Substituted [1,2,4]triazolo[4,3-A]pyrazine 11-beta-hydroxysteroid dehydrogenase inhibitors

• US 8,546,394 B2
• Filed: 04/16/2008
• Issued: 10/01/2013
• Est. Priority Date: 04/17/2007
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Li, Jun, Li, James J., O'Connor, Stephen P., Wang, Haixia, Kennedy, Lawrence J., Robl, Jeffrey A., Hamann, Lawrence G.
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US12/595,524
• Publication Number:
  US 20100144744A1
• Time in Patent Office: 1,994 Days
• Field of Search: 514/249, 544/350
• US Class Current: 514/249
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 9/12 Antihypertensives
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/14 Ortho-condensed systems

Abstract

Novel compounds are provided which are 1 1-beta-hydroxysteroid dehydrogenase type I inhibitors. 1 1-beta-hydroxysteroid dehydrogenase type I inhibitors are useful in treating, preventing, or slowing the progression of diseases requiring 1 1-beta-hydroxysteroid dehydrogenase type I inhibitor therapy. These novel compounds have the structure: W-L-Z or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein W, L are defined herein and Z is selected from the following bicyclic heteroaryl groups: (a), (b), (c), (d).

Claims

1. A compound of formula (Ia)

W-L-Z (Ia) and/or enantiomers, diastereomers or pharmaceutically acceptable salts thereof, wherein:

W is —

C(=O)R₆, —

C(OH)R₆(R₆), —

C(=O)OR₆, —

C(=O)NR₆R₆, alkyl, alkenyl, aryl, cycloalkyl, heteroaryl or heterocyclyl, wherein the alkyl, alkenyl, aryl, cycloalkyl, heteroaryl or heterocyclyl may be optionally substituted with R₁, R_1a, R_1b, R_1c and R_1d;

R₁, R_1a, R_1b, R_1c and R_1d are independently hydrogen, halogen, —

OH, —

CN, −

NO₂, —

CO₂R₆, —

CONR₆R₆, —

SO₂NR₆R₆, —

SOR₆, —

SO₂R₆, —

NR₆SO₂R₆, —

NR₆CO₂R₆, —

OCONR₆R₆, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

or alternatively any two R₁, R_1a, R_1b, R_1c and R_1d can be taken together to form a fused cycloalkyl, aryl, heteroaryl, heterocyclyl ring or spiro heterocyclyl ring;

L is a bond, 0, SO, SO₂, C(=O), alkenyl, cycloalkyl, CR₂R_2a, CR₂R₆, CR₂R_2aCR_2bR_2c, SO₂NR₆, OCR₂R_2a, OCR₂R_2aCR_2bR_2c, CR₂R_2aO, CR_2bR_2cCR₂R_{2aO, N(R5})CR₂R_{2a, CR2}R_2aSO, CR₂R_2aSO₂, SOCR₂R_2a, SO₂CR₂R₂, CR₂R_2aOCR_2bR_2c, CR₂R_2aSCR_2bR_2c, CR₂R_2aSO₂CR_2bR_2c, SO₂NR₆CR_2aR_2b, COCR₂R_2a , CR₂R_2aCO, CONR₆CR_2aR_2b, CR₂R_2aCR_2bR_2cS, CR₂R_2aCR_2bR_2cSO, CR₂R_2aCR_2bR_2cSO₂;

R₂, R_2a, R_2b and R_2c are independently hydrogen, halogen, —

OH, alkyl, cycloalkyl, aryl, or haloalkyl;

or alternatively any two R₂, R_2a, R_2b, and R_2c can be taken together to which the atom they are attached to form a cycloalkyl, halogen substituted cycloalkyl or heterocyclyl ring;

Z is;

2. The compound as defined in claim 1, wherein W is alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl, all of which may be optionally substituted with R₁, R_1a, R_1b, R_1c and R_1d.

3. The compound as defined in claim 1, wherein W is phenyl or cyclopropyl, both of which are optionally substituted with R₁, R_1a, R_1b, R_1c and R_1d.

4. The compound as defined in claim 1, wherein:

R₄ is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —

OH, —

OR₆, —

SR₆, —

OCOR₆, —

CN, —

NR₆COR₆, —

NR₆SO₂R₆, —

COR_E, —

CO₂R₆, —

CO₂H, —

OCONR₆R₆, —

CONR₆R₆, —

NR₆CO₂R₆, —

SO₂R₆, alkyl, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

or

R₄ is alkyl substituted with one or more substituents selected from —

OH, —

OR₆, —

SR₆, —

OCOR₆, —

CN, —

NR₆COR₆, —

NR₆SO₂R₆, —

COR₆, —

OCONR₆R₆, —

CONR₆R₆, —

NR₆CO₂R₆, —

SO₂R₆, alkyl, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₅, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, haloalkyl, COR₆, CO₂R₆, SO₂NR₆R₆, or SO₂R₆;

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₇, R_7a, R_7b, and R_7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, —

OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —

NO₂, —

CN, —

CO₂H, tetrazolyl or thiol, wherein the alkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino or tetrazolyl may be optionally substituted with R₈, R_8a, R_8b, and R_8c; and

R₈, R_8a, R_8b, and R_8c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, —

OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —

NO₂, —

CN, —

CO₂H, tetrazolyl or thiol.

5. The compound as defined in claim 1, wherein:

W is alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl, all of which may be optionally substituted with R₁, R_1a, R_1b, R_1c and R_1d;

R₁, R_1a, R_1b, R_1c and R_1d are independently hydrogen, halogen, —

OH, —

CN, —

NO₂, —

CO₂R₆, —

CONR₆R₆, —

SO₂NR₆R₆, —

SOR₆, —

SO₂R₆, —

NR₆SO₂R₆, —

NR₆CO₂R₆, —

OCONR₆R₆, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇,

R_7a, R_7b, and R_7c;

L is a bond, SO₂, C(=O), CR₂R_2a, CR₂R₆, SO₂NR₆, OCR₂R_2a, OCR₂R_2aCR_2bR_2c, CR₂R_2aO, CR_2bR_2cCR₂R_2aO, CR₂R_2aSO, CR₂R_2aSO, SO₂CR₂R_2a, CR₂R_2aOCR_2bR_2c, CR₂R_2aSCR_2bR_2c, CR₂R_2aSO₂CR_2bR_2c, SO₂NR₆CR_2aR_2b, COCR₂R_2a, CR₂R_2aCO, CONR₆CR_2aR_2b, CR₂R_2aCR_2bR_2c, CR₂R_2aCR_2bR_2cSO or CR₂R_2aCR_2bR_2cSO₂;

R₂, R_2a, R_2b and R₂ are independently hydrogen, halogen, —

OH, alkyl, cycloalkyl, aryl or haloalkyl;

R₃ is hydrogen, halogen, —

OH, —

CN, —

NO₂, —

CO₂R₆, —

CONR₆R₆, —

SO₂NR₆R₆, —

SOR₆, —

SO₂R₆, —

NR₆SO₂R₆, —

NR₆CO₂R₆, —

OCONR₆R₆, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R_3a is hydrogen, halogen, —

OH, —

CN, —

NO₂, —

CO₂R₆, —

CONR₆R₆, —

SO₂NR₆R₆, —

SOR₆, —

SO₂R₆, —

NR₆SO₂R₆, —

NR₆CO₂R₆, —

OCONR₆R₆, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₄ is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —

OH, —

OR₆, —

SR₆, —

OCOR₆, —

CN, —

NR₆COR₆, —

NR₆SO₂R₆, —

COR₆, —

CO₂R₆, —

CO₂H, —

OCONR₆R₆, —

CONR₆R₆, —

NR₆CO₂R₆, —

SO₂R₆, alkyl, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

or

R₄ is alkyl substituted with one or more substituents selected from halogen, OH, -OR₆, ^-SR₆, —

OCOR₆, —

CN, —

NR₆COR₆, —

NR₆SO₂R₆, —

COR₆, —

OCONR₆R₆, —

CONR₆R₆, —

NR₆CO₂R₆, —

SO₂R₆, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₅, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, haloalkyl, COR₆ or

CO₂R₆;

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₇, R_7a, R_7b, and R_7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, -OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, -NO₂, -CN, -CO₂H, tetrazolyl or thiol, wherein the alkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino or tetrazolyl may be optionally substituted with R₈, R_8a, R_8b, and R_8c; and

R₈, R_8a, R_8b, and R_8c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, -OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —

NO₂, —

CN, —

CO₂H, tetrazolyl or thiol.

6. The compound as defined in claim 1, wherein:

W is alkyl, aryl, cycloalkyl or heteroaryl, all of which may be optionally substituted with R₁, R_1a, R_1b, R_1c and R_1d;

R₁, R_1a, R_1b, R_1c and R_1d are independently hydrogen, halogen, —

OH, —

CN, —

NO₂, —

CO₂R₆, —

CONR₆R₆, —

SO₂NR₆R₆, —

SOR₆, —

SO₂R₆, —

OCONR₆R₆, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

L is a bond, O, SO, SO₂, C(=O), CR₂R_2a, CR₂R₆, CR₂R_2aCR_2bR_2c, OCR₂R_2a, CR₂R_2aO, CR₂R_2aOCR2bR_2c, CR₂R_2aSCR_2bR_2c, CR₂R_2aSO₂CR_2bR_2c or SO₂NR₆CR_2aR_2b;

R₂, R_2a, R_2b and R_2c are independently hydrogen, halogen, —

OH, alkyl, cycloalkyl, aryl or haloalkyl;

R₃ is hydrogen, halogen, —

OH, —

CN, —

NO₂, —

CO₂R₆, —

CONR₆R₆, —

SO₂NR₆R₆, —

SOR₆, —

SO₂R₆, —

OCONR₆R₆, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇,

R_7a, R_7b, and R_7c;

R_3a is hydrogen, halogen, —

OH, —

CN, —

NO₂, —

CO₂R₆, —

CONR₆R₆, —

SO₂NR₆R₆, —

SOR₆, —

SO₂R₆, —

OCONR₆R₆, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₄ is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —

OH, —

OR₆, —

SR₆, —

OCOR₆, —

CN, —

COR₆, —

CO₂R₆, —

CO₂H, —

OCONR₆R₆, —

CONR₆R₆, —

SO₂R₆, alkyl, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

or

R₄ is alkyl substituted with one or more substituents selected from —

OH, —

OR₆, —

SR₆, —

OCOR₆, —

CN, —

COR₆, —

OCONR₆R₆, —

CONR₆R₆, —

SO₂R₆, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₇, R_7a, R_7b, and R_7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, —

OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —

NO₂, —

CN, —

CO₂H, tetrazolyl or thiol, wherein the alkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino or tetrazolyl may be optionally substituted with Rg, R_8a, R_8b, and R_8c; and

R₈, R_8a, R_8b, and R_8c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, —

OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —

NO₂, —

CN, —

CO₂H, tetrazolyl or thiol.

7. The compound as defined in claim 1, wherein:

W is alkyl, aryl or cycloalkyl, all of which may be optionally substituted with R₁, R_1a, R_1b, R_1c and R_1d;

R₁, R_1a, R_1b, R_1c and R_1d are independently hydrogen, halogen, —

OH, —

CN, —

NO₂, —

CO₂R₆, —

CONR₆R₆, —

SO₂NR₆R₆, —

OCONR₆R₆, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

L is a bond, O, SO, SO₂, C(=O), CR₂R_2a, CR₂R₆, OCR₂R_2a, CR₂R_2aO, SO₂NR₆CR_2aR_2b or CR₂R_2aOCR2bR_2c;

R₂, R_2a, R_2b and R₂ are independently hydrogen, halogen, —

OH, alkyl, cycloalkyl, aryl or haloalkyl;

R₃ is hydrogen, halogen, —

OH, —

CN, —

NO₂, —

CO₂R₆, —

CONR₆R₆, —

SO₂NR₆R₆, —

OCONR₆R₆, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R_3a is hydrogen, halogen, —

OH, —

CN, —

NO₂, —

CO₂R₆, —

CONR₆R₆, —

SO₂NR₆R₆, —

OCONR₆R₆, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₄ is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —

OH, —

OR₆, —

SR₆, —

OCOR₆, —

CN, —

COR₆ , —

CO₂R₆, -CO₂H, -OCONR₆R₆, -CONR₆R₆, —

SO₂R₆, alkyl, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

or

R₄ is alkyl substituted with one or more substituents selected from —

OH, —

OR₆, —

SR₆, —

OCOR₆, —

CN, —

COR₆, —

OCONR₆R₆, —

CONR₆R₆, —

SO₂R₆, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₇, R_7a, R_7b, and R_7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, —

OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —

NO₂, —

CN, —

CO₂H, tetrazolyl or thiol, wherein the alkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino or tetrazolyl may be optionally substituted with R₈, R_8a, R_8b, and R_8c; and

R₈, R_8a, R_8b, and R_8c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, -OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —

NO₂, —

CN, —

CO₂H, tetrazolyl or thiol.

8. The compound as defined in claim 1, wherein:

W is alkyl, aryl or cycloalkyl, all of which may be optionally substituted with R₁, R_1a, R_1b, R_1c and R_1d;

R₁, R_1a, R_1b, R_1c and R_1d are independently hydrogen, halogen, —

OH, —

CN, —

NO₂, —

CO₂R₆, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

L is a bond, O, SO, SO₂, C(=O), CR₂R_2a, CR₂R₆, OCR₂R_2a, CR₂R_2aO, SO₂NR₆CR_2aR_2b or CR₂R_2aOCR_2bR_2c;

R₂, R_2a, R_2b and R₂ are independently hydrogen, halogen, —

OH, alkyl, cycloalkyl, aryl or haloalkyl;

R₃ is hydrogen, halogen, —

OH, —

CN, —

NO₂, —

CO₂R₆, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R_3a is hydrogen, halogen, —

OH, —

CN, —

NO₂, —

CO₂R₆, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₄ is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —

OH, —

OR₆, —

SR₆, —

CN, —

COR_E, —

CO₂R₆, —

CO₂H, —

CONR₆R₆, —

SO₂R₆, alkyl, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

or

R₄ is alkyl substituted with one or more substituents selected from —

OH, —

OR₆, —

SR₆, —

CN, —

COR₆, —

CONR₆R₆, —

SO₂R₆, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₇, R_7a, R_7b, and R_7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, -OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, -NO₂, -CN, -CO₂H, tetrazolyl or thiol, wherein the alkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino or tetrazolyl may be optionally substituted with R₈, R_8a, R_8b, and R_8c; and

R₈, R_8a, R_8b, and R_8c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, -OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —

NO₂, —

CN, —

CO₂H, tetrazolyl or thiol.

9. The compound as defined in claim 1, wherein:

W is alkyl, aryl or cycloalkyl, all of which may be optionally substituted with R₁, R_1a, R_1b, R_1c and R_1d;

R₁, R_1a, R_1b, R_1c and R_1d are independently hydrogen, halogen, —

OH, —

CN, —

NO₂, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c,

L is a bond, O, SO, SO₂, C(=O), CR₂R_2a, CR₂R₆, OCR₂R_2a, CR₂R_{2aO, SO2}NR₆CR_2aR_2b or CR₂R_2aOCR_2bR_2c;

R₂, R_2a, R_gb and R_2c are independently hydrogen, halogen, —

OH, alkyl, cycloalkyl, aryl or haloalkyl;

R₃ is hydrogen, halogen, —

OH, —

CN, —

NO₂, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R_3a is hydrogen, halogen, —

OH, —

CN, —

NO₂, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₄ is alkyl substituted with one or more substituents selected from —

OH, OR₆, —

SR₆, —

CN, —

COR₆, —

CONR₆R₆, —

SO₂R₆, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₇, R_7a, R_7b, and R_7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, -OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, -NO₂, -CN, -CO₂H, tetrazolyl or thiol, wherein the alkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino or tetrazolyl may be optionally substituted with R₈, R_8a, R_8b, and R_8c; and

R₈, R_8a, R_8b, and R_8c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, -OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —

NO₂, —

CN, —

CO₂H, tetrazolyl or thiol.

10. The compound as defined in claim 1, wherein:

W is aryl or cycloalkyl, both of which may be optionally substituted with R₁, R_1a, R_1b, R_1c and R_1d;

R₁, R_1a, R_1b, R_1c and R_1d are hydrogen, halogen, —

OH, —

CN, —

NO₂, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

L is a bond, O, C(=O), CR₂R_2a, CR₂R₆, OCR₂R_2a, CR₂R_2a0 or CR₂R_2aOCR2bR_2c;

R₂, R_2a, R_2b and R₂ are independently hydrogen, halogen, —

OH, alkyl, cycloalkyl, aryl or haloalkyl;

R₃ is hydrogen, halogen, —

OH, —

CN, —

NO₂, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R_3a is hydrogen, halogen, —

OH, —

CN, —

NO₂, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₄ is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —

OH, —

OR₆, —

SR₆, —

CN, —

COR₆, —

CO₂R₆, —

CO₂H, alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

or

R₄ is alkyl substituted with one or more substituents selected from —

OH, —

OR₆, —

SR₆, —

CN, —

COR₆, —

CONR₆R₆, —

SO₂R₆, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl;

R₇, R_7a, R_7b, and R_7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, —

OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —

NO₂, —

CN, —

CO₂H, tetrazolyl or thiol, wherein the alkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino or tetrazolyl may be optionally substituted with R₈, R_8a, R_8b, and R_8c; and

R₈, R_8a, R_8b, and R_8c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, —

OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —

NO₂, —

CN, —

CO₂H, tetrazolyl or thiol.

11. The compound as defined in claim 1, wherein:

W is phenyl or cyclopropyl, both of which may be optionally substituted with R₁, R_1a, R_1b, R_1c and R_1d;

R₁, R_1a, R_1b, R_1c and R_1d are independently hydrogen, halogen, —

OH, —

CN, —

NO₂, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, aryl, heteroaryl or heterocyclyl;

L is a bond, O, C(=O), CHR₆, OCH₂, CH₂O or CH₂OCH₂;

R₃ is hydrogen, halogen, —

OH, —

CN, —

NO₂, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aryl, heteroaryl or heterocyclyl;

R_1a is hydrogen, halogen, —

OH, —

CN, —

NO₂, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, aryl, heteroaryl or heterocyclyl;

R₄ is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —

OH, —

OR₆, —

SR₆, —

CN, alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

or

R₄ is alkyl substituted with one or more substituents selected from —

OH, —

OR₆, —

SR₆, —

CN, —

COR₆, —

CONR₆R₆, —

SO₂R₆, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, spiro cycloalkyl, spiro heterocycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl;

R₇, R_7a, R_7b, and R_7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylalkyl, cycloalkyl, amino, -OH, hydroxyalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, alkylthio, arylalkylthio, -NO₂, -CN, -CO₂H or tetrazolyl;

wherein the alkyl, alkoxy, aryl, aryloxy, arylalkyl, cycloalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, alkylthio, arylalkylthio or tetrazolyl may be optionally substituted with R₈, R_8a, R_8b, and R_8c; and

R₈, R_8a, R_8b, and R_8c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, -OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —

NO₂, —

CN, —

CO₂H, tetrazolyl or thiol.

12. The compound as defined in claim 1, wherein L is a bond or O.

13. The compound as defined in claim 1 selected from the compounds of the structure:

14. A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier.

15. A compound of formula (Ib)

W-L-Z

(Ib)

and/or enantiomers, diastereomers or pharmaceutically acceptable salts thereof, wherein:

W is —

C(=O)R₆, —

C(OH)R₆(R₆), —

C(=O)OR₆, —

C(=O)NR₆R₆, alkyl, alkenyl, aryl, or cycloalkyl, heteroaryl or heterocyclyl, wherein the alkyl, alkenyl, aryl, cycloalkyl, heteroaryl or heterocyclyl may be optionally substituted with R₁, R_1a, R_1b, R_1c and R_1d;

R₁, R_1a, R_1b, R_1c and R_1d are independently hydrogen, halogen, —

OH, —

CN, —

NO₂, —

CO₂R₆, —

CONR₆R₆, —

SO₂NR₆R₆, —

SOR₆, —

SO₂R₆, —

NR₆SO₂R₆, —

NR₆CO₂R₆, —

OCONR₆R₆, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇,

R_7a, R_7b, and R_7c;

or alternatively any two R₁, R_1a, R_1b, R_1c and R_1d can be taken together to form a fused cycloalkyl, aryl, heteroaryl, heterocyclyl ring or spiro heterocyclyl ring;

L is a bond or O;

16. The compound as defined in claim 15 wherein W is cycloalkyl, aryl, alkenyl or alkyl, wherein the cycloalkyl, aryl, alkenyl or alkyl may be optionally substituted with R₁, R_1a, R_1b, R_1c and R_1d, R₃ is H, and R_3a is H.

17. The compound as defined in claim 15 having the following structure;

18. A compound of formula (I)

W-L-Z 

 

(I)

and/or enantiomers, diastereomers or pharmaceutically acceptable salts thereof, wherein;

W is alkyl, alkenyl, aryl, or cycloalkyl, wherein the alkyl, alkenyl, aryl, or cycloalkyl may be optionally substituted with R₁, R_1a, R_1b, R_1c and R_1d;

R₁, R_1a, R_1b, R_1c and R_1d are independently hydrogen, halogen, —

OH, —

CN, —

NO₂, —

CO₂R₆, —

CONR₆R₆, —

SO₂NR₆R₆, —

SOR₆, —

SO₂R₆, —

NR₆SO₂R₆, —

NR₆CO₂R₆, —

OCONR₆R₆, tetrazolyl, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the tetrazolyl, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇, R_7a, R_7b, and R_7c;

or alternatively any two R₁, R_1a, R_1b, R_1c and R_1d can be taken together to form a fused cycloalkyl, aryl, heteroaryl, heterocyclyl ring or spiro heterocyclyl ring;

L is O;

Z is

19. The compound as defined in claim 18 wherein W is aryl, which may be optionally substituted with R₁, R_1a, R_1b, R_1c and R_1d, R₃ is H, R_3a is H, and R₄ is cycloalkyl, which may be optionally substituted with R₇, R_7a, R_7b, and R_7c.