Substituted triazole diamine derivatives as kinase inhibitors Number:6,924,302 from the United States Patent and Trademark Office (PTO) owispatent The present invention provides substituted triazole diamine derivatives as selective kinase or dual-kinase inhibitors and a method for treating or ameliorating a selective kinase or dual-kinase mediated disorder. derivatives, Substituted, Substituted, triazole, diamine, derivati, 6924302.html, Patent, pto, 6924302

Title: Substituted triazole diamine derivatives as kinase inhibitors

Abstract: The present invention provides substituted triazole diamine derivatives as selective kinase or dual-kinase inhibitors and a method for treating or ameliorating a selective kinase or dual-kinase mediated disorder.

Patent Number: 6,924,302 Issued on 08/02/2005 to Lin, et al.

Inventors: Lin; Ronghui (East Brunswick, NJ); Connolly; Peter J. (New Providence, NJ); Wetter; Steven K. (Flemington, NJ); Huang; Shenlin (Edison, NJ); Emanuel; Stuart L. (Doylestown, PA); Gruninger; Robert H. (Easton, PA); Middleton; Steven A. (Flemington, NJ)

Assignee: Ortho McNeil Pharmaceutical, Inc. (Raritan, NJ)

Appl. No.: 029750

Filed: December 21, 2001

Current U.S. Class: 514/383; 514/384; 548/265.2; 548/266.2

Intern'l Class: A61K 031/49.6; C07D 249//08; A61P 035//00

Field of Search: 548/2652,266.2 514/383,384

References Cited [Referenced By]

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5750545	May., 1998	Akahoshi et al.
Foreign Patent Documents
1 065 964	Apr., 1967	GB.
WO 9503286	Jul., 1994	WO.
WO 9921845	May., 1999	WO.
WO 0109106	Feb., 2001	WO.

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Primary Examiner: Desai; Rita
Assistant Examiner: Shiao; Robert

Parent Case Text

This Application claims priority from U.S. provisional patent application No. 60/257,703 entitled "1,2,4-triazole-3,5-diamine derivatives" filed Dec. 22, 2000 the contents of which are hereby incorporated by reference.

Claims

1. A compound of the following formula: ##STR41##

wherein

R₄ is selected from the group consisting of:

C_1-8alkyl, which is optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C_1-8)alkyl, -CO₂H, -CO₂(C_1-8)alkyl, amino, amino substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl, cyano, (halo)_1-3, hydroxy, nitro, cycloalkyl, aryl, thienyl, imidazolinyl, and triazolyl;

C_1-8alkoxy or C_1-8alkoxy substituted on a terminal carbon with a substituent selected from the group consisting of (halo)_1-3 and hydroxy;

-C(O)H, -C(O)(C_1-8)alkyl, -CO₂H, -CO₂(C_1-8)alkyl;

amino, or amino substituted with two substituents independently selected from the group consisting of C_1-8alkyl and -SO₂-(C_1-8)alkyl;

-C(O)amino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl;

-SO₂-, substituted with one substituent selected from the group consisting of thienyl, imidazolinyl, triazolyl and amino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C_1-8alkyl, -C_1-8alkylamino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl, thienyl, imidazolinyl, and triazolyl;

cycloalkyl, aryl, thienyl, imidazolinyl, and triazolyl; wherein cycloalkyl, aryl, thienyl, imidazolinyl, and triazolyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of C_1-8alkyl, wherein alkyl is optionally substituted on a terminal carbon with a substituent selected from the group consisting of amino, or amino substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl, cyano, (halo)_1-3, hydroxy and nitro, C_1-8alkoxy, amino, substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl), cyano, halo, hydroxy and nitro; and, wherein thienyl, imidazolinyl, or triazolyl are optionally substituted with 1 to 2 oxo substituents;

X is selected from the group consisting of -C(O)-, -C(S)- and -SO₂-; and,

R₃ is selected from the group consisting of:

C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, wherein alkyl, alkenyl and alkynyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C_1-8)alkyl, -CO₂H, -CO₂(C_1-8)alkyl, or amino substituted with two substituents independently selected from the group consisting of hydrogen, cyano, (halo)_1-3, hydroxy, nitro, aryl and thienyl, imidazolinyl, or triazolyl; wherein aryl, thienyl, imidazolinyl, or triazolyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of C_1-8alkyl, cyano, halo, (halo)_1-3(C_1-8)alkyl, (halo)_1-3(C_1-8)alkoxy, hydroxy, hydroxy(C_1-8)alkyl, hydroxy(C_1-8)alkoxy and nitro;

cycloalkyl, thienyl, imidazolinyl, triazolyl, and aryl, wherein cycloalkyl, thienyl, imidazolinyl, triazolyl, and aryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; and, wherein cycloalkyl, aryl, thienyl, imidazolinyl, or triazolyl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of:

C_1-8alkyl, C_2-8alkenyl, wherein alkyl and alkenyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C_1-8)alkyl, -CO₂H, -CO₂(C_1-8)alkyl, amino, amino substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl, cyano, (halo)_1-3, hydroxy, nitro, cycloalkyl, thienyl, imidazolinyl, triazolyl, and aryl, -CH(OH)-C_1-8)alkyl,

C_1-8alkoxy, optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)_1-3 and hydroxy;

-C(O)H, -C(O)(C_1-8)alkyl, -CO₂H, -CO₂(C_1-8)alkyl,

amino, or amino substituted with two substituents independently selected from the group consisting of hydrogen, C_1-8alkyl and -C(O)(C_1-8)alkyl,

-C(O)amino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl,

-SO₂-, substituted with one substituent selected from the group consisting of thienyl, imidazolinyl, triazolyl and amino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C_1-8alkyl and -C_1-8alkylamino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl;

-NH-SO₂-(C_1-8)alkyl,

cycloalkyl, thienyl, imidazolinyl, triazolyl, optionally substituted with 1 to 2 oxo substituents, aryl, thienyl, imidazolinyl, and triazolyl, with a proviso when R₃ is amino substituted with two substitutents, the two substitutents independently are not selected from hydrogen and aryl, wherein aryl is phenyl;

and pharmaceutically acceptable salts thereof.

2. A compound of the following formula: ##STR42##

wherein

R₄ is selected from the group consisting of:

amino, and amino substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl and -SO₂-(C_1-4)alkyl);

-SO₂-, substituted with one substituent selected from the group consisting of amino, or amino substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, -C_1-4alkylamino, wherein -C_1-4alkylamino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl;

X is selected from the group consisting of -CO(O)-, -C(S)- and -SO₂-;

and R₃ is selected from the group consisting of:

C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, wherein alkyl, alkenyl and alkynyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C_1-8)alkyl, -CO₂H, -CO₂(C_1-8)alkyl, amino or amino substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl, cyano, (halo)_1-3, hydroxy, nitro, aryl and thienyl, imidazolinyl, or triazolyl; wherein aryl, thienyl, imidazolinyl, or triazolyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of C_1-8alkyl, cyano, halo, (halo)_1-3(C_1-8)alkyl, (halo)_1-3(C_1-8)alkoxy, hydroxy, hydroxy(C_1-8)alkyl, hydroxy(C_1-8)alkoxy and nitro;

cycloalkyl, thienyl, imidazolinyl, triazolyl, and aryl, wherein cycloalkyl, thienyl, imidazolinyl, triazolyl, and aryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; and, wherein cycloalkyl, aryl, thienyl, imidazolinyl, or triazolyl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of:

C_1-8alkyl, C_2-8alkenyl, wherein alkyl and alkenyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C_1-8)alkyl, -CO₂H, -CO₂(C_1-8)alkyl, amino, amino substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl, cyano, (halo)_1-3, hydroxy, nitro, cycloalkyl, thienyl, imidazolinyl, triazolyl, and aryl,

-CH(OH)-(C_1-8)alkyl,

C_1-8alkoxy, optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)_1-3 and hydroxy;

-C(O)H, -C(O)(C_1-8)alkyl, -CO₂H, -CO₂(C_1-8)alkyl,

amino, or amino substituted with two substituents independently selected from the group consisting of hydrogen, C_1-8alkyl and -C(O)(C_1-8)alkyl,

-C(O)amino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl,

-SO₂-, substituted with one substituent selected from the group consisting of thienyl, imidazolinyl, triazolyl and amino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C_1-8alkyl and -C_1-8alkylamino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl;

-NH-SO₂-(C_1-8)alkyl,

cycloalkyl, thienyl, imidazolinyl, triazolyl, optionally substituted with 1 to 2 oxo substituents, aryl, thienyl, imidazolinyl, and triazolyl;

and pharmaceutically acceptable salts thereof.

3. A compound of the following formula: ##STR43##

wherein

R₄ is selected from the group consisting of:

-SO₂-, substituted with one substituent selected from the group consisting of thienyl, imidazolinyl, triazolyl and amino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C_1-8alkyl, -C_1-8alkylamino, wherein -C_1-8alkylamino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl, thienyl, imidazolinyl, and triazolyl; and

X is selected from the group consisting of -C(O)-, -C(S)- and -SO₂-;

R₃ is selected from the group consisting of:

C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, cycloalkyl, thienyl, imidazolinyl, triazolyl, and phenyl;

wherein the C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, cycloalkyl, thienyl, imidazolinyl, triazolyl, and phenyl substituents are optionally substituted with 1 to 3 substituents independently selected from the group consisting of C_1-8alkyl, C_1-8 alkyl(mono-, di- or tri-halo), C_1-8alkoxy, cyano, halo, hydroxy and nitro -C(O)(C_1-8)alkyl and -CH(OH)(C_1-8)alkyl;

and pharmaceutically acceptable salts thereof.

4. The compound of claim 3 wherein X, R₃ and R₄are dependently selected from the group consisting of: X R₃ R₄ C(O) (2,6-F₂)Ph 4-SO₂-NH₂; C(O) (2,6-F₂-3-CH₃)Ph 4-SO₂-NH₂; C(O) (2,4,6-F₃)Ph 4-SO₂-NH₂; C(O) (2-F)Ph 4-SO₂-NH₂; C(O) (2,4-F₂)Ph 4-SO₂-NH₂; C(O) (2-F-6-CF₃)Ph 4-SO₂-NH₂; C(O) (2,6-Cl₂)Ph 4-SO₂-NH₂; C(O) (2,4,6-Cl₃)Ph 4-SO₂-NH₂; C(O) (2-NO₂)Ph 4-SO₂-NH₂; C(O) [2,6-(OCH₃)₂]Ph 4-SO₂-NH₂; C(O) [2,4,6-(CH₃)₃]Ph 4-SO₂-NH₂; C(O) Ph 4-SO₂-NH₂; C(O) 2-thienyl 4-SO₂-NH₂; C(O) (3-CH₃)2-thienyl 4-SO₂-NH₂; C(O) (3-F)2-thienyl 4-SO₂-NH₂; C(O) (3-Cl)2-thienyl 4-SO₂-NH₂; C(O) (3-OCH₂CH₃)2-thienyl 4-SO₂-NH₂; C(O) (3-NHCOCH₃)2-thienyl 4-SO₂-NH₂; C(O) (5-CH₃)2-thienyl 4-SO₂-NH₂; C(O) (5-Br)2-thienyl 4-SO₂-NH₂; C(O) (5-COCH₃)2-thienyl 4-SO₂-NH₂; C(O) 3-thienyl 4-SO₂-NH₂; C(O) 3a, 7a-dihydrobenzo[b]thien-2-yl 4-SO₂-NH₂; C(O) (5-CH₂CH₃)2-thienyl 4-SO₂-NH₂; C(O) [3,5-(CH₃)₂]2-thienyl 4-SO₂-NH₂; C(O) (3-Br)2-thienyl 4-SO₂-NH₂; C(O) Cyclopentyl 4-SO₂-NH₂; C(O) Cyclohexyl 4-SO₂-NH₂; C(O) 2-thienyl-CH₂ 4-SO₂-NH₂; C(O) 2-thienyl-(CH)₂ 4-SO₂-NH₂; C(O) (2,6-F₂)-Ph-CH₂ 4-SO₂-NH₂; C(O) (2,6-F₂)Ph(CH)₂ 4-SO₂-NH₂; C(O) Cycloheptyl 4-SO₂-NH₂; C(O) 4-CH₃-cyclohexyl 4-SO₂-NH₂; C(O) 4-CH₃-cyclohexyl 4-SO₂-NH₂; C(O) 4-(CH₂)₃CH₃-cyclohexyl 4-SO₂-NH₂; C(O) 5-(2-pyridinyl)2-thienyl 4-SO₂-NH₂; C(O) 3-(1H-pyrrol-1-yl)2-thienyl 4-SO₂-NH₂; C(O) 5-[C(CH₃)₃]2-thienyl 4-SO₂-NH₂;

C(O) 5-[(CH)₂C(O)OC(CH₃)₃]2-thienyl 4-SO₂-NH₂; C(O) (2,6-F₂-3-NO₂)Ph 4-SO₂-NH₂; C(O) (2,6-F₂-3-NH₂)Ph 4-SO₂-NH₂; C(O) [2,6-(CH₃)₂]Ph 4-SO₂-NH₂; C(O) (2-CH₃)Ph 4-SO₂-NH₂; C(O) [2,6-F₂-3-CH(OH)CH₃]Ph 4-SO₂-NH₂; C(O) (2,6-F₂)Ph 4-SO₂-NH₂; C(O) (2,6-F₂3-CH₃)Ph 4-SO₂-NH₂; C(S) -NH[(2,6-F₂)Ph] 4-SO₂-NH₂; C(O) -NH[(2,6-F₂)Ph] 4-SO₂-NH₂; SO₂ (2,6-F₂)Ph 4-SO₂-NH₂; C(O) (2-Cl-3-CH₃-6-F)Ph 4-SO₂-NH₂; C(O) (2-Cl-6-F)Ph 4-SO₂-NH₂; and C(O) (2,6-F₂-5-Cl)Ph 4-SO₂-NH₂.

5. The compound of claim 3 wherein X, R₃ and R₄are dependently selected from the group consisting of: X R₃ R₄ C(O) (2,6-F₂)Ph 4-SO₂-NH₂; C(O) (2,6-F₂-3-CH₃)Ph 4-SO₂-NH₂; and C(S) -NH[(2,6-F₂)Ph] 4-SO₂-NH₂.

6. The compound of claim 3 which is selected from the group consisting of:

5-amino-3-[[4-(aminosulfonyl)phenyl]amino]-N-(2,6-difluorophenyl)-1H-1,2,4-triazole-1-carbothioamide;

5-amino-3-[[4-(aminosulfonyl)phenyl]amino]-N-(2,6-difluorophenyl)-1H-1,2,4-triazole-1-carboxamide;

4-[[5-amino-1-(2-chloro-6-fluoro-3-methylbenzoyl)-1H-1,2,4-triazol-3-yl]amino]-benzenesulfonamide;

4-[[5-amino-1-(2-chloro-6-fluorobenzoyl)-1H-1,2,4-triazol-3-yl]amino]-benzenesulfonamide;

4-[[5-amino-1-(2,6-difluoro-3-methylbenzoyl)-1H-1,2,4-triazol-3-yl]amino]-N-methyl-benzenesulfonamide;

4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazol-3-yl]amino]-N-methyl-benzenesulfonamide;

4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazol-3-yl]amino]-N-[2-(dimethylamino)ethyl]-benzenesulfonamide;

1-[4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazol-3-yl]amino]phenyl]-2-imidazolidinone.

7. The compound of claim 3 wherein X, R₃ and R₄are dependently selected from the group consisting of: X R₃ R₄ C(O) (2,6-F₂)Ph 4-SO₂-NH(CH₂CH₃); C(O) (2,6-F₂)Ph 4-SO₂-NH(CH₃); C(O) (2,6-F₂-3-CH₃)Ph 4-SO₂-NH(CH₃); C(O) (3-CH₃)2-thienyl 4-SO₂-NH(CH₃); C(O) [3,5-(CH₃)₂]2-thienyl 4-SO₂-NH(CH₃); C(O) (5-CH₂CH₃)2-thienyl 4-SO₂-NH(CH₃); C(O) [3,5-(CH₃)₂]2-thienyl 4-SO₂-N(CH₃)₂; C(O) (5-CH₂CH₃)2-thienyl 4-SO₂-N(CH₃)₂; C(O) (3-CH₃)2-thienyl 4-SO₂-N(CH₃)₂; C(O) (2,6-F₂-3-CH₃)Ph 4-SO₂-N(CH₃)₂; and C(O) (2,6-F₂)Ph 4-SO₂-N(CH₃)₂.

8. The compound of claim 3 wherein X, R₃ and R₄are dependently selected from the group consisting of: X R₃ R₄ C(O) (2,6-F₂-3-CH₃)Ph 4-(1-H-1,2,4-triazol-1-yl); C(O) (2,6-F₂)Ph 4-(1-H-1,2,4-triazol-1-yl); C(O) (5-CH₂CH₃)2-thienyl 4-(1-H-1,2,4-triazol-1-yl); C(O) [3,5-(CH₃)₂]2-thienyl 4-(1-H-1,2,4-triazol-1-yl); C(O) (3-CH₃)2-thienyl 4-(1-H-1,2,4-triazol-1-yl); C(O) (2,6-F₂)Ph 4-(1-H-1,3,4-triazol-1-yl); C(O) (2,6-F₂-3-CH₃)Ph 4-(1-H-1,3,4-triazol-1-yl); and C(O) (3-CH₃)2-thienyl 4-(1-H-1,3,4-triazol-1-yl).

9. The compound of claim 3 wherein X, R₃ and R₄are dependently selected from the group consisting of: X R₃ R₄ C(O) (2,6-F₂-3-CH₃)Ph 4-(1-H-1,2,4-triazol-1-yl); C(O) (2,6-F₂)Ph 4-(1-H-1,2,4-triazol-1-yl); C(O) (5-CH₂CH₃)2-thienyl 4-(1-H-1,2,4-triazol-1-yl); C(O) [3,5-(CH₃)₂]2-thienyl 4-(1-H-1,2,4-triazol-1-yl); C(O) (3-CH₃)2-thienyl 4-(1-H-1,2,4-triazol-1-yl); C(O) (2,6-F₂-3-CH₃)Ph 4-(1-H-1,3,4-triazol-1-yl); C(O) (3-CH₃)2-thienyl 4-(1-H-1,3,4-triazol-1-yl).

10. The compound of claim 3 wherein X, R₃ and R₄are dependently selected from the group consisting of: X R₃ R₄ C(O) (5-CH₂CH₃)2-thienyl 4-SO₂-NH[(CH₂)₂N(CH₃)₂]; C(O) (3-CH₃)2-thienyl 4-SO₂-NH[(CH₂)₂N(CH₃)₂]; C(O) (2,6-F₂-3-CH₃)Ph 4-SO₂-NH[(CH₂)₂N(CH₃)₂]; C(O) (2,6-F₂)Ph 4-SO₂-NH[(CH₂)₂N(CH₃)₂]; C(O) [3,5-(CH₃)₂]2-thienyl 4-SO₂-NH[(CH₂)₂N(CH₃)₂]; C(O) [3,5-(CH₃)₂]2-thienyl 4-NH-SO₂-CH₃; C(O) (3-CH₃)2-thienyl 4-NH-SO₂-CH₃; C(O) (5-CH₂CH₃)2-thienyl 4-NH-SO₂-CH₃; C(O) (2,6-F₂)Ph 4-NH-SO₂-CH₃; and C(O) (2,6-F₂-3-CH₃)Ph 4-NH-SO₂-CH₃.

11. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

Description

FIELD OF THE INVENTION

The present invention provides substituted triazole diamine derivatives as selective kinase or dual-kinase inhibitors and a method of use thereof. More particularly, the present invention provides substituted 1,2,4-triazole-3,5-diamine derivatives as selective kinase or dual-kinase inhibitors and a method for treating or ameliorating a selective kinase or dual-kinase mediated disorder.

BACKGROUND OF THE INVENTION

Patent application WO 99/21845 describes 4-aminothiazole derivatives as inhibitors of cyclin dependent kinases of the formula: ##STR1##
wherein
R₁ is a substituted or unsubstituted group selected from: C_1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl); C_1-6-alkenyl; C_1-6-alkynyl; C_1-6-alkoxyl; C_1-6-alcohol; carbocyclic or heterocyclic cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) or heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, morpholinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); carbonyl (e.g., carboxyl, ester, aldehyde, or ketone); ether; (C_1-6alkyl)-carbonyl; (C_1-6alkyl)-aryl; (C_1-6alkyl)-cycloalkyl; (C_1-6alkyl)-(C_1-6-alkoxyl); aryl-(C_1-6-alkoxyl); thioether (e.g., aryl-S-aryl, cycloalkyl-S-aryl, cycloalkyl-S-cycloalkyl, or dialkyl sulfide); thiol; and sulfonyl; and R₂is a substituted or unsubstituted: carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, ring structure; where each optional substituent for R₁and R₂is independently a halogen (e.g., chloro, iodo, bromo, or fluoro); oxygen (═O); haloalkyl (e.g., trifluoromethyl); C_1-6alkyl; C_1-6-alkenyl; C_1-6-alkynyl; hydroxyl; C_1-6-alkoxyl; carbocyclic cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; or ester; (ii) pharmaceutically acceptable salts of compounds of the Formula; and (iii) prodrugs and pharmaceutically active metabolites of compounds of the Formula or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier.

Patent application WO 01/09106 describes diamino-1,2,4-triazole-carboxylic and derivatives as GSK-3 (glycogen synthase kinase) inhibitors of formula (I): ##STR2##
wherein
the R³CZ-moiety may be attached to the nitrogen atom at position I or the nitrogen atom at position 2; R¹is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic; R²is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic, or R¹and R²together with the nitrogen atom to which they are attached may form a heterocyclic ring which ring may be unsubstituted or substituted; R³is alkyl, aryl, aralkyl, aryl(Q)alkyl, where Q is O or S, aralkenyl, alicyclic, heteroaryl, heteroaralkyl, arylcarbonylalkyl, alicyclylalkyl, diarylalkyl, or NR⁶R⁷; R⁴is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic; R⁵is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic, or R⁴and R⁵together with the nitrogen atom to which they are attached may form a heterocyclic ring which ring may be unsubstituted or substituted; R⁶is hydrogen, aryl or alicyclic; R⁷is hydrogen, aryl or alicyclic, and; Z is oxygen or sulphur. Suitably, R¹is hydrogen or unsubstituted or substituted phenyl, wherein the substituents for the phenyl group are independently selected from up to three of C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkoxy(C₁-C₆)alkyl, aryl, aryloxy, halo, hydroxy, carboxy, cyano, and nitro. Favourably, R¹is phenyl either unsubstituted or substituted with up to three of methyl, methoxy, or chloro. Suitably, R²is hydrogen or unsubstituted or substituted phenyl, wherein the substituents for the phenyl group are independently selected from up to three of C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkoxy(C₁-C₆)alkyl, aryl, aryloxy, halo, hydroxy, carboxy, cyano, and nitro. Favourably, R²is hydrogen. Suitably, R³is unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted benzyl, unsubstituted or substituted thienylmethyl, unsubstituted or substituted phenylthiomethyl, unsubstituted or substituted naphthylmethyl, unsubstituted or substituted furylethenyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted pyridyl, unsubstituted or substituted indolylmethyl, unsubstituted or substituted phenylcarbonylethyl, unsubstituted or substituted cyclopentenylmethyl, unsubstituted or substituted phenylpropyl, unsubstituted or substituted diphenylethyl, wherein the substituents for the R³aryl groups are selected from -O(CH₂)_nO-, where n is 1 to 3, or up to three of halo, aryl, perfluoro(C₁-C₆)alkyl, nitro, arylcarbonyl, aryloxy, C₁-C₆acyl; or R³is NR⁶R⁷where R⁶and R⁷are each independently hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted C₁-C₆alicyclic, wherein the substituents for the R⁶and R⁷groups are independently selected from up to three of halo, aryl, aryloxy, alkyl, nitro, and alkoxy. Favourably, R³is phenyl either unsubstituted or substituted with up to three of chloro, bromo, phenyl, trifluoromethyl, nitro, benzoyl, phenoxy, acetyl, or 3,4-OCH₂O-; naphthyl; benzyl either unsubstituted or substituted with up to three of phenyl or fluoro; 2-thienylmethyl; phenylthiomethyl 2-naphthylmethyl; cyclohexyl; 3-pyridyl; 3-indolylmethyl; phenylcarbonylethyl; cyclopent-2-enylmethyl; phenylpropyl; 2,2-diphenylethyl; or 2-furylethenyl; or NR⁶R⁷where R⁶and R⁷are each independently hydrogen, phenyl either unsubstituted or substituted with up to three of chloro, phenyl, phenoxy, methyl, bromo, nitro, or methoxy; cyclohexyl; or 1-naphthyl. Suitably, R⁴is hydrogen. Suitably, R⁵is hydrogen. Suitably, R⁶is unsubstituted or substituted aryl or unsubstituted or substituted alicyclic. Favourably R⁶is cyclohexyl, naphthyl or phenyl which phenyl group may be either unsubstituted or substituted with up to three of chloro, bromo, phenyl, methyl, phenoxy, nitro or methoxy. Suitably, R⁷is hydrogen.

U.S. Pat. No. 5,750,545 describes triazole derivatives, as agents for the prophylaxis and treatment of immune-related diseases, of formula (I) and formula (III): ##STR3##
wherein

X is an oxygen atom or a sulfur atom; W is -NR⁴R⁵or -SR⁶; R¹is a hydrogen atom, lower alkyl, -NR¹⁰R¹¹, -N═R¹³or a group of the formula (II) ##STR4##
wherein

Y is a hydrogen atom, a lower alkyl, a lower alkoxy, a halogen, a cyano, a nitro, a lower alkyl substituted by halogen, -N¹⁴R¹⁵, a tetrazolyl, an optionally substituted phenyl, a hydroxy or a carboxyl, L is a direct bond, an oxygen atom, a sulfur atom, an alkylene, a vinylene or an ethynylene, and n is an integer of 1 to 3, provided that when n is 2 or 3, Y may be the same or different; and R²and R³are the same or different and each is a hydrogen atom or a lower alkyl; wherein R⁴and R⁵are the same or different and each is a hydrogen atom, an optionally substituted lower alkyl, cycloalkyl, a phenyl or -(CH₂)_mCOOR¹⁶, R¹⁶is a hydrogen atom or a lower alkyl, m is an integer of 1 to 6, R⁶is a lower alkyl, R¹⁰and R¹¹are the same or different and each is a hydrogen atom, an optionally substituted benzoyl, an optionally substituted phenyl, a lower alkylcarbonyl or -COCOOR¹⁷, R¹⁷is a lower alkyl, R¹³is an optionally substituted methylene, R¹⁴and R¹⁵are the same or different and each is a hydrogen atom, a lower alkyl, -COCOOR¹⁷or -CSNHR¹⁸, and R¹⁸is a lower alkyl, or a pharmaceutically acceptable salt thereof.

Accordingly, it is an object of the present invention to provide substituted triazole diamine derivatives as selective kinase or dual-kinase inhibitors and a method of use thereof. It is an object of the present invention to provide substituted 1,2,4-triazole-3,5-diamine derivatives as selective kinase or dual-kinase inhibitors and a method of use for treating or ameliorating a selective kinase or dual-kinase mediated disorder.

SUMMARY OF THE INVENTION

The present invention provides a compound of Formula (I): ##STR5##
wherein

R₁ is selected from the group consisting of C_1-8alkyl,

cycloalkyl, heterocyclyl, aryl and heteroaryl {wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with a substituent selected from the group consisting of:

C_1-8alkyl (optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C_1-8)alkyl, -CO₂H, -CO₂(C_1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl), cyano, (halo)_1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),
C_1-8alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)_1-3 and hydroxy),
-C(O)H, -C(O)(C_1-8)alkyl, -CO₂H, -CO₂(C_1-8)alkyl,
amino (substituted with two substituents independently selected from the group consisting of hydrogen, C_1-8alkyl and -SO₂-(C_1-8)alkyl),
-C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl),
-SO₂- {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C_1-8alkyl, -C_1-8alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl) and heteroaryl)},
cycloalkyl, heterocyclyl, aryl and heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with a substituent selected from the group consisting of C_1-8alkyl (wherein alkyl is optionally substituted on a terminal carbon with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl), cyano, (halo)_1-3, hydroxy and nitro), C_1-8alkoxy and amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl)}};

R₂ is selected from the group consisting of hydrogen, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl and hydroxy(C_1-8)alkyl;

X is selected from the group consisting of -C(O)-, -C(S)- and -SO₂-; and,

R₃ is selected from the group consisting of:

C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl {wherein alkyl, alkenyl and alkynyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C_1-8)alkyl, -CO₂H, -CO₂(C_1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl), cyano, (halo)_1-3, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C_1-8alkyl, cyano, halo, (halo)_1-3(C_1-8)alkyl, (halo)_1-3(C_1-8)alkoxy, hydroxy, hydroxy(C_1-8)alkyl, hydroxy(C_1-8)alkoxy and nitro)},
cycloalkyl, heterocyclyl, aryl, heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of:
- C_1-8alkyl, C_2-8alkenyl (wherein alkyl and alkenyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C_1-8)alkyl, -CO₂H, -CO₂(C_1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl), cyano, (halo)_1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),
- -CH(OH)-(C_1-8)alkyl,
- C_1-8alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)_1-3 and hydroxy),
- -C(O)H, -C(O)(C_1-8)alkyl, -CO₂H, -CO₂(C_1-8)alkyl,
- amino (substituted with two substituents independently selected from the group consisting of hydrogen, C_1-8alkyl and -C(O)(C_1-8)alkyl),
- -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl),
- -SO₂- {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C_1-8alkyl and -C_1-8alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-8alkyl))},
- -NH-SO₂-(C_1-8)alkyl,
- cycloalkyl, heterocyclyl (optionally substituted with 1 to 2 oxo substituents), aryl and heteroaryl} and

amino {substituted with two substituents independently selected from the group consisting of hydrogen, C_1-8alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C_1-8alkyl, cyano, halo, (halo)_1-3(C_1-8)alkyl, (halo)_1-3(C_1-8)alkoxy, hydroxy, hydroxy(C_1-8)alkyl, hydroxy(C_1-8)alkoxy and nitro)};

and pharmaceutically acceptable salts thereof.

An embodiment of the present invention is a method for treating or ameliorating a selective kinase or dual-kinase mediated disorder.

An embodiment of the present invention includes a method for producing the instant compounds and pharmaceutical compositions and medicaments thereof.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention include compounds of Formula (I) wherein, preferably, R₁ is selected from the group consisting of: C_1-4alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl (wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with a substituent selected from the group consisting of:

C_1-4alkyl (optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C_1-4)alkyl, -CO₂H, -CO₂(C_1-4)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl), cyano, (halo)_1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),
C_1-4alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)_1-3 and hydroxy),
-C(O)H, -C(O)(C_1-4)alkyl, -CO₂H, -CO₂(C_1-4)alkyl,
amino (substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl and -SO₂-(C_1-4)alkyl),
-C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl),
-SO₂- {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, -C_1-4alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl) and heteroaryl)},
cycloalkyl, heterocyclyl, aryl and heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with a substituent selected from the group consisting of C_1-4alkyl (wherein alkyl is optionally substituted on a terminal carbon with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl), cyano, (halo)_1-3, hydroxy and nitro), C_1-4alkoxy and amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl)}}.

More preferably, R₁ is selected from the group consisting of C_1-4alkyl and aryl {wherein aryl is substituted with a substituent selected from the group consisting of:

C_1-4alkyl (optionally substituted on a terminal carbon with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl), cyano, (halo)_1-3, hydroxy and nitro),
C_1-4alkoxy,
amino (substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl and -SO₂-(C_1-4)alkyl),
-SO₂- {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, -C_1-4alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl) and heteroaryl)},
heterocyclyl (wherein heterocyclyl is optionally substituted with 1 to 2 substituents independently selected from the group consisting of C_1-4alkyl and oxo) and heteroaryl}.

Most preferably, R₁ is selected from the group consisting of C_1-4alkyl and phenyl {wherein phenyl is substituted with a substituent selected from the group consisting of: amino (substituted with two substituents independently selected from the group consisting of:

hydrogen, C_1-4alkyl and -SO₂-(C_1-4)alkyl),
-SO₂- {substituted with one substituent selected from the group consisting of piperidinyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, -C_1-4alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl) and pyridinyl)}, and
piperazinyl (wherein piperazinyl is optionally substituted with 1 to 2 C_1-4alkyl substituents), imidazolidinyl, isothiazolidinyl (wherein imidazolidinyl and isothiazolidinyl are optionally substituted with 1 to 2 oxo substituents), imidazolyl and triazolyl}.

Embodiments of the present invention include compounds of Formula (I) wherein, preferably, R₂ is selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl and hydroxy(C_1-4)alkyl.

More preferably, R₂ is selected from the group consisting of hydrogen and C_1-4alkyl.

Most preferably, R₂ is hydrogen.

Embodiments of the present invention include compounds of Formula (I) wherein, preferably, X is selected from the group consisting of -C(O)-, -C(S)- and -SO₂-.

Embodiments of the present invention include compounds of Formula (I) wherein, preferably, R₃ is selected from the group consisting of:

C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl {wherein alkyl, alkenyl and alkynyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C_1-4)alkyl, -CO₂H, -CO₂(C_1-4)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl), cyano, (halo)_1-3, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independent