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NZ745349B2 - Urea compound, preparation method therefor and medical use thereof - Google Patents

Urea compound, preparation method therefor and medical use thereof Download PDF

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Publication number
NZ745349B2
NZ745349B2 NZ745349A NZ74534917A NZ745349B2 NZ 745349 B2 NZ745349 B2 NZ 745349B2 NZ 745349 A NZ745349 A NZ 745349A NZ 74534917 A NZ74534917 A NZ 74534917A NZ 745349 B2 NZ745349 B2 NZ 745349B2
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New Zealand
Prior art keywords
phenyl
butyl
tert
urea
benzimidazolyl
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NZ745349A
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NZ745349A (en
Inventor
Meifeng Jiang
Jutong Si
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Ancureall Pharmaceutical (Shanghai) Co Ltd
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Publication date
Priority claimed from CN201610142049.XA external-priority patent/CN107176951A/en
Application filed by Ancureall Pharmaceutical (Shanghai) Co Ltd filed Critical Ancureall Pharmaceutical (Shanghai) Co Ltd
Publication of NZ745349A publication Critical patent/NZ745349A/en
Publication of NZ745349B2 publication Critical patent/NZ745349B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • 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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

Provided are a urea compound represented by general formula (I), a pharmaceutically acceptable salt thereof, and a preparation method therefor, and use thereof as an FLT3 tyrosine protein kinase inhibitor, particularly in the prevention and/or treating of cancers.

Claims (17)

What is claimed is:
1. A compound of general formula (I) or the pharmaceutically acceptable salts thereof, Wherein: the group is selected from the following structure: R and R are each independently selected from the group consisting of hydrogen, halogen, C -C alkyl, C -C alkoxy, C -C haloalkyl, C -C haloalkoxy; 1 6 1 6 1 6 1 6 W and Z are each independently selected from N and C-BR ; In the absence of R , B is identical or different and each is independently selected from the group consisting of hydrogen, halogen, and C -C alkyl, said C -C alkyl is 1 6 1 6 optionally further substituted by one or more of Q groups; In the presence of R , B is identical or different and each is independently selected from the group consisting of -O- and -NR -; and R is identical or different and each is independently selected from the group consisting of hydrogen, C -C alkyl, C -C 1 10 3 7 cycloalkyl, 5- to 7-membered heterocyclyl, C -C aryl, 5- to 7-membered heteroaryl, u x u x u y z y z u y z -R OR , -R C (O) OR , -R N(R )(R ), -C(O)N(R )(R ), -R S(O) N(R )(R ), -R S(O) R ; the C -C alkyl, C -C cycloalkyl, 5- to 7-membered heterocyclyl, C -C n 1 10 3 7 5 7 aryl, 5- to 7-membered heteroaryl groups are optionally further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxy, alkyl, alkoxy, hydroxyalkyl, hydroxyalkoxy, amido, cycloalkyl, heterocyclyl, aryl, haloaryl, heteroaryl, cycloalkyl-heteroaryl; R is selected from the group consisting of hydrogen, and C -C alkyl, or R and R together with the nitrogen atom attached 1 10 4 1 them form a 5- to 7-membered heterocyclyl group, and the 5- to 7-membered heterocyclyl group is optionally further substituted by one or more groups selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy; When R is hydrogen, G is selected from 5-membered heteroaryl, and the 5-membered heteroaryl is optionally further substituted by one or more groups selected from the group consisting of halogen, C -C alkyl, C -C alkoxy, amino, 1 6 1 6 -C(O)R wherein R is C -C alkyl, C -C cycloalkyl, 5- to 7-membered heterocyclic, 1 6 3 7 C -C aryl, and 5- to 7-membered heteroaryl, wherein said C -C alkyl, C -C alkoxy, 5 7 1 6 1 6 C -C cycloalkyl, 5- to 7-membered heterocyclic, C -C aryl, or 5- to 7-membered 3 7 5 7 heteroaryl is optionally further substituted by one or more groups selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, alkoxy, halo alkoxy, cycloalkyl, and -C(O)OR wherein R is C -C alkyl ; or, When R is not hydrogen, G and R together with the nitrogen atom attached them form a 5-membered heteroaryl, the 5-membered heteroaryl group is optionally further substituted by one or more groups selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, C3-C7 cycloalkyl, 5- to 7-membered heterocyclyl, C -C aryl, and 5- to 7-membered heteroaryl, wherein said C -C alkyl, C -C alkoxy, 5 7 1 6 1 6 C -C cycloalkyl, 5- to 7-membered heterocyclyl, C -C aryl, or 5- to 7-membered 3 7 5 7 heteroaryl is optionally further substituted by one or more groups selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, and -C(O)OR wherein R is C -C alkyl ; R is hydrogen; R is selected from a bond, or C -C alkylene; R is selected from hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6haloalkyl; or u x u x The oxygen in -R OR - together with R and R attached to them form an oxygen-containing 3-7 membered heterocyclic ring, which is optionally substituted by one or more of Q groups; R and R are each independently selected from the group consisting of hydrogen, C -C alkyl, C -C cycloalkyl, and C -C haloalkyl; or, 1 6 3 7 1 6 R and R together with the nitrogen atom attached to them form a 5- to 7-membered heterocyclyl, and the 5- to 7-membered heterocyclyl is optionally further substituted by one or more groups selected from the group consisting of halogen, haloalkyl, and alkyl groups; Q is selected from the group consisting of hydrogen, halogen, amino, C -C alkyl, C -C alkoxy, C -C cycloalkyl, 5- to 7-membered heterocyclyl, and the amino, 1 6 3 7 C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 5- to 7-membered heterocyclyl is optionally further substituted by one or more groups selected from the group consisting of hydroxy, halogen and alkyl; n is an integer from 0 to 2.
2. The compound of general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein W, Z are selected from the following four ways: a) W and Z are CQ; b) W and Z are N; C) W is CQ and Z is N; d) Z is CQ and W is N; wherein, Q is selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, C -C alkyl, C -C haloalkyl, C -C alkoxy, C -C haloalkoxy, C -C 1 6 1 6 1 6 1 6 3 7 cycloalkyl, C -C aryl, 5- to 7-membered heterocyclyl group, and 5- to 7-membered heteroaryl group.
3. The compound of general formula (I) or the pharmaceutically acceptable salt thereof according to any one of claims 1or 2, wherein, In the absence of R , B is selected from the group consisting of hydrogen, halogen, C -C alkyl, C -C haloalkyl; 1 6 1 6 In the presence of R , B is identical or different and each is independently selected from -O- and -NR4-, preferably -O-; and Rl is identical or different and each is independently selected from the group consisting of hydrogen, C -C alkyl, and the alkyl is optionally further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxy, C -C alkoxy, 4- to 6-membered heterocyclyl group, C5-C7 aryl, C5-C7 haloaryl, 5- to 7-membered heteroaryl group, C3-C6 cycloalkyl or 7-membered heteroaryl group, wherein the 4- to 6-membered heterocyclyl group is preferably selected from a 4- to 6-membered heterocyclyl group containing oxygen or nitrogen; and the C -C aryl or C -C haloaryl is preferably 5 7 5 7 phenyl or halophenyl; R is as defined in claim 1.
4. The compound of general formula (I) or the pharmaceutically acceptable salt thereof according to claims 1 or 2, wherein, In the absence of R , B is selected from the group consisting of hydrogen, halogen, C -C alkyl, C -C haloalkyl; 1 6 1 6 In the presence of R , B is identical or different and each is independently selected from -O- and -NR4-, preferably -O-; and Rl is identical or different and is each u x u x independently selected from -R OR -, wherein R is selected from C -C alkylene, R is selected from hydrogen, C -C alkyl, C -C hydroxyalkyl, and C -C haloalkyl; 1 6 1 6 1 6 R is as defined in claim 1.
5. The compound of general formula (I) or the pharmaceutically acceptable salt thereof according to claims 1 or 2, wherein, In the absence of R , B is selected from the group consisting of hydrogen, halogen, C -C alkyl, C -C haloalkyl; 1 6 1 6 In the presence of R , B is identical or different and each is independently selected from -O- and -NR -, preferably -O-; and R is identical or different and is each y z y z independently selected from –C(O)N(R )(R ), wherein R and R are each independently selected from the group consisting of hydrogen, C -C alkyl, C -C 1 6 1 6 haloalkyl, and C -C cycloalkyl; or, R and R together with the nitrogen atom attached to them form a 5- to 7-membered heterocyclyl group, preferably a 6-membered heterocyclyl group, more preferably morpholinyl, piperidinyl, piperazinyl; the 5- to 7-membered heterocyclyl group is optionally further substituted by one or more groups selected from the group consisting of halogen, C -C alkyl, C -C haloalkyl; 1 6 1 6 R is as defined in claim 1.
6. The compound of general formula (I) or the pharmaceutically acceptable salt thereof according to claims 1or 2, wherein, In the absence of Rl, B is selected from the group consisting of hydrogen, halogen, C -C alkyl, C -C haloalkyl; 1 6 1 6 In the presence of R , B is identical or different and each is independently selected from -O- or -NR -, preferably -O-; and R is identical or different and is each u y z u independently selected from -R N(R )(R ), wherein R is selected from C1-C6 alkylene; R and R are each independently selected from the group consisting of hydrogen, C -C alkyl, C -C haloalkyl, C -C cycloalkyl; or, 1 6 1 6 3 7 R and R together with the nitrogen atom attached to them form a 5- to 7-membered heterocyclyl group, preferably morpholinyl, piperidinyl, piperazinyl, azepanyl, and the 5- to 7-membered heterocyclyl group is optionally further substituted by one or more groups selected from the group consisting of halogen, C -C alkyl, and C -C 1 6 1 6 haloalkyl; R4 is as defined in claim 1.
7. The compound of general formula (I) or the pharmaceutically acceptable salt thereof according to claims 1 or 2, wherein, In the absence of R , B is selected from the group consisting of hydrogen, halogen, C -C alkyl, C -C haloalkyl; 1 6 1 6 In the presence of R , B is identical or different and each is independently selected from -O- or -NR -, preferably -O-; and R is identical or different and is each u x u independently selected from -R C(O)OR , wherein, R is selected from C -C alkylene; R is selected from the group consisting of hydrogen, C -C alkyl, C -C 1 6 1 6 hydroxyalkyl, C -C haloalkyl; R is as defined in claim 1.
8. The compound of general formula (I) or the pharmaceutically acceptable salt thereof according to claims 1or 2, wherein, In the absence of R , B is selected from the group consisting of hydrogen, halogen, C -C alkyl, C -C haloalkyl; 1 6 1 6 In the presence of R , B is identical or different and each is independently selected from -O- or -NR -, preferably -O-; and R is identical or different and is each independently selected from thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl, phenyl, pyridyl, and pyrimidinyl,which is optionally further substituted by one or more groups selected from the group consisting of C3-C6 cycloalkyl groups, 5- to 7-membered heterocyclyl groups, and amido group; R4 is as defined in claim 1.
9. The compound of general formula (I) or the pharmaceutically acceptable salt thereof according to any one of claims 3 to 8, wherein, R is selected from selected from hydrogen and C -C alkyl, or 4 1 6 R and R together with the nitrogen atom attached to them form a 5- to 7-membered heterocyclyl group, preferably piperidinyl, piperazinyl, morpholinyl, pyridyl, pyrimidinyl, and the 5- to 7-membered heterocyclyl group is optionally further substituted by one or more groups selected from the group consisting of halogen, C -C alkyl, C -C haloalkyl, C -C alkoxyl, C -C haloalkoxyl. 1 6 1 6 1 6 1 6
10. The compound of general formula (I) or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein, When R is hydrogen, G is selected from which is optionally further substituted by one or more groups selected from the group consisting of halogen, C -C alkyl, C -C haloalkyl, C -C alkoxy, C -C haloalkoxy, 1 6 1 6 1 6 1 6 amino, -C(O)R wherein R is C -C alkyl, C -C cycloalkyl, 5- to 7-membered 1 6 3 7 heterocyclyl group , C -C aryl,and 5- to 7-membered heteroaryl group; the C -C 5 7 1 6 alkyl, C -C alkoxyl, C -C cycloalkyl, 5- to 7-membered heterocyclyl group, C -C 1 6 3 7 5 7 aryl, or 5- to 7-membered heteroaryl group is optionally further substituted by one or more groups selected from the group consisting of halogen, hydroxy, C -C alkyl, C -C alkoxy, C -C haloalkyl, C -C haloalkoxy, and -C(O)OR wherein R is C -C 1 6 1 6 1 6 1 6 alkyl; or When R is not hydrogen, G and R2 together with the nitrogen atom attached to them form pyrrolyl, pyrazolyl, imidazolyl; which is optionally further substituted by one or more groups selected from the group consisting of halogen, C -C alkyl, C -C 1 6 1 6 haloalkyl, C -C alkoxy, C -C haloalkoxy, hydroxy, amino, C -C cycloalkyl, 5- to 1 6 1 6 3 7 7-membered heterocyclyl group, C -C aryl group, and 5- to 7-membered heteroaryl group.
11. A compoundor the pharmaceutically acceptable salt thereofwherein, the compound is selected from the group consisting of: 1-(4-benzimidazolyl-phenyl)3-isoxazolyl-urea; 1-(4-benzimidazolyl-phenyl)(5-methyl-isoxazolyl)-urea; 1-(4-benzimidazolyl-phenyl)(5-tert-butyl-isoxazolyl)-urea; 1-(5-tert-butyl-isoxazolyl)[4-(5-hydroxy-benzimidazolyl)-phenyl]-urea; 1-(5-tert-butyl-isoxazolyl)[4-(5-methoxyl-benzimidazolyl)-phenyl]-urea; 1-(5-tert-butyl-isoxazolyl)[4-(5-ethoxyl-benzimidazolyl)-phenyl]-urea; 1-(5-tert-butyl-isoxazolyl)[4-(5-hexyloxyl-benzimidazolyl)-phenyl]-urea; 1-(5-tert-butyl-isoxazolyl)[4-(5-isopropoxy-benzimidazolyl)-phenyl]-urea; l-(5-tert-butyl-isoxazolyl){4-[5-(3-methyl-oxetanylmethoxy)-benzimidazol-1 -yl]-phenyl}-urea; 1-(5-tert-butyl-isoxazolyl){4-[5-(tetrahydrofuranylmethoxy)-benzimidazol yl]-phenyl}-urea; 1-(5-tert-butyl-isoxazolyl){4-[5-(2-hydroxy-ethoxyl)-benzimidazolyl]-phenyl] urea; 1-(5-tert-butyl-isoxazolyl){4-[5-(2-methoxyl-ethoxyl)-benzimidazolyl]-phen yl] urea; 1-(5-tert-butyl-isoxazolyl){4-[5-(2-ethoxyl-ethoxyl)-benzimidazolyl]-phenyl] urea; 1-(5-tert-butyl-isoxazolyl)(4-{5-[2-(2-hydroxy-ethoxyl)-ethoxyl]-benzimidazol- 1-yl}-phenyl)-urea; 1-{4-[3-(5-tert-butyl-isoxazolyl)-carbamido]-phenyl}-1H-benzimidazolyl morpholinecarboxylicate; 1-(5-tert-butyl-isoxazolyl){4-[5-(2-morpholinyl-ethoxyl)-benzimidazolyl]- phenyl}-urea; 1-(5-tert-butyl-isoxazolyl){4-[5-(2-piperidineyl-ethoxyl)-benzimidazolyl]- phenyl}-urea; 1-{4-[5-(2-azacycloheptanyl-ethoxyl)-benzimidazolyl]-phenyl}(5-tert-butyl-i soxazolyl)-urea; 1-(5-tert-butyl-isoxazolyl)(4-{5-[3-(4-methyl-piperazinyl)-propoxyl]-benzimi dazolyl}-phenyl)-urea; 1-(5-tert-butyl-isoxazolyl){4-[5-(2-dimethylamino-ethoxyl)-benzimidazolyl]- phenyl}-urea; 1-(5-tert-butyl-isoxazolyl)[4-(5-trifluoromethoxy-benzimidazolyl)-phenyl]-ur 1-(5-tert-butyl-isoxazolyl)[4-(5-fluor-benzimidazolyl)-phenyl]-urea; 1-(5-tert-butyl-isoxazolyl)[4-(5-trifluoromethyl-benzimidazolyl)-phenyl]-ure 1-(5-tert-butyl-isoxazolyl)[4-(5-methyl-benzimidazolyl)-phenyl]-urea; 1-(5-tert-butyl-isoxazolyl)[4-(6-methoxyl-benzimidazolyl)-phenyl]-urea; 1-(5-tert-butyl-isoxazolyl){4-[6-(2-methoxyl-ethoxyl)-benzimidazolyl]-phen yl] urea; 1-(5-tert-butyl-isoxazolyl){4-[6-(2-morpholinyl-ethoxyl)-benzimidazolyl]- phenyl}-urea; 1-(5-tert-butyl-isoxazolyl)(4-{6-[(2-dimethylamino-ethyl)-methyl-amino]-benzi midazolyl}-phenyl)-urea; 1-(5-tert-butyl-isoxazolyl){4-[6-(4-methyl-piperazinyl)-benzimidazolyl]-p henyl}-urea; 1-(5-tert-butyl-isoxazolyl){4-[7-(2-morpholinyl-ethoxyl)-benzimidazolyl]- phenyl}-urea; 1-(5-tert-butyl-isoxazolyl)[4-(5,6-dimethoxyl-benzimidazolyl)-phenyl]-urea; l-(5-tert-butyl-isoxazolyl)[4-(5,6-dimethyl-benzimidazolyl)-phenyl]-urea; 1-(5-tert-butyl-isoxazolyl)[4-(5-fluoromethyl-benzimidazolyl)-phenyl]-ure 1-(5-tert-butyl-isoxazolyl)[4-(4-fluor-benzimidazolyl)-phenyl]-urea; 1-(5-tert-butyl-isoxazolyl)[4-(2-methyl-benzimidazolyl)-phenyl]-urea; 1-(5-tert-butyl-isoxazolyl)[4-(2-chlorobenzimidazoleyl)-phenyl]-urea; 1-(4-benzimidazolylmethyl-phenyl)(5-tert-butyl-isoxazolyl)-urea; 1-(4-benzimidazolylchloro-phenyl)(5-tert-butyl-isoxazolyl)-urea; 1-(4-benzimidazolylfluoro-phenyl)(5-tert-butyl-isoxazolyl)-urea; 1-(4-benzimidazolyl-3, 5-difluoro-phenyl)(5-tert-butyl-isoxazolyl)-urea; 1-(4-benzimidazolylchloro-phenyl)(5-tert-butyl-isoxazolyl)-urea; 1-(6-benzimidazolyl-pyridinyl)(5-tert-butyl-isoxazolyl)-urea; 1-(2-benzimidazolyl-pyrimidinyl)(5-tert-butyl-isoxazolyl)-urea; 1-(5-tert-butyl-isoxazolyl)(4-indazolyl-phenyl)-urea; 1-(5-tert-butyl-isoxazolyl)[4-(6-fluoro-indazolyl)-phenyl]-urea; 1-(5-tert-butyl-isoxazolyl)[4-(7-fluoro-indazolyl)-phenyl]-urea; 1-(4-benzotriazolyl-phenyl)(5-tert-butyl-isoxazolyl)-urea; 1-(5-tert-butyl-isoxazolyl)(4-pyrrolo[2,3-b]pyridinyl-phenyl)-urea; 1-(5-tert-butyl-isoxazolyl)(4-imidazo[4,5-b]pyridinyl-phenyl)-urea; 1-[4-(6-bromo-imidazo[4,5-b]pyridinyl)-phenyl](5-tert-butyl-isoxazolyl)-ure 1-(5-tert-butyl-isoxazolyl)[4-(6-trifluoromethyl-imidazo[4,5-b]pyridinyl)-phe nyl]-urea; 1-(5-tert-butyl-isoxazolyl)[4-(5-chloroimidazo[4,5-b]pyridinyl)-phenyl]-urea; 1-(5-tert-butyl-isoxazolyl)[4-(5-methylimidazo[4,5-b]pyridinyl)-phenyl]-urea 1-(5-tert-butyl-isoxazolyl)[4-(7-methylimidazo[4,5-b]pyridinyl)-phenyl]-urea 1-(5-tert-butyl-isoxazolyl)(4-imidazo[4,5-b]pyridinyl-phenyl)-urea; 1-(5-tert-butyl-isoxazolyl)[4-(6-methoxyl-purinyl)-phenyl]-urea; 1-(5-tert-butyl-isoxazolyl)[4-(6-methoxyl-purinyl)-phenyl]-urea; 1-(5-tert-butyl-isoxazolyl)[4-(6-dimethylamino-purineyl)-phenyl]-urea; 1-(4-benzimidazolyl-phenyl)thiazolyl-urea; 1-(4-benzimidazolyl-phenyl)(4-methyl-thiazoleyl)-urea; 1-(4-benzimidazolyl-phenyl)[1,3,4]thiadiazoleyl-urea; 1-(4-benzimidazolyl-phenyl)(5-tert-butyl-[1,3,4]thiadiazoleyl)-urea; 1-(4-benzimidazolyl-phenyl)(5-methyl-1H-pyrazolyl)-urea; 1-(4-benzimidazolyl-phenyl)(5-phenyl-1H-pyrazolyl)-urea; 1-(4-benzimidazolyl-phenyl)(5-cyclopropyl-2H-pyrazolyl)-urea; l-(4-benzimidazolyl-phenyl)(5-trifluoromethyl-2H-pyrazoleyl)-urea; 1-(4-benzimidazolyl-phenyl)(5-tert-butyl-2H-pyrazoleyl)-urea; 1-(5-tert-butyl-2H-pyrazoleyl)[4-(5-fluor-benzimidazolyl)-phenyl]-urea; 1-(5-tert-butyl-2H-pyrazoleyl)[4-(5-trifluoromethyl-benzimidazolyl)-phenyl] -urea; 1-(5-tert-butyl-2H-pyrazoleyl)[4-(5-methoxyl-benzimidazolyl)-phenyl]-urea; 1-(5-tert-butyl-2H-pyrazoleyl)[4-(5-ethoxyl-benzimidazolyl)-phenyl]-urea; 1-(5-tert-butyl-2H-pyrazoleyl)[4-(5-hexyloxyl-benzimidazolyl)-phenyl]-urea; 1-(5-tert-butyl-2H-pyrazoleyl)[4-(5-isopropoxy-benzimidazolyl)-phenyl]-ure 1-[4-(5-sec-butoxyl-benzimidazolyl)-phenyl](5-tert-butyl-2H-pyrazolyl)-urea 1-(5-tert-butyl-2H-pyrazolyl)[4-(5-isobutoxy-benzimidazolyl)-phenyl]-urea; 1-(5-tert-butyl-2H-pyrazolyl){4-[5-(2-methoxyl-ethoxyl)-benzimidazolyl]-ph enyl}-urea; 1-(5-tert-butyl-2H-pyrazolyl){4-[5-(2-ethoxyl-ethoxyl)-benzimidazolyl]-phe nyl}-urea; 1-(5-tert-butyl-2H-pyrazolyl){4-[5-(2-hydroxy-ethoxyl)-benzimidazolyl]-phe nyl] urea; 1-(5-tert-butyl-2H-pyrazolyl){4-[5-(2-hydroxymethoxyl-propoxyl)-benzimid azolyl]-phenyl] urea; 1-(5-tert-butyl-2H-pyrazolyl){4-[5-(3-dimethylamino-propoxyl)-benzimidazol-1 -yl]-phenyl }-urea; 1-(5-tert-butyl-2H-pyrazolyl){4-[5-(3-dibutylaminopropyloxyl)-benzimidazol-1 -yl]-phenyl }-urea; 1-(5-tert-butyl-2H-pyrazolyl)[4-(5-cyanomethoxy-benzimidazolyl)-phenyl]-u 1-(5-tert-butyl-2H-pyrazolyl)[4-(5-trifluoromethoxy-benzimidazolyl)-phenyl] -urea; 1-(5-tert-butyl-2H-pyrazolyl){4-[5-(3-methyl-oxetanylmethoxy)-benzimidaz ole yl]-phenyl] urea; 1-(5-tert-butyl-2H-pyrazolyl){4-[5-(tetrahydrofuranylmethoxyl)-benzimidazo lyl]-phenyl}-urea; 1-(5-tert-butyl-2H-pyrazolyl){4-[5-(tetrahydrofuranylmethoxyl)-benzimidazo lyl]-phenyl}-urea; Ethyl (1-{4-[3-(5-tert-butyl-2H-pyrazoleyl)-carbamido]-phenyl}-1H-benzimidazol yloxy)- acetate; 1-(5-tert-butyl-2H-pyrazolyl){4-[5-(2-morpholinyl-ethoxyl)-benzimidazol yl]-phenyl}-urea; 1-(5-tert-butyl-2H-pyrazolyl){4-[5-(2-piperidineyl-ethoxyl)-benzimidazol yl]-phenyl}-urea; 1-{4-[5-(2-azacycloheptanyl-ethoxyl)-benzimidazolyl]-phenyl}(5-tert-butyl- 2H-pyrazolyl)-urea; 1-(5-tert-butyl-2H-pyrazolyl)(4-{5-[3-(4-methyl-piperazinyl)-propoxyl]-benz imidazolyl}-phenyl)-urea; 1-(5-tert-butyl-2H-pyrazolyl){4-[5-(3-fluoro-benzyloxy)-benzimidazolyl]-ph enyl] urea; 1-(5-tert-butyl-2H-pyrazolyl)(4-{5-[4-(1-cyclohexyl-1H-tetrazolyl)-butoxy]- benzimidazolyl}-phenyl)-urea; 1-(5-tert-butyl-2H-pyrazolyl){4-[5-(4-morpholinyl-[1,2,5]thiadiazolyloxy) -benzimidazolyl]-phenyl] urea; 4-(1-{4-[3-(5-tert-butyl-2H-pyrazolyl)-carbamido]-phenyl}-lH-benzimidazolylo xy)-pyridincarboxylic acid methylamine; 1-(5-tert-butyl-2H-pyrazolyl)[4-(5-fluoromethyl-benzimidazolyl)-phenyl]- urea; 1-(5-tert-butyl-2H-pyrazolyl){4-[6-(2-methoxyl-ethoxyl)-benzimidazolyl]-ph enyl}-urea; 1-(5-tert-butyl-2H-pyrazolyl)[4-(5,6-dimethoxyl-benzimidazolyl)-phenyl]-ur 1-(4-benzimidazolyl-phenyl)(5-tert-butylmethyl-2H-pyrazolyl)-urea; 1-(5-tert-butylmethyl-2H-pyrazolyl){4-[5-(2-methoxyl-ethoxyl)-benzimidazo lyl]-phenyl] urea; 1-(5-tert-butylmethyl-2H-pyrazolyl){4-[5-(2-morpholinyl-methoxyl)-benz imidazolyl]-phenyl}-urea; 1-(4-benzimidazolyl-phenyl)[5-tert-butyl(2-hydroxy-ethyl)-2H-pyrazolyl]- urea; 1-(4-benzimidazolyl-phenyl)(5-tert-butylphenyl-2H-pyrazolyl)-urea; 1-(4-benzimidazolyl-phenyl)(5-tert-butylp-tolyl--2H-pyrazolyl)-urea; 1-(4-benzimidazolyl-phenyl)[5-tert-butyl(4-methoxyl-phenyl)-2H-pyrazole-3 -yl]-urea; 1-(4-benzimidazolyl-phenyl)[5-tert-butyl(4-trifluoromethoxy-phenyl)-2H-pyr azolyl]-urea; 1-(4-benzimidazolyl-phenyl)[5-tert-butyl(4-fluoro-phenyl)-2H-pyrazolyl]- urea; 1-(4-benzimidazolyl-phenyl)[5-tert-butyl(2-fluoro-phenyl)-2H-pyrazolyl]- urea; 1-(4-benzimidazolyl-phenyl)(5-tert-butylpyridinyl-2H-pyrazolyl)-urea; 4-{5-[3-(4-benzimidazolyl-phenyl)-carbamido]tert-butyl-pyrazolyl}-benzoat 1-(4-( 1H-benzo[d]imidazolyl)phenyl)(1-acryloyl(tert-butyl)- 1H-pyrazolyl) urea; 3-aminomethylpyrazolcarboxylic acid (4-benzimidazolyl-phenyl)-amide; 5-aminocyclopropylpyrazolcarboxylic acid (4-benzimidazolyl-phenyl)-amide; 5-aminotrifluoromethylpyrazolcarboxylic acid (4-benzimidazolyl-phenyl)-amide; 5-aminotert-butyl-pyrazolcarboxylic acid (4-benzimidazolyl-phenyl)-amide; 5-aminotert-butyl-pyrazolcarboxylic acid [4-(5-hexyloxyl-benzimidazolyl)-phenyl]-amide; 5-aminotert-butyl-pyrazolcarboxylic acid (4-{5-[3-(4-methyl-piperazinyl)-propoxyl]-benzimidazolyl}phenyl)-amide; 5-aminotert-butyl-pyrazolcarboxylic acid {4-[5-(2-morpholinyl-ethoxyl)-benzimidazolyl]-phenyl}-amide; 5-aminotert-butyl-pyrazolcarboxylic acid {4-[5-(2-methoxyl-ethoxyl)-benzimidazolyl]-phenyl}-amide; 5-aminotert-butyl-pyrazolcarboxylic acid {4-[5-(2-hydroxy-ethoxyl)-benzimidazolyl]-phenyl}-amide; 5-aminotert-butyl-pyrazolcarboxylic acid {4-[5-(tetrahydrofuranylmethoxyl)-benzimidazolyl]-phenyl}-amide; 5-aminotert-butyl-pyrazolcarboxylic acid {4-[5-(tetrahydrofuranylmethoxy)-benzimidazolyl]-phenyl}-amide; (1-{4-[(5-aminotert-butyl-pyrazolcarbonyl)-amino]-phenyl}-1H-benzimidazol-5 -yloxyl)-acetic acid; 5-aminotert-butyl-pyrazolcarboxylic acid [4-(5-fluoro-benzimidazolyl)-phenyl]-amide; 5-aminotert-butyl-pyrazolcarboxylic acid [4-(5-trifluoromethyl-benzimidazolyl)-phenyl]-amide; 4-(1-{4-[(5-aminotert-butyl-pyrazolcarbonyl)-amino]-phenyl}-1H-benzimidazol yloxyl)-pyridincarboxylate acid methylamide 5-aminotert-butyl-pyrazolcarboxylic acid {4-[6-(2-methoxyl-ethoxyl)-benzimidazolyl]-phenyl}-amide; 5-aminotert-butyl-pyrazolcarboxylic acid [4-(5,6-dimethoxyl-benzimidazolyl)-phenyl]-amide; 3-tert-butyl-pyrazolcarboxylic acid (4-benzimidazolyl-phenyl)-amide; 1-(4-benzimidazolyl-phenyl)(3,4-dimethyl-isoxazolyl)-urea; 1-(4-benzimidazolyl-phenyl)(3-isopropyl-isoxazolyl)-urea; 1-(4-benzimidazolyl-phenyl)(3-tert-butyl-isoxazolyl)-urea.
12. A method for preparing a compound of general formula (I) or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, comprising the following steps: B X N A B Y Solvent Z Base ( ?) N ( ?) NH the compound of formula (II) is reacted with a compound of formula (III) in the present of a base in a suitable solvent at a suitable temperature and pH to give the compound of general formula (I); the solvent is preferably THF, acetonitrile, dichloromethane, or toluene, and the base is preferably triethylamine, N,N-diisopropylethylamine, DMAP, or pyridine; X, Y, A, Al, Z, W, Rl, B, R2, G, R3 are as defined in claim 1.
13. A method for preparing a compound of general formula (I) or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, comprising the following steps: Solvent ( ?) ( ?) N ( ?) R the compound of formula (IV) is reacted with the compound of formula (V) in the present of a base in a suitable solvent at a suitable temperature and pH to give the compound of general formula (I); the solvent is preferably THF, acetonitrile, dichloromethane, or toluene, and the base is preferably triethylamine, N,N-diisopropylamine, DMAP, or pyridine; X, Y, A, Al, Z, W, Rl, B, R2, G, R3 are as defined in claim 1.
14. A pharmaceutical composition comprising a therapeutically effective amount of the compound of general formula (I) or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, as well as one or more pharmaceutically acceptable carriers.
15. Use of a compound of general formula (I) or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, or a pharmaceutical composition according to claim 14 in the preparation of medicaments for the prevention and/ or treatment of cancers in mammals including humans, wherein the compound acts via the FTL3 tyrosine protein kinase modulation pathway.
16. The use according to claim 15, wherein the cancer includes non-solid tumors such as leukemia, solid tumors such as skin cancer, melanoma, lung cancer, gastric cancer, breast cancer, pancreatic cancer, liver cancer, and colon cancer.
17. The use according to claim 15 or 16, wherein the mammal is a human.
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