Cyclopropanecarboxamido-substitute aromatic compounds as anti-tumor agents
Provided are cyclopropanecarboxamido-substituted aromatic compounds that inhibit protein kinases and their use in anti-tumor area. In particular, tyrosine-kinase inhibitors and Raf-kinase inhibitors as anti-tumor agents, their preparation, pharmaceutical composition, and their use in the treatment of cancer are also provided.
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof
wherein:
R 1 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, halo or cyano;
M is CH or N;
L is O, NH or N(CH 3 );
A is CR 5 or N;
W is CR 6 or N;
R 2 , R 5 and R 6 are independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, halo, C 3-7 cycloalkyl or cyano;
X, Y, and Z are independently CH or N; and
R 3 and R 4 are independently hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, di-(C 1-6 alkylamino)-C 1-6 alkyl, amino, C 1-6 alkylamino, C 3-7 cycloalkylamino, di-(C 1-6 alkyl)amino, amino-C 1-6 alkylamino, C 1-6 alkoxy-C 1-6 alkylamino, C 1-6 alkoxycarbonyl-C 1-6 alkylamino, di-(C 1-6 alkoxy-C 1-6 alkyl)amino, aminocarbonyl, C 1-6 alkylaminocarbonyl, di-(C 1-6 alkyl)aminocarbonyl, C 3-7 cycloalkylaminocarbonyl, C 1-6 alkoxy, C 3-7 cycloalkoxy, hydroxyl-C 1-6 alkoxy, C 1-6 haloalkoxy, amino-C 1-6 alkyl, amino-C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 2-6 alkenylsulfonyl, C 3-7 cycloalkylsulfonyl, heterocyclyl optionally substituted by B, aryl optionally substituted by B, heteroaryl optionally substituted by B, C 1-6 alkylsulfonylamino, C 2-6 alkenylsulfonylamino, C 3-7 cyclooalkylsulfonylamino, amido, C 1-6 alkylcarbonylamino, C 2-6 alkenylcarbonylamino, C 3-7 cyclooalkylcarbonylamino, C 1-6 alkoxycarbonylamino, C 3-7 cycloalkoxycarbonylamino, ureido, C 3-7 cycloalkyl, C 3-7 halocycloalkyl, heterocyclyl-oxy, piperidinylamino, N-methyl-piperidinyl-4-carbonyl, piperazinyl-C 1-6 alkyl, pyrrolylcarbonylamino, N-methyl-piperidinylcarbonylamino or heterocyclyl-C 1-6 alkoxy; or
R 3 and R 4 together form a 3 to 8-membered ring with the atoms in the aromatic ring to which they are attached; and
B is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, halo, hydroxyl, aryl, amino, C 1-6 alkylamino, C 3-7 cycloalkylamino, di-(C 1-6 alkyl)amino, cyano, or C 3-7 cycloalkyl.
2. The compound of claim 1 , wherein the NHCONH and L substituents on the central aromatic ring are in a 1,3-configuration.
3. The compound of claim 1 , wherein the NHCONH and L substituents on the central aromatic ring are in a 1,4-configuration.
4. The compound according to claim 1 , wherein L is O.
5. The compound according to claim 1 , wherein L is NH or N(CH 3 ).
6. The compound according to claim 1 , wherein X, Y, and Z are all CH.
7. The compound according to claim 1 , wherein one of X, Y, or Z is N and the other two are CH.
8. The compound according to claim 1 , wherein M is CH.
9. The compound according to claim 1 , wherein M is N.
10. The compound according to claim 1 , wherein A is CR 5 .
11. The compound according to claim 1 , wherein A is N.
12. The compound according to claim 1 , wherein W is CR 6 .
13. The compound according to claim 1 , wherein W is N.
14. The compound according to claim 1 , wherein R 1 is hydrogen or C 1-3 alkyl.
15. The compound according to claim 1 , wherein R 2 , R 5 and R 6 are independently hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, halo, or cyano.
16. The compound according to claim 1 , wherein R 3 and R 4 are independently hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, di-(C 1-6 alkylamino)-C 1-6 alkyl, amino, C 1-6 alkylamino, C 3-7 cycloalkylamino, di-(C 1-6 alkyl)amino, amino-C 1-6 alkylamino, C 1-6 alkoxy-C 1-6 alkylamino, C 1-6 alkoxycarbonyl-C 1-6 alkylamino, di-(C 1-6 alkoxy-C 1-6 alkyl)amino, aminocarbonyl, C 1-6 alkylaminocarbonyl, di-(C 1-6 alkyl)aminocarbonyl, C 3-7 cycloalkylaminocarbonyl, C 1-6 alkoxy, C 3-7 cycloalkoxy, hydroxyl-C 1-6 alkoxy, C 1-6 haloalkoxy, amino-C 1-6 alkyl, amino-C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 2-6 alkenylsulfonyl, C 3-7 cycloalkylsulfonyl, heterocycle optionally substituted by B, aryl optionally substituted by B, heteroaryl optionally substituted by B, C 1-6 alkylsulfonylamino, C 2-6 alkenylsulfonylamino, C 3-7 clcyoalkylsulfonylamino, amido, C 1-6 alkylcarbonylamino, C 2-6 alkenylcarbonylamino, C 3-7 clcyoalkylcarbonylamino, C 1-6 alkoxycarbonylamino, C 3-7 cycloalkoxycarbonylamino, ureido, C 3-7 cycloalkyl, C 3-7 halocycloalkyl, heterocyclyl-oxy, piperidinylamino, N-methyl-piperidinyl-4-carbonyl, piperazinyl-C 1-6 alkyl, pyrrolylcarbonylamino, N-methyl-piperidinylcarbonylamino or heterocyclyl-C 1-6 alkoxy.
17. The compound of claim 16 , wherein one or both of R 3 and R 4 are independently a heterocyclyl-oxy group selected from pyrrolyloxy, piperidinyloxy, furanyloxy and azetidinyloxy.
18. The compound of claim 16 , wherein one or both of R 3 and R 4 are independently an optionally substituted aryl group selected from phenyl and naphthyl.
19. The compound of claim 16 , wherein one or both of R 3 and R 4 are independently an optionally substituted hereroaryl group selected from furyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, quniolinyl and isoquinolinyl.
20. The compound of claim 19 , wherein the hereroaryl is pyridinyl, oxazolyl, or triazolyl.
21. The compound of claim 16 , wherein one or both of R 3 and R 4 are independently an optionally substituted heterocyclyl group selected from piperidinyl, piperazinyl, homopiperazinyl, azepinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, imidazolinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, thiadiazolidinyl, benzothiazolidinyl, benzopyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxothiomorpholinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl.
22. The compound of claim 21 , wherein the optionally substituted heterocyclyl is N(R 7 )piperazinyl, N(R 7 )piperidin-4-yl, pyrrolidinyl, 2-oxopyrrolidinyl, morpholinyl, 2-methylmorpholinyl, 2,6-dimethylmorpholinyl, 2-oxomorpholinyl, 3-(dimethylamino)pyrrolidinyl, 2-oxo-5-methyloxazolidin-3-yl, 3,3-difluoroazetidinyl, fluoropiperidinyl, hydroxylpiperidinyl, or 1,1,-dioxothiomorpholinyl, and R 7 is hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, C 1-5 acyl, or C 3-6 cycloalkylacyl.
23. The compound according to claim 18 , wherein B is hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, halo, hydroxyl, aryl, amino, C 1-3 alkylamino, C 3-5 cycloalkylamino, di-(C 1-3 alkyl)amino, cyano, or C 3-5 cycloalkyl.
24. The compound of claim 23 , wherein B is hydrogen, halo, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl, or di-(C 1-3 alkyl)amino.
25. The compound of claim 16 , wherein R 3 and R 4 are independently halo, cyano or C 1-3 haloalkyl.
26. The compound according to claim 1 , wherein R 3 and R 4 together form a 3 to 8-membered ring with the atoms in the aromatic ring to which they are attached.
27. The compound according to claim 1 , having following structures:
or pharmaceutically acceptable salts thereof.
28. A process of preparing a compound of Formula (I) according to claim 1 :
comprising reacting of compound (II):
with compound (III):
Wherein M, L, A, W, X, Y, Z and R 1 to R 4 are as defined in claim 1 .
29. A process of preparing a compound of Formula (I) according to claim 1 :
comprising reacting of compound (II):
with compound (IV):
Wherein M, L, A, W, X, Y, Z and R 1 to R 4 are as defined in claim 1 .
30. A process of preparing a compound of Formula (I) according to claim 1 :
comprising reacting of compound (V):
with compound (VI):
Wherein M, L, A, W, X, Y, Z and R 1 to R 4 are as defined in claim 1 .
31. A pharmaceutical composition comprising a compound according claim 1 , together with a pharmaceutically acceptable carrier or excipient.
32. A method of treating cancer comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1 , wherein the cancer is breast cancer, colon cancer, lung or prostate cancer.