# US 8,541,444 B2 · Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors

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- Number: US 8,541,444 B2
- Document ID: US8541444B2
- Status: Granted
- Kind: B2
- Application number: 13/197,273
- Filed: 2011-08-03
- Published: 2011-11-24
- Granted: 2013-09-24
- Earliest claimed: 2007-10-01
- Assignees: Bristol-Myers Squibb Company
- Applicants: Jun Li; Jeffrey A. Robl; James J. Li; Lawrence J. Kennedy; Haixia Wang; Jie Jack Li; Chenkou Wei; Michael Galella
- Inventors: Jun Li; Jeffrey A. Robl; James J. Li; Lawrence J. Kennedy; Haixia Wang; Jie Jack Li; Chenkou Wei; Michael Galella
- Web page: https://patentgrep.com/patent/US8541444B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/08: for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
- A61P 5/38: of the suprarenal hormones
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 25/00: Drugs for disorders of the nervous system
- 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
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Novel compounds are provided which are 11-beta-hydroxysteroid dehydrogenase type I inhibitors. 11-beta-hydroxysteroid dehydrogenase type I inhibitors are useful in treating, preventing, or slowing the progression of diseases requiring 11-beta-hydroxysteroid dehydrogenase type I inhibitor therapy. These novel compounds of formula I: or stereoisomers or pharmaceutically acceptable salts thereof, wherein G, Q, X, Y, R3, R3a, and R3b are defined herein.

## Claims

### Claim 1

A compound of formula I
enantiomers, diastereomers, or salts thereof wherein:
Q is L, Laa or Lee;
X is C and Y is N;
G is R4, R4aa or R4ee;
L is -alkenyl-(W1)n, -cycloalkyl-(W1)n or -alkyl-(W2)n;
Laa is -alkenyl-(W1)n or -alkyl-(W2aa)n;
Lee is -alkenyl-(W1ee)n, -cycloalkyl-(W1)n or -alkyl-(W2ee)n;
n is 1 to 3;
W1, at each occurrence, is independently halogen, —OH, —CN, —CO2R6, —CONR8R8a, —OCONR8R8a, —SO2NR8R8a, —SOR6, —SO2R6, —NR9SO2R9a, —NR9CO2R9a, —NR9COR9a, alkyl, cycloalkyl, haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, amino, aminoalkyl, arylamino or heteroarylamino;
W1ee is independently halogen, —OH, —CN, —CO2R6, —CONR8R8a, —OCONR8R8a, —SO2NR8R8a, —SOR6, —SO2R6, —NR9SO2R9a, —NR9CO2R9a, —NR9COR9a, cycloalkyl, alkyl, haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, amino, aminoalkyl, arylamino or heteroarylamino;
W2 is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, —NR9CO2R9a, —NR9COR9a, cycloalkyl, alkyl, haloalkyl, alkoxy, alkenyl, haloalkoxy, alkylthio, alkylamino, amino or aminoalkyl;
W2aa is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, —NR9CO2R9a, —NR9COR9a, —OR9bOR9bSi(R9b)3, cycloalkyl, alkyl, haloalkyl, alkoxy, alkenyl, haloalkoxy, alkylthio, alkylamino, amino or aminoalkyl;
W2ee is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, —NR9CO2R9a, —NR9COR9a, cycloalkyl, alkyl, haloalkyl, alkenyl, haloalkoxy, alkylthio, amino, aminoalkyl, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
provided that W2aa or W2ee are not only alkyl;
R3, R3a and R3b are independently hydrogen, halogen, —OH, —NO2, —CO2R8a, —CONR8R8a, —SO2NR8R8a, —SOR8a, —SO2R8a, —NR8SO2R6, —NR8CO2R6, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4 is alkyl, cycloalkyl or heterocyclyl, all of which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —OCOR6, —CN, —NR5COR6, —NR5SO2R6, —COR6, —CO2R6, —CO2H, —OCONR8R8a, —CONR8R8a, —NR5CO2R6, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4aa is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —OCOR6, —CN, —NR5COR6, —NR5SO2R6, —COR6, —CO2R6, —CO2H, —OCONR8R8a, —CONR8R8a, —NR5CO2R6, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4ee is alkyl or cycloalkyl, both of which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —OCOR6, —CN, —NR5COR6, —NR5SO2R6, —COR6, —CO2R6, —CO2H, —OCONR8R8a, —CONR8R8a, —NR5CO2R6, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R5, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, haloalkyl, COR8a, CO2R8a, SO2NR8R8a, or SO2R8a;
R6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R7, R7a, R7b, and R7c;
R7, R7a, R7b, and R7c, at each occurrence, are independently halo, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, —CO2R8, —CONR8R8a, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, alkylsilicaalkyloxy, —SO2R9b—NO2, —CN or thiol, wherein the aryl or heteroaryl may be optionally substituted with R10, R10a, R10b, and R10c;
R8 and R8a, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
or alternatively R8 and R8a can be taken together with the nitrogen to which they are attached to form a heterocyclyl ring containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S, which may be optionally substituted with R10, R10a, R10b, and R10c;
R9 and R9a, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heterocyclyl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
R9b, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R10, R10a, R10b, and R10c; and
R10, R10a, R10b, and R10c, at each occurrence, are independently halo, alkyl, haloalkyl, cyanoalkyl, 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 or thiol;
provided that:
(a) W1, W1ee, W2, or W2aa is not cycloalkyl when n is 1 and R4, R4aa or R4ee are cycloalkyl;
(b) W2ee is not cycloalkyl, aryl, heteroaryl or heterocyclyl when n is 1 and R4ee is cycloalkyl;
(c) R7, R7a, R7b, and R7c must be substituted with at least one R10, R10a, R10b, or R10c when (i) Lee is cycloalkyl, (ii) R4ee is cycloalkyl substituted with aryl, heterocyclyl or heteroaryl, (iii) the aryl, heteroaryl or heterocyclyl is substituted with R7, R7a, R7b, or R7c; and (iv) R7, R7a, R7b, and R7c is aryl, heteroaryl or heterocyclyl;
(d) Laa and Lee are not C1-3alkyl when R4aa or R4ee are substituted with an optionally substituted aryl moiety; and
(e) W2ee is not alkyl, haloalkyl or aryl when R4ee is alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula Iaa, Idd or Iee:
provided that:
(a) W1, W1ee, W2, or W2aa is not cycloalkyl when n is 1 and R4, R4aa or R4ee are cycloalkyl;
(b) W2ee is not cycloalkyl, aryl, heteroaryl or heterocyclyl when n is 1 and R4ee is cycloalkyl;
(c) R7, R7a, R7b, and R7c must be substituted with at least one R10, R10a, R10b, or R10c when (i) Lee is cycloalkyl, (ii) R4ee is cycloalkyl substituted with aryl, heterocyclyl or heteroaryl, (iii) the aryl, heteroaryl or heterocyclyl is substituted with R7, R7a, R7b, or R7c; and (iv) R7, R7a, R7b, and R7c is aryl, heteroaryl or heterocyclyl;
(d) Laa and Lee are not C1-3alkyl when R4aa or R4ee are substituted with an optionally substituted aryl moiety; and
(e) W2ee is not alkyl, haloalkyl or aryl when R4ee is alkyl.

### Claim 3 (depends on 2)

The compound of claim 2, wherein:
L is -alkenyl-(W1)n or -alkyl-(W2)n;
Laa is -alkenyl-(W1)n or -alkyl-(W2aa)n;
Lee is -alkenyl-(W1ee)n, -cycloalkyl-(W1)n or -alkyl-(W2ee)n;
n is 1 to 3;
W1, at each occurrence, is independently halogen, —OH, —CN, —CO2R6, —CONR8R8a, —OCONR8R8a, —SO2NR8R8a, —SOR6, —SO2R6, —NR9SO2R9a, —NR9CO2R9a, alkyl, cycloalkyl, haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino or heteroarylamino;
W1ee is independently halogen, —OH, —CN, —CO2R6, —CONR8R8a, —OCONR8R8a, —SO2NR8R8a, —SOR6, —SO2R6, —NR9SO2R9a, —NR9CO2R9a, cycloalkyl, alkyl, haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino or heteroarylamino;
W2 is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, —NR9CO2R9a, —NR9COR9a, cycloalkyl, alkyl, haloalkyl, alkoxy, alkenyl, haloalkoxy, alkylthio, alkylamino, amino or aminoalkyl;
W2aa is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, —NR9CO2R9a, —NR9COR9a, —OR9bOR9bSi(R9b)3, cycloalkyl, alkyl, haloalkyl, alkoxy, alkenyl, haloalkoxy, alkylthio, alkylamino, amino or aminoalkyl;
W2ee is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, —NR9CO2R9a, —NR9COR9a, cycloalkyl, alkyl, haloalkyl, alkenyl, haloalkoxy, alkylthio, aminoalkyl, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R3, R3a and R3b are independently hydrogen, halogen, —OH, —NO2, —CO2R8a, —CONR8R8a, —SO2NR8R8a, —SOR8a, —SO2R8a, —NR8SO2R6, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4 is alkyl or cycloalkyl, both of which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —OCOR6, —CN, —NR5COR6, —NR5SO2R6, —COR6, —CO2R6, —CO2H, —OCONR8R8a, —CONR8R8a, —NR5CO2R6, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4aa is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —OCOR6, —CN, —NR5COR6, —NR5SO2R6, —COR6, —CO2R6, —CO2H, —OCONR8R8a, —CONR8R8a, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4ee is alkyl or cycloalkyl, both of which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —OCOR6, —CN, —NR5COR6, —NR5SO2R6, —COR6, —CO2R6, —CO2H, —OCONR8R8a, —CONR8R8a, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R5, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, haloalkyl, COR8a or CO2R8a;
R6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R7, R7a, R7b, and R7c;
R7, R7a, R7b, and R7c, at each occurrence, are independently halo, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, —CO2R8, —CONR8R8a, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —SO2R9b—NO2, —CN or thiol, wherein the aryl or heteroaryl may be optionally substituted with R10, R10a, R10b, and R10c;
R8 and R8a, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
or alternatively R8 and R8a can be taken together with the nitrogen to which they are attached to form a heterocyclyl ring containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S, which may be optionally substituted with R10, R10a, R10b, and R10c;
R9 and R9a, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heterocyclyl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
R9b, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
R10, R10a, R10b, and R10c, at each occurrence, are independently halo, alkyl, haloalkyl, cyanoalkyl, 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 or thiol;
provided that:
(a) W1, W1ee, W2, or W2aa is not cycloalkyl when n is 1 and R4, R4aa or R4ee are cycloalkyl;
(b) W2ee is not cycloalkyl, aryl, heteroaryl or heterocyclyl when n is 1 and R4ee is cycloalkyl;
(c) R7, R7a, R7b, and R7c must be substituted with at least one R10, R10a, R10b, or R10c when (i) Lee is cycloalkyl, (ii) R4ee is cycloalkyl substituted with aryl, heterocyclyl or heteroaryl, (iii) the aryl, heteroaryl or heterocyclyl is substituted with R7, R7a, R7b, or R7c; and (iv) R7, R7a, R7b, and R7c is aryl, heteroaryl or heterocyclyl;
(d) Laa and Lee are not C1-3alkyl when R4aa or R4ee are substituted with an optionally substituted aryl moiety;
(e) W2ee is not alkyl, haloalkyl or aryl when R4ee is alkyl.

### Claim 4 (depends on 2)

The compound of claim 2, wherein:
L is -alkenyl-(W1)n or -alkyl-(W2)n;
Laa is -alkenyl-(W1)n or -alkyl-(W2aa)n;
Lee is -alkenyl-(W1ee)n, -cycloalkyl-(W1)n or -alkyl-(W2ee)n;
n is 1 to 3;
W1, at each occurrence, is independently halogen, —OH, —CN, —CO2R6, —CONR8R8a, —OCONR8R8a, —SO2NR8R8a, —SOR6, —SO2R6, —NR9SO2R9a, alkyl, haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino or heteroarylamino;
W1ee is independently halogen, —OH, —CN, —CO2R6, —CONR8R8a, —OCONR8R8a, —SO2NR8R8a, —SOR6, —SO2R6, —NR9SO2R9a, alkyl, haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino or heteroarylamino;
W2 is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, —NR9COR9a, alkyl, haloalkyl, alkoxy, alkenyl, haloalkoxy, alkylthio, alkylamino, amino or aminoalkyl;
W2aa is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, —NR9COR9a, —OR9bOR9bSi(R9b)3, alkyl, alkoxy, alkenyl, haloalkoxy, alkylthio, alkylamino, amino or aminoalkyl;
W2ee is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, —NR9CO2R9a, alkyl, alkenyl, haloalkoxy, alkylthio or aminoalkyl;
R3, R3a and R3b are independently hydrogen, halogen, —OH, —NO2, —CO2R8a, —CONR8R8a, —SO2NR8R8a, —SOR8a, —SO2R8a, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4 is alkyl or cycloalkyl, both of which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —OCOR6, —CN, —COR6, —CO2R6, —CO2H, —OCONR8R8a, —CONR8R8a, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4aa is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —OCOR6, —CN, —COR6, —CO2R6, —CO2H, —OCONR8R8a, —CONR8R8a, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4ee is alkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —OCOR6, —CN, —COR6, —CO2R6, —CO2H, —OCONR8R8a, —CONR8R8a, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R7, R7a, R7b, and R7c;
R7, R7a, R7b, and R7c, at each occurrence, are independently halo, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, —CO2R8, —CONR8R8a, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —SO2R9b—NO2, —CN or thiol, wherein the aryl or heteroaryl may be optionally substituted with R10, R10a, R10b, and R10c;
R8 and R8a, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
or alternatively R8 and R8a can be taken together with the nitrogen to which they are attached to form a heterocyclyl ring containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S, which may be optionally substituted with R10, R10a, R10b, and R10c;
R9 and R9a, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heterocyclyl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
R9b, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R10, R10a, R10b, and R10c; and
R10, R10a, R10b, and R10c, at each occurrence, are independently halo, alkyl, haloalkyl, cyanoalkyl, 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 or thiol.

### Claim 5 (depends on 2)

The compound of claim 2, wherein:
L is -alkenyl-(W1)n or -alkyl-(W2)n;
Laa is -alkenyl-(W1)n or -alkyl-(W2aa)n;
Lee is -cycloalkyl-(W1)n or -alkyl-(W2ee)n;
n is 1 to 3;
W1, at each occurrence, is independently halogen, —OH, —CN, —CO2R6, —CONR8R8a, —OCONR8R8a, —SO2NR8R8a, —SOR6, —SO2R6, —NR9SO2R9a, alkyl, haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, aminoalkyl, arylamino or heteroarylamino;
W2 is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, —NR9COR9a, alkyl, haloalkyl, alkoxy, alkenyl, haloalkoxy, alkylthio, alkylamino or aminoalkyl;
W2aa is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, —NR9COR9a, —OR9bOR9bSi(R9b)3, alkyl, alkoxy, alkenyl, haloalkoxy, alkylthio, alkylamino or aminoalkyl;
W2ee is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, alkyl, alkenyl, haloalkoxy, alkylthio or aminoalkyl;
R3, R3a and R3b are independently hydrogen, halogen, —OH, —NO2, —CO2R8a, —CONR8R8a, —SO2NR8R8a, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4 is alkyl or cycloalkyl, both of which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —OCOR6, —CN, —COR6, —CO2R6, —CO2H, —OCONR8R8a, —CONR8R8a, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4aa is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —OCOR6, —CN, —COR6, —CO2R6, —CO2H, —OCONR8R8a, —CONR8R8a, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4ee is alkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —OCOR6, —CN, —COR6, —CO2R6, —CO2H, —OCONR8R8a, —CONR8R8a, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R7, R7a, R7b, and R7c;
R7, R7a, R7b, and R7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, —CO2R8, —CONR8R8a, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —SO2R9b—NO2, —CN or thiol, wherein the aryl or heteroaryl may be optionally substituted with R10, R10a, R10b, and R10c;
R8 and R8a, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
R9 and R9a, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heterocyclyl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
R9b, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R10, R10a, R10b, and R10c; and
R10, R10a, R10b, and R10c, 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 or thiol.

### Claim 6 (depends on 2)

The compound of claim 2, wherein:
L is -alkyl-(W2)n;
Laa is -alkenyl-(W1)n or -alkyl-(W2aa)n;
Lee is -cycloalkyl-(W1)n or -alkyl-(W2ee)n;
n is 1 to 2;
W1, at each occurrence, is independently halogen, —OH, —CN, —CO2R6, —CONR8R8a, —OCONR8R8a, —SO2NR8R8a, —SOR6, —SO2R6, alkyl, haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, aminoalkyl, arylamino or heteroarylamino;
W2 is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, —NR9COR9a, alkyl, haloalkyl, alkoxy, alkenyl, haloalkoxy, alkylthio, alkylamino or aminoalkyl;
W2aa is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, alkyl, alkoxy, alkenyl, haloalkoxy, alkylthio, alkylamino or aminoalkyl;
W2ee is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, alkyl, alkenyl, haloalkoxy, alkylthio or aminoalkyl;
R3, R3a and R3b are independently hydrogen, halogen, —OH, —NO2, —CO2R8a, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4 is alkyl or cycloalkyl, both of which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —CN, —COR6, —CO2R6, —CO2H, —CONR8R8a, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4aa is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —CN, —COR6, —CO2R6, —CO2H, —CONR8R8a, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4ee is alkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —CN, —COR6, —CO2R6, —CO2H, —CONR8R8a, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R7, R7a, R7b, and R7c;
R7, R7a, R7b, and R7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, —CO2R8, —CONR8R8a, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —SO2R9b—NO2, —CN or thiol, wherein the aryl or heteroaryl may be optionally substituted with R10, R10a, R10b, and R10c;
R8 and R8a, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
R9 and R9a, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl or heteroaryl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
R9b, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R10, R10a, R10b, and R10c; and
R10, R10a, R10b, and R10c, 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 or thiol.

### Claim 7 (depends on 2)

The compound of claim 2, wherein:
L is -alkyl-(W2)n;
Laa is -alkenyl-(W1)n or -alkyl-(W2aa)n;
Lee is -cycloalkyl-(W1)n or -alkyl-(W2ee)n;
n is 1 to 2;
W1, at each occurrence, is independently halogen, —OH, —CN, —CO2R6, —CONR8R8a, —OCONR8R8a, —SO2NR8R8a, —SOR6, —SO2R6, alkyl, haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, arylamino or heteroarylamino;
W2 is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, alkyl, haloalkyl, alkoxy, alkenyl, haloalkoxy, alkylthio, alkylamino or aminoalkyl;
W2aa is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, alkyl, alkoxy, alkenyl, haloalkoxy or alkylthio;
W2ee is independently —OH, —CO2H, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, alkyl, alkenyl, haloalkoxy or alkylthio;
R3, R3a and R3b are independently hydrogen, halogen, —OH, —NO2, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4 is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —CN, —COR6, —CO2R6, —CO2H, —CONR8R8a, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4aa is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —COR6, —CO2R6, —CO2H, —CONR8R8a, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4ee is alkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —COR6, —CO2R6, —CO2H, —CONR8R8a, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R7, R7a, R7b, and R7c;
R7, R7a, R7b, and R7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, —CO2R8, —CONR8R8a, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —SO2R9b—NO2, —CN or thiol, wherein the aryl or heteroaryl may be optionally substituted with R10, R10a, R10b, and R10c;
R8 and R8a, at each occurrence, is independently hydrogen, alkyl, aryl or heteroaryl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
R9 and R9a, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
R9b, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R10, R10a, R10b, and R10c; and
R10, R10a, R10b, and R10c, 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 or thiol.

### Claim 8

A compound, enantiomers, diastereomers, or salts thereof, that is:

### Claim 9 (depends on 2)

A pharmaceutical composition comprising a compound of claim 2.

### Claim 10 (depends on 9)

The pharmaceutical composition of claim 9 further comprising a pharmaceutically acceptable carrier, and optionally at least one additional therapeutic agent.

### Claim 11 (depends on 8)

A pharmaceutical composition comprising the compound of claim 8, a pharmaceutically acceptable carrier, and optionally at least one additional therapeutic agent.

### Claim 12 (depends on 2)

The compound of claim 2, wherein:
L is -alkyl-(W2)n;
L, is -alkyl-(W2aa)n;
Lee is -alkyl-(W2ee)n;
n is 1 to 2;
W2 is independently —OH, —CO2H, —CN, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, alkyl, haloalkyl, alkoxy or haloalkoxy;
W2aa is independently —OH, —CN, —CO2H, —CO2R6, —CONR8R8a, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, alkyl, alkoxy, alkenyl or haloalkoxy;
W2ee is independently —OH, —CN, —CO2H, —CO2R6, —CONR8R8a, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, alkyl, alkoxy, alkenyl or haloalkoxy;
R3, R3a and R3b are independently hydrogen, halogen, —OH, —CN, —NO2, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino or aminoalkyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4 is a 3- to 10-membered cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —CN, —COR6, —CO2R6, —CO2H, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4aa is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —CN, —COR6, —CO2R6, —CO2H, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4ee is alkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —CN, —COR6, —CO2R6, —CO2H, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl;
R7, R7a, R7b, and R7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, —CO2R8, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —SO2R9b—NO2, —CN or thiol, wherein the aryl or heteroaryl may be optionally substituted with R10, R10a, R10b, and R10c;
R8 and R8a, at each occurrence, is independently hydrogen, alkyl or aryl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
R9 and R9a, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
R9b, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl; and
R10, R10a, R10b, and R10c, 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 or thiol.

### Claim 13 (depends on 2)

The compound of claim 2, wherein:
L is -alkyl-(W2)n;
Laa is -alkyl-(W2aa)n;
Lee is -alkyl-(W2ee)n;
n is 1 to 2;
W2 is independently —OH, —CO2H, —CN, —CO2R6, —CONR8R8a, —OCOR6, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, alkyl or haloalkyl;
W2aa is independently —OH, —CN, —CO2H, —CO2R6, —CONR8R8a, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, alkyl, alkoxy or haloalkoxy;
W2ee is independently —OH, —CN, —CO2H, —CO2R6, —CONR8R8a, —OCONR8R8a, —SO2NR8R8a, —SO-alkyl, —SO2-alkyl, —NR9SO2R9a, alkyl, alkoxy or haloalkoxy;
R3, R3a and R3b are independently hydrogen, halogen, —OH, —CN, —NO2, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino or aminoalkyl;
R4 is a 3- to 7-membered cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —CN, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4aa is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —CN, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4ee is alkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —CN, —COR6, —CO2R6, —CO2H, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl;
R7, R7a, R7b, and R7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, aryloxy, arylaryl, arylalkyl, cycloalkyl, amino, —OH, —CO2R8, hydroxyalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, alkylthio, arylalkylthio, —NO2 or —CN, wherein the aryl or heteroaryl may be optionally substituted with R10, R10a, R10b, and R10c;
R8 and R8a, at each occurrence, is independently hydrogen or alkyl, wherein the alkyl may be optionally substituted with R10, R10a, R10b, and R10c; and
R9 and R9a, at each occurrence, is independently hydrogen, alkyl, aryl or heteroaryl, all of which may be optionally substituted with R10, R10a, R10b, and R10c;
R9b, at each occurrence, is independently alkyl, aryl or heteroaryl; and
R10, R10a, R10b, and R10c, 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 or thiol.

### Claim 14 (depends on 2)

The compound of claim 2, wherein:
L is -alkyl-(W2)n;
Laa is -alkyl-(W2aa)n;
Lee is -alkyl-(W2ee)n;
n is 1 to 2;
W2 is independently —OH, —CN, —CO2R6, —SO-alkyl, —SO2-alkyl, alkyl, or haloalkyl;
W2aa is independently —OH, —CN, —CO2R6, —SO-alkyl, —SO2-alkyl, alkyl, alkoxy, or haloalkoxy;
W2ee is independently —OH, —CN, —CO2R6, —SO-alkyl, —SO2-alkyl, alkyl or haloalkoxy;
R3, R3a and R3b are independently hydrogen, halogen, —OH, —CN, —NO2, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino or aminoalkyl;
R4 is a 3- or 4-membered cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —CN, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4aa is cycloalkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —CN, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4ee is alkyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —CN, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl; and
R7, R7a, R7b, and R7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylalkyl, cycloalkyl, amino, —OH, hydroxyalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, alkylthio, arylalkylthio, —NO2, or —CN.

### Claim 15 (depends on 2)

The compound of claim 2, wherein:
R4aa is cyclopropyl or cyclobutyl, both of which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —OCOR6, —CN, —NR5COR6, —NR5SO2R6, —COR6, —CO2R6, —CO2H, —OCONR8R8a, —CONR8R8a, —NR5CO2R6, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c; and
R4ee is isopropyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —SR6, —OCOR6, —CN, —NR5COR6, —NR5SO2R6, —COR6, —CO2R6, —CO2H, —OCONR8R8a, —CONR8R8a, —NR5CO2R6, —SO2R6, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c.

### Claim 16 (depends on 2)

The compound of claim 2, wherein the compound is a compound of formula Iaa or Iee:

### Claim 17 (depends on 2)

The compound of claim 2 having the formula Iaa or Iee:
wherein:
La is -alkyl-OH;
Lee is -alkyl-OH;
R3, R3a and R3b are independently selected from hydrogen, halogen, —CF3, OCF3, alkyl or alkoxy.

### Claim 18 (depends on 17)

The compound of claim 17, wherein:
R3, R3a and R3b are independently selected from hydrogen or halogen;
R4aa is cyclopropyl or cyclobutyl, both of which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —CN, —COR6, —CO2R6, —CO2H, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R4ee is isopropyl, which may be optionally substituted with one or more substituents selected from halogen, —OH, —OR6, —CN, —COR6, —CO2R6, —CO2H, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c;
R6, at each occurrence, is independently alkyl, or cycloalkyl; and
R7, R7a, R7b, and R7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylalkyl, cycloalkyl, amino, —OH, hydroxyalkyl, heteroaryl, heteroaryloxy, alkylthio, —NO2, or —CN.

### Claim 19 (depends on 16)

A pharmaceutical composition comprising the compound of claim 16, a pharmaceutically acceptable carrier, and optionally at least one additional therapeutic agent.

### Claim 20 (depends on 17)

A pharmaceutical composition comprising the compound of claim 17, a pharmaceutically acceptable carrier, and optionally at least one additional therapeutic agent.