CN112292374B - 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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CN112292374B
CN112292374B CN201980036339.8A CN201980036339A CN112292374B CN 112292374 B CN112292374 B CN 112292374B CN 201980036339 A CN201980036339 A CN 201980036339A CN 112292374 B CN112292374 B CN 112292374B
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CN112292374A (en
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张龙
宋国伟
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Innovent Biologics Suzhou Co Ltd
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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Abstract

The invention belongs to the field of medicinal chemistry, and discloses a novel phosphoinositide 3-kinase inhibitor, and a preparation method and application thereof. The phosphoinositide 3-kinase (PI 3K) inhibitor has a structure shown in a formula I, and has various pharmacological activities of resisting tumors, neurodegenerative diseases, 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 (PI 3K) inhibitor, a preparation method thereof, a pharmaceutical composition containing the same, and medical application thereof, in particular to application in preparing medicaments for preventing and/or treating diseases at least partially mediated by PI 3K.
Background
Phosphoinositide 3-kinases (PI 3 ks) are a large class of enzymes whose primary function is phosphorylation of the inositol ring of phosphoinositides. PI3 ks are divided into three classes (I, II and III) based on structural similarity, type of regulatory subunit and specificity of various phosphoinositide substrates (MaroneR, et al, biochim. Biophysis. Acta,2008 1784, with the most extensive studies on class I PI3 ks. All members of this class consist of a catalytic subunit and an associated regulatory component for catalyzing phosphorylation of phosphatidylinositol 4, 5-bisphosphate (PIP 2) 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 (baker jm., et al, nat. Cell. Biol., 2005. This type is further divided into two subgroups (IA and IB). Three subtypes, PI3K α, PI3K β, and PI3K γ, which are members of class IA, 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. Roles of these two kinases in many biological functions are enhanced by embryonic lethality observed in mice lacking either PI3K α or PI3K β. Due to their role in homeostasis, the 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 is different, 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.
PI3K γ subtypes are expressed in immune cells and have 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, 287, 1040-1046, hirsch E., et al, science, 2000. PI3K γ signaling is particularly important for myeloid cell function, downstream of G protein-coupled receptors (GPCRs), such as chemokine receptors, and RAS. Furthermore, 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 in which the PI3K γ gene is inactivated (Schmid m.c., et., cancer Cell,2011 19, 715-727, joshi S., et al, mol. Cancer res.,2014 12. 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. 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. 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 (WO 2017214269, WO2016054491, CN106456628, WO 2015051241). Therefore, from the existing data analysis, the development of a 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 regulating or inhibiting effects on PI3K activity, 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 GWB0000003434010000031
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 4 and R 6 Each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, hetero spiro, bridged, hetero bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (= O) (OR) 7 ) (ii) a And R is 1 、R 3 、R 4 And R 6 The hydrogen in (A) can optionally be replaced by 0 up to more than one R 7 Substitution;
X 0 is-CH 2 -、-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 13 And X 14 Each independently is CH, CR 7 Or N;
X 4 and X 8 Each independently is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -；
Or X 4 And X 5 Form a double bond therebetween, wherein: x 5 Is C, X 4 Is CH, CR 7 Or N;
R 0 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and when R is 0 When not hydrogen, R 0 Wherein hydrogen is optionally substituted with deuterium or halogen;
R 2 and R 5 Each independently is NH, NR 7 NOH, S or O;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, 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 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- (dimethylphosphinoyl) -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- (sulfamoylamino) 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- (sulfamoylamino) 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-carboxamide;
(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] diazaphosphophenantrenin-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-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-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-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-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-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-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 preparing 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 GWB0000003434010000091
s1: replacement of X in Compound IA-1-1 with R 3 To 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; x 4 Is CH or CR 7 ；X 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R 7 As defined in the following compounds of formula IA; or
The specific steps are as follows:
Figure GWB0000003434010000092
s1: by replacing X in compound IA-2-1 with R 3 To 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 provide a compound having the structure of formula IA;
wherein: x is chlorine, bromine or iodine; x 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 2 、R 3 、R 4 、R 5 And R 6 Is shown in the following formulaA compound of formula IA;
2) The preparation method of the compound with the structure of the formula IB comprises the following specific steps:
Figure GWB0000003434010000101
s1: replacement of X in Compound IB-1-1 with R 3 To 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; x 4 Is CH or CR 7 ；X 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R 7 As defined in compounds of formula IB below; or
The specific steps are as follows:
Figure GWB0000003434010000102
s1: replacement of X in Compound IB-2-1 with R 3 To 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 the 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; x 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 2 、R 3 、R 4 、R 5 And R 6 As 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 GWB0000003434010000111
s1: replacement of X in Compound IC-1-1 by R 3 To 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; x 4 Is CH or CR 7 ；X 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 5 、R 6 And R 7 As defined in the following formula IC compounds; or alternatively
The specific steps are as follows:
Figure GWB0000003434010000112
s1: replacement of X in Compound IC-2-1 by R 3 To 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; x 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 5 And R 6 As defined in the following formula IC compounds; or
The specific steps are as follows:
Figure GWB0000003434010000121
s1: replacement of X in Compound IC-3-1 by R 3 To 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 hydrogen atom of the amino group in the Compound IC-3-5 by S (O) n R 7 To obtain a compound having the structure of formula IC;
wherein: x is chlorine, bromine or iodine; x 4 Is CH or N; r 6 Is NH 2 ；X 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 5 And R 7 As 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 of the formula ID comprises the following specific steps:
Figure GWB0000003434010000122
s1: replacement of X in Compound ID-1-1 by R 3 To 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-1-3 1 To 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; x 1 、X 2 、X 3 、X 4 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 6 And R 7 As defined in the following formula ID compounds; or
The specific steps are as follows:
Figure GWB0000003434010000131
s1: replacement of X in Compound ID-2-1 with R 3 To 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 R 7 ；X 4 Is CH or CR 7 ；X 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 6 And R 7 As 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 GWB0000003434010000132
s1: reacting the compound IE-1-1 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 R 3 To 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; x 1 、X 2 、X 3 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 5 And R 6 As 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 GWB0000003434010000141
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 R 3 To 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; x 1 、X 2 、X 3 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 5 And R 6 As 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 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, for use as a PI3K inhibitor.
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 preparation of a medicament for the prevention and/or treatment of diseases 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, those formed by the reaction of a compound of the invention with a pharmaceutically acceptable inorganic/organic acid or inorganic/organic base, also known as acid 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, and 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 spatial 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. Due to the presence of asymmetric centers and other chemical structures in the compounds of the present invention that may lead to stereoisomers, these stereoisomers and mixtures thereof are also encompassed by the present invention. Since the compounds of the present invention and their salts include 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 a mixture of enantiomeric products followed by separation or resolution, e.g., conversion to a mixture of diastereomers followed by separation or recrystallization, chromatography, use of chiral resolving agents, or direct separation of the enantiomers on a chiral column. 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. Included among the compounds of the present invention, unless otherwise indicated, are H, C, N, O, F, P, SVarious isotopes of Cl, e.g. 2 H(D)、 3 H(T)、 13 C、 14 C、 15 N、 17 O、 18 O、 18 F、 31 P、 32 P、 35 S、 36 S and 37 Cl。
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 that increase the bioavailability of the compounds of the invention when administered to a patient (e.g., 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 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 via a single bond to the phosphorus atom 2 ). 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 (- = O) (Alk) groups 2 E.g. dimethylphosphoryl), diarylphosphoryl (- = O) (Ar) 2 E.g. diphenylphosphinyl), alkylarylphosphinityl (-P (= O) (Alk) (Ar), e.g. methylphenylphosphinityl), diphosphorylAlkoxy phosphoryl (- = O) (OAlk) 2 Such 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) via a single bond to the phosphorus atom 2 )。
The term "alkyl" refers to a monovalent straight or branched alkane group consisting of carbon and hydrogen atoms, containing no unsaturation, and connected to the parent nucleus by a single bond, preferably C 1 -C 6 Alkyl, more preferably C 1 -C 4 An alkyl group; common alkyl groups include, but are not limited to, methyl (-CH) 3 ) Ethyl (-CH) 2 CH 3 ) N-propyl (-CH) 2 CH 2 CH 3 ) Isopropyl group (-CH (CH)) 3 ) 2 ) N-butyl (-CH) 2 CH 2 CH 2 CH 3 ) Sec-butyl (-CH (CH) 3 )CH 2 CH 3 ) Isobutyl (-CH) 2 CH(CH 3 ) 2 ) T-butyl (-C (CH)) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) Neopentyl (-CH) 2 C(CH 3 ) 3 ) And so on.
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 C 2 -C 6 An 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 so on.
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 C 2 -C 6 An alkynyl group; common alkynesGroups 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 GWB0000003434010000171
Pentyn-1-yl
Figure GWB0000003434010000172
Figure GWB0000003434010000172
1, 3-diacetylene-1-yl (-C.ident.C-C.ident.CH), 1, 4-pentadiyne-1-yl
Figure GWB0000003434010000173
And so on.
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 C 1 -C 4 An alkoxy group; common alkoxy groups include, but are not limited to, methoxy (-OCH) 3 ) Ethoxy (-OCH) 2 CH 3 ) N-propoxy group (-OCH) 2 CH 2 CH 3 ) I-propoxy (-OCH (CH) 3 ) 2 ) N-butoxy (-OCH) 2 CH 2 CH 2 CH 3 ) Sec-butoxy (-OCH (CH) 3 )CH 2 CH 3 ) Isobutoxy (-OCH) 2 CH(CH 3 ) 2 ) T-butoxy (-OC (CH)) 3 ) 3 ) N-pentyloxy (-OCH) 2 CH 2 CH 2 CH 2 CH 3 ) Neopentyloxy (-OCH) 2 C(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 C 1 -C 4 An alkyl acyl group; common alkylacyl groups include, but are not limited to, formyl (-C (= O) H), acetyl (-C (= O) CH 3 ) N-propionyl group (- = O) CH 2 CH 3 ) N-butyryl group (- = O) CH 2 CH 2 CH 3 )、Isobutyryl (-C (= O) CH (CH) 3 ) 2 ) N-pentanoyl (-C (= O) CH 2 CH 2 CH 2 CH 3 ) Pivaloyl (- = 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 C 1 -C 4 An alkylamido group; common alkylamido groups include, but are not limited to, formylamino (-NHC (= O) H), acetamido (-NHC (= O) CH 3 ) N-propionylamino (-NHC (= O) CH 2 CH 3 ) N-butylamido (-NHC (= O) CH 2 CH 2 CH 3 ) Isobutyramido (-NHC (= O) CH (CH) 3 ) 2 ) N-valerylamino (- = O) CH 2 CH 2 CH 2 CH 3 ) Pivaloylamido (- = 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 C 1 -C 4 An alkyl acyloxy group; common alkylacyloxy groups include, but are not limited to, formyloxy (-OC (= O) H), acetyloxy (-OC (= O) CH 3 ) N-propionyloxy (-OC (= O) CH 2 CH 3 ) N-butyryloxy (-OC (= O) CH 2 CH 2 CH 3 ) Isobutyryloxy (-OC (= O) CH (CH) 3 ) 2 ) N-valeryloxy (-OC (= O) CH 2 CH 2 CH 2 CH 3 ) Pivaloyloxy (-OC (= O) C (CH) 3 ) 3 ) And the like.
The term "alkoxycarbonyl" 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 C 1 -C 4 An alkoxycarbonyl group; common alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl (-C (= O) OCH 3 ) Ethoxycarbonyl (-C (= O) OCH 2 CH 3 ) N-propoxycarbonyl (- = O) OCH 2 CH 2 CH 3 ) Isopropyloxycarbonyl (- = O) OCH (CH) 3 ) 2 ) N-butoxycarbonyl (-C (= O) OCH 2 CH 2 CH 2 CH 3 ) T-butyloxycarbonyl (- = O) OC (CH) 3 ) 3 ) And so on.
The term "cycloalkyl" refers to a monovalent monocyclic, non-aromatic ring system consisting only of carbon and hydrogen atoms, containing no unsaturation, and linked 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 of two monocycles sharing a common carbon atom, consisting of carbon and hydrogen atoms only, containing no unsaturation, and linked 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 "heterospiroyl" refers to a monovalent non-aromatic ring system of two monocycles sharing a single carbon atom, consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing no unsaturation, and 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 [2.2.1.0 2.6 ]Heptane-1-yl, 1-adamantyl, and the like.
The term "heterobridged ring radical" refers to a monovalent, non-aromatic ring system of any two monocyclic rings that share two carbon atoms not directly connected, that is composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus, that does not contain unsaturation, and that is 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 alkyl radical consisting only of carbon and hydrogen atoms, containing at least one aryl group, and linked to the parent nucleus by a single bond, preferably C 6 -C 10 aryl-C 1 -C 6 Alkyl, more preferably C 6 -C 10 aryl-C 1 -C 4 An 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 only of carbon and hydrogen atoms, containing at least one double bond and at least one aryl group, and connected by a single bondTo the mother nucleus, preferably C 6 -C 10 aryl-C 2 -C 6 An 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) 2 Ph), 2-phenyl-1-propen-1-yl (-CH = CPh-CH) 3 ) 4-phenyl-1, 3-butadien-1-yl (-CH = CH-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-chain or branched alkyne group consisting only of 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 C 6 -C 10 aryl-C 2 -C 6 An alkynyl group; common arylalkynyl groups include, but are not limited to, phenylethynyl (-C ≡ CPh), 3-phenyl-1-propyn-1-yl (-C ≡ C-CH) 2 Ph), 3-diphenyl-1-propyn-1-yl (-C.ident.C-CHPh) 2 ) 4-phenyl-1, 3-diacetylene-1-yl (-C.ident.C-C.ident.CPh), and the like.
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-C 1 -C 6 Alkyl, more preferably 5-10 membered heteroaryl-C 1 -C 4 An 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 linear or branched alkene radical 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-C 2 -C 6 An 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-chain or branched 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-C 2 -C 6 Alkynyl; 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) by a single bond 2 ). The term "alkylureido" refers to a monovalent group formed after the alkyl group has replaced a hydrogen atom in the ureido group (the site of replacement is typically on the nitrogen atom in another amino group) and is attached to the parent nucleus (-NHC (= O) NHAlk or-NHC (= O) NAlk) by a single bond 2 )。
The term "pentafluoro- λ 6 -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 bond 5 )。
[ Compound of the formula ]
The present invention provides a compound of formula I:
Figure GWB0000003434010000191
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 4 and R 6 Each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, hetero spiro, bridged, hetero bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (= O) (OR) 7 ) (ii) a And R is 1 、R 3 、R 4 And R 6 The hydrogen in (A) can optionally be replaced by 0 up to more than one R 7 Substitution;
X 0 is-CH 2 -、-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 13 And X 14 Each independently is CH, CR 7 Or N;
X 4 and X 8 Each independently is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -；
Or X 4 And X 5 Form a double bond therebetween, wherein: x 5 Is C, X 4 Is CH, CR 7 Or N;
R 0 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and when R is 0 When not hydrogen, R 0 Wherein hydrogen is optionally substituted with deuterium or halogen;
R 2 and R 5 Each independently is NH, NR 7 NOH, S or O;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, 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 GWB0000003434010000192
wherein:
R 1 、R 3 、R 4 and R 6 Each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, hetero spiro, bridged, hetero bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (= O) (OR) 7 ) (ii) a And R is 1 、R 3 、R 4 And R 6 The hydrogen in (1) may optionally be replaced by 0 to more than one R 7 Substitution;
X 1 、X 2 、X 3 、X 4 、X 6 、X 9 、X 10 、X 11 、X 12 、X 13 and X 14 Each independently is CH, CR 7 Or N;
X 8 is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -；
R 2 And R 5 Each independently is NH, NR 7 NOH, S or O;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, 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 GWB0000003434010000201
wherein:
R 0 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and when R is 0 When not hydrogen, R 0 Wherein hydrogen is optionally substituted with deuterium or halogen;
R 1 、R 3 、R 4 and R 6 Each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, hetero spiro, bridged, hetero bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (= O) (OR) 7 ) (ii) a And R is 1 、R 3 、R 4 And R 6 The hydrogen in (1) may optionally be replaced by 0 to more than one R 7 Substitution;
X 1 、X 2 、X 3 、X 4 、X 6 、X 9 、X 10 、X 11 、X 12 、X 13 and X 14 Each independently is CH, CR 7 Or N;
X 8 is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -；
R 2 And R 5 Each independently is NH, NR 7 NOH, S or O;
each R 7 Each independently is deuterium, halogen, alkyl, heteroalkylAlkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro-cyclic, hetero-spiro-cyclic, bridged cyclic, hetero-bridged cyclic, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0,1 or 2.
In some preferred embodiments of the present invention, the compound of formula I above is a compound of formula IC:
Figure GWB0000003434010000211
wherein:
R 1 、R 3 、R 4 and R 6 Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (= O) (OR) 7 ) (ii) a And R is 1 、R 3 、R 4 And R 6 The hydrogen in (A) can optionally be replaced by 0 up to more than one R 7 Substitution;
X 1 、X 2 、X 3 、X 4 、X 6 、X 9 、X 10 、X 11 、X 12 、X 13 and X 14 Each independently is CH, CR 7 Or N;
X 8 is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -；
R 2 Is NH, NR 7 NOH, S or O;
R 5 NH, NR, NOH or S;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, 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 GWB0000003434010000212
wherein:
R 3 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Phosphoryl or substituted or unsubstituted phosphoryl hypo; and R is 3 Optionally substituted by at least one R 7 Substitution;
R 1 、R 4 and R 6 Each is independentAnd is independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (= O) (OR) 7 ) (ii) a And R is 1 、R 4 And R 6 The hydrogen in (1) may optionally be replaced by 0 to more than one R 7 And (3) substitution:
X 1 、X 2 、X 3 、X 4 、X 6 、X 7 、X 9 、X 10 、X 11 、X 12 、X 13 and X 14 Each independently is CH, CR 7 Or N; or X 7 And R 4 May form a 3-6 membered ring;
X 8 is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -；
R 2 Optionally independently NH, NR 7 NOH, S or O;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;
each n is independently 0,1 or 2;
if and only if X 6 Is N, X 7 Is CH, X 8 is-NH-or-NR 7 -, and R 2 When is O, R 1 And R 3 At least one group selected from spiro ring group, hetero-spiro ring group, bridged ring group, hetero-bridged ring group, - (CH) 2 ) n SF 5 Substituted or unsubstituted phosphoryl, SF 5 Substituted 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 GWB0000003434010000221
wherein:
R 1 、R 3 、R 4 and R 6 Each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, hetero spiro, bridged, hetero bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (= O) (OR) 7 ) (ii) a And R is 1 、R 3 、R 4 And R 6 The hydrogen in (1) may optionally be replaced by 0 to more than one R 7 Substitution;
X 0 is-CH 2 -、-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 13 And X 14 Each independently is CH, CR 7 Or N;
X 8 is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -；
R 0 Is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, hetero spiro, bridged, hetero bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and when R is 0 When not hydrogen, R 0 Hydrogen in (a) is optionally substituted with deuterium or halogen;
R 2 and R 5 Each independently is NH, NR 7 NOH, S or O;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, 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 GWB0000003434010000231
wherein:
R 1 、R 3 、R 4 and R 6 Each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, hetero spiro, bridged, hetero bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (= O) (OR) 7 ) (ii) a And R is 1 、R 3 、R 4 And R 6 The hydrogen in (A) can optionally be replaced by 0 up to more than one R 7 Substitution;
X 1 、X 2 、X 3 、X 5 、X 6 、X 9 、X 10 、X 11 、X 12 、X 13 and X 14 Each independently is CH, CR 7 Or N;
X 4 and X 8 Each independently is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -；
R 2 And R 5 Each independently is NH, NR 7 NOH, S or O;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfinylAmino, 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 1 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, or heterocyclyloxy, preferably hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, more preferably aryl or heteroaryl;
R 3 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted 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 4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;
R 6 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycleA group, spiro ring group, hetero-spiro ring group, bridged ring group, hetero-bridged ring group, aryl group, arylalkyl group, arylalkenyl group, arylalkynyl group, heteroaryl group, heteroarylalkyl group, heteroarylalkenyl group, heteroarylalkynyl group, alkoxy group, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR 7 Amino group, -NHS (= O) R 7 Spiro-, hetero-spiro-, bridged-or hetero-bridged ring group, more preferably amino group or-NHS (= O) R 7 ；
And R is 1 、R 3 、R 4 And R 6 The hydrogen in (1) may optionally be replaced by 0 to more than one R 7 Substitution;
X 1 、X 2 、X 3 and X 4 Each independently is CH, CR 7 Or N, preferably CH or CR 7 More preferably CH;
X 6 is N;
X 9 、X 10 、X 11 、X 12 、X 13 and X 14 Each independently is CH, CR 7 Or N, preferably X 9 、X 13 、X 14 Is N, more preferably X 9 、X 13 And X 14 And is N at the same time;
X 8 is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -, preferably-NH-or-NR 7 -；
R 2 And R 5 Each independently is NH, NR 7 NOH, S or O;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, 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 IB above:
R 0 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, heteroaryl or heteroarylalkyl, and when R is 0 When not hydrogen, R 0 Wherein hydrogen 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 1 is 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 3 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, preferably hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkenyl, arylalkyneA group, 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 4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;
R 6 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR 7 Amino group, -NHS (= O) R 7 Spiro-, hetero-spiro-, bridged-or hetero-bridged ring group, more preferably amino or-NHS (= O) R 7 ；
And R is 1 、R 3 、R 4 And R 6 The hydrogen in (1) may optionally be replaced by 0 to more than one R 7 Substitution;
X 1 、X 2 、X 3 and X 4 Each independently is CH, CR 7 Or N, preferably CH or CR 7 More preferably CH;
X 6 is N;
X 9 、X 10 、X 11 、X 12 、X 13 and X 14 Each independently is CH, CR 7 Or N, preferably X 9 、X 13 、X 14 Is N, more preferably X 9 、X 13 And X 14 And is N at the same time;
X 8 is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -, preferably-NH-or-NR 7 -；
R 2 And R 5 Each independently is NH, NR 7 NOH, S or O;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, 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 1 is 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 3 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido radicals, preferably hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroCyclyl, bridged cyclyl, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, more preferably alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged cyclyl, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, phosphoryl or substituted or unsubstituted hypophosphoryl;
R 4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;
R 6 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR 7 Amino group, -NHS (= O) R 7 Spiro-, hetero-spiro-, bridged-or hetero-bridged ring group, more preferably amino group or-NHS (= O) R 7 ；
And R is 1 、R 3 、R 4 And R 6 The hydrogen in (A) can optionally be replaced by 0 up to more than one R 7 Substitution;
X 1 、X 2 、X 3 and X 4 Each independently is CH, CR 7 Or N, preferably CH or CR 7 More preferably CH;
X 6 is N;
X 9 、X 10 、X 11 、X 12 、X 13 and X 14 Each independently is CH, CR 7 Or N, preferably X 9 、X 13 、X 14 Is N, more preferably X 9 、X 13 And X 14 And is N at the same time;
X 8 is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -, preferably-NH-or-NR 7 -；
R 2 Is NH, NR 7 NOH, S or O;
R 5 is NH, NR 7 NOH or S;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, 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 3 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, or- (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Phosphoryl or substituted or unsubstituted phosphoryl hypo;
R 1 is 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 4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;
R 6 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, -NHCOR 7 Ammonia, ammoniaRadical, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR 7 Amino group, -NHS (= O) R 7 Spiro, hetero spiro, bridged or hetero bridged ring, more preferably hydrogen, alkyl, -NHCOR 7 Amino or-NHS (= O) R 7 ；
And R is 1 、R 3 、R 4 And R 6 The hydrogen in (1) may optionally be replaced by 0 to more than one R 7 Substitution;
X 1 、X 2 、X 3 and X 4 Each independently is CH, CR 7 Or N, preferably CH or CR 7 More preferably CH;
X 6 is N;
X 7 is CH, CR 7 Or N; or X 7 And R 4 May form a 3-6 membered ring;
X 9 、X 10 、X 11 、X 12 、X 13 and X 14 Each independently is CH, CR 7 Or N, preferably X 9 、X 13 、X 14 Is N, more preferably X 9 、X 13 And X 14 And is N at the same time;
X 8 is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -, preferably-CH 2 -、-CHR 7 -, -NH-or-NR 7 -；
R 2 Is NH, NR 7 NOH, S or O;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, alkylamidoA group, 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 3 is spiro ring group, bridged ring group, hetero spiro ring group, hetero bridged ring group, -SF 5 Phosphoryl or substituted or unsubstituted phosphoryl hypo; and R is 3 The hydrogen in (1) may optionally be replaced by 0 to more than one R 7 Substitution;
R 1 、R 4 and R 6 Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (= O) (OR) 7 ) (ii) a And R is 1 、R 4 And R 6 The hydrogen in (A) can optionally be replaced by 0 up to more than one R 7 Substitution;
X 1 、X 2 、X 3 、X 4 、X 6 、X 7 、X 9 、X 10 、X 11 、X 12 、X 13 and X 14 Each independently is CH, CR 7 Or N; or X 7 And R 4 May form a 3-6 membered ring;
X 8 is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -；
R 2 Is NH, NR 7 NOH, S or O;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, 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 3 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, spiro, hetero-spiro, bridged, hetero-bridged, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Phosphoryl or substituted or unsubstituted phosphoryl hypo; and when R is 3 When not hydrogen, R 3 The hydrogen in (1) may optionally be replaced by 0 to more than one R 7 Substitution;
R 1 is spiro ring group, hetero spiro ring group, bridged ring group, hetero bridged ring group, aryl or heteroaryl; and R is 1 The hydrogen in (1) may optionally be replaced by 0 to more than one R 7 Substitution;
R 4 and R 6 Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (= O) (OR) 7 ) (ii) a And R is 4 And R 6 The hydrogen in (1) may optionally be replaced by 0 to more than one R 7 Substitution;
X 1 、X 2 、X 3 、X 4 、X 6 、X 7 、X 9 、X 10 、X 11 、X 12 、X 13 and X 14 Each independently is CH, CR 7 Or N; or X 7 And R 4 May form a 3-6 membered ring;
X 8 is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -；
R 2 Is NH, NR 7 NOH, S or O;
each R 7 Each independently deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, hetero spiro, bridged, hetero bridged, aryl (including substituted aryl, such as phenyl substituted with thio pentafluoride, dimethylphosphinyl, or phosphoryl), arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, 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 3 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, spiro, hetero-spiro, bridged, hetero-bridged, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Phosphoryl or substituted or unsubstituted hypophosphoryl(ii) a And R is 3 The hydrogen in (A) can optionally be replaced by 0 up to more than one R 7 Substitution;
R 1 、R 4 and R 6 Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (= O) (OR) 7 ) (ii) a And R is 1 、R 4 And R 6 The hydrogen in (1) may optionally be replaced by 0 to more than one R 7 Substitution;
X 1 、X 2 、X 3 、X 4 、X 6 、X 7 、X 9 、X 10 、X 11 、X 12 、X 13 and X 14 Each independently is CH, CR 7 Or N; or X 7 And R 4 May form a 3-6 membered ring;
X 8 is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -or-C (= R) 2 )-；
R 2 Is NH, NR 7 NOH, S or O;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, alkylamidoAmino, 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 3 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, spiro, hetero-spiro, bridged, hetero-bridged, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Phosphoryl or substituted or unsubstituted phosphoryl hypo; and R is 3 Optionally substituted by 0 to multiple R 7 Substitution;
R 1 、R 4 and R 6 Each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, hetero spiro, bridged, hetero bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (= O) (OR) 7 ) (ii) a And R is 1 、R 4 And R 6 The hydrogen in (1) may optionally be replaced by 0 to more than one R 7 Substitution;
X 1 、X 2 、X 3 、X 4 、X 6 、X 9 、X 10 、X 11 、X 12 、X 13 and X 14 Each independently is CH, CR 7 Or N;
X 7 is CR 7 Or N; or X 7 And R 4 May form a 3-6 membered ring;
X 8 for the purpose ofCH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -；
R 2 Is NH, NR 7 NOH, S or O;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, 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 1 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, or heterocyclyloxy, preferably hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, more preferably aryl or heteroaryl;
R 3 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted 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 4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;
R 6 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR 7 Amino group, -NHS (= O) R 7 Spiro-, hetero-spiro-, bridged-or hetero-bridged ring groups, more preferably hydrogen, alkyl, -NHCOR 7 Amino or-NHS (= O) R 7 ；
And R is 1 、R 3 、R 4 And R 6 The hydrogen in (A) can optionally be replaced by 0 up to more than one R 7 Substitution;
X 0 is-CH 2 -、-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 2 And X 3 Each independently is CH, CR 7 Or N, preferably CH or CR 7 More preferably CH;
X 5 and X 6 Each independently is CH, CR 7 Or N, preferably CH or N;
X 9 、X 10 、X 11 、X 12 、X 13 and X 14 Each independently is CH, CR 7 Or N, preferably X 9 、X 13 、X 14 Is N, more preferably X 9 、X 13 And X 14 And is N at the same time;
X 8 is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -, preferably-NH-or-NR 7 -；
R 0 Is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, hetero spiro, bridged, hetero bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and when R is 0 When not hydrogen, R 0 Wherein hydrogen is optionally substituted with deuterium or halogen;
R 2 and R 5 Each independently is NH, NR 7 NOH, S or O;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, 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 1 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, or heterocyclyloxy, preferably hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocycloalkyl, heterocyclyloxy, or mixtures thereof,Heterocyclyl, spiro-cyclic, bridged cyclic, aryl, arylalkyl, heteroaryl or heteroarylalkyl, more preferably aryl or heteroaryl;
R 3 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) 2 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxy, nitro, -SO 2 R 7 、-NHSO 2 R 7 、-OP(＝O)(OR 7 ) 2 Substituted or unsubstituted phosphinate, phosphoryl, or alkylureido groups, preferably hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, substituted or unsubstituted phosphinate, phosphoryl, or alkylureido groups, more preferably alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, phosphoryl, or substituted or unsubstituted phosphinate;
R 4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;
R 6 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, -NHCOR 7 Amino group, -COR 7 、-OCOR 7 Alkoxycarbonyl, -NHS (= O) R 7 Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR 7 Amino group, -NHS (= O) R 7 Spiro-, hetero-spiro-, bridged-or hetero-bridged ring groups, more preferably hydrogen, alkyl, -NHCOR 7 Amino group or-NHS (= O))R 7 ；
And R is 1 、R 3 、R 4 And R 6 The hydrogen in (A) can optionally be replaced by 0 up to more than one R 7 Substitution;
X 1 、X 2 and X 3 Each independently is CH, CR 7 Or N, preferably CH or CR 7 More preferably CH;
X 5 and X 6 Each independently is CH, CR 7 Or N, preferably CH or N, more preferably N;
X 9 、X 10 、X 11 、X 12 、X 13 and X 14 Each independently is CH, CR 7 Or N, preferably X 9 、X 13 、X 14 Is N, more preferably X 9 、X 13 And X 14 And is N at the same time;
X 4 is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -, preferably-CH 2 -or-CHR 7 -；
X 8 is-CH 2 -、-CHR 7 -、-C(R 7 ) 2 -、-C(＝R 2 ) -, -NH-or-NR 7 -, preferably-NH-or-NR 7 -；
R 2 And R 5 Each independently is NH, NR 7 NOH, S or O;
each R 7 Each 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 ) n SF 5 、-(CH 2 ) n NHSO 2 NH 2 Heterocyclyloxy, alkylamido, 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, and the specific structure and the name of the compound are shown in the following table:
Figure GWB0000003434010000291
Figure GWB0000003434010000301
Figure GWB0000003434010000311
Figure GWB0000003434010000321
Figure GWB0000003434010000331
Figure GWB0000003434010000341
Figure GWB0000003434010000351
Figure GWB0000003434010000361
Figure GWB0000003434010000371
Figure GWB0000003434010000381
Figure GWB0000003434010000391
Figure GWB0000003434010000401
Figure GWB0000003434010000411
Figure GWB0000003434010000421
Figure GWB0000003434010000431
Figure GWB0000003434010000441
Figure GWB0000003434010000451
[ 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 GWB0000003434010000461
s1: replacement of X in Compound IA-1-1 with R 3 (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; x 4 Is CH or CR 7 ；X 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R 7 As defined above for compounds of formula IA (preferably X) 4 Is CH, X 6 Is N, X 8 is-NH-); or
The method comprises the following specific steps:
Figure GWB0000003434010000462
s1: replacement of X in Compound IA-2-1 with R 3 (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; x 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 AndR 1 、R 2 、R 3 、R 4 、R 5 and R 6 As defined above for compounds of formula IA (preferably X) 6 Is N, X 8 is-NH-);
2) The preparation method of the compound shown in the formula IB comprises the following specific steps:
Figure GWB0000003434010000471
s1: replacement of X in Compound IB-1-1 with R 3 (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; x 4 Is CH or CR 7 ；X 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R 7 As defined above for compounds of formula IB (preferably X) 4 Is CH, X 6 Is N, X 8 is-NH-); or alternatively
The method comprises the following specific steps:
Figure GWB0000003434010000472
s1: replacement of X in Compound IB-2-1 with R 3 (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: reacting compound IB-2-3 with compound IB-d (preferably by condensation reaction) to give compound IB-2-4;
s4: and (3) performing ring closing reaction on the compound IB-2-4 under the nitro reduction condition (preferably 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; x 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 2 、R 3 、R 4 、R 5 And R 6 As defined above for compounds of formula IB (preferably X) 6 Is N, X 8 is-NH-);
3) The preparation method of the compound of the formula IC comprises the following specific steps:
Figure GWB0000003434010000481
s1: replacement of X in Compound IC-1-1 by R 3 (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; x 4 Is CH or CR 7 ；X 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 5 、R 6 And R 7 As defined above for compounds of formula IC (preferably X) 6 Is N, X 8 is-NH-); or
The specific steps are as follows:
Figure GWB0000003434010000482
s1: replacement of X in Compound IC-2-1 by R 3 (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: and (3) 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; x 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 5 And R 6 As defined above for compounds of formula IC (preferably X) 6 Is N, X 8 is-NH-); or
The specific steps are as follows:
Figure GWB0000003434010000491
s1: replacement of X in Compound IC-3-1 by R 3 (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 hydrogen atom of the amino group in the Compound IC-3-5 by S (O) n R 7 (preferably by sulfonylation) to give a compound having the structure of formula IC;
wherein: x is chlorine, bromine or iodine; x 4 Is CH or N; r 6 Is NH 2 ；X 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 5 And R 7 As defined in the following formula IC compound (preferably X) 6 Is N, X 8 is-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 GWB0000003434010000492
s1: replacement of X in Compound ID-1-1 by R 3 (preferably by coupling or substitution) to give compound ID-1-2;
s2: under the action of compound ID-a (preferably sodium methoxide/methanol), the compound ID-1-2 undergoes a ring closure reaction to obtain a compound ID-1-3:
s3: introduction of R into Compound ID-1-3 1 (preferably by substitution) to give compound ID-1-4;
s4: reaction of compound ID-1-4 with compound ID-b, preferably by substitution, 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: reacting compound ID-1-6 with compound ID-d (preferably by substitution) to give compound ID;
wherein: x is chlorine, bromine or iodine; x 1 、X 2 、X 3 、X 4 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 6 And R 7 As defined above for compounds of formula ID (preferably X) 4 Is CH); or
The specific steps are as follows:
Figure GWB0000003434010000501
s1: replacement of X in Compound ID-2-1 by R 3 (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: reacting compound ID-2-5 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 R 7 ；X 4 Is CH or CR 7 ；X 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 6 And R 7 As defined above for compounds of formula ID (preferably X) 6 Is N, X 8 is-NH-);
5) The preparation method of the compound with the structure of the formula IE comprises the following specific steps:
Figure GWB0000003434010000502
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 R 3 (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; x 1 、X 2 、X 3 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 5 And R 6 As 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 GWB0000003434010000511
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 (TI) 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 R 3 (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; x 1 、X 2 、X 3 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 5 And R 6 As 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), stele 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 a PI3K inhibitor. 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 a mixture thereof in any proportion, or a pharmaceutical composition as described above, as a PI3K inhibitor.
In addition, the application also provides the application of the compound of the formula I or the pharmaceutically acceptable salt, the solvate, the hydrate, the stereoisomer, the tautomer, the isotopic marker, the prodrug or the mixture of the prodrug in any proportion or the pharmaceutical composition in the preparation of medicines for preventing and/or treating diseases at least partially mediated 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 the 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.
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, oesophageal, 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-purines (e.g., pentostatin, etc.), anti-pyrimidines (e.g., fluorouracil), antifolates (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-pro-drug (e.g., asparaginase), interfering tubulin forming agents (e.g., paclitaxel), interfering ribosomal 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 GWB0000003434010000531
The synthesis steps are as follows:
s1: to compound 3-1 (50g, 0.29mol) and DMF (0.5 mL) in CH at room temperature 2 Cl 2 To a stirred solution in (250 mL) was added oxalyl chloride (27.4 mL, 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 CH 2 Cl 2 (250 mL) solution was added intermediate 3-2 (54g, 0.29mol) in CH 2 Cl 2 Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100 mL) was added. The organic layer was separated and washed with brine, na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, rinsed with petroleum ether (500 mL), and further dried in vacuo to give intermediate 3-4 (70g, 95% yield) as a yellow solid. LC-MS:246 2[ M ] +1] + 。
S3: a solution of intermediate 3-4 (30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250 mL) was cooled to-78C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added to it, 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, tert-butyl (S) - (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (Compound 3-5) (36.9 g, 0.16mol)) Anhydrous tetrahydrofuran (100 mL). A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was added slowly at-78C. The reaction mixture was stirred at the same temperature for 30 minutes and then added to the above reaction mixture. Stir at-78C for 1 hour. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. Intermediates 3-6 (70 g crude) were used in the next reaction without further purification. LC-MS:417[ 2] M +1] + 。
S4: to a solution of intermediate 3-6 (70g, 168mmol) in MeOH (360 mL) 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 (1000 mL) and extracted with ethyl acetate (200 mL. Times.2). Then using K 2 CO 3 Basified the aqueous layer and precipitate formed. The solid was collected by filtration and dried to give intermediate 3-7 (20g, 40% yield). LC-MS:299 2[ C ], [ M ] +1] + 。
S5: to a solution of intermediate 3-7 (3.0 g,10 mmol) in EtOH (100 mL) was added saturated aqueous NaHCO 3. NaHCO at room temperature 3 (10 mL) and Boc 2 O (2.2g, 10mmol). 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 (20 mL) were added compound 3-9 (207mg, 2.65mmol), xantphos (69mg, 0.12mmol) and K 3 PO 4 (414mg, 2.0mmol). By vacuum/then N 2 The 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 H 2 And (4) diluting with O. 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 (270 mg, yield 36%) as a yellow solid. LC-MS:441[ M ] +1] + 。
S7: to a solution of intermediate 3-10 (270mg, 0.62mmol) in dioxane (10 mL) 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 2[ M ] +1] + 。
S8: to intermediate 3-11 (200mg, 0.53mmol) and compound 3-12 (146mg, 0.53mmol) in CH 3 DIPEA (0.18mL, 1.06mmol) was added to the mixture in CN (10 mL). 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[ 2], [ M ] +1] + 。 1 H-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 and the other operations were unchanged to give compound 1.LC-MS:501[ 2], [ 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[ 2], [ M ] +1] + 。
Example 4: synthesis of Compound 9.
Figure GWB0000003434010000541
The synthesis steps are as follows:
s1: to intermediate 3-1 (5g, 22.2mmol) was added CH 2 Cl 2 To a solution (100 mL) was added triethylamine (4.48 g,44.4 mmol) and compound 3-2 (2.02g, 22.2mol). 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 (6.0 g,96% yield) as a yellow solid. LC-MS:282[ 2] M +1] + 。
S2: a solution of intermediate 3-3 (280mg, 1mmol) and HMPA (0.17mL, 1mmol) in dry tetrahydrofuran (20 mL) 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 (10 mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (1.2 mL,1.2 mmol) was added dropwise 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 (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. The products 3-5 (300 mg crude) were used in the next reaction without further purification. LC-MS:453[ deg. ] M +1] + 。
S3: to a solution of intermediate 3-5 (300mg, 0.66mmol) in MeOH (10 mL) 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 (50 mL) and extracted with ethyl acetate (20 mL. Times.2). Then the aqueous layer was washed with K 2 CO 3 Basified and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine and dried. After concentration, intermediate 3-6 was obtained (180 mg, yield 82%). LC-MS:335[ 2] M +1] + 。
S4: to intermediate 3-6 (180mg, 0.45mmol) and compound 7 (5.5g, 0.53mmol) was added CH 3 CN (10 mL) solution was added with K 3 PO 4 (190mg, 0.90mmol), xphos (40mg, 0.090mmol) and Pd 2 (dba) 3 (40mg, 0.045mmol). Adding N to the reaction mixture 2 Then heated to reflux and stirredOvernight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: to give intermediates 3-8 (140mg, 76% yield). LC-MS:405 2, M +1] + 。
S5: to intermediate 3-8 (140mg, 0.34mmol) and compound 3-9 (93mg, 0.34mmol) in CH 3 DIPEA (0.12mL, 0.68mmol) was added to the mixture in CN (10 mL). 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[ deg. ] M +1] + 。 1 H-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[ deg. ] 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[ 2] M +1] + 。
Example 7: synthesis of Compound 12.
Figure GWB0000003434010000551
The synthesis steps are as follows:
s1: at-60 deg.CLDA (11mL, 11mmol) was added dropwise to a solution of compound 12-1' (2.0 g,8.4 mmol) in THF (50 mL). After the addition, the mixture was stirred at this temperature for 1 hour. Then, phNTf2 (compound 12-2') (3.6g, 10mmol) was added to the mixture. The resulting reaction mixture was slowly warmed and stirred at room temperature overnight. The reaction solution was quenched with aqueous solution. Adjusted with NH4Cl (100 mL) and the aqueous layer extracted with ethyl acetate (2X 150 mL). The combined organic layers were washed with brine (150 mL), 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[ 2] M +1] + 。
S2: to a solution of intermediate 12-3 '(1.0 g, 2.69mmol) and compound 12-4' (0.8 g, 3.16mmol) in dioxane (100 mL) was added KOAc (0.3 g, 3.16mmol), pd (dppf) Cl 2 (0.2g, 0.27mmol). Adding N to the reaction mixture 2 Then heated to reflux and stirred overnight. The reaction mixture was then filtered, the filtrate was 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[ 2], [ M ] +1] + 。
S3: to compound 12-1 (50g, 0.29mol) and DMF (0.5 mL) in CH at room temperature 2 Cl 2 Oxalyl chloride (27.4 mL, 0.32mol) was added dropwise to the stirred solution in (250 mL) 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 CH 2 Cl 2 (250 mL) solution was added intermediate 12-2 (54g, 0.29mol) in CH 2 Cl 2 Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100 mL) was added. The organic layer was separated and washed with brine, na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, rinsed with petroleum ether (500 mL), and further dried in vacuo to give an intermediateBody 12-4 (70g, 95% yield) as a yellow solid. LC-MS:246[ 2] M +1] + 。
S5: a solution of intermediate 12-4 (30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250 mL) was cooled to-78 deg.C and then a solution of n-butyllithium in hexane (2.5M, 146mL) was added to it slowly over 30 minutes with 0.37mol. 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 (36.9 g, 0.16mol) in dry tetrahydrofuran (100 mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was slowly added 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 (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. Intermediate 12-6 (70 g crude) was used in the next reaction without further purification. LC-MS:417[ 2] M +1] + 。
S6: to a solution of intermediate 12-6 (70g, 168mmol) in MeOH (360 mL) 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 (1000 mL) and extracted with ethyl acetate (200 mL. Times.2). Then using K 2 CO 3 The 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 2[ C ], [ 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 (2.5 mL) was added K 2 CO 3 (0.16g, 1.14mmol) and Pd (dppf) Cl 2 (41mg, 0.057 mmol). Adding N to the reaction mixture 2 And then heated under reflux for 2 hours. The reaction mixture is then filtered, the filtrate is concentrated and passed through column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to afford the desired intermediate 12-9 (100mg, 36% yield). LC-MS:486 2M +1] + 。
S8: to compound 12-9 (100mg, 0.2mmol) in EtTo the OH (10 mL) solution was added Pd/C (20 mg). Mixing the mixture in H 2 Stir overnight at room temperature under balloon. The reaction was filtered and concentrated to give intermediate 12-10 (100mg, 99% yield) as a yellow solid. LC-MS:2, 488 2M +1] + 。
S9: to intermediate 12-10 (1g, 2.05mmol) and compound 11 (621mg, 2.25mmol) in CH 3 DIPEA (0.50mL, 3.07mmol) was added to the mixture in CN (50 mL). The mixture was stirred at reflux overnight. The reaction mixture is concentrated and subjected to column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to give the desired intermediate 12-12 (1.2g, 90% yield). LC-MS:648[ c ] M +1] + 。
S10: ice-water cooled intermediate 12-12 (200mg, 0.30mmol) in CH 2 Cl 2 (5 mL) solution CF was added 3 COOH (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[ 2], [ M ] +1] + 。
S11: to a solution of ice-water cooled intermediate 12-13 (150mg, 0.27mmol) in DMF (2 mL) was added 37% aqueous formaldehyde (0.5 mL) and one drop of acetic acid. After stirring for 30 minutes, naBH was added to the mixture 3 CN (20mg, 0.3mmol). 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 (150 mL), 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 2[ M ] +1] + 。 1 H-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, compound (S) - (1- (methoxy (methyl) amino) -1)-oxopropan-2-yl) carbamic acid tert-butyl ester is replaced with (1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamic acid tert-butyl ester and the other steps are left unchanged to yield the title compound 10.LC-MS:562 2[ 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 2[ M ] +1] + 。
Example 10: synthesis of Compound 15.
Figure GWB0000003434010000571
The synthesis steps are as follows:
s1: to compound 15-1 (50g, 0.29mol) and DMF (0.5 mL) in CH at room temperature 2 Cl 2 To a stirred solution in (250 mL) was added oxalyl chloride (27.4 mL, 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 CH 2 Cl 2 (250 mL) solution was added intermediate 15-2 (54g, 0.29mol) in CH 2 Cl 2 Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100 mL) was added. The organic layer was separated and washed with brine, na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, rinsed with petroleum ether (500 mL), and further dried in vacuo to give intermediate 15-4 (70g, 95% yield) as a yellow solid. LC-MS:246[ 2] M +1] + 。
S3: a solution of intermediate 15-4 (30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250 mL) was cooledTo-78 deg.C, a solution of n-butyllithium in hexane (2.5M, 146mL) was then added, and 0.37mol was slowly added thereto 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 (36.9 g, 0.16mol) in anhydrous tetrahydrofuran (100 mL) 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 (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. Intermediate 15-6 (70 g crude) was used in the next reaction without further purification. LC-MS:417[ alpha ], [ M ] +1] + 。
S4: to a solution of intermediate 15-6 (70g, 168mmol) in MeOH (360 mL) 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 (1000 mL) and extracted with ethyl acetate (200 mL. Times.2). Then using K 2 CO 3 The 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 2[ C ], [ M ] +1] + 。
S5: to a solution of intermediate 15-7 (598mg, 2mmol) and compound 15-8 (678mg, 3mmol) in dioxane (10 mL) was added Cs 2 CO 3 (1303mg, 4mmol), xphos (190mg, 0.4mmol) and Pd 2 (dba) 3 (183mg, 0.2mmol). Adding N to the reaction mixture 2 Then heated to reflux overnight. The reaction mixture was then filtered, the filtrate was 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[ 2] M +1] + 。
S6: to intermediate 15-9 (240mg, 0.49mmol) and compound 15-10 (148mg, 0.54mmol) in CH 3 DIPEA (64mg, 0.49mmol) was added to the mixture in CN (10 mL). The mixture was stirred at reflux overnight. The reaction mixture was concentrated and purified by column chromatography (eluent: 100% ethyl acetate)) The residue was purified to give the desired intermediate 15-11 (250mg, 79% yield). LC-MS:649 2[ M ] +1] + 。 1 H-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 CH 2 Cl 2 (5 mL) solution CF was added 3 COOH (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: 2[ 2], [ M ] +1] + 。 1 H-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 intermediate 15-12 (100mg, 0.18 mmol) in DMF (2 mL) cooled in ice water was added 37% aqueous formaldehyde (0.5 mL) and one drop of acetic acid. After stirring for 30 minutes, naBH was added to the mixture 3 CN (19mg, 0.3mmol). 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 (50 mL), 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] + 。 1 H-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 and the other steps were kept unchanged to obtain the objective compound 13.LC-MS:563[ 2] 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 GWB0000003434010000591
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 (150 mL) 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 mixture 3 CN (1.18g, 19.0mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with 20% aqueous sodium hydroxide. Extracted with ethyl acetate (500 mL. Times.2). The combined organic layers were then washed with brine, washed with Na 2 SO 4 Dried 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[ 2], [ M ] +1] + 。
S2: to a solution of intermediate 24-2 (3.2g, 9.6 mmol) in THF (100 mL) 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 (2 mL), 15% aqueous sodium hydroxide (2 mL). Filtering, concentrating the filtrate to obtain the desired productIntermediate 24-3 (2.2g, 94% yield). LC-MS:245[ 2] M +1] + 。
S3: to a solution of intermediate 24-3 (2.2 g,9 mmol) in MeOH (20 mL) was added Pd (OH) 2 C (800 mg). Mixing the mixture in H 2 Stirred overnight at 50 deg.C (60 psi). The reaction was filtered and concentrated to give intermediate 24-4 (1.3 g,99% yield) as a yellow solid. LC-MS:155 2[ M ] +1] + 。
S4: ice-water cooled intermediate 24-4 (3 g,19.3 mol) and triethylamine (2.7ml, 21.1mol) in CH 2 Cl 2 To the solution (50 mL) 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 (50 mL) was added. The organic layer was separated and washed with brine, na 2 SO 4 Dried 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[ 2], [ M ] +1] + 。
S5: a solution of intermediate 24-6 (800mg, 2.6 mol) and HMPA (0.56mL, 3.1mol) in anhydrous tetrahydrofuran (50 mL) 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, 3.4 mmol) in dry tetrahydrofuran (20 mL) 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 (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. The product 24-7 (800 mg crude) was used in the next reaction without further purification. LC-MS:478 2, M +1] + 。
S6: to a solution of intermediate 24-7 (800mg, 1.68mmol) in MeOH (20 mL) 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 taken up in waterDissolved in (1000 mL) and extracted with ethyl acetate (100 mL. Times.2). Then the aqueous layer was washed with K 2 CO 3 Basified and extracted with ethyl acetate (100 mL × 2). Extracting with Na 2 SO 4 Dried and then concentrated. By column chromatography (eluent: CH) 2 Cl 2 MeOH = 10: 1) to afford the desired intermediate 24-8 (400mg, 66% yield). LC-MS:360[ deg. ] M +1] + 。
S7: to CH of intermediate 24-8 (400mg, 1.11mmol) and compound 24-9 (170mg, 1.60mmol) 3 CN (10 mL) solution was added with K 3 PO 4 (280mg, 1.32mmol), xphos (56mg, 0.12mmol) and Pd 2 (dba) 3 (50mg, 0.06mmol). Adding N to the reaction mixture 2 Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to afford the desired intermediate 24-10 (80mg, 17% yield). LC-MS:430[ 2] M +1] + 。
S8: to intermediate 24-10 (80mg, 0.19mmol) and compound 24-11 (54mg, 0.19mmol) in CH 3 To the mixture in CN (10 mL) was added DIPEA (40mg, 0.3 lmmol). 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 2[ M ] +1] + 。 1 H-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 target compoundCompound 22.LC-MS:590 2[ 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 2[ C ], [ M ] +1] + 。
Example 16: synthesis of Compound 27.
Figure GWB0000003434010000601
The synthesis steps are as follows:
s1: to the CH of the compound 27-2 (5.6g, 30mmol) and triethylamine (7.8mL, 60mmol) 2 Cl 2 (50 mL) to the solution was added dropwise CH of Compound 27-1 (5.1g, 30mmol) 2 Cl 2 (50 mL) 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[ 2] M +1] + 。
S2: a solution of intermediate 27-3 (2.5g, 8.25mmol) and HMPA (1.6 mL, 9.07mmol) in dry tetrahydrofuran (50 mL) was cooled to-78 deg.C, and 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 (50 mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (10mL, 9.98mmol) was slowly added 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 (10 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated. By column chromatography (eluent: petroleum ether/ethyl acetate)Ethyl acid ester = 10: 1 to 2: 1) to give the desired intermediate 27-5 (3.3g, 85% yield). LC-MS:475 2[ M +1]] + 。
S3: to a solution of ice water cooled intermediate 27-5 (475mg, lmmol) in EtOH (10 mL) was added NaBH 4 (45mg, 1.2mmol). The mixture was stirred at room temperature for 3 hours. Then using NH 4 The reaction solution was quenched with aqueous Cl. Extraction was performed with ethyl acetate (50 mL. Times.2). The combined organic layers were washed with Na 2 SO 4 Drying and then concentration gave the desired intermediate 27-6 (460mg, 96% yield). LC-MS:477[ 2] M +1] + 。
S4: ice-water cooled intermediate 27-6 (400mg, 0.84mmol) and triethylamine (0.25mL, 1.7 mmol) in CH 2 Cl 2 (10 mL) to the solution was added MsCl (0.10mL, 1.25mmol) dropwise. After addition, it was stirred at room temperature overnight. The reaction mixture is then quenched with NaHCO 3 And (4) quenching the aqueous solution. By CH 2 Cl 2 (50 mL. Times.2) was extracted. The combined organic layers were washed with Na 2 SO 4 Drying, followed by concentration gave the desired intermediate 27-7 (450mg, 95% yield). LC-MS:555[ 2] M +1] + 。
S5: to a solution of intermediate 27-7 (450mg, 0.8 mmol) in DMF (10 mL) cooled in ice water was added NaH (60% wt,80mg, 2mmol). 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 (50 mL), 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[ alpha ], [ M ] +1] + 。
S6: ice Water cooled intermediate 27-8 (300mg, 0.66mmol) in CH 2 Cl 2 (5 mL) to the solution was added CF 3 COOH (1 mL). The mixture was stirred for 3 hours. The reaction solution was then 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 (50 mL), 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 (10 mL) was added EtN (i-Pr) 2 (0.18mL, 1.12mmol). The resulting mixture was heated by microwave at 150 ℃ for 6 hours. The reaction mixture was concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to afford the desired intermediate 27-11 (100mg, 34% yield). LC-MS:519 2[ M +1]] + 。
S8: to intermediate 27-11 (200mg, 0.39mmol) and compound 27-12 (50mg, 0.46mmol) in CH 3 CN (10 mL) solution was added with K 3 PO 4 (100mg, 0.47mmol), xphos (4mg, 7.8. Mu. Mol) and Pd2 (dba) 3 (10 mg, 3.9. Mu. Mol). Adding N to the reaction mixture 2 Then 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[ 2] M +1] + 。 1 H-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[ 2] 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 compound26。LC-MS：589[M+1] + 。
Example 19: synthesis of Compound 31.
Figure GWB0000003434010000621
The synthesis steps are as follows:
s1: a solution of compound 31-1 (2.45g, 10mmol) and HMPA (1.79g, 10mmol) in anhydrous tetrahydrofuran (50 mL) was cooled to-78 ℃, and then a solution of n-butyllithium in hexane (2.5M, 10mL) was added thereto, and 25mmol was slowly added thereto 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 (3.4 g,13.8 mol) in anhydrous tetrahydrofuran (20 mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (8mL, 15mol) was slowly added at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. The mixture was stirred at-78 ℃ for 1 hour. The reaction mixture was quenched with water (10 mL), then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. Intermediate 31-3 (3 g crude) was used in the next reaction without further purification. LC-MS:431[ 2], [ M ] +1] + 。
S2: to a solution of intermediate 31-3 (1g, 2.3 mmol) in dioxane (10 mL) 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 (100 mL × 2). Extracting with Na 2 SO 4 Dried and then concentrated. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 2: 1) to give intermediate 31-4 (500mg, 69% yield). LC-MS:313[ deg. ] M +1] + 。
S3: to intermediate 31-4 (300mg, 0.96mmol) and compound 31-5 (160mg, 1.5mmol) was added CH 3 CN (10 mL) solution was added with K 3 PO 4 (254.7mg, 1.2mmol), xphos (48mg, 0.096mmol) and Pd 2 (dba) 3 (46mg, 0.048 mmol). Adding into the reaction mixtureN 2 Then heated to reflux and stirred overnight. The reaction mixture was then filtered, the filtrate was 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 2[ C ], [ M ] +1] + 。
S4: to intermediate 31-6 (176mg, 0.46mmol) and compound 31-7 (132mg, 0.48mmol) in CH 3 DIPEA (0.1mL, 0.60mmol) was added to the mixture in CN (10 mL). 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[ 2], [ M ] +1] + 。 1 H-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 GWB0000003434010000631
The synthesis steps are as follows:
s1: to NaOH (28.3 g, 0.71mol) in CH at 15 deg.C 3 CN (1L) suspension Compound 35-1' (40g, 0.75mol) was added slowly. After the addition, stirring was continued for 2 hours. Then, 2-chloroethyl chloroformate (50.6 g, 0.35mol) in CH was added at 15-30 deg.C 3 CN (100 mL) 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 35-2' (45 g, yield 35%) was obtained. LC-MS:184[ 2] M +1] + 。
S2: to a solution of intermediate 35-2' (75g, 0.04mol) in 1-propanol (1L) was added NH at room temperature 3 ·H 2 O (38 mL), stirred for 1.5 h. Then adding NH to the mixture 2 NH 2 ·H 2 O (38 mL), and stirred at 70 ℃ for 2 hours. The resulting mixture was concentrated and re-mixed with 1-butanol (1L)Dissolved 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[ 2] M +1] + 。
S3: to intermediate 35-4' (48g, 0.28mol) CH 3 To the COOH (400 mL) solution was added 1, 3-tetramethoxypropane (46g, 0.28mol). 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[ 2] M +1] + 。
S4: to intermediate 35-5' (46g, 0.22mol) in MeOH (150 mL)/water (300 mL) was added LiOH. H 2 O (41.3g, 0.98mol). The reaction mixture was stirred at 60 ℃ for 2 hours. It was then acidified with 1MHCl to pH =5 and 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 (300 mL) were added N-hydroxysuccinimide (8.4g, 73mmol) and EDCI (14g, 73mmol). The reaction mixture was stirred at room temperature for 48 hours. Water (300 mL) 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[ 2], [ M ] +1]] + 。
S6: intermediate 35-1 (50g, 0.29mol) and DMF (0.5 mL) in CH at room temperature 2 Cl 2 Oxalyl chloride (27.4 mL, 0.32mol) was added dropwise to the stirred solution in (250 mL) 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 CH 2 Cl 2 (250 mL) solution was added intermediate 35-2 (54g, 0.29mol) in CH 2 Cl 2 Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100 mL) was added. The organic layer was separated and washed with brine, na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000 mL) and washed with waterStir at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500 mL), and further dried in vacuo to give intermediate 35-4 (70g, 95% yield) as a yellow solid. LC-MS:246[ 2] M +1] + 。
S8: a solution of intermediate 35-4 (30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250 mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added to it slowly over 30 minutes with 0.37mol. 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 (36.9 g, 0.16mol) in dry tetrahydrofuran (100 mL) 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 (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. Intermediate 35-6 (70 g crude) was used in the next reaction without further purification. LC-MS:417[ 2] M +1] + 。
S9: to intermediate 35-6 (70g, 168mmol) in MeOH (360 mL) 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 (1000 mL) 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 35-7 (20g, 40% yield). LC-MS:299[ deg. ] M +1] + 。
S10: to intermediate 35-7 (11g, 36.9mmol) and compound 35-8 (5.5g, 51.9mmol, 1.2eq.) in CH 3 CN (200 mL) solution was added K 3 PO 4 (9.4g, 44.3mmol), xphos (0.88g, 1.834). mmol) and Pd 2 (dba) 3 (841mg, 0.918mmol). Adding N to the reaction mixture 2 Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and passed through column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to give the productIntermediate 35-9 (9.8g, 72% yield) was required. LC-MS:369[ 2] M +1] + 。
S11: to intermediate 35-9 (12.7g, 34.5mmol) and intermediate 35-10 (9.9g, 36.2mmol) was added CH 3 CN (200 mL) was added to the mixture DIPEA (6.3 mL, 38mmol). 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] + 。 1 H-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 (10 mL) was added DIPEA (1 mL) and PCl 5 (50mg, 0.25mmol). 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 compound 35-12 (200mg, 0.36mmol) and NH 2 A mixture of OH HCl (100mg, 1.44mmol) in dioxane (10 mL) 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[ 2] 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[ 2] 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 (R) - (1)Tert-butyl- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate and the remaining steps are left unchanged to yield the title compound 34.LC-MS:544[ 2] M +1] + 。
Example 23: synthesis of Compound 47.
Figure GWB0000003434010000651
The synthesis steps are as follows:
s1: to compound 47-1 (50g, 0.29mol) and DMF (0.5 mL) in CH at room temperature 2 Cl 2 Oxalyl chloride (27.4 mL, 0.32mol) was added dropwise to the stirred solution in (250 mL) 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 CH 2 Cl 2 (250 mL) solution was added intermediate 47-2 (54g, 0.29mol) in CH 2 Cl 2 Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100 mL) was added. The organic layer was separated and washed with brine, na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500 mL), and further dried in vacuo to give intermediate 47-4 (70g, 95% yield) as a yellow solid. LC-MS:246 2[ M ] +1] + 。
S3: a solution of intermediate 47-4 (30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250 mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added to it slowly over 30 minutes with 0.37mol. 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 (36.9 g, 0.16mol) in anhydrous tetrahydrofuran (100 mL) was cooled. A solution of isopropyl magnesium chloride in tetrahydrofuran (88mL, 0.18mol) was added slowly at-78 ℃. The reaction mixture was kept at the same temperatureStirred for 30 minutes and then added to the reaction mixture. Stirring was carried out at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. Intermediate 47-6 (70 g crude) was used in the next reaction without further purification. LC-MS:417[ alpha ], [ M ] +1] + 。
S4: to a solution of intermediate 47-6 (500mg, 1.2mmol) in acetic acid (10 mL) was added diiodophenyl iodide (420mg, 1.3mmol). The resulting mixture was heated at 50 ℃ overnight. By NaHCO 3 The reaction mixture was quenched with aqueous solution (50 mL) and extracted with ethyl acetate (50 mL. Times.2). The organic layer was washed with Na 2 SO 4 Dried 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 2[ M +1]] + 。
S5: to a solution of compound 47-7 (150mg, 0.32mmol) in methanol (10 mL) 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 (50 mL) and extracted with ethyl acetate (20 mL. Times.2). Then the aqueous layer was washed with K 2 CO 3 Basified and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed, dried and concentrated to give intermediate 47-8 (100mg, 95% yield). LC-MS:315[ 2] M +1] + 。
S6: to intermediate 47-8 (100mg, 0.32mmol) and compound 47-9 (51mg, 0.48mmol) in CH 3 CN (5 mL) solution was added with K 3 PO 4 (81mg, 0.38mmol), xphos (3mg, 0.004mmol) and Pd 2 (dba) 3 (2.9mg, 0.008mmol). Adding N to the reaction mixture 2 Then heated to reflux and stirred overnight. The reaction mixture was then filtered, the filtrate was concentrated and purified by column chromatography (eluent: DCM/MeOH =100:1 to 10: 1) to give the desired intermediate 47-10 (60mg, 49% yield). LC-MS:385[ sic ] M +1] + 。
S7: to intermediate 47-10 (60mg, 0.1699 mmol) and compound 47-11 (52mg, 0.19mmol) in CH 3 CN (5 mL) was added DIPEA (42 mg)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 (5 mg,6% yield) as a white solid. LC-MS:545[ M ] +1] + 。 1 H-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 give 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 GWB0000003434010000661
Figure GWB0000003434010000671
Synthesis procedure
S1: to NaOH (28.3g, 0.71mol) in CH at 15 deg.C 3 CN (1L) suspension Compound 50-1' (40g, 0.75mol) was added slowly. After the addition, stirring was continued for 2 hours. Then adding at 15-30 deg.CInto the CH of 2-chloroethyl chloroformate (50.6 g, 0.35mol) 3 CN (100 mL) 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 as 50-2' (45 g, 35% yield). LC-MS:184[ 2] M +1] + 。
S2: to a solution of intermediate 50-2' (75g, 0.04mol) in 1-propanol (1L) was added NH at room temperature 3 ·H 2 O (38 mL), stirred for 1.5 h. Then adding NH to the mixture 2 NH 2 ·H 2 O (38 mL), and stirred at 70 ℃ for 2 hours. The resulting mixture was concentrated and redissolved with 1-butanol (1L) and stirred at 110 deg.C for 2 days. After cooling, the solid was filtered and dried to give intermediate 50-4' (45g, 66% yield). LC-MS:171[ 2] M +1] + 。
S3: to intermediate 50-4' (48g, 0.28mol) CH 3 To the COOH (400 mL) solution was added 1,1, 3-tetramethoxypropane (46g, 0.28mol). 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[ 2] M +1] + 。
S4: to intermediate 50-5' (46g, 0.22mol) in MeOH (150 mL)/water (300 mL) was added LiOH H 2 O (41.3g, 0.98mol). The reaction mixture was stirred at 60 ℃ for 2 hours. It was then acidified with 1MHCl to pH =5, and 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 (300 mL) were added N-hydroxysuccinimide (8.4g, 73mmol) and EDCI (14g, 73mmol). The reaction mixture was stirred at room temperature for 48 hours. Water (300 mL) 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[ 2], [ M ] +1]] + 。
S6: to compound 50-1 (50g, 0.29mol) and DMF (0.5 mL) in CH at room temperature 2 Cl 2 Adding grass dropwise into the stirred solution (250 mL)Acid chloride (27.4 ml, 0.32mol) 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 CH 2 Cl 2 (250 mL) solution was added intermediate 50-2 (54g, 0.29mol) CH 2 Cl 2 Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100 mL) was added. The organic layer was separated and washed with brine, na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, rinsed with petroleum ether (500 mL), and further dried in vacuo to give intermediate 50-4 (70g, 95% yield) as a yellow solid. LC-MS:246 2[ M ] +1] + 。
S8: a solution of intermediate 50-4 (30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250 mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added to it slowly over 30 minutes with 0.37mol. 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 (36.9 g, 0.16mol) in dry tetrahydrofuran (100 mL) 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 (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. Intermediate 50-6 (70 g crude) was used in the next reaction without further purification. LC-MS:417[ 2] M +1] + 。
S9: to a solution of intermediate 50-6 (70g, 168mmol) in MeOH (360 mL) 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 (1000 mL) and extracted with ethyl acetate (200 mL. Times.2). Then basifying the aqueous layer with K2CO3 to formAnd forming a precipitate. The solid was collected by filtration and dried to give compound 50-7 (20g, 40% yield). LC-MS:299 2[ C ], [ M ] +1] + 。
S10: to intermediate 50-7 (11g, 36.9mmol) and compound 50-8 (5.5g, 51.9mmol, 1.2eq.) in CH 3 CN (200 mL) solution was added K 3 PO 4 (9.4g, 44.3mmol), xphos (0.88g, 1.834mmol) and Pd 2 (dba) 3 (841mg, 0.918mmol). Adding N to the reaction mixture 2 Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and passed through column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to give the desired intermediate 50-9 (9.8g, 72% yield). LC-MS:369 2M +1] + 。
S11: to intermediate 50-9 (12.7g, 34.5mmol) and intermediate 50-10 (9.9g, 36.2mmol) was added CH 3 CN (200 mL) was added to the mixture DIPEA (6.3 mL, 38mmol). 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] + 。 1 H-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 ice water cooled tert-butanol (46mg, 0.63mmol) in CH 2 Cl 2 To the solution (10 mL) was added chlorosulfonyl isocyanate (89mg, 0.63mmol). The resulting mixture was stirred for 10 minutes. Then, to the mixture were added CH of the compounds 50-11 (300mg, 0.57mmol) and triethylamine (115mg, 1.14mmol) 2 Cl 2 (10 mL) 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 (10 mL), and a 10M dioxane solution (1 mL) of hydrogen chloride was added to the solution. After 30 minutes, the reaction mixture was concentrated. Purifying the residue by preparative HPLC to giveTo compound 50 (28mg, 40% yield) as a yellow solid. LC-MS:608 2[ 2] M +1] + 。 1 H-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, 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 48.LC-MS:608 2[ 2] 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 give the objective compound 49.LC-MS:608[ 2], [ M ] +1] + 。
Example 29: synthesis of Compound 71.
Figure GWB0000003434010000691
The synthesis steps are as follows:
s1: a solution of compound 71-1 (6 g, 24mmol) and HMPA (5 mL, 28mmol) in dry tetrahydrofuran (100 mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 29.2 mL) was added and 74mmol was slowly added thereto 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 anhydrous tetrahydrofuran (50 mL) was cooled to-78 ℃. A solution of isopropyl magnesium chloride and tetrahydrofuran (17.6 mL, 36mmol) was added slowly. The reaction mixture was stirred at the same temperature for 30 minutes, and then the above was addedIn the reaction mixture. The mixture was stirred at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. Intermediate 71-3 (8 g crude) was used in the next reaction without further purification. LC-MS:429[ 2] M +1] + 。
S2: to a solution of intermediate 71-3 (3.7g, 8.6 mmol) in 1, 4-dioxane (5 mL) was added 4M hydrogen chloride/1, 4-dioxane (5 mL). The resulting mixture was stirred at 120 ℃ for 60 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue is taken up in NaHCO 3 The aqueous solution was basified and then extracted with ethyl acetate (100 mL. Times.2). Extracting with Na 2 SO 4 Dried 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[ 2] M +1] + 。
S3: to intermediate 71-4 (1g, 3.2mmol) and compound 71-5 (420mg, 4.0mmol) in CH was added 3 CN (20 mL) solution was added with K 3 PO 4 (820mg, 3.86mmol), xphos (153mg, 0.32mmol) and Pd 2 (dba) 3 (147mg, 0.16mmol). Adding N to the reaction mixture 2 Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to afford the desired intermediate 71-6 (0.86g, 70% yield). LC-MS:381[ 2] M +1] + 。
S4: to intermediate 71-6 (0.86g, 2.2mmol) and compound 71-7 (0.75g, 2.7mmol) in CH 3 CN (50 mL) was added DIPEA (0.5mL, 3.0 mmol). 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 2[ M ] +1] + 。 1 H-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 GWB0000003434010000701
S1: to compound 79-1 (50g, 0.29mol) and DMF (0.SmL) in CH at room temperature 2 Cl 2 Oxalyl chloride (27.4 mL, 0.32mol) was added dropwise to the stirred solution in (250 mL) 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 CH 2 Cl 2 (250 mL) solution was added intermediate 79-2 (54g, 0.29mol) in CH 2 Cl 2 Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100 mL) was added. The organic layer was separated and washed with brine, na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500 mL), and further dried in vacuo to give intermediate 79-4 (70g, 95% yield) as a yellow solid. LC-MS:246[ 2] M +1] + 。
S3: a solution of intermediate 79-4 (30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250 mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added to it slowly over 30 minutes with 0.37mol. 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 (36.9 g, 0.16mol) in dry tetrahydrofuran (100 mL) 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 (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Drying, then decompressingAnd (4) concentrating. Intermediate 79-6 (70 g crude) was used in the next reaction without further purification. LC-MS:417[ 2] M +1] + 。
S4: to a solution of intermediate 79-6 (70g, 168mmol) in MeOH (360 mL) 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 (1000 mL) and extracted with ethyl acetate (200 mL. Times.2). Then using K 2 CO 3 The 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[ deg. ] M +1] + 。
S5: to intermediate 79-7 (11g, 36.9mmol) and compound 79-8 (5.5g, 51.9mmol, 1.2eq.) in CH 3 CN (200 mL) solution was added K 3 PO 4 (9.4g, 44.3mmol), xphos (0.88g, 1.834mmol) and Pd 2 (dba) 3 (841mg, 0.918mmol). Adding N to the reaction mixture 2 Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to give the desired intermediate 79-9 (9.8g, 72% yield). LC-MS:369[ 2] M +1] + 。
S6: to intermediate 79-9 (12.7g, 34.5mmol) and compound 79-10 (9.9g, 36.2mmol) in CH 3 CN (200 mL) was added DIPEA (6.3 mL, 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[ 2], [ M ] +1] + 。 1 H-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 CH 2 Cl 2 (5 mL) to the solution were added N-methylaminosulfonyl chloride (120mg, 1.0 mmol) 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 79 (140mg, 30% yield) as a yellow solid. LC-MS:622 2[ M ] +1] + 。 1 H-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 2[ 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 obtain the objective compound 82.LC-MS:622 2[ M ] +1] + 。
Example 33: synthesis of Compound 80.
Figure GWB0000003434010000711
S1: to compound 80-1 (50g, 0.29mol) and DMF (0.5 mL) in CH at room temperature 2 Cl 2 To a stirred solution in (250 mL) was added oxalyl chloride (27.4 mL, 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 CH 2 Cl 2 (250 mL) solution was added intermediate 80-2 (54g, 0.29mol) in CH 2 Cl 2 Solutions of(50 mL). The resulting mixture was stirred at room temperature overnight, then water (100 mL) was added. The organic layer was separated and washed with brine, na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, rinsed with petroleum ether (500 mL), and further dried in vacuo to give intermediate 80-4 (70g, 95% yield) as a yellow solid. LC-MS:246[ 2] M +1] + 。
S3: a solution of intermediate 80-4 (30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250 mL) was cooled to-78 deg.C and then a solution of n-butyllithium in hexane (2.5M, 146mL) was added to it slowly over 30 minutes with 0.37mol. 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 (36.9 g, 0.16mol) in anhydrous tetrahydrofuran (100 mL) 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. The mixture was stirred at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. Intermediate 80-6 (70 g crude) was used in the next reaction without further purification. LC-MS:417[ 2] M +1] + 。
S4: to a solution of intermediate 80-6 (70g, 168mmol) in MeOH (360 mL) 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 (1000 mL) and extracted with ethyl acetate (200 mL. Times.2). Then using K 2 CO 3 The 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[ deg. ] M +1] + 。
S5: to intermediate 80-7 (11g, 36.9mmol) and compound 80-8 (5.5g, 51.9mmol, 1.2eq.) in CH 3 CN (200 mL) solution was added K 3 PO 4 (9.4g, 44.3mmol), xphos (0.88g, 1.834mmol) and Pd 2 (dba) 3 (841mg, 0.918mmol). Adding N to the reaction mixture 2 Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to afford the desired intermediate 80-9 (9.8g, 72% yield). LC-MS:369[ 2] M +1] + 。
S6: to intermediate 80-9 (12.7g, 34.5mmol) and compound 80-10 (9.9g, 36.2mmol) in CH 3 CN (200 mL) was added DIPEA (6.3 mL, 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] + 。 1 H-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 CH 2 Cl 2 To the solution (10 mL) 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] + 。 1 H-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 GWB0000003434010000721
Figure GWB0000003434010000731
Synthesis procedure
S1: to the CH of compound 86-1' (570mg, 10mmol) at 0 deg.C 2 Cl 2 (10 mL) solution was added chlorosulfonic acid (0.22M, 3.3 mmol) in CH 2 Cl 2 (20 mL) 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' (1.0 g,77% yield) as a white solid.
S2: to a suspension of intermediate 86-2' (1g, 7.2mmol) in toluene (10 mL) was added PCl 5 (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 (1.0 g,88% yield). Used in the next step without further purification.
S3: to compound 86-1 (50g, 0.29mol) and DMF (0.5 mL) in CH at room temperature 2 Cl 2 To a stirred solution in (250 mL) was added oxalyl chloride (27.4 mL, 0.32mol) dropwise, and the resulting mixture was stirred at room temperatureAfter stirring for 2 hours, the mixture was concentrated in vacuo to give 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 CH 2 Cl 2 (250 mL) solution was added intermediate 86-2 (54g, 0.29mol) in CH 2 Cl 2 Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100 mL) was added. The organic layer was separated and washed with brine, na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500 mL), and further dried in vacuo to give intermediate 86-4 (70g, 95% yield) as a yellow solid. LC-MS:246 2[ M ] +1] + 。
S5: a solution of intermediate 86-4 (30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250 mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added to it slowly over 30 minutes with 0.37mol. 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 (36.9 g, 0.16mol) in dry tetrahydrofuran (100 mL) 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 (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. Intermediate 86-6 (70 g crude) was used in the next reaction without further purification. LC-MS:417[ alpha ], [ M ] +1] + 。
S6: to a solution of intermediate 86-6 (70g, 168mmol) in MeOH (360 mL) 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 (1000 mL) and extracted with ethyl acetate (200 mL. Times.2). Then using K 2 CO 3 Basified the aqueous layer and precipitate formed. Filtering to collect the solidDrying gave 86-7 (20g, 40% yield). LC-MS:299[ deg. ] M +1] + 。
S7: to intermediate 86-7 (11g, 36.9mmol) and compound 86-8 (5.5g, 51.9mmol, 1.2eq.) in CH 3 CN (200 mL) solution was added K 3 PO 4 (9.4g, 44.3mmol), xphos (0.88g, 1.834mmol) and Pd 2 (dba) 3 (841mg, 0.918mmol). Adding N to the reaction mixture 2 Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to give the desired intermediate 86-9 (9.8g, 72% yield). LC-MS:369 2M +1] + 。
S8: to intermediate 86-9 (12.7g, 34.5mmol) and compound 86-10 (9.9g, 36.2mmol) in CH 3 CN (200 mL) was added to the mixture DIPEA (6.3 mL, 38mmol). 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] + 。 1 H-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 the CH of compound 86-11 (150mg, 0.28mmol) 2 Cl 2 (10 mL) to the solution were added intermediate 86-12 (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] + 。 1 H-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 GWB0000003434010000741
The synthesis steps are as follows:
s1: to compound 92-1 (50g, 0.29mol) and DMF (0.SmL) in CH at room temperature 2 Cl 2 Oxalyl chloride (27.4 mL, 0.32mol) was added dropwise to the stirred solution in (250 mL) 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 CH 2 Cl 2 (250 mL) solution was added intermediate 92-2 (54g, 0.29mol) in CH 2 Cl 2 Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100 mL) was added. The organic layer was separated and washed with brine, na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500 mL), and further dried in vacuo to give intermediate 92-4 (70g, 95% yield),as a yellow solid. LC-MS:246[ 2] M +1] + 。
S3: a solution of intermediate 92-4 (30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250 mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added to it slowly over 30 minutes with 0.37mol. 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 (36.9 g, 0.16mol) in anhydrous tetrahydrofuran (100 mL) 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. The mixture was stirred at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. Intermediate 92-6 (70 g crude) was used in the next reaction without further purification. LC-MS:417[ 2] M +1] + 。
S4: to intermediate 92-6 (70g, 168mmol) in MeOH (360 mL) 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 (1000 mL) and extracted with ethyl acetate (200 mL. Times.2). Then using K 2 CO 3 The 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 2[ C ], [ M ] +1] + 。
S5: to intermediate 92-7 (11g, 36.9mmol) and compound 92-8 (5.5g, 51.9mmol, 1.2eq.) in CH 3 CN (200 mL) solution was added K 3 PO 4 (9.4g, 44.3mmol), xphos (0.88g, 1.834mmol) and Pd 2 (dba) 3 (841mg, 0.918mmol). Adding N to the reaction mixture 2 Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to afford the desired intermediate 92-9 (9.8g, 72% yield). LC-MS:369[ 2] M +1] + 。
S6: to intermediate 92-CH of 9 (12.7g, 34.5mmol) and of 92-10 (9.9g, 36.2mmol) 3 CN (200 mL) was added to the mixture DIPEA (6.3 mL, 38mmol). 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[ 2], [ M ] +1] + 。 1 H-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 (10 mL) was added dimethylsulfamoyl chloride (109mg, 0.76mmol). 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[ 2] M +1] + 。 1 H-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 give the title compound 91.LC-MS:636[ 2] 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[ 2] M +1] + 。
Example 42: synthesis of Compound 95.
Figure GWB0000003434010000761
The synthesis steps are as follows:
s1: to compound 95-1 (50g, 0.29mol) and DMF (0.SmL) in CH at room temperature 2 Cl 2 Oxalyl chloride (27.4 mL, 0.32mol) was added dropwise to the stirred solution in (250 mL) 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 CH 2 Cl 2 (250 mL) solution was added intermediate 92-2 (54g, 0.29mol) in CH 2 Cl 2 Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100 mL) was added. The organic layer was separated and washed with brine, na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, rinsed with petroleum ether (500 mL), and further dried in vacuo to afford intermediate 95-4 (70g, 95% yield) as a yellow solid. LC-MS:246[ 2] M +1] + 。
S3: a solution of intermediate 95-4 (30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250 mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added to it slowly over 30 minutes with 0.37mol. 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 (36.9 g, 0.16mol) in dry tetrahydrofuran (100 mL) 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. The mixture was stirred at-78 ℃ for 1 hour. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. Intermediate 95-6 (70 g crude) was used in the next reaction without further purification. LC-MS:417[ 2] M +1] + 。
S4: to a solution of intermediate 95-6 (70g, 168mmol) in MeOH (360 mL) 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 (1000 mL) and extracted with ethyl acetate (200 mL. Times.2). Then using K 2 CO 3 The 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 2[ C ], [ M ] +1] + 。
S5: intermediate 95-7 (11g, 36.9mmol) and compound 95-8 (5.5g, 51.9mmol, 1.2eq.) were added in CH 3 CN (200 mL) solution was added K 3 PO 4 (9.4g, 44.3mmol), xphos (0.88g, 1.834mmol) and Pd 2 (dba) 3 (841mg, 0.918mmol). Adding N to the reaction mixture 2 Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to give the desired intermediate 95-9 (9.8g, 72% yield). LC-MS:369 2M +1] + 。
S6: to intermediate 95-9 (12.7g, 34.5mmol) and compound 95-10 (9.9g, 36.2mmol) in CH 3 CN (200 mL) was added to the mixture DIPEA (6.3 mL, 38mmol). 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[ 2], [ M ] +1] + 。 1 H-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 (20 mL) was added pyrrolidine-1-sulfonyl chloride (385mg, 2.27mmol). 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 2[ M +1]] + 。 1 H-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 2[ M +1]] + 。
Example 45: synthesis of Compound 98.
Figure GWB0000003434010000771
The synthesis steps are as follows:
s1: to compound 98-1 (500mg, 1.67mmol) and ethynyltrimethylsilane (0.33mL, 2.34mmol) in CH was added 3 CN (20 mL) solution was added with K 3 PO 4 (425mg, 2.00mmol), xphos (50mg, 0.1mmol) and Pd 2 (dba) 3 (50mg, 0.05mmol). Adding N to the reaction mixture 2 Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH) 2 Cl 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 CH 3 DIPEA (0.2 mL,1.1 mmol) was added to the mixture in CN (20 mL). The mixture was heated to reflux overnight. The reaction mixture is then concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to give the desired intermediate 98-4 (400mg, 77% yield). LC-MS:521[ 2], [ M ] +1] + 。
S3: to a solution of intermediate 98-4 (400mg, 0.77mmol) in THF (10 mL) 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) 2 Cl 2 MeOH =100:1 to 10: 1) to give the desired intermediate 98-5 (170mg, 49% yield). LC-MS:449[ deg. ] M +1] + 。
S4: to intermediate 98-5 (112mg, 0.25mmol) and compound 98-6 (83mg, 0.30mmol) was added CH 3 CN (10 mL) solution was added DIPEA (0.05mL, 0.33mmol), cuI (1mg, 0.005mmol) and PdCl 2 (PPh 3 ) 2 (0.53mg, 0.75. Mu. Mol). Adding N to the reaction mixture 2 Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to afford the desired intermediate 98-7 (130mg, 87% yield). LC-MS:597[ M ] +1] + 。
S5: to ice water cooled tert-butanol (50mg, 0.66mmol) in CH 2 Cl 2 To the solution (5 mL) was added chlorosulfonyl isocyanate (93mg, 0.66mmol). The resulting mixture was stirred for 10 minutes. Intermediate 98-7 (130mg, 0.21mmol) and triethylamine (0.3mL, 2.2mmol) in CH were then added to the mixture 2 Cl 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 CH 2 Cl 2 (10 mL) redissolved and CF added 3 COOH (1 mL). After completion of the reaction, the reaction mixture was basified with aqueous sodium bicarbonate. The reaction mixture was extracted with ethyl acetate (100 mL), 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 2[ 2] M +1] + 。 1 H-NMR(400MHz，DMSO-d 6 )：δ9.19(m，1H)，8.97(m，1H)，8.58(s，1H)，8.01-7.95(1m，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, 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 97.LC-MS:676 2[ 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 kept unchanged to obtain the objective compound 99.LC-MS:676 2[ M ] +1] + 。
Example 48: synthesis of compound 104.
Figure GWB0000003434010000781
Synthesis procedure
S1: to compound 104-1 (50g, 0.29mol) and DMF (0.5 mL) in CH at room temperature 2 Cl 2 To a stirred solution in (250 mL) was added oxalyl chloride (27.4 mL, 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: compound 104-3 (2) cooled in ice water8.7g, 0.30mol) and triethylamine (90ml, 0.60mol) in CH 2 Cl 2 (250 mL) solution was added intermediate 104-2 (54g, 0.29mol) in CH 2 Cl 2 Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100 mL) was added. The organic layer was separated and washed with brine, na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500 mL), and further dried in vacuo to afford intermediate 104-4 (70g, 95% yield) as a yellow solid. LC-MS:246 2[ M ] +1] + 。
S3: a solution of intermediate 104-4 (30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250 mL) was cooled to-78 deg.C and then a solution of n-butyllithium in hexane (2.5M, 146mL) was added to it slowly over 30 minutes with 0.37mol. 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 (36.9 g, 0.16mol) in dry tetrahydrofuran (100 mL) 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 (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. Intermediate 104-6 (70 g crude) was used in the next reaction without further purification. LC-MS:417[ 2] M +1] + 。
S4: to a solution of intermediate 104-6 (70g, 168mmol) in MeOH (360 mL) 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 (1000 mL) and extracted with ethyl acetate (200 mL. Times.2). Then using K 2 CO 3 The 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[ deg. ] M +1] + 。
S5: to intermediate 104-7 (500mg, 1.68mmol) and compound 104-8 (0)33mL, 2.34mmol) of CH 3 CN (10 mL) solution was added with K 3 PO 4 (425mg, 2.01mmol), xphos (50mg, 0.11mmol) and Pd 2 (dba) 3 (50mg, 0.054mmol). Adding N to the reaction mixture 2 Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to give the desired intermediate 104-9 (360mg, 60% yield).
S6: to intermediate 104-9 (360mg, 1.0 mmol) and compound 104-10 (289mg, 1.05mmol) in CH 3 DIPEA (0.2mL, 1.1mmol) was added to the mixture in CN (20 mL). The mixture was heated to reflux overnight. It is then concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to give the desired intermediate 104-11 (400mg, 77% yield). LC-MS:521[ deg. ] M +1] + 。
S7: TBAF (1.2 mL, 1.2mmol) was added to a mixture of intermediate 104-11 (400mg, 0.77mmol) in THF (10 mL). The mixture was stirred at ambient temperature for 2 hours. The reaction mixture is concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to give the desired intermediate 104-12 (170mg, 50% yield). LC-MS:449[ deg. ] M +1] + 。
S8: ice-Water cooled tert-Butanol (84.5mg, 1.14mmol) in CH 2 Cl 2 Chlorosulfonyl isocyanate (160mg, 1.14mmol) was added to the solution (10 mL). 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 mixture 2 Cl 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 a crude product of intermediate 104-13 (230mg, 95% yield). LC-MS:628[ 2] M +1] + 。
S9: to intermediate 104-13 (230mg, 0.36mmol) in CH 2 Cl 2 (10 mL) solution CF was added 3 COOH (1 mL). After completion of the reaction, the reaction mixture was basified with aqueous sodium bicarbonate. With ethyl acetate (100 mL)) The reaction mixture was extracted, 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[ 2] M +1] + 。 1 H-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 objective compound 103.LC-MS:528[ 2] 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[ 2] M +1] + 。
Example 51: synthesis of Compound 107.
Figure GWB0000003434010000801
Synthesis procedure
S1: to compound 107-1 (50g, 0.29mol) and DMF (0.5 mL) in CH at room temperature 2 Cl 2 Oxalyl chloride (27.4 mL, 0.32mol) was added dropwise to the stirred solution in (250 mL) 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 CH 2 Cl 2 (250 mL) solution was added intermediate 107-2 (54g, 0.29mol) in CH 2 Cl 2 Solution (50 mL). The resulting mixture was stirred at room temperature overnight, then water (100 mL) was added. The organic layer was separated and washed with brine, na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (1000 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, washed with petroleum ether (500 mL), and further dried in vacuo to give intermediate 107-4 (70g, 95% yield) as a yellow solid. LC-MS:246 2[ M ] +1] + 。
S3: a solution of intermediate 107-4 (30g, 0.12mol) and HMPA (25mL, 0.14mol) in dry tetrahydrofuran (250 mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (2.5M, 146mL) was added to it slowly over 30 minutes with 0.37mol. 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 (36.9 g, 0.16mol) in anhydrous tetrahydrofuran (100 mL) 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 (50 mL) and then extracted with ethyl acetate. Extracting with Na 2 SO 4 Dried and then concentrated under reduced pressure. Intermediate 107-6 (70 g crude) was used in the next reaction without further purification. LC-MS:417[ 2] M +1] + 。
S4: to a solution of intermediate 107-6 (70g, 168mmol) in MeOH (360 mL) 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 (1000 mL) and extracted with ethyl acetate (200 mL. Times.2). Then using K 2 CO 3 Basified the aqueous layer and precipitate formed. The solid was collected by filtration and dried to give intermediate 107-7 (20g, 40% yield). LC-MS:299[ deg. ] M +1] + 。
S5: to intermediate 107-7 (500mg, 1.68mmol) and compound 104-8 (0.33mL, 2.34mmol) was added CH 3 CN (10 mL) solution was added with K 3 PO 4 (425mg, 2.01mmol), xphos (50mg, 0.11mmol) and Pd 2 (dba) 3 (50mg, 0.054mmol). Adding N to the reaction mixture 2 Then heated to reflux and stirred overnight. The reaction mixture is then filtered, the filtrate is concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to give the desired intermediate 107-9 (360mg, 60% yield).
S6: intermediate 107-9 (360mg, 1.0 mmol) and compound 107-10 (289mg, 1.05mmol) were added in CH 3 DIPEA (0.2 mL,1.1 mmol) was added to the mixture in CN (20 mL). The mixture was heated to reflux overnight. It is then concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to give the desired intermediate 107-11 (400mg, 77% yield). LC-MS:521[ 2], [ M ] +1] + 。
S7: TBAF (1.2 mL, 1.2mmol) was added to a mixture of intermediates 107-11 (400mg, 0.77mmol) in THF (10 mL). The mixture was stirred at ambient temperature for 2 hours. The reaction mixture is concentrated and purified by column chromatography (eluent: CH) 2 Cl 2 MeOH =100:1 to 10: 1) to give the desired intermediate 107-12 (170mg, 50% yield). LC-MS:449[ 2] M +1] + 。
S8: to compound 107-12 (200mg, 0.38mmol) in CH 2 Cl 2 To the solution (10 mL) 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 2[ M +1]] + 。 1 H-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(methyl) amino) -1-oxopropan-2-yl) carbamic acid tert-butyl ester, the other steps remaining unchanged, gives the title compound 106.LC-MS:568 2[ 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 2[ M +1]] + 。
Example 54: synthesis of Compound 115.
Figure GWB0000003434010000811
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 (20 mL) was added Cs 2 CO 3 (650mg, 2mmol), xantphos (115mg, 0.2mmol) and Pd 2 (dba) 3 (92mg, 0.1mmol). Adding N to the reaction mixture 2 Then heated to reflux overnight. The reaction mixture was then filtered, the filtrate was 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[ 2], [ M ] +1] + 。
S2: to intermediate 115-3 (250mg, 0.50mmol) and compound 115-4 (165mg, 0.6mmol) in CH 3 DIPEA (0.17mL, 1mmol) was added to the mixture in CN (10 mL). 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, 0.3 mmol) in CH 2 Cl 2 (5 mL) to the solution was added CF 3 COOH (1 mL). The mixture was stirred for 3 hours. The reaction solution was then concentrated to give intermediate 115-6 (200mg, 95%)Yield) as a yellow solid. LC-MS:563[ 2] M +1] + 。 1 H-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 (2 mL) was added 37% aqueous formaldehyde (0.5 mL). After stirring for 30 minutes, naBH was added to the mixture 3 CN (1695g, 0.25mmol). 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 (50 mL), 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[ 2] M +1] + 。 1 H-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[ 2] M +1] + 。
Example 56: synthesis of Compound 117.
Referring to example 54, 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 give the objective compound117。LC-MS：577[M+1] + 。
Example 57: synthesis of compound 118.
Figure GWB0000003434010000821
The synthesis steps are as follows:
s1: to a solution of compound 118-1 (468mg, 1mmol) in pyridine (10 mL) was added P2S5 (222mg, 1mmol). N2 was added to the reaction mixture, which was then 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 2[ M ] +1] + 。
S2: to intermediate 118-2 (300mg, 0.62mmol) was added CH 2 Cl 2 (10 mL) to the mixture was added CF 3 COOH (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 2, M +1] + 。
S3: to a mixture of intermediate 118-3 (300mg, 0.6 mmol) and compound 118-4 (275mg, 1mmol) in pyridine (5 mL) 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] + 。 1 H-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.
Promega ADP-Glo was used TM Max test kit determines IC50 values of class I α, β, δ and γ 4 subtypes of human PI3K (Millipore). The compounds of the invention were incubated with 20nM PI3K α, PI3K δ or 40nM PI3K β, PI3K γ samples in reaction buffer (15mM HEPES pH =7.4, 20mM NaCl, 1mM EGTA, 0.02% Tween 20, 10mM MgCl. RTM.) at room temperature 2 0.2mg/mL bovine-gamma-globulin) for 15min, then the ATP/diC8-PIP2 mixture 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 stop solution (Promega kit). After 40min incubation at room temperature, 50 μ L of detection mix (Promega) was added and incubated at room temperature for 1h, envision plate reader plate reading. Data were converted to% inhibition and then plotted as% inhibition vs compound concentration and fitted to a four parameter logistic equation to determine IC 50 The value is obtained.
Figure GWB0000003434010000831
Note: a represents < 50nM; b represents < 300nM; c represents > 3000nM; d represents > 5000nM.
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, and the compounds show high selectivity on PI3K gamma subtype and PI3K delta subtype, and can be used as high-efficiency PI3K inhibitors.
Experimental example 2: in vitro PI3K gamma and PI3K delta kinase inhibition assays.
1) Reagents and consumables:
Figure GWB0000003434010000832
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)/3 mM (δ) in DMSO at 10 doses. 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 (GSK 2126458 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 × analysis buffer solution: 50mM HEPES (pH 7.5); 3mM MgCl 2 (ii) a 1mM EGTA;0.03% CHAPS;100mM NaCl;2mM DTT (added when used).
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 delta was 0.25. Mu.g/mL.
D:2.5 × substrate assay solution: PIP2: the final concentration of 3PS is 0.025mg/mL; ATP was present at a final concentration of 25. Mu.M.
Compound testing:
a: to a 384 well white ProxiPlate plate was added 2. Mu.L of 2.5 XPI 3 K.gamma./.delta.assay 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 gamma/delta test solution; incubate at room temperature for 15 minutes.
D: to each 384 well was added 2. Mu.L of 2.5 Xsubstrate assay solution 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 0.005nM. 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; delta is 30000, 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72,4.57 and 1.52. Mu.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 10mM 2 ADP-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 GWB0000003434010000841
Figure GWB0000003434010000842
Mean RLU of positive controls across the plate;
Figure GWB0000003434010000843
average RLU of blank controls over the entire plate;
Figure GWB0000003434010000844
RLU for each well of the microplate to test compounds.
C: IC50 and plotted effect-dose curves for the test compounds were calculated:
IC was calculated by fitting the logarithm of% inhibition to compound concentration to a non-linear regression (dose response-variable slope) using Graphpad 5.0 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 was derived from the reader and analyzed manually.
C: RLU values were converted to% inhibition. All IC 50's were calculated using% inhibition by Prism GraphPad 6.0.
D: using the RLU values, the IC50 was again calculated to check the accuracy of the analysis results.
E: ensure that all compound IDs are correct.
6) As a result:
Figure GWB0000003434010000851
* IPI549, reference: acsmed, chem, lett, 2016,7:862-867.
As can be seen from the data in the table above, 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 (PI 3K 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 solutions:
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 (10 mM) was placed in its appropriate 96-well rack in sequence. 970 μ L of PBS (pH 7.4) was added to each vial of the uncovered soluble sample plate. The assays were performed in duplicate. Add a stir bar to each vial and use molded PTFE/silicone stoppersAnd (5) sealing. 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, transferring the sample from the dissolvable sample plate 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 added 2 A mixture of O and acetonitrile. A certain proportion of ultrapure water diluent is used 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) 2 A 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 standards of known concentration using LC bound mass spectral peak identification and quantification. The solubility values for the test and control compounds were calculated as follows:
Figure GWB0000003434010000861
[ 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 GWB0000003434010000862
* IPI549, reference: ACS med, chem, lett, 2016,7:862-867.
As can be seen from the above table data, compound 50 has better solubility in PBS (pH 7.4) than IPI-549.
Experimental example 4: the drug effect of the compound in a CT26 tumor-bearing Balb/C mouse is studied.
The anti-tumor effect of different molecular dosing was studied using Balb/C mice bearing tumors of CT26 (mouse intestinal cancer cells).
1) The test method comprises the following steps:
Balb/C mice, purchased from Beijing Wintolite laboratory animal technology Limited, were subcutaneously inoculated with CT26 cells in an amount of 0.3X 106 cells/mouse, and established tumor-bearing models; on day 7 post-inoculation, tumor-bearing mice were randomly and evenly divided into 8 groups, i.e., isotype (1 mg/kg), IPI549 (15 mg/kg), and compound 50 (17.2 mg/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) The investigation indexes are as follows:
the tumor inhibition rate formula is as follows:
tumor inhibition ratio TGI (%) = (Tvol) control -Tvol treated )/(Tvol contro l-Tvol predose )×100％
Tvol control -Tvol treated : tumor terminal volume after administration to control group-tumor terminal volume after administration to the group;
Tvol control -Tvol predose : tumor terminal volume after control dosing-tumor volume before control dosing.
3) As a result:
Figure GWB0000003434010000863
Figure GWB0000003434010000871
as can be seen from the data in the table above, at day 20 after inoculation, both the IPI549 group and the compound 50 group exhibited single drug anti-tumor activity relative to the Isotype group. Moreover, compound 50 has a better anti-tumor effect than the reference compound IPI 549. In addition, no mortality occurred in each group of mice during the experimental 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, can be used for preventing and/or treating diseases at least partially mediated by PI3K, and has multiple purposes of resisting tumors, resisting neurodegenerative diseases (such as Alzheimer disease), resisting inflammation, resisting infection and the like.

Claims (8)

1. A compound having the structure of formula I:
Figure FDA0003938065430000011
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 1 is C 6 -C 10 An aryl group;
R 3 is C 2 -C 6 Alkynyl, C 6 -C 10 aryl-C 2 -C 6 Alkynyl, 5-10 membered heteroaryl-C 2 -C 6 Alkynyl or di (C) 1 -C 6 Alkyl) hypophosphoryl;
R 4 is C 1 -C 6 An alkyl group;
R 6 is-NHSO 2 NH 2 (ii) a And R is 6 Wherein hydrogen is optionally substituted by 0 to more than one R 7 Substituted in which each R 7 Each independently is C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group;
X 0 is-C (= R) 2 ) -, wherein R 2 NOH, S or O;
X 1 is CH;
X 2 is CH;
X 3 is CH;
X 4 is-C (= R) 2 ) -, wherein R 2 Is O;
X 5 is CH or N;
or X 4 And X 5 Form a double bond therebetween, wherein: x 5 Is C, X 4 Is CH;
X 6 is N;
X 7 is CH;
X 8 is-CH 2 -or-NH-;
X 9 is N;
X 10 is CH;
X 11 is CH;
X 12 is CH;
X 13 is N;
X 14 is N;
R 5 is NR 7 NOH or O, wherein R 7 Is C 1 -C 6 An alkyl group.
2. The compound of claim 1, having the structure of formula I, wherein: which is a compound of formula IC:
Figure FDA0003938065430000012
wherein:
R 1 is C 6 -C 10 An aryl group;
R 3 is C 2 -C 6 Alkynyl, C 6 -C 10 aryl-C 2 -C 6 Alkynyl, 5-10 membered heteroaryl-C 2 -C 6 Alkynyl or di (C) 1 -C 6 Alkyl) hypophosphoryl;
R 4 is C 1 -C 6 An alkyl group;
R 6 is-NHSO 2 NH 2 (ii) a And R is 6 Optionally substituted with 0 to more than one R 7 Substituted in which each R 7 Each independently is C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group;
X 1 is CH;
X 2 is CH;
X 3 is CH;
X 4 is CH;
X 6 is N;
X 8 is-CH 2 -or-NH-;
X 9 is N;
X 10 is CH;
X 11 is CH;
X 12 is CH;
X 13 is N;
X 14 is N;
R 5 is NR 7 Or NOH, wherein R 7 Is C 1 -C 6 An alkyl group.
3. A compound having the structure of formula I according to claim 1, characterized in that: which is a compound of formula ID:
Figure FDA0003938065430000021
wherein:
R 1 is C 6 -C 10 An aryl group;
R 3 is C 2 -C 6 Alkynyl, C 6 -C 10 aryl-C 2 -C 6 Alkynyl, 5-10 membered heteroaryl-C 2 -C 6 Alkynyl or di (C) 1 -C 6 Alkyl) hypophosphoryl;
R 4 is C 1 -C 6 An alkyl group;
R 6 is-NHSO 2 NH 2 (ii) a And R is 6 Optionally substituted with 0 to more than one R 7 Substituted in which each R 7 Each independently is C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group;
X 1 is CH;
X 2 is CH;
X 3 is CH;
X 4 is CH;
X 6 is N;
X 7 is CH;
X 8 is-CH 2 -or-NH-;
X 9 is N;
X 10 is CH;
X 11 is CH;
X 12 is CH;
X 13 is N;
X 14 is N;
R 2 is NOH, S or O.
4. The compound of claim 1, having the structure of formula I, wherein: which is a compound of formula IE:
Figure FDA0003938065430000031
wherein:
R 1 is C 6 -C 10 An aryl group;
R 3 is C 2 -C 6 Alkynyl, C 6 -C 10 aryl-C 2 -C 6 Alkynyl, 5-10 membered heteroaryl-C 2 -C 6 Alkynyl or di (C) 1 -C 6 Alkyl) hypophosphoryl;
R 4 is C 1 -C 6 An alkyl group;
R 6 is-NHSO 2 NH 2 (ii) a And R is 6 Optionally substituted with 0 to more than one R 7 Substituted in which each R 7 Each independently is C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group;
X 0 is-C (= R) 2 ) -, wherein R 2 NOH, S or O;
X 1 is CH;
X 2 is CH;
X 3 is CH;
X 5 is CH or N;
X 6 is N;
X 8 is-CH 2 -or-NH-;
X 9 is N;
X 10 is CH;
X 11 is CH;
X 12 is CH;
X 13 is N;
X 14 is N;
R 5 is NR 7 NOH or O, wherein R 7 Is C 1 -C 6 An alkyl group.
5. The following compound, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from:
Figure FDA0003938065430000032
Figure FDA0003938065430000041
Figure FDA0003938065430000051
Figure FDA0003938065430000061
6. a process for the preparation of a compound having the structure of formula I according to any one of claims 1 to 4, comprising:
1) The preparation method of the compound with the structure of formula IC comprises the following steps:
Figure FDA0003938065430000071
s1: replacement of X in Compound IC-1-1 by R 3 To 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; x 4 Is CH; x 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 5 And R 6 A compound of formula IC as defined in claim 2;
2) The preparation method of the compound with the structure of the formula ID comprises the following specific steps:
Figure FDA0003938065430000072
s1: replacement of X in Compound ID-2-1 with R 3 To 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 OH; x 4 Is CH; x 1 、X 2 、X 3 、X 6 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 And R 6 As defined in the compound of formula ID as described in claim 3; and
3) The preparation method of the compound with the structure of the formula IE comprises the following specific steps:
Figure FDA0003938065430000081
s1: the compound IE-1-1 reacts with the compound IE-a to obtain a compound IE-1-2;
s2: reacting the compound IE-1-2 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 R 3 To obtain the 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; x 1 、X 2 、X 3 、X 9 、X 10 、X 11 、X 12 、X 13 And X 14 And R 1 、R 3 、R 4 、R 5 And R 6 A compound of formula IE as defined in claim 4.
7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof.
8. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 7, in the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by PI 3K.
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