7And R4May form a 3-6 membered ring;
X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N, preferably X9、X 13、X 14Is N, more preferably X9、X 13And X14And is N at the same time;
X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-, preferably-CH2-、-CHR 7-, -NH-or-NR7-；
R 2Is NH, NR7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In some more preferred embodiments of the invention, in the compounds of formula I or formula ID above:
R 3is spiro ring group, bridged ring group, hetero spiro ring group, hetero bridged ring group, -SF5Phosphoryl or substituted or unsubstituted phosphoryl hypo; and R is3The hydrogen in (1) can optionally beIs substituted by 0 to multiple R7Substitution;
R 1、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 1、X 2、X 3、X 4、X 6、X 7、X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N; or X7And R4May form a 3-6 membered ring;
X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
R 2Is NH, NR7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterocycylSpirocyclyl, bridged cyclic, heterobridged cyclic, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In some more preferred embodiments of the invention, in the compounds of formula I or formula ID above:
R 3is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, spiro, hetero-spiro, bridged, hetero-bridged, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Phosphoryl or substituted or unsubstituted phosphoryl hypo; and when R is3When not hydrogen, R3The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
R 1is spiro ring group, hetero spiro ring group, bridged ring group, hetero bridged ring group, aryl or heteroaryl; and R is1The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitroRadical, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 1、X 2、X 3、X 4、X 6、X 7、X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N; or X7And R4May form a 3-6 membered ring;
X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
R 2Is NH, NR7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, hetero-spiro, bridged, hetero-bridged, aryl (including substituted aryl, such as phenyl substituted with sulfur pentafluoride, dimethylphosphinyl, or phosphoryl), arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In some more preferred embodiments of the invention, in the compounds of formula I or formula ID above:
R 3is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, spiro, hetero-spiro, bridged, hetero-bridged, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Phosphoryl or substituted or unsubstituted phosphoryl hypo; and R is3The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
R 1、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 1、X 2、X 3、X 4、X 6、X 7、X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N; or X7And R4May form a 3-6 membered ring;
X 8is-CH2-、-CHR 7-、-C(R 7) 2-or-C (═ R)2)-；
R 2Is NH, NR7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In some more preferred embodiments of the invention, in the compounds of formula I or formula ID above:
R 3is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, spiro, hetero-spiro, bridged, hetero-bridged, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Phosphoryl or substituted or unsubstituted phosphoryl hypo; and R is3Optionally substituted by 0 to multiple R7Substitution;
R 1、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR 7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 1、X 2、X 3、X 4、X 6、X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N;
X 7is CR7Or N; or X7And R4May form a 3-6 membered ring;
X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
R 2Is NH, NR7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In some more preferred embodiments of the invention, in the above compound of formula I or formula IE:
R 1is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclyl, bridged cyclic, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, or heterocyclyloxy, preferably hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclyl, bridged cyclic, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, more preferably aryl or heteroaryl;
R 3is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, preferably hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged cyclic, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, more preferably alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged cyclic, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, phosphoryl or substituted or unsubstituted hypophosphoryl;
R 4is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;
R 6is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cyclicAlkyl, heterocyclyl, spirocyclyl, heterospirocyclyl, bridged, heterobridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR7Amino, -NHS (═ O) R7Spiro-, hetero-spiro-, bridged-or hetero-bridged ring groups, more preferably hydrogen, alkyl, -NHCOR7Amino or-NHS (═ O) R7；
And R is1、R 3、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 0is-CH2-、-C(＝R 2)-、-S(＝R 2) n-or-P (═ R)2)(R 0) -, preferably-C (═ R)2) -or-S (═ R)2) n-；
X 1、X 2And X3Each independently is CH, CR7Or N, preferably CH or CR7More preferably CH;
X 5and X6Each independently is CH, CR7Or N, preferably CH or N;
X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N, preferably X9、X 13、X 14Is N, more preferably X9、X 13And X14And is N at the same time;
X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-, preferably-NH-or-NR7-；
R 0Is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and when R is0When not hydrogen, R0Hydrogen in (a) is optionally substituted with deuterium or halogen;
R 2and R5Each independently is NH, NR7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0, 1 or 2.
In some more preferred embodiments of the invention, in the compounds of formula I or formula IF above:
R 1is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclyl, bridged cyclic, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, or heterocyclyloxy, preferably hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclyl, bridged cyclic, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, more preferably aryl or heteroaryl;
R 3is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, arylalkenylArylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, preferably hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged cyclic, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, more preferably alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged cyclic, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, phosphoryl or substituted or unsubstituted hypophosphoryl;
R 4is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;
R 6is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR7Amino, -NHS (═ O) R7Spiro-, hetero-spiro-, bridged-or hetero-bridged ring groups, more preferably hydrogen, alkyl, -NHCOR7Amino or-NHS (═ O) R7；
And R is1、R 3、R 4And R 6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
X 1、X 2and X3Each independently is CH, CR7Or N, preferably CH or CR7More preferably CH;
X 5and X6Each independently is CH, CR7Or N, preferably CH or N, more preferably N;
X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N, preferably X9、X 13、X 14Is N, more preferably X9、X 13And X14And is N at the same time;
X 4is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-, preferably-CH2-or-CHR7-；
X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-, preferably-NH-or-NR7-；
R 2And R5Each independently is NH, NR7NOH, S or O;
each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamidoA group, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano, or hydroxy;
each n is independently 0, 1 or 2.
In addition, the invention also provides the compound of the formula I, wherein the specific structure and name are shown in the following table:
Figure PCTCN2019089027-APPB-000023
Figure PCTCN2019089027-APPB-000024
Figure PCTCN2019089027-APPB-000025
Figure PCTCN2019089027-APPB-000026
Figure PCTCN2019089027-APPB-000027
Figure PCTCN2019089027-APPB-000028
Figure PCTCN2019089027-APPB-000029
Figure PCTCN2019089027-APPB-000030
Figure PCTCN2019089027-APPB-000031
Figure PCTCN2019089027-APPB-000032
Figure PCTCN2019089027-APPB-000033
Figure PCTCN2019089027-APPB-000034
Figure PCTCN2019089027-APPB-000035
Figure PCTCN2019089027-APPB-000036
Figure PCTCN2019089027-APPB-000037
Figure PCTCN2019089027-APPB-000038
Figure PCTCN2019089027-APPB-000039
[ production method ]
The present invention provides a process for the preparation of a compound of formula I as described above, which comprises:
1) the preparation method of the compound of the formula IA comprises the following steps:
Figure PCTCN2019089027-APPB-000040
s1: replacement of X in Compound IA-1-1 with R3(preferably by coupling or substitution) to give compound IA-1-2;
s2: reacting compound IA-1-2 with compound IA-a, preferably by condensation, to give compound IA-1-3;
s3: reaction of compound IA-1-3 with compound IA-b (preferably in the presence of a Grignard reagent and a metalorganic compound, more preferably in the presence of isopropyl magnesium chloride and n-butyl lithium) to provide compound IA-1-4;
s4: reacting compound IA-1-4 with compound IA-c, preferably by condensation, to give a compound of formula IA;
wherein: x is chlorine, bromine or iodine; x4Is CH or CR7；X 1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 2、R 3、R 4、R 5、R 6And R7As defined above for compounds of formula IA (preferably X)4Is CH, X6Is N, X8is-NH-); or
The specific steps are as follows:
Figure PCTCN2019089027-APPB-000041
s1: by replacing X in compound IA-2-1 with R3(preferably by coupling or substitution) to give compound IA-2-2;
s2: reacting compound 1A-2-2 with compound IA-a (preferably by condensation) to give compound IA-2-3;
s3: reacting compound IA-2-3 with compound IA-d, preferably by condensation, to give compound IA-2-4;
s4: and (3) carrying out ring closing reaction on the compound IA-2-4 under the nitro reduction condition (preferably zinc powder/acetic acid condition) to obtain a compound IA-2-5:
s5: reacting compound IA-2-5 with compound IA-c, preferably by condensation, to give a compound of formula IA;
wherein: x is chlorine, bromine or iodine; x1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 2、R 3、R 4、R 5And R6As defined above for compounds of formula IA (preferably X)6Is N, X8is-NH-);
2) the preparation method of the compound shown in the formula IB comprises the following specific steps:
Figure PCTCN2019089027-APPB-000042
s1: replacement of X in Compound IB-1-1 by R3(preferably by coupling or substitution) to give compound IB-1-2;
s2: reacting compound IB-1-2 with compound IB-a (preferably by condensation) to give compound IB-1-3;
s3: reacting compound IB-1-3 with compound IB-b (preferably in the presence of a Grignard reagent and a metal organic compound, more preferably in the presence of isopropyl magnesium chloride and n-butyl lithium) to provide compound IB-1-4;
s4: reacting compound IB-1-4 with compound IB-c (preferably by condensation) to give a compound of formula IB;
wherein: x is chlorine, bromine or iodine; x4Is CH or CR7；X 1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 2、R 3、R 4、R 5、R 6And R7As defined above for compounds of formula IB (preferably X)4Is CH, X6Is N, X8is-NH-); or
The specific steps are as follows:
Figure PCTCN2019089027-APPB-000043
s1: replacement of X in Compound IB-2-1 with R3(preferably by coupling or substitution) to give compound IB-2-2;
s2: reacting compound 1B-2-2 with compound IB-a (preferably by condensation) to give compound IB-2-3;
s3: compound IB-2-3 is reacted (preferably by condensation) with compound IB-d to provide compound IB-2-4;
s4: performing ring closing reaction on the compound IB-2-4 under a nitro reduction condition (preferably a zinc powder/acetic acid condition) to obtain a compound IB-2-5;
s5: compound IB-2-5 is reacted (preferably by condensation) with compound IB-c to provide a compound of formula IB;
wherein: x is chlorine, bromine or iodine; x1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 2、R 3、R 4、R 5And R6As defined above for compounds of formula IB (preferably X)6Is N, X8is-NH-);
3) the preparation method of the compound of the formula IC comprises the following specific steps:
Figure PCTCN2019089027-APPB-000044
s1: replacement of X in Compound IC-1-1 by R3(preferably by coupling or substitution) to give compound IC-1-2;
s2: reacting compound IC-1-2 with compound IC-a (preferably by condensation) to give compound IC-1-3;
s3: reacting compound IC-1-3 with compound IC-b (preferably in the presence of a Grignard reagent and an organolithium compound, more preferably in the presence of isopropyl magnesium chloride and n-butyllithium) to give compound IC-1-4;
s4: reacting compound IC-1-4 with compound IC-c, preferably by condensation, to give a compound of formula IC;
wherein: x is chlorine, bromine or iodine; x4Is CH or CR7；X 1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 5、R 6And R7As defined above for compounds of formula IC (preferably X)6Is N, X8is-NH-); or
The specific steps are as follows:
Figure PCTCN2019089027-APPB-000045
s1: replacement of X in Compound IC-2-1 by R3(preferably by coupling or substitution) to give compound IC-2-2;
s2: compound 1C-2-2 is reacted (preferably by condensation) with compound IC-a to give compound IC-2-3;
s3: reacting compound IC-2-3 with compound IC-d, preferably by condensation, to give compound IC-2-4;
s4: performing ring closing reaction on the compound IC-2-4 under the nitro reduction condition (preferably zinc powder/acetic acid condition) to obtain a compound IC-2-5;
s5: reacting compound IC-2-5 with compound IC-c, preferably by condensation, to give a compound of formula IC;
wherein: x is chlorine, bromine or iodine; x1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 5And R6As defined above for compounds of formula IC (preferably X)6Is N, X8is-NH-); or
The specific steps are as follows:
Figure PCTCN2019089027-APPB-000046
s1: replacement of X in Compound IC-3-1 by R3(preferably by coupling or substitution) to give compound IC-3-2;
s2: compound 1C-3-2 is reacted (preferably by condensation) with compound IC-a to give compound IC-3-3;
s3: reacting compound IC-3-3 with compound IC-b (preferably in the presence of a Grignard reagent and an organolithium compound, more preferably in the presence of isopropyl magnesium chloride and n-butyllithium) to give compound IC-3-4;
s4: reacting compound IC-3-4 with compound IC-c, preferably by condensation, to give compound IC-3-5;
s5: replacement of one of the hydrogen atoms of the amino group of Compound IC-3-5 by S (O)nR 7(preferably by sulfonylation) to give a compound having the structure of formula IC;
wherein: x is chlorine, bromine or iodine; x4Is CH or N; r6Is NH2；X 1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 5And R7As defined in the following formula IC compound (preferably X)6Is N, X8is-NH-); each n is independently 0, 1 or 2;
4) the preparation method of the compound shown in the formula ID comprises the following specific steps:
Figure PCTCN2019089027-APPB-000047
s1: replacement of X in Compound ID-1-1 by R3(preferably by coupling or substitution) to give compound ID-1-2;
s2: under the action of a compound ID-a (preferably sodium methoxide/methanol), carrying out a ring closing reaction on the compound ID-1-2 to obtain a compound ID-1-3;
s3: introduction of R into Compound ID-1-31(preferably by substitution reaction) to give Compound ID-1-4；
S4: reaction of compound ID-1-4 with compound ID-b (preferably by a substitution reaction) gives compound ID-1-5;
s5: reaction of compound ID-1-5 with compound ID-c (preferably by condensation) gives compound ID-1-6;
s6: reaction of compound ID-1-6 with compound ID-d (preferably by a substitution reaction) to give compound ID;
wherein: x is chlorine, bromine or iodine; x1、X 2、X 3、X 4、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 6And R7As defined above for compounds of formula ID (preferably X)4Is CH); or
The specific steps are as follows:
Figure PCTCN2019089027-APPB-000048
s1: replacement of X in Compound ID-2-1 by R3(preferably by coupling or substitution) to give compound ID-2-2;
s2: compound ID-2-2 is reacted (preferably by condensation) with compound ID-e to give compound ID-2-3;
s3: reacting compound ID-2-3 with compound ID-f (preferably in the presence of a Grignard reagent and an organolithium compound, more preferably in the presence of isopropyl magnesium chloride and n-butyllithium) to give compound ID-2-4;
s4: reacting the compound ID-2-4 with a Lawson reagent and a compound ID-g to obtain a compound ID-2-5;
s5: compound ID-2-5 is reacted with compound ID-c (preferably in the presence of a Grignard reagent and an organolithium compound, more preferably in the presence of isopropyl magnesium chloride and n-butyllithium) to give a compound of formula ID;
wherein: x is chlorine, bromine or iodine; r is H, OH or R7；X 4Is CH or CR7；X 1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 6And R7As defined above for compounds of formula ID (preferably X)6Is N, X8is-NH-);
5) the preparation method of the compound with the structure of the formula IE comprises the following specific steps:
Figure PCTCN2019089027-APPB-000049
s1: the compound IE-1-1 reacts with the compound IE-a to obtain a compound IE-1-2;
s2: reaction of compound IE-1-2 with compound IE-b, preferably by a substitution reaction, to give compound IE-1-3;
s3: reaction of compound IE-1-3 with compound IE-c (preferably by chlorination) to give compound IE-1-4;
s4: carrying out ammonolysis reaction on the compound IE-1-4 to obtain a compound IE-1-5;
s5: replacement of X in Compound IE-1-5 by R3(preferably by coupling or substitution) to give compound IE-1-6;
s6: reacting (preferably by condensation) compound IE-1-6 with compound IE-d to give compound IE;
wherein: x is chlorine, bromine or iodine; r is alkyl; x1、X 2、X 3、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、 R 4、R 5And R6As defined above for the compound of formula IE;
6) the preparation method of the compound with the structure of the formula IF comprises the following specific steps:
Figure PCTCN2019089027-APPB-000050
s1: reacting compound IF-1-1 with compound IF-a (preferably in the presence of a catalyst, more preferably in the presence of polymethoxysilane/tin (II) trifluoromethanesulfonate/oxygen) to give compound IF-1-2;
s2: reacting compound IF-1-2 with compound IF-b (preferably by substitution) to give compound IF-1-3;
s3: reaction of compound IF-1-3 with compound IF-c (preferably by chlorination) affords compound IF-1-4;
s4: replacement of X in Compound IF-1-4 by R3(preferably by coupling or substitution) to give compound IF-1-5;
s5: carrying out ammonolysis reaction on the compound IF-1-5 to obtain a compound IF-1-6;
s6: reacting compound IF-1-6 with compound IF-d (preferably by condensation) to give compound IF;
wherein: x is chlorine, bromine or iodine; r is alkyl; x1、X 2、X 3、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 5And R6As defined above for compounds of formula IF.
In some embodiments of the present invention, the Coupling Reaction in the above preparation method includes, but is not limited to, Suzuki Reaction (Suzuki Reaction), Heck Reaction (Heck Reaction), Stille Reaction (Stille Reaction), germ Coupling Reaction (Sogonoshira Coupling), panda Coupling Reaction (kumada Coupling), root-shore Coupling (negishi Coupling), juniper Coupling (Hiyama Coupling), and the like. It will be appreciated that the experimental conditions for the above-described coupling reaction are well known to those skilled in the art.
When the compound of the formula I has a specific configuration, the invention also provides a corresponding preparation method so as to obtain the compound with the specific configuration. These compounds having a specific configuration and the process for their preparation are likewise part of the present invention.
[ pharmaceutical composition ]
The term "pharmaceutical composition" refers to a composition that can be used as a medicament, comprising a pharmaceutically active ingredient (API) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient that is compatible with the pharmaceutically active ingredient and not deleterious to the subject, including, but not limited to, diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickening agents, glidants, flavoring agents, preservatives, antioxidants, pH adjusters, solvents, co-solvents, surfactants, and the like.
The present invention provides a pharmaceutical composition comprising a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion.
In some embodiments of the present invention, the above pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
[ medical use ]
Whether a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or mixture thereof, in any proportion, or a pharmaceutical composition as described above, is useful as an inhibitor of PI 3K. Accordingly, the present invention provides the use of a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion, or a pharmaceutical composition as described above, as an inhibitor of PI 3K.
In addition, the present application also provides the use of a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or a mixture thereof in any proportion, or a pharmaceutical composition as described above, for the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by PI 3K.
The term "a disease mediated at least in part by PI 3K" refers to a disease that involves at least a portion of the factors associated with PI3K in its pathogenesis, including, but not limited to, cancer (e.g., cervical cancer), neurodegenerative disease (e.g., alzheimer's disease), viral infection (e.g., AIDS), bacterial infection (e.g., streptococcal infection), ocular disease (e.g., cataract), autoimmune disease (e.g., rheumatoid arthritis), depression, anxiety, and psychological disorders.
[ method of treatment ]
The present invention provides a method for the prevention and/or treatment of a disease mediated at least in part by PI3K, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion, or a pharmaceutical composition as described above.
The term "therapeutically effective amount" refers to a dose of a pharmaceutically active ingredient that is capable of inducing a biological or medical response in a cell, tissue, organ or organism (e.g., a patient).
The term "administering" refers to the process of applying a pharmaceutically active ingredient (such as a compound of the invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (e.g., a pharmaceutical composition of the invention) to a patient or a cell, tissue, organ, biological fluid, etc. site thereof, such that the pharmaceutically active ingredient or pharmaceutical composition contacts the patient or the cell, tissue, organ, biological fluid, etc. site thereof. Common modes of administration include, but are not limited to, oral administration, subcutaneous administration, intramuscular administration, intraperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, and the like.
The term "in need thereof refers to a judgment by a physician or other caregiver that a patient needs or will benefit from a prophylactic and/or therapeutic procedure, the judgment being made based on various factors of the physician or other caregiver in their area of expertise.
The term "patient" (or subject) refers to a human or non-human animal (e.g., a mammal).
[ combination drug ]
The present invention provides a pharmaceutical combination comprising a compound of formula I as described above or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any proportion, or a pharmaceutical composition as described above, and at least one additional cancer therapeutic agent.
The term "cancer" refers to a cellular disorder characterized by uncontrolled or deregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and/or the ability to establish new growth at an ectopic site. Common cancers include, but are not limited to, brain, liver, gall bladder, bronchial, lung, bladder, ovarian, cervical, testicular, lip, tongue, hypopharynx, larynx, esophageal, stomach, intestinal (e.g., colon, rectum), thyroid, salivary gland, pancreatic, breast, prostate, blood (or leukemia), lymph (or lymphoma), bone, and skin cancers.
The term "cancer therapeutic agent" refers to a pharmaceutical composition or pharmaceutical formulation that is effective in controlling and/or combating cancer. Common cancer therapeutic agents include, but are not limited to, anti-puring agents (e.g., pentostatin, etc.), anti-pyrimidinium agents (e.g., fluorouracil), antifolate agents (e.g., methotrexate), DNA polymerase inhibitors (e.g., cytarabine), alkylating agents (e.g., cyclophosphamide), platinum-based complexes (e.g., cisplatin), DNA-destroying antibiotics (e.g., mitomycin), topoisomerase inhibitors (e.g., camptothecin), intercalating DNA interfering nucleic acid synthesizers (e.g., epirubicin), anti-feed drugs (e.g., asparaginase), interfering tubulin forming agents (e.g., paclitaxel), interfering ribosome function agents (e.g., cephalotaxine), cytokines (e.g., IL-1), thymopeptides, tumor cell proliferation viruses (e.g., adenovirus ONYX-015), and the like.
In addition, the present invention provides a method for preventing and/or treating cancer, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion, or a pharmaceutical composition as described above, and at least one additional cancer therapeutic.
The invention will be further illustrated with reference to 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. If the experimental procedures in the following examples do not specify particular conditions, conventional conditions or conditions recommended by the manufacturer are generally followed. Unless otherwise indicated, percentages and parts appearing in the following examples are by weight.
Example 1: synthesis of Compound 3.
Figure PCTCN2019089027-APPB-000051
The synthesis steps are as follows:
s1: to compound 3-1(50g, 0.29mol) and DMF (0.5mL) in CH at room temperature2Cl 2To a stirred solution in (250mL) was added oxalyl chloride (27.4mL, 0.32mol) dropwise and the resulting mixture was stirred at room temperature for 2 hours, then the mixture was concentrated in vacuo to give the crude intermediate 3-2, which was used directly in the next step.
S2: Ice-Water cooled Compound 3-3(28.7g, 0.30mol) and Triethylamine (90ml, 0.60mol) in CH2Cl 2(250mL) solution was added intermediate 3-2(54g, 0.29mol) CH2Cl 2Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100mL) was added. The organic layer was separated and washed with brine, Na2SO 4Dried and filtered. The filtrate was vacuumedAnd (5) concentrating. The product was suspended in petroleum ether (1000mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500mL), and further dried in vacuo to afford intermediate 3-4(70g, 95% yield) as a yellow solid. LC-MS: 246[ M +1]] +。
S3: a solution of intermediates 3-4(30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added to which 0.37mol was slowly added over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (compound 3-5) (36.9g, 0.16mol) in anhydrous tetrahydrofuran (100mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. Intermediates 3-6(70g crude) were used in the next reaction without further purification. LC-MS: 417[ M +1]] +。
S4: to a solution of intermediate 3-6(70g, 168mmol) in MeOH (360mL) was added concentrated HCl (180 mL). The resulting mixture was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (1000mL) and extracted with ethyl acetate (200 mL. times.2). Then using K2CO 3The aqueous layer was alkalinized and a precipitate formed. The solid was collected by filtration and dried to give intermediate 3-7(20g, 40% yield). LC-MS: 299[ M +1]] +。
S5: to a solution of intermediate 3-7(3.0g, 10mmol) in EtOH (100mL) was added saturated aqueous NaHCO3 solution. NaHCO at room temperature3(10mL) and Boc2O (2.2g, 10 mmol). The resulting solution was stirred at room temperature overnight. The reaction was concentrated under reduced pressure to remove ethanol, the solid was washed with water and filtered. After drying, the desired intermediate 3-8 was obtained (3.9g, 95% yield)。LC-MS：399[M+1] +。
S6: to a solution of intermediate 3-8(690mg, 1.72mmol) in DMF (20mL) was added compound 3-9(207mg, 2.65mmol), Xantphos (69mg, 0.12mmol) and K3PO 4(414mg, 2.0 mmol). By vacuum/then N2The backfill time purges the reaction flask to degas the mixture. The reaction was then heated to 150 ℃ by microwave and held for 2 hours. The reaction was cooled to room temperature and quenched with H2And (4) diluting with oxygen. The mixture was extracted with ethyl acetate (3X 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and then purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 10: 1 to 5: 1) to give intermediate 3-10(270mg, 36% yield) as a yellow solid. LC-MS: 441[ M +1]] +。
S7: to a solution of intermediate 3-10(270mg, 0.62mmol) in dioxane (10mL) was added HCl/dioxane (10 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to give intermediate 3-11(200mg, 86% yield) as a yellow solid. LC-MS: 341[ M +1]] +。
S8: to intermediate 3-11(200mg, 0.53mmol) and compound 3-12(146mg, 0.53mmol) in CH3To the mixture in CN (10mL) was added DIPEA (0.18mL, 1.06 mmol). The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by preparative. HPLC and lyophilization gave compound 3(140mg, 52% yield) as a white solid. LC-MS: 501[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.94(d，J＝8.0Hz，1H)，8.56(d，J＝8.0Hz，1H)，8.41-8.36(m，1H)，8.05(d，J＝8.0Hz，1H)，7.93-7.84(m，2H)，7.59-7.41(m，5H)，7.04(t，J＝8.0Hz，1H)，6.90(s，1H)，4.57-4.54(m，1H)，1.77(dd，J＝16.0Hz，4.0Hz，6H)，1.37(d，J＝6.8Hz，3H)。
Example 2: synthesis of Compound 1.
Referring to example 1, compound 3-5 in step S3 was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate, which wasIt was worked up unchanged to give compound 1. LC-MS: 501[ M +1]] +。
Example 3: synthesis of Compound 2.
Referring to example 1, compound 3-5 in step S3 was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other procedures were unchanged to give compound 2. LC-MS: 501[ M +1]] +。
Example 4: synthesis of Compound 9.
Figure PCTCN2019089027-APPB-000052
The synthesis steps are as follows:
s1: to intermediate 3-1(5g, 22.2mmol) in CH2Cl 2To a solution (100mL) were added triethylamine (4.48g, 44.4mmol) and compound 3-2(2.02g, 22.2 mol). The reaction mixture was stirred at room temperature overnight. It was then concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 2: 1) to give intermediate 3-3(6.0g, 96% yield) as a yellow solid. LC-MS: 282[ M +1]] +。
S2: a solution of intermediate 3-3(280mg, 1mmol) and HMPA (0.17mL, 1mmol) in dry tetrahydrofuran (20mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 0.48mL) was added and 1.2mol was added dropwise. After the addition, the reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (compound 3-4) (270mg, 1.2mmol) in anhydrous tetrahydrofuran (10mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (1.2mL, 1.2mmol) was added dropwise at-78 deg.C. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. Products 3-5(300 mg)Crude) was used for the subsequent reaction without further purification. LC-MS: 453[ M +1]] +。
S3: to a solution of intermediate 3-5(300mg, 0.66mmol) in MeOH (10mL) was added concentrated HCl (5 mL). The resulting mixture was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (50mL) and extracted with ethyl acetate (20 mL. times.2). Then the aqueous layer was washed with K2CO 3Basified and extracted with ethyl acetate (50mL × 2). The combined organic layers were washed with brine and dried. After concentration, intermediate 3-6(180mg, yield 82%) was obtained. LC-MS: 335[ M +1]] +。
S4: to intermediate 3-6(180mg, 0.45mmol) and compound 7(5.5g, 0.53mmol) in CH3CN (10mL) solution was added with K3PO 4(190mg, 0.90mmol), Xphos (40mg, 0.090mmol) and Pd2(dba) 3(40mg, 0.045 mmol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH ═ 100: 1 to 10:), to give intermediate 3-8(140mg, 76% yield). LC-MS: 405[ M +1]] +。
S5: to intermediate 3-8(140mg, 0.34mmol) and compound 3-9(93mg, 0.34mmol) in CH3To the mixture in CN (10mL) was added DIPEA (0.12mL, 0.68 mmol). The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by preparative. HPLC and lyophilization afforded compound 9(25mg, 13% yield) as a white solid. LC-MS: 565[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.94(d，J＝8.0Hz，1H)，8.53(d，J＝8.0Hz，1H)，8.03(s，1H)，7.92(d，J＝8.0Hz，1H)，7.67-7.62(m，4H)，7.40-7.36(m，3H)，7.19-7.17(m，2H)，7.02-7.01(m，2H)，7.00-6.97(m，2H)，6.45(s，2H)，4.64-4.60(m，1H)，3.83(s，3H)，1.43(d，J＝6.8Hz，3H)。
Example 5: synthesis of Compound 7.
Referring to example 4, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the title compound 7. LC-MS: 565[ M +1]] +。
Example 6: synthesis of Compound 8.
Referring to example 4, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) -1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the title compound 8. LC-MS: 565[ M +1]] +。
Example 7: synthesis of Compound 12.
Figure PCTCN2019089027-APPB-000053
The synthesis steps are as follows:
s1: LDA (11mL, 11mmol) was added dropwise to a solution of compound 12-1' (2.0g, 8.4mmol) in THF (50mL) at-60 deg.C. After the addition, the mixture was stirred at this temperature for 1 hour. Then adding PhNTf to the mixture2(Compound 12-2') (3.6g, 10 mmol). The resulting reaction mixture was slowly warmed and stirred at room temperature overnight. The reaction solution was quenched with aqueous solution. By NH4Cl (100mL) and the aqueous layer extracted with ethyl acetate (2X 150 mL). The combined organic layers were washed with brine (150mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column on silica gel (eluent: petroleum ether/ethyl acetate 4: 1) to give compound 12-3' (2.5g, 80% yield) as a yellow solid. LC-MS: 372[ M +1]] +。
S2: to a solution of intermediate 12-3 '(1.0 g, 2.69mmol) and compound 12-4' (0.8g, 3.16mmol) in dioxane (100mL) was added KOAc (0.3g, 3.16mmol), Pd (dppf) Cl2(0.2g, 0.27 mmol). Adding N to the reaction mixture2Then, thenHeat to reflux and stir overnight. The reaction mixture was then filtered, the filtrate concentrated and purified by column chromatography (eluent: petroleum ether/ethyl acetate 4: 1) to give the desired intermediate 12-8(0.2g, 21% yield). LC-MS: 350[ M +1]] +。
S3: to compound 12-1(50g, 0.29mol) and DMF (0.5mL) in CH at room temperature2Cl 2To a stirred solution in (250mL) was added oxalyl chloride (27.4mL, 0.32mol) dropwise and the resulting mixture was stirred at room temperature for 2 hours, then the mixture was concentrated in vacuo to give the crude intermediate 12-2, which was used directly in the next step.
S4: Ice-Water cooled mixture 12-3(28.7g, 0.30mol) and triethylamine (90ml, 0.60mol) in CH2Cl 2(250mL) solution was added intermediate 12-2(54g, 0.29mol) in CH2Cl 2Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100mL) was added. The organic layer was separated and washed with brine, Na2SO 4Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500mL), and further dried in vacuo to afford intermediate 12-4(70g, 95% yield) as a yellow solid. LC-MS: 246[ M +1]] +。
S5: a solution of intermediate 12-4(30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added, to which was slowly added 0.37mol over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (36.9g, 0.16mol) in dry tetrahydrofuran (100mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting liquidWith Na2SO 4Dried and then concentrated under reduced pressure. Intermediate 12-6(70g crude) was used in the next reaction without further purification. LC-MS: 417[ M +1]] +。
S6: to a solution of intermediate 12-6(70g, 168mmol) in MeOH (360mL) was added concentrated HCl (180 mL). The resulting mixture was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (1000mL) and extracted with ethyl acetate (200 mL. times.2). Then using K2CO 3The aqueous layer was alkalinized and a precipitate formed. The solid was collected by filtration and dried to give compound 12-7(20g, 40% yield). LC-MS: 299[ M +1]] +。
S7: to a solution of intermediate 12-8(200mg, 0.57mmol) and intermediate 12-7(200mg, 0.67mmol) in dioxane (10 mL)/water (2.5mL) was added K2CO 3(0.16g, 1.14mmol) and Pd (dppf) Cl2(41mg, 0.057 mmol). Adding N to the reaction mixture2And then heated under reflux for 2 hours. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH ═ 100: 1 to 10: 1) to afford the desired intermediate 12-9(100mg, 36% yield). LC-MS: 486[ M +1]] +。
S8: to a solution of compound 12-9(100mg, 0.2mmol) in EtOH (10mL) was added Pd/C (20 mg). Mixing the mixture in H2Stir under balloon at room temperature overnight. The reaction was filtered and concentrated to give intermediate 12-10(100mg, 99% yield) as a yellow solid. LC-MS: 488[ M +1]] +。
S9: to intermediate 12-10(1g, 2.05mmol) and compound 11(621mg, 2.25mmol) in CH3To the mixture in CN (50mL) was added DIPEA (0.50mL, 3.07 mmol). The mixture was stirred at reflux overnight. The reaction mixture is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH 100: 1 to 10: 1) to afford the desired intermediate 12-12(1.2g, 90% yield). LC-MS: 648[ M +1]] +。
S10: to iceWater-cooled intermediate 12-12(200mg, 0.30mmol) in CH2Cl 2(5mL) to the solution was added CF3COOH (1 mL). The mixture was stirred for 3 hours. The reaction solution was then concentrated to give intermediate 12-13(200mg, 99% yield) as a yellow solid. LC-MS: 548[ M +1]] +。
S11: to a solution of ice-water cooled intermediate 12-13(150mg, 0.27mmol) in DMF (2mL) was added 37% aqueous formaldehyde (0.5mL) and one drop of acetic acid. After stirring for 30 minutes, NaBH was added to the mixture3CN (20mg, 0.3 mmol). The resulting mixture was stirred for 30 minutes and quenched with aqueous solution. Adjusted with sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (2X 50 mL). The combined organic layers were washed with brine (150mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give compound 12(35mg, 23% yield) as a yellow solid. LC-MS: 562[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.93(d，J＝8.0Hz，1H)，8.55(d，J＝8.0Hz，1H)，7.98(d，J＝8.0Hz，1H)，7.62-7.45(m，8H)，7.02-7.01(m，1H)，6.68(s，1H)，6.42(s，2H)，4.60-4.54(m，2H)，2.23-2.19(m，6H)，2.09(s，3H)，1.78-1.74(m，2H)，1.64-1.60(m，2H)，1.46-1.40(m，2H)，1.32(d，J＝6.8Hz，3H)。
Example 8: synthesis of Compound 10.
Referring to example 7, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the title compound 10. LC-MS: 562[ M +1]] +。
Example 9: synthesis of Compound 11.
Referring to example 7, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the objective compound 11. LC-MS: 562[ M +1]] +。
Example 10: synthesis of Compound 15.
Figure PCTCN2019089027-APPB-000054
The synthesis steps are as follows:
s1: to compound 15-1(50g, 0.29mol) and DMF (0.5mL) in CH at room temperature2Cl 2To a stirred solution in (250mL) was added oxalyl chloride (27.4mL, 0.32mol) dropwise and the resulting mixture was stirred at room temperature for 2 hours, then the mixture was concentrated in vacuo to give the crude intermediate 15-2, which was used directly in the next step.
S2: Ice-Water cooled Compound 15-3(28.7g, 0.30mol) and Triethylamine (90ml, 0.60mol) in CH2Cl 2(250mL) solution was added intermediate 15-2(54g, 0.29mol) in CH2Cl 2Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100mL) was added. The organic layer was separated and washed with brine, Na2SO 4Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500mL), and further dried in vacuo to afford intermediate 15-4(70g, 95% yield) as a yellow solid. LC-MS: 246[ M +1]] +。
S3: a solution of intermediate 15-4(30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added, to which was slowly added 0.37mol over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (36.9g, 0.16mol) in dry tetrahydrofuran (100mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. At-78 deg.CStirred for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. Intermediate 15-6(70g crude) was used in the next reaction without further purification. LC-MS: 417[ M +1]] +。
S4: to a solution of intermediate 15-6(70g, 168mmol) in MeOH (360mL) was added concentrated HCl (180 mL). The resulting mixture was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (1000mL) and extracted with ethyl acetate (200 mL. times.2). Then using K2CO 3The aqueous layer was alkalinized and a precipitate formed. The solid was collected by filtration and dried to give compound 15-7(20g, 40% yield). LC-MS: 299[ M +1]] +。
S5: to a solution of intermediate 15-7(598mg, 2mmol) and compound 15-8(678mg, 3mmol) in dioxane (10mL) was added Cs2CO 3(1303mg, 4mmol), Xphos (190mg, 0.4mmol) and Pd2(dba) 3(183mg, 0.2 mmol). Adding N to the reaction mixture2Then heated to reflux overnight. The reaction mixture was then filtered, the filtrate concentrated and purified by column chromatography (eluent: petroleum ether/ethyl acetate 1: 2 to 0: 1) to give the desired intermediate 15-9(250mg, 26% yield). LC-MS: 489[ M +1]] +。
S6: to intermediate 15-9(240mg, 0.49mmol) and compound 15-10(148mg, 0.54mmol) in CH3To the mixture in CN (10mL) was added DIPEA (64mg, 0.49 mmol). The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (eluent: 100% ethyl acetate) to give the desired intermediate 15-11(250mg, 79% yield). LC-MS: 649[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.92(d，J＝8.0Hz，1H)，8.55(d，J＝8.0Hz，1H)，8.47(s，2H)，7.95(d，J＝8.0Hz，1H)，7.54-7.29(m，6H)，7.02-7.01(m，1H)，6.83(d，J＝8.0Hz，1H)，6.50(s，1H)，6.42-6.38(m，3H)，4.60-4.54(m，1H)，3.72-3.56(m，4H)，3.27-3.20(m，4H)，1.59-1.50(m，4H)，1.38(s，9H)，1.32(d，J＝6.8Hz，3H)。
S7: Ice-Water cooled intermediate 15-11(150mg, 0.27mmol) in CH2Cl 2(5mL) to the solution was added CF3COOH (1 mL). The mixture was stirred for 3 hours. The reaction solution was then concentrated and purified by preparative HPLC to give intermediate 15-12(110mg, 87% yield) as a yellow solid. LC-MS: 549[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.92(d，J＝8.0Hz，1H)，8.55(d，J＝8.0Hz，1H)，8.47(s，2H)，7.95(d，J＝8.0Hz，1H)，7.54-7.29(m，6H)，7.02-7.01(m，1H)，6.83(d，J＝8.0Hz，1H)，6.50(s，1H)，6.42-6.38(m，3H)，4.60-4.54(m，1H)，3.70-3.54(m，4H)，2.77-2.70(m，4H)，1.59-1.50(m，4H)，1.32(d，J＝6.8Hz，3H)。
S8: to a solution of ice-water cooled intermediate 15-12(100mg, 0.18mmol) in DMF (2mL) was added 37% aqueous formaldehyde (0.5mL) and one drop of acetic acid. After stirring for 30 minutes, NaBH was added to the mixture3CN (19mg, 0.3 mmol). The resulting mixture was stirred for 30 minutes and quenched with aqueous solution. Adjusted with sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (2X 50 mL). The combined organic layers were washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give compound 15(19mg, 19% yield) as a yellow solid. LC-MS: 563[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)δ8.72(d，J＝8.0Hz，1H)，8.52(d，J＝8.0Hz，1H)，8.01-7.85(m，3H)，7.63-7.55(m，4H)，7.48(d，J＝8.0Hz，1H)，7.16(s，1H)，7.00-6.98(m，1H)，4.77-4.74(m，4H)，4.10-3.97(m，2H)，3.77-3.52(m，4H)，2.99(s，3H)，2.45-2.19(m，4H)，1.49(d，J＝6.8Hz，3H)。
Example 11: synthesis of Compound 13.
Referring to example 10, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate, othersThe procedure was kept unchanged to give the title compound 13. LC-MS: 563[ M +1]] +。
Example 12: synthesis of Compound 14.
Referring to example 10, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the objective compound 14. LC-MS: 563[ M +1]] +。
Example 13: synthesis of compound 24.
Figure PCTCN2019089027-APPB-000055
The synthesis steps are as follows:
s1: to a solution of intermediate 24-1(4.5g, 18.8mmol) and benzylamine (2.5g, 23.3mmol) in MeOH (150mL) at 0 deg.C was added acetic acid (3 mL). After the addition, the mixture was stirred at this temperature for 30 minutes. Then adding NaBH to the mixture3CN (1.18g, 19.0 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with 20% aqueous sodium hydroxide. Extraction was carried out with ethyl acetate (500 mL. times.2). The combined organic layers were then washed with brine, over Na2SO 4Dried and concentrated. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate 1: 1 to 0: 1) to give the desired intermediate 24-2(3.2g, 52% yield). LC-MS: 331[ M +1]] +。
S2: to a solution of intermediate 24-2(3.2g, 9.6mmol) in THF (100mL) was added LiAlH4(1.1g, 34.7 mmol). The mixture was stirred at reflux for 1 hour. The reaction mixture was cooled and quenched by the addition of water (2mL), 15% aqueous sodium hydroxide (2 mL). After filtration, the filtrate was concentrated to give the desired intermediate 24-3(2.2g, 94% yield). LC-MS: 245[ M +1]] +。
S3: to a solution of intermediate 24-3(2.2g, 9mmol) in MeOH (20mL) was added Pd (OH)2C (800 mg). Mixing the mixture in H 2(60psi) at 50 ℃ stirring overnight. The reaction was filtered and concentrated to give intermediate 24-4(1.3g, 99% yield) as a yellow solid. LC-MS: 155[ M +1]] +。
S4: Ice-Water cooled intermediate 24-4(3g, 19.3mol) and triethylamine (2.7ml, 21.1mol) in CH2Cl 2To a solution (50mL) was added a solution of compound 24-5(3.6g, 19.3mol) in DCM (10 mL). The resulting mixture was stirred at room temperature overnight, then water (50mL) was added. The organic layer was separated and washed with brine, Na2SO 4Dried and concentrated. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate 1: 1 to 0: 1) to give the desired intermediate 24-6(0.8g, 14% yield). LC-MS: 307[ M +1]] +。
S5: a solution of intermediate 24-6(800mg, 2.6mol) and HMPA (0.56mL, 3.1mol) in dry tetrahydrofuran (50mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 3.12mL) was added, to which 7.8mmol was slowly added over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (790mg, 3.4mmol) in dry tetrahydrofuran (20mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (1.86mL, 3.78mmol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. The product 24-7(800mg crude) was used in the next reaction without further purification. LC-MS: 478[ M +1]] +。
S6: to a solution of intermediate 24-7(800mg, 1.68mmol) in MeOH (20mL) was added concentrated HCl (10 mL). The resulting mixture was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (1000mL) and extracted with ethyl acetate (100 mL. times.2). Then the aqueous layer was washed with K2CO 3Basifying, and adding ethyl acetate (100)mL. times.2). Extracting with Na2SO 4Dried and then concentrated. By column chromatography (eluent: CH)2Cl 2MeOH ═ 10: 1) purification of the residue afforded the desired intermediate 24-8(400mg, 66% yield). LC-MS: 360[ M +1]] +。
S7: to intermediate 24-8(400mg, 1.11mmol) and compound 24-9(170mg, 1.60mmol) in CH3CN (10mL) solution was added with K3PO 4(280mg, 1.32mmol), Xphos (56mg, 0.12mmol) and Pd2(dba) 3(50mg, 0.06 mmol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH 100: 1 to 10: 1) to afford the desired intermediate 24-10(80mg, 17% yield). LC-MS: 430[ M +1]] +。
S8: to intermediate 24-10(80mg, 0.19mmol) and compound 24-11(54mg, 0.19mmol) in CH3To the mixture in CN (10mL) was added DIPEA (40mg, 0.31 mmol). The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by preparative HPLC and lyophilized to give compound 24(8mg, 7% yield) as a yellow solid. LC-MS: 590[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.09(d，J＝8.0Hz，1H)，7.76(brs，3H)，7.63(s，1H)，7.29-7.26(m，2H)，6.89-6.84(m，2H)，6.58(d，J＝8.0Hz，1H)，6.27(d，J＝8.0Hz，1H)，6.02(s，1H)，4.81-4.80(m，1H)，4.20-4.15(m，1H)，3.93-3.91(m，2H)，3.33-3.22(m，5H)，3.12(s，3H)，2.12-2.08(m，2H)，2.03-1.98(m，2H)，1.27-1.26(m，1H)，1.06-0.90(m，6H)。
Example 14: synthesis of Compound 22.
Referring to example 13, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to obtain the targeted compoundCompound 22. LC-MS: 590[ M +1]] +。
Example 15: synthesis of Compound 23.
Referring to example 13, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the objective compound 23. LC-MS: 590[ M +1]] +。
Example 16: synthesis of Compound 27.
Figure PCTCN2019089027-APPB-000056
The synthesis steps are as follows:
s1: to compound 27-2(5.6g, 30mmol) and triethylamine (7.8mL, 60mmol) in CH2Cl 2(50mL) to the solution was added dropwise CH solution of Compound 27-1(5.1g, 30mmol)2Cl 2(50mL) of the solution. After addition, it was stirred at room temperature overnight. The reaction mixture was then concentrated and purified by column chromatography (eluent: petroleum ether/ethyl acetate 10: 1 to 2: 1) to give the desired intermediate 27-3(9.3g, 90% yield). LC-MS: 304[ M +1]] +。
S2: a solution of intermediate 27-3(2.5g, 8.25mmol) and HMPA (1.6mL, 9.07mmol) in dry tetrahydrofuran (50mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 8.25mL) was added to which 20.62mmol was slowly added over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (2.1g, 9.07mol) in anhydrous tetrahydrofuran (50mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (10mL, 9.98mmol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (10mL) and then extracted with ethyl acetate. Extracting with Na 2SO 4Dried and then concentrated. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate 10: 1 to 2: 1) to give the desired intermediate 27-5(3.3g, 85% yield). LC-MS: 475[ M +1]] +。
S3: to a solution of ice-water cooled intermediate 27-5(475mg, 1mmol) in EtOH (10mL) was added NaBH4(45mg, 1.2 mmol). The mixture was stirred at room temperature for 3 hours. Then using NH4The reaction solution was quenched with aqueous Cl. Extraction was performed with ethyl acetate (50 mL. times.2). The combined organic layers were washed with Na2SO 4Drying, followed by concentration gave the desired intermediate 27-6(460mg, 96% yield). LC-MS: 477[ M +1]] +。
S4: Ice-Water cooled intermediate 27-6(400mg, 0.84mmol) and triethylamine (0.25mL, 1.7mmol) in CH2Cl 2(10mL) to the solution was added MsCl (0.10mL, 1.25mmol) dropwise. After addition, it was stirred at room temperature overnight. The reaction mixture was then washed with NaHCO3And (4) quenching the aqueous solution. By CH2Cl 2(50 mL. times.2) was extracted. The combined organic layers were washed with Na2SO 4Drying, followed by concentration gave the desired intermediate 27-7(450mg, 95% yield). LC-MS: 555[ M +1]] +。
S5: to a solution of ice-water cooled intermediate 27-7(450mg, 0.8mmol) in DMF (10mL) was added NaH (60% wt, 80mg, 2 mmol). After stirring at this temperature for 30 minutes, the reaction mixture was quenched with aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (50 mL. times.2). The combined organic layers were washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate 50: 1 to 10: 1) to give the desired intermediate 27-8(300mg, 82% yield). LC-MS: 459[ M +1]] +。
S6: Ice-Water cooled intermediate 27-8(300mg, 0.66mmol) in CH2Cl 2(5mL) to the solution was added CF3COOH (1 mL). The mixture was stirred for 3 hours. Then using sodium bicarbonate aqueous solutionThe reaction solution was quenched. The aqueous layer was extracted with ethyl acetate (50 mL. times.2). The combined organic layers were washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the desired intermediate 27-9(200mg, 85% yield). LC-MS: 359[ M +1]] +。
S7: to a solution of intermediate 27-9(200mg, 0.56mmol) and compound 27-10(184mg, 0.67mmol, 1.2eq.) in dioxane (10mL) was added EtN (i-Pr)2(0.18mL, 1.12 mmol). The resulting mixture was heated by microwave at 150 ℃ for 6 hours. The reaction mixture is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH ═ 100: 1 to 10: 1) to afford the desired intermediate 27-11(100mg, 34% yield). LC-MS: 519[ M +1]] +。
S8: to intermediate 27-11(200mg, 0.39mmol) and compound 27-12(50mg, 0.46mmol) in CH3CN (10mL) solution was added with K3PO 4(100mg, 0.47mmol), Xphos (4mg, 7.8. mu. mol) and Pd2(dba)3(10mg, 3.9. mu. mol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture was then filtered, the filtrate concentrated and purified by preparative HPLC to give the desired compound 27(15mg, 6.5% yield). LC-MS: 589[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.68(d，J＝8.0Hz，1H)，8.50(d，J＝4.0Hz，1H)，7.79(s，1H)，7.58(s，1H)，8.01-7.85(m，3H)，7.37-7.27(m，3H)，6.98-6.95(m，1H)，4.23-4.20(m，1H)，3.96-3.94(m，1H)，3.89(s，3H)，3.00-2.95(m，1H)，2.84-2.78(m，1H)，2.06(s，6H)，1.91(s，3H)，1.66-1.56(m，6H)，1.33(d，J＝8.0Hz，3H)。
Example 17: synthesis of Compound 25.
Referring to example 16, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to obtain the objective compound 25. LC-MS: 589[ M +1]] +。
Example 18: synthesis of compound 26.
Referring to example 16, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the objective compound 26. LC-MS: 589[ M +1]] +。
Example 19: synthesis of Compound 31.
Figure PCTCN2019089027-APPB-000057
The synthesis steps are as follows:
s1: a solution of compound 31-1(2.45g, 10mmol) and HMPA (1.79g, 10mmol) in dry tetrahydrofuran (50mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 10mL) was added, to which 25mmol was slowly added over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (3.4g, 13.8mol) in dry tetrahydrofuran (20mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (8mL, 15mol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (10mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. Intermediate 31-3(3g crude) was used in the next reaction without further purification. LC-MS: 431[ M +1]] +。
S2: to a solution of intermediate 31-3(1g, 2.3mmol) in dioxane (10mL) was added 12M hydrogen chloride (gas)/dioxane (10 mL). The resulting mixture was stirred at reflux for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, followed by extraction with ethyl acetate (100mL × 2). Extracting with Na2SO 4Dried and then concentrated. By column chromatography (eluent: petroleum ether/ethyl acetate ═ 2)1) to yield intermediate 31-4(500mg, 69% yield). LC-MS: 313[ M +1]] +。
S3: to intermediate 31-4(300mg, 0.96mmol) and compound 31-5(160mg, 1.5mmol) in CH3CN (10mL) solution was added with K3PO 4(254.7mg, 1.2mmol), Xphos (48mg, 0.096mmol) and Pd2(dba) 3(46mg, 0.048 mmol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture was then filtered, the filtrate concentrated and purified by column chromatography (eluent: DCM/MeOH ═ 100: 1 to 10: 1) to give intermediate 31-6(200mg, 54% yield). LC-MS: 383[ M +1]] +。
S4: to intermediate 31-6(176mg, 0.46mmol) and compound 31-7(132mg, 0.48mmol) in CH3To the mixture in CN (10mL) was added DIPEA (0.1mL, 0.60 mmol). The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give compound 31(100mg, 40% yield) as a white solid. LC-MS: 543[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.90(dd，J＝8.0Hz，1.6Hz，1H)，8.28(d，J＝8.0Hz，1H)，7.96(s，1H)，7.70-7.66(m，2H)，7.58-7.50(m，2H)，7.32-6.98(m，8H)，6.46(s，1H)，4.57-4.54(m，1H)，3.79(s，3H)，1.71(s，6H)。
Example 20: synthesis of Compound 35.
Figure PCTCN2019089027-APPB-000058
The synthesis steps are as follows:
s1: to NaOH (28.3g, 0.71mol) in CH at 15 deg.C3To the CN (1L) suspension was added slowly compound 35-1' (40g, 0.75 mol). After the addition, stirring was continued for 2 hours. Then, 2-chloroethyl chloroformate (50.6g, 0.35mol) in CH was added at 15-30 deg.C3CN (100mL) solution. After the addition was complete, the solution was refluxed for 2 hours. Will be reversedThe mixture was cooled to room temperature and the formed NaCl was removed by filtration. The solution was concentrated and the residue was washed with cooled MeOH. After drying, the desired crude product 35-2' (45g, yield 35%) was obtained. LC-MS: 184[ M +1]] +。
S2: to a solution of intermediate 35-2' (75g, 0.04mol) in 1-propanol (1L) was added NH at room temperature3·H 2O (38mL), stirred for 1.5 h. Then adding NH to the mixture2NH 2·H 2O (38mL), and stirred at 70 ℃ for 2 hours. The resulting mixture was concentrated and redissolved with 1-butanol (1L) and stirred at 110 ℃ for 2 days. After cooling, the solid was filtered and dried to give intermediate 35-4' (45g, 66% yield). LC-MS: 171[ M +1]] +。
S3: to intermediate 35-4' (48g, 0.28mol) CH3To the COOH (400mL) solution was added 1, 1, 3, 3-tetramethoxypropane (46g, 0.28 mol). The reaction mixture was stirred at reflux overnight and then concentrated in vacuo. The residue was washed with acetone to give intermediate 35-5' as a pale yellow solid (46g, 82% yield). LC-MS: 207[ M +1]] +。
S4: to intermediate 35-5' (46g, 0.22mol) in MeOH (150 mL)/water (300mL) was added LiOH. H2O (41.3g, 0.98 mol). The reaction mixture was stirred at 60 ℃ for 2 hours. It was then acidified to pH 5 with 1MHCl, the solid was filtered and dried to give intermediate 35-6' (40g, 99% yield). LC-MS: 179[ M +1]] +。
S5: to a mixture of intermediate 35-6' (10g, 56.2mmol) and DMF (300mL) was added N-hydroxysuccinimide (8.4g, 73mmol) and EDCI (14g, 73 mmol). The reaction mixture was stirred at room temperature for 48 hours. Water (300mL) was then added to the reaction mixture over 1 hour, and the solid was filtered and dried to give intermediate 35-10(12.5g, 80% yield). LC-MS: 276[ M +1]] +。
S6: intermediate 35-1(50g, 0.29mol) and DMF (0.5mL) in CH at room temperature2Cl 2To the stirred solution (250mL) was added oxalyl chloride (27.4mL,0.32mol) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 2 hours, then the mixture was concentrated in vacuo to give the crude intermediate 35-2, which was used directly in the next step.
S7: Ice-Water cooled Compound 35-3(28.7g, 0.30mol) and Triethylamine (90ml, 0.60mol) in CH2Cl 2(250mL) solution was added intermediate 35-2(54g, 0.29mol) CH2Cl 2Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100mL) was added. The organic layer was separated and washed with brine, Na2SO 4Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500mL), and further dried in vacuo to give intermediate 35-4(70g, 95% yield) as a yellow solid. LC-MS: 246[ M +1]] +。
S8: a solution of intermediate 35-4(30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added, to which was slowly added 0.37mol over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (36.9g, 0.16mol) in dry tetrahydrofuran (100mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. Intermediate 35-6(70g crude) was used in the next reaction without further purification. LC-MS: 417[ M +1]] +。
S9: to a solution of intermediate 35-6(70g, 168mmol) in MeOH (360mL) was added concentrated HCl (180 mL). The resulting mixture was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (1000mL)Then, the mixture was extracted with ethyl acetate (200 mL. times.2). The aqueous layer was then basified with K2CO3 to form a precipitate. The solid was collected by filtration and dried to give compound 35-7(20g, 40% yield). LC-MS: 299[ M +1]] +。
S10: to intermediate 35-7(11g, 36.9mmol) and compound 35-8(5.5g, 51.9mmol, 1.2eq.) in CH3CN (200mL) solution was added K3PO 4(9.4g, 44.3mmol), Xphos (0.88g, 1.834). mmol) and Pd2(dba) 3(841mg, 0.918 mmol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH 100: 1 to 10: 1) to afford the desired intermediate 35-9(9.8g, 72% yield). LC-MS: 369[ M +1]] +。
S11: to intermediate 35-9(12.7g, 34.5mmol) and intermediate 35-10(9.9g, 36.2mmol) in CH3CN (200mL) was added DIPEA (6.3mL, 38mmol) to the mixture. The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by reverse phase ISCO and recrystallized from EtOH/water to give compound 35-11(9.2g, 50% yield) as a white solid. LC-MS: 529[ M +1] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.94(dd，J＝8.0Hz，1.6Hz，1H)，8.56(dd，J＝8.0Hz，1.6Hz，1H)，8.07-7.91(m，2H)，7.63-7.55(m，5H)，7.52-7.46(m，3H)，7.39-7.37(m，2H)，7.03(dd，J＝6.8Hz，4.8Hz，1H)，7.99(s，1H)，6.42(s，2H)，4.57-4.54(m，1H)，3.82(s，3H)，1.36(d，J＝6.8Hz，3H)。
S12: to a solution of compound 35-11(200mg, 0.38mmol) in dry toluene (10mL) was added DIPEA (1mL) and PCl5(50mg, 0.25 mmol). The resulting mixture was heated to reflux for 30 minutes. It was then concentrated under reduced pressure. The crude compound 35-12(200 mg) was used in the next reaction without further purification.
S13: mixing 35-12(200mg, 0.36mmol) and NH2HCl (100mg, 1.44mmol) in bisThe mixture in dioxane (10mL) was heated to reflux for 2 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give compound 35(20mg, 10% yield) as a white solid. LC-MS: 544[ M +1]] +。
Example 21: synthesis of Compound 33.
Referring to example 20, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the title compound 33. LC-MS: 544[ M +1]] +。
Example 22: synthesis of compound 34.
Referring to example 20, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the objective compound 34. LC-MS: 544[ M +1]] +。
Example 23: synthesis of Compound 47.
Figure PCTCN2019089027-APPB-000059
The synthesis steps are as follows:
s1: to compound 47-1(50g, 0.29mol) and DMF (0.5mL) in CH at room temperature2Cl 2To a stirred solution in (250mL) was added oxalyl chloride (27.4mL, 0.32mol) dropwise and the resulting mixture was stirred at room temperature for 2 hours, then the mixture was concentrated in vacuo to give the crude intermediate 47-2, which was used directly in the next step.
S2: Ice-Water cooled Compound 47-3(28.7g, 0.30mol) and Triethylamine (90ml, 0.60mol) in CH2Cl 2(250mL) solution was added intermediate 47-2(54g, 0.29mol) in CH2Cl 2Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100mL) was added). The organic layer was separated and washed with brine, Na2SO 4Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500mL), and further dried in vacuo to give intermediate 47-4(70g, 95% yield) as a yellow solid. LC-MS: 246[ M +1]] +。
S3: a solution of intermediate 47-4(30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added, to which was slowly added 0.37mol over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (36.9g, 0.16mol) in dry tetrahydrofuran (100mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. Intermediate 47-6(70g crude) was used in the next reaction without further purification. LC-MS: 417[ M +1]] +。
S4: to a solution of intermediate 47-6(500mg, 1.2mmol) in acetic acid (10mL) was added diiodophenyl iodide (420mg, 1.3 mmol). The resulting mixture was heated at 50 ℃ overnight. By NaHCO3The reaction mixture was quenched with aqueous solution (50mL) and extracted with ethyl acetate (50 mL. times.2). The organic layer was washed with Na2SO 4Dried and then concentrated under reduced pressure. The residue was purified by column chromatography (eluent: DCM/MeOH ═ 100: 1 to 10: 1) to give the desired intermediate 47-7(150mg, 26% yield). LC-MS: 475[ M +1]] +。
S5: to a solution of compound 47-7(150mg, 0.32mmol) in methanol (10mL) was added concentrated HCl (5 mL). The resulting mixture was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressureThe residue was dissolved in water (50mL) and extracted with ethyl acetate (20 mL. times.2). Then the aqueous layer was washed with K2CO 3Basified and extracted with ethyl acetate (50mL × 2). The combined organic layers were washed, dried and concentrated to give intermediate 47-8(100mg, 95% yield). LC-MS: 315[ M +1]] +。
S6: to intermediate 47-8(100mg, 0.32mmol) and compound 47-9(51mg, 0.48mmol) in CH3CN (5mL) solution was added with K3PO 4(81mg, 0.38mmol), Xphos (3mg, 0.004mmol) and Pd2(dba) 3(2.9mg, 0.008 mmol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture was then filtered, the filtrate concentrated and purified by column chromatography (eluent: DCM/MeOH ═ 100: 1 to 10: 1) to afford the desired intermediate 47-10(60mg, 49% yield). LC-MS: 385[ M +1]] +。
S7: to intermediate 47-10(60mg, 0.16mmol) and compound 47-11(52mg, 0.19mmol) in CH3To the mixture in CN (5mL) was added DIPEA (42mg, 0.32 mmol). The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give compound 47(5mg, 6% yield) as a white solid. LC-MS: 545[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.93(d，J＝8.0Hz，1H)，8.56(d，J＝2.0Hz，1H)，8.35(s，1H)，7.99(d，J＝2.0Hz，1H)，7.87(s，1H)，7.60-7.59(m，2H)，7.43-7.26(m，3H)，7.28-7.24(m，3H)，7.05-7.03(m，1H)，7.01(s，1H)，6.42(s，2H)，4.55(d，J＝8.0Hz，1H)，4.51-4.47(m，1H)，3.84(s，3H)，1.35(d，J＝8.0Hz，3H).
Example 24: synthesis of Compound 45.
Referring to example 23, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to obtain the title compound 45. LC-MS: 545[ M +1]] +。
Example 25: synthesis of compound 46.
Referring to example 23, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the objective compound 46. LC-MS: 545[ M +1]] +。
Example 26: synthesis of Compound 50.
Figure PCTCN2019089027-APPB-000060
Figure PCTCN2019089027-APPB-000061
Synthesis procedure
S1: to NaOH (28.3g, 0.71mol) in CH at 15 deg.C3To the CN (1L) suspension was added slowly compound 50-1' (40g, 0.75 mol). After the addition, stirring was continued for 2 hours. Then 2-chloroethyl chloroformate (50.6g, 0.35mol) in CH was added at 15-30 deg.C3CN (100mL) solution. After the addition was complete, the solution was refluxed for 2 hours. The reaction mixture was cooled to room temperature and the formed NaCl was removed by filtration. The solution was concentrated and the residue was washed with cooled MeOH. After drying, the desired crude product was obtained in 50-2' (45g, yield 35%). LC-MS: 184[ M +1]] +。
S2: to a solution of intermediate 50-2' (75g, 0.04mol) in 1-propanol (1L) was added NH at room temperature3·H 2O (38mL), stirred for 1.5 h. Then adding NH to the mixture2NH 2·H 2O (38mL), and stirred at 70 ℃ for 2 hours. The resulting mixture was concentrated and redissolved with 1-butanol (1L) and stirred at 110 ℃ for 2 days. After cooling, the solid was filtered and dried to give intermediate 50-4' (45g, 66% yield). LC-MS: 171[ M +1]] +。
S3: to intermediate 50-4' (48g, 0.28mol) CH3To the COOH (400mL) solution was added 1, 1, 3, 3-tetramethoxypropane (46g, 0.28 mol). The reaction mixture was stirred at reflux overnight and then concentrated in vacuo. The residue was washed with acetone to give intermediate 50-5' as a pale yellow solid (46g, 82% yield). LC-MS: 207[ M +1]] +。
S4: to intermediate 50-5' (46g, 0.22mol) in MeOH (150 mL)/water (300mL) was added LiOH. H2O (41.3g, 0.98 mol). The reaction mixture was stirred at 60 ℃ for 2 hours. It was then acidified to pH 5 with 1MHCl, the solid was filtered and dried to give intermediate 50-6' (40g, 99% yield). LC-MS: 179[ M +1]] +。
S5: to a mixture of intermediate 50-6' (10g, 56.2mmol) and DMF (300mL) was added N-hydroxysuccinimide (8.4g, 73mmol) and EDCI (14g, 73 mmol). The reaction mixture was stirred at room temperature for 48 hours. Water (300mL) was then added to the reaction mixture over 1 hour, and the solid was filtered and dried to give intermediate 50-10(12.5g, 80% yield). LC-MS: 276[ M +1]] +。
S6: to compound 50-1(50g, 0.29mol) and DMF (0.5mL) in CH at room temperature2Cl 2To a stirred solution in (250mL) was added oxalyl chloride (27.4mL, 0.32mol) dropwise and the resulting mixture was stirred at room temperature for 2 hours, then the mixture was concentrated in vacuo to give crude 50-2, which was used directly in the next step.
S7: Ice-Water cooled intermediate 50-3(28.7g, 0.30mol) and Triethylamine (90ml, 0.60mol) in CH2Cl 2(250mL) solution was added intermediate 50-2(54g, 0.29mol) CH2Cl 2Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100mL) was added. The organic layer was separated and washed with brine, Na2SO 4Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000mL) and stirred at room temperature overnight. The precipitate was collected by filtration, rinsed with petroleum ether (500mL), and addedOne step vacuum drying afforded intermediate 50-4(70g, 95% yield) as a yellow solid. LC-MS: 246[ M +1]] +。
S8: a solution of intermediate 50-4(30g, 0.12mol) and HMPA (25mL, 0.14mol) in anhydrous tetrahydrofuran (250mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added to which 0.37mol was slowly added over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (36.9g, 0.16mol) in dry tetrahydrofuran (100mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. Intermediate 50-6(70g crude) was used in the next reaction without further purification. LC-MS: 417[ M +1]] +。
S9: to a solution of intermediate 50-6(70g, 168mmol) in MeOH (360mL) was added concentrated HCl (180 mL). The resulting mixture was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (1000mL) and extracted with ethyl acetate (200 mL. times.2). The aqueous layer was then basified with K2CO3 to form a precipitate. The solid was collected by filtration and dried to give compound 50-7(20g, 40% yield). LC-MS: 299[ M +1]] +。
S10: to intermediate 50-7(11g, 36.9mmol) and compound 50-8(5.5g, 51.9mmol, 1.2eq.) in CH3CN (200mL) solution was added K3PO 4(9.4g, 44.3mmol), Xphos (0.88g, 1.834mmol) and Pd2(dba) 3(841mg, 0.918 mmol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH)2Cl 2/MeOH 100: 1 to 10: 1) to obtainTo the desired intermediate 50-9(9.8g, 72% yield). LC-MS: 369[ M +1]] +。
S11: to intermediate 50-9(12.7g, 34.5mmol) and intermediate 50-10(9.9g, 36.2mmol) in CH3CN (200mL) was added DIPEA (6.3mL, 38mmol) to the mixture. The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by reverse phase ISCO and recrystallized from EtOH/water to give compound 50-11(9.2g, 50% yield) as a white solid. LC-MS: 529[ M +1] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.94(dd，J＝8.0Hz，1.6Hz，1H)，8.56(dd，J＝8.0Hz，1.6Hz，1H)，8.07-7.91(m，2H)，7.63-7.55(m，5H)，7.52-7.46(m，3H)，7.39-7.37(m，2H)，7.03(dd，J＝6.8Hz，4.8Hz，1H)，7.99(s，1H)，6.42(s，2H)，4.57-4.54(m，1H)，3.82(s，3H)，1.36(d，J＝6.8Hz，3H)。
S12: Ice-Water cooled tert-Butanol (46mg, 0.63mmol) in CH2Cl 2To the solution (10mL) was added chlorosulfonyl isocyanate (89mg, 0.63 mmol). The resulting mixture was stirred for 10 minutes. Then, to the mixture were added CH of the compound 50-11(300mg, 0.57mmol) and triethylamine (115mg, 1.14mmol)2Cl 2(10mL) of the solution. After 10 minutes, the ice bath was removed. The reaction mixture was then stirred at ambient temperature for 3 hours. The reaction solution was concentrated and redissolved in dioxane (10mL), and a 10M dioxane solution (1mL) of hydrogen chloride was added to the solution. After 30 minutes, the reaction mixture was concentrated. The residue was purified by preparative HPLC to give compound 50(28mg, 40% yield) as a yellow solid. LC-MS: 608[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.94(d，J＝8.0Hz，1H)，8.56(d，J＝2.0Hz，1H)，8.43(s，2H)，8.00-7.99(m，2H)，7.64-7.37(m，8H)，7.03-7.00(m，1H)，6.74(s，1H)，6.43(s，1H)，4.57-4.54(m，1H)，3.82(s，3H)，1.36(d，J＝8.0Hz，3H)。
Example 27: synthesis of Compound 48.
Referring to example 26, compound (S) - (1- (methoxy (methyl) amino) -1-oxoPropane-2-yl) carbamic acid tert-butyl ester was replaced with (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamic acid tert-butyl ester and the other steps were left unchanged to afford title compound 48. LC-MS: 608[ M +1]] +。
Example 28: synthesis of Compound 49.
Referring to example 26, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to obtain the objective compound 49. LC-MS: 608[ M +1]] +。
Example 29: synthesis of Compound 71.
Figure PCTCN2019089027-APPB-000062
The synthesis steps are as follows:
s1: a solution of compound 71-1(6g, 24mmol) and HMPA (5mL, 28mmol) in dry tetrahydrofuran (100mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 29.2mL) was added, to which 74mmol was slowly added over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In a separate flask, a solution of tert-butyl (1- (methoxy (methyl) carbamoyl) cyclopropyl) carbamate (7.08g, 32mmol) in dry tetrahydrofuran (50mL) was cooled to-78 ℃. A solution of isopropyl magnesium chloride and tetrahydrofuran (17.6mL, 36mmol) was added slowly. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. Intermediate 71-3(8g crude) was used in the next reaction without further purification. LC-MS: 429[ M +1]] +。
S2: to a solution of intermediate 71-3(3.7g, 8.6mmol) in 1, 4-dioxane (5mL) was added 4M hydrogen chloride/1, 4-dioxane (5 mL). Mixing the obtained mixture inStirred at 120 ℃ for 60 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue is taken up in NaHCO3The aqueous solution was basified and then extracted with ethyl acetate (100 mL. times.2). Extracting with Na2SO 4Dried and then concentrated. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate 2: 1) to give the desired intermediate 71-4(1g, 38% yield). LC-MS: 311[ M +1]] +。
S3: to intermediate 71-4(1g, 3.2mmol) and compound 71-5(420mg, 4.0mmol) in CH3CN (20mL) solution was added with K3PO 4(820mg, 3.86mmol), Xphos (153mg, 0.32mmol) and Pd2(dba) 3(147mg, 0.16 mmol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH ═ 100: 1 to 10: 1) to afford the desired intermediate 71-6(0.86g, 70% yield). LC-MS: 381[ M +1]] +。
S4: to intermediate 71-6(0.86g, 2.2mmol) and compound 71-7(0.75g, 2.7mmol) in CH3CN (50mL) was added DIPEA (0.5mL, 3.0mmol) to the mixture. The mixture was heated to reflux overnight. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give compound 71(450mg, 26% yield) as a white solid. LC-MS: 541[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.87(dd，J＝8.0Hz，1.6Hz，1H)，8.40(d，J＝2.0Hz，1H)，7.98(s，1H)，7.69-7.68(m，5H)，7.38-7.33(m，3H)，6.99-6.96(m，2H)，6.46(s，2H)，3.80(s，3H)，1.40-1.23(m，2H)，0.85-0.81(m，2H)。
Example 30: synthesis of Compound 79.
Figure PCTCN2019089027-APPB-000063
S1: at room temperature to the compound79-1(50g, 0.29mol) and DMF (0.5mL) in CH2Cl 2To a stirred solution in (250mL) was added oxalyl chloride (27.4mL, 0.32mol) dropwise and the resulting mixture was stirred at room temperature for 2 hours, then the mixture was concentrated in vacuo to give the crude intermediate 79-2, which was used directly in the next step.
S2: Ice-Water cooled Compound 79-3(28.7g, 0.30mol) and Triethylamine (90mL, 0.60mol) in CH2Cl 2(250mL) solution was added intermediate 79-2(54g, 0.29mol) in CH2Cl 2Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100mL) was added. The organic layer was separated and washed with brine, Na2SO 4Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500mL), and further dried in vacuo to give intermediate 79-4(70g, 95% yield) as a yellow solid. LC-MS: 246[ M +1]] +。
S3: a solution of intermediate 79-4(30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added, to which was slowly added 0.37mol over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (36.9g, 0.16mol) in dry tetrahydrofuran (100mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. Intermediate 79-6(70g crude) was used in the next reaction without further purification. LC-MS: 417[ M +1]] +。
S4: to intermediate 79-6(70g, 168mmol) in MeOH (360mL) was added concentrated HCl (180 mL). Will getThe resulting mixture was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (1000mL) and extracted with ethyl acetate (200 mL. times.2). Then using K2CO 3The aqueous layer was alkalinized and a precipitate formed. The solid was collected by filtration and dried to give intermediate 79-7(20g, 40% yield). LC-MS: 299[ M +1]] +。
S5: to intermediate 79-7(11g, 36.9mmol) and compound 79-8(5.5g, 51.9mmol, 1.2eq.) in CH3CN (200mL) solution was added K3PO 4(9.4g, 44.3mmol), Xphos (0.88g, 1.834mmol) and Pd2(dba) 3(841mg, 0.918 mmol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH 100: 1 to 10: 1) to afford the desired intermediate 79-9(9.8g, 72% yield). LC-MS: 369[ M +1]] +。
S6: to intermediate 79-9(12.7g, 34.5mmol) and compound 79-10(9.9g, 36.2mmol) in CH3CN (200mL) was added DIPEA (6.3mL, 38mmol) to the mixture. The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by reverse phase ISCO and recrystallized from EtOH/water to give intermediate 79-11(9.2g, 50% yield) as a white solid. LC-MS: 529[ M +1] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.94(dd，J＝8.0Hz，1.6Hz，1H)，8.56(dd，J＝8.0Hz，1.6Hz，1H)，8.07-7.91(m，2H)，7.63-7.55(m，5H)，7.52-7.46(m，3H)，7.39-7.37(m，2H)，7.03(dd，J＝6.8Hz，4.8Hz，1H)，7.99(s，1H)，6.42(s，2H)，4.57-4.54(m，1H)，3.82(s，3H)，1.36(d，J＝6.8Hz，3H)。
S7: to intermediate 79-11(400mg, 0.76mmol) in CH2Cl 2To the solution (5mL) was added N-methylaminosulfonyl chloride (120mg, 1.0mmol) and pyridine (1 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture is then concentrated and purified by preparative HPLCCompound 79(140mg, 30% yield) was obtained as a yellow solid. LC-MS: 622[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ9.48(s，1H)，9.15(brs，1H)，8.78(brs，1H)，8.00-7.97(m，1H)，7.65-7.32(m，11H)，6.83(s，1H)，4.64-4.60(m，1H)，3.82(s，3H)，2.54(s，3H)，1.39(d，J＝8.0Hz，1H)。
Example 31: synthesis of Compound 76.
Referring to example 30, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to obtain the objective compound 76. LC-MS: 622[ M +1]] +。
Example 32: synthesis of Compound 82.
Referring to example 30, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the title compound 82. LC-MS: 622[ M +1]] +。
Example 33: synthesis of Compound 80.
Figure PCTCN2019089027-APPB-000064
S1: to compound 80-1(50g, 0.29mol) and DMF (0.5mL) in CH at room temperature2Cl 2To a stirred solution in (250mL) was added oxalyl chloride (27.4mL, 0.32mol) dropwise and the resulting mixture was stirred at room temperature for 2 hours, then the mixture was concentrated in vacuo to give the crude intermediate 80-2, which was used directly in the next step.
S2: Ice-Water cooled Compound 80-3(28.7g, 0.30mol) and Triethylamine (90ml, 0.60mol) in CH2Cl 2(250mL) solution was added intermediate 80-2(54g, 0.29mol) CH2Cl 2Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100mL) was added. The organic layer was separated and washed with brine, Na2SO 4Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500mL), and further dried in vacuo to afford intermediate 80-4(70g, 95% yield) as a yellow solid. LC-MS: 246[ M +1]] +。
S3: a solution of intermediate 80-4(30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added, to which was slowly added 0.37mol over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (36.9g, 0.16mol) in dry tetrahydrofuran (100mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. Intermediate 80-6(70g crude) was used in the next reaction without further purification. LC-MS: 417[ M +1]] +。
S4: to a solution of intermediate 80-6(70g, 168mmol) in MeOH (360mL) was added concentrated HCl (180 mL). The resulting mixture was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (1000mL) and extracted with ethyl acetate (200 mL. times.2). Then using K2CO 3The aqueous layer was alkalinized and a precipitate formed. The solid was collected by filtration and dried to give intermediate 80-7(20g, 40% yield). LC-MS: 299[ M +1]] +。
S5: to intermediate 80-7(11g, 36.9mmol) and compound 80-8(5.5g, 51.9mmol, 1.2eq.) in CH3CN (200mL) solution was added K3PO 4(9.4g, 44.3mmol), Xphos (0.88g, 1.834mmol) and Pd2(dba) 3(841mg, 0.918 mmol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH 100: 1 to 10: 1) to afford the desired intermediate 80-9(9.8g, 72% yield). LC-MS: 369[ M +1]] +。
S6: to intermediate 80-9(12.7g, 34.5mmol) and compound 80-10(9.9g, 36.2mmol) in CH3CN (200mL) was added DIPEA (6.3mL, 38mmol) to the mixture. The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by reverse phase ISCO and recrystallized from EtOH/water to give intermediate 80-11(9.2g, 50% yield) as a white solid. LC-MS: 529[ M +1] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.94(dd，J＝8.0Hz，1.6Hz，1H)，8.56(dd，J＝8.0Hz，1.6Hz，1H)，8.07-7.91(m，2H)，7.63-7.55(m，5H)，7.52-7.46(m，3H)，7.39-7.37(m，2H)，7.03(dd，J＝6.8Hz，4.8Hz，1H)，7.99(s，1H)，6.42(s，2H)，4.57-4.54(m，1H)，3.82(s，3H)，1.36(d，J＝6.8Hz，3H)。
S7: to intermediate 80-11(400mg, 0.76mmol) in CH2Cl 2To the solution (10mL) was added N-ethylsulfamoyl chloride (143mg, 1.00mmol) and pyridine (1 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then concentrated and purified by preparative HPLC to give compound 80(130mg, 27% yield) as a yellow solid. LC-MS: 636[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ9.50(s，1H)，9.17(d，J＝2.0Hz，1H)，8.78(d，J＝2.0Hz，1H)，8.00(s，1H)，7.97(d，J＝8.0Hz，1H)，7.83(t，J＝2.0Hz，1H)，7.69-7.62(m，5H)，7.48-7.44(m，3H)，7.32-7.24(m，2H)，6.82(s，1H)，4.64-4.60(m，1H)，3.82(s，3H)，3.00(d，J＝13.2Hz，7.2Hz，2H)，1.41(d，J＝8.0Hz，1H)，1.01(t，J＝8.0Hz，3H)。
Example 34: synthesis of Compound 77.
Referring to example 33, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were left unchanged to obtain the objective compound 77. LC-MS: 636[ M +1] +.
Example 35: synthesis of Compound 83.
Referring to example 33, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the objective compound 83. LC-MS: 636[ M +1]] +。
Example 36: synthesis of Compound 86.
Figure PCTCN2019089027-APPB-000065
Figure PCTCN2019089027-APPB-000066
Synthesis procedure
S1: to compound 86-1' (570mg, 10mmol) in CH at 0 deg.C2Cl 2(10mL) solution was added chlorosulfonic acid (0.22M, 3.3mmol) in CH2Cl 2(20mL) of the solution. After the addition, the mixture was stirred for another 30 minutes. The ice bath was then removed and stirring was continued at room temperature for 1 hour. The precipitate was collected by filtration and dried under high vacuum to give intermediate 86-2' (1.0g, 77% yield) as a white solid.
S2: to a suspension of intermediate 86-2' (1g, 7.2mmol) in toluene (10mL) was added PCl5(686mg, 3.3 mmol). The mixture was stirred at 75 ℃ for 2 hours, cooled to room temperature and filtered. The solid residue was washed with toluene. The filtrate was evaporated and dried under high vacuum to give intermediate 86-12(1.0g, 88% yield). Used in the next step without further purification.
S3: to compound 86-1(50g, 0.29mol) and DMF (0.5mL) in CH at room temperature2Cl 2To a stirred solution in (250mL) was added oxalyl chloride (27.4mL, 0.32mol) dropwise and the resulting mixture was stirred at room temperature for 2 hours, then the mixture was concentrated in vacuo to give the crude intermediate 86-2, which was used directly in the next step.
S4: Ice-Water cooled Compound 86-3(28.7g, 0.30mol) and Triethylamine (90mL, 0.60mol) in CH2Cl 2(250mL) solution was added intermediate 86-2(54g, 0.29mol) in CH2Cl 2Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100mL) was added. The organic layer was separated and washed with brine, Na2SO 4Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500mL), and further dried in vacuo to give intermediate 86-4(70g, 95% yield) as a yellow solid. LC-MS: 246[ M +1]] +。
S5: a solution of intermediate 86-4(30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added, to which was slowly added 0.37mol over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (36.9g, 0.16mol) in dry tetrahydrofuran (100mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. Intermediate 86-6(70g crude) was used in the next reaction without further purification. LC-MS: 417[ M +1]] +。
S6: to a solution of intermediate 86-6(70g, 168mmol) in MeOH (360mL) was added concentrated HCl (180 mL). The resulting mixture was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (1000mL) and extracted with ethyl acetate (200 mL. times.2). Then using K2CO 3The aqueous layer was alkalinized and a precipitate formed. The solid was collected by filtration and dried to give compound 86-7(20g, 40% yield). LC-MS: 299[ M +1]] +。
S7: to intermediate 86-7(11g, 36.9mmol) and compound 86-8(5.5g, 51.9mmol, 1.2eq.) in CH3CN (200mL) solution was added K3PO 4(9.4g, 44.3mmol), Xphos (0.88g, 1.834mmol) and Pd2(dba) 3(841mg, 0.918 mmol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH 100: 1 to 10: 1) to afford the desired intermediate 86-9(9.8g, 72% yield). LC-MS: 369[ M +1]] +。
S8: to intermediate 86-9(12.7g, 34.5mmol) and compound 86-10(9.9g, 36.2mmol) in CH3CN (200mL) was added DIPEA (6.3mL, 38mmol) to the mixture. The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by reverse phase ISCO and recrystallized from EtOH/water to give compound 86-11(9.2g, 50% yield) as a white solid. LC-MS: 529[ M +1] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.94(dd，J＝8.0Hz，1.6Hz，1H)，8.56(dd，J＝8.0Hz，1.6Hz，1H)，8.07-7.91(m，2H)，7.63-7.55(m，5H)，7.52-7.46(m，3H)，7.39-7.37(m，2H)，7.03(dd，J＝6.8Hz，4.8Hz，1H)，7.99(s，1H)，6.42(s，2H)，4.57-4.54(m，1H)，3.82(s，3H)，1.36(d，J＝6.8Hz，3H)。
S9: to compound 86-11(150mg, 0.28mmol) in CH2Cl 2(10mL) to the solution was added the intermediate86-12(53mg, 0.34mmol) and pyridine (1 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then concentrated and purified by preparative HPLC to give compound 86(20mg, 11% yield) as a yellow solid. LC-MS: 648[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.94(d，J＝8.0Hz，1H)，8.86(d，J＝2.0Hz，1H)，8.25(s，1H)，8.00(s，1H)，7.65-7.42(m，9H)，7.03-7.02(m，1H)，6.82(s，1H)，4.58-4.56(m，1H)，3.82(s，3H)，2.32-2.30(m，1H)，1.35(d，J＝8.0Hz，3H)，0.45-0.34(m，4H)。
Example 37: synthesis of Compound 85.
Referring to example 36, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to obtain the objective compound 85. LC-MS: 648[ M +1]] +。
Example 38: synthesis of Compound 87.
Referring to example 36, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the objective compound 87. LC-MS: 648[ M +1]] +。
Example 39: synthesis of Compound 92.
Figure PCTCN2019089027-APPB-000067
The synthesis steps are as follows:
s1: to compound 92-1(50g, 0.29mol) and DMF (0.5mL) in CH at room temperature2Cl 2To a stirred solution in (250mL) was added oxalyl chloride (27.4mL, 0.32mol) dropwise and the resulting mixture was stirred at room temperature for 2 hours, then the mixture was concentrated in vacuo to give the crude intermediate 92-2, which was used directly in the next step.
S2: Ice-Water cooled Compound 92-3(28.7g, 0.30mol) and triethylamine (90ml, 0.60mol) in CH2Cl 2(250mL) solution was added intermediate 92-2(54g, 0.29mol) CH2Cl 2Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100mL) was added. The organic layer was separated and washed with brine, Na2SO 4Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500mL), and further dried in vacuo to give intermediate 92-4(70g, 95% yield) as a yellow solid. LC-MS: 246[ M +1]] +。
S3: a solution of intermediate 92-4(30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added, to which was slowly added 0.37mol over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (36.9g, 0.16mol) in dry tetrahydrofuran (100mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. Intermediate 92-6(70g crude) was used in the next reaction without further purification. LC-MS: 417[ M +1]] +。
S4: to a solution of intermediate 92-6(70g, 168mmol) in MeOH (360mL) was added concentrated HCl (180 mL). The resulting mixture was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (1000mL) and extracted with ethyl acetate (200 mL. times.2). Then using K2CO 3The aqueous layer was alkalinized and a precipitate formed. The solid was collected by filtration and dried to give intermediate 92-7(20g, 40% yield). LC-MS: 299[ M +1]] +。
S5: to intermediate 92-7(11g, 36.9mmol) and compound 92-8(5.5g, 51.9mmol, 1.2eq.) in CH3CN (200mL) solution was added K3PO 4(9.4g, 44.3mmol), Xphos (0.88g, 1.834mmol) and Pd2(dba) 3(841mg, 0.918 mmol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH 100: 1 to 10: 1) to give the desired intermediate 92-9(9.8g, 72% yield). LC-MS: 369[ M +1]] +。
S6: to intermediate 92-9(12.7g, 34.5mmol) and compound 92-10(9.9g, 36.2mmol) in CH3CN (200mL) was added DIPEA (6.3mL, 38mmol) to the mixture. The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by reverse phase ISCO and recrystallized from EtOH/water to give compound 92-11(9.2g, 50% yield) as a white solid. LC-MS: 529[ M +1] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.94(dd，J＝8.0Hz，1.6Hz，1H)，8.56(dd，J＝8.0Hz，1.6Hz，1H)，8.07-7.91(m，2H)，7.63-7.55(m，5H)，7.52-7.46(m，3H)，7.39-7.37(m，2H)，7.03(dd，J＝6.8Hz，4.8Hz，1H)，7.99(s，1H)，6.42(s，2H)，4.57-4.54(m，1H)，3.82(s，3H)，1.36(d，J＝6.8Hz，3H)。
S7: to a solution of compound 92-11(200mg, 0.38mmol) in pyridine (10mL) was added dimethylsulfamoyl chloride (109mg, 0.76 mmol). The reaction mixture was heated to 60 ℃ and stirred for 3 days. The reaction mixture was then concentrated and purified by preparative HPLC to give compound 92(8mg, 3% yield) as a yellow solid. LC-MS: 636[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.82(s，1H)，8.31-8.25(m，2H)，8.01(s，1H)，7.64-7.47(m，8H)，6.86(s，1H)，6.76(s，1H)，4.65-4.62(m，1H)，3.82(s，3H)，2.62(m，6H)，1.42(d，J＝8.0Hz，3H)。
Example 40: synthesis of Compound 91.
Referring to example 39, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to obtain the title compound 91. LC-MS: 636[ M +1]] +。
Example 41: synthesis of compound 93.
Referring to example 39, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the objective compound 93. LC-MS: 636[ M +1]] +。
Example 42: synthesis of Compound 95.
Figure PCTCN2019089027-APPB-000068
The synthesis steps are as follows:
s1: to compound 95-1(50g, 0.29mol) and DMF (0.5mL) in CH at room temperature2Cl 2To a stirred solution in (250mL) was added oxalyl chloride (27.4mL, 0.32mol) dropwise and the resulting mixture was stirred at room temperature for 2 hours, then the mixture was concentrated in vacuo to give the crude intermediate 95-2, which was used directly in the next step.
S2: Ice-Water cooled Compound 95-3(28.7g, 0.30mol) and Triethylamine (90ml, 0.60mol) in CH2Cl 2(250mL) solution was added intermediate 92-2(54g, 0.29mol) CH2Cl 2Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100mL) was added. The organic layer was separated and washed with brine, Na2SO 4Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000mL) and stirred at room temperature overnight. Filtering and collecting the precipitateThe material was washed with petroleum ether (500mL) and further dried in vacuo to afford intermediate 95-4(70g, 95% yield) as a yellow solid. LC-MS: 246[ M +1]] +。
S3: a solution of intermediate 95-4(30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added, to which was slowly added 0.37mol over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (36.9g, 0.16mol) in dry tetrahydrofuran (100mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. Intermediate 95-6(70g crude) was used in the next reaction without further purification. LC-MS: 417[ M +1]] +。
S4: to a solution of intermediate 95-6(70g, 168mmol) in MeOH (360mL) was added concentrated HCl (180 mL). The resulting mixture was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (1000mL) and extracted with ethyl acetate (200 mL. times.2). Then using K2CO 3The aqueous layer was alkalinized and a precipitate formed. The solid was collected by filtration and dried to give intermediate 95-7(20g, 40% yield). LC-MS: 299[ M +1]] +。
S5: to intermediate 95-7(11g, 36.9mmol) and compound 95-8(5.5g, 51.9mmol, 1.2eq.) in CH3CN (200mL) solution was added K3PO 4(9.4g, 44.3mmol), Xphos (0.88g, 1.834mmol) and Pd2(dba) 3(841mg, 0.918 mmol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH) 2Cl 2MeOH 100: 1 to 10: 1) to give the desired intermediate 95-9(9.8g, 72% yield). LC-MS: 369[ M +1]] +。
S6: to intermediate 95-9(12.7g, 34.5mmol) and compound 95-10(9.9g, 36.2mmol) in CH3CN (200mL) was added DIPEA (6.3mL, 38mmol) to the mixture. The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by reverse phase ISCO and recrystallized from EtOH/water to give compound 95-11(9.2g, 50% yield) as a white solid. LC-MS: 529[ M +1] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.94(dd，J＝8.0Hz，1.6Hz，1H)，8.56(dd，J＝8.0Hz，1.6Hz，1H)，8.07-7.91(m，2H)，7.63-7.55(m，5H)，7.52-7.46(m，3H)，7.39-7.37(m，2H)，7.03(dd，J＝6.8Hz，4.8Hz，1H)，7.99(s，1H)，6.42(s，2H)，4.57-4.54(m，1H)，3.82(s，3H)，1.36(d，J＝6.8Hz，3H)。
S7: to a solution of compound 95-11(1000mg, 1.89mmol) in pyridine (20mL) was added pyrrolidine-1-sulfonyl chloride (385mg, 2.27 mmol). The reaction mixture was heated to 60 ℃ and stirred for 3 days. The reaction mixture was then concentrated and purified by preparative HPLC to give compound 95(60mg, 8% yield) as a yellow solid. LC-MS: 661[ M +1] +。 1H-NMR(400MHz，DMSO-d 6)：δ9.55(s，1H)，8.26(d，J＝8.0Hz，1H)，8.80(d，J＝2.0Hz，1H)，8.00-7.95(m，2H)，7.67-7.58(m，5H)，7.48-7.27(m，3H)，7.33-7.27(m，2H)，6.83(s，1H)，4.65-4.62(m，1H)，3.82(s，3H)，3.45-3.43(m，4H)，1.80-1.77(m，4H)，1.42(d，J＝8.0Hz，3H)。
Example 43: synthesis of Compound 94.
Referring to example 42, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to obtain the objective compound 94. LC-MS: 661[ M +1] +。
Example 44: synthesis of Compound 96.
Referring to example 42, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the objective compound 96. LC-MS: 661[ M +1] +。
Example 45: synthesis of Compound 98.
Figure PCTCN2019089027-APPB-000069
The synthesis steps are as follows:
s1: to compound 98-1(500mg, 1.67mmol) and ethynyltrimethylsilane (0.33mL, 2.34mmol) in CH3CN (20mL) solution was added with K3PO 4(425mg, 2.00mmol), Xphos (50mg, 0.1mmol) and Pd2(dba) 3(50mg, 0.05 mmol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH)2Cl 2/MeOH ═ 100: 1 to 10: 1) to give the desired intermediate 98-2(360mg, 60% yield). LC-MS: 361[ M +1]] +。
S2: to intermediate 98-2(360mg, 1.0mmol) and compound 98-3(288mg, 1.05mmol) in CH3To the mixture in CN (20mL) was added DIPEA (0.2mL, 1.1 mmol). The mixture was heated to reflux overnight. The reaction mixture is then concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH ═ 100: 1 to 10: 1) to give the desired intermediate 98-4(400mg, 77% yield). LC-MS: 521[ M +1]] +。
S3: to a solution of intermediate 98-4(400mg, 0.77mmol) in THF (10mL) was added TBAF (1.2mL, 1.2mmol, 1M in THF). After completion of the reaction, the reaction mixture was concentrated. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH ═ 100: 1 to 10: 1) to give the desired intermediate 98-5(170mg, 49% yield). LC-MS: 449[ M +1]] +。
S4: to intermediate 98-5(112mg, 0.25mmol) and compound 98-6(83mg, 0.30mmol) in CH3CN (10mL) solution was added DIPEA (0.05mL, 0.33mmol), CuI (1mg, 0.005mmol) and PdCl2(PPh 3) 2(0.53mg, 0.75. mu. mol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH 100: 1 to 10: 1) to afford the desired intermediate 98-7(130mg, 87% yield). LC-MS: 597[ M +1]] +。
S5: Ice-Water cooled tert-Butanol (50mg, 0.66mmol) in CH2Cl 2To the solution (5mL) was added chlorosulfonyl isocyanate (93mg, 0.66 mmol). The resulting mixture was stirred for 10 minutes. Intermediate 98-7(130mg, 0.21mmol) and triethylamine (0.3mL, 2.2mmol) in CH was then added to the mixture2Cl 2(10 mL). After 10 minutes, the ice bath was removed. The reaction mixture was then stirred at ambient temperature overnight. The reaction solution was concentrated and used with CH2Cl 2(10mL) redissolved and CF added3COOH (1 mL). After completion of the reaction, the reaction mixture was basified with aqueous sodium bicarbonate. The reaction mixture was extracted with ethyl acetate (100mL), and the organic layer was washed and dried. After concentration, the residue was purified by preparative HPLC to give compound 98(29mg, 20% yield) as a yellow solid. LC-MS: 676[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ9.19(m，1H)，8.97(m，1H)，8.58(s，1H)，8.01-7.95(m，2H)，7.95-7.61(m，11H)，7.28(s，1H)，7.07-7.04(m，1H)，6.44(s，1H)，5.24-5.20(m，2H)，4.85-4.82(m，1H)，1.56(d，J＝8.0Hz，3H)。
Example 46: synthesis of Compound 97.
Referring to example 45, compounds (S) - (1)Tert-butyl (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were left unchanged to give the title compound 97. LC-MS: 676[ M +1]] +。
Example 47: synthesis of Compound 99.
Referring to example 45, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were left unchanged to obtain the objective compound 99. LC-MS: 676[ M +1]] +。
Example 48: synthesis of compound 104.
Figure PCTCN2019089027-APPB-000070
Synthesis procedure
S1: to compound 104-1(50g, 0.29mol) and DMF (0.5mL) in CH at room temperature2Cl 2To a stirred solution in (250mL) was added oxalyl chloride (27.4mL, 0.32mol) dropwise and the resulting mixture was stirred at room temperature for 2 hours, then the mixture was concentrated in vacuo to give the crude intermediate 104-2, which was used directly in the next step.
S2: Ice-Water cooled Compound 104-3(28.7g, 0.30mol) and Triethylamine (90ml, 0.60mol) in CH2Cl 2(250mL) solution was added intermediate 104-2(54g, 0.29mol) in CH2Cl 2Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100mL) was added. The organic layer was separated and washed with brine, Na2SO 4Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500mL), and further dried in vacuo to afford intermediate 104-4(70g, 95% yield) as a yellow solid. LC-MS: 246[ M +1]] +。
S3: a solution of intermediate 104-4(30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added, to which was slowly added 0.37mol over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (36.9g, 0.16mol) in dry tetrahydrofuran (100mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. Intermediate 104-6(70g crude) was used in the next reaction without further purification. LC-MS: 417[ M +1]] +。
S4: to a solution of intermediate 104-6(70g, 168mmol) in MeOH (360mL) was added concentrated HCl (180 mL). The resulting mixture was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (1000mL) and extracted with ethyl acetate (200 mL. times.2). Then using K2CO 3The aqueous layer was alkalinized and a precipitate formed. The solid was collected by filtration and dried to give intermediate 104-7(20g, 40% yield). LC-MS: 299[ M +1]] +。
S5: to intermediate 104-7(500mg, 1.68mmol) and compound 104-8(0.33mL, 2.34mmol) in CH3CN (10mL) solution was added with K3PO 4(425mg, 2.01mmol), Xphos (50mg, 0.11mmol) and Pd2(dba) 3(50mg, 0.054 mmol). Adding N to the reaction mixture2Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH ═ 100: 1 to 10: 1) to give the desired intermediate 104-9(360mg, 60% yield).
S6: to intermediate 104-9(360mg, 1.0mmol) and compound 104-10(289mg, 1.05mmol) in CH3To the mixture in CN (20mL) was added DIPEA (0.2mL, 1.1 mmol). The mixture was heated to reflux overnight. It is then concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH ═ 100: 1 to 10: 1) to give the desired intermediate 104-11(400mg, 77% yield). LC-MS: 521[ M +1]] +。
S7: to a mixture of intermediate 104-11(400mg, 0.77mmol) in THF (10mL) was added TBAF (1.2mL, 1.2 mmol). The mixture was stirred at ambient temperature for 2 hours. The reaction mixture is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH 100: 1 to 10: 1) to give the desired intermediate 104-12(170mg, 50% yield). LC-MS: 449[ M +1]] +。
S8: Ice-Water cooled tert-Butanol (84.5mg, 1.14mmol) in CH2Cl 2To the solution (10mL) was added chlorosulfonyl isocyanate (160mg, 1.14 mmol). The resulting mixture was stirred for 10 minutes. Intermediate 104-12(170mg, 0.38mmol) and triethylamine (0.5mL, 3.8mmol) in CH were then added to the mixture2Cl 2(10 mL). After 10 minutes, the ice bath was removed. The reaction mixture was then stirred at ambient temperature overnight. The reaction solution was concentrated to give crude intermediate 104-13(230mg, 95% yield). LC-MS: 628[ M +1]] +。
S9: to intermediate 104-13(230mg, 0.36mmol) in CH2Cl 2(10mL) to the solution was added CF3COOH (1 mL). After completion of the reaction, the reaction mixture was basified with aqueous sodium bicarbonate. The reaction mixture was extracted with ethyl acetate (100mL), and the organic layer was washed and dried. After concentration, the residue was purified by preparative HPLC to give compound 104(20mg, 11% yield) as a yellow solid. LC-MS: 528[ M +1]] +。 1H-NMR(400MHz，DMSO-d 6)：δ8.94(d，J＝8.0Hz，1H)，8.56(d，J＝2.0Hz，1H)，8.29(s，1H)，8.01(d，J＝8.0Hz，1H)，7.60-7.38(m，9H)，7.03-7.02(m，1H)，6.80(s，1H)，6.42(s，1H)，4.56-4.54(m，1H)，4.30(s，1H)，1.35(d，J＝8.0Hz，3H)。
Example 49: synthesis of compound 103.
Referring to example 48, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the title compound 103. LC-MS: 528[ M +1]] +。
Example 50: synthesis of compound 105.
Referring to example 48, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the title compound 105. LC-MS: 528[ M +1]] +。
Example 51: synthesis of compound 107.
Figure PCTCN2019089027-APPB-000071
Synthesis procedure
S1: to compound 107-1(50g, 0.29mol) and DMF (0.5mL) in CH at room temperature2Cl 2To a stirred solution in (250mL) was added oxalyl chloride (27.4mL, 0.32mol) dropwise and the resulting mixture was stirred at room temperature for 2 hours, then the mixture was concentrated in vacuo to give the crude intermediate 107-2, which was used directly in the next step.
S2: Ice-Water cooled Compound 107-3(28.7g, 0.30mol) and Triethylamine (90ml, 0.60mol) in CH2Cl 2(250mL) solution was added intermediate 107-2(54g, 0.29mol) CH2Cl 2Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100mL) was added. The organic layer was separated and washed with brine, Na2SO 4Is dried andand (5) filtering. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500mL), and further dried in vacuo to afford intermediate 107-4(70g, 95% yield) as a yellow solid. LC-MS: 246[ M +1]] +。
S3: a solution of intermediate 107-4(30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added, to which was slowly added 0.37mol over 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, a solution of tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (36.9g, 0.16mol) in dry tetrahydrofuran (100mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was added slowly at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50mL) and then extracted with ethyl acetate. Extracting with Na2SO 4Dried and then concentrated under reduced pressure. Intermediate 107-6(70g of crude) was used in the next reaction without further purification. LC-MS: 417[ M +1]] +。
S4: to a solution of intermediate 107-6(70g, 168mmol) in MeOH (360mL) was added concentrated HCl (180 mL). The resulting mixture was stirred at reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (1000mL) and extracted with ethyl acetate (200 mL. times.2). Then using K2CO 3The aqueous layer was alkalinized and a precipitate formed. The solid was collected by filtration and dried to give intermediate 107-7(20g, 40% yield). LC-MS: 299[ M +1]] +。
S5: to intermediate 107-7(500mg, 1.68mmol) and compound 104-8(0.33mL, 2.34mmol) in CH3CN (10mL) solution was added with K3PO 4(425mg, 2.01mmol), Xphos (50mg, 0.11mmol) and Pd2(dba) 3(50mg, 0.054 mmol). Adding N to the reaction mixture2Then, thenHeat to reflux and stir overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH ═ 100: 1 to 10: 1) to give the desired intermediate 107-9(360mg, 60% yield).
S6: to intermediate 107-9(360mg, 1.0mmol) and compound 107-10(289mg, 1.05mmol) in CH3To the mixture in CN (20mL) was added DIPEA (0.2mL, 1.1 mmol). The mixture was heated to reflux overnight. It is then concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH ═ 100: 1 to 10: 1) to give the desired intermediate 107-11(400mg, 77% yield). LC-MS: 521[ M +1]] +。
S7: to a mixture of intermediate 107-11(400mg, 0.77mmol) in THF (10mL) was added TBAF (1.2mL, 1.2 mmol). The mixture was stirred at ambient temperature for 2 hours. The reaction mixture is concentrated and purified by column chromatography (eluent: CH)2Cl 2MeOH 100: 1 to 10: 1) to afford the desired intermediate 107-12(170mg, 50% yield). LC-MS: 449[ M +1]] +。
S8: to compound 107-12(200mg, 0.38mmol) in CH2Cl 2To the solution (10mL) was added N-cyclopropylsulfamoyl chloride (78mg, 0.50mmol) and pyridine (1 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then concentrated and purified by preparative HPLC to give compound 107(90mg, 42% yield) as a yellow solid. LC-MS: 568[ M +1] +。 1H-NMR(400MHz，DMSO-d 6)：δ9.59(s，1H)，9.11(brs，1H)，8.74(brs，1H)，8.32-8.00(s，2H)，7.68-7.22(m，9H)，6.83(s，1H)，4.62(brs，1H)，4.31(s，1H)，2.31-2.30(m，1H)，1.38(d，J＝8.0Hz，1H)，0.45(brs，4H)。
Example 52: synthesis of compound 106.
Referring to example 51, the compound (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamic acid tert-butyl ester was replaced with (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamic acid tert-butyl esterEster, the other steps remain unchanged, yielding the target compound 106. LC-MS: 568[ M +1] +。
Example 53: synthesis of compound 108.
Referring to example 51, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (R) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the objective compound 108. LC-MS: 568[ M +1] +。
Example 54: synthesis of compound 115.
Figure PCTCN2019089027-APPB-000072
The synthesis steps are as follows:
s1: to a solution of compound 115-1(300mg, 1mmol) and compound 115-2(240mg, 1mmol) in 1, 4-dioxane (20mL) was added Cs2CO 3(650mg, 2mmol), Xantphos (115mg, 0.2mmol) and Pd2(dba) 3(92mg, 0.1 mmol). Adding N to the reaction mixture2Then heated to reflux overnight. The reaction mixture was then filtered, the filtrate concentrated and purified by column chromatography (eluent: petroleum ether/ethyl acetate 1: 2 to 0: 1) to give the desired intermediate 115-3(250mg, 50% yield). LC-MS: 503[ M +1]] +。
S2: to intermediate 115-3(250mg, 0.50mmol) and compound 115-4(165mg, 0.6mmol) in CH3To the mixture in CN (10mL) was added DIPEA (0.17mL, 1 mmol). The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (eluent: 100% ethyl acetate) to give the desired intermediate 115-5(200mg, 60% yield). LC-MS: 663[ M +1]] +。
S3: Ice-Water cooled intermediate 115-5(200mg, 0.3mmol) in CH2Cl 2(5mL) to the solution was added CF3COOH (1 mL). Stirring the mixtureStirring for 3 hours. The reaction solution was then concentrated to give intermediate 115-6(200mg, 95% yield) as a yellow solid. LC-MS: 563[ M +1]] +。 1H-NMR(400MHz，DMSO-d6)：δ8.92(d，J＝8.0Hz，1H)，8.55(d，J＝8.0Hz，1H)，8.47(s，2H)，8.01(s，1H)，7.69-7.38(m，7H)，7.02-7.01(m，1H)，6.76(s，1H)，6.44(s，2H)，4.60-4.54(m，1H)，3.70-3.68(m，2H)，3.02-3.00(m，2H)，1.84-1.80(m，4H)，1.34(d，J＝6.8Hz，3H)。
S4: to a solution of ice-water cooled intermediate 115-6(130mg, 0.23mmol) in DMF (2mL) was added 37% aqueous formaldehyde (0.5 mL). After stirring for 30 minutes, NaBH was added to the mixture3CN (16mg, 0.25 mmol). The resulting mixture was stirred for 30 minutes and quenched with aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (2X 50 mL). The combined organic layers were washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give compound 115(15mg, 11% yield) as a yellow solid. LC-MS: 577[ M +1]] +。 1H-NMR(400MHz，DMSO-d6)：δ8.94(d，J＝8.0Hz，1H)，8.56(d，J＝8.0Hz，1H)，8.01-7.85(m，1H)，7.58-7.57(m，1H)，7.52-7.44(m，7H)，7.02(d，J＝4.0Hz，1H)，6.77(d，J＝8.0Hz，1H)，6.44(m，2H)，4.53-4.50(m，4H)，3.66-3.61(m，2H)，3.07-3.05(m，1H)，2.83-2.82(m，1H)，2.52-2.50(m，1H)，2.14(m，2H)，2.02-2.01(m，1H)，1.80-1.78(m，2H)，1.35(d，J＝6.8Hz，3H)。
Example 55: synthesis of compound 116.
Referring to example 54, the compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate was replaced with tert-butyl (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the other steps were kept unchanged to give the title compound 116. LC-MS: 577[ M +1]] +。
Example 56: synthesis of Compound 117.
Referring to example 54, the compound (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamic acid tert-butyl ester was replaced with (R)) Tert-butyl- (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate, the other steps remaining unchanged, gives the title compound 117. LC-MS: 577[ M +1]] +。
Example 57: synthesis of compound 118.
Figure PCTCN2019089027-APPB-000073
The synthesis steps are as follows:
s1: to a solution of compound 118-1(468mg, 1mmol) in pyridine (10mL) was added P2S 5(222mg, 1 mmol). Adding N to the reaction mixture2Then heated to reflux overnight. The reaction mixture was then concentrated and purified by column chromatography (eluent: petroleum ether/ethyl acetate 2: 1 to 1: 1) to give the desired intermediate 118-2(300mg, 62% yield). LC-MS: 485[ M +1]] +。
S2: to intermediate 118-2(300mg, 0.62mmol) in CH2Cl 2(10mL) to the mixture was added CF3COOH (1 mL). The mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated to give crude intermediate 118-3 as a TFA salt (300mg, 95% yield). LC-MS: 385[ M +1]] +。
S3: to a mixture of intermediate 118-3(300mg, 0.6mmol) and compound 118-4(275mg, 1mmol) in pyridine (5mL) was heated to 80 ℃ overnight. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give compound 118(35mg, 9.1% yield) as a white solid. LC-MS: 545[ M +1]] +。 1H-NMR(400MHz，CDCl 3-d)：δ10.24(d，J＝4.0Hz，1H)，8.51(d，J＝2.0Hz，1H)，8.45(d，J＝4.0Hz，1H)，7.69-7.59(m，3H)，7.54-7.44(m，4H)，7.38-7.36(m，2H)，6.91-6.88(m，1H)，6.46(s，2H)，6.55(s，1H)，5.25-5.22(m，1H)，3.85(s，1H)，1.53(d，J＝8.0Hz，3H)。
Example 58: synthesis of compound 119.
Referring to example 57, compound 118-1 was replaced from the S-isomer to the R-isomer with the other steps being kept unchanged to give the objective compound 119. LC-MS: 545[ M +1]] +。
Experimental example 1: PI3K in vitro inhibition assay.
Using Promega ADP-GloTMMax detection kit for determining IC of I-type alpha, beta, delta and gamma 4 subtypes of human PI3K (Millipore)50The value is obtained. Compounds of the invention were mixed with 20nM PI3K α, PI3K δ, or 40nM PI3K β, PI3K γ samples in reaction buffer (15mM HEPES pH7.4, 20mM NaCl, 1mM EGTA, 0.02% Tween 20, 10mM MgCl) at room temperature20.2mg/mL bovine-gamma-globulin) for 15min, then an ATP/diC8-PIP2 mix was added to give a final concentration of 3mM ATP and 500 μ M substrate for diC8-PIP2 (for class I PI 3K). The reaction was incubated at room temperature for 2h and then stopped by adding 25. mu.L of stop solution (Promega kit). After 40min incubation at room temperature, 50. mu.L of detection mix (Promega) was added and incubated for 1h at room temperature with an Envision plate reader. Data were converted to% inhibition and then plotted as% inhibition vs compound concentration and fitted to a four parameter logistic equation to determine IC50The value is obtained.
Figure PCTCN2019089027-APPB-000074
Note: a represents < 50 nM; b represents < 300 nM; c represents > 3000 nM; d represents > 5000 nM.
The data in the table show that a series of compounds with novel structures in the formula I can generate an inhibition effect on human PI3K, the effect is obvious, high selectivity is shown on PI3K gamma subtype and PI3K delta subtype, and the compounds can be used as high-efficiency PI3K inhibitors.
Experimental example 2: in vitro PI3K γ and PI3K δ kinase inhibition assays.
1) Reagents and consumables:
Figure PCTCN2019089027-APPB-000075
2) preparation and storage of the compounds:
A. all compounds were reconstituted to 10mM DMSO stock according to standard protocols.
B. Compounds were serially diluted 3-fold from 300 μ M (γ)/3mM (δ) for 10 doses in DMSO. A total of 10 doses and 1 DMSO control.
C. GSK2126458 was serially diluted 3-fold from 10 μ M in DMSO 10 times.
D.1% DMSO as vehicle control, 100 μ M GSK2126458 as positive control (GSK2126458 is a non-selective inhibitor of PI3K, used as positive control, with the aim of ensuring the accuracy of the data for each test).
E. Plates were shaken on a plate shaker for 5 minutes.
3) The experimental steps are as follows:
preparing a reagent:
a: 1 × assay buffer: 50mM HEPES (pH 7.5); 3mM MgCl2(ii) a 1mM EGTA; 0.03% CHAPS; 100mM NaCl; 2mM DTT (added at the time of use).
B: 2.5 × lipid buffer solution: 62.5mM HEPES (pH 7.5); 1.25mM EGTA.
C: 2.5 × PI3K test solution: the final concentration of PI3K gamma is 1.25 mu g/mL; the final concentration of PI3K δ was 0.25 μ g/mL.
D: 2.5 × substrate assay solution: PIP 2: the final concentration of 3PS is 0.025 mg/mL; the final ATP concentration was 25. mu.M.
Compound testing:
a: to a 384 well white ProxiPlate plate was added 2. mu.L of a 2.5 XPI 3K γ/δ experimental solution.
B: mu.L of the compound was added to 384-well white ProxiPlate microplates of the PI3K γ/δ experimental solution.
C: mixing the compound with a PI3K γ/δ test solution; incubate at room temperature for 15 minutes.
D: to each 384 well 2. mu.L of a 2.5 Xsubstrate assay solution was added to initiate the reaction. Thus, the final concentration of the reference compound: 100, 33.33, 11.11, 3.70, 1.23, 0.41, 0.14, 0.05, 0.015 and 0.005 nM. Test compounds final concentrations γ of 3000, 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46 and 0.15 μ M; δ is 30000, 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57 and 1.52 μ M. The final DMSO concentration was 1%.
E: the assay plate was sealed.
F: incubate at room temperature for 60 minutes.
G: to each well of a 384 well white plate was added 5. mu.l MgCl containing 10mM2ADP-Glo reagent buffer (2). Incubate at room temperature for 40 minutes.
H: add 10. mu.l of kinase detection reagent. Incubate at room temperature for 40 minutes.
I: the value of RLU (relative luminescence units) was read on Envision.
4) Data analysis
A: luminescence signal (RLU) was detected for each well.
B: the% inhibition was calculated as follows
Figure PCTCN2019089027-APPB-000076
Figure PCTCN2019089027-APPB-000077
Mean RLU of positive controls across the plate;
Figure PCTCN2019089027-APPB-000078
average RLU of blank controls over the entire plate;
RLU cmpd: RLU for each well of the microplate to test compounds.
C: calculating IC of test Compound50And plotting the effect-dose curve:
by using Graphpad5.0IC was calculated by fitting the logarithm of% inhibition to compound concentration to a non-linear regression (dose response-variable slope)50。
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))
X: the logarithm of compound concentration;
y: % inhibition;
bottom: fitting the inhibition rate of low points in the curve;
top: fitting the inhibition rate of high points in the curve;
HillSlope: the absolute value of the maximum slope of the fitted curve.
5) Report double check:
a: one analyst completes the report and the other analyst reviews the report again to ensure that the data is analyzed correctly.
B: data is derived from the reader and analyzed manually.
C: RLU values were converted to% inhibition. All ICs were calculated using% inhibition of Prism GraphPad 6.050。
D: using the RLU value, the IC is recalculated50To check the accuracy of the analysis results.
E: ensure that all compound IDs are correct.
6) As a result:
Figure PCTCN2019089027-APPB-000079
*IPI549, reference: ACS med.chem.lett., 2016, 7: 862-867.
As can be seen from the data in the above table, compounds 47, 50, 79, 80, 86, 98, 104, 107 and 118 all showed higher PI3K γ enzyme inhibitory activity than the reference compound IPI-549(PI3K γ highly selective inhibitor). In addition, compounds 50, 79 and 86 have higher selectivity for PI3K δ while having higher PI3K γ enzyme inhibitory activity.
Experimental example 3: solubility of the compounds in PBS (pH7.4).
1) Preparation of stock solution:
stock solutions of the test compound and the control compound diclofenac were prepared at a concentration of 10mM in DMSO.
2) The process of solubility determination:
30 μ L of each stock solution (10mM) was placed in its appropriate 96-well rack in sequence. 970. mu.L of PBS (pH7.4) was added to each vial of the uncovered soluble sample plate. The assays were performed in duplicate. One stir bar was added to each vial and sealed using a molded PTFE/silicone stopper. The lysis sample plates were then transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 1100RPM for 2 hours at 25 ℃. After 2 hours was completed, the stopper was removed and the stir bar was removed with a large magnet and the sample from the soluble sample plate was transferred to the filter plate. All samples were filtered using a vacuum manifold. A10. mu.L aliquot was removed from the filtrate and 990. mu.L of H containing the internal standard (1: 1) was added2A mixture of O and acetonitrile. The diluent is diluted with ultrapure water in a certain ratio according to the peak shape. The dilution factor was varied according to the solubility value and the LC-MS signal response.
3) Prepare 3 μ M Standard (STD):
from 10mM DMSO STD plates, 30. mu.L were transferred to the remaining empty plates, and 970. mu.L of DMSO was then added to the plates to bring the STD concentration to 300. mu.M. From 300. mu.M PMSO STD plates, 10. mu.L were transferred to the remaining empty plates, and then 990. mu.L of H containing an internal standard (1: 1)2A mixture of O and acetonitrile was added to the plate to give a final STD concentration of 3 μ M. The diluent is diluted with ultrapure water in a certain ratio according to the peak shape. The concentration of the standard sample is changed according to the LC-MS signal response.
4) And (3) sample analysis:
the plate was placed in a well plate autosampler. The samples were evaluated by LC-MS/MS analysis.
5) And (3) data analysis:
all calculations were performed using Microsoft Excel.
The filtrate was analyzed and quantified against a standard of known concentration using LC binding mass spectral peak identification and quantification. The solubility values for the test and control compounds were calculated as follows:
Figure PCTCN2019089027-APPB-000080
[ Sample ]: the solubility of the sample;
Area ratio sample: peak area ratio of the sample;
INJ VOL STD: sample introduction volume of the standard;
DF sample: dilution factor of the sample;
[ STD ]: the concentration of the standard;
Area ratio STD: peak area ratio of the standard;
INJ VOL sample: sample volume of sample.
6) As a result:
Figure PCTCN2019089027-APPB-000081
*IPI549, reference: ACS med.chem.lett., 2016, 7: 862-867.
As can be seen from the data in the table above, compound 50 has better solubility in PBS (pH7.4) than IPI-549.
Experimental example 4: the drug effect of the compound in a Balb/C mouse with CT26 tumor is studied.
The anti-tumor effect of different molecular dosing was studied using Balb/C mice bearing tumors, CT26 (mouse intestinal cancer cells).
1) The test method comprises the following steps:
Balb/C mice, purchased from Beijing Wittingle laboratory animal technology Ltd, were subcutaneously inoculated with CT26 cells in an inoculum size of 0.3X 106Establishing a tumor-bearing model for each cell; on day 7 post-inoculation, tumor-bearing mice were picked and randomized into groups of mean, each group8 were divided into Isotype group (1mg/kg), IPI549 group (15mg/kg), and Compound 50 group (17.2mg/kg, equivalent to IPI 549). The test compound is administered by oral gavage at a frequency of 1 time per day for 3 weeks on day 7 after cell inoculation; mice body weight, tumor tissue maximum major axis (L) and maximum broad axis (W) were monitored twice a week for about 3 weeks with euthanasia treatment given if mice lost more than 20% weight. After the experiment is finished, the tumor volume index and the relative tumor inhibition rate of each group of mice are calculated.
2) And (4) investigation indexes are as follows:
the tumor inhibition rate formula is as follows:
tumor inhibition rate TGI (%) - (Tvol)control-Tvol treated)/(Tvol control-Tvol predose)×100％
Tvol control-Tvol treated: tumor terminal volume after administration in control group-tumor terminal volume after administration in administration group;
Tvol control-Tvol predose: tumor terminal volume after administration to control group-tumor volume before administration to control group.
3) As a result:
Figure PCTCN2019089027-APPB-000082
Figure PCTCN2019089027-APPB-000083
as can be seen from the data in the above table, at day 20 post-inoculation, both the IPI549 group and the compound 50 group exhibited single-drug anti-tumor activity relative to the Isotype group. Furthermore, compound 50 had a better anti-tumor effect than the reference compound IPI 549. In addition, no mortality occurred in the groups of mice during the test period.
From the results, the series of compounds with novel structures in the formula I provided by the invention can generate an inhibition effect on human PI3K, have a remarkable effect, show high selectivity on PI3K gamma subtype and PI3K delta subtype, can be used as a high-efficiency PI3K inhibitor, are used for preventing and/or treating diseases at least partially mediated by PI3K, and have multiple purposes of resisting tumors, neurodegenerative diseases (such as Alzheimer disease), inflammation, infection and the like.

Claims (16)

  1. A compound having the structure of formula I:
    Figure PCTCN2019089027-APPB-100001
    or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion thereof, wherein:
    R 1、R 3、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 3、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R 7Substitution;
    X 0is-CH2-、-C(＝R 2)-、-S(＝R 2) n-or-P (═ R)2)(R 0)-；
    X 1、X 2、X 3、X 5、X 6、X 7、X 9、X 10、X 11、X 12、X 13And X14Each independently is CH, CR7Or N; or X7And R4May form a 3-6 membered ring;
    X 4and X8Each independently is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
    Or X4And X5Form a double bond therebetween, wherein: x5Is C, X4Is CH, CR7Or N;
    R 0is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and when R is0When not hydrogen, R0Hydrogen in (a) is optionally substituted with deuterium or halogen;
    R 2and R5Each independently is NH, NR7NOH, S or O;
    each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkylHeteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
    each n is independently 0, 1 or 2.
  2. The compound of claim 1, having the structure of formula I, wherein: which are compounds of formula IA:
    Figure PCTCN2019089027-APPB-100002
    wherein:
    R 1、R 3、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 3、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
    X 1、X 2、X 3、X 4、X 6、X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N;
    X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
    R 2And R5Each independently is NH, NR7NOH, S or O;
    each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
    each n is independently 0, 1 or 2.
  3. The compound of claim 1, having the structure of formula I, wherein: which are compounds of formula IB:
    Figure PCTCN2019089027-APPB-100003
    wherein:
    R 0is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cyclicAlkyl, heterocyclyl, spirocyclyl, heterospirocyclyl, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and when R is0When not hydrogen, R0Hydrogen in (a) is optionally substituted with deuterium or halogen;
    R 1、R 3、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 3、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
    X 1、X 2、X 3、X 4、X 6、X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N;
    X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR 7-；
    R 2And R5Each independently is NH, NR7NOH, S or O;
    each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
    each n is independently 0, 1 or 2.
  4. The compound of claim 1, having the structure of formula I, wherein: which is a compound of formula IC:
    Figure PCTCN2019089027-APPB-100004
    wherein:
    R 1、R 3、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl group、-NHS(＝O)R 7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 3、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
    X 1、X 2、X 3、X 4、X 6、X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N;
    X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
    R 2Is NH, NR7NOH, S or O;
    R 5NH, NR, NOH or S;
    each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
    each n is independently 0, 1 or 2.
  5. The compound of claim 1, having the structure of formula I, wherein: which is a compound of formula ID:
    Figure PCTCN2019089027-APPB-100005
    wherein:
    R 3is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Phosphoryl or substituted or unsubstituted phosphoryl hypo; and R is3Optionally substituted with at least one R7Substitution;
    R 1、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 4And R6The hydrogen in (1) may optionally be replaced by 0 to more than one R7Substitution;
    X 1、X 2、X 3、X 4、X 6、X 7、X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N; or X7And R4May form a 3-6 membered ring;
    X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
    R 2Optionally independently NH, NR7NOH, S or O;
    each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
    each n is independently 0, 1 or 2;
    if and only if X6Is N, X7Is CH, X8is-NH-or-NR7-, and R2When is O, R1And R3At least one group selected from spiro ring group, hetero-spiro ring group, bridged ring group, hetero-bridged ring group, - (CH)2) nSF 5Substituted or unsubstituted, etcPhosphoryl, substituted or unsubstituted phosphoryl, SF5Substituted aryl or heteroaryl, substituted or unsubstituted phosphoryl-substituted aryl or heteroaryl.
  6. The compound of claim 1, having the structure of formula I, wherein: which is a compound of formula IE:
    Figure PCTCN2019089027-APPB-100006
    wherein:
    R 1、R 3、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 3、R 4And R6The hydrogen in (1) can optionally be substituted with 0 to more than one R7Substitution;
    X 0is-CH2-、-C(＝R 2)-、-S(＝R 2) n-or-P (═ R)2)(R 0)-；
    X 1、X 2、X 3、X 5、X 6、X 9、X 10、X 11、X 12、X 13And X14Each independently is CH, CR7Or N;
    X 8is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
    R 0Is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and when R is0When not hydrogen, R0Hydrogen in (a) is optionally substituted with deuterium or halogen;
    R 2and R5Each independently is NH, NR7NOH, S or O;
    each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
    each n is independently 0, 1 or 2.
  7. The compound of claim 1, having the structure of formula I, wherein: which are compounds of formula IF:
    Figure PCTCN2019089027-APPB-100007
    wherein:
    R 1、R 3、R 4and R6Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, -NHCOR7Amino group, -COR7、-OCOR 7Alkoxycarbonyl, -NHS (═ O) R7Halogen, cyano, hydroxy, nitro, -SO2R 7、-NHSO 2R 7、-OP(＝O)(OR 7) 2Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)7) (ii) a And R is1、R 3、R 4And R6The hydrogen in (1) can optionally be substituted with 0 to more than one R7Substitution;
    X 1、X 2、X 3、X 5、X 6、X 9、X 10、X 11、X 12、X 13and X14Each independently is CH, CR7Or N;
    X 4and X8Each independently is-CH2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2) -, -NH-or-NR7-；
    R 2And R5Each independently is NH, NR7NOH, S or O;
    each R7Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)2) nSF 5、-(CH 2) nNHSO 2NH 2Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
    each n is independently 0, 1 or 2.
  8. A compound having the structure of formula I according to claim 1, comprising:
    Figure PCTCN2019089027-APPB-100008
    Figure PCTCN2019089027-APPB-100009
    Figure PCTCN2019089027-APPB-100010
    Figure PCTCN2019089027-APPB-100011
    Figure PCTCN2019089027-APPB-100012
    Figure PCTCN2019089027-APPB-100013
    Figure PCTCN2019089027-APPB-100014
  9. a process for the preparation of a compound having the structure of formula I according to any one of claims 1 to 7, comprising:
    1) a method for preparing a compound having the structure of formula IA comprises the following steps:
    Figure PCTCN2019089027-APPB-100015
    s1: replacement of X in Compound IA-1-1 with R3To obtain compound IA-1-2;
    s2: reacting compound IA-1-2 with compound IA-a to obtain compound IA-1-3;
    s3: reacting compound IA-1-3 with compound IA-b to obtain compound IA-1-4;
    s4: reacting compound IA-1-4 with compound IA-c to obtain a compound having the structure of formula IA;
    wherein: x is chlorine, bromine or iodine; x4Is CH or CR7；X 1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R 1、R 2、R 3、R 4、R 5、R 6And R7A compound of formula IA as defined in claim 2; or
    The specific steps are as follows:
    Figure PCTCN2019089027-APPB-100016
    s1: by replacing X in compound IA-2-1 with R3To obtain compound IA-2-2;
    s2: reacting the compound 1A-2-2 with a compound IA-a to obtain a compound IA-2-3;
    s3: reacting the compound IA-2-3 with the compound IA-d to obtain a compound IA-2-4;
    s4: performing ring closing reaction on the compound IA-2-4 under the nitro reduction condition to obtain a compound IA-2-5;
    s5: reacting compound IA-2-5 with compound IA-c to obtain a compound having the structure of formula IA;
    wherein: x is chlorine, bromine or iodine; x1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 2、R 3、R 4、R 5And R6A compound of formula IA as defined in claim 2;
    2) the preparation method of the compound with the structure of the formula IB comprises the following specific steps:
    Figure PCTCN2019089027-APPB-100017
    s1: replacement of X in Compound IB-1-1 by R3To obtain a compound IB-1-2;
    s2: reacting the compound IB-1-2 with the compound IB-a to obtain a compound IB-1-3;
    s3: reacting the compound IB-1-3 with the compound IB-b to obtain a compound IB-1-4;
    s4: reacting the compound IB-1-4 with a compound IB-c to obtain a compound with a structure of a formula IB;
    wherein: x is chlorine, bromine or iodine; x4Is CH or CR7；X 1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 2、R 3、R 4、R 5、R 6And R7A compound of formula IB as defined in claim 3; or
    The specific steps are as follows:
    Figure PCTCN2019089027-APPB-100018
    s1: replacement of X in Compound IB-2-1 with R3To obtain a compound IB-2-2;
    s2: reacting the compound 1B-2-2 with a compound IB-a to obtain a compound IB-2-3;
    s3: reacting the compound IB-2-3 with a compound IB-d to obtain a compound IB-2-4;
    s4: performing ring closing reaction on the compound IB-2-4 under the nitro reduction condition to obtain a compound IB-2-5;
    s5: reacting the compound IB-2-5 with a compound IB-c to obtain a compound with a structure of a formula IB;
    wherein: x is chlorine, bromine or iodine; x1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 2、R 3、R 4、R 5And R6A compound of formula IB as defined in claim 3;
    3) the preparation method of the compound with the structure of formula IC comprises the following steps:
    Figure PCTCN2019089027-APPB-100019
    s1: replacement of X in Compound IC-1-1 by R3To obtain a compound IC-1-2;
    s2: reacting the compound IC-1-2 with the compound IC-a to obtain a compound IC-1-3;
    s3: reacting the compound IC-1-3 with the compound IC-b to obtain a compound IC-1-4;
    s4: reacting the compound IC-1-4 with a compound IC-c to obtain a compound with a formula IC structure;
    wherein: x is chlorine, bromine or iodine; x4Is CH or CR7；X 1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 5、R 6And R7A compound of formula IC as defined in claim 4; or
    The specific steps are as follows:
    Figure PCTCN2019089027-APPB-100020
    s1: replacement of X in Compound IC-2-1 by R3To obtain a compound IC-2-2;
    s2: reacting the compound 1C-2-2 with a compound IC-a to obtain a compound IC-2-3;
    s3: reacting the compound IC-2-3 with the compound IC-d to obtain a compound IC-2-4;
    s4: performing ring closing reaction on the compound IC-2-4 under the nitro reduction condition to obtain a compound IC-2-5;
    s5: reacting the compound IC-2-5 with a compound IC-c to obtain a compound with a formula IC structure;
    wherein: x is chlorine, bromine or iodine; x1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 5And R6A compound of formula IC as defined in claim 4; or
    The specific steps are as follows:
    Figure PCTCN2019089027-APPB-100021
    s1: replacement of X in Compound IC-3-1 by R3To obtain a compound IC-3-2;
    s2: reacting the compound 1C-3-2 with a compound IC-a to obtain a compound IC-3-3;
    s3: reacting the compound IC-3-3 with the compound IC-b to obtain a compound IC-3-4;
    s4: reacting the compound IC-3-4 with the compound IC-c to obtain a compound IC-3-5;
    s5: replacement of one of the hydrogen atoms of the amino group of Compound IC-3-5 by S (O)nR 7To obtain a compound with a structure of formula IC;
    wherein: x is chlorine, bromine or iodine; x 4Is CH or N; r6Is NH2；X 1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 5And R7A compound of formula IC as defined in claim 4; each n is independently 0, 1 or 2;
    4) the preparation method of the compound with the structure shown in the formula ID comprises the following specific steps:
    Figure PCTCN2019089027-APPB-100022
    s1: replacement of X in Compound ID-1-1 by R3To obtain compound ID-1-2;
    s2: under the action of the compound ID-a, the compound ID-1-2 undergoes a ring closure reaction to obtain a compound ID-1-3;
    s3: introduction of R into Compound ID-1-31To obtain compound ID-1-4;
    s4: reacting the compound ID-1-4 with the compound ID-b to obtain a compound ID-1-5;
    s5: reacting the compound ID-1-5 with the compound ID-c to obtain a compound ID-1-6;
    s6: reacting the compound ID-1-6 with the compound ID-d to obtain a compound ID;
    wherein: x is chlorine, bromine or iodine; x1、X 2、X 3、X 4、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 6And R7The process of claim 5 wherein said process is ID-basedDefined in the compound; or
    The specific steps are as follows:
    Figure PCTCN2019089027-APPB-100023
    s1: replacement of X in Compound ID-2-1 by R3To obtain compound ID-2-2;
    s2: reacting the compound ID-2-2 with the compound ID-e to obtain a compound ID-2-3;
    s3: reacting the compound ID-2-3 with the compound ID-f to obtain a compound ID-2-4;
    s4: reacting the compound ID-2-4 with a Lawson reagent and a compound ID-g to obtain a compound ID-2-5;
    s5: reacting the compound ID-2-5 with the compound ID-c to obtain a compound with a structure shown in a formula ID;
    wherein: x is chlorine, bromine or iodine; r is H, OH or R7；X 4Is CH or CR7；X 1、X 2、X 3、X 6、X 8、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 6And R7A compound of formula ID as defined in claim 5;
    5) the preparation method of the compound with the structure of the formula IE comprises the following specific steps:
    Figure PCTCN2019089027-APPB-100024
    s1: the compound IE-1-1 reacts with the compound IE-a to obtain a compound IE-1-2;
    s2: the compound IE-1-2 reacts with the compound IE-b to obtain a compound IE-1-3;
    s3: the compound IE-1-3 reacts with the compound IE-c to obtain a compound IE-1-4;
    s4: carrying out ammonolysis reaction on the compound IE-1-4 to obtain a compound IE-1-5;
    s5: replacement of X in Compound IE-1-5 by R3To obtain a compound IE-1-6;
    s6: reacting the compound IE-1-6 with the compound IE-d to obtain a compound IE;
    wherein: x is chlorine, bromine or iodine; r is alkyl; x1、X 2、X 3、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 5And R6A compound of formula IE as defined in claim 6; and
    6) the preparation method of the compound with the structure of the formula IF comprises the following specific steps:
    Figure PCTCN2019089027-APPB-100025
    s1: reacting the compound IF-1-1 with the compound IF-a to obtain a compound IF-1-2;
    s2: reacting the compound IF-1-2 with the compound IF-b to obtain a compound IF-1-3;
    s3: reacting the compound IF-1-3 with the compound IF-c to obtain a compound IF-1-4;
    s4: replacement of X in Compound IF-1-4 by R3To obtain a compound IE-1-5;
    s5: carrying out amino reaction on the compound IF-1-5 to obtain a compound IF-1-6;
    s6: reacting compound IF-1-6 with compound IF-d to obtain compound IF;
    wherein: x is chlorine, bromine or iodine; r is alkyl; x1、X 2、X 3、X 9、X 10、X 11、X 12、X 13And X14And R1、R 3、R 4、R 5And R6A compound of formula IF as defined in claim 7.
  10. A pharmaceutical composition comprising a compound having the structure of formula I according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion.
  11. A compound having the structure of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any ratio or a pharmaceutical composition according to claim 10 for use as a PI3K inhibitor.
  12. Use of a compound having the structure of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any ratio, or a pharmaceutical composition according to claim 10, as an inhibitor of PI 3K.
  13. Use of a compound having the structure of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any proportion, or a pharmaceutical composition according to claim 10, for the preparation of a medicament for the prevention and/or treatment of a disease which is mediated at least in part by PI 3K.
  14. A method for the prevention and/or treatment of a disease mediated at least in part by PI3K, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound having the structure of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion, or a pharmaceutical composition according to claim 10.
  15. A pharmaceutical combination comprising a compound having the structure of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any proportion, or a pharmaceutical composition according to claim 10 and at least one additional cancer therapeutic.
  16. A method for preventing and/or treating cancer, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound having the structure of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any proportion, or a pharmaceutical composition according to claim 10, and at least one additional cancer therapeutic.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118440001A (en) * 2024-04-30 2024-08-06 江苏海洋大学 Synthesis method of Du Weili siberian intermediate

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113620958A (en) 2014-03-19 2021-11-09 无限药品股份有限公司 Heterocyclic compounds for the treatment of PI 3K-gamma mediated disorders
CA2998469A1 (en) 2015-09-14 2017-03-23 Infinity Pharmaceuticals, Inc. Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same
WO2023051495A1 (en) * 2021-09-28 2023-04-06 中山医诺维申新药研发有限公司 Isoquinolinone and quinazolinone compounds, and composition and use thereof
CA3237199A1 (en) 2021-11-02 2023-05-11 Flare Therapeutics Inc. Pparg inverse agonists and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013154878A1 (en) * 2012-04-10 2013-10-17 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
WO2015051241A1 (en) * 2013-10-04 2015-04-09 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
CN105793255A (en) * 2013-10-04 2016-07-20 无限药品股份有限公司 Heterocyclic compounds and uses thereof
WO2018022992A1 (en) * 2016-07-29 2018-02-01 Flx Bio, Inc. Chemokine receptor modulators and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013154878A1 (en) * 2012-04-10 2013-10-17 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
WO2015051241A1 (en) * 2013-10-04 2015-04-09 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
CN105793255A (en) * 2013-10-04 2016-07-20 无限药品股份有限公司 Heterocyclic compounds and uses thereof
WO2018022992A1 (en) * 2016-07-29 2018-02-01 Flx Bio, Inc. Chemokine receptor modulators and uses thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118440001A (en) * 2024-04-30 2024-08-06 江苏海洋大学 Synthesis method of Du Weili siberian intermediate

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