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6/9/23, 10:50 AM CN111808077B - 哌嗪酰胺衍生物，其制备方法及其在医药上的用途 - Google Patents
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Piperazinamide derivative, its preparation method and its use in medicine
Abstract
CN111808077B
The present invention relates to a piperazinamide derivative represented by formula (I) or a
China
pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, and they are
used as a therapeutic agent, especially as a rearrangement (RET) during selective transfection Use
1 2 3 4 1 2 3 4 ', , 6' 7 Find Prior Art Similar
of Kinase Inhibitors. a-ring, e-ring, X , X , X , X , R , R , R , R 4 , R ', R 5 , R 5 R6 R ,R ,
7 8
R ', R , the definitions of m and n are the same as those in the specification. Other languages: English
Inventor: Zhang Panpan, Yan Sunli, Dedulla H. Reddy, Li Ying,

Classifications Guo Chenli, Qian Wenjian, Ye Cheng, Hu Taishan, Chen Lei
Current Assignee : Zhejiang Hisun Pharmaceutical Co Ltd

C07D401/14 Heterocyclic compounds containing two or more hetero rings, having nitrogen
atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one
Worldwide applications
nitrogen atom containing three or more hetero rings
2019 CN 2020 JP US WO EP TW
View 4 more classifications
Application CN201910294193.9A events
2019-04-12 Application filed by Zhejiang Hisun

Pharmaceutical Co Ltd
2019-04-12 Priority to CN201910294193.9A
2020-10-23 Publication of CN111808077A
2023-05-02 Application granted
2023-05-02 Publication of CN111808077B
Status Active
2039-04-12 Anticipated expiration
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Info: Patent citations (14), Legal events, Similar documents,

Priority and Related Applications
External links: Espacenet, Global Folder, Discuss
Claims (12) Hide Dependent
1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
in:
ring a is pyrazolyl;
1
R is selected from hydrogen, C -C alkyl or C -C cycloalkyl, and the C -C alkyl is optionally further substituted by one or more halogen atoms;
1 3 3 6 1 3
is
X1 selected from CH or N;
2
R is selected from hydrogen or C -C alkyl;
1 6
3 9 10
R is selected from hydrogen, cyano, C -C alkyl, C -C primary alcohol, C -C tertiary alcohol, C -C alkoxy, C -C cycloalkyl, -R CO R , the C -C alkyl is
1 6 1 5 3 7 1 3 3 6 2 1 6
optionally further substituted by one or more halogen atoms;
2 3
Or R and R form a phenyl group together with the two C atoms they are connected to, and the phenyl group is optionally further substituted by one or more halogen atoms or
C -C alkyl groups;
1 6
9
R is selected from chemical bonds or C -C alkylene;
1 4
10
1 6
2 3 4 2 3 4 is N; when X 2 3 4
X , X , X are selected from CH or N; when X is N, at most one of X and X is CH, both X and X are CH;
https://patents.google.com/patent/CN111808077B/zh 1/26
4 4' 5 5' 6 6' 7 7'
R ,R ,R ,R ,R ,R ,R ,R are independently selected from hydrogen, C -C alkyl or C -C alkoxy, The C -C alkyl group is optionally further substituted by one or
1 3 1 4 1 3
more hydroxyl, carboxyl or nitrile groups;
4 4' 5 5' 6 6' 7 7'

Or R and R , R and R , R and R or R and R joined together to form -(CH ) -, -(CH ) -, -CH (CH )CH -, -OCH CH - or -CH OCH -;
2 2 2 3 3 2 2 2 2 2
4 5 4 6 4 7 4' ' R7 ,R and 6 5 7 5' 6' 5' 7' 6 7 6' 7'

or R and R , R and R , R and R , R and R 5' , R 4' and R 6' , R 4 and ' 5 R , R and R , R and R ,R and R , R and R or R and R are linked
together to form -(CH )q- or -(CH OCH )-;

2 2 2
e ring is selected from pyrazolyl, pyridyl, phenyl or 3-azabicyclo[3.1.0]hexan-3-yl;
8
R is independently selected from hydrogen, halogen, cyano, C -C alkyl, C -C alkoxy, C -C alkyl or C -C cycloalkyl, said C -C alkyl is optionally further substituted by
1 3 1 3 1 3 3 6 1 3
one or more halogen atoms;
m is 1 or 2;
n is 1, 2 or 3;
q is 2 or 3.
selected
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said R is from hydrogen, cyano, C -C alkyl, -CH OH, -C(CH )
1 6 2 3 2
9 10 2 3
OH, C -C alkoxy, C -C cycloalkyl, -R CO R , the C -C alkyl is optionally further replaced by one or more halogen atoms Substituted, or R , R form a phenyl
1 3 3 6 2 1 6
group together with the two C atoms they are connected to, and the phenyl group is optionally further substituted by one or more halogen atoms or C -C alkyl groups,
1 6
9 10
and R is selected from chemical bond or C -C alkylene, R is selected from hydrogen or C -C alkyl.
1 4 1 6
3
3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein said R is selected from hydrogen, methyl, trifluoromethyl, -CH OH, -C(CH
2
2 3
) OH, -COOH, -COOMe, or R , R together with the two C atoms they are connected to form a benzene ring.
3 2
4 4' 5 5' 6 6' 7 7'

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said R , R ,R ,R ,R ,R ,R ,R each independently selected
R4 , and ' R6 R6' R7 R7 ' 4
from hydrogen, methyl, -CH2OH -CH2CH2OH or and ' R5 R5 , and or and linked together to form -(CH ) -, -OCH CH - or -CH OCH -, or R
, , R4 2 2 2 2 2 2
5 4 6 4 7 4' 5' 4' 6' 4' 7' 5 6 5 7 5' 6' 5' 7' 6 7 6' 7'
and R , R and R , R and R , R and R ,R and R ,R and R , R and R , R and R , R and R ,R and R , R and R or R and R are linked together
to form -CH OCH - or -(CH ) -.

2 2 2 2
8
5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said R is independently selected from hydrogen, halogen, cyano or C -C
1 3
alkyl.
6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the halogen is selected from fluorine or chlorine, and the C -C alkyl
1 3
group is selected from methyl.
7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the specific structure of the compound comprises:
8. A pharmaceutical composition, which contains an effective dose of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7,
and pharmaceutically acceptable carriers and excipients or a combination of them.
9. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in
the preparation of a rearrangement kinase inhibitor during transfection.
10. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the
preparation of a drug for treating diseases driven by rearranged genes during transfection use in .
11. The use according to claim 10, characterized in that the disease is cancer.
12. The use according to claim 11, characterized in that the cancer is lung cancer, thyroid cancer, colon cancer, breast cancer or pancreatic cancer.
Description
Piperazinamide derivative, its preparation method and its use in medicine
technical field
The present invention relates to the technical field of medicine, especially a novel piperazinamide derivative, a pharmaceutical composition containing the derivative and
its use as a therapeutic agent, especially as a rearrangement (RET) kinase inhibitor during selective transfection .
Background technique
The gene rearranged during transfection (RET gene) is a proto-oncogene that encodes a tyrosine kinase receptor in the human body and regulates cell proliferation and
survival. The activation of this gene needs to form a dimer by cooperating with the receptors of the glial cell-derived neurotrophic factor family and the α-receptor of the
family, and through phosphorylation, regulates signaling pathways, performs signal transduction and regulates life The function of the activity. Abnormal expression of
RET gene is associated with various cancer diseases. The gene can be fused with other genes through chromosomal rearrangement or site-specific mutation, and can be
continuously activated independently of ligands, resulting in abnormal signaling pathways, resulting in excessive cell proliferation and cancer.
In recent years, more and more evidence has shown that RET gene fusion and mutation are the driving force induced by some cancers, and they do not overlap with other
driving genes and have significant specificity. RET gene fusion is more common in papillary thyroid cancer and non-small cell lung cancer, such as 30% of sporadic
papillary thyroid cancer and 70% of radiation-induced papillary thyroid cancer and about 2% of non-small cell lung cancer are driven by the fusion of RET gene . RET gene
mutation is more common in medullary thyroid carcinoma, for example, more than 50% of medullary thyroid carcinoma and almost all congenital medullary carcinoma
and multiple endocrine neoplasia are caused by site-directed mutation of RET gene.
The current treatment methods mainly adopt multi-target kinase inhibitors with RET kinase inhibitory activity to treat cancer patients with RET gene fusion or mutation.
However, under this condition, the dose of the drug was insufficient to achieve a level sufficient to suppress abnormal RET gene expression due to off-target effects and
drug toxicity. In addition, during the treatment of cancer, cancer cells can develop drug resistance through mutation. Once drug resistance develops, patients' treatment
options will become very limited. Therefore, there is a great need for a selective RET kinase inhibitor to treat patients with RET gene fusion or mutation.
There is no drug that selectively targets RET kinase in the market, and a series of patents on selective RET kinase inhibitors have been published, including
WO2016127074, WO2017079140, WO2017011776, WO2017161269, WO2018017983, WO2018022761, WO2018071454, WO2018 136661, WO2018136663, etc. , the
drugs currently in clinical trials are Blu-667, Loxo-292 and GSK-3352589. However, these are far from enough for anti-tumor research, and it is still necessary to research
and develop new selective RET kinase inhibitors to address unmet medical needs.
Contents of the invention
In order to overcome the deficiencies in the prior art, one of the objectives of the present invention is to disclose a compound shown in formula (I) or its stereoisomers,
tautomers or pharmaceutically acceptable salts thereof:
in:
Ring a is selected from pyrazolyl, pyridyl or pyridonyl;
1
R is selected from hydrogen, C -C alkyl or C -C cycloalkyl, and the C -C alkyl is optionally further substituted by one or more halogen atoms;
1 3 3 6 1 3
is
X1 selected from CH or N;
2
1 6
3 9 10
R is selected from hydrogen, cyano, C -C alkyl, C -C primary alcohol, C -C tertiary alcohol, C -C alkoxy, C -C cycloalkyl, -R CO R , the C -C alkyl is
1 6 1 5 3 7 1 3 3 6 2 1 6
optionally further substituted by one or more halogen atoms;
2 3
Or R and R form an aryl group together with the two C atoms they are connected to, and the aryl group is optionally further substituted by one or more halogen atoms
or C -C alkyl groups;
1 6
9
R is selected from chemical bonds or C -C alkylene;
1 4
10
1 6
2 3 4 2 3 4 is N; when X 2 3 4
X , X , X are selected from CH or N; when X is N, at most one of X and X is CH, both X and X are CH;
4 4' 5 5' 6 6' 7 7'

R ,R ,R ,R ,R ,R ,R ,R are independently selected from hydrogen, C -C alkyl or C -C alkoxy, The C -C alkyl group is optionally further substituted by
1 3 1 4 1 3
one or more hydroxyl, carboxyl or nitrile groups;
4 4' 5 5' 6 6' 7 7'

Or R and R , R and R , R and R or R and R joined together to form -(CH ) -, -(CH ) -, -CH (CH )CH -, -OCH CH - or -CH OCH -;
2 2 2 3 3 2 2 2 2 2
4 5 4 6 4 7 4' ' R7 ,R and 6 5 7 5' 6' 5' 7' 6 7 6' 7'

or R and R , R and R , R and R , R and R 5' , R 4' and R 6' , R 4 and ' 5 R , R and R , R and R ,R and R , R and R or R and R are linked
together to form -(CH )q- or -(CH OCH )-;

2 2 2
4 4' 5 5' 6 6' 7 7'

or R and R , R and R , R and R or R and R together represent =O;
e ring is selected from pyrazolyl, pyridyl, phenyl or 3-azabicyclo[3.1.0]hexan-3-yl;
8
R is independently selected from hydrogen, halogen, cyano, C -C alkyl, C -C alkoxy, C -C alkyl or C -C cycloalkyl, said C -C alkyl is optionally further
1 3 1 3 1 3 3 6 1 3
substituted by one or more halogen atoms;
m is 1 or 2;
n is 1, 2 or 3;
q is 2 or 3.
In a preferred embodiment of the present invention, a compound represented by formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a
compound represented by formula (II) or its stereoisomer isomers, tautomers or pharmaceutically acceptable salts thereof:
in:
1 2 3 4 1 2 3 4 5 , R 5 ', R 6 ' 7 7 8
e ring, X , X , X , X , R , R , R , R 4 , R ', R , R 6 , R , R ', R , m and n are as defined in formula (I).
A preferred version of the present invention, a compound represented by formula (I) or formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts
, 9 10
thereof, the R3 is selected from hydrogen cyanide radical, C -C alkyl, hydroxymethyl, hydroxyisopropyl, C -C alkoxy, C -C cycloalkyl, -R CO R , the C - C
1 6 1 3 3 6 2 1 6
2 3
alkyl is optionally further substituted by one or more halogen atoms, or R and R form an aryl group together with the two C atoms they are connected to, and the aryl
9 10
group is optionally further substituted by one or more halogen atoms Or C -C alkyl substitution, R is selected from chemical bonds or C -C alkylene, R is
1 6 1 4
selected from hydrogen or C -C alkyl.

1 6
In a preferred embodiment of the present invention, a compound represented by formula (I) or formula (II) or its stereoisomer, tautomer or pharmaceutically acceptable
, 2 3
salt thereof, said R is selected from hydrogen formazan radical, trifluoromethyl, hydroxymethyl, hydroxyisopropyl, -COOH, -COOMe, or R , R together with the two C
atoms they are connected to form a benzene ring.
R ' 5 5' 6 6' 7 7' 4 4' 5 5' 6
salt thereof, said R 4 , 4 ,R ,R ,R ,R ,R ,R are each independently selected from hydrogen, methyl, -CH OH, -CH CH OH, or R and R , R and R ,R
2 2 2
6' 7 7' 4 5 4 6 4 7 4' 5' 4' 4' 7
and R or R and R are linked together to form -(CH ) -, -OCH CH - or -CH OCH -, or R and R , R and R , R and R , R and R ,R and R 6' , R and R
2 2 2 2 2 2
' 5 6 5 7 5' 6' 5' 7' 6 7 6' 7'
, R and R , R and R , R and R ,R and R , R and R or R and R are connected together to form -CH 2 OCH 2 - or -(CH 2 ) 2 -.
from
salt thereof, said R is independently selected hydrogen , halogen, cyano or C -C alkyl; said halogen is preferably fluorine or chlorine, and said C -C alkyl is
1 3 1 3
preferably methyl.
The specific structures of the compounds represented by formula (I) of the present invention include, but are not limited to:
Or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.
The present invention provides a kind of pharmaceutical composition, described pharmaceutical composition contains the compound described in formula (I), formula
(II) or its stereoisomer, tautomer or its pharmaceutically acceptable dosage Salt, and pharmaceutically acceptable carrier, excipient or their combination.
The present invention provides a compound described in formula (I), formula (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its
pharmaceutical composition rearranged during the preparation of transfection Use in kinase inhibitors.
The present invention provides a compound described in formula (I), formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or its
pharmaceutical composition during the preparation of the treatment by transfection Use in medicine for diseases driven by rearrangement genes, wherein said disease is
preferably cancer, wherein said cancer is preferably lung cancer, thyroid cancer, colon cancer, breast cancer or pancreatic cancer.
Detailed Description of the Invention
The definitions of some terms used in the present invention in the specification and claims are as follows:
"Alkyl" when taken as a group or a part of a group means to include straight chain or branched aliphatic hydrocarbon groups. Examples of alkyl groups include, but are not
limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-
methylbutyl, 3-methylbutyl, n-hexyl, 1- Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl base, 1,3-dimethylbutyl, 2-
ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. . Alkyl groups can be substituted or unsubstituted.
"Cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged and spiro carbocyclic rings. Examples of monocyclic cycloalkyl groups include, but are
not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc., preferably cyclopropyl, cyclohexyl Alkenyl.
"Aryl" means a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes aromatic
groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferred aryl groups are C -C aryl groups, more preferred aryl groups are phenyl and naphthyl, most preferably
6 10
phenyl.
"Alkoxy" means an "alkyl-O-" group. C -C alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-
1 6
butoxy, and the like.
"C -C primary alcohol group" means a monohydric primary alcohol group containing 1 to 5 carbon atoms, examples of which include -CH OH, -CH CH OH, -CH
1 5 2 2 2 2
CH CH OH, -CH(CH )CH OH, -(CH ) OH, -CH(CH )CH CH OH, -CH CH(CH )CH OH, -C(CH ) CH OH, -(CH ) OH, -CH CH CH(CH )CH OH、-CH
2 2 3 2 2 4 3 2 2 2 3 2 3 2 2 2 5 2 2 3 2
CH(CH )CH CH OH、-CH(CH )CH CH CH OH、-CH C(CH ) OH、-CH(CH OH)CH (CH ) 、-CH(CH )CH(CH )CH OH。
2 3 2 2 3 2 2 2 2 3 2 2 3 2 3 3 2
"C -C tertiary alcohol group" refers to a monohydric tertiary alcohol group containing 3-7 carbon atoms, examples include -C(CH ) OH, -CH C(CH ) OH, -CH CH
3 7 3 2 2 3 2 2
C(CH ) OH, -CH(CH )C(CH ) OH, -CH CH CH C(CH ) OH, -CH CH(CH )C( CH ) OH, -CH(CH )CH C(CH ) OH、-C(CH3)2C(CH3)2OH、-
2 3 2 3 3 2 2 2 2 3 2 2 3 3 2 3 2 3 2
(CH2)4C(CH3)2OH、-CH2CH2CH(CH3)C(CH3)2OH、-CH2CH(CH3)CH2C(CH3)2OH、-CH(CH3)CH2CH2C(CH3)2OH、-CH(CH3)CH(CH3)C(CH3)2OH、-CH C(CH ) C(CH
2 3 2 3
) OH、-C(CH ) CH C(CH ) OH。
2 3 2 2 3 2
"Hydroxy" means -OH. "Halogen" means fluorine, chlorine, bromine and iodine, preferably chlorine, bromine and fluorine. "Amino" refers to . "Cyano" refers to -CN.
-NH2
"Benzyl" means -CH2 phenyl. "Carboxy" refers to -C(O)OH. "Ester group" refers to -C(O)O(alkyl) or (cycloalkyl), wherein the definitions of alkyl and cycloalkyl are as above.
-
"DMSO" means dimethylsulfoxide. "Boc" means t-butoxycarbonyl. "DIPEA" means: Diisopropylethylamine. "Pd (dba) " refers to: tris(dibenzylideneacetone)dipalladium.
2 3
"t-BuXPhos" refers to: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl. "DMAc" refers to: N,N-dimethylacetamide. "DMF" refers to: N,N-dimethylformamide. "PCy "
3
means: tricyclohexylphosphine. "HATU" refers to: 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate. "PyBOP" refers to: benzotriazol-1-yl-
oxytripyrrolidinylphosphonium hexafluorophosphate. "T3P" refers to: propyl phosphoric anhydride. "Bpin" refers to: boric acid pinacol ester. "NMP" means: N-
methylpyrrolidone.
"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the
corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can
determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be
unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
The definition of stereochemistry and the usage of conventions in the present invention generally refer to the following documents:
SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic
Compounds", John Wiley & Sons, Inc., New York, 1994 . The compounds of the present invention may contain asymmetric or chiral centers and thus exist as different
stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers and mixtures
thereof, such as racemic mixtures, constitute the present invention part. Diastereoisomers can be separated into individual diastereoisomers on the basis of their
physicochemical differences by methods such as chromatography, crystallization, distillation or sublimation. Enantiomers can be separated by converting a chiral
isomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g. a chiral auxiliary such as a chiral alcohol or Mosher's acid
chloride) , the diastereoisomers are separated and the individual diastereomers are converted into the corresponding pure enantiomers. The intermediates and
compounds of the invention may also exist in different tautomeric forms and all such forms are included within the scope of the invention. Many organic compounds
exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S
are used to indicate the absolute configuration of the molecular chiral center. The prefixes d, l or (+), (-) are used to name the symbol of the plane polarized light rotation
of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. The atoms or groups of atoms of
these stereoisomers are connected to each other in the same order, but their three-dimensional structures are different. A particular stereoisomer may be an enantiomer,
and a mixture of isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is known as a racemic mixture or racemate, which can result in
no stereoselectivity or stereospecificity during a chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid
of optical activity.
"Tautomer" or "tautomeric form" means that isomers of structures of different energies can be interconverted through a low energy barrier. For example, proton
tautomers (ie, prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Atomic (valency)
tautomers include interconversions of rearranged bonding electrons. Unless otherwise indicated, the structural formulas described in the present invention include all
isomeric forms (such as enantiomers, diastereomers, and geometric isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of the
double bond, and conformational isomers of (Z), (E). Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures of
enantiomers, diastereomers, or geometric isomers are within the scope of the present invention.
The "base" in the present invention refers to Bronsted base or Lewis base.
"Pharmaceutically acceptable salt" refers to certain salts of the compounds of the present invention that can maintain the original biological activity and are suitable for
medical use. The pharmaceutically acceptable salt of the compound represented by the formula (I) is an amine salt formed with a suitable acid, and the suitable acid
includes an inorganic acid and an organic acid, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid , ethanesulfonic acid, fumaric
acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, nitric acid,
phosphoric acid, succinic acid , sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc.
"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other
chemical components, as well as other components such as physiologically acceptable carriers and excipients. Forming agent. The purpose of the pharmaceutical
composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
The synthetic method of compound of the present invention
In order to accomplish the purpose of the present invention, the present invention can adopt following technical scheme to realize:
Formula (I) compound of the present invention is divided into following three kinds of preparation methods according to the difference of group:
method one:
3 3' 3' 9 10'

When R is R , and R is selected from hydrogen, cyano, C -C alkyl, C -C alkoxy, C -C cycloalkyl, -R CO R , the C -C alkyl group is optionally further
1 6 1 3 3 6 2 1 6
2 3'
substituted by one or more halogen atoms; or R , R together with the two C atoms they are connected to form an aryl group, the aryl The group is optionally further
9 10'
substituted by one or more halogen atoms or a C -C alkyl group; R is selected from a chemical bond or a C -C alkylene group; R is selected from a C -C The
1 6 1 4 1 6
compound of the formula (I) of the alkyl group is the compound of the formula (Ia), which is obtained by reacting the compound of the formula (B) or its salt and the
compound of the formula (A) or its salt under the action of a condensing agent:
The reaction temperature of the above reaction is 0-40°C; the reaction solvent is dichloromethane, acetonitrile or N,N-dimethylformamide, preferably N,N-
dimethylformamide; the condensing agent is HATU, PyBOP or T3P, HATU or PyBOP is preferred; the above reaction is carried out under alkaline conditions, and the base
1 2 3 4 1 2 4 4 5 5 6 6 7 7
used is diisopropylethylamine or triethylamine, preferably diisopropylethylamine; wherein, ring a, ring e, X , X , X , X , R , R , R , R ', R , R ', R , R ', R , R ',
8
R , m and n Definitions are as described in formula (I).
Wherein, the preparation method of the compound shown in formula (A) is as follows:
1
One, when X is N, its reaction steps include:
The compound of formula (1-2) and the compound of formula (1-1) undergo nucleophilic aromatic substitution reaction to obtain the compound of formula (1-3); the
compound of formula (1-4) undergoes nucleophilic aromatic substitution with the compound of formula (1-3) Reaction to obtain the compound of formula (1-5); the
, 2
compound of formula (1-5) removes the tert-butoxycarbonyl group under acidic conditions to obtain the compound of formula (A-1) or its salt; wherein: ring a, R 1 R , R
3' 4 4 5 5 6 6 7 7
, R , R ', R , R ', R , R ', R , R ' and m are as defined in formula (Ia).
When
Its two, when X being CH, its reaction step comprises:
Formula (1-4) compound and formula (2-1) compound generation nucleophilic aromatic substitution reaction obtains formula (2-2) compound; Formula (1-2) compound
and formula (2-2) compound under palladium catalyzed condition Reaction to obtain the compound of formula (2-3); the compound of formula (2-3) removes the tert-
, 2 3' 4 4 5 5 6 6 7 7
butoxycarbonyl group under acidic conditions to obtain the compound of formula (A-2) or its salt; wherein, ring a, R 1 R , R , R , R ', R , R ', R , R ', R , R ' and
m are as defined in formula (Ia).
The preparation method of the compound shown in formula (B) comprises two kinds:
First, when the atom connecting ring e to ring d is N atom:
The compound of formula (3-2) undergoes nucleophilic aromatic substitution reaction with the compound of formula (3-1) to obtain the compound of formula (3-3); the
2 3 4 8
compound of formula (3-3) is hydrolyzed to generate the compound of formula (B-1). Wherein, Hal1 is fluorine, chlorine, bromine or iodine, and ring e, X , X , X , R
and n are as defined in formula (Ia).
Second, when the atom connecting the ring e to the ring d is a C atom:
M is -B(OH) or Bpin,
2
Formula (4-2) compound and formula (4-1) compound generation Suzuki coupling reaction obtains formula (4-3) compound; Formula (4-3) compound hydrolysis
8
generates formula (B-2) compound; Wherein Hal is chlorine , bromine or iodine; and ring e, X , X , X , R and n are as defined in formula (Ia).
2 3 4
Method Two:
3 9
When R is R COOH, the compound of formula (I) is the compound of formula (Ic), which is prepared by reacting the compound of formula (Ib) with alkali (lithium
hydroxide, sodium hydroxide or potassium hydroxide, etc.):
9 10' 1 2 3 4 1 2 4 4′ 5 5′
Among them, R is selected from chemical bonds or C -C alkylene, R is selected from C -C alkyl; and a ring, e ring, X , X , X , X , R , R , R , R ,R ,R
1 4 1 6
6 6 7 7 8
, R , R ′ , R , R ′, R , m and n are as defined in formula (I).
Method three:
3″ 3″
When R is R , and R is a C -C primary alcohol group, the compound of formula (I) is the compound of formula (Id), which is passed through the compound of
1 5
formula (Ib) and reducing agent (NaBH , LiAlH etc.) reaction preparation obtains:
4 4
9 10' 1 2 3 4 1 2 4 4′ 5 5′
1 4 1 6
6 6 7 7 8
Method four:
3"' 3"'
When R is R and R is a C -C tertiary alcohol group, the compound of formula (I) is the compound of formula (Ie), which is obtained by the compound of formula
3 7
(Ib) and methyl iodide Magnesium chloride or methylmagnesium bromide reaction preparation generates:
9 10' 1 2 3 4 1 2 4 4′ 5 5′
1 4 1 6
6 6 7 7 8
Detailed ways
Example
The examples give the preparation of specific compounds represented by formula (I) and relevant structural identification data. It must be noted that the following
examples are used to illustrate the present invention rather than limit the present invention. Compound structures were determined by nuclear magnetic resonance
The 1
(NMR) and mass spectroscopy (MS). H NMR spectrum was determined by a Bruker instrument (400 MHz), and the chemical shift was expressed in ppm, using
Notation in 1
tetramethylsilane internal standard (0.00 ppm). H NMR: s=singlet, d=doublet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If the
coupling constant is provided, its unit is Hz. Mass spectrometry was performed with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model:
Finnigan LCQadvantage MAX).
The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer
chromatography (TLC) is 0.15mm-0.2mm, and the specification used for thin-layer chromatography separation and purification products is 0.4 mm ~ 0.5mm silica gel
preparation plate.
Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.
The known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH &
Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (AccelaChemBio Inc), Darui Chemicals , Bi De Pharmaceutical and other companies.
In the examples, unless otherwise specified, the reactions were carried out under air atmosphere.
The nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a volume of about 1 L.
Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.
Unless otherwise specified in the examples, the reaction temperature is room temperature, and the room temperature ranges from 20°C to 30°C.
The monitoring of the reaction progress in the embodiment adopts thin-layer chromatography (TLC), and the system of the developing agent used has: methylene
chloride and methanol system, n-hexane and ethyl acetate system, and the volume ratio of developing agent is according to the polarity of compound Adjust for gender
differences.
Example 1
The first step: the synthesis of 2-chloro-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine
6-methyl-2,4-dichloropyrimidine (1a) (9.72g, 60mmol), 5-methyl-1H-3-aminopyrazole (1b) (7.0g, 72mmol) and DIPEA (11.6g, 72mmol) was dissolved in 30mL DMSO,
stirred at 60°C for reaction, TLC monitored the reaction until the raw materials disappeared, lowered the temperature to room temperature, added 10mL water to quench
the reaction, added 200mL ethyl acetate, and washed the organic phase three times with water (30mL×3) , washed once with saturated brine, dried over anhydrous
sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a brownish-yellow viscous liquid, which was dissolved in 80 mL of
dichloromethane and left to stand for 3 hours to precipitate a white solid 2-chloro-6-methyl-N -(5-Methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (1c) 9.9 g, yield 74%.
MS m/z(ESI):224.3[M+1]
The second step: Synthesis of tert-butyl 4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperazine-1-carboxylate
2-Chloro-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (1c) (892mg, 4mmol), 1-tert-butoxycarbonylpiperazine ( 1d) (1.49g, 8mmol) and K CO (1.66g,
2 3
12mmol) were dissolved in 25mL DMF, reacted at 140°C for 6 hours, the reaction solution was cooled to room temperature, 10mL water was added to quench the
reaction, and 150mL acetic acid was added Ethyl ester, the organic phase was washed three times with water (15mL×3), washed once with saturated brine, dried over
anhydrous sodium sulfate, filtered, and after removing the solvent under reduced pressure, silica gel column chromatography (eluent and volume ratio: dichloromethane :
Methanol=20:1), to get 4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperazine-1-carboxylic acid tertiary Butyl ester (1e) 1.01 g, yield 67%.
MS m/z(ESI):374.2[M+1]
The third step: the synthesis of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(1-piperazinyl)pyrimidin-4-amine hydrochloride
4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1e) (1.24g ,3.3mmol) in 25mL of 1,4-dioxane, add dropwise
25mL of HCl/1,4-dioxane solution with a concentration of 2.6mol/L, react at 50°C for 4h, and filter after the reaction , the filtrate was washed with ethyl acetate and ether
respectively, and dried in vacuo to give a light yellow solid 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(1-piperazinyl ) pyrimidin-4-amine hydrochloride (1f) 1.1 g, yield>99%.
MS m/z(ESI):274.2[M+1]
The fourth step: the synthesis of methyl 6-(4-fluoro-1H-pyrazol-1-yl)nicotinate
Dissolve 6-fluoronicotinic acid methyl ester (1g) (3.10g, 20mmol), 4-fluoropyrazole (1h) (2.07g, 24mmol) and K CO (6.91g, 50mmol) in 25mL DMF, in React at 100°C
2 3
for 6 hours, cool the reaction solution to room temperature, add 10 mL of water to quench the reaction, add 150 mL of ethyl acetate, wash the organic phase three times
with water (15 mL×3), wash with saturated saline once, dry over anhydrous sodium sulfate, and filter , after removing the solvent under reduced pressure, silica gel
column chromatography (eluent and volume ratio: dichloromethane: methanol = 20:1) to obtain 6-(4-fluoro-1H-pyrazol-1-yl) smoke Acid methyl ester (1i) 3.6g, yield 82%.
MS m/z(ESI):222.1[M+1]
The fifth step: the synthesis of 6-(4-fluoro-1H-pyrazol-1-yl)nicotinic acid
Dissolve methyl 6-(4-fluoro-1H-pyrazol-1-yl)nicotinate (1i) (3.6 g, 16.2 mmol) and lithium hydroxide monohydrate (1.36 g, 32.4 mmol) in 40 mL of methanol and 20 mL In
the mixed solvent prepared by distilled water, react at 50°C for 2 hours, monitor the reaction by TLC until the raw materials disappear, cool the reaction solution to room
temperature, remove the solvent under reduced pressure, add 100mL distilled water, add 1mol/L dilute hydrochloric acid to adjust the pH value to 2 -5, stirred for 1 hour,
filtered, and dried the filter cake at 50°C to obtain 3.1 g of 6-(4-fluoro-1H-pyrazol-1-yl)nicotinic acid (1j), with a yield of 92%.
MS m/z(ESI):208.1[M+1]
The sixth step: (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)(4-(4-methyl-6-((5-methyl-1H-pyrazole- Synthesis of 3-yl)amino)pyrimidin-2-yl)piperazin-1-yl)methanone
Dissolve 6-(4-fluoro-1H-pyrazol-1-yl)nicotinic acid (1j) (83mg, 0.4mmol) and HATU (228mg, 0.6mmol) in 4mL DMF, cool to 0°C, add DIPEA ( 163mg, 1.6mmol), after
stirring for 2 minutes, add 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(1-piperazinyl)pyrimidine-4-amine salt Salt (1f) (140mg, 0.45mmol), kept at 0°C for 30 minutes, added
10mL of water to quench the reaction, added 100mL of ethyl acetate, washed three times with water (15mL×3), washed once with saturated saline, dried over anhydrous
sodium sulfate , filtered, and after removing the solvent under reduced pressure, silica gel column chromatography (eluent and volume ratio: dichloromethane:
methanol=30:1), the crude product was further separated by silica gel preparation plate (developing agent and volume ratio: Dichloromethane:methanol=10:1), (6-(4-
fluoro-1H-pyrazol-1-yl)pyridin-3-yl)(4-(4-methyl-6-((5- Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperazin-1-yl)methanone 80 mg, yield 43%.
1H NMR(400MHz,DMSO-d
6)δ11.81(s,1H),9.28(s,1H),8.76(d,J＝4.5Hz,1H),8.57(s,1H),8.09(d,J＝8.2Hz,1H),7.99(t,J＝7.2Hz,2H),6.24(s,1H),6.11(s,1H),3.81-3.73(m,6H),3.51-
3.46(m,2H),2.18(s,3H),2.13(s,3H)ppm.
MS m/z(ESI):463.2[M+1].
With reference to Example 1, the following compounds can be prepared:
Compound (I-2):
6)δ11.80(s,1H),9.26(s,1H),8.74(d,J＝4.6Hz,1H),8.55(s,1H),8.07(d,J＝8.5Hz,1H),7.99-7.97(m,2H),6.22(s,1H),6.11(s,1H),4.52-4.49(s,2H),3.17-
2.94(s,3H),2.18(s,3H),2.12(s,3H),1.19(d,J＝6.8Hz,3H)ppm.
MS m/z(ESI):477.2[M+1].
Compound (I-3):
6)δ11.84(s,1H),9.29(s,1H),8.75(d,J＝4.5Hz,1H),8.57(s,1H),8.09(d,J＝8.5Hz,1H),8.02-7.93(m,2H),6.21(s,1H),6.14(s,1H),5.01-4.21(m,4H),3.65-
3.35(m,3H),3.14-2.84(m,3H),2.18(s,3H),2.12(s,3H)ppm.MS m/z(ESI):493.2[M+1].
Compound (I-4):
6)δ11.81(s,1H),9.27(s,1H),8.76(d,J＝4.4Hz,1H),8.64(s,1H),8.17(d,J＝8.5Hz,1H),8.02-7.98(m,2H),6.23(s,1H),6.12(s,1H),4.81-4.79(m,1H),4.50-
4.37(m,2H),4.21-4.18(m,1H),3.13-3.09(m,2H),2.19(s,3H),2.12(s,3H),1.95-1.83(m,2H),1.71-1.61(m,2H)ppm.
MS m/z(ESI):489.2[M+1].
Compound (I-5):
6)δ12.12(s,1H),10.03(s,1H),8.77(d,J＝4.5Hz,1H),8.66(s,1H),8.38(d,J＝8.2Hz,1H),8.23-8.07(m,1H),8.06-7.90(m,2H),7.56(t,J＝7.7Hz,1H),7.33(d,J
＝8.4Hz,1H),7.11(t,J＝7.6Hz,1H),6.44(s,1H),4.84(s,1H),4.74-4.38(m,2H),4.24(s,1H),3.23-3.20(m,2H),2.26(s,3H),1.91(s,2H),1.71-1.68(m,2H)ppm.
MS m/z(ESI):525.2[M+1].
Compound (I-6):
6)δ11.85(s,1H),9.26-9.22(m,2H),8.88(s,1H),8.82(d,J＝4.5Hz,1H),8.13(d,J＝4.0Hz,1H),6.23(s,1H),6.12(s,1H),4.86-4.85(m,1H),4.81-
4.65(m,1H),4.52-4.50(m,1H),4.42-4.39(m,1H),3.17-3.08(m,2H),2.20(s,3H),2.12(s,3H),1.91(d,J＝11.7Hz,2H),1.70(d,J＝8.2Hz,2H)ppm.
MS m/z(ESI):490.2[M+1].
Compound (I-7):
6)δ9.22(s,1H),8.77(d,J＝4.5Hz,1H),8.62(s,1H),8.14(s,2H),8.01(t,J＝7.0Hz,2H),6.15(brs,2H),5.09-4.41(m,3H),4.20-3.63(m,5H),3.25-
3.17(m,2H),2.18(s,3H),2.12(s,3H)ppm.
MS m/z(ESI):505.5[M+1]
Compound (I-8):
6)δ11.83(s,1H),9.25(s,1H),8.86(s,1H),8.65(s,1H),8.19(d,J＝8.7Hz,1H),8.03(s,1H),8.01-7.94(m,1H),6.23(s,1H),6.12(s,1H),4.86-4.75(m,1H),4.52-
4.35(m,2H),4.23-4.17(m,1H),3.14-3.06(m,2H),2.19(s,3H),2.12(s,3H),1.96-1.83(m,2H),1.75-1.62(m,2H)ppm.
MS m/z(ESI):505.2[M+1].
Compound (I-9):
1H NMR(400MHz,DMSO-
d6)δ11.84(s,1H),9.48(s,1H),9.28(s,1H),8.71(s,1H),8.48(s,1H),8.24(s,1H),8.06(s,1H),6.23(s,1H),6.11(s,1H),4.81(s,1H),4.49(s,1H),4.38(s,1H),4.19(s,1H),3.33(s,2H),2.19(s,3H),
2.11(s,3H),1.90(s,2H),1.66(s,2H)ppm.
MS m/z(ESI):496.2[M+1].
Compound (I-10):
6)δ11.82(s,1H),9.27(s,1H),8.30(d,J＝2.5Hz,1H),7.67(dd,J＝8.7,2.3Hz,1H),6.43(d,J＝8.7Hz,1H),6.21(s,1H),6.13(s,1H),4.43-4.8(m,3H),3.65-
3.20(m,5H),3.07(d,J＝12.6Hz,2H),2.20(s,3H),2.11(s,3H),1.89-1.40(m,6H),1.06(s,3H),0.83(s,3H)ppm.
MS m/z(ESI):514.3[M+1]
Compound (I-11):
6)δ12.00(s,1H),9.90(s,1H),8.76(d,J＝4.4Hz,1H),8.65(d,J＝2.0Hz,1H),8.18(dd,J＝8.5,2.2Hz,1H),8.09-
7.89(m,2H),6.80(s,1H),6.29(s,1H),4.83(s,1H),4.49-4.35(m,2H),4.24(s,1H),3.81(s,3H),3.22-3.15(m,2H),2.21(s,3H),1.91(s,2H),1.83-1.61(m,2H)ppm.
MS m/z(ESI):533.2[M+1]
Compound (I-12):
MS m/z(ESI):489.2[M+1]
Example 2
The first step: 3-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-3,8-diazabicyclo[3.2. 1] Synthesis of tert-butyl octane-8-carboxylate
2-Chloro-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (1c) (2.01g, 9mmol), 3,8-diazabicyclo [3.2.1] Octane-8-carboxylic acid tert-butyl ester (2a) (3.82g,
18mmol) and K CO (3.73g, 27mmol) were dissolved in 25mL DMAc, reacted at 140°C, TLC monitored the reaction At the end, the reaction solution was cooled to room
2 3
temperature, 5 mL of water was added to quench the reaction, 150 mL of ethyl acetate was added, the organic phase was washed three times with water (15 mL×3),
washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure , separated by silica gel column
chromatography (eluent and volume ratio: dichloromethane:methanol=20:1), to obtain 3-(4-methyl-6-((5-methyl-1H-pyrazole-3 -yl)amino)pyrimidin-2-yl)-3,8-
diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2b) 2.81g, yield 77%.
MS m/z(ESI):400.5[M+1]
The second step: 2-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl) Synthesis of pyrimidin-4-amine hydrochloride
3-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane Alkane-8-carboxylic acid tert-butyl ester (2b) (2.6g, 6.5mmol) was dissolved
in 40mL 1,4-dioxane, and 40mL of HCl/1,4-dioxane with a concentration of 2.6mol/L was added dropwise ring solution, reacted at 50°C for 4h, filtered, washed the filter
cake with ethyl acetate and diethyl ether, and dried in vacuum to obtain 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6- Methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine
hydrochloride (2c) 2.2g, yield >99%.
MS m/z(ESI):300.3[M+1]
The third step: the synthesis of methyl 6-(4-fluoro-1H-pyrazol-1-yl)pyridazine-3-carboxylate
Dissolve 4-fluoro-1H-pyrazole (1h) (2.4g, 27.8mmol) in 40mL DMF, cool to 0°C, slowly add sodium hydride (1.4g, 34.8mmol), react at 0°C for 30min, add 6-Chloro-
pyridazine-3-methyl carboxylate (2d) (4.0g, 23.2mmol), TLC monitors the reaction until the raw material disappears, adds 10mL of ice water to quench the reaction, adds
200mL of ethyl acetate, and washes the organic phase three times with water ( 30mL×3), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered,
and the solvent was removed under reduced pressure, separated by silica gel column chromatography (eluent and volume ratio: dichloromethane:methanol=20:1), to
obtain 4.53 g of methyl 6-(4-fluoro-1H-pyrazol-1-yl)pyridazine-3-carboxylate (2f), yield 88%.
MS m/z(ESI):223.2[M+1]
Step 4: Synthesis of 6-(4-fluoro-1H-pyrazol-1-yl)pyridazine-3-carboxylic acid
Methyl 6-(4-fluoro-1H-pyrazol-1-yl)pyridazine-3-carboxylate (2f) (4.53g, 20.4mmol), lithium hydroxide monohydrate (1.71g, 40.8mmol) and distilled water Dissolve 20mL in
50mL methanol, react at 40°C for 2 hours, monitor the reaction by TLC until the raw materials disappear, cool the reaction liquid to room temperature, remove methanol
under reduced pressure, add 100mL distilled water, add 1mol/L dilute hydrochloric acid to adjust the pH value to 2- 5. Stir for 1 hour, filter, and dry the filter cake at 50°C to
obtain 3.81 g of 6-(4-fluoro-1H-pyrazol-1-yl)pyridazine-3-carboxylic acid (2 g), with a yield of 90%.
MS m/z(ESI):209.1[M+1]
The fifth step: (6-(4-fluoro-1H-pyrazol-1-yl)pyridazin-3-yl)(3-(4-methyl-6-((5-methyl-1H-pyrazole Synthesis of -3-yl)amino)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-

yl)methanone
2-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4 -amine hydrochloride (2c) (700mg, 2.1mmol), 6-(4-fluoro-1H-pyrazol-1-

yl)pyridazine-3-carboxylic acid (2g) (390mg, 1.9mmol) and PyBOP (1.63 g, 3.1mmol) was dissolved in 20mL DMF, cooled to 0°C, added DIPEA (810mg, 6.3mmol), kept at
0°C for 30 minutes, added 10mL water to quench the reaction, added 150mL ethyl acetate, washed three times with water (20mL× 3), washed once with saturated brine,
dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure, then separated by silica gel column chromatography (eluent and
volume ratio: dichloromethane:methanol=20:1), and the crude product was further obtained. Separation by silica gel preparation plate (developing solvent and volume
ratio: dichloromethane:methanol=10:1) to obtain (6-(4-fluoro-1H-pyrazol-1-yl)pyridazin-3-yl)( 3-(4-Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-3,8-
diazabicyclo[3.2.1]octane -8-yl)methanone (I-13) 400 mg, yield 43%.
6)δ11.85(s,1H),9.27(s,1H),9.08(d,J＝4.4Hz,1H),8.34(d,J＝9.1Hz,1H),8.21(d,J＝9.2Hz,1H),8.15(d,J＝4.0Hz,1H),6.19(s,1H),6.14(s,1H),4.89(d,J＝
5.6Hz,1H),4.74(d,J＝5.4Hz,1H),4.55(d,J＝12.8Hz,1H),4.43(d,J＝12.6Hz,1H),3.20(d,J＝12.7Hz,1H),3.12(d,J＝12.6Hz,1H),2.20(s,3H),2.12(s,3H),1.92(d,J＝
9.3Hz,2H),1.71(d,J＝9.0Hz,2H)ppm.
MS m/z(ESI):490.2[M+1].
Compound (I-14):
6)δ11.89(s,1H),9.42(s,1H),9.09(d,J＝4.5Hz,1H),8.35(d,J＝9.1Hz,1H),8.22(d,J＝9.2Hz,1H),8.15(d,J＝4.1Hz,1H),7.89(d,J＝
5.7Hz,1H),6.33(s,1H),6.16(s,1H),4.95-4.84(m,1H),4.84-4.69(m,1H),4.54(d,J＝12.7Hz,1H),4.43(d,J＝12.5Hz,1H),3.21(d,J＝12.5Hz,1H),3.17-3.08(m,1H),2.21(s,3H),1.93(d,J
＝9.1Hz,2H),1.71(d,J＝8.5Hz,2H)ppm.
MS m/z(ESI):476.3
Compound (I-15):
6)δ11.86(s,1H),9.30(s,1H),9.05(d,J＝4.4Hz,1H),8.34(d,J＝9.1Hz,1H),8.14(d,J＝3.9Hz,1H),8.12(d,J＝
9.2Hz,1H),6.24(s,1H),6.12(s,1H),3.86(s,2H),3.78(s,2H),3.75(s,2H),3.59(s,2H),2.18(s,3H),2.13(s,3H)ppm.
MS m/z(ESI):464.2[M+1].
Compound (I-16):
6)δ12.06(s,1H),10.10(s,1H),9.08(d,J＝4.4Hz,1H),8.35(d,J＝9.1Hz,1H),8.22(d,J＝9.2Hz,1H),8.15(d,J＝4.0Hz,1H),6.59-
6.26(brs,2H),4.93(s,1H),4.79(s,1H),4.63-4.27(m,2H),3.26-3.14(m,2H),2.23(s,3H),2.07-1.81(m,2H),1.71(d,J＝8.7Hz,2H)ppm.
MS m/z(ESI):544.2[M+1].
Compound (I-17):
6)δ11.86(s,1H),9.30(s,1H),9.18(s,1H),8.34(d,J＝9.1Hz,1H),8.23(d,J＝9.1Hz,1H),8.16(s,1H),6.20(s,1H),6.14(s,1H),4.89(s,1H),4.74(s,1H),4.55(d,J
＝11.7Hz,1H),4.43(d,J＝12.2Hz,1H),3.28-3.08(m,2H),2.20(s,3H),2.13(s,3H),1.93(d,J＝8.8Hz,2H),1.74-1.72(m,2H)ppm.
MS m/z(ESI):506.2[M+1].
Compound (I-18):
6)δ11.82(s,1H),9.22(s,1H),9.07(d,J＝4.4Hz,1H),8.36(d,J＝9.2Hz,1H),8.19(d,J＝9.0Hz,1H),8.15(d,J＝4.0Hz,1H),6.16(brs,2H),4.94(s,1H),4.75(d,J
＝13.4Hz,1H),4.66(s,1H),4.25(s,1H),4.00(d,J＝11.6Hz,1H),3.92-3.69(m,3H),3.17(d,J＝5.1Hz,1H),2.19(s,3H),2.12(s,3H)ppm.
MS m/z(ESI):506.2[M+1].
Example 3
2-(8-(6-(4-fluoro-1H-pyrazol-1-yl)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-( Synthesis of (5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxylic acid
2-(8-(6-(4-fluoro-1H-pyrazol-1-yl)nicotinoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- ((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxylic acid methyl ester (I-11) (80mg,

0.15mmol) and lithium hydroxide monohydrate (42mg, 1mmol) were dissolved in 2.5 In mL methanol/water (V:V=5:1) mixed solvent, react overnight at room temperature,
remove methanol under reduced pressure, add 10 mL of water to dilute, adjust pH value to 2-3 with 1mol/L dilute hydrochloric acid, add ethyl acetate Extracted three
times (20mL×3), combined the organic phases, washed once with saturated brine, dried, filtered, and separated by silica gel column chromatography (eluent and volume
ratio: dichloromethane:methanol=10:1) to obtain 2-( 8-(6-(4-fluoro-1H-pyrazol-1-yl)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-((5- Methyl-1H-pyrazol-3-
yl)amino)pyrimidine-4-carboxylic acid (I-19) 55 mg, yield 71%.
6)δ12.12(s,1H),10.02-9.62(m,1H),8.77(d,J＝4.5Hz,1H),8.65(s,1H),8.18(d,J＝8.6Hz,1H),8.00(t,J＝7.7Hz,2H),6.85(s,1H),6.23(s,1H),4.92-
4.03(m,4H),3.48-3.00(m,2H),2.21(s,3H),1.91(s,2H),1.68-1.65(m,2H)ppm.
MS m/z(ESI):519.2[M+1].
实施例4
(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)(3-(4-(羟甲基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮的合成
将2-(8-(6-(4-氟-1H-吡唑-1-基)烟酰基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-甲酸甲酯(I-11)(53mg,0.1mmol)溶于1.5mL四氢呋喃中，冷却至
0℃，加入LiAlH4(11mg,0.3mmol)，缓慢恢复至室温反应，TLC监测反应至原料消失，加入少量十水合硫酸钠淬灭，过滤，乙酸乙酯洗涤滤液，收集有机相，减压除去溶
剂，加入30mL乙酸乙酯，水洗三次(5mL×3)，饱和食盐水洗一次，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析分离(洗脱剂及体积比为：二氯甲烷：甲醇＝20:1)得(6-(4-
氟-1H-吡唑-1-基)吡啶-3-基)(3-(4-(羟甲基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮(I-20)10mg,产率20％。
6)δ11.85(s,1H),9.38(s,1H),8.76(d,J＝4.4Hz,1H),8.64(d,J＝2.2Hz,1H),8.17(dd,J＝8.4,2.2Hz,1H),8.07-7.90(m,2H),6.49(s,1H),6.15(s,1H),5.21(t,J＝
5.9Hz,1H),4.79(s,1H),4.54-4.29(m,2H),4.21(d,J＝6.0Hz,3H),3.11(d,J＝12.8Hz,2H),2.19(s,3H),1.89(s,2H),1.65(s,2H)ppm.
MS m/z(ESI):505.2[M+1]
Example 5
(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)(3-(4-(2-hydroxypropyl-2-yl)-6-((5-methyl- Synthesis of 1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-

yl)methanone
2-(8-(6-(4-fluoro-1H-pyrazol-1-yl)nicotinoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- ((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxylic acid methyl ester (I-11) (265mg,

0.5mmol), dissolved in 5mL THF, cooled to 0°C in a nitrogen atmosphere , slowly add 3mol/L methylmagnesium iodide ether solution dropwise, the dropwise addition is
completed, return to room temperature reaction, TLC monitoring until the end of the reaction, add saturated ammonium chloride aqueous solution to quench the reaction,
add 100mL ethyl acetate, wash three times with water (20mL ×3), washed once with saturated brine, dried, filtered, and separated by silica gel column chromatography
(eluent and volume ratio: dichloromethane:methanol=30:1) to obtain (6-(4-fluoro-1H-pyrazole -1-yl)pyridin-3-yl)(3-(4-(2-hydroxypropyl-2-yl)-6-((5-methyl-1H-pyrazol-3-
yl)amino)pyrimidine -2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (I-21) 56 mg, yield 22%.
6)δ11.84(s,1H),9.34(s,1H),8.76(d,J＝4.5Hz,1H),8.65(s,1H),8.18(d,J＝8.7Hz,1H),8.02(d,J＝4.2Hz,1H),7.99(d,J＝
8.7Hz,1H),6.59(s,1H),6.15(s,1H),4.95(s,1H),4.52-4.17(m,4H),3.14-3.09(m,2H),2.20(s,3H),1.91(s,2H),1.67(s,2H),1.32(s,6H)ppm.
MS m/z(ESI):533.3[M+1]
Example 6
The first step: the synthesis of methyl 6-(1-methyl-1H-pyrazol-4-yl)pyridazine-3-carboxylate
6-Chloro-pyridazine-3-carboxylic acid methyl ester (2d) (1.73g, 10mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid pinacol ester (7a) (4.16g, 20mmol), Pd (dba) (410mg,
2 3
0.5mmol), PCy (280mg, 1mmol) and potassium phosphate (6.4g, 30mmol) were dissolved in 35mL dioxane/water (V:V=6:1) In a mixed solvent, react at 100° C.
3
overnight in a nitrogen atmosphere. After the reaction, the temperature of the reaction solution was lowered to room temperature, filtered with diatomaceous earth,
washed with ethyl acetate, the organic solvent was removed under reduced pressure, 300 mL of ethyl acetate was added, washed three times with water (40 mL×3),
washed once with saturated brine, dried, and Column chromatography separation (eluent and volume ratio: dichloromethane:methanol=30:1) gave 6-(1-methyl-1H-
pyrazol-4-yl)pyridazine-3-carboxylic acid methyl ester ( 7b) 1.4 g, 65% yield.
MS m/z(ESI):219.1[M+1]
The second step: the synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyridazine-3-carboxylic acid
Dissolve methyl 6-(1-methyl-1H-pyrazol-4-yl)pyridazine-3-carboxylate (7b) (1.4 g, 7 mmol) and lithium hydroxide monohydrate (580 mg, 14 mmol) in 50 mL of methanol
/water (V:V=2:1) mixed solvent, react at 50°C, monitor by LC-MS until the end of the reaction, remove methanol under reduced pressure, add 10mL of water, adjust the pH
value to 2- 3. The solid was precipitated, filtered and dried to obtain 580 mg of 6-(1-methyl-1H-pyrazol-4-yl)pyridazine-3-carboxylic acid (7c), with a yield of 20%.
MS m/z(ESI):205.2[M+1]
The third step: (6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)(3-(4-methyl-6-((5-methyl-1H-pyridine Synthesis of oxazol-3-yl)amino)pyrimidin-2-yl)-3,8-

diazabicyclo[3.2.1]octane-8-yl)methanone
2-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4 -amine hydrochloride (2c) (201mg, 0.6mmol), 6-(1-methyl-1H-pyrazol-4-

yl)pyridazine-3-carboxylic acid (7c) (123mg, 0.6mmol) and PyBOP ( 468mg, 0.9mmol) was dissolved in 6mL DMF, cooled to 0°C, added DIPEA (310mg, 2.4mmol), kept at
0°C for 30 minutes, added 5mL water to quench the reaction, added 100mL ethyl acetate, washed three times with water (15mL× 3), washed once with saturated brine,
dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure, then separated by silica gel column chromatography (eluent and
volume ratio: dichloromethane:methanol=20:1), and the crude product was further obtained. Separation by preparative plates (developing solvent and volume ratio:
dichloromethane:methanol=10:1) to give (6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)( 3-(4-Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-3,8-
diazabicyclo[3.2.1]octane -8-yl)methanone (I-22) 62 mg, yield 22%.
6)δ11.86(s,1H),9.29(s,1H),8.56(s,1H),8.22(s,1H),8.10(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,1H),6.22(s,1H),6.16(s,1H),4.88(d,J＝
5.8Hz,1H),4.79(s,1H),4.54(d,J＝12.7Hz,1H),4.44(d,J＝12.6Hz,1H),3.94(s,3H),3.19(d,J＝12.7Hz,1H),3.11(d,J＝12.8Hz,1H),2.20(s,3H),2.12(s,3H),1.92(d,J＝
8.4Hz,2H),1.71(d,J＝8.2Hz,2H)ppm.
MS m/z(ESI):486.3[M+1].
Compound (I-23):
6)δ13.16(s,1H),11.84(s,1H),9.27(s,1H),8.67(s,1H),8.42(s,1H),8.13(s,1H),7.92(d,J＝8.2Hz,1H),7.78(d,J＝8.2Hz,1H),6.22(s,1H),6.13(s,1H),5.08-
4.13(m,4H),3.10(d,J＝12.8Hz,2H),2.19(s,3H),2.12(s,3H),1.88(s,2H),1.65(d,J＝9.7Hz,2H)ppm.
MS m/z(ESI):471.2[M+1].
Compound (I-24):
6)δ11.84(s,1H),9.28(s,1H),8.67(s,1H),8.37(s,1H),8.07(s,1H),7.92(dd,J＝8.1,2.2Hz,1H),7.73(d,J＝8.1Hz,1H),6.21(s,1H),6.13(s,1H),4.78(s,1H),4.55-
4.32(m,2H),4.21(s,1H),3.90(s,3H),3.10(d,J＝12.7Hz,2H),2.19(s,3H),2.12(s,3H),1.88(s,2H),1.65(d,J＝9.8Hz,2H)ppm.
MS m/z(ESI):485.3[M+1].
Compound (I-25):
6)δ11.84(s,1H),9.27(s,1H),8.82(s,1H),8.21(dd,J＝8.5,5.5Hz,2H),8.06(t,J＝6.5Hz,2H),7.35(t,J＝8.7Hz,2H),6.22(s,1H),6.13(s,1H),4.86-
4.75(m,1H),4.55-4.35(m,2H),4.24-4.16(m,1H),3.13-3.10(m,2H),2.19(s,3H),2.12(s,3H),1.93-1.86(m,2H),1.67-1.65(m,2H)ppm.
MS m/z(ESI):499.2[M+1].
Compound (I-26):
6)δ11.86(s,1H),9.29(s,1H),8.41(d,J＝8.9Hz,1H),8.31(d,J＝8.6Hz,2H),8.09(d,J＝8.8Hz,1H),7.43(t,J＝8.7Hz,2H),6.23(s,1H),6.15(s,1H),4.93-
4.87(m,1H),4.74(s,1H),4.56(d,J＝12.7Hz,1H),4.45(d,J＝12.6Hz,1H),3.15-3.12(m,2H),2.20(s,3H),2.12(s,3H),1.94(d,J＝10.9Hz,2H),1.72(d,J＝8.7Hz,2H)ppm.
MS m/z(ESI):500.2[M+1].
Compound (I-27):
6)δ9.46-9.10(m,1H),8.41(d,J＝8.7Hz,1H),8.30(dd,J＝8.4,5.5Hz,2H),8.15(s,1H),8.00(d,J＝8.7Hz,1H),7.44(t,J＝
8.6Hz,2H),6.23(s,1H),6.12(s,1H),3.92-3.84(m,2H),3.84-3.67(m,4H),3.59-3.57(m,2H),2.18(s,3H),2.13(s,3H)ppm.
MS m/z(ESI):474.2[M+1].
Compound (I-28):
6)δ11.85(s,1H),9.30(s,1H),8.89(s,1H),8.74(s,2H),8.23(d,J＝8.1Hz,1H),8.13(d,J＝11.7Hz,3H),6.21(s,1H),6.13(s,1H),4.82(s,1H),4.44(d,J＝
44.1Hz,2H),4.18-4.11(m,1H),3.20-3.03(m,2H),2.19(s,3H),2.12(s,3H),1.91(s,2H),1.66(s,2H)ppm.
MS m/z(ESI):482.2[M+1].
Compound (I-29):
6)δ11.84(s,1H),9.28(s,1H),8.95(s,1H),8.61(d,J＝4.6Hz,1H),8.14(d,J＝8.0Hz,1H),7.84(d,J＝7.8Hz,2H),7.67(d,J＝7.8Hz,2H),7.52(dd,J＝
7.9,4.8Hz,1H),6.23(s,1H),6.13(s,1H),4.80(s,1H),4.47(s,1H),4.38(s,1H),4.18(s,1H),3.12-3.08(m,2H),2.19(s,3H),2.12(s,3H),1.87(s,2H),1.66(s,2H)ppm.
MS m/z(ESI):481.3[M+1].
Example 7
The first step: Synthesis of methyl 3-(6-bromo-4-methylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
2-fluoro-4-methyl-6-bromo-pyridine (8a) (1.9g, 10mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2a) (2.54g, 12mmol), K CO (4.14g, 30mmol) were
2 3
dissolved in 25mL DMF, stirred at 110°C for reaction, TLC monitored the reaction until the raw materials disappeared, returned to room temperature, added 10mL water to
quench the reaction, added 150mL Ethyl acetate, the organic phase was washed three times with water (25mL×3), washed once with saturated brine, dried over
anhydrous sodium sulfate, filtered, and after removing the solvent under reduced pressure, the product was separated by silica gel column chromatography (developing
agent and volume ratio: petroleum ether : ethyl acetate=7:1), vacuum drying to get 3-(6-bromo-4-methylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid Methyl
ester (8b) 820mg, yield 22%.
MS m/z(ESI):382.1[M+1]
The second step: 3-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)-3,8-diazabicyclo[3.2. 1] Synthesis of octane-8-methyl carboxylate
Under nitrogen atmosphere, methyl 3-(6-bromo-4-methylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8b) (754mg , 1.97mmol), 5-methyl-1H-3-aminopyrazole

(1b) (380mg, 3.94mmol), Pd (dba) (357mg, 0.39mmol), t-BuXphos (336mg, 0.79mmol) and Potassium acetate (579mg, 5.91mmol) was dissolved in 17mL of DMAc,
2 3
and the reaction was stirred at 140°C. After the reaction was monitored by TLC, the reaction solution was returned to room temperature, 100mL of ethyl acetate was
added, and the organic phase was washed three times with water (20mL×3). Wash once with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and
separate the product by silica gel column chromatography (eluent and ratio: petroleum ether: ethyl acetate = 1:1) to obtain 3-(4-methyl-6 -((5-Methyl-1H-pyrazol-3-
yl)amino)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid methyl ester (8c) 520 mg, 61% yield.
MS m/z(ESI):399.3[M+1]
The third step: 6-(3,8-diazabicyclo[3.2.1]octane-3-yl)-4-methyl-N-(5-methyl-1H-pyrazol-3-yl) Synthesis of Pyridin-2-amine Hydrochloride
3-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane Methyl alkane-8-carboxylate (8c) (520 mg, 1.3 mmol) was dissolved in 8 mL of
1,4-dioxane, and 10 mL of 1,4-dioxane solution with a concentration of 2.6 mol/L hydrogen chloride was added dropwise, React at 50°C, monitor the reaction with LC-MS
until the raw materials disappear, return to room temperature, remove the solvent under reduced pressure, add 20 mL of ethyl acetate, stir for 10 minutes, filter, wash the
filter cake with ethyl acetate and ether, and dry in vacuo to obtain 6-(3,8-diazabicyclo[3.2.1]octane-3-yl)-4-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyridine-2- Amine
hydrochloride (8d) 324mg, yield 74%.
MS m/z(ESI):299.2[M+1]
The fourth step: 6-(4-fluoro-1H-pyrazol-1-yl)pyridazin-3-yl)(8-(4-methyl-6-((5-methyl-1H-pyrazole- Synthesis of 3-yl)amino)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-

yl)methanone
6-(3,8-diazabicyclo[3.2.1]octane-3-yl)-4-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyridine-2 -Amine hydrochloride (8d) (184mg, 0.55mmol), 6-(4-fluoro-1H-pyrazol-1-
yl)pyridazine-3-carboxylic acid (2g) (104mg, 0.5mmol) and PyBOP (289mg , 0.75mmol) was dissolved in 5mL DMF, the reaction solution was cooled to 0°C, DIPEA
(204mg, 2mmol) was added, kept at 0°C for 20 minutes, the reaction was quenched by adding 3mL water, 50mL ethyl acetate was added, and the organic phase was
separated Washed three times with water (10mL×3), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by
silica gel column chromatography (eluent and ratio: dichloromethane:methanol=15:1) to obtain (6-( 4-fluoro-1H-pyrazol-1-yl)pyridazin-3-yl)(8-(4-methyl-6-((5-methyl-1H-
pyrazol-3-yl)amino)pyridine -2-yl)-3,8-diazabicyclo[3.2.1]octane-3-yl)methanone (I-30) 63 mg, yield 26%.
1H NMR(400MHz,DMSO)δ9.07(d,J＝4.2Hz,1H),8.61(s,1H),8.34(d,J＝9.1Hz,1H),8.21(d,J＝9.1Hz,1H),8.15(d,J＝
3.4Hz,2H),6.34(s,1H),5.99(s,1H),5.90(s,1H),4.91(s,1H),4.78(s,1H),4.11(d,J＝12.1Hz,1H),3.98(d,J＝11.4Hz,1H),3.16(d,J＝8.3Hz,1H),3.04(d,J＝
11.7Hz,1H),2.18(s,3H),2.12(s,3H),1.95(d,J＝8.9Hz,2H),1.80(d,J＝8.4Hz,2H)ppm.
MS m/z(ESI):489.3[M+1]
biological evaluation
Test example 1, the assay of compound of the present invention to RET kinase activity
This method uses Cisbio's
KinEASE-TK Tyrosine Kinase Kit (Catalog No. 62TK0PEB), by measuring the degree of phosphorylation of biotinylated polypeptide substrates, is determined by time-
resolved-fluorescence resonance energy transfer (TR-FRET). Human RET protein (RET kinase) was purchased from Carna bioscience (Japan, Cat. No. 08-159-5 μg).
The experimental steps are as follows:
(1) The compound to be tested (the compound of the present invention and compound 164 in WO2018017983A1 as a control) was dissolved in 100% DMSO to make the
final concentration 10 mM.
(2) Dissolve 4uL of the test compound solution prepared in step (1) with 46uL of 100% DMSO, and code the solution obtained in this step as No. 2.
(3) Subsequent serial dilution of the No. 2 solution, the dilution factor is 5 times (that is, 20 μL of 100% DMSO plus 5 μL of the compound), and a total of 9 gradients are
diluted, numbered from 3 to 11.
Note: No. 2 is not used for the dilution in step (4).
(Unless otherwise specified, the following steps need to be performed on ice)
(4) Use the buffer provided in the kit (Cisbio, Cat. No. 62TK0PEB) to continue to serially dilute the solutions No. 3 to No. 11, and the dilution factor is 20 times (that is, add
19 μL of buffer to the solutions No. 3 to 11). At this time, the final concentration range of the test compound in systems Nos. 3 to 11 is 3200 nM-0.008 nM (9 gradients),
and the final concentration of DMSO is 2%.
(5) Add the test compound solutions of 9 gradient concentrations in step (4) into the 384-well plate in sequence according to the concentration, 4 μL per well, and set up
two duplicate wells.
(6) Add 2 μL of human RET protein to each well and incubate on ice for 10 minutes.
(7) Add 2 μL of ATP (Sigma#A7699) and 2 μL of biotinylated peptide substrate (Cisbio, Cat. No. 62TK0PEB) to each well to start the phosphorylation reaction. Incubate
for half an hour at 37 °C.
(8) Add 5 μL of anti-phosphotyrosine antibody coupled with europium series element compound (provided in the kit, product number 62TK0PEB) and 5 μL of streptavidin
coupled with modified allophycocyanin XL665 ( Cisbio, Cat. No. 62TK0PEB).
⑼Continue to incubate at room temperature for 1 hour. After the incubation, use the TF-FRET mode of a microplate reader (BMG Labtech, model: FLUOStarOmega) to
measure the excitation wavelength of each well at 304nM, read the fluorescence intensity of each well at the emission wavelength of 615nM and 665nM, and calculate
the ratio automatically.
⑽Compared with the fluorescence intensity ratio of the control group, the inhibition rate of the compound at each concentration was calculated, and then the curve fitting was carried out by GraphPad
value of the compound was calculated, as shown in Table 2 below.
Prism5 based on the logarithmic concentration-inhibition rate, and the IC 50
The selected control kinase is KDR, another receptor tyrosine kinase similar in structure to RET kinase. Purchased from Carna bioscience (Japan, Cat. No. 08-191-5 μg).
The gradient dilution step is the same as that of RET kinase, so that the final concentration range of the test compound in the reaction system is 16000nM～0.04nM (the
gradient dilution of step 4 is carried out with No. 2-10 solution), other reaction conditions are the same as above, and the final concentration of DMSO is 2 %.
The calculation
value of the test compound for the inhibition of KDR kinase is the same as the calculation method of the IC value of the inhibition of RET kinase.
method of the IC 50 50
values of compounds of the present invention and compound 164 for RET kinase and KDR kinase inhibition
Table 2. IC50
It can be seen from the above table that the compound of the present invention has a significant inhibitory effect on RET kinase activity, and the inhibitory effect is better
than compound 164 in WO2018017983A1. The inhibitory activity of the compounds of the present invention on RET kinase is superior to that on KDR kinase. The
compounds of the present invention are therefore useful as a class of potent and selective RET kinase inhibitors.
Remarks: The structural formula of compound 164 is shown below, and its preparation method can be found in WO2018017983A1.
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6/9/23, 10:50 AM CN111808077B - 哌嗪酰胺衍生物，其制备方法及其在医药上的用途 - Google Patents

Piperazinamide derivative, its preparation method and its use in medicine

Inventor: Zhang Panpan, Yan Sunli, Dedulla H. Reddy, Li Ying,

Current Assignee : Zhejiang Hisun Pharmaceutical Co Ltd

Application CN201910294193.9A events

2019-04-12 Application filed by Zhejiang Hisun

2019-04-12 Priority to CN201910294193.9A

2020-10-23 Publication of CN111808077A

2023-05-02 Application granted

2023-05-02 Publication of CN111808077B

2039-04-12 Anticipated expiration

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Info: Patent citations (14), Legal events, Similar documents,

External links: Espacenet, Global Folder, Discuss

Claims (12) Hide Dependent

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

4 4' 5 5' 6 6' 7 7'

4 5 4 6 4 7 4' ' R7 ,R and 6 5 7 5' 6' 5' 7' 6 7 6' 7'

together to form -(CH )q- or -(CH OCH )-;

e ring is selected from pyrazolyl, pyridyl, phenyl or 3-azabicyclo[3.1.0]hexan-3-yl;

one or more halogen atoms;

4 4' 5 5' 6 6' 7 7'

to form -CH OCH - or -(CH ) -.

Piperazinamide derivative, its preparation method and its use in medicine

Contents of the invention

Ring a is selected from pyrazolyl, pyridyl or pyridonyl;

4 4' 5 5' 6 6' 7 7'

4 4' 5 5' 6 6' 7 7'

4 5 4 6 4 7 4' ' R7 ,R and 6 5 7 5' 6' 5' 7' 6 7 6' 7'

together to form -(CH )q- or -(CH OCH )-;

4 4' 5 5' 6 6' 7 7'

e ring is selected from pyrazolyl, pyridyl, phenyl or 3-azabicyclo[3.1.0]hexan-3-yl;

selected from hydrogen or C -C alkyl.

Or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

Detailed Description of the Invention

The synthetic method of compound of the present invention

3 3' 3' 9 10'

First, when the atom connecting ring e to ring d is N atom:

The first step: the synthesis of 2-chloro-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine

The second step: Synthesis of tert-butyl 4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperazine-1-carboxylate

The third step: the synthesis of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(1-piperazinyl)pyrimidin-4-amine hydrochloride

The fourth step: the synthesis of methyl 6-(4-fluoro-1H-pyrazol-1-yl)nicotinate

The fifth step: the synthesis of 6-(4-fluoro-1H-pyrazol-1-yl)nicotinic acid

The sixth step: (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)(4-(4-methyl-6-((5-methyl-1H-pyrazole- Synthesis of 3-yl)amino)pyrimidin-2-yl)piperazin-1-yl)methanone

With reference to Example 1, the following compounds can be prepared:

The first step: 3-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-3,8-diazabicyclo[3.2. 1] Synthesis of tert-butyl octane-8-carboxylate

The second step: 2-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl) Synthesis of pyrimidin-4-amine hydrochloride

The third step: the synthesis of methyl 6-(4-fluoro-1H-pyrazol-1-yl)pyridazine-3-carboxylate

Step 4: Synthesis of 6-(4-fluoro-1H-pyrazol-1-yl)pyridazine-3-carboxylic acid

The fifth step: (6-(4-fluoro-1H-pyrazol-1-yl)pyridazin-3-yl)(3-(4-methyl-6-((5-methyl-1H-pyrazole Synthesis of -3-yl)amino)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-

2-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4 -amine hydrochloride (2c) (700mg, 2.1mmol), 6-(4-fluoro-1H-pyrazol-1-

With reference to Example 2, the following compounds can be prepared:

2-(8-(6-(4-fluoro-1H-pyrazol-1-yl)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-( Synthesis of (5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxylic acid

2-(8-(6-(4-fluoro-1H-pyrazol-1-yl)nicotinoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- ((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxylic acid methyl ester (I-11) (80mg,

(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)(3-(4-(2-hydroxypropyl-2-yl)-6-((5-methyl- Synthesis of 1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-

2-(8-(6-(4-fluoro-1H-pyrazol-1-yl)nicotinoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- ((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxylic acid methyl ester (I-11) (265mg,

The first step: the synthesis of methyl 6-(1-methyl-1H-pyrazol-4-yl)pyridazine-3-carboxylate

The second step: the synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyridazine-3-carboxylic acid

The third step: (6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)(3-(4-methyl-6-((5-methyl-1H-pyridine Synthesis of oxazol-3-yl)amino)pyrimidin-2-yl)-3,8-

2-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4 -amine hydrochloride (2c) (201mg, 0.6mmol), 6-(1-methyl-1H-pyrazol-4-

With reference to Example 6, the following compounds can be prepared:

The first step: Synthesis of methyl 3-(6-bromo-4-methylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

The second step: 3-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)-3,8-diazabicyclo[3.2. 1] Synthesis of octane-8-methyl carboxylate

AU2017208998B2 2021-07-15 Bruton's tyrosine kinase inhibitors