CN111757878A - Pyridazine derivative inhibitor, and preparation method and application thereof - Google Patents
Pyridazine derivative inhibitor, and preparation method and application thereof Download PDFInfo
- Publication number
- CN111757878A CN111757878A CN202080001485.XA CN202080001485A CN111757878A CN 111757878 A CN111757878 A CN 111757878A CN 202080001485 A CN202080001485 A CN 202080001485A CN 111757878 A CN111757878 A CN 111757878A
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- China
- Prior art keywords
- cycloalkyl
- alkyl
- radical
- amino
- cyano
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title abstract description 203
- 239000003112 inhibitor Substances 0.000 title abstract description 4
- 150000004892 pyridazines Chemical class 0.000 title abstract description 4
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 229940123371 Tyrosine kinase 2 inhibitor Drugs 0.000 claims abstract description 4
- -1 amino, mercapto Chemical group 0.000 claims description 830
- 125000000623 heterocyclic group Chemical group 0.000 claims description 252
- 150000003254 radicals Chemical class 0.000 claims description 226
- 229910052739 hydrogen Inorganic materials 0.000 claims description 215
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 209
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 153
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- 150000002367 halogens Chemical group 0.000 claims description 128
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 111
- 125000003118 aryl group Chemical group 0.000 claims description 91
- 229910052760 oxygen Inorganic materials 0.000 claims description 75
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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Abstract
The invention relates to a pyridazine derivative inhibitor, and a preparation method and application thereof. In particular to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application thereof in preparing TYK2 inhibitor medicaments.
Description
The invention belongs to the field of medicine synthesis, and particularly relates to a pyridazine derivative inhibitor and a preparation method and application thereof.
Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates the signaling and activation of various cytokines. The JAK kinase family is divided into four subtypes of JAK1, JAK2, JAK3 and TYK2, each subtype mediates different types of cytokine signal pathways, JAK-1, JAK-2 and TYK-2 are expressed in each tissue cell of a human body, and JAK-3 is mainly expressed in each hematopoietic tissue cell. A common feature of cytokine receptors is that the receptor itself has no kinase activity, but the intracellular segment of the receptor has a binding site for the tyrosine kinase JAK. After the cell factor receptor is combined with a ligand thereof, JAKs coupled with the receptor are activated, so that the receptor is phosphorylated, a phosphorylated tyrosine site can be combined with STAT protein containing an SH2 structural domain, STAT is recruited to the receptor and is phosphorylated through JAKs, then phosphotyrosine mediates STAT dimerization, and the activated STAT dimer is transferred to a cell nucleus and activates target gene transcription of the cell nucleus, so that multiple functions of growth, activation, differentiation and the like of multiple cells are regulated.
TYK2 is a subtype discovered at the earliest in JAK family, mediates the functions of cytokines such as IFN-alpha, IL-6, IL-10, IL-12, IL-23 and the like, and researches show that the deletion mutation of TYK2 can effectively inhibit the generation of immunological diseases such as allergy, autoimmunity, inflammation and the like. IL-23 plays a crucial role in the development process of psoriasis, and recent research shows that the pathogenesis of psoriasis is that endogenous unknown antigen activates antigen presenting cells, APC secretes IL-23, IL-23 activates Th17 cells and secretes cytokines such as IL-17, etc., keratinocyte differentiation and division are induced, IL-23 is secreted, and inflammation and keratinocyte proliferation are further stimulated to generate psoriasis. TYK2 and JAK2 jointly mediate a downstream signal pathway of IL-23, and inhibition of JAK2 can cause anemia and other blood-related side effects, so that targeting TYK2 is a good strategy for inhibiting the IL-23 signal pathway to treat psoriasis.
Early TYK2 inhibitors such as Tofacitinib belong to JAK non-selective inhibitors, are the first oral JAK inhibitors, and have obvious inhibitory activity on JAK1, 2 and 3 subtypes. The activity inhibition of other subtypes such as JAK1, JAK2 and JAK3 increases the curative effect of tofacitinib, but also brings more serious side effects, and adverse reactions comprise infection, tuberculosis, tumor, anemia, liver injury, cholesterol increase and the like. Because the activity of JAK2 is related to erythroid cell differentiation and lipid metabolism processes, part of adverse reactions such as anemia are considered to be possibly related to insufficient selectivity of Tofacitinib on JAK-2, and are caused by non-selective inhibition of the medicine. At present, no TYK2 selective inhibitor is on the market, and the early JAK inhibitor mainly plays a role by competing the binding of a kinase domain and ATP, so that the problem of low selectivity generally exists.
The compound is intermediate between the good curative effect of the JAK non-selective inhibitor and the relevant serious side effect of various targets, and the development of a TYK2 selective inhibitor medicament with higher safety has huge clinical application potential for treating inflammatory diseases such as psoriasis and the like. BMS international applications WO2015069310A1 and WO2018081488A1 report TYK2 selective inhibitors, and developed BMS-986165 achieves good curative effect in the second clinical stage at present and enters the third clinical stage, so that the advantages of the TYK2 selective inhibitors are reflected, and the TYK2 selective inhibitors have great clinical application values.
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:
wherein:
r is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -ORaa、-SRaa、-C(O)Raa、-C(O)ORaa、-S(O)m1Raa、-NRaaRbb、-C(O)NRaaRbb、-NRaaC(O)Rbbor-NRaaS(O)m1Rbb;
R1Selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, -Raa、-(CH2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-NRaaCRbb=NRcc、-NRaaCRbb=CRccRdd、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1Raa、-(CH2)n1NRaaC(O)C(O)RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R2selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, -Raa、-C(O)Raa、-(CH2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-NRaaCRbb=NRcc、-NRaaCRbb=CRccRdd、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R3selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl or alkynyl;
R4、R5、R6and R7In the presence or absence, selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-SRaa、-(CH2)n1C(O)Raa、-C(O)ORaa、-S(O)m1Raa、-NRaaRbb、-C(O)NRaaRbb、-NRaaC(O)Rbbor-NRaaS(O)m1Rbb;
Or, R4And R6Or R6And R7Linked to form a cycloalkyl, heterocyclyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxy, alkoxy, heteroaryl, alkoxy, heteroaryl, and heteroarylAlkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
Raa、Rbb、Rccand RddEach independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
or, any two adjacent or non-adjacent Raa、Rbb、RccAnd Rdd(ii) linked to form a cycloalkyl, heterocyclyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
x is an integer of 0, 1,2 or 3;
m1 is an integer of 0, 1 or 2; and is
n1 is an integer of 0, 1,2, 3, 4 or 5.
The preferable scheme is as follows: r is selected from hydrogen, deuterium and C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy, halogen, amino, mercapto, -ORaa、-SRaa、-S(O)m1Raaor-NRaaRbbPreferably hydrogen, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy, halo C1-3Alkoxy, fluoro, chloro, bromo, -ORaa、-SRaa、-S(O)m1Raaor-NRaaRbbMore preferably hydrogen, methyl, ethyl, propyl, FCH2-、F2CH-、F3C-、ClCH2-、Cl2CH-、Cl3C-、CH3O-、CH3CH2O-、CH3CH2CH2O-、FCH2O-、F2CHO-、F3CO-, fluoro, chloro, -ORaa、-SRaa、-S(O)m1Raaor-NRaaRbbFurther, CH is preferable3O-、(CH3)2N-、CH3S-、F3CO-、F2HCO-, F-or CH3S(O)2-;
Wherein R isaaOr RbbEach independently selected from hydrogen, deuterium, hydroxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl, cyano, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Cycloalkyl or 3-7 membered heterocyclyl, preferably hydrogen, hydroxy, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl, cyano, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl or 3-6 membered heterocyclyl containing 1-3N, O or S atoms, more preferably hydrogen, methyl, ethyl, -CD3、-CD2CD3Propyl, hydroxymethyl, hydroxyethyl, ethenyl, propenyl, ethynyl, propynyl, FCH2-、F2CH-、F3C-, cyano, cyclopropyl, cyclobutyl, cyclohexyl, epoxyethyl, epoxypropyl, epoxybutyl, epoxypentyl, tetrahydropyrrolyl or piperidinyl; further preferably hydrogen, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;
R1is selected from C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl, 3-7 membered heteroaryl, -NRcC(O)Rd、-NRcC(O)NRdRe、-NRcS(O)m1Rd、-NRcCRd=NRe、-NRcCRd=CReRf、-NRcC(O)ORd、-(CH2)n1S(O)m1Rc、-(CH2)n1NRcC(O)C(O)RgOr- (CH)2)n1NRcS(O)m1Rd、-NRcCRdReRf、-NRcC(S)Rd、-OC=ONRcRdor-CReRfC=ONRcRdPreferably C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl, 3-6 membered heteroaryl, -NRcC(O)Rd、-NRcC(O)NRdRe、-NRcS(O)m1Rd、-NRcCRd=NRe、-NRcCRd=CReRf、-NRcC(O)ORd、-(CH2)n1S(O)m1Rc、-(CH2)n1NRcC(O)C(O)RgOr- (CH)2)n1NRcS(O)m1Rd、-NRcCRdReRf、-NRcC(S)Rd、-OC=ONRcRdor-CReRfC=ONRcRdMore preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl with 1-3N, O or S atoms, phenyl, naphthyl, 3-6 membered heteroaryl with 1-3N, O or S atoms, -NRcC(O)Rd、-NRcC(O)NRdRe、-NRcS(O)m1Rd、-NRcCRd=NRe、-NRcCRd=CReRf、-NRcC(O)ORd、-(CH2)n1S(O)m1Rc、-(CH2)n1NRcC(O)C(O)RgOr- (CH)2)n1NRcS(O)m1Rd、-NRcCRdReRf、-NRcC(S)Rd、-OC=ONRcRdor-CReRfC=ONRcRdFurther, it is preferable
Rc、Rd、Re、RfOr RgEach independently selected from hydrogen, deuterium, hydroxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, halogen, cyano, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-12Aryl and 3-7 membered heteroaryl, preferably hydrogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, cyano, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl and 3-6 membered heteroaryl containing 1-3N, O or S atoms, more preferably hydrogen, methyl, ethyl, -CD3、-CD2CD3Propyl, hydroxymethyl, hydroxyethyl, ethenyl, propenyl, ethynyl, propynyl, FCH2-、F2CH-、F3C-, cyano, fluoro, chloro, CH3O-、CH3CH2O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Further preferred are hydrogen, methyl, ethyl, -CD3、-CD2CD3Propyl, hydroxymethyl, hydroxyethyl, ethenyl, propenyl, ethynyl, propynyl, FCH2-、F2CH-、F3C-, cyano, fluoro, chloro, CH3O-、CH3CH2O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Or, any two adjacent or non-adjacent Rc、Rd、ReOr RfAre linked to form a C3-7Cycloalkyl, 3-7 membered heterocyclyl, aryl and 3-7 membered heteroaryl, preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-12Aryl and 3-6 membered heteroaryl, more preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl and 3-6 membered heteroaryl having 1-2N, O or S atoms, further preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Further preferred are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
R2Is selected from C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl, 3-7 membered heteroaryl, C1-6Hydroxyalkyl, -C (O) Rhh、-(CH2)n1ORii、-(CH2)n1NRhhRii、-NRhhC(O)Rii、-NRhhC(O)NRiiRjj、-C(O)NRhhRii、-NRhhS(O)m1Rii、-NRhhCRii=NRjj、-NRhhCRii=CRjjRkk、-(CH2)n1S(O)m1NRhhRii、-(CH2)n1C(O)Rhh、-NRhhC(O)ORii、-(CH2)n1S(O)m1RhhOr- (CH)2)n1NRhhS(O)m1RiiWherein said C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl or 3-7 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Alkoxy or C3-6One or more substituents in the cycloalkyl group; preferably C3-6Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, C6-10Aryl, substituted or unsubstituted 3-6 membered heteroaryl, C1-3Hydroxyalkyl, -C (O) Rhh、-(CH2)n1ORii、-(CH2)n1NRhhRii、-NRhhC(O)Rii、-NRhhC(O)NRiiRjj、-C(O)NRhhRii、-NRhhS(O)m1Rii、-NRhhCRii=NRjj、-NRhhCRii=CRjjRkk、-(CH2)n1S(O)m1NRhhRii、-(CH2)n1C(O)Rhh、-NRhhC(O)ORii、-(CH2)n1S(O)m1RhhOr- (CH)2)n1NRhhS(O)m1RiiWherein said C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl or 3-7 membered heteroaryl, optionally substituted by hydrogen, deuterium, fluoro, chloro, bromo, C1-3Alkyl or C3-5One or more substituents in the cycloalkyl group; more preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, phenyl, naphthyl, 3-6 membered heteroaryl containing 1-3N, O or S atoms, C1-3Hydroxyalkyl, -C (O) Rhh、-(CH2)n1ORii、-(CH2)n1NRhhRii、-C(O)NRhhRii、-(CH2)n1S(O)m1NRhhRii、-(CH2)n1C(O)Rhh、-(CH2)n1S(O)m1RhhOr- (CH)2)n1NRhhS(O)m1RiiWherein said C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl or 3-7 membered heteroaryl, optionally substituted with one or more substituents of hydrogen, deuterium, fluoro, chloro, bromo, methyl, ethyl, propyl, cyclopropyl, cyclopentyl or cyclohexyl; further preferred is HOCH2-、HOCH2CH2-、HOCH2C(O)-、CH3NHC(O)-、D3CNHC(O)-、CH3NHS(O)2-、D3CNHS(O)2-、
Rhh、Rii、RjjOr RkkEach independently selected from hydrogen, deuterium, hydroxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, halogen, cyano, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl or 3-6 membered heterocyclyl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, cyano, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl or 3-6 membered heterocyclyl containing 1-3N, O or S atoms, more preferably hydrogen, deuterium, methyl, ethyl, -CD3、-CD2CD3Propyl, hydroxymethyl, hydroxyethyl, ethenyl, propenyl, ethynyl, propynyl, FCH2-、F2CH-、F3C-, cyano, fluoro, chloro, CH3O-、CH3CH2O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, tetrahydropyrrole or piperidinyl;
R3selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy or cyano, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy or cyano, more preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, fluoro, chloro, hydroxy or cyano;
R4、R5、R6and R7In the presence or absence, selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy, cyano, oxo, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Cycloalkyl, 3-7 membered heterocyclyl, aryl, 3-7 membered heteroaryl, - (CH)2)n1Rll、-(CH2)n1ORll、-SRll、-(CH2)n1C(O)Rll、-C(O)ORll、-S(O)m1Rll、-NRllRmm、-C(O)NRllRmm、-NRllC(O)Rmmor-NRllS(O)m1RmmPreferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy, cyano, oxo, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C6-12Aryl, 3-6 membered heteroaryl containing 1-3N, O or S atoms, - (CH)2)n1Rll、-(CH2)n1ORll、-SRll、-(CH2)n1C(O)Rll、-C(O)ORll、-S(O)m1Rll、-NRllRmm、-C(O)NRllRmm、-NRllC(O)Rmmor-NRllS(O)m1RmmMore preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy, cyano, oxo, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl, 3-6 membered heteroaryl containing 1-3N, O or S atoms, - (CH)2)n1Rll、-(CH2)n1ORllor-NRllRmmMore preferred are hydrogen, methyl, ethyl, propyl, isopropyl, butyl and (CH)3)3C-、CF3CH2-, fluorine, chlorine, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, vinyl, CH2=CHCH2-, ethynyl group,Cyano, CNCH2-、CNCH2CH2-、CH3OCH2-、CH3OCH2CH2-、CF3C(CH3)2-、
RllOr RmmEach independently selected from hydrogen, deuterium, hydroxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, halogen, cyano, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl or 3-6 membered heterocyclyl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, cyano, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl or 3-6 membered heterocyclyl containing 1-3N, O or S atoms, more preferably hydrogen, deuterium, methyl, ethyl, -CD3、-CD2CD3Propyl, hydroxymethyl, hydroxyethyl, ethenyl, propenyl, ethynyl, propynyl, FCH2-、F2CH-、F3C-, cyano, fluoro, chloro, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, tetrahydropyrrolyl or piperidinyl;
or, R4And R6Or R6And R7Linked to form a heterocyclic or heteroaryl group, wherein said heterocyclic or heteroaryl group is optionally substituted with hydrogen, deuterium, halogen, C1-6Alkyl or C3-6One or more substituents in the cycloalkyl group; preferably 3-6 membered heterocyclyl or 3-7 membered heteroarylWherein said heterocyclyl or heteroaryl is optionally substituted by hydrogen, deuterium, fluoro, chloro, bromo, C1-3Alkyl or C3-5One or more substituents in the cycloalkyl group; more preferably a 3-6 membered heterocyclyl containing 1-3N, O or S atoms or a 3-7 membered heteroaryl containing 1-3N, O or S atoms, wherein said heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, cyclopropyl, cyclopentyl and cyclohexyl; further preferred is
The invention also provides a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is further shown in the general formula (II):
wherein:
R~R6and x is as described in formula (I).
The invention also provides a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is further shown in the general formula (III):
wherein:
R、R1、R3~R6and x is as described in formula (I).
The invention also provides a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is further shown in the general formula (IV):
wherein:
ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably a heteroaryl group;
R8selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably hydrogen, halogen, amino, cyano, alkyl, haloalkyl or cycloalkyl;
y is 0, 1,2 or 3;
R、R1、R3~R6and x is as described in formula (I). The preferable scheme is as follows: ring A is selected from C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl or 3-7 membered heteroaryl, preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 3-6 membered heteroaryl, more preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, phenyl, naphthyl or3-6 membered heteroaryl having 1-3N, O or S atoms, further preferred Further preferred is
R8Selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-6Haloalkyl, hydroxy, amino, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl and 3-7 membered heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-3Haloalkyl, hydroxy, amino, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl and 3-6 membered heteroaryl containing 1-3N, O or S atoms, more preferably hydrogen, deuterium, methyl, ethyl, propyl, chloro-substituted methyl, chloro-substituted ethyl, fluoro-substituted methyl, fluoro-substituted ethyl, fluoro, chloro, bromo, cyano, nitro, hydroxy, amino, ethenyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bromo,
the invention also provides a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is further shown in the general formula (V):
wherein:
R9selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-SRaa、-(CH2)n1C(O)Raa、-C(O)ORaa、-S(O)m1Raa、-NRaaRbb、-C(O)NRaaRbb、-NRaaC(O)Rbbor-NRaaS(O)m1RbbWherein said alkyl, haloalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, haloalkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R、R3~R6、Raa、Rbband x is as described in formula (I).
The preferable scheme is as follows: r9Selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-6Haloalkyl, hydroxy, amino, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Cycloalkyl radicals3-7 membered heterocyclic group, C6-12Aryl or 3-7 membered heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-SRaa、-(CH2)n1C(O)Raa、-C(O)ORaa、-S(O)m1Raa、-NRaaRbb、-C(O)NRaaRbb、-NRaaC(O)Rbbor-NRaaS(O)m1RbbPreferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-3Haloalkyl, hydroxy, amino, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 3-6 membered heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-SRaa、-(CH2)n1C(O)Raa、-C(O)ORaa、-S(O)m1Raa、-NRaaRbb、-C(O)NRaaRbb、-NRaaC(O)Rbbor-NRaaS(O)m1RbbMore preferably hydrogen, deuterium, hydroxy-substituted C1-3Alkyl radical, C1-3Cycloalkyl-substituted C1-3Alkyl, hydroxy substituted C1-3Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-3Haloalkyl, hydroxy, C3-6Cycloalkyl-substituted amino, halogen-substituted C2-5Alkenyl, halogen substituted C2-5Alkynyl, halogen substituted C3-6Cycloalkyl radical, C1-3Alkyl substituted C3-6Cycloalkyl, cyano-substituted C3-6Cycloalkyl radical, C1-3Alkoxy-substituted C3-6Cycloalkyl radical, C1-3Haloalkyl-substituted C3-6Cycloalkyl, 3-7 membered heterocyclyl having 1-3N, O or S atoms, phenyl, naphthyl or 3-7 membered heteroaryl having 1-3N, O or S atoms, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)Raaor-NRaaRbbFurther preferred is
RaaOr RbbIndependently selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, halogen, cyano, nitro, C1-6Haloalkyl, hydroxy, amino, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl or 3-7 membered heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-3Haloalkyl, hydroxy, amino, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl or 3-7 membered heteroaryl containing 1-3N, O or S atoms, more preferably hydrogen, methyl, ethyl, propyl, fluoro, chloro, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl or biphenyl;
m1 is 0, 1,2 or 3;
n1 is 0, 1,2 or 3.
The present invention also provides a preferred embodiment, wherein the compound represented by the general formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof, is further represented by the general formula (VI):
wherein:
ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably a heteroaryl group;
R10selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkylHeterocyclyl, aryl and heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably hydrogen, halogen, amino, cyano, alkyl, haloalkyl or cycloalkyl;
z is 0, 1,2 or 3;
R、R3~R6and x is as described in formula (I). The preferable scheme is as follows: ring B is selected from C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl or 3-7 membered heteroaryl, preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 3-6 membered heteroaryl, more preferably C3-6Cycloalkyl, 3-6 membered heterocyclic group containing 1-3N, O or S atoms, phenyl, naphthyl or 3-6 membered heteroaryl group containing 1-3N, O or S atoms, and further preferred is Further preferred is
R10 is selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-6Haloalkyl groupHydroxy, amino, alkenyl, alkynyl, C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl and 3-7 membered heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-3Haloalkyl, hydroxy, amino, alkenyl, alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl or 3-6 membered heteroaryl containing 1-3N, O or S atoms, more preferably hydrogen, methyl, ethyl, propyl, fluoro, chloro, hydroxy, amino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The invention also provides a preferable scheme, the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is further shown in the general formula (VII):
wherein:
m is S, NRccOr CRccRdd;
R11Selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterated alkyl, deuterium, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably hydrogen, halogen, amino, cyano, alkyl, haloalkyl or cycloalkyl;
Rccand RddEach independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
or RccAnd Rdd(ii) linked to form a cycloalkyl or heterocyclyl, wherein said cycloalkyl or heterocyclyl is optionally further substituted with one or more substituents selected from deuterated alkyl, deuterium, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R、R3~R6and x is as described in formula (I).
R11Selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, halogen, cyano, nitro, C1-6Haloalkyl, hydroxy, amino, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-12Aryl and 3-8 membered heteroaryl, preferably hydrogen, C1-3Alkyl radical, C1-3Deuterated alkyl, halogen, amino, cyano, alkyl, C1-3Haloalkyl or C3-5Cycloalkyl, more preferably methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoro, chloro, bromo, difluoromethyl, difluoroethyl, trifluoromethyl or trifluoroethyl;
Rccand RddEach independently selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, fluoro, chloro, bromo, cyano, nitro, hydroxy, amino, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-12Aryl or 3-6 membered heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, fluoro, chloro, bromo, cyano, nitro, hydroxy, amino, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S, C6-10Aryl or a 3-6 membered heteroaryl group containing 1-3N, O or S, more preferably hydrogen, methyl, ethyl, propyl, fluoro, chloro, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, hydroxy or cyano;
or RccAnd RddAre linked to form a C3-6Cycloalkyl or 3-6 membered heterocyclyl, preferably C3-6Cycloalkyl or a 3-6 membered heterocyclic group containing 1-3N, O or S, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
The invention also provides a preferable scheme, wherein the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is further shown in a general formula (VIII):
wherein:
R3~R6and x is as described in formula (I).
Preferably, the solution is
R3Selected from hydrogen, deuterium, fluorine, chlorine or bromine, preferably hydrogen, deuterium or fluorine, more preferably hydrogen or fluorine;
R4is selected from C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, wherein said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, optionally further substituted one or more substituents selected from methyl, ethyl, fluoro or chloroSubstituted; preferably C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C3-5Cycloalkyl, 3-5 membered heterocyclyl, more preferably C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C3-5Cycloalkyl, a 3-to 5-membered heterocyclic group containing 1 to 3N, O or S atoms, more preferably methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
R5or R6Each independently is hydrogen or deuterium;
x is 0, 1,2 or 3.
The invention also provides a preferable scheme, any one of the compounds shown in the general formulas, the stereoisomer or the pharmaceutically acceptable salt thereof, wherein,
ring a and ring B are selected from the following groups:
the invention also provides a preferable scheme, any one of the general formulas, the stereoisomer or the pharmaceutically acceptable salt thereof, wherein,
r is selected from hydrogen and C1-6Alkoxy radical, C1-6Haloalkoxy, -ORaa、-SRaaor-NRaaRbb;
R1Selected from 3-8 membered heterocyclyl, 5-8 membered heteroaryl, - (CH)2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(=S)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaC(O)ORbb、-NRaaS(O)m1Rbb、-(CH2)n1NRaaC(O)C(O)Raa、-NRaaCRbb=NRccor-NRaaCRbb=CRccRddWherein said 3-8 membered heterocyclyl and 5-8 membered heteroaryl are optionally further selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, halogen, hydroxy, amino, cyano, oxo and C3-8Cycloalkyl substituted with one or more substituents;
R2selected from 3-8 membered heterocyclyl, 5-8 membered heteroaryl, -C (O) Raa、-(CH2)n1ORaa、-C(O)NRaaRbbor-S (O)m1NRaaRbbWherein said 3-8 membered heterocyclyl and 5-8 membered heteroaryl are optionally further selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, halogen, hydroxy, amino, cyano and C3-8Cycloalkyl substituted with one or more substituents;
R3selected from hydrogen, halogen, cyano, C1-6Alkyl or C1-6A haloalkyl group;
R5selected from hydrogen, halogen, cyano, C1-6Alkyl or C1-6A haloalkyl group;
R4and R6Each independently selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl or- (CH)2)n1Raa(ii) a Preferably hydrogen, cyclopropyl or
Or R4And R6Are linked to form a C3-8A cycloalkyl group; preferably a cyclopentyl group;
R7selected from absent, hydrogen, halogen, cyano, C1-6Alkyl or C1-6A haloalkyl group;
or R6And R7Are linked to form a C3-8A cycloalkyl group; preferably a cyclopentyl group;
R8and R10Each independently selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl or C3-8A cycloalkyl group;
R9selected from hydrogen, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)Raa、-C(O)ORaa、-NRaaRbbor-C (O) NRaaRbbWherein said C1-6Alkyl radical, C3-8Cycloalkyl and 3-8 membered heterocyclyl are optionally further selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, halogen, hydroxy, amino, oxo, nitro, cyano, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl and 5-8 membered heteroaryl;
R11selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, halogen, cyano, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl or 5-8 membered heteroaryl;
Raa、Rbb、Rccand RddEach independently selected from hydrogen, deuterium, cyano, halogen, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein said C is1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl and 5-8 membered heteroaryl optionally further substituted with one or more substituents selected from hydrogen, deuterium, C1-6Alkyl, halogen, hydroxy, amino, oxo, cyano, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl, hydroxyalkyl,C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl and 5-8 membered heteroaryl;
or, RccAnd RddAre linked to form a C3-8Cycloalkyl, wherein said C3-8Cycloalkyl is optionally further selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, halogen, amino, oxo, cyano, hydroxy, C1-6Alkoxy radical, C1-6Haloalkoxy and C1-6Substituted with one or more substituents in the hydroxyalkyl group.
The invention also relates to a technical scheme, and provides a compound shown as a general formula (IX), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein:
ring C is selected from the following groups:
R12independently selected from-ORee、-C(O)NReeRff、-(CH2)n1NReeRffor-S (O)m2NReeRff;
R17Selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl or- (CH)2)n1Raa;
ReeAnd RffEach independently selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein said C is1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl and 5-8 membered heteroaryl optionally further substituted with one or more substituents selected from hydrogen, deuterium, C1-6Alkyl, halogen, hydroxy, amino, oxo, cyano, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl and 5-8 membered heteroaryl;
n1 is 0, 1 or 2;
m2 is 0, 1 or 2, and
q is 0, 1,2 or 3.
The preferable scheme is as follows:
R17Selected from hydrogen, halogen, cyano, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Haloalkyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl or- (CH)2)n1RaaPreferably hydrogen, halogen, cyano, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C substituted by 1-3 fluorine, chlorine or bromine atoms1-3Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms or- (CH)2)n1RaaMore preferred is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxocyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, thietanyl, allyl, propargyl, CF3CH2-、(CH3)2CF3C-、CN-、CNCH2-、CNCH2CH2-、
RaaSelected from alkoxy, hydroxyalkyl, haloalkoxy, nitro, hydroxy, cyano, amino, aryl or heteroaryl, preferably C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, nitro, hydroxy, cyano, amino, C6-12Aryl or 3-12 membered heteroaryl, more preferably C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, nitro, hydroxy, cyano, amino, C6-10Aryl or 5-to 8-membered heteroaryl, further preferably methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, C substituted with 1 to 3 fluorine, chlorine or bromine atoms1-3Alkoxy, nitro, hydroxy, cyano, amino, aryl and 3-6 membered heteroaryl containing 1-3N, O or S atoms;
n1 is 1 or 2.
The invention also relates to a technical scheme, and provides a compound shown as a general formula (X), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein:
R13and R14Each independently selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl;
R15selected from 3-8 membered heterocyclyl, 5-8 membered heteroaryl, - (CH)2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(=S)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaC(O)ORbb、-NRaaS(O)m1Rbb、-(CH2)n1NRaaC(O)C(O)Raa、-NRaaCRbb=NRccor-NRaaCRbb=CRccRddWherein said 3-8 membered heterocyclyl and 5-8 membered heteroaryl are optionally further selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, halogen, hydroxy, amino, cyano and C3-8Cycloalkyl substituted with one or more substituents;
R16selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl or- (CH)2)n1Raa;
Raa、Rbb、RccAnd RddEach independently selected from hydrogen, deuterium, cyano, halogen, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein said C is1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl and 5-8 membered heteroaryl, optionally further substituted by a group selected from hydrogen, deuterium, C1-6Alkyl, halogen, hydroxy, amino, oxo, cyano, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl and 5-8 membered heteroaryl;
n1 is 0, 1 or 2; and is
m1 is 0, 1 or 2.
The invention also relates to a technical scheme, and provides a compound shown as a general formula (XI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein:
R18selected from hydrogen, deuterium, halogen, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-8 membered heterocyclyl or- (CH)2)n1RaaPreferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, hydroxy, cyano, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl or- (CH)2)n1RaaMore preferably hydrogen, methyl, cyclopropyl, methyl, ethyl, propyl, isopropyl,
R19Selected from hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, amino, hydroxy or cyano, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, amino, hydroxy or cyano, more preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, fluoro, chloro, hydroxy or cyano;
Raaselected from hydrogen, deuterium, cyano, hydroxy, halogen, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl or 3-8 membered heterocyclyl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy, fluorine, chlorine, bromine, cyano, C2-5Alkenyl radical, C2-5Alkynyl or C3-6Cycloalkyl, more preferably hydrogen, methyl, ethynyl or cyclopropyl;
n1 is 0, 1 or 2;
r is 0, 1,2 or 3.
The invention also relates to a technical scheme, a method for preparing the compound shown in the general formula (V) or the stereoisomer and the pharmaceutically acceptable salt thereof, which comprises the following steps,
the general formula (V-1) reacts with the general formula (V-2) to obtain a general formula (V-3), and the general formula (V-3) further reacts to obtain a compound shown in the general formula (V) or a stereoisomer and pharmaceutically acceptable salts thereof;
wherein:
x is selected from halogen;
R3~R6、R9and x is as described for formula (V).
The invention also relates to a technical scheme, a method for preparing the compound shown in the general formula (V) or the stereoisomer and the pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps,
the general formula (V-4) reacts with the general formula (V-5) to obtain a general formula (V-6), the general formula (V-6) further reacts with the general formula (V-2) to obtain a compound shown by the general formula (V) or a stereoisomer and pharmaceutically acceptable salts thereof;
wherein:
x is selected from halogen;
R3~R6、R9and x is as described for formula (V).
The invention also relates to a technical scheme, a pharmaceutical composition, which comprises therapeutically effective dose of the compound of the general formula (I), the compound of the general formula (IX) and the compound of the general formula (X), the stereoisomer or the pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention also relates to a technical scheme, and the application of the compound of the general formula (I), the compound of the general formula (IX) shown in any one, the compound of the general formula (X) shown in any one, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of TYK2 inhibitor drugs.
The invention also relates to a technical scheme, the application of the compound of the general formula (I), the compound of the general formula (IX) and the compound of the general formula (X) and the stereoisomer or the pharmaceutically acceptable salt thereof, or the application of the pharmaceutical composition in preparing medicines for treating inflammatory diseases and autoimmune diseases; wherein the inflammatory and autoimmune diseases are selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease).
The invention further relates to a method for preparing a compound shown in the general formula (I), a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating inflammatory diseases.
The invention also relates to a method for the treatment, prevention and/or treatment of a pre-prepared treatment for an autoimmune 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 TYK2 kinase dysfunction.
The present invention also relates to a method of treating a hyperproliferative disorder in a mammal comprising administering to said 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 the treatment of conditions such as cancer, bone disease, inflammatory disease, immune disease, neurological disease, metabolic disease, respiratory disease, and cardiac disease.
In some embodiments, the present methods relate to the inflammatory and autoimmune diseases are selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and crohn's disease).
The methods of treatment provided herein comprise administering to a subject a therapeutically effective amount of a compound of the invention. In one embodiment, the invention provides a method of treating an inflammatory disorder, including an autoimmune disease, in a mammal. The method comprises 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.
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, and 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, halogen, 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, alkoxyAlkyl sulfide, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, heterocyclic alkyl, aryl, heteroaryl, naphthenic oxy, heterocyclic alkoxy, naphthenic sulfide and heterocyclic alkyl sulfide.
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 8 carbon atoms, and most 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 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:
spirocycloalkyl groups also containing a single spirocycloalkyl group with a heterocycloalkyl group sharing a spiro atom, non-limiting examples include:
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:
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:
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 monocyclic or polycyclic cyclic hydrocarbon substituent, which isContaining 3 to 20 ring atoms, wherein one or more 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. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, thietanyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetanyl, pyrrolidinonyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl 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 3 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 none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified 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, according to the number of spiro atoms shared between rings. More preferably a 3-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl group. Non-limiting examples of spiro heterocyclic groups include:
the term "fused heterocyclic radical" means5-to 20-membered polycyclic heterocyclic groups in which each ring in the system shares an adjacent pair of atoms with other rings in the system, 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, wherein 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 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 3-to 5-membered, 4-to 5-membered or 5-to 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
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 completely 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 preferably 7 to 10. 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:
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:
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 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
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 10 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 triazolyl, thienyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl and thiazolyl; more preferably triazolyl, pyrrolyl, thienyl, thiazolyl, pyridyl and pyrimidinyl. 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:
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.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH2。
"cyano" means-CN.
"nitro" means-NO2。
"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.
"DMAP" refers to 4-dimethylaminopyridine.
"SEM-Cl" refers to chloromethyl trimethylsilylethyl ether.
"Xantphos" refers to 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene.
"DCM" refers to dichloromethane.
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.
Figure 1 is the results of PASI scoring of different compounds in an imiquimod-induced mouse psoriasis model.
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 () 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 carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 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
6- (bicyclo [ 1.1.1)]Pentane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
The first step is as follows: preparation of 2-methoxy-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline
3-bromo-2-methoxyaniline (2.02g,10mmol), bis-pinacolylboron (3.05g,12mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (816.6mg,1mmol), potassium acetate (2.45g,25mmol) were mixed in dioxane (20mL), the reaction system was replaced with nitrogen three times, reacted at 100 ℃ overnight, cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was washed with water and CH2Cl2The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound, 2-methoxy-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (2.0g, 80%).
1H NMR(400MHz,CDCl3)1.36(s,12H),3.83(s,3H),6.92-6.99(m,2H),7.16-7.20(m,2H);
MS m/z(ESI):250.1[M+H]+.
The second step is that: preparation of 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline
2-methoxy-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (2.0g,8mmol), 3-bromo-1-methyl-1H-1, 2, 4-triazole (1.61g,10mmol), Cs2CO3(7.6g,20mmol), tetrakis (triphenylphosphine) palladium (924.5mg,0.8mmol), mixed in 1,4-dioxane (40mL) and water (5mL), the reaction system was replaced with nitrogen three times, reacted at 100 ℃ overnight, cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was washed with water and CH2Cl2The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound, 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (1.14g, 70%).
1H NMR(400MHz,CDCl3)3.77(s,3H),3.99(s,3H),6.81-6.86(m,1H),6.96-7.02(m,1H),7.32-7.37(m,1H),8.1(s,1H);
MS m/z(ESI):205.1[M+H]+.
The third step: preparation of lithium 4, 6-dichloropyridazine-3-carboxylate
Methyl 4, 6-dichloropyridazine-3-carboxylate (2.07g,10mmol), lithium bromide (2.6g,30mmol) were dissolved in acetonitrile (20mL) and water (2mL), cooled to 0 deg.C, DIPEA (5.2mL,30mmol) was added dropwise, the mixture was allowed to naturally warm to room temperature and reacted for 1 hour, the reaction solution was filtered, the filter cake was washed with acetonitrile (2 mL. times.4), the filter cake was collected and dried to give the title compound, lithium 4, 6-dichloropyridazine-3-carboxylate (1.73g, 87%).
MS m/z(ESI):193.1[M+H]+.
The fourth step: preparation of ((6-chloro-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazine-3-carbonyl) oxo) zinc
2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (1.02g,5.0mmol), lithium 4, 6-dichloropyridazine-3-carboxylate (1.19g,6.0mmol) and zinc acetate (1.1g,6.0mmol) were mixed in isopropanol (1mL) and water (7mL) and reacted at 65 ℃ overnight. The reaction was cooled to room temperature, water (6mL) was added, stirring was carried out for 1H, the reaction solution was filtered, the filter cake was washed with water (6mL × 2) and THF (6mL), the filter cake was collected, and drying was carried out to give the title compound ((6-chloro-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazine-3-carbonyl) oxo) zinc (1.44g, 73%).
MS m/z(ESI):361.1[M+H]+.
The fifth step: preparation of ((6- (bicyclo [1.1.1] pentane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazine-3-carbonyl) oxo) zinc
((6-chloro-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazine-3-carbonyl) oxo) Zinc (157mg,0.4mmol), bicyclo [1.1.1]Pentane-1-carboxamide (111mg,1.0mmol), DBU (61mg,0.4mmol), potassium carbonate (110mg,0.8mmol) were mixed in toluene (1.2mL) and acetonitrile (0.6mL), palladium acetate (4.5mg,0.02mmol) and (R) - (-) -1- [ (S) -2- (dicyclohexylphosphine) ferrocene were added]Ethyl di-tert-butylphosphine (22mg,0.04mmol), reaction three times with nitrogen substitution, reaction at 75 ℃ overnight, reaction cooled to room temperature, water (4mL) and acetic acid (2mL) added, washed with petroleum ether (6mL × 2), aqueous phase separated, water (2mL), CH, added to the aqueous phase2Cl2(5mL × 3) and the organic phases were combined, washed with saturated aqueous NaCl solution, the separated organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to give the title compound ((6- (bicyclo [ 1.1.1.1)]Pentane-1-carboxamido) -4- ((2-methyl)Oxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazine-3-carbonyl) oxo) zinc (122mg, 65.2%).
MS m/z(ESI):436.2[M+H]+.
And a sixth step: 6- (bicyclo [ 1.1.1)]Pentane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
((6- (bicyclo [ 1.1.1)]Pentane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazine-3-carbonyl) oxo) zinc (94mg,0.2mmol), deuterated methylamine hydrochloride (71mg,1.0mmol), DIPEA (258mg,2.0mmol) were mixed in DMF (1mL), HATU (380mg,1.0mmol) was added, and reaction was carried out overnight at 40 ℃. The reaction was cooled to room temperature and saturated aqueous sodium bicarbonate solution was used with CH2Cl2Separating, washing the organic phase with saturated NaCl aqueous solution, drying with anhydrous sodium sulfate, concentrating the organic solvent under reduced pressure, and performing column chromatography to obtain the title compound 6- (bicyclo [ 1.1.1)]Pentane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamide (41mg, 45%).
1H NMR(400MHz,CDCl3)2.17(s,6H),2.53(s,1H),3.80(s,3H),4.00(s,3H),7.23-7.29(m,1H),7.51(dd,J=7.9,1.3Hz,1H),7.81(dd,J=7.9,1.4Hz,1H),8.09-8.14(m,2H),8.21(s,1H),8.39(s,1H),11.03(s,1H);
MS m/z(ESI):452.2[M+H]+.
Example 2
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- (oxetanyl-3-carboxamido) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- (oxetanyl-3-carboxamido) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):442.2[M+H]+.
Example 3
6- (Cyclobutanecarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
6- (Cyclobutanecarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)1.85-2.05(m,2H),2.16-2.27(m,2H),2.45-2.33(m,2H),3.33-3.43(m,1H),3.82(s,3H),4.01(s,3H),7.26-7.33(m,1H),7.55(dd,J=7.0Hz,1H),7.83(dd,J=7.8,1.1Hz,1H),8.03-8.15(m,2H),8.29(s,1H),9.18(s,1H),11.06(s,1H);
MS m/z(ESI):440.2[M+H]+.
Example 4
6- ((1R,2R) -2-fluorocyclopropane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
6- ((1R,2R) -2-fluorocyclopropane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)1.18-1.28(m,1H),1.88-2.06(m,2H),3.81(s,3H),4.01(s,3H),4.65-4.95(m,1H),7.24-7.30(m,1H),7.53(dd,J=7.9,1.3Hz,1H),7.81(dd,J=7.9,1.4Hz,1H),8.02(s,1H),8.11(s,1H),8.27(s,1H),9.82(s,1H),11.07(s,1H);
MS m/z(ESI):444.2[M+H]+.
Example 5
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- ((1S,2R) -2-methylcyclopropane-1-carboxamido) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- ((1S,2R) -2-methylcyclopropane-1-carboxamido) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):440.2[M+H]+.
Example 6
6- ((3-cyclopropyloxetan-3-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
6- ((3-cyclopropyloxetan-3-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):454.2[M+H]+.
Example 7
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- ((3-methyloxetan-3-yl) amino) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- ((3-methyloxetan-3-yl) amino) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):428.2[M+H]+.
Example 8
6- ((1-cyclopropyl-2, 2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
6- ((1-cyclopropyl-2, 2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):480.2[M+H]+.
Example 9
(R) -6- ((1-cyclopropyl-2, 2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
(R) -6- ((1-cyclopropyl-2, 2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):480.2[M+H]+.
Example 10
(S) -6- ((1-cyclopropyl-2, 2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) ammoniaRadical) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
(S) -6- ((1-cyclopropyl-2, 2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):480.2[M+H]+.
Example 11
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- ((1,1, 1-trifluoropropan-2-yl) amino) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- ((1,1, 1-trifluoropropan-2-yl) amino) pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):454.2[M+H]+.
Example 12
(R) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- ((1,1, 1-trifluoropropan-2-yl) amino) pyridazine-3-carboxamide
(R) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- ((1,1, 1-trifluoropropan-2-yl) amino) pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):454.2[M+H]+.
Example 13
(S) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- ((1,1, 1-trifluoropropan-2-yl) amino) pyridazine-3-carboxamide
(S) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- ((1,1, 1-trifluoropropan-2-yl) amino) pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):454.2[M+H]+.
Example 14
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- (1-methylcyclopropane-1-carboxamido) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- (1-methylcyclopropane-1-carboxamido) pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CD3OD)0.77-0.78(m,2H),1.23-1.25(m,2H),1.48(s,3H),3.73(s,3H),4.01(s,3H),7.32(t,J=8.0Hz,1H),7.58(dd,J=8.0,1.2Hz,1H),7.68(dd,J=8.0,1.2Hz,1H),8.18(s,1H),8.47(s,1H);
MS m/z(ESI):440.2[M+H]+.
Example 15
6- (1-cyanocyclopropane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
6- (1-cyanocyclopropane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)1.20-1.31(m,2H),1.63-1.67(m,2H),3.76(s,3H),4.01(s,3H),7.23-7.27(m,1H),7.45(dd,J=8.0,1.2Hz,1H),7.80(dd,J=8.0,1.2Hz,1H),7.96(s,1H),8.11(s,1H),8.16(br s,1H),9.00(br s,1H),10.99(br s,1H);
MS m/z(ESI):451.2[M+H]+.
Example 16
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- (1- (trifluoromethyl) cyclopropane-1-carboxamido) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- (1- (trifluoromethyl) cyclopropane-1-carboxamido) pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CD3OD)1.28-1.38(m,2H),1.40-1.48(m,2H),3.73(s,3H),4.01(s,3H),7.29-7.33(m,1H),7.58(dd,J=8.0,1.2Hz,1H),7.70(dd,J=8.0,1.2Hz,1H),8.12(s,1H),8.48(s,1H);
MS m/z(ESI):494.2[M+H]+.
Example 17
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (1-methoxycyclopropane-1-carboxamido) -N- (methyl-d)3) Preparation of pyridazine-3-carboxamides
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (1-methoxycyclopropane-1-carboxamido) -N- (methyl-d)3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):456.2[M+H]+.
Example 18
(S) -6- (2, 2-dimethylcyclopropane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
(S) -6- (2, 2-dimethylcyclopropane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):454.2[M+H]+.
Example 19
(R) -6- (2, 2-dimethylcyclopropane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
(R) -6- (2, 2-dimethylcyclopropane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):454.2[M+H]+.
Example 20
(R) -6- (2, 2-difluorocyclopropane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
(R) -6- (2, 2-difluorocyclopropane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):462.2[M+H]+.
Example 21
(S) -6- (2, 2-difluorocyclopropane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
(S) -6- (2, 2-difluorocyclopropane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):462.2[M+H]+.
Example 22
6- (Cyclopropanesulfonylamino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
6- (Cyclopropanesulfonylamino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CD3OD)0.80-0.87(m,2H),0.90-0.93(m,2H),2.51-2.55(m,1H),3.65(s,3H),3.92(s,3H),7.08(s,1H),7.21(t,J=8.20Hz,1H),7.48(dd,J=8.0,1.2Hz,1H),7.62(dd,J=8.0,1.2Hz,1H),8.38(s,1H);
MS m/z(ESI):462.2[M+H]+.
Example 23
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- ((methyl-d)3) Preparation of carbamoyl) pyridazin-3-yl) morpholine-4-carboxamide
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- ((methyl-d)3) Preparation of carbamoyl) pyridazin-3-yl) morpholine-4-carboxamide reference is made to example 1.
MS m/z(ESI):471.2[M+H]+.
Example 24
6- (3-Cyclopropylureido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
6- (3-Cyclopropylureido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)0.64-0.66(m,2H),0.82-0.87(m,2H),2.71-2.73(m,1H),3.79(s,3H),4.01(s,3H),7.23-7.27(m,1H),7.45(dd,J=8.0,1.2Hz,1H),7.84(dd,J=8.0,1.2Hz,1H),8.11(s,1H),11.01(br s,1H);
MS m/z(ESI):441.2[M+H]+.
Example 25
Cyclopropyl (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- ((methyl-d)3) Preparation of carbamoyl) pyridazin-3-yl) carbamates
Cyclopropyl (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- ((methyl-d)3) Preparation of carbamoyl) pyridazin-3-yl) carbamates reference is made to example 1.
MS m/z(ESI):442.2[M+H]+.
Example 26
6- (2-Cyclopropylacetylamino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
6- (2-Cyclopropylacetylamino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CD3OD)0.24-0.28(m,2H),0.57-0.61(m,2H),1.12-1.15(m,1H),2.37(d,J=8.0Hz,2H),3.76(s,3H),4.04(s,3H),7.32(t,J=8.0Hz,1H),7.64(dd,J=8.0,1.2Hz,1H),7.70(dd,J=8.0,1.2Hz,1H),8.20(s,1H),8.50(s,1H);
MS m/z(ESI):440.2[M+H]+.
Example 27
(E) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxycyclopropanecarboxamido) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
(E) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxycyclopropanecarbonylIminimido) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):455.2[M+H]+.
Example 28
(E) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxyacetyiiminoamido) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
(E) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxyacetyiiminoamido) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):429.2[M+H]+.
Example 29
(Z) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxycyclopropanecarboxamido) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
(Z) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxycyclopropanecarboxamido) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):455.2[M+H]+.
Example 30
(Z) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxyacetyiiminoamido) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
(Z) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxyacetyiiminoamido) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):429.2[M+H]+.
Example 31
(E) -6- (N' -Cyanocyclopropanecarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
(E) -6- (N' -Cyanocyclopropanecarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):450.2[M+H]+.
Example 32
(E) -6- (N' -cyanoacetimidoamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
(E) -6- (N' -cyanoacetimidoamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):424.2[M+H]+.
Example 33
(Z) -6- (N' -Cyanocyclopropanecarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d)3) Preparation of pyridazine-3-carboxamides
(Z) -6- (N' -Cyanocyclopropanecarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):450.2[M+H]+.
Example 34
(Z) -6- (N' -cyanoacetimidoamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
(Z) -6- (N' -cyanoacetimidoamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):424.2[M+H]+.
Example 35
6- ((cyclopropylidenefluoromethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
6- ((cyclopropylidenefluoromethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):428.2[M+H]+.
Example 36
(Z) -6- ((1-fluoroprop-1-en-1-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
(Z) -6- ((1-fluoroprop-1-en-1-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):416.2[M+H]+.
Example 37
6- ((1-cyclopropyl-2, 2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
6- ((1-cyclopropyl-2, 2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):478.2[M+H]+.
Example 38
(E) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- ((1,1, 1-trifluorobut-2-en-2-yl) amino) pyridazine-3-carboxamide
(E) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3)-6-((1,1,1-Preparation of trifluorobut-2-en-2-yl) amino) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):466.2[M+H]+.
Example 39
6- ((1-cyclopropyl-2, 2-difluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
6- ((1-cyclopropyl-2, 2-difluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):460.2[M+H]+.
Example 40
(E) -6- ((1, 1-difluorobut-2-en-2-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
(E) -6- ((1, 1-difluorobut-2-en-2-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):448.2[M+H]+.
EXAMPLE 41
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- ((1-methylcyclopropyl) amino) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- ((1-methylcyclopropyl) amino) pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):412.2[M+H]+.
Example 42
6- (5-cyclopropyl-4H-1, 2, 4-triazol-3-yl) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamides
6- (5-cyclopropyl-4H-1, 2, 4-triazol-3-yl) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):450.2[M+H]+.
Example 43
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) -6- (5-methyl-4H-1, 2, 4-triazol-3-yl) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- (5-methyl-4H-1, 2, 4-triazol-3-yl) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):424.2[M+H]+.
Example 44
6- (5-cyclopropyl-1H-imidazol-2-yl) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamides
6- (5-cyclopropyl-1H-imidazol-2-yl) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):449.2[M+H]+.
Example 45
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) -6- (5-methyl-1H-imidazol-2-yl) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- (5-methyl-1H-imidazol-2-yl) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):423.2[M+H]+.
Example 46
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) -6- (pyridine-2-sulfonylamino) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- (pyridine-2-sulfonylamino) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):499.2[M+H]+.
Example 47
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) -6- ((1-methyl-1H-pyrazole) -3-sulfonylamino) pyridazine-3-Carboxamides
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -6- ((1-methyl-1H-pyrazole) -3-sulfonylamino) pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):502.2[M+H]+.
Example 48
6- (Cyclopropanecarboxamido) -4- ((2- (dimethylamino) -3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamides
6- (Cyclopropanecarboxamido) -4- ((2- (dimethylamino) -3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):439.2[M+H]+.
Example 49
6- (Cyclopropanecarboxamido) -N- (methyl-d3) -4- ((3- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylthio) phenyl) amino) pyridazine-3-carboxamide
6- (Cyclopropanecarboxamido) -N- (methyl-d3) Preparation of (e) -4- ((3- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylthio) phenyl) amino) pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)0.87-0.92(m,2H),1.09-1.12(m,2H),1.88-1.96(m,1H),2.27(s,3H),3.99(s,3H),7.41-7.49(m,2H),7.57-7.59(m,1H),8.04(s,1H),8.14(s,1H),8.30(s,1H),10.20(s,1H),11.30(s,1H);
MS m/z(ESI):442.2[M+H]+.
Example 50
6- (Cyclopropanecarboxamido) -N- (methyl-d3) -4- ((3- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (trifluoromethoxy) phenyl) amino) pyridazine-3-carboxamide
6- (Cyclopropanecarboxamido) -N- (methyl-d3) Preparation of (E) -4- ((3- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (trifluoromethoxy) phenyl) amino) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):480.2[M+H]+.
Example 51
6- (Cyclopropanecarboxamido) -4- ((2- (difluoromethoxy) -3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamides
6- (Cyclopropanecarboxamido) -4- ((2- (difluoromethoxy) -3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)0.85-0.99(m,2H),1.03-1.12(m,2H),1.73-1.81(m,1H),4.00(s,3H),6.63-7.01(m,1H),7.43-7.48(m,1H),7.54-7.58(m,1H),7.92-7.99(m,2H),8.08-8.16(m,2H),9.83(s,1H),11.16(s,1H);
MS m/z(ESI):462.2[M+H]+.
Example 52
6- (Cyclopropanecarboxamido) -4- ((6-fluoro-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamides
6- (Cyclopropanecarboxamido) -4- ((6-fluoro-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)0.84-0.95(m,2H),1.02-1.11(m,2H),1.67-1.76(m,1H),3.78(s,3H),4.00(s,3H),7.06-7.13(m,1H),7.63-7.67(m,1H),7.91-7.97(m,1H),7.98-8.02(m,1H),8.08-8.12(m,1H),9.77(s,1H),10.80(s,1H);
MS m/z(ESI):444.2[M+H]+.
Example 53
6- (Cyclopropanecarboxamido) -4- ((6-fluoro-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamides
6- (Cyclopropanecarboxamido) -4- ((6-fluoro-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)0.89-0.94(m,2H),1.11-1.15(m,2H),1.78-1.84(m,1H),3.81(s,3H),4.01(s,3H),7.23-7.26(m,1H),7.53-7.56(m,1H),8.04(s,1H),8.11(s,1H),8.30(s,1H),9.73(s,1H),11.17(s,1H);
MS m/z(ESI):444.2[M+H]+.
Example 54
6- (Cyclopropanecarboxamido) -4- ((4-fluoro-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamides
6- (Cyclopropanecarboxamido) -4- ((4-fluoro-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):444.2[M+H]+.
Example 55
4- ((6-cyano-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d3) Pyridazine-3-carboxamides
4- ((6-cyano-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):451.2[M+H]+.
Example 56
4- ((5-cyano-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d3) Pyridazine-3-carboxamides
4- ((5-cyano-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):451.2[M+H]+.
Example 57
4- ((4-cyano-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d3) Pyridazine-3-carboxamides
4- ((4-cyano-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):451.2[M+H]+.
Example 58
6- (Cyclopropanecarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamides
First step preparation of 2-methoxy-3-nitrobenzamide
Methyl 2-methoxy-3-nitrophenylate (5g,23.7mmol), dissolved in methanolic ammonia (100mL,7M), was added aqueous ammonia (28 wt%, 50mL) at room temperature, the mixture was stirred overnight at room temperature, diluted with ethyl acetate (300mL) and the organic phase was successively diluted with saturated NaHCO3The organic phase was separated and dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure and column chromatography was performed to give the title compound, 2-methoxy-3-nitrobenzamide (4.3g, 92%).
MS m/z(ESI):197.1[M+H]+.
Second step preparation of 3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole
2-methoxy-3-nitrobenzamide (4.2g,21.4mmol) was dissolved in DMF-DMA (28.6ml)Heating to 95 ℃ for reaction for 1 hour, and concentrating under reduced pressure to obtain a crude DMF-DMA addition product, which is dissolved in ethanol (20mL) for use. After stirring for 5 minutes, hydrazine hydrate (80 wt.%, 10.5mL) was slowly added dropwise and stirring was continued for 15 minutes, then an ethanol solution of the above crude DMF-DMA addition product was added dropwise, slowly warmed to room temperature, and stirring was continued for 4 hours at room temperature. The reaction was concentrated under reduced pressure, diluted with ethyl acetate (300mL) and the organic phase was successively diluted with saturated NaHCO3The title compound, 3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (4.5g, 95%), was obtained by washing the aqueous solution (300mL × 2) with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography.
MS m/z(ESI):221.1[M+H]+.
The third step is the preparation of 1-cyclopropyl-3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole
3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (200mg,0.91mmol), copper acetate (198mg,1.1mmol), 2, 2' -bipyridine (170mg,1.1mmol), and sodium carbonate (192mg,1.8mmol) were mixed in 1, 2-dichloroethane (5mL), cyclopropylboronic acid (234mg,2.72mmol) was added at room temperature, and the mixture was heated to 85 ℃ and stirred overnight. After the reaction solution was cooled to room temperature, it was diluted with a large amount of ethyl acetate. The organic phase was washed with saturated brine several times, then the separated organic phase was dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure and column chromatography was performed to separate the title compound, 1-cyclopropyl-3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (125mg, 53%).
1H NMR(400MHz,CDCl3)1.15-1.21(m,2H),1.24-1.29(m,2H),3.70-3.79(m,1H),3.94(s,3H),7.23-7.31(m,1H),7.78-7.81(m,1H),8.20-8.23(m,1H),8.36(s,1H);
MS m/z(ESI):261.1[M+H]+.
Fourth step preparation of 3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyaniline
To a solution of 1-cyclopropyl-3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (120mg,0.46mmol) in methanol (5mL) was added palladium on carbon (30mg), and the mixture was reacted under a hydrogen atmosphere at normal temperature and pressure for 12 hours, followed by filtering off the catalyst with celite. The filtrate was concentrated under reduced pressure to give the title compound, 3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyaniline (102mg), which was used directly in the next reaction.
MS m/z(ESI):231.1[M+H]+.
Fifth step preparation of Zinc 6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylate
3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyaniline (100mg,0.4mmol), lithium 4, 6-dichloropyridazine-3-carboxylate (103.7mg,0.5mmol) and zinc acetate (95.6mg,0.5mmol) were mixed in isopropanol (0.5mL) and water (3.5mL) and heated to 80 ℃ for reaction overnight. The reaction was cooled to room temperature, water (3mL) was added, stirring was carried out for 1H, the reaction was filtered, the filter cake was washed with water (3 mL. times.2) and THF (2mL), and the filter cake was collected and dried to give the title compound, zinc 6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylate (130mg, 78%).
MS m/z(ESI):387.1[M+H]+.
Sixth step preparation of Zinc 6- (Cyclopropanecarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylate
6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) ammoniaYl) pyridazine-3-carboxylic acid zinc (130mg,0.31mmol), cyclopropylamide (86mg,1.0mmol), DBU (61mg,0.4mmol), potassium carbonate (110mg,0.8mmol) were mixed in toluene (1.2mL) and acetonitrile (0.6mL), and palladium acetate (4.5mg,0.02mmol) and (R) - (-) -1- [ (S) -2- (dicyclohexylphosphine) ferrocene were added]Ethyl di-tert-butylphosphine (22mg,0.04mmol), the reaction system was replaced with nitrogen three times, heated to 75 ℃ for reaction overnight, the reaction was cooled to room temperature, water (4mL) and acetic acid (2mL) were added, washed with petroleum ether (6mL × 2), the aqueous phase was separated, and water (2mL), CH, was added to the aqueous phase2Cl2(5mL × 3) and the combined organic phases were washed with saturated aqueous NaCl solution, the separated organic phase was dried over anhydrous sodium sulfate and the organic solvent was concentrated under reduced pressure to give the title compound zinc 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylate (109mg, 75%).
MS m/z(ESI):436.1[M+H]+.
Seventh step preparation of 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Zinc 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylate (90mg,0.19mmol), deuterated methylamine hydrochloride (71mg,1.0mmol), DIPEA (258mg,2.0mmol) were mixed in DMF (1mL), HATU (380mg,1.0mmol) was added, and the mixture was reacted at 50 ℃ overnight. The reaction was cooled to room temperature and saturated aqueous sodium bicarbonate solution was used with CH2Cl2The organic phase was washed with saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (35mg, 38%).
1H NMR(400MHz,CDCl3)0.86-0.99(m,2H),1.07-1.18(m,4H),1.22-1.26(m,2H),1.73-1.82(m,1H),3.65-3.72(m,1H),3.81(s,3H),7.27-7.29(m,1H),7.48-7.52(m,1H),7.81-7.84(m,1H),7.96(s,1H),8.17-8.24(m,2H),9.87(s,1H),11.27(s,1H);
MS m/z(ESI):452.2[M+H]+.
Example 59
6- (Cyclopropanecarboxamido) -4- ((3- (1-isopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamides
6- (Cyclopropanecarboxamido) -4- ((3- (1-isopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide example 58 was referenced.
MS m/z(ESI):454.2[M+H]+.
Example 60
6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (oxetan-3-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamides
6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (oxetan-3-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide example 58 was referenced.
1H NMR(400MHz,CDCl3)0.90-0.96(m,2H),1.08-1.13(m,2H),1.74-1.80(m,1H),3.87(s,3H),5.07-5.09(m,2H),5.17-5.21(m,2H),5.57-5.64(m,1H),7.27-7.32(m,1H),7.53-7.56(m,1H),7.84-7.87(m,1H),8.02(s,1H),8.23-8.27(m,2H),9.64(s,1H),11.21(s,1H);
MS m/z(ESI):468.2[M+H]+.
Example 61
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1- (2-methoxyethyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl)-d3) Pyridazine-3-carboxamides
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1- (2-methoxyethyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide example 58 was referenced.
1H NMR(400MHz,CDCl3)0.80-0.95(m,2H),1.05-1.15(m,2H),1.85-1.93(m,1H),3.35(s,3H),3.77-3.86(m,5H),4.36-4.44(m,2H),7.23-7.30(m,1H),7.52(dd,J=7.6Hz,1H),7.82(dd,J=7.7Hz,1H),8.02(s,1H),8.17-8.30(m,2H),10.14 (s,1H),11.06(s,1H);
MS m/z(ESI):470.2[M+H]+.
Example 62
4- ((3- (1- (2-cyanoethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d3) Pyridazine-3-carboxamides
4- ((3- (1- (2-cyanoethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide example 58 was referenced.
1H NMR(400MHz,CDCl3)0.86-0.94(m,2H),1.07-1.12(m,2H),1.22-1.26(m,2H),1.74-1.80(m,1H),3.08(t,J=8.0Hz,2H),3.81(s,3H),4.53(t,J=8.0Hz,2H),7.27-7.31(m,1H),7.53-7.55(m,1H),7.81-7.83(m,1H),8.05(s,1H),8.23(s,1H),8.26(s,1H),9.57(br s,1H),11.11(br s,1H);
MS m/z(ESI):465.2[M+H]+.
Example 63
6- (Cyclopropanecarboxamido) -4- ((3- (6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl) -2-methoxyphenyl) amino-N- (methyl-d3) Pyridazine-3-methylAmides of carboxylic acids
6- (Cyclopropanecarboxamido) -4- ((3- (6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl) -2-methoxyphenyl) amino-N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)0.90-0.95(m,2H),1.08-1.12(m,2H),1.68-1.75(m,1H),2.72-2.79(m,2H),2.98-3.05(m,2H),3.80(s,3H),4.21-4.27(m,2H), 7.23-7.28(m,1H),7.46-7.49(m,1H),7.81-7.84(m,1H),8.00(s,1H),8.19(s,1H),9.42(s,1H),11.12(s,1H);
MS m/z(ESI):452.2[M+H]+.
Example 64
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamides
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)0.94-1.02(m,2H),1.07-1.11(m,2H),1.76-1.84(m,1H),3.48(s,3H),3.83(s,3H),7.30-7.42(m,2H),7.57-7.61(m,1H),7.97-8.02(m,2H),8.19(s,1H),9.97(s,1H),11.28(s,1H);
MS m/z(ESI):426.2[M+H]+.
Example 65
6- (Cyclopropanecarboxamido) -4- ((3- (6, 7-dihydro-5H-pyrrolo [2, 1-c)][1,2,4]Triazol-3-yl) -2-methoxyphenyl) amino-N- (methyl-d3) Pyridazine-3-carboxamides
6- (Cyclopropanecarboxamido) -4- ((3- (6, 7-dihydro-5H-pyrrolo [2, 1-c)][1,2,4]Triazol-3-yl) -2-methoxyphenyl) amino-N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)0.91-0.97(m,2H),1.08-1.12(m,2H),1.96-2.02(m,2H),1.71-1.76(m,1H),2.76-2.80(m,2H),3.13-3.16(m,2H),3.57(s,3H),4.16-4.19(m,2H),7.41-7.43(m,1H),7.50-7.52(m,1H),7.69-7.71(m,1H),7.79(s,1H),8.09(s,1H),11.84(s,1H);
MS m/z(ESI):452.2[M+H]+.
Example 66
6- (Cyclopropanecarboxamido) -4- ((3- (5-fluoro-1-methyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamides
6- (Cyclopropanecarboxamido) -4- ((3- (5-fluoro-1-methyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):444.2[M+H]+.
Example 67
6- (Cyclopropanecarboxamido) -5-fluoro-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamides
6- (Cyclopropanecarboxamido) -5-fluoro-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):444.2[M+H]+.
Example 68
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5-methyl-N- (methyl-d)3) Pyridazine-3-carboxamides
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5-methyl-N- (methyl-d)3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):440.2[M+H]+.
Example 69
5-cyano-6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamides
5-cyano-6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):451.2[M+H]+.
Example 70
N- (6- (1H-imidazol-2-yl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide
Preparation of N- (6- (1H-imidazol-2-yl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide reference is made to example 1.
MS m/z(ESI):432.2[M+H]+.
Example 71
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (4H-1,2, 4-triazol-3-yl) pyridazin-3-yl) cyclopropanecarboxamide
Preparation of N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (4H-1,2, 4-triazol-3-yl) pyridazin-3-yl) cyclopropanecarboxamide reference is made to example 1.
MS m/z(ESI):433.2[M+H]+.
Example 72
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (1H-tetrazol-5-yl) pyridazin-3-yl) cyclopropanecarboxamide
Preparation of N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (1H-tetrazol-5-yl) pyridazin-3-yl) cyclopropanecarboxamide reference is made to example 1.
MS m/z(ESI):434.2[M+H]+.
Example 73
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (5-methyl-1H-imidazol-2-yl) pyridazin-3-yl) cyclopropanecarboxamide
Preparation of N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (5-methyl-1H-imidazol-2-yl) pyridazin-3-yl) cyclopropanecarboxamide reference is made to example 1.
MS m/z(ESI):446.2[M+H]+.
Example 74
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (5-methyl-4H-1, 2, 4-triazol-3-yl) pyridazin-3-yl) cyclopropanecarboxamide
Preparation of N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (5-methyl-4H-1, 2, 4-triazol-3-yl) pyridazin-3-yl) cyclopropanecarboxamide reference is made to example 1.
MS m/z(ESI):447.2[M+H]+.
Example 75
N- (6- (5-cyclopropyl-1H-imidazol-2-yl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide
Preparation of N- (6- (5-cyclopropyl-1H-imidazol-2-yl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide reference is made to example 1.
MS m/z(ESI):472.2[M+H]+.
Example 76
N- (6- (5-cyclopropyl-4H-1, 2, 4-triazol-3-yl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide
Preparation of N- (6- (5-cyclopropyl-4H-1, 2, 4-triazol-3-yl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide reference is made to example 1.
MS m/z(ESI):473.2[M+H]+.
Example 77
N6-cyclopropyl-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N3- (methyl-d)3) Pyridazine-3, 6-dicarboxamides
N6-cyclopropyl-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N3- (methyl-d)3) Preparation of pyridazine-3, 6-dicarboxamide reference example 1.
1H NMR(400MHz,CDCl3)0.67-0.72(m,2H).0.86-0.90(m,2H),2.92-2.99(m,1H),3.79(s,3H),4.02(s,3H),7.23-7.27(m,1H),7.43-7.45(m,1H),7.88-7.90(m,2H),8.16(s,1H),8.22(s,1H),8.29(s,1H),11.15(s,1H);
MS m/z(ESI):426.2[M+H]+.
Example 78
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N- (methyl-d)3) Sulphonamide) pyridazin-3-yl) cyclopropanecarboxamides
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N- (methyl-d)3) Sulfonamide) pyridazin-3-yl) cyclopropanecarboxamide preparation method reference was made to example 1.
MS m/z(ESI):462.2[M+H]+.
Example 79
N- (6- (hydroxymethyl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide
Preparation of N- (6- (hydroxymethyl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide reference is made to example 1.
MS m/z(ESI):396.2[M+H]+.
Example 80
N- (6- (2-hydroxyacetyl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide
Preparation of N- (6- (2-hydroxyacetyl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide reference is made to example 1.
MS m/z(ESI):424.2[M+H]+.
Example 81
2- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Pyrimidine-5-carboxamides
2- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Pyrimidine-5-carboxamide preparation method reference is made to example 1.
MS m/z(ESI):426.2[M+H]+.
Example 82
3- (Cyclopropanecarboxamido) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) -1,2, 4-triazine-6-carboxamide
3- (Cyclopropanecarboxamido) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of (E) -1,2, 4-triazine-6-carboxamide reference is made to example 1.
MS m/z(ESI):427.2[M+H]+.
Example 83
6-methoxy-N2- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -N4- (5-methyl-1H-pyrazol-3-yl) pyrimidine-2, 4-diamines
6-methoxy-N2- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -N4Preparation of (5-methyl-1H-pyrazol-3-yl) pyrimidine-2, 4-diamine reference is made to example 1.
MS m/z(ESI):408.2[M+H]+.
Example 84
2- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methylpyrimidine-5-carboxamide
Preparation of 2- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methylpyrimidine-5-carboxamide reference is made to example 1.
1H NMR(400MHz,DMSO-d6)0.76-0.95(m,4H),2.09-2.21(m,1H),2.82(d,J=4.4Hz,3H),3.80(s,3H),3.95(s,3H),7.15(t,J=8.1Hz,1H),7.49(dd,J=7.8,1.6Hz,1H),8.55(s,1H),8.67(d,J=4.7Hz,1H),8.75(s,1H),10.92(s,1H),11.90(s,1H);
MS m/z(ESI):423.2[M+H]+.
Example 85
N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5- (N-methylsulfamoyl) pyridin-2-yl) cyclopropanecarboxamide
Preparation of N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5- (N-methylsulfamoyl) pyridin-2-yl) cyclopropanecarboxamide reference is made to example 1.
MS m/z(ESI):458.2[M+H]+.
Example 86
3- (cyclopropylcarboxamido) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-1, 2, 4-triazine-6-carboxamide
Preparation of 3- (cyclopropylcarboxamido) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-1, 2, 4-triazine-6-carboxamide reference is made to example 1.
MS m/z(ESI):424.2[M+H]+.
Example 87
6- (2-cyclopropyl-2-carbonylacetamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Pyridazine-3-carboxamides
6- (2-cyclopropyl-2-carbonylacetamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):454.2[M+H]+.
Example 88
6- (Cyclopropanecarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
First step preparation of 3- (5-fluoro-2-methoxyphenyl) -1H-1,2, 4-triazole
5-fluoro-2-methoxybenzamide (3.5g,20.7mmol) was dissolved in DMF-DMA (25mL), heated to 95 deg.C for 1 hour, and concentrated under reduced pressure to give the crude DMF-DMA addition product, which was dissolved in ethanol (20mL) for use. After stirring for 5 minutes, hydrazine hydrate (80 wt.%, 8.4mL) was added dropwise and stirring was continued for 15 minutes, then an ethanol solution of the crude DMF-DMA addition product was added dropwise, slowly warmed to room temperature, and stirring was continued for 4 hours at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (300mL) and saturated NaHCO3The resulting aqueous solution (300mL × 2) was washed, the organic phase was separated and washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound, 3- (5-fluoro-2-methoxyphenyl) -1H-1,2, 4-triazole (3.1g, 77%).
MS m/z(ESI):194.2[M+H]+.
Second step preparation of 3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole
3- (5-fluoro-2-methoxyphenyl) -1H-1,2, 4-triazole (1.1g,5.69mmol) was dissolved in concentrated sulfuric acid (10mL), nitric acid (68 wt.%, 1.05g,11.39mmol) was added dropwise under ice bath, and after the addition was completed, stirring was continued for 2 hours under ice bath. The reaction mixture was poured into ice water, ammonia was slowly added dropwise to adjust the pH to about 9, ethyl acetate was extracted, the organic phase was separated and dried, and the organic solvent was concentrated under reduced pressure to give the title compound, 3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole, as a crude product (1.26g), which was used directly in the next reaction.
MS m/z(ESI):239.2[M+H]+.
The third step is the preparation of 1-cyclopropyl-3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole
3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (600mg,2.52mmol), copper acetate (688mg,3.8mmol), 2, 2' -bipyridine (590mg,3.8mmol), sodium carbonate (534mg,5.0mmol) were mixed in 1, 2-dichloroethane (5mL), cyclopropylboronic acid (865mg,10.0mmol) was added at room temperature, and the mixture was heated to 85 ℃ and stirred overnight. After the reaction solution was cooled to room temperature, it was diluted with a large amount of ethyl acetate. The organic phase was washed with saturated brine several times, then the separated organic phase was dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure and column chromatography was performed to separate the title compound, 1-cyclopropyl-3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (260mg, 38%).
1H NMR(400MHz,CDCl3)1.16-1.20(m,2H),1.24-1.27(m,2H),3.64-3.73(m,1H),3.94(s,3H),7.52-7.54(m,1H),7.98-8.01(m,1H),8.23(s,1H);
MS m/z(ESI):279.0[M+H]+.
Fourth step preparation of 3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyaniline
To a solution of 1-cyclopropyl-3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (260mg,0.93mmol) in methanol (5mL) was added palladium on carbon (60mg), and the mixture was reacted under a hydrogen atmosphere at room temperature and pressure for 8 hours, followed by filtration of the catalyst through celite. The filtrate was concentrated under reduced pressure to give the title compound, 3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyaniline (230mg), which was used directly in the next reaction.
MS m/z(ESI):249.2[M+H]+.
Fifth step preparation of 6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
To a solution of 3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyaniline (230mg,0.93mmol) and 4, 6-dichloro-N- (methyl-d 3) pyridazine-3-carboxamide (194mg,0.93mmol) in tetrahydrofuran (8mL) was added dropwise a solution of LiHMDS (1M,2.78mL,2.78mmol) in tetrahydrofuran at room temperature, and the reaction mixture was stirred at room temperature for 2 hours and then quenched with a saturated aqueous ammonium chloride solution. The reaction mixture was diluted with methylene chloride, and the organic phase was washed with saturated brine several times, then the organic phase was separated, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure and column chromatography was performed to give the title compound 6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (290mg, 74%).
MS m/z(ESI):421.2[M+H]+.
Sixth step preparation of 6- (Cyclopropanecarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (155mg,0.37mmol), cyclopropylamide (62mg,0.74mmol), and cesium carbonate (360mg,1.1mmol) were mixed in dioxane (5mL), and tris (dibenzylideneacetone) dipalladium (101mg,0.11mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (127mg,0.22mmol) were added, nitrogen was deoxygenated for 5 minutes, and microwave reaction was carried out at 145 ℃ for 2 hours. The reaction mixture was diluted with methylene chloride, and the organic phase was washed with saturated brine several times, then the organic phase was separated, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure and column chromatography was performed to give the title compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (116mg, 67%).
1H NMR(400MHz,CDCl3)0.90-0.95(m,2H),1.11-1.16(m,4H),1.21-1.26(m,2H),1.74-1.80(m,1H),3.65-3.71(m,1H),3.80(s,3H),7.22-7.25(m,1H), 7.51-7.54(m,1H),8.03(s,1H),8.19(s,1H),8.29(s,1H),9.59(s,1H),11.21(s,1H);
MS m/z(ESI):470.2[M+H]+.
Example 89
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-5-methyl-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-5-methyl-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):440.2[M+H]+.
Example 90
6- (Cyclopropanecarboxamido) -4- ((2-fluoro-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((2-fluoro-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)0.86-0.93(m,2H),1.06-1.11(m,2H),1.78-1.87(m,1H),4.04(s,3H),7.27-7.33(m,1H),7.46-7.52(m,1H),7.90-7.96(m,1H),8.03(s,1H),8.08-8.15(m,2H),9.99(s,1H),10.95(s,1H);
MS m/z(ESI):414.2[M+H]+.
Example 91
4- ((3- (1-allyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d 3) pyridazine-3-carboxamide
First step preparation of 3- (2-methoxy-3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole
To a solution of 3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (1.00g,4.54mmol), DMAP (55.0mg,0.454mmol) and DIPEA (1.05mL,6.36mmol) in dichloromethane (20mL) at-20 deg.C was slowly added SEM-Cl (0.964mL,5.45mmol) in dichloromethane (10 mL). After the addition was complete, the temperature was slowly raised to-10 ℃ and stirred at this temperature overnight. The reaction solution was washed with saturated brine, the organic phase was separated and dried, and the organic solvent was concentrated under reduced pressure after filtration to give crude 3- (2-methoxy-3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole for direct use in the next reaction.
MS m/z(ESI):351.2[M+H]+.
Second step preparation of 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline
The above crude product was dissolved in a mixture of ethanol (30mL) and water (5mL), followed by addition of ammonium chloride solid (1.60g,30.0mmol) and reduced iron powder (1.67g,30.0mmol) in this order, stirring at 50 ℃ for 2 hours, cooling the reaction system, filtering off insoluble matter with celite, concentrating the filtrate, dissolving the residue with dichloromethane, washing with saturated brine, separating the organic phase, drying with a drying agent, filtering, concentrating the organic solvent under reduced pressure, and separating by column chromatography to give the title compound, 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline (650mg, two-step yield: 45%).
MS m/z(ESI):321.2[M+H]+.
Third step preparation of 6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
To a solution of 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline (640mg,2.00mmol), 4, 6-dichloro-N- (methyl-d 3) pyridazine-3-carboxamide (417mg,2.00mmol) in THF (20mL) at 0 ℃ was added dropwise LiHMDS (1M in THF,5.00mL), and after completion of dropwise addition, the mixture was slowly warmed to room temperature and stirred at room temperature for 2 hours. Quenched with saturated brine, extracted twice with DCM, the organic phases were combined, dried and the organic solvent was concentrated under reduced pressure and isolated by column chromatography to give the title compound 6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (780mg, 79%).
MS m/z(ESI):493.2[M+H]+.
Fourth step preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (850mg,1.73mmol), cyclopropylamide (372mg,4.38mmol) and cesium carbonate (2.14g,6.57mmol) were mixed in 1,4-dioxane (20mL), the reaction solution was deoxygenated by elution with nitrogen for 5 minutes, and Pd was added successively2(dba)3(400mg,0.438mmol) and Xantphos (506mg,0.876 mmol). The reaction was heated under nitrogen with a microwave at 130 ℃ for 90 minutes, cooled to room temperature, concentrated under reduced pressure and the organic solvent was concentrated under reduced pressure and then subjected to column chromatography to give the title compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (680mg, 73%).
MS m/z(ESI):542.3[M+H]+.
Fifth step preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
To a solution of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (630mg,1.16mmol) in DCM at 0 ℃ was added TFA (6.0mL) and the mixture was stirred at room temperature overnight. The organic solvent was concentrated under reduced pressure the next day, the residue was dissolved in DCM, washed with saturated aqueous sodium bicarbonate solution and saturated brine in that order, the organic phase was dried and concentrated under reduced pressure, and column chromatography was performed to give the title compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (270mg, 57%).
1H NMR(400MHz,CDCl3)0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88(m,1H),3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H);
MS m/z(ESI):412.2[M+H]+.
Sixth step preparation of 4- ((3- (1-allyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d 3) pyridazine-3-carboxamide
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (30mg,0.073mmol), allyl bromide (8.7mg, 0.073mmol) and potassium carbonate (20mg,0.15mmol) were mixed in MeCN (3mL) and stirred at 0 ℃ for 2 days. The reaction mixture was concentrated under reduced pressure, and column chromatography was performed to isolate the title compound, 4- ((3- (1-allyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d 3) pyridazine-3-carboxamide (12mg, 39%).
1H NMR(400MHz,CDCl3)0.88-0.92(m,2H),1.10-1.12(m,2H),1.80-1.85(m,1H),3.80(s,3H),4.86-4.88(m,2H),5.35-5.38(m,2H),6.03-6.11(m,1H),7.27-7.31(m,1H),7.52(d,J=8.0Hz,1H),7.80(d,J=8.0Hz,1H),8.03(s,1H),8.15(s,1H),8.24(s,1H),9.88(br s,1H),11.05(s,1H);
MS m/z(ESI):452.2[M+H]+.
Example 92
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
First step preparation of 3- (2-methoxy-3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole
To a solution of 3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (1.00g,4.54mmol), DMAP (55.0mg,0.454mmol) and DIPEA (1.05mL,6.36mmol) in dichloromethane (20mL) at-20 deg.C was slowly added SEM-Cl (0.964mL,5.45mmol) in dichloromethane (10 mL). After the addition was complete, the temperature was slowly raised to-10 ℃ and stirred at this temperature overnight. The reaction solution was washed with saturated brine, the organic phase was separated and dried, and the organic solvent was concentrated under reduced pressure after filtration to give crude 3- (2-methoxy-3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole for direct use in the next reaction.
MS m/z(ESI):351.2[M+H]+.
Second step preparation of 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline
The above crude product was dissolved in a mixture of ethanol (30mL) and water (5mL), followed by addition of ammonium chloride solid (1.60g,30.0mmol) and reduced iron powder (1.67g,30.0mmol) in this order, stirring at 50 ℃ for 2 hours, cooling the reaction system, filtering off insoluble matter with celite, concentrating the filtrate, dissolving the residue with dichloromethane, washing with saturated brine, separating the organic phase, drying with a drying agent, filtering, concentrating the organic solvent under reduced pressure, and separating by column chromatography to give the title compound, 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline (650mg, two-step yield: 45%).
MS m/z(ESI):321.2[M+H]+.
Third step preparation of 6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
To a solution of 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline (640mg,2.00mmol), 4, 6-dichloro-N- (methyl-d 3) pyridazine-3-carboxamide (417mg,2.00mmol) in THF (20mL) at 0 ℃ was added dropwise LiHMDS (1M in THF,5.00mL), and after completion of dropwise addition, the mixture was slowly warmed to room temperature and stirred at room temperature for 2 hours. Quenched with saturated brine, extracted twice with DCM, the organic phases were combined, dried and the organic solvent was concentrated under reduced pressure and isolated by column chromatography to give the title compound 6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (780mg, 79%).
MS m/z(ESI):493.2[M+H]+.
Fourth step preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (850mg,1.73mmol), cyclopropylamide (372mg,4.38mmol) and cesium carbonate (2.14g,6.57mmol) were mixed in 1,4-dioxane (20mL), the reaction solution was deoxygenated by elution with nitrogen for 5 minutes, and Pd was added successively2(dba)3(400mg,0.438mmol) and Xantphos (506mg,0.876 mmol). The reaction was heated under nitrogen at 130 ℃ for 90 minutes under microwave heating, cooled to room temperature, the organic solvent was concentrated under reduced pressure and the title compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was obtained by column chromatography (680mg, 73%)。
MS m/z(ESI):542.3[M+H]+.
Fifth step preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
To a solution of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (630mg,1.16mmol) in DCM (20mL) at 0 ℃ was added TFA (6.0mL) and the mixture was stirred at room temperature overnight. The organic solvent was concentrated under reduced pressure the next day, the residue was dissolved in DCM, washed with saturated aqueous sodium bicarbonate solution and saturated brine in that order, the organic phase was dried and concentrated under reduced pressure, and column chromatography was performed to give the title compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (270mg, 57%).
1H NMR(400MHz,CDCl3)0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88(m,1H),3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H);
MS m/z(ESI):412.2[M+H]+.
Sixth step preparation of 6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (30mg,0.073mmol), bromopropyne (8.7mg, 0.073mmol) and potassium carbonate (20mg,0.15mmol) were mixed in MeCN (3mL) and stirred at 0 ℃ for 2 days. The reaction mixture was concentrated under reduced pressure, and column chromatography was performed to isolate the title compound, 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (10mg, 31%).
1H NMR(400MHz,CDCl3)0.88-0.93(m,2H),1.10-1.14(m,2H),1.75-1.82(m,1H),2.62(s,1H),3.81(s,3H),5.07(s,2H),7.26-7.30(m,1H),7.52(d,J=8.0Hz,1H),7.82(d,J=8.0Hz,1H),8.00(s,1H),8.23(s,1H),8.38(s,1H),9.88(br s,1H),11.13(s,1H);
MS m/z(ESI):450.2[M+H]+.
Example 93
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):494.2[M+H]+.
Example 94
4- ((3- (1- (tert-butyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 4- ((3- (1- (tert-butyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):468.2[M+H]+.
Example 95
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1- (1,1, 1-trifluoro-2-methylpropan-2-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (1,1, 1-trifluoro-2-methylpropan-2-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):522.2[M+H]+.
Example 96
4- ((3- (1- (bicyclo [1.1.1] pentane-1-yl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 4- ((3- (1- (bicyclo [1.1.1] pentan-1-yl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):478.2[M+H]+.
Example 97
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1- (thietanyl-3-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (thietanyl-3-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):484.2[M+H]+.
Example 98
6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (3-methyloxetan-3-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (3-methyloxetan-3-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)0.91-0.93(m,2H),1.08-1.13(m,2H),1.72-1.75(m,1H),2.07(s,3H),3.86(s,3H),4.71(d,J=6.6Hz,2H),5.25(d,J=6.4Hz,2H),7.28-7.30(m,1H),7.52-7.55(m,1H),7.82-7.85(m,1H)8.05(s,1H),8.23-8.25(m,2H),9.31(s,1H),11.16(s,1H);
MS m/z(ESI):482.2[M+H]+.
Example 99
6- (cyclopropylmethylthioamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylmethylthioamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):442.2[M+H]+.
Example 100
6- (Cyclopropanecarboxamido) -4- ((2- (dimethylphosphide) -3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((2- (dimethylphosphide) -3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):472.2[M+H]+.
Example 101
6- (Cyclopropanecarboxamido) -N- (methyl-d 3) -4- ((3- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfonyl) phenyl) amino) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylcarboxamido) -N- (methyl-d 3) -4- ((3- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfonyl) phenyl) amino) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):474.2[M+H]+.
Example 102
4- ((3- (1- (cyanomethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 4- ((3- (1- (cyanomethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):451.2[M+H]+.
Example 103
4- ((3- (1- (bicyclo [1.1.1] pentan-1-ylmethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 4- ((3- (1- (bicyclo [1.1.1] pentan-1-ylmethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):492.2[M+H]+.
Example 104
6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (oxetan-3-ylmethyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (oxetan-3-ylmethyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference example 92.
1H NMR(400MHz,CDCl3)0.91-0.94(m,2H),1.08-1.14(m,2H),3.55-3.62(m,1H),3.81(s,3H),4.54-4.59(m,4H),4.80-4.90(m,2H),7.27-7.29(m,1H),7.50-7.52(m,1H),7.80-7.82(m,1H),8.06(s,1H),8.13(s,1H),8.20(s,1H),9.14(s,1H),11.09(s,1H);
MS m/z(ESI):482.2[M+H]+.
Example 105
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) -6- (4-carbonyl-5-azaspiro [2.4] heptan-5-yl) pyridazine-3-carboxamide
Preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) -6- (4-carbonyl-5-azaspiro [2.4] heptan-5-yl) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):452.2[M+H]+.
Example 106
6- ((cyano (cyclopropyl) methyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- ((cyano (cyclopropyl) methyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):437.2[M+H]+.
Example 107
(R) -6- ((cyano (cyclopropyl) methyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of (R) -6- ((cyano (cyclopropyl) methyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):437.2[M+H]+.
Example 108
(S) -6- ((cyano (cyclopropyl) methyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of (S) -6- ((cyano (cyclopropyl) methyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):437.2[M+H]+.
Example 109
6- (1-fluorocyclopropane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (1-fluorocyclopropane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)1.38-1.50(m,4H),3.81(s,3H),4.00(s,3H),7.23-7.29(m,1H),7.49(dd,J=7.9,1.4Hz,1H),7.81(dd,J=7.9,1.5Hz,1H),8.09-8.22(m,3H),9.09(s,1H),11.00(s,1H);
MS m/z(ESI):444.2[M+H]+.
Example 110
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) -6- ((3-vinyloxetan-3-yl) amino) pyridazine-3-carboxamide
Preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) -6- ((3-vinyloxetan-3-yl) amino) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):440.2[M+H]+.
Example 111
6- ((3-ethynyloxetan-3-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- ((3-ethynyloxetan-3-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):438.2[M+H]+.
Example 112
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
First step preparation of 3- (2-methoxy-3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole
To a solution of 3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (1.00g,4.54mmol), DMAP (55.0mg,0.454mmol) and DIPEA (1.05mL,6.36mmol) in dichloromethane (20mL) at-20 deg.C was slowly added SEM-Cl (0.964mL,5.45mmol) in dichloromethane (10 mL). After the addition was complete, the temperature was slowly raised to-10 ℃ and stirred at this temperature overnight. The reaction solution was washed with saturated brine, the organic phase was separated and dried, and the organic solvent was concentrated under reduced pressure after filtration to give crude 3- (2-methoxy-3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole for direct use in the next reaction.
MS m/z(ESI):351.2[M+H]+.
Second step preparation of 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline
The above crude product was dissolved in a mixture of ethanol (30mL) and water (5mL), followed by addition of ammonium chloride solid (1.60g,30.0mmol) and reduced iron powder (1.67g,30.0mmol) in this order, stirring at 50 ℃ for 2 hours, cooling the reaction system, filtering off insoluble matter with celite, concentrating the filtrate, dissolving the residue with dichloromethane, washing with saturated brine, separating the organic phase, drying with a drying agent, filtering, concentrating the organic solvent under reduced pressure, and separating by column chromatography to give the title compound, 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline (650mg, two-step yield: 45%).
MS m/z(ESI):321.2[M+H]+.
Third step preparation of 6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
To a solution of 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline (640mg,2.00mmol), 4, 6-dichloro-N- (methyl-d 3) pyridazine-3-carboxamide (417mg,2.00mmol) in THF (20mL) at 0 ℃ was added dropwise LiHMDS (1M in THF,5.00mL), and after completion of dropwise addition, the mixture was slowly warmed to room temperature and stirred at room temperature for 2 hours. Quenched with saturated brine, extracted twice with DCM, the organic phases were combined, dried and the organic solvent was concentrated under reduced pressure and isolated by column chromatography to give the title compound 6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (780mg, 79%).
MS m/z(ESI):493.2[M+H]+.
Fourth step preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (850mg,1.73mmol), cyclopropylamide (372mg,4.38mmol) and cesium carbonate (2.14g,6.57mmol) were mixed in 1,4-dioxane (20mL), the reaction solution was deoxygenated by elution with nitrogen for 5 minutes, and Pd was added successively2(dba)3(400mg,0.438mmol) and Xantphos (506mg,0.876 mmol). The reaction was carried out under nitrogen at 130 ℃ for 90 minutes under microwave, cooled to room temperature, and the organic solvent was concentrated under reduced pressure and then subjected to column chromatography to give the title compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (680mg, 73%).
MS m/z(ESI):542.3[M+H]+.
Fifth step preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
To a solution of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (630mg,1.16mmol) in DCM at 0 ℃ was added TFA (6.0mL) and the mixture was stirred at room temperature overnight. The organic solvent was concentrated under reduced pressure the next day, the residue was dissolved in DCM, washed with saturated aqueous sodium bicarbonate solution and saturated brine in that order, the organic phase was dried and concentrated under reduced pressure, and column chromatography was performed to give the title compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (270mg, 57%).
1H NMR(400MHz,CDCl3)0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88(m,1H),3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H);
MS m/z(ESI):412.2[M+H]+.
Example 113
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,DMSO)0.79-0.86(m,4H),2.04-2.12(m,1H),3.71(s,3H),3.95(s,3H),7.24-7.25(m,1H),7.49-7.52(m,1H),7.63-7.67(m,1H),7.89(s,1H),8.16(s,1H),8.53-8.58(m,2H),11.06(s,1H),11.33(s,1H);
MS m/z(ESI):409.2[M+H]+.
Example 114
6- (Cyclopropanecarboxamido) -4- ((5-fluoro-2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((5-fluoro-2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 92.
1H NMR(400MHz,DMSO-d6)0.84-0.87(m,2H),1.23-1.34(m,2H),2.09-2.12(m,1H),3.60(s,1H),3.75(s,3H),5.24(s,2H),7.39-7.47(m,2H),8.26(s,1H),8.72(s,1H),9.19(s,1H),11.20(s,1H),11.41(s,1H);
MS m/z(ESI):468.2[M+H]+.
Example 115
6- (Cyclopropanecarboxamido) -4- ((3- (1- (cyclopropylmethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((3- (1- (cyclopropylmethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)0.44-0.48(m,2H),0.70-0.76(m,2H),0.86-0.93(m,2H),1.08-1.11(m,2H),1.33-1.40(m,1H),1.82-1.89(m,1H),3.82(s,3H),4.10(d,J=7.2Hz,2H),7.25-7.30(m,1H),7.50-7.54(m,1H),7.80-7.83(m,1H),8.02(s,1H),8.23-8.25(m,2H),9.98(s,1H),11.04(s,1H);
MS m/z(ESI):466.2[M+H]+.
Example 116
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide referring to example 92, example 116 is one of the products of the sixth reaction.
1H NMR(400MHz,CDCl3)0.88-0.93(m,2H),1.10-1.14(m,2H),1.75-1.82(m,1H),2.39(s,1H),3.48(s,3H),4.94(d,J=6.4Hz,2H),7.26-7.36(m,1H),7.43(d,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),8.07(s,1H),8.12(s,1H),9.64(br s,1H),11.07(s,1H);
MS m/z(ESI):450.2[M+H]+.
Example 117
6- (Cyclopropanecarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-5-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-5-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CDCl3)0.93-1.02(m,4H),1.05-1.11(m,4H),1.75-1.82(m,1H),3.48(s,3H),3.61-3.70(m,1H),7.13-7.17(m,1H),7.29-7.33(m,1H),7.93(s,2H),8.18(s,1H),10.61(s,1H),11.59(s,1H);
MS m/z(ESI):470.1[M+H]+.
Example 118
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (4- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (4- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide referring to example 92, example 118 is one of the products of the sixth reaction.
1H NMR(400MHz,CDCl3)0.88-0.93(m,2H),1.10-1.14(m,2H),1.75-1.82(m,1H),1.71(s,1H),3.81(s,3H),5.71(d,J=6.4Hz,2H),7.22-7.30(m,1H),7.52(d,J=8.0Hz,1H),7.82(d,J=8.0Hz,1H),8.07(s,1H),8.20(s,1H),8.29(s,1H),9.10(br s,1H),11.07(s,1H);
MS m/z(ESI):450.2[M+H]+.
Example 119
6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) nicotinamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) nicotinamide proceeds according to example 92.
1H NMR(400MHz,DMSO-d6)0.88-0.91(m,2H),1.03-1.09(m,2H),1.55-1.65(m,1H),3.81(s,3H),5.06(s,2H),6.79(s,1H),7.26-7.77(m,2H),8.06-8.37(m,3H),9.01(br s,1H),10.63(br s,1H);
MS m/z(ESI):449.2[M+H]+.
Example 120
6- (Cyclopropanecarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) nicotinamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) nicotinamide proceeds according to example 1.
1H NMR(400MHz,CDCl3)0.84-0.89(m,2H),1.03-1.08(m,2H),1.11-1.14(m,2H),1.21-1.25(m,2H),1.51-1.57(m,1H),3.63-3.70(m,1H),3.81(s,3H),6.46(s,1H),7.19-7.24(m,1H),7.51-7.54(m,1H),7.68-7.70(m,1H),8.06(s,1H),8.17(s,1H),8.30(s,1H),8.60(s,1H),10.41(s,1H);
MS m/z(ESI):451.1[M+H]+.
Example 121
6- (Cyclopropanecarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) nicotinamide
Preparation of 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) nicotinamide proceeds according to example 1.
1H NMR(400MHz,CDCl3)0.87-0.94(m,2H),1.06-1.16(m,4H),1.20-1.25(m,2H),1.56-1.66(m,1H),3.65-3.69(m,1H),3.81(s,3H),6.84(s,1H),7.44-7.50(m,1H),8.13-8.17(m,2H),8.47(s,1H),9.12(s,1H),10.77(s,1H);
MS m/z(ESI):469.2[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.
Test example 1 determination of the inhibitory Effect of the Compound of the present invention on the cellular TYK2 Signal pathway
Purpose of the experiment: the purpose of this test example was to test the activity of the compounds on inhibition of the cellular TYK2 signaling pathway.
An experimental instrument:
centrifuge (5702R) was purchased from Eppendorf corporation,
pipettes were purchased from the Eppendorf company,
the microplate reader is purchased from BioTek company of America, and is a SynergyH1 full-function microplate reader.
The experimental method is that the U266 cell line expressing TYK2 is adopted in the experiment, the TYK2 signal channel is stimulated and activated through INF- α, the inhibition activity of the compound on the downstream STAT3 phosphorylation is detected, and the half inhibition concentration IC of the compound on the activity of the TYK2 signal channel is obtained50。
The specific experimental operations were as follows:
spreading 3-12 μ L of U266 fine powder with cell number of 100-300K in each well in 384-well detection plate, adding 2 μ L of compound solution diluted in gradient, incubating in carbon dioxide incubator for 2 hr, adding 2 μ L of INF- α - α with final concentration of 1000U/mL after 2 hr, shaking at room temperature for 20min, adding 2-5 μ L (5X) of LANCE Ultra lysine Buffer2 solution, shaking at room temperature for 2 hr, adding 5 μ L of LANCE Ultra Eu-labeled Anti-STAT5 (Y6)94/Y699) antibody (PerkinElmer) and a solution of LANCE Ultra high-labeled Anti-STAT5 antibody (PerkinElmer) at a final concentration of 20nM, incubated overnight at room temperature. Measuring 665nm fluorescence signal value of each plate hole by a microplate reader, calculating inhibition rate through the fluorescence signal value, and obtaining IC of the compound through curve fitting according to the inhibition rates of different concentrations50。
The experimental data processing method comprises the following steps:
percent inhibition data {% inhibition 100- [ (test compound value-negative control value) for wells treated with compound was calculated by counting the percent inhibition data from positive control wells (DMSO control wells) and negative control wells (no cells) on the plate](Positive control value-negative control value) × 100} IC was calculated using GraphPad prism to fit the different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula50The value is obtained.
And (4) experimental conclusion:
the activity test data of the compounds of the present invention in inhibiting the cell TYK2 signaling pathway obtained by the above protocol are shown in the following table:
compound numbering | Cell Activity U266 pSTAT3(nM) |
Example 3 | 4.36 |
Example 4 | 4.22 |
Example 53 | 2.43 |
Example 58 | 1.41 |
Example 60 | 6.01 |
Example 88 | 0.83 |
Example 89 | 4.95 |
Example 91 | 0.34 |
Example 92 | 0.13 |
Example 98 | 0.90 |
Example 104 | 1.88 |
Example 112 | 4.6 |
Example 114 | 2.10 |
Example 115 | 3.43 |
Example 118 | 1.27 |
Example 119 | 4.22 |
Example 120 | 1.65 |
Example 121 | 3.01 |
Test example 2 measurement of inhibitory Effect of the Compound of the present invention on the cellular JAK2 Signal pathway
Purpose of the experiment: the purpose of this test example was to test the activity of the compounds on inhibition of the cellular JAK2 signaling pathway.
An experimental instrument:
centrifuge (5702R) was purchased from Eppendorf corporation,
pipettes were purchased from the Eppendorf company,
the microplate reader is purchased from BioTek company of America, and is a SynergyH1 full-function microplate reader.
The experimental method comprises the following steps: the experiment adopts TF-1 cell line, stimulates and activates JAK2 signal channel through IL6, detects the inhibition activity of the compound on downstream STAT3 phosphorylation, and obtains the half inhibition concentration IC of the compound on the activity of JAK2 signal channel50。
The specific experimental operations were as follows:
3-12 mu L of TF-1 cells are paved in a 384-well detection plate, the number of the cells in each well is 100-300K, 2 mu L of compound solution diluted in a gradient way is added, and the mixture is incubated for 2 hours in a carbon dioxide incubator. After 2 hours, 2. mu.L of IL6 was added, IL6 was added to a final concentration of 30ng/mL, and the mixture was shaken at room temperature for 20 min. Add 2-5. mu.L (5X) of LANCE Ultra Lysis Buffer2 solution and shake at 4 ℃ for 2 h. After 2h, 5. mu.L of a final 2nM solution of LANCE Ultra Eu-labeled Anti-STAT3(Tyr705) Anti (PerkinElmer) and 20nM of a final LANCE Ultra high-labeled Anti-STAT3 Anti (PerkinElmer) was added and incubated overnight at room temperature. The value of 665nm fluorescence signal of each plate hole is measured by a microplate reader and is measured by fluorescenceCalculating the inhibition rate according to the light signal value, and obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations50。
The experimental data processing method comprises the following steps:
percent inhibition data {% inhibition 100- [ (test compound value-negative control value) for wells treated with compound was calculated by counting the percent inhibition data from positive control wells (DMSO control wells) and negative control wells (no cells) on the plate](Positive control value-negative control value) × 100} IC was calculated using GraphPad prism to fit the different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula50The value is obtained.
And (4) experimental conclusion:
the activity test data of the compound shown in the invention in inhibiting the cell JAK2 signal channel are shown in the following table:
and (4) experimental conclusion: as can be seen from the data in the table, the example compounds are more selective for JAK2 cell activity compared to TYK2 cell activity.
Test example 3 plasma protein binding Rate test in mice
1. The research aims are as follows:
the purpose of this experiment was to evaluate the protein binding rate of example 58, example 88 and example 92 (5. mu.M) in mouse plasma using equilibrium dialysis.
2. Compounds and experimental materials:
1) test compounds were formulated as 10mM stock solutions in DMSO and stored at-20 ℃ in a refrigerator for use;
2) frozen plasma of the desired species, dialysate (100mM phosphate buffer (Lot # SLBS7904 and Lot # SLBR3106V), pH 7.4).
3. Laboratory apparatus
The device comprises a 96-pore plate (Lot #07917415), a detection membrane device (Lot # SD2369421), a liquid chromatography-mass spectrometer (LC-MS/MS) (LC-20AD, API4000), a centrifuge (Eppendorf 5804R/5424R), a VORTEX instrument (IKA VORTEX GENIUS 3), a liquid-transfering gun (Eppendorf 10-100 mu L (PIP-100 minus 002), Eppendorf 100-1000 mu L (PIP-1000 minus 002), RAININ 0.5-10 mu L (PIP-10-002)), and a water bath kettle (Shanghai Hengke).
4. Experimental procedure
4.1 preparation of the dialysate
4.01mL of 1M K2HPO4(AR grade) and 0.99mL of 1M KH2PO4(AR grade) were diluted with ultrapure water to 50mL to prepare 100mM phosphate buffer (pH 7.4) as a dialysate.
4.2 preparation of plasma
The frozen plasma was thawed in a water bath at room temperature or 37 ℃ and centrifuged at 3500rpm for 5min to obtain the supernatant.
4.3 preparation of reaction stop solution
Acetonitrile (or other suitable solution) containing the internal standard was used as a stop solution and stored in a refrigerator at 2-8 ℃ and the specific concentration of the internal standard was reported at the end.
4.4 preparation of working solution of Compound
Preparing a working solution of the compound: stock solutions were diluted to a final concentration of 1mM in DMSO.
4.5 preparation of plasma solution
Add 4. mu.L of compound working solution into 796. mu.L of blank plasma with a final concentration of 5. mu.M, shake and mix.
4.6 equilibrium dialysis
1) Preparing a balance dialysis device, and putting the detection membrane device into a balance dialysis 96-well plate;
2) adding 200 mul of prepared plasma solution into the membrane, wherein n is 2;
3) taking another 4 mu L of plasma solution, diluting the plasma solution by 10 times by using 36 mu L of blank plasma of the same species, adding 160 mu L of acetonitrile stop solution containing an internal standard, and storing the solution in a refrigerator at the temperature of 20 ℃ below zero to obtain a T0(Total) sample;
4) add 350 μ L dialysate (100mM phosphate buffer) outside the membrane;
5) sealing the dialysis plate, and putting the dialysis plate into a water bath kettle at the temperature of 37 ℃ for incubation for 6 hours;
6) after dialysis, 4 μ L of each sample was removed from the intramembrane wells and diluted 10-fold with 36 μ L of blank plasma of the same species; respectively taking out 40 mu L of dialysate from the sample hole outside the membrane, and adding 160 mu L of acetonitrile stop solution with an internal standard to obtain a T6(Total) sample and a F6(Total) sample;
7) centrifuging the T0(Total) and T6(Total) samples and taking the supernatant;
8) LC-MS analysis.
5. Results of the experiment
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 compounds example 58, example 88 and example 92, administered orally at a dose of 5mg/kg to plasma in mice.
2. Test protocol
2.1 test drugs:
inventive example 58, example 88 and example 92, homemade.
2.2 test animals:
Balb/C Mouse 18 (6/example), male, Shanghai Jie Si laboratory animals Ltd, animal production license number (SCXK 2013-.
2.3 administration:
Balb/C mice 18, male; p.o. after fasting overnight, the dose was 5mg/kg and the administration volume was 10 mL/kg.
2.4 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 ℃.
2.5 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 API4000 Mass Spectroscopy
● column chromatography: phenomenex Gemiu 5um C1850 x 4.6mm
● 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:
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 the following table:
compound (I) | t max(h) | C max(ng/mL) | AUC 0-t(ng/mL*h) | AUC 0-∞(ng/mL*h) | t 1/2(h) | MRT 0-∞(h) |
BMS-986165 | 1.0 | 696 | 1987 | 2038 | 1.4 | 2.3 |
Example 53 | 0.5 | 2043 | 6250 | 6348 | 1.3 | 2.3 |
Example 58 | 0.5 | 3930 | 13590 | 14473 | 1.9 | 3.0 |
Example 88 | 1.0 | 2190 | 20991 | 21001 | 2.1 | 5.6 |
Example 92 | 1.0 | 939 | 2466 | 2637 | 2.0 | 2.8 |
Example 118 | 0.5 | 1927 | 3391 | 3719 | 2.7 | 2.5 |
And (4) experimental conclusion: as can be seen from the data in the table, the AUC of the drug-induced exposure of the example compounds in mice0-t(ng/mL h) is superior to reference compound BMS-986165, especially example 58 and example 88, and the drug exposure is much superior to reference compound BMS-986165, 6 and more than 10 times better than the reference compound.
Test example 5 determination of the efficacy of the compounds of the invention in an imiquimod-induced psoriasis-like model in mice
1. Purpose of the experiment:
compounds were evaluated for efficacy in an imiquimod-induced psoriasis-like model in mice.
2. Main experimental instrument and reagent
2.1 instruments
Name of instrument and equipment | Model number | Manufacturer of the product |
Electronic balance | SQP type SECURA225D-1CN | Sartorius |
Electronic balance | MP5002 type | Constant flow of Shunhu Shanghai |
2.2 reagents
Name (R) | Batch number | Brand/goods number |
Imiquimod Cream | GRI015A | Aldara |
CMC-Na | 079K0054V | Sigma-C9481-500G |
3. Experimental procedure
3.1 Molding
Day 0 animals were shaved on the back test sites. Day 1-Day 6 were applied to the test sites on the backs of the animals with 62.5mg of imiquimod once a Day.
3.2 administration of drugs
Day 1-Day 7 were administered to each group of animals according to the protocol, and the experimental design of the imiquimod-induced psoriasis-like model in mice is shown in the following table:
3.3 dermatitis severity index score
The redness, scaling and thickening degrees of the animal back test parts are respectively scored according to 0-4 by Day 1-Day 7. 0, no damage; 1, slight; 2, moderate; 3, apparent; 4, very clearly. The total score indicates the severity of the injury
4. Test data
4.1 comparison of the results of the PASI scores of different compounds in the imiquimod-induced mouse psoriasis model are given in the following table:
4.2 results of PASI scores in the imiquimod-induced mouse psoriasis model for different compounds are shown in fig. 1, where data points represent the mean PASI score in the group, N-8, p <0.001 compared to the Vehicle group using One-way ANOVA.
5. Results of the experiment
From the above results, it can be seen that examples 58, 88 and 92 of this patent are effective in improving psoriasis symptoms in an imiquimod-induced psoriasis-like model in mice, with a very significant difference compared to the Vehicle group, P <0.001, superior to the reference compound BMS-986165(P < 0.01).
Claims (29)
- A compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,wherein:r is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -ORaa、-SRaa、-C(O)Raa、-C(O)ORaa、-S(O)m1Raa、-NRaaRbb、-C(O)NRaaRbb、-NRaaC(O)Rbbor-NRaaS(O)m1Rbb;R1Selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, -Raa、-(CH2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-NRaaCRbb=NRcc、-NRaaCRbb=CRccRdd、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1Raa、-(CH2)n1NRaaC(O)C(O)RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkylSubstituted with one or more substituents selected from the group consisting of haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;R2selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, -Raa、-C(O)Raa、-(CH2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-NRaaCRbb=NRcc、-NRaaCRbb=CRccRdd、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;R3selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl or alkynyl;R4、R5、R6and R7In the presence or absence, selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitroRadical, hydroxyl, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-SRaa、 -(CH2)n1C(O)Raa、-C(O)ORaa、-S(O)m1Raa、-NRaaRbb、-C(O)NRaaRbb、-NRaaC(O)Rbbor-NRaaS(O)m1Rbb;Or, R4And R6Or R6And R7(ii) linked to form a cycloalkyl, heterocyclyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;Raa、Rbb、Rccand RddEach independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;or, any two adjacent or non-adjacent Raa、Rbb、RccAnd RddLinked to form a cycloalkyl group,Heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;x is 0, 1,2 or 3;m1 is 0, 1 or 2; and isn1 is 0, 1,2, 3, 4 or 5.
- A compound, stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1, characterized in that it isR is selected from hydrogen, deuterium and C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy, halogen, amino, mercapto, -ORaa、-SRaa、-S(O)m1Raaor-NRaaRbbPreferably hydrogen, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy, halo C1-3Alkoxy, fluoro, chloro, bromo, -ORaa、-SRaa、-S(O)m1Raaor-NRaaRbbMore preferably hydrogen, methyl, ethyl, propyl, FCH2-、F2CH-、F3C-、ClCH2-、Cl2CH-、Cl3C-、CH3O-、CH3CH2O-、CH3CH2CH2O-、FCH2O-、F2CHO-、F3CO-, fluoro, chloro, -ORaa、-SRaa、-S(O)m1Raaor-NRaaRbbFurther, CH is preferable3O-、(CH3)2N-、CH3S-、F3CO-、F2HCO-, F-or CH3S(O)2-;Wherein R isaaOr RbbEach independently selected from hydrogen, deuterium, hydroxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl, cyano, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Cycloalkyl or 3-7 membered heterocyclyl, preferably hydrogen, hydroxy, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl, cyano, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl or 3-6 membered heterocyclyl containing 1-3N, O or S atoms, more preferably hydrogen, methyl, ethyl, -CD3、-CD2CD3Propyl, hydroxymethyl, hydroxyethyl, ethenyl, propenyl, ethynyl, propynyl, FCH2-、F2CH-、F3C-, cyano, cyclopropyl, cyclobutyl, cyclohexyl, epoxyethyl, epoxypropyl, epoxybutyl, epoxypentyl, tetrahydropyrrolyl or piperidinyl; further preferably hydrogen, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;R1is selected from C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl, 3-7 membered heteroaryl, -NRcC(O)Rd、-NRcC(O)NRdRe、-NRcS(O)m1Rd、-NRcCRd=NRe、-NRcCRd=CReRf、-NRcC(O)ORd、-(CH2)n1S(O)m1Rc、-(CH2)n1NRcC(O)C(O)RgOr- (CH)2)n1NRcS(O)m1Rd、-NRcCRdReRf、-NRcC(S)Rd、-OC=ONRcRdor-CReRfC=ONRcRdPreferably C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl, 3-6 membered heteroaryl, -NRcC(O)Rd、-NRcC(O)NRdRe、-NRcS(O)m1Rd、-NRcCRd=NRe、-NRcCRd=CReRf、-NRcC(O)ORd、-(CH2)n1S(O)m1Rc、-(CH2)n1NRcC(O)C(O)RgOr- (CH)2)n1NRcS(O)m1Rd、-NRcCRdReRf、-NRcC(S)Rd、-OC=ONRcRdor-CReRfC=ONRcRdMore preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl with 1-3N, O or S atoms, phenyl, naphthyl, 3-6 membered heteroaryl with 1-3N, O or S atoms, -NRcC(O)Rd、-NRcC(O)NRdRe、-NRcS(O)m1Rd、-NRcCRd=NRe、-NRcCRd=CReRf、-NRcC(O)ORd、-(CH2)n1S(O)m1Rc、-(CH2)n1NRcC(O)C(O)RgOr- (CH)2)n1NRcS(O)m1Rd、-NRcCRdReRf、-NRcC(S)Rd、-OC=ONRcRdor-CReRfC=ONRcRdFurther, it is preferableRc、Rd、Re、RfOr RgEach independently selected from hydrogen, deuterium, hydroxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, halogen, cyano, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-12Aryl and 3-7 membered heteroAryl, preferably hydrogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, cyano, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl and 3-6 membered heteroaryl containing 1-3N, O or S atoms, more preferably hydrogen, methyl, ethyl, -CD3、-CD2CD3Propyl, hydroxymethyl, hydroxyethyl, ethenyl, propenyl, ethynyl, propynyl, FCH2-、F2CH-、F3C-, cyano, fluoro, chloro, CH3O-、CH3CH2O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Further preferred are hydrogen, methyl, ethyl, -CD3、-CD2CD3Propyl, hydroxymethyl, hydroxyethyl, ethenyl, propenyl, ethynyl, propynyl, FCH2-、F2CH-、F3C-, cyano, fluoro, chloro, CH3O-、CH3CH2O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,Or, any two adjacent or non-adjacentRc、Rd、ReOr RfAre linked to form a C3-7Cycloalkyl, 3-7 membered heterocyclyl, aryl and 3-7 membered heteroaryl, preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-12Aryl and 3-6 membered heteroaryl, more preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl and 3-to 6-membered aryl having 1 to 2N, O or S atoms, further preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Further preferred are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,R2Is selected from C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl, 3-7 membered heteroaryl, C1-6Hydroxyalkyl, -C (O) Rhh、-(CH2)n1ORii、-(CH2)n1NRhhRii、-NRhhC(O)Rii、-NRhhC(O)NRiiRjj、-C(O)NRhhRii、-NRhhS(O)m1Rii、-NRhhCRii=NRjj、-NRhhCRii=CRjjRkk、-(CH2)n1S(O)m1NRhhRii、-(CH2)n1C(O)Rhh、-NRhhC(O)ORii、-(CH2)n1S(O)m1RhhOr- (CH)2)n1NRhhS(O)m1RiiWherein said C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl or 3-7 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Alkoxy or C3-6One or more substituents in the cycloalkyl group; preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl, 3-6 membered heteroaryl, C1-3Hydroxyalkyl, -C (O) Rhh、-(CH2)n1ORii、-(CH2)n1NRhhRii、-NRhhC(O)Rii、-NRhhC(O)NRiiRjj、-C(O)NRhhRii、-NRhhS(O)m1Rii、-NRhhCRii=NRjj、-NRhhCRii=CRjjRkk、-(CH2)n1S(O)m1NRhhRii、-(CH2)n1C(O)Rhh、-NRhhC(O)ORii、-(CH2)n1S(O)m1RhhOr- (CH)2)n1NRhhS(O)m1RiiWherein said C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl or 3-7 membered heteroaryl, optionally substituted by hydrogen, deuterium, fluoro, chloro, bromo, C1-3Alkyl or C3-5One or more substituents in the cycloalkyl group; more preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, phenyl, naphthyl, 3-6 membered heteroaryl containing 1-3N, O or S atoms, C1-3Hydroxyalkyl, -C (O) Rhh、-(CH2)n1ORii、-(CH2)n1NRhhRii、-C(O)NRhhRii、-(CH2)n1S(O)m1NRhhRii、-(CH2)n1C(O)Rhh、-(CH2)n1S(O)m1RhhOr- (CH)2)n1NRhhS(O)m1RiiWherein said C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl or 3-7 membered heteroaryl, optionally substituted with one or more substituents of hydrogen, deuterium, fluoro, chloro, bromo, methyl, ethyl, propyl, cyclopropyl, cyclopentyl or cyclohexyl; further preferred is HOCH2-、HOCH2CH2-、HOCH2C(O)-、CH3NHC(O)-、D3CNHC(O)-、CH3NHS(O)2-、D3CNHS(O)2-、Rhh、Rii、RjjOr RkkEach independently selected from hydrogen, deuterium, hydroxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, halogen, cyano, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl or 3-6 membered heterocyclyl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, cyano, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl or 3-6 membered heterocyclyl containing 1-3N, O or S atoms, more preferably hydrogen, deuterium, methyl, ethyl, -CD3、-CD2CD3Propyl, hydroxymethyl, hydroxyethyl, ethenyl, propenyl, ethynyl, propynyl, FCH2-、F2CH-、F3C-, cyano, fluoro, chloro, CH3O-、CH3CH2O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, tetrahydropyrrole or piperidinyl;R3selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy or cyano, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy or cyano, more preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, fluoro, chloro, hydroxy or cyano;R4、R5、R6and R7In the presence or absence, selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy, cyano, oxo, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Cycloalkyl, 3-7 membered heterocyclyl, aryl, 3-7 membered heteroaryl, - (CH)2)n1Rll、-(CH2)n1ORll、-SRll、-(CH2)n1C(O)Rll、-C(O)ORll、-S(O)m1Rll、-NRllRmm、-C(O)NRllRmm、-NRllC(O)Rmmor-NRllS(O)m1RmmPreferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy, cyano, oxo, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C6-12Aryl, 3-6 membered heteroaryl containing 1-3N, O or S atoms, - (CH)2)n1Rll、-(CH2)n1ORll、-SRll、-(CH2)n1C(O)Rll、-C(O)ORll、-S(O)m1Rll、-NRllRmm、-C(O)NRllRmm、-NRllC(O)Rmmor-NRllS(O)m1RmmMore preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy, cyano, oxo, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl, 3-6 membered heteroaryl containing 1-3N, O or S atoms, - (CH)2)n1Rll、-(CH2)n1ORllor-NRllRmmMore preferred are hydrogen, methyl, ethyl, propyl, isopropyl, butyl and (CH)3)3C-、CF3CH2-, fluorine, chlorine, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, vinyl, CH2=CHCH2-, ethynyl group,Cyano, CNCH2-、CNCH2CH2-、CH3OCH2-、CH3OCH2CH2-、CF3C(CH3)2-、RllOr RmmEach independently selected from hydrogen, deuterium, hydroxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, halogen, cyano, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl or 3-6 membered heterocyclyl, preferably hydrogen,Deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, cyano, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl or 3-6 membered heterocyclyl containing 1-3N, O or S atoms, more preferably hydrogen, deuterium, methyl, ethyl, -CD3、-CD2CD3Propyl, hydroxymethyl, hydroxyethyl, ethenyl, propenyl, ethynyl, propynyl, FCH2-、F2CH-、F3C-, cyano, fluoro, chloro, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, tetrahydropyrrolyl or piperidinyl;or, R4And R6Or R6And R7Linked to form a heterocyclic or heteroaryl group, wherein said heterocyclic or heteroaryl group is optionally substituted with hydrogen, deuterium, halogen, C1-6Alkyl or C3-6One or more substituents in the cycloalkyl group; preferably 3-6 membered heterocyclyl or 3-7 membered heteroaryl, wherein said heterocyclyl or heteroaryl is optionally substituted by hydrogen, deuterium, fluoro, chloro, bromo, C1-3Alkyl or C3-5One or more substituents in the cycloalkyl group; more preferably a 3-6 membered heterocyclyl containing 1-3N, O or S atoms or a 3-7 membered heteroaryl containing 1-3N, O or S atoms, wherein said heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, cyclopropyl, cyclopentyl and cyclohexyl; further preferred is
- The compound of claim 1, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the general formula (I) is further represented by general formula (IV):wherein:ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably heteroaryl;R8selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, amino, cyano, alkyl, haloalkyl or cycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, halogen, hydroxyl, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;y is 0, 1,2 or 3;R、R1、R3~R6and x is as defined in claim 1.
- The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 5, wherein said compound isRing A is selected from C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl or 3-7 membered heteroaryl, preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 3-6 membered heteroaryl, more preferably C3-6Cycloalkyl, 3-6 membered heterocyclic group containing 1 to 3N, O or S atoms, phenyl, naphthyl or 3-6 membered heteroaryl group containing 1 to 3N, O or S atoms, further preferred Further preferred isR8Selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-6Haloalkyl, hydroxy, amino, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl and 3-7 membered heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-3Halogenated alkyl, hydroxyRadical, amino radical, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl and 3-6 membered heteroaryl containing 1-3N, O or S atoms, more preferably hydrogen, deuterium, methyl, ethyl, propyl, chloro-substituted methyl, chloro-substituted ethyl, fluoro-substituted methyl, fluoro-substituted ethyl, fluoro, chloro, bromo, cyano, nitro, hydroxy, amino, ethenyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl,
- A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which formula (I) is further represented by formula (V):wherein:R9selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-SRaa、-(CH2)n1C(O)Raa、-C(O)ORaa、-S(O)m1Raa、-NRaaRbb、-C(O)NRaaRbb、-NRaaC(O)Rbbor-NRaaS(O)m1RbbWherein said alkyl, haloalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further selected from hydrogen, deuterium, alkyl, haloAlkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;R、R3~R6、Raa、Rbband x is as defined in claim 1.
- The compound, its stereoisomers, or pharmaceutically acceptable salts thereof, according to claim 7, wherein said compound isR9Selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-6Haloalkyl, hydroxy, amino, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl or 3-7 membered heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-SRaa、-(CH2)n1C(O)Raa、-C(O)ORaa、-S(O)m1Raa、-NRaaRbb、-C(O)NRaaRbb、-NRaaC(O)Rbbor-NRaaS(O)m1RbbPreferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-3Haloalkyl, hydroxy, amino, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 3-6 membered heteroaryl, - (CH)2)n1Raa、-(CH2)n1ORaa、-SRaa、-(CH2)n1C(O)Raa、-C(O)ORaa、-S(O)m1Raa、-NRaaRbb、-C(O)NRaaRbb、-NRaaC(O)Rbbor-NRaaS(O)m1RbbMore preferably hydrogen, deuterium, hydroxy-substituted C1-3Alkyl radical, C1-3Cycloalkyl-substituted C1-3Alkyl, hydroxy substituted C1-3Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-3Haloalkyl, hydroxy, C3-6Cycloalkyl-substituted amino, halogen-substituted C2-5Alkenyl, halogen substituted C2-5Alkynyl, halogen substituted C3-6Cycloalkyl radical, C1-3Alkyl substituted C3-6Cycloalkyl, cyano-substituted C3-6Cycloalkyl radical, C1-3Alkoxy-substituted C3-6Cycloalkyl radical, C1-3Haloalkyl-substituted C3-6Cycloalkyl, 3-7 membered heterocyclyl containing 1-3N, O or S atoms, phenyl, naphthyl or 3-7 membered heteroaryl containing 1-3N, O or S atoms, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)Raaor-NRaaRbbFurther preferred isRaaOr RbbIndependently selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, halogen, cyano, nitro, C1-6Haloalkyl, hydroxy, amino, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl or 3-7 membered heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-3Haloalkyl, hydroxy, amino, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl or 3-6 membered heteroaryl containing 1-3N, O or S atoms, more preferably hydrogen, methyl, ethyl, propyl, fluoro, chloro, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl or biphenyl;m1 is 0, 1,2 or 3;n1 is 0, 1,2 or 3.
- A compound according to claim 1, a stereoisomer or a pharmaceutically acceptable salt thereof, which is further represented by formula (VI):wherein:ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably heteroaryl;R10selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably hydrogen, halogen, amino, cyano, alkyl, haloalkyl or cycloalkyl;z is 0, 1,2 or 3;R、R3~R6and x is as defined in claim 1.
- A compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 9, characterized in that it isRing B is selected from C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl or 3-7 membered heteroaryl, preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 3-6 membered heteroaryl, more preferably C3-6Cycloalkyl, 3-6 membered heterocyclic group containing 1-3N, O or S atoms, phenyl, naphthyl or 3-6 membered heteroaryl group containing 1-3N, O or S atoms, and further preferred isR10Selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-6Haloalkyl, hydroxy, amino, alkenyl, alkynyl, C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-12Aryl and 3-7 membered heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C1-3Haloalkyl, hydroxy, amino, alkenyl, alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl and 3-6 membered heteroaryl containing 1-3N, O or S atoms, more preferably hydrogen, methyl, ethyl, propyl, fluoro, chloro, hydroxy, amino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
- The compound of claim 1, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the general formula (I) is further represented by general formula (VII):wherein:m is S, NRccOr CRccRdd;R11Selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein saidAlkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, amino, cyano, alkyl, haloalkyl or cycloalkyl, optionally further substituted with one or more substituents selected from deuterated alkyl, deuterium, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;Rccand RddEach independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;or RccAnd Rdd(ii) linked to form a cycloalkyl or heterocyclyl, wherein said cycloalkyl or heterocyclyl is optionally further substituted with one or more substituents selected from deuterated alkyl, deuterium, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;R、R3~R6and x is as defined in claim 1.
- A compound, stereoisomer or pharmaceutically acceptable salt thereof, according to claim 11, wherein the compound is a pharmaceutically acceptable salt thereofR11Selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, halogen, cyano, nitro, C1-6Haloalkyl, hydroxy, amino, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-12Aryl and 3-to 8-membered heteroaryl,preferably hydrogen, C1-3Alkyl radical, C1-3Deuterated alkyl, halogen, amino, cyano, alkyl, C1-3Haloalkyl or C3-5Cycloalkyl, more preferably methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoro, chloro, bromo, difluoromethyl, difluoroethyl, trifluoromethyl or trifluoroethyl;Rccand RddEach independently selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, fluoro, chloro, bromo, cyano, nitro, hydroxy, amino, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-12Aryl or 3-6 membered heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, fluoro, chloro, bromo, cyano, nitro, hydroxy, amino, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S, C6-10Aryl or a 3-6 membered heteroaryl group containing 1-3N, O or S, more preferably hydrogen, methyl, ethyl, propyl, fluoro, chloro, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, hydroxy or cyano;
- A compound, stereoisomer or pharmaceutically acceptable salt thereof, according to claim 13, wherein the compound is a pharmaceutically acceptable salt thereofR3Selected from hydrogen, deuterium, fluorine, chlorine or bromine, preferably hydrogen, deuterium or fluorine, more preferably hydrogen or fluorine;R4is selected from C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, wherein said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, optionally substituted with one or more substituents further selected from methyl, ethyl, fluoro or chloro; preferably C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C3-5Cycloalkyl, 3-5 membered heterocyclyl, more preferably C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C3-5Cycloalkyl, a 3-to 5-membered heterocyclic group containing 1 to 3N, O or S atoms, more preferably methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,R5or R6Each independently is hydrogen or deuterium;x is 0, 1,2 or 3.
- the compound, its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15,r is selected from hydrogen and C1-6Alkoxy radical, C1-6Haloalkoxy, -ORaa、-SRaaor-NRaaRbb;R1Selected from 3-8 membered heterocyclyl, 5-8 membered heteroaryl, - (CH)2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(=S)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaC(O)ORbb、-NRaaS(O)m1Rbb、-(CH2)n1NRaaC(O)C(O)Raa、-NRaaCRbb=NRccor-NRaaCRbb=CRccRddWherein said 3-8 membered heterocyclyl and 5-8 membered heteroaryl are optionally further selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, halogen, hydroxy, amino, cyano, oxo and C3-8Cycloalkyl substituted with one or more substituents;R2selected from 3-8 membered heterocyclyl, 5-8 membered heteroaryl, -C (O) Raa、-(CH2)n1ORaa、-C(O)NRaaRbbor-S (O)m1NRaaRbbWherein said 3-8 membered heterocyclyl and 5-8 membered heteroaryl are optionally further selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, halogen, hydroxy, amino, cyano and C3-8Cycloalkyl substituted with one or more substituents;R3selected from hydrogen, halogen, cyano, C1-6Alkyl or C1-6A haloalkyl group;R5selected from hydrogen, halogen, cyano, C1-6Alkyl or C1-6A haloalkyl group;R4and R6Each independently selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl or- (CH)2)n1Raa(ii) a Preferably hydrogen, cyclopropyl orOr R4And R6Are linked to form a C3-8Cycloalkyl, preferably cyclopentyl;R7in the presence or absence, selected from hydrogen, halogen, cyano, C1-6Alkyl or C1-6A haloalkyl group;or R6And R7Are linked to form a C3-8Cycloalkyl, preferably cyclopentyl;R8and R10Each independently selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl or C3-8A cycloalkyl group;R9selected from hydrogen, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, - (CH)2)n1Raa、-(CH2)n1ORaa、-(CH2)n1C(O)Raa、-C(O)ORaa、-NRaaRbbor-C (O) NRaaRbbWherein said C1-6Alkyl radical, C3-8Cycloalkyl and 3-8 membered heterocyclyl are optionally further selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, halogen, hydroxy, amino, oxo, nitro, cyano, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl and 5-Substituted with one or more substituents in an 8-membered heteroaryl group;R11selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, halogen, cyano, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl or 5-8 membered heteroaryl;Raa、Rbb、Rccand RddEach independently selected from hydrogen, deuterium, cyano, halogen, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein said C is1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl and 5-8 membered heteroaryl optionally further substituted with one or more substituents selected from hydrogen, deuterium, C1-6Alkyl, halogen, hydroxy, amino, oxo, cyano, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl and 5-8 membered heteroaryl;or, RccAnd RddAre linked to form a C3-8Cycloalkyl, wherein said C3-8Cycloalkyl is optionally further selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, halogen, amino, oxo, cyano, hydroxy, C1-6Alkoxy radical, C1-6Haloalkoxy and C1-6Substituted with one or more substituents in the hydroxyalkyl group.
- a compound represented by the general formula (IX):wherein:ring C is selected from the following groups:R12independently selected from-ORee、-C(O)NReeRff、-(CH2)n1NReeRffor-S (O)m2NReeRff;R17Selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl or- (CH)2)n1Raa;ReeAnd RffEach independently selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein said C is1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl and 5-8 membered heteroaryl, optionally further substituted by a group selected from hydrogen, deuterium, C1-6Alkyl, halogen, hydroxy, amino, oxo, cyano, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl and 5-8 membered heteroaryl;n1 is 0, 1 or 2;m2 is 0, 1 or 2; and isq is 0, 1,2 or 3.
- A compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 18, wherein the compound is a pharmaceutically acceptable salt thereofR17Selected from hydrogen, halogen, cyano, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Haloalkyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl or- (CH)2)n1RaaPreferably hydrogen, halogen, cyano, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C substituted by 1-3 fluorine, chlorine or bromine atoms1-3Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms or- (CH)2)n1RaaMore preferred is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxocyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, thietanyl, allyl, propargyl, CF3CH2-、(CH3)2CF3C-、CN-、CNCH2-、CNCH2CH2-、RaaSelected from alkoxy, hydroxyalkyl, haloalkoxy, nitro, hydroxy, cyano, amino, aryl or heteroaryl, preferably C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, nitro, hydroxy, cyano, amino, C6-12Aryl or 3-12 membered heteroaryl, more preferably C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, nitro, hydroxy, cyano, amino, C6-10Aryl or 5-to 8-membered heteroaryl, further preferably methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, C substituted with 1 to 3 fluorine, chlorine or bromine atoms1-3Alkoxy, nitro, hydroxy, cyano, amino, phenyl, naphthyl, or a 3-6 membered heteroaryl containing 1-3N, O or S atoms;n1 is selected from 1 or 2.
- a compound represented by the general formula (X), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,wherein:R13and R14Each independently selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl;R15selected from 3-8 membered heterocyclyl, 5-8 membered heteroaryl, - (CH)2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(=S)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaC(O)ORbb、-NRaaS(O)m1Rbb、-(CH2)n1NRaaC(O)C(O)Raa、-NRaaCRbb=NRccor-NRaaCRbb=CRccRddWherein said 3-8 membered heterocyclyl and 5-8 membered heteroaryl are optionally further selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, halogen, hydroxy, amino, cyano and C3-8Cycloalkyl substituted with one or more substituents;R16selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl or- (CH)2)n1Raa;Raa、Rbb、RccAnd RddEach independently selected from hydrogen, deuterium, cyano, halogen, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical、C3-8Cycloalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein said C is1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl and 5-8 membered heteroaryl optionally further substituted with one or more substituents selected from hydrogen, deuterium, C1-6Alkyl, halogen, hydroxy, amino, oxo, cyano, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl and 5-8 membered heteroaryl;n1 is 0, 1 or 2; and ism1 is 0, 1 or 2.
- a compound of formula (XI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:wherein:R18selected from hydrogen, deuterium, halogen, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-8 membered heterocyclyl or- (CH)2)n1RaaPreferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, hydroxy, cyano, C2-5Alkenyl radical, C2-5Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl or- (CH)2)n1RaaMore preferably hydrogen, methyl, cyclopropyl, methyl, ethyl, propyl, isopropyl,R19Selected from hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, amino, hydroxy or cyano, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, fluoro, chloro, bromo, amino, hydroxy or cyano, more preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, fluoro, chloro, hydroxy or cyano;Raaselected from hydrogen, deuterium, cyano, hydroxy, halogen, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl or 3-8 membered heterocyclyl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy, fluorine, chlorine, bromine, cyano, C2-5Alkenyl radical, C2-5Alkynyl or C3-6Cycloalkyl, more preferably hydrogen, methyl, ethynyl or cyclopropyl;n1 is 0, 1 or 2;r is 0, 1,2 or 3.
- a process for preparing a compound of the general formula (V) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof according to claim 7, which comprises the steps of,the general formula (V-1) reacts with the general formula (V-2) to obtain a general formula (V-3), and the general formula (V-3) further reacts to obtain a compound shown in the general formula (V) or a stereoisomer and pharmaceutically acceptable salts thereof;wherein:x is selected from halogen;R3~R6、R9and x is as defined in claim 7.
- A process for preparing a compound of the general formula (V) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof according to claim 7, which comprises the steps of,the general formula (V-4) reacts with the general formula (V-5) to obtain a general formula (V-6), the general formula (V-6) further reacts with the general formula (V-2) to obtain a compound shown by the general formula (V) or a stereoisomer and pharmaceutically acceptable salts thereof;wherein:x is selected from halogen;R3~R6、R9and x is as defined in claim 7.
- A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 24, and stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
- The use of a compound according to any one of claims 1 to 24, and stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 27, in the manufacture of a TYK2 inhibitor medicament.
- Use of a compound according to any one of claims 1 to 24, and stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 27, for the manufacture of a medicament for the treatment of inflammatory and autoimmune diseases; wherein the inflammatory and autoimmune diseases are selected from rheumatoid arthritis, dermatitis, psoriasis or inflammatory bowel disease.
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CN114650990A (en) * | 2020-03-11 | 2022-06-21 | 北京诺诚健华医药科技有限公司 | Heterocyclic compounds inhibiting TYK2 activity |
CN114650990B (en) * | 2020-03-11 | 2023-02-03 | 北京诺诚健华医药科技有限公司 | Heterocyclic compounds for inhibiting TYK2 activity |
CN113735837A (en) * | 2020-05-28 | 2021-12-03 | 江苏先声药业有限公司 | Pyridazine compound and application thereof |
CN113735836A (en) * | 2020-05-28 | 2021-12-03 | 江苏先声药业有限公司 | Pyridazine compound and application thereof |
CN113735836B (en) * | 2020-05-28 | 2023-05-30 | 江苏先声药业有限公司 | Pyridazine compound and application thereof |
CN113735837B (en) * | 2020-05-28 | 2023-09-01 | 江苏先声药业有限公司 | Pyridazine compound and use thereof |
CN115667246A (en) * | 2020-07-24 | 2023-01-31 | 上海翰森生物医药科技有限公司 | Crystal form of pyridazine derivative free base and preparation method and application thereof |
CN115160297A (en) * | 2020-12-22 | 2022-10-11 | 益方生物科技(上海)股份有限公司 | Heteroaryl compounds, their preparation and use |
US11613548B2 (en) | 2021-02-19 | 2023-03-28 | Sudo Biosciences Limited | Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors |
CN116162093A (en) * | 2023-04-25 | 2023-05-26 | 中南大学湘雅医院 | TYK2 inhibitor compound and application thereof |
CN116162093B (en) * | 2023-04-25 | 2023-06-23 | 中南大学湘雅医院 | TYK2 inhibitor compound and application thereof |
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CN117263918A (en) | 2023-12-22 |
TW202043210A (en) | 2020-12-01 |
CN115448910A (en) | 2022-12-09 |
JP2022524279A (en) | 2022-05-02 |
CN111757878B (en) | 2023-07-28 |
WO2020156311A1 (en) | 2020-08-06 |
CN115448910B (en) | 2024-04-19 |
KR20210119426A (en) | 2021-10-05 |
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