CN118201908A - Azabiphenyls and uses thereof - Google Patents

Azabiphenyls and uses thereof Download PDF

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Publication number
CN118201908A
CN118201908A CN202280073839.0A CN202280073839A CN118201908A CN 118201908 A CN118201908 A CN 118201908A CN 202280073839 A CN202280073839 A CN 202280073839A CN 118201908 A CN118201908 A CN 118201908A
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membered
alkylamino
alkyl
ring
halo
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戈伟智
张国利
李韶龙
罗云富
陈曙辉
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
Medshine Discovery Inc
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
Medshine Discovery Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

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Abstract

An aza-biphenyl compound and application thereof, in particular discloses a compound shown in a formula (A) and pharmaceutically acceptable salts thereof.

Description

Azabiphenyls and uses thereof
Citation of related application
The present application claims priority and benefit from chinese application patent application number 202111316594.3 filed at 11 month 08 of 2021, chinese application patent application number 202210678010.5 filed at 06 month 15 of 2022, chinese application patent application number 202211358693.2 filed at 11 month 01 of 2022 to chinese state intellectual property office, the entire disclosure of which is incorporated herein by reference.
Technical Field
The present disclosure relates to the technical field of pharmaceutical chemistry, and in particular relates to an aza-biphenyl compound and application thereof, and specifically relates to a compound represented by formula (a) and pharmaceutically acceptable salts thereof.
Background
IgA nephropathy (IgA Nephropathy) is one of the most common primary glomerulonephritis, accounting for about 25% -50% of primary glomerulonephritis in China. And IgA nephropathy is more frequent in young and middle-aged people. Of those older than 20 years, about 40% will develop end stage renal disease.
Endothelin (endothelin, ET) is a naturally occurring bicyclic peptide consisting of 21 amino acids that is present in plasma. Under the conditions of various pathophysiological factors (aging, diabetes, insulin resistance, obesity, immune system activation, dyslipidemia, active oxygen formation, nitric oxide deficiency, etc.), endothelial cell synthesis is induced and endothelin-1 (ET-1) is released. Endothelin is known as two receptors, the endothelin A receptor (ETR-A) and the endothelin B receptor (ETR-B). Binding of endothelin to ETR-a on vascular smooth muscle cells causes vasoconstriction, cell proliferation and extracellular matrix deposition. Endothelin binds to ETR-B on endothelial cells and can promote vasodilation, anti-cell proliferation and anti-fibrosis by mediating nitric oxide production. The action of endothelin on ETA receptors of kidney cells can produce various physiological effects including vasoconstriction, endothelial cell injury, thickening of vessel walls, tissue infiltration, inflammatory response, mesangial cell proliferation, podocyte injury, etc. Excessive activation of the renal ETA receptor can cause kidney injury and kidney fibrosis, leading to the development and progression of chronic kidney disease, FSGS, igA kidney disease.
Disclosure of Invention
The present disclosure provides a compound of formula (a), or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
Wherein,
Z 1 is selected from N or CR Z1;
Z 2 is selected from N or CR Z2;
R Z1 or R Z2 are each independently selected from H, halogen, -OH, -NH 2、-CN、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di C 1-6 alkylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, halogenated C 1-6 alkylamino, or halogenated di C 1-6 alkylamino;
X is selected from O or NH;
Ring a is selected from the following groups optionally substituted with one or more R a: 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl;
r a is each independently selected from halogen, -OH, oxo 、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-NHC(O)NR a1R a2、-NR a1C(O)OR a2、-OC(O)R a1、-C(O)OR a1、-OC(O)OR a1、-OC(O)NR a1R a2、-C 1-6 alkylene C (O) NR a1R a2、-C 1-6 alkylene NR a1C(O)R a2、-C 1-6 alkylene NHC (O) NR a1R a2、-C 1-6 alkylene NR a1C(O)OR a2、-C 1-6 alkylene OC (O) R a1、-C 1-6 alkylene C (O) OR a1、-C 1-6 alkylene OC (O) NR a1R a2, OR the following optionally substituted with 1 OR more R a3 groups: c 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, 3-12 cycloalkyl, 3-12 heterocycloalkyl, 5-10 heterocyclyl, 6-10 aryl, or 5-10 heteroaryl;
Each R a1、R a2 is independently selected from H or C 1-6 alkyl;
r a3 is each independently selected from halogen, -OH, -NH 2、-CN、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di-C 1-6 alkylamino, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 1-6 alkylthio, halo C 1-6 alkylamino, or halo di-C 1-6 alkylamino;
L is selected from a single bond, -O-, -S-, -NH-, -C (O) -, or the following optionally substituted with one or more R L: -CH 2-、-N(C 1-6 alkyl) -, or-CH (C 1-6 alkyl) -;
R L is each independently selected from halogen, -OH, -NH 2、-CN、C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di-C 1-6 alkylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, halogenated C 1-6 alkylamino, or halogenated di-C 1-6 alkylamino;
Ring D is selected from the following groups optionally substituted with one or more R b: 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
r b is each independently selected from halogen, -OH, -NH 2、-CN、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di-C 1-6 alkylamino, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 1-6 alkylthio, halo C 1-6 alkylamino, or halo di-C 1-6 alkylamino;
Y 1 is selected from-O-, -S-, or-NH-;
Y 2 is selected from -O-、-S-、-NH-、-SO 2-、-NHSO 2-、-SO 2NH-、-NHSO 2NH-、-C(O)NH-、-NHC(O)-、-OC(O)NH-、-NHC(O)O-、 or-NHC (O) NH-;
m is selected from 1, 2, 3, 4, 5, or 6;
Ring C is selected from 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
n is selected from 0, 1, 2, 3, or 4;
R 1 is each independently selected from halogen, -OH, -NH 2、-CN、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di-C 1-6 alkylamino, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 1-6 alkylthio, halo C 1-6 alkylamino, or halo di-C 1-6 alkylamino;
R 2 is selected from H, halogen, -OH, -NH 2, -CN, or the following optionally substituted with one or more R 2a: c 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di C 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
R 2a is each independently selected from oxo, halogen, -OH, -NH 2、-CN、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di-C 1-6 alkylamino, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 1-6 alkylthio, halo C 1-6 alkylamino, or halo di-C 1-6 alkylamino;
R Z1、R Z2、X、R a、R a1、R a2、R a3、R L、R b、R 1、R 2、R 2a、 Ring a, ring D, or ring C are optionally substituted with one or more substituents.
In some embodiments, Z 1 is selected from N.
In some embodiments, Z 1 is selected from CR Z1.
In some embodiments, Z 2 is selected from N.
In some embodiments, Z 2 is selected from CR Z2.
In some embodiments, Z 1 and Z 2 are selected from N.
In some embodiments, Z 1 is selected from CR 1 and Z 2 is selected from CR Z2.
In some embodiments, one of Z 1 and Z 2 is selected from N.
In some embodiments, each R Z1 or R Z2 is independently selected from H, halogen, -OH, -NH 2、-CN、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di C 1-4 alkylamino, halo C 1-4 alkyl, halo C 1-4 alkoxy, halo C 1-4 alkylthio, halo C 1- 4 alkylamino, or halo di C 1-4 alkylamino.
In some embodiments, each R Z1 or R Z2 is independently selected from H, halogen, -OH, -NH 2、-CN、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy.
In some embodiments, each R Z1 or R Z2 is independently selected from H, F, cl, br, -OH, -NH 2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
In some embodiments, each R Z1 or R Z2 is independently selected from H, F, cl, br, -OH, -NH 2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
In some embodiments, R Z1 or R Z2 are each independently selected from H.
In some embodiments, X is selected from O.
In some embodiments, X is selected from NH.
In some embodiments, ring a is selected from the following groups optionally substituted with one or more R a: 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl.
In some embodiments, ring a is selected from the following groups optionally substituted with one or more R a: 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl.
In some embodiments, ring a is selected from the following groups optionally substituted with one or more R a: cyclopropane, cyclobutane, cyclopentane, cyclohexenyl, cycloheptane, bicyclo [1.1.1] pentyl, bicyclo [3.1.0] hexyl, bicyclo [3.2.0] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.3.0] octyl, spiro [3.3] heptyl, spiro [3.4] octyl, oxetane, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxaheptyl, azepanyl, azabicylo [3.1.0] hexyl, oxabicyclo [3.2.0] heptyl, azabicyclo [3.2.0] heptyl, oxabicyclo [2.2.2] octyl, oxabicyclo [3.3.0] octyl, azabicyclo [3.3.0] octyl, oxaspiro [3.3] heptyl, azaspiro [3.3] heptyl, oxaspiro [ 3.0] heptyl, oxaspiro [3.1.0] octyl, oxaspiro [3.4] spiro [3.4] octyl, or spiro [3.4] octyl.
In some embodiments, ring a is selected from the following groups optionally substituted with one or more R a: cyclopropane, spiro [3.3] heptyl, tetrahydrofuranyl, piperidinyl, or oxaspiro [3.3] heptyl.
In some embodiments, ring a is selected from the following groups optionally substituted with one or more R a:
In some embodiments, each R a is independently selected from halogen, -OH, oxo 、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-NHC(O)NR a1R a2、-NR a1C(O)OR a2、-OC(O)R a1、-C(O)OR a1、-OC(O)OR a1、-OC(O)NR a1R a2、-C 1-4 alkylene C (O) NR a1R a2、-C 1-4 alkylene NR a1C(O)R a2、-C 1-4 alkylene NHC (O) NR a1R a2、-C 1-4 alkylene NR a1C(O)OR a2、-C 1-4 alkylene OC (O) R a1、-C 1-4 alkylene C (O) OR a1、-C 1-4 alkylene OC (O) NR a1R a2, OR a group optionally substituted with 1 OR more R a3 of: c 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heterocyclyl, phenyl, or 5-6 heteroaryl.
In some embodiments, each R a is independently selected from halogen, -OH, oxo 、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-OC(O)R a1、-C(O)OR a1、-C 1-4 alkylene C (O) NR a1R a2、-C 1-4 alkylene NR a1C(O)R a2、-C 1-4 alkylene OC (O) R a1、-C 1-4 alkylene C (O) OR a1, OR a group optionally substituted with 1 OR more R a3 of: c 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heterocyclyl, phenyl, or 5-6 heteroaryl.
In some embodiments, each R a is independently selected from F, cl, br, -OH, oxo 、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-OC(O)R a1、-C(O)OR a1、-C 1-2 alkylene C (O) NR a1R a2、-C 1-2 alkylene NR a1C(O)R a2、-C 1-2 alkylene OC (O) R a1、-C 1-2 alkylene C (O) OR a1, OR a group optionally substituted with 1 OR more R a3 of: methyl, ethyl, methoxy, ethoxy, methylamino, or dimethylamino.
In some embodiments, each R a is independently selected from F, cl, br, -OH, oxo, -NH 2、-CN、-C(O)NR a1R a2、-C(O)OR a1, or the following optionally substituted with 1 or more R a3: methyl, ethyl, methoxy, ethoxy, methylamino, or dimethylamino.
In some embodiments, each R a1、R a2 is independently selected from H or C 1-4 alkyl.
In some embodiments, each R a1、R a2 is independently selected from H, methyl, or ethyl.
In some embodiments, each R a1、R a2 is independently selected from H or methyl.
In some embodiments, each R a3 is independently selected from halogen, -OH, -NH 2、-CN、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di C 1-4 alkylamino, halo C 1-4 alkyl, halo C 1-4 alkoxy, halo C 1-4 alkylthio, halo C 1-4 alkylamino, or halo di C 1-4 alkylamino.
In some embodiments, each R a3 is independently selected from H, halogen, -OH, -NH 2、-CN、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di C 1-4 alkylamino, halo C 1-4 alkyl, or halo C 1-4 alkoxy.
In some embodiments, each R a3 is independently selected from H, F, cl, br, -OH, -NH 2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
In some embodiments, each R a3 is independently selected from H, F, cl, br, -OH, -NH 2, -CN, methoxy, or methylamino.
In some embodiments, each R a is independently selected from F, cl, br, -OH, oxo, -NH 2、-CN、-C(O)NR a1R a2、-C(O)OR a1, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
In some embodiments, each R a is independently selected from-C (O) NH 2、-C(O)NHCH 3、-COOH、-COOCH 3, methyl, or methoxy.
In some embodiments, ring a is selected from the following groups optionally substituted with one or more R a: Wherein each R a is independently selected from-C (O) NH 2、-C(O)NHCH 3、-COOH、-COOCH 3, methyl, or methoxy.
In some embodiments, ring a is selected from the following groups:
in some embodiments, L is selected from a single bond, -O-, -S-, -NH-, -C (O) -, or the following optionally substituted with one or more R L: -CH 2-、-N(C 1-3 alkyl) -, or-CH (C 1-3 alkyl) -.
In some embodiments, L is selected from a single bond, -O-, -S-, -NH-, -C (O) -, or the following optionally substituted with one or more R L: -CH 2-、-N(CH 3) -, or-CH (CH 3) -.
In some embodiments, L is selected from a single bond, -O-, -S-, -NH-, -C (O) -, -CH 2-、-N(CH 3) -, or-CH (CH 3) -.
In some embodiments, L is selected from a single bond.
In some embodiments, each R L is independently selected from halogen, -OH, -NH 2、-CN、C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di C 1-4 alkylamino, halo C 1-4 alkyl, halo C 1-4 alkoxy, halo C 1-4 alkylthio, halo C 1-4 alkylamino, or halo di C 1-4 alkylamino.
In some embodiments, each R L is independently selected from H, halogen, -OH, -NH 2、-CN、C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy.
In some embodiments, each R L is independently selected from H, F, cl, br, -OH, -NH 2, -CN, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
In some embodiments, the ring D has at least 1N, O or S atoms in its ring atoms.
In some embodiments, the ring D has at least 2N atoms, at least 1N atom and 1S atom, or at least 2O atoms in its ring atoms.
In some embodiments, the ring atoms of ring D contain only 2N atoms, only 1N atom and 1S atom, or only 2O atoms in addition to the C ring atom.
In some embodiments, ring D is selected from the following groups optionally substituted with one or more R b: 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.
In some embodiments, ring D is selected from the following groups optionally substituted with one or more R b: a 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.
In some embodiments, ring D is selected from the following groups optionally substituted with one or more R b: Wherein ring B is selected from 5-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl, and T 1 is selected from C, or N.
In some embodiments, ring B is selected from
In some embodiments, ring D is selected from the following groups optionally substituted with one or more R b: benzo 5-6 membered cycloalkenyl, benzo 5-6 membered heterocyclyl, pyrido 5-6 membered heterocyclyl, phenyl, naphthyl, or 9-10 membered heteroaryl.
In some embodiments, ring D is selected from the following groups optionally substituted with one or more R b: phenyl, naphthyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, and, Quinolinyl, isoquinolinyl, or benzopyrimidinyl.
In some embodiments, ring D is selected from the following groups optionally substituted with one or more R b: Benzothiazolyl, or
In some embodiments, ring D is selected from the following groups optionally substituted with one or more R b:
In some embodiments, ring D is selected from
In some embodiments, each R b is independently selected from halogen, -OH, -NH 2、-CN、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di C 1-4 alkylamino, halo C 1-4 alkyl, halo C 1-4 alkoxy, halo C 1-4 alkylthio, halo C 1-4 alkylamino, or halo di C 1-4 alkylamino.
In some embodiments, each R b is independently selected from halogen, -OH, -NH 2、-CN、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy.
In some embodiments, each R b is independently selected from F, cl, br, -OH, -NH 2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
In some embodiments, each R b is independently selected from F, cl, br, -OH, -NH 2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
In some embodiments, Y 1 is selected from-O-.
In some embodiments of the present invention, in some embodiments, Y 2 is selected from the group consisting of-O-, -S-, -NH-, -SO 2-、-NHSO 2-、-SO 2 NH-; -C (O) NH-, or-NHC (O) -.
In some embodiments of the present invention, in some embodiments, Y 2 is selected from the group consisting of-O-; -S-, or-NH-.
In some embodiments, Y 2 is selected from-O-.
In some embodiments, Y 1 is selected from-O-, and Y 2 is selected from-O-.
In some embodiments, m is selected from 1,2,3, or 4.
In some embodiments, m is selected from 2,3, or 4.
In some embodiments, m is selected from 2.
In some embodiments, at least 1N, O or S atoms are contained in the ring atoms of ring C.
In some embodiments, the ring C contains 1,2, or 3N atoms, or 1S atom in the ring atoms.
In some embodiments, the ring atoms of ring C contain only N atoms or S atoms in addition to the C ring atoms.
In some embodiments, the ring atoms of ring C contain only 1,2, or 3N atoms, or only 1N atom and 1S atom in addition to the C ring atoms.
In some embodiments, ring C is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.
In some embodiments, ring C is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.
In some embodiments, ring C is selected from 6-10 membered aryl or 5-10 membered heteroaryl.
In some embodiments, ring C is selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, imidazo [1,2-b ] pyridazinyl, pyrazolo [1,5-a ] pyridinyl, quinolinyl, isoquinolinyl, or benzopyrimidinyl.
In some embodiments, ring C is selected from phenyl, naphthyl, thiazolyl, pyridinyl, pyrimidinyl, triazinyl, or imidazo [1,2-b ] pyridazinyl.
In some embodiments, ring C is selected from pyrimidinyl, pyridinyl, thiazolyl, imidazopyridazinyl, and triazinyl.
In some embodiments, ring C is selected from
In some embodiments, n is selected from 0,1, or 2.
In some embodiments, n is selected from 0 or 1.
In some embodiments, each R 1 is independently selected from halogen, -OH, -NH 2、-CN、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di C 1-4 alkylamino, halo C 1-4 alkyl, halo C 1-4 alkoxy, halo C 1-4 alkylthio, halo C 1-4 alkylamino, or halo di C 1-4 alkylamino.
In some embodiments, each R 1 is independently selected from halogen, -OH, -NH 2、-CN、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy.
In some embodiments, each R 1 is independently selected from F, cl, br, -OH, -NH 2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
In some embodiments, each R 1 is independently selected from F, cl, br, -OH, -NH 2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
In some embodiments, each R 1 is independently selected from F, cl, br, or trifluoromethoxy.
In some embodiments, R 2 is selected from H, halogen, -OH, -NH 2, -CN, or the following groups optionally substituted with one or more R 2a: c 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di C 1-4 alkylamino, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkylyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.
In some embodiments, R 2 is selected from H, halogen, -OH, -NH 2, -CN, or the following groups optionally substituted with one or more R 2a: c 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di C 1-4 alkylamino, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl.
In some embodiments, R 2 is selected from H, halogen, -OH, -NH 2, -CN, or the following groups optionally substituted with one or more R 2a: c 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl.
In some embodiments, R 2 is selected from H, F, cl, br, -OH, -NH 2, -CN, or the following groups optionally substituted with one or more R 2a: methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexenyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl.
In some embodiments, R 2 is selected from H, F, cl, br, or the following groups optionally substituted with one or more R 2a: methyl or morpholinyl.
In some embodiments, R 2 is selected from H, methyl, or morpholinyl.
In some embodiments, each R 2a is independently selected from oxo, halogen, -OH, -NH 2、-CN、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di-C 1-4 alkylamino, halo C 1-4 alkyl, halo C 1-4 alkoxy, halo C 1-4 alkylthio, halo C 1-4 alkylamino, or halo di-C 1-4 alkylamino.
In some embodiments, each R 2a is independently selected from oxo, halogen, -OH, -NH 2、-CN、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di C 1-4 alkylamino, halo C 1-4 alkyl, or halo C 1-4 alkoxy.
In some embodiments, each R 2a is independently selected from oxo, F, cl, br, -OH, -NH 2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
In some embodiments, each R 2a is independently selected from oxo, F, cl, br, -OH, -NH 2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
In some embodiments, the compound of formula (A) or a pharmaceutically acceptable salt thereof, wherein,
Z 1 is selected from N;
z 2 is selected from N;
X is selected from O or NH;
Ring a is selected from the following groups optionally substituted with one or more R a: 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;
Each R a is independently selected from-C (O) NH 2、-C(O)NHCH 3、-COOH、-COOCH 3、C 1-4 alkyl, or C 1-4 alkoxy;
L is selected from single bonds;
R L is each independently selected from H, halogen, -OH, -NH 2、-CN、C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy;
Ring D is selected from the following groups optionally substituted with one or more R b: benzo 5-6 membered cycloalkenyl, benzo 5-6 membered heterocyclyl, pyrido 5-6 membered heterocyclyl, phenyl, naphthyl, or 9-10 membered heteroaryl;
R b is each independently selected from F, cl, br, -OH, -NH 2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy;
Y 1 is selected from-O-;
Y 2 is selected from-O-;
m is selected from 1, 2, 3, or 4;
Ring C is selected from 6-10 membered aryl or 5-10 membered heteroaryl;
n is selected from 0, 1, or 2;
Each R 1 is independently selected from halogen, CN, C 1-3 alkyl, and C 1-3 haloalkyl;
r 2 is selected from H, C 1-3 alkyl and C 5-6 heterocycloalkyl.
In some embodiments, the 3-12 membered is selected from 3-10 membered, 3-6 membered, 5-8 membered, or 5-10 membered.
In some embodiments, the heterocycloalkyl contains 1 or 2 heteroatoms selected from N or O.
In some embodiments, the heterocycloalkyl group contains 1N atom.
In some embodiments, the heterocycloalkyl group contains 1O atom.
In some embodiments, the heterocycloalkyl group contains 1N atom and 1O atom.
In some embodiments, the heterocyclyl or heteroaryl contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, the heterocyclyl or heteroaryl contains 1 or 2N atoms.
In some embodiments, the heterocyclyl or heteroaryl contains 1N atom and 1O atom.
In some embodiments, the heterocyclyl or heteroaryl contains 1N atom and 1S atom.
In some embodiments, the heterocyclyl or heterocycloalkyl group includes a monocyclic, spiro, fused or bridged ring form. In some embodiments, the heterocycloalkyl group includes a monocyclic or spiro form. In some embodiments, the heterocyclyl or heterocycloalkyl group includes a monocyclic or bridged ring form.
In some embodiments, the C 1-6 alkyl is selected from C 1-4 alkyl, C 1-3 alkyl, or C 1-2 alkyl.
In some embodiments, the C 1-6 alkylene is selected from C 1-4 alkylene, C 1-3 alkylene, or C 1-2 alkylene.
In some embodiments, the halogen is selected from fluorine, chlorine, bromine, or iodine.
In some embodiments, the halo is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.
In some embodiments, the "one or more" refers to an integer within one to ten, for example "one or more" is selected from 1,2, 3,4,5,6, 7,8, 9, or 10. In some embodiments, the "one or more" is selected from 1,2, 3,4,5, or 6. In some embodiments, the "one or more" is selected from 1,2, 3,4, or 5. In some embodiments, the "one or more" is selected from 1,2, 3, or 4. In some embodiments, the "one or more" is selected from 1,2, or 3.
The present disclosure relates to compounds of formula (A-1), formula (A-2), formula (A-3) or formula (A-4) or a pharmaceutically acceptable salt thereof,
Wherein R 1、R 2、Y 1、Y 2, X, m, n, L, ring A, ring D, and ring C are as defined in the disclosure (A).
In some embodiments, the present disclosure includes the variables defined above and embodiments thereof, as well as any combination thereof.
The present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
Wherein,
T 1 is selected from C and N;
Ring B is selected from 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl;
Structural unit Optionally substituted with one or more R b;
R 1、R 2、R b, X, n, ring A and ring C are as defined in the disclosure for formula (A) above.
In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein,
R 1 is selected from halogen, CN, C 1-3 alkyl and C 1-3 haloalkyl;
R 2 is selected from H, C 1-3 alkyl and C 5-6 heterocycloalkyl;
X is selected from O and NH;
t 1 is selected from C and N;
Ring a is selected from C 3-10 cycloalkyl and 5-10 membered heterocycloalkyl, which C 3-10 cycloalkyl and 5-10 membered heterocycloalkyl are optionally substituted with 1,2 or 3R a;
Ring B is selected from 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl;
Ring C is selected from 5-10 membered heteroaryl;
R a is selected from halogen, CN, C 1-3 alkyl, C 1-3 alkoxy and-C (O) R;
R is selected from-OH, C 1-3 alkoxy, -NH 2, and C 1-3 alkylamino;
n is selected from 1 and 2.
In some aspects of the disclosure, in the compound of formula (a) or formula (II), or a pharmaceutically acceptable salt thereof, R 1 is selected from F, cl, br, CH 3 and CF 3, and the other variables are as defined in the disclosure.
In some aspects of the disclosure, in the compound of formula (a) or formula (II), or a pharmaceutically acceptable salt thereof, R 2 is selected from H, CH 3 and morpholinyl, and the other variables are as defined in the disclosure.
In some embodiments of the present disclosure, in the compounds of formula (a) or (II), or pharmaceutically acceptable salts thereof, R a is selected from methyl and methoxy, and the other variables are as defined in the disclosure.
In some aspects of the disclosure, in the compound of formula (a) or formula (II), or a pharmaceutically acceptable salt thereof, ring a is selected from cyclopropyl, bicyclo [1.1.1] pentyl, spiro [3.3] heptyl, 2-oxospiro [3.3] heptyl, piperidinyl, and tetrahydrofuranyl, the cyclopropyl, bicyclo [1.1.1] pentyl, spiro [3.3] heptyl, piperidinyl, and tetrahydrofuranyl being optionally substituted with 1,2, or 3R a, and the other variables are as defined in the disclosure.
In some embodiments of the present disclosure, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, ring a is selected from The other variables are as defined in the disclosure.
In some embodiments of the present disclosure, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, ring B is selected from The other variables are as defined in the disclosure.
In some embodiments of the present disclosure, the compound of formula (II), or a pharmaceutically acceptable salt thereof, ring C is selected from pyrimidinyl, pyridinyl, thiazolyl, imidazopyridazinyl, and triazinyl, and the other variables are as defined herein.
In some embodiments of the present disclosure, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, ring C is selected from The other variables are as defined in the disclosure.
The present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from:
Wherein,
R 1 is selected from halogen, CN, C 1-3 alkyl or C 1-3 haloalkyl;
X is selected from O or NH;
T 1 is selected from C or N;
ring a is selected from C 3-10 cycloalkyl or 5-10 membered heterocycloalkyl, said C 3-10 cycloalkyl and 5-10 membered heterocycloalkyl being optionally substituted by 1,2 or 3R a;
Ring B is selected from 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl;
Ring C is selected from 5-10 membered heteroaryl;
R a is selected from halogen, CN, C 1-3 alkyl or C 1-3 alkoxy;
The "hetero" of the heterocycloalkyl, heterocycloalkenyl, or heteroaryl group includes 1,2, or 3 heteroatoms independently selected from N, O, S or Se.
In some aspects of the disclosure, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 is selected from F, cl, br, CH 3 or CF 3, and the other variables are as defined in the disclosure.
In some embodiments of the present disclosure, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, R a is selected from methyl or methoxy, and the other variables are as defined in the disclosure.
In some aspects of the disclosure, in the compound of formula (I), or a pharmaceutically acceptable salt thereof, ring a is selected from cyclopropyl, bicyclo [1.1.1] pentyl, spiro [3.3] heptyl, 2-oxospiro [3.3] heptyl, or tetrahydrofuranyl, optionally substituted with 1,2, or 3R a, and the other variables are as defined herein.
In some embodiments of the present disclosure, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, ring a is selected fromThe other variables are as defined in the disclosure.
In some embodiments of the present disclosure, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, ring B is selected from The other variables are as defined in the disclosure.
In some embodiments of the present disclosure, the compound of formula (I), or a pharmaceutically acceptable salt thereof, ring C is selected from pyrimidinyl, and the other variables are as defined herein.
Still other aspects of the present disclosure are derived from any combination of the variables described above.
The present disclosure also provides a compound of the formula or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
In another aspect, the present disclosure relates to pharmaceutical compositions comprising a compound of formula (I), formula (II), formula (A-1), formula (A-2), formula (A-3), or formula (A-4) of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions of the present disclosure further comprise a pharmaceutically acceptable excipient.
In another aspect, the present disclosure relates to a method of treating ETA receptor-related disorders in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I), formula (II), formula (A-1), formula (A-2), formula (A-3), or formula (A-4), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
In another aspect, the present disclosure relates to the use of a compound of formula (I), formula (II), formula (A-1), formula (A-2), formula (A-3), or formula (A-4), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating an ETA receptor-related disorder.
In another aspect, the present disclosure relates to the use of a compound of formula (I), formula (II), formula (A-1), formula (A-2), formula (A-3), or formula (A-4), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, in the treatment of an ETA receptor-related disorder.
In another aspect, the present disclosure relates to a compound of formula (I), formula (II), formula (A-1), formula (A-2), formula (A-3), or formula (A-4), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in treating an ETA receptor-related disorder.
In some embodiments of the disclosure, the ETA receptor related disease is selected from IgA nephropathy.
The disclosure also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing medicaments related to IgA nephropathy.
The present disclosure also provides the following test methods:
test method 1: in vitro test of ETA receptor antagonistic effect in human body
The purpose of the experiment is as follows:
Antagonist activity of the compounds at human ET A receptor expressed endogenously in SK-N-MC cells was assessed by measuring the effect of the compounds on human ET A receptor agonist-induced changes in cytoplasmic Ca 2+ ion signal using fluorescence detection methods. Functional activity of ET A receptor antagonism was tested at Eurofins-Cerep SA according to the current standard procedure.
Experimental protocol:
1. Cells were suspended in Dulbecco's modified Eagle medium solution (DMEM, invitrogen) supplemented with 1% fcsd and then distributed in 384 plates (100 μl/well) at a density of 5×10 4 cells/well;
2. Carboxybenzenesulfonamide was mixed with fluorescent probes (Fluo 4NW, invitrogen) in Hank's balanced salt solution (HBSS, invitrogen) supplemented with 20mm 4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid (Hepes, invitrogen) (ph 7.4), added to each well, then equilibrated with cells at 37 ℃ for 60 minutes, and then equilibrated with cells at 22 ℃ for 15 minutes;
3. The assay plate was placed in a microplate reader (CellLux, perkinElmer), a DMSO solution or HBSS buffer of appropriate concentration of test compound and positive control was added, and after 5 minutes 1nM endothelin-1 or HBSS buffer (base control) was added, and then the change in fluorescence intensity was measured in proportion to the Ca 2+ ion concentration of free cytosol;
4. The result is a percent inhibition of control response to 1nM endothelin-1;
5. The standard positive control was BQ-123, several concentrations were tested in each experiment, and the compound IC 50 values were calculated using Prism analysis data to generate a concentration-response curve.
Test method 2: in vitro test of human ETB receptor antagonistic effect
The purpose of the experiment is as follows:
Antagonist activity of the compounds at human ET B receptor expressed in transfected CHO cells was assessed by measuring the effect of the compounds on human ET B receptor agonist-induced changes in cytoplasmic Ca 2+ ion signal using fluorescence detection methods. Functional activity of ET B receptor antagonism was tested at Eurofins-Cerep SA according to the current standard procedure.
Experimental protocol:
1. Cells were suspended in DMEM buffer (Invitrogen) and then distributed in 384 plates (100 μl/well) at a density of 3×10 4 cells/well;
2. Carboxybenzenesulfonamide was mixed with fluorescent probes (Fluo 4 Direct, invitrogen) in HBSS buffer (Invitrogen) supplemented with 20mM Hepes (Invitrogen) (ph 7.4), added to each well, then equilibrated with cells for 60 min at 37 ℃ and 15 min at 22 ℃;
3. The assay plate was placed in a microplate reader (CellLux, perkinElmer), a DMSO solution or HBSS buffer of appropriate concentration of test compound and positive control was added, and after 5 minutes 0.3nM endothelin-1 or HBSS buffer (base control) was added, and then the change in fluorescence intensity was measured in proportion to the Ca 2+ ion concentration of free cytosol;
4. The result is a percent inhibition of the control response to 0.3nM endothelin-1;
5. The standard positive control was BQ-788, several concentrations were tested in each experiment, and the compound IC 50 values were calculated using Prism analysis data to generate a concentration-response curve.
Test method 3: pharmacokinetic testing of rats
The purpose of the experiment is as follows: pharmacokinetic parameters of the compounds in SD rats were determined.
The experimental method comprises the following steps:
1. The project uses 4 male SD rats, and a group of 2 SD rats are administrated by intravenous injection, wherein the administration dosage is 2mg/kg, and the administration concentration is 0.5mg/mL; an additional group of 2 SD rats was orally administered at a dose of 10mg/kg at a concentration of 1mg/mL;
2. Plasma samples were collected at 0.083 (intravenous group only), 0.25, 0.5, 1,2, 4, 6, 8, 24h post-dose.
3. Blood samples were collected and placed on ice and the plasma was centrifuged within 1 hour (centrifugation conditions: 6000g,3 minutes, 2-8 ℃). The plasma samples were stored in a-80 ℃ freezer prior to analysis.
4. The collected samples were then subjected to LC-MS/MS analysis and data were collected. The collected analytical data was used to calculate relevant pharmacokinetic parameters using Phoenix WinNonlin.2.0 software.
Test method 4: in vivo efficacy study
Test purpose: exploring the therapeutic effect of the tested medicine on Thy1 nephritis
Experimental protocol:
1. 50 rats were anesthetized with isoflurane gas. After general anesthesia, unilateral nephrectomy was performed on the right side of the rat; right kidney was resected, followed by suture administration of antibiotics; control rats were operated in the same model group but without kidney excision. One week after unilateral kidney excision, the tail of a model group rat is injected with 1mg/kg of anti-Thy1 anti-body intravenously, a control group rat is injected with an equal volume of normal saline intravenously, and the urine of the rat is collected for 24 hours on the third day after injection, so that the total protein content of the urine is detected; the rats with unsuccessful modeling were removed and the modeling rats were randomly divided into 6 groups, group-2, group-3, group-4, group-5, group-6, group-7, using a simple random method based on urine protein data.
2. The fourth day after antibody injection, groups-1 and-2 rats are infused with the same volume of solvent once a day, the gastric infusion volume is 1mL/100g, and the administration is continued for 4 weeks; group-3 rats were gavaged 5mg/kg prednisone once daily with a gavage volume of 1mL/100g for 4 weeks; group-4 rats were gavaged twice a day with a gavage volume of 1mL/100g for 28 consecutive days; group-5, group-6 and Group-7 rats were given a gavage of 1mL/100g, once a day, for 28 consecutive days. Group-4, 5, 6, after the end of the last administration and 24 hours urine protein collection, the administration is carried out once again according to the corresponding dosage, blood is collected in a crossing way at 0, 0.5, 1,4, 8, 24 hours after the administration, and three plasma samples of rats are collected at each time point and stored at-80 ℃.
3. The third day after antibody injection, the 7 th day after administration and the 28 th day after administration respectively collect 24h urine of the rat, and detect the 24h urine protein content; after urine collection, blood samples of each group of rats were taken to detect hematocrit.
4. After the blood collection, the rats are euthanized by a CO 2 method, kidney tissues are collected, and PAS staining is performed to observe the pathological changes of the kidney tissues.
Technical effects
The compounds of the present disclosure all exhibit extremely high activity in vitro antagonism of the human ET A receptor, have good in vivo efficacy, and have good exposure and bioavailability, and are capable of alleviating rat kidney injury.
Definition and description
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present disclosure prepared from the compounds of the present disclosure which have a particular substituent with a relatively non-toxic acid or base. When relatively acidic functionalities are included in the compounds of the present disclosure, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When relatively basic functional groups are included in the compounds of the present disclosure, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in a pure solution or in a suitable inert solvent. Certain specific compounds of the present disclosure contain basic and acidic functionalities that can be converted to either base or acid addition salts.
Pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
The words "comprise" or "include" and variations thereof such as "comprises" or "comprising" are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to.
Unless otherwise indicated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.
The compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present disclosure.
Unless otherwise indicated, when there is a double bond structure in a compound, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is attached to two different substituents (of the double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is considered as one substituent to which it is attached), if a wavy line is used between the atom on the double bond and its substituent in the compoundThe term "attached" means the (Z) isomer, (E) isomer or a mixture of both isomers of the compound.
Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.
Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" is caused by the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely.
Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers of a molecule having two or more chiral centers and having a non-mirror relationship between the molecules.
Unless otherwise indicated, "(+)" means dextrorotation, "(-)" means levorotatory, "(±)" means racemization.
Unless otherwise indicated, with solid wedge bondsAnd a wedge-shaped dotted bondRepresenting the absolute configuration of a solid centre by straight solid keysAnd straight dotted line keyRepresenting the relative configuration of the three-dimensional center by wavy linesSolid key representing wedge shapeOr wedge-shaped dotted bondOr by wave linesRepresenting straight solid keysOr straight dotted line key
Unless otherwise indicated, the terms "enriched in one isomer", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100% and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or enantiomers. For example, where one isomer or enantiomer is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomer excess (ee value) is 80%.
Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Or when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), forms a diastereomeric salt with an appropriate optically active acid or base, and then undergoes diastereomeric resolution by conventional methods well known in the art, followed by recovery of the pure enantiomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).
The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine isomerisation. A specific example of a proton tautomer is an imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include tautomers by recombination of some bond-forming electrons.
The compounds of the present disclosure may have one or more atropisomers, which refer to photoactive isomers resulting from the blockage of free rotation between single bonds, unless otherwise indicated. The chiral axis containing compounds of the present disclosure may be isolated in racemic form. When the single bond free rotation energy barrier of the present disclosure containing chiral axis compounds is sufficiently high, the atropisomers thereof may be isolated in a photoactive pure form.
The compounds of the present disclosure may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with a radioisotope, such as tritium (3 H), iodine-125 (125 I) or C-14 (14 C). For example, deuterium can be substituted for hydrogen to form a deuterated drug, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, so that the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life of the drug and the like compared with the non-deuterated drug. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.
The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl can be unsubstituted (CH 2CH 3), monosubstituted (e.g., CH 2CH 2 F), polysubstituted (e.g., CHFCH 2F、CH 2CHF 2, etc.), or fully substituted (CF 2CF 3). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, which may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =o), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group. The term "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.
The "substituents" as referred to herein include all substituents mentioned in the present context, such as the terms "alkyl", "heteroalkyl", "alkoxy", "alkylamino", "dialkylamino", "alkylsulfonyl", "alkylthio", "alkenyl", "alkynyl", "cycloalkyl", "cycloalkenyl", "heterocyclyl", "heterocycloalkyl", "aryl", "heteroaryl" and the like as referred to hereinafter, and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include hydroxy, mercapto, halogen, amino, nitro, nitroso, cyano, azido, sulfoxide, sulfone, sulfonamide groups, Carboxy, aldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, heterocycloalkyl, halo-heterocycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, arylalkylene, arylalkyloxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkylene, heteroarylalkoxy, heteroarylalkylthio, heterocycloalkylthio, heterocycloalkyloxy, heterocyclylthio, heterocycloalkylene, heterocycloalkyloxy, heterocyclylalkylthio, acyl, acyloxy, carbamate, amide, urea, epoxy, ester, oxo, and the like, optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH 2, -C (O) NH-alkyl, -C (O) N (alkyl) 2, -NHC (O) -alkyl, -C (O) -alkyl, -S (O) 2 -alkyl, -S (O) 2NH 2、-S(O) 2 NH-alkyl, -S (O) 2 N (alkyl) 2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocyclylalkylene, heterocyclylalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
In some embodiments herein, the substituents are selected from the group consisting of hydroxy, mercapto, halogen, amino, nitro, nitroso, cyano, azido, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 alkyl, halo-C 1-12 alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, halo-3-12 membered heterocycloalkyl, C 2-12 alkenyl, halo-C 2-12 alkenyl, 3-12 membered cycloalkenyl, halo-3-12 membered cycloalkenyl, C 2-12 alkynyl, halo-C 2-12 alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkynyl, C 1-12 heteroalkyl, halo-C 1-12 heteroalkyl, C 1-12 alkoxy, C 1-12 alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 alkylene, 6-10 membered arylC 1-12 alkoxy, 6-10 membered arylC 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclyl C 1-12 alkylene, 3-12 membered heterocyclyl C 1-12 alkoxy, 3-12 membered heterocyclyl C 1-12 alkylthio, C 1-12 acyl, C 1-12 acyloxy, carbamate group, C 1-12 amido, Ureido, epoxy, C 2- 12 ester groups, and oxo, said substituents optionally being substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, C 1-12 alkylamino, di C 1-12 alkylamino, halogenated C 1-12 alkylamino, Halogenated di-C 1-12 alkylamino, carboxy, -C (O) O-C 1-12 alkyl, -OC (O) -C 1-12 alkyl, -C (O) NH 2、-C(O)NH-C 1-12 alkyl, -C (O) N (C 1-12 alkyl) 2、-NHC(O)-C 1-12 alkyl, -C (O) -C 1-12 alkyl, -S (O) -C 1-12 alkyl, -S (O) 2-C 1-12 alkyl, -S (O) 2NH 2、-S(O) 2NH-C 1-12 alkyl, -S (O) 2N(C 1-12 alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyl C 1-12 alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl C 1-12 alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl C 1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl C 1-12 alkylene or 6-10 membered aryloxy.
Unless otherwise specified, the term "halo" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
Herein, C m-n is that portion having an integer number of carbon atoms in the given range. For example, "C 1-6" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if one group is substituted with 2R's, then each R has an independent option.
When the number of one linking group is 0, such as- (CH 2) 0) -it means that the linking group is a covalent bond.
When one of the variables is selected from a covalent bond, the two groups representing its attachment are directly linked, e.g., when L in A-L-Z represents a covalent bond, it is meant that the structure is actually A-Z. When the exemplified linking group does not indicate its linking direction, its linking direction is arbitrary, such as in A-L-Z, the linking group L is-M-W-, in which case it means that the structure may be A-M-W-Z or A-W-M-Z.
When the bond of a substituent is cross-linked to two atoms on a ring, the substituent may be bonded to any atom on the ring. For example, structural unitsMeaning that it may be substituted at any one position on the cyclohexyl or cyclohexadiene.
The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
The term "hydroxy" refers to an-OH group.
The term "cyano" refers to a-CN group.
The term "mercapto" refers to a-SH group.
The term "amino" refers to the-NH 2 group.
The term "nitro" refers to the-NO 2 group.
The term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, sulfur, silicon and phosphorus. In one embodiment, the heteroatom is selected from N, O and S.
The term "alkylene" refers to a saturated straight or branched chain divalent hydrocarbon radical of the general formula C nH 2n, typically having 1 to 20, 1 to 18, 1 to 16, 1 to 14, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1-6 alkylene" refers to an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2CH 2 -), propylene (-CH 2CH 2CH 2 -or-CH 2CH(CH 3) -), butylene (-CH 2CH 2CH 2CH 2-、-CH 2CH(CH 3)CH 2 -or-CH 2CH 2CH(CH 3) -), pentylene, hexylene, heptylene, octylene, nonylene, decylene, and the like. The alkylene group is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group of the general formula C nH 2n+1, typically having 1 to 12,1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl group may be straight or branched and typically has 1 to 12,1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms. For example, the term "C 1- 6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). The term "C 1-3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms, said C 1-3 alkyl group including C 1-2 and C 2-3 alkyl groups and the like; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like. The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy. Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio have the same definition as above.
The term "C 1-6 haloalkyl" or "halo C 1-6 alkyl" means, unless otherwise specified, monohaloalkyl and polyhaloalkyl groups containing from 1 to 6 carbon atoms.
The term "C 1-6 haloalkyl" or "halo C 1-6 alkyl" means, unless otherwise specified, monohaloalkyl and polyhaloalkyl groups containing from 1 to 6 carbon atoms. The "C 1-6 haloalkyl" or "halogenated C 1-6 alkyl" includes C 1-5、C 1-4、C 1-3、C 1-2、C 2-5、C 2-4、C 2-3、C 6、C 5、C 4、C 3、C 2、 and C 1 haloalkyl, and the like. The C 1-3 haloalkyl includes C 1-2、C 2-3、C 3、C 2 and C 1 haloalkyl, and the like. Examples of C 1-3 haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, 2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, 3-bromopropyl, and the like.
The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and the hydrogen atoms attached thereto) are each independently replaced with the same or a different heteroatom group. Unless otherwise indicated, the heteroalkyl group contains 1,2, or 3 heteroatom groups, non-limiting examples of which include O, S, N or NH, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1- 6 heteroalkyl" refers to a heteroalkyl group containing 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom group may be placed at any position (e.g., an internal or terminal position) of the heteroalkyl group, including the position where the heteroalkyl group is attached to the remainder of the molecule. Typically, where more than one heteroatom group is present, the heteroatom groups are not adjacent to each other. Exemplary heteroalkyl groups include, but are not limited to, alkoxy, alkoxyalkylene, alkylamino, alkylaminoalkylene, dialkylamino, dialkylaminoalkylene, and the like. The heteroalkyl is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
The term "alkoxy" refers to an-O-alkyl group, typically having 1 to 12,1 to 8,1 to 6,1 to 4,1 to 3, or 1 to 2 carbon atoms. Wherein the alkyl moiety is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
The term "alkylamino" refers to an-NH-alkyl group, typically having 1 to 12,1 to 8,1 to 6,1 to 4,1 to 3, or 1 to 2 carbon atoms. Wherein the alkyl moiety is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
The term "dialkylamino" refers to-N (alkyl) 2, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, e.g., di C 1-12 alkylamino refers to-N (C 1-12 alkyl) 2, having 1 to 12 carbon atoms. Wherein the alkyl moiety is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
The term "alkylsulfonyl" refers to an-SO 2 -alkyl group, typically having 1 to 12,1 to 8,1 to 6, 1 to 4,1 to 3, or 1 to 2 carbon atoms. Wherein the alkyl moiety is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
The term "alkylthio" refers to an-S-alkyl group, typically having 1 to 12,1 to 8,1 to 6,1 to 4,1 to 3, or 1 to 2 carbon atoms. Wherein the alkyl moiety is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond consisting of carbon atoms and hydrogen atoms, typically having 2 to 12, 2 to 8,2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like. The alkenyl group is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one triple bond consisting of carbon atoms and hydrogen atoms, typically having 2 to 12, 2 to 8, 2 to 6,2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), 1-propynyl (-C.ident.C-CH 3), 2-propynyl (-CH 2 -C.ident.CH), 1, 3-butanediynyl (-C.ident.C-C.ident.CH), and the like. The alkynyl group is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
The term "cycloalkyl" refers to a carbocycle that is fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the carbocycle is typically a3 to 12 membered ring, a3 to 10 membered ring, a3 to 8 membered ring, a3 to 6 membered ring, a 5 to 8 membered ring, or a 5 to 6 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, norbornane (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantane, and the like. The cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH 2, -C (O) NH-alkyl, -C (O) N (alkyl) 2, -NHC (O) -alkyl, -C (O) -alkyl, -S (O) 2 -alkyl, -S (O) 2NH 2、-S(O) 2 NH-alkyl, -S (O) 2 N (alkyl) 2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
Unless otherwise specified, "C 3-10 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 10 carbon atoms, which includes monocyclic, bicyclic, and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, fused, and bridged rings. The C 3-10 cycloalkyl group comprises C 3-8、C 3-6、C 3-5、C 4-10、C 4-8、C 4-6、C 4-5、C 5-8, C 5-6 and the like; it may be monovalent, divalent or multivalent. Examples of C 3-10 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] bicyclooctane, and the like.
The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is partially unsaturated, has at least one double bond, and may exist as a single ring, bridged ring, and ring or spiro ring. Unless otherwise indicated, the carbocycle is typically a3 to 10 membered ring, a 4 to 8 membered ring, a 5 to 8 membered ring, or a 5 to 6 membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like. The cycloalkenyl is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH 2, -C (O) NH-alkyl, -C (O) N (alkyl) 2, -NHC (O) -alkyl, -C (O) -alkyl, -S (O) 2 -alkyl, -S (O) 2NH 2、-S(O) 2 NH-alkyl, -S (O) 2 N (alkyl) 2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
The term "carbocyclyl" refers to a non-aromatic carbocycle that is partially unsaturated and may exist as a single ring, bridged ring, and ring or spiro ring. Unless otherwise indicated, the carbocycle is typically a3 to 12 membered, 3 to 10 membered, 3 to 8 membered, 4 to 8 membered, 5 to 6 membered, 3 to 7 membered, 3 to 6 membered, or 4 to 6 membered ring. Non-limiting examples of carbocyclyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, benzocyclopentenyl, benzocyclopentadienyl, benzocyclohexenyl, benzocyclohexadienyl, and the like. The carbocyclyl is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH 2, -C (O) NH-alkyl, -C (O) N (alkyl) 2, -NHC (O) -alkyl, -C (O) -alkyl, -S (O) 2 -alkyl, -S (O) 2NH 2、-S(O) 2 NH-alkyl, -S (O) 2 N (alkyl) 2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
The term "heterocyclyl" refers to a non-aromatic ring that is partially unsaturated and may exist as a single ring, bridged ring, and ring, or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3 to 12 membered, 3 to 10 membered, 3 to 8 membered, 4 to 8 membered, 5 to 6 membered, 3 to 7 membered, 3 to 6 membered, or 4 to 6 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and/or boron. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, and the like. The heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH 2, -C (O) NH-alkyl, -C (O) N (alkyl) 2, -NHC (O) -alkyl, -C (O) -alkyl, -S (O) 2 -alkyl, -S (O) 2NH 2、-S(O) 2 NH-alkyl, -S (O) 2 N (alkyl) 2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
Unless otherwise specified, the term "5-6 membered heterocycloalkenyl" alone or in combination with other terms, respectively, denotes a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond, 1,2, 3 or 4 of which are heteroatoms independently selected from O, S, N and Se, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e. NO and S (O) p, p is 1 or 2). It includes both monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings, and any ring of such a system is non-aromatic. In addition, with respect to the "5-6 membered heterocycloalkenyl", the heteroatom may occupy the position of attachment of the heterocycloalkenyl to the remainder of the molecule. The 5-6 membered heterocycloalkenyl group includes 5-and 6-membered heterocycloalkenyl groups and the like. Examples of 5-6 membered heterocycloalkenyl groups include, but are not limited to
The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3 to 12 membered, 3 to 10 membered, 4 to 8 membered, 5 to 10 membered, 5 to 8 membered, 5 to 6 membered, 3 to 7 membered or 4 to 6 membered ring containing 1 to 4 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from O, S, N, se, P, si and/or B, wherein the nitrogen atoms are optionally quaternized and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e. NO and S (O) p, p is 1 or 2). The heterocycloalkyl groups include monocyclic, bicyclic, and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, fused, and bridged rings. In addition, in the heterocycloalkyl group, the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the remainder of the molecule. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, mercaptoethane, cyclic aziridine, non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thioxalkyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, Examples of 1, 4-dithianyl, 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepinyl, thiepanyl. The heterocycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH 2, -C (O) NH-alkyl, -C (O) N (alkyl) 2, -NHC (O) -alkyl, -C (O) -alkyl, -S (O) 2 -alkyl, -S (O) 2NH 2、-S(O) 2 NH-alkyl, -S (O) 2 N (alkyl) 2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
Unless otherwise specified, the term "5-10 membered heterocycloalkyl" by itself or in combination with other terms, denotes a saturated cyclic group consisting of 3 to 10 ring atoms, 1,2, 3 or 4 of which are heteroatoms independently selected from O, S, N and Se, the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e. NO and S (O) p, p is 1 or 2), respectively. It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, fused and bridged rings. In addition, with respect to the "5-10 membered heterocycloalkyl" group, the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the remainder of the molecule. The 5-10 membered heterocycloalkyl group includes 5-8 membered, 5-6 membered, 5-membered and 6-membered heterocycloalkyl groups and the like. Examples of 5-10 membered heterocycloalkyl groups include, but are not limited to, 5-pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, or dioxacycloheptyl, etc.
The term "aryl" refers to an all-carbon monocyclic or fused-polycyclic aromatic ring radical having a conjugated pi-electron system. For example, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl, among others. The aryl group is optionally substituted with one or more substituents selected from the group consisting of: hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH 2, -C (O) NH-alkyl, -C (O) N (alkyl) 2, -NHC (O) -alkyl, -C (O) -alkyl, -S (O) 2 -alkyl, -S (O) 2NH 2、-S(O) 2 NH-alkyl, -S (O) 2 N (alkyl) 2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocyclylalkylene, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic system containing at least one ring atom selected from N, O, S and Se, the remaining ring atoms being C, typically having 5 to 14, 5 to 12, 5 to 10, 5 to 8, 5 to 7 or 5 to 6 membered rings, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p, p is 1 or 2). The heteroaryl group may be attached to the remainder of the molecule through a heteroatom or carbon atom. Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 6 membered ring, or multiple fused rings containing 5 to 14, especially 5 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like. The heteroaryl is optionally substituted with one or more substituents selected from the group consisting of: hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C (O) O-alkyl, -OC (O) -alkyl, -C (O) NH 2, -C (O) NH-alkyl, -C (O) N (alkyl) 2, -NHC (O) -alkyl, -C (O) -alkyl, -S (O) 2 -alkyl, -S (O) 2NH 2、-S(O) 2 NH-alkyl, -S (O) 2 N (alkyl) 2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocyclylalkylene, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
The term "5-10 membered heteroaryl" is, unless otherwise specified, a cyclic group with conjugated pi electron system consisting of 5 to 10 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S, N and Se, the remainder being carbon atoms. It may be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. Wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p, p is 1 or 2). The 5-10 membered heteroaryl group may be attached to the remainder of the molecule through a heteroatom or carbon atom. The 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered, 6 membered heteroaryl, and the like. Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl and the like), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl and the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl and the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl and the like), triazolyl (1H-1, 2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl and the like), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl and the like), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl and the like), furanyl (including 2-furanyl and 3-furanyl and the like), thienyl (including 2-thienyl and 3-thienyl and the like), pyridyl (including 2-pyridyl, 3-pyridyl, and the like), pyrimidyl (including 2-pyridyl, 4-pyridyl, 5-pyridyl, and the like), pyrimidyl (including the like), pyrimidyl, and the like), and the pyrimidyl (including the 2-pyridyl (including the 2-thiazolyl, 4-thiazolyl, the 4-isoxazolyl, the 5-pyridyl and the like), isoquinolinyl (including 1-isoquinolinyl, 5-isoquinolinyl, and the like), quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl, and the like), or quinolinyl (including 3-quinolinyl, 6-quinolinyl, and the like).
The term "5-6 membered heteroaryl" means, unless otherwise specified, a monocyclic group having a conjugated pi-electron system consisting of 5 to 6 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S, N and Se, the remainder being carbon atoms. Wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p, p is 1 or 2). The 5-6 membered heteroaryl group may be attached to the remainder of the molecule through a heteroatom or carbon atom. The 5-6 membered heteroaryl groups include 5-and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl and the like), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl and the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl and the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl and the like), triazolyl (1H-1, 2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl and the like), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl and the like), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl and the like), furanyl (including 2-furanyl and 3-furanyl and the like), thienyl (including 2-thienyl and the like), pyridyl (including 2-pyridyl and the 3-pyridyl (including the 2-pyridyl and the 4-pyridyl group and the like), pyrimidyl and the like.
The groups Y 1 and Y 2 in the present disclosure are linked in a left to right reading order, corresponding to the left and right groups linked to Y 1 or Y 2 in the general formula shown.
Radicals in the present disclosureIncluding but not limited to
It should be understood that structural fragmentsThe C atom in (2) is a ring atom of ring A and is bonded to an S atom outside ring A.
The term "treating" means administering a compound or formulation described in the present disclosure to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) Inhibiting a disease or disease state, i.e., inhibiting its progression;
(ii) The disease or condition is alleviated, even if the disease or condition subsides.
The term "preventing" means that the compounds or formulations described in the present disclosure are administered to prevent a disease or one or more symptoms associated with the disease, including preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state, but has not yet been diagnosed as having the disease state.
The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and disclosure.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.
The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
The pharmaceutical compositions of the present disclosure may be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of the compounds of the present disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present disclosure may be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, and the like.
In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, troches, dragees, capsules, gels, slurries, suspensions and the like for oral administration to a patient.
The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
In all methods of administration of the compounds of formula (I) of the present disclosure, the daily dosage is from 0.01 to 200mg/kg body weight, and the compounds of the present disclosure may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining with other chemical synthetic methods, and equivalents well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.
The compounds of the present disclosure may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.
Some of the compounds of formula (a) of the present disclosure may be prepared by one skilled in the art of organic synthesis via scheme 1,
Route 1
Wherein Y 1 and Y 2 may be O; r 1、R 2, X, m, n, L, ring A, ring D, and ring C are as defined in the disclosure (A).
The compounds of formula (I) of the present disclosure may be prepared by one skilled in the art of organic synthesis via scheme 2,
Route 2
Wherein R 1、n、T 1, ring A, ring B, and ring C are as defined in the disclosure (I).
Each of the products obtained by the reactions in the above schemes may be obtained by conventional separation techniques including, but not limited to, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials may be synthesized by themselves or purchased from commercial institutions (e.g., without limitation Adrich or Sigma). These materials can be characterized using conventional means such as physical constants and spectral data. The compounds described in this disclosure may be synthesized using synthetic methods to give a single isomer or a mixture of isomers.
The compounds of the present disclosure may be structured by conventional methods well known to those skilled in the art, and if the present disclosure relates to the absolute configuration of a compound, the absolute configuration may be confirmed by conventional means in the art. For example, single crystal X-ray diffraction (SXRD), the grown single crystal is collected from diffraction intensity data using a Bruker D8vent diffractometer, and the light source is cukα radiation, scanning: after scanning and collecting the related data, the crystal structure is further analyzed by a direct method (Shelxs, 97), so that the absolute configuration can be confirmed.
The solvents used in the present disclosure are commercially available.
Compounds are either prepared according to the general nomenclature of the art or are usedSoftware naming, commercial compounds are referred to by vendor catalog names.
Detailed Description
The present disclosure is described in detail below by way of examples, but is not meant to be limiting in any way. The present disclosure has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the disclosure without departing from the spirit and scope of the disclosure.
Example 1
The synthetic route is as follows:
Step 1: synthesis of Compound 001_2
Cyclopropanesulfonamide (318.41 mg) was dissolved in dimethylsulfoxide (15 mL) under the protection of nitrogen at room temperature, potassium tert-butoxide (491.48 mg) was added thereto at 25℃and after stirring for 30 minutes, 001_1 (500.00 mg) was slowly added thereto, and after the addition was completed, stirring was carried out at room temperature for 15 hours. At the end of the reaction, water (100 mL) was added for dilution, pH was adjusted to 6 using 2M dilute hydrochloric acid, extraction was performed with ethyl acetate (200 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product obtained is separated by column chromatography (eluent: dichloromethane/methanol=100/1-30/1, volume ratio) to obtain the compound 001_2. 1H NMR(400MHz,CDCl 3)δ:8.60(s,1H),7.84(s,1H),3.46–3.17(m,1H),1.53–1.44(m,2H),1.21–1.14(m,2H)
Step 2: synthesis of Compound 001_3
Potassium tert-butoxide (2.30 g) was added to ethylene glycol (42.58 g) at room temperature under nitrogen atmosphere, the reaction system was warmed to 40℃and stirred for thirty minutes, 001_2 (3.2 g) dissolved in ethylene glycol dimethyl ether (20 mL) was added thereto, and the reaction system was warmed to 110℃and stirred for 18 hours. After the reaction, the reaction system was cooled to room temperature, diluted with water (100 mL), pH was adjusted to 6 with 2M dilute hydrochloric acid, extracted with ethyl acetate (200 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product obtained is separated by column chromatography (eluent: petroleum ether/ethyl acetate=10/1-0/1, volume ratio) to obtain the compound 001_3. 1H NMR(400MHz,CDCl 3)δ:8.42(s,1H),7.61(s,1H),4.64–4.55(m,2H),4.06–3.96(m,2H),3.42–3.25(m,1H),1.54–1.38(m,2H),1.19–1.08(m,2H)
Step 3: synthesis of Compound 001_4
001_3 (200.00 Mg), 5-benzothiazole pinacol borate (154.44 mg) and potassium carbonate (245.21 mg) were placed in a dry reaction flask at room temperature under nitrogen protection, and 1, 4-dioxane (20 mL) and water (1 mL) were added to dissolve. 1, 1-bis (diphenylphosphine) ferrocene palladium chloride (43.27 mg) was added at 25℃and then heated to 80℃and stirred for 13 hours. At the end of the reaction, water (100 mL) was added for dilution, pH was adjusted to 6 using 2M dilute hydrochloric acid, extraction was performed with ethyl acetate (200 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product obtained is separated by column chromatography (eluent: petroleum ether/ethyl acetate=10/1-0/1, volume ratio) to obtain the compound 001_4. 1H NMR(400MHz,CDCl 3)δ:9.08(s,1H),8.58(s,1H),8.10(d,J＝7.6Hz,2H),7.39(d,J＝9.6Hz,1H),7.08(s,1H),4.51(d,J＝4.2Hz,2H),3.84(d,J＝4.7Hz,2H),3.38(s,1H),2.04(s,1H),1.37(s,2H),1.11(d,J＝7.2Hz,2H)
Step 4: synthesis of Compound 001
Sodium hydride (122.40 mg, content 60%) was dissolved in anhydrous tetrahydrofuran (20 mL) at room temperature under nitrogen atmosphere, 001_4 (150.00 mg) dissolved in a mixed solvent of anhydrous tetrahydrofuran (2 mL) and N, N-dimethylformamide (2 mL) was added at 25℃and then 5-bromo-2-chloropyrimidine (147.86 mg) dissolved in anhydrous tetrahydrofuran (2 mL) was added, and the reaction system was stirred at 70℃for 2 hours. After the reaction, the reaction system was cooled to room temperature, quenched by adding a saturated ammonium chloride solution (100 mL), pH was adjusted to 4 with 2M dilute hydrochloric acid, extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was dispersed in methanol (1 mL), stirred at room temperature for 1 hour, filtered, the solid collected and dried to give the compound 001.MS-ESI m/z:549.0,551.0[M+H] +. 1H NMR(400MHz,CDCl 3)δ:9.06(s,1H),8.56(s,1H),8.42(s,2H),8.10(t,J＝ 6.0Hz,2H),7.44(d,J＝8.4Hz,1H),7.02(s,1H),4.81(t,J＝4.0Hz,2H),4.68(t,J＝4.4Hz,2H),3.39(d,J＝4.5Hz,1H),1.36(s,2H),1.10(d,J＝7.0Hz,2H).
Example 2
The synthetic route is as follows:
step 1: synthesis of Compound 002_1
3, 4-Methylenedioxybenzene boronic acid pinacol ester (7.26 g), 001_3 (3.3 g) and potassium hydroxide (1.64 g) were dissolved in absolute ethanol (100 mL) and water (10 mL) under a nitrogen atmosphere at room temperature, 1-bis (diphenylphosphine) ferrocene palladium chloride (357.01 mg) was added thereto, nitrogen was replaced three times, and the reaction was warmed to 85 ℃ and stirred for 12 hours. After the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, diluted with water (30 mL), filtered, the filtrate was collected, the pH of the filtrate was adjusted to 3-4 with 3M dilute hydrochloric acid solution, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated brine (50 mL. Times.2) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product obtained is separated by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-1/1, volume ratio) to obtain the compound 002_1. 1H NMR(400MHz,CDCl 3)δ:8.51(s,1H),7.11–6.97(m,1H),6.93(d,J＝8.3Hz,1H),6.80–6.74(m,2H),6.05(s,2H),4.53–4.45(m,2H),3.89–3.81(m,2H),3.53–3.24(m,1H),1.44–1.34(m,2H),1.15–1.06(m,2H).
Step 2: synthesis of Compound 002
Sodium hydride (109.60 mg, content 60%) was dissolved in anhydrous tetrahydrofuran (20 mL) at room temperature under nitrogen atmosphere, and 002_1 (130.00 mg) dissolved in a mixed solvent of anhydrous tetrahydrofuran (2 mL) and N, N-dimethylformamide (2 mL) was added at 25 ℃. Then, 5-bromo-2-chloropyrimidine (132.56 mg) dissolved in anhydrous tetrahydrofuran (2 mL) was added, and the reaction system was stirred at 70℃for 2 hours. After the reaction, the reaction system was cooled to room temperature, quenched by adding saturated ammonium chloride solution (10 mL), adjusted to pH 4 with 2M diluted hydrochloric acid, extracted with ethyl acetate (40 ml×3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue obtained is separated and purified by preparative HPLC (mobile phase: acetonitrile/water; neutral: NH 4HCO 3) to give the compound 002.MS-ESI m/z:536.1,538.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ:8.50(s,3H),6.98(s,1H),6.86(d,J＝8.5Hz,1H),6.76–6.69(m,2H),6.03(s,2H),4.77–4.71(m,2H),4.68–4.63(m,2H),3.47–3.26(m,1H),1.43–1.34(m,2H),1.15–1.05(m,2H).
Example 3
The synthetic route is as follows:
step 3: synthesis of Compound 003_1
001_3 (300.00 Mg), pyrazolo [1,5-a ] pyridine-6-pinacol borate (154.44 mg) and potassium carbonate (367.82 mg) were placed in a dry reaction flask at room temperature under nitrogen protection, and 1, 4-dioxane (20 mL) and water (2 mL) were added for dissolution. 1, 1-bis (diphenylphosphine) ferrocene palladium chloride (64.91 mg) was added at 25℃and then heated to 80℃and stirred for 13 hours. At the end of the reaction, water (100 mL) was added for dilution, pH was adjusted to 6 using 2M dilute hydrochloric acid, extraction was performed with ethyl acetate (200 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product obtained is separated by column chromatography (eluent: petroleum ether/ethyl acetate=10/1-0/1, volume ratio) to obtain the compound 003_1. 1H NMR(400MHz,CDCl 3)δ:8.58(s,1H),8.42(s,1H),7.97(d,J＝2.4Hz,1H),7.65(d,J＝9.2Hz,1H),7.00(d,J＝9.2Hz,2H),6.57(s,1H),4.52(t,J＝2.4Hz,2H),3.86(s,2H),2.65(s,1H),1.40(t,J＝7.4Hz,4H).
Step 4: synthesis of Compound 003
Sodium hydride (122.40 mg, content 60%) was dissolved in anhydrous tetrahydrofuran (20 mL) at room temperature under nitrogen atmosphere, and 003_1 (150.00 mg) dissolved in a mixed solvent of anhydrous tetrahydrofuran (2 mL) and N, N-dimethylformamide (2 mL) was added at 25 ℃. Then, 5-bromo-2-chloropyrimidine (147.86 mg) dissolved in anhydrous tetrahydrofuran (2 mL) was added, and the reaction system was stirred at 70℃for 2 hours. After the reaction, the reaction system was cooled to room temperature, quenched by adding a saturated ammonium chloride solution (100 mL), pH was adjusted to 4 with 2M dilute hydrochloric acid, extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue obtained is separated and purified by preparative HPLC (mobile phase: acetonitrile/water; neutral: NH 4HCO 3) to give the compound 003.MS-ESI m/z:532.0,534.0[M+H] +. 1H NMR(400MHz,CDCl 3)δ:8.54(s,1H),8.41(d,J＝2.2Hz,3H),7.90(d,J＝2.2Hz,1H),7.51(d,J＝9.2Hz,1H),6.96(d,J＝9.0Hz,1H),6.50(d,J＝2.2Hz,1H),4.73-4.75(m,2H),4.62-4.64(m,2H),3.36(s,1H),1.34-1.36(m,2H),1.08-1.10(m,2H).
Example 4
The synthetic route is as follows:
Step 1: synthesis of Compound 004_1
1-Methylcyclopropane sulfonamide (1.00 g) was dissolved in dimethyl sulfoxide (20 mL) under the protection of nitrogen at room temperature, potassium t-butoxide (1.66 g) was added thereto at 25℃and after stirring for 30 minutes, 001_1 (2.02 g) was slowly added thereto, and after the addition was completed, stirring was carried out at 25℃for 15 hours. After the completion of the reaction, water (60 mL) was added for dilution, pH was adjusted to 4 with 1M diluted hydrochloric acid, extraction was performed with ethyl acetate (30 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product obtained is separated by column chromatography (eluent: petroleum ether/ethyl acetate=10/1-1/1, volume ratio) to obtain the compound 004_1. 1H NMR(400MHz,CDCl 3)δ:8.58(s,1H),7.64(s,1H),1.96-1.81(m,2H),1.58(s,3H),1.04-0.95(m,2H).
Step 2: synthesis of Compound 004_2
Potassium tert-butoxide (549.71 mg) was added to ethylene glycol (8.00 mL) at room temperature under nitrogen atmosphere, the reaction system was warmed to 40℃and stirred for thirty minutes, 004_1 (800.00 mg) dissolved in ethylene glycol dimethyl ether (20 mL) was added thereto, and the reaction system was warmed to 110℃and stirred for 15 hours. After the reaction, the reaction system was cooled to room temperature, diluted with water (30 mL), pH was adjusted to 4 with 1M dilute hydrochloric acid, extracted with ethyl acetate (100 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product obtained was separated by column chromatography (eluent: dichloromethane/methanol=20/1, volume ratio) to give the compound 004_2. 1H NMR(400MHz,CDCl 3)δ:8.41(s,1H),7.48(s,1H),4.68-4.40(m,2H),4.11-3.86(m,2H),2.44(t,J＝6.0Hz,1H),1.96-1.78(m,2H),1.60(s,3H),1.14-0.60(m,2H).
Step 3: synthesis of Compound 004_3
004_2 (400.00 Mg), 5-benzothiazole pinacol borate (357.25 mg) and 1, 1-bis (diphenylphosphine) ferrocene palladium chloride (83.41 mg) were placed in a dry reaction flask at room temperature under nitrogen protection, and 1, 4-dioxane (20 mL) and water (1 mL) were added for dissolution. Potassium carbonate (472.68 mg) was added at 25℃and the mixture was warmed to 80℃and stirred for 13 hours. After the completion of the reaction, most of the solvent was removed by concentration under reduced pressure, diluted with water (30 mL), pH was adjusted to 5 with 1M dilute hydrochloric acid, extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product obtained was separated by column chromatography (eluent: petroleum ether/ethyl acetate=1/2-0/1, volume ratio) to give compound 004_3.MS-ESI m/z 407.0[ M+H ] +.
Step 4: synthesis of Compound 004
Sodium hydride (141.70 mg, content 60%) was dissolved in anhydrous tetrahydrofuran (20 mL) at room temperature under nitrogen protection. 004_3 (180.00 mg) dissolved in anhydrous N, N-dimethylformamide (2 mL) was added at 25deg.C. Then, 5-bromo-2-chloropyrimidine (171.31 mg) dissolved in anhydrous tetrahydrofuran (1 mL) was added, and the reaction system was stirred at 70℃for 2 hours. After the reaction, the reaction system was cooled to room temperature, quenched by adding saturated ammonium chloride solution (20 mL), pH was adjusted to 4 with 1M dilute hydrochloric acid, extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was dispersed in methanol (10 mL), stirred at room temperature for 1 hour, filtered, the solid collected and dried to give the compound 004.MS-ESI m/z:562.9,564.9[M+H] +. 1H NMR(400MHz,CDCl 3)δ:9.08(s,1H),8.54(s,1H),8.43(s,2H),8.09-7.99(m,2H),7.36(d,J＝8.6Hz,1H),6.86(s,1H),4.79-4.68(m,2H),4.66-4.57(m,2H),1.87(s,2H),1.52(s,3H),0.95(s,2H).
Example 5
The synthetic route is as follows:
Step 1: synthesis of Compound 005_1
3, 4-Methylenedioxybenzene boronic acid pinacol ester (311.09 mg), 004_2 (400.00 mg) and potassium carbonate (470.89 mg) were dissolved in 1, 4-dioxane (20 mL) and water (2 mL) under a nitrogen atmosphere at room temperature, 1-bis (diphenylphosphine) ferrocene palladium chloride (83.10 mg) was added thereto, nitrogen was replaced three times, and the reaction was warmed to 80 ℃ and stirred for 15 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, diluted with water (30 mL), adjusted to pH 3-4 with 1M dilute hydrochloric acid solution, extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to remove the solvent. The crude product obtained was separated by column chromatography (eluent: petroleum ether/ethyl acetate=1/2-0/1, volume ratio) to give compound 005_1.MS-ESI m/z 394.0[ M+H ] +.
Step 2: synthesis of Compound 005
Sodium hydride (194.86 mg, content 60%) was dissolved in anhydrous tetrahydrofuran (20 mL) at room temperature under nitrogen blanket, and 005_1 (400.00 mg) dissolved in anhydrous N, N-dimethylformamide (2 mL) was added at 25 ℃. Then, 5-bromo-2-chloropyrimidine (235.57 mg) dissolved in anhydrous tetrahydrofuran (2 mL) was added, and the reaction system was stirred at 70℃for 2 hours. After the reaction, the reaction system was cooled to room temperature, quenched by adding saturated ammonium chloride solution (10 mL), adjusted to pH 4 with 2M diluted hydrochloric acid, extracted with ethyl acetate (20 ml×3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue obtained is separated and purified by preparative HPLC (mobile phase: acetonitrile/water; neutral: NH 4HCO 3) to give the compound 005.MS-ESI m/z:549.9,551.9[M+H] +. 1H NMR(400MHz,CDCl 3)δ:8.55-8.09(m,3H),6.87-6.67(m,4H),6.03(s,2H),4.75-4.69(m,2H),4.68-4.62(m,2H),1.85(s,2H),1.51(s,3H),0.93(s,2H).
Example 6
The synthetic route is as follows:
step 1: synthesis of Compound 006_2
Compound 006_1 (800.00 mg) was dissolved in anhydrous tetrahydrofuran (20 mL) at room temperature under nitrogen, and aqueous ammonia (8.76 g, concentration: 28%) was added thereto, and the reaction system was stirred at 25℃for 12 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, the residue was diluted with water (50 mL), pH was adjusted to 5-6 with 1M dilute hydrochloric acid solution, extraction was performed with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to give Compound 006_2, and the crude product was directly taken to the next step.
Step 2: synthesis of Compound 006_3
006_2 (600.00 Mg) was dissolved in dimethyl sulfoxide (20 mL) under the protection of nitrogen at room temperature, potassium tert-butoxide (1.34 g) was added thereto at 25℃and after stirring for one hour, 001_1 (904.37 mg) was slowly added thereto, and after the addition was completed, stirring was carried out at 25℃for 11 hours. After the completion of the reaction, the reaction mixture was poured into water (100 mL), the pH was adjusted to 5 with 1M diluted hydrochloric acid, extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product obtained is separated by column chromatography (eluent: petroleum ether/ethyl acetate=10/1-1/2, volume ratio) to obtain the compound 006_3. 1H NMR(400MHz,DMSO_d 6)δ:8.58(s,1H),4.53(s,1H),4.11(dd,J＝4.6,9.8Hz,1H),3.95(t,J＝9.0Hz,1H),3.90–3.82(m,1H),3.74–3.68(m,2H),2.38–2.18(m,2H).
Step 3: synthesis of Compound 006_4
Potassium tert-butoxide (250.56 mg) was added to a mixed solvent of ethylene glycol (7.62 g) and ethylene glycol dimethyl ether (10 mL) at room temperature under nitrogen atmosphere, and the reaction system was warmed to 40℃and stirred for thirty minutes. 006_3 (255.00 mg) dissolved in ethylene glycol dimethyl ether (20 mL) was added thereto, and the reaction system was warmed to 110℃and stirred for 15 hours. After the reaction, the reaction system was cooled to room temperature, diluted with water (100 mL), pH was adjusted to 5 with 2M dilute hydrochloric acid, extracted with ethyl acetate (60 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product obtained is separated by column chromatography (eluent: petroleum ether/ethyl acetate=3/1-1/4, volume ratio) to obtain the compound 006_4. 1H NMR(400MHz,CDCl 3)δ:8.33(s,1H),7.49(s,1H),4.75(s,1H),4.53(t,J＝4.6Hz,2H),4.22(dd,J＝5.4,10.2Hz,1H),4.09–3.97(m,2H),3.93(t,J＝4.4Hz,2H),3.86–3.77(m,1H),2.52–2.38(m,1H),2.33–2.21(m,2H).
Step 4: synthesis of Compound 006_5
3, 4-Methylenedioxybenzene boronic acid pinacol ester (192.02 mg) and 006_4 (190.00 mg) were dissolved in 1, 4-dioxane (20 mL) and water (2 mL) at room temperature under nitrogen. To this was added potassium carbonate (213.96 mg) and stirred at 25℃for minutes, then 1, 1-bis (diphenylphosphine) ferrocene palladium chloride (113.27 mg) was added, nitrogen was replaced three times, and the reaction was warmed to 80℃and stirred for 12 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, diluted with water (30 mL), adjusted to pH 3 to 4 with a 1M diluted hydrochloric acid solution, extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to remove the solvent. The crude product obtained is separated by column chromatography (eluent: petroleum ether/ethyl acetate=5/1-1/3, volume ratio) to obtain the compound 006_5. 1H NMR(400MHz,CDCl 3)δ:8.42(s,1H),6.87(d,J＝8.0Hz,2H),6.72–6.63(m,2H),6.00(s,2H),4.43(t,J＝4.6Hz,2H),4.14(dd,J＝5.8,9.8Hz,1H),4.09–3.99(m,2H),3.95–3.86(m,1H),3.83–3.81(m,1H),3.80(t,J＝4.4Hz,2H),2.44–2.33 (m,1H),2.31–2.20(m,1H).
Step 5: synthesis of Compound 006
Sodium hydride (103.17 mg, content 60%) was dissolved in anhydrous tetrahydrofuran (20 mL) at room temperature under nitrogen blanket, and 006_5 (132.00 mg) dissolved in anhydrous N, N-dimethylformamide (2 mL) was added at 25 ℃. Then, 5-bromo-2-chloropyrimidine (124.73 mg) dissolved in anhydrous tetrahydrofuran (1 mL) was added, and the reaction system was stirred at 70℃for 2 hours. After the reaction, the reaction system was cooled to room temperature, quenched by adding saturated ammonium chloride solution (30 mL), pH was adjusted to 5 with 1M dilute hydrochloric acid, extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue obtained is separated and purified by preparative HPLC (mobile phase: acetonitrile/water; neutral: NH 4HCO 3) to give the compound 006.MS-ESI m/z:566.1,568.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ:8.42(s,2H),8.40(s,1H),6.80(d,J＝8.4Hz,1H),6.67–6.60(m,2H),5.96(s,2H),4.80(s,1H),4.66(t,J＝4.6Hz,2H),4.57(t,J＝4.6Hz,2H),4.16–4.09(m,1H),4.07–3.99(m,1H),3.95–3.87(m,1H),3.85–3.75(m,1H),2.42–2.33(m,1H),2.29–2.20(m,1H).
Example 7
The synthetic route is as follows:
Step 1: synthesis of Compound 007
002_1 (200 Mg) was dissolved in anhydrous tetrahydrofuran (3 mL) at room temperature under nitrogen atmosphere, cesium carbonate (721.40 mg) was added, 2, 5-dichloropyrimidine (102.10 mg) was added at 25℃and the reaction system was warmed to 75℃and stirred for 12 hours. After the reaction, the reaction system was cooled to room temperature, diluted with water (10 mL), pH was adjusted to 3-4 with 3M dilute hydrochloric acid, extracted with ethyl acetate (15 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue obtained is separated and purified by preparative HPLC (mobile phase: acetonitrile/water; neutral: NH 4HCO 3) to give the compound 007.MS-ESI m/z:492.1[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.90(s,1H),8.66(s,2H),8.50(s,1H),6.90(d,J＝8.0Hz,1H),6.77–6.62(m,2H),6.03(s,2H),4.69–4.63(m,2H),4.62–4.58(m,2H),3.33–3.31(m,1H),1.09–0.97(m,4H).
Example 8
The synthetic route is as follows:
Step 1: synthesis of Compound 008
002_1 (124 Mg) was dissolved in anhydrous tetrahydrofuran (1 mL) at room temperature under nitrogen atmosphere, cesium carbonate (447.27 mg) was added, 2-chloro-5- (trifluoromethyl) -pyrimidine (102.10 mg) was added at 25℃and the reaction system was warmed to 75℃and stirred for 12 hours. After the reaction, the reaction system was cooled to room temperature, diluted with water (10 mL), pH was adjusted to 3-4 with 3M dilute hydrochloric acid, extracted with ethyl acetate (15 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue obtained is separated and purified by preparative HPLC (mobile phase: acetonitrile/water; acidity: HCl) to give the compound 008.MS-ESI m/z:526.1[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.91(s,1H),9.02(d,J＝0.8Hz,2H),8.51(s,1H),6.89(d,J＝8.0Hz,1H),6.75–6.64(m,2H),6.02(s,2H),4.70(s,4H),3.30–3.25(m,1H),1.11–0.95(m,4H).
Example 9
The synthetic route is as follows:
Step 1: synthesis of Compound 009
002_1 (300 Mg) was dissolved in anhydrous tetrahydrofuran (6 mL) at room temperature under nitrogen atmosphere, cesium carbonate (1.08 g) was added, 2-chloro-5-bromopyridine (304.35 mg) was added at 25℃and the reaction system was warmed to 75℃and stirred for 12 hours. After the reaction, the reaction system was cooled to room temperature, diluted with water (10 mL), pH was adjusted to 3-4 with 3M dilute hydrochloric acid, extracted with ethyl acetate (15 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue obtained is separated and purified by preparative HPLC (mobile phase: acetonitrile/water; acidity: HCl) to give the compound 009.MS-ESI m/z:535.1,537.0[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.91(s,1H),8.51(s,1H),8.22(d,J＝2.4Hz,1H),7.88(dd,J＝2.4,8.8Hz,1H),6.91(d,J＝8.0Hz,1H),6.79(d,J＝8.8Hz,1H),6.74(s,1H),6.69(d,J＝8.0Hz,1H),6.03(s,2H),4.71–4.58(m,2H),4.56–4.45(m,2H),3.30–3.25(m,1H),1.13–0.95(m,4H).
Example 10
The synthetic route is as follows:
Step 1: synthesis of Compound 010
002_1 (110 Mg) and 6-chloroimidazo [1,2-b ] pyridazine (57.88 mg) were dissolved in anhydrous N, N-dimethylformamide (2 mL) at room temperature under nitrogen atmosphere, cesium carbonate (377.87 mg) was added at 25℃and the reaction system was warmed to 120℃and stirred for 12 hours. After the reaction, the reaction system was cooled to room temperature, the pH was adjusted to 3 to 4 with 3M diluted hydrochloric acid, extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined. The organic phase was washed with half-saturated brine (10 mL. Times.2), saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45℃to remove the solvent. The residue obtained is separated and purified by preparative HPLC (mobile phase: acetonitrile/water; acidity: HCl) to give the compound 010.MS-ESI m/z:497.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.74(s,1H),8.48(s,1H),8.35(s,1H),8.27(d,J＝10.0Hz,1H),8.07(s,1H),7.36(d,J＝9.6Hz,1H),6.95(d,J＝8.0Hz,1H),6.77(s,1H),6.75–6.71(m,1H),6.03(s,2H),4.66(t,J＝4.4Hz,2H),4.38(t,J＝4.4Hz,2H),3.17–3.13(m,1H),1.08–0.96(m,4H).
Example 11
The synthetic route is as follows:
step 1: synthesis of Compound 011
002_1 (500 Mg) was dissolved in anhydrous N, N-dimethylformamide (3 mL) at room temperature under a nitrogen-protected atmosphere, the reaction system was cooled to 0℃under a nitrogen-protected atmosphere, sodium hydride (131.78 mg, content 60%) was added thereto in portions, the reaction system was stirred at 0℃for 0.5 hours, 2, 5-dibromothiazole (480.22 mg) was added thereto, and the reaction was warmed to 20℃and stirred for 12 hours. After the completion of the reaction, 1M diluted hydrochloric acid was added to the reaction mixture to adjust the pH to 2 to 3, the mixture was extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue is separated by preparative HPLC (mobile phase: acetonitrile/water; neutral: NH 4HCO 3) for separation, purification and freeze-drying, and the obtained solid is separated by preparative HPLC (mobile phase: acetonitrile/water; acidic HCl) for separation and purification to obtain the compound 011.MS-ESI m/z:541.0,543.0[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.92(s,1H),8.52(s,1H),7.27(s,1H),6.93(d,J＝8.0Hz,1H),6.75(s,1H),6.69(d,J＝7.6Hz,1H),6.05(s,2H),4.64(s,4H),3.31–3.23(m,1H),1.14–0.94(m,4H).
Example 12
The synthetic route is as follows:
step 1: synthesis of Compound 012_1
2-Chloro-5-bromopyrimidine (14 g) was dissolved in tetrahydrofuran (210 mL) under the protection of nitrogen at room temperature, and potassium carbonate (47.01 g) was added. After the reaction system was warmed to 45℃and then ethylene glycol (6.74 g) was added thereto, the mixture was stirred at 45℃for 12 hours. After the completion of the reaction, the reaction mixture was quenched by pouring into water (500 mL), extracted with ethyl acetate (200 mL. Times.3), the organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, whereby Compound 012_1 was obtained, and the crude product was directly taken to the next step.
Step 2: synthesis of Compound 012_3
012_2 (5 G) was dissolved in anhydrous toluene (75 mL) under the protection of nitrogen at room temperature, diethyl malonate (4.38 g), tri-t-butylphosphine (2.01 g,10% -14% toluene solution) and potassium phosphate (15.84 g) were added thereto at 25℃and, after replacing nitrogen three times, bis (dibenzylideneacetone) palladium (286.05 mg) was added thereto, and after replacing nitrogen again, the reaction system was warmed to 70℃and stirred for 12 hours. After the reaction, the pH was adjusted to 5 to 6 with 3M diluted hydrochloric acid, diluted with water (50 mL), extracted with ethyl acetate (80 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product obtained is separated by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-4/1, volume ratio) to obtain the compound 012_3. 1H NMR(400MHz,DMSO_d 6)δ:6.95(d,J＝1.8Hz,1H),6.83–6.73(m,2H),5.94(s,2H),4.51(s,1H),4.26–4.15(m,4H),1.28–1.23(m,6H).
Step 3: synthesis of Compound 012_4
Sodium ethoxide (1.04 g) was dissolved in absolute ethanol (2.5 mL) at room temperature under nitrogen blanket, and formamidine acetate (144.87 mg) was added. 012_3 (0.3 g) dissolved in absolute ethanol (1.1 mL) was added after stirring the reaction system at 25℃for 20 minutes, and stirring was continued at 25℃for 12 hours after the addition was completed. After the reaction is finished, the reaction system is directly decompressed, concentrated to remove the solvent, diluted by adding water (5 mL), added with 3M dilute hydrochloric acid to adjust the pH to 6-7, filtered, collected into solid, dried in vacuum to remove the solvent to obtain the compound 012_4, and the crude product is directly thrown into the next step.
Step 4: synthesis of Compound 012_5
012_4 (110 Mg) was dissolved in phosphorus oxychloride (0.5 mL) at room temperature under nitrogen, and the reaction system was warmed to 90℃and stirred for 1 hour. After the reaction, the reaction system was cooled to room temperature, slowly poured into water (5 mL) and quenched, the pH was adjusted to 7 to 8 using aqueous ammonia, dichloromethane (5 ml×3) was used for extraction, the organic phases were combined, washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained is separated by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-5/1, volume ratio) to obtain the compound 012_5. 1H NMR(400MHz,CDCl 3)δ:8.77(s,1H),6.95(d,J＝8.3Hz,1H),6.82–6.73(m,2H),6.08(s,2H).
Step 5: synthesis of Compound 012_6
012_5 (92.7 Mg) was dissolved in anhydrous toluene (3 mL) at room temperature under nitrogen, and 012_1 (67.91 mg) was added. The reaction system was cooled to 0℃and potassium tert-butoxide (77.31 mg) was added thereto and stirred at 0℃for 0.5 hours. After the completion of the reaction, the pH was adjusted to 4 to 5 with 3M diluted hydrochloric acid, diluted with water (10 mL), extracted with ethyl acetate (15 mL. Times.3), the organic phases were combined, washed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product obtained is separated by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-5/1, volume ratio) to obtain the compound 012_6. 1H NMR(400MHz,CDCl 3)δ:8.59–8.46(m,3H),6.87–6.81(m,1H),6.79–6.75(m,2H),6.02(s,2H),4.80–4.73(m,2H),4.71–4.65(m,2H).
Step 6: synthesis of Compound 012_7
4-Sulfamoyl piperidine-1-carboxylic acid tert-butyl ester (0.5 g) and 012_6 (533.94 mg) were dissolved in dimethyl sulfoxide (10 mL) at room temperature under nitrogen, and potassium carbonate (735.23 mg) and tetrabutylammonium fluoride (1M, 2.36 mL) were added thereto and the reaction system was stirred at 70℃for 5 hours. After the completion of the reaction, water (10 mL) was added for dilution, 3M diluted hydrochloric acid was added for pH 3-4, ethyl acetate (15 mL. Times.3) was used for extraction, the organic phases were combined, washed with saturated brine (10 mL. Times.2) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product obtained is separated by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-1/4, volume ratio) to obtain compound 012_7, the crude product is directly fed to the next step.
Step 7: synthesis of Compound 012_8
012_7 (0.2 G) was dissolved in ethyl acetate hydrochloride (4M, 4 mL) at room temperature under nitrogen, and the reaction system was stirred at 25℃for 12 hours. After the reaction is finished, the reaction system is decompressed and concentrated to remove the solvent to obtain a compound 012_8, and the crude product is directly put into the next step.
Step 8: synthesis of Compound 012
012_8 (120 Mg) was dissolved in methylene chloride (2 mL) at room temperature under nitrogen blanket. The reaction system was cooled to 0℃under a nitrogen atmosphere, methyl chloroformate (23.94 mg) and N, N-diisopropylethylamine (75.55 mg) were added thereto, the reaction system was warmed to 25℃and stirred for 2 hours. At the end of the reaction, the reaction was quenched by addition of methanol (1 mL), and the solvent was directly concentrated under reduced pressure. The residue obtained is separated and purified by preparative HPLC (mobile phase: acetonitrile/water; acidity: HCl) to give the compound 012.MS-ESI m/z:636.8,638.8[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.02(s,1H),8.71(s,2H),8.50(s,1H),6.92(d,J＝7.6Hz,1H),6.77–6.64(m,2H),6.05(s,2H),4.66(s,2H),4.62–4.55(m,2H),4.12–3.94(m,3H),3.59(s,3H),2.99–2.75(m,2H),2.04–1.93(m,2H),1.59–1.44(m,2H).
Example 13
The synthetic route is as follows:
Step 1: synthesis of Compound 013
Compound 002_1 (900 mg) was dissolved in N, N-dimethylformamide (15 mL) at room temperature under a nitrogen atmosphere, and the reaction system was cooled to 0 ℃. Sodium hydride (284.64 mg, 60% content) was added to the reaction system, stirred at 0℃for 0.5 hours, 3-methylsulfanyl-1, 2, 4-triazine (452.51 mg) was added, heated to 20℃and stirred for 2 hours. After the reaction, the reaction mixture was slowly poured into ice water (20 mL) to quench the reaction, the pH was adjusted to 2 to 3 with 2M diluted hydrochloric acid, ethyl acetate (20 mL. Times.3) was added to extract the reaction mixture, the organic phases were combined, washed with saturated brine (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue is separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=17/3-3/2, volume ratio) to obtain crude product, and the crude product is separated and purified by preparative HPLC (mobile phase: acetonitrile/water; neutral: NH 4HCO 3) to obtain compound 013.MS–ESI m/z:459.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.13(d,J＝2.4Hz,1H),8.65(d,J＝2.4Hz,1H),8.00(s,1H),6.81(d,J＝1.2Hz,1H),6.76–6.72(m,1H),6.71–6.67(m,1H),6.33(s,1H),5.94(s,2H),4.63–4.51(m,4H),3.12–3.00(m,1H),0.78–0.67(m,2H),0.64–0.54(m,2H).
Example 14
The synthetic route is as follows:
Step 1: synthesis of Compound 014_2
Compound 014_1 (3 g) was dissolved in methylene chloride (60 mL) at room temperature under nitrogen protection, and N-methylmorpholine (1.94 mL) was added at 25 ℃. The reaction system was cooled to-30℃under nitrogen protection, isobutyl chloroformate (2.41 g) was added dropwise and stirred at 0℃for 15 minutes, and 2-mercaptopyridine nitroxide sodium salt (2.90 g) was added to the reaction solution under dark conditions and stirred at 0℃for 2 hours under dark conditions. After the reaction is finished, the reaction system is directly decompressed and concentrated to remove the solvent to obtain the compound 014_2, and the crude product is directly put into the next step.
Step 2 Synthesis of Compound 014_3
Compound 014_2 (4.93 g) was dissolved in chlorobenzene (100 mL) at room temperature under nitrogen blanket, and compound 2, 2-bipyridine disulfide (5.83 g) was added at 20 ℃. The reaction system was stirred for 2 hours under nitrogen protection by irradiation with a metal halide lamp (500W). After the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue obtained was purified by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-23/2, volume ratio) to give the compound 014_3. 1H NMR(400MHz,CDCl 3)δ:8.53–8.39(m,1H),7.56–7.47(m,1H),7.26–7.21(m,1H),7.09–7.00(m,1H),3.70(s,3H),2.46(s,6H).
Step 3 Synthesis of Compound 014_4
Compound 014_3 (1.2 g) was dissolved in methylene chloride (15 mL) at room temperature under nitrogen protection, and cooled to 0℃under nitrogen protection. To the reaction system was added m-chloroperoxybenzoic acid (3.11 g, content: 85%), and the mixture was warmed to 20℃and stirred for 12 hours. After the reaction was completed, the reaction system was filtered, the cake was rinsed with methylene chloride (10 mL), and the filtrates were combined and concentrated under reduced pressure to remove the solvent. The residue obtained was purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-7/3, volume ratio) to give the compound 014_4. 1H NMR(400MHz,CDCl 3)δ:8.79(d,J＝4.8Hz,1H),8.11–8.06(m,1H),7.99(dt,J＝1.2,7.6Hz,1H),7.58(dd,J＝5.2,7.2Hz,1H),3.69(s,3H),2.45(s,6H).
Step 4 Synthesis of Compound 014_5
Compound 014_4 (1 g) was dissolved in a mixed solvent of tetrahydrofuran (15 mL), methanol (5 mL) and water (5 mL) at room temperature under nitrogen protection. Lithium hydroxide monohydrate (392.48 mg) was added to the reaction system and stirred at 20℃for 12 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, the resulting residue was diluted with water (10 mL), pH was adjusted to 2 to 3 with 1M dilute hydrochloric acid, extraction was performed with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Compound 014_5, and the crude product was directly taken to the next step.
Step 5 Synthesis of Compound 014_6
Compound 014_5 (840 mg) was dissolved in methylene chloride (10 mL) at room temperature under nitrogen atmosphere, and triethylamine (1.68 g,2.31 mL) and 4-dimethylaminopyridine (141.81 mg) were added to the reaction system in this order. The reaction system was cooled to 0℃under a nitrogen atmosphere, and di-tert-butyl dicarbonate (3.05 mL) dissolved in methylene chloride (5 mL) was added dropwise thereto. After the completion of the dropwise addition, the reaction system was stirred at 20℃for 12 hours. After the reaction, the reaction system is directly decompressed and concentrated to remove the solvent. The residue obtained was purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-7/3, volume ratio) to give the compound 014_6. 1H NMR(400MHz,CDCl 3)δ:8.79(d,J＝4.8Hz,1H),8.08(d,J＝8.0Hz,1H),8.01–7.95(m,1H),7.60–7.55(m,1H),2.39(s,6H),1.43(s,9H)
Step 6 Synthesis of Compound 014_7
Tetrahydrofuran (3.5 mL) was placed in a reaction flask at room temperature under nitrogen protection, cooled to 0℃under nitrogen protection, and sodium hydride (95.02 mg, content 60%) was added. To the reaction system was added dropwise ethanethiol (196.82 mg) at 0℃under nitrogen atmosphere, and after the completion of the addition, the mixture was stirred at 0℃for 1 hour. 014_6 (490 mg) dissolved in tetrahydrofuran (1.5 mL) was added dropwise to the reaction system at 0℃and the mixture was stirred for 12 hours at 20℃after the completion of the addition. After the reaction, methyl tert-butyl ether (10 mL) is added into the reaction system for dilution, filtration is carried out, the filter cake is leached by the methyl tert-butyl ether (10 mL), the filter cake is collected, the solvent is removed by vacuum drying, and the compound 014_7 is obtained, and the crude product is directly thrown into the next step.
Step 7 Synthesis of Compound 014_8
Compound 014_7 (400 mg) was dissolved in water (5 mL) at room temperature under nitrogen atmosphere, hydroxylamine-O-sulfonic acid (222.38 mg) and potassium acetate (192.98 mg) were added in this order, and the reaction system was stirred at 20℃for 12 hours. After the reaction was completed, the reaction system was cooled to 0 ℃, filtered, the cake was rinsed with water (5 mL), the cake was dissolved with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 014_8 was obtained. 1H NMR(400MHz,DMSO_d 6 ) Delta 6.93 (s, 2H), 2.20 (s, 6H), 1.40 (s, 9H).
Step 8 Synthesis of Compound 014_9
Compound 012_6 (426.69 mg) and compound 014_8 (257 mg) were dissolved in dimethyl sulfoxide (7 mL) at room temperature under nitrogen-protected atmosphere. Potassium carbonate (391.69 mg) and a 1M tetrabutylammonium fluoride tetrahydrofuran solution (1.89 mL) were successively added to the reaction system, and the reaction system was warmed to 70℃and stirred for 12 hours. After the completion of the reaction, the reaction mixture was diluted with water (10 mL), pH was adjusted to 3 to 4 with 1M diluted hydrochloric acid, extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue obtained was purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-3/1, volume ratio) to give the compound 014_9. 1H NMR(400MHz,CDCl 3)δ:8.52–8.44(m,3H),6.90–6.83(m,2H),6.75–6.66(m,2H),6.03(s,2H),4.76–4.61(m,4H),2.49(s,6H),1.45(s,9H).
Step 9 Synthesis of Compound 014
Compound 014_9 (60 mg) was dissolved in 4M dioxane hydrochloride solution (1.20 mL) under a nitrogen atmosphere at room temperature. The reaction system was stirred at 20℃for 6 hours. After the reaction, the reaction system was concentrated directly under reduced pressure to remove the solvent, and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water; acid: HCl). Obtaining the compound 014.MS–ESI m/z:606.2,608.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:12.77(s,1H),10.06(s,1H),8.71(s,2H),8.48(s,1H),6.94–6.66(m,3H),6.03(s,2H),4.67(s,2H),4.62–4.52(m,2H),2.41–2.11(m,6H).
Example 15
The synthetic route is as follows:
Step 1: synthesis of Compound 015
014 (40 Mg) was dissolved in tetrahydrofuran (1 mL) under a nitrogen atmosphere at room temperature, and methylamine (2 mol/L, 49.47. Mu.L) tetrahydrofuran solution, triethylamine (26.70 mg) and n-propylphosphoglycoside (58.85. Mu.L, 50% ethyl acetate solution) were added in this order. The reaction system was stirred at 20℃for 1 hour. After the reaction, the reaction system is directly decompressed and concentrated to remove the solvent. The residue obtained was purified by preparative HPLC (mobile phase: acetonitrile/water; acid: HCl) to give the compound 015.MS–ESI m/z:619.1,621.1[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.25–9.68(m,1H),8.72(s,2H),8.44(s,1H),7.87(d,J＝4.8Hz,1H),6.89(d,J＝8.0Hz,1H),6.79–6.58(m,2H),6.03(s,2H),4.74–4.49(m,4H),2.55(d,J＝4.8Hz,3H),2.34–2.12(m,6H).
Example 16
The synthetic route is as follows:
Step 1: synthesis of Compound 016
014 (100 Mg) was dissolved in tetrahydrofuran (1 mL) at room temperature under nitrogen atmosphere, and triethylamine (25.03 mg) was added to the reaction system. The reaction system was cooled to-15℃under nitrogen atmosphere, isobutyl chloroformate (23.82. Mu.L) was added dropwise, and the reaction system was stirred at 0℃for 1 hour. Ammonia water (1.26 mL, 25% content) was added to the reaction system, and the reaction system was stirred at 20℃for 1 hour. After the reaction, the reaction system was concentrated directly under reduced pressure to remove the solvent, and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water; acid: HCl). Obtaining the compound 016.MS–ESI m/z:605.2,607.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.12–9.78(m,1H),8.72(s,2H),8.46(s,1H),7.40(s,1H),7.11(s,1H),6.89(d,J＝8.4Hz,1H),6.81–6.64(m,2H),6.03(s,2H),4.72–4.54(m,4H),2.36–2.10(m,6H).
Example 17
The synthetic route is as follows:
Step 1: synthesis of Compound 017
014 (200 Mg) was dissolved in methylene chloride (4 mL) at room temperature under nitrogen atmosphere, triphenylphosphine (108.13 mg) and 2-mercaptopyridine nitroxide (99.86 mg) were added, and the reaction system was stirred at 20℃for 1 hour under dark conditions. After the reaction, the reaction system was concentrated under reduced pressure under a dark condition to remove the solvent. The crude product was dissolved in chloroform (4 mL) and irradiated under a nitrogen blanket under a metal halide lamp (500W) for 2 hours. After the reaction, the reaction system is directly concentrated under reduced pressure to remove the solvent, and the obtained residue is separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-7/3, volume ratio) to obtain crude product. Separating and purifying the crude product by preparative HPLC (mobile phase: acetonitrile/water; acidity: HCl) to obtain the compound 017.MS–ESI m/z:562.2,564.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.24–9.38(m,1H),8.71(s,2H),8.44(s,1H),6.89(d,J＝8.0Hz,1H),6.77–6.64(m,2H),6.03(s,2H),4.69–4.55(m,4H),2.65(s,1H),2.20–2.03(m,6H).
Example 18
The synthetic route is as follows:
step 1 Synthesis of Compound 018_2
Compound 018_1 (1 g) was dissolved in methylene chloride (15 mL) at room temperature under nitrogen atmosphere, and the reaction system was cooled to 0 ℃. Sodium cyanoborohydride (1.87 g) was added in portions to the reaction system, and after the addition was completed, two drops of acetic acid were added dropwise, and the reaction system was stirred at 20℃for 12 hours. After the completion of the reaction, the reaction was quenched by pouring a saturated aqueous ammonium chloride solution (50 mL), the organic phase was collected by separation, the aqueous phase was extracted with methylene chloride (20 mL. Times.3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue obtained was purified by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-3/2, volume ratio) to give the compound 018_2. 1H NMR(400MHz,CDCl 3)δ:4.23–4.11(m,1H),3.67(s,3H),3.10–2.96(m,1H),2.54–2.44(m,1H),2.41–2.26(m,3H),2.25–2.13(m,2H),1.99–1.84(m,2H),1.72(s,1H).
Step 2 Synthesis of Compound 018_3
Compound 018_2 (927 mg) was dissolved in methylene chloride (15 mL) at room temperature under nitrogen atmosphere, and 1, 8-bis (dimethylamino) naphthalene (4.79 g) and trimethyloxonium tetrafluoroborate (2.50 g) were added sequentially at 25 ℃. The reaction system was stirred at 25℃for 2 hours. After the reaction was completed, the reaction system was filtered, the cake was rinsed with methylene chloride (10 mL), and the filtrates were combined. The filtrate was adjusted to pH 2-3 with 1M dilute hydrochloric acid, the organic phase was collected, the aqueous phase was extracted with dichloromethane (30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated directly under reduced pressure to remove the solvent. The residue obtained was purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-17/3, volume ratio) to give the compound 018_3. 1H NMR(400MHz,CDCl 3)δ:3.80–3.70(m,1H),3.66(s,3H),3.20(s,3H),3.08–2.99(m,1H),2.45–2.35(m,1H),2.34–2.11(m,5H),1.99–1.83(m,2H).
Step 3 Synthesis of Compound 018_4
Compound 018_3 (880 mg) was dissolved in a mixed solvent of tetrahydrofuran (10 mL), methanol (3 mL) and water (3 mL) at room temperature under nitrogen atmosphere. Lithium hydroxide monohydrate (501.11 mg) was added to the reaction system, and stirred at 20℃for 12 hours. After the reaction, the reaction system was directly concentrated under reduced pressure to remove the solvent, the obtained residue was diluted with water (10 mL), the pH was adjusted to 2 to 3 with 1M diluted hydrochloric acid, extracted with ethyl acetate (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to give compound 018_4, and the crude product was directly fed to the next step.
Step 4 Synthesis of Compound 018_5
Compound 018_4 (380 mg) was dissolved in methylene chloride (6 mL) at room temperature under nitrogen blanket, and N-methylmorpholine (245.46. Mu.L) was added. The reaction system was cooled to-15℃under nitrogen protection, isobutyl chloroformate (293.19. Mu.L) was added dropwise, and after the addition was completed, the reaction system was stirred at 0℃for half an hour. To the reaction system was added sodium pyrithione oxynitride (365.97 mg) under protection from light and stirred at 0℃for 2 hours under protection from light. After the reaction is finished, the reaction system is directly decompressed and concentrated to remove the solvent, and the compound 018_5 is obtained, and the crude product is directly put into the next step.
Step 5 Synthesis of Compound 018_6
Compound 018_5 (623 mg) was dissolved in chlorobenzene (15 mL) at room temperature under nitrogen blanket, 2-bipyridine disulfide (737.00 mg) was added, and the mixture was irradiated under a metal halide lamp (500W) under nitrogen blanket for 2 hours. The reaction liquid is directly concentrated to remove the solvent, and the obtained crude product is separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-47/3, volume ratio) to obtain the compound 018_6. 1H NMR(400MHz,CDCl 3)δ:8.47–8.35(m,1H),7.49–7.45(m,1H),7.07(d,J＝8.0Hz,1H),6.98–6.95(m,1H),4.24–4.16(m,1H),3.82–3.75(m,1H),3.21(s,3H),2.66–2.53(m,2H),2.52–2.46(m,1H),2.38–2.30(m,1H),2.19–2.11(m,2H),2.04–1.94(m,2H).
Step 6 Synthesis of Compound 018_7
Compound 018_6 (205 mg) was dissolved in methylene chloride (5 mL) at room temperature under nitrogen blanket, and cooled to 0deg.C under nitrogen blanket. To the reaction system was added m-chloroperoxybenzoic acid (530.53 mg, content 85%) in portions and stirred at room temperature for 2 hours. After the completion of the reaction, methylene chloride (10 mL) was added to the reaction system to dilute it, a saturated aqueous solution (10 mL) of sodium bisulphite was added thereto, and the reaction was quenched by stirring for 10 minutes. The organic phase was separated, washed with 1M aqueous sodium hydroxide (10 mL), saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to remove the solvent. The crude product is separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-9/1, volume ratio) to obtain the compound 018_7. 1H NMR(400MHz,CDCl 3)δ:8.77–8.66(m,1H),8.07(d,J＝8.0Hz,1H),7.98–7.91(m,1H),7.60–7.47(m,1H),4.30–4.18(m,1H),3.83–3.71(m,1H),3.20(s,3H),2.72–2.57(m,2H),2.47–2.34(m,2H),2.33–2.15(m,2H),2.03–1.90(m,2H).
Step 7 Synthesis of Compound 018_8
Tetrahydrofuran (3 mL) was placed in a reaction flask at room temperature under nitrogen protection, cooled to 0℃under nitrogen protection, and sodium hydride (36.35 mg, content 60%) was added. To the reaction system was added dropwise ethanethiol (89.64. Mu.L) at 0℃and, after the completion of the addition, the mixture was stirred at 0℃for 1 hour. To the reaction system was added compound 018_7 (162 mg) dissolved in (1 mL) tetrahydrofuran, and the mixture was stirred at room temperature for 12 hours. After the reaction, methyl tert-butyl ether (2 mL) is added into the reaction system for dilution, filtration is carried out, the filter cake is rinsed by methyl tert-butyl ether (2 mL), the filter cake is collected, the solvent is removed by vacuum drying, and the compound 018_8 is obtained, and the crude product is directly thrown into the next step.
Step 8 Synthesis of Compound 018_9
Compound 018_8 (70 mg) was dissolved in water (2 mL) at room temperature under nitrogen atmosphere, and potassium acetate (40.46 mg) and hydroxylamine sulfonic acid (46.62 mg) were added to stir the reaction system at room temperature for 12 hours. After the reaction, the reaction system is directly decompressed and concentrated to remove the solvent. The crude product is separated and purified by column chromatography (eluent: dichloromethane/methanol=1/0-9/1, volume ratio) to obtain the compound 018_9. 1H NMR(400MHz,DMSO_d 6)δ:6.69(s,2H),3.79–3.53(m,1H),3.08(s,3H),2.97–2.93(m,1H),2.38–2.16(m,6H),1.88–1.73(m,2H).
Step 9 Synthesis of Compound 018
Compound 012_6 (60.01 mg) and compound 018_9 (30 mg) were dissolved in dimethyl sulfoxide (1.5 mL) at room temperature under nitrogen-protected atmosphere. To the reaction system was successively added 1M tetrahydrofuran solution (265.72. Mu.L) of tetrabutylammonium fluoride, potassium carbonate (55.09 mg), and the mixture was stirred under nitrogen atmosphere at a temperature of 70℃for 5 hours. After the completion of the reaction, the reaction system was cooled to room temperature, the pH was adjusted to 3 to 4 with 1M diluted hydrochloric acid, the mixture was extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The crude product is separated and purified by preparative HPLC (mobile phase: acetonitrile/water; acidity: HCl) to obtain the compound 018.MS–ESI m/z:619.8,621.9[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.81(s,1H),8.70(s,2H),8.47(s,1H),6.90(d,J＝8.0Hz,1H),6.72–6.62(m,2H),6.03(s,2H),4.69–4.55(m,4H),4.54–4.39(m,1H),3.73–3.62(m,1H),3.06(s,3H),2.42–2.16(m,6H),1.88–1.73(m,2H).
Example 19
The synthetic route is as follows:
Step 1: synthesis of Compound 019_2
Sodium methoxide (10.22 g) was dissolved in ethanol (120 mL) under the protection of nitrogen at room temperature, 019_1 (4.07 g) was added, and the reaction system was stirred at 25℃for 20 minutes. 012_3 (5.3 g) dissolved in ethanol (60 mL) was added to the reaction system, and stirred at 25℃for 2 hours. After the reaction, the reaction system was directly concentrated under reduced pressure to remove the solvent, the obtained residue was diluted with water (100 mL), the pH was adjusted to 6 to 7 with 3M diluted hydrochloric acid, stirred for 10 minutes, filtered, the cake was collected, the solvent was removed by vacuum drying, and the crude product was directly fed to the next step.
Step 2: synthesis of Compound 019_3
019_2 (2 G) was dissolved in phosphorus oxychloride (16.50 g) under the protection of nitrogen at room temperature, and the reaction system was warmed to 90℃and stirred for 6 hours. After the reaction, the reaction system was concentrated under reduced pressure, the resulting residue was diluted with dichloromethane (20 mL), the pH was adjusted to 8 to 9 with saturated aqueous sodium bicarbonate, the solution was separated, the organic phase was collected, the aqueous phase was extracted with dichloromethane (20 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue obtained is separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-7/3, volume ratio) to obtain 019_3. 1H NMR(400MHz,CDCl 3)δ:6.91–6.86(m,1H),6.75–6.69(m,2H),6.03(s,2H),3.89–3.82(m,4H),3.81–3.72(m,4H).
Step 3: synthesis of Compound 019_4
019_3 (800 Mg) and 012_1 (593.68 mg) were dissolved in tetrahydrofuran (14 mL) at room temperature under nitrogen. The reaction system was cooled to 0℃under a nitrogen atmosphere, sodium hydride (108.41 mg, content: 60%) was added in portions, the temperature was increased to 20℃and the mixture was stirred for 12 hours. After the completion of the reaction, the reaction system was poured into water (20 mL), the pH was adjusted to 3 to 4 with 2M diluted hydrochloric acid, extraction was performed with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue obtained was purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-3/1, volume ratio) to give the compound 019_4. 1H NMR(400MHz,CDCl 3)δ:8.50(s,2H),6.81–6.76(m,1H),6.74–6.68(m,2H),5.98(s,2H),4.70–4.59(m,4H),3.77(d,J＝4.0Hz,8H).
Step 4: synthesis of Compound 019
019_4 (560 Mg) was dissolved in dimethyl sulfoxide (7 mL) at room temperature under nitrogen atmosphere, cyclopropanesulfonamide (139.04 mg), potassium carbonate (432.58 mg) and tetrabutylammonium fluoride (1M in tetrahydrofuran, 2.09 mL) were added sequentially to the reaction system, and the mixture was stirred at 100℃for 12 hours. After the completion of the reaction, water (20 mL) was added to the reaction system to dilute the mixture, the pH was adjusted to 3 to 4 with 1M diluted hydrochloric acid, the mixture was extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue obtained is purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-7/3, volume ratio) to give crude product, and then by preparative HPLC (mobile phase: acetonitrile/water; acidity: HCl) to give compound 019.MS–ESI m/z:621.2,623.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.41(s,1H),8.73(s,2H),6.86(d,J＝8.0Hz,1H),6.70–6.53(m,2H),6.01(s,2H),4.71–4.51(m,4H),3.65(s,8H),3.24–3.10(m,1H),1.10–0.88(m,4H).
Example 20
The synthetic route is as follows:
step 1: synthesis of Compound 020_1
Sodium methoxide (11.57 g) was dissolved in ethanol (50 mL) under the protection of nitrogen at room temperature, acetamidine hydrochloride (2.63 g) was added and stirred at 25℃for 20 minutes. To the reaction system was added 012_3 (6 g) of ethanol (24 mL) solution and stirred at 25℃for 3 hours. After the reaction, the reaction system is directly decompressed and concentrated to remove the solvent, the obtained residue is diluted by adding water (50 mL), filtered, the pH value of the filtrate is regulated to 2-3 by 3M dilute hydrochloric acid, the mixture is stirred for 10 minutes, filtered, a filter cake is collected, and the filter cake is dried in vacuum to remove the solvent to obtain the compound 020_1. 1H NMR(400MHz,DMSO_d 6)δ:12.76–11.60(m,2H),7.18–7.02(m,2H),6.89–6.76(m,2H),5.95(s,1H),2.27(s,3H).
Step 2: synthesis of Compound 020_2
020_1 (2.8 G) was dissolved in phosphorus oxychloride (24.75 g) under the protection of nitrogen at room temperature, and the reaction system was stirred for 2 hours at 90 ℃. After the reaction, the reaction system was concentrated under reduced pressure, the residue was dissolved in methylene chloride (50 mL), the pH was adjusted to 8 to 9 with saturated aqueous sodium bicarbonate solution, the solution was separated, the organic phase was collected, the aqueous phase was extracted with methylene chloride (20 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue obtained was purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-9/1, volume ratio) to give compound 020_2.MS-ESI m/z 282.9, 284.8.
Step 3: synthesis of Compound 020_3
020_2 (1.4 G) and 012_1 (974.83 mg) were dissolved in toluene (25 mL) under nitrogen, and cooled to 0deg.C under nitrogen. Potassium tert-butoxide (1.11 g) was added in portions to the reaction system, and stirred at 0℃for 1 hour. After the completion of the reaction, the reaction system was poured into water (10 mL), the pH was adjusted to 3 to 4 with 2M diluted hydrochloric acid, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue obtained is purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-13/7, volume ratio). Obtaining 020_3. 1H NMR(400MHz,CDCl 3)δ:8.50(s,2H),6.86–6.79(m,1H),6.78–6.70(m,2H),6.00(s,2H),4.80–4.71(m,2H),4.69–4.60(m,2H),2.59(s,3H).
Step 4: synthesis of Compound 020
020_3 (1.5 G) and cyclopropanesulfonamide (429.28 mg) were dissolved in dimethyl sulfoxide (20 mL) at room temperature under nitrogen blanket. Tetrabutylammonium fluoride (1M tetrahydrofuran, 6.44 mL) and potassium carbonate (1.34 g) were added to the reaction system, replaced with nitrogen three times, and stirred for 12 hours at 70℃under nitrogen protection. After the completion of the reaction, the reaction system was poured into water (10 mL), the pH was adjusted to 3 to 4 with 3M diluted hydrochloric acid, extraction was performed with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue obtained is separated by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-3/2, volume ratio) to obtain crude product, and then separated and purified by preparative HPLC (mobile phase: acetonitrile/water; acidity: HCl) to obtain compound 020.MS–ESI m/z:549.8,551.8[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.73(s,1H),8.72(s,2H),6.90(d,J＝8.0Hz,1H),6.76–6.50(m,2H),6.03(s,2H),4.75–4.48(m,4H),3.31–3.23(m,1H),2.44(s,3H),1.13–0.90(m,4H).
Biological testing:
experimental example 1: in vitro test of ETA receptor antagonistic effect in human body
The purpose of the experiment is as follows:
Antagonist activity of the compounds at human ET A receptor expressed endogenously in SK-N-MC cells was assessed by measuring the effect of the compounds on human ET A receptor agonist-induced changes in cytoplasmic Ca 2+ ion signal using fluorescence detection methods. Functional activity of ET A receptor antagonism was tested at Eurofins-Cerep SA according to the current standard procedure.
Experimental protocol:
1. Cells (human endogenous (SK-N-MC cells)) were suspended in Dulbecco's modified Eagle's Medium solution (DMEM, invitrogen) supplemented with 1% FCSd and then distributed in 384 plates (100. Mu.L/well) at a density of 5X 10 4 cells/well;
2. Carboxybenzenesulfonamide was mixed with fluorescent probes (Fluo 4NW, invitrogen) in Hank's balanced salt solution (HBSS, invitrogen) supplemented with 20mm 4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid (Hepes, invitrogen) (ph 7.4), added to each well, then equilibrated with cells at 37 ℃ for 60 minutes, and then equilibrated with cells at 22 ℃ for 15 minutes;
3. The assay plate was placed in a microplate reader (CellLux, perkinElmer), a DMSO solution or HBSS buffer of appropriate concentration of test compound and positive control was added, and after 5 minutes 1nM endothelin-1 or HBSS buffer (base control) was added, and then the change in fluorescence intensity was measured in proportion to the Ca 2+ ion concentration of free cytosol;
4. The result is a percent inhibition of control response to 1nM endothelin-1;
5. The standard positive control was BQ-123 (CAS registry number: 136553-81-6), several concentrations were tested in each experiment, and the data was analyzed using Prism to generate a concentration-response curve, calculating the IC 50 value of the compound.
Experimental example 2: in vitro test of human ETB receptor antagonistic effect
The purpose of the experiment is as follows:
Antagonist activity of the compounds at human ET B receptor expressed in transfected CHO cells was assessed by measuring the effect of the compounds on human ET B receptor agonist-induced changes in cytoplasmic Ca 2+ ion signal using fluorescence detection methods. Functional activity of ET B receptor antagonism was tested at Eurofins-Cerep SA according to the current standard procedure.
Experimental protocol:
1. Cells (human recombinant (CHO cells)) were suspended in DMEM buffer (Invitrogen) and then distributed in 384 plates (100 μl/well) at a density of 3×10 4 cells/well;
2. Carboxybenzenesulfonamide was mixed with fluorescent probes (Fluo 4 Direct, invitrogen) in HBSS buffer (Invitrogen) supplemented with 20mM Hepes (Invitrogen) (ph 7.4), added to each well, then equilibrated with cells for 60 min at 37 ℃ and 15 min at 22 ℃;
3. The assay plate was placed in a microplate reader (CellLux, perkinElmer), a DMSO solution or HBSS buffer of appropriate concentration of test compound and positive control was added, and after 5 minutes, 0.3nM endothelin-1 or HBSS buffer (base control) was added, followed by measurement
A change in fluorescence intensity in an amount proportional to the concentration of Ca 2+ ions in free cytosol;
4. The result is a percent inhibition of the control response to 0.3nM endothelin-1;
5. the standard positive control was BQ-788 sodium salt (CAS registry number: 156161-89-6), and several concentrations were tested in each experiment using Prism
The data were analyzed to generate a concentration-response curve and the IC 50 values for the compounds were calculated.
Experimental results: the results of some experiments are shown in Table 1.
TABLE 1 data on the antagonistic activity of the compounds of the present disclosure on human ETA and ETB receptors and the selectivity of ETB receptors thereof
Compounds of formula (I) ETA-IC 50(nM) ETB-IC 50(nM) ETB/ETA selection coefficient
002 1.8 230000 127778
007 6.5 84000 12923
008 3.3 >300000 >90909
018 3.1 >100000 >32258
020 4.3 >100000 >23255
Conclusion of experiment: the compounds of the present disclosure exhibit high inhibitory activity against human ETA receptors in vitro experiments; meanwhile, part of compounds have high selectivity to human ETA and ETB receptors, and the selection coefficient is more than 10000 times.
Experimental example 3: in vivo pharmacokinetic property study
The purpose of the experiment is as follows: pharmacokinetic parameters of the compounds in SD rats were determined.
Experimental materials:
sprague Dawley rats (Male, 200-300g, 7-9 weeks old, beijing vitamin Tong Lihua)
The experimental method comprises the following steps:
1. The project used 4 male SD rats, which were weighed prior to dosing, calculated from body weight, and then divided into two groups. A group of 2 SD rats were given by intravenous injection at a dose of 2mg/kg and a concentration of 0.5mg/mL; an additional group of 2 SD rats was orally administered at a dose of 10mg/kg at a concentration of 1mg/mL;
2. Plasma samples were collected at 0.083 (intravenous group only), 0.25, 0.5, 1,2, 4, 6, 8, 24h post-dose. Each sample was taken approximately 0.05mL, heparin sodium was anticoagulated, and placed on wet ice after collection.
3. Blood samples were collected and placed on ice and the plasma was centrifuged within 1 hour (centrifugation conditions: 6000g,3 minutes, 2-8 ℃). The plasma samples were stored in a-80 ℃ freezer prior to analysis.
4. The collected samples were subjected to LC-MS/MS analysis and data were collected. The collected analytical data was used to calculate relevant pharmacokinetic parameters using Phoenix WinNonlin.2.0 software.
Experimental results: the results of some experiments are shown in Table 2.
TABLE 2 in vivo pharmacokinetic experiment results
Conclusion: the compound disclosed by the disclosure has better exposure and bioavailability.
Experimental example 4: in vivo efficacy study
Test purpose: exploring the therapeutic effect of the tested medicine on Thy1 nephritis
The experimental procedure is as follows:
1. 50 rats (SD rats, hemsl Kavens test animal Co.) were anesthetized with isoflurane gas. After general anesthesia, unilateral nephrectomy was performed on the right side of the rat; right kidney was resected, followed by suture administration of antibiotics; control rats (Group-1) were operated in the same model Group but without kidney excision. One week after unilateral kidney excision, the tail of a model group rat is injected with 1mg/kg of anti-Thy1 anti-body intravenously, a control group rat is injected with an equal volume of normal saline intravenously, and the urine of the rat is collected for 24 hours on the third day after injection, so that the total protein content of the urine is detected; the rats with unsuccessful modeling were removed and the modeling rats were randomly divided into 6 groups, group-2, group-3, group-4, group-5, group-6, group-7, using a simple random method based on urine protein data.
2. The fourth day after antibody injection, groups-1 and-2 rats were perfused with an equal volume of vehicle (5% DMSO+20% PEG400+10% HS) once a day, with a lavage volume of 1mL/100g, for 4 weeks; group-3 rats were gavaged 5mg/kg prednisone once daily with a gavage volume of 1mL/100g for 4 weeks; group-4 rats were gavaged with atrasentan (10 mg/kg), once daily, 1mL/100g gavage volume, for 4 weeks; group-5 rats were gavaged once a day with a gavage volume of 1mL/100g for 4 weeks following administration of the presently disclosed example compound (1 mg/kg); group-6 rats were gavaged once daily with a gavage volume of 1mL/100g for 4 weeks; group-7 rats were gavaged with the compound of the examples of the present disclosure (10 mg/kg) once daily, with a gavage volume of 1mL/100g, for 4 weeks.
3. The third Day (Day 0) after antibody injection, the 7 th Day and the 28 th Day of administration respectively collect 24h urine of the rat, and detect the 24h urine protein content; after urine collection, blood samples of each group of rats were taken to detect hematocrit.
4. After the blood collection, the rats are euthanized by a CO 2 method, kidney tissues are collected, and PAS staining is performed to observe the pathological changes of the kidney tissues.
Statistical analysis:
Data were analyzed and plotted using GRAPHPAD PRISM (Version 5.01), and collated using Adobe Illustrator CS6 (Version 16.0.0). All data are expressed in means±sd, and statistical differences between groups were examined using one-way ANOVA and Tukey's, with P values less than 0.05 considered significant differences.
Conclusion of experiment: the compound disclosed by the disclosure can reduce the proteinuria content of rats, improve the hematocrit, relieve the kidney injury of rats and inhibit the phenomena of mesangial cell proliferation, mesangial matrix increase and glomerular wall thickening.

Claims (15)

  1. A compound of formula (a) or a pharmaceutically acceptable salt thereof, selected from:
    Wherein,
    Z 1 is selected from N or CR Z1;
    Z 2 is selected from N or CR Z2;
    R Z1 or R Z2 are each independently selected from H, halogen, -OH, -NH 2、-CN、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1- 6 alkylamino, di C 1-6 alkylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, halogenated C 1-6 alkylamino, or halogenated di C 1-6 alkylamino;
    X is selected from O or NH;
    Ring a is selected from the following groups optionally substituted with one or more R a: 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl;
    R a is each independently selected from halogen, -OH, oxo 、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-NHC(O)NR a1R a2、-NR a1C(O)OR a2、-OC(O)R a1、-C(O)OR a1、-OC(O)OR a1、-OC(O)NR a1R a2、-C 1-6 alkylene C (O) NR a1R a2、-C 1-6 alkylene NR a1C(O)R a2、-C 1-6 alkylene NHC (O) NR a1R a2、-C 1-6 alkylene NR a1C(O)OR a2、-C 1-6 alkylene OC (O) R a1、-C 1-6 alkylene C (O) OR a1、-C 1-6 alkylene OC (O) NR a1R a2, OR the following optionally substituted with 1 OR more R a3 groups: c 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, 3-12 cycloalkyl, 3-12 heterocycloalkyl, 5-10 heterocyclyl, 6-10 aryl, or 5-10 heteroaryl;
    Each R a1、R a2 is independently selected from H or C 1-6 alkyl;
    r a3 is each independently selected from halogen, -OH, -NH 2、-CN、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di-C 1-6 alkylamino, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 1-6 alkylthio, halo C 1-6 alkylamino, or halo di-C 1-6 alkylamino;
    L is selected from a single bond, -O-, -S-, -NH-, -C (O) -, or the following optionally substituted with one or more R L: -CH 2-、-N(C 1- 6 alkyl) -, or-CH (C 1-6 alkyl) -;
    R L is each independently selected from halogen, -OH, -NH 2、-CN、C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di-C 1-6 alkylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, halogenated C 1-6 alkylamino, or halogenated di-C 1-6 alkylamino;
    Ring D is selected from the following groups optionally substituted with one or more R b: 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
    r b is each independently selected from halogen, -OH, -NH 2、-CN、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di-C 1-6 alkylamino, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 1-6 alkylthio, halo C 1-6 alkylamino, or halo di-C 1-6 alkylamino;
    Y 1 is selected from-O-, -S-, or-NH-;
    Y 2 is selected from -O-、-S-、-NH-、-SO 2-、-NHSO 2-、-SO 2NH-、-NHSO 2NH-、-C(O)NH-、-NHC(O)-、-OC(O)NH-、-NHC(O)O-、 or-NHC (O) NH-;
    m is selected from 1, 2, 3, 4, 5, or 6;
    ring C is selected from 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
    n is selected from 0, 1, 2, 3, or 4;
    R 1 is each independently selected from halogen, -OH, -NH 2、-CN、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di-C 1-6 alkylamino, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 1-6 alkylthio, halo C 1-6 alkylamino, or halo di-C 1-6 alkylamino;
    R 2 is selected from H, halogen, -OH, -NH 2, -CN, or the following optionally substituted with one or more R 2a: c 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di C 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
    R 2a is each independently selected from oxo, halogen, -OH, -NH 2、-CN、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di-C 1-6 alkylamino, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 1-6 alkylthio, halo C 1-6 alkylamino, or halo di-C 1-6 alkylamino;
    R Z1、R Z2、X、R a、R a1、R a2、R a3、R L、R b、R 1、R 2、R 2a、 Ring a, ring D, or ring C are optionally substituted with one or more substituents.
  2. A compound of formula (a) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from the following groups optionally substituted with one or more R a: 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl;
    Or ring a is selected from the following groups optionally substituted with one or more R a: 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;
    Or ring a is selected from the following groups optionally substituted with one or more R a: cyclopropane, cyclobutane, cyclopentane, cyclohexenyl, cycloheptane, bicyclo [1.1.1] pentyl, bicyclo [3.1.0] hexyl, bicyclo [3.2.0] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.3.0] octyl, spiro [3.3] heptyl, spiro [3.4] octyl, oxetane, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxaheptyl, azepanyl, azaheptyl, azabicyclo [3.1.0] hexyl, oxabicyclo [3.2.0] heptyl, azabicyclo [3.2.0] heptyl, oxabicyclo [2.2.2] octyl, oxabicyclo [3.3.0] octyl, azabicyclo [3.3.0] octyl, oxaspiro [3.3] heptyl, azaspiro [3.3] heptyl, oxaspiro [ 3.0] octyl, oxaspiro [3.3] heptyl, oxaspiro [3.1.0] octyl, oxaspiro [3.4] spiro [3.4] octyl, or spiro [3.4] octyl;
    Or ring a is selected from the following groups optionally substituted with one or more R a: cyclopropane, spiro [3.3] heptyl, tetrahydrofuranyl, piperidinyl, or oxaspiro [3.3] heptyl;
    Or ring a is selected from the following groups optionally substituted with one or more R a:
    Or ring a is selected from the following groups optionally substituted with one or more R a: Wherein each R a is independently selected from-C (O) NH 2、-C(O)NHCH 3、-COOH、-COOCH 3, methyl, or methoxy;
    Or ring a is selected from the following groups:
  3. A compound of formula (a) according to claim 1 OR 2, OR a pharmaceutically acceptable salt thereof, wherein R a is each independently selected from halogen, -OH, oxo 、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-NHC(O)NR a1R a2、-NR a1C(O)OR a2、-OC(O)R a1、-C(O)OR a1、-OC(O)OR a1、-OC(O)NR a1R a2、-C 1-4 alkylene C (O) NR a1R a2、-C 1-4 alkylene NR a1C(O)R a2、-C 1-4 alkylene NHC (O) NR a1R a2、-C 1-4 alkylene NR a1C(O)OR a2、-C 1-4 alkylene OC (O) R a1、-C 1-4 alkylene C (O) OR a1、 -C 1-4 alkylene OC (O) NR a1R a2, OR the following optionally substituted with 1 OR more R a3: c 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;
    OR each R a is independently selected from halogen, -OH, oxo 、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-OC(O)R a1、-C(O)OR a1、-C 1-4 alkylene C (O) NR a1R a2、-C 1-4 alkylene NR a1C(O)R a2、-C 1-4 alkylene OC (O) R a1、-C 1-4 alkylene C (O) OR a1, OR the following optionally substituted with 1 OR more R a3: c 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;
    OR R a is each independently selected from F, cl, br, -OH, oxo 、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-OC(O)R a1、-C(O)OR a1、-C 1-2 alkylene C (O) NR a1R a2、-C 1-2 alkylene NR a1C(O)R a2、-C 1-2 alkylene OC (O) R a1、-C 1-2 alkylene C (O) OR a1, OR the following optionally substituted with 1 OR more R a3 groups: methyl, ethyl, methoxy, ethoxy, methylamino, or dimethylamino;
    Or R a are each independently selected from F, cl, br, -OH, oxo, -NH 2、-CN、-C(O)NR a1R a2、-C(O)OR a1, or the following optionally substituted with 1 or more R a3: methyl, ethyl, methoxy, ethoxy, methylamino, or dimethylamino;
    Or R a is each independently selected from F, cl, br, -OH, oxo, -NH 2、-CN、-C(O)NR a1R a2、-C(O)OR a1, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy;
    or R a is each independently selected from-C (O) NH 2、-C(O)NHCH 3、-COOH、-COOCH 3, methyl, or methoxy.
  4. A compound of formula (a) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein L is selected from a single bond, -O-, -S-, -NH-, -C (O) -, or the following optionally substituted with one or more R L: -CH 2-、-N(C 1-3 alkyl) -, or-CH (C 1-3 alkyl) -;
    Or L is selected from a single bond, -O-, -S-, -NH-, -C (O) -, or the following optionally substituted with one or more R L: -CH 2-、-N(CH 3) -, or-CH (CH 3) -;
    Or L is selected from a single bond, -O-, -S-, -NH-, -C (O) -, -CH 2-、-N(CH 3) -, or-CH (CH 3) -;
    or L is selected from a single bond.
  5. A compound of formula (a) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein ring D is selected from the following groups optionally substituted with one or more R b: 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
    Or ring D is selected from the following groups optionally substituted with one or more R b: a 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
    Or ring D is selected from the following groups optionally substituted with one or more R b: Wherein ring B is selected from 5-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl, T 1 is selected from C, or N;
    Or ring D is selected from the following groups optionally substituted with one or more R b: benzo 5-6 membered cycloalkenyl, benzo 5-6 membered heterocyclyl, pyrido 5-6 membered heterocyclyl, phenyl, naphthyl, or 9-10 membered heteroaryl;
    or ring D is selected from the following groups optionally substituted with one or more R b: phenyl, naphthyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, and, A quinolyl, isoquinolyl, or benzopyrimidinyl group;
    or ring D is selected from the following groups optionally substituted with one or more R b: Benzothiazolyl, or
    Or ring D is selected from the following groups optionally substituted with one or more R b:
    Or ring D is selected from
  6. A compound of formula (a) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein each R b is independently selected from halogen, -OH, -NH 2、-CN、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di-C 1-4 alkylamino, halo C 1- 4 alkyl, halo C 1-4 alkoxy, halo C 1-4 alkylthio, halo C 1-4 alkylamino, or halo di-C 1-4 alkylamino;
    or each R b is independently selected from halogen, -OH, -NH 2、-CN、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1- 4 alkylamino, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy;
    Or R b is each independently selected from F, cl, br, -OH, -NH 2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy;
    Or R b is each independently selected from F, cl, br, -OH, -NH 2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
  7. A compound of formula (a) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y 2 is selected from-O-, -S-, -NH-, -SO 2-、-NHSO 2-、-SO 2 NH-, -C (O) NH-, or-NHC (O) -;
    Or Y 2 is selected from-O-, -S-, or-NH-;
    Or Y 2 is selected from-O-.
  8. A compound of formula (a) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
    Or ring C is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
    Or ring C is selected from 6-10 membered aryl or 5-10 membered heteroaryl;
    Or ring C is selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, imidazo [1,2-b ] pyridazinyl, pyrazolo [1,5-a ] pyridyl, quinolinyl, isoquinolinyl, or benzopyrimidinyl;
    or ring C is selected from phenyl, naphthyl, thiazolyl, pyridyl, pyrimidinyl, triazinyl, or imidazo [1,2-b ] pyridazinyl;
    or ring C is selected from pyrimidinyl, pyridinyl, thiazolyl, imidazopyridazinyl and triazinyl;
    Or ring C is selected from
  9. A compound of formula (a) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected from halogen, -OH, -NH 2、-CN、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di-C 1-4 alkylamino, halo C 1- 4 alkyl, halo C 1-4 alkoxy, halo C 1-4 alkylthio, halo C 1-4 alkylamino, or halo di-C 1-4 alkylamino;
    Or each R 1 is independently selected from halogen, -OH, -NH 2、-CN、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1- 4 alkylamino, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy;
    Or R 1 is each independently selected from F, cl, br, -OH, -NH 2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy;
    Or R 1 is each independently selected from F, cl, br, -OH, -NH 2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy;
    Or R 1 is each independently selected from F, cl, br, or trifluoromethoxy.
  10. A compound of formula (a) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, halogen, -OH, -NH 2, -CN, or the following groups optionally substituted with one or more R 2a: c 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di C 1-4 alkylamino, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
    Or R 2 is selected from H, halogen, -OH, -NH 2, -CN, or the following optionally substituted with one or more R 2a: c 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di C 1-4 alkylamino, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl;
    Or R 2 is selected from H, halogen, -OH, -NH 2, -CN, or the following optionally substituted with one or more R 2a: c 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl;
    Or R 2 is selected from H, F, cl, br, -OH, -NH 2, -CN, or the following groups optionally substituted with one or more R 2a: methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexenyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl;
    Or R 2 is selected from H, F, cl, br, or the following optionally substituted with one or more R 2a: methyl or morpholinyl;
    Or R 2 is selected from H, methyl, or morpholinyl.
  11. The compound of formula (A) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, which is selected from the group consisting of the compounds of formula (A-1), formula (A-2), formula (A-3) and formula (A-4) or a pharmaceutically acceptable salt thereof,
    Wherein R 1、R 2、Y 1、Y 2, X, m, n, L, ring A, ring D and ring C are as defined in any of claims 1 to 10.
  12. The compound of formula (A) or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, which is selected from the group consisting of a compound of formula (II) or a pharmaceutically acceptable salt thereof,
    Wherein,
    T 1 is selected from C and N;
    Ring B is selected from 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl;
    Structural unit Optionally substituted with one or more R b;
    r 1、R 2、R b, X, n, ring A and ring C are as defined in any of claims 1 to 10.
  13. The following compounds or pharmaceutically acceptable salts thereof,
  14. A pharmaceutical composition comprising a compound of formula (a) as defined in any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof; optionally, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.
  15. Use of a compound of formula (a) as defined in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 14, in the manufacture of a medicament for the treatment of a ETA receptor-related disorder; optionally, the ETA receptor related disease is selected from IgA nephropathy.
CN202280073839.0A 2021-11-08 2022-11-08 Azabiphenyls and uses thereof Pending CN118201908A (en)

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CN202211358693 2022-11-01
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* Cited by examiner, † Cited by third party
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RU2086544C1 (en) * 1991-06-13 1997-08-10 Хоффманн-Ля Рош АГ Benzenesulfonamide derivatives of pyrimidine or their salts, pharmaceutical composition for treatment of diseases associated with endothelin activity
TW287160B (en) * 1992-12-10 1996-10-01 Hoffmann La Roche
IL111959A (en) * 1993-12-17 2000-07-16 Tanabe Seiyaku Co N-(polysubstituted pyrimidin-4-yl) benzenesulfonamide derivatives their preparation and pharmaceutical compositions containing them
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