WO2009103007A2

WO2009103007A2 - Steroid hormone receptor modulator compounds and methods

Info

Publication number: WO2009103007A2
Application number: PCT/US2009/034131
Authority: WO
Inventors: Steven L. Roach; Andrew R. Hudson; Lino J. Valdez; Robert I. Higuchi; Lin Zhi; Angie C. Vassar; Adrienne Landry-Bayle; Mark E. Adams; Charlene V. Rowley; Ryan B. Lamer; Virginia Heather Sharron Grant
Original assignee: Ligand Pharmaceuticals Incorporated
Priority date: 2008-02-13
Filing date: 2009-02-13
Publication date: 2009-08-20
Also published as: WO2009103007A3

Abstract

This invention relates to compounds that bind to intracellular receptors and/or modulate activity of intracellular receptors, and to methods for making and using such compounds.

Description

STEROID HORMONE RECEPTOR MODULATOR COMPOUNDS AND METHODS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119 to U.S. Provisional Application Serial No. 61/028,405, filed February 13, 2008 which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION Field of the Invention

[0002] This invention relates to compounds that bind to intracellular receptors and/or modulate activity of intracellular receptors, and to methods for making and using such compounds.

Description of the Related Art

[0003] Certain intracellular receptors (IRs) have been shown to regulate transcription of certain genes. See e.g., R. M. Evans, Science, 240, 889 (1988). Certain of such IRs are steroid receptors, such as androgen receptors, glucocorticoid receptors, estrogen receptors, mineralocorticoid receptors, and progesterone receptors. Gene regulation by such receptors typically involves binding of an IR by a ligand.

[0004] In certain instances, a ligand binds to an IR, forming a receptor/ligand complex. That receptor/ligand complex may then translocate to the nucleus of a cell, where it may bind to the DNA of one or more gene regulatory regions. Once bound to the DNA of a particular gene regulatory region, a receptor/ligand complex may modulate the production of the protein encoded by that particular gene. In certain instances, a receptor/ligand complex regulates expression of certain proteins. In certain instances, a receptor/ligand complex may interact directly with the DNA of a particular gene regulatory region. In certain instances, a receptor/ligand complex may interact with other transcription factors, such as activator protein- 1 (AP-I) or nuclear factor KB (NFKB). In certain instances, such interactions result in modulation of transcriptional activation.

Summary of the Invention

[0005] In certain embodiments, the present invention provides a compound of Formula I, II, or III:

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:

[0006] R¹ and R² are each independently selected from the group consisting of hydrogen, a halogen, -CN, -OR¹⁶, an optionally substituted Ci-Cs alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted C]-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0007] R³ is selected from the group consisting of (a), (b), (c), (d), (e), (f), (g), (h), (i), 0), (k), (1), (m), and (n) :

(a) (b) (C)

(d) (e) (f)

(g) (h) (0

ϋ) (k)

(1) (m) (n)

[0008] wherein,

[0009] R¹¹ is selected from the group consisting of hydrogen, a halogen, -CN, - OR¹⁶, -NR¹⁷R¹⁸, -CH₂R¹⁶, -COR²⁰, -CO₂R²⁰, -CONR²⁰R³⁷, -SOR²⁰, -SO₂R²⁰, -NO₂, NR¹⁷(OR¹⁶), an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted C]-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0010] R¹² is selected from the group consisting of hydrogen, a halogen, -CN, - COR²⁰, -CO₂R²⁰, - CONR²⁰R³⁷, - NR¹⁷SO₂R²⁰, -NR¹⁷CO₂R²⁰, -NO₂, -OR¹⁶, - NR¹⁷R¹⁸, NR¹⁷(OR¹⁶), an optionally substituted C]-C₈ alkyl, an optionally substituted C]-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl or R¹² taken together with R¹¹ form a 3-7 membered ring;

[0011] each R¹³ is independently selected from the group consisting of hydrogen, a halogen, CN, -NO₂, OR¹⁶, an optionally substituted C]-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted C]-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl or R¹³ taken together with R¹² form a 3-7 membered ring;

[0012] R²¹ is selected from the group consisting of hydrogen, an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted C]-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅- C₈ aryl, an optionally substituted C₃-C₈ heteroaryl, OR¹⁶, NR¹⁷R¹⁸, COR²⁰, -CO₂R²⁰, and -CONR²⁰R³⁷;

[0013] R²² is selected from the group consisting of hydrogen, a halogen, an optionally substituted C]-C₈ alkyl, an optionally substituted C]-C₈ heteroalkyl, an optionally substituted CpC₈ haloalkyl, an optionally substituted Cj-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, an optionally substituted C₃-C₈ heteroaryl, OR¹⁶, NR¹⁷R¹⁸, COR²⁰, -CO₂R²⁰, and -CONR²⁰R³⁷;

[0014] R³² and R³³ are each independently selected from the group consisting of hydrogen, a halogen, -OR¹⁶, -CN, COR²⁰, an optionally substituted Cj-C₈ alkyl, an optionally substituted C]-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0015] each R²³ is independently selected from the group consisting of hydrogen, a halogen, OR¹⁶, an optionally substituted Ci-C₈ alkyl, an optionally substituted C]-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0016] each R²⁴ is independently selected from the group consisting of hydrogen, a halogen, and -OR¹⁶;

[0017] R²⁵ is selected from the group consisting of hydrogen, a halogen, -OR¹⁶, - CN, an optionally substituted Ci-C₈ alkyl, an optionally substituted CpC₈ heteroalkyl, an optionally substituted Cj-C₈ haloalkyl, an optionally substituted C]-C₈ heterohaloalkyl, an optionally substituted C₃-Cs cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0018] R²⁶ is selected from the group consisting of hydrogen, a halogen, -OR¹⁶, - CN, an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0019] each R²⁹ is independently selected from the group consisting of hydrogen, a halogen, and -OR 16.

[0020] U is selected from the group consisting of oxygen, sulfur, and -NR 17. ; [0021] Q and T are each selected from the group consisting of S, O, -NR¹⁷, and

CR³⁴ wherein [0022] either Q is -CR³⁴ and T is selected from the group consisting of S, O, and -

NR 17

[0023] or T is CR³⁴ and Q is selected from the group consisting of S, O, and -

NR 17.

[0024] V is selected from the group consisting of O, S, and -NR , 17. [0025] W is selected from the group consisting of -CR 27 and N; [0026] Y is selected from the group consisting of -NR³⁶, S, and O; [0027] Z and L are each selected from the group consisting of CH₂, -NR²⁸, and O, wherein

[0028] either Z is CH₂ and L is selected from the group consisting of -NR 28 and

O,

[0029] or L is CH₂ and Z is selected from the group consisting of -NR²⁸ and O; [0030] K is selected from the group consisting of O and -NR³⁵; [0031] J is selected from the group consisting of O and S; [0032] B is selected from the group consisting of O and C(R 27N )₂; [0033] M is selected from the group consisting of O and NOR 30. [0034] each P is independently selected from the group consisting of N and CR ₃i , provided that no more than two of the Ps are N;

[0035] n is selected from 0, 1, 2, 3, and 4; and

[0036] q is selcted from 0, 1, and 2;

[0037] R⁴ is selected from the group consisting of hydrogen, a halogen, NO₂, OR¹⁶, NR¹⁷R¹⁸, CN, C=N(OR¹⁶), CO₂R²⁰, CONR²⁰R³⁷, NR¹⁷(OR¹⁶), CR³(OR¹⁶), an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Cj-C₈ haloalkyl, an optionally substituted CpC₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0038] R⁵ is selected from the group consisting of hydrogen, NR^xR^y, an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Cj-C₈ haloalkyl, an optionally substituted C]-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-Cg heterocycle, an optionally substituted C5- C₈ aryl, and an optionally substituted C₃-Cg heteroaryl;

[0039] R^x and R^y are each independently selected from the group consisting of hydrogen, COR¹⁹, CO₂R¹⁹, SO₂R¹⁹, S(O)R¹⁹, CONR¹⁹, an optionally substituted C₁-C₈ alkyl, an optionally substituted CpC₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₃-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl; or R^x and R^y are linked to form a 3 to 7 membered ring;

[0040] R⁶ is selected from the group consisting of -OC(O)R¹⁹, OC(O)NR¹⁹R¹⁹, - NR¹⁵C(O)R¹⁹, NR¹⁵C(O)NR¹⁹R¹⁹, -C(O)R¹⁹, NR¹⁷R¹⁸, hydrogen, and OR¹⁶;

[0041] R⁷ and R⁸ are each independently selected from the group consisting of hydrogen, an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-Cg heteroaryl;

[0042] R⁹ is selected from the group consisting of hydrogen, OR¹⁶, an optionally substituted C]-Cg alkyl, an optionally substituted Cj-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted C]-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅- C₈ aryl, and an optionally substituted C₃-Cg heteroaryl;

[0043] R¹⁰ is selected from the group consisting of hydrogen and OR¹⁶; and

[0044] X is selected from the group consisting of O, and NOR¹⁶;

[0045] wherein:

[0046] R¹⁶ is selected from the group consisting of hydrogen, an optionally substituted Ci-Cg alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Cj-C₈ heterohaloalkyl, an optionally substituted C₃-Cg cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cr- C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0047] R¹⁵ is selected from the group consisting of hydrogen, an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₃- C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0048] R¹⁷ and R¹⁸ are each independently selected from the group consisting of hydrogen, COR²⁰, CO₂R²⁰, SO₂R²⁰, S(O)R²⁰, an optionally substituted C ,-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted CpC₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cy-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl; or R¹⁷ and R¹⁸ together form a 3 to 7 membered ring;

[0049] Each R¹⁹ is independently selected from the group consisting of hydrogen, an optionally substituted C]-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted CpC₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₃-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl.

[0050] R²⁰ and R³⁷ are each independently selected from the group consisting of hydrogen, an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Cj-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl; or R³⁷ and R²⁰ together form a 3-7 membered ring;

[0051] R³⁴ is selected from the group consisting of hydrogen, a halogen, -NO₂, - OR¹⁶, -NR¹⁷R¹⁸, -CN, -COR²⁰, NR¹⁷(OR¹⁶), an optionally substituted C-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted C]-C₈ haloalkyl, an optionally substituted CpC₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0052] R³⁶ is selected from the group consisting of hydrogen, an optionally substituted Ci-C₈ alkyl, an optionally substituted CpC₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted CpC₈ heterohaloalkyl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted C₂-Cs heterocycle, an optionally substituted C₅- C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0053] Each R²⁷ is independently selected from the group consisting of hydrogen, a halogen, CO₂R²⁰, COR²⁰, CONR²⁰R³⁷, C=N(OR¹⁶), an optionally substituted C₁-C₈ alkyl, an optionally substituted Cj-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted C)-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl or R²⁷ taken together with R²⁶ form a 3-7 membered ring;

[0054] R²⁸ is selected from the group consisting of hydrogen, -COR²⁰, -CO₂R²⁰, - CONR²⁰R³⁷, SO₂R²⁰, an optionally substituted C₁-C₈ alkyl, an optionally substituted Q-C₈ heteroalkyl, an optionally substituted Cj-C₈ haloalkyl, an optionally substituted C₁-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0055] R^3S is selected from the group consisting of hydrogen, -COR²⁰, -CO₂R²⁰, CONR²⁰R³⁷, SO₂R²⁰, an optionally substituted C)-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0056] R³⁰ is selected from the group consisting of hydrogen an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅- C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0057] R³¹ is selected from the group consisting of hydrogen, a halogen, and - OR¹⁶;

[0058] wherein,

[0059] at least one of R¹ , R² and R⁴ is not hydrogen; and

[0060] at least one of R¹¹, R¹², and one R¹³ is not hydrogen;

[0061] R³⁸ is selected from the group consisting of (o), (p), (q), (r), (s) and (t) :

(O) (P) (q)

(r) (S) (t)

wherein,

[0062] R³⁹ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -CONR⁵¹R⁵², -OR⁵³, COR⁵³, -SR⁵³, -SO₂NR⁵¹R⁵², an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl;

[0063] R⁴⁰ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -OR⁵³, -SR⁵³, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl;

[0064] R⁴¹ is selected from hydrogen, F, Cl, Br, CN, -OR⁵³, -SR⁵³, an optionally substituted alkyl, an optionally substituted haloalkyl, and an optionally substituted heteroalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl; or

[0065] R³⁹ and R⁴⁰ together form an optionally substituted 5-6 member ring and R⁴¹ is selected from hydrogen, F, Cl, Br, CN, -OR⁵³, -SR⁵³, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl; or

[0066] R⁴⁰ and R⁴¹ together form an optionally substituted 4-6 member ring and R³⁹ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -CONR⁵¹R⁵², -OR⁵³, COR⁵³, - SR⁵³, -SO₂NR⁵¹R⁵², an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl; [0067] R⁴² is selected from hydrogen, F, Cl, Br, optionally substituted alkyl, -SR⁵³ and -OR⁵³;

[0068] R⁴³ is selected from hydrogen, F, Cl, Br, an optionally substituted alkyl;

[0069] R⁴⁴ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -CONR⁵¹R⁵², -SO₂NR⁵¹R⁵², an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl;

[0070] R⁴⁵ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -OR⁵³, -SR⁵³, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl;

[0071] R⁴⁶ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted haloalkyl, and an optionally substituted heteroalkyl, or

[0072] R⁴⁴ and R⁴⁵ together form an optionally substituted 5-6 member ring and R⁴⁶ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, or

[0073] R⁴⁵ and R⁴⁶ together form an optionally substituted 4-6 member ring and R⁴⁴ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -CONR⁵¹R⁵², and an optionally substituted aryl;

[0074] R⁴⁷ is selected from hydrogen, F, Cl, Br, an optionally substituted alkyl; and

[0075] R⁴⁸ is selected from the group consisting of hydrogen, a halogen, -CN, - OR¹⁶, -NR¹⁷R¹⁸, -CH₂R¹⁶, -COR²⁰, -CO₂R²⁰, -CONR²⁰R³⁷, -SOR²⁰, -SO₂R²⁰, -NO₂, NR¹⁷(OR¹⁶), an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted C]-C₈ haloalkyl, an optionally substituted Ci -C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0076] R⁴⁹ is selected from the group consisting of hydrogen, a halogen, -CN, - COR²⁰, -CO₂R²⁰, - CONR²⁰R³⁷, - NR¹⁷SO₂R²⁰, -NR¹⁷CO₂R²⁰, -NO₂, -OR¹⁶, - NR¹⁷R¹⁸, NR¹⁷(OR¹⁶), an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Cj-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted C₂-Cs heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

[0077] R⁵⁰ is selected from the group consisting of hydrogen, a halogen, CN, - NO₂, OR¹⁶, an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted CpC₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl, or

[0078] R⁴⁸ and R⁴⁹ together form an optionally substituted 5-6 member ring and R⁵⁰ is selected from hydrogen, F, Cl, Br, CN, CONR⁵¹R⁵², an optionally substituted alkyl, an optionally substituted haloalkyl, and an optionally substituted heteroalkyl, or

[0079] R⁴⁹ and R⁵⁰ together form an optionally substituted 4-6 member ring and R⁴⁸ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -CONR⁵¹R⁵², an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl,

[0080] R⁵¹ and R⁵² are each independently selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted haloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl and an optionally substituted heteroalkyl, or

[0081] R⁵¹ and R⁵² together form an optionally substituted 4-7 member ring;

[0082] R⁵³ is selected from hydrogen, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl;

[0083] G is selected from O, S, and NR⁵⁴;

[0084] R⁵⁴ is selected from hydrogen and an optionally substituted alkyl, an optionally substituted alkenyl and an optionally substituted alkynyl; and

[0085] wherein the substituents on the alkyl, aralkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl groups, when present, are each individually and independently selected from one to four group(s) selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, alkoxyalkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, imino, hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyiminothiocarbonyl, O-carbamyl, N- carbamyl, O-thiocarbamyl, N- thiocarbamyl, C- amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy and amino; including mono- and all-substituted amino groups, and the protected derivatives of amino groups;

[0086] wherein at least one position selected from R³⁹, R⁴⁰, R⁴¹, R⁴², and R⁴³ is not hydrogen;

[0087] at least one position selected from R⁴⁴, R⁴⁵, R⁴⁶, and R⁴⁷ is not hydrogen;

[0088] if R⁴¹ is F, then at least one position selected from R³⁹, R⁴⁰, R⁴² and R⁴³ is not hydrogen;

[0089] if R⁴⁰ is F, then at least one position selected from R³⁹, R⁴¹, R⁴², and R⁴³ is not hydrogen; and

[0090] if any two positions selected from R³⁹, R⁴⁰, R⁴¹, R⁴², and R⁴³ are both F, then at least one of the other three positions selected from R³⁹, R⁴⁰, R⁴¹, R⁴², and R⁴³ is not hydrogen.

[0091] In certain embodiments, the invention provides a steroid receptor modulator. In certain embodiments, the invention provides a selective glucocorticoid receptor modulator. In certain embodiments, the invention provides a selective glucocorticoid receptor agonist. In certain embodiments, the invention provides a selective glucocorticoid receptor antagonist. In certain embodiments, the invention provides a selective glucocorticoid receptor partial agonist. In certain embodiments, the invention provides a selective glucocorticoid receptor binding compound.

[0092] In certain embodiments, the invention provides a selective androgen receptor modulator. In certain embodiments, the invention provides a selective androgen receptor agonist. In certain embodiments, the invention provides a selective androgen receptor antagonist. In certain embodiments, the invention provides a selective androgen receptor partial agonist. In certain embodiments, the invention provides a selective androgen receptor binding compound. [0093] In certain embodiments, the invention provides a selective glucocorticoid/androgen receptor modulator. In certain embodiments, the invention provides a selective glucocorticoid/androgen receptor agonist. In certain embodiments, the invention provides a selective glucocorticoid/androgen receptor antagonist. In certain embodiments, the invention provides a selective glucocorticoid/androgen receptor partial agonist. In certain embodiments, the invention provides a selective glucocorticoid/androgen receptor binding compound.

[0094] In certain embodiments, the invention provides a pharmaceutical agent comprising a physiologically acceptable carrier, diluent, and/or excipient; and one or more compound of the present invention.

[0095] In certain embodiments, the invention provides a compound for treating a patient. In certain embodiments, the invention provides a compound for the treatment of a condition selected from the group consisting of, inflammation, transplant rejection, psoriasis, dermatitis, autoimmune disorder, malignancy, adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, granulomatous disease, immune proliferation/apoptosis, conditions of the HPA axis, hypercortisolemia, cytokine imbalance, kidney disease, liver disease, stroke, spinal cord injury, hypercalcemia, hyperglycemia, cerebral edema, thrombocytopenia, Little's syndrome, Addison's disease, cystic fibrosis, myasthenia gravis, autoimmune hemolytic anemia, uveitis, pemphigus vulgaris, multiple sclerosis, nasal polyps, sepsis, infections, type II diabetes, obesity, metabolic syndrome, depression, schizophrenia, mood disorders, Cushing's syndrome, anxiety, sleep disorders, poor memory, glaucoma, wasting, heart disease, fibrosis, hypertension, hyperaldosteronism, and sodium and/or potassium imbalance.

[0096] In certain embodiments, the invention provides a method for modulating activity of a glucocorticoid receptor. Certain such methods comprise contacting a glucocorticoid receptor with one or more compounds of the present invention.

[0097] In certain embodiments, the invention provides a method for modulating activity of an androgen receptor. Certain such methods comprise contacting an androgen receptor with one or more compounds of the present invention.

[0098] In certain embodiments, the invention provides a method for modulating both the activity of a glucocorticoid receptor and the activity of an androge n receptor. Certain such methods comprise contacting an androgen receptor and a glucocorticoid receptor with one or more compounds of the present invention. [0099] In certain embodiments, the invention provides a method for identifying a compound that is capable of modulating activity of a glucocorticoid receptor and/or an androgen receptor comprising contacting a cell expressing a glucocorticoid receptor and/or an androgen receptor with a compound of the present invention and monitoring an effect on the cell. In certain such embodiments, the compound is a quinoline. In certain such embodiments, the compound is derived from a quinoline. In certain embodiments, the compound is a 6-arylquinoline.

[0100] In certain embodiments, the invention provides methods of treating a patient comprising administering to the patient a compound of the present invention. In certain embodiments, the invention provides a method of treating a condition selected from the group consisting of inflammation, transplant rejection, psoriasis, dermatitis, autoimmune disorder, malignancy, adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, granulomatous disease, immune proliferation/apoptosis, conditions of the HPA axis, hypercortisolemia, cytokine imbalance, kidney disease, liver disease, stroke, spinal cord injury, hypercalcemia, hyperglycemia, cerebral edema, thrombocytopenia, Little's syndrome, Addison's disease, cystic fibrosis, myasthenia gravis, autoimmune hemolytic anemia, uveitis, pemphigus vulgaris, multiple sclerosis, nasal polyps, sepsis, infections, type II diabetes, obesity, metabolic syndrome, depression, schizophrenia, mood disorders, Cushing's syndrome, anxiety, sleep disorders, poor memory, glaucoma, wasting, heart disease, fibrosis, hypertension, hyperaldosteronism, and sodium and/or potassium imbalance.

Detailed Description

[0101] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "includes," and "included," is not limiting.

[0102] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose. Definitions

[0103] Unless specific definitions are provided, the nomenclatures utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard chemical symbols are used interchangeably with the full names represented by such symbols. Thus, for example, the terms "hydrogen" and "H" are understood to have identical meaning. Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques may be performed e.g., using kits according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), which is incorporated herein by reference for any purpose.

[0104] As used herein, the following terms are defined with the following meanings, unless expressly stated otherwise.

[0105] The term "selective binding compound" refers to a compound that selectively binds to any portion of one or more target receptors.

[0106] The term "selective glucocorticoid receptor binding compound" refers to a compound that selectively binds to any portion of a glucocorticoid receptor.

[0107] The term "selective androgen receptor binding compound" refers to a compound that selectively binds to any portion of an androgen receptor.

[0108] The term "selective glucocorticoid/androgen receptor binding compound" refers to a compound that selectively binds to any portion of a glucocorticoid receptor and that also binds to any portion of an androgen receptor.

[0109] The term "selectively binds" refers to the ability of a selective binding compound to bind to a target receptor with greater affinity than it binds to a non-target receptor. In certain embodiments, selective binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, or 1000 times greater than the affinity for a non- target. [0110] The term "target receptor" refers to a receptor or a portion of a receptor capable of being bound by a selective binding compound. In certain embodiments, a target receptor is a glucocorticoid receptor. In certain embodiments, a target receptor is an androgen receptor. In certain embodiments, glucocorticoid receptors and androgen receptors are both target receptors.

[0111] The term "modulator" refers to a compound that alters an activity of a molecule. For example, a modulator may cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity of a molecule. In certain embodiments the presence of a modulator results in an activity that does not occur in the absence of the modulator.

[0112] The term "selective modulator" refers to a compound that selectively modulates a target activity.

[0113] The term "selective glucocorticoid receptor modulator" refers to a compound that selectively modulates at least one activity associated with a glucocorticoid receptor.

[0114] The term "selective androgen receptor modulator" refers to a compound that selectively modulates at least one activity associated with an androgen receptor.

[0115] The term "selective glucocorticoid/androgen receptor modulator" refers to a compound that selectively modulates at least one activity associated with a glucocorticoid receptor and at least one activity associated with an androgen receptor.

[0116] The term "selectively modulates" refers to the ability of a selective modulator to modulate a target activity to a greater extent than it modulates a non-target activity.

[0117] The term "target activity" refers to a biological activity capable of being modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, and inflammation or inflammation-related processes.

[0118] The term "receptor mediated activity" refers to any biological activity that results, either directly or indirectly, from binding of a ligand to a receptor. [0119] The term "agonist" refers to a compound, the presence of which results in a biological activity of a receptor that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the receptor.

[0120] The term "partial agonist" refers to a compound the presence of which results in a biological activity of a receptor that is of the same type as that resulting from the presence of a naturally occurring ligand for the receptor, but of a lower magnitude.

[0121] The term "antagonist" refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of a receptor. In certain embodiments, the presence of an antagonist results in complete inhibition of a biological activity of a receptor.

[0122] The term "alkyl" refers to an aliphatic hydrocarbon group. An alkyl may be a "saturated alkyl," which means that it does not contain any alkene or alkyne groups. An alkyl group may be an "unsaturated alkyl," which means that it comprises at least one alkene or alkyne group. An alkyl, whether saturated or unsaturated, may be branched or straight chain. Alkyls may be substituted or unsubstituted. Alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, ethynyl, butynyl, propynyl, and the like, each of which may be optionally substituted.

[0123] In certain embodiments, an alkyl comprises 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that an alkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the term "alkyl" also includes instances where no numerical range of carbon atoms is designated).

[0124] The term "lower alkyl" refers to an alkyl comprising 1 to 5 carbon atoms. The term "medium alkyl" refers to an alkyl comprising 5 to 10 carbon atoms. An alkyl may be designated as "C₁-C₄ alkyl" or similar designations. By way of example only, "C₁-C₄ alkyl" indicates an alkyl having one, two, three, or four carbon atoms (e.g., methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl).

[0125] The term "alkenyl" refers to an alkyl group comprising at least one carbon- carbon double bond.

[0126] The term "alkynyl" refers to an alkyl group comprising at least one carbon-carbon triple bond. [0127] The term "haloalkyl" refers to an alkyl in which at least one hydrogen atom is replaced with a halogen atom. In certain of the embodiments in which two or more hydrogen atom are replaced with halogen atoms, the halogen atoms are all the same as one another. In certain of such embodiments, the halogen atoms are not all the same as one another.

[0128] The term "heteroalkyl" refers to a group comprising an alkyl and one or more heteroatoms. Certain heteroalkyls are acylalkyls, in which the one or more heteroatoms are within an alkyl chain. Certain other heteroalkyls are acylalkyls, in which the heteroatom is not within the alkyl chain. Examples of heteroalkyls include, but are not limited to, CH₃CC=O)CH₂-, CH₃CC=O)CH₂CH₂-, CH₃CH₂CC=O)CH₂CH₂-, CH₃CC=O)CH₂CH₂CH₂-, CH₃OCH₂CH₂-, CH₃NHCH₂-, and the like.

[0129] The term "heterohaloalkyl" refers to a heteroalkyl in which at least one hydrogen atom is replaced with a halogen atom.

[0130] The term "carbocycle" refers to a group comprising a covalently closed ring, wherein each of the atoms forming the ring is a carbon atom. Carbocylic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycles may be optionally substituted.

[0131] The term "heterocycle" refers to a group comprising a covalently closed ring wherein at least one atom forming the ring is a heteroatom. Heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Any number of those atoms may be heteroatoms (i.e., a heterocyclic ring may comprise one, two, three, four, five, six, seven, eight, nine, or more than nine heteroatoms). In heterocyclic rings comprising two or more heteroatoms, those two or more heteroatoms may be the same or different from one another. Heterocycles may be optionally substituted. Binding to a heterocycle can be at a heteroatom or via a carbon atom. For example, binding for benzo-fused derivatives, may be via a carbon of the benzenoid ring. Examples of heterocycles include, but are not limited to the following:

wherein D, E, F, and G independently represent a heteroatom. Each of D, E, F, and G may be the same or different from one another.

[0132] The term "heteroatom" refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorus, but are not limited to those atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may all be the same as one another, or some or all of the two or more heteroatoms may each be different from the others.

[0133] The term "aromatic" refers to a group comprising a covalently closed ring having a delocalized π-electron system. Aromatic rings may be formed by five, six, seven, eight, nine, or more than nine atoms. Aromatics may be optionally substituted. Examples of aromatic groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl. The term aromatic includes, for example, benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from the group consisting of an aryl, a heteroaryl, a cycloalkyl, a non-aromatic heterocycle, a halo, a hydroxy, an amino, a cyano, a nitro, an alkylamido, an acyl, a Q.6 alkoxy, a Ci_-6 alkyl, a Ci_6 hydroxyalkyl, a Ci_-6 aminoalkyl, a Ci^ alkylamino, an alkylsulfenyl, an alkylsulfinyl, an alkylsulfonyl, an sulfamoyl, or a trifluoromethyl. In certain embodiments, an aromatic group is substituted at one or more of the para, meta, and/or ortho positions. Examples of aromatic groups comprising substitutions include, but are not limited to, phenyl, 3-halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4- methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 3- cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4-moφholin-4-ylphenyl, 4- pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidin-l- yl)phenyl.

[0134] The term "aryl" refers to an aromatic group wherein each of the atoms forming the ring is a carbon atom. Aryl rings may be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups may be optionally substituted.

[0135] The term "heteroaryl" refers to an aromatic group wherein at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heteroaryl groups may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C_3-8 heterocyclic groups comprising one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fiised derivatives, for example, connected via one of the ring-forming carbon atoms. In certain embodiments, heteroaryl groups are optionally substituted with one or more substituents, independently selected from the group consisting of halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci-₆-alkoxy, Ci-6-alkyl, Q- ₆-hydroxyalkyl, Ci-₆-aminoalkyl, Ci-₆-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3- oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, 0-Ci_-6- alkyl, Ci-₆-alkyl, hydroxy-Ci.₆-alkyl, and amino-Ci-₆-alkyl.

[0136] The term "non-aromatic ring" refers to a group comprising a covalently closed ring that does not have a delocalized π-electron system.

[0137] The term "cycloalkyl" refers to a group comprising a non-aromatic ring wherein each of the atoms forming the ring is a carbon atom. Cycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Cycloalkyls may be optionally substituted. In certain embodiments, a cycloalkyl comprises one or more unsaturated bonds. Examples of cycloalkyls include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, and cycloheptene.

[0138] The term "non-aromatic heterocycle" refers to a group comprising a non- aromatic ring wherein one or more atoms forming the ring is a heteroatom. Non-aromatic heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Non-aromatic heterocycles may be optionally substituted. In certain embodiments, non-aromatic heterocycles comprise one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups. Examples of non-aromatic heterocycles include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4- oxathiane, tetrahydro-l,4-thiazine, 2H-l,2-oxazine , maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-l,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane.

[0139] The term "arylalkyl" refers to a group comprising an aryl group bound to an alkyl group.

[0140] The term "carbocycloalkyl" refers to a group comprising a carbocyclic cycloalkyl ring. Carbocycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycloalkyl groups may be optionally substituted.

[0141] The term "ring" refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non- aromatic heterocycles), aromatics (e.g., aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings may be optionally substituted. Rings may form part of a ring system.

[0142] The term "ring system" refers to two or more rings, wherein two or more of the rings are fused. The term "fused" refers to structures in which two or more rings share one or more bonds.

[0143] The term "linked to form a ring" and similar terms refer to instances where two atoms that are bound either to a single atom or to atoms that are bonded or linked through a linking group, are each bound to a linking group, such that the resulting structure forms a ring. That resulting ring includes the two atoms that are linked to form a ring, the atom (or atoms) that previously linked those atoms and the linker. For example, if A and B below are "linked to form a ring"

the resulting ring includes A, B, C and a linking group. Unless otherwise indicated, that linking group may be of any length and may be optionally substituted. Referring to the above example, resulting structures include, but are not limited to:

In certain embodiments, the two substituents that together form a ring are not immediately bound to the same atom. For example, if A and B, below, are linked to form a ring:

the resulting ring includes A, B, the two atoms that already link A and B and a linking group. Examples of resulting structures include, but are not limited to:

; and the like.

In certain embodiments, the atoms that together form a ring are separated by three or more atoms. For example, if A and B, below, are linked to form a ring:

, the resulting ring includes A, B, the 3 atoms that already link A and B and a linking group. Examples of resulting structures include, but are not limited to:

[0144] The substituent "R" appearing by itself and without a number designation refers to a substituent selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon).

[0145] The term "O-carboxy" refers to a group of formula RC(=O)O-.

[0146] The term "C-carboxy" refers to a group of formula -C(=O)OR.

[0147] The term "acetyl" refers to a group of formula -C(=O)CH₃.

[0148] The term "trihalomethanesulfonyl" refers to a group of formula X₃CS(¹¹O)₂- where X is a halogen.

[0149] The term "cyano" refers to a group of formula -CN.

[0150] The term "isocyanato" refers to a group of formula -NCO.

[0151] The term "thiocyanato" refers to a group of formula -CNS.

[0152] The term "isothiocyanato" refers to a group of formula -NCS.

[0153] The term "sulfonyl" refers to a group of formula -S(=O)-R.

[0154] The term "S-sulfonamido" refers to a group of formula -S(O)₂NR.

[0155] The term "N-sulfonamido" refers to a group of formula RS(=O)₂NH-.

[0156] The term "trihalomethanesulfonamido" refers to a group of formula X₃CS(=O)₂NR-.

[0157] The term "O-carbamyl" refers to a group of formula -OC(=O)-NR.

[0158] The term "N-carbamyl" refers to a group of formula ROC(O)NH-.

[0159] The term "O-thiocarbamyl" refers to a group of formula -OC(=S)-NR.

[0160] The term "N-thiocarbamyl" refers to a group of formula ROC(=S)NH-.

[0161] The term "C-amido" refers to a group of formula -C(O)-NR₂.

[0162] The term "N-amido" refers to a group of formula RC(O)NH-.

[0163] The term "ester" refers to a chemical moiety with formula -(R)_n-COOR', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon), where n is O or 1.

[0164] The term "amide" refers to a chemical moiety with formula -(R)_n-C(O)NHR' or -(R)_n-NHC(O)R', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), where n is O or 1. In certain embodiments, an amide may be an amino acid or a peptide.

[0165] The terms "amine," "hydroxy," and "carboxyl" include such groups that have been esterified or amidified. Procedures and specific groups used to achieve esterification and amidification are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety.

[0166] Unless otherwise indicated, the term "optionally substituted," refers to a group in which none, one, or more than one of the hydrogen atoms has been replaced with one or more group(s) individually and independently selected from the group consisting of: alkyl, heteroalkyl, haloalkyl, heteroholoalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non- aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives of amino groups. Such protective derivatives (and protecting groups that may form such protective derivatives) are known to those of skill in the art and may be found in references such as Greene and Wuts, above. In embodiments in which two or more hydrogen atoms have been substituted, the substituent groups may together form a ring.

[0167] The term "carrier" refers to a compound that facilitates the incorporation of another compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier for improving incorporation of certain organic compounds into cells or tissues.

[0168] The term "pharmaceutical agent" refers to a chemical compound or composition capable of inducing a desired therapeutic effect in a patient. In certain embodiments, a pharmaceutical agent comprises an active agent, which is the agent that induces the desired therapeutic effect. In certain embodiments, a pharmaceutical agent comprises a prodrug. In certain embodiments, a pharmaceutical agent comprises inactive ingredients such as carriers, excipients, and the like.

[0169] The term "therapeutically effective amount" refers to an amount of a pharmaceutical agent sufficient to achieve a desired therapeutic effect.

[0170] The term "prodrug" refers to an pharmaceutical agent that is converted from a less active form into a corresponding more active form in vivo,

[0171] The term "pharmaceutically acceptable" refers to a formulation of a compound that does not significantly abrogate the biological activity, a pharmacological activity and/or other properties of the compound when the formulated compound is administered to a patient. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a patient. [0172] The term "co-administer" refers to administering more than one pharmaceutical agent to a patient. In certain embodiments, co-administered pharmaceutical agents are administered together in a single dosage unit. In certain embodiments, coadministered pharmaceutical agents are administered separately. In certain embodiments, coadministered pharmaceutical agents are administered at the same time. In certain embodiments, co-administered pharmaceutical agents are administered at different times.

[0173] The term "patient" includes human and animal subjects.

[0174] The term "substantially pure" means an object species (e.g., compound) is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition). In certain embodiments, a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all species present. In certain embodiments, a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all species present in the composition. In certain embodiments, the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single species.

[0175] The term "tissue-selective" refers to the ability of a compound to modulate a biological activity in one tissue to a greater or lesser degree than it modulates a biological activity in another tissue. The biological activities in the different tissues may be the same or they may be different. The biological activities in the different tissues may be mediated by the same type of target receptor. For example, in certain embodiments, a tissue-selective compound may modulate receptor mediated biological activity in one tissue and fail to modulate, or modulate to a lesser degree, receptor mediated biological activity in another tissue type.

[0176] The term "monitoring" refers to observing an effect or absence of any effect. In certain embodiments, one monitors cells after contacting those cells with a compound of the present invention. Examples of effects that may be monitored include, but are not limited to, changes in cell phenotype, cell proliferation, receptor activity, or the interaction between a receptor and a compound known to bind to the receptor.

[0177] The term "cell phenotype" refers to physical or biological characteristics. Examples of characteristics that constitute phenotype included, but are not limited to, cell size, cell proliferation, cell differentiation, cell survival, apoptosis (cell death), or the utilization of a metabolic nutrient (e.g., glucose uptake). Certain changes or the absence of changes in cell phenotype are readily monitored using techniques known in the art. [0178] The term "cell proliferation" refers to the rate at which cells divide. The number of cells growing in a vessel can be quantified by a person skilled in the art (e.g., by counting cells in a defined area using a light microscope, or by using laboratory apparatus that measure the density of cells in an appropriate medium). One skilled in that art can calculate cell proliferation by determining the number of cells at two or more times.

[0179] The term "contacting" refers to bringing two or more materials into close enough proximity that they may interact. In certain embodiments, contacting can be accomplished in a vessel such as a test tube, a petri dish, or the like. In certain embodiments, contacting may be performed in the presence of additional materials. In certain embodiments, contacting may be performed in the presence of cells. In certain of such embodiments, one or more of the materials that are being contacted may be inside a cell. Cells may be alive or may dead. Cells may or may not be intact. Certain compounds

[0180] Certain compounds that bind to glucocorticoid receptors and/or androgen receptors and/or certain compounds that modulate an activity of such receptors play a role in health (e.g., normal growth, development, and/or absence of disease). In certain embodiments, compounds of the present invention are useful for treating any of a variety of diseases or conditions.

[0181] Certain compounds have been previously described as receptor modulators or as possible receptor modulators. See e.g., U. S. Patent Nos. 6,462,038, 5,693,646; 6,380,207; 6,506,766; 5,688,810; 5,696,133; 6,569,896, 6,673,799; 4,636,505; 4,097,578; 3,847,988; U.S. Application No. 10/209,461 (Pub. No. US 2003/0055094); WO 01/27086; WO 02/22585; WO2006/019716; Zhi, et.al. Bioorganic & Medicinal Chemistry Letters 2000, 10, 415-418; Pooley, et. al., J. Med. Chem. 1998, 41, 3461 ; Hamann, et al. J. Med Chem. 1998, 41(4), 623; and Yin, et al, Molecular Pharmacology, 2003, 63 (1), 211-223 the entire disclosures of which are incorporated in their entirety.

[0182] In certain embodiments, the present invention provides selective glucocorticoid and/or androgen receptor modulators. In certain embodiments, the invention provides selective glucocorticoid and/or androgen receptor binding agents. In certain embodiments, the invention provides methods of making and methods of using selective glucocorticoid and/or androgen receptor modulators and/or selective glucocorticoid and/or androgen binding agents. In certain embodiments, selective glucocorticoid and/or androgen modulators are agonists, partial agonists, and/or antagonists for the glucocorticoid and/or androgen receptor. [0183] In certain embodiments, the present invention relates to compounds of Formula I, II, or III:

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.

[0184] In certain embodiments, R¹ is selected from the group consisting of hydrogen, a halogen, -CN, -OR¹⁶, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-Cs cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R¹ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R¹ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R¹ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R^! is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R¹ is methyl. In certain embodiments, R¹ is trifiuoromethyl. In certain of the embodiments where R¹ is a halogen, R¹ is F or Cl.

[0185] In certain embodiments, R² is selected from the group consisting of hydrogen, a halogen, -CN, -OR¹⁶, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R² is an optionally substituted CpCg alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R² is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R² is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R² is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R² is methyl. In certain embodiments, R² is trifluoromethyl. In certain of the embodiments where R² is a halogen, R² is F or Cl.

[0186] In certain embodiments, R³ is selected from the group consisting of (a), (b), (C), (d), (e), (f), (g), (h), (i), 0), (k), (1), (m), and (n) :

(a) (b) (C)

(d) (e) (f)

(g) (h) (i)

(1) (m) (n)

[0187] In certain embodiments, R³ is selected from the group consisting of an optionally substituted 2-indolyl, an optionally substituted 3-indolyl, an optionally substituted 4-indolyl, an optionally substituted 6-indolyl, an optionally substituted 7-indolyl, and an optionally substituted 7-indolinyl. In certain embodiments, R³ is a pyridyl, optionally substituted with a CpC₆ alkyl, where that alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R³ is 3-methylpyrid-2-yl. In certain embodiments, R³ is an optionally substituted dibenzofuranyl. In certain embodiments, R³ is 2,3-dihydro-l,4-benzodioxin-6-yl. In certain embodiments, R³ is

[0188] In certain embodiments, R⁴ is selected from the group consisting of hydrogen, a halogen, NO₂, OR⁹, NR¹⁰R¹¹, CN, C=N(OR¹⁶), CO₂R²⁰, CONR²⁰R³⁷, NR¹⁷(OR¹⁶), CR³(OR¹⁶), an optionally substituted Ci-C₆ alkyl, an optionally substituted Q- C₆ heteroalkyl, an optionally substituted Ci-Ce haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R⁴ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R⁴ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R⁴ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R⁴ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R⁴ is methyl. In certain embodiments, R⁴ is trifiuoromethyl. In certain of the embodiments where R⁴ is a halogen, R⁴ is F or Cl.

[0189] In certain embodiments at least one of R¹, R² and R⁴ is not hydrogen. In certain embodiments at least two of R¹, R² and R⁴ are not hydrogen. In certain embodiments, at least one of R¹, R² and R⁴ is not methyl. In certain embodiments, if one of R¹, R² and R⁴ is hydrogen, then at least one of the other two of those groups is not methyl.

[0190] In certain embodiments, R⁵ is selected from the group consisting of hydrogen, a halogen, NR^xR^y, an optionally substituted Ci-C₆ alkyl, an optionally substituted C)-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted C]-C₆ heterohaloalkyl, an optionally substituted C₃-Cg cycloalkyl, an optionally substituted C₂-Cs heterocycle, an optionally substituted Cs-Cg aryl, and an optionally substituted C₃-Cg heteroaryl. In certain embodiments, R⁵ is an optionally substituted CpCg alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R⁵ is an optionally substituted Ci-Cg alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R⁵ is selected from the group consisting of an optionally substituted C₂-Cg alkenyl, an optionally substituted C₂-Cg alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R⁵ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R⁵ is methyl. In certain embodiments, R⁵ is trifiuoromethyl. In certain of the embodiments where R⁵ is a halogen, R⁵ is F or Cl.

[0191] In certain embodiments in which R⁵ is a heteroalkyl, the heteroatom of that heteroalkyl is not sulfur or oxygen. In certain of the embodiments where R⁵ is an optionally substituted alkyl, that optionally substituted alkyl is optionally substituted with one or more substituents selected from the group consisting of an aryl, a heteroaryl, a cycloalkyl, and a heterocycle. In certain such embodiments, the optionally substituted alkyl is optionally substituted phenyl. In certain of the embodiments where R⁵ is an optionally substituted alkenyl, that optionally substituted alkenyl is selected from the group consisting of optionally substituted ethenyl, propenyl, butenyl, and pentenyl each of which is optionally substituted with one or more substituents selected from the group consisting of alkyl, aryl, heteroaryl, cycloalkyl, and heterocycle. In certain embodiments, R⁵ is selected from the group consisting of hydrogen, methyl, benzyl, 3-methyl-2-butenyl, and 2-propenyl. [0192] In certain embodiments, R^x and R^y are each independently selected from the group consisting of hydrogen, COR²⁰, CO₂R²⁰, SO₂R²⁰, S(O)R²⁰, an optionally substituted Ci-Cg alkyl, an optionally substituted Ci-Cg heteroalkyl, an optionally substituted Ci-Cg haloalkyl, an optionally substituted CpCg heterohaloalkyl, an optionally substituted C₃-Cg cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₃-Cg aryl, and an optionally substituted C₃-Cg heteroaryl; or R^x and R^y are linked to form a 3 to 7 membered ring;

[0193] In certain embodiments, R⁶ is selected from the group consisting of - OC(O)R¹⁹, OC(O)NR¹⁹R¹⁹, -NR¹⁵C(O)R¹⁹, NR¹⁵C(O)NR¹⁹R¹⁹, -C(O)R¹⁹.

[0194] In certain embodiments, each of R and R is independently selected from the group consisting of hydrogen, a halogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted C]-C₆ heterohaloalkyl, an optionally substituted C₃-Cg cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R⁷ and/or R⁸ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R⁷ and/or R⁸ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-Cg cycloalkyl that is not fully saturated. In certain such embodiments, R⁷ and/or R⁸ is selected from the group consisting of an optionally substituted C₂-Cg alkenyl, an optionally substituted C₂-Cg alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R⁷ and/or R⁸ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R⁷ and/or R⁸ is methyl. In certain embodiments, R⁷ and/or R⁸ is trifluoromethyl. In certain of the embodiments where R⁷ and/or R⁸ is a halogen, R⁷ and/or R⁸ is F or Cl. In certain embodiments, R⁷ is methyl. In certain embodiments R⁸ is methyl. In certain embodiments, R⁷ is methyl and R⁸ is methyl. In certain embodiments, at least one of R⁷ and R⁸ is not methyl. In certain embodiments, at least one of R⁷ and R⁸ is not hydrogen. In certain embodiments, if R⁷ is hydrogen, then R⁸ is not methyl.

[0195] In certain embodiments, R⁹ is selected from the group consisting of hydrogen, OR¹⁶, a halogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-Cg cycloalkyl, an optionally substituted C₂-Cg heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-Cg heteroaryl. In certain embodiments, R⁹ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R⁹ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R⁹ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R⁹ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R⁹ is methyl. In certain embodiments, R⁹ is trifiuoromethyl. In certain of the embodiments where R⁹ is a halogen, R⁹ is F or Cl. In certain embodiments, R⁹ is selected from the group consisting of hydrogen, methyl, and hydroxy.

[0196] In certain embodiments, R¹⁰ is selected from the group consisting of hydrogen and OR¹⁶. In certain embodiments, R¹⁰ is hydroxy.

[0197] In certain embodiments, R^{1 1} is selected from the group consisting of hydrogen, a halogen, -CN, -OR¹⁶, -NR¹⁷R¹⁸, -CH₂R¹⁶, -COR²⁰, -CO₂R²⁰, -CONR²⁰R³⁷, - SOR²⁰, -SO₂R²⁰, -NO₂, NR¹⁷(OR¹⁶), an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-Cβ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R¹¹ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R^{1 1} is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-Cg cycloalkyl that is not fully saturated. In certain such embodiments, R¹¹ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R¹¹ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R¹¹ is methyl. In certain embodiments, R¹¹ is trifiuoromethyl. In certain of the embodiments where R¹¹ is a halogen, Rⁿ is F or Cl. In certain embodiments, where R¹¹ is an optionally substituted alkenyl, that optionally substituted alkenyl is selected from the group consisting of optionally substituted ethenyl, propenyl, butenyl, and pentenyl. In certain embodiments where R¹¹ is an optionally substituted alkenyl, that optionally substituted alkenyl is optionally substituted with one or more substituents, independently selected from the group consisting of an alkyl, an aryl, a heteroaryl, a cycloalkyl, and a heterocycle. In certain embodiments, R¹ ' is a perfluoroalkyl. In certain such embodiments, R¹¹ is trifluoromethyl. In certain embodiments, R¹¹ is an aryl. In certain such embodiments, R¹¹ is phenyl. In certain embodiments, R¹¹ is selected from the group consisting of methyl, hydroxy, methoxy, benzyloxy, phenyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, - NH₂, -NO₂, -C(O)CH₃, and 2-methyl-2-butenyl.

[0198] In certain embodiments, R¹² is selected from the group consisting of hydrogen, a halogen, -CN, -NR¹⁷SO₂R²⁰, - COR²⁰, -CO₂R²⁰, -CONR²⁰R²⁰, NR¹⁷CO₂R²⁰, - NO₂, -OR¹⁶, -CN, -NH₂, -NHC(O)OCH₃, -NHC(O)OtBu, -NHSO₂CH₃, -NR¹⁷R¹⁸, NR¹⁷(OR¹⁶), an optionally substituted Cj-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R¹² is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R¹² is an optionally substituted Cj-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R¹² is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R¹² is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R¹² is methyl. In certain embodiments, R¹² is trifluoromethyl. In certain of the embodiments where R¹² is a halogen, R¹² is F or Cl. In certain of the embodiments where R¹² is an optionally substituted haloalkyl, that optionally substituted haloalkyl is an optionally substituted fluoroalkyl. In certain embodiments, R¹¹ and R¹² are linked together to form a 3-7 membered ring. In one embodiment, the 3-7 membered ring is a phenyl group.

[0199] In certain embodiments, each R¹³ is independently selected from the group consisting of hydrogen, a halogen, CN, -NO₂, -OCH₃, OR¹⁶, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted C]-C₆ haloalkyl, an optionally substituted C)-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R¹³ is an optionally substituted CpC₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R¹³ is an optionally substituted Cj-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R¹³ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-Cg alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R¹³ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R¹³ is methyl. In certain embodiments, R¹³ is trifluoromethyl. In certain of the embodiments where R¹³ is a halogen, R¹³ is F or Cl. In certain embodiments, R¹² and R¹³ are linked together to form a 3-7 membered ring. In one embodiment, the 3-7 membered ring is a phenyl group.

[0200] In certain embodiments, at least one of R¹¹, R¹², and one R¹³ is not hydrogen. In certain embodiments, at least two of R¹ ', R¹², and one R¹³ are not hydrogen. In certain embodiments, if any of R^{1 1}, R¹², or one R¹³ is hydrogen, then at least one of the other two of those groups is not methyl.

[0201] In certain embodiments, R¹⁵ is selected from the group consisting of hydrogen, an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₃-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R¹⁵ is an optionally substituted CpC₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R¹⁵ is an optionally substituted Q- C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R¹⁵ is selected from the group consisting of an optionally substituted C₂- C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R¹⁵ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R¹⁵ is methyl. In certain embodiments, R¹⁵ is trifluoromethyl. In certain embodiments, R¹⁵ is methyl.

[0202] In certain embodiments, each R¹ is independently selected from the group consisting of hydrogen, a halogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted C_I-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R¹⁶ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R¹⁶ is an optionally substituted Ci-Cg alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R¹⁶ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R¹⁶ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R¹⁶ is methyl. In certain embodiments, R¹⁶ is trifluoromethyl. In certain of the embodiments where R¹⁶ is a halogen, R¹⁶ is F or Cl. In certain such embodiments, those optionally substituted methyl, ethyl, isopropyl, butyl, sec-butyl, and tert- butyl groups are optionally substituted with one or more substituents independently selected from the group consisting of optionally substituted alkyl, aryl, heteroaryl, cycloalkyl, and heterocycle. In certain embodiments, R¹⁶ is a perfluoroalkyl.

[0203] In certain embodiments, each R^!7 is independently selected from the group consisting of hydrogen, a halogen, COR²⁰, CO₂R²⁰, SO₂R²⁰, and S(O)R²⁰, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci-Cβ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C5- C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R¹⁷ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R¹⁷ is an optionally substituted C]-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R¹⁷ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R¹⁷ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R¹⁷ is methyl. In certain embodiments, R¹⁷ is trifluoromethyl. In certain of the embodiments where R¹⁷ is a halogen, R¹¹ is F or Cl.

[0204] In certain embodiments, each R¹⁸ is independently selected from the group consisting of hydrogen, a halogen, COR²⁰, CO₂R²⁰, SO₂R²⁰, and S(O)R²⁰, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted CI-C_O haloalkyl, an optionally substituted C]-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C5- C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R¹⁸ is an optionally substituted Ci-Ce alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R¹⁸ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R¹⁸ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R¹⁸ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R¹⁸ is methyl. In certain embodiments, R¹⁸ is trifluoromethyl. In certain of the embodiments where R¹⁸ is a halogen, R¹⁸ is F or Cl.

[0205] In certan embodiments, R¹⁷ and R¹⁸ are linked to form a ring. In certain such embodiments, the ring has 3-7 members. In certain embodiments, the ring is aromatic. In certain embodiments, the ring is non-aromatic.

[0206] In certain embodiments, each R¹⁹ is independently selected from the group consisting of hydrogen, a halogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R¹⁹ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R¹⁹ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R¹⁹ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R¹⁹ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl.

[0207] In certain embodiments, each R²⁰ is independently selected from the group consisting of hydrogen, a halogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted C]-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R²⁰ is an optionally substituted CpC₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R²⁰ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R²⁰ is selected from the group consisting of an optionally substituted C₂-Cs alkenyl, an optionally substituted C₂-Cg alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-Cs cycloalkynyl. In certain of the embodiments, R²⁰ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R²⁰ is methyl. In certain embodiments, R²⁰ is trifluoromethyl. In certain of the embodiments where R²⁰ is a halogen, R²⁰ is F or Cl.

[0208] In certain embodiments, each R³⁷ is independently selected from the group consisting of hydrogen, a halogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted C]-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R³⁷ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R³⁷ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R³⁷ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R³⁷ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R³⁷ is methyl. In certain embodiments, R³⁷ is trifluoromethyl. In certain of the embodiments where R³⁷ is a halogen, R³⁷ is F or Cl.

[0209] In certain embodiments, R²⁰ and R³⁷ are linked to form a ring. In certain such embodiments, the ring has 3-7 members. In certaim embodiments, the ring is aromatic. In certain embodiments, the ring is non-aromatic.

[0210] In certain embodiments, R²¹ is selected from the group consisting of hydrogen, a halogen, an optionally substituted Cj-C₆ alkyl, an optionally substituted C]-C₆ heteroalkyl, an optionally substituted Cj-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R²¹ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R²¹ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R²¹ is selected from the group consisting of an optionally substituted C₂-Cs alkenyl, an optionally substituted C₂-Cg alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R²¹ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R²¹ is methyl. In certain embodiments, R²¹ is trifluoromethyl. In certain of the embodiments where R²¹ is a halogen, R²¹ is F or Cl.

[0211] In certain embodiments, R²² is selected from the group consisting of hydrogen, a halogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-Ce haloalkyl, an optionally substituted Ci -C_O heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R²² is an optionally substituted CpC₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R²² is an optionally substituted C]-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R²² is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R²² is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R²² is methyl. In certain embodiments, R²² is trifluoromethyl. In certain of the embodiments where R²² is a halogen, R²² is F or Cl.

[0212] In certain embodiments, each R²³ is independently and selected from the group consisting of hydrogen, a halogen, an optionally substituted Q-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R²³ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R²³ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R²³ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R²³ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R²³ is methyl. In certain embodiments, R²³ is trifluoromethyl. In certain of the embodiments where R²³ is a halogen, R²³ is F or Cl.

[0213] In certain embodiments, R²⁴ is selected from the group consisting of hydrogen, a halogen, -OR¹⁶, an optionally substituted Ci-C₆ alkyl, an optionally substituted Q-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R²⁴ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R²⁴ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R²⁴ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R²⁴ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R²⁴ is methyl. In certain embodiments, R²⁴ is trifluoromethyl. In certain of the embodiments where R²⁴ is a halogen, R²⁴ is F or Cl. In certain embodiments, R²⁴ is methoxy.

[0214] In certain embodiments, R²⁵ is selected from the group consisting of hydrogen, a halogen, -OR¹⁶, -CN, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R²⁵ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R²⁵ is an optionally substituted Cj-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R²⁵ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R²⁵ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R²⁵ is methyl. In certain embodiments, R²⁵ is trifluoromethyl. In certain of the embodiments where R²⁵ is a halogen, R²⁵ is F or Cl. In certain embodiments, R²⁵ is methoxy. [0215] In certain embodiments, R²⁶ is selected from the group consisting of hydrogen, a halogen, CO₂R²⁰, COR²⁰, CONR²⁰R³⁷, C=N(OR¹⁶), an optionally substituted C,- C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R²⁶ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R²⁶ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R²⁶ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R²⁶ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R²⁶ is methyl. In certain embodiments, R²⁶ is trifluoromethyl. In certain of the embodiments where R²⁶ is a halogen, R²⁶ is F or Cl.

[0216] In certain embodiments, each R²⁷ is independently selected from the group consisting of hydrogen, a halogen, an optionally substituted CJ-C_O alkyl, an optionally substituted C)-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R²⁷ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R²⁷ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R²⁷ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R²⁷ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R²⁷ is methyl. In certain embodiments, R¹¹ is trifluoromethyl. In certain of the embodiments where R²⁷ is a halogen, R²⁷ is F, Br, or Cl. In certain embodiments R²⁷ is -CH₂CH₂C(O)CH₃. In certain embodiments, R²⁶ and R²⁷ are linked together to form a 3-7 membered ring. In one embodiment, the 3-7 membered ring is a phenyl group. [0217] In certain embodiments, R²⁸ is selected from the group consisting of hydrogen, a halogen, -COR²⁰, -CO₂R²⁰, -CONR²⁰, -CONR²⁰R³⁷, SO₂R²⁰, an optionally substituted Q-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted C]-C₆ heterohaloalkyl, an optionally substituted C₃-Cg cycloalkyl, an optionally substituted C₂-Cg heterocycle, an optionally substituted C5- Cg aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R²⁸ is an optionally substituted Ci-Cg alkyl or an optionally substituted C₃-Cg cycloalkyl that is fully saturated. In certain embodiments, R²⁸ is an optionally substituted Ci-Cg alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R²⁸ is selected from the group consisting of an optionally substituted C₂-Cg alkenyl, an optionally substituted C₂-Cg alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-Cg cycloalkynyl. In certain of the embodiments, R²⁸ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R²⁸ is methyl. In certain embodiments, R²⁸ is trifiuoromethyl. In certain of the embodiments where R²⁸ is a halogen, R²⁸ is F or Cl.

[0218] In certain embodiments, R²⁹ is selected from the group consisting of hydrogen, a halogen, -OR¹⁶, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci -C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R²⁹ is an optionally substituted C]-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R²⁹ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R²⁹ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-Cg alkynyl, an optionally substituted C₃-Cg cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R²⁹ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R²⁹ is methyl. In certain embodiments, R²⁹ is trifiuoromethyl. In certain of the embodiments where R²⁹ is a halogen, R²⁹ is F or Cl.

[0219] In certain embodiments, R³⁰ is selected from the group consisting of hydrogen, a halogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted CpC₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-Cs heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C3-C8 heteroaryl. In certain embodiments, R³⁰ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R³⁰ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R³ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R³⁰ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R³⁰ is methyl. In certain embodiments, R³⁰ is trifluoromethyl. In certain of the embodiments where R³⁰ is a halogen, R³⁰ is F or Cl.

[0220] In certain embodiments, R³¹ is selected from the group consisting of hydrogen, a halogen, -OR¹⁶, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R³¹ is an optionally substituted C]-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R³¹ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R³¹ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R³¹ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R³¹ is methyl. In certain embodiments, R³¹ is trifluoromethyl. In certain of the embodiments where R³¹ is a halogen, R³¹ is F or Cl.

[0221] In certain embodiments, R³² is selected from the group consisting of hydrogen, a halogen, -OR¹⁶, -CN, -COR²⁰, an optionally substituted C_t-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted C]-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R³² is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R³² is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R³² is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R³² is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R³² is methyl. In certain embodiments, R³² is trifluoromethyl. In certain of the embodiments where R³² is a halogen, R³² is F or Cl.

[0222] In certain embodiments, R³³ is selected from the group consisting of hydrogen, a halogen, -OR¹⁶, -CN, -COR²⁰, an optionally substituted Ci-C₆ alkyl, an optionally substituted C ₁-C₆ heteroalkyl, an optionally substituted Ci -C₆ haloalkyl, an optionally substituted C]-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R³³ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R³³ is an optionally substituted Cj-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R³³ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R³³ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R³³ is methyl. In certain embodiments, R³³ is trifluoromethyl. In certain of the embodiments where R³³ is a halogen, R³³ is F or Cl.

[0223] In certain embodiments, R³⁴ is selected from the group consisting of hydrogen, a halogen, -NO₂, -OR¹⁶, -NR¹⁷R¹⁸, -CN, -COR²⁰, NR¹⁷(OR¹⁶), an optionally substituted C]-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted C]-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅- C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R³⁴ is an optionally substituted CpC₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R³⁴ is an optionally substituted C]-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R³⁴ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C3-C8 cycloalkynyl. In certain of the embodiments, R³⁴ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R³⁴ is methyl. In certain embodiments, R³⁴ is trifluoromethyl. In certain of the embodiments where R³³ is a halogen, R³⁴ is F or Cl.

[0224] In certain embodiments, R³⁵ is selected from the group consisting of hydrogen, a halogen, -COR²⁰, -CO₂R²⁰, -CONR²⁰, -CONR²⁰R³⁷, an optionally substituted Ci- C₆ alkyl, an optionally substituted Ci -C₆ heteroalkyl, an optionally substituted Ci-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R³⁵ is an optionally substituted Cj-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R³⁵ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R³⁵ is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R³⁵ is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R³⁵ is methyl. In certain embodiments, R³⁵ is trifluoromethyl. In certain of the embodiments where R ⁵ is a halogen, R ⁵ is F or Cl.

[0225] In certain embodiments, R³⁶ is selected from the group consisting of hydrogen, a halogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ heteroalkyl, an optionally substituted Cj-C₆ haloalkyl, an optionally substituted Ci-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl. In certain embodiments, R³⁶ is an optionally substituted C]-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is fully saturated. In certain embodiments, R³⁶ is an optionally substituted Ci-C₈ alkyl or an optionally substituted C₃-C₈ cycloalkyl that is not fully saturated. In certain such embodiments, R is selected from the group consisting of an optionally substituted C₂-C₈ alkenyl, an optionally substituted C₂-C₈ alkynyl, an optionally substituted C₃-C₈ cycloalkenyl, and an optionally substituted C₃-C₈ cycloalkynyl. In certain of the embodiments, R is selected from the group consisting of an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R³⁶ is methyl. In certain embodiments, R²⁶ is trifluoromethyl. In certain of the embodiments where R³⁶ is a halogen, R³⁶ is F or Cl.

[0226] In certain embodiments, U is selected from the group consisting of oxygen, sulfur, nitrogen, and -NR¹⁷.

[0227] In certain embodiments, Q is selected from the group consisting of nitrogen, phosphorous, sulfur, oxygen, -NR¹⁷, and -CR³⁴. In certain embodiments, T selected from the group consisting of nitrogen, phosphorous, sulfur, oxygen, -NR¹⁷, and -CR³⁴. In certain embodiments, Q is -CR³⁴ and T is selected from the group consisting of sulfur, oxygen, and -NR¹⁷. In certain embodiments, T is CR³⁴ and Q is selected from the group consisting of sulfur, oxygen, and -NR¹⁷. In certain embodiments, either one of Q or T is - CR³⁴ and the other is selected from the group consisting of sulfur, oxygen, and -NR¹⁷.

[0228] In certain embodiments, V is selected from the group consisting of nitrogen, phosphorous, oxygen, sulfur, and -NR¹⁷.

[0229] In certain embodiments, n is selected from the group consisting of 0, 1, 2, 3, and 4. In certain embodiments, q is selected from the group consisting of 0, 1, and 2.

[0230] In certain embodiments, W is selected from the group consisting of -CR²⁷ and nitrogen;

[0231] In certain embodiments, Y is selected from the group consisting of -NR³⁶, sulfur, and oxygen.

[0232] In certain embodiments, Z is selected from the group consisting of CH₂, - NR²⁸, and oxygen. In certain embodiments, L is selected from the group consisting of CH₂, - NR²⁸, and oxygen. In certain embodiments, Z is CH₂ and L is -NR²⁸ or oxygen. In certain embodiments, L is CH₂, and Z is -NR²⁸ or oxygen. In certain embodiments, either one of L or Z is CH₂ and the other is selected from the group consisting of -NR²⁸ and oxygen.

[0233] In certain embodiments, K is oxygen or -NR³⁵.

[0234] In certain embodiments, J is oxygen or sulfur.

[0235] In certain embodiments, B is selected from the group consisting of oxygen, or CR²⁷, CH₂ and C(R²⁷)₂.

[0236] In certain embodiments, M is oxygen or NOR³⁰.

[0237] In certain embodiments, P is nitrogen or -CR³¹. In certain embodiments, at least five P are -CR³¹.

[0238] In certain embodiments, X is selected from the group consisting of oxygen, sulfur, and NOR¹⁶. [0239] In certain embodiments, R³⁸ is selected from the group consisting of (o), (P), (q), (r), (S) and (t) :

(o) (P) (q)

(r) (S) (t)

[0240] In certain embodiments, R³⁹ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -CONR⁵¹R⁵², -OR⁵³, COR⁵³, -SR⁵³, -SO₂NR⁵¹R⁵², an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl.

[0241] In certain embodiments, R⁴⁰ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -OR⁵³, -SR⁵³, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl.

[0242] In certain embodiments, R⁴¹ is selected from hydrogen, F, Cl, Br, CN, - OR⁵³, -SR⁵³, an optionally substituted alkyl, an optionally substituted haloalkyl, and an optionally substituted heteroalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl.

[0243] In certain embodiments, R³⁹ and R⁴⁰ together form an optionally substituted 5-6 member ring and R⁴¹ is selected from hydrogen, F, Cl, Br, CN, -OR⁵³, -SR⁵³, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl.

[0244] In certain embodiments, R⁴⁰ and R⁴¹ together form an optionally substituted 4-6 member ring and R³⁹ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, - CONR⁵¹R⁵², -OR⁵³, COR⁵³, -SR⁵³, -SO₂NR⁵¹R⁵², an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl.

[0245] In certain embodiments, R⁴² is selected from hydrogen, F, Cl, Br, optionally substituted alkyl, -SR⁵³ and -OR⁵³.

[0246] In certain embodiments, R⁴³ is selected from hydrogen, F, Cl, Br, an optionally substituted alkyl.

[0247] In certain embodiments, R⁴⁴ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -CONR⁵¹R⁵², -SO₂NR⁵¹R⁵², an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl.

[0248] In certain embodiments, R⁴⁵ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -OR⁵³, -SR⁵³, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl.

[0249] In certain embodiments, R⁴⁶ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, and an optionally substituted heteroalkyl.

[0250] In certain embodiments, R⁴⁴ and R⁴⁵ together form an optionally substituted 5-6 member ring and R⁴⁶ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl.

[0251] In certain embodiments, R⁴⁵ and R⁴⁶ together form an optionally substituted 4-6 member ring and R⁴⁴ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, - CONR⁵¹R⁵², and an optionally substituted aryl.

[0252] In certain embodiments, R⁴⁷ is selected from hydrogen, F, Cl, Br, an optionally substituted alkyl.

[0253] In certain embodiments, R⁴⁸ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, hydroxyiminoalkyl, alkoxyiminoalkyl, aryloxyiminoalkyl, -CONR⁵¹R⁵², SO₂NR⁵¹R⁵², OR⁵³, - COR⁵³, -SR⁵³, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl. [0254] In certain embodiments, R⁴⁹ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -OR⁵³, SR⁵³, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl.

[0255] In certain embodiments, R⁵⁰ is selected from hydrogen, F, Cl, Br, CN, CONR⁵¹R⁵², an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted haloalkyl, and an optionally substituted heteroalkyl.

[0256] In certain embodiments, R⁴⁸ and R⁴⁹ together form an optionally substituted 5-6 member ring and R⁵⁰ is selected from hydrogen, F, Cl, Br, CN, CONR⁵¹R⁵², an optionally substituted alkyl, an optionally substituted haloalkyl, and an optionally substituted heteroalkyl.

[0257] In certain embodiments, R⁴⁹ and R⁵⁰ together form an optionally substituted 4-6 member ring and R⁴⁸ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, - CONR⁵¹R⁵², an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl.

[0258] In certain embodiments, R⁵¹ and R⁵² are each independently selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted haloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl and an optionally substituted heteroalkyl.

[0259] In certain embodiments, R⁵¹ and R⁵² together form an optionally substituted 4-7 member ring.

[0260] In certain embodiments, R⁵³ is selected from hydrogen, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl.

[0261] In certain embodiments, each P is independently selected from the group consisting of N and CR³¹, provided that no more than two of the Ps are N;

[0262] In certain embodiments, G is selected from O, S, and NR⁵⁴.

[0263] In certain embodiments, R⁵⁴ is selected from hydrogen and an optionally substituted alkyl, an optionally substituted alkenyl and an optionally substituted alkynyl. In certain embodiments, the substituents on the alkyl, aralkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl groups, when present, are each individually and independently selected from one to four group(s) selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, non- aromatic heterocycle, hydroxy, alkoxy, alkoxyalkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, imino, hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyiminothiocarbonyl, O-carbamyl, N- carbamyl, O-thiocarbamyl, N- thiocarbamyl, C- amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diary lam inocarbonyloxy and amino; including mono- and all-substituted amino groups, and the protected derivatives of amino groups. In certain embodiments, at least one position selected from R³⁹, R⁴⁰, R⁴¹, R⁴², and R⁴³ is not hydrogen. In certain embodiments, at least one position selected from R⁴⁴, R⁴⁵, R⁴⁶, and R⁴⁷ is not hydrogen. In certain embodiments, if R⁴¹ is F, then at least one position selected from R³⁹, R⁴⁰, R⁴² and R⁴³ is not hydrogen. In certain embodiments, if R⁴⁰ is F, then at least one position selected from R³⁹, R⁴¹, R⁴², and R⁴³ is not hydrogen. In certain embodiments, if any two positions selected from R³⁹, R⁴⁰, R⁴¹, R⁴², and R⁴³ are both F, then at least one of the other three positions selected from R³⁹, R⁴⁰, R⁴¹, R⁴², and R⁴³ is not hydrogen.

[0264] In embodiments in which two or more of a particular group are present, the identities of those two or more particular groups are selected independently and, thus, may be the same or different from one another. For example, certain compounds of the invention comprise two or more R¹⁶ groups. The identities of those two or more R¹⁶ groups are each selected independently. Thus, in certain embodiments, those R¹⁶ groups are all the same as one another; in certain embodiments, those R¹⁶ groups are all different from one another; and in certain embodiments, some of those R¹⁶ groups are the same as one another and some are different from one another. This independent selection applies to any group that is present in a compound more than once.

[0265] In certain embodiments, a compound of Formula I, Formula II, or Formula III is a selective glucocorticoid receptor modulator. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a selective glucocorticoid receptor agonist. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a selective glucocorticoid receptor antagonist. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a selective glucocorticoid receptor partial agonist. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a tissue-specific selective glucocorticoid receptor modulator. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a gene-specific selective glucocorticoid receptor modulator. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a selective glucocorticoid receptor binding compound.

[0266] In certain embodiments, a compound of Formula I, Formula II, or Formula III is a selective androgen receptor modulator. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a selective androgen receptor agonist. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a selective androgen receptor antagonist. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a selective androgen receptor partial agonist. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a tissue-specific selective androgen receptor modulator. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a gene-specific selective androgen receptor modulator. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a selective androgen receptor binding compound.

[0267] In certain embodiments, a compound of Formula I, Formula II, or Formula III is a selective glucocorticoid/androgen receptor modulator. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a selective glucocorticoid/androgen receptor agonist. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a selective glucocorticoid/androgen receptor antagonist. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a selective glucocorticoid/androgen receptor partial agonist. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a tissue-specific selective glucocorticoid/androgen receptor modulator. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a gene-specific selective glucocorticoid/androgen receptor modulator. In certain embodiments, a compound of Formula I, Formula II, or Formula III is a selective glucocorticoid/androgen receptor binding compound.

[0268] In certain embodiments, the invention provides compounds selected from the group consisting of:

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α-trimethyl-3β- (phenylcarbamoyloxy)quinoline (Compound 101); (±)-6-(3-Chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro-2,2,4α-trimethyl-3β- (phenylcarbamoyloxy)quinoline (Compound 102);

(±)-3β-(Benzylcarbamoyloxy)-3-(chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro-2,2,4α- trimethylquinoline (Compound 103);

(±)-6-(3-Chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro-3β-(isopropylcarbamoyloxy)- 2,2,4α-trimethylquinoline (Compound 104);

(±)-6-(3-Chloroindol-7-yl)-3β-(cyclohexylcarbamoyloxy)-5,7-difluoro-l,2,3,4-tetrahydro- 2,2,4α-trimethylquinoline (Compound 105);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α-trimethyl-3β-(methyl- phenylcarbamoyloxy)quinoline (Compound 106);

(±)-6-(3-Chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro-2,2,4α-trimethyl-3β-(methyl- phenylcarbamoyloxy)quinoline (Compound 107);

(±)-3β-(Cyclohexylcarbamoyloxy)-5,7-difluoro-l,2,3,4-tetrahydro-2,2,4α-trimethyl-6-(3- methylindol-7-yl)quinoline (Compound 108);

(±)-3β-(3-Cyanophenylcarbamoyloxy)-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α- trimethylquinoline (Compound 109);

(±)-3β-(4-Cyanophenylcarbamoyloxy)-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α- trimethylquinoline (Compound 1 10);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α-trimethyl-3β-[4-nitro-2- (trifluoromethyl)phenylcarbamoyloxy]quinoline (Compound 1 1 1);

(±)-3β-(4-Chlorophenylcarbamoyloxy)-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α- trimethylquinoline (Compound 1 12);

(±)-3β-(2,4-Dimethylphenylcarbamoyloxy)-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)- 2,2,4α-trimethylquinoline (Compound 1 13);

(±)-3β-(3-Chloro-4-methoxyphenylcarbamoyloxy)-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol- 7-yl)-2,2,4α-trimethylquinoline (Compound 1 14);

(±)-3β-[2-Chloro-4-(trifluoromethyl)phenylcarbamoyloxy]-5,7-difluoro-l,2,3,4-tetrahydro-6- (indol-7-yl)-2,2,4α-trimethylquinoline (Compound 1 15);

(±)-5,7-Difluoro-3β-[2-fluoro-6-(trifluoromethyl)phenylcarbamoyloxy]-l,2,3,4-tetrahydro-6- (indol-7-yl)-2,2,4α-trimethylquinoline (Compound 1 16);

(±)-5,7-Difluoro-3 β-[4-fluoro-2-(trifluoromethyl)phenylcarbamoyloxy]- 1 ,2,3,4-tetrahydro-6- (indol-7-yl)-2,2,4α-trimethylquinoline (Compound 117); (±)-3β-(2-Chloro-4,6-dlmethylphenylcarbamoyloxy)-5,7-difluoro-l,2,3,4-tetrahydro-6- (indol-7-yl)-2,2,4α-trimethylquinoline (Compound 1 18);

(±)-3β-[3,5-Bis(trifluoromethyl)phenylcarbamoyIoxy]-5,7-difluoro-l,2,3,4-tetrahydro-6- (indol-7-yl)-2,2,4α-trimethylquinoline (Compound 1 19);

(±)-3β-[4-(Dimethylamino)phenylcarbamoyloxy]-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7- yl)-2,2,4α-trimethylquinoline (Compound 120);

(±)-3β-(3-Cyclohexylcarbamoyloxy)-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α- trimethylquinoline (Compound 121);

(±)-6-(3-Chloroindol-7-yl)-3β-(3-chloro-4-methoxyphenylcarbamoyloxy)-5,7-difluoro- l,2,3,4-tetrahydro-2,2,4α-trimethylquinoline (Compound 122); (±)-6-(3-Chloroindol-7-yl)-3β-(3-cyanophenylcarbamoyloxy)-5,7-difluoro-l, 2,3,4- tetrahydro-2,2,4α-trimethylquinoline (Compound 123);

(±)-3β-[(Benzo[l,3]dioxol-5-yl)carbamoyloxy]-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7- yl)-2,2,4α-trimethylquinoline (Compound 124);

(±)-3β-(4-Ethoxycarbonylphenylcarbamoyloxy)-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7- yl)-2,2,4α-trimethylquinoline (Compound 125);

(±)-3β-[3,5-Bis(methoxycarbonyl)phenylcarbamoyloxy]-5,7-difluoro-l ,2,3,4-tetrahydro-6- (indol-7-yl)-2,2,4α-trimethylquinoline (Compound 126);

(±)-3β-(3-Acetylphenylcarbamoyloxy)-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α- trimethylquinoline (Compound 127);

(±)-3β-[(2,6-Dichloropyrid-4-yl)carbamoyloxy]-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7- yl)-2,2,4α-trimethylquinoline (Compound 128);

(±)-3β-(Benzo[l,2,5]thiadiazol-yl)phenylcarbamoyloxy )-5,7-difluoro-l,2,3,4-tetrahydro-6- (indol-7-yl)-2,2,4α-trimethylquinoline (Compound 129);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α-trimethyl-3β-(pyrazol-3- yl)phenylcarbamoyloxy)quinoline (Compound 130);

(±)-3β-Cyclopropylcarbamoyloxy-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α- trimethylquinoline (Compound 131);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-imidazolyl-6-(indol-7-yl)-2,2,4α-trimethyl- phenylcarbamoyloxy)quinoline (Compound 132);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α-trimethyl-3β-[3-(5- methyl[l,2,4]oxadiazol-3-yl)phenylcarbamoyloxy]quinoline (Compound 133); (±)-3β-(4-Acetylphenylcarbamoyloxy)-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α- trimethylquinoline (Compound 134);

(±)-3β-[(6-Chloropyrid-3-yl)carbamoyloxy]-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)- 2,2,4α-trimethylquinoline (Compound 135);

(±)-3β-[(3,5-Dimethylisoxazol-4-yl)carbamoyloxy]-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol- 7-yl)-2,2,4α-trimethylquinoline (Compound 136);

(±)-3β-(Cyclohexylcarbamoyloxy)-7-fluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α,8- tetramethylquinoline (Compound 137);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α-trimethyl-3β- (methylcarbamoyloxy)quinoline (Compound 138);

(±)-6-(3-Chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro-2,2,4α-trimethyl-3β- (methylcarbamoyloxy)quinoline (Compound 139);

(±)-3β-(Cyclopentylcarbamoyloxy)-7-fluoro-l,2,3,4-tetrahydro-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yl)quinoline (Compound 140);

(±)-6-(3-Chloroindol-7-yl)-3β-(cyclopentylcarbamoyloxy)-5,7-difluoro-l,2,3,4-tetrahydro- 2,2,4α-trimethylquinoline (Compound 141);

(±)-3β-(Cyclohexylcarbamoyloxy)-6-(3,5-dimethylisoxazol-4-yl)-5-fluoro- 1,2,3,4- tetrahydro-2,2,4α,8-tetramethylquinoline (Compound 142);

(±)-3β-(4-Acetylphenylcarbamoyloxy)-(3-chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro- 6-2,2,4α-trimethylquinoline (Compound 143);

(±)-5-Chloro-3β-(cyclohexylcarbamoyloxy)-8-fluoro-l,2,3,4-tetrahydro-2,2,4α-trimethyl-6- (3-methylindol-7-yl)quinoline (Compound 144);

(±)-5-Chloro-3β-(cyclopentylcarbamoyloxy)-8-fluoro-l ,2,3,4-tetrahydro-2,2,4α-trimethyl-6- (3-methylindol-7-yl)quinoline (Compound 145);

(±)-6-(3-Chloroindol-7-yl)-3β-(cyclohexylcarbamoyloxy)-7,8-difluoro-l,2,3,4-tetrahydro- 2,2,4α-trimethylquinoline (Compound 146);

(±)-6-(3-Chloroindol-7-yl)-3α-[4-(dimethylamino)phenylcarbamoyloxy]-7,8-difluoro- l,2,3,4-tetrahydro-2,2,4β-trimethylquinoline (Compound 147);

(±)-3β-(2,2-Dimethylpropionyloxy)-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α- trimethylquinoline (Compound 148)

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α-trimethyl-3β-(propionyl oxy)quinoline (Compound 149) (±)-6-(3-Chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro-2,2,4α-trimethyl-3β- (propionyloxy)quinoline (Compound 150)

(±)-3β-[2-(Dimethylamino)ethoxycarbonyloxy]-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7- yl)-2,2,4α-trimethylquinoline (Compound 151)

(E)-6-(3-Chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one O-t- butyl oxime (Compound 201a);

(Z)-6-(3-Chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one O-t- butyl oxime (Compound 201b);

(E)-5,7-Difluoro-6-(indol-7-yl)-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one oxime

(Compound 202);

(E)-5,7-Difluoro-6-(indol-7-yl)-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one 0-methyl oxime (Compound 203);

(E)-6-(3-Chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one O- methyl oxime (Compound 204);

(E)-5,7-Difluoro-6-(indol-7-yl)-2,3-dihydro-2,2-dimethyI-lH-quinolin-4-one O- carboxymethoxy oxime (Compound 205);

(E)-5,7-Difluoro-6-(indol-7-yl)-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one O-allyl oxime (Compound 206);

(E)-5,7-Difluoro-6-(indol-7-yl)-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one O-ethyl oxime (Compound 207);

(E)-(±)-5,7-Difluoro-6-(indol-7-yl)-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one O-/-butyl oxime (Compound 208);

(E)-5,7-Difluoro-6-(indol-7-yl)-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one (9-phenyl oxime (Compound 209);

(E)-8-Chloro-6-(3-chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-2,2-dimethyl-lH-quinolin-4- one O-allyl oxime (Compound 210);

(E)-8-Chloro-6-(3-chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-2,2-dimethyl-lH-quinolin-4- one O-t-butyl oxime (Compound 21 1);

(E)-8-Chloro-6-(3-chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-2,2-dimethyl-lH-quinolin-4- one O-phenyl oxime (Compound 212);

(E)-(±)-6-(3-Chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-lH- quinolin-4-one O-ethyl oxime (Compound 213a);

(Z)-(±)-6-(3-Chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-lH- quinolin-4-one O-ethyl oxime (Compound 213b); (E)-5,7-Dlfluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4- one O-t-butyl oxime (Compound 214a);

(Z)-(±)-5,7-Difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-lH- quinolin-4-one O-r-butyl oxime (Compound 214b);

(E)-(±)-5,7-Difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-lH- quinolin-4-one O-methyl oxime (Compound 215a);

(Z)-(±)-5,7-Difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-lH- quinolin-4-one O-methyl oxime (Compound 215b);

(E)-(±)-5,7-Difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-lH- quinolin-4-one O-ethyl oxime (Compound 216a);

(Z)-(±)-5,7-Difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-lH- quinolin-4-one O-ethyl oxime (Compound 216b);

(Z)-(±)-6-(3-Chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-lH- quinolin-4-one O-methyl oxime (Compound 217); (Z)-(±)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-3- (phenylcarbamoyl)oxy-lH-quinolin-4-one O-ethyl oxime (Compound 218); (E)-(±)-7,8-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-3-hydroxy-lH- quinolin-4-one O-methyl oxime (Compound 219a);

(Z)-(±)-7,8-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-3-hydroxy-lH- quinolin-4-one O-methyl oxime (Compound 219b); (E)-(±)-7,8-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-3- (phenylcarbamoyl)oxy-lH-quinolin-4-one O-ethyl oxime (Compound 220a); (Z)-(±)-7,8-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-3- (phenylcarbamoyl)oxy-lH-quinolin-4-one O-ethyl oxime (Compound 220b); (E)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one O-t- butyl oxime (Compound 221a);

(Z)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one O-t- butyl oxime (Compound 221b);

(E)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one O- benzyl oxime (Compound 222);

(E)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one O- phenyl oxime (Compound 223);

(E)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one oxime (Compound 224); (E)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one O- isopropyl oxime (Compound 225);

(E)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-l H-quinolin-4-one O-(l - ethoxycarbonyl-l-methyl)ethyl oxime (Compound 226);

(E)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one O-(l- methoxycarbonyl-l-methyl)ethyl oxime (Compound 227);

(E)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one O-(l- carboxy-l-methyl)ethyl oxime (Compound 228);

(E)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one O-(l- diethylcarbamoyl-l-methyl)ethyl oxime (Compound 229);

(E)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-l H-quinolin-4-one O-(2- hydroxy-l,l-dimethyl)ethyl oxime (Compound 230);

(E)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one O-[l - methyl-l-(2,2,2-trifluoroethylcarbamoyl)ethyl] oxime (Compound 231); (E)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one O- (l,l-dimethyl-2-oxo)ethyl oxime (Compound 232);

(E)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one O-3- carboxy-l, l-dimethylallyl oxime (Compound 233);

(E)-5,7-Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindoI-7-yl)-lH-quinolin-4-one O-(2- ethoxyimino)-l,l-dimethylethyl oxime (Compound 234);

(E)-(±)-6-(3-Chloroindol-7-yl)-5-fluoro-2,3-dihydro-3-hydroxy-2,2,8-trimethyl-lH-quinolin- 4-one O-t-butyl oxime (Compound 235);

(Z)-(±)-6-(3-Chloroindol-7-yl)-5-fluoro-2,3-dihydro-3-hydroxy-2,2,8-trimethyl-lH-quinolin- 4-one O-ethyl oxime (Compound 236);

(E)-(±)-6-(3-Chloroindol-7-yl)-5-fluoro-2,3-dihydro-3-hydroxy-2,2,8-trimethyl-lH-quinolin- 4-one O-ethyl oxime (Compound 237);

(E)-6-(3-Chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one O-ethyl oxime (Compound 238);

(E)-6-(3-Chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one O- isopropyl oxime (Compound 239);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-(m- tolylethynyl)quinoline (Compound 301);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5- (phenylethynyl)quinoline (Compound 302); (±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-(o- tolylethynyl)quinoline (Compound 303);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-[4- (trifluoromethyl)phenylethynyl]quinoline (Compound 304); (±)-5-(3-Chloro-2-methylphenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 305);

(±)-5-(2-Acetylphenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yl)quinoline (Compound 306);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-[3- (trifluoromethyl)phenylethynyl]quinoline (Compound 307);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-[2- (trifluoromethyl)phenylethynyl]quinoline (Compound 308);

(±)-5-(2-Fluorophenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yl)quinoline (Compound 309);

(±)-5-(3-Fluorophenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yl)quinoline (Compound 310);

(±)-5-(2-Acetylphenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yl)quinoline (Compound 311);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-5-[2-(hydroxymethyl)phenylethynyl]-2,2,4α,8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 312); (±)- 1 ,2,3,4-Tetrahydro-3 β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-(p- tolylethynyl)quinoline (Compound 313);

(±)-5-(3,5-Dimethylphenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6- (3-methylindol-7-yl)quinoline (Compound 314);

(±)-5-(2,4-Dimethylphenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6- (3-methylindol-7-yl)quinoline (Compound 315);

(±)-5-(2,4-Difluorophenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yl)quinoline (Compound 316);

(-t)-l,2,3,4-Tetrahydro-3β-hydroxy-5-(2-isopropylphenylethynyl)-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yl)quinoline (Compound 317);

(±)-5-(4-Fluorophenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yl)quinoline (Compound 318); (±)-5-(2-Fluoro-5-methylphenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 319); (±)- 1 ,2,3 ,4-Tetrahydro-3 β-hydroxy-5 -[3 -(hydroxymethy l)phenylethyny l)-2,2,4α,8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 320);

(±)-5-(3-Chloro-2-fluorophenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl- 6-(3-methylindol-7-yl)quinoline (Compound 321 );

(±)-5-(2-Fluoro-3-methylphenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 322);

(±)-5-(3-Cyanophenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yl)quinoline (Compound 323);

(-t)-5-(5-Difluoromethyl-2-fluorophenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 324); (±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-(3- propionylphenylethynyl)quinoline (Compound 325); (±)-l,2,3,4-Tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α,8-tetramethyl-5- (phenylethynyl)quinollne (Compound 326);

(±)-l,2,3,4-Tetrahydro-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-3β-phenylcarbamoyloxy- 5-(m-tolylethynyl)quinoline (Compound 327);

(±)-7-Fluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α-trimethyl-6-(3-methylindol-7-yl)-5-(m- tolylethynyl)quinoline (Compound 328);

(±)-6-(3,5-Dimethylisoxazol-4-yl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-5-(m- tolylethynyl)quinoline (Compound 329);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5- [(thiophen-2-yl)ethynyl]quinoline (Compound 330);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5- [(thiophen-3-yl)ethynyl]quinoline (Compound 331);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-[(5- methylthiophen-2-yl)ethynyl]quinoline (Compound 332);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-(3- morpholinophenylethynyl)quinoline (Compound 333);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-5-(3-hydroxyphenylethynyl)-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yl)qulnoline (Compound 334); (±)-5-(3-Aminophenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yl)quinoline (Compound 335);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-[(3- methylthiophen-2-yl)ethynyl]quinoline (Compound 336);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5- [(pyrimidin-2-yl)ethynyl]quinoline (Compound 337);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-[(pyridin- 3-yl)ethynyl]quinoline (Compound 338);

(±)-5-(5-Acetyl-2-fluorophenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl- 6-(3-methylindol-7-yl)quinoline (Compound 339);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-(3- sulfamoylphenylethynyl)quinoline (Compound 340);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-[3-(l - morpholinocarbonyl)phenylethynyl]quinoline (Compound 341); (±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-(3- diethylsulfamoylphenylethynyl)quinoline (Compound 342);

(±)-5-[(2-Acetylthiophen-3-yl)ethynyl]-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl- 6-(3-methylindol-7-yl)quinoline (Compound 343);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-5-(3-methoxyphenylethynyl)-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yl)quinoline (Compound 344);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-5-[3-(methylamino)phenylethynyl]- 6-(3-methylindol-7-yl)quinoline (Compound 345);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-5-{[2-(l-methoxyiminoethyl)thiophen-3-yl]ethynyl}- 2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 346); (±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-[(5- methylthiophen-3-yl)ethynyl]quinoline (Compound 347);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-5-[2-(methoxycarbonylthiophen-3-yl)ethynyl]-2,2,4α,8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 348);

(±)-5-[3-(Ethoxycarbonylthiophen-2-yl)ethynyl]-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 349);

(±)-l,2,3,4-Tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)-5-[(pyridin- 2-yl)ethynyl]quinoline (Compound 350); (±)-6-(3,5-Dimethylisoxazol-4-yl)-5-[3-(ethoxycarbonylthiophen-2-yl)ethynyl]-l, 2,3,4- tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline (Compound 351); (±)-l,2,3,4-Tetrahydro-3β-hydroxy-5-[3-(hydroxymethyl)thiophen-2-yl]ethynyI]-2,2,4α,8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 352);

(±)-5-[(3-Acetylthiophen-2-yl)ethynyl]-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl- 6-(3-methylindol-7-yl)quinoline (Compound 353);

(±)- 1 ,2,3 ,4-Tetrahydro-3 β-hydroxy-5 - { [3 -( 1 -hydroxy- 1 -methyethy l)thiophen-2-y l]ethyny 1} - 2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 354). (±)-4α-Benzylamino-6-(3-chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2- dimethylquinoline (Compound 401);

(±)-6-(3-Chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-4α- [(thiophen-2-ylmethyl)amino]quinoline (Compound 402);

(±)-4α-Benzylamino-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3- methylindol-7-yl)quinoline (Compound 403);

(±)-4α-Amino-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3-methylindol-7- yl)quinoline (Compound 404);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-4α-(3- phenylureido)quinoline (Compound 405);

(±)-4α-[(3-Benzo[l,3]dioxo-5-yl)ureido]-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2- dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 406);

(±)-4α-(3-Cyclopentylureido)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3- methylindol-7-yl)quinoline (Compound 407);

(±)-4α-[3-(4-Acetylphenylureido)]-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl- 6-(3-methylindol-7-yl)quinoline (Compound 408);

(±)-4α-[3-(3-Chloro-4-methoxyphenylureido)]-5,7-difluoro-l ,2,3,4-tetrahydro-3β-hydroxy- 2,2-dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 409);

(±)-4α-[3-(4-Chlorophenylureido)]-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl- 6-(3-methylindol-7-yl)quinoline (Compound 410);

(±)-4α-Acetamido-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3- methylindol-7-yl)quinoline (Compound 411);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-4α- (phenoxycarbonylamino)quinoline (Compound 412); (±)-4α-(Ethoxycarbonylamino)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6- (3-methylindol-7-yl)quinoline (Compound 413);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-4α-(methoxycarbonylamino)- 6-(3-methylindol-7-yl)quinoline (Compound 414);

(±)-4α-(Cyclohexylmethylamino)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl- 6-(3-methylindol-7-yl)quinoline (Compound 415);

(±)-6-(3-Chloroindol-7-yl)-5,7-difluoro-4α-(furan-2-ylmethylamino)-l,2,3,4-tetrahydro-3β- hydroxy-2,2-dimethylquinoline (Compound 416);

(±)-4α-bis(furan-2-ylmethylamino)-6-(3-chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro- 3β-hydroxy-2,2-dimethylquinoline (Compound 417);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-4α-(isopropoxycarbonylamino)-2,2- dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 418);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-4α-(methylamino)-2,2-dimethyl-6-(3- methylindol-7-yl)quinoline (Compound 419);

(±)-4α-(Dimethylamino)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3- methylindol-7-yl)quinoline (Compound 420);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-4α-(pyridine-2-ylmethylamino)-2,2- dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 421);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-4α-(pyridine-3-ylmethylamino)-2,2- dimethyl-6-(3-methyllndol-7-yl)quinoline (Compound 422);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-4α-(pyridine-4-ylmethylamino)-2,2- dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 423);

(±)-4α-(Chlorobenzylamino)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3- methylindol-7-yl)quinoline (Compound 424);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-4α-(4-methylbenzylamino)-6- (3-methylindol-7-yl)quinoline (Compound 425);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-4α-(methylamino)-2,2-dimethyl-6-(3- methylindol-7-yl)quinoline (Compound 426);

(±)-4α-[Benzyl(ethoxycarbonyl)amino)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2- dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 427);

(±)-4α-Dibenzylamino-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3- methylindol-7-yl)quinoline (Compound 428); (±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-4α- [(naphthalen-l-ylmethyl)amino]quinoline (Compound 429);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-4α- [(naphthalen-2-ylmethyl)amino]quinoline (Compound 430);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-4α- [(thiazol-2-ylmethyl)amino]quinoline (Compound 431);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-4α-[(4- methylthiazol-5-ylmethyl)amino]quinoline (Compound 432); (±)-4α-[(2,4-Dimethylthiazol-5-ylmethyl)amino]-5,7-difluoro-l,2,3,4-tetrahydro-3β- hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-quinoline (Compound 433); (±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-4α-[(5- methylisoxazol-3-ylmethyl)amino]quinoline (Compound 434);

(±)-4α-Benzylmethylamino-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3- methylindol-7-yl)quinoline (Compound 435);

(±)-4α-Ethylamino-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3- methylindol-7-yl)quinoline (Compound 436);

(±)-4α-But-2-enylamino-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3- methylindol-7-yl)quinoline (Compound 437);

(±)-4α-Butylamino-5 ,7-difluoro- 1 ,2,3 ,4-tetrahydro-3 β-hydroxy-2,2-dimethy l-6-(3 - methylindol-7-yl)quinoline (Compound 438);

(±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-4α-isobutylamino-2,2-dimethyl-6-(3- methylindol-7-yl)quinoline (Compound 439);

(±)-4α-Diethylamino-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-6-(3- methylindol-7-yl)quinoline (Compound 440).

[0269] Certain compounds of the present inventions may exist as stereoisomers including optical isomers. The present disclosure is intended to include all stereoisomers and both the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are known in the art or that may be excluded by synthesis schemes known in the art designed to yield predominantly one enantomer relative to another. Certain Synthesis Methods

[0270] Certain synthesis schemes are now provided. The synthesis schemes are provide only to illustrate possible ways to make certain compounds of the invention and do not limit the invention in any way. One of skill in the art will recognize that compounds of the present invention may be synthesized through any of a variety of schemes using a variety of different starting materials.

[0271] In certain embodiments, synthesis of 6-aryl- and 6-heteroaryl-3- substituted-l,2,3,4-tetrahydroquinoline compounds (e.g. Structures 7, (+)-7, and (-)-7) is accomplished using Scheme I.

Scheme I

acylate

[0272] The process of Scheme I begins with Skraup quinoline synthesis of an aniline (Structure 1), with a ketone, for example, acetone in the presence of iodine heated in a sealed tube at elevated temperatures to afford a dihydroquinoline (Structure 2). See Pooley, C. L. F., et.al, J. Med. Chem. 41 :3461 (1998). The olefin of the dihydroquinoline can be functionalized in a number of ways. The dihydroquinoline can be hydrated by, for example, treatment with a hydroborating agent, for example diborane, and subsequently treated with an oxidant, such as hydrogen peroxide, in the presence of a base, for example, sodium hydroxide to afford a compound of Structure 3. Alternatively, the dihydroquinoline can be oxidized by treatment with an oxidant, for example, osmium tetraoxide, to afford a 3,4-dihydroxy-l,2,3,4- tetrahydroquinoline (Structure 3, R⁹ = OH). Structure 3 can be halogenated at the 6-position by treatment with a brominating agent, for example, N-bromosuccinimide, to afford a compound of Structure 4. Treatment of Structure 4 with an organometallic reagent, for example, an aryl boronic acid, in the presence of a transition metal catalyst, for example, [l, r-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of a base, for example, aqueous sodium carbonate, affords a compound of Structure 6.

[0273] A compound of Structure 4 can be metallated to a compound of Structure 5 by treatment with a boronating agent, for example, 4,4,5, 5-tetramethyl-l,3,2-dioxaborolane, in the presence of a transition metal catalyst, for example, [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of a base, for example, triethylamine, to afford a compound of Structure 5. Treatment of Structure 4 with a halide, for example, an aryl bromide, in the presence of a transition metal catalyst, for example, [l,l '-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of a base, for example, aqueous sodium carbonate, affords a compound of Structure 6. Treatment of Structure 6 with an acylating agent, for example, an isocyanate, affords a compound of Structure 7. Alternatively, treatment of Structure 6 with an activating agent, for example, carbonyldiimidazole, affords a compound of Structure 9, which in turn, may be treated with an amine, for example, methylamine, to afford a compound of Structure 7.

[0274] Tetrahydroquinoline compounds of Structure 7 (or any chiral synthetic precursor of Structure 7) can be separated into their corresponding enantiomers, (+)-7 and (-)- 7 by chiral HPLC, with, for example, a preparative Chiracel OJ column eluted with hexanes:isopropanol. Alternatively, the enantiomers (+)-7 and (-)-7 could be prepared in enantiomerically enriched form via an enantiospecific synthesis of a synthetic precursor of Structure 7, for example, by asymmetric hydroboration of Structure 2 to afford a compound of Structure 3 in enantiomerically enriched form.

[0275] Alternatively, a compound of Structure 6 can be treated with an acylating agent, for example, trimethylacetyl chloride, to afford a compound of Structure 10.

1. bromination

2. deprotection

Ar-B(OH)₂

Aryl coupling

Ar = aryl or heteroaryl

[0276] In certain embodiments, synthesis of 6-aryl-lH-quinolin-4-one and 6-aryl- lH-quinolin-4-one oxime compounds (e. g. Structures 17 and 18) is accomplished using Scheme II. The process of Scheme II begins with the treatment of a an aniline, for example, 5,7-difluoroaniline, and a propargyl alkylating agent, for example, 3-acetoxy-3-methyl-l- butyne, in the presence of a catalyst, for example, CuCl, to afford a compound of Structure 12. The quinoline nitrogen in Structure 12 is then protected with, for example, t-Boc anhydride to afford a compound of Structure 13. The dihydroquinoline can be hydrated by, for example, treatment with a hydroborating agent, for example diborane, and subsequently treated with an oxidant, such as hydrogen peroxide, in the presence of a base, for example, sodium hydroxide to afford a 4-hydroxy-l,2,3,4-tetrahydroquinoline (Structure 14, R⁶ = H). Alternatively, the dihydroquinoline can be oxidized by treatment with an oxidant, for example, osmium tetraoxide, to afford a 3,4-dihydroxy-l,2,3,4-tetrahydroquinoline (Structure 14, R⁶ = OH). Structure 14 can be oxidized by treatment with an oxidizing agent, for example, IBX, to afford a compound of Structure 15. Structure 15 can be halogenated at the 6-position by treatment with a brominating agent, for example, N-bromosuccinimide, followed by removal of the protecting group with, for example, trifluoroacetic acid, to afford a compound of Structure 16. Treatment of Structure 16 with an organometallic reagent, for example, an aryl boronic acid, in the presence of a transition metal catalyst, for example, [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of a base, for example, aqueous sodium carbonate, to afford a compound of Structure 17. A compound of Structure 17 can be treated with an oxime forming reagent, for example, an alkoxyamine hydrochloride, to afford a compound of Structure 18.

1 H₂NOR*

2 Deprotect

[0277] In certain embodiments, the synthesis of compounds of Structure 18 is alternatively accomplished using Scheme III, using similar transformations to those described in Scheme II. Scheme IV

[0278] In certain embodiments, the synthesis of compounds of Structure 25, 26, 27, 28 and 29 is accomplished using Scheme IV. The process of Scheme IV begins with treatment of Structure 13 with an epoxidation reagent, for example, mCPBA, buffered with a base, for example, sodium hydrogen carbonate, to afford a compound of Structure 22. Treatment of Structure 22 with an amine source, for example, benzylamine, followed by concommitant deprotection, or deprotection in a separate transformation, affords a compound of Structure 23. Structure 23 can be halogenated at the 6-position by treatment with a brominating agent, for example, N-bromosuccinimide, to afford a compound of Structure 24. Treatment of Structure 24 with an organometallic reagent, for example, an aryl boronic acid, in the presence of a transition metal catalyst, for example, [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of a base, for example, aqueous sodium carbonate, affords a compound of Structure 25. The benzyl group of Structure 25 can be removed by treatment with, for example, Pd(OH)2 in a hydrogen atmosphere, to afford a compound of Structure 26. The amine group of Structure 26 can be treated in a variety of ways. Structure 26 may be treated with an acylating agent, for example, methyl chloroformate, to afford a compound of Structure 27. Alternatively, Structure 26 may be treated with an acylating agent, for example, phenyl isocyanate, to afford a compound of Structure 28. Alternatively, a compound of Structure 26 can be treated with an aldehyde or aldehyde equivalent, for example, 2-furaldehyde, in the presence of a reducing agent, for example sodium cyanoborohydride, to afford a compound of Structure 29.

Scheme V

[0279] In certain embodiments, the synthesis of compounds of Structure 37 is accomplished using Scheme V. The process of Scheme V begins with treatment of Structure 30 with a cyanating agent, for example zinc cyanide, in the presence of a catalyst, for example, a combination of Pd₂(dba)₃ and diphenylphosphino ferrocene (dppf), to afford a compound of Structure 31. The dihydroquinoline can be hydrated by, for example, treatment with a hydroborating agent, for example diborane, and subsequently treated with an oxidant, such as hydrogen peroxide, in the presence of a base, for example, sodium hydroxide to afford a compound of Structure 32. The nitrile of Structure 32 can be reduced to the aldehyde by treatment with, for example, diisobutylaluminum hydride, to afford a compound of Structure 33. Conversion of the aldehyde of Structure 33 to an acetylene can be accomplished by treatment of Structure 33 with dimethyl l-diazo-2-oxopropylphosphonate (Structure 34) to afford a compound of Structure 35. Structure 35 can be halogenated at the 6-position by treatment with a brominating agent, for example, N-bromosuccinimide, to afford a compound of Structure 36. Treatment of Structure 36 with an organometallic reagent, for example, an aryl boronic acid, in the presence of a transition metal catalyst, for example, [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of a base, for example, aqueous sodium carbonate, affords a compound of Structure 37. Arylation of the acetylene of Structure 37 can be accomplished by treatment with an aryl halide, for example, iodobenzene, in the presence of copper (I) catalyst, for example, copper iodide, and a palladium catalyst, for example, Pd(PPlIs)₄, to afford a compound of Structure 38.

[0280] In certain embodiments, the synthesis of compounds of Structure 38 is alternatively accomplished using Scheme VI, using similar transformations to those described in Scheme V.

[0281] Compounds of Structure 10, 17, 18, 25, 26, 27, 28, 29, 38 (or any chiral synthetic precursor) can be separated into their corresponding enantiomers, by chiral HPLC, with, for example, a preparative Chiracel OJ column eluted with hexanes:isopropanol.

[0282] In certain embodiments, the invention provides a salt corresponding to any of the compounds provided herein. In certain embodiments, the invention provides a salt corresponding to a selective glucocorticoid receptor modulator, a selective androgen receptor modulator and/or a selective glucocoroticoid/androgen receptor modulator. In certain embodiments, the invention provides a salt corresponding to a selective glucocorticoid receptor binding agent, a selective androgen receptor binding agent and/or a selective glucocoroticoid/androgen receptor binding agent. In certain embodiments, a salt is obtained by reacting a compound with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like. In certain embodiments, a salt is obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.

[0283] In certain embodiments, one or more carbon atoms of a compound of the present invention is replaced with silicon. See e.g., WO 03/037905A1 ; Tacke and Zilch, Endeavour, New Series, 10, 191-197 (1986); Bains and Tacke, Curr. Opin. Drug Discov Devel. Jul:6(4):526-43(2003). In certain embodiments, compounds of the present invention comprising one or more silicon atoms possess certain desired properties, including, but not limited to, greater stability and/or longer half-life in a patient, when compared to the same compound in which none of the carbon atoms have been replaced with a silicon atom. Certain Assays

[0284] In certain embodiments, compounds of the present invention are capable of modulating activity of glucocorticoid and/or androgen receptors in a "co-transfection" assay (also called a "cis-trans" assay), which has been discussed previously. See e.g., Evans et al., Science, 240:889-95 (1988); U.S. Patent Nos. 4,981,784 and 5,071 ,773; Pathirana et al., "Nonsteroidal Human Progesterone Receptor Modulators from the Marie Alga Cymopolia Barbata," MoI. Pharm. 47:630-35 (1995)). Modulating activity in a co- transfection assay has been shown to correlate with in vivo modulating activity. Thus, in certain embodiments, such assays are predictive of in vivo activity. See, e.g, Berger et al., J. Steroid Biochem. Molec. Biol. A\ :113 (1992).

[0285] In certain co-transfection assays, two different co-transfection plasmids are prepared. In the first co-transfection plasmid, cloned cDNA encoding an intracellular receptor {e.g., glucocorticoid or mineralocoticoid receptor) is operatively linked to a constitutive promoter (e.g., the SV 40 promoter). In the second co-transfection plasmid, cDNA encoding a reporter protein, such as firefly luciferase (LUC), is operatively linked to a promoter that is activated by a receptor-dependant activation factor. Both co-transfection plasmids are co-transfected into the same cells. Expression of the first co-transfection plasmid results in production of the intracellular receptor protein. Activation of that intracellular receptor protein (e.g., by binding of an agonist) results in production of a receptor-dependant activation factor for the promoter of the second co-transfection plasmid. That receptor-dependant activation factor in turn results in expression of the reporter protein encoded on the second co-transfection plasmid. Thus, reporter protein expression is linked to activation of the receptor. Typically, that reporter activity can be conveniently measured (e.g., as increased luciferase production).

[0286] Certain co-transfection assays can be used to identify agonists, partial agonists, and/or antagonists of intracellular receptors. In certain embodiments, to identify agonists, co-transfected cells are exposed to a test compound. If the test compound is an agonist or partial agonist, reporter activity is expected to be higher compared to co- transfected cells in the absence of the test compound. In certain embodiments, to identify antagonists, the cells are exposed to a known agonist (e.g., the natural ligand for the receptor) in the presence and absence of a test compound. If the test compound is an antagonist, reporter activity is expected to be lower than that of cells exposed only to the known agonist. [0287] In certain embodiments, compounds of the invention are used to detect the presence, quantity and/or state of receptors in a sample. In certain of such embodiments, samples are obtained from a patient. In certain embodiments, compounds are radio- or isotopically-labeled. For example, compounds of the present invention that selectively bind glucocorticoid and or androgen receptors may be used to determine the presence or amount of such receptors in a sample, such as cell homogenates and lysates. Certain Pharmaceutical Agents

[0288] In certain embodiments, at least one selective glucocoroticoid receptor modulator, or pharmaceutically acceptable salt, ester, amide, and/or prodrug thereof, either alone or combined with one or more pharmaceutically acceptable carriers, forms a pharmaceutical agent. In certain embodiments, at least one selective androgen receptor modulator, or pharmaceutically acceptable salt, ester, amide, and/or prodrug thereof, either alone or combined with one or more pharmaceutically acceptable carriers, forms a pharmaceutical agent. In certain embodiments, at least one selective glucocoroticoid/androgen receptor modulator, or pharmaceutically acceptable salt, ester, amide, and/or prodrug thereof, either alone or combined with one or more pharmaceutically acceptable carriers, forms a pharmaceutical agent. In certain embodiments, the pharmaceutical agent comprises at least one compound of Formula I, II, or III, as defined and described herein. Techniques for formulation and administration of compounds of the present invention may be found for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990, which is incorporated herein by reference in its entirety.

[0289] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention, such as a compound of Formula I, II, or III, is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.

[0290] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is a liquid (e.g., a suspension, elixir and/or solution). In certain of such embodiments, a liquid pharmaceutical agent comprising one or more compounds of the present invention is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.

[0291] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is a solid (e.g., a powder, tablet, and/or capsule). In certain of such embodiments, a solid pharmaceutical agent comprising one or more compounds of the present invention is prepared using ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.

[0292] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is formulated as a depot preparation. Certain of such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0293] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention comprises a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical agents including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.

[0294] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention comprises one or more tissue-specific delivery molecules designed to deliver the pharmaceutical agent to specific tissues or cell types. For example, in certain embodiments, pharmaceutical agents include liposomes coated with a tissue-specific antibody.

[0295] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention comprises a co-solvent system. Certain of such co- solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water- miscible organic polymer, and an aqueous phase. In certain embodiments, such co-solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™ , and 65% w/v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

[0296] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention comprises a sustained-release system. A non-limiting example of such a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers. In certain embodiments, sustained-release systems may, depending on their chemical nature, release compounds over a period of hours, days, weeks or months.

[0297] Certain compounds used in pharmaceutical agent of the present invention may be provided as pharmaceutically acceptable salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.

[0298] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention comprises an active ingredient in a therapeutically effective amount. In certain embodiments, the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.

[0299] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is formulated as a prodrug. In certain embodiments, prodrugs are useful because they are easier to administer than the corresponding active form. For example, in certain instances, a prodrug may be more bioavailable {e.g., through oral administration) than is the corresponding active form. In certain instances, a prodrug may have improved solubility compared to the corresponding active form. In certain embodiments, a prodrug is an ester. In certain embodiments, such prodrugs are less water soluble than the corresponding active form. In certain instances, such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility. In certain embodiments, the ester in such prodrugs is metabolically hydrolyzed to carboxylic acid. In certain instances the carboxylic acid containing compound is the corresponding active form. In certain embodiments, a prodrug comprises a short peptide (polyaminoacid) bound to an acid group. In certain of such embodiments, the peptide is metabolized to form the corresponding active form.

[0300] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is useful for treating a conditions or disorder in a mammalian, and particularly in a human patient. Suitable administration routes include, but are not limited to, oral, rectal, transmucosal, intestinal, enteral, topical, suppository, through inhalation, intrathecal, intraventricular, intraperitoneal, intranasal, intraocular and parenteral (e.g., intravenous, intramuscular, intramedullary, and subcutaneous). In certain embodiments, pharmaceutical intrathecals are administered to achieve local rather than systemic exposures. For example, pharmaceutical agents may be injected directly in the area of desired effect (e.g., in the renal or cardiac area).

[0301] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is administered in the form of a dosage unit (e.g., tablet, capsule, bolus, etc.). In certain embodiments, such dosage units comprise a selective glucocorticoid and/or minerlaocorticoid receptor modulator in a dose from about 1 μg/kg of body weight to about 50 mg/kg of body weight. In certain embodiments, such dosage units comprise a selective glucocorticoid and/or minerlaocorticoid receptor modulator in a dose from about 2 μg/kg of body weight to about 25 mg/kg of body weight. In certain embodiments, such dosage units comprise a selective glucocorticoid and/or minerlaocorticoid receptor modulator in a dose from about 10 μg/kg of body weight to about 5 mg/kg of body weight. In certain embodiments, pharmaceutical agents are administered as needed, once per day, twice per day, three times per day, or four or more times per day. It is recognized by those skilled in the art that the particular dose, frequency, and duration of administration depends on a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the pharmaceutical agent.

[0302] In certain embodiments, a pharmaceutical agent comprising a compound of the present invention is prepared for oral administration. In certain of such embodiments, a pharmaceutical agent is formulated by combining one or more compounds of the present invention with one or more pharmaceutically acceptable carriers. Certain of such carriers enable compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient. In certain embodiments, pharmaceutical agents for oral use are obtained by mixing one or more compounds of the present invention and one or more solid excipient. Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). In certain embodiments, such a mixture is optionally ground and auxiliaries are optionally added. In certain embodiments, pharmaceutical agents are formed to obtain tablets or dragee cores. In certain embodiments, disintegrating agents (e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate) are added.

[0303] In certain embodiments, dragee cores are provided with coatings. In certain of such embodiments, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to tablets or dragee coatings.

[0304J In certain embodiments, pharmaceutical agents for oral administration are push-fit capsules made of gelatin. Certain of such push-fit capsules comprise one or more compounds of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In certain embodiments, pharmaceutical agents for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain soft capsules, one or more compounds of the present invention are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

[0305] In certain embodiments, pharmaceutical agents are prepared for buccal administration. Certain of such pharmaceutical agents are tablets or lozenges formulated in conventional manner.

[0306] In certain embodiments, a pharmaceutical agent is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In certain of such embodiments, a pharmaceutical agent comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks' s solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical agents for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical agents for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Certain solvents suitable for use in pharmaceutical agents for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0307] In certain embodiments, a pharmaceutical agent is prepared for transmucosal administration. In certain of such embodiments penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0308] In certain embodiments, a pharmaceutical agent is prepared for administration by inhalation. Certain of such pharmaceutical agents for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer. Certain of such pharmaceutical agents comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In certain embodiments using a pressurized aerosol, the dosage unit may be determined with a valve that delivers a metered amount. In certain embodiments, capsules and cartridges for use in an inhaler or insufflator may be formulated. Certain of such formulations comprise a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

[0309] In certain embodiments, a pharmaceutical agent is prepared for rectal administration, such as a suppositories or retention enema. Certain of such pharmaceutical agents comprise known ingredients, such as cocoa butter and/or other glycerides.

[0310] In certain embodiments, a pharmaceutical agent is prepared for topical administration. Certain of such pharmaceutical agents comprise bland moisturizing bases, such as ointments or creams. Exemplary suitable ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, lanolin and water in oil emulsions such as Eucerin™, available from Beiersdorf (Cincinnati, Ohio). Exemplary suitable cream bases include, but are not limited to, Nivea™ Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream (USP), Purpose Cream™, available from Johnson & Johnson (New Brunswick, New Jersey), hydrophilic ointment (USP) and Lubriderm™, available from Pfizer (Morris Plains, New Jersey).

[0311] In certain embodiments, the formulation, route of administration and dosage for a pharmaceutical agent of the present invention can be chosen in view of a particular patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1). In certain embodiments, a pharmaceutical agent is administered as a single dose. In certain embodiments, a pharmaceutical agent is administered as a series of two or more doses administered over one or more days.

[0312] In certain embodiments, a pharmaceutical agent of the present invention is administered to a patient between about 0.1% and 500%, 5% and 200%, 10% and 100%, 15% and 85%, 25% and 75%, or 40% and 60% of an established human dosage. Where no human dosage is established, a suitable human dosage may be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies.

[0313] In certain embodiments, a daily dosage regimen for a patient comprises an oral dose of between 0.1 mg and 2000 mg, 5 mg and 1500 mg, 10 mg and 1000 mg, 20 mg and 500 mg, 30 mg and 200 mg, or 40 mg and 100 mg of a compound of the present invention. In certain embodiments, a daily dosage regimen is administered as a single daily dose. In certain embodiments, a daily dosage regimen is administered as two, three, four, or more than four doses.

[0314] In certain embodiments, a pharmaceutical agent of the present invention is administered by continuous intravenous infusion. In certain of such embodiments, from 0.1 mg to 500 mg of a composition of the present invention is administered per day.

[0315] In certain embodiments, a pharmaceutical agent of the invention is administered for a period of continuous therapy. For example, a pharmaceutical agent of the present invention may be administered over a period of days, weeks, months, or years.

[0316] Dosage amount, interval between doses, and duration of treatment may be adjusted to achieve a desired effect. In certain embodiments, dosage amount and interval between doses are adjusted to maintain a desired concentration on compound in a patient. For example, in certain embodiments, dosage amount and interval between doses are adjusted to provide plasma concentration of a compound of the present invention at an amount sufficient to achieve a desired effect. In certain of such embodiments the plasma concentration is maintained above the minimal effective concentration (MEC). In certain embodiments, pharmaceutical agents of the present invention are administered with a dosage regimen designed to maintain a concentration above the MEC for 10-90% of the time, between 30-90% of the time, or between 50-90% of the time.

[0317] In certain embodiments in which a pharmaceutical agent is administered locally, the dosage regimen is adjusted to achieve a desired local concentration of a compound of the present invention.

[0318] In certain embodiments, a pharmaceutical agent may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0319] In certain embodiments, a pharmaceutical agent is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Certain Combination Therapies

[0320] In certain embodiments, one or more pharmaceutical agents of the present invention are co-administered with one or more other pharmaceutical agents. In certain embodiments, such one or more other pharmaceutical agents are designed to treat the same disease or condition as the one or more pharmaceutical agents of the present invention. In certain embodiments, such one or more other pharmaceutical agents are designed to treat a different disease or condition as the one or more pharmaceutical agents of the present invention. In certain embodiments, such one or more other pharmaceutical agents are designed to treat an undesired effect of one or more pharmaceutical agents of the present invention. In certain embodiments, one or more pharmaceutical agents of the present invention is co-administered with another pharmaceutical agent to treat an undesired effect of that other pharmaceutical agent. In certain embodiments, one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are administered at the same time. In certain embodiments, one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are administered at the different times. In certain embodiments, one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are prepared together in a single formulation. In certain embodiments, one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are prepared separately.

[0321] Examples of pharmaceutical agents that may be co-administered with a pharmaceutical agent of the present invention include, but are not limited to, analgesics (e.g., acetaminophen); anti-inflammatory agents, including, but not limited to non-steroidal anti- inflammatory drugs (e.g., ibuprofen, COX-I inhibitors, and COX-2, inhibitors); salicylates; antibiotics; antivirals; antifungal agents; antidiabetic agents (e.g., biguanides, glucosidase inhibitors, insulins, sulfonylureas, and thiazolidenediones); adrenergic modifiers; diuretics; hormones (e.g., anabolic steroids, androgen, estrogen, calcitonin, progestin, somatostan, and thyroid hormones); immunomodulators; muscle relaxants; antihistamines; osteoporosis agents (e.g., biphosphonates, calcitonin, and estrogens); prostaglandins, antineoplastic agents; psychotherapeutic agents; sedatives; poison oak or poison sumac products; antibodies; and vaccines. Certain Indications

[0322] In certain embodiments, the invention provides methods of treating a patient comprising administering one or more compounds of the present invention. In certain embodiments, such patient suffers from a glucocorticoid receptor mediated condition. In certain embodiments, such patient suffers from an androgen receptor mediated condition. In certain embodiments, such patient suffers from a glucocorticoid/minerlaocorticoid receptor mediated condition. In certain embodiments, a patient is treated prophylactically to reduce or prevent the occurrence of a condition.

[0323] In certain embodiments, one or more compounds of the present invention is used to treat inflammation, including, but not limited to, rheumatoid arthritis, asthma (acute or chronic), chronic obstructive pulmonary disease, lupus, osteoarthritis, rhinosinusitis, allergic rhinitis, inflammatory bowel disease, polyarteritis nodosa, Wegener's granulomatosis, giant cell arteritis, urticaria, angiodema, tendonitis, bursitis, autoimmune chronic hepatitis, and cirrhosis; transplant rejection; psoriasis; dermatitis; an autoimmune disorder; malignancy, including, but not limited to, leukemia, myeomas, and lymphomas; adrenal insufficiency; congenital adrenal hyperplasia; rheumatic fever; granulomatous disease; immune proliferation/apoptosis; conditions of the HPA axis; hypercortisolemia; cytokine imbalance, including, but not limited to Th/1/Th2 cytokine imbalance; kidney disease; liver disease; stroke; spinal cord injury; hypercalcemia; hyperglycemia; cerebral edema; thrombocytopenia; Little's syndrome; Addison's disease; cystic fibrosis; myasthenia gravis; autoimmune hemolytic anemia; uveitis; pemphigus vulgaris; multiple sclerosis; nasal polyps; sepsis; infections, including, but not limited to, bacterial, viral, rickettsial, and parasitic; type II diabetes; obesity; metabolic syndrome; schizophrenia; mood disorders, including, but not limited to depression; Cushing's syndrome; anxiety; sleep disorders; poor memory; glaucoma; wasting; heart disease; fibrosis; hypertension; hyperaldosteronism; and sodium and/or potassium imbalance. EXAMPLES

[0324] The following examples, including experiments and results achieved, are provided for illustrative purposes only and are not to be construed as limiting the present invention.

EXAMPLE 1

|0325] f±)-5.7-Difluoro-1.2.3.4-tetrahvdro-6-(indol-7-vn-2.2.4α-trimethyl-3β- (phenylcarbamoyloxy)quinoline (Compound 101).

[0326] 5,7-Difiuoro-l,2-dihydro-2,2,4-trimethylquinoline was prepared from 3,5- difluoroaniline using General Method 1.

[0327] General Method 1 : Skraup cyclization of an aniline to a l,2-dihydro-2,2,4- trimethylquinoline. A solution of an aniline (1.0 equiv), iodine (0.2-0.4 equiv), NO- bis(trimethylsilyl)acetamide (2 equiv) in acetone (0.1-0.2 M) is heated in a sealed tube (110- 130 ⁰C) for 16-24 h . After heating, the solution is then processed by either a non-aqueous workup or by an aqueous work-up. In the non-aqueous workup, the solution is evaporated under reduced pressure and chromatographed using silica gel and EtOAc:hexanes to afford the desired product as an oil. In the aqueous workup, the solution is mixed with an aqueous solution of sodium thiosulfate and a first organic layer of a 1 :1 mixture of EtOAc:hexanes. The first organic layer is collected. The aqueous layer is then extracted a second time with a second layer of EtOAc:hexanes (1 : 1). The first and second organic layers are combined and that combined organic solution is washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (using silica gel) of the product of that process affords the desired compound.

[0328] (±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α-trimethylquinoline is prepared from 5,7-difluoro-l,2-dihydro-2,2,4-trimethylquinoline using General Method 2.

[0329] General Method 2: Hydroboration reaction. This compound was prepared by the hydroboration of a 4-alkyl-l,2-dihydroquinoline to produce a 4α-alkyl- 1,2,3,4- tetrahydro-3β-hydroxyquinoline (trans-ϊsomer), as follows. To a rapidly stirring solution of 5.0 g (22.6 mmol) of a l,2-dihydro-2,2,4-tetramethylquinoline in 100 mL of anhydrous tetrahydrofuran (0.23 M) at 0 ⁰C under nitrogen was added dropwise, over 20 minutes, 27.0 mL of a 1.5 M solution of borane in tetrahydrofuran (1.8 equiv). After addition of the borane was complete, the mixture was stirred at for an additional 20 minutes at 0 ⁰C and then at room temperature for 5 hours to produce an intermediate organoborane. That intermediate organoborane was oxidized by adding, successively, 25 mL of a 2.0 N aqueous potassium hydroxide solution (2.2 equiv) and 20 mL of 30 % hydrogen peroxide (8.7 equiv) at 0 ⁰C. That mixture was then stirred at room temperature for 2 hours and then the mixture was diluted with 80 mL of water, resulting in a first organic layer and an aqueous layer. The first organic layer was collected and the aqueous phase was extracted with ethyl acetate. The organic layer from that extraction was combined with the first organic layer and that combined organic layer was washed with brine and dried over sodium sulfate. Filtration and concentration of the filtrate in vacuo gave a brown oil which was chromatographed on silica gel. Elution with hexanes-ethyl acetate (4:1) provided 3.47 g (65%) of (±)-5-chloro- 1,2,3,4- tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline, as a white solid.

[0330] (±)-6-Bromo-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α- tetramethylquinoline is prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α- tetramethylquinoline using General Method 3.

[0331] General Method 3: Aromatic bromination of a 1,2,3,4- tetrahydroquinoline. To a solution of a 1,2,3,4-tetrahydroquinoline (1 equiv) in chloroform (0.2 M) at -10 ⁰C is added N-bromosuccinimide (1.03 equiv) in portions over 15 minutes. After 1.5 hours, the mixture is washed with water, resulting in an aqueous layer and a first organic layer. The first organic layer is collected and the aqueous layer is extracted with a second organic layer of dichloromethane. The first and second organic layers are combined and that combined organic layer is washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (silica gel) affords the desired 6-bromo-l,2,3,4-tetrahydroquinoline.

[0332] (±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α- trimethylquinoline was prepared from (±)-6-bromo-5,7-difluoro-l,2,3,4-tetrahydro-3β- hydroxy-2,2,4α-tetramethylquinoline and 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indole using General Method 4.

[0333] General Method 4: Palladium-catalyzed Suzuki cross-coupling of an aryl halide and an aryl boronic acid or aryl pinacol boronate. In a Schlenck reaction flask, a mixture of an aryl bromide (1 equiv); an aryl boronic acid or aryl pinacol boronate (1.0-1.3 equiv); and [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (3-10 mol %) is placed under vacuum, and back-filled with nitrogen. Dioxane (0.1-0.2 M) and 2M sodium carbonate (2 equiv) are introduced sequentially. The mixture is heated (95-100 ⁰C) for 16-24 h. The mixture is partitioned between saturated ammonium chloride and EtOAc, resulting in a first organic layer and an aqueous layer. The first organic layer is collected and the aqueous layer is extracted with EtOAc. The organic layer from that extraction is combined with the first collected organic layer and that combined organic layer is washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (silica gel, EtOAc/hexanes or other specified solvent), preparative thin-layer chromatography (prep TLC, EtOAc/hexanes or other specified solvents), preparative HPLC and/or recrystallization affords the desired compound.

[03341 (±)-5,7-Difluoro-1.2.3.4-tetrahvdro-6-(indol-7-vn-2.2.4α-trimethyl-3β- (phenylcarbamoyloxy)quinoline (Compound 101). This compound was prepared in 38% yield from (±)-5,7-difluoro-l ,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α- trimethylquinoline and phenyl isocyanate using General Method 5 (EXAMPLE 1). IH NMR (500MHz, CDC13) δ 8.06 (br s, IH), 7.66 (dd, J=7.2, 1.8 Hz, IH), 7.42 (d, J=7.3 Hz, 2H), 7.33 (t, J=7.3 Hz, 2H), 7.21 (dd, J=3.2, 2.5 Hz, IH), 7.20 (m, IH), 7.18 (t, J=7.2 Hz, IH), 7.09 (t, J=7.3 Hz, IH), 6.73 (br s, IH), 6.60 (dd, J=3.2, 2.1 Hz, IH), 6.24 (dd, J=I 0.8, 1.5 Hz, IH), 4.90 (d, J=6.8 Hz, IH), 3.99 (br s, IH), 3.08 (qn, J=6.8 Hz, IH), 1.46 (dd, J=6.8, 1.3 Hz, 3H), 1.33 (s, 3H), 1.24 (s, 3H).

[0335] General Method 5: Formation of carbamate 7 from an alcohol and an isocyanate.

[0336] To a solution of an alcohol (620 mg, 1.65 mmol) in 12 mL of dry toluene was added DMAP (0.5 mmol, 0.3 equiv, 60 mg) followed by an isocyanate (2.47 mmol, 1.5 equiv, 268 μL). The reaction was heated to reflux for 16 h, cooled to room temperature and poured into 100 mL of ethyl acetate:water (1 :1). The aqueous layer was extracted with an additional 50 mL of ethyl acetate, the organic layers were combined and washed with brine (1 X 100 mL), dried over sodium sulfate, and filtered. The residue obtained after evaporation was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 4:1) to give a carbamate as a white powder.

fO3371 (±)-6-(3-Chloroindol-7-yl)-5J-difluoro-1.2.3.4-tetrahvdro-2.2.4α- trimethyl-3β-(phenylcarbamoyloxy)quinoline (Compound 102).

[0338] (±)-6-(3-Chloroindol-7-yl)-5,7-difiuoro-l,2,3,4-tetrahydro-3β-hydroxy- 2,2,4α-trimethylquinoline is prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6- (indol-7-yl)-2,2,4α-trimethylquinoline in 54% yield using General Method 6.

[0339] General Method 6: Chlorination of an indole at the 3 -position. To a solution of an indole (1 equiv) in chloroform (10 mL/mmol) at 0 ⁰C is added N- chlorosuccinimide (1.05 equiv) in two portions over 15 minutes. After 1.5 hours, the mixture is washed with water, resulting in an aqueous layer and a first organic layer. The first organic layer is collected and the aqueous layer is extracted with a second organic layer of dichloromethane. The first and second organic layers are combined and that combined organic layer is washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (silica gel, 2: 1 hexanesxthyl acetate) affords the desired 3-chloroindole. r03401 (±)-6-(3-Chloroindol-7-yl)-5J-difluoro-L23.4-tetrahydro-2,2,4α- trimethyl-3β-(phenylcarbamoyloxy)quinoline (Compound 102). This compound was prepared from (±)-6-(3-chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α- trimethyl quinoline and phenyl isocyanate using General Method 5 (EXAMPLE 1). IH ΝMR (500MHz, CDC13) δ 7.97 (br s, IH), 7.66 (m, IH), 7.45-7.39 (m, 2H), 7.37-7.31 (m, 3H), 7.26 (m, IH), 7.18 (d, J=2.2 Hz, IH), 7.09 (t, J=7.4 Hz, I H), 6.72 (br s, IH), 6.24 (d, J=I LO Hz, IH), 4.90 (d, J=6.8 Hz, IH), 4.02 (br s, IH), 3.07 (qn, J=6.8 Hz, I H), 1.46 (d, J=6.8 Hz, 3H), 1.34 (s, 3H), 1.24 (s, 3H).

EXAMPLE 3

(03411 (±)-3B-(Benzylcarbamoyloxy)-3-(chloroindol-7-yl)-5.7-difluoro-l,2.3,4- tetrahydro-2,2,4α-trimethylquinoline (Compound 103). This compound was prepared from (±)-6-(3-chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α-trimethyl quinoline and benzyl isocyanate using General Method 5 (EXAMPLE 1). ¹H ΝMR (500MHz, CDCl₃) δ 7.96 (br s, IH), 7.66 (m, IH), 7.36-7.24 (m, 7H), 7.18 (d, J=2.7 Hz, IH), 6.21 (dd, J=I LO, 1.1 Hz, IH), 5.09 (t, J=5.8 Hz, IH), 4.83 (d, J=6.8 Hz, I H), 4.42 (d, J=5.8 Hz, 2H), 2.99 (qn, J=6.8 Hz, IH), 1.43 (dd, J=6.8, 1.1 Hz, 3H), 1.30 (s, 3H), 1.18 (s, 3H).

[03421 (±)-6-(3-Chloroindol-7-yl)-SJ-difluoro-l,2,3,4-tetrahvdro-3β- (isopropylcarbamoyloxy)-2,2,4α-trimethylquinoline (Compound 104). This compound was prepared from (±)-6-(3-chloroindol-7-yl)-5,7-difIuoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α- trimethyl quinoline and isopropyl isocyanate using General Method 5 (EXAMPLE 1). IH NMR (500MHz, CDC13) δ 7.96 (br s, IH), 7.66 (m, IH), 7.27-7.25 (m, 2H), 7.18 (d, J=2.7 Hz, IH), 6.21 (d, J=I 1.0 Hz, IH), 4.77 (d, J=6.8 Hz, IH), 4.60 (m, IH), 3.98 (s, IH), 3.85 (m, IH), 2.97 (qn, J=6.8 Hz, IH), 1.41 (dd, J=6.8, 1.2 Hz, 3H), 1.28 (s, 3H) 1.19 (d, J=6.6 Hz, 6H), 1.17 (s, 3H).

[0343] (±)-6-(3-Chloroindol-7-yl)-3β-(cvclohexylcarbamoyloxy)-5J-difluoro- L2,3,4-tetrahydro-2,2,4α-trirnethylquinoline (Compound 105). This compound was prepared from (±)-6-(3-chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α-trimethyl quinoline and cyclohexyl isocyanate using General Method 5 (EXAMPLE 1). IH NMR (500MHz, CDC13) δ 7.96 (br s, IH), 7.66 (m, IH), 7.28-7.24 (m, 2H), 7.18 (d, J=2.7 Hz, IH), 6.21 (d, J=I LO Hz, IH), 4.77 (d, J=6.8 Hz, IH), 4.66 (m, IH), 3.98 (br s, IH), 3.51 (m, IH), 2.97 (qn, J=6.8 Hz, IH), 1.97 (m, 2H), 1.72 (m, 2H), 1.65-1.58 (m, 2H), 1.41 (dd, J=6.8, 1.2 Hz, 3H), 1.38-1.30 (m, 2H), 1.28 (s, 3H), 1.17 (s, 3H), 1.20-1.12 (m, 2H). EXAMPLE 6

[03441 (±)-5J-Difluoro-l,23,4-tetrahydro-6-(indol-7-yl)-2.2,4α-trimethyl-3β- (methyl-phenylcarbamoyloxy)quinoline (Compound 106). (±)-6-Bromo-5,7-difluoro- 1 ,2,3,4- tetrahydro-2,2,4α-trimethyl-3β-(phenylcarbamoyloxy)quinoline. To a solution of (±)-6- bromo-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α-tetramethylquinoline (EXAMPLE 1) (100 mg, 1 equiv) in 4 mL toluene was added phenyl isocyanate (1.05 equiv, 42 mg) and DMAP (0.1 equiv, 4 mg). The reaction was heated to 100 ⁰C for 4 hr, cooled to room temperature and poured into 10 mL of water. The layers were separated and the aqueous layer was extracted with 10 mL of ethyl acetate. The combined organics were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (±)-6-bromo-5,7-difluoro-l,2,3,4-tetrahydro-2,2,4α-trimethyl-3β-(phenylcarbamoyloxy) quinoline after flash chromatography.

[0345] (±)-6-Bromo-5,7-difluoro-l,2,3,4-tetrahydro-2,2,4α-trimethyl-3β-(methyl- phenylcarbamoyloxy)quinoline. To a solution of (±)-6-bromo-5,7-difluoro- 1,2,3,4- tetrahydro-2,2,4α-trimethyl-3β-(phenylcarbamoyloxy)quinoline (100 mg, 0,24 mmol) in 1 mL of dimethylformamide at 0 ⁰C was added sodium hydride (60 % wt, 1.2 equiv). The reaction was stirred for 0.5 h, followed by the addition of iodomethane (1.1 equiv, 35 mg). Upon completion of addition, the reaction was allowed to warm to rt over 2 h, poured into water (10 mL) and extracted with ethyl acetate (20 mL). Flash chromatography gave the (±)- 6-bromo-5,7-difluoro-l,2,3,4-tetrahydro-2,2,4α-trimethyl-3β-(methyl- phenylcarbamoyloxy)quinoline. fO3461 (±)-5.7-Difluoro-1.2.3.4-tetrahvdro-6-(indol-7-yl)-2.2,4α-trimethyl-3β- (methyl-phenylcarbamoyloxy)quinoline (Compound 106). This compound was prepared from 6-bromo-5,7-difluoro-l,2,3,4-tetrahydro-2,2,4α-trimethyl-3β-(methyl- phenylcarbamoyloxy)quinoline and 7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)indole according to General Method 12 (EXAMPLE 52). IH NMR (500MHz, CDC13) δ 8.06 (br s, IH), 7.65 (m, IH), 7.38-7.33 (m, 2H), 7.26-7.16 (m, 6H), 6.58 (dd, J=3.2, 2.0 Hz, IH), 6.17 (d, J=10.7 Hz, IH), 4.81 (d, J=7.8 Hz, IH), 3.91 (br s, IH), 3.34 (s, 3H), 2.87 (m, IH), 1.41 (d, J=6.6 Hz, 3H), 1.23 (s, 6H). EXAMPLE 7

103471 (±)-6-(3-Chloroindol-7-yl)-5J-difluoro-l,2,3,4-tetrahydro-2,2,4α- trimethyl-3β-(methyl-phenylcarbamoyloxy)quinoline (Compound 107). To a solution of Compound 106 (EXAMPLE 6) (380 mg, 1.1 1 mmol) in chloroform (10 mL) at 0 ⁰C is added N-chlorosuccinimide (1.05 equiv, 157 mg) in two portions over 15 minutes. After 1.5 hours, the mixture is washed with water, resulting in an aqueous layer and a first organic layer. The first organic layer is collected and the aqueous layer is extracted with a second organic layer of dichloromethane. The first and second organic layers are combined and that combined organic layer is washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (silica gel, 2:1 hexanes:ethyl acetate) affords Compound 107 (225 mg, 54%) as a white powder. ¹H ΝMR (500MHz, CDCl₃) δ 7.96 (br s, IH), 7.65 (dd, J=7.3, 1.6 Hz, IH), 7.38-7.34 (m, 2H), 7.28-7.21 (m, 5H), 7.17 (d, J=2.7 Hz, IH), 6.18 (d, J=10.5 Hz, IH), 4.81 (d, J=7.6 Hz, IH), 3.35 (s, 3H), 2.87 (m, IH), 1.41 (d, J=6.6 Hz, 3H), 1.26 (s, 6H).

EXAMPLE 8

[0348] (±)-3β-(Cvclohexylcarbamoyloxy)-5.7-difluoro-l,2.3.4-tetrahvdro-2,2,4α- trimethyl-6-(3-methylindol-7-yl)quinoline (Compound 108).

[0349] (±)-5,7-Difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α-trimethyl-6-(3- methylindol-7-yl)quinoline is prepared from (±)-6-bromo-5,7-difluoro-l,2,3,4-tetrahydro-3β- hydroxy-2,2,4α-tetramethylquinoline and 3-methyl-7-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)indole using General Method 4 (EXAMPLE 1).

[03501 ^-Sβ-rCvclohexylcarbamoyloxy'i-SJ-difluoro-l^J^-tetrahvdro-Σ^Jα- trimethyl-6-(3-methylindol-7-yDquinoline (Compound 108). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α-trimethyl-6-(3-methyIindol-7- yl)quinoline and cyclohexyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (300MHz, CDCl₃) δ 7.79 (br s, IH), 7.60 (m, IH), 7.21-7.17 (m, 2H), 6.98 (m, IH), 6.21 (dd, J=10.8, 1.3 Hz, IH), 4.77 (d, J=6.7 Hz, IH), 4.67 (d, J=8.2 Hz, IH), 3.93 (br s, IH), 3.51 (m, IH), 2.97 (m, IH), 2.36 (s, 3H), 2.02-1.90 (m, 2H), 1.78-1.67 (m, 2H), 1.62 (m, IH), 1.41 (dd, J=6.4, 1.4 Hz, 3H), 1.37-1.1 1 (m, 5H), 1.28 (s, 3H), 1.17 (s, 3H).

EXAMPLE 9

[0351 J (±)-3β-(3-Cvanophenylcarbamoyloxy)-5J-difluoro-l,2,3,4-tetrahydro-6- (indol-7-yl)-2,2,4α-trimethylquinoline (Compound 109). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α-trimethylquinoline and 3-cyanophenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.06 (s, IH), 7.85 (s, IH), 7.70 (m, IH), 7.58 (m, IH), 7.42 (t, J=7.8 Hz, IH), 7.37 (dd, J=7.8, 1.1 Hz, IH), 7.23-7.16 (m, 3H), 6.86 (br s, IH), 6.60 (m, IH), 6.26 (d, J=10.7 Hz, IH), 4.91 (d, J=5.6 Hz, IH), 4.02 (br s, IH), 3.09 (m, IH), 1.47 (d, J=6.8 Hz, 3H), 1.35 (s, 3H), 1.25 (s, 3H). EXAMPLE 10

[0352) (±)-3β-(4-Cvanophenylcarbamoyloxy)-5J-difluoro-l,2,3,4-tetrahydro-6- (indol-7-yl)-2,2,4α-trimethylquinoline (Compound 110). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α-trimethylquinoline and 4-cyanophenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.04 (br s, IH), 7.67 (m, IH), 7.62 (d, J=8.7 Hz, 2H), 7.55 (d, J=8.7 Hz, 2H), 7.23- 7.17 (m, 3H), 6.92 (br s, IH), 6.60 (dd, J=3.1, 2.1 Hz, IH), 6.26 (d, J=10.5 Hz, IH), 4.92 (d, J=6.3 Hz, IH), 3.09 (m, IH), 1.47 (d, J=6.6 Hz, 3H), 1.35 (s, 3H), 1.25 (s, 3H).

EXAMPLE 11

fO3531 (±)-5,7-Difluoro-1.2.3.4-tetrahvdro-6-(indol-7-yl)-2.2.4α-trimethyl-3β-[4- nitro-2-(trifluoromethyl)phenylcarbamoyloxy1quinoline (Compound 1 11). This compound was prepared from (±)-5,7-difluoro-l ,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α- trimethylquinoline and 4-nitro-2-(trifluoromethyl)phenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.55 (d, J=9.4 Hz, IH), 8.53 (d, J=2.5 Hz, IH), 8.44 (dd, J=9.4, 2.5 Hz, IH), 8.05 (br s, IH), 7.68 (dd, J=7.0, 1.6 Hz, IH), 7.31 (s, I H), 7.23-7.17 (m, 3H), 6.61 (dd, J=3.2, 2.0 Hz, IH), 6.26 (d, J=10.5 Hz, IH), 4.94 (d, J=7.1 Hz, IH), 3.12 (m, IH), 1.48 (d, J=6.8 Hz, 3H), 1.34 (s, 3H), 1.25 (s, 3H).

EXAMPLE 12

103541 (±)-3β-(4-Chlorophenylcarbamoyloxy)-5,7-difluoro-1.2.3.4-tetrahvdro-6- (indol-7-yl)-2,2,4α-trimethylquinoline (^"Compound 112). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α-trimethylquinoline and 4-chlorophenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.05 (br s, IH), 7.67 (m, IH), 7.40-7.34 (m, 2H), 7.29 (d, J=9.0 Hz, 2H), 7.21 (dd, J=3.2, 2.4 Hz, IH), 7.20 (m, IH), 7.18 (t, J=7.0 Hz, IH), 6.71 (br s, IH), 6.60 (dd, J=3.2, 2.1 Hz, IH), 6.25 (d, J=10.7 Hz, IH), 4.89 (d, J=6.3 Hz, IH), 3.08 (qn, J=6.3 Hz, IH), 1.46 (d, J=6.3 Hz, 3H), 1.34 (s, 3H), 1.24 (s, 3H).

EXAMPLE 13

[0355] (±)-3β-(^"2.4-Dimethylphenylcarbamoyloxy)-5,7-difluoro-l,2.3,4- tetrahvdro-6-(indol-7-yl)-2,2,4α-trimethylquinoline (Compound 113). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α- trimethylquinoline and 2,5-dimethylphenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.06 (br s, IH), 7.66 (dd, J=7.2, 1.5 Hz, IH), 7.63 (m, IH), 7.21 (dd, J=3.1, 2.6 Hz, IH), 7.20 (m, IH), 7.18 (t, J=7.2 Hz, IH), 7.04-6.99 (m, 2H), 6.60 (dd, J=3.1, 2.1 Hz, IH), 6.40 (br s, IH), 6.23 (d, J=10.7 Hz, IH), 4.89 (d, J=7.1 Hz, IH), 3.98 (br s, IH), 3.07 (m, IH), 2.29 (s, 3H), 2.24 (s, 3H), 1.46 (d, J=6.3 Hz, 3H), 1.33 (s, 3H), 1.23 (s, 3H).

EXAMPLE 14

[0356] (±)-3β-r3-Chloro-4-methoxyphenylcarbamoyloxy)-5.7-difluoro-1.2.3.4- tetrahydro-6-(indol-7-yD-2,2.4α-trimethylquinoline (Compound 114). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α- trimethylquinoline and 3-chloro-4-methoxyphenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.05 (br s, IH), 7.67 (m, IH), 7.53 (m, IH), 7.25 (m, IH), 7.22-7.16 (m, 3H), 6.88 (d, J=9.0 Hz, IH), 6.60 (dd, J=3.2, 2.0 Hz, IH), 6.60 (m, IH), 6.25 (m, IH), 4.88 (d, J=6.6 Hz, IH), 4.00 (br s, IH), 3.88 (s, 3H), 3.07 (m, IH), 1.46 (d, J=6.8 Hz, 3H), 1.34 (s, 3H), 1.24 (s, 3H).

EXAMPLE 15

[03571 (±)-3β-[2-Chloro-4-(trifluoromethyl)phenylcarbamoyloxy]-5J-difluoro- 1.2,3,4-tetrahvdro-6-(indol-7-yD-2,2,4α-trimethylquinoline (Compound 1 15). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)- 2,2,4α-trimethylquinoline and 2-chloro-4-(trifluoromethyl)phenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.06 (br s, IH), 7.72-7.61 (m, 3H), 7.55 (dd, J=8.6, 1.7 Hz, IH), 7.38 (s, IH), 7.21 (dd, J=3.2, 2.4 Hz, IH), 7.20 (m, IH), 7.19 (t, J=7.2 Hz, IH), 6.60 (dd, J=3.2, 2.2 Hz, IH), 6.26 (m, IH), 4.93 (d, J=6.6 Hz, IH), 4.05 (br s, IH), 3.12 (m, IH), 1.48 (d, J=6.8 Hz, 3H), 1.35 (s, 3H), 1.27 (s, 3H).

EXAMPLE 16

[0358] (±)-5,7-Difluoro-3β-r2-fluoro-6-(trifluoromethyl)phenylcarbamoyloxyl- l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α-trimethylquinoline (Compound 1 16). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)- 2,2,4α-trimethylquinoline and 2-fluoro-6-(trifluoromethyl)phenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.06 (br s, IH), 8.00 (br s, IH), 7.67 (dd, J=7.1, 1.3 Hz, IH), 7.34 (dd, J=8.3, 2.9 Hz, IH), 7.28 (m, IH), 7.21 (dd, J=3.2, 2.5 Hz, IH), 7.20 (m, IH), 7.19 (t, J=7.1 Hz, IH), 6.84 (m, IH), 6.60 (dd, J=3.2, 2.1 Hz, IH), 6.24 (d, J=10.7 Hz, IH), 4.88 (d, J=7.3 Hz, IH), 3.08 (m, IH), 1.46 (dd, J=6.7, 1.3 Hz, 3H), 1.32 (s, 3H), 1.22 (s, 3H).

EXAMPLE 17

[0359] (±)-5J-Difluoro-3β-[4-fluoro-2-(trifluoromethyl)phenylcarbamoyloxy]- l,2,3.4-tetrahvdro-6-(indol-7-yl)-2,2,4α-trimethylquinoline (Compound 117). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)- 2,2,4α-trimethylquinoline and 4-fluoro-2-(trifluoromethyl)phenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.06 (br s, IH), 8.00 (br s, I H), 7.67 (dd, J=7.2, 1.8 Hz, IH), 7.34 (dd, J=8.3, 2.9 Hz, IH), 7.28 (m, IH), 7.21 (dd, J=3.2, 2.5 Hz, IH), 7.20 (m, IH), 7.19 (t, J=7.2 Hz, I H), 6.84 (m, IH), 6.60 (dd, J=3.2, 2.1 Hz, IH), 6.24 (d, J=10.7 Hz, IH), 4.88 (d, J=7.3 Hz, IH), 3.08 (m, IH), 1.46 (dd, J=6.7, 1.3 Hz, 3H), 1.32 (s, 3H), 1.22 (s, 3H).

EXAMPLE 18

[0360] (-fc:)-3β-(2-Chloro-4.6-dimethvbhenylcarbamoyloxy)-5.7-difluoro-1.2.3.4- tetrahvdro-6-(indol-7-yl)-2,2,4α-trimethylquinoline (Compound 1 18). This compound was prepared from (±)-5,7-difluoro-l ,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α- trimethylquinoline and 2-chloro-4,6-dimethylphenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.07 (br s, IH), 7.66 (m, IH), 7.22-7.16 (m, 3H), 7.10 (m, IH), 6.96 (br s, IH), 6.59 (dd, J=3.0, 2.1 Hz, IH), 6.31 (br s, IH), 6.22 (d, J=10.0 Hz, IH), 4.87 (d, J=7.1 Hz, IH), 3.07 (m, IH), 2.29 (s, 3H), 2.28 (s, 3H), 1.45 (m, 3H), 1.33 (s, 3H), 1.25 (s, 3H). EXAMPLE 19

[0361] (±)-3β-[3,5-Bis(trifluoromethyl)phenylcarbamoyloxy1-5,7-difluoro- l,2,3,4-tetrahvdro-6-πndol-7-vn-2,2,4α-trimethylquinoline (Compound 1 19^s). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)- 2,2,4α-trimethylquinoline and 3,5-bis(trifluoromethyl)phenyl isocyanate using General Method 5 (EXAMPLE 1). IH NMR (500MHz, CDC13) δ 8.05 (br s, IH), 7.92 (br s, 2H), 7.67 (m, IH), 7.58 (s, IH), 7.22-7.16 (m, 3H), 7.05 (s, IH), 6.60 (m, IH), 6.25 (d, J=10.7 Hz, IH), 4.92 (d, J=6.3 Hz, IH), 4.03 (s, IH), 3.09 (m, IH), 1.47 (d, J=6.8 Hz, 3H), 1.34 (s, 3H), 1.24 (s, 3H).

EXAMPLE 20

[0362] (±)-3β-f4-(Dimethylamino)phenylcarbamoyloxy1-5.7-difluoro-l,2,3,4- tetrahydro-6-(indol-7-yl)-2,2,4α-trimethylquinoline (Compound 120). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α- trimethylquinoline and 4-(dimethylamino)phenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.06 (br s, IH), 7.66 (dd, J=7.2, 1.5 Hz, IH), 7.30 (m, 2H), 7.21 (dd, J=3.2, 2.4 Hz, IH), 7.20 (m, IH), 7.18 (t, J=7.2 Hz, IH), 6.77 (m, 2H), 6.60 (dd, J=3.2, 2.0 Hz, IH), 6.56 (br s, IH), 6.23 (dd, J=10.9, 1.1 Hz, IH), 4.88 (d, J=6.8 Hz, IH), 3.98 (br s, IH), 3.06 (qn, J=6.8 Hz, IH), 2.93 (s, 6H), 1.46 (dd, J=6.8, 1.0 Hz, 3H), 1.33 (s, 3H), 1.23 (s, 3H). EXAMPLE 21

fO3631 (±V3β-f3-CvclohexylcarbamoyloxyV5.7-difluoro-l,2,3.4-tetrahvdro-6- (indol-7-yl)-2,2,4α-trimethylquinoline (Compound 121V This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α-trimethylquinoline and piperidine using General Method 7 except dichloromethane was used as the solvent instead of toluene. ¹H NMR (500MHz, CDCl₃) δ 8.07 (br s, IH), 7.66 (dd, J=7.1, 1.9 Hz, IH), 7.21 (dd, J=3.2, 2.5 Hz, IH), 7.20 (m, IH), 7.18 (t, J=7.1 Hz, IH), 6.60 (dd, J=3.2, 2.2 Hz, IH), 6.21 (dd, J=10.9, 1.6 Hz, IH), 4.81 (d, J=7.8 Hz, IH), 3.95 (br s, IH), 3.50-3.44 (m, 4H), 2.99 (m, IH), 1.62 (m, 2H), 1.59-1.52 (m, 4H), 1.41 (dd, J=6.8, 1.7 Hz, 3H), 1.27 (s, 3H), 1.18 (s, 3H).

[0364] General Method 7: Formation of a carbamate (Structure 8) from intermediate acyl imidazole and an amine. To a solution of an alcohol (1 equiv) in 20 mL/mmol of dry toluene was added l,l '-carbonyldiimidazole (2 equiv). The reaction was heated to reflux for 3 h then cooled to room temperature. An amine (5 equiv) was added via syringe and the reaction was heated to reflux for 16h, cooled to room temperature and poured into ethyl acetate:water (1: 1 mixture). The aqueous layer was extracted with an additional ethyl acetate, and organic layers were combined and washed with brine, dried over sodium sulfate, and filtered. The residue obtained after evaporation was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 4:1) to give the carbamate. An analytical sample was purified by reverse-phase HPLC (70/30 acetonitrile/water).

EXAMPLE 22

[0365] (±)-6-(3-Chloroindol-7-yl)-3β-(3-chloro-4-methoxyphenylcarbamoyloxy)- 5J-difluoro-l,2,3,4-tetrahvdro-2,2,4α-trimethylquinoline (Compound 122). This compound was prepared from (±)-6-(3-chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy- 2,2,4α-trimethyl quinoline and 3-chloro-4-methoxyphenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 7.97 (br s, IH), 7.66 (m, IH), 7.53 (m, IH), 7.29-7.23 (m, 2H), 7.18 (d, J=2.4 Hz, IH), 6.88 (d, J=8.8 Hz, IH), 6.62 (m, IH), 6.24 (d, J=10.5 Hz, IH), 4.87 (d, J=6.6 Hz, IH), 3.88 (s, 3H), 3.06 (m, IH), 1.45 (dd, J=7.0, 1.0 Hz, 3H), 1.33 (s, 3H), 1.23 (s, 3H).

[0366] (±)-6-(3-Chloroindol-7-vπ-3β-(3-cyanophenylcarbamoyloxy)-5,7- difluoro-l,2,3,4-tetrahvdro-2,2,4α-trimethylquinoline (Compound 123). This compound was prepared from (±)-6-(3-chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α- trimethyl quinoline and cyanophenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 7.95 (br s, IH), 7.67 (m, IH), 7.62 (d, J=8.5 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.29-7.24 (m, 2H), 7.18 (dd, J=2.4 Hz, IH), 6.93 (s, IH), 6.25 (d, J=I 1.0 Hz, IH), 4.91 (d, J=6.8 Hz, IH), 4.04 (br s, IH), 3.08 (qn, J=6.8 Hz, IH), 1.46 (d, J=6.8 Hz, 3H), 1.34 (s, 3H), 1.25 (s, 3H).

EXAMPLE 24

[03671 (±ySβ-KBenzorUidioxol-S-yncarbarnoyloxyl-SJ-difluoro- 1.2.3.4- tetrahydro-6-(indol-7-yl)-2,2,4α-trimethylquinoline (Compound 124). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α- trimethylquinoline and 5-isocyanato-benzo[l,3]dioxole using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.07 (br s, IH), 7.67 (d, 3=7 Λ Hz, IH), 7.22-7.10 (m, 3H), 6.76-6.59 (m, 4H), 6.23 (d, J=IOJ Hz, IH), 5.94 (s, 2H), 4.87 (d, J=6.8 Hz, IH), 3.99 (br s, IH), 3.06 (qn, J=6.8 Hz, IH), 1.45 (d, J=6.8 Hz, 3H), 1.32 (s, 3H), 1.22 (s, 3H). EXAMPLE 25

[0368] (±)-3β-(4-Ethoxycarbonylphenylcarbamoyloxy)-5,7-difluoro-l,2,3,4- tetrahvdro-6-(indol-7-yl)-2,2,4α-trirnethylquinoline (Compound 125^"). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α- trimethylquinoline and 4-(ethoxycarbonyl)phenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.05 (br s, IH), 8.02 (d, J=8.7 Hz, 2H), 7.67 (dd, J=7.0, 1.7 Hz, IH), 7.49 (d, J=8.7 Hz, 2H), 7.21 (dd, J=3.2, 2.4 Hz, IH), 7.20 (m, I H), 7.18 (t, J=7.0 Hz, IH), 6.89 (br s, IH), 6.60 (dd, J=3.2, 2.0 Hz, IH), 6.25 (dd, J=10.9, 1.3 Hz, IH), 4.91 (d, J=6.6 Hz, IH), 4.36 (q, J=7.1 Hz, 2H), 3.99 (br s, IH), 3.09 (m, IH), 1.47 (dd, J=7.0, 0.9 Hz, 3H), 1.39 (t, J=7.1 Hz, 3H), 1.35 (s, 3H), 1.25 (s, 3H).

EXAMPLE 26

[0369] (±)-3β-[3,5-Bis(methoxycarbonvπphenylcarbamoyloxy]-5,7-difluoro- l,2,3,4-tetrahvdro-6-(indol-7-vπ-2,2,4α-trimethylquinoline (Compound 126). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)- 2,2,4α-trimethylquinoline and 5-isocyanato-isophthalic acid dimethyl ester using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.41 (t, J=I .5 Hz, I H), 8.30 (br s, 2H), 8.07 (br s, IH), 7.67 (m, IH), 7.22 (dd, J=3.1, 2.5 Hz, I H), 7.20 (m, IH), 7.18 (t, J=7.1 Hz, IH), 6.93 (br s, IH), 6.60 (dd, J=3.1, 2.0 Hz, IH), 6.25 (dd, J=10.7, 1.0 Hz, IH), 4.93 (d, J=6.7 Hz, IH), 4.00 (br s, IH), 3.95 (s, 6H), 3.10 (qn, J=6.7 Hz, IH), 1.47 (dd, J=6.7, 0.9 Hz, 3H), 1.35 (s, 3H), 1.25 (s, 3H). EXAMPLE 27

103701 (±l-Sβ-O-AcetylphenylcarbamoyloxyVSJ-difluoro-l^J^-tetrahvdro-ό- (indol-7-yl)-2,2,4α-trimethylquinoline (Compound 127). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α-trimethylquinoline and 3-acetylphenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.07 (br s, IH), 7.98 (t, J=I .5 Hz, IH), 7.72-7.65 (m, 3H), 7.43 (t, J=7.9 Hz, IH), 7.21 (dd, J=3.2, 2.4 Hz, IH), 7.20 (m, IH), 7.18 (t, J=7.1 Hz, IH), 6.86 (br s, IH), 6.60 (dd, J=3.2, 2.2 Hz, IH), 6.25 (dd, J=10.7, 1.5 Hz, IH), 4.91 (d, J=6.8 Hz, IH), 4.00 (br s, IH), 3.09 (qn, J=6.8 Hz, IH), 2.61 (s, 3H), 1.47 (dd, J=6.8, 1.1 Hz, 3H), 1.35 (s, 3H), 1.25 (s, 3H).

EXAMPLE 28

rO3711| (±)-3β-f(2.6-Dichloropyrid-4-yl)carbamoyloxyl-5.7-difluoro-1.2.3,4- tetrahvdro-6-(indol-7-yl)-2,2,4α-trimethylquinoline (Compound 128). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α- trimethylquinoline and 2,6-dichloro-4-isocyanato-pyridine using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.03 (br s, IH), 7.67 (m, IH), 7.38 (s, 2H), 7.21 (dd, J=3.2, 2.4 Hz, IH), 7.20-7.16 (m, 2H), 7.03 (s, IH), 6.60 (dd, J=3.2, 2.2 Hz, IH), 6.25 (dd, J=10.7, 1.5 Hz, IH), 4.91 (d, J=6.7 Hz, IH), 4.00 (br s, IH), 3.08 (qn, J=6.7 Hz, IH), 1.46 (dd, J=6.7, 0.9 Hz, 3H), 1.34 (s, 3H), 1.24 (s, 3H). EXAMPLE 29

[0372] (±)-3β-(Benzo[lΛ51thiadiazol-yl)phenylcarbamoyloxy)-5,7-difluoro- l,23,4-tetrahvdro-6-(indol-7-yl)-2.2,4α-trimethylquinoline (Compound 129). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)- 2,2,4α-trimethylquinoline and 4-isocyanato-benzo[l,2,5]thiadiazole using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.20 (m, IH), 8.08 (s, IH), 8.07 (s, IH), 7.67 (dd, J=8.8, 1.0 Hz, IH), 7.67 (m, IH), 7.62 (dd, J=8.8, 7.4 Hz, IH), 7.21 (m, IH), 7.21 (dd, J=3.2, 2.4 Hz, IH), 7.18 (t, J=7.3 Hz, IH), 6.60 (dd, J=3.2, 2.0 Hz, IH), 6.27 (dd, J=I 1.0, 1.5 Hz, IH), 4.98 (d, J=6.8 Hz, IH), 4.02 (br s, IH), 3.15 (qn, J=6.8 Hz, IH), 1.49 (dd, J=6.8, 1.2 Hz, 3H), 1.37 (s, 3H), 1.29 (s, 3H).

EXAMPLE 30

[0373] (±)-5.7-Difluoro- 1.2.3.4-tetrahvdro-6-(indol-7-yl)-2.2.4α-trimethyl-3 β- (pyrazol-3-yl)phenylcarbamoyloxy)quinoline (Compound 130). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α- trimethylquinoline and 3-aminopyrazole using General Method 7 (EXAMPLE 21). ¹H NMR (500MHz, CDCl₃) δ 8.10 (s, IH), 7.90 (m, IH), 7.67 (dd, J=IA , 1.6 Hz, IH), 7.22 (dd, J=3.1, 2.4 Hz, IH), 7.20 (m, IH), 7.18 (t, J=7.1 Hz, IH), 6.60 (dd, J=3.1 2.0 Hz, IH), 6.26 (dd, J=10.7, 1.5 Hz, IH), 5.90 (d, J=2.9 Hz, IH), 5.08 (d, J=7.0 Hz, IH), 4.07 (s, 2H), 3.22 (qn, J=7.0 Hz, IH), 1.47 (dd, J=7.0, 1.5 Hz, 3H), 1.34 (s, 3H), 1.29 (s, 3H). EXAMPLE 31

[0374] (±)-3β-Cyclopropylcarbamoyloxy-5,7-difluoro-l,2,3,4-tetrahydro-6- (indol-7-yO-2,2,4α-trimethylquinoline (Compound 131V This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α-trimethylquinoline and cyclopropylamine using General Method 7 (EXAMPLE 21). ¹H NMR (500MHz, CDCl₃) δ 8.06 (s, IH), 7.66 (m, IH), 7.21 (dd, J=3.2, 2.4 Hz, IH), 7.19 (m, IH), 7.18 (t, J=6.9 Hz, IH), 6.59 (dd, J=3.2, 2.2 Hz, IH), 6.21 (dd, J=10.7, 1.5 Hz, IH), 4.98 (s, IH), 4.79 (d, J=7.1 Hz, IH), 3.96 (br s, IH), 2.98 (m, IH), 2.63 (m, IH), 1.41 (dd, J=6.8, 1.5 Hz, 3H), 1.28 (s, 3H), 1.17 (s, 3H), 0.75 (m, 2H), 0.54 (m, 2H).

EXAMPLE 32

[0375] (±)-5,7-Difluoro-1.2.3.4-tetrahvdro-3β-imidazolyl-6-(indol-7-vn-2.2.4α- trimethylquinoline (Compound 132). This compound was prepared from (±)-5,7-difluoro- l,2,3,4-tetrahydro-3β-hydroxy-6-(indoI-7-yl)-2,2,4α-trimethylquinoline using General Method 7 (EXAMPLE 21) except no amine is added and the acyl imidazole is isolated. ¹H NMR (500MHz, CDCl₃) δ 8.18 (dd, J=0.9, 1.2 Hz, IH), 8.06 (s, IH), 7.68 (m, IH), 7.47 (dd, J=I.2, 1.6 Hz, IH), 7.22 (dd, J=3.2, 2.5 Hz, IH), 7.20 (m, IH), 7.19 (t, J=7.3 Hz, IH), 7.12 (dd, J=0.9, 1.6 Hz, IH), 6.61 (dd, J=3.2, 2.1 Hz, IH), 6.28 (dd, J=10.6, 1.6 Hz, IH), 5.08 (d, J=6.8 Hz, IH), 4.03 (s, IH), 3.20 (qn, J=6.8 Hz, IH), 1.49 (dd, J=6.8, 1.2 Hz, 3H), 1.36 (s, 3H), 1.29 (s, 3H). EXAMPLE 33

[03761 (±)-5,7-Difluoro-1.2.3,4-tetrahvdro-6-(indol-7-vn-2,2.4α-trimethyl-3β-r3- (5-methyl[l,2,41oxadiazol-3-yl)phenylcarbamoyloxy]quinoline (Compound 133). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)- 2,2,4α-trimethylquinoline and 3-(5-methyl[l,2,4]oxadiazol-3-yl)phenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.08 (br s, IH), 8.07 (t, J=1.6 Hz, IH), 7.78 (ddd, J=7.8, 1.6, 1.1 Hz, IH), 7.67 (dd, J=7.2, 1.5 Hz, IH), 7.65 (m, IH), 7.44 (t, J=7.8 Hz, IH), 7.21 (dd, J=3.2, 2.4 Hz, IH), 7.20 (m, IH), 7.18 (t, J=7.2 Hz, I H), 6.84 (br s, IH), 6.60 (dd, J=3.2, 2.0 Hz, IH), 6.25 (dd, J=10.8, 0.9 Hz, IH), 4.92 (d, J=6.8 Hz, IH), 4.01 (br s, IH), 3.09 (qn, J=6.8 Hz, IH), 2.65 (s, 3H), 1.47 (dd, J=6.8, 1.1 Hz, 3H), 1.34 (s, 3H), 1.25 (s, 3H).

EXAMPLE 34

[03771 (±)-3B-(4-Acetylphenylcarbamoyloxy)-5.7-difluoro-1.2.3.4-tetrahvdro-6- (indol-7-yl)-2,2,4α-trimethylquinoline (Compound 134). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α-trimethylquinoline and 4-acetylphenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.06 (s, IH), 7.95 (d, J=8.4 Hz, 2H), 7.67 (m, IH), 7.51 (d, J=8.4 Hz, 2H), 7.22- 7.16 (m, 3H), 6.96 (m, IH), 6.60 (m, IH), 6.26 (d, J=10.7 Hz, IH), 4.92 (d, J=6.8 Hz, IH), 4.00 (br s, IH), 3.09 (qn, J=6.8 Hz, IH), 2.58 (s, 3H), 1.47 (d, J=6.8 Hz, 3H), 1.35 (s, 3H), 1.25 (s, 3H). EXAMPLE 35

[0378] (±V3β-[(6-Chloropyrid-3-vncarbamoyloxyl-5.7-difluoro-1.2.3.4- tetrahydro-6-(indol-7-vD-2,2,4α-trimethylquinoline (Compound 135). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α- trimethylquinoline and 2-chloro-5-isocyanato-pyridine using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.31 (m, IH), 8.10-7.98 (m, 2H), 7.67 (m, IH), 7.31 (d, J=8.5 Hz, IH), 7.22 (dd, J=3.2, 2.4 Hz, I H), 7.19 (m, IH), 7.18 (t, J=7.2 Hz, IH), 6.84 (br s, IH), 6.60 (dd, J=3.2, 2.2 Hz, IH), 6.25 (dd, J=10.9, 1.3 Hz, IH), 4.90 (d, J=6.3 Hz, IH), 3.99 (br s, IH), 3.09 (m, IH), 1.47 (dd, J=6.9, 1.0 Hz, 3H), 1.34 (s, 3H), 1.24 (s, 3H).

EXAMPLE 36

103791 (±)-3β-r(3.5-Dimethylisoxazol-4-vncarbamoyloxyl-5.7-difluoro-1.2,3.4- tetrahydro-6-(indol-7-yl)-2,2,4α-trimethylquinoline (Compound 136). This compound was prepared from (±)-5,7-difiuoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α- trimethylquinoline and 3,5-dimethylisoxazol-4-yl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.05 (s, IH), 7.67 (m, IH), 7.22 (dd, J=3.2, 2.5 Hz, IH), 7.21-7.17 (m, 2H), 6.61 (dd, J=3.2, 2.2 Hz, IH), 6.24 (m, IH), 5.85 (br s, IH), 4.87 (d, J=6.8 Hz, IH), 3.98 (br s, IH), 3.06 (m, IH), 2.35 (s, 3H), 2.22 (s, 3H), 1.45 (m, 3H), 1.33 (s, 3H), 1.24 (s, 3H). EXAMPLE 37

[0380] f-fc't-Sβ-fCvclohexylcarbamoyloxyVy-fluoro-l^JΛ-tetrahvdro-e-dndol-?- yl)-2,2,4α,8-tetramethylquinoline (Compound 137).

[0381] (±)-6-Bromo-7-fluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethylquinoline. This compound was prepared in a manner similar to that described for (±)-6-bromo-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α-trimethylquinoline (EXAMPLE 1) using General Methods 1-3 (EXAMPLE 1) except 3-fluoro-2-methylaniline was used as the aniline starting material.

[0382] (±)-7-Fluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α,8- tetramethylquinoline. This compound was prepared in a manner similar to that for (±)-5,7- difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α-trimethylquinoline (EXAMPLE 1) using General Method 4 (EXAMPLE 1) except (±)-6-bromo-7-f!uoro-l,2,3,4-tetrahydro- 3β-hydroxy-2,2,4α,8-tetramethylquinoline was used as the starting material.

[0383] (±)-3β-(Cyclohexylcarbamoyloxy^')-7-fluoro-l,2,3.4-tetrahvdro-6-(indol-7- yl)-2,2,4α,8-tetramethylquinoline (Compound 137). This compound was prepared from (±)- 7-fluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α,8-tetramethylquinoline and cyclohexyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.22 (s, IH), 7.63 (m, IH), 7.22 (dd, J=3.2, 2.6 Hz, IH), 7.20-7.16 (m, 3H), 6.59 (dd, J=3.2, 2.2 Hz, IH), 4.73 (d, J=10.0 Hz, IH), 4.67 (d, J=8.1 Hz, IH), 3.72 (br s, IH), 3.53 (m, IH), 2.90 (m, IH), 2.10 (d, J=I .5 Hz, 3H), 1.98 (m, 2H), 1.73 (m, 2H), 1.62 (m, 2H), 1.35 (m, 2H), 1.31 (d, J=6.8 Hz, 3H), 1.30 (s, 3H), 1.18 (m, 2H), 1.16 (s, 3H)

EXAMPLE 38

103841 (±)-5.7-Difluoro-1.2.3,4-tetrahydro-6-(indol-7-yl)-2,2.4α-trimethyl-3β- (methylcarbamoyloxy)quinoline (Compound 138). This compound was prepared from (±)- 5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α-trimethylquinoline and cyclopropylamine using General Method 7 (EXAMPLE 21). ¹H NMR (500MHz, CDCl₃) δ 8.05 (br s, IH), 7.66 (m, IH), 7.21 (dd, J=3.1, 2.4 Hz, IH), 7.19 (m, I H), 7.18 (t, J=7.0 Hz, IH), 6.60 (dd, J=3.1, 2.0 Hz, IH), 6.22 (dd, J=I 0.9, 1.3 Hz, IH), 4.79 (d, J=7.0 Hz, IH), 4.72 (d, J=5.0 Hz, IH), 3.94 (br s, IH), 2.98 (qn, J=7.0 Hz, IH), 2.85 (d, J=5.0 Hz, 3H), 1.42 (dd, J=7.0, 1.6 Hz, 3H), 1.29 (s, 3H), 1.17 (s, 3H).

[0385] (±)-6-(3-Chloroindol-7-vn-5,7-difluoro-1.2.3.4-tetrahvdro-2.2.4α- trimethyl-3β-(methylcarbamoyloxy)quinoline (Compound 139). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-6-(indol-7-yl)-2,2,4α-trimethyl-3β- (methylcarbamoyloxy)quinoline according to General Method 6 (EXAMPLE 2). ¹H NMR (500MHz, CDCl₃) δ 7.96 (br s, IH), 7.66 (m, IH), 7.28-7.24 (m, 2H), 7.18 (d, J=2.4 Hz, IH), 6.21 (dd, J=10.9, 1.3 Hz, IH), 4.78 (d, J=6.8 Hz, IH), 4.71 (d, J=5.0 Hz, IH), 2.97 (qn, J=6.8 Hz, IH), 2.85 (d, J=5.0 Hz, 3H), 1.41 (dd, J=6.8, 1.5 Hz, 3H), 1.29 (s, 3H), 1.17 (s, 3H).

EXAMPLE 40

[0386] (±)-3β-(CvclopentylcarbamoyloxyV7-fluoro-l,2Λ4-tetrahvdro-2,2,4α,8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 140).

[0387] (±)-7-Fluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yl)quinoline. This compound was prepared from (±)-6-bromo-7-fluoro- l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline (EXAMPLE 37) and 3-methyl- 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indole using General Method 4 (EXAMPLE

1). yO388] (^"±^N)-3β-(CvclθDentylcarbamoyloxy)-7-fluoro-1.2.3.4-tetrahvdro-2,2,4α,8- tetramethyl-6-(3-methylindol-7-vπquinoline (Compound 140). This compound was prepared from (±)-7-fluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7- yl)quinoline and cyclopentyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (300MHz, CDCl₃) δ 7.99 (br s, IH), 7.61 (m, IH), 7.21-7.15 (m, 3H), 6.97 (d, J=2.3 Hz, IH), 4.78-4.66 (m, 2H), 4.01 (m, IH), 3.70 (br s, IH), 2.97 (m, IH), 2.36 (s, 3H), 2.09 (s, 3H), 1.97 (m, 2H), 1.70-1.55 (m, 4H), 1.42 (m, 2H), 1.30 (d, J=6.8 Hz, 3H), 1.23 (s, 3H), 1.15 (s, 3H).

EXAMPLE 41

[0389] (±)-6-(3 -Chloroindol-7-yl)-3 β-(cyclopentylcarbamoyloxy)-5 J-difluoro- L2,3,4-tetrahydro-2,2,4α-trimethylquinoline (Compound 141). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α-trimethyl-6-(3-methylindol-7- yl)quinoline (EXAMPLE 8) and cyclopentyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (300MHz, CDCl₃) δ 7.96 (br s, IH), 7.66 (m, IH), 7.28-7.21 (m, 2H), 7.18 (d, J=2.7 Hz), 6.21 (d, J=I LO Hz, IH), 4.78-4.70 (m, 2H), 4.03-3.97 (m, 2H), 2.97 (m, IH), 2.10-1.97 (m, 2H), 1.71-1.60 (m, 4H), 1.41 (dd, J=6.8, 1.2 Hz, 3H), 1.28 (s, 3H), 1.17 (s, 3H).

[0390] (±)-3β-(Cyclohexylcarbamoyloxy)-6-(3.5-dimethylisoxazol-4-yl)-5-fluoro- L2,3,4-tetrahydro-2,2,4α.8-tetramethylquinoline (Compound 142). [0391] (±)-6-Bromo-5-fluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethylquinoline. This compound was prepared in a manner similar to that of (±)-6- bromo-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α-trimethylquinoline (EXAMPLE 1) using General Methods 1-3 (EXAMPLE 1) except 5-fiuoro-2-methylaniline was used as the starting material.

[0392] (±)-6-(3,5-Dimethylisoxazol-4-yl)-5-fluoro-l,2,3,4-tetrahydro-3β- hydroxy-2,2,4α,8-tetramethylquinoline. This compound was prepared from (±)-6-bromo-5,7- difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α-tetramethylquinoline and 3,5-dimethyl-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole using General Method 4 (EXAMPLE

1).

[0393] (±)-3β-(Cvclohexylcarbamoyloxy)-6-(3,5-dimethylisoxazol-4-vπ-5-fluoro- l,2,3,4-tetrahydro-2,2,4α,8-tetramethylquinoline (Compound 142). This compound was prepared from (±)-6-(3,5-dimethylisoxazol-4-yl)-5-fluoro-l,2,3,4-tetrahydro-3β-hydroxy- 2,2,4α,8-tetramethylquinoline and cyclohexyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (300MHz, CDCl₃) δ 6.71 (d, J=7.6 Hz, IH), 4.77 (d, J=6.8 Hz, IH), 4.66 (m, IH), 3.63 (br s, IH), 3.51 (m, IH), 2.97 (qn, J=6.8 Hz), 2.32 (s, 3H), 2.20 (s, 3H), 2.09 (s, 3H), 1.98 (m, 2H), 1.74 (m, 2H), 1.61-1.59 (m, 2H), 1.41 (dd, J=6.8, 1.5 Hz, 3H), 1.38-1.30 (m, 2H), 1.29 (s, 3H), 1.20-1.12 (m, 2H), 1.13 (s, 3H).

EXAMPLE 43

[0394] (±)-3β-(4-Acetylphenylcarbamoyloxy)-(3-chloroindol-7-yl)-5J-difluoro- l,2,3,4-tetrahydro-6-2,2,4α-trimethylquinoline (Compound 143). This compound was prepared from (±)-6-(3-chloroindol-7-yl)-5,7-difluoro- 1 ,2,3,4-tetrahydro-3 β-hydroxy-2,2,4α- trimethyl quinoline (EXAMPLE 2) and 4-acetylphenyl isocyanate using General Method 5 (EXAMPLE 1). ^!H NMR (300MHz, CDCl₃) δ 7.96-7.94 (m, 3H), 7.66 (m, IH), 7.53 (m, 2H), 7.27-7.21 (m, 2H), 7.19 (d, J=2.7 Hz, IH), 6.95 (br s, IH), 6.24 (d, J=I 1.0 Hz, IH), 4.91 (d, J=6.8 Hz, IH), 4.03 (br s, IH), 3.1 1 (m, IH), 2.58 (s, 3H), 1.44 (dd, J=6.8, 1.2 Hz, 3H), 1.34 (s, 3H), 1.24 (s, 3H). EXAMPLE 44

[03951 (±V5-Chloro-3β-(cvclohexylcarbamoyloxy)-8-fluoro- 1,2,3, 4-tetrahvdro- 2,2,4α-trimethyl-6-(3-methylindol-7-yQquinoline (Compound 144V

[0396] (±)-6-Bromo-5-chloro-8-fluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethylquinoline. This compound was prepared in a manner similar to that described for (±)-6-bromo-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α-trimethylquinoline (EXAMPLE 1) using General Methods 1-3 (EXAMPLE 1) except 2-fluoro-5-chloroaniline was used as the aniline starting material.

[0397] (±)-5-Chloro-8-fluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)- 2,2,4α,8-tetramethylquinoline. This compound was prepared from (±)-6-bromo-5-chloro-8- fluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline and 7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)indole using General Method 12 (EXAMPLE 52).

[0398] (±)-5-Chloro-3β-(cyclohexylcarbamoyloxy)-8-fluoro-l,2,3,4-tetrahydro- 2,2,4α-trimethyl-6-(3-rnethylindol-7-yl)quinoline (Compound 144). This compound was prepared from (±)-5-chloro-8-fluoro-l ,2,3,4-tetrahydro-3 β-hydroxy-6-(indol-7-yl)-2,2,4α,8- tetramethylquinoline and cyclohexyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 7.76 (s, IH), 7.60 (d, J=7.8, IH), 7.18 (t, J=7.3 Hz, IH), 7.06-7.14 (m, IH), 6.94-7.00 (m, 2H), 4.96 (s, IH), 4.65 (d, J=2.2 Hz, IH), 4.06 (s, IH), 3.51 (s, IH), 3.22 (s, IH), 2.37 (s, 3H), 1.92-1.99 (m, 2H), 1.67-1.75 (m, 2H), 1.52-1.64 (m, 5H), 1.39 (s, 3H), 1.31-1.39 (m, 2H), 1.25 (s, 3H), 1.08-1.20 (m, 2H).

EXAMPLE 45

[0399] (±)-5-Chloro-3β-(cvclopentylcarbamoyloxyV8-fluoro-K2,3,4-tetrahydro- 2,2,4α-trimethyl-6-(3-methylindol-7-yl)quinoline (Compound 145V This compound was prepared from (±)-5-chloro-8-fluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α,8- tetramethylquinoline and cyclopentyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 7.76 (s, IH), 7.60 (d, J=7.7 Hz, IH), 7.18 (t, J=7.3 Hz, IH), 7.06- 7.15 (m, IH), 6.94-7.02 (m, 2H), 4.96 (s, IH), 4.71 (d, J=5.8 Hz, IH), 4.06 (s, IH), 4.01 (s, IH), 3.23 (s, IH), 2.37 (d, J=1.0 Hz, 3H), 1.93-2.02 (m, 2H), 1.53-1.72 (m, 7H), 1.35- 1.45 (s, 5H), 1.24-1.28 (m, 3H).

[04001 (±)-6-(3-Chloroindol-7-yl')-3B-(cvclohexylcarbamoyloxy^')-7.8-difluoro- L2,3,4-tetrahydro-2,2,4α-trimethylquinoline (Compound 146).

[0401] (±)-6-(3-Chloroindol-7-yl)-7,8-difluoro-3β-hydroxy-l,2,3,4-tetrahydro- 2,2,4α-trimethylquinoline. This compound is prepared in a manner similar to (±)-6-(3- chloroindol-7-yl)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α-trimethylquinoline using General Methods 1-6 (EXAMPLES 1 and 2) excepte 2,3-difluoroaniline was used as the starting material.

[0402] (±)-6-(3-Chloroindol-7-vn-3β-(cyclohexylcarbamoyloxyV7.8-difluoro- L2,3,4-tetrahydro-2,2,4α-trimethylquinoline (Compound 146). This compound was prepared from (±)-6-(3-chloroindol-7-yl)-7,8-difluoro-3β-hydroxy-l,2,3,4-tetrahydro-2,2,4α- trimethylquinoline and cyclohexyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (300MHz, CDCl₃) δ 8.10 (br s, IH), 7.66 (m, IH), 7.29-7.21 (m, 3H), 7.05 (d, J=7.3 Hz, IH), 4.75 (d, J=I LO Hz, IH), 4.66 (m, IH), 4.13 (br s, IH), 3.51 (m, IH), 2.97 (m, IH), 1.97 (m, 2H), 1.72 (m, 2H), 1.65-1.58 (m, 2H), 1.41-1.33 (m, 5H), 1.30 (s, 3H), 1.20-1.12 (m, 2H), 1.18 (s, 3H). EXAMPLE 47

[0403] (±yό-β-ChloroindoI^-yO-Sα-^^dimethylamino^phenylcarbamoyloxy]- 7,8-difluoro-l,2,3,4-tetrahydro-2,2,4β-trimethylquinoline (Compound 147). This compound was prepared from (±)-6-(3-chloroindol-7-yl)-7,8-difluoro-3β-hydroxy-l,2,3,4-tetrahydro- 2,2,4α-trimethylquinoline (EXAMPLE 46) and 4-(dimethylamino)phenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (300MHz, CDCl₃) δ 8.12 (br s, IH), 7.66 (dd, J=7.2, 1.5 Hz, IH), 7.30-7.19 (m, 4H), 7.06 (d, J=6.9 Hz, I H), 6.77 (m, 2H), 6.53 (br s, I H), 4.85 (d, J=6.8 Hz, IH), 4.15 (br s, IH), 3.06 (qn, J=6.8 Hz, IH), 2.93 (s, 6H), 1.39 (dd, J=6.8, 1.0 Hz, 3H), 1.35 (s, 3H), 1.23 (s, 3H).

EXAMPLE 48

104041 (±)-3β-(2.2-Dimethylpropionyloxy)-5.7-difluoro-1.2.3,4-tetrahvdro-6- (indol-7-yl)-2,2,4α-trimethylquinoline (Compound 148). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α-trimethylquinoline and pivaloyl chloride in 60% yield using General Method 8. ¹H NMR (300MHz, CDCl₃) δ 8.05 (br s, IH), 7.67 (m, IH), 7.21 (dd, J=3.2, 2.6 Hz, IH), 7.21-7.15 (m, 2H), 6.60 (dd, J=3.2, 2.1 Hz, IH), 6.22 (dd, J=10.8, 1.8 Hz, IH), 4.90 (d, J=8.4 Hz, IH), 3.96 (s, IH), 2.97 (m, IH), 1.34 (dd, J=6.7, 1.9 Hz, 3H), 1.27 (s, 9H), 1.21 (s, 3H), 1.18 (s, 3H).

[0405] General Method 8: Formation of an ester from an alcohol. To a solution of an alcohol (I equiv) in 1 mL of dry pyridine at 0 ⁰C was added an acid chloride or acid anhydride (1.5 equiv). The reaction was allowed to warm to room temperature and stirred an additional 16 h and poured into 10 mL of ethyl acetate:water (1 : 1). The aqueous layer was extracted with an additional 10 mL of ethyl acetate, the organic layers were combined and washed with aqueous CuSO₄ (2 X 10 mL), brine (1 X 20 mL), dried over sodium sulfate, and filtered. The residue obtained after evaporation was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 4: 1) to give the corresponding ester.

EXAMPLE 49

104061 (±)-5,7-Difluoro-1.2.3.4-tetrahvdro-6-(indol-7-vn-2.2.4α-trimethyl-3β- (propionyl oxy)quinoline (Compound 149). (±)-6-Bromo-5,7-difIuoro-l ,2,3,4-tetrahydro- 2,2,4α-trimethyl-3β-(propionyl oxy)quinoline. A solution of (±)-6-bromo-5,7-difluoro- l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α-tetramethylquinoline (30 mg, 1 equiv), propionic anhydride (2 equiv), DMAP (0.1 equiv) and pyridine (1.5 equiv) in dichloromethane was stirred at room temperature for 1 hour. The mixture was washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Flash chromatotraphy afforded (±)-6-bromo-5,7-difluoro- 1,2,3,4- tetrahydro-2,2,4α-trimethyl-3β-(propionyloxy)quinoline.

104071 (±)-5,7-Difluoro-l,2,3,4-tetrahvdro-6-(indol-7-yl)-2,2,4α-trimethyl-3β- (propionyl oxy)quinoline (Compound 149). This compound was prepared from (±)-6- bromo-5,7-difluoro-l,2,3,4-tetrahydro-2,2,4α-trimethyl-3β-(propionyloxy)quinoline and 3- chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indole according to General Method 12 (EXAMPLE 52). ¹H NMR (500MHz, CDCl₃) δ 8.05 (br s, IH), 7.67 (dd, J=7.0, 2.0 Hz, IH), 7.21 (dd, J=3.2, 2.5 Hz, IH), 7.19 (m, IH), 7.18 (t, J=7.0 Hz, IH), 6.60 (dd, J=3.2, 2.1 Hz, IH), 6.23 (dd, J=10.8, 1.5 Hz, IH), 4.94 (d, J=7.6 Hz, IH), 3.95 (br s, IH), 2.98 (dq, J=7.6, 6.8 Hz, IH), 2.43 (q, J=7.6 Hz, 2H), 1.37 (dd, J=6.8, 1.5 Hz, 3H), 1.24 (s, 3H), 1.21 (t, J=7.6 Hz, 3H), 1.18 (s, 3H).

104081 (±)-6-(3-Chloroindol-7-yl)-5J-difluoro-l,23,4-tetrahvdro-2,2,4α- trimethyl-3β-(propionyloxy)quinoline (Compound 150). This compound was prepared from Compound 149 (EXAMPLE 49) using General Method 6 (EXAMPLE 2). IH NMR (500MHz, CDC13) δ 7.97 (br s, IH), 7.66 (m, IH), 7.28-7.24 (m, 2H), 7.18 (d, J=2.7 Hz, IH), 6.22 (dd, J= 10.7, 1.7 Hz, IH), 4.93 (d, J=6.8 Hz, IH), 3.99 (br s, IH), 2.98 (qn, J=6.8 Hz, IH), 2.42 (q, J=7.6 Hz, 2H), 1.37 (dd, J=6.8, 1.6 Hz, 3H), 1.24 (s, 3H), 1.20 (t, J=7.6 Hz, 3H), 1.18 (s, 3H).

EXAMPLE 51

[0409] (±)-3β-[2-(Dimethylamino)ethoxycarbonyloxy]-5,7-difluoro-l,2,3,4- tetrahydro-6-(indol-7-yl)-2,2_i4α-trimethylquinoline (Compound 151). To a solution of (±)- 5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α-trimethylquinoline (30 mg, 0.088 mmol) in 2 mL of dry toluene was added 1,1 '- carbonyldiimidazole (28 mg, 0.175 mmol, 2 equiv). The reaction was heated to reflux for 3 h then cooled to room temperature. N,N-dimethylethanolamine (90 μL, 0.88 mmol, 10 equiv) was added via syringe and the reaction was heated to reflux for 16h, cooled to room temperature and poured into 20 mL of ethyl acetate:water (1 : 1). The aqueous layer was extracted with an additional 10 mL of ethyl acetate, the organic layers were combined and washed with brine (1 X 20 mL), dried over sodium sulfate, and filtered. The residue obtained after evaporation was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 4: 1) to give Compound 151 (15 mg, 38%) as a white powder. An analytical sample was purified by reverse-phase HPLC (60/40 acetonitrile/water). ¹H NMR (500MHz, CDCl₃) δ 8.21 (s, IH), 7.66 (m, IH), 7.21 (dd, J=3.2, 2.5 Hz, IH), 7.18 (m, I H), 7.17 (t, J=7.2 Hz, IH), 6.59 (dd, J=3.2, 2.0 Hz, I H), 6.23 (dd, J=10.7, 1.5 Hz, IH), 4.72 (d, J=6.1 Hz, IH), 4.48 (dt, J=12.3, 5.3 Hz, IH), 4.42 (dt, J=12.3, 5.3 Hz, IH), 3.94 (s, IH), 3.11 (m, IH), 3.07 (t, J=5.3 Hz, 2H), 2.62 (s, 6H), 1.44 (dd, J=7.0, 1.1 Hz, 3H), 1.31 (s, 3H), 1.23 (s, 3H).

EXAMPLE 52

[04101 (E)-6-(3-Chloroindol-7-yl)-5J-difluoro-2,3-dihydro-2.2-dimethyl-lH- quinolin-4-one O-t-butyl oxime (Compound 201a); and (Z)-6-(3-chloroindol-7-yl)-5,7- difluoro-2,3-dihvdro-2,2-dimethyl-lH-quinolin-4-one O-t-butyl oxime (Compound 201b).

[0411] 5,7-Difluoro-l,2-dihydro-2,2-dimethylquinoline was prepared from 3,5- difluoroaniline using General Method 9.

[0412] General Method 9. Copper-catalyzed cyclization of an aniline and a propargyl acetated to form a 1,2-dihydroquinoline. A mixture of an aniline (1 equiv), 3- acetoxy-3-methylbut-l-yne (1.2 equiv), CuCI (0.1 equiv) in THF (0.5-1 M) was heated at reflux for 1-3 days. The mixture was poured into saturated ammonium chloride and extracted with ethyl acetate. The separated aqueous layer was extracted with EtOAc, and the combined organic layers were washed with saturated ammonium chloride, dried over sodium sulfate, filtered, and concentrated. Flash chromatography (20 % hexanes/EtOAc) afforded the 1,2- dihydro-2,2-dimethylquinoline.

[0413] 5,7-Difluoro-2,2-dimethyl-2H-quinoline-l-carboxylic acid /-butyl ester was prepared in 66% yield from 5,7-difluoro-l,2-dihydro-2,2-dimethylquinoline using General Method 10.

[0414] General Method 10. N-Boc-protection of a 1,2-dihydroquinoline. A solution of the 1,2-dihydroquinoline (1 equiv) in ether (0.1 M) was cooled to -78 ⁰C. n- butyllithium (2M in cyclohexanes) was added dropwise. After stirring for 10 min, a solution of di-/-butyl dicarbonate (1.3 equiv) in ether was added, and the mixture was allowed to warm to room temperature and was stirred for 2 hours. The mixture was poured into saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. Flash chromatography (0-20% hexanes/EtOAc) afforded the N-Boc-protected l,2-dihydro-2,2-dimethylquinoline.

[0415] 5,7-Difluoro-4-hydroxy-3,4-dihydro-2,2-dimethyl-2H-quinoline-l- carboxylic acid /-butyl ester was prepared in 89% yield using General Method 2 (EXAMPLE

1).

[0416] 5,7-Difluoro-3,4-dihydro-2,2-dimethyl-4-oxo-2H-quinoline-l-carboxylic acid /-butyl ester was prepared in 40% yield using General Method 11. [0417] General Method 1 1. PCC oxidation of an alcohol to a ketone. A mixture of the alcohol (1 equiv) and pyridinium chlorochromate (1.1 equiv) in dichloromethane (0.3 M) was stirred at room temperature for 4 hours. Silica gel was added to the reaction mixture, and the solvents were removed under reduced pressure. The resultant solid was loaded directly on to a silica gel column and subjected to flash chromatography (0-20% hexanes/EtOAc) to afford the ketone.

[0418] 6-Bromo-5,7-difluoro-3,4-dihydro-2,2-dimethyl-4-oxo-2H-quinoline-l - carboxylic acid t-butyl ester was prepared in 87 % yield using Method 3 (EXAMPLE 1) except DMF was used as the solvent instead of chloroform.

[0419] 6-Bromo-5,7-difluoro-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one is prepared by treating a solution of 6-bromo-5,7-difluoro-3,4-dihydro-2,2-dimethyl-4-oxo-2H- quinoline-1-carboxylic acid /-butyl ester (3.7 g) in 16 mL dichloromethane with 94 mL of a 2:1 solution of dichloromethane:trifluoroacetic acid at 0 ⁰C. The mixture was allowed to warm to room temperature, and stirred for 1 hour. The reaction mixture was quenched with water and extracted with dichloromethane. The aqueous layer was extracted again with dichloromethane. The organic layers were combined and washed first with saturated sodium bicarbonate, then with saturated ammonium chloride, dried over sodium sulfate, and filtered. The solvents were removed under reduced pressure, and the residue purified by flash chromatography (0-25% EtOAc/hexanes).

[0420] 6-(3-Chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-2,2-dimethyl-lH- quinolin-4-one was prepared from 6-bromo-5,7-difluoro-2,3-dihydro-2,2-dimethyl-lH- quinolin-4-one and 3-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indole in 70% yield using General Metlrod 12.

[0421] General Method 12: Palladium-catalyzed Suzuki cross-coupling of an aryl halide and an aryl boronic acid or aryl pinacol boronate. In a reaction flask, a mixture of an aryl bromide (1 equiv); an aryl boronic acid or aryl pinacol boronate (1.0-1.3 equiv); and tetrakis(triphenylphosphine)palladium (0) (3-5 mol %) is flushed with nitrogen. A 2: 1 solution of toluene:ethanol (0.04 M) and 10% sodium carbonate (0.4 M) are introduced sequentially, and the flask if flushed again with nitrogen. The mixture is heated at reflux 16- 24 hours. The mixture is filtered through celite then partitioned between saturated ammonium chloride and EtOAc. The organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (silica gel, EtOAc/hexanes) or preparative ΗPLC (eluting with acetonitrile/water) affords the desired compound.

[0422] (E)-6-(3-Chloroindol-7-yl)-5.7-difluoro-2.3-dihvdro-2,2-dimethyl-lΗ- quinolin-4-one O-t-butyl oxime (Compound 201a); and (Z)-6-(3-Chloroindol-7-yl)-5,7- difluoro-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one O-t-butyl oxime (Compound 201b). These compounds were prepared from 6-(3-chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-2,2- dimethyl-lH-quinolin-4-one and t-butylhydroxylamine HCl using General Method 13.

[0423] General Method 13. Formation of an oxime from a ketone and a hydroxylamine HCl or alkoxyamine HCl salt. A solution of a ketone (1 equiv), a hydroxylamine or alkoxyamine HCl salt (5 equiv), NaOAc (5 equiv) in ethanol (0.03-0.1 M) is stirred at 60 ⁰C for 16-24 hours. The solution was washed with water, and the aqueous layer was extracted with EtOAc. The combined organic layers was washed with saturated ammonium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (0-30% EtOAc/hexanes) or HPLC (acetonitrile/water) afforded the desired compounds.

[0424] Compound 201a: ¹H NMR (300MHz, CDCl₃) δ 8.08 (br s, IH), 7.66 (m, IH), 7.28-7.24 (m, 3H), 7.18 (d, J=2.5 Hz, IH), 6.19 (dd, J=10.8, 1.1 Hz, IH), 4.10 (br s, IH), 2.77 (s, 2H), 1.30 (s, 6H), 1.29 (s, 9H).

[0425] Compound 201b: ¹H NMR (300MHz, CDCl₃) δ 8.10 (br s, IH), 7.65 (m, IH), 7.29-7.24 (m, 2H), 7.12 (d, J=2.5 Hz, IH), 6.15 (d, J=10.7 Hz, IH), 4.27 (br s, IH), 2.48 (s, 2H), 1.36 (s, 9H), 1.29 (s, 6H).

EXAMPLE 53

[0426] (E)-5.7-Difluoro-6-(indol-7-yl)-2,3-dihvdro-2,2-dimethyl-lH-quinolin-4- one oxime (Compound 202). This compound was prepared from 5,7-difluoro-2,3-dihydro- 2,2-dimethyl-6-(indol-7-yl)-lH-quinolin-4-one and hydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (300MHz, CDCl₃) δ 8.1 1 (br s, IH), 7.67 (m, IH), 7.21-7.16 (m, 3H), 6.59 (m, IH), 6.23 (dd, J=10.7, 1.4 Hz, IH), 4.16 (br s, IH), 2.85 (s, 2H), 1.32 (s, 6H).

[04271 (E)-5,7-Difluoro-6-(indol-7-yl)-2,3-dihvdro-2.2-dimethyl-lH-quinolin-4- one O-methyl oxime (Compound 203). This compound was prepared from 5,7-difluoro-2,3- dihydro-2,2-dimethyl-6-(indol-7-yl)-lH-quinolin-4-one and hydroxylamine hydrochloride using General Method 13 (EXAMPLE 52) and O-methylhydroylamine. ¹H NMR (300MHz, CDCl₃) δ 8.14 (s, IH), 7.65 (m, IH), 7.21-7.13 (m, 3H), 6.58 (dd, J=3.2, 2.1 Hz, IH), 6.20 (dd, J=10.7, 1.6 Hz, IH), 4.13 (br s, IH), 3.94 (s, 3H), 2.79 (s, 2H), 1.31 (s, 6H).

EXAMPLE 55

[04281 (E)-6-(3-Chloroindol-7-yl)-5J-difluoro-2,3-dihvdro-2,2-dimethyl-lH- quinolin-4-one O-methyl oxime (Compound 204). This compound was prepared from 6-(3- chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one and O- methylhydroylamine. ¹H NMR (300MHz, CDCl₃) δ 8.08 (s, IH), 7.65 (m, IH), 7.27-7.23 (m, 2H), 7.17 (d, J=2.5 Hz, IH), 6.21 (dd, J=10.8, 1.7 Hz, IH), 4.16 (br s, IH), 3.94 (s, 3H), 2.78 (s, 2H), 1.31 (s, 6H).

EXAMPLE 56

[0429] (E)-5,7-Difluoro-6-(indol-7-yl)-2,3-dihvdro-2.2-dlmethyl-lH-quinolin-4- one O-carboxymethoxy oxime (Compound 205). This compound was prepared from 5,7- difluoro-2,3-dihydro-2,2-dimethyl-6-(indol-7-yl)-lH-quinolin-4-one and hydroxylamine hydrochloride using General Method 13 (EXAMPLE 52) and aminooxyacetic acid hydrochloride. ¹H NMR (300MHz, CDCl₃) δ 8.16 (s, IH), 7.66 (m, IH), 7.20 (dd, J=3.1, 2.5 Hz, IH), 7.18-7.15 (m, 2H), 6.58 (dd, J=3.1, 2.1 Hz, IH), 6.21 (dd, J=10.7, 1.6 Hz, IH), 4.69 (s, 2H), 2.89 (s, 2H), 1.35 (s, 6H). EXAMPLE 57

[0430] (E)-5,7-Difluoro-6-findol-7-vn-2,3-dihvdro-2.2-dimethyl-lH-quinolin-4- one O-allyl oxime (Compound 206^*). This compound was prepared from 5,7-difluoro-2,3- dihydro-2,2-dimethyl-6-(indol-7-yl)-lH-quinolin-4-one and O-allylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (300MHz, CDCl₃) δ 8.16 (br s, IH), 7.66 (m, IH), 7.21-7.13 (m, 3H), 6.58 (dd, J=3.2, 2.1 Hz, IH), 6.20 (dd, J=10.7, 1.8 Hz, IH), 6.03 (ddt, J=I 7.3, 10.4, 5.7 Hz, IH), 5.29 (ddt, J=17.3, 1.6, 1.4 Hz, I H), 5.19 (ddt, J=10.4, 1.6, 1.4 Hz, IH), 4.64 (dt, J=5.7, 1.4 Hz, 2H), 4.13 (br s, IH), 2.82 (s, 2H), 1.31 (s, 6H).

EXAMPLE 58

[04311 (E)-5,7-Difluoro-6-(indol-7-yl)-2.3-dihvdro-2.2-dimethyl-lH-quinolin-4- one O-ethyl oxime (Compound 207). This compound was prepared from 5,7-difluoro-2,3- dihydro-2,2-dimethyl-6-(indol-7-yl)-lH-quinolin-4-one and O-ethylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (300MHz, CDCl₃) δ 8.17 (br s, IH), 7.66 (m, IH), 7.21-7.13 (m, 3H), 6.58 (dd, J=3.2, 2.1 Hz, IH), 6.19 (dd, J=10.7, 1.6 Hz, IH), 4.18 (q, J=7.0 Hz, 2H), 4.15 (br s, IH), 2.80 (s, 2H), 1.31 (s, 6H), 1.28 (t, J=7.0 Hz, 3H).

EXAMPLE 59

[04321 (E)- 5J-Difluoro-6-(indol-7-yl)-23-dihydro-2.2-dimethyl-lH-quinolin-4- one O-f-butyl oxime (Compound 208). This compound was prepared from 5,7-difIuoro-2,3- dihydro-2,2-dimethyl-6-(indol-7-yl)-lH-quinolin-4-one and O-/-butylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (300MHz, CDCl₃) δ 8.16 (br s, IH), 7.66 (m, IH), 7.23-7.14 (m, 3H), 6.59 (dd, JN3.0, 2.3 Hz, IH), 6.19 (dd, J=I 0.7, 1.7 Hz, IH), 4.08 (br s, IH), 2.77 (s, 2H), 1.37 (s, 3H), 1.29 (s, 9H), 1.30 (s, 3H).

EXAMPLE 60

fO4331 (E)-5,7-Difluoro-6-(indol-7-yl)-2,3-dihvdro-2,2-dimethyl-lH-quinolin-4- one 6>-phenyl oxime (Compound 209). This compound was prepared from 5,7-difluoro-2,3- dihydro-2,2-dimethyl-6-(indol-7-yl)-lH-quinolin-4-one and O-phenylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (300MHz, CDCl₃) δ 8.14 (br s, IH), 7.69 (m, IH), 7.28-7.19 (m, 7H), 6.98 (m, IH), 6.61 (dd, J=3.2, 2.1 Hz, I H), 6.25 (dd, J=10.6, 1.7 Hz, IH), 4.23 (br s, IH), 3.02 (s, 2H), 1.38 (s, 6H).

EXAMPLE 61

104341 (E)-8-Chloro-6-(3-chloroindol-7-yl)-5.7-difluoro-2,3-dihydro-2,2- dimethyl-lH-quinolin-4-one O-allyl oxime (Compound 210). This compound was prepared from 8-chloro-5,7-difluoro-2,3-dihydro-2,2-dimethyl-6-(indol-7-yl)-lH-quinolin-4-one and O-allylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (300MHz, CDCl₃) δ 8.08 (br s, IH), 7.68 (m, IH), 7.35-7.22 (m, 2H), 7.18 (d, J=2.6 Hz, IH), 6.02 (ddt, J=17.2, 10.4, 5.8 Hz, IH), 5.30 (ddt, J=17.2, 1.6, 1.4 Hz, IH), 5.21 (ddt, J=10.4, 1.6, 1.4 Hz, IH), 4.80 (br s, IH), 4.65 (dt, J=5.8, 1.4 Hz, 2H), 2.84 (s, 2H), 1.36 (s, 6H). EXAMPLE 62

[0435] (E)-8-Chloro-6-(3-chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-2,2- dimethyl-lH-quinolin-4-one O-t-butyl oxime (Compound 21 1). This compound was prepared from 8-chloro-5,7-difluoro-2,3-dihydro-2,2-dimethyl-6-(indol-7-yl)-lH-quinolin-4- one and O-allylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (300MHz, CDCl₃) δ 8.05 (br s, IH), 7.68 (m, IH), 7.32-7.27 (m, 2H), 7.19 (d, J=2.6 Hz, IH), 4.75 (s, IH), 2.79 (s, 2H), 1.35 (s, 3H), 1.35 (s, 3H), 1.29 (s, 9H).

EXAMPLE 63

rO436] (E)-8-Chloro-6-(3-chloroindol-7-yl)-5,7-difluoro-2.3-dihvdro-2,2- dimethyl-lH-quinolin-4-one O-phenyl oxime (Compound 212). This compound was prepared from 8-chloro-5,7-difluoro-2,3-dihydro-2,2-dimethyl-6-(indol-7-yl)-lH-quinolin-4- one and O-allylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (300MHz, CDCl₃) δ 8.03 (br s, IH), 7.71 (m, IH), 7.32-7.27 (m, 6H), 7.20 (d, J=2.5 Hz, IH), 7.00 (m, IH), 4.90 (br s, IH), 3.05 (s, 2H), 1.43 (s, 6H).

EXAMPLE 64

[0437] (EV(±)-6-(3-Chloroindol-7-yl)-5.7-difluoro-2,3-dihydro-3-hvdroxy-2,2- dimethyl-lH-quinolin-4-one O-ethyl oxime (Compound 213a) and (Z)-(±)-6-(3-chloroindol- 7-vπ-5,7-difluoro-2,3-dihvdro-3-hydroxy-2,2-dimethyl-lH-quinolin-4-one O-ethyl oxime (Compound 213b).

[0438] (±)-5,7-Difluoro-3,4-dihydroxy-3,4-dihydro-2,2-dimethyl-2H-quinoline-l- carboxylic acid /-butyl ester. This compound was prepared from 5,7-difluoro-2,2-dimethyl- 2H-quinoline-l-carboxylic acid /-butyl ester using Method 14 (EXAMPLE 64).

[0439] General Method 14: Dihydroxylation of an olefin. A mixture of an olefin (1.0 equiv), K₃Fe(CN)₆ (3 equiv), potassium carbonate (3 equiv), methanesulfonamide (10 equiv), osmium tetroxide (0.1 equiv) and pyridine (2 equiv) in t-butanol:water (1 : 1, 0.1 M) was stirred at room temperature overnight. The mixture was treated with excess sodium sulfite, water, and TΗF and stirred for 3 hours. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated ammonium chloride, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography (0-50% ethyl acetate:hexanes) afforded the desired diol.

[0440] (±)-6-Bromo-5,7-difluoro-3,4-dihydroxy-3,4-dihydro-2,2-dimethyl-2H- quinoline-1-carboxylic acid /-butyl ester. This compound was prepared from 5,7-difluoro- 3,4-dihydroxy-3,4-dihydro-2,2-dimethyl-2H-quinoline-l-carboxylic acid /-butyl ester using Method 3 (EXAMPLE 1) except DMF was used as the solvent.

[0441] (±)-6-Bromo-5,7-difluoro-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-oxo-2H- quinoline-1-carboxylic acid /-butyl ester. This compound was prepared from (±)-6-bromo- 5,7-difluoro-3,4-dihydroxy-3,4-dihydro-2,2-dimethyl-2H-quinoline-l-carboxylic acid /-butyl ester in 47% yield using General Method 15 (EXAMPLE 64).

[0442] General Method 15: Oxidation of an alcohol with 2-iodoxybenzoic acid. A solution of a diol (1 equiv), 2-iodoxybenzoic acid (1.1 equiv) in ethyl acetate (0.05 M) was heated at reflux for 6 hours. The precipitate was filtered, and water was added to the filtrate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated ammonium chloride, dried over sodium sulfate, and concentrated. Flash chromatography (0-25% ethyl acetate:hexanes) afforded the desired ketone.

[0443] (±)-6-Bromo-5,7-difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-lH- quinolin-4-one. This compound is prepared by is prepared by treating a solution of (±)-6- bromo-SJ-difluoro-S^-dihydro-S-hydroxy^^-dimethyM-oxo^H-quinoline-l-carboxylic acid /-butyl ester (1.3 g, 1.0 equiv) in 5 mL dichloromethane with 31 mL of a 2:1 solution of dichloromethaneitrifluoroacetic acid at 0 ⁰C. The mixture was allowed to warm to room temperature, and stirred for 1 hour. The reaction mixture was quenched with water and extracted with dichloromethane. The aqueous layer was extracted again with dichloromethane. The organic layers were combined and washed first with saturated sodium bicarbonate, then with saturated ammonium chloride, dried over sodium sulfate, and filtered. The solvents were removed under reduced pressure, and the residue purified by flash chromatography (0-25% EtOAc/hexanes).

[0444] (±)-6-(3-Chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-3-hydroxy-2,2- dimethyl-lH-quinolin-4-one. This compound was prepared from (±)-6-bromo-5,7-difluoro- 2,3-dihydro-3-hydroxy-2,2-dimethyl-lH-quinolin-4-one and 3-chloro-7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)indole in 70% yield using General Method 12 (EXAMPLE 52).

[0445] (EV(±)-6-G-Chloroindol-7-vn-5.7-difluoro-2.3-dihvdro-3-hvdroxy-2.2- dimethyl-lΗ-quinolin-4-one O-ethyl oxime (Compound 213a) and (Z)-(-t-)-6-(3-chloroindol- 7-yl)-5,7-difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-lH-quinolin-4-one O-ethyl oxime (Compound 213b). These compounds were prepared from (±)-6-(3-chloroindol-7-yl)-5,7- difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-lH-quinolin-4-one and O-ethylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52).

[0446] Compound 213a: ¹H NMR (300MHz, CDCl₃) δ 7.84 (br s, IH), 7.60 (m, IH), 7.20-7.16 (m, 2H), 6.97 (m, IH), 6.26 (dd, J= 10.6, 1.5 Hz, IH), 4.95 (s, IH), 4.31 (s, IH), 4.25 (q, J=7.0 Hz, 2H), 1.37 (s, 3H), 1.35 (t, J=7.0 Hz, 3H), 1.21 (s, 3H).

[0447] Compound 213b: ¹H NMR (300MHz, CDCl₃) δ 8.06 (br s, IH), 7.62 (m, IH), 7.24-7.22 (m, 2H), 7.18 (m, IH), 6.26 (dd, J=10.6, 1.5 Hz, IH), 4.95 (s, I H), 4.18 (q, J=7.0 Hz, 2H), 4.08 (s, IH), 1.41 (s, 3H), 1.28 (t, J=7.0 Hz, 3H), 1.22 (s, 3H).

EXAMPLE 65

104481 (EV(±)-5.7-Difluoro-2,3-dihvdro-3-hvdroxy-2,2-dimethyl-6-(3- methylindol-7-yl)-lH-quinolin-4-one O-t-butyl oxime (Compound 214a) and (Z)-(±)-5,7- difluoro-2,3-dihvdro-3-hvdroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one Q-/- butyl oxime (Compound 214b). (±)-5,7-Difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-6-(3- methylindol-7-yl)-lH-quinolin-4-one. This compound was prepared from (±)-6-bromo-5,7- difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-lH-quinolin-4-one and 3-methyl-7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)indole using General Method 12 (EXAMPLE 52). 104491 (E)-(±)-5.7-Difluoro-2,3-dihydro-3-hvdroxy-2.2-dimethyl-6-(3- methylindol-7-yO-lH-quinolin-4-one O-t-butyl oxime (Compound 214a) and (Z)-(±)-5J- difluoro-2.3-dihvdro-3-hvdroxy-2,2-dimethyl-6-(3-methylindol-7-vπ-lH-quinolin-4-one 0-/- butyl oxime (Compound 214b). These compounds were prepared from (±)-5,7-difluoro-2,3- dihydro-3-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one and O-t- butylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52).

[0450] Compound 214a: ¹H NMR (300MHz, CDCl₃) δ 7.89 (br s, IH), 7.60 (dd, J=7.1, 1.5 Hz, IH), 7.21 (m, IH), 7.18 (t, J=7.1 Hz, IH), 6.93 (q, J= 1.1 Hz, IH), 6.16 (dd, J=I LO, 1.2 Hz, IH), 4.36-4.22 (m, 2H), 2.36 (d, J=Ll Hz, 3H), 1.37 (s, 9H), 1.36 (s, 3H), 1.15 (s, 3H).

[0451] Compound 214b: ¹H NMR (300MHz, CDCl₃) δ 7.84 (s, IH), 7.61 (m, IH), 122-1 Al (m, 2H), 6.98 (s, IH), 6.25 (d, J= 10.6 Hz, IH), 4.93 (s, IH), 4.02 (s, IH), 2.64 (s, IH), 2.36 (s, 3H), 1.40 (s, 3H), 1.31 (s, 9H), 1.22 (s, 3H).

EXAMPLE 66

[04521 (E)-(±)-5.7-Difluoro-2,3-dihvdro-3-hvdroxy-2,2-dimethyl-6-(3- methylindol-7-yl)-lH-quinolin-4-one O-methyl oxime (Compound 215a) and (Z)-(±)-5.7- difluoro-2,3-dihvdro-3-hvdroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one O- methyl oxime (Compound 215b). These compounds were prepared from (±)-5,7-difluoro- 2,3-dihydro-3-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one and O- methylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52).

[0453] Compound 215a: ¹H NMR (300MHz, CDCl₃) δ 7.83 (br s, IH), 7.61 (m, IH), 7.22-7.15 (m, 2H), 6.97 (m, IH), 6.18 (dd, J=10.9, 1.0 Hz, IH), 4.31-4.25 (m, 2H), 3.97 (s, 3H), 2.36 (s, 3H), 1.36 (s, 3H), 1.21 (s, 3H).

[0454] Compound 215b: ¹H NMR (300MHz, CDCl₃) δ 7.84 (br s, IH), 7.60 (m, IH), 7.20-7.16 (m, 2H), 6.97 (m, IH), 6.26 (dd, J=I 0.6, 1.5 Hz, IH), 4.95 (s, IH), 4.08 (s, IH), 3.97 (s, 3H), 2.35 (d, J=0.6 Hz, 3H), 1.41 (s, 3H), 1.22 (s, 3H). EXAMPLE 67

[04551 (E)-(±)-5J-Difluoro-23-dihvdro-3-hydroxy-2.2-dimethyl-6-(3- methylindol-7-yl)-lH-quinolin-4-one O-ethyl oxime (Compound 216a) and (Z)-(±)-5,7- difluoro-2,3-dihvdro-3-hvdroxy-2,2-dimethyl-6-(3-methylindol-7-vπ-lH-quinolin-4-one O- ethyl oxime (Compound 216b). These compounds were prepared from (±)-5,7-difluoro-2,3- dihydro-3-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one and O- ethylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52).

[0456] Compound 216a: ¹H NMR (300MHz, CDCl₃) δ 7.86 (s, IH), 7.61 (m, IH), 7.23-7.16 (m, 2H), 6.96 (q, J=1.0 Hz, IH), 6.18 (dd, J=10.8, 1.5 Hz, IH), 4.29-4.25 (m, 2H), 4.24 (q, J=7.1 Hz, 2H), 2.36 (d, J=I.0 Hz, 3H), 1.36 (s, 3H), 1.32 (t, J=7.1 Hz, 3H), 1.20 (s, 3H).

[0457] Compound 216b: ¹H NMR (300MHz, CDCl₃) δ 7.84 (s, IH), 7.60 (m, IH), 7.21-7.14 (m, 2H), 6.97 (q, J=LO Hz, IH), 6.25 (dd, J=10.5, 1.5 Hz, IH), 4.96 (s, IH), 4.22 (q, J=7.0 Hz, 2H), 4.07 (s, IH), 2.45 (m, IH), 2.35 (d, J=LO Hz, 3H), 1.41 (s, 3H), 1.30 (t, J=7.0 Hz, 3H), 1.22 (s, 3H).

EXAMPLE 68

[04581 (Z)-(±)-6-(3-Chloroindol-7-yl)-5.7-difluoro-2,3-dihvdro-3-hvdroxy-2,2- dimethyl-lH-quinolin-4-one O-methyl oxime (Compound 217). This compound was prepared from (±)-6-(3-chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl- lH-quinolin-4-one (EXAMPLE 64) and O-methylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (300MHz, CDCl₃) δ 7.84 (br s, IH), 7.60 (m, IH), 7.20-7.16 (m, 2H), 6.97 (m, IH), 6.26 (dd, J=10.6, 1.5 Hz, IH), 4.95 (s, IH), 4.08 (s, IH), 3.97 (s, 3H), 1.41 (s, 3H), 1.22 (s, 3H). EXAMPLE 69

[0459] (ZV(±)-5J-Difluoro-23-dihvdro-2.2-dimethyl-6-(3-methylindol-7-yl)-3- (phenylcarbamovDoxy-lH-quinolin-4-one O-ethyl oxime (Compound 218). This compound was prepared from Compound 216b (EXAMPLE 67) and phenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (300MHz, CDCl₃) δ 7.88 (br s, IH), 7.60 (m, IH), 7.42 (d, J=7.3 Hz, 2H), 7.33 (t, J=7.3 Hz, 2H), 7.21-7.14 (m, 2H), 7.18 (t, J=7.2 Hz, IH), 6.97 (q, J=LO Hz, IH), 6.38 (dd, J=3.2, 2.1 Hz, IH), 6.25 (dd, J=10.5, 1.5 Hz, IH), 4.22 (s, 2H), 4.08 (s, IH), 2.35 (d, J=LO Hz, 3H), 1.41 (s, 3H), 1.29 (t=7.0 Hz, 3H), 1.22 (s, 3H).

EXAMPLE 70

[04601 (E)-(±)-7.8-Difluoro-2.3-dihvdro-2,2-dimethyl-6-(3-methylindol-7-yl)-3- hydroxy-lH-quinolin-4-one O-methyl oxime (Compound 219a) and (Z)-(±)-7,8-difluoro- 2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-3-hydroxy-lH-quinolin-4-one O-methyl oxime (Compound 219b).

[0461] (±)-6-Bromo-7,8-difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-lH- quinolin-4-one. This compound was prepared in a manner similar to (±)-6-bromo-5,7- difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-lH-quinolin-4-one (EXAMPLE 64) except that 2,3-difluoroaniline was used as the starting material.

[0462] (±)-7,8-Difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-6-(3-methylindol-7- yl)-lH-quinolin-4-one. This compound was prepared from (±)-6-bromo-7,8-difluoro-2,3- dihydro-3-hydroxy-2,2-dimethyl-lH-quinolin-4-one and 3-methyl-7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)indole using General Method 12 (EXAMPLE 52). [04631 (E)-(±)-7,8-Difluoro-23-dihvdro-2,2-dimethyl-6-(3-methylindol-7-yl)-3- hydroxy-lH-quinolin-4-one O-methyl oxime (Compound 219a) and (Z)-(±)-7,8-difluoro- 2,3-dihvdro-2,2-dimethyl-6-(3-methylindol-7-ylV3-hvdroxy-lH-quinolin-4-one O-methyl oxime (Compound 219b). These compounds were prepared from (±)-7,8-difluoro-2,3- dihydro-3-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one and O- methylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52).

[0464] Compound 219a: ¹H NMR (500MHz, CDCl₃) δ 8.40 (dd, J=7.3, 1.9 Hz, IH), 8.01 (s, IH), 7.60 (t, J=4.8 Hz, IH), 7.18-7.24 (m, 2H), 7.00 (q, J=I .0 Hz, IH), 4.42 (s, IH), 4.21 (d, J=5.6 Hz, IH), 3.97 (s, 3H), 3.46 (d, J=4.4 Hz, IH), 2.37 (d, J= 1.4 Hz, 3H), 1.41 (s, 3H), 1.23 (s, 3H).

[0465] Compound 219b: ¹H NMR (500MHz, CDCl₃) δ 7.97(s, IH), 7.80 (dd, J=6.8, 2.4 Hz, IH), 7.60 (dd, J=6.9, 2.9 Hz, IH), 7.18-7.24 (m, 2H), 7.01 (q, J=LO Hz, I H), 4.81 (dd, J=7.8, 1.5 Hz, IH), 4.12 (s, IH), 3.96 (s, 3H), 2.52 (d, J=7.3 Hz, IH), 2.37 (s, 3H), 1.46 (s, 3H), 1.22 (s, 3H).

EXAMPLE 71

[04661 (E)-(±)-7,8-Difluoro-2.3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-3- (phenylcarbamoyl)oxy-lH-quinolin-4-one O-ethyl oxime (Compound 220a) and (Z)-(±)-7,8- Difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-3-(phenylcarbamoyl)oxy-lH- quinolin-4-one O-ethyl oxime (Compound 220b). These compounds were prepared from (±)- 7,8-difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one and O-ethylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52).

[0467] Compound 220a: ¹H NMR (500MHz, CDCl₃) δ 8.46 (dd, J=7.8, 2.5 Hz, IH), 8.07 (s, IH), 7.60 (dd, J=8.3, 1.0 Hz, IH), 7.18-7.24 (m, 2H), 6.99 (q, J=LO Hz, IH), 4.42 (d, J=2.0 Hz, IH), 4.23 (q, J=6.8 Hz, 2H), 3.54 (d, J=4.4 Hz, IH), 2.37 (d, J=LO Hz, 3H), 1.41 (s, 3H), 1.31 (t, J=7.3 Hz, 3H), 1.22 (s, 3H).

[0468] Compound 220b: ¹H NMR (500MHz, CDCl₃) δ 7.98 (s, IH), 7.80 (dd, J=8.3, 1.9 Hz, IH), 7.60 (dd, J=5.9, 2.0 Hz, IH), 7.18-7.22 (m, 2H), 7.00 (q, J=1.7 Hz, IH), 4.83 (dd, J=6.9, 1.4 Hz, IH), 4.21 (q, J=6.9 Hz, 2H), 4.12 (s, IH), 2.63 (d, J=7.9 Hz, I H), 2.37 (s, 3H), 1.46 (s, 3H), 1.30 (t, J=6.8 Hz, 3H), 1.22 (s, 3H).

EXAMPLE 72

104691 (E)-5,7-Difluoro-2.3-dihvdro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH- quinolin-4-one O-/-butyl oxime (Compound 221a) and (Z)-5,7-difluoro-2,3-dihydro-2,2- dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one O-f-butyl oxime (Compound 221b). These compounds were prepared from 5,7-difluoro-2,3-dihydro-2,2-dimethyl-6-(3- methylindol-7-yl)-lH-quinolin-4-one and O-r-butylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52).

[0470] Compound 221a: ¹H NMR (500MHz, CDCl₃) δ 7.87 (br s, IH), 7.60 (m, IH), 7.21-7.16 (m, 2H), 6.97 (q, J=I .0 Hz, IH), 6.18 (dd, J=10.7, 1.5 Hz, IH), 4.06 (br s, IH), 2.77 (s, 2H), 2.36 (d, J=LO Hz, 3H), 1.30 (s, 6H), 1.29 (s, 9H).

[0471] Compound 221b: ¹H NMR (500MHz, CDCl₃) δ 7.93 (s, IH), 7.59 (ddd, J=7.5, 1.4, 0.6 Hz, IH), 7.21 (ddd, J=7.5, 2.0, 1.4 Hz, IH), 7.18 (t, J=7.5 Hz, IH), 6.92 (q, J=Ll Hz, IH), 6.14 (dd, J=I LO, 1.5 Hz, IH), 4.22 (br s, IH), 2.48 (s, 3H), 2.36 (d, J=Ll Hz, 3H), 1.36 (s, 9H), 1.29 (s, 6H).

EXAMPLE 73

[04721 (E)-5,7-Difluoro-2.3-dihvdro-2,2-dimethyl-6-(3-methylindol-7-vn-lH- quinolin-4-one O-benzyl oxime (Compound 222). This compound was prepared from 5,7- difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one and O- benzylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (500MHz, CDCl₃) δ 7.85 (br s, IH), 7.60 (m, IH), 7.40-7.28 (m, 5H), 7.20-7.15 (m, 2H), 6.96 (q, J=1.0 Hz, IH), 6.18 (dd, J=10.7, 1.5 Hz, IH), 5.17 (s, 2H), 4.10 (br s, IH), 2.82 (s, 2H), 2.36 (d, J=I .0 Hz, 3H), 1.28 (s, 6H).

EXAMPLE 74

(04731 (E)-5,7-Difluoro-2.3-dihvdro-2.2-dimethyl-6-(3-methylindol-7-yl)-lH- quinolin-4-one O-phenyl oxime (Compound 223). This compound was prepared from 5,7- difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one and O- phenylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (500MHz, CDCl₃) δ 7.86 (br s, IH), 7.63 (m, IH), 7.29-7.23 (m, 4H), 7.22-7.18 (m, 2H), 7.00-6.95 (m, 2H), 6.25 (dd, J=10.5, 1.5 Hz, IH), 4.21 (br s, IH), 3.02 (s, 2H), 2.37 (d, J=I .0 Hz, 3H), 1.38 (s, 6H).

EXAMPLE 75

[0474| (E)-5.7-Difluoro-2,3-dihvdro-2.2-dimethyl-6-(3-methylindol-7-yl)-l H- quinolin-4-one oxime (Compound 224). This compound was prepared from 5,7-difluoro-2,3- dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one and hydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (500MHz, CDCl₃) δ 10.18 (s, IH), 9.86 (s, IH), 7.53 (m, IH), 7.09 (t, J=7.4 Hz, IH), 7.07 (q, J=Ll Hz, IH), 7.05 (m, IH), 6.35 (dd, J=I 1.3, 1.6 Hz, IH), 5.95 (br s, IH), 2.84 (s, 2H), 2.32 (d, J=Ll Hz, 3H), 1.30 (s, 6H). EXAMPLE 76

[04751 (EV5J-Difluoro-23-dihydro-2.2-dimethyl-6-(3-methylindol-7-yl)-lH- quinolin-4-one O-isopropyl oxime (Compound 225). This compound was prepared from 5,7- difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH-quinolin-4-one and O- isopropylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (500MHz, CDCl₃) δ 7.86 (br s, IH), 7.59 (m, IH), 7.19 (m, IH), 7.17 (t, J=7.0 Hz, IH), 6.96 (q, J=Ll Hz, IH), 6.19 (dd, J=10.7, 1.5 Hz, IH), 4.39 (sept, J=6.3 Hz, IH), 4.09 (s, IH), 2.79 (s, 2H), 2.35 (d, J=Ll Hz, 3H), 1.31 (s, 6H), 1.25 (d, J=6.3 Hz, 6H).

EXAMPLE 77

[04761 (E)-5J-Difluoro-2,3-dihvdro-2,2-dimethyl-6-(3-methylindol-7-yl)-lH- quinolin-4-one O-(l-ethoxycarbonyl-l-methyl)ethyl oxime (Compound 226). This compound was prepared from 5,7-difluoro-2,3-dihydro-2,2-dimethyl-6-(3-methylindol-7-yl)- lH-quinolin-4-one and ethyl 2-aminooxy-2-methylpropionate hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (300MHz, CDCl₃) δ 7.85 (br s, IH), 7.59 (m, IH), 7.21-7.14 (m, 2H), 6.95 (q, J=0.8 Hz, IH), 6.17 (dd, J=10.8, 1.5 Hz, IH), 4.12 (q, J=7.2 Hz, 2H), 4.12 (br s, IH), 2.82 (s, 2H), 2.35 (d, J=0.8 Hz, 3H), 1.52 (s, 6H), 1.31 (s, 6H), 1.19 (t, J=7.2 Hz, 3H). EXAMPLE 78

fO477] (EV5.7-Difluoro-2.3-dihvdro-2.2-dimethyl-6-(3-methylindol-7-vn-lH- quinolin-4-one O-d-methoxycarbonyl-l-methyDethyl oxime (Compound 227). A mixture of Compound 226 (EXAMPLE 77) (30 mg, 0.64 mmol) and sodium borohydride (37 mg) in 1.3 mL methanol was stirred at room temperature, then heated at reflux. The mixture was quenched with saturated ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (0-33% ethyl acetate: hexanes) afforded Compound 227. ¹H NMR (300MHz, CDCl₃) δ 7.87 (br s, IH), 7.59 (m, IH), 7.21-7.15 (m, 2H), 6.96 (q, J=0.8 Hz, IH), 6.17 (dd, J=10.8, 1.5 Hz, IH), 4.12 (br s, IH), 3.65 (s, 3H), 2.82 (s, 2H), 2.35 (d, J=0.8 Hz, 3H), 1.53 (s, 6H), 1.32 (s, 6H).

EXAMPLE 79

[0478] (E)-5,7-Difluoro-2.3-dihydro-2.2-dimethyl-6-(3-methylindol-7-yl)-l H- quinolin-4-one O-(l-carboxy-l-methyl)ethyl oxime (Compound 228). To a solution of Compound 226 (EXAMPLE 77) (135 mg) in 0.7 mL methanol and 2.9 mL THF was added a solution of LiOH (7.2 mg) in 0.7 mL water. The reaction was stirred at room temperature overnight, and the reaction mixture was treated with 0.29 mL IM HCl, then extracted with ethyl acetate. Flash chromatography (33% ethyl acetate:hexanes) afforded Compound 228. ¹H NMR (300MHz, CDCl₃) δ 7.78 (br s, IH), 7.62 (m, IH), 7.22-7.16 (m, 2H), 6.97 (q, J=0.9 Hz, IH), 6.25 (dd, J=IOJ, 1.8 Hz, IH), 2.85 (s, 2H), 2.36 (d, J=0.9 Hz, 3H), 1.55 (s, 6H), 1.35 (s, 6H). EXAMPLE 80

fO4791 (EV5.7-Difluoro-2.3-dihvdro-2,2-dimethyl-6-(3-methylindol-7-vn-lH- quinolin-4-one O-(l-diethylcarbamoyl-l-methyl^*)ethyl oxime (Compound 229). To a solution of Compound 228 (EXAMPLE 79) (13 mg, 1 equiv), diethylamine (3.4 microliters, 1.1 equiv) and diisopropylethylamine (5.6 microliters, 1.1 equiv) in 0.3 mL DMF was added O- (7-aza-lH-benzotriazol-l -yl)-N,N,N',N^>-tetramethyluiOnium hexafluorophosphate (12 mg, 1.1 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride, dried over sodium sulfate, filtered, and concentrated. Flash chromatography (0-33% ethyl acetate: hexanes) afforded Compound 229. ¹H ΝMR (300MHz, CDCl₃) δ 7.87 (br s, IH), 7.58 (m, IH), 7.20-7.13 (m, 2H), 6.94 (q, J=0.8 Hz, IH), 6.19 (dd, J=10.8, 1.7 Hz, IH), 4.15 (br s, IH), 3.61 (q, J=6.9 Hz, 2H), 3.30 (q, J=6.9 Hz, 2H), 2.77 (s, 2H), 2.35 (d, J=0.8 Hz, 3H), 1.54 (s, 6H), 1.31 (s, 6H), 1.1 1 (t, J=6.9 Hz, 3H), 1.05 (t, J=6.9 Hz, 3H).

EXAMPLE 81

r0480] (E)-5,7-Difluoro-2.3-dihvdro-2,2-dimethyl-6-(3-methylindol-7-vn-lH- quinolin-4-one O-(2-hydroxy-lJ-dirnethyl)ethyl oxime (Compound 230). A mixture of Compound 226 (EXAMPLE 77) (53 mg, 1 equiv) lithium triethylborohydride (1.7 mL of 1 M solution in THF) in 4.5 mL THF was stirred at 0 °C and was allowed to warm to room temperature and stirred overnight. The mixture was quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (0-33% ethyl acetate: hexanes) afforded Compound 230. ¹H ΝMR (300MHz, CDCl₃) δ 7.78 (br s, IH), 7.59 (m, IH), 7.21-7.14 (m, 2H), 6.96 (q, J=I .0 Hz, IH), 6.20 (dd, J=10.6, 1.5 Hz, IH), 4.13 (br s, IH), 3.78-3.65 (m, 3H), 2.77 (s, 2H), 2.35 (d, J=LO Hz, 3H), 1.31 (s, 6H), 1.29 (s, 6H).

EXAMPLE 82

[0481] (EV5.7-Difluoro-2,3-dihvdro-2.2-dimethyl-6-(3-methylindol-7-vn-lH- quinolin-4-one Q-[I -methyl- l-(2,2,2-trifluoroethylcarbamoyl)ethyl^"| oxime (Compound 231). To a solution of Compound 228 (EXAMPLE 79) (22 mg, 1 equiv), trifluoroethylamine (4.3 microliters, 1.1 equiv) and diisopropylethylamine (9.6 microliters, 1.1 equiv) in 0.5 mL DMF was added O-^-aza-lH-benzotriazol-l-yO-N.N.N'.N'-tetramethyluronium hexafluorophosphate (21 mg, 1.1 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride, dried over sodium sulfate, filtered, and concentrated. Flash chromatography (0-33% ethyl acetate:hexanes) afforded Compound 231. ¹H ΝMR (300MHz, CDCl₃) δ 7.79 (br s, IH), 7.61 (m, IH), 7.22-7.15 (m, 2H), 6.96 (q, J=LO Hz, IH), 6.22 (dd, J=10.7, 1.6 Hz, IH), 4.21 (br s, IH), 3.86 (qd, J=9.2, 6.4 Hz, 2H), 2.82 (s, 2H), 2.36 (d, J=LO Hz, 3H), 1.52 (s, 6H), 1.33 (s, 6H).

EXAMPLE 83

[0482] (E)-5,7-Difluoro-2,3-dihvdro-2.2-dimethyl-6-(3-methylindol-7-yl)-lH- quinolin-4-one O-(Ll-dimethyl-2-oxo)ethyl oxime (Compound 232). This compound was prepared according to General Method 15 (EXAMPLE 64) from Compound 230 (EXAMPLE 81) to afford Compound 232. ¹H ΝMR (300MHz, CDCl₃) δ 9.67 (s, IH), 7.80 (br s, IH), 7.59 (m, IH), 7.21-7.13 (m, 2H), 6.96 (m, IH), 6.18 (dd, J=10.6, 1.4 Hz, IH), 4.15 (s, IH), 2.83 (s, 2H), 2.35 (s, 3H), 1.36 (s, 6H), 1.32 (s, 6H).

EXAMPLE 84

[04831 (EV5.7-Difluoro-2,3-dihvdro-2.2-dimethyl-6-(3-methylindol-7-vn-lH- quinolin-4-one O-3-carboxy-U-dimethylallyl oxime (Compound 233). To a mixture of triethylphosphonoacetate (18 mg, 1.8 equiv) and sodium hydride (60% mineral oil dispersion, 2.8 mg, 1.5 equiv) in 0.5 mL THF was added Compound 232 at 0 °C. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture was quenched with water and ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (0-33% ethyl acetate :hexanes) afforded Compound 233. ¹H NMR (300MHz, CDCl₃) δ 7.87 (br s, IH), 7.59 (m, IH), 7.21-7.16 (m, 2H), 7.15 (d, J=16.0 Hz, IH), 6.96 (q, J=0.8 Hz, IH), 6.19 (dd, J=10.8, 1.4 Hz, IH), 5.88 (d, J=16.0 Hz, IH), 2.79 (s, 2H), 2.34 (d, J=0.8 Hz, 3H), 1.44 (s, 6H), 1.32 (s, 6H).

EXAMPLE 85

[04841 (E)-5J-Difluoro-2,3-dihvdro-2,2-dimethyl-6-(3-methylindol-7-ylVlH- quinolin-4-one O-(2-ethoxyimino)-l,l-dimethylethyl oxime (Compound 234). This compound was prepared according to General Method 13 (EXAMPLE 52) from Compound 232 (EXAMPLE 83) and O-ethylhydroxylamine hydrochloride to afford Compound 234. ¹H NMR (300MHz, CDCl₃) δ 7.85 (br s, IH), 7.61 (m, IH), 7.58 (s, IH), 7.18 (d, J=2.5 Hz, IH), 6.98 (s, IH), 6.19 (dd, J=10.8, 1.1 Hz, IH), 4.10-4.04 (m, 3H), 2.77 (s, 2H), 2.49 (s, 6H), 1.32 (s, 6H), 1.22 (t=7.0 Hz, 3H).

rO4851 (E)-(±)-6-(3-Chloroindol-7-yl)-5-fluoro-23-dihydro-3-hvdroxy-2,2,8- trimethyl-lH-quinolin-4-one O-t-butyl oxime (^"Compound 235).

[0486] (±)-6-Bromo-5-fluoro-2,3-dihydro-3-hydroxy-2,2,8-trimethyl-lH- quinolin-4-one. This compound was prepared in a manner similar to (±)-6-bromo-5,7- difluoro-2,3-dihydro-3-hydroxy-2,2-dimethyl-lH-quinolin-4-one (EXAMPLE 64) except that 5-fluoro-2-methylaniline was used as the starting material.

[0487] (±)-6-(3-Chloroindoi-7-yl)-5-fluoro-2,3-dihydro-3-hydroxy-2,2,8- trimethyl-lH-quinolin-4-one. This compound was prepared from (±)-6-bromo-5-fluoro-2,3- dihydro-3-hydroxy-2,2,8-trimethyl-lH-quinolin-4-one and 3-chloro-7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)indole using General Method 12 (EXAMPLE 52). fO4881 (E)-(±)-6-(3-Chloroindol-7-yl)-5-fluoro-23-dihydro-3-hvdroxy-2.2.8- trimethyl-lΗ-quinolin-4-one O-t-butyl oxime (Compound 235). This compound was prepared from 6-(3-chloroindol-7-yl)-5-fluoro-2,3-dihydro-2,2,8-trimethyl-lH-quinolin-4- one and O-f-butylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (300MHz, CDCl₃) δ 7.84 (br s, IH), 7.60 (m, IH), 7.20-7.16 (m, 2H), 7.10 (d, J=7.8 Hz, IH), 6.97 (m, IH), 4.08 (s, IH), 2.79 (s, 2H), 2.14 (s, 3H), 1.31 (s, 6H), 1.29 (s, 9H).

EXAMPLE 87

fO4891 fZ)-(±)-6-(3-Chloroindol-7-yl)-5-fluoro-2.3-dihvdro-3-hvdroxy-2,2.8- trimethyl-lH-quinolin-4-one O-ethyl oxime (Compound 236) and (E)-(±)-6-(3-Chloroindol- 7-yl)-5-fluoro-2,3-dihydro-3-hvdroxy-2,2,8-trimethyl-lH-quinolin-4-one O-ethyl oxime (Compound 237). These compounds was prepared from 6-(3-chloroindol-7-yl)-5-fluoro-2,3- dihydro-2,2,8-trimethyl-lH-quinolin-4-one (EXAMPLE 86) and O-ethylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52).

[0490] Compound 236: MS (ESI): 400 (M + Η).

[0491] Compound 237: ¹H NMR (300MHz, CDCl₃) δ 7.84 (br s, IH), 7.60 (m, IH), 7.20-7.16 (m, 2H), 7.10 (d, J=7.8 Hz, IH), 6.97 (m, IH), 4.18 (q, J=7.0 Hz, 2H), 4.08 (s, IH), 2.79 (s, 2H), 2.14 (s, 3H), 1.31 (s, 6H), 1.28 (t, J=7.0 Hz, 3H).

[04921 (E)-6-(3-Chloroindol-7-yl>5.7-difluoro-2.3-dihvdro-2,2-dimethyl-lH- quinolin-4-one O-ethyl oxime (Compound 238). This compound was prepared from 6-(3- chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one and O- ethylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (300MHz, CDCl₃) δ 8.08 (br s, IH), 7.66 (m, IH), 7.28-7.24 (m, 3H), 7.18 (d, J=2.5 Hz, IH), 6.19 (dd, J=10.8, 1.1 Hz, IH), 4.29-4.25 (m, 2H), 4.10 (br s, IH), 2.77 (s, 2H), 1.32 (s, 6H), 1.28 (t=7.0 Hz, 3H).

[04931 (EV6-(3-Chloroindol-7-ylV5.7-difluoro-2.3-dihvdro-2.2-dimethyl-lH- quinolin-4-one O-isopropyl oxime (Compound 239). This compound was prepared from 6- (3-chloroindol-7-yl)-5,7-difluoro-2,3-dihydro-2,2-dimethyl-lH-quinolin-4-one and O- isopropylhydroxylamine hydrochloride using General Method 13 (EXAMPLE 52). ¹H NMR (300MHz, CDCl₃) δ 8.08 (br s, IH), 7.66 (m, IH), 7.28-7.24 (m, 3H), 7.18 (d, J=2.5 Hz, IH), 6.19 (dd, J=10.8, 1.1 Hz, IH), 4.4 (m, IH), 4.14 (br s, IH), 2.77 (s, 2H), 1.32 (s, 6H), 1.27 (d, J=6.3 Hz, 6H). EXAMPLE 90

[0494] (±)- 1.2.3 ,4-Tetrahvdro-3 β-hvdroxy-2.2.4α.8-tetramethyl-6-(3- methylindol-7-yl)-5-(m-tolylethvnyl)quinoline (Compound 301).

[0495] 5-Chloro-l,2-dihydro-2,2,4,8-tetramethylquinoline was prepared from 5- chloro-2-methylaniline using General Method 1 (EXAMPLE 1).

[0496] 5-Cyano-l,2-dihydro-2,2,4,8-tetramethylquinoline was prepared from 5- chloro-l,2-dihydro-2,2,4,8-tetramethylquinoline using General Method 18.

[0497] General Method 18: Cyanation of an aryl chloride. A representative procedure is described. Pd₂(dba)3 (990 mg, 1.08 mmol), dppf (1.2 g, 2.2 mmol), zinc powder (420 mg, 6.5 mmol) and zinc cyanide (1.92 g, 16.2 mmol) were added to a solution of 5- chloro-l,2-dihydro-2,2,4,8-tetramethylquinoline (6.0 g, 27 mmol) in N.N-dimethylacetamide (120 ml). The reaction vessel was evacuated-purged with nitrogen twice and then heated at 150 ⁰C for 48 h. The reaction was allowed to cool to room temperature, poured into water (500 ml) and extracted with ethyl acetate (3 ^χ 100 ml). The combined organic extracts were washed with a saturated solution of ammonium chloride (300 ml), dried (Na₂SO₄) and concentrated under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate:hexanes gave 5-cyano-l,2-dihydro-2,2,4,8-tetramethylquinoline (2.45 g, 42 %).

[0498] (±)-5-Cyano-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline is made from 5-cyano-l,2-dihydro-2,2,4,8-tetramethylquinoline using General Method 2 (EXAMPLE 1).

[0499] (±)-5-Formyl-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethylquinoline was prepared from (±)-5-cyano- 1,2,3, 4-tetrahydro-3β-hydroxy- 2,2,4oc,8-tetramethylquinoline using General Method 19.

[0500] General Method 19: Reduction of a nitrile to an aldehyde. A representative procedure is described. IM DIBAL in hexanes (16 ml, 16 mmol) was added dropwise to a solution of (±)-5-cyano-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethylquinoline (1.0 g, 4.3 mmol) in dichloromethane (200 ml) at 0 ⁰C. The solution was stirred at 0 ⁰C for 0.25 h then quenched with the dropwise addition of a saturated solution of Rochelle's salt (100 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3 x 100 ml). The combined organic extracts were washed with a I M hydrochloric acid solution (300 ml), a saturated solution of ammonium chloride (300 ml), dried (Na₂SO₄) and concentrated under reduced pressure to give (±)-5-formyl-l, 2,3,4- tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline (770 mg, 76 %).

[0501] (±)-5-Ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethylquinoline was prepared from (±)-5-formyl-l,2,3,4-tetrahydro-3β-hydroxy- 2,2,4α,8-tetramethylquinoline using General Method 20. [0502] General Method 20: Formation of an alkyne from an aldehyde. A representative procedure is described. Dimethyl(l-diazo-2-oxopropyl)phosphonate (1.08 g, 5.63 mmol) was added dropwise to a solution of (±)-5-formyl-l,2,3,4-tetrahydro-3β-hydroxy- 2,2,4α,8-tetramethylquinoline (1.10 g, 4.7 mmol) and potassium carbonate (1.95 g, 14.1 mmol) in methanol at 0 ⁰C. The reaction was allowed to warm to room temperature and stirred for 15 h. The reaction was poured into water (50 ml), extracted with ethyl acetate (3 x 50 ml), combined organics washed with a saturated solution of ammonium chloride (100 ml), dried (Na₂SO₄) and concentrated under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate:hexanes gave (±)-5-ethynyl-l,2,3,4-tetrahydro- 3β-hydroxy-2,2,4α,8-tetramethylquinoline (482 mg, 45 %).

[0503] (±)-6-Bromo-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethylquinoline was prepared in 69% yield from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β- hydroxy-2,2,4α,8-tetramethylquinoline using General Method 3 (EXAMPLE 1).

[0504] (±)-5-Ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)- 2,2,4α,8-tetramethylquinoline. This compound was prepared in 64% yield from (±)-6- bromo-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline and 3-methyl- 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indole using General Method 12 (EXAMPLE 52).

105051 (±)-l,2.3.4-Tetrahvdro-3β-hvdroxy-2.2.4α.8-tetramethyl-6-(3- methylindol-7-y0-5-(m-tolylethynvDquinoIine (Compound 301). This compound was prepared in 41% yield from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7- yl)-2,2,4α,8-tetramethylquinoline and 3-iodotoluene using General Method 21.

[0506] General Method 21 : Coupling of an alkyne and an aryl halide. A representative procedure is described. (±)-5-Ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3- methylindol-7-yl)-2,2,4α,8-tetramethylquinoline (200 mg, 0.56 mmol), 3-iodotoluene (0.29 ml, 2.3 mmol), tetrakis(triphenylphosphine)palladium (0) (107 mg, 0.093 mmol), copper (I) iodide (18 mg, 0.095 mmol), diisopropylamine (4 ml) and toluene (20 ml) were stirred at room temperature for 15 h. The reaction was poured into water (100 ml), extracted with ethyl acetate (3 x 50 ml), combined organics washed with a saturated solution of ammonium chloride (100 ml), dried (Na₂SO₄) and concentrated under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate :hexanes gave Compound 301 (103 mg, 41 %). ¹H NMR (500MHz, CDCl₃) δ 8.00 (br s, IH), 7.59 (m, IH), 7.24 (m, IH), 7.19 (dd, J=7.7, 7.2 Hz, IH), 7.11 (t, J=0.6 Hz, IH), 7.05 (t, J=7.6 Hz, IH), 6.99 (m, IH), 6.96 (m, IH), 6.75 (m, IH), 6.60 (m, IH), 3.60 (dd, J=7.3, 5.5 Hz, IH), 3.57 (br s, IH), 3.24 (qd, J=6.8, 5.5 Hz, IH), 2.40 (d, J=I .2 Hz, 3H), 2.22 (s, 3H), 2.20 (d, J=0.5 Hz, 3H), 1.91 (d, J=7.3 Hz, IH), 1.71 (d, J=6.8 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 91

10507] (±)-1.2.3.4-Tetrahvdro-3β-hvdroxy-2.2,4α,8-tetramethyl-6-(3- rnethylindol-7-yl)-5-(phenylethvnyl)quinoline (Compound 302). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and iodobenzene using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.99 (br s, IH), 7.58 (m, IH), 7.26 (m, IH), 7.21-7.14 (m, 4H), 7.12 (m, IH), 6.95 (m, IH), 6.91 (m, 2H), 3.61 (dd, J=7.5, 5.4 Hz, IH), 3.58 (s, IH), 3.25 (dq, J=5.4, 7.0 Hz, IH), 2.39 (d, J=I .2 Hz, 3H), 2.20 (d, J=0.5 Hz, 3H), 1.91 (d, J=7.5 Hz, I H), 1.71 (d, J=7.0 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 92

f05081 (±)-1.2.3.4-Tetrahvdro-3β-hvdroxy-2.2.4α,8-tetramethyl-6-(3- methylindol-7-yl)-5-(o-tolylethvnyl)quinoline (Compound 303). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 2-iodotoluene using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.92 (br s, IH), 7.55 (m, IH), 7.17 (dd, J=7.6, 7.2 Hz, IH), 7.08 (m, IH), 7.07 (m, IH), 7.03-6.96 (m, 2H), 6.92 (m, IH), 6.89 (m, IH), 3.62 (dd, J=7.7, 5.3 Hz, IH), 3.57 (br s, IH), 3.27 (dd, J=7.0, 5.3 Hz, IH), 2.36 (d, J=I .2 Hz, 3H), 2.20 (d, J=0.5 Hz, 3H), 1.90 (d, J=7.7 Hz, IH), 1.82 (s, 3H), 1.72 (d, J=7.0 Hz, 3H), 1.39 (s, 3H), 1.24 (s, 3H).

EXAMPLE 93

105091 (±V1.2.3.4-Tetrahvdro-3β-hvdroxy-2.2.4α,8-tetramethyl-6-(3- methylindol-7-yl)-5-[4-(trifluoromethyl)phenylethynyl]quinoline (Compound 304). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3- methylindol-7-yl)-2,2,4α,8-tetramethylquinoline and 4-iodobenzotrifluoride using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.95 (br s, IH), 7.60 (m, IH), 7.41 (d, J=8.1 Hz, 2H), 7.24 (m, IH), 7.19 (t, J=7.4 Hz, IH), 7.13 (q, J=0.6 Hz, IH), 6.97- 6.94 (m, 3H), 3.63-3.59 (m, 2H), 3.23 (qd, J=7.0, 5.6 Hz, I H), 2.39 (d, J=I .0 Hz, 3H), 2.21 (d, J=0.6 Hz, 3H), 1.94 (d, J=7.6 Hz, IH), 1.70 (d, J=7.0 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 94

[0510] (±)-5-(3-Chloro-2-methylphenylethynyl)-l,2,3,4-tetrahvdro-3β-hvdroxy- 2,2,4α.8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 305). This compound was prepared from (±)-5-ethynyl-l ,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 2-chloro-6-iodotoluene using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.89 (br s, IH), 7.56 (m, IH), 7.17 (t, J=7.3 Hz, IH), 7.08 (s, IH), 6.94-6.90 (m, 2H), 6.79 (dd, J=7.8, 1.0 Hz, IH), 3.61 (dd, J=7.6, 5.2 Hz, IH), 3.59 (br s, IH), 3.25 (m, IH), 2.37 (d, J=I.0 Hz, 3H), 2.20 (m, 3H), 1.91 (d, J=7.6 Hz, IH), 1.86 (s, 3H), 1.70 (d, J=7.1 Hz, 3H), 1.39 (s, 3H), 1.24 (s, 3H).

EXAMPLE 95

105111 (±V5-(2-Acetylphenylethvnvn-1.2.3.4-tetrahvdro-3β-hvdroxy-2.2,4α,8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 306). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 3-iodoacetophenone using General Method 21 (EXAMPLE 90). ¹H NMR (300MHz, CDCl₃) δ 8.00 (br s, IH), 7.77 (m, IH), 7.60 (m, IH), 7.31-7.17 (m, 4H), 7.14-7.09 (m, 2H), 6.97 (s, IH), 3.65-3.57 (m, 2H), 3.25 (m, IH), 2.50 (s, 3H), 2.38 (s, 3H), 2.21 (s, 3H), 1.96 (d, J=6.3 Hz, IH), 1.71 (d, J=7.0 Hz, 3H), 1.39 (s, 3H), 1.24 (s, 3H).

EXAMPLE 96

10512] a)-1.2.3.4-Tetrahvdro-3β-hvdroxy-2.2.4α.8-tetramethyl-6-(3- methylindol-7-yl)-5-r3-(trifluoromethyl)phenylethvnvnquinoline (Compound 307). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3- methylindol-7-yl)-2,2,4α,8-tetramethylquinoline and 3-iodobenzotrifiuoride using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.95 (br s, IH), 7.61 (dd, J=7.3, 1.2 Hz, IH), 7.41 (m, IH), 7.28 (m, IH), 7.22 (m, IH), 7.20 (t, J=7.2 Hz, IH), 7.13 (s, IH), 7.07 (m, IH), 6.97-6.94 (m, 2H), 3.61 (dd, J=7.2, 5.6 Hz, IH), 3.60 (br s, IH), 3.23 (dd, J=6.9, 5.6 Hz, IH), 2.39 (d, J=LO Hz, 3H), 2.21 (m, 3H), 1.94 (d, J=7.2 Hz, IH), 1.70 (d, J=6.9 Hz, 3H), 1.39 (s, 3H), 1.23 (s, 3H).

EXAMPLE 97

fO5131 (±)-1.2.3.4-Tetrahvdro-3β-hvdroxy-2.2,4α,8-tetramethyl-6-r3- methylindol-7-yl)-5-f2-(trifluoromethyl)phenylethvnyl]quinoline (Compound 308). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3- methylindol-7-yl)-2,2,4α,8-tetramethylquinoline and 2-iodobenzotrifluoride using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.95 (br s, IH), 7.59 (m, IH), 7.52 (m, IH), 7.25-7.18 (m, 4H), 7.11 (s, IH), 6.93 (br s, IH), 6.41 (m, IH), 3.60 (dd, J=7.6, 5.5 Hz, IH), 3.59 (br s, IH), 3.22 (qd, J=6.9, 5.5 Hz, IH), 2.38 (d, J=0.7 Hz, 3H), 2.20 (s, 3H), 1.79 (d, J=7.6 Hz, IH), 1.64 (d, J=6.9 Hz, 3H), 1.39 (s, 3H), 1.23 (s, 3H).

EXAMPLE 98

[05141 (±)-5-(2-Fluorophenylethvnyl)-1.2.3,4-tetrahvdro-3β-hvdroxy-2.2.4α.8- tetramethyl-6-(3-rnethylindol-7-yl)quinoline (Compound 309). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 2-fluoro-l-iodobenzene using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.98 (br s, IH), 7.58 (m, IH), 7.28 (dd, J=7.3, 1.0 Hz, IH), 7.19 (dd, J=7.7, 7.3 Hz, IH), 7.16 (m, IH), 7.12 (m, IH), 6.98-6.93 (m, 2H), 6.91 (td, J=7.5, 1.1 Hz, IH), 6.65 (t, J=7.0 Hz, IH), 3.61 (dd, J=7.8, 5.3 Hz, IH), 3.58 (br s, IH), 3.27 (qd, J=6.9, 5.3 Hz, IH), 2.38 (d, J=I.2 Hz, 3H), 2.20 (d, J=0.5 Hz, 3H), 1.86 (d, J=7.8 Hz, IH), 1.70 (d, J=6.9 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 99

[05151 (±)-5-(3-Fluorophenylethvnvn-1.2.3.4-tetrahvdro-3B-hvdroxy-2.2.4α.8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 310). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 3-fluoro-l-iodobenzene using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.96 (br s, IH), 7.60 (m, IH), 7.24 (m, IH), 7.20 (t, J=7.4 Hz, IH), 7.15-7.09 (m, 2H), 6.96 (q, J=LO Hz, IH), 6.88 (tdd, J=8.5, 2.6, 1.0 Hz, IH), 6.70 (ddd, J=7.6, 1.3, 1.0 Hz, IH), 6.51 (ddd, J=9.6, 2.6, 1.3 Hz, IH), 3.60 (dd, J=7.5, 5.6 Hz, IH), 3.59 (br s, IH), 3.22 (qd, J=7.0, 5.6 Hz, IH), 2.39 (d, J=LO Hz, 3H), 2.20 (d, J=0.5 Hz, 3H), 1.92 (d, J=7.5 Hz, IH), 1.69 (d, J=7.0 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 100

[05161 (±)-5-(2-Acetylphenylethvnvn-1.2.3.4-tetrahvdro-3β-hvdroxy-2.2.4α.8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 31 1). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 2-iodoacetophenone using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.95 (br s, IH), 7.58-7.55 (m, 2H), 7.26 (m, IH), 7.24 (m, IH), 7.21 (m, IH), 7.16 (t, J=7.4 Hz, IH), 7.08 (m, IH), 6.91 (m, IH), 6.83 (m, IH), 3.62 (m, IH), 3.59 (br s, IH), 3.29 (m, IH), 2.36 (d, J=0.9 Hz, 3H), 2.20 (d, J=0.5 Hz, 3H), 2.12 (s, 3H), 1.99 (m, IH), 1.69 (d, J=6.8 Hz, 3H), 1.39 (s, 3H), 1.23 (s, 3H).

EXAMPLE 101

[05171 (±H.23,4-Tetrahydro-3β-hydroxy-5-r2-(hydroxymethyl)phenylethynyl1- 2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 312). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 2-iodobenzylalcohol using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.92 (br s, IH), 7.62 (m, IH), 7.25-7.1 1 (m, 6H), 7.05 (m, IH), 6.95 (m, IH), 5.29 (m, IH), 3.84 (m, 2H), 3.62 (dd, J=6.7, 5.6 Hz, IH), 3.59 (br s, I H), 3.26 (m, IH), 2.38 (d, J=0.7 Hz, 3H), 2.20 (s, 3H), 1.94 (d, J=6.7 Hz, IH), 1.72 (d, J=7.1 Hz, 3H), 1.39 (s, 3H), 1.24 (s, 3H).

EXAMPLE 102

[05181 (±)-l,2.3.4-Tetrahvdro-3β-hvdroxy-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yQ-5-(p-tolylethynyl)quinoline (Compound 313). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 4-iodotoluene using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.99 (s, IH), 7.58 (d, J=7.7 Hz, IH), 7.25 (d, J=7.4 Hz, IH), 7.19 (dd, J=7.7, 7.4 Hz, IH), 7.11 (s, IH), 6.98 (d, J=8.0 Hz, 2H), 6.95 (d, J=LO Hz, IH), 6.81 (d, J=8.0 Hz, 2H), 3.62 (d, J=5.1 Hz, IH), 3.24 (m, IH), 2.39 (d, J=LO Hz, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 1.71 (d, J=7.1 Hz, 3H), 1.39 (s, 3H), 1.23 (s, 3H).

EXAMPLE 103

[0519] (±)-5-(3,5-Dimethylphenylethynyl)-l,2,3,4-tetrahydro-3β-hydroxy- 2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 314). This compound was prepared from (±)-5-ethynyl-l ,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 5-iodo-w-xylene using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 8.00 (s, IH), 7.59 (dd, J=7.6, 0.8 Hz, IH), 7.23 (dd, 3=73, 0.8 Hz, IH), 7.20 (dd, J=7.6, 7.3 Hz, IH), 7.10 (s, IH), 6.96 (m, IH), 6.81 (m, IH), 6.45 (m, 2H), 3.62-3.56 (m, 2H), 3.23 (m, IH), 2.40 (d, J=LO Hz, 3H), 2.20 (s, 3H), 2.18 (s, 6H), 1.91 (m, IH), 1.71 (d, J=7.1 Hz, 3H), 1.38 (s, 3H), 1.22 (s, 3H).

EXAMPLE 104

[05201 (±)-5-(2,4-Dimethylphenylethvnyl)-1.2.3.4-tetrahvdro-3β-hvdroxy- 2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 315). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 5-iodo-w-xylene using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 8.00 (s, IH), 7.58 (dd, J=7.8, 0.8 Hz, IH), 7.24 (dd, J=7.4, 0.8 Hz, IH), 7.19 (dd, J=7.8, 7.4 Hz, IH), 7.10 (s, IH), 6.95 (m, IH), 6.92 (d, J=7.8 Hz, IH), 6.69 (dd, J=7.8, 1.6 Hz, IH), 6.56 (m, IH), 3.65-3.54 (m, 2H), 3.23 (m, IH), 2.39 (d, J=LO Hz, 3H), 2.19 (d, J=0.6 Hz, 3H), 2.18 (s, 3H), 2.12 (s, 3H), 1.70 (d, J=7.1 Hz, 3H), 1.37 (s, 3H), 1.22 (s, 3H).

[0521| (±)-5-(2,4-Difluorophenylethvnyl)-L2,3,4-tetrahvdro-3β-hvdroxy- 2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 316). This compound was prepared from (±)-5-ethynyl-l ,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 3,5-difluoro-l-iodobenzene using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.92 (s, IH), 7.61 (m, IH), 7.21 (m, IH), 7.20 (t, J=6.9 Hz, IH), 7.13 (s, IH), 6.96 (q, J=I .0 Hz, IH), 6.64 (tt, J=9.0, 2.3 Hz, IH), 6.36-6.30 (m, 2H), 3.60 (d, J=5.6 Hz, IH), 3.19 (qd, J=6.9, 5.6 Hz, IH), 2.40 (d, J=1.0 Hz, 3H), 2.21 (d, J=0.6 Hz, 3H), 1.68 (d, J=6.9 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 106

[0522] (±)-l,2,3,4-Tetrahvdro-3β-hydroxy-5-(2-isopropylphenylethvnyl)- 2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 317). This compound was prepared from (±)-5-ethynyl-l ,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 2-iodo-l-isopropylbenzene using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.90 (s, IH), 7.57 (m, IH), 7.20-7.14 (m, 3H), 7.09 (d, J=7.7 Hz, IH), 7.05 (m, IH), 7.02-7.00 (m, 2H), 6.92 (br s, IH), 3.62 (d, J=5.2 Hz, IH), 3.27 (qd, J=7.0, 5.2 Hz, IH), 2.36 (d, J=LO Hz, 3H), 2.19 (d, J=0.5 Hz, 3H), 1.72 (d, J=7.0 Hz, 3H), 1.60 (m, IH), 1.39 (s, 3H), 1.25 (s, 3H), 0.86 (d, J=6.8 Hz, 3H), 0.80 (d, J=7.2 Hz, 3H). EXAMPLE 107

f 05231 (±)-5-(4-Fluorophenylethvnyl)-L2,3,4-tetrahydro-3β-hydroxy-2,2,4α.8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 318). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 4-fluoro-l-iodobenzene using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.98 (br s, IH), 7.58 (ddd, J=7.5, 1.3, 0.6 Hz, IH), 7.25 (dd, J=7.5, 1.3 Hz, IH), 7.19 (t, J=7.5 Hz, IH), 7.11 (q, J=0.5 Hz, IH), 6.95 (q, J=LO Hz, IH), 6.87-6.84 (m, 4H), 3.63-3.56 (m, 2H), 3.22 (m, IH), 2.39 (d, J=LO Hz, 3H), 2.20 (d, J=0.5 Hz, 3H), 1.92 (m, IH), 1.69 (d, J=7.0 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 108

[0524] (±)-5-(2-Fluoro-5-methylphenylethvnyl)-L2,3,4-tetrahvdro-3β-hydroxy- 2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 319). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 4-fluoro-3-iodotoluene using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.98 (s, IH), 7.59 (dd, J=7.7, 1.0 Hz, IH), 7.25 (dd, J=7.3, 1.0 Hz, IH), 7.20 (dd, J=7.7, 7.3 Hz, IH), 7.11 (q, J=0.5 Hz, IH), 6.96 (q, J=Ll Hz, IH), 6.93 (ddd, J=8.6, 5.2, 2.4 Hz, IH), 6.82 (t, J=8.6 Hz, IH), 6.28 (m, IH), 3.60 (d, J=5.4 Hz, IH), 3.26 (qd, J=7.1, 5.4 Hz, IH), 2.39 (d, J=Ll Hz, 3H), 2.20 (d, J=0.5 Hz, 3H), 2.15 (s, 3H), 1.70 (d, J=7.1 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H). EXAMPLE 109

fO5251 (±)-1.2.3.4-Tetrahvdro-3B-hvdroxy-5-r3-fhvdroxymethvnphenylethvnvn- 2,2,4α,8-tetramethyl-6-(3-rnethylindol-7-yl)quinoline (Compound 320). This compound was prepared from (±)-S-ethynyl-l ,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 3-iodobenzyl alcohol using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.99 (s, IH), 7.59 (m, IH), 7.25 (m, IH), 7.19 (t, J=7.5 Hz, IH), 7.19 (m, IH), 7.16 (t, J=7.5 Hz, IH), 7.11 (m, IH), 6.96 (q, J=LO Hz, IH), 6.85 (m, IH), 6.77 (m, IH), 4.56 (s, 2H), 3.60 (d, J=5.5 Hz, IH), 3.24 (qd, J=6.9, 5.5 Hz, IH), 2.40 (d, J=LO Hz, 3H), 2.20 (d, J=0.5 Hz, 3H), 1.92 (m, IH), 1.71 (d, J=6.9 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 110

|0526| (±)-5-(3-Chloro-2-fluorophenylethvnyl)-1.2.3,4-tetrahvdro-3β-hydroxy- 2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 321). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 3-chloro-2-fluoro-l-iodobenzene using General Method 21 (EXAMPLE 90). ¹H NMR (300MHz, CDCl₃) δ 7.95 (s, IH), 7.58 (m, IH), 7.26 (dd, J=7.2, 1.2 Hz, IH), 7.24-7.16 (m, 2H), 7.13 (q, J=0.7 Hz, IH), 6.95 (q, J=Ll Hz, IH), 6.84 (td, J=7.8, 1.1 Hz, IH), 6.50 (m, J=7.8, 6.2, 1.3 Hz, IH), 3.60 (d, J=5.2 Hz, IH), 3.59 (br s, IH), 3.25 (qd, J=7.0, 5.2 Hz, IH), 2.38 (d, J=Ll Hz, 3H), 2.21 (d, J=0.7 Hz, 3H), 1.87 (m, IH), 1.70 (d, J=7.0 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 111

[0527] (±)-5-(2-Fluoro-3-methylphenylethvnyl)-L2Λ4-tetrahvdro-3β-hydroxy- 2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 322). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 3-bromo-2-fluorotoluene using General Method 21 (EXAMPLE 90). ¹H NMR (300MHz, CDCl₃) δ 7.98 (s, IH), 7.57 (m, IH), 7.28 (m, IH), 7.19 (dd, J=7.6, 7.3 Hz, IH), 7.12 (s, IH), 7.01 (m, IH), 6.94 (q, J=LO Hz, IH), 6.79 (t, J=7.6 Hz, IH), 6.46 (m, IH), 3.61 (t, J=5.4 Hz, IH), 3.27 (qd, J=7.1, 5.4 Hz, IH), 2.38 (d, J=LO Hz, 3H), 2.21 (d, J=2.0 Hz, 3H), 2.20 (d, J=0.6 Hz, 3H), 1.87 (m, IH), 1.71 (d, J=7.1 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 1 12

[0528] (±)-5-(3-Cvanophenylethvnyl)-L2,3,4-tetrahvdro-3β-hvdroxy-2,2,4α,8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 323). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 3-iodobenzonitrile using General Method 21 (EXAMPLE 90). ¹H NMR (300MHz, CDCl₃) δ 7.93 (br s, IH), 7.62 (m, IH), 7.43 (m, IH), 7.30-7.19 (m, 3H), 7.13 (s, IH), 7.09 (m, IH), 6.98-6.93 (m, 2H), 3.64-3.57 (m, 2H), 3.20 (m, IH), 2.42 (s, 3H), 2.21 (s, 3H), 1.94 (d, J=7.3 Hz, IH), 1.69 (d, J=7.0 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 1 13

[05291 (±)-5-f5-Difluoromethyl-2-fluorophenylethvnyl)-l,2,3,4-tetrahvdro-3β- hydroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 324). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3- methylindol-7-yl)-2,2,4α,8-tetramethylquinoline and 2-bromo-4-(difluoromethyl)-l- fluorobenzene using General Method 21 (EXAMPLE 90). ¹H NMR (300MHz, CDCl₃) δ 7.96 (br s, IH), 7.60 (m, IH), 7.35-7.16 (m, 3H), 7.13 (s, IH), 7.03 (t, J=8.4 Hz, IH), 6.96 (s, IH), 6.58 (m, IH), 6.43 (t, J=56.6 Hz, IH), 3.60 (m, IH), 3.25 (m, IH), 2.39 (s, 3H), 2.21 (s, 3H), 1.89 (m, IH), 1.70 (d, J=7.2 Hz, 3H), 1.38 (s, 3H), 1.24 (s, 3H).

EXAMPLE 114

[05301 (±)-1.2.3.4-Tetrahvdro-3β-hvdroxy-2.2.4α,8-tetramethyl-6-(3- methylindol-7-yl)-5-(3-propionylphenylethvnyl)quinoline (Compound 325). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)- 2,2,4α,8-tetramethylquinoline and 3-bromopropiophenone using General Method 21 (EXAMPLE 90). ¹H NMR (300MHz, CDCl₃) δ 8.00 (br s, IH), 7.78 (d, J=8.1 Hz, IH), 7.61 (m, IH), 7.34-7.17 (m, 4H), 7.14-7.09 (m, 2H), 6.97 (s, IH), 3.61 (m, 2H), 3.25 (m, IH), 2.86 (q, J=7.3 Hz, 2H), 2.39 (s, 3H), 2.21 (s, 3H), 1.94 (m, I H), 1.72 (d, J=7.0 Hz, 3H), 1.39 (s, 3H), 1.24 (s, 3H), 1.21 (t, J=7.3 Hz, 3H).

EXAMPLE 115

[05311 (±)-l,2,3,4-Tetrahvdro-3β-hvdroxy-6-(indol-7-yl)-2,2,4α,8-tetramethyl-5- (phenylethvnyl)quinoline (Compound 326).

[0532] (±)-5-Ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α,8- tetramethylquinoline. This compound was prepared from (±)-6-bromo-5-ethynyl-l,2,3,4- tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline and 7-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)indole using General Method 12 (EXAMPLE 52).

[05331 (±)-l,2.3.4-Tetrahvdro-3β-hydroxy-6-(indol-7-yl)-2.2.4α,8-tetramethyl-5- (phenylethynyl)quinoline (Compound 326). This compound was prepared from (±)-5- ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(indol-7-yl)-2,2,4α,8-tetramethylquinoline and iodobenzene using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 8.27 (s, IH), 7.65 (m, IH), 7.24 (m, IH), 7.21-7.14 (m, 5H), 7.12 (q, J=0.6 Hz, IH), 6.88 (m, 2H), 6.62 (dd, J=3.2, 2.1 Hz, IH), 3.61 (dd, J=7.7, 5.5 Hz, IH), 3.59 (br s, IH), 3.26 (dq, J=5.5, 7.0 Hz, IH), 2.21 (d, J=0.6 Hz, 3H), 1.92 (d, J=7.7 Hz, IH), 1.72 (d, J=7.0 Hz, 3H), 1.39 (s, 3H), 1.24 (s, 3H). EXAMPLE 116

105341 (±V1.2,3,4-Tetrahvdro-2,2,4α.8-tetramethyl-6-(3-methylindol-7-ylV3β- phenylcarbamoyloxy-5-(m-tolylethynyl)quinoline (Compound 327). This compound was prepared from Compound 301 and phenyl isocyanate using General Method 5 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 7.99 (br s, IH), 7.59 (d, J=7.8 Hz, IH), 7.46-7.39 (m, 2H), 7.35-7.29 (m, 2H), 7.25 (m, IH), 7.19 (m, IH), 7.14 (s, IH), 7.06 (m, IH), 7.04 (t, J=7.5 Hz, IH), 7.00-6.94 (m, 2H), 6.75-6.72 (m, 2H), 6.59 (m, IH), 5.08 (d, J=5.0 Hz, IH), 3.61 (br s, IH), 3.40 (qd, J=7.2, 5.0 Hz, IH), 2.39 (d, J=LO Hz, 3H), 2.22 (s, 3H), 2.20 (s, 3H), 1.71 (d, J=7.2 Hz, 3H), 1.42 (s, 3H), 1.27 (s, 3H).

EXAMPLE 117

[05351 (±V7-Fluoro- 1.2.3.4-tetrahvdro-3 β-hvdroxy-2.2,4α-trimethyl-6-(3- methylindol-7-vD-5-(m-tolylethynyl)quinoline (Compound 328).

[0536] 5-Chloro-7-fluoro-l,2-dihydro-2,2,4,8-tetramethylquinoline was prepared from 3-chloro-5-fluoroaniline using General Method 1 (EXAMPLE 1).

[0537] 5-Cyano-7-fluoro-l,2-dihydro-2,2,4-trimethylquinoline was prepared from 5-chloro-l,2-dihydro-2,2,4,8-tetramethylquinoline using General Method 18 (EXAMPLE 90).

[0538] (±)-5-Cyano-7-fluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α- trimethylquinoline is made from 5-cyano-7-fluoro-l,2-dihydro-2,2,4-trimethylquinoline using General Method 2 (EXAMPLE 1).

[0539] (±)-7-Fluoro-5-formyl-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α- trimethylquinoline was prepared from (±)-5-cyano-7-fluoro- 1,2,3, 4-tetrahydro-3 β-hydroxy- 2,2,4α-trimethylquinoline using General Method 19 (EXAMPLE 90).

[0540] (±)-5-Ethynyl-7-fluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α- trimethylquinoline was prepared from (±)-7-fluoro-5-forrnyl-l,2,3,4-tetrahydro-3β-hydroxy- 2,2,4α-trimethylquinoline using General Method 20 (EXAMPLE 90).

[0541 ] (±)-6-Bromo-5-ethyny 1-7-fluoro- 1 ,2,3 ,4-tetrahydro-3 β-hydroxy-2,2,4α- trimethylquinoline was prepared from (±)-5-ethynyl-7-fluoro-l,2,3,4-tetrahydro-3β-hydroxy- 2,2,4α-trimethylquinoline using General Method 3 (EXAMPLE 1).

[0542] (±)-5-Ethynyl-7-fiuoro-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7- yl)-2,2,4α-trimethylquinoline. This compound was prepared from (±)-6-bromo-5-ethyny 1-7- fluoro- l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α-trimethylquinoline and 3-methyl-7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)indole using General Method 12 (EXAMPLE 52).

[05431 (±)-7-Fluoro-l,2,3,4-tetrahvdro-3β-hvdroxy-2,2,4α-trimethyl-6-(3- methylindol-7-yπ-5-(m-tolylethynvπquinoline (Compound 328). This compound was prepared from (±)-5-ethynyl-l ,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α- trimethylquinoline and 3-iodotoluene using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.83 (br s, 0.5H), 7.82 (br s, 0.5H), 7.63 (m, IH), 7.28 (m, 0.5H), 7.25 (m, 0.5H), 7.21 (m, 0.5H), 7.20 (m, 0.5H), 7.06 (m, 0.5H), 7.05 (m, 0.5H), 7.01 (m, IH), 6.97 (q, J=LO Hz, 0.5H), 6.94 (q, J=LO Hz, 0.5H), 6.73 (m, IH), 6.59 (m, IH), 6.39 (d, J=IOJ Hz, 0.5H), 6.38 (d, J=IOJ Hz, 0.5H), 3.78 (br s, IH), 3.58 (m, IH), 3.15 (m, IH), 2.39 (d, J=LO Hz, 1.5H), 2.39 (d, J=LO Hz, 1.5H), 2.22 (d, J=2.0 Hz, 3H), 1.91 (d, J=7.6 Hz, 0.5H), 1.87 (d, J=7.6 Hz, 0.5H), 1.68 (d, J=7.1 Hz, 1.5H), 1.67 (d, J=7.1 Hz, 1.5H), 1.35 (s, 3H), 1.24 (s, 1.5H), 1.22 (s, 1.5H). EXAMPLE 118

[05441 f±)-6-(3.5-Dimethylisoxazol-4-vn-1.2.3.4-tetrahvdro-3β-hvdroxy- 2,2,4α,8-tetramethyl-5-(m-tolylethynyl)quinoline (Compound 329).

[0545] (±)-6-(3,5-Dimethylisoxazol-4-yl)-5-ethynyI-l,2,3,4-tetrahydro-3β- hydroxy-2,2,4α,8-tetramethylquinoline. This compound was prepared from (±)-6-bromo-5- ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline and 3,5-dimethyl-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole using General Method 12 (EXAMPLE 52).

[0546] This compound was prepared from (±)-6-(3,5-dimethylisoxazol-4-yl)-5- ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline and 3-iodotoluene using General Method 21 (EXAMPLE 90). ¹H NMR (300MHz, CDCl₃) δ 7.18 (m, IH), 7.13-7.08 (m, 3H), 6.78 (s, IH), 3.57 (m, 2H), 3.19 (m, IH), 2.34 (s, 1.5H), 2.32 (s, 3H), 2.31 (s, 1.5H), 2.25 (s, 1.5H), 2.21 (s, 1.5H), 2.17 (s, 3H), 1.67 (d, J=7.0 Hz, 1.5H), 1.67 (d, J=7.0 Hz, 1.5H), 1.36 (s, 3H), 1.20 (s, 3H). EXAMPLE 1 19

[05471 (±)-1.2.3.4-Tetrahydro-3β-hvdroxy-2,2,4α.8-tetramethyl-6-(3- methylindol-7-vπ-5-r(thiophen-2-yl)ethvnyllquinoline (Compound 330).

[0548] (±)- 1 ,2,3,4-Tetrahydro-3 β-hydroxy-2,2,4α,8-tetramethyl-5-[(thiophen-2- yl)ethynyl]quinoline. This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro- 3β-hydroxy-2,2,4α,8-tetramethylquinoline and 2-iodothiophene using General Method 21 (EXAMPLE 90).

[0549] (±)-6-Bromo-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-5- [(thiophen-2-yl)ethynyl]quinoline. This compound was prepared from (±)-l, 2,3,4- tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-5-[(thiophen-2-yl)ethynyl]quinoline using

General Method 3 (EXAMPLE 1).

r05501 (±)- 1.2.3.4-Tetrahvdro-3 β-hydroxy-2.2.4α, 8-tetramethy l-6-(3 - methylindol-7-yπ-5-f(thiophen-2-vπethvnyl1quinoline (Compound 330). This compound was prepared from (±)-6-bromo- 1,2,3, 4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethy 1-5- [(thiophen-2-yl)ethynyl]quinoline and 3-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indole using General Method 12 (EXAMPLE 52). ¹H NMR (300MHz, CDCl₃) δ 7.97 (br s, IH), 7.57 (d, J=7.4 Hz, IH), 7.25 (m, IH), 7.18 (t, J=7.4 Hz, IH), 7.14 (dd, J=5.2, 1.0 Hz, IH), 7.1 1 (s, IH), 6.96 (m, IH), 6.85 (dd, J=5.2, 3.6 Hz, IH), 6.72 (dd, J=3.6, 1.0 Hz, IH), 3.62-3.56 (m, 2H), 3.19 (m, IH), 2.38 (d, J=0.6 Hz, 3H), 2.20 (s, 3H), 1.91 (d, J=7.6 Hz, I H), 1.67 (d, J=7.0 Hz, 3H), 1.37 (s, 3H), 1.22 (s, 3H).

EXAMPLE 120

[0551] (±)-l,2,3.4-Tetrahvdro-3β-hvdroxy-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yl)-5-[(thiophen-3-yl)ethynvπquinoline (Compound 331). This compound was prepared from from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethylquinoline and 3-iodothiophene using the sequence described for Compound 330 (EXAMPLE 1 19, General Methods 21, 3, and 12) to afford Compound 331. ¹H NMR (300MHz, CDCl₃) δ 7.99 (br s, IH), 7.57 (m, IH), 7.24 (m, IH), 7.18 (t, J=7.4 Hz, IH), 7.12 (dd, J=5.0, 3.0 Hz, IH), 7.10 (s, IH), 6.96 (m, IH), 6.92 (dd, J=3.0, 1.0 Hz, IH), 6.63 (dd, J=5.0, 1.0 Hz, IH), 3.59 (dd, J=7.3, 5.5 Hz, IH), 3.57 (br s, IH), 3.21 (m, IH), 2.39 (d, J=0.7 Hz, 3H), 2.19 (s, 3H), 1.92 (d, J=7.3 Hz, IH), 1.69 (d, J=7.0 Hz, 3H), 1.37 (s, 3H), 1.22 (s, 3H). EXAMPLE 121

fO552] (±V1.2.3,4-Tetrahvdro-3β-hvdroxy-2.2.4α.8-tetramethyl-6-(3- methylindol-7-vπ-5-r(5-methylthiophen-2-yl)ethvnyllquinoline (Compound 332). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethylquinoline and 2-iodo-5-methylthiophene using the sequence described for Compound 330 (EXAMPLE 119, General Methods 21, 3, and 12) to afford Compound 332. ¹H NMR (500MHz, CDCl₃) δ 7.96 (br s, IH), 7.56 (dd, J=7.7, 0.9 Hz, IH), 7.25 (m, IH), 7.18 (dd, J=7.7, 7.3 Hz, IH), 7.10 (q, J=0.5 Hz, IH), 6.96 (q, J=LO Hz, IH), 6.53 (d, J=3.6 Hz, IH), 6.50 (dq, J=3.6, 1.0 Hz, IH), 3.59 (dd, J=7.8, 5.5 Hz, IH), 3.56 (br s, IH), 3.17 (qd, J=7.1, 5.5 Hz, IH), 2.39 (d, J=LO Hz, 3H), 2.38 (d, J=LO Hz, 3H), 2.19 (d, J=0.5 Hz, 3H), 1.88 (d, J=7.8 Hz, IH), 1.66 (d, J=7.1 Hz, 3H), 1.37 (s, 3H), 1.22 (s, 3H).

EXAMPLE 122

rO5531 (±)-L2.3,4-Tetrahvdro-3β-hvdroxy-2.2.4α,8-tetramethyl-6-(3- methylindol-7-yl)-5-(3-morpholinophenylethvnyl)quinoline (Compound 333). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3- methylindol-7-yl)-2,2,4α,8-tetramethylquinoline and 4-(3-bromobenzoyl)morpholine using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 8.02 (s, IH), 7.56 (m, IH), 7.23 (m, IH), 7.19 (t, J=7.4 Hz, IH), 7.09 (s, IH), 7.08 (dd, J=8.3, 7.6 Hz, IH), 6.97 (m, IH), 6.74 (ddd, J=8.3, 2.2, 0.7 Hz, IH), 6.60 (ddd, J=7.6, 1.4, 0.7 Hz, IH), 6.15 (dd, J=2.2, 1.4 Hz, IH), 3.84 (t, J=4.9 Hz, 4H), 3.60 (dd, J=6.8, 5.5 Hz, IH), 3.25 (m, IH), 3.01 (t, J=4.9 Hz, 4H), 2.36 (d, J=0.7 Hz, 3H), 2.20 (s, 3H), 1.91 (m, IH), 1.71 (d, J=6.8 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 123

[0554] (±)- 1 ,2,3 ,4-Tetrahydro-3 β-hydroxy-5 -(3 -hydroxypheny lethyny l)-2,2,4α, 8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 334). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 3-iodophenol using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 7.98 (s, IH), 7.58 (d, J=7.7 Hz, IH), 7.25 (m, IH), 7.19 (dd, J=7.7, 7.3 Hz, IH), 7.09 (s, IH), 7.03 (t, J=8.0 Hz, IH), 6.95 (q, J=LO Hz, IH), 6.67 (ddd, J=8.0, 2.5, 1.0 Hz, IH), 6.53 (m, IH), 6.28 (dd, J=2.5, 1.5 Hz, IH), 3.61 (d, J=5.3 Hz, IH), 3.18 (qd, J=7.1, 5.3 Hz, IH), 2.39 (d, J=LO Hz, 3H), 2.19 (d, J=0.4 Hz, 3H), 1.68 (d, J=7.1 Hz, 3H), 1.37 (s, 3H), 1.23 (s, 3H).

EXAMPLE 124

[05551 (±)-5-(3-Aminophenylethvnyl)-L2.3.4-tetrahvdro-3β-hvdroxy-2.2.4α.8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 335). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 3-iodoaniline using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 8.00 (s, IH), 7.58 (d, J=7.6 Hz, IH), 7.25 (m, IH), 7.19 (dd, J=7.6, 7.3 Hz, IH), 7.10 (q, J=0.5 Hz, IH), 6.96 (q, J=I.0 Hz, IH), 6.95 (t, J=8.0 Hz, IH), 6.52 (ddd, JM8.0, 2.3, 1.0 Hz, IH), 6.39 (m, IH), 6.12 (dd, J=2.3, 1.5 Hz, IH), 3.60 (d, J=5.5 Hz, I H), 3.23 (qd, J=7.0, 5.5 Hz, IH), 2.39 (d, J=LO Hz, 3H), 2.19 (d, J=0.5 Hz, 3H), 1.70 (d, J=7.0 Hz, 3H), 1.37 (s, 3H), 1.22 (s, 3H).

EXAMPLE 125

105561 (±)-1.2.3.4-Tetrahvdro-3β-hvdroxy-2,2.4α.8-tetramethyl-6-(3- methylindol-7-yl)-5-r(3-methylthiophen-2-yl)ethvnyllquinoline (Compound 336). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethylquinoline and 2-bromo-3-methylthiophene using the sequence described for Compound 330 (EXAMPLE 1 19, General Methods 21, 3, and 12) to afford Compound 336. ¹H NMR (500MHz, CDCl₃) δ 7.92 (s, IH), 7.54 (d, J=7.6 Hz, IH), 7.22 (dd, J=7.2, 0.8 Hz, IH), 7.16 (dd, J=7.6, 7.2 Hz, IH), 7.08 (s, IH), 7.03 (d, J=5.0 Hz, IH), 6.93 (q, J=L l Hz, IH), 6.67 (d, J=5.0 Hz, IH), 3.60 (dd, J=7.8, 5.3 Hz, IH), 3.57 (s, IH), 3.21 (qd, J=6.9, 5.3 Hz, IH), 2.36 (d, J=Ll Hz, 3H), 2.19 (d, J=0.5 Hz, 3H), 1.90 (d, J=7.8 Hz, IH), 1.72 (s, 3H), 1.69 (d, J=6.9 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 126

fO557| (±H.2.3.4-Tetrahydro-3β-hvdroxy-2,2,4α.8-tetramethyl-6-(3- methylindol-7-yl)-5-[(pyrimidin-2-yl)ethynyllquinoline (Compound 337). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethylquinoline and 2-bromo-pyrimidine using the sequence described for Compound 330 (EXAMPLE 1 19, General Methods 21, 3, and 12) to afford Compound 337. ¹H NMR (300MHz, CDCl₃) δ 8.00 (s, IH), 7.67 (m, IH), 7.56-7.45 (m, 2H), 7.36 (m, IH), 7.19 (d, J=7.8 Hz, IH), 7.14 (m, IH), 7.10 (t, J=4.9 Hz, IH), 6.94 (m, IH), 3.62-3.56 (m, 2H), 3.29 (m, IH), 2.33 (d, J=LO Hz, 3H), 2.20 (d, J=0.5 Hz, 3H), 1.81 (m, IH), 1.72 (d, J=7.0 Hz, 3H), 1.37 (s, 3H), 1.20 (s, 3H).

EXAMPLE 127

[05581 (±)-L2,3,4-Tetrahvdro-3β-hvdroxy-2,2,4α,8-tetramethyl-6-(3- methylindol-7-yl)-5-[(pyridin-3-yl)ethynyl]quinoline (Compound 338). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline and 3-iodo-pyridine using the sequence described for Compound 330 (EXAMPLE 1 19, General Methods 21, 3, and 12) to afford Compound 338. ¹H NMR (300MHz, CDCl₃) δ 8.39 (m, IH), 8.14 (m, IH), 7.94 (m, IH), 7.59 (m, IH), 7.24 (m, IH), 7.20 (m, IH), 7.17-7.1 1 (m, 3H), 6.96 (m, IH), 3.64-3.56 (m, 2H), 3.23 (m, IH), 2.39 (d, J=LO Hz, 3H), 2.21 (d, J=0.5 Hz, 3H), 1.92 (m, IH), 1.70 (d, J=7.0 Hz, 3H), 1.39 (s, 3H), 1.24 (s, 3H).

EXAMPLE 128

[0559] (^-S^S-Acetyl-∑-fluorophenylethvnylVL∑J^-tetrahydro-Sβ-hydroxy- 2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 339). This compound was prepared from (±)-5-ethynyl- 1 ,2,3,4-tetrahydro-3 β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 3-bromo-4-fluoroacetophenone using General Method 21 (EXAMPLE 90). ¹H NMR (300MHz, CDCl₃) δ 8.00 (br s, I H), 7.80 (ddd, J=8.8, 5.1, 2.4 Hz, IH), 7.60 (dd, J=7.3, 1.5 Hz, I H), 7.26 (dd, J=7.3, 1.5 Hz, IH), 7.21 (t, J=7.3 Hz, I H), 7.12 (m, IH), 7.06 (dd, J=6.6, 2.4 Hz, IH), 7.03 (t, J=8.8 Hz, IH), 6.97 (q, J=LO Hz, IH), 3.65-3.58 (m, 2H), 3.26 (qd, J=6.9, 5.5 Hz, IH), 2.45 (s, 3H), 2.37 (d, J=LO Hz, 3H), 2.21 (d, J=0.6 Hz, 3H), 1.91 (m, IH), 1.71 (d, J=6.9 Hz, 3H), 1.39 (s, 3H), 1.24 (s, 3H).

EXAMPLE 129

105601 (±)-L2.3.4-Tetrahvdro-3β-hvdroxy-2,2,4α.8-tetramethyl-6-(3- methylindol-7-yl)-5-(3-sulfamoylphenylethynyl)quinoline (Compound 340). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)- 2,2,4α,8-tetramethylquinoline and 3-bromo-benzenesulfbnamide using General Method 21 (EXAMPLE 90). ¹H NMR (300MHz, CDCl₃) δ 7.98 (br s, IH), 7.70 (m, IH), 7.60 (m, IH), 7.39 (t, J=I .6 Hz, IH), 7.29 (t, J=7.8 Hz, IH), 7.24 (m, IH), 7.20 (t, J=7.2 Hz, IH), 7.12 (s, IH), 7.00 (m, IH), 6.97 (m, IH), 4.81 (s, 2H), 3.61 (d, J=5.6 Hz, IH), 3.61 (br s, IH), 3.22 (qd, J=6.9, 5.7 Hz, IH), 2.39 (d, J=0.8 Hz, 3H), 2.21 (s, 3H), 1.69 (d, J=6.9 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 130

[05611 f±)-1.2.3.4-Tetrahvdro-3β-hvdroxy-2.2.4α.8-tetramethyl-6-(3- methylindol-7-yl)-5-[3-(l-morpholinocarbonyl)phenylethynyl]quinoline (Compound 341 ). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3- methylindol-7-yl)-2,2,4α,8-tetramethylquinoline and 4-(3-bromobenzoyl)morpholine using General Method 21 (EXAMPLE 90). ¹H NMR (300MHz, CDCl₃) δ 7.97 (m, IH), 7.59 (m, IH), 7.24-7.21 (m, 3H), 7.19 (t, J=7.3 Hz, IH), 7.11 (s, IH), 6.99-6.94 (m, 2H), 6.80 (m, IH), 3.83-3.71 (m, 4H), 3.61 (d, J=5.3 Hz, IH), 3.54 (m, 2H), 3.28 (m, 2H), 3.23 (m, IH), 2.38 (d, J=0.9 Hz, 3H), 2.20 (s, 3H), 1.69 (d, J=7.0 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 131

fO5621 (±)-l,2,3,4-Tetrahvdro-3β-hvdroxy-2.2,4α.8-tetramethyl-6-(3- methylindol-7-yD-5-(3-diethylsulfamoylphenylethvnv0quinoline (Compound 342). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3- rnethylindol-7-yl)-2,2,4α,8-tetrarnethylquinoline and 3-bromo-N,N- diethylbenzenesulfonamide using General Method 21 (EXAMPLE 90). ¹H NMR (300MHz, CDCl₃) δ 7.96 (br s, IH), 7.63-7.57 (m, 2H), 7.32 (t, J= 1.6 Hz, IH), 7.31-7.22 (m, 2H), 7.19 (t, J=7.3 Hz, IH), 7.12 (s, IH), 7.02-6.96 (m, 2H), 3.61 (d, J=5.4 Hz, IH), 3.23 (m, IH), 3.15 (q, J=7.2 Hz, 4H), 2.40 (s, 3H), 2.21 (s, 3H), 1.69 (d, J=7.0 Hz, 3H), 1.39 (s, 3H), 1.24 (s, 3H), 1.10 (t, J=7.2 Hz, 6H).

EXAMPLE 132

[0563] (±)-5-r(2-Acetylthiophen-3-vπethvnyl1-U2,3,4-tetrahvdro-3β-hvdroxy- 2,2,4α,8-tetrarnethyl-6-(3-methylindol-7-yl)quinoline (Compound 343). This compound was prepared from (±)-5-ethynyl-l ,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline and 2-acetyl-3-iodothiophene using the sequence described for Compound 330 (EXAMPLE 119, General Methods 21, 3, and 12) to afford Compound 343. ¹H NMR (500MHz, CDCl₃) δ 7.87 (s, IH), 7.54 (d, J=8.0 Hz, IH), 7.37 (d, J=5.0 Hz, IH), 7.16 (m, IH), 7.14 (m, IH), 7.06 (s, IH), 6.92 (m, IH), 6.69 (m, IH), 3.63-3.59 (m, 2H), 3.22 (m, IH), 2.35 (d, J=LO Hz, 3H), 2.20 (s, 3H), 1.97 (d, J=6.8 Hz, IH), 1.88 (s, 3H), 1.70 (d, J=6.8 Hz, 3H), 1.39 (s, 3H), 1.24 (s, 3H).

EXAMPLE 133

[0564] (±)-l,2,3,4-Tetrahydro-3β-hydroxy-5-(3-methoxyphenylethynyl)-2,2,4α,8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 344). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3-methylindol-7-yl)-2,2,4α,8- tetramethylquinoline and 3-iodoanisole using General Method 21 (EXAMPLE 90). ¹H NMR (500MHz, CDCl₃) δ 8.01 (br s, IH), 7.57 (m, IH), 7.24 (m, IH), 7.19 (t, J=7.4 Hz, IH), 7.10 (m, IH), 7.08 (dd, J=8.3, 7.7 Hz, IH), 6.97 (q, J=LO Hz, IH), 6.74 (ddd, J=8.3, 2.7, 1.0 Hz, IH), 6.62 (ddd, J=7.7, 1.3, 1.0 Hz, IH), 6.24 (dd, J=2.7, 1.3 Hz, IH), 3.68 (s, 3H), 3.60 (dd, J=7.5, 5.5 Hz, IH), 3.58 (s, IH), 3.24 (qd, J=7.0, 5.5 Hz, IH), 2.37 (d, J=LO Hz, 3H), 2.20 (d, J=0.5 Hz, 3H), 1.91 (d, J=7.5 Hz, IH), 1.71 (d, J=7.0 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H). EXAMPLE 134

fO565] C--:^')-l,2,3,4-Tetrahvdro-3β-hvdroxy-2,2,4α.8-tetramethyl-5-r3- (methylamino)phenylethvnyll-6-(3-rnethylindol-7-v0quinoline (Compound 345). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-6-(3- methylindol-7-yl)-2,2,4α,8-tetramethylquinoline and 3-bromo-N-methylaniline using General Method 21 (EXAMPLE 90). ¹H NMR (300MHz, CDCl₃) δ 8.02 (br s, IH), 7.57 (m, IH), 7.25 (m, IH), 7.19 (t, J=7.5 Hz, IH), 7.10 (s, IH), 6.98 (dd, J=8.2, 7.6 Hz, IH), 6.97 (m, IH), 6.45 (ddd, J=8.2, 2.4, 0.8 Hz, IH), 6.41 (ddd, J=7.6, 1.4, 0.8 Hz, IH), 5.97 (dd, J=2.4, 1.4 Hz, IH), 3.60 (d, J=5.3 Hz, IH), 3.58 (m, IH), 3.25 (m, IH), 2.73 (s, 3H), 2.37 (d, J=0.9 Hz, 3H), 2.20 (s, 3H), 1.71 (d, J-7.0 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 135

[0566] (±)- 1 ,2,3,4-Tetrahydro-3 β-hydroxy-5- { [2-( 1 -methoxy iminoethy Dthiophen- 3-yl1ethynyl}-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 346). This compound was prepared by treatment of Compound 343 (EXAMPLE 132) (10 mg, 0.021 mmol), O-methyl hydroxylamine hydrochloride (18 mg, 0.22 mmol), NaOAc (17 mg, 0.21 mmol) in ethanol (4 mL) heated at 60 ⁰C for 15 h to afford Compound 346 as a 2:1 mixture of isomers. ¹H NMR (500MHz, CDCl₃) δ 7.90 (br s, IH), 7.55 (m, IH), 7.19 (m, IH), 7.15 (t, J=7.3 Hz, IH), 7.05 (m, IH), 7.00 (d, J=5.1 Hz, IH), 6.92 (s, IH), 6.47 (m, IH), 3.91 (s, 3H), 3.62-3.56 (m, 2H), 3.18 (m, IH), 2.36 (d, J=1.0 Hz, 3H), 2.19 (d, J=0.5 Hz, 3H), 1.78 (s, 3H), 1.66 (d, J=6.6 Hz, 3H), 1.38 (s, 3H), 1.22 (s, 3H). EXAMPLE 136

[05671 (±V 1 ,2,3 ,4-Tetrahvdro-3 β-hydroxy-2,2,4α, 8-tetramethyl-6-(3 - methylindol-7-v0-5-r(5-methylthiophen-3-yl)ethynyllquinoline (Compound 347). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethylquinoline and 4-bromo-2-methylthiophene using the sequence described for Compound 330 (EXAMPLE 119, General Methods 21, 3, and 12) to afford Compound 347. ¹H NMR (500MHz, CDCl₃) δ 7.99 (br s, IH), 7.57 (d, J=7.8 Hz, IH), 7.24 (m, IH), 7.18 (m, IH), 7.10 (s, IH), 6.97 (m, IH), 6.69 (m, IH), 6.27 (m, IH), 3.59 (m, IH), 3.57 (s, IH), 3.20 (qn, J=7.0 Hz, IH), 2.39 (m, 3H), 2.36 (m, 3H), 2.19 (s, 3H), 1.89 (d, J=7.1 Hz, IH), 1.68 (d, J=7.0 Hz, 3H), 1.37 (s, 3H), 1.22 (s, 3H).

EXAMPLE 137

[05681 (-t:)-l,2,3,4-Tetrahvdro-3β-hvdroxy-5-r2-(methoxycarbonylthiophen-3- yl)ethynyl1-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 348). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethylquinoline and methyl 3-(iodothiophen-2-yl)carboxylate using the sequence described for Compound 330 (EXAMPLE 119, General Methods 21, 3, and 12) to afford Compound 348. ¹H NMR (500MHz, CDCl₃) δ 8.04 (br s, IH), 7.57 (d, J=7.7 Hz, IH), 7.24 (m, IH), 7.22 (d, J=5.1 Hz, IH), 7.18 (t, J=7.7 Hz, IH), 7.10 (s, IH), 6.92 (m, IH), 6.14 (d, J=5.1 Hz, IH), 3.84 (s, 3H), 3.62 (m, IH), 3.37 (qd, J=6.9, 5.4 Hz, IH), 2.37 (s, 3H), 2.20 (d, J=LO Hz, 3H), 1.70 (d, J=6.9 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 138

[05691 (±)-5-f3-fEthoxycarbonylthiophen-2-yl)ethvnyll-L2.3.4-tetrahvdro-3B- hvdroxy-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 349).

[0570] (±)-5-[3-(Ethoxycarbonylthiophen-2-yl)ethynyl]-l,2,3,4-tetrahydro-3β- hydroxy-2,2,4α,8-tetramethylquinoline. This compound was prepared from (±)-5-ethynyl- l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline and ethyl 2-(bromothiophen-3- yl)carboxylate using General Method 21 (EXAMPLE 90).

[0571] (±)-6-Bromo-5-[3-(ethoxycarbonylthiophen-2-yl)ethynyl]- 1,2,3,4- tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline. This compound was prepared from (±)-5-[3-(ethoxycarbonylthiophen-2-yl)ethynyl]-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8- tetramethylquinoline using General Method 3 (EXAMPLE 1).

[0572] (±V5-r3-(Ethoxycarbonylthiophen-2-vnethvnyll-1.2.3.4-tetrahvdro-3B- hydroxy-2,2,4α,8-tetrarnethyl-6-(3-methylindol-7-yl)quinoline (Compound 349). This compound was prepared from (±)-6-bromo-5-[3-(ethoxycarbonylthiophen-2-yl)ethynyl]- 1 ,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline and 3-methyl-7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)indole using General Method 12 (EXAMPLE 52). ¹H NMR (500MHz, CDCl₃) δ 8.02 (s, IH), 7.56 (d, J=7.6 Hz, IH), 7.31 (d, J=5.3 Hz, IH), 7.25 (m, IH), 7.18 (t, J=7.6 Hz, I H), 7.1 1 (s, I H), 7.03 (d, J=5.3 Hz, IH), 6.93 (s, IH), 4.27 (m, 2H), 3.60 (d, J=5.4 Hz, IH), 3.33 (m, IH), 2.36 (s, 3H), 2.20 (s, 3H), 1.68 (d, J=7.0 Hz, 3H), 1.38 (s, 3H), 1.29 (t, J=7.0 Hz, 3H), 1.23 (s, 3H).

EXAMPLE 139

[0573] (±)-1.2.3.4-Tetrahvdro-3β-hvdroxy-2.2.4α.8-tetramethyl-6-(3- methylindol-7-vD-5-[(pyridin-2-vDethvnγl1quinoline (Compound 350). This compound was prepared from (±)-5-ethynyl-l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline and 2-iodopyridine using the sequence described for Compound 330 (EXAMPLE 1 19, General Methods 21, 3, and 12) to afford Compound 350. ¹H NMR (500MHz, CDCl₃) δ 8.47 (d, J=4.8 Hz, IH), 7.58 (d, J=7.7 Hz, IH), 7.42 (td, J=7.7, 1.9 Hz, IH), 7.27 (m, IH), 7.19 (dd, J=7.7, 7.4 Hz, IH), 7.09 (s, IH), 7.07 (ddd, J=7.7, 4.8, 1.1 Hz, IH), 6.96 (m, IH), 6.48 (m, IH), 3.53 (m, 2H), 3.17 (m, IH), 2.38 (d, J=I .0 Hz, 3H), 2.14 (s, 3H), 1.80 (m, IH), 1.69 (d, J=6.7 Hz, 3H), 1.35 (s, 3H), 1.14 (s, 3H).

EXAMPLE 140

[0574] (±)-6-(3,5-DimethvHsoxazol-4-yl)-5-[3-(ethoxycarbonylthiophen-2- yl)ethvnyl1-l,2,3,4-tetrahvdro-3β-hydroxy-2,2,4α,8-tetramethylquinoline (Compound 351). This compound was prepared from (±)-6-bromo-5-[3-(ethoxycarbonylthiophen-2-yl)ethynyl]- l,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethylquinoline (EXAMPLE 138) and 3,5- dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole using General Method 12 (EXAMPLE 52). ¹H NMR (500MHz, CDCl₃) δ 7.40 (d, J=5.4 Hz, IH), 7.15 (d, J=5.3 Hz, IH), 6.78 (d, J=2.4 Hz, IH), 4.34 (m, 2H), 3.58 (m, 2H), 3.25 (m, IH), 2.35 (s, 1.5H), 2.31 (s, 1.5H), 2.24 (s, 1.5H), 2.19 (s, 1.5H), 2.18 (s, 3H), 1.65 (d, J=4.9 Hz, 3H), 1.36 (s, 3H), 1.33 (t, J=7.3Hz, 3H), 1.20 (s, 3H).

EXAMPLE 141

[0575] (±)-l,2,3,4-Tetrahydro-3β-hydroxy-5-[3-(hydroxymethyl)thiophen-2- yl]ethynyl]-2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 352). IM Lithium triethylborohydride in THF (0.62 ml, 0.62 mmol) was added dropwise to a solution of Compound 349 (EXAMPLE 138) (30 mg, 0.059 mmol) in THF (5 ml) at -40 ⁰C. The reaction was allowed to warm to 0 ⁰C and stirred for 10 minutes. The reaction was poured into a saturated solution of ammonium chloride (10 ml), diluted with ethyl acetate (15 ml), the layers separated and the aqueous layer was extracted with ethyl acetate (3 ^χ 5 ml). The combined organics were washed with a saturated solution of ammonium chloride (30 ml), dried (Na₂SO₄) and concentrated under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate :hexanes gave Compound 352 (11 mg, 40 %). ¹H NMR (500MHz, CDCl₃) δ 7.84 (s, IH), 7.61 (m, IH), 7.22 (m, 2H), 7.1 1 (d, J=5.4 Hz, IH), 7.06 (s, IH), 6.96 (s, IH), 6.89 (d, J 5.4 Hz, IH), 4.31 (m, IH), 3.84 (m, 2H), 3.60 (m, 2H), 3.18 (m, IH), 2.38 (d, J=1.0 Hz, 3H), 2.20 (s, 3H), 1.96 (d, J=6.9Hz, IH), 1.68 (d, J=7.3Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H).

EXAMPLE 142

rO5761 (±)-5-r(3-Acetylthiophen-2-yl)ethvnyl1-1.2.3,4-tetrahvdro-3β-hvdroxy- 2,2,4α,8-tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 353) and (±)- 1,2,3,4- tetrahvdro-3β-hvdroxy-5-{[3-(l-hydroxy-l-methvethyl)thiophen-2-yllethvnyl}-2,2,4α,8- tetramethyl-6-(3-methylindol-7-yl)quinoline (Compound 354). 1.6 M Methyl lithium in Et₂O (0.39 ml, 0.62 mmol) was added dropwise to a solution of Compound 349 (30 mg, 0.059 mmol) in Et₂O (5 ml) at -78 ⁰C. The reaction was allowed to warm to room temperature and stirred for 15 minutes. The reaction was poured into a saturated solution of ammonium chloride (10 ml) and extracted with ethyl acetate (3 x 10 ml). The combined organics were washed with a saturated solution of ammonium chloride (30 ml), dried (Na₂SO₄) and concentrated under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate:hexanes gave Compound 353 (4 mg, 14 %) and Compound 354 (12 mg, 41 %).

[0577] Compound 353: ¹H NMR (500MHz, CDCl₃) δ 7.86 (s, IH), 7.54 (m, IH), 7.31 (d, J=5.4 Hz, IH), 7.16 (m, 2H), 7.06 (m, 2H), 6.92 (s, I H), 3.62 (s, 2H), 3.20 (m, I H), 2.37 (d, J=I .0 Hz, 3H), 2.20 (s, 3H), 1.83 (s, 3H), 1.68 (d, J=7.3 Hz, 3H), 1.39 (s, 3H), 1.25 (s, 3H).

[0578] Compound 354: ¹H NMR (500MHz, CDCl₃) δ 7.86 (s, IH), 7.55 (m, IH), 7.18 (d, J=5.8 Hz, IH), 7.03 (m, 2H), 6.93 (s, IH), 6.90 (d, J=5.4 Hz, IH), 3.60 (d, J 5.3 Hz, 2H), 3.16 (m, IH), 2.36 (d, J=LO Hz, 3H), 2.18 (s, 3H), 1.68 (d, J=7.3 Hz, 3H), 1.38 (s, 3H), 1.23 (s, 3H), 1.15 (s, 6H).

EXAMPLE 143

10579] (±)-4α-Benzylamino-6-(3-chloroindol-7-yl)-5J-difluoro-L2Λ4- tetrahvdro-3β-hydroxy-2,2-dirnethylquinoline (Compound 401).

[0580] 5,7-Difluoro-l,2-dihydro-2,2-dimethy-l-(trifluoroacetyl)quinoline. This compound was prepared as follows. 5,7-Difluoro-l,2-dihydro-2,2-dimethylquinoline (EXAMPLE 52) (1.0 equiv) was dissolved in pyridine (4.0 equiv) in dichloromethane at 0 ⁰C, then trifluoroacetic anhydride (1.5 equiv) was added over 0.5 h. Upon completion of addition, the reaction was stirred an additional 1.5 h and poured into water. The layers were separated and the organic layer was washed with IM HCl, brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 5,7-difluoro-l,2- dihydro-2,2-dimethy-l-(trifluoroacetyl)quinoline.

[0581] (±)-4α-Benzylamino-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2- dimethylquinoline. This compound was prepared as follows. To 5,7-difluoro-l,2-dihydro- 2,2-dimethy-l-(trifluoroacetyl)quinoline (150 mg, 0.52 mmol, 1 equiv) in dichloromethane (5.5 mL) at room temperature was added sodium bicarbonate (219 mg, 2.58 mmol, 5 equiv), followed by m-chloro(peroxy)benzoic acid (444 mg, 2.58 mmol). After 15 hours, the mixture was quenched with 5 mL of a saturated aqueous sodium bicarbonate solution, resulting in an aqueous layer and a first organic layer. The first organic layer is collected and the aqueous layer is extracted with a second organic layer of dichloromethane. The first and second organic layers are combined and that combined organic layer is washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (silica gel) afforded a white, powder (76%). This material (2.66 mmol, 1 equiv) was treated with ethanol (25 mL) at room temperature, then benzylamine (2.32 mL, 21.3 mmol, 8 equiv) was added. The reaction was heated to reflux for 15 h, cooled to room temperature and diluted with 25 mL of ethyl acetate and washed with 50 mL of saturated aqueous ammonium chloride solution. The first organic layer is collected and the aqueous layer is extracted with a second organic layer of ethyl acetate. The first and second organic layers are combined and that combined organic layer is washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (silica gel) afforded (±)-4α-benzylamino-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethylquinoline (73%).

rO5821 (±V4α-Benzylamino-6-(3-chloroindol-7-vn-5.7-difluoro-1.2.3.4- tetrahydro-3β-hydroxy-2,2-dimethylquinoline (Compound 401). This compound was prepared from (±)-4α-benzylamino-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2- dimethylquinoline and 3-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indole using General Methods 3 and 4 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 7.96 (br s, IH), 7.68 (m, IH), 7.33-7.28 (m, 4H), 7.27-7.24 (m, 3H), 7.17 (d, J=2.4 Hz, IH), 6.24 (dd, J=I 1.0, 1.5 Hz, IH), 4.05 (br s, IH), 4.01 (d, J=8.8 Hz, IH), 3.74 (d, J=8.8 Hz, IH), 3.70 (d, J=12.7 Hz, IH), 3.65 (d, J=12.7 Hz, IH), 3.21 (br s, IH), 1.43 (s, 3H), 1.22 (s, 3H). EXAMPLE 144

[05831 (±)-6-(3-Chloroindol-7-ylV5J-difluoro-l,23,4-tetrahvdro-3β-hvdroxy- 2,2-dimethyl-4α-F(thiophen-2-ylmethyl)aminolquinoline (Compound 402).

[0584] (±)-5,7-Difϊuoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-4α- [(thiophen-2-ylmethyl)amino]quinoline. This compound was prepared in a manner similar to (±)-4α-benzylamino-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethylquinoline (EXAMPLE 143) except 2-(aminomethyl)thiophene was used instead of benzylamine.

[0585| (±)-6-(3-Chloroindol-7-yl)-5J-difluoro-1.23.4-tetrahvdro-3β-hvdroxy- 2,2-dimethyl-4α-[(thiophen-2-ylmethyl)amino1quinoline (Compound 402). This compound was prepared from (±)-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethyl-4α- [(thiophen-2-ylmethyl)amino]quinoline and 3-chloro-7-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)indole using General Methods 3 and 4 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 8.00 (s, IH), 7.71 (m, IH), 7.35-7.31 (m, 2H), 7.23 (dd, J=S-I, 1.0 Hz, IH), 7.22 (d, J=2.4 Hz, IH), 6.92 (dd, J=5.1, 3.4 Hz, IH), 6.89 (m, IH), 6.21 (dd, J=10.7, 1.5 Hz, IH), 3.99 (s, IH), 3.94 (m, 2H), 3.89 (d, J=9.0 Hz, IH), 3.55 (d, J=9.0 Hz, IH), 2.88 (s, IH), 1.32 (s, 3H), 1.04 (s, 3H). EXAMPLE 145

[05861 f±)-4α-Benzylamino-5,7-difluoro-l,2,3,4-tetrahvdro-3β-hydroxy-2,2- dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 403). This compound was prepared from (±)-4α-benzylamino-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethylquinoline and 3-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indole using General Methods 3 and 4 (EXAMPLE 1). ¹H NMR (500MHz, CDCl₃) δ 7.80 (s, IH), 7.62 (m, IH), 7.31-7.28 (m, 4H), 7.24 (m, IH), 7.22-7.19 (m, 2H), 6.96 (s, IH), 6.22 (d, J=I LO Hz, IH), 4.02-3.98 (m, 2H), 3.73 (m, IH), 3.68 (d, J=12.4 Hz, IH), 3.65 (d, J=12.4 Hz, IH), 3.25 (s, I H), 2.37 (m, 3H), 1.42 (s, 3H), 1.21 (s, 3H).

EXAMPLE 146

[0587] (±)-4α-Amino-5,7-difluoro-L2,3,4-tetrahydro-3β-hvdroxy-2,2-dimethyl- 6-(3-methylindol-7-yl)quinoline (Compound 404). (±)-4α-Amino-5,7-difluoro-l, 2,3,4- tetrahydro-3β-hydroxy-2,2-dimethylquinoline. This compound was prepared as follows. To a solution of (±)-4α-benzylamino-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2- dimethylquinoline (70 mg, 1 equiv) in ethyl acetate (3 mL) at room temperature was added palladium hydroxide (15 mg, 8 equiv). The reaction was flushed with hydrogen, then stirred under 1 atmosphere of hydrogen pressure for 15 h, after which time the mixture was filtered through Celite using ethyl acetate. The filtrate was concentrated under reduced pressure to afford Compound 404 (75%). ¹H NMR (500MHz, CDCl₃) δ 7.60 (dd, J=7.2, 1.5 Hz, IH), 7.18 (t, J=7.2 Hz, IH), 7.16 (m, IH), 6.87 (br s, IH), 6.16 (dd, J=10.7, 1.2 Hz, IH), 4.00 (s, IH), 3.90 (m, IH), 3.39 (d, J=8.8 Hz, IH), 2.34 (d, J=0.7 Hz, 3H), 1.27 (s, 3H), 1.14 (s, 3H). EXAMPLE 147

[05881 (±)-5,7-Difluoro-l,2.3,4-tetrahvdro-3β-hvdroxy-2,2-dimethyl-6-(^'3- methylindol-7-yl)-4α-(3-phenylureido)quinoline (Compound 405). This compound was prepared from Compound 404 (EXAMPLE 146) and phenyl isocyanate using General Method 22. ¹H NMR (500MHz, DMSO-d₆) δ 10.50 (s, IH), 8.17 (s, IH), 7.45 (d, J=7.8 Hz, IH), 7.35 (m, 2H), 7.18 (t, J=7.3 Hz, 2H), 7.04 (s, IH), 7.01 (m, IH), 6.93 (m, IH), 6.85 (t, J=7.3 Hz, IH), 6.42 (br s, IH), 6.35 (br s, IH), 6.32 (d, J=11.7 Hz, IH), 5.26 (m, IH), 4.80 (m, IH), 3.51 (m, IH), 2.25 (s, 3H), 1.22 (s, 3H), 1.15 (s, 3H).

[0589] General Method 22: Formation of a urea from an amine. To a solution of an amine (0.056 mmol, 1 equiv) in ethanol (2 mL) at room temperature was added an isocyanate (1.3 equiv). The reaction was heated to reflux for 12 h, cooled and poured into 20 mL of 1 : 1 ethyl acetate:water. The first organic layer is collected and the aqueous layer is extracted with a second organic layer of ethyl acetate. The first and second organic layers are combined and that combined organic layer is washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (silica gel) affords the desired urea compound (43%).

EXAMPLE 148

[05901 (±)-4α-f(3-Benzo[1.31dioxo-5-yl)ureidol-5.7-difluoro-1.2,3,4-tetrahvdro- 3β-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 406). This compound was prepared from Compound 404 (EXAMPLE 146) and 5-isocyanato-benzo[l,3]dioxole using General Method 22 (EXAMPLE 147). ¹H NMR (500MHz, acetone-d₆) δ 7.89 (s, I H), 7.52 (d, J=7.3 Hz, I H), 7.23 (s, IH), 7.10-7.03 (m, 3H), 6.71 (m, IH), 6.68 (m, IH), 6.35 (d, J=I 1.7 Hz, IH), 6.10 (m, IH), 5.92 (s, 2H), 5.73 (s, IH), 4.91 (t, J=6.7 Hz, IH), 3.71 (m, IH), 2.31 (d, J=LO Hz, 3H), 1.31 (s, 3H), 1.22 (s, 3H).

EXAMPLE 149

[0591] (-b)-4α-(3-Cvclopentylureido)-5.7-difluoro-l,2.3,4-tetrahvdro-3B-hvdroxy- 2,2-dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 407). This compound was prepared from Compound 404 (EXAMPLE 146) and cyclopentyl isocyanate using General Method 22 (EXAMPLE 147). ¹H NMR (500MHz, DMSOd₆) δ 10.19 (s, IH), 7.46 (d, J=7.8 Hz, IH), 7.04-7.00 (m, 2H), 6.95 (d, J=7.4 Hz, IH), 6.31 (d, J=I 1.5 Hz, IH), 6.20 (s, I H), 5.23 (s, IH), 4.66 (t, J=6.5 Hz, IH), 3.88-3.80 (m, 2H), 3.48 (dd, J=6.2, 4.3 Hz, IH), 2.27 (d, J=LO Hz, 3H), 1.75 (m, 2H), 1.55 (m, 2H), 1.46 (m, 2H), 1.26 (m, 2H), 1.20 (s, 3H), 1.12 (s, 3H).

EXAMPLE 150

10592) (±)-4α-[3-(4-Acetylphenylureido)1-5.7-difluoro-1.2.3.4-tetrahvdro-3β- hydroxy-2,2-dirnethyl-6-(3-methylindol-7-yl)quinoline (Compound 408). This compound was prepared from Compound 404 (EXAMPLE 146) and 4-acetylphenyl isocyanate using General Method 22 (EXAMPLE 147). ¹H NMR (500MHz, acetone-d₆) δ 8.31 (s, I H), 7.87 (d, J=8.9 Hz, 2H), 7.57 (d, J=8.9 Hz, 2H), 7.51 (m, IH), 7.07 (t, J=7.3 Hz, IH), 7.05 (m, IH), 7.04 (s, IH), 6.35 (dd, J=I 1.6, 1.6 Hz, IH), 6.27 (m, IH), 5.76 (s, IH), 4.98 (t, J=7.1 Hz, IH), 4.87 (s, IH), 3.75 (m, IH), 2.49 (s, 3H), 2.30 (d, J=I .2 Hz, 3H), 1.32 (s, 3H), 1.25 (s, 3H).

EXAMPLE 151

[0593] (±)-4α-[3-(3-Chloro-4-methoxyphenylureido)l-5J-difluoro-l,2.3.4- tetrahvdro-3β-hvdroxy-2,2-dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 409). This compound was prepared from Compound 404 (EXAMPLE 146) and 3-chloro-4- methoxyphenyl isocyanate using General Method 22 (EXAMPLE 147). ¹H NMR (500MHz, acetone-d₆) δ 7.93 (s, IH), 7.67 (s, IH), 7.52 (dd, J=7.3, 1.4 Hz, IH), 7.23 (dd, J=9.0, 2.6 Hz, IH), 7.08 (t, J=7.3 Hz, IH), 7.06-7.03 (m, 2H), 6.97 (d, J=9.0 Hz, IH), 6.35 (dd, J=I 1.6, 1.6 Hz, IH), 6.16 (m, IH), 5.73 (s, IH), 4.92 (t, J=7.0 Hz, IH), 3.82 (s, 3H), 3.72 (d, J=7.0 Hz, IH), 2.30 (d, J=LO Hz, 3H), 1.31 (s, 3H), 1.23 (s, 3H).

EXAMPLE 152

10594] (±)-4α-[3-(4-Chlorophenylureido)l-5,7-difluoro-1.2.3,4-tetrahvdro-3β- hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 410). This compound was prepared from Compound 404 (EXAMPLE 146) and 4-chlorophenyl isocyanate using General Method 22 (EXAMPLE 147). ¹H NMR (500MHz, acetone-d₆) δ 7.53 (d, 1=7.6, 2H), 7.50-7.46 (m, 2H), 7.23-7.20 (m, 2H), 7.08-6.99 (m, 3H), 6.35 (d, J=I 1.7Hz), 6.21 (br s, IH), 5.7 (s, IH), 4.93 (t, IH, J=6.8 Hz), 3.72 (m, IH), 2.3 (s, 3H), 1.31 (s, 3H), 1.23 (s, 3H).

EXAMPLE 153

[05951 (±)-4α-Acetamido-5.7-difluoro-l,2,3,4-tetrahvdro-3β-hvdroxy-2.2- dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 41 1). To a solution of Compound 404 (EXAMPLE 146) (20 mg, 0.056 mmol, 1 equiv) in dichloromethane (2 mL) at O⁰C was added acetyl chloride (10 uL, 0.17 mmol, 3 equiv). The reaction was stirred for 5 hours and then diluted with 5 mL of water, resulting in a first organic layer and an aqueous layer. The first organic layer was collected and the aqueous phase was extracted with dichloromethane. The organic layer from that extraction was combined with the first organic layer and that combined organic layer was washed with brine and dried over sodium sulfate. Filtration and concentration of the filtrate under reduced pressure yielded a brown oil which was chromatographed on silica gel to provide Compound 411 (40%). ¹H NMR (500MHz, acetone-de) δ 7.56 (s, IH), 7.53 (dd, J=7.4, 1.2 Hz, IH), 7.08 (t, J=7.4 Hz, IH), 7.08-7.03 (m, 2H), 6.34 (dd, J=I 1.5, 1.2 Hz, IH), 5.70 (s, IH), 4.98 (t, J=7.0 Hz, IH), 3.66 (d, J=7.0 Hz, IH), 2.31 (d, J=LO Hz, 3H), 1.92 (s, 3H), 1.29 (s, 3H), 1.20 (s, 3H).

EXAMPLE 154

105961 (±)-5.7-Difluoro-1.2.3.4-tetrahvdro-3B-hvdroxy-2.2-dimethyl-6-(3- methylindol-7-yl)-4α-(phenoxycarbonylamino)quinoline (Compound 412). This compound was prepared from Compound 404 (EXAMPLE 146) (1 equiv) and phenyl chloroformate (3 equiv) stirred in dichloromethane at 0 ⁰C. The reaction was stirred for 1 hour and then diluted with saturated aqueous sodium bicarbonate solution, resulting in a first organic layer and an aqueous layer. The first organic layer was collected and the aqueous phase was extracted with dichloromethane. The organic layer from that extraction was combined with the first organic layer and that combined organic layer was washed with brine and dried over sodium sulfate. Filtration and concentration of the filtrate under reduced pressure yielded an oil which was chromatographed on silica gel to provide the carbamate as a white solid. ¹H NMR (500MHz, CDCl₃) δ 7.87 (s, IH), 7.62 (m, IH), 7.35-7.30 (m, 2H), 7.22-7.17 (m, 3H), 7.09 (m, 2H), 6.95 (s, IH), 6.24 (d, J= 10.7 Hz, IH), 5.37 (m, IH), 4.91 (m, IH), 4.05 (s, IH), 3.83 (m, IH), 3.33 (m, IH), 2.36 (s, 3H), 1.36 (s, 3H), 1.25 (s, 3H).

EXAMPLE 155

[05971 (±)-4a-(Ethoxycarbonylamino)-5,7-difluoro- 1,2,3.4-tetrahvdro-3β- hvdroxy-2,2-dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 413). This compound was prepared from Compound 404 (EXAMPLE 146) and ethyl chloroformate using the procedure described for Compound 412 (EXAMPLE 154). ¹H NMR (500MHz, acetone-d₆) δ 7.52 (m, IH), 7.10-7.03 (m, 3H), 6.41 (d, J=7.3 Hz, IH), 6.32 (d, J=I 1.5 Hz, IH), 5.71 (s, IH), 4.78 (t, J=7.3 Hz, IH), 4.49 (s, IH), 4.02 (m, 2H), 3.71 (m, IH), 2.31 (d, J=LO Hz, 3H), 1.31 (s, 3H), 1.23 (s, 3H), 1.14 (t, J=7.1 Hz, 3H).

EXAMPLE 156

[0598] (^"±)-5,7-Difluoro-1.2.3.4-tetrahvdro-3β-hvdroxy-2.2-dimethyl-4α- (methoxycarbonylamino)-6-(3-methylindol-7-yl)quinoline (Compound 414). This compound was prepared from Compound 404 (EXAMPLE 146) and methyl chloro formate using the procedure described for Compound 412 (EXAMPLE 154). ¹H NMR (500MHz, acetone-d₆) δ 7.53 (d, J=8.3 Hz, IH), 7.09-7.05 (m, 3H), 6.43 (m, IH), 6.32 (d, J=I 1.2 Hz, IH), 5.70 (m, IH), 4.77 (t, IH), 4.54 (m, IH), 3.70 (m, IH), 3.59 (m, IH), 3.56 (s, 3H), 2.31 (s, 3H), 1.31 (s, 3H), 1.22 (s, 3H).

EXAMPLE 157

[0599] (±)-4α-(Cyclohexylmethylamino)-5J-difluoro-l,2,3,4-tetrahydro-3β- hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl^')quinoline (Compound 415). This compound was prepared from Compound 404 (EXAMPLE 146) (1 equiv) in 0.1 M methanol, cyclohexanecarboxaldehyde (4 equiv), acetic acid (4 equiv), and sodium cyanoborohydride (4 equiv) stirred at 0 °C. The reaction was stirred for 1 hour and then diluted with saturated aqueous sodium bicarbonate solution, resulting in a first organic layer and an aqueous layer. The first organic layer was collected and the aqueous phase was extracted with ethyl acetate. The organic layer from that extraction was combined with the first organic layer and that combined organic layer was washed with brine and dried over sodium sulfate. Filtration and concentration of the filtrate under reduced pressure yielded a brown solid which was chromatographed on silica gel to provide Compound 415. ¹H NMR (500MHz, CDCl₃) δ 7.79 (s, IH), 7.61 (dd, J=7.3, 1.2 Hz, IH), 7.20 (t, J=7.3 Hz, I H), 7.17 (m, IH), 6.97 (q, J=I .0 Hz, IH), 6.18 (dd, J=I LO, 1.2 Hz, IH), 3.96 (s, IH), 3.88 (d, J=9.0 Hz, IH), 3.60 (d, J=9.0 Hz, IH), 3.36 (br s, IH), 2.36 (d, J=LO Hz, 3H), 2.32 (dd, J=I Ll, 6.3 Hz, IH), 2.27 (dd, J=I Ll, 6.8 Hz, IH), 1.81-1.56 (m, 6H), 1.39 (s, 3H), 1.36-1.19 (m, 3H), 1.18 (s, 3H), 1.17-1.10 (m, 2H). EXAMPLE 158

[06001 (±V6-(3-ChIoroindol-7-yl)-5J-difluoro-4α-(furan-2-ylmethylamino)- l,2,3,4-tetrahydro-3β-hydroxy-2,2-dimethylquinoline (Compound 416) and (±)-4α-bis(furan- 2-ylmethylamino^')-6-(3-chloroindol-7-yπ-5,7-d}fluoro-l,2,3,4-tetrahvdro-3β-hvdroxy-2.2- dimethylquinoline (Compound 417). This compound was prepared from Compound 404 (EXAMPLE 146), 2-furaldehyde, and sodium cyanoborohydride in a manner similar to that described for Compound 415 (EXAMPLE 157) to afford the desired compounds after flash chromatography.

[0601] Compound 416: ¹H NMR (500MHz, CDCl₃) δ 7.83 (br s, IH), 7.64 (m, IH), 7.31 (m, IH), 7.25-7.22 (m, 2H), 7.01 (q, J=Ll Hz, IH), 6.23 (dd, J=3.2, 2.0 Hz, I H), 6.18 (dd, J=10.9, 1.3 Hz, IH), 6.04 (m, IH), 3.98 (s, IH), 3.81 (d, J=9.5 Hz, IH), 3.65 (m, IH), 3.52 (d, J=9.5 Hz, IH), 2.38 (d, J=Ll Hz, 3H), 1.35 (s, 3H), 1.08 (s, 3H).

[0602] Compound 417: ¹H NMR (500MHz, CD₃OD) δ 7.51 (dd, J=7.8, 1.0 Hz, IH), 7.36 (m, 2H), 7.33 (m, 2H), 7.07 (dd, J=7.3, 7.8 Hz, IH), 7.01 (d, J=7.3 Hz, IH), 6.95 (q, J=LO Hz, IH), 6.31 (m, 2H), 6.29 (dd, J=I 1.2, 1.1 Hz, IH), 3.99 (d, J=7.6 Hz, IH), 3.74 (d, J=7.6 Hz, IH), 3.63 (m, 2H), 3.54 (m, 2H), 2.34 (d, J=LO Hz, 3H), 1.29 (s, 3H), 1.05 (s, 3H).

EXAMPLE 159

[06031 (±)-5 J-Difluoro-1.2.3.4-tetrahydro-3β-hydroxy-4α-

(isopropoxycarbonylamino)-2,2-dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 418). This compound was prepared from Compound 404 (EXAMPLE 146) and isopropyl chloroformate using the procedure described for Compound 412 (EXAMPLE 154). MS (ESI): 444.2 (M + H)⁺.

EXAMPLE 160

[06041 (±)-5.7-Difluoro-l,2,3,4-tetrahvdro-3β-hvdroxy-4α-(methylaminoV2,2- dirnethyl-6-(3-methylindol-7-y0quinoline (Compound 419). This compound was prepared by treatment of Compound 435 (EXAMPLE 176) with 10% palladium on carbon in methanol under an atmosphere of hydrogen. The mixture was filtered through a pad of Celite using ethyl acetate and the compound purified by flash chromatography to afford Compound 419.

EXAMPLE 161

[06051 (±)-4α-(Dimethylamino^')-5,7-difluoro-L2.3,4-tetrahvdro-3β-hvdroxy-2.2- dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 420). This compound was prepared from Compound 404 (EXAMPLE 146) and formaldehyde using the procedure described for Compound 415 (EXAMPLE 157) to afford Compound 420. ¹H NMR (300 MHz, CDCl₃) δ 7.98 (s, IH), 7.62 (m, IH), 7.24-7.10 (m, 2H), 7.01 (s, IH), 6.36 (d, J = 10.5 Hz, IH), 4.25 (d, J = 7.8 Hz, IH), 4.10 (s, IH), 3.94 (d, J = 8.1 Hz, IH), 2.77 (s, 6H), 2.38 (s, 3H), 1.39 (s, 3H), 1.17 (s, 3H). EXAMPLE 162

f0606] f±V5.7-Difluoro-1.2.3,4-tetrahvdro-3β-hvdroxy-4α-(pyridine-2- ylmethylamino)-2,2-dimethyl-6-(3-methylindol-7-yQquinoline (Compound 421). This compound was prepared from Compound 404 (EXAMPLE 146) (1 equiv) in 0.1 M methanol with 2-pyridinecarboxaldehyde (1.2 equiv) to form the inline. Sodium borohydride (3 equiv) was added and the reaction was allowed to stir till the cessation of effervescence. The reaction was diluted with 1.0M sodium hydroxide solution, resulting in a first organic layer and an aqueous layer. The first organic layer was collected and the aqueous phase was extracted with ethyl acetate. The organic layer from that extraction was combined with the first organic layer and that combined organic layer was dried over sodium sulfate. Filtration and concentration of the filtrate under reduced pressure yielded a brown solid which was chromatographed on silica gel to provide Compound 421. MS (ESI): 449.2 (M + H)⁺.

EXAMPLE 163

[06071 (±)-5.7-Difluoro-1.2.3.4-tetrahvdro-3B-hvdroxy-4α-(pyridine-3- ylmethylamino)-2,2-dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 422). This compound was prepared from Compound 404 (EXAMPLE 146) and 3- pyridinecarboxaldehyde using the procedure described for Compound 421 (EXAMPLE 162) to afford Compound 422. MS (ESI): 449.20 (M + H)⁺. EXAMPLE 164

[06081 (±)-5,7-Difluoro-l,2.3,4-tetrahvdro-3β-hvdroxy-4α-(pyridine-4- ylmethylarnino)-2.2-dimethyl-6-(3-methylindol-7-yr)quinoline (Compound 423). This compound was prepared from Compound 404 (EXAMPLE 146) and 3- pyridinecarboxaldehyde using the procedure described for Compound 421 (EXAMPLE 162) to afford Compound 423. MS (ESI): 449.2 (M + H)⁺.

EXAMPLE 165

[06091 (-fc)-4α-(Chlorobenzylamino)-5.7-difluoro-1.2.3,4-tetrahvdro-3β-hvdroxy- 2,2-dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 424). This compound was prepared from Compound 404 (EXAMPLE 146) and 4-chlorobenzaldehyde using the procedure described for Compound 421 (EXAMPLE 162) to afford Compound 424. MS (ESI): 482.2 (M + H)⁺.

EXAMPLE 166

10610] (±>5J-Difluoro-1.23,4-tetrahvdro-3β-hydroxy-2.2-dimethyl-4α-(4- methylbenzylamino)-6-(3-methylindol-7-yl)quinoline (Compound 425). This compound was prepared from Compound 404 (EXAMPLE 146) and 4-tolyIaldehyde using the procedure described for Compound 421 (EXAMPLE 162) to afford Compound 425. MS (ESI): 462.2 (M + H)⁺.

EXAMPLE 167

[06111 (±)-5.7-Difluoro-1.2.3.4-tetrahvdro-3β-hvdroxy-4α-(methylamino)-2.2- dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 426). This compound was prepared from Compound 404 (EXAMPLE 146) and 4-anisaldehyde using the procedure described for Compound 421 (EXAMPLE 162) to afford Compound 426. MS (ESI): 478.2 (M + H)⁺.

EXAMPLE 168

[0612] (±)-4a-fBenzyl(ethoxycarbonyl)amino)-5J-difluoro-l,2,3,4-tetrahydro- 3β-hvdroxy-2,2-dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 427). This compound was prepared from Compound 403 (EXAMPLE 145) and ethyl chloroformate using the procedure described for Compound 412 (EXAMPLE 154). MS (ESI): 520.2 (M + H)⁺. EXAMPLE 169

10613] (±V4α-Dibenzylamino-5,7-difluoro-1.2.3.4-tetrahvdro-3β-hvdroxy-2.2- dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 428). This compound was prepared from Compound 403 (EXAMPLE 145) (1 equiv) in 0.1 M acetonitrile with benzyl bromide (1.2 equiv) and potassium carbonate (4 equiv) at room temperature. The reaction was allowed to stir for 13 hours then diluted with water, and ethyl acetate, resulting in a first organic layer and an aqueous layer. The first organic layer was collected and the aqueous phase was extracted with ethyl acetate. The organic layer from that extraction was combined with the first organic layer and that combined organic layer was dried over sodium sulfate. Filtration and concentration of the filtrate under reduced pressure yielded a white solid which was chromatographed on silica gel to provide Compound 428. MS (ESI): 538.2 (M + H)⁺.

EXAMPLE 170

[0614] (±)-5.7-Difluoro-1.2.3.4-tetrahvdro-3β-hvdroxy-2.2-dimethyl-6-(3- methylindol-7-yl)-4α-[(naphthalen- 1 -ylmethyl)amino]quinoline (Compound 429). This compound was prepared from Compound 404 (EXAMPLE 146) and 1-naphthaldehyde using the procedure described for Compound 421 (EXAMPLE 162) to afford Compound 429. EXAMPLE 171

[06151 (±V5.7-Difluoro-1.2.3.4-tetrahvdro-3B-hvdroxy-2.2-dimethyl-6-(3- methvIindol-7-yl)-4α-r(naphmalen-2-ylmethyl)aminolquinoline (Compound 430). This compound was prepared from Compound 404 (EXAMPLE 146) and 2-naphthaldehyde using the procedure described for Compound 421 (EXAMPLE 162) to afford Compound 430.

EXAMPLE 172

106161 (±)-5.7-Difluoro-1.2.3.4-tetrahvdro-3β-hvdroxy-2.2-dimethyl-6-(3- methylindol-7-yl)-4α-r(thiazol-2-ylmethyl)amino1quinoline (Compound 431). This compound was prepared from Compound 404 (EXAMPLE 146) and 2- thiazolecarboxaldehyde using the procedure described for Compound 421 (EXAMPLE 162) to afford Compound 431.

EXAMPLE 173

106171 (±)-5.7-Difluoro-1.2.3.4-tetrahydro-3B-hydroxy-2.2-dimethyl-6-(3- methylindol-7-yl)-4α-f(4-methylthiazol-5-ylmethyl)amino]quinoline (Compound 432). This compound was prepared from Compound 404 (EXAMPLE 146) and 4-methyl-5- formylthiazole using the procedure described for Compound 421 (EXAMPLE 162) to afford Compound 432.

EXAMPLE 174

[06181 (±)-4α-r(2,4-Dimethylthiazol-5-ylmethyl)amino1-5J-difluoro- 1,2,3,4- tetrahvdro-3β-hydroxy-2,2-dimethyl-6-(3-methylindol-7-yl)-quinoline (Compound 433). This compound was prepared from Compound 404 (EXAMPLE 146) and 2,4-dimethyl-5- formylthiazole using the procedure described for Compound 421 (EXAMPLE 162) to afford Compound 433.

EXAMPLE 175

[0619] (±)-5.7-Difluoro-1.2,3,4-tetrahvdro-3β-hvdroxy-2,2-dimethyl-6-(3- methylindol-7-ylV4α-[(5-methylisoxazol-3-ylmethyl)amino1quinoline (Compound 434). This compound was prepared from Compound 404 (EXAMPLE 146) and 5- methylisoxazolyl-3-carboxaldehyde using the procedure described for Compound 421 (EXAMPLE 162) to afford Compound 434. EXAMPLE 176

106201 (±V4α-Benzylmethylamino-5,7-difluoro-L2,3.4-tetrahydro-3β-hydroxy- 2,2-dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 435). This compound was prepared from Compound 403 (EXAMPLE 145), paraformaldehyde, and sodium cyanoborohydride in acetic acid and methanol in a manner similar to that described for Compound 415 (EXAMPLE 157) to afford Compound 435.

EXAMPLE 177

[06211 (±)-4α-Ethylamino-5J-difluoro-l,2,3,4-tetrahvdro-3β-hvdroxy-2,2- dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 436). This compound was prepared from Compound 404 (EXAMPLE 146), acetaldehyde, sodium triacetoxyborohydride and acetic acid in dichloromethane in a manner similar to that described for Compound 415 (EXAMPLE 157) to afford Compound 436.

EXAMPLE 178

[06221 (dh)-4α-But-2-enylamino-5,7-difluoro-l,2,3,4-tetrahydro-3β-hydroxy-2,2- dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 437). This compound was prepared in a manner similar to that described for Compound 436 (EXAMPLE 177) from crotonaldehyde and sodium triacetoxyborohydride to afford Compound 437.

EXAMPLE 179

[06231 (±V4α-Butylamino-5,7-difluoro-1.2.3.4-tetrahvdro-3β-hvdroxy-2.2- dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 438). This compound was prepared in a manner similar to that described for Compound 436 (EXAMPLE 177) from butyraldehyde and sodium triacetoxyborohydride to afford Compound 438.

EXAMPLE 180

[0624] (±)-S,7-Difluoro-l,2,3,4-tetrahvdro-3β-hvdroxy-4α-isobutylamino-2,2- dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 439). This compound was prepared in a manner similar to that described for Compound 436 (EXAMPLE 177) from isobutyraldehyde and sodium triacetoxyborohydride to afford Compound 439.

EXAMPLE 181

[0625] (±)-4α-Diethylamino-5.7-difluoro-1.2.3,4-tetrahvdro-3B-hvdroxy-2,2- dimethyl-6-(3-methylindol-7-yl)quinoline (Compound 440). This compound was prepared from Compound 404 (EXAMPLE 146) (1 equiv) in 0.1 M methanol, acetaldehyde (2 equiv), acetic acid (2 equiv), and sodium cyanoborohydride (2 equiv) stirred at ambient temperature. The reaction was stirred for 8 hours at 25 ⁰C, 7 hours at 50 ⁰C and then diluted with saturated aqueous sodium bicarbonate solution, resulting in a first organic layer and an aqueous layer. The first organic layer was collected and the aqueous phase was extracted with ethyl acetate. The organic layer from that extraction was combined with the first organic layer and that combined organic layer was washed with brine and dried over sodium sulfate. Filtration and concentration of the filtrate under reduced pressure yielded a brown solid which was purified by chromatography on silica gel to provide Compound 440.

EXAMPLE 182 Glucocorticoid Binding Assays

Preparation of GR

[0626] A baculovirus expression plasmid comprising cDNA encoding the human glucocorticoid receptor protein (GR) was prepared using standard techniques. See e.g., E. A. Allegretto et. al. 268 J. Biol. Chem., 26625 (1993); G. Srinivasan and B. Thompson, 4 MoI. Endo., 209 (1990); and D. R. O'Reilly et. al., in "Baculovirus Expression Vectors", D. R. O'Reilly et. al., eds., W. H. Freeman, New York, N. Y., pp. 139-179 (1992). The expression plasmid was infected together with wild type Autographa californica multiple nuclear polyhedrosis virus DNA into Spodopter frugiperda-21 (Sf-21) cells to generate recombinant virus comprising GR cDNA. See e.g., O'Reilly, D.R., Miller, L.K., Luckow, V.A., Regulation of expression of a baculovirus ecdysteroid UDP glucosyltransferase gene. "Baculovirus Expression Vectors." WH Freeman, NY, 139-179 (1992). The recombinant virus comprising GR cDNA was collected.

[0627] A suspension culture of uninfected Sf21 cells was grown to a density of 1.2xlO⁶ cells/ml and then infected with the recombinant virus comprising GR cDNA at a multiplicity of infection of 2. The infected Sf21 cells were incubated for 48 hours and then collected by centrifugation at 1000 x g for 10 minutes at 4⁰C. The resulting cell pellets were resuspended in lysis buffer (50 mM Potassium Phosphate buffer, pH 7.0, 10 mM Monothioglycerol, 5 mM DTT, 20 mM Sodium Molybdate, 1 mM PMSF, 1 μg/mL aprotinin, and 10 μg/mL leupeptin) and incubated for 15 minutes on ice. The resuspended cell pellets were homogenized using a Dounce homogenizer and a B pestle. A volume of 2 M KCI was added to the homogenized cell pellets to a final concentration of 0.4 M. The resulting GR lysates were centrifuged at 100,000 x g for 60 min at 4⁰C and stored for use in binding assays.

Binding Assays

[0628] Binding assay samples were prepared in separate mini-tubes in a 96-welI format at 4⁰C. Each binding assay sample was prepared in a volume of 250 μl of GR-Assay Buffer (10% glycerol, 25 mM sodium phosphate, 10 mM potassium fluoride, 10 mM sodium molybdate, 0.25 mM CHAPS, 2 mM DTT and 1 mM EDTA, (adjusted to pH 7.5)) containing 50 μg of GR lysate; 2-4 nM of [³H]dexamethasone at 84 Ci/mmol; and either a reference compound or a test compound. Test compounds included selective glucocorticoid binding compounds of the present invention. Reference compounds were unlabeled dexamethasone and prednisone, which have been previously shown to bind to glucocorticoid receptors. Each reference compound and test compound was assayed at varying concentrations, ranging from 3.2 x 10^"10 to 10^"5 M. Each concentration of each reference compound and each test compound was assayed in triplicate. The assay samples were incubated for 16 hours at 4⁰C.

[0629] After incubation, 200 μl of 6.25% hydroxylapatite in assay buffer was added to each assay sample to precipitate the protein. The assay samples were then centrifuged and the supernatants were discarded. The resulting pellets were washed twice with assay buffer lacking DTT. Radioactivity in counts per minute (CPM) of each washed pellet was determined by liquid scintillation counter (MicroBeta™, Wallach).

[0630] Specific binding for a particular sample was calculated using the equation:

(Sample CPM) - (Average Non-specific CPM)

Average Non-specific CPM was defined as the amount of radioactivity from samples comprising an excess (i.e. 1000 nM) of unlabeled dexamethasone. IC₅0 values (the concentration of test compound required to decrease specific binding by 50%) were determined using the log-logit (Hill) method. K, values were determined using the Cheng- Prusoff equation using a previously determined K_d value for dexamethasone:

K, = IC_5O/(1 + [L]/Kd)

[L] = concentration of labeled dexamethasone

K_d = dissociation constant of labeled dexamethasone

For a discussion of the calculation of K₁, see e.g., Cheng, Y. C. and Prusoff, W. H. Biochem.

Pharmacol. 22:3099 (1973). K, values for certain glucocorticoid binding compounds are shown in Table 1. Table 1. GR Binding Data

EXAMPLE 183

Steroid Receptor Modulator Activity

[0631] Utilizing the co-transfection, or transcriptional activation assay described by Evans et al., Science, 240:889-95 (May 13, 1988), the disclosure of which is incorporated by reference herein, the compounds of the present invention were tested and found to have strong, specific activity as modulators of GR. This assay is described in further detail in U.S. Patent Nos. 4,981,784 and 5,071,773, the disclosures of which are incorporated herein by reference.

[0632] The co-transfection assay provides a method for identifying functional agonists and partial agonists that mimic, or antagonists that inhibit, the effect of endogenous hormones, and quantifying their activity for responsive IR proteins. In this regard, the co- transfection assay mimics an in vivo system in the laboratory. Importantly, activity in the co- transfection assay correlates very well with known in vivo activity, such that the co- transfection assay functions as a qualitative and quantitative predictor of a tested compounds in vivo pharmacology. See, e.g., T. Berger et al. 41 J. Steroid Biochem. Molec. Biol. 733 (1992), the disclosure of which is herein incorporated by reference.

[0633] In the co-transfection assay, a cloned cDNA for an IR (e.g., human PR, AR or GR) under the control of a constitutive promoter (e.g., the SV 40 promoter) is introduced by transfection (a procedure to induce cells to take up foreign genes) into a background cell substantially devoid of endogenous IRs. This introduced gene directs the recipient cells to make the IR protein of interest. A second gene is also introduced (co- transfected) into the same cells in conjunction with the IR gene. This second gene, comprising the cDNA for a reporter protein, such as firefly luciferase (LUC), is controlled by an appropriate hormone responsive promoter containing a hormone response element (HRE). This reporter plasmid functions as a reporter for the transcription-modulating activity of the target IR. Thus, the reporter acts as a surrogate for the products (mRNA then protein) normally expressed by a gene under control of the target receptor and its native hormone.

[0634] The co-transfection assay can detect small molecule agonists or antagonists of target IRs. Exposing the transfected cells to an agonist ligand compound increases reporter activity in the transfected cells. This activity can be conveniently measured, e.g., by increasing luciferase production, which reflects compound-dependent, IR- mediated increases in reporter transcription. To detect antagonists, the co-transfection assay is carried out in the presence of a constant concentration of an agonist to the target IR (e.g., dexamethasone for GR) known to induce a defined reporter signal. Increasing concentrations of a suspected antagonist will decrease the reporter signal (e.g., luciferase production). The co-transfection assay is therefore useful to detect both agonists and antagonists of specific IRs. Furthermore, it determines not only whether a compound interacts with a particular IR, but whether this interaction mimics (agonizes) or blocks (antagonizes) the effects of the native regulatory molecules on target gene expression, as well as the specificity and strength of this interaction.

[0635] The activity of selected steroid receptor modulator compounds of the present invention were evaluated utilizing the co-transfection assay according to the following protocol. Co-transfection assay

[0636] A mammalian cell line lacking endogenous hGR (CV-I cells) was used in the LUC reporter assay. CV-I cells were maintained in T-225 flasks in 35 mis of DMEM containing 10% FBS. Twenty-four hours prior to transient transfection, 2.5 x 10⁶ cells were plated in T-225 flasks in 35 mis DMEM containing 10% FBS. Twenty hours after transient transfection, cells were harvested using trypsin, resuspended in DMEM containing 10% CA- FBS, and 1 xlO⁴ cells are plated in 96-well microtiter plates.

[0637] CV-I cells were transiently transfected with an expression plasmid containing the cDNA for the nuclear receptor and appropriate LUC reporter plasmid using a non-liposomal formulation, the FuGeneό transfection reagent (Roche, Indianapolis, IN), according to manufacturer's specifications. The Fugene 6/DNA mixture was added to the media bathing the cells in T-225 flasks, and cells were incubated for 20 hours at 37°C in a humidified incubator. Cells were plated into 96-well microtiter plates using a Biohit 8- channel Pipettor at a density of 10,000 cells per well.

[0638] Solvated compounds, in either ethanol or DMSO, were diluted to 100 μM in DMEM containing 10% CA-FBS. Serial dilutions of up to ten incremental concentrations ranging from 10^"11 to 10^"5 M were prepared in DMEM containing 10% CA-FBS using a Biomek 2000 Automated Workstation. For antagonist experiments, compounds were prepared and diluted in medium containing an EC50 concentration of reference agonist. Two replicates were prepared for each concentration. Compound dilutions were added to 96-well microtiter plates using Biomek 2000 Automated Workstation. In order to limit the photoisomerization of the two compounds were prepared, diluted and added to the cells in light-controlled conditions.

[0639] After 20 hours incubation with compound, the medium was removed from the cells, and the cells were lysed with a detergent-containing buffer. LUC activity was measured in cell extracts to determine the level of transcriptional activation. LUC Assay Buffer was added to each well of the 96-well plate and LUC activity was measured using a luminometer

[0640] For each replicate, the normalized response (NR) was calculated as:

LUC response/β-Gal rate

where β-Gal rate = β-Gal/β-Gal incubation time. [0641] The mean and Standard error of the mean (SEM) of the NR were calculated. Data was plotted as the response of the compound compared to the reference compounds over the range of the dose-response curve. For agonist experiments, the effective concentration that produced 50% of the maximum response (EC50) was quantified. Agonist efficacy was a function (%) of LUC expression relative to the maximum LUC production by the reference agonist for GR. Antagonist activity was determined by testing the amount of LUC expression in the presence of a fixed amount of dexamethasone as a GR agonist at the EC50 concentration. The concentration of test compound that inhibited 50% of LUC expression induced by the reference agonist was quantified (IC50). In addition, the efficacy of antagonists was determined as a function (%) of maximal inhibition.

EXAMPLE 184 E-Selectin Repression assay

[0642] E-selectin is a cell adhesion protein expressed on the surface of endothelial cells in response to inflammatory signals. Inflammatory cytokines TNFα and IL-I β will induce E-selectin expression through cytokine responsive promoter elements. The glucocorticoid receptor, when appropriately activated by a ligand, will interact with and inhibit the activity of transcription factors necessary for the cytokine activation of the promoter. An in vitro E-selectin reporter assay was developed to measure the potential anti- inflammation activity of GR modulating compounds. A 600 base pair fragment of the E- selectin promoter was cloned and placed upstream of the luciferase gene, creating a cytokine inducible mammalian reporter construct. When introduced into an appropriate cell background along with a GR expression construct, inflammatory signaling can be induced and the anti-inflammatory activity of GR compounds can be measured. The activity of GR modulators in repressing the cytokine activated E-selectin reporter can be measured, and the assay is described below.

[0643] Hep-G2, a human hepatocellular carcinoma cell line (ATCC# HB-8065), was used in the E-selectin cotransfection experiments. This cell line is maintained in a liquid culture consisting of EMEM medium (Cambrex, Walkersville, MD) containing 10% fetal bovine serum (FBS, Hyclone, Logan, UT), 2 mM glutamine (Hyclone) and 50mcG/mL gentamycin (Cambrex).

[0644] Two plasmid constructs were used in the E-selectin cotransfection assays. The reporter plasmid consisted of a 600 base-pair fragment of the human E-selectin promoter containing GR-sensitive regulatory elements inserted in front of the coding sequence for firefly luciferase. A plasmid consisting of the coding sequence for human Glucocorticoid Receptor (hGR) behind the early promoter sequence of the Rous Sarcoma Virus (RSV) was used to express hGR in the Hep-G2 cells.

[0645] TNFα and ILl-β, used to induce the E-se lectin promoter, were purchased from R&D Systems (Minneapolis, MN). Stock solutions of all compounds tested were prepared in either 100% ethanol or dimethyl sulfoxide (DMSO).

[0646] Compounds were diluted in medium consisting of DMEM (Cambrex), 10% Charcoal-Absorbed FBS, 2 mM glutamine and 50 μg/mL gentamycin in preparation for addition to the cell culture medium.

[0647] Cell extracts we prepared in a lysis buffer consisting of 0.1% Triton X- 100. Luciferase activity in cell extracts were assayed in Luciferase Assay Buffer (2O mM Tricine pH 7.8, 12 mM MgSO4, 0.1 mM EDTA, 30 mM ditthiothreitol) and Luciferin/Coenzyme A Solution (0.3 mM Coenzyme A, 0.55 mM ATP, 0.55 mM luciferin in 0.5 mM HEPES, pH 6.0).

[0648] Plasmids were transiently transfected into Hep-G2 cells using the Fugene- 6 transfection reagent (Roche, Indianapolis, IN) according to the manufacturer's instructions. After the Fugene-6/Plasmid DNA complex was formed, the complex solution was added to the tissue culture flasks containing the Hep-G2 cultures.

[0649] Dilution of compounds in medium was performed on the Biomek 2000 Automated Workstation (Beckman, Fullerton, CA). Compound additions were done with the Multimek 96 (Beckman) in light-controlled conditions. Removal of medium and addition of lysis buffer, as well as the Luciferase Assay Buffer and Luciferin/Coenzyme A reagents were performed on a plate washer (Titertek, Huntsville, AL). Luciferase activities of the treated cell lysates were measured using a luminometer (LJL Analyst from Molecular Devices, Sunnyvale, CA).

[0650] In this assay, Hep-G2 cells, were transfected with two plasmid constructs, one a reporter plasmid containing a cytokine responsive fragment of the human E-selectin promoter, the other a mammalian expression construct possessing the coding sequence for hGR. After overnight incubation, the cells were harvested by trypsin treatment, washed in assay medium and sub-cultured into 96-well culture plates and allowed to adhere to the plate before induction with 10 ng/mL TNFα and 1 ng/mL IL-I β. Test compounds were diluted, and added to the cytokine-induced cultures and the assay plates returned to a tissue culture incubator for overnight incubation. The next day, the medium was aspirated and the cells lysed. After a brief incubation in lysis buffer, luciferin reagent was added and luciferase activity measured to determine the degree that test compounds repressed E-selectin activation.

[0651] For each replicate, the response was calculated as relative luciferase units (RLU), a measurement of the light intensity generated from the cell lysates. The mean and the standard error of the mean (SEM) of the RLU at each point of compound concentration tested were reported. The data was plotted graphically as mean RLU over the range of compound concentrations tested in each assay. Repression efficacy was measured as the activity of compound in reducing the luciferase activity of the E-selectin promoter to the level of maximum repression achieved by dexamethasone. The potency of the compound was determined as the concentration at which half the minimum RLU was achieved.

EXAMPLE 185 IL-6 Repression assay

[0652] One of the mechanisms by which glucocorticoids suppress inflammation is to inhibit the production of inflammatory cytokines.(2, 3) IL-6 is an important inflammatory cytokine. See e.g., Kishimoto, T. Blood 74:1-10 (1989). In vitro studies have indicated that the glucocorticoid dexamethasone can repress TNFα-induced expression of many cytokines including IL-6. See e.g., Tobler, A., Meier, R., Seitz, M., Dewald, B., Baggiolini, M., Fey, M. F. Blood 79:45-51 (1992). Glucocortocoids regulate IL-6 expression by regulating transcription factors such as NFKB and AP-I. See e.g. De Bosscher, K., Vanden Berghe, W., Haegeman, G. Endocr. Rev. 24:488-522 (2003). Therefore, the GR-mediated modulation of IL-6 production provides an excellent marker for studying the anti-inflammatory activity of glucocorticoids.

[0653] A human IL-6 repression assay was used to measure the ability of the GR modulators to suppress IL-6 production in human dermal fibroblast cells. NHDF-neo (normal human dermal fibroblast -newborn male) cells (Cambrex, Walkersville, MD) were used for assay. The cells were maintained in liquid culture with Fibroblast growth medium and supplement components (Cambrex, Walkersville, MD). The assay was performed in Dulbecco's modified essential medium (DMEM; Cambrex, Walkersville, MD) containing 1.75% bovine serum albumin (test medium).

[0654] Dexamethasone was purchased from SIGMA Chemical Company (St. Louis, Mo), hIL-l β was purchased from R&D Systems (Minneapolis, MN). Anti-human IL- 6 monoclonal and biotinylated antibody was purchased from Endogen Inc. (Rockford, IL). EuNl labeled streptavidin and enhancement reagent was purchased from PerkinElmer Life and Analytical Sciences (Boston, MA). Reactibind^R white opaque EIA plates were purchased from Pierce (Rockford, IL).

[0655] Stock solutions of compounds were prepared in 100% dimethyl sulfoxide (DMSO). Test compounds were diluted in medium (DMEM) containing 1.75% bovine serum albumin (test medium). The induction medium was prepared by addition of 8 ng/mL hIL-l β to the test medium. Blocking buffer and antibody dilution buffer were prepared by the addition of 1% and 0.1% BSA in PBS. Capture antibody solution was prepared by the addition of 0.5 μg/mL anti-human IL-6 monoclonal antibody to antibody dilution buffer. Detection antibody solution was prepared with 0.5 μg/mL anti-human IL-6 monoclonal biotinylated antibody in antibody dilution buffer. Wash buffer contained 5OmM Tris pH7.0- 7.5 and 0.2% Tween-20.

[0656] Dilutions of compounds in medium, and addition of compounds to the cells were performed on a Biomek 2000 Automated Workstation (Beckman Coulter, Fullerton, CA). Removal of medium and addition of test medium was performed on a plate washer (Titertek, Huntsville, AL). Time-resolved fluorescence was measured using Analyst HT (Molecular Devices, Sunnyvale, CA).

[0657] For the assay, the NHDF-neo cells were plated in a 96-well plate at 5 x 10³ cells per well. After an overnight incubation, the media was replaced with the test medium for four to six hours. Incremental concentrations of test compounds ranging from IxIO^"10 to IxIO^"7 M was added to the cells, and the cells were induced with the induction medium containing IL- lβ. Two or three replicates were used for each concentration. After 24 hours, the cell supernatants were collected and the quantity of hIL-6 was measured in a time- resolved fluorescence based immunoassay. For the TRF immunoassay, the 96-well EIA plates were coated with the capture antibody solution and then blocking buffer was added to the plates. After one hour incubation, the blocking buffer was removed, and buffer containing detection antibody was added. The supernatant from the compound treated cells were added to the EIA plates containing the detection antibody. After an overnight incubation at 4°C, the supernatant and detection antibody solution was removed, the plate was washed three times with the wash buffer and detecting reagent was added. After one hour incubation, the plate was washed three times with the wash buffer and enhancement reagent was added. The plate was incubated for 10 minutes before reading the time resolved fluorescence units on Analyst HT.

[0658] For each replicate, the response was calculated as time-resolved fluorescence Units (TFU). The mean and standard error of the mean (SEM) of the TFU at each concentration of compound was calculated. The data is plotted graphically as the mean TFU of the compound over the range of the concentration-response curve. The effective concentration that produced 50% of the maximum response (IC50) was determined for each compound by interpolation between two concentrations spanning the midpoint of the concentration-response curve. The efficacy for test compounds is calculated as a percent of TFU relative to the maximum TFU by the reference glucocorticoid (i.e., dexamethasone).

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I, II, or III:

R¹ and R² are each independently selected from the group consisting of hydrogen, a halogen, -CN, -OR¹⁶, an optionally substituted C]-Cg alkyl, an optionally substituted Ci-Cg heteroalkyl, an optionally substituted C]-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C3-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

R³ is selected from the group consisting of (a), (b), (c), (d), (e), (f), (g), (h), (i), Q), (k), (1), (m), and (n) :

(a) (b) (C)

(d) (e) (0

(1) (m) (n)

wherein,

R¹¹ is selected from the group consisting of hydrogen, a halogen, -CN, -OR¹⁶, -NR¹⁷R¹⁸, -CH₂R¹⁶, -COR²⁰, -CO₂R²⁰, -CONR²⁰R³⁷, -SOR²⁰, -SO₂R²⁰, -NO₂, NR^!7(OR¹⁶), an optionally substituted Cj-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

R¹² is selected from the group consisting of hydrogen, a halogen, -CN, - COR²⁰, -CO₂R²⁰, -CONR²⁰R³⁷, -NR¹⁷SO₂R²⁰, -NR¹⁷CO₂R²⁰, -NO₂, -OR¹⁶, -NR¹⁷R¹⁸, NR¹⁷(OR¹⁶), an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl or R¹² taken together with R¹¹ form a 3-7 membered ring; each R¹³ is independently selected from the group consisting of hydrogen, a halogen, CN, -NO₂, OR¹⁶, an optionally substituted C)-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl or R¹³ taken together with R¹² form a 3-7 membered ring;

R²¹ is selected from the group consisting of hydrogen, an optionally substituted Ci-C₈ alkyl, an optionally substituted CpC₈ heteroalkyl, an optionally substituted CpC₈ haloalkyl, an optionally substituted C)-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, an optionally substituted C₃-C₈ heteroaryl, OR¹⁶, NR¹⁷R¹⁸, COR²⁰, -CO₂R²⁰, and -CONR²⁰R³⁷;

R²² is selected from the group consisting of hydrogen, a halogen, an optionally substituted Ci-C₈ alkyl, an optionally substituted CpC₈ heteroalkyl, an optionally substituted CpC₈ haloalkyl, an optionally substituted CpC₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, an optionally substituted C₃-C₈ heteroaryl, OR¹⁶, NR¹⁷R¹⁸, COR²⁰, -CO₂R²⁰, and -CONR²⁰R³⁷;

R³² and R³³ are each independently selected from the group consisting of hydrogen, a halogen, -OR¹⁶, -CN, COR²⁰, an optionally substituted Ci-C₈ alkyl, an optionally substituted CpC₈ heteroalkyl, an optionally substituted CpC₈ haloalkyl, an optionally substituted CpC₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅- C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl; each R²³ is independently selected from the group consisting of hydrogen, a halogen, OR¹⁶, an optionally substituted Ci-C₈ alkyl, an optionally substituted CpC₈ heteroalkyl, an optionally substituted CpC₈ haloalkyl, an optionally substituted CpC₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl and an optionally substituted C₃-C₈ heteroaryl; each R²⁴ is independently selected from the group consisting of hydrogen, a halogen, and -OR¹⁶;

R²⁵ is selected from the group consisting of hydrogen, a halogen, -OR¹⁶, -CN, an optionally substituted Ci-C₈ alkyl, an optionally substituted C]-C₈ heteroalkyl, an optionally substituted CpC₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

R²⁶ is selected from the group consisting of hydrogen, a halogen, -OR¹⁶, -CN, an optionally substituted Ci-C₈ alkyl, an optionally substituted CpC₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Cj-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl; each R²⁹ is independently selected from the group consisting of hydrogen, a halogen, and -OR¹⁶;

U is selected from the group consisting of oxygen, sulfur, and -NR¹⁷;

Q and T are each selected from the group consisting of S, O, -NR¹⁷, and CR³⁴ wherein either Q is -CR³⁴ and T is selected from the group consisting of S, O, and -NR¹⁷, or T is CR³⁴ and Q is selected from the group consisting of S, O, and -

NR 17.

V is selected from the group consisting of O, S, and -NR¹⁷;

W is selected from the group consisting of -CR²⁷ and N; Y is selected from the group consisting of -NR³⁶, S, and O; Z and L are each selected from the group consisting of CH₂, -NR²⁸, and O, wherein either Z is CH₂ and L is selected from the group consisting of -NR²⁸ and O, or L is CH₂ and Z is selected from the group consisting of -NR²⁸ and O; K is selected from the group consisting of O and -NR³⁵;

J is selected from the group consisting of O and S;

B is selected from the group consisting of O and C(R 27x )₂; M is selected from the group consisting of O and NOR³⁰; each P is independently selected from the group consisting of N and CR³¹, provided that no more than two of the Ps are N; n is selected from 0, 1, 2, 3, and 4; and q is selcted from 0, 1, and 2;

R⁴ is selected from the group consisting of hydrogen, a halogen, NO₂, OR¹⁶, NR¹⁷R¹⁸, CN, C=N(OR¹⁶), CO₂R²⁰, CONR²⁰R³⁷, NR^!7(OR¹⁶), CR³(OR¹⁶), an optionally substituted Ci-C₈ alkyl, an optionally substituted CpC₈ heteroalkyl, an optionally substituted CpC₈ haloalkyl, an optionally substituted C]-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

R⁵ is selected from the group consisting of hydrogen, NR^xR^y, an optionally substituted Ci-C₈ alkyl, an optionally substituted CpC₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted C]-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

R^x and R^y are each independently selected from the group consisting of hydrogen, COR¹⁹, CO₂R¹⁹, SO₂R¹⁹, S(O)R¹⁹, CONR¹⁹, an optionally substituted C-C₈ alkyl, an optionally substituted CpC₈ heteroalkyl, an optionally substituted CpC₈ haloalkyl, an optionally substituted CpC₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₃-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl; or R^x and R^y are linked to form a 3 to 7 membered ring;

R⁶ is selected from the group consisting of -OC(O)R¹⁹, OC(O)NR¹⁹R¹⁹, - NR¹⁵C(O)R¹⁹, NR¹⁵C(O)NR¹⁹R¹⁹, -C(O)R¹⁹, NR¹⁷R¹⁸, hydrogen, and OR¹⁶;

R⁷ and R⁸ are each independently selected from the group consisting of hydrogen, an optionally substituted C]-C₈ alkyl, an optionally substituted CpC₈ heteroalkyl, an optionally substituted CpC₈ haloalkyl, an optionally substituted CpC₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl; R⁹ is selected from the group consisting of hydrogen, OR¹⁶, an optionally substituted Ci-C₈ alkyl, an optionally substituted Cj-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

R¹⁰ is selected from the group consisting of hydrogen and OR¹⁶; and

X is selected from the group consisting of O, and NOR¹⁶; wherein:

R¹⁶ is selected from the group consisting of hydrogen, an optionally substituted Cj-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted CpC₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

R¹⁵ is selected from the group consisting of hydrogen, an optionally substituted Ci-C₈ alkyl, an optionally substituted Cj-C₈ heteroalkyl, an optionally substituted C]-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₃-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

R¹⁷ and R¹⁸ are each independently selected from the group consisting of hydrogen, COR²⁰, CO₂R²⁰, SO₂R²⁰, S(O)R²⁰, an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Cj-C₈ haloalkyl, an optionally substituted C]-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl; or R¹⁷ and R¹⁸ together form a 3 to 7 membered ring;

Each R¹⁹ is independently selected from the group consisting of hydrogen, a halogen, an optionally an optionally substituted C]-C₆ alkyl, an optionally substituted C]-Ce heteroalkyl, an optionally substituted C]-C₆ haloalkyl, an optionally substituted C]-C₆ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₃-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl.

R²⁰ and R³⁷ are each independently selected from the group consisting of hydrogen, an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Cj-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl; or R³⁷ and R²⁰ together form a 3-7 membered ring;

R³⁴ is selected from the group consisting of hydrogen, a halogen, -NO₂, -OR¹⁶, - NR¹⁷R¹⁸, -CN, -COR²⁰, NR¹⁷(OR¹⁶), an optionally substituted C₁-C₈ alkyl, an optionally substituted C]-Cg heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

R³⁶ is selected from the group consisting of hydrogen, an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted CpC₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

Each R²⁷ is independently selected from the group consisting of hydrogen, a halogen, CO₂R²⁰, COR²⁰, CONR²⁰R³⁷, C=N(OR¹⁶), an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted CpC₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl or R²⁷ taken together with R²⁶ form a 3-7 membered ring;

R²⁸ is selected from the group consisting of hydrogen, -COR²⁰, -CO₂R²⁰, - CONR²⁰R³⁷, SO₂R²⁰, an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

R³⁵ is selected from the group consisting of hydrogen, -COR²⁰, -CO₂R²⁰, CONR²⁰R³⁷, SO₂R²⁰, an optionally substituted Ci-C₈ alkyl, an optionally substituted CpC₈ heteroalkyl, an optionally substituted CpC₈ haloalkyl, an optionally substituted CpC₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

R³⁰ is selected from the group consisting of hydrogen an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted CpC₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-Cs heterocycle, an optionally substituted Cs-C₈ Αtyl, and an optionally substituted C₃-C₈ heteroaryl;

R³¹ is selected from the group consisting of hydrogen, a halogen, and -OR¹⁶; wherein, at least one of R¹, R² and R⁴ is not hydrogen; and at least one of R^{1 1}, R¹², and one R¹³ is not hydrogen;

R³⁸ is selected from the group consisting of (o), (p), (q), (r), (s) and (t) :

(o) (P) (q)

(r) (S) (t) wherein,

R³⁹ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -CONR⁵¹R⁵², -OR⁵³, COR⁵³, -SR⁵³, -SO₂NR⁵¹R⁵², an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl;

R⁴⁰ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -OR⁵³, -SR⁵³, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl;

R⁴¹ is selected from hydrogen, F, Cl, Br, CN, -OR⁵³, -SR⁵³, an optionally substituted alkyl, an optionally substituted haloalkyl, and an optionally substituted heteroalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl; or

R³⁹ and R⁴⁰ together form an optionally substituted 5-6 member ring and R⁴¹ is selected from hydrogen, F, Cl, Br, CN, -OR⁵³, -SR⁵³, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl; or

R⁴⁰ and R⁴¹ together form an optionally substituted 4-6 member ring and R³⁹ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -CONR⁵¹R⁵², -OR⁵³, COR⁵³, - SR⁵³, -SO₂NR⁵¹R⁵², an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl;

R⁴² is selected from hydrogen, F, Cl, Br, optionally substituted alkyl, -SR⁵³ and - OR⁵³;

R⁴³ is selected from hydrogen, F, Cl, Br, an optionally substituted alkyl;

R⁴⁴ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -CONR⁵¹R⁵², - SO₂NR⁵¹R⁵², an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl;

R⁴⁵ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -OR⁵³, -SR⁵³, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl;

R⁴⁶ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, and an optionally substituted heteroalkyl, or

R⁴⁴ and R⁴⁵ together form an optionally substituted 5-6 member ring and R⁴⁶ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, or

R⁴⁵ and R⁴⁶ together form an optionally substituted 4-6 member ring and R⁴⁴ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -CONR⁵¹R⁵², and an optionally substituted aryl;

R⁴⁷ is selected from hydrogen, F, Cl, Br, an optionally substituted alkyl; and

R⁴⁸ is selected from the group consisting of hydrogen, a halogen, -CN, -OR¹⁶, - NR¹⁷R¹⁸, -CH₂R¹⁶, -COR²⁰, -CO₂R²⁰, -CONR²⁰R³⁷, -SOR²⁰, -SO₂R²⁰, -NO₂, NR¹⁷(OR¹⁶), an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl; R⁴⁹ is selected from the group consisting of hydrogen, a halogen, -CN, -COR²⁰, - CO₂R²⁰, -CONR²⁰R³⁷, -NR¹⁷SO₂R²⁰, -NR¹⁷CO₂R²⁰, -NO₂, -OR¹⁶, -NR¹⁷R¹⁸, NR¹⁷(OR¹⁶), an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted C]-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-Cs cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl;

R⁵⁰ is selected from the group consisting of hydrogen, a halogen, CN, -NO₂, OR¹⁶, an optionally substituted Cj-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted CpC₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted Cs-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl, or

R⁴⁸ and R⁴⁹ together form an optionally substituted 5-6 member ring and R⁵⁰ is selected from hydrogen, F, Cl, Br, CN, CONR⁵¹R⁵², an optionally substituted alkyl, an optionally substituted haloalkyl, and an optionally substituted heteroalkyl, or

R⁴⁹ and R⁵⁰ together form an optionally substituted 4-6 member ring and R⁴⁸ is selected from hydrogen, F, Cl, Br, CN, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, -CONR⁵¹R⁵², an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl,

R⁵¹ and R⁵² are each independently selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted haloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl and an optionally substituted heteroalkyl, or

R⁵¹ and R^s2 together form an optionally substituted 4-7 member ring;

R⁵³ is selected from hydrogen, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted cycloalkyl;

G is selected from O, S, and NR⁵⁴; and

R⁵⁴ is selected from hydrogen and an optionally substituted alkyl, an optionally substituted alkenyl and an optionally substituted alkynyl; and wherein the substituents on the alkyl, aralkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl groups, when present, are each individually and independently selected from one to four group(s) selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, non- aromatic heterocycle, hydroxy, alkoxy, alkoxyalkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, imino, hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyiminothiocarbonyl, O-carbamyl, N- carbamyl, O-thiocarbamyl, N- thiocarbamyl, C- amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy and amino; including mono- and all-substituted amino groups, and the protected derivatives of amino groups; wherein at least one position selected from R³⁹, R⁴⁰, R⁴¹, R⁴², and R⁴³ is not hydrogen; at least one position selected from R⁴⁴, R⁴⁵, R⁴⁶, and R⁴⁷ is not hydrogen; if R⁴¹ is F, then at least one position selected from R³⁹, R⁴⁰, R⁴² and R⁴³ is not hydrogen; if R⁴⁰ is F, then at least one position selected from R³⁹, R⁴¹, R⁴², and R⁴³ is not hydrogen; and if any two positions selected from R³⁹, R⁴⁰, R⁴¹, R⁴², and R⁴³ are both F, then at least one of the other three positions selected from R³⁹, R⁴⁰, R⁴¹, R⁴², and R⁴³ is not hydrogen.

2. The compound of claim 1, wherein

R³ is selected from the group consisting of (a), (b), (c), (d), (e), (f), (g), (h), (i),

0), (k), (l), and (m):

(a) (b) (C)

(d) (e) (f)

ϋ) (k)

(1) (m)

R⁴ is selected from hydrogen, a halogen, NO₂, OR¹⁶, NR¹⁷R¹⁸, an optionally substituted C]-Ce alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted C)-C₈ haloalkyl, an optionally substituted C]-C₈ heterohaloalkyl, an optionally substituted C₃-Q cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C5- C₈ aryl, and an optionally substituted C₃-Q heteroaryl;

R¹⁷ and R¹⁸ are each independently selected from the group consisting of hydrogen, COR²⁰, CO₂R²⁰, SO₂R²⁰, S(O)R²⁰, an optionally substituted C)-C₈ alkyl, an optionally substituted CpC₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted C)-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅-C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl; R²⁰ and R³⁷ is selected from the group consisting of hydrogen, an optionally substituted Cj-Cs alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅- C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl; and

R²⁷ is selected from the group consisting of hydrogen, a halogen, an optionally substituted Ci-C₈ alkyl, an optionally substituted Ci-C₈ heteroalkyl, an optionally substituted Ci-C₈ haloalkyl, an optionally substituted Ci-C₈ heterohaloalkyl, an optionally substituted C₃-C₈ cycloalkyl, an optionally substituted C₂-C₈ heterocycle, an optionally substituted C₅- C₈ aryl, and an optionally substituted C₃-C₈ heteroaryl.

3. The compound of claim 1, wherein R¹ is selected from the group consisting of hydrogen and an optionally substituted Ci-C₆ alkyl.

4. The compound of claim 3, wherein the alkyl from which R¹ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

5. The compound of claim 1, wherein R¹ is hydrogen or methyl.

6. The compound of claim 1, wherein R² is selected from the group consisting of hydrogen, a halogen, and an optionally substituted Ci-C₆ alkyl.

7. The compound of claim 6, wherein the alkyl from which R² is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

8. The compound of claim 6, wherein the halogen from which R² is selected is chloro or bromo.

9. The compound of claim 1, wherein R² is hydrogen or chloro.

10. The compound of claim 1, wherein R⁴ is selected from the group consisting of hydrogen, a halogen, and an optionally substituted Ci-C₆ alkyl.

1 1. The compound of claim 10, wherein the alkyl from which R⁴ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

12. The compound of claim 10, wherein the halogen is fluoro or chloro.

13. The compound of claim 1, wherein R⁴ is selected from the group consisting of hydrogen, methyl, fluoro, and chloro.

14. The compound of claim 1, wherein R⁵ is selected from the group consisting of hydrogen, and an optionally substituted Cj-C₈ alkyl.

15. The compound of claim 14, wherein the alkyl from which R⁵ is selected is optionally substituted with one or more substituents selected from the group consisting of an aryl, a heteroaryl, a cycloalkyl, and a heterocycle.

16. The compound of claim 15, wherein the alkyl from which R⁵ is selected is optionally substituted with an optionally substituted aryl.

17. The compound of claim 16, wherein the aryl optionally substituting R⁵ is an optionally substituted phenyl.

18. The compound of claim 14, wherein the alkyl from which R⁵ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

19. The compound of claim 14, wherein the alkyl from which R⁵ is selected is a C₂-C₈ alkenyl optionally substituted with one or more substituents selected from the group consisting of an alkyl, an aryl, a heteroaryl, a cycloalkyl, and a heterocycle.

20. The compound of claim 19, wherein the alkenyl from which R⁵ is selected is selected from the group consisting of ethenyl, propenyl, butenyl, and pentenyl.

21. The compound of claim 1, wherein R⁵ is selected from the group consisting of hydrogen, methyl, benzyl, 3-methyl-2-butenyl, and 2-propenyl.

22. The compound of claim 1 , wherein R⁶ is hydrogen or OR¹⁶.

23. The compound of claim 22, wherein R¹⁶ is hydrogen or Ci-C₆ alkyl.

24. The compound of claim 23, wherein the alkyl from which R¹⁶ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

25. The compound of claim 1, wherein R⁶ is hydrogen or hydroxy.

26. The compound of claim 1, wherein R⁷ and R⁸ are each independently hydrogen or a Ci-C₈ alkyl.

27. The compound of claim 26, wherein the alkyl from which R⁷ and R⁸ are selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, and tert-butyl.

28. The compound of claim 1, wherein R⁷ and R⁸ are each methyl.

29. The compound of claim 1, wherein R⁹ is selected from the group consisting of hydrogen, OR¹⁶, and a Ci-C₈ alkyl.

30. The compound of claim 29, wherein the alkyl from which R⁹ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

31. The compound of claim 29, wherein R¹⁶ is hydrogen or Ci-C₆ alkyl.

32. The compound of claim 31, wherein the alkyl from which R¹⁶ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

33. The compound of claim 1, wherein R⁹ is selected from the group consisting of hydrogen, methyl, and hydroxy.

34. The compound of claim 1, wherein R¹⁰ is hydrogen or OR¹⁶.

35. The compound of claim 34, wherein R¹⁶ is hydrogen or a Q-C₆ alkyl.

36. The compound of claim 35, wherein the alkyl from which R¹⁶ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

37. The compound of claim 1, wherein R¹⁰ is hydrogen or hydroxy.

38. The compound of claim 1, wherein R³ is selected from the group consisting of an optionally substituted indolyl, an optionally substituted indolinyl; an optionally substituted pyridyl, an optionally substituted dibenzofuranyl, an optionally substituted benzodioxinyl and an optionally substituted benzothiophenyl.

39. The compound of claim 38, wherein R¹¹ is hydrogen.

40. The compound of claim 38, wherein R^u is a halogen.

41. The compound of claim 40, wherein the halogen from which R¹¹ is selected is fluoro or chloro.

42. The compound of claim 38, wherein R¹¹ is -OR¹⁶, and R¹⁶ is selected from the group consisting of hydrogen, an optionally substituted Ci-C₆ alkyl, and optionally substituted Ci-C₆ haloalkyl.

43. The compound of claim 42, wherein the optionally substituted alkyl from which R¹⁶ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

44. The compound of claim 42, wherein the optionally substituted alkyl from which R¹⁶ is selected is substituted with one or more substituents selected from the group consisting of an alkyl, an aryl, a heteroaryl, a cycloalkyl, and a heterocycle.

45. The compound of claim 44, wherein the optionally substituted alkyl from which R¹⁶ is selected is substituted with phenyl.

46. The compound of claim 42, wherein the haloalkyl from which R¹⁶ is selected is a perfluoroalkyl.

47. The compound of claim 42, wherein the perfluoroalkyl from which R¹⁶ is selected is trifluoromethyl.

48. The compound of claim 38, wherein R¹¹ is -NR¹⁷R¹⁸, and wherein R¹⁷ and R¹⁸ are each independently hydrogen or a Ci-C₆ alkyl.

49. The compound of claim 48, wherein the alkyl from which R¹⁷ and R¹⁸ are selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, and tert-butyl.

50. The compound of claim 48, wherein R is -NH₂.

51. The compound of claim 38, wherein R^{1 1} is -COR²⁰, wherein R²⁰ is hydrogen or a Ci-C₆ alkyl.

52. The compound of claim 51, wherein the alkyl from which R² is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

53. The compound of claim 38, wherein R^{1 1} is an alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

54. The compound of claim 38, wherein R^{1 1} is an alkenyl selected from the group consisting of ethenyl, propenyl, butenyl, and pentenyl.

55. The compound of claim 54, wherein the alkenyl from which R¹¹ is selected is optionally substituted with one or more substituents selected from the group consisting of an alkyl, an aryl, a heteroaryl, a cycloalkyl, and a heterocycle.

56. The compound of claim 38, wherein R¹¹ is a haloalkyl.

57. The compound of claim 56, wherein R¹ ' is a perfluoroalkyl.

58. The compound of claim 57, wherein R¹¹ is trifluoromethyl.

59. The compound of claim 38, wherein R¹¹ is an aryl.

60. The compound of claim 59, wherein R^{1 1} is phenyl.

61. The compound of claim 38, wherein R¹¹ is selected from the group consisting of hydrogen, methyl, hydroxy, methoxy, benzyloxy, phenyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, -NH₂, -NO₂, -C(O)CH₃, and 2-methy-2-butenyl.

62. The compound of claim 38, wherein R¹² is selected from the group consisting of hydrogen, a halogen, a C,-C₃ haloalkyl, -CN, -NR¹⁷SO₂R²⁰, -NR¹⁷CO₂R²⁰, -NO₂, -OR¹⁶, and -NR¹⁷R¹⁸.

63. The compound of claim 62, wherein the halogen from which R¹² is selected is fluoro or chloro.

64. The compound of claim 62, wherein the haloalkyl from which R¹² is selected is a perfluoroalkyl.

65. The compound of claim 64, wherein the perfluoroalkyl from which R¹² is selected is trifluoromethyl.

66. The compound of claim 62, wherein R¹⁷ and R¹⁸ are each independently selected from the group consisting of hydrogen, a Ci-C₆ alkyl, and a Cj-C₆ heteroalkyl.

67. The compound of claim 66, wherein the alkyl from which R¹⁷ and R¹⁸ are selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, and tert-butyl.

68. The compound of claim 62, wherein R¹⁷ and R¹⁸ are each hydrogen.

69. The compound of claim 62, wherein R²⁰ is hydrogen or a Ci -C₆ alkyl.

70. The compound of claim 69, wherein the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

71. The compound of claim 62, wherein R¹⁶ is selected from the group consisting of hydrogen, an optionally substituted Ci-C₆ alkyl, and a Ci-C₆ haloalkyl.

72. The compound of claim 71, wherein the alkyl from which R¹⁶ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

73. The compound of claim 62, wherein R¹² is selected from the group consisting of hydrogen, hydroxy, methoxy, chloro, trifluoromethyl, -CN, -NH₂, -NHC(O)OCH₃, -NHC(O)OtBu, -NHSO₂CH₃.

74. The compound of claim 38, wherein each R¹³ is independently and optionally selected from the group consisting of hydrogen, a halogen, CN, -NO₂, and OR¹⁶.

75. The compound of claim 74, wherein the halogen from which each R¹³ is selected is fluoro or chloro.

76. The compound of claim 74, wherein R¹⁶ is selected from the group consisting of hydrogen, an optionally substituted C_I-C₆ alkyl, and a Ci-C₆ haloalkyl.

77. The compound of claim 76, wherein the alkyl from which R¹⁶ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

78. The compound of claim 38, wherein each R¹³ is independently selected from the group consisting of hydrogen, chloro, CN, -NO₂, and -OCH₃.

79. The compound of claim 1, wherein R³ is Formula V,

wherein

U is oxygen or -NR¹⁷;

R²¹ is selected from the group consisting of hydrogen, a Ci-C₆ alkyl, and a Ci-C₆ haloalkyl; and

R²² is selected from the group consisting of hydrogen, a halogen, a Ci -C₆ alkyl, a Ci-C₆ a heteroalkyl, a Ci-C₆ haloalkyl, a Ci-C₆ heterohaloalkyl -OR¹⁶, -NR¹⁷R¹⁸, an aryl, and a heteroaryl.

80. The compound of claim 79, wherein U is oxygen.

81. The compound of claim 80, wherein R²¹ is hydrogen or a Ci-C₆ alkyl.

82. The compound of claim 81, wherein the alkyl from which R²¹ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

83. The compound of claim 80, wherein R²² is selected from the group consisting of hydrogen, a Ci-C₆ alkyl, -NR¹⁷R¹⁸, and an aryl.

84. The compound of claim 83, wherein the alkyl from which R²² is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

85. The compound of claim 83, wherein R¹⁷ and R¹⁸ are each independently selected from the group consisting of hydrogen, a Ci-C₆ alkyl, and a Cj-C₆ heteroalkyl.

86. The compound of claim 85, wherein the alkyl from which R¹⁷ and R¹⁸ are selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, and tert-butyl.

87. The compound of claim 85, wherein R¹⁷ and R¹⁸ are each hydrogen.

88. The compound of claim 83, wherein the aryl from which R²² is selected is phenyl.

89. The compound of claim 79, wherein U is -NR¹⁷.

90. The compound of claim 89, wherein R¹⁷ is selected from the group consisting of hydrogen, a Ci-C₆ alkyl, and -COR²⁰.

91. The compound of claim 1, wherein R³ is Formula VI,

wherein U is sulfur and R²¹ and R²² are each independently selected from the group consisting of hydrogen, a Ci-C₆ alkyl, and a Ci-C₆ heteroalkyl.

92. The compound of claim 91, wherein the alkyl from which R²¹ and R²² are selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, and tert-butyl.

93. The compound of claim 91, wherein R²¹ and R²² are each hydrogen.

94. The compound of claim 1, wherein R³ is Formula VII,

wherein

R³⁴ is selected from the group consisting of hydrogen, a halogen, -NO₂, -OR¹⁶, -NR¹⁷R¹⁸, -CN, -COR²⁰, an optionally substituted Ci-C₆ alkyl, and an optionally substituted C]-C₆ haloalkyl; and

R³² and R³³ are each independently selected from the group consisting of hydrogen, a halogen, -OR¹⁶, -CN, -COR²⁰, an optionally substituted Ci-C₆ alkyl, and an optionally substituted Ci-C₆ haloalkyl.

95. The compound of claim 94, wherein R³⁴ is selected from the group consisting of hydrogen, -COR²⁰, and a C-C₆ alkyl.

96. The compound of claim 95, wherein the alkyl from which R³⁴ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

97. The compound of claim 95, wherein R²⁰ is hydrogen or a Cj -C₆ alkyl.

98. The compound of claim 97, wherein the alkyl from which R²⁰ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

99. The compound of claim 94, wherein R³² and R³³ are each independently selected from the group consisting of hydrogen, -COR²⁰, and a Ci-C₆ alkyl.

100. The compound of claim 99, wherein R²⁰ is hydrogen or a C_I -C_O alkyl.

101. The compound of claim 100, wherein the alkyl from which R²⁰ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

102. The compound of claim 94, wherein R³² is hydrogen.

103. The compound of claim 94, wherein R³³ is hydrogen or -COCH₃.

104. The compound of claim 1, wherein R³ is Formula VIII,

wherein each R²³ is independently and selected from the group consisting of hydrogen, a halogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted Ci-C₆ haloalkyl, and OR¹⁶.

105. The compound of claim 104, wherein V is sulfur or -NR¹⁷.

106. The compound of claim 105, wherein R¹⁷ is selected from the group consisting of hydrogen, a Cj-C₆ alkyl, and a Ci-C₆ heteroalkyl.

107. The compound of claim 106, wherein the alkyl from which R¹⁷ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

108. The compound of claim 104, wherein R^!7 is hydrogen.

109. The compound of claim 104, wherein V is sulfur.

1 10. The compound of claim 109, wherein R is selected from the group consisting of hydrogen, a Ci-C₆ alkyl, and a Ci -C₆ heteroalkyl.

111. The compound of claim 110, wherein the alkyl from which R²³ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

1 12. The compound of claim 104, wherein R²³ is hydrogen.

113. The compound of claim 1, wherein R is Formula IX,

wherein R²⁴ is selected from the group consisting of hydrogen, a halogen, and -OR¹⁶; R²⁵ is selected from the group consisting of hydrogen, a halogen, -OR¹⁶, -CN, an optionally substituted Ci-C₆ alkyl, and an optionally substituted Ci-C₆ haloalkyl;

R²⁶ is selected from the group consisting of hydrogen, a halogen, and -OR¹⁶; and n is 0, 1, or 2.

114. The compound of claim 113, wherein R³⁶ is selected from the group consisting of hydrogen, a C i-C₆ alkyl, and a Cj -C₆ heteroalkyl.

115. The compound of claim 114, wherein the alkyl from which R³⁶ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

116. The compound of claim 113, wherein R³⁶ is hydrogen.

117. The compound of claim 113, wherein R²⁷ is selected from the group consisting of hydrogen, a Ci-C₆ alkyl, and a Ci-C₆ heteroalkyl.

118. The compound of claim 117, wherein the alkyl from which R²⁷ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

119. The compound of claim 113, wherein R²⁷ is hydrogen.

120. The compound of claim 113, wherein R²⁴, R²⁵, and R³⁶ are each independently selected from the group consisting of hydrogen, a Ci-C₆ alkyl, and a Ci-C₆ heteroalkyl.

121. The compound of claim 120, wherein the alkyl from which R²⁴, R²⁵, and R³⁶ are selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

122. The compound of claim 113, wherein R²⁴, R²⁵, and R³⁶ are each hydrogen.

123. The compound of claim 1, wherein R³ is Formula X,

wherein

R²⁴ is selected from the group consisting of hydrogen, a halogen, and -OR¹⁶;

R²⁵ is selected from the group consisting of hydrogen, a halogen, -OR¹⁶, -CN, an optionally substituted Ci-C₆ alkyl, and an optionally substituted Ci-C₆ haloalkyl;

R²⁶ is selected from the group consisting of hydrogen, halogen, -OR¹⁶, -CN, an optionally substituted C]-C₆ alkyl, and an optionally substituted Cj-C₆ haloalkyl; and n is 0, 1, or 2.

124. The compound of claim 123, wherein R³⁶ is selected from the group consisting of hydrogen, a Ci-C₆ alkyl, and a CpC₆ heteroalkyl.

125. The compound of claim 124, wherein the alkyl from which R³⁶ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

126. The compound of claim 123, wherein R³⁶ is hydrogen or methyl.

127. The compound of claim 123, wherein R²⁷ is selected from the group consisting of hydrogen, a halogen, a Ci-C₆ alkyl, and a Ci-C₆ heteroalkyl.

128. The compound of claim 127, wherein the alkyl from which R²⁷ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

129. The compound of claim 127, wherein the halogen from which R²⁷ is selected is selected from the group consisting of fluoro, chloro, and bromo.

130. The compound of claim 129, wherein the halogen from which R²⁷ is selected is bromo.

131. The compound of claim 127, wherein the heteroalkyl from which R²⁷ is selected is -CH₂CH₂C(O)CH₃.

132. The compound of claim 123, wherein R is selected from the group consisting of hydrogen, a halogen, and -OR¹⁶.

133. The compound of claim 132, wherein the halogen from which R²⁴ is selected is selected from the group consisting of fluoro, chloro, and bromo.

134. The compound of claim 132, wherein R¹⁶ is hydrogen or a Ci-C₆ alkyl.

135. The compound of claim 134, wherein the alkyl from which R¹⁶ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

136. The compound of claim 132, wherein R²⁴ is selected from the group consisting of hydrogen, fluoro, chloro, and methoxy.

137. The compound of claim 123, wherein R²⁵ is hydrogen or -OR¹⁶.

138. The compound of claim 137, wherein R¹⁶ is hydrogen or a Cj-C₆ alkyl.

139. The compound of claim 138, wherein the alkyl from which R¹⁶ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

140. The compound of claim 123, wherein R²⁵ is hydrogen or methoxy.

141. The compound of claim 123, wherein R²⁶ is hydrogen or a Cj-C₆ alkyl.

142. The compound of claim 141, wherein the alkyl from which R²⁶ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

143. The compound of claim 123, wherein R²⁶ is hydrogen or methyl.

144. The compound of claim 1, wherein R³ is Formula XI,

wherein

R is selected from the group consisting of hydrogen, a halogen, and -OR¹ ; R²⁵ is selected from the group consisting of hydrogen, a halogen, -OR¹⁶, -CN, an optionally substituted CpC₆ alkyl, and an optionally substituted C]-C₆ haloalkyl; and n is 0, 1, or 2.

145. The compound of claim 144, wherein L is CH₂.

146. The compound of claim 144, wherein Z is -NR²⁸.

147. The compound of claim 144, wherein R²⁴, R²⁵, and R²⁸ are each independently selected from the group consisting of hydrogen, a Ci-C₆ alkyl, and a Cj-C₆ heteroalkyl.

148. The compound of claim 147, wherein the alkyl from which R²⁴, R²⁵, and R²⁸ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, and tert-butyl.

149. The compound of claim 144, wherein R²⁴, R²⁵, and R²⁸ are each hydrogen.

150. The compound of claim 1, wherein R³ Formula XII,

wherein each R¹³ is independently selected from the group consisting of hydrogen, a halogen, an optionally substituted C)-C₆ alkyl, an optionally substituted Ci-C₆ haloalkyl, CN, -NO₂, and OR¹⁶; and n is 0, 1, 2, or 3;

R³⁵ is selected from the group consisting of hydrogen, an optionally substituted C₁-C₄ alkyl, an optionally substituted Ci-C₄ haloalkyl, an optionally substituted Cj-C₄ heteroalkyl, an optionally substituted heterohaloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, and q is 0 or 1.

151. The compound of claim 150, wherein R¹³ is hydrogen or a Ci-C₆ alkyl.

152. The compound of claim 151, wherein the alkyl from which R¹³ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

153. The compound of claim 150, wherein R¹³ is hydrogen.

154. The compound of claim 150, wherein J is oxygen.

155. The compound of claim 150, wherein B is oxygen.

156. The compound of claim 150, wherein each R²⁷ is independently hydrogen or a Ci-C₆ alkyl.

157. The compound of claim 156, wherein the alkyl from which each R²⁷ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, and tert-butyl.

158. The compound of claim 150, wherein B is CH₂.

159. The compound of claim 150, wherein K is -NR³⁵.

160. The compound of claim 159, wherein R³⁵ is hydrogen or a Ci -Ce alkyl.

161. The compound of claim 160, wherein the alkyl from which R³⁵ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

162. The compound of claim 150, wherein R³⁵ is hydrogen or methyl.

163. The compound of claim 1 , wherein R³ is Formula XIII,

wherein

R²⁹ is selected from the group consisting of hydrogen, a halogen, and -OR¹⁶; R³⁰ is hydrogen or an optionally substituted C]-C₄ alkyl; q is 1 or 2; and n is 1 or 2.

164. The compound of claim 163, wherein M is oxygen.

165. The compound of claim 164, wherein R³⁰ is hydrogen or a Ci-C₆ alkyl.

166. The compound of claim 165, wherein the alkyl from which R³⁰ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

167. The compound of claim 163, wherein R³⁰ is hydrogen.

168. The compound of claim 164, wherein R²⁹ is hydrogen or a C_I -C_O alkyl.

169. The compound of claim 168, wherein the alkyl from which R²⁹ is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

170. The compound of claim 168, wherein R²⁹ is hydrogen.

171. The compound of claim 1 , wherein R³ is Formula XIV,

wherein

R³¹ is selected from the group consisting of hydrogen, a halogen, and -OR¹⁶.

172. The compound of claim 171, wherein R³¹ is hydrogen or a C_I -C_O alkyl.

173. The compound of claim 172, wherein the alkyl from which R^3! is selected is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

174. The compound of claim 171, wherein R³¹ is hydrogen.

175. The compound of claim 171, wherein R³ is

176. The compound of claim 1, wherein R³ is selected from the group consisting of an optionally substituted 2-indolyl, an optionally substituted 3-indolyl, an optionally substituted 4-indolyl, optionally substituted 6-indolyl, an optionally substituted 7-indolyl, and an optionally substituted 7-indolinyl.

177. The compound of claim 1 , wherein R³ is pyridyl, optionally substituted with a C₁-C₆ alkyl.

178. The compound of claim 177, wherein the alkyl which optionally substitutes R³ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

179. The compound of claim 1, wherein R³ is 3-methylpyrid-2-yl.

180. The compound of claim 1, wherein R is an optionally substituted dibenzofuranyl.

181. The compound of claim 1, wherein R³ is 2,3-dihydro-l,4-benzodioxin-6-yl.

182. A compound of claim 1 that is a steroid receptor modulator.

183. A compound of claim 1 that is a selective glucocorticoid receptor modulator.

184. A compound of claim 1 that is a selective androgen receptor modulator.

185. A compound of claim 1 that is a selective glucocorticoid/androgen receptor modulator.

186. The compound of claim 183 that is a glucocorticoid receptor agonist.

187. The compound of claim 183 that is a glucocorticoid receptor antagonist.

188. The compound of claim 183 that is a glucocorticoid receptor partial agonist.

189. The compound of claim 184 that is an androgen receptor agonist.

190. The compound of claim 184 that is an androgen receptor antagonist.

191. The compound of claim 184 that is an androgen receptor partial agonist.

192. A selective glucocorticoid receptor binding compound of claim 1.

193. A selective androgen receptor binding compound of claim 1.

194. A selective glucocorticoid/androgen receptor binding compound of claim 1.

195. The compound of claim 183, wherein the compound is a tissue-specific modulator.

196. The compound of claim 184, wherein the compound is a tissue-specific modulator.

197. The compound of claim 185, wherein the compound is a tissue-specific modulator.

198. The compound of claim 183, wherein the compound is a gene-specific modulator.

199. The compound of claim 184, wherein the compound is a gene-specific modulator.

200. The compound of claim 185, wherein the compound is a gene-specific modulator.

201. A method for modulating an activity of a glucocorticoid receptor comprising contacting the receptor with a compound of claim 1.

202. A method for modulating an activity of an androgen receptor comprising contacting the receptor with a compound of claim 1.

203. A method for modulating an activity of a glucocorticoid receptor and an activity of an androgen receptor comprising contacting the glucocorticoid receptor and the androgen receptor with a compound of claim 1.

204. A method comprising contacting a cell expressing a glucocorticoid receptor with a compound of claim 1 and monitoring an effect on the cell.

205. A method comprising contacting a cell expressing an androgen receptor with a compound of claim 1 and monitoring an effect on the cell.

206. A method comprising contacting a cell expressing a glucocorticoid receptor and an androgen receptor with a compound of claim 1 and monitoring an effect on the cell.

207. A method of treating a patient suffering from an androgen receptor related disorder or a glucocorticoid receptor related disorder, comprising identifying a patient in need thereof and contacting said patient with a compound of claim 1.

208. The method of claim 207 wherein the patient suffers from a condition selected from the group consisting of: inflammation, transplant rejection, psoriasis, dermatitis, autoimmune disorder, malignancy, adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, granulomatous disease, immune proliferation/apoptosis, conditions of the HPA axis, hypercortisolemia, cytokine imbalance, kidney disease, liver disease, stroke, spinal cord injury, hypercalcemia, hyperglycemia, cerebral edema, thrombocytopenia, Little's syndrome, Addison's disease, cystic fibrosis, myasthenia gravis, autoimmune hemolytic anemia, uveitis, pemphigus vulgaris, multiple sclerosis, nasal polyps, sepsis, infections, type II diabetes, obesity, metabolic syndrome, depression, schizophrenia, mood disorders, Cushing's syndrome, anxiety, sleep disorders, poor memory, glaucoma, wasting, heart disease, fibrosis, hypertension, hyperaldosteronism, and sodium and/or potassium imbalance.

209. A pharmaceutical agent comprising a physiologically acceptable carrier, diluent, or excipient; and a compound of claim 1.

210. A pharmaceutical agent comprising a physiologically acceptable carrier, diluent, or excipient; and a compound of claim 182.

211. The pharmaceutical agent of claim 209 or claim 210 for use in treating a condition selected from the group consisting of: inflammation, transplant rejection, psoriasis, dermatitis, autoimmune disorder, malignancy, adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, granulomatous disease, immune proliferation/apoptosis, conditions of the HPA axis, hypercortisolemia, cytokine imbalance, kidney disease, liver disease, stroke, spinal cord injury, hypercalcemia, hyperglycemia, cerebral edema, thrombocytopenia, Little's syndrome, Addison's disease, cystic fibrosis, myasthenia gravis, autoimmune hemolytic anemia, uveitis, pemphigus vulgaris, multiple sclerosis, nasal polyps, sepsis, infections, type II diabetes, obesity, metabolic syndrome, depression, schizophrenia, mood disorders, Cushing's syndrome, anxiety, sleep disorders, poor memory, glaucoma, wasting, heart disease, fibrosis, hypertension, hyperaldosteronism, and sodium and/or potassium imbalance.