CN115141195B - NUAK inhibitor and application thereof - Google Patents

NUAK inhibitor and application thereof Download PDF

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CN115141195B
CN115141195B CN202210180849.6A CN202210180849A CN115141195B CN 115141195 B CN115141195 B CN 115141195B CN 202210180849 A CN202210180849 A CN 202210180849A CN 115141195 B CN115141195 B CN 115141195B
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alkylene
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CN115141195A (en
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李进
张登友
龚义
白晓光
邓宁
赵洪川
周贤思
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Hitgen Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention provides a NUAK inhibitor and application thereof. The invention provides a compound shown in a formula I, or a deuterated compound, or a stereoisomer or a pharmaceutically acceptable salt thereof, and application thereof in preparing a medicament for treating diseases. The compound provided by the invention has NUAK inhibition effect and provides a new medicinal possibility.

Description

NUAK inhibitor and application thereof
Technical Field
The present invention relates to a novel class of compounds having NUAK inhibitory effect and their use in the treatment of disease.
Background
AMP-dependent protein kinases (AMP-activated protein kinase, AMPK) are an important class of protein kinases, the family of which has 12 members: MARK1, MARK2, MARK3, MARK4, MELK, QIK, QSK, SIK, BRSK1, BRSK2, NUAK1 and NUAK2.AMPK has important biological roles such as regulation of the immune system, regulation of gene transcription, control of cell polarity, and maintenance of cellular energy levels.
NUAK subtypes NUAK1 (ARK 5) and NUAK2 (SNARK) are important members of the AMPK family, are Ser/Thr kinases, can be phosphorylated and activated by LKB1 tumor suppressor protein kinase, and play an important role in cancer progression, cell adhesion, cell proliferation and metastasis, and glycometabolism. Studies have shown that NUAK subtypes are involved in many important functions, such as neuronal polarity and axonal branching, aging, cell adhesion, and control of embryonic development. NUAK also acts as a survival factor in MYC-driven tumors, promoting cancer cell invasion and controlling cell division by its ability to stimulate proliferation. Because of their critical function in cell signaling, their deregulation is associated with a number of serious diseases, including neurodegenerative diseases, metastatic cancers and diabetes. They are therefore potential therapeutic targets for metabolic diseases and cancers.
At present, no NUAK inhibitor medicine is marketed, so that the development of the medicine with NUAK inhibition activity has great market value.
Disclosure of Invention
The invention provides a compound shown in a formula I, or a deuterated compound, or a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein,
x is selected from N or CH;
R 1 selected from hydrogen, halogen, cyano, nitro, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR 12 、-C 0～4 alkylene-OC (O) R 12 、-C 0～4 alkylene-C (O) R 12 、-C 0～4 alkylene-C (O) OR 12 、-C 0～4 alkylene-C (O) NR 12 R 13 、-C 0～4 alkylene-NR 12 R 13 、-C 0～4 alkylene-NR 12 C(O)R 13 、-C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R 11 Substitution;
each R 11 Are independently selected from hydrogen, halogen, cyano, nitro, oxo, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, -C 0～4 alkylene-OR 1a 、-C 0～4 alkylene-C (O) R 1a 、-C 0～4 alkylene-C (O) NR 1a R 1b 、-C 0～4 alkylene-NR 1a R 1b 、-C 0～4 alkylene-NR 1a C(O)R 1b 、-C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R 1c Substitution;
R 12 、R 13 are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle);
R 1a 、R 1b are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle);
each R 1c Are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O (C) 1～6 Alkyl), -O (halogen substituted C 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C) 1～6 Alkyl), -C 0～4 alkylene-OR 1d 、-C 0～4 alkylene-C (O) R 1d 、-C 0～4 alkylene-OC (O) R 1d 、-C 0～4 alkylene-C (O) OR 1d 、-C 0～4 alkylene-C (O) NHR 1d 、-C 0～4 alkylene-NHC (O) R 1d 、-C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle);
each R 1d Are respectively and independently selected from hydrogen and C 1～6 Alkyl, halogen substituted C 1～6 Alkyl, halogen, -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C) 1～6 Alkyl), -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle);
R 2 selected from-C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen extractionsubstituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 1～4 alkylene-OR 22 、-C 1～4 alkylene-OC (O) R 22 、-C 1～4 alkylene-C (O) R 22 、-C 1～4 alkylene-C (O) OR 22 、-C 1～4 alkylene-C (O) NR 22 R 23 、-C 1～4 alkylene-NR 22 C(O)R 23 、-C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R 21 Substitution;
R 22 、R 23 are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle);
each R 21 Independently selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, -C 0～4 alkylene-OR 2a 、-C 0～4 alkylene-C (O) R 2a 、-C 0～4 alkylene-C (O) NR 2a R 2b 、-C 0～4 alkylene-NR 2a R 2b 、-C 0～4 alkylene-NR 2a C(O)R 2b 、-C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R 2c Substitution;
R 2a 、R 2b are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle);
each R 2c Are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O (C) 1～6 Alkyl), -O (halogen substituted C 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C) 1～6 An alkyl group);
R 3 selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, -C 0～4 Alkylene- (3-5 membered cycloalkyl), -C 0～4 Alkylene- (3-5 membered heterocycloalkyl);
when R is 3 R is selected from trifluoromethyl 1 Phenyl is not taken;
R 7 selected from- (5-10 membered aromatic heterocycle), -NR 4 (3-to 10-membered cycloalkyl), -NR 4 (3-to 10-membered heterocycloalkyl), -NR 4 (5-to 10-membered aromatic ring), -NR 4 (5-10 membered aromatic heterocycle), -O (5-10 membered aromatic heterocycle); wherein said cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R 71 Substitution;
R 4 selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl);
each R 71 Are independently selected from hydrogen and-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O (C) 1～6 Alkyl), -O (halogen substituted C 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C) 1～6 Alkyl), -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein said alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R 72 Substitution;
each R 72 Are independently selected from hydrogen and-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O (C) 1～6 Alkyl), -O (halogen substituted C 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C) 1～6 Alkyl), -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl).
As preferable: the compound of formula I is shown in formula Ia:
wherein,
x is selected from N or CH;
R 1 selected from hydrogen, halogen, cyano, nitro, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR 12 、-C 0～4 alkylene-OC (O) R 12 、-C 0～4 alkylene-C (O) R 12 、-C 0～4 alkylene-C (O) OR 12 、-C 0～4 alkylene-C (O) NR 12 R 13 、-C 0～4 alkylene-NR 12 R 13 、-C 0～4 alkylene-NR 12 C(O)R 13 、-C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R 11 Substitution;
each R 11 Are independently selected from hydrogen, halogen, cyano, nitro, oxo, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, -C 0～4 alkylene-OR 1a 、-C 0～4 alkylene-C (O) R 1a 、-C 0～4 alkylene-C (O) NR 1a R 1b 、-C 0～4 alkylene-NR 1a R 1b 、-C 0～4 alkylene-NR 1a C(O)R 1b 、-C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R 1c Substitution;
R 12 、R 13 are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle);
R 1a 、R 1b are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle);
each R 1c Are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O (C) 1～6 Alkyl), -O (halogen substituted C 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C) 1～6 Alkyl), -C 0～4 alkylene-C (O) (3-10 membered cycloalkyl);
R 2 selected from-C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 1～4 alkylene-OR 22 、-C 1～4 alkylene-OC (O) R 22 、-C 1～4 alkylene-C (O) R 22 、-C 1～4 alkylene-C (O) OR 22 、-C 1～4 alkylene-C (O) NR 22 R 23 、-C 1～4 alkylene-NR 22 C(O)R 23 、-C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R 21 Substitution;
R 22 、R 23 are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle);
each R 21 Independently selected from hydrogenHalogen, cyano, nitro, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, -C 0～4 alkylene-OR 2a 、-C 0～4 alkylene-C (O) R 2a 、-C 0～4 alkylene-C (O) NR 2a R 2b 、-C 0～4 alkylene-NR 2a R 2b 、-C 0～4 alkylene-NR 2a C(O)R 2b 、-C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R 2c Substitution;
R 2a 、R 2b are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle);
each R 2c Are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O (C) 1～6 Alkyl), -O (halogen substituted C 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C) 1～6 An alkyl group);
R 3 selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, -C 0～4 Alkylene- (3-5 membered cycloalkyl), -C 0～4 Alkylene- (3-5 membered heterocycloalkyl);
R 4 selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl);
R 5 selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl);
R 6 selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, -C 0～4 alkylene-OR 6a 、-C 0～4 alkylene-C (O) R 6a 、-C 0～4 alkylene-C (O) NR 6a R 6b 、-C 0～4 alkylene-NR 6a R 6b 、-C 0～4 alkylene-NR 6a C(O)R 6b 、-C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R 6c Substitution;
R 6a 、R 6b are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle);
each R 6c Are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O (C) 1～6 Alkyl), -O (halogen substituted C 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C) 1～6 Alkyl).
Further, the compound of formula I is shown as formula IIa:
wherein,
ring A is selected from the group consisting of-C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R 11 Substitution;
each R 11 Are independently selected from hydrogen, halogen, cyano, nitro, oxo, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, -C 0～4 alkylene-OR 1a 、-C 0～4 alkylene-C (O) R 1a 、-C 0～4 alkylene-C (O) NR 1a R 1b 、-C 0～4 alkylene-NR 1a R 1b 、-C 0～4 alkylene-NR 1a C(O)R 1b 、-C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R 1c Substitution;
R 1a 、R 1b are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterogenies)A ring);
each R 1c Are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O (C) 1～6 Alkyl), -O (halogen substituted C 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C) 1～6 Alkyl), -C 0～4 alkylene-C (O) (3-10 membered cycloalkyl).
Still further, the method further comprises the steps of,
the ring A is selected from benzene ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, 5-6-membered carbocycle and 5-8-membered heterocycle; wherein the benzene ring, aromatic heterocycle, carbocycle, heterocycle may be further substituted with one, two or three independent R 11 And (3) substitution.
Further specifically, the method comprises the steps of,
ring A is selected from Wherein the ring selected from the A ring may be further substituted with one, two or three independent R 11 And (3) substitution.
Still more particularly, the method comprises the steps of,
ring A is selected from
Further, the compound of formula I is shown as formula IIb or formula IIc:
wherein,
R 2 selected from-C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl); wherein the alkylene, cycloalkyl, heterocycloalkyl groups may be further substituted with one, two or three independent R 21 Substitution;
each R 21 Independently selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, -C 0～4 alkylene-OR 2a 、-C 0～4 alkylene-C (O) R 2a 、-C 0～4 alkylene-C (O) NR 2a R 2b 、-C 0～4 alkylene-NR 2a R 2b 、-C 0～4 alkylene-NR 2a C(O)R 2b 、-C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R 2c Substitution;
R 2a 、R 2b are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle);
each R 2c Are respectively and independently selected from hydrogen and C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O (C) 1～6 Alkyl), -O (halogen substituted C 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C) 1～6 Alkyl).
In some embodiments of the present invention,
R 2 is selected from 5-8 membered cycloalkyl, 5-8 membered heterocycloalkyl and C 0～2 Alkylene- (5-10 membered aromatic ring); wherein the cycloalkyl, heterocycloalkyl, and aromatic rings may be further substituted with one, two, or three independent R 21 And (3) substitution.
Further, the method comprises the steps of,
R 2 selected from the group consisting of Wherein R is 2 The selected ring may be further substituted with one, two or three independent R 21 And (3) substitution.
Still further, the method further comprises the steps of,
R 2 selected from the group consisting of
In some embodiments of the present invention,
R 3 selected from hydrogen, -C 1～6 Alkyl, halogen substituted-C 1～6 An alkyl group; r is R 4 Selected from hydrogen, -C 1～6 An alkyl group; r is R 5 Selected from hydrogen, -C 1～6 An alkyl group.
Further, R 3 Selected from hydrogen, methyl, halogen substituted methyl; r is R 4 Selected from hydrogen, methyl; r is R 5 Selected from hydrogen, methyl.
In some embodiments of the present invention,
R 6 selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl.
Advancing oneStep by step, R 6 Selected from methyl, ethyl,
In some embodiments of the invention, R 7 Selected from- (5-10 membered aromatic heterocycle), -NR 4 (5-to 10-membered aromatic ring), -NR 4 (5-10 membered aromatic heterocycle), -O (5-10 membered aromatic heterocycle); wherein the aromatic ring, aromatic heterocyclic ring may be further substituted with one, two or three independent R 71 Substitution;
R 4 selected from hydrogen, -C 1～6 An alkyl group;
each R 71 Are independently selected from hydrogen and-C 1～6 Alkyl, halogen substituted C 1～6 Alkyl, -O (C) 1～6 Alkyl), -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl); wherein said alkyl, cycloalkyl, heterocycloalkyl may be further substituted with one, two or three independent R 72 Substitution;
Each R 72 Are independently selected from hydrogen and-C 1～6 An alkyl group.
As preferable: the R is 7 Selected from 5-6 membered aromatic heterocycle, 9 membered aromatic heterocycle, -N (C) 1～6 Alkyl) (5-membered aromatic heterocycle), -NH (5-6 membered aromatic heterocycle), -NH (6-membered aromatic ring), -O (5-6 membered aromatic heterocycle); wherein the aromatic ring, aromatic heterocyclic ring may be further substituted with one, two or three independent R 71 Substitution;
each R 71 Are independently selected from hydrogen and-C 1～3 Alkyl, -O (C) 1～3 Alkyl), - (3-to 6-membered cycloalkyl), - (3-to 6-membered heterocycloalkyl); wherein said alkyl, cycloalkyl, heterocycloalkyl may be further substituted with one, two or three independent R 72 Substitution;
each R 72 Are independently selected from hydrogen and-C 1～3 An alkyl group.
Still further: the R is 7 Selected from the group consisting of
In a specific embodiment of the present invention, the compound of formula I is specifically:
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the invention also provides the application of any one of the compounds, or stereoisomers thereof, or deuterated compounds thereof, or pharmaceutically acceptable salts thereof in preparing NUAK inhibitor medicines.
The invention also provides the application of any one of the compounds, or stereoisomers thereof, or deuterated compounds thereof, or pharmaceutically acceptable salts thereof in preparing medicines for treating cancers or tumors.
The invention also provides a pharmaceutical composition, which comprises any one of the compounds, or stereoisomers thereof, or deuterated compounds thereof, or pharmaceutically acceptable salts thereof, and a preparation prepared by adding pharmaceutically acceptable carriers, auxiliary materials and vehicles.
The compounds and derivatives provided in the present invention may be named according to IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, columbus, OH) naming system.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
"substituted" means that a hydrogen atom in the molecule is replaced with a different atom or group.
"further substituted" means that "substitution" may, but need not, occur, and that the description includes situations that may or may not occur.
The minimum and maximum values of the carbon atom content of the hydrocarbon groups are indicated by a prefix, e.g. prefix C a～b Alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1～6 Alkyl refers to alkyl groups containing 1 to 6 carbon atoms.
"alkyl" means having the indicated number of ingredientsSaturated hydrocarbon chains of member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of other groups such as-O (C 1～6 Alkyl).
"alkylene" refers to a divalent saturated aliphatic hydrocarbon group having the indicated number of member atoms. C (C) a ～ b Alkylene refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbyl groups. For example, the term "propylene" may be exemplified by the following structure:likewise, the term "dimethylbutylene" may be exemplified, for example, by any of the following structures: />
"cycloalkyl", "cycloalkane" as used herein refers to a saturated or partially saturated cyclic group having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings (fused, bridged). For polycyclic systems having aromatic and non-aromatic rings that do not contain ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8, -tetrahydronaphthalen-5-yl) applies when the point of attachment is at a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of cycloalkyl groups comprising a multicycloalkyl ring system are dicyclohexyl, dicyclopentyl, bicyclooctyl, and the like. Two such bicycloalkyl polycyclic structures are exemplified and named below: Dicyclohexyl and->Dicyclohexyl group.
"heterocycle", "heterocycloalkyl", "heterocycloalkane" as used herein refers to a saturated or non-aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom, etc. Typically a monovalent saturated or partially unsaturated mono-or bicyclic ring system representing a plurality of ring atoms, comprising 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two rings sharing two ring atoms, i.e. the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl,thiomorpholinyl, 1-dioxo-thiomorpholin-4-yl, azepanyl, diazepayl, homopiperazinyl or oxaazepanyl. An example of a bicyclic saturated heterocycloalkyl group is 8-aza-bicyclo [3.2.1]Octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1 ]Octyl, 9-aza-bicyclo [3.3.1]And (3) nonyl. Examples of partially unsaturated heterocycloalkyl groups are dihydrofuryl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl.
As used herein, "aromatic ring" refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl is typically a monocyclic, bicyclic or tricyclic aryl group having multiple carbon atoms. Furthermore, the term "aryl" as used herein refers to an aromatic substituent that may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.
"aromatic heterocycle" as used herein refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom, etc. An aromatic mono-or bicyclic hydrocarbon typically comprising a plurality of ring atoms, wherein one or more of the ring atoms is selected from heteroatoms of O, N, S. Preferably one to three heteroatoms. Heteroaryl represents, for example: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl.
"halogen" as used herein refers to fluorine, chlorine, bromine or iodine.
"halogen-substituted alkyl" as used herein means that one or more hydrogen atoms in the alkyl group are replaced with halogen; such as trifluoromethyl.
As used herein, "OR", "-NRR", etc. means that the R group is attached to the oxygen OR nitrogen atom by a single bond.
In the present invention, "-C (O) R", "-S (O) 2 The oxygen atom in R' and the like is doubly bonded to a carbon atom or a sulfur atom.
The terms "=o", "=s" as used herein refer to an oxygen atom and a sulfur atom attached to a substitution site by a double bond.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising the pharmaceutical dosage form, and physiologically compatible with the recipient.
The terms "salts" and "pharmaceutically acceptable salts" refer to the acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. The compound may be obtained by mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base as appropriate (for example, equivalent). These salts may be obtained by precipitation in solution and collected by filtration, or recovered after evaporation of the solvent, or by lyophilization after reaction in an aqueous medium. The salts of the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoric, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate salts of the compounds.
In certain embodiments, one or more compounds of the present invention may be used in combination with one another. The compounds of the invention may alternatively be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds may be administered to a subject simultaneously, separately or sequentially.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The structure of the compounds was determined by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). NMR shift (. Delta.) is given in units of 10-6 (ppm). NMR was performed using a nuclear magnetic resonance apparatus (Bruker Avance III 400 and Bruker Avance 300) with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard is Tetramethylsilane (TMS).
LC-MS was measured using Shimadzu LC-MS 2020 (ESI). HPLC was performed using a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A). MPLC (medium pressure preparative chromatography) uses Gilson GX-281 reverse phase preparative chromatograph. The specification of the thin layer chromatography separation and purification product adopted by the smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The known starting materials of the present invention may be synthesized using or according to methods known in the art, or may be purchased from An Naiji chemical, chengkoulochemical, shaoshan chemical technology, carbofuran technology, and the like.
The reaction was carried out under nitrogen atmosphere without specific explanation in examples. The examples are not specifically described, and the solution refers to an aqueous solution. The temperature of the reaction was room temperature, unless otherwise specified in the examples. In the examples, M is mol/liter unless otherwise specified.
The reagent abbreviations are as follows: DIPEA: n, N-diisopropylethylamine; TEA: triethylamine; HBTU: benzotriazol-N, N' -tetramethylurea hexafluorophosphate; DAST: diethylaminosulfur trifluoride; tf (Tf) 2 O: trifluoroacetic anhydride; TFA: trifluoroacetic acid; pd (dppf) Cl 2 : [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; pd (Pd) 2 (dba) 3 : tris (dibenzylideneacetone) dipalladium; cuTC: thiophene-2-carboxylic acid copper (I); BPhen:4, 7-diphenyl-1, 10-phenanthroline; BTMG: 2-tert-butyl-1, 3-tetramethylguanidine; xantphos:4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene; DMF: n, N-dimethylformamide; DCM: dichloromethane; CH (CH) 3 CN: acetonitrile; DMSO: dimethyl sulfoxide; PE: petroleum ether; EA: ethyl acetate; dioxane:1, 4-dioxane; tolutene: toluene; THF: tetrahydrofuran.
Preparation of intermediate Z-1
To a solution of 2, 6-dichloro-4-methylpyridine (30 g,185.17 mmol) in trifluoroacetic anhydride (150 mL) at zero degrees HNO was added dropwise 3 (24.50 g,388.85 mmol) and the resulting reaction solution was slowly warmed to room temperature and stirred for 18 hours. After the reaction was completed, the reaction mixture was slowly added to a cooled aqueous solution of sodium bisulphite (35.40 g,186.21 mmol) and the mixture was dissolved in water (240 mL)The solution was stirred for 2 hours. The reaction solution was adjusted to pH 7 by adding 8N NaOH solution, and then extracted twice by adding dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration to give intermediate Z-1 (35 g,169.07mmol,91.31% yield) as a white solid. MS (ESI) m/z=208 [ m+1 ] ] + 。
Preparation of intermediate Z-2
Step 1, preparation of intermediate Z-2-1
KOTBu (1.34 g,11.94 mmol) was added to a solution of 1H-pyrazole-4-carbaldehyde (960 mg,9.99 mmol) in DMF (12 mL), and the reaction was stirred at room temperature for 5min, followed by t-butyl bromoacetate (2.13 g,10.92 mmol). The resulting reaction mixture was stirred at room temperature for 2h. After the completion of the reaction, a saturated sodium carbonate and ethyl acetate solution were added, and the separated organic phase was washed with water, saturated brine, filtered and concentrated to give a crude product, which was purified by silica gel column separation (15-100% EA in PE) to give Z-2-1 (1.25 g,5.95mmol,59.51% yield). MS (ESI) m/z=211 [ m+1 ]] + 。
Step 2, preparation of intermediate Z-2-2
To a solution of Z-2-1 (1.25 g,5.95 mmol) in dioxane (18 mL) was added 4N HCl (18 mL), and the reaction mixture was stirred overnight at room temperature, after the completion of the reaction, the solvent was removed by spinning to give crude Z-2-2 (900 mg,5.84mmol,98.21% yield) which was used in the next reaction without further purification.
Step 3, preparation of intermediate Z-2
To a solution of Z-2-2 (47 mg, 304.95. Mu. Mol) in DCM (4 mL) were added HBTU (138.69 mg, 365.94. Mu. Mol) and DIPEA (78.82 mg, 609.90. Mu. Mol, 106.23. Mu.L), stirred at room temperature for 10min, then morpholine (26 mg, 298.44. Mu. Mol) was added and the reaction mixture stirred at room temperature for 4h. After completion of the reaction, water was added to dilute, DCM was added to extract, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography on silica gel to give Z-2 (60 mg,268.78 μmol,88.14% yield). MS (ESI) m/z=224 [ m+1 ] ] + 。
Preparation of intermediate Z-3
Step 1, preparation of intermediate Z-3-1
To a solution of N-Boc-4-hydroxypiperidine (5.03 g,24.99 mmol) in DCM (50 mL) at zero temperature were added TEA (3.79 g,37.49mmol,5.23 mL) and MsCl (3.44 g,29.99 mmol), and the reaction mixture was stirred at zero temperature for 10min and then warmed to room temperature and stirred for 2h. After completion of the reaction, DCM (200 ml) was added for dilution, and the mixture was washed successively with 2M sodium carbonate solution and saturated brine, and the separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate Z-3-1 (6.98 g,24.99mmol,100.00% yield). It was used in the next reaction without further purification. MS (ESI) m/z=280 [ m+1 ]] + 。
Step 2, preparation of intermediate Z-3-2
To a solution of intermediate Z-3-1 (3.07 g,10.99 mmol) and 1H-pyrazole-4-carbaldehyde (960 mg,9.99 mmol) in DMF (50 mL) was added Cs 2 CO 3 (8.14 g,24.98 mmol) and the mixture was warmed to 80℃and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, and EA/H was added 2 O extraction, drying the combined organic phases with anhydrous sodium sulfate, filtering and concentrating the crude product to obtain intermediate Z-3-2 (1.2 g,4.30mmol,43.00% yield), MS (ESI) m/z=280 [ M+1] + 。
Step 3, preparation of intermediate Z-3-3
To a solution of intermediate Z-3-2 (470 mg,1.18 mmol) in DCM (8 mL) was added TFA (1.5 mL) and the mixture was stirred at room temperature for 1h, then concentrated under reduced pressure to give intermediate Z-3-3 (350 mg,1.17mmol,99.42% yield) which was used in the next reaction without further purification.
Step 4, preparation of intermediate Z-3
To a solution of cyclopropylformic acid (97.99 mg,1.14 mmol) in DCM (10 mL) were added HBTU (569 mg,1.50 mmol) and DIPEA (245.18 mg,1.90mmol, 330.44. Mu.L), the mixture was stirred at room temperature for 10min, then intermediate Z-3-3 (170 mg, 948.56. Mu. Mol) was added and the reaction mixture was stirred at room temperature for 4h.After completion of the reaction, water was added to dilute, DCM was added to extract, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give crude product, which was purified by silica gel column separation to give intermediate Z-3 (178 mg,719.80 μmol,75.88% yield). MS (ESI) m/z=248 [ m+1 ]] + 。
Preparation of intermediate Z-4
Step 1, preparation of intermediate Z-4-1
To a solution of tetrahydro-2 2-dimethyl-4H-pyran-4-one (80 g,624.18 mmol) in EtOH (800 mL) was added hydroxylamine hydrochloride (65.06 g,936.27 mmol) and CH 3 COOH (153.55 g,1.87 mol), the reaction mixture was gradually brought to 60℃and stirred overnight. After the completion of the reaction, the solvent was removed by rotation, and the obtained crude product was dissolved in EA, filtered, and the filtrate was concentrated to obtain crude product, which was purified by silica gel column separation to obtain intermediate Z-4-1 (58 g,405.08mmol,64.90% yield) as an oil.
Step 2, preparation of intermediate Z-4
To a solution of intermediate Z-4-1 (28 g,195.55 mmol) in THF (200 mL) was added in portions LiAlH under ice-bath and nitrogen protection 4 (11.13 g,293.33 mmol) and the reaction mixture was warmed to room temperature and stirred for 3h. Then the temperature is raised to 60 ℃, and the reaction is continued with stirring for 2h. After the completion of the reaction, the mixture was cooled to 0℃and quenched with water, 10% aqueous NaOH (11 mL) and water (33 mL) were added, vigorously stirred for several minutes, then filtered, and the crude product obtained by concentration of the filtrate was purified by column chromatography on silica gel to give intermediate Z-4 (10.2 g,78.95mmol,40.37% yield). MS (ESI) m/z=130 [ m+1 ]] + 。
Preparation of example 1
Step 1, preparation of intermediate 1-1
To a solution of ammonia in methanol (7.0M, 17.52mmol,2.5 ml) was added 4-oxapalone (200 mg, 1.7)5 mmol), stirring and reacting the mixture at room temperature for 30min, then adding AcOH to adjust the pH to 5-6, and then adding NaCNBH 3 (165.16 mg,2.63 mmol). The resulting mixture was stirred overnight at room temperature. After completion of the reaction, the mixture was concentrated, the crude product was diluted with water, DCM/meoh=10/1, v/v extracted, the combined organic phases were successively washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give crude intermediate 1-1 (100 mg,0.87mmol,49.5% yield) which was used directly in the next reaction without further purification. MS (ESI) m/z=116 [ m+1 ]] + 。
Step 2, preparation of intermediate 1-2
CH to intermediate 1-1 (116.83 mg,1.01 mmol) 3 DIPEA (499.44 mg,3.86mmol,673.11 uL) was added dropwise to a solution of CN (5 mL), followed by 2, 6-dichloro-4-methyl-3-nitro-pyridine (200 mg,966.12 umol), and the resulting mixture was slowly warmed to 70℃and stirred overnight. After the completion of the reaction, the reaction mixture was cooled to 0 ℃, quenched with water, extracted with ethyl acetate, and the combined organic phases were successively washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product, which was purified by pre-HPLC to give intermediate 1-2 (120 mg,419.98umol,43.47% yield) as a white solid. MS (ESI) m/z=285.9 [ m+1 ]] + 。
Step 3, preparation of intermediate 1-3
DIPEA (271.39 mg,2.10mmol,365.76 uL) was added slowly in portions to a solution of 1-2 (120 mg, 419.98. Mu. Mol) in DMSO (3 mL) at room temperature, followed by 5-cyclopropyl-1H-pyrazol-3-amino (155.17 mg,1.26 mmol), and the reaction mixture was slowly raised to 100deg.C and stirred overnight. After completion of the reaction, cooled to room temperature, quenched with water, then extracted with ethyl acetate, and the combined organic phases were washed successively with water, saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give crude product which was purified by pre-HPLC to give intermediate 1-3 (150 mg,402.77umol,95.90% yield) as a white solid. MS (ESI) m/z=373.2 [ m+1 ] ] + 。
Step 4, preparation of intermediates 1 to 4
SnCl was slowly added in portions to a solution of intermediate 1-3 (75 mg, 201.39. Mu. Mol) in EtOH (5 mL) at room temperature 2 2H 2 O(181.73mg,805.54umol), the mixture was warmed to 80℃and stirred for 1h. After the completion of the reaction, the reaction solution was filtered, the crude product obtained by concentrating the filtrate was diluted with water, ethyl acetate was added for extraction, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give crude intermediate 1-4 (60 mg,0.17mmol,87% yield) which was directly used for the next reaction without further purification. MS (ESI) m/z=343.2 [ m+1 ]] + 。
Step 5 preparation of the compound of example 1
1-methyl-1H-pyrazole-4-carbaldehyde (8.04 mg, 73.01. Mu. Mol) was slowly added to a solution of intermediate 1-4 (25 mg, 73.01. Mu. Mol) in EtOH (2 mL) at room temperature, the mixture was warmed to 60℃and then I was added 2 (5.56 mg,21.90 umol) and stirred for 3h. After the completion of the reaction, the reaction solution was filtered, the filtrate was concentrated and diluted with water, ethyl acetate was added to extract, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated after filtration to give crude product, which was purified by pre-HPLC to give Compound 1 (5 mg,11.56umol,15.83% yield.) MS (ESI) m/z=433.1 [ M+1 ]] + 。 1 H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.76(s,1H),7.05(s,1H),6.56(s,1H),6.04(s,1H),4.71(d,J＝4.9Hz,1H),4.01(s,3H),3.95(dt,J＝12.8,5.3Hz,2H),3.86–3.72(m,2H),3.15–2.97(m,3H),2.59(s,3H),2.15–2.05(m,1H),2.03–1.79(m,4H),0.97(dd,J＝8.4,2.4Hz,2H),0.79(dd,J＝5.0,2.0Hz,2H).
Example 2 preparation
Referring to the procedure of step 1 to step 5 in the synthetic route of example 1, in step 1, oxaheptyl-4-amine was used instead of 4-oxapal-none, and the remaining operations and steps were the same, to obtain example 2.MS (ESI) m/z=433.1 [ m+1 ] ] + 。
Preparation of examples 3 to 7
Referring to the procedure of step 2 to step 5 in the synthetic route of example 1, the intermediate 1-1 in step 2 of example 1 was replaced with an amine of the structure shown in the table, and the remaining reagents were operated unchanged, to obtain examples of the corresponding structures in the table.
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Example 8 preparation
Referring to the procedure of step 1 to step 6 in the synthetic route of example 35, substituting tert-butyl cis-4-aminocyclohexyl methyl carbamate with tert-butyl trans- (4-aminocyclohexyl) carbamate in step 1, substituting 3-pyridylaldehyde with 1-methyl-1H-pyrazole-4-carbaldehyde in step 6, the remaining operations and reagents were the same, to give example compound 8, ms (ESI) m/z=500.2 [ m+1 ]] + 。 1 H NMR(400MHz,Methanol-d 4 )δ8.39(s,1H),8.08(s,1H),7.03(s,1H),5.97(s,1H),4.67(tt,J＝12.4,3.9Hz,1H),4.10(s,1H),4.09(s,3H),3.08–2.94(m,2H),2.58(s,3H),2.04(d,J＝13.8Hz,2H),1.93(dd,J＝9.2,3.8Hz,3H),1.79(t,J＝14.0Hz,2H),1.31(dt,J＝7.9,3.4Hz,1H),1.06–1.00(m,2H),0.84(p,J＝4.0,3.5Hz,2H),0.78–0.69(m,4H).
Preparation of example 9, example 10 and example 11
Referring to the procedure of step 1 to step 5 in the synthetic route of example 8, the procedure was the same with the remaining reagents except that the amine in the table was used in step 1 to replace tert-butyl trans- (4-aminocyclohexyl) carbamate, and the corresponding examples 9 to 11 in the table were obtained.
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Example 12 preparation
Step 1, preparation of intermediate 12-1
DAST (4.84 g,30.00 mmol) was added to a solution of 2, 6-dichloropyridine-4-methanol (1.78 g,10.00 mmol) in anhydrous DCM (20 mL) at-20deg.C under nitrogen, the reaction mixture was stirred overnight at room temperature, quenched after completion of the reaction by pouring into ice water and saturated NaHCO 3 The aqueous solution was washed, the combined aqueous phases were extracted with DCM (3 mL. Times.20 mL), the combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered and dried by spinning. The crude product was purified by column chromatography on silica gel (PE/ea=20:1) to give intermediate 12-1 (1.65 g,9.17mmol,91.67% yield).
Step 2, preparation of intermediate 12-2
To a solution of intermediate 12-1 (1.65 g,9.17 mmol) in trifluoroacetic anhydride (8 mL) was added dropwise HNO3 (1.21 g,19.25 mmol) at zero, and the resulting solution was stirred at room temperature for 18h. The reaction mixture was slowly added to the cooled aqueous solution of sodium bisulfite and stirred for 2 hours. The reaction solution was adjusted to pH 7 with 8N NaOH solution, and then extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration to give intermediate 12-2 (1.5 g,6.67mmol,72.73% yield) as a white solid.
Step 3, preparation of intermediate 12-3
Intermediate 12-2 (67 mg,2.99 mmol), cyclohexylamine (312 mg,3.15 mmol) and DIPEA (771.98 mg,5.97mmol,1.04 mL) were miscible in CH 3 CN (10 mL), the reaction mixture was warmed to 70℃and stirred overnight, after the completion of the reaction, the reaction mixture was concentrated, the crude product was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated, and the crude product was purified by separation on a silica gel column (PE/EA=40:1-20:1, v/v) to give intermediate 12-3 (618 mg,1.97mmol,66.10% yield). MS (ESI) m/z=288 [ m+1 ] ] + 。
Step 4, preparation of intermediate 12-4
To intermediate 12-3 (882.11 mg,3.07 mmol) in DMSO (10 mL) was added 5-cyclopropyl-1H-pyrazole-3-amino (830.68 mg,6.74 mmol) in sequence, DIPEA (1.58 g,12.26mmol,2.14 mL), the reaction mixture was warmed to 100deg.C and stirred overnight, after completion of the reaction, cooled to room temperature, diluted with water, ethyl acetate was added, the combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to give crude product which was purified by separation on silica gel column (DCM/MeOH=25:1-15:1, v/v) to give intermediate 12-4 (680 mg,1.82mmol,59.24% yield). MS (ESI) m/z=375 [ m+1 ]] + 。
Step 5, preparation of example 12
Referring to the procedure of step 4 and step 5 of example 1, substituting intermediate 12-4 for intermediate 1-3 and the remaining operating reagents were identical, example compound 12, ms (ESI) m/z=435 [ m+1] + 。
Example 13 preparation
Referring to the procedure of step 2 to step 5 in the synthetic route of example 12, example 13 was obtained by substituting 2, 6-dichloro-4- (difluoromethyl) pyridine for intermediate 12-1 in step 2 of the synthetic route of example 12, and the remaining operating reagents were the same. MS (ESI) m/z=453 [ m+1 ]] + 。
Example 14 preparation
Referring to the procedure of step 2 to step 5 in the synthetic route of example 1, wherein cyclopropylamine was used instead of intermediate 1-1 and 2, 6-dichloro-3-nitropyridine was used instead of intermediate Z-1, the remaining reagents were operated identically, example compound 14, ms (ESi) m/z=403.1 [ m+1 ] was obtained ] + 。
Example 15 preparation
Step 1, preparation of intermediate 15-1
CH to Z1 (10 g,48.31 mmol) and cyclopropylamine (5 g,50.42 mmol) 3 DIPEA (12.49 g,96.61mmol,16.83 mL) was added to a solution of CN (100 mL), and the reaction mixture was warmed to 70℃and stirred overnight. After the completion of the reaction, the reaction mixture was concentrated, the obtained crude product was diluted with water and extracted with ethyl acetate, the separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was purified by separation on a silica gel column (PE/ea=50:1, v/v) to obtain intermediate 15-1 (5.4 g,20.02mmol,41.44% yield), MS (ESI) m/z=270.1 [ m+1 ]] + 。
Step 2, preparation of intermediate 15-2
To a solution of intermediate 15-1 (5.4 g,20.02 mmol) in DMSO (100 mL) was added DIPEA (10.35 g,80.08mmol,13.95 mL) and 5-cyclopropyl-1H-pyrazole-3-amino (4.94 g,40.11 mmol) in sequence, and the reaction mixture was warmed to 100deg.C and stirred overnight. After completion of the reaction, cooled to room temperature, diluted with water, the combined organic phases were extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was washed by trituration with MeOH/EA/PE to give intermediate 15-2 (6.84 g,19.19mmol,95.86% yield), MS (ESI) m/z=357.1 [ M+1 ] ] + 。
Step 3, preparation of intermediate 15-3
To a solution of 15-2 (6.84 g,19.19 mmol) in EtOH (150 mL) at room temperature was added SnCl in portions 2 2H 2 O (17.32 g,76.76 mmol), and the reaction mixture was heated to 80℃and stirred for 2 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated to give a crude product, the crude product was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was separated and purified by mHPLC to give intermediate 15-3 (5.6 g,17.2mmol,90% yield), MS (ESI) m/z=327.3 [ m+1:] + 。
step 4, preparation of example 15
Intermediate 15-3 (33 mg,101.09 umol) and 1-isopropyl-1H-pyrazole-4-carbaldehyde(13.97 mg,101.09 umol) in ethanol was stirred at room temperature for 0.5h. Then add I 2 (7.70 mg, 30.33. Mu. Mol), the reaction mixture was heated to 60℃and stirred for 3 hours. After completion of the reaction, the reaction mixture was concentrated, and the crude product was purified by mHPLC to give example compound 15 (2.5 mg,4.39umol,4.34% yield, 98.1% purity), MS (ESI) m/z=327.3 [ m+1 ]] + 。 1 H NMR(400MHz,Methanol-d 4 )δ8.38(s,1H),8.02(s,1H),6.89(s,1H),6.37(s,1H),4.74(hept,J＝6.6Hz,1H),4.52(tt,J＝12.1,3.8Hz,1H),2.84(q,J＝12.1,11.0Hz,2H),2.56(s,3H),2.06–1.98(m,4H),1.95(ddd,J＝13.5,8.9,5.1Hz,1H),1.87–1.81(m,1H),1.61(s,3H),1.59(s,3H),1.55–1.46(m,3H),1.06–0.97(m,2H),0.81–0.72(m,2H).
Preparation of examples 16 to 30
Referring to the procedure of step 4 of the preparation route of example 15, the corresponding aldehyde in the following table was used in place of 1-isopropyl-1H-pyrazole-4-carbaldehyde, and the remaining reagents were operated unchanged to give the corresponding structural examples in the table.
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Example 23 preparation
Step 1, preparation of intermediate 23-1
A solution of intermediate 15-3 (33 mg,101.09 umol) and N- (N-BOC-piperidino) pyrazole-4-carbaldehyde (28.24 mg,101.09 umol) in ethanol (1 mL) was stirred at room temperature for 0.5h. Then, elemental iodine (7.70 mg,30.33 umol) was added, and the reaction mixture was heated to 60℃and stirred for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to give crude intermediate 23-1 (17.7 mg,30.22umol,29.89% yield, from LCMS) which was used in the next reaction without purification. MS (ESI) m/z=586.3 [ m+1 ]] + 。
Step 2, preparation of example 23
To a solution of intermediate 23-1 (17.7 mg, 30.22. Mu. Mol) in DCM (1 mL) was added TFA (0.5 mL) and the reaction stirred at room temperature for 1 hour. After completion of the reaction, the crude product obtained by concentrating the reaction mixture was separated and purified by pre-HPLC to give example compound 23 (2.33 mg,7.93umol,26% yield, 89.2% purity). MS (ESI) m/z=486.3 [ m+1 ]] + 。 1 H NMR(400MHz,Methanol-d4)δ8.47(s,1H),8.10(s,1H),6.92(s,1H),6.41(s,1H),4.85–4.74(m,1H),4.53(tt,J＝11.8,3.5Hz,1H),3.62(dq,J＝11.9,3.7Hz,2H),3.31–3.21(m,2H),2.91–2.76(m,2H),2.57(s,3H),2.48–2.35(m,4H),2.08–1.92(m,5H),1.89–1.79(m,1H),1.50(d,J＝8.2Hz,3H),1.10–1.01(m,2H),0.85–0.74(m,2H).
Example 32 preparation
To a solution of intermediate 15-3 (32.6 mg, 99.87. Mu. Mol) in DMF (2 mL) was slowly added trimethyl orthoformate (105.98 mg, 998.66. Mu. Mol) at room temperature, followed by MgSO 4 (11.98 mg, 99.87. Mu. Mol) and the reaction mixture was warmed to 120℃and stirred for 2 hours. After the reaction was completed, the reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic phases were concentrated to give crude product, which was purified by pre-HPLC to give example compound 32 (10 mg, 21.98. Mu. Mol,22.01% yield, 99% purity) as white color A solid. MS (ESI) m/z=337.0 [ m+1 ]] + 。 1 H NMR(400MHz,Methanol-d 4 )δ9.22(s,1H),6.97(s,1H),6.29(s,1H),4.78–4.70(m,1H),2.58(s,3H),2.31(d,J＝11.7Hz,2H),2.07–1.91(m,5H),1.86(d,J＝13.2Hz,1H),1.69–1.55(m,2H),1.48–1.38(m,1H),1.12–1.05(m,2H),0.84–0.78(m,2H).
Example 33 preparation
Referring to the preparation of example 32, substituting intermediate 1-4 for intermediate 15-3 and operating the same reagents, example 33, ms (ESI) m/z=353.1 [ m+1 ] was obtained] + 。 1 H NMR(400MHz,Methanol-d 4 )δ9.30(s,1H),6.98(s,1H),5.19–5.06(m,1H),3.95(ddd,J＝17.7,13.0,4.8Hz,2H),3.88–3.79(m,2H),3.77(s,1H),2.61(s,3H),2.57–2.43(m,2H),2.38(d,J＝14.4Hz,1H),2.27(d,J＝16.2Hz,1H),2.08–1.88(m,3H),1.18–1.09(m,2H),0.95–0.86(m,2H).
Example 34 preparation
Step 1, preparation of intermediate 34-1
At zero degrees, 4-chloro-7-azaindole (1.53 g,10.03 mmol) and Pd (dppf) Cl 2 To a solution of (146.74 mg, 200.55. Mu. Mol) in toluene (45 mL) was added methyl magnesium bromide (4.78 g,40.11mmol,1M in THF), the reaction mixture was warmed to 80℃under nitrogen and stirred for 5 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, slowly poured into ice water, ethyl acetate and saturated aqueous ammonium chloride solution were added, and the separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (PE/EA 5:1, v/v) to give intermediate 34-1 (1.18 g,8.93mmol,89.04% yield), MS (ESI) m/z=133.1 [ M+1 ]] + 。
Step 2, preparation of intermediate 34-2
At the temperature of zero degrees, the temperature of the liquid,to a solution of intermediate 34-1 (2.89 g,21.87 mmol) in DCM (40 mL) was added dropwise a solution of m-chloroperoxybenzoic acid (9.06 g,52.48 mmol) in DCM (100 mL). The reaction mixture was gradually warmed to room temperature and stirred for 4 hours. After the reaction is completed, naHCO is added 3 The aqueous solution was adjusted to pH 10, the organic and aqueous phases were concentrated under reduced pressure to give crude product, the crude product was dissolved in MeOH/DCM (2:1) (150 mL), the suspension was filtered, the filter cake was washed with MeOH/DCM, the crude product obtained by concentrating the filtrate was purified by column chromatography over silica gel (DCM/MeOH=30:1-15:1) to give intermediate 34-2 (2.4 g,16.20mmol,74.08% yield),
step 3, preparation of intermediate 34-3
To a solution of intermediate 34-2 (2.4 g,16.20 mmol) and ditrimethylsilamine (5 mL) in THF (55 mL) at zero degrees was added dropwise methyl chloroformate (4.29 g,45.36 mmol). After the completion of the dropping, the reaction mixture was warmed to room temperature and stirred for 1.5 hours. After the completion of the reaction, the reaction mixture was concentrated, and the crude product was dissolved in MeOH (50 mL), then aqueous NaOH (1.30 g,32.40 mmol) was added (2.5 mL), and after stirring at room temperature for 5min, the concentrated crude product was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column separation (EA/PE=1/10, v/v) to give intermediate 34-3 (961 mg,5.77mmol,35.61% yield). MS (ESI) m/z=167.1 [ m+1 ]] + 。
Step 4, preparation of intermediate 34-4
Ir (F-Meppy) 2 (dtbbpy) PF6 (9.80 mg,10.02 umol), intermediate 34-3 (67 mg,1.00 mmol), iodom-trimethylbenzene dicyclohexyl formate (1.00 g,2.00 mmol), cuTC thiophene-2-carboxylic acid copper (I) (38.23 mg,200.47 umol) and 4, 7-diphenyl-1, 10-phenanthroline (99.96 mg,300.71 umol) were mixed in a solution of Dioxane (24 mL), and then 2-t-butyl-1, 3-tetramethylguanidine (343.37 mg,2.00 mmol) was added, and the reaction solution was sonicated in an sonicator for 1-3min until the reaction solution was uniformly mixed. After nitrogen substitution several times, the reaction solution was stirred under 34W blue LED lamp irradiation (3 cm away, fan cooled to maintain the reaction temperature at room temperature) for 3 hours. After the completion of the reaction, the light source was removed, cooled to room temperature, diluted with water, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the vinegar bottle was purified by column chromatography over silica gel to give intermediate 34-4 (119 mg,478.39umol,47.73% yield).
Step 5, preparation of intermediate 34-5
To a mixture of intermediate 34-4 (53 mg,213.06 umol), 3-cyclopropyl-1- (((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-5-amine (64.79 mg,255.68 umol) and NaOtBu (26.62 mg,276.98 umol) in toluene (1 mL) was added Pd 2 (dba) 3 (9.76 mg, 10.65. Mu. Mol) and Xantphos (12.33 mg, 21.31. Mu. Mol), the reaction mixture was purged several times with nitrogen and then heated to 100℃under nitrogen protection and the reaction was stirred overnight. After completion of the reaction, cooled to room temperature, the reaction mixture was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was purified by separation on a silica gel column (PE: ea=5:1, v/v) to give intermediate 34-5 (27 mg,57.98umol,27.21% yield). MS (ESI) m/z=466.1 [ m+1 ]] + 。
Step 6 preparation of example 34
To a solution of intermediate 34-5 (27 mg,57.98 umol) in DCM (1 mL) was added TFA (1.5 mL) and the reaction stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude product was purified by Pre-HPLC to give example compound 34 (2 mg,4.16umol,7.17% yield, 93.4% purity), MS (ESI) m/z=336.1 [ m+1] + 。 1 H NMR(400MHz,Methanol-d 4 )δ7.33(d,J＝3.6Hz,1H),6.64–6.58(m,2H),5.83(s,1H),4.42(tt,J＝12.0,3.8Hz,1H),2.59(s,3H),2.15(d,J＝12.4Hz,2H),2.06–1.93(m,3H),1.94–1.79(m,3H),1.72–1.57(m,2H),1.43(qt,J＝12.6,3.4Hz,1H),1.15–1.04(m,2H),0.88–0.77(m,2H).
Example 35 preparation
Step 1, preparation of intermediate 35-1
To intermediate Z1 (470 mg,2.30 mmol) and tert-butyl cis-4-aminocyclohexyl methyl carbamate (500 mg,2.19 mmol) in CH 3 DIPEA (618 mg,4.39mmol, 765.50. Mu.L) was added to a solution of CN (10 mL), and the reaction mixture was warmed to 70℃CAnd stirred overnight. After the completion of the reaction, the reaction mixture was concentrated, diluted with water, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the obtained crude product was purified by separation on a silica gel column (PE/ea=20:1-15:1) to give intermediate 35-1 (719 mg,1.30mmol,56.59% yield), MS (ESI) m/z=399.1 [ m+1 ]] + 。
Step 2, preparation of intermediate 35-2
To a solution of intermediate 35-1 (399 mg,1.30 mmol) in DCM (8 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure to give crude intermediate 35-2 (380 mg,1.27mmol,97.75% yield) which was used in the next reaction without further purification.
Step 3, preparation of intermediate 35-3
Cyclopropanecarboxylic acid (164.24 mg,1.91 mmol), HBTU (807.24 mg,3.18 mmol) and DIPEA (493.14 mg,3.82mmol, 664.61. Mu.L) were dissolved in DCM (6 mL) and the mixture stirred at room temperature for 10min, then a solution of intermediate 35-2 (380 mg,1.27 mmol) in DCM (3 mL) was added and the reaction stirred at room temperature for 4 h. After the reaction was completed, the reaction mixture was diluted with water, extracted with DCM, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give crude product which was purified by separation on a silica gel column (PE/ea=3:1, v/v) to give intermediate 35-3 (457mg, 1.23mmol,96.66% yield).
Step 4, preparation of intermediate 35-4
Intermediate 35-3 (450 mg,1.23 mmol), 5-cyclopropyl-1H-pyrazol-3-amino (370 mg,3.00 mmol) and DIPEA (634.15 mg,4.91mmol, 854.65. Mu.L) were dissolved in DMSO (5 mL) and the reaction was heated to 100deg.C and stirred overnight. After completion of the reaction, cooled to room temperature, diluted with water, extracted with EA, the combined organic phases were washed successively with water, saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give crude product which was triturated with DCM/PE and slurried to give intermediate 35-4 (390 mg,864.32 μmol,70.46% yield). MS (ESI) m/z=454 [ m+1 ]] + 。
Step 5, preparation of intermediate 35-5
To a solution of 35-4 (196 mg, 432. Mu. Mol) in EtOH (8 mL) at room temperature was added SnCl in portions 2 2H 2 O (390 mg, 1.73. Mu. Mol) and the reaction mixture was heated to 80℃and stirred for 2 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated to give a crude product, the crude product was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was separated and purified by mHPLC to give intermediate 35-5 (220 mg,0.4mmol,94% yield), MS (ESI) m/z=538 [ m+1] + 。
Step 6 preparation of example 35
A solution of intermediate 35-5 (85 mg, 200.68. Mu. Mol) and 3-pyridinecarboxaldehyde (21.50 mg, 200.68. Mu. Mol) in EtOH (2 mL) was stirred at room temperature for 0.5h. Then, elemental iodine (15.28 mg, 60.20. Mu. Mol) was added thereto, and the reaction mixture was warmed to 60℃and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by pre-HPLC to give example 35 (44.6 mg, 68.19. Mu. Mol,33.98% yield, 95.5% purity), MS (ESI) m/z=551 [ M+1 ] ] + 。 1 H NMR(400MHz,Methanol-d 4 )δ9.02(s,1H),8.94(d,J＝5.1Hz,1H),8.38(dd,J＝8.0,1.9Hz,1H),7.88(dd,J＝8.0,5.1Hz,1H),6.97(s,1H),6.22(s,1H),4.34(tt,J＝12.4,3.8Hz,1H),3.43(d,J＝7.5Hz,2H),2.81(qd,J＝13.5,12.9,3.9Hz,2H),2.64(s,3H),2.06(tt,J＝8.7,5.0Hz,1H),2.01-1.94(m,1H),1.93–1.83(m,4H),1.65(ddt,J＝17.3,8.4,4.4Hz,3H),1.17(td,J＝7.1,4.6Hz,2H),0.95(dt,J＝7.1,4.7Hz,2H),0.93–0.84(m,2H),0.82–0.76(m,2H).
Preparation of examples 36 to 42
Referring to the procedure of step 1 to step 6 in the synthetic route of example 35, tert-butyl cis-4-aminocyclohexyl methyl carbamate in step 1 was replaced with the corresponding structural amine in the table, and 3-pyridinecarboxaldehyde in step 6 was replaced with the corresponding structural aldehyde in the table. The rest reagents are operated identically, and the compounds of the corresponding structural examples in the table can be obtained.
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Example 43 preparation
Referring to the procedure of step 2 to step 5 in the synthetic route of example 1, substituting tetrahydropyran-4-carbaldehyde for intermediate 1-1 in example 1 in the initial step and 1-methyl-1H-imidazole-4-carbaldehyde for 1-methyl-1H-pyrazole-4-carbaldehyde in step 4, the remaining operations are the same, giving example 43, ms (ESI) m/z=419.1 [ m+1 ]] + 。 1 H NMR(400MHz,Methanol-d 4 )δ8.08(s,1H),8.03(s,1H),6.92(s,1H),6.52(s,1H),5.67(t,J＝12.1Hz,1H),4.17(dd,J＝11.8,4.7Hz,2H),3.92(s,3H),3.60(t,J＝12.0Hz,2H),3.18(qd,J＝12.5,5.0Hz,2H),2.59(s,3H),2.01–1.89(m,3H),1.10–1.02(m,2H),0.96–0.88(m,2H).
Example 44 preparation
Referring to the procedure of step 5 of the synthetic route of example 1, substituting intermediate 43-4 for intermediate 1-4 and 3-pyridylaldehyde for 1-methyl-1H-pyrazole-4-carbaldehyde, the remainder of the procedure was identical, affording example 44, ms (ESI) m/z=416 [ m+1] + 。 1 H NMR(400MHz,Methanol-d 4 )δ9.01(s,1H),8.92(d,J＝5.1Hz,1H),8.34(d,J＝8.1Hz,1H),7.84(dd,J＝8.0,5.1Hz,1H),6.92(s,1H),6.66(s,1H),4.63(tt,J＝12.0,4.6Hz,1H),4.14(dd,J＝11.8,4.7Hz,2H),3.52(t,J＝12.1Hz,2H),3.13(qd,J＝12.5,4.9Hz,2H),2.63(s,3H),2.07–1.91(m,3H),1.20–1.12(m,2H),1.06–1.00(m,2H).
Example 45 preparation
Referring to the procedure of step 5 of the synthetic route of example 1, substituting intermediate 14-3 for intermediate 1-4 and 3-pyridylaldehyde for 1-methyl-1H-pyrazole-4-carbaldehyde, the remainder of the procedure was identical, giving example 45, ms (ESI) m/z=400 [ m+1 ] + 。 1 H NMR(400MHz,Methanol-d 4 )δ8.94(s,1H),8.89(d,J＝4.9Hz,1H),8.24(d,J＝7.8Hz,1H),8.02–7.96(m,1H),7.78(dd,J＝7.8,5.1Hz,1H),7.08(d,J＝8.9Hz,1H),6.50(s,1H),4.34(tt,J＝11.8,3.2Hz,1H),2.78(q,J＝13.1,12.3Hz,2H),2.09–1.96(m,5H),1.82(d,J＝7.4Hz,1H),1.44(q,J＝13.1Hz,3H),1.11(q,J＝5.5,4.5Hz,2H),0.85(q,J＝5.0Hz,2H).
Preparation of examples 46 to 55
Referring to the procedure of step 5 in the synthetic route of example 1, the corresponding structural examples in the tables can be obtained by substituting intermediate 14-3 for intermediate 1-4 and substituting the aldehyde group in the following tables for 1-methyl-1H-pyrazole-4-carbaldehyde, and the remaining operations are the same.
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Example 54 preparation
Step 1, preparation of intermediate 54-1
To 14-3 (62 mg, 189.93. Mu. Mol) and 3-formyl-8-azabicyclo [3.2.1]To a solution of tert-butyl octane-8-carboxylate (59 mg, 246.54. Mu. Mol) in ethanol (2.00 mL) was added I 2 (51.48 mg, 202.83. Mu. Mol) and the reaction mixture was heated to 60℃and stirred for 1 hour. After the reaction was completed, concentrated under reduced pressure, saturated sodium sulfite was added, EA was added to extract, the combined organic phases were dried over anhydrous sodium sulfate, and the crude product obtained by concentration after filtration was purified by separation on a silica gel column (DCM/meoh=30:1-20:1) to give intermediate 54-1 (61 mg,111.78 μmol,58.85% yield), MS (ESI) m/z=546 [ m+1] + 。
Step 2 preparation of example 54
TFA (1 mL) was added to a solution of 54-1 (73.51 mg, 134.70. Mu. Mol) in DCM (2 mL), the mixture was stirred at room temperature for 1h, after completion of the reaction, the crude product obtained by concentration under reduced pressure was isolated and purified by mHPLC to give example 54 (45.84 mg, 81.42. Mu. Mol,60.45% yield, 99.4% purity). MS (ESI) m/z=446 [ M+1) ] + 。 1 H NMR(600MHz,Methanol-d 4 )δ6.85(s,1H),6.44(s,1H),4.54(d,J＝12.7Hz,1H),4.32–4.19(m,2H),3.90(tt,J＝11.8,5.2Hz,1H),2.73(q,J＝12.7Hz,2H),2.60(s,3H),2.58–2.50(m,2H),2.33–2.23(m,4H),2.17(dt,J＝14.6,3.8Hz,2H),2.07–1.94(m,5H),1.89(d,J＝13.4Hz,1H),1.71–1.60(m,2H),1.55–1.44(m,1H),1.17–1.09(m,2H),0.90–0.82(m,2H).
Example 55 preparation
Referring to the synthesis of example 54, 1-tert-butoxycarbonylpiperidine-4-carbaldehyde was used in place of 3-formyl-8-azabicyclo [3.2.1 ] in step 1]Tert-butyl octane-8-carboxylate, the remaining reagents and procedures were the same, giving example 55.MS (ESI) m/z=554 [ m+1 ]] + 。 1 H NMR(400MHz,Methanol-d 4 )δ6.87(d,J＝1.1Hz,1H),6.47(s,1H),4.66–4.55(m,1H),3.80(tt,J＝10.4,5.1Hz,1H),3.67–3.57(m,2H),3.37–3.25(m,2H),2.84–2.67(m,2H),2.60(d,J＝0.9Hz,3H),2.39–2.22(m,4H),2.11–1.94(m,5H),1.93–1.84(m,1H),1.75–1.41(m,3H),1.18–1.09(m,2H),0.87(dt,J＝6.9,4.6Hz,2H).
Example 56 preparation
Referring to the procedure of step 5 in the synthetic route of example 1, example 56 was obtained by substituting intermediate 14-3 for intermediate 1-4 and substituting intermediate Z-2 for 1-methyl-1H-pyrazole-4-carbaldehyde, and the remaining procedures were the same. MS (ESI) m/z=532 [ m+1 ]] + 。 1 H NMR(400MHz,Methanol-d 4 )δ8.46(d,J＝0.7Hz,1H),8.12(d,J＝0.7Hz,1H),6.97(d,J＝1.1Hz,1H),6.61(s,1H),5.41(s,2H),4.94–4.86(m,1H),4.17(dd,J＝11.8,4.7Hz,2H),3.80–3.75(m,2H),3.74–3.69(m,2H),3.68–3.56(m,6H),3.16(qd,J＝12.5,4.8Hz,2H),2.61(d,J＝1.0Hz,3H),2.04–1.92(m,3H),1.14–1.06(m,2H),0.98(dt,J＝7.3,4.6Hz,2H).
Preparation of examples 57 to 64
Referring to the procedure of step 5 in the synthetic route of example 1, the corresponding structural examples in the table were obtained by substituting intermediate 43-4 for intermediate 1-4 and substituting aldehyde for 1-methyl-1H-pyrazole-4-carbaldehyde in the following chart, and the remaining procedures were the same.
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Example 65 preparation
Step 1, preparation of intermediate 65-1
CH to Z-1 (16.9 g,81.64 mmol) and Z-4 (9.7 g,75.08 mmol) 3 DIPEA (21.10 g,163.27mmol,28.44 mL) was added to CN (200 mL), and the reaction mixture was warmed to 70℃and stirred overnight. After the completion of the reaction, the crude product was concentrated under reduced pressure, diluted with water, extracted with EA, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was purified by separation over a silica gel column (PE/ea=20:1) to give intermediate 65-1 (8.3 g,27.69mmol,33.92% yield). MS (ESI) m/z=300.2 [ m+1 ] ] + 。
Step 2, preparation of intermediate 65-2
A mixture of intermediate 65-1 (8.3 g,27.69 mmol), 5-cyclopropyl-1H-pyrazol-3-amino (6.81 g,55.31 mmol) and DIPEA (14.31 g,110.76mmol,19.29 mL) in DMSO (150 mL) was warmed to 100deg.C and stirred overnight. The reaction mixture was cooled to room temperature, diluted with water, extracted with EA, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was slurried by EA/PE washing to afford intermediate 65-2 (7.48 g,19.36mmol,69.90% yield). MS (ESI) m/z=387.2 [ m+1 ]] + 。
Step 3, preparation of intermediate 65-3
To a solution of intermediate 65-2 (7.48 g,19.36 mmol) in EtOH (150 mL) was added SnCl 2 ·2H 2 O (17.47 g,77.42 mmol), the reaction mixture was warmed to 80℃and stirred overnight, after the reaction was completed, cooled to room temperature, and Na was added 2 CO 3 The aqueous solution was neutralized to pH 7, the reaction was filtered, a 4N HCl EA solution was added in advance to the receiver flask, the filter cake was washed with EA, the obtained filtrate was concentrated under reduced pressure, and the crude product was isolated and purified by mHPLC to give intermediate 65-3 (8.2 g,17.43mmol,90.04% yield). MS (ESI) m/z=357.2 [ m+1 ]] + 。
Step 4, preparation of example 65
Intermediate 65-3 (7.48 g,15.90 mmol) and 1-methyl-1H-pyrazole-4-carbaldehyde (2.31 g,20.98 mmol) were miscible in EtOH (30 mL) and reacted for 0.5H with stirring. Adding I to the solution 2 (4.25 g,16.74 mmol) and warmed to 60℃and stirred for 1h. The crude product after concentration under reduced pressure was isolated and purified by mHPLC to afford example 65 (6.7 g,98% purity). MS (ESI) m/z= 447.2[M+1] + 。 1 H NMR(400MHz,Methanol-d 4 )δ8.35(s,1H),8.04(d,J＝0.8Hz,1H),6.91(d,J＝1.1Hz,1H),6.52(s,1H),4.98(tt,J＝12.6,4.4Hz,1H),4.09(s,3H),3.99–3.85(m,2H),3.18(qd,J＝12.2,6.1Hz,1H),2.97(t,J＝12.9Hz,1H),2.57(d,J＝1.0Hz,3H),2.04–1.84(m,3H),1.34(d,J＝2.5Hz,6H),1.04–0.84(m,4H).
Preparation of examples 66 to 75
Referring to the synthetic route of example 65, Z-4 was replaced with an amine of the structure shown in the following table in step 1, and the remaining reagents and steps were identical, giving examples of the corresponding structures in the table.
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Preparation of examples 76 to 86
Referring to the synthetic route of example 65, in step 2, 5-cyclopropyl-1H-pyrazol-3-amino was replaced with an amine in the following table, and the remaining reagents and procedures were the same, to obtain the corresponding structural examples in the table.
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Preparation of examples 87 to 104
Referring to the synthetic method of example 65, 1-methyl-1H-pyrazole-4-carbaldehyde was replaced with the aldehydes in the following table in step 4. The remaining reagents and procedures were the same, giving the corresponding examples in the tables.
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Example 105 preparation
Step 1, preparation of intermediate 105-1
A mixture of intermediate 65-3 (107 mg, 227.42. Mu. Mol) and tert-butyl 4-formyl-2-methylpiperidine-1-carboxylate (68.42 mg, 301.02. Mu. Mol) in EtOH (3 mL) was stirred at room temperature for 30min and then added with I 2 (60.61 mg, 238.79. Mu. Mol) and then the mixture was warmed to 60℃and stirred for further reaction for 1 hour. The reaction was diluted with EA/MeOH (15:1) and saturated Na was added 2 SO 3 The solution was washed, the separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product obtained after concentration was purified by separation on a silica gel column (DCM/meoh=20:1) to give intermediate 105-1 (119 mg,211.09 μmol,92.82% yield). MS [ (MS)ESI)m/z＝564[M+1] + 。
Step 2, preparation of example 105
To a solution of intermediate 105-1 (119 mg, 211.09. Mu. Mol) in DCM (2 mL) was added TFA (1 mL), and the mixture was stirred at room temperature for 1h, and the crude product obtained after concentration under reduced pressure was isolated and purified by Pre-HPLC to give example 105 (104.3 mg, 179.84. Mu. Mol,85.19% yield, 99.6% purity). MS (ESI) m/z=564 [ m+1 ]] + 。 1 H NMR(600MHz,Methanol-d 4 )δ6.79(d,J＝10.3Hz,1H),4.91–4.77(m,1H),4.16–3.84(m,4H),3.69–3.48(m,1H),3.48–3.40(m,1H),3.10–2.98(m,1H),2.86(t,J＝12.8Hz,1H),2.60(s,3H),2.48–1.98(m,5H),1.88(dd,J＝44.2,12.8Hz,2H),1.49(d,J＝5.2Hz,3H),1.44(s,3H),1.34(s,3H),1.22–0.97(m,4H).
Preparation of examples 106 to 108
Referring to the synthesis of example 105, in step 1, 4-formyl-2-methylpiperidine-1-carboxylic acid tert-butyl ester was replaced with the aldehyde in the table, and the remaining reagents and procedures were the same, to obtain the corresponding structural examples in the table.
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Example 109 preparation
Referring to the synthetic route of example 13, substituting intermediate Z-4 for cyclohexylamine in step 2, the remaining reagents and procedures were the same, and subjected to the same procedure and procedure to afford example 109.MS (ESI) m/z=483 [ m+1 ]] + 。 1 H NMR(400MHz,Methanol-d 4 )δ8.30(s,1H),8.01(s,1H),7.33–7.01(m,2H),6.58(s,0H),4.99(dd,J＝8.3,4.2Hz,1H),4.07(s,3H),4.00–3.84(m,2H),3.14(qd,J＝12.3,6.0Hz,1H),2.92(t,J＝12.9Hz,1H),2.04–1.86(m,3H),1.34(d,J＝1.7Hz,6H),1.06(dd,J＝8.5,3.5Hz,2H),1.03–0.88(m,2H).
Example 110 preparation
Step 1, preparation of intermediate 110-1
To a suspension of NaH (1.95 g,81.20 mmol) in THF (100 mL) under ice-bath and nitrogen protection was added dropwise a solution of 5-cyclopropyl-1H-pyrazol-3-amino (5 g,40.60 mmol) in THF, the reaction was continued with stirring for 1H, SEMCl (6.77 g,40.60 mmol) was then added and stirring was continued at room temperature overnight. After the reaction was completed, 30% NH was added 4 The aqueous Cl solution was quenched, and extracted three times with EA. The crude product of the combined EA layers concentrated was purified by mHPLC to afford intermediate 110-1 (2.3 g,9.08mmol,22.36% yield) as a brown oil. MS (ESI) m/z=254 [ m+1 ]] + 。
Step 2, preparation of intermediate 110-2
TEA (1.80 g,17.76mmol,2.48 mL) was added to a solution of intermediate 110-1 (1.5 g,5.92 mmol) in DMF (5 mL), cooled to 0deg.C, chloroacetyl chloride (464.64 mg,5.92 mmol) was slowly added, the mixture warmed to room temperature after dropwise addition, the reaction was continued for 30min with stirring, DCM was added after completion of the reaction, 10% NaHCO was added 3 The pH value of the aqueous solution is regulated to 7-8, and the separated organic phase is treated by anhydrous Na 2 SO 4 After drying, the crude intermediate 110-2 (1.3 g,4.40mmol,74.34% yield) was obtained by filtration and concentration. MS (ESI) m/z=296 [ m+1 ]] + 。
Step 3, preparation of intermediate 110-3
To a solution of intermediate 110-2 (1.3 g,4.40 mmol) in DMF (15 mL) was added Cs 2 CO 3 (4.30 g,13.20 mmol) and CH 3 I (936.81 mg,6.60 mmol) was stirred at room temperature for 4h. After completion of the reaction, water was added for dilution, EA was added for extraction, and the combined organic phases were concentrated to give crude intermediate 110-3 (1.36 g,4.39 mmol) which was used directly in the next reaction without further purification. MS (ESI) m/z=310 [ m+1 ]] + 。
Step 4, preparation of intermediate 110-4
EtOH (10 mL)/H to intermediate 110-3 (1.36 g,4.39 mmol) 2 KOH (493.15 mg,8.79 mmol) was added to a mixture of O (2 mL), and the reaction was warmed to 80℃and stirred overnight. After the reaction was completed, the solvent was removed by concentration under reduced pressure, the crude product obtained was diluted with EA and water, and the EA phase obtained by concentration and separation was purified by mHPLC to obtain intermediate 110-4 (1.18 g,4.41 mmol). MS (ESI) m/z=268 [ m+1 ]] + 。
Step 5, preparation of intermediate 110-5
To a solution of intermediate 110-4 (100 mg, 373.91. Mu. Mol) and intermediate 65-1 (112.08 mg, 373.91. Mu. Mol) in 1,4-dioxane (3 mL) was added Pd (dppf) Cl 2 (27.36 mg, 37.39. Mu. Mol) and Cs 2 CO 3 (365.49 mg,1.12 mmol) was replaced with liquid nitrogen and the reaction mixture was warmed to 100℃and stirred overnight under nitrogen, after the completion of the reaction, the solvent was removed by concentration under reduced pressure, and the crude product obtained was purified by column chromatography on silica gel to give intermediate 110-5 (198mg, 373.07. Mu. Mol,99.77% yield). MS (ESI) m/z=531 [ m+1 ]] + 。
Step 6, preparation of intermediate 110-6
EtOH (2 mL)/H to intermediate 110-5 (100 mg, 188.42. Mu. Mol) 2 Zn (61.61 mg, 942.09. Mu. Mol) and NH were added to the O (0.5 mL) mixture 4 Cl (50.40 mg, 942.09. Mu. Mol) was reacted at room temperature with stirring for 30min. After completion of the reaction, EA/HCl (4M, 0.5ml,2 mmol) was added and the mixture was concentrated under reduced pressure to give a crude product which was dissolved in EtOH and filtered to remove insoluble material, and the filtrate obtained was used in the next reaction without further treatment, calculated as 100% conversion, with intermediate 110-6 (94.35 mg, 188.42. Mu. Mol). MS (ESI) m/z=501 [ m+1 ] ] + 。
Step 7, preparation of example 110
A mixture of intermediate 110-6 (80 mg, 159.76. Mu. Mol) and 1-methyl-1H-pyrazole-4-carbaldehyde (17.59 mg, 159.76. Mu. Mol) in EtOH (3 mL) was stirred at room temperature for 10min, then I was added to the mixture 2 (405.49. Mu.g, 1.60. Mu. Mol) and the reaction mixture was heated to 60℃and stirred for 2hr. After the completion of the reaction, the reaction solution was subjected to Pre. HPLC separation and purification gave example 110 (3.35 mg, 5.83. Mu. Mol,3.65% yield), MS (ESI) m/z=483 [ M+1 ]] + 。 1 H NMR(600MHz,Methanol-d 4 )δ8.38(s,1H),8.06(s,1H),6.86(s,1H),4.97(dd,J＝10.4,5.4Hz,1H),4.09(s,3H),3.89(t,J＝9.8Hz,2H),3.50(s,3H),3.13(dd,J＝13.4,6.6Hz,1H),2.98(t,J＝12.8Hz,1H),2.51(s,3H),1.95(q,J＝12.6,10.4Hz,3H),1.33(d,J＝5.4Hz,7H),1.04(d,J＝8.6Hz,2H),0.88–0.73(m,2H).
Example 111 preparation
Step 1, preparation of intermediate 111-1
To a solution of intermediate 65-1 (100 mg, 333.61. Mu. Mol) and 1,4-Dioxane (3 mL)/water (0.3 mL) of 1-methylpyrazole-4-boronic acid pinacol ester (104.12 mg, 500.41. Mu. Mol) was added Na 2 CO 3 (141.45 mg,1.33 mmol) and Pd (dppf) Cl 2 (24.39 mg, 33.36. Mu. Mol) and the reaction mixture was purged several times with nitrogen, then slowly heated to 100℃under nitrogen and stirred overnight. After completion of the reaction, cooled to room temperature, extracted with EtOAc (2×15 ml), the combined organic phases were washed with water, washed with saturated brine, and concentrated to give crude product, which was purified by column chromatography on silica gel (DCM: meoh=20:1) to give intermediate 111-1 (115 mg,332.95 μmol,99.80% yield). MS (ESI) m/z=346 [ m+1 ]] + 。
Step 2, preparation of intermediate 111-2
To a solution of intermediate 111-1 (115 mg, 332.95. Mu. Mol) in EtOH (5 mL) was added SnCl 2 .2H 2 O (75.13 mg, 332.95. Mu. Mol). The reaction mixture was warmed to 80 ℃ and stirred for reaction for 12h. The reaction was concentrated, and the resulting crude product was purified by mHPLC to give intermediate 111-2 (80 mg, 253.64. Mu. Mol,76.18% yield). MS (ESI) m/z=316 [ m+1 ]] + 。
Step 3, preparation of example 111
To a solution of 111-2 (80 mg, 253.64. Mu. Mol) and 1-methyl-1H-pyrazole-4-carbaldehyde (27.93 mg, 253.64. Mu. Mol) in EtOH (3 mL) was added I 2 (64.38 mg, 253.64. Mu. Mol). The reaction mixture was stirred at room temperature for 4h. After the reaction is completed, na is added 2 SO 3 Quenching with water, extracting with EA, and saturating the combined organic phasesAnd brine, and concentrating, and separating and purifying the crude product by pre.HPLC to give example 111 (14.7 mg, 28.30. Mu. Mol,11.16% yield), MS (ESI) m/z=406 [ M+1 ]] + 。 1 H NMR(400MHz,MeOD)δ8.44(s,1H),8.31(s,1H),8.12(dd,J＝3.1,0.6Hz,2H),7.72(d,J＝0.8Hz,1H),5.06(tt,J＝12.6,4.2Hz,1H),4.11(s,3H),3.99(s,3H),3.98–3.85(m,2H),3.24(td,J＝11.9,6.4Hz,1H),3.02(t,J＝12.7Hz,1H),2.69(d,J＝0.6Hz,3H),2.08–1.88(m,2H),1.36(s,6H).
Preparation of examples 112 and 113
Referring to the synthetic route of example 111, pinacol ester 1-methylpyrazole-4-boronic acid pinacol ester was replaced with pinacol ester in the following table, and the other reagents and procedures were the same, to give the corresponding structural examples in the table.
Example 114 preparation
Referring to the synthetic route of example 111, substituting 1-Boc-pyrazole-4-boronic acid pinacol ester for 1-methylpyrazole-4-boronic acid pinacol ester in step 1, the remaining reagents and procedures were the same and the same procedure were followed to give example 114.MS (ESI) m/z=378 [ m+1 ] ] + 。 1 H NMR(600MHz,Methanol-d 4 )δ8.46(s,1H),8.31(s,2H),8.13(s,1H),7.79(s,1H),5.08(ddd,J＝15.8,10.1,5.4Hz,1H),4.11(s,3H),4.04–3.88(m,2H),3.29–3.20(m,1H),3.05(t,J＝12.7Hz,1H),2.70(s,3H),2.01(dd,J＝21.4,12.7Hz,2H),1.36(s,6H).
Preparation of examples 115 to 119
Referring to the synthetic route of example 114, pinacol ester 1-Boc-pyrazole-4-boronic acid pinacol ester was replaced with pinacol ester in the following table in step 1, with the remaining reagents and procedures being identical. The corresponding structural embodiments in the table can be obtained by undergoing the same steps.
Example 119 preparation
Step 1, preparation of intermediate 119-1
To a solution of intermediate 65-1 (300 mg,1.00 mmol) in DMF (5 mL) was added 3-methylpyrazol-5-ol (103.09 mg,1.05 mmol) and Na 2 CO 3 (120 mg,1.13 mmol) and the reaction mixture was warmed to 90℃and stirred for 6h. After the reaction was completed, cooled to room temperature, diluted with water and extracted with EA, the combined organic phases were separated and purified by a silica gel column (PE: ea=1:1) to give intermediate 119-1 (270 mg,747.11 μmol,74.65% yield), MS (ESI) m/z=362 [ m+1:] + 。
step 2, preparation of intermediate 119-2
To a solution of intermediate 119-1 (306 mg, 846.72. Mu. Mol) in EtOH (9.6 mL) was added Zn (276.83 mg,4.23 mmol) and NH 4 Cl (226.46 mg,4.23 mmol) in water (3 mL), the reaction mixture was stirred at room temperature under the protection of liquid nitrogen, after the reaction was completed, the reaction solution was filtered, the EA solution of HCl (4N) was added in advance to a receiving flask, the cake was washed several times with EA/MeOH, and the filtrate was concentrated only to obtain intermediate 119-2 (300 mg, 815.50. Mu. Mol,96.31% yield, CL) which was used directly in the next reaction without further purification.
Step 3, preparation of example 119
A mixture of intermediate 119-2 (154.51 mg, 420.00. Mu. Mol, CL) and 1-methyl-1H-pyrazole-4-carbaldehyde (60.12 mg, 546.00. Mu. Mol) in EtOH (2 mL) was stirred at room temperature for 15min, then I was added 2 (111.93 mg, 441.00. Mu. Mol), and the reaction mixture was stirred at 60℃for 1 hour. Concentrating under reduced pressure to obtain crude product, dissolving in EA/MeOH (15:1), adding saturated Na 2 SO 3 The organic phase obtained by separation was dried over anhydrous sodium sulfate, and the crude product obtained by concentration under reduced pressure was separated and purified by Pre-HPLC to give example 119 (125 mg, 229.68. Mu. Mol,54.69% yield, 98.4% purity). MS (ESI) m/z=435 [ m+1 ]] + 。 1 H NMR(400MHz,Methanol-d 4 )δ8.37(s,1H),8.05(d,J＝0.8Hz,1H),7.07(d,J＝1.0Hz,1H),5.99(d,J＝0.9Hz,1H),4.96–4.90(m,1H),4.08(s,3H),3.85–3.77(m,2H),2.86–2.72(m,2H),2.67(d,J＝1.0Hz,3H),2.34(d,J＝0.7Hz,3H),1.88–1.78(m,2H),1.28(s,3H),1.25(s,3H).
In order to illustrate the beneficial effects of the present invention, the present invention provides the following test examples.
Test example 1, NUAK1 and NUAK2 enzymatic test
The inhibition of NUAK1 and NUAK2 enzyme activity by the small molecule inhibitors was quantitatively detected by ADP-GLO kit (Promega, cat#V9102). The reaction buffer used in the experiment comprises the following components: 40mM Tris,pH 7.5,5mM MgCl2, 50. Mu.M DTT,1mg/mL BSA,0.1mM EGTA. For NUAK1, 10. Mu.L of the reaction system included 4nM NUAK1 (SignalChem, cat#N19-10G), 300. Mu.M LATS1 substrate (PNIPVRSNSFNNPLGPRRR), 50. Mu.M ATP and various concentrations of test compounds. For NUAK2, 10. Mu.L of the reaction system included 4nM NUAK2, 150. Mu.M LATS1 substrate, 25. Mu.M ATP and various concentrations of the test compound. The reaction system was incubated on a 25℃shaker in 384 well plates (Corning, cat # 3574) for 60 minutes. mu.L of the reaction solution was pipetted into a 384-well plate, and 5. Mu.L of ADP-Glo was added TM reagent was incubated on a 25℃shaker for 40 minutes. After addition of 10 mu Lkinase detection reagent and incubation on a 25 degree shaker for 40 minutes, luminencement was detected using a TECAN Spark 20M. The experimental data are analyzed and processed by GraphPad Prism 6 software to obtain the IC 50 Values.
The compounds prepared in the examples were tested for NUAK1 and NUAK2 inhibition activity as described above and the test results are shown in Table 1, wherein the IC of each compound was determined 50 By way of illustration, in table 1:
"x" means that IC50 measurements are less than 10 μm and greater than 1 μm;
"x" means that IC50 measured values are less than 1 μm and greater than 100nM;
", means that IC50 assay is less than 100nM;
"NA" means undetected;
TABLE 1 inhibition activity of compounds on NUAK1/NUAK2
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The experimental results show that the compound has the activity of inhibiting NUAK1 and NUAK2 and can become a novel NUAK inhibitor medicament.

Claims (10)

1. A compound of formula IIa or a pharmaceutically acceptable salt thereof:
wherein,
the ring A is selected from benzene ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, 5-6-membered carbocycle and 5-8-membered heterocycle; wherein the benzene ring, aromatic heterocycle, carbocycle, heterocycle may be further substituted with one, two or three independent R 11 Substitution;
each R 11 Are independently selected from hydrogen, oxo, -C 1～6 Alkyl, -C 0～4 alkylene-OR 1a 、-C 0～4 alkylene-C (O) R 1a (3-membered cycloalkyl), - (3-to 10-membered heterocycloalkyl) wherein alkylene, alkyl, cycloalkyl, heterocycloalkyl may be further substituted with one, two or three independent R 1c Substitution;
R 1a selected from hydrogen, -C 1～6 Alkyl, - (3-to 10-membered cycloalkyl), - (3-to 10-membered heterocycloalkyl);
each R 1c Independently selected from hydrogen, -C (O) (3-10 membered cycloalkyl);
R 2 is selected from 5-8 membered cycloalkyl, 5-8 membered heterocycloalkyl and C 0～2 Alkylene- (5-10 membered aromatic ring); wherein the cycloalkyl, heterocycloalkyl, and aromatic rings may be further substituted with one, two, or three independent R 21 Substitution;
each R 21 Are independently selected from hydrogen, halogen and C 1～6 Alkyl, halogen substituted-C 1～6 Alkyl, - (3-membered cycloalkyl), -C 0～4 alkylene-NR 2a C(O)R 2b ；
R 2a 、R 2b Independently selected from hydrogen, - (3 membered cycloalkyl);
R 3 selected from hydrogen, -C 1～6 Alkyl, halogen substituted-C 1～6 An alkyl group;
R 4 selected from hydrogen, -C 1～6 An alkyl group;
R 5 selected from hydrogen;
R 6 selected from- (3-membered cycloalkyl);
the heterocycle and the heterocycloalkyl refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; wherein heteroatom means a nitrogen atom, an oxygen atom;
the aromatic heterocyclic ring refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom refers to nitrogen atom, oxygen atom and sulfur atom.
2. A compound according to claim 1, characterized in that:
ring A is selected from Wherein the ring selected from the A ring may be further substituted with one, two or three independent R 11 And (3) substitution.
3. A compound according to claim 2, characterized in that:
ring A is selected from
4. A compound according to claim 1, characterized in that:
R 2 selected from the group consisting of Wherein R is 2 The selected ring may be further substituted with one, two or three independent R 21 And (3) substitution.
5. A compound according to claim 4, characterized in that: r is R 2 Selected from the group consisting of
6. A compound according to claim 1, characterized in that:
R 3 selected from hydrogen, methyl, halogen substituted methyl; r is R 4 Selected from hydrogen, methyl; r is R 5 Selected from hydrogen.
7. A compound according to claim 1, characterized in that: r is R 6 Selected from the group consisting of
8. The compounds shown are in particular:
9. use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in the manufacture of a NUAK inhibitor medicament.
10. A pharmaceutical composition comprising a formulation of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, vehicle.
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