CN118005609A - 2-Aminopyrimidine compound and application thereof - Google Patents
2-Aminopyrimidine compound and application thereof Download PDFInfo
- Publication number
- CN118005609A CN118005609A CN202211399109.8A CN202211399109A CN118005609A CN 118005609 A CN118005609 A CN 118005609A CN 202211399109 A CN202211399109 A CN 202211399109A CN 118005609 A CN118005609 A CN 118005609A
- Authority
- CN
- China
- Prior art keywords
- amino
- phenyl
- piperidin
- piperazine
- pyrimidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 2-Aminopyrimidine compound Chemical class 0.000 title claims description 147
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000000651 prodrug Substances 0.000 claims abstract description 16
- 229940002612 prodrug Drugs 0.000 claims abstract description 16
- 239000012453 solvate Substances 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 11
- 208000002250 Hematologic Neoplasms Diseases 0.000 claims abstract description 10
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims abstract description 10
- 150000005006 2-aminopyrimidines Chemical class 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 54
- 229910052736 halogen Inorganic materials 0.000 claims description 45
- 150000002367 halogens Chemical class 0.000 claims description 45
- 125000000623 heterocyclic group Chemical group 0.000 claims description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- 125000004509 1,3,4-oxadiazol-2-yl group Chemical group O1C(=NN=C1)* 0.000 claims description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 claims description 17
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 16
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- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 13
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 12
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
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- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 8
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 8
- 125000005862 (C1-C6)alkanoyl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
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- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
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- 125000003277 amino group Chemical group 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- IVXQBCUBSIPQGU-UHFFFAOYSA-N piperazine-1-carboxamide Chemical compound NC(=O)N1CCNCC1 IVXQBCUBSIPQGU-UHFFFAOYSA-N 0.000 claims description 6
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- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 2
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
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Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to 2-aminopyrimidine compounds shown in a general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof, a preparation method thereof and a pharmaceutical composition containing the compounds, wherein R 1、R2 and Ar, X, Y, Z, m, n have the meanings given in the specification. The invention also relates to the use of the compounds of formula I for producing medicaments for the treatment and/or prophylaxis of hematological malignancies and inflammatory bowel diseases.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a 2-aminopyrimidine compound and application thereof in preparing medicaments for treating and/or preventing malignant blood diseases and other proliferative diseases.
Background
Hematological malignancies are a group of malignant clonal diseases originating in the tissue domain of the hematopoietic system, mainly including myelodysplastic syndrome, myeloproliferative diseases, malignant lymphomas, leukemias, and the like. Among them, acute myeloid leukemia (acute myeloid leukemia, AML) is mainly characterized by the retardation of differentiation of bone marrow from external Zhou Zhongyuan progenitor and naive myeloid cells, leading to abnormal proliferation and accumulation of primitive myeloid cells at different differentiation stages, while the production of normal functioning erythrocytes, platelets and leukocytes is drastically reduced. AML is common in all ages, especially in the elderly (> 60 years). In recent years, the incidence rate has been generally increasing, and there is a tendency to be younger.
The Janus kinase (Janus kinases, JAKs)/signal transduction and transcription activator (signal transducer and activator of transcription, STAT) signal pathway is a downstream pathway of numerous cytokine signal transduction, and is widely involved in the processes of proliferation, differentiation, apoptosis, inflammation, etc. of cells. Activation of this pathway is closely related to the development and progression of a variety of diseases, particularly hematological neoplasms and inflammation. JAKs include four subtypes JAK1, JAK2, JAK3, and TYK 2. Among them, JAK2 alone mediates cytokines such as erythropoietin (Erythropoietin, EPO), which forms a signal transduction pathway with downstream STAT5, and plays an important role in the process of bone marrow, erythrocytes and platelets production. When JAK2 levels are elevated or mutated in humans (a common JAK2-V617F mutation), it causes excessive activation of the JAK2-STAT5 pathway, thereby causing the development of hematological malignancies.
Inflammatory bowel disease (inflammatory bowel disease, IBD) is a chronic inflammatory disease with a prevalence of about 0.3% affecting the small intestine, colon and rectum, including both ulcerative colitis and crohn's disease types. In IBD, IL-6, IL-12 and IL-23 are important drivers of disease activity. Among these inflammatory factors, IL-6 signaling is through the JAK1/JAK2/TYK2-STAT3 pathway, and IL-12 and IL-23 signaling is dependent on the JAK2/TYK2-STAT4 pathway. Thus, JAK/STAT pathway signaling is one of the major targets for the treatment of IBD.
FMS-like tyrosine kinase 3 (FMS like tyrosine kinase, FLT 3) is an important type III receptor tyrosine kinase that plays an important role in the proliferation, survival and differentiation of multifunctional hematopoietic stem cells. FLT3 is highly expressed in tumor cells in nearly 90% of AML patients, with mutations in FLT3 gene in about 30% of AML patients. With the development of this class of inhibitors, point mutations in the FLT3 kinase domain (FLT 3-TKD, mainly secondary mutations at residues F691 and D835) have become the leading cause of clinically acquired resistance to FLT3 inhibitors. Thus, inhibition of FLT3 and mutants thereof is an effective method for the treatment of related hematological disorders, in particular AML.
Abnormal activation of JAK2 and FLT3 is closely related to the occurrence of hematological malignancy, and both have a synergistic effect. Therefore, the selective JAK2/FLT3 dual inhibitor can synergistically and downwards regulate the content of p-STAT5, more effectively control the development process of AML, overcome the acquired drug resistance problem faced by single inhibition of FLT3 and reduce the generation of adverse reactions, and is a new field for treating the diseases.
Currently approved marketed JAK2/FLT3 small molecule inhibitors are Pacritinib and Fedratinib. Of these Fedratinib is a dual JAK2/FLT3 inhibitor developed by Impact Biomedicines, with IC 50 values for FLT3 and JAK2 of 15nM and 3nM, respectively, and month 2019 approved by the FDA for the treatment of moderate or high risk primary or acquired (post-polycythemia vera or post-primary thrombocythemia) myelofibrosis adult patients.
Based on previous studies, the present inventors have designed and synthesized a series of compounds having improved selectivity and high inhibitory activity.
The invention comprises the following steps:
The invention aims at a 2-aminopyrimidine compound and application thereof in preparing a medicament for treating and/or preventing malignant blood diseases and other proliferative diseases.
In order to achieve the above purpose, the invention adopts the technical scheme that:
2-aminopyrimidine compounds, wherein the compounds are 2-aminopyrimidine compounds of general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,
Wherein,
R 1 is independently selected from hydrogen, halogen, (C 1-C6) alkyl, (C 1-C6) haloalkyl;
Ar is (C 6-C10) aryl, 5-10 membered heteroaryl, optionally substituted with 1-3R 3, which may be the same or different;
R 3 is hydroxy, halogen, nitro, amino, cyano, (C 1-C6) alkyl, (C 1-C6) alkoxy, (C 1-C6) alkyl or (C 1-C6) alkoxy optionally substituted by hydroxy or amino or halogen, (C 1-C6) alkylamido, amino substituted by 1-2 (C 1-C6) alkyl groups, free or salified or esterified or amidated carboxy, (C 1-C6) alkylsulfinyl, (C 1-C6) alkylsulfonyl, (C 1-C6) alkanoyl, carbamoyl substituted by 1-2 (C 1-C6) alkyl, (C 1-C3) alkylenedioxy, (C 6-C10) aryl, (C 3-C10) cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl;
m and n are each independently an integer between 1 and 3;
Y and Z are each independently selected from N or CH;
X is N or CH;
R 2 is-NR 4R5 when X is CH, R 2 is a 4-10 membered heterocyclic group when X is N;
R 4 and R 5 are the same or different and are each independently selected from hydrogen, (C 1-C6) alkyl, (C 3-C7) cycloalkyl, (C 1-C6) alkanoyl, (C 1-C6) alkyl optionally substituted by hydroxy or amino or halogen; or R 4 and R 5 together with the N atom to which they are attached form a 4-10 membered heterocyclyl or a 5-10 membered heteroaryl;
The heterocyclic or heteroaryl groups in the foregoing R 2、R4 and R 5 are optionally substituted with 0-3R 6, which may be the same or different; the heterocyclic group or heteroaryl group optionally contains 1-4 heteroatoms which are the same or different and are selected from N, O, S, wherein the heterocyclic group optionally comprises 0-2 carbon-carbon double bonds or carbon-carbon triple bonds;
R 6 is oxo, halogen, (C 1-C6) alkyl or (C 1-C6) alkanoyl.
Preferably, the 2-aminopyrimidine compound in the general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,
Wherein,
R 1 is independently selected from hydrogen, halogen, (C 1-C4) alkyl, (C 1-C4) haloalkyl;
Ar is (C 6-C10) aryl, 5-6 membered heteroaryl, optionally substituted with 1-3R 3, which may be the same or different;
R 3 is hydroxy, halogen, nitro, amino, cyano, (C 1-C4) alkyl, (C 1-C4) alkoxy, (C 1-C4) alkyl or (C 1-C4) alkoxy optionally substituted by hydroxy or amino or halogen, (C 1-C4) alkylamido, amino substituted by 1-2 (C 1-C4) alkyl groups, free or salified or esterified or amidated carboxy, (C 1-C4) alkylsulfinyl, (C 1-C4) alkylsulfonyl, (C 1-C4) alkanoyl, carbamoyl substituted by 1-2 (C 1-C4) alkyl, (C 1-C3) alkylenedioxy, (C 6-C10) aryl, (C 3-C7) cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl;
m and n are each independently an integer between 1 and 3;
Y and Z are each independently selected from N or CH;
X is N or CH;
R 2 is-NR 4R5, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, when X is N, R 2 is not NR 4R5;
r 4 and R 5 are the same or different and are each independently selected from hydrogen, (C 1-C4) alkyl, (C 3-C7) cycloalkyl, (C 1-C4) alkanoyl, (C 1-C4) alkyl optionally substituted by hydroxy or amino or halogen; or R 4 and R 5 together with the N atom to which they are attached form a 4-6 membered heterocyclyl;
The heterocyclic groups in the foregoing R 2、R4 and R 5 are optionally substituted with 0 to 3R 6, which are the same or different; the heterocyclic group optionally contains 1-4 heteroatoms which are the same or different and are selected from N, O, S, and optionally contains 0-2 carbon-carbon double bonds or carbon-carbon triple bonds;
R 6 is oxo, halogen, (C 1-C6) alkyl, (C 1-C6) alkanoyl.
Preferably, the 2-aminopyrimidine compound in the general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,
Wherein,
R 1 is independently selected from hydrogen, halogen, (C 1-C4) alkyl, trifluoromethyl;
Ar is (C 6-C10) aryl, 5-6 membered heteroaryl, optionally substituted with 1-3R 3, which may be the same or different;
R 3 is hydroxy, halogen, nitro, amino, cyano, (C 1-C4) alkyl, (C 1-C4) alkoxy, (C 1-C4) alkyl optionally substituted by hydroxy or amino or halogen or (C 1-C4) alkoxy, (C 1-C4) alkylamido, free or salified or esterified or amidated carboxy, (C 1-C4) alkylsulfinyl, (C 1-C4) alkylsulfonyl, (C 1-C4) alkanoyl, carbamoyl substituted by 1-2 (C 1-C4) alkyl, (C 1-C3) alkylenedioxy, (C 3-C6) cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl;
m and n are each independently 1 or 2;
Y and Z are each independently selected from N or CH;
X is CH;
R 2 is-NR 4R5;
R 4 and R 5 are the same or different and are each independently selected from hydrogen, (C 1-C4) alkyl, (C 3-C6) cycloalkyl, (C 1-C4) alkanoyl, (C 1-C4) alkyl optionally substituted by hydroxy, amino or halogen; or R 4 and R 5 together with the N atom to which they are attached form a 4-6 membered heterocyclyl;
The heterocyclic groups in the foregoing R 2、R4 and R 5 are optionally substituted with 0 to 3R 6, which are the same or different; the heterocyclic group optionally contains 1-4 heteroatoms which are the same or different and are selected from N, O, S, and optionally contains 0-2 carbon-carbon double bonds or carbon-carbon triple bonds;
R 6 is oxo, halogen, (C 1-C4) alkyl, (C 1-C4) alkanoyl.
Further preferred, the 2-aminopyrimidine compound of the general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,
Wherein X is C;
m and n are the same or different and are 1 or 2;
r 1 is independently selected from hydrogen, halogen, (C 1-C4) alkyl, trifluoromethyl;
Ar is (C 6-C10) aryl, 5-6 membered heteroaryl, optionally substituted with 1-3R 3, which may be the same or different;
R 3 is hydroxy, halogen, nitro, amino, cyano, (C 1-C4) alkyl, (C 1-C4) alkoxy, (C 1-C4) alkyl optionally substituted by hydroxy, amino or halogen or (C 1-C4) alkoxy, (C 1-C4) amino substituted by 1-2 (C 1-C4) alkyl, (C 1-C4) alkylamido, free or salified or esterified or amidated carboxy, (C 1-C4) alkylsulfinyl, (C 1-C4) alkylsulfonyl, (C 1-C4) alkanoyl, carbamoyl substituted by 1-2 (C 1-C4) alkyl, (C 1-C3) alkylenedioxy, (C 3-C6) cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl;
Y and Z are each independently selected from N or CH;
R 4 and R 5 are the same or different and are each independently selected from (C 1-C4) alkyl, (C 1-C4) alkyl optionally substituted by hydroxy; or R 4 and R 5 together with the N atom to which they are attached form a 4-6 membered heterocyclyl;
The heterocyclic group is optionally substituted with 0 to 3 identical or different R 6; the heterocyclic group optionally contains 1-4 heteroatoms which are the same or different and are selected from N, O, S, and optionally contains 0-2 carbon-carbon double bonds or carbon-carbon triple bonds;
R 6 is oxo, halogen, (C 1-C4) alkyl, (C 1-C4) alkanoyl.
Still further preferred, the 2-aminopyrimidine compounds of the general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,
R 1 is independently selected from hydrogen, halogen, (C 1-C4) alkyl;
X is C;
m and n are the same or different and are 1 or 2;
Ar is phenyl optionally substituted with 1 to 3R 3, which may be the same or different;
R 3 is hydroxy, halogen, nitro, amino, cyano, (C 1-C4) alkyl, (C 1-C4) alkoxy, (C 1-C4) alkyl optionally substituted by hydroxy, amino or halogen or (C 1-C4) alkoxy, (C 1-C4) alkylamido, free, salified, esterified and amidated carboxy, (C 1-C4) alkylsulfinyl, (C 1-C4) alkylsulfonyl, (C 1-C4) alkanoyl, (C 1-C4) alkylcarbamoyl, (C 1-C3) alkylenedioxy, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl;
Y and Z are CH;
R 4 and R 5 are the same or different and are each independently selected from (C 1-C4) alkyl, (C 1-C4) alkyl optionally substituted by hydroxy; or R 4 and R 5 together with the N atom to which they are attached form
More preferably, 2-aminopyrimidines of formula I:
n- (4-acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- (4-acetylphenyl) -4- [2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- (4-acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- (4-acetylphenyl) -4- [2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- (4-acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (piperidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (piperidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [2- ({ 4- [4- (piperidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- (4-acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- { 5-chloro-2- [ (4- {4- [ (2-hydroxyethyl) (methyl) amino ] piperidin-1-yl } phenyl) amino ] pyrimidin-4-yl } piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- { 5-chloro-2- [ (4- {4- [ (methyl) (propyl) amino ] piperidin-1-yl } phenyl) amino ] pyrimidin-4-yl } piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- { 5-chloro-2- ({ 4- [3- (morpholin-4-yl) pyrrolidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- { 5-chloro-2- [ (4- {3- [ (2-hydroxyethyl) (methyl) amino ] pyrrolidin-1-yl } phenyl) amino ] pyrimidin-4-yl } piperazine-1-carboxamide;
n- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
The compounds of formula I of the present invention may form pharmaceutically acceptable salts thereof with acids according to some general methods in the art to which the present invention pertains. Preferred acids are hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid and aspartic acid.
The invention also includes prodrugs of the derivatives of the invention. Prodrugs of the derivatives of the invention are derivatives of formula I which may themselves have a relatively weak or even no activity, but are converted to the corresponding biologically active form after administration under physiological conditions (e.g. by metabolism, solvolysis or otherwise).
The term "halogen" as used herein, unless otherwise indicated, refers to fluorine, chlorine or bromine; "alkyl" refers to a straight or branched chain alkyl group; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "alkoxy" refers to straight or branched chain alkoxy; "alkenyl" refers to straight or branched chain alkenyl groups; "alkynyl" refers to straight or branched chain alkynyl groups; "aryl" refers to phenyl groups that are unsubstituted or substituted; "heteroaryl" means a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, the ring system being aromatic, such as imidazolyl, pyridyl, pyrazolyl, furanyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, and the like; "saturated or partially saturated heterocyclyl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiazolinyl, and the like.
The invention also includes pharmaceutical compositions comprising as active ingredient a compound of formula I and pharmaceutically acceptable salts and/or solvates thereof, in combination with a pharmaceutically acceptable carrier; the compounds of the invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The carriers used in the pharmaceutical compositions of the invention are of the usual types available in the pharmaceutical arts, including: binders, lubricants, disintegrants, cosolvents, diluents, stabilizers, suspending agents, pigment-free agents, flavoring agents and the like for oral preparations; preservatives, solubilizing agents, stabilizers and the like for injectable formulations; matrix for topical formulations, diluents, lubricants, preservatives and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if some drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
Through enzyme activity tests of JAK2, JAK3 and FLT3, the compound has remarkable JAK2 and FLT3 inhibiting activity, has a strong inhibiting effect on blood cancer cells with high expression of JAK2 or FLT3, and improves selectivity of partial compounds.
Through in vitro experiments of inhibiting the activity of human erythroleukemia cells HEL and human myelomonocytic leukemia cells MV4-11, the compounds have remarkable anti-tumor activity, so that the compounds can be used for preparing medicines for treating or preventing various proliferative diseases or malignant blood diseases, such as myelofibrosis, multiple myeloma, polycythemia vera, essential thrombocythemia, acute myelogenous leukemia, acute lymphoblastic leukemia and the like.
The precise amount of a compound of the invention required to treat inflammatory bowel disease or hematological malignancy will vary from subject to subject, depending on the type of subject, the age and general condition, the severity of the condition being treated, the particular compound used, and the mode of administration, e.g., route and frequency of administration, and the like. One of ordinary skill in the art can determine the appropriate effective amount using only routine experimentation.
The hematological malignancy includes: leukemia, myelodysplastic syndrome, malignant lymphoma, multiple myeloma, and myeloproliferative diseases.
The leukemia comprises: acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, and chronic myeloid leukemia.
The myeloproliferative disease includes: polycythemia vera, chronic myelogenous leukemia, primary thrombocythemia and myelofibrosis.
The inflammatory bowel disease includes: ulcerative colitis and Crohn's disease.
The amount of the compound administered may be from about 0.1 to 100mg/kg body weight per day, preferably 1 to 50mg/kg body weight per day. It will be appreciated that the dosage may vary depending on the patient's requirements, the severity of the proliferative disease or hematological malignancy being treated, and the particular compound being used. Moreover, it will be appreciated that the initial dose administered may be increased beyond an upper limit in order to rapidly reach the desired blood level, or the initial dose may be less than optimal, and the daily dose may be gradually increased during treatment, depending on the particular situation. If desired, the daily dose may also be divided into multiple doses, for example 2-4 times per day.
Mammal means a human or an animal.
The amount of active ingredient, i.e. the compound according to the invention, in the pharmaceutical composition and unit dosage forms thereof may vary depending on the particular application, the potency of the particular compound and the desired concentration. Generally, the content of active ingredient will be between 0.5% and 90% by total weight of the composition.
In combination therapy, the compound of the invention and the other compound may be administered simultaneously or separately, and in the case of simultaneous administration, the compound of the invention and the other compound may be combined in a single pharmaceutical composition or in separate compositions.
The examples and preparations provided below further illustrate and exemplify the compounds of the invention and methods of preparing the same. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way.
The following synthetic schemes describe the preparation of the derivatives of formula I of the present invention, all starting materials being prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry, or are commercially available. All of the final compounds of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variable factors applied in these schematic drawings are as defined below or as defined in the claims.
The derivatives of the general formula I according to the invention are exemplified in the present synthetic route by the following compounds: the definition of the substituent R 1、R4、R5 and Y, Z, m, n, ar is the same as that of the claims.
Synthesis of Compound I-I
In the route A, the aromatic amine A and phenyl chloroformate undergo a condensation reaction to obtain an intermediate B; the intermediate C and small molecular amine undergo reductive amination reaction to obtain an intermediate D, and then the intermediate D is subjected to Boc removal protection, substitution and reduction to obtain an intermediate H; the intermediate I and N-Boc piperazine undergo substitution reaction to obtain an intermediate J, and the intermediate H and the intermediate J undergo nucleophilic substitution and Boc protection removal to form urea to obtain a target compound I-I
Synthesis of Compound I-ii
In the route B, the aromatic amine A and phenyl chloroformate undergo a condensation reaction to obtain an intermediate B; the intermediate M and small molecular amine undergo reductive amination reaction to obtain an intermediate N, and then the intermediate N is subjected to Boc removal protection, substitution and reduction to obtain an intermediate Q; and carrying out substitution reaction on the intermediate I and N-Boc piperazine to obtain an intermediate J, and carrying out nucleophilic substitution on the intermediate Q and the intermediate J to remove Boc protection and form urea to obtain the target compound I-ii.
The specific embodiment is as follows:
in the examples below, the methods of preparing some of the compounds are depicted. It will be appreciated that the following methods, as well as other methods known to those of ordinary skill in the art, may be applicable to the preparation of all compounds described herein. The examples are intended to illustrate, but not limit the scope of the invention. The nuclear magnetic resonance hydrogen spectrum of the compound is measured by Bruker ARX-600, and the mass spectrum is measured by Agilent 1100 LC/MSD; the reagents used are analytically pure or chemically pure. The compounds of examples 1-35 were prepared by reacting various substituted phenyl carbamates B starting from intermediate L or intermediate S according to the procedure of example 1.
EXAMPLE 1 preparation of N- (4-Acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
Synthesis of tert-butyl 4- (morpholin-4-yl) piperidine-1-carboxylate (D)
N-Boc-4-piperidone (2.0 g,10.04 mmol), morpholine (1.05 g,12.05 mmol) and acetic acid (0.72 g,12.05 mmol) were dissolved in methanol (20 mL) at room temperature and stirred for 4h, after which sodium cyanoborohydride (1.89 g,30.12 mmol) was added and the reaction was continued for 6h. After the completion of the reaction, 10% aqueous sodium hydrogencarbonate (20 mL) was added to quench, the organic solvent was distilled off under reduced pressure, the aqueous phase was extracted with ethyl acetate (20 mL. Times.3), the organic phase was collected, and the organic solvent was distilled off under reduced pressure to give 2.0g of a yellow oil, yield 74.1%.
Synthesis of 4- (piperidin-4-yl) morpholine (E)
Intermediate D (2.0 g,7.41 mmol) was dissolved in 1, 4-dioxane (10 mL) at room temperature, dioxane hydrogen chloride solution (10 mL) was slowly added, and the reaction was completed at room temperature for 4h. After the reaction, a small amount of 1, 4-dioxane (2 mL) was used for washing the filter cake, and the filter cake was dried to obtain 1.1g of a white solid with a yield of 87.3%.
1.3.4- [1- (4-Nitrophenyl) piperidin-4-yl ] morpholine (G)
Intermediate E (1 g,4.84 mmol), p-fluoronitrobenzene (0.72 g,5.08 mmol) and anhydrous potassium carbonate (2.0 g,14.52 mmol) were dissolved in DMSO (10 mL) at room temperature and warmed to 80℃for 4h. After the reaction, water (20 mL) was added, the aqueous phase was extracted with ethyl acetate (20 ml×3), the organic phase was collected, washed with aqueous lithium chloride (20 ml×3), the organic solvent was distilled off under reduced pressure, and purified by column chromatography (DCM: meoh=20:1) to give 1.0g of yellow solid in 71.4% yield.
1.4.4- [4- (Morpholin-4-yl) piperidin-1-yl ] aniline (H)
Intermediate G (1.0G, 3.44 mmol) and 55% palladium on carbon (0.1G) were dissolved in absolute ethanol (10 mL) at room temperature under hydrogen and reacted at room temperature for 6h. After the reaction, the filter cake was washed with ethanol (20 mL) and the filtrate was collected and distilled off under reduced pressure to give 0.6g of a brown solid, which was dried, with a yield of 67.4%.
Synthesis of 1.5.4- (2, 4, 5-trichloropyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (J)
2,4, 5-Trichloropyrimidine (20.0 g,110 mmol) was dissolved in DMF (200 mL), potassium carbonate (19.0 g,132 mmol) was added, N-Boc-piperazine (21.5 g,115.5 mmol) was added in portions, and the reaction was completed at room temperature for 2h. After the completion of the reaction, water (1L) was added to the reaction mixture, followed by stirring, suction filtration, washing of the cake with water (100 mL) and drying to give 30.0g of a white solid, with a yield of 82.2%.
Synthesis of 1.6.4-chloro-2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxylic acid tert-butyl ester (K)
Intermediate J (0.5 g,1.92 mmol) and intermediate H (0.67 g,2.02 mmol) were dissolved in isopropanol (5 mL) at room temperature, trifluoroacetic acid (0.66 g,5.76 mmol) was added and the temperature was raised to 85℃for 6H. After the completion of the reaction, the solvent was concentrated under reduced pressure, water (10 mL) was added to the residue, the pH was adjusted to 8 with saturated sodium bicarbonate solution, suction filtration was performed, the cake was washed with water (20 mL), and dried to give 0.7g of a white solid with a yield of 66%.
Synthesis of N- (4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl) -5-chloro-4- (piperazin-1-yl) pyrimidin-2-amine (L)
Intermediate K (0.7 g 1.26 mmol) was added to 7mL of dichloromethane at room temperature, 7mL of trifluoroacetic acid was slowly added dropwise, and the reaction was carried out at room temperature for 4h. After the completion of the reaction, the solution was concentrated under reduced pressure, water (5 mL) was added to the residue, the pH was adjusted to 10 with a 20% sodium hydroxide solution, suction filtration was performed, the cake was washed with water (20 mL), and 0.5g of a gray solid was obtained after drying, and the yield was 87.7%.
Synthesis of phenyl N- (4-acetylphenyl) carbamate (B)
To a mixed solution of ethyl acetate-tetrahydrofuran-water (3:1:1, 200 mL) was added (20 g,148 mmol) of 4-aminoacetophenone and (9.42 g,88.8 mmol) of sodium carbonate at room temperature, phenyl chloroformate (27.7 g,178 mmol) was added dropwise under ice bath, and the mixture was reacted at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, water (100 mL) was added to the residue, the pH was adjusted to 5 with 1M hydrochloric acid solution, suction filtration was performed, and the cake was washed with water (100 mL) and dried to give 30g of a white solid in a yield of 81.1%.
Synthesis of N- (4-acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide (I)
Intermediate L (0.2 g,0.44 mmol), DIPEA (0.07 g,0.53 mmol) and intermediate B (0.13 g,0.53 mmol) were added to 1, 4-dioxane (2 mL) at room temperature and allowed to react at 80℃for 4h. After the reaction, the mixture was cooled to room temperature, the solvent was concentrated under reduced pressure, water (5 mL) was added to the residue, pH was adjusted to 10 with 5% NaOH solution, and the mixture was suction-filtered and dried to obtain a crude product. The crude product was purified by column chromatography (dichloromethane: methanol=20:1) to give 0.15g of a white solid in 55.6% yield.
EXAMPLE 2 preparation of N- (4-Acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate L was synthesized following the synthesis of 1.5-1.7 in example 1 starting from 2, 4-dichloro-5-methylpyrimidine, followed by N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide following the synthesis of 1.9 in example 1. The yield thereof was found to be 61.2%.
EXAMPLE 3 preparation of N- (4-Acetylphenyl) -4- [2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2, 4-dichloropyrimidine, and N- (4-acetylphenyl) -4- [2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 58.7%.
EXAMPLE 4 preparation of N- (4-Acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from N-methylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene, the key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2,4, 5-trichloropyrimidine, and finally N- (4-acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 62.7%.
EXAMPLE 5 preparation of N- (4-Acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from N-methylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene, the key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2, 4-dichloro-5-methylpyrimidine, and finally N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 65.1%.
EXAMPLE 6 preparation of N- (4-Acetylphenyl) -4- [2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized from N-methylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene according to the method of synthesis of 1.1-1.4 in example 1, the key intermediate L was synthesized from 2, 4-dichloropyrimidine according to the method of synthesis of 1.5-1.7 in example 1, and finally N- (4-acetylphenyl) -4- [2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the method of synthesis of 1.9 in example 1. The yield thereof was found to be 56.5%.
EXAMPLE 7 preparation of N- (4-Acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized from tetrahydropyrrole, N-Boc-4-piperidone and p-fluoronitrobenzene according to the method of synthesis of 1.1-1.4 in example 1, then 2,4, 5-trichloropyrimidine was used as the starting material, the key intermediate L was synthesized according to the method of synthesis of 1.5-1.7 in example 1, and finally N- (4-acetylphenyl) -4- [2- ({ 4- [4- (4-pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the method of synthesis of 1.9 in example 1. The yield thereof was found to be 63.5%.
EXAMPLE 8 preparation of N- (4-Acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized from tetrahydropyrrole, N-Boc-4-piperidone and p-fluoronitrobenzene according to the method of synthesis of 1.1-1.4 in example 1, then 2, 4-dichloro-5-methylpyrimidine was used as the raw material, the key intermediate L was synthesized according to the method of synthesis of 1.5-1.7 in example 1, and finally N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the method of synthesis of 1.9 in example 1. The yield thereof was found to be 68.1%.
EXAMPLE 9 preparation of N- (4-Acetylphenyl) -4- [2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized from tetrahydropyrrole, N-Boc-4-piperidone and p-fluoronitrobenzene according to the method of synthesis of 1.1-1.4 in example 1, the key intermediate L was synthesized from 2, 4-dichloropyrimidine according to the method of synthesis of 1.5-1.7 in example 1, and finally N- (4-acetylphenyl) -4- [2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the method of synthesis of 1.9 in example 1. The yield thereof was found to be 70.4%.
EXAMPLE 10 preparation of N- (4-Acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (piperidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting with piperidine, N-Boc-4-piperidone and p-fluoronitrobenzene, the key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting with 2,4, 5-trichloropyrimidine, and finally N- (4-acetylphenyl) -4- [2- ({ 4- [4- (piperidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 56.2%. EXAMPLE 11 preparation of N- (4-Acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (piperidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from piperidine, N-Boc-4-piperidone and p-fluoronitrobenzene, the key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2, 4-dichloro-5-methylpyrimidine, and finally N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (piperidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 68.7%.
EXAMPLE 12 preparation of N- (4-Acetylphenyl) -4- [2- ({ 4- [4- (piperidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting with piperidine, N-Boc-4-piperidone and p-fluoronitrobenzene, the key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting with 2, 4-dichloropyrimidine, and finally N- (4-acetylphenyl) -4- [2- ({ 4- [4- (piperidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 64.5%. EXAMPLE 13 preparation of N- (4-Acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from N-ethylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene, the key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2,4, 5-trichloropyrimidine, and finally N- (4-acetylphenyl) -4- [2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 69.1%.
EXAMPLE 14 preparation of N- (4-Acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized from N-ethylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene according to the method of synthesis of 1.1-1.4 in example 1, the key intermediate L was synthesized from 2, 4-dichloro-5-methylpyrimidine according to the method of synthesis of 1.5-1.7 in example 1, and finally N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide according to the method of synthesis of 1.9 in example 1. The yield thereof was found to be 74.2%.
EXAMPLE 15 preparation of N- (4-Acetylphenyl) -4- [2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized from N-ethylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene according to the 1.1-1.4 synthesis method in example 1, the key intermediate L was synthesized from 2, 4-dichloropyrimidine according to the 1.5-1.7 synthesis method in example 1, and finally N- (4-acetylphenyl) -4- [2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the 1.9 synthesis method in example 1. The yield thereof was found to be 70.5%.
EXAMPLE 16 preparation of N- (4-Acetylphenyl) -4- { 5-chloro-2- [ (4- {4- [ (2-hydroxyethyl) (methyl) amino ] piperidin-1-yl } phenyl) amino ] pyrimidin-4-yl } piperazine-1-carboxamide
The key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from N-methylethanolamine, N-Boc-4-piperidone and p-fluoronitrobenzene, the key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2,4, 5-trichloropyrimidine, and finally N- (4-acetylphenyl) -4- {2- [ (4- {4- [ (2-hydroxyethyl) (methyl) amino ] piperidin-1-yl } phenyl) amino ] pyrimidin-4-yl } piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 57.8%.
EXAMPLE 17 preparation of N- (4-Acetylphenyl) -4- { 5-chloro-2- [ (4- {4- [ (methyl) (propyl) amino ] piperidin-1-yl } phenyl) amino ] pyrimidin-4-yl } piperazine-1-carboxamide
The key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from N-methylpropylamine, N-Boc-4-piperidone and p-fluoronitrobenzene, the key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2,4, 5-trichloropyrimidine, and finally N- (4-acetylphenyl) -4- {2- [ (4- {4- [ (methyl) (propyl) amino ] piperidin-1-yl } phenyl) amino ] pyrimidin-4-yl } piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 57.5%.
EXAMPLE 18 preparation of N- (4-Acetylphenyl) -4- { 5-chloro-2- ({ 4- [3- (morpholin-4-yl) pyrrolidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
Key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from morpholine, N-Boc-3-pyrrolidone and p-fluoronitrobenzene, key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2,4, 5-trichloropyrimidine, and finally N- (4-acetylphenyl) -4- { 5-chloro-2- ({ 4- [3- (morpholin-4-yl) pyrrolidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 62.5%.
EXAMPLE 19 preparation of N- (4-Acetylphenyl) -4- { 5-chloro-2- [ (4- {3- [ (2-hydroxyethyl) (methyl) amino ] pyrrolidin-1-yl } phenyl) amino ] pyrimidin-4-yl } piperazine-1-carboxamide
N- (4-acetylphenyl) -4- { 5-chloro-2- [ (4- {3- [ (2-hydroxyethyl) (methyl) amino ] pyrrolidin-1-yl } phenyl) amino ] pyrimidin-4-yl } piperazine-1-carboxamide was synthesized from N-methylethanolamine, N-Boc-3-pyrrolidone and p-fluoronitrobenzene as raw materials according to the synthesis method of 1.1-1.4 in example 1, then 2,4, 5-trichloropyrimidine as raw materials according to the synthesis method of 1.5-1.7 in example 1, and finally N- (4-acetylphenyl) -4- { 5-chloro-2- [ (4- {3- [ (2-hydroxyethyl) (methyl) amino ] pyrrolidin-1-yl } phenyl) amino ] pyrimidin-4-yl } piperazine-1-carboxamide as the synthesis method of 1.9 in example 1. The yield thereof was found to be 66.5%.
EXAMPLE 20 preparation of N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from N-methylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene, the key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2, 4-dichloro-5-methylpyrimidine, and the N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] carbamic acid phenyl ester was synthesized according to the synthesis of 1.9 in example 1 starting from [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide. The yield thereof was found to be 53.6%. EXAMPLE 21 preparation of N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
N-methylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene are used as raw materials, a key intermediate H is synthesized according to a synthesis method of 1.1-1.4 in the example 1, 2, 4-dichloropyrimidine is used as a raw material, a key intermediate L is synthesized according to a synthesis method of 1.5-1.7 in the example 1, and finally [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] carbamic acid phenyl ester is used as a raw material, and N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide is synthesized according to a synthesis method of 1.9 in the example 1. The yield thereof was found to be 56.7%.
EXAMPLE 22 preparation of N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from tetrahydropyrrole, N-Boc-4-piperidone and p-fluoronitrobenzene, the key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2, 4-dichloro-5-methylpyrimidine, and the N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1 starting from phenyl [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide. The yield thereof was found to be 70.4%.
EXAMPLE 23 preparation of N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from N-ethylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene, the key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2, 4-dichloro-5-methylpyrimidine, and the N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] carbamic acid phenyl ester was synthesized according to the synthesis of 1.9 in example 1 starting from [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide. The yield thereof was found to be 62.1%.
EXAMPLE 24 preparation of N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
N-ethylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene are used as raw materials, a key intermediate H is synthesized according to a synthesis method of 1.1-1.4 in the example 1, 2, 4-dichloropyrimidine is used as a raw material, a key intermediate L is synthesized according to a synthesis method of 1.5-1.7 in the example 1, and finally phenyl [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] carbamate is used as a raw material, and N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide is synthesized according to a synthesis method of 1.9 in the example 1. The yield thereof was found to be 64.3%.
EXAMPLE 25 preparation of N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H is synthesized by taking pyrrolidine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials according to the synthesis method of 1.1-1.4 in the example 1, the key intermediate L is synthesized by taking 2, 4-dichloropyrimidine as raw materials according to the synthesis method of 1.5-1.7 in the example 1, and finally the N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide is synthesized by taking phenyl [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] carbamate as raw materials according to the synthesis method of 1.9 in the example 1. The yield thereof was found to be 54.2%.
EXAMPLE 26 preparation of N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
Key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from morpholine, N-Boc-4-piperidone and p-fluoronitrobenzene, key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2, 4-dichloro-5-methylpyrimidine, and N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1 starting from phenyl [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] carbamate. The yield thereof was found to be 61.3%.
EXAMPLE 27 preparation of N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from morpholine, N-Boc-4-piperidone and p-fluoronitrobenzene, the key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2, 4-dichloropyrimidine, and finally N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1 starting from phenyl [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] carbamate. The yield thereof was found to be 51.8%.
EXAMPLE 28 preparation of N- (4-Acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (4-acetylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
Key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from acetylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene, key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2, 4-dichloro-5-methylpyrimidine, and finally N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (4-acetylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 45.7%.
EXAMPLE 29 preparation of N- (4-Acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (thiomorpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
Key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from thiomorpholine, N-Boc-4-piperidone and p-fluoronitrobenzene, key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2, 4-dichloro-5-methylpyrimidine, and finally N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (thiomorpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 53.1%.
EXAMPLE 30 preparation of N- (4-Acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (1-oxothiomorpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
Key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from 1-oxothiomorpholine, N-Boc-4-piperidone and p-fluoronitrobenzene, key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2, 4-dichloro-5-methylpyrimidine, and finally N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (1-oxothiomorpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 56.4%.
EXAMPLE 31 preparation of N- (4-Acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (1, 2-dioxothiomorpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
Key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from 1, 2-dioxothiomorpholine, N-Boc-4-piperidone and p-fluoronitrobenzene, key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2, 4-dichloro-5-methylpyrimidine, and finally N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (1, 2-dioxothiomorpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 52.5%.
EXAMPLE 32 preparation of N- (4-Acetylphenyl) -4- [ 5-methyl-2- ({ 5- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] pyridin-2-yl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from N-methylpiperazine, N-Boc-4-piperidone and 5-fluoro-2-nitropyridine, the key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2, 4-dichloro-5-methylpyrimidine, and finally N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 5- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] pyridin-2-yl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 48.1%.
EXAMPLE 33 preparation of N- (4-Acetylphenyl) -4- [ 5-methyl-2- ({ 6- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] pyridin-3-yl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate H was synthesized according to the synthesis of 1.1-1.4 in example 1 starting from N-methylpiperazine, N-Boc-4-piperidone and 2-fluoro-5-nitropyridine, the key intermediate L was synthesized according to the synthesis of 1.5-1.7 in example 1 starting from 2, 4-dichloro-5-methylpyrimidine, and finally N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 6- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] pyridin-3-yl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the synthesis of 1.9 in example 1. The yield thereof was found to be 45.4%.
EXAMPLE 34 preparation of N- (4-Acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
The key intermediate Q is synthesized according to the synthesis method of 1.1-1.4 in the example 1 by taking N-methylpiperidone, N-Boc-piperazine and p-fluoronitrobenzene as raw materials, the key intermediate S is synthesized according to the synthesis method of 1.5-1.7 in the example 1 by taking 2, 4-dichloro-5-methylpyrimidine as raw materials, and finally the N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide is synthesized according to the synthesis method of 1.9 in the example 1. The yield thereof was found to be 67.8%.
EXAMPLE 35 preparation of N- (4-Acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (oxetan-3-yl) piperazin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide
Key intermediate Q was synthesized from oxetanone, N-Boc-piperazine and p-fluoronitrobenzene according to the method of synthesis of 1.1-1.4 in example 1, key intermediate S was synthesized from 2, 4-dichloro-5-methylpyrimidine according to the method of synthesis of 1.5-1.7 in example 1, and N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (oxetan-3-yl) piperazin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide was synthesized according to the method of synthesis of 1.9 in example 1. The yield thereof was found to be 55.5%.
The structures and 1 H-NMR and MS data of the compounds of the examples are shown in the following Table.
TABLE 1 Structure of the Compounds of examples and 1 H-NMR and MS data
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The results of in vitro enzyme activity and cell antiproliferative activity of some of the compounds prepared according to the present invention are shown below
The compounds of the 2-aminopyrimidine skeleton of formula I according to the present invention were tested for in vitro JAK2, JAK3 and FLT3 kinase activity using Mobility SHIFT ASSAY.
The kinase buffer consisted of 50mM HEPEs (pH 7.5), 0.0015% BRIJ-35. Stop buffer contained a mixture of 100mM HEPES (pH 7.5), 0.015% BRIJ-35, 0.2% coating reagent #3 and 50mM EDTA. The initial concentration of the compounds was set at 100nM (JAK 2 and FLT 3) or 1000nM (JAK 3), and the test compounds were diluted with 100% DMSO to 50-fold the highest concentration required in the reaction. Dilutions of the test compounds (100 μl) were transferred to wells of a 96-well plate. Then, by adding 100mL DMSO to both wells as a control group, labeled as source plate. Transfer 10 μl of compound from the source plate to a new 96-well plate to prepare an intermediate plate. In the middle plate, an additional 90 μl of kinase buffer was added per well. The intermediate plate was shaken for 10min, and then 5 μl of each well on the 96-well intermediate plate was replicated as an assay plate onto 384-well plates. To each well in 384-well plates 10 μl of the prepared enzyme solution was added, followed by incubation at room temperature for 10min, and then 10 μl of the prepared peptide solution (FAM-labeled peptide and ATP in kinase-based buffer) was added. The samples were incubated at 28℃for 1h, then 30. Mu.L of stop buffer was added. The conversion data is copied from the Caliper program and converted to a suppression rate.
Inhibition (%) = (max-conversion)/(max-min) ×100.
IC 50 values were obtained using XLfit excel fitting data. Y=bottom+ (Top-Bottom)/(1+ (IC 50/X) ≡ HillSlope)
Results of in vitro kinase assays for some of the compounds are shown in tables 2-3.
TABLE 2
a Not determined.
TABLE 3 Table 3
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Further, the above-described compound having a 2-aminopyrimidine skeleton was used for in vitro inhibition of the activity of human erythroleukemia cells HEL and human myelomonocytic leukemia cells MV 4-11.
After resuscitating and passaging for 2-3 times for stabilization, 10. Mu.L of the cell suspension is aspirated and counted in a cell counting plate, and the cell concentration is adjusted to 5X 10 4/mL. 100. Mu.L of the cell suspension or medium was placed in 96-well plates using Matrix 12 pipettor. And the remaining wells were filled with 200 μ LPBS, and different concentrations of the compound to be tested were added to the 96-well plates. After 72h incubation in the incubator, 22. Mu.L of Alamar-Blue solution was added to the 96-well plate and incubation was continued for 4h. The 96-well plate was shaken at room temperature for 10 seconds, and then absorbance at a wavelength of 530/590nm was measured with a microplate reader, and the inhibition ratio of cell growth was calculated according to the following formula:
Inhibition (%) = [ (control-a dosing)/(control-a blank) ]x100
IC 50 is the drug concentration required to inhibit half of the cell growth, and IC 50 was calculated using GRAPHPAD PRISM software throughput effect curve based on drug concentration and inhibition results.
The results of experiments on human erythroleukemia cells HEL and human acute monocytic leukemia cells MV4-11 of some compounds are shown in Table 4.
TABLE 4 Table 4
| Examples | HEL IC50(nM) | MV4-11 IC50(nM) |
| Example 1 Compounds | 567 | 6.8 |
| Example 5 Compounds | 644 | 9.43 |
| Example 6 Compounds | 1955 | 22.9 |
| Example 8 Compounds | 1105 | 6.08 |
| Example 14 Compounds | 1468 | 7.87 |
| Example 15 Compounds | 3206 | 15.4 |
| Fedratinib | 1425 | 79 |
Preliminary in vitro kinase test results show that the compound of the general formula I to be protected has good JAK2, FLT3 and the inhibition activities of mutant enzymes of the two, the selectivity of part of the compound to JAK3 is improved, part of the compound has the inhibition activities of JAK1 and TYK2, and meanwhile, the part of the compound is equivalent to or better than the positive control drug Fedratinib. Preliminary cell activity test results show that the compound of the general formula I to be protected by the invention has good cell activity, and part of the compounds are equivalent to the positive control drug Fedratinib.
Claims (15)
1. A 2-aminopyrimidine compound characterized by: the compound is a 2-aminopyrimidine compound shown in a general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,
Wherein,
R 1 is independently selected from hydrogen, halogen, (C 1-C6) alkyl, (C 1-C6) haloalkyl;
Ar is (C 6-C10) aryl, 5-10 membered heteroaryl, optionally substituted with 1-3R 3, which may be the same or different;
R 3 is hydroxy, halogen, nitro, amino, cyano, (C 1-C6) alkyl, (C 1-C6) alkoxy, (C 1-C6) alkyl or (C 1-C6) alkoxy optionally substituted by hydroxy or amino or halogen, (C 1-C6) alkylamido, amino substituted by 1-2 (C 1-C6) alkyl groups, free or salified or esterified or amidated carboxy, (C 1-C6) alkylsulfinyl, (C 1-C6) alkylsulfonyl, (C 1-C6) alkanoyl, carbamoyl substituted by 1-2 (C 1-C6) alkyl, (C 1-C3) alkylenedioxy, (C 6-C10) aryl, (C 3-C10) cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl;
m and n are each independently an integer between 1 and 3;
Y and Z are each independently selected from N or CH;
X is N or CH;
R 2 is-NR 4R5 when X is CH, R 2 is a 4-10 membered heterocyclic group when X is N;
R 4 and R 5 are the same or different and are each independently selected from hydrogen, (C 1-C6) alkyl, (C 3-C7) cycloalkyl, (C 1-C6) alkanoyl, (C 1-C6) alkyl optionally substituted by hydroxy or amino or halogen; or R 4 and R 5 together with the N atom to which they are attached form a 4-10 membered heterocyclyl or a 5-10 membered heteroaryl;
The heterocyclic or heteroaryl groups in the foregoing R 2、R4 and R 5 are optionally substituted with 0-3R 6, which may be the same or different; the heterocyclic group or heteroaryl group optionally contains 1-4 heteroatoms which are the same or different and are selected from N, O, S, wherein the heterocyclic group optionally comprises 0-2 carbon-carbon double bonds or carbon-carbon triple bonds;
R 6 is oxo, halogen, (C 1-C6) alkyl or (C 1-C6) alkanoyl.
2. 2-Aminopyrimidines according to claim 1, wherein: the 2-aminopyrimidine compound shown in the general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,
Wherein,
R 1 is independently selected from hydrogen, halogen, (C 1-C4) alkyl, (C 1-C4) haloalkyl;
Ar is (C 6-C10) aryl, 5-6 membered heteroaryl, optionally substituted with 1-3R 3, which may be the same or different;
R 3 is hydroxy, halogen, nitro, amino, cyano, (C 1-C4) alkyl, (C 1-C4) alkoxy, (C 1-C4) alkyl or (C 1-C4) alkoxy optionally substituted by hydroxy or amino or halogen, (C 1-C4) alkylamido, amino substituted by 1-2 (C 1-C4) alkyl groups, free or salified or esterified or amidated carboxy, (C 1-C4) alkylsulfinyl, (C 1-C4) alkylsulfonyl, (C 1-C4) alkanoyl, carbamoyl substituted by 1-2 (C 1-C4) alkyl, (C 1-C3) alkylenedioxy, (C 6-C10) aryl, (C 3-C7) cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl;
m and n are each independently an integer between 1 and 3;
Y and Z are each independently selected from N or CH;
X is N or CH;
R 2 is-NR 4R5 when X is CH, R 2 is a 4-10 membered heterocyclic group when X is N;
R 4 and R 5 are the same or different and are each independently selected from hydrogen, (C 1-C4) alkyl, (C 3-C7) cycloalkyl, (C 1-C4) alkanoyl, (C 1-C4) alkyl optionally substituted by hydroxy or amino or halogen; or R 4 and R 5 together with the N atom to which they are attached form a 4-6 membered heterocyclyl;
The heterocyclic groups in the foregoing R 2、R4 and R 5 are optionally substituted with 0 to 3R 6, which are the same or different; the heterocyclic group optionally contains 1-4 heteroatoms which are the same or different and are selected from N, O, S, and optionally contains 0-2 carbon-carbon double bonds or carbon-carbon triple bonds;
R 6 is oxo, halogen, (C 1-C6) alkyl, (C 1-C6) alkanoyl.
3. 2-Aminopyrimidines according to claim 2, characterized in that: the 2-aminopyrimidine compound shown in the general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,
Wherein,
R 1 is independently selected from hydrogen, halogen, (C 1-C4) alkyl, trifluoromethyl;
Ar is (C 6-C10) aryl, 5-6 membered heteroaryl, optionally substituted with 1-3R 3, which may be the same or different;
R 3 is hydroxy, halogen, nitro, amino, cyano, (C 1-C4) alkyl, (C 1-C4) alkoxy, (C 1-C4) alkyl optionally substituted by hydroxy or amino or halogen or (C 1-C4) alkoxy, (C 1-C4) alkylamido, free or salified or esterified or amidated carboxy, (C 1-C4) alkylsulfinyl, (C 1-C4) alkylsulfonyl, (C 1-C4) alkanoyl, carbamoyl substituted by 1-2 (C 1-C4) alkyl, (C 1-C3) alkylenedioxy, (C 3-C6) cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl;
m and n are each independently 1 or 2;
Y and Z are each independently selected from N or CH;
X is CH;
R 2 is-NR 4R5;
R 4 and R 5 are the same or different and are each independently selected from hydrogen, (C 1-C4) alkyl, (C 3-C6) cycloalkyl, (C 1-C4) alkanoyl, (C 1-C4) alkyl optionally substituted by hydroxy, amino or halogen; or R 4 and R 5 together with the N atom to which they are attached form a 4-6 membered heterocyclyl;
The heterocyclic groups in the foregoing R 2、R4 and R 5 are optionally substituted with 0 to 3R 6, which are the same or different; the heterocyclic group optionally contains 1-4 heteroatoms which are the same or different and are selected from N, O, S, and optionally contains 0-2 carbon-carbon double bonds or carbon-carbon triple bonds;
R 6 is oxo, halogen, (C 1-C4) alkyl, (C 1-C4) alkanoyl.
4. A 2-aminopyrimidine compound as claimed in claim 3 wherein: the 2-aminopyrimidine compound shown in the general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,
Wherein X is C;
m and n are the same or different and are 1 or 2;
r 1 is independently selected from hydrogen, halogen, (C 1-C4) alkyl, trifluoromethyl;
Ar is (C 6-C10) aryl, 5-6 membered heteroaryl, optionally substituted with 1-3R 3, which may be the same or different;
R 3 is hydroxy, halogen, nitro, amino, cyano, (C 1-C4) alkyl, (C 1-C4) alkoxy, (C 1-C4) alkyl optionally substituted by hydroxy, amino or halogen or (C 1-C4) alkoxy, (C 1-C4) amino substituted by 1-2 (C 1-C4) alkyl, (C 1-C4) alkylamido, free or salified or esterified or amidated carboxy, (C 1-C4) alkylsulfinyl, (C 1-C4) alkylsulfonyl, (C 1-C4) alkanoyl, carbamoyl substituted by 1-2 (C 1-C4) alkyl, (C 1-C3) alkylenedioxy, (C 3-C6) cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl;
Y and Z are each independently selected from N or CH;
R 4 and R 5 are the same or different and are each independently selected from (C 1-C4) alkyl, (C 1-C4) alkyl optionally substituted by hydroxy; or R 4 and R 5 together with the N atom to which they are attached form a 4-6 membered heterocyclyl;
The heterocyclic group is optionally substituted with 0 to 3 identical or different R 6; the heterocyclic group optionally contains 1-4 heteroatoms which are the same or different and are selected from N, O, S, and optionally contains 0-2 carbon-carbon double bonds or carbon-carbon triple bonds;
R 6 is oxo, halogen, (C 1-C4) alkyl, (C 1-C4) alkanoyl.
5. The 2-aminopyrimidine compound of claim 4 wherein: the 2-aminopyrimidine compound shown in the general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,
Wherein,
R 1 is independently selected from hydrogen, halogen, (C 1-C4) alkyl;
Ar is phenyl optionally substituted with 1 to 3R 3, which may be the same or different;
X is C;
m and n are the same or different and are 1 or 2;
R 3 is hydroxy, halogen, nitro, amino, cyano, (C 1-C4) alkyl, (C 1-C4) alkoxy, (C 1-C4) alkyl optionally substituted by hydroxy, amino or halogen or (C 1-C4) alkoxy, (C 1-C4) alkylamido, free, salified, esterified and amidated carboxy, (C 1-C4) alkylsulfinyl, (C 1-C4) alkylsulfonyl, (C 1-C4) alkanoyl, (C 1-C4) alkylcarbamoyl, (C 1-C3) alkylenedioxy, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl;
Y and Z are CH;
R 4 and R 5 are the same or different and are each independently selected from (C 1-C4) alkyl, (C 1-C4) alkyl optionally substituted by hydroxy; or R 4 and R 5 together with the N atom to which they are attached form
6. 2-Aminopyrimidines of the general formula I:
n- (4-acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- (4-acetylphenyl) -4- [2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- (4-acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- (4-acetylphenyl) -4- [2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- (4-acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (piperidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (piperidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [2- ({ 4- [4- (piperidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- (4-acetylphenyl) -4- [ 5-chloro-2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [ 5-methyl-2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- [2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- { 5-chloro-2- [ (4- {4- [ (2-hydroxyethyl) (methyl) amino ] piperidin-1-yl } phenyl) amino ] pyrimidin-4-yl } piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- { 5-chloro-2- [ (4- {4- [ (methyl) (propyl) amino ] piperidin-1-yl } phenyl) amino ] pyrimidin-4-yl } piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- { 5-chloro-2- ({ 4- [3- (morpholin-4-yl) pyrrolidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- (4-acetylphenyl) -4- { 5-chloro-2- [ (4- {3- [ (2-hydroxyethyl) (methyl) amino ] pyrrolidin-1-yl } phenyl) amino ] pyrimidin-4-yl } piperazine-1-carboxamide;
n- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (4-ethylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
N- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (pyrrolidin-1-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [ 5-methyl-2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;
n- [4- (1, 3, 4-oxadiazol-2-yl) phenyl ] -4- [2- ({ 4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide.
7. A 2-aminopyrimidine compound as claimed in any one of claims 1 to 6 wherein: the compound salt is a salt formed with an acid selected from the group consisting of: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid or aspartic acid.
8. A pharmaceutical composition characterized by: the composition comprises a compound of formula I as defined in any one of claims 1 to 7, and a pharmaceutically acceptable salt, solvate or prodrug thereof.
9. Use of a compound according to claim 1, characterized in that: use of a compound according to any one of claims 1 to 7, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, in the manufacture of a medicament for the prevention or treatment of a disease associated with a JAK kinase inhibitor.
10. Use of a compound according to claim 1, characterized in that: use of a compound according to any one of claims 1 to 7, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, for the manufacture of a medicament for the prevention or treatment of diseases associated with FLT3 kinase inhibitors.
11. Use according to any one of claims 9-10, characterized in that: the diseases include: inflammatory bowel disease and hematological malignancies.
12. The use according to claim 11, wherein: the hematological malignancy includes: leukemia, myelodysplastic syndrome, malignant lymphoma, multiple myeloma, and myeloproliferative diseases.
13. The use according to claim 12, wherein: the leukemia comprises: acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, and chronic myeloid leukemia.
14. The use according to claim 12, wherein: the myeloproliferative disease includes: polycythemia vera, chronic myelogenous leukemia, primary thrombocythemia and myelofibrosis.
15. The use according to claim 11, characterized in that: the inflammatory bowel disease includes: ulcerative colitis and Crohn's disease.
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