Piperazine derivatives and methods of use

• US 20050014749A1
• Filed: 06/21/2004
• Published: 01/20/2005
• Est. Priority Date: 06/20/2003
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Zhu, Jiawang, Harried, Scott, Liu, Qingyian, Li, Aiwen, Yang, Kevin, Nguyen, Thomas, Han, Nianhe, Yuan, Chester Chenguang, Chen, Jian J., Fotsch, Christopher H., Biswas, Kaustav, D'Amico, Derin C., Qian, Wenyuan, Peterkin, Tanya, Nomak, Rana, Chau, Jennifer N., Nishimura, Nobuku, Riahi, Babak, Askew, Ben C.
• Granted Patent: US 7,393,852 B2
• Time in Patent Office: Days
• US Class Current: 514/227.500
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/32 : Alcohol-abuse
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/16 : Otologicals
• 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 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
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• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 241/08 : with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 243/08 : not condensed with other rings
• CPC Class Codes: C07D 245/02 : not condensed with other rings
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings

Abstract

Selected compounds are effective for treatment of pain and diseases, such as inflammation mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving pain, inflammation, and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

Claims

1. A compound of Formula I

2. Compound of claim 1 wherein q is 1-2;

and wherein t is 1.

3. Compound of claim 2 wherein q is 1.

4. Compound of claim 1 wherein X is selected from NH and NR^a;

and wherein R¹ is (C_1-3)alkyl.

5. Compound of claim 4 wherein X is NH.

6. Compound of claim 1 wherein R is selected from 9-11 membered fused bicyclic carbocyclic or heterocyclic ring substituted with one to two basic moieties, and optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, oxo, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, —

NR⁸C(O)R^8′

, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl.

7. Compound of claim 6 wherein R is a partially unsaturated carbocyclic ring;

substituted with a basic moiety, optionally substituted with chloro.

8. Compound of claim 7 wherein R is 1,2,3,4-tetrahydronaphthyl;

substituted with a basic moiety, optionally substituted with chloro.

9. Compound of claim 7 wherein R is indanyl;

substituted with a basic moiety, optionally substituted with chloro.

10. The compound of claim 7 wherein R is selected from 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl and indan-2-yl;

substituted with a basic moiety, optionally substituted with chloro.

11. The compound of claim 1 wherein R is partially unsaturated heterocyclyl;

substituted with a basic moiety, optionally substituted with chloro.

12. The compound of claim 11 wherein R is chroman;

substituted with a basic moiety, optionally substituted with chloro.

13. The compound of claim 11 wherein R is 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl;

substituted with a basic moiety, optionally substituted with chloro.

14. The compound of claim 11 wherein R is chroman-4-yl or 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-4-yl;

substituted with a basic moiety, optionally substituted with chloro.

15. Compound of claim 1 wherein R is selected from phenyl and 5-6 membered heteroaryl;

wherein R is substituted with one to two basic moieties, and optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, oxo, (C₁-C₆)alkoxy, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, —

NR⁸C(O)R^8′

, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl.

16. Compound of claim 15 wherein R is phenyl substituted with a basic moiety selected from (C₁-C₆)alkylamino(C₁-C₆)alkyl, C_1-4-alkylamino-C_2-6-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C_2-6-alkenyl, and heterocyclyl-C₁-C₆)alkylamino(C₂-C₆)alkyl.

17. Compound of claim 16 wherein R is selected from 3-((piperidin-1-ylethyl)aminomethyl)phenyl and 4-imidazolin-2-ylphenyl.

18. Compound of claim 1 wherein R is phenyl-(C_1-3)-alkyl substituted with a basic moiety.

19. Compound of claim 18 wherein R is selected from 4-(imidazolin-2-yl)phenylmethyl, 4-(imidazolin-2-yl)phenylethyl and 4-(imidazolin-2-yl)phenylpropyl.

20. Compound of claim 1 wherein R¹ is H or methyl.

21. Compound of claim 1 wherein R² is selected from phenyl-(C_2-4)-alkenyl, phenyl, naphthyl, 5-membered nitrogen containing heteroaryl, 5-membered sullfur containing heteroaryl, 6-membered nitrogen containing heteroaryl, 9-membered heterocyclyl, and 10-membered heterocyclyl.

22. Compound of claim 21 wherein R² is selected from phenyl-CH═

CH—

, tetrahydronaphthyl, naphtho[2,3-d]dioxolyl, benzofuranyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, 2-thienyl, isoxazolthienyl, benzothienyl, thieno[3,2-c]pyridinyl, naphthyl, phenyl, 3-pyridinyl, tetrahydroisoquinolinyl, quinolinyl and isoquinolinyl;

wherein R² is optionally substituted with one to five groups independently selected from halo, —

NH₂, hydroxyl, cyano, C₁-C₆)alkylamino, oxo, C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, di(C₁-C₆)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, —

NR⁸C(O)R^8′

, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl, wherein each substituted (C₁-C₆)alkyl, substituted aryl substituted heteroaryl and substituted saturated or partially saturated heterocyclyl is optionally substituted with one to three groups independently selected from halo, —

NH₂, hydroxyl, cyano, C₁-C₄)alkylamino, (C₁-C₄)haloalkyl, oxo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl, C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, di(C₁-C₄)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, and —

NR⁸C(O)R^8′

.

23. Compound of claim 22 wherein R² is selected from phenyl-CH═

CH—

, tetrahydronaphthyl, 2,1,3-benzoxadiazol-4-yl, thien-2-yl, 2-naphthyl, phenyl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl; and

wherein R² is optionally substituted.

24. Compound of claim 1 wherein R² is selected from 2,4,6-trimethylphenyl, 3,4-dichlorophenyl, 3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-chlorophenyl and 4-tert-butylphenyl.

25. Compound of claim 1 wherein the basic substituent on R is selected from amino, cycloalkylamino(C₁-C₆)alkyl, cycloalkyl(C₁-C₆)alkylamino(C₁-C₆)alkyl, heterocyclylamino(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkylamino(C₁-C₆)alkyl, arylamino(C₁-C₆)alkyl, aryl(C₁-C₆)alkylamino(C₁-C₆)alkyl, C_1-6-alkylamino-C_1-6-alkoxy, C_1-6-alkylamino-C_1-6-alkoxy-C_1-6-alkoxy, amino(C₁-C₆)alkoxy, amino(C₁-C₆)alkyl, C₁-C₆)alkylamino(C₁-C₆)alkyl, C_1-4-alkylamino-C_2-6-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C_2-6-alkenyl, heterocyclyl-(C₁-C₆)alkylamino(C₂-C₆)alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl;

and wherein each of said basic substituents is optionally substituted with one to three groups independently selected from halo, —

NH₂, hydroxyl, cyano, —

CF₃, (C₁-C₆)alkylamino, oxo, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, di(C₁-C₆)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, —

NR⁸C(O)R^8′

, C₁-C₆)alkyl, substituted C₁-C₆)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl, wherein each substituted (C₁-C₆)alkyl, substituted aryl substituted heteroaryl and substituted saturated or partially saturated heterocyclyl is optionally substituted with one to three groups independently selected from halo, —

NH₂, hydroxyl, cyano, C₁-C₆)alkylamino, (C₁-C₆)haloalkyl, oxo, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, di(C₁-C₆)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, and —

NR⁸C(O)R^8′

;

and pharmaceutically acceptable derivatives thereof.

26. The compound of claim 25 wherein the basic substituent on R is selected from amino, mono-C_1-4-alkylamino-C_1-4-alkyl, di-C_1-4-alkylamino-C_1-4-alkyl, mono-C_1-4-alkylamino-C_2-4-alkenyl, di-C_1-4-alkylamino-C_2-4-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C_2-4-alkenyl, optionally substituted 5-6 membered nitrogen-containing heterocyclyl and 5-8 membered nitrogen-containing heterocyclyl-C_1-4-alkyl;

and pharmaceutically acceptable derivatives thereof.

27. The compound of claim 26 wherein the basic substituent on R is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1 ]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.

28. The compound of claim 1 wherein R³ and R^3a together form oxo;

wherein R⁴ and R^4a are independently selected from H and C_1-3 alkyl; and

wherein R⁵ and R^5a are independently H.

29. The compound of claim 28 wherein R³ and R^3a together form oxo;

wherein R⁴ and R^4a are independently selected from H and methyl; and

wherein R⁵ and R^5a are independently H.

30. The compound of claim 1 wherein R⁸ and R^8′

independently are H or selected from lower alkyl, aryl and heteroaryl, each of which is optionally substituted with one, two or three groups independently selected from lower alkyl, halogen, lower alkoxy, hydroxy, amino, mono-alkylamino, dialkylamino, and trifluoromethyl.

31. Compound of claim 1 wherein R^x is H, methyl or trifluoromethyl.

32. Compound of claim 1 wherein R^x is H.

107. The compound of claim 1 and/or pharmaceutically acceptable derivatives thereof selected from:

2-((2R,S)-1-((5-chloro-1-benzothien-2-yl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((1R,S)-1-((2-methylpropyl)amino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1,2,3,6-tetrahydro-4-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-(2-methylpropyl)-1,2,3,6-tetrahydro-4-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-propyl-1,2,3,6-tetrahydro-4-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((1R,S)-1-((2-methylpropyl)amino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-(phenylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-(((1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;

2-((2R,S)-1-((5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methyl-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((²R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-(1-piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;

2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-5-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-5-oxo-2-piperazinyl)-N-((1R)-6-(1-(1-piperidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-(1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-((2-methylpropyl)amino)-1-propynyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-((2-methylpropyl)amino)propyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-piperidinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-piperidinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-((2-methylpropyl)amino)propyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-3-oxo-1-((4-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-(1-piperidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((1 S)-1-methyl-2-(1-piperidinyl)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-(((2-methylpropyl)amino)methyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-(1-pyrrolidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

3-((5R)-5-((((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetyl)amino)-5,6,7,8-tetrahydro-2-naphthalenyl)benzamide;

methyl 3-((5R)-5-((((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetyl)amino)-5,6,7,8-tetrahydro-2-naphthalenyl)benzoate;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

3-((5R)-5-((((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetyl)amino)-5,6,7,8-tetrahydro-2-naphthalenyl)benzoic acid;

2-fluoro-4-((5R)-5-((((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetyl)amino)-5,6,7,8-tetrahydro-2-naphthalenyl)benzoic acid;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-(((2-methylpropyl)amino)methyl)phenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-(1-piperidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-(1-pyrrolidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((4-methyl-1-piperazinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((3-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((2-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((3-chloro-4-fluorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chloro-2-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((2-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-3-oxo-1-(phenylsulfonyl)-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-3-oxo-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((3-bromo-5-chloro-2-thienyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((5-chloro-2-thienyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-((4-methyl-piperazinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;

2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-((4-methyl-1-piperazinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;

2-((2R)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2,2-dimethylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-(((2,2-dimethylpropyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;

2-((2R)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((cyclobutylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-(1-pyrrolidinyl)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S) 1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(4-morpholinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((phenylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-(1-piperidinyl)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

methyl (2E)-3-((5R)-5-((((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetyl)amino)-5,6,7,8-tetrahydro-2-naphthalenyl)-2-propenoate;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(4-morpholinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((4-methyl-1-piperazinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2,2-dimethylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((phenylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-phenylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-(2-fluorophenyl)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((cyclobutylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-(1-pyrrolidinyl)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((3-methylbutyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((4-fluoro-1-piperidinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((1-naphthalenylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-(2-(methyloxy)phenyl)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-(1-piperidinyl)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-((2-methylpropyl)amino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-((1,1-dimethylethyl)amino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-((2,2-dimethylpropyl)amino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-(cyclobutylamino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-((phenylmethyl)amino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-(4-morpholinyl)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-(1-pyrrolidinyl)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((2R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-2-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((2R)-6-(2-((2-(1-pyrrolidinyl)ethyl)amino)ethyl)-1,2,3,4-tetrahydro-2-naphthalenyl)acetamide;

2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((((1 S)-1-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-(1-pyrrolidinyl)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-(1-piperidinyl)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(2-(1-piperidinyl)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(4-morpholinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-(pentafluoroethyl)phenyl)sulfonyl)-2-piperazinyl)acetamide;

N-((1R)-6-((1R,S)-1-(cyclopentylamino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methyl-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2S)-1-((4-methyl-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((2,2-dimethylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methyl-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide d_—

2_;

N-((1R)-6-(hydroxymethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methyl-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((2,2-dimethylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-((4-fluoro-1-piperidinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)acetamide;

N-((1R)-6-(3-cyanophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(3-(bis(2-methylpropyl)amino)propyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(3-((cyclopentylmethyl)amino)propyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(3-aminopropyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(3-aminopropyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(3-(bis(2-methylpropyl)amino)propyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-piperazinyl)acetamide;

N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-piperazinyl)acetamide;

N-((1R)-6-(((cyclopropylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-piperazinyl)acetamide;

N-((1R)-6-(((1-methylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-piperazinyl)acetamide;

N-((1R)-6-((cyclobutylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-piperazinyl)acetamide;

N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)acetamide;

N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)acetamide;

N-((1R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)acetamide;

N-((1R)-6-(1-(1-piperidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)acetamide;

N-((1R)-6-(1-(((1,1-dimethylethyl)amino)methyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(1-(((cyclopropylmethyl)amino)methyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(1-((cyclobutylamino)methyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(1-(1-azetidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(1-((4-fluoro-1-piperidinyl)methyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(3-(acetylamino)phenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(3-(hydroxymethyl)phenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(3-((cyclobutylamino)methyl)phenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(3-((cyclopentylamino)methyl)phenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(1-(((2,2-dimethylpropyl)amino)methyl)ethenyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-((4-fluoro-1-piperidinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((3-methylbutyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((3,3-dimethylbutyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((cyclohexylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((2-(2-fluorophenyl)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(aminomethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-chlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((2,2-dimethylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((3-methylbutyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((cyclohexylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((²R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-((cyclohexylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((cyclopropylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-((cyclopropylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(1-azepanylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((3R,S)-3-hydroxy-1-piperidinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((2-(methyloxy)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((1R)-6-(((2-hydroxyethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-((4-methyl-1-piperazinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;

2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-((tetrahydro-2H-pyran-4-ylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;

2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-(((cyclopropylmethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;

2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((4R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)acetamide;

2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((4-methyl-1-piperazinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((tetrahydro-2H-pyran4-ylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((cyclopropylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-((4-pyridinylmethyl)amino)propyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(3-((tetrahydro-2H-pyran-4-ylmethyl)amino)propyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((4-chloro-2,5-dimethylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

N-((4R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((4R)-1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((4R)-6-chloro-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2R,S)-3-oxo-1-((2,4,6-trimethylphenyl)sulfonyl)-2-piperazinyl)acetamide;

N-((4R)-6-chloro-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((4R)-6-chloro-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2R,S)-1-(2-naphthalenylsulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((4R)-6-chloro-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((4R)-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-piperazinyl)acetamide;

N-((4R)-6-chloro-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

N-((4R)-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-5,5-dimethyl-3-oxo-2-piperazinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

1,1-dimethylethyl 4-((5R)-5-((((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetyl)amino)-5,6,7,8-tetrahydro-2-naphthalenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate;

2-((2R,S)-1-((4-(1,1-dimethylethyl)phenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((2,5-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-5-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-((4-fluoro-1-piperidinyl)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-pyrrolidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1-((3,4-dichlorophenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R,S)-1R-((3,5-dibromo-4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2R)-1-((3,5-dibromo-4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((2,2-dimethylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

2-((2S)-1-((3,5-dibromo-4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

N-((1R)-6-(1-(cyclopropylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide; and

N-((1R)-6-(1-(cyclohexylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide.

108. A pharmaceutically acceptable salt of a compound according to claim 1.

109. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1.

110. A method of treating pain comprising administering an effective amount a compound according to claim 1.

111. A pharmaceutical composition for the treatment of disease conditions mediated by bradykinin, in a mammalian subject, which comprises a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

112. A pharmaceutical composition for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer'"'"'s disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis, neovascularization, corneal haze, glaucoma, ocular pain, ocular hypertension or angio edema, which comprises a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

113. A method for the treatment of disease conditions mediated by bradykinin, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound according to claim 1.

114. A method for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer'"'"'s disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis, neovascularization, corneal haze, glaucoma, ocular pain, ocular hypertension or angio edema, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound according to claim 1.

115. A pharmaceutical formulation comprising a compound according to claim 1, a pharmaceutically acceptable carrier and, optionally, one or more other pharmacologically active ingredients.

116. A method of treating, preventing, or ameliorating a disease or condition associated with B1 activity comprising administering to a human or animal subject a therapeutically effective amount of a compound according to claim 1.

117. The method according to claim 116 wherein the disease or condition is selected from the group of inflammation, inflammatory pain, acute pain, dental pain, back pain, lower back pain, pain from trauma, surgical pain, inflammatory bowel disorders, asthma, and allergic rhinitis.

33. A compound of Formula II

34. Compound of claim 33 wherein X is selected from NH and NR^a;

and wherein R^a is (C_1-3)alkyl.

35. Compound of claim 34 wherein X is NH.

36. Compound of claim 33 wherein R is selected from 9-11 membered fused bicyclic carbocyclic or heterocyclic ring substituted with one to two basic moieties, and optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, oxo, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, —

NR⁸C(O)R^8′

, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl.

37. Compound of claim 36 wherein R is a partially unsaturated carbocyclic ring;

substituted with a basic moiety, optionally substituted with chloro.

38. Compound of claim 37 wherein R is 1,2,3,4-tetrahydronaphthyl;

substituted with a basic moiety, optionally substituted with chloro.

39. Compound of claim 37 wherein R is indanyl;

substituted with a basic moiety, optionally substituted with chloro.

40. The compound of claim 37 wherein R is selected from 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl and indan-2-yl;

substituted with a basic moiety, optionally substituted with chloro.

41. The compound of claim 33 wherein R is partially unsaturated heterocyclyl;

substituted with a basic moiety, optionally substituted with chloro.

42. The compound of claim 41 wherein R is chroman;

substituted with a basic moiety, optionally substituted with chloro.

43. The compound of claim 41 wherein R is 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl;

substituted with a basic moiety, optionally substituted with chloro.

44. The compound of claim 41 wherein R is chroman-4-yl or 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-4-yl;

substituted with a basic moiety, optionally substituted with chloro.

45. Compound of claim 33 wherein R is selected from phenyl and 5-6 membered heteroaryl;

wherein R is substituted with one to two basic moieties, and optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, oxo, (C₁-C₆)alkoxy, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, —

NR⁸C(O)R^8′

, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl.

46. Compound of claim 45 wherein R is phenyl substituted with a basic moiety selected from (C₁-C₆)alkylamino(C₁-C₆)alkyl, C₁₄-alkylamino-C_2-6-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C_2-6-alkenyl, and heterocyclyl-C₁-C₆)alkylamino(C₂-C₆)alkyl.

47. Compound of claim 46 wherein R is selected from 3-((piperidin-1-ylethyl)aminomethyl)phenyl and 4-(imidazolin-2-yl)phenyl.

48. Compound of claim 33 wherein R is phenyl-(C_1-3)-alkyl substituted with a basic moiety.

49. Compound of claim 48 wherein R is selected from 4-(imidazolin-2-yl)phenylmethyl, 4-(imidazolin-2-yl)phenylethyl and 4-(imidazolin-2-yl)phenylpropyl.

50. Compound of claim 33 wherein R¹ is H or methyl.

51. Compound of claim 33 wherein R² is selected from phenyl-(C_2-4)-alkenyl, phenyl, naphthyl, 5-membered nitrogen containing heteroaryl, 5-membered sullfur containing heteroaryl, 6-membered nitrogen containing heteroaryl, 9-membered heterocyclyl, and 10-membered heterocyclyl.

52. Compound of claim 51 wherein R² is selected from phenyl-CH═

CH—

, tetrahydronaphthyl, naphtho[2.3-d]dioxolyl, benzofuranyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, 1H-pyrazolyl, thienyl, isoxazolthienyl, benzothienyl, thieno[3,2-c]pyridinyl, naphthyl, phenyl, pyridinyl, tetrahydroisoquinolinyl, quinolinyl and isoquinolinyl;

wherein R² is optionally substituted with one to five groups independently selected from halo, —

NH₂, hydroxyl, cyano, (C₁-C₆)alkylamino, oxo, C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, di(C₁-C₆)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, —

NR⁸C(O)R^8′

, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl, wherein each substituted (C₁-C₆)alkyl, substituted aryl substituted heteroaryl and substituted saturated or partially saturated heterocyclyl is optionally substituted with one to three groups independently selected from halo, —

NH₂, hydroxyl, cyano, (C₁-C₄)alkylamino, (C₁-C₄)haloalkyl, oxo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, di(C₁-C₄)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, and —

NR⁸C(O)R^8′

.

53. Compound of claim 52 wherein R² is selected from phenyl-CH═

CH—

, tetrahydronaphthyl, 2,1,3-benzoxadiazol-4-yl, thien-2-yl, 2-naphthyl, phenyl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl; and

wherein R² is optionally substituted.

54. Compound of claim 33 wherein R² is selected from 2,4,6-trimethylphenyl, 3,4-dichlorophenyl, 3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-chlorophenyl and 4-tert-butylphenyl.

55. Compound of claim 33 wherein the basic substituent on R is selected from amino, cycloalkylamino(C₁-C₆)alkyl, cycloalkyl(C₁-C₆)alkylamino(C₁-C₆)alkyl, heterocyclylamino(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkylamino(C₁-C₆)alkyl, arylamino(C₁-C₆)alkyl, aryl(C₁-C₆)alkylamino(C₁-C₆)alkyl, C_1-6-alkylamino-C_1-6-alkoxy, C_1-6-alkylamino-C_1-6-alkoxy-C_1-6-alkoxy, amino(C₁-C₆)alkoxy, amino(C₁-C₆)alkyl, C₁-C₆)alkylamino(C₁-C₆)alkyl, C_1-4-alkylamino-C_2-6-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C_2-6-alkenyl, heterocyclyl-(C₁-C₆)alkylamino(C₂-C₆)alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl;

and wherein each of said basic substituents is optionally substituted with one to three groups independently selected from halo, —

NH₂, hydroxyl, cyano, —

CF₃, (C₁-C₆)alkylamino, oxo, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, di(C₁-C₆)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, —

NR⁸C(O)R^8′

, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl, wherein each substituted (C₁-C₆)alkyl, substituted aryl substituted heteroaryl and substituted saturated or partially saturated heterocyclyl is optionally substituted with one to three groups independently selected from halo, —

NH₂, hydroxyl, cyano, C₁-C₆)alkylamino, (C₁-C₆)haloalkyl, oxo, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, di(C₁-C₆)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, and —

NR⁸C(O)R^8′

;

and pharmaceutically acceptable derivatives thereof.

56. The compound of claim 55 wherein the basic substituent on R is selected from amino, mono-C_1-4-alkylamino-C_1-4-alkyl, di-C_1-4-alkylamino-C_1-4-alkyl, mono-C_1-4-alkylamino-C_2-4-alkenyl, di-C_1-4-alkylamino-C_2-4-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C_2-4-alkenyl, optionally substituted 5-6 membered nitrogen-containing heterocyclyl and 5-8 membered nitrogen-containing heterocyclyl-C_1-4-alkyl;

and pharmaceutically acceptable derivatives thereof.

57. The compound of claim 56 wherein the basic substituent on R is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.

58. The compound of claim 33 wherein R³ and R^3a together form oxo;

wherein R⁴ and R^4a are independently selected from H, and C_1-3 alkyl;

wherein R⁵ and R^5a are independently H.

59. The compound of claim 58 wherein R³ and R^3a together form oxo;

wherein R⁴ and R^4a are independently selected from H and methyl;

wherein R⁵ and R^5a are independently H.

60. Compound of claim 33 wherein R⁸ and R^8′

independently are H or selected from lower alkyl, aryl and heteroaryl, each of which is optionally substituted with one, two or three groups independently selected from lower alkyl, halogen, lower alkoxy, hydroxy, amino, mono-alkylamino, dialkylamino, and trifluoromethyl.

61. Compound of claim 33 wherein R^x is selected from H, methyl and trifluoromethyl.

62. Compound of claim 61 wherein R^x is H.

63. A compound of Formula III

64. The compound of claim 63 wherein R is a partially unsaturated carbocyclic ring;

substituted with a basic moiety, optionally substituted with chloro.

65. The compound of claim 64 wherein R is 1,2,3,4-tetrahydronaphthyl;

substituted with a basic moiety, optionally substituted with chloro.

66. The compound of claim 64 wherein R is indanyl;

substituted with a basic moiety, optionally substituted with chloro.

67. The compound of claim 64 wherein R is selected from 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl and indan-2-yl;

substituted with a basic moiety, optionally substituted with chloro.

68. The compound of claim 63 wherein R is partially unsaturated heterocyclyl;

substituted with a basic moiety, optionally substituted with chloro.

69. The compound of claim 68 wherein R is chroman;

substituted with a basic moiety, optionally substituted with chloro.

70. The compound of claim 68 wherein R is 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl;

substituted with a basic moiety, optionally substituted with chloro.

71. The compound of claim 68 wherein R is chroman-4-yl or 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-4-yl;

substituted with a basic moiety, optionally substituted with chloro.

72. The compound of claim 63 wherein each R² is selected from phenyl-CH═

CH—

, tetrahydronaphthyl, naphtho[2.3d]dioxolyl, benzofuranyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, 1H-pyrazolyl, thienyl, isoxazolthienyl, benzothienyl, thieno[3,2-c]pyridinyl, naphthyl, phenyl, pyridinyl, tetrahydroisoquinolinyl, quinolinyl and isoquinolinyl;

wherein R² is optionally substituted with one to five groups independently selected from halo, —

NH₂, hydroxyl, cyano, —

CF₃, (C₁-C₆)alkylamino, oxo, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, di(C₁-C₆)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, —

NR⁸C(O)R^8′

, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl;

wherein each substituted (C₁-C₆)alkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl and substituted saturated or partially saturated heterocyclyl is substituted with one to three groups independently selected from halo, —

NH₂, hydroxyl, cyano, (C₁-C₆)alkylamino, halo(C₁-C₆)alkyl, oxo, (C₁-C₆)alkoxy, C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, di(C₁-C₆)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, and —

NR⁸C(O)R^8′

;

wherein R¹ is selected from H and C_1-2-alkyl;

wherein the basic substituent on R is selected from amino, cycloalkylamino(C₁-C₆)alkyl, cycloalkyl(C₁-C₆)alkylamino(C₁-C₆)alkyl, heterocyclylamino(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkylamino(C₁-C₆)alkyl, arylamino(C₁-C₆)alkyl, aryl(C₁-C₆)alkylamino(C₁-C₆)alkyl, C_1-6-alkylamino-C_1-6-alkoxy, C_1-6-alkylamino-C_1-6-alkoxy-C_1-6-alkoxy, amino(C₁-C₆)alkoxy, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, C_1-4-alkylamino-C_2-6-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C_2-6-alkenyl, heterocyclyl-(C₁-C₆)alkylamino(C₂-C₆)alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl; and

wherein each of said basic substituents is optionally substituted with one to three groups independently selected from halo, —

NH₂, hydroxyl, cyano, —

CF₃, (C₁-C₆)alkylamino, oxo, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, di(C₁-C₆)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, —

NR⁸C(O)R^8′

, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl, wherein each substituted C₁-C₆)alkyl, substituted aryl substituted heteroaryl and substituted saturated or partially saturated heterocyclyl is optionally substituted with one to three groups independently selected from halo, —

NH₂, hydroxyl, cyano, (C₁-C₄)alkylamino, (C₁-C₄)haloalkyl, oxo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, di(C₁-C₄)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, and —

NR⁸C(O)R^8′

;

and pharmaceutically acceptable derivatives thereof.

73. The compound of claim 72 wherein R² is selected from phenyl-CH═

CH—

, tetrahydronaphthyl, 2,1,3-benzoxadiazol-4-yl, thien-2-yl, 2-naphthyl, phenyl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl;

wherein each R² is said optionally substituted;

wherein R¹ is H; and

wherein the basic substituent on R is selected from amino, mono-C_1-4-alkylamino-C_1-4-alkyl, di-C_1-4-alkylamino-C_1-4-alkyl, mono-C_1-4-alkylamino-C_2-4-alkenyl, di-C_1-4-alkylamino-C_2-4-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C_2-4-alkenyl, optionally substituted 5-6 membered nitrogen-containing heterocyclyl and 5-8 membered nitrogen-containing heterocyclyl-C_1-4-alkyl;

and pharmaceutically acceptable derivatives thereof.

74. The compound of claim 63 wherein R¹ is H.

75. The compound of claim 63 wherein the basic substituent on R is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.

76. The compound of claim 63 and/or pharmaceutically acceptable derivatives thereof selected from

2-[3-Oxo-1-(2,4,6-trimethylbenzenesulfonyl)-piperizin-2(R,S)-yl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide;

N-((1R)-6-(((1,1-Dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

2-[3-Oxo-1-(toluene-4-sulfonyl)piperizin-2-yl]-N-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide;

N-7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(toluene-4-sulfonyl)-piperazin-2-yl]-acetamide;

N-[7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(4-methoxy-benzenesulfonyl)-piperazin-2-yl]-acetamide;

N-[7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(4-chloro-benzenesulfonyl)-piperazin-2-yl]-acetamide;

N-[7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(3-trifluoromethyl-benzenesulfonyl)-piperazin-2-yl]-acetamide; and

N-((4R)-2,2-dimethyl-7-(2-piperidinyl)-3,4dihydro-2H-chromen-4-yl)-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide.

77. A compound of Formula IV

78. The compound of claim 77 wherein R⁹ and R¹¹ are H;

and wherein R¹⁰ is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.

79. The compound of claim 77 wherein R¹⁰ and R¹¹ are H;

and wherein R⁹ is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.

80. The compound of claim 77 wherein R⁹ and R¹⁰ are H;

and wherein R¹¹ is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.

81. The compound of claim 77 wherein the C ring is selected from

82. The compound of claim 81 wherein the C ring is

83. The compound of claim 77 wherein R² is selected from phenyl-CH═

CH—

, tetrahydronaphthyl, naphtho[2.3-d]dioxol-6-yl, 1-benzofur-2-yl, 2,1,3-benzoxadiazol-4-yl, 2,1,3-benzothiadiazol-4-yl, 1,3-benzothiazol-2-yl, 1H-pyrazol-4-yl, thien-2-yl, 5-isoxazolthien-2-yl, benzothien-2-yl, thieno[3,2-c]pyridin-2-yl, 2-naphthyl, phenyl, 3-pyridyl, tetrahydroisoquinolyl, 8-quinolyl and 5-isoquinolyl;

wherein R² is selected from phenyl-CH═

CH—

, tetrahydronaphthyl, 2,1,3-benzoxadiazol-4-yl, thien-2-yl, 2-naphthyl, phenyl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl;

wherein each R² is optionally substituted with one to five groups independently selected from halo, —

NH₂, hydroxyl, cyano, —

CF₃, (C₁-C₆)alkylamino, oxo, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, di(C₁-C₆)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, —

NR⁸C(O)R^8′

, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl;

wherein each substituted C₁-C₆)alkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl and substituted saturated or partially saturated heterocyclyl is substituted with one to three groups independently selected from halo, —

NH₂, hydroxyl, cyano, (C₁-C₆)alkylamino, C₁-C₆)haloalkyl, oxo, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, di(C₁-C₆)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, and —

NR⁸C(O)R^8′

.

84. The compound of claim 77 wherein R² is selected from 2-naphthyl, 1-naphthyl, phenyl, 3-chlorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 2,4,6-trichlorophenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-biphenyl, 3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-methylphenyl, 2,1,3-benzoxadiazol-4-yl, thien-2-yl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl.

85. The compound of claim 77 wherein R¹ is H or methyl.

86. The compound of claim 77 wherein R² is 2-naphthyl.

87. The compound of claim 77 wherein R² is 3,4-dichlorophenyl.

88. The compound of claim 77 wherein R² is 3-trifluoromethylphenyl.

89. A compound of Formula V

90. The compound of claim 89 wherein R⁷ is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.

91. The compound of claim 89 wherein R⁷ is at position 7.

92. The compound of claim 89 wherein R² is 2-naphthyl, 3,4-dichlorophenyl or 3-trifluoromethylphenyl.

93. A compound of Formula VI

94. The compound of claim 93 wherein R is a partially unsaturated carbocyclic ring;

substituted with a basic moiety, optionally substituted with chloro.

95. The compound of claim 94 wherein R is 1,2,3,4-tetrahydronaphthyl;

substituted with a basic moiety, optionally substituted with chloro.

96. The compound of claim 94 wherein R is indanyl;

substituted with a basic moiety, optionally substituted with chloro.

97. The compound of claim 94 wherein R is selected from 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl and indan-2-yl;

substituted with a basic moiety, optionally substituted with chloro.

98. The compound of claim 93 wherein R is partially unsaturated heterocyclyl;

substituted with a basic moiety, optionally substituted with chloro.

99. The compound of claim 98 wherein R is chroman;

substituted with a basic moiety, optionally substituted with chloro.

100. The compound of claim 98 wherein R is 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl;

substituted with a basic moiety, optionally substituted with chloro.

101. The compound of claim 98 wherein R is chroman-4-yl or 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-4-yl;

substituted with a basic moiety, optionally substituted with chloro.

102. The compound of claim 93 wherein each R² is selected from phenyl-CH═

CH—

, tetrahydronaphthyl, naphtho[2.3-d]dioxolyl, benzofuranyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, 1H-pyrazolyl, thienyl, isoxazolthienyl, benzothienyl, thieno[3,2-c]pyridinyl, naphthyl, phenyl, pyridinyl, tetrahydroisoquinolinyl, quinolinyl and isoquinolinyl;

wherein R² is optionally substituted with one to five groups independently selected from halo, —

NH₂, hydroxyl, cyano, —

CF₃, (C₁-C₆)alkylamino, oxo, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, di(C₁-C₆)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, —

NR⁸C(O)R^8′

, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl;

wherein each substituted (C₁-C₆)alkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl and substituted saturated or partially saturated heterocyclyl is substituted with one to three groups independently selected from halo, —

NH₂, hydroxyl, cyano, (C₁-C₆)alkylamino, halo(C₁-C₆)alkyl, oxo, (C₁-C₆)alkoxy, C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, di(C₁-C₆)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, and —

NR⁸C(O)R^8′

;

wherein R¹ is selected from H and C_1-2-alkyl;

wherein the basic substituent on R is selected from amino, cycloalkylamino(C₁-C₆)alkyl, cycloalkyl(C₁-C₆)alkylamino(C₁-C₆)alkyl, heterocyclylamino(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkylamino(C₁-C₆)alkyl, arylamino(C₁-C₆)alkyl, aryl(C₁-C₆)alkylamino(C₁-C₆)alkyl, C_1-6-alkylamino-C_1-6-alkoxy, C_1-6-alkylamino-C_1-6-alkoxy-C_1-6-alkoxy, amino(C₁-C₆)alkoxy, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, C_1-4-alkylamino-C_2-6-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C_2-6-alkenyl, heterocyclyl-C₁-C₆)alkylamino(C₂-C₆)alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclyl-alkyl; and

wherein each of said basic substituents is optionally substituted with one to three groups independently selected from halo, —

NH₂, hydroxyl, cyano, —

CF₃, (C₁-C₆)alkylamino, oxo, (C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, di(C₁-C₆)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, —

NR⁸C(O)R^8′

, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, substituted saturated or partially saturated heterocyclyl and unsubstituted saturated or partially saturated heterocyclyl, wherein each substituted (C₁-C₆)alkyl, substituted aryl substituted heteroaryl and substituted saturated or partially saturated heterocyclyl is optionally substituted with one to three groups independently selected from halo, —

NH₂, hydroxyl, cyano, (C₁-C₄)alkylamino, (C₁-C₄)haloalkyl, oxo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, di(C₁-C₄)alkylamino, —

C(O)R⁸, —

COOR⁸, —

C(O)NR⁸R^8′

, and —

NR⁸C(O)R^8′

;

and pharmaceutically acceptable derivatives thereof.

103. The compound of claim 102 wherein R² is selected from phenyl-CH═

CH—

, tetrahydronaphthyl, 2,1,3-benzoxadiazol-4-yl, thien-2-yl, 2-naphthyl, phenyl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl;

wherein each R² is said optionally substituted;

wherein R^a is H; and

wherein the basic substituent on R is selected from amino, mono-C_1-4-alkylamino-C_1-4-alkyl, di-C_1-4-alkylamino-C_1-4-alkyl, mono-C_1-4-alkylamino-C_2-4-alkenyl, di-C(_1-4-alkylamino-C_2-4-alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C_2-4-alkenyl, optionally substituted 5-6 membered nitrogen-containing heterocyclyl and 5-8 membered nitrogen-containing heterocyclyl-C_1-4-alkyl;

and pharmaceutically acceptable derivatives thereof.

104. The compound of claim 93 wherein R¹ is H.

105. The compound of claim 93 wherein the basic substituent on R is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl and 4-methylpiperazin-1-ylmethyl.

106. The compound of claim 93 and/or pharmaceutically acceptable derivatives thereof selected from 2-((2R,S)-5,5-dimethyl-3-oxo-1-((2,4,6-trimethylphenyl)sulfonyl)-2-piperazinyl)-N-(1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;

N-[6-(tert-Butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[5,5-dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2(R,S)-yl]-acetamide

N-((1R,S)-6-(((1, 1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-5,5-dimethyl -1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;

2-[5,5-Dimethyl-3-oxo-1-(toluene-4-sulfonyl)-piperizin-2(R,S)-yl]-N-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydronaphthalen-1(R)-yl)-acetamide; and

N-((4R)-6-Chloro-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2R,S)-5,5-dimethyl-3-oxo-1-((2,4,6-trimethylphenyl)sulfonyl)-2-piperazinyl)acetamide.