CN112409331A - Heterocyclic derivative inhibitor, preparation method and application thereof - Google Patents

Heterocyclic derivative inhibitor, preparation method and application thereof Download PDF

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CN112409331A
CN112409331A CN202010852140.7A CN202010852140A CN112409331A CN 112409331 A CN112409331 A CN 112409331A CN 202010852140 A CN202010852140 A CN 202010852140A CN 112409331 A CN112409331 A CN 112409331A
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肖华玲
蔡加强
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Abstract

The invention relates to a heterocyclic derivative inhibitor, a preparation method and application thereof. In particular, the invention relates to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound serving as a P2X3 inhibitor in treating P2X3 receptor dysfunction diseases, in particular application in treating neurogenic diseases.

Description

Heterocyclic derivative inhibitor, preparation method and application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a heterocyclic derivative inhibitor, and a preparation method and application thereof.
Background
The P2X receptor (P2X receptors) or the so-called P2X purine receptor (P2X purinorecteptor) is a family of cation permeable ATP ligand gated ion channels that bind extracellular ATP. The P2X receptor has seven subunits, either homotrimeric or heterotrimeric, which are expressed predominantly in nerve terminals of the nervous system (presynaptic and postsynaptic) and modulate synaptic transmission. The P2X3 receptor is one of the P2X family members, is a key sensory receptor that senses upper respiratory tract irritation and triggers the cough reflex, is believed to play a key role in sensitization (sensitization) of specific sensory nerves, is involved in pain and cough, and is involved in the perception of bone cancer pain, and blocking P2X3 can suppress the signal stimulus of cough.
Cough is defensive nerve reflex of the body, is beneficial to clearing respiratory tract secretion and harmful factors, and can cause serious influence on work, life and social activities of patients and the like due to frequent and violent cough. Cough is classified into acute, subacute and chronic cough. Chronic cough (Chronic cough) is a person with cough time of more than 8 weeks, with cough as the main or only symptom, and no obvious lesion in lung detected by chest imaging. Chronic cough has long been recognized as a consequence of various diseases such as asthma/eosinophilic bronchitis, rhinitis and gastroesophageal reflux disease. However, recent evidence suggests that chronic cough is a clinical symptom, with a distinct neuropsychiatric feature of intrinsic pathophysiology. The chronic cough or idiopathic cough with unknown cause is mainly manifested as chronic irritant dry cough, which is sensitive to external stimuli, and has high cough sensitivity, which is a physiopathological mechanism. Cough-related afferent nerve abnormalities may be the cause of intractable or unexplained chronic cough. Chronic cough can cause cardiovascular, digestive, neurological, urinary, musculoskeletal and other systemic complications, such as urinary incontinence, syncope, insomnia, anxiety, and the like.
Based on the pathophysiological characteristics of cough hypersensitivity syndrome, treatment should be aimed at reducing cough sensitivity. Current treatment options are limited, including drug and non-drug treatments. Clinical research results show that the neuroregulation factor medicine gabapentin is effective in treatment, and other medicines such as amitriptyline, baclofen, carbamazepine, pregabalin and the like can also be selected. Antitussives can be appropriately administered for severe cough, and are mainly classified into central antitussives and peripheral antitussives. The central antitussive is classified into dependent antitussive (morphine alkaloid and its derivatives) and non-dependent antitussive (artificially synthesized dextromethorphan and pentoxyverine), the former has side effects of addiction and anesthesia, and the latter has wide clinical application. Peripheral antitussives, also known as peripheral antitussives, act by suppressing a certain link in the cough reflex arc, including local anesthetics (narcotine, benzonatate) and mucosal protectants (benproperine and moguisteine).
At present, no P2X3 receptor antagonist small-molecule drug which is approved to be on the market is available on the market. The P2X3 receptor antagonist drug at present in clinical stage is Merck & Co MK-7264, which is used for treating diseases such as pain and pulmonary fibrosis, has low selectivity to P2X3/P2X2/3 and good safety but has side effects such as taste loss, and the chronic cough as an indication has been studied in clinical stage III at present. BLU5937 in Bellis Health (Bellus Health) has high selectivity and no side effects such as taste and the like in phase I clinical test; 6.7.2020, Belles health promulgated the primary findings of the BLU-5937 phase 2 RELIEF test in refractory chronic cough patients: in the phase II clinical study, the RELIEF test did not reach statistical significance for the primary endpoint of reduced cough frequency following placebo adjustment at any dose. But are well tolerated, taste effects including taste changes and partial taste loss are rare at all dose levels, and are mostly mild in nature, with no patients reporting complete loss of taste. In addition, Bayer 'S BAY-1817080 and Shionogi' S S-600918, chronic cough, an indication, is currently in clinical stage I/II. Therefore, the development of P2X3 receptor inhibitor drugs with good safety, non-addictive narcotic property and high selectivity for treating diseases such as chronic cough is urgently needed to meet the huge market demand.
The compounds of the present examples have better stability of liver microsomes and less taste side effects than belleville healthy BLU 5937.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
Figure BDA0002645089080000021
wherein:
L1and L2Each independently selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1NRaa(CRbbRcc)n2-、-(CH2)n1C(O)NRaa-、-(CRaaRbb)n1O(CH2)n2-、-(CRaaRbb)n1(CH2)n2O-、-(CH2)n1NRaaC(O)-、-(CH2)n1(CRaaRbb)n2-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CH2)n1S(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-、-(CH2)n1C(O)(CRaaRbb)n2-、-(CH2)n1P(O)Raa-、-(CH2)n1S(O)n2-、-(CH2)n1S(O)n2NRaa-or- (CH)2)n1NRaaS(O)n2-；
Ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
ring C is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
Raselected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)ORaa、-(CH2)n1ORaa、-(CH2)n1SRaa、-(CH2)n1NRaaC(O)Rbb、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1NRaaC(O)NRbbRcc、-(CH2)n1NRaaRbb、-NRaa(CH2)n1Rbb、-(CH2)n1C(O)NRaaRbb、-(CH2)n1C(O)Raa、-OC(RaaRbb)n1(CH2)n2Rcc、-C(RaaRbb)n1(CH2)n2ORcc、-(CH2)n1S(O)n2Raa、-(CH2)n1NRaaS(O)n2Rbb、-CH＝CH(CH2)n1Raa、-CH＝CH(CH2)n1NRaaRbb、-CH＝CH(CH2)n1NRaaC(O)Rbbor-CH ═ CH (CH)2)n1NRaaC(O)NRbbRccSaid amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally may be further substituted;
Rbselected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, heteroaryloxy, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)ORaa、-(CH2)n1ORaa、-(CH2)n1SRaa、-(CH2)n1NRaaC(O)Rbb、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1NRaaC(O)NRbbRcc、-(CH2)n1NRaaRbb、-NRaa(CH2)n1Rbb、-(CH2)n1C(O)NRaaRbb、-(CH2)n1C(O)Raa、-OC(RaaRbb)n1(CH2)n2Rcc、-(CH2)n1S(O)n2Raa、-(CH2)n1NRaaS(O)n2Rbb、-CH＝CH(CH2)n1Raa、-CH＝CH(CH2)n1NRaaRbb、-CH＝CH(CH2)n1NRaaC(O)Rbbor-CH ═ CH (CH)2)n1NRaaC(O)NRbbRccSaid amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally may be further substituted;
Rcselected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)ORaa、-(CH2)n1ORaa、-(CH2)n1SRaa、-(CH2)n1NRaaC(O)Rbb、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1NRaaC(O)NRbbRcc、-(CH2)n1NRaaRbb、-NRaa(CH2)n1Rbb、-(CH2)n1C(O)NRaaRbb、-(CH2)n1C(O)Raa、-OC(RaaRbb)n1(CH2)n2Rcc、-(CH2)n1S(O)n2Raa、-(CH2)n1NRaaS(O)n2Rbb-CH＝CH(CH2)n1Raa、-CH＝CH(CH2)n1NRaaRbb、-CH＝CH(CH2)n1NRaaC(O)Rbbor-CH ═ CH (CH)2)n1NRaaC(O)NRbbRccThe amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocycloalkyl, or cycloalkyl group,Cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;
Raa、Rbband RccEach independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
or, Raa、RbbAnd RccAny two of which are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally may be further substituted;
x is an integer of 0-6;
y is an integer of 0 to 6;
z is an integer of 0 to 6;
n1 is 0, 1,2 or 3; and is
n2 is 0, 1,2 or 3.
In a preferred embodiment of the invention, L1Selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1C(O)NRaa-、-(CH2)n1(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2O-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CH2)n1S(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-、-(CH2)n1NRaa(CRbbRcc)n2-、-(CH2)n1C(O)(CRaaRbb)n2-、-(CH2)n1NRaaC(O)-、-(CH2)n1S(O)n2-、-(CH2)n1S(O)n2NRaa-or- (CH)2)n1NRaaS(O)n2-。
In a further preferred embodiment of the invention, L1Selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1O-、-(CH2)n1S-、-(CH2)n1NRaa-、-(CH2)n1C(O)NRaa-or- (CH)2)n1NRaaC(O)-。
In a further preferred embodiment of the invention, L1Is selected from the group consisting of a bond, -CH2-, -O-, -S-, -NH-, -C (O) NH-or-NHC (O) -.
The invention also provides a preferred scheme, L2Selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1C(O)NRaa-、-(CH2)n1(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2O-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CH2)n1S(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-、-(CH2)n1NRaa(CRbbRcc)n2-、-(CH2)n1C(O)(CRaaRbb)n2-、-(CH2)n1NRaaC(O)-、-(CH2)n1S(O)n2-、-(CH2)n1S(O)n2NRaa-or- (CH)2)n1NRaaS(O)n2-。
In a further preferred embodiment of the invention, L2Selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1(CRaaRbb)n2-、-(CH2)n1O-、-(CH2)n1S-、-(CH2)n1NRaa-、-(CH2)n1C(O)(CRaaRbb)n2-、-(CH2)n1C(O)NRaa-or- (CH)2)n1NRaaC(O)-。
In a further preferred embodiment of the invention, L2Is selected from the group consisting of a bond, -CH2-、-O-、-S-、-NH-、-CH2C(O)-、-CH2C (O) NH-or
Figure BDA0002645089080000041
In a preferred embodiment of the invention, ring B is selected from C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl;
in a further preferred embodiment of the invention, ring B is selected from C6-14Aryl or 5-14 membered heteroaryl, more preferably phenyl, benzo 5-8 membered nitrogen containing heterocyclyl, benzo 5-8 membered nitrogen containing heteroaryl, further selected from the group consisting of:
Figure BDA0002645089080000042
in a preferred embodiment of the invention, ring C is selected from C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl;
in a further preferred embodiment of the invention, ring C is selected from C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl, more preferably cyclobutyl, piperidinyl, phenyl, pyridinyl or morpholinyl, further selected from the group consisting of:
Figure BDA0002645089080000051
in a preferred embodiment of the invention, RaSelected from hydrogen, deuteriumHalogen, amino, hydroxy, cyano, nitro, oxo, thio, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)ORaa、-(CH2)n1ORaa、-(CH2)n1SRaa、-(CH2)n1NRaaC(O)Rbb、-C(RaaRbb)n1(CH2)n2ORcc、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1NRaaC(O)NRbbRcc、-(CH2)n1NRaaRbb、-NRaa(CH2)n1Rbb、-(CH2)n1C(O)NRaaRbb、-(CH2)n1C(O)Raa、-OC(RaaRbb)n1(CH2)n2Rcc、-(CH2)n1S(O)n2RaaOr- (CH)2)n1NRaaS(O)n2RbbSaid amino group, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
in a further preferred embodiment of the inventionIn the formula, RaSelected from hydrogen, oxo, C1-6Alkyl radical, C2-6Alkenyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, - (CH)2)n1NRaaRbb、-(CH2)n1SRaa、-(CH2)n1C(O)NRaaRbb、-(CH2)n1NRaaC(O)Rbbor-C (R)aaRbb)n1(CH2)n2ORccSaid C is1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, 3-8 membered heterocyclyl and 5-10 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl;
in a further preferred embodiment of the invention, RaSelected from hydrogen, halogen, oxo, C1-6Alkyl radical, C2-6Alkenyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, - (CH)2)n1NRaaRbb、-(CH2)n1SRaa、-(CH2)n1C(O)NRaaRbb、-(CH2)n1NRaaC(O)Rbbor-C (R)aaRbb)n1(CH2)n2ORccSaid C is1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, 3-8 membered heterocyclyl and 5-10 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl;
in a further preferred embodiment of the invention, RaSelected from hydrogen, oxo, methyl, ethyl, isopropyl, difluoroisobutyl, methyldiazolyl, vinyl, cyclopropyl, cyclobutyl, -NRaaRbb、-SRaa、-C(O)NRaaRbb、-NRaaC(O)Rbbor-C (R)aaRbb)n1(CH2)n2ORcc。
In a preferred embodiment of the invention, RbSelected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl radical, C6-14Aryloxy, 5-14 membered heteroaryl, 5-14 membered heteroaryloxy, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)ORaa、-(CH2)n1ORaa、-(CH2)n1SRaa、-(CH2)n1NRaaC(O)Rbb、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1NRaaC(O)NRbbRcc、-(CH2)n1NRaaRbb、-NRaa(CH2)n1Rbb、-(CH2)n1C(O)NRaaRbb、-(CH2)n1C(O)Raa、-OC(RaaRbb)n1(CH2)n2Rcc、-(CH2)n1S(O)n2RaaOr- (CH)2)n1NRaaS(O)n2RbbSaid amino group, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl radical, C6-14Aryloxy, 5-14 membered heteroaryl and 5-14 membered heteroaryloxy, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
in a further preferred embodiment of the invention, RbSelected from hydrogen, halogen, oxo, C1-3Alkyl, -ORaaor-C (O) NRaaRbb；
In a further preferred embodiment of the invention, RbSelected from hydrogen, halogen, oxo, C1-6Alkyl, - (CH)2)n1ORaa、-(CH2)n1C(O)NRaaRbb、-(CH2)n1NRaaC(O)Rbb、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1S(O)n2NRaaRbb、-(CH2)n1NRaaS(O)n2RbbOr- (CH)2)n1NRaaS(O)n2NRbbRcc(ii) a Preferably hydrogen, halogen, oxo, C1-3Alkyl, -ORaa、-C(O)NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)ORbb、-S(O)2NRaaRbb、-NRaaS(O)2Rbbor-NRaaS(O)2NRbbRcc。
In a further preferred embodiment of the invention, RbSelected from hydrogen, halogen, oxo, C1-6Alkyl, - (CH)2)n1ORaa、-(CH2)n1C(O)NRaaRbb、-(CH2)n1NRaaC(O)Rbb、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1S(O)n2Raa、-(CH2)n1S(O)n2NRaaRbb、-(CH2)n1NRaaS(O)n2Rbb、-(CH2)n1S(O)(＝NRaa)Rbb、-(CH2)n1NRaaS(O)(＝NRbb)RccOr- (CH)2)n1NRaaS(O)n2NRbbRcc(ii) a Preferably hydrogen, halogen, oxo, C1-3Alkyl, -ORaa、-C(O)NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)ORbb、-S(O)2Raa、-S(O)2NRaaRbb、-NRaaS(O)2Rbb、-S(O)(＝NRaa)Rbb、-NRaaS(O)(＝NRbb)Rccor-NRaaS(O)2NRbbRcc；
In a further preferred embodiment of the invention, RbSelected from hydrogen, fluoro, chloro, bromo, oxo, methyl, ethyl, isopropyl, -C (O) NHCH3、-C(O)NHC(CH3)CH2OCH3、-NHC(O)OCH3、-NHC(O)CHF2、-NHS(O)2CH3、-NHS(O)2N(CH3)2、-S(O)2CH3、-S(O)2NHCH3、-S(O)2N(CH3)2、-S(O)2NHCH(CH3)2、-S(O)(＝NH)CH3、-NHS(O)(＝NH)CH3、
Figure BDA0002645089080000071
In a preferred embodiment of the invention, RcSelected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n1C(O)Raa、-(CH2)n1C(O)ORaaOr- (CH)2)n1C(O)NRaaRbbSaid amino group, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
in a further preferred embodiment of the invention, RcSelected from hydrogen, halogen, C1-3Alkyl, halophenyl, -C (O) RaaOR-C (O) ORaa。
In a further preferred embodiment of the invention, RcSelected from hydrogen, halogen, C1-6Alkyl, halophenyl, - (CH)2)n1C(O)Raa、-(CH2)n1C(O)ORaa、-(CH2)n1S(O)n2RaaOr- (CH)2)n1S(O)n2NRaaRbb(ii) a Preferably hydrogen, halogen, C1-6Alkyl, halophenyl, -C (O) Raa、-C(O)ORaa、-S(O)2Raaor-S (O)2NRaaRbb。
In a further preferred embodiment of the invention, RcSelected from hydrogen, fluorine, chlorine, bromine, C1-6Alkyl, methyl, ethyl, isopropyl, chlorophenyl, -C (O) CH3、-C(O)CHF2、-C(O)CH2CH3、-C(O)OCH3、-C(O)OC(CH3)3、-S(O)2CH3、-S(O)2CH2CH3、-S(O)2N(CH3)2、
Figure BDA0002645089080000072
Figure BDA0002645089080000073
In a preferred embodiment of the invention, Raa、RbbAnd RccEach independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-to 14-membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
or, Raa、RbbAnd RccAny two links forming C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-12 membered heteroaryl, said C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
in a further preferred embodiment of the present invention, there is provided a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the specific structure:
Figure BDA0002645089080000081
in a further preferred embodiment of the present invention, there is provided a compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the specific structure:
Figure BDA0002645089080000082
wherein:
M1selected from N or CR9(ii) a Preferably N, CH or CF;
R9、R10and R13Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
preferably hydrogen, fluorine, chlorine, bromine or iodine;
R11and R12Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)ORaa、-(CH2)n1ORaa、-(CH2)n1SRaa、-(CH2)n1NRaaC(O)Rbb、-C(RaaRbb)n1(CH2)n2ORcc、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1NRaaC(O)NRbbRcc、-(CH2)n1NRaaRbb、-NRaa(CH2)n1Rbb、-(CH2)n1C(O)NRaaRbb、-(CH2)n1C(O)Raa、-OC(RaaRbb)n1(CH2)n2Rcc、-(CH2)n1S(O)n2RaaOr- (CH)2)n1NRaaS(O)n2RbbSaid amino group, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl; preferably hydrogen, methyl, ethyl, isopropyl, vinyl, methoxy, methylthio, cyclopropyl, cyclobutyl or-NHCH3；
Or R11And R12Linked to the carbon atom to which it is attached to form C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
R11and R12A ring linked to the carbon atom to which it is attached, preferably a 5-6 membered nitrogen containing heterocyclyl or heteroaryl, a 5-6 membered oxygen containing heterocyclyl or heteroaryl or a 5-6 membered sulfur containing heterocyclyl or heteroaryl;
further preferred are the following groups:
Figure BDA0002645089080000091
R14selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyanoSubstituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)ORaa、-(CH2)n1ORaa、-(CH2)n1SRaa、-(CH2)n1NRaaC(O)Rbb、-C(RaaRbb)n1(CH2)n2ORcc、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1NRaaC(O)NRbbRcc、-(CH2)n1NRaaRbb、-NRaa(CH2)n1Rbb、-(CH2)n1C(O)NRaaRbb、-(CH2)n1C(O)Raa、-OC(RaaRbb)n1(CH2)n2Rcc、-(CH2)n1S(O)n2RaaOr- (CH)2)n1NRaaS(O)n2RbbSaid amino group, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl; preferably hydrogen, halogen, methyl, ethyl, isopropyl, -C (O) OCH3、-C(O)CH2CH3、-C(O)OCH2CH3。
In a further preferred embodiment of the invention, R14Selected from hydrogen, halogen, C1-6Alkyl, halophenyl, - (CH)2)n1C(O)Raa、-(CH2)n1C(O)ORaa、-(CH2)n1S(O)n2RaaOr- (CH)2)n1S(O)n2NRaaRbb(ii) a Preferably hydrogen, halogen, C1-6Alkyl, halophenyl, -C (O) Raa、-C(O)ORaa、-S(O)2Raaor-S (O)2NRaaRbb(ii) a More preferably hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, -C (O) OCH3、-C(O)CH2CH3、-C(O)CHF2、-C(O)OCH2CH3、-S(O)2CH3、-S(O)2CH2CH3、-S(O)2N(CH3)2、
Figure BDA0002645089080000101
Figure BDA0002645089080000102
In a further preferred embodiment of the present invention, there is provided a compound of formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the specific structure:
Figure BDA0002645089080000103
wherein:
R14is-C (O) Raa；
RaaIs selected from C1-6Alkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
preferably C1-3Alkyl radical, C1-3Haloalkyl or C1-3An alkoxy group;
more preferably methyl, ethyl, difluoromethyl, methoxy or ethoxy.
The invention also relates to a method for preparing the compound shown in the general formula (IV) or the stereoisomer and the pharmaceutically acceptable salt thereof, which specifically comprises the following steps,
Figure BDA0002645089080000111
carrying out condensation reaction on the compound shown in the general formula (IV-1) or the salt thereof and the compound shown in the general formula (IV-2) to obtain the compound shown in the general formula (IV) or a stereoisomer and a pharmaceutically acceptable salt thereof;
wherein the content of the first and second substances,
x is selected from hydroxyl, chlorine or bromine;
R14is-C (O) Raa；
RaaIs selected from C1-6Alkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
preferably C1-3Alkyl radical, C1-3Haloalkyl or C1-3An alkoxy group;
more preferably methyl, ethyl, difluoromethyl, methoxy or ethoxy.
The invention further relates to an intermediate compound shown in formula (IV-1) for preparing the compound shown in formula (IV) or a stereoisomer and pharmaceutically acceptable salts thereof, wherein the intermediate compound shown in formula (IV-1) is a compound or a salt thereof, and the specific structure is shown as follows:
Figure BDA0002645089080000112
the invention further relates to a method for preparing the compound shown in the general formula (IV-1) or the salt thereof, which specifically comprises the following steps,
Figure BDA0002645089080000113
deprotecting the general formula (IV-3) to obtain a compound represented by the general formula (IV-1) or a salt thereof;
wherein:
Pg1is an amino protecting group selected from allyloxycarbonyl, trifluoroacetyl, 2, 4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, fluorenyl methoxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl or p-methoxyphenyl; tert-butyloxycarbonyl is preferred.
The invention also relates to a method for preparing the compound shown in the general formula (IV) or the stereoisomer and the pharmaceutically acceptable salt thereof, which specifically comprises the following steps,
Figure BDA0002645089080000121
the invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds of general formula (I), stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to an application of any of the compounds shown in the general formula (I), stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in preparation of P2X3 receptor inhibitor drugs.
The invention further relates to an application of the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof in preparing a medicament for treating neurogenic diseases, wherein the neurogenic diseases are selected from gynecological diseases, urinary tract disease states, respiratory disorder diseases or pain related diseases or symptoms and the like.
The invention further relates to a method for preparing the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof for treating the neurogenic disease.
The invention also relates to a method for the treatment, prevention and/or treatment of a pre-prepared neurogenic disease, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
The invention also provides methods of using the compounds or pharmaceutical compositions of the invention to treat disease conditions, including but not limited to conditions associated with P2X3 receptor dysfunction.
The present invention also relates to a method of treating a neurogenic disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.
In some embodiments, the methods relate to conditions such as gynecological diseases, urinary tract disease states, respiratory disorders, or pain-related diseases or conditions.
In some embodiments, the present methods relate to the treatment of conditions such as endometriosis, overactive bladder, pulmonary fibrosis, or chronic cough.
In some embodiments, the methods relate to neuropathic pain or pain and discomfort associated with uterine fibroids.
Chronic cough and neuropathic pain are preferred;
more preferably chronic cough.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH2-, "ethylene" means- (CH)2)2-, "propylene" means- (CH)2)3-, "butylene" means- (CH)2)4-and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 3-membered/6-membered, 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered, spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
Figure BDA0002645089080000141
etc.;
spirocycloalkyl groups also containing a single spirocycloalkyl group with a heterocycloalkyl group sharing a spiro atom, non-limiting examples include:
Figure BDA0002645089080000142
and the like.
The term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:
Figure BDA0002645089080000143
and the like.
The term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:
Figure BDA0002645089080000151
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms; further preferred is a 3-8 membered heterocyclic group containing 1-3 nitrogen atoms, optionally substituted with 1-2 oxygen atoms, sulfur atoms, oxo groups, including a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing spiro heterocyclic group or a nitrogen-containing fused heterocyclic group.
Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dioxazolyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azeptyl, 1, 4-diazepanyl, pyranyl, and the like, with azetidinyl, pyrrolidinyl, tetrahydropyranyl, dioxazolyl, morpholinyl, piperidinyl, azeptyl, 1, 4-diazepanyl, and piperazinyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.
The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. According to ring-to-ring spiro-atom sharingThe number of spiro heterocyclic groups is to divide the spiro heterocyclic group into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:
Figure BDA0002645089080000161
Figure BDA0002645089080000162
and the like.
The term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure BDA0002645089080000163
Figure BDA0002645089080000164
and the like.
The term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferablyIs 7 to 10 yuan. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure BDA0002645089080000171
Figure BDA0002645089080000172
and the like.
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure BDA0002645089080000173
Figure BDA0002645089080000174
and the like.
The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused on a heteroaryl, heterocyclic or cycloalkyl ring and comprises benzo 5-10-membered heteroaryl, benzo 3-8-membered cycloalkyl and benzo 3-8-membered heteroalkyl, preferably benzo 5-6-membered heteroaryl, benzo 3-6-membered cycloalkyl and benzo 3-6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms and sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.
Wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
Figure BDA0002645089080000175
Figure BDA0002645089080000181
and the like.
The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably pyridyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, pyrimidinyl or thiazolyl; more preferably pyridyl, thiazolyl, oxadiazolyl, pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure BDA0002645089080000182
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"alkenyl" refers to alkenyl, also known as alkenylene, wherein the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"alkynyl" refers to (CH ≡ C-), wherein said alkynyl may be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
The term "alkenylcarbonyl" refers to-C (O) - (alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl groups include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH2。
"cyano" means-CN.
"nitro" means-NO2。
"carbonyl" means-C (O) -.
"carboxy" refers to-C (O) OH.
"THF" refers to tetrahydrofuran.
"EtOAc" refers to ethyl acetate.
"MeOH" refers to methanol.
"DMF" refers to N, N-dimethylformamide.
"DIPEA" refers to diisopropylethylamine.
"TFA" refers to trifluoroacetic acid.
"MeCN" refers to acetonitrile.
"DMA" refers to N, N-dimethylacetamide.
“Et2O "means diethyl ether.
"DCE" refers to 1,2 dichloroethane.
"DIPEA" refers to N, N-diisopropylethylamine.
"NBS" refers to N-bromosuccinimide.
"NIS" refers to N-iodosuccinimide.
"Cbz-Cl" refers to benzyl chloroformate.
“Pd2(dba)3"refers to tris (dibenzylideneacetone) dipalladium.
"Dppf" refers to 1, 1' -bisdiphenylphosphinoferrocene.
"HATU" refers to 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"LiHMDS" refers to lithium bistrimethylsilyl amide.
"MeLi" refers to methyllithium.
"n-BuLi" refers to n-butyllithium.
“NaBH(OAc)3"refers to sodium triacetoxyborohydride.
Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.
All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
Detailed Description
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Examples
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated methanol (CD)3OD) and deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200 Infinity Series Mass spectrometer. HPLC was measured using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C)18150X 4.6mm column).
The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.
Example 1
4- (1- (2- ((5-chloropyridin-2-yl) amino) -2-oxoethyl) -5-methyl-1H-benzo [ d ] imidazol-2-yl) -3-fluoro-N-methylbenzamide
Figure BDA0002645089080000211
The first step is as follows: preparation of 2-bromo-N- (5-fluoropyridin-2-yl) acetamide
Figure BDA0002645089080000212
Bromoacetyl bromide (1.9g, 7.92mmol) dissolved in 5mL of toluene was added dropwise to a solution of 5-fluoro-pyridin-2-ylamine (1g, 7.78mmol) and 0.3mL of pyridine in 20mL of toluene under ice-cooling. After 2 hours, a white solid precipitated, and the precipitate was separated by filtration and recrystallized from toluene to obtain example 1-1(1.8g, yield: 70%) as a white solid.
MS m/z(ESI):249.23[M+H]+.
1H NMR(400MHz,MeOD)δ8.29(d,J＝2.7Hz,1H),8.12(d,J＝8.9Hz,1H),7.80(dd,J＝8.9,2.7Hz,1H),4.04(s,2H).
The second step is that: preparation of 4- (bromomethyl) -3-fluorobenzoic acid
Figure BDA0002645089080000221
3-fluoro-4-methyl-benzoic acid (7g, 45.4mmol) and NBS (8.08g, 45.4mmol) in CHCl3The suspension in (150mL) was heated to reflux until the solution was homogeneous. AIBN (100mg, 0.61mmol) was added to the reaction mixture and the resulting mixture was stirred at reflux overnight. The reaction was cooled to room temperature and concentrated in vacuo to afford an orange solid. This material was washed with DCMA mixture of (50mL) and n-hexane (50mL) was slurried and the by-products were filtered off. The filtrate was concentrated in vacuo and purified by column chromatography, eluting with petroleum ether in ethyl acetate (0-100%). The aimed compound, example 1-2(5.22g, 13.4mmol, yield: 30%) was isolated as a white solid.
MS m/z(ESI):233.23[M+H]+.
The third step: preparation of 4- (bromomethyl) -3-fluoro-N-methylbenzamide
Figure BDA0002645089080000222
Example 1-2(1.12g, 5.20mmol) was dissolved in toluene (30mL), thionyl chloride (7.59mL, 104mmol) was added, and the mixture was stirred under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in THF (20 mL). To this were added methylammonium hydrochloride (0.67g, 4.11mmol), triethylamine (0.86mL, 6.17mmol), and then stirred at room temperature for 1 hour. The precipitated solid was filtered, and the precipitated solid was collected and washed with diethyl ether to give example 1-3(1.28g, 60%).
MS m/z(ESI):246.13[M+H]+.
The fourth step: preparation of 3-fluoro-N-methyl-4- (5-methyl-1H-benzo [ d ] imidazol-2-yl) benzamide
Figure BDA0002645089080000223
Examples 1-3(2g, 8.19mmol), pyridine-N-oxide (1.95g, 20.5mmol) and 4-methylbenzene-1, 2-diamine (1g, 8.19mmol), toluene (30mL) were mixed well in a 100mL round bottom flask and placed under heating and reflux for 4h with a magnetic stirrer. After completion of the reaction (TLC, ethyl acetate: petroleum ether ═ 1:1), the organic mixture was washed with dilute NaOH and filtered off. Recrystallization from toluene gave examples 1-4(2g, yield: 86%).
MS m/z(ESI):284.32[M+H]+.
The fifth step: preparation of 4- (1- (2- ((5-fluoropyridin-2-yl) amino) -2-oxoethyl) -5-methyl-1H-benzo [ d ] imidazol-2-yl) -3-fluoro-N-methylbenzamide
Figure BDA0002645089080000231
Examples 1-14(100mg,0.35mmol) and examples 1-1(88mg, 0.35mmol), K2CO3(97.6mg, 0.7mmol) was heated to 50 ℃ in DMF (5mL) and reacted for 2h, LCMS detected reaction was complete, 10mL of water and 20mL of ethyl acetate were added and extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product which was eluted with a solution of petroleum ether in ethyl acetate (0-100%) by silica gel chromatography to give example 1(50mg, yield: 30%).
MS m/z(ESI):452.23[M+H]+.
Example 2
(S) -6- (3- ((4-acetylmorpholin-2-yl) methyl) -7-methylimidazol [1,2-a ] pyridin-2-yl) -5, 7-difluoro-2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one
Figure BDA0002645089080000232
The first step is as follows: preparation of 5, 7-difluoro-2-methyl-3, 4-dihydroisoquinoline-1 (2H) -one
Figure BDA0002645089080000233
Example 2-1(800mg, 5mmol) was dissolved in acetonitrile (10ml), and 1-chloromethyl-4-fluoro-1, 4-diazobicyclo [2.2.2] octane bis (tetrafluoroborate) (3.54g, 10mmol) was added to the solution, and the mixture was heated at 80 ℃ and refluxed overnight. After the reaction was cooled to room temperature, it was concentrated and purified by silica gel column to obtain example 2-2(460mg, 47% yield).
MS m/z(ESI):198.0[M+H]+；
The second step is that: preparation of 5, 7-difluoro-2-methyl-1-oxo-1, 2,3, 4-tetrahydroquinoline-6-carbaldehyde
Figure BDA0002645089080000241
To a solution of example 2-2(460mg, 2.33mmol) in 2-methyltetrahydrofuran (6mL) was added TMEDA (595mg, 5.13mmol) at room temperature. The resulting solution was cooled to-78 ℃ and n-butyllithium (1M, 2.6ml) was added dropwise. After stirring the mixture at-78 ℃ for 1.5 h, anhydrous methyl formate (290mg, 4.8mmol) was added, stirring was continued at-78 ℃ for 45 min, and the dry ice bath was removed. The mixture was stirred at room temperature for 18 hours, then the mixture was cooled to 0-5 ℃ and the excess base was quenched with 6M aqueous HCI and the aqueous layer was extracted 3 times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was slurried with minimal ethyl acetate, filtered, washed with hexane and dried under vacuum to give example 2-3(180mg, 34% yield).
MS m/z(ESI):226.1[M+H]+；
The third step: preparation of (S) -6- (3- ((4-acetylmorpholin-2-yl) methyl) -7-methylimidazol [1,2-a ] pyridin-2-yl) -5, 7-difluoro-2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one
Figure BDA0002645089080000242
In N2A mixture of 4-methylpyridin-2-amine (54mg, 0.50mmo1), example 2-3(100mg, 0.50mmo1), (S) -1- (2-ethynylmorpholine) ethan-1-one (75mg, 0.50mmol), cuprous chloride (15mg, 0.15mmol), copper bis (trifluoromethylsulfonyloxy) 54mg, 0.15mmo1, and toluene (2mL) was then added to the reactor, heated to 85 deg.C, then N, N-dimethylacetamide (0.1mL) was added and the mixture was stirred at 85 deg.C for an additional 5 hours, then overnight at room temperature. The reaction was concentrated under reduced pressure and purified by preparative HPLC to give example 2(16mg, 7% yield).
MS m/z(ESI):469.0[M+H]+.
Example 3
(S) -6- (3- ((4-acetylmorpholin-2-yl) methyl) -7-methylimidazol [1,2-a ] pyridin-2-yl) -5, 7-difluoro-2-methylisoquinolin-1 (2H) -one
Figure BDA0002645089080000251
Synthetic method for example 3 referring to example 2, substituting 2-methylisoquinolin-1 (2H) -one for example 1-1, example 3 was obtained (23mg, 10% yield).
MS m/z(ESI):467.1[M+H]+.
Example 4
((S) -5- (3- ((4-acetylmorpholin-2-yl) methyl) -7-methylimidazol [1,2-a ] pyridin-2-yl) -4, 6-difluoro-2-methylisoindol-1-one
Figure BDA0002645089080000252
Synthetic method for example 4 was prepared by substituting 2-methylisoindolin-1-one for example 1-1, reference example 2, to give example 4(18mg, 7% yield).
MS m/z(ESI):455.0[M+H]+.
Example 5
N- (4- (4-chlorobenzyl) -5-oxo-2- (4- (pyridin-2-yloxy) phenyl) -4, 5-dihydropyrazolo [1,5-a ] pyrimidin-6-yl) tetrahydro-2H-pyran-4-carboxamide
Figure BDA0002645089080000253
The first step is as follows: preparation of methyl 4- (pyridin-2-yloxy) benzoate
Figure BDA0002645089080000254
Example 5-1(2g, 9.29mmol) was dissolved in toluene (20mL), thionyl chloride (7.5mL, 93mmol) was added, and the mixture was stirred under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in MeOH (50 mL). The precipitated solid was collected by spin drying and washed with diethyl ether to give example 5-2(2g, 93% yield).
MS m/z(ESI):230.0[M+H]+.
The second step is that: preparation of 4- (bromomethyl) -3-fluorobenzoic acid
Figure BDA0002645089080000261
A1M solution of LHMDS in dry THF (26.3mL, 26.3mmol) was cooled to-78 deg.C and acetonitrile (1.43mL, 27.5mmol) was added dropwise over 2 minutes. The mixture was stirred at-78 deg.C for 1 hour and a solution of example 5-2(5.75g, 25.0mmol) in dry THF (50mL) was added. The mixture was stirred for 3 hours, the dry ice bath was removed and the mixture was allowed to reach ambient temperature. The reaction was complete by TLC and 1M HCl was added dropwise to the solution to pH 3 (initial pH 12). The mixture was extracted with ethyl acetate (2 x 80mL) and the combined extracts were taken over Na2SO4And (5) drying. The crude product was chromatographed on silica gel with petroleum ether in ethyl acetate (0-50%). Example 5-3 was obtained as a colorless oil (4g, 67% yield).
MS m/z(ESI):239.1[M+H]+.
The third step: preparation of 3- (4- (pyridin-2-yloxy) phenyl) -1H-pyrazol-5-amine
Figure BDA0002645089080000262
Example 5-3(2g, 8.39mmol) was dissolved in ethanol (25mL) at room temperature and glacial acetic acid (1mL) and hydrazine hydrate (1.26g, 25.18mmol) were added. The mixture was heated to 80 ℃ and stirred for 2 hours. After the mixture was cooled to room temperature, NaHCO was added3The solution was extracted three times with ethyl acetate. The organic phase was washed with brine, dried and concentrated to give example 5-4(1.5g, 70% yield).
MS m/z(ESI):253.1[M+H]+.
The fourth step: preparation of ethyl 5-oxo-2- (4- (pyridin-2-yloxy) phenyl) -4, 5-dihydropyrazolo [1,5-a ] pyrimidine-6-carboxylate
Figure BDA0002645089080000263
Example 5-4(1.5g, 5.95mmol) was dissolved in ethanol (35mL) at room temperature and diethyl 2-ethoxymethylenemalonate (1.46g, 6.54mmol) and sodium ethoxide (0.607g, 8.92mmol) were added to the mixture. The mixture was heated to 100 ℃ and stirred for 5 hours. After cooling, the precipitate was filtered and washed with ethanol to give example 5-5(1.6g, 71% yield) as a white powder.
MS m/z(ESI):377.1[M+H]+.
The fifth step: preparation of ethyl 4- (4-chlorobenzyl) -5-oxo-2- (4- (pyridin-2-yloxy) phenyl) -4, 5-dihydropyrazolo [1,5-a ] pyrimidine-6-carboxylate
Figure BDA0002645089080000271
Example 5-5(1g, 2.66mmol) was dissolved in DMF (15mL) at room temperature and 1- (bromomethyl) -4-chlorobenzene (0.82g, 3.99mmol) and potassium carbonate (0.73g, 5.31mmol) were added to the mixture. The mixture was heated to 50 ℃ and stirred for 2 hours. After cooling, 30mL of water were added, the mixture was extracted with ethyl acetate (2 x 40mL) and the combined extracts were taken over Na2SO4And (5) drying. The crude product was spun dry and slurried with petroleum ether (30mL) to give examples 5-6(1.1g, 83% yield) as a white powder.
MS m/z(ESI):501.2[M+H]+.
And a sixth step: preparation of 4- (4-chlorobenzyl) -5-oxo-2- (4- (pyridin-2-yloxy) phenyl) -4, 5-dihydropyrazolo [1,5-a ] pyrimidine-6-carboxylic acid
Figure BDA0002645089080000272
Examples 5-6(0.2g, 0.4mmol) were dissolved in THF (6mL) and water (1.5mL) at room temperature, and lithium hydroxide (20mg, 0.48mmol) was added to the mixture. The mixture was stirred at room temperature for 2 hours. Adding 1M HCl to pH 3, addingThe mixture was extracted with ethyl acetate (2 x 40mL) and the combined extracts were taken over Na2SO4And (5) drying. The crude product was spun dry and slurried with petroleum ether (10mL) to give examples 5-7(0.15g, 80% yield) as a white powder.
MS m/z(ESI):473.0[M+H]+.
The seventh step: preparation of tert-butyl (4- (4-chlorobenzyl) -5-oxo-2- (4- (pyridin-2-yloxy) phenyl) -4, 5-dihydropyrazolo [1,5-a ] pyrimidin-6-yl) carbamate
Figure BDA0002645089080000273
Examples 5-7(140mg, 0.3mmol) were dissolved in tert-butanol (5ml), triethylamine (50mg, 0.5mmol) was added and stirring was carried out for 30 minutes followed by the addition of DPPA (138mg, 0.5 mmol). The reaction mixture was heated to 100 ℃ and stirred overnight. After cooling, the solvent was removed by concentration and slurried with TBME to give examples 5-8(102mg, 63% yield)
MS m/z(ESI):544.2[M+H]+.
Eighth step: preparation of 6-amino-4- (4-chlorobenzyl) -2- (4- (pyridin-2-yloxy) phenyl) pyrazolo [1,5-a ] pyrimidin-5 (4h) -one
Figure BDA0002645089080000281
Examples 5-8(102mg, 0.19mmol) were dissolved in DCM (6mL) and a mixture of TFA (3mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated to give examples 5-9(82mg, 63% yield)
MS m/z(ESI):444.1[M+H]+.
Step 9: preparation of N- (4- (4-chlorobenzyl) -5-oxo-2- (4- (pyridin-2-yloxy) phenyl) -4, 5-dihydropyrazolo [1,5-a ] pyrimidin-6-yl) tetrahydro-2H-pyran-4-carboxamide
Figure BDA0002645089080000282
Examples 5-9(20mg, 0.042mmol) were dissolved at room temperatureDMF (1mL) was added to the mixture with HATU (16mg, 0.084mmol) and DIEA (11mg, 0.084 mmol). The mixture was stirred at room temperature for 10 min. Then, tetrahydro-2H-pyran-4-carboxylic acid (5.13mg, 0.05mmol) was added thereto, and the mixture was stirred at room temperature for 16 hours. To the reaction was added 10mL of water, the mixture was extracted with ethyl acetate (2 x 10mL), and the combined extracts were taken over Na2SO4Drying, spin-drying and p-TLC (dichloro: methanol ═ 20:1) of the crude product afforded example 5(11mg, yield: 43%) as a white powder.
MS m/z(ESI):557.0[M+H]+.
Example 6
4- (4-chlorobenzyl) -5-oxo-2- (4- (pyridin-2-yloxy) phenyl) -N- (tetrahydro-2H-pyran-4-yl) -4, 5-dihydropyrazolo [1,5-a ] pyrimidine-6-carboxamide
Figure BDA0002645089080000291
The first step is as follows: preparation of methyl 4- (pyridin-2-yloxy) benzoate
Figure BDA0002645089080000292
4- (pyridin-2-yloxy) benzoic acid (2g, 9.29mmol) was dissolved in toluene (20mL), thionyl chloride (7.5mL, 93mmol) was added, and the mixture was stirred under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in MeOH (50 mL). The precipitated solid was collected by spin-drying, and then washed with diethyl ether to obtain example 6-1(2g, yield: 93%).
MS m/z(ESI):230.12[M+H]+.
The second step is that: preparation of 4- (bromomethyl) -3-fluorobenzoic acid
Figure BDA0002645089080000293
A1M solution of LHMDS in dry THF (26.3mL, 26.3mmol) was cooled to-78 deg.C and acetonitrile was added dropwise over 2 minutes(1.43mL, 27.5 mmol). The mixture was stirred at-78 deg.C for 1 hour and a solution of example 6-1(5.75g, 25.0mmol) in dry THF (50mL) was added. The mixture was stirred for 3 hours, the dry ice bath was removed and the mixture was allowed to reach ambient temperature. The reaction was complete by TLC and 1M HCl was added dropwise to the solution to pH 3 (initial pH 12). The mixture was extracted with ethyl acetate (2 x 80mL) and the combined extracts were taken over Na2SO4And (5) drying. The crude product was chromatographed on silica gel with petroleum ether in ethyl acetate (0-50%). Example 6-2 was obtained as a colorless oil (4g, 67%).
MS m/z(ESI):239.12[M+H]+.
The third step: preparation of 3- (4- (pyridin-2-yloxy) phenyl) -1H-pyrazol-5-amine
Figure BDA0002645089080000294
Example 6-2(2g, 8.39mmol) was dissolved in ethanol (25mL) at room temperature and glacial acetic acid (1mL) and hydrazine hydrate (1.26g, 25.18mmol) were added. The mixture was heated to 80 ℃ and stirred for 2 h. After the mixture was cooled to room temperature, NaHCO was added3The solution was extracted three times with ethyl acetate. The organic phase was washed with brine, dried and concentrated to give example 6-3(1.5g, yield: 70%).
MS m/z(ESI):253.10[M+H]+.
The fourth step: preparation of ethyl 5-oxo-2- (4- (pyridin-2-yloxy) phenyl) -4, 5-dihydropyrazolo [1,5-a ] pyrimidine-6-carboxylate
Figure BDA0002645089080000301
Example 6-3(1.5g, 5.95mmol) was dissolved in ethanol (35mL) at room temperature and diethyl 2-ethoxymethylenemalonate (1.46g, 6.54mmol) and sodium ethoxide (0.607g, 8.92mmol) were added to the mixture. The mixture was heated to 100 ℃ and stirred for 5 h. After cooling, the precipitate was filtered and washed with ethanol to give example 6-4(1.6g, 71%) as a white powder.
MS m/z(ESI):377.12[M+H]+.
The fifth step: preparation of ethyl 4- (4-chlorobenzyl) -5-oxo-2- (4- (pyridin-2-yloxy) phenyl) -4, 5-dihydropyrazolo [1,5-a ] pyrimidine-6-carboxylate
Figure BDA0002645089080000302
Example 6-4(1g, 2.66mmol) was dissolved in DMF (15mL) at room temperature and 1- (bromomethyl) -4-chlorobenzene (0.82g, 3.99mmol) and potassium carbonate (0.73g, 5.31mmol) were added to the mixture. The mixture was heated to 50 ℃ and stirred for 2 h. After cooling, 30mL of water were added, the mixture was extracted with ethyl acetate (2 x 40mL) and the combined extracts were taken over Na2SO4And (5) drying. The crude product was roto-dried and slurried with petroleum ether (30mL) to give examples 6-5(1.1g, yield: 83%) as a white powder.
MS m/z(ESI):501.13[M+H]+.
And a sixth step: preparation of 4- (4-chlorobenzyl) -5-oxo-2- (4- (pyridin-2-yloxy) phenyl) -4, 5-dihydropyrazolo [1,5-a ] pyrimidine-6-carboxylic acid
Figure BDA0002645089080000303
Example 6-5(0.2g, 0.4mmol) was dissolved in THF (6mL) and water (1.5mL) at room temperature and lithium hydroxide (20mg, 0.48mmol) was added to the mixture. The mixture was stirred at room temperature for 2 h. 1M HCl was added to pH 3, the mixture was extracted with ethyl acetate (2 × 40mL), and the combined extracts were extracted over Na2SO4And (5) drying. The crude product was roto-dried and slurried with petroleum ether (10mL) to give examples 6-6(0.15g, yield: 80%) as a white powder.
MS m/z(ESI):473.09[M+H]+.
The seventh step: preparation of 4- (4-chlorobenzyl) -5-oxo-2- (4- (pyridin-2-yloxy) phenyl) -N- (tetrahydro-2H-pyran-4-yl) -4, 5-dihydropyrazolo [1,5-a ] pyrimidine-6-carboxamide
Figure BDA0002645089080000311
Examples 6-6(20mg, 0.042mmol) were dissolved in DMF (1mL) at room temperature and HATU (16mg, 0.084mmol) and DIEA (11mg, 0.084mmol) were added to the mixture. The mixture was stirred at room temperature for 10 min. Then tetrahydro-2H-pyran-4-amine (5.13mg, 0.05mmol) was added thereto, and the mixture was stirred at room temperature for 16 hours. To the reaction was added 10mL of water, the mixture was extracted with ethyl acetate (2 x 10mL), and the combined extracts were taken over Na2SO4Dried, spun-dried and the crude product was purified by p-TLC (dichloro: methanol ═ 20:1) to give example 6(10mg, yield: 43%) as a white powder.
MS m/z(ESI):556.17[M+H]+.
Example 7
4- (4-chlorobenzyl) -6- (3-methyl-1, 2, 4-oxadiazol-5-yl) -2- (4- (pyridin-2-yloxy) phenyl) pyrazolo [1,5-a ] pyrimidin-5 (4H) -one
Figure BDA0002645089080000312
The first step is as follows: preparation of N-hydroxyacetamidine
Figure BDA0002645089080000313
To a solution of (0.57g, 14.2mmol) NaOH in 5mL of water was added (1.00g, 14.2mmol) hydroxylamine. 15mL of acetonitrile was added dropwise and the mixture was stirred at 37 ℃ overnight at room temperature. Acetonitrile and water were removed in vacuo and ethanol was added to the crude product. The product was filtered off and washed with ethanol to give example 7-1(0.6g, yield: 60%).
1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),5.33(br,2H),1.60(s,3H).
The second step is that: preparation of 4- (4-chlorobenzyl) -6- (3-methyl-1, 2, 4-oxadiazol-5-yl) -2- (4- (pyridin-2-yloxy) phenyl) pyrazolo [1,5-a ] pyrimidin-5 (4H) -one
Figure BDA0002645089080000321
Example 6-5(50mg, 0.1mmol) was added to toluene (5mL) followed by N-hydroxyacetamide (15mg, 0.2 mmol). The reaction mixture was heated to reflux, stirred for 16 hours and then cooled to room temperature. The reaction mixture was concentrated and prepared as example 7(25mg, yield: 50%).
MS m/z(ESI):499.13[M+H]+.
1HNMR(400MHz,DMSO-d6)δ7.80(s,1H),7.39–7.34(m,2H),7.29(dt,J＝7.5,1.1Hz,2H),5.72(s,1H),5.30(d,J＝1.1Hz,2H),3.84–3.77(m,2H),3.79–3.71(m,2H),3.01–2.92(m,1H),2.44(s,2H),2.31(qd,J＝7.1,3.4Hz,4H).
Example 8
1- (4-chlorobenzyl) -6- (4- ((2, 6-difluoropyridin-4-yl) oxy) phenyl) -3-ethyl-1, 7-dihydro-2H-pyrrolo [2,3-D ] pyrimidine-2, 4(3H) -dione
Figure BDA0002645089080000322
The first step is as follows: preparation of 5-bromo-2- ((4-chlorobenzyl) amino) -N-ethyl-1H-pyrrole-3-carboxamide
Figure BDA0002645089080000323
Example 8-1(1.2g, 5.2mmol) was dissolved in methanol (15ml) at room temperature, 4-chlorobenzaldehyde (0.73g, 5.2mmol) was added to the mixture, the mixture was stirred at room temperature for 5 hours, and NaBH was added to the reaction solution4(0.4g, 10.38 mmol). The mixture was heated to 50 ℃ and stirred for 2 hours. After cooling, 20mL of water was added, extracted with ethyl acetate (2 x 30mL), the organic phase was suspended and the crude material was purified by column chromatography to give examples 15-4 as a white solid (1.4g, 75% yield).
MS m/z(ESI):356.1[M+H]+.
The second step is that: preparation of 6-bromo-1- (4-chlorobenzyl) -3-ethyl-1, 7-dihydro-2H-pyrrolo [2,3-D ] pyrimidine-2, 4(3H) -dione
Figure BDA0002645089080000331
Example 8-2(1.28g,3.6mmol) was dissolved in DMF (15mL) and NaH (0.17g, 7.18mmol) was added to the mixture. The reaction was stirred at 0 ℃ for 1 hour under nitrogen atmosphere. CDI (0.87g, 5.38mmol) was added, and the reaction solution was heated to 75 ℃ for 2 hours. The reaction solution was cooled to room temperature, water (80mL) was added to stop the reaction, the reaction was filtered, and the filter cake was dried to afford example 8-3(1.07g, 78% yield).
MS m/z(ESI):382.0[M+H]+.
The third step: preparation of 1- (4-chlorobenzyl) -3-ethyl-6- (4-hydroxyphenyl) -1, 7-dihydro-2H-pyrrolo [2,3-D ] pyrimidine-2, 4(3H) -dione
Figure BDA0002645089080000332
To a reaction vessel containing example 8-3(1g, 2.6mmol), p-hydroxyphenylboronic acid (720mg, 5.2mmol), Pd (dppf) Cl at room temperature2A round-bottomed flask (95mg, 0.13mmol) and potassium carbonate (1.07g, 7.8mmol) was charged with Dioxane (10mL) as a solvent and water (2mL), and after replacing nitrogen, the mixture was heated to 80 ℃ and stirred for reaction for 3 hours. The mixture was cooled to room temperature, concentrated and purified on a flash silica gel column to give example 8-4(1.65g, 82% yield).
MS m/z(ESI):777.1[M+H]+.
The fourth step: preparation of 1- (4-chlorobenzyl) -6- (4- ((2, 6-difluoropyridin-4-yl) oxy) phenyl) -3-ethyl-1, 7-dihydro-2H-pyrrolo [2,3-D ] pyrimidine-2, 4(3H) -dione
Figure BDA0002645089080000341
Example 8-4(100mg, 0.13mmol) was dissolved in DMF (2mL) at room temperature and 2,4, 6-trifluoropyridine (26mg, 0.2mmol) and cesium carbonate (100mg,0.3mmol) were added to the mixture. The reaction solution was heated to 80 ℃ for 2 hours. The mixture was cooled to room temperature, concentrated and purified by preparative HPLC to give example 8(37mg, 56% yield).
MS m/z(ESI):509.0[M+H]+.
Example 9
(S) -N- (5-Chloropyridin-2-yl) -2- (6- (1-methoxypropan-2-yl) -4, 7-dioxo-2- ((4- (pyridin-2-yloxy) phenyl) amino) -4,5,6, 7-tetrahydro-1H-pyrrolo [3,4-D ] pyrimidin-1-yl) acetamide
Figure BDA0002645089080000342
The first step is as follows: preparation of 2-amino-N- (5-fluoropyridin-2-yl) acetamide
Figure BDA0002645089080000343
Example 9-1(1g, 4.29mmol) and ammonium carbonate (3.3g, 34.33mmol) were dissolved in acetonitrile (30mL) and heated to 50 ℃. After 10 hours, a white solid precipitated, which was isolated by filtration and recrystallized from toluene to give example 9-2(0.6g, 83% yield).
MS m/z(ESI):170.2[M+H]+.
The second step is that: preparation of N- (5-fluoropyridin-2-yl) thiourea acetamide
Figure BDA0002645089080000351
Example 9-2(0.5g, 2.96mmol) and benzoyl isothiocyanate (0.53g, 3.25mmol) were reacted in DCM (10mL) for 2h at room temperature. After the reaction solution was spin-dried, K2CO3(817mg, 5.91mmol) was added to the reaction mixture, and the resulting mixture was stirred at reflux overnight. The reaction was cooled to room temperature and concentrated in vacuo to afford an orange solid. This material was washed with water (50mL) to give the title compound, example 9-3(0.4g, 60% yield).
MS m/z(ESI):229.0[M+H]+.
The third step: preparation of (S) -N- (4-chlorophenyl) -2- (2-mercapto-6- (1-methoxypropan-2-yl) -4, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrrolo [3,4-D ] pyrimidin-1-yl) acetamide
Figure BDA0002645089080000352
Example 9-3(0.4g, 1.75mmol) was dissolved in EtOH (20mL), NaOEt (143mg, 2.1mmol), ethyl (S) -4-hydroxy-1- (1-methoxypropan-2-yl) -5-oxo-2, 5-dihydro-1H-pyrrole-3-carboxylate (425mg, 1.75mmol) was added, and the mixture was stirred under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in dichloro (20 mL). The precipitated solid was filtered, and the precipitated solid was collected and washed with diethyl ether to give example 10-3(350mg, 46% yield).
MS m/z(ESI):423.1[M+H]+.
The fourth step: preparation of (S) -N- (4-chlorophenyl) -2- (6- (1-methoxypropan-2-yl) -2- (methylthio) -4, 7-dioxy-4, 5,6, 7-tetrahydro-1H-pyrrolo [3,4-D ] pyrimidin-1-yl) acetamide
Figure BDA0002645089080000353
Examples 9-4(350mg,0.8mmol), iodomethane (184mg,0.88mmol) and K2CO3(220mg,1.6mmol), DMF (10mL) was mixed well in a 100mL round bottom flask and placed in a magnetic stirrer to react at room temperature for 4 h. After completion of the reaction, purification on silica gel column afforded examples 9-5(180mg, 50% yield).
MS m/z(ESI):437.0[M+H]+.
The fifth step: preparation of (S) -N- (5-chloropyridin-2-yl) -2- (6- (1-methoxypropan-2-yl) -4, 7-dioxo-2- ((4- (pyridin-2-yloxy) phenyl) amino) -4,5,6, 7-tetrahydro-1H-pyrrolo [3,4-D ] pyrimidin-1-yl) acetamide
Figure BDA0002645089080000361
Example 9-5(50mg,0.11mmol), 4- (pyridin-2-yloxy) aniline (50mg,0.26mmol), a mixture of AcOH (0.25mL) and t-BuOH (2mL) was stirred at 100 ℃ for 2 h. The reaction was cooled, concentrated and purified by preparative HPLC to afford example 9(23mg, 37% yield).
MS m/z(ESI):576.2[M+H]+.
Example 10
2- (2- ((4- ((2, 6-difluoropyridin-4-yl) oxy) phenyl) amino) -6-isopropyl-4, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrrolo [3,4-d ] pyrimidin-1-yl) -N- (5-fluoropyridin-2-yl) acetamide
Figure BDA0002645089080000362
The first step is as follows: preparation of 2-amino-N- (5-fluoropyridin-2-yl) acetamide
Figure BDA0002645089080000363
2-bromo-N- (5-fluoropyridin-2-yl) acetamide (1g, 4.29mmol) and ammonium carbonate (3.3g, 34.33mmol) were dissolved in acetonitrile (30mL) and heated to 50 ℃. After 10 hours, a white solid precipitated, and the precipitate was isolated by filtration and recrystallized from toluene to give example 10-1(0.6g, 83%) as a white solid.
MS m/z(ESI):170.23[M+H]+.
The second step is that: preparation of N- (5-fluoropyridin-2-yl) thiourea acetamide
Figure BDA0002645089080000371
2-amino-N- (5-fluoropyridin-2-yl) acetamide (0.5g, 2.96mmol) and benzoyl isothiocyanate (0.53g, 3.25mmol) in CH2Cl2(10mL) was reacted at room temperature for 2 hours. After the reaction solution was spin-dried, K was added to the reaction mixture2CO3(817mg, 5.91mmol), and mixing the two solutionsThe mixture was stirred at reflux overnight. The reaction was cooled to room temperature and concentrated in vacuo to afford an orange solid. The material was washed with water (50 mL). The title compound, example 10-2(0.4g, 60% yield) was obtained as a yellow solid.
MS m/z(ESI):229.05[M+H]+.
The third step: preparation of N- (5-fluoropyridin-2-yl) -2- (6-isopropyl-2-mercapto-4, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrrolo [3,4-d ] pyrimidin-1-yl) acetamide
Figure BDA0002645089080000372
Example 10-2(0.4g, 1.75mmol) was dissolved in EtOH (20mL), and NaOEt (143mg, 2.1mmol), ethyl 4-hydroxy-1-isopropyl-5-oxo-2, 5-dihydro-1H-pyrrole-3-carboxylate (374mg, 1.75mmol) was added, followed by stirring under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in dichloro (20 mL). The precipitated solid was filtered, and the precipitated solid was collected and then washed with diethyl ether to give example 10-3(0.3g, 45%).
MS m/z(ESI):378.13[M+H]+.
The fourth step: preparation of N- (5-fluoropyridin-2-yl) -2- (6-isopropyl-2- (methylthio) -4, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrrolo [3,4-d ] pyrimidin-1-yl) acetamide
Figure BDA0002645089080000381
Example 10-3(300mg,0.8mmol), iodomethane (184mg,0.88mmol) and K2CO3(220mg,1.6mmol, DMF (10mL) was mixed well in a 100mL round bottom flask and placed in a magnetic stirrer to react at room temperature for 4h after completion of the reaction (TLC, DCM: MeOH ═ 10:1), example 10-4(0.2g, 51%) was obtained by passage through a plate.
MS m/z(ESI):392.12[M+H]+.
The fifth step: preparation of 2- (2- ((4- ((2, 6-difluoropyridin-4-yl) oxy) phenyl) amino) -6-isopropyl-4, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrrolo [3,4-d ] pyrimidin-1-yl) -N- (5-fluoropyridin-2-yl) acetamide
Figure BDA0002645089080000382
Example 10-4(50mg,0.13mmol) and 4- ((2, 6-difluoropyridin-4-yl) oxy) aniline (28.4mg,0.13mmol), Cs2CO3(83.2mg,0.26mmol) was heated to 80 ℃ in DMF (5mL) and reacted for 2h, upon completion of the reaction by LCMS, 10mL of water and 20mL of ethyl acetate were added and the organic phase was extracted with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which was eluted with silica gel chromatography in dichloromethane (0-10%) to give example 10(20mg, 28%).
MS m/z(ESI):566.17[M+H]+.
Example 11
N- (4- (4-chlorobenzyl) -2- (cyclopentylamine) -5-oxo-4, 5-dihydropyrazolo [1,5-a ] pyrimidin-6-yl) tetrahydro-2H-pyran-4-carboxamide
Figure BDA0002645089080000391
The first step is as follows: preparation of N- (4- (4-chlorobenzyl) -2- (cyclopentylamine) -5-oxo-4, 5-dihydropyrazolo [1,5-a ] pyrimidin-6-yl) tetrahydro-2H-pyran-4-carboxamide
Figure BDA0002645089080000392
Example 11-1(220mg,0.47mmol), RuPhos Pd G2(35mg,0.047mmol) and RuPhos ((21mg,0.047mmol)), LiHMDS (1M in THF) (2.35mL,2.35mmol) were dissolved in anhydrous dioxane (5mL) followed by addition of lithium chloride (198mg,4.7mmol), cyclopentylamine (80mg,0.94 mmol). The reaction solution was stirred at 100 ℃ for 2 hours with a microwave. Saturated NaCl solution was added and extracted three times with ethyl acetate. The organic phase was washed with brine, dried, concentrated and column purified to give example 11(20mg, 9% yield).
MS m/z(ESI):470.1[M+H]+.
Example 12
3- (4-chlorobenzyl) -6-ethyl-2- ((4- (isoxazole-3-acyloxy) phenyl) amino) -5, 6-dihydro-3H-pyrrolo [3,4-d ] pyrimidine-4, 7-dione
Figure BDA0002645089080000393
The first step is as follows: preparation of ethyl 3-chloro-1-isopropyl-4, 5-dioxopyrrolidine-3-carboxylate
Figure BDA0002645089080000394
Compound 1-isopropyl-4, 5-dioxopyrrolidine-3-carboxylic acid ethyl ester (4g, 18.7mmol) was suspended in a mixed solution of acetic acid (5mL) and water (5mL), cooled to 0 deg.C, and a solution of sodium hypochlorite (30mL, 21mmol, 0.7M) was added dropwise. The mixture was slowly warmed to room temperature for 1 h. Excess sodium chloride was added, extracted with dichloromethane (30mL 5), the combined organic phases dried over anhydrous sodium sulfate and dried under high vacuum. Ether (20mL) was added and stirred for 10min, filtered, the filter cake washed with ether and dried to give example 12-1(3.7g, 75%) as a white solid.
MS m/z(ESI):248.1[M+H]+.
1HNMR：(400MHz，CDCl3)δ4.67-4.61(m,1H),4.38-4.28(m,3H),3.77(d,J＝11.5Hz,1H),1.37-1.27(m,9H).
The second step is that: preparation of N- (6-isopropyl-4, 7-dioxo-4, 5,6, 7-tetrahydro-3H-pyrrolo [3,4-D ] pyrimidin-2-yl) acetamide
Figure BDA0002645089080000401
Acetylguanidine (2.54g, 25.2mmol) was dissolved in ethanol (15mL), cooled to 0 deg.C, and ethyl 3-chloro-1-isopropyl-4, 5-dioxopyrrolidine-3-carboxylate (2.5g, 10.1mmol) and 4A molecular sieves (3g) were added and the reaction stirred for 2 h. Then the freshly prepared chromium chloride solution (126mmol) was added dropwise, the ice bath was removed after the addition was complete, and the reaction was stirred at room temperature for 3 h. Water (100mL) was added for dilution, dichloromethane was extracted (50mL × 4), the combined organic phases were dried over anhydrous sodium sulfate, dried by spinning, and column chromatographed (methanol/dichloromethane ═ 0 to 4%) to give example 12-3(1.8g, 71%) as a yellow solid.
MS m/z(ESI):251.1[M+H]+.
1HNMR：(400MHz，CDCl3)δ10.8(s,1H),4.65–4.61(m,1H),4.12(s,2H),1.28(d,J＝6.8Hz,6H).
The third step: preparation of N- (3- (4-chlorobenzyl) -6-ethyl-4, 7-dioxo-4, 5,6, 7-tetrahydro-3H-pyrrolo [3,4-d ] pyrimidin-2-yl) acetamide
Figure BDA0002645089080000402
N- (6-isopropyl-4, 7-dioxo-4, 5,6, 7-tetrahydro-3H-pyrrolo [3,4-D ] pyrimidin-2-yl) acetamide (1.8g, 7.2mmol) was dissolved in N, N-dimethylformamide (30mL), cooled to 0 deg.C, sodium hydride (432mg, 10.8mmol, 60% in oil) was added in portions, stirred for 30min, 4-chlorobenzyl bromide (1.77g, 8.64mmol) was added, and slowly warmed to room temperature for 4H. The reaction was quenched with 100mL of water, extracted with ethyl acetate (60mL × 3), combined organic phases washed with water (50mL × 2), washed with saturated brine (50mL), dried over anhydrous sodium sulfate, spin-dried, and column chromatographed (methanol/dichloromethane ═ 0-5%) to give example 12-4(1.1g, 42%) as a yellow solid.
MS m/z(ESI):375.1[M+H]+.
1HNMR：(400MHz，CDCl3)δ7.42(d,J＝8.4Hz,2H),7.13(d,J＝8.4Hz,2H),5.76(s,2H),4.65–4.61(m,1H),4.12(s,2H),1.28(d,J＝6.8Hz,6H).
The fourth step: preparation of 2-amino-3- (4-chlorobenzyl) -6-isopropyl-5, 6-dihydro-3H-pyrrolo [3,4-d ] pyrimidine-4, 7-dione hydrochloride
Figure BDA0002645089080000411
N- (3- (4-chlorobenzyl) -6-ethyl-4, 7-dioxo-4, 5,6, 7-tetrahydro-3H-pyrrolo [3,4-d ] pyrimidin-2-yl) acetamide (1.1g,2.94mmol) was dissolved in 4M hydrochloric acid and reacted at 110 ℃ under reflux for 4H. After completion of the reaction, the reaction was spin-dried to give example 12-5(1.0g, 100%).
MS m/z(ESI):333.1[M+H]+.
1HNMR：(400MHz，CDCl3)δ10.8(s,1H),4.65–4.61(m,1H),4.12(s,2H),1.28(d,J＝6.8Hz,6H).
The fifth step: preparation of 3- (4-chlorobenzyl) -2- ((4-hydroxyphenyl) amino) -6-isopropyl-5, 6-dihydro-3H-pyrrolo [3,4-D ] pyrimidine-4, 7-dione
Figure BDA0002645089080000412
2-amino-3- (4-chlorobenzyl) -6-isopropyl-5, 6-dihydro-3H-pyrrolo [3,4-d ] pyrimidine-4, 7-dione hydrochloride (200mg, 0.601mmol) was dissolved in 1, 4-dioxane (6mL), 4-bromophenol (208mg, 1.20mmol), palladium acetate (7mg, 0.03mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (17mg, 0.03mmol) and cesium carbonate (293mg, 0.901mmol) were added, and the reaction was carried out at 100 ℃ for 2H under microwave. Cooling to room temperature, filtering, spin-drying the filtrate, and column chromatography (methanol/dichloromethane 0-10%) gave example 12-6(85mg, 34%).
MS m/z(ESI):411.1[M+H]+.
And a sixth step: preparation of 3- (4-chlorobenzyl) -6-ethyl-2- ((4- (isoxazole-3-acyloxy) phenyl) amino) -5, 6-dihydro-3H-pyrrolo [3,4-D ] pyrimidine-4, 7-dione
Figure BDA0002645089080000421
Referring to examples 12-6, starting with 3- (4-chlorobenzyl) -2- ((4-hydroxyphenyl) amino) -6-isopropyl-5, 6-dihydro-3H-pyrrolo [3,4-D ] pyrimidine-4, 7-dione (50mg, 0.122mmol) and 3-bromoisoxazole (36mg, 0.243mmol), respectively, example 12(11mg, 20%) was obtained.
MS m/z(ESI):478.1[M+H]+.
Example 13
4- (4-chlorobenzyl) -7-oxo-2- (tetrahydro-2H-pyran-4-yl) -N- (2,2, 2-trifluoromethyl) -4, 7-dihydropyrazolo [1,5-a ] pyrimidine-6-carboxamide
Figure BDA0002645089080000422
The first step is as follows: preparation of N- (4-chlorobenzyl) -2-fluoro-4-iodoformamide
Figure BDA0002645089080000423
2-fluoro-4-iodonicotinic acid (5g, 18.7mmol) was dissolved in N, N-dimethylformamide (30mL), O- (7-azobenzotriazol-1-yloxy) -N, N ", N" -tetramethyluronium hexafluorophosphate (7.8g, 20.6mmol) was added thereto, and the mixture was stirred for 15min, p-4-chlorobenzylamine (2.65g, 18.7mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. Poured into water (100mL), extracted with ethyl acetate (60mL × 3), combined organic phases washed with water (60mL), washed with saturated brine (60mL), dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography (methanol/dichloromethane ═ 0 to 5%) to obtain example 13-2(6.6g, 91%).
MS m/z(ESI):391.0[M+H]+.
The second step is that: preparation of 2-amino-N- (4-chlorobenzyl) -4-iodoformamide
Figure BDA0002645089080000431
N- (4-chlorobenzyl) -2-fluoro-4-iodoformamide (1.5g, 16.9mmol) was dissolved in dimethyl sulfoxide (10mL), and ammonia (2mL) was added and reacted at 110 ℃ for 3 hours under microwave. The reaction mixture was poured into water (40mL), extracted with ethyl acetate (30mL × 3), washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and subjected to column chromatography (methanol/dichloromethane ═ 0 to 10%) to obtain example 13-3(1.3g, 87%).
MS m/z(ESI):388.0[M+H]+.
The third step: preparation of N- (4-chlorobenzyl) -4-iodo-2- ((triphenyl-l 5-phosphonyl) amino) nicotinamide
Figure BDA0002645089080000432
2-amino-N- (4-chlorobenzyl) -4-iodoformamide (1.3g, 3.36mmol) was dissolved in toluene (20mL), triphenylphosphine (0.88g, 3.36mmol) and hexachloroethane (0.795g, 3.36mmol) were added and the reaction refluxed for 2h under nitrogen. Cooling to room temperature, filtering, spin-drying the filtrate, and performing column chromatography (50% to 100% ethyl acetate/petroleum ether) to obtain example 13-4(1.8g, 83%).
MS m/z(ESI):648.0[M+H]+.
The fourth step: preparation of 3- (4-chlorobenzyl) -5-iodo-2- ((4-methoxyphenyl) amino) pyridin [2,3-d ] pyrimidin-4 (3h) -one
Figure BDA0002645089080000433
N- (4-chlorobenzyl) -4-iodo-2- ((triphenyl-l 5-phosphonyl) amino) nicotinamide (1.8g, 2.78mmol) was dissolved in xylene (50mL), p-methoxy isocyanate (1.24g, 8.33mmol) was added, and the reaction was refluxed at 150 ℃ for 3 hours. Cooled to room temperature, spin-dried, and subjected to column chromatography (methanol/dichloromethane 0-10%) to obtain example 13-5(920mg, 64%).
MS m/z(ESI):519.0[M+H]+.
The fifth step: preparation of 3- (4-chlorobenzyl) -2- ((4-methoxyphenyl) amino) -5- ((tetrahydro-2H-pyran-4-yl) amino) pyridine [2,3-D ] pyrimidin-4 (3H) -one
Figure BDA0002645089080000441
Referring to examples 12-7, starting from 3- (4-chlorobenzyl) -2- ((4-methoxyphenyl) amino) -5- ((tetrahydro-2H-pyran-4-yl) amino) pyridin [2,3-D ] pyrimidin-4 (3H) -one (300mg, 0.579mmol) and 4-aminotetrahydropyran (88mg,0.869mmol), respectively, example 13-6(162mg, 57%) was obtained.
MS m/z(ESI):492.2[M+H]+.
And a sixth step: preparation of 3- (4-chlorobenzyl) -2- ((4-methoxyphenyl) amino) -5- ((tetrahydro-2H-pyran-4-yl) amino) pyridine [2,3-D ] pyrimidin-4 (3H) -one
Figure BDA0002645089080000442
3- (4-chlorobenzyl) -2- ((4-methoxyphenyl) amino) -5- ((tetrahydro-2H-pyran-4-yl) amino) pyridin [2,3-D ] pyrimidin-4 (3H) -one (162mg, 0.330mmol) was dissolved in dichloromethane (10mL), cooled to 0 deg.C, and a solution of boron tribromide in dichloromethane (1Ml,1mmol,1M) was added dropwise, slowly warmed to room temperature and reacted for 1H. Poured into an ice-water solution of sodium bicarbonate (50mL), extracted with dichloromethane (30mL × 2), combined with an organic phase, washed with brine (30mL), dried over anhydrous sodium sulfate, filtered, spun-dried, and subjected to column chromatography (methanol/dichloromethane ═ 0-10%) to give example 13-7(90mg, 58%).
MS m/z(ESI):478.2[M+H]+.
The seventh step: preparation of 3- (4-chlorobenzyl) -2- ((4- (isoxazol-3-oxy) phenyl) amino) -5- ((tetrahydro-2H-pyran-4-yl) amino) pyridine [2,3-D ] pyrimidin-4 (3H) -one
Figure BDA0002645089080000451
Referring to examples 12-5, starting from 3- (4-chlorobenzyl) -2- ((4-methoxyphenyl) amino) -5- ((tetrahydro-2H-pyran-4-yl) amino) pyridin [2,3-D ] pyrimidin-4 (3H) -one (30mg, 0.063mmol), example 13(17mg, 50%) was obtained.
MS m/z(ESI):545.2[M+H]+.
Example 14
4- (4-chlorobenzyl) -6- ((2, 6-difluoropyridin-4-yl) oxy) -1-ethyl-1, 4-dihydro-9 h-imidazo [4,5-b ] [1,8] naphthyridin-9-one
Figure BDA0002645089080000452
The first step is as follows: preparation of 1-ethyl-4-nitroimidazole
Figure BDA0002645089080000453
Example 14-1(1.13g, 10mmol) and DMF (10mL) were charged to a round bottom flask and potassium carbonate (2.07g, 15mmol) and iodoethane (2.34g, 15mmol) were added. The mixture was heated to 80 ℃ and stirred for 2 hours. After the mixture was cooled to room temperature, water (50ml) was added and filtered to give example 14-2(1.1g, 78%) as a yellow solid.
MS m/z(ESI):142.1[M+H]+.
The second step is that: preparation of 1-ethyl-4-aminoimidazole
Figure BDA0002645089080000454
Example 14-2(1.1g, 7.8mmol), methanol (20mL) and palladium on carbon (200mg) were added to a round-bottom flask, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, it was filtered and concentrated to give example 14-3(830mg, 96%) as a white solid.
MS m/z(ESI):112.2[M+H]+.
The third step: preparation of 6-chloro-2- ((1-ethyl-1H-imidazol-4-yl) amino) nicotinic acid
Figure BDA0002645089080000461
Example 14-3(830mg, 7.5mmol) was dissolved in THF (15mL) and lithium bis (trimethylsilyl) amide (1M, 11mL) was added dropwise at-75 deg.C under nitrogen and stirred at this temperature for 1 hour. Subsequently, a solution of 2, 6-dichloronicotinic acid (720mg, 3.8mmol) in THF (6ml) was added dropwise to the mixture, and the mixture was stirred at room temperature for 12 hours. After the reaction is finished, quenching with water, then cooling in an ice bath, and acidifying with a 5N HCl solution until the pH is 2-3. The aqueous phase was then extracted several times with ethyl acetate and the organic phase was dried and concentrated to give example 14-4(608mg, 61%) as a yellow solid.
MS m/z(ESI):267.1[M+H]+.
The fourth step: preparation of 6-chloro-1-ethyl-1, 4-dihydro-9H-imidazo [4,5-B ] [1,8] naphthyridin-9-one
Figure BDA0002645089080000462
Examples 14-4(608mg, 2.3mmol) and (8mL) were added to a round bottom flask and the mixture was stirred at 120 ℃ for 5 hours. After the reaction was complete, it was quenched with water and filtered to give example 14-5(319mg, 56%) as a pale yellow solid.
MS m/z(ESI):249.1[M+H]+.
The fifth step: preparation of 6-chloro-4- (4-chlorobenzyl) -1-ethyl-1, 4-dihydro-9H-imidazo [4,5-B ] [1,8] naphthyridin-9-one
Figure BDA0002645089080000463
Example 14-5(319mg, 1.3mmol) and DMF (5mL) were charged to a round bottom flask and potassium carbonate (415mg, 3mmol) and p-chlorobenzyl bromide (612mg, 3mmol) were added. The mixture was heated to 60 ℃ and stirred for 2 hours. After the mixture was cooled to room temperature, water (30ml) was added and filtered to give example 14-6(435mg, 78%) as a white solid.
MS m/z(ESI):373.2[M+H]+.
And a sixth step: preparation of 4- (4-chlorobenzyl) -6- ((2, 6-difluoropyridin-4-yl) oxy) -1-ethyl-1, 4-dihydro-9 h-imidazo [4,5-b ] [1,8] naphthyridin-9-one
Figure BDA0002645089080000471
Example 14-6(100mg, 0.27mmol) and DMF (2mL) were added to a round bottom flask and potassium carbonate (415mg, 3mmol) and 2, 6-difluoropyridin-4-ol (35mg, 0.27mmol) were added. The mixture was heated to 100 ℃ and stirred for 2 hours. The mixture was cooled to room temperature and filtered and purified by preparative HPLC to give example 14(45mg, 36%) as a white solid.
MS m/z(ESI):468.1[M+H]+.
Example 15
4- (4-chlorobenzyl) -5- ((4- ((2, 6-difluoropyridin-4-yl) oxy) phenyl) amino) -1-ethyl-1, 4-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one
Figure BDA0002645089080000472
The first step is as follows: preparation of 4-nitro-1H-pyrazole-3-carboxamide
Figure BDA0002645089080000473
The compound 4-nitro-1H-pyrazole-3-carboxylic acid (15.7g, 99.95mmol) was placed in a 500mL three-necked round bottom flask, followed by the addition of THF (250mL) and oxalyl chloride (13.9g, 109.51mmol), one drop of DMF. The reaction was stirred at 25 ℃ for 0.5 h. The reaction was then cooled in an ice bath, aqueous ammonium hydroxide (36mL, 5.00 eq) was added, and the reaction was stirred at 25 ℃ for 2 hours. The resulting mixture was concentrated in vacuo. The crude material is treated with H2O wash gave example 15-1(15g, 93%) as a white solid.
MS m/z(ESI):157.03[M+H]+.
1H NMR(400MHz,DMSO-d6)δ14.10(s,6H),8.72(s,6H),8.03(d,J＝33.5Hz,8H),7.77(d,J＝58.7Hz,8H),1.25(d,J＝8.9Hz,1H).
The second step is that: preparation of 1-ethyl-4-nitro-1H-pyrazole-5-carboxamide
Figure BDA0002645089080000481
Example 15-1(5.0g, 32.03mmol, 1.00 eq.) was placed in a 500mL 3-necked round bottom flask. Then adding K2CO3(8.8g, 63.2mmol, 2.0 equiv.), DMF (150mL) and iodoethane (10g, 64.12mmol, 2.00 equiv.). The reaction was stirred at 25 ℃ for 5 hours. Subjecting the resulting solution to H2Dilute O and extract with EtOAc. Combination of Chinese herbsAnd the organic layer was washed with brine, over anhydrous Na2SO4Dried and concentrated in vacuo. The crude material was purified by column chromatography to give example 15-2 as a white solid (1.8g, 31%).
MS m/z(ESI):185.06[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.30(d,J＝9.3Hz,2H),4.16(q,J＝7.2Hz,2H),1.37(t,J＝7.2Hz,3H).
The third step: preparation of 4-amino-1-ethyl-1H-pyrazole-5-carboxamide
Figure BDA0002645089080000482
Example 15-2(1.5g, 8.15mmol, 1.00 eq.) was placed in a 100mL round bottom flask and dissolved in MeOH (20 mL). Pd-C (0.15g) was then added and the resulting suspension was stirred under a hydrogen atmosphere at 25 ℃ for 3 hours. The solid was filtered off. The resulting mixture was concentrated in vacuo to afford example 15-3(0.9g, 72%) as a purple solid.
MS m/z(ESI):155.10[M+H]+.
The fourth step: preparation of 4- ((4-chlorophenylmethyl) amino) -1-ethyl-1H-pyrazole-5-carboxamide
Figure BDA0002645089080000483
Example 15-3(0.8g, 5.19mmol) was dissolved in methanol (15ml) at room temperature, 4-chlorobenzaldehyde (0.73g, 5.19mmol) was added to the mixture, the mixture was stirred at room temperature for 5 hours, and NaBH was added to the reaction solution4(0.4g, 10.38 mmol). The mixture was heated to 50 ℃ and stirred for 2 h. After cooling, 20ml of water was added, extracted with ethyl acetate (2 x 30ml), the organic phase was suspended and the crude material was purified by column chromatography to give examples 15-4 as white solids (1g, 69.4%).
MS m/z(ESI):279.09[M+H]+.
The fifth step: preparation of 4- (4-chlorobenzyl) -1-ethyl-1, 4-dihydro-5H-pyrazolo [4,3-d ] pyrimidine-5, 7(6H) -dione
Figure BDA0002645089080000491
Example 15-4(1g,3.59mmol) was dissolved in DMF (15ml) and NaH (0.17g, 7.18mmol) was added to the mixture. The reaction was stirred at 0 ℃ for 1 hour under nitrogen atmosphere. Bis (1H-imidazol-1-yl) methanethioketone (0.89g, 5.38mmol) was added, and the reaction solution was heated to 75 ℃ for reaction for 2 hours. The reaction solution was cooled to room temperature, quenched by the addition of water (80mL), filtered, and the filter cake dried to give example 15-5(0.9g, 81%) as a white powder.
MS m/z(ESI):321.07[M+H]+.
And a sixth step: preparation of 5-chloro-4- (4-chlorobenzyl) -1-ethyl-1, 4-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one
Figure BDA0002645089080000492
Example 15-5(0.9g,2.81mmol) was dissolved in DMF (6ml) at room temperature, iodomethane (0.8g,5.61mmol) was added and the reaction was allowed to proceed for 2h at room temperature. The reaction mixture was added to water (20ml), and insoluble materials were filtered off to give example 15-6(0.8g, 85%) as a white powder.
MS m/z(ESI):335.04[M+H]+.
The seventh step: preparation of 4- (4-chlorobenzyl) -1-ethyl-5- ((4-hydroxyphenyl) amino) -1, 4-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one
Figure BDA0002645089080000501
Example 15-6(30mg,0.09mmol) was dissolved in t-BuOH (2mL), CH at room temperature3COOH (0.5mL) to the solution was added 4-hydroxyaniline (30mg, 0.27 mmol). The reaction solution was heated to 100 ℃ for 6 hours. To the reaction was added 10mL of water, the mixture was extracted with EtOAc (2 x 10mL), and the combined extracts were taken over Na2SO4Dried, spun dry and the crude product purified by p-TLC (dichloro: methanol ═ 20:1) example 15-7(20mg, 56%) was obtained as a white powder.
MS m/z(ESI):396.11[M+H]+.
Eighth step: preparation of 4- (4-chlorobenzyl) -5- ((4- ((2, 6-difluoropyridin-4-yl) oxy) phenyl) amino) -1-ethyl-1, 4-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one
Figure BDA0002645089080000502
Example 15-7(30mg,0.075mmol) was dissolved in DMF (1mL) at room temperature and 2,4, 6-trifluoropyridine (15mg, 0.114mmol) and cesium carbonate (49mg, 0.15mmol) were added to the mixture. The reaction solution was heated to 80 ℃ for 2 hours. To the reaction was added 10mL of water, the mixture was extracted with EtOAc (2 x 10mL), and the combined extracts were taken over Na2SO4Dry, spin dry, and use p-TLC (dichloro: methanol ═ 20:1) to give example 15(8mg, 21%) as a white powder.
MS m/z(ESI):509.12[M+H]+.
Example 16
4- (4-chlorobenzyl) -5- ((4- ((2, 6-difluoropyridin-4-yl) oxy) phenyl) amino) -1-ethyl-1, 4-dihydro-7 h- [1,2,3] triazolo [4,5-d ] pyrimidin-7-one
Figure BDA0002645089080000503
The first step is as follows: preparation of N- ((4-chlorobenzyl) carbamic acid sulfenyl) benzamide
Figure BDA0002645089080000511
Example 16-1(1.63g,10mmol) was dissolved in THF, cooled to 0 deg.C, and p-chlorobenzylamine (1.55g,11mmol) was added dropwise. After the mixture was stirred at room temperature for 2 hours, the reaction solution was concentrated, and the solid was slurried with petroleum ether and filtered to give example 16-2(2.7g, 90%) as a white solid.
The second step is that: preparation of 1- (4-chlorobenzyl) thiourea
Figure BDA0002645089080000512
Example 16-2(2.7g, 9mmol) was dissolved in ethanol (20mL) and water (20mL) at room temperature, and potassium carbonate (2.5g, 18mmol) was added. The mixture was heated to 100 ℃ and stirred for 3 hours. After the mixture was cooled to room temperature, it was concentrated to remove ethanol and then filtered, and the solid was washed with water to give example 16-3(1.7g, 94%) as a white solid.
MS m/z(ESI):201.1[M+H]+.
The third step: preparation of 6-amino-1- (4-chlorobenzyl) -2-mercapto-5-nitrosopyrimidin-4 (1H) -one
Figure BDA0002645089080000513
To a solution of sodium ethoxide prepared from sodium (460mg, 20mmol) and 10ml ethanol were added example 16-3(1.2g, 6mmol) and ethyl cyanoacetate 2-oxime (1.4g, 10 mmol). The orange mixture was stirred under heating at reflux for 2 hours. The mixture was cooled to 0 deg.C, water (15mL) and 1N HCl (20mL) were added, filtered, and the solid was washed three times with water to give example 16-4(1.2g, 63%) as a cyan solid.
MS m/z(ESI):297.1[M+H]+.
The fourth step: preparation of tert-butyl (3- (4-chlorobenzyl) -2-mercapto-5-nitroso-6-oxo-3, 6-dihydropyrimidin-4-yl) carbamate
Figure BDA0002645089080000521
To a solution of examples 16-4(1g,3.37mmol) in DCM (20mL) was added (Boc)2O (0.88g,4.04mmol) and triethylamine (0.68g,6.74mmol) were added and the mixture was stirred at room temperature for 3 h. DCM was removed in vacuo and ethyl acetate was added to the crude product. The product was filtered off and washed with ethyl acetate to afford example 16-5(1.1g, 82%).
MS m/z(ESI):397.07[M+H]+.
The fifth step: preparation of tert-butyl (5-amino-3- (4-chlorobenzyl) -2-mercapto-6-oxo-3, 6-dihydropyrimidin-4-yl) carbamate
Figure BDA0002645089080000522
Example 16-5(1g, 2.52mmol) was added to dioxane (20mL) and water (5mL) followed by Na2S2O4(877mg, 5.04 mmol). The reaction mixture was stirred at room temperature for 2 hours. Adding water (20mL), extracting with ethyl acetate (20 mL. times.2), combining the organic phases, and extracting with anhydrous Na2SO4Drying and concentration gave examples 16-6(850mg, 88%).
MS m/z(ESI):383.10[M+H]+.
And a sixth step: preparation of tert-butyl (3- (4-chlorobenzyl) -5- (ethylamino) -2-mercapto-6-oxo-3, 6-dihydropyrimidin-4-yl) carbamate
Figure BDA0002645089080000523
Examples 16-6(1g, 2.61mmol) were placed in a 100mL round bottom flask and dissolved in MeOH (20 mL). Acetaldehyde (0.13g, 2.87mmol) was then added, stirring for 5 minutes, and NaBH was added3CN (0.25g, 3.92mmol) was stirred at room temperature for 3 hours. Water (20mL) was added, extracted with ethyl acetate (20mL x 2), the organic phases combined, dried and concentrated, and the crude product was purified on silica gel column to give examples 16-7(800mg, 75%).
MS m/z(ESI):411.12[M+H]+.
The seventh step: preparation of 6-amino-1- (4-chlorobenzyl) -5- (ethylamino) -2-mercaptopyrimidin-4-one
Figure BDA0002645089080000531
Examples 16-7(0.8g, 1.95mmol) in HCl dioxane (10ml, 6M) was stirred at room temperature for 1 hour and suspended directly to give examples 16-8(0.58g, 95%) as a white solid.
MS m/z(ESI):311.09[M+H]+.
Eighth step: preparation of 4- (4-chlorobenzyl) -1-ethyl-5-mercapto-1, 4-dihydro-7H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-one
Figure BDA0002645089080000532
Examples 16-8(0.5g, 1.61mmol) were dissolved in concentrated HCl (5ml) and NaNO2(0.17g, 2.41mmol) was added to the mixture. The reaction was stirred at 0 ℃ for 2 hours under nitrogen. Adding NaHCO3The aqueous solution of (2) was adjusted to PH 7, filtered and the filter cake dried to give examples 16-9(0.3g, 58%) as a white powder.
MS m/z(ESI):322.07[M+H]+.
The ninth step: preparation of 4- (4-chlorobenzyl) -1-ethyl-5- (methylthio) -1, 4-dihydro-7H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-one
Figure BDA0002645089080000533
Examples 16-9(0.2g,0.62mmol) were dissolved in DMF (6ml) and water (1ml) at room temperature and the reaction was stirred at room temperature for 2h with the addition of NaOH (106mg,0.75mmol) and MeI (30mg,0.75 mmol). Water (20mL) was added, extracted with ethyl acetate (2 x 40mL), the combined organic phases were dried and concentrated, and the crude product was purified by silica gel column to give examples 16-10(120mg, 57%).
MS m/z(ESI):336.06[M+H]+.
The tenth step: preparation of 4- (4-chlorobenzyl) -5- ((4- ((2, 6-difluoropyridin-4-yl) oxy) phenyl) amino) -1-ethyl-1, 4-dihydro-7H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-one
Figure BDA0002645089080000541
Examples 16-10(30mg,0.089mmol) were dissolved in tert-butyl acetate at room temperatureButanol (3mL) and acetic acid (1mL), 4- ((2, 6-difluoropyridin-4-yl) oxy) aniline (20mg, 0.089mmol) was added to the mixture. The reaction solution was heated to 100 ℃ for 16 hours. To the reaction was added 10mL of water, the mixture was extracted with EtOAc (2 x 10mL), and the combined extracts were taken over Na2SO4Dry, spin dry, and use p-TLC (dichloro: methanol ═ 20:1) to give example 16(10mg, 22%) as a white powder.
MS m/z(ESI):510.12[M+H]+.
Example 17
7- (4-chlorobenzyl) -6- ((4- ((2, 6-difluoropyridin-4-yl) oxy) phenyl) amino) -3-ethylisoxazole [5,4-d ] pyrimidin-4 (7h) -one
Figure BDA0002645089080000542
The first step is as follows: preparation of 2- (1-ethoxypropyl) malononitrile
Figure BDA0002645089080000543
To malononitrile (1g,15mmol) was added example 17-1(2.7g,15mmol) and the mixture was stirred at 90 ℃ for 1.5 h. After cooling to room temperature, concentration afforded example 17-2(2g, 91%) as a yellow oil.
The second step is that: preparation of 3-ethyl-4-nitrile-5-aminoisoxazole
Figure BDA0002645089080000551
A solution of example 17-2(2g, 13.3mmol) in ethanol (10mL) was added to a mixture of hydroxylamine hydrochloride (1.39g, 20mmol), NaOH (800mg, 20mmol) and water (10mL), and the reaction was stirred at room temperature for 6 hours. After the reaction was complete, concentration was carried out, and washing with water gave example 17-3(1.3g, 73%) as a white solid.
MS m/z(ESI):138.0[M+H]+.
The third step: preparation of 5-amino-3-ethyl isoxazole-4-carboxamide
Figure BDA0002645089080000552
Example 17-3(1.3g,9.5mmol) and concentrated sulfuric acid (8mL) were added to a round bottom flask and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into ice water (30mL) and filtered to give example 17-4(1.3g, 90%) as a white solid.
MS m/z(ESI):156.1[M+H]+.
The fourth step: preparation of 5- ((4-chlorobenzyl) amino) -3-ethylisoxazole-4-carboxamide
Figure BDA0002645089080000553
Example 17-4(1.3g, 8.3mmol), p-chlorobenzaldehyde (1.16g, 8.3mmol) and methanol (15mL) were added to a round bottom flask, acetic acid (1mL) was added dropwise, sodium cyanoborohydride (1.04g, 16.6mmol) was added in portions, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, quench with water, followed by multiple extractions of the aqueous phase with ethyl acetate, drying of the organic phase, concentration and purification on silica gel flash column afforded example 17-5(1.8g, 80%) as a pale yellow solid.
MS m/z(ESI):280.3[M+H]+.
The fifth step: preparation of 7- (4-chlorobenzyl) -3-ethylisoxazo [5,4-d ] pyrimidine-4, 6(5h, 7h) -dione
Figure BDA0002645089080000561
Example 17-5(1.4g,5mmol) and DCM (30mL) were charged into a round bottom flask, and CDI (810mg, 5mmol) and p-chlorobenzyl bromide (612mg, 3mmol) were added. The mixture was stirred at room temperature for 5 hours. After the reaction was complete, concentration was carried out, and purification by flash silica gel column gave example 17-6(1.1g, 73%) as a white solid.
MS m/z(ESI):306.0[M+H]+.
And a sixth step: preparation of 4-chloro-7- (4-chlorobenzyl) -3-ethylisoxazo [5,4-d ] pyrimidin-6 (7h) -one
Figure BDA0002645089080000562
Examples 17-6(1.1g,3.6mmol) and phosphorus oxychloride (10mL) were added to a round bottom flask. The mixture was heated to 110 ℃ and stirred for 2 hours. The mixture was cooled to room temperature and concentrated to give example 17-7(1.1g, 95%) as an oil.
MS m/z(ESI):324.0[M+H]+.
The seventh step: preparation of 7- (4-chlorobenzyl) -6- ((4- ((2, 6-difluoropyridin-4-yl) oxy) phenyl) amino) -3-ethylisoxazole [5,4-d ] pyrimidin-4 (7h) -one
Figure BDA0002645089080000563
Example 17-7(100mg,0.3mmol), 4- ((2, 6-difluoropyridin-4-yl) oxy) aniline (23mg,0.1mmol) and ethanol (2mL) were added to a round bottom flask. The mixture was heated to 100 ℃ and stirred for 2 hours. The mixture was cooled to room temperature and concentrated, which was purified by preparative HPLC to give example 17(15mg, 30%) as a white solid.
MS m/z(ESI):510.1[M+H]+.
Example 18
7- (4-chlorobenzyl) -6- ((4- ((2, 6-difluoropyridin-4-yl) oxy) phenyl) amino) -3-ethylisoxazole [3,4-d ] pyrimidine-4 (7h) -1
Figure BDA0002645089080000571
Example 18 was prepared by the synthetic method of example 18, referring to the synthetic method of example 17, 3-amino-5-ethylisoxazole-4-carbonitrile instead of example 17-3, and example 18 was obtained by a reaction of 5 steps.
MS m/z(ESI):510.2[M+H]+.
Example 19
N- (3- (4-chlorobenzyl) -7-ethyl-6-oxo-6, 7-dihydro-3H-purin-2-yl) -4- ((2, 6-difluoropyridin-4-yl) oxy) benzamide
Figure BDA0002645089080000572
The first step is as follows: preparation of 5, 6-diamino-1- (4-chlorobenzyl) -2-mercaptopyrimidin-4 (1H) -one
Figure BDA0002645089080000573
Example 16-4(600mg, 2mmol) was dissolved in Dioxane (8mL) and water (8mL), and 1N aqueous NaOH (8mL) and Na were added2S2O4(1.2g, 7 mmol). The mixture was stirred at room temperature for 1 hour and filtered to give example 19-1(450mg, 80%) as a yellow solid.
MS m/z(ESI):283.2[M+H]+.
The second step is that: preparation of 3- (4-chlorobenzyl) -2-mercapto-3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000574
Example 19-1(450mg,1.6mmol) and formic acid (6mL) were added to a round bottom flask and the mixture was heated to 100 ℃ and the reaction stirred for 5 hours. After the mixture was cooled to room temperature, it was filtered to give example 19-2(400mg, 85%) as a pale yellow solid.
MS m/z(ESI):293.1[M+H]+.
The third step: preparation of 3- (4-chlorobenzyl) -2- (methylthio) -3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000581
A mixture of example 19-2(292mg, 1mmol), sodium hydroxide (40mg, 1mmol), methyl iodide (0.12mL, 2mmol) and water (5mL) was stirred at room temperature overnight and then filtered to give example 19-3(245mg, 80%) as a yellow solid.
MS m/z(ESI):307.2[M+H]+.
The fourth step: preparation of 3- (4-chlorobenzyl) -7-ethyl-2- (methylthio) -3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000582
Example 19-3(150mg,0.5mmol) and DMF (5mL) were charged to a round bottom flask and potassium carbonate (276mg, 2mmol) and iodoethane (312mg, 2mmol) were added. The mixture was heated to 80 ℃ and stirred for 2 hours. After the mixture was cooled to room temperature, water (10ml) was added and filtered to give example 19-4(108mg, 65%) as a white solid.
MS m/z(ESI):334.1[M+H]+.
The fifth step: preparation of 2-amino-3- (4-chlorobenzyl) -7-ethyl-3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000583
Example 19-4(100mg,0.3mmol) and methanolic ammonia (6mL) were added to a round bottom flask and the mixture was heated to 80 ℃ and the reaction stirred for 12 hours. After the mixture was cooled to room temperature, it was concentrated to give example 19-5(90mg, 95%) as a pale yellow solid.
MS m/z(ESI):304.3[M+H]+.
And a sixth step: preparation of N- (3- (4-chlorobenzyl) -7-ethyl-6-oxo-6, 7-dihydro-3H-purin-2-yl) -4-hydroxybenzamide
Figure BDA0002645089080000591
Example 19-5(41mg, 0.3mmol) and HATU (114mg, 0.3mmol) were dissolved in N, N-dimethylformamide (2mL), and DIPEA (129mg, 1mmol) was added to the above mixture, which was stirred at room temperature for 2 hours. After the reaction was complete, water (5ml) was added and filtered to give example 19-6(95mg, 80%).
MS m/z(ESI):424.1[M+H]+.
The seventh step: preparation of N- (3- (4-chlorobenzyl) -7-ethyl-6-oxo-6, 7-dihydro-3H-purin-2-yl) -4- ((2, 6-difluoropyridin-4-yl) oxy) benzamide
Figure BDA0002645089080000592
To DMF (2ml) from example 19-6(85mg,0.2mmol) were added 2,4, 6-trifluoropyridine (66mg, 0.5mmol) and potassium carbonate (69mg, 0.5 mmol). The mixture was heated to 80 ℃ and stirred for 3 hours. Filtration after the reaction was complete and purification by preparative HPLC gave example 19(25mg, 23%).
MS m/z(ESI):537.2[M+H]+.
Example 20
3- (4-chlorobenzyl) -2- (3- ((2, 6-difluoropyridin-4-yl) oxy) azaidin-1-yl) -7-ethyl-3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000593
The first step is as follows: preparation of 1- (tert-butoxycarbonyl) -3- ((2, 6-difluoropyridin-4-yl) oxy) azetidine
Figure BDA0002645089080000601
To example 20-1(1.7g,10mmol) in DMF (15ml) was added 2,4, 6-trifluoropyridine (1.3g, 10mmol) and potassium carbonate (1.4g, 10 mmol). The mixture was heated to 80 ℃ and stirred for 3 hours. After the reaction was completed, water was added to quench (80mL), extracted with ethyl acetate (300mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (petroleum ether: ethyl acetate ═ 5: 1) to obtain example 20-2(2.5g, 87%).
MS m/z(ESI):287.2[M+H]+.
The second step is that: preparation of 3- ((2, 6-difluoropyridin-4-yl) oxy) azetidine
Figure BDA0002645089080000602
Trifluoroacetic acid (8mL) was added to DCM (15mL) from example 20-2(1.43g,5mmol) under an ice bath, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, concentration gave example 20-3(960mg, 87%).
MS m/z(ESI):187.2[M+H]+.
The third step: preparation of 3- (4-chlorobenzyl) -2- (3- ((2, 6-difluoropyridin-4-yl) oxy) azaidin-1-yl) -7-ethyl-3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000603
Example 19-4(100mg,0.3mmol), ethanol (5mL) and example 20-3(395mg,2mmol) were added to a round bottom flask and the mixture was heated to 100 deg.C and the reaction stirred for 12 hours. The mixture was cooled to room temperature and filtered and purified by preparative HPLC to give example 20(36mg, 26%).
MS m/z(ESI):473.3[M+H]+.
Example 21
1- (4-chlorobenzyl) -2- ((4- ((2, 6-difluoropyridin-4-yl) oxy) phenyl) amino) -6-isopropyl-5, 6-dihydro-1H-pyrrolo [3,4-d ] pyrimidine-4, 7-dione
Figure BDA0002645089080000611
The synthesis of example 21 was performed according to the synthesis of example 10.
MS m/z(ESI):538.1[M+H]+.
Example 22
3- (4-chlorobenzyl) -7- (2, 2-difluoroethyl) -2- ((2-ethyl-3-oxoisoindol-5-yl) amino) -3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000612
The first step is as follows: preparation of 3- (4-chlorobenzyl) -7- (2, 2-difluoroethyl) -2- (methylthio) -3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000613
The synthesis of example 22-1 was carried out in accordance with the synthesis of example 19-4 except that 1, 1-difluoro-2-iodoethane was used instead of iodoethane to give example 22-1(200mg, 75%).
MS m/z(ESI):371.0[M+H]+.
The second step is that: preparation of 3- (4-chlorobenzyl) -7- (2, 2-difluoroethyl) -2- ((2-ethyl-3-oxoisoindol-5-yl) amino) -3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000621
The procedure for the synthesis of example 22 was repeated in accordance with the procedure for the synthesis of example 20, substituting example 22-1 for example 19-4 and 6-amino-2-ethylisoindol-1-one for example 20-3 to give example 22(16mg, 31%).
MS m/z(ESI):499.1[M+H]+.
Example 23
3- (4-chlorobenzyl) -7-ethyl-2- ((2-ethyl-3-oxoisoindol-5-yl) amino) -3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000622
The first step is as follows: preparation of 3- (4-chlorobenzyl) -7-ethyl-2- ((2-ethyl-3-oxoisoindol-5-yl) amino) -3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000623
The procedure for the synthesis of example 23 was repeated in accordance with the procedure for the synthesis of example 20 except for using 6-amino-2-ethylisoindole 1-one instead of example 20-3 to give example 23(18mg, 30%).
MS m/z(ESI):463.2[M+H]+.
Example 24
3- (4-chlorobenzyl) -2- ((4- ((2, 6-difluoropyridinyl-4-yl) oxy) phenyl) amino) -7-ethyl-3, 7-dihydro-6H-purin-6-one
Figure BDA0002645089080000631
The first step is as follows: preparation of 2- ((5-bromothiazol-2-yl) amino) -3- (4-chlorobenzyl) -7-ethyl-3, 7-dihydro-6H-purin-6-one
Figure BDA0002645089080000632
Example 24-1(50mg,0.15mmol) was dissolved in t-butanol (3mL) and acetic acid (1mL) at room temperature and 5-bromothiazol-2-amine (32mg, 0.18mmol) was added to the mixture. The reaction solution was heated to 100 ℃ for 6 hours. To the reaction was added 10mL of water, the mixture was extracted with EtOAc (2 x 10mL), and the combined extracts were taken over Na2SO4Dry, spin dry, and use p-TLC (dichloro: methanol ═ 20:1) to give example 24-2(30mg, 43%) as a white powder.
MS m/z(ESI):465.12[M+H]+.
The second step is that: preparation of 3- (4-chlorobenzyl) -2- ((4- ((2, 6-difluoropyridinyl-4-yl) oxy) phenyl) amino) -7-ethyl-3, 7-dihydro-6H-purin-6-one
Figure BDA0002645089080000633
Example 24-2(30mg, 0.064mmol) was added to DMF (2mL) followed by 2, 6-difluoropyridin-4-ol (13mg, 0.096mmol), Cs2CO3(31.5mg, 0.096 mmol). Mixing the reaction solutionThe reaction was heated to 80 ℃ for 2 hours. To the reaction was added 10mL of water, the mixture was extracted with EtOAc (2 x 10mL), and the combined extracts were taken over Na2SO4Dry, spin dry, and crude product was purified by p-TLC (dichloro: methanol ═ 20:1) to give example 24(10mg, 31%) as a white powder.
MS m/z(ESI):509.12[M+H]+.
Example 25
3- (1- (4-chlorophenyl) cyclopropyl) -2- ((4- ((2, 6-difluoropyridin-4-yl) oxy) phenyl) amino) -7-ethyl-3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000641
The first step is as follows: preparation of N- ((1- (4-chlorophenyl) cyclopropyl) carbamoyl) benzamide
Figure BDA0002645089080000642
The procedure for the synthesis of example 25-1 was repeated in accordance with the procedure for the synthesis of example 16-2, except for using 1- (4-chlorophenyl) cyclopropane-1-amine instead of p-chlorobenzylamine, to give example 25-1(3.8g, 92%).
The second step is that: preparation of 1- (1- (4-chlorophenyl) cyclopropyl) thiourea
Figure BDA0002645089080000643
Example 25-2(2.7g, 90%) was obtained by substituting example 25-1 for example 16-2 in the synthesis method of example 25-2 with reference to example 16-3.
MS m/z(ESI):227.0[M+H]+.
The third step: preparation of 6-amino-1- (1- (4-chlorophenyl) cyclopropyl) -2-mercapto-5-nitrosopyrimidin-4 (1H) -one
Figure BDA0002645089080000644
Example 25-3(2.1g, 80%) was obtained by substituting example 25-2 for example 16-3 in the synthesis method of example 25-4.
MS m/z(ESI):323.2[M+H]+.
The fourth step: preparation of 5, 6-diamino-1- (1- (4-chlorophenyl) cyclopropyl) -2-mercaptopyrimidin-4 (1H) -one
Figure BDA0002645089080000651
Example 25-4(1.6g, 80%) was obtained by substituting example 25-3 for example 16-4 in the synthesis method of example 25-4 in reference to example 19-1.
MS m/z(ESI):309.0[M+H]+.
The fifth step: preparation of 3- (1- (4-chlorophenyl) cyclopropyl) -2-mercapto-3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000652
Example 25-5(1.6g, 80%) was obtained by substituting example 25-4 for example 19-1 in the synthesis of example 25-5 with reference to the synthesis of example 19-2.
MS m/z(ESI):319.1[M+H]+.
And a sixth step: preparation of 3- (1- (4-chlorophenyl) cyclopropyl) -2- (methylthio) -3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000653
Example 25-6(1.6g, 80%) was obtained by substituting example 25-5 for example 19-2 in the synthesis of example 25-6 in reference to the synthesis of example 19-3.
MS m/z(ESI):333.2[M+H]+.
The seventh step: preparation of 3- (1- (4-chlorophenyl) cyclopropyl) -7-ethyl-2- (methylthio) -3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000661
Example 25-7 was prepared by the method of example 19-4, but example 25-6 was used instead of example 19-3 to obtain example 25-7(1.6g, 80%).
MS m/z(ESI):361.1[M+H]+.
Eighth step: preparation of 3- (1- (4-chlorophenyl) cyclopropyl) -2- (3- ((2, 6-difluoropyridin-4-yl) oxy) azaidin-1-yl) -7-ethyl-3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000662
Example 25(1.6g, 80%) was prepared by substituting example 25-7 for example 19-4 in the synthesis of example 25 with reference to example 20.
MS m/z(ESI):535.1[M+H]+.
Example 26
3- (2- (4-chlorophenyl) -2-oxoethyl) -2- ((4- ((2, 6-difluoropyridin-4-yl) oxy) phenyl) amino) -7-ethyl-3, 7-dihydro-6H-purin-6-one
Figure BDA0002645089080000663
Example 26 was synthesized according to the method of example 25, substituting 2-amino-1- (4-chlorophenyl) ethane-1-one for 1- (4-chlorophenyl) cyclopropane-1-amine, and carrying out the reaction in 8 steps to obtain example 26.
MS m/z(ESI):537.2[M+H]+.
Example 27
3- (3- (4-chlorophenyl) cyclobutyl) -2- ((4- ((2, 6-difluoropyridin-4-yl) oxy) phenyl) amino) -7-ethyl-3, 7-dihydro-6 h-purin-6-one
Figure BDA0002645089080000671
Example 27 was prepared according to the procedure for the preparation of example 25, substituting 3- (4-chlorophenyl) cyclobutane-1-amine for 1- (4-chlorophenyl) cyclopropane-1-amine through 8 steps.
MS m/z(ESI):549.1[M+H]+.
Example 28
(S) -2- (((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7) -vinylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester
Figure BDA0002645089080000672
The first step is as follows: preparation of tert-butyl (S) -2- ((7-bromo-2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) imidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000673
A mixture of 4-bromopyridin-2-amine (0.86g, 0.005mol), 3, 5-difluoro-4-formyl-N-methylbenzamide (1g, 0.005mol), (5) -tert-butyl 2-ethynylmorpholine 4-carboxylate (1.057g, 0.005mol), copper (I) chloride (0.15g, 0.0015mol), copper bis (trifluoromethylsulfonyloxy) chloride (0.54g, 0.0015mol) and toluene (60mL) were charged in a 250mL jacketed reactor and heated to N2 at a temperature of 110 ℃ over 5 min. N, N-dimethylacetamide (0.1mL) was then added, and the resulting mixture was stirred at 110 ℃ for 16 hours. The toluene layer was separated from the solid residue by decantation and then concentrated under reduced pressure. The resulting crude material was loaded onto a dry silica gel column (25g) and eluted with ethyl acetate-petroleum ether 1:1 to 3:1 to give example 28-1 as a grey solid (0.4g, 15%).
MS m/z(ESI):565.13[M+H]+.
The second step is that: preparation of tert-butyl (S) -2- (((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-vinylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000681
Example 28-1(0.2g, 0.354mmol), potassium vinylfluoroborate (95mg, 0.71mol), K2CO3(147mg，1.06mmol)，Pd(dppf)Cl2(26mg, 0.0354mmol) was dissolved in dioxane (10mL) and water (1mL) and the resulting mixture was stirred at 100 ℃ for 2 h. Concentrate under reduced pressure and spin dry. The crude material obtained was loaded onto a dry silica gel column (25g) and washed with CH2Cl2: MeOH ═ 20:1 gave example 28-2 as a yellow solid (0.1g, 55%).
MS m/z(ESI):513.22[M+H]+.
1H NMR(400MHz,CDCl3)δ7.73–7.68(m,2H),7.62–7.58(m,1H),6.83(q,J＝3.7Hz,1H),6.78(dt,J＝7.5,1.4Hz,1H),6.66(t,J＝16.7,9.9,1.3Hz,1H),5.87(dd,J＝10.1,1.5Hz,1H),5.83(dd,J＝16.7,1.4Hz,1H),4.27(t,J＝7.0Hz,1H),3.99–3.90(m,2H),3.79(dd,J＝12.5,7.0Hz,1H),3.72(td,J＝7.2,1.4Hz,2H),3.56(dd,J＝12.4,7.0Hz,1H),3.37(dd,J＝12.3,7.0Hz,1H),3.22(dd,J＝12.3,7.0Hz,1H),2.91(d,J＝3.7Hz,3H),1.46(s,9H).
The third step: preparation of (S) -3, 5-difluoro-N-methyl-4- (3- (morpholin-2-ylmethyl) -7-vinylimidazo [1,2-a ] pyridin-2-yl) benzamide
Figure BDA0002645089080000682
Example 28-2(0.1g, 0.2mol) was dissolved in an ethanol solution (5mL) of hydrochloric acid, and the resulting mixture was stirred at room temperature for 1 hour. The solution was suspended to dryness to give example 28-3 as a white solid (50mg, 62%).
MS m/z(ESI):413.23[M+H]+.
The fourth step: preparation of methyl (S) -2- (((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7) -vinylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000691
Example 28-3(50mg,0.12mmol), DIEA (31mg,0.24mmol) and methyl chloroformate (23mg,24mmol) were dissolved in DCM (6mL), mixed well in a 50mL round bottom flask and placed in a magnetic stirrer to react at room temperature for 0.5 h. After completion of the reaction (TLC, DCM: MeOH ═ 20:1), the plates were run through to give example 28(20mg, 35%).
MS m/z(ESI):471.18[M+H]+.
1H NMR(400MHz,CDCl3)δ7.73–7.68(m,2H),7.62–7.58(m,1H),6.83(q,J＝3.7Hz,1H),6.78(dt,J＝7.5,1.4Hz,1H),6.66(t,J＝16.7,9.9,1.3Hz,1H),5.87(dd,J＝10.1,1.5Hz,1H),5.83(dd,J＝16.7,1.4Hz,1H),4.27(t,J＝7.0Hz,1H),3.99–3.90(m,2H),3.79(dd,J＝12.5,7.0Hz,1H),3.72(td,J＝7.2,1.4Hz,2H),3.70(s,3H)3.56(dd,J＝12.4,7.0Hz,1H),3.37(dd,J＝12.3,7.0Hz,1H),3.22(dd,J＝12.3,7.0Hz,1H),2.91(d,J＝3.7Hz,3H).
Example 29
(S) -2- (((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7) - (methylthio) imidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester
Figure BDA0002645089080000692
Synthesis of example 29 the procedure of example 28 was referenced to obtain the title compound (15mg, 48% yield).
MS m/z(ESI):491.15[M+H]+.
Example 30
(S) -2- (((7-cyclopropyl-2- (2, 6-difluoro-4- (methylcarbamoyl)) phenyl) imidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester
Figure BDA0002645089080000701
Synthesis of example 30 the procedure of example 28 was referenced to give the title compound (18mg, 58% yield).
MS m/z(ESI):485.15[M+H]+.
Example 31
(S) -2- (((7-cyclobutyl-2- (2, 6-difluoro-4- (methylcarbamoyl)) phenyl) imidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester
Figure BDA0002645089080000702
Synthesis of example 31 the procedure of example 28 was referenced to give the title compound (14mg, 48% yield).
MS m/z(ESI):499.21[M+H]+.
Example 32
(S) -methyl 2- ((2- (4- (cyclopropylcarbamoyl) -2, 6-difluorophenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000703
Synthesis of example 32 referring to the procedure of example 28, the specific synthetic route is as follows:
the first step is as follows: preparation of 3, 5-difluoro-4-formylbenzoic acid
Figure BDA0002645089080000704
3, 5-difluorobenzoic acid (2.0g, 12.6mmol) was dissolved in tetrahydrofuran (30mL), N, N, N ', N' -tetramethylethylenediamine (3.2g,27.8mmol) was added, the mixture was cooled to-78 ℃ under nitrogen protection, a solution of N-butyllithium in N-hexane (1.6M, 17.4mL, 27.8mmol) was added dropwise, and the mixture was reacted at that temperature for 1.5 hours. Ethyl formate (1.86g, 25.2mmol) was added and the reaction was slowly warmed to room temperature for 4 hours. The reaction solution was slowly poured into a solution of diluted hydrochloric acid in ice water and extracted with ethyl acetate (50mL × 3). The combined organic phases were washed with water (50mL), brine (50mL), dried over anhydrous sodium sulfate, filtered and spun to give the crude product as a white solid (2.3g, 97%).
1HNMR(400MHz,DMSO-d6)δ13.95(s,1H),10.22(s,1H),7.65(d,J＝9.2Hz,2H).
MS m/z(ESI):185.1[M-H]-；
The second step is that: preparation of N-cyclopropyl-3, 5-difluoro-4-formylbenzamide
Figure BDA0002645089080000711
3, 5-difluoro-4-formylbenzoic acid (2.3g, 12.4mmol) was dissolved in dichloromethane (30mL), N-dimethylformamide (92mg, 1.24mmol) was added, cooled to 0 deg.C, and oxalyl chloride (1.88g, 14.8mmol) was added dropwise. After 4 hours at room temperature, the reaction mixture was spin-dried. The mixture was dissolved in methylene chloride (30mL), and triethylamine (3.13g, 62.0mmol) and cyclopropylamine (1.41g, 24.8mmol) were added under ice-bath to react at room temperature for 0.5 hour. Poured into 100mL of water and extracted with dichloromethane (60mL x 3). The organic phases were combined and washed with water (60mL), brine (60mL), dried over anhydrous sodium sulfate, filtered, spun-dried, and subjected to column chromatography (ethyl acetate/petroleum ether ═ 0-35%) to obtain a white solid (1.6g, 66%).
1HNMR(400MHz,DMSO-d6)δ8.65(s,1H),7.47(d,J＝9.2Hz,2H),2.87-2.82(m,1H),0.82-0.78(m,2H),0.66-0.62(m,2H).
MS m/z(ESI):226.1[M+H]+；
The third step: preparation of tert-butyl (S) -2- ((2- (4- (cyclopropylcarbamoyl) -2, 6-difluorophenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000712
The compounds 4-methylpyridin-2-amine (500mg,4.63mmol), tert-butyl (S) -2-ethynylmorpholine-4-carboxylate (977mg, 4.63mmol), N-cyclopropyl-3, 5-difluoro-4-formylbenzamide (1.04g, 4.63mmol), cuprous chloride (138mg, 1.39mmol), copper triflate (503mg, 1.39mmol) were dissolved in toluene (20mL), heated to 85 ℃ with stirring under nitrogen protection. N, N-dimethylacetamide (0.2mL) was added and the reaction was carried out at 85 ℃ overnight. Cooled to room temperature, poured into 100mL of water, filtered and extracted with ethyl acetate (50mL × 3). The organic phases were combined, washed with water (50mL), brine (50mL), dried over anhydrous sodium sulfate, filtered, spun-dried, and subjected to column chromatography (methanol/dichloromethane ═ 0 to 10%) to obtain a yellow solid (390mg, 16.0%).
1HNMR(400MHz，DMSO-d6)δ8.32(d,J＝8.0Hz,1H),7.67(s,1H),7.51(d,J＝7.2Hz,2H),6.87(d,J＝6.0Hz,1H),3.89-3.70(m,3H),3.59-3.51(m,1H),3.41-3.30(m,1H),3.02-2.91(m,3H),2.87-2.75(m,1H),2.59-2.54(m,1H),2.48(s,3H),1.42(s,9H),0.90-0.86(m,2H),0.76-0.69(m,2H).
MS m/z(ESI):527.2[M+H]+；
The fourth step: preparation of (S) -N-cyclopropyl-3, 5-difluoro-4- (7-methyl-3- (morpholin-2-ylmethyl) imidazo [1,2-a ] pyridin-2-yl) benzamide hydrochloride
Figure BDA0002645089080000721
Tert-butyl (S) -2- ((2- (4- (cyclopropylcarbamoyl) -2, 6-difluorophenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (360mg, 0.575mmol) was dissolved in dichloromethane (10mL), and 1M dioxane hydrochloride solution (5mL) was added and reacted at room temperature for 4 hours. Spin dry to give a yellow solid (320mg, 100%).
1HNMR(400MHz，DMSO-d6)δ8.68(d,J＝4.0Hz,1H),8.38(d,J＝7.2Hz,1H),7.65(d,J＝8.0Hz,2H),7.35(s,1H),6.83(d,J＝7.2Hz,1H),3.48–3.44(m,1H),3.28–3.22(m,1H),3.01–2.95(m,1H),2.91–2.86(m,2H),2.63–2.57(m,2H),2.38(s,3H),2.29–2.21(m,1H),2.06–1.97(m,1H),0.76–0.71(m,2H),0.63–0.59(m,2H).
MS m/z(ESI):427.2[M+H]+；
The fifth step: preparation of methyl (S) -2- ((2- (4- (cyclopropylcarbamoyl) -2, 6-difluorophenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000722
(S) -N-cyclopropyl-3, 5-difluoro-4- (7-methyl-3- (morpholin-2-ylmethyl) imidazo [1,2-a ] pyridin-2-yl) benzamide hydrochloride (35mg, 0.076mmol) was dissolved in dichloromethane (2mL), triethylamine (23mg, 0.227mmol) was added, methyl chloroformate (14mg, 0.152mmol) was added dropwise, and the reaction was carried out at room temperature for 1 hour. Poured into 20mL of water and extracted with ethyl acetate (20mL x 2). The organic phases were combined and washed with water (20mL), brine (20mL), dried over anhydrous sodium sulfate, filtered, spun-dried, and the reverse direction to afford the title compound (14mg, 45% yield).
MS m/z(ESI):485.5[M+H]+.
1H NMR(400MHz,DMSO-d6):8.67(d,J＝4.0Hz,1H),8.43(d,J＝7.2Hz,1H),7.64(d,J＝8.4Hz,1H),7.36(s,1H),6.84(d,J＝6.8HZ,1H),3.77–3.61(m,4H),3.55(s,3H),3.49–3.43(m,1H),3.25–3.19(m,1H),3.06–3.00(m,2H),2.91–2.85(m,1H),2.83–2.74(m,1H),2.38(s,3H),0.76–0.71(m,2H),0.63–0.59(m,2H).
Example 33
(2S) -methyl 2- ((2- (2, 6-difluoro-4- ((1-methoxypropan-2-yl) carbamoyl) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000731
Synthesis of example 33 the procedure of example 28 was referenced to obtain the title compound (10mg, 41% yield).
MS m/z(ESI):517.6[M+H]+.
Example 34
(S) -methyl 2- ((2- (2, 6-difluoro-4- ((tetrahydro-2H-pyran-4-yl) carbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000732
Synthesis of example 34 the procedure of example 28 was referenced to obtain the title compound (10mg, 41% yield).
MS m/z(ESI):529.6[M+H]+.
Example 35
(S) -2- ((2- (2, 6-difluoro-4- (3-hydroxyazetidine-1-carbonyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester
Figure BDA0002645089080000741
Synthesis of example 35 the procedure of example 28 was referenced to obtain the title compound (12mg, 41% yield).
MS m/z(ESI):501.5[M+H]+.
Example 36
(S) -3- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) -4, 4-difluoropiperidine-1-carboxylic acid methyl ester
Figure BDA0002645089080000742
Synthesis of example 36 the procedure of example 28 was referenced to obtain the title compound (12mg, 41% yield).
MS m/z(ESI):493.5[M+H]+.
Example 37
(S) -4- (3- ((4, 4-difluoro-1-propionylpiperidin-3-yl) methyl) -7-methylimidazol [1,2-a ] pyridin-2-yl) -3, 5-difluoro-N-methylbenzamide
Figure BDA0002645089080000743
Synthesis of example 37 the procedure of example 28 was referenced to obtain the title compound (12mg, 41% yield).
MS m/z(ESI):491.5[M+H]+.
Example 38
(S) -4- (3- ((1-ethyl-4, 4-difluoropiperidin-3-yl) methyl) -7-methylimidazo [1,2-a ] pyridin-2-yl) -3, 5-difluoro-N-methylbenzamide
Figure BDA0002645089080000751
Synthesis of example 38 the procedure of example 28 was referenced to obtain the title compound (12mg, 41% yield).
MS m/z(ESI):463.5[M+H]+.
Example 39
1- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) -2-oxo-5-azabicyclo [2.2.1] heptane-5-carboxylic acid methyl ester
Figure BDA0002645089080000752
Synthesis of example 39 the procedure of example 28 was referenced to obtain the title compound (12mg, 41% yield).
MS m/z(ESI):471.5[M+H]+.
Example 40
(S) -2- (((7-methyl-2- (4-methyl-6- (methylcarbamoyl) pyridin-3-yl) imidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester
Figure BDA0002645089080000753
The first step is as follows: preparation of 5-formyl-N, 4-dimethylpyridine formamide
Figure BDA0002645089080000754
Mixing 6-bromo-4-methylnicotine (2g, 10mmol)Dissolved in DMSO (30mL), methylammonium hydrochloride (1.5g, 15mmol), triethylamine (2.02g, 20mmol), Pd (dppf) Cl was added2(0.7g, 1mmol) was stirred under a CO balloon at 100 ℃ for 5 hours. To the reaction was added 50mL of water, the mixture was extracted with EtOAc (2 x 50mL), and the combined extracts were taken over Na2SO4Dry, spin dry, and use a column (dichloro: methanol ═ 50: 1) to afford example 40-1(0.9g, 50.5%) as a white solid.
MS m/z(ESI):179.03[M+H]+.
The synthesis of example 40 was performed according to the method of example 31 to obtain the objective compound (17mg, 49% yield).
MS m/z(ESI):438.21[M+H]+.
EXAMPLE 41
(S) -2- (((7-methyl-2- (3-methyl-5- (methylcarbamoyl) thiophen-2-yl) imidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester
Figure BDA0002645089080000761
The first step is as follows: preparation of N, 4-dimethylthiophene-2-carboxamides
Figure BDA0002645089080000762
4-methylthiophene-2-carboxylic acid (5g, 35.17mmol) was dissolved in toluene (80mL), thionyl chloride (12.55g, 106mmol) was added, and the mixture was stirred under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in THF (80 mL). To this were added methylammonium hydrochloride (4.5g, 70.34mmol), triethylamine (14.4mL, 105.5mmol), and then stirred at room temperature for 1 hour. The precipitated solid was filtered, and the precipitated solid was collected and washed with diethyl ether to give example 41-1(4.5g, 82%).
MS m/z(ESI):156.03[M+H]+.
The second step is that: preparation of 5-formyl-N, 4-dimethylthiophene-2-carboxamide
Figure BDA0002645089080000763
Example 41-1(1g, 6.44mmol) was added to DMF (20mL) followed by POCl3(2.96g, 19.33 mmol). The reaction solution was heated to 80 ℃ for 5 hours. To the reaction was added 50mL of water, the mixture was extracted with EtOAc (2 x 50mL), and the combined extracts were taken over Na2SO4Dry, spin dry, and use a column (dichloro: methanol ═ 20:1) to afford example 41-2(0.8g, 68%) as a white solid.
MS m/z(ESI):184.04[M+H]+.
The synthesis of example 41 was performed according to the method of example 31 to obtain the objective compound (15mg, 47% yield).
MS m/z(ESI):443.18[M+H]+.
Example 42
(R) -5- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) -3, 3-difluoropiperidine-1-carboxylic acid methyl ester
Figure BDA0002645089080000771
The first step is as follows: preparation of 1- (tert-butyl) 3-methyl 5-oxopiperidine-1, 3-dicarboxylate
Figure BDA0002645089080000772
The compound 4-nitro-1H-pyrazole-3-carboxylic acid (5g, 19.28mmol) was placed in a 250mL round bottom flask, then DCM (100mL) and Dess Martin (9.8g, 23.14 mmol) were added and the reaction stirred at 25 ℃ for 16H, then water (80mL) was added, extracted with DCM, the organic layers combined, washed with brine, over anhydrous Na2SO4Dried and concentrated in vacuo. The crude material was purified by column chromatography to afford example 42-1 as a white solid (4g, 80%).
MS m/z(ESI):258.13[M+H]+.
The synthesis of example 42 was performed according to the procedure of example 36 to obtain the objective compound (14mg, 48% yield).
1H NMR(400MHz,CDCl3)δ7.99–7.88(m,1H),7.56–7.48(m,3H),6.87(d,J＝6.8Hz,1H),4.24–3.98(m,2H),3.66(s,3H),3.02(s,3H),2.91–2.71(m,2H),2.48(s,3H),2.23-1.94(m,5H).
MS m/z(ESI):493.18[M+H]+.
Example 42A
(S) -5- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) -3, 3-difluoropiperidine-1-carboxylic acid methyl ester
Figure BDA0002645089080000781
Synthesis of example 42A the procedure of example 36 was referenced to give the title compound (9.6mg, 23% yield).
1H NMR(400MHz,CDCl3)δ7.99–7.88(m,1H),7.56–7.48(m,3H),6.87(d,J＝6.8Hz,1H),4.24–3.98(m,2H),3.66(s,3H),3.02(s,3H),2.91–2.71(m,2H),2.48(s,3H),2.23-1.94(m,5H).
MS m/z(ESI):493.18[M+H]+.
Example 43
(R) -4- (3- (((5, 5-difluoro-1-propionylpiperidin-3-yl) methyl) -7) -methylimidazo [1,2-a ] pyridin-2-yl) -3, 5-difluoro-N-methylbenzamide
Figure BDA0002645089080000782
Synthesis of example 43 the procedure of example 36 was followed to give the title compound (18mg, 53% yield).
MS m/z(ESI):491.20[M+H]+.
Example 44
((S) -N-cyclopropyl-3, 5-difluoro-4- (7-methyl-3- ((4-propionylmorpholin-2-yl) methyl) imidazo [1,2-a ] pyridin-2-yl) benzamide
Figure BDA0002645089080000783
Synthesis of example 44 the procedure of example 28 was referenced to give the title compound (18.1mg, 54% yield).
1H NMR(400MHz,DMSO-d6)δ8.66(d,J＝3.6Hz,1H),8.45–8.41(m,1H),7.68–7.61(m,2H),7.35(s,1H),6.86–6.81(m,1H),4.14–4.04(m,1H),3.71–3.60(m,2H),3.49–3.39(m,2H),3.24–3.20(m,1H),3.08–2.99(m,2H),2.91–2.83(m,1H),2.75–2.68(m,1H),2.38(s,3H),2.30–2.16(m,2H),0.92(t,J＝7.2Hz,3H),0.76–0.71(m,2H),0.63-0.59(m,2H).
MS m/z(ESI):483.5[M+H]+.
Example 45
(S) -2- ((2- (4- (cyclopropylcarbamoyl) -2, 6-difluorophenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid ethyl ester
Figure BDA0002645089080000791
Synthesis of example 45 the procedure of example 28 was referenced to give the title compound (18.1mg, 54% yield).
MS m/z(ESI):499.5[M+H]+.
1H NMR(400MHz,DMSO-d6):8.70–8.67(m,1H),8.42(d,J＝6.8Hz,1H),7.65(d,J＝8.4Hz,1H),7.36(s,1H),6.87–6.83(m,1H),4.04–3.93(m,2H),3.71–3.59(m,4H),3.52–3.42(m,1H),3.25–3.19(m,1H),3.09–3.01(m,2H),2.91–2.85(m,1H),2.82–2.73(m,1H),2.38(s,3H),1.13(t,J＝7.2Hz,3H),0.77–0.70(m,1H),0.63–0.57(m,2H).
Example 46
(S) -methyl 2- ((2- (3-fluoro-5- (methylcarbamoyl) pyridin-2-yl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000792
Synthesis of example 46 the procedure of example 28 was referenced to give the title compound (10mg, 42% yield).
MS m/z(ESI):442.5[M+H]+.
Example 47
(S) -methyl 2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -8-fluoro-7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000801
Synthesis of example 47 the procedure of example 28 was referenced to obtain the title compound (10mg, 42% yield).
MS m/z(ESI):477.5[M+H]+.
Example 48
Methyl (S) -2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methoxyimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000802
Synthesis of example 48 the procedure of example 28 was referenced to obtain the title compound (10mg, 42% yield).
MS m/z(ESI):475.5[M+H]+.
Example 49
(S) -methyl 2- ((8-chloro-2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000803
Synthesis of example 49 the procedure of example 28 was referenced to give the title compound (10mg, 42% yield).
MS m/z(ESI):493.9[M+H]+.
Example 50
(S) -methyl 2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methoxy-6- (methylamino) imidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000811
Synthesis of example 50 the procedure of example 28 was referenced to obtain the title compound (10mg, 42% yield).
MS m/z(ESI):504.5[M+H]+.
Example 51
(S) -2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) imidazo [1,2-a ] thiophen [3,2-d ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester
Figure BDA0002645089080000812
Synthesis of example 51 the procedure of example 28 was referenced to obtain the title compound (10mg, 42% yield).
MS m/z(ESI):501.5[M+H]+.
Example 52
(S) -methyl 2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -6-methyl-6H-imidazo [1,2-a ] pyrrolo [3,2-d ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000813
Synthesis of example 52 the procedure of example 28 was referenced to obtain the title compound (10mg, 42% yield).
MS m/z(ESI):498.5[M+H]+.
Example 53
(S) -methyl 2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) furan [3,2-d ] imidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000821
Synthesis of example 53 the procedure of example 28 was referenced to obtain the title compound (10mg, 42% yield).
MS m/z(ESI):485.5[M+H]+.
Example 54
(S) -methyl 2- ((7- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) imidazo [1,2-a ] thiazole [5,4-d ] pyridin-6-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000822
Synthesis of example 54 the procedure of example 28 was referenced to obtain the title compound (10mg, 42% yield).
MS m/z(ESI):502.5[M+H]+.
Example 55
(S) -methyl 2- ((6- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) imidazo [1,2-a ] thiazole [4,5-d ] pyridin-7-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000823
Synthesis of example 55 according to the method of example 28, the title compound (10mg, 42% yield) was obtained.
MS m/z(ESI):502.5[M+H]+.
Example 56
(S) -methyl 2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) imidazole [2,1-g ] [1,7] naphthyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000831
Synthesis of example 56 the procedure of example 28 was referenced to obtain the title compound (10mg, 42% yield).
MS m/z(ESI):496.5[M+H]+.
Example 57
(S) -methyl 2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazol [2,1-g ] [1,7] naphthyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000832
Synthesis of example 57 the procedure of example 28 was referenced to obtain the title compound (10mg, 42% yield).
MS m/z(ESI):510.5[M+H]+.
Example 58
(S) -N-cyclopropyl-4- (3- ((4- (2, 2-difluoroacetyl) morpholin-2-yl) methyl) -7-methylimidazo [1,2-a ] pyridin-2-yl) -3, 5-difluorobenzamide
Figure BDA0002645089080000833
Synthesis of example 58 the procedure of example 28 was referenced to obtain the title compound (30mg, 81% yield).
1H NMR(400MHz,Chloroform-d)δ8.42(s,1H),7.98(s,1H),7.57(s,2H),7.03(d,J＝25.7Hz,1H),6.07(t,J＝53.5Hz,1H),4.30(d,J＝13.2Hz,1H),4.04–3.73(m,2H),3.67(s,1H),3.44(m,1H),3.24(s,1H),3.00(d,J＝51.7Hz,3H),2.55(m,4H),0.89(d,J＝7.2Hz,2H),0.74(d,J＝7.2Hz,2H).
MS m/z(ESI):505.5[M+H]+.
Example 59
(S) -methyl 2- ((2- (2, 6-difluoro-4- (N-methylsulfamoyl) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000841
Synthesis of example 59 the procedure of example 28 was referenced to give the title compound (70mg, 60% yield).
1HNMR：(400MHz,DMSO-d6)δ8.44(d,J＝7.2Hz,1H),7.82(s,1H),7.59(d,J＝6.1Hz,2H),7.36(s,1H),6.85(d,J＝7.0Hz,1H),3.77(d,J＝13.1Hz,1H),3.63(d,J＝12.2Hz,2H),3.55(s,3H),3.49–3.45(m,3H),3.23(d,J＝11.6Hz,1H),3.13–2.98(m,2H),2.53(s,3H),2.38(s,3H).
MS m/z(ESI):495.1[M+H]+.
Example 60
Cyclopropyl (S) -2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000842
Synthesis of example 60 the procedure of example 28 was referenced to obtain the title compound (25mg, 86% yield).
1H NMR(400MHz,DMSO-d6)δ8.70(d,J＝5.2Hz,1H),8.42(d,J＝7.1Hz,1H),8.35(s,1H),7.65(d,J＝8.1Hz,1H),7.36(s,1H),6.84(d,J＝7.1Hz,1H),3.93(s,1H),3.62(s,2H),3.03(d,J＝6.4Hz,2H),2.83(d,J＝4.4Hz,3H),2.72-2.67(m,1H),2.38(s,5H),2.00(q,J＝7.2,6.6Hz,2H),0.91–0.82(m,1H),0.64–0.49(m,3H).
MS m/z(ESI):485.5[M+H]+.
Example 61
(S) -methyl 2- ((7-methyl-2- (2,3, 6-trifluoro-4- (methylcarbamoyl) phenyl) imidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000851
Synthesis of example 61 the procedure of example 28 was referenced to obtain the title compound (25mg, 86% yield).
MS m/z(ESI):477.5[M+H]+.
Example 62
Cyclopropyl (S) -2- ((7-methyl-2- (2,3, 6-trifluoro-4- (methylcarbamoyl) phenyl) imidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000852
Synthesis of example 62 the procedure of example 28 was referenced to give the title compound (18mg, 86% yield).
MS m/z(ESI):503.5[M+H]+.
Example 63
(S) -methyl 2- ((2- (2, 6-difluoro-4- ((2,2, 2-trifluoroethyl) carbamoyl) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000853
Synthesis of example 63 the procedure of example 28 was referenced to obtain the title compound (21mg, 86% yield).
MS m/z(ESI):527.5[M+H]+.
Example 64
Cyclopropyl (S) -2- ((2- (2, 6-difluoro-4- ((2,2, 2-trifluoroethyl) carbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000861
Synthesis of example 64 the procedure of example 28 was referenced to obtain the title compound (11mg, 45% yield).
MS m/z(ESI):553.5[M+H]+.
Example 65
(S) -3, 5-difluoro-4- (7-methyl-3- ((4-methylsulfonyl) morpholin-2-yl) methyl) imidazo [1,2-a ] pyridin-2-yl) -N- (2,2, 2-trifluoroethyl) benzamide
Figure BDA0002645089080000862
Synthesis of example 65 the procedure of example 28 was referenced to give the title compound (15mg, 75% yield).
MS m/z(ESI):547.5[M+H]+.
Example 66
(S) -4- (3- ((4- (cyclopropylsulfonyl) morpholin-2-yl) methyl) -7-methylimidazo [1,2-a ] pyridin-2-yl) -3, 5-difluoro-N- (2,2, 2-trifluoroethyl) benzamide
Figure BDA0002645089080000863
Synthesis of example 66 the procedure of example 28 was referenced to give the title compound (15mg, 72% yield).
MS m/z(ESI):573.6[M+H]+.
Example 67
(S) -4- (3- ((4- (ethylsulfonyl) morpholin-2-yl) methyl) -7-methylimidazo [1,2-a ] pyridin-2-yl) -3, 5-difluoro-N-methylbenzamide
Figure BDA0002645089080000871
Synthesis of example 67 according to the method of example 28, the title compound (11mg, 72% yield) was obtained.
MS m/z(ESI):493.5[M+H]+.
Example 68
(S) -4- (3- ((4- (N, N-dimethylsulfamoyl) morpholin-2-yl) methyl) -7-methylimidazol [1,2-a ] pyridin-2-yl) -3, 5-difluoro-N- (2,2, 2-trifluoroethyl) benzamide
Figure BDA0002645089080000872
Synthesis of example 68 according to the method of example 28, the title compound (11mg, 61% yield) was obtained.
MS m/z(ESI):576.6[M+H]+.
Example 69
(S) -4- (3- ((4- ((cyclopropylmethyl) sulfonyl) morpholin-2-yl) methyl) -7-methylimidazo [1,2-a ] pyridin-2-yl) -3, 5-difluoro-N- (2,2, 2-trifluoroethyl) benzamide
Figure BDA0002645089080000873
Synthesis of example 69 the procedure of example 28 was referenced to give the title compound (14mg, 58% yield).
MS m/z(ESI):587.6[M+H]+.
Example 70
(S) -4- (3- ((4- (2, 2-difluoroacetyl) morpholin-2-yl) methyl) -7-methylimidazol [1,2-a ] pyridin-2-yl) -3, 5-difluoro-N-methylbenzenesulfonamide
Figure BDA0002645089080000881
Synthesis of example 70 the procedure of example 59 was referenced to give the title compound (14mg, 58% yield).
MS m/z(ESI):515.5[M+H]+.
Example 71
(S) -methyl 2- ((2- (4- (2, 2-difluoroacetamide) -2, 6-difluorophenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000882
Synthesis of example 71 the procedure of example 28 was referenced to give the title compound (14mg, 58% yield).
MS m/z(ESI):587.6[M+H]+.
Example 72
(S) -2- ((2- (2, 6-difluoro-4- (methylsulfonylamino) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester
Figure BDA0002645089080000883
Synthesis of example 72 the procedure of example 71 was followed to give the title compound (14mg, 30% yield).
MS m/z(ESI):495.5[M+H]+.
Example 73
(S) -methyl 2- ((2- (4- ((N, N-dimethylsulfamoyl) amino) -2, 6-difluorophenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000891
Synthesis of example 73 the procedure of example 71 was followed to give the title compound (18mg, 28% yield).
MS m/z(ESI):524.6[M+H]+.
Example 74
(S) -methyl 2- ((2- (2, 6-difluoro-4- ((methoxycarbonyl) amino) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000892
Synthesis of example 74 the procedure of example 71 was followed to give the title compound (21mg, 50% yield).
MS m/z(ESI):475.5[M+H]+.
Example 75
Cyclopropyl (S) -2- ((2- (2, 6-difluoro-4- (N-methylsulfamoyl) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000893
Synthesis of example 75 the procedure of example 59 was referenced to give the title compound (24mg, 50% yield).
MS m/z(ESI):521.6[M+H]+.
Example 76
(S) -3, 5-difluoro-N-methyl-4- (7-methyl-3- ((4-methylsulfonyl) morpholin-2-yl) methyl) imidazo [1,2-a ] pyridin-2-yl) benzenesulfonamide
Figure BDA0002645089080000901
Synthesis of example 76 the procedure of example 59 was referenced to give the title compound (20mg, 40% yield).
MS m/z(ESI):515.6[M+H]+.
Example 77
(S) -methyl 2- ((2- (2, 6-difluoro-4- (N-isopropylsulfamoyl) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000902
Synthesis of example 77 the procedure of example 59 was referenced to obtain the title compound (46mg, 41% yield).
MS m/z(ESI):523.6[M+H]+.
Example 78
(S) -methyl 2- ((2- (2, 6-difluoro-4- (N-cyclopropylsulfamoyl) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000903
Synthesis of example 78 the procedure of example 59 was referenced to give the title compound (42mg, 41% yield).
MS m/z(ESI):521.6[M+H]+.
Example 79
(S) -methyl 2- ((2- (4- (N, N-dimethylsulfamoyl) -2, 6-difluorophenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000911
Synthesis of example 79 the procedure of example 59 was referenced to obtain the title compound (31mg, 41% yield).
MS m/z(ESI):509.5[M+H]+.
Example 80
(S) -methyl 2- ((2- (4- (cyclopropanesulfonamide) -2, 6-difluorophenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000912
Synthesis of example 80 the procedure of example 71 was followed to give the title compound (33mg, 47% yield).
MS m/z(ESI):521.6[M+H]+.
Example 81
(S) -methyl 2- ((2- (4- (cyclopropylamide) -2, 6-difluorophenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000913
Synthesis of example 81 the procedure of example 71 was followed to give the title compound (30mg, 47% yield).
MS m/z(ESI):485.5[M+H]+.
Example 82
(S) -methyl 2- ((2- (2, 6-difluoro-4- (methylsulfonyl) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000921
Synthesis of example 82 according to the method of example 59, the title compound (30mg, 47% yield) was obtained.
MS m/z(ESI):480.5[M+H]+.
Example 83
(S) -2- ((2- (2, 6-difluoro-4- (cyclopropylsulfo) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester
Figure BDA0002645089080000922
Synthesis of example 83 the procedure of example 59 was referenced to give the title compound (30mg, 47% yield).
MS m/z(ESI):506.5[M+H]+.
Example 84
(2S) -2- ((2- (2, 6-difluoro-4- (S-methylsulfamoyl) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester
Figure BDA0002645089080000923
The first step is as follows: preparation of methyl (2S) -2- ((2- (2, 6-difluoro-4- (methylsulfonyl) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000924
Synthesis of example 84-1 the procedure of example 59 was followed to give the title compound (100mg, 54% yield).
MS m/z(ESI):464.5[M+H]+.
The second step is that: preparation of methyl (2S) -2- ((2- (2, 6-difluoro-4- (methylsulfonyl) phenyl) -7-methylimidazol [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000931
Example 84-1(100mg) and trifluoroacetamide (41.2mg) were dissolved in dichloromethane (4mL), followed by addition of MgO (37.5mg) and Rh2(OAc)4(2mg)，Finally, iodobenzene acetate (90.1mg) was added thereto and the mixture was stirred at room temperature overnight, filtered, and the solid was washed with methylene chloride, the solution was concentrated, and the product was purified by column chromatography to obtain example 84-2(30mg, 20% yield).
MS m/z(ESI):575.5[M+H]+.
The third step: preparation of methyl (2S) -2- ((2- (2, 6-difluoro-4- (S-methylsulfamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate
Figure BDA0002645089080000932
Example 84-2(30mg) was dissolved in methanol (2mL), potassium carbonate (120mg) was added thereto, and the mixture was stirred at room temperature for 2 hours, water and ethyl acetate were added, the pH was adjusted to 6 with a 3N hydrochloric acid solution, and the mixture was separated, concentrated, dried, and isolated and purified to give example 84(13mg, yield 52%).
MS m/z(ESI):479.5[M+H]+.
Example 85
(2S) -2- ((2- (4- (cyclopropanesulfonylimino) -2, 6-difluorophenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester
Figure BDA0002645089080000941
Synthesis of example 85 according to the method of example 84, the title compound (21mg, 47% yield) was obtained.
MS m/z(ESI):505.6[M+H]+.
Example 86
(2S) -2- ((2- (4- (methylsulfonylimino) -2, 6-difluorophenylamino) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester
Figure BDA0002645089080000942
Synthesis of example 86 the procedure of example 84 was followed to give the title compound (11mg, 30% yield).
MS m/z(ESI):494.5[M+H]+.
Biological test evaluation
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
1. Cell function test
Test example 1 determination of the Effect of the Compounds of the invention on the calcium ion flux in cells stably expressing the HEK293-hP2X3 receptor
1. Purpose of the experiment:
the inhibitory effect of the compounds on the HEK293-hP2X3 receptor was measured.
2. Laboratory instruments and reagents:
2.1 Experimental apparatus:
384 well-assay plate (Corning; 3712);
pipette (Axygen);
FLIPR(Molecular Devices)。
2.2 Experimental reagents:
DMEM(Invitrogen；11965)；
fetal bovine serum (Biowest; S1810-500);
dialyzed serum (S-FBS-AU-065; Serana);
penicillin and streptomycin (Biowest; L0022-100);
hygromycin B (cabaochem, 400052);
Matrigel(BD；354230)；
DMSO(Sigma；D2650)；
HBSS(Invitrogen；14065)；
HEPES(Invitrogen；15630080)；
Probenecid(Sigma；P8761)；
BSA(renview；FA016)；
trypsin (HDB; 0458);
cell stabilizing: HEK293-hP2X3 (available from Kanglong Kangcheng (Beijing) New drug technology corporation). 3. The experimental method comprises the following steps:
1. preparing a buffer solution: 1 XHBSS, 20mM HEPES, 2.5mM probenecid (400 mM stock in 1M NaOH), 0.1% BSA. Probenecid and BSA were added fresh the day of the experiment. The assay buffer includes dye buffer and compound dilution buffer.
2. Cells were trypsinized and then treated at 1X 104The density of individual cells/well was seeded to 384 well-assay plates and incubated for 16-24 hours (at least overnight).
3. The broth was discarded and 20 μ L of dye was added. Incubate at 37 ℃ in the dark for 60min, read the calcium signal.
4. Antagonists were prepared prior to the experiment. 5u L/well concentration 5x antagonist compounds were added to 384 well-assay plates and incubated at room temperature for 15min in the dark. The assay plates were transferred to a FLIPR and 5. mu.L/well 6X concentration of agonist compound was added. Values are read and data saved using FLIPR. The total assay volume was 30. mu.L, including 20. mu.L/well dye buffer, 5. mu.L/well 5X concentration of test compound and 5. mu.L/well 6X concentration of agonist compound. 4. The experimental data processing method comprises the following steps:
calcium signal values were read by FLIPR. The calculated output for each sampling time point in the experiment is the ratio of the 340/510nm to 380/510nm wavelength signals. The maximum minus the minimum is calculated from the ratio signal curve.
IC of compound was calculated using GraphPad prism to fit the percent inhibition and ten-point concentration data to parametric nonlinear logistic formula50The value is obtained.
5. The experimental results are as follows:
the results of the compounds of the examples of the invention in the HEK293-hP2X3 receptor cell functional calcium flux assay are shown in table 1:
TABLE 1
Figure BDA0002645089080000951
Figure BDA0002645089080000961
6. And (4) experimental conclusion:
the scheme shows that the compound provided by the invention shows good inhibition effect in a HEK293-hP2X3 receptor cell functional calcium flow test.
Test example 2 determination of the Effect of the Compounds of the invention on the calcium ion flux in cells stably expressing 1321N1-hP2X3 receptor
1. Purpose of the experiment:
measuring the inhibitory effect of a compound on 1321N1-hP2X3 cell activity 2 experimental instruments and reagents:
2.1 Experimental apparatus:
384 well-assay plate (Corning; 3712);
384 well-Compound plates (Corning; 3657);
384 well-assay plates (LABCYTE; P-05525);
FLIPR(Molecular Devices)。
2.2 Experimental reagents:
DMEM(Gibco；11965)；
FBS(Gibco；10099-141)；
dialyzed serum (S-FBS-AU-065; Serana);
penicillin and streptomycin (Biowest; L0022-100);
hygromycin B (Invitrogen, 10687010);
Matrix(Thermo；5416)；
DMSO(Sigma；D2650)；
HBSS(Invitrogen；14025)；
HEPES(Invitrogen；15630080)；
Probenecid(Sigma；P8761)；
Versene(Gibco；15040066)；
G418(Sigma；G5013)；
Figure BDA0002645089080000962
Calcium 4 Assay Kit(Molecular Devices；R8141)；
α，β-meATP；
cell stabilizing: 1321N1-hP2X3 (supplied by Shanghai Ruizi chemical research, Inc.).
3. The experimental method comprises the following steps:
1. preparing a buffer solution: prepare the assay buffer and dilute Dye to 1 ×.
2. Cells were trypsinized and then treated at 1X 104The density of individual cells/well was seeded to 384 well-assay plates and incubated for 16-24 hours (at least overnight).
3. The culture was discarded, 30. mu.L of dye was added, and incubated at 37 ℃ in the dark for 60 min.
4. Preparation of 3X compound plate: transfer 500nl 180X compound to compound plate (source plate for FLIPR) using ECHO, add 30ul of assay buffer per well and shake gently for 20-40 minutes. And (3) computer detection: 15uL 3X compound was added to the cell plate per well (sample was added with a FLIPR instrument) and calcium signal was detected. After 15 minutes, 22.5uL 3X agonist (EC) per well was added80Concentration), calcium signal is detected.
4. The experimental data processing method comprises the following steps:
calcium signal values were read by FLIPR. The calculated output for each sampling time point in the experiment is the ratio of the 340/510nm to 380/510nm wavelength signals. The maximum minus the minimum is calculated from the ratio signal curve.
IC of compound was calculated using GraphPad prism to fit the percent inhibition and ten-point concentration data to parametric nonlinear logistic formula50The value is obtained.
5. The experimental results are as follows:
the results of the compounds of the examples of the present invention in the 1321N1-hP2X3 receptor cell functional calcium flux assay are shown in Table 2:
TABLE 2
Name of Compound 1321N1-hP2X3 IC50(nM)
Example 32 75.03
Example 42 39.00
Example 42A 50.10
Example 44 31.68
Example 58 40.84
Example 59 57.50
Example 60 54.40
6. And (4) experimental conclusion:
the scheme shows that the compound shows better inhibition effect in a 1321N1-hP2X3 receptor cell functional calcium flow test.
Test example 3 determination of the Effect of the Compounds of the present invention on the calcium flux Activity in cells stably expressing P2X2/3 receptor
1. Purpose of the experiment:
the inhibitory effect of the compounds on the P2X2/3 receptor was measured.
2. Laboratory instruments and reagents:
2.1 Experimental apparatus:
384 well-assay plate (Corning; 3712);
384 well-Compound plates (Corning; 3657);
384 well-assay plates (LABCYTE; P-05525);
pipette (Axygen);
FLIPR(Molecular Devices)。
2.2 Experimental reagents:
DMEM(Invitrogen；11965)；
fetal bovine serum (Biowest; S1810-500);
dialyzed serum (S-FBS-AU-065; Serana);
penicillin and streptomycin (Biowest; L0022-100);
hygromycin B (cabaochem, 400052);
Matrigel(BD；354230)；
DMSO(Sigma；D2650)；
HBSS(Invitrogen；14065)；
HEPES(Invitrogen；15630080)；
Probenecid(Sigma；P8761)；
BSA(renview；FA016)；
trypsin (HDB; 0458);
FBS(Gibco；10099-141)；
Matrix(Thermo；5416)；
Versene(Gibco；15040066)；
G418(Sigma；G5013)；
Figure BDA0002645089080000981
Calcium 4Assay Kit(Molecular Devices；R8141)；
α，β-meATP；
cell stabilizing: 1321N1-hP2X2/3 (supplied by Shanghai Ruizi chemical research, Inc.).
3. The experimental steps are as follows:
3.1 Experimental method one:
1. preparing a buffer solution: 1 XHBSS, 20mM HEPES, 2.5mM probenecid (400 mM stock in 1M NaOH), 0.1% BSA. Probenecid and BSA were added fresh the day of the experiment. The experimental buffer comprises a dye buffer, a compound dilution buffer and the like.
2. Cells were trypsinized and then treated at 1X 104The density of individual cells/well was seeded to 384 well-assay plates and incubated for 16-24 hours (at least overnight).
3. The broth was discarded and 20 μ L of dye was added. Incubate at 37 ℃ in the dark for 60min, read the calcium signal.
4. Antagonists were prepared prior to the experiment. 5uL/well concentration 5 Xantagonist compound was added to 384 well-assay plates and incubated at room temperature for 15min in the dark. The assay plates were transferred to a FLIPR and 5. mu.L/well 6X concentration of agonist compound was added. Values are read and data saved using FLIPR. The total assay volume was 30uL, and included 20. mu.L/well dye buffer, 5. mu.L/well 5X concentration of test compound, and 5. mu.L/well 6X concentration of agonist compound. 3.2 Experimental method two:
1. preparing a buffer solution: prepare the assay buffer and dilute Dye to 1 ×.
2. Cells were trypsinized and then treated at 1X 104The density of individual cells/well was seeded to 384 well-assay plates and incubated for 16-24 hours (at least overnight).
3. The broth was discarded and 30. mu.L of dye was added. Incubate at 37 ℃ for 60min in the dark.
4. Preparation of 3X compound plate: transfer 500nl 180X compound to compound plate (source plate for FLIPR) using ECHO, add 30ul of assay buffer per well and shake gently for 20-40 minutes. And (3) computer detection: 15uL 3X compound was added to the cell plate per well (sample was added with a FLIPR instrument) and calcium signal was detected. After 15 minutes, 22.5uL 3X agonist (EC) per well was added80Concentration), calcium signal is detected.
4. The experimental data processing method comprises the following steps:
calcium signal values were read by FLIPR. The calculated output for each sampling time point in the experiment is the ratio of the 340/510nm to 380/510nm wavelength signals. The maximum minus the minimum is calculated from the ratio signal curve.
IC of compound was calculated using GraphPad prism to fit the percent inhibition and ten-point concentration data to parametric nonlinear logistic formula50The value is obtained.
5. The experimental results are as follows:
the inhibition of the compound on the P2X2/3 receptor can be measured by the two experimental protocols, and the test of the compound in the example on the 1321N1-hP2X2/3 receptor cell functional calcium flow is carried out by the invention by adopting the second experimental method, and the results are shown in the table 3:
TABLE 3
Name of Compound 1321N1-hP2X2/3 IC50(nM)
BLU-5937 3381
Example 28 16890
Example 32 13420
Example 42 27100
Example 42A 15960
Example 44 11610
Example 58 13060
Example 60 9615
6. And (4) experimental conclusion:
the scheme shows that the compound shown in the invention shows smaller inhibition effect in a P2X2/3 receptor cell functional calcium flow test.
Test example 4 measurement of pharmacokinetics of Balb/C mice
1. The research aims are as follows:
Balb/C mice were used as test animals to study the pharmacokinetic behavior of the following compounds in the examples given below, administered orally at a dose of 5mg/kg in plasma in mice.
2. Test protocol
2.1 test drugs:
the embodiment of the invention is self-made.
2.2 test animals:
Balb/C Mouse 6 per example, male, Shanghai Jie Si laboratory animals Ltd, animal production license number (SCXK (Shanghai) 2013) 0006N 0.311620400001794).
2.3, preparing the medicine:
5g of hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200Cps) was weighed, dissolved in 1000mL of purified water, and 10g of Tween80 was added. Mix well to get a clear solution.
2.4 administration:
Balb/C mice, male; p.o. after fasting overnight, the dose was 5mg/kg and the administration volume was 10 mL/kg.
2.5 sample collection:
before and after administration, at 0, 0.5, 1,2,4, 6, 8 and 24 hours, the mice were bled by orbital bleeding 0.1mL, and placed in EDTA-K2The plasma was separated by centrifugation at 6000rpm for 6min at 4 ℃ in a test tube and stored at-80 ℃.
2.6 sample treatment:
1) plasma samples 40uL added 160uL acetonitrile precipitation, after mixing 3500 x g centrifugal 5 ~ 20 minutes.
2) Taking 100uL of the treated supernatant solution for LC/MS/MS analysis to analyze the concentration of the compound to be detected.
2.6 liquid phase analysis
Liquid phase conditions: shimadzu LC-20AD pump
Mass Spectrometry conditions AB Sciex API 4000 Mass Spectroscopy
Column chromatography: phenomenex Gemiu 5um C1850 x 4.6mm
The mobile phase: the solution A is 0.1% formic acid water solution, and the solution B is acetonitrile
Flow rate: 0.8mL/min
Elution time: 0-4.0 min, eluent as follows:
Figure BDA0002645089080001001
3. test results and analysis:
the main pharmacokinetic parameters were calculated using WinNonlin 6.1, and the results of the mouse pharmacokinetic experiments are shown in table 4 below:
TABLE 4 mouse pharmacokinetic experiment results
Figure BDA0002645089080001002
Figure BDA0002645089080001011
4. And (4) experimental conclusion:
as can be seen from the results of the mouse pharmacokinetic experiments in the table, the compounds of the embodiment of the invention have good metabolic properties, exposure AUC and maximum blood concentration CmaxAll performed well.
Test example 5 liver microsome metabolic stability test
1. Purpose of the experiment:
the purpose of this experiment was to examine the stability of the compounds of the examples in mouse, rat, dog and human liver microsomes.
2. The experimental steps are as follows:
2.1 preparation of working solutions of Compounds
Preparing a working solution of the compound: the compound stock solution was added to phosphate buffer to a final concentration of 20. mu.M.
2.2 preparing the liver microsome working solution
Diluted with 100mM phosphate buffer to a final concentration of 0.625 mg/mL.
2.3 preparation of NADPH and UDPGA
NADPH (reduced nicotinamide adenine dinucleotide phosphate) and UDPGA (uridine diphosphate glucuronate) were weighed and added to 100mM phosphate buffer to a final concentration of 20mM each.
2.4 preparation of perforating agent
1mg of Alamethicin (Promethrin) was weighed out and added to 200. mu.L of DMSO to prepare a solution of 5 mg/mL. Then diluted with phosphate buffer to a final concentration of 50. mu.g/mL.
2.5 preparing a reaction stop solution
Stopping liquid: cold acetonitrile containing labetalol hydrochloride at 100ng/mL and tolbutamide at 400ng/mL as internal standards.
2.6 incubation protocol
400 μ L of the prepared liver microsomes, 25 μ L of the compound working solution and 25 μ L of Alamethicin were sequentially added to a 96-well plate and preincubated at 37 ℃ for 10 min. Then 50. mu.L of prepared NADPH/UDPGA is added to start the reaction, and the reaction is incubated at 37 ℃, the total volume of the reaction system is 500. mu.L, and the final contents of the components are as follows:
composition (I) Content (wt.)
Liver microsome 0.5mg/mL
Compound (I) 1μM
NADPH 2mM
UDPGA 2mM
Alamethicin 2.5μg/mL
2.7 analysis of samples
2.7.1 chromatographic conditions:
the instrument comprises the following steps: shimadzu LC-30 AD;
a chromatographic column:
Figure BDA0002645089080001021
c18(50 × 4.6mm, 5 μm particle size);
mobile phase: a: 0.1% formic acid solution, B: methanol
Washing gradient: 0.2-1.6 min 5% A to 95% A, 3.0-3.1 min 95% A to 5% A
Operating time: 4.0 min.
2.7.2 Mass Spectrometry conditions:
the instrument comprises the following steps: API5500 liquid chromatography-mass spectrometer, AB Sciex corporation;
an ion source: an electrospray ionization source (ESI);
drying gas: n is a radical of2At a temperature of 500 ℃;
electrospray voltage: 5000V;
the detection mode is as follows: detecting positive ions;
the scanning mode is as follows: reaction Monitoring (MRM) mode.
3. The experimental results are as follows:
table 5: example Compounds hepatic microsomal metabolic stability results
Figure BDA0002645089080001022
4. And (4) experimental conclusion:
the above data show that the compound of example 32 of the present invention has good metabolic stability in mouse, rat, dog and human liver microsomes, and better stability compared to the reference compound BLU-5937.
Test example 6 taste sensitivity test in BALB/c mice
1. Purpose of the experiment:
in the experiment, compounds with small toxic and side effects on animal taste are screened out through a quinine bitter water experiment.
2. Main instruments and materials for experiments
2.1 Instrument:
1. superclean bench (CJ-2F, Suzhou von Willebrand Experimental animals facilities, Inc.);
2. electronic balance (CPA2202D, sartorius);
3. electronic balance (BSA2202S-CW, Sadolis);
4. a water purifier (Pacific TII, Thermo).
2.2 reagent:
quinine monohydrochloride dihydrate (6119-47-7, Adamas).
2.3 animals:
BALB/c mice, 6-8 weeks,
Figure BDA0002645089080001023
purchased from Shanghai Spiral-BiKai laboratory animals Co.
3. The experimental steps are as follows:
3.1 animal screening
1 day before the experiment, all BALB/c mice were weighed and animals with too high or too low body weight were rejected.
3.2 grouping and Water Disable
BALB/c mice were randomized according to body weight, and were deprived of water and fasted 12-16 hours prior to dosing.
3.3 preparation of an aqueous solution of quinine
Weighing a proper amount of quinine monohydrochloride dihydrate, and preparing into a quinine hydrochloric acid aqueous solution with the concentration of 3mmol/L by using ultrapure water for later use.
3.4 preparation of test Compounds
Weighing appropriate amount of compound to be tested, and preparing into target concentration with corresponding solvent according to experimental design for use. 3.5 dosing and animal quinine Water intake testing
Dosing and fasting: on the day of the experiment, animals were weighed, fasted, bedding changed, and dosed according to the experimental design.
Quinine water intake test:
1. rinse the corresponding clean mouse drinking bottle with ultrapure water and 3mmol/L of quinine HCl solution prepared separately for 2-3 times, then fill with water and weigh and record the weight as Wi0。
2. According to the experimental design, after a certain period of administration, the filled water bottle is gently placed on the corresponding mouse cage, timing is started, after 30min, the water bottle is gently taken out, weighing is carried out, and the weight is recorded as Wi30。
3. Calculating the water intake of each group of animals: Δ ww (g) ═ Wi30-Wi0(ii) a Calculating the water intake of a single mouse: Δ pww (g) ═ Δ WW/N, N is the number of animals in each group.
4. The gustatory disorder ratio ═ 100% (drinking water as an aqueous solution of quinine hydrochloride and given to the test drug group Δ pWW-drinking water as an aqueous solution of quinine hydrochloride and given to the solvent control group Δ pWW)/(drinking water as ultrapure water and given to the solvent control group Δ pWW-drinking water as an aqueous solution of quinine hydrochloride and given to the solvent control group Δ pWW). The data processing is carried out by software such as Excel.
5. Animals were euthanized after the experiment was completed.
4. And (3) test results:
table 6: taste results of the example Compounds
Figure BDA0002645089080001031
5. And (4) experimental conclusion:
from the above results, it can be seen that the compound of example 32 of the present patent has a significant advantage of having less side effects on the mouse taste at the same dose as the reference compound BLU-5937.

Claims (21)

1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0002645089070000011
wherein:
L1and L2Each independently selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1NRaa(CRbbRcc)n2-、-(CH2)n1C(O)NRaa-、-(CRaaRbb)n1O(CH2)n2-、-(CRaaRbb)n1(CH2)n2O-、-(CH2)n1NRaaC(O)-、-(CH2)n1(CRaaRbb)n2-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CH2)n1S(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-、-(CH2)n1C(O)(CRaaRbb)n2-、-(CH2)n1P(O)Raa-、-(CH2)n1S(O)n2-、-(CH2)n1S(O)n2NRaa-or- (CH)2)n1NRaaS(O)n2-；
Ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
ring C is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
Raselected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)ORaa、-(CH2)n1ORaa、-(CH2)n1SRaa、-(CH2)n1NRaaC(O)Rbb、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1NRaaC(O)NRbbRcc、-(CH2)n1NRaaRbb、-NRaa(CH2)n1Rbb、-(CH2)n1C(O)NRaaRbb、-(CH2)n1C(O)Raa、-OC(RaaRbb)n1(CH2)n2Rcc、-C(RaaRbb)n1(CH2)n2ORcc、-(CH2)n1S(O)n2Raa、-(CH2)n1NRaaS(O)n2Rbb、-CH＝CH(CH2)n1Raa、-CH＝CH(CH2)n1NRaaRbb、-CH＝CH(CH2)n1NRaaC(O)Rbbor-CH ═ CH (CH)2)n1NRaaC(O)NRbbRccSaid amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally may be further substituted;
Rbselected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, heteroaryloxy, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)ORaa、-(CH2)n1ORaa、-(CH2)n1SRaa、-(CH2)n1NRaaC(O)Rbb、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1NRaaC(O)NRbbRcc、-(CH2)n1NRaaRbb、-NRaa(CH2)n1Rbb、-(CH2)n1C(O)NRaaRbb、-(CH2)n1C(O)Raa、-OC(RaaRbb)n1(CH2)n2Rcc、-(CH2)n1S(O)n2Raa、-(CH2)n1NRaaS(O)n2Rbb、-CH＝CH(CH2)n1Raa、-CH＝CH(CH2)n1NRaaRbb、-CH＝CH(CH2)n1NRaaC(O)Rbbor-CH ═ CH (CH)2)n1NRaaC(O)NRbbRccSaid amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally may be further substituted;
Rcselected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)ORaa、-(CH2)n1ORaa、-(CH2)n1SRaa、-(CH2)n1NRaaC(O)Rbb、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1NRaaC(O)NRbbRcc、-(CH2)n1NRaaRbb、-NRaa(CH2)n1Rbb、-(CH2)n1C(O)NRaaRbb、-(CH2)n1C(O)Raa、-OC(RaaRbb)n1(CH2)n2Rcc、-(CH2)n1S(O)n2Raa、-(CH2)n1NRaaS(O)n2Rbb-CH＝CH(CH2)n1Raa、-CH＝CH(CH2)n1NRaaRbb、-CH＝CH(CH2)n1NRaaC(O)Rbbor-CH ═ CH (CH)2)n1NRaaC(O)NRbbRccSaid amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally may be further substituted;
Raa、Rbband RccEach independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
or, Raa、RbbAnd RccAny two of which are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally may be further substituted;
x is an integer of 0-6;
y is an integer of 0 to 6;
z is an integer of 0 to 6;
n1 is 0, 1,2 or 3; and is
n2 is 0, 1,2 or 3.
2. The compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof according to claim 1, wherein ring B is selected from C3-12Cycloalkyl radicals3-12 membered heterocyclic group, C6-14Aryl or 5-14 membered heteroaryl; preferably C6-14Aryl or 5-14 membered heteroaryl, more preferably phenyl, benzo 5-8 membered nitrogen containing heterocyclyl, benzo 5-8 membered nitrogen containing heteroaryl, further selected from the group consisting of:
Figure FDA0002645089070000021
3. a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that ring C is selected from C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl; preferably C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl, more preferably cyclobutyl, piperidinyl, phenyl, pyridinyl or morpholinyl, further selected from the group consisting of:
Figure FDA0002645089070000031
4. the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R isaSelected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)ORaa、-(CH2)n1ORaa、-(CH2)n1SRaa、-(CH2)n1NRaaC(O)Rbb、-C(RaaRbb)n1(CH2)n2ORcc、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1NRaaC(O)NRbbRcc、-(CH2)n1NRaaRbb、-NRaa(CH2)n1Rbb、-(CH2)n1C(O)NRaaRbb、-(CH2)n1C(O)Raa、-OC(RaaRbb)n1(CH2)n2Rcc、-(CH2)n1S(O)n2RaaOr- (CH)2)n1NRaaS(O)n2RbbSaid amino group, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
preferably hydrogen, oxo, C1-6Alkyl radical, C2-6Alkenyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, - (CH)2)n1NRaaRbb、-(CH2)n1SRaa、-(CH2)n1C(O)NRaaRbb、-(CH2)n1NRaaC(O)Rbbor-C (R)aaRbb)n1(CH2)n2ORccSaid C is1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, 3-8 membered heterocyclyl and 5-10 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl;
more preferably hydrogen, oxo, methyl, ethyl, isopropyl, difluoroisobutyl, methyldiazolyl, vinyl, cyclopropyl, cyclobutyl, -NRaaRbb、-SRaa、-C(O)NRaaRbb、-NRaaC(O)Rbbor-C (R)aaRbb)n1(CH2)n2ORcc；
Raa～RccN1 and n2 are as defined in claim 1.
5. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R isbSelected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl radical, C6-14Aryloxy, 5-14 membered heteroaryl, 5-14 membered heteroaryloxy, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)ORaa、-(CH2)n1ORaa、-(CH2)n1SRaa、-(CH2)n1NRaaC(O)Rbb、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1NRaaC(O)NRbbRcc、-(CH2)n1NRaaRbb、-NRaa(CH2)n1Rbb、-(CH2)n1C(O)NRaaRbb、-(CH2)n1C(O)Raa、-OC(RaaRbb)n1(CH2)n2Rcc、-(CH2)n1S(O)n2RaaOr- (CH)2)n1NRaaS(O)n2RbbSaid amino group, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl radical, C6-14Aryloxy, 5-14 membered heteroaryl and 5-14 membered heteroaryloxy, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
preferably hydrogen, halogen, oxo, C1-3Alkyl, -ORaaor-C (O) NRaaRbb；
Raa～RccN1 and n2 are as defined in claim 1.
6. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R isbSelected from hydrogen, halogen, oxo, C1-6Alkyl, - (CH)2)n1ORaa、-(CH2)n1C(O)NRaaRbb、-(CH2)n1NRaaC(O)Rbb、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1S(O)n2Raa、-(CH2)n1S(O)n2NRaaRbb、-(CH2)n1NRaaS(O)n2Rbb、-(CH2)n1S(O)(＝NRaa)Rbb、-(CH2)n1NRaaS(O)(＝NRbb)RccOr- (CH)2)n1NRaaS(O)n2NRbbRcc；
Preferably hydrogen, halogen, oxo, C1-3Alkyl, -ORaa、-C(O)NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)ORbb、-S(O)2Raa、-S(O)2NRaaRbb、-NRaaS(O)2Rbb、-S(O)(＝NRaa)Rbb、-NRaaS(O)(＝NRbb)Rccor-NRaaS(O)2NRbbRcc；
Further preferred is hydrogen, fluorine, chlorine, bromine, oxo, methyl, ethyl, isopropyl, -C (O) NHCH3、-C(O)NHC(CH3)CH2OCH3、-NHC(O)OCH3、-NHC(O)CHF2、-NHS(O)2CH3、-NHS(O)2N(CH3)2、-S(O)2CH3、-S(O)2NHCH3、-S(O)2N(CH3)2、-S(O)2NHCH(CH3)2、-S(O)(＝NH)CH3、-NHS(O)(＝NH)CH3、
Figure FDA0002645089070000041
Figure FDA0002645089070000042
Figure FDA0002645089070000051
7. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R iscSelected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n1C(O)Raa、-(CH2)n1C(O)ORaaOr- (CH)2)n1C(O)NRaaRbbSaid amino group, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
preferably hydrogen, halogen, C1-3Alkyl, halophenyl, -C (O) RaaOR-C (O) ORaa；
Raa～RbbAnd n1 is as claimed in claim 1.
8. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1,Raa、Rbband RccEach independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-to 14-membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
or, Raa、RbbAnd RccAny two links forming C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-12 membered heteroaryl, said C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl.
9. The compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 1, further represented by formula (II):
Figure FDA0002645089070000061
10. the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, further represented by formula (III):
Figure FDA0002645089070000062
wherein:
M1selected from N or CR9(ii) a Preferably N, CH or CF;
R9、R10and R13Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl,C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
preferably hydrogen, fluorine, chlorine, bromine or iodine;
R11and R12Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)ORaa、-(CH2)n1ORaa、-(CH2)n1SRaa、-(CH2)n1NRaaC(O)Rbb、-C(RaaRbb)n1(CH2)n2ORcc、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1NRaaC(O)NRbbRcc、-(CH2)n1NRaaRbb、-NRaa(CH2)n1Rbb、-(CH2)n1C(O)NRaaRbb、-(CH2)n1C(O)Raa、-OC(RaaRbb)n1(CH2)n2Rcc、-(CH2)n1S(O)n2RaaOr- (CH)2)n1NRaaS(O)n2RbbSaid amino group, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
preferably hydrogen, methyl, ethyl, isopropyl, vinyl, methoxy, methylthio, cyclopropyl, cyclobutyl or-NHCH3；
Or, R11And R12Linked to the carbon atom to which it is attached to form C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
R11and R12A ring linked to the carbon atom to which it is attached, preferably a 5-6 membered nitrogen containing heterocyclyl or heteroaryl, a 5-6 membered oxygen containing heterocyclyl or heteroaryl or a 5-6 membered sulfur containing heterocyclyl or heteroaryl;
further preferred are the following groups:
Figure FDA0002645089070000071
R14selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)ORaa、-(CH2)n1ORaa、-(CH2)n1SRaa、-(CH2)n1NRaaC(O)Rbb、-C(RaaRbb)n1(CH2)n2ORcc、-(CH2)n1NRaaC(O)ORbb、-(CH2)n1NRaaC(O)NRbbRcc、-(CH2)n1NRaaRbb、-NRaa(CH2)n1Rbb、-(CH2)n1C(O)NRaaRbb、-(CH2)n1C(O)Raa、-OC(RaaRbb)n1(CH2)n2Rcc、-(CH2)n1S(O)n2RaaOr- (CH)2)n1NRaaS(O)n2RbbSaid amino group, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkanesBase, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
preferably hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, -C (O) OCH3、-C(O)CH2CH3or-C (O) OCH2CH3。
11. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 10, wherein R is14Selected from hydrogen, halogen, C1-6Alkyl, halophenyl, - (CH)2)n1C(O)Raa、-(CH2)n1C(O)ORaa、-(CH2)n1S(O)n2RaaOr- (CH)2)n1S(O)n2NRaaRbb；
Preferably hydrogen, halogen, C1-6Alkyl, halophenyl, -C (O) Raa、-C(O)ORaa、-S(O)2Raaor-S (O)2NRaaRbb(ii) a More preferably hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, -C (O) OCH3、-C(O)CH2CH3、-C(O)CHF2、-C(O)OCH2CH3、-S(O)2CH3、-S(O)2CH2CH3、-S(O)2N(CH3)2、
Figure FDA0002645089070000081
12. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 10, further represented by general formula (IV):
Figure FDA0002645089070000082
wherein:
R14is-C (O) Raa；
RaaIs selected from C1-6Alkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
preferably C1-3Alkyl radical, C1-3Haloalkyl or C1-3An alkoxy group;
more preferably methyl, ethyl, difluoromethyl, methoxy or ethoxy.
13. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, characterized in that it is selected from the following compounds:
Figure FDA0002645089070000091
Figure FDA0002645089070000101
Figure FDA0002645089070000111
14. a process for preparing the compound of claim 12, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the process for preparing the compound of the general formula (IV),
Figure FDA0002645089070000112
carrying out condensation reaction on the compound shown in the general formula (IV-1) or the salt thereof and the compound shown in the general formula (IV-2) to obtain the compound shown in the general formula (IV) or a stereoisomer and a pharmaceutically acceptable salt thereof;
wherein the content of the first and second substances,
x is selected from hydroxyl, chlorine or bromine;
R14is-C (O) Raa；
RaaIs selected from C1-6Alkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
preferably C1-3Alkyl radical, C1-3Haloalkyl or C1-3An alkoxy group;
more preferably methyl, ethyl, difluoromethyl, methoxy or ethoxy.
15. A compound shown as an intermediate formula (IV-1) or a salt thereof for preparing the compound shown as the general formula (IV) or the stereoisomer or the pharmaceutically acceptable salt thereof according to claim 12,
Figure FDA0002645089070000121
16. a process for producing the compound represented by the general formula (IV-1) or a salt thereof according to claim 15, which comprises the steps of,
Figure FDA0002645089070000122
deprotection of the general formula (IV-3) to obtain a compound represented by the formula (IV-1) or a salt thereof;
wherein:
Pg1is an amino protecting group selected from allyloxycarbonyl, trifluoroacetyl, 2, 4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, fluorenyl methoxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl or p-methoxyphenyl; tert-butyloxycarbonyl is preferred.
17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 13, in association with one or more pharmaceutically acceptable carriers, diluents or excipients.
18. Use of a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 17 for the preparation of a P2X3 inhibitor medicament.
19. Use of a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 17, for the preparation of a medicament for the treatment of a neurogenic disease; wherein the neurogenic disease is selected from a gynecological disease, a urinary tract disease state, a respiratory disorder disease or a pain related disease or disorder.
20. The use according to claim 19, wherein the disease is selected from endometriosis, overactive bladder, pulmonary fibrosis or chronic cough.
21. Use according to claim 19, wherein the pain-related disease or condition is selected from neuropathic pain or pain and discomfort associated with uterine fibroids.
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