Derivatives of 1-(substituted sulfonyl)-2-aminoimidazoline as antitumor and antiproliferative agents

1. A method of treating a hyperproliferative disorder in a mammal, wherein the hyperproliferative disorder is colorectal cancer, ovarian cancer, liver cancer or lung cancer, the method comprising administering to said mammal a therapeutically effective amount of a compound of Formula (I):

wherein:

R 1 is

(a) a hydrogen atom;

(b) a substituted or unsubstituted alkyl;

(c) a substituted or unsubstituted aryl or heteroaryl;

(d) if R 1 is not H, its configuration may be either S or R;

R 2 is

(a) a substituted or unsubstituted alkyl;

(b) a substituted or unsubstituted phenyl;

(c) a 5- or 6-membered, optionally substituted, saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur;

(d) a saturated or unsaturated fused ring carbocyclic group, optionally substituted, having from 8 to 10 ring atoms;

(e) a saturated or unsaturated fused ring heterocyclic group, optionally substituted, having from 8 to 10 ring atoms including one to three heteroatoms selected from nitrogen, oxygen and sulfur;

X is a hydrogen atom, carbonyl, thiocarbonyl or imine.

If X is a hydrogen atom then R 3 is null.

If X is not hydrogen then R 3 is:

(a) a substituted or unsubstituted linear, branched or cyclic alkyl which additionally can be connected to an aromatic or heterocyclic moiety,

(b) a substituted or unsubstituted phenyl,

(c) a 5- or 6-membered, saturated or unsaturated heterocyclic group, optionally substituted, having from one to three heteroatoms selected from nitrogen, oxygen and sulfur;

(d) NR′(CH 2 ) n R″ where

R′ is hydrogen or alkyl,

n is 0-3,

R″ is unsubstituted or substituted alkyl, cycloalkyl, phenyl, benzyl, a 5- or 6-membered, optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, and

R′ and R″ can be connected or not,

(e) O(CH 2 ) n R″ or S(CH 2 ) n R″ where R″ and n are as defined above,

or a tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof.

2. A method of claim 1 wherein the hyperproliferative disorder is colorectal cancer.

3. A method of claim 1 , wherein the hyperproliferative disorder is lung cancer.

4. A method of claim 1 , wherein the hyperproliferative disorder is ovarian cancer.

5. The method of claim 1 wherein R 1 is unsubstituted or substituted alkyl, cycloalkyl, aryl, benzyl, 5- or 6-membered heterocycle, saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, with all of them optionally having 1-3 substituents selected from halo, alkyl, alkenyl, alkynyl, hydroxy, amino and alkoxy groups.

6. The method of claim 1 , wherein R 1 is attached to the 4,5-dihydro-1H-imidazol ring with S stereochemistry.

7. The method of claim 6 , wherein R 1 is phenyl optionally substituted with lower alkyl, halide or alkoxy groups.

8. The method of claim 1 , wherein R 2 is a heterocyclic moiety having more than 6 carbon atoms and one or more nitrogen, sulfur and/or oxygen atoms; the moieties may contain the atoms in a single ring or in fused rings and may be saturated or unsaturated and additionally substituted with amino or carboxy groups.

9. The method of claim 8 , wherein R 2 is indolyl, quinolyl, chromanyl, benzimidazolyl, benzoxazolyl, benzothienyl, benzofuranyl, or quinolinyl.

10. The method of claim 8 , wherein R 2 is indolinyl and X represents carbonyl moiety attached at position 1.

11. The method of claim 1 , wherein R 3 is unsubstituted or substituted alkyl, heteroalkyl, aryl, benzyl, 5- or 6-membered heterocycle, saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, with all of them optionally having 1-3 substituents selected from halo, alkyl, alkenyl, alkynyl, hydroxy, amino and alkoxy groups.

12. The method of claim 1 , wherein R 3 is:

(a) alkoxy, alkylthio, aryloxy or arylthio group optionally having 1-3 substituents selected from halo, alkyl, alkenyl, alkynyl, hydroxy, amino and alkoxy groups, or

(b) NR′(CH 2 ) n R″ wherein R′ is hydrogen or alkyl; n is 0-3; R″ is hydroxy or amino group, unsubstituted or substituted alkyl, phenyl, benzyl, a 5- or 6-membered, optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, and R′ and R″ can be connected or not.

13. The method of claim 1 , wherein R 3 is NH(CH 2 ) n R′″; n is 0-3; R′″ is lower alkyl, branched lower alkyl or cycloalkyl ring containing 3-7 carbon atoms.

14. The method of claim 1 , wherein the compound is selected from the group consisting of:

1-(phenylsulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(phenylsulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(4-N-methylamino-phenylsulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(4-N-acetyl-N-methylamino)-phenylsulfonyl-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[4-(2-furanoylamino)-phenylsulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[4-(1-pyrrolidin-2-onyl)-phenylsulfonyl]-4,5-dihydro-1H-imidazol-2-amine, and

(S)-4-phenyl-1-[4-(1-pyrrolidine-2,5-dionyl)-phenylsulfonyl]-4,5-dihydro-1H-imidazol-2-amine.

15. The method of claim 1 , wherein the compound is selected from the group consisting of:

(S)-4-phenyl-1-((N-1-methyl-1H-pyrrol-2-yloyl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(furan-2-yloylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-(5-(2-amino-4-isopropyl-4,5-dihydro-1H-imidazol-1-ylsulfonyl)indolin-1-yl)(furan-2-yl)methanone,

(S)-(5-(2-amino-4-cyclohexyl-4,5-dihydro-1H-imidazol-1-ylsulfonyl)indolin-1-yl)(furan-2-yl)methanone,

(S)-4-phenyl-1-(thiophene-2-yloylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(acetylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(propionylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(butyrylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(isobutyrylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(thiophen-2-ylacetylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(benzoylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(4-nitrobenzoylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(4-dimethylaminobenzoyl)-indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(4-ethoxybenzoylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(phenylacetylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(methoxycarbonylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(1-acetyl-piperidin-4-yloyl)-indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(cyclohexanyloyl-indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(naphthalen-4-yloyl)-indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(pyridin-3-yloyl)-indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(4-aminobenzoyl)-2-methylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(isopropylaminothiocarbonyl)-indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[1-butanoyl-3,4-dihydroquinoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(R)-4-phenyl-1-[1-butanoylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(4-fluorophenyl)-1-(furan-2-yloylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(4-fluorophenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(2,4-difluorophenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(4-chlorophenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(4-methoxyphenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(3-chlorophenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(2-chlorophenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(3-methylphenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(2-methylphenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-methyl-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(3,5-dichlorophenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(pyrimidin-2-yl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-1-(indolin-5-ylsulfonyl)-4-phenyl-4,5-dihydro-1H-imidazol-2-amine

(S)-4-phenyl-1-[(3-dimethylaminopropylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(3-dimethylaminopropyl-methylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(2-methoxyethanamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

1-[(2-methoxyethanamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(2-aminoethylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

1-[(2-aminoethylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(1-benzylpiperidin-4-ylamino)carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-isopropyl-1-[(3-dimethylaminopropylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-cyclohexyl-1-[(3-dimethylaminopropylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(4-fluorophenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(4-methoxyphenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(3-chlorophenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(3-methylphenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(2-methylphenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(2-chlorophenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(4-fluorophenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(4-methoxyphenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(3-chlorophenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(3-methylphenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(2-methylphenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(2-chlorophenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(4-chlorophenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(isopropylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(cyclopropylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[((cyclopropylmetyl)aminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[((cyclopropylethyl)aminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(isobutylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(tert-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(neopentylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(2-methylphenyl)-1-[(cyclopropylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(2-methylphenyl)-1-[((cyclopropylmetyl)aminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(2-methylphenyl)-1-[((cyclopropylethyl)aminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(2-methylphenyl)-1-[(neopentylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(2-methylphenyl)-1-[(tert-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine, and

(S)-4-(2-methylphenyl)-1-[(isobutylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine.

16. The method of claim 1 wherein the compound is administered with an anti-cancer agent.