CN112313213A - 3-amino pyrazole compound and application thereof - Google Patents

3-amino pyrazole compound and application thereof Download PDF

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CN112313213A
CN112313213A CN201980022751.4A CN201980022751A CN112313213A CN 112313213 A CN112313213 A CN 112313213A CN 201980022751 A CN201980022751 A CN 201980022751A CN 112313213 A CN112313213 A CN 112313213A
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amino
oxy
pyrazole
methyl
carboxamide
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CN112313213B (en
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丁克
耿美玉
陈成斌
丁健
谈理
艾菁
张章
彭霞
任小梅
季寅淳
段云鑫
戴阳
涂正超
陆小云
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Shanghai Institute of Materia Medica of CAS
Jinan University
Shanghai Haihe Pharmaceutical Co Ltd
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Shanghai Institute of Materia Medica of CAS
Jinan University
Shanghai Haihe Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

The invention relates to a 3-aminopyrazole compound with a structure shown in a formula (I), or pharmaceutically acceptable salt thereof, or stereoisomer thereof, or prodrug molecule thereof, or deuteron thereof and application thereof. The compound and the pharmaceutical composition thereof can be used as a protein kinase inhibitor, effectively inhibit the activity of AXL protein kinase and inhibit the proliferation, migration and invasion of various tumor cells.

Description

3-amino pyrazole compound and application thereof Technical Field
The invention relates to the technical field of chemical medicines, and particularly relates to a 3-aminopyrazole compound and application thereof.
Background
AXL is a class of receptor tyrosine kinases belonging to the TAM receptor tyrosine kinase family, which also includes two other members: mer and Tyro 3. TAMs were first found in tumor cells and their overexpression and ectopic expression were closely associated with immune regulation, tumor proliferation, growth and migration, etc. AXL was isolated in 1988 from chronic myelogenous leukemia patients and chronic myeloproliferative diseases. AXL is widely expressed in tissues such as brain, immune cells, platelets, endothelial cells, skeletal muscle, heart, liver and kidney. Vitamin K-dependent Protein kinase Gas6(growth arm-specific 6) is the most widely studied AXL ligand found at present, and other ligands of the TAM family include Protein S, Tubby, Tulp-1, Galectin-3. The family of TAMs have similar protein structures and consist essentially of three parts, an extracellular domain, which includes two N-terminal immunoglobulin-like regions Ig, and two fibronectin iii repeats (FN iii), a transmembrane region, and an intracellular domain. Binding of Gas6 to the extracellular domain of AXL induces AXL dimerization, triggering trans autophosphorylation of the intracellular domain, thereby activating intracellular signaling pathways and regulating a range of physiological activities. Modulating growth and proliferation of cells, such as through the Src/MAPK/ERK pathway; stimulating expression of anti-apoptotic proteins through the PI3K/AKT pathway; cell migration and proliferation are regulated by the PI3K/p38/MAPK pathway. AXL can be activated in a ligand independent manner in addition to Gas6 dependent activation. AXL is involved in the adhesion and immunoregulation of normal cells, and the over-expression of AXL is found to be present in various tumor cells, and Gas6/AXL regulated signal pathways are closely related to the occurrence and development of various tumors, such as chronic myelogenous leukemia, breast cancer, prostate cancer, non-small cell lung cancer, pancreatic cancer, melanoma, glioma and renal cell carcinoma. Inhibition of AXL expression has been shown to reduce the proliferation and growth of pancreatic cancer cells, inhibiting the invasion and migration of breast cancer cells. In non-small cell lung cancer, gene silencing AXL can inhibit tumor growth. Meanwhile, high expression of AXL is also associated with tumor recurrence and tolerance of other anticancer drugs, such as imatinib (Gliver), erlotinib (Tarceva), lapatinib (Tyverb). These evidence suggest AXL is an effective tumor-targeting therapeutic target.
Marketed drugs such as Bosutinib (SKI606, PF5208763, Bosulif; Pfizer, 2012), Cabozantinib (XL184, Cometriq; Exelixis, 2012), Sunitinib (SU11248, Sutent; Pfizer, 2006) are multi-target drugs and are not specific, although they have AXL activity. BGB324 (R428; Rigel Pharmaceuticals, BergenBio) is currently known as the most specific small molecule inhibitor of AXL, in phase II clinical studies, at 12 months 2014, and FDA awards an orphan drug title to BGB324 for the treatment of AML. Currently, no small molecule inhibitors against AXL kinase are on the market.
Disclosure of Invention
Based on the above, the invention provides a novel 3-amino pyrazole compound, which has strong inhibition activity on AXL kinase.
The specific technical scheme is as follows:
a3-aminopyrazole compound with a structure shown as a formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof or a deuteride thereof:
Figure PCTCN2019079733-APPB-000001
wherein X is selected from: CH or N;
z is selected from: o or NH;
b is selected from: c5～C 10Aryl, 5-to 10-membered heteroaryl, C3～C 6Cycloalkyl radical, C7～C 13A polycyclic alkyl group;
R 1、R 2with ring A forming a substituted or unsubstituted heterocyclic ring
Figure PCTCN2019079733-APPB-000002
m is 2 or 3, Y is selected from C, N or O;
R 3selected from: hydrogen, halogen-substituted C1～C 6Alkyl radical, C1～C 6Alkoxy or C1～C 6An alkyl group;
R 4selected from: hydrogen, C1～C 5Alkyl radical, C3～C 6Cycloalkyl radical, C1～C 3Alkoxy or
Figure PCTCN2019079733-APPB-000003
R 21Selected from: hydrogen, halogen, C1～C 5Alkyl radical, C3～C 6Cycloalkyl or C1～C 5An alkoxy group;
R 5、R 6each independently selected from: hydrogen, alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, aralkyl, substituted or unsubstituted heteroaryl, heteroaralkyl, substituted or unsubstituted polycycloalkyl; or, R5、R 6And the N atom to which they are attached, together form a monocyclic heterocycle or a fused heterocycle.
In some of these embodiments, the 3-aminopyrazole compound has the structure of formula (II):
Figure PCTCN2019079733-APPB-000004
x is selected from: CH or N.
In some of these embodiments, the substituted or unsubstituted fused heterocycle
Figure PCTCN2019079733-APPB-000005
Selected from the following structures:
Figure PCTCN2019079733-APPB-000006
wherein X is CH or N;
R 12、R 13each independently selected from: -O (CR)15R 16) OR 14；
Wherein o is an integer of 0-6;
R 14、R 15、R 16each independently selected from: -H, C1～C 5Alkyl, halogen substituted C1～C 5Alkyl, halogen substituted C1～C 5Alkoxy, -OH, -COOH, -COOR19、-(C＝O)-NR 19R 20、-SO m-NR 19R 20、-CHR 19R 20、-OR 19or-NR19R 20；m＝1～2；
R 19、R 20Each independently selected from: hydrogen, halogen, C1～C 6Alkyl, or R19And R20Form a saturated or unsaturated R22Substituted 5An 8 membered heterocyclic group wherein R22Selected from: -H, C1～C 5An alkyl group;
or, R12、R 13C containing 1 to 4 hetero atoms5～C 18An aliphatic cycloalkyl group.
In some of these embodiments, R14、R 15、R 16Each independently selected from: r14、R 15、R 16Each independently selected from: -H, C1～C 5Alkyl, -OR19or-NR19R 20；
R 19、R 20Each independently selected from: hydrogen, C1～C 6Alkyl, or R19、R 20And N to which they are attached together form a saturated or unsaturated R22A substituted 5-to 8-membered heterocyclic group wherein R22Selected from: -H, C1～C 5An alkyl group.
In some of these embodiments, R15And R16Are all hydrogen;
R 14selected from: -H, -OR19or-NR19R 20；
R 19、R 20Each independently selected from: c1～C 3Alkyl, or R19、R 20And N attached thereto together form saturated R22A substituted 5-to 8-membered heterocyclic group wherein R22Selected from: -H, C1～C 3An alkyl group.
In some of these embodiments, R12、R 13Each independently selected from: -O (CH)2) OR 14(ii) a o is an integer of 0 to 4.
In some of whichIn, R12And R13One of them is selected from C1～C 4Alkoxy, the other being selected from: -O (CH)2) OR 14；
o is an integer between 1 and 4;
R 14selected from: H. -OR19or-NR19R 20；
R 19、R 20Each independently selected from: c1～C 3Alkyl, or R19、R 20And N attached thereto together form R22Substituted 6-membered saturated heterocyclic group, wherein R22Selected from: -H, C1～C 3An alkyl group.
In some of these embodiments, R12And R13Each independently selected from: methoxy, ethoxy, propoxy, morpholinyl substituted propoxy, methoxy substituted ethoxy, methoxy substituted propoxy, dimethylamino substituted propoxy, piperidine substituted propoxy, N-methylpiperazine substituted propoxy.
In some of these embodiments, R3Selected from: H. halogen, trifluoromethyl, C1～C 3Alkyl radical, C1～C 3An alkoxy group.
In some of these embodiments, R3Selected from: H. f, Cl, Br, methyl, ethyl, methoxy and ethoxy.
In some of these embodiments, R4Selected from: c1～C 3An alkyl group.
In some of these embodiments, R5、R 6Each independently selected from: hydrogen, C1～C 8Alkyl radical, R8Substituted C3～C 10Cycloalkyl radical, R8Substituted 3-10 membered heterocycloalkyl, R10Substituted C5-C 10Aryl, aralkyl, R10Substituted 5-10 membered heteroaryl, heteroaralkyl, R8Substituted C7～C 13A polycyclic alkyl group; or, R5、R 6And the N atom to which they are attached form a 3-to 10-membered monocyclic heterocycle or fused-ring heterocycle;
R 8selected from: hydrogen, C1～C 6Alkyl, halogen;
R 10selected from: hydrogen, halogen, C1～C 6Alkyl radical, C1～C 6Alkoxy, cyano, halogen substituted C1～C 6Alkyl, halogen substituted C1～C 6Alkoxy, cyano-substituted C1～C 6An alkyl group.
In some of these embodiments, R5、R 6Each independently selected from: hydrogen, C1～C 8Alkyl radical, R8Substituted C3～C 8Cycloalkyl radical, R8Substituted 6-8 membered heterocycloalkyl, R10Substituted phenyl, adamantyl, R10Substituted 5-10 membered heteroaryl; or, R5、R 6And the N atom to which they are attached, together form a 3-to 10-membered monocyclic heterocycle or fused heterocycle.
In some of these embodiments, R6Selected from: hydrogen, C1～C 5An alkyl group; r5Selected from: c2～C 8Alkyl radical, R8Substituted C3～C 8Cycloalkyl radical, R8Substituted 6-8 membered heterocycloalkyl, R10Substituted phenyl, adamantyl; or, R5、R 6And the N atom to which they are attached, together form a 3-to 10-membered monocyclic heterocycle or fused heterocycle.
In some of these embodiments, R6Selected from: hydrogen, C 1～C 5An alkyl group; r5Selected from: c4～C 8Alkyl radical, R8Substituted C4～C 8Cycloalkyl radical, R10Substituted phenyl, R8Substituted 6-8 membered heterocycloalkyl, adamantyl; or, R5、R 6And the N atom to which they are attached, together form a 3-to 10-membered monocyclic heterocycle or fused heterocycle.
In some of these embodiments, R6Selected from: hydrogen, C1～C 3An alkyl group; r5Selected from: r8Substituted C5～C 8Cycloalkyl radical, R10Substituted phenyl, adamantyl.
In some of these embodiments, R8Selected from: hydrogen, halogen; r10Selected from: hydrogen, halogen, C1～C 2Alkyl, methoxy.
In some of these embodiments, the 3-aminopyrazole compound has the structure of formula (III):
Figure PCTCN2019079733-APPB-000007
wherein R is3Selected from: H. halogen, C1～C 3Alkyl radical, C1～C 3An alkoxy group;
R 6selected from: hydrogen, C1～C 2An alkyl group;
R 5selected from: c5～C 8Cycloalkyl radical, R10Substituted phenyl, 6-8 membered heterocycloalkyl; or, R5、R 6And the N atom to which they are attached form a 3-to 10-membered monocyclic heterocycle or fused-ring heterocycle;
R 10selected from: hydrogen, halogen, C1～C 2Alkyl, methoxy, halogen substituted C1～C 2An alkoxy group;
R 13selected from: -O (CH)2) OR 14(ii) a o is an integer between 1 and 4;
R 14selected from: H. -OR19or-NR19R 20；
R 19、R 20Each independently selected from: c1～C 3Alkyl, or R19、R 20And N attached thereto together form R22Substituted 6-membered saturated heterocyclic group, wherein R22Selected from: -H, C1～C 3An alkyl group.
In some of these embodiments, the 3-aminopyrazole compound is selected from:
3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N, 1-dimethyl-1H-pyrazole-4-carboxamide,
3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N-ethyl-1-methyl-1H-pyrazole-4-carboxamide,
N-cyclopropyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-tert-butyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclopentyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cycloheptyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclooctyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
(3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazol-4-yl) (piperidin-1-yl) methanone,
(3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazol-4-yl) (octahydroquinolin-1 (2H) -yl) methanone,
N- (4, 4-difluorocyclohexyl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N- (tetrahydro-2H-pyran) -1H-pyrazole-4-carboxamide,
N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N, 1-dimethyl-1H-pyrazole-4-carboxamide,
N- (adamantan-1-yl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N-phenyl-1H-pyrazole-4-carboxamide,
3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N- (o-tolyl) -1H-pyrazole-4-carboxamide,
3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N- (m-tolyl) -1H-pyrazole-4-carboxamide,
3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N- (3-ethylphenyl) -1H-pyrazole-4-carboxamide,
3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N- (p-tolyl) -1H-pyrazole-4-carboxamide,
3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (2-methoxyphenyl) -1-methyl-1H-pyrazole-4-carboxamide,
3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (3-methoxyphenyl) -1-methyl-1H-pyrazole-4-carboxamide,
3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4-methoxyphenyl) -1-methyl-1H-pyrazole-4-carboxamide,
N- (3-chlorophenyl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N- (4-chlorophenyl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (3-fluorophenyl) -1-methyl-1H-pyrazole-4-carboxamide,
3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4-fluorophenyl) -1-methyl-1H-pyrazole-4-carboxamide,
3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4-cumyl) -1-methyl-1H-pyrazole-4-carboxamide,
3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4- (trifluoromethoxy) phenyl) -1-methyl-1H-pyrazole-4-carboxamide,
N- (4- (difluoromethoxy) phenyl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N- (4- (cyanomethyl) phenyl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -2-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -2-tolyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
3- ((3-chloro-4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) amino) -N-cyclohexyl-1-methyl-1H-pyrazole-4-carboxamide,
N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-tolyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-methoxyphenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclohexyl-3- ((4- ((7-ethoxy-6-methoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7-propoxyquinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (2-methoxyethoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (3-methoxypropoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclohexyl-3- ((4- ((7- (3- (dimethylamine) propoxy) -6-methoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cycloheptyl-3- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
N-cyclopentyl-3- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
3- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -N- (4-fluorophenyl) -1-methyl-1H-pyrazole-4-carboxamide.
The invention also provides application of the 3-aminopyrazole compound or pharmaceutically acceptable salt or stereoisomer thereof.
The specific technical scheme is as follows:
the 3-aminopyrazole compound or pharmaceutically acceptable salt thereof, or stereoisomer thereof or prodrug molecule thereof is applied to the preparation of the AXL kinase inhibitor.
The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof, or stereoisomer thereof, or prodrug molecule thereof, or deuteron thereof is applied to preparing the medicine for preventing and treating tumors.
In some of these embodiments, the tumor is: hematologic tumors, gastrointestinal stromal tumors, histiocytic lymphoma, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, and nasopharyngeal cancer. Such as leukemia and the like.
The invention also provides a pharmaceutical composition for preventing and treating tumors.
The specific technical scheme is as follows:
a pharmaceutical composition for preventing and treating tumors comprises the 3-aminopyrazole compound or pharmaceutically acceptable salts thereof or stereoisomers thereof or prodrug molecules thereof or deuterons thereof and a pharmaceutically acceptable carrier.
The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof, or stereoisomer thereof, prodrug molecule thereof or deuteron thereof can effectively inhibit the function of protein kinases such as AXL and the like, thereby inhibiting the proliferation, migration and invasion of various tumor cells, being used for preparing antitumor drugs and being used for preparing drugs for preventing and/or treating hyperproliferative diseases such as tumors of human beings and other mammals.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.
In the compounds of the invention, when any variable (e.g. R)1R, etc.) occur more than one time in any constituent, then the definition of each occurrence is independent of the definition of each other occurrence. Also, allow to getCombinations of substituents and variables provided such combinations stabilize the compound. The line drawn from a substituent into the ring system indicates that the indicated bond can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It is to be understood that substituents and substituted forms of the compounds of the present invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by those skilled in the art and by the methods set forth below from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stable.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C 5Alkyl radical "middle" C1-C 5The definition of "includes groups having 1, 2, 3, 4 or 5 carbon atoms in a linear or branched arrangement. For example, "C1-C 5Alkyl "specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "heteroaryl" as used herein represents a stable monocyclic or bicyclic carbon ring of up to 5 atoms in the ring, wherein at least one ring is aromatic and contains 1 to 4 heteroatoms selected from O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to: imidazolyl, pyrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyrimidinyl, pyrrolyl. For the following definition of heteroaryl, "heteroaryl" is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group. In the case where the heteroaryl substituent is bicyclic and contains one ring that is non-aromatic or does not contain heteroatoms, it is understood that each is attached via an aromatic ring or via a heteroatom-containing ring.
The term "heterocycle" or "heterocyclyl" as used herein refers to a 5-to 6-membered aromatic or nonaromatic heterocycle containing 1 to 4 heteroatoms selected from O, N and S and includes bicyclic groups. "Heterocyclyl" thus includes the above-mentioned heteroaryl groups, as well as the dihydro and tetrahydro analogues thereof. Further examples of "heterocyclyl" include, but are not limited to: imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl (oxyethanyl), pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, oxazolyl. Attachment of the heterocyclic substituent may be through a carbon atom or through a heteroatom.
As understood by those skilled in the art, "halo" or "halogen" as used herein is meant to include chloro, fluoro, bromo, and iodo.
Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl substituents may be unsubstituted or substituted. For example, (C)1～C 6) Alkyl groups may be substituted with one, two or three substituents selected from OH, halogen, nitro, cyano, alkoxy, dialkylamino or heterocyclyl, e.g. morpholinyl, piperidinyl and the like.
The invention includes the free forms of the compounds of formulae I-III, as well as pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine-based compounds. The term "free form" refers to the amine compound in a non-salt form. Included pharmaceutically acceptable salts include not only the exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I. The free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a dilute aqueous solution of a suitable base, such as a dilute aqueous NaOH solution, a dilute aqueous potassium carbonate solution, dilute aqueous ammonia, and a dilute aqueous sodium bicarbonate solution. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.
Thus, pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present invention and an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-monobenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.
If a compound of the invention is acidic, an appropriate "pharmaceutically acceptable salt" refers to a salt prepared by a pharmaceutically acceptable non-toxic base including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, piperdine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Berg et al, "Pharmaceutical Salts," J.pharm.Sci.1977:66:1-19. the preparation of the pharmaceutically acceptable Salts described above and other typical pharmaceutically acceptable Salts is described in more detail.
Since acidic moieties such as carboxyl groups deprotonated in a compound under physiological conditions may be anionic and such charge may then be balanced out by a protonated or alkylated basic moiety such as a quaternary nitrogen atom bearing a cation internally, it should be noted that the compounds of the present invention are potential internal salts or zwitterions.
In addition to standard methods known in the literature or exemplified in experimental procedures, the compounds of the invention can be prepared using reactions as shown in the following schemes. The following illustrative schemes are therefore for illustrative purposes and are not limited to the compounds listed or any particular substituents. The number of substituents shown in the schemes does not necessarily correspond to the number used in the claims and for the sake of clarity a single substituent is shown attached to the compound allowing polysubstitution under the definition of formula (I) above.
Synthetic schemes
The compounds of formula (I) as shown in scheme a can be synthesized by 4-step reaction starting from 6, 7-dimethoxy-4-chloroquinoline.
Scheme A:
Figure PCTCN2019079733-APPB-000008
the compounds of formula (I) as shown in scheme B can be synthesized by 6-step reaction starting from 6-methoxy-7-benzyloxy-4-chloroquinoline.
Scheme B:
Figure PCTCN2019079733-APPB-000009
the 3-aminopyrazole compound or pharmaceutically acceptable salt or stereoisomer thereof provided by the invention can be used for treating hyperproliferative diseases or symptoms such as human or other mammal tumors and the like. In particular to the preparation of the drugs for treating or controlling the hyperproliferative diseases such as gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostatic cancer, liver cancer, skin cancer, epithelial cell cancer, prostatic cancer, nasopharyngeal carcinoma, leukemia, and the like.
The compound and the pharmaceutically acceptable salt or the stereoisomer thereof designed by the invention can be used as the current estrogen receptor modulator, androgen receptor modulator, retina-like receptor modulator, cytotoxin/cytostatic agent, antiproliferative agent, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV protein kinase inhibitor, reverse transcriptase inhibitor, angiogenesis inhibitor, cell proliferation and survival signal inhibitor, cell cycle checkpoint interfering drug and apoptosis inducer, cytotoxic drug, tyrosine protein inhibitor, EGFR inhibitor, VEGFR inhibitor, serine/threonine protein inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, MEK inhibitor, MMP inhibitor, topoisomerase inhibitor, HIV-CoA reductase inhibitor, VEGF inhibitor, MMP inhibitor, topoisomerase inhibitor, or a pharmaceutically acceptable salt or a stereoisomer thereof, The clinical effect of the pharmaceutical composition is enhanced by the combined use of medicaments such as histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon-alpha, interleukin-12, COX-2 inhibitors, p53 activators, VEGF antibodies, EGF antibodies and the like.
The compound with the structure of formula (I) and the pharmaceutically acceptable salt thereof or the stereoisomer thereof or the pharmaceutical composition thereof can be used for preparing medicines for preventing and treating the following diseases and other diseases which are not listed below:
(1) human or other mammalian breast cancers include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
(2) Cancers of the respiratory tract in humans or other mammals include, but are not limited to, small cell & non-small cell lung cancer as well as bronchial adenomas and pleural pneumococcal carcinomas.
(3) Brain cancers of humans or other mammals include, but are not limited to, brain stem and sub-ocular gliomas, cerebellum and brain astrocytomas, ependymomas, and neuroectodermal and pineal tumor bodies.
(4) Tumors of male and female reproductive organs of humans or other mammals, including but not limited to prostate and testicular cancer; tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal and vulvar cancers, as well as intrauterine tumors.
(5) Tumors of the digestive tract of humans or other mammals, including but not limited to anal, colon, colorectal, esophageal, gastric, pancreatic, rectal, small bowel or salivary gland cancers.
(6) Tumors of the urinary tract of humans or other mammals, including but not limited to bladder, penile, kidney, renal pelvis, ureter, or urinary tract cancer.
(7) Eye cancers of humans or other mammals, including but not limited to intraocular melanoma and retinoblastoma.
(8) Liver cancers in humans or other mammals, including but not limited to hepatoma (stem cell cancer with or without fibroplasia), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma.
(9) Human or other mammalian skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merck's cell skin cancer, and nonmelanoma cell cancer.
(10) Head and neck cancers in humans or other mammals, including but not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancers, and lip and oral cancers.
(11) Human or other mammalian lymphomas, including but not limited to AIDS-related lymphomas, non-Hodgkin's lymphomas, cutaneous T-cell lymphomas, Hodgson's disease, and central nervous system lymphomas.
(12) Sarcomas in humans or other mammals include, but are not limited to, soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, sarcomas, and rhabdomyosarcomas.
(13) Human or other mammalian leukemias, including, but not limited to, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
Dosage form and dosage range
The compounds of the present invention may be administered to a mammal, preferably a human, either alone or in pharmaceutical compositions in combination with a pharmaceutically acceptable recipient, adjuvant or diluent, in accordance with standard pharmaceutical techniques. The compounds can be administered orally or subcutaneously, intramuscularly, intraperitoneally, intravenously, rectally, and topically, ocularly, pulmonarily, nasally, parenterally.
In one embodiment, the compound of formula (I) is used for the preparation of a medicament for treating or controlling cancer and the like in a dosage range of 0.1 to 500 mg/day/kg body weight per oral administration. Suitable modes of administration are single daily administration or multiple administrations of two, three, four etc. times daily administration or administration using sustained release techniques. For many large mammals, the preferred dosage range is 0.1-1500 mg/day/kg body weight, preferably 0.5-100 mg/day/kg body weight. The daily dosage of the composition is 1-500 mg for patients with the average weight of 70 kg. For some particularly highly active compounds, the daily dose for adult patients may be as low as 0.1 mg/day.
Drug metabolites and prodrugs
Metabolites of the compounds and pharmaceutically acceptable salts thereof to which the present invention relates, and prodrugs which can be converted in vivo into the structures of the compounds and pharmaceutically acceptable salts thereof to which the present invention relates, are also included in the claims of the present application.
Combination drug
The compounds of formula (I) may be combined with other drugs known to treat or ameliorate similar conditions. When the combination is administered, the mode of administration and the dosage of the original drug remain unchanged, while the compound of formula (I) is administered simultaneously or subsequently. When the compound of formula (I) is administered simultaneously with one or more other drugs, it is preferable to use a pharmaceutical composition containing both one or more known drugs and the compound of formula (I). The pharmaceutical combination also comprises the administration of a compound of formula (I) in an overlapping time period with one or more other known drugs. When a compound of formula (I) is administered in a pharmaceutical combination with one or more other drugs, the dose of the compound of formula (I) or known drug may be lower than the dose when they are administered alone.
Drugs or active ingredients that may be used in pharmaceutical combination with the compounds of formula (I) include, but are not limited to:
estrogen receptor modulators, androgen receptor modulators, retinal-like receptor modulators, cytotoxins/cytostatics, antiproliferatives, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, inhibitors of apoptosis, inhibitors of tumor growth, and the like, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon-alpha, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibodies, EGF antibodies, and the like.
In one embodiment, drugs or active ingredients that may be used in pharmaceutical combination with the compounds of formula (I) include, but are not limited to: aldesleukin, alendronic acid, interferon, atrazine, allopurinol sodium, palonosetron hydrochloride, hexamethylmelamine, aminoglutethimide, amifostine, amrubicin, ambrolidine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, anoxin, 5-azacytidine, azathioprine, bacillus calmette or tide bacillus calmette, betadine, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromouroxime, bortezomib, busulfan, calcitonin, alezomab injection, capecitabine, carboplatin, custard, cefesone, simon, daunorubicin, phenylbutyric acid azone, mustard, cladribine, clodronate, cyclophosphamide, alexanide, dacarbazine, actinomycin, dexamethasone, estramustin phosphate, estramustine, dexamethasone, estradiol phosphate, estradiol valerate phosphate, valproate, doxylamine, and mixtures thereof, Dinil interleukin 2, dibume, deslorelin, delazoxan, diethylstilbestrol, tolbutan, docetaxel, doxifluridine, doxorubicin, dronabinol, azulene-166-chitosan complex, eligard, labyrinase, epirubicin hydrochloride, aprepitant, epirubicin, alfafurtine, erythropoietin, eptaplatin, levamisole, estradiol formulations, 17-beta-estradiol, estramustine sodium phosphate, ethinylestradiol, amifostine, hydroxyphosphoric acid, pirimiphoside, etoposide, favuzole, tamoxifen formulations, filgrastim, phenastidine, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, flumetmesterone, flunomide, fulvestrant, 1-beta-D-arabinofuranosylcytisidine-5 '-stearoyl-5' -stearoyl phosphate, flutamide, fluvastatin, Fotemustine, fulvestrant, gamma globulin, gemcitabine, gemtuzumab ozogamicin, imatinib mesylate, carmustine wafer capsule, goserelin, glanesilong hydrochloride, histrelin, and meclizine, hydrocortisone, erythro-hydroxynonyladenine, hydroxyurea, temin bemomab, idarubicin, ifosfamide, interferon alpha 2A, interferon alpha 2B, interferon alpha nl, interferon alpha n3, interferon beta, interferon gamma la, interleukin 2, intron A, iressa, irinotecan, kateride, lentinan sulfate, letrozole, leucovorin, leuprolide, leuprorelin, levamisole acetate, levamisole, calcium levofolinate, sodium levothyroxine preparation, Lomustine, lonidamine, dronabinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-ryopurine, mesna, methotrexate, methyl aminoacetonate, miltefosine, milbemycin, mitomycin C, mitotane, mitoxantrone, trilostane, doxorubicin citrate liposome, nedaplatin, pegylated filgrastim, omprex interleukin, neupogen, nilutamide, tamoxifen, NSC-631570, recombinant human interleukin 1-beta, octreotide, ondansetron hydrochloride, hydrocortisone oral solution, oxaliplatin, paclitaxel, prednisone sodium phosphate formulation, pemetrexed, domethacin, pentostatin, streptolysin formulation, pilocarpine hydrochloride, bordeauxins, plicamycin, pemetrexen, phenomycin, and prednisone, Sportandrone, prednisone, pemetrexed, procarbazine, recombinant human erythropoietin, raltitrexed, ribi, rhenium-186 etidronate, merosal, dydrin-A, romopeptide, pilocarpine hydrochloride tablets, octreotide, samostin, semustine, Sizopyran, sobuzosin, Succinum methylprednisolone, Pafoscarnet, Stem cell therapy, streptozocin, strontium chloride-89, levothyroxine sodium, tamoxifen, tamsulosin, tasolomide, Tatolactone, Tetharidin, Texithiozine, temozolomide, teniposide, testosterone propionate, Methyltestosterone, thioguanine, Thiotepipa, thyrotropine, Teluzosin, topotecan, Tourette, Trastuzumab, Osotuzumab, Van, methotrexate tablets, trimetrexate, Trimethoxamine, triptorelin acetate, troxate, topotecan, Tourethrin, Tritrexate, Tritrex, Trimethoprim, Tritrex, Tritre, Triptorelin pamoate, eufordine, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vinblastine amide, vinorelbine, vilulizine, dexpropinimine, neat stastine ester, pindolin, paclitaxel protein stabilizing formulations, acolbifene, interferon r-lb, affinitak, aminopterin, azoxifene, aspristil, atamestane, atrasentan, BAY 43-9006, avastin, CCI-779, CDC-501, celecoxib, cetuximab, clinacatto, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, eocharin, eflornithine, irinotecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implants, banorelin-166 holmium-DOTMP, ibandrosphonic acid, gamma-loxabenzene, loxabenzein, PEG-loxapine, keyhole limpet, hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafamib, mirepredfene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, orlimerson, onco-TCS, osidmem, paclitaxel polyglutamate, pamil sodium, PN-401, QS-21, quasisal, R-1549, raloxifene, ranpirnase, 13-cis-tretinoin, satraplatin, oxcalciferol, T-138067, tarceva, paclitaxel docosate, thymosin alpha L, gazofurin, tipifarnib, telazamide, TLK-286, toremifene, trans MID-7R, valsartan, pravastatin, valatib, tiprofen, vinpocetine-100, and mixtures thereof.
The reagents used in the following examples are commercially available.
The following are specific examples:
example 1: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4-fluorophenyl) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3049)
Scheme A.
Figure PCTCN2019079733-APPB-000010
Step a 1: preparation of 4- (4-bromo-2-fluorophenoxy) -6, 7-dimethoxyquinoline (Compound 2)
4-chloro-6, 7-dimethoxyquinoline (compound 1) (2.2g, 10mmol) and 4-bromo-2-fluorophenol (2.2mL, 20mmol) were combined and heated to 140 deg.C and stirred overnight. Cooling to room temperature, adding saturated sodium carbonate solution, extracting with dichloromethane, mixing organic phases, washing with saturated saline solution, anhydrous Na2SO 4Drying, filtering and spin-drying, separating by column chromatography to obtain solid 3.2g (84.6%).1H NMR(300MHz,DMSO-d 6)δ8.82(d,J＝6.3Hz,1H),7.98(dd,J＝10.2,2.0Hz,1H),7.73(d,J＝7.7Hz,1H),7.70–7.57(m,1H),7.03(d,J＝6.3Hz,1H),4.03(d,J＝2.3Hz,3H).MS(ESI),m/z:378[M+H] +。
Step a 2: preparation of ethyl 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxylate (Compound 3)
4- (4-bromo-2-fluorophenoxy) -6, 7-dimethoxyquinoline (compound 2) (3.8g, 10mmol), ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate (1.7g, 10mmol), Pd2(dba) 3(275mg, 0.3mmol), Xantphos (579mg, 1mmol) and cesium carbonate (6.5g, 20mmol) were dissolved in 50mL anhydrous dioxane and refluxed overnight under argon. Cooled to room temperature, filtered through celite, spin-dried, and chromatographed to give a solid (3.5 g, 75.0%).1H NMR(300MHz,DMSO-d 6)δ8.51–8.39(m,1H),8.21(s,1H),7.90(d,J＝13.9Hz,1H),7.54(s,1H),7.49(d,J＝9.5Hz,1H),7.42–7.30(m,1H),6.43(d,J＝5.1Hz,1H),4.27(q,J＝7.0Hz,1H),3.95(s,3H),3.82(s,2H),1.30(t,J＝7.0Hz,1H).MS(ESI),m/z:467[M+H] +。
Step a 3: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxylic acid (Compound 4)
Ethyl 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxylate (compound 3) (2.3g, 5mmol) and sodium hydroxide (600mg, 15mmol) were dissolved in a combined solvent of 15mL of ethanol and 5mL of water and reacted at 60 ℃ for 2 hours. Cool to room temperature, spin dry ethanol and make weak acidity with 1N HCl solution, filter, dry to get 2.0g (91.3%) solid.1H NMR(300MHz,DMSO-d 6)δ8.76(s,1H),8.47(d,J＝5.2Hz,1H),8.08(s,1H),7.89(dd,J＝13.7,2.1Hz,1H),7.54(s,1H),7.48–7.28(m,2H),6.44(d,J＝5.1Hz,1H),3.95(s,3H),3.80(s,2H).MS(ESI),m/z:439[M+H] +。
Step a 4: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4-fluorophenyl) -1-methyl-1H-pyrazole-4-carboxamide (CCB-049)
3- ((4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxylic acid (compound 4) (219mg, 0.5mmol), p-fluoroaniline (57. mu.L, 0.6mmol) and HATU (285mg, 0.75mmol) was dissolved in 10mL DMF and DIEA (259. mu.L, 1.5mmol) was added and stirred at room temperature overnight. Adding saturated sodium chloride solution, extracting with dichloromethane, mixing organic phases, washing with saturated brine for three times, and collecting anhydrous Na2SO 4Drying, filtering, spin-drying and isolating by column chromatography to give 191mg (71.9%) of solid.1H NMR(300MHz,DMSO-d 6)δ9.93(s,1H),9.25(s, 1H),8.63(d,J＝5.7Hz,1H),8.39(s,1H),7.95(dd,J＝13.7,2.3Hz,1H),7.71(m,2H),7.64(s,1H),7.52–7.33(m,3H),7.20(t,J＝8.9Hz,2H),6.67(d,J＝5.7Hz,1H),3.99(s,6H),3.88(s,3H)。MS(ESI),m/z:532[M+H] +。
Example 2: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N, 1-dimethyl-1H-pyrazole-4-carboxamide (CCB-3152)
Figure PCTCN2019079733-APPB-000011
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.39(s,1H),8.47(d,J＝5.2Hz,1H),8.21–8.00(m,2H),7.93–7.78(m,1H),7.55(s,1H),7.46–7.23(m,3H),6.44(dd,J＝5.3,1.1Hz,1H),3.96(d,J＝1.6Hz,6H),3.82(s,3H),2.76(d,J＝4.5Hz,3H).MS(ESI),m/z:452[M+H] +。
Example 3: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N-ethyl-1-methyl-1H-pyrazole-4-carboxamide (CCB-3151)
Figure PCTCN2019079733-APPB-000012
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.39(s,1H),8.46(d,J＝5.2Hz,1H),8.27(t,J＝5.5Hz,1H),8.20(s,1H),7.91–7.80(m,1H),7.54(s,1H),7.40(s,1H),7.37–7.28(m,2H),6.43(d,J＝5.2Hz,1H),3.95(m,6H),3.81(s,3H),3.25(m,2H),1.11(t,J＝7.2Hz,3H).MS(ESI),m/z:465[M+H] +。
Example 4: preparation of N-cyclopropyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3088)
Figure PCTCN2019079733-APPB-000013
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.38(s,1H),8.47(d,J＝5.2Hz,1H),8.16(d,J＝2.9Hz,1H),8.08(s,1H),7.86(d,J＝13.5Hz,1H),7.54(s,1H),7.40(s,1H),7.34(d,J＝5.7Hz,2H),6.43(d,J＝5.2Hz,1H),3.95(s,6H),3.80(s,3H),2.76(m,1H),0.69(m,2H),0.51(m,2H).MS(ESI),m/z:478[M+H] +。
Example 5: preparation of N-tert-butyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3069)
Figure PCTCN2019079733-APPB-000014
The synthesis was as in example 1.
1H NMR(300MHz,DMSO-d 6)δ9.35(s,1H),8.47(d,J＝5.2Hz,1H),8.28(s,1H),7.87(d,J＝13.5Hz,1H),7.54(s,1H),7.47–7.24(m,4H),6.43(d,J＝5.2Hz,1H),3.95(s,6H),3.80(s,3H),1.37(s,9H).MS(ESI),m/z:494[M+H] +。
Example 6: preparation of N-cyclopentyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3091)
Figure PCTCN2019079733-APPB-000015
The synthesis was as in example 1.
1H NMR(300MHz,DMSO-d 6)δ9.40(s,1H),8.47(d,J＝5.1Hz,1H),8.20(s,1H),7.97– 7.80(m,2H),7.54(s,1H),7.40(s,1H),7.33(m,2H),6.43(d,J＝5.1Hz,1H),4.20(m,1H),3.95(s,6H),3.81(s,3H),1.88(m,2H),1.78–1.62(m,2H),1.62–1.39(m,4H).MS(ESI),m/z:506[M+H] +。
Example 7: preparation of N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3087)
Figure PCTCN2019079733-APPB-000016
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.43(s,1H),8.47(d,J＝5.2Hz,1H),8.20(s,1H),7.93–7.81(m,2H),7.54(s,1H),7.40(s,1H),7.38–7.29(m,2H),6.43(d,J＝5.2Hz,1H),3.95(s,6H),3.81(s,3H),3.74(m,1H),1.83(m,2H),1.79–1.67(m,2H),1.61(m,1H),1.21(m,5H).MS(ESI),m/z:520[M+H] +。
Example 8: preparation of N-cycloheptyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3146)
Figure PCTCN2019079733-APPB-000017
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.47(d,J＝5.2Hz,1H),8.21(s,1H),7.91(d,J＝7.9Hz,1H),7.88–7.81(m,1H),7.54(s,1H),7.40(s,1H),7.33(m,2H),6.43(d,J＝5.2Hz,1H),3.94(m,7H),3.81(s,3H),1.92–1.79(m,2H),1.72–1.36(m,10H).MS(ESI),m/z:534[M+H] +。
Example 9: preparation of N-cyclooctyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3263)
Figure PCTCN2019079733-APPB-000018
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.41(s,1H),8.47(d,J＝5.2Hz,1H),8.22(s,1H),7.86(m,2H),7.54(s,1H),7.40(s,1H),7.33(m,2H),6.48–6.39(d,J＝5.2Hz,1H),4.07–3.98(m,1H),3.95(s,6H),3.81(s,3H),1.82–1.42(m,14H).MS(ESI),m/z:548[M+H] +。
Example 10: preparation of (3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazol-4-yl) (piperidin-1-yl) methanone (CCB-3245)
Figure PCTCN2019079733-APPB-000019
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.02(s,1H),8.47(d,J＝5.2Hz,1H),8.05(s,1H),7.80(dd,J＝13.8,2.3Hz,1H),7.53(s,1H),7.40(s,1H),7.38–7.25(m,2H),6.42(d,J＝5.2Hz,1H),3.95(s,6H),3.82(s,3H),3.65–3.53(m,4H),1.64(m,2H),1.59–1.48(m,4H).MS(ESI),m/z:506[M+H] +。
Example 11: preparation of (3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazol-4-yl) (octahydroquinolin-1 (2H) -yl) methanone (CCB-3252)
Figure PCTCN2019079733-APPB-000020
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.27(s,1H),8.47(d,J＝5.2Hz,1H),8.01(s,1H),7.81(dd,J＝13.8,2.3Hz,1H),7.54(s,1H),7.40(s,1H),7.38–7.25(m,2H),6.42(d,J＝5.2Hz,1H),3.95(s,6H),3.93–3.86(m,1H),3.82(s,3H),3.46–3.34(m,2H),2.08(m,1H),1.80–1.56(m,7H),1.44–1.20(m,3H),1.07(m,2H).MS(ESI),m/z:560[M+H] +。
Example 12: preparation of N- (4, 4-difluorocyclohexyl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3269)
Figure PCTCN2019079733-APPB-000021
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.36(s,1H),8.47(d,J＝5.2Hz,1H),8.19(s,1H),7.97(d,J＝7.7Hz,1H),7.90–7.80(m,1H),7.54(s,1H),7.40(s,1H),7.38–7.27(m,2H),6.47–6.39(d,J＝5.2Hz,1H),3.95(m,7H),3.82(s,3H),1.98(m,6H),1.58(m,2H).MS(ESI),m/z:556[M+H] +。
Example 13: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N- (tetrahydro-2H-pyran) -1H-pyrazole-4-carboxamide (CCB-3048)
Figure PCTCN2019079733-APPB-000022
The synthesis was as in example 1.
1H NMR(300MHz,DMSO-d 6)δ9.37(s,1H),8.47(d,J＝5.2Hz,1H),8.19(s,1H),7.99(d,J＝7.6Hz,1H),7.85(d,J＝13.3Hz,1H),7.54(s,1H),7.40(s,1H),7.33(m,2H),6.43(d,J＝5.2Hz,1H),4.03–3.84(m,9H),3.82(s,3H),3.40(d,J＝10.8Hz,2H),1.77(d,J＝10.8Hz,2H),1.51(m,2H).MS(ESI),m/z:522[M+H] +。
Example 14: preparation of N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N, 1-dimethyl-1H-pyrazole-4-carboxamide (CCB-3143)
Figure PCTCN2019079733-APPB-000023
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.53(s,1H),8.47(d,J＝5.2Hz,1H),8.09(s,1H),7.83(dd,J＝13.8,1.8Hz,1H),7.54(s,1H),7.40(s,1H),7.38–7.26(m,2H),6.43(d,J＝5.2,1H),4.19(m,1H),3.97(s,6H),3.83(s,3H),2.99(s,3H),1.78(m,2H),1.70–1.44(m,5H),1.42–1.24(m,2H),1.13(m,1H).MS(ESI),m/z:534[M+H] +。
Example 15: preparation of N- (adamantan-1-yl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3109)
Figure PCTCN2019079733-APPB-000024
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.34(s,1H),8.47(d,J＝5.2Hz,1H),8.29(s,1H),7.87(d,J＝13.6Hz,1H),7.54(s,1H),7.44–7.20(m,4H),6.43(d,J＝5.2Hz,1H),3.95(s,6H),3.79(s,3H),2.06(s,9H),1.66(s,6H).MS(ESI),m/z:572[M+H] +。
Example 16: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N-phenyl-1H-pyrazole-4-carboxamide (CCB-3037)
Figure PCTCN2019079733-APPB-000025
The synthesis was as in example 1.
1H NMR(300MHz,DMSO-d 6)δ9.87(s,1H),9.29(s,1H),8.66(d,J＝6.0Hz,1H),8.42(s,1H),7.96(dd,J＝13.7,2.4Hz,1H),7.75–7.62(m,3H),7.52–7.40(m,3H),7.40–7.30(m,2H),7.09(t,J＝7.4Hz,1H),6.72(d,J＝6.0Hz,1H),4.00(s,6H),3.88(s,3H).MS(ESI),m/z:514[M+H] +。
Example 17: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N- (o-tolyl) -1H-pyrazole-4-carboxamide (CCB-3099)
Figure PCTCN2019079733-APPB-000026
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.54(s,1H),9.26(s,1H),8.47(d,J＝5.2Hz,1H),8.35(s,1H),7.93–7.83(m,1H),7.54(s,1H),7.40(s,1H),7.37(m,2H),7.34–7.31(m,1H),7.28(d,J＝7.4Hz,1H),7.19(m,2H),6.44(d,J＝5.2Hz,1H),3.95(s,6H),3.88(s,3H),2.25(s,3H).MS(ESI),m/z:528[M+H] +。
Example 18: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N- (m-tolyl) -1H-pyrazole-4-carboxamide (CCB-3067)
Figure PCTCN2019079733-APPB-000027
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.78(s,1H),9.26(s,1H),8.54(d,J＝5.4Hz,1H),8.42(s,1H),7.94(dd,J＝13.6,2.2Hz,1H),7.58(m,2H),7.46(m,2H),7.42(s,1H),7.37(t,J＝9.0Hz,1H),7.23(t,J＝7.5Hz,1H),6.91(d,J＝7.5Hz,1H),6.55(d,J＝5.4Hz,1H),3.97(s,6H),3.88(s,3H),2.31(s,3H).MS(ESI),m/z:528[M+H] +。
Example 19: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N- (3-ethylphenyl) -1H-pyrazole-4-carboxamide (CCB-3046)
Figure PCTCN2019079733-APPB-000028
The synthesis was as in example 1.
1H NMR(300MHz,DMSO-d 6)δ9.79(s,1H),9.25(s,1H),8.54(d,J＝5.5Hz,1H),8.42(s,1H),7.94(dd,J＝13.7,2.5Hz,1H),7.58(m,2H),7.55–7.41(m,3H),7.37(t,J＝8.9Hz,1H),7.25(t,J＝7.5Hz,1H),6.94(d,J＝7.5Hz,1H),6.55(d,J＝5.5Hz,1H),3.97(s,6H),3.88(s,3H),2.61(q,J＝7.8Hz,2H),1.20(t,J＝7.8Hz,3H).MS(ESI),m/z:542[M+H] +。
Example 20: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N- (p-tolyl) -1H-pyrazole-4-carboxamide (CCB-3068)
Figure PCTCN2019079733-APPB-000029
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.80(s,1H),9.30(s,1H),8.65(d,J＝5.9Hz,1H),8.40(s,1H),7.95(dd,J＝13.6,2.0Hz,1H),7.66(s,1H),7.58(d,J＝8.2Hz,2H),7.51–7.36(m,3H),7.16(d,J＝8.2Hz,2H),6.71(d,J＝5.9Hz,1H),4.00(s,6H),3.87(s,3H),2.28(s,3H).MS(ESI),m/z:528[M+H] +。
Example 21: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (2-methoxyphenyl) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3070)
Figure PCTCN2019079733-APPB-000030
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.20(s,2H),8.46(m,2H),7.79(m,2H),7.54(s,1H),7.40(s,1H),7.35(m,2H),7.21–7.05(m,2H),6.96(t,J＝7.6Hz,1H),6.43(d,J＝5.2Hz,1H),3.95(s,6H),3.86(s,3H),3.83(s,3H).MS(ESI),m/z:544[M+H] +。
Example 22: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (3-methoxyphenyl) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3071)
Figure PCTCN2019079733-APPB-000031
The synthesis was as in example 1.
1H NMR(300MHz,DMSO-d 6)δ9.83(s,1H),9.25(s,1H),8.65(d,J＝6.0Hz,1H),8.43(s,1H),7.96(dd,J＝13.7,2.3Hz,1H),7.66(s,1H),7.54–7.36(m,4H),7.26(m,2H),6.69(m,2H),4.00(s,6H),3.88(s,3H),3.76(s,3H).MS(ESI),m/z:544[M+H] +。
Example 23: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4-methoxyphenyl) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3072)
Figure PCTCN2019079733-APPB-000032
The synthesis was as in example 1.
1H NMR(300MHz,DMSO-d 6)δ9.77(s,1H),9.29(s,1H),8.56(d,J＝5.7Hz,1H),8.36(s, 1H),7.93(dd,J＝13.6,2.4Hz,1H),7.60(s,2H),7.57(s,1H),7.49–7.32(m,3H),6.95(s,1H),6.92(s,1H),6.58(d,J＝5.7Hz,1H),3.98(s,6H),3.87(s,3H),3.74(s,3H).MS(ESI),m/z:544[M+H] +。
Example 24: preparation of N- (3-chlorophenyl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (DL-026)
Figure PCTCN2019079733-APPB-000033
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ10.02(s,1H),9.16(s,1H),8.62–8.32(m,2H),8.10–7.85(m,2H),7.68–7.26(m,6H),7.15(dd,J＝7.8,2.1Hz,1H),6.45(d,J＝5.2Hz,1H),4.06–3.91(m,6H),3.89(s,3H).MS(ESI),m/z:548[M+H] +。
Example 25: preparation of N- (4-chlorophenyl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (DL-025)
Figure PCTCN2019079733-APPB-000034
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.99(s,1H),9.19(s,1H),8.57–8.30(m,2H),7.97–7.82(m,2H),7.55(d,J＝1.9Hz,1H),7.50–7.28(m,6H),6.45(dt,J＝4.5,2.2Hz,1H),3.96(d,J＝1.7Hz,6H),3.89(s,3H).MS(ESI),m/z:548[M+H] +。
Example 26: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (3-fluorophenyl) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3098)
Figure PCTCN2019079733-APPB-000035
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ10.04(s,1H),9.17(s,1H),8.48(d,J＝5.2Hz,1H),8.42(s,1H),7.93(dd,J＝13.6,2.6Hz,1H),7.73(dt,J＝11.9,2.2Hz,1H),7.55(s,1H),7.52–7.25(m,5H),6.99–6.86(m,1H),6.45(dd,J＝5.3,1.1Hz,1H),3.96(d,J＝1.8Hz,6H),3.89(s,3H).MS(ESI),m/z:532[M+H] +。
Example 27: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4-cumyl) -1-methyl-1H-pyrazole-4-carboxamide (DL-040)
Figure PCTCN2019079733-APPB-000036
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.82(s,1H),9.32(s,1H),8.67(d,J＝6.0Hz,1H),8.43(s,1H),7.96(dd,J＝13.6,2.5Hz,1H),7.73–7.56(m,3H),7.56–7.34(m,3H),7.29–7.16(m,2H),6.74(d,J＝5.9Hz,1H),4.01(s,6H),3.88(s,3H),2.87(hept,J＝6.9Hz,1H),1.21(d,J＝6.9Hz,6H).MS(ESI),m/z:556[M+H] +。
Example 28: preparation of 3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4- (trifluoromethoxy) phenyl) -1-methyl-1H-pyrazole-4-carboxamide (DL-037)
Figure PCTCN2019079733-APPB-000037
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ10.05(s,1H),9.19(s,1H),8.48(dd,J＝5.2,1.7Hz,1H),8.42(s,1H),7.88–7.76(m,2H),7.60–7.23(m,7H),6.45(ddd,J＝5.0,3.8,1.1Hz,1H),3.96(d,J＝1.7Hz,6H),3.89(s,3H).MS(ESI),m/z:598[M+H] +。
Example 29: preparation of N- (4- (difluoromethoxy) phenyl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (DL-036)
Figure PCTCN2019079733-APPB-000038
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.95(s,1H),9.22(s,1H),8.48(d,J＝5.3Hz,1H),8.41(s,1H),7.92(dd,J＝13.5,2.6Hz,1H),7.75(d,J＝9.0Hz,2H),7.55(s,1H),7.49–7.13(m,6H),6.46(d,J＝5.2Hz,1H),4.02–3.92(m,6H),3.89(s,3H).MS(ESI),m/z:580[M+H] +。
Example 30: preparation of N- (4- (cyanomethyl) phenyl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (DL-032)
Figure PCTCN2019079733-APPB-000039
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.94(s,1H),9.22(s,1H),8.48(d,J＝5.2Hz,1H),8.43(s,1H),7.93(dd,J＝13.6,2.5Hz,1H),7.74(d,J＝8.4Hz,2H),7.55(s,1H),7.51–7.28(m,5H),6.52–6.41(m,1H),4.01(s,2H),3.96(d,J＝1.9Hz,6H),3.89(s,3H).MS(ESI),m/z:553[M+H] +。
Example 31: preparation of N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (TL-140)
Figure PCTCN2019079733-APPB-000040
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.28(s,1H),8.45(d,J＝5.2Hz,1H),8.17(s,1H),7.83(d,J＝7.9Hz,1H),7.69–7.59(m,2H),7.53(s,1H),7.38(s,1H),7.22–7.12(m,2H),6.41(d,J＝5.3Hz,1H),3.94(d,J＝1.1Hz,6H),3.79(s,3H),3.77–3.66(m,0H),1.82(d,J＝10.7Hz,2H),1.79–1.68(m,2H),1.61(d,J＝12.7Hz,1H),1.39–1.21(m,4H),1.21–1.06(m,1H).MS(ESI),m/z:502[M+H] +。
Example 32: preparation of N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -2-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (TL-145)
Figure PCTCN2019079733-APPB-000041
The synthesis was as in example 1.
1H NMR(400MHz,Chloroform-d)δ9.19(d,J＝3.2Hz,1H),8.48(d,J＝5.3Hz,1H),8.44–8.34(m,1H),7.56(s,1H),7.49(s,1H),7.41(s,1H),7.02–6.92(m,2H),6.48(d,J＝5.3Hz,1H),5.45(d,J＝8.2Hz,1H),4.06(s,3H),4.05(s,3H),4.02–3.90(m,1H),3.85(s,3H),2.09–1.96(m,3H),1.75(dt,J＝13.6,3.6Hz,2H),1.67(s,4H),1.50–1.33(m,2H),1.30–1.09(m,3H).MS(ESI),m/z:520[M+H] +。
Example 33: preparation of N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -2-tolyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (TL-151)
Figure PCTCN2019079733-APPB-000042
The synthesis was as in example 1.
1H NMR(400MHz,Chloroform-d)δ8.92(s,1H),8.45(d,J＝5.3Hz,1H),8.31(d,J＝8.8Hz,1H),7.61(s,1H),7.49(s,1H),7.41(s,1H),7.04(dd,J＝8.7,2.8Hz,1H),6.99(d,J＝2.8Hz,1H),6.46(d,J＝5.3Hz,1H),5.44(d,J＝8.3Hz,1H),4.05(d,J＝4.9Hz,6H),3.96(tdd,J＝8.1,5.4,3.5Hz,1H),3.85(s,3H),2.42(s,3H),2.09–1.94(m,3H),1.75(dt,J＝13.5,3.7Hz,2H),1.71–1.66(m,1H),1.51–1.35(m,2H),1.31–1.06(m,3H).MS(ESI),m/z:516[M+H] +。
Example 34: preparation of 3- ((3-chloro-4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) amino) -N-cyclohexyl-1-methyl-1H-pyrazole-4-carboxamide (TL-156)
Figure PCTCN2019079733-APPB-000043
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.46(d,J＝5.2Hz,1H),8.20(s,1H),8.02(d,J＝2.7Hz,1H),7.88(d,J＝7.8Hz,1H),7.54(s,1H),7.50(dd,J＝8.9,2.7Hz,1H),7.40(s,1H),7.34(d,J＝8.9Hz,1H),6.33(d,J＝5.3Hz,1H),3.95(s,6H),3.81(s,3H),3.73(tdd,J＝10.2,7.0,3.6Hz,1H),1.83(d,J＝10.5Hz,2H),1.74(dd,J＝9.3,3.5Hz,2H),1.61(d,J＝12.4Hz,1H),1.39–1.08(m,6H).MS(ESI),m/z:536[M+H] +。
Example 35: preparation of N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-tolyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (TL-154)
Figure PCTCN2019079733-APPB-000044
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.24(s,1H),8.43(d,J＝5.2Hz,1H),8.17(s,1H),7.82(d,J＝7.8Hz,1H),7.60–7.53(m,2H),7.46(d,J＝2.8Hz,1H),7.39(s,1H),7.10(d,J＝8.7Hz,1H),6.28(d,J＝5.2Hz,1H),3.95(s,3H),3.94(s,3H),3.79(s,3H),3.72(ddd,J＝10.9,7.5,3.9Hz,1H),2.07(s,3H),1.90–1.67(m,4H),1.61(d,J＝12.7Hz,1H),1.40–1.06(m,5H).MS(ESI),m/z:516[M+H] +。
Example 36: preparation of N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-methoxyphenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (TL-170)
Figure PCTCN2019079733-APPB-000045
The synthesis was as in example 1.
1H NMR(400MHz,DMSO-d 6)δ9.31(s,1H),8.41(d,J＝5.2Hz,1H),8.18(s,1H),7.84(d,J＝7.8Hz,1H),7.52(s,1H),7.36(d,J＝3.0Hz,2H),7.32(dd,J＝8.6,2.5Hz,1H),7.13(d,J＝8.6Hz,1H),6.29(d,J＝5.2Hz,1H),3.94(s,6H),3.79(s,3H),3.72(s,4H),1.92–1.67(m,4H),1.61(d,J＝12.6Hz,1H),1.40–1.06(m,5H).MS(ESI),m/z:532[M+H] +。
Example 37: preparation of N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3233)
Scheme B: .
Figure PCTCN2019079733-APPB-000046
Step b 1: preparation of 7- (benzyloxy) -4- (4-bromo-2-fluorophenoxy) -6-methoxyquinoline (Compound 6)
7- (benzyloxy) -4-chloro-6-methoxyquinoline (compound 5) (3.0g, 10mmol) and 4-bromo-2-fluorophenol (2.2mL, 20mmol) were added to 12mL DIEA, 6mL xylene was added, and the mixture was heated to 140 ℃ and stirred overnight. When the temperature is reduced to room temperature, a solid is precipitated, filtered, washed by ethanol and dried by suction to obtain 3.7g (81.0%) of a white solid.1H NMR(400MHz,DMSO-d 6)δ8.48(d,J＝5.2Hz,1H),7.88(dd,J＝10.2,2.2Hz,1H),7.61–7.49(m,5H),7.49–7.40(m,3H),7.37(d,J＝7.2Hz,1H),6.53(d,J＝5.2Hz,1H),5.31(s,2H),3.95(s,3H).。MS(ESI),m/z:454[M+H] +。
Step b 2: preparation of ethyl 3- ((4- ((7- (benzyloxy) -6-methoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxylate (Compound 7)
7- (benzyloxy) -4- (4-bromo-2-fluorophenoxy) -6-methoxyquinoline (compound 6) (4.5g, 10mmol), 3-amino-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester(1.7g，10mmol)，Pd 2(dba) 3(275mg, 0.3mmol), Xantphos (579mg, 1mmol) and cesium carbonate (6.5g, 20mmol) were dissolved in 50mL anhydrous dioxane and refluxed overnight under argon. Cooled to room temperature, filtered through celite, spin-dried, and chromatographed to give a solid 3.9g (72.0%).1H NMR(400MHz,DMSO-d 6)δ8.54–8.39(m,2H),8.21(s,1H),7.91(dd,J＝13.6,2.6Hz,1H),7.57(s,1H),7.54(d,J＝1.4Hz,1H),7.53–7.47(m,3H),7.46–7.40(m,2H),7.36(dd,J＝9.7,8.3Hz,2H),6.43(dd,J＝5.2,0.9Hz,1H),5.31(s,2H),4.27(q,J＝7.1Hz,2H),3.96(s,3H),3.82(s,3H),1.30(t,J＝7.1Hz,3H).。MS(ESI),m/z:543[M+H] +。
Step b 3: preparation of 3- ((4- ((7- (benzyloxy) -6-methoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxylic acid (Compound 8)
Ethyl 3- ((4- ((7- (benzyloxy) -6-methoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxylate (compound 7) (2.7g, 5mmol) and sodium hydroxide (600mg, 15mmol) were dissolved in a combined solvent of 15mL of ethanol and 5mL of water and reacted at 60 ℃ for 2 hours. Cool to room temperature, spin dry ethanol and make weak acidity with 1N HCl solution, filter, dry to get 2.4g (92.3%) solid.1H NMR(400MHz,DMSO-d 6)δ12.57(br,1H),8.69(d,J＝6.0Hz,1H),8.59(s,1H),8.15(s,1H),7.95(dd,J＝13.6,2.5Hz,1H),7.72(d,J＝10.9Hz,2H),7.59–7.49(m,3H),7.48–7.36(m,4H),6.78(d,J＝6.0Hz,1H),5.36(s,2H),4.01(s,3H),3.82(s,3H).。MS(ESI),m/z:515[M+H] +。
Step b 4: preparation of 3- ((4- ((7- (benzyloxy) -6-methoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N-cyclohexyl-1-methyl-1H-pyrazole-4-carboxamide (Compound 9)
3- ((4- ((7- (benzyloxy) -6-methoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxylic acid (compound 8) (2.6g, 5mmol), cyclohexylamine (687. mu.L, 6mmol) and HATU (2.9g, 7.5mmol) were dissolved in 30mL of DMF, DIEA (2.6mL, 15mmol) was added, and the mixture was stirred at room temperature overnight. Adding saturated sodium chloride solution, extracting with dichloromethane, mixing organic phases, and adding saturated salineWashing for three times with anhydrous Na2SO 4Drying, filtering and spin-drying, and separating by column chromatography to obtain solid 2.2g (75.0%).1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),8.57(d,J＝5.7Hz,1H),8.22(s,1H),7.96–7.83(m,2H),7.63(s,1H),7.55(dd,J＝9.9,8.5Hz,3H),7.48–7.41(m,2H),7.41–7.32(m,3H),6.61(d,J＝5.5Hz,1H),5.34(s,2H),3.99(s,3H),3.81(s,3H),3.78–3.65(m,1H),1.89–1.66(m,4H),1.61(d,J＝12.5Hz,1H),1.40–1.09(m,5H).。MS(ESI),m/z:596[M+H] +。
Step b 5: preparation of N-cyclohexyl-3- ((3-fluoro-4- ((7-hydroxy-6-methoxyquinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (Compound 10)
3- ((4- ((7- (benzyloxy) -6-methoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N-cyclohexyl-1-methyl-1H-pyrazole-4-carboxamide (compound 9) (2.5g, 5mmol) was dissolved in a combined solvent of 20mL of ethanol and 10mL of DMF, Pd/C (250mg) was added, and the mixture was stirred at room temperature overnight. Filtering with diatomaceous earth, adding saturated sodium chloride solution, extracting with dichloromethane, mixing organic phases, washing with saturated brine for three times, and collecting anhydrous Na2SO 4Drying, filtering, spin-drying, and separating by column chromatography to obtain solid 2.2g (86.0%).1H NMR(400MHz,DMSO-d 6)δ10.12(s,1H),9.42(s,1H),8.40(d,J＝5.2Hz,1H),8.20(s,1H),7.95–7.79(m,2H),7.52(s,1H),7.32(dd,J＝4.2,1.6Hz,2H),7.28(d,J＝3.0Hz,1H),6.35(dd,J＝5.2,0.8Hz,1H),3.96(s,3H),3.82(d,J＝7.6Hz,3H),3.73(dd,J＝7.3,3.5Hz,1H),1.83(d,J＝9.7Hz,2H),1.74(dd,J＝9.4,2.9Hz,2H),1.61(d,J＝12.6Hz,1H),1.35–1.08(m,5H).。MS(ESI),m/z:506[M+H] +。
Step b 6: preparation of N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3233)
N-cyclohexyl-3- ((3-fluoro-4- ((7-hydroxy-6-methoxyquinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (Compound 10) (202mg, 0.4mmol), N- (3-chloropropyl) morpholine (131mg, 0.8mmol) and potassium carbonate (166mg, 1.2mmol) were dissolved in 2mL of DMFThe reaction was carried out at 80 ℃ for 3 hours. Cooling to room temperature, adding saturated sodium chloride solution, extracting with dichloromethane, mixing organic phases, washing with saturated brine for three times, and collecting anhydrous Na2SO 4Drying, filtering, spin-drying and separating by column chromatography to obtain 164mg (65.2%) of solid.1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.46(d,J＝5.2Hz,1H),8.20(s,1H),7.86(dd,J＝19.4,5.2Hz,2H),7.53(s,1H),7.39(s,1H),7.37–7.26(m,2H),6.42(dd,J＝5.2,0.9Hz,1H),4.20(t,J＝6.4Hz,2H),3.95(s,3H),3.82(d,J＝7.2Hz,3H),3.73(dd,J＝7.5,3.5Hz,1H),3.63–3.54(m,4H),2.47(t,J＝7.2Hz,2H),2.39(s,4H),2.03–1.93(m,2H),1.83(d,J＝9.8Hz,2H),1.74(dd,J＝9.4,2.9Hz,2H),1.61(d,J＝12.5Hz,1H),1.37–1.21(m,4H),1.17–1.10(m,1H).。MS(ESI),m/z:633[M+H] +。
Example 38: preparation of N-cyclohexyl-3- ((4- ((7-ethoxy-6-methoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3236)
Figure PCTCN2019079733-APPB-000047
The synthesis was as in example 37.
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.46(d,J＝5.2Hz,1H),8.20(s,1H),7.86(m,2H),7.53(s,1H),7.38(s,1H),7.36–7.27(m,2H),6.42(d,J＝5.2Hz,1H),4.21(q,J＝7.0Hz,2H),3.95(s,3H),3.81(s,3H),3.73(m,1H),1.83(m,2H),1.78–1.67(m,2H),1.59(m,1H),1.43(t,J＝7.0Hz,3H),1.27(m,5H).MS(ESI),m/z:534[M+H] +。
Example 39: preparation of N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7-propoxyquinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3243)
Figure PCTCN2019079733-APPB-000048
The synthesis was as in example 37.
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.46(d,J＝5.2Hz,1H),8.20(s,1H),7.92–7.81(m,2H),7.54(s,1H),7.37(s,1H),7.36–7.29(m,2H),6.42(d,J＝5.2Hz,1H),4.11(t,J＝6.6Hz,2H),3.96(s,3H),3.82(s,3H),3.78–3.68(m,1H),1.84(m,4H),1.78–1.68(m,2H),1.61(m,1H),1.37–1.11(m,5H),1.04(t,J＝7.4Hz,3H).MS(ESI),m/z:548[M+H] +。
Example 40: preparation of N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (2-methoxyethoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3237)
Figure PCTCN2019079733-APPB-000049
The synthesis was as in example 37.
1H NMR(400MHz,DMSO-d 6)δ9.43(s,1H),8.46(d,J＝5.2Hz,1H),8.20(s,1H),7.86(m,2H),7.54(s,1H),7.41(s,1H),7.38–7.29(m,2H),6.43(d,J＝5.2Hz,1H),4.33–4.23(m,2H),3.96(s,3H),3.81(s,3H),3.79–3.66(m,3H),3.35(s,3H),1.83(m,2H),1.79–1.68(m,2H),1.61(m,1H),1.37–1.07(m,5H).MS(ESI),m/z:564[M+H] +。
Example 41: preparation of N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (3-methoxypropoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3235)
Figure PCTCN2019079733-APPB-000050
The synthesis was as in example 37.
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.46(d,J＝5.2Hz,1H),8.19(s,1H),7.86(m,2H),7.54(s,1H),7.38(s,1H),7.36–7.28(m,2H),6.43(d,J＝5.2Hz,1H),4.20(t,J＝6.4Hz,2H),3.96(s,3H),3.81(s,3H),3.79–3.68(m,1H),3.53(t,J＝6.4Hz,2H),3.28(s,3H),2.05(m,2H),1.83(m,2H),1.74(m,2H),1.61(m,1H),1.36–1.15(m,5H).MS(ESI),m/z:578[M+H] +。
Example 42: preparation of N-cyclohexyl-3- ((4- ((7- (3- (dimethylamine) propoxy) -6-methoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3256)
Figure PCTCN2019079733-APPB-000051
The synthesis was as in example 37.
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.46(d,J＝4.8Hz,1H),8.20(s,1H),7.92–7.81(m,2H),7.53(s,1H),7.34(m,3H),6.42(d,J＝4.8Hz,1H),4.18(t,J＝6.5Hz,2H),3.95(s,3H),3.81(s,3H),3.78–3.68(m,1H),2.41(t,J＝7.1Hz,2H),2.19(s,6H),1.95(m,2H),1.83(m,2H),1.74(m,2H),1.61(m,1H),1.34–1.13(m,5H).MS(ESI),m/z:591[M+H] +。
Example 43: preparation of N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3244)
Figure PCTCN2019079733-APPB-000052
The synthesis was as in example 37.
1H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),8.46(d,J＝5.2Hz,1H),8.19(s,1H),7.86(m,2H),7.53(s,1H),7.34(m,3H),6.42(d,J＝5.2Hz,1H),4.18(t,J＝6.4Hz,2H),3.95(s,3H),3.80(s,3H),3.77–3.67(m,1H),2.43(t,J＝7.1Hz,2H),2.35(br,4H),2.01–1.90(m,2H),1.83(m,2H),1.74(m,2H),1.61(m,1H),1.51(m,4H),1.39(m,2H),1.33–1.12(m,5H).MS(ESI),m/z: 631[M+H] +。
Example 44: preparation of N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3265)
Figure PCTCN2019079733-APPB-000053
The synthesis was as in example 37.
1H NMR(400MHz,DMSO-d 6)δ9.43(s,1H),8.46(d,J＝5.2Hz,1H),8.20(s,1H),7.87(m,2H),7.53(s,1H),7.46–7.26(m,3H),6.42(d,J＝5.2Hz,1H),4.17(t,J＝6.2Hz,2H),3.95(s,3H),3.81(s,3H),3.77–3.65(m,1H),2.42(m,7H),2.14(s,3H),2.03–1.89(m,2H),1.83(m,2H),1.78–1.68(m,2H),1.60(m,1H),1.35–1.08(m,6H),0.95(t,J＝7.1Hz,2H).MS(ESI),m/z:646[M+H] +。
Example 45: preparation of N-cycloheptyl-3- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3266)
Figure PCTCN2019079733-APPB-000054
The synthesis was as in example 37.
1H NMR(400MHz,DMSO-d 6)δ9.41(s,1H),8.46(d,J＝5.2Hz,1H),8.21(s,1H),7.94–7.81(m,2H),7.53(s,1H),7.39(s,1H),7.33(m,2H),6.42(d,J＝5.2Hz,1H),4.20(t,J＝6.4Hz,2H),3.94(m,4H),3.81(s,3H),3.65–3.50(m,4H),2.46(m,2H),2.39(m,4H),2.03–1.92(m,2H),1.85(m,2H),1.70–1.37(m,10H).MS(ESI),m/z:647[M+H] +。
Example 46: preparation of N-cyclopentyl-3- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3299)
Figure PCTCN2019079733-APPB-000055
The synthesis was as in example 37.
1H NMR(400MHz,DMSO-d 6)δ9.40(s,1H),8.46(d,J＝5.2Hz,1H),8.21(s,1H),7.93(d,J＝7.2Hz,1H),7.90–7.78(m,1H),7.54(s,1H),7.39(s,1H),7.33(d,J＝5.9Hz,2H),6.42(dd,J＝5.2,0.9Hz,1H),4.19(m,3H),3.95(s,3H),3.81(s,3H),3.64–3.52(m,4H),2.46(d,J＝7.1Hz,2H),2.39(s,4H),1.98(dd,J＝8.7,4.9Hz,2H),1.93–1.82(m,2H),1.74–1.60(m,2H),1.52(m,4H).MS(ESI),m/z:619[M+H] +。
Example 47: preparation of 3- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -N- (4-fluorophenyl) -1-methyl-1H-pyrazole-4-carboxamide (CCB-3330)
Figure PCTCN2019079733-APPB-000056
The synthesis was as in example 37.
1H NMR(400MHz,DMSO-d 6)δ9.94(s,1H),9.22(s,1H),8.46(d,J＝5.3Hz,1H),8.39(s,1H),7.92(dd,J＝13.6,2.6Hz,1H),7.80–7.64(m,2H),7.54(s,1H),7.50–7.29(m,3H),7.27–7.13(m,2H),6.43(dd,J＝5.2,0.9Hz,1H),4.20(t,J＝6.4Hz,2H),3.95(s,3H),3.88(s,3H),3.59m,4H),2.48–2.30(m,6H),2.05–1.86(m,2H).MS(ESI),m/z:645[M+H] +
Example 48: IC of 3-amino pyrazole compound on AXL kinase50Testing
And (3) kinase activity detection: the inhibitory activity of the compound on the kinase is detected by using enzyme-linked immunosorbent assay (ELISA) technology. The enzyme reaction substrate Poly (Glu, Tyr)4:1 was diluted to 20. mu.g/mL with PBS (10mM sodium phosphate buffer, 150mM NaCl, pH7.2-7.4) without potassium ion, coated on a 125. mu.L/well microplate, and reacted at 37 ℃ for 12-16 hours. The wells were discarded and the plate washed three times with 5 minutes each of 200. mu.L/well of T-PBS (0.1% Tween-20 in PBS). The microplate was dried in an oven at 37 ℃ for 1-2 hours. Counter for addition per wellBuffer (50mM HEPES pH 7.4,50mM MgCl)2,0.5mM MnCl 2,0.2mM Na 3VO 41mM DTT) was added to the sample at a final concentration of 5. mu.M. The compounds were diluted to appropriate concentrations in DMSO, 1. mu.L/well or with appropriate concentrations of DMSO (negative control wells), and reactions were initiated by adding AXL kinase domain recombinant protein (eurofins, 14-512) diluted in 49. mu.L of reaction buffer, with two wells of enzyme-free control wells being required for each experiment. The reaction was carried out on a shaker (100rpm) at 37 ℃ for 1 hour. The plate was washed three times with T-PBS. 100 μ L of primary PY 99-resistant diluent was added to the reaction mixture in a shaker at 37 ℃ for 0.5 hour. The plate was washed three times with T-PBS. Adding 100 mu L/hole of IgG diluent of a second antibody horseradish peroxidase labeled goat anti-mouse, and reacting for 0.5 hour at 37 ℃ by a shaking table. The plate was washed three times with T-PBS. Adding OPD developing solution 2mg/ml 100 μ L/well (containing 0.03% H)2O 2Diluted with 0.1M citric acid-sodium citrate buffer (pH 5.4), and reacted at 25 ℃ for 1 to 10 minutes in the absence of light. (ultrasonic wave is needed when dissolving OPD, and the color developing solution needs to be prepared at present). 2M H was added2SO 4The reaction was stopped at 50. mu.L/well and read by a wavelength-tunable microplate reader SPECTRA MAX 190 at 490 nm.
The inhibition ratio of the sample was obtained by the following formula:
Figure PCTCN2019079733-APPB-000057
IC 50the values were determined by regression with a four parameter method using a microplate reader random plus software.
As can be seen from the results of table 1: in a competition experiment of 3-aminopyrazole compounds and ATP, the compounds of the invention show strong inhibition activity on AXL kinase.
Table 1 compound number and stress enzyme activity results.
Compds AXL IC 50(nM) Compds AXL IC 50(nM)
CCB-3152 >10000 CCB-3072 86.7
CCB-3151 237.8 DL-025 29.5
CCB-3088 585.6 DL-037 >500
CCB-3069 142.2 CCB-3049 39.7
CCB-3087 11.4 CCB-3236 9.4
CCB-3269 65 CCB-3243 21.6
CCB-3091 5.1 CCB-3235 8.6
CCB-3146 4.0 CCB-3237 7.8
CCB-3263 12.5 CCB-3244 5.6
CCB-3143 5.5 CCB-3265 2.9
CCB-3245 333 CCB-3256 3.2
CCB-3252 46.0 CCB-3233 1.6
CCB-3109 13.2 CCB-3266 7.7
CCB-3037 25.4 DL-026 155
CCB-3099 12.0 DL-036 64.0
CCB-3067 23.5 DL-040 >10000
CCB-3068 23.1 DL-032 >1000
CCB-3046 42.0 CCB-3048 119.7
CCB-3070 80.0 CCB-3098 266
TL140 35.0 CCB-3299 3.8
CCB-3071 34.0 CCB-3330 4.1
TL-145 6.5 TL-156 16.6
TL-151 38.9 TL-170 136.6
TL-154 40.4
Example 49: AXL-mediated cell proliferation IC of 3-aminopyrazole compounds50Testing
The test method comprises the following steps: inhibition of BaF3/TEL-AXL cell proliferation by the compound was examined using the CCK-8 cell counting kit (Dojindo). The method comprises the following specific steps: BaF3/TEL-AXL cells in logarithmic growth phase were seeded at an appropriate density into 96-well culture plates at 90. mu.L per well, cultured overnight, and then a compound at various concentrations was added for 72hr and a solvent control group (negative control) was set. After the compound acts on cells for 72 hours, the influence of the compound on cell proliferation is detected by a CCK-8 cell counting kit (Dojindo), 10 mu L of CCK-8 reagent is added into each hole, the hole is placed in an incubator at 37 ℃ for 2 to 4 hours, then a SpectraMax 190 reading is carried out by a full-wavelength microplate reader, and the measurement wavelength is 450 nm.
The inhibition (%) of the tumor cell growth by the compound was calculated using the following formula:
inhibition (%) - (OD control well-OD administration well)/OD control well X100%
IC 50The values were determined by regression with a four parameter method using a microplate reader random plus software.
The results of the experiment are shown in table 2.
TABLE 2 IC inhibition of BaF3/TEL-AXL cell proliferation by compounds50Value of
Numbering IC 50(nM)
CCB-3233 4.7
CCB-3256 11.6
CCB-3265 9.0
CCB-3299 5.7
CCB-3330 6.7
R428 98.9
Gilteritinib 16.8
As can be seen from the results of table 2: the 3-aminopyrazole compound shows strong inhibition activity on AXL-mediated cell proliferation.
Example 50: MV4-11 cell proliferation IC of 3-amino pyrazole compound50Testing
The cell MV4-11 (acute myeloid leukemia cell line) used in this experiment was from ATCC. 3000-10000 of the above cells were inoculated into a 96-well plate, and then treated with different concentrations of compounds (0-3. mu.M) for 72 hours in succession. Adding a CCK8 reagent, continuously incubating for 1-3 hours, measuring the absorbance values of the cells at 450nm and 650nm by using a super enzyme-labeling instrument, calculating the actual absorbance value A of each well as OD450-OD650, and calculating the cell survival rate of each processing well according to the A value; cell viability data and concentrations of compounds were then input into GraphPad Prism 5Demo software and IC of compounds versus cells was calculated using a non-linear regression model50The value is obtained.
The results of the experiment are shown in table 3.
TABLE 3 IC inhibition of MV4-11 leukemia cell proliferation by compounds50Value of
Numbering IC50(μM)
CCB-3087 0.244
CCB-3091 0.383
CCB-3233 0.021
CCB-3266 0.013
R428 0.306
As can be seen from the results of table 3: the 3-amino pyrazole compound shows strong inhibitory activity on MV4-11 leukemia cell proliferation.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (23)

  1. A3-aminopyrazole compound with a structure shown as a formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof or a deuteride thereof:
    Figure PCTCN2019079733-APPB-100001
    wherein X is selected from: CH or N;
    z is selected from: o or NH;
    b is selected from: c5～C 10Aryl, 5-to 10-membered heteroaryl, C3～C 6Cycloalkyl radical, C7～C 13A polycyclic alkyl group;
    R 1、R 2with ring A forming a substituted or unsubstituted heterocyclic ring
    Figure PCTCN2019079733-APPB-100002
    m is 2 or 3, Y is selected from C, N or O;
    R 3selected from: hydrogen, halogen-substituted C1～C 6Alkyl radical, C1～C 6Alkoxy or C1～C 6An alkyl group;
    R 4selected from: hydrogen, C1～C 5Alkyl radical, C3～C 6Cycloalkyl radical, C1～C 3Alkoxy or
    Figure PCTCN2019079733-APPB-100003
    R 21Selected from: hydrogen, halogen, C1～C 5Alkyl radical, C3～C 6Cycloalkyl or C1～C 5An alkoxy group;
    R 5、R 6each independently selected from: hydrogen, alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, aralkyl, substituted or unsubstituted heteroaryl, heteroaralkyl, substituted or unsubstituted polycycloalkyl; or, R5、R 6And with itThe attached N atoms together form a monocyclic heterocycle or a fused heterocycle.
  2. The 3-aminopyrazole compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof or a deuteron thereof according to claim 1, wherein the 3-aminopyrazole compound has a structure represented by formula (ii):
    Figure PCTCN2019079733-APPB-100004
    x is selected from: CH or N.
  3. The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof or deuteron thereof according to claim 1 or 2, wherein the substituted or unsubstituted heterocycle is
    Figure PCTCN2019079733-APPB-100005
    Selected from the following structures:
    Figure PCTCN2019079733-APPB-100006
    wherein X is CH or N;
    R 12、R 13each independently selected from: -O (CR)15R 16) OR 14；
    Wherein o is an integer of 0-6;
    R 14、R 15、R 16each independently selected from: -H, C1～C 5Alkyl, halogen substituted C1～C 5Alkyl, halogen substituted C1～C 5Alkoxy, -OH, -COOH, -COOR19、-(C＝O)-NR 19R 20、-SO m-NR 19R 20、-CHR 19R 20、-OR 19or-NR19R 20；m＝1～2；
    R 19、R 20Each independently selected from: hydrogen, halogen, C1～C 6Alkyl, or R19And R20Form a saturated or unsaturated R22A substituted 5-to 8-membered heterocyclic group wherein R22Selected from: -H, C1～C 5An alkyl group;
    or, R12、R 13C containing 1 to 4 hetero atoms5～C 18An aliphatic cycloalkyl group.
  4. The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof or deuteron thereof according to claim 3, wherein R is14、R 15、R 16Each independently selected from: -H, C1～C 5Alkyl, -OR19or-NR19R 20；
    R 19、R 20Each independently selected from: hydrogen, C1～C 6Alkyl, or R19、R 20And N to which they are attached together form a saturated or unsaturated R22A substituted 5-to 8-membered heterocyclic group wherein R22Selected from: -H, C1～C 5An alkyl group.
  5. The 3-aminopyrazole compound according to claim 4, or a pharmaceutically acceptable salt orA stereoisomer thereof or a prodrug molecule thereof or a deuterate thereof, wherein R is15And R16Are all hydrogen;
    R 14selected from: -H, -OR19or-NR19R 20；
    R 19、R 20Each independently selected from: c1～C 3Alkyl, or R19、R 20And N attached thereto together form saturated R22A substituted 5-to 8-membered heterocyclic group wherein R22Selected from: -H, C1～C 3An alkyl group.
  6. The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof or deuteron thereof according to claim 3, wherein R is12、R 13Each independently selected from: -O (CH)2) OR 14(ii) a o is an integer of 0 to 4.
  7. The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof or deuteron thereof according to claim 6, wherein R is12And R13One of them is selected from C1～C 4Alkoxy, the other being selected from: -O (CH)2) OR 14；
    o is an integer between 1 and 4;
    R 14selected from: H. -OR19or-NR19R 20；
    R 19、R 20Each independently selected from: c1～C 3Alkyl, or R19、R 20And withN to which they are attached together form R22Substituted 6-membered saturated heterocyclic group, wherein R22Selected from: -H, C1～C 3An alkyl group.
  8. The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof or deuteron thereof according to claim 6, wherein R is12And R13Each independently selected from: methoxy, ethoxy, propoxy, morpholinyl substituted propoxy, methoxy substituted ethoxy, methoxy substituted propoxy, dimethylamino substituted propoxy, piperidine substituted propoxy, N-methylpiperazine substituted propoxy.
  9. The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof or deuteron thereof according to claim 1 or 2, wherein R is3Selected from: H. halogen, trifluoromethyl, C1～C 3Alkyl radical, C1～C 3An alkoxy group.
  10. The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof or deuteron thereof according to claim 9, wherein R is3Selected from: H. f, Cl, Br, methyl, ethyl, methoxy and ethoxy.
  11. The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof or deuteron thereof according to claim 1 or 2, wherein R is4Selected from: c1～C 3An alkyl group.
  12. 3-aminopyrazole compound according to claim 1 or 2 or pharmaceutically acceptable thereofA salt or a stereoisomer thereof or a prodrug molecule thereof or a deutero-derivative thereof, wherein R is5、R 6Each independently selected from: hydrogen, C1～C 8Alkyl radical, R8Substituted C3～C 10Cycloalkyl radical, R8Substituted 3-10 membered heterocycloalkyl, R10Substituted C5-C 10Aryl, aralkyl, R10Substituted 5-10 membered heteroaryl, heteroaralkyl, R8Substituted C7～C 13A polycyclic alkyl group; or, R5、R 6And the N atom to which they are attached form a 3-to 10-membered monocyclic heterocycle or fused-ring heterocycle;
    R 8selected from: hydrogen, C1～C 6Alkyl, halogen;
    R 10selected from: hydrogen, halogen, C1～C 6Alkyl radical, C1～C 6Alkoxy, cyano, halogen substituted C1～C 6Alkyl, halogen substituted C1～C 6Alkoxy, cyano-substituted C1～C 6An alkyl group.
  13. The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof or deuteron thereof according to claim 12, wherein R is5、R 6Each independently selected from: hydrogen, C1～C 8Alkyl radical, R8Substituted C3～C 8Cycloalkyl radical, R8Substituted 6-8 membered heterocycloalkyl, R10Substituted phenyl, adamantyl, R10Substituted 5-10 membered heteroaryl; or, R5、R 6And the N atom to which they are attached form a 3-to 10-membered monocyclic heterocycle orAnd (3) a cyclic heterocyclic ring.
  14. The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof or deuteron thereof according to claim 13, wherein R is6Selected from: hydrogen, C1～C 5An alkyl group; r5Selected from: c2～C 8Alkyl radical, R8Substituted C3～C 8Cycloalkyl radical, R8Substituted 6-8 membered heterocycloalkyl, R10Substituted phenyl, adamantyl; or, R5、R 6And the N atom to which they are attached, together form a 3-to 10-membered monocyclic heterocycle or fused heterocycle.
  15. The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof or deuteron thereof according to claim 14, wherein R is6Selected from: hydrogen, C1～C 5An alkyl group; r5Selected from: c4～C 8Alkyl radical, R8Substituted C4～C 8Cycloalkyl radical, R10Substituted phenyl, R8Substituted 6-8 membered heterocycloalkyl, adamantyl; or, R5、R 6And the N atom to which they are attached, together form a 3-to 10-membered monocyclic heterocycle or fused heterocycle.
  16. The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof or deuteron thereof according to claim 15, wherein R is6Selected from: hydrogen, C1～C 3An alkyl group; r5Selected from: r8Substituted C5～C 8Cycloalkyl radical, R10Substituted phenyl, goldA rigid alkyl group.
  17. The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof or deuteron thereof according to claim 12, wherein R is8Selected from: hydrogen, halogen; r10Selected from: hydrogen, halogen, C1～C 2Alkyl, methoxy.
  18. The 3-aminopyrazole compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, or a deuteride thereof, wherein the 3-aminopyrazole compound has a structure represented by formula (iii):
    Figure PCTCN2019079733-APPB-100007
    wherein R is3Selected from: H. halogen, C1～C 3Alkyl radical, C1～C 3An alkoxy group;
    R 6selected from: hydrogen, C1～C 2An alkyl group;
    R 5selected from: c5～C 8Cycloalkyl radical, R10Substituted phenyl, 6-8 membered heterocycloalkyl; or, R5、R 6And the N atom to which they are attached form a 3-to 10-membered monocyclic heterocycle or fused-ring heterocycle;
    R 10selected from: hydrogen, halogen, C1～C 2Alkyl, methoxy, halogen substituted C1～C 2An alkoxy group;
    R 13selected from: -O (CH)2) OR 14(ii) a o is an integer between 1 and 4;
    R 14selected from: H. -OR19or-NR19R 20；
    R 19、R 20Each independently selected from: c1～C 3Alkyl, or R19、R 20And N attached thereto together form R22Substituted 6-membered saturated heterocyclic group, wherein R22Selected from: -H, C1～C 3An alkyl group.
  19. The 3-aminopyrazole compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof or deuteron thereof according to claim 1, wherein the 3-aminopyrazole compound is selected from:
    3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N, 1-dimethyl-1H-pyrazole-4-carboxamide,
    3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N-ethyl-1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclopropyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-tert-butyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclopentyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cycloheptyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclooctyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    (3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazol-4-yl) (piperidin-1-yl) methanone,
    (3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazol-4-yl) (octahydroquinolin-1 (2H) -yl) methanone,
    N- (4, 4-difluorocyclohexyl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N- (tetrahydro-2H-pyran) -1H-pyrazole-4-carboxamide,
    N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N, 1-dimethyl-1H-pyrazole-4-carboxamide,
    N- (adamantan-1-yl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N-phenyl-1H-pyrazole-4-carboxamide,
    3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N- (o-tolyl) -1H-pyrazole-4-carboxamide,
    3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N- (m-tolyl) -1H-pyrazole-4-carboxamide,
    3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N- (3-ethylphenyl) -1H-pyrazole-4-carboxamide,
    3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-N- (p-tolyl) -1H-pyrazole-4-carboxamide,
    3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (2-methoxyphenyl) -1-methyl-1H-pyrazole-4-carboxamide,
    3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (3-methoxyphenyl) -1-methyl-1H-pyrazole-4-carboxamide,
    3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4-methoxyphenyl) -1-methyl-1H-pyrazole-4-carboxamide,
    N- (3-chlorophenyl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N- (4-chlorophenyl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (3-fluorophenyl) -1-methyl-1H-pyrazole-4-carboxamide,
    3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4-fluorophenyl) -1-methyl-1H-pyrazole-4-carboxamide,
    3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4-cumyl) -1-methyl-1H-pyrazole-4-carboxamide,
    3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4- (trifluoromethoxy) phenyl) -1-methyl-1H-pyrazole-4-carboxamide,
    N- (4- (difluoromethoxy) phenyl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N- (4- (cyanomethyl) phenyl) -3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -2-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -2-tolyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    3- ((3-chloro-4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) amino) -N-cyclohexyl-1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-tolyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclohexyl-3- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-methoxyphenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclohexyl-3- ((4- ((7-ethoxy-6-methoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7-propoxyquinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (2-methoxyethoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (3-methoxypropoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclohexyl-3- ((4- ((7- (3- (dimethylamine) propoxy) -6-methoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclohexyl-3- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cycloheptyl-3- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    N-cyclopentyl-3- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -1-methyl-1H-pyrazole-4-carboxamide,
    3- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -N- (4-fluorophenyl) -1-methyl-1H-pyrazole-4-carboxamide.
  20. Use of the 3-aminopyrazole compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, or a deuteron thereof, for the preparation of an AXL kinase inhibitor.
  21. The use of the 3-aminopyrazole compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, or a deuteron thereof, for the manufacture of a medicament for the prevention or treatment of a tumor.
  22. The use of claim 21, wherein the tumor is: hematologic tumors, gastrointestinal stromal tumors, histiocytic lymphoma, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer or nasopharyngeal carcinoma.
  23. A pharmaceutical composition for preventing and treating tumor, comprising the 3-aminopyrazole compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, or a deuteron thereof, and a pharmaceutically acceptable carrier.
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