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AU2019203896B2 - Compounds useful for treating cancer - Google Patents

Compounds useful for treating cancer Download PDF

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AU2019203896B2
AU2019203896B2 AU2019203896A AU2019203896A AU2019203896B2 AU 2019203896 B2 AU2019203896 B2 AU 2019203896B2 AU 2019203896 A AU2019203896 A AU 2019203896A AU 2019203896 A AU2019203896 A AU 2019203896A AU 2019203896 B2 AU2019203896 B2 AU 2019203896B2
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group
amine
quinolin
trifluoromethoxy
phenyl
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AU2019203896A1 (en
Inventor
Carsten BROCK
Nathalie CAHUZAC
Gilles Gadea
Florence Mahuteau
Romain Najman
Pierre Roux
Didier Scherrer
Jamal Tazi
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Centre National de la Recherche Scientifique CNRS
Institut Curie
Universite de Montpellier
Abivax SA
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Centre National de la Recherche Scientifique CNRS
Institut Curie
Universite de Montpellier
Abivax SA
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Priority claimed from EP09162630A external-priority patent/EP2261214A1/en
Priority claimed from EP20090305540 external-priority patent/EP2266972A1/en
Priority claimed from AU2010258294A external-priority patent/AU2010258294B2/en
Application filed by Centre National de la Recherche Scientifique CNRS, Institut Curie, Universite de Montpellier, Abivax SA filed Critical Centre National de la Recherche Scientifique CNRS
Priority to AU2019203896A priority Critical patent/AU2019203896B2/en
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Abstract

The present invention relates to compound (I) x W, - - U Rn V R'n' R" z N Y T 5 wherein: z means a pyridazine, a pyrimidine or a pyrazine group, R independently represent a hydrogen atom, a halogen atom or a group chosen among a -CN group, a hydroxyl group, a -COOR group, a (Ci-C3)fluoroalkyl group, a (Ci-C3)fluoroalkoxy group, a -NO2 group, a -NRiR 2 group, a (C-C4)alkoxy group, a 10 phenoxy group and a (C1-C3)alkyl group, said alkyl being optionally mono-substituted by a hydroxyl group, n is 1, 2 or 3, n' is 1 or 2, R' is a hydrogen atom, a halogen atom or a group chosen among a (C1-C3)alkyl group,, a hydroxyl group, a -COOR 1 group, a -NO 2 group, a -NRiR 2 group, a morpholinyl 15 or a morpholino group, a N-methylpiperazinyl group, a (C1-C3)fluoroalkyl group, a (Ci-C 4)alkoxy group and a -CN group, Z is N or C, Y is N or C, X is N or C, W is N or C, T is N or C, U is N or C, for use as an agent for preventing, inhibiting or treating cancer. Some of said compounds are new and also form part of the invention.

Description

Compounds useful for treating cancer
This application is a divisional of Australian patent application 2017202500, which is a divisional of Australian application 2015203256, which is a divisional of Australian application 2010258294, which is a national phase entry in Australia of PCT international application PCT/1B2010/052650 (published as W02010/143168), filed 14 June 2010, all of which are incorporated herein by reference.
FIELD OF THE INVENTION The present invention is generally dedicated to the use of compounds for the manufacture of compositions useful to treat cancer.
BACKGROUND OF THE INVENTION In most of the cancers, mortality is not due to the primary tumor but rather to the derived metastases. This malignant progression which leads to tumor invasion and is clinically defined by the appearance of metastases is the final outcome of the primary loss of cell adhesion and increase of cell motility which together allow invasive cell to leave the initial tumor site and colonize various target tissues. Metastases are considered as a recurrent feature of uncontrolled malignant progression of cancer. During this process, tumor cells complete their malignant transformation by increasing their migratory capacity. Cancer cells can then disseminate and establish tumor foci in far away sites. Spreading of cancer cells in the organism is the outcome of a series of events called « metastatic cascade »: invasion of the tissues around the tumor, venous or lymphatic intravasation, migration and establishment in a distant place of a new colony that escapes from all the defence mechanisms of the organism. Metastatic invasion, against which there is no efficient therapeutic option available at this time, is by far the major cause of death. Due to the frequency of cancers diagnosed at the metastatic stage and to the therapeutic impasse they represent, the development of molecules that specifically target metastatic invasion is thus a crucial requirement for a major breakthrough in cancer treatments.
The present invention is in keeping with the evidence as published during the last twenty years of a link between changes in RNA alternative splicing and metastatic invasion which has opened to new therapeutic strategies. In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.
SUMMARY OF THE INVENTION It has now been found that derivatives of formula (I) as defined in formula (I) hereinafter are able to correct defects of alternative splicing, as illustrated in the experimental data hereinafter, a mechanism closely associated with the invasive progression of metastatic cancers, and on the basis of such activity, the compounds are useful in the treatment of cancer. In a first aspect the present invention provides a use of a compound of formula (Ib) or any one of its pharmaceutically acceptable salts in the manufacture of a medicament to prevent, inhibit or treat breast cancer, pancreatic cancer, prostate cancer, lung cancer, non-small cell lung cancer, thyroid cancer, liver cancer, and kidney cancer:
Rn R'n'
R" (Ib) wherein: R independently represents a hydrogen atom, a halogen atom or a group chosen among a -CN group, a hydroxyl group, a -COOR 1 group, a (Ci-C3)fluoroalkyl group, a (Ci-C3)fluoroalkoxy group, a -NO2 group, a -NRiR 2 group, a (Ci-C4)alkoxy group, a phenoxy group and a (Ci-C3)alkyl group, said alkyl being optionally mono-substituted by a hydroxyl group, Ri and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, n is 1, 2 or 3, n' is 1 or 2, R' is a hydrogen atom, a halogen atom or a group chosen among a (Ci-C3)alkyl group, a hydroxyl group, a -COOR 1 group, a -NO 2 group, a -NRR 2 group, a morpholinyl or a morpholino group, a N-methylpiperazinyl group, a (Ci-C 3)fluoroalkyl group, a (Ci-C 4)alkoxy group and a -CN group, R" is a hydrogen atom or a (Ci-C4)alkyl group.
In a second aspect the present invention provides a use of a compound in the manufacture of a medicament to prevent, inhibit or treat breast cancer, pancreatic cancer, prostate cancer, lung cancer, non-small cell lung cancer, thyroid cancer, liver cancer, and kidney cancer, said compound being chosen among: - (8) Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine - (75) 4-N-(8-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine - (76) N-(4-methoxyphenyl)quinolin-2-amine - (77) 8-chloro-N-(4-methoxyphenyl)quinolin-2-amine - (78) 4-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (79) N-(4-methoxyphenyl)-3-methylquinolin-2-amine - (80) 3-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (81) 1-N,1-N-dimethyl-4-N-(3-methylquinolin-2-yl)benzene-1,4-diamine - (82) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (83) N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine - (84) N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine - (85) N-(4-nitrophenyl)quinolin-2-amine - (86) N-(3-fluorophenyl)quinolin-2-amine - (87) 8-chloro-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine - (88) 8-chloro-N-(3-fluorophenyl)quinolin-2-amine - (89) 2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride - (90) 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (91) 3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (92) 3-methyl-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine - (93) 3-methyl-N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine
- (94) 8-chloro-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (95) 3-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride - (96) 6-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine - (97) 4-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride - (98) 8-bromo-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (99) 8-fluoro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (100) 8-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (101) N-(4-butoxyphenyl)-8-chloroquinolin-2-amine - (102) N-(4-phenoxyphenyl)quinolin-2-amine - (103) 8-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (104) 8-chloro-N-[3-chloro-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (155) N-(4-butoxyphenyl)-3-methylquinolin-2-amine - (156) 4-N-(6-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine - (157) 8-chloro-N-(3-chloro-4-methoxyphenyl)quinolin-2-amine - (158) N-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine - and their pharmaceutically acceptable salts.
In a third aspect the present invention provides a method of preventing, inhibiting or treating breast cancer, pancreatic cancer, prostate cancer, lung cancer, non small cell lung cancer, thyroid cancer, liver cancer, and kidney cancer, which comprises at least one step consisting in administering to a patient suffering therefrom an effective amount of a compound of formula (Ib) or any one of its pharmaceutically acceptable salts
Rn R'n'
R" (Ib) wherein: R independently represents a hydrogen atom, a halogen atom or a group chosen among a -CN group, a hydroxyl group, a -COOR group, a (Ci-C3)fluoroalkyl group, a
(Ci-C3)fluoroalkoxy group, a -NO2 group, a -NRiR 2 group, a (Ci-C4)alkoxy group, a phenoxy group and a (Ci-C3)alkyl group, said alkyl being optionally mono-substituted by a hydroxyl group, R1 and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, nis1,2or3, n' is 1 or 2, R' is a hydrogen atom, a halogen atom or a group chosen among a (Ci-C3)alkyl group, a hydroxyl group, a -COOR 1 group, a -NO 2 group, a -NRR 2 group, a morpholinyl or a morpholino group, a N-methylpiperazinyl group, a (Ci-C3)fluoroalkyl group, a
(C1-C 4)alkoxy group and a -CN group, R" is a hydrogen atom or a (Ci-C4)alkyl group.
In a fourth aspect the present invention provides a method of preventing, inhibiting or treating breast cancer, pancreatic cancer, prostate cancer, lung cancer, non-small cell lung cancer, thyroid cancer, liver cancer, and kidney cancer, which comprises at least one step consisting in administering to a patient suffering therefrom an effective amount of a compound, said compound being chosen among: - (8) Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine - (75) 4-N-(8-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine - (76) N-(4-methoxyphenyl)quinolin-2-amine - (77) 8-chloro-N-(4-methoxyphenyl)quinolin-2-amine - (78) 4-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (79) N-(4-methoxyphenyl)-3-methylquinolin-2-amine - (80) 3-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (81) 1-N,1-N-dimethyl-4-N-(3-methylquinolin-2-yl)benzene-1,4-diamine - (82) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (83) N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine - (84) N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine - (85) N-(4-nitrophenyl)quinolin-2-amine - (86) N-(3-fluorophenyl)quinolin-2-amine - (87) 8-chloro-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine - (88) 8-chloro-N-(3-fluorophenyl)quinolin-2-amine
- (89) 2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride - (90) 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (91) 3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (92) 3-methyl-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine - (93) 3-methyl-N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine - (94) 8-chloro-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (95) 3-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride - (96) 6-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine - (97) 4-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride - (98) 8-bromo-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (99) 8-fluoro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (100) 8-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (101) N-(4-butoxyphenyl)-8-chloroquinolin-2-amine - (102) N-(4-phenoxyphenyl)quinolin-2-amine - (103) 8-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (104) 8-chloro-N-[3-chloro-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (155) N-(4-butoxyphenyl)-3-methylquinolin-2-amine - (156) 4-N-(6-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine - (157) 8-chloro-N-(3-chloro-4-methoxyphenyl)quinolin-2-amine - (158) N-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine - and their pharmaceutically acceptable salts.
The present disclosure also relates to compounds of formula (I) as defined below for use as agents for preventing, inhibiting or treating cancer. The present disclosure also relates to a method of preventing, inhibiting or treating cancer, which comprises at least one step consisting in administering to a patient suffering therefrom an effective amount of a compound as defined in formula (I) below or one of its pharmaceutically acceptable salts. Also described are some particular derivatives as such, as defined below.
Also described are pharmaceutical compositions comprising at least one of said particular compounds. In the description in this specification reference may be made to subject matter which is not within the scope of the appended claims. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the appended claims.
DETAILED DESCRIPTION OF THE INVENTION In a first embodiment described is a compound of formula (I)
Rn V R'n' z N Y T
(I) wherein:
z means an aromatic ring wherein V is C or N and when V is N, V is in
ortho, meta or para of Z, i.e. forms respectively a pyridazine, a pyrimidine or a pyrazine group, R independently represent a hydrogen atom, a halogen atom or a group chosen among a -CN group, a hydroxyl group, a -COOR 1 group, a (Ci-C3)fluoroalkyl group, a (Ci-C3)fluoroalkoxy group, a -NO2 group, a -NRiR 2 group, a (Ci-C4)alkoxy group, a phenoxy group and a (C1-C 3 )alkyl group, said alkyl being optionally mono-substituted by a hydroxyl group, Ri and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, n is 1, 2 or 3, n' is 1 or 2, R' is a hydrogen atom or a group chosen among a (Cl-C3)alkyl group, a halogen atom, a hydroxyl group, a -COOR 1 group, a -NO 2 group, a -NRR 2 group, a morpholinyl or a morpholino group, a N-methylpiperazinyl group, a (Ci-C3)fluoroalkyl group, a (C1-C 4)alkoxy group and a -CN group,
R" is a hydrogen atom or a (Ci-C4)alkyl group, Z is N or C, Y is N or C, X is Nor C, W is N or C, T is N or C, U is N or C, and wherein at most four of the groups V, T, U, Z, Y, X and W are N, and at least one of the groups T, U, Y, X and W is N, or anyone of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
Also described is a compound of formula (I) as defined above, wherein Z is N, V is C, Y is N, X U C,isCU is C and W is C, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is C, V is C, Y is N, X U C,isCU is C and W is C, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is N, V is C, Y is C, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is N, V is C, Y is C, X U C,isCU is C and W is N, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is N, V is N and is in para of Z, Y is N, X is C, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is C, V is N and is in para of Z, Y is C, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.
Also described is a compound of formula (I) as defined above, wherein Z is C, V is N and is in meta of Z and is in para of the bond linked to NR", Y is N, X is C, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is C, V is N and is in meta of Z and is in para of the bond linked to NR", Y is C, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is C, V is C, Y is C, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is C, V is C, Y is N, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is N, V is N and is in meta of Z and in ortho of the bond linked to NR", Y is N, X is C, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is N, V is N and is in para of Z, Y is C, X is C, T is C, U is C and W is N, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is N, V is N and is in para of Z, Y is C, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is N, V is C, Y is N, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is N, V is N and is in meta of Z and is in ortho of the bond linked to NR", Y is N, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is C, V is C, Y is C, X is C, T is N, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.
Also described is a compound of formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C, T is N, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is N, V is C, Y is CXisC, T is C, U is N and W is C, for use as an agent for preventing, inhibiting or treating cancer.
Also described is a compound of formula (I) as defined above, wherein Z is N, V is C, Y is N, X U C,isCU is C and W is C, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is N, V is N and is in para of Z, Y is N, X is C, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is C, V is C, Y is s C, X is CisNUisCandWisC , for use as an agent for preventing, inhibiting or treating cancer. Also described is a compound of formula (I) as defined above, wherein Z is N, V is C, Y is CXisC, T is C, U is N and W is C, for use as an agent for preventing, inhibiting or treating cancer.
The compounds described herein may exist in the form of free bases or of addition salts with pharmaceutically acceptable acids. Suitable physiologically acceptable acid addition salts of compounds of formula (I) include hydrobromide, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetate and fumarate. The compounds of formula (I) and or salts thereof may form solvates (e.g. hydrates) and the disclosure includes all such solvates. In the context of the present invention, the term: - "comprising" as used in this specification and claims means "consisting at least in part of'. When interpreting statements in this specification and claims which include the term "comprising", other features besides the features prefaced by this term in each statement can also be present. Related terms such as "comprise" and "comprises" are to be interpreted in similar manner, - "halogen" is understood to mean chlorine, fluorine, bromine, or iodine, and in particular denotes chlorine, fluorine or bromine, - "(C1-C3)alkyl" as used herein respectively refers to Ci-C 3 normal, secondary or tertiary saturated hydrocarbon. Examples are, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, - "(Ci-C 3)alkoxy" as used herein respectively refers to 0-(Ci-C3)alkyl moiety, wherein alkyl is as defined above. Examples are, but are not limited to, methoxy, ethoxy, 1 propoxy, 2-propoxy, - "fluoroalkyl group" and "fluoroalkoxy group" refers respectively to alkyl group and alkoxy group as above-defined, said groups being substituted by at least one fluorine atom. Examples are perfluoroalkyl groups, such as trifluoromethyl or perfluoropropyl, and - "patient" may extend to humans or mammals, such as cats or dogs.
According to a particular embodiment, an additional subject-matter described herein is a compound of formula (a)
Rn R'n'
N N N
R (Ia) wherein: R independently represent a hydrogen atom, a halogen atom or a group chosen among a (C1-C3)alkyl group, a -CN group, a hydroxyl group, a -COOR 1 group, a (C1-C3)fluoroalkyl group, a -NO 2 group, a -NRR 2 group and a (C1-C3)alkoxy group, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom, a halogen atom or a group chosen among a (Ci-C3)alkyl group, a -NO 2 group, a (Ci-C3)alkoxy group and a -NRR 2 group,
Ri and R 2 are a hydrogen atom or a (Ci-C3)alkyl group, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (Ib)
Rn R'n'
R" (Ib) wherein: R independently represent a hydrogen atom, a halogen atom or a group chosen among a (C1-C3)alkyl group, a -NRiR 2 group, a (Ci-C3)fluoroalkoxy group, a -NO 2 group, a phenoxy group and a (C1-C4)alkoxy group, R 1 and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is preferably 1 or 2, n' is as defined above and is preferably 1, R' is a hydrogen atom, a halogen atom or a group chosen among a (Ci-C 3 )alkyl group and a (C1-C 4)alkoxy group, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (Ic)
Rn N R'n'
R" (Ic) wherein:
R independently represent a hydrogen atom or a group chosen among a (Ci-C3)alkyl group, a (Ci-C3)fluoroalkyl group, a -NRiR 2 group, a -COOR1 group, a -NO 2
group and a (Ci-C3)alkoxy group, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom, R 1 and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (Id)
Rn R'n'
R" (Id) wherein: R independently represent a hydrogen atom or a group chosen among a (Ci-C3)alkyl group, a (C1-C3)fluoroalkyl group and a (C1-C 3)alkoxy group, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (Ie)
Rn N R'n'
(Je) wherein: R represents a hydrogen atom, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom, a halogen atom or a group chosen among a (Ci-C3)alkyl group and a (C1-C 3)alkoxy group, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (If)
Rn R'n'
R"
wherein: R represents a hydrogen atom, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (Ig)
Rn N R'n' N '_N
R" (Ig (g wherein: R represents a hydrogen atom, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom or a halogen atom, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (Ih) N Rn N R'n' N
R" (Ih) wherein: R represents a hydrogen atom, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (Ii) N Rn R'n' N
R" IIi
wherein: R independently represent a hydrogen atom or a group chosen among a (Ci-C3)fluoroalkoxy group and a (Ci-C3)alkoxy group, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (Ij)
Rn R'n' N 'N
R"(D
wherein: R independently represent a hydrogen atom or a group chosen among a (C1-C 3)fluoroalkoxy group and a (C1-C 3 )alkyl group, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (1k)
Rn R'n'
R" (1k) wherein: R represents a hydrogen atom, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom, a halogen atom or a (Ci-C3)alkyl group, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (Il)
Rn N R'n' N'N
R" IIl
wherein: R represents a hydrogen atom, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (Im)
Rn R'n' N'N
R" (Im) wherein: R represents a hydrogen atom, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (o)
Rn R'n' N"N N
R" (10 wherein: R independently represent a hydrogen atom or a halogen atom or a group chosen among, a -NO2 group, a -CN group and a (Ci-C 3 )alkyl group, said alkyl being optionally mono-substituted by a hydroxyl group, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom, a halogen atom or a (Ci-C3)fluoroalkyl group, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (Ip)
Rn R'n'
R" (Jr) wherein: R represents a hydrogen atom, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (Iq)
Rn R'n'
R"(q)
wherein: R independently represent a hydrogen atom, a (Ci-C 3)alkoxy group or a (C1-C3)fluoroalkoxy group, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom or a group chosen among a -NRR 2 group, a N methylpiperazinyl group, a (Ci-C 3)alkoxy group and a morpholino group,
R 1 and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (Ir)
RnN R'n'
R"(Ir)
wherein: R independently represent a hydrogen atom or a (Ci-C3)alkyl group, R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 1, R' is a hydrogen atom or a group chosen among a -NRR 2 group, a morpholino group and a (C-C3)alkoxy group, Ri and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, an additional subject-matter described herein is a compound of formula (lee)
Rn N R'n'
R" (lee) wherein: R independently represent a hydrogen atom, a (Ci-C3)alkyl group or a (Ci-C3)fluoroalkyl group,
R" is as defined above and is advantageously a hydrogen atom, n is as defined above and is advantageously 1, n' is as defined above and is advantageously 2, R' is a hydrogen atom or a (Ci-C3)alkyl group, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
Among the previous defined families of compounds of formulae (a) to (Iee), some are more particularly preferred for their use as an agent for preventing, inhibiting or treating cancer. These preferred compounds particularly belong to formulae (a), (Ie), (Iq) and (Iee), as defined above or one of its pharmaceutically acceptable salts.
Accordingly the present idisclosure further relates to a compound chosen among compounds of formulae (Ta), (Ie), (Iq) and (Iee), and their pharmaceutically acceptable salts for use as an agent for preventing, inhibiting or treating cancer.
According to a particular embodiment, described is a compound of formula (a) wherein: R independently represent a hydrogen atom, a halogen atom or a group chosen among a (Ci-C 3 )alkyl group, a -CN group, a -COOR 1 group and a (Ci-C3)fluoroalkyl group, R" is as defined above and more preferably is a hydrogen atom, R 1 is as defined above, n is as defined above, n' is as defined above, R' is a halogen atom, a (Ci-C4)alkyl group, a (C-C 4)alkoxy group or a -NO 2
group, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, described is a compound of formula (e) wherein: R represents a hydrogen atom or a (Ci-C4)alkyl group, R" is as defined above and more preferably is a hydrogen atom, n is as defined above, n' is as defined above, R' is a halogen atom, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, described is a compound of formula (Iq) wherein: R', R", n and n' are as defined in formula (I), and R is a (Ci-C3)fluoroalkoxy group, or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
According to another particular embodiment, described is a compound of formula (lee) wherein: R is independently a hydrogen atom or a (Ci-C4)alkyl group, R', R", n and n' are as defined in formula (I), or one of its pharmaceutically acceptable salt, for use as an agent for preventing, inhibiting or treating cancer.
In a particular embodiment, the present disclosure relates to a compound of formula (Ia) or (Ie) as defined above or one of its pharmaceutically acceptable salts, for use as an agent for preventing, inhibiting or treating cancer.
According to a preferred embodiment described herein, the compound for use as an agent for preventing, inhibiting or treating cancer, is chosen from: - (1) (8-Chloro-quinolin-2-yl)-pyridin-2-yl-amine
- (2) 2-(Quinolin-2-ylamino)-isonicotinic acid - (3) (4-Methyl-pyridin-2-yl)-quinolin-2-yl-amine - (4) Pyridin-2-yl-quinolin-2-yl-amine - (5) 2-(8-Chloro-quinolin-2-ylamino)-isonicotinic acid - (6) (8-Chloro-quinolin-2-yl)-(4-methyl-pyridin-2-yl)-amine - (7) 6-(Quinolin-2-ylamino)-nicotinonitrile - (8) Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine - (9) Pyridin-2-yl-quinolin-3-yl-amine - (10) (3-Methoxy-pyridin-2-yl)-quinolin-3-yl-amine - (11) Quinolin-3-yl-(5-trifluoromethyl-pyridin-2-yl)-amine - (12) (5-Nitro-pyridin-2-yl)-quinolin-3-yl-amine - (13) (5-Methyl-pyridin-2-yl)-quinolin-3-yl-amine - (14) 2-(Quinolin-3-ylamino)-isonicotinic acid - (15) Quinolin-6-yl-(5-trifluoromethyl-pyridin-2-yl)-amine - (16) (6-Methyl-pyridin-2-yl)-quinolin-6-yl-amine - (17) N-(6-methylpyridin-2-yl)quinolin-2-amine - (18) 8-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine - (19) 4-methyl-N-(pyridin-2-yl)quinolin-2-amine - (20) 4-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine - (21) 3-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine - (22) 3-methyl-N-(pyridin-2-yl)quinolin-2-amine - (23) 6-((4-methylquinolin-2-yl)amino)nicotinonitrile - (24) 6-((3-methylquinolin-2-yl)amino)nicotinonitrile - (25) 6-chloro-N-(4-methylpyridin-2-yl)quinolin-2-amine - (26) 6-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine - (27) 4-methyl-N-(5-nitropyridin-2-yl)quinolin-2-amine - (28) N-(3-nitropyridin-2-yl)quinolin-2-amine - (29) 8-chloro-N-(3-nitropyridin-2-yl)quinolin-2-amine - (30) 2-((4-methylquinolin-2-yl)amino)nicotinonitrile - (31) N-(3-methylpyridin-2-yl)quinolin-2-amine - (32) N-(5-methylpyridin-2-yl)quinolin-2-amine - (33) 2-(quinolin-2-ylamino)isonicotinonitrile
- (34) N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine - (35) 8-chloro-N-(3-methylpyridin-2-yl)quinolin-2-amine - (36) 8-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine - (37) 8-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine - (38) N-(3-methoxypyridin-2-yl)quinolin-2-amine - (39) N-(5-nitropyridin-2-yl)quinolin-2-amine - (40) 6-((8-chloroquinolin-2-yl)amino)nicotinonitrile - (41) N-(5-fluoropyridin-2-yl)quinolin-2-amine - (42) N-(6-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine - (43) 8-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine - (44) 2-((8-chloroquinolin-2-yl)amino)nicotinic acid - (45) 4-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine - (46) 3-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine - (47) 5-cyano-2-(quinolin-2-ylamino)pyridin-1-ium chloride - (48) 2-((8-chloroquinolin-2-yl)amino)-4-methylpyridin-1-ium chloride - (49) 8-chloro-N-(4-ethylpyridin-2-yl)quinolin-2-amine - (50) 8-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine - (51) 8-chloro-N-(4,6-dimethylpyridin-2-yl)quinolin-2-amine - (52) 6-((8-chloroquinolin-2-yl)amino)-2-methylnicotinonitrile - (53) 8-chloro-N-(4-chloropyridin-2-yl)quinolin-2-amine - (54) 8-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine - (55) N-(5-bromo-4-methylpyridin-2-yl)-8-chloroquinolin-2-amine - (56) 8-chloro-N-(3-ethyl-6-methylpyridin-2-yl)quinolin-2-amine - (57) 8-fluoro-N-(4-methylpyridin-2-yl)quinolin-2-amine - (58) 8-bromo-N-(4-methylpyridin-2-yl)quinolin-2-amine - (59) methyl 6-(quinolin-2-ylamino)nicotinate - (60) methyl 6-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate - (61) methyl 6-[(3-methylquinolin-2-yl)amino]pyridine-3-carboxylate - (62) methyl 2-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate - (63) 8-methoxy-N-(4-methylpyridin-2-yl)quinolin-2-amine - (64) N-(4-methylpyridin-2-yl)-5-nitroquinolin-2-amine - (65) 2-N-(4-methylpyridin-2-yl)quinoline-2,8-diamine
- (66) N-(4-methylpyridin-2-yl)-5-aminoquinolin-2-amine - (67) methyl 6-[(4-methylquinolin-2-yl)amino]pyridine-3-carboxylate - (68) 8-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine - (69) 2-[(8-chloroquinolin-2-yl)amino]pyridin-3-ol - (70) 8-chloro-N-[6-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine - (71) 6-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine - (72) N-(6-ethylpyridin-2-yl)-3-methylquinolin-2-amine - (73) N-(5-fluoropyridin-2-yl)-3-methylquinolin-2-amine - (74) 3-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine - (75) 4-N-(8-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine - (76) N-(4-methoxyphenyl)quinolin-2-amine - (77) 8-chloro-N-(4-methoxyphenyl)quinolin-2-amine - (78) 4-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (79) N-(4-methoxyphenyl)-3-methylquinolin-2-amine - (80) 3-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (81) 1-N,1-N-dimethyl-4-N-(3-methylquinolin-2-yl)benzene-1,4-diamine - (82) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (83) N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine - (84) N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine - (85) N-(4-nitrophenyl)quinolin-2-amine - (86) N-(3-fluorophenyl)quinolin-2-amine - (87) 8-chloro-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine - (88) 8-chloro-N-(3-fluorophenyl)quinolin-2-amine - (89) 2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride - (90) 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (91) 3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (92) 3-methyl-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine - (93) 3-methyl-N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine - (94) 8-chloro-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (95) 3-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride - (96) 6-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine
- (97) 4-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride - (98) 8-bromo-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (99) 8-fluoro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (100) 8-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (101) N-(4-butoxyphenyl)-8-chloroquinolin-2-amine - (102) N-(4-phenoxyphenyl)quinolin-2-amine - (103) 8-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (104) 8-chloro-N-[3-chloro-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (105) N-(6-methylpyridin-2-yl)quinolin-3-amine - (106) N-(3-nitropyridin-2-yl)quinolin-3-amine - (107) N-(5-methylpyridin-2-yl)quinolin-6-amine - (108) N-(3-methoxypyridin-2-yl)quinolin-6-amine - (109) 6-chloro-N-(pyrazin-2-yl)quinolin-2-amine - (110) 8-bromo-N-(pyrazin-2-yl)quinolin-2-amine - (111) 8-methyl-N-(pyrazin-2-yl)quinolin-2-amine - (112) 8-chloro-N-(pyrazin-2-yl)quinolin-2-amine - (113) N-(pyrazin-2-yl)quinolin-2-amine - (114) 4-methyl-N-(pyrazin-2-yl)quinolin-2-amine - (115) 3-methyl-N-(pyrazin-2-yl)quinolin-2-amine - (116) 8-fluoro-N-(pyrazin-2-yl)quinolin-2-amine - (117) 8-methoxy-N-(pyrazin-2-yl)quinolin-2-amine - (118) N-(pyridin-3-yl)quinolin-3-amine - (119) 8-chloro-N-(pyridin-4-yl)quinolin-2-amine - (120) N-(pyridin-4-yl)quinolin-2-amine - (121) N-(pyridin-4-yl)quinolin-3-amine - (122) N-[4-(trifluoromethoxy)phenyl]quinolin-3-amine - (123) N-(4-methoxyphenyl)quinolin-3-amine - (124) N-[4-(trifluoromethoxy)phenyl]quinoxalin-2-amine - (125) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinoxalin-2-amine - (126) N-[3-(trifluoromethoxy)phenyl]quinoxalin-2-amine - (127) N-[2-(trifluoromethoxy)phenyl]quinoxalin-2-amine
- (128) N-(pyrimidin-2-yl)quinolin-2-amine - (129) 8-chloro-N-(pyrimidin-2-yl)quinolin-2-amine - (130) 4-methyl-N-(pyrimidin-2-yl)quinolin-2-amine - (131) N-(pyrazin-2-yl)quinolin-6-amine - (132) N-(pyrazin-2-yl)quinolin-3-amine - (133) 6-methyl-N-(naphthalen-2-yl)pyridin-2-amine - (134) N-(naphthalen-2-yl)pyridin-2-amine - (135) N-(pyridin-2-yl)quinoxalin-2-amine - (136) N-(4-methylpyridin-2-yl)quinoxalin-2-amine - (137) 6-(quinoxalin-2-ylamino)pyridine-3-carbonitrile - (138) N-(6-methylpyridin-2-yl)quinoxalin-2-amine - (139) N-(4-methylpyridin-2-yl)-3-(trifluoromethyl)quinoxalin-2-amine - (140) N-(3,5-dichloro-4-methylpyridin-2-yl)quinoxalin-2-amine - (141) N-(4-methyl-3-nitropyridin-2-yl)quinoxalin-2-amine - (142) N-(pyrimidin-2-yl)quinoxalin-2-amine - (143) 4-N,4-N-dimethyl-7-N-[4-(trifluoromethoxy)phenyl]quinoline-4,7 diamine - (144) 4-(morpholin-4-yl)-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine - (145) 4-methoxy-N-(pyridin-2-yl)quinolin-7-amine - (146) 4-methoxy-N-(4-methylpyridin-2-yl)quinolin-7-amine - (147) 4-N,4-N-dimethyl-7-N-(4-methylpyridin-2-yl)quinoline-4,7-diamine - (148) 5,8-dimethyl-N-(5-methylpyridin-2-yl)isoquinolin-6-amine - (149) 5,8-dimethyl-N-(5-trifluoromethylpyridin-2-yl)isoquinolin-6-amine - (150) N-(4-methylpyridin-2-yl)-8-nitroquinolin-2-amine - (151) 6-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine - (152) 6-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine - (153) 6-chloro-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine - (154) N2-(8-chloroquinolin-2-yl)-4-methylpyridine-2,3-diamine - (155) N-(4-butoxyphenyl)-3-methylquinolin-2-amine - (156) 4-N-(6-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine - (157) 8-chloro-N-(3-chloro-4-methoxyphenyl)quinolin-2-amine - (158) NI-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine
- (159) N-(3-aminopyridin-2-yl)quinolin-3-amine - (160) 6-chloro-N-(4-methylpyridin-2-yl)quinoxalin-2-amine - (161) N-(4-ethylpyridin-2-yl)quinoxalin-2-amine - (162) N-(5-bromo-4-methylpyridin-2-yl)quinoxalin-2-amine - (163) N-(4,6-dimethylpyridin-2-yl)quinoxalin-2-amine - (164) [2-(quinoxalin-2-ylamino)pyridin-4-yl]methanol - (165) N-(4-methyl-5-nitropyridin-2-yl)quinoxalin-2-amine - (166) N-(4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)quinolin-7-amine - (167) 4-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine - (168) N-(4-methylpyridin-2-yl)-4-(morpholin-4-yl)quinolin-7-amine - and their pharmaceutically acceptable salts.
Among said compounds, compounds (6), (18), (30), (35), (36), (37), (45), (48), (51), (52), (53), (55), (56), (58), (61), (63), (64), (109), (110), (112), (143), (144) and (148) are of particular interest. The present disclsoure therefore extends to compounds (6), (18), (30), (35), (36), (37), (45), (48), (51), (52), (53), (55), (56), (58), (61), (63), (64), (109), (110), (112), (143), (144) and (148) or one of its pharmaceutically acceptable salts for use as an agent for preventing, inhibiting or treating cancer.
Some of said preceding compounds are new and form part of the present disclosure: (6), (18), (30), (35), (36), (37), (48), (51), (52), (53), (55), (56), (58), (61), (63), (64), (109), (110), (112), (143) and (144).
The compounds of formulae (I), (a), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (1k), (Il), (Tm), (Io), (Ip), (Iq), (Ir) and (Tee) can comprise one or more asymmetric carbon atoms. They can thus exist in the form of enantiomers or of diastereoisomers. These enantiomers, diastereoisomers and their mixtures, including the racemic mixtures, are encompassed within the scope of the present disclosure. Among the compounds of formula (I), some of them are new and form part of the present disclosure, as well as their pharmaceutically acceptable salts, such as hydrobromide, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetate and fumarate.
According to a particular embodiment, the present disclosure encompasses compounds of formula (Ig) wherein: R independently represent a hydrogen atom, a halogen atom or a group chosen among a (Ci-C 3 )alkyl group, a -CN group, a hydroxyl group, a -COOR 1 group, a (Ci-C3)fluoroalkyl group, a (C1-C3)fluoroalkoxy group, a -NO 2 group, a -NRR 2 group, and a (C1-C 3)alkoxy group, n is 1 or 2, n' is 1 or 2, R' is a hydrogen atom or a group chosen among a (Ci-C3)alkyl group, a halogen atom, a hydroxyl group, a -COOR 1 group, a -NO 2 group, a -NRR 2 group, a (C1-C3)alkoxy group and a -CN group, R" is a hydrogen atom or a (Ci-C4)alkyl group, R 1 and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, with the proviso that R and R' are not simultaneously a hydrogen atom, and when n and n' are 1 and R is a hydrogen atom then R' is not a -COOH group, or anyone of its pharmaceutically acceptable salt.
According to another particular embodiment, described are compounds of formula (If) wherein: R independently represent a hydrogen atom, a halogen atom or a group chosen among a (Ci-C3)alkyl group, a -CN group, a hydroxyl group, a -COOR1 group, a (Ci-C3)fluoroalkyl group, a (C1-C3)fluoroalkoxy group, a -NO 2 group, a -NRR 2 group, and a (C1-C3)alkoxy group, nis lor2, n' is 1 or 2,
R' is a hydrogen atom or a group chosen among a (Cl-C3)alkyl group, a halogen atom, a hydroxyl group, a -COOR 1 group, a -NO 2 group, a -NRR 2 group, a (Ci-C3)alkoxy group and a -CN group, R" is a hydrogen atom or a (Cl-C4)alkyl group, Ri and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, or anyone of its pharmaceutically acceptable salt.
According to another particular embodiment, described are compounds of formula (Ih) wherein: R independently represent a hydrogen atom, a halogen atom or a group chosen among a (C1-C3)alkyl group, a -CN group, a hydroxyl group, a -COOR 1 group, a (Ci-C3)fluoroalkyl group, a (Ci-C3)fluoroalkoxy group, a -NO 2 group, a -NRR 2 group, and a (C1-C 3)alkoxy group, nis lor2, n' is 1 or 2, R' is a hydrogen atom or a group chosen among a (C-C 3 )alkyl group, a halogen atom, a hydroxyl group, a -COOR 1 group, a -NO 2 group, a -NRR 2 group, a (C1-C3)alkoxy group and a -CN group, R" is a hydrogen atom or a (Ci-C 4 )alkyl group, R 1 and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, or anyone of its pharmaceutically acceptable salt.
According to another particular embodiment, described are compounds of formula (Il) wherein: R independently represent a hydrogen atom, a halogen atom or a group chosen among a (C1-C3)alkyl group, a -CN group, a hydroxyl group, a -COOR 1 group, a (Ci-C3)fluoroalkyl group, a (C-C3)fluoroalkoxy group, a -NO 2 group, a -NRR 2 group, and a (C1-C 3)alkoxy group, n is 1 or 2, n' is 1 or 2,
R' is a hydrogen atom or a group chosen among a (Cl-C3)alkyl group, a halogen atom, a hydroxyl group, a -COOR 1 group, a -NO 2 group, a -NRR 2 group, a (Ci-C3)alkoxy group and a -CN group, R" is a hydrogen atom or a (Cl-C4)alkyl group, Ri and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, with the proviso that R and R' are not simultaneously a hydrogen atom, or anyone of its pharmaceutically acceptable salt.
According to another particular embodiment, described are compounds of formula (Im) wherein: R independently represent a hydrogen atom, a halogen atom or a group chosen among a (Ci-C3)alkyl group, a -CN group, a hydroxyl group, a -COOR 1 group, a (Ci-C3)fluoroalkyl group, a (C-C3)fluoroalkoxy group, a -NO 2 group, a -NRR 2 group, and a (Ci-C3)alkoxy group, n is 1 or 2, n' is 1 or 2, R' is a hydrogen atom or a group chosen among a (Ci-C 3 )alkyl group, a halogen atom, a hydroxyl group, a -COOR 1 group, a -NO 2 group, a -NRR 2 group, a (C1-C3)alkoxy group and a -CN group, R" is a hydrogen atom or a (Ci-C4)alkyl group, R 1 and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, with the proviso that when n and n' are 1 and R is a hydrogen atom, R' is not a chlorine atom, or anyone of its pharmaceutically acceptable salt.
For a sake of simplification, the following compounds and their corresponding definitions are called "new compounds".
According to another particular embodiment, described are compounds of formula (Ia), as such,
Rn R'n' N N N
(Ia) wherein: R"and n are as defined in formula (a), n' is 1, R independently represent a hydrogen atom, a halogen atom or a group chosen among a (C1-C3)alkyl group, a -CN group, a hydroxyl group, a -COOR 1 group, a (C1-C 3)fluoroalkyl group, a -NO 2 group, a (Ci-C3)fluoroalkoxy group and a (C-C 3)alkoxy group, R' is a hydrogen atom or a halogen atom or a group chosen among a (CiC3)alkyl group, a -COOR 1 group, and a -CN group, R 1 is a hydrogen atom or a (Ci-C3)alkyl group: with the proviso that when R and R' are not simultaneously a hydrogen atom, when n is 1, R is not a methyl group in ortho or para position with respect to Z, Z being N, when R' is a hydrogen atom, R is not a bromine atom or a chlorine atom, when R is a hydrogen atom, R' is not a methyl or ethyl group, a -COOH group, a COOC 2 H 5 group or a bromine atom, said bromine atom being in ortho position of the bond linked to NR", or one of its pharmaceutically acceptable salt. Still according to this particular embodiment, the present disclosure more particularly focuses on compounds of formula (a), as such, wherein, R independently represent a hydrogen atom or a (Ci-C 3 ) alkyl group, R" is as defined in formula (a), R' is a hydrogen atom, a halogen atom, a (Ci-C3)alkoxy group or a -NO 2
group, n' is 1, n is 1, with the proviso that when n is 1, R is not a methyl group in ortho or para position with respect to Z, Z being N, or one of its pharmaceutically acceptable salt. Still according to this particular embodiment, the present disclosure more preferably focuses on compounds of formula (Ta'), as such,
Rn N N N
R" CI (a') wherein, R independently represent a hydrogen atom, a (Ci-C 3 ) alkyl group, a (C1-C 3)fluoroalkyl group, a halogen atom or a hydroxyl group, R" is as defined in formula (a), n is 1 or 2, or one of its pharmaceutically acceptable salt.
According to another particular embodiment, described are compounds of formula (Ie)
Rn N R'n'
R" (e)
wherein: R, R', R" n and n' are as defined in formula (I), with the proviso that when R is a hydrogen atom, R' is not a bromine atom, or one of its pharmaceutically acceptable salt.
Also described is a compound of formula (Iq) as defined above, as such
Rn R'n'
(Iq) wherein: R, R', R" and n' are as defined in formula (I), n is 1 or 2, with the proviso that R' and R are not simultaneously a hydrogen atom, when R' is a hydrogen atom, R is not a -NO 2 group or a -NH 2 group, when n is 2 and R' is a hydrogen atom, R is not a COOC 2H 5 group or a chlorine atom, or one of its pharmaceutically acceptable salt.
Still according to this particular embodiment, described are compounds of formula (Iq), as such, wherein R', R", n and n' are as defined in formula (I), and R is a (Ci-C3)fluoroalkoxy group, or one of its pharmaceutically acceptable salt.
Still according to this particular embodiment, described are compounds of formula (Iq), as such, wherein R, R", n and n' are as defined in formula (I), and R' is a -NRR 2 group, Ri and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, or one of its pharmaceutically acceptable salt.
Still according to this particular embodiment, described are compounds of formula (Iq), as such, wherein R, R", n and n' are as defined in formula (I), and R' is a morpholinyl group, a morpholino group or a N-methylpiperazinyl group, or one of its pharmaceutically acceptable salt.
Also described is a compound of formula (lee) as defined above, as such
Rn N R'n' N' N
R" (lee)
wherein: R, R', R", n and n' are as defined in formula (I), or one of its pharmaceutically acceptable salt, with the exclusion of the following compound
N N H (148) and with the exclusion of compounds wherein R is a -NO 2 group or a -NH 2 group when R' is a hydrogen or a methyl group.
Still according to this particular embodiment, described are compounds of formula (lee), as such, wherein R', R", n and n' are as defined in formula (I), and R is a (C-C 3)fluoroalkyl group, or one of its pharmaceutically acceptable salt.
Among said compounds as such, compounds (1), (2), (5)-(8), (10)-(16), (18), (21)-(44), (46)-(75), (77)-(84), (86)-(119), (121), (124)-(130), (132), (135)-(141), (143) (147), (149)-(168) and their pharmaceutically acceptable salts are of particular interest. Also described are compounds (1), (2), (5)-(8), (10)-(16), (18), (21)-(44), (46) (75), (77)-(84), (86)-(119), (121), (124)-(130), (132), (135)-(141), (143)-(147), (149)-(168) and their pharmaceutically acceptable salts, as such.
More preferably, compounds (143), (144), (149), (166), (167) and their pharmaceutically acceptable salts are of particular interest. Also described are compounds (143), (144), (149), (166), (167) and their pharmaceutically acceptable salts, such as hydrobromide, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetate and fumarate. Still more preferably, disclosed are compounds (143), (144) and their pharmaceutically acceptable salts, such as hydrobromide, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetate and fumarate.
The new compounds described herein, i.e. compounds of formulae (Ia), (Ie), (Iq) and (lee) and the specific compounds as listed above, are not only useful as agent for inhibiting, preventing or treating cancer but can also be useful for inhibiting, preventing or treating premature aging or progeria and for inhibiting, preventing or treating AIDS. According to an aspect of the disclosure, said compounds may be useful to inhibit, prevent and/or treat diseases with premature aging and that are likely related to an aberrant splicing of the nuclear lamin A gene. Among all, said disease may include Hutchinson Guilford Progeria Syndrome (HGPS), progeria, premature aging associated with HIV infection, muscular dystrophy, Charcot-Marie-Tooth disorder, Werner syndrome, but also atherosclerosis, insulin resistant type II diabetes, cataracts, osteoporosis and aging of the skin such as restrictive dermopathy.
The compounds described herein can be prepared by conventional methods of organic synthesis practiced by those skilled in the art. The general reaction sequences outlined below represent a general method useful for preparing the compounds described herein and are not meant to be limiting in scope or utility. The compounds of general formula (I) can be prepared according to scheme 1 below.
Scheme 1
"'- 'LJRn V R'n' R
(III)
Rn Rn (A) V (B) R'n'
z NHR' (IV) (VI)
x W, Rn V R'n' z N Y T
(I) As appears in said scheme two routes are available for recovering a compound of formula (I) according to the present disclosure. The synthesis is based on a coupling reaction alternatively starting from a halogeno-bicycle of formula (III), wherein X, Y, W, T, U, n', R' and R" are as defined above and X' is a chlorine atom or a bromine atom or from a chloro-monocycle of formula (V), wherein Z, V, n and R are as defined above and X' is a chlorine atom or a bromine atom. According to route (A), the compound of formula (III) is placed in a protic solvent such as tert-butanol. The compound of formula (IV) is then added in a molar ratio ranging from 1 to 1.5 with respect to the compound of formula (III) in presence of an inorganic base, such as Cs2CO3 or K2 C3 in a molar ratio ranging from 1 and 2, in the presence of a diphosphine, such as Xantphos (4,5-Bis(diphenylphosphino)-9,9 dimethylxanthene) or X-Phos (2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) in an amount ranging from 2mol% to 10mol% relative to the total amount of compound of formula (III), and in the presence of a catalyst, such as Pd(OAc) 2 or Pd 2dba 3 in an amount ranging from 2mol% to 10mol% relative to the total amount of compound of formula (III). The reaction mixture can then be heated at a temperature ranging from 80 to 120°C, for example at 90°C and stirred for a time ranging form 15 to 25 hours, for example during 20 hours under inert gas and for example argon. The reaction mixture can be concentrated under reduced pressure. According to route (B) the compound of formula (V) is placed in a protic solvent such as tert-butanol. The compound of formula (VI) is then added in a molar ratio ranging from 1 to 1.5 with respect to the compound of formula (V) in presence of an inorganic base, such as Cs2CO3 or K2 CO3 in a molar ratio ranging from 1 to 2, in the presence of a diphosphine, such as Xantphos (4,5-Bis(diphenylphosphino)-9,9 dimethylxanthene) or X-Phos (2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) in an amount ranging from 2 mol% to 10 mol% relative to the total amount of compound of formula (V), and in the presence of a catalyst, such as Pd(OAc) 2 or Pd 2dba 3 in an amount ranging from 2 mol% to 10 mol% relative to the total amount of compound of formula (V). The reaction mixture can then be heated at a temperature ranging from 80 to 120°C, for example at 90°C and stirred for a time ranging form 15 to 25 hours, for example during 20 hours under inert gas and for example argon. The reaction mixture can be concentrated under reduced pressure. The starting compounds of formula (III), (IV), (V) and (VI) are commercially available or can be prepared according to methods known to the person skilled in the art.
The chemical structures and spectroscopic data of some compounds of formula (I) described herein are illustrated respectively in the following Table I and Table II. Table I (I)
Rn UR'n' z NYT II
Formula (1a)
a N
N' N N H ci
O OH
N~ N N
N NN H N N N H
N N N H c
6 N' N N Hci
NC
7 N N
17 - N 'N N N N H
18N N N H cI
19 N O N N N H
N N
N NNo H
21 N~ N N H
22
NCN N' N' N H
NC 234~ N N N
CN' N N N H NCl
24N N N N
H N N N" H
NO 28
N N N H NO
29 N N N H Ci
1 -
aN'N
31K- NK N N' N H
32 - N N N N
CN N N" N" H
34 F "
N N ' N:: H
35 N H N K-C CI
36 N N- N H cI
FEF
37 H cI
N N N H
02 N ,',aN
39 N": N N N H
NC N.a
N N" N' N H c
41 N N N H
42NNN H F
N" N "N H cI
0
44 -OH
N N -N H cI
N N2N:
N N N NC
47 +N N N CI
- N N
49 N
N N N CI N N- N CI
51I
NC
52N N N- N H CI
CI
53I
54I N N N
Br
- N N N' N N
Cl
56N N N' N- N
57 `- : ,, - l 1
N N N
58 1 N' N"N
Br
0
59 N 0 - [ N N
0
-.- ~ ' N N N H c
61N 0 -N N N N N
0
62 N N N N N- H cI
63 K- L N
1 0
NO 2
64 N NN N 0
K N N '1'N
NH 2
66 K
, CN N 'N H H
0
67 0 n
, N N N' H F F F
68 N
. N 05N -N H cI
OH
69I N N -- N H cI
70~ ~ F F~N~ F0 N N- N H cI
71- N N N N H
N72 ~ 72 N N H
73- N N N N N H
FF
74 F N .
N N N H
150 N N
NO 2 c 151 N N' N c 152 N N N
153 FN - CI
- N N
NH 2
154 N N N ci
Formula (Tb) F 0N~N
8 FXF '
H
77N N" H
79 )
N N H F
80F 0 I
. 80 FN N H
81 -aN N'; H F
82 FN N
83 FO N' N
W N 84 F H
F
0. 2 N
84 F H
F
85N N H
F N N H
FH FtCI
F
N9 N H +
CI F
F "a N N H cI F
91 FO -C- N NN H
92 F' -a N F H
93 F N N ' 1H F 0O F
F 0
94 F N H c
F
F N N N+ H cI F cI
96 F*N NN
F
0'aNN H
F
98 FN N
H Br
F
99 F N H F
F F 0 100 F O~ N H
101 K- H-' ?
102N N H
F
103 FN N H
ci F
F*N 104 H ci
155 =
156 N. I
CC'
157 ' N H
F NH2 F*0
158 F N N H ci
Formula (1c)
9 L -,C
N N H N N H
N 11F N- N
H N ON 12 12N N= H
N
13 N N= H
0 OH
N 14
N N' H N
1056 H
N N
159 H N N
Formula (1d) F
F _ N N H
N. N 16 16N N H
107 N 1 H
0 N 108 N N H
Formula (Ie) ci 109 NI N' N H 110
110 111i H Br
N'N N H
112 N N N 114 ~ H ci
113 N N N H
114 N N N3 H
115 N' N H N c
116N N N H F
117 N N N H
Formula (If) N N
118 U N .N H
Formula (1g)
N, a 119 N :N H ci
120N N N H
Formula (1h) N N N
121 1 H
Formula (Ii)
122 F~<
N
123 N
Formula (1j) F
124F
F
125F
N
126 FF 0 N N
F
127 F N N F 0
F
Formula (1k)
128 N" N N H
129 N N N
130 N N N H
Formula (I)
131 (N N H
Formula (m) N CN 132 H
Formula (o)
135
136 H
NCa N
137 - ~ N N N H
138I
N N N') H
139 - c. N
N N 'N H
h NI NN 140 N N" N H
NO1 N
141
N.
N N 'N 0H
161 N
N N Nl
Br4
N N 16O0N
N "N 4ND
Formula (1p) N
142 ~ N NCN' H
Formula (1q)
N F 143
* F N4 ]N H
144 F F 0,
F N N N N
166 0 0~ F 167 F - N
H
Formula (1r) N 0
N N W 'N H
146 N.O N N 'N H
N
147
H
N 168
Formula (Iee)
N. 148
. N N N F F
149 FF N NN
Table 11
Ex Characterizations
1 MS (ESI) [M+H]*=256
2 'H NMR (300 MHz, D 2 0) 6 8.31 (d, J= 5.1, 1H), 8.21 (d, J= 9.3, 1H), 7.60 (d, J= 7.5, 3H), 7.34 (dd, J= 6.2, 15.6, 2H), 7.18 (s, 1H), 6.99 (d, J= 9.1, 1H) MS (ESI) [M+H]=266 5 MS (ESI) [M+H]*=300
6 'H NMR (300 MHz, DMSO) 6 10.23 (s, 1H), 8.96 (s, 1H), 8.18 (d, J= 8.8, 2H), 7.78 (dd, J= 7.7, 13.7, 2H), 7.46 (d, J= 8.9, 1H), 7.31 (t, J= 7.8, 1H), 6.86 (d, J= 4.3, 1H), 2.37 (s, 3H). 13 C NMR (75 MHz, DMSO) 6 153.63, 153.61, 148.37, 147.32, 142.65, 137.52, 129.68, 129.47, 126.82, 125.06, 123.26, 118.36, 115.10, 113.31, 21.24.
MS (ESI) [M+H]*=270
Ex Characterizations
7 'HNMR(300 MHz, DMSO) 6 10.71 (s, 1H), 8.71 (d,J= 1.4, 1H), 8.62 (d,J= 8.9, 1H), 8.24 (d,J= 8.9, 1H), 8.17 (dd,J= 1.9,8.9, 1H), 7.89-7.74 (m, 2H), 7.66 (dd,J=7.9,14.2,2H), 7.42 (t,J=7.3, 1H). 13 C NMR (75 MHz, DMSO) 6 156.09, 152.40, 152.11, 146.24, 141.07, 137.83, 129.87, 127.67, 126.78, 124.50,124.21, 118.04, 114.49, 111.67, 100.12.
MS (ESI) [M+H]*=247
8 THNMR(300 MHz, CDC 3 ) 6 7.92 (d,J= 8.9, 1H), 7.79 (d,J= 8.4, 1H), 7.65 (t,J = 7.7,3H), 7.59 (dd,J= 7.1,8.3, 1H), 7.31 (t,J=7.0, 1H), 7.20 (d,J= 8.5,2H), 6.88 (d, J= 8.9, 1H), 6.80 (s, 1H) 13 C NMR (75 MHz, CDC13) 6 153.88, 147.62, 144.35, 139.26, 138.11, 130.13, 127.65, 127.12, 124.43, 123.70, 122.20, 120.95, 112.25. MS (ESI) [M+H]=305 'HNMR (300 MHz, CDC 3 ) 6 9.10 (d, J= 2.5, 1H), 8.83 (d, J= 2.6, 1H), 8.02 (d, J = 7.9, 1H), 7.94 (dd, J= 1.3,5.0, 1H), 7.85 - 7.79 (m, 1H), 7.52 (pd, J= 1.5,6.9, 2H), 7.33 (s, 1H), 7.04 (dd, J= 1.2,7.9, 1H), 6.81 (dd, J= 5.1, 7.9, 1H), 3.95 (s, 3H) 11 MS (ESI) [M+H]=290
12 'HNMR (300 MHz, CDC 3) 69.18 (d, J= 2.7, 1H), 8.86 (d, J= 2.5, 1H), 8.56 (d, J = 2.3, 1H), 8.33 (dd, J= 2.7,9.2, 1H), 8.08 (d, J= 8.5, 1H), 7.83 (d, J= 8.5, 1H), 7.71 - 7.63 (m, 2H), 7.57 (t, J= 7.4, 2H), 6.82 (d, J= 9.1, 1H) 13 'HNMR (300 MHz, CDC 3) 6 8.83 (d, J= 2.6, 1H), 8.37 (d, J= 2.3, 1H), 8.00 (d, J = 8.2, 1H), 7.71 (d, J= 7.7, 1H), 7.59 - 7.51 (m, 1H), 7.46 (dd, J= 7.3, 15.1, 2H), 6.71 (d, J= 8.3, 1H), 6.67 (d, J= 7.4, 1H), 2.49 (s, 3H) 13 C NMR (75 MHz, CDC1 3) 6 157.13, 154.59, 145.81, 144.43, 138.78, 134.54, 129.22,128.86,127.41, 127.27,121.48,115.41, 106.50,24.18. MS (ESI) [M+H]=236 14 MS (ESI) [M+H]= 266
MS (ESI) [M+H]= 290
16 'H NMR (300 MHz, CDC 3) 6 8.77 (dd, J= 1.5, 4.2, 1H), 8.04 (dd, J= 4.7, 8.7, 2H), 7.92 (d, J= 2.4, 1H), 7.59 (dd, J= 2.5, 9.1, 1H), 7.47 (t, J= 7.8,1H), 7.35 (dd, J= 4.2, 8.3, 1H), 6.87 (s, 1H), 6.81 (d, J= 8.2, 1H), 6.70 (d, J= 7.4, 1H), 2.50 (s, 3H) MS (ESI) [M+H]*=236 18 'HNMR (300 MHz, CDC 3) 6 8.53 (d, J= 59.9,2H), 7.76 (d, J= 8.6, 1H), 7.58 (t, J= 8.3,2H), 7.42 (d, J= 7.8, 1H), 7.09 (t, J= 7.7, 1H), 6.95 (d, J= 8.7, 1H), 6.71 (d, J= 7.3, 1H), 2.38 (s, 3H) 21 'H NMR (300 MHz, CDC 3) 68.78 (s, 1H), 8.13 (d, J= 5.1, 1H), 7.89 (d, J= 8.3, 1H), 7.79 (s, 1H), 7.63 (d, J= 8.0, 1H), 7.56 (d, J= 7.3, 1H), 7.38 (s, 1H), 7.33 (t, J = 7.5, 1H), 6.79 (d, J= 4.9, 1H), 2.44 (s, 6H) 22 'H NMR (300 MHz, CDC 3) 6 8.95 (d, J= 8.4, 1H), 8.28 (d, J= 5.7, 1H), 7.87 (d, J = 8.3, 1H), 7.78 (s, 1H), 7.76 - 7.70 (m, 1H), 7.62 (d, J= 8.0, 1H), 7.60 - 7.52 (m, 1H), 7.42 (s, 1H), 7.32 (t, J= 7.4, 1H), 6.95 (dd, J= 5.1, 6.5, 1H), 2.45 (s, 3H)
Ex Characterizations
23 'HNMR(300 MHz, CDCl 3) 8.64(d,J= 8.4, 1H), 8.55 (d,J=2.1, 1H), 8.03 (s, 1H), 7.90 (d, J= 8.5, 4H), 7.66 (t, J= 7.6, 1H), 7.44 (t, J= 7.6, 1H), 7.06 (s, 1H), 2.67 (s, 4H) 24 'H NMR (300 MHz, CDCl 3) 6 9.09 (d, J= 8.9, 1H), 8.53 (d, J= 1.7, 1H), 7.94 (dd, J= 2.2, 8.9, 1H), 7.92 - 7.84 (m, 2H), 7.67 (d, J= 8.6, 2H), 7.65 - 7.58 (m, 1H), 7.40 (t, J= 7.4, 1H), 2.49 (s, 3H) 'H NMR (300 MHz, CDC 3) 68.16 (d, J= 5.2, 1H), 8.10 (s, 1H), 7.90 (d, J= 8.8, 1H), 7.79 (d, J= 9.0, 1H), 7.66 (d, J= 2.2, 1H), 7.55 (dd, J= 2.3, 8.9, 1H), 7.39 (d, J= 9.0, 1H), 6.79 (d, J= 5.2, 1H), 2.42 (s, 3H) MS (ESI) [M+H]*=270 26 'H NMR (300 MHz, CDC13) 6 8.06 (d, J= 8.3, 1H), 7.70 (d, J= 9.0, 1H), 7.64 (d, J = 8.9, 1H), 7.49 (t, J= 7.9, 2H), 7.40 (dd, J= 2.3, 8.9, 1H), 7.18 (d, J= 8.9, 1H), 6.68 (d, J= 7.4, 1H), 2.38 (s, 3H) MS (ESI) [M+H]=270 27 'HNMR (300 MHz, CDC 3 ) 69.17 (d, J= 2.5, 1H), 8.71 (s, 1H), 8.49 (dd, J= 2.6, 9.0, 1H), 7.99 (s, 1H), 7.93 (d, J= 8.9,2H), 7.74 - 7.64 (m, 1H), 7.48 (dd, J= 4.2, 11.4, 1H), 7.09 (s, 1H), 2.71 (s, 3H) 28 'H NMR (300 MHz, CDC 3) 6 8.64 - 8.51 (m, 3H), 8.18 (d, J= 9.0, 1H), 7.93 (d, J = 8.4, 1H), 7.79 (d, J= 8.1, 1H), 7.73 - 7.64 (m, 1H), 7.51 - 7.41 (m, 1H), 7.00 (dd, J= 4.6, 8.2, 1H), 6.75 (dd, J= 4.6, 8.3, OH) 29 'H NMR (300 MHz, CDC 3) 6 10.77 (s, 1H), 8.60 (s, 3H), 8.19 (d, J= 8.2, 1H), 7.76 (dd, J= 6.6, 25.5, 2H), 7.38 (d, J= 7.2, 1H), 7.04 (d, J= 4.4, 1H) 'H NMR (300 MHz, CDC 3) 68.46 (dd, J= 1.9, 5.0, 1H), 7.87 (dd, J= 2.0, 7.6, 1H), 7.82 (d, J= 7.3, 1H), 7.60 (t, J= 7.3, 2H), 7.43 - 7.33 (m, 1H), 6.90 (dd, J= 5.0, 7.6, 1H), 2.64 (s, 3H) 31 'H NMR (300 MHz, CDC 3) 6 8.44 (d, J= 9.1, 1H), 8.17 (d, J= 4.8, 1H), 8.03 (d, J = 9.1, 1H), 7.78 (d, J= 8.4, 1H), 7.68 (d, J= 8.0, 1H), 7.62 - 7.54 (m, 1H), 7.39 (d, J= 7.3, 1H), 7.32 (t, J= 7.5, 1H), 6.82 (dd, J= 5.0, 7.3, 1H), 2.31 (s, 3H) MS (ESI) [M+H]=236 32 'HNMR (300 MHz, CDC 3) 68.23 (d, J= 8.5, 1H), 8.10 (s, 1H), 7.91 (d, J= 8.9, 1H), 7.82 (d, J= 8.4, 1H), 7.62 (d,J= 8.3, 1H), 7.56 (d,J= 7.3, 1H), 7.50 (dd,J= 1.8, 8.5, 1H), 7.37 - 7.24 (m, 2H), 2.26 (s, 3H) MS (ESI) [M+H]=236 33 'H NMR (300 MHz, CDC 3) 68.87 (s, 1H), 8.32 (d, J= 5.0, 1H), 7.95 (d, J= 8.8, 1H), 7.84 (d, J= 8.3, 1H), 7.60 (dd, J= 7.4,14.1,2H), 7.32 (t, J= 7.5, 1H), 7.04 (dd, J= 5.0, 9.0, 2H) MS (ESI) [M+H]=247 34 'H NMR (300 MHz, CDC 3) 68.52 (s, 1H), 8.45 (d, J= 8.6, 1H), 8.01 (d, J= 8.8, 1H), 7.87 (dd, J= 2.5, 8.5, 2H), 7.72 - 7.56 (m, 2H), 7.39 (d, J= 9.0, 2H) MS (ESI) [M+H]*=290 'H NMR (300 MHz, CDC 3) 6 8.32 (d, J= 9.1, 1H), 8.07 (d, J= 4.8, 1H), 7.93 (d, J = 9.1, 1H), 7.59 (t, J= 7.9, 1H), 7.52 (d, J= 8.0, 1H), 7.36 (d, J= 7.2, 1H), 7.14 (t, J= 7.8, 1H), 6.77 (dd, J= 5.0, 7.3, 1H), 2.29 (s, 3H) MS (ESI) [M+H]=270
Ex Characterizations
36 'H NMR (300 MHz, CDCl 3) 68.70 (d, J= 7.2, 1H), 8.01 (s, 1H), 7.82 (d, J= 8.9, 1H), 7.62 (d, J= 7.6, 1H), 7.53 (dd, J= 1.8, 8.6, 1H), 7.46 (d, J= 7.9, 1H), 7.12 (t, J= 7.8, 1H), 7.05 (d, J= 8.8, 1H), 2.21 (s, 3H) MS (ESI) [M+H]=270 37 'H NMR (300 MHz, CDC 3) 69.08 (d, J= 8.5, 1H), 8.55 (s, 1H), 8.36 (s, 1H), 8.02 (d, J= 8.1, 2H), 7.77 (d, J= 7.2, 1H), 7.62 (d, J= 7.6, 1H), 7.35 - 7.24 (m, 1H), 7.12 (d, J= 8.8, 1H) MS (ESI) [M+H]*=324 38 'H NMR (300 MHz, CDC 3) 68.69 (d, J= 9.1, 1H), 7.97 (d, J= 9.1, 1H), 7.80 7.74 (m, 1H), 7.70 (d, J= 8.4, 1H), 7.59 (d, J= 8.0, 1H), 7.54 - 7.45 (m, 1H), 7.22 (t, J= 7.5, 1H), 6.87 (d, J= 7.9, 1H), 6.68 (dd, J= 5.0,7.9, 1H), 3.73 (s, 3H) MS (ESI) [M+H]*=252 39 'H NMR (300 MHz, CDC 3) 6 8.57 (d, J= 29.4, 1H), 7.80 (d, J= 8.8, 1H), 7.66 (t, J= 6.7, 2H), 7.46 (d, J= 7.9, 1H), 7.14 (t, J= 7.8, 1H), 7.06 (d, J= 8.8, 1H), 6.79 (d, J= 7.3, 1H), 2.73 (dd, J= 7.6, 15.2, 2H), 1.28 (t, J= 7.7, 3H) 'H NMR (300 MHz, DMSO) 6 9.75 (s, 1H), 9.12 (d, J= 2.3, 1H), 8.50 (d, J= 2.2, 1H), 8.48 (s, 1H), 8.13 (s, 1H), 7.83 (s, 1H), 7.80 (s, 1H), 7.64 (t, J= 7.7, 1H), 7.45 (t, J = 7.8, 1 H) 41 'H NMR (300 MHz, CDC 3) 68.52 (dd, J= 2.8, 8.6, 1H), 8.35 (s, 1H), 8.15 (d, J= 2.3, 1H), 7.94 (d, J= 8.8, 1H), 7.84 (d, J= 8.2, 1H), 7.65 (d, J= 7.8,1H), 7.59 (d, J= 7.2, 1H), 7.50 - 7.40 (m, 1H), 7.33 (t, J= 7.4, 1H), 7.11 (d, J= 8.9, 1H) MS (ESI) [M+H]*=240 42 'H NMR (300 MHz, CDC 3) 6 8.55 (d, J= 6.8, 1H), 8.01 (d, J= 8.9, 2H), 7.82 (dd, J= 9.1, 17.3, 2H), 7.69 (d, J= 8.0, 1H), 7.63 (t, J= 7.6, 1H), 7.37 (t, J= 7.5, 1H), 7.32 - 7.18 (m, 2H) MS (ESI) [M+H]*=290 43 'H NMR (300 MHz, DMSO) 6 10.41 (s, 1H), 9.08 (dd, J= 4.1, 9.3, 1H), 8.31 (d, J = 2.9, 1H), 8.20 (d, J= 8.9, 1H), 7.88 - 7.70 (m, 3H), 7.44 (d, J= 8.9, 1H), 7.32 (t, J = 7.8, 1H) 13 C NMR (75 MHz, DMSO) 6 156.30, 153.32, 153.04, 150.17, 142.55, 137.73, 135.06, 134.74, 129.58, 129.49, 126.86, 125.29, 125.14, 125.04, 123.36, 114.91, 113.36.
MS (ESI) [M+H]*=274 44 'H NMR (300 MHz, CDC 3) 611.09 (s, 1H), 8.78 (d, J= 9.0, 1H), 8.42 (dd, J 1.9, 4.7, 1H), 8.28 (dd, J= 1.9, 7.8, 1H), 8.11 (d, J= 9.1, 1H), 7.73 (d, J= 7.5, 1H), 7.65 (d, J= 8.1, 1H), 7.27 (dd, J= 6.4, 9.2, 1H), 6.88 (dd, J= 4.8, 7.8, 1H) MS (ESI) [M+H]*=300 46 'H NMR (300 MHz, CDC 3) 68.59 (d, J= 8.3, 1H), 7.73 (d, J= 8.3, 1H), 7.57 (s, 1H), 7.51 (t, J= 7.9, 1H), 7.43 (t, J= 9.2, 2H), 7.17 (t, J= 7.4, 1H), 6.67 (d, J= 7.4, 1H), 2.36 (s, 3H), 2.28 (s, 3H) 47 'H NMR (300 MHz, MeOD) 68.99 (s, 1H), 8.76 (d, J= 9.2, 1H), 8.32 (d, J= 8.7, 1H), 8.22 (d, J= 8.6, 1H), 8.11 (d, J= 7.8, 1H), 8.01 (t, J= 7.1, 1H), 7.76 (t, J= 7.4, 1H), 7.55 - 7.43 (m, 2H) MS (ESI) [M+H]=247
Ex Characterizations
48 'HNMR(300 MHz, MeOD)6 8.48(d,J=9.1, 1H), 8.40(d,J=6.7, 1H), 7.94(d, J= 8.4, 1H), 7.90 (d, J= 7.8, 1H), 7.54 (t, J= 8.0, 1H), 7.38 (d, J= 8.6, 1H), 7.30 (s, 2H), 2.58 (s, 3H) MS (ESI) [M+H]=270 49 'H NMR (300 MHz, CDC 3) 69.34 (s, 1H), 8.95 (s, 1H), 8.21 (d, J= 5.1, 1H), 7.87 (d, J= 8.9, 1H), 7.71 (d, J= 7.5, 1H), 7.52 (d, J= 7.9, 1H), 7.19 (t, J= 7.8, 1H), 7.05 (d, J= 8.9, 1H), 6.84 (d, J= 5.1, 1H), 2.76 (q, J= 7.6, 2H), 1.37 (t, J= 7.6, 3H) 'H NMR (300 MHz, CDC13) 6 8.57 (d, J= 29.4, 1H), 7.80 (d, J= 8.8, 1H), 7.66 (t, J= 6.7, 2H), 7.46 (d, J= 7.9, 1H), 7.14 (t, J= 7.8, 1H), 7.06 (d, J= 8.8, 1H), 6.79 (d, J= 7.3, 1H), 2.73 (dd, J= 7.6, 15.2, 2H), 1.28 (t, J= 7.7, 3H) 51 'H NMR (300 MHz, CDC 3) 68.64 (s, 1H), 8.06 (s, 1H), 7.89 (d, J= 8.7, 1H), 7.71 (d, J= 7.4, 1H), 7.54 (d, J= 7.8, 1H), 7.20 (t, J= 7.7, 1H), 7.02 (d, J= 8.8, 1H), 6.67 (s, 1H), 2.43 (s, 3H), 2.39 (s, 3H) 13 C NMR (75 MHz, CDC1 3) 6 156.15, 153.17, 152.82, 150.16, 143.70, 137.92, 131.34, 129.89, 126.49, 125.47, 123.43, 118.62, 114.47, 111.02, 24.13, 21.70. MS (ESI) [M+H]*=284 52 'H NMR (300 MHz, CDC 3) 68.89 (d, J= 8.8, 1H), 8.05 (d, J= 8.8, 1H), 8.01 (s, 1H), 7.93 (d, J= 8.8, 1H), 7.79 (d, J= 7.5, 1H), 7.64 (d, J= 8.0, 1H), 7.32 (t, J= 7.8, 1H), 7.13 (d, J= 8.8, 1H), 2.67 (s, 3H) 53 'H NMR (300 MHz, CDC 3) 69.27 (s, 1H), 8.33 (d, J= 5.7, 1H), 8.13 (d, J= 5.2, 1H), 8.00 (d, J= 8.8, 1H), 7.76 (d, J= 7.4, 1H), 7.60 (d, J= 8.0, 1H), 7.29 (d, J= 7.9, 1H), 7.07 (d, J= 8.9, 1H), 6.97 (d, J= 4.8, 1H) 54 MS (ESI) [M+H]*=250
'H NMR (300 MHz, CDC 3) 68.19 (s, 1H), 7.90 (d, J= 9.0, 1H), 7.63 (d, J= 7.5, 1H), 7.52 (d, J= 7.9, 1H), 7.33 (d, J= 7.4, 1H), 7.14 (t, J= 7.8, 1H), 6.69 (d, J= 7.5, 1H), 2.70 (dd, J= 7.3, 14.8, 2H), 2.47 (s, 3H), 1.26 (t, J= 7.7, 3H) 56 'H NMR (300 MHz, CDC 3) 68.20 (s, 1H), 7.90 (d, J= 9.0, 1H), 7.63 (d, J= 7.5, 1H), 7.52 (d, J= 7.9, 1H), 7.33 (d, J= 7.4, 1H), 7.14 (t, J= 7.8, 1H), 6.69 (d, J= 7.5, 1H), 2.70 (dd, J= 7.3, 14.8, 2H), 2.47 (s, 3H), 1.25 (dd, J= 7.5, 15.5, 3H) 57 MS (ESI) [M+H]*=253
58 MS (ESI) [M+H]=314-316
59 'H NMR (300 MHz, CDC 3) 6 8.91 (d, J= 1.7, 1H), 8.46 (d, J= 8.8, 1H), 8.28 (dd, J= 2.0, 8.8, 1H), 8.23 (s, 1H), 8.03 (d, J= 8.8, 1H), 7.88 (d, J= 8.3, 1H), 7.70 (d, J = 8.0, 1H), 7.67 - 7.58 (m, 1H), 7.38 (t, J= 7.4, 1H), 7.32 (d, J= 8.8, 2H), 3.91 (s, 3H) 'H NMR (300 MHz, CDC 3) 68.94 (d, J= 8.9, 1H), 8.91 (d, J= 1.8, 1H), 8.37 (dd, J= 2.2, 8.8, 1H), 8.04 (d, J= 8.9, 2H), 7.77 (d, J= 7.5, 1H), 7.62 (d, J= 7.2, 1H), 7.30 (t, J= 7.8, 2H), 7.19 (d, J= 8.8, 2H), 3.92 (s, 3H) 61 'H NMR (300 MHz, CDC 3) 6 8.96 (d, J= 8.8, 1H), 8.85 (d, J= 1.3, 1H), 8.28 (d, J = 9.9, 1H), 7.84 (d, J= 8.0, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.59 (d, J= 8.4, 2H), 7.53 (d, J= 8.4, 1H), 7.31 (t, J= 7.4, 1H), 3.88 (s, 4H), 2.42 (s, 4H) MS (ESI) [M+H]*=294
Ex Characterizations
62 'HNMR(300 MHz, CDCl 3)6 11.02 (s, 1H), 8.75 (d,J=9.2, 1H), 8.44(d,J=3.7, 1H), 8.31 (d,J=7.9, 1H), 8.10(d,J=9.0, 1H),7.72(d,J=7.5, 1H), 7.64(d,J= 8.2, 1H), 7.27 (d,J=8.1, 1H), 6.88 (dd,J=4.7,7.8, 1H), 3.97 (s, 3H) MS (ESI) [M+H]=314 63 MS (ESI) [M+H]=266
64 'HNMR(300 MHz, DMSO)6 10.38(s, 1H), 8.56(s, 1H), 8.28 (d,J=9.1, 1H), 8.20 - 8.03 (m, 3H), 7.50 (d, J= 8.7, 1H), 7.45 (d, J= 8.0, 1H), 6.88 (d, J= 4.4, 1H), 2.37 (s, 3H) MS (ESI) [M+H]=314-316
66 MS (ESI) [M+H]*=250
67 'HNMR (300 MHz, DMSO) 6 10.51 (s, 1H), 8.83 (d, J= 2.3, 1H), 8.62 (d, J= 9.3, 1H), 8.24 (dd, J= 2.7,9.1, 1H), 7.96 (d, J= 8.9, 1H), 7.81 (d, J= 7.8, 1H), 7.67 (t, J= 7.6, 1H), 7.45 (d, J= 11.2,2H), 3.86 (s, 3H), 2.62 (s, 3H) MS (ESI) [M+H]*=294 68 'H NMR (300 MHz, CDC 3) 69.57 (s, 1H), 8.44 (d, J= 4.8, 1H), 8.05 (d, J= 8.8, 1H), 7.86 (s, 1H), 7.80 (d, J= 7.5, 1H), 7.64 (d, J= 8.0, 1H), 7.31 (t, J= 7.8, 1H), 7.19 (d, J= 4.3, 1H), 7.04 (d, J= 8.8, 1H) 69 'H NMR (300 MHz, CDC 3 ) 69.12 (s, 1H), 7.94 (d, J= 8.6, 1H), 7.71 (d, J= 7.5, 1H), 7.57 (d, J= 7.8, 1H), 7.40 (s, 1H), 7.25 (d, J= 10.2,2H), 7.17 (s, 1H), 7.05 (s, 1H) 'H NMR (300 MHz, CDC 3) 69.07 (d, J= 8.5, 1H), 7.97 (d, J= 8.8, 1H), 7.90 (t, J = 8.0, 1H), 7.84 (s, 1H), 7.75 (dd, J= 1.1, 7.5, 1H), 7.62 - 7.55 (m, 1H), 7.31 (d, J = 7.6, 1H), 7.27 (t, J= 7.8, 1H), 7.08 (d, J= 8.8, 1H) MS (ESI) [M+H]=274 71 MS (ESI) [M+H]=274
72 'H NMR (300 MHz, CDC13) 68.67 (d, J= 7.9, 1H), 7.83 (d, J= 8.3, 1H), 7.71 (s, 1H), 7.69 - 7.61 (m, 1H), 7.57 (d, J= 7.9, 2H), 7.52 (d, J= 7.1, 1H), 7.28 (t, J= 7.4, 1H), 2.74 (q, J= 7.6, 2H), 2.42 (s, 3H), 1.31 (t, J= 7.6, 3H) MS (ESI) [M+H]*=264 73 'H NMR (300 MHz, CDC 3) 68.91 (dd, J= 3.8, 9.0, 1H), 8.11 (d, J= 2.9, 1H), 7.81 (d, J= 8.3, 1H), 7.71 (s, 1H), 7.56 (dd, J= 7.4, 14.1, 2H), 7.51 - 7.42 (m, 1H), 7.29 (d, J= 7.2, 1H), 2.38 (s, 3H) MS (ESI) [M+H]*=254 74 'HNMR (300 MHz, CDC 3) 68.96 (d, J= 8.3, 1H), 8.49 (s, 1H), 7.89 (dd, J= 1.9, 9.0, 1H), 7.82 (d,J= 8.2, 1H), 7.72 (s, 1H), 7.57 (t, J= 8.7,3H), 7.33 (t,J= 7.4, 1H), 2.37 (s, 3H) MS (ESI) [M+H]=304 'HNMR (300 MHz, CDC 3 ) 6 7.83 (d, J= 9.0, 1H), 7.69 (dd, J= 1.3,7.6, 1H), 7.53 (dd, J= 1.2, 8.0, 1H), 7.42 (d, J= 8.9,2H), 7.15 (t, J= 7.8, 1H), 6.89 (d, J= 8.9, 2H), 6.79 (d, J= 8.9, 2H), 2.97 (s, 6H)
Ex Characterizations
77 'HNMR(300 MHz, CDCl 3 )6 7.83 (d,J= 8.8, 1H), 7.70 (d,J= 7.6, 1H), 7.59 (d,J = 8.6,2H), 7.52 (d,J=7.3, 1H), 7.16 (t,J=7.7,1H), 6.94 (d,J= 8.4,3H), 6.86 (d, J= 8.8, 1H), 3.82 (s, 3H) 13 C NMR (75 MHz, CDCl 3) 6 156.40, 155.54, 144.29, 138.09, 132.96, 130.44, 129.99, 126.61, 125.22, 123.29, 122.66, 114.73, 112.16, 55.74.
MS (ESI) [M+H]=285 78 'HNMR(300 MHz, CDC 3 ) 6 7.80 (t,J= 7.6,2H), 7.64 (d,J= 8.9,2H), 7.61 7.55 (m, 1H), 7.33 (t, J= 7.6, 1H), 7.19 (d, J= 8.7,2H), 2.59 (s, 3H) 79 'H NMR (300 MHz, CDC 3 ) 6 7.78 (d, J= 8.4, 1H), 7.76 - 7.71 (m, 2H), 7.69 (s, 1H), 7.57 (dd,J= 1.1, 8.0, 1H), 7.51 (ddd,J= 1.5,7.0,8.4, 1H), 7.29 -7.21 (m, 1H), 6.96 - 6.90 (m, 2H), 3.82 (s, 3H), 2.35 (s, 3H) 'H NMR (300 MHz, CDC 3 ) 6 7.92 (d, J= 8.9 Hz, 2H), 7.84 (d, J= 8.3 Hz, 1H), 7.78 (s, 1H), 7.62 (d, J= 8.0 Hz, 1H), 7.57 (t, J= 7.7 Hz, 1H), 7.32 (t, J= 7.4 Hz, 1H), 7.24 (d, J= 8.7 Hz, 2H), 6.53 (s, 1H), 2.42 (s, 3H) 13 C NMR (75 MHz, CDC1 3) 6 152.46, 146.25, 143.86, 139.33, 136.83, 128.93, 126.96, 126.71, 124.75, 123.56, 121.88, 120.44, 119.95, 17.77.
MS (ESI) [M+H]*=319 81 'H NMR (300 MHz, CDC 3 ) 6 7.75 (d, J= 8.3, 1H), 7.66 (d, J= 8.5, 3H), 7.55 (d, J = 7.8, 1H), 7.48 (t, J= 7.6, 1H), 7.20 (d, J= 7.2, 1H), 6.80 (d, J= 8.8, 2H), 6.32 (s, 1H), 2.93 (s, 7H), 2.35 (s, 3H) 82 'H NMR (300 MHz, CDC 3 ) 6 7.92 (d, J= 8.9, 1H), 7.82 - 7.70 (m, 2H), 7.66 (d, J = 7.8, 1H), 7.59 (t, J= 7.6, 1H), 7.30 (dd, J= 6.0, 13.5, 1H), 7.14 (s, 1H), 7.11 (s, 1H), 6.84 (d, J= 8.9, 1H), 2.32 (s, 3H) MS (ESI) [M+H]*=319 83 'H NMR (300 MHz, CDC 3 ) 6 7.93 - 7.86 (m, 1H), 7.85 (s, 1H), 7.82 (d, J= 8.4, 1H), 7.59 (dd, J= 8.2, 15.5, 2H), 7.44 - 7.38 (m, 1H), 7.29 (dd, J= 8.3, 16.8, 2H), 6.91 (d, J= 9.0, 1H), 6.87 (d, J= 8.3, 1H) MS (ESI) [M+H]=305 84 'HNMR (300 MHz, CDC 3) 68.67 (d, J= 8.1, 1H), 7.92 (d, J= 8.9, 1H), 7.85 (d, J = 8.4, 1H), 7.63 (d, J= 7.6, 1H), 7.58 (d, J= 7.3, 1H), 7.30 (dd, J= 6.8,14.8,3H), 7.02 (t, J= 7.8, 1H), 6.89 (d, J= 8.9, 1H) MS (ESI) [M+H]=305 86 'HNMR (300 MHz, CDC 3 ) 6 7.93 (d, J= 8.9, 1H), 7.83 (d, J= 8.3, 1H), 7.70 (d, J = 12.0, 1H), 7.61 (dd, J= 7.9, 18.1, 2H), 7.32 (d, J= 7.9, 1H), 7.31 - 7.25 (m, 1H), 7.21 (t, J= 6.5, 1H), 6.92 (d, J= 8.9, 1H), 6.79 - 6.68 (m, 1H) MS (ESI) [M+H]*=239 87 'H NMR (300 MHz, CDC 3) 68.27 (s, 1H), 7.76 (d, J= 8.9, 1H), 7.67 (d, J= 7.5, 1H), 7.51 (d, J= 8.2, 1H), 7.45 (d, J= 7.9, 1H), 7.28 (d, J= 8.2, 1H), 7.14 (t, J= 7.8, 1H), 6.86 (d, J= 10.1, 1H), 6.76 (d, J= 8.9, 1H) MS (ESI) [M+H]=339
Ex Characterizations
88 'H NMR (300 MHz, CDCl 3) 6 8.11 (dt, J= 2.1, 12.1, 1H), 7.76 (d, J= 8.9, 1H), 7.66 (dd, J= 1.2, 7.6, 1H), 7.45 (dd, J= 1.1, 8.0, 1H), 7.22 (dd, J= 1.4, 7.2, 2H), 7.18 (d, J= 7.6, 1H), 7.12 (d, J= 7.8, 1H), 6.75 (d, J= 8.9, 1H), 6.69 (d, J= 7.9, 1H) MS (ESI) [M+H]*=273 89 'H NMR (300 MHz, DMSO) 6 11.38 (s, 1H), 8.41 (d, J= 9.1, 1H), 7.93 (d, J= 7.8, 1H), 7.80 (dt, J= 8.1, 20.9, 4H), 7.50 (d, J= 7.8, 3H), 7.36 (d, J= 9.3, 1H) 'H NMR (300 MHz, CDC 3 ) 6 7.84 (d, J= 9.1, 2H), 7.79 (d, J= 8.9, 1H), 7.67 (dd, J= 1.2, 7.6, 1H), 7.48 (dd, J= 1.1, 8.0, 1H), 7.18 (s, 3H), 6.89 (s, 1H), 6.75 (d, J= 8.9, 1H) 13 C NMR (75 MHz, CDC1 3) 6 153.88, 144.30, 143.91, 139.00, 138.25, 131.13, 130.13,126.55,125.42,123.45,122.50,122.17,120.49,119.10,113.24.
MS (ESI) [M+H]=339 91 'H NMR (300 MHz, CDC 3) 68.74 (s, 1H), 8.54 (s, 1H), 8.46 (d, J= 8.8, 1H), 7.91 (dd, J= 5.5, 14.5, 2H), 7.79 (d, J= 8.9, 1H), 7.67 (d, J= 2.1, 1H), 7.56 (dd, J= 2.3, 8.9, 1H), 7.35 (d, J= 8.9, 1H) 92 'H NMR (300 MHz, CDC13) 68.67 (d, J= 7.9, 1H), 7.83 (d, J= 8.3, 1H), 7.71 (s, 1H), 7.69 - 7.61 (m, 1H), 7.55 (dd, J= 7.5, 14.4, 2H), 7.29 (d, J= 7.8, 1H), 6.80 (d, J= 7.4, 1H) 93 'H NMR (300 MHz, CDC 3) 69.21 (dd, J= 1.5, 8.4, 1H), 7.85 (d, J= 8.4, 1H), 7.73 (s, 1H), 7.58 (d, J= 7.8, 1H), 7.53 (dd, J= 1.3, 8.3, 1H), 7.40 - 7.35 (m, 1H), 7.32 (dd, J= 1.1, 4.6, 1H), 7.31 - 7.24 (m, 2H), 7.04 (s, 1H), 7.02 - 6.94 (m, 1H), 2.38 (s, 3H) 94 'H NMR (300 MHz, CDC 3) 6 8.16 (d, J= 8.7, 1H), 7.83 (d, J= 8.9, 1H), 7.63 (d, J = 7.6, 1H), 7.48 (d, J= 8.0, 1H), 7.13 (t, J= 7.8,1H), 7.08 (s, 1H), 7.04 (s, 2H), 6.81 (d, J= 8.9, 2H), 2.27 (s, 3H) MS (ESI) [M+H]=353 'H NMR (300 MHz, MeOD) 6 8.42 (s, 1H), 7.94 (d, J= 7.9, 1H), 7.83 (d, J= 8.1, 1H), 7.78 (d, J= 7.1, 1H), 7.72 (d, J= 8.7,2H), 7.58 (d, J= 8.2, 3H), 2.60 (s, 3H) MS (ESI) [M+H]=319 96 'H NMR (300 MHz, CDC 3 ) 6 7.79 (d, J= 8.9, 1H), 7.70 (d, J= 8.9, 1H), 7.64 (d, J = 8.9, 2H), 7.59 (d, J= 2.1, 1H), 7.50 (dd, J= 2.3, 8.9, 1H), 7.19 (d, J= 8.6,2H), 6.85 (d, J= 8.9, 1H) MS (ESI) [M+H]=281 97 'H NMR (300 MHz, MeOD) 68.11 (d, J= 8.4, 1H), 7.81 (s, 2H), 7.62 (d, J= 8.7, 3H), 7.51 (d, J= 8.3, 2H), 7.12 (s, 1H), 2.77 (s, 3H) MS (ESI) [M+H]*=319 98 MS (ESI) [M+H]*=383-385
99 MS (ESI) [M+H]=320
100 MS (ESI) [M+H]=316
Ex Characterizations
101 'H NMR (300 MHz, CDCl 3 ) 6 7.82 (d, J= 8.9, 1H), 7.70 - 7.63 (m, 1H), 7.51 (dd, J=5.3,7.6,3H), 7.14 (t,J=7.8,1H), 6.91 (d,J= 8.8,3H), 6.85 (d,J=9.0,2H), 3.96(t,J=6.5,2H), 1.84- 1.68 (m, 3H), 1.49 (dd,J=7.4,15.0,3H), 0.97 (t,J= 7.4, 3H) MS (ESI) [M+H]*=327 102 'HNMR (300 MHz, CDC 3 ) 6 7.89 (d, J= 8.9, 1H), 7.76 (d, J= 8.5, 1H), 7.63 (d, J = 8.1, 1H), 7.59 (s, 1H), 7.54 (d, J= 8.8,2H), 7.38 - 7.24 (m, 3H), 7.09 (d, J= 7.4, 1H), 7.02 (dd, J= 2.4, 8.8, 4H), 6.90 (d, J= 8.9, 1H) MS (ESI) [M+H]*=313 103 MS (ESI) [M+H]*=334
104 'HNMR (300 MHz, CDC1 3) 6 8.49 (d, J= 2.5, 1H), 7.89 (d, J= 8.8, 1H), 7.72 (d, J = 7.6, 1H), 7.63 (dd, J= 2.5, 8.9, 1H), 7.53 (d, J= 8.0, 1H), 7.23 (dd, J= 6.2,14.0, 2H), 7.04 (s, 1H), 6.81 (d, J= 8.8, 1H) MS (ESI) [M+H]=373 105 {HNMR (300 MHz, CDC 3) 6 8.85 (d, J= 2.6, 1H), 8.45 (d, J= 2.3, 1H), 8.01 (d, J = 8.1, 1H), 7.71 (d, J= 7.8, 1H), 7.58 (s, 1H), 7.53 (d, J= 7.6, 1H), 7.51 - 7.45 (m, 2H), 7.45 - 7.36 (m, 1H), 6.72 - 6.62 (m, 2H), 2.48 (s, 3H) 13C NMR (75 MHz, CDC1 3) 6 157.18, 154.80,145.42, 143.80,138.17, 135.04, 128.88, 128.76, 127.17, 127.04, 120.69, 115.22, 106.73, 24.38 106 'H NMR (300 MHz, DMSO) 6 10.24 (s, 1H), 9.06 (d, J= 2.3, 1H), 8.65 (d, J= 1.8, 1H), 8.60 (d, J= 8.3, 1H), 8.56 (d, J= 4.5, 1H), 7.97 (dd, J= 8.2,14.4,2H), 7.69 (t, J= 6.9, 1H), 7.59 (t, J= 7.4, 1H), 7.08 (dd, J= 4.6, 8.3, 1H) MS (ESI) [M+H]*=267 107 'H NMR (300 MHz, CDC13) 6 8.77 (dd, J= 1.5, 4.3, 1H), 8.06 (dd, J= 10.8, 18.4, 3H), 7.93 (d, J= 2.4, 1H), 7.57 (dd, J= 2.4, 9.0, 1H), 7.39 (ddd, J= 3.1, 8.3,12.5, 3H), 6.93 (d, J= 8.4, 1H), 6.89 (s, 1H), 2.29 (s, 3H) 108 'H NMR (300 MHz, CDC1 3) 6 8.72 (dd, J= 1.6,4.2, 1H), 8.61 (d, J= 2.4, 1H), 8.11 (d, J= 8.3, 1H), 8.00 (d, J= 9.0, 1H), 7.91 (dd, J= 1.2, 5.0, 1H), 7.69 (dd, J= 2.4, 9.1, 1H), 7.35 - 7.26 (m, 2H), 7.01 (dd, J= 1.2, 7.9, 1H), 6.77 (dd, J= 5.1, 7.8, 1H), 3.93 (s, 3H) 109 'H NMR (300 MHz, CDC13) 6 9.68 (s, 1H), 8.21 (s, 2H), 7.94 (d, J= 8.9, 1H), 7.79 (d, J= 9.2, 1H), 7.67 (d, J= 2.3, 1H), 7.56 (dd, J= 2.3, 8.9, 1H), 7.34 (d, J= 8.9, 1H) MS (ESI) [M+H]*=257 110 1H NMR (300 MHz, CDC 3) 6 10.32 (s, 1H), 8.33 - 8.21 (m, 2H), 8.05 (d, J= 8.9, 1H), 8.00 (dd, J = 1.2, 7.6, 1H), 7.69 (dd, J = 1.1, 7.8, 1H), 7.61 (s, 1H), 7.30 7.22 (m, 3H), 7.16 (d, J = 8.8, 1H). MS (ESI) [M+H]=301-303 111 'H NMR (300 MHz, CDC 3 ) 6 7.82 (d, J= 8.9, 1H), 7.70 - 7.63 (m, 1H), 7.51 (dd, J= 5.3, 7.6, 3H), 7.14 (t, J= 7.8, 1H), 6.91 (d, J= 8.8, 3H), 6.85 (d, J= 9.0, 2H), 3.96 (t, J= 6.5, 2H), 1.84 - 1.68 (m, 3H), 1.49 (dd, J= 7.4,15.0, 3H), 0.97 (t, J= 7.4, 36H)
Ex Characterizations
112 'HNMR(300 MHz, CDCl 3 )6 7.89 (d,J= 8.9, 1H), 7.76 (d,J= 8.5, 1H), 7.63 (d,J = 8.1, 1H), 7.59 (s, 1H), 7.54 (d,J=8.8,2H), 7.38-7.24(m, 3H), 7.09 (d,J=7.4, 1H), 7.02 (dd, J= 2.4, 8.8, 4H), 6.90 (d, J= 8.9, 1H) 13 C NMR (75 MHz, DMSO) 6 152.94, 150.19, 142.48, 142.18, 138.20, 137.55, 135.74,129.71, 126.99, 125.35, 123.84,114.75.
MS (ESI) [M+H]=255 113 'H NMR (300 MHz, CDC 3) 6 9.74 (s, 1H), 8.20 (s, 2H), 8.03 (d, J= 8.6, 1H), 7.87 (d, J= 7.6, 1H), 7.80 (s, 1H), 7.70 (d, J= 8.0, 1H), 7.63 (t, J= 7.7, 1H), 7.37 (t, J= 7.4, 1H), 7.30 (d, J= 8.7, 1H) 114 'H NMR (300 MHz, CDC 3 ) 69.67 (s, 1H), 8.34 - 8.12 (m, 2H), 7.84 (d, J= 8.0, 2H), 7.70 - 7.54 (m, 1H), 7.38 (t, J= 7.6, 1H), 7.17 (s, 1H), 2.61 (s, 3H) MS (ESI) [M+H]=237 115 'H NMR (300 MHz, CDC 3) 6 10.15 (s, 1H), 8.24 - 8.12 (m, 2H), 7.79 (s, 1H), 7.71 (s, 1H), 7.55 (t, J= 8.3, 2H), 7.30 (t, J= 7.9, 1H), 2.38 (s, 3H) MS (ESI) [M+H]=237 116 MS (ESI) [M+H]=240
117 MS (ESI) [M+H]*=253
118 MS (ESI) [M+H]=222
119 MS (ESI) [M+H]*=256
121 MS (ESI) [M+H]=222
124 'H NMR (300 MHz, CDC 3) 68.42 (s, 1H), 7.95 (dd, J= 1.3, 8.2, 1H), 7.87 - 7.78 (m, 3H), 7.70 - 7.61 (m, 1H), 7.55 - 7.47 (m, 1H), 7.26 (dd, J= 2.4,6.5,3H), 6.90 (s, 1H) MS (ESI) [M+H]=306 125 'H NMR (300 MHz, CDC 3) 6 8.42 (s, 1H), 8.03 (d, J= 9.5, 1H), 7.92 (d, J= 8.2, 1H), 7.73 (d, J= 8.2, 1H), 7.61 (t, J= 7.3, 1H), 7.46 (t, J= 7.2, 1H), 7.13 (s, 2H), 6.84 (s, 1H), 2.35 (s, 3H) 126 'H NMR (300 MHz, CDC 3) 6 8.40 (s, 1H), 8.03 (s, 1H), 7.94 (d, J= 8.2, 1H), 7.84 (d, J= 8.2, 1H), 7.65 (t, J= 7.4, 1H), 7.53 (d, J= 7.1, 1H), 7.48 (d, J= 7.2, 1H), 7.35 (t, J= 8.2, 1H), 7.22 (s, 1H), 6.94 (d, J= 8.1, 1H) 127 'H NMR (300 MHz, CDC 3) 68.85 (dd, J= 1.0, 8.3, 1H), 8.47 (s, 1H), 7.96 (d, J 8.2, 1H), 7.85 (d, J= 8.3, 1H), 7.72 - 7.61 (m, 1H), 7.57 - 7.47 (m, 1H), 7.42 7.36 (m, 1H), 7.33 (d, J= 10.0, 1H), 7.14 (s, 1H), 7.13 - 7.04 (m, 1H) 128 'H NMR (300 MHz, CDC 3) 6 9.17 (s, 1H), 8.68 (d, J= 9.1, 1H), 8.64 (d, J= 4.8, 2H), 8.15 (d, J= 9.1, 1H), 7.87 (d, J= 8.4, 1H), 7.76 (d, J= 8.1, 1H), 7.64 (t, J= 7.7, 1H), 7.39 (t, J= 7.5, 1H), 6.87 (t, J= 4.8, 1H) 13 C NMR (75 MHz, CDCl3) 6 158.34, 138.07, 129.85, 127.63, 127.31, 124.34, 114.20,113.90. 129 'H NMR (300 MHz, CDC13 ) 69.14 (s, 1H), 8.73 (d, J= 21.2, 3H), 8.17 (s, 1H), 7.73 (d, J= 20.3, 2H), 7.28 (d, J= 9.6, 2H), 6.91 (s, 1H)
Ex Characterizations
130 'HNMR(300 MHz, CDCl 3)6 9.05 (s, 1H), 8.64(d,J=4.8,2H), 8.52 (s, 1H), 7.89 (dd,J=8.5, 14.6,2H), 7.63 (t,J=7.5, 1H), 7.41 (t,J=7.4,1H), 6.86 (t,J=4.8, 1H), 2.74 (s, 3H) MS (ESI) [M+H]=237 132 'HNMR (300 MHz, CDC 3) 6 8.86 (d, J= 2.6, 1H), 8.70 (d, J= 2.5, 1H), 8.32 (d, J = 1.1, 1H), 8.25 - 8.21 (m, 1H), 8.10 (d, J= 2.7, 1H), 8.06 (d, J= 8.3, 1H), 7.82 (dd, J= 1.2, 7.9, 1H), 7.66 - 7.51 (m, 3H), 6.89 (s, 1H) 135 'H NMR (300 MHz, CDC 3) 6 9.09 (s, 1H), 8.71 (s, 1H), 8.54 (d, J= 8.4, 1H), 8.37 (dd, J= 1.0, 4.9, 1H), 7.96 (d, J= 8.2, 1H), 7.85 (d, J= 8.3, 1H), 7.82 - 7.74 (m, 1H), 7.66 (t, J= 7.6, 1H), 7.52 (dd, J= 7.0, 8.1, 1H), 7.02 (dd, J= 5.0, 7.2, 1H) MS (ESI) [M+H]*=223 136 'H NMR (300 MHz, CDC 3 ) 6 9.02 (s, 1H), 8.70 (s, 1H), 8.30 (s, 1H), 8.20 (d, J= 5.1, 1H), 7.94 (d, J= 8.1, 1H), 7.84 (d, J= 8.2, 1H), 7.64 (t, J= 7.6, 1H), 7.49 (t, J = 8.1, 1H), 6.83 (d, J= 5.0, 1H), 2.43 (s, 3H) 13 C NMR (75 MHz, CDC1 3) 6 153.28, 150.20, 148.55, 147.40, 140.93, 139.83, 138.35,130.44,129.16,127.18,126.28,119.70,113.75,21.87. MS (ESI) [M+H]*=237 137 'HNMR (300 MHz, DMSO) 6 11.10 (s, 1H), 9.03 (s, 1H), 8.82 - 8.75 (m, 1H), 8.56 (d, J= 8.9, 1H), 8.24 (dd, J= 2.3, 8.9, 1H), 7.96 (dd, J= 1.2,8.2, 1H), 7.87 (dd, J= 1.0, 8.3, 1H), 7.79 - 7.71 (m, 1H), 7.61 (ddd, J= 1.4,7.0,8.3, 1H)
MS (ESI) [M+H]*=248
138 'H NMR (300 MHz, CDC 3) 6 8.72 (s, 1H), 8.53 (s, 1H), 8.20 (d, J= 8.3, 1H), 7.93 (d, J= 8.2, 1H), 7.81 (d, J= 8.3, 1H), 7.62 (td, J= 3.4, 8.1, 2H), 7.53 - 7.43 (m, 1H), 6.83 (d, J= 7.4, 1H), 2.48 (s, 3H) 13 C NMR (75 MHz, CDC1 3) 6 156.86, 152.27, 148.40, 140.92, 139.70, 139.00, 138.35,130.42,129.13,127.14,126.27,117.76,110.01, 24.15. MS (ESI) [M+H]=237 139 'H NMR (300 MHz, CDC 3) 6 8.53 (s, 1H), 8.20 (d, J= 4.8, 1H), 8.04 (d, J= 8.3, 1H), 7.92 (d, J= 8.4, 1H), 7.87 (s, 1H), 7.79 (t, J= 7.6, 1H), 7.60 (t, J= 7.6, 1H), 6.88 (d, J= 4.7, 1H), 2.46 (s, 3H) 140 'H NMR (300 MHz, CDC 3 ) 6 9.93 (s, 1H), 8.19 (s, 1H), 8.05 (d, J= 8.1, 1H), 7.99 (s, 1H), 7.82 (d, J= 8.2, 1H), 7.69 (t, J= 7.6, 1H), 7.59 (t, J= 8.2, 1H), 2.53 (s, 4H) 141 'H NMR (300 MHz, CDC 3 ) 69.72 (s, 1H), 9.35 (s, 1H), 8.30 (d, J= 5.0, 1H), 8.05 (d, J= 7.7, 1H), 7.87 (d, J= 7.0, 1H), 7.66 (dd, J= 7.4, 16.9, 3H), 6.92 (d, J= 4.9, 1H), 2.58 (s, 3H) 143 'H NMR (300 MHz, DMSO) 6 8.85 (s, 1H), 8.42 (d, J= 5.3, 1H), 7.96 (d, J= 9.1, 1H), 7.44 (s, 1H), 7.30 (s, 4H), 7.28 - 7.21 (m, 2H), 6.66 (d, J= 5.3, 1H), 2.99 (s, 6H) 13 C NMR (75 MHz, DMSO) 6 156.82, 150.25, 149.69, 143.79, 141.71, 125.95, 122.33,118.88,117.37,115.95,109.39,104.92,43.57 MS (ESI) [M+H]+= 348 144 MS (ESI) [M+H]=390
Ex Characterizations
145 MS (ESI) [M+H]*=252
146 'H NMR (300 MHz, DMSO) 6 9.34 (s, 1H), 8.59 (d, J= 5.2, 1H), 8.53 (s, 1H), 8.13 (d, J= 5.1, 1H), 7.98 (d, J= 9.0, 1H), 7.66 (d, J= 9.1, 1H), 6.80 (d, J= 5.2, 1H), 6.76 (s, 1H), 6.69 (d, J= 4.9, 1H), 4.00 (s, 3H), 2.26 (s, 3H) 13 C NMR (75 MHz, DMSO) 6 161.31, 155.67, 151.63, 150.25, 147.77, 147.01, 142.97, 121.56, 119.16, 116.61, 114.75, 112.60, 111.41, 98.91, 55.78, 20.66. MS (ESI) [M+H]= 266
147 MS (ESI) [M+H]=279
149 MS (ESI) [M+H]=318
150 MS (ESI) [M+H]=280
151 'H NMR (300 MHz, CDC 3) 68.35 (s, 1H), 8.04 (d, J= 8.3, 1H), 7.82 (d, J= 8.9, 1H), 7.74 (d, J= 8.9, 1H), 7.60 (t, J= 7.8, 2H), 7.50 (dd, J= 2.3, 8.9, 1H), 7.36 (d, J= 8.9, 1H), 6.79 (d, J= 7.4, 1H), 2.75 (q, J= 7.6, 2H), 1.30 (t, J= 7.6, 3H). MS (ESI) [M+H]*= 284 152 'H NMR (300 MHz, CDC 3) 68.30 (d, J= 8.5, 1H), 8.08 (s, 1H), 7.90 (d, J= 9.0, 1H), 7.77 (d, J= 8.9, 1H), 7.65 (d, J= 2.2, 1H), 7.55 (td, J= 2.0, 8.8, 2H), 7.39 (d, J= 9.0, 1H), 2.31 (s, 3H). MS (ESI) [M+H]= 270 153 'H NMR (300 MHz, CDC 3) 6 8.75 (s, 1H), 8.54 (s, 1H), 8.46 (d, J= 8.8, 1H), 7.91 (dd, J= 5.5, 14.5, 2H), 7.79 (d, J= 8.9, 1H), 7.67 (d, J= 2.1, 1H), 7.56 (dd, J= 2.3, 8.9, 1H), 7.35 (d, J= 8.9, 1H). MS (ESI) [M+H]*= 324 154 'H NMR (300 MHz, DMSO) 6 9.08 (s, 1H), 8.12 (d, J= 8.4, 1H), 7.73 (d, J= 8.2, 2H), 7.66 (d, J= 10.0, 1H), 7.53 (s, 1H), 7.25 (s, 1H), 6.82 (s, 1H), 5.10 (s, 2H), 2.16 (s, 4H). MS (ESI) [M+H]= 285 155 'H NMR (300 MHz, CDC 3 ) 6 7.68 (d, J= 8.3, 1H), 7.61 (s, 1H), 7.56 (d, J= 11.5, 2H), 7.44 (d, J= 8.3, 1H), 7.38 (d, J= 7.8, 1H), 7.13 (t, J= 7.4, 1H), 6.80 (d, J= 8.7, 2H), 3.85 (t, J= 6.5, 2H), 2.18 (s, 3H), 1.73 - 1.58 (m, 2H), 1.48 - 1.31 (m, 2H), 0.88 (t, J= 7.3, 3H) MS (ESI) [M+H]= 307 156 'H NMR (300 MHz, CDC1 3 ) 6 7.75 (d, J= 9.1, 1H), 7.62 (d, J= 8.9, 1H), 7.58 (d, J = 2.2, 1H), 7.48 (dd, J= 2.4, 8.9, 1H), 7.30 (d, J= 8.9,2H), 6.86 (d, J= 9.0, 1H), 6.77 (d, J= 8.9, 2H), 6.71 (s, 1H), 2.97 (s, 6H) MS (ESI) [M+H]= 298 157 'H NMR (300 MHz, CDC13 ) 6 7.98 (d, J= 2.6, 1H), 7.89 (d, J= 8.9, 1H), 7.72 (d, J = 7.5, 1H), 7.62 (dd, J= 2.6, 8.8, 1H), 7.55 (d, J= 7.8, 1H), 7.20 (t, J= 7.8, 1H), 6.95 (d, J= 8.9, 1H), 6.84 (d, J= 8.9, 1H), 6.79 (s, 1H), 3.91 (s, 3H) MS (ESI) [M+H]= 319
Ex Characterizations
158 'HNMR(300 MHz, CDCl 3)67.89 (d,J= 9.0, 1H),7.70(dd,J= 1.2,7.5, 1H), 7.56(dd,J= 1.1, 8.0, 1H), 7.30(d,J=8.6, 1H),7.20(t,J=7.8, 1H),6.71 (t,J= 5.9, 2H), 6.64 (d, J= 9.5, 1H). MS (ESI) [M+H]= 354 159 'H NMR (300 MHz, CDCl 3) 6 8.80 (d, J= 2.6, 1H), 8.37 (d, J= 2.6, 1H), 8.01 (d, J = 8.1, 1H), 7.91 (dd, J= 1.6,4.9, 1H), 7.78 - 7.70 (m, 1H), 7.58 - 7.43 (m, 2H), 7.09 (dd, J= 1.6, 7.6, 1H), 6.84 (dd, J= 4.9, 7.6, 1H), 6.69 (s, 1H), 3.82 - 3.07 (m, 2H). 160 'H NMR (300 MHz, CDCl 3) 6 9.68 - 8.90 (m, 1H), 8.77 (s, 1H), 8.35 (s, 1H), 8.14 (d, J= 5.0, 1H), 7.96 (s, 1H), 7.79 (d, J= 8.8, 1H), 7.61 (d, J= 8.5, 1H), 6.88 (d, J = 4.8, 1H), 2.46 (s, 3H) 161 'H NMR (300 MHz, CDCl3) 69.98 (s, 1H), 8.70 (s, 1H), 8.45 (s, 1H), 8.27 (d, J= 5.2, 1H), 7.94 (d, J= 8.1, 1H), 7.84 (d, J= 8.2, 1H), 7.63 (t, J= 7.5, 1H), 7.48 (t, J = 7.5, 1H), 6.87 (d, J= 5.0, 1H), 2.74 (q, J= 7.6,2H), 1.34 (t, J= 7.6, 3H). MS (ESI) [M+H]*= 251 162 'H NMR (300 MHz, CDCl3) 6 8.73 (s, 1H), 8.70 - 8.60 (m, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 7.98 (d, J= 8.1, 1H), 7.86 (d, J= 7.9, 1H), 7.68 (t, J= 8.2, 1H), 7.54 (t, J 8.1, 1H), 2.49 (s, 3H) MS (ESI) [M+H]= 315 163 'H NMR (300 MHz, CDCl3) 6 8.75 (s, 1H), 8.68 (s, 1H), 8.01 (s, 1H), 7.95 (d, J= 8.2, 1H), 7.84 (d, J= 8.3, 1H), 7.64 (t, J= 8.2, 1H), 7.49 (t, J= 7.0, 1H), 6.69 (s, 1H), 2.45 (s, 3H), 2.38 (s, 3H) MS (ESI) [M+H]= 251 164 'H NMR (300 MHz, DMSO) 6 10.46 (s, 1H), 9.00 (s, 1H), 8.41 (s, 1H), 8.24 (d, J = 3.0, 1H), 7.90 (d, J= 8.2, 1H), 7.79 (d, J= 8.3, 1H), 7.69 (t, J= 7.0, 1H), 7.52 (t, J= 7.4, 1H), 6.98 (d, J= 4.8, 1H), 5.45 (q, J= 5.6, 1H), 4.58 (d, J= 5.7, 2H). MS (ESI) [M+H]*= 253 165 'H NMR (300 MHz, CDCl 3) 6 9.07 (s, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 8.18 (s, 1H), 8.09 - 8.01 (m, 1H), 7.94 (d, J= 8.4, 1H), 7.81 - 7.71 (m, 1H), 7.69 - 7.59 (m, 1H), 2.80 (s, 3H) MS (ESI) [M+H]= 282 166 'H NMR (300 MHz, CDC1 3) 6 8.49 (d, J= 5.0, 1H), 7.77 (d, J= 9.0, 1H), 7.32 (d, J = 2.0, 1H), 7.12 (d, J= 9.0,2H), 6.99 (dd, J= 2.0, J= 9.0, 1H), 6.82 (d, J= 9.0, 2H), 6.57 (d, J= 5.0, 1H), 5.78 (s, 1H), 3.74 (s, 3H), 3.17 (s, 4H), 2.62 (s, 4H), 2.34 (s, 3H) 167 MS (ESI) [M+H]=335
168 MS (ESI) [M+H]=321
The following examples illustrate in detail the preparation of compounds (51), (64), (110), (143) and (148) according to the invention. The structures of the products obtained have been confirmed at least by NMR spectra.
EXAMPLES According to route (A), the compound of formula (III) is placed in a protic solvent such as tert-butanol. The compound of formula (IV) is then added in a 1.1 molar ratio with respect to the compound of formula (III) in presence of an inorganic base, such as Cs2 CO3 or K 2 CO 3 , in a 2.8 molar ratio, in the presence of a diphosphine, such as Xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene), or X-Phos 2 Dicyclohexylphosphino-2',4',6'-triisopropylbipheny in a 2 mol% amount relative to the total amount of compound of formula (III), and in the presence of a catalyst, such as Pd(OAc) 2 or Pd 2dba3 in a 2 mol% amount relative to the total amount of compound of formula (III). The reaction mixture is then heated at 90°C, and stirred during 20 hours, under argon. The reaction mixture is concentrated under reduced pressure and the resulting residue is diluted with ethyl acetate. The organic phase is then washed twice with water, dried on magnesium sulphate, filtered and concentrated under reduced pressure. The residue could then be purified by column chromatography on silica gel to yield pure compounds (51), (64), (110), and (143).
According to route (B), the compound of formula (V) is placed in a protic solvent such as tert-butanol. The compound of formula (VI) is then added in a 1.1 molar ratio with respect to the compound of formula (V) in presence of Cs 2 CO 3 in a 2.8 molar ratio, in the presence of Xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) in a 2mol% amount relative to the total amount of compound of formula (V), and in the presence of a Pd(OAc) 2 , in a 2 mol% amount relative to the total amount of compound of formula (V). The reaction mixture is then heated at 90°C, and stirred during 20 hours, under argon. The reaction mixture is concentrated under reduced pressure and the resulting residue is diluted with ethyl acetate. The organic phase is then washed twice with water, dried on magnesium sulphate, filtered and concentrated under reduced pressure. The residue could then be purified by column chromatography on silica gel to yield pure compound (148).
Example 1: compound (51) of table I
According to route (A), a mixture of 2,8-dichloroquinoline (98.5mg) and 2-amino-4,6-dimethylpyridine (67.1mg), Pd(OAc) 2 (2.2mg), XantPhos (5.8mg) and Cs2CO3 (456mg) in 2mL of t-BuOH gave compound (51) (99.7mg).
Example 2: compound (64) of table I According to route (A), a mixture of 2-chloro-5-nitroquinoline (100.0 mg) and 2-amino-4-methylpyridine (57.6mg), Pd 2dba 3 (20mg), XantPhos (30mg) and K2 CO3 (270mg) in 3mL of t-BuOH gave compound (64) (14.0mg).
The preparation of 2-chloro-5-nitroquinoline is described in Patent application W02009/23844.
Example 3: compound (110) of table I According to route (A), a mixture of 8-bromo-2-chloroquinoline (500mg) and aminopyrazine (216mg), Pd 2dba 3 (95mg), XantPhos (120mg) and K2 CO3 (1.15g) in 12mL of t-BuOH gave compound (110) (245mg). The preparation of 8-bromo-2-chloroquinoline is described in Cottet, F. et al. Eur. J. Org. Chem. 2003, 8, 1559.
Example 4: compound (143) of table I According to route (A), a mixture of 7-chloro-4-(N,N dimethylamino)quinoline (500 mg), 4-trifluoromethoxyaniline (0.257mL), Pd 2dba 3 (110mg), XPhos (115mg) and K2 CO3 (1g) in lOmL of t-BuOH gave compound (143) (410mg). The preparation of 7-chloro-4-(N,N-dimethylamino)quinoline is described in Sanchez-Martin, R. et al. J. Med. Chem. 2005, 48, 3354.
Example 5: compound (148) of table I According to route (B), a mixture of 5,8-dimethylisoquinolin-6-amine (59mg) and 2-bromo-5-methylpyridine (86mg), Pd(OAc) 2 (2.2mg), XantPhos (5.8mg) and Cs2CO3 (456mg) in 2mL of t-BuOH gave compound (148) (48mg).
The preparation of 5,8-dimethylisoquinolin-6-amine is described in Australian Journal of Chemistry 1969, 22, 2489. 1H NMR (300 MHz, CDC3) 6 9.32 (s, 1H), 8.52 (d, J= 6.0, 1H), 8.07 (s, 1H), 7.72 (d, J = 6.0, 1H), 7.51 (s, 1H), 7.36 (dd, J = 2.1, 8.4, 1H), 6.69 (d, J = 8.3, 2H), 2.72 (s, 3H), 2.48 (s, 3H), 2.26 (s, 3H) MS (ESI) [M+H]+= 264
Example 6: Pharmacological data Standard operating procedure: Effect of drug compounds on invasion of MDA-MB231-D3H2LN cells into collagen
Background A key step in the generation of tumor metastasis is the invasion of tumor cells into the extracellular matrix, a major component of which is collagen. Therefore, the invasion of tumor cells into collagen in vitro may be indicative of the generation of metastasis in vivo. E. g., MDA-MB231-luc-D3H2LN mouse breast cancer cells display indeed both higher invasion into collagen in vitro and a higher metastatic potential in vivo as compared to MDA-MB231 cells (from which they were derived). Using these MDA MB231-luc-D3H2LN cells as a model, the aim of the experiment described here is to identify drug compounds that inhibit the invasion of tumor cells into collagen in vitro, therefore potentially inhibiting also the generation of tumor metastasis in vivo.
Assay principle. Step 1: Preparation of cells at the bottom of a collagen gel: Cells are suspended in a liquid collagen solution (4°C), distributed into BSA-coated wells, and then collected at the bottom of the wells by centrifugation. The collagen is then solidified by incubation at 37°C. The BSA coating improves the adhesion of the collagen gel. Step 2: Pre-treatment with the compounds to be tested: Concentrated drug solutions are then added on top of the collagen, and cells are pre-incubated for 24 h with the drugs at low serum conditions (0,025% FBS).
Step 3: Stimulation of invasion: Medium with 5% FBS is then added in order to stimulate invasion of the cells into the collagen gel. Step 4: Fixation and staining: Following another 24 h incubation, cells are fixed and nuclei are stained. Step 5: Analysis: Finally, plates are analyzed using an automated microscope. Fluorescent beads that have been included into the BSA coating serve to detect the bottom of the wells. Pictures of the stained nuclei are taken at the same level (0pm) as well as 25pm and 50pm above.
Note: In order to detect possible toxic effects, all compounds are tested in parallel in a viability assay. The viability assay is performed in parallel on serum-starved cells (as in the invasion assay) vs. cells under normal culture conditions (10% FBS).
Materials: General equipment: Freezer (- 20°C), refrigerator (4°C), ice machine, water bath (37°C), incubator (37°C / 5% C02 ), cell culture hood, vortex, vacuum pump, microscope, Malassez cell, Pipet aid, micropipettes (for pipetting 1 - 1000pl), multichannel pipettes (for pipetting 20 - 200ptl), standard cell culture centrifuge, refrigerated centrifuge for 96 well plates
General consumables: Sterile 96 well cell culture plates (for the viability assay), sterile tubes (1.5 / 15 / 50ml), sterile pipettes (5 / 10 / 25ml), sterile micropipette tips (for pipetting 1 - 1000pl), sterile Pasteur pipettes, sterile reagent reservoirs
General products: Sterile PBS, sterile Milli-Q water, DMSO, decomplemented FBS (frozen aliquots), 0.1 N NaOH, 1 M Hepes, MEM without serum (not older than 1 month), 2.5 x MEM without serum (not older than 1 month), MEM with 10% FBS (not older than one month), 0.25% trypsin / 1 mM EDTA solution, 37% formaldehyde solution
Specific equipment. plate reader: Tecan Infinite F200 automated microscope: Cellomics ArrayScan VTI HCS Reader
Specific consumables: sterile black 96 well plates (for the invasion assay): Perkin Elmer ViewPlate-96 F TC, ref. 6005225 sterile 96 deep well polypropylene plates (for drug preparation): Starlab, ref. S1896-5110
Specific products: rat tail collagen, type 1: BD Biosciences, ref. 354236 (note: each new lot has to be validated) red fluorescent beads (1 m diameter): Invitrogen, ref. F13083 Y-27632 (5 mM aqueous solution): Calbiochem, ref. 688001 (in solution) or 688000 (dry powder) BSA without fatty acids (sterile-filtered 4 % aqueous solution): Sigma, ref. A8806 (dry powder) Hoechst 33342 nuclear stain (10 mg/ml): Invitrogen, ref. H3570 MITS reagent: Promega CellTiter CellTiter 96* AQueous One Solution Reagent, ref. G3581 drug compounds to be tested: generally 25 or 50 mM in 100 % DMSO (aliquots stored at - 20 0C, then at 4 0 C for max. 3 months)
MDA-MB231-luc-D3H2LN cells: Limits for the cell cultures to be used in the assays: total passage number: max. 30 last passage: between 2 and 4 days before, between 1:3 and 1:20 cell density: between 50 and 90% (optimally 70 %) (between 1 and 2 x 106 cells per 100 mm dish)
Experimental procedures:
General considerations:Controls and plate maps:
Invasion assay: Negative control: No drug (just DMSO at equivalent concentration). Positive control: 10 pM Y-27632. To avoid edge effects, only the 60 central wells B2 - Gilare used; lines A and H as well as columns 1 and 12 remain free. Each drug is tested at least in triplicate. The positive and negative controls should be tested in double triplicates at different positions on each plate. Typical plate map(- = negative control, += positive control, 1 - 16 = 16 different drug compounds):
1 2 3 4 5 6 7 8 9 10 11 12 A B -1 2 3 4 5 6 7 8
+ C -1 2 3 4 5 6 7 8
+ D -1 2 3 4 5 6 7 8
+ E + 9 10 11 12 13 14 15 16 F + 9 10 11 12 13 14 15 16 G + 9 10 11 12 13 14 15 16 H
Viability assays: No additional controls. The MTS viability assay is based on colorimetric detection of a product generated by the mitochondrial activity of the cells. Each drug is tested at least in duplicate. To detect potential direct interactions with the assay substrate, each drug is also tested in absence of cells (background signals). Typical plate map (controls and drug compounds as in the invasion assay, lines A - B and E - F: with cells, lines C - D and G - H: without cells; each 1 plate with 10% vs. 0.025% FBS): 1 2 3 4 5 6 7 8 9 10 11 12 A - 1 2 3 4 5 6 7 8 +
B - 1 2 3 4 5 6 7 8 +
C - 1 2 3 4 5 6 7 8 +
D -1 2 3 4 5 6 7 8 +
E + 9 10 11 12 13 14 15 16 F + 9 10 11 12 13 14 15 16 G + 9 10 11 12 13 14 15 16 H + 9 10 11 12 13 14 15 16
The volumes or other quantities indicated in the following are required for testing 16 drug compounds per 96 wells-plate at 5pM each (+ controls) in an invasion assay and each one viability assay on serum-starved cells vs. cells under normal culture conditions according to the plate maps above. According to the number of tested compounds, the volumes and other quantities should be adapted for testing more or less compounds or different concentrations.
Day 1: Preparation and treatment of the cells (all steps are performed under a cell culture hood):
Preparation of 100 x concentrated drug solutions in 10% DMSO: prepare 10% DMSO in sterile PBS: 1.8 ml sterile PBS + 0.2 ml DMSO prepare 100pl/well 10% DMSO in PBS in 16 wells of a sterile 96 well polypropylene plate add each 1 or 2pl of the 50 or 25mM compound stock solutions, respectively mix by pipetting up and down
Preparation of 4 x concentrated drug and control solutions in 0.4% DMSO in MEM+ 0.1%FBS: prepare MEM + 0.1% FBS: 12ml MEM without serum + 12pl FBS (freshly thawed aliquot) prepare 480pl/well MEM + 0.1% FBS in 20 wells of a sterile 96 deep well polypropylene plate negative controls (no drug): add each 20pl 10% DMSO in sterile PBS positive controls (Y-27632): add each 14 pl sterile PBS + 2pl DMSO + 4pl 5 mM Y-27632 (freshly thawed aliquot) drug compounds: add each 20pl of the 100 x concentrated drug solutions in 10% DMSO mix by pipetting up and down store at RT until use
Coating of the plates for the invasion assay: mix 9.5ml MEM without serum + 0.5 ml 4% BSA without fatty acids + 1Il vortexed fluorescent beads (i. e. dilute 1:10000), vortex, distribute 100pl/well into the plate for the invasion assay centrifuge 30' with 1800 x g at 4°C (e. g. 3000 rpm in a Jouan GR412 centrifuge) remove supernatants by aspiration
Preparation of a 10 x 106 cells/ml cell suspension (during the centrifugation of the plates): remove medium, wash cells with ~ 10 ml/dish PBS, add 1 ml/dish 0.25% trypsin / 1mM EDTA incubate 30 - 60 s at 37°C add 5 - 10ml/dish pre-warmed MEM + 10% FBS homogenize by pipetting up and down using a 10ml pipette, pool all count cells using a Malassez cell centrifuge 2 x 106 (or more) cells for 5' with 150 x g at RT (850 rpm in a std. cell culture centrifuge) remove supernatant, resuspend cell pellet in 0.2ml (or more, respectively) MEM without serum, yielding 10 x 106 cells/ml
Preparation of the invasion assay (on ice; start during the centrifugation of the cells): mix on ice in a pre-chilled tube: example for a 3.4mg/ml collagen stock solution; volumes of collagen and water to be adapted according to the stock concentration of each collagen lot: 2.8ml 2.5 x MEM 441pwater 140pl 1 M Hepes 49pl 1 N NaOH 3.5ml 3.4mg/ml collagen stock solution (yielding 1.7mg/ml collagen in 7ml) homogenize by pipetting gently up and down (keep on ice) add 70pl of the 10 x 106 cells/ml cell suspension, homogenize by pipetting gently up and down (yields 0.1 x 106 cells/ml in 1.7mg/ml collagen in 7ml 1 x MEM +
20pM Hepes) (keep on ice) distribute 100pl/well (i. e. 10000 cells/well) into the coated wells of the plate for the invasion assay (all on ice) centrifuge 5' with 200 x g at 4°C (e. g. 1000 rpm in a Jouan GR412 centrifuge) add 200pl/well PBS to all free wells incubate 30' at 37 °C / 5% CO 2 (solidification of the collagen)
Preparation of the viability assay on serum-starved cells: add 50pl of the 10 x 106 cells/ml cell suspension to 5 ml MEM without serum (yields 0.1 x 106 cells/ml) distribute 100 pl/well of this suspension (i. e. 10000 cells/well) or MEM without serum without cells, respectively, into a standard 96 well tissue culture plate, according to the plate map above add 200pl/well PBS to all free wells incubate 30' at 37°C / 5% CO 2
Preparation of the viability assay on cells under normal culture conditions: add 30pl of the 10 x 106 cells/ml cell suspension to 5ml MEM + 10% FBS (yields 0.06 x 106 cells/ml) distribute 100pl/well of this suspension (i. e. 6000 cells/well) or MEM + 10% FBS without cells, respectively, into a standard 96 well tissue culture plate, according to the plate map above add 200pl/well PBS to all free wells incubate 30' at 37°C / 5% CO 2
Treatment with the drugs: add each 33pl/well of the 4 x concentrated drug solutions in MEM + 0.1%FBS to the corresponding wells in all three plates, according to the plate maps above incubate 24 h at 37°C / 5% CO 2
Day 2: Addition of FBS to stimulate the invasion:
Microscopic observation after 24 h of treatment: examine the cells of the viability assays
Addition of FBS (under a cell culture hood): prepare MEM + 5% FBS: 7.2ml MEM without serum + 0.8ml FBS (freshly thawed aliquot or rest of the aliquot thawed the day before if kept at 4°C) add 33ptl/well to all wells of invasion and viability assays incubate 24 h at 37C / 5% CO 2
Day 3: Stop:
Microscopic observation after 48 h of treatment: examine the cells of the viability assays
Viability assays: MITS assay: add each 33ptl/well of the MITS reagent, incubate 2.5 h at 37C / 5% CO 2 shake and read absorbance at 490nm (proportional to the viability) calculate the background-corrected signals by substracting the means of the background signals in absence of cells from the corresponding signals in presence of cells normalize the background-corrected signals with respect to the mean signal of the negative controls (no drug) (viabilities are thus expressed in "% of control")
Invasion assays: fixation and staining (formaldehyde must be manipulated under a fume cupboard): freshly prepare lpg/ml Hoechst 33342 in 18.5% formaldehyde: 5 ml PBS (not necessarily sterile) + 5ml 37% formaldehyde + 1 l 10 mg/ml Hoechst 33342 (note: for one plate, a smaller volume would be sufficient, but the minimal pipetted volume should not be below 1Il) add 50pl/well to all wells of the invasion assay (yields 4.3% formaldehyde final) seal with black film (provided with the plates) incubate at least 7 h at RT
Day 3: 17 (min. 7 h / max. 2 weeks after fixation and staining): Analysis of the invasion assay:
Lecture using the Cellomics ArrayScan VTI HCS Reader: BioApplication: SpotDetector.V3 Plate type: Perkin Elmer 96 well Parameters of the Assay Protocol: objective: 10 x (NA.45) apotome: yes (resulting optical slice: 11.7pM) fields per well: 8 autofocus in each field autofocus channel: 1 channel 1 (autofocus on, and photo of the fluorescent beads at the bottom of the wells): filter: XF93 - TRITC; exposure time: usually between 0.002 and 0.01 s channel 2 (photo of the stained cells at the same level as the fluorescent beads): filter: XF100 - Hoechst; exposure time: usually between 0.02 and 0.1 s; z offset: 0M channel 3 (photo of the stained cells 25pM above the fluorescent beads): filter: XF100 - Hoechst; exposure time: usually between 0.02 and 0.1 s; z offset: - 25pM channel 4 (photo of the fluorescent cells 50pM above the fluorescent beads): filter: XF100 - Hoechst; exposure time: usually between 0.02 and 0.1 s; z offset: - 50piM object identification: method: fixed threshold: 100 - 32767 object selection parameters: min. max. SpotArea: 20 1000000000000 SpotShapeBFR: 0.2 1000 SpotShapeBAR: 0 1000 SpotAvglnten: 200 32767 SpotTotallnten: < 4000 (thus not limiting) 1000000000000 TargetAvglnten: 0 32767 TargetTotalInten: 0 1000000000000 Analysis of the results of the scan using vHCS Viewer: export the results: for each well: number of valid fields number of objects in each valid field in each of the channels 2, 3 and 4 ("field details") mean numbers of objects per valid field for each well, in each of the channels 2, 3 and 4 exclude wells with less than 6 valid fields per well from further analysis visually check all photos for any apparent problems, such as bad focusing or obviously inhomogeneous collagen structure ("bubbles", ... ), ... ; in case of apparent problems: document, then exclude the corresponding wells from further analysis
Further analysis of the results of the invasion assay (using e. g. Excel): for each well, calculate the mean invasion distance of the counted cells: (25pm x number of cells at 25pm + 50pm x number cells at 50pm) / sum of cells at 0, 25 and 50ptm for all four parameters (number of cells at Opm, number of cells at 25pm, number of cells at 50pm, mean invasion distance of the counted cells), calculate means, SD and CV of the replicates (n = 6 for the controls; n = 3 for the samples) invalidate any replicate with a CV > 50% (compound to be re-tested, or assay to be repeated if CV > 50% for the untreated negative control or the compound Y-27632 treated positive control). Y27632 is a selective inhibitor of the Rho-associated protein kinase p160ROCK of the following formula
S0 NH 2
N N CH 3
validate the assay only if the mean invasion distance of the cells treated with 10pM Y-27632 (positive control) is decreased by > 40% as compared to the untreated negative control
plot graphs of all four parameters (number of cells at Opm, number of cells at 25pm, number of cells at 50pm, mean invasion distance of the counted cells)
RESULTS Anti-invasive effect at 5 M on MDA-MB231 breast cancer cells (fold effect compared to 10pM Y-27632 ref. compound)
Compound Invasion of MDA MB231 cells at 5mM (family) (fold effect of positive control)
148 (lee) 0.54 109 (le) 0.41 110 (le) 0.64 112 (le) 0.26 143 (Iq) 0.8 144 (Iq) 0.73 63 (Ia) 0.69 64 (Ia) 1.16 6 (Ia) 0.63 18 (Ia) 0.52 45 (Ia) 0.50 30 (Ia) 0.33 35 (Ia) 0.26 36 (Ia) 0.43 37 (Ia) 0.34 48 (Ia) 0.63 53 (Ia) 0.27 51 (Ia) 1.06 52 (Ia) 0.27 58 (Ia) 0.33 61 (Ia) 0.34 58 (Ia) 0.33 55 (Ia) 0.27 56 (Ia) 0.26
The compounds according to the present invention demonstrate an anti invasive effect predictive for their activity against cancer.
Therefore, the result of the tests carried out on the compounds disclosed in the present invention show that said compounds may be useful to inhibit, prevent and/or treat cancer. The following type of cancer may more particularly be treated by the compounds according to the present invention: colorectal cancer, pancreatic cancer, lung cancer including non-small cell lung cancer, breast cancer, bladder cancer, gall bladder cancer, thyroid cancer, melanoma, liver cancer, uterine/cervical cancer, oesophageal cancer, kidney cancer, ovarian cancer, prostate cancer, head and neck cancer, and stomach cancer, etc. For this purpose an effective amount of a said compound may be administered to a patient suffering from cancer.
The present disclosure is also related to the use of at least a compound chosen among a compound of anyone of formula (I), (a), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (1k), (Il), (m), (Io), (Ip), (Iq), (Ir) or (Tee) as defined above, and compounds (1) to (168) as defined above, or one of its pharmaceutically acceptable salts according to the present disclosure for the manufacture of a pharmaceutical composition intended for the treatment of cancer. Also described are pharmaceutical compositions comprising at least a compound chosen among new compounds of formula (Iq) or (Tee) as defined above and compounds (143), (144), (149), (166) and (167) as defined above or any pharmaceutically acceptable salt thereof. Thus, these pharmaceutical compositions contain an effective amount of said compound, and one or more pharmaceutical excipients. The aforementioned excipients are selected according to the dosage form and the desired mode of administration. In this context they can be present in any pharmaceutical form which is suitable for enteral or parenteral administration, in association with appropriate excipients, for example in the form of plain or coated tablets, hard gelatine, soft shell capsules and other capsules, suppositories, or drinkable, such as suspensions, syrups, or injectable solutions or suspensions, in doses which enable the daily administration of from 0.1 to 1000 mg of active substance. The present disclosure is also related to the use of a compound of anyone of formula (I), (Ta), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (1k), (Il), (m), (Io), (Ip), (Iq), (Ir) or (Tee) as defined above, and compounds (1) to (168) as defined above, or one of its pharmaceutically acceptable salts described herein for the manufacture of a pharmaceutical composition intended for inhibiting, preventing and/or treating cancer. The present disclosure further relates to a method of treatment of patients suffering from cancer, which comprises at least a step of administration to a patient suffering thereof of an effective amount of a compound of anyone of formula (I),(a), (b), (Ic), (Td), (Te), (If), (Tg), (Th), (Ii), (j), (Tk), (Tl), (Tm), (o), (p), (Iq), (Ir) or (Tee) as defined above and (1) to (168) or one of its pharmaceutically acceptable salts.

Claims (6)

1. Use of a compound of formula (Ib) or any one of its pharmaceutically acceptable salts in the manufacture of a medicament to prevent, inhibit or treat breast cancer, pancreatic cancer, prostate cancer, lung cancer, non-small cell lung cancer, thyroid cancer, liver cancer, and kidney cancer:
Rn R'n'
R" (Ib) wherein: R independently represents a hydrogen atom, a halogen atom or a group chosen among a -CN group, a hydroxyl group, a -COOR group, a (C-C3)fluoroalkyl group, a (Ci-C3)fluoroalkoxy group, a -NO2 group, a -NRiR 2 group, a (C-C 4)alkoxy group, a phenoxy group and a (Ci-C 3 )alkyl group, said alkyl being optionally mono-substituted by a hydroxyl group, R 1 and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, n is 1, 2 or 3, n' is 1 or 2, R' is a hydrogen atom, a halogen atom or a group chosen among a (Ci-C 3 )alkyl group, a hydroxyl group, a -COOR 1 group, a -NO 2 group, a -NRR 2 group, a morpholinyl or a morpholino group, a N-methylpiperazinyl group, a (Ci-C3)fluoroalkyl group, a (Ci-C 4)alkoxy group and a -CN group, R" is a hydrogen atom or a (Ci-C4)alkyl group.
2. Use of a compound of formula (Ib) or any one of its pharmaceutically acceptable salts according to claim 1, wherein: R independently represent a hydrogen atom, a halogen atom or a group chosen among a (Ci-C3)alkyl group, a -NR1 R 2 group, a (Ci-C3)fluoroalkoxy group, a -NO 2 group, a phenoxy group and a (Ci-C4)alkoxy group, Ri and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group,
R" is a hydrogen atom or a (Ci-C4)alkyl group, n is 1, 2 or 3, n' is 1 or 2, R' is a hydrogen atom, a halogen atom or a group chosen among a (Ci-C3)alkyl group and a (C1-C 4)alkoxy group.
3. Use of a compound in the manufacture of a medicament to prevent, inhibit or treat breast cancer, pancreatic cancer, prostate cancer, lung cancer, non-small cell lung cancer, thyroid cancer, liver cancer, and kidney cancer, said compound being chosen among: - (8) Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine - (75) 4-N-(8-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine - (76) N-(4-methoxyphenyl)quinolin-2-amine - (77) 8-chloro-N-(4-methoxyphenyl)quinolin-2-amine - (78) 4-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (79) N-(4-methoxyphenyl)-3-methylquinolin-2-amine - (80) 3-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (81) 1-N,1-N-dimethyl-4-N-(3-methylquinolin-2-yl)benzene-1,4-diamine - (82) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (83) N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine - (84) N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine - (85) N-(4-nitrophenyl)quinolin-2-amine - (86) N-(3-fluorophenyl)quinolin-2-amine - (87) 8-chloro-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine - (88) 8-chloro-N-(3-fluorophenyl)quinolin-2-amine - (89) 2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride - (90) 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (91) 3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (92) 3-methyl-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine - (93) 3-methyl-N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine - (94) 8-chloro-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine
- (95) 3-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride - (96) 6-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine - (97) 4-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride - (98)8-bromo-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (99) 8-fluoro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (100) 8-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (101) N-(4-butoxyphenyl)-8-chloroquinolin-2-amine - (102) N-(4-phenoxyphenyl)quinolin-2-amine - (103) 8-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (104) 8-chloro-N-[3-chloro-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (155) N-(4-butoxyphenyl)-3-methylquinolin-2-amine - (156) 4-N-(6-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine - (157) 8-chloro-N-(3-chloro-4-methoxyphenyl)quinolin-2-amine - (158) N-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine - and their pharmaceutically acceptable salts.
4. A method of preventing, inhibiting or treating breast cancer, pancreatic cancer, prostate cancer, lung cancer, non-small cell lung cancer, thyroid cancer, liver cancer, and kidney cancer, which comprises at least one step consisting in administering to a patient suffering therefrom an effective amount of a compound of formula (Ib) or any one of its pharmaceutically acceptable salts
Rn R'n'
R" (Ib) wherein: R independently represents a hydrogen atom, a halogen atom or a group chosen among a -CN group, a hydroxyl group, a -COOR group, a (Ci-C3)fluoroalkyl group, a (Ci-C3)fluoroalkoxy group, a -NO2 group, a -NRiR 2 group, a (Ci-C4)alkoxy group, a phenoxy group and a (Ci-C3)alkyl group, said alkyl being optionally mono-substituted by a hydroxyl group, Ri and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, n is 1, 2 or 3, n'is 1or2, R' is a hydrogen atom, a halogen atom or a group chosen among a (Ci-C 3 )alkyl group, a hydroxyl group, a -COOR 1 group, a -NO 2 group, a -NRR 2 group, a morpholinyl or a morpholino group, a N-methylpiperazinyl group, a (Ci-C3)fluoroalkyl group, a (Ci-C 4)alkoxy group and a -CN group, R" is a hydrogen atom or a (Ci-C4)alkyl group.
5. A method of preventing, inhibiting or treating breast cancer, pancreatic cancer, prostate cancer, lung cancer, non-small cell lung cancer, thyroid cancer, liver cancer, and kidney cancer according to claim 4, wherein: R independently represent a hydrogen atom, a halogen atom or a group chosen among a (Ci-C3)alkyl group, a -NRiR 2 group, a (Ci-C3)fluoroalkoxy group, a -NO 2 group, a phenoxy group and a (Ci-C4)alkoxy group, R 1 and R 2 are independently a hydrogen atom or a (Ci-C3)alkyl group, R" is a hydrogen atom or a (Ci-C4)alkyl group, nis1,2or3, n' is 1 or 2, R' is a hydrogen atom, a halogen atom or a group chosen among a (Ci-C3)alkyl group and a (C1-C 4)alkoxy group.
6. A method of preventing, inhibiting or treating breast cancer, pancreatic cancer, prostate cancer, lung cancer, non-small cell lung cancer, thyroid cancer, liver cancer, and kidney cancer, which comprises at least one step consisting in administering to a patient suffering therefrom an effective amount of a compound, said compound being chosen among: - (8)Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine - (75) 4-N-(8-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine
- (76) N-(4-methoxyphenyl)quinolin-2-amine - (77) 8-chloro-N-(4-methoxyphenyl)quinolin-2-amine - (78) 4-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (79) N-(4-methoxyphenyl)-3-methylquinolin-2-amine - (80) 3-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (81) 1-N,1-N-dimethyl-4-N-(3-methylquinolin-2-yl)benzene-1,4-diamine - (82) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (83) N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine - (84) N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine - (85) N-(4-nitrophenyl)quinolin-2-amine - (86) N-(3-fluorophenyl)quinolin-2-amine - (87) 8-chloro-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine - (88) 8-chloro-N-(3-fluorophenyl)quinolin-2-amine - (89) 2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride - (90) 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (91) 3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (92) 3-methyl-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine - (93) 3-methyl-N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine - (94) 8-chloro-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (95) 3-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride - (96) 6-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine - (97) 4-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride - (98) 8-bromo-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (99) 8-fluoro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (100) 8-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (101) N-(4-butoxyphenyl)-8-chloroquinolin-2-amine - (102) N-(4-phenoxyphenyl)quinolin-2-amine - (103) 8-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine - (104) 8-chloro-N-[3-chloro-4-(trifluoromethoxy)phenyl]quinolin-2-amine - (155) N-(4-butoxyphenyl)-3-methylquinolin-2-amine
- (156) 4-N-(6-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine - (157) 8-chloro-N-(3-chloro-4-methoxyphenyl)quinolin-2-amine - (158) N-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine - and their pharmaceutically acceptable salts.
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