Tricyclic pyrazole kinase inhibitors

• US 7,468,371 B2
• Filed: 03/24/2005
• Issued: 12/23/2008
• Est. Priority Date: 03/24/2004
• Status: Expired due to Fees

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbott Laboratories Incorporated (Abbott Laboratories)
• Inventors: Dixon, Richard W., Rafferty, Paul, Akritopoulou-Zanze, Irini, Djuric, Stevan W., Steinman, Douglas H., Michaelides, Michael R., Holms, James H., Zhang, Henry Q., Gasiecki, Alan F., Gracias, Vijaya J., Xia, Zhiren, Wada, Carol K., Muckey, Melanie A., Dinges, Jürgen, Arnold, Lee D., Ericsson, Anna M., Fischer, Kimba, Takeshita, Makoto
• Primary Examiner(s): SHAMEEM, GOLAM M
• Application Number:
  US11/089,473
• Publication Number:
  US 20060014816A1
• Time in Patent Office: 1,370 Days
• Field of Search: 544/358, 544/359, 544/366, 544/371, 548/356.1, 548/358.1, 548/359.1, 514/252.12, 514/252.13, 514/254.01, 514/254.05, 514/254.06, 514/403, 514/406
• US Class Current: 514/254.05
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 231/54 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/14 : Ortho-condensed systems

Abstract

Compounds of the present invention are useful for inhibiting protein tyrosine kinases. Also disclosed are methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

Claims

1. A compound of formula (I)

2. The compound of claim 1 wherein R⁴ is (CH₂)_nNR⁶C(O)NR⁷R⁸.

3. The compound of claim 1 wherein R⁴ is (CH₂)_nNR⁶C(O)OR⁸.

4. The compound of claim 1 wherein R⁴ is (CH₂)_nNR⁶C(NCN)NR⁷R⁸.

5. The compound of claim 1 wherein R⁴ is (CH₂)_nOC(O)NR⁷R⁸.

6. The compound of claim 1 wherein R⁴ is CH═

NNR⁶C(O)NR⁷R⁸.

7. The compound of claim 1 wherein R⁴ is CH═

NOR⁸.

8. The compound of claim 1 wherein R⁴ is CH═

NOCH₂C(O)NR⁷R⁸.

9. The compound of claim 1 wherein R⁴ is C≡

CR⁵.

10. The compound of claim 1 wherein

X¹ is selected from the group consisting of C and N;

X² is selected from the group consisting of CH₂ and O;

R^A is hydrogen;

R^B is selected from the group consisting of heteroaryl, heteroarylalkoxy, heteroarylalkyl, heteroarylcarbonyl, heteroaryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, R^aR^bN—

, (R^aR^bN)alkoxy, (R^aR^bN)alkyl, (R^aR^bN)carbonyl, (NR^aR^bN)carbonylalkoxy, and (R^aR^bN)carbonylalkyl;

R^C is selected from the group consisting of hydrogen, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, carboxy, and halogen;

R^D is absent or selected from the group consisting of hydrogen and halogen;

R^a and R^b are independently selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, alkylcarbonyl, formyl, heteroarylalkyl, heterocyclealkyl, and (Z¹Z²N)alkyl;

Z¹ and Z² are independently selected from the group consisting of hydrogen, alkyl, formyl, and alkylcarbonyl;

R⁴ is C≡

CR⁵;

R⁵ is selected from the group consisting of alkoxyalkoxyalkyl, alkoxycarbonylalkoxyalkyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkyl, cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, haloalkoxyalkoxyalkyl, heteroaryl, heteroaryloxyalkyl, heterocycle, heterocyclecarbonylalkyl, heterocyclecarbonyloxyalkyl, heterocycleoxyalkyl, (NR^aR^b)carbonylalkoxyalkyl, (NR^cR^d)alkyl;

R^c is selected from the group consisting of hydrogen and alkyl; and

R^d is selected from the group consisting of alkylsulfonyl, arylsulfonyl, heteroarylcarbonyl, and heteroarylcarbonyl.

11. The compound of claim 1 wherein

X¹ is selected from the group consisting of C and N;

X² is selected from the group consisting of CH₂ and O;

R^A is hydrogen;

R^B is selected from the group consisting of hydrogen, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, carboxy, and halogen;

R^C is selected from the group consisting of heteroaryl, heteroarylalkoxy, heteroarylalkyl, heteroarylcarbonyl, heteroaryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, R^aR^bN—

, (R^aR^bN)alkoxy, (R^aR^bN)alkyl, (R^aR^bN)carbonyl, (NR^aR^bN)carbonylalkoxy, and (R^aR^bN)carbonylalkyl;

R^D is absent or selected from the group consisting of hydrogen and halogen;

R^a and R^b are independently selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, alkylcarbonyl, formyl, heteroarylalkyl, heterocyclealkyl, and (Z¹Z²N)alkyl;

Z¹ and Z² are independently selected from the group consisting of hydrogen, alkyl, formyl, and alkylcarbonyl;

R⁴ is C≡

CR⁵;

R⁵ is selected from the group consisting of alkoxyalkoxyalkyl, alkoxycarbonylalkoxyalkyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkyl, cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, haloalkoxyalkoxyalkyl, heteroaryl, heteroaryloxyalkyl, heterocycle, heterocyclecarbonylalkyl, heterocyclecarbonyloxyalkyl, heterocycleoxyalkyl, (NR^aR^b)carbonylalkoxyalkyl, (NR^cR^d)alkyl;

R^c is selected from the group consisting of hydrogen and alkyl; and

R^d is selected from the group consisting of alkylsulfonyl, arylsulfonyl, heteroarylcarbonyl, and heteroarylcarbonyl.

12. The compound of claim 1 wherein R⁴ is C≡

CR⁵; and

R⁵ is selected from the group consisting of alkoxyalkoxyalkyl and haloalkoxyalkoxyalkyl.

13. The compound of claim 1 wherein R⁴ is C≡

CR⁵;

R⁵ is selected from the group consisting of alkoxyalkoxyalkyl and haloalkoxyalkoxyalkyl;

R^B is selected from the group consisting of heteroarylalkyl and heterocyclealkyl; and

R^A, R^C, R^D, R², and R³ are hydrogen.

14. The compound according to claim 13 selected from the group consisting of

3-{5-[3-(2-methoxyethoxy)-1-propynyl]-3-thienyl}-7-[(4-methyl-1-piperazinyl)methyl]-1,4-dihydroindeno[1,2-c]pyrazole;

7-(1H-imidazol-1-ylmethyl)-3-{5-[3-(2-methoxyethoxy)-1-propynyl]-3-thienyl}-1,4-dihydroindeno[1,2-c]pyrazole;

3-{5-[3-(2-ethoxyethoxy)-1-propynyl]-3-thienyl}-7-(1H-1,2,4-triazol-1-ylmethyl)-1,4-dihydroindeno[1,2-c]pyrazole;

3-{5-[3-(2-isopropoxyethoxy)-1-propynyl]-3-thienyl}-7-(1H-1,2,4-triazol-1-ylmethyl)-1,4-dihydroindeno[1,2-c]pyrazole;

-{5-[3-(2-methoxyethoxy)-1-propynyl]-3-thienyl}-7-(1H-1,2,4-triazol-1-ylmethyl)-1,4-dihydroindeno[1,2-c]pyrazole;

3-{4-[3-(2-methoxyethoxy)-1-propynyl]-2-thienyl}-7-(1H-1,2,4-triazol-1-ylmethyl)-1,4-dihydroindeno[1,2-c]pyrazole;

3-{5-[3-(2-isopropoxyethoxy)-1-propynyl]-3-thienyl}-7-(1H-1,2,3-triazol-1-ylmethyl)-1,4-dihydroindeno[1,2-c]pyrazole; and

3-{5-[3-(2-isopropoxyethoxy)-1-propynyl]-3-thienyl}-7-(2H-1,2,3-triazol-2-ylmethyl)-1,4-dihydroindeno[1,2-c]pyrazole.

15. The compound of claim 1 wherein R⁴ is C≡

CR⁵;

R⁵ is selected from the group consisting of alkoxyalkoxyalkyl and haloalkoxyalkoxyalkyl;

R^C is selected from the group consisting of heteroarylalkyl and heterocyclealkyl; and

R^A, R^B, R^D, R², and R³ are hydrogen.

16. The compound according to claim 15 selected from the group consisting of

3-{5-[3-(2-methoxyethoxy)-1-propynyl]-3-thienyl}-6-[(4-methyl-1-piperazinyl)methyl]-1,4-dihydroindeno[1,2-c]pyrazole;

3-{5-[3-(2-isopropoxyethoxy)-1-propynyl]-3-thienyl}-6-[(4-methyl-1-piperazinyl)methyl]-1,4-dihydroindeno[1,2-c]pyrazole;

3-{5-[3-(2-ethoxyethoxy)-1-propynyl]-3-thienyl}-6-[(4-methyl-1-piperazinyy)methyl]-1,4-dihydroindeno[1,2-c]pyrazole;

3-{5-[3-(2-isobutoxyethoxy)-1-propynyl]-3-thienyl}-6-[(4-methyl-1-piperazinyl)methyl]-1,4-dihydroindeno[1,2-c]pyrazole;

3-{5-[3-(2-methoxy-1-methylethoxy)-1-propynyl]-3-thienyl}-6-[(4-methyl-1-piperazinyl)methyl]-1,4-dihydroindeno[1,2-c]pyrazole;

6-[(4-isopropyl-1-piperazinyl)methyl]-3-{5-[3-(2-methoxyethoxy)-1-propynyl]-3-thienyl}-1,4-dihydroindeno[1,2-c]pyrazole;

6-[(4-ethyl-1-piperazinyl)methyl]-3-{5-[3-(2-methoxyethoxy)-1-propynyl]-3-thienyl}-1,4-dihydroindeno[1,2-c]pyrazole;

6-(1H-imidazol-1-ylmethyl)-3-{5-[3-(2-methoxyethoxy)-1-propynyl]-3-thienyl}-1,4-dihydroindeno[1,2-c]pyrazole;

3-{5-[3-(2-methoxyethoxy)-1-propynyl]-3-thienyl}-6-(1H-1,2,4-triazol-1-ylmethyl)-1,4-dihydroindeno[1,2-c]pyrazole;

3-{5-[3-(2-ethoxyethoxy)-1-propynyl]-2-thienyl}-6-[(4-methyl-1-piperazinyl)methyl]-1,4-dihydroindeno[1,2-c]pyrazole;

3-{5-[3-(2-isopropoxyethoxy)-1-propynyl]-2-thienyl}-6-[(4-methyl-1-piperazinyl)methyl]-1,4-dihydroindeno[1,2-c]pyrazole; and

3-{4-[3-(2-methoxyethoxy)-1-propynyl]-2-thienyl}-6-[(4-methyl-1-piperazinyl)methyl]-1,4-dihydroindeno[1,2-c]pyrazole.

17. The compound according to claim 9 which is 3-(5-{3-[2-(difluoromethoxy)ethoxy]-1-propynyl}-3-thienyl)-6-[(4-methyl-1-piperazinyl)methyl]-1,4-dihydroindeno[1,2-c]pyrazole.

18. The compound according to claim 1 selected from the group consisting of

3-[5-(3-Cyclopropylmethoxy-prop-1-ynyl)-thiophen-3-yl]-7-fluoro-6-(4-methyl-piperazin-1-yl)-1,4-dihydro-indeno[1,2-c]pyrazole;

1-{3-[5-(3-Cyclopropylmethoxy-prop-1-ynyl)-thiophen-3-yl]-1,4-dihydro-indeno[1,2-c]pyrazol-6-ylmethyl}-4-methyl-piperazin-2-one;

6-(4-Cyclopropyl-piperazin-1-yl)-3-{5-[3-(2-fluoro-ethoxy)-prop-1-ynyl]-thiophen-3-yl}-1,4-dihydro-indeno[1,2-c]pyrazole;

3-[5-(3-Isopropoxy-prop-1-ynyl)-thiophen-3-yl]-6-(4-methyl-piperazin-1-yl)-1,4-dihydro-indeno[1,2-c]pyrazole; and

6-(4-cyclopropylpiperazin-1-yl)-3-[5-(3-isopropoxyprop-1-ynyl)thien-3-yl]-1,4-dihydroindeno[1,2-c]pyrazole.

19. A pharmaceutical composition comprising a compound of formula (I) or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.

20. A method for inhibiting a protein kinase in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of formula (I), or a therapeutically acceptable salt thereof.