HK1205507B - Protein kinase inhibitors - Google Patents
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- HK1205507B HK1205507B HK15106058.9A HK15106058A HK1205507B HK 1205507 B HK1205507 B HK 1205507B HK 15106058 A HK15106058 A HK 15106058A HK 1205507 B HK1205507 B HK 1205507B
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Description
Technical Field
The present invention relates to novel acetylene derivatives having an inhibitory activity on protein kinases, pharmaceutical compositions thereof, and methods for preventing or treating diseases including abnormal cell proliferation thereof.
Background
Protein kinases are a group of enzymes that catalyze the phosphorylation of hydroxyl groups in serine, threonine, and tyrosine in proteins. They play a very important role in the intracellular signaling pathway that regulates a series of physiological processes such as cell growth, differentiation, proliferation, etc. Human protein kinases can be classified into tyrosine protein kinases and serine/threonine protein kinases. Tyrosine protein kinases can be further classified into receptor kinases and cytoplasmic/non-receptor kinases (Manning et al, Science,2002,298,1912). Receptor tyrosine kinases occupy the cell surface and interact with growth factors, and cytoplasmic tyrosine kinases direct the phosphorylation of tyrosine. In this way, growth factors can bind to growth factor receptor sites, thereby initiating tyrosine kinase receptor polymerization and autophosphorylation of cytoplasmic tyrosine. Subsequently, the sequential phosphorylation of the protein subfamilies continues as a signal transduction process, resulting in the overexpression of transcription factors and ultimately cancer. Mutation or overexpression of a particular protein kinase may affect signal transduction in normal cells, resulting in an imbalance in the body's homeostasis. For example, continuous signal transduction may lead to cancer, inflammation, metabolic syndrome, and central nervous system disorders.
The bcr/abl fusion gene existing in chronic myelogenous leukemia is reconstructed by a c-abl proto-oncogene on a chromosome 9 and a breakpoint cluster region (bcr) on a chromosome 22. This chromosome containing the bcr/abl gene is also known as the Philadelphia chromosome (Nowell, J.Natl.cancer Inst., 1960; 25: 85). In a bcr/abl fusion gene, the bcr gene portion contains an oligomerization region and the abl gene portion contains a tyrosine region. It has been reported that the three major portions of the bcr/abl gene (p190, p210and p230kDa) are determined by the mutation points of the bcr gene. Gleevec (imatinib mesylate, STI-571) was the first antitumor targeted therapeutic drug developed by novain in 2002. The gleevec can selectively inhibit bcr/abl genes by inhibiting tyrosine kinases of abl genes. Gleevec is often used as a standard therapeutic for chronic myelogenous leukemia, but acquired resistance is its sideSerious problems are caused. There are various mechanisms for producing acquired resistance, including amplification of the bcr/abl gene, reduction of the bcr/abl gene, and point mutations in the bcr/abl gene. The most important factor is the mutation of the T315I-bcr/abl target gene point in the abl kinase region. How to overcome the drug resistance of gleevec is a very important issue at present. Currently marketed small molecule kinase inhibitors such as nilotinib and dasatinib are effective at inhibiting many point mutations in the abl kinase domain caused by gleevec resistance. However, nilotinib and dasatinib were not effective against the T315I-bcr/abl mutation. Therefore, a great deal of work is being carried out to try to develop a drug effective against the T315I-bcr/abl mutation. Vascular Endothelial Growth Factors (VEGFs) regulate many biological processes of endothelial cells, such as growth, proliferation, differentiation, angiogenesis and metastasis of cells. Vascular Endothelial Growth Factors (VEGFs) are produced primarily by vascular endothelium, hematopoietic stem cells when stimulated by hypoxia or growth factors such as TGFs, PDGFs or interleukins. Vascular Endothelial Growth Factors (VEGFs) are attached to vascular endothelial growth factor receptors (VEGFR-1, -2, and-3) that have a high affinity for their specificity. Each vascular endothelial growth factor subtype binds to specific subunits of these receptors, thereby constituting single and promiscuous dimers to activate discrete signaling pathways and perform biological functions such as angiogenesisCébe-Suarez S,Zehnder- A,Ballmer-Hofer K.Cell Mol Life Sci.2006Mar；63(5):601-15]. The new blood vessels provide a pathway for tumor nutrition, oxygen, and cancer cell spread. Therefore, the neovasculature is important for the proliferation and spread of cancer cells. Neovascularization is a common balance in normal humans through stimulation and inhibition of angiogenesis. However, in an unbalanced cancer cell, a vascular endothelial growth factor receptor is activated by a growth factor having a large role in vascular endothelial cells such as VEGFAnn Hoeben,Bart Landuyt,Martin S.Highley,Hans Wildiers,Allan T.Van OosteromAndErnst A.De Bruijn.Pharmacological Reviews.2004vol.56(4):549-580]. Various vascular endothelial growth factor receptor tyrosine kinase inhibitors (synthetic small molecule compounds) are being developed, which are mostly effective for solid tumors and capable of inhibiting angiogenesis activated only in cancer cells, and have enormous medical uses and comparatively low side effects.
Disclosure of Invention
The present invention relates to compounds having protein kinase inhibitory activity which are pharmaceutically active compounds useful for the treatment of abnormal cell growth diseases such as tumors in cancer patients.
In one aspect, the invention relates to compounds having formula (I) or pharmaceutically acceptable salts, isomers, hydrates, and solvates thereof.
Wherein the content of the first and second substances,
ring A is a 4 to 8 membered heterocyclic ring containing 1-2 heteroatoms selected from O, N and S, a 5 to 10 membered heteroaromatic ring containing 1-3 heteroatoms selected from O, N and S, or a 6 to 12 membered aromatic ring, wherein the heterocyclic, heteroaromatic and aromatic rings are optionally and independently (R)2) m is substituted;
R2independently of each other is hydrogen, halogen, CN, CH2CN,NO2,CF3,OCF3,NH2,C1-C6Alkyl radical, C3-C6Cycloalkyl, OR, SR, NRaS(O)2Rb,(CR2)v-S(O)pRc,C(O)ORc,NRaC(O)Rd,NRaC(O)ORd,NReRfOr (CR)g 2)t-S(O)2Rc；
R1Is aryl, heteroaryl, heterocycle, alkyl, or cycloalkyl, whichWherein aryl, heteroaryl, heterocycle, alkyl and cycloalkyl are optionally and independently substituted with halogen, CN, CH2CN,NO2,CF3,OCF3,NH2,C1-C6Alkyl radical, C3-C6Cycloalkyl, OR, SR, NRaS(O)2Rb,(CR2)v-S(O)pRc,C(O)ORc,NRaC(O)Rd,NRaC(O)ORd,NReRf,(CRg 2)t-S(O)2RcAryl, heterocyclyl, or heteroaryl;
each RaIndependently of one another is hydrogen, C1-C6Alkyl radical, C3-C10Cycloalkyl, heteroaryl or aryl, wherein alkyl, cycloalkyl, heteroaryl and aryl are optionally and independently substituted with aryl, heteroaryl or heterocyclyl;
each RbIndependently is C1-C6Alkyl radical, C3-C10Cycloalkyl or aryl, wherein said alkyl, cycloalkyl and aryl are optionally and independently selected from group 1-3C3-C10Cycloalkyl and halogen substituents;
each RcIndependently of one another is hydrogen, C1-C6Alkyl radical, C3-C10Cycloalkyl, heteroaryl or aryl, wherein said alkyl, cycloalkyl, heteroaryl and aryl are optionally and independently substituted with aryl, heteroaryl or heterocyclyl;
each RdIndependently of one another is hydrogen, C1-C6Alkyl or aryl, wherein said alkyl and aryl are optionally and independently substituted with 1-3 halo substituents;
each ReAnd RfIndependently is C1-C6Alkyl or a 4 to 8 membered heterocyclic ring containing 1-2 heteroatoms independently selected from O, S or N, wherein the heterocyclic ring and alkyl are optionally and independently substituted with 1-4 groups selected from halogen and alkyl;
each RgIndependently of one another is hydrogen, fluorine, C1-C6Alkyl, aryl or CF3Wherein said alkyl and aryl are optionally and independently selected from the group consisting of aryl, CF, by groups 1-33And halogen substituents;
each R is independently hydrogen, C1-C6Alkyl or C3-C10Cycloalkyl, wherein said alkyl and cycloalkyl are optionally and independently substituted with 1-4 halo substituents;
m is 0,1,2 or 3;
v is 0,1,2 or 3;
p is 0,1 or 2;
t is 0,1,2 or 3; and is
G is selected from:
wherein the content of the first and second substances,
R3independently of one another is hydrogen, halogen, C1-C6Alkyl radical, C3-C6Cycloalkyl group, (CH)2)k- (5-or 6-membered) heteroaryl or (CH)2)k- (5-or 6-membered) heterocycle, wherein the heteroaryl, heterocycle, alkyl and cycloalkyl are independently and optionally substituted by halogen, CN, CH2CN,CF3,OCF3,NH2,C1-C6Alkyl radical, C3-C6Cycloalkyl, OR, SR, NRaS(O)2Rb,(CR2)v-S(O)pRc,C(O)ORc,NReRf,(CRg 2)t-S(O)2Rc,NRaC(O)Rd,NRaC(O)ORdAryl, heterocyclyl or heteroaryl substituted;
R6independently of one another is halogen, CN, CH2CN,NO2,CF3,OCF3,NH2,C1-C6Alkyl radical, C3-C6Cycloalkyl, OR, SR, NRaS(O)2Rb,(CR2)v-S(O)pRc,C(O)ORc,NRaC(O)Rd,NRaC(O)ORd,NReRfOr (CR)g 2)t-S(O)2Rc；
X is NH or O;
y is CH or N;
z, D, E and Q are independently CH or N;
k is 0,1,2 or 3;
n is 0,1,2 or 3;
q is 1 or 2; and is
u is 0,1, or 3.
In a further aspect, the present invention provides a pharmaceutical composition comprising at least one compound represented by formula 1 or a salt, hydrate, isomer, or solvate thereof and one or more pharmaceutically acceptable carriers and/or additives.
In a further aspect, the present invention provides a method for inhibiting protein kinases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula 1 or a salt, hydrate, isomer or solvate thereof.
In a still further aspect, the present invention provides a method for treating cancer in a patient in need thereof, comprising administering a therapeutically effective amount of a compound represented by formula 1 or a salt, hydrate, isomer or solvate thereof.
In a still further aspect, the present invention provides a method for treating inflammation in a patient in need thereof, comprising administering a therapeutically effective amount of a compound represented by formula 1 or a salt, hydrate, isomer or solvate thereof.
In a further aspect, the present invention provides a use of a compound represented by formula 1, or a salt, hydrate, isomer, or solvate thereof, for the preparation of a medicament for treating cancer or inflammation.
Disclosure of Invention
It is an object of the present invention to provide novel compounds described by formula I above. In particular, the compounds of the present invention are kinase inhibitors. Accordingly, the present invention provides a compound represented by formula 1 and a pharmaceutically acceptable salt, hydrate, isomer or solvate thereof. The following paragraphs will describe the defined and specific ranges for the variables in formula I.
In one embodiment, R1Independently an aryl or heteroaryl ring selected from:
wherein the content of the first and second substances,
R4independently of each other is hydrogen, halogen, CN, CH2CN,NO2,CF3,OCF3,NH2,C1-C6Alkyl radical, C3-C6Cycloalkyl, OR, SR, NRaS(O)2Rb,(CR2)v-S(O)pRc,C(O)ORc,NRaC(O)Rd,NRaC(O)ORd,NReRfOr (CR)g 2)t-S(O)2Rc；
R5Is hydrogen, C1-C6Alkyl radical, C3-C6Cycloalkyl, phenyl or benzyl; and is
s is 0,1 or 2.
In one embodiment of the compounds of formula I, G isHaving the structure of formula II below and all other variables are as defined in formula I above.
In one embodiment of the compounds of formula II, ring A is a phenyl ring having the structure of formula III:
wherein the content of the first and second substances,
R2independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R3Is that
R4Independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R5Independently of one another is hydrogen, C1-C6Alkyl radical, C3-C6Cycloalkyl, phenyl or benzyl;
R7independently of one another is hydrogen, C1-C6Alkyl or C3-C6A cycloalkyl group;
R8independently hydrogen, halogen, CN, NO2,CF3,NH2,NReRf,C1-C6Alkyl or C3-C6A cycloalkyl group;
Reand RfIndependently is C1-C6An alkyl group;
m is 0,1 or 2;
n is 0,1 or 2;
w is 0,1 or 2; and is
s is a number of atoms of 0,1 or 2,
and all other variables are as defined above for formula I.
In another embodiment of the compounds of formula III, the compounds are represented by formula IIIa, formula IIIb or formula IIIc:
wherein the content of the first and second substances,
R2independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R3Is that
R4Independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R5Independently of one another is hydrogen, C1-C6Alkyl radical, C3-C6Cycloalkyl, phenyl or benzyl;
R6independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R7Independently of one another is hydrogen, C1-C6Alkyl or C3-C6A cycloalkyl group;
R8independently hydrogen, halogen, CN, NO2,CF3,NH2,NReRf,C1-C6Alkyl or C3-C6A cycloalkyl group;
Reand RfIndependently is C1-C6An alkyl group;
m is 0,1 or 2;
w is 0,1 or 2;
s is 0,1 or 2; and is
u is a number of 0,1 or 2,
and all other variables are as defined above for formula I.
In another embodiment of the compounds of formulae IIIa to IIIc, R2Is hydrogen, CH3Or Cl; r3Is thatR5Is cyclopropyl, cyclobutyl or isopropyl; and R is6Is hydrogen or CF3(ii) a And u is 0, s is 0, and m is 0 or 1.
In another embodiment of the compounds of formula I, G isHaving the structure of formula IV below and all other variables are as defined in formula I above.
In another embodiment of the compounds of formula IV, ring a is a phenyl ring having the structure of formula V:
wherein the content of the first and second substances,
R2independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R3Is that
R4Independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R5Independently of one another is hydrogen, C1-C6Alkyl radical, C3-C6Cycloalkyl, phenyl or benzyl;
R7independently of one another is hydrogen, C1-C6Alkyl or C3-C6A cycloalkyl group;
R8independently hydrogen, halogen, CN, NO2,CF3,NH2,NReRf,C1-C6Alkyl or C3-C6A cycloalkyl group;
Reand RfIndependently is C1-C6An alkyl group;
m is 0,1 or 2;
n is 0,1 or 2;
w is 0,1 or 2; and is
s is a number of atoms of 0,1 or 2,
and all other variables are as defined above for formula IV.
In another embodiment of the compounds of formula V, the compounds are represented by formula Va or Vb:
wherein the content of the first and second substances,
R2independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R3Is that
R4Independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6CycloalkanesBasic group, OCH3,COOCH3Or NHCOCH2CH3；
R5Independently of one another is hydrogen, C1-C6Alkyl radical, C3-C6Cycloalkyl, phenyl or benzyl;
R6independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R7Independently of one another is hydrogen, C1-C6Alkyl or C3-C6A cycloalkyl group;
R8independently hydrogen, halogen, CN, NO2,CF3,NH2,NReRf,C1-C6Alkyl or C3-C6A cycloalkyl group;
Reand RfIndependently is C1-C6An alkyl group;
m is 0,1 or 2;
w is 0,1 or 2;
s is 0,1 or 2;
and all other variables are as defined above for formula I.
In another embodiment of the compounds of formulae Va-Vb, R2Is hydrogen, CH3Or chlorine; r3Is thatR5Is cyclopropyl, cyclobutyl or isopropyl; r6Is hydrogen or CF3(ii) a And s is 0, w is 1, and m is 0 or 1.
In another embodiment of the compounds of formula IV, ring a is heterocyclyl, having the structure of formula VI:
wherein the content of the first and second substances,
R2independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R3Is that
R4Independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R5Independently of one another is hydrogen, C1-C6Alkyl radical, C3-C6Cycloalkyl, phenyl or benzyl;
R7independently of one another is hydrogen, C1-C6Alkyl or C3-C6A cycloalkyl group;
R8independently hydrogen, halogen, CN, NO2,CF3,NH2,NReRf,C1-C6Alkyl or C3-C6A cycloalkyl group;
Reand RfIndependently is C1-C6An alkyl group;
m is 0,1 or 2;
n is 0,1 or 2;
w is 0,1 or 2;
s is 0,1 or 2; and is
q is 1 or 2;
and all other variables are as defined above for formula IV.
In another embodiment of the compounds of formula VI, the compounds are represented by formula VIa:
wherein the content of the first and second substances,
q is 1 or 2; n is 0,1 or 2; and all other variables are as defined in formulas IIIa-IIIc above.
In another embodiment of the compound of formula VIa, R2Is hydrogen; r3Is thatR6Is hydrogen or CF3(ii) a And s is 0, w is 1, m is 0, and n is 1.
In another embodiment of the compounds of formula I, G isHaving the structure of formula VII:
wherein the content of the first and second substances,
R6independently of one another is halogen, CN, CH2CN,NO2,CF3,OCF3,NH2,C1-C6Alkyl radical, C3-C6Cycloalkyl, OR, SR, NRaS(O)2Rb,(CR2)v-S(O)pRc,C(O)ORc,NRaC(O)Rd,NRaC(O)ORd,NReRfOr (CR)g 2)t-S(O)2Rc；
u is 0,1,2 or 3;
q is 1 or 2;
and all other variables are as defined above for formula I.
In another embodiment of the compounds of formula VII, ring a is phenyl, having the structure of formula VIII:
wherein the content of the first and second substances,
R2independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R3Is that
R4Independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R5Independently of one another is hydrogen, C1-C6Alkyl radical, C3-C6Cycloalkyl, phenyl or benzyl；
R6Independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R7Independently of one another is hydrogen, C1-C6Alkyl or C3-C6A cycloalkyl group;
R8independently hydrogen, halogen, CN, NO2,CF3,NH2,NReRf,C1-C6Alkyl or C3-C6A cycloalkyl group;
Reand RfIndependently is C1-C6An alkyl group;
m is 0,1 or 2;
n is 0,1 or 2;
w is 0,1 or 2;
s is 0,1 or 2;
u is 0,1 or 2; and is
q is a number of 1 or 2,
and all other variables are as defined above for formula VII.
In another embodiment of the compound of formula VIII, the compound is represented by formula VIIIa, formula VIIIb, or formula VIIIc:
wherein the content of the first and second substances,
q is 1 or 2; n is 0,1 or 2; and all other variables are as defined in formulas IIIa-IIIc above.
In another formula VIIIa to VIIIcIn the examples of (A) and (B), R2Is hydrogen, CH3Or chlorine; r3Is thatR5Is cyclopropyl, cyclobutyl or isopropyl; r6Is hydrogen or CF3And s is 0, q is 1, u is 0, m is 0 or 1, and n is 1.
In another embodiment of the compounds of formula I, G isHaving the structure of formula IX, wherein u ═ 0,1, or 2; and all other variables are as defined above for formula VII.
In another embodiment of the compound of formula IX, ring a is phenyl, having the structure of formula X:
wherein the content of the first and second substances,
R2independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R3Is that
R4Independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R5Independently of one another is hydrogen, C1-C6Alkyl radical, C3-C6Cycloalkyl, phenyl or benzyl;
R6independently hydrogen, halogen, CN, NO2,CF3,OCF3,NH2,NReRf,C1-C6Alkyl radical, C3-C6Cycloalkyl radicals, OCH3,COOCH3Or NHCOCH2CH3；
R7Independently of one another is hydrogen, C1-C6Alkyl or C3-C6A cycloalkyl group;
R8independently hydrogen, halogen, CN, NO2,CF3,NH2,NReRf,C1-C6Alkyl or C3-C6A cycloalkyl group;
Reand RfIndependently is C1-C6An alkyl group;
m is 0,1 or 2;
n is 0,1 or 2;
w is 0,1 or 2;
s is 0,1 or 2;
u is 0,1 or 2; and is
q is 1 or 2;
and all other variables are as defined above for formula VII.
In another embodiment of the compounds of formula X, the compounds are represented by formula Xa, formula Xb or formula Xc:
wherein the content of the first and second substances,
u is 0,1 or 2;
q is 1 or 2;
n is 0,1 or 2;
and all other variables are as defined in formulas IIIa-IIIc above.
Some specific compounds of the invention include:
unless otherwise defined, "alkyl" as used herein includes branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. Common abbreviations for the use of alkyl groups in the present inventionWords such as "Me" or CH for methyl3Or symbolDenotes "Et" or CH for ethyl2CH3Denotes that the propyl group is substituted by "Pr" or CH2CH2CH3Representing the butyl group as "Bu" or CH2CH2CH2CH3Representation, and the like. "C1-6Alkyl "(or" C)1-C6Alkyl ") refers to a branched or straight chain alkyl group having the specified number of carbon atoms, including all isomers. C1-6Alkyl includes all hexyl alkyl and amyl alkyl isomers, also including n-, iso-and tert-butyl, n-and iso-propyl, ethyl, methyl. If the number of carbon atoms of the branched and straight chain alkyl groups is not given, it may be 1to 10 carbon atoms. C1-6The alkyl group may be unsubstituted or substituted with 1to 3 fluorine or 1to 3 chlorine atoms.
"cycloalkyl" is defined as C containing no heteroatoms3-10A carbocyclic ring. For example, cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthyl, and the like.
"aryl" means a monocyclic or bicyclic aromatic group containing 6 to 12 carbon atoms and includes, but is not limited to, phenyl, naphthyl, indenyl, and the like. Aryl also includes monocyclic fused aryl groups such as tetrahydronaphthyl and indanyl and the like.
Unless otherwise specified, "heterocyclyl" in the present invention means a four-, five-, six-, seven-or eight-membered saturated monocyclic ring containing 1to 2 heteroatoms selected from N, O and S, the linking site of which may be a carbon atom or a nitrogen atom. Examples of "heterocyclyl" include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, azapiperidinyl, pyrrolidinyl, oxazolidinyl, imidazolidinyl, 2, 3-dihydrofuran (2,3-b) pyridyl, benzoxazinyl, and the like. Heterocyclyl also includes partially unsaturated monocyclic rings which are not aromatic, for example, nitrogen-linked 2-or 4-pyridonyl or N-substituted (1H,3H) -pyrimidine-2, 4-diketonyl (N-substituted uracil). Heterocyclic groups also include charged forms such as pyridinium salts and the like.
"heteroaryl" as used herein refers to a monocyclic or bicyclic aromatic ring or ring system containing 5 to 10 atoms and containing 1to 3 heteroatoms selected from the group consisting of N, O, and S. Examples include, but are not limited to, oxadiazolyl, thiadiazolyl, pyrrolyl, furanyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, isoxazolyl, triazolyl, isothiazolyl, pyrazolyl, imidazolyl, pyridyl, oxazolyl, thiazolyl, tetrazolyl, and the like. Heteroaryl also includes aromatic heterocyclic groups fused to heterocycles which are not aromatic or partially aromatic in nature, and aromatic heterocyclic groups fused to cycloalkyl rings. Examples of other heteroaryl groups include, but are not limited to, imidazopyridyl, imidazopyridazinyl, pyrazolopyrazolyl, indazolyl, thienopyrazolyl, pyrazolopyridyl, imidazothiazolyl. Heteroaryl groups also include charged forms such as pyridinium salts. In one embodiment, heteroaryl is imidazolyl, oxadiazolyl, pyrazolyl, oxazolyl, and pyridyl.
Unless otherwise specified, "heterocycloalkyl group" in the present invention includes a straight-chain or branched saturated aliphatic hydrocarbon group attached to a carbon atom or a nitrogen atom of a heterocycle as described above.
Halogen (or halo) in the present invention includes fluoro, chloro, bromo, iodo. In one embodiment, the halogen is chlorine or fluorine.
Substituents on a ring (e.g., aromatic, heteroaromatic, or saturated heterocyclic) can be located on any atom thereof, so long as such substitution is chemically permissible and can result in stable compounds. "stable" compounds can be prepared and isolated while retaining their structure and properties or while retaining their structure and properties substantially unchanged over time, and compounds that meet the above effects can be used.
The present invention uses standard nomenclature, with the side chain ends named first, followed by the functional group attached to the point of attachment. E.g. C1-5alkyl-COOR is equal to C1-5Alkyl radical
In the compounds of the invention, when any variable (e.g. R, R)xEtc.) occur more than one time in any component or formula, each occurrence is defined independently of the other occurrences. In addition, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
In selecting the compounds of the present invention, one skilled in the art can select various substituents (i.e., R)1,R2R, etc.) will conform to the general rules of attachment and stability of compound structures.
The term "substituted" as used herein includes substituents having multiple degrees of substitution. When there are multiple substituents, the substituted compounds may be independently substituted with one or more substituents. Independently substituted means that two or more substituents may be the same or different.
When a substituent or variable has multiple definitions, the substituent or variable is defined as being selected from the group consisting of the specified definitions.
Isomers: (optical isomers, diastereoisomers, tautomers, atropisomers, geometric isomers):
the compounds of formula (I) may include one or more chiral centers and may result in racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention encompasses all of the above isomers of the compounds having formula (I).
The compounds of formula (I) may be isolated by fractional crystallization in a suitable solvent or by chiral column chromatography on an optically active stationary phase to give their respective enantiomers or diastereomers. The absolute configuration can be determined by X-ray crystal diffraction of the crystalline product or intermediate, or from the chirality of the chiral starting material purchased.
Stereoisomers of compounds of structure (I) may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known absolute configuration.
Racemic mixtures can be separated by well-known methods, for example, chiral chromatography, fractional crystallization, coupling of racemic mixtures of compounds with pure optically isomeric compounds to form diastereomeric mixtures, and separation of the individual diastereomers by chromatography. The coupling reaction may use pure optically isomeric acids or bases to form the salt. The diastereomeric derivatives can then be converted into their pure optical isomers by removal of the chiral auxiliary.
Some of the compounds of the present invention may exist as tautomers in which the hydrogen in different positions is occupied by one or more double bonds. For example, ketones and enols are referred to as keto-enol tautomers. Both individual tautomers and mixtures of tautomers are included in the compounds of the invention.
The olefinic double bond of the compounds of the present invention includes both E and Z configurations unless otherwise specified.
The compounds of formula (I) include all atropisomers and are suitable for use in the present invention. Atropisomers are due to the fact that the rotation of a single bond is hindered sufficiently to enable it to separate out its stable conformer. Atropisomers can be separated by chiral separation methods such as chiral chromatography or selective recrystallization.
In the compounds of formula (I), natural isotopes of atoms may be present. Alternatively, one or more atoms may be artificially enriched for their particular isotopic abundance, having the same number of atoms but an atomic mass different from the atomic mass prevailing in nature. The present invention encompasses all stable isotopic isomers of the compounds of formula (I). For example, the different isotopes of hydrogen comprise protium (1H) And deuterium (2H, also denoted D). Deuterium enrichment may offer certain therapeutic advantages, for example, increased metabolic stability and in vivo half-life or reduced dosage requirements, or may provide a useful biomarker. A compound of formula (I)Isotopic enhancers of the compounds can be prepared by conventional techniques.
The invention encompasses all stereoisomers of the compounds of formula (I) as described above as well as mixtures of stereoisomers in all ratios.
Salt:
the compounds of the formula (I) according to the invention also encompass pharmaceutically acceptable salts thereof, as well as pharmaceutically unacceptable salts as precursors of the free compounds or their pharmaceutically acceptable salts or converted forms of the salts.
The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable acid or base, including organic or inorganic acids or bases. Pharmaceutically acceptable salts of basic compounds refer to non-toxic salts of the compounds of the present invention which are generally formed by the reaction of the free base and a suitable organic or inorganic acid. Representative salts of the basic compounds of the present invention include, but are not limited to, these compounds: acetate, ascorbate, benzenesulfonate, benzoate, bicarbonate, bisulfate; bitartrate, borate, bromate, butyrate, camphorate, camphorsulfonate, dexcamphorsulfonate, carbonate, hydrochloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, selenosilicate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, hydroxyacetamidophenylarsonic acid, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodate, hydroxynaphthoate, isothionate, lactate, lactobionate, selenoate, malate, maleate, mandelate, methanesulfonate, methylbromate, methylnitrate, methylsulfate, methanesulfonate, galactarate, naphthalenesulfonate, nitrate, N-methylglucamine ammonium salt, oxalate, oleate, pamoate, Palmitate, pantothenate, phosphate/hydrogen phosphate, polygalacturonate, propionate, salicylate, stearate, sulfate, hypoacetate, succinate, tannate, tartrate, 8-chlorotheyl salt, thiocyanate, tosylate, triiodonium, valerate, and the like. Suitable pharmaceutically acceptable salts formed with the acids of formula (I) in the present invention include, but are not limited to, salts formed with inorganic bases including aluminum, ammonium, calcium, copper, iron, ferrous iron, lithium, magnesium, manganese, potassium, sodium, zinc, and the like. Pharmaceutically acceptable organic non-toxic bases for salt formation include: primary amines, secondary amines, tertiary amines, cyclic amines, dicyclohexylamines, basic ion exchange resins, such as arginine, betaine, caffeine, choline, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, meglumine, morpholine, piperazine, piperidine, polyurethane, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
If the compound of the present invention has a carboxyl group (-COOH) or a hydroxyl group, a pharmaceutically acceptable carboxylic acid ester such as methyl ester, ethyl ester, pivaloyl methyl ester or an acyl derivative of alcohol such as O-acetyl, O-pivaloyl, O-benzoyl, O-aminoacyl may be used. Including ester and acyl groups as are known in the art which may be used to modify the solubility or hydrolysis characteristics of the sustained release or prodrug dosage form.
If both acidic and basic groups are included in the compounds of formula (I) of the present invention, the inner or betaine (zwitterion) may be obtained by conventional methods as understood by the skilled person. For example, a compound may be combined with an organic or inorganic acid or base in a solvent or dispersant, or obtained by exchanging anions or cations with other salts. The invention also includes all forms of salts of the compounds of formula (I) which may be pharmaceutically unacceptable but which may be used to prepare physiologically acceptable salts.
The invention also includes compounds of formula (I) and solvates and hydrates thereof.
Also provided in the present invention are synthetic methods for preparing compounds of formula (I), as described hereinafter.
One aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, isomer or solvate thereof for use in a method of treatment of a human.
Another aspect of the present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt, hydrate, isomer or solvate thereof as an anticancer drug for human. Wherein said cancers include, but are not limited to, Chronic Myelogenous Leukemia (CML) and Acute Lymphocytic Leukemia (ALL).
Another aspect of the present invention is directed to a method of treating inflammation in a patient comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, isomer or solvate thereof.
The invention also relates to a pharmaceutical preparation or a pharmaceutical composition comprising as active ingredient at least one therapeutically effective amount of a compound of formula (I) or a physiologically acceptable salt, hydrate, isomer or solvate thereof, together with one or more pharmaceutically acceptable carrier substances and/or additives.
The pharmaceutical composition according to the present invention may be formulated into oral administration forms (e.g., pills, tablets, granules, hard and soft gelatin capsules, coatings, sugar-coated tablets, aqueous preparations, syrups, alcoholic or oily solutions, emulsions, suspensions, etc.); rectal administration forms (e.g., suppositories); parenteral administration; subcutaneous administration; intramuscular injection or intravenous injection (injection or infusion); transdermal or topical administration (such as ointments, tinctures, sprays, or transdermal delivery systems); or inhalants (e.g., nasal sprays or aerosols, microcapsules, implants or embedded rods). The preferred form of administration depends on the course and severity of the disease being treated.
The compounds of formula (I) and their physiologically acceptable salts, hydrates, isomers or solvates according to the invention can be administered to animals, in particular humans, as medicaments alone or in admixture with other pharmaceutical preparations.
A therapeutically effective amount is an amount of a drug or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal or human.
The amount of the active compound represented by the formula (I) and/or a physiologically acceptable salt, hydrate, isomer or solvate thereof in the pharmaceutical preparation of the present invention is 1to 2000 mg, preferably 1to 500 mg, in a single dose, but may be increased as appropriate depending on the type of the pharmaceutical preparation. The compounds of formula (I) or their physiologically acceptable salts are generally present in the pharmaceutical preparations in an amount of from 0.5% to 90% by weight. One or more compounds of the compounds of formula (I) or physiologically acceptable salts thereof can be combined with one or more solid or liquid carriers and/or additives (or adjuvants) to form a pharmaceutical preparation, and if desired with other therapeutically active substances, to form a suitable preparation for administration to humans or animals.
For the manufacture of pills, tablets, sugar-coated tablets and hard gelatine capsules, it is possible to use lactose and starches, for example corn starch, starch derivatives, talc, stearic acid or stearates and the like. Carriers for the manufacture of soft gelatin capsules and suppositories include fats, waxes, semi-solid substances, liquid polyols, natural or solidified oils and the like. Suitable carriers for preparing liquid preparations such as injections, emulsions or syrups include, for example, water, physiological saline, alcohols such as ethanol, glycerol, polyols, sucrose, mannitol, vegetable oils, invert sugar, glucose and the like. The compound shown in the formula (I) or the physiologically acceptable salt thereof can be prepared into freeze-dried powder and can be used for preparing injections or transfusions. Suitable carriers for the preparation of microcapsules, implants or slugs are, for example, copolymers of lactic acid and glycolic acid.
In addition to the active compounds and the carriers, the pharmaceutical preparations may contain conventional additives, for example, perfumes, buffer substances, fillers, diluents, disintegrants, dispersants, binders, colorants, flavorants, emulsifiers, lubricants, preservatives, stabilizers, thickeners, sweeteners, wetting agents, solvents, solubilizers, substances for long-acting preparations, salts for varying the osmotic pressure, coating agents or antioxidants.
The dosage of the active compound of formula (I) and/or a physiologically acceptable salt thereof will depend on the individual, for example, the nature and severity of the condition to be treated, sex, age, body weight, individual response capability of the human or animal, potency and duration of action of the compound, whether the treatment is acute, chronic or prophylactic, or whether other compounds than the compound of formula (I) are used. In general, the daily dose for an adult to obtain the desired therapeutic effect is about 0.01 to 100 mg/kg, preferably 0.3 to 10 mg/kg (mg/kg body weight). The daily dose may be a single dose or multiple doses.
The above compounds may be used in combination with other pharmaceutically active compounds. Other active compounds may be used in combination with the compounds of the present invention, either as a combination or in a combination formulation, including but not limited to anticancer alkylating or chimerizing agents, antimetabolites, purine or pyrimidine antagonists, spindle inhibitors, podophyllotoxins, antibiotics, nitrosoureas, inorganic ions, enzymes, hormones, mTOR inhibitors, protease inhibitors, NF-kB inhibitors, other kinase inhibitors (e.g., Src, Brc/Abl, kdr, Flt3, Aurora, GSK-3, EGFR, VEGFR, FGFR, JNK, PKC, CDKs, Syk, JAK, PDGFR, MEK, AKT, cmpi 3K, c-kit, fit-3, IGFR, ErbB2, and the like), antibodies, other soluble receptors or receptor antagonists that antagonize receptors or hormones in cancer, and the like.
The combination with the compound shown in the formula (I) can be combined or form active ingredients of a compound preparation, including but not limited to:
mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide, methotrexate, 6-mercaptopurine, 5-fluorouracil, arabinoside, gemcitabine, vinblastine, vincristine, vinorelbine, paclitaxel, etoposide, irinotecan, topotecan, doxorubicin, bleomycin, mitomycin, carmustine, lomustine, cisplatin, carboplatin, oxaliplatin, asparaginase, tamoxifen, leuprolide, flutamide, megestrol, sirolimus, carcinosite, everolimus, AP23573, velcade, iressa, tarceva, herceptin, avastin, erbitux, allopurinol, alemtuzumab, altretamine, amifostine, anastrozole, MLN-591, MLN591RL, MLN2704, arsenic trioxide, clofibrate, busabine, busulfan, capecitabine, carmustine, film-forming agents, and film-forming agents, Chlorambucil, cisplatin-epinephrine gel, cladribine, cytarabine liposome, daunorubicin, dexrazoxane, docetaxel, doxorubicin, Elliott's B solution, epirubicin, estramustine, etoposide phosphate, etoposide, exemestane, fludarabine, fulvestrant, gemtuzumab ozogate, goserelin acetate, hydroxyurea, idarubicin, imatinib mesylate, irinotecan, MLN576, letrozole, leucovorin, levamisole, melphalan, mesna, mitomycin C, mitoxantrone, methoxsalene, MLN518, MLN608, mitoxantrone, merozoite, talc, temozolomide, teniposide, VM-26, pegase, pentostatin, porfimer sodium, 2C4, tretinoin, trans-tretinoin, valrubicin, pamidronate sodium, and zoledronic acid.
Furthermore, the present invention relates to a method for inhibiting protein kinases, which comprises using a therapeutically effective amount of a compound represented by formula (I) or a salt, hydrate, isomer or solvate thereof as described above, or a pharmaceutical composition as described above. Such protein kinases include, but are not limited to, Bcr-Abl.
The compound of formula (I) was synthesized according to the following reaction scheme, and specific examples are given. Preferred methods include, but are not limited to, the following. Unless otherwise indicated, abbreviations in the equations and examples refer to the following meanings:
ac is acetate, or acetyl;
aq is an aqueous solution;
AIBN: azobisisobutyronitrile, 2,2' -azobis (2-methylpropionitrile);
ar is an aryl group;
bn is benzyl;
boc is tert-butyloxycarbonyl;
br is broad;
bu is butyl;
tbu is tert-butyl;
the celite isDiatomaceous earth;
cpr is cyclopropyl;
DCM is dichloromethane;
DIPEA is N, N-diisopropylethylamine;
DMAP is 4-dimethylaminopyridine;
DMF is N, N-dimethylformamide;
DMSO is dimethyl sulfoxide;
EDCI is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride;
EDTA is ethylene diamine tetraacetic acid;
ES-MS is electrospray ion mass spectrometry;
et is ethyl;
Et3n is triethylamine;
Et2o is diethyl ether;
EtOH is an alcohol which is a basic alcohol,
EtOAc is ethyl acetate;
halo is halogen (preferably fluoro and chloro);
HetAr or HAR is heteroaryl;
1HNMR is nuclear magnetic resonance H spectrum;
HOBt is 1-hydroxybenzotriazole;
HPLC is high performance liquid chromatography;
hz is Hertz;
i is iso;
kg is kilogram;
LC/MS is liquid chromatography-mass spectrometry;
m is mole;
me is methyl;
μ g is μ g;
MeCN is acetonitrile;
MeOH is methanol;
MHz is megahertz;
mm is millimeter;
μ L is μ L;
mM is millimolar;
μ Μ is micromolar;
mmol is millimole;
MS is mass spectrometry, as the result obtained by LC-MS can be expressed in ES;
mw is microwave;
m/z is the ratio of the nuclei;
n is normal;
NBS is N-bromosuccinimide;
nm is nanometer;
nPr is n-propyl;
p is para;
PE is petroleum ether;
ph is phenyl;
pr is propyl;
rt is room temperature;
sec is secondary;
tbu is tert-butyl;
tBuOH is tert-butanol;
tert is tertiary;
TBAF is tetrabutylammonium fluoride;
TFA is trifluoroacetic acid;
THF is tetrahydrofuran;
TLC is thin layer chromatography;
TMSA is trimethylsilyl acetylene;
u is a unit;
UV is ultraviolet;
reaction type
Schemes 1-12 describe the synthesis of compounds of formula (I). Unless otherwise indicated, all abbreviations are as defined above and all substituents are as defined in formula (I).
The synthesis of the compounds of the present invention is illustrated by the following equations and examples. All starting materials are commercially available or can be prepared according to known methods or by the methods described herein.
Reaction scheme 1 preparation of benzimidazole product (1c)
As shown in equation 1, target product 1c was prepared by a palladium-catalyzed Sonogashira coupling reaction. In reaction scheme 1, the Sonogashira coupling reaction is carried out between an alkynyl compound 1a and a benzimidazole compound 1b having a reactive group, wherein the reactive group W is I, Br or other reactive group that can undergo the Sonogashira coupling reaction.
The following equations 2-4 describe the general preparation of some exemplary alkynyl compounds based on known transformation methods:
reaction formula 23-ethynylimidazole [1,2-b]Preparation of pyridazine (1a-1)
Reaction scheme 35-ethynyl-N-cyclopropylpyrimidin-2-amine (1a-2) preparation
Preparation of reaction formula 46-ethynyl-N-substituted pyridazin-2-amines (1 a-3-1 a-5)
The following equations 5-6 describe some representative methods for synthesizing benzimidazole compounds, key intermediates of the coupling reaction in equation 1, shown in equation 1 b.
Equation 5 describes the synthesis of formulas 1b-1 and 1b-2, where R3 is (4-methylpiperazin-1-yl) methyl and R2 is methyl and chlorine, respectively.
Reaction formula 5
Equation 6 describes the synthesis of formula 1b-3, where R3 is 4-methyl-1H-imidazol-1-yl and R2 is methyl.
Reaction formula 6
Preparation of benzamide product (2c) of reaction formula 7
As shown in reaction formula 1, in reaction formula 7, an alkynyl compound 1a and a benzamide compound 2b are subjected to Sonogashira coupling reaction to obtain a benzamide product 2 c.
Schemes 8-10 describe some representative synthetic methods for the synthesis of the benzamide compound of formula 2b, which is used as a key intermediate in the coupling reaction described in scheme I.
Schemes 8 and 9 describe the synthesis of 2b, where R3 is 4-methyl-1H-imidazol-1-yl and R2 is methyl and chloro, respectively. Some representative intermediate structures are as follows:
reaction formula 8
Reaction formula 9
Equation 10 describes the synthesis of 2b, where R3 is (4-methylpiperazin-1-yl) methyl and R2 is methyl and chlorine, respectively.
Reaction scheme 10
Reaction scheme 11 preparation of Urea-based product (3c)
As shown in reaction formula 11, amine compound 3a containing alkynyl group and aromatic amine 3b with substituent group are condensed to obtain urea compound 3c.
Equation 12 describes the synthesis of 3a as a key intermediate for carrying out the condensation reaction in equation 11. The synthesis of the aromatic amine compound 3b has been described in the synthesis of 2b-1 to 2b-6 in the reaction scheme 8-10.
Reaction formula 12
Reaction scheme 13 preparation of bicyclic benzamide product (4C)
As shown in reaction formula 1, in reaction formula 13, an alkynyl compound 1a and a benzamide compound 4b are subjected to Sonogashira coupling reaction to obtain a benzamide derivative 4c.
Equation 14 describes the synthesis of 4b, where R3 is (4-methylpiperazin-1-yl) methyl and R2 is methyl.
SCHEME 14
Examples
The following representative examples are intended to further illustrate the present invention, however, the scope of the present invention is not limited to the following examples.
Example 1
N-cyclobutyl-6- (2- (2-methyl-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) pyridazin-3-amine
Step 1.6-bromo-N-cyclobutylpyridazin-3-amine
3, 6-dibromopyridazine (1.19g,5mmol) was dissolved in 1, 4-dioxane (5mL), and cyclobutylamine (0.39g,5.5mmol) and triethylamine (0.60g,6mmol) were added to the solution, followed by reaction at 90 ℃ for 0.45 hour with 150W microwave. The crude product was isolated by silica gel column chromatography (mobile phase: n-hexane containing 30% ethyl acetate) to give the title compound (0.63g, 55.3%) as monitored by thin layer chromatography.1H NMR(300MHz,CDCl3):7.25-7.28(1H,d,J＝9.0Hz),6.49-6.52(1H,d,J＝9.0Hz),5.27(1H,s),4.16-4.24(1H,m),2.40-4.49(2H,m),1.87-1.95(2H,m),1.75-1.84(2H,m).
Step 2. N-cyclobutyl-6- (2- (trimethylsilyl) ethynyl) pyridazin-3-amine
6-bromo-N-cyclobutylpyridazin-3-amine (0.60g,2.63mmol), Trimethylsilylacetylene (TMSA) (1.29g,13.1mmol), Pd (PPh)3)4(0.15g), CuI (0.04mg) was placed in a bottle with a rubber stopper, purged three times with argon, DMF (3.0mL) and N, N-diisopropylethylamine (0.41g,3.2mmol) were added, the reaction mixture was stirred at 80 ℃ for 16 hours and concentrated, and an off-white solid (0.48g, 74.5%) was isolated by silica gel column chromatography (mobile phase: N-hexane containing 30% ethyl acetate, 0.5% triethylamine to ethyl acetate).1H NMR(300MHz,CDCl3):7.26-7.29(1H,d,J＝9.0Hz),6.50-6.53(1H,d,J＝9.0Hz),5.55(1H,s),4.17-4.24(1H,m),2.40-2.46(2H,m),1.89-1.98(2H,m),1.77-1.85(2H,m),0.28(9H,s).
Step 3. N-cyclobutyl-6-ethynyl-pyridazin-3-amines
N-cyclobutyl-6- (2- (trimethylsilyl) ethynyl) pyridazin-3-amine (0.49g,2mmol) was dissolved in dichloromethane, tetrabutylammonium fluoride (TBAF) was added and the reaction was monitored by thin layer chromatography. The reaction mixture was concentrated and then subjected to silica gel column chromatography (mobile phase: n-hexane containing 30% ethyl acetate, ethyl acetate to which 0.5% triethylamine was added) to separate it into an off-white solid (0.26g, 75.1%).1H NMR(300MHz,CDCl3):7.26-7.29(1H,d,J＝9.0Hz),6.51-6.54(1H,d,J＝9.0Hz),5.57(1H,s),4.17-4.24(1H,m),3.21(1H,s),2.40-2.46(2H,m),1.89-1.98(2H,m),1.77-1.85(2H,m).
Step 4.(3, 4-dinitrophenyl) - (4-methylpiperazin-1-yl) methanone
A mixture of 3,4 dinitrobenzoic acid (10.6g,50mmol) and thionyl chloride (50mL) was heated at reflux for 6 h. Thionyl chloride was evaporated in vacuo to dryness, the residue was dissolved in dichloromethane (50mL), cooled to 5 ℃ and a mixture of N-methylpiperazine (5.5g,55mmol), triethylamine (5.5g,55mmol) and dichloromethane (50mL) was added dropwise to the resulting dichloromethane solution and stirred at room temperature overnight. The organic phase was washed with 100mL water, dried over sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (mobile phase 5% methanol in dichloromethane) to give a yellow solid (14.0g, 95.2%).1H NMR(300MHz,DMSO-d6):8.29(1H,s),8.25-8.27(1H,d,J＝9.0Hz),7.95-7.98(1H,d,J＝9.0Hz),3.62(2H,m),3.28(2H,m),2.38(2H,m),2.26(2H,m),2.19(3H,s).
Step 5.1- (3, 4-dinitrophenyl) -4-methylpiperazine
(3, 4-dinitrophenyl) - (4-methylpiperazin-1-yl) methanone (5.88g,20mmol) was dissolved in tetrahydrofuran, cooled to-5 ℃, added with powdered sodium borohydride (1.89g,50mmol) and kept at a temperature below 5 ℃, followed by dropwise addition of boron trifluoride in ether solution (6.4mL,50mmol), slowly warmed to room temperature over 2 hours after completion of the dropwise addition, stirring at room temperature for further 3 hours, then methanol was carefully added, and after stirring for 10 minutes, concentration was carried out, the residue was partitioned between ethyl acetate (150mL) and saturated aqueous sodium bicarbonate solution (150mL), the organic layer was washed with water (100mL) and saturated brine (100mL), dried over sodium sulfate, filtered and concentrated to obtain a yellow solid (4.5g, 80.3%) which was isolated by silica gel column chromatography (mobile phase is 2% methanol in dichloromethane).1H NMR(300MHz,CDCl3):7.90-7.92(1H,d,J＝6.0Hz),7.90(1H,s),7.69-7.71(1H,d,J＝6.0Hz),3.73(2H,s),3.07-3.10(2H,m),2.94-2.99(2H,m),2.76-2.81(2H,m),2.67(3H,s),2.53-2.56(2H,m).
Step 6.1- (3, 4-diaminophenyl) -4-methylpiperazine
1- (3, 4-dinitrophenyl) -4-methylpiperazine (2.8g,10mmol) was dissolved in DMF: MeOH (1:1,20mL), stirred with 10% Pd/C (280mg) under hydrogen atmosphere for 12 h, and the reaction was monitored by TLC. The mixture was filtered and concentrated to give a black solid, which was used in the next reaction without separation.
Step 7.2- (3-iodo-4-methylphenyl) -6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazole
1- (3, 4-diaminophenyl) -4-methylpiperazine (10mmol), 3-iodo-4-methylbenzoic acid (2.6g,10mmol), EDCI (11mmol) and HOBt (11mmol) were mixed in dry DMF (25mL), the reaction mixture was stirred at room temperature for 24 hours, the mixture was concentrated under reduced pressure, the obtained residue was dissolved in dichloromethane (100mL), washed with water (100mL) and saturated brine (100mL), dried over sodium sulfate, the residue was dissolved in acetic acid (30mL) after concentration by filtration, heated under reflux for 3 hours, the reaction mixture was concentrated under reduced pressure and separated by silica gel column chromatography (mobile phase was a dichloromethane solution containing 10% methanol to which 0.5% triethylamine was added) to give a yellow solid (1.35g, 30.3%).1H NMR(300MHz,CDCl3):8.50(1H,s),7.94-7.97(1H,d,J＝9.0Hz),7.53-7.56(1H,d,J＝9.0Hz),7.52-7.55(1H,d,J＝9.0Hz),7.30(1H,s),7.20-7.23(1H,d,J＝9.0Hz),3.60(2H,s),2.54(8H,brs),2.45(3H,s),2.32(3H,s).
Step 8N-cyclobutyl-6- (2- (2-methyl-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) pyridazin-3-amine
N-cyclobutyl-6-ethynylpyridazin-3-amine (62mg,0.36mmol), 2- (3-iodo-4-methyl-l-ethyl-)Phenyl) -6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d]Imidazole (134mg,0.3mmol), Pd (PPh)3)4(18mg,0.015mmol), CuI (4.3mg,0.023mmol) were placed in a two-necked flask with rubber stopper, purged three times with argon, a solution of DMF (2.0mL) and N, N-Diisopropylethylamine (DIPEA) (58mg,0.45mmol) was injected into it, the mixture was stirred at room temperature for 20 hours, then poured into 25mL of water, extracted with dichloromethane (20mL × 3), the organic phase washed with saturated brine, dried over sodium sulfate, filtered, concentrated in vacuo, and the residue was subjected to silica gel column chromatography (mobile phase from CH)2Cl2/CH3OH97:3 to CH2Cl2/CH3OH97:6) to give 0.12g of crude product, which is subjected to preparative thin-layer Chromatography (CH)2Cl2/CH3OH 120:8) to yield 87mg of a pale yellow solid. Mp 148-150 deg.C;1H NMR(300MHz,CDCl3):8.07-8.10(1H,d,J＝9.0Hz),7.90(1H,s),7.63-7.66(1H,d,J＝9.0Hz),7.63(1H,s),7.26-7.24(1H,d,J＝6.0Hz),7.20(1H,m),7.15(1H,m),6.60-6.63(1H,d,J＝9.0Hz),5.63(1H,s),4.26-4.33(1H,m),3.62(2H,s),2.58(8H,brs),2.35(3H,s),2.31(3H,s),1.94-2.03(2H,m),1.82-1.85(2H,m).HRMS(ESI-TOF+):m/z[M+H]+calcd for C30H34N7:492.2870；found:492.2856.
example 2
N-cyclopropyl-6- (2- (2-methyl-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) pyridazin-3-amine
Using a synthesis analogous to example 1, starting from N-cyclopropyl-6-ethynylpyridazin-3-amine and 2- (3-iodo-4-methylphenyl) -6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d]Imidazole (preparation method see example 1) is used as a raw material to synthesize a target compound. Preparation of intermediate N-cyclopropyl-6-ethynylpyridazin-3-amine the procedure of reference example 1The method (see steps 1to 3) is completed, and the spectral data are as follows:1H NMR(300MHz,CDCl3):7.38-7.41(1H,d,J＝9.0Hz),6.96-6.99(1H,d,J＝9.0Hz),5.99(1H,s),3.25-3.27(1H,m),2.57(1H,s),0.87-0.89(2H,s),0.61-0.63(2H,s).
the target compound is a carmine colored solid. Mp 145-146 deg.C;1H NMR(300MHz,CDCl3):8.14(1H,s),8.11-8.13(1H,d,J＝6.0Hz),7.64(2H,m),7.37-7.40(1H,d,J＝9.0Hz),7.21-7.24(1H,d,J＝9.0Hz),7.14-7.17(1H,d,J＝7.0Hz),7.01-7.04(1H,d,J＝9.0Hz),6.19(1H,s),3.67(2H,s),2.74(8H,brs),2.58(1H,m),2.50(3H,s),2.34(3H,s),0.84-0.87(2H,m),0.64(2H,m)；HRMS(ESI-TOF+):m/z[M+H]+calcd for C29H32N7:478.2714；found:478.2708.
example 3
3- (2- (2-methyl-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) imidazo [1,2-b ] pyridazine
Using a synthesis analogous to example 1, with 3-ethynylimidazo [1,2-b ]]Pyridazine and 2- (3-iodo-4-methylphenyl) -6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d]Imidazole (preparation method see example 1) is used as a raw material to synthesize a target compound. Intermediate 3-ethynylimidazo [1,2-b]Preparation of pyridazine referring to the synthesis in example 1 (see steps 1to 3), the spectral data are as follows:1H NMR(300MHz,DMSO-d6):8.63-8.64(1H,m),8.18-8.21(1H,m),8.10(1H,s),7.32-7.35(1H,m),4.94(1H,s).
the title compound was a pale yellow solid. Mp: 114-;1H NMR(300MHz,CDCl3):8.46-8.48(1H,d,J＝6.0Hz),8.25(1H,s),8.15(1H,s),8.09-8.12(1H,d,J＝9.0Hz),7.96-7.99(1H,d,J＝9.0Hz),7.59(1H,s),7.35-7.37(1H,d,J＝9.0Hz),7.26(1H,s),7.22(1H,s),7.10-7.15(1H,m),3.64(2H,s),2.60(8H,brs),2.58(3H,s),2.34(3H,s).HRMS(ESI-TOF+):m/z[M+H]+calcd for C28H28N7:462.2401；found:462.2413.
example 4
N-isopropyl-6- (2- (2-methyl-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) pyridazin-3-amine
Using a synthesis analogous to example 1, starting from N-isopropyl-6-ethynylpyridazin-3-amine and 2- (3-iodo-4-methylphenyl) -6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d]Imidazole (preparation method see example 1) is used as a raw material to synthesize a target compound. Preparation of intermediate N-isopropyl-6-ethynylpyridazin-3-amine the synthesis procedure of reference example 1 (see steps 1to 3) was followed by the following spectral data:1H NMR(300MHz,CDCl3):7.26-7.29(1H,d,J＝9.0Hz),6.54-6.57(1H,d,J＝9.0Hz),5.00(1H,s),3.97-4.04(1H,m),3.25(1H,s),1.29(3H,s),1.27(3H,s).
the title compound was a pale yellow solid. Mp:129-130 deg.C;1H NMR(300MHz,CDCl3):8.06-8.08(1H,d,J＝6.0Hz),7.87(1H,s),7.65(2H,m),7.27(1H,s),7.25(1H,s),7.19-7.21(1H,d,J＝9.0Hz),6.61-6.64(1H,d,J＝9.0Hz),5.01-5.04(1H,d,J＝9.0Hz),4.11-4.15(1H,m),3.61(2H,s),2.43(8H,brs),2.32(3H,s),2.27(3H,s),1.25-1.32(6H,m).HRMS(ESI-TOF+):m/z[M+H]+calcd for C29H34N7:480.2870；found:480.2847.
example 5
N-cyclopropyl-5- (2- (2-methyl-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) pyrimidin-2-amine
Step 1.5-bromo-N-cyclopropylpyrimidin-2-amine
5-bromo-2-chloropyrimidine (3.87g,20mmol) and cyclopropylamine (5.7g,0.1mol) were dissolved in 20mL of tetrahydrofuran, reacted at 65 ℃ for 5 hours in a sealed tube, concentrated under reduced pressure, and the residue was added with ethanol, filtered, and the filter cake was washed with ethanol to give 4.07g of a colorless solid (95.5%).1H NMR(300MHz,CDCl3):8.32(2H,s),5.58(1H,brs),2.72(1H,brs),0.82-0.84(2H,m),0.54(2H,brs).LCMS:m/z[M+H]+214.0011.
Step 2. N-cyclopropyl-5-ethynylpyrimidin-2-amine
5-bromo-N-cyclopropylpyrimidin-2-amine (1.06g,5mmol), trimethylsilylacetylene (2.5g,25mmol), Pd (PPh)3)4(289mg,0.25mmol) and CuI (71mg,0.375mmol) are placed in a two-necked flask with rubber stopper and purged three times with argon, a solution of DMF (10mL) and N, N-Diisopropylethylamine (DIPEA) (968mg,0.45mmol) is poured in, the mixture is stirred at 80 ℃ for 15 hours, poured into 50mL of water, extracted with ethyl acetate (30mL × 3), the organic phase is washed with saturated brine, dried over sodium sulfate, filtered, the filtrate is concentrated in vacuo, the residue is separated by silica gel column chromatography (mobile phase from PE/82: 18 to PE/EtOAc 64:36) to give 1.1-1.1 g N-cyclopropyl-5- (2- (trimethylsilyl) ethynyl) pyrimidin-2-amine which is dissolved in 20mL of dichloromethane and then 10mL of a solution of tetrabutylammonium fluoride (TBAF) (1.3g,5mmol) in dichloromethane is added dropwise,the reaction mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography (mobile phase from PE/EtOAc 82:18 to PE/EtOAc 64:36) to give 0.55g of a pale yellow solid (72.8%).1H NMR(300MHz,CDCl3):8.43(2H,s),5.77(1H,brs),3.18(1H,s),2.76-2.81(1H,m),0.82-0.87(2H,m),0.54-0.59(2H,m).LCMS:m/z[M+H]+160.0863.
Step 3. N-cyclopropyl-5- (2- (2-methyl-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) pyrimidin-2-amine
Using a synthesis analogous to example 1, starting from N-cyclopropyl-5-ethynylpyrimidin-2-amine (prepared as above) and 2- (3-iodo-4-methylphenyl) -6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d [ -d [ ]]Imidazole (preparation method see example 1) as a raw material to synthesize a target compound to obtain a brown solid. Mp:136-137 deg.C;1H NMR(300MHz,CDCl3):8.40(2H,s),8.21(1H,s),7.96-7.99(1H,d,J＝9.0Hz),7.52-7.55(1H,d,J＝9.0Hz),7.49-7.52(1H,d,J＝9.0Hz),7.23-7.26(1H,d,J＝9.0Hz),7.15-7.18(1H,d,J＝9.0Hz),5.81(1H,s),5.28(1H,s),3.57(2H,s),2.78(1H,s),2.55(8H,brs),2.46(3H,s),2.32(3H,s),0.83-0.87(2H,m),0.56(2H,brs).HRMS(ESI-TOF+):m/z[M+H]+calcd for C29H32N7:478.2714；found:478.2718.
example 6
3- (2- (2-chloro-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) imidazo [1,2-b ] pyridazine
Using a synthesis similar to that of example 1, with 3-ethynylimidazo [1,2-b ]]Pyridazine (preparation method see example 3) and 2- (4-chloro-3-iodophenyl) -6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d]Target compound synthesized by taking imidazole as raw materialA compound (I) is provided. Intermediate 2- (4-chloro-3-iodophenyl) -6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d]Preparation of imidazole reference example 1 synthesis (see steps 4 to 7) with spectral data as follows:1H NMR(300MHz,CDCl3):8.52(1H,s),7.95-7.98(1H,d,J＝9.0Hz),7.45-7.48(1H,d,J＝9.0Hz),7.43-7.46(1H,d,J＝9.0Hz),7.23(1H,s),7.21-7.24(1H,d,J＝9.0Hz),3.59(2H,s),2.51(8H,brs),2.29(3H,s).
the target compound is a carmine colored solid. Mp: 156-;1H NMR(300MHz,CDCl3):8.43(1H,s),8.36(1H,s),8.11-8.14(1H,d,J＝9.0Hz),8.11(1H,s),7.92-7.95(1H,d,J＝9.0Hz),7.54-7.57(2H,m),7.45-7.45(1H,d,J＝9.0Hz),7.18-7.21(1H,d,J＝9.0Hz),7.10-7.11(1H,m),3.60(2H,s),2.61(8H,brs),2.31(3H,s).HRMS(ESI-TOF+):m/z[M+H]+calcd forC27H25ClN7:482.1854；found:482.1841.
example 7
6- (2- (2-chloro-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) -N-cyclopropylpyridazin-3-amine
Using a synthesis similar to example 1, starting with N-cyclopropyl-6-ethynylpyridazin-3-amine and 2- (4-chloro-3-iodophenyl) -6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d]Imidazole is used as a raw material to synthesize a target compound. The target compound is a khaki solid, Mp:130-131 ℃;1H NMR(300MHz,CDCl3):8.11-8.13(1H,d,J＝6.0Hz),7.86(1H,s),7.64(2H,m),7.42-7.45(1H,d,J＝9.0Hz),7.39-7.42(1H,d,J＝9.0Hz),7.22(1H,s),7.01-7.04(1H,d,J＝9.0Hz),6.00(1H,s),3.61(2H,s),2.60(1H,m),2.44(8H,brs),2.27(3H,s),0.87-0.89(2H,m),0.65(2H,m).HRMS(ESI-TOF+):m/z[M+H]+calcd forC28H29ClN7:498.2167；found:498.2150.
example 8
6- (2- (2-chloro-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) -N-cyclobutylpyridazin-3-amine
Using a synthesis similar to example 1, starting with N-cyclobutyl-6-ethynylpyridazin-3-amine and 2- (4-chloro-3-iodophenyl) -6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d]Imidazole is used as a raw material to synthesize a target compound. The title compound was a pale yellow solid. Mp 161-163 deg.C;1H NMR(300MHz,CDCl3):8.13-8.15(1H,d,J＝6.0Hz),7.95(1H,s),7.62-7.65(1H,d,J＝9.0Hz),7.65(1H,s),7.36-7.39(1H,d,J＝9.0Hz),7.29-7.32(1H,d,J＝9.0Hz),7.18-7.21(1H,d,J＝9.0Hz),6.63-6.66(1H,d,J＝9.0Hz),5.80(1H,s),4.28-4.30(1H,m),3.63(2H,s),2.63(8H,brs),2.40-2.44(2H,m)2.40(3H,s),1.96-2.02(2H,m),1.79-1.81(2H,m).HRMS(ESI-TOF+):m/z[M+H]+calcd for C29H31ClN7:512.2324；found:512.2303.
example 9
6- (2- (2-chloro-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) -N-isopropylpyridazin-3-amine
Using a synthesis similar to example 1, starting with N-isopropyl-6-ethynylpyridazin-3-amine and 2- (4-chloro-3-iodophenyl) -6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d]Imidazole is used as a raw material to synthesize a target compound. The target compound isIts color solid. Mp 127-128 ℃;1H NMR(300MHz,CDCl3):8.11-8.13(1H,d,J＝6.0Hz),7.82(1H,s),7.64(2H,m),7.53(1H,s),7.35-7.38(1H,d,J＝9.0Hz),7.29-7.32(1H,d,J＝9.0Hz),6.66-6.69(1H,d,J＝9.0Hz),5.22(1H,s),4.12-4.14(1H,m),3.62(2H,s),2.51(8H,brs),2.31(3H,s),1.25-1.31(6H,m).HRMS(ESI-TOF+):m/z[M+H]+calcd forC28H31ClN7:500.2324；found:500.2313.
example 10
5- (2- (2-chloro-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) -N-cyclopropylpyrimidin-2-amine
Using a synthesis analogous to example 1, starting from N-cyclopropyl-5-ethynylpyrimidin-2-amine and 2- (4-chloro-3-iodophenyl) -6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d]Imidazole is used as a raw material to synthesize a target compound. The target compound was a brown solid. Mp 160-162 deg.C;1H NMR(300MHz,CDCl3):8.43-8.45(2H,d,J＝6.0Hz),8.12-8.15(1H,d,J＝6.0Hz),7.58-7.60(1H,d,J＝6.0Hz),7.52(1H,s),7.45-7.47(1H,d,J＝6.0Hz),7.38-7.40(1H,d,J＝6.0Hz),7.15-7.17(1H,d,J＝6.0Hz),5.80(1H,s),3.60(2H,s),2.80(8H,brs),2.59(3H,s),1.35-1.39(1H,m),0.82-0.88(2H,m),0.58-0.60(2H,m).HRMS(ESI-TOF+):m/z[M+H]+calcd for C28H29ClN7:498.2167；found:498.2163.
example 11
3- (2- (2-methyl-5- (6- (4-methyl-1H-imidazol-1-yl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) imidazo [1,2-b ] pyridazine
Step 1.4- (4-methyl-1H-imidazol-1 yl) -2-nitroaniline
A suspension of 4-bromo-2-nitroaniline (4.34g,20mmol), 4-methylimidazole (1.97g,24mmol), potassium carbonate (3.04g,22mmol), copper iodide (CuI) (0.57g,3mmol) and 8-hydroxyquinoline (0.44g,3mmol) in 20mL of LDMSO was added thereto in a sealed tube, the reaction was conducted under argon gas at 120 ℃ for 29 hours, the mixture was cooled to room temperature, 28% aqueous ammonia (10mL) was added, water and ethyl acetate were then added, the aqueous phase was extracted with ethyl acetate (80mL × 3), the organic phase was washed with saturated salt water, sodium sulfate was dried, the filtrate was concentrated under reduced pressure after filtration, and the residue was washed with PE/EtOAc to give 2.47g of a red solid (56.6%).1H NMR(300MHz,DMSO-d6):8.03(1H,d,J＝2.1Hz),7.64-7.68(1H,dd,J＝2.1and 9.0Hz),7.53(2H,brs),7.10-7.13(1H,d,J＝9.0Hz),2.12(3H,s).LCMS:m/z[M+H]+219.0895.
Step 2.2-amino-4- (4-methyl-1H-imidazol-1-yl) aniline
4- (4-methyl-1H-imidazol-1-yl) -2-nitroaniline (0.22g,1mmol) was suspended in 20mL of anhydrous methanol, 0.11g of Raney's nickel was added, and reduction was carried out at 40psi for 7 hours. Raney nickel was removed by filtration, and the filtrate was concentrated to give 0.18g of the title compound as a yellow solid (95.7%).
Step 3.N- (2-amino-4- (4-methyl-1H-imidazol-1-yl) phenyl) -3-iodo-4-methylbenzamide
3-iodo-4-methylbenzoic acid (0.26g,1mmol) was dissolved in thionyl chloride (5mL) and heated under reflux for 2 hours, and the excess thionyl chloride was removed by concentration under reduced pressure. The residue was dissolved in 5mL of anhydrous tetrahydrofuran, and a solution of triethylamine (0.12g,1.2mmol), 2-amino-4- (4-methyl-1H-imidazol-1-yl) aniline (0.18g,1mmol) and DMAP (24mg) in 5mL of anhydrous tetrahydrofuran was added dropwise. The reaction mixture was stirred at room temperature for 20 hours. Concentrating under reduced pressure, and subjecting the residue to silica gel column Chromatography (CH)2Cl2/CH3OH97:3) gave 0.16g of a pale yellow solid (37.0%). LC/MS M/z [ M + H ]]+433.0520.
Step 4.2- (3-iodo-4-methylphenyl) -6- (4-methyl-1H-imidazol-1-yl) -1H-benzo [ d ] imidazole
Dissolving N- (2-amino-4- (4-methyl-1H-imidazol-1-yl) phenyl) -3-iodo-4-methylbenzamide (0.16g,0.37mmol) in 5mL of glacial acetic acid, heating under reflux for 8 hours, concentrating the reaction solution under reduced pressure, and subjecting the residue to silica gel column Chromatography (CH)2Cl2/CH3OH97:3 to CH2Cl2/CH3OH 94:6) gave 0.1g of a pale yellow solid (65.3%). LC/MS M/z [ M + H ]]+415.0415.
Step 5.3- (2- (2-methyl-5- (5- (4-methyl-1H-imidazol-1-yl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) imidazo [1,2-b ] pyridazine
Using a synthesis similar to that of example 1, with 3-ethynylimidazo [1,2-b ]]Pyridazine and 2- (3-iodo-4-methylphenyl) -6- (4-methyl-1H-imidazol-1-yl) -1H-benzo [ d]Imidazole (prepared as above) is used as a raw material to synthesize a target compound. The title compound was a pale yellow solid. Mp 182-184 deg.C;1H NMR(400MHz,CD3OD):8.57(2H,brs),8.26(1H,s),7.98-8.05(3H,m),7.74(1H,s),7.68-7.70(1H,d,J＝8.4Hz),7.46-7.48(2H,m),7.42-7.44(1H,d,J＝8.4Hz),7.29-7.33(1H,dd,J＝4.4and9.2Hz),2.61(3H,s),2.31(3H,s).HRMS(ESI-TOF+):m/z[M+H]+calcd for C26H20N7:430.1775；found:430.1778.
example 12
3- (2- (6-cyclopropylamino) pyridazin-3-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
Step 1.1- (bromomethyl) -2- (trifluoromethyl) -4-nitrobenzene
NBS (5.4g,30mmol) and AIBN (493mg,3mmol) were added to a solution of 1-methyl-4-nitro-2-trifluorotoluene (4.1g,20mmol) in carbon tetrachloride (30mL), the reaction was refluxed overnight, poured into water, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated, and the product was used in the next reaction without separation.
Step 2.4-methyl-1- (4-nitro-2- (trifluoromethyl) benzyl) piperazine
Crude 1- (bromomethyl) -2- (trifluoromethyl) -4-nitrobenzene (13.7mmol, 60% purity) was dissolved in dichloromethane (20mL) and triethylamine (1.5g,15mmol) and 4-methylpiperazine (1.5g,15mmol) were added. After the reaction mixture was stirred at room temperature for 5 hours, 50mL of water was added, and the mixture was extracted with 50mL of dichloromethane. The organic phase is dried over sodium sulfate and concentrated by filtrationThe residue was subjected to silica gel column chromatography (mobile phase: CH with 10% MeOH)2Cl2) The product was isolated (67.4%, 2.8 g).1H NMR(300MHz,CDCl3):8.52(1H,s),8.37-8.40(1H,d,J＝9.0Hz),8.00-8.03(1H,d,J＝9.0Hz),3.85(2H,s),3.09-3.15(2H,m),2.90-2.93(2H,m),2.80-2.83(2H,m),2.67(3H,s),2.53-2.59(2H,m).
Step 3.4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline
4-methyl-1- (4-nitro-2- (trifluoromethyl) benzyl) piperazine (1.5g,5mmol) was dissolved in methanol (250mL) and Raney nickel (0.15g,10 wt%) was added. The suspension was hydrogenated under hydrogen atmosphere (50psi) for 24 h and monitored by TLC. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the desired product (100%, 1.36 g).1H NMR(300MHz,CDCl3):7.43-7.46(1H,d,J＝9.0Hz),6.91(1H,s),6.77-6.80(1H,d J＝9.0Hz),3.77(2H,s),3.54(2H,s),2.53(8H,brs),2.34(3H,s)。
Step 4.3-iodo-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
3-iodo-4-methylbenzoyl chloride (1.06g,3.8mmol) prepared from 3-iodo-4-methylbenzoic acid and thionyl chloride was added to a solution of 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline (1.00g,3.6mmol), triethylamine (0.36g, 3.6mmol) and a catalytic amount of DMAP in tetrahydrofuran (20mL), and after stirring at room temperature for 2 hours, the reaction was quenched with water. Adding ethyl acetate, separating, mixing organic phases, concentrating to dryness, and performing silica gel column chromatography (mobile phase: CH containing 5% MeOH)2Cl2MeOH with 0.5% triethylamine) was isolated to give the title product as an off-white solid (67.2%, 1.25 g).1H NMR(300MHz,CDCl3):8.29(1H,s),8.00(1H,s),7.85((1H,m),7.73-7.76((2H,m),7.31-7.34((1H,d,J＝9.0Hz),3.64(2H,s),2.53(8H,brs),2.49(3H,s),2.33(3H,s)。
Step 5.3- (2- (6- (cyclopropylamino) pyridazin-3-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
Using a synthesis method similar to example 1, the title compound was synthesized starting from N-cyclopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (prepared as above). The product was a pale yellow solid. Mp is 68-69 ℃;1H NMR(300MHz,CDCl3):8.84(1H,s),7.99-8.01(2H,d,J＝6.0Hz),7.95-7.98(1H,d,J＝9.0Hz),7.82-7.85(1H,d,J＝9.0Hz),7.71-7.73(1H,d,J＝6.0Hz),7.40-7.43(1H,d,J＝9.0Hz),7.29-7.32(1H,d,J＝9.0Hz),6.99-7.02(1H,d,J＝9.0Hz),5.85(1H,s),3.63(2H,s),2.53(8H,brs),2.34(3H,s),2.03(3H,s),1.43(1H,m),0.86-0.88(2H,m),0.61-0.63(2H,m).HRMS(ESI-TOF+):m/z[M+H]+calcd forC30H32F3N6O:549.2584；found:549.2568.
example 13
3- (2- (6- (cyclobutylamino) pyridazin-3-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide using a synthesis method similar to that of example 1. The product was obtained as a pale yellow solid. Mp 120-121 deg.C;1H NMR(300MHz,CDCl3):9.10(1H,s),8.05(1H,s),7.97-7.80(1H,d,J＝9.0Hz),7.94(1H,s),7.81-7.83(1H,d,J＝6.0Hz),7.64-7.66(1H,d,J＝6.0Hz),7.28-7.31(1H,d,J＝9.0Hz),7.26-7.28(1H,d,J＝6.0Hz),6.57-5.59(1H,d,J＝2.0Hz),5.53(1H,s),4.22-4.27(1H,m),3.64(2H,s),2.65(8H,brs),2.49(3H,s),2.45(3H,s),2.44(2H,m),1.93-1.99(2H,m),1.83-1.89(2H,m).HRMS(ESI-TOF+):m/z[M+H]+calcdfor C31H34F3N6O:563.2741；found:563.2768.
example 14
3- (2- (6-isopropylamino) pyridazin-3-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
The title compound was synthesized using N-isopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide by a synthesis method similar to that of example 1. The product was obtained as a pale yellow solid. Mp is 67-68 ℃;1H NMR(300MHz,CDCl3):8.97(1H,s),8.06(1H,s),7.98-8.01(1H,d,J＝9.0Hz),7.97(1H,s),7.83-7.85(1H,d,J＝6.0Hz),7.58-7.60(1H,d,J＝6.0Hz),7.30-7.32(2H,m),6.61-6.64(1H,d,J＝9.0Hz),5.05(1H,s),4.02-4.05(1H,m),3.70(2H,s),2.79-2.99(8H,brs),2.66(3H,s),2.52(3H,s),1.29(6H,m).HRMS(ESI-TOF+):m/z[M+H]+calcd for C30H34F3N6O:551.2741；found:551.2734.
example 15
4-chloro-3- (2- (6- (cyclopropylamino) pyridazin-3-yl) ethynyl) -N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
The title compound was synthesized using N-cyclopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide using a synthesis method similar to that used in example 1. Preparation of intermediate 4-chloro-3-iodo-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide the synthesis procedure in reference example 12 (steps 1to 4) was followed by the following spectroscopic data:1H NMR(300MHz,DMSO-d6):10.66(1H,s),8.53(1H,s),8.19(1H,s),8.02-8.05(1H,d,J＝6.0Hz),7.98-8.01(1H,d,J＝6.0Hz),7.77(1H,s),7.70-7.73(1H,d,J＝6.0Hz),3.62(2H,s),3.33(2H,m),2.82(2H,m),2.54(4H,m),2.50(3H,s).
the title compound was a pale yellow solid. Mp:133-134 deg.C;1H NMR(300MHz,CDCl3):9.57(1H,s),8.05-8.08(1H,d,J＝9.0Hz),7.85-7.88(1H,J＝9.0Hz),7.67-7.70(1H,d,J＝9.0Hz),7.42-7.45(2H,m),7.00-70.3(1H,d,J＝9.0Hz),6.00(1H,s),3.61(2H,s),2.53(8H,brs),2.35(3H,s),1.25(1H,s),0.87(2H,m),0.63(2H,m).HRMS(ESI-TOF+):m/z[M+H]+calcd forC29H29ClF3N6O:569.2038；found:569.2000.
example 16
4-chloro-3- (2- (6- (cyclobutylamino) pyridazin-3-yl) ethynyl) -N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
Using a synthesis similar to that of example 1, starting from N-cyclobutyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamideSynthesizing the target compound. The product was obtained as a pale yellow solid. Mp: 132-;1H NMR(300MHz,CDCl3):9.53(1H,s),8.10(1H,s),8.00(2H,m),7.85-7.87(1H,d,J＝6.0Hz),7.66-7.69(1H,d,J＝9.0Hz),7.43-7.45(1H,d,J＝6.0Hz),7.33-7.36(1H,d,J＝9.0Hz),6.58-6.61(1H,d,J＝9.0Hz),5.56(1H,s),4.23-4.25(1H,m),3.64(2H,s),2.61(8H,brs),2.44(3H,s),2.43(2H,m),1.91-1.97(2H,m),1.81-1.86(1H,brs).HRMS(ESI-TOF+):m/z[M+H]+calcd for C30H31ClF3N6O:583.2194；found:583.2174.
example 17
4-chloro-3- (2- (6- (isopropylamino) pyridazin-3-yl) ethynyl) -N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
The title compound was synthesized using N-isopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide as starting materials by a synthesis method similar to that of example 1. The product was obtained as a pale yellow solid. Mp:133-134 deg.C;1H NMR(300MHz,CDCl3):9.62(1H,s),8.11(1H,s),8.05(1H,s),8.01-8.03(1H,d,J＝9.0Hz),7.86-7.88(1H,d,J＝6.0Hz),7.60-7.63(1H,d,J＝6.0Hz),7.44-7.47(1H,d,J＝9.0Hz),7.33-7.36(1H,d,J＝9.0Hz),6.63-6.66(1H,d,J＝9.0Hz),3.99-4.07(1H,m),3.67(2H,s),2.84(8H,brs),2.56(3H,s),1.25-1.30(6H,m).HRMS(ESI-TOF+):m/z[M+H]+calcd for C29H30ClF3N6O:571.2194；found:571.2209.
example 18
3- (2- (6- (cyclopropylamino) pyridazin-3-yl) ethynyl) -4-methyl-N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide
Step 1.4-methyl-1- (2- (trifluoromethyl) -4-nitrophenyl) -1H-imidazole
4-methylimidazole (0.63g,7.67mmol), 1-fluoro-2- (trifluoromethyl) -4-nitrobenzene (1.06g,5.1mmol) and potassium carbonate (1.06g,7.67mmol) were combined in acetonitrile (20mL) and heated to reflux for 6 h. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography (PE/EtOAc 1:1) to give 1.13g (81.8%) of a pale green oil.1H NMR(300MHz,CDCl3):8.71(1H,s),8.52-8.55(1H,d,J＝8.4Hz),7.59-7.62(2H,m),6.90(1H,s),2.32(3H,s).LCMS:m/z[M+H]+272.0660.
Step 2.4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) aniline
4-methyl-1- (2- (trifluoromethyl) -4-nitrophenyl) -1H-imidazole (1.1g,4.1mmol) was suspended in 50mL of anhydrous ethanol. The mixture was hydrogenated with 0.11g 10% Pd/C at 40psi for 3 hours. The Pd/C was removed by filtration. The filtrate was concentrated to give 1.0g of a yellow solid product (102.0%).1H NMR(300MHz,CDCl3):7.42(1H,s),7.08-7.11(1H,d,J＝8.4Hz),6.99(1H,d,J＝2.4Hz),6.80-6.84(1H,dd,J＝2.1and 8.4Hz),6.74(1H,s),4.14(2H,brs),2.27(3H,s).LCMS:m/z[M+H]+242.0957.
Step 3.3-iodo-4-methyl-N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide
A solution of 3-iodo-4-methylbenzoic acid (0.26g,1mmol) in thionyl chloride (5mL) was heated under reflux for 3 hours, then excess thionyl chloride was evaporated under reduced pressure, the residue was dissolved in 5mL of anhydrous tetrahydrofuran, a mixed solution of triethylamine (0.12g,1mmol), 4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) aniline (0.24g,1mmol) and DMAP (12mg) in 5mL of anhydrous tetrahydrofuran was added dropwise, the reaction solution was stirred at room temperature for 40 hours, concentrated under reduced pressure, water was added to the residue and extracted with ethyl acetate (20mL × 3), the organic phase was washed with saturated salt, dried over sodium sulfate, filtered, and the filtrate was subjected to silica gel column chromatography (CH ×)2Cl2/CH3OH97:3) 0.4g of crude product are isolated. The crude product was triturated with PE/EtOAc to give 0.35g of a pale yellow solid (72.2%).1HNMR(300MHz,CDCl3):8.91(1H,s),8.37(1H,s),8.08-8.12(2H,m),7.86-7.83(1H,d,J＝8.4Hz),7.54(1H,s),7.34-7.36(2H,m),6.84(1H,s),2.50(3H,s),2.29(3H,s).LCMS:m/z[M+H]+486.0493.
Step 4.3- (2- (6- (cyclopropylamino) pyridazin-3-yl) ethynyl) -4-methyl-N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide
The title compound was synthesized using N-cyclopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide (prepared as above) by a synthetic method similar to example 1. The product was obtained as a pale yellow solid. Mp:125-126 deg.C;1H NMR(300MHz,CDCl3):9.94(1H,s),8.34(1H,s),8.20-8.23(1H,d,J＝8.7Hz),8.02(1H,s),7.86-7.89(1H,d,J＝8.1Hz),7.53(1H,s),7.39-7.42(1H,d,J＝9.0Hz),7.30-7.32(2H,m),7.02-7.05(1H,d,J＝9.2Hz),6.80(1H,s),6.02(1H,s),2.58(1H,m),2.48(3H,s),2.29(3H,s),0.87(2H,m),0.64(2H,brs).HRMS(ESI-TOF+):m/z[M+2H]+2calcd for C28H25F3N6O:259.1015；found:259.1023.
example 19
3- (2- (6- (isopropylamino) pyridazin-3-yl) ethynyl) -4-methyl-N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide
The title compound was synthesized using N-isopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide using a synthesis method similar to that used in example 1. The product was obtained as a pale yellow solid. Mp 141-143 deg.C;1H NMR(300MHz,CDCl3):9.82(1H,s),8.34(1H,s),8.20-8.23(1H,d,J＝7.8Hz),7.96(1H,s),7.84-7.86(1H,d,J＝8.1Hz),7.54(1H,s),7.29-7.31(3H,m),6.81(1H,s),6.63-6.66(1H,d,J＝8.4Hz),5.11(1H,brs),4.08(1H,m),2.46(3H,s),2.29(3H,s),1.28-1.31(6H,d,J＝6.3Hz).HRMS(ESI-TOF+):m/z[M+H]+calcdfor C28H26F3N6O:519.2115；found:519.2116.
example 20
4-chloro-3- (2- (6- (cyclopropylamino) pyridazin-3-yl) ethynyl) -N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide
The title compound was synthesized using N-cyclopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide using a synthesis procedure similar to that used in example 1. Intermediate 4-chloro-3-iodo-N- (4- (4-methyl-1H-imidazol-1-yl) -3-Preparation of (trifluoromethyl) phenyl) benzamide the synthesis procedure in reference example 18 (steps 1to 3) was followed with the following spectroscopic data:1H NMR(300MHz,DMSO-d6):10.78(1H,s),8.55(1H,d,J＝2.1Hz),8.26(1H,s),8.22(1H,s),8.11(1H,s),7.99-8.03(1H,dd,J＝2.1and 8.1Hz),7.76-7.80(2H,m),7.49(1H,s),2.19(3H,s).LCMS:m/z[M+H]+505.9663.
the title compound was a pale yellow solid. Mp 150-152 deg.C;1H NMR(300MHz,CDCl3):10.45(1H,s),8.38(1H,s),8.24-8.27(1H,d,J＝8.1Hz),8.10(1H,s),7.85-7.87(1H,d,J＝6.9Hz),7.42-7.52(3H,m),7.29-7.32(1H,d,J＝9.0Hz),7.07(1H,s),6.80(1H,s),6.09(1H,s),2.59(1H,brs),2.28(3H,s),0.88-0.89(2H,m),0.65(2H,brs).HRMS(ESI-TOF+):m/z[M+2H]+2calcdfor C27H22ClF3N6O:269.0742；found:269.0735.
example 21
4-chloro-3- (2- (6-cyclobutylamino) pyridazin-3-yl) ethynyl) -N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide
The title compound was synthesized using N-cyclobutyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide using a synthesis method similar to that of example 1. The product was obtained as a pale yellow solid. Mp:153-155 deg.C;1H NMR(300MHz,CDCl3):10.34(1H,s),8.36(1H,s),8.24-8.27(1H,d,J＝8.1Hz),8.03(1H,s),7.82-7.85(1H,d,J＝8.1Hz),7.48(1H,s),7.41-7.44(1H,d,J＝8.7Hz),7.34-7.37(2H,t,J＝9.3and 8.7Hz),6.80(1H,s),6.61-6.64(1H,d,J＝9.6Hz),5.57-5.59(1H,d,J＝6.0Hz),4.22-4.29(1H,m),2.45-2.48(2H,m),2.28(3H,s),1.76-2.01(4H,m).HRMS(ESI-TOF+):m/z[M+2H]+2calcd for C28H24ClF3N6O:276.0821；found:276.0817.
example 22
4-chloro-3- (2- (6- (isopropylamino) pyridazin-3-yl) ethynyl) -N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide
The title compound was synthesized using N-isopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide using a synthesis method similar to that used in example 1. The product was obtained as a pale yellow solid. Mp: 133-;1H NMR(300MHz,CDCl3):10.46(1H,s),8.40(1H,s),8.28-8.31(1H,d,J＝8.1Hz),8.04(1H,s),7.82-7.84(1H,d,J＝8.1Hz),7.53(1H,s),7.41-7.43(1H,d,J＝8.4Hz),7.34-7.36(2H,m),6.81(1H,s),6.66-6.69(1H,d,J＝9.3Hz),5.13-5.15(1H,d,J＝6.3Hz),4.08(1H,m),2.29(3H,s),1.30-1.32(6H,d,J＝6.0Hz).HRMS(ESI-TOF+):m/z[M+H]+calcd for C27H23ClF3N6O:539.1568；found:539.1592.
example 23
3- (2- (6- (cyclopropylamino) pyridazin-3-yl) ethynyl) -4-methyl-N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide
Using a synthesis similar to example 1, starting with N-cyclopropyl-6-ethynylpyridazin-3-amine and 4-methyl-3-iodo-N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl)) Phenyl) benzamide is used as a raw material to synthesize a target compound. The product was obtained as a colorless solid. Mp:226-228 deg.C;1H NMR(300MHz,DMSO-d6):10.72(1H,s),8.30(1H,s),8.18-8.24(2H,m),7.94-7.98(1H,dd,J＝1.5and 8.1Hz),7.72-7.74(2H,m),7.55-7.59(2H,m),7.50(1H,s),6.93-6.96(1H,d,J＝9.6Hz),2.66(1H,m),2.57(3H,s),2.23(3H,s),0.75-0.81(2H,m),0.47-0.52(2H,m).HRMS(ESI-TOF+):m/z[M+H]+calcd for C28H24F3N6O:517.1958；found:517.1950.
example 24
3- (2- (6- (cyclobutylamino) pyridazin-3-yl) ethynyl) -4-methyl-N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide
Step 1.3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline
Suspending 3-bromo-5- (trifluoromethyl) aniline (4.8g,20mmol), 4-methylimidazole (1.97g,24mmol), potassium carbonate (3.04g,22mmol), cuprous iodide (0.57g,3mmol) and 8-hydroxyquinoline (0.44g,3mmol) in 20mL of DMSO under the protection of argon, stirring and reacting at 120 ℃ in a sealed tube for 16 hours, cooling the mixture to 50 ℃, adding 28% ammonia water (10mL), keeping the temperature of the mixture for 1 hour, cooling to room temperature, adding water and ethyl acetate, extracting the aqueous phase with ethyl acetate (60mL × 3), washing the organic phase with saturated saline, drying with sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography (CH ×)2Cl2/CH3OH97:3) gave 2.85g of a pale yellow solid (59.1%).1H NMR(300MHz,CDCl3):7.76(1H,s),7.01(1H,s),6.94(1H,s),6.84(1H,s),6.78(1H,s),4.11(2H,brs),2.29(3H,s).LCMS:m/z[M+H]+242.0966.
Step 2.3-iodo-4-methyl-N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide
3-iodo-4-methylbenzoic acid (1.31g,5mmol) was refluxed in thionyl chloride (10mL) for 2 hours, excess thionyl chloride was evaporated under reduced pressure, the residue was dissolved in 5mL anhydrous tetrahydrofuran, DIPEA (0.77g,6mmol), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (1.21g,5mmol) and DMAP (24mg) in 10mL anhydrous tetrahydrofuran solution were added dropwise the resulting mixture was stirred at room temperature for reaction for 20 hours, concentrated under reduced pressure, the residue was added with water, extracted with ethyl acetate (50mL × 3) and then with dichloromethane, combined and concentrated under reduced pressure to give a crude product, which was concentrated with CH2Cl2EtOAc trituration afforded 2.04g of the product as a colorless solid (84.3%).1H NMR(300MHz,DMSO-d6):10.67(1H,s),8.46(1H,d,J＝1.5Hz),8.27(1H,s),8.21(1H,s),8.14(1H,s),7.93-7.96(1H,dd,J＝1.5and 7.5Hz),7.74(1H,s),7.50-7.55(2H,m),2.46(3H,s),2.19(3H,s).LCMS:m/z[M+H]+486.0211.
Step 3.3- (2- (6- (cyclopropylamino) pyridazin-3-yl) ethynyl) -4-methyl-N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide
The title compound was synthesized using N-cyclobutyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide (prepared as above) by a synthesis method similar to example 1. The product was obtained as a pale yellow solid. Mp:223-225 deg.C;1H NMR(300MHz,DMSO-d6):10.72(1H,s),8.31(1H,s),8.17-8.22(2H,m),7.94-7.96(1H,dd,J＝1.5and 8.1Hz),7.75(1H,s),7.47-7.61(4H,m),6.77-6.80(1H,d,J＝9.0Hz),4.42(1H,m),2.56(3H,s),2.33-2.35(2H,m),2.19(3H,brs),1.88-1.99(2H,m),1.72-1.78(2H,m).HRMS(ESI-TOF+):m/z[M+H]+calcdfor C29H26F3N6O:531.2115；found:531.2113.
example 25
3- (2- (6- (isopropylamino) pyridazin-3-yl) ethynyl) -4-methyl-N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide
The title compound was synthesized using N-isopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide using a synthesis method similar to that used in example 1. The product was obtained as a pale yellow solid. Mp 192-194 ℃;1H NMR(300MHz,DMSO-d6):10.73(1H,s),8.33(1H,s),8.17-8.22(2H,m),7.94-7.96(1H,d,J＝7.2Hz),7.76(1H,s),7.54-7.57(1H,d,J＝7.8Hz),7.45-7.48(1H,d,J＝8.4Hz),7.15-7.18(1H,d,J＝7.5Hz),6.79-6.82(1H,d,J＝9.0Hz),4.14-4.20(1H,m),2.56(3H,s),2.19(3H,brs),1.20-1.22(6H,d,J＝6.3Hz).HRMS(ESI-TOF+):m/z[M+H]+calcd for C28H26F3N6O:519.2115；found:519.2121.
example 26
4-chloro-3- (2- (6- (cyclopropylamino) pyridazin-3-yl) ethynyl) -N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide
Using a synthesis similar to example 1, with N-cyclopropyl-6-ethynylpyridazineSynthesizing the target compound by using (E) -3-amine and 4-chloro-3-iodo-N- (3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) phenyl) benzamide as raw materials. Preparation of intermediate 4-chloro-3-iodo-N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide the synthesis procedure in reference example 24 (steps 1to 2) was followed with the spectral data:1H NMR(300MHz,DMSO-d6):10.78(1H,s),8.55(1H,d,J＝2.1Hz),8.26(1H,s),8.22(1H,s),8.11(1H,s),7.99-8.03(1H,dd,J＝2.1and 8.1Hz),7.76-7.80(2H,m),7.49(1H,s),2.19(3H,s).LCMS:m/z[M+H]+505.9663.
the title compound was obtained as a colorless solid. Mp 213-215 deg.C;1H NMR(300MHz,DMSO-d6):10.83(1H,s),8.37(1H,d,J＝2.1Hz),8.28(1H,s),8.15(1H,s),8.01-8.05(1H,dd,J＝2.1and8.4Hz),7.76-7.86(3H,m),7.52-7.63(2H,m),6.94-6.97(1H,d,J＝9.3Hz),2.67(1H,m),2.19(3H,s),0.75-0.81(2H,m),0.48-0.53(2H,m).HRMS(ESI-TOF+):m/z[M+H]+calcd forC27H21ClF3N6O:537.1412；found:537.1413.
example 27
4-chloro-3- (2- (6- (cyclobutylamino) pyridazin-3-yl) ethynyl) -N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide
The title compound was synthesized using N-cyclobutyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide using a synthesis method similar to that of example 1. The product was obtained as a pale yellow solid. Mp: 225-;1H NMR(300MHz,DMSO-d6):10.82(1H,s),8.35(1H,d,J＝2.1Hz),8.27(1H,s),8.13(1H,s),7.99-8.03(1H,dd,J＝2.1and 8.1Hz),7.81-7.84(1H,d,J＝8.7Hz),7.76(1H,s),7.66-7.68(2H,m),7.46-7.49(1H,d,J＝9.0Hz),6.76-6.80(1H,d,J＝9.3Hz),4.40(1H,m),2.32-2.34(2H,m),2.17(3H,brs),1.87-1.97(2H,m),1.71-1.76(2H,m).HRMS(ESI-TOF+):m/z[M+2H]+2calcd for C28H24ClF3N6O:276.0821；found:276.0819.
example 28
3- (2- (2- (cyclopropylamino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide
The title compound was synthesized using N-cyclopropyl-5-ethynylpyrimidin-3-amine and 3-iodo-4-methyl-N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide using a synthesis method similar to that used in example 1. The product was obtained as a pale yellow solid. Mp: 131-;1H NMR(300MHz,CDCl3):8.49(2H,brs),8.34(1H,s),8.10(2H,m),7.99(1H,s),7.78-7.81(1H,d,J＝8.4Hz),7.61(1H,brs),7.37-7.40(2H,m),6.83(1H,brs),5.58(1H,s),2.82(1H,m),2.57(3H,s),2.31(3H,s),0.87-0.89(2H,m),0.60(2H,brs).
HRMS(ESI-TOF+):m/z[M+H]+calcd for C28H24F3N6O:517.1958；found:517.1960.
example 29
4-chloro-3- (2- (2- (cyclopropylamino) pyrimidin-5-yl) ethynyl) -N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide
The title compound was synthesized using N-cyclopropyl-5-ethynylpyrimidin-3-amine and 4-chloro-3-iodo-N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide using a synthesis method similar to that used in example 1. The product was obtained as a colorless solid. Mp 141-143 deg.C;1H NMR(300MHz,CDCl3):8.72(1H,s),8.50(1H,s),8.06-8.09(3H,m),7.82-7.85(1H,d,J＝8.4Hz),7.55-7.58(2H,m),7.35-7.38(1H,d,J＝8.1Hz),6.83(1H,s),5.64(1H,s),2.82(1H,brs),2.29(3H,s),0.88-0.89(2H,m),0.59(2H,brs).HRMS(ESI-TOF+):m/z[M+H]+calcd for C27H21ClF3N6O:537.1412；found:537.1417.
example 30
3- (2- (imidazo [1,2-b ] pyridazin-3-yl) ethynyl) -4-methyl-N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide
Using a synthesis similar to that of example 1, with 3-ethynylimidazo [1,2-b ]]Pyridazine and 3-iodo-4-methyl-N- (4- (4-methyl-1H-imidazole-1-yl) -3- (trifluoromethyl) phenyl) benzamide are used as raw materials to synthesize a target compound. The target product was obtained as a pale yellow solid. Mp 124-126 deg.C;1H NMR(300MHz,CDCl3):9.00(1H,s),8.48(1H,d,J＝4.8Hz),8.17(1H,s),8.09(3H,m),7.93-7.95(1H,d,J＝8.7Hz),7.86-7.89(1H,d,J＝8.1Hz),7.55(1H,s),7.39-7.42(1H,d,J＝8.1Hz),7.34-7.36(1H,d,J＝8.4Hz),7.11-7.16(1H,dd,J＝4.2and 8.4Hz),6.82(1H,s),2.64(3H,s),2.29(3H,s).HRMS(ESI-TOF+):m/z[M+H]+calcd for C27H20F3N6O:501.1645；found:501.1626.
example 31
4-chloro-3- (2- (imidazo [1,2-b ] pyridazin-3-yl) ethynyl) -N- (4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide
Using a synthesis similar to that of example 1, with 3-ethynylimidazo [1,2-b ]]Pyridazine and 4-chloro-3-iodo-N- (4- (4-methyl-1H-imidazole-1-yl) -3- (trifluoromethyl) phenyl) benzamide are used as raw materials to synthesize a target compound. The target product was obtained as a pale yellow solid. Mp:153-155 deg.C;1H NMR(300MHz,CDCl3):9.39(1H,s),8.49(1H,d,J＝3.3Hz),8.08-8.18(4H,m),7.91-7.94(2H,m),7.57-7.60(2H,m),7.34(1H,brs),7.14-7.16(1H,m),6.85(1H,brs),2.28(3H,s).HRMS(ESI-TOF+):m/z[M+H]+calcd forC26H17ClF3N6O:521.1099；found:521.1092.
example 32
4-chloro-3- (2- (imidazo [1,2-b ] pyridazin-3-yl) ethynyl) -N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide
Using a synthesis similar to that of example 1, with 3-ethynylimidazo [1,2-b ]]Pyridazine and 4-chloro-3-iodo-N- (3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) phenyl) benzamide are used as raw materials to synthesize a target compound. The target product was obtained as a pale yellow solid. Mp 153-154 deg.C;1H NMR(300MHz,CDCl3):9.35(1H,s),8.48-8.49(1H,d,J＝3.6Hz),8.25(1H,s),8.15(2H,brs),7.89-7.92(4H,m),7.57-7.60(1H,d,J＝8.4Hz),7.37(1H,s),7.12-7.16(1H,dd,J＝4.2and 9.3Hz),2.27(3H,s).HRMS(ESI-TOF+):m/z[M+2H]+2calcd for C26H18ClF3N6O:261.0586；found:261.0584.
example 33
4-chloro-3- (2- (2- (cyclopropylamino) pyrimidin-5-yl) ethynyl) -N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide
The title compound was synthesized using N-cyclopropyl-5-ethynylpyrimidin-3-amine and 4-chloro-3-iodo-N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide using a synthesis method similar to that used in example 1. The product was obtained as a colorless solid. Mp 163-165 ℃;1H NMR(300MHz,DMSO-d6):10.79(1H,s),8.53(3H,brs),8.19-8.25(2H,m),8.12(1H,s),7.95-8.00(2H,m),7.75-7.79(2H,m),2.75(1H,brs),2.16(3H,s),0.68-0.79(2H,m),0.51(2H,brs).HRMS(ESI-TOF+):m/z[M+H]+calcd forC27H21ClF3N6O:537.1412；found:537.1399.
example 34
3- (2- (imidazo [1,2-b ] pyridazin-3-yl) ethynyl) piperidine-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -1-carboxamide
Step 1.1-BOC-3-formylpiperidine
1-BOC-3-hydroxymethylpiperidine (2.15g,10mmol) and triethylamine (3.03g,30mmol) were dissolved in 10mL of DMSO and SO was added3Py (4.77g,30mmol) in 15mL of LDMSO was added dropwise to the mixture and the resulting mixture stirred at room temperature for 2 h, the reaction was poured into 100mL of ice water, extracted with ethyl acetate (100mL × 3), the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (PE/EtOAc 5:1) to give 1.46g (68.5%) of a colorless oily product.1H NMR(300MHz,CDCl3):9.70(1H,s),3.91-3.93(1H,m),3.62-3.67(1H,m),3.29-3.36(1H,m),3.05-3.13(1H,m),2.40-2.45(1H,m),1.95-1.97(1H,m),1.63-1.72(1H,m),1.49-1.59(1H,m),1.46(9H,s).
Step 2.1-BOC-3-ethynylpiperidine
1-BOC-3-formylpiperidine (1.46g,6.85mmol) and dimethyl (diazomethyl) phosphonate (1.79g,11.94mmol) were dissolved in 50mL methanol, stirred for 10 minutes in an ice bath, potassium carbonate (1.96g,14.2mmol) was added thereto, and after stirring for 2 hours in an ice bath, stirred at room temperature overnight.1H NMR(300MHz,CDCl3):3.90(1H,brs),3.70-3.75(1H,m),2.95-3.02(2H,m),2.40-2.47(1H,m),2.05(1H,d,J＝2.1Hz),1.94-1.99(1H,m),1.69-1.73(1H,m),1.50-1.63(2H,m),1.46(9H,s).
Step 3.1-BOC-3- (2- (imidazo [1,2-b ] pyridazin-3-yl) ethynyl) piperidine
Reacting 3-bromoimidazo [1.2-b ]]Pyridazine (0.40g,2mmol), 1-BOC-3-ethynylpiperidine (0.55g,2.6mmol), Pd (PPh)3)2Cl2(70mg,0.1mmol), cuprous iodide (29mg,0.15mmol) and DIPEA (0.39g,3mmol) were added to DMF (20mL) and stirred at 80 ℃ for 6 h under argon protection, the reaction was poured into 100mL of water and extracted with ethyl acetate (60mL × 3), the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and the crude product was isolated by silica gel column chromatography (PE/EtOAc 7:3 to 3:2) to give 0.39g of a yellow oily product (60.0%).1H NMR(300MHz,CDCl3):8.50(1H,d,J＝4.2Hz),7.98-8.08(2H,m),7.13-7.17(1H,dd,J＝4.5and 8.7Hz),4.09(1H,brs),3.76-3.82(1H,m),3.19(1H,brs),3.02-3.09(1H,m),2.81-2.88(1H,m),2.32(1H,brs),2.11-2.15(1H,m),1.67-1.81(2H,m),1.46(9H,s).LCMS:m/z[M+H]+327.2112.
Step 4.3- (2- (imidazo [1,2-b ] pyridazin-3-yl) ethynyl) piperidine
1-BOC-3- (2- (imidazo [1,2-b ]) is reacted with]Pyridazin-3-yl) ethynyl) piperidine (0.39g,1.2mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (1.23g,10.8mmol) was added and the mixture stirred at room temperature overnight and concentrated under reduced pressure the residue was added with 10mL 10% aqueous potassium carbonate, extracted with ethyl acetate (20mL × 3), dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 0.33g of the product as a yellow oil (107.0%).1H NMR(300MHz,CDCl3):8.43(1H,d,J＝4.5Hz),7.93-7.97(1H,dd,J＝1.8and 9.0Hz),7.91(1H,s),7.05-7.09(1H,dd,J＝4.5and9.0Hz),2.82-2.98(4H,m),2.08-2.11(1H,m),1.75-1.84(2H,m),1.53-1.58(2H,m).
Step 5.3- (2- (imidazo [1,2-b ] pyridazin-3-yl) ethynyl) piperidine-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -1-carboxamide
4- ((4-Methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline (as in example 12 Steps 1to 3Preparation) (0.1g,0.37mmol) was dissolved in 15mL of anhydrous 1, 4-dioxane, pyridine (0.036mL,0.45mmol) and 4-nitrophenyl chloroformate (90mg,0.45mmol) were added and the mixture was stirred at 60 ℃ for 2 hours, then cooled to room temperature and 3- (2- (imidazo [1,2-b ] was added]Pyridazin-3-yl) ethynyl) piperidine (0.1g,0.44mmol) was added thereto. The reaction mixture was then stirred at 60 ℃ for 9 hours and concentrated under reduced pressure. Subjecting the residue to silica gel column Chromatography (CH)2Cl2/CH3OH 25:1) to obtain 140mg of crude product, and subjecting the crude product to preparative thin layer Chromatography (CH)2Cl2/CH3OH 120:15) to yield 60mg of product as a pale yellow solid. Mp 65-70 ℃.1HNMR(300MHz,CDCl3):8.38(1H,s),7.97(1H,d,J＝9.0Hz),7.88(1H,s),7.58-7.61(2H,m),7.42-7.44(1H,d,J＝7.8Hz),7.06-7.10(1H,m),7.03(1H,s),3.95(1H,m),3.65(4H,m),3.49-3.53(2H,m),3.02(4H,m),2.79(4H,brs),2.69(3H,s),2.13(1H,brs),1.93(2H,m),1.63(1H,brs).HRMS(ESI-TOF+):m/z[M+H]+calcd for C27H31F3N7O:526.2537；found:526.2536.
Example 35
3- (2- (imidazo [1,2-b ] pyridazin-3-yl) ethynyl) pyrrole-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -1-carboxamide
Step 1.1-BOC-3-formylpyrrole
The synthesis of the target compound was carried out by the method of step 1 in reference example 30 using 1-BOC-3-hydroxymethylpyrrole as a starting material. The product was obtained as a colorless oil.1H NMR(300MHz,CDCl3):9.68(1H,s),3.70(1H,m),3.48-3.51(1H,m),3.37(2H,brs),2.99-3.03(1H,m),2.05-2.24(2H,m),1.45(9H,s).
Step 2.1-BOC-3-ethynylpyrrolidine
The synthesis of the title compound was carried out starting from 1-BOC-3-formylpyrrole (prepared as described above) according to the procedure of step 2 in example 30. The product was obtained as a colorless oil.1H NMR(300MHz,CDCl3):3.47-3.60(2H,m),3.30(2H,brs),2.90-2.95(1H,m),2.12-2.18(1H,m),2.10(1H,d,J＝1.8Hz),1.90-1.96(1H,m),1.45(9H,s).
Step 3.1-BOC-3- (2- (imidazo [1,2-b ] pyridazin-3-yl) ethynyl) pyrrole
The synthesis of the target compound was carried out starting from 1-BOC-3-ethynylpyrrolidine (prepared as above) according to the procedure of step 3 in example 30. The product obtained was a yellow oil.1H NMR(300MHz,CDCl3):8.43(1H,d,J＝3.6Hz),7.92-7.99(2H,m),7.07-7.11(1H,dd,J＝4.2and 9.0Hz),3.76(1H,m),3.60(1H,m),3.32-3.45(2H,m),2.25-2.32(1H,m),2.12(1H,m),1.71(1H,m),1.47(9H,s).
Step 4.3- (2- (imidazo [1,2-b ] pyridazin-3-yl) ethynyl) pyrrole
The target compound is synthesized by 1-BOC-3- (2- (imidazo [1,2-b ]]Pyridazin-3-yl) ethynyl) pyrrole (prepared as above was prepared according to the procedure of step 4 of example 30. The product obtained was a yellow oil.1H NMR(300MHz,CDCl3):8.43(1H,d,J＝4.2Hz),7.94-7.97(1H,d,J＝9.0Hz),7.91(1H,s),7.06-7.10(1H,dd,J＝4.2and 9.0Hz),3.10-3.35(5H,m),2.24-2.31(1H,m),2.05-2.09(1H,m).
Step 5.3- (2- (imidazo [1,2-b ] pyridazin-3-yl) ethynyl) pyrrole-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -1-carboxamide
The synthesis of the object compound was carried out in a similar manner to that in example 30 using 3- (2- (imidazo [1,2-b ])]Pyridazin-3-yl) ethynyl) pyrrole (prepared as above) and 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline (prepared as in example 12 steps 1to 3) were the starting materials for the synthesis of the title compounds. The product was obtained as a pale yellow solid. Mp 83-85 ℃.1H NMR(300MHz,CDCl3):8.44(1H,s),7.92-7.98(2H,m),7.58-7.64(3H,m),7.07-7.12(1H,dd,J＝4.5and 9.0Hz),6.37(1H,s),3.88-3.93(1H,m),3.76(1H,m),3.49-3.70(4H,m),2.62(8H,brs),2.44(4H,brs),2.29-2.31(2H,m).HRMS(ESI-TOF+):m/z[M+H]+calcd forC26H29F3N7O:512.2380；found:512.2375.
Example 36
N- (1, 1-difluoro-2, 3-dihydro-3- (4-methylpiperazin-1-substituted) -1H-indan-6-yl) -3- (2- (imidazo [1,2-b ] pyridazin-3-yl) ethynyl) -4-methylbenzamide
Step 1.6-Nitro-1-indanone
1-indanone (13.2g,0.1mol) was added in one portion to concentrated sulfuric acid (80mL) at 0 ℃. Potassium nitrate (10) was added dropwise in small portions over 40 minutes1g,0.1mol) of concentrated sulfuric acid (30 mL). The mixture was stirred at 0 ℃ for 1 hour and then poured into 500g of ice. Filtering, washing and air drying. The crude product was subjected to silica gel column chromatography to obtain 11.58g (65.4%) of a colorless solid product.1HNMR(300MHz,CDCl3):2.81-2.85(2H,t,J＝6.3Hz),3.26-3.29(2H,t,J＝6.3Hz),7.65-7.68(1H,d,J＝8.4Hz),8.43-8.47(1H,dd,J＝8.4and 2.1Hz),8.57(1H,s).
Step 2.6-Nitro-1H-inden-1-one
Triethylamine (2.55mL,18mmol) and trimethylsilyl trifluoromethanesulfonate (TMSOTf) (2.85mL,15mmol) were added to a solution of 6-nitro-1-indanone (2.66g,15mmol) in dry toluene (100mL) at 0 deg.C under an argon blanket. The mixture was stirred at room temperature for 1 hour. The reaction mixture was again cooled to 0 ℃ and diethyl ether (100mL) and saturated aqueous sodium bicarbonate (150mL) were added. The layers were separated and the aqueous layer was extracted with ether (3X 50 mL). The combined organic layers were washed with saturated brine and then dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a silyl enol ether as a pale yellow oil.
The silyl enol ether was dissolved in dichloromethane (30mL) and dropped under argon into an aluminum foil-wrapped reaction flask containing palladium acetate (3.3g,15mmol) in dry acetonitrile (80 mL). After the mixture was stirred at room temperature for 2 hours, the reaction solution was filtered through a short silica gel column. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed on silica gel (9% -21% EtOAc/PE) to give 0.69g of the product as a yellow solid (26.3%).1H NMR(300MHz,CDCl3):6.23-6.25(1H,d,J＝6.3Hz),7.27-7.30(1H,d,J＝8.1Hz),7.71-7.73(1H,d,J＝6.0Hz),8.26(1H,s),8.32-8.35(1H,dd,J＝7.8and 2.4Hz).
Step 3.2, 3-dihydro-3- (4-methylpiperazin-1-yl) -6-nitroindan-1-one
N-methylpiperazine (0.87mL,7.8mmol) was added to a solution of 6-nitro-1H-inden-1-one (690mg,3.9mmol) in tetrahydrofuran (10mL), and the resulting reaction mixture was stirred at room temperature for 12 hours. The tetrahydrofuran was evaporated off under reduced pressure and the residue was chromatographed on a silica gel column (DCM/methanol 10:1) to give 0.86g of the product as a black oil (80.3%).1H NMR(300MHz,CDCl3):2.31(3H,s),2.43-2.48(6H,m),2.61(2H,brs),2.71-2.80(1H,dd,J＝7.2and 12.3Hz),2.88-2.94(1H,m),4.66(1H,brs),7.89-7.92(1H,d,J＝8.1Hz),8.48-8.50(1H,d,J＝8.1Hz),8.56(1H,s).
Step 4.1, 1-Dithioacetal-2, 3-dihydro-3- (4-methylpiperazin-1-yl) -6-nitroindane
2, 3-dihydro-3- (4-methylpiperazin-1-yl) -6-nitroindan-1-one (0.86g,3.1mmol) and 1, 2-ethanedithiol (0.62mL,7.4mmol) were dissolved in 25mL of dichloromethane and cooled to-15 ℃ under argon. A boron trifluoride-diethyl ether complex solution (2.2mL,8.4mmol) was added dropwise thereto at the same temperature. The mixture was stirred at-15 ℃ for 3 hours and then at room temperature overnight. The reaction solution was carefully poured into saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted three times with dichloromethane, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column Chromatography (CH)2Cl2Methanol 20:1to 15:1) gave 0.6g of product as a black solid (55.6%). LCMS M/z [ M + H ]]+352.1149.
Step 5.1- (1, 1-difluoro-2, 3-dihydro-6-nitro-1H-indan-3-yl) -4-methylpiperazine
Under the protection of argon, 2.03mL of 70% pyridine hydrogen fluoride solution was added dropwise to 15mL of dichloro-1, 3-dibromo-5, 5-Dimethylhydantoin (DBH) (2g,7mmol)In a methane suspension. The temperature of the mixture was reduced to-74 ℃ and a solution of 1, 1-dithioacetal-2, 3-dihydro-3- (4-methylpiperazin-1-yl) -6-nitroindan (0.6g,1.7mmol) in 5mL of methylene chloride was added dropwise to the mixture, and the temperature was maintained at-65 ℃ or lower. The cooling bath was removed after 5 hours. The reaction mixture was stirred at room temperature overnight and poured into 50mL of 2N sodium hydroxide solution containing 3mL of 39% sodium bisulfite solution. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Chromatography of the residue on a silica gel column gave 90mg of product as a black solid (18%). LCMS M/z [ M + H ]]+298.1333.
Step 6.1- (1, 1-difluoro-2, 3-dihydro-6-amino-1H-indan-3-yl) -4-methylpiperazine
1- (1, 1-difluoro-2, 3-dihydro-6-nitro-1H-inden-3-yl) -4-methylpiperazine (90mg,0.3mmol) was suspended in 10mL of absolute ethanol and hydrogenated with 50mg of 10% Pd-C under normal pressure for 5 hours. Pd-C was then removed by filtration, and the filtrate was concentrated to give the desired product 78mg as a yellow oil (97.5%).
Step 7N- (1, 1-difluoro-2, 3-dihydro-3- (4-methylpiperazin-1-yl) -1H-indan-6-yl) -3-iodo-4-methylbenzamide
3-iodo-4-methylbenzoic acid (79mg,0.3mmol) was dissolved in thionyl chloride (5mL), heated under reflux for 3 hours, and then the remaining thionyl chloride was evaporated under reduced pressure. The residue was dissolved in 5mL of anhydrous THF and added dropwise to triethylamine (37mg,0.36mmol), 1- (1, 1-difluoro-2, 3-dihydro-6-amino-1H-indan-3-yl) -4-methylpiperazine (78mg,0.3mmol) and DMAP (2mg) in 5mL of anhydrous THF. The resulting mixture was stirred at room temperature for 26 hours and concentrated under reduced pressure. The residue was subjected to silica gel column Chromatography (CH)2Cl2/CH3OH97:3) to obtain 140mg of productThe material was a pale yellow solid (91.5%). LCMS: M/z [ M + H]+512.1049.
Step 8N- (1, 1-difluoro-2, 3-dihydro-3- (4-methylpiperazin-1-yl) -1H-indan-6-yl) -3- (2- (imidazo [1,2-b ] pyridazin-3-yl) ethynyl) -4-methylbenzamide
The target compound is prepared by 3-ethynylimidazo [1,2-b]Pyridazine and N- (1, 1-difluoro-2, 3-dihydro-3- (4-methylpiperazin-1-yl) -1H-indan-6-yl) -3-iodo-4-methylbenzamide were prepared using a similar method to that of example 1. The product was obtained as a pale yellow solid. Mp 111-113 ℃.1H NMR(300MHz,CDCl3):0.83-0.87(2H,m),2.31(3H,s),2.49(6H,brs),2.58-2.67(5H,m),4.50-4.52(1H,m),7.11-7.16(1H,dd,J＝9.0and4.5Hz),7.38-7.41(1H,d,J＝8.1Hz),7.46-7.49(1H,d,J＝8.1Hz),7.80-7.89(3H,m),7.96-8.00(1H,dd,J＝9.6and 1.5Hz),8.05(1H,d,J＝1.8Hz),8.09(1H,s),8.18(1H,s),8.48-8.49(1H,d,J＝4.2Hz).HRMS(ESI-TOF+):m/z[M+2H]+2calcd for C30H30F2N6O:264.1219；found:264.1212.
Example 37
3- (2- (2- (cyclopropylamino) pyrimidin-5-yl) ethynyl) -N- (1, 1-difluoro-2, 3-dihydro-3- (4-methylpiperazin-1-yl) -1H-indan-6-yl) -4-methylbenzamide
The title compound was prepared from N-cyclopropyl-5-ethynylpyrimidin-3-amine and N- (1, 1-difluoro-2, 3-dihydro-3- (4-methylpiperazin-1-yl) -1H-indan-6-yl) -3-iodo-4-methylbenzamide (prepared as in example 36, steps 1to 7) using a similar method to example 1. The obtained product isLight yellow solid. Mp 95-97 ℃.1HNMR(300MHz,CDCl3):0.60-0.62(2H,m),0.85-0.94(4H,m),2.30(3H,s),2.47(5H,brs),2.56-2.67(6H,m),2.82(1H,m),4.49-4.51(1H,m),7.35-7.38(1H,d,J＝8.1Hz),7.46-7.49(1H,d,J＝7.8Hz),7.74-7.79(2H,m),7.83-7.86(1H,d,J＝8.1Hz),7.91(1H,s),7.95(1H,s),8.50(2H,s).HRMS(ESI-TOF+):m/z[M+2H]+2calcd for C31H34F2N6O:272.1376；found:272.1370.
Biological assay
The antagonistic activity of the compounds of the present invention against mineralocorticoid receptors can be evaluated using the following method.
Apoptosis assay evaluation
Apoptosis test methods:
experiment 1:
k562 cell (1.5X 10)5Individual cells/ml/well) were plated on 24-well fine culture plates and treated with AP-245234 and test compound at a dose of 100nM for 48 hours. Cells were collected by centrifugation at 4000rpm x 4min and then resuspended in 150ul PBS. Viable cells were counted by trypan blue method with TC 10.
And (3) testing results:
table 1 activity of compounds against K562 cells at 100nM (% live cells versus control)
| Compound (I) | % living cells | Compound (I) | % living cells |
| 3 | 11.3 | 28 | 12.7 |
| 5 | 10.8 | 29 | 5.87 |
| 6 | 10.1 | 30 | 12.6 |
| 10 | 11 | 31 | 14.4 |
| 12 | 10.1 | 32 | 9.57 |
| 13 | 8.9 | 33 | 7.97 |
| 14 | 8.37 | 34 | 12 |
| 15 | 17 | 35 | 11.3 |
| 16 | 8.46 | 36 | 9.48 |
| 17 | 18.3 | 37 | 4.32 |
| 23 | 8.6 | Negative control | 100 |
| 24 | 16.4 | AP-24534* | 10.1 |
| 26 | 18.3 |
AP-245734 is of the following structure (j.med.chem.,2010,53,4701-,
experiment 2:
k562 cells (2X 10)5Individual cells/ml) were seeded onto 24-well fine culture plates and treated with DMSO or other reagents. After treating with DMSO or other reagent for 48h, the mixture is filteredCells were harvested by centrifugation for 5 minutes and then resuspended in an appropriate volume of PBS. 10uL of the cell suspension was mixed with 10uL of trypan blue solution and viable cells were counted by TC10(Bio-Rad, Richmond, Calif.).
And (3) testing results:
TABLE 2 some representative Compounds IC50Value of
| Compound (I) | IC50(nM) |
| 3 | 3 |
| 12 | 4 |
| 13 | 11 |
| 23 | 16 |
| 30 | 3.6 |
| 36 | 0.87 |
| 37 | 3.4 |
As shown in the above experiment 2, IC of the compound of the present invention50Values greater than 0nM and less than 20nM are set as "A" scale, IC50Values greater than or equal to 20nM and less than 1000nM are set as "B" levels.
Claims (10)
1. A compound shown in formula III or pharmaceutically acceptable salt and hydrate thereof,
wherein the content of the first and second substances,
R1selected from:
wherein the content of the first and second substances,
R4independently is hydrogen;
R5is C1-C6Alkyl or C3-C6A cycloalkyl group;
R2independently hydrogen, halogen, or C1-C6An alkyl group;
R3independently is (CH)2)k- (5-or 6-membered) heteroaryl or (CH)2)k- (5-or 6-membered) heterocycle, wherein, heteroaryl, heterocycle are independently and optionally substituted by C1-C6Alkyl substitution;
s is 1;
k is 0,1,2 or 3;
m is 0,1,2 or 3;
n is 0,1,2 or 3.
2. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate thereof, wherein:
R2independently hydrogen, halogen, or C1-C6An alkyl group;
R3is that
R4Independently is hydrogen;
R5independently is C1-C6Alkyl or C3-C6A cycloalkyl group;
R7independently is hydrogen or C1-C6An alkyl group;
R8independently is hydrogen or C1-C6An alkyl group;
m is 0,1 or 2;
n is 0,1 or 2;
w is 0,1 or 2; and is
s is 1.
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate thereof, wherein the compound is of formula (IIIa), (IIIb) or (IIIc):
wherein the content of the first and second substances,
R2independently of one another is hydrogen, halogen or C1-C6An alkyl group;
R3is that
R4Independently is hydrogen;
R5independently is C1-C6Alkyl or C3-C6A cycloalkyl group;
R6independently is hydrogen;
R7independently is hydrogen or C1-C6An alkyl group;
R8independently is hydrogen or C1-C6An alkyl group;
m is 0,1 or 2;
w is 0,1 or 2;
s is 1; and is
u is 1.
4. A compound according to claim 3, or a pharmaceutically acceptable salt, hydrate thereof, wherein R2Is hydrogen, CH3Or chlorine; r3Is thatR5Is cyclopropyl, cyclobutyl or isopropyl; r6Is hydrogen; and ism is 0 or 1.
5. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate thereof, wherein the compound is a compound selected from the group consisting of:
n-cyclobutyl-6- (2- (2-methyl-5- (6- ((4-methylpiperazin-1-yl) methyl-1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) pyridazin-3-amine;
n-cyclopropyl-6- (2- (2-methyl-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) pyridazin-3-amine;
3- (2- (2-methyl-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) imidazo [1,2-b ] pyridazine;
n-isopropyl-6- (2- (2-methyl-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) pyridazin-3-amine;
n-cyclopropyl-5- (2- (2-methyl-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) pyrimidin-2-amine;
3- (2- (2-chloro-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) imidazo [1,2-b ] pyridazine;
6- (2- (2-chloro-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) -N-cyclopropylpyridazin-3-amine;
6- (2- (2-chloro-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) -N-cyclobutylpyridazin-3-amine;
6- (2- (2-chloro-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) -N-isopropylpyridazin-3-amine;
5- (2- (2-chloro-5- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) -N-cyclopropylpyrimidin-2-amine;
3- (2- (2-methyl-5- (6- (4-methyl-1H-imidazol-1-yl) -1H-benzo [ d ] imidazol-2-yl) phenyl) ethynyl) imidazo [1,2-b ] pyridazine.
6. A compound as shown in the following or pharmaceutically acceptable salt and hydrate thereof:
n- (1, 1-difluoro-2, 3-dihydro-3- (4-methylpiperazin-1-yl) -1H-indan-6-yl) -3- (2- (imidazo [1,2-b ] pyridazin-3-yl) ethynyl) -4-methylbenzamide; or
3- (2- (2- (cyclopropylamino) pyrimidin-5-yl) ethynyl) -N- (1, 1-difluoro-2, 3-dihydro-3- (4-methylpiperazin-1-yl) -1H-indan-6-yl) -4-methylbenzamide.
7. A pharmaceutical composition comprising at least one compound as claimed in any one of claims 1to 6, or a pharmaceutically acceptable salt, hydrate thereof, and one or more pharmaceutically acceptable carriers and/or additives.
8. Use of a compound of any one of claims 1to 6, or a pharmaceutically acceptable salt, hydrate thereof, or a pharmaceutical composition of claim 7, for the manufacture of a medicament for inhibiting a protein kinase.
9. The use according to claim 8, wherein the protein kinase is a Bcr-Abl protein kinase.
10. Use of a compound of any one of claims 1to 6, or a pharmaceutically acceptable salt, hydrate thereof, or a pharmaceutical composition of claim 7, for the manufacture of a medicament for treating a cancer disease or treating an inflammatory disease in a patient.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13/561,960 US8859553B2 (en) | 2012-07-30 | 2012-07-30 | Protein kinase inhibitors |
| US13/561,960 | 2012-07-30 | ||
| PCT/CN2013/000897 WO2014019338A1 (en) | 2012-07-30 | 2013-07-30 | Protein kinase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1205507A1 HK1205507A1 (en) | 2015-12-18 |
| HK1205507B true HK1205507B (en) | 2018-05-04 |
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