CN117069724A - Fused ring compounds, pharmaceutical compositions and uses - Google Patents

Fused ring compounds, pharmaceutical compositions and uses Download PDF

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Publication number
CN117069724A
CN117069724A CN202210509485.1A CN202210509485A CN117069724A CN 117069724 A CN117069724 A CN 117069724A CN 202210509485 A CN202210509485 A CN 202210509485A CN 117069724 A CN117069724 A CN 117069724A
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heteroatom
mmol
substituted
membered
bromo
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王非
陈南阳
孙勇
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Shanghai Simr Biotechnology Co ltd
Shanghai Semerode Biotechnology Co ltd
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Shanghai Simr Biotechnology Co ltd
Shanghai Semerode Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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 discloses a fused ring compound, a pharmaceutical composition and application. Specifically disclosed are imidazopyridazine derivatives represented by formula I, stereoisomers thereof, tautomers thereof, or pharmaceutically acceptable salts of any one of the foregoing, or solvates of any one of the foregoing. The pair of compounds contains alpha 2/3 GABA of subunit A The receptor has higher affinity.

Description

Fused ring compounds, pharmaceutical compositions and uses
Technical Field
The invention relates to a fused ring compound, a pharmaceutical composition and application.
Background
Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the mammalian central nervous system. Substances that modulate gabaergic neurotransmission are widely used in the treatment of various disorders such as epilepsy, anxiety and depression. In nature, there are two classes of GABA receptors, one class being GABA A Receptors, which are members of the ligand-gated ion channel superfamily, are of the other class GABA B Receptors, which are members of the superfamily of G protein-coupled receptors. GABA in mammals A The receptor subunits have found to have the subunits alpha 1-6, beta 1-4, gamma 1-3, delta, epsilon, theta and rho 1-2, wherein the alpha, beta and gamma subunit pairs form a complete functional GABA A The receptor is indispensable, and the alpha subunit is the alpha subunit of benzodiazepines and GABA A Binding of the receptor is critical.
The agent that binds at an allosteric binding site may be a positive (or positive) allosteric modulator that increases receptor activity, a negative (or reverse) allosteric modulator that decreases receptor activity, or a neutral allosteric modulator that does not alter receptor activity (this refers to a compound that binds to an allosteric binding site but does not modulate receptor activity). Recent evidence suggests that a is involved 2 Or alpha 3 GABA of subunit A Receptors (referred to herein as alpha 2/3 -GABA A Receptors) may be involved in certain pain states, and positive allosteric modulators of these receptors may be potentAnalgesic (Mirza, N.R. and Munro, G. Drug News and Perspectives,2010,23 (6), 351-360;).
International patent applications PCT/GB01/04948 (published as WO 2002/038568) and PCT/GB02/03114 (published as WO 2003/008418) describe 7-phenylimidazo [1,2-b][1,2,4]Triazine derivatives, their use as inhibitors of alpha 2 、α 3 And/or alpha 5 Subunits have affinity. International patent application PCT/US99/14935 (published as WO 2000/001697) discloses inter alia 4-phenyl-7H-imidazo [4,5-c]Pyridazine derivatives which are corticotropin releasing factor antagonists. International patent applications PCT/IB2013/060631 (published as WO 2014/091368) and PCT/IB2015/054200 (published as WO 2015/189744) and Robert M.Owen's article (Robert M.Owen's J.Med. Chem.2019,62, 5773-5796) describe 4- (biphenyl-3-yl) -7H-imidazo [4, 5-c) ]Pyridazine derivatives and alpha 2/3 -GABA A Receptors have interactions and are useful in the treatment of a variety of diseases including pain. Such compounds are also used for the treatment of pruritis (international patent application PCT/US2019/033598, publication No. WO2019/26820 A1) and epilepsy (Duveau, CNS Neurosci ther.2019.25 (2): p.255-260.).
The main stream view considers that the alpha is contained 1 GABA of subunit A The modulating activity of the receptor is GABA A Side effects (such as sedation, addiction, somnolence, amnesia) of positive allosteric modulators (such as benzodiazepines) are mainly sourced (Uwe Rudolph and Nature Reviews of Frederic Knoflach: drug Discovery,2011,10 (9), 685-697;). So find and GABA A Alpha of receptor interaction 1 -GABA A Novel compounds with fewer receptor-related side effects would have great therapeutic potential. Thus, further research is being conducted on 4- (biphenyl-3-yl) -7H-imidazo [4,5-c ]]In the pyridazine derivative, a series of compounds with novel structure are obtained, and the compounds contain alpha 2/3 GABA of subunit A Receptors have high affinity and good efficacy as positive allosteric modulators, whereas receptors for other alpha subunits (in particular those containing alpha 1 Subunit receptor) has low positive allosteric modulating activity.
These drug candidates should additionally have one or more of the following properties: is fully absorbed from the gastrointestinal tract; has metabolic stability; has good metabolic characteristics, in particular with regard to the toxicity or allergy of any metabolite formed; or have favorable pharmacokinetic properties while still retaining its active characteristics. They should be non-toxic and exhibit few side effects. The ideal drug candidate should exist in a physical form that is stable, non-hygroscopic and easy to formulate.
Disclosure of Invention
The invention aims to solve the technical problems that the prior P alpha 2/3 -GABA A The structure of the compound with the receptor having the regulatory function is single, so the invention provides a fused ring compound, a pharmaceutical composition and application. The pair of compounds contains alpha 2/3 GABA of subunit A The receptor has higher affinity and better relative alpha 1 Functional selectivity of subunits.
The present invention provides an imidazopyridazine derivative shown in formula I, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing (referring to the imidazopyridazine derivative shown in formula I, a stereoisomer thereof, or a tautomer thereof), or a solvate of any of the foregoing (referring to the imidazopyridazine derivative shown in formula I, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing);
wherein,
R 0 is H, halogen or C 1 -C 6 Alkyl or C substituted by 1, 2 or 3 halogens 1 -C 6 An alkyl group;
R 1 is C 1 -C 6 Alkyl, substituted with 1, 2, 3, 4 or 5R 1-1 Substituted C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl or is substituted by 1, 2, 3, 4 or 5R 1-2 Substituted C 3 -C 7 Cycloalkyl, R 1-1 And R is 1-2 Independently halogen, OH, CN, oxo, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or "heteroatom selected from 1, 2 or 3 of N, O and S, heteroatom number 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl";
L 1 Is absent, -O-, -C (O) -orWherein the end a is connected with the ring A, and the end B is connected with the ring B;
is-> Wherein, the c end and L 1 Connected with d-terminal and->Are connected;
X 1 CH or N;
R 2 is halogen or C substituted by 1, 2 or 3 halogens 1 -C 6 An alkyl group;
is->
Ring C is a benzene ring, a "heteroatom is selected from 1, 2 or 3 of N, O and S, the number of heteroatoms is 1, 2 or 3, 5-6 membered, a monocyclic aromatic heterocycle" or "heteroatom is selected from 1, 2 or 3 of N, O and S, the number of heteroatoms is 1, 2 or 3, 3-12 membered, a monocyclic or bicyclic alicyclic heterocycle";
R 3 is-NO 2 、-L 2 -R 3-1 "heteroatom is selected from 1, 2 or 3 of N, O and S, heteroatom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl", substituted by 1, 2 or 3R 3-13 The substituted hetero atom is selected from 1, 2 or 3 of N, O and S, the hetero atom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl, and is substituted by 1, 2 or 3R 3-3 Substituted C 1 -C 6 Alkoxy group,Is covered by 1, 2 or 3R 3-6 Substituted C 3 -C 7 Cycloalkyl,/-> Is covered by 1, 2 or 3R 3-11 Substituted C 1 -C 6 Alkyl,/->
L 2 is-O-, -C (O) -, -CH 2 -、Wherein, the e end and R 3-1 Are connected;
R 3-1 is "heteroatom selected from 1, 2 or 3 of N, O and S, heteroatom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl", is substituted by 1, 2 or 3R 3-1-1 Substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, heteroatom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl", "heteroatom is selected from 1, 2 or 3 of N, O and S, heteroatom number is 1, 2 or 3, 5-12 membered, monocyclic or bicyclic heteroaryl", is substituted with 1, 2 or 3R 3-1-2 The substituted hetero atom is selected from 1, 2 or 3 of N, O and S, the hetero atom number is 1, 2 or 3, 5-12 membered, monocyclic or bicyclicHeteroaryl ";
each R is 3-13 And R is 3-1-1 Independently oxo (=o), C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, a "heteroatom selected from 1, 2 or 3 of N, O and S, a heteroatom number of 1, 2 or 3, a 3-12 membered, a monocyclic or bicyclic heterocycloalkyl" or-C (O) -C 1 -C 6 An alkyl group;
each R is 3-1-2 Independently C 1 -C 6 Alkyl, substituted by 1, 2 or 3R 3-2-1 Substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, substituted by 1, 2 or 3R 3-2-2 Substituted C 1 -C 6 Alkoxy, 1, 2 or 3 hetero atoms selected from N, O and S, 1, 2 or 3 hetero atoms, 3-12 membered, mono-or bicyclic heterocycloalkyl, substituted by 1, 2 or 3R 3-2-3 The substituted hetero atom is selected from 1, 2 or 3 of N, O and S, the hetero atom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl, C 3 -C 7 Cycloalkyl, substituted by 1, 2 or 3R 3-2-4 Substituted C 3 -C 7 Cycloalkyl or-NR 3-2-5 R 3-2-6 ；
Each R is 3-2-1 And R is 3-2-2 Independently is halogen, C 1 -C 6 Alkoxy or-NR 3-2-1-1 R 3-2-1-2 ；
R 3-2-1-1 And R is 3-2-1-2 Independently hydrogen, C 1 -C 6 Alkyl, or R 3-2-1-1 、R 3-2-1-2 Together with the atoms to which they are attached form a "heteroatom selected from 1, 2 or 3 of N, O and S, a heteroatom number of 1, 2 or 3, a 3-12 membered, mono-or bicyclic heterocycloalkyl" or a heterocyclic group containing 1, 2 or 3R 3-2-1-3 The substituted hetero atom is selected from 1, 2 or 3 of N, O and S, the hetero atom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl;
each R is 3-2-1-3 Independently C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl, halogen, oxo, hydroxy or CN;
each R is 3-2-3 And R is 3-2-4 Independently C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl, halogen, oxo, hydroxy or CN;
R 3-2-5 and R is 3-2-6 Independently hydrogen, C 1 -C 6 Alkyl, substituted with 1, 2, 3, 4 or 5R 3-2-5-1 Substituted C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl or is substituted by 1, 2, 3, 4 or 5R 3-2-5-2 Substituted C 3 -C 7 Cycloalkyl, R 3-2-5-1 And R is 3-2-5-2 Independently halogen, OH, CN, oxo, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or "heteroatom selected from 1, 2 or 3 of N, O and S, heteroatom number 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl";
each R is 3-3 independently-CN, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl or C substituted by 1, 2 or 3 CNs 3 -C 7 Cycloalkyl;
R 3-4 and R is 3-5 Independently C 1 -C 6 An alkyl group;
R 3-6 is-CN, -C (O) NH 2 or-S (O) 2 -R 3-6-1 ；R 3-6-1 Is C 1 -C 6 An alkyl group;
each R is 3-7 Independently C 1 -C 6 An alkyl group;
each R is 3-8 Independently C 1 -C 6 An alkoxy group;
each R is 3-11 Independently halogen, cyano or C 1 -C 6 An alkoxy group;
R 3-12 、R 3-9 and R is 3-10 Independently C 1 -C 6 An alkyl group;
n is 0, 1, 2, 3 or 4;
each R is 4 Is independently CN, OH, halogen, C 1 -C 6 Alkyl, substituted by 1, 2 or 3R 4-1 SubstitutedC 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C substituted by 1, 2 or 3 halogen 1 -C 6 Alkoxy, -NR 4-2 R 4-3 ；
Each R is 4-1 Independently halogen or C 1 -C 6 An alkoxy group;
R 4-2 and R is 4-3 Independently C 1 -C 6 Alkyl, or R 4-2 、R 4-3 Together form- (CH) 2 ) m-; m is 2, 3, 4 or 5;
each Y 6 independently-N-or-CH-;
each R is 8 Independently C 1 -C 6 An alkyl group;
each R is 9 Independently C 1 -C 6 An alkoxy group;
Y 7 is-CH 2 -or-C (O) -; r is R 10 Is C 1 -C 6 Alkyl or "heteroatom is selected from 1, 2 or 3 of N, O and S, 3-12 membered heterocycloalkyl with 1, 2 or 3 heteroatoms.
In certain preferred embodiments of the present invention, certain groups in the solvate of the imidazopyridazine derivative of formula I, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of either of the foregoing (meaning the imidazopyridazine derivative of formula I, a stereoisomer thereof, or a tautomer thereof), or of either of the foregoing (meaning the imidazopyridazine derivative of formula I, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of either of the foregoing), are as defined below, the unrecited groups are as described in any of the embodiments of the present invention (in one of the embodiments of the present invention for short),
R 0 、R 1 、R 2 、R 3 、R 3-1-1 、R 3-1-2 、R 3-2-1-1 、R 3-2-1-2 、R 3-2-1-3 、R 3-2-3 、R 3-2-4 、R 3-2-5 、R 3-2-6 、R 3-4 、R 3 -5 、R 3-6-1 、R 3-7 、R 3-9 、R 3-10 、R 3-12 、R 3-13 、R 4 、R 4-2 、R 4-3 、R 8 And R is 10 In the above, the C 1 -C 6 Alkyl and said substituted C 1 -C 6 In the alkyl group, each C 1 -C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl, n-propyl or isopropyl.
In one embodiment of the invention, R 0 、R 1-1 、R 1-2 、R 2 、R 3-2-1 、R 3-2-2 、R 3-2-1-3 、R 3-2-3 、R 3-2-4 、R 3-2-5-1 、R 3 -2-5-2 、R 3-11 、R 4 And R is 4-1 Wherein each halogen is independently F, cl, br or I, for example F.
In one embodiment of the invention, R 3 、R 3-1-1 、R 3-1-2 、R 3-2-1 、R 3-2-2 、R 3-2-1-3 、R 3-2-3 、R 3-2-4 、R 3-2-5-1 、R 3 -2-5-2 、R 3-3 、R 3-8 、R 3-11 、R 3-13 、R 4 、R 4-1 And R is 9 In the above, the C 1 -C 6 Alkoxy and said substituted C 1 -C 6 In the alkoxy group, each C 1 -C 6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy or ethoxy.
In one embodiment of the invention, in ring C, the "heteroatom is selected from 1, 2 or 3 of N, O and S, the number of heteroatoms is 1, 2 or 3, 5-6 membered, and the monocyclic aromatic heterocyclic ring" is "heteroatom is N, the number of heteroatoms is 1 or 2, 5 or 6 membered, monocyclic aromatic heterocyclic ring", for example For another example
In one embodiment of the invention, R 3-1 In which the "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5-12 membered, monocyclic or bicyclic heteroaryl" and the substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5-12 membered, monocyclic or bicyclic heteroaryl", each "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5-12 membered, monocyclic or bicyclic heteroaryl" is independently "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5 or 6 membered, monocyclic heteroaryl", e.g., oxadiazolyl (e.g. ) Triazolyl (e.g.)> ) Thiadiazolyl (e.g) Pyrazolyl (e.g.)>) Isoxazolyl (e.g.)>) Pyridyl (e.g.)>) Pyridazinyl (e.g.)>) Pyrazinyl (e.g.)>) Or pyrimidinyl (e.g.)>)。
In one embodiment of the invention, R 3 And R is 3-1 Wherein the "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" and the substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl", each "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" is independently "heteroatom is selected from 1 or 2 of N and O, the heteroatom number is 1 or 2, 4-12 membered, mono-or bicyclic heterocycloalkyl", e.g., azetidinyl (e.g.) Glycidylyl group (e.g.)>) Tetrahydrofuranyl (e.g) Pyrrolidinyl (e.g.)>) Oxazolidinyl groups (e.g.)>) Imidazolidinyl groups (e.g.)>)、Tetrahydropyranyl (e.g.)>) Piperidinyl (e.g.)>) Morpholinyl (e.g.)>) Piperazinyl (e.g.)>) Oxazinoalkyl (e.g.) >) Or 2-oxo-6-azaspiro [3.3 ]]Heptyl (e.g.)>)。
In one embodiment of the invention, R 1 、R 3 、R 3-1-2 、R 3-2-1-3 、R 3-2-3 、R 3-2-4 、R 3-2-5 、R 3-2-6 And R is 3-3 In the above, the C 3 -C 7 Cycloalkyl and said substituted C 3 -C 7 In cycloalkyl groups, each C 3 -C 7 Cycloalkyl is independently cyclopropane, cyclobutyl, cyclopentane or cyclohexenyl, e.g., cyclopropane.
In one embodiment of the invention, R 1-1 、R 1-2 、R 3-13 、R 3-1-1 、R 3-1-2 、R 3-2-1-1 、R 3-2-1-2 、R 3-2-5-1 、R 3-2-5-2 And R is 10 Wherein the "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" and the substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" each "heteroatom is selected from 1 of N, O and SSpecies, 2 or 3, having 1, 2 or 3 heteroatoms, 3-12 membered, monocyclic or bicyclic heterocycloalkyl "independently being" having 1 or 2 heteroatoms selected from N and O, having 1 or 2 heteroatoms, 4, 5 or 6 heteroatoms, monocyclic heterocycloalkyl ", for example azetidinyl (for example ) Glycidylyl group (e.g.)>) Pyrrolidinyl (e.g.)>) Or piperazinyl (e.g.)>)。
In one embodiment of the invention, R 0 H, cl, F, CF of a shape of H, cl, F, CF 3 Or CH (CH) 3 The method comprises the steps of carrying out a first treatment on the surface of the Preferably H.
In one embodiment of the invention, R 1 is-CH (CH) 3 ) 2 or-CH 2 CH 3 preferably-CH 2 CH 3 。
In one aspect of the invention, L 1 Is absent, -O-, or
In one aspect of the present invention,is->
In one embodiment of the invention, R 2 F.
In certain aspects of the inventionIn one aspect of the present invention,is-> Preferably +.>
In one aspect of the present invention,is->
In one embodiment of the invention, ring C is a benzene ring or a pyridine ring.
In one embodiment of the invention, R 3 is-NO 2 、-L 2 -R 3-1 "heteroatom is selected from 1, 2 or 3 of N, O and S, heteroatom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl", substituted by 1, 2 or 3R 3-13 The substituted hetero atom is selected from 1, 2 or 3 of N, O and S, the hetero atom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl, and is substituted by 1, 2 or 3R 3-3 Substituted C 1 -C 6 Alkoxy, substituted by 1, 2 or 3R 3-6 Substituted C 3 -C 7 Cycloalkyl group, Is covered by 1, 2 or 3R 3-11 Substituted C 1 -C 6 Alkyl or->Preferably, R 3 is-L 2 -R 3-1 "heteroatom is selected from 1, 2 or 3 of N, O and S, heteroatom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl", substituted by 1, 2 or 3R 3-13 The substituted hetero atom being selected from 1, 2 or 3 of N, O and S, the hetero atom number being 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl "or being substituted by 1, 2 or 3R 3-3 Substituted C 1 -C 6 An alkoxy group.
In one embodiment of the invention, n is 1 or 2.
In one embodiment of the invention, each R 4 Independently halogen, is covered by 1C 1 -C 6 Alkoxy substituted C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy radicals, e.g. F, -O-CH 3 、-O-CH 2 CH 3 or-CH 2 -O-CH 3 。
In one embodiment of the invention, there are at least 1R 4 Is 1C 1 -C 6 Alkoxy substituted C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy (e.g. -O-CH 3 、-O-CH 2 CH 3 or-CH 2 -O-CH 3 ) The rest R 4 Halogen (e.g., F) or absent.
In one aspect of the present invention,is->
The imidazopyridazine derivative shown in the formula I has a structure shown in the formula I-1:
wherein the ring C, L 1 、R 1 、R 3 、R 4 And n is as defined in any one of the embodiments of the invention.
In one embodiment of the present invention, the imidazopyridazine derivative represented by formula I is any one of the following:
scheme one: r is R 3 is-L 2 -R 3-1 ；
R 3-1 Is "a 5-12 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from 1, 2 or 3 of N, O and S", is substituted with 1, 2 or 3R 3-1-2 The substituted "heteroatom is selected from 1, 2 or 3 in N, O and S, the heteroatom number is 1, 2 or 3 5-12 membered heteroaryl";
n is 1 or 2;
ring C is a benzene ring or pyridine ring;
when ring C is a benzene ring, at least 1R 4 Is C 1 -C 6 Alkoxy (e.g. -O-CH 3 ) The rest R 4 Halogen (e.g., F) or absent;
When ring C is a pyridine ring, there are at least 1R 4 Is 1C 1 -C 6 Alkoxy substituted C 1 -C 6 Alkyl (e.g. -CH 2 -O-CH 3 ) The rest R 4 Halogen (e.g., F) or absent.
Scheme II: r is R 3 Is 1, 2 or 3R 3-3 Substituted C 1 -C 6 An alkoxy group.
Scheme III: r is R 3 Is 1, 2 or 3R 3-11 Substituted C 1 -C 6 Alkyl, ring C is a pyridine ring, and at least 1R 4 Is C 1 -C 6 Alkoxy (e.g. -O-CH 3 ) The rest R 4 Halogen (e.g., F) or absent.
The present invention also provides an imidazopyridazine derivative, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing (referring to the imidazopyridazine derivative, stereoisomer thereof, or tautomer thereof) or a solvate of any of the foregoing (referring to the imidazopyridazine derivative, stereoisomer thereof, tautomer thereof, or pharmaceutically acceptable salt of any of the foregoing) as shown below:
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the necessary starting materials or reagents for preparing the imidazopyridazine derivatives of formula I are commercially available or may be prepared by synthetic methods known in the art. The compounds of the invention may be prepared as free bases or as salts thereof with acids, as described in the experimental section below.
The imidazopyridazine derivatives of formula I may have one or more chiral carbon atoms and may thus be isolated as optically pure isomers, e.g. as pure enantiomers, or as racemates, or as mixed isomers. Pure single isomers may be obtained by separation methods in the art, such as chiral crystallization to form salts, or chiral preparative column separation.
The chemicals used in the synthetic route described in the present invention include solvents, reagents, catalysts and protecting groups, deprotecting groups, protecting groups including t-butoxycarbonyl (Boc). The above-described methods may additionally include steps prior to or subsequent to the steps specifically described herein, and suitable protecting groups may be added or removed to provide the subject compounds. In addition, the various synthetic steps may be performed alternately or sequentially to obtain the final target product.
The present invention also provides a pharmaceutical composition comprising:
(1) The imidazopyridazine derivative of any one of the preceding claims, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any one of the preceding claims (referring to the imidazopyridazine derivative of the preceding claims, a stereoisomer thereof, or a tautomer thereof), or a solvate of any one of the preceding claims (referring to the imidazopyridazine derivative of the preceding claims, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the preceding claims); and
(2) A pharmaceutically acceptable carrier.
Although the imidazopyridazine derivatives for use in the treatment of the present invention may be administered in the form of a starting compound, the active ingredient, optionally in the form of a physiologically acceptable salt, is preferably admixed with one or more additives, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical excipients to form a pharmaceutical composition.
In a preferred embodiment, the present invention provides a pharmaceutical composition comprising a solvate of any one of the foregoing imidazopyridazine derivatives of formula I, stereoisomers thereof, tautomers thereof, or pharmaceutically acceptable salts of any one of the foregoing (referring to the imidazopyridazine derivatives of formula I, stereoisomers thereof, or tautomers thereof), or any one of the foregoing (referring to the imidazopyridazine derivatives of formula I, stereoisomers thereof, tautomers thereof, or pharmaceutically acceptable salts of any one of the foregoing), wherein any one of the foregoing imidazopyridazine derivatives of formula I, stereoisomers thereof, tautomers thereof, or pharmaceutically acceptable salts of any one of the foregoing (referring to the imidazopyridazine derivatives of formula I, stereoisomers thereof, or tautomers thereof), or a pharmaceutically acceptable salt of any one of the foregoing (referring to the imidazopyridazine derivatives of formula I, stereoisomers thereof, or pharmaceutically acceptable salts of any one of the foregoing) and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or mixture thereof, and a pharmaceutically acceptable carrier or a pharmaceutically acceptable carrier thereof, and a therapeutic agent. The carrier must be "acceptable", i.e., compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The pharmaceutical compositions for use in the present invention may be those suitable for oral, rectal, bronchial, nasal, pulmonary, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for inhalation or spray administration, including powder and liquid aerosol administration, or sustained release system administration. Examples of suitable slow release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, wherein the matrices are in the form of shaped articles, e.g., films, or microcapsules.
The compounds used in the present invention may thus be formulated with conventional additives, or diluents, into pharmaceutical compositions and unit dosage forms thereof. Such forms include solid (especially tablet, filled capsule, powder and pill forms), and liquid (especially aqueous or non-aqueous solutions, suspensions, emulsions, elixirs), and capsules filled with the above forms, all oral forms, rectal suppositories, and parenterally administered sterile injectable solutions. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the desired daily application dosage range.
The compounds useful in the present invention may be administered in a variety of oral and parenteral dosage forms. The following dosage forms may contain the compounds of the present invention or pharmaceutically acceptable salts thereof as active ingredients, as will be apparent to those skilled in the art.
For the preparation of the compounds for use in the present invention into pharmaceutical compositions, the pharmaceutically acceptable carrier may be solid or liquid. Solid form preparations include powders, tablets, nine agents, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances that also function as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is admixed with the finely divided active ingredient.
In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compressed into the desired shape and size.
The powders and tablets preferably contain 5% or 10% to about 7 0% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "formulation" includes formulations containing the active compound formulated with an encapsulating material as a carrier, the encapsulating material providing a capsule in which the active ingredient, with or without a carrier, is surrounded by a carrier, so as to be associated therewith. Likewise, formulations include cachets and lozenges. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.
To prepare suppositories, a low melting wax, such as a fatty acid glyceride or a cocoa butter paste, is first melted and the active ingredient is then dispersed homogeneously therein by stirring. The melted homogeneous mixture is then poured into a suitably sized mold, allowed to cool and thereby solidify.
Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Liquid formulations include solutions, suspensions and emulsions, for example, aqueous solutions or water-propylene glycol solutions. For example, parenteral injection liquid preparations may be formulated as a solution of water-polyethylene glycol.
The compounds for use in the present invention may thus be formulated for parenteral administration (e.g. injection, such as bolus injection or continuous infusion) and may be presented in unit dosage form with the added preservative in ampoules, pre-filled syringes, small volume infusion bags or in multi-dose containers. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in the form of a powder, obtainable from sterile solid sterile isolation or from solution lyophilization for reconstitution with a suitable carrier such as sterile, pyrogen-free water just prior to use.
Aqueous solutions suitable for oral administration may be prepared by dissolving the active ingredient in water and adding the desired colorants, flavors, stabilizers, and thickeners.
Aqueous suspensions suitable for oral administration can be prepared by dispersing the finely divided active ingredient in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
Also included are solid formulations designed for conversion to liquid formulations for oral administration shortly before use. Such liquid formulations include solutions, suspensions and emulsions. Such formulations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickeners, solubilizing agents, and the like.
For topical application to the epidermis, the compounds of the invention may be formulated as ointments, creams or lotions or transdermal patches. For example, ointments and creams may be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, typically sucrose and acacia or tragacanth; pastilles (pastilles) comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.
The solution or suspension may be applied directly to the nasal cavity by conventional means, for example by means of a dropper, pipette or nebulizer. The composition may be in single or multiple dose form.
Respiratory administration may also be achieved by aerosol formulations wherein the active ingredient is contained in a pressurized package with a suitable propellant, including chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gases. The aerosol formulation may also suitably contain a surfactant, such as lecithin. The dosage of the drug may be controlled by a throughput valve.
Alternatively the active ingredient may be in the form of a dry powder, for example a powder mixture of the compound with a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). The powder carrier may conveniently form a gel within the nasal cavity. The powder composition may be present in unit dosage form, for example in a capsule or cartridge (such as a gelatin gum or cartridge) or in a blister pack where the powder may be administered via an inhaler.
In compositions for respiratory administration (including intranasal compositions), the compounds typically have a small particle size, for example, on the order of 5 microns or less. Such particle sizes may be obtained by methods known in the art, for example by micronization.
Compositions suitable for sustained release of the active ingredient may be used, if desired.
The pharmaceutical formulation is preferably in unit dosage form. In such forms, the formulation is subdivided into unit doses of appropriate quantities of the active ingredient. The unit dosage form may be a packaged formulation wherein the sealed package contains discrete quantities of the formulation, such as packaged tablets, capsules, and powders in vials or ampoules. Furthermore, the unit dosage form may be a capsule, tablet, a tablet or lozenge itself, or may be any encapsulated form of the appropriate amounts of capsules, tablets, etc. described above.
Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
More details about formulation and administration techniques can be found on the latest version of Remington's Pharmaceutical Sciences (ramington pharmaceutical science) (Maack Publishing co., easton, PA).
The amount of active ingredient in a unit dosage formulation may vary depending upon the particular application and the potency of the active ingredient, and may be adjusted from 0.01mg to about 0.1g. For example, in pharmaceutical use, the medicament may be administered in capsules of 0.01 to about 100mg three times per day, and the composition may also contain other compatible therapeutic agents if necessary.
The invention also provides an imidazopyridazine derivative according to any one of the preceding claims, a stereoisomer thereof, a tautomer thereof,or a pharmaceutically acceptable salt of any of the foregoing (referring to the foregoing imidazopyridazine derivative, stereoisomer thereof, or tautomer thereof), or a solvate of any of the foregoing (referring to the foregoing imidazopyridazine derivative, stereoisomer thereof, tautomer thereof, or pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition of any of the foregoing, in the preparation of a 2/3 -GABA A Use of receptor modulators.
In said application, said α 2/3 -GABA A Receptor modulators may be used in mammalian organisms; it is also useful in vitro, mainly as an experimental use, for example: as standard or control sample for comparison, or as kit according to conventional method in the art, is alpha 2/3 -GABA A Receptor modulating effects provide rapid detection.
The invention also provides the use of an imidazopyridazine derivative according to any one of the preceding claims, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any one of the preceding claims (referring to an imidazopyridazine derivative, a stereoisomer thereof or a tautomer thereof) or a solvate of any one of the preceding claims (referring to an imidazopyridazine derivative, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt of any one of the preceding claims), or a pharmaceutical composition according to any one of the preceding claims, for the manufacture of a medicament for the treatment and/or prophylaxis of a disease associated with alpha 2/3 -GABA A Receptor-related disorders, relief of pain, epilepsy, anxiety, itching, or depression.
The invention also provides the use of an imidazopyridazine derivative according to any one of the preceding claims, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any one of the preceding claims (referring to the imidazopyridazine derivative, stereoisomer thereof or tautomer thereof), or a solvate of any one of the preceding claims (referring to the imidazopyridazine derivative, stereoisomer thereof, tautomer thereof or pharmaceutically acceptable salt of any one of the preceding claims), or a pharmaceutical composition according to any one of the preceding claims, for the manufacture of a medicament for the treatment and/or prophylaxis of: pain, epilepsy, anxiety, itching and depression.
The invention also provides for the treatment and/or prophylaxis of alpha 2/3 -GABA A A method of receptor-related diseases comprising administering to a subject in need thereof a therapeutically effective amount of an imidazopyridazine derivative of any one of the foregoing, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing (referring to the imidazopyridazine derivative of the foregoing, a stereoisomer thereof, or a tautomer thereof), or a solvate of any one of the foregoing (referring to the imidazopyridazine derivative of the foregoing, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition of any of the foregoing.
The present invention also provides a method of treating and/or preventing pain, epilepsy, anxiety, itch, and depression comprising administering to a subject in need thereof a therapeutically effective amount of an imidazopyridazine derivative, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing (referring to the imidazopyridazine derivative, stereoisomer thereof, or tautomer thereof), or a solvate of any of the foregoing (referring to the imidazopyridazine derivative, stereoisomer thereof, tautomer thereof, or pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition of any of the foregoing.
In the use and method, preferably, the disease is selected from pain, epilepsy, anxiety, itch and depression.
In the methods and uses, preferably, the pain is acute pain, chronic pain, neuropathic pain, inflammatory pain, somatic pain, visceral pain, dysfunctional pain, or cancerous pain. The epilepsy includes epilepsy and epilepsy-related disorders including Lennox-Gastaut syndrome, delaviret's (Dravet) disease and generalized epilepsy plus febrile attacks (gefs+). The anxiety disorder includes panic disorder, phobia, warfarin anxiety disorder, stress disorder and obsessive compulsive disorder.
In the use and method, preferably, the pain is selected from: headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, back pain, lower limb pain, muscle and bone pain, vascular pain, gout, arthritic pain, visceral pain, pain resulting from infectious diseases (such as AIDS and post-herpetic neuralgia), multi-bone pain, sickle cell anemia, autoimmune diseases, pain associated with multiple sclerosis or inflammation, chronic pain resulting from injury or surgery, nociceptive pain, painful diabetes, trigeminal neuralgia, lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic nerve reflex pain, reflex sympathetic dystrophy, nerve root avulsion, cancer, chemical injury, toxins, nutritional deficiency, viral or bacterial infection, pain associated with degenerative osteoarthropathy.
In therapeutic use, the compounds used in the present invention are administered at an initial dose of 0.001mg/kg to 10mg/kg body weight per day. However, these dosages may vary depending on the patient's needs, the severity of the condition being treated and the compound being used, and generally treatment will begin with a smaller dosage than the optimum dosage of the compound, after which the dosage is increased by a small amount to achieve the optimum effect, and the total daily dosage may be subdivided for administration in portions of the day if desired, for convenience.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
Unless otherwise specified, all technical and scientific terms used herein have the standard meaning of the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control.
The naming convention used in the present invention is based on AutoNomTM 2000 for generating the Beilstein Institute computerized system of IUPAC system naming. The chemical structures presented herein are obtained using ChemDraw version 12. Any open valence occurring on a carbon, oxygen, sulfur, or nitrogen atom in the structures presented herein indicates the presence of a hydrogen atom.
Those skilled in the art will appreciate that in accordance with conventional practices used in the artThe present invention describes the structural formula of the group used inMeaning that the corresponding group is linked to other fragments, groups in the compound through this site.
As used herein, substituents may be preceded by a single dash "-" indicating that the named substituent is attached to the parent moiety through a single bond.
If a certain linking group is indicated as "absent", the structures on both sides of the linking group are directly linked by a single bond, e.g. -A-B-C-, when B is absent, -A-B-C-is-A-C-.
The term "pharmaceutically acceptable" refers to salts, solvents, excipients, and the like, which are generally non-toxic, safe, and suitable for patient use. The "patient" is preferably a mammal, more preferably a human.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, diethanolamine salt. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in pure solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. See, for example, berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: properties, selection, and Use (P.Heinrich Stahl and Camille G.Wermuth, ed., wiley-VCH, 2002).
The term "stereoisomer" refers to a cis, trans or optical isomer. These stereoisomers may be isolated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and may be obtained by chiral resolution by bonding (chemical bonding, etc.) or salifying (physical bonding, etc.) other chiral compounds.
The term "solvate" refers to a substance formed by combining a compound of the invention with a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvate may be present in an ordered or unordered arrangement. Such solvents include, but are not limited to: water, methanol, ethanol, and the like.
The terms "pharmaceutically acceptable salts" and "solvates" in "solvates of pharmaceutically acceptable salts" refer, as described above, to the compounds of the invention formed by combining 1 with 2, prepared with a relatively non-toxic, pharmaceutically acceptable acid or base, with a stoichiometric or non-stoichiometric amount of a solvent. The "solvate of a pharmaceutically acceptable salt" includes, but is not limited to, the hydrochloride monohydrate of the compound of the invention.
When any variable (e.g. R 3-2 ) In the definition of a compound, the definition of each position of the variable appears independently of the definition of the other positions, itThe meanings of the two are independent of each other and do not influence each other. Thus, if a group is substituted with 1, 2 or 3R 3-2 The radical is substituted, that is to say, it may be substituted by up to 3R 3-2 Substituted, at position R 3-2 Definition of (d) and the remaining position R 3-2 Are defined independently of each other. In addition, combinations of substituents and/or variables are allowed only if the combination yields a stable compound.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and the like.
The term "alkoxy" refers to the group-O-R X Wherein R is X Are alkyl groups as defined above.
The term "cycloalkyl" refers to a compound having the indicated number of ring carbon atoms (e.g., C 3 ～C 6 ) Saturated monocyclic ring groups having ring atoms consisting only of carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "heterocycloalkyl" refers to a cyclic group of a specified number of heteroatoms (e.g., 1, 2, or 3) having a specified number of ring atoms (e.g., 3-12 members), of a specified heteroatom species (1, 2, or 3 of N, O and S), which is monocyclic or bicyclic, and when bicyclic, is bridged or spiro, and each ring is saturated. Heterocycloalkyl includes, but is not limited to, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepinyl, oxazepinyl, and the like.
The term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably an aromatic 5-6 membered monocyclic or 7-12 membered bicyclic ring containing 1, 2 or 3 atoms independently selected from nitrogen, oxygen and sulfur, and when bicyclic, at least one ring has aromaticity, such as furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzisozolyl, quinolinyl, isoquinolinyl, and the like.
As used herein, "cancerous pain" refers to pain that occurs in a malignant tumor during its development, and the occurrence of cancerous pain is currently thought to have three mechanisms, namely: pain directly caused by cancer progression, pain caused after cancer treatment, and pain-associated diseases in cancer patients.
As used herein, "neuropathic pain" is pain that is stimulated or caused by primary damage and dysfunction of the nervous system.
As used herein, "inflammatory pain" is pain caused by local acute inflammation or chronic inflammation stimulating nerves.
As used herein, "chronic pain" is defined as a reasonable period of time that lasts beyond the usual course of an acute disease or injury cure, or is associated with a chronic pathological process that causes persistent pain, or pain recurs at intervals for months or years, and is considered chronic if pain is still present after cure has been reached or beyond the usual therapeutic process. The length of time that pain needs to elapse depends on the nature of the pain and the course of treatment associated with the pain, which is chronic if it exceeds the usual course of treatment. Chronic pain includes, but is not limited to, headache, facial pain, neck pain, shoulder pain, chest pain, abdominal pain, back pain, low back pain, lower limb pain, musculoskeletal pain, pain associated with somatosensory and mental disorders, visceral pain, painful diabetic neuropathy, vascular pain, gout, arthritic pain, cancer pain, autonomic nerve reflex pain, pain resulting from infectious diseases such as aids and shingles, pain resulting from autoimmune diseases (rheumatism), pain resulting from acute and chronic inflammation, postoperative pain, and post-burn pain.
The disclosed medicaments are effective in treating chronic pain as defined above, and are useful in treating pain associated with other conditions, including hyperalgesia, allodynia, increased pain sensation and increased pain memory, which will improve the treatment of pain thereof.
As used herein, "headache" can be divided into primary headache and secondary headache, primary headache including tension headache, migraine and cluster headache, secondary headache being due to other diseases. Various headaches may be caused when the pain sensitive tissues of the head and face are diseased or stimulated, including the scalp, face, mouth and throat, etc., and these tissues may be caused when they are injured because they are mainly muscles or blood vessels of the head, contain abundant nerve fibers, and are relatively sensitive to pain.
As used herein, "facial pain" includes, but is not limited to, trigeminal neuralgia, atypical facial pain, facial paralysis, and facial spasm.
As used herein, "trigeminal neuralgia" is a unique chronic painful condition, also known as painful tic, which refers to the appearance of transient, paroxysmal and recurrent shock-like severe pain in the region of the trigeminal nerve distribution, or with ipsilateral muscle spasticity. Trigeminal neuralgia is classified into primary and secondary, wherein primary trigeminal neuralgia refers to clinical condition of the nervous system not found and organic lesions not found; the secondary trigeminal neuralgia refers to the clinical symptoms of nervous system, and the clinical symptoms of the secondary trigeminal neuralgia are detected to have organic lesions such as tumors, inflammations and the like.
As used herein, "atypical facial pain" refers to pain caused by a variety of etiologies. Manifested as sustained burning-like pain, no intermittent, independent of specific movements or triggering stimuli, pain is mostly bilateral, pain often goes beyond the distribution of the trigeminal nerve and even involves the cervical skin. The etiology can be pain caused by the stimulation or injury of trigeminal nerve caused by sinusitis, malignant tumor, jaw and skull base infection, etc.
As used herein, "neck pain, back pain, shoulder pain" refers to pain caused by acute and chronic muscle strain, degeneration of bone joints, trauma, and the like. Common diseases causing neck, shoulder and upper limb pain are neck and shoulder myofascitis, xiang Rendai inflammation, cervical spondylosis, scapulohumeral periarthritis, thoracic outlet syndrome, external humeral epicondylitis and the like, or pain caused by autoimmune diseases is commonly caused by diseases such as rheumatoid arthritis, ankylosing spondylitis, rheumatic arthritis and the like, other diseases possibly causing neck pain, back pain and shoulder pain, tumors of the neck and shoulder, neuritis, arteriovenous diseases, various infections, and pain involved by pathological changes of thoracic and abdominal organs and the like.
As used herein, "chest, abdomen, and back pain" refers to pain due to diseases of the chest and abdomen viscera, chest and abdomen wall tissue, including, but not limited to, intercostal neuralgia, intercostal chondritis, angina, abdominal pain (acute abdominal visceral pain), and lumbar back myofascial syndrome.
As used herein, "low back, low limb pain" refers to lower back, lumbosacral, sacroiliac, hip, low limb pain. Pain in the waist and lower extremities is often not an independent disease, but is a common feature of various diseases, and has various clinical manifestations and quite complex etiology, and is often marked by degenerative and injury, including but not limited to pain related to lumbar disc herniation, acute lumbar sprain, sciatica, osteoporosis, third lumbar transverse process syndrome, piriformis syndrome, knee osteoarthritis, tail pain, heel pain and the like.
As used herein, "musculoskeletal pain" includes, but is not limited to, myofascial pain, trauma induced pain, and chronic regional pain syndrome.
As used herein, "painful diabetes" refers to pain caused by nerve damage that is concurrent with diabetes, the nerve damage in diabetes being caused at least in part by reduced blood flow and hyperglycemia. Some diabetics do not develop neuropathy, while others develop the disease early, and diabetic neuropathy can be divided into mononeuropathy involving one or more focal sites and systemic polyneuropathy, which can be diffuse and symmetrical, usually primarily involving sensory modalities (Merrit's Textbook of Neurology, 9 th edition, LPRowland LP edit). The manifestations of diabetic neuropathy may include autonomic dysfunction, resulting in dysregulation including heart, smooth muscle and glands, leading to hypotension, diarrhea, constipation and sexual disability. Diabetic neuropathy often progresses in stages, early in the peripheral nerve region, in the foot when it occurs in autonomic nerve or sensory neuropathy, around the face and eyes when it occurs in brain neuropathy, with intermittent pain and tingling, more intense pain and frequent occurrences in the subsequent stages, and finally, when pain is lost in a certain area, it occurs as painless neuropathy, with no pain as an indication of injury, greatly increasing the risk of severe tissue damage.
As used herein, "visceral pain" includes, but is not limited to, pain associated with Irritable Bowel Syndrome (IBS), with or without Chronic Fatigue Syndrome (CFS), inflammatory Bowel Disease (IBD), and interstitial cystitis.
As used herein, "vascular pain" is pain that results from one or more of the following factors. First, the perfusion of the tissue is improper. Causing temporary or continuous ischemia, such as occurs in limb muscles during exercise; second, late changes. Such as ulcers or gangrene in the skin or abdominal viscera; third, abrupt or accelerated changes in large vessel caliber. Such as changes in aneurysms; fourth, the aorta is ruptured. The result is extravasation of blood, stimulating nociceptive fibres in the peritoneal or pleural wall layer; fifth, strong spasticity due to severe irritation of arterial endothelium by intra-arterial injection; sixth, damage to venous blood reflux, with the result of rapid distension of the fascial compartment for massive edema (Bonica et al, the Management of Pain, first volume (second edition), philadelphia; lea & Feboger, 1990). Examples include, but are not limited to, occlusive arteriosclerosis, occlusive thromboangiitis, acute arterial closure, embolism, congenital arteriovenous tumors, vasospastic diseases, rayaud's disease, cyanosis of hands and feet, acute venous closure, thrombophlebitis, varicose veins, and lymphedema.
As used herein, "autonomic reflex pain" refers to pain caused by "reflex sympathetic atrophy. Reflex sympathetic atrophy refers to severe spontaneous pain after acute and chronic injury, and can be accompanied by edema and blood circulation disorder, and skin and musculoskeletal nutritional disorder and atrophy.
As used herein, "post-operative pain" refers to a complex physiological response of the body to disease itself and to surgically-induced tissue damage that manifests as an unpleasant experience in both psychological and behavioral aspects.
As used herein, "arthritic pain" includes, but is not limited to, pain resulting from diseases such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthropathy, gout, pseudogout, infectious arthritis, tendinitis, bursitis, bone damage, and joint soft tissue inflammation.
As used herein, "nociceptive pain" is pain caused by a process of tissue damage afferent to a nociceptor, or by prolonged excitation of a nociceptor. Pain caused by prolonged excitation of nociceptors may be due to persistent harmful stimulation of nociceptors or sensitization thereof or both, or they may be caused by these factors and prolonged by their persistence, various reflex mechanisms and other factors.
The term "treatment" refers to therapeutic therapy. When specific conditions are involved, treatment refers to: (1) alleviating a disease or one or more biological manifestations of a disorder, (2) interfering with (a) one or more points in a biological cascade that results in or causes a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of a disorder or one or more biological manifestations of a disorder.
The term "preventing" refers to a reduced risk of acquiring or developing a disease or disorder.
The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat a disease or disorder described herein when administered to a patient. The "therapeutically effective amount" will vary depending on the compound, the condition and severity thereof, and the age of the patient to be treated, but can be adjusted as desired by one of ordinary skill in the art.
The term "patient" refers to any animal, preferably a mammal, most preferably a human, that is about to or has received administration of the compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being preferred.
The invention has the positive progress effects that:
the compound of the invention is used for preparing alpha 2-GABA A Has good affinity activity and allosteric regulation function selectivity, low risk of genetic toxicity and high safety.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1
1-1:1- (4-bromo-3-methoxyphenyl) ethan-1-one O-methyloxime
O-methyl hydroxylamine hydrochloride (145 mg,1.74 mmol), 1- (4-bromo-3-methoxyphenyl) ethan-1-one (200 mg,0.87 mmol), and triethylamine (176 mg,1.74 mmol) were added to absolute ethanol (4 ml) and reacted at 90℃for 2 hours. The reaction was subjected to thin layer chromatography (petroleum ether/ethyl acetate=15/1) to give the title compound as a yellow oil (190 mg, 84.61%). LC-MS: M/z [ M+H ]] + ＝258,260.
1:1- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-pyridin-4-yl) ethan-1-one O-methyloxime
1- (4-bromo-3-methoxyphenyl) ethyl-1-one O-methyloxime (60 mg,0.23 mmol), (5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenyl) boronic acid (67 mg,0.23 mmol), dichloro [1,1' -bis (di-tert-butylphosphine) ferrocene palladium (II) (cas: 95408-45-0, 14mg,0.02 mmol), cesium carbonate (162 mg,0.5 mmol) is added to 1, 4-dioxane/water (5 ml/1 ml). Under the protection of argon, the reaction is carried out for 4 hours at 100 ℃. The reaction solution was purified by direct thin layer chromatography (dichloromethane/methanol=20/1) to give the title compound as a pale yellow solid (14 mg, 14.51%).
1 HNMR(400MHz,CHLOROFORM-d)d＝9.37(br.s.,1H),8.33-8.16(m,3H),7.37(d,J＝3.4Hz,2H),7.34-7.28(m,2H),4.58(q,J＝7.2Hz,2H),4.04(s,3H),3.89(s,3H),2.28(s,3H),1.69(br.s.,3H).LC-MS:m/z[M+H] + ＝420.
Example 2
2-1:3- (3-bromo-5-fluoro-2-methoxyphenyl) oxazolidin-2-one
Chloroethyl chloroformate (160 mg,1.14 mmol), 3-bromo-5-fluoro-2-methoxyaniline (260 mg,0.95 mmol) was added to dichloromethane (5 ml), and pyridine (90 mg,1.14 mmol) was slowly added to the reaction solution, and stirred at room temperature for 2 hours. After the reaction mixture was concentrated to dryness, cesium carbonate (541 mg,1.66 mmol) was added to N, N-dimethylformamide (2 ml) and reacted at 90℃for 4 hours. The reaction was subjected to thin layer chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound as a yellow oil (230 mg, 69.57%). LC-MS: M/z [ M+H ]] + ＝272,274.
2:3- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2', 5-difluoro-2-methoxy- [1,1' ] p Biphenyl]-3-yl) oxazolidin-2-one
Experimental procedure Using 3- (3-bromo-5-fluoro-2-methoxyphenyl) oxazolidin-2-one (60 mg,0.21 mmol) as raw material gave the title compound as a pale yellow solid (14 mg, 14.77%). LC-MS: M/z [ M+H)] + ＝452. 1 H NMR(400MHz,CHLOROFORM-d)d＝9.38(s,1H),8.34-8.28(m,3H),7.39(s,1H),7.32(d,J＝8.8Hz,1H),7.11(d,J＝8.3Hz,1H),4.63-4.52(m,4H),4.12(t,J＝7.6Hz,2H),3.53(s,3H),1.70(t,J＝6.8Hz,3H).
Example 3
3-1:3- (3-bromo-2-methoxyphenyl) oxazolidin-2-one
Experimental procedure Using 3-bromo-2-methoxyaniline (380 mg,1.88 mmol) as the starting material, the title compound was obtained as a yellow oily liquid (200 mg, 59.76%). LC-MS: M/z [ M+H)] + ＝272,274.
3:3- (5' - (7-ethyl-7H-imidazo [4, 5-c) ]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-3-yl) oxazolidin-2-one
The procedure was as in example 1, starting from 3- (3-bromo-2-methoxyphenyl) oxazolidin-2-one (80 mg,0.29 mmol) to give the title compound as a pale yellow solid (14 mg, 11.30%). LC-MS: M/z [ M+H ]] + ＝434. 1 H NMR(400MHz,CHLOROFORM-d)d＝9.39(s,1H),8.29(br.s.,3H),7.52(d,J＝7.8Hz,1H),7.41-7.35(m,2H),7.30(br.s.,1H),4.62-4.53(m,4H),4.10(t,J＝7.8Hz,2H),3.58(s,3H),1.69(t,J＝7.3Hz,3H).
Example 4
4-1: 1-bromo-4-iodo-2- (methoxymethyl) benzene
(2-bromo-5-iodophenyl) methanol (10 g,31.96 mmol) was added to tetrahydrofuran (50 mL), then sodium hydride (1.5 g,63.9 mmol) was added to the reaction system, stirred at room temperature for 0.5 hours, then methyl iodide (9.0 g,63.9 mmol) was added, and stirred at room temperature for 3 hours. To the reaction solution was added 100ml of water, followed by extraction with ethyl acetate (3×200 ml), which was washed once with saturated brine, and then dried over anhydrous sodium sulfate, and concentrated to give the title compound (10 g, 95.7%) as a yellow oil.
4-2:7- (4-bromo-3- (methoxymethyl) phenyl) -5,6,7, 8-tetrahydroimidazo [1,2-a]Pyrazine compounds
1-bromo-4-iodo-2- (methoxymethyl) benzene (200 mg,0.61 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (70 mg,0.12 mmol), tris (dibenzylideneacetone) dipalladium (35 mg,0.061 mmol), cesium carbonate (596 mg,1.83 mmol), 5,6,7, 8-tetrahydroimidazo [1,2-a ]]Pyrazine (150 mg,1.22 mmol) was added to 1, 4-dioxane (10 ml) and stirred overnight at 100 ℃. The reaction solution was concentrated directly, and then purified by thin layer chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (120 mg, 61%) as a yellow oil. LC-MS: M/z [ M+H ] ] + ＝322.
4:4- (4' - (5, 6-dihydroimidazo [1, 2-a)]Pyrazin-7 (8H) -yl) -6-fluoro-2' - (methoxymethyl) - [1, 1' -biphenyls]-3-yl) -7-ethyl-7H-imidazo [4,5-c]Pyridazine (PYRIZE)
The procedure was as in example 1, starting from 7- (4-bromo-3- (methoxymethyl) phenyl) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyrazine (120 mg,0.37 mmol) to give the title compound (46 mg, 24.01%) as a yellow solid.
1 H NMR(400MHz,CHLOROFORM-d)d ppm 1.72-1.80(m,3H)3.29(br.s.,3H)3.80(br.s.,2H)4.17(br.s.,2H)4.35(br.s.,2H)4.56(d,J＝6.85Hz,2H)4.71(br.s.,2H)6.84-7.04(m,2H)7.19-7.32(m,4H)8.13(d,J＝4.40Hz,1H)8.26(br.s.,2H)9.34(br.s.,1H)，LC-MS:m/z[M+H] + ＝484
Example 5
5-1:7- (4-bromo-3- (methoxymethyl) phenyl) -3-methyl-5, 6,7, 8-tetrahydro- [1,2,4]The amino acid sequence of the triazolo [ 4], 3-a]pyrazine compounds
Experimental procedures were carried out in the same manner as in 4-2 Synthesis example 4, using 3-methyl-5, 6,7, 8-tetrahydro- [1,2,4]Triazolo [4,3-a ]]Pyrazine (169 mg,1.22 mmol) was found to beStarting material, the title compound (200 mg, 97.23%) was obtained as a yellow oil. LC-MS: M/z [ M+H ]] + ＝337.
5:7- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2' -fluoro-2- (methoxymethyl) - [1, 1' -biphenyls]-4-yl) -3-methyl-5, 6,7, 8-tetrahydro- [1,2,4]Triazolo [4,3-a ]]Pyrazine compounds
The experimental procedure was as in example 1 starting from 7- (4-bromo-3- (methoxymethyl) phenyl) -3-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine (180 mg,0.53 mmol) to give the title compound (40 mg, 13.31%) as a brown solid.
1 H NMR(400MHz,CHLOROFORM-d)d ppm 1.71-1.84(m,3H)2.46(s,3H)3.33(s,3H)3.79-3.87(m,2H)4.02(d,J＝4.40Hz,2H)4.38(s,2H)4.59(q,J＝7.34Hz,2H)4.68(s,2H)7.00(d,J＝8.80Hz,1H)7.27-7.28(m,1H)7.29-7.40(m,2H)8.15(d,J＝6.85Hz,1H)8.28(s,2H)9.37(s,1H)，LC-MS:m/z[M+H] + ＝499
Example 6
6-1:3- (4-bromo-3- (methoxymethyl) phenyl) -1, 3-oxazinan-2-one
Experimental procedure the same 4-2 synthesis as in example 4 was used to give the title compound (150 mg, 81.9%) as LC-MS/M/z [ M+H ] from 1-bromo-4-iodo-2- (methoxymethyl) benzene (200 mg,0.61 mmol) and 1, 3-oxazahex-2-one (122 mg,1.22 mmol)] + ＝300
6:3- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2' -fluoro-2- (methoxymethyl) - [1, 1' -biphenyls]-4-yl) -1, 3-oxazinan-2-1
The procedure was as in example 1, starting from 3- (4-bromo-3- (methoxymethyl) phenyl) -1, 3-oxazinan-2-one (140 mg,0.47 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (209 mg,0.56 mmol) the title compound (58 mg, 25.7%) was obtained.
1 H NMR(400MHz,CHLOROFORM-d)1.66(t,J＝7.34Hz,3H)2.21-2.25(m,2H)3.30(s,3H)3.80(t,J＝5.87Hz,2H)4.37(s,2H)4.44(t,J＝5.14Hz,2H)4.54-4.59(m,2H)7.30-7.35(m,1H)7.37(s,2H)7.57(s,1H)8.19(d,J＝6.85Hz,1H)8.24-8.33(m,2H)9.35(s,1H).LC-MS:m/z[M+H] + ＝462
Example 7
7-1:4- (4-bromo-3- (methoxymethyl) phenyl) -1-methylpiperazin-2-one
Experimental procedure the synthesis of 4-2 in example 4 was followed using 1-bromo-4-iodo-2- (methoxymethyl) benzene (200 mg,0.61 mmol) and 1-methylpiperazin-2-one (139 mg,1.22 mmol) as starting material to give the title compound (120 mg, 62.8%) as LC-MS/M/z [ M+H] + ＝313
7:4- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2' -fluoro-2- (methoxymethyl) - [1, 1' -biphenyls]-4-yl) -1-methylpiperazin-2-one
Experimental procedure Using 4- (4-bromo-3- (methoxymethyl) phenyl) -1-methylpiperazine-2-1 (120 mg,0.38 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ]Pyridazine (140 mg,0.38 mmol) was used as the starting material to give the title compound (11 mg, 5.48%). LC-MS: M/z [ M+H ]] + ＝475
1 H NMR(400MHz,CHLOROFORM-d)ppm 1.68-1.73(m,3H)3.07(s,3H)3.32(s,3H)3.45-3.65(m,4H)3.98(s,2H)4.37(s,2H)4.58(d,J＝7.34Hz,2H)6.90(d,J＝7.34Hz,1H)7.14(br.s.,1H)7.28-7.38(m,2H)8.14(d,J＝5.87Hz,1H)8.27(br.s.,2H)9.37(s,1H)
Example 8
8-1: 4-bromo-3- (methoxymethyl) benzoic acid
Methyl 4-bromo-3- (methoxymethyl) benzoate (200 mg,0.77 mmol) was dissolved in 10mL ethanol, 4M aqueous sodium hydroxide (10 mL) was added and stirred at room temperature for 2 hours, water was added for dilution, 1M hydrochloric acid was used for neutralization, and the solid was filtered and dried to give the title compound (150 mg, 79%) as a white solid. LC-MS: M/z [ M+H ]] + ＝245.
8-2: 4-bromo-3- (methoxymethyl) -N, N-dimethylbenzamide
4-bromo-3- (methoxymethyl) benzoic acid (150 mg,0.61 mmol), HATU (463 mg,1.2 mmol), dimethylamine hydrochloride (100 mg,1.5 mmol) and DIPEA (1 mL) were added sequentially to 10mL of dichloromethane, followed by stirring at room temperature for 2 hours. Purification of the plates (dichloromethane: methanol=20:1) was prepared by washing with saturated aqueous ammonium chloride and drying to give the title compound (120 mg, 72%) as a colourless liquid. LC-MS: M/z [ M+H ]] + ＝272.
8:5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2' -fluoro-2- (methoxymethyl) -N, N-dimethyl Base- [1,1' -biphenyl]-4-carboxamide
The procedure was as in example 3 starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (150 mg,0.41 mmol) and 4-bromo-3- (methoxymethyl) -N, N-dimethylbenzamide (110 mg,0.41 mmol) to give the title compound (94 mg, 53%) as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.37(s,1H)8.27-8.37(m,2H)8.19(dd,J＝6.85,1.96Hz,1H)7.67(s,1H)7.43-7.49(m,1H)7.32-7.42(m,2H)4.58(q,J＝7.17Hz,2H)4.40(s,2H)3.30(s,3H)3.04-3.19(m,6H)1.68(t,J＝7.34Hz,3H).LC-MS:m/z[M+H] + ＝434.
Example 9
9-1:1- (4-bromo-3- (methoxy)Methyl) phenyl) pyrrolidin-2-one
Experimental procedure the synthesis of 4-2 from example 4 was followed using 1-bromo-4-iodo-2- (methoxymethyl) benzene (200 mg,0.61 mmol) and 2-pyrrolidone (104 mg,1.22 mmol) as starting material to give the title compound (100 mg, 57.69%) as LC-MS/M/z [ M+H] + ＝284
9:1- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2' -fluoro-2- (methoxymethyl) - [1, 1' -biphenyls]-4-yl) pyrrolidin-2-one
The procedure was as in example 1 starting from 1- (4-bromo-3- (methoxymethyl) phenyl) pyrrolidin-2-one (100 mg,0.35 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (130 mg,0.35 mmol) to give the title compound (27.4 mg, 16%) as white solid in appearance.
1 H NMR(400MHz，DMSO-d6)1.51-1.58(m，3H)2.05-2.14(m，2H)2.53-2.57(m，2H)3.16(s，3H)3.86-3.93(m,2H)4.30-4.35(m,2H)4.46-4.54(m,2H)7.34-7.38(m,1H)7.50-7.58(m,1H)7.67-7.72(m,1H)7.83-7.86(m,1H)8.43-8.53(m,2H)8.83-8.87(m,1H)9.54-9.57(m,1H).LC-MS:m/z[M+H] + ＝446
Example 10
10-1:1- (4-bromo-3- (methoxymethyl) phenyl) -3-methylimidazolin-2-one
Experimental procedure the synthesis of 4-2 in example 4 was followed using 1-bromo-4-iodo-2- (methoxymethyl) benzene (200 mg,0.61 mmol) and 1-methyl-2-imidazolidinone (122 mg,1.22 mmol) as starting material to give the title compound (100 mg, 54.8%) as LC-MS/M/z [ M+H] + ＝299
10:1- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2' -fluoro-2- (methoxymethyl) - [1, 1' -biphenyls]-4-yl) -3-methylimidazolin-2-one
Experimental procedure Using 1- (4-bromo-3- (methoxymethyl) phenyl) -3-methylimidazolin-2-one (100 mg,0.35 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (130 mg,0.35 mmol) as starting material, the title compound (10.5 mg, 6.2%) was obtained as a white solid in appearance.
1 H NMR(400MHz,DMSO-d 6 )1.54(s,3H)2.79(s,3H)3.16(s,3H)3.43-3.51(m,2H)3.81-3.89(m,2H)4.31(s,2H)4.46-4.54(m,2H)7.27-7.34(m,1H)7.49-7.56(m,1H)7.59-7.64(m,1H)7.73-7.78(m,1H)8.41-8.51(m,2H)8.83-8.88(m,1H)9.52-9.57(m,1H).LC-MS:m/z[M+H] + ＝461
Example 11
11-1:3- (4-bromo-3- (methoxymethyl) phenyl) oxazolidin-2-one
Experimental procedure the synthesis of 4-2 from example 4 was followed using 1-bromo-4-iodo-2- (methoxymethyl) benzene (200 mg,0.61 mmol) and 2-oxazolidinone (104 mg,1.22 mmol) as starting material to give the title compound (100 mg, 57.3%) as LC-MS/M/z [ M+H] + ＝286
11:3- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2' -fluoro-2- (methoxymethyl) - [1, 1' -biphenyls]-4-yl) oxazolidin-2-one
Experimental procedure Using 3- (4-bromo-3- (methoxymethyl) phenyl) oxazolidin-2-one (100 mg,0.35 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (130 mg,0.35 mmol) as starting material gave the title compound (51 mg, 32.4%).
1 H NMR(400MHz,DMSO-d 6 )1.54(t,J＝7.09Hz,3H)3.17(s,3H)4.13(t,J＝8.07Hz,2H)4.33(s,2H)4.43-4.54(m,4H)7.38(d,J＝8.31Hz,1H)7.54(s,1H)7.60(dd,J＝8.31,1.96Hz,1H)7.76(s,1H)8.45(d，J＝7.34Hz，2H)8.86(s，1H)9.55(s，1H).LC-MS:m/z[M+H] + ＝448
Example 12
12-1:1- (4-bromo-3-methoxyphenyl) pyrrolidin-2-one
Experimental procedure the same as in example 4, 4-2, 2-bromo-5-iodoanisole (CAS: 755027-18-0 200mg,0.64 mmol) was used as starting material to give pyrrolidin-2-one (54 mg,0.64 mmol) as the title compound (130 mg, 75%) as yellow solid.
12:1- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) pyrrolidin-2-one
The procedure was as in example 1 starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (150 mg,0.41 mmol) and 1- (4-bromo-3-methoxyphenyl) pyrrolidin-2-one (110 mg,0.41 mmol) to give the title compound (10 mg, 6%) as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.37(s,1H)8.27(s,2H)8.20(d,J＝5.38Hz,1H)7.76(s,1H)7.33-7.41(m,2H)7.03(d,J＝7.83Hz,1H)4.58(q,J＝7.17Hz,2H)3.95(t,J＝6.85Hz,2H)3.87(s,3H)2.67(t,J＝8.07Hz,2H)2.17-2.26(m,2H)1.70(t,J＝7.09Hz,3H).LC-MS:m/z[M+H] + ＝432.
Example 13
13-1:1- (4-bromo-3-methoxyphenyl) -3-methylimidazolin-2-one
Experimental procedure the same as in example 4 for the synthesis of 4-2 using 2-bromo-5-iodoanisole (CAS: 755027-18-0 200mg,0.64 mmol) and 1-methylimidazoline-2-one (77 mg,0.77 mmol) as starting material gave the title compound (130 mg, 71%) as a yellow solid.
13:1- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) -3-methylimidazolidin-2-one
The procedure was as in example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (150 mg,0.41 mmol) and 1- (4-bromo-3-methoxyphenyl) -3-methylimidazolin-2-one (120 mg,0.41 mmol) to give the title compound (98 mg, 53%) as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.37(s,1H)8.22-8.30(m,2H)8.14-8.21(m,1H)7.89(s,1H)7.28-7.36(m,2H)6.81(d,J＝6.85Hz,1H)4.58(q,J＝7.01Hz,2H)3.85-3.91(m,2H)3.53(t,J＝8.07Hz,2H)2.94(s,3H)1.69(t,J＝7.34Hz,3H).LC-MS:m/z[M+H] + ＝447.
Example 14
14-1:3- (4-bromo-3-methoxyphenyl) oxazolidin-2-one
Experimental procedure the same as in example 4 for the synthesis of 4-2 using 2-bromo-5-iodo-anisole (CAS: 755027-18-0 200mg,0.64 mmol) and 1, 3-oxazolidin-2-one (75 mg,0.77 mmol) as starting material gave the title compound (120 mg, 69%) as a yellow solid.
14:3- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) oxazolidin-2-one
Experimental procedure is as in example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (150 mg,0.41 mmol) and 3- (4-bromo-3-methoxyphenyl) oxazolidin-2-one (110 mg,0.41 mmol) to give the title compound (70 mg, 40%) as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δppm 9.33-9.41(m,1H)8.23-8.31(m,2H)8.20(d,J＝6.85Hz,1H)7.69(s,1H)7.36(t,J＝8.07Hz,2H)6.91(d,J＝6.85Hz,1H)4.56-4.63(m,2H)4.51-4.56(m,2H)4.14(t,J＝8.07Hz,2H)3.88(s,3H)1.70(t,J＝7.34Hz,3H).LC-MS:m/z[M+H] + ＝434.
Example 15
15-1: 2-fluoro-6-methoxypyridin-4-amine
2, 6-Difluoropyridin-4-amine (5 g,38.43 mmol) was added to tetrahydrofuran (100 ml), and sodium methoxide methanol solution (9.2 mL,5N,46.12 mmol) was added to the reaction system and stirred at room temperature overnight. The reaction solution was filtered, concentrated, and purified by column chromatography (PE: ea=10:1-1:1) to give the title compound (4.1 g, yield 75%) as an off-white solid. LC-MS M/z [ m+h ] +=143.0
15-2: 3-bromo-6-fluoro-2-methoxypyridin-4-amine
2-fluoro-6-methoxypyridin-4-amine (3.6 g,25.33 mmol), NBS (5.41 g,30.39 mmol) was added to dichloromethane (100 mL), stirred at room temperature under nitrogen for 3h, the reaction solution was poured into aqueous sodium bicarbonate (100 mL), extracted with ethyl acetate (100 mL x 3), concentrated, and purified by column chromatography (PE: EA=10:1-1:1) to give the title compound (3 g, yield 53%) as an off-white solid. LC-MS: M/z [ M+H ] ] + ＝221.0
15-3: 3-bromo-6- (ethylsulfanyl) -2-methoxypyridin-4-amine
3-bromo-6-fluoro-2-methoxypyridin-4-amine (0.5 g,2.26 mmol), sodium ethanethiol (0.57 g,6.79 mmol) were added to DMF (5 mL), the reaction solution was stirred for 3h at 120℃under microwave, poured into aqueous sodium bicarbonate (100 mL), extracted with ethyl acetate (30 mL x 3), concentrated, and purified by column chromatography (DCM: meOH=100:1-10:1) to give the title compound (0.283 g, 15% yield) as an off-white solid. LC-MS: M/z [ M+H ]] + ＝263.0
15-4: 3-bromo-6- (ethylsulfanyl) -4-fluoro-2-methoxypyridine
3-bromo-6- (ethylsulfanyl) -2-methoxypyridin-4-amine (0.2 g,0.76 mmol) was dissolved in pyridine hydrofluoric acid solution (20 mL), and stirred at 0deg.C for 15 minutes, to the reaction solution was added an aqueous solution (2 mL) of sodium nitrite (0.1 g,1.52 mmol), and the reaction was stirred at room temperature for 3 days. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL x 3), concentrated, and purified by column chromatography (DCM: meoh=100:1-10:1) to give the title compound (0.116 g, yield 55%) as an off-white solid. LC-MS M/z [ m+h ] += 266.0
15-5: 3-bromo-6- (ethylsulfonyl) -4-fluoro-2-methoxypyridine
3-bromo-6- (ethylsulfanyl) -4-fluoro-2-methoxypyridine (0.116 g,0.44 mmol), potassium monopersulfate (1.34 g,2.2 mmol) was added to a mixed solution of water (3 mL), methanol (2 mL) and tetrahydrofuran (4 mL), stirred at room temperature for 17h, the reaction solution was poured into an aqueous solution (20 mL), extracted with ethyl acetate (30 mLx 3), and dried and concentrated to give the title compound (80 mg, yield 62%) as an off-white solid. LC-MS: M/z [ M+H ] ] + ＝298.0
15: 7-ethyl-4- (3- (6- (ethylsulfonyl) -4-fluoro-2-methoxypyridin-3-yl) -4-fluorophenyl) -7H-o-f- Imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using as in example 1 starting from 3-bromo-6- (ethylsulfonyl) -4-fluoro-2-methoxypyridine (50 mg,0.17 mmol) and (5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenyl) boronic acid (48 mg,0.17 mmol), the title compound (20 mg, 25%) is obtained as a white solid.
1 H NMR(400MHz,CDCl 3 )δ：9.41(s,1H),8.46–8.35(m,1H),8.34–8.23(m,2H),7.38(t,1H),7.29(t,1H),4.58(q,2H),3.93(s,3H),3.10–2.94(m,1H),2.92–2.80(m,1H),1.69(dd,3H),1.21(t,3H).LC-MS:m/z[M+H] + ＝460.
Example 16
16: 7-ethyl-4- (4-fluoro-3- (5- (trifluoromethyl) pyridin-2-yl)) Phenyl) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using as in example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (120 mg,0.33 mmol) and 2-bromo-5- (trifluoromethyl) pyridine (74 mg,0.33 mmol), the title compound (54 mg, 40.94%) is obtained as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)d＝9.46(s,1H),9.05(s,1H),8.97(d,J＝7.3Hz,1H),8.43-8.35(m,1H),8.32(s,1H),8.05(s,2H),7.47-7.39(m,1H),4.61(q,J＝7.3Hz,2H),1.71(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝388.
Example 17
17: 7-ethyl-4- (4-fluoro-3- (2- (trifluoromethyl) pyrimidin-5-yl) phenyl) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
The procedure was as in example 1 starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (140 mg,0.38 mmol) and 5-bromo-2- (trifluoromethyl) pyrimidine (86 mg,0.38 mmol) to give the title compound as a pale yellow solid (33 mg, 21.86%).
1 H NMR(400MHz,CHLOROFORM-d)d＝9.41(s,1H),9.21(s,2H),8.61(d,J＝5.4Hz,1H),8.31(s,2H),7.49(t,J＝9.5Hz,1H),4.64-4.58(m,2H),1.71(t,J＝7.1Hz,3H).LC-MS:m/z[M+H] + ＝389.
Example 18
18: 7-ethyl-4- (4-fluoro-3- (4- (trifluoromethyl) pyridin-2-yl) phenyl) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
The procedure was as in example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (100 mg,0.27 mmol) and 2-bromo-4- (trifluoromethyl) pyridine (61 mg,0.27 mmol) to give the title compound as a pale yellow solid (54 mg, 50.88%).
1 H NMR(400MHz,CHLOROFORM-d)d＝9.45(s,1H),9.02-8.84(m,2H),8.37(br.s.,1H),8.31(s,1H),8.11(s,1H),7.54(d,J＝4.4Hz,1H),7.42(t,J＝9.8Hz,1H),4.60(q,J＝7.3Hz,2H),1.70(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝388.
Example 19
19-1: 7-ethyl-4- (4-fluoro-3- ((3-nitropyridin-2-yl) oxy) phenyl) -7H-imidazo [4,5-c]Pyridazine (Da) Oxazine
5- (7-Ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenol (100 mg,0.39 mmol), cesium carbonate (381 mg,1.17 mmol) and 2-fluoro-3-nitropyridine (90 mg,0.43 mmol) are added to DMF (3 mL) and stirred overnight at 80 ℃. The reaction was purified by plate separation (petroleum ether/ethyl acetate=1/1) to give the title compound (50 mg, 36.9%).
19-2:2- (5- (7-ethyl 7H imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenoxy) pyridin-3-amine
7-ethyl-4- (4-fluoro-3- ((3-nitropyridin-2-yl) oxy) phenyl) -7H-imidazo [4,5-c]Pyridazine (40 mg,0.11 mmol), pd/C (20 mg) was added to methanol (2 mL) and ethyl acetate (2 mL) H 2 Stir at 35 ℃ for two hours. The reaction was directly purified by prep. plate separation (dichloromethane/methanol=20/1) to give the title compound (16 mg, 43.5%).
19: n- (2- (5- (7-ethyl-7H-imidazo [4, 5-c))]Pyridazin-4-yl) -2-fluorophenoxy) pyridin-3-yl) ethan Sulfonamide compounds
2- (5- (7-Ethyl 7H imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenoxy) pyridin-3-amine 6-bromo-7-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinoline (16 mg,0.05 mmol), pyridine (59.3 mg,0.25 mmol) and ethylcarbamoyl chloride (12.8 mg,0.1 mmol) were added to chloroform (2/0.5 mL) and stirred overnight at 90 ℃. The reaction was concentrated, extracted three times with ethyl acetate and water, and the organic phase was concentrated to give the title compound (5 mg, 22.6%) as a plate for purification (dichloromethane/methanol=30/1).
1 HNMR(400MHz,METHANOL-d 4 )9.38(s,1H),8.73(s,1H),8.33(dd,J＝2.0,7.3Hz,1H),8.22(ddd,J＝2.2,4.3,8.7Hz,1H),7.96(dd,J＝1.5,7.8Hz,1H),7.88-7.80(m,1H),7.54-7.42(m,1H),7.12(dd,J＝4.9,7.8Hz,1H),4.61-4.56(m,2H),3.21(q,J＝7.3Hz,2H),1.63(t,J＝7.3Hz,3H),1.42(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝443.
Example 20
20-1: 4-bromo-3-fluorobenzenesulfonyl hydrazides
4-bromo-3-fluorobenzenesulfonyl chloride (2.0 g,7.31 mmol) was dissolved in tetrahydrofuran (20.0 mL) and cooled to 0deg.C, hydrazine hydrate (1.25 mL,25.59 mmol) was slowly added to the reaction solution at 0deg.C, reacted at room temperature for 16h, concentrated to give a crude product which was slurried with petroleum ether and filtered to give the title product (1.77 g, white solid) in 89.9% yield of LCMS MS m/z (ESI): 269.0[ M+1]
20-2: 1-bromo-4- (ethylsulfonyl) -2-fluorobenzene
4-bromo-3-fluorobenzenesulfonyl hydrazine (2.66 g,9.93 mmol), iodoethane (3.97 mL,49.63 mmol), sodium acetate (4.89 g,59.58 mmol) were dissolved in ethanol (80.0 mL) and reacted at 80℃for 16h after concentration to give a crude product which was purified by silica gel column (PE: EA) to give the title product (1.90 g, white solid) in 71.4% yield. 1 H NMR(400MHz,CDCl 3 )δ7.80(m,1H),7.66(m,1H),7.58(m,1H),3.13(q,J＝7.4Hz,2H),1.36–1.26(m,3H).LCMS m/z(ESI):267.0[M+1].
20-3:1- (2-bromo-5- (ethylsulfonyl) phenyl) azetidine
1-bromo-4- (ethyl)By dissolving phenylsulfonyl) -2-fluorobenzene (500.0 mg,1.87 mmol), diisopropylethylamine (0.5 mL) in DMSO (5.0 mL) and azetidine (106.8 mg,1.87 mmol) was added and microwaved at 150℃under nitrogen for 1h the reaction was poured into water (50 mL), extracted with ethyl acetate (50 mLx 3) and concentrated to give crude product which was purified in reverse phase (0.5% HCOOH-acetonitrile) to give the title product (241.5 mg, white solid) in 42.4% yield. 1 H NMR(400MHz,DMSO-d 6 )δ7.67(d,J＝8.2Hz,1H),7.09(dd,J＝8.2,2.0Hz,1H),6.89(d,J＝2.0Hz,1H),4.10(t,J＝7.4Hz,4H),3.30–3.25(m,2H),2.34–2.14(m,2H),1.10(t,J＝7.4Hz,3H).LCMS MS m/z(ESI):304[M+1].
20:4- (2 ' - (azetidin-1-yl) -4' - (ethylsulfonyl) -6-fluoro- [1,1' -biphenyl)]3-yl) -7- ethyl-7H-imidazo [4,5-c ]]Pyridazine (PYRIZE)
The experimental procedure was as in example 1, starting from 1- (2-bromo-5- (ethylsulfonyl) phenyl) azetidine (160.0 mg,0.53 mmol) and (5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenyl) boronic acid (151.6 mg,0.53 mmol), to give the title product (80.1 mg, white solid) in 32.6% yield.
1 H NMR(400MHz,DMSO)δ9.57(s,1H),8.87(s,1H),8.62–8.38(m,2H),7.55(t,1H),7.40(d,1H),7.27(m,1H),6.94(d,1H),4.52(q,J＝7.3Hz,2H),3.57(m,4H),3.35(m,2H),2.09(m,2H),1.55(t,J＝7.3Hz,3H),1.18(t,J＝7.3Hz,3H).LCMS:m/z(ESI):466.1[M+1].
Example 21
21-1: 3-bromo-6- (ethylsulfonyl) pyridin-2-ol
3-bromo-6- (ethylsulfonyl) -2-methoxypyridine (1 g,3.57 mmol) was added to 5mL of concentrated hydrochloric acid, and the mixture was heated to 110℃with microwaves and reacted for 1h. The reaction solution was cooled to room temperature, concentrated, and the solid was washed with saturated sodium bicarbonate and dried to give the title compound (300 mg, yield 32%). LC-MS: M/z [ M+H ] ] + ＝266
21-2: 3-bromo-2- (difluoromethoxy) -6- (ethylsulfonyl) pyridine
3-bromo-6- (ethylsulfonyl) pyridin-2-ol (250 mg,0.94 mmol) was added to acetonitrile (20 ml), 2-difluoro-2- (fluorosulfonyl) acetic acid (334.59 mg,1.88 mmol) and sodium sulfate (146.80 mg,1.13 mmol) were added to the reaction system and stirred at room temperature overnight. The reaction solution was filtered, concentrated, and purified by column chromatography (PE: ea=3:1) to give the title compound (330 mg, yield 92.59%). LC-MS: M/z [ M+H ]] + ＝316
21:4- (3- (2- (difluoromethoxy) -6- (ethylsulfonyl) pyridin-3-yl) -4-fluorophenyl) -7-ethyl-7H- Imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure is as in example 1 with 3-bromo-2- (difluoromethoxy) -6- (ethylsulfonyl) pyridine (130 mg,0.41 mmol) and (5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenyl) boronic acid (117.66 mg,0.41 mmol) was used as a starting material to give the title compound as a white solid (100 mg, yield 51.13%). LC-MS: M/z [ M+H ]] + ＝477.9。 1 H NMR(400MHz,DMSO-d 6 )δ：9.58(s,1H),8.90(s,1H),8.73–8.57(m,2H),8.44(d,1H),8.08(d,1H),7.68-7.90(m,2H),4.53(q,J＝7.3Hz,2H),3.59(q,J＝7.4Hz,2H),1.57(t,J＝7.3Hz,3H),1.24(t,J＝7.4Hz,3H).
Example 22
22-1:2- (ethylthio) -3, 6-difluoropyridine
2,3, 6-trifluoropyridine (5.0 g,37.6 mmol), ethanethiol (3.08 g,37.6 mmol), dissolved in DMF (30.0 mL) sodium hydride (1.58 g,37.6mmol,60% dispersed in mineral oil) was added portionwise at room temperature, reacted for 3 hours, the reaction solution poured into water (100 mL), extracted with ethyl acetate (100 mL. Times.3), concentrated and purified by column chromatography (PE: EA=10:1) to give a clear liquid (4.0 g, 60.8% yield). LCMS: m/z (ESI): 176[ M+H ] ]. 1 H NMR(400MHz,DMSO-d 6 )δ7.84(td,J＝8.6,6.1Hz,1H),6.96(dt,J＝8.6,3.0Hz,1H),3.14(q,J＝7.3Hz,2H),1.31(t,J＝7.3Hz,3H).
22-2:2- (ethylthio) -3, 6-difluoro-5-iodopyridine
2- (ethylthio) -3, 6-difluoropyridine (300 mg,1.71 mmol) was dissolved in anhydrous tetrahydrofuran (5.0 mL), and lithium diisopropylamide (2 mL,2.0mmol,1 mol/L) was added dropwise at-78℃for 1.5 hours. Iodine (473 mg,1.87 mmol) in tetrahydrofuran (2 mL) was added dropwise at low temperature, the reaction solution was transferred to room temperature and reacted for 0.5 hours, and the reaction solution was poured into water (50 mL). Extraction with ethyl acetate (50 ml x 3) gave after concentration the crude product, which after purification gave the title product (200 mg, 38.9% yield). LCMS M/z (ESI) [ M+H ]] + ＝302
22-3: 7-ethyl-4- (3- (6- (ethylsulfanyl) -2, 5-difluoropyridin-3-yl) -4-fluorophenyl) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
The procedure was as in example 1, starting from 2- (ethylsulfanyl) -3, 6-difluoro-5-iodopyridine (300 mg,1.0 mmol) and (5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenyl) boronic acid (284 mg,1.0 mmol) to give a grey solid (150 mg, 36.1% yield).
LCMS:m/z(ESI)415.9[M+1]. 1 H NMR(400MHz,DMSO-d 6 )δ9.61(s,1H),8.91(s,1H),8.73–8.65(m,1H),8.60(dd,1H),7.68(t,1H),7.41–7.14(m,1H),4.52(q,J＝7.3Hz,2H),3.22(q,J＝7.3Hz,2H),1.56(t,J＝7.2Hz,3H),1.36(t,J＝7.3Hz,3H).
22-4: 7-ethyl-4- (3- (6- (ethylsulfanyl) -5-fluoro-2-methoxypyridin-3-yl) -4-fluorophenyl) -7H-mi-ne Azolo [4,5-c ]]Pyridazine (PYRIZE)
7-ethyl-4- (3- (6- (ethylsulfanyl) -2, 5-difluoropyridin-3-yl) -4-fluorophenyl) -7H-imidazo [4,5-c]Pyridazine (50 mg,0.12 mmol) was dissolved in a mixed solvent of DMF (2 mL) and MeOH (8 mL), and sodium methoxide (7.7 mg,0.14mmol,30% wt) was added thereto and reacted at 10℃for 5 hours. To the reaction was added a few drops of water, the methanol was concentrated off and sent to preparative HPLC to give the grey product (20 mg, 39.0% yield). LCMS M/z (ESI) [ M+H ] ] + ＝428.1
22: 7-ethyl-4- (3- (6- (ethylsulfonyl)) -5-fluoro-2-methoxypyridin-3-yl) -4-fluorophenyl) -7H- Imidazo [4,5-c]Pyridazine (PYRIZE)
7-ethyl-4- (3- (6- (ethylsulfanyl) -5-fluoro-2-methoxypyridin-3-yl) -4-fluorophenyl) -7H-imidazo [4,5-c ] pyridazine (20.0 mg,0.047 mmol) was dissolved in acetic acid (5.0 mL), sodium acetate (10 mg,0.12 mmol) was added dropwise hydrogen peroxide (3.5 mg,0.10 mmol), and the reaction was reacted at 50℃for 16 hours. The reaction solution was concentrated and purified by preparative HPLC to give the white product (2.7 mg, 12.5% yield).
1 H NMR(400MHz,DMSO-d 6 )δ9.57(s,1H),8.87(s,1H),8.73(dd,1H),8.51(d,1H),7.93(s,1H),7.49(d,1H),4.51(d,J＝7.3Hz,2H),3.93(s,3H),3.59(q,J＝7.4Hz,2H),1.56(t,J＝7.2Hz,3H),1.29(t,J＝7.4Hz,3H).LCMS:m/z(ESI)[M+H] + ＝460.
Example 23
23-1:2- ((5-bromo-6-methoxypyridin-2-yl) thio) acetic acid methyl ester
3-bromo-6-chloro-2-methoxypyridine (CAS: 1211526-62-3 900mg,4 mmol) was dissolved in 10mL DMF, methyl 2-mercaptoacetate (640 mg,6 mmol) and cesium carbonate (2.6 g,8 mmol) were added, heated to 50deg.C and stirred for 2 hours, diluted with water, extracted with ethyl acetate, and concentrated to give the title compound (300 mg, 25%) as a white solid. LC-MS: M/z [ M+H ]] + ＝292.
23-2:2- ((5-bromo-6-methoxypyridin-2-yl) sulfonyl) acetic acid methyl ester
Methyl 2- ((5-bromo-6-methoxypyridin-2-yl) thio) acetate (300 mg,1 mmol) was dissolved in 10mL of a mixed solution of tetrahydrofuran, water, and methanol (1:2:2), 40% potassium hydrogen persulfate (3 g,5 mmol) was added and stirred at room temperature for 2 hours, diluted with water, extracted with ethyl acetate, and concentrated to give the title compound (350 mg, 100%) as a white solid after plate purification (dichloromethane: methanol=50:1). LC-MS: M/z [ M+H ] ] + ＝324.
23-3: 3-bromo-6- ((difluoromethyl) sulfonyl) -2-methoxypyridine
Methyl 2- ((5-bromo-6-methoxypyridin-2-yl) sulfonyl) acetate (350 mg,1 mmol) was dissolved in 10mL of tetrahydrofuran, NFSI (660 mg,2 mmol), DBU (450 mg,3 mmol) and one drop of water were added and heated to 50 degrees celsius and stirred overnight, diluted with water, extracted with ethyl acetate, and concentrated to give the title compound as a white solid (100 mg, 33%) as a plate purification (petroleum ether: ethyl acetate=10:1). LC-MS: M/z [ M+H ]] + ＝302.
23:4- (3- (6- ((difluoromethyl) sulfonyl) -2-methoxypyridin-3-yl) -4-fluorophenyl) -7-ethyl-7H- Imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (121 mg,0.33 mmol) and 3-bromo-6- ((difluoromethyl) sulfonyl) -2-methoxypyridine (100 mg,0.33 mmol), the title compound (35 mg, 23%) is obtained as a white solid.
1H NMR(400MHz,CHLOROFORM-d)δppm 9.33-9.43(m,1H)8.26-8.38(m,3H)7.86-8.03(m,2H)7.41(t,J＝9.05Hz,1H)6.46-6.79(m,1H)4.60(q,J＝7.34Hz,2H)4.02-4.11(m,3H)1.70(t,J＝7.34Hz,3H).LC-MS:m/z[M+H]+＝464.
Example 24
24: 7-ethyl-4- (4-fluoro-3- (imidazo [1, 2-a)]Pyridin-3-ylmethoxy) phenyl) -7H-imidazo [4, 5-c]pyridazine (PYRIZE)
5- (7-Ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenol (125 mg,0.49 mmol), DIAD (202 mg,1 mmol), triphenylphosphine (262 mg,1 mmol) and imidazo [1,2-a ] pyridin-3-yl-methanol (90 mg,0.61 mmol) are added to a solvent of anhydrous tetrahydrofuran (3 ml) and stirred overnight at 35 ℃. The reaction solution was concentrated to prepare a plate for separation and purification (petroleum ether/ethyl acetate=1/1) to give the title compound (10 mg, 5.3%).
1 H NMR(400MHz,DMSO-d 6 )9.60(s,1H),8.92(s,1H),8.58(d,J＝6.8Hz,1H),8.48(d,J＝7.8Hz,1H),8.12(br.s.,1H),7.88(s,1H),7.66(d,J＝8.3Hz,1H),7.47-7.33(m,2H),7.06(t,J＝6.6Hz,1H),5.75(s,2H),4.54-4.49(m,2H),1.56(t,J＝7.1Hz,3H).LC-MS:m/z[M+H] + ＝389.
Example 25
25-1: 3-bromo-2-chloro-6- (ethylsulfanyl) pyridine
3-bromo-2-chloro-6-fluoropyridine (1.9 g,9.03 mmol), ethanethiol (0.65 mL,9.03 mmol) was dissolved in anhydrous tetrahydrofuran (38.0 mL) and cooled to 0deg.C under nitrogen, 60% sodium hydride (361.2 mg,9.03 mmol) was slowly added to the reaction solution at 0deg.C, warmed to room temperature for 16h, the reaction solution was diluted with ethyl acetate (100 mL), and saturated aqueous sodium chloride solution 50mL was added, extracted with ethyl acetate (100 mLx 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, silica gel column (PE-CH 2 Cl 2 ) Purification gave the title product (1.8 g, yellow oil) in 78.9% yield. 1 H NMR(400MHz,CDCl 3 )δ7.61(d,J＝8.1Hz,1H),6.88(d,J＝8.1Hz,1H),3.17(q,J＝7.4Hz,2H),1.45–1.36(m,3H).LCMS MS m/z(ESI):252.0[M+1].
25-2:2- (azetidin-1-yl) -3-bromo-6- (ethylsulfanyl) pyridine
3-bromo-2-chloro-6- (ethylthio) pyridine (1.5 g,5.94 mmol), azetidine (678.1 mg,11.88 mmol), cesium carbonate (3.87 g,11.88 mmol) were dissolved in acetonitrile (15.0 mL) and reacted at 85℃for 16h the reaction solution was diluted with ethyl acetate (100 mL) and 50mL of saturated aqueous sodium chloride solution was added, extracted with ethyl acetate (100 mLx 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, silica gel column (PE-CH 2 Cl 2 ) Purification gave the title product (1.2 g, yellow oil) in 74.1% yield. 1 H NMR(400MHz,CDCl 3 )δ7.43(d,J＝8.4Hz,1H),6.05(d,J＝8.4Hz,1H),4.08(t,J＝7.5Hz,4H),3.13(q,J＝7.3Hz,2H),2.49–2.33(m,2H),1.38(t,J＝7.3Hz,3H).LCMS MS m/z(ESI):273[M+1].
25-3:2- (azetidin-1-yl) -3-bromo-6- (ethylsulfonyl) pyridine
2- (azetidin-1-yl) -3-bromo-6- (ethylsulfanyl) pyridine (1.5 g,5.49 mmol), m-chloroperoxybenzoic acid (3.34 g,16.47 mmol) were dissolved in 1, 2-dichloroethane (30.0 mL) and reacted at 45℃for 16h the reaction solution was poured into water (50 mL), extracted with dichloromethane (50 mL x 3) and concentrated to give a crude product which was purified in reverse phase (0.5% HCOOH-acetonitrile) to give the title product (112.1 mg, white solid) in 6.7% yield. 1 H NMR(400MHz,DMSO-d 6 )δ7.87(d,J＝8.8Hz,1H),6.54(d,J＝8.8Hz,1H),4.00(t,J＝7.5Hz,4H),3.57(q,J＝7.3Hz,2H),2.41–2.29(m,2H),1.29(t,J＝7.3Hz,3H).LCMS MS m/z(ESI):305[M+1].
25:4- (3- (2- (azetidin-1-yl) -6- (ethylsulfonyl) pyridin-3-yl) -4-fluorophenyl) -7-ethane Base 7H imidazo [4,5-c ]]Pyridazine (PYRIZE)
The experimental procedure was as in example 1 starting from 2- (azetidin-1-yl) -3-bromo-6- (ethylsulfonyl) pyridine (100.0 mg,0.33 mmol) and (5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenyl) boronic acid (93.8 mg,0.33 mmol) to give the title product (73.6 mg, white solid) in 48.2% yield.
1 H NMR(400MHz,DMSO)δ9.51(s,1H),8.86(s,1H),8.53–8.46(m,1H),8.43(m,1H),7.70(d,1H),7.46(t,1H),6.74(d,1H),4.51(q,J＝7.2Hz,2H),4.09(t,J＝7.4Hz,4H),3.43(q,J＝7.3Hz,2H),2.47–2.32(m,2H),1.55(t,J＝7.3Hz,3H),1.17(t,J＝7.3Hz,3H).LCMS MS m/z(ESI):467.1[M+1].
Example 26
26: 7-ethyl-4- (4-fluoro-3- ((1-methyl-1H-imidazol-2-yl) methoxy) phenyl) -7H-imidazo [4,5-c ] pyridazine
4-chloro-7-ethyl-7H-imidazo [4,5-c ] pyridazine (30 mg,0.23 mmol), potassium carbonate (66 mg,0.48 mmol) and 5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenol (40 mg,0.16 mmol) are added to DMF (3 mL) and stirred overnight at 30 ℃. The reaction was directly purified by prep. plate (petroleum ether/ethyl acetate=1/1) to give the title compound (33 mg, 58.9%).
1 H NMR(400MHz,CHLOROFORM-d)9.33(s,1H),8.28(s,1H),8.18(d,J＝7.3Hz,1H),7.82(dt,J＝2.4,4.2Hz,1H),7.26(s,1H),7.04(br.s.,1H),6.94(s,1H),5.36(s,2H),4.58(q,J＝7.3Hz,2H),3.81(s,3H),1.69(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝353.
Example 27
27-1: 2-chloro-4- (ethylthio) pyridine
2-chloro-4-fluoropyridine (300 mg,2.28 mmol), ethanethiol (425 mg,3.84 mmol), and cesium carbonate (1.8 g,5.56 mmol) were added to acetonitrile (6 ml) and stirred at room temperature for 2 hours. The reaction was concentrated, poured into water, extracted with dichloromethane, and the organic phase was concentrated to give the title compound (350 mg, 88.8%).
27-2: 2-chloro-4- (ethylsulfonyl) pyridine
2-chloro-4- (ethylsulfanyl) pyridine (350 mg,2 mmol) and potassium hydrogen persulfate (3.7 g,6 mmol) were added to THF (6 mL), meOH (6 mL) and H 2 O (3 ml) was stirred at room temperature overnight. The reaction solution was filtered, and the supernatant was concentrated to prepare a plate for purification (petroleum ether/ethyl acetate=5/1) to give the title compound (210 mg, 51.2%).
27: 7-ethyl-4- (3- ((4- (ethylsulfonyl) pyridin-2-yl) oxy) -4-fluorophenyl) -7H-imidazo [4,5-c ] pyridazine
2-chloro-4- (ethylsulfonyl) pyridine (25 mg,0.12 mmol), cesium carbonate (117 mg 0.36 mmol) and 5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenol (30 mg,0.12 mmol) were added to DMF (2 ml) and stirred at 100℃for 4 hours. The reaction solution was directly purified by climbing a preparative plate (petroleum ether/ethyl acetate=2/1) to give the title compound (15 mg, 29.4%).
1 H NMR(400MHz,CHLOROFORM-d)9.38(br.s.,1H),8.38(d,J＝5.4Hz,1H),8.32-8.22(m,2H),8.19(br.s.,1H),7.56(s,1H),7.52-7.37(m,2H),4.59(q,J＝7.7Hz,2H),3.21(q,J＝7.3Hz,2H),1.72-1.68(m,3H),1.37(t,J＝7.6Hz,3H).LC-MS:m/z[M+H] + ＝428.
Example 28
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28:2- ((5- (7-ethyl-7H-imidazo [4, 5-c) ]Pyridazin-4-yl) -2-fluorophenoxy) methyl) oxazoles
5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenol (50 mg,0.19 mmol), 2- (chloromethyl) oxazole (CAS: 185246-17-7 45mg,0.4 mmol) and potassium carbonate (60 mg,0.4 mmol) were dissolved in 5mL of DMF and stirred at 80℃for 2 hours. Dilution with water, extraction with dichloromethane, concentration, prep. plate purification (dichloromethane: methanol=20:1) afforded the title compound (20 mg, 31%) as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δppm 9.34(s,1H)8.29(s,1H)8.11(d,J＝7.83Hz,1H)7.86(br.s.,1H)7.73(s,1H)7.32(d,J＝9.78Hz,1H)7.18(s,1H)5.36(s,2H)4.59(q,J＝7.01Hz,2H)1.70(t,J＝7.34Hz,3H).LC-MS:m/z[M+H] + ＝340.
Example 29
29-1: (3-bromo-2-methoxyphenyl) (ethyl) sulfane
1-bromo-3-fluoro-2-methoxybenzene (CAS: 845829-94-9 300mg,1.5 mmol) was dissolved in 10mL of LDMF, ethanethiol (0.3 mL,3 mmol) and cesium carbonate (1 g,3 mmol) were added, stirred overnight at room temperature, cesium carbonate was filtered, diluted with water, extracted with dichloromethane, concentrated, and plate-purified (stone) was preparedOily ether) to give the title compound (50 mg, 14%) as a colourless liquid. LC-MS: M/z [ M+H ]] + ＝247.
29-2: 1-bromo-3- (ethylsulfonyl) -2-methoxybenzene
(3-bromo-2-methoxyphenyl) (ethyl) sulfane (50 mg,0.2 mmol) was dissolved in 10mL of a mixed solution of tetrahydrofuran, methanol and water (2:2:1), 40% potassium hydrogen persulfate (610 mg,1 mmol) was added and stirred at room temperature for 2 hours, diluted with water, extracted with dichloromethane, and concentrated to give the title compound (50 mg, 89%) as a brown liquid. LC-MS: M/z [ M+H ] ] + ＝279.
29: 7-ethyl-4- (3 ' - (ethylsulfonyl) -6-fluoro-2 ' -methoxy- [1,1' -biphenyl)]-3-yl) -7H-imidazole And [4,5-c ]]Pyridazine (PYRIZE)
The experimental procedure was as in example 1 starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (66 mg,0.18 mmol) and 1-bromo-3- (ethylsulfonyl) -2-methoxybenzene (50 mg,0.18 mmol) to give the title compound (19 mg, 24%) as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.39(s,1H)8.22-8.41(m,3H)8.05(d,J＝7.34Hz,1H)7.71(d,J＝7.34Hz,1H)7.36-7.47(m,2H)4.60(q,J＝7.34Hz,2H)3.58(s,3H)3.50(q,J＝7.34Hz,2H)1.70(t,J＝7.34Hz,3H)1.32(t,J＝7.09Hz,3H).LC-MS:m/z[M+H] + ＝441.
Example 30
30-1: 9-ethyl-6- (5-fluoropyridin-2-yl) -9H-imidazo [4,5-c]Pyridazine (PYRIZE)
The compound 4-chloro-7-ethyl-7H-imidazo [4,5-c]Pyridazine (1.8 g,9.86 mmol), (5-fluoropyridin-2-yl) boronic acid (2.0 g,14.79 mmol) and potassium carbonate (4.1 g,29.58 mmol) were added Pd (dppf) Cl under nitrogen in dioxane/water (20 mL/5.mL) 2 (0.7 g,0.98 mmol). The reaction mixture was subjected to a nitrogen atmosphere at 85Stirred at c for 8 hours. The reaction mixture was cooled to room temperature. To the reaction mixture was added water (50 mL) and extracted with DCM (50 mL x 4). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM: meoh=30:1) to give the crude product. The crude product was purified by prep HPLC to give the desired product (490 mg,21% yield) as a yellow solid in appearance.
1 H NMR(400MHz,DMSO-d 6 ):9.80(s,1H),9.14-9.11(m,1H),8.97(s,1H),8.85-8.84(m,1H),8.05-8.00(m,1H),4.53(q,J＝7.2Hz,2H),1.57(t,J＝7.2Hz,3H).MS:m/z＝244.1(M+1,ESI+).
30-2:2- (9-ethyl-9H-imidazo [4, 5-c)]Pyridazin-6-yl) -5-fluoropyridine 1-oxide
9-Ethyl-6- (5-fluoropyridin-2-yl) -9H-imidazo [4,5-c ] pyridazine (490 mg,2.02 mmol) is dissolved in chloroform (10 mL) and m-CPBA (697.1 mg,4.04 mmol) is added. The reaction mixture was stirred at 70℃for 5 hours. Cooled to room temperature, water (30 mL) was added and extracted with DCM (30 mL x 4). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give the desired product as a yellow solid (300 mg,58% yield).
1 H NMR(400MHz,CDCl 3 ):9.14(s,1H),9.10-9.06(m,1H),8.63-8.62(m,1H),8.20(s,1H),7.63-7.58(m,1H),4.35(q,J＝7.2Hz,2H),1.60(t,J＝7.2Hz,3H).MS:m/z＝260(M+1,ESI+)
30-3:6- (6-bromo-5-fluoropyridin-2-yl) -9-ethyl-9H-imidazo [4,5-c]Pyridazine (PYRIZE)
Compound 5 (200 mg,0.59 mmol) was combined in POBr 3 The mixture in (400 mg) was stirred at 100℃for 1 hour. The reaction mixture was cooled to room temperature, diluted with aqueous sodium bicarbonate and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse flow column to give the title product as a white solid (100 mg, 52%).
1 H NMR(400MHz,DMSO-d 6 ):8.86(s,1H),8.81-8.80(m,1H),8.00-7.95(m,1H),7.85-7.82(m,1H),4.51-4.46(m,2H),1.56-1.53(m,3H).LCMS(ES,m/z):[M+H] + ＝322
30: 7-ethyl-4- (6- (4- (ethylsulfonyl) -2-methoxyphenyl) -5-fluoropyridin-2-yl) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using 4- (6-bromo-5-fluoropyridin-2-yl) -7-ethyl-7H-imidazo [4,5-c ] pyridazine (50 mg,0.16 mmol) and 2- (4- (ethylsulfonyl) -2-methoxyphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (100 mg,0.31 mmol) as starting material gave the title compound (13 mg, 18.9%).
1 H NMR(400MHz，CHLOROFORM-d)ppm 1.32-1.34(m，3H)1.73(t，J＝7.34Hz，3H)3.16(q，J＝7.50Hz,2H)3.39(s,3H)4.57-4.67(m,2H)7.23(s,1H)7.46(br.s.,1H)7.65(d,J＝7.34Hz,1H)7.73(dd,J＝8.31,4.40Hz,1H)7.88(d,J＝7.83Hz,1H)8.36(d,J＝15.65Hz,2H).LC-MS:m/z[M+H] + ＝442
Example 31
31-1:3- ((4-bromo-3-methoxyphenyl) thio) propan-1-ol
1-bromo-4-iodo-2-methoxybenzene (8 g,25.6 mmol) 3-mercapton-propanol (4.7 g,51.2 mmol), cuprous iodide (243 mg,1.28 mmol), potassium carbonate (7.1 g,51.2 mmol), ethylene glycol (3.2 g,51.2 mmol) and isopropanol (80 mL) were added to a reaction flask, reacted at 80℃for 20 hours under argon protection, the reaction solution was poured into water (120 mL), extracted with ethyl acetate (120 mLx 3), the organic phases were combined, washed twice with saturated brine (300 mLx 2) and dried, concentrated, and purified by column chromatography (PE: EA=1:1) to give a white solid (5.4 g, yield 76.0%). LC-MS M/z [ m+h ] += 276.9
31-2: (4-bromo-3-methoxyphenyl) (3-chloropropyl) sulfane
3- ((4-bromo-3-methoxyphenyl) thio) propan-1-ol (1.38 g,5.0 mmol) was added to dichloromethane (12 mL), then thionyl chloride (6 mL) was added dropwise, triethylamine (1.8 g,18 mmol) was added dropwise under ice-water bath, after addition, the ice bath was removed, after stirring at room temperature for 16 hours, the reaction was completed, the reaction was concentrated directly, and after column chromatography purification (PE: EA=1:1), a yellow oily liquid (1.0 g, yield 68.0%) was obtained. LC-MS M/z [ m+h ] += 295.0
31-3: (4-bromo-3-methoxyphenyl) (3-chloropropyl) (imino) -sulfonone
After dissolving (4-bromo-3-methoxyphenyl) (3-chloropropyl) sulfane (150 mg,0.5 mmol) in methanol (3 mL), iodobenzene diacetate (401 mg,1.25 mmol) was added, and ammonium carbamate (97.5 mg,1.25 mmol) was stirred at room temperature for 2 hours to complete the reaction. Saturated sodium bicarbonate solution (30 mL) was poured, extracted with dichloromethane (30 mL x 3), the organic phases combined, dried, concentrated and purified by column chromatography (PE: ea=1:1) to give a yellow oily liquid (120 mg, 73.6% yield). LC-MS M/z [ m+h ] +=326
31-4:1- (4-bromo-3-methoxyphenyl) -4, 5-dihydro-3H-isothiazole 1-oxide
(4-bromo-3-methoxyphenyl) (3-chloropropyl) (imino) -sulphone (90 mg,0.3 mmol) and aqueous ammonia (0.1%, 3 mL) were added to a microwave tube and the reaction was subjected to microwave reaction at 80 ℃ for 1 hour, the reaction solution was concentrated directly and purified by column chromatography (DCM: meoh=16:1) to give the compound as a colourless oil (80 mg, 75.0% yield). LC-MS M/z [ m+h ] += 289.9
31:1- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) -4, 5-dihydro-3H-isothiazole 1-oxide
Experimental procedure Using 1- (4-bromo-3-methoxyphenyl) -4, 5-dihydro-3H-isothiazole 1-oxide (60 mg,0.2 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl-7H-imidazo [4,5-c ] pyridazine (59 mg,0.2 mmol) as starting material gave the title compound (56 mg, 60.1% yield).
1 H NMR(400MHz,DMSO-d 6 )δ9.56(s,1H),8.86(s,1H),8.57–8.42(m,2H),7.70–7.43(m,4H),4.51(q,J＝7.2Hz,2H),3.95–3.79(m,4H),3.72(m,1H),3.55(m,1H),3.47–3.37(m,1H),2.28(m,2H),1.56(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝452
Example 32 and example 33
32-1:5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) pyridin-2 (1H) -ones
Experimental procedure Using 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -1 (400 mg,1.8 mmol), 4-chloro-7-ethyl-7H-imidazo [4,5-c ] pyridazine (330 mg,1.8 mmol) as the starting material gave the title compound (200 mg, 45.9%). LC-MS M/z [ m+h ] +=242
32:5- (7-ethyl 7H imidazo [4, 5-c)]Pyridazin-4-yl) -1- (4- (ethylsulfonyl) -2-methoxyphenyl) Pyridin-2 (1H) -ones
2- (4- (ethylsulfonyl) -2-methoxyphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (81 mg,0.25 mmol), 5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) pyridin-2 (1H) -one (60 mg,0.25 mmol) was dissolved in DCM (10 mL) and pyridine (40 mg,0.5 mmol), et3N (50 mg,0.5 mmol) and Cu (OAc) were added sequentially 2 And 4A molecular sieve, sleeving a drying tube, heating and stirring at 30 ℃ for 60 hours, adding 50mLDCM, filtering, and using NH for mother liquor 4 Cl (aq, 100 mL), prep plate prepared the first compound as a pale yellow solid (7 mg,6.4%, developer DCM: meoh=10:1, rf=0.4).
1 H NMR(400MHz,CHLOROFORM-d)d＝8.72(br.s.,1H),8.48(br.s.,1H),8.27(br.s.,1H),7.72-7.53(m,3H),7.08(br.s.,1H),6.88(br.s.,1H),4.63(br.s.,2H),3.93(s,3H),3.21(q,J＝7.3Hz,2H),1.67-1.57(m,3H),1.40(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝440.
33: 7-ethyl-4- (6- (4- (ethylsulfonyl) -2-methoxyphenoxy) pyridin-3-yl) -7H-imidazo [4, 5-c]Pyridazine (PYRIZE)
The second compound was obtained as a pale yellow solid (5 mg,6.4%, developer DCM: meoh=10:1, rf=0.5).
1 H NMR(400MHz,CHLOROFORM-d)d＝9.24-9.05(m,1H),8.96(br.s.,1H),8.70(br.s.,1H),8.36(br.s.,1H),7.59(d,J＝7.3Hz,1H),7.54(s,1H),7.38(d,J＝7.8Hz,1H),7.24(br.s.,1H),4.60(d,J＝6.4Hz,2H),3.85(d,J＝11.7Hz,3H),3.18(q,J＝7.3Hz,2H),1.73-1.61(m,3H),1.37(t,J＝7.6Hz,3H).LC-MS:m/z[M+H] + ＝440.
Example 34 and example 35
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34-1:1- (4-bromo-3-methoxyphenyl) ethan-1-ol
4-bromo-3-methoxybenzaldehyde (2 g,9.30 mmol) was dissolved in anhydrous tetrahydrofuran (20.0 mL) and cooled to-30℃under nitrogen. Methyl magnesium bromide (3.0M, 6.20ml,18.60 mmol) was added, and the mixture was stirred at room temperature for 16h. The reaction solution was poured into ice water, a saturated aqueous ammonium chloride solution was added, extraction was performed with ethyl acetate (100 ml×3), washing was performed with saturated brine (50 mL), drying was performed with anhydrous sodium sulfate, and the title product (2.1 g, yellow oil) was obtained after concentration in 97.6% yield.
1 H NMR(400MHz,CDCl 3 )δ7.49(d,J＝8.1Hz,1H),6.97(d,J＝1.8Hz,1H),6.82(dd,J＝8.1,1.8Hz,1H),4.88(m,1H),3.92(s,3H),1.86(d,J＝3.2Hz,1H),1.49(d,J＝6.5Hz,3H).
34-2: 1-bromo-4- (1-bromoethyl) -2-methoxybenzene
Liquid bromine (1.53 g,9.54 mmol) was slowly added to a dichloromethane solution (20.0 mL) of triphenylphosphine (2.51 g,9.64 mmol) at 0deg.C and reacted at 0deg.C for 10min, then 1- (4-bromo-3-methoxyphenyl) ethan-1-ol (2.1 g,9.09 mmol) was dissolved in dichloromethane (10.0 mL) and added. The reaction mixture was warmed to room temperature and reacted for 16 hours. The reaction mixture was quenched by the addition of ethanol (5.0 mL) and poured into saturated aqueous sodium bicarbonate (100 mL). Extracted with dichloromethane (100 mL x 3), washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. After concentration, the title product (2.3 g, yellow oil) was obtained in 86.1% yield.
1 H NMR(400MHz,CDCl 3 )δ7.49(d,J＝8.1Hz,1H),6.97(d,J＝2.0Hz,1H),6.91(dd,J＝8.1,2.0Hz,1H),5.15(m,1H),3.92(s,3H),2.03(d,J＝6.9Hz,3H).
34-3: (1- (4-bromo-3-methoxyphenyl) ethyl) (methyl) sulfane
Cesium carbonate (12.744 g,39.12 mmol) was added to anhydrous acetonitrile (40.0 mL), cooled to 0℃under nitrogen, 1-bromo-4- (1-bromoethyl) -2-methoxybenzene (2.3 g,7.82 mmol) was added, sodium methyl mercaptide (85% content, 3.225g,39.12 mmol) was added to the reaction solution and the temperature was controlled to 0 ℃. After 15min, the reaction mixture was warmed to room temperature and reacted for 16h. The reaction mixture was poured into 100mL of water, extracted with ethyl acetate (50 mL. Times.3), washed once with saturated brine (50 mL), and dried over anhydrous sodium sulfate. Concentration gave crude product which was purified by column chromatography (PE: ea=2:1) to give the title product (1.8 g, yellow oil) in 86.1% yield
1 H NMR(400MHz,DMSO-d 6 )δ7.50(d,J＝8.1Hz,1H),7.07(d,J＝1.8Hz,1H),6.88(dd,J＝8.1,1.8Hz,1H),3.94(m,1H),3.84(s,3H),1.89(s,3H),1.49(d,J＝7.0Hz,3H).
34-4: 1-bromo-2-methoxy-4- (1- (methylsulfonyl) ethyl) benzene
(1- (4-bromo-3-methoxyphenyl) ethyl) (methyl) sulfane (1.8 g,1.89 mmol) was dissolved in acetic acid (36.0 mL), sodium acetate (2.83 g,34.46 mmol) was added, and 30% hydrogen peroxide (1.55 mL,15.16 mmol) was added. The reaction was carried out at 50℃for 16h. The reaction mixture was poured into 100mL of water, extracted with ethyl acetate (50 mL. Times.3), washed once with saturated brine (50 mL), and dried over anhydrous sodium sulfate. Concentration gave crude product which was purified by column chromatography (PE: ea=3:1) to give the title product (1.0 g, yellow oil) in 49.5% yield
1 H NMR(400MHz,DMSO-d 6 )δ7.60(d,J＝8.2Hz,1H),7.17(d,J＝1.9Hz,1H),6.99(dd,J＝8.2,1.9Hz,1H),4.55(q,J＝7.1Hz,1H),3.86(s,3H),2.84(s,3H),1.63(d,J＝7.2Hz,3H).
34: rel- (S) -7-ethyl-4- (6-fluoro-2 ' -methoxy-4 ' - (1- (methylsulfonyl) ethyl) - [1,1' -bi- Benzene]-3-yl) -7H-imidazo [4,5-c]Pyridazine or rel- (R) -7-ethyl-4- (6-fluoro-2 '-methoxy-4' - (1- (methyl) Sulfonyl) ethyl) - [1,1' -biphenyl]-3-yl) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using 1-bromo-2-methoxy-4- (1- (methylsulfonyl) ethyl) benzene (200.0 mg,0.68 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (215 mg,0.75 mmol) as starting material, a white solid (310 mg, white solid) was obtained. Chiral resolution of 90mg gave the title compound (first peak, 34.8mg, ee% >99.5%, white solid). The splitting method comprises the following steps: instrument: MG II preparative SFC (supercritical fluid chromatography, SFC-1); chromatographic column: chiralPak AD, 250X 30mm I.D.,10 μm; mobile phase: a is CO2, B is isopropanol; b is 55vt%; flow rate: 80mL/min; column temperature: 38 ℃; wavelength: 220nm.
1 H NMR(400MHz,DMSO-d 6 )δ9.56(s,1H),8.85(s,1H),8.53–8.41(m,2H),7.55–7.46(m,1H),7.40(d,1H),7.24(s,1H),7.19(d,1H),4.63(q,1H),4.51(q,J＝7.3Hz,2H),3.79(s,3H),2.92(s,3H),1.71(d,J＝7.2Hz,3H),1.55(t,J＝7.3Hz,3H)。LCMS MS m/z(ESI):455[M+1]
35: rel- (R) -7-ethyl-4- (6-fluoro-2 ' -methoxy-4 ' - (1- (methylsulfonyl) ethyl) - [1,1' -bi- Benzene]-3-yl) -7H-imidazo [4,5-c]Pyridazine or rel- (S) -7-ethyl-4- (6-fluoro-2 '-methoxy-4' - (1- (methyl) Sulfonyl) ethyl) - [1,1' -biphenyl]-3-yl) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Chiral resolution of 90mg gave the title compound (second peak, 35.1mg, ee% >99.5%, white solid).
1 H NMR(400MHz,DMSO-d 6 )δ9.56(s,1H),8.85(s,1H),8.57–8.38(m,2H),7.58–7.44(m,1H),7.39(d,1H),7.24(s,1H),7.19(d,1H),4.63(q,J＝7.2Hz,1H),4.51(q,J＝7.3Hz,2H),3.79(s,3H),2.91(s,3H),1.71(d,J＝7.2Hz,3H),1.55(t,J＝7.3Hz,3H).LCMS MS m/z(ESI):455[M+1]
Example 36
36-1: 3-bromo-2-ethylpyridine 1-oxide
3-bromo-2-ethylpyridine (CAS: 38749-81-4 g,5.4 mmol) was dissolved in 10mL of dichloromethane, and m-chloroperoxybenzoic acid (1.8 g,10.4 mmol) was added, followed by stirring at room temperature for 3 hours. Concentration and column chromatography purification (petroleum ether: ethyl acetate=4:1) afforded the title compound (950 mg, 86%) as a yellow solid. LC-MS: M/z [ M+H ]] + ＝202.
36-2: 3-bromo-6-chloro-2-ethylpyridine
3-bromo-2-ethylpyridine 1-oxide (700 mg,3.5 mmol) was dissolved in 10mL of DMF, oxalyl chloride (900 mg,7 mmol) was added, then heated to 40℃and stirred overnight. Dilution with water, extraction with dichloromethane, concentration, and plate purification (petroleum ether) was prepared to give the title compound (350 mg, 46%) as a colorless liquid. LC-MS: M/z [ M+H ]] + ＝220.
36-3: 3-bromo-2-ethyl-6- (ethylsulfanyl) pyridine
3-bromo-6-chloro-2-ethylpyridine (350 mg,1.6 mmol) was dissolved in 10mL of DMF, ethanethiol (1 mL) and cesium carbonate (1.5 g,5 mmol) were added, then heated to 80℃and stirred overnight. Dilution with water, extraction with dichloromethane, concentration, and plate purification (petroleum ether) was prepared to give the title compound (150 mg, 38%) as a colorless liquid. LC-MS: M/z [ M+H ] ] + ＝246.
36-4: 3-bromo-2-ethyl-6- (ethylsulfonyl) pyridine
3-bromo-2-ethyl-6- (ethylthio) pyridine (150 mg,0.6 mmol) was dissolved in 10mL of a mixed solution of tetrahydrofuran, methanol and water (2:2:1), 40% potassium hydrogen persulfate (1.9 g,3 mmol) was added, stirred overnight at room temperature, diluted with water, extracted with dichloromethane, and concentrated to prepare a plate-purified (petroleum ether: ethyl acetateEster=1: 1) The title compound (70 mg, 42%) was obtained as a white solid. LC-MS: M/z [ M+H ]] + ＝278.
36: 7-ethyl-4- (3- (2-ethyl-6- (ethylsulfonyl) pyridin-3-yl) -4-fluorophenyl) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
The experimental procedure was as in example 1 starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (80 mg,0.22 mmol) 3-bromo-2-ethyl-6- (ethylsulfonyl) pyridine (70 mg,0.22 mmol) to give the title compound (36 mg, 37%) as a brown solid.
1 H NMR(400MHz,CHLOROFORM-d)δppm 9.31-9.44(m,1H)8.21-8.37(m,3H)8.03(d,J＝7.83Hz,1H)7.87(d,J＝7.83Hz,1H)7.42(t,J＝8.80Hz,1H)4.59(q,J＝7.01Hz,2H)3.53(q,J＝7.34Hz,2H)2.86(q,J＝7.34Hz,2H)1.69(t,J＝7.34Hz,3H)1.40(t,J＝7.58Hz,3H)1.27(t,J＝7.34Hz,3H).LC-MS:m/z[M+H] + ＝440.
Example 37
37-1: 3-bromo-2-methoxy-6- (pyridin-3-yloxy) pyridine
3-bromo-6-chloro-2-methoxypyridine (CAS: 1211526-62-3 200mg,0.9 mmol) was dissolved in 10mL DMF, pyridin-3-ol (180 mg,1.8 mmol) and cesium carbonate (1 g,3 mmol) were added and heated to 100deg.C and stirred for 3 hours, cesium carbonate was filtered, diluted with water, extracted with dichloromethane, and concentrated to afford the title compound as a brown liquid (100 mg, 40%) that was purified by plates (petroleum ether: ethyl acetate=3:1). LC-MS: M/z [ M+H ] ] + ＝281.
37: 7-ethyl-4- (4-fluoro-3- (2-methoxy-6- (pyridin-3-yloxy) pyridin-3-yl) phenyl) -7H-mi-ne Azolo [4,5-c ]]Pyridazine (PYRIZE)
The procedure was as in example 1 starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (100 mg,0.27 mmol) and 3-bromo-2-methoxy-6- (pyridin-3-yloxy) pyridine (100 mg,0.27 mmol) to give the title compound (33 mg, 27%) as a brown solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.36(s,1H)8.61(br.s.,1H)8.48(br.s.,1H)8.17-8.32(m,3H)7.74(d,J＝8.31Hz,1H)7.60(d,J＝8.31Hz,1H)7.29-7.42(m,2H)6.63(d,J＝7.83Hz,1H)4.59(q,J＝7.34Hz,2H)3.74(s,3H)1.70(br.s.,3H).LC-MS:m/z[M+H] + ＝443.
Example 38
38-1: 3-bromo-2-methoxy-6- ((tetrahydrofuran-3-yl) oxy) pyridine
3-bromo-6-chloro-2-methoxypyridine (CAS: 1211526-62-3 200mg,0.9 mmol) was dissolved in 10mL of DMF, tetrahydrofuran-3-ol (200 mg,1.8 mmol) and cesium carbonate (1 g,3 mmol) were added, heated to 100deg.C and stirred overnight, cesium carbonate was filtered, diluted with water, extracted with dichloromethane, and concentrated to afford the title compound as a white solid (80 mg, 32%) as a plate for purification (petroleum ether: ethyl acetate=10:1). LC-MS: M/z [ M+H ]] + ＝274.
38: 7-ethyl-4- (4-fluoro-3- (2-methoxy-6- ((tetrahydrofuran-3-yl) oxy) pyridin-3-yl) phenyl) propanoic acid 7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using as in example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (90 mg,0.24 mmol) and 3-bromo-2-methoxy-6- ((tetrahydrofuran-3-yl) oxy) pyridine (80 mg,0.24 mmol), the title compound (41 mg, 33%) is obtained as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.36(s,1H)8.12-8.37(m,3H)7.61(d,J＝7.83Hz,1H)7.33(t,J＝9.05Hz,1H)6.44(d,J＝7.83Hz,1H)5.57(br.s.,1H)4.58(q,J＝7.01Hz,2H)4.12(dd,J＝10.27,4.89Hz,1H)3.97-4.08(m,2H)3.86-3.97(m,4H)2.13-2.37(m,2H)1.69(t,J＝7.34Hz,3H).LC-MS:m/z[M+H] + ＝436.
Example 39
39-1: 1-bromo-4-fluoro-2-methoxybenzene
2-bromo-5-fluorophenol (10.0 g,52.3 mmol) and potassium carbonate (8.7 g,62.8 mmol) were dissolved in 100mL of DMF under nitrogen at room temperature and methyl iodide (8.18 g,57.6 mmol) was slowly added. After stirring at room temperature for 12 h. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium chloride and extracted with ethyl acetate (50 ml. Times.3). The organic phase was concentrated and purified by column chromatography to give the title product 1-bromo-4-fluoro-2-methoxybenzene (9.6 g, colorless liquid) in 90% yield.
39-2: (4-bromo-3-methoxyphenyl) (ethyl) sulfane
Ethanethiol (1.0 g,16.1 mmol) was dissolved in 50mL DMF under nitrogen, and sodium hydride (774 mg,19.3 mmol) was slowly added at zero degrees. After stirring at room temperature for 0.5h, 1-bromo-4-fluoro-2-methoxybenzene (3.47 g,16.9 mmol) was added. After the reaction solution was stirred at room temperature for 12 hours, the reaction was completed. Quench with saturated aqueous sodium chloride and extract with ethyl acetate (50 ml x 3). The organic phase was concentrated and purified by column chromatography to give the title product (4-bromo-3-methoxyphenyl) (ethyl) sulfane (600 mg, colorless oil.) in 15.1% yield.
1 H NMR(400MHz,CDCl 3 )δ7.43(d,J＝8.2Hz,1H),6.86(d,J＝2.0Hz,1H),6.80(dd,J＝8.2,2.0Hz,1H),3.89(s,3H),2.94(d,J＝7.4Hz,2H),1.32(t,J＝7.4Hz,3H).
39-3: (4-bromo-3-methoxyphenyl) (ethyl) (imino) -sulfonone
(4-bromo-3-methoxyphenyl) (ethyl) sulfane (546 mg,2.21 mmol) was dissolved in 5mL of methanol, and then iodobenzene diacetic acid (1.78 g,5.52 mmol) and ammonium carbamate (345 mg,4.42 mmol) were sequentially added to the reaction solution, and reacted at room temperature for 2 hours with an opening. Quenched with saturated sodium bicarbonate and extracted with dichloromethane (50 ml x 3). The organic phase was concentrated and Prep-TLC (EA) purified to give the title product (460 mg, colorless oil) in 75% yield. LCMS m/z (ESI): 278,280[ M+1]
39-4: (4-bromo-3-methoxyphenyl) (ethyl) (methylimino) -sulphone
(4-bromo-3-methoxyphenyl) (ethyl) (imino) -sulphonone (460 mg,1.66 mmol) and methylboronic acid (200 mg,3.32 mmol) were dissolved in 10mL 1, 4-dioxane under nitrogen and copper acetate (460 mg,2.50 mmol) and pyridine (264 mg,4.98 mmol) were added to the reaction. The reaction was carried out at 100℃for 2h. At the end of the reaction, the pH was adjusted to 6-7 with 1M dilute HCl, diluted with water, extracted with dichloromethane (50 mLx 3), the organic phase concentrated and purified by Prep-TLC (EA) to give the title product (400 mg, deep yellow oil.) in 83% yield. LCMS m/z (ESI): 292,294[ M+1]
39: ethyl (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) (methylimino) -sulphone
At N 2 Protected, (4-bromo-3-methoxyphenyl) (ethyl) (methylimino) -sulphonone (50 mg,0.17 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c]Pyridazine (76 mg,0.21 mmol) was dissolved in 4mL of 1, 4-dioxane and 1mL of water, and tetrakis triphenylphosphine palladium (20 mg,0.017 mmol) and cesium carbonate (62 mg,0.19 mmol) were added to the reaction solution. The reaction was carried out for 2 hours at 100℃with microwaves. At the end of the reaction, diluted with water, extracted with dichloromethane (50 ml x 3), the organic phase concentrated and Prep-TLC (EA) purified to give crude product which was prepared by Prep-HPLC to give the title product (20 mg, white solid) in 25.6% yield.
LCMS:m/z(ESI):454[M+1]. 1 H NMR(400MHz,CDCl 3 )δ9.75–9.63(m,1H),8.92–8.82(m,1H),8.62–8.53(m,1H),8.47–8.35(m,1H),8.14–8.05(m,1H),7.89–7.80(m,1H),7.77–7.69(m,1H),7.52–7.42(m,1H),4.78–4.59(m,2H),4.56–4.39(m,1H),4.24–4.10(m,1H),4.06–3.93(m,3H),2.91–2.74(m,3H),1.80–1.70(m,3H),1.59–1.50(m,3H).
Example 40
40-1: 3-bromo-2-methoxy-6- ((tetrahydro-2H-pyran-4-yl) oxy) pyridine
3-bromo-6-chloro-2-methoxypyridine (CAS: 1211526-62-3 200mg,0.9 mmol) was dissolved in 10mL of LDMF, tetrahydro-2H-pyran-4-ol (20 mg,1.8 mmol) and cesium carbonate (1 g,3 mmol) were added, heated to 100℃and stirred for 3 hours, cesium carbonate was filtered, diluted with water, extracted with dichloromethane, concentrated, and prepared for plate purification (petroleum ether: ethyl acetate=10:1) to give the title compound (70 mg, 27%) as a brown liquid. LC-MS: M/z [ M+H ]] + ＝288.
40: 7-ethyl-4- (4-fluoro-3- (2-methoxy-6- ((tetrahydro-2H-pyran-4-yl) oxy) pyridin-3-yl) phenyl) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
The experimental procedure was as in example 1 starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (90 mg,0.24 mmol) 3-bromo-2-methoxy-6- ((tetrahydro-2H-pyran-4-yl) oxy) pyridine (70 mg,0.24 mmol) to give the title compound as a brown solid (45 mg, 41%).
1 H NMR(400MHz,CHLOROFORM-d)δppm 9.30-9.44(m,1H)8.28(s,1H)8.16-8.25(m,2H)7.62(d,J＝7.83Hz,1H)7.33(t,J＝9.05Hz,1H)6.44(d,J＝7.83Hz,1H)5.25(dt,J＝7.95,4.10Hz,1H)4.58(q,J＝7.34Hz,2H)3.99-4.08(m,2H)3.87-3.95(m,3H)3.60-3.69(m,2H)2.13(d,J＝9.78Hz,2H)1.85-1.89(m,2H)1.71(s,3H).LC-MS:m/z[M+H] + ＝450.
Example 41
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41-1: ((4-chloro-3-methoxyphenyl) imino) dimethyl-l 6-sulfonone
(4-chloro-3-methoxyphenyl) boronic acid (800 mg,4.29 mmol), copper acetate (195 mg,1.07 mmol) and S-methylsulfenamide (500 mg,5.37 mmol) were added to methanol (10 mL) and stirred at 35℃for two hours. The reaction solution was concentrated, and then purified by plate separation (ethyl acetate) to give the title compound (430 mg, 43.1%).
41: ((5' - (7-ethyl 7H) imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl]- 4-yl) imino) dimethyl-l 6-sulphonone
Experimental procedure was as in example 1, using ((4-chloro-3-methoxyphenyl) imino) dimethyl-16-sulphone (200 mg,0.86 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c]Pyridazine (266 mg,0.69 mmol) was used as the starting material to give the title compound (60 mg, 19.8%). 1 H NMR(400MHz,CHLOROFORM-d)9.36(s,1H),8.33-8.20(m,2H),8.17(d,J＝5.9Hz,1H),7.31(t,J＝9.0Hz,1H),7.22(d,J＝7.8Hz,1H),6.81(d,J＝7.8Hz,1H),6.74(s,1H),4.57(q,J＝7.3Hz,2H),3.81(s,3H),3.23(s,6H),1.69(br.s.,3H).LC-MS:m/z[M+H] + ＝440.
Example 42
42: 7-ethyl-4- (4-fluoro-3- (3-methoxy-2-methylpyridin-4-yl) phenyl) -7H-imidazo [4,5-c] Pyridazine (PYRIZE)
Experimental procedure Using example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (70 mg,0.25 mmol), 4-bromo-3-methoxy-2-methylpyridine (CAS: 1227592-47-3.50 mg,0.25 mmol) the title compound (10 mg, 14%) is obtained as a brown solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.38(s,1H)8.24-8.40(m,4H)7.41(t,J＝9.29Hz,1H)7.22(d，J＝4.40Hz，1H)4.59(q，J＝7.34Hz，2H)3.54(s，3H)2.63(s，3H)1.69(t，J＝7.34Hz，3H).LC-MS:m/z[M+H] + ＝364.
Example 43
43-1: 5-bromo-6-methoxypyridine carboxamide
Methyl 5-bromo-6-methoxypyridine carboxylate (200 mg,0.81 mmol) and aqueous ammonia (2 mL) were added to methanol (2 mL) and stirred for 4 hours at 100 ℃. The reaction solution was directly purified by preparative plate separation (dichloromethane/methanol=30/1) to give the title compound (130 mg, 66.7%).
43-2: 5-bromo-6-methoxypyridine carbonitrile
5-bromo-6-methoxypyridine carboxamide (130 mg,0.54 mmol), triethylamine (0.5 mL) and trifluoroacetic anhydride (2 mL) were added to dichloromethane (4 mL) and stirred at room temperature for 2 hours. The reaction was directly purified by prep. plate (dichloromethane/methanol=20/1) to give the title compound (77 mg, 35.8%).
43:5- (5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenyl) -6-methoxypyridine carbonitrile
Experimental procedure was as in example 1 starting from 5-bromo-6-methoxypyridine carbonitrile (77 mg,0.36 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (110 mg,0.3 mmol) to give the title compound (22 mg, 19.6%).
1 H NMR(400MHz,CHLOROFORM-d)9.38(br.s.,1H),8.30(s,3H),7.79(d,J＝7.3Hz,1H),7.44(d,J＝7.3Hz,1H),7.38(t,J＝9.3Hz,1H),4.59(q,J＝7.2Hz,2H),4.00(s,3H),1.70(s,3H).LC-MS:m/z[M+H] + ＝375.
Example 44
44:3- ((5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenoxy methyl) -5-methylisoxy Oxazole compounds
5- (7-Ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenol (70 mg,0.25 mmol), 3- (chloromethyl) -5-methylisoxazole (CAS: 35166-37-1 50mg,0.38 mmol) and potassium carbonate (100 mg,0.8 mmol) are dissolved in 5mL of DMF and then stirred at 80℃for 2 hours. Dilution with water, extraction with dichloromethane, concentration, prep. plate purification (dichloromethane: methanol=10:1) afforded the title compound (37 mg, 39%) as a yellow solid.
1 H NMR(400MHz,CHLOROFORM-d)δppm 9.33(s,1H)8.29(s,1H)8.10(d,J＝7.83Hz,1H)7.79(d,J＝1.96Hz,1H)7.28-7.32(m,1H)6.22(s,1H)5.31(s,2H)4.58(q,J＝7.01Hz,2H)2.44(s,3H)1.69(t,J＝7.34Hz,3H).LC-MS:m/z[M+H] + ＝354.
Example 45
45-1: 3-bromo-2-methoxy-6- (trifluoromethyl) pyridine
3-bromo-2-chloro-6- (trifluoromethyl) pyridine (CAS: 1159512-34-1 200mg,0.77 mmol) was dissolved in 10mL of methanol, sodium methoxide (200 mg,3.8 mmol) was added and heated to reflux overnight, the solid was filtered and concentrated to give the title compound (100 mg, 45%) as a white solid as a plate for purification (petroleum ether: ethyl acetate=30:1). LC-MS: M/z [ M+H ]] + ＝256.
45: 7-ethyl-4- (4-fluoro-3- (2-methoxy-6- (trifluoromethyl) pyridin-3-yl) phenyl) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (60 mg,0.16 mmol), 3-bromo-2-methoxy-6- (trifluoromethyl) pyridine (50 mg,0.16 mmol), the title compound (29 mg, 42%) is obtained as a brown solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.37(s,1H)8.24-8.35(m,3H)7.83(d,J＝7.34Hz,1H)7.36-7.43(m,2H)4.59(q,J＝7.17Hz,2H)4.03(s,3H)1.70(t,J＝7.09Hz,3H).LC-MS:m/z[M+H] + ＝418.
Example 46
46: 7-ethyl-4- (6-fluoro-2 ' -methoxy-4 ' -nitro- [1,1' -biphenyl)]-3-yl) -7H-imidazo [4,5 ] c]Pyridazine (PYRIZE)
Experimental procedure Using example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (70 mg,0.25 mmol), 1-bromo-2-methoxy-4-nitrobenzene (CAS: 77337-82-7 50mg,0.25 mmol) the title compound (20 mg, 28%) is obtained as a yellow solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.37(br.s.,1H)8.19-8.33(m,3H)7.97(d,J＝8.31Hz,1H)7.88(br.s.,1H)7.54(d,J＝8.80Hz,1H)7.38(t,J＝8.80Hz,1H)4.59(d,J＝6.85Hz,2H)3.95(br.s.,3H)1.70(t,J＝6.85Hz,3H).LC-MS:m/z[M+H] + ＝394.
Example 47
47:2- ((5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenoxy methyl) -5-methyl- 1,3, 4-oxadiazole
5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenol (70 mg,0.23 mmol), 2- (chloromethyl) -5-methyl-1, 3, 4-oxadiazole (50 mg,0.6 mmol) and potassium carbonate (100 mg,0.6 mmol) are dissolved in 5mL of DMF and then stirred at 80℃for 2 hours. Dilution with water, extraction with dichloromethane, concentration, prep. plate purification (dichloromethane: methanol=20:1) afforded the title compound (27 mg, 30%) as a yellow solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.34(s,1H)8.29(s,1H)8.18(d,J＝7.83Hz,1H)7.83(br.s.,1H)7.29-7.37(m,1H)5.42(s,2H)4.59(q,J＝7.01Hz,2H)2.59(s,3H)1.70(t,J＝7.34Hz,3H).LC-MS:m/z[M+H] + ＝355.
Example 48
48-1: 3-bromo-6- (ethylthio) -2-methoxypyridine
3-bromo-6-chloro-2-methoxypyridine (500 mg,2.25 mmol), cs 2 CO 3 (1.46 g,4.5 mmol) and ethanethiol (209 mg,3.37 mmol) were added to DMF (10 mL) and stirred at 90℃for two hours. The reaction was taken up in 50mL of water and extracted with dichloromethane (50 mL. Times.3) and the organic phase concentrated to give the title compound (400 mg, 71.7%).
48-2: 3-bromo-6- (ethylsulfonyl) -2-methoxypyridine
3-bromo-6- (ethylsulfanyl) -2-methoxypyridine (500 mg,2.25 mmol) and potassium hydrogen persulfate (4.9 g,16 mmol) were added to H2O/THF/MeOH (4/8/8 mL) and stirred at room temperature for two hours. The reaction solution was concentrated directly, extracted 3 times with ethyl acetate and water, and the organic phase was concentrated to give the title compound (250 mg, 56.1%).
48:4- (3- (6- (ethylsulfonyl) -2-methoxypyridin-3-yl) -4-fluorophenyl) -7-isopropyl-7H-imidazo [4,5-c ] pyridazine
Experimental procedure is as in example 1 with 3-bromo-6- (ethylsulfonyl) -2-methoxypyridine (28 g,0.1 mmol) and 7-isopropyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c]Pyridazine (40 mg,0.1 mmol) was used as a starting material to give the title compound (17 mg, 37.8%) as a white solid in appearance. LC-MS: M/z [ M+H ]] + ＝456. 1 H NMR(400MHz,CHLOROFORM-d)9.36(br.s.,1H),8.33(s,1H),8.29(d,J＝5.9Hz,2H),7.91(d,J＝7.6Hz,1H),7.81(d,J＝7.0Hz,1H),7.38(t,J＝8.8Hz,1H),5.22(td,J＝6.7,13.1Hz,1H),4.03(s,3H),3.45(q,J＝7.0Hz,2H),1.76(d,J＝6.5Hz,6H),1.40(t,J＝7.3Hz,3H)
Example 49
49-1: 7-ethyl-4-iodo-7H-imidazo [4,5-c]Pyridazine (PYRIZE)
4-chloro-7-ethyl-7H-imidazo [4,5-c]Pyridazine (500 mg,2.74 mmol) and sodium iodide (820 mg,5.48 mmol) were added to hydrogen iodide (10 ml). Stirring was carried out at 70℃for 2 hours. The reaction mixture was brought to pH with aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate (200 ml. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound (700 mg, 93%) as LC-MS/M/z [ M+H ]] + ＝275
49-2:4- (6-bromopyridin-2-yl) -7-ethyl-7H-imidazo [4,5-c]Pyridazine (PYRIZE)
7-ethyl-4-iodo-7H-imidazo [4,5-c]Pyridazine (300 mg,1.1 mmol), 2-bromo-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (372 mg,1.31 mmol), potassium carbonate (457 mg,3.3 mmol) and tetrakis (triphenylphosphine) palladium (126 mg,0.11 mmol) were added to ethylene glycol dimethyl ether/water (4 ml/1 ml). Stirring overnight at 100℃under argon. The reaction solution was purified by direct thin layer chromatography (dichloromethane/methanol=20/1) to give the title compound (100 mg, 30%). LC-MS: M/z [ M+H ] ] + ＝305
49: 7-ethyl-4- (6- (4- (ethylsulfonyl) -2-methoxyphenyl) pyridin-2-yl) -7H-imidazo [4,5 ] c]Pyridazine (PYRIZE)
Experimental procedure the synthesis of 49-2 in ketone example 49 starting from 4- (6-bromopyridin-2-yl) -7-ethyl-7H-imidazo [4,5-c ] pyridazine (50 mg,0.16 mmol) and 2- (4- (ethylsulfonyl) -2-methoxyphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (64 mg,0.19 mmol) gave the title compound (34 mg, 48.6%).
1 H NMR(400MHz,CHLOROFORM-d)ppm 1.36(t,J＝7.34Hz,3H)1.71(br.s.,3H)3.20(q,J＝7.34Hz,2H)4.00(s,3H)4.61(q,J＝7.34Hz,2H)7.55(s,1H)7.67(d,J＝7.83Hz,1H)7.93-7.99(m,1H)8.01-8.07(m,1H)8.27(d,J＝8.31Hz,1H)8.35(s,1H)8.96(d,J＝7.34Hz,1H)10.16(s,1H)LC-MS:m/z[M+H] + ＝424
Example 50
50-1:4- (5-bromothiophen-2-yl) -7-ethyl-7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure the synthesis of 49-2 from ketone example 49 was performed using 2- (5-bromothiophen-2-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (380 mg,1.31 mmol) as starting material to give the title compound (280 mg, 83.1%). LC-MS: M/z [ M+H ]] + ＝309
50: 7-ethyl-4- (5- (4- (ethylsulfonyl) -2-methoxyphenyl) thiophen-2-yl) -7H-imidazo [4,5 ] c]Pyridazine (PYRIZE)
Experimental procedure is as in example 49, using 4- (5-bromothiophen-2-yl) -7-ethyl-7H-imidazo [4,5-c]Pyridazine (50 mg,0.16 mmol), 2- (4- (ethylsulfonyl) -2-methoxyphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (64 mg,0.19 mmol) was used as the starting material to give the title compound (32 mg, 51.2%). LC-MS: M/z [ M+H ]] + ＝429
1 H NMR(400MHz,CHLOROFORM-d)ppm 1.33(t,J＝7.34Hz,3H)1.68(br.s.,3H)3.17(q,J＝7.17Hz,2H)4.08(s,3H)4.56(q,J＝7.34Hz,2H)7.50-7.56(m,2H)7.76(d,J＝3.91Hz,1H)7.93(d,J＝7.83Hz,1H)8.20-8.32(m,2H)9.43(s,1H)
Example 51
51-1:3, 6-dichloro-2- (difluoromethyl) pyridine
3, 6-dichloropyridine-formaldehyde (500 mg,2.84 mmol) was added to dichloromethane (5 mL) and diethylaminosulfur trifluoride (2 mL) was added at room temperature. Stir at room temperature overnight. Dichloromethane (300 ml) was added to the reaction solution, followed by washing (100 ml. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound (600 mg, 100%) as LC-MS:m/z[M+H] + ＝198
51-2: 6-chloro-2- (difluoromethyl) -3- (ethylthio) pyridine
51-2': 3-chloro-2- (difluoromethyl) -6- (ethylthio) pyridine
3, 6-dichloro-2- (difluoromethyl) pyridine (600 mg,3 mmol), ethanethiol (150 mg,2.4 mmol), cesium carbonate (2000 mg,6.1 mmol) were added to N, N-dimethylformamide (10 ml), and stirred overnight at room temperature. Direct thin layer chromatography of the reaction solution (petroleum ether/ethyl acetate=20/1) gave 6-chloro-2- (difluoromethyl) -3- (ethylthio) pyridine (180 mg, 25%) and 3-chloro-2- (difluoromethyl) -6- (ethylthio) pyridine (120 mg, 17%) LC-MS: M/z [ M+H)] + ＝224
51-3: 6-chloro-2- (difluoromethyl) -3- (ethylsulfonyl) pyridine
6-chloro-2- (difluoromethyl) -3- (ethylsulfanyl) pyridine (180 mg,0.8 mmol), potassium hydrogen persulfate (1200 mg,4 mmol) was added to tetrahydrofuran (8 ml), water (2 ml), methanol (2 ml). Stir at room temperature overnight. Direct thin layer chromatography of the reaction (petroleum ether/ethyl acetate=5/1) gave the title compound (140 mg, 68%) as LC-MS/M/z [ M+H ] + ＝256
51:4- (3- (6- (difluoromethyl) -5- (ethylsulfonyl) pyridin-2-yl) -4-fluorophenyl) -7-ethyl-7H-mi-ne Azolo [4,5-c ]]Pyridazine (PYRIZE)
The procedure was as in example 1 starting from 6-chloro-2- (difluoromethyl) -3- (ethylsulfonyl) pyridine (42 mg,0.16 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (50 mg,0.13 mmol) to give the title compound (21 mg, 33.5%).
1 H NMR(400MHz,CHLOROFORM-d)1.36(t,J＝7.34Hz,3H)1.70(t,J＝7.09Hz,3H)3.32(q,J＝7.34Hz,2H)4.59(q,J＝7.17Hz,2H)7.40-7.69(m,2H)8.23(d,J＝8.31Hz,1H)8.31(s,1H)8.37-8.50(m,2H)9.06(d,J＝6.85Hz,1H)9.43(s,1H).LC-MS:m/z[M+H] + ＝462
Example 52
52-1: 3-chloro-2- (difluoromethyl) -6- (ethylsulfonyl) pyridine
3-chloro-2- (difluoromethyl) -6- (ethylsulfanyl) pyridine (300 mg,1.35 mmol), potassium hydrogen persulfate (2000 mg,6.7 mmol) was added to tetrahydrofuran (8 ml), water (2 ml), methanol (2 ml). Stir at room temperature overnight. Direct thin layer chromatography of the reaction (petroleum ether/ethyl acetate=5/1) gave the title compound (120 mg, 35%) as LC-MS/M/z [ M+H] + ＝256
52:4- (3- (2- (difluoromethyl) -6- (ethylsulfonyl) pyridin-3-yl) -4-fluorophenyl) -7-ethyl-7H-mi-ne Azolo [4,5-c ]]Pyridazine (PYRIZE)
The experimental procedure was as in example 1 starting from 3-chloro-2- (difluoromethyl) -6- (ethylsulfonyl) pyridine (42 mg,0.16 mmol) 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (50 mg,0.13 mmol) to give the title compound (11 mg, 17.6%).
1 H NMR(400MHz,CHLOROFORM-d)ppm 1.42(t,J＝7.34Hz,3H)1.66(d,J＝5.38Hz,3H)3.55(q,J＝7.34Hz,2H)4.58(q,J＝7.17Hz,2H)6.58-6.90(m,1H)7.44(t,J＝8.80Hz,1H)8.12(d,J＝7.83Hz,1H)8.26-8.44(m,4H)9.37(s,1H).LC-MS:m/z[M+H] + ＝462
Example 53
53-1: 2-chloro-6- (ethylthio) pyridine
2, 6-dichloropyridine (2000 mg,13.5 mmol), ethanethiol (640 mg,10.8 mmol), cesium carbonate (8800 mg,27 mmol) was added to 2, 6-dichloropyridine (20 ml). Stir at room temperature overnight. The reaction mixture was washed with water (200 ml. Times.3) and then dried over anhydrous sodium sulfate and concentrated to give the title compound (2200 mg, 94.1%) as LC-MS/M/z [ M+H)] + ＝174
53-2: 3-bromo-2-chloro-6- (ethylsulfanyl) pyridine
2-chloro-6- (ethylsulfanyl) pyridine (2200 mg,12.7 mmol), NBS (2200 mg,12.7 mmol) was added to acetonitrile (10 ml). Stir at 90 degrees celsius overnight. The reaction mixture was directly passed through a normal phase column to give the title compound (1000 mg, 31.5%) as LC-MS/M/z [ M+H] + ＝252
53-3: 3-bromo-2-chloro-6- (ethylsulfonyl) pyridine
3-bromo-2-chloro-6- (ethylsulfanyl) pyridine (1000 mg,4 mmol), potassium hydrogen persulfate (3700 mg,12 mmol) were added to tetrahydrofuran (8 ml), water (1 ml), and methanol (1 ml). Stir at room temperature overnight. Ethyl acetate (300 ml) was added to the reaction mixture, which was then washed with water (100 ml. Times.3), and the ethyl acetate was dried over anhydrous sodium sulfate and concentrated to give the title compound (850 mg, 75.4%) as LC-MS/M/z [ M+H ]] + ＝284
53-4: 3-bromo-2-ethoxy-6- (ethanesulfonyl) pyridine
3-bromo-2-chloro-6- (ethylsulfonyl) pyridine (200 mg,0.71 mmol), sodium ethoxide (3 ml) was added to ethanol (5 ml). Stir at room temperature overnight. Direct thin layer chromatography of the reaction (petroleum ether/ethyl acetate=30/1) gives the title compound (50 mg, 24%) as LC-MS/M/z [ M+H ] + ＝294
53:4- (3- (2-ethoxy-6- (ethylsulfonyl) pyridin-3-yl) -4-fluorophenyl) -7-ethyl 7H imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using 3-bromo-2-ethoxy-6- (ethanesulfonyl) pyridine (50 mg,0.16 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (50 mg,0.13 mmol) as starting material gives the title compound (13 mg, 21%).
1 H NMR(400MHz,CHLOROFORM-d)ppm 1.31-1.47(m,6H)1.70(d,J＝6.85Hz,3H)3.44(q,J＝7.01Hz,2H)4.50(q,J＝6.68Hz,2H)4.59(d,J＝6.85Hz,2H)7.38(t,J＝9.05Hz,1H)7.78(d,J＝7.34Hz,1H)7.91(d,J＝7.34Hz,1H)8.20-8.36(m,3H)9.37(br.s.,1H).LC-MS:m/z[M+H] + ＝456
Example 54
54:4- (3- (2-chloro-6- (ethylsulfonyl) pyridin-3-yl) -4-fluorophenyl) -7-ethyl-7H-imidazo [4, 5-c]pyridazine (PYRIZE)
Experimental procedure Using 3-bromo-2-chloro-6- (ethylsulfonyl) pyridine (46 mg,0.16 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (50 mg,0.13 mmol) as starting material gave the title compound (12 mg, 20%).
1 H NMR(400MHz,CHLOROFORM-d)ppm 1.41(t,J＝7.34Hz,3H)1.69(s,3H)3.48-3.54(m,2H)4.59(q,J＝7.34Hz,2H)7.44(t,J＝8.56Hz,1H)8.06(d,J＝7.83Hz,1H)8.12-8.17(m,1H)8.30(s,1H)8.34(d,J＝5.87Hz,2H)9.38(s,1H).LC-MS:m/z[M+H] + ＝446
Example 55
55-1: 2-chloro-4- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) benzaldehyde
(3-chloro-4-formylphenyl) boronic acid (200 mg,1.09 mmol), 4-chloro-7-ethyl-7H-imidazo [4, 5-c)]Pyridazine (300 mg,1.63 mmol), sodium carbonate (230 mg,2.2 mmol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (47 mg,0.05 mmol) was added to 1, 4-dioxane/water (5 ml/1 ml). Stirring is carried out for 2 hours at 90 ℃ under the protection of argon. The reaction was extracted directly with water and dichloromethane, washed with dichloromethane (100 ml x 3), dried over anhydrous sodium sulfate and concentrated to give the title compound (200 mg, 64.5%). LC-MS: M/z [ M+H ] ] + ＝287
55-2:4- (3-chloro-4- (difluoromethyl) phenyl) -7-ethyl-7-hydro-imidazo [4,5-c]Pyridazine (PYRIZE)
2-chloro-4- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) benzaldehyde (200 mg,0.74 mmol) was added to dichloromethane (10 mL), and diethylaminosulfur trifluoride (2 mL) was added at room temperature. Stir at room temperature overnight. Direct thin layer chromatography of the reaction (petroleum ether/ethyl acetate=1/1) gave the title compound (100 mg, 46.5%) as LC-MS/M/z [ M+H] + ＝309
55:4- (6- (difluoromethyl) -4' - (ethylsulfonyl) -2' -methoxy- [1,1' -biphenyl)]-3-yl) -7-ethyl base-7H-imidazo [4,5-c ]]Pyridazine (PYRIZE)
Experimental procedure is as in example 1, using 4- (3-chloro-4- (difluoromethyl) phenyl) -7-ethyl-7H-imidazo [4,5-c]Pyridazine (50 mg,0.16 mmol), 2- (4- (ethylsulfonyl) -2-methoxyphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (106 mg,0.32 mmol) was used as the starting material to give the title compound (14 mg, 18.3%). LC-MS: M/z [ M+H ]] + ＝473
1 H NMR(400MHz,CHLOROFORM-d)ppm 1.23-1.28(m,3H)1.38(t,J＝7.09Hz,3H)3.21(d,J＝7.34Hz,2H)3.87(br.s.,3H)4.59(d,J＝6.85Hz,2H)6.30-6.61(m,1H)7.51(br.s.,2H)7.62(d,J＝7.34Hz,1H)7.96(d,J＝6.85Hz,1H)8.09(br.s.,1H)8.30(br.s.,1H)8.37(d,J＝7.83Hz,1H)9.39(br.s.,1H)
Example 56
56-1: 1-chloro-4- (1, 1-difluoroallyl) -2-methoxybenzene
(4-chloro-3-methoxyphenyl) boronic acid (372 mg,2 mmol), 3-bromo-3, 3-difluoro-1-propene (470 mg,3.0313 mmol), tris (benzalacetone) dipalladium (7 mg,0.008 mmol), potassium carbonate (8238 mg,6 mmol), water (18 mg,0.96 mmol) were added to 1, 4-dioxane (3 ml), and reacted overnight at 80℃in a sealed tube. The reaction solution was filtered off with suction and concentrated to give the title compound as a colourless oil (166 mg, 38.07%) by thin layer chromatography (pure petroleum ether). 1 H NMR(400MHz,CHLOROFORM-d)d＝7.58(d,J＝8.3Hz,1H),7.01(s,1H),6.96(d,J＝7.8Hz,1H),6.21-6.05(m,1H),5.58(d,J＝17.6Hz,1H),5.50(d,J＝10.8Hz,1H),3.92(s,3H).
56-2: 1-chloro-4- (1, 1-difluoropropyl) -2-methoxybenzene
1-chloro-4- (1, 1-difluoroallyl) -2-methoxybenzene (166 mg,0.758 mmol) and palladium on carbon (20 mg) were added to methanol (2 ml) and reacted overnight at 25 ℃. The reaction solution was filtered with suction and concentrated to give the title compound (60 mg, 35.98%). 1 H NMR(400MHz,CHLOROFORM-d)d＝7.57(d,J＝8.3Hz,1H),6.98(s,1H),6.93(d,J＝8.3Hz,1H),3.93(s,3H),2.24-2.07(m,2H),0.99(t,J＝7.3Hz,3H).
56:4- (4 ' - (1, 1-difluoropropyl) -6-fluoro-2 ' -methoxy- [1,1' -biphenyl)]-3-yl) -7-ethyl-7H-mi Azolo [4,5-c ]]Pyridazine (PYRIZE)
7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (100 mg,0.3 mmol), 1-chloro-4- (1, 1-difluoropropyl) -2-methoxybenzene (60 mg,0.280 mmol), tris (dibenzylideneacetone) dipalladium (CAS: 51364-51-3 10mg,0.01 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (Xphos) (40 mg,0.01 mmol) and potassium phosphate (220 mg,1 mmol) were dissolved in 5mL toluene and stirred overnight at 100 ℃. The reaction was filtered and concentrated to give a plate for purification (dichloromethane: methanol=30:1) to give the title compound (2 mg, 1.67%) as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)d＝9.38(br.s.,1H),8.30(s,2H),8.20(d,J＝5.4Hz,1H),7.41(d，J＝7.8Hz，1H)，7.34(t，J＝9.0Hz，1H)，7.16(d，J＝7.8Hz，1H)，7.11(s，1H)，4.62-4.55(m，2H),3.86(s,3H),2.28-2.13(m,2H),1.69(s,3H),1.06(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝427.
Example 57
57:4- (3- (2, 4-dimethoxypyrimidin-5-yl) -4-fluorophenyl) -7-ethyl-7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (70 mg,0.19 mmol), 5-bromo-2, 4-dimethoxypyrimidine (CAS: 56686-16-9 40mg,0.19 mmol) as the starting material gave the title compound (30 mg, 42%) as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δppm 9.36(s,1H)8.20-8.35(m,4H)7.35(t,J＝9.29Hz,1H)4.59(q,J＝7.34Hz,2H)4.07(s,3H)4.03(s,3H)1.69(t,J＝7.34Hz,3H).LC-MS:m/z[M+H] + ＝481.
Example 58
58-1: 1-bromo-4- (difluoromethyl) -2-methoxybenzene
4-bromo-3-methoxybenzaldehyde (500 mg, 2.33 mmol) was added to dichloromethane (5 mL), and diethylaminosulfur trifluoride (1.5 mL) was added at room temperature. Stirred at room temperature for 2 hours. The reaction solution was concentrated directly to give a crude product, which was slurried three times with ethyl acetate and filtered to give the title compound (200 mg, 36.3%).
58:4- (4 ' - (difluoromethyl) -6-fluoro-2 ' -methoxy- [1,1' -biphenyl)]-3-yl) -7-ethyl-7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using 1-bromo-4- (difluoromethyl) -2-methoxybenzene (50 mg,0.2 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (50 mg,0.13 mmol) as the starting material gave the title compound (12 mg, 22.2%).
1 H NMR(400MHz,DMSO-d6)ppm 1.51-1.57(m,3H)3.82(s,3H)4.46-4.55(m,2H)6.92-7.24(m,1H)7.27-7.31(m,1H)7.33-7.36(m,1H)7.47-7.54(m,2H)8.44-8.51(m,2H)8.82-8.85(m,1H)9.52-9.56(m,1H).LC-MS:m/z[M+H] + ＝399
Example 59
59-1:1- (4-bromo-3-methoxyphenyl) piperidin-2-one
Experimental procedure the same as in example 4 for the synthesis of 4-2 using 2-bromo-5-iodoanisole (CAS: 755027-18-0,160mg,0.5 mmol) and 2-piperidone (57 mg,0.55 mmol) as starting material gave the title compound (130 mg, 90%) as a yellow solid. LC-MS: M/z [ M+H ]] + ＝284.
59:1- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) piperidin-2-one
Experimental procedure Using example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (70 mg,0.2 mmol), 1- (4-bromo-3-methoxyphenyl) piperidin-2-one (65 mg,0.2 mmol), the title compound (56 mg, 65%) is obtained as a yellow solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.36(s,1H)8.20-8.30(m,3H)7.39(d,J＝7.83Hz,1H)7.33(t,J＝9.05Hz,1H)6.91-7.00(m,2H)4.58(q,J＝7.34Hz,2H)3.83(s,3H)3.70-3.76(m,2H)2.62(t,J＝5.87Hz,2H)1.99(br.s.,4H)1.68-1.71(m,3H).LC-MS:m/z[M+H] + ＝446.
Example 60
60-1:2- ((5-bromo-6-methoxypyridin-2-yl) thio) ethan-1-ol
Methyl 2- ((5-bromo-6-methoxypyridin-2-yl) thio) acetate (123 mg, 0.426 mmol was added to THF (2 ml), lithium aluminum hydride (29 mg,0.773 mmol) was added to the reaction solution in two portions, stirred at room temperature for 30 minutes, sodium sulfate decahydrate (100 mg) was added, stirred for 10 minutes, the reaction solution was filtered with suction, concentrated, and the crude product was directly (53 mg) directly fed to the next step LC-MS: M/z [ M+H)] + ＝264,266.
60-2: 3-bromo-2-methoxy-6- ((2-methoxyethyl) thio)]Pyridine compound
2- ((5-bromo-6-methoxypyridin-2-yl) thio) ethan-1-ol (50 mg,0.190 mmol) was added to THF (2 ml), sodium hydride (6 mg,0.228 mmol) was added to the reaction solution, stirred at room temperature for 1 hour, methyl iodide (54 mg,0.380 mmol) was added to the reaction solution, reacted at room temperature for 4 hours, the reaction solution was filtered off with suction, and concentrated, and the crude product (77 mg) was directly fed to the next step.
60-3: 3-bromo-2-methoxy-6- ((2-methoxyethyl) sulfonyl) pyridine
3-bromo-2-methoxy-6- ((2-methoxyethyl) thio)]Pyridine (77 mg,0.278 mmol), potassium hydrogen persulfate (211 mg,0.687 mmol) were added to tetrahydrofuran (2 ml), methanol (1 ml) and water (1 ml), stirred at room temperature for 1 hour, and the reaction mixture was poured into water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give the title compound (76 mg, 88.2%) by thin layer chromatography (petroleum ether/ethyl acetate=3/1). LC-MS: M/z [ M+H ]] + ＝310,312.
60: 7-ethyl-4- (4-fluoro-3- (2-methoxy-6- ((2-methoxyethyl) sulfonyl) pyridin-3-yl) benzene Radical) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using 3-bromo-2-methoxy-6- ((2-methoxyethyl) sulfonyl) pyridine (60 mg,0.196 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (60 mg,0.163 mmol) as starting material gave the title compound (12 mg, 15.6%).
1 H NMR(400MHz,CHLOROFORM-d)d＝9.35(br.s.,1H),8.28(s,3H),7.89(d,J＝7.3Hz,1H),7.77(d,J＝7.8Hz,1H),7.36(t,J＝9.0Hz,1H),4.57(q,J＝7.2Hz,2H),4.02(s,3H),3.89-3.82(m,2H),3.74-3.65(m,2H),3.29(s,3H),1.68(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝472.
Example 61
61:5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -4- (ethylsulfonyl) -2 '-fluoro- [1,1' ] fluoro Biphenyl]-2-alcohols
7-ethyl-4- (4 ' - (ethylsulfonyl) -6-fluoro-2 ' -methoxy- [1,1' -biphenyl ] -3-yl) -7H-imidazo [4,5-c ] pyridazine (200 mg,0.5 mmol) was dissolved in 5mL of a solution of boron tribromide in dichloromethane (1M), followed by stirring overnight at room temperature. Water was added, neutralized with aqueous sodium bicarbonate, extracted with dichloromethane, concentrated, and purified by prep. plate (dichloromethane: methanol=10:1) to give the title compound (100 mg, 50%) as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δ10.49-10.68(m,1H)9.51-9.62(m,1H)8.80-8.92(m,1H)8.45-8.56(m,2H)7.47-7.64(m,2H)7.37-7.48(m,2H)4.44-4.58(m,2H)3.35-3.40(m,2H)1.55(s,3H)1.17(s,3H).LC-MS:m/z[M+H] + ＝427.
Example 62
62-1: 3-bromo-6- (isopropylsulfanyl) -2-methoxypyridine
Experimental procedure the same as in example 48-1 was used for the synthesis of 3-bromo-6-chloro-2-methoxypyridine (200 mg,0.9 mmol), and isopropyl mercaptan (76 mg,1.0 mmol) as starting material to give crude product (220 mg), which was directly fed to the next step. LC-MS: M/z [ M+H ]] + ＝262,264
62-2: 3-bromo-6- (isopropylsulfonyl) -2-methoxypyridine
Experimental procedure the synthesis of 48-2 in example 48 was followed using 3-bromo-6- (isopropylthio) -2-methoxypyridine (210 mg,0.800 mmol) as the starting material to give the title compound (147 mg, 62.5%). LC-MS: M/z [ M+H)] + ＝294,296.
62: 7-ethyl-4- (3- (6- (isopropylsulfonyl) -2-methoxypyridin-3-yl) -4-fluorophenyl) -7H-imidazole And [4,5-c ]]Pyridazine (PYRIZE)
The procedure was as in example 1, starting from 3-bromo-6- (isopropylsulfonyl) -2-methoxypyridine (71 mg,0.261 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (80 mg,0.217 mmol), affording the title compound (12 mg, 12.2%).
1 H NMR(400MHz,CHLOROFORM-d)d＝9.35(br.s.,1H),8.29(br.s.,3H),7.95-7.75(m,2H),7.37(t,J＝8.8Hz,1H),4.64-4.52(m,2H),4.02(s,3H),3.87-3.72(m,1H),1.68(t,J＝6.8Hz,3H),1.40(d,J＝6.8Hz,6H).LC-MS:m/z[M+H] + ＝456.
Example 63
63-1: 3-bromo-6- (n-propylsulfanyl) -2-methoxypyridine
Experimental procedure the same as in example 48-1 was used for the synthesis of 3-bromo-6-chloro-2-methoxypyridine (200 mg,0.9 mmol), n-propanethiol (76 mg,1.0 mmol) as a starting material to give crude product (210 mg), which was directly fed to the next step LC-MS: M/z [ M+H ] ] + ＝262,264
63-2: 3-bromo-6- (n-propylsulfonyl) -2-methoxypyridine
Experimental procedure the same as in example 48-2 was used for the synthesis of the title compound (120 mg, 52.7%) from 3-bromo-6- (n-propylsulfanyl) -2-methoxypyridine (210 mg,0.800 mmol). LC-MS: M/z [ M+H ]] + ＝294,296.
63: 7-ethyl-4- (3- (6- (n-propylsulfonyl) -2-methoxypyridin-3-yl) -4-fluorophenyl) -7H-imidazole And [4,5-c ]]Pyridazine (PYRIZE)
The procedure was as in example 1, starting from 3-bromo-6- (n-propylsulfonyl) -2-methoxypyridine (71 mg,0.261 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (80 mg,0.217 mmol), affording the title compound (50 mg, 50.6%).
1 H NMR(400MHz,CHLOROFORM-d)d＝9.36(s,1H),8.32-8.24(m,3H),7.91(d,J＝7.3Hz,1H),7.80(d,J＝7.3Hz,1H),7.38(t,J＝9.0Hz,1H),4.58(q,J＝7.3Hz,2H),4.03(s,3H),3.44-3.33(m,2H),1.91-1.82(m,2H),1.69(t,J＝7.3Hz,3H),1.09(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝456.
Example 64
64-1: 2-bromo-6-methoxypyridin-3-ol
6-methoxypyridin-3-ol (500 mg,4 mmol) and NBS (1 g,5.62 mmol) were added sequentially to a mixed solution of acetonitrile and water (V/V=4:1, 20 mL), stirred at room temperature for 16 hours, filtered, and the mother liquor was concentrated to prepare a pale yellow solid of the title compound (400 mg, 49%). LC-MS: M/z [ M+H ]] + ＝204,206.
64-2: 6-bromo-5-hydroxypyridin-2 (1H) -one
2-bromo-6-methoxypyridin-3-ol (100 mg,0.50 mmol) was added to aqueous hydrobromic acid (40%, 2 mL), stirred at 90℃for 4 hours, cooled, a large amount of white solid precipitated, filtered, and the filter cake evaporated to dryness to give the title compound as a white solid (70 mg, 75%). LC-MS: M/z [ M+H ] ] + ＝190,192.
64-3: 6-bromo-5-methoxy-1-methylpyridin-2 (1H) -one
6-bromo-5-hydroxypyridin-2 (1H) -one (70 mg,0.37 mmol), potassium carbonate (200 mg,1.45 mmol) and methyl iodide (250 mg,1.76 mmol) were added sequentially to methanol (5 mL), stirred at room temperature for 16 hours, filtered, and the mother liquor concentrated to prepare a plate to give the title compound as a pale yellow solid (15 mg, 19%). LC-MS: M/z [ M+H ]] + ＝218,220.
64:6- (5- (7-ethyl 7H imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenyl) -5-methoxy-1-methylpyridine Pyridin-2 (1H) -ones
The procedure was as in example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (25 mg,0.07 mmol) 6-bromo-5-methoxy-1-methylpyridin-2 (1H) -one (15 mg,0.07 mmol) to give a brown solid (6 mg, 23% yield).
1 H NMR(400MHz,CHLOROFORM-d)9.38(s,1H),8.51-8.22(m,3H),7.48-7.37(m,2H),6.72(d,J＝9.3Hz,1H),4.59(q,J＝7.3Hz,2H),3.62(s,3H),3.40(s,3H),1.71-1.69(m,3H).LC-MS:m/z[M+H] + ＝380.
Example 65
65-1: 2-bromo-5-fluoro-N, N-dimethylaniline
2-bromo-5-fluoroaniline (CAS: 1003-99-2,500mg,1.6 mmol) was dissolved in 10mL of tetrahydrofuran, sodium hydrogen (190 mg,4.7 mmol) and methyl iodide (0.2 mL) were added, and the mixture was heated to 40℃and stirred for 2 hours. Concentration, prep. plate purification (petroleum ether) gave the title compound (150 mg, 26%) as a yellow liquid. LC-MS: M/z [ M+H ]] + ＝218.
65-2: 2-bromo-5- (ethylsulfanyl) -N, N-dimethylaniline
2-bromo-5-fluoro-N, N-dimethylaniline (150 mg,0.7 mmol), ethanethiol (0.5 mL), cesium carbonate (500 mg,1.5 mmol) were dissolved in 5mL DMF in this order, and then stirred overnight at 100 ℃. The reaction solution was filtered, concentrated, and purified by prep. plate (petroleum ether=1) to give the title compound (150 mg, 83%) as a white solid. LC-MS: M/z [ M+H ]] + ＝260.
65-3: 2-bromo-5- (ethylsulfonyl) -N, N-dimethylaniline
2-bromo-5- (ethylsulfanyl) -N, N-dimethylaniline (150 mg,0.6 mmol) was dissolved in 5mL of methylene chloride, and m-chloroperoxybenzoic acid (200 mg,1.5 mmol) was added thereto and stirred at room temperature for 2 hours. Concentration, prep. plate purification (dichloromethane: methanol=20:1) afforded the title compound as a colorless liquid(100mg,59％)。LC-MS:m/z[M+H] + ＝292.
65:5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -4- (ethylsulfonyl) -2' -fluoro-N, N-di Methyl- [1,1' -biphenyl]-2-amine
The procedure was as in example 1 starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (50 mg,0.14 mmol) 2-bromo-5- (ethylsulfonyl) -N, N-dimethylaniline (50 mg,0.16 mmol) to give the title compound (15 mg, 19%) as a brown solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.35(br.s.,1H)8.21-8.38(m,3H)7.55(s,1H)7.44-7.52(m,2H)7.38(t,J＝8.80Hz,1H)4.58(q,J＝6.85Hz,2H)3.18(q,J＝7.17Hz,2H)2.65(s,6H)1.69(t,J＝6.85Hz,3H)1.37(t,J＝7.09Hz,3H).LC-MS:m/z[M+H] + ＝454.
Example 66
66-1: 5-bromo-6-methoxynicotinamide
Methyl 5-bromo-6-methoxynicotinate (300 mg,1.22 mmol) was added to a methanolic ammonia solution (15%, 5 mL), tube sealed at 110℃and stirred for 16 h, concentrated, and the title compound was prepared as a white solid (200 mg, 71%).
66-2: 5-bromo-6-methoxynicotinonitrile
5-bromo-6-methoxynicotinamide (60 mg,0.26 mmol) and triethylamine (150 mg,1.5 mmol) are added to dichloromethane (5 mL) and trifluoroacetic anhydride (210 mg,1 mmol) is added dropwise to the solution, stirred at room temperature for 2 hours, washed with saturated aqueous ammonium chloride (5 mL), and the organic phase concentrated to give the title compound as a white solid (40 mg, 72%) prepared as a plate.
66:5- (5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenyl) -6-methoxy nicotinonitrile
The experimental procedure was as in example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (60 mg,0.16 mmol), 5-bromo-6-methoxynicotinonitrile (40 mg,0.19 mmol) to give a white solid (5 mg, 8% yield).
1 H NMR(400MHz,CHLOROFORM-d)9.37(br.s.,1H),8.55(s,1H),8.30-8.24(m,3H),7.91(s,1H),7.38(t,J＝9.0Hz,1H),4.61-4.56(m,2H),4.03(s,3H),1.71-1.68(m,3H).LC-MS:m/z[M+H] + ＝375.
Example 67
67-1: 4-bromo-5-methoxy-1-methylpyridin-2 (1H) -one
4-bromo-2-chloro-5-methoxypyridine (CAS: 1020253-15-9,200mg,0.9 mmol) was dissolved in 5mL of dimethyl sulfate and then heated under reflux overnight. Cooled to room temperature, acetonitrile (10 ml), saturated aqueous sodium bicarbonate (10 ml) was added, and stirred at room temperature overnight. Extraction with dichloromethane, drying, concentration, preparation plate purification (dichloromethane: methanol=30:1) afforded the title compound (50 mg, 25%) as a white solid. LC-MS: M/z [ M+H ] ] + ＝219.
67:4- (5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenyl) -5-methoxy-1-methyl Pyridin-2 (1H) -ones
The experimental procedure was as in example 1 starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (70 mg,0.22 mmol) and 4-bromo-5-methoxy-1-methylpyridin-2 (1H) -one (50 mg,0.22 mmol) to give the title compound (24 mg, 27%) as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.35(s,1H)8.18-8.34(m,3H)7.34(t,J＝8.80Hz,1H)6.87(s,1H)6.70(s,1H)4.58(q,J＝7.17Hz,2H)3.69(s,3H)3.62(s,3H)1.69(t,J＝7.09Hz,3H).LC-MS:m/z[M+H] + ＝380.
Example 68
68-1: (5-bromo-6-methoxypyridin-2-yl) methanol
Methyl 5-bromo-6-methoxypicolinate (300 mg,1.22 mmol) was added to a mixed solution of tetrahydrofuran and methanol (V/v=1:1, 10 mL), followed by sodium borohydride (300 mg,7.9 mmol), stirred at room temperature for 1 hour, and concentrated to prepare a plate to give the title compound as a white solid (160 mg, 60%). LC-MS: M/z [ M+H ]] + ＝218,220.
68-2: 3-bromo-6- (bromomethyl) -2-methoxypyridine
(5-bromo-6-methoxypyridin-2-yl) methanol (150 mg,0.69 mmol), carbon tetrabromide (660 mg,2 mmol) and triphenylphosphine (365 mg,1.4 mmol) were added to anhydrous tetrahydrofuran (10 mL), and the plates were prepared as white solids (100 mg, 52%) under argon, stirred at room temperature for 16 hours, concentrated and the title compound was obtained. LC-MS: M/z [ M+H ] ] + ＝280，282，284.
68-3: 3-bromo-2-methoxy-6- ((methylsulfonyl) methyl) pyridine
3-bromo-6- (bromomethyl) -2-methoxypyridine (95 mg,0.34 mmol) and sodium methylsulfinate (100 mg,1 mmol) were added to a mixed solution of dioxane and water (V/v=5:1, 5 ml), stirred at 30 ℃ for 5 hours, concentrated, and the plates were prepared to give the title compound as a white solid (70 mg, 74%). LC-MS: M/z [ M+H ]] + ＝280，282.
68: 7-Ethyl-4- (4-fluoro-3- (2-methoxy-6- ((methylsulfonyl) methyl) pyridin-3-yl) phenyl) -7H-o-f Imidazo [4,5-c]Pyridazine (PYRIZE)
The procedure was as in example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (50 mg,0.14 mmol) 3-bromo-2-methoxy-6- ((methylsulfonyl) methyl) pyridine (38 mg,0.14 mmol) to give a brown solid (40 mg, 65% yield).
1 H NMR(400MHz,CHLOROFORM-d)9.36(s,1H),8.31-8.21(m,3H),7.74(d,J＝7.3Hz,1H),7.35(t,J＝9.0Hz,1H),7.18(d,J＝7.3Hz,1H),4.58(q,J＝7.3Hz,2H),4.39(s,2H),3.96(s,3H),3.06(s,3H),1.71-1.67(m,3H).LC-MS:m/z[M+H] + ＝442.
Example 69
69-1:1- (ethylsulfonyl) -3-methoxy-1H-pyrazole
3-methoxy-1H-pyrazole (CAS: 215610-30-3,200mg,2 mmol) was dissolved in 10mL of anhydrous tetrahydrofuran, sodium hydrogen (100 mg,2.5 mmol) was added and stirred for 10 minutes, and then ethanesulfonyl chloride (0.5 mL) was added and then stirred at room temperature for 1 hour. Concentration, prep. plate purification (petroleum ether: ethyl acetate=3:1) gave the title compound (300 mg, 100%) as a colorless liquid. LC-MS: M/z [ M+H ] ] + ＝191.
69-2: 4-bromo-1- (ethylsulfonyl) -3-methoxy-1H-pyrazole
1- (ethylsulfonyl) -3-methoxy-1H-pyrazole (300 mg,1.1 mmol) was dissolved in 10mL of water, NBS (200 mg,1.3 mmol) was added, and then stirred at room temperature overnight. Water was added, extracted with dichloromethane, concentrated, and prepared for plate purification (petroleum ether: ethyl acetate=3:1) to give the title compound (150 mg, 35%) as a colorless liquid. LC-MS: M/z [ M+H ]] + ＝269.
69: 7-ethyl-4- (3- (1- (ethylsulfonyl) -3-methoxy-1H-pyrazol-4-yl) -4-fluorophenyl) -7H-mi-ne Azolo [4,5-c ]]Pyridazine (PYRIZE)
The experimental procedure was as in example 1 starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (50 mg,0.14 mmol) 4-bromo-1- (ethylsulfonyl) -3-methoxy-1H-pyrazole (50 mg,0.16 mmol) to give the title compound (30 mg, 53%) as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.38(s,1H)8.73(dd,J＝7.34,1.96Hz,1H)8.34(d,J＝2.93Hz,1H)8.31(s,1H)8.18-8.25(m,1H)7.34(dd,J＝10.76,8.80Hz,1H)4.59(q,J＝7.17Hz,2H)4.07-4.18(m,3H)3.50(q,J＝7.34Hz,2H)1.70(t,J＝7.09Hz,3H)1.30-1.37(m,3H).LC-MS:m/z[M+H] + ＝431.
Example 70
70-1: 2-bromo-5- (ethylsulfonyl) -1, 3-difluorobenzene
4-bromo-3, 5-difluorobenzenesulfonyl chloride (CAS: 518057-63-1,700mg,2.4 mmol) was dissolved in 10mL of tetrahydrofuran, cooled to 0 ℃, hydrazine hydrate (0.5 mL) was added, stirred at room temperature for 1 hour, concentrated, and plate-purified (petroleum ether: ethyl acetate=5:1) was prepared to give an intermediate dissolved in 10mL of ethanol, sodium acetate (1.9 g,24 mmol) and ethyl iodide (0.3 mL) were added, and heated to reflux for 3 hours. Concentration, prep. plate purification (petroleum ether: ethyl acetate=5:1) gave the title compound (110 mg, 16%) as a white solid. LC-MS: M/z [ M+H ] ] + ＝285.
70-2: 2-bromo-5- (ethylsulfonyl) -1-fluoro-3-methoxybenzene
2-bromo-5- (ethylsulfonyl) -1, 3-difluorobenzene (100 mg,0.35 mmol) and potassium carbonate (100 mg,0.7 mmol) were added sequentially to 5mL of DMF, 1mL of methanol was added, and then heated to 45℃for 2 hours. Water was added, extracted with ethyl acetate, dried, concentrated, and prepared for plate purification (petroleum ether: ethyl acetate=3:1) to give the title compound (60 mg, 60%) as a white solid. LC-MS: M/z [ M+H ]] + ＝297.
70: 7-ethyl-4- (4 '- (ethylsulfonyl) -2', 6-difluoro-6 '-methoxy- [1,1' -biphenyl)]3-yl) 7H-imidazo [4,5-c]Pyridazine (PYRIZE)
The experimental procedure was as in example 1 starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (50 mg,0.14 mmol), 2-bromo-5- (ethylsulfonyl) -1-fluoro-3-methoxybenzene (40 mg,0.16 mmol) to give the title compound (3 mg, 5%) as a yellow solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.37(s,1H)8.36(br.s.,1H)8.29(s,1H)8.21(d,J＝5.87Hz,1H)7.37-7.46(m,2H)7.34(s,1H)4.59(q,J＝7.01Hz,2H)3.91(s,3H)3.21(q,J＝7.34Hz,2H)1.68-1.73(m,3H)1.39(t,J＝7.34Hz,3H).LC-MS:m/z[M+H] + ＝459.
Example 71
71-1: 5-bromo-1-ethyl-4-methoxypyrimidin-2 (1H) -one
5-bromo-2, 4-dimethoxypyrimidine (500 mg,2.29 mmol), iodoethane (1 g,6.41 mmol) and sodium carbonate (800 mg,7.55 mmol) were added to dichloromethane (10 mL), the vessel was sealed, stirred at 60℃for 48 hours, filtered, concentrated and the plate was prepared to give the title compound as a white solid (150 mg, 28%). LC-MS: M/z [ M+H ] ] + ＝233，235.
71: 1-ethyl-5- (5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenyl) -4-methoxy group Pyrimidin-2 (1H) ones
The procedure was as in example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (50 mg,0.14 mmol) 5-bromo-1-ethyl-4-methoxypyrimidin-2 (1H) -one (32 mg,0.14 mmol) to give a brown solid (15 mg, yield 27%).
1 H NMR(400MHz,CHLOROFORM-d)9.35(s,1H),8.29(s,1H),8.23(d,J＝6.8Hz,2H),7.61(s,1H),7.35(t,J＝9.0Hz,1H),4.59(q,J＝7.0Hz,2H),4.06-3.94(m,5H),1.70(t,J＝7.3Hz,3H),1.42(t,J＝7.1Hz,3H).LC-MS:m/z[M+H] + ＝395.
Example 72
72-1: 3-bromo-2-methoxy-5- (2-methoxyethoxy) pyridine
3-bromo-5-fluoro-2-methoxypyridine (CAS: 884494-81-9,200mg,0.5 mmol), 2-methoxyethanol (150 mg,2 mmol) and cesium carbonate (300 mg,1 mmol) were added sequentially to 10mL of DMF, followed by overnight at 100 ℃. Water was added, extracted with ethyl acetate, dried, concentrated, and prepared for plate purification (petroleum ether: ethyl acetate=20:1) to give the title compound (80 mg, 31%) as a colorless liquid. LC-MS: M/z [ M+H ]] + ＝263.
72: 7-ethyl-4- (4-fluoro-3- (2-methoxy-5- (2-methoxyethoxy) pyridin-3-yl) phenyl) -7H-mi-ne Azolo [4,5-c ]]Pyridazine (PYRIZE)
The experimental procedure was as in example 1 starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (50 mg,0.14 mmol) 3-bromo-2-methoxy-5- (2-methoxyethoxy) pyridine (40 mg,0.16 mmol) to give the title compound (12 mg, 21%) as a brown solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.37(s,1H)8.24-8.30(m,3H)7.93(d,J＝2.93Hz,1H)7.40(d,J＝2.93Hz,1H)7.35(t,J＝9.29Hz,1H)4.59(q,J＝7.34Hz,2H)4.15-4.21(m,2H)3.93(s,3H)3.75-3.80(m,2H)3.47(s,3H)1.68-1.73(m,3H).LC-MS:m/z[M+H] + ＝424.
Example 73
73-1: 4-bromo-5-methoxy-2- (oxetan-3-yloxy) pyridine
4-bromo-2-fluoro-5-methoxypyridine (100 mg,0.49 mmol), cesium carbonate (178 mg,1.47 mmol) and oxetan 3-ol (72.6 mg,0.98 mmol) were added to acetonitrile (4 ml), and stirred at 65℃for 16 hWhen (1). The reaction solution was extracted with ethyl acetate and water, and the organic phase was concentrated to prepare a plate for separation and purification (dichloromethane/methanol=12/1) to give the title compound (25 mg, 19.7%). LC-MS: M/z [ M+H ]] + ＝261，263.
73: 7-ethyl-4- (4-fluoro-3- (5-methoxy-2- (oxetan-3-yloxy) pyridin-4-yl) phenyl) propan-e 7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using 4-bromo-5-methoxy-2- (oxetan-3-yloxy) pyridine (25 mg,0.1 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (31 mg,0.8 mmol) as starting material gave the title compound (10 mg, 29.8%).
1 H NMR(400MHz,CDCl3)δ9.36(s,1H),8.33-8.28(m,2H),8.23(d,J＝6.4Hz,1H),7.80(s,1H),7.36(t,J＝8.8Hz,1H),6.85(s,1H),5.60(t,J＝5.9Hz,1H),5.01(t,J＝6.8Hz,2H),4.76(t,J＝6.4Hz,2H),4.58(q,J＝7.2Hz,2H),3.83(s,3H),1.73-1.68(m,3H).LC-MS:m/z[M+H] + ＝422.
Example 74
74-1: (5-bromo-6-methoxypyridin-3-yl) methanol
Methyl 5-bromo-6-methoxynicotinate (CAS: 93349-99-6,250mg,1 mmol) was dissolved in 10mL of tetrahydrofuran, cooled to 0 ℃,1M diisobutylaluminum hydride (1 mL,1 mmol) was added thereto, stirred for 10 minutes, and then quenched with water. Concentration, prep. plate purification (dichloromethane: methanol=20:1) gave the title compound (100 mg, 46%) as a colorless liquid. LC-MS: M/z [ M+H ] ] + ＝218.
74-2: 3-bromo-2-methoxy-5- (methoxymethyl) pyridine
(5-bromo-6-methoxypyridin-3-yl) methanol (200 mg,1 mmol) was dissolved in 10mL of tetrahydrofuran, sodium hydrogen (80 mg,2 mmol) was added, and after stirring for 10 minutes, methyl iodide (300 mg,2 mmol) was addedAnd then stirred at room temperature for 30 minutes. Concentration, prep. plate purification (petroleum ether: ethyl acetate=5:1) afforded the title compound (100 mg, 50%) as a white solid. LC-MS: M/z [ M+H ]] + ＝232.
74: 7-ethyl-4- (4-fluoro-3- (2-methoxy-5- (methoxymethyl) pyridin-3-yl) phenyl) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (63 mg,0.17 mmol), 3-bromo-2-methoxy-5- (methoxymethyl) pyridine (40 mg,0.17 mmol) the title compound (10 mg, 15%) is obtained as a brown solid.
1 H NMR(400MHz，CHLOROFORM-d)δ9.37(s，1H)8.21-8.31(m，3H)8.19(s，1H)7.70(s，1H)7.35(t,J＝9.05Hz,1H)4.59(q,J＝7.34Hz,2H)4.47(s,2H)3.98(s,3H)3.42(s,3H)1.70(t,J＝7.34Hz,3H).LC-MS:m/z[M+H] + ＝394.
Example 75
75-1: 5-bromo-4-methoxy-1-methylpyrimidin-2 (1H) -one
5-bromo-2, 4-dimethoxypyrimidine (500 mg,2.29 mmol), methyl iodide (1.42 g,10 mmol) and sodium carbonate (800 mg,7.55 mmol) were added to dichloromethane (10 mL), the vessel was sealed, stirred at 60℃for 16 hours, filtered, and concentrated to give the title compound as a white solid (330 mg, 66%) which was prepared as a plate. LC-MS: M/z [ M+H ] ] + ＝219,221.
75:5- (5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenyl) -4-methoxy-1-methyl Pyrimidin-2 (1H) ones
The procedure was as in example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (36 mg,0.1 mmol) 5-bromo-4-methoxy-1-methylpyrimidin-2 (1H) -one (22 mg,0.1 mmol) to give a brown solid (11 mg, 29% yield).
1 H NMR(400MHz,CHLOROFORM-d)9.34(s,1H),8.29(s,1H),8.25-8.16(m,2H),7.61(s,1H),7.34(t,J＝8.8Hz,1H),4.59(q,J＝7.0Hz,2H),4.00(s,3H),3.58(s,3H),1.73-1.69(m,3H).LC-MS:m/z[M+H] + ＝381.
Example 76
76-1: 2-bromo-1-methoxy-4- (methoxymethyl) benzene
3-bromo-4-methoxybenzyl alcohol (CAS: 38493-59-3,200mg,1 mmol) was dissolved in 10mL of tetrahydrofuran, sodium hydrogen (60 mg,1.5 mmol) was added and stirred for 10 minutes, and then methyl iodide (150 mg,1 mmol) was added and then stirred at room temperature for 30 minutes. Concentration, prep. plate purification (petroleum ether: ethyl acetate=5:1) gave the title compound (100 mg, 45%) as a colorless liquid. LC-MS: M/z [ M+H ]] + ＝232.
76: 7-ethyl-4- (6-fluoro-2 ' -methoxy-5 ' - (methoxymethyl) - [1,1' -biphenyl)]-3-yl) -7H-imidazole And [4,5-c ]]Pyridazine (PYRIZE)
Experimental procedure Using example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (50 mg,0.14 mmol), 2-bromo-1-methoxy-4- (methoxymethyl) benzene (50 mg,0.16 mmol), the title compound (16 mg, 27%) is obtained as a brown solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.37(s,1H)8.26-8.32(m,2H)8.17(dd,J＝6.85,2.45Hz,1H)7.39(d,J＝8.31Hz,1H)7.34(d,J＝6.36Hz,2H)7.01(d,J＝8.31Hz,1H)4.58(q,J＝7.01Hz,2H)4.46(s,2H)3.84(s,3H)3.41(s,3H)1.70(d,J＝2.93Hz,3H).LC-MS:m/z[M+H] + ＝393.
Example 77
77-1: 5-bromo-4-chloro-1-methylpyridin-2 (1H) -one
5-bromo-4-chloropyridin-2- (1H) -one (160 mg,0.77 mmol), potassium carbonate (250 mg,1.81 mmol) and methyl iodide (500 mg,3.52 mmol) were added sequentially to methanol (5 mL), stirred at room temperature for 16H, filtered, and the mother liquor concentrated to give the title compound as a white solid (140 mg, 82%) prepared as a plate. LC-MS: M/z [ M+H ]] + ＝222，224，226.
77-2: 5-bromo-4-methoxy-1-methylpyridin-2 (1H) -one
5-bromo-4-chloro-1-methylpyridin-2 (1H) -one (140 mg,0.63 mmol) was added to a methanolic solution of sodium methoxide (0.5M, 5 mL), stirred at 60℃for 16 hours, concentrated, and the title compound was prepared as a white solid (140 mg, 98%). LC-MS: M/z [ M+H ]] + ＝218，220.
77:5- (5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenyl) -4-methoxy-1-methyl Pyridin-2 (1H) -ones
Experimental procedure is as in example 1, using 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c]Pyridazine (30 mg,0.08 mmol), 5-bromo-4-methoxy-1-methylpyridin-2 (1H) -one (20 mg,0.09 mmol) was used as a starting material to give a brown solid (10 mg, 33% yield). 1 H NMR(400MHz,CHLOROFORM-d)9.35(s,1H),8.29(s,1H),8.25-8.18(m,1H),8.15(dd,J＝2.2,7.1Hz,1H),7.35-7.28(m,2H),6.05(s,1H),4.65-4.53(m,2H),3.79(s,3H),3.56(s,3H),1.69(t,J＝7.1Hz,3H).LC-MS:m/z[M+H] + ＝380.
Example 78
78-1: (4-bromo-3- (methoxymethyl) phenyl) (ethyl) sulfane
1-bromo-4-iodo-2- (methoxymethyl) benzene (380 mg,1.16 mmol), ethanethiol (72 mg,1.16 mmol), ethylene glycol (144 mg,2.32 mmol), potassium carbonate (320 mg,2.32 mmol) and cuprous iodide (22 mg,0.116 mmol) were added to isopropanol (10 mL), and stirred at 80℃under argon for 16 hours. The reaction solution was concentrated after filtration, and the title compound (290 mg, 96%) was isolated as a colorless oil by thin layer chromatography (petroleum ether).
78-2: 1-bromo-4- (ethylsulfonyl) -2- (methoxymethyl) benzene
(4-bromo-3- (methoxymethyl) phenyl) (ethyl) sulfane (290 mg,1.11 mmol), potassium hydrogen persulfate (10200 mg,3.33 mmol) and methylene chloride (5 mL) were added to methanol (5 mL) and stirred at room temperature for 16 hours. The reaction solution was concentrated after filtration, and the title compound (160 mg, 49%) was isolated as a colorless oily liquid by preparative thin layer chromatography (petroleum ether/ethyl acetate=3/1).
78: 7-ethyl-4- (4 ' - (ethylsulfonyl) -6-fluoro-2 ' - (methoxymethyl) - [1,1' -biphenyl]3-yl) 7H-imidazo [4,5-c]Pyridazine (PYRIZE)
The experimental procedure was as in example 1 starting from 1-bromo-4- (ethylsulfonyl) -2- (methoxymethyl) benzene (160 mg,0.55 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (200 mg,0.55 mmol) to give the title compound (21 mg, 8%) as a brown solid.
1 H NMR(400MHz,CHLOROFORM-d)δ＝9.36(s,1H),8.33(ddd,J＝2.4,4.8,8.4Hz,1H),8.29(s,1H),8.21(dd,J＝2.0,6.8Hz,1H),8.17(s,1H),7.92(dd,J＝1.7,8.1Hz,1H),7.55(d,J＝7.8Hz,1H),7.39(t,J＝8.8Hz,1H),4.58(q,J＝7.3Hz,2H),4.43(s,2H),3.33(s,3H),3.19(q,J＝7.5Hz,2H),1.68(t,J＝7.3Hz,3H),1.34(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝455.
Example 79
79-1：(4-Bromide)-3-methoxyphenyl) (2-oxa-6-azaspiro [3.3]]Hept-6-yl) methanones
4-bromo-3-methoxybenzoic acid (231 mg,1.00 mmol), 2-oxa-6-azaspiro [3.3]]Heptane oxalate (189 mg,1.00 mmol), HOBt (270 mg,2.00 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (191 mg,2.00 mmol) was added to dichloromethane (10 mL), triethylamine (303 mg,3.00 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction was dropped into a saturated aqueous ammonium chloride solution (30 mL), extracted with dichloromethane (30 ml×3), the organic phases were combined, washed with saturated brine (30 mL), and the organic phase was concentrated to prepare a thin layer chromatography (dichloromethane/methanol=30/1) to separate the title compound (250 mg, 80%) as a white solid. LC-MS: M/z [ M+H ]] + ＝312,314.
79: (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl]- 4-yl) (2-oxa-6-azaspiro [3.3]]Hept-6-yl) methanones
Experimental procedure Using (4-bromo-3-methoxyphenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (34 mg,0.11 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (40 mg,0.11 mmol) as the starting material gave the title compound (7 mg, 13%) as a yellow solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.50-9.39(m,1H),8.39(s,1H),8.31(br.s.,1H),8.20(br.s.,1H),7.41-7.33(m,3H),7.22(d,J＝6.8Hz,1H),4.84(d,J＝13.7Hz,4H),4.62-4.50(m,4H),4.39(br.s.,2H),3.86(s,3H),1.32(br.s.,3H).LC-MS:m/z[M+H] + ＝474.
Example 80
80: 7-ethyl-4- (3- (6- (ethylsulfonyl) -2-methoxypyridin-3-yl) -4-fluorophenyl) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
The procedure was as in example 1 starting from 3-bromo-6- (ethylsulfonyl) -2-methoxypyridine (80 mg, 0.284 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (96 mg,0.260 mmol) to give the title compound (50 mg, 43.5%).
1 H NMR(400MHz，CHLOROFORM-d)d＝9.37(s，1H)，8.35-8.24(m，3H)，7.92(d，J＝6.8Hz，1H),7.81(d,J＝7.3Hz,1H),7.39(t,J＝8.8Hz,1H),4.59(q,J＝7.0Hz,2H),4.03(s,3H),3.45(q,J＝7.3Hz,2H),1.69(t,J＝7.3Hz,3H),1.40(t,J＝7.6Hz,3H).LC-MS:m/z[M+H] + ＝442.
Example 81
81-1: (4-bromo-3-methoxyphenyl) methanol
Methyl 4-bromo-3-methoxybenzoate (2.0 g,8.163 mmol) was added to THF (10 ml), lithium aluminum hydride (930 mg,24.48 mmol) was added to the reaction solution in three 45 min, stirred at room temperature for 15 min, sodium sulfate decahydrate (1.0 g) was added to the reaction solution, suction filtered, concentrated, and column chromatographed (petroleum ether/ethyl acetate=5/1) to give the title compound (788 mg, 44.5%).
81-2: 1-bromo-4- (bromomethyl) -2-methoxybenzene
(4-bromo-3-methoxyphenyl) methanol (788 mg,3.637 mmol), carbon tetrabromide (3.605 g,11.0 mmol), triphenylphosphine (1.902 g,7.260 mmol) were added to DCM (10 ml) and stirred overnight at room temperature under argon protection the reaction solution was concentrated and column chromatographed (petroleum ether) to give the title compound (788 mg, 77.4%).
81-3: (4-bromo-3-methoxybenzyl) (methyl) sulfane
Bromo-4- (bromomethyl) -2-methoxybenzene (788 mg,2.814 mmol), sodium methyl mercaptide (40% in water) (1.4 ml,8.442 mmol) and cesium carbonate (1.834 g, 5.428 mmol) were added to DMF (2 ml) and stirred at room temperature for 4 hours, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated and the crude product (877 mg) was directly added to the next step.
81-4: 1-bromo-2-methoxy-4- ((methylsulfonyl) methyl) benzene
(4-bromo-3-methoxybenzyl) (methyl) sulfane (877 mg,2.814 mmol), potassium hydrogen persulfate (1.88 g,5.766 mmol) and THF (10 ml), methanol (5 ml) and water (2 ml) were added, and the mixture was stirred at room temperature for 4 hours, and the reaction solution was filtered with suction and concentrated to give the title compound (178 mg, 61.2%) by thin layer chromatography (petroleum ether/ethyl acetate=20/1).
81-5: 1-bromo-2-methoxy-4- (1- (methylsulfonyl) cyclopropyl) benzene
1-bromo-2-methoxy-4- ((methylsulfonyl) methyl) benzene (40 mg,0.143 mmol) and 1, 2-dibromoethane (40 mg,0.21 mmol) were stirred in aqueous potassium hydroxide (50%, 2 mL) overnight at room temperature, extracted with dichloromethane (10 mL x 3), and the organic phase was concentrated to give 20mg of crude product which was used directly in the next step.
81: 7-ethyl-4- (6-fluoro-2 ' -methoxy-4 ' - (1- (methylsulfonyl) cyclopropyl) - [1,1' -biphenyl)]-3- Radical) -7H-imidazo [4,5-c ]Pyridazine (PYRIZE)
The experimental procedure was as in example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (30 mg,0.08 mmol), 1-bromo-2-methoxy-4- (1- (methylsulfonyl) cyclopropyl) benzene (20 mg,0.08 mmol) to give a brown solid (2 mg, 5% yield).
1 H NMR(400MHz,CHLOROFORM-d)9.36(br.s.,1H),8.27(s,2H),8.19(d,J＝4.9Hz,1H),7.35(t,J＝6.8Hz,2H),7.28-7.26(m,1H),7.19(d,J＝6.8Hz,1H),4.57(q,J＝7.3Hz,2H),3.86(s,3H),2.86(s,3H),1.88(s,2H),1.68(t,J＝7.1Hz,3H),1.36(s,2H).LC-MS:m/z[M+H] + ＝467.
Example 82
82: 7-ethyl-4- (7- (ethylsulfonyl) dibenzo [ b, d)]Furan-2-yl) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
5' - (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -4- (ethylsulfonyl) -2' -fluoro- [1,1' -biphenyl ] -2-ol (70 mg,0.14 mmol) and cesium carbonate (91 mg,0.28 mmol) are added to DMF (4 mL), under argon, and stirred at 100℃for two hours. The reaction was directly purified by prep. plate (dichloromethane/methanol=30/1) to give the title compound (8 mg, 14.1%).
1 H NMR(400MHz,CDCl3)δ9.48(s,1H),8.95(s,1H),8.43(d,J＝9.3Hz,1H),8.33(s,1H),8.26(d,J＝7.3Hz,1H),8.19(s,1H),7.95(d,J＝7.8Hz,1H),7.84(d,J＝9.3Hz,1H),4.61(d,J＝6.8Hz,2H),3.22(d,J＝7.8Hz,2H),1.71(t,J＝7.1Hz,3H),1.36-1.32(m,3H).LC-MS:m/z[M+H] + ＝407.
Example 83
83-1:3- (4-bromo-3-methoxyphenyl) oxetane
(4-bromo-3-methoxyphenyl) boric acid (100 mg,0.43 mmol), 3-iodooxetane (100 mg,0.54 mmol), nickel diiodide (10 mg,0.03 mmol), (1R, 2R) -2-aminocyclohexanol (cas: 931-16-8,5mg,0.04 mmol), sodium bis (trimethylsilyl) amide (cas: 1070-89-9,2M,0.5 mL) were added to isopropyl alcohol (2 mL), the mixture was sealed, reacted at 100℃for 16 hours, and concentrated to prepare a plate to give a reddish-colored oil (10 mg, yield 10%).
83: 7-ethyl-4- (6-fluoro-2 ' -methoxy-4 ' - (oxetan-3-yl) - [1,1' -biphenyl)]-3-yl) -7H- Imidazo [4, 5-c-pyridazines
The experimental procedure was as in example 1 starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (30 mg,0.08 mmol) 3- (4-bromo-3-methoxyphenyl) oxetan (15 mg,0.06 mmol) to give a brown solid (5 mg, 21% yield).
1 H NMR(400MHz,CHLOROFORM-d)＝9.35(s，1H)，8.28-8.18(m,3H),7.40-7.28(m,2H),7.13-7.03(m,2H),5.12(t,J＝7.1Hz,2H),4.90-4.75(m,2H),4.57(d,J＝7.3Hz,2H),4.35-4.21(m,1H),3.86(s,3H),1.68(s,3H).LC-MS:m/z[M+H] + ＝405.
Example 84
84-1:5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-alcohols
Experimental procedure Using 4-bromo-3-methoxyphenol (663 mg,3.26 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c]Pyridazine (1200 mg,3.26 mmol) was used as starting material to give the title compound (540 mg, 45%). LC-MS: M/z [ M+H ]] + ＝365.
84-2: tert-butyl 3- ((5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2' -fluoro-2-methoxy- & gt [1,1' -Biphenyl]-4-yl) oxy) azetidine-1-carboxylate
5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl]4-alcohol (200 mg,0.55 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (311 mg,1.10 mmol) and cesium carbonate (178 mg,1.65 mmol) were added to N, N-dimethylformamide (8 mL) and stirred at 80℃for 16 h. The reaction was diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phases combined and washed with saturated brine (30 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude title compound (280 mg, crude). LC-MS: M/z [ M+H ] ] + ＝520.
84-3:4- (4 ' - (azetidin-3-yloxy) -6-fluoro-2 ' -methoxy- [1,1' -biphenyl)]3-yl) -7- ethyl-7H-imidazole [4,5-c ]]Pyridazine (PYRIZE)
Tert-butyl 3- ((5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1 ]'-biphenyl]-4-yl) oxy) azetidine-1-carboxylate (280 mg, crude) was added to dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added and stirred at room temperature for 16 hours. The reaction mixture was concentrated, diluted with methanol (1 mL), PH-adjusted to weak base with saturated sodium bicarbonate, filtered, and the filtrate was subjected to thin layer chromatography (dichloromethane/methanol=10/1) to separate the title compound (140 mg,60% two-step yield) as a yellow solid. LC-MS: M/z [ M+H ]] + ＝420.
84: 7-ethyl-4- (6-fluoro-2 '-methoxy-4' - ((1- (oxetan-3-yl) azetidin-3-yl) oxy) Group) - [1,1' -biphenyl]-3-yl) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
4- (4 ' - (azetidin-3-yloxy) -6-fluoro-2 ' -methoxy- [1,1' -biphenyl ] -3-yl) -7-ethyl-7H-imidazo [4,5-c ] pyridazine (30 mg,0.07 mmol), 3-oxetanone (10 mg,0.14 mmol) and sodium cyanoborohydride (8.8 mg,0.14 mmol) are added to methanol (5 mL) and stirred at room temperature for 1 hour. To the reaction solution was added 2 drops of aqueous sodium hydroxide (1M), followed by addition of water 10 (mL), extraction with dichloromethane (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (30 mL) and concentrated to give the title compound (6 mg, 18%) as a yellow solid by thin layer chromatography (dichloromethane/methanol=20/1).
1 H NMR(400MHz,DMSO-d6)δ＝9.54-9.50(m,1H),8.87-8.83(m,1H),8.43-8.36(m,2H),7.48-7.42(m,1H),7.26-7.22(m,1H),6.65-6.61(m,1H),6.56-6.51(m,1H),4.99-4.93(m,1H),4.61-4.56(m,2H),4.53-4.47(m,2H),4.40-4.36(m,2H),3.84-3.78(m,3H),3.75(s,3H),3.22-3.17(m,2H),1.55(s,3H).LC-MS:m/z[M+H] + ＝476.
Example 85
85-1: 3-bromo-2-methoxy-5- (oxetan-3-yloxy) pyridine
3-bromo-5-fluoro-2-methoxypyridine (CAS: 884494-81-9,200mg,0.5 mmol), 3-oxetan (150mg,2 mmol) and cesium carbonate (300 mg,1 mmol) were added sequentially to 10mL of DMF and then heated at 100deg.C overnight. Water was added, extracted with ethyl acetate, dried, concentrated, and prepared for plate purification (petroleum ether: ethyl acetate=30:1) to give the title compound (20 mg, 15%) as a colorless liquid. LC-MS: M/z [ M+H ]] + ＝261.
85: 7-ethyl-4- (4-fluoro-3- (2-methoxy-5- (oxetan-3-yloxy) pyridin-3-yl) phenyl) propan-3-yl) 7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (30 mg,0.1 mmol), 3-bromo-2-methoxy-5- (oxetan-3-yloxy) pyridine (20 mg,0.1 mmol), the title compound (13 mg, 32%) is obtained as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.37(s,1H)8.22-8.34(m,3H)7.65(d,J＝1.96Hz,1H)7.36(t,J＝9.29Hz,1H)7.24(br.s.,1H)5.23(t,J＝5.38Hz,1H)4.98(t,J＝6.60Hz,2H)4.74-4.87(m,2H)4.59(q,J＝7.01Hz,2H)3.92(s,1H)1.70(t,J＝7.09Hz,1H).LC-MS:m/z[M+H] + ＝422.
Example 86
86:1- (3- ((5' - (7-ethyl-7H-imidazo [4, 5-c))]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' ] p Biphenyl]-4-yl) oxy) azetidin-1-yl) ethan-1-one
4- (4 ' - (azetidin-3-yloxy) -6-fluoro-2 ' -methoxy- [1,1' -biphenyl ] -3-yl) -7-ethyl-7H-imidazo [4,5-c ] pyridazine (50 mg,0.12 mmol), acetic anhydride (18 mg,0.18 mmol) and triethylamine (25 mg,0.24 mmol) are added to dichloromethane (5 mL) and stirred at room temperature for 1 hour. The reaction was dropped into a saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with saturated brine (30 mL) and the organic phase was concentrated to give the title compound (19 mg, 34%) as a white solid by thin layer chromatography (dichloromethane/methanol=30/1).
1 H NMR(400MHz,DMSO-d6)δ＝9.50(s,1H),8.82(s,1H),8.42-8.34(m,2H),7.47-7.39(m,1H),7.28-7.23(m,1H),6.65-6.61(m,1H),6.53-6.48(m,1H),5.12-5.07(m,1H),4.60-4.55(m,1H),4.51-4.45(m,2H),4.32-4.27(m,1H),4.13-4.09(m,1H),3.81-3.77(m,1H),3.74(s,3H),1.79(s,3H),1.52(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝462.
Example 87
87: 7-ethyl-4- (6-fluoro-2 ' -methoxy-4 ' - ((1-methylazetidin-3-yl) oxy) - [1,1' ] for use in the treatment of cancer Biphenyl]-3-yl) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
The experiment was conducted in the same manner as in example 163 using 4- (4 ' - (azetidin-3-yloxy) -6-fluoro-2 ' -methoxy- [1,1' -biphenyl ] -3-yl) -7-ethyl-7H-imidazo [4,5-c ] pyridazine (50 mg,0.12 mmol) and aqueous formaldehyde (0.18 mmol) as starting material to give the title compound as hydrochloride (37 mg, 64%) as a yellow solid.
1 H NMR(400MHz,DMSO-d6)δ＝9.67(br.s.,1H),9.03(br.s.,1H),8.42(d,J＝6.8Hz,2H),7.51-7.44(m,1H),7.31-7.25(m,1H),6.67-6.62(m,1H),6.57-6.50(m,1H),5.11-5.03(m,1H),4.77-4.71(m,1H),4.49(d,J＝6.8Hz,2H),4.43-4.36(m,1H),4.31-4.24(m,1H),4.07-4.01(m,1H),3.75(s,3H),2.89(br.s.,3H),1.53(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝434.
Example 88
88-1: (4-bromo-3-methoxyphenyl) (oxetan-3-yl) methanone
2-bromo-5-iodoanisole (200 mg,0.637 mmol), oxetane-3-carbaldehyde (66 mg,0.768 mmol), palladium acetate (15 mg,0.064 mmol), silver oxide (178 mg,0.768 mmol), tert-butyl hydroperoxide (70% aqueous solution) (166 mg,1.27 mmol) were added to a sealed tube and argon flow was bubbled for 1 minute to react overnight at 80 ℃ the reaction solution was filtered off with suction and concentrated to give the title compound (16 mg, 9.3%) by thin layer chromatography (petroleum ether/ethyl acetate=20/1).
88: (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl]- 4-yl) (oxetan-3-yl) methanones
Experimental procedure Using (4-bromo-3-methoxyphenyl) (oxetan-3-yl) methanone (16 mg,0.059 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (21 mg,0.059 mmol) as the starting material gave the title compound (3 mg, 11.8%).
1 H NMR(400MHz,CHLOROFORM-d)d＝9.36(s,1H),8.27(s,2H),8.21(d,J＝6.8Hz,1H),7.60(s,1H),7.46(d,J＝7.3Hz,1H),7.38-7.29(m,2H),5.06-4.96(m,4H),4.75-4.64(m,1H),4.58(q,J＝7.3Hz,2H),3.90(s,3H),1.70-1.67(m,3H).LC-MS:m/z[M+H] + ＝433.
Example 89
89-1: 3-bromo-4-methoxybenzenesulfonyl hydrazide
3-bromo-4-methoxybenzenesulfonyl chloride (200 mg,0.7 mmol) and hydrazine hydrate (105 mg,2.1 mmol) were successively added to anhydrous tetrahydrofuran (6 mL) and stirred at room temperature for one hour. The reaction solution was concentrated and then slurried with petroleum ether to give the title compound (180 mg, 91.8%). LC-MS: M/z [ M+H ]] + ＝281，283.
89-2: 2-bromo-4- (ethylsulfonyl) -1-methoxybenzene
3-bromo-4-methoxybenzenesulfonyl hydrazide (180 mg,0.64 mmol), sodium acetate (525 mg,6.4 mmol) and iodoethane (300 mg,1.92 mmol) were added to ethanol (5 mL), and stirred at 80℃for 16 hours. The reaction solution was concentrated and then extracted with ethyl acetate and water, and the title compound (50 mg, 28.1%) was obtained by preparative plate separation and purification (petroleum ether/ethyl acetate=3/1).
89: 7-ethyl-4- (5 ' - (ethylsulfonyl) -6-fluoro-2 ' -methoxy- [1,1' -biphenyl)]-3-yl) -7H-imidazole And [4,5-c ]]Pyridazine (PYRIZE)
Experimental procedure was as in example 1 starting from 2-bromo-4- (ethylsulfonyl) -1-methoxybenzene (40 mg,0.15 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (69.8 mg,0.18 mmol) to give the title compound (30 mg, 37.9%).
1 H NMR(400MHz,CDCl3)δ9.34(s,1H),8.27(br.s.,2H),8.20(d,J＝6.4Hz,1H),7.94(d,J＝8.3Hz,1H),7.87(br.s.,1H),7.39-7.28(m,1H),7.13(d,J＝8.8Hz,1H),4.56(q,J＝7.0Hz,2H),3.90(s,3H),3.12(q,J＝7.3Hz,2H),1.67(t,J＝7.3Hz,3H),1.30(t,J＝7.1Hz,3H).LC-MS:m/z[M+H] + ＝441.
Example 90
90:3- ((5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) oxy) propionitrile
5' - (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2' -fluoro-2-methoxy- [1,1' -biphenyl ] -4-ol (40 mg,0.11 mmol), 3-bromopropanenitrile (30 mg,0.22 mmol) and cesium carbonate (108 mg,0.33 mmol) are added to N, N-dimethylformamide (3 mL) and stirred at 80℃for 16H. Preparative thin layer chromatography (dichloromethane/methanol=10/1) separated the title compound (15 mg, 32%) as a yellow solid.
1 H NMR(400MHz,CHLOROFORM-d)δ＝10.41(s,1H),8.95(s,1H),8.48(d,J＝5.9Hz,2H),7.26-7.24(m,1H),7.09(d,J＝8.8Hz,1H),6.41(br.s.,2H),5.39(br.s.,2H),4.51(d,J＝7.3Hz,2H),3.66(br.s.,3H),3.39(d,J＝6.4Hz,2H),1.62(t,J＝7.1Hz,3H).LC-MS:m/z[M+H] + ＝418.
Example 91
91-1:1- (3-bromo-4-methoxyphenyl) cyclopropane-1-carbonitrile
2- (3-bromo-4-methoxyphenyl) acetonitrile (50 mg,0.22 mmol), 1, 2-dibromoethane (82.6 mg,0.44 mmol) and tetrabutylammonium bromide (5 mg) were added to an aqueous potassium hydroxide solution (3 mL), and stirred at 50℃for 16 hours. The reaction solution was concentrated and then extracted with ethyl acetate and water, and the title compound (47 mg, 84.8%) was obtained by preparative plate separation and purification (petroleum ether/ethyl acetate=3/1).
91:1- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-6-methoxy- [1,1' -biphenyl Benzene]-3-yl) cyclopropane-1-carbonitrile
Experimental procedure was as in example 1 starting from 1- (3-bromo-4-methoxyphenyl) cyclopropane-1-carbonitrile (40 mg,0.15 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (58 mg,0.15 mmol) to give the title compound (15 mg, 24.2%).
1 H NMR(400MHz,CDCl3)δ9.36(br.s.,1H),8.30-8.23(m,2H),8.20-8.12(m,1H),7.42-7.30(m,2H),7.24(br.s.,1H),6.98(d,J＝8.8Hz,1H),4.57(q,J＝7.3Hz,2H),3.82(s,3H),1.68(s,4H),1.43-1.34(m,3H).LC-MS:m/z[M+H] + ＝414.
Example 92
92-1:2- (4-bromo-3-fluorophenyl) -2-methylpropanenitrile
2- (4-bromo-3-fluorophenyl) acetonitrile (500 mg,2.34 mmol), methyl iodide (1 g,7 mmol), and tetrabutylammonium bromide (50 mg) were added to a 20% aqueous potassium hydroxide solution (10 mL), and stirred at 50℃for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated to prepare the title compound (450 mg, 79.5%) which was purified by plate separation (petroleum ether/ethyl acetate=3/1).
92-2:2- (4-bromo-3-fluorophenyl) -2-methylpropanamide
2- (4-bromo-3-fluorophenyl) -2-methylpropanenitrile (450 mg,1.77 mmol), H 2 O 2 (2 ml) and 5% aqueous sodium hydroxide solution (2 ml) were added to a mixed solvent of EtOH (4 ml) and DMSO (1 ml), and stirred at 80℃for 16 hours. The reaction mixture was concentrated, poured into water, extracted with methylene chloride, and the organic phase was concentrated to give 1.2g of crude title compound. LC-MS: M/z [ M+H ]] + ＝260，262.
92-3:2- (4-bromo-3-methoxyphenyl) -2-methylpropanamide
2- (4-bromo-3-fluorophenyl) -2-methylpropanamide (600 mg,2.3 mmol), naOH (370 mg 9.2 mmol) and methanol (254 mg,9.2 ml) were added to DMSO (8 ml) and stirred at room temperature for 16 hours. The reaction solution was concentrated, poured into water, extracted with ethyl acetate, and the organic phase was concentrated to a thin layer (petroleum ether/ethyl acetate=3/1) to give the title compound (50 mg, 5.7%).
92-4:2- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) -2-methylpropanamide
Experimental procedure Using 2- (4-bromo-3-methoxyphenyl) -2-methylpropanamide (50 mg,0.19 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (72 mg,0.19 mmol) as starting material gave the title compound (60 mg, 75.6%).
92:2- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) -2-methylpropanenitrile
2- (5 ' - (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2' -fluoro-2-methoxy- [1,1' -biphenyl ] -4-yl) -2-methylpropanamide (60 mg,0.14 mmol), trifluoroacetic anhydride (1 ml) and triethylamine (0.5 ml) were successively added to a dichloromethane (2 ml) solvent, and stirred at room temperature for 16 hours. The reaction solution was concentrated, poured into water, extracted with ethyl acetate, and the organic phase was concentrated to prepare a plate for purification (dichloromethane/methanol=12/1) to give the title compound (22 mg, 36.7%).
1 H NMR(400MHz,CDCl3)δ9.35(s,1H),8.31-8.22(m,2H),8.19(d,J＝7.3Hz,1H),7.41-7.29(m,2H),7.16-7.10(m,2H),4.57(q,J＝7.3Hz,2H),3.87(s,3H),1.79(s,6H),1.69(t,J＝1.0Hz,3H).LC-MS:m/z[M+H] + ＝416.
Example 93
93:1- (((5' - (7-ethyl-7H-imidazo [4, 5-c))]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) oxy) methyl) cyclopropane-1-carbonitrile
5' - (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2' -fluoro-2-methoxy- [1,1' -biphenyl ] -4-ol (50 mg,0.14 mmol), 1- (hydroxymethyl) cyclopropan-1-carbonitrile (13 mg,0.14 mmol), triphenylphosphine resin (1 mmol/g) (280 mg,0.28 mmol) and diisopropyl azodicarboxylate (71 mg,0.35 mmol) were added to anhydrous tetrahydrofuran (5 mL), protected with argon and stirred at room temperature for 16H. The reaction solution was concentrated after filtration, and the title compound (2 mg, 3%) was isolated as a white solid by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1).
1 H NMR(400MHz,CHLOROFORM-d)δ＝9.36(br.s.,1H),8.28(s,1H),8.24(br.s.,1H),8.14(d,J＝4.9Hz,1H),7.34-7.27(m,2H),6.64(d,J＝1.5Hz,1H),6.53(d,J＝8.3Hz,1H),4.57(q,J＝7.2Hz,2H),4.02(s,2H),3.81(s,3H),1.68(t,J＝7.3Hz,3H),1.44-1.41(m,2H),1.16(br.s.,2H).LC-MS:m/z[M+H] + ＝444.
Example 94
94：7-ethyl-4- (6-fluoro-2 ' -methoxy-4 ' - (pyridin-4-yloxy) - [1,1' -biphenyl)]-3-yl) -7H- Imidazo [4,5-c]Pyridazine (PYRIZE)
5' - (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2' -fluoro-2-methoxy- [1,1' -biphenyl ] -4-ol (40 mg,0.11 mmol), 4-fluoropyridine hydrochloride (30 mg,0.22 mmol) and potassium carbonate (76 mg,0.55 mmol) are added to N, N-dimethylformamide (3 mL) and stirred at 100deg.C for 16H. Preparation by thin layer chromatography (ethyl acetate) the title compound (13 mg, 27%) was isolated as a white solid.
1 H NMR(400MHz，CHLOROFORM-d)9.37(s，1H)，8.52(br.s.,2H)，8.30-8.24(m，2H)，8.21(d，J＝6.8Hz,1H),7.39(d,J＝8.3Hz,1H),7.34(t,J＝9.0Hz,1H),6.96(d,J＝5.4Hz,2H),6.81-6.74(m,2H),4.58(q,J＝7.3Hz,2H),3.80(s,3H),1.69(t,J＝7.1Hz,3H).LC-MS:m/z[M+H] + ＝442.
Example 95
95-1:3- (3-bromo-4-methoxyphenoxy) oxetane
3-bromo-4-methoxyphenol (203 mg,1 mmol), 3-iodooxetane (552 mg,3 mmol), potassium carbonate (414 mg,3 mmol) was added to N-N dimethylformamide (2 ml), and the mixture was heated to 80℃and stirred overnight. The reaction mixture was diluted with water (100 ml), followed by extraction with methylene chloride (200 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude product which was subjected to thin layer chromatography (dichloromethane/methanol=50/1) to give the title compound as a pale yellow oil 210mg (81.1%).
95: 7-ethyl-4- (6-fluoro-2 ' -methoxy-5 ' - (oxetan-3-yloxy) - [1,1' -biphenyl)]3-yl) 7H-imidazo [4,5-c]Pyridazine (PYRIZE)
The procedure was as in example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (37 mg,0.1 mmol) 3- (3-bromo-4-methoxyphenoxy) oxetan (29 mg,0.11 mmol) to give a brown solid (36 mg, 85% yield).
1 H NMR(400MHz,CHLOROFORM-d)9.35(s,1H),8.26(s,2H),8.18(d,J＝6.8Hz,1H),7.32(t,J＝9.0Hz,1H),6.93(d,J＝8.8Hz,1H),6.80-6.67(m,2H),5.19(t,J＝5.6Hz,1H),4.96(t,J＝6.4Hz,2H),4.78(t,J＝6.1Hz,2H),4.57(q,J＝7.0Hz,2H),3.77(s,3H),1.70-1.66(m,3H).LC-MS:m/z[M+H] + ＝421.
Example 96
96-1: 2-chloro-5- (oxetan-3-yloxy) pyridine
6-Chloropyridin-3-ol (129 mg,1 mmol), 3-iodooxetane (552 mg,3 mmol), potassium carbonate (414 mg,3 mmol) were added to N-N dimethylformamide (2 ml), and the mixture was warmed to 80℃and stirred overnight. The reaction mixture was diluted with water (20 ml) and suction filtered to give 130mg (70.3%) of the title compound as a white solid, LC-MS: M/z [ M+H] + ＝186，188.
96: 7-ethyl-4- (4-fluoro-3- ((5- (oxetan-3-yloxy) pyridin-2-yl) oxy) phenyl) -7H-mi-ne Azolo [4,5-c ]]Pyridazine (PYRIZE)
5- (7-Ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenol (52 mg,0.2 mmol), 2-chloro-5- (oxetan-3-yloxy) pyridine (40 mg,0.22 mmol), xantPhos (23 mg,0.04 mmol), palladium acetate (9 mg,0.04 mmol) and cesium carbonate (100 mg,0.3 mmol) are added to dioxane (5.0 ml), reacted at 110℃for 16 hours, filtered, and the filtrate concentrated to give a large plate as a white solid (5 mg, yield 6%).
1 H NMR(400MHz,CHLOROFORM-d)＝9.34(s，1H)，8.26(s，1H)，8.18--8.06(m,2H),7.51(d,J＝2.9Hz,1H),7.37(t,J＝9.5Hz,1H),7.22(dd,J＝2.9,8.8Hz,1H),7.02(d,J＝8.8Hz,1H),5.16(t,J＝5.6Hz,1H),4.93(t,J＝6.6Hz,2H),4.75(t,J＝6.4Hz,2H),4.57(q,J＝7.0Hz,2H),1.70-1.66(m,3H).LC-MS:m/z[M+H] + ＝408.
Example 97
97-1:6- (4-bromo-3-methoxybenzyl) -2-oxa-6-azaspiro [3.3]Heptane (heptane)
1-bromo-4- (bromomethyl) -2-methoxybenzene (100 mg,0.36 mmol), 2-oxa-6-azaspiro [3.3 ]]Heptane oxalate (200 mg,1.1 mmol) and potassium carbonate (1 g,7 mmol) were added sequentially to 20mL of acetonitrile, and then reacted at room temperature overnight. The reaction solution was filtered and concentrated to give a plate for purification (dichloromethane: methanol=10:1) to give the title compound (50 mg, 50%) as a colorless liquid. LC-MS: M/z [ M+H ] ] + ＝298.
97:6- (((5' - (7-ethyl-7H-imidazo [4, 5-c))]Pyridazin-4-yl]) -2 '-fluoro-2-methoxy- [1,1' ] Biphenyl]-4-yl) methyl) -2-oxa-6-azaspiro [3.3]Heptane (heptane)
Experimental procedure Using 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (50 mg,0.14 mmol), 6- (4-bromo-3-methoxybenzyl) -2-oxa-6-azaspiro [3.3] heptane (50 mg,0.16 mmol) as starting material gave the title compound (24 mg, 39%) as a yellow solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.36(s,1H)8.27(s,2H)8.18(d,J＝5.38Hz,1H)7.27-7.38(m,2H)6.89-6.99(m,2H)4.79(s,4H)4.58(q,J＝7.34Hz,2H)3.76-3.92(m,3H)3.63(s,2H)3.47(s,4H)1.65-1.75(m,3H).LC-MS:m/z[M+H] + ＝460.
Example 98
98-1: (4-bromo-3-methoxyphenyl) (3-methoxyazetidin-1-yl) methanone
4-bromo-3-methoxybenzoic acid (200 mg, 0.87mmol), 3-methoxyazetidine (151 mg,1.732 mmol), 1-hydroxybenzotriazole (350 mg,2.598 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (498 mg,2.598 mmol), triethylamine (4397 mg,4.326 mmol) were added to dichloromethane (2 ml) and stirred overnight at room temperature. The reaction was concentrated, and thin layer chromatography (petroleum ether/ethyl acetate=3/1) was performed to give the title compound (110 mg, 42.5%).
98: (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl]- 4-yl) (3-methoxyazetidin-1-yl) methanones
Experimental procedure Using (4-bromo-3-methoxyphenyl) (3-methoxyazetidin-1-yl) methanone (30 mg,0.100 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (37 mg,0.100 mmol) as the starting material gave the title compound (31 mg, 67%).
1 H NMR(400MHz,CHLOROFORM-d)d＝9.36(br.s.,1H),8.27(br.s.,2H),8.19(d,J＝6.8Hz,1H),7.41-7.29(m,3H),7.22(d,J＝7.8Hz,1H),4.57(q,J＝7.0Hz,2H),4.52-4.36(m,2H),4.26(d,J＝3.9Hz,2H),4.11(br.s.,1H),3.86(s,3H),3.33(s,3H),1.68(d,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝462.
Example 99
99-1: azetidin-1-yl (4-bromo-3-methoxyphenyl) methanone
4-bromo-3-methoxybenzoic acid (200 mg, 0.87mmol), azetidine hydrochloride (122 mg,1.752 mmol), 1-hydroxybenzotriazole (350 mg,2.598 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (498 mg,2.598 mmol), triethylamine (437 mg,4.326 mmol) were added to dichloromethane (2 ml) and stirred overnight at room temperature. The reaction was concentrated and thin layer chromatography (petroleum ether/ethyl acetate=3/1) was performed to give the title compound (119 mg, 50.6%).
99: azetidin-1-yl (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2' -fluoro-2-methoxy Base- [1,1' -biphenyl]-4-yl) methanones
Experimental procedure Using azetidin-1-yl (4-bromo-3-methoxyphenyl) methanone (30 mg,0.111 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (40 mg,0.111 mmol) as starting material gives the title compound (28 mg, 58.5%).
1 H NMR(400MHz,CHLOROFORM-d)d＝9.35(s,1H),8.30-8.23(m,2H),8.18(dd,J＝2.0,6.8Hz,1H),7.40-7.28(m,3H),7.23(d,J＝7.3Hz,1H),4.56(q,J＝7.3Hz,2H),4.45-4.18(m,4H),3.85(s,3H),2.39-2.35(m,2H),1.67(t,J＝7.1Hz,3H).LC-MS:m/z[M+H] + ＝432.
Example 100
100-1:6- (4-bromo-3-methoxyphenyl) -2-oxa-6-azaspiro [3.3]Heptane (heptane)
1-bromo-4-iodo-2-methoxybenzene (CAS: 755027-18-0,200mg,0.64 mmol), 2-oxa-6-azaspiro [3.3]Heptane oxalate (109 mg,0.57 mmol), cuprous iodide (24 mg,0.12 mmol), (1 r,2 r) - (-) -N, N-dimethyl-1, 2-cyclohexanediamine (9 mg,0.06 mmol) and potassium t-butoxide (143 mg,1.3 mmol) were added sequentially to 5mL dioxane, followed by reflux reaction overnight. The reaction solution was filtered, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give the title compound (30 mg, 11%) as a white solid. LC-MS: M/z [ M+H ]] + ＝284.
100:6- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) -2-oxa-6-azaspiro [3.3]Heptane (heptane)
Experimental procedure Using 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (50 mg,0.14 mmol), 6- (4-bromo-3-methoxyphenyl) -2-oxa-6-azaspiro [3.3] heptane (30 mg,0.14 mmol) as starting material gave the title compound (4 mg, 8%) as a yellow solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.36(s,1H)8.21-8.33(m,2H)8.14(d,J＝6.85Hz,1H)7.29-7.34(m,1H)7.21(d,J＝7.83Hz,1H)6.16(d,J＝7.83Hz,1H)6.08(s,1H)4.87(s,4H)4.57(q,J＝7.17Hz,2H)4.11(s,4H)3.82(s,3H)1.69(t,J＝7.34Hz,3H).LC-MS:m/z[M+H] + ＝446.
Example 101
101-1: 3-bromo-2-methoxy-6- (oxetan-3-yloxy) pyridine
3-bromo-6-chloro-2-methoxypyridine (CAS: 1211526-62-3,100mg,0.45 mmol), 3-oxetan (67 mg,0.9 mmol), and sodium hydrogen (54 mg,1.3 mmol) were added sequentially to 4mL of anhydrous tetrahydrofuran and 1mL of dried N, N dimethylformamide, and then reacted at 100℃overnight. Water was added, extracted with dichloromethane, concentrated, and prepared for plate purification (petroleum ether: ethyl acetate=5:1) to give the title compound (100 mg, 85%) as a colorless liquid. LC-MS: M/z [ M+H ] ] + ＝260.
101: 7-ethyl-4- (4-fluoro-3- (2-methoxy-6- (oxetan-3-yloxy) pyridin-3-yl) phenyl) propan-3-yl) 7H-imidazo [4,5-c]Pyridazine (PYRIZE)
The procedure was as in example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (70 mg,0.22 mmol) 3-bromo-2-methoxy-6- (oxetan-3-yloxy) pyridine (50 mg,0.22 mmol) to give the title compound (18 mg, 22%) as a brown solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.36(s,1H)8.18-8.33(m,3H)7.64(d,J＝8.31Hz,1H)7.33(t,J＝9.05Hz,1H)6.49(d,J＝8.31Hz,1H)5.65(t,J＝5.62Hz,1H)5.02(t,J＝6.60Hz,2H)4.84(t,J＝6.36Hz,2H)4.58(q,J＝7.01Hz,2H)3.88(s,3H)1.69-1.73(m,3H).LC-MS:m/z[M+H] + ＝422.
Example 102
102-1:4- (4-bromo-3-methoxyphenyl) morpholine
Experimental procedure the same as in example 100 for the synthesis of 100-1, starting from 1-bromo-4-iodo-2-methoxybenzene (CAS: 755027-18-0,200mg,0.64 mmol) and morpholine (50 mg,0.57 mmol), the title compound (60 mg, 35%) was obtained as a white solid. LC-MS: M/z [ M+H ]] + ＝272.
102:4- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) morpholines
Experimental procedure Using example 1, starting from 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (80 mg,0.22 mmol), 4- (4-bromo-3-methoxyphenyl) morpholine (60 mg,0.22 mmol) gives the title compound (40 mg, 42%) as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.35(s,1H)8.25(br.s.,2H)8.15(d,J＝6.36Hz,1H)7.27-7.36(m,1H)7.25(br.s.,1H)6.49-6.68(m,2H)4.56(q,J＝6.85Hz,2H)3.88(br.s.,4H)3.82(s,3H)3.24(br.s.,4H)1.65-1.71(m,3H).LC-MS:m/z[M+H] + ＝434.
Example 103
103: 7-ethyl-4- (6-fluoro-2 ' -methoxy-4 ' - ((methylsulfonyl) methyl) - [1,1' -biphenyl)]3-yl) 7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure was as in example 1 starting from bromo-2-methoxy-4- ((methylsulfonyl) methyl) benzene (200 mg, 0.719 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (176 mg,0.498 mmol) giving the title compound (44 mg, 20.1%).
1 H NMR(400MHz,CHLOROFORM-d)d＝9.36(s,1H),8.32-8.17(m,3H),7.44-7.29(m,2H),7.12-7.03(m,2H),4.58(q,J＝7.3Hz,2H),4.31(s,2H),3.86(s,3H),2.86(s,3H),1.71-1.67(m,3H).LC-MS:m/z[M+H] + ＝441.
Example 104
104-1: 5-bromo-4-methoxy-2- (oxetan-3-yloxy) pyridine
5-bromo-2-chloro-4-methoxypyridine (CAS: 880870-13-3,100mg,0.45 mmol), 3-oxetan (67 mg,0.9 mmol) and sodium hydrogen (54 mg,1.3 mmol) were added sequentially to 5mL of anhydrous DMF, and then reacted at 100℃overnight. Water was added, extracted with dichloromethane, concentrated, and prepared for plate purification (petroleum ether: ethyl acetate=5:1) to give the title compound (20 mg, 17%) as a yellow solid. LC-MS: M/z [ M+H ]] + ＝260.
104: 7-ethyl-4- (4-fluoro-3- (4-methoxy-6- (oxetan-3-yloxy) pyridin-3-yl) phenyl) propan-3-yl) 7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (28 mg,0.08 mmol), 5-bromo-4-methoxy-2- (oxetan-3-yloxy) pyridine (20 mg,0.08 mmol) as the starting material gave the title compound (11 mg, 34%) as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.36(s,1H)8.23-8.31(m,2H)8.17(dd,J＝6.85,2.45Hz,1H)7.96(s,1H)7.34(t,J＝9.05Hz,1H)6.40(s,1H)5.66-5.70(m,1H)5.03(t,J＝6.85Hz,2H)4.73-4.82(m,2H)4.59(q,J＝7.34Hz,2H)3.86(s,3H)1.67-1.72(m,3H).LC-MS:m/z[M+H] + ＝422.
Example 105
105:1- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-propane-1-carbonitrile
1- (5 ' - (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2' -fluoro-2-methoxy- [1,1' -biphenyl ] -4-ylcyclopropane-1-carboxamide (40 mg,0.09 mmol), trifluoroacetic anhydride (1 ml) and triethylamine (0.5 ml) were successively added to a solvent of dichloromethane (2 ml), stirred at room temperature for 16 hours.
1 H NMR(400MHz,CDCl3)δ9.35(br.s.,1H),8.31-8.22(m,2H),8.19-8.13(m,1H),7.37-7.29(m,2H),7.04(s,1H),6.89(d,J＝7.8Hz,1H),4.61-4.53(m,2H),3.86(d,J＝1.0Hz,3H),1.81-1.75(m,2H),1.70-1.66(m,3H),1.50-1.47(m,2H).LC-MS:m/z[M+H] + ＝414.
Example 106
106-1:1- (4-bromo-3-fluorophenyl) cyclopropane-1-carbonitrile
2- (4-bromo-3-fluorophenyl) acetonitrile (2 g,9.34 mmol), tetrabutylammonium bromide (200 mg), and 1, 2-dibromoethane (3.5 g,18.68 mmol) were added to a 20% aqueous potassium hydroxide solution (20 ml), and stirred at 50℃for one hour. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated to a thin layer (petroleum ether/ethyl acetate=5/1) to give the title compound (1.3 g, 57.1%).
106-2:1- (4-bromo-3-fluorophenyl) cyclopropane-1-carboxamide
1- (4-bromo-3-fluorophenyl) cyclopropane-1-carbonitrile (600 mg,2.5 mmol), H 2 O 2 (5 ml) and 5% aqueous sodium hydroxide solution (1 ml) were added to a mixed solvent of EtOH (10 ml) and DMSO (5 ml), and stirred at 80℃for 16 hours. The reaction solution was concentrated, poured into water, extracted with ethyl acetate, and the organic phase was concentrated to a thin layer (dichloromethane/methanol=20/1) to give the title compound (500 mg, 77.9%). LC-MS: M/z [ M+H ] ] + ＝258，260
106-3:1- (4-bromo-3-methoxyphenyl) cyclopropane-1-carboxamide
1- (4-bromo-3-fluorophenyl) cyclopropane-1-carboxamide (500 mg,1.93 mmol), naOH (310 mg,7.74 mmol) and methanol (250 mg,7.74 ml) were added to DMSO (10 ml) and stirred at room temperature for 16 hours. The reaction solution was concentrated, poured into water, extracted with ethyl acetate, and the organic phase was concentrated to a thin layer (petroleum ether/ethyl acetate=3/1) to give the title compound (250 mg, 50%). LC-MS: M/z [ M+H ]] + ＝270，272.
106:1- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) cyclopropane-1-carboxamide
Experimental procedure Using 1- (4-bromo-3-methoxyphenyl) cyclopropane-1-carboxamide (50 mg,0.19 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (72 mg,0.19 mmol) as starting material gave the title compound (48 mg, 58.6%).
1 H NMR(400MHz,CDCl3)δ9.35(s,1H),8.29-8.23(m,2H),8.20-8.16(m,1H),7.37-7.31(m,2H),7.14(d,J＝7.8Hz,1H),7.08(s,1H),4.57(d,J＝7.3Hz,2H),3.84(s,3H),1.68(s,2H),1.27(d,J＝3.4Hz,2H),1.25-1.22(m,3H).LC-MS:m/z[M+H] + ＝432.
Example 107
107-1:2- (4-bromo-3-methyl)Oxyphenyl) isothiazolidines 1, 1-dioxides
1-bromo-4 iodo-2 methoxybenzene (80 mg,0.256 mmol), isothiazolidine 1, 1-dioxide (36 mg,0.280 mmol), cuprous iodide (4 mg,0.012 mmol), N.N-dimethylethylenediamine (12 mg,0.128 mmol), potassium carbonate (84 mg,0.768 mmol) were added to DMF (1 ml), reacted overnight at 70℃and the reaction solution cooled to room temperature, suction filtered, concentrated to give the title compound (43 mg, 55%) by thin layer chromatography (petroleum ether/ethyl acetate=3/1) LC-MS: M/z [ M+H ] + ＝305,307.
107:2- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) isothiazolidines 1, 1-dioxides
Experimental procedure Using 2- (4-bromo-3-methoxyphenyl) isothiazolidine 1, 1-dioxide (43 mg,0.140 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (62 mg,0.169 mmol) as starting material gave the title compound (21 mg, 26.6%).
1 H NMR(400MHz,CHLOROFORM-d)d＝9.35(s,1H),8.25(s,2H),8.19(d,J＝6.4Hz,1H),7.38-7.27(m,2H),7.03(s,1H),6.85(d,J＝7.8Hz,1H),4.57(q,J＝7.2Hz,2H),3.88-3.82(m,5H),3.43(t,J＝7.6Hz,2H),2.57(t,J＝7.1Hz,2H),1.68(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝468.
Example 108
108-1: 1-bromo-2-methoxy-4- (2-methoxyethoxy) benzene
4-bromo-3-methoxyphenol (100 mg,0.49 mmol), 1-bromo-2-methoxyethane (3411 mg,2.45 mmol) and potassium carbonate (203 mg,1.47 mmol) were added to N, N-dimethylformamide (5 mL), and stirred at 80℃for 16 hours. The reaction solution was concentrated after filtration, and the title compound (100 mg, 78%) was isolated as a colorless oily liquid by preparative thin layer chromatography (petroleum ether/ethyl acetate=5/1))。LC-MS:m/z[M+H] + ＝261,263.
108: 7-ethyl-4- (6-fluoro-2 ' -methoxy-4 ' - (2-methoxyethoxy) - [1,1' -biphenyl)]3-yl) 7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using 1-bromo-2-methoxy-4- (2-methoxyethoxy) benzene (100 mg,0.38 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (140 mg,0.38 mmol) as starting material gives the title compound (23 mg, 14%) as a yellow solid.
1 H NMR(400MHz，CHLOROFORM-d)δ＝9.35(s，1H)，8.28-8.20(m，2H)，8.14(d，J＝6.8Hz，1H),7.34-7.25(m,2H),6.65(s,1H),6.60(d,J＝8.3Hz,1H),4.56(q,J＝7.3Hz,2H),4.18(d,J＝4.4Hz,2H),3.82-3.75(m,5H),3.47(s,3H),1.67(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝423.
Example 109
109-1:3- ((4-bromo-3-methoxyphenoxy) methyl) oxetane
Experimental procedure the synthesis of example 93 was followed using 4-bromo-3-methoxyphenol (100 mg,0.49 mmol) and oxetan-3-ylmethanol (86 mg,0.98 mmol) as starting material to give the title compound (100 mg, 74%) as a pale yellow oil.
109: 7-ethyl-4- (6-fluoro-2 ' -methoxy-4 ' - (oxetan-3-ylmethoxy) - [1,1' -biphenyl)]-3- Radical) -7H-imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using 3- ((4-bromo-3-methoxyphenoxy) methyl) oxetane (100 mg,0.36 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (132 mg,0.36 mmol) as starting material gives the title compound (33 mg, 21%) as a yellow solid.
1 H NMR(400MHz,CHLOROFORM-d)δ＝9.35(br.s.,1H),8.25(br.s.,2H),8.14(d,J＝5.4Hz,1H),7.36-7.26(m,2H),6.61(br.s.,2H),4.90(t,J＝6.8Hz,2H),4.58(dd,J＝6.4,13.7Hz,4H),4.25(d,J＝6.4Hz,2H),3.81(br.s.,3H),3.46(br.s.,1H),1.25(d,J＝5.9Hz,3H).LC-MS:m/z[M+H] + ＝435.
Example 110
110-1:3- (4-bromo-3-methoxyphenoxy) tetrahydrofuran
Experimental procedure the same as in example 108 for the synthesis of 108-1 using 4-bromo-3-methoxyphenol (100 mg,0.49 mmol) and 3-iodotetrahydrofuran (194 mg,0.98 mmol) as starting material gave the title compound as a pale yellow oil (50 mg, 37%).
110: 7-ethyl-4- (6-fluoro-2 ' -methoxy-4 ' - ((tetrahydrofuran-3-yl) oxy) - [1,1' -biphenyl)]-3- Radical) -7H-imidazole [4,5-c ]Pyridazine (PYRIZE)
Experimental procedure Using 3- (4-bromo-3-methoxyphenoxy) tetrahydrofuran (50 mg,0.18 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (67 mg,0.18 mmol) as starting material gave the title compound (41 mg, 52%) as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δ＝9.35(s,1H),8.27-8.21(m,2H),8.15(dd,J＝2.4,6.8Hz,1H),7.33-7.28(m,1H),7.28-7.26(m,1H),6.57(d,J＝2.4Hz,1H),6.52(dd,J＝2.4,8.3Hz,1H),4.99(qd,J＝2.9,5.6Hz,1H),4.59-4.53(m,2H),4.05-3.99(m,3H),3.92(dt,J＝4.9,8.1Hz,1H),3.80(s,3H),2.28-2.17(m,2H),1.68(t,J＝7.1Hz,3H).LC-MS:m/z[M+H] + ＝435.
Example 111
111-1:4- (ethylthio) -2-methoxypyridine
4-iodo-2-methoxypyridine (2 g,8.51 mmol), cuprous iodide (162 mg,0.8 mmol), and potassium carbonate (2.348 mg,17 mmol) were added to isopropanol (10 ml). Ethyl mercaptan (1.319 g,21.28 mmol), ethylene glycol (106 mg,1.7 mmol) was dissolved in isopropanol (4 ml), and the mixture was injected under argon to react at 80℃for 24 hours, and the reaction solution was filtered off with suction, concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (960 mg, 66.7%). LC-MS: M/z [ M+H ]] + ＝170.
111-2:4- (ethylthio) pyridin-2-ols
4- (ethylsulfanyl) -2-methoxypyridine (960 mg,5.676 mmol), sodium iodide (2.65 g,17.65 mmol) was added to 6ml acetic acid and reacted at 90℃for 12 hours, the reaction solution was poured into an aqueous sodium carbonate solution, extracted with dichloromethane/methanol=10/1, concentrated, and subjected to column chromatography (ethyl acetate) to give 965mg of the title compound. LC-MS: M/z [ M+H ]] + ＝156.
111-3:1- (5-bromo-2-fluorophenyl) -4- (ethylsulfanyl) pyridin-2 (1H) -one
4- (ethylsulfanyl) pyridin-2-ol (292 mg,4.075 mmol), 4-bromo-1-fluoro-2-iodobenzene (1.473 g,4.075 mmol), cuprous bromide (58 mg,0.407 mmol), ethyl 2-cyclohexanone carboxylate (208 mg,1.222 mmol), cesium carbonate (2.657 mg,8.150 mmol) is dissolved in DMSO (6 ml). Under the protection of argon, the reaction is carried out for 24 hours at 80 ℃. The reaction solution was filtered with suction, concentrated, extracted with ethyl acetate, and subjected to thin layer chromatography (petroleum ether/ethyl acetate=40/1) to give the title compound (100 mg, 7.5%). LC-MS: M/z [ M+H ]] + ＝327,329
111-4:1- (5- (7-ethyl 7H imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenyl) -4- (ethylsulfanyl) pyridine 2 (1H) -ones
1- (5-bromo-2-fluorophenyl) -4- (ethylsulfanyl) pyridin-2 (1H) -one (100 mg,0.305 mmol), bis-pinacolato borate (155 mg,0.610 mmol), 1-bis (diphenylphosphorus) ferrocene palladium chloride (25 mg,0.031 mmol), potassium acetate (60 mg,0.610 mmol) were added to 1, 4-dioxane (1 ml), and reacted at 105℃under argonAnd (5) at night. After cooling the reaction to room temperature, 4-chloro-7-ethyl-7H-imidazo [4,5-c]Pyridazine (67 mg,0.367 mmol), cesium carbonate (199mg, 0.610 mmol), 1-bis (diphenylphosphorus) ferrocene palladium chloride (25 mg,0.031 mmol) were added to the reaction solution, and 1, 4-dioxane (1 ml) and water (0.5 ml) were further added to react at 100℃for 6 hours under the protection of argon. The reaction solution was filtered off with suction and concentrated, and thin layer chromatography (ethyl acetate/dichloromethane=1/1) was performed to give the title compound (69 mg, 57.2%). LC-MS: M/z [ M+H ] ] + ＝396.
111:1- (5- (7-ethyl 7H imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenyl) -4- (ethylsulfonyl) pyrazine Pyridin-2 (1H) -ones
1- (5- (7-Ethyl 7H imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenyl) -4- (ethylsulfanyl) pyridin-2 (1H) -one (39 mg,0.101 mmol), potassium hydrogen persulfate (61 mg,0.203 mmol) was added to a solution of THF (2 ml), methanol (1 ml) and water (0.5 ml), and stirred at room temperature for 2 hours. The reaction solution was poured into water, extracted with methylene chloride/methanol=10/1 solution, dried over anhydrous sodium sulfate, and concentrated. Thin layer chromatography (EA) afforded the title compound (3 mg, 6.9%).
1 H NMR(400MHz,CHLOROFORM-d)d＝9.37(s,1H),8.37(d,J＝5.4Hz,1H),8.28(s,1H),8.25(d,J＝7.3Hz,1H),8.17(br.s.,1H),7.56(s,1H),7.50-7.38(m,2H),4.58(q,J＝6.8Hz,2H),3.20(q,J＝7.7Hz,2H),1.69(t,J＝7.3Hz,3H),1.37(s,3H).LC-MS:m/z[M+H] + ＝428.
Example 112
112-1: n- (3-bromo-4-methoxyphenylethyl) -N- (methoxymethyl) -4-methylbenzenesulfonamide
N- (3-bromo-4-methoxyphenylethyl) -4-methylbenzenesulfonamide (500 mg,1.3 mmol), 60% H 2 SO 4 (2 mL) and dimethoxymethane (10 mL) were added to xylene (20 mL), protected by argon, and stirred overnight at 50 ℃. The reaction mixture was concentrated, extracted with ethyl acetate and water, and purified by plate separation (dichloromethane)Methanol=20/1) to give the title compound (300 mg, 58.3%). LC-MS: M/z [ M+H ]] + ＝428，430.
112: n- (3- (5- (7-ethyl-7H-imidazo [4, 5-c))]Pyridazin-4-yl]-2-fluorophenoxy) -4-methoxybenzene Ethyl) -N- (methoxymethyl) -4-methylbenzenesulfonamide
Experimental procedure the same as in example 1 was used, starting from N- (3-bromo-4-methoxyphenylethyl) -N- (methoxymethyl) -4-methylbenzenesulfonamide (50 mg,0.13 mmol) and 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (46.3 mg,0.13 mmol), the title compound (18 mg) was obtained.
1 H NMR(400MHz,CDCl3)δ9.37(s,1H),8.28(s,2H),8.19-8.13(m,J＝6.8Hz,1H),7.72(d,J＝8.3Hz,2H),7.32(t,J＝1.0Hz,1H),7.24(br.s.,2H),7.20-7.15(m,J＝8.8Hz,1H),7.10(s,1H),6.92(d,J＝8.3Hz,1H),4.69(s,2H),4.57(q,J＝7.3Hz,2H),3.80(s,3H),3.40(t,J＝7.8Hz,2H),3.28(s,3H),2.88(t,J＝7.8Hz,2H),2.37(s,3H),1.68(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝606.
Example 113
113:2- (5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenoxy) -6- (oxetan-o-p- 3-yl) -7, 8-dihydro-1, 6-naphthyridin-5 (6H) -one
2- (5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenoxy) -6- (oxetan-3-yl) -5,6,7, 8-tetrahydro-1, 6-naphthyridine (50 mg,0.02 mmol), I 2 (242.6 mg,0.17 mmol) and sodium bicarbonate (65.1 mg,0.22 mmol) were added to THF/H 2 O (5/2 mL), stirring at room temperature for 16 hours. Quenched with aqueous sodium thiosulfate, the reaction was poured into water, extracted with ethyl acetate, and the organic phase was concentrated to give the title compound (18 mg, 35.3%) as isolated and purified by plate (dichloromethane/methanol=15/1).
1 H NMR(400MHz,CDCl3)δ9.35(s,1H),8.39-8.25(m,2H),8.17(br.s.,2H),7.39(t,J＝9.3Hz,1H),6.98(d,J＝8.3Hz,1H),5.73-5.59(m,J＝6.6,6.6Hz,1H),4.93(t,J＝7.1Hz,2H),4.75(t,J＝6.4Hz,2H),4.62-4.53(m,2H),3.77(t,J＝1.0Hz,2H),3.05(t,J＝1.0Hz,2H),1.34-1.23(m,3H).LC-MS:m/z[M+H] + ＝461.
Example 114
114-1: n- (4-bromo-3-methoxyphenyl) methanesulfonamide
4-bromo-3-methoxyaniline (100 mg,0.5 mmol), methanesulfonic anhydride (87 mg,0.5 mmol), triethylamine (101 mg,1 mmol) were added to THF (2 ml), and stirred at room temperature overnight. The reaction solution was filtered off with suction, concentrated and purified by thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound (66 mg, 47.1%).
114: n- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) methanesulfonamide
Experimental procedure Using N- (4-bromo-3-methoxyphenyl) methanesulfonamide (55 mg,0.195 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (60 mg,0.163 mmol) as starting material gave the title compound (30 mg, 41.2%).
1 H NMR(400MHz,CHLOROFORM-d)d＝9.36(s,1H),8.27(s,2H),8.18(d,J＝6.4Hz,1H),7.38-7.30(m,2H),6.98(s,1H),6.86(d,J＝7.8Hz,1H),6.68(s,1H),4.64-4.54(m,2H),3.84(s,3H),3.09(s,3H),1.69(t,J＝7.1Hz,3H).LC-MS:m/z[M+H] + ＝442.
Example 115
115-1: (4-bromo-3-methoxyphenyl) bisMethyl phosphine oxide
1-bromo-4-iodo-2-methoxybenzene (300 mg,0.99 mmol), dimethylphosphine oxide (117 mg,1.5 mmol), tris (dibenzylideneacetone) dipalladium (10 mg,0.01 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (12 mg,0.02 mmol) and triethylamine (303 mg,3.0 mmol) were added to 1, 4-dioxane (10 mL), protected with argon, and stirred at 100℃for 16 hours. The reaction was concentrated, and the title compound (40 mg, 15%) was isolated as a pale yellow oil by thin layer chromatography (ethyl acetate). LC-MS: M/z [ M+H ]] + ＝263,265.
115: (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2 '-fluoro-2-methoxy- [1,1' -biphenyl Benzene]-4-yl) dimethylphosphine oxide
Experimental procedure Using (4-bromo-3-methoxyphenyl) dimethylphosphine oxide (40 mg,0.15 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (55 mg,0.15 mmol) as starting material gives the title compound (25 mg, 39%) as a brown solid.
1 H NMR(400MHz,CHLOROFORM-d)δ＝9.35(s,1H),8.27(s,2H),8.20(d,J＝6.8Hz,1H),7.56-7.44(m,2H),7.34(t,J＝8.8Hz,1H),7.23(br.s.,1H),4.57(q,J＝7.3Hz,2H),3.90(s,3H),1.81(s,3H),1.78(s,3H),1.68(t,J＝7.1Hz,3H).LC-MS:m/z[M+H] + ＝425
Example 116
116-1: 3-chloro-4-methoxy-6- (methylthio) pyridazine
3, 6-dichloro-4-methoxypyridazine (1000 mg,5.56 mmol) was added to DMF (4 ml), stirred in an ice bath for 15 minutes, and sodium methyl mercaptide (40% aqueous solution) (0.5 ml, 5.554 mmol) was added to the reaction solution in portions and stirred at room temperature for 1 hour. Filtering the reaction liquid, and directly adding the obtained white solid into the reaction liquid to perform the next reaction ] + ＝191,193.
116-2：3-chloro-4-methoxy-6- (methylsulfonyl) pyridazine
3-chloro-4-methoxy-6- (methylthio) pyridazine (979 mg,5.15 mmol) was added to a mixed solution of THF (10 ml), methanol (5 ml) and water (5 ml), and stirred at room temperature for 5 minutes. Potassium hydrogen persulfate (7.260 g,12 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into a saturated aqueous sodium chloride solution, extracted with dichloromethane, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=3/1) to give the title compound (620 mg, 54.2%). LC-MS: M/z [ M+H ]] + ＝223,225.
116: 7-ethyl-4- (4-fluoro-3- (4-methoxy-6- (methylsulfonyl) pyridazin-3-yl) phenyl) -7H-imidazole And [4,5-c ]]Pyridazine (PYRIZE)
Experimental procedure Using 3-chloro-4-methoxy-6- (methylsulfonyl) pyridazine (162 mg, 0.720 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (267 mg, 0.720 mmol) as the starting material gave the title compound (17 mg, 5.4%).
1 H NMR(400MHz,CHLOROFORM-d)d＝9.43(s,1H),9.07(d,J＝6.8Hz,1H),8.45(br.s.,1H),8.30(s,1H),7.68(s,1H),7.46(t,J＝9.8Hz,1H),4.59(d,J＝7.3Hz,2H),4.16(s,3H),3.56(s,3H),1.72-1.69(m,3H).LC-MS:m/z[M+H] + ＝429.
Example 117
117-1: 3-chloro-4-methoxy-6- (ethylsulfanyl) pyridazine
3, 6-dichloro-4-methoxypyridazine (1.5 g,8.37 mmol) was added to DMF (4 ml), and stirred in an ice bath for 15 minutes, and ethanethiol (510 mg,8.37 mmol) was slowly dropped into the reaction solution under an ice bath. The reaction was carried out at 0℃for 1 hour. The reaction solution is poured into water, extracted with methylene dichloride, concentrated and the crude product is directly put into the next step. LC-MS: M/z [ M+H ] ] + ＝205,207.
117-2: 3-chloro-4-methylOxy-6- (ethylsulfonyl) pyridazines
3-chloro-4-methoxy-6- (ethylsulfanyl) pyridazine (1.0 g,5 mmol) was added to a mixed solution of THF (10 ml), methanol (5 ml) and water (5 ml), and stirred at room temperature for 5 minutes. Potassium hydrogen persulfate (4.5 g,10 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into a saturated aqueous sodium chloride solution, extracted with dichloromethane, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=3/1) to give the title compound (437mg, 36.9%). LC-MS: M/z [ M+H ]] + ＝237,239.
117: 7-ethyl-4- (4-fluoro-3- (4-methoxy-6- (ethylsulfonyl) pyridazin-3-yl) phenyl) -7H-imidazole And [4,5-c ]]Pyridazine (PYRIZE)
Experimental procedure Using 3-chloro-4-methoxy-6- (ethylsulfonyl) pyridazine (206 mg,0.868 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (319 mg,0.868 mmol) as starting material gave the title compound (169 mg, 44.0%).
1 H NMR(400MHz,CHLOROFORM-d)d＝9.43(s,1H),9.07(d,J＝6.8Hz,1H),8.45(br.s.,1H),8.30(s,1H),7.67(s,1H),7.53-7.40(m,1H),4.59(d,J＝7.8Hz,2H),4.15(s,3H),3.88-3.69(m,2H),1.70(t,J＝7.3Hz,3H),1.56(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝443.
Example 118
118:4- (4 ' - (((1, 1-dichloroethyl) sulfonyl) -6-fluoro-2 ' -methoxy- [1,1' -biphenyl)]3-yl) -7- ethyl-7H-imidazole [4,5-c ]]Pyridazine (PYRIZE)
7-Ethyl-4- (4 ' - (ethylsulfonyl) -6-fluoro-2 ' -methoxy- [1,1' -biphenyl ] -3-yl) -7H-imidazo [4,5-c ] pyridazine (60 mg,0.14 mmol), carbon tetrachloride (0.2 mL) and potassium tert-butoxide (30 mg,0.27 mmol) were added sequentially to DMF (0.5 mL) and reacted at room temperature for 16 hours to give a brown solid (14 mg, 20% yield) as a large plate.
1 H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.34-8.22(m,3H),7.79(d,J＝8.3Hz,1H),7.66(s,1H),7.60(d,J＝7.8Hz,1H),7.37(t,J＝9.0Hz,1H),4.58(q,J＝7.0Hz,2H),3.91(s,3H),2.49(s,3H),1.69(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝509,511.
Example 119
119-1: 2-chloro-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridine
2-chloro-5, 6,7, 8-tetrahydro-1, 6-naphthyridine hydrochloride (500 mg,3.23 mmol) and NaBH3CN (580 mg,9.69 mmol) were added to MeOH (20 mL) and stirred at room temperature for ten minutes, then paraformaldehyde (750 mg,32.3 mmol) was added to the reaction system and stirred at room temperature for 16 hours. Quenched with methanol, concentrated, extracted with ethyl acetate and water, and the organic phase concentrated, purified by brushing on a thin layer (dichloromethane/methanol=20/1) to give the title compound as an oil (520 mg, 96.1%). LC-MS: M/z [ M+H ]] + ＝183，185.
119:2- (5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenoxy) -6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridine
2-chloro-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridine (50 mg,0.19 mmol), xantphos (22 mg,0.04 mmol), palladium acetate (8.5 mg,0.04 mmol), cesium carbonate (185.7 mg,0.57 mmol) and 5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenol (34.7 mg,0.19 mmol) are added to dioxane (4 mL), protected with argon and stirred at 110℃for 16H. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated to prepare the title compound (10 mg, 12.8%) by plate separation and purification (dichloromethane/methanol=30/1).
1 H NMR(400MHz,CDCl3)δ9.33(s,1H),8.27(s,1H),8.16-8.06(m,2H),7.40-7.32(m,2H),6.78(d,J＝7.8Hz,1H),4.64-4.51(m,J＝7.3Hz,2H),3.59(br.s.,2H),2.94-2.72(m,4H),2.49(s,3H),1.68(t,J＝7.1Hz,3H).LC-MS:m/z[M+H] + ＝405.
Example 120
120-1: 2-chloro-6-methyl-7, 8-dihydro-1, 6-naphthyridin 5 (6H) -one
2-chloro-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridine (500 mg,2.73 mmol), I 2 (5.2 g,20.53 mmol) and sodium bicarbonate (2.3 g,27.3 mmol) were added to THF/H 2 O (42/17 mL) was stirred at room temperature for 16 hours. Quenched with aqueous sodium thiosulfate, the reaction was poured into water, extracted with ethyl acetate, and the organic phase was concentrated to a thin layer (petroleum ether/ethyl acetate=5/1) to give the title compound (360 mg, 67.2%). LC-MS: M/z [ M+H ]] + ＝197.
120:2- (5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenoxy) -6-methyl-7, 8-di Hydrogen-1, 6-naphthyridin-5 (6H) -one
The procedure was as in example 119, starting from 2-chloro-6-methyl-7, 8-dihydro-1, 6-naphthyridine 5 (6H) -one (50 mg,0.2 mmol) and 5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenol (78 mg,04 mmol) to give the title compound (8 mg, 10%).
1H NMR(400MHz,CDCl3)δ9.35(s,1H),8.36(d,J＝8.3Hz,1H),8.28(s,1H),8.21-8.12(m,2H),7.43-7.33(m,J＝9.3,9.3Hz,1H),6.96(d,J＝8.3Hz,1H),4.58(q,J＝7.3Hz,2H),3.57(t,J＝6.8Hz,2H),3.12(s,3H),2.99(t,J＝6.6Hz,2H),1.71-1.67(m,3H).LC-MS:m/z[M+H]+＝419.
Example 121
121-1：2-chloro-6- (oxetan-3-yl) -5,6,7, 8-tetrahydro-1, 6-naphthyridine
2-chloro-5, 6,7, 8-tetrahydro-1, 6-naphthyridine hydrochloride (500 mg,3.23 mmol) and NaBH 3 CN (580 mg,9.69 mmol) was added to MeOH (20 m)L) stirring at room temperature for ten minutes, then oxetan-3-one (1.16 g,16.15 mmol) was added to the reaction system and stirred at room temperature for 16 hours. Quenched with methanol, concentrated, extracted with ethyl acetate and water, and the organic phase was concentrated and purified by brushing on a thin layer (dichloromethane/methanol=20/1) to give the title compound as an oil (530 mg, 79.5%). LC-MS: M/z [ M+H ] ] + ＝225，227.
121:2- (5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenoxy) -6- (oxetan-o-p- 3-yl) -5,6,7, 8-tetrahydro-1, 6-naphthyridine
The procedure was as in example 119, starting from 2-chloro-6- (oxetan-3-yl) -5,6,7, 8-tetrahydro-1, 6-naphthyridine (86 mg,0.47 mmol) and 5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenol (100 mg,0.39 mmol) to give the title compound (43 mg, 24.7%).
1 H NMR(400MHz,CDCl3)δ9.33(s,1H),8.28(s,1H),8.20-8.01(m,2H),7.49-7.32(m,2H),6.80(d,J＝8.3Hz,1H),4.82-4.63(m,4H),4.57(q,J＝7.3Hz,2H),3.81-3.62(m,1H),3.48(s,2H),2.96-2.76(m，2H)，2.72-2.54(m，2H)，1.68(t，J＝7.1Hz，3H).LC-MS:m/z[M+H] + ＝447.
Example 122
122-1:1- ((4-bromo-3-fluorophenyl) sulfonyl) azetidine
4-bromo-3-fluorobenzenesulfonyl chloride (500 mg,1.8 mmol) and azetidine (104 mg,1.8 mmol) were dissolved in 10mL of methylene chloride, triethylamine (1 mL) was added, and then stirred at room temperature overnight. Saturated aqueous ammonium chloride was added and concentrated by extraction with dichloromethane to give the title compound (350 mg, 84%) as a white solid. LC-MS: M/z [ M+H ]] + ＝294.
122-2:1- ((4-bromo-3-methoxyphenyl) sulfonyl) azetidine
1- ((4-bromo-3-fluorophenyl) sulfonyl) azetidine (450)mg,1.5 mmol) was dissolved in 4mL of methanol, 4M sodium methoxide in methanol (4 mL) was added, and then heated under reflux overnight. Water was added, neutralized to neutrality with 1M hydrochloric acid, and concentrated by extraction with dichloromethane to give the title compound (350 mg, 78%) as a white solid. LC-MS: M/z [ M+H ] ] + ＝306.
122-3:1- ((3-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) sulfonic acid Acyl) azetidines
1- ((4-bromo-3-methoxyphenyl) sulfonyl) azetidine (300 mg,1 mmol) ferrocene, [1,1' -bis (diphenylphosphine)]Palladium dichloride dichloromethane complex (160 mg,0.2 mmol), pinacol diboronate (1000 mg,3.94 mmol), potassium acetate (580 mg,5.91 mmol) were added to 1, 4-dioxane (10 ml) and stirred overnight at 100℃under argon. The reaction solution was concentrated directly, and then purified by thin layer chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (150 mg,42%. LC-MS: M/z [ M+H) as a white solid] + ＝354.
122:4- (4 ' - (azetidin-1-ylsulfonyl) -6-fluoro-2 ' -methoxy- [1,1' -biphenyl)]3-yl) -7- ethyl-7H-imidazo [4, 5-c-pyridazine
Experimental procedure Using 4- (3-chloro-4-fluorophenyl) -7-ethyl-7H-imidazo [4,5-c ] pyridazine (60 mg,0.22 mmol) and 1- ((3-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) sulfonyl) azetidine (74 mg,0.22 mmol) as starting material gives the title compound (5 mg, 2%) as a brown solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.39(s,1H)8.21-8.34(m,3H)7.52-7.62(m,2H)7.45(s,1H)7.38(t,J＝9.05Hz,1H)4.59(q,J＝7.34Hz,2H)3.92(s,3H)3.85-3.91(m,4H)2.16-2.20(m,2H)1.70(s,3H).LC-MS:m/z[M+H] + ＝468.
Example 123
123-1: 4-bromo-3-fluoro-N, N-dimethylbenzenesulfonamide
Experimental procedure the same as in example 122 for the synthesis of 122-1, starting from 4-bromo-3-fluorobenzenesulfonyl chloride (CAS: 351003-51-5, 500mg,1.8 mmol) and dimethylamine hydrochloride (294 mg,3.7 mmol), the title compound (400 mg, 77%) is obtained as a white solid. LC-MS: M/z [ M+H ] ] + ＝282.
123-2: 4-bromo-3-methoxy-N, N-dimethylbenzenesulfonamide
Experimental procedure the same as in example 122-2 was used to give the title compound (350 mg, 85%) as a white solid starting from (4-chloro-2-methoxy-1-methyl-1, 2-dihydropyridin-3-yl) methanol (500 mg,2.9 mmol). LC-MS: M/z [ M+H ]] + ＝294.
123-3: 3-methoxy-N, N-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzene Sulfonamide compounds
Experimental procedure the same as in example 122 was used for the synthesis of 122-3 from 4-bromo-3-methoxy-N, N-dimethylbenzenesulfonamide (350 mg,1.2 mmol) and pinacol borate (227 mg,3.6 mmol) to give the title compound (400 mg, 100%) as a white solid. LC-MS: M/z [ M+H ]] + ＝342.
123:5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2' -fluoro-2-methoxy-N, N-dimethyl- & gt [1,1' -Biphenyl]-4-sulfonamides
The experimental procedure was as in example 1 starting from 4- (3-chloro-4-fluorophenyl) -7-ethyl-7H-imidazo [4,5-c ] pyridazine (60 mg,0.22 mmol) 3-methoxy-N, N-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzenesulfonamide (74 mg,0.22 mmol) to give the title compound (15 mg, 15%) as a white solid.
1 H NMR(400MHz,CHLOROFORM-d)δ9.38(s,1H)8.26-8.31(m,2H)8.23(d,J＝4.89Hz,1H)7.52-7.59(m,1H)7.45-7.51(m,1H)7.34-7.41(m,2H)4.59(d,J＝7.34Hz,2H)3.91(br.s.,3H)2.82(s,6H)1.70(t,J＝6.85Hz,1H).LC-MS:m/z[M+H] + ＝456.
Example 124
124-1:3- (4-bromo-3-methoxyphenoxy) oxetane
Experimental procedure the same as in example 108 for the synthesis of 108-1 using 4-bromo-3-methoxyphenol (500 mg,2.46 mmol) and 3-iodooxetane (457 mg,2.46 mmol) as starting material gave the title compound as a pale yellow oil (450 mg, 70%). LC-MS: M/z [ M+H ]] + ＝259,261.
124-2:2- (2-methoxy-4- (oxetan-3-yloxy) phenyl) -4, 5-tetramethyl-1, 3, 2-di Oxaboranes
Experimental procedure the synthesis of 122-3 from example 122 was performed using 3- (4-bromo-3-methoxyphenoxy) oxetane (450 mg,1.74 mmol) and pinacol biborate (884 mg,3.48 mmol) as starting material to give the title compound (479 mg, 90%) as a yellow solid. LC-MS: M/z [ m+h ] +=307.
124: 7-ethyl-4- (6-fluoro-2 ' -methoxy-4 ' - (oxetan-3-yloxy) - [1,1' -biphenyl)]-3- Radical) -7H-imidazole [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using 2- (2-methoxy-4- (oxetan-3-yloxy) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (60 mg,0.20 mmol) and 4- (3-chloro-4-fluorophenyl) -7-ethyl-7H-imidazo [4,5-c ] pyridazine (55 mg,0.20 mmol) as starting material gives the title compound (45 mg, 53%) as a brown solid.
1 H NMR(400MHz,CHLOROFORM-d)δ＝9.35(s,1H),8.26(s,2H),8.14(d,J＝5.9Hz,1H),7.31(t,J＝9.0Hz,1H),7.24(s,1H),6.52(s,1H),6.26(d,J＝8.3Hz,1H),5.27(t,J＝5.6Hz,1H),5.00(t,J＝6.6Hz,2H),4.81(t,J＝6.1Hz,2H),4.57(q,J＝7.0Hz,2H),3.81(s,3H),1.68(t,J＝7.1Hz,3H).LC-MS:m/z[M+H] + ＝421.
Example 125
125-1: (5-bromo-2-fluorophenyl) (1, 1-thiomorpholino) methanone
5-bromo-2-fluorobenzoic acid (0.81 g,3.70 mmol), thiomorpholine 1, 1-dioxide (0.50 g,3.70 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.40 g,7.40 mmol), 1-hydroxybenzotriazole (1.00 g,7.40 mmol) and triethylamine (1.20 g,9.90 mmol) were added to dichloromethane (20 mL) and stirred at room temperature for 16 hours. Water (30 mL) was added to the reaction, extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated aqueous sodium chloride (30 mL) and the organic phase was separated by spin-dry column chromatography (dichloromethane) to give the title compound (1.09 g, 88%). LC-MS: M/z [ M+H ] ] + ＝336,338.
125: (1, 1-thiomorpholino) (5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluoro Phenyl) methanones
(5-bromo-2-fluorophenyl) (1, 1-thiomorpholino) methanone (150 mg,0.45 mmol), pinacol biboronate (115 mg,0.45 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (37 mg,0.045 mmol) and sodium acetate (111 mg,1.35 mmol) were added to 1, 4-dioxane (10 mL), under argon, and stirred at 100℃for 5 hours. Then, 4-chloro-7-ethyl-7H-imidazo [4,5-c ] pyridazine (41 mg,0.225 mmol), sodium carbonate (143 mg,1.35 mmol), water (1 mL) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (37 mg,0.045 mmol) were added in this order, again under argon protection, and stirred at 100℃for 16 hours. The reaction solution was concentrated after filtration, and the title compound (13 mg, 14%) was isolated as a white solid by preparative thin layer chromatography (dichloromethane/methanol=30/1).
1 H NMR(400MHz,CHLOROFORM-d)δ＝9.36(s,1H),8.45-8.40(m,1H),8.30(s,2H),7.41-7.33(m,1H),4.59(d,J＝7.3Hz,2H),4.39-4.27(m,2H),3.93(br.s.,2H),3.22-3.13(m,4H),1.71-1.67(m,3H).LC-MS:m/z[M+H] + ＝404.
Example 126
126-1:3- (5-chloro-6- (methoxymethyl) pyridin-2-yl) oxazolidin-2-one
3, 6-dichloro-2- (methoxymethyl) pyridine (192 mg,1.0 mmol), 2-oxazolidinone (175 mg,2.0 mmol), pd 2 (dba) 3 (91.5 mg,0.1 mmol), X-phos (84.8 mg,0.2 mmol), cesium carbonate (652 mg,2.0 mmol) and 1, 4-dioxane (5 mL) were added to a microwave tube, stirred at 100℃for 2 hours under argon, filtered, the filtrate concentrated, and column chromatography (PE: EA=3:1) purified to give the title compound (100 mg, 41.3%) as a yellow oily liquid. LC-MS: M/z [ M+H ] ] + ＝243
126:3- (5- (5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenyl) -6- (methoxymethyl Group) pyridin-2-yl) oxazolidin-2-one
Experimental procedure Using as a starting material 3- (5-chloro-6- (methoxymethyl) pyridin-2-yl) oxazolidin-2-one (80 mg,0.33 mmol), (5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenyl) boronic acid (98 mg,0.33 mmol) gave the title product (20 mg, 13.5%) as an off-white solid in appearance.
1 H NMR(400MHz,DMSO-d6)δ 1 H NMR(400MHz,CDCl 3 )δ9.48(s,1H),8.47(s,1H),8.38(dd,J＝9.5,5.9Hz,2H),8.30(d,J＝8.6Hz,1H),7.75(d,J＝8.7Hz,1H),7.41(t,J＝8.7Hz,1H),4.60(q,J＝7.3Hz,2H),4.54(t,J＝8.2Hz,2H),4.46(s,2H),4.40(t,J＝8.2Hz,2H),3.31(s,3H),1.71(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝449.0
Example 127
127-1:4- (5-chloro-6- (methoxymethyl) pyridin-2-yl) -1-methylpiperazin-2-one
ExperimentThe same procedures used in example 126 were repeated except for using 3, 6-dichloro-2- (methoxymethyl) pyridine (192 mg,1.0 mmol) and 1-methylpiperazin-2-one (228 mg,2.0 mmol) as the starting material to give the title compound (135 mg, 50%) as a yellow oily liquid. LC-MS: M/z [ M+H ]] + ＝243.0
127:4- (5- (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2-fluorophenyl) -6- (methoxymethyl Yl) pyridin-2-yl) -1-methylpiperazin-2-one
Experimental procedure Using as a starting material 4- (5-chloro-6- (methoxymethyl) pyridin-2-yl) -1-methylpiperazin-2-one (135 mg,0.5 mmol) and (143 mg,0.5 mmol) of (5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenyl) boronic acid (143 mg,0.5 mmol) gave the title product (4.5 mg, 1.9%) as an off-white solid.
1 H NMR(400MHz,DMSO-d6)δ9.44(s,1H),8.51–8.19(m,3H),7.61(d,J＝8.5Hz,1H),7.37(t,J＝8.9Hz,1H),6.68(d,J＝8.7Hz,1H),4.59(d,J＝7.3Hz,2H),4.46(s,2H),4.19(s,2H),4.10(d,J＝5.1Hz,2H),3.62–3.50(m,2H),3.33(s,3H),3.07(s,3H),1.70(t,J＝7.3Hz,3H).LC-MS:m/z[M+H] + ＝476.0
Example 128
128-1：(3-bromo-6- (trifluoromethyl) pyridin-2-yl) methanol
Methyl 3-bromo-6- (trifluoromethyl) picolinate (250 mg,0.88 mmol), sodium borohydride (166.5 mg,4.4 mmol) were added sequentially to a mixed solvent of methanol (4 mL) and tetrahydrofuran (4 mL), and stirred at room temperature for two hours. The reaction solution was directly subjected to preparative plate separation and purification (petroleum ether/ethyl acetate=1/1) to give the title compound (170 mg, 75.9%). LC-MS: M/z [ M+H ]] + ＝256,258.
128-2: 3-bromo-2- (methoxymethyl) -6- (trifluoromethyl) pyridine
(3-bromo-6- (trifluoromethyl) pyridin-2-yl) methanol (150 mg,0.56 mmol), sodium hydride (60%, 70mg,1.68 mmol) and iodomethylAlkane (238 mg,1.68 mmol) was added to tetrahydrofuran (6 mL) and stirred at room temperature for one hour. The reaction solution was directly purified by plate separation (dichloromethane/methanol=20/1) to give the title compound (110 mg, 73.3%). LC-MS: M/z [ M+H ]] + ＝270,272.
128: 7-ethyl-4- (4-fluoro-3- (2- (methoxymethyl) -6- (trifluoromethyl) pyridin-3-yl) phenyl) -7H-) Imidazo [4,5-c]Pyridazine (PYRIZE)
Experimental procedure Using 3-bromo-2- (methoxymethyl) -6- (trifluoromethyl) pyridine (110 mg,0.38 mmol) and (5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenyl) boronic acid (102 mg,0.38 mmol) as starting materials gave the title compound (60 mg, 36.6%).
LC-MS:m/z[M+H] + ＝432. 1 H NMR(400MHz,CHLOROFORM-d)9.37(s,1H),8.39-8.31(m,2H),8.28(s,1H),7.91(d,J＝7.8Hz,1H),7.75(d,J＝8.3Hz,1H),7.40(t,J＝8.8Hz,1H),4.61-4.55(m,4H),3.29(s,3H),1.68(t,J＝7.3Hz,3H).
Example 129
129: 7-ethyl-4- (6-fluoro-2 ' -methoxy-4 ' - (trifluoromethyl) - [1,1' -biphenyl)]-3-yl) -7H-imidazole And [4,5-c ]]Pyridazine (PYRIZE)
Experimental procedure Using (5- (7-ethyl-7H-imidazo [4,5-c ] pyridazin-4-yl) -2-fluorophenyl) boronic acid (100 mg,0.35 mmol) and 1-bromo-2-methoxy-4- (trifluoromethyl) benzene (89 mg,0.35 mmol) as starting materials gave the title compound (70 mg, 48.3%).
LC-MS:m/z[M+H] + ＝417. 1 H NMR(400MHz,CHLOROFORM-d)＝9.37(s，1H)，8.28(s，2H)，8.21(d,J＝6.8Hz,1H),7.48(d,J＝7.8Hz,1H),7.39-7.31(m,2H),7.23(s,1H),4.58(q,J＝7.3Hz,2H),3.89(s,3H),1.71-1.68(m,3H).
Example 130
130-1:7- (4-bromo-3- (methoxymethyl) phenyl) -6, 7-dihydroimidazo [1,2-a]Pyrazin-8 (5H) -ones
7- (4-bromo-3- (methoxymethyl) phenyl) -5,6,7, 8-tetrahydroimidazo [1,2-a]Pyrazine (260 mg,0.81 mmol), sodium periodate (173 mg,0.81 mmol), ruthenium oxide hydrate (12 mg,0.1 mmol) were added to acetonitrile (1.5 ml)/water (3 ml)/dichloromethane (1.5 ml) and stirred at room temperature for 1 hour. The reaction solution was purified by direct thin layer chromatography (petroleum ether/ethyl acetate=3/1) to give the title compound (100 mg, 36.72%) as a white solid. LC-MS: M/z [ M+H ]] + ＝336.
130:7- (5' - (7-ethyl-7H-imidazo [4, 5-c)]Pyridazin-4-yl) -2' -fluoro-2- (methoxymethyl) - [1, 1' -biphenyls]-4-yl) -6, 7-dihydroimidazo [1,2-a]Pyrazin-8 (5H) -ones
Experimental procedure Using 7- (4-bromo-3- (methoxymethyl) phenyl) -6, 7-dihydroimidazo [1,2-a ] pyrazine-8 (5H) -1 (100 mg,0.3 mmol), 7-ethyl-4- (4-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -7H-imidazo [4,5-c ] pyridazine (86 mg,0.3 mmol) as the starting material gave the title compound (47 mg, 30.65%) as a yellow solid.
1 H NMR(400MHz,CHLOROFORM-d)ppm 1.67(t,J＝7.09Hz,3H)3.30(s,3H)4.26(br.s.,2H)4.35-4.46(m，4H)4.57(q，J＝7.34Hz，2H)7.08(s，1H)7.28-7.44(m，4H)7.59(s，1H)8.21(d，J＝6.85Hz，1H)8.28(s,2H)9.34(s,1H).LC-MS:m/z[M+H] + ＝498
Biological experimental method
1. The compounds of the present invention are useful for the treatment of GABA of different subtypes A Affinity activity of receptors
By competition 3 Binding of H-flutrazepam to HEK293 cells stably expressing human α1β3γ2, α2β3γ2, α3β3γ2 and α5β3γ2 receptors to determine compound pair GABA A Affinity of each subtype of receptor.
Cells were suspended in 50mM Tris-HCl buffer (pH=7.4), homogenized on ice for 10 times for 20 seconds by a homogenizer, and centrifuged at 1000g for 10min at 4 ℃. Taking the supernatant, and repeating the steps. The supernatant was centrifuged at 4℃for 60min (33800 g; thermo, rotor: A27-8X 50) and the pellet was resuspended in Tris buffer (50 mM Tris-HCl,10mM MgCl2,0.5mM EDTA,10%glycerol). Protein was assayed (BCA method, pierce), 1ml aliquots were prepared and stored at-80 ℃.
Radioligand competition binding assays were performed in a 200 μl system (96 well plates) with 100 μl of cell membrane loaded. 3 The concentration of H-flutrazepam was 1nM and the concentration of test compound was 1X10 -5 -10 -6 M range. Flumazinil was used as a control. Low signal control wells (Low control, LC) were added with 1. Mu.L of 2mM flusiznil (final concentration 10. Mu.M) and High signal control wells (High control, HC) were added with 1. Mu.L of DMSO. The final target membrane protein concentration was 5. Mu.g/well. All test compound sample stock solutions were 10mM. The working concentration of the samples was obtained by diluting all samples to 0.2mM with DMSO, followed by 4-fold serial gradient dilution for a total of 8 concentration gradients. The 96-well plate was sealed with a sealing plate membrane and then incubated on a shaker at room temperature for 1 hour. Simultaneously, the GF/C filter plates were soaked with a plate-soaking buffer (0.3% PEI, stored at 4 ℃) for at least 0.5 hours. After the incubation, the binding was collected on GF/C filter plates using a cell collector and washed 4 times with plate wash buffer (50 mM Tris-HCl, pH 7.4, stored at 4 ℃). After drying in an oven at 50 ℃ for 1 hour, the bottom of the dried GF/C filter plate is sealed, the residual radioactivity of the filter membrane is detected by liquid scintillation counting, 50 mu L of scintillation liquid is added to each well, and the mixture is sealed and read by Microbeta 2. Calculating the pair of samples to be measured 3 H-flutrazepam and GABA A Inhibition activity of receptor membrane protein binding IC of each test sample was calculated by curve fitting (GraphPad Prism 5 software) 50 And through IC 50 Calculating the affinity (Ki) of the sample, thereby evaluating the sample for GABA A Binding capacity of each subtype of receptor.
Expression of human GABA by the above assay A Representative assay results obtained by the method of HEK293 cell binding affinity of the receptor are shown in the following table.
Compounds of table 1 against alpha 2-GABA A Affinity activity of receptors
2. Cell level screening
Detection of alpha 1/alpha 2-GABA of a drug to be detected by electrophysiological method A Positive regulatory activity of the receptor. The specific method is as follows:
GABA (gamma-amino-acid-gamma-amino- A Simultaneous expression of different subunits of receptor in HEK293 cell line to construct GABA with complete function A A receptor. The alpha subunit, beta subunit and gamma subunit pair form a complete functional GABA A The receptor is indispensable. In this example, the present invention establishes the following cell model: the alpha 1 subunit (protein sequence is shown in GenBank accession number: NM_ 000806.5) or alpha 2 subunit (protein sequence is shown in GenBank accession number: NM_ 000807.4), beta 3 subunit (protein sequence is shown in GenBank accession number: NM_ 000814.5) and gamma 2 subunit (protein sequence is shown in GenBank accession number: NM_ 000816.3) are simultaneously expressed in HEK293 cell lines, and monoclonal stable transgenic cell lines are respectively screened. The cell strain expresses alpha 1-GABA with complete function A Receptors or alpha 2-GABA A A receptor. The method separately tests the compound pair alpha 1-GABA A Receptors or alpha 2-GABA A Functional activity of the receptor.
Will express alpha 1-GABA A Receptors or alpha 2-GABA A HEK293 cell monoclonal stable transgenic strain is cultured on a 10cm culture dish, and the HEK293 cell stable transgenic strain is passaged after the HEK293 cell grows to 80% -90%. At passage, the medium was aspirated off first, and 3mL of DPBS phosphate buffer (Gibco TM ) Add to the dish, shake the dish slightly and suck DPBS off. 1mL of pancreatin TrypLE Express, gibco was added TM Digestion is carried out at 37℃for 1-2 minutes. Then 3mL of complete medium (DMEM+10% FBS (Gibco) TM ) Cells on the bottom of the dish were blown off, transferred to a 15mL centrifuge tube (Corning), and centrifuged at 200g for 3 minutes. The supernatant was discarded, 4mL of complete medium was added, gently swirled, and the cells resuspended for use.One part of the suspension cells was transferred to fresh complete medium for subculture and another part of the suspension cells was used for electrophysiological testing.
There are 2 treatments of suspended cells for electrophysiology: the suspension cells were transferred to 24-well plates (Corning) TM ) In 24-well plates, each well was pre-placed with poly-D lysine coated glass slide and 1ml complete medium. The seed density per well was about 0.5 x 10 4 And each ml. The cells are cultured for no more than 36 hours prior to use in an electrophysiological test; alternatively, as a rapid alternative, a suitable amount of suspension cells were dropped onto a 35mm dish (Corning) 0.5-2 hours prior to electrophysiological experiments TM ) Extracellular fluid is added into the culture dish, and cells are adhered to the slide glass for electrophysiological experiments. Both treatments require that the cells on the slide are mostly in a single, independent state.
Compound concentration settings: the final concentration of the compounds used for compound screening was 100nM. To induce stable stress currents of not less than 50pA, the experiment used different GABA concentrations according to different cell line characteristics (the same cell line also slightly varied due to the continuous passage of GABA concentrations): for expression of alpha 1-GABA A Cell lines of the receptor with GABA concentration of 0.05-0.07. Mu.M (about EC 2～4 ) The method comprises the steps of carrying out a first treatment on the surface of the For expression of alpha 2-GABA A Cell lines of the receptor with GABA concentration of 0.10-0.11. Mu.M (about EC 7～8 ). Electrophysiological tests employ whole cell patch clamp techniques, which can be found in the literature (Nickolls, S.A., et al British Journal of Pharmacology,2018, 175:708-725). The composition of the extracellular fluid (ECS) for electrophysiology was as follows: 150mM NaCl,5mM KCl,2.5mM CaCl 2 ，1mM MgCl 2 10mM HEPES and 10mM glucose (pH 7.4); an electrode inner liquid (ICS) formulation for electrophysiology is as follows: 140mM CsCl,11mM EGTA,10mM HEPES,2mM CaCl 2 ，1mM MgCl 2 4mM MgATP,2mM TEA (pH 7.3). Preparing GABA powder into mother liquor by pure water, and diluting in ECS; compounds were first prepared as 4mM stock solution in DMSO and then gradually diluted in GABA-ECS at the corresponding concentrations. Solutions were all freshly prepared prior to electrophysiological testing.
Electrophysiological signal acquisitionThe set uses EPC 10 amplifier and PatchMaster software (HEKA) or Axon700B amplifier and clamtex software (Axon). The recording electrode was drawn using borosilicate glass, and the electrode resistance was 4 to 6mΩ. ALA-VC-8PG is used for extracellular administration TM The system. And selecting single independently grown cells, and forming a complete cell mode by breaking membranes after the glass electrode and the cells form good sealing. Cell membrane potential was clamped at-60 mV and recorded in gap-free mode. In the test, extracellular fluid was first applied extracellularly for about 20 seconds. Waiting for baseline (I) prebaseline ) After stabilization, extracellular fluid is switched to GABA-ECS until the current reaches a peak or plateau. At this time, a GABA-induced current (I gaba ). After about 10-20 seconds, after the current has stabilized, the extracellular fluid is switched to a mixed solution of the compound and GABA-ECS until
At this time, the current (I) treatment ). Finally, the solution was switched to extracellular fluid and the test was terminated by recording for 20-40 seconds. Only baseline plateau, control current magnitude (I gaba -I prebaseline ) Cells with absolute values greater than 40pA and relatively smooth currents for 10-20 seconds were used for compound testing.
For the EPC 10 amplifier, experimental results analysis employed either PatchMaster v2x90.1 or PatchMaster v2x90.3 software. For the Axon700B amplifier and the clamtex 10.6 software. The current value of each stage is calculated according to the average value of the current after stabilizing under the corresponding condition. We define the control current as I gaba -I prebaseline The peak or steady state current average after compound treatment is defined as I treatment -I prebaseline . The functional activity of the compounds is expressed in percent and is calculated according to the following formula: functional activity = [ (I) treatment -I gaba )/(I gaba -I prebaseline )]X 100%. If the number is negative, it indicates that the modulation of GABA receptors by the test compound is deregulated. If the number is positive, it indicates that the modulation of GABA receptors by the test compound is positively modulated. For comparison purposes, normalization was performed using the positive compound CVL-865 (example 4 of patent WO2014091368A 1) as a reference.
The results of the screening of the compounds are shown in the following table:
The compounds of Table 2 are useful for the treatment of alpha 1, 2-GABA A Positive allosteric modulation of the receptor.
The compound of the embodiment of the invention has better selectivity compared with the reference compound CVL-865. In maintaining proper alpha 2-GABA A In the case of receptor electrophysiological activity, such that alpha 1-GABA A The receptor electrophysiological activity is less than 80% of CVL-865, so that the efficacy in vivo is maintained, and meanwhile, less side effects are caused.

Claims (13)

1. An imidazopyridazine derivative of formula I, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing;
wherein,
R 0 is H, halogen or C 1 -C 6 Alkyl or C substituted by 1, 2 or 3 halogens 1 -C 6 An alkyl group;
R 1 is C 1 -C 6 Alkyl, substituted with 1, 2, 3, 4 or 5R 1-1 Substituted C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl or is substituted by 1, 2, 3, 4 or 5R 1-2 Substituted C 3 -C 7 Cycloalkyl, R 1-1 And R is 1-2 Independently halogen, OH, CN, oxo, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy groups or "hetero atoms" selected from 1, 2, or S of N, O3, 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl ";
L 1 is absent, -O-, -C (O) -orWherein the end a is connected with the ring A, and the end B is connected with the ring B;
is-> Wherein, the c end and L 1 Connected with d-terminal and- >Are connected;
X 1 CH or N;
R 2 is halogen or C substituted by 1, 2 or 3 halogens 1 -C 6 An alkyl group;
is->
Ring C is a benzene ring, a "heteroatom is selected from 1, 2 or 3 of N, O and S, the number of heteroatoms is 1, 2 or 3, 5-6 membered, a monocyclic aromatic heterocycle" or "heteroatom is selected from 1, 2 or 3 of N, O and S, the number of heteroatoms is 1, 2 or 3, 3-12 membered, a monocyclic or bicyclic alicyclic heterocycle";
R 3 is-NO 2 、-L 2 -R 3-1 "heteroatom is selected from 1, 2 or 3 of N, O and S, heteroatom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl", substituted by 1, 2 or 3R 3-13 The substituted hetero atom is selected from 1, 2 or 3 of N, O and S, the hetero atom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl, and is substituted by 1, 2 or 3R 3-3 Substituted C 1 -C 6 Alkoxy group,Is covered by 1, 2 or 3R 3-6 Substituted C 3 -C 7 Cycloalkyl,/-> Is covered by 1, 2 or 3R 3-11 Substituted C 1 -C 6 Alkyl,/->
L 2 is-O-, -C (O) -, -CH 2 -、Wherein, the e end and R 3-1 Are connected;
R 3-1 is "heteroatom selected from 1, 2 or 3 of N, O and S, heteroatom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl", is substituted by 1, 2 or 3R 3-1-1 The substituted hetero atom is selected from 1, 2 or 3 of N, O and S, the hetero atom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl group, the hetero atom is selected from 1, 2 or 3 of N, O and S, and the hetero atom number is 1, 2 or 3 3, 5-12 membered, mono-or bicyclic heteroaryl ", substituted with 1, 2 or 3R 3-1-2 The substituted "heteroatom is selected from 1, 2 or 3 in N, O and S, the heteroatom number is 1, 2 or 3, 5-12 membered, monocyclic or bicyclic heteroaryl";
each R is 3-13 And R is 3-1-1 Independently oxo (=o), C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, a "heteroatom selected from 1, 2 or 3 of N, O and S, a heteroatom number of 1, 2 or 3, a 3-12 membered, a monocyclic or bicyclic heterocycloalkyl" or-C (O) -C 1 -C 6 An alkyl group;
each R is 3-1-2 Independently C 1 -C 6 Alkyl, substituted by 1, 2 or 3R 3-2-1 Substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, substituted by 1, 2 or 3R 3-2-2 Substituted C 1 -C 6 Alkoxy, 1, 2 or 3 hetero atoms selected from N, O and S, 1, 2 or 3 hetero atoms, 3-12 membered, mono-or bicyclic heterocycloalkyl, substituted by 1, 2 or 3R 3-2-3 The substituted hetero atom is selected from 1, 2 or 3 of N, O and S, the hetero atom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl, C 3 -C 7 Cycloalkyl, substituted by 1, 2 or 3R 3-2-4 Substituted C 3 -C 7 Cycloalkyl or-NR 3-2-5 R 3-2-6 ；
Each R is 3-2-1 And R is 3-2-2 Independently is halogen, C 1 -C 6 Alkoxy or-NR 3-2-1-1 R 3-2-1-2 ；
R 3-2-1-1 And R is 3-2-1-2 Independently hydrogen, C 1 -C 6 Alkyl, or R 3-2-1-1 、R 3-2-1-2 Together with the atoms to which they are attached form a "heteroatom selected from 1, 2 or 3 of N, O and S, a heteroatom number of 1, 2 or 3, a 3-12 membered, mono-or bicyclic heterocycloalkyl" or a heterocyclic group containing 1, 2 or 3R 3-2-1-3 The substituted hetero atom is selected from 1, 2 or 3 of N, O and S, the hetero atom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl;
each R is 3-2-1-3 Independently C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl, halogen, oxo, hydroxy or CN;
each R is 3-2-3 And R is 3-2-4 Independently C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl, halogen, oxo, hydroxy or CN;
R 3-2-5 and R is 3-2-6 Independently hydrogen, C 1 -C 6 Alkyl, substituted with 1, 2, 3, 4 or 5R 3-2-5-1 Substituted C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl or is substituted by 1, 2, 3, 4 or 5R 3-2-5-2 Substituted C 3 -C 7 Cycloalkyl, R 3-2-5-1 And R is 3-2-5-2 Independently halogen, OH, CN, oxo, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or "heteroatom selected from 1, 2 or 3 of N, O and S, heteroatom number 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl";
each R is 3-3 independently-CN, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl or C substituted by 1, 2 or 3 CNs 3 -C 7 Cycloalkyl;
R 3-4 and R is 3-5 Independently C 1 -C 6 An alkyl group;
R 3-6 is-CN, -C (O) NH 2 or-S (O) 2 -R 3-6-1 ；R 3-6-1 Is C 1 -C 6 An alkyl group;
each R is 3-7 Independently C 1 -C 6 An alkyl group;
each R is 3-8 Independently C 1 -C 6 An alkoxy group;
each R is 3-11 Independently halogen, cyano or C 1 -C 6 An alkoxy group;
R 3-12 、R 3-9 and R is 3-10 Independently C 1 -C 6 An alkyl group;
n is 0, 1, 2, 3 or 4;
each R is 4 Is independently CN, OH, halogen, C 1 -C 6 Alkyl, substituted by 1, 2 or 3R 4-1 Substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C substituted by 1, 2 or 3 halogen 1 -C 6 Alkoxy, -NR 4-2 R 4-3 ；
Each R is 4-1 Independently halogen or C 1 -C 6 An alkoxy group;
R 4-2 and R is 4-3 Independently C 1 -C 6 Alkyl, or R 4-2 、R 4-3 Together form- (CH) 2 ) m-; m is 2, 3, 4 or 5;
each Y 6 independently-N-or-CH-;
each R is 8 Independently C 1 -C 6 An alkyl group;
each R is 9 Independently C 1 -C 6 An alkoxy group;
Y 7 is-CH 2 -or-C (O) -; r is R 10 Is C 1 -C 6 Alkyl or "heteroatom is selected from 1, 2 or 3 of N, O and S, 3-12 membered heterocycloalkyl with 1, 2 or 3 heteroatoms.
2. The imidazopyridazine derivative according to claim 1, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, wherein the imidazopyridazine derivative according to formula I meets one or more of the following conditions:
(1)R 0 、R 1 、R 2 、R 3 、R 3-1-1 、R 3-1-2 、R 3-2-1-1 、R 3-2-1-2 、R 3-2-1-3 、R 3-2-3 、R 3-2-4 、R 3-2-5 、R 3-2-6 、R 3-4 、R 3-5 、R 3-6-1 、R 3-7 、R 3-9 、R 3-10 、R 3-12 、R 3-13 、R 4 、R 4-2 、R 4-3 、R 8 and R is 10 In the above, the C 1 -C 6 Alkyl and said substituted C 1 -C 6 In the alkyl group, each C 1 -C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
(2)R 0 、R 1-1 、R 1-2 、R 2 、R 3-2-1 、R 3-2-2 、R 3-2-1-3 、R 3-2-3 、R 3-2-4 、R 3-2-5-1 、R 3-2-5-2 、R 3-11 、R 4 and R is 4-1 Wherein each halogen is independently F, cl, br or I;
(3)R 3 、R 3-1-1 、R 3-1-2 、R 3-2-1 、R 3-2-2 、R 3-2-1-3 、R 3-2-3 、R 3-2-4 、R 3-2-5-1 、R 3-2-5-2 、R 3-3 、R 3-8 、R 3-11 、R 3 -13 、R 4 、R 4-1 and R is 9 The C is 1 -C 6 Alkoxy and said substituted C 1 -C 6 In the alkoxy group, each C 1 -C 6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;
(4) In the ring C, the heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5-6 membered, the monocyclic aromatic heterocycle is N, the heteroatom number is 1 or 2, 5 or 6 membered, and the monocyclic aromatic heterocycle is;
(5)R 3-1 wherein the "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5-12 membered, monocyclic or bicyclic heteroaryl" and the substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5-12 membered, monocyclic or bicyclic heteroaryl", each "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5-12 membered, monocyclic or bicyclic heteroaryl" is independently "heteroatom is selected from 1, 2 or 3 of N, O and SSpecies or 3, heteroatom number 1, 2 or 3, 5 or 6 membered, monocyclic heteroaryl ";
(6)R 3 and R is 3-1 Wherein the "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" and the substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl", each "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" is independently "heteroatom is selected from 1 or 2 of N and O, the heteroatom number is 1 or 2, 4-12 membered, mono-or bicyclic heterocycloalkyl";
(7)R 1 、R 3 、R 3-1-2 、R 3-2-1-3 、R 3-2-3 、R 3-2-4 、R 3-2-5 、R 3-2-6 And R is 3-3 In the above, the C 3 -C 7 Cycloalkyl and said substituted C 3 -C 7 In cycloalkyl groups, each C 3 -C 7 Cycloalkyl is independently cyclopropane, cyclobutane, cyclopentane or cyclohexane;
(8)R 1-1 、R 1-2 、R 3-13 、R 3-1-1 、R 3-1-2 、R 3-2-1-1 、R 3-2-1-2 、R 3-2-5-1 、R 3-2-5-2 and R is 10 Wherein the "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" and the substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" each "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" is independently "heteroatom is selected from 1 or 2 of N and O, the heteroatom number is 1 or 2, 4, 5 or 6 membered, mono-cyclic heterocycloalkyl".
3. The imidazopyridazine derivative according to claim 1, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, wherein the imidazopyridazine derivative according to formula I meets one or more of the following conditions:
(1)R 0 、R 1 、R 2 、R 3 、R 3-1-1 、R 3-1-2 、R 3-2-1-1 、R 3-2-1-2 、R 3-2-1-3 、R 3-2-3 、R 3-2-4 、R 3-2-5 、R 3-2-6 、R 3-4 、R 3-5 、R 3-6-1 、R 3-7 、R 3-9 、R 3-10 、R 3-12 、R 3-13 、R 4 、R 4-2 、R 4-3 、R 8 and R is 10 In the above, the C 1 -C 6 Alkyl and said substituted C 1 -C 6 In the alkyl group, each C 1 -C 6 Alkyl is independently methyl, ethyl, n-propyl or isopropyl;
(2)R 0 、R 1-1 、R 1-2 、R 2 、R 3-2-1 、R 3-2-2 、R 3-2-1-3 、R 3-2-3 、R 3-2-4 、R 3-2-5-1 、R 3-2-5-2 、R 3-11 、R 4 and R is 4-1 Wherein each halogen is independently F;
(3)R 3 、R 3-1-1 、R 3-1-2 、R 3-2-1 、R 3-2-2 、R 3-2-1-3 、R 3-2-3 、R 3-2-4 、R 3-2-5-1 、R 3-2-5-2 、R 3-3 、R 3-8 、R 3-11 、R 3 -13 、R 4 、R 4-1 and R is 9 In the above, the C 1 -C 6 Alkoxy and said substituted C 1 -C 6 In the alkoxy group, each C 1 -C 6 Alkoxy is independently methoxy or ethoxy;
(4) In ring C, the "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5-6 membered, monocyclic aromatic heterocycle" is
(5)R 3-1 Wherein the "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5-12 membered, monocyclic or bicyclic heteroaryl" and the substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5-12 membered, monocyclic or bicyclic heteroaryl", each "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5-12 membered, monocyclic or bicyclic heteroaryl" is independently oxadiazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrazinyl or pyrimidinyl;
(6)R 3 and R is 3-1 Wherein the "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" and the substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" each "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" is independently azetidinyl, glycidyl, tetrahydrofuranyl, pyrrolidinyl, oxazolidinyl, imidazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, oxazinyl or 2-oxo-6-azaspiro [3.3 ] ]A heptyl group;
(7)R 1 、R 3 、R 3-1-2 、R 3-2-1-3 、R 3-2-3 、R 3-2-4 、R 3-2-5 、R 3-2-6 and R is 3-3 In the above, the C 3 -C 7 Cycloalkyl and said substituted C 3 -C 7 In cycloalkyl groups, each C 3 -C 7 Cycloalkyl is independently cyclopropane;
(8)R 1-1 、R 1-2 、R 3-13 、R 3-1-1 、R 3-1-2 、R 3-2-1-1 、R 3-2-1-2 、R 3-2-5-1 、R 3-2-5-2 and R is 10 Wherein the "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" and the substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" each "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" is independently azetidinyl, glycidyl, pyrrolidinyl or piperazinyl.
4. The imidazopyridazine derivative according to claim 1, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, wherein the imidazopyridazine derivative according to formula I meets one or more of the following conditions:
(1) In ring C, the "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5-6 membered, monocyclic aromatic heterocycle" is
(2)R 3-1 Wherein the "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5-12 membered, monocyclic or bicyclic heteroaryl" and the substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5-12 membered, monocyclic or bicyclic heteroaryl" each "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 5-12 membered, monocyclic or bicyclic heteroaryl" is independently
(3)R 3 And R is 3-1 Wherein the "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" and the substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" each "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" is independently
(4)R 3-13 、R 3-1-1 、R 3-1-2 、R 3-2-1-1 、R 3-2-1-2 And R is 10 Wherein the "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" and the substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" each "heteroatom is selected from 1, 2 or 3 of N, O and S, the heteroatom number is 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl" is independently
5. The imidazopyridazine derivative according to claim 1, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, wherein the imidazopyridazine derivative according to formula I meets one or more of the following conditions:
(1)R 1 is-CH (CH) 3 ) 2 or-CH 2 CH 3 ；
(2)L 1 Is absent, -O-, or
(3)Is->
(4)R 2 F is the same as F;
(5)is->
(6) Ring C is a benzene ring or pyridine ring;
(7)R 3 is-NO 2 、-L 2 -R 3-1 "heteroatom is selected from 1, 2 or 3 of N, O and S, heteroatom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl", substituted by 1, 2 or 3R 3-13 The substituted hetero atom is selected from 1, 2 or 3 of N, O and S, the hetero atom number is 1, 2 or 3, 3-12 membered, monocyclic or bicyclic heterocycloalkyl, and is substituted by 1, 2 or 3R 3-3 Substituted C 1 -C 6 Alkoxy, substituted by 1, 2 or 3R 3-6 Substituted C 3 -C 7 Cycloalkyl group,Is covered by 1, 2 or 3R 3-11 Substituted C 1 -C 6 Alkyl or->
(8) n is 1 or 2;
(9) Each R is 4 Independently halogen, is covered by 1C 1 -C 6 Alkoxy substituted C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group;
(10) At least 1R 4 Is 1C 1 -C 6 Alkoxy substituted C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy (e.g. -O-CH 3 、-O-CH 2 CH 3 or-CH 2 -O-CH 3 ) The rest R 4 Halogen (e.g., F) or absent;
(11)R 0 H, cl, F, CF of a shape of H, cl, F, CF 3 Or CH (CH) 3 。
6. The imidazopyridazine derivative according to claim 1, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, wherein the imidazopyridazine derivative according to formula I meets one or more of the following conditions:
(1)R 1 is-CH 2 CH 3 ；
(2)Is-> Preferably +.>
(3)R 3 is-L 2 -R 3-1 "heteroatom is selected from 1, 2 or 3 of N, O and S, the number of heteroatom is 1, 2 or3, 3-12 membered, mono-or bicyclic heterocycloalkyl, substituted by 1, 2 or 3R 3-13 The substituted hetero atom being selected from 1, 2 or 3 of N, O and S, the hetero atom number being 1, 2 or 3, 3-12 membered, mono-or bicyclic heterocycloalkyl "or being substituted by 1, 2 or 3R 3-3 Substituted C 1 -C 6 An alkoxy group;
(4) Each R is 4 Is independently F, -O-CH 3 、-O-CH 2 CH 3 or-CH 2 -O-CH 3 ；
(5)R 0 H.
7. The imidazopyridazine derivative of formula I, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, according to claim 1,is that
8. The imidazopyridazine derivative according to claim 1, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, wherein the imidazopyridazine derivative according to formula I is any one of the following:
Scheme one: r is R 3 is-L 2 -R 3-1 ；
R 3-1 Is "a 5-12 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from 1, 2 or 3 of N, O and S", is substituted with 1, 2 or 3R 3-1-2 The substituted "heteroatom is selected from 1, 2 or 3 in N, O and S, the heteroatom number is 1, 2 or 3 5-12 membered heteroaryl";
n is 1 or 2;
ring C is a benzene ring or pyridine ring;
when ring C is a benzene ring, at least 1R 4 Is C 1 -C 6 Alkoxy (e.g. -O-CH 3 ) The rest R 4 Halogen (e.g., F) or absent;
when ring C is a pyridine ring, there are at least 1R 4 Is 1C 1 -C 6 Alkoxy substituted C 1 -C 6 Alkyl (e.g. -CH 2 -O-CH 3 ) The rest R 4 Halogen (e.g., F) or absent;
scheme II: r is R 3 Is 1, 2 or 3R 3-3 Substituted C 1 -C 6 An alkoxy group;
scheme III: r is R 3 Is 1, 2 or 3R 3-11 Substituted C 1 -C 6 Alkyl, ring C is a pyridine ring, and at least 1R 4 Is C 1 -C 6 Alkoxy (e.g. -O-CH 3 ) The rest R 4 Halogen (e.g., F) or absent.
9. The imidazopyridazine derivative according to claim 1, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, wherein the imidazopyridazine derivative according to formula I has the structure according to formula I-1:
Wherein the ring C, L 1 、R 1 、R 3 、R 4 And n is as defined in any one of claims 1 to 8.
10. An imidazopyridazine derivative shown below, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing,
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11. a pharmaceutical composition, the pharmaceutical composition comprising:
(1) The imidazopyridazine derivative, stereoisomer thereof, tautomer thereof, or pharmaceutically acceptable salt of any one of the foregoing, or solvate of any one of the foregoing, according to any one of claims 1-10, and
(2) A pharmaceutically acceptable carrier.
12. The imidazopyridazine derivative according to any one of claims 1 to 10, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any one of the preceding, or a solvate of any one of the preceding, or the pharmaceutical composition according to claim 11 for use in the preparation of α 2/3 -GABA A Use of receptor modulators.
13. Use of an imidazopyridazine derivative according to any one of claims 1 to 10, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any one of the preceding, or a solvate of any one of the preceding, or a pharmaceutical composition according to claim 11 for the manufacture of a medicament for the treatment and/or prophylaxis of a-d 2/3 -GABA A Receptor-related disorders, relief of pain, epilepsy, anxiety, itching, or depression.
CN202210509485.1A 2022-05-10 2022-05-10 Fused ring compounds, pharmaceutical compositions and uses Pending CN117069724A (en)

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