US 2004/0006078 A1Published application

Compounds useful as reversible inhibitors of cysteine proteases

AssigneeBoehringer Ingelheim Pharmaceuticals, Inc.

InventorsYounes Bekkali, Eugene R. Hickey, Weimin Liu, Usha R. Patel, Denice M. Spero, Sanxing Sun, David S. Thomson, Yancey D. Ward, Erick R. R. Young

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Abstract

Disclosed are novel cathepsin S, K, F, L and B reversible inhibitory compounds of the formula (Ia) and (Ib) where R2, R3, R4, R5, R6, R7, R8, Het and X are defined herein. The compounds are useful for treating autoimmune and other diseases. Also disclosed are processes for making such novel compounds. 1

Claims17

Dependent claims

A compound of the formula (Ia):

588
wherein for the Formula (Ia), the components
589
is chosen from A1-A27 in the table below;
590
is chosen from B1-B49 in the table below and
591
is chosen from C1-C48 in the table below;
2 A 592 B 593 C 594 A1 595 B1 596 C1 597 A2 598 B2 599 C2 600 A3 601 B3 602 C3 603 A4 604 B4 605 C4 606 A5 607 B5 608 C5 609 A6 610 B6 611 C6 612 A7 613 B7 614 C7 615 A8 616 B8 617 C8 618 A9 619 B9 620 C9 621 A10 622 B10 623 C10 624 A11 625 B11 626 C11 627 A12 628 B12 629 C12 630 A13 631 B13 632 C13 633 A14 634 B14 635 C14 636 A15 637 B15 638 C15 639 A16 640 B16 641 C16 642 A17 643 B17 644 C17 645 A18 646 B18 647 C18 648 A19 649 B19 650 C19 651 A20 652 B20 653 C20 654 A21 655 B21 656 C21 657 A22 658 B22 659 C22 660 A23 661 B23 662 C23 663 A24 664 B24 665 C24 666 A25 667 B25 668 C25 669 A26 670 B26 671 C26 672 A27 673 B27 674 C27 675 B28 676 C28 677 B29 678 C29 679 B30 680 C30 681 B31 682 C31 683 B32 684 C32 685 B33 686 C33 687 B34 688 C34 689 B35 690 C35 691 B35 692 C36 693 B37 694 C37 695 B38 696 C38 697 B39 698 C39 699 B40 700 C40 701 B41 702 C41 703 B42 704 C42 705 B43 706 C43 707 B44 708 C44 709 B45 710 C45 711 B46 712 C46 713 B47 714 C47 715 B48 716 C48 717 B49 718
or the pharmaceutically acceptable salts, esters, tautomers, individual isomers and mixtures of isomers thereof.

7 more elements

A compound chosen from:

N-(2-Cyano-octahydro-quinolizin-2-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-1λ--benzo-3-ylamino)-propionamide;
N-(4-Cyano-1-propyl-piperidin-4-yl)-4-cyclohexyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;
N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(5,6-difluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-propionamide;
2-(5,6-Difluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-4,4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide;
2-(6-Fluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-4,4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide;
N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(6-fluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-propionamide;
5,5-Dimethyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(6-methyl-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide;
2-(6-Chloro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-4,4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2,3-dihydro-1H-quinazolin-4-ylideneamino)-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide;
2-(7-Chloro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-4,4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide;
5-Methyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(1-methyl-2-oxo-1,2-dihydro-quinazolin-4-ylamino)-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide;
3-tert-Butylsulfanyl-N-(4-cyano-1-propyl-piperidin-4-yl)-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;
3-Benzylsulfanyl-N-(4-cyano-1-propyl-piperidin-4-yl)-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;
N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cyclooctyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;
N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cycloheptyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(1-benzyl-4-cyano-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid[4-cyano-1-(5-methyl-thiophen-2-ylmethyl)-piperidin-4-yl]-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid[4-cyano-1-(4-fluoro-benzyl)-piperidin-4-yl]-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(4-cyano-1-ethyl-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(4-cyano-1-methyl-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(4-cyano-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(4-cyano-1-phenethyl-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid[4-cyano-1-(2,2-dimethyl-propyl)-piperidin-4-yl]-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid[4-cyano-1-(3,3-dimethyl-butyl)-piperidin-4-yl]-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(4-cyano-1-pentyl-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(1-butyl-4-cyano-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid[4-cyano-1-(3,3,3-trifluoro-propyl)-piperidin-4-yl]-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(4-cyano-1-cyclohexylmethyl-piperidin-4-yl)-amide;
N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(4,4-dimethyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;
N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(4,4-dipropyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;
N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(4-tert-butyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;
N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(3,3,5,5-tetramethyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;
N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(7,8-difluoro-2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;
3-Cyano-3-[4,4-dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoylamino]-azepane-1-carboxylic acid benzyl ester;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(3-cyano-1-propyl-azepan-3-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(4-cyano-1-propyl-azepan-4-yl)-amide;
N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(6-methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;
N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(6-fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;
N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(7-fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;
2-(7-Fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-yldeneamino)-5,5-dimethyl-hexanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide;
N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(7-methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;
2-(7-Methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-yldeneamino)-5,5-dimethyl-hexanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide;
N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;
or the pharmaceutically acceptable salts, esters, tautomers, individual isomers and mixtures of isomers thereof.

44 more elements

A compound chosen from:

5,5-Dimethyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-hexanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide;
N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(7-fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;
2-(7-Fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-yldeneamino)-5,5-dimethyl-hexanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide;
N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(7-methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;
2-(7-Methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-yldeneamino)-5,5-dimethyl-hexanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide;
N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;
4,4-Dimethyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2,3-dihydro-1H-quinazolin-4-ylideneamino)-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide;
2-(7-Chloro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-4,4-dimethyl-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(1-methyl-2-oxo-1,2-dihydro-quinazolin-4-ylamino)-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide;
N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cyclooctyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;
N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cycloheptyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(1-benzyl-4-cyano-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid[4-cyano-1-(5-methyl-thiophen-2-ylmethyl)-piperidin-4-yl]-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid[4-cyano-1-(4-fluoro-benzyl)-piperidin-4-yl]-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(4-cyano-1-ethyl-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(4-cyano-1-methyl-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(4-cyano-1-phenethyl-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid[4-cyano-1-(2,2-dimethyl-propyl)-piperidin-4-yl]-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid[4-cyano-1-(3,3-dimethyl-butyl)-piperidin-4-yl]-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(4-cyano-1-pentyl-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(1-butyl-4-cyano-piperidin-4-yl)-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid[4-cyano-1-(3,3,3-trifluoro-propyl)-piperidin-4-yl]-amide;
4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(4-cyano-1-cyclohexylmethyl-piperidin-4-yl)-amide;
N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(4,4-dimethyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide and
N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(7,8-difluoro-2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;
or the pharmaceutically acceptable salts, esters, tautomers, individual isomers and mixtures of isomers thereof.

24 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/261,994Filed 1 Oct 2002
Priority: 8 Sep 2000
Published: 8 Jan 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification32 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…

Family

Application09/655,351Continuation in part · filed 8 Sep 2000
Application09/808,439Division · filed 14 Mar 2001
Application09/808,439Continuation in part · filed 14 Mar 2001
Application10/261,994Division · filed 1 Oct 2002
US 2002/0137932 A1Published application
US 6,420,364 B1Related patent
US 6,525,052 B2Related patent
US 6,787,540 B2Related patent
US 2004/0006078 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Facts

Application

10/261,994Filed 1 Oct 2002

Priority

8 Sep 2000

Published

8 Jan 2004

Term ends

Not estimatedThe source records don’t support an estimate.

Classification32 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…

Family

Application09/655,351Continuation in part · filed 8 Sep 2000

Application09/808,439Division · filed 14 Mar 2001

Application09/808,439Continuation in part · filed 14 Mar 2001

Application10/261,994Division · filed 1 Oct 2002

US 2002/0137932 A1Published application

US 6,420,364 B1Related patent

US 6,525,052 B2Related patent

US 6,787,540 B2Related patent

US 2004/0006078 A1This patent

From the US filing history. Foreign family members aren’t listed.