CN107652273B - Pyrimidine derivative and preparation method and application thereof - Google Patents
Pyrimidine derivative and preparation method and application thereof Download PDFInfo
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- CN107652273B CN107652273B CN201610591859.3A CN201610591859A CN107652273B CN 107652273 B CN107652273 B CN 107652273B CN 201610591859 A CN201610591859 A CN 201610591859A CN 107652273 B CN107652273 B CN 107652273B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
The invention belongs to the field of drug synthesis, and relates to a novel pyrimidine derivative, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug of the derivative, a preparation method of the derivative and application of the derivative in preparation of a therapeutic agent, in particular to preparation of a PAK inhibitor. The derivative is shown as a general formula (I) or (II), and the definition of each substituent is described in the claims.
Description
Technical Field
The invention belongs to the field of drug synthesis, and relates to a novel pyrimidine derivative, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug of the derivative, a preparation method of the derivative and application of the derivative in preparation of a therapeutic agent, in particular to preparation of a PAK inhibitor.
Background
Protein kinases are the largest protein superfamily known at present, and since the activity of the protein kinases was discovered in 1954, research in the field has been rapidly developed, and about 538 protein kinases are discovered at present, and encoding genes of the protein kinases account for about 2% of the human genome. As follows:
protein kinases catalyze the transfer of the terminal phosphate group of ATP to a specific amino acid of a substrate in vivo to phosphorylate the substrate, and they are classified into 5 types according to the kind of amino acid residues phosphorylated on the substrate protein: serine/threonine (Ser/Thr) protein kinases, tyrosine (Tyr) protein kinases, histidine protein kinases, tryptophan protein kinases, aspartyl/glutamyl protein kinases, protein kinases have two major roles in signal transduction: one is to regulate the activity of proteins through phosphorylation, phosphorylation and dephosphorylation are common mechanisms of reversible activation of most signal pathway components, and some proteins have activity after phosphorylation and some have activity after dephosphorylation; secondly, the signals are amplified step by step through the step by step phosphorylation of the proteins, so as to cause cell reaction, and the phosphorylation of the proteins is an activation step of a plurality of signal conduction paths. Research shows that protein kinase plays a key role in regulating a plurality of important physiological processes in vivo, abnormal phosphorylation activity of protein kinase can cause cell proliferation regulation disorder, and further cause tumor occurrence, and in addition, abnormal expression of protein kinase is closely related to invasion, metastasis, angiogenesis and chemotherapy resistance of tumor, so that research of protein kinase inhibitor becomes one of hot spots of research of antitumor drugs. In the aspect that more than 150 kinase inhibitors currently under clinical research mainly relate to about 42 kinase targets, about 50% of the inhibitors under study are targeted to kinases of existing marketed drugs, research on the kinases with less research or the kinases without the marketed drugs is easier to generate breakthrough, and the research on the protein kinase inhibitors still has huge development space.
p21 activated kinases (PAKs) are a class of serine/threonine protein kinases that are downstream target proteins of the Rho family of small G proteins, first discovered by Manser et al in 1994, and so far the PAKs family has 6 family members: PAK1-6, based on their structural features and sequence homology, can be divided into two broad categories: PAK class I (PAK1-3) and PAK class II (PAK 4-6).
The research finds that PAK can interact with a plurality of proteins in cells, which indicates that PAKs are multifunctional kinases, regulate and control a plurality of biological functions such as cytoskeletal recombination, cell migration movement, apoptosis, mitosis and the like through participating in a plurality of signal paths in cells, besides participating in regulating normal physiological activities of cells, PAK is also found to be closely related to the occurrence and development of a plurality of diseases, particularly to the occurrence and development of malignant tumors, and therefore, PAK becomes a new target for the research of antitumor drugs. A series of PAK inhibitors (Joachim R, James J.C, Klaus P.H, et al J. Med. chem.,2015,58(1), 111-129) have been disclosed (e.g., Staurosporine, PF3758309, KY04031, etc.), wherein KY04031 is a PAK4 inhibitor containing indole, triazine and indazole structural fragments discovered by high throughput screening techniques reported in 2014 by SeongHwan Kim and SangYong Park topic groups in Korea (PAK4 IC)50790 ± 50nM) (Ryu B j., Kim s., Min B., et al. cancer letters,2014,349, 45-50). The research shows that KY-04031 can inhibit the proliferation and invasion of prostate cancer cells. Although a series of PAK inhibitors have been disclosed, no PAK inhibitor drug is currently on the market, and there is still a need to develop a compound having a novel structure and a better drug efficacy. The invention designs compounds with structures shown in general formulas (I) and (II), and finds that the compounds with the structures show better PAK4 inhibitory activity.
The invention content is as follows:
the invention aims to provide a novel pyrimidine derivative shown as a general formula (I) or (II), a geometric isomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
wherein the content of the first and second substances,
Z1、Z2is independently selected from C or N, and Z1、Z2At least one is C.
The A ring is selected from a 5-6 membered aromatic ring, a 5-6 membered aromatic heterocycle, a 5-7 membered saturated aliphatic ring and a 5-7 membered unsaturated aliphatic ring. The aromatic heterocyclic ring contains 1-3 heteroatoms of N, O or S. The A ring may be further substituted by one or more RxAnd (4) substituting.
X, Y is selected from N, O, S, when X, Y is selected from N, can be replaced by-H, (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C6) The fluoroalkyl group is further substituted.
Ring B is selected from RxSubstituted or unsubstituted 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle, 5-7 membered saturated aliphatic ring, 5-7 membered unsaturated aliphatic ring. The aromatic heterocyclic ring contains 1-3 heteroatoms of N, O or S.
n is an integer between 0 and 3.
M is selected from N, C-Ra，RaSelected from-H, (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C6) Fluoroalkyl, halogen.
The C ring may be further substituted by R selected from-H, halogen, (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C6) Fluoroalkyl, (C)1-C6) Fluorine-containing cycloalkyl, [ (C)1-C3) Alkylene radical]-[(C3-C6) Cycloalkyl radicals]、(C2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)5-C7) Aryl group, (C)5-C7) Heteroaryl, - [ (C)1-C3) Alkylene radical]-[(C5-C7) Aryl radicals]-、[(C1-C3) Alkylene radical]-[(C5-C7) Heteroaryl radical]And aryl and heteroaryl are optionally 1-3RxAnd (4) substitution.
Rxis-H, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group.
The invention preferably selects the novel pyrimidine derivatives shown in the general formula (I) or (II), and geometrical isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof.
Wherein the content of the first and second substances,
Z1、Z2is independently selected from C or N, and Z1、Z2At least one is C.
The A ring is selected from benzene ring, 5-6 membered aromatic heterocycle, 5-7 membered saturated fat ring, 5-7 membered unsaturated fat ring. The aromatic heterocyclic ring is selected from furan ring, thiophene ring, pyrrole ring, thiazole ring, oxazole ring, pyridine ring, pyrimidine ring and triazine ring. The A ring may be further substituted by one or more RxAnd (4) substituting.
X, Y is selected from N, O, S, when X, Y is selected from N, can be replaced by-H, (C)1-C6) Alkyl, (C)1-C6) The fluoroalkyl group is further substituted.
Ring B is selected from RxSubstituted or unsubstituted benzene ring, 5-6 membered aromatic heterocycle, 5-7 membered saturated aliphatic ring, 5-7 membered unsaturated aliphatic ring and ring. The aromatic heterocyclic ring is selected from furan ring, thiophene ring, pyrrole ring, thiazole ring, oxazole ring, pyridine ring, pyrimidine ring and triazine ring.
n is an integer between 0 and 3.
M is selected from N, C-Ra，RaSelected from-H, (C)1-C6) Alkyl, (C)1-C6) Fluoroalkyl, halogen.
The C ring may be further substituted by R selected from-H, halogen, (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C6) A fluoroalkyl group.
Rxis-H, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group.
The invention preferably selects novel pyrimidine derivatives shown in general formula (I) or (II), geometrical isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein the content of the first and second substances,
Z1、Z2is independently selected from C or N, and Z1、Z2At least one is C.
The A ring is selected from benzene ring, 5-6 membered aromatic heterocycle, 5-7 membered saturated fat ring. The aromatic heterocyclic ring is selected from furan ring, thiophene ring, pyrrole ring, thiazole ring, oxazole ring,Pyridine ring, pyrimidine ring, triazine ring. The A ring may be further substituted by one or more RxAnd (4) substituting.
When X, Y is selected from N, it can be replaced by-H, (C)1-C6) Alkyl is further substituted.
Ring B is selected from RxSubstituted or unsubstituted benzene ring, 5-6 membered aromatic heterocycle. The aromatic heterocyclic ring is selected from furan ring, thiophene ring, pyrrole ring, thiazole ring, oxazole ring, pyridine ring, pyrimidine ring and triazine ring.
n is an integer of 1 or 2.
M is selected from N, C-Ra，RaSelected from-H, (C)1-C6) Alkyl, trifluoromethyl, halogen. The C ring may be further substituted by R selected from-H, halogen, (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C6) A fluoroalkyl group.
Rxis-H, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group.
The invention preferably selects novel pyrimidine derivatives shown in general formulas (I) and (II), geometrical isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein the content of the first and second substances,
Z1、Z2is independently selected from C or N, and Z1、Z2At least one is C.
The A ring is selected from benzene ring, 5-6 membered aromatic heterocycle, 5-7 membered saturated fat ring. The aromatic heterocyclic ring is selected from furan ring, thiophene ring, pyrrole ring, thiazole ring, oxazole ring, pyridine ring, pyrimidine ring and triazine ring. The A ring may be further substituted by one or more RxAnd (4) substituting.
When X, Y is selected from N, it may be further substituted by-H, methyl.
Ring B is selected from RxSubstituted or unsubstituted benzene ring, 5-6 membered aromatic heterocycle. The aromatic heterocyclic ring is selected from furan ring, thiophene ring, pyrrole ring, thiazole ring, oxazole ring, pyridine ring, pyrimidine ring and triazine ring.
n is an integer of 1 or 2.
M is selected from N, C-Ra，RaSelected from-H, (C)1-C6) Alkyl, trifluoromethyl, -F, -Cl, -Br and-I. The C ring may be further substituted by R selected from the group consisting of-H, -F, -Cl, -Br, methyl.
Rxis-H, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group.
The invention preferably selects novel pyrimidine derivatives shown in general formula (I) or (II), geometrical isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein the content of the first and second substances,
Z1、Z2is independently selected from C or N, and Z1、Z2At least one is C.
The A ring is selected from benzene ring, 5-6 membered aromatic heterocycle, 5-7 membered saturated fat ring. The aromatic heterocyclic ring is selected from furan ring, thiophene ring, pyridine ring and pyrimidine ring. The A ring may be further substituted by one or more RxAnd (4) substituting.
When X, Y is selected from N, it may be further substituted by-H, methyl.
Ring B is selected from RxSubstituted or unsubstituted benzene ring, 5-6 membered aromatic heterocycle. The aromatic heterocyclic ring is selected from furan ring, thiophene ring, pyridine ring and pyrimidine ring.
n is an integer of 1 or 2.
M is selected from N, C-Ra，RaSelected from-H, (C)1-C6) Alkyl, trifluoromethyl, -F, -Cl, -Br and-I. The C ring may be further substituted by R selected from the group consisting of-H, -F, -Cl, -Br, methyl.
Rxis-H, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, (C)1-C6) Alkyl acyl, aminoFormyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group.
The compounds represented by the general formula (I) or (II) of the present invention and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof are preferably the following compounds, but these compounds are not meant to limit the present invention in any way:
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) quinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6-methoxyquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -7-methoxyquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -thieno [3,2-d]Pyrimidine 2, 4-diamines
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -thieno [2,3-d]Pyrimidine 2, 4-diamines
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -furo [3,2-d]Pyrimidine 2, 4-diamines
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -furo [2,3-d]Pyrimidine 2, 4-diamines
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -7-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -pyrido [3,2-d]Pyrimidine 2, 4-diamines
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -5,6,7, 8-tetrahydroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6, 7-dihydro-5H-cyclopenta [ d]QuinazolesQuinoline-2, 4-diamines
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -7-methyl-5, 6,7, 8-tetrahydropyridine [3,4-d]Pyrimidine-2, 4-diamines
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -N4-methyl-6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -N2-methyl-6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) methyl) -N2- (1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-pyrrol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (5-fluoro-1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-pyrazolo [3, 4-b)]Pyridin-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (7-chloro-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (7-bromo-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (7-iodo-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (7-methyl-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (6-methyl-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (6-fluoro-1H-indazol-5-yl) -6-chloroquinazoline-2,4-diamines
N4- (2- (1H-indol-3-yl) ethyl) -N2- (4-methyl-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) quinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-methoxyquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -7-methoxyquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -thieno [3,2-d]Pyrimidine 2, 4-diamines
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -thieno [2,3-d]Pyrimidine 2, 4-diamines
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -furo [3,2-d]Pyrimidine 2, 4-diamines
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -furo [2,3-d]Pyrimidine 2, 4-diamines
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -7-chloroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -pyrido [3,2-d]Pyrimidine 2, 4-diamines
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -5,6,7, 8-tetrahydroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6, 7-dihydro-5H-cyclopenta [ d]Quinazoline-2, 4-diamines
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -7-methyl-5, 6,7, 8-tetrahydropyridine [3,4-d]Pyrimidine-2, 4-diamines
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -N4-methyl-6-chloroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -N2-methyl-6-chloroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) methyl) -6-chloroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-pyrrol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (5-fluoro-1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (1H-pyrazolo [3, 4-b)]Pyridin-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (7-chloro-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (7-bromo-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (7-iodo-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (7-methyl-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (6-methyl-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (6-fluoro-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (4-methyl-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
Furthermore, the derivatives of the general formulae (I) and (II) of the present invention may form pharmaceutically acceptable salts with acids according to some conventional methods in the art to which the present invention pertains. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are derivatives of the general formulae (I) and (II) which may themselves be less active or even inactive, but which, upon administration, are converted under physiological conditions (e.g. by metabolism, solvolysis or otherwise) to the corresponding biologically active form.
"halo" in the present invention means fluoro, chloro, bromo or iodo substituents; "alkyl" refers to straight or branched chain alkyl; "alkylene" refers to straight or branched chain alkylene; "alicyclic ring" means a cyclic saturated hydrocarbon group, which may be monocyclic and, if permitted, bicyclic or polycyclic. The alicyclic ring may be optionally substituted with at least one substituent. "unsaturated aliphatic ring" refers to a cyclic unsaturated hydrocarbon group that may contain one or more double bonds, but which does not have a fully conjugated pi-electron system in the ring. The unsaturated aliphatic ring may be optionally substituted with at least one substituent. "aromatic ring" refers to an organic group obtained by removing two hydrogen atoms at one or different positions in an aromatic hydrocarbon, such as phenyl, naphthyl; "heteroaromatic ring" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, which ring system refers to an organic group having aromaticity and obtained by removing two hydrogen atoms at one or different positions in the ring system, such as thiazolyl, imidazolyl, pyridyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, furyl, thienyl, pyrrolyl, indolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, and the like; heterocycloalkyl refers to a monocyclic ring system containing one or more heteroatoms selected from N, O, S, such as tetrahydropyrrolyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyrazolidinyl, tetrahydroimidazolidinyl, thiazolidinyl, and the like.
The invention can contain the derivatives of general formula (I) or (II) and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof as active ingredients, and the derivatives are mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and prepare a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipients refer to any diluents, auxiliary agents and/or carriers which can be used in the pharmaceutical field. The derivatives of the present 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 pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt the dosage forms of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment, etc.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binder, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment-free, correctant, antiseptic, solubilizer, matrix, etc. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention in any way. The compounds of formula I according to the invention can be prepared according to the method of scheme 1 and the compounds of formula II according to the invention can be prepared according to the method of scheme 2, all the variables used in these schemes being as defined in the claims.
Route 1
As shown in scheme 1, the synthesis of a portion of the compounds is essentially two steps:
step 1, taking the synthesized fragment 1-A as a raw material, wherein M1 and M2 can be-Cl or-Br, preferably-Cl, and are subjected to substitution reaction with fused C-ring or non-fused pyrrole substituted amine, wherein a reaction solvent can be dichloromethane, trichloromethane, tetrahydrofuran, DMF and the like, preferably DMF, and the reaction temperature is-40-100 ℃, preferably-20-30 ℃; step 2, taking the synthesized fragment 2-A as a raw material, and carrying out substitution reaction with the C ring fragment, wherein the substitution reaction condition can be protonic acid or base catalysis, HCl is preferred, the reaction solvent can be tetrahydrofuran, ethanol, methanol, DMF and the like, ethanol is preferred, and the reaction temperature is 60-150 ℃, and 80-130 ℃ is preferred.
Route 2
As shown in scheme 2, the synthesis of a portion of the compounds is essentially two steps:
step 1, taking the synthesized fragment 1-A as a raw material, wherein M1 and M2 can be-Cl or-Br, preferably-Cl, and carry out substitution reaction with the C ring fragment, a reaction solvent can be dichloromethane, trichloromethane, tetrahydrofuran, DMF and the like, preferably DMF, and the reaction temperature is-40-100 ℃, preferably-20-30 ℃; step 2 is to take the synthesized fragment 2-A as a raw material to perform substitution reaction with a condensed C ring or a non-condensed pyrrole fragment, wherein the substitution reaction condition can be protonic acid or base catalysis, HCl is preferred, the reaction solvent can be tetrahydrofuran, ethanol, methanol, DMF and the like, ethanol is preferred, and the reaction temperature is 60-150 ℃, 80-130 ℃ is preferred.
The specific implementation mode is as follows:
the examples are intended to illustrate, but not to limit, the scope of the invention. NMR of the compounds was measured using BrukeraRx-400 and Mass Spectroscopy was measured using Agilent 1100 LC/MSD; all reagents used were analytically or chemically pure.
TABLE 1 structural formulas of examples 1-27
Preparation of A-B fused pyrimidine ring parent nucleus
(method A)
Preparation of 2, 4-dihydroxy-6-chloroquinazoline (M1)
Mixing 2-amino-5-chlorobenzoic acid (15.0g, 0.087mol) and urea (52.3g, 0.87mol), heating to melt at 200 ℃ for reaction for 3 hours, stopping heating, cooling, adding 300ml of water, stirring, heating and refluxing for 1 hour, carrying out suction filtration while hot, and drying the solid to obtain 13.77g of light yellow solid with the yield of 80.5%.
ESI-MS(m/z)：197[M+H]+.
Preparation of 2,4, 6-trichloroquinazoline (M2)
Adding 2, 4-dihydroxy-6-chloroquinazoline (M1) (16.0g, 0.081mol) into a reaction bottle, adding phosphorus oxychloride (47ml, 0.515mol), dropwise adding N, N-dimethylaniline (31ml, 0.243mol) under stirring at room temperature, heating and refluxing for 3 hours, stopping heating, cooling, pouring into 500ml of ice water, precipitating a brownish black solid, performing suction filtration, drying, and performing column chromatography (petroleum ether-ethyl acetate) to obtain 8.74g of a light yellow solid with the yield of 46.2%.
ESI-MS(m/z)：233[M+H]+.
The preparation method comprises the following steps:
preparation of 2,4, 7-trichloroquinazoline
The preparation method is the same as the above by taking 2-amino-4-chlorobenzoic acid as a starting material. ESI-MS (m/z): 233[ M + H]+.
Preparation of 2, 4-dichloro-6-methoxyquinazoline
The preparation method is the same as the above by using 2-amino-5-methoxybenzoic acid as a starting material. ESI-MS (m/z): 229[ M + H]+.
Preparation of 2, 4-dichloro-7-methoxyquinazoline
The preparation method is the same as the above by using 2-amino-4-methoxybenzoic acid as a starting material. ESI-MS (m/z): 229[ M + H]+.
(method B)
Preparation of 2, 4-dihydroxythieno [3,2-d ] pyrimidine (M1)
3-amino-2-thiophenecarboxylic acid methyl ester (5.5g, 0.035mol) and 75ml sodium cyanate (4.55g) aqueous solution were mixed, added dropwise to 150ml 50% glacial acetic acid aqueous solution, stirred at room temperature for 5 hours to give a white solid, filtered, dissolved in 75ml 2N sodium hydroxide solution, cooled to 0 ℃ for reaction, adjusted with hydrochloric acid to precipitate a solid, which was 3.20g off-white solid with a yield of 54.2%.
ESI-MS(m/z)：169[M+H]+.
Preparation of 2, 4-chlorothieno [3,2-d ] pyrimidine (M2)
2, 4-dihydroxythieno [3,2-d ] pyrimidine (M1) (3.38g, 0.020mol) was charged into a reaction flask, phosphorus oxychloride (11.6ml, 0.127mol) was added, N-dimethylaniline (7.44ml, 0.058mol) was added dropwise with stirring at room temperature, heating and refluxing were carried out for 3 hours, the heating was stopped, the mixture was allowed to cool and poured into 100ml of ice water, a tan solid was precipitated, the mixture was filtered by suction, dried, and column chromatography was carried out (petroleum ether-ethyl acetate: 3:1) to obtain 2.10g of a pale yellow solid, and the yield was 51.2%.
ESI-MS(m/z)：205[M+H]+.
The preparation method comprises the following steps:
preparation of 2, 4-chlorothieno [2,3-d ] pyrimidines
The preparation method is the same as the above by using 2-amino-3-thiophene methyl formate as a starting material.
ESI-MS(m/z)：205[M+H]+.
Preparation of 2, 4-chlorofuro [3,2-d ] pyrimidines
The preparation method is the same as the above by using 3-amino-2-furancarboxylic acid methyl ester as a starting material.
ESI-MS(m/z)：189[M+H]+.
Preparation of 2, 4-chlorofuro [2,3-d ] pyrimidines
The preparation method is the same as the above by using methyl 2-amino-3-furancarboxylate as a starting material.
ESI-MS(m/z)：189[M+H]+.
Preparation of 2, 4-dichloroquinazoline
The preparation method is the same as the above by using methyl 2-aminobenzoate as a starting material.
ESI-MS(m/z)：199[M+H]+.
Preparation of 2, 4-dichloro-5, 6,7, 8-tetrahydroquinazoline
The preparation method is the same as the above by taking 2-amino-1-cyclohexene-1-ethyl formate as a raw material.
ESI-MS(m/z)：203[M+H]+.
Preparation of 2, 4-dichloro-6, 7-dihydro-5H-cyclopenta [ d ] pyrimidine
The preparation method is the same as the above by taking the 2-amino-1-cyclopentene-1-ethyl formate as a raw material.
ESI-MS(m/z)：189[M+H]+.
Preparation of 2, 4-dichloro-6-pyrido [3,2-d ] pyrimidine
The preparation method is the same as the above by using 3-aminopyridine-2-carboxylic acid methyl ester as a raw material.
ESI-MS(m/z)：200[M+H]+.
Preparation of 2, 4-dichloro-7-methyl-5, 6,7, 8-tetrahydropyrido [3,2-d ] pyrimidine
The preparation method is the same as the above by taking 5-amino-1-methyl-3, 6-dihydro-2H-pyridine-4-ethyl formate as a raw material.
ESI-MS(m/z)：218[M+H]+.
Example 1: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2Preparation of- (1H-indazol-5-yl) quinazoline-2, 4-diamine
Step A-1 preparation of N- (2- (1H-indol-3-yl) ethyl) -2-chloroquinazolin-4-amine (1)
Dispersing 1.98g (0.01mol) of 2, 4-dichloroquinazoline and 1.76g (0.0011mol) of tryptamine in 50ml of DMF, slowly adding 0.32g (0.025mol) of DIEA into the solution under stirring in an ice bath, pouring the solution into 300ml of ice water after reacting at the reaction temperature of 0 ℃ for 2 hours after dripping, precipitating a light yellow solid, filtering, and drying to obtain 2.70g of the light yellow solid, wherein the yield is 83.4%, and ESI-MS (m/z): 323[ M + H]+。
Step A-2N4- (2- (1H-indol-3-yl) ethyl) -N2Preparation of- (1H-indazol-5-yl) quinazoline-2, 4-diamine
Adding 0.32g (0.001mol) of the intermediate (1) and 0.27g (0.002mol) of 5-aminoindazole into a sealed tube, adding 10ml of absolute ethanol and 10uL of hydrochloric acid, reacting at 120 ℃ for 10 hours, cooling to room temperature, evaporating to remove the solvent, and performing column chromatography (dichloromethane-methanol is 20:1) to obtain 0.21g of light yellow solid, wherein the yield is 50.0%, and ESI-MS (m/z): 420[ M + H]+。
According to the method of example 1, substituted condensed dichloropyrimidine is used as a raw material, and the substituted condensed dichloropyrimidine and substituted C ring fragment amine are subjected to a first aromatic nucleophilic addition elimination reaction to prepare an intermediate 1, and then are subjected to a second aromatic nucleophilic addition elimination reaction with substituted D ring fragment amine to prepare a product 2, namely, examples 2-15.
Example 2: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6-methoxyquinazoline-2, 4-diamine
ESI-MS(m/z)：450[M+H]+。
Example 3: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -7-methoxyquinazoline-2, 4-diamine
ESI-MS(m/z)：450[M+H]+。
Example 4: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -thieno [3,2-d]Pyrimidine 2, 4-diamines
ESI-MS(m/z)：426[M+H]+。
Example 5: n is a radical of4- (2- (1H-indol-3-yl)Ethyl) -N2- (1H-indazol-5-yl) -thieno [2,3-d]Pyrimidine 2, 4-diamines
ESI-MS(m/z)：426[M+H]+。
Example 6: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -furo [3,2-d]Pyrimidine 2, 4-diamines
ESI-MS(m/z)：410[M+H]+。
Example 7: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -furo [2,3-d]Pyrimidine 2, 4-diamines
ESI-MS(m/z)：410[M+H]+。
Example 8: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：454[M+H]+。
Example 9: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -7-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：454[M+H]+。
Example 10: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -pyrido [3,2-d]Pyrimidine 2, 4-diamines
ESI-MS(m/z)：421[M+H]+。
Example 11: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -5,6,7, 8-tetrahydroquinazoline-2, 4-diamine
ESI-MS(m/z)：424[M+H]+。
Example 12: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6, 7-dihydro-5H-cyclopenta [ d]Quinazoline-2, 4-diamines
ESI-MS(m/z)：424[M+H]+。
Example 13: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -7-methyl-5, 6,7, 8-tetrahydropyridine [3,4-d]Pyrimidine-2, 4-diamines
ESI-MS(m/z)：439[M+H]+。
Example 14：N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -N4-methyl-6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：468[M+H]+。
Example 15: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -N2-methyl-6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：468[M+H]+。
Example 16: n is a radical of4- (2- (1H-indol-3-yl) methyl) -N2- (1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：440[M+H]+。
Example 17: n is a radical of4- (2- (1H-pyrrol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：404[M+H]+。
Example 18: n is a radical of4- (2- (5-fluoro-1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：472[M+H]+。
Example 19: n is a radical of4- (2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：455[M+H]+。
Example 20: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-pyrazolo [3, 4-b)]Pyridin-5-yl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：455[M+H]+。
Example 21: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (7-chloro-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：488[M+H]+。
Example 22: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (7-bromo-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：532[M+H]+。
Example 23: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (7-iodo-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：580[M+H]+。
Example 24: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (7-methyl-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：468[M+H]+。
Example 25: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (6-methyl-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：468[M+H]+。
Example 26: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (6-fluoro-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：472[M+H]+。
Example 27: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2- (4-methyl-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：468[M+H]+。
TABLE 2 structural formulas of examples 28-54
Example 28: n is a radical of4- (2- (1H-indol-3-yl) ethyl) -N2Preparation of- (1H-indazol-5-yl) quinazoline-2, 4-diamine
Step A-1 preparation of N-2- (1H-indazol-5-yl) -2-chloroquinazolin-4-amine (1)
Dispersing 1.98g (0.01mol) of 2, 4-dichloroquinazoline and 1.46g (0.0011mol) of 5-aminoindazole in DMF50ml, slowly adding 0.32g (0.025mol) of DIEA into the solution under stirring in an ice bath, after dropwise reaction at a reaction temperature of 0 ℃ for 2 hours, pouring into 300ml of ice water to precipitate a light yellow solid, performing suction filtration and drying to obtain 2.30g of the light yellow solid, wherein the yield is 71.8%, and ESI-MS (m/z): 295[ M + H]+。
Step A-2N4- (2- (1H-indol-3-yl) ethyl) -N2Preparation of- (1H-indazol-5-yl) quinazoline-2, 4-diamine (2)
Adding 0.30g (0.001mol) of the intermediate (1) and 0.32g (0.002mol) of tryptamine into a sealed tube, adding 10ml of absolute ethyl alcohol and 10uL of hydrochloric acid, reacting at 120 ℃ for 10 hours, cooling to room temperature, evaporating to remove the solvent, and performing column chromatography (dichloromethane-methanol is 20:1) to obtain 0.17g of light yellow solid, wherein the yield is 40.4%, and ESI-MS (m/z): 420[ M + H]+。
Following the procedure of example 28, substituted fused dichloropyrimidines were each prepared starting with substituted D ring segment amines by a first aromatic nucleophilic addition elimination reaction to give intermediate 1, and then with substituted C ring segment amines by a second aromatic nucleophilic addition elimination reaction to give product 2, examples 29-54.
Example 29: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-methoxyquinazoline-2, 4-diamine
ESI-MS(m/z)：450[M+H]+。
Example 30: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -7-methoxyquinazoline-2, 4-diamine
ESI-MS(m/z)：450[M+H]+。
Example 31: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -thieno [3,2-d]Pyrimidine 2, 4-diamines
ESI-MS(m/z)：426[M+H]+。
Example 32: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -thieno [2,3-d]Pyrimidine 2, 4-diamines
ESI-MS(m/z)：426[M+H]+。
Example 33: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -furo [3,2-d]Pyrimidine 2, 4-diamines
ESI-MS(m/z)：410[M+H]+。
Example 34: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -furo [2,3-d]Pyrimidine 2, 4-diamines
ESI-MS(m/z)：410[M+H]+。
Example 35: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：454[M+H]+。
Example 36: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -7-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：454[M+H]+。
Example 37: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -pyrido [3,2-d]Pyrimidine 2, 4-diamines
ESI-MS(m/z)：421[M+H]+。
Example 38: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -5,6,7, 8-tetrahydroquinazoline-2, 4-diamine
ESI-MS(m/z)：424[M+H]+。
Example 39: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6, 7-dihydro-5H-cyclopenta [ d]Quinazoline-2, 4-diamines
ESI-MS(m/z)：424[M+H]+。
Example 40: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -7-methyl-5, 6,7, 8-tetrahydropyridine [3,4-d]Pyrimidine-2, 4-diamines
ESI-MS(m/z)：439[M+H]+。
Example 41: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -N4-methyl-6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：468[M+H]+。
Example 42: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -N2-methyl-6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：468[M+H]+。
Example 43: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) methyl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：440[M+H]+。
Example 44: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-pyrrol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：404[M+H]+。
Example 45: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (5-fluoro-1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：472[M+H]+。
Example 46: n is a radical of4- (1H-indazol-5-yl) -N2- (2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：455[M+H]+。
Example 47: n is a radical of4- (1H-pyrazolo [3, 4-b)]Pyridin-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：455[M+H]+。
Example 48: n is a radical of4- (7-chloro-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：488[M+H]+。
Example 49: n is a radical of4- (7-bromo-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：532[M+H]+。
Example 50: n is a radical of4- (7-iodo-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：580[M+H]+。
Example 51: n is a radical of4- (7-methyl-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：468[M+H]+。
Example 52: n is a radical of4- (6-methyl-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：468[M+H]+。
Example 53: n is a radical of4- (6-fluoro-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：472[M+H]+。
Example 54: n is a radical of4- (4-methyl-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
ESI-MS(m/z)：468[M+H]+。
Example 55: in vitro enzyme inhibitory Activity Studies of partial products of the invention
Experimental materials:
Tecan
f500 microplate reader.
The experimental method comprises the following steps:
the first step is as follows: and (3) kinase reaction. A compound sample was first prepared as a 20mM solution in DMSO, and then diluted with a kinase reaction buffer solution to 100. mu.M, 10. mu.M, 1. mu.M, etc., as required for the test. PAK4 kinase (concentration 0.0256 ng/. mu.l), ATP (4. mu.M), biotin-labeled polypeptide substrate S2 (1. mu.M) and compound sample (4. mu.l) were then added to 10. mu.l kinase reaction buffer solution (containing MgCl25mM and DTT 1mM) and incubated at room temperature for 40 minutes, the kinase phosphorylates substrate S2. Then, 10. mu.l of a detection reagent containing EDTA was added to detect the phosphorylated product.
The second step is that: detecting the phosphorylated product. Rare earth element europium (Eu)3+) The labelled antibody recognises the phosphorylated substrate and XL665 labelled streptavidin binds to the biotin on the substrate. Eu (Eu)3+Is a fluorescence donor, XL665 is a fluorescence acceptor, when Eu3+Close to XL665, Eu3+The energy is transferred to XL665, which generates the HTRF signal.
And (3) a result evaluation method: the fluorescent signal is formed by Eu3+620nm and XL665 nm. The ratio of the HTRF signal (665/620) for each well plate reaction was calculated.
Computing IC50: with the addition of compound, the DF% of kinase activity is plotted on the Y-axis and the log of the concentration of compound is plotted on the X-axis. IC (integrated circuit)50Values were obtained by fitting the data to a quantitative response curve.
TABLE 3 percentage of PAK4 inhibitory Activity of some example compounds at 1. mu.M, 10. mu.M concentration in vitro
| Examples | 1 μ M inhibition rate | Inhibition rate of 10. mu.M |
| Example 1 | 93.75％ | 100％ |
| Example 2 | 72.60％ | 90.27％ |
| Example 3 | 81.59％ | 95.20％ |
| Example 4 | 84.30％ | 87.63％ |
| Example 5 | 80.17％ | 89.59％ |
| Example 8 | 94.10％ | 99.47％ |
| Example 9 | 94.37％ | 100％ |
| Example 20 | 92.90％ | 99.13％ |
| Example 21 | 93.42％ | 99.37％ |
| Example 22 | 88.52％ | 90.82％ |
| Example 23 | 85.81％ | 98.84％ |
| Example 28 | 52.70％ | 68.93％ |
| Example 29 | 52.67％ | 65.77％ |
| Example 30 | 51.39％ | 57.42％ |
| Example 31 | 50.27％ | 68.39％ |
| Example 32 | 50.11％ | 63.27％ |
| Example 35 | 84.24％ | 94.40％ |
| Example 36 | 67.39％ | 85.10％ |
Example 56: effect of partial products of the invention on tumor cell cycle and apoptosis
Cells of human A549 tumor cells in logarithmic growth phase were taken, and after 24 hours, various concentrations of compound 8 of example (administration group) and 0.1% DMSO (control group) were added. After 24h of action, collecting cells, digesting and centrifuging by pancreatin, removing supernatant, adding precooled PBS to wash for 1-2 times, blowing and transferring to a centrifuge tube, centrifuging for 10min, removing supernatant, adding 1mL of 70% cold ethanol to fix, and standing at-20 ℃ overnight. Washing with cold PBS for 1 time, centrifuging for 10min, removing the fixative, washing with PBS, adding RNase A, shaking, incubating at 37 deg.C for 1h, adding propidium iodide (PI,500 μ L), dark staining at 4 deg.C for 1h, detecting with FACSCalibur flow cytometer, and analyzing cell cycle with CellQuest software. As shown in table 4, example compound 8 can have a significant effect on the cell cycle of human a549 tumor cells.
Table 4 examples the effect that compound 8 can have on the cell cycle of human a549 tumor cells
| DMSO | 2 μmol Compound 8 | 3 μmol Compound 8 | 4 μmol Compound 8 | |
| Number of cells at G1 stage | 68.83％ | 73.84％ | 78.23％ | 83.65％ |
| Number of cells in s phase | 29.70％ | 22.09％ | 16.34％ | 12.20％ |
Example 57: the partial product of the invention has the activity of inhibiting the proliferation of tumor cells
The human A549 tumor cells were inoculated in RPMI-1640 medium containing 10% fetal bovine serum, 100U/mL penicillin, and 100. mu.g/mL streptomycin, and the culture flask was placed at 37 ℃ and 5% CO2Culturing in saturated humidity incubator with culture medium change every 1-2 days. When the cells grew enough to cover most of the surface of the bottom wall of the flask, adherent cells were digested with 0.25% trypsin and passaged.
Cells in logarithmic growth phase were cultured in 96-well plates at 37 ℃ in a volume of 100. mu.L/well (approximately 3000 tumor cells in each well) in 5% CO2Culturing in an incubator. The following day, the dosing groups were dosed with compounds containing different concentrations, 9-10 dose groups per cell, each group having at least three parallel wells. Adding solvent with the same volume as the administered group into the control group, standing at 37 deg.C and 5% CO2Culturing in an incubator. After 48 hours, the culture medium was discarded, and 50. mu.L of 1mg/mL MTT solution (media preparation) was added to each well. Incubate 4h at 37 ℃, discard the supernatant, add 150 μ L DMSO per well to dissolve formazan particles, and dissolve with gentle shaking. Measuring Optical Density (OD) value with enzyme labeling instrument at 490nm wavelength, using the cell treated with solvent control as control group, calculating the inhibition rate of drug on cell with the following formula, and obtaining the inhibition rate of each concentration according to the calculation. Experiments show that the compound 8 and the compound 35 of the embodiment can obviously inhibit the proliferation of human A549 tumor cells at the concentration of 2 mu mol.
The compounds of formula (I) and (II) of the present invention may be administered alone, but are generally administered in admixture with a pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice, the following procedures are respectively employed for the preparation of various pharmaceutical dosage forms of such compounds, e.g., tablets, capsules, injections, aerosols, suppositories, films, dripping pills, liniments and ointments, illustrating their novel use in the pharmaceutical arts.
Example 58: tablet formulation
10g of the compound of claim 1 (in the case of the compound of example 8) is mixed with 20g of excipients according to a general pharmaceutical tableting method, and the mixture is compressed into 100 tablets, wherein each tablet weighs 300 mg.
Example 59: capsule preparation
10g of the compound containing the compound in claim 1 (taking the compound in the example 8 as an example) is mixed with 20g of auxiliary materials according to the requirement of a pharmaceutical capsule, and then the mixture is filled into empty capsules, wherein each capsule weighs 300 mg.
Example 60: injection preparation
Using 10g of the compound of claim 1 (exemplified by the compound of example 8) as a carrier, adsorbing with activated carbon, filtering through a 0.65 μm microporous membrane, and filling into nitrogen gas bottles to obtain water-injection preparations (2 mL each) and filling 100 bottles in total.
Example 61: aerosol formulation
Dissolving 10g of the compound of claim 1 (example 8) in propylene glycol, adding distilled water and other additives, and making into 500mL of clear solution.
Example 62: suppository
50 suppositories are prepared by grinding 10g of the compound of claim 1 (example 8) with the appropriate amount of glycerin, mixing well, adding molten glycerin gelatin, grinding well, pouring into lubricant-coated molds
Example 63: film agent
Using 10g of the compound containing the compound of claim 1 (in the case of the compound of example 8), polyvinyl alcohol, medicinal glycerin, water and the like were swollen with stirring and then dissolved by heating, and then the compound of example 18 was added to the filtrate and dissolved with stirring, and 100 sheets were formed into a film by a film coating machine.
Example 64: drop pills
10g of the compound containing the compound of claim 1 (taking the compound in example 35 as an example) and 50g of a matrix such as gelatin are heated, melted and mixed uniformly, and then dropped into low-temperature liquid paraffin to prepare 1000 pills.
Example 65: external liniment
The compound of claim 1 (example 8) 10g is mixed with adjuvants such as emulsifier 2.5g, and then ground, and added with distilled water to 200 mL.
Example 66: ointment formulation
Prepared by grinding 10g of the compound containing the compound of claim 1 (taking the compound in example 35 as an example), and then uniformly grinding the ground product with 500g of an oily matrix such as vaseline.
While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims (7)
1. Novel pyrimidine derivatives shown in general formula (I) or (II) or pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
in the formula (I), the compound is shown in the specification,
Z1、Z2independently selected from C;
the A ring is selected from a benzene ring, a 5-6-membered aromatic heterocycle and a 5-7-membered saturated aliphatic ring; the aromatic heterocyclic ring is selected from furan ring, pyrrole ring, thiazole ring, oxazole ring, pyridine ring, pyrimidine ring and triazine ring, and the A ring can be further substituted by one or more RxSubstituted;
x, Y is selected from N, and may be substituted by-H, (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C6) Further substituted by fluoroalkyl;
ring B is selected from RxSubstituted or unsubstituted benzene ring, furan ring, thiophene ring, pyrrole ring, thiazole ring, oxazole ring, pyridine ring, pyrimidine ring, triazine ring;
n is an integer between 0 and 3;
m is selected from C-Ra，RaSelected from-H, (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C6) Fluoroalkyl, halogen;
the C ring may be further substituted by R selected from-H, halogen, (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C6) Fluoroalkyl, (C)1-C6) Fluorine-containing cycloalkyl, [ (C)1-C3) Alkylene radical]-[ (C3-C6) Cycloalkyl radicals]、(C2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)5-C7) Aryl group, (C)5-C7) Heteroaryl, - [ (C)1-C3) Alkylene radical]-[ (C5-C7) Aryl radicals]-、[(C1-C3) Alkylene radical]-[(C5-C7) Heteroaryl radical]And aryl and heteroaryl are optionally 1-3RxSubstitution;
Rxis-H, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido radical, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted aminomethylAcyl, (C)1-C3) An alkylenedioxy group;
in the formula (II), the compound is shown in the specification,
Z1、Z2independently selected from C;
the A ring is selected from a benzene ring, a 5-6-membered aromatic heterocycle and a 5-7-membered saturated aliphatic ring; the aromatic heterocyclic ring is selected from furan ring, pyrrole ring, thiazole ring, oxazole ring, pyridine ring, pyrimidine ring and triazine ring, and the A ring is further substituted by one or more RxSubstituted;
x, Y is selected from N, and may be substituted by-H, (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C6) Further substituted by fluoroalkyl;
ring B is selected from RxSubstituted or unsubstituted benzene ring, furan ring, thiophene ring, pyrrole ring, thiazole ring, oxazole ring, pyridine ring, pyrimidine ring, triazine ring;
n is an integer between 0 and 3;
m is selected from C-Ra，RaSelected from-H, (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C6) Fluoroalkyl, halogen;
the C ring may be further substituted by R selected from-H, halogen, (C)3-C6) Cycloalkyl group, (C)1-C6) Fluoroalkyl, (C)1-C6) Fluorine-containing cycloalkyl, [ (C)1-C3) Alkylene radical]-[ (C3-C6) Cycloalkyl radicals]、(C2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)5-C7) Aryl group, (C)5-C7) Heteroaryl, - [ (C)1-C3) Alkylene radical]-[ (C5-C7) Aryl radicals]-、[(C1-C3) Alkylene radical]-[(C5-C7) Heteroaryl radical]And aryl and heteroaryl are optionally 1-3RxSubstitution;
Rxis hydroxy, halogen, nitro, amino, cyano, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido radical, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group.
2. The novel pyrimidine derivative represented by the general formula (I) or (II) according to claim 1, wherein,
n is an integer of 1 or 2.
3. The following novel pyrimidine derivatives or pharmaceutically acceptable salts thereof are selected from:
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) quinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6-methoxyquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -7-methoxyquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -thieno [3,2-d]Pyrimidine 2, 4-diamines
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -thieno [2,3-d]Pyrimidine 2, 4-diamines
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -furo [3,2-d]Pyrimidine 2, 4-diamines
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -furo [2,3-d]Pyrimidine 2, 4-diamines
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -7-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -pyrido [3,2-d]Pyrimidine 2, 4-diamines
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -5,6,7, 8-tetrahydroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6, 7-dihydro-5H-cyclopenta [ d]Quinazoline-2, 4-diamines
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -7-methyl-5, 6,7, 8-tetrahydropyridine [3,4-d]Pyrimidine-2, 4-diamines
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -N4-methyl-6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -N2-methyl-6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) methyl) -N2- (1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-pyrrol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (5-fluoro-1H-indol-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethyl) -N2- (1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (1H-pyrazolo [3, 4-b)]Pyridin-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (7-chloro-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (7-bromo-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (7-iodo-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (7-methyl-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (6-methyl-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (6-fluoro-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (2- (1H-indol-3-yl) ethyl) -N2- (4-methyl-1H-indazol-5-yl) -6-chloroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -7-chloroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -pyrido [3,2-d]Pyrimidine 2, 4-diamines
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -5,6,7, 8-tetrahydroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6, 7-dihydro-5H-cyclopenta [ d]Quinazoline-2, 4-diamines
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -7-methyl-5, 6,7, 8-tetrahydropyridine [3,4-d]Pyrimidine-2, 4-diamines
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -N4-methyl-6-chloroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -N2-methyl-6-chloroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) methyl) -6-chloroquinazoline-2, 4-diamine
N4- (1H-indazole)-5-yl) -N2- (2- (1H-pyrrol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (5-fluoro-1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (1H-indazol-5-yl) -N2- (2- (1H-pyrrolo [3, 2-b)]Pyridin-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (1H-pyrazolo [3, 4-b)]Pyridin-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (7-chloro-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (7-bromo-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (7-iodo-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (7-methyl-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (6-methyl-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (6-fluoro-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine
N4- (4-methyl-1H-indazol-5-yl) -N2- (2- (1H-indol-3-yl) ethyl) -6-chloroquinazoline-2, 4-diamine.
4. A pharmaceutical composition comprising a pyrimidine derivative as claimed in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier.
5. Use of a pyrimidine derivative as claimed in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a composition as claimed in claim 4 in the manufacture of a medicament for the treatment and/or prophylaxis of proliferative diseases.
6. Use of a pyrimidine derivative as claimed in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a composition as claimed in claim 4 in the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
7. Use of a pyrimidine derivative as defined in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a composition as defined in claim 4 for the preparation of an inhibitor of p21-activated kinase.
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| CN101328186A (en) * | 1997-11-11 | 2008-12-24 | 辉瑞产品公司 | Thienopyrimidine and thienopyridine derivatives useful as anticancer agents |
| WO2003030909A1 (en) * | 2001-09-25 | 2003-04-17 | Bayer Pharmaceuticals Corporation | 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer |
| WO2003059913A1 (en) * | 2002-01-10 | 2003-07-24 | Bayer Healthcare Ag | Roh-kinase inhibitors |
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