AU2003248406A1

AU2003248406A1 - Steroid receptor modulator compounds and methods

Info

Publication number: AU2003248406A1
Application number: AU2003248406A
Authority: AU
Inventors: Robert J Davis; James E Edwards; Luc J Farmer; Mark E Goldman; Lawrence G Hamann; Todd K Jones; Charlotte L F Pooley; Christopher M Tegley; Sarah J West; David T Winn; Lin Zhi
Original assignee: Ligand Pharmaceuticals Inc
Current assignee: Ligand Pharmaceuticals Inc
Priority date: 1994-12-22
Filing date: 2003-09-26
Publication date: 2003-11-06

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Applicant: LIGAND PHARMACEUTICALS INCORPORATED Invention Title: STEROID RECEPTOR MODULATOR COMPOUNDS AND METHODS The following statement is a full description of this invention, including the best method of performing it known to us: I STEROID RECEPTOR MODULATOR COMPOUNDS AND METHODS Field of the Invention This invention relates to non-steroidal compounds that are modulators agonists and antagonists) of steroid receptors progesterone receptor, androgen receptor, estrogen receptor, glucocorticoid receptor and mineralocorticoid receptor), and to methods for the making and use of such compounds.

Background of the Invention Intracellular receptors (IRs) form a class of structurally-related genetic regulators scientists have named "ligand dependent transcription factors." R.M. Evans, 240 Science, 889 (1988). Steroid receptors are a recognized subset of the IRs, including the progesterone receptor androgen receptor estrogen receptor glucocorticoid receptor (GR) and mineralocorticoid receptor Regulation of a gene by such factors requires both the IR itself and a corresponding ligand which has the ability to selectively bind to the IR in a way that affects gene transcription.

Ligands to the IRs can include low molecular weight native molecules, such as the hormones progesterone, estrogen and testosterone, as well as synthetic derivative compounds such as medroxyprogesterone acetate, diethylstilbesterol and 19nortestosterone. These ligands, when present in the fluid surrounding a cell, pass through the outer cell membrane by passive diffusion and bind to specific IR proteins to create a ligand/receptor complex. This complex then translocates to the cell's nucleus, where it binds to a specific gene or genes present in the cell's DNA. Once bound to DNA, the complex modulates the production of the protein encoded by that gene. In this regard, a compound which binds an IR and mimics the effect of the native ligand is referred to as an "agonist", while a compound that inhibits the effect of the native ligand is called an "antagonist." 2 Ligands to the steroid receptors are known to play an important role in health of both women and men. For example, the native female ligand, progesterone, as well as synthetic analogues, such as norgestrel (1 8 -homonorethisterone) and norethisterone (17a-ethinyl-19nortestosterone), are used in birth control formulations, typically in combination with the female hormone estrogen or synthetic estrogen analogues, as effective modulators of both PR and ER. On the other hand, antagonists to PR are potentially useful in treating chronic disorders, such as certain hormone dependent cancers of the breast, ovaries, and uterus, and in treating non-malignant conditions such as uterine fibroids and endometriosis, a leading cause of infertility in women. Similarly, AR antagonists, such as cyproterone acetate and flutamide have proved useful in the treatment of hyperplasia and cancer of the prostate.

The effectiveness of known modulators of steroid receptors is often tempered by their undesired side-effect profile, particularly during long-term administration. For example, the effectiveness of progesterone and estrogen agonists, such as norgestrel and diethylstilbesterol respectively, as female birth control agents must be weighed against the increased risk of breast cancer and heart disease to women taking such agents. Similarly, the progesterone antagonist, mifepristone (RU486), if administered for chronic indications, such as uterine fibroids, endometriosis and certain hormone-dependent cancers, could lead to homeostatic imbalances in a patient due to its inherent cross-reactivity as a GR antagonist. Accordingly, identification of compounds which have good specificity for one or more steroid receptors, but which have reduced or no cross-reactivity for other steroid or intracellular receptors, would be of significant value in the treatment of male and female hormone responsive diseases.

A group of quinoline analogs having an adjacent polynucleic ring system of the indene or fluorene series or an adjacent polynucleic heterocyclic ring system with substituents having a nonionic character have been described as photoconductive reducing agents, stabilizers, laser dyes and antioxidants. See U.S. Patent Nos. 3,798,031; 3,830,647; 3,832,171; 3,928,686; 3,979,394; 4,943,502 and 5,147,844 as well as Soviet Patent No. 555,119; R.L. Atkins and D.E. Bliss, "Substituted Coumarins and Azacoumarins: Synthesis and Fluorescent Properties", 43 J. Org. Chem., 1975 (1978), E.R.

Bissell et al., "Synthesis and Chemistry of 7 -Amino-4-(trifluoromethyl)coumarin and Its Amino Acid and Peptide Derivatives", 45 J. Org. Chem., 2283 (1980) and G.N. Gromova and K.B. Piotrovskii, "Relative Volatility of Stabilizers for Polymer Materials," 43 Khim.

3 Prom-st., 97 (Moscow, 1967). However, no biological activity of any kind has been ascribed to these compounds.

Summary of the Invention The present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by steroid receptors. More particularly, the invention relates to non-steroidal compounds and compositions which are high affinity, high specificity agonists, partial agonists and antagonists for the PR, AR, ER, GR and MR steroid receptors, as well as to compounds with combined activity on one or more of these receptors. Also provided are methods of making such compounds and pharmaceutical compositions, as well as critical intermediates used in their synthesis.

These and various other advantages and features of novelty which characterize the invention are pointed out with particularity in the claims annexed hereto and forming a part hereof. However, for a better understanding of the invention, its advantages, and objects obtained by its use, reference should be had to the accompanying drawings and descriptive matter, in which there is illustrated and described preferred embodiments of the invention.

Definitions and Nomenclature As used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise. Furthermore, in an effort to maintain consistency in the naming of compounds of similar structure but differing substituents, the compounds described herein are named according to the following general guidelines. The numbering system for the location of substituents on such compounds is also provided.

The term alkyl, alkenyl, alkynyl and allyl includes straight-chain, branched-chain, cyclic, saturated and/or unsaturated structures, and combinations thereof.

The term aryl refers to an optionally substituted six-membered aromatic ring, including polyaromatic rings.

The term heteroaryl refers to an optionally substituted five-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of carbon, oxygen, nitrogen and sulfur, including polycyclic rings, or a six-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of carbon and nitrogen, including polycyclic rings.

A quinoline is defined by the following structure, and may be recognized as a benzannulated pyridine. Compounds of structures 4, 5, 13,79, 83 and 86 herein are named as quinolines.

4 6 3 7 N 2 8 1 An indeno[1,2-g]quinoline is defined by the following structure. Compounds'of structures 16 and 20 herein are named as indeno[ 1,2-g]quinolines.

7 6 8 3 9 N 2 11 1 An indeno[2,1-jiquinoline is defined by the following structure. Compounds of structure 17 herein are named as indeno[2, I -fjquinoLines.

7 6 8\ 4 N 2 11 A benzo~b]furano(3,2-glquinoline is defined by the folowing structure.

Compounds of structure 16 herein are named as benzo~blfurano[3,2-glquino lines.

7 6 5 4 11 1 A benzo[blfuirano[2,3-flquinoline is defined by the following structure.

Compounds of structure 17 herein are named as benzo~b]furanoE2,3-flquinolines.

8 4 9 N N 2 11 1 An indolo[3,2-glquinoline is defined by the following structure. Compounds of structure 16 herein are named as indolo[3, 2 -glquno lines.

7 6

N

11 1 An indolo[2,3-flquinoline is defined by the following structure. Compounds of structures 17 and 29 herein are named as indolo [2,3-f]quino lines.

11 1 A cournarino[3,4-flquinoline is defined by the following structure. Compound 159 and compounds of structures 41 and 88 herein are named as coumarino[3,4-flquinoajes.

12 1 A SH-chromeno[3,4-fAquinoline is defined by the following structure. Compounds of structures 34, 35, 42, 45 to 54, 93, 95, 97 to 99, 1A, 4A, 7A to 11A, 17A to 19A and to 27A herein are named as 5 H-chromeno[3,4-Ilquinolines.

I

12 1 An 8 -pyranono[5,6.glquinoline is defined by the following structure. Compounds of structures 57 60 63 69 73 28A 33A, 34A, 37A (X0O), 38A (X0O), 40A 41A 45A, 65A and 67A herein are named as 8 -pyrano no [5,6-gj quino lines.

6 5 4 N3 8 9 10 1 A lO-isocoumnarino[4,3-g]quinoline is defined by the following structure.

Compounds of structures 57 (R2=R 3 =benzo, 60 (R 2

=R

3 =benzo, and 63

(R

2

=R

3 =benzo, herein are named as lO-isocoumarino[4,3-g~quinolines.

7 8 N 6 9 N 3 o 0

N

2 12 11 A lO-isoquinolino[4,3-glquinoline is defined by the following structure.

Compounds of structures 57 (R 2

=R

3 =benzo, Z=NH), 60 (R2=R 3 =benzo, Z=NH), and 63

(R

2

=R

3 =benzo, Z=-NH) herein are named as lO-isoquinolino[4,3-glquinolines.

7 8 NG I 0 N N3 1H 12 1 An 8-pyridono[5,6-glquinoline is defined by the following structure. Compounds of structures 57 60 63 69 73 28A 37A 38A 40A 41A 47A, 53A, 62A, 63A, 65A 67A 70A, 72A, 74A, 79A, 80A, 81A and 84A herein are named as 8-pyridono[5,6g]quinolines.

6 5 4 753 8 2 0 N N 1 A 1OH-isochromeno[4,3-glquinoline is defined by the following structure. Compounds of structures 61 (R 2

=R

3 =benzo, Z-O) and 62 (R 2

=R

3 =benzo, Z=O) herein are named as 1OHisochromeno[4,3-g]quinolines.

7 8 Y6 4 9 \3 0 N 11 12 1 An 8H-pyrano[3,2-glquinoline is defined by the following structure. Compounds of structures 61 and 62 herein are named as 8 H-pyrano[3,2-g]quinolines.

6 5 4 754 9 10 1 A 10-tbioisoquinolino[4,3-gjquinoline is defined by the following structure.

Compounds of structures 58 (R 2

=R

3 =benzo, Z--NH) and 76 (R 2

=R

3 =benzo, Z-NH) herein are named as 1 0-thioisoquinolino [4,3-g]quinolines.

7 8 %6 4 9 3 1 S LI' 2 12 1 A 9-pyrido[3,2-g]quinoline is defined by the following structure. Compounds of structures 71 and 75 herein are named as 9-pyrido[3,2-g]quinolines.

6 5 4 9 N

N

10 1 An 8-thiopyranono[5,6-g]quinoline is defined by the following structure.

Compounds of structures 58 76 and 29A herein are named as 8thiopyranono[5,6-g]quinolines.

6 5 4 8 2 9 10 1 An 6-pyridono[5,6-g]quinoline is defined by the following structure. Compounds of structures 70 and 74 herein are named as 6-pyridono[5,6-g]quino lines.

O

7 6 5 4 8 N N 2 9 H 10 1 A 9-thiopyran-8-ono[5,6-g]quinoline is defined by the following structure.

Compounds of structure 57 28A 37A 38A 40A 41A 65A and 67A herein are named as 9-thiopyran-8-ono(5,6-g]quinolines.

6 5 4 9 10 1 An 7-pyridono[5,6-f]indoline is defined by the following structure. Compounds of structures 49A, 50A, 57A, and 83A are named as 7-pyridono[5,6-fjindolines.

6 5 4 3 7 2 An 5H-isochromenO[3,4-flquinohine is defined by the following structure.

Compounds of structures 22A, 23A and 24A are named as 5H-isochromeno[3,4flquinolines.

7 6 8 0 9 4 2 12 1 Detailed Description of Embodimnents of the Invention Compounds of the present invention are defined as those having the formulae: R 4

R

3 N-

R

1 0

A

6 H R

OR

143N 14 Rio OR

U

R 1 3 I HR9 202

(IV)

IR163

(VI)

(VII)

OR

(VIfl)

(IX)

OaI) .Rio

(XII)

(XIH)

(XIV)

OR

(XV)

OR N R11

-R

6

H

OR

(XVI)

23 R 24

R

2 6 21 R32 S R Y Z N28 R23 R 24

R

26 21R3 R23 R27 Y Z N 28

R

22 .R2 7 (XVlI wherein: R is a heteroaryl optionally substituted with a C 1

C

4 alkyl, F, Cl, Br, NO 2

CO

2

H,

2 2

CO

2 R CHO, CN, CF 3

CH

2 0H or COCH 3 where R is hydrogen, a C 1

C

4 alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, and where said R 1 heteroaryl is attached to compounds of formulas I and X through a carbon or nitrogen atom;

R

3 is hydrogen, a C 1

C

4 alkyl or perfluoroalkyl, hydroxymethyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl; R through R each independently are hydrogen, F, Cl, Br, I, NO 2

CO

2 H, CO 2

R

2 COR CN, CF 3

CH

2 0H, a C 1

-C

4 alkyl or perfluoroalkyl, OR 2

SR

2

S(O)R

2

SO

2

R

2

SO

3 H, S(NR2R )R 2 S(0)(NR2R 7)R 2 NR2R aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, where R 2 has the definition given above, R 7 is hydrogen, a C 1

C

4 alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl or arylmethyl, OR or NHR where R is hydrogen, a CI C 6 alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl or arylmethyl, SO 2

R

2 or S(O)R2; R and R1 0 each independently are hydrogen, a C 1

C

6 alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or R 9 and R 10 taken together can form a three- to seven-membered ring optionally substituted with 2 27 2 7 hydrogen, F, OR or NR2R 7 where R and R have the definitions given above; R through R each independently are hydrogen, F, Cl, Br, I, NO 2

CO

2

H,

2 2 2 2 2

CO

2 R COR CN, CF 3

CH

2 0H, a Ci-C 4 alkyl or perfluoroalkyl, OR 2

SR

2

S(O)R

2

SO

2

R

2

SO

3 H, S(NR2R )R2, S(O)(NR2R )R 2 NR 2R 7 aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, where R 2

R

7 and R 8 have the definitions given above; W is 0, NH, NR 7

CH

2 CHOH, C=O, OC=O, O=CO, NR C=O, NHC=O, O=CNR O=CNH, SC=O, O=CS, or CHOCOR 7 where R has the definition given above, except that when W is NH, CH 2 or 0 in the compounds of formula III, then R 11 through R and R cannot all be hydrogen when R R and R 10 are all CH 3 nor can they be a single F, Cl or Br substituent with the remaining substituents all being hydrogen when R 3 R and R1 0 are all CH 3 and further except that when W is 0 or NH in the compounds of formula IV, then R 5 through R 6 and R 1 l through R 14 cannot all be hydrogen when R 3

R

9 and R 10 are all CH 3 X is CH 2 0, S or NR where R has the definition given above; R is hydrogen, OH, OR SR 7 NR R optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, heteroaryl or Ci C 10 alkyl, where R 1 7 is a CI C 1 0 alkyl or perfluoroalkyl, or is an optionally substituted allyl, arylmethyl, aryl or heteroaryl, and where

R

2 and R have the definitions given above; R and R 19 each independently are hydrogen, a Ci C 6 alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or R 18 and

R

19 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, OR or NR7R where R 2

R

7 and R have the definitions given above; R 20 is a CI C 6 alkyl or an optionally substituted allyl, arylmethyl, alkenyl, aryl or heteroaryl;

R

21 is hydrogen, a CI C 4 alkyl or optionally substituted allyl, arylmethyl, aryl or heteroaryl; R is hydrogen, a C1 C4 alkyl, F, CI, Br, I, OR 2 N2R R or SR 2 where R 2 and R have the definitions given above;

R

23 is hydrogen, Cl, Br, F, OR 8 NR2R a Ci C 4 alkyl or perhaloalkyl, or is an optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl or heteroaryl, where R 2

R

and R have the definitions given above;

R

24 is hydrogen, F, Br, C1, a Ci C 4 alkyl or perhaloalkyl, aryl, heteroaryl, CF 3

CF

2 0R 25

CH

2 0R 25 or OR 25 where R 25 is a CI C 4 alkyl, except that R 24 cannot be

CH

3 when Z is 0, R 22

R

23

R

26 and R 29 are all hydrogen and R 3

R

27 and R 28 all are CH 3 R is hydrogen, a CI C4 alkyl, F, CI, Br, I, OR 2 N2R 7 R or SR 2 where R 2 and R 7 have the definitions given above;

R

27 and R 28 each independently are hydrogen, a C 1

C

4 alkyl or perfluoroalkyl, heteroaryl, optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or an aryl optionally substituted with hydrogen, F, Cl, Br, OR or NR2R 7 or R 27 and R 28 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR 2 or NR2 R 7 where R 2 and R 7 have the definitions given above;

R

29 is hydrogen, a C 1 C(6 alkyl or an optionally substituted allyl, arylmethyl, aryl or heteroaryl;

R

30 and R 3 1 each independently are hydrogen, a C 1

C

6 alkyl or an optionally substituted allyl, arylmethyl, aryl or heteroaryl, or R 30 and R 3 1 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, OR 2 or NR2R where R 2 and R 7 have the definitions given above; 32 33 R and R each independently are hydrogen, a Ci C 4 alkyl or an aryl optionally substituted with hydrogen, F, Cl, Br, OR 2 or NR2R or R 32 and R 33 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR 2 2 7 2 7 or NR R where R and R have the definitions given above; n is 0 or 1; Y is O or S; Z is 0, S, NH, NR 2 or NCOR 2 where R 2 has the same definition given above; the wavy line in the compounds of formulas VII, XII, XIII and XVI represent an olefin bond in either the cis or trans configuration; and the dotted lines in the structures depict optional double bonds, except that when there is a C 3 C4 double bond in the nitrogen bearing ring of compounds of formula II, then R through R 15 cannot all be hydrogen and R 3

R

9 and RI 0 cannot all be methyl, and further except when R 23 is an aryl, R 22

R

24 and R 29 are all hydrogen, R 3 is CH3 and Z is

NR

2 then R 2 cannot be a CI C4 alkyl.

Preferably, the compounds of formulae I, II, m, IV, X and XI comprise PR antagonists, the compounds of formulae V and VI comprise PR modulators (Le. both PR agonists and antagonists), the compounds of formulae VII, VIII, XII, XII, XIV, XV and XVI comprise PR agonists, and the compounds of formulae IX, XVII and XVIII comprise AR modulators both AR agonists and antagonists). More preferably, the compounds of formulae IX and XVII comprise AR antagonists.

The present invention also provides a pharmaceutical composition comprising an effective amount of steroid receptor modulating compounds of the formulae: R'

R

9 R'10. R 9

R

2 R R 2 4 OR R 4 OR R4 R wherein:

R

1 through R 3 each independently are hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl;

R

4 is hydrogen, a Cl C6 alkyl, or R 5 C=0, OR 6 or NR 6

R

7 where R 5 is hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, and wherein R 6 and R each independently are hydrogen, a C1 C6 alkyl, optionally substituted allyl, arylmethyl, aryl, or heteroaryl;

R

9 through RI 0 each independently are hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl;

R

11 is hydrogen, a Cl C6 alkyl, OR 6 or optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, where R 6 has the same definition given above, or R 1 and R 2

R

2 and R 3

R

1 and R 9

R

10 and R 11

R

1 and R 10 and/or R and R when taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, OR or NR R where R through R have the definitions given above, provided, however, that R R R and R cannot form more than two three- to seven-membered rings at a time; Y is 0, CHR or NR where R has the same definition given above; and Z is an aryl or heteroaryl group, including mono- and poly-cyclic structures, optionally substituted at one or more positions with hydrogen, a C 1

-C

6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, heteroaryl, F, Cl, Br, I, CN, R 5

C=O,

R

6

R

7 NC=O, R 6 OC=O, perfluoroalkyl, haloalkyi, a C 1

C

6 straight-chain hydroxy alkyl,

HOCR

5

R

8 nitro, R 6 0CH2, R 6 0, NH2, or R 6

R

7 N, where R 5 through R 7 have the definitions given above and where R 8 is hydrogen, a C1 C6 alkyl or optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl; and a pharmaceutically acceptable carrier.

Preferred Z groups, wherein the dashed lines indicate the preferred mode of attachment to the nitrogen-bearing ring, include the following: [rest of page left purposely blank] CD\ 0 0 0 j z 0 o oov

N

dh O

O

SN O 0 S N

NNN

N Nf N0

S-

N N

N

The present invention further provides a method of modulating processes mediated by steroid receptors comprising administering to a patient an effective amount of a compound of the formula: R

R

9 R 10 R R SzI R 2 R OR R OR R wherein R through R and Z have the same definitions as given above.

In a preferred aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a steroid receptor modulating compound of the formulae: R 4 R 3

R

5

N

6

HR

OR

R 13 R 1 R 1 1 4

R

R 4 15 1IN Ri R

R

5 R 6 HR9

(ID)

OR

R 12 R" R 4

R

3 R 13 I R Ri1 4 WN 9

OR

/W R'

R

1 1 I 1 0

OR

(VI)

(VII)

(Vii)

(IX)

(XI)

21 x r Ri 0

(XII)

(XIIII)

()GV)

R 14 R 1 6

R

3 0

R

3 R 2 1 R12 x

.X

R" H'NR

H

5

OR

6 rR

(XV)

R13 R1 6 2 R 21 R12 R 1 1R i H

(XVI)

OR

23 R 2 4 R 26 21 R33 1 R-2

(XVI)

OR

R23 R 24 R 26 R21 R3 x I4Z R 27 Y Z N 28

R

22 A2d

(XVWM

wherein: R is a heteroaryl optionally substituted with a C 1

C

4 alkyl, F, Cl, Br, N0 2 C0 2 1-, C0 2 R 2, CHO, CN, CF 3

CH

2 0H- or COCH 3 where R 2is hydrogen, a C 1

C

4 alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, and where said R. heteroaryl is attached to compounds of formulas I and X through a carbon or nitrogen atom;

R

3 is hydrogen, a Ci C 4 alkyl or perfluoroalkyl, hydroxymethyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl; R through R each independently are hydrogen, F, Cl, Br, I, NO 2 C02H, CO 2

R

2 COR CN, CF 3

CH

2 0H, a C 1

-C

4 alkyl or perfluoroalkyl,

OR

2

SR

2

S(O)R

2 SO0 2

R

2

SO

3 H, S(NR 2R)R 2 S(O)(NR2R

)R

2 NR2R 7 aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, where R 2 has the definition given above, R 7 is hydrogen, a CI C 4 alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl or arylmethyl,

OR

8 or NHR 8 where R 8 is hydrogen, a CI C 6 alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl,

SO

2

R

2 or S(O)R2 R and R 1 0 each independently are hydrogen, a Ci C 6 alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or R and R 10 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, OR or NR2R where R 2 and R 7 have the definitions given above;

R

11 through R 15 each independently are hydrogen, F, Cl, Br, I, NO 2

CO

2

H,

CO

2

R

2

COR

2 CN, CF 3

CH

2 0H, a Ci-C 4 alkyl or perfluoroalkyl, OR SR 2

S(O)R

2

SO

2 R2, SO 3 H, S(NR R )R 2 S(O)(NR2R

)R

2 NR2R aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, where R 2 R and R have the definitions given above; W is 0, NH, NR 7

CH

2 CHOH, C=0O, OC=O, O=CO, NRC-=0, NHC=O, O=CNR O=CNH, SC=O, O=CS, or CHOCOR where R has the definition given above; X is CH 2 O0, S or NR where R has the definition given above;

R

16 is hydrogen, OH, OR 17 SR 17 NR 2R, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, heteroaryl or CI CI 0 alkyl, where R 17 is a CI C 1 0 alkyl or perfluoroalkyl, or is an optionally substituted allyl, arylmethyl, aryl or heteroaryl, and where

R

2 and R have the definitions given above;

R

18 and R 19 each independently are hydrogen, a CI C 6 alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or R 18 and

R

19 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, OR 2 or NR R where R 2

R

7 and R 8 have the definitions given above;

R

20 is a C 1

C

6 alkyl or an optionally substituted allyl, arylmethyl, alkenyl, aryl or heteroaryl;

R

21 is hydrogen, a Ci C 4 alkyl or optionally substituted allyl, arylmethyl, aryl or heteroaryl;

R

22 is hydrogen, a C1 C4 alkyl, F, Cl, Br, I, OR 2 NR 7 or SR 2 where R 2 and R have the definitions given above;

R

23 is hydrogen, CI, Br, OR 8 NR2R 7 a Ci C 4 alkyl or perhaloalkyl, or is an optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl or heteroaryl, where R 2

R

7 and R have the definitions given above; R is hydrogen, F, Br, Cl, a C 1

C

4 alkyl or perhaloalkyl, aryl, heteroaryl, CF 3

CF

2 0R 2 5

CH

2 0R 25 or OR 25 where R 25 is a C 1

C

4 alkyl; R is hydrogen, a C 1 C4 alkyl, F, CI, Br, I, OR 2 N2R or SR 2 where R 2 and R have the definitions given above;

R

27 and R each independently are hydrogen, a CI C 4 alkyl or perfluoroalkyl, heteroaryl, optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or an aryl optionally substituted with hydrogen, F, Cl, Br, OR 2 or NR R or R 27 and R 28 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR 2 2 7 2 7 or NR R where R and R have the definitions given above; R29 is hydrogen, a C 1

C

6 alkyl or an optionally substituted allyl, arylmethyl, aryl or heteroaryl;

R

30 and R 3 1 each independently are hydrogen, a CI C 6 alkyl or an optionally substituted allyl, arylmethyl, aryl or heteroaryl, or R 30 and R 3 1 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, OR 2 or NR2R 7 2 7 where R and R have the definitions given above;

R

32 and R 3 3 each independently are hydrogen, a C 1

C

4 alkyl or an aryl optionally substituted with hydrogen, F, Cl, Br, OR 2 or NR2R 7 or R 32 and R 33 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR 2 2 7 2 7 or NR R where R and R have the definitions given above; n is 0 or 1; Y is O or S; Z is 0, S, NH, NR or NCOR 2 where R 2 has the same definition given above; the wavy line in the compounds of formulas VII, XII, XIII and XVI represent an olefin bond in either the cis or trans configuration; the dotted lines in the structures depict optional double bonds; and a pharmaceutically acceptable carrier.

Preferably, the compounds of formulae I, II, m, IV, X and XI comprise PR antagonists, the compounds of formulae V and VI comprise PR modulators both PR agonists and antagonists), the compounds of formulae VII, VIII, XII, XIII, XIV, XV and XVI comprise PR agonists, and the compounds of formulae IX, XVII and XVIII comprise AR modulators both AR agonists and antagonists). More preferably, the compounds of formulae IX and XVII comprise AR antagonists.

In a further preferred aspect, the present invention comprises a method of modulating processes mediated by steroid receptors comprising administering to a patient an effective amount of a compound of the formulae I through XVIII shown above, wherein 1 R through R W, X, Y and Z all have the same definitions as those given above for the.

preferred pharmaceutical composition of the present invention.

Any of the compounds of the present invention can be synthesized as pharmaceutically acceptable salts for incorporation into various pharmaceutical compositions. As used herein, pharmaceutically acceptable salts include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, hydrofluoric, sulfuric, citric, maleic, acetic, lactic, nicotinic, succinic, oxalic, phosphoric, malonic, salicylic, phenylacetic, stearic, pyridine, ammonium, piperazine, diethylamine, nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic, methylamino, methanesulfonic, picric, tartaric, triethylamino, dimethylamino, and tris(hydoxymethyl)aminomethane.

Additional pharmaceutically acceptable salts are known to those skilled in the art.

The PR agonist, partial agonist and antagonist compounds of the present invention are particularly useful for female hormone replacement therapy and as modulators of fertility as contraceptives, contragestational agents or abortifacients), either alone or in conjunction with ER modulators. The PR active compounds are also useful in the treatment of dysfunctional uterine bleeding, dysmenorrhea, endometriosis, leiomyomas (uterine fibroids), hot flashes, mood disorders, meningiomas as well as in various hormonedependent cancers, including, without limitation, cancers of the ovaries, breast, endometrium and prostate.

AR agonist, partial agonist and antagonist compounds of the present invention will prove useful in the treatment of acne, male-pattern baldness, male hormone replacement therapy, wasting diseases, hirsutism, stimulation of hematopoiesis, hypogonadism, prostatic hyperplasia, various hormone-dependent cancers, including, without limitation, prostate and breast cancer and as anabolic agents.

ER agonists, partial agonists and antagonists compounds of the present invention are useful in female hormone replacement therapy and as fertility modulators, typically in combination with a PR modulator a progestin, such as Premarin®). ER modulator compounds are also useful to treat atrophic vaginitis, kraurosis vulvae, osteoporosis, hirsutism, hot flashes, vasomotor symptoms, mood disorders, neuroendocrine effects, acne, dysmenorrhea and hormonally dependent cancers, including, without limitation, breast and prostate cancer.

GR and MR agonists, partial agonists and antagonists of the present invention can be used to influence the basic, life sustaining systems of the body, including carbohydrate, protein and lipid metabolism, electrolyte and water balance, and the functions of the cardiovascular, kidney, central nervous, immune, skeletal muscle and other organ and tissue systems. In this regard, GR and MR modulators have proved useful in the treatment of inflammation, tissue rejection, auto-immunity, hypertension, various malignancies, such as leukemias, lymphomas and breast and prostate cancers, Cushing's syndrome, glaucoma, obesity, rheumatoid arthritis, acute adrenal insufficiency, congenital adrenal hyperplasia, osteoarthritis, rheumatic fever, systemic lupus erythematosus, polymyositis, polyarteritis nodosa, granulomatous polyarteritis, allergic diseases such as urticaria, drug reactions and hay fever, asthma, a variety of skin diseases, inflammatory bowel disease, hepatitis and cirrhosis. Accordingly, GR and MR active compounds have been used as immuno stimulants and repressors, wound healing tissue repair agents, catabolic/antianabolic activators and as anti-viral agents, particularly in the treatment of exacerbated herpes simplex virus.

It will be understood by those skilled in the art that while the compounds of the present invention will typically be employed as a selective agonists, partial agonists or antagonists, that there may be instances where a compound with a mixed steroid receptor profile is preferred. For example, use of a PR agonist progestin) in female contraception often leads to the undesired effects of increased water.retention and acne flare ups. In this instance, a compound that is primarily a PR agonist, but also displays some AR and MR modulating activity, may prove useful. Specifically, the mixed MR effects would be useful to control water balance in the body, while the AR effects would help to control any acne flare ups that occur.

Furthermore, it will be understood by those skilled in the art that the compounds of the present invention, including pharmaceutical compositions and formulations containing these compounds, can be used in a wide variety of combination therapies to treat the conditions and diseases described above. Thus, the compounds of the present invention can be used in combination with other hormones and other therapies, including, without limitation, chemotherapeutic agents such as cytostatic and cytotoxic agents, immunological modifiers such as interferons, interleukins, growth hormones and other cytokines, hormone therapies, surgery and radiation therapy.

Representative PR antagonist compounds according to the present invention include: 1,2,3,4-Tetrahydro-2,2,4-trimethyl-6-phenylquinoline (Compound 100); 1,2-Dihydro-2,2,4trimethyl-6-(1,2,3-thiadiazol-5-yl)quinoline (Compound 101); 1,2-Dihydro-2,2,4-trimethyl- 6-(1, 3 -oxazol-5-yl)quinoline (Compound 102); 6 4 ,5-Dichloroimidazol-1-yl)-1,2-dihydro- 2 2 4 -trimethylquinoline (Compound 103); 6-(4-Bromo- 1-methylpyrazol-3-yl)- 1,2-dihydro- 2 ,2,4-timethylquino line (Compound 104); 1 ,2-Dihydro-2,2,4-inethy16-(3pyridyl)quinoline (Compound 105); 6 4 -Fluorophenyl)- 1 ,2,-dihydro-2,2,4trimethyiquino line (Compound 106); l, 2 -Dihydro-6-(3-trifluoromethylpheny1)..2,2,4 trimethyiquino line (Compound 107); l, 2 -Dihydro-2,2,4-trimethy..6(4.

nitrophenyl)quinoline (Compound 108); 6 2 ,3-Dichlorophenyl)- 1,2-dihydro-2,2,4trirnethyiquino line (Compound 109); l, 2 -DiIydro- 6 -(2-hydroxycarbonyl.4-nitrophenyl).

2 ,2,4-timethylquino line (Compound 110); 6 3 4 -Dichlorophenyl).1 ,2-dihydro-2,2,4trirnethylquinoline (Compound 111); 4-Ethyl- l, 2 rdihydro-2,2-dimethy-6-phenylquinoline (Compound 112); 1, 2 -D ihydro- 2 2 -dimethy1-6pheny14-propylquino lie (Compound 113); 6 2 -Chloropheny)-1,2dhydro2,2,4-timethylquinoijne (Compound 114); 1,2-Dihydro- 2 2 4 -trimethylindeno [1,2-glquino line (Compound 115); 1,2-Dihiydro-2,2,4trirnethylindeno[2, 1 -Aquinoline (Compound 116); 8-Bromo-1I,2-dihydro-2,2,4trimethylindeno I 2 -glquino line (Compound 117); 1 ,2-Dihydro-2,2,4trimethylbenzo~blfarano[3,2,glquinoline (Compound 118); 1 ,2-Dihydro-2,2,4trirethylbenzo~b~furano[2,3..Aquinoline (Compound 119); 6-Fluoro- 1,2-dihydro-2,2,4trimethylindeno(2,1I-J]quinoline (Compound 120); 9-Fluoro- 1,2-dihydro-2,2,4trimethylindeno 1 2 -glquino line (Compound 121); 1 2 -Dihydro-9-hydroxylrethy1.224 trimethylindeno[ 1,2-glquinoline (Compound 122); 8-Chioro- 1,2-dihydro-2,2,4trimethylindeno 1 ,2-g]quinoline (Compound 123); 8-Fluoro- 1,2-dihydro-2,2,4triiethylindeno[ 1, 2 -gjlquinoline (Compound 124); 8-Acetyl- 1,2-dihydro-2,2,4trnethylindeno[ 1,2-g]quinoline (Compound 125); 6-Fluoro- 1,2-dihydro-2,2,4trimethylindeno[ 1, 2 -glquinoline (Compound 126); 7-Bromo-1 ,2-dihydro-2,2,4trimethylindeno[2, l-flquinoline (Compound 127); l, 2 -Dihydro-2,2,4-timethy1-7 nitroindeno[(2, 1 -Aquino line (Compound 128); 1 2 -Dihydro-2,2,4-trimfethyl-8.

nitroindeno[ I ,2-glquinoline (Compound 129); 6,9-Difluoro- 1 ,2-dihydro-2,2,4triinethylindeno[ 1, 2 -g]quinoline (Compound 130); 7-Fluoro-1I, 2 -dihydro-2,2,4-trimethyl.

I1-(thiomethyl)indeno[2,1-fAquinoline (Compound 131); 5,8-Difluoro- 1,2-dihydro- hydroxy-2,2,4-trirethylijideno[ 1,2-gjquinoline (Compound 132); 7,9-Difluoro- 1,2-dihydro- IlO-hydroxy-2,2,4-trimethyljiideno I 2 -glquinoiline (Compound 133); 7, 10-Difluoro- 1,2dihydro-2,2,4timethyl-5-oxoindeno[32-qunoJjne (Compound 134); 7,9-Difluoro- 1,2dihydro-2,2,4-trimethyl-.1 0-oxoindenoflI, 2 -g]quinolinie (Compound 135); 8-Fluoro- 1,2dihydro- I O-hydroxy-2,2,4-trinethylindeno[ I 2 -glquinolme (Compound 136); 8-Fluoro- 1,2dihydro-2,2,4-trimethyl- 10-oxoindeno [1 2 -glquinoline (Compound 137), 7-Fluoro- 1,2d ihydro-2,2,4-trimethyl-8- nitro indeno[f 1 2 -glquinoline (Compound 138); 5-Chloro- 1,2dihydro- Il0-hydroxy- 2,2,4-trimethylindeno f 1 2 -gjquino line (Compound 139); 6-Fluoro- 1,2dihydro-2,2,4-trimTethyl- 1 0-oxoindeno[ 1 2 -g]quinoline (Compound 140); 6-Fluoro- 1,2dihydro- 1 -hydroxy-2,2,4-trimethylindeno[1I,2-g]quinoline (Compound 141); 5,8-Difluoro- 1 ,2-dihydro-2,2,4-trimethyl- 10- (trifluoroacetoxy) indeno[ I ,2-g]quino line (Compound 142); 6-(3,5-Difluorophenyl)- l, 2 3 4 -tetrahydro-2,2,4-trimethylquinoline (Compound 143); 1,2- Dihydro-2,2,4-trimethylindolo[3,2.gquinohne (Compound 144); 5-Ethyl-i ,2-dihydro- 2 2 4 -timethylindolo[2,3-flquinoline (Compound 145); 6-(3-Chlorophenyl)-1I,2-dihydro- 2 ,2,4-trixnethylquinoline (Compound 146); 6-(3,5-Difluorophenyl)-1I,2-dihydro-2,2,4trirnethyiquinoline (Compound 147); 6-(3-Fluorophenyl)- 1,2-dihydro-2,2,4trimethylquinoline (Compouand 148); 1,-iyr-,,-iehl--4pyi lqioln (Compound 149); 6-(3-Cyanophenyl)- l, 2 -dihydro-2,2,4-tirethylquinoline (Compound 150); 6-(3,5-Dichlorophenyl)- l, 2 -dihydro-2,2,4-trirnethylquino line (Compound 151); 6- (2,3-Difluorophenyl)- l, 2 -dihydro-2,2,4-timethylquinoline (Compound 152); 1 ,2-Dihydro- 2 2 4 -trimethy1-6-(pentafluoropheny)quino line (Compound 153); 1 ,2-Dihydro-2,2,4trimethyl- 6 4 -(trifluoroacetyl)phenyllquino line (Compound 154); 1 ,2-Dihydro-2,2,4trixnethyl-6- (1 3 -pyriniid-5-yl)quino line (Compound 155); 6-(3-Cyanophenyl)- 1,2,3,4tetrahydro-2,2,4-tirnethylquino line (Compound 156); 5,8-Difluoro-1I,2-dihydro-2,2,4tirethylindeno[ 1,2-g]quinoline (Compound 157); 7, 10-Difluoro- 1,2-dihydro-2,2,4trinethylindeno[2,1I-fjquinoline (Compound 158); 8-Cyano- 1,2-dihydro-2,2,4trimethylindeno[3,2-e]quinoline (Compound 270); 6 -(3-Cyano-5-fluorophenyl)- 1,2dihydro-2,2,4-.trimethylquinoline (Compound 271); 6 -(3-Cyano-4-fluorophenyl)- 1,2dihydro-2,2,4-trimethylquino line (Compound 272); 6 3 -Cyano-6-fluorophenyl)- 1,2dihydro-2,2,4.-trimethylquinoline (Compound 273); 6 -Ii-fluoro-3-(trifluoromethyl)phenyl].

I 2 -dihydro-2,2,4-trimnethylquinoline (Compound 274); 6 3 -chloro-2-methylphenyl)- 1,2dihydro-2,2,4-tirethylquinoline (Compound 275); 1 ,2-Dihydro-2,2,4-trimethyl-6-(3.

nitrophenyl)quinoline (Compound 276); 6-(3-Acetylphenyl)- 1,2-dihydro-2,2,4trimethyiquino line (Compound 277); 6 3 -cyano-2-methylphenyl). 1,2-dihydro-2,2,4trimethyiquinoline (Compound 278); l, 2 -Dihydro-2,2,4-trimethy1.6-(3methylp henyl)qu ino line (Compound 279); 6 -(5-Fluoro-3-nitrophenyl)-.1 ,2-dihydro-2,2,4trimethyiquinoline (Compound 280); l, 2 -Dihydro-6-(3-Methoxyphenyly224trimethylquino line (Compound 28 6 -(5-Cyano-3-pyriiyl). I,2-dihydro-2,2,4trimethyiquino line (Compound 282); l, 2 -Dihydro-2,2,4-trimethy1&(2-methy13nitrophenyl)qu ino line (Compound 283); 6 2 -Amino-3,5-difluorophenyl) 1 ,2-dihydro- 2 ,2,4-trimethylquino line (Compound 284); 6 3 -Bromo-2-chloro-5-fluorophenyl). 1,2dihydro -2,2,4-trixnethylquino line (Compound 285); 6 -(3-Cyano-5-fluorophenyl)- 1,2dihydro- 2 ,2,4-utrethyl-3-qumo lone (Compound 286); 6 -(3-Fluoro-2-methylphenyl) 1,2dihydro-2,2,4-tirethylquino line (Compound 287); 1 7 2 -Dihydro-2,2,4-trimethyl6(3.

methylthiophenyl)quinolie (Compound 288); 6-(5-Chloro-2-thienyl)- 1,2-diliydro-2,2,4trimethyiquinoline (Compound 289); l, 2 -Dihydro-2,2,4.trinethyl..&(3-methyl.2.

thienyl)quinoline (Compound 290); 8-Fluoro-1I,2-dihydro-2,2,4-trimethyl&6(3nitrophenyl)quinoline (Compound 291); 1 2 -Dihydro-6-(3..nitrophenyl).2,2,48tetramethyiquinoline (Compound 292); 6 -(5-Bromo-3-pyridyl)- 1,2-dihydro-2,2,4trimethylquinoline (Compound 293); 6 -(3-Bromo-2-pyridyl)- 1,2-dihydro-2,2,4trimethyiquino line (Compound 294); 6 3 -Bromo-2-thienyl)-1 ,2-dilfydro-2,2,4trimethyiquino line (Compound 295); I, 2 -Dihydro-6-(2,3,5,tefluoro4pyridy)224 triinethylquinoline (Compound 296); 5,8-Difluoro- l,2-dihydro-6-(3-nitrophenyl-22,4 tximethylquino line (Compound 297); 2,4-Diethyl-8-fluoro-1I,2-dihydro-2-methyl-6-(3.

nitrophenyl)quinoline (Compound 298); 6-(3-Bromophenyl)- 1,2-dihydro-2,2,4trimethyiquinoline (Compound 299); I, 2 -Dihydro-2,2,4-nethy16-(5-itro-2 thienyl)quinoline (Compound 300); 1, 2 -Dilhydro-6-(2,4,5.tffluoropheny).2,2,4 trimethyiquinoline (Compound 301); 6 3 -Bromo-5-fluoropienyl).1 ,2-diliydro-2,2,4trirnethyiquinoline (Compound 302); 6 -(5-Carboxaldehyde-3-tienyl) 1 ,2-diliydro-2,2,4t-methylquinoline (Compound 303); I, 2 -Dihydro-2,2,4,7-tetramethyl.6(3.

nitrophenyl)quinolie (Compound 304); 6 -(5-Fluoro-2-methoxy-3-nitrophenyl) 1,2d ihydro-2,2,4-trimethylquino line (Compound 305); 6 3 -Chloro-2-methoxyphenyl)- 1,2dihydro-2,2,4-trimethylquinoljne (Compound 306); 1 ,2-Dihydro-2,2,4-trimnethyl-6-(2,3,4-.

trifluorophenyl)quinoline (Compound 307); 6 3 -Bromo-2-methylphenyl)- 1 ,2-dihydro- 2 2 ,4-trimethylquinoline (Compound 308); 7-Chloro-1I,2-dihydro-2,2,4-trirnthyl-6-(3nitrophenyl)quinoline (Compound 309); 5-Chloro-1I, 2 -dihydro-2,2,4-trimethyl6(3nitrophenyl)quinoline (Compound 3 10); 8-Chloro- 1 ,2-dihydro-2,2,4-timthyl.6.(3 nitrophenyl)qu ino line (Compound 31 8-Ethyl- I, 2 -dihydro-2,2,4-timrethyI.6-(3nitrophenyl)quino line (Compound 312); 9-Chloro- 1 2 -dihydro- 2,2-dimethyI..$.

co umarino[(3,4-J]quino line (Compound 313); l, 2 -Dihydro-9-methoxy-2,2,4t.inethy-5coumiarino[3,4-fjquino line (Compound 314); 9-Fluoro- 1 ,2-dihydro-2,2,4, 11- co umarino [3,4-f]lquino line (Compound 315); l, 2 -Dihydro-2,2,4,9-tetrarnethy..5.

co umarino[3,4-flquinoline (Compound 316); 7-Chloro- l, 2 -dihydro-2,2,4-trimnethyl.5coumarino[3,4-flquino line (Compound 317); (R/S)-9-Chloro- 1,2-dihydro-5-methoxy22,4.

[3,4..]quino ie (Compound 319); (R/S)-9-Fluoro- 1,2-dihydro- 2 2 4 -trirnethyl-5H-chromeno [3,4-AIquino line (Compound 328); 6-(5-Cyano-2-thienyl)-.1,2dihydro-2,2,4trnethylquinojjne (Compound 45 6 -(5-Cyano-3-thienyl)- I ,2-dihydro- 2 2 4 -trirnethylquinoaie (Compound 452); 6 -(3-Formylphenyl)-1I,2-dihydro-2,2,4trirethylquino line (Compound 453); 1 2 -Dihydro-2,2,4-trimethyI..6.j3.

(methylsulfonyl)phenyllquinoline (Compound 454); (R/S)-6-(3-Cyano-5-fluoropheny1>l.

2 3 4 -Tetrahydro-2,2,4-trimethylquinofine (Compound 455); and (R/S)-9-Chloro-1,2d hdo224trmty--hnl5-homn 34jqioln (Compound 456).

Representative PR modulator compounds agonists and antagonists) according to the present invention include: (R/S)-5-Butyl- 1 2 -dihydro-2,2,4.timethyl..SHchromeno[3,4-JAqujnoline (Compound 160); (RIS)- l, 2 -Dihydro-2,2,4-.trinethyl-5pheny..

SH-chromeno[3,4.J]quinoline (Compound 161); (RIS)- 1 2 ,34-Tetrahydro-2,2-dim-ethyl-4 (Compound 162); Chiorophenyl)- l, 2 -dihydro- 2 iethyl-SHchromeno[34j"quinoline (Compound 163); (R/S)-5-(4-Chlorophenyl). 1,,,-erhdo22dmty--ehldn-H chromeno[3 4 -flquinoline (Compound 164); (R/S)-5-(4-Fluorophenyl) 1 ,2-dihydro-2,2,4trimethyl-SH-chromeno [3,41]Aquino line (Compound 165); (R/S)-5-(4-Acetylphenyl).1,2dihydro-2,2,4rmethyl.SH-chromen 0 E3,4-fjquinoline (Compound 166); (RIS)-1I,2-Dihydro- (Compound 167); (RIS)- 1,-iyr--4rehxpey)224t~ty-Hcrreo34Aun~n (Compound 168); (RIS)- l, 2 -Dil1ydro 2 2,4riethyl5[4-(ffluoromethyl)phenyl]5Hchro meno [3,4-fquino line (Compound 169); (RIS)- I, 2 -Dihydro-2,2,4tinethyl-5-(thiophen.

3 -yl)-SH-chromeno [3,4-flquino line (Compound 170); 1,2-Dihydro-2,2,4-rimethyl-5-.(4methylphenyl)-SH-chromeno [3,4-fjquino line (Compound 171); (-)-5-(4-ChlorophenyI)- 1,2dihydro-2,2,4-trimethyl-5H-chromeno 3 ,4-JAquinoline (Compound 172); (RIS)- I ,2-Dihydro- 2 2 4 -timethyI-5-(3-methylphenyl)-sH-chromeno[3,4.jjquinoline (Compound 173); (41,51)-5-(4-Chlorophenyl)- l, 2 3 4 -tetrahydro-2,2,4- bethyl-5H-c hro meno [3 4 -fAquino line (Compound 174); 4 l,5!)-5-(4-Chloropheny1)- 1 2 3 4 -tetrahydro-2,2,4-trirethyl5Hchromeno[3,4-Aquinoline (Compound 175); (RIS-41,5u)-S-(4-Chlorophenyl)-.1,2,3,4tetrahydro-2,2,4-timthyl-SH-chromeno [3, 4 -fAquinoiine (Compound 176); (RIS)-5-(3- Chiorophenyl)- li 2 -dihydro- 2 2 4 -trmethyl-.5H-chromeno(3,4-.Jquinoline (Compound 177); (R/S)-5-(3-Chlorophenyl)- l, 2 3 4 -tetrahydro-2,2-diethy4methylidene-5Hchromeno[(3,4-j]quino line (Compound 178); (R/S)-5-(4-Bromophenyl)- 1,2-dihydro-2,2,4trnethyl-SH-cbromeno[3,4-f]quinoline (Compound 179); (R/S)-5-(4-Bromophenyl)- 1,,,-erhdo22drehl4mthldn-Hcrreo34Aunln (Compound 180); (R/S)-5-(3-Bromophenyl)- 1, (Compound 181); (RIS)-5-(3-Bromophenyl)-1I 2 3 ,4-tetrahydro-2,2-dimethyl-4methylidene-SH-chomeno[3,4-fAquinoie (Compound 182); (R/S)-5-(3,4-Dichlorophenyl).

1, 2 -dihydro-2,2,4-trimethyl-SH-chromeno[3,4JAquinoline (Compound 183); Bromo-2-pyridyl)- 1, 2 -dihydro-2,24-timethyl-SH-chromeno[3 4 -flquinoline (Compound 184); (RIS)- l, 2 -Dihydro-5-hydroxy-2,2,4-riethy1.SH..chromeno 3 4 -flquinoline (Compound 185); mty--ehxy5-hoeo34 fAquinoline (Compound 186); (RIS)- l, 2 -Dihydro-2,2,4-trimthy-5-propoxy.SH chromeno[3,4-]]quinoline (Compound 187); (RIS)-5-Allyl- 1,2-dihydro-2,2,4-trimethyl-5Hchromeno[3,4-JAquinoline (Compound 188); (RIS)- 1 2 -Dihydro-2,2,4--trirnethyl-5-propyl1 SH-chromeno[3,4-fAquinoline (Compound 189); (RIS)-1I,2-Dihydro-2,2,4.timethy-5-(2pyridyl)-SH-chromeno[3,4-flquinoline (Compound 190); (R/S)-5-(3-Fluorophenyl)- 1,2dilhydro-2,2,4-nethy-SH-chroffeno[3,4flquinoline (Compound 191); Fluorophenyl)-1,,,-erhdo22dmty -ehyiee5-hofeo34Aunln (Compound 192); (RIS)- 1,2Dhdo224 iehl5prplho5-hofeo34 JAquinoline (Compound 193); (RIS)- l, 2 -Dihydro-5-(3-methoxypheny)2,2,4-rimr.ethyl-5H chromeno[3,4-fAquinoline (Compound 194); (RIS) I 2 -Dihydro-2,2,4-trimethyl-5-[3- (trifluoromethy1)phenyI]-sH-chromeno[3,4.Jcquinolie (Compound 195); Fluoro-4-methylphenyl)- 1,-iyr-,,-rmty-5-hoeo34Aunln (Compound 196); (R/S)-5-(4-Bromo-3-pyridyl)- 1 2 -dihydro-2,2,4-trirnethyl-5Hchro meno[3 ,4-fjquinoline (Compound 197); (RIS)- 1, 2 -Dihydro-2,2,4i-tiethyls.-(3.

pyridyl)-S5i-chromenot3,4-.fquinoline (Compound 198); (R/S)-5-(4-Chloro-3fluorophenyl)- 1 2 -diI ydro- 2 ,2,4-trimethyl-SH-chromeno[3, 4 -fjquino lne (Compound 199); (RIS)- l, 2 -Dilhydro 2 2 4 ,-tetramethy5Hcronno[3, 4 -f]quinoline (Compound 200); (RIS)- l, 2 -Dihydro-5-hexyl-2,2,4-t-iJmethyl-5H..chromno[3, 4 -IAquiino line (Compound 201); 1 ,2-Dihydro-2,2,4- -inethyl-5H-c hromeno (3 4 -flquino line (Compound 202); (RIS)- 1,2- Diyr--3mtybtl-,,--hehl5-hoeo34Aunln (Compound 203); (R/S)-5-(4-Chlorobutyl)- 1,-iyr-,,-rmty-5-hoeo34Aunln (Compound 204); (R/S)-5-Benzyl-

I,

2 -dihydro-2,2,4-triethy-5H-chromeno 3 4 -flquinoiine (Compound 205); (R/S)-5-(4-Bromfobutyl)- iydo22,-r [y-Hchoeo3,4fjquinoline (Compound 206); (R/S)-5-Butyl-9-fluoro-.1 2 -dihydro-2,2,4-trimethyl-SH.

chromeno[3,4-flquinoiine (Compound 210); (R/S)-5-Butyl-8-fluoro- 1,2-dihydro-2,2,4.

trimethyl-SH-chromeno [3,4-fAquinolie (Compound 211); (RIS)-5-(3-Chlorophenyl).9 fluoro-1,-iyro224timty-Hchoeo3 4 -Jjquinoline (Compound 212); 4 -Chloro-3-methylphenyl)-9-fluoro- l, 2 -dihydro-2,2,4-rimethy1-5Hchromeno[34 flquinoline (Compound 213); (RIS)-5-(4-Chloropheny)-9.fluoro-.1 ,2-dihydro-2,2,4trimethyl-SH-chromeno[3,4.flquinoline (Compound 214); (R/S)-9-Fluoro- 1,2-diliydro-5-(4methoxypheny1)-2,2,4tijnthy1SHchomeno [3,4-fAquinoline (Compound 215); Fluoro- 2 -dihydro-5-methoxy-2,2,4-triethyl-SH-chromeno[3,4fquino line (Compound 216); (R/S)-5-(4-Chlorophenyly8-fluoro-. l 2 -dihydro-2,2,4- nmethyl-SH-chromeno[3,4flquinoline (Compound 217); and (RIS)-9-Chloro-5-(4-chloropheny).1 ,2-dihydro-2,2,4trimethy1-5H-chromeno[3,4-fAquinoline (Compound 218); 9-Chloro-1I,2-dihydro-2,2,4trimethyl-5H-chromeno[3,4.fjquinoline (Compound 320); (RIS)-9-Fluoro- 1,2-dihydra-5mehx-,,-rmhl5-hoeo34Aunln (Compound 322); (R/S)-9-Fluoro- 1,-iyr-,,-iehl5tiprpx-Hcr-mo34Aunln (Compound 323); (R/S)-9-Fluoro-1,-iyr-,,-rmty--rpx-Hcrfin[, qinl (Compound 324); (RIS)- I, 2 -Dihydro- 9 -mthoxy2,2,4-trithyl-5H-chromeno[3,Afiquinoline (Compound 329); l, 2 -DiIhydro-2,2,4,9..tetrarnthy-5H..chromeno[3,4 Aquinoline (Compound 330); (R/S)-7-Chloro- 1 2-dihydro-2,2,4-trimethylI5H.

chromeno[3,4-fAquinoljne (Compound 331); (R/S)-5-(4-Bromo-3-pyridyl)-.1,2,3,4tetrahydro-2,2-dimethy[-4methylidene5Hchomeno [3,4-Aquinoline (Compound 347); (R/S)-5-(3,5-Difluorophenyl). 1,-iyr-,,-rmty-S-hoeo34Aunln (Compound 348); (R/S)-5-(3-Bromo-5.fluorophenyl). l, 2 3 4 -tetrahyro-2,2direthy.4methylidene-5H-chromeno[34-Aquinoline (Compound 352); ,2,-Dillydro-5-(2,4,6timtybnyfee-,,4-timlbenzY-idene)224ethy1S3,4ofno[ 3 4 o line (Compound 364); 5-Benzylidene-9-fluoro. I,2-dihydro-2,2,4,1 I -tetramethy1-5H..cho meno[3,4-fquino line (Compound 377); (R/S)-5-(4-Chlorophenyl) Ji 2 3 4 -tetahydro22dirnethyl15Hchromeno[3,4-fI-4-quinolinone (Compound 378); (R/S)-5-(4-Chlorophenyl)-.1,2,3,4terhdo2233ttaehl5Hcrmn[,---unlnn (Compound 379); (RIS)- 5-(4-Chlorophenyl)- 1,-iyr-,-imty-Hcrmn 4 -fAquino line (Compound 380); 4 ,S5..5(4-.ChlorophenyI). l 2 3 4 -tetrahydro-2,2,4-wiriJethylI5Hchromeno[3,4-j]-3-qunoione (Compound 381); 4 ,SI)-5-(4-Chloropheny)-.1,2,3,4terhdo224tiehl5-crmn[,---unlnn (Compound 382); Chiorophenyl)-1,,,-erhdo22dmty (Compound 383); (RS--3Flooezl I -looenyjee-, 2 ,3,4-tetrahydro.3 (Compound 384); 1,,,-erhdo3hdoy224uinty-Hcrmn[,-~unln (Compound 385); (R/S)-5-Butyl-1,,,-er do224tiehl-Hcrmn[,---unlnn (Compound 386); (RIS-41,SO)-1, 2 3 4 -Tetrahydro..2,2,4..trim.ethy15.phenyI-5Hchromeno[3,4-A-.3..quinolinone (Compound 387); (R/S-41,Su)-1I, 2 ,3,4-Tetrahydro-2,2,4ftmethyI-5-pheny-sHchrono[3,A3-quinolione (Compound 388); (R/S-41,6u)- 1,,,-erhdo224tiehl6penl5-scrmn[,---unlnn (Compound 390); (R/S-41,60)-

I

2 3 4 -Tetrahydro-2,2,4tirethy6phenylSHisochromeno 3 4 -A-3-quinolinone (Compound 391); (R/S- 3 1 ,4u,Su)-5(4-Chlorophenyl).

1,,,-erhdo3=hx-,,-riehl5-hoeo34Aunln (Compound 397); (R/S- 3 1 4 u,50-5-(4.Ciiorophenyl)-. l 2 3 4 -tetrahydro-3-etoxy2,2,4iethy1-5Hchromeno[3,4-flquino line (Compound 398); (R/S- 3 1, 4 u,S-5-(4-Cfioropheny)-.1,2,3,4tetrahydro- 3 .propy xy22,4tiethy5Hcoffeo[ 3 4 A (Compound 399);

(RIS-

3 l, 4 u,Su)-5-(4..Chlorophenyl). 1,,,-erhdo3poylx-,,-imty-H chromeno quino line (Compound 400); and (R/S- 4 l,SI)-3-Benzylidene.5(4chl orophenyl)- l, 2 3 4 -tetrahydro-2,2,4- iethyl-.5H-chomeno[34flquinoin (Compound 401).

Representative PR agonists according to the present invention include: 1,-iyr-,,-rmty-Hcrmn 34fqioln (Compound 219);

I,

2 -dihydro-2,2,4-trimethy1-5H-chromeno [3,4-f]quino Line (Compound 220); (Z)-5-(4-Fluorobenzylidene)- l, 2 -dihydro- 2 ,2,4-iethyl5H-chromeno[3,4-Aquinolie (Compound 221); (Z)-5-(4-Bromo benzylidene)- 1 2-dihydro-2,2,4-trimethyI-5Hchro meno [3,4-flquino line (Compound 222); (Z)-5-(3-Bromobl -nzylidene). I,2-dihydro- 2 2 4 -trimethyl-SH-chromeno(3,4-Ilquinoline (Compound 223); Chlorobenzylidene)- 1 2 -dihydro- 2 2 ,4-rimethyl-SH-chromeno[3,4.jjquinoline (Compound 224); (Z)-5-(3-Fluorobenzylidene)- 1 2 -dihydro-2,2,4-ftrmthyl-5H-chromeno[3,4 ]]quinoline (Compound 225); (Z)-5-(2-Chlorobenzylidene)- 1,2-dihydro-2,2,4-tiethy-SHchromeno[3,4-fAquinoline (Compound 226); (Z)-5-(2-Bromobenzylidene)-1I,2-dihyclro- 2 2 4 -trixethyl-SH-chromieno[3,4-fAquinoline (Compound 227); Fluorobenzylidene)- l, 2 -dihydro- 2 2 4 -timethyl-SH-chromeno[3,4-fAquinoline (Compound 228); (Z)-5-(2,3-Difluorobenzylidene)- 1, 2 -dihydro-2,2,4-trimethyl-SH-chromeno[34 A~quino line (Compound 229); (Z)-5-(2,5-Difluorobenzylidene).1 ,2-dihydro-2,2,4-rfinethyl- SH-chromeno [3,4-flquino line (Compound 230); (Z)-9-Fluoro-5-(3-fluorobenzylidene) 1,2dihydro-2,2,4-trimethyl-5H-chromeno[3,4-]quinoine (Compound 231); (Z)-9-Fluoro-5-(3methoxybenzylidene)- l, 2 -dihydro-2,2,4-triethy-5H-chromeno[34Jc~quinoline (Compound 232); 8 -Fluoro-5-(3-fluororbenzylideney. I,2-dihydro-2,2,4rfimethy-5Hchromenol3,4-fAquinoline (Compound 233); (R/S-41, 5u)-5-(4-Chlorophenyl)- 1,2,3,4tetrahycfro-2,2,4-iethyl-sHchomeno[343quioinone (Compound 234); (R/S-41, 51)-5-(4-Chlorophenyl)- 1,23 ttayr-224tmty-H-hoeo34A3 quinolinone (Compound 235); and (R/S)-5-(4-Chlorophenyl)-1 ,2,3,4-tetrahydro-2,2,4,4tetramethyl-5H-chronmeno[3,4-f]-3-quinolinone (Compound 236); 5-(3-Fluorobenzyl)- 1,2dihydro-2,2,4-amethy1-5H-chromeno[34-Aquioline (Compound 318); (R/S)-9-Chloro- 1 ,2-dihydro-2,2,4- tiethyl-5-propyloxy-5H..cbronieno[3 4 -IAquinoline (Compound 321); (R/S)-5-Butyl-9-chloro- l, 2 -dihydro- 2 ,2,4-nmethy1-5H-chroieno [3,4-f~quino ie (Compound 325); (R/S)-5-Butyl-1I 2 -dihydro-9-methoxy-2,2,4-trirnethy1.5Hchromeno[3,4 f]quinoline (Compound 326); (R/S)-9-Fluoro- 1 2 -dihydro-2,2,4,5-tetramethyl-5H chro meno [3,4-f quino line (Compound 327); (R/S)-9-Chloro- 1,2-dihydro-2,2,4,5- [3 ,4-Jlquino line (Compound 332); (R/S)-5-(4-Bromophenyl)-9chloro- 1 2 -dihydro-2,2,4-trimethy-5H-chromeno[3,4-fquinoline (Compound 333); Chloro-5-(3-chlorophenyl)- 1, 2 -d ihydro- 2 ,2,4-tmethyl-5Hcho meno 34]quino ie *(Compound 334); (R/S)-9-Chloro- l, 2 -dihydro-2,2,4--inmthyl-5-(3.methylpheny).5H.

chro meno [3,4-flquino Line (Compound 335); (R/S)-9-Chloro-5-(4-chloro-3-methylphenyl)- I 2 -dihydro-2,2,4-trimethyl-5H-chromeno[3,4-fjquinoline (Compound 336); Chioro- I ,2-dihydro-5-[3-(trifluoro methyl)phenyl] 2 2 4 -triniethyl-5H-chro meno [3,4flquinoiine (Compound 337); (R/S)-9-Chloro-5-(3,5-dichlorophenyl)-1 ,2-dihydro-2,2,4- [3,4-J]quinoline (Compound 338); (R/S)-9-Chloro- 1,2-dihydro-5-(4mehxpey)224tiehl-Hcrmn 34fqioln (Compound 339); (RIS)-9- Chloro-5-(3-fluoro-4-methoxypheny)- 1 2 -dihydro-2,2,4-trimnethyl-5H-chromeno[3,4.

JAquinoline (Compound 340); (R/S)-9-Chloro-5-(4-fluoropheny1I,2-dihydro-2,2,4trixnethyl-5H-chromeno[3,4-Aquinoiine(Comipound 341); (R/S)-9-Chloro-5-(3-chloro-4methyiphenyl)- l, 2 -dihydro- 2 ,2,4-trmethyl-5H-choneno[34jjquioline (Compound 342); 9 -Chloro-5-(4-fluoro-3-methylpheny11 2-dihydro-2,2,4-trimethyl- [3,-Jlquino line (Compound 343); (RIS)-9-Ch~oro-5-(3-fluoropheny)- 1,2dihydro- 2 ,2, 4 -timethyl-5H-chromeno[3,4I'quinoljne (Compound 344); (RIS)- 1,2-Dihydro- 2,,-iehl5[34nehlneix hnl-Hcrmn[,-quinoline (Compound 345); (RIS)-5-(4-Chloro-3-methylphenyl). I 2 -dihydro-2,2,4-trimethy1-5H-chromeno[3,4.

f]quinoline (Compound 346); (R/S)-5-(3,5-Dichlorophenyl) 1 ,2-dihydro-2,2,4-rimethy-5Hchromeno [3,4-fAquino line (Compound 349); (R/S')-5-(3-Bromo-5-methylphenyl)- 1,2dihydro-2,2,4-timethyl-5H-chronieno[3 ,4-flquinoline (Compound 350); (RIS)-5-(3-Bromo- 5-fluorophenyl)-1,-iyro224timty-Hchoeo34-fllquinoline (Compound 351); (R/S)-5-[4-Fluoro-3-(trifluoromethyl)phenyl].1 ,2-dihydro-2,2,4-tiirethyl-5Hchrormno[3,4-jlquinoline (Compound 353); (R/S)-9-Fluoro-1I,2-dihydro-2,2,4-trinethyl-5.

3 -methylphenyl)-5Hchromeno[3,4..~quino lie (Compound 354); (RIS)- 1 ,2-Dihydro-9mehx-,,-rmty--3mtyphnl-Hcimn[,-~unln (Compound 355); (R/S)-9-Fluoro-5-(3-fluoro-4-methoxyphenyl)-1 ,2-dihydro-2,2,4-trimnethyl-5Iichro meno[3,4-fAquinoline (Compound 356); (R/S)-9-Fluoro- 1 2-dihydro-2,2,4-trimethyl-5- 3 -(trifluoroniethyl)phenyl] -5H-chro meno[(3,4-flquinolfine (Compound 357); (RIS)-9- Fluoro-5-(4-fluoro-3-methylphenyl)- l, 2 -dihydro-2,2,4-rrimethyl-5-chromeno[3,4- Ilquinoline (Compound 358); 2 4 -Difluorobenzylidene). I,2-dihydro-2,2,4-timethy1- SH-chromeno [3,4-flquino line (Compound 359); (Z)-5-(3,4-Difluorobenzylidene)- 1,2dihydro-2,2, 4 -trethyl-sH..chronieno[3,4fquino line (Compound 360); Fluoro benzyfidene)- 1,,,-erhdo (Compound 361); 2 6 -Difluorobenzylidene)-I, 2 -dihydro-2,2,44rimethy..SH chromeno (3,4-IAquino line (Compound 362); l, 2 ,-Dihydro-5..(2..methylbenzylidene)- 2 2 4 -tmethy..SH.chromeno[3,4-Aquino ine (Compound 363); (Z)-9-Chloro..5-(2,5difluoro benzylidene)- l, 2 -dihydro-2,2,4- tiethyl-5H-chromenof3,4-Aq un (Compound 365); (Z)-5-Benzylidene-9.cWoro-12dhdo224 imhl5-hoieo34fqion (Compound 366); (Z)-9-Chloro-

I,

2 -dilhydro2,2,4trimethyI-5(2..methylbenzylidene)-5Hchro meno[(3,4..Aquino line (Compound 367); (Z)-5-Benzyidene9chloro-1 ,2-dihydro-2,2dimethyI..5H.chromeno[34..quno~e (Compound 368); (Z)-9-Chloro-5-(2fluorobenzylidene)- l, 2 -diIhydro-2,2,4-tiethyl..SH.chomeno[34fquino~ne (Compound 369); 9 -Chloro-5..(3..fluorobenzyidene)-1,l 2 dihyro2,2,4fimthy5Hchromeno[34 *t]quinoline (Compound 370); (E/Z)-5-Benzylidene-9-.fluoro-. l2-dihydro-2,2,4.trimthy..

5H-chromeno[3,4.flquinoline (Compound 371); (Z)-5-Benzylidene-8-.fluoro-.1 ,2-dihydro- 2,,-rmty-Hcrneo34jqion (Compound 372); (Z)-5-Benzylidene. 1,2diyr--ehx-,,-rmty-Hcrmn[,-qion (Compound 373); Fluoro-1,-iyr-,,- ehl5(-ehlbnydn)5-hoeo34Aunln (Compound 374); (Z)-8-Fluoro- l, 2 -dihydro2,2,4tmethy-5(2-methylbenzylidene)5Hchromieno[3,4-jAquinoline (Compound 375); l, 2 -Dihydro.9.methoxy224finethyl.5- (2mtybnyiee-Hcrmn(,-~un~ (Compound 376); Fluorobenzylideney l, 2 3 ,A tetrahydro-2,2,4-. thyl..SH.chomeno[34A3-quinolino ne (Compound 389); (Z)-(R/S)-5-(Benzylidene). l 2 3 4 -tetrahydro2,2,4.imthyl.5Hchromeno[3,4-A-.3.quinolinone (Compound 392); (R/S- 4 1,Su)-5-(3..Fluoropheny). 1,2,3,4tetrahydro 2 2 ,4..ethy5Hcomeno[34A 3 quinolio (Compound 393); (R/S-41,SO)- 5-(3-Fluorophenyl)-1,,,-erhdo22 tiehl-Hcrmn[,---unlnn (Compound 394); (R/S4-41,-l 2 3 4 -Tetrahydro-2,2,4.trimethyI.5-[ 3 (Compound 395); (RIS-41,Su).

1,,,-erhdo224tmty--3(rflooehlpey]S-hoin[,-l3 quinolinone (Compound 396); (R/S-4I,Su)-5-(4..Chorophenyl) 1 2 ,3,4-tetrahydro-2,2,4trimethyl-5H..chromeno[3,4A-3-quino lnone (Compound 402); (RIS-41,S1')-5-(4- Chlorophenyl)- l, 2 3 4 -tetrahydro..2,2,4-trimethyl..5llchro meno[3 4 -fI-3-quinolinone (Compound 403); and utyl- l, 2 -dihydro-2,2,4,9-tetramethyl...H chro meno [3,4flquinotine (Compound 457).

Representative AR modulator compounds agonists and antagonists) according to the present invention include: l, 2 -Dihydro2,2,4timethyI6methoxymethyl 8 pyranono[5,6-glquinojjne (Compound 237); 1, 2 -Dihydro2,2,4iethy6-trifuoromethyl 8 -pyrano no5,6-g]quino ie (Compound 238); l, 2 -Dihydro-2,2,4Uimthy1 isocoumarino 4 3 -g]quinoline (Compound 239); l, 2 -Dihydro-2,2,4.rinethy.. isoquinolono 4 3 -g~quinoline(Compound 240); l, 2 -Dihydro2,2,4,6teramthyI8.

pyridono[5,6-g]quinoline (Compound 241); 1 ,2-Dihydro- lO-hydroxy-2,2,4-iethy1 1 OHisochromeno(4,3-gjquinoline (Compound 242); 2 -Dihydro2,2,4,-temthyl.8Hpyrano[ 3 ,2-glquinoline (Compound 243); isoquinolono[4,3-g]quinoline (Compound 244); l, 2 -Dihydro-2,2,4-trinethy.. thioisoquinolono[4,3.gquioline (Compound 245); 2 3 -Tetrahydro224wifthyl lO-isoquinolono[4,3..gjquinoline (Compound 246); l, 2 -Dihydro-2,2,4-timethy..6 trifluoromiethy18pyridono[5,6.g]quinoie (Compound 247); (RIS)- l, 2 3 4 -Tetrahydro- 2,,-r~hl6tiloofehl8prnn[,-~unln (Compound 250); 1,2- Diyr-,,-tiehl6tflooehl8tiprnn[,-junln (Compound 251); (RIS)-1,,,-erhdo224-iehl6tilooety--hoyaoo56 giquinoline (Compound 252); 6 -Chloro(difluoro)mthyl1, 2 -dihydro-2,2,4p-iethy..8 pyranono[5,6-glquinoline (Compound 253); 9-Acetyl- l, 2 -dihydro-2,2,4-triethy.6trfurnehl8prdn[,-lunln (Compound 254); 1,2-Dillydro-224,10tetarmthyl-6-tifuoromethy8pidono[ 6 g]noi (Compound 255); 1 ,2-Dihydro- 2 ,2,4-ftimethy1-6&(1,1 22pnalorehl--yaon[,-lunln (Compound 256); (R/S)-6-Chloro(difluoro)ffithyI ,,,-etayr-,,4u~hl8pyaoo56 glquinoline (Compound 257); 7-Chloro- l, 2 -dihydro-2,2,4- ithyl-6tifluoromthyl 8pyranono[5,6-gjquinoline (Compound 258); (R/S)-7-Chloro. 1 2 3 4 -tetrahydro-2,2,4trimethyl-6trffuoromethy8pyanono

[S,

6 -g]quinolfine (Compound 259); 1,2,3,4- Tetrahydro-2,2, mtirethyl-6-tifuoromethyl-8-prdon n lin (Compound 260); 1,-iyr-,,,-ernehl6tilurmty--yioo56gqioln (Compound 261); 1,-iyr-,,-rmty--rfur'ehl6prdn[,-lunln (Compound 262); 6- [Dichloro(ethoxy)methyl]-1,l 2 -dihydro-2,2,4trirmthyl18..pyanono[5, 6 giquinoline (Compound 263); Furyl)y l, 2 -dihydro-2,2,4-tithyl-8-pyranono [5,6giquinoline (Compound 264); 1 ,2-Dihydro- l, 2 2 4 -tetramethy1-6-trifluoromethy.8 pyranono[5,6-glquino line (Compound 265); l, 2 -Dihydro-6-tr~ffluoromiethy[-2,2,4-timethy- 9-thiiopyran-8-ono[5,6-g] quinoline (Compound 266); 1 ,2-Dihydro- 1 2 2 4 9 -pentamethyl-6trifluoromethyl- 8-pyridono [5,6-gjquino line (Compound 267); 7-Chloro-1I,2-dihydro-2,2,4trmty--rfurmty-8prdn[,-junln (Compound 268); and 6- Chloro(difluoro)methyl- 1,-iyr-,,-rmty-8prdn 56gqioln (Compound 269); (R/S)-1I, 2 ,3,4-Tetrahydro- 1 2 2 4 -tetramethy-6tifluoromethy1.8 pyranono[5,6-glquinoline (Compound 404); (RIS)-5-(3-Furyl)-1I, 2 ,3,4-tetrahydro-2,2,4-.

trimethyl-8-pyranono[,6-glquini~ine (Compound 405); 5-(3-Furyl)-1I,2-dihydro- 1,2,2,4tetranmethyl-8-pyranono[5,6&gquinoie (Compound 406); 5-(3-Furyl)- 1,2-dihydro- 1,2,2,4tetramethyl-8-ciopyranono [,6gjquioline (Compound 407); 6-Chloro-5-(3-fiiryl).1,2dihydro- l, 2 2 4 -tetramfethy1-8-pyranono [5,6-g]quino line (Compound 408); 1,2,3,4- Tetrahydro-2,2,4, lO-tetram~ethyl-6-triluoromethyl-8-pyridono[5,6glquinoline (Compound 409); (RIS)- 1,,,-erhdo4mty--rfurmty--yaoo56gqioln (Compound 410); 1,-iyr-,-iehl6tilooehl8prnn[,-lunln (Compound 411); 1,,,-erhdo22dmty--tilooity--yaoo56 glquinoline (Compound 412); lt 2 3 4 -Tetrahydro-6-triJluoromethy-8-pyranoio [5,6glquinoline (Compound 413); (R/S)-4-Ethyl-

I,

2 3 4 -tetrahydro-6-triIuoromethylg..

pyranono [5,6-glquinoline (Compound 414); (RIS)- 1, 2 ,3,4-Tetrahydro-1I,4-dimethyl-8pyranono[5,6-g]quinoline (Compound 415); (R/S)-4-Ethyl- 1,2,3,4-tetrahydro-l1-methyl-8pyranono[(5,6-gjquino line (Compound 416); 2,2-Dimethyl-1I,2,3,4-tetrahydro-6trifloromethyl-8-pyridono[5,6..Aquino line (Compound 417); (RIS)- 1,2,3,4-tetrahydro-6trifluoromethyl 2 ,2,4niethy1.8pyridono[,6-3-quinohnone (Compound 418); Trifluoromethyl-7-pyridono[5,6&ejindoijne (Compound 419); 8-(4-Chlorobenzoyl)-5trifluoromethyl-7-pyridono[5,6e]indoljne (Compound 420); 7 -tert-Butyloxycarbamoyl 1,2dihydro-2,2,8-trirnethylquinoline (Compound 421); I, 2 3 4 -Tetrahydro-6-riluoroithy18.

pyridono [5,6-flquinoline. (Compound 422); 1 7 2 -Dihydro-6-trifluoromethyl. 1,2,2,4tetramethyl-8-pyridono [5, 6 -Jjquinoline (Compound 423); 3 3 7 -pyridono 75,6-elindo line (Compound 424); (RIS)- 1 2,3,4-Tetrahydro-4-methy..6 (trifluoromethyl)-8-pyridono [5,6-g]quinoline (Compound 425); (RIS)- 1,2,3,4-Tetrahydro-4methyl- 6 -(trifluorometliyl)-8 .pyridono (5,6g] quino line (Compound 426); 1 ,2,2,-Trimethyl- 1,23,4terahdro6-tffuroetyl--p yanoo[56-~qunoline (Compound 427); 1, 2 3 4 -Tetrahydro-4-propy 146trifluoro ehy-th-yIpnnoo[ 6 gjun ln (Compound 428); I, 2 ,3, 4 -Tetrahydro-2,2,4-trlimethyp.6-tifuoromethy-9-thiopyr.an8ono[5,6gjquinoline (Compound 429); 1 ,2-Dihydro-

I,

2 2 4 -tetramethyl-6-triffuoromethyl.9 thiopyran- 8-ono[5,6-g]quino lie (Compound 430); 1 2 ,3,4-Tetrahydro.

I,

2 2 -trethyl-6.

trifluoromnethy1-8-pyridono(5,6-g~quinoline (Compound 431); 1 2 3 ,4-Tetrahydro-l -methyl- 4 -propyl- 6 trfluoromethy[-8-pyanono (5,6-g]quino lie (Compound 432); 1,2,3,4- Tetrahydro-10hdoyehl224tiehl6-rfurmty--yioo56 giquinoline (Compound 433); 1 2 3 ,4-Tetrahydro- l, 2 2 4 -etramethyl-6-trffluoromethy-9thiopyran-8-ono[5,6&gquinoie (Compound 434); 1,234Ttahdo229-imhl6 trifluoromfethy1.8-pyridono[5,6&gquinolie (Compound 435); (R/S)-1I, 2 3 ,4-Tetrahydro-3 methyl 6 trfluoromethy8pyidono[,6-glquinolie (Compound 436); 1 2 3 4 -Tetrahydro- 3,-iehl6tilooehl8prdn[,-lunln (Compound 437); (RIS) 1,2,3,4- Terhdo223tiehl6-flooehl8prdn [5,6-gjquino line (Compound 438); (R/S-21,4u)-1,23 Ttrhdo2,-iehy -rfuoromethyl8pyridono[S, 6 -g~quinoline (Compound 439); (R/S-21,4u)-4-Ethyu-,,,-erhdo2mty--rfurnehl8 pyranono[5,6-g]quinoline (Compound 440); (RIS-21,3u)- l, 2 3 4 -Tetrahydro-2,3-dimethyl-6 m~ooehl8prdn[,-~unln (Compound 441); 1,2,3,4- Terhdo23dmty--rfurmty--yioo56gqioln (Compound 442); (RIS)-1,,,-erhdo233 iehl6tilooity-8prdn(,-~unln (Compound 443); (RIS)-1,,,-erhdo2-ehl6tflooety--yioo56 giuinoline (Compound 444); (R/S)-4-Ethyl- 1,234ttayr--afurnchl8 pyridono [5,6..glquino line (Compound 445); (RIS-21, 3u)- l, 2 3 4 -Tetrahydro-2,3,9-trirnethy- 6 -tifluoromethy1-8pyidono[56g]quinolin (Compound 446); l, 2 ,3,4-Tetrahydro-4prpl6tilooehl8pyion 56gqioln (Compound 447); (RIS)-3-Ethyl- 1,,,-erhdo22dmty--rfur ehl -yioo56gqioln (Compound 448); (RIS)-1,,,-erhdo22dmty--rflooehl3poy--yiooS6 glquinoline (Compound 449); and I-ehl5tilooehl7prdn[,-id~n (Compound 450).

Compounds of the present invention, comprising classes of quinoline compounds and their derivatives, that can be obtained by routine chemical synthesis by those skilled in the art, by modification of the quinoline compounds disclosed or by a total synthesis approach.

The sequence of steps for several general schemes to synthesize the compounds of the present invention are shown below. In each of the Schemes the R groups R R 2 correspond to the specific substitution patterns noted in the Examples. However, it will be understood by those skilled in the art that other functionalities disclosed herein at the indicated positions of compounds of formulas I throught XVIII also comprise potential substituents for the analogous positions on the structures within the Schemes.

Scheme I F HN03, H 2

SO

4 R' N H 2 Pd/C

R

NH

1 2 3 H1 3 1

CH

3 acetone, 12 H CH H2, Pd/C R

CH

"N

3 N 4 CH 3 H CH 3 The process of Scheme I begins with the nitration of an arene (structure 1) with, for example, nitric acid in combination with sulfuric acid. The nitro compound (structure 2) is then reduced to the corresponding aniline (structure 3) with, for example, hydrogen over a metal catalyst such as palladium on carbon. The aniline is converted to a 1,2-dihydro-2,2,4trimethylquinoline (structure 4) by treatment with acetone and a catalyst in a process known as the Skraup reaction. See R.H.F. Manske and M. Kulka, "The Skraup Synthesis of Quinolines", Organic Reactions 1953, 7, 59, the disclosure of which is herein incorporated by reference. The catalyst may be an acid, such as p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, or trifluoroacetic acid, or preferably the catalyst may be iodine. The dihydroquinoline may be reduced with, for example, hydrogen catalyzed by a metal catalyst such as palladium on carbon, to afford a 1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (structure Note that many nitro compounds (structure 2) and anilines (structure 3) are commercially available, and the synthesis of compound of structure 4 would thus start with the commercially available material.

Scheme H1 Br

)NH

2 6 acetone, 1 1) n -BuLi dl-t -butYldicarbonate 7

H

Br OH 3

OH

3 I N1) t -B u L i (H O 2 B N

OH

3 2)trimethylborate

CH

t Buo/ Ot -BuO 0

R

1 Br, Pd(PPh 3 4

K

2 00 3 toluene, EtCH 1) SeO 2 dioxane 2) NaBH 4 MeCH

OH

3

R'N

OH

3

TFA

10 O H 3 t -BuO 0 4

H

PhAP Clr4 Br

NRN

OH

3 12 N OH 3 t -BU 0 1) R 2 MgBr, Oul ether 2) TFA The process of Scheme 11 begins with the conversion of 4-bromoaniline (Compound 6) to 6 -bromo-l, 2 -dihyro-2,2,4-tixnethylquino line (Compound 7) by treatment with acetone and a catalyst as described above (the Skraup reaction). The aniline nitrogen is then protected. For example, protection as the t-butyl carbamnate requires deprotonation with a strong base, for example, n-butyllithium, followed by reaction with di-t-butyldicarbonate to afford the protected quinoline (Compound The bromine of Compound 8 is then replaced with lithium by a lithium-halogen exchange reaction with an alkyllithium, for example, tbutyllithium. The organolithium intermediate is then allowed to react with a trialkylborate such as trimethylborate to afford, after mild acid hydrolysis, the boronic acid (Compound Treatment of Compound 9 with an aryl, heteroaryl, or vinylbromide compound in the presence of a catalytic amount of a palladium species, for example, tetrakis(triphenylphosphine) palladium, and aqueous base affords a 6-substituted quinoline (structure 10), via a so-called Suzuki crossed-coupling. See A. Suzuki, "Synthetic Studies via the Cross-Coupling Reaction of Organoboron Derivatives with Organic Halides", Pure Appl. Chem. 1991, 63, 419, the disclosure of which is herein incorporated by reference.

Deprotection of a compound of structure 10 with acid, for example, trifluoroacetic acid affords the 6-substituted- 1,2-dihydro-2,2,4-trimethylquinoline (structure 4).

Alternatively, the C(4) methyl group of a compound of structure 10 may be oxidized with, for example, selenium dioxide to afford the 4 -(hydroxymethyl)quinoline (structure 11), which may in turn be converted to the corresponding bromo compound (structure 12), for example with triphenylphosphine and carbon tetrachloride. The bromine atom of a compound of structure 12 may be replaced with an alkyl, aryl, or heteroaryl group by treatment with the corresponding organomagnesium compound in the presence of a copper salt such as copper(I) iodide. Removal of the protecting group with acid, for example, trifluoroacetic acid affords the 4,6-disubstituted-l, 2 -dihydro-2,2,-dimethylquinoline (structure 13).

Scheme III

CH

3 Br H 3 8 N OH3 t-BuO- 0O

R

1 B(OH), Pd(PPh 3 4

K

2

CO

3 toluene, EtOH RO

CH

3

OCH

3 10 CH 3 t-BuO O

TFA

IN

CH

3 CH3 H CH 3 4 The process of Scheme III involves the direct coupling of Compound 8 with an organoboron species, for example phenylboronic acid, in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium and a base such as potassium carbonate. The coupled product (structure 10) is then deprotected with acid, for example, trifluoracetic acid, to afford the dihydroquinoline 4.

Scheme IV

R

4 R R2

H

2 Pd/C R R R 1R 6 X NH 2

'NO

2 acetone, 12 16 17 The process of Scheme IV begins with a polycyclic aromatic nitro compound (structure 14) and is similar to the conversion of compounds of structure 2 to compounds of structure 4 (Scheme Thus, reduction of the nitro group with, for example, hydrogen over a metal catalyst such as palladium on carbon, followed by cyclization with acetone in the presence of a catalyst such as iodine affords two regioisomeric dihydroquinolines (structures 16 and 17).

Scheme V

CH

3 CH 3 COH23 DIBAI-H CH

CH

3 0 2 C N H-N- N HON H CH, H H 3 18 122 The process of Scheme V involves the reduction of an ester such as Compound 18 to the corresponding methyl alcohol (Compound 122) with a metal hydride reagent, for example, diisobutylaluminum hydride or lithium aluminum hydride.

Scheme VI 4

R

3

R

2

CH

3 3

H

3

R

5 n DIBAI-H Rs' /CH3 R N R N 0 CH 3 HO CH 3 19 The process of Scheme VI involves the reduction of the fluorenone (structure 19) to a fluorenol (structure 20) with a reducing agent, for example a metal hydride such as diisobutylaluminum hydride, sodium borohydride, or lithium aluminum hydride.

Scheme VII Br F 1) Cu, 190 C, 2h I F COMe I 2) 10% aq. NaOH e THF,A F CO 2

H

21 22 23 F F 1) SOCI 2 PhH, A F 90% HNO 3

F

2) CF 3

SO

3 H, CH 2

CI

2 24 NO2 -78 C F F CH 3

H

2 5% Pd/C F N 1) acetone, 12 FCH 3 0 NH 2 2) DIBAJ-H" HO I CH 3 26 132 57% HI, P(red) CH3CO 2

H

F F

SNH

2 27 The process of Scheme VII involves the preparation of a fluorene from acyclic precursors. The process of Scheme VII begins with the copper-mediated coupling of methyl 2 -bromo-5-fluorobenzoate (Compound 21) with 2 -fluoroiodobenzene (Compound 22) with, for example, copper powder at elevated temperatures, a process known as an Ullman coupling reaction. See M. Sainsbury, "Modem Methods of Aryl-Aryl Bond Formation", Tetrahedron 1980, 36, 3327, the disclosure of which is herein incorporated by reference. Hydrolysis of the methyl ester with base, for example, potassium hydroxide, affords the corresponding 2 -biphenylcarboxylic acid (Compound 23). Intramolecular Freidel-Crafts acylation of the corresponding mixed anhydride, prepared by treatment of Compound 23 with, for example, thionyl chloride followed by a strong acid such as trifluoromethanesulfonic acid (See B. Hulin and M. Koreeda, "A Convenient, Mild Method for the Cyclization of 3- and 4-Arylalkanoic Acids via Their Trifluoromethanesulfonic Anhydride Derivatives", J. Org. Chem. 1984, 49, 207, the disclosure of which is herein incorporated by reference), affords 2 ,5-difluorofluorenone (Compound 24). Nitration of Compound 24 with, for example, concentrated nitric acid affords 4,7-difluoro-2nitrofluorenone (Compound 25). Reduction of Compound 25 with, for example, hydrogen over a metal catalyst such as palladium on carbon, affords the corresponding aniline (Compound 26). Conversion to the dihydroquinoline with acetone and a catalyst such as iodine, followed by reduction of the ketone with a reducing agent such as diisobutylaluminum hydride, affords Compound 132.

Alternatively, the ketone functionality of Compound 26 may be exhaustively reduced to the methylene compound (Compound 27) with, for example, hydroiodic acid, red phosphorous, and acetic acid. See M.J. Namkung, T.L. Fletcher and W.H. Wetzel, "Derivatives of Fluorene. XX. Fluorofluorenes. V. New Difluoro-2-acetamidofluorenes for the Study of Carcinogenic Mechanisms", J. Med. Chem. 1965, 8, 551, the disclosure of which is herein incorporated by reference.

Scheme VIII Rs R Rs R 6 4 3 7 7 R NaH, RX R4 R 3 3 R CH 3 R 2 N R2

R

1

HCH

3 R CH 28 29 The process of Scheme VII involves the alkylation of N(5) of an indolo[2,3fJquinoline (structure 28) by deprotonation with a strong base, for example, sodium hydride, followed by alkylation with an alkylating agent such as iodomethane.

Scheme IX C02H 1) HN03 0O 0

CO

2 H 1)HN- O Oacetone, 12 2) DMA, heat I 3) Pd/C, H 2 NH 2 115 oC 31

N

0 R CH 0 0 CHN

CH

3 1) RMet CH3 H32

CH

3 2) CF 3

CO

2 H, Et 3 SiH CHs or O A 159

BF

3 -OEt 2 Et 3 SiH

N

H CH 3 33 The process of Scheme IX begins with the nitration of 2-biphenylcarboxylic acid with, for example, concentrated nitric acid, to afford a mixture of nitro compounds, including 4 2 '-dinitro-2-biphenylcarboxylic acid. The crude material is heated to 150-170°C in a high-boiling solvent such as dimethylacetamide to effect cyclization of 4,2'-dinitro-2biphenylcarboxylic acid to the corresponding benzocoumarin. See G.I. Migachev, "Investigations in the Series of Ortho-Substituted Bi-phenyls. I. Nitration of 2- Biphenylcarboxylic Acid and the Chemical Properties of its Nitro Derivatives", Zh.

Organich. Khim. 1979, 15, 567, the disclosure of which is herein incorporated by reference.

Reduction of the nitro group with, for example, hydrogen over a metal catalyst, affords Compound 31. Treatment of Compound 31 with acetone in the presence of a catalyst, for example, iodine, affords Compound 159. The addition of an organometallic reagent, such as an organolithium or organomagnesium reagent, to Compound 159, affords an intermediate which may be reduced by a trialkylsilane, such as triethylsilane, in the presence of a strong protic acid such as trifluoroacetic acid or a Lewis acid such as boron trifluoride. One or both of two regioisomeric products, structures 32 and 33, are thus obtained.

Scheme X 0 RCH CHH3 H CH 3 N CH 3

CCH

3

N

H CH 3 The process of Scheme X involves the reduction of a d ihydroquino line (structure 32) to a midxture of two diastereomeric l, 2 3 4 -tetrahydroquino lines (structures 34 and with, for example, hydrogen over a metal catalyst such as palladium on carbon.

[rest of page left purposely blank] Scheme XI Ri OCH3 R 3 Br 36 1) n-BuLl, THF, -78 °C 2) B(OCH 3 3 3) H 3 0' Ri ,OCH 3 R2 B(OH) 2 37

CO

2

CH

3 Br N

NO

2 37, 2.0 M Na 2 COa, DME (Ph 3

P)

4 Pd (cat) 1) KOH, EtOH, HI0, THF 2) SOCI 2 3) AICI3 4) Pd/C, H 2 acetone, 12 120 °C 2 1) RMet I

A,

CH3 2

BF

3 -Et20, Et 3 SiH "ICH 3 1 CH3 42 CH3 41 42 The process of Scheme XI involves the preparation of benzocoumarins from acyclic precursors. Thus, an ortho-bromoanisole (structure 36) is lithiated with an alkyllithium, for example, n-butyllithium, and allowed to react with a trialkylborate such as trimethylborate.

Hydrolysis of the intermediate with acid, for example, dilute hydrochloric acid, affords the corresponding boronic acid (structure 37). Palladium-catalyzed coupling of a 2methoxyphenylboronic acid (structure 37) with methyl 2 (Compound 38) with a palladium catalyst such as tetrakis(triphenylphosphine)palladium and an aqueous base such as aqueous potassium carbonate, affords the biphenyl carboxylate (structure 39). Hydrolysis of the ester with base, for example, potassium hydroxide, is followed by conversion of the acid to the acid chloride with, for example, thionyl chloride.

Intramolecular acylation is then effected by a Lewis acid such as aluminum trichloride.

Reduction of the nitro group with, for example, hydrogen over a metal catalyst, affords the desired aniline (structure 40). Treatment of compounds of structure 40 with acetone and a catalyst such as iodine affords the dihydroquinoline (structure 41). The addition of an organometallic reagent, for example an organolithium or organomagnesium reagent, to a compound of structure 41, followed by treatment of the intermediate with a strong protic or Lewis acid and a trialkylsilane, for example, boron trifluoride and triethylsilane, affords a compound of structure 42.

Scheme XII RCOCH3 0 2

H

B YBr H 2.0 M Na 2 003, DME R2, B(OH) B( 2

NO

2 (Ph 3

P)

4 Pd (cat) 37 43

SOCH

3 1) SOC l 2 1 0 0 R2N I 2) AlCl 3 R 2

HO

2 C NO 2 3) Pd/C, H 2 I 44

NH

2 The process of Scheme XII is an alternative synthesis of compounds of structure Thus, direct coupling of a 2 -methoxyphenylboronic acid (structure 37) with nitrobenzoic acid (Compound 43) affords the biphenylcarboxylic acid (structure 44).

Treatment of a compound of structure 44 with, for example, thionyl chloride, followed by the addition of a Lewis acid, for example aluminum trichloride, and reduction with, for example hydrogen over palladium on carbon, affords compounds of structure Compounds of structure 40 may be converted to compounds of structure 42 as described in Scheme XI.

Scheme XIII 1) R 3

CH

2 MgX or R 3

CH

2 L! R 32) p-TSA, CF 2 C1 2

R

2 The process of Scheme XII involves the addition of an organometallic reagent, for example an organomagnesium. or organolithiurn reagent, to a compound of structure 41.

Dehydration of the intermediate thus derived may be catalyzed by an acid, for example, para-toluenesulphonic acid, to afford compounds of structure Scheme

XIV

2' 0 N DIBAI-H

OH

3 H CH 3 41 R' N 0

OH

I

OH

3 C H 3

N

H OH 3 46 R 3 XH, p-TSA N, 02

XR

3

N

H

OH

3 RG TMSOTf The process of Scheme XIV involves the reduction of a compound of structure 41 with a metal hydride, for example, diisobutylaluminum hydride, to afford a compound of structure 46. Treatment of a compound of structure 46 with an alcohol such as methanol or a thiol such as propanethiol in the presence of an acid such as para-toluenesulphonic acid affords a compound of structure 47 0 or Treatment of a ketal of structure 47 (X=0) with an allyl silane and a Lewis acid such as trimethylsilyl trifluoromethanesulfonate affords a compound of structure 48.

Scheme XV 1) n- BuLi

;H

3 2) BOC20 R' ROH R2 CH3

CH

3

N

i CH 3 49

BOC

1) BH 3

-THF

2) HO22 R N O H

R

2 O -H3 OH

CH

3

CH

3 51

BOC

1) PCC 2) TFA 1) PCC 2) TFA 52 53

R

1 0 R 1) PCCO H 3

OH

3 or 51 R2 N

O

2) NaH, CH 3 1 N CH 3 3) TFA H CH 3 The process of Scheme XV begins with the protection of the nitrogen atom of a compound of structure 42, which involves deprotonation with a strong base, for example, nbutyllithium, followed by reaction with an anhydride, for example, di-tert-butyl dicarbonate. Hydroboration of a compound of structure 49 with a borane species, for example, borane-tetrahydrofuran, followed by an oxidative work-up using, for example, basic hydrogen peroxide, affords a mixture of two diastereomeric 3hydroxyltetrahydroquinolines (structures 50 and 51). Separation of the isomers followed by oxidation with typical oxidant, for example, pyridinium chlorochromate, and deprotection with a strong acid, for example, trifluoroacetic acid, affords compounds of structures 52 and 53.

Alternatively, a compound of structure 50 or 51 may be oxidized with, for example, pyridinium chlorochromate, deprotonated at the C(4) position with a strong base such as sodium hydride, and alkylated with an alkylating agent such as iodomethane. Deprotection with strong acid, for example, trifluoroacetic acid then affords a compound of structure 54.

[rest of page left purposely blank] Scheme XVI R 3 0 z N0 2

H

2 Pd/C_ acetone, 12

A

Lawesson's reagent base, R 4

X

H

2 Pd/C R2 R 3

OH

3 0 2 C H 3 63

R

1 H OH 3

DIBAI-H

RO

H

3 R 2 *lo Z OH 3 62 CH 3 The process of Scheme XVI begins with the reduction of a nitro aromatic compound of structure 55 with, for example, hydrogen over a metal catalyst such as palladium on carbon. Treatment of an aniline of structure 56 with acetone and a catalyst such as iodine affords a compound of structure 57. A compound of structure 57 may be converted to the corresponding thio-compound (structure 58) by treatment with Lawesson's reagent [2,4bis(4-methoxyphenyl)-1 3 -dithia- 2 ,4diphosphetane24disulfde]. See B.S. Pedersen,

S.

Scheibye, K. Clausen and S.O. Lawesson, "Studies on Organophosphorus Compounds.

XXI. The Dimer of p-Methoxyphenylthionophos-phine sulfide as Thiation Reagent.

A

New Route to O-Substituted Thioesters and Dithioesters", Bull. Soc. Chim. Belg. 1978, 87, 293, the disclosure of which is herein incorporated by reference.

Alternatively, N(9) of a compound of structure 57 may be alkylated by deprotonation with a strong base, for example, sodium hydride, followed by alkylation with an alkylating agent such as iodomethane.

Alternatively, N(l) of a compound of structure 57 (Z=0O) may be alkylated by deprotonation with a strong base, for example, sodium hydride, followed by alkylation with an alkylating agent, for example, iodomethane, to afford a compound of structure 60. In addition, N(1) of a compound of structure 57 may be alkylated by treatment with an aldehyde or paraformaldehyde in the presence of sodium cyanoborohydride and acetic acid.

See R.O. Hutchins and N.R. Natale, "Cyanoborohydride. Utility and Applications in Organic Synthesis. A Review", Org. Prep. Proced. Int. 1979, 11, 201, the disclosure of which is herein incorporated by reference.

Alternatively, the C(8) ester group of a compound of structure may be reduced with a metal hydride, for example, diisobutylaluminum hydride, to afford one or both of two compounds (structures 61 and 62).

Alternatively, the olefin of a compound of structure 57 may be reduced with, for example, hydrogen over a metal catalyst such as palladium on carbon, to afford the 1, 2 3 4 -tetrahydroquinoline (structure 63).

[rest of page left purposely blank] Scheme XVII HZ-

NO

2

R

1 0 P ^X 0 P Z 9

NH

2 66 acetone, 12 A- SH 2 Pd/C .N O 2 H

R'

CH

3 P Z CH 3 R1 H CH 3 67

R

3

CH

3 I H

CH

3 57 de-protect 0 0 R3 OR4 R 68 Lewis acid 0 CH 3 R3

R

1 H C

H

3 O+ N R1 H

CH

3 71 The process of Scheme XVII begins with the acylation of a 3-nitrophenol (structure 64, Z=0) or 3-nitroaniline (structure 64, Z=NH) with an acylating agent, for example, ditert-butyl dicarbonate or trimethylacetyl chloride, to afford a compound of structure Reduction of the nitro group with, for example, hydrogen over a metal catalyst such as palladium on carbon, affords the corresponding aniline (structure 66). Treatment of a compound of structure 66 with acetone and a catalyst such as iodine affords a compound of structure 67. Deprotection by either acid or base, followed by treatment of the corresponding aniline or phenol with a P3-keto ester (structure 68) in the presence of a Lewis acid such as zinc chloride, affords one or more of four compounds (structures 57, 69, and 71). The cyclization of a phenol as described above is known as a Pechmann reaction.

See S. Sethna and R. Phadke, "The Pechmann Reaction", Organic Reactions 1953, 7, 1, the disclosure of which is herein incorporated by reference. The cyclization of an aniline as described above is known as a Knorr cylization. See G. Jones, "Pyridines and their Benzo Derivatives: Synthesis". In Comprehensive Heterocyclic Chemistry, Katritzky, A. R.; Rees, C. eds. Pergamon, New York, 1984. Vol. 2, chap. 2.08, pp 421-426, the disclosure of which is herein incorporated by reference. A compound of structure 69 may be converted to a compound of structure 57 by treatment with an acid, for example, paratoluenesulphonic acid. In addition, a compound of structure 71 may be converted to a compound of structure 57 by treatment with, for example, para-chlorophenoL [rest of page left purposely blank] Scheme XVMII 0 P Z'

H

2 Pd/C 0 0 R3 kOR4 de-protect

R

2 68 Lewis acid

CH

3 R' H CH 3 72

R

3 CH3 R 1 H

CH

3 63

R

2

R

3 OH CH 3

CH

3 73 0

CH

3 R+ 3

CH

3 74

R

3

CH

3

R

5 0 Z N CH 3 1 H C H The process of Scheme XVIII begins with the reduction of a compound of structure 67 with, for example, hydrogen over a metal catalyst such as palladium on carbon.

Deprotection by either acid or base, followed by treatment of the corresponding aniline or phenol with a 13-keto ester (structure 68) in the presence of a Lewis acid such as zinc chloride, as described above in Scheme XVII, affords one or more of four compounds (structures 63, 73, 74, and 64 Scheme XIX R2 R3C 3CH 3 Lawesson's reagent 0- R2 R -H

CH

3 0 Z N zN R H C3 R IH OH 3 63 76 The process of Scheme XIX involves the conversion of a compound of structure 63 to the corresponding thio-compound (structure 78) by treatment with Lawesson's reagent 2 ,4-bis(4-methoxyphenyl). l, 3 -dithia-2,4-diphosphetane2,4dsulfidel.

Scheme XX 3

R

3

O

3 1) BH 3 -THF

CH

3

OH

P

77 78 R 2 1) POCR3 C

OH

3 ON- 0 2) OF 3 C0 2 H R

OH

3

N

H OH 3 79 The process of Scheme XX begins with a protected 6-aryl- 1,2-diliydro-2,2,4triniethylquinoline (structure 77), which can be prepared as described in Scheme II.

Hydroboration of a compound of structure 77 with a borane species, for example, boranetetrahydrofuran, followed by an oxidative work-up using, for example, basic hydrogen peroxide, affords a 3 -hydroxyltetrahydroquino line (structure 78). Oxidation of the alcohol with a typical oxidant, for example pyridiniumn chlorochromate, and deprotection with a strong acid such as trifluoroacetic acid affords a compound of structure 79.

Scheme XXI

R

6 Br

A

7

NH

2 Ra (Ph 3

P)

4 Pd, base heat

B(OH)

2 RU 1 G 0R R R 6 R 9

OH

3 A 9

CH

R R7

R

R NH 2 1 2 heat R N R 8

R

8 H OH 3 82 8 The process of Scheme XXI begins with a palladium-catalyzed cross-coupling' reaction of an aryl boronic acid (a compound of structure 80) and a 4-bromoaniline (a compound of structure 81) using, for example, tetrakis(triphenylphosphine)pallacium as the catalyst, to afford a substituted 4 -aminobiphenyl (a compound of structure 82). A Skraup reaction using an ailkyl methyl. ketone, for example acetone or 2-butanone, affords a compound of structure 83.

Scheme XXIGI E~r-I?,NH 2

OH

3 84 acetone, 12, heat

CH

3 Br N

CH

3 OH H 3 (Ph 3

P)

4 Pd, base heat R2

OH

3 R H 3

OH

3 H~ CH 3 The process of Scheme XXII begins with a Skraup reaction using 4 -bromo-2methylaniline (Compound 84) and acetone to afford Compound 85. A palladium-catalyzed cross-coupling reaction using, for example, tetrakis(triphenylphosphine) palladium as the catalyst, between an aryl boronic acid (a compound of structure 80) and Compound affords a compound of structure 86.

Scheme XXIII S t AcO R 7 R 00T H R 8

R

2 O O

R

A

4 CuX, heat

R

3

NH

2 5 R N 8 R 6

R

6 H R 87 88

(R

9

H)

The process of Scheme XXIII involves the reaction of an aminobenzocoumarin (a compound of structure 87) with a propargyl acetate in the presence of a copper salt, such as copper(I) chloride, to afford a compound of structure 88. See N. R. Easton and D. R.

Cassady, "A Novel Synthesis of Quinolines and Dihydroquinolines.", J. Org. Chem. 1962, 27, 4713, and N. R. Easton and G. F. Hennion, "Metal Catalyst Process for Converting a- Amino-Acetylenes to Dihydroquinoline", U. S. Patent 3,331,846 (1967), the disclosure of which is herein incorporated by reference.

[rest of page left purposely blank] Scheme XXIV 1) n -BuLl, THF, -78 OC 2) B(OCH 3 3 3) H 3 0+

R

2

NOCH

3 R 3

B(OH)

2

CO

2

CH

3 Br R 5 N0

R

6 90, 2.0 M Na 2

CO

3 OME 3 (Ph3P) 4 Pd (cat) 'NO 2 1) KOH, EtOH, H 2 0, THF 2) SOC1 2 3) AIC1 3 4) Pd/C, H 2

R

2 acetone, 12 120 0

C

1) DIBAL-H 2) BF 3 -OEt 2 Et 3

SIH

The process of Scheme XXIV involves the preparation of benzocoumarins from acyclic precursors. Thus, an ortho-bromoanisole (structure 89) is lithiated with, for example, nbutyllithium and allowed to react with a trialkylborate such as trimethylborate. Hydrolysis of the intermediate with, for example, dilute hydrochloric acid affords the corresponding boronic acid (structure 90). Palladium-catalyzed coupling of a 2 -methoxyphenylboronic acid (structure 90) with a methyl 2 -bromo-5-nitrobenzoate (structure 91) with, for example, tetrakis(triphenylphosphine)palladium and potassium carbonate, affords the biphenyl carboxylate (structure 92). Hydrolysis of the ester with, for example, Potassium hydroxide, chloride. Intramolecular Friedel-Crafts acylation is then effected by a Lewis acid such as aluminum trichloride. Reduction of the nitro group with, for example, hydrogen over palladium on carbon, affords the desired aniline (structure 87). Treatment of compounds of structure 87 with acetone and iodine affords the dihydroquinoline (structure 88). The reduction of a compound of structure 88 with, for example, diisobutylaluminum hydride, followed by treatment of the intermediate with, for example, boron trifluoride and triethylsilane, affords a compound of structure 93.

Scheme XXV

R

1

RI

R 0 R R2 OH OH R 88 94 R2 DIBAL-H RO I R 9

R

6 6 H R R H 93 The process of Scheme XXV involves the reduction of a compound of structure 88 with a reducing agent, for example, diisobutylaluminum hydride, to a compound of structure 94. Conversion of the benzyl alcohol to a leaving group by treatment with, for example, thionyl chloride, in the presence of a base such as triethylamine, effects ring closure to a compound of structure 93.

Scheme XXVI R

R

1 RiO

RO

2 R 0 0 9 R 2 R n 3 R 1) R 3

CH

2 MgX or R3CH 2 Li

R

9 R 3 1 4 l NRN R 5 N r 8 2) p-TSA, ChCl 2 R R 6 H R R R R H R 88 The process of Scheme XXVI begins with the addition of an organolithium or organomagnesium reagent to a compound of structure 88, followed by treatment of the intermediate thus obtained with an acid such as para-toluenesulfonic acid, to afford a compound of structure Scheme XXVII I1) n BuLi H CH 3 3) 03

S

R TFA 0

O

S N CH

CH

3 96 Boc 97 H The process of Scheme XXVII begins with the protection of the nitrogen atom of a compound of structure 33 by treatment with a base, for example n-butyllithium, followed by the addition of an acylating agent such as di-tert-butyldicarbonate. Ozonolysis of the olefin affords a compound of structure 96. Subsequent removal of the protecting group with, for example, trifluoroacetic acid, affords a compound of structure 97.

Scheme XXVII 0 R 1 R

CH

3

CH,

98 1) base, R 1

X

2) TFA

-CH

3 96 BOC The process of Scheme XXVMI begins with the deprotonation of a compound of structure 96 with, for example, sodium hydride or lithium dilsopropylamide, followed by the addition of an alkylating agent such as iodomethane, to afford a mono-ailkylated product, or a midxture of monci- and di-alkylated products. Subsequent removal of the protecting group with, for example, trifluoroacetic acid, affords either one or both compounds of structures 98 and 99.

Scheme XXIX 1) NaBH 4 2) p-TSA 1) n -BuUl 2) t -Boc 2

O

0 R C31) 8H 3

-THF

O H 3 2) H 2 0 2 2A BOC 3) Cr0 3

TFA

The process of Scheme XXIX begins with the reduction of a compound of structure 97 with, for example sodium borohydride, followed by dehydration of the resulting alcohol by treatment with an acid such as para-toluenesulfonic acid, to afford a compound of structure 1A. The nitrogen atom of a compound of structure IA is then protected by treatment with a base, for example n-butyllithium, followed by the addition of an acylating agent such as di-tert-butyldicarbonate, to afford a compound of structure 2A.

Hydroboration of a compound of structure 2A with a borane species, for example, boranetetrahydrofuran, followed by an oxidative work-up using, for example, basic hydrogen peroxide, affords a 3-hydroxyltetrahydroquinoline. Oxidation of the alcohol with a typical oxidant, for example chromium trioxide, affords a compound of structure 3A, and deprotection with a strong acid such as trifluoroacetic acid affords a compound of structure 4A.

Scheme XXX R 0 R 0 O0 CH 3 CH3

S)

3 1)n -BuLi 3 R2 1 R2! .OH I 0

CH

3 2) t-Boc 2 O I CH 3 CHa 3) BH 3 -THF CH3 41 4) H 2 0 2 5A Boc C r 3 R 0 0 C H 0 T F A R I 0 0 C H RH2 H 3 TFA I OH 3 N CH 3 N CH 3

I

3 H OH 3 6A Boc 7A

R

3 1) R3CH 2 MgX or R 3

CH

2 Li I T CH OH R2)

CH

2

R

3 2) p-TSA, CH 2

CI

2 M CH 3 The process of Scheme XXX begins with the protection of the nitrogen atom of a compound of structure 41 by treatment with a base, for example n-butyllithium, followed by the addition of an acylating agent such as di-tert-butyldicarbonate. Hydroboration with a borane species, for example, borane-tetrahydrofuran, followed by an oxidative work-up using, for example, basic hydrogen peroxide, affords a 3 -hydroxyltetrahydroquinoline of structure 5A. Oxidation of the alcohol with, for example, chromium trioxide, affords a compound of structure 6A. Removal of the protecting group with, for example, trifluoroacetic acid, affords a compound of structure 7A. The addition of an organolithium or organomagnesium reagent to a compound of structure 7A, followed by dehydration of the intermediate hemiketal with, for example, para-toluenesulfonic acid, affords a compound of structure 8A.

Scheme XXXI RI 0 0 CH3 1) R 3 MgXorR 3 LI T T

CH

3

OH

HR2O R2 R 3 N CH3 2) TFA, Et 3 SiH N CH 3 H CHH

CH

3 7A 9A The process of Scheme XXXI begins with the addition of an organolithium or organomagnesium reagent to a compound of structure 7A, followed by reduction of the intermediate hemiketal with, for example, trifluoroacetic acid and triethylsilane, to afford a compound of structure 9A.

Scheme XXXII R' 0 R 3 R2o CH 3 R2 0 R 0 0

CH

3 2 OCH 0 1) R Xor RL 10A3 S cH 3 2 Nt 2) TFA, Et 3 SiH The process of Scheme XXXII begins with the addition of an organolithiumn or organomagnesiumn reagent to a compound of structure 6A, followed by reduction of the intermediate hemiketal with, for example, trifluoroacetic acid and triethylsilane, to afford a diastereomeric mixture of compounds of structures IOA and IIA.

Scheme XXXIIEI RI 0 RCH 3 1)nOui R

H

3 2 I- N OH 3 N OH 3 42 H CH 3 2) t 12Oi0 H 3 1) BH 3 -THF O H 3 R

H

2) H 2 0 2 2 O H R2 OH N OH 3 N OH 3 jOH 3 OCH, 3 13A 8c 14A 6C 'Cr0 3 Cr0 3 R N 0 O H 3 R' 0 R 3

C

OH

3 3 N H m OH 3 OH

N

Booc 16A BOG 'TFA

ITFA

RI 0 R H 0 R3 H F 0R2'N 0 N OH 3 O H 3 17A H C3H

H

The process of Scheme XXXIII begins with the protection of the nitrogen atom of a compound of structure 42 by treatment with a base, for example n-butyllithium, followed by the addition of an acylating agent such as di-tert-butyldicarbonate. Hydroboration with a borane species, for example, borane-tetrahydrofuran, followed by an oxidative work-up using, for example, basic hydrogen peroxide, affords two diastereomeric 3hydroxyltetrahydroquinolines of structures 13A and 14A. Independently, each diastereomer may be oxidized with, for example, chromium trioxide, to afford the 3ketotetrahydroquinolines 15A and 16A, which may subsequently be deprotected with, for example, trifluroacetic acid, to afford compounds of structures 17A and 18A.

Scheme XXXIV

R

3 R 0 0

R

1 0 HT 3 1) R 3

CH

2 MgX or R 3

CH

2 Li CH 3

R

2 0 R- R 0 N CH 3 2)TFA H C- 6A Boc CH3 6 A 19A The process of Scheme XXXIV begins with the addition of an organolithium or organomagnesium reagent to a compound of structure 6A. Deprotection of the nitrogen atom and dehydration of the hemiketal with, for example, trifluoroacetic acid, affords a compound of structure 19A.

[rest of page left purposely blank] Scheme XXXV 0 0 0 lacetone, I 12 H heat N CH3

NH

2 N H 3 H CH 3 21A

R

1 1) n-BuLi 1) R 1 MgXor RLi CH 2) t-Boc 2

O

3) BH,-THF

CH

3 2) TFA, Et 3 SiH N C H 4) H 2 0 2 22A 5) Cr0 3 6) TFA S O CH 3 0 CH 3 0

N

0

CH

3

OH

3 CHa

CH

23A 24A The process of Scheme XXXV begins with a Skraup reaction using Compound and acetone to afford Compound 21A. The addition of an organolithium or organomagnesium reagent to a compound of structure 21A, followed by reduction of the intermediate hemiketal with, for example, trifluoroacetic acid and triethylsilane, affords a compound of structure 22A. Protection of the nitrogen atom of a compound of structure 22A is accomplished by treatment with a base, for example n-butyllithium, followed by the addition of an acylating agent such as di-tert-butyldicarbonate. Hydroboration with a borane species, for example, borane-tetrahydrofuran, followed by an oxidative work-up using, for example, basic hydrogen peroxide, affords a mixture of two diastereomeric 3hydroxyltetrahydroquinolines, which is oxidized with, for example, chromium trioxide, to afford the 3-ketotetrahydroquinolines. The mixture of 3-ketotetrahydroquinolines may subsequently be deprotected with, for example, trifluroacetic acid, to afford compounds of structures 23A and 24A.

Scheme XXXVI Ri 0 R 3 R O

R

CH3 R 2

.OH

S N CH3

CH

3 13A Boc

OR

RI O R C 3

CH

3 R2

OR'

I CH 3

OR

1) NaH, R 4

X

2) TFA The process of Scheme XXXVI involves the alkylation of the oxygen atom of a compound of structure 13A or 14A. The addition of a base such as sodium hydride and an alkylating agent such as.iodomethane, followed by deprotection of the nitrogen atom with, for example, trifluoroacetic acid, affords a.compound of structure 25A (from a compound of structure 13A) or structure 26A (from a compound of structure 14A).

Scheme XXXVII R N 3 i 'N R 3 R o R3 C1 3 1) R4CH 2 MgX or R 4

CH

2 Li 3

CH

3

R

4 R 2R 2 N C H 3 2) Burgess reagent- N CH3 H CH 3 H CH 3 17A 27A The process of Scheme XXX VII begins with the addition of an organolithium or organomagnesium reagent to a compound of structure 17A, followed by dehydration of tertiary alcohol with, for example, the Burgess reagent [(methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt], to afford a compound of structure 27A.

Scheme XXXVIII

R

3

OH

3

R

3

CH

3

R

2 R base, RCH 2 X R 3

SCOH

3

CH

3 R H CH 3 or R 5 CHO, NaCNBH 3 Z N CH R' R I 63 28A R The process of Scheme XXXVIII involves the alkylation of N(l) of a compound of structure 63, which can be accomplished in one of two ways. Treatment of a compound of structure 63 with a base, such as sodium hydride, and an alkylating agent, such as benzyl bromide, affords a compound of structure 28A. Alternatively, treatment of a compound of structure 63 with an aldehyde, for example acetaldehyde or para-formaldehyde, in the presence of a reducing agent, for example sodium cyanoboro-hydride or sodium (triacetoxy)borohydride, affords a compound of structure 28A.

Scheme XXXIX R CH 3

R

3

CH

3

R

2 5 I N N base, R 5

CH

2 X A

N

SzCHN- S Z N 1 H CH 3 or RSCHO, NaCNBH 3 R1 CH 1 5 5 8 29A R The process of Scheme XXXIX involves the alkylation of N(l) of a compound of structure 58, which can be accomplished in one of two ways. Treatment of a compound of structure 58 with a base, such as sodium hydride, and an alkylating agent, such as benzyl bromide, affords a compound of structure 29A. Alternatively, treatment of a compound of structure 58 with an aldehyde, for example acetaldehyde or para-formaldehyde, in the presence of a reducing agent, for example sodium cyanoboro-hydride or sodium (triacetoxy)borohydride, affords a compound of structure 29A.

Scheme XL

R

2

C

O

2 H

R

1 0 R 3 heat 1) R Met

CH

3 O NH 2 2) PPA CH 3 0 N R 3 R1 3) t-Boc 2 O, DMAP R 2 Boc 2) Pd/C, H 2 3) TFA 31A

R

1

R

4

R

5

R

1

R

4 JL 1) BB 3 6 I

R

3 0 2) 0- R 3 R RS CO 2

R

7

R

R ZnCl 2 32A 33A

R

5

R

1

R

4

R

8

CH

2 X, base R 6 or R 8 CHO, NaCNBH 3 R

R

34A The process of Scheme XL begins with reaction of a 3-methoxyaniline (a compound of structure 30A) with an acrylic acid, for example, crotonic acid, followed by treatment with an acid such as polyphosphoric acid to afford a 4-quinolone. Protection of the nitrogen atom by treatment with a base, for example n-butyllithium, followed by the addition of an acylating agent such as di-tert-butyldicarbonate, affords a compound of structure 31A.

Addition of an organomagnesium or organolithium reagent (R 4 alkyl, aryl, etc.), or a reducing agent such as sodium borohydride (R 4 hydrogen), affords an alcohol. Reduction of the alcohol with, for example hydrogen over palladium on carbon, followed by deprotection of the nitrogen atom, affords a compound of structure 32A. Demethylation of the methyl ether with, for example, boron tribromide, followed by a Pechman cyclization with a P3-keto ester effected by, for example, zinc chloride, affords a compound of structure 33A. A compound of structure 33A may further be transformed to a compound of structure 34A by alkylation of the nitrogen atom, which can be accomplished in one of two ways.

Treatment of a compound of structure 33A with a base, such as sodium hydride, and an alkylating agent, such as benzyl bromide, affords a compound of structure 34A.

Alternatively, treatment of a compound of structure 33A with an aldehyde, for example acetaldehyde or paraformaldehyde, in the presence of a reducing agent, for example sodium cyanoborohydride or sodium (triacetoxy)borohydride, affords a compound of structure 34A.

Scheme XLI

R

2

R

2 O H CuCI, heat 0 NH2 O A c 3 PR X 4

R

PNHR 3 4 1 X R 3 RI R 36A 1) deprotect

R

5

R

2 2) O R4

R

s C 02R 7 X

R

6 ZnCI 2 37A

R

s

R

2

R

8

CH

2 X, base R 6 or R 8 CHO, NaCNBH 3 X N R R 8 38A The process of Scheme XLI begins with the reaction of an aniline of structure with a propargyl acetate in the presence of a copper salt such as copper(I) chloride to afford a compound of structure 36A. Deprotection of the heteroatom with, for example ethanolic potassium hydroxide, followed by a Pechman cyclization (X 0 or S) or Knorr cyclization (X NH) with a 13-keto ester effected by, for example, zinc chloride, affords a compound of structure 37A. A compound of structure 37A may further be transformed to a compound of structure 38A by alkylation of the nitrogen atom, which can be accomplished in one of two ways. Treatment of a compound of structure 37A with a base, such as sodium hydride, and an alkylating agent, such as benzyl bromide, affords a compound of structure 38A.

Alternatively, treatment of a compound of structure 37A with an aldehyde, for example acetaldehyde or paraformaldehyde, in the presence of a reducing agent, for example sodium cyanoborohydride or sodium (triacetoxy)borohydride, affords a compound of structure 38A.

Scheme XLII

R

2

R

2 0 Pd/C,

H

2 0 1 X P X N 3 R H R 36A 39A 1) deprotect

R

5

R

2 2) O I 4 R02 C0NR n,3

R

6 ZnCI 2

R

5

R

2

R

8

CH

2 X, base R 6 or R 8 CHO, NaCNBH3 X N R 3

R'

R

8 41A The process of Scheme XLH begins with the reduction of a compound of structure 36A with, for example, hydrogen over palladium on carbon. Deprotection of the heteroatom with, for example ethanolic potassium hydroxide, followed by a Pechman cyclization (X 0 or S) or Knorr cyclization (X NH) with a (3-keto ester effected by, for example, zinc chloride, affords a compound of structure 40A. A compound of structure 40A may further be transformed to a compound of structure 41A by alkylation of the nitrogen atom, which can be accomplished in one of two ways. Treatment of a compound of structure 40A with a base, such as sodium hydride, and an alkylating agent, such as benzyl bromide, affords a compound of structure 41A. Alternatively, treatment of a compound of structure 39A with an aldehyde, for example acetaldehyde or paraformaldehyde, in the presence of a reducing agent, for example sodium cyanoborohydride or sodium (triacetoxy)borohydride, affords a compound of structure 41A.

Scheme XLIII C-O H 2

NOH-HCI

CH34 O0 0 42A 43A N'OH LiAIH 4

CH

3 O nN

H

1) deprotect 2) 0 R I COg 2

R

3

R

2 ZnCI 2 The process of Scheme XLIII begins with 6-methoxy-1-tetralone (Compound 42A) which is treated with hydroxylamine hydrochloride to afford the corresponding oxime, Compound 43A. A reductive Beckman rearrangement effected by, for example, lithium aluminum hydride, affords Compound 44A. Demethylation of the methyl ether with, for example, boron tribromide, followed by a Pechman cyclization with a P-keto ester effected by, for example, zinc chloride, affords a compound of structure Scheme XLIV R CH 3 R 3

CH

3

R

2 1) base 2 I CH 3 2) t -Boc 2 0 R

CH

3 SH CH 3 3) base O CH3 4) t-Boc 2 O Boc R Boc 57 46A

R

3

CH

3 1) BH 3 -THF R2 R 2) H 2 0 2 CH3 3) PCC 0 N H CH 3 4) TFA 47A The process of Scheme XLIV begins with the protection of both nitrogen atoms of a compound of structure 57 (Z=NH) by two sequential treatments with a base, for example nbutyllithium, followed by an acylating agent, for example di-tert-butyldicarbonate, to afford a compound of structure 46A. Hydroboration with a borane species, for example, boranetetrahydrofuran, followed by an oxidative work-up using, for example, basic hydrogen peroxide, affords a 3 -hydroxyltetrahydroquinoline, which is oxidized with, for example, pyridinium chlorochromate, to afford the 3 -ketotetrahydroquinoline. The 3-ketotetrahydroquinoline may subsequently be deprotected with, for example, trifluroacetic acid, to afford a compound of structure 47A.

(rest of page left purposely blank] Scheme XLV

R

1 1) Pd/C,

H

2

R

0 2 N H 2) 0

N

48A R C 0 2R3 H 49A

R

2 ZnCI 2 Ri 1) base R2

N

2) R 4 COCI H O

R

4 The process of Scheme XLV begins with the reduction of 6-nitroindoline (Compound 48A) with, for example, hydrogen over palladium on carbon. A Pechman cyclization with a 03-keto ester effected by, for example, zinc chloride, affords a compound of structure 49A. A compound of structure 49A may further be transformed to a compound of structure 50A by acylation of the quinolone nitrogen atom, which may be effected by deprotonation with, for example, sodium hydride, followed by the addition of an acylating agent, such as 3-nitrobenzoyl chloride.

Scheme XLVI

R

1 R1 R 1) HNO 3

R

2

R

3 2) Pd/C, H 2

H

2 NN

R

51A 52A R4 RC4 R1 R 4 C 0 2R 6 R R 5 1 1 R 2 ZnCI 2 The process of Scheme XLVI begins with the nitration of a 1,2,3,4tetrahydroquinoline (a compound of structure 51A) by the action of nitric acid in the presence of, for example, sulfuric acid. Reduction of the nitro group with, for example, hydrogen over palladium on carbon, affords a 7 -amino-1,2,3,4-tetrahydroquinoline of structure 52A. A Knorr cyclization with a 0-keto ester effected by, for example, zinc chloride, affords a compound of structure 53A.

Scheme XLVII NaH, XI ThR2 Br R N B r 0 2 N a NH 2 0 2 N'N ;R 2 2or, Na(OAc)3BH, OHC 2 N HN R 54A R 5 5AH R

R'

SR

2 Pd(ll), base, NaO 2 CH

R

al- 0 2 N N

H

56A 1) Pd/C. H 2 R3 R 2 R 4

R'

2) O T T

R

3

CO

2 Rs O N

N

R

4 ZnCI H H 57A The process of Scheme XLVII begins with the alkylation of 2 (Compound 54A) which may be accomplished in one of two ways. Treatment of Compound 54A with a base such as sodium hydride and an allylating agent, for example, 1bromo-3-methyl-2-butene, affords a compound of structure 55A. Alternatively, Compound 54A may be treated with an oP-unsaturated aldehyde, for example, cinnamaldehyde, in the presence of a reducing agent such as sodium triacetoxyborohydride to afford a compound of structure 55A. A palladium-catalyzed cyclization reaction catalyzed by, for example, palladium(II) acetate, affords a compound of structure 56A. Reduction of the nitro group with, for example, hydrogen over palladium on carbon, affords the aniline, and a Knorr cyclization with a j3-keto ester effected by, for example, zinc chloride, affords a compound of structure 57A.

Scheme XLVI 58A R 2 "C2H 1) toluene, A 2) PPA 59A 1) Boc 2 O, DMAP 2) R 4 Met 3) H 2 Pd/C 4) TFA 1) HNO 3

H

2 S0 4 2) H 2 Pd/C ZnCI 2 EtOH 61A 62A

R

8

CH

2 X, base or R 8 CHQ, NaCNBH 3 63A The process of Scheme XLVIII begins with the reaction of an aniline (structure 58A) with an acrylic acid, for example crotonic acid, followed by a cyclization reaction mediated by, for example, polyphosphoric acid to afford a 4 -quinolinone of structure 59A.

The nitrogen atom is then protected by treatment with a base, for example n-butyllithium, followed by the addition of an acylating agent such as di-tert-butyldicarbonate. Addition of an organomagnesium or organolithium reagent (R 4 alkyl, aryl, etc.), or a reducing agent such as sodium borohydride

(R

4 hydrogen), affords an alcohol. Reduction of the alcohol with, for example hydrogen over palladium on carbon, followed by deprotection of the nitrogen atom, affords a compound of structure 60A. Nitration of a compound of structure 60A by the action of nitric acid in the presence of, for example, sulfuric acid, followed by reduction of the nitro group with, for example, hydrogen over palladium on carbon, affords a 7 -amino-1, 2 ,3,4-tetrahydroquinoline of structure 61A. A Knorr cyclization with a 3-keto ester effected by, for example, zinc chloride, affords a compound of structure 62A. A compound of structure 62A may be further transformed into a compound of structure 63A by alkylation of the nitrogen atom, which can be accomplished in one of two ways.

Treatment of a compound of structure 62A with a base, such as sodium hydride, and an alkylating agent, such as benzyl bromide, affords a compound of structure 63A.

Alternatively, treatment of a compound of structure 62A with an aldehyde, for example acetaldehyde or paraformaldehyde, in the presence of a reducing agent, for example sodium cyanoborohydride or sodium (triacetoxy)borohydride, affords a compound of structure 63A.

Scheme XLIX

R

6

R

1

R

5

R

6

R

1

R

R R4 Et 3 SiH/TFA R

I

4 O X N 0 X 033 R2 H R3 2 R 64A The process of Scheme XLIX involves the reduction of a compound of structure 64A by treatment with, for example, triethylsilane in the presence of trifluoroacetic acid, to afford a compound of structure Scheme L 7 F6 R' IR

R

6 R' FR R O SeO 2 A

R

7

W

0OX N 3 RX

R

2 R 2

OH

66A 67A The process of Scheme L involves the oxidation of benzylic substituent of a compound of structure 66A by treatment with, for example, selenium dioxide, to afford a compound of structure 67A.

Scheme LI R 2 C2H 0 1) toluene, A N 2) NP R 2o 58A 3) Boc 2 O, DMAP 68A 0R4 base, R3X I' 1 etR 3 11 R'Me H2RdC 1

N

R, Boc R)~H 2

P~

69A 3) TFA The process of Scheme LI begins with the reaction of an aniline (structure 58A) with an acrylic acid, for example crotonic acid, followed by a cyclization reaction mediated by, for example, polyphosphoric acid to afford a 4 -quinolinone. The nitrogen atom is then protected by treatment with a base, for example, 4 -dimethylaminopyridine, followed by the addition of an acylating agent such as di-tert-butyldicarbonate to afford a compound of structure 68A. The 4-quinolone is then deprotonated with a base, for example, sodium hydride, and treated with an alkylating agent such as iodomethane, to afford a compound of aAP" k-\4pM 59776STEOD RECEP70R4o. 1 9 MIJ00 structure 69A. Addition of an organomagnesium or organolithium reagent (R 4 alkyl, aryl, etc.), or a reducing agent such as sodium borohydride

(R

4 hydrogen), affords an alcohol.

Reduction of the alcohol with, for example hydrogen over palladium on carbon, followed by deprotection of the nitrogen atom, affords a compound of structure 60A. Compounds of structure 60A may be transformed into compounds of structure 62A as described in Scheme

XLVIII.

Scheme LII O O 4 R 3 base, R 4 X. 3 1 R 5Met

R

2 N R 2

R

1 Boc R 1 Boc 2) H 2 Pd/C 69A 70A 3) TFA Rs 4 R5 0 0

R

3 1) HN0 3

H

2 S0 4 R3 RY N 2

R

7 H 2) H, Pd/C H 2 N R 2 ZnCI 2 EtOH

R

71A 72A

R

3

R

9

CH

2 X, base R R S0 N N R1 or R 9 CHO, NaCNBH 3 H R 1

R

73A 74A The process of Scheme LII begins with the deprotonation of a compound of structure 69A with a base, for example, sodium hydride, and treatment with an alkylating agent such as iodomethane, to afford a compound of structure 70A. Addition of an organomagnesium or organolithium reagent (R 5 alkyl, aryl, etc.), or a reducing agent such as sodium borohydride

(R

5 hydrogen), affords an alcohol. Reduction of the alcohol with, for example, hydrogen over palladium on carbon, followed by deprotection of the nitrogen atom, affords a compound of structure 71A. Nitration of a compound of structure 71A by the action of nitric acid in the presence of, for example, sulfuric acid, followed by reduction of the nitro group with, for example, hydrogen over palladium on carbon, affords a 7amino-1, 2 3 ,4-tetrahydroquinoline of structure 72A. A Knorr cyclization with a 0-keto ester effected by, for example, zinc chloride, affords a compound of structure 73A. A compound of structure 73A may be further transformed into a compound of structure 74A by alkylation of the nitrogen atom, which can be accomplished in one of two ways.

Treatment of a compound of structure 73A with a base, such as sodium hydride, and an alkylating agent, such as benzyl bromide, affords a compound of structure 74A.

Alternatively, treatment of a compound of structure 73A with an aldehyde, for example acetaldehyde or paraformaldehyde, in the presence of a reducing agent, for example sodium cyanoborohydride or sodium (triacetoxy)borohydride, affords a compound of structure 74A.

[rest of page left purposely blank] Scheme LIII P8 NH2 58A 1) CuCI, El 2) CuCI, A 1) Boc20O, DMAP

*R

3 2) BH 3 -THF, then 2 P"- 3) PCC 1) base, R 4

X

2) RsMet 3) H2, Pd/C 4) TFA 1) HN03, H 2 SO4 2) H 2 Pd/C 76A 77A

R'CH

2 X, base or R 8 CHO, NaCNBH 3 R 3

R

8 The process of Scheme LIII begins with the reaction of an aniline (structure 58A) with a propargyl acetate in the presence of a copper salt such as copper(I) chloride to afford a compound of structure 75A. The nitrogen atom is then protected by treatment with a base, for example 4-dimethylaminopyridine, followed by the addition of an acylating agent such as di-tert-butyldicarbonate. Hydroboration of the olefin with, for example, boranetetrahydrofuran, followed by an oxidative work-up with, for example, basic hydrogen peroxide, affords the 4 -hydroxytetrahydroquinoline, which may be oxidized with, for example, pyridinium chlorochromate, to afford a compound of structure 76A. A compound of structure 76A may then be deprotonated with a base, for example, sodium hydride, and treated with an alkylating agent such as iodomethane. Addition of an organomagnesium or organolithium reagent (R 5 alkyl, aryl, etc.), or a reducing agent such as sodium borohydride (R 5 hydrogen), affords an alcohol. Reduction of the alcohol with, for example, hydrogen over palladium on carbon, followed by deprotection of the nitrogen atom, affords a compound of structure 77A. Nitration of a compound of structure 77A by the action of nitric acid in the presence of, for example, sulfuric acid, followed by reduction of the nitro group with, for example, hydrogen over palladium on carbon, affords 7-amino- 1,2,3,4-tetrahydroquinolines of structure 78A. A Knorr cyclization with a 13-keto ester effected by, for example, zinc chloride, affords a compound of structure 79A. A compound of structure 79A may be further transformed into a compound of structure 80A by alkylation of the nitrogen atom, which can be accomplished in one of two ways. Treatment of a compound of structure 79A with a base, such as sodium hydride, and an alkylating agent, such as benzyl bromide, affords a compound of structure 80A. Alternatively, treatment of a compound of structure 79A with an aldehyde, for example acetaldehyde or paraformaldehyde, in the presence of a reducing agent, for example sodium cyanoborohydride or sodium (triacetoxy)borohydride, affords a compound of structure Scheme LIV

R

s R R s

R

4 R 6 Y R 3

R

8

CH

2 X, base R 6 R 3 O N R 2 OXN R 2 R' H 8R) R' 62A 81A The process of Scheme LIV involves the deprotonation of a compound of structure 62A with, for example, sodium hydride, followed by treatment with an alkylating agent such as iodomethane to afford a compound of structure 81A.

Scheme LV R 4 R0 3

R

1, R RH R3 SR 2R 1

R

6

CH

2 X, base R 5

RRR

2 I

N

O N N 30IR H L H 0 N^-N Sor

R

6 CHO, Na(CN)BH 3 a i 6 82A 83A 83A The process of Scheme LV involves the conversion of a compound of structure 82A into a compound of structure 83A by alkylation of the nitrogen atom, which can be accomplished in one of two ways. Treatment of a compound of structure 82A with a base, such as sodium hydride, and an alkylating agent, such as benzyl bromide, affords a compound of structure 83A. Alternatively, treatment of a compound of structure 82A with an aldehyde, for example acetaldehyde or paraformaldehyde, in the presence of a reducing agent, for example sodium cyanoborohydride or sodium (triacetoxy)borohydride, affords a compound of structure 83A.

Scheme LVI

R

4

R

1

R

4

R

1 R R 4~ R R CH 2 X, base RS R4 '2 O N

R

53A R 84A The process of Scheme LVI involves the deprotonation of a compound of structure 53A with, for example, sodium hydride, followed by treatment with an alkylating agent such as iodomethane to afford a compound of structure 84A.

It will be understood by those skilled in the art that certain modifications can be made to the above-described methods that remain within the scope of the present invention.

In a further aspect, the present invention provides several novel processes for the preparation of the compounds of the present invention. Each of these processes is illustrated in one or more of the Schemes shown above, and is described with particularity as follows.

Process I is depicted in Scheme II and begins with the conversion of a 4bromoaniline (Compound 6) to 6 -bromo-1,2-dihydro-2,2,4-trimethylquinoline (Compound 7) by treatment with acetone (0.01 M to 10 M) and 0.01-100 mol% of one or more catalysts (for example, para-toluenesulfonic acid, sulfuric acid, hydrochloric acid, boron trifluoride etherate, magnesium sulfate, or iodine) at -20 0 C to 300 0 C. Additives that inhibit polymerization (for example, 4 -tert-butylcatechol) can also be used in addition to the catalyst(s). The aniline nitrogen is then protected. For example, protection as the t-butyl carbamate requires treatment of a solution (typical solvents include toluene, ether, THF) of Compound 7 with a strong base (for example, n-butyllithiurm, sodium hydride, potassium hydride) at -100 0 C to 100°C, followed by reaction with di-t-butyldicarbonate at -100°C to 100°C to afford the 6-substituted-1,2-dihydro N-i protected quinoline (Compound The important steps of process 1 then begins when the halogen bromine) of Compound 8 is replaced with either lithium by a lithium-halogen exchange reaction by treatment of a solution (typical solvents include toluene, ether, THF) of Compound 8 with an alkyllithium (for example, t-butyllithium, n-butyllithium) at -100 0 C to 100 0 C, or with a reactive metal(s), such as magnesium by treatment with magnesium metals (turnings or powder) or zinc, and either iodine or ethylene dibromide in an inert solvent (typical solvents include ether, THF, pentane) at -20 0 C to 200*C. The organolithium or organomagnesium intermediate is then allowed to react with a trialkylborate (for example, trimethylborate, triisopropylborate) at 100°C to 100°C. The organoborate intermediate is hydrolyzed with acid (for example, dilute aqueous hydrochloric acid or sulfuric acid) at -40 0 C to 100 0 C to afford the boronic acid 6-boro-1,2-dihydro N-I protected quinoline: Compouhd Alternatively, the organolithium or organomagnesium intermediate may be treated with an organotin species (for example, trimethyltin chloride, tributyltin chloride, etc.) at -100 0 C to 200 0 C to afford a trialkyltin quinolinoyl compound, a species useful in the coupling processes described in J.K.Stille et al., 4 -Methoxy-4'-nitrobiphenyl", Organic Syntheses 1992, 71, 97, and T.N.

Mitchell, "Palladium-Catalyzed Reactions of Organotin Compounds" Synthesis 1992, 803, the disclosures of which are herein incorporated by reference. Treatment of a solution (typical solvents include toluene, DME, DMF) of Compound 9 with a coupling partner (an aryl, heteroaryl, or vinylbromide; an aryl, heteroaryl, or vinyliodide; or an aryl, heteroaryl, or vinyl triflate) in the presence of a catalytic amount of a palladium species [for example, tetrakis(triphenylphosphine)-palladium, allylpalladium chloride dimer, bis(triphenylphosphine)palladium dichloride], and aqueous base (for example, sodium carbonate, potassium carbonate) at -40 0 C to 200°C affords a 6-substituted- 1,2-dihydro Nprotected quinoline (structure 10). Deprotection of a compound of structure 10, for example, with acid (for example, trifluoroacetic acid) at -80°C to 200°C, affords the corresponding 6-substituted-1,2-dihydroquinoline structure 4).

Process 2 is depicted in Scheme I and involves the treatment of a solution (typical solvents include toluene, DME, DMF) of 6-halo- 1,2-dihydro N- protected quinoline (Compound 8) with an organoboron species (for example, phenylboronic acid, 3nitrophenylboronic acid) or an organotin species [such as tributylphenyl tin or trimethyl(4methoxyphenyl) tin] in the presence of a coupling partner and a catalytic amount of a palladium species [for example, tetrakis (triphenylphosphine)paladium, allylpalladium chloride dimer, bis(triphenylphosphine)palladium dichloride], and aqueous base (for example, sodium carbonate, potassium carbonate) at -40 0 C to 200 0 C to afford a 6substituted-1,2-dihydro N-1 protected quinoline (structure 10). Deprotection of a compound of structure 10 with acid (for example, trifluoroacetic acid) at -80 0 C to 200°C affords the 6-substituted-1,2-dihydroquinoline (structure 4).

Process 3 is depicted in Scheme XI and involves the preparation of benzocoumarins from acyclic precursors. Thus, an ortho-bromoanisole (structure 36) is lithiated with an alkyllithium (for example, n-butyllithium, t-butyllithium) at -100 0 C to 80 0 C in an inert solvent (typical solvents include toluene, ether, THF), and allowed to react with a trialkylborate (for example, trimethylborate, triisopropylborate) at -100 0 C to 100 0

C.

Hydrolysis of the intermediate with acid (for example, dilute hydrochloric acid or sulfuric acid) at -40°C to 100 0 C, affords the corresponding 2-methoxyphenyl boronic acid (structure 37). Alternatively, the organolithium or organomagnesium intermediate may be treated with a trialkyltin halide (for example, trimethyltin chloride, tributyltin chloride, etc.) at -100°C to 200 0 C to afford a trialkyltin aryl compound, a species useful in the coupling processes described above in Process 1. The important steps of process 3 begin with the palladiumcatalyzed coupling of a 2-methoxyphenyl boronic acid (structure 37) with a nitrobenzoic acid derivative (typical derivatives include the acid; any one of a number of esters, including methyl, ethyl, allyl, t-butyl, phenyl; or any one of a number of amides, including dimethyl, methyl, diallyl, allyl, dibenzyl) with a palladium catalyst (for example, tetrakis(triphenylphosphine) palladium, allylpalladium chloride dimer, bis(triphenylphosphine)palladium dichloride), and aqueous base (for example, sodium carbonate, potassium carbonate) at -40°C to 200°C affords the biaryl carboxylate (structure 39). The product obtained from use of the acid as a coupling partner may be used directly; alternatively, deprotection by hydrolysis of the ester or the amide is accomplished with aqueous base (for example, potassium hydroxide or sodium hydroxide) or aqueous acid (for example, trifluoroacetic acid, hydrochloric acid, sulfuric acid) at -60 0 C to 300 0 C. The acid is converted to the acid chloride with, for example, thionyl chloride in an inert solvent (typical solvents include methylene dichloride, toluene, or 1,2-dichloroethane) at -80 0 C to 300°C. Intramolecular cyclization (acylation) is then effected by treatment of a solution of the acid chloride in an inert solvent (typical solvents include methylene dichloride, toluene, or 1,2-dichloroethane) with a Lewis acid (for example, aluminum trichloride, boron trifluoride) at -80°C to 300 0 C to yield the nitrobenzocoumarin. Reduction of the nitro group of the nitrobenzocoumarin with, for example, 1-200 atmospheres of hydrogen over a metal catalyst (for example, Pd/C, PtO 2 affords the desired aminobenzocoumarin (structure Treatment of compounds of structure 40 with acetone and a catalyst such as iodine affords the coumarino[3,4-j]quinoline (structure 41), as described above in Process 1. The addition of an organometallic reagent, for example an organolithium or organomagnesium reagent, to a solution of a compound of structure 41 in an inert solvent at -100 0 C to 100 0 C affords an adduct. This adduct may be reduced by treatment of a solution of the adduct in an inert solvent (such as dichloromethane or toluene) with a strong protic or Lewis acid and a trialkylsilane, (for example, boron trifluoride or trifluoroacetic acid and triethylsilane or methyldiphenylsilane) at -80°C to 200 0 C, to afford a 5H-chromeno[3,4-f]quinoline (Compound of structure 42).

Process 4 is depicted in Scheme XIII and involves the addition of an organometallic reagent, for example an organomagnesium or organolithium reagent, to a solution of a compound of structure 41 a coumarino[3,4-f]quinoline) in an inert solvent (typical solvents include ether, THF, toluene) at -100 0 C to 100 0 C. Dehydration of the intermediate thus derived may be effect by treatment of a solution of the intermediate (typical solvents include in dichloromethane, ethanol, or toluene) with an acid (for example, paratoluenesulphonic acid, methanesulphonic acid), to afford compounds of structure 5H-chromeno[3,4-f]quinolines).

Process 5 is depicted in Scheme XVII and begins with the acylation of a 3nitroaryl, a 3-nitrophenol (structure 64, 3 -nitroaniline (structure 64, Z=NH), or 3-nitrothiophenol (structure 64, with an acylating agent (for example, di-tert-butyl dicarbonate or trimethylacetyl chloride), either with or without the addition of a base (for example, 4 -dimethylaminopyridine, triethylamine, pyridine) in an inert solvent (typical solvents include dichloromethane, THF, toluene) at -100°C to 200 0 C, to afford the protected 3-nitroaryl compound of structure 65. Reduction of the nitro group with, for example, 1-200 atmospheres of hydrogen over a metal catalyst (for example, Pd/C, PtO2), affords the corresponding 5-protected 3-aminoaryl (structure 66). Treatment of a compound of structure 66 with acetone and a catalyst such as iodine and addition of a 1,2dihydroquinoline affords the 5-protected 1, 2 -dihydroquinoline compound of structure 67, as described above in Process 1. Deprotection, for example, by either acid (for example, hydrochloric acid, trifluoroacetic acid, sulfuric acid) or base (for example, sodium hydroxide) at -40 0 C to 300 0 C, followed by treatment of a solution (typical solvents include ethanol, toluene, methanol) of the corresponding aniline or phenol with a P-keto ester (structure 68) in the presence of a Lewis acid (for example, zinc chloride, boron trifluoride, aluminum trichloride) at -40 0 C to 300 0 C, affords one or more of the four linear tricyclic 1,2-dihydroquinoline compounds (structures 57, 69, 70, and 71). A compound of structure 69 may be converted to a compound of structure 57 by treatment of a solution (typical solvents include toluene, dichloromethane) of a compound of structure 69 with an acid (for example, para-toluenesulphonic acid, hydrochloric acid) at -40 0 C to 300*C. In addition, a compound of structure 71 may be converted to a compound of structure 57 by treatment of a solution (typical solvents include toluene, dichloromethane) of a compound of structure 71 with, for example, para-chlorophenol.

Process 6 is a modification of Process 5. Thus, a solution (typical solvents include ether, THF, toluene) of a 3 -aminoaryl, preferably 3-amino thioaryl, is treated with a strong base (for example, sodium hydride, n-butyllithium) at -100 0 C to 100 0 C, followed by the addition of an acylating agent (typical acylating agents include di-t-butyl dicarbonate, trimethylacetyl chloride, acetic anhydride) at -100 0 C to 200 0 C, to afford the corresponding the corresponding 5-protected 3 -aminoaryl compound of structure 66 The conversion of a compound of structure 66 to the linear tricyclic 1, 2 -dihydroquinoline compounds of structures 57, 69, 70 and 71 is accomplished as described above in Process Process 7 is depicted in Scheme XLVI, and also is included as parts of Schemes XLVIII, LIl, and LIII. Process 7 begins with the nitration of a 1,2, 3 4 -tetrahydroquinoline (for example, a compound of structure 51A in Scheme XLVI, or of structure 60A in Scheme XLVIII, etc) with a nitrating agent. For example a mixture of sulfuric acid and nitric acid is added to a solution of the tetrahydroquinoline in sulfuric acid or sulfuric acid and a second, inert solvent such as nitromethane, at -80 °C to +40 oC. The nitro group of the resulting 7 -nitro-1, 2 3 4 -tetrahydroquinoline is then reduced by hydrogenation over a metal catalyst (for example, Pd/C, PtO 2 under 1-200 atmosperes of hydrogen, to afford the corresponding aniline (a compound of structure 52A in Scheme XLVI or of structure 72A in Scheme LII, for example). Treatment of a solution (typical solvents include ethanol, toluene, methanol) of the aniline with a O-keto ester (structure 68) in the presence of a Lewis acid (for example, zinc chloride, boron trifluoride, aluminum trichloride) at -40 °C to +300 affords the desired quinoline, a compound of structure 53A in Scheme XLVI, or of structure 73A in Scheme LH, etc.

In yet another aspect, the present invention provides novel intermediates useful in the preparation of the steroid modulator compounds of the present invention. The intermediates of the present invention are defined as those having the formulae:

R

6

R

7 R8

R

5 Z N 9 R R

(I)

R1 3 R 6 R 7 2R R8 OR (n) HO R 13R 6 R 7

R

12 0 N N 9 H R" W~OR OR

M

14

R

R N R 9 R 1 wherein:

(IV)

Z is 0, S, or NRI, where RI is hydrogen, R 2 C=O, R 2 C=S, R 3 OC-O, R 3

SC=O,

R

3 OC=S, R 3 SC=S or R 3

R

4 NC=O, where R 2 is hydrogen, a Cl C26 alkyl or perfluoroalkyl, optionally substituted allyl or aryl methyl, alkenyl, alkynyl, aryl or heteroaryl, and where R 3 and R 4 each independently are hydrogen, a Ci C6 alkyl, optionally substituted allyl, arylinethyl, aryl or heteroaryl;

R

5 is hydrogen, R 2 C=O, R 2 C=S, R 3 OC=O, R 3 SC=O, R 3 OC=S, R 3 SC=S, or

R

3

R

4 NC=O, where R 2

R

3 and R 4 have the same definitions as given above;

R

6 is hydrogen, a Ci C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl,.

ailcynyl, aryl, heteroaryl,

R

3 0, HOCH2, R 3

OCH

2 F, Cl, Br, 1, cyano, R 3

R

4 N or perfluoroalkyl, where R 3 and R 4 have the same definitions as given above;

R

7 through R 9 each independently are hydrogen, a C I C6 alkyl, allyl or optionally substituted ally!, arylmethyl, alkynyl, ailkenyl, aryl, or heteroaryl, or R8and R 9 taken together form a three- to seven-membered carbocylic or heterocyclic ring; RIO is hydrogen, a Ci C6 alkyl, optionally substituted allyl, arylmethyl, aryl, or heteroaryl,

R

2 C0O, R 2 C=S, R 3 OC=O, R 3 SC=O, R 3 OC=S, R 3 SC=S or R 3

R

4

NC=O,

where R 2through R 4have the same definitions as given above; R I I and R 12 each independently represent hydrogen, a Ci C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, alkynyl, aryl, heteroaryl,

R

3 0, HOCH2,

R

3

OCH

2

F,

Cl, Br, I, cyano, R 3

R

4 N or perfluoroalkyl, where R 3and R4 have the samne definitions as given above; R 13 is hydrogen, a ClI C6 alkyl, optionally su bstituted ally!, aryl methyl, alkenyl, alkynyl, aryl, -heteroaryl,

R

3 0, f{OCH2,

R

3

OCH

2

R

3

R

4 N, CF2CI. CF2OR 3 or perfiluoroalkyl, where R 3and R 4have the same definitions as given above;

R

14 is hydrogen, a Cl C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, alkynyl, aryl, heteroaryl,

R

3 0, HOd-I 2

R

3 OCH2, F, CL. Br, I, cyano, R 3

R

4 N or perfiuoroalcyl where R 3and R 4have the same definitions as given above; and

R

15 is F, Cl, Br, I, B(0R 1 6 2 SnRI 7

RI

8 RI9 or 0S02R 20 where R 16 is hydrogen or a Cl C6 alkyl, R 17 through R 19 each independently represent a C1 C6 alkyl, R 2 0 or heteroaryl,

R

20 is a Ci C6 alkyl, perfluoroalkyl, aryl, or heteroaryl, and R 2 has the same definition as given above.

Representative intermediate compounds useful in the preparation of the steroid modulator compounds of the present invention include: 1, 2 -Dihydro-2,2,4-trirnethyls5 coumarino [3,4-IAquino ie (Compound 159); 9-Fluoro- l, 2 -dihydro2,2,4triethyls5 coumarino[3,4-Aquinoie (Compound 207); 8-Fluoro-1, 2 -dihydro-2,2,4trimethyl-5 cournarino[(3,4-flquino line (Compound 208); 9-Chloro- 1 2 -dihydro-2,2,4-trinithyls..

co um-arino[3,4-flquinoline (Compound 209); 8-Ethoxy- l, 2 -dihydro-2,2,4-imethy..6 trifluoromethyl-8-pyrido[5,6-gjquinoline (Compound 248); and 1,2,6,7-Tetrahydro-6hydroxy-2,2,4-trimethyl-6-trifluoromethyl-8-pyridono [5,6_gquinoline (Compound 249).

The compounds of the present invention also includes racemate, stereoisomers and mixtures of said compounds, including isotopically-labeled and radio-labeled compounds.

Such isomers can be isolated by standard resolution techniques, including fractional crystallization and chiral column chromatography.

As noted above, any of the steroid modulator compounds of the present invention can be combined in a mixture with a pharmaceutically acceptable carrier to provide pharmaceutical compositions useful for treating the biological conditions or disorders noted herein in mammalian, and more preferably, in human patients. The particular carrier employed in these pharmaceutical compositions may take a wide variety of forms depending upon the type of administration desired, intravenous, oral, topical, suppository or parenteral.

In preparing the compositions in oral liquid dosage forms suspensions, elixirs and solutions), typical pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be employed. Similarly, when preparing oral solid dosage forms powders, tablets and capsules), carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like will be employed. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage form for the pharmaceutical compositions of the present invention.

For parenteral administration, the carrier will typically comprise sterile water, although other ingredients that aid in solubility or serve as preservatives, may also be included. Furthermore, injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like will be employed.

For topical administration, the compounds of the present invention may be formulated using bland, moisturizing bases, such as ointments or creams. Examples of suitable ointment bases are petrolatum, petrolatum plus volatile silicones, lanolin, and water in oil emulsions such as Eucerin T M (Beiersdorf). Examples of suitable cream bases are Nivea

T

m Cream (BeiersdorO, cold cream (USP), Purpose CreamM (Johnson Johnson) hydrophilic ointment (USP), and Lubriderm

T

m (Warner-Lambert).

EDITORIAL

NOTE

APPLICATION NUMBER 27761/00 This specification does not contain pages 101 to 110.

2.6 mmol) in refluxing 4:1 methanol/water over a period of 3 h. The hydrolyzed product was isolated by extraction with ethyl acetate. The crude product was purified by SGC (200 mL silica, 30% ethyl acetate/hexane to 50% ethyl acetate/hexane) to afford 490 mg (guant) of N-tert- butyloxycarbonyl- 1 2 -dihydro-6-(2-hydroxycarbonyl-4-nitrophenyl)..2,2,4 trimethylquinoline. N-tert-butylo xycarbonyl- 1,2-dihydro-6-(2-hydroxycarbony[-4 nitrophenyl)-2,2,4-trimethylquino line (49.0 mg, 0. 11 mmol) was then treated with trifluoroacetic acid (0.34 mL, 4.5 mmol) to remove the tert-butyl carbonate group minutes, QOC). The quenched reaction midxture was purified by silica gel chromatography (SGC) (50 mL silica, 40% ethyl acetate/hexane) to afford 1.2 mg of Compound 110.

Data for Compound 110: 1 H NMR (400 MHz, acetone-d6) 8.43 J 2.4, IN), 8.33 (dd, J 8, 2.4, IH), 7.72 J 8, IM, 7.08 2, 11H), 7.02 (dd, J1 8, 2, 1H), 6.57 J 1IH), 5.62 (br s, INH), 5.41 I1H), 1.96 J 2.4, 3H), 1.28 6H).

EXAMPLE 12 6-(3.4-Dichlorophenyfl- 1.

2 -ihvdro-2.2.4-trimethvlguinoline (Compound 111. structure 4 of Scheme H, where R=.4-dichlorophenyl) This compound was prepared according to General Method 2 (EXAMPLE From Compound 9 (78.4 mg, 0.25 mrnol) and commercially available 3,4-dichloro bromo benzene (56.7 mg, 0.25 mmol, Lancaster) was obtained a crude product which was isolated and purified by preparative thin layer chromatography (PTLC) (1000 g~m, 10% ethyl acetate/hexane) to afford 22 mg of Compound 111. Data for Compound Ill: 1

H

NMR (400 MHz, acetone-d6) 7.73 1H), 7.52 J 1.2, 2H), 7.32 J 2, 1H), 7.26 (dd, J 8, 2, 1 6.57 J 8, 1LH), 5.42 (br s, IlH), 5.37 IHM, 2.03 J 1.2, 3H), 1.27 6H).

EXAMPLE 13 4-Ethyl- 1.

2 -dihvdro-2.2-dimethyl1-6-phenvlguinoline (Compound 112. structure 13 of Scheme HI. where R I Ephenyl. R 2 =methyl) N-tert-B utyloxycarbonyl- 1.

2 -dihydro-2.2-dimethyl..4-hydroxymthy1phenyI guinoline (structure 11. where R 1 =phenyl): A solution of N-tert-butyloxycarbonyl- 1,2-dihydro-2,2,4trimethyl-6-phenyl quinoline (structure 10, where R I=phenyl) (310 mg, 0.888 mmol) and selenium dioxide (345 mg, 3. 11 mrnol) in 17 mL of dioxane was heated to reflux for 3 h.

The reaction mixture was quenched with 1: 1 Na 2

SO

3 NaHCO3 extracted with dichioro methane, dried (MgSO4), and the organic phase was concentrated in vacuc.

Purification by flash chromatography (silica gel, hexane/ethyl acetate, 4:1) gave 212 mg of the intermediate aldehyde along with 75 mg of the desired alcohol of structure 11, where Rl=phenyl. The aldehyde was treated with sodium borohydride in 25 mL of methanol at 0 0 C. After 1 h at O 0 C, the reaction mixture was quenched with water, extracted with ethyl acetate and concentrated in vacuo to give an oil that was purified by flash chromatography (silica gel, hexane/ethyl acetate, 4:1) providing structure 11, where R 1 =phenyl (240 mg, IH NMR (acetone d6) 7.68 J 9, 2H), 7.61 J 1.8, 18H), 7.47 (dd, J 6.2, 1.8, IH), 7.41 J 6.4, 2H), 7.29 5.80 lET), 4.51 J 6.8, 28), 4.12 J =6.8,1 1. 52 (hr s, N-tert-Butvlo x ycarbo nvl4-rmmty l.2iyr -22din etyl.heny Iuinoline (structure]2. where R-hnvI To a solution of N-tert-butyloxycarbonyl- 1,2.dihydro- 2,-iehl4hdoyehl6peyqioie(structure 11, where R' phenyl) (230 mg, 0.630 mmol) and carbon tetrabromide (220 mg, 0.662 mmol) in 5 mL of dichioromethane at 0 0 C was added triphenylphosphine (174 mg, 0.662 mmol) in 2 ML of dichioromethane. The reaction mixture was allowed to warm to rt and stirred for 1 h. The mixture was concentrated in vacuo to a residue that was subjected to flash chromatography (silica gel, hexane/ethyl acetate, 9: 1) to give structure 12, where R 1=phenyl (72 mg, 27%).

IH NMR (acetone d6) 7.67 (in, 3H), 7.52 (dd, J 8.7, 2. 1, 18H), 7.45 2H), 7.32 (in, 2H), 6.07 18), 4.60 28), 1.55 6H), 1.53 914).

4 ~tY~.~ivr22.iehI.peyqiol' e (C mon ^12. stutr 13o Scheme 11. where R =phenvl. =methl): To a solution of N-tert-butyloxycarbonyl-4 bromomethyl-1,-iyr-,-iehy--hnlunln (structure 12, where R 1 =phenyl) mng, 0.047 inmol) and copper iodide (4 mg, 0.02 inmol) in I mL of anhydrous ether at 0 0 C was added MeMgBr (0.060 mL, 3 M in ether). After 30 mmii of stirring at 0 0 C, the reaction mixture was quenched with saturated NH4CI and extracted with ethyl acetate. The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to provide an oil which was purified by SGC (silica gel, hexane/ethyl acetate, 9:1) giving N-tertbutyloxycarbonyl-4-ethyl- 1,2-dihydro-2,2dimethyl-6-phenylquinoline (16 mg, 1

H

NMR (acetone-d6) 7.65 J 8.7, 2H), 7.51 (dd, J 8.0, 1.7, IH), 7.29 2H), 7.43 3H), 5.56 1H), 2.55 J 8.9, 2H), 1.51 6H), 1.57 9H), 1.19 J 8.9, 3H). To a solution of N-tert-butyloxycarbonyl-4-ethyl- 1, 2 -dihydro-2,2-dimethyl-6phenylquinoline (16 mg, 0.044 mmol) in 1 mL of dichloromethane at 0 C was added 0.3 mL of trifluoroacetic acid. After 10 min of stirring, the reaction was quenched with saturated NaHCO3, and extracted with dichloromethane. The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to provide an oil that was purified by SGC (silica gel, hexane/ethyl acetate, 7:3) to provide 3 mg of Compound 112. Data for Compound 112: IH NMR (acetone-d6) 7.55 J 8.6, 2H), 7.37 3H), 7.23 (m, 2H), 6.59 J 8.26, IH), 5.38 3.76 1H), 2.48 J 7.4, 2H), 1.29 6H), 1.17 J= 7.4, 3H).

EXAMPLE 14 2 -Dihydro-2.2-dimethyl-6-phenyl.4-propylquinoline (Compound 113, structue 13 o Scheme II, where R-=phenvl. R 2 =ethyl To a solution of N-tert-butyloxycarbonyl-4-bromomethyl-1,2-dihydro-2,2-dimethyl-6phenyl quinoline (structure 12, where R =phenyl) (20 mg, 0.047 mmol) and copper (I) iodide (4 mg, 0.019 mmol) in I mL of anhydrous ether at 0 C was added EtMgBr (0.06 mL, 3M in ether). After 30 min of stirring at 0°C, the reaction mixture was quenched with saturated NH4CI and extracted with ethyl acetate. The organic layers were combined, dried (Na2SO 4 and concentrated in vacuo to provide an oil that was used directly in the next step. To the crude quinoline (20 mg, 0.053 mmol) in 1 mL of dichloromethane at 0°C was added 0.3 mL of trifluoroacetic acid. After 10 min of stirring, the reaction was quenched with aqueous saturated solution of NaHCO3 and extracted with dichloromethane. The organic layers were combined, dried (Na2SO 4 and concentrated in vacuo to provide an oil that was chromatographed (silica gel, hexane/ethyl acetate, 7:3) to give Compound 113 (9 mg, 6 1 Data for Compound 113: IH NMR (acetone-d 6 7.53 (in, 211), 7.40 (in, 3H), 7.24 (mn, 2H), 6.58 J= 8.14, 18H), 5.38 11H), 3.76 I 2.45 J= 7.40, 28), 1.60 (sx, J 7.39, 2H1), 1.29 614), 0.99 J =7.27, 3H).

EXAMffPLE 6 2 -Chlorophenvl).. 1-4*dhydro-22. ietluoin (Compund 114.,tutue4o Schemne I.hrR 1 chopenl This compound was prepared according to General Method 2 (EXAMPLE From Compound 9 (48.5 mg, 0.15 minol) and commercially available 2 -chloro bromo benzene (17.8 mL, 0. 15 mmnol, Lancaster) 15 mg of Compound 114 was isolated. Data for Compound 114: IH NMR (400 MHz, acetone-d 6 7.45 (dd, J 8, 1.2, 111), 7.36 (dd, J 8,2, 1H), 7.33 (ddd,J= 16,8, 1.2, 1H), 7.23 (ddd,J= 16,8,2, IH), 7.11 J= 2, 1 H), 7.03 (dd, J 8, 2, 1 6.53 J 8, 1IH), 5.35 11H), 5.31 (br s, 1ff), 1. 97 J 1. 6, 3H), 1.28 6H).

EXAMPLE 16 1.

2 -Dihvdro-2.24.4pmethyljndenor.2 1- -guinon (Comon 116. stutre7 of Shm IV- whereI

R

1 6

X=CU

2 General Mthod1 3 I ')-iycrgin n fortinfrom aaie To a dry 500-mi. r. b.

flask equipped with a magnetic stirring bar and a water cooled reflux condenser was added structure 15 along with 12 (0.05-0.2 equiv) dissolved in acetone 1-0.5 The resulting red solution was heated at reflux with constant stirring for 60 h. The reaction was followed by TLC (hexane/EtOAc, 3: 1, visualized by short wave UJV, the product appearing as a bright blue spot). After cooling to room temperature, Celitem (2.0 g) was added and the midxture was concentrated under reduced pressure to give a free flowing powder which was purified by flash column chromatography (70 g silica gel 60, 240 mesh, hexane/EtOAc, 5: 1) to afford a midxture of isomers of structures 16 and 17.

IV heeR X=cH~ This compound was prepared according to General Method 3 from structure 15 (where R I 6

X=CH

2 (5.0 g, 27 inmol) to afford a mixture of Compound 115 (structure 16 of Scheme TV, where RI- 6 X=CH2)(1 .64 g, 22.7%) and Compound 116 (336 mg, 4.65 in an 85:15 ratio (as determined by I H NMR). Data for Compound 116: Rf=- 0.57 (silica gel, hexane/EtOAc, 3: IH NMR (400 MHz, C6D)6) 7.62 J 8.0, IH), 7.45 J 8.0, 11M1, 7.28 J 7.3, 1 6,31 J 8.0, 11-), 5.19 I 3.74 2 3.28 (br s, 1 1.98 J 1.2, 3 1.08 6 H).

EXAMPLE 17 8-Bromo- l.-Idiydro-2.2.4-trimethylindenor 1 2 1Uinolin (Compound 117.srcue1 of Scheme wV were

R

2 -4 R 6

R

5 XC2) This compound was prepared according to General Method 3 (EXAMPLE 16) from structure 15 (where R 1 4

R

6 R 5=Br, X=CH2) (2.0 g, 7.7 mmol) to afford 376 mg of Compound 117 as a rose colored solid (along with Compound 127, Example 18).

Data for Compound 117: Rf 0.53 (silica gel, hexane/EtOAc, 3: 1 H NMR (400 MHz, C61)6) 7.38 (mn, 3H), 6.17 I 5. 15 1 3.34 2 3.27 (br s, I 1. 93 J 1.0, 3 1.08 6 H).

EXAMPLE 18 7-Bromo- l.

2 -dihy-dr-o-2.2.4-trliethylindenor2. 1 -gioline oond 1)7.ucue1 of Scheme IV. where R 1 4

R

6 R =Br. X=CHj~j This compound was prepared according to General Method 3 (EXAMPLE 16) from strutur 15(wh re R -4.R6= R=Br, X=CH2) (2.0 g, 7.7 mrnol) to afford a mixture of Compounds 117 and 127. Purification by silica gel chromatography afforded pure 117 (376 mg, 49%) (EXAMPLE 17) and mixed fractions containing 117 and 127. Compound 127 was purified by reverse phase HPLC (ODS column, 95% methanol/water, 3.0 mL/min).

Data for Compound 127: Rf 0.53 (silica gel, hexane/EtOAc, 3: IH NMR (400 MHz, C6D6) 7.38 J 1 7.31 I 7.29 J 8.0, 1 7.19 J 8.0, 1 H), 6.25 J 8. 1, 1 5.16 I 3.52 2 3.32 (br s, 1 1.91 J 1.4, 3 H), 1.05 6 H).

EXAMPLE 19 1.

2 -Diivdro-2.2.4..trim-ethylbe zrlfrano F.-guino line (Compond 11.I rcue1 of Scheme TV- where R 2 X=0) This compound was prepared according to General Method 3 (EXAMPLE 16) from structure 15 (where RI- 6 X=O) (1.0 g, 5.5 mmol) to afford Compound 118 (264 mg, 18.4%) as a yellow solid, and Compound 119 (936 mg, 65%) as a clear colorless oil. Data for Compound 118: Rf 0.44 (hexane/EtOAc, 3: IH NMR (400M1-z, C6D6) 7.61

J

6.9, 1lH), 7.56 1 7.41 J 1IH), 7.13 (in, 2 6.38 I 5.12 1 H), 3.28 (br s, 1 1.91 3 1.05 6 H).

EXAMPLE 1.-iyr-..-rmtylezobfuao (Cmon 1M, structure 17 of Scheme IV. where R- 6

O

This compound was prepared according to General Method 3 (EXAMPLE 16) from structure 15 (where Rl' 6 X=Q) to afford Compound 118 (264 mg, 1.00 mmol, 18.4%) as a yellow solid and Compound 119 (936 mg, 3.55 mmol, 65. as a clear colorless oil..- Data for Comp ound 119: Rf-= 0.44 (silca gel, hexane/EtOAc, 3: 1 H NMR (400 NMz, C6D6) 7.63 (dd, J 7.4, 1.5, 1 7.41 J 8.2, 1 7.35 J 7.3, 1 7.11 (mn, 2 6.19 J 8.4, 1 W, 5.11 1 3.38 (br s,1I 2.49 J 1.2, 3 1.06 6

H).

EXAMPLE 21 6-loo iyfo2-Atir~ ndn nln (Compoun 120. rcture 7 Scheme IV. where Rl' 5 6 F. X=CH) This compound was prepared according to General Method 3 (EXAMPLE 16) from structure 15 (where R 1 5

R

6 X=CH2) (1.0 g, 5.0 minol) to afford 248 mg of a mixture of Comnpounds 120 and 121. Pure samples of Compounds 120 and 121 were obtained by preparative thin layer chromatography (PTLC) (1000 Aim, hexane/EtOAc, 9: 1).

Data for Compound 120: Rf 0.70 (hexane/ EtOAc 3: IH NMR (400 MJ-z, C6D6) 7. 38 J 8.0, 1 7.29 J 7.5, 1 7.09 (dd, J 8.1, 5.3, 1 6.8 (dd, J 8.6, 8.6, 1 6.26 J 8.0, 1 5.13 1 3.81 2 3.32 (br s, I 1.88 J 1.2, 3 H) 1.05 6H).

EXAMPLE 22 9-Floo l.-iyro224methylindenor l.

2 luinotine (C oond 121. Strucue1 of Scheme TV, where R 2 5

R

6 X=CH2) This compound was obtained as described above for Compound 120 (EXAMPLE 21). Data for Compound 121: Rf 0.71 (silica gel, hexane/EtOAc, 3: 1H NMR (400 MHz, C6D36) 7.48 1 7.25 J 7.4, 1 7.07 (dd, J 7.8, 5.4, 1 6.80 (dd, J 8.7, 8.7, 1 6.13 I 5.15 I 3.63 2 3.28, (br s, INH), 1. 93 J 1. 2, 3 H) 1.09 6 H).

EXAMPLE 23 1,-ihdo 1 oxgqinln (Cmpun 122.

Scheme V.

Methvl 2 -dihdro-2.2.4-trimethvlindenorl. I iniie9-ahx e(tucture 6 f Schee I whre R=CQ2BIKCF_ This compound was prepared according to General Process 1 from methyl 2 -aminofluoreno-8carboxylate to afford 872.

mg of methyl l, 2 -dihydro-2,2,4-tiimethylindeno [1 2 -glquinoline-8-carboxylate (structure 16 of Scheme IV where R 2 5

R

6 =CO2CH 3 X=-CH2) as an off white solid.

Data for methyl l.

2 dihydro-2,2,4trimethyliiideno[ l, 2 -g~quinoline-9-carboxylate: 1Hi NMR (400 mHz, C6D6) 8.03 J 7.8, 1 7.56 J 7.4, 1 7.50 I 7.20 (dd, J= 15, 7.5, 1 6.32 1 5.17 I 4.28 2H), 3.55 3H), 1.97 J 1.3, 3 1. 10 6H1).

1.-iyr--yfoxIeh1- lni.nn 2 -plioe(opud12 Scheme V In a r.b. flask equipped with a magnetic stirring bar was dissolved methyl 1,2diyr-,,-rmtyidnf,-lunln--abxlt (23 mg, 72.1 pmol) in 10 mL dry THP. The solution was stirred at -78TC for 10 min and DIBAI-H (1.0 M in hexanes; 0.43 rnL, 6 equiv) was slowly added. After stirring for 20 min the reaction was quenched with Na2SO4- 10H20 (100 mg) and the solution was warmed to rt, at which time the reaction mixture became a white gelatinous suspension. The suspension was filtered and washed repeatedly with EtOAc. The washings and filtrate were combined and concentrated in vacuo to give 10 mg of Compound 122 as a white solid. Data for Compound 122: Rf 0.23 (silica gel, hexane/EtOAc, 3: IH NMR (400 MHz, acetone-d6) 7.55 J 7.4, 1IH), 7.50 IlH); 7.26 (dd, J 15, 7.5, 1H); 7.18 J 7.4, 1lH); 6.73 IH); 5.36 1H); 5.21 IH); 4.72 J 5.8, 2H); 4.06 (dd, J 11.4, 5.7, 1IH); 3.20 2H); 2.78 3H); 1.28 6H).

EXAMPLE 24 8-Chloro- 1 2 -dihydro-2.2.4-rJ ethvlindeno f I 2 -glguinoline (Compound 123. structure 16.

Scheme IV. where R 2 4R 6

R

5 =Cl, X=CH2) 2 -Amino-7-chlorofluorene structure 15, Scheme IV. where RI 1 4

.R

6 g 5 =CI. XFCH2)' A 100 mL round-bottom flask was charged with structure 14 (where, R 2 4

,R

6

R

5

=CI,

X=CH2) (496 mg, 2.02 mmol) and methylene chloride (20 mL) and 10% Pd/C (0.5g) was added to the solution. The reaction vessel was flushed with nitrogen and stirred under an atmosphere of hydrogen overnight (-15 hours), at which time the starting material was completely consumed as judged by TLC (50% ethyl acetate/hexane). The flask was flushed with nitrogen before exposing the mixture to air. The product mixture was diluted with ethyl acetate (50 mL) and washed with brine (3 x 30 mL). The organic layers were combined, dried (Na 2

SO

4 and concentrated. The crude product, structure 15 (where RI- 4

,R

6

R

5 =CI, X=CH2)(400 mg, was used in the next step without purification.

8-Chloro-1I.

2 -dihydro-2.2.4I-trim-ethylndeno r i.

2 -glguinoline (Compond 13 tutr Scheme IV, where R 2 -4R 6

R

5 =CI. X=CHf~l This compound was prepared according to General Method 3 (EXAMPLE 16) from structure 15 (where Rb- 4

,R

6

R

5

=-CI,

X=CH2)(400 mg, 1.85 mmol) and acetone (60 mL, Aldrich reagent grade) to afford Compound 123 and structure 17, where R 2 -4R 6

R

5 =CI, X=CH2. Purification by PTLC (reverse phase, 80% methanol/water) provided 1.8 of Compound 123.

Data for Compound 123: IH NMR: (400 MHz, acetone-d6) 7.59 J 8, 18), 7.46 (s, I 7.39 J 2, 18H), 7.24 (dd, J 8, 2, 18H), 6.67 I 5.3 5 I 5.26 (br s, I H), 3.71 28), 1.98 3H), 1.24 6H).

EXAMPLE 8-Fluoro- l.

2 -dihvdro-2.2,4-trimethylienl W& 2 -glgu inp (Compound 124. A stuue16.

Scheme TV. where R 2 4

R

6

R

5 X=CH2) This compound was prepared according to General Method 3 (EXAMPLE 16) from 2am-ino-7-fluorofluorene (structure 15, where RI- 4

,R

6

R

5 X=CH2) (100 mg, 500 pmol) to afford 43 mg (3 1 of a mixture of Compound 124 and structure 17, where Rl- 4

,R

6

R

5 X=CH2, in a 9:1 ratio. A small aliquot of this mixture was dissolved in acetone and purified by reverse phase preparative TLC 18, 20 x 20 cm, 1000 p m, MeOH H20, 5: 1) to give Compound 124 as a brown solid. Data for Compound 124: Rf 0.59 (silca gel, hexane/EtOAc, 3: lfl NMR (400 MHz, C61)6) 7.43 1 7.24 1 H), 6.96 (nm, 2 6.21 I 5.18 1 IH), 3.38 2 1.96 3 1. 11 6 H).

EXAMPLE 26 8-Acetyl- l.

2 -dihydro-2.2-4-riethylindenor 1 2 -gunone( mp nd15stctr16 Scheme IV, were R 2 4

,R

6

R

5 =COHI. X=CH2) In a r.b. flask equipped with a magnetic stir bar was dissolved Compound 115 (EXAMPLE 16) (54 mg, 0.02 1 mmol) in CH2CI2 (3 mL). To this solution was added freshly distilled acetyl chloride (20 p L, 1.3 equiv). The reaction mixture was stirred for 10 min, and AlC13 mg) was added. The reaction was followed by TLC (hexane/EtOAc, 3: 1, visualized by short wave UV). After 30 min, the black solution was quenched with H20 (10 mL), stirred for 2 h, then extracted with EtOAc (2 x 20 ML), washed with brine (2 x 20 mL), dried (Na2SO4), and concentrated on Celitem. Purification by flash column chromotography g silica gel 60, 240 mesh, hexane/EtOAc, 5: 1) provided 3.7 mg of Compound 125 as a light yellow solid. Data for Compound 125: Rf 0.59 (silca gel, hexane/EtOAc, 3: 'H NMR (400 MHz, C6D6) 8.06 1 7.94 J 8.0, 1 7.53 I 7.46 J 1 6.22 I 5.16 I 3.50 2 2.28 3 1.94 J1= 1.4, 3M), 1.10 6 H).

EXAMVPLE 27 6-Fluoro- l.

2 -dihydro- 2 2 .4-rrn ivlnoI 2 guione(mpnd1.srcte16 Scheme IV. where R 2

,R

4 6

R

3 X=CH2) This compound was prepared according to General Method 3 (EXAMPLE 16) from 2amino- 5-fluorofluorene (structure 15, where R 2

,R

4 6 =,RFXC )(30m,17 rmol) to afford 125 mg of Compound 126 as a light brown solid.. Data for Compound 126: Rf 0.63 (silca gel, hexane/EtOAc, 3: IH NMR (400 MHz, acetoned6): 7.55 1 7.25 J 7.3, 1 7.12 (in, I 7.02 J 10, 1 H) 6.73 I H), 5.39 1H), 3.81 2 H) 2.87 3 1.28 6 H).

EXAMPLE 28 1.

2 -Dihydro-2. 2,4-trimeth nitoinde-no f 2. 1 -Ilguino line (Compound 128. structure 17.

Scheme IV -where R 1

AR

6 0=H. 5 =NOZ)

I

2 This compound was prepared according to General Method 3 (EXAMPLE 16) from 2amiino-7-nitrofluorene (100 mng, 0.44 mmnol) to afford 2 mg of Compound 128 as a red solid. Data for Compound 128: Rf 0.46 (silica gel, 25% EtOAc: hexane); 1 H NMR (400 M~lz, acetone-d6) 8.25 1 8.19 J 7.8, 1 7.80 J 7.7, 1 7.65 1 6.77 1 5.70 (br s, 1 5.45 I 3.88 2 2. 10 3 1.31 6 H).

EXAMPLE 29 l.

2 -Dihydrom 2 2 4-trjimethyl..8-.iridnr1.-lunln (Compound 122. structure 16.

Scheme IV. where

R

2 4 .Ro 6

R

5 =,.XC2 This compound was prepared according to General Method 1 from 2 -amino-7-nitrofluorene (100 mng, 0.44 inmol) to afford 1.0 mg of Compound 129 as a red solid. Data for Compound 129: Rf 0.46 (silica gel, 25% EtOAc: hexane); IH NMR (400 MHz, acetoned6) 8.30 I 8.19 J 8.0, 1 7.78 J 7.7, 1 7.59 J 7.8, 1 6.70 J 7.8, 1 5.70 (br s, 1 5.43 I 4.26 2 2.30 3 1.31 6 H).

EXAMPLE 6.9-Difluoro- I 2 -dihydro-2.2.4- rmehlinden U1 gunoline(Compud10 tutr 16, Scheme IV. where R 2

,R

4 5 H, R 3

.R

6 X=CH2) This compound was prepared according to General Method 3 (EXAMPLE 16) from 2amino-5,8-difluorofluorene (structure 15, where R 2

,R

4 5

R

3

,R

6 X=CH2) (460 mg, 2.03 nfimol) to afford 94 mg of Compound 130 as a light brown solid. Data for Compound 130: Rf 0.56 (silica gel, hexane/EtOAc, 3: IH NMR (400 MHz, C61)6) 7.92 1 6.68 (ddd, J 6.3, 3.6, 1 6.49 (ddd, J 8.5, 6.0, 3.5, 11-1), 6.07 1 5.09 I 3.55 2 1.88 J= 1. 1, 1 1.06 6 H).

EXAMPLE 31 7-Fluoro- I .2-dihydro-2.2.4.trimethyl. 11 -(thiomethyl)indenoF2. I -flginoline (Compound 131. structure 1ofSeme IV. whee R l=SCH3. R 2 4

R

6 H 5 =17 X=CH2) This compound was prepared according to General Method 3 (EXAMPLE 16) from 2amino- 7 -fluoro-3-nmethylthiofluorene (structure 15, where R 1 =SCH3, R 2 4

R

6

RS=F)-

(250 mg, 1. 17 nimol) to afford 29 mg of Compound 131 as a white solid. Data for compound 131: Rf 0.55 (silica gel, hexane/EtOAc, 1 H NMR (400 mHz, C6D6) 7.78 1 7.19 (in, 1 6.90 I 6.88 IH), 5.44 1 5.22 1 3.54 (s, 2H), 2.05 3H), 1.92 J 1.2, 3 1.68 6 H).

EXAMPLE 32 5.8-Difluoro-t1.2-dihydro- I -hydrx -292.4-trimethylneo 1.-luioi(Cmon 132. Scheme VI).

3 2 '-Difluoro-2-biphenic aid (ompound 23. Scheme VI: A flame-dried 50 mL r.b. flask fitted with an air-cooled condenser containing methyl 2 (Compound 21, Scheme VII) (4.00 g, 17.16 mol) and 2 -iodofluorobenzene (Compound 22, Scheme Vif) (19.05 g, 85.82 mmnol, 5.00 equiv) was heated to 176*C, at which time unactivated copper powder (15.0 g, 236 mmcd, 13.8 equiv) was added portion-wise over min as the temperature was gradually raised to 190*C. After an additional 40 min at 190'C, the mixture was allowed to cool to rt and was filtered through a bed of CeliteTM on a fittedglass funnel, rinsing with 250 rnL ethyl acetate. Concentration under reduced pressure afforded an oil which was shown by IH NMR to be composed of the desired Ullmann hetero-coupling product, along with some 2 2 '-difluorobiphenyl, and a small amount of uncoupled methyl 2 -bromo-5-fluorobenzoate. This crude product mixture was then dissolved in 60 mL THF, and the ester was hydrolyzed by treatment with a large excess of 10% aqueous NaOH at reflux. After 24 h, thin layer chromatography (TLC) analysis indicated complete consumption of starting material, and the crude reaction mixture was neutralized to pH 4 with 1 L aqueous HCL The reaction mixture was then extracted with ethyl acetate (150 mL), and the organic phase was washed with brine (50 mL), dried (Na2SO4), and concentrated. Purification by silica gel chromatography (silica gel, hexanes/ethyl acetate, gradient elution) afforded 2.64 g of Compound 23 as a colorless, oily solid. Data for 23: 1 H NMR (400 MHz, CDCI3) 7.76 (dd, J 9.1, 2.2, IH), 7.32 3H), 7.26 (ddd, J 9.5, 7.8, 1.8, IH), 7.18 (ddd, J 8.1, 7.4, 0.9, 1H), 7.06 (dd, J= 9.5, 8.8, 1H).

2 .5-Difluorofluorenone (Compound 24. Scheme VII): To a flame-dried 100 mL flask containing 3 2 '-difluoro-2-biphenic acid (Compound 23, Scheme VI) (2.00 g, 8.54 mmol) in 12 mL benzene was added SOC12 (1.25 mL, 17.1 mmol, 2.00 equiv) and the mixture was heated to reflux for 90 min. The excess SOC12 and benzene were removed by distillation at ambient pressure. Benzene (6 mL) and CH2Cl2 (5 mL) were then sequentially added and removed by distillation. Anhydrous CH2CI 2 (30 mL) was added and the mixture was cooled to -78 0 C. Trifluoroacetic acid (0.76 mL, 8.54 mmol, 1.00 equiv) was then added and the mixture was allowed to warm to rt overnight. The reaction mixture was poured into 100 mL ice-water, rinsing with 50 mL CH2C12. The layers were separated and the aqueous phase was extracted with an additional 100 mL CH2C12. The combined organic extracts were washed successively with sat'd aqueous NaHCO3, water, and brine, dried (Na2SO4), and concentrated under reduced pressure to give 1.85 g (quantitative) of Compound 24 as a pale yellow solid. Recrystallization (ethanol) afforded Compound 24 as feathery pale yellow needles (mp 149-150°C, literature mp 147.5 0 C [Namkung et aL, "Derivatives of Fluorene XX, Fluorofluorenes, V, New Difluoro-2-acetamidofluorenes for the Study of Carcinogenic Mechanisms", J. Med. Chem. 1965, 8, 551-554.]).

4 7 -Difluoro-2-nitrofluorenone (Compound 25. Scheme VII): 2 (Compound 24, Scheme VII) (0.200 g, 0.925 mmol) was added portion-wise to 0.40 mL fumidng nitric acid at OTC in a 5 mL round-bottomed flask. The ice bath was removed and the reaction mixture was gently heated to 50'C for 2 miii with a water bath. The reaction mixture was then cooled to rt before the addition of 3.5 mL ice-water. The precipitated product was collected by vacuum filtration, yielding 232 mg of Compound 25 as a bright yellow solid (mp 207*C, literature mp 207-208'C which was carried on to the next step without further purification.

2 -Amino- 4 .7-.difluorofluorenone(Comou nd 132. Scheme VI): 4,7-Difluoro-2nitrofluorenone (Compound 25, Scheme VII) (1.00 g, 3.83 mmol) was dissolved in 175 mL ethyl acetate and 10% palladium on carbon was added (10 mol%). The mixture was stirred under an atmosphere of hydrogen gas maintained by a balloon for 105 miii, and was then filtered to remove the catalyst, rinsing with an additional 150 mL ethyl acetate. Removal of the solvent under diminished pressure yielded 885 mg (quantitative) of Compound 132 as a dark purple-red solid (mp 236 0 C, literature mp 234-235*C Data for Compound 132' Ifj NMR (400 MHz, CDCl3) 7.46 (dd, J 8.1, 4.5, 1 7.29 J 1. 5, 1N), 7.11 (dd, J 8.5, 6.0, IN), 6.79 J 1.9, IH), 6.42 Ad, J 10.9, 1.9, lIH), 3.99 (br s, 2H)J.

U.-Difluoro- 1 dibydro-2.2.4.trimethyl.1-ooneo 11 gun e(stucture 19 of Scheme V. where R 2 R=F. R 3 4

R

6 This compound was prepared according to General Method 3 (EXAMPLE 16) from Compound 132 (1.0 g, 4.6 mmol) to afford 5,8difluoro- l, 2 -dihydro-2,2,4-trimethy.. 1O-oxoindeno[1 2 -glquinoline (structure 19 of Scheme VI, where R 2

R

5

R

3 4

R

6 Data for 5,8-difluoro- I 2 -dihydro-2,2,4-atrethyl- oxoindeno[1,2-g]quinoline: Rf 0.49 (silca gel, hexane/EtOAc, IH NMR (400 MHz, acetone-d6) 7.50 (dd, J 8.1, 4.6, 1 7.27 (in, 2 6.73 I 6.03 (br s, I 5.47 I 2.16 (dd, J 7.1, 1.5, 3 1.29 6 H).

General Method 4: Reduction of a fluorenone (structure 19 of Scheme VI) to a hydroxyv:2,2.4-trimethylindenor1.2-glquinoline (sucture 20 of Scheme VID: To a flame dried 25-mL r.b. flask equipped with a magnetic stir bar was added structure 19 dissolved in anhydrous CH2CI2 (0.05-0. 1 The resulting purple solution was cooled to -78 0 C and to it. was added DIBAI-H (1.0 M in hexane, 3-4 equiv) under a blanket of N2. The resulting light yellow solution was stirred at -78'C for 30 min and to it was then added an excess of Na 2 S 04. 10 H20 (10-20 equiv). The resulting suspension was warmed to rt during which time the solution became a thick white gel. After stirring for 45 min, the gel was partially dissolved with EtOAc, filtered, and washed repeatedly with EtOAc. The ethyl acetate washes and filtrate were combined and concentrated under reduced pressure to afford structure 5.8-Difluoro- 1 2-dihydr- l0-hydr 1-l2.24 thlindeoi.-lunln Cmon 132. Scheme VF: Compound 132 was prepared according to General Method 4 from structure 19 (where R 2

,R

5

R

3 4

R

6 (46 mg, 0. 15 mmol) and DIBAI-H (1.0 M in hexane, 0.5 miL, 3.2 equiv) to afford 29 mg of Compound 132 as an off-white solid.

Data for Compound 132: Rf 0.10 (hexane/EtOAc, 1 H NMR (400 MHz, acetone-d6) 7.54 (dd, J 8.3, 5.0, 1 7.24 (dd, J1 8.6, 2.3, 1 7.06 (ddd, J 11.3, 9.3, 2.5, 1 H), 6.68 111), 5.63 (br s, I 5.44 J 7.9, 1 5.34 1 4.79 J 8.0, 1 H), 2.16 (dd, J 6.7, 1.2, 3 1.27 (s 3H), 1.25 3H).

EXAMPLE 33 7.9-1)luro l..dhdo224tiethvl..1- -oxoindeno 1 2 luinolN (ompound structujre 19. Scheme I hr 2 5 H R =F) This compound was prepared according to General Method 3 (EXAdVpLE 16) from 2amidno- 6 ,8-difluoro-9-fluorenone (750 mg, 3.2 mmol) to afford 29 mg of Compound 135 as a bright purple solid. Data for Compound 135: Rf 0.57 (silica gel, hexane/EtOAc, 3: 1 H NMR (400 MHz, acetone-d6) 7.46 I 7.22 (dd, J 8.5, 1.9, 1 6.76

I

6.68 (ddd, J 9.6, 5.8, 2.3, 1 5.89 (br s, I 5.52 I 2.06 3 1.30 6

H).

EXAMIPLE 34 7.9-Difluoro- 1 2-di'ydro- I 0-hyrryv-*).~ru~ty -neo 2 gginn (Cmpun 133. structure 20, Scheme VI. where RL 2 3

,R

5

R

4

.R

6 In a 25 mL r.b. flask equipped with a magnetic stirring bar was dissolved Compound 135 (EXAMPLE 33) (10 mg, 32 pmol) in 6 mL anhydrous CH2CI2. The solution was cooled to -78'C and then DIIBALH (0.5 mL, 1.0 M in hexanes) was added. The solution was stirred for 30 mini, and then Na2SO4. 10H20 (150 mg) was added. Upon warming to rt, the suspension congealed to a viscous white gel which was washed with ethyl acetate (4 x mL) and concentrated to afford 9.3 mng of Compound 133 as an off-white solid.

Data for Compound 133: 1 H NMR (4.00 MHz, C6D6) 7.40 I 7.09 (dd, J 8.7, 2. 1, I 6.84 1 6.55 (ddd, J 10, 5.7, 2.0, 1 5.65 I 5.31 I 4.54 J 1 2.00 J 1.0, 3 1.28 3 1.26 3 H).

EXAMPLE 7.1 0-Difluoro-JI.

2 -dihydro-2.2.4-trimethvl..SoxoindenoF2 1 -fquinoline (Compound 134.

structure 17 of Scheme IV where R 2

R

5 =F RI. R 2 4

R

6

X=C=Q)

This compound was prepared according to General Method 3 (EXAMPLE 16) from 2amino-4,7-difluoro-9-fluorenone (Compound'132, Scheme VII) (1 .0 g, 4.6 irol) to afford 22 mg of Compound 134 as a purple solid. Data for Compound 134: Rf 048 (silica gel, hexane/EtOAc, 3: 1H NMR (400 MHz, acetone-d6) 7.47 (mn, 1 7.24 (mn, 2 6.52 J 11, 1 6.12 (br s, 1 5.66 1 M, 2.25 J= 1.5, 3 1.27 6 H).

EXAMPLE 36 8-Fluoro- I 2-dihydro-2.2.4-trimethyL- 1-o--xoideno rl1.2-glquunoline mpound]37.

structure 16 of Scheme IV., where R 2 4

R

6

R

5

X=C=O)

To a dry 250-ni r.b. flask equipped with a magnetic stir bar and a water-cooled condenser was added 2 -amino-7-fluorofluorenone (5.00 g, 23.5 minol), along with iodine 15 mng)* and mesityl oxide (20 inL, 0.175 mol). The resulting red solution was heated at reflux with constant stirring for 2 days. The reaction was followed by TLC (20% ethyl acetate/hexane).

After cooling to rt, the crude product mixture was concentrated and purified by silica gel chromatography (400 mL silica, hexane) which afforded an impure sample of Compound 137. Repurification by silica gel chromatography (hexanes) afforded 64 mg of Compound 137. Data for Compound 137: 1 H NMR (400 MHz, acetone-d6) 7.53 (m, 1H), 7.36 1H), 7.21 (dd, J 10, 8, 1H), 7.16 (dd, J= 10, 8, 1H), 6.78 1H), 5.66 (br s, 1H), 5.51 IH), 2.04 3H), 1.29 6H).

EXAMPLE 37 8-Fluoro- 2-dihydro- 10-hdroxy-2.2,4-trimethylindenor 1.

2 -g]quinoline (Compound 136 structure 16 of Scheme IV, where R 2 -4 R 6

R

5

X=CHOH)

This compound was prepared according to General Method 4 (EXAMPLE 34) from Compound 137 (18.2 mg, 0.05 mmol) and DIBALH (1.0 M in hexanes, 0.2 mL) to afford, after purification by PTLC (1000 pm silica, 19/1 hexane/EA) 0.9 mg of Compound 136 as a white solid. Data for Compound 136: 1H NMR (400 MHz, acetone-d6) 7.52 (m, 1H), 7.37 7.21 (dd, J 8, 2.4, 1H), 7.02 (ddd, J 16, 8, 2.4, IH), 6,77 1H), 5.38 J =12, 1H), 5.37 5.31 (br s, 1H), 4.59 (d,J 8, 1H), 2.03 J 3H), 1.28 3H), 1.26 3H).

EXAMPLE 38 7-Fluoro-1, 2 -dihydro- 2 .2,4-trimethyl-8-nitroindeno ,2-glquinoline (Compound 138.

structure 16. Scheme IV, where R2-3.R 6 =H R 4 =FP R 5 NO?. X=CHI) This compound was prepared according to General Method 3 (EXAMPLE 16) from 2amino-6-fluoro-7-nitrofluorene (1.00 g, 4.00 mmol) to afford 98 mg of Compound 138 as a bright purple solid. Data for Compound 138: Rf 0.23 (silica gel, hexane/EtOAc, 1 H NMR (400 MHz, acetone-d6) 8.13 J 8.3, 1 7.66 J 12, 1 6.64 1 5.47 1 3.85 2 2.77 J 1.0, 3 1.36 6 H).

EXAMPLE 39 1.2-dihydro- lO.hydrOOy- 2 2 4-trim ethyfinde-nn 1I2ggioie(opud19 structure 20, Scheme VI. where R 2 =CL R 3 6 A solution of 2 -amino-4-chloro-9-fluorenot (300 mg, 1.30 mrnol), 12 (H mg) and acetone (20 mL) was heated in a sealed tube at 100 0 C for 16 h. To the cooled reaction mixture was added Celite~hi (0.5 and the slurry was concentrated in vacuo to afford a free-flowing powder which was purified by SGC (230-400 mesh, 2.5 x 15 cm) using a 10- 100% EtOAc:hexane gradient to afford 2.6 mg: of Compound 139 as a white solid. Data for Compound 139: Rf 0. 14 (silica gel, 25% EtOAc:hexane); 1 Hl NMR (400 MHz, acetoned6) 8.18 J 7.7, 1 7.78 J 7.9, 1 7.52 J 7.8, 1 7.19 J 7.8, 1 6.90 1 5.70 (br s, 1 5.50 1 5.40 I 4.59 J 8.5, 1 2.35 (s, 3 1.32 3 H) and 1.21 3 H).

.EXAMPLE 6-Fluoro- 1.

2 -dihydr -2.2.4-trimethyl- I0-oxoindenof 1 2 -glguinoline (Compound 140.

structure 19. Scheme VT. where 2 .R 6

R

3

-P)

This compound was prepared from 5-fluoro-2-nitrofluorenone (1.0 g, 4.1 mmol) in two steps in the manner previously described for Compound 123 (EXAMPLE 24), affording 0.74 g (6 of Compound 140 as a dark purple solid. Data for Compound 140: lIH NMR (400 MHz, CDCI3) 7.33 1H), 7.26 (mn, 3H), 6.75 IH), 5.45 3.96 (br s, lH), 2.05 J 1.5, 3 M, 1.31 6H).

EXAMPLE 41 6-Fluoro-1I.2-dihydro- lO-hydroxvy2.2.4- ethylindeno 1 2 luinoline Cmpound 141.

structuire 20 Scheme VI, where R 2

R

4 6

R

3

=F)

This compound was prepared by General Method 4 from Compound 140 (0.30 g, 1.0 inmol) to afford 0.25 g of Compound 141 as a pale reddish-purple solid. Data for Compound 141: IH NMR (400 MHz, CDCI3) 7.49 lH), 7.32 J1= 7.3, 1 7.12 (dt, J 7.8, 4.8, 1 7.00 (dd, J 9.8, 8.3, 1 6.71 IlH), 5.47 5.37 (d,IJ= 1. 2, 1 3.88 (br s, lH), 2.06 J 1.2, 3 1.31 3 1.30 3 H).

EXAM4PLE 42 8-Difluoro.., l 2 -dihydro-2 2 4.t* nehyI-. lO-(truoroae tox ne n o I1 'ginlje (Compound 142. structure 16. Schemne IV, where R 2 R-F R 3 R- 6 H XCHOCOCF 3 To a flame-dried 25 mL r.b. flask containinrg 5, 8 -difluoro 1,2.dihydro- 1hydroxy 2 2 4 trimethylindenofl,2-g]quinoline, Compound 132, EXAMPLE 32, (15.0 mg, 0.048 minol) in 2 mL dichioromethane at 0 0 C was added trifluoroacetic: anhydride (10 mL, 0.071 mmol, equiv) and 4 -NtN-dimthylaminopyridine (18.0 mg, 0. 147 inmol, 3.0 equiv), and the mfixture was allowed to stir for 10 mini. The reaction mixture was then transferred to a separatory funnel with ethyl acetate (20 mL), pH 7 potassium phosphate buffer (10 m.L) was added and the layers were separated. The organic phase was dried (Na 2

SO

4 and concentrated under diminished pressure. Purification by flash column chromatography (silica gel, heicanes/ethyl acetate, gradient elution) afforded 14.1 mg of Compound 142 as a light yellow oily solid. Data for Compound 142: IH NMR (400 MHz, CDCI3) 7.59 (dd, J 8.4, 5.0, 18), 7.15 (dd, J 8.2, 2.4, 18), 7.09 (dt, J 8.8, 2.5, 1H), 6.64 (s, 1H), 6.47 1H), 2.19 (dd, J= 6.7, 1.2, 3H), 1.29 3 1.28 38H).

EXAMPLE 43 6 4( 3 .5-iloohnl. ntygiolin (Comud 143.

structure 5 of-Scheme I where A dry 10 mL r.b. flask was charged with Compound 147 (EXAMPLE 47) (17.4 mg, 0.06 mniol) and 0.3 mnL ethyl acetate. To this solution was added 10% Pd/C (20 mng). The reaction mixture was stirred under an atmosphere of hydrogen for 1 h. The reaction was purged with nitrogen until all of the hydrogen had been removed from the flask. The product mixture was filtered through a plug of cotton and Celitl"M to remove the solids, rinsed with ethyl acetate (50 rnL) and concentrated. The crude material was purified by HPLC (reverse phase, ODS semi-preparatory column, 85% methanol/water, 3.0 mL 4 1 min).

The major peak was isolated and identified as Compound 143 (3.5 mng, 20%) by NMR.

Data for Compound 143: IH NMR (400 MHz, methanol-d4) 7.38 J 2.3, 18); 7.20 (dd, J 8.5, 1.6, 18H); 7.09 (in, 2H); 6.72 (in, 18H); 6.56 J 8.2, 18H); 2.96 (in, 18H); 1.79 (dd, J 12.9, 5.8, 18H); 1.39 (mn 4H); 1.24 3H); 1. 17 3H).

EXAMPLE 44 1.

2 -Dihydro- 2 2 4 -trimnetbylindo or3.2- guino fine (Compound 44. tu r 6o Scee IV, where R 1 6 X=NI-fl 2 -Aminocarbazole (structure 15 of Scheme TV. where R- 6 2 -Nitrocarbazole [Mendenhall, G. Smith, P. A. S. Org. Syn. Coll. Vol. 5 1973, 829, the disclosure of which is herein incorporated by reference] (structure 14 of Scheme IV, where R 1 6 =141 X=NH) (1.0 g, 4.7 mmol) in 50 mL of ethyl acetate was hydrogenated over 10% Pd/C mg) under an atmosphere of hydrogen for 1.5 h at rt giving, after filtration through CeliteTM, 840 mg (100%) of 2 -aminocarbazole. Data for 2 -amidnocarbazole: I H NMR (400 MI-Iz, CDC13) 7.94 I 9.0, 1H), 7.83 J 8.0, 1H), 7.80 (br s, 18), 7.35 (in, 2H), 7.15 (dd, J 8.2, 1 6.67 J 1. 8, 1 6.58 (dd, J 9.0, 1.8, INR), 3.73 (br s, 2H).

1.

2 -Dihydro-2.2.4trethy-lindofor. Zglq uino~ne oond 144. strte 1I ofSAm IV, where R I- 6 X=N~H: A solution of 2 -aminocarbazole (structure 15 of Scheme WV, where RI- 6 X=NH) (840 mg, 4.7 mmol) in 10 mL of acetone and one crystal (10 mg) of iodine was heated at 1 00*C for 14 h in a sealed tube. The acetone was removed in vacuo to afford a dark oil which was purified by silica gel chromatography (silica gel, hexane/ethyl acetate, 8:2) to afford 738 mg of Compound 144 and 121 mg of 1,2-dihydro-2,2,4trimethyidolo[2,3-flquinoline (structure 17 of Scheme IV, where R 1 6 X=NH) (71% combined yield). Data for Compound 144: IH NMR (400 MHz, CDCl3) 7.90 J 18); 7.80 (br s, 18), 7.66 (br s, 18), 7.23 (br s, 2H), 7.12 (in, 11H), 6.30 (br s, 18), 5.32 (br s, 18), 3.75 (br s, 18), 2.13 3H), 1.39 18).

EXAMPLE 5-ty-tmdivr-..~ ethlindoo23.iuinoline monZ4. tutr 9 of Scheme VIII. where RI- 6 H. R 7 =Et) To a suspension of sodium hydride (60% in mineral oil, 16 mg, 0.405 minol) in I mL of THF at 0 0 C was slowly added l, 2 -dihydro-2,2,4-trimethylindolo[23-Ac quinoline (structure 28 of Scheme VEII, where R 1 6 (30 mg, 0. 116 inmol) in 1 mL of THF and the resulting mixture was stirred at 0 0 C for 30 minutes. lodoethane (9.3 mL, 0. 116 mmol) was added dropwise via a midcrosyringe and the reaction mixture was brought to rt and stirred for 16 h.

The reaction was quenched with 1 mL of water and extracted with 10 mL of ethyl acetate.

The organic phase was dried (Na2SO4) and concentrated in vacua to a residue that was purified by flash chromatography (silica gel, hexane/ethyl acetate, 9: 1) which gave 27 mg (8 1 of Compound 145. Data for Compound 145: 1H NMR (400 MI-z, CDCI3) 7.81 (d, J 7. 1, 1IH), 7.63 J 8. 1; 1IH); 7.34 J 8.0, 1I-H); 7.25 (br s, I1-H); 7.12 (apparent t, J 7.4, 1H); 6.51 (br s, 1H); 5.38 (br s, IH); 4.25 J 7.0, 4.22 (br s, IN); 2.16 (s, 3H); 1.26 6H); 0.91 J 7.0, 3H).

EXAMPLE 46 6-(3-Chlorophenfl)- l.

2 -dihydro-2.2.4-trirnethylguinoline (Compound 146. structur 4 of Scheme where R=3-chlorophenyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (91 mg, 0.29 mmol) and 3 -bromochlorobenzene (33.6 mg, 0.29 mmol). The crude product was isolated and purified by silica gel chromatography (50 mL silica, ethyl acetate/hexane) and PTLC (reverse phase, 1000 pIrm plate, 95% methanol/water) to yield 54 mg (8 of Compound 146. Data for. Compound 146: IfH NMR (400 MHz, acetone-d6) 7.56 J 4.0, 1H); 7.50 J 8.0, 114); 7.34 (apparent t, J 8.0, IH); 7.31 J 4.0, 1H); 7.24 (dd, J 8.0, 4.0, 1iH); 7.23 (dd, J 8.0, 4.0, IN); 6.57 J IN); 5.60 1H); 2.03 3H); 1.27 6H).

EXAM'PLE 47 6-(3.5-Difluorophenyl)- 1 2 -dih dr -2,2 4- rethy uo- ii Copud 4.stutre4o Scheme ff. where R 1 This compound was prepared according to General Method 2 (EXAMPLE from Compound 9 (59.7 mg, 0. 19 mrnol) and I- bromo-3,5-difluoro benzene (21.6 mL, 0. 19 mmol, Lancaster) a crude reaction mixture was isolated and purified by HPLC (reverse phase, semni-preparative column, 85% methanol/water) to yield 5.6 mg of Compound 147 and 0.9 mg of Compound 148 (EXAMPLE 48) combined yield). Data for Compound 147: 1 H NMR (400 MHz, aceto ne-d6) 7.34 J 1 7.28 (dd, J 8.4, 2.3, INH); 7.19 (in, 6.80 (mn, I 6.57 J 8.3, I 5.47 I 5.3 8 I 2.04 3 H); 1.28 6H).

EXA ME 48 6-(3-Fluorophenv 1 .2-dih d-11.~rnthlunln (CmonA4.srcue4o Scheme 11, where R-uophnl This compound was obtained along with Compound 147 as described above (EXAMPLE 47). Data for Compound 148: IH NMR (400 MHz, acetone-d6) 7.45 J 8.0, 1H); 7.35 (mn, 2H); 7.26 (dd, J= 7.7, 2.2, IN); 7. 10 J= 2.0, lH); 7.03 (dd, J= 8.1, 2.0, IH); 6.54 J 8.2, 111); 5.35 111); 5.29 IN); 1.97 3H1); 1.28 6H).

EXAMPLE 49 1.

2 -Dihdio-2.2.4-riethyl.44.vrd1)gun~n (Cmo' I4"srcue fShm This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (23.8 mg, 0.07 mrnol) and 4 -broinopyridine hydrochloride (14.5 mg, 0.07 inmol, Aldrich). The crude product was isolated and purified by silica gel chromatography mL silica, 5% ethyl acetate/hexane) and recrystallized twice (hexane/CH-2C12, then Et2O) to afford 7.3 mg of Compound 149. Data for Compound 149: 'H NMR (400 MHz, acetone-d6) 8.59 J 6.0, 2H); 7.55 (mn, 211); 7.45"(d, J 2.2, 1iH); 7.40 (dd, J 8.3, 2. 1, 1 6.60 J 8.2, 1IH); 5.40 I1H); 2.06 3H1); 1.30 611).

EXAMPLE 6 -(3-Cvanophenyl)- l.

2 dihydo 4trmth luinoline (Compund 5 structure 4 of Scheme where Rls3-canohnl This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (81.4 mg, 0.26 mmol) and 3-bromobenzonitrile (46.6 mg, 0.26 mmol, Lancaster). The crude product was isolated and purified by silica gel chromatography mL silica, 5% ethyl acetate/hexane) to afford 51.6 mg (74% of Compound 150 as pale yellow crystals. Data for Compound 150: IH NMR (400 MHz, acetone-d6) 7.94 J 1. 1, IH); 7.88 (in, lH); 7.56 (mn, 2H); 7.38 J= 2.2, 7.31 (dd, J 8.3, 2.2, 2H); 6.59 J 8.3, 1H); 5.42 18); 5.38 2.01 3H1); 1.28 6H).

EXAMPLE 51 6-(3.5-Dichlorophenyl)- 1 .2-dihydro-2.2.4-triniethylguino line (Compound 151. structure 4 of Scheme U1. where R 1 This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (40.4 mg, 0. 13 mmol) and I1-bromo-3,5-dichlorobenzene (28.7 mg, 0. 13 mmol, Aldrich). The crude product was isolated and purified by silica gel chromatography mL silica, 5% ethyl acetate/hexane) to afford 32 mg of Compound 151. Data for Compound 151: IH NMR (400 MHz, acetone-d6) 7.53 J 2H); 7.34 J 1.8, 11H); 7.27 (mn, 211); 6.57 J 8.3, 11H); 5.3 8 I1H); 2.04 3H); 1.28 6H1).

EXAMPLE 52 6-(2.3-Difluorophenyl)-1I.2-dihydro-2.2.4-tirnethylg~uinoline (Compound 152. structure 4 ot Scheme IT, where R=23-difluorophenyfl This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (28.7 mg, 0.09 inmol) and 1-bromo-2,3-difluorobenzene (10 pL, 0.09 mmol, Aldrich). The crude product was isolated and purified by silica gel chromatography (75 mL silica, 5% ethyl acetate/hexane) to afford 16 mg of Compound 152. Data for Compound 152: IH NMR (400 MHz, acetone-d6) 7.21 (in, 5H); 6.57 J 8.3, 1 H); 5.37 18); 1.99 38); 1.28 6H).

EXAMPLE 53 I 2 -Dihydro-2.2.4-trimethyl-6-(pentafluorophenyl)guino line (Compound 153. structre 4 f Schem~e HI. where RIE=pentafluorophenyfl This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (55.3 mg, 0.17 mmol) and 1-bromopentafluorobenzene (21.7 mL, 0.17 mm-ol, Lancaster). The crude product was isolated and purified by silica gel chromatography mL silica, 5% ethyl acetate/hexane) to afford 2.5 mg of Compound 153. Data for Compound 153: 1H NMR (400 MHz, acetone-d6) 7.11 J 1.2, ifH); 7.03 (dd, J 1.6, 6.60 KdJ= 8.3, 111); 5.57 1.95 3H1); 1.29 6H).

EXAMPLE54 1 2 -Dihydro- 2 .2.4-trimethyL-6-[ 4-(trifluoroacetylphenyllguino line (Compound 154.

structr 4 of Scheme HI. where R '=4-(trifluoroacetyvflphenyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (49.1 mg, 0.15 mmol) and 4 '-bromo-2,2,2-trifluoroacetophenone (23.5 p.L, 0. 15 mmnol, Aldrich). The crude product was isolated and purified by silica gel chromatography (75 mL silica, hexane) to afford 50 mg of Compound 154. Data for .Compound 154: 1 H NMR (400 MHz, acetone-d6) 8.06 (dd, J 8.5, 0.8, 7.80 (dd, J 1.7, 2H); 7.41 (m 2H); 5.41 IfH); 4.97 IfH); 2.04 3H1); 1.27 611).

1 2 -Dihydro-2.2.4-trimethyl-6(1.3-pyrimid--5s-y)guinoine (Compound 155. structure 4 of Scheme where R 1 This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (74.4 mg, 0.23 mmol) and 5-bromopyrimidine (37.1 mg, 0.23 minol, Aldrich).

The crude product was isolated and purified by recrystallization (Et2O/hexanes) to afford 2.1I mg of Compound 155. Data for Compound 155: 1H NMR (400 MHz, acetoned6) 8.97 8.94 2H); 7.39 J 1.9,1WH); 7.32 (dd, J 8.4, 2.2, 6.63

J

8.3, 1H); 5.39 2.05 3H); 1.29 6H).

EXAM6PLE 56 6 3 -CyanophenyD- 1.2.34tetrhyo22.iet hylquino line (Compound 15.srcture of Scheme I were R3-canqxphen1l) A dry 10 mL r.b. flask was charged with Compound 150 (EXAMPLE 50) (16.7 mg, 0.06 minol) and 0.5 mL ethyl acetate. To this solution 10% Pd/C (20 mg) was added. The flask was stirred under an atmosphere of hydrogen for I h. The reaction was then purged with nitrogen until all of he hydrogen had been removed from the flask. The product mixture was filtered through a plug of cotton and CeliteTm to remove the solids, rinsing with ethyl acetate (50 mL). The crude material was purified by HPLC (reverse phase, ODS semnipreparatory colunm, 85% methanol/water, 3.0 mL,/min). The major peak was isolated and identified as Compound 156 (1.8 mg, I1I%) by NMR. Data for Compound 156: 1Hi NMR (400 MHz, acetone-d6) 7.93 J 1.3, 1H); 7.88 (in, 1H); 7.55 2H); 7.51 (d J 1.4, 1H); 7.28 (dd, J 8.7, 1.4, 1W); 6.59 J 8.4, 1W); 2.95 (in, 1H); 1.80 (dd, J 12.8, 5.4, 1W); 1.39 (mn, 4H); 1.25 3H); 1.19 3H).

EXAMPLE 57 5,8-Difluoro- l.

2 -dihy(dro-2 2 4-trimethylindeno 1 2 -glguinoline (oMound 157 structure 16 of Scheme IV. where R 2

=R

5 F.R R 4 R= XC 4 7 -Difluoro-2-fluorenamine (Nainkung, M. Fletcher,T. Wetzel, W. H. Derivatives of Fluorene. XX. Fluorofluorenes. V. New Difluoro- 2 -acetamidofluorenes for the Study of Carcinogenic Mechanisms. J. Med. Chem. 1965, 8, 55 1-554, the disclosure of which is herein incorporated by reference). To a 25 ml, round-bottomed flask containing 4,7difluoro-9-oxo-2-fluorenamine (EXAMPLE 32) (158.5 mg, 0.686 mmol) in 4.25 mL glacial acetic acid was added red phosphorous (425 mg, 13.7 rnmol, 20 equiv) and 57% aqueous HI (0.51 mL). The mixture was heated to reflux for 40 h, then evaporated to near-dryness by distillation. Boiling water (5 mL) was added, and the hot mixture was filtered. Upon addition of 10% NH 4 OH (20 mL), a white precipitate formned, and was filtered, washed with water, and dried under vacuum to afford 127 mg of 4 7 -difluoro-2-flaorenamine as a white solid, mp I I19-120 0 C (lit. mp 119.5-121 0 Data for 4 7 -difluoro-2-fluorenanmjne: IH NMR (400 MHz, CDCI 3 7.70 (dd, J 8.4, 5.2, 1 7.15 (dd, J 9.0, 2.0, 1 7.03 (app dt, J 9.0, 2.0 j1 6.63 I1-H), 6.39 (dd, J =11.6, 1.7, 1 3.83 2 3.80 (br s, 2 H).

5.8-Difluoro-1I.

2 -dihydro-2.2.4-trimethylinden[ I 2- iuinoline Compud17 tutr 16 of Scheme IV, where R 2

=R

5

R

3

=R

4

=R

6

X=CH

2 This compound was prepared by General Method 3 from 4 7 -difluoro-2-fluorenan-une (127 mg, 0.58 mmol). Purification by flash column chromatography (silica gel, hexanes ethyl acetate, gradient elution) afforded 42 mg of the less polar angular Compound 158 (EXAMPLE 58) as a yellow oil, along with 63 mg of the more polar Compqound 157 as a white solid. Data for Compound 157: IH NMR (400 MlHz, CDC1 3 7.68 J1= 8.4, 5.3 1 H, 7.12 (dd, J 8.8, 2.3, 1 H, 7.00 (apparent dt, J 9.1, 2.3, 1 H, 6.44 I H, I11-H), 5.30 1 H, 3.86 (br s, 1 H, NH), 3.78 2 H, 10-H), 2.22 (dd, J 6.7, 1.5, 3 H, 4-CH 3 1.28 6H, 2-(CH 3 2 EXAMPLE 58 7.1 0-Difluoro- l.

2 -dihydro-2.2.4t-trimethylindenor2. -flguino line Comp nd 58.stu cr 17 of Scheme IV. where R 2

=R

5

R

3

R

4

=R

6

X=CH

2 Compound 158 was obtained along with Compound 157 as described above (EXAMPLE 57). Data for Compound 158: 'H NMR (400 MHz, CDC1 3 7.69 (dd, J 8.3, 5.3, 1 H, 6- 7.11 (dd, J 8.7, 2.4, 1 H, 7.09 (apparent dt, J 9.1, 2.4, 1 H, 6.23 J 11.0, 1 H, 11-H), 5.34 1 H, 4.08 2 H, 3.84 (br s, 1 H, NH), 2.23 3 H, 4-

CH

3 1.26 6 H, 2-(CH 3 2 EXAMPLE 59 1.2-Dihydro-2,2,4-trimethyl-5-coumarinof3.4-flquinoline (Compound 159, Scheme IX) The intermediate 2 -nitro-3,4-benzocoumarin was prepared by a modified literature procedure. See J. Org. Chem., 15 503 (1979), the disclosure of which is herein incorporated by reference. To a flask charged with 2 -biphenylcarboxylic acid (5 g, mmol) was added 7 mL of 70 nitric acid and the resulting yellow slurry was stirred at rt for 30 min. To this slurry 20 mL of fuming nitric acid was introduced dropwise, giving rise to a clear yellow solution. The reaction mixture was stirred at rt for 15 h, and was then poured into ice water (100 mL). The crude mixture was extracted with ethyl acetate (3 x mL) and the combined extracts were washed with water (2 x 20 mL) and brine (2 x 20 mL).

Removal of solvent under reduced pressure afforded a crude yellow solid, which was a 2:1 mixture of two regioisomers. The mixture of the dinitrobiphenylcarboxylic acids was dissolved in 80 mL of DMA and the solution was heated at reflux for 12 hours. The reaction was cooled to rt and diluted with 20 mL of water. The desired product precipitated from the solution upon standing at rt overnight. Filtration of the mixture afforded 2.9 g of 2 -nitro-3,4-benzocoumarin, which was used directly in next reaction without further purification. 2 -Nitro-3,4-benzocoumarin (2.9 g, 12 mmol) was dissolved in 600 mL of ethyl acetate and treated with 10% Pd/C (1.0 g, 0.94 mmol) and stirred under a hydrogen balloon for 24 h. Filtration of the catalyst and removal of solvent afforded 2.2 g of 2amino-3,4-benzocoumarin as a yellowish solid. An Ace-Thred pressure tube charged with 2 -amino-3,4-benzocoumarin (2.2 g, 10.4 mmol), iodine (0.8 g, 3.1 mmol) and acetone (150 mL) was sealed. The tube was heated in an oil bath at 80-120 OC for 24 h and then cooled to rt. The dark reaction mixture was concentrated under reduced pressure and the crude residue was purified by silica gel chromatography (hexane/EtOAc, 4/1) to give 1.5 g of Compound 159 as a yellow solid. Data for Compound 159: mp 190-191 oC; ER (KBr) 3352, 2966, 2924, 1712, 1626, 1450, 1356, 1251, 1205; IH NMR (400 MHz, CDC13) 7.90 J 7.8, 1 7.78 J 8.4, 1 7.38-7.22 3 7.01 J 8.4, 1 5.58 1 4.31 (br s, 1 2.12 3 1.33 6 13 C NMR (100 MHz, CDC1 3 160.3, 150.5, 145.7, 132.4, 131.6, 128.4, 124.2, 122.0, 121.4, 121.2, 119.3, 118.4, 117.2, 50.8, 29.9, 28.6; Anal. Calcd for C19H 17 NO2: C, 78.33; H, 5.88; N, 4.81. Found: C, 78.19; H, 6.12; N, 4.52.

EXAMPLE (R/S)-5-Butyl-1.

2 -dihydro-2.2.4-trimethyl_5H-chromeno r3.4-quinoline (Compound 160, structure 32 of Scheme IX where R=n-butvl) GENERAL METHOD 5: Preparation of compounds of structures 32 and 33 from Compound 159. This transformation involved a two step sequence: addition of a nucleophile (either a commercial reagent or prepared in situ from a metal-halogen exchange reaction), followed by reduction of the resulting cyclic hemiacetal. To a solution of an aryl bromide compound in THF (0.1-0.3 M) at 78 oC was slowly added 1.1 equiv. of n-BuLi (as a hexane solution) and the resulting reaction mixture was allowed to stir at -78oC until the anion was formed. A yellow solution (0.2-0.5 M) of Compound 159 in THF was cannulated into the above solution and the resulting dark red mixture was slowly allowed to warm. As soon as the red color faded (around 30 oC), the reaction was quenched with water to give a light yellow solution. The reaction mixture was extracted with ethyl acetate and the combined extracts were washed with brine. Removal of solvent under reduced pressure and purification of the crude residue on a silica gel column using a 1:3 mixture of ethyl acetate and hexane as eluents afforded the hemiacetal intermediate as a yellow oil. To a solution of the hemiacetal intermediate in dichloromethane (0.1 M) at 78 0 C was added equiv of trifluoroacetic acid and triethylsilane (or, alternatively, 2-3 equiv of boron trifluoride etherate and 5-6 equiv of triethylsilane) and the resulting slurry was allowed to warm to rt, giving rise to a dark green solution. The mixture was allowed to stir at rt or reflux in some cases, until the reaction went to completion. The reaction was then quenched with 5% NaOH (aq) and was extracted with ethyl acetate. The combined extracts were washed with brine and concentrated. The crude mixture was purified on a silica gel column using a 1: 5 mixture of ethyl acetate and hexane as eluents, affording the desired product in moderate yield. A second silica gel chromatography was needed in several cases to remove the silane oxide and/or separate the isomers of structures 32 and 33 using a 1:2 mixture of dichloromethane and hexane as eluents.

(R/S)-5-Butyl- 1.

2 -dihydro-2,2,4trinmethvl-SHchromeno r3.4-flquinoline (Compound 160, structure 32 of Scheme IX where R=n-butvl) This compound was prepared by General Method 5 from n-BuLi (1.6 M, 0.2 mL) and Compound 159 (50 mg, 0.17 mmol) to afford 40 mg of Compound 160 as a colorless oil. Data for Compound 160: IR (neat) 3388, 2980, 1593, 1468 and 1435 cm-l; IH NMR (400 MHz,

CDCI

3 7.62(d,J= 7.8, 1 8.3, 1 7.14 7.8, 1 6.98 J= 7.8, 1 6.92 J 7.8, 1 6.59 J 8.3, 1 5.88 (dd, J 9.8, 3.1, 1 5.49 (s, 1 3.88 (br s, 1 2.25 3 1.90-1.79 1 1.55-1.25 5 1.28 3 H), 1.20 3 0.84 J 7.3, 3 H).

EXAMPLE 61 12-Dihydro-2.2,4-trimethyl-5-phenl-5H-chromeno34-fluinolin (Compound 161, structure 32 of Scheme IX. where R=phenyl) This compound was prepared by General Method 5 (EXAMPLE 60) from bromobenzene (0.15 mL, 1.4 mmol) and Compound 159 (50 mg, 0.17 mmol) to afford mg of Compound 161 as a colorless oil, along with 6 mg of Compound 162 (EXAMPLE 62). Data for Compound 161: IH NMR (400 MHz, CDC13) 7.53 J 7.8, 1 7.50 J 8.2, 1 7.22-7.12 5 7.00 J 7.8, 1 6.92 1 6.88 (t, J 7.8, 1 6.83 J 7.8, 1 6.69 J 8.2, 1 5.46 1 3.92 (br s, 1 H), 1.99 3 1.29 3 1.26 3 H).

EXAMPLE 62 (RIS)- I.

2 3 4 -Tetrahydro-2 2-dimethy-14 xtyi mn[.4flguinoline (Compound 162. s!utr 3fShm IX. where R phenyl) This compound (6 mg, 10%) was obtained along with Compound 161 as described above (EXAMPLE 61). Data for Compound 162: 1 H NMR (400 MI-z, CDCI 3 7.53 J 7.3, 1 7.51 Kd J 8.4, 1 7.24-7.12 (in, 5 6.97 J 7.3, 1 6.87 J 7.3, 11H), 6.80 J 7.3, 1 6.64 I 6.59 J 8.4, 1 4.93 I 4.64 1 H), 4.09 (br s, 1 2.44 J =12. 1, 1 2.18 J 12. 1, 1 1. 34 3 H) and 1. 13 3

H).

EXAMPLE 63 (R/S-5-(4-Chloropheny. -i r- ~rm (Compound 163, structure 32 of Scheme IX. where R 4chlorophenul) This compound was prepared by General Method 5 (EXAMPLE 60) from 4bromochloro benzene (1.4 g, 7 mrnol) and Compound 159 (0.5 g, 1.7 minol) to afford 0.27 g of Compound 163 as a white solid, in addition to 60 mng of Compound 164 (EXAMPLE 64). Data for Compound 163: mp 139-140 OC; IR (KBr) 3371, 2964, 1593, 1469, 1435 cm- 1 1 H NMR (400 MHz, acetone-d 6 7.59 J 1 7.56 J 8.4, 1 7.24 J 9.1, 2 7.21 J= 9.1, 2 6.98 J 7.8, 1 6.92 1 H), 6.86 J 7.8, 1 6.83 J 8.4, 1 6.77 J 7.8, 1 5.54 (br s, I 5.48 1 1.99 3 1.26 3 1.24 3 H).

EXAMPLE 64 (R/S)-544- h1rpenp. I 2 3 4 -tetahvd--'2.2)imethI4.mtyiee chromenor3.4-flpuinoline ompound 164. structure. 33 of Scheme IX. where R=4chlorophenyl) This compound (60 mg, was obtained along with Compound 163 as described above (EXAMPLE 63). Data for Compound 164: 1 H NMR (400 MHz, CDC1 3 7.53 J 1 7.51 J 8.3, 1 7.18 J 2 7.15 I 8.7, 2 6.99 J 7.7, 1 6.90 J 7.7, 1 6.79 J 7.7, 1 6.59 I 6.58 J 8.3, 1 H), 4.93 I 4.59 1 4.09 (br s, 1 2.43 J 12.3, 1 2.18 J 12.3, 1 H), 1.34 3H) 1. 13 3H).

EXAMPLE (R/S)-5-(4-FluorophenIY.L. 2 -dihydro-2.2.4-r JehI5-ronf3k A-fuinoline Compound 165. structure 32 of Scheme IX, where R=4-fluorophenyl) This compound was prepared by General Method 5 (EXAMPLE 60) from 4fluorophenylmagnesium. bro mide (1.0 M in THF, I mL) and Compound 159 (30 mg, 0. 1 mmol) to afford 15 mg of Compound 165 as a colorless oil. Data for Compound 165: ERI 3360, 2962, 1707, 1601, 1506, 1469, 1221, 1157 cn- 1 IH NMR (400 MHz, acetone-d 6 7.60 J 7.8, 1 7.56 J 8.3, 1 7.26 (dd, J 8.7, 5.7, 2 H), 6.98 J 8.7, 2 6.97 J 7.8, 1 6.92 1 6.87 J 7.8, 1 6.83 J 8.3, 1 6.76 J 7.8, 1 5.54 (br s, I 5.47 I 1.99 3 1.26 3 H), 1.24 3 H).

EXAMPLE 66 (R/S-5-(4-Acetylpheyl.

(Cofmound 166. structure 32 of Scheme IX. where R4-cetlIhen 1) This compound was prepared by General Method 5 (EXAMPLE 60) firom 2-(4bromophenyl)-2methyl3-dioxane (219 mg, 1.0 mmol) and Compound 159 (30 mg, 0.1 mmol) to afford 4.5 mg of Compound 166 as a colorless oil Data for Compound 166: IH NMR (400 MHz, acetone-cl 6 7.83 J 8.3, 2 7.60 J 1 57 J 8.4, 1 7.36 J 8.3, 2 6.99 I 6.98 J 7.6, 1 6.89-6.79 (in, 3 5.56 (hr s, 1 5.50 1 2.49 3 2.00 3 1.28 3 1.25 3 H).

EXAMPLE 67 (RIS)- 1.-i n cr o34 J1 (Comijoun 167 structure 32 of Scheme DC. where R4-mthlphenyl) This compound was prepared by General Method 5 (EXAMPLE 60) from 4 -bromotoluene (171 mg, 1.0 nol) and Compound 159 (20 mg, 0.07 mmol) to afford 15 mg of Compound 167 as a colorless oil. Data for Compound 167: IR (KBr) 3362, 2964, 1707, 1593, 1469, 1437, 1259, 1169 cm- 1 IH NMR (400 MHz, acetone-d 6 7.58 J 7.9, 1 7.54 8.5, 1 7. 10(d, J 2H), 7.00o(d, J 8.0, 2H), 6.97 (tJ7.9, 1 6.89 1 6.84 7.9, 1 6.81 J 8.5, 1 6.75 J 7.9, 1 5.47 (bs, I 5.45 1 2.19 31-H), 1.99 3 1.25 3 1.23 311).

EXAMWPLE 68 o13S 34fioline (Compound 168, structure3ofSem .whr

R=

4 -methoxvpenvl This compound was prepared by General Method 5 (EXAMvPLE 60) from 4 -bromoanisole (187 mg, 1.0 mmol) and Compound 159 (10 mg, 0.03 mmol) to afford 2 .5 mg of Compound 168 as a colorless oil. Data for Compound 168: IH NMR (400 MHz, acetoned 6 7.59 J 7.7, 1 7.54 J 8.4, 1 7.13 J 8.7, 2 6.95 J 7.7, 1 6.87 I 6.86 J 7.7, 1 6.81 J 8.4, 1 6.75 J 8.7, 2 H), 6.74 J 7.7, 1 5.47 (br s, I 5.45 1 3.69 3 1.99 3 1.25 3 1.23 3 H).

EXAMPLE 69 (RIS- 1.-Wcrmo.

flauinoline (Compound 169 suctur 32 of, Scheme TY. whr=4- This compound was prepared by General Method 5 (EXAMPLE 60) from 4bromobenzotrifluoride (130 mg, 1.0 mmol) and Compound 159 (20 mg, 0.07 mmol) to afford 10 mg of Comp ound 169 as a colorless oil. Data for Compound 169: IH NMR (400 MHz, acetone-d 6 7.6 1-7.56 (in, 4 7.45 J 8.3, 2 7.01 I 6.97 J 7.7, 1 6.86 J 7.7, 1 6.85 I 8.4, 1 6.81 J 7.7, 1 5.57 (br s, I 5.49 I 1.99 3 H 1.27 311), 1.25 3 H).

EXA vPLE (RIS) I i n (Complound 170 rtuire 2 ofScheme IX where R=thiohen-3.yI) This compound was prepared by General Method 5 (EXAMPLE 60) from 3bromothiophene (163 mg, 1 .0 mmol) and Compound 159 (8 mg, 0.03 mmol) to afford 1. 1 mng (11I%) of Compound 170 as a colorless oil. Data for Compound 170: IH NMR (400 MHz, acetone-d 6 7.60 J 7.3, 1 7.54 J 8.4, 1 7.31 (dd, J 5.0, 3.0, 1 7.08 J 5.0, 1 6.98 J 7.3, 1 6 .93 1 6.89 i 7.3, 1 6.88 J 3.0, 1 6.79 i 8.1, 2 5.48 (br s, I 2.06 3 1.25 3 '1.24 3 H).

EXAMdPLE 71 (Copond17. trctre32 of Shme h Re R-ehlphenl) This compound was prepared by optical resolution of Comnpound 167 via IIPLC using a chiral column, Chiracel OD-R, using a 9:1 mixture of methanol and water as the mobile phase. The optical purity of Compound 171 was determined by HPLC to be 99% [a] 2 0 D =-246 (MeQI-).

EXAMPLE 72 f-)-5-(-Coopenf. l.di ro2241e -th-LsH crwonor4 4 9Wone (Cmpun 1 2 srutue32ofScee hr =4-chl moph l) This compound was prepared by optical resolution of Compound 163 via HPLC using a chiral column, Chiracel OD-R, using a 9:1 mixture of methanol and water as mobile phase. The optical purity of Compound 172 was determined by HPLC to be 99% e.e.; [ctI 2 OpD 254 (MeON).

EXAMPLE 73 (Cmpun 1 3 srutu32 of Schem IX. whr t=-ehlhnvy) This compound was prepared by General Method 5 (EXAMPLE 60) from 3bromotoluene (171 mg, 1.0 mmol) and Compound 159 (15 mg, 0.05 mmol) to afford 3.6 mg of Compound 173 as a colorless oil. Data for Compound 173: 1 H NMR (400 Mliz, acetone-d 6 7.59 J 7.8, 1 7.54 J 8.4, 1 7.10-6.94 (in, 5 6.89 1 H), 6.85 J 7.8, 1 6.82 1 8.4, 1 6.77 J 8.0,.l 5.49 (br s, I 5.46 I 2.19 3 2.00 3 H 1. 26 3 1. 24 3 EXAMPLE 74 4 l5fl5-(-Chorohenl)- l.

2 3 4 -tetrahy-dro2.2.4-trimt-thyl-54-h,-----r* A34 flguinoline (Compound 174.tructure 34 of Scheme X.were Ra4,chorophenvl) Hydrogenation of Compound 163 (15 mg, 0.04 mmol) in the presence of 10% Pd/C afforded 12 mg of (R/S-41,5I)-5-(4..chlorophenyl1)l 2 3 4 -tetrahydro-2,2,4.jiethyl1 SH-chromeno[(3,4-.fquino line as a white solid in addition to 1.1 mg of Compound 176 (EXAMPLE 76) as a white solid. The enantiomers of (R/S- 4 l,50-5-(4-chlorophenyl)- 1,,,-erhdo224tiehy-Hcrrxo34Aunln were resolved via HPLC using a chiral column, Chiracel OD-R, using a 9:1 mixture of methanol and water as mobile phase (0.55 mL/min). A 10 mg sample of (R/S-41,5I-5-(4-chloropheny).123 tetrahydro2,2,4methyscromeno34unline afforded 3.1 mg of the first eluting, ()enantiomer (Compound 174) (24 mini), and 3.0 mg of the second eluting, enantiomer (Compound 175, EXAMPLE 75) (30 mini). The optical purity of Compound 174 was determined by HPLC to be >99% exe. Data for Compound 174: nip 158-159 0 C; IH NMR (400 MHz, acetone-cl 6 7.63 J 7.8, 1 7.53 J 8.5, 1 7.24 4 6.94

J

7.8, 1 6.87 J 7.8, 1 6.76 J 8.5, 1 6.68 J 7.8, 1 6.51 1 5. 10 (br s, I 3.25 (mn, 1 1.89 (dcl, J 13.5, 6.4, 1 1.76 (dd, J 13.5, 4.4, 1 1.30 3 1.21 3 0.83 J 7.3, 3 13 C NMR (100 MHz, CDCI 3 150.6, 144.5, 138.6, 134.0, 130.9, 130.5, 128.4, 127.6, 124.9, 123.2, 122.2, 121.9, 120.2, 118.0, 115.8, 74.5,50.0, 44.3, 31.6, 31.3, 27.5, 22.8. [cZ] 20 D =+287 (MeOH).

EXAMPLE 4 4LST-5-C-hl rophenyll-. l 3 4 teAhdr24hyscoieo 3 flauinol'ne (Cm oun 15 sttr 3 fSheme X where R= 4 -clrpenyl) This compound was prepared by resolution of (R/S- 4 I,5SO-5-(4..choropheny).

1,,,-erhdo224Mmthl5-hoeo34Aunln as described above (EXAMPLE 74) via HPLC using a chiral column, Chiracel OD-R, using a 9:1 mixture of methanol and water as mobile phase. The optical purity of Compound 175 was determined by HPLC to be 9 [aI] 20 D 260 (MeQH).

EXAMPLE 76 fR/S-4150).-( 4 -Chlorophe "l-I .!.-erhdo.4-trimethyl-5Hce eo [Iquino line (Compound V76, structure 35 of Sceev where R=4-chopenl This compound (1.1 mg, was obtained along with (R/S-41,5O)-5(4.

chlorophenyl)-1234ttrhdo224umty-Hcrmn (34jqioln as described above (EXAMPLE 75). Data for Compound 176: IH NMR (400 MHz, CDCI 3 7.54

J

7.6, 1 7.47 J= 8.4, 1 7.15 J= 6.5, 2 7. 10 J= 6.5, 2 7. 01 (t,J 7.6, 1 6.89 J 7.6, 1 6.83 J1 7.6, 1 6.59 J 8.4, 1 6.47 I H), 3.73 (br s, 1 2.82 (mn, I 1.76 (dd, J 13.5, 7.0, 1 1.73 (dd, J 13.5, 4.5, 1 H), 1.46 J 7.1, 3 1.36 3 1.19 3 13 C NMR (100 MHz, CDCI 3 150.5, 143.9, 138.4, 134.0, 130.3, 129.4, 128.6, 127.6, 124.2, 122.6, 122.1, 119.6, 118.0, 115.4, 74.4, 50.1, 42.9, 32.2, 31.8, 27.3, 22.3.

EXAM4PLE 77 (RISi)-5-(3.Chilorophenyly. l.

2 dihydro-.).. ty- chon r4-guoline (Compound 177 structure 32 of SceeI.weeR- hloohenyl) This compound was prepared by General Method 5 (EXAMPLE 60) from 3bro mochloro benzene (195 mg, 1.0 minol) and Compound 159 (20 mg, 0.07 minol) to afford 14 mg of Compound 177 as a colorless oil along with 2.3 mng of Compound 178 (EXAMPLE 78) as a colorless oil. Data for Compound 177: Iff NMR (400 M.Hz, acetone-d 6 7.61 J 7.8, 1 7.57 J 8.4, 1 7.28-7.18 4 7.00

J

7.8, 1 6.95 1 6.89 d, J 7.8, 1 6.84 J 8.4, 1 6.82 J 8. 1, 1 5.58 (be s, 1 5.49 1 2.01 3 1.27 3 1.25 3 H).

EXAMjPLE 78 (RDS-5(Chopen1. 3 4 tetra ydro22.dethvIjethyi e-Hchromeo34lunn (C m ound 178 stucturel 33 f Schem IX. where R=3chloropbenyl) This compound (2.3 mng, was obtained along with Compound 177 as described above (EXAMPLE 77). Data for Compound 178: 1H NMR (400 MHz, acetone-d 6 7.61 J 6.7, 1 7.59 J1 8.6, 1 7.29-7.20 (in,4 4 6.98 J1 6.7, 1 6.88 J 6.7, 1 6.79 J 6.7, 1 6.77 J 8.6, 1 H) 6.62 I 4.99 1 4.59 I H), 2.41 J 12.2, 1 2.27 J 12.2, 1 1.35 3 1. 13 3 H).

EXAM4PLE 79 (R/S)-5-(4-B3romophenyl)-.. l, ,A 2 dVdro-224i hylH.ciAJmeo3 4 .fgu in ne (Compound 179. structure 32 of SceeIw eeR=4-bromophenyl) This compound was prepared by General Method 5 (EXAMPLE 60) from l, 4 -dibromo benzene (250 mg, mmol) and Compound 159 (20 mg, 0.07 mmol) to afford 16 mg of Compound 179 as a colorless oil, along with 2.5 mg of Compound 180 (EXAMPLE 80) as a Colorless oil. Data for Compound 179: 1 H NMR (400 MHz, acetone-d 6 7.58 J 7.8, 1 7.55 J 8.4, 1 7.39 J 8.5, 2 7.16 (d J 8.5, 2 6.98 J 7.8, 1 6.90 (s, I 6.86 J 7.8, 1 6.83 J 8.4, 1 6.77 J 7.8, 1 5.54 (br s, 1 H), 5.47 I 1.99 3 1.26 3 1.23 3 H).

EXAMPLE (RIS'-54-Brmhey. etay .2 2-.d'ethyL..4..methylidene5Hchromeno[3.4-tl uinolne ComTound, 18'srcue3 fScheme IX. where R=4bom np T'his compound (2.5 mg, was obtained along with Comnpound 179 as described above (EXAMPLE 79). Data for Compound 180: 1 H NMR (400 M11z, acetoned6) 7.61 J 6.3, 1 7.59 J= 8.7, 1 M, 7.41 J= 8.5, 2 7.19 J= 8.5, 2 6.95 J 6.3, 1 6.86 J 6.3, 1 6.75 J 8.7, 1 6.57 1 4.97 (s, 1 4.80 1 2.40 J 12.2, 1 M, 2.26 J 12.2, 1 1.34 3 1. 11 3

H).

EXAMPLE 81 (R/').5-(3-B~romoPheniyl. m. W.dhdo224.r~etv.sc1o~o 3 n ine (Compound 181. structure 32 of Scheme IX where R--bromphenl) This compound was prepared by General Method 5 (EXAMPLE 60) from l, 3 -dibromo benzene (250 mg, mmol) and Compound 159 (15 mg, 0.05 mmol) to afford 13 mug of Compound 181 as a colorless oil, along With 2.0 mg of Compound 182 (EXAMPLE 82) as a colorless oil. Data for Compound 181: ER (neat) 3364, 2962, 1699, 1591, 1469, 143 cm- 1 IH NMR (400 MHz, acetone-d 6 7.61 J 7.8, 1 7.57 J 8.4, 1 7.38 1 7.36 J 8.5, 1 7.26 J 6.6, 1 7.19 J 1 H),.7.00 J 8.3, 1 6.98 1 H), 6.8 1-6.90 (in, 3 5.60 (br s, 1 5.50 I 2.01 3 1.27 3 1.25 3 H).

EXAMVPLE 82 (R/S)-5-(3-Bromophnl. l...~erhdo22ieh1iehldne5Hchro menor3.4.flguino line Copound 182. structure 33 of Scheme TY hreR3 kgomopheny) This compound (2.0 mg, was obtained along with Compound 181 as described above (EXAMPLE 8 Data for Compound 182: 1 H NMR (400 Mjjz, CDC1 3 7.55 J 1 7.51 J 8.4, 1 7.28 J 8.0,1 7.12 J 7.9, 1 H), 7.05 Kd J 7.8, 1 7.01 J 7.8, 1 6.92 J 7.4, 1 6.82 J 8.0, 1 H), 6.60 J= 8.5, 1 6.59 1 4.95 I 4.58 I 2.43 J 12.3, 1 2.19 J 12.3, 1 1. 32 3 1. 14 3 H).

EXAMPLE 83 (RIM'-5-034ihoopey'. dbdo2 2 4 pth-Lsqc.ono34Uunoin (Comound 183, strcture 32 of Schemne IX, where R 3 4-dichlorophenl) This compound was prepared by General Method 5 (EXAMPLE 60) from 1-bromo-3,4dichlorobenzene (226 mg, 1.0 mnmol) and Compound 159 (20 mg, 0.07 mmnol) to afford 8.7 mg of Compound 183 as a colorless oil. Data for Compound 183: IH NMR (400 MHz, CDCl 3 7.53 J 7.8, 1 7.50 J 8.3, 1 7.28-7.22 (mn, 2 7.20-7.12 (in, 2 6.92 J 7.5, 1 6.85 J 8.2, 1 6.83 1 6.71 J 8.4, 1 H), 5.48 1 4.0 (br s, 1 1.97 Cs, 3 1.30 3 1.26 3 H).

EXAMPLE 84 (R/S-l-5-(3-Brom-2.2..ptridvIth. COM Dound 184 structure 32 of Scheme IX. where R=3-brom -2-prci1 This compound was prepared by General Method 5 (EXAMPLE 60) from 2 6 -dibromopyricline (237 mg, inmol) and Compound 159 (20 ing, 0.07 mmol) to afford 20 mg of Compound* 184 as a colorless oil. Data for Compound 184: IH NMR (400 MHz, acetone-d 6 7.63 (dd, J 7.8, 1.5, 1 7.54 (d,1J 8.5, 1 M),7.52 J 1 7.39 J=7.9, 1 7.13 J 7.6, 1 7.03 J 7.6, 1 6.92-6.80 (mn, 4 5.52 I 5.48 1 2.03 3 1.25 3 1.24 3 H).

EXAMPLE (RIS)- I.

2 -Dih do5hdro -2 24- *ethl-SH-clrnen

F

3 4- lu 0 ne (Comp2ound 185. structure 46 of Scheme XIV. wher R=R 2

=H)

To a yellow solution of Compound 159 (20 mg, 0.07 mmol) in 1 mL toluene at -78 OC was added 0. 10 mL of DIIBALH (1.5 M in toluene, 0.075 mmol) and the resulting solution was stirred at -50 10 OC for 20 min. The reaction was quenched with water (1 mL) and was extracted with ethyl acetate (2 x 5 mL). Removal of solvent and chromatography of the crude residue on a silica gel column using 20% ethyl acetate/hexane as eluents provided 6 mg of Compound 185 as a colorless oil. Data for Compound 185: 1 H NMR (400 M.Hz, CDCl 3 7.71 J 7.5, 1 7.53 J 8.4, 1 7.19 J 1 7.08 J 7.5, 1 7.07 J 8.4, 1 6.85 J 5.8, 1 6.70

J

1 5.52 1 3.92 (br s, I 2.94 J 5.8, 1 2.37 3 1.32 3H) 1.20 3 H).

EXAMPLE 86 (RIS- 1.

2 -Dihydro Mehl~ehxvHho~o 3 gioe (Compound 186 strutue 47 of Sciheme XV whr;RF 2 H. 3 =methl) To a solution of Compound 185 (25 mg, 0.085 mmol) in MeOH (7 mL) was added a catalytic amount of p-toluenesulphonic acid (-0.25 mg) and the solution was allowed to stir at rt for 5 mmd. The reaction mixture was quenched with a 10% NaQH solution 1 mL) then partitioned between EtOAc (10 mL) and water (3 mL). The organic layer was separated and washed with water (3 x 1 mL) and brine (3 x I mL) then dried (Na2S 04) and concentrated in vacuo The crude product was purified on a 20 x 20 cm, 250 g~m. TLC plate, eluting with 25% EtOAc: hexane to afford 8.2 mg of Compound 186 as a colorless oil. Data for Compound 186: Rf 0.28 (silica gel, 25% EtOAc: Hexane);

IH

NMR (400 MHz, CDCI3) 7.69 J 7.7, 1 M, 7.48 J 8.3, 1 7.15 J 7.7, 1 7.05 (in, 2 6.65 J1 8.3, 1 6.35 I 5.50 I 3.90 (br s, 1 3.49 3 2.28 3 1.33 3 1.28 3 H).

EXM PLE 87 (RIS)- I1.2-rD iihvrlrn-o I n rel h 1 0 lcb me o 4-roo 5 ~i e o 187. structure 47 of Scheme XIV. where nI=R 2 =Hi X=O. R 3 =n-rpl This compound was prepared in a manner Similar to that Of Compound 186 (EXAMPLE 86) from Compound 185 (12 mng) and n-propanol to afford 7.2 mg of Compound 187 as a colorless oil Data for Compound 187: Rf 0.43 (silica gel, 25% EtOAc: hexane);

IH

NMR (400 MHz, CDC13) 7.68 J 7.7, 1 7.49 I 8.3, 1 7.17 (t i 7.6, 1 7.05 (mn, 2 6.65 J 8.4, 1 6.42 1 5.50 I 3.90 (br s, 1 3.84 (cit. J 9.2, 6.7, 1 3.54 (dt, J 9.3, 6.8, 1 2.28 3 1.49 (mn, 2 1.33 3 1. 18 3 0. 77 J= 7.4, 3 H).

EXAM4PLE 88 l 2 dh ro 2 4-leth Hchrom n r4- n o line Comound 8 structure 48 of Scheme' XJV whreRR 2 R4 5=R 6H) To a solution of Compound 186 (12 ing, 0.04 inmol) in dichloromethane (1.5 mL) at 00 C was added allyltrimethylsilane (0.005 inL, 0.062 iniol) and TMSOTf (0.01 mL, 0.057 inmol) under nitrogen. The reaction was stirred 5 h at rt. The reaction mixture was concentrated in vacuo and purified on a Rx20 cm, 250 jIM, TLC plate, eluting with 25 EtOAc in hexane to afford 2.3 mg of Compound 188 as a colorless oil. Data for Compound 188: Rf 0.50 (silica gel, 25% EtOAc: Hexane); 1 Hf NMR. (400 MHz, acetoned6) 7.67 J 7.4, 1 7.49 J 1 7.12 7.4, 1 6.98 J 7.4, 1 6.87 J 7.4, 1 6.70 J 8.3, 1 K) 5.96-5.85 (mn, 2 5.52 I 5.04 (s, 1 5.00 J 8.6, 1 2.54 (mn, 1 HU), 2 25 4 1.27 3fH), 1. 18 31H).

EXAMdPLE 89 (RIS-l l 2 Dhdo2.2.trthl.5proy 1 -5.-lunlne(o pud1 9 structure 32 f Scheme- X h reR nprp This compound was prepared by General Method 5 (EXAMPLE 60) from a 2.0 M solution of allylinagnesium chloride (0.2 inL, 0.4 iniol) in THF and Compound 159 (25 mng, 0.086 inmol) to afford 5.0 mng of Compound 189 as a yellow oil. Data for Compound 189: Rf 0.27 (silica gel, 25% EtOAc: Hexane); IH NMR (400 MI-z, CDCl3) 7.59 J 7.7, 1 7.43 J= 8.4, 1 7.13 J 7.7, 1 6.98 0,J 7.7, 1 6.91 J= 7.7, 1 6.57 J 8.4, 111), 5.89 J =10.4, 1 5.49 1 3.90 (br s, I 2.25 (s, 3 1.84 (in, 2 1.49-1.35 2 1.29 3 1.20 3 0.89 J 7.4, 3 H).

~EXAM4PLE 190, Structuare 32 of Schem hr =2prdl To a solution Of Compound 184 (10 mg, 0.023 mmol) in I mL of THIF at 78 O(C was added a 1 .0 M hexane solution of n-BuLj (0.05 mL, 0.07 mmnol), giving rise to a yellow then dark red solution. The mixture *was allowed to stir for 15 min and was quenched with water (I mL)- The mixture was extracted with ethyl acetate (2 x 10 niL) and the combined extracts were concentrated. Chromatography of the crude mixture on a silica gel column using ethyl acetate hexane as eluents afforded 7 mg of Compound 190 as a colorless oil Dat a for Compound 190: 1H NMR (400 MHz, acetone-4l) 8.48 (dd, J 5.4, 1.8, 1 7.61 (dcl, J 7.8, 1.6, 1 7.57 (td, J 7.8, 1.8, 1 7.54 J 8.3, 1 7.16- 7.13 (in, 2 6.99 (td, J 7.8, 1.6, 1 6.93 I 6.88 (td, J 7.9, 1.0, 1 FD, 6.80 J= 8.5, 1IH), 6.77 (dci,1J 7.9, 1. 1, 1IH), 5.48 (bs, 1 H)5.44 IlH), 1. 9 8 3H), 1.23 3 1.22 3 H).

EXAMPLE 91 t Fluorohenyl)..

(Comoun 19 srucur32 of Shm X hr =-loohnl T'his compound was prepared by General Method 5 (EXAMPLE 60) from 1-bromo-3fluorobenzene (175 mg, 1.0 mmol) and Compound 159 (20 mg, 0.07 nimol) to afford 12 mng of Compound 191 as a colorless oil, along with 1.5 mg of Compound 192 (EXAMPLE 92) as a colorless oil. Data for Compound 191: IH NMR (400 MHz, acetoned 6 7.60 J 7.9, 1 7.57 J 8.4, 1 7.26 (td, J 7.9, 5.9, 1 7.06 J 7. 1, 1 7.01-6.81 8 5.58 (br s, I 5.49 I 2.02 3 1.27 3 1 3H).

EXAM4PLE 92 chromenor3.4qqui line (Compund 192, srcue3 fShm X where R=3fluorohenyl) This compound (1.5 mg, was obtained along with Compound 191 as described above (EXAMPLE 91). Data for Compound 192: IH NMR (400 MHz, CDCI 3 7.54 J1 1 7.51 J= 8.5, 1 7.15 (td, J= 7.9, 5.9, 1 H)D,7.06-6.81 (mn, 6 6.61 1 H), 6.59 J 8.0, 1 4.94 I HI), 4.61 I 2.43 J 12.3, 1 2.19

J

12.3, 1 1.34 3 1. 14 3H.

EXAMPLE 9 (RIS)- 1.

2 -Dihydr 2 24..rjrnthv1.5. rllaginSH 193. structure 4ofShmX .wee Rb=R7-H. X=S. R =n-propvn1 To a solution of Compound 185 (12 mg, 0.04 rnol) in a 1: 1 mixture of I1propanethiol and methylene chloride (2 niL) was added 2 mg of p-TsOH at rt. The reaction was complete after 1 hour by TLC and was quenched with saturated aqueous NaHCO 3 The reaction mixture was extracted with EtOAc (2 x 10 mL) and the combined organic layers were washed with water and brine then dried over Na 2 S 04. Removal of solvent in vacuo followed by purification on a 5x.20 cm, 250 g~m, TLC plate, eluting with EtOAc:hexane, afforded 14 mng of Compound 193 as a yellow oil. Data for Compound 193: Rf 0.43 (silica gel, 25% EtOAc: Hexane); 1 H NMR (400 MHz, acetoned6) 7.69 J= 7.6, 1 7.49 J= 8.4, 1lH), 7.16 J= 7.6, 1IH), 7.05 J 1 6.93 J 7.6, 1 6.72 J 8.4, 1 5.51 1 2.79-2.73 1 2.62- 2.57 (in, I 2.47 3 1.70 (mn, 2 1.25 3 1.20 3 0.99 J1= 7.3, 3

H).

EXAMPLE 94 (RIS)- I dro5--4 tfx enu1 2 4 thne (Compound 194 stucture 32 ofSchemeT -X hrR=3-ethxvphenvl) This compound was prepared by General Method 5 (EXAMPLE 60) from 3 -bromoanisole (187 mig, 1.0 minol) and Compound 159 (20 mng, 0.07 minol) to afford 2.6 mg of Compound 194 as a colorless oil. Data for Compound 194: IH NMR (400 MHz, acetoned6) 7.59 J 7.8, 1 7.55 J 8.4, 1 7.12 J 7.9, 1 6.98 J 7.2, 1 6.91 I 6.88-6.7 1 (mn, 6 5.52 (br s, 1 5.47 11-1), 3.67 3 2.03 3 1.26 3 1.25 3 H).

EXAMPLE (RIS) I 2 -Dbyidro-2 2.4-trimethyl.5-. 3 -(nrfluoronithv1Iphen I meor~ finuinoline (Compound 195. structure.32 of Scheme IXJ where R=3- (trifluoromethLWhhenvl) This compound was prepared by General Method 5 (EXAMPLE 60) from 3bromobenzotrifluoride (225 mg, 1.0 mmol) and Compound 159 (20 mg, 0.07 mrnol) to afford 10 mg of Compound 195 as a colorless oil. Data for Compound 195: IH NMR (400 MHz, acetone-cl 6 7.61 J 7.6, 1 7.60 J 9.0, 1 7.56-7.45 (in, 4 7.04 1 6.98 J 7.6, 1 6.89-6.83 (mn, 3 5.60 1 5.55 1 2.02 3 1.27 6 H).

EXAMPLE 96 R/S)-S-(3-Fluoro-4-meth Ihen1. l-1 figuinotine (compound 196. structure 32 of Scheme IX, where R=3-fluoro-4inethylphenvi) This compound was prepared by General Method 5 (EXAMPLE 60) from 4-bromo-2fluorotoluene (189 mg, 1.0 minol) and Compound 159 (20 mng, 0.07 inmol) to afford 15 mg of Compound 196 as a colorless oil. Data for Compound 196: 111 NMR (400 MHz, acetone-d 6 7.60 J 7.8, 1 7.56 J 8.4, 1 7.08 J 7.9, 1 6.98 J 7.9, 1 6.94 J 8.0, 1 6.91 1 6.90-6. 80 (in, 4 5.55 (br s, I 5.48 (s, I 2.12 3 2.01 3 1.26 3 1.24 3 H).

EXAMPLE 97 (RIS-5-(4..Broo-3-pyridvl)- l.

2 -dih dro-2.2.4-trieth Hc rmenor34nguinioline (Compound 197 structure 32 of Schem IX.where R=4-bromo-3:pvivl) This compound was prepared by General Method 5 (EXAMPLE 60) from dibromopyridine (237 mng, 1.0 mxnol) and Compound 159 (20 mng, 0.07 minol) to afford 7 mg of Compound 197 as a colorless oil. Data for Compound 197: 1 H NMR (400 MHz, acetone-cl 6 8.24 J 1 7.62 (dd, J 8.0, 1.3, 1 7.57 J 8.4, 1 7.34 I 7.27 J 1 7.06 (td, J 7.4, 1.3, 1 6.97 1 6.94-6.88 (in, I 6.86 (d J 8.4, 1 5.68 (br s, 1 5.55 I 2.06 3 1.29 3 H), 1.28 3H).

EXAMPLE 98 1. 2 -Dihydro- 2 .2.4trmethvI5(3-pvd' -dl)Hc r nflA uioi (opon 198. structure 32 of Scheme .weeR3prdl) This compound was prepared in a manner similar to that of Compound 190 (EXAMPLE from Compound 197 (5 mg, 0.06 inmol) to afford 4 mg (quant) of Compound 198 as a colorless oil Data for Compound 198: IH NMR (400 MHz, acetone-cl 6 8.42 (mn, 2 H), 7.58 (dd, J 7.7, 1.3, 1 7.56 J 8.4, 1 7.18 J 5.9, 2 7.01 J 7.8, 1 6.95 1 6.89-6.83 (in, 3 5.61 (br s, 1 5.52 1 2.03 3 1.28 (s, 3 1.26 3 H).

EXAMPLE 99 (RIS)-5-(4-Chloro-3-fluoro~henyD-) 2- (rh choeo3 flguinoline (ompound 199. tructure 32 of Scheme IX where R= 4 -choro-3-florophenvl) This compound was prepared by General Method 5 (EXAMPLE 60) from bromofluorobenzene (209 mng, 1.0 mmol) and Compound 159 (15 mg, 0.05 inmol) to afford 13 mng of Compound 199 as a colorless oil. Data for Compound 199: IH NMR (400 MHz, acetone-cl 6 7.61 (dcl, J 7.7, 1.4, 1 7.57 J 8.3, 1 7.38 J 7.9, 1 H), 7.13 (dcl, I 10. 3, 1.8, 1 7.05 J 7.8, 1 7.00 (dd, J 7.7, 1.3, 1 6.93 I 6.91-6.81 (in, 3 5.62 (br s, 1 5.50 I 2.02 3 1.27 3 1.25 3

H).

EXAMPLE 100 (RIS- 1.2-Dhy-gr-2.ol,5-ter(Compound 200.

structure 32 of Schemre IX. wjhere ethvl) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 159 (8 mg) to afford 4.8 mg Of Compound 200 as a yellow oil. Data for Compound 200: Rf 0.44 (silica gel, 25% EtOAc: hexane), 'H NMR (400 MJ-z, CDC13) 7.60 J =7.8, 1 7.43 J 1IH), 7. 15(t,J1 8.0, 18H), 7.00 J= 8.0, 1 6.91 J 8. 1, 1 6.57 J= 8. 1, 18H), 6.60 KJ= 6. 1, 18H), 5.49 11-1), 3.85 (br s, I 2.26 3 1.38 J 6.6,38H), 1.27 38H), 1.22 31H).

EXAMPLE 101 (RIS) -ihdo.-e 2- structure 32 of Scheme IX. whee R=n-hexvl) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 159 (8 mg) and 1-iodohexane to afford 4.8 mg of Compound 201 as a yellow oil. Data for Compound 201: Rf 0.33 (silica gel, 25% EtOAc: Hexane); 1 H{ NMR (400 MHz, CDCI3) 7.59 J 7.8, .1 7.43 J 8.3, 1 7.12 J 7.6, 1 6.98 J= 7.4, 1 6.91 J= 7.7, 1 6.56 J 1, 18), 5.86 J= 7.4, 1IH), 5 .49 I 2.25 3 1.83 (in, 2 1.41 (mn, 3 1.28 3 1.20 3 0.84 J 6.7, 3 H).

EXAMPLE 102

L

2 -Dihydro-2 4tieth.H.clmeo3.uioie(op nd2 .srcte32f Scheme IX where

RFI)

To a solution of Compound 185 (EXAMPLE 85) (9.5 mg, 0.03 inmol) in mnethylene chloride (5 mL) maintained at -78 *C was added trifluoroacetic acid (10 mL) and triethylsilane (25 mL). The reaction mixture was allowed to warm to rt, quenched with I N NaOH (3 mL), and partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was washed with brine (3 x 3 mL), dried (Na2SO4), filtered, and concentrated.

Purification by PTLC (250 tpnm. 10/1 hexane/EtOAc) afforded 4.6 mg of Compound 202. Data for Compound 202: Rf 0.36 (silica gel, 25% EtOAc: Hexane); 'H NMR (400 MI-z, CDCI3) 7.58 J 8.0, 1 7.38 J 8.3, 1 7.15 J 8.0, 1 7.02 (t, J 8.0, 1 6.94 J 8.0, 1 6.58 J 8.3, 1 5.47 I 5.32 2 H), 3 9 0(brs,IH),2.10(s3H1.27(s 6 EXAMPLE 103 (Rig)- l.

2 -Dihydro -meth I A ~h~ttSH (Compound 203. structure 32 of Scheme EX. wher R=3-mhvbt) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 159 (13 mg) and l-bromo-3-methylbutane to afford I mg of Compound 203 as a yellow oil Data for Compound 203: TLC: Rf 0.29 (silica gel, 25% EtOAc: hexane); 1H NMR (400 MHz, CDCI3) 7.58 J 8.0, 1 7.43 J 8.3, 1 7.17 J 8. 1, 1H) 6.98 J= 8. 1, 1lH), 6.91 J= 7.9, 1 6.58 J 8.0, 1lH), 5.81 J 1 H), 5.49 1 3.90 (br s, I 2.24 3 1.80 (mn, I 1.44 (mn, 2 1.28 (in, 5 H), 1.21 3 0.79 J1= 6.2, 3 0.70 J 6.2, 3 H).

EXAMPLE 104 (RMS-5-(4-Chl tobuty. 1 L 2 -dihydro-2.4- nethyI-5H-ckrpflOQU 3 fLguinollne (Compound 204, structure 32 of "Scheme X. where R=4-chlorobutvl) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 159 (8.3 mg) and I-bromo-4-chlorobutane to afford 2.2 mg of Compound 204 as a yellow oil. Data for Compound 204: Rf 0.38 Csilica gel, 25% EtOAc: Hexane); IH NMR (400 MHz, CDCI3) 7.59 J 8.0, 1 7.43 J 8.3, 1 M, 7.13 Ct, J 7.7, 1 7.00 (t, j 8.4, 1 6.91 J 7.8, 1 6.57 Cd, J 8.3, 1 5.86 J 10.4, 1 5.49 1 3.90 (br s, I 2.25 Cs, 3 1.83 (mn, 2 1.41 (nm, 4 1.29 3 1.20 3 0.84 J= 7.3, 2H).

EXAMPLE 105 (R/S)-5-Benzyl-12 ih (Cmpun 205.--hrmwa4 structure 32 of Scheme KX. wher R=bnzyl) T'his compound was prepared by General Method 5 (EXAMPLE 60) from Compound 159 (16.8 mg) and benzylniagnesium chloride to afford 2.6 mg 16%) of Compound 205 as a yellow oil. Data for Compound 205: TLC: Rf 0.20 (silica gel, 25% EtOAc: Hexane); IH NMR (400 MHz, CDCI3) 7.66 J 7.8, 1 7.48 Cd, J 8.4, 1 7.30-7.15 (mn, 6 7. 10 Ct, J 7.8, 1 6.89 J 8.4, 1 6.61 J 8.4, 1 6.13 (dd, J 10.2, 3.4, 1 5.49 I 3.92 (hr s, I 3. 11 (dd, J 14.6, 10.2, 1 2.73 (dd. J 14.6, 3.4, 11-H), 2.31 3 1.54 3 H,1.29 3 H).

EXAMPLE 106 (80S-54(4-roobtyl-1 I.~ivr.. ehl-Hconor--jgioln (Compound 206. structure 32 of Scheme IX wer R=4-brmouDl This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 159 (13.7 mg) and 1,4-dibromobutane to afford 6.0 mg of Compound 206 as a yellow oil.

Data for Compound 206: Rf 0.22 (silica gel, 1:1 CH2CI2/hexane); IH NMR (400 MiHz, CDC1 3 7.59 J 8.0, 1 7.44 J 8.3, 1 7.12 J 7.7, 1 6.98 J 1 6.93 J 8.0, 1 6.57 J 8.3, 1 5.85 J 10.4, 1 5.49

I

3.90 1 2.25 3 1.83 (in, 2 1.41 (in, 4 1.29 3 1.20 3 H), 0. 84 J 7.3, 2 H).

EXAMPLE 107 9-Fuoro-I l 2 ih do-2 2.41-trimety1..5coun an B3.4.luioe( mp nd27 structure 41 of Schemie XI, where R I=H, R 2

FM

S-uoo~~netoxhevboro acd(trur 37 ofShemXlwhrR 1

.R

2 In a 200-mL flask, a solution of 2 -bromo-4fluoroanisole (Aldrich: 4.00 inL, 30.8 mmol) in THE (50 mL) was cooled to -'78'C (CQ9JIIPA). To this solution n-BuLj (Aldrich: 2.5 M in hexanes; 12.4 mL, 31 minol, 1.0 equiv) was added dropwise over a 30 min period. The reaction mixture was stirred at -78*C for 60 mini and treated with trimethyl borate (Aldrich: 10.5 mL, 92.4 inmol, 3.0 equiv). The reaction mixture was allowed to slowly warm to rt, stirred overnight (12 and cooled to 0 0 C (icefH2O). The solution was treated with HCl until the pH reached 6. The reaction midxture was poured into satU NH4CI (80 niL) and extracted with CH2CI2 (3 x 100 inL). The extracts were washed with sat'd NH4Cl (1 x mL), combined, dried (MgSO4), filtered through a pad of CeliteTM, and concentrated to afford 4.90 g of a white semid-solid. Data for 5-fluoro-2-methoxyphenylboronic acid: IH NMR (400 MHz, acetone-d 6 7.47 (dd, J 8.8, 3.3, 1 7.17 (mn, I 7.05 (dd, J 9.0, 3.9, 1 3.93 3 H).

Methyl~)xla (5-,uro2' (structure 39 of Scheme XI.

where R 1

R

2 In a 250-mL flask, a solution of methyl 2 bromo-5- nitro) bnzoate (Compound 38, Scheme XI) (Aldrich: 5.00 g, 19.2 mmol) in DME (60 mL) was treated with tetrais(triphenylphosphine)palladium (Aldrich: 0.67 g, 0.58 mmol, 3.0 mol%). The reaction mixture was stirred at rt for 10 min. A solution of 5-fluoro-2methoxyphenylboronic acid (4.90 g, 29 mrnol, 1.5 equiv) in EtQH (8 mL) was added, followed by 2.0 M Na2CO3 (29 ML, 58 mmol, 3 equiv). The reaction mixture was heated to 80 0 C for 6 h, cooled to Mt poured into 2.0 M Na2CQ3 (100 mL), and extracted with EtOAc (3 x 100 mL). The extracts were washed 'with brine (1 x 100 mL), combined, dried (MgSQ4), filtered, and concentrated to an orange oil Purification by SOC (hexane/EtOAc, 10/1) afforded 4.25 g of methyl (5-loo2-ehx--ito2bpey~abxlt as a yellow-orange solid. Data for methyl (5L'fluoro-2 methoxy-4-nitro-2 biphenyl)carboxylate: 1H NMR (400 MHz, CDC13) 8.73 J 2.4, 1 8.39 (dd, J 8.3, 2.4, 1 7.49 J 8.3, 1 7.09 (td, J 8.5, 3. 1, 1 7.00 (dd, J 8.5, 3. 1, 1 6.85 (dd, J 8.9, 3.2, 1 3.76 3 3.70 3 H).

5!uoro2tmethoxy-4.'nitro bih nl~oyic acid In a 200-mL flask, a solution of methyl (5 'fluoro-2 '-methoxy-4-nitro-2-bphenyl)carboxylate (4.24 g, 13.9 mmol) in THF (50 mL) was cooled to 0 0 C (icefH12O) and treated with EtOH (10 mL) and 20% KOH (10 mL). The reaction mixture was allowed to warm to rt and stirred overnight, acidified to pHlO (pH paper) with 10% HCI, and extracted with EtOAc (3 x 75 mL). The extracts were washed with brine (I x 80 mL), combined, dried (MgSO4), filtered, and concentrated to afford 3.68 g (9 of5fur-tehx--ito2bpeycroyi acid as a yellow solid. Data for 5'-fluoro-2'tmethoxy4..ntro2biphenylcarboxylic acid: 1H NMR (400 MHz, acetone-d 6 8.68 J 2.6, 1 8.46 (dd, J 8.5, 2.6, 1 7.68 J 8.5, 1 7.16 (in, 2 7.05 (dd, J 8.8, 4.4, 1 3.73'(s, 3 H).

6 -Fluoro-2-ni tro-34benzocoumarin In a 250-mL flask, a suspension of 5t-fluoro-2t.

methoxy-4nitro-2-biphenylcarboxyic acid (3.60 g, 12.3 mmol) in dichloroethane (30 mL) was treated with SOC12 (0.92 mL, 12.6 minol, 1.0 equiv) and heated to a gentle reflux for 90 min. The reaction vessel was cooled to 0 0 C (ice/H20) and AIC13 (0.91 g, 6.8 minol, 0.55 equiv) was added portion-wise. The reaction mixture was allowed to slowly warm to rt, stirred 5 h, and quenched with 5% HCI (100 mL). The crude product was extracted with EtOAc (4 x 150 rnL. The extracts were washed with sat'd NH4Cj (1 x 100 m-L), combined, dried (MgSO4), filtered, and concentrated to afford 3.19 g (quant) of 6-fluoro-2nitro-3,4-benzocoumiain as a yellow solid. Data for 6-loo2nto34bnoomrn IH NMR (400 MHz, DMSO-d 6 8.84 (di, J 2.3, 1 8.67 (in, 2 8.40 (di, J 9.2, 1 7.55 (in, 2 H).

2 -Amino- 6 -fluro3 4enzcou iin rcture 40 of Scheme XI. where R=H. R 2 In a 500-mL flask, a suspension of 6 -fluoro-2-nitro-3,4beurocouniarin (3.18 g, 12.2 inm-ol) in EtOAc (300 mL) was treated with 10% Pd/C (2.0 g) and AcOff (0.2 mL), and stirred under an atmosphere of H12 for I h. The reaction mixture was filtered and the solids rinsed with acetone (200 mL). Concentration of the filtrate afforded 2.19 g of 2 -amino-6-fluoro- 3 4 -benzocoumarin as a yellow solid. Data for 2-ndo6fur-34bnoomrn

IH

NMR (400 MI-z, acetone-cl 6 8.09 (di, J 8.6, 1 7.86 (dcl, J 9.8, 3.0, 1 7.55 (di, J 2.6, 1 7.33 (dci, J 9.2, 4.9, 1 7.28 (dci, J 9.2, 2.6, 1 7.17 (cit, J 9.0,1 H).

9-Fluoro- 1.

2 -dihydro-2.2.4-trmethy1..s.isocou io 3 4- fpqinoline (opon 27 structure 41 of Scheme X1, where R=H. R 2 In a 200-nL resealable pressure tube, a suspension of 2 -amino- 6 -fluoro-3,4-benzocoumarin (1.10 g) in acetone (100 mL) was treated with iodine (Aldrich: 0.50 g) and heated to 110 *C for 32 h. The reaction mixture was cooled to rt, concentrated to remove the bulk of the acetone, and dissolved in CH2CI2 (200 inL). The organic layer was washed with 0.5 N Na2S2O 3 (2 x 200 mnL) and sat'd NaHCO3 (0 x 100 mnL). The aqueous layers were extracted with CH2CI2 (2 x 100 m.

The combined organic layers were dried (K2C03), filtered, and concentrated to afforded an orange solid. Purification by SGC (hexane/EtOAc, 511) afforded 0.51 g of Compound 207 as a bright yellow solid. Data for Compound 207: ljj NMR (400 MHz,' acetone-cl 6 7.96 (ci, J 8.6, 1 7.83 10.0, 2.9, 1 7.30 (cid, J 9.0, 4.9, 1 7.22 (ci, J 8.6, 1 7.17 (mn, 1 6.25 (br s, I 5.54 I 1.30 6 The acetone inultiplet obscures the C(4) methyl group.

EXAMOPLE 108 8 lu r 2- ih d o 2 2 ri ne h~ s o i o 3. g in l e( o p und 208.

structure 41 of Scheme X1. where R 1 g 2

=H)

2 -Bromo-5-fjuoroanisole (structure 36 of Sc-heme XI where R 1

R

2 H) In a 250 ml, r.b. flask, a solution of 2 -bromo-5-fluorophenol (Lancaster: 7.0 mL, 64 mmol, 1.0 equiv) in acetone (140 mL) was treated with iodomethane (Aldrich: 4.8 mL, 77 mm-ol, 1.2 equiv), potassium carbonate (8 and water (I mL). The reaction mixture was heated at reflux for 6 h, cooled to rt, clarified with H20 (40 mL), and the bulk of the volatiles was removed under reduced pressure. The reaction midxture was extracted with EtOAc (3 x 120 mL); the extracts were washed with brine (1 x 80 mL), combined, dried (K2C0 3 filtered, and concentrated to a clear oil. Bulb-to-bulb distillation (60-65 0 C, 0.7 Torr) afforded 13.22 g (quant) of 2 -bromo-5-fluoroanisole as a colorless liquid. Data for 2-rm--luraioe 1 H NMR (400 MHz, CDCl3): 7.46 (dd, J 10.6, 8.7, 1 6.64 (dd, J 10.4, 2.8, 1 H); 5.58 (dt, J 10.4, 2.4, 1 3.88 3 H).

4 -Fluoro-2-methoxy henvlooicai (tutue3 f cee I heeR=F 2

H

In a 100 rnL r.b. flask, a solution of 2 -bromo-5-fluoroanisole (5.50 g, 26.8 mmol, 1.0 equiv) in THF (30 mL) was cooled to -78*C (CO2J1PA) and ,z-BuLi (2.5 M in hexanes; 10.7 mL, 27 mol, 1.0 equiv) was added via syringe over a 15 min period. The reaction mixture was stirred at -78'C for 45 min. Trimethyl borate (Aldrich: 9.1 mL, 80 mmol, 3.0 equiv) was added slowly via syringe. The reaction mixture was allowed to warm to rt, stirred an additional 10 h, and cooled to 0 TC. The reaction midxture was brought to pH6 with HCI, poured into sat'd NI-4C1 (60 mL), and extracted with methylene chloride (3 x 80 mL).

The extracts were washed with sat'd NH4CI (1 x 50 mL), combined, dried (MgSO4), filtered, and concentrated to afford 4.22 g of crude 4 -fluoro- 2 -methoxyphenylboronic acid as a white solid, which was used without fuirther purification.

7-lo 2nt In a 200 mL. r.b. flask, a solution of nitrobenzoic acid (Compound 43, Scheme XII) (Aldrich: 4.10 g, 16.7 mmol, 1.0 equiv) in DME (65 mL) was treated with tetrakis(triphenylphosphine) palladium (Aldrich: 0.58 g, 0.50 mmol, 3.0 mol%). The reaction mixture was stirred at rt for 10 min. A solution of 4fluoro- 2 -methoxyphenylboronic acid (4.20 g, 25 mmol, 1.5 equiv) in EtOH (10 mL) was added, followed by 2.0 M Na2CO 3 (30 The reaction mixture was heated to 80 0 C for 6 h, cooled to rt, poured into 5% HCl (100 mQ., and extracted with EtoAc (3 x 100 The extracts were washed with sat'd NH4CI (1 x 100 mL) and brine (1 x 100 mL), combined, dried (MgSQ4), filtered, and concentrated to an orange solid. This crude material, consisting of impure 4 '-fluoro-2'-methoxy.4-ntro- 2 biphenylcarboxylic acid (structure 44 of Schemne XLI, where R 1

R

2 was suspended in l, 2 -dichloroethane (80 mQ., treated with thionyl chloride (1.2 and heated at reflux for 90 mmd. The reaction mixture was cooled to rM treated with aluminum trichloride (0.4 and allowed to react overnight (I11 h).

The reaction mixture was poured into 20% KOHI (80 mL) and extracted with methylene chloride (3 x 80 The extracts were combined, dried (MgSO4), filtered, and concentrated to an orange oil. The crude material was dissolved in methylene chloride adsorbed onto CeliteTM (1 and concentrated to a fluffy orange powder. This powder was applied to a pad of silica gel in a 250 mL Buchner funnel (50 x 50 mm). The pad was rinsed -with 100 mi. of 2:1 hexane:EtOAc, which was discarded, and then 400 m.

of 1: 1 hexane:EtOAc. The filtrate was concentrated to afford 2.08 g of 7-fluoro-2nitro-3,4-benzocoun,,rin as an orange solid. Data for 7 -fluoro-2-nitro3,4enzocouffirin 1H NMR (400 MHz, acetone-cl 6 9.02 J 1 8.71 (dd, J 8.8, 2.4, 1 8.65 J 8.8, 1 8.53 (dd, J= 9.6, 6. 1, 1 7.34 (in, 2 2 -Amino7fuoro34 nzou~i (stcture of Shm I.w eeR=.R= In a 250-mi. flask, a suspension of 7-fluoro-2-nitro-3,4-benzocounmarin (2.04 g, 7.9 mmol) in EtOAc (150 mi.) was treated with 10% Pd/C (1.2 g) and AcQH (0.2 and stirred under an atmosphere of H2 for I h. The reaction mixture was filtered and the solids rinsed with acetone (200 mQ.. Concentration of the filtrate afforded 1.61 g of 2-ainno-7fluoro-3,4-benocoumarin as a yellow solid. Data for 2 -amidno.7-fluoro.3,4..

benzocoumarin: 1H NMR (400 MHz, acetone-cl 6 8.15 (dd, J 9.6, 6. 1, 1 8.05 1 8.6, 1 7.55 J 2.5, 1 7.28 (dd, J 8.6, 2.5, 1 7.14 (mn, 1 7.12 J 9.6, 1 5.4 (br s, 2 H).

8-Fluoro- l.

2 -dihYdro-2.2 4..trimpthvL....Z inF 4- Uinnpieo pud2 8 structuire 39 of Scheme X where R =F R=H) In a 200-mi. resealable pressure tube, a suspension of 2-an no-7-fluoro..3,4-benzocoumarin (1.61 g) in acetone (100 mL) was treated with iodine (Aldrich: 0.50 g) and heated to I 10 0 C for 32 h. The reaction mixture was cooled to Mt concentrated to remove the bulk of the acetone, and dissolved in CH2CI 2 (200 niL). The organic layer was washed with 0.5 N Na2S2O 3 (2 x 200 mL) and sat'd NaHCO3 (1 x 100 rnL). The aqueous layers were extracted with CH2CI2 (2 x 100 mL).

The combined organic layers were dried (K2C03), filtered, and concentrated to afford an orange solid. Purification by SGC (hexane/EtOAc, 511) afforded 0.46 g (2 of Compound 208 as a bright yellow solid. Data for Compound 208: 'H NMR (400 MHz, acetone-d 6 8.12 (dd, J 9.6, 5.9, 1 7.92 J 9.6, 1 7.22 J 8.6, 1 7.11 (mn, 2 6.1 (br s, I 5.53 J1= 1.2, 1 1.29 6 The acetone multiplet obscures the C(4) methyl group.

EXAMPLE 109 9-Chloro- l.

2 -dihvrorn-) 2.4p et -c U inor3.4n~j~(opud29 structuire 41 of Scheme I. where R I=H. R 2

=CI)

2 -Br:omo-4..chloronse (srctr 36 of ceme X where R I=H. R 2 =Cl) In a 250 nL r.b. flask, a solution of 2 -bromio-4-chlorophenol (Lancaster: 16.94 g, 81.6 mmol, equiv) in acetone (160 mL) was treated sequentially with iodomethane 10 mL, 98 inmol, 1.2 equiv), potassium carbonate (12 and water (4 mL). The reaction mixture was heated at reflux for 3 h, cooled to it, and the bulk of the volatiles was removed under reduced pressure. The residue was poured into water (140 mL) and extracted with EtOAc (3 x 150 inL). The extracts were washed with brine (I x 100 mQL, combined, dried 3 filtered through a pad of CeliteTM, and concentrated to a clear oil. Short-path distillation (80-85 I Torr) afforded 17.74 g of 2 -bromo-4-cf1oroaiole as a clear liquid. Data for 2-rm--hlraioe IH NMR (400 MH acetone-A 6 7.53

J=

1 7.24 (dd, J 9.7, 2.5, 1 6.81 (dA, J 9.7, 1 3.88 3 H).

S-Clor-2.ethxvpenyboronic acid (structure 37 of.Scheme X1. where R 1 =H R= l This compound was prepared in a manner similar to that of 5-fluoro-2methoxyphenylboronic acid (EXAMPLE 107) from 2 -bromo-4-chloroanisole (2.00 g, minol, 1.0 equiv), n-BuLi (2.5 M in hexanes; 3.62 mL, 9.0 mnmol, 1.0 equiv), and trimethylborate (3.0 mL, 26 mmol, 2.9 equiv) to afford 1.30 g of crude 5-chloro-2methoxyphenylboronic acid as a white semi-solid. This compound was used in the next reaction with no further purification.

Methyl (5'-chloro- 2 '-methoxy-4.nitro.2.biphenyl~carbox where R 1

R

2 This compound was prepared in a manner similar to that of methyl- '-fluoro-2 -methoxy-4-nitro-2-biphenyl)carboxylate (EXAMPLE 107) from methyl 2- (1.25 g, 4.8 mmol, 1.0 equiv), tetrakis(triphenylphosphine) palladium (Aldrich: 0.16 g, 0.14 mmol, 2.9 mol%), and 5-chloro-2-methoxyphenylboronic acid (1.30 g, 6.9 mmol, 1.5 equiv) to afford 0.85 g of methyl-5'-chloro-2'-methoxy-4nitro- 2 -biphenylcarboxylate as a yellow-orange solid. Data for methyl 5'-chloro-2'methoxy-4-nitro-2-biphenylcarboxylate: 1 H NMR (400 MHz, CDC1 3 8.73 J 2.4, 1 8.38 (dd, J 8.5, 2.5, 1 7.49 J 8.5, 1 7.36 (dd, J 8.7, 2.5, 1 7.23

J

2.5, 1 6.85 J 8.7, 1 3.76 3 3.70 3 H).

me ~ro-2.bi hen I x li acid This compound was prepared in a manner similar to that of 5-fluoro-2'methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl 5'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate (0.83 g, 2.6 mmol) to afford 0.75 g of 5-chloro-2'-methoxy-4-nitro-2-biphenylcarboxyic acid as a yellow solid. Data for (5Schloro-2'-mthoxy-4-nitro-2-biphenyl)carboxylic acid: 1H NMR (400 MHz, acetone-d 6 8.69 J 2.5, 1 8.46 (dd, J 8.3, 2.6, 1 7.68

J

8.5, 1 7.41 (dd, J 8.9, 2.7, 1 7.33 J 2.8, 1 7.08 J 8.6, 1 3.75 3 H).

h 2 4maria This compound was prepared in a manner similar to that of 6 -fluoro-2-nitro-3,4-benzocoumarin (EXAMPLE 107) from 5'-chloro-2!-methoxy-4nitro- 2 -biphenylcarboxylic acid (0.74 g, 2.3 mmol), SOC12 (0.17 mL, 2.3 mmol), and AICl3 (0.30 g, 2.5 mmol) to afford 0.64 g (quant) of 6-chloro-2-nitro-3,4-benzocoumarin as a yellow solid. Data for 6 -chloro-2-nitro-3,4-benzocoumarin: 1 H NMR (400 MHz, acetoned) 9.04 J 2.3, 1 8.73 2 8.51 J 2.4, 1 7.72 (dd, J 8.6, 2.4, 1 7.50 J 8.7, 1 H).

2 -AmiJ--6-choro34nocu~ (srcue4 fShm hre RI=.R=I This compound was prepared in manner similar to that of 2 -amino-6-fluoro..3,4benzocoumarin from 6-hoo2nto3,-ezcuai (0.64 g, 2.3 mmol) to afford 0.50 g of 2 -amino- 6 -chloro-3, -bnzocoumain as a yellow solid. Data for 2-amno-6chloro-3,4-benzocoumarin: IH NMR (400 MI-z, acetone-d 6 8.11 2 7.55

J

1 7.39 (dd, J 8.6, 2.5, 1 7.28 (in, 2 H).

9-Chloro-1. 2 dihyvdro-2.2.4- Co mpXounWdM9 structuire 41 of Schemne X.w ere R 1

R

2 -C1) This compound was preparedl in a manner similar to that of Compound 207 from 2 -amino-6-chloro-3,4-benzbcoumarin (0.50 g) to afford 0.14 g of Compound 209 as a bright yellow solid. Data for Compound 209: IH NMR (400 MHz, acetone-cl 6 8. 10 J 2.4, 1 8.00 J 8.7, 1 7.39 (dd, J 8.7, 2.3, 1 7.26 J 8.8, 1 7.23 J 8.6, 1 5.55 I 1.30 (s, 6 The acetone multiplet obscures the C(4) methyl group.

EXAMPLE 110 (RM'-5-Butyl.9..fluioro- .2-i n (Comoun 21 srucure42 of Sc!heme Y wh r =n-butyL R=H. -1, This compound was prepared by General Method 5 (EXAMVPLE 60) from Compound 207 (0.53 g, 1.7 inmol) and n-BuLi (2.5 M in hexanes, 2.7 mnL, 6.8 mrnol, 4.0 equiv) to afford 0.34 g of Compound 210 as a yellow foamn. Data for Compound 210: III NMR (400 MHz, acetone-d 6 7.54 J 8.5, 1 7.49 (dcl, J 10.2, 2.9, 1 7.03 (dcl, J 8.8, 4.9, 1 6.88 (dt, J 2.9, 8.8, 1 6.75 J 8.5, 1 5.80 (hr s, 1 5.49 1 4.83 J 7.6, 1 2.36 J 7.5, 2 2.05 3 1.46 (sextet, J 7.4, 2 H); 1.10 (hr s, 8H); 0. 93 J1= 7.4, 3 H).

fR/S)-S-Buty1l-8-fluoro-. 0 e (Comnound 211. structure 42 of Schemep XI. w hr R D--uv.R 2

H

This compound was prepared by General Method 5 (EXAMVPLE 60) from Compound 208 (29 mg, 0.09 mxnol) and n-BuLi (2.5 M in hexanes, 0.16 ruL, 0.40 mmol) to afford 6.5 mg of Compound 211 as a yellow foam. Data for Compound 211: 1 H NMR (400 MHz, acetone-d6): 7.77 (dd, J 6.3, 1 7.51 J 8.5, 1 6.85 (in, 3 5.80 (br s, 1 5.49 1 4.84 J 7.5, 1 2.37 J 7.5, 2 2.07 3 1.47 (sextet, J 7.4, 2 1.10 (br s, 8H); 0. 93 J 7.4, 3 H).

EXAMPLE 112 (R/S')-5-(3ChornhnyI -9flupro l 2 i dr24-iiity5Hl~.~ 3 tlguinoline (Compo)und 212. sructure 42 of SchemeY X...eR-hlrpev R This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 rug, 0.16 inmol) and 3 bromochoro benene (120 ruL) to afford 46 rmg of Compound 212 as a colorless Solid. Data for Compound 212: 1H NMR (400 MWz, acetone-d 6 7.56 J 1 7.36 (dd, J 9.8, 2.9, 1 7.25 (mn 4 6.95

I

6.85 J 1 );6.81 (in, I 6.74 (td, J 8.5, 2.9, 1 5.51 I 2.00 (d, J 1.0, 3H); 1.28 3H); 1.

2 6 3H).

EXAMPLE 113 (RS-S( I r...mehlheny1fl I dihyd- .2eh1-S1c1 OinenoF 3

Q

tlguinoline (Comound 213. sucture 42 f Scheme I. where RZ=4-chloro-.3 inethyWphen L R =HR 2

=F

This compound was prepared by General Method 5 (EXAMVPLE 60) from Compound 207 mug, 0. 16 minol) and 5-bromo-2-chlorotoluene (0.21 g) to afford 42 mg of Compound 213 as a colorless solid. Data for Compound 213: 1H[ NMR (400 MHz, acetone-d 6 7.55 J 8.4, 1 7-34 (dd, J 10.0, 2.8, 1 7.22 (in, 2 7.00 (br d, J -10.3, 1 6.89 I 6.84 J 8.4, 1 6.75 (in, 2 5.49 I 2.24 3 H); 1.99 J 1.2,3 1.27 3 1.25 3 H).

EXAMPLE 114 (R/S')-5-(4-Ch~orophenyl)-9-fluoro-. 2 -dihydro-2.2.4-trimeth l-5H-clromeno F3flguinoline (ComDound 214. structure 42 of Scheme XT. wihe-re R=-choopev. 1 This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 mg, 0. 16 rnmol) and 4 bromochloro benzene 19 g) to afford 33 mg of Compound 214 as a pale yellow oil. Data for Compound 214: 1 H NMR (400 MH z, acetone-cl 6 7.55 J 8.4, 1 7.34 (dd, J 10.0, 2.8, 1 7.27 J 8.6, 2 7.22 J 8.6, 2 6.92 I 6.84 J 8.5, 1 6.75 2 5.60 (br s, 1 5.48 J= 1.3, 1 1.99 J= 1.3,'3 1.27 3H); 1.24 3H).

EXAMPLE 115 (R/S)-9-Fluo o- 2-i A-%tn flguinoline (Compound 215. structr 42 of Scheme XL. where R=4-methoxyphenl.

R I=H, R 2

=F

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 mg, 0. 16 mmol) and 4-bromoanisole 13 mL) to afford 8 mg of Compound 215 as a pale yellow oil. Data for Compound 215: IH NMR (400 MHz, acetone-cl 6 7.53 J 8.4, 1 7.34 (dd, J= 10.0, 2.8, 1IH); 7.11 J= 8.8, 2HW; 6.86 1 6.82 (d,J 8.4, 1 6.76 J 8.6, 2 6.70 (in, 2 5.6 (br s, 1 5.46 1 3.70 3 H); 1.99 3 1.26 3 1.23 3 H).

EXAMPLE 116 (R/S')-8-Fluoro- 2 -dihYdro-S5meth xy..224-.rt-hy1..sH.c rneoF.-guol (Comp~ound 216. structure 47 o F Scheme Xff. _we R I=F, 2 R 3 =methv I =0 (,R/S)-8-Fluoro- (structure 46ofSchemne V. where R=F. R 2 This compound was prepared in a manner similar to that of Compound 185 (EXAkMPLE 85) from Compound 208 (170 mg) and DIBALH (1.0 M in hexane; 1.25 mL) to afford 27 mg of (R/S)-8-fluoro-1,2diyr--yrxl224tinthl5-ho-n[,-lunln as a white solid. Data for (R/S)-8-fluoro-. l 2 dihydro5hydroxy224 ethlHcrmn[,-~unb:I NMR (400 MI-z, acetone-cl 6 7.74 (dd, J 8.6, 6.3, 1 7.50 J 8.4, 1. 6.85

I

6 7 9 2H); 6.72 J 99 2 7 1 5.51 J 1 2.82 3H); 1.

3 0 (s, 3 1. 17 3 H).

(R/S)-8-Fluoro-.2dh-r5m t (COmpOWn 216. structure 47 of'Scheme XV.V where

R

1

R

2 H=p mehl This Compound Was prepared in a manner similar to that of Compound 186 (EXAMPLE 86) from (R/S)-8-fiuoro-12dhdo5hdoy2.,-rmty-Hcrmn (34fqioln (24 mg) to afford 25 mg (quant) of Compound 216 as a white solid. Data for Compound 216: IH NMR (400 MHz, acetone-cl 6 7.74 (dd, J 8.5, 6.2, 1 FO; 7.50 J 8.4, 1 H); 6.85 (in, 2 6.79 J 8.4, 1 6.38 1 5.52 J 1 3.46 3 2.26 J 3HM; 1.31 3H); 1.1 5(s, 3H).

EXAMPLE 117 (R/S)~S(4~h~orphey1)fluoro l.

2 -dihdrfrn-24t7A-n-iethys cIjoin 3 4 flguinoline Compond 217.trcue4 of Scheme XI. whre

R=

4 L-choOenYl.

R=F

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 208 (42 mng, 0. 13 inmol) and 4 -bromochloro benzene 19 g) to afford 10 mng of Compound 217 as a pale yellow oil. Data for Compound 217: 1 H NMR (400 MiHz, acetone-cl 6 7.62 (dd, J 8.6, 6.3, 1 7.53 I 8.4, 1 7.27 J 8.7, 2 7.23 J 8.7, 2 6.96 1 6.83 J 8.2, 1 6.67 (in, 1 6.58 (dcl, J= 8.7, 2.5, 1 5.48 J= 1.3, 1 1.99 J= 1.2, 3H); 1.

2 6 3H); 1.

2 3 3H).

EXAMPLE 118

(RS)

9 ~h~ro.54clooh nv ivr~. 4 -trinethyl ho 34 fipinlie Coi~onc 2 8 structure 42 of Scheme- I. wh reR -chlooenv

R

1

=H

This compound was prepared by General Method 5 (EXAMVPLE 60) from Compound 209 mng, 0. 12 mrnol) and 4 -bromochlorobenzene 19 g) to afford 23 mg of Compound 218 as an off-white oil. Data for Compound 218: IH NMR (400 MHz, acetone-d 6 7.59 J 2.5, 1 7.58 J 8.4, 1 7.27 J 8.6, 2 7.22

J

8.6, 2 6.96 (dd, J 8.5, 2.4, 1 6.94 1 6.84 J 8.4, 1 6.78 J 1 5.7 (br s, 1 5.49 J 1.1, 1 1.99 J 1.1, 3 1.27 3 1.24 3

H).

EXAMPLE 119 2 -dih dro_2.2,,4iethy.5H.lmen34f inline (Cm-pound 219. structure 45 of Scheme X .ere l=R 2

R

3 =n-hro General Method Pr ton of cture45 frn Com und 159 or compounds of structure 41. This transformation involves the addition of a Grignard reagent (or, alternatively, an organolithium reagent) to Compound 159 or compounds of structure 41 followed by an acid catalyzed dehydration reaction. To a flame-dried flask charged with magnesium powder (8-10 equiv) and iodine under nitrogen was added one fourth of a solution of the corresponding benzyl bromide (or chloride) (8-10 equiv) in 2-3 mL of THF or ether. The mixture was allowed to stir for 5-10 min until the reaction initiated (a few drops of 1, 2 -dibromoethane might be necessary to initiate the reaction), and then the rest of the benzyl bromide (chloride) solution was added and the reaction went to completion in several min to give a colorless solution. The Grignard reagent solution was cannulated into a yellow solution of Compound 159 or a compound of structure 41 in 1-2 mL of THF and the resulting dark red mixture was allowed to stir at rt for 20-66 min until the red c6olor faded. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (2 x mL). Removal of the solvent under reduced pressure afforded the crude lactol as a yellow oil, which was dissolved in 5 mL of methylene chloride and was treated with ptoluenesulfonic acid (5-10 mol%). The reaction was stirred at rt for 30 min and was quenched with a 2% NaOH aqueous solution (2 mL). The mixture was extracted with ethyl acetate (20 mL) and was washed with brine (5 mL), and was then concentrated.

Chromatography of the crude mixture on a silica gel column using 10 ethyl acetate/hexane as the eluent afforded the compound of structure 45 as a bright yellow oil or solid in good yield.

FH-chro menor3.441gn lin (opund 219, structure 45 of Schemne xm where RLI=R 2

R

3 =n1M-opv)Thscmonwa prepared by General Method 6 from 1.6 M hexane solution of n-butyllithium (0.2 mL, 0.32 mmol) and Compound 159 (20 mg, 0.07 mmol) to afford 4.8 mg (2 1 of Compound 219 as a bright yellow oil. Data for Compound 219: Rf 0.62 (silica gel, 25% EtOAc: hexa 1H NMR (400 MHz, acetone-d6) 7.74 J 1 7.54 J 1 H), 7.14 (t J= 7.5, 1 7 .0 3 -6.98 2H), 6.74 (dJ~ 8.4, 1 5.48 I 4.81 (t,J= 1 2.40-2.35 (in, 2 2.09 3 1.49-1.44 (mn, 2 1.27 (br s, 6 0.93

J=

7.3, 3 H).

EXA-MpLE 120 1.

2 -d lhydro-22..ti-te 1 5 1 1 eoBAzluj n 220. tructure 45 of Scheme X Ell. wheeR

R

2 F.R phn) This compound was prepared by General Method 6 (EXAMPLE 119) from benzyl bromide (171 mg, 1.0 inmol) and Compound 159 (20 mg, 0.07 numol) to afford 6.3 mg of Compound 220 as a bright yellow oil. Data for Compound 220: Rf 0.50 (silica gel, EtOAc: hexane); 1H NMR (400 MHz, acetone-d6) 7.82 J 7.6, 3 7.64 J 8.4, I 7.38 (t J 7.6, 2 7.24-7.20 (mn, 3 (7.09-7.06) 1 6.84 J 8.4, 1 5.68 1 5.55 (s IH),2.11 3H), 1.29 (br s, 6H).

EXAMPLE 121 QZ--Fuoo3pzjdf) l.dhdo2..-tyschro enor 4 gqio~he (CompLound 221. structu-re 45of Scheme XIIIwheR=R 2

=H.R

3 4-fuorophenvl) This compound was prepared by General Method 6 (EXAMPLE 119) from 4 -fluorobenzyl chloride (145 mg, 1.0 minol) and Compound 159 (20 mg, 0.07 mnmol) to afford 17 mg of Compound 221 as a bright yellow oil. Data for Compound 221: Rf 0.56 (silica gel, 25% EtOAc: hexane); 1 H NMR (400 MHz, acetone-d6) 7.87-7.82 (in, 3 7.64

J

1 7. 22-7.05 (mn, 5 6.82 J 8.4, 1 5.68 I 5.54 I 2. 10 (s, 3 1.32 (br s, 6H).

EXAMPLE 122 Compound 22 structure 45 Schem XIT here 1 2 -ri R 3 4-rooI-- v This compound was prepared by General Method 6 (EXAMPLE- 119) from 4 -bromobenzyl bromide (250 mg, 1 .0 mnmol) and C ompound 159 (20 mg, 0.07 mmol) to afford 24 mg of Compound 222 as a bright yellow oil. Data for Compound 222: IH NMR (400 MHz, acetone-d6) 7.83 J 1 7.77 J 8.6, 2 7.65 J 8.4, 1 H), 7.55 J 8.6, 2 7.26-7.17 (in, 2 7.11-7.06 (in, I 6.84 J 8.3, 1 5.66 1 5.55 1 2.09 3 1.34 (br s, 6 H).

EXAMPLE 123 0Z-5-3-Bromobenzylidene). 1.

2 -dih r.

2 2 4rhehl.H.c-ieo3 fl-quinoline (Cmpound 223. stru tre 45 of Scheme XIII where RlF=R 2

R

3 =3bromophenfl) This compound was prepared by General Method 6 (EXAMPLE 119) from 3bromobenzyl bromide (250 mg, 1.0 inmol) and Compound 159 (15 mg, 0.05 mrnol) to afford 22 mg of Compound 223 as a bright yellow oil. Data for Compound 223: IH NMR (400 MHz, acetone-d6) 8.03 I 7.85 J 7.9, 1 7.78 J 7.9, 1 H), 7.66 J= 8.4, 1 7.41-7.17 (in, 4 7.09 J= 7.9, 1 6.85 J= 8.3, 1 H), 5.67 1 5.55 1 2.10 3 1.33 (br s, 6 H).

EXAMPLE 124 fZ)-5-(3-Chl rbnzyli A.L..yr-.24eh1~criep3 flguinoline ompound 224. structure 45 of Scheme XII where R=R 2

R

3 =3chlorophgmyf This compound was prepared by General Method 6 (EXAMAPLE 119) from 3chlorobenzyl chloride (161 mg, 1.0 inmol) and Compound 159 (10 mg, 0.035 innol) to afford 6.3 mg of Compound 224 as a bright yellow oil. Data for Compound 224: Rf =0.33 (silica gel, 25% EtOAc: hexane); IH NMR (400 MHz, acetone-d6) 7.88-7.85 (in, 2 7.72 J 8.0, 1 7.67 J 8.4, 1 7.40 J 8.0, 1 7.26-7.20 (mn, 3 H), 7.12-7.08 (in, I 6.85 J 8.4, 1 5.68 1 5.56 I 2. 10 3 1.29 (br s, 6 H).

EXAMPLE 125 3 -F2l4uoroylbenzylideo3ne). .unoli (Compound 225 structure 45 of Scheme XII! wher 1

R

2 H R 3 =3flu'ophny This compound was prepared by General Method 6 (EXAMVPLE 119) from 3 -fluorobenzyl bromide (189 mg, 1.0 mrnol) and Compound 159 (20 mg, 0.07 mmol) to afford 5.4 mg of Compound 225 as a bright yellow oil. Data for Compound 225: Rf 0.50 (silica gel, 25% EtOAc: hexane); IH NMR (400 MHz, acetone-d 6 7.85 J 7.9, 1 7.66 (d, 1J 8.6, 2 7.52 J 7.9, 1 7.43- 7.38 (in, I 7 2 5 7 23(n, 2 7.11-7.07 (mn, I 7.02-6.97 (in, I 6.85 I 8.6, 1 5.70 1 5.55 I 2. 10 3 1.29 (br s, 6 H).

EXAM4PLE 126 2 -Cheorobenzvlidene~ (Comp~ound 226 strutr 45 ofqrScheme X L- re RI :R 2 R-choohnI This compound was prepared by General Method 6 (EXAMPLE 119) from 2 -chlorobenzyl chloride (161 mg, 1.0 mmol) and Compound 159 (20 mg, 0.07 mmnol) to afford 8.4 mg of Compound 226 as a bright yellow oil. Data for Compound 226: Rf 0.44 (silica gel, 25% EtOAc: hexane); 1 Hj NMR (400 MHz, acetone-d 6 8.44 J 7.9, 1 7.85 (di, J 7.9, 1 7.67 J 8.5, 1 7.45-7.37 2 Hi), 7 2 5- 7 .2 1(m, 3 7 2 0- 7 .l11(m, 1 6.86 J 8.5, 1 6.20 1 HM, 5.55 1 2.15 3 1.29 (br s, 6 H).

EXAMPLE 127 (Z--2Boybnyiee Qio (Cmpud 2 tucue 5ofSheeXII ee R=R=H.OR 2-ompen This compound was prepared by General Method 6 (EXAMPLE 119) from 2 -bromobenzyl bromide (250 mg, 1.0 minol) and Compound 159 20 mg, 0.07 inmol) to afford 2.8 mng of Compound 227 as a bright yellow oil Data for Compound 227: Rf 0.44 (silica gel, 25% EtOAc: hexane); IH NMR (400 MvHz, acetone-d6) 8.45 J 7.9, 1 7.85 J 7.9, 1 7.67 J 8.5, 1 7.64 J 7.9, 1 7.45 J 8.5, 1 7.23 7.07 (in, 4 6.87 J= 8.5, 1 6.19 I 5.55 I 2.15 3 1.29 (br s, 6 H).

EXAMPLE 128 (Z-5-(2-Flu orok xth bezliee- 2 ido-2.2.4 ~sc ~~mnr4-tguinoline (Compound 228. structure 45 of Scheme XIHI where R 1

=R

2

R

3 2-fluorohenyl) This compound was prepared by General Method 6 (EXAMPLE 119) from 2 -fluorobenzyl bromide (189 mg, 1.0 mmol) and Compound 159 (10 mg, 0.034 mmol) to afford 2.1 mg of Compound 228 as a bright yellow oil. Data for Compound 228: IH NM4R(400 MHz, acetone-d6) 8.39 I 7.85 J 7.4, 1 7.67 J 8.5, 1 7.30-7.06 (mn, 6 6.86 J 8.5, 1 5.96 I 5.90 1 5.55 1 2.13 3 H), 1.32 (br s, 6 H).

EXAMPL E 129 (Z')-5-(2.3-Difluoiro benzylidene). l.

2 -diiydro2.2.4et--ehy Icomnor4,.

(Comp~ound 229. struct re 45of Scheme III where Rl=R 2

R

3 iloohnl This compound was prepared by General Method 6 (EXAMPLE 119) from 2,3difluorobenzyl bromidde (207 mg, 1.0 mniol) and Compound 159 (10 mg, 0.034 minol) to afford 4.8 mg of Compound 229 as a bright yellow oil. Data for Compound 229: 1

H

NMR (400 MHz, acetone-d6) 8.18 (dd, J 8.0, 6.6, 1 7.87 I 7.5, 1 7.69

J

8.5, 1 7.30-7.08 (mn, 5 6.89 1 8.4, 1 5.94 1 5.57 1 2.12 (s, 3 1.31 (br s, 6H).

EXAMPLE 130 2 5-D'f o obnydee. A-*ehI (Compound 230 structre 45 of Scheme XIII. where R= 2

HR

3 2.-difluro henl) This compound was prepared by General Method 6 (EXAMPLE 119) from difluorobenzyl bromide (207 mg, 1.0 inmol) and Compound 159 (15 mng, 0.05 inmol) to afford 17 mg of Compound 230 as a bright yellow oil. Data for Compound 230: IH NMR (400 MHz, acetone-d6) 8.12 (in, I 7.88 J 8.3, 1 7.69 J 8.5, 1 H), 7.30-7.00 (mn, 5 6.89 J 8.4, 1 5.93 1 5.94 I 5.56 I 2.11 (s, 3 1.32 (hr s, 6 H).

EXAMPLE 131 (Z')-9-Fluoro-5-(3-fluorobenzylidene)-!, I L-ihydro-2.2,4-tiethvL-SH-chro mno[3 .4flguinoline (Compound 231. structure 45 of Scheme XIII. where R 1

R

2

R

3 =3fluorophenyl) This compound was prepared by General Method 6 (EXAMPLE 119) from 3-fluorobenzyl chloride 17 g) and Compound 207 (31 mg) to afford 7.5 mg of Compound 231 as a yellow oil. Data for Compound 231: IH NMR (400 MHz, acetone-d6) 7.65 J 8.4, I 7.64 (in, I 7.60 (dd, J =10.0, 3.0, 1 7.52 J 7.6, 1 7.40 (mn, I H); 7.26 (dd, J 8.9, 4.8, 1 7.00 (mn, 2 6.86 J 8.3, 1 5.72 1 5.57 J 1 2. 10 3 1.40 (br s, 6 H).

EXAMPLE 132 9 -Fluoro-5-(3-methoxbezyi ee).1 -dIhyr-..-rmty-Hcrm 34 Nluinoline (Compound 232. structure 45 of Scheme XWI where R=H. R 2 =17, R 3 =3methQoxlphny This compound was prepared by General Method 6 (EXAMPLE 119) from 3methoxylbenzyl chloride 18 g) and Compound 207 (31 mg) to afford I11 mg of Compound 232 as a yellow oil. Data for Compound 232: IH NMR (400 MHz, aceton ed6) 7.63 J 5, 1 7.58 (dd, J 10.0, 2.9, 1 7.48 (br s, 1 7.28 J 5.1, 2 7.22 (Mn 1 6.98 1 6.83 J 9.6, 1 6.82 1 5.68 I 5.56 (s, I 3.86 3 2. 10 3 1.35 (br s, 6 H).

EXAMPLE 133 0Z-8-Fluoro-5-(3-fluororenzgy icLene)-1 .2 -dihyd ro-2 .2 .4-rimet hyl-SH-c hro neno[34.

figuinoline (Compound 233. sutre 45 f Sc-heme II wher R 2

H.R

3 fluorophenyl) This compound was prepared by General Method 6 (EXAMPLE 119) from 3-fluorobenzyl chloride 17 g) and Compound 208 (31 mg) to afford 7.5 mng of Compound 233 as a yellow oil. Data for Compound 233: IH NMR (400 MHz, acetoned6) 7.88 (dd, J 9.7, 6.2, 1 7.63 J 8.5, 1 7.58 (mn, 2 7.42 (dd, J 6.4, 1 7.09 (dd, J 9.5, 2.7, 1 7.00 (in, I 6.92 (mn, 1 6.85 J 8.2, 1 H); 5.7 3 1 5.63 1 2. 10 3 1. 35 (br s, 6 H).

EXAMPLE 134 (RIS-41. 5u)-5- 4-Chloohnl. Amtv-Hcrmeo3.-1 gquinolinone Comound 234. structure 52 of Scheme XV. where R=4-chlorophenv R 1

=R

2

=H)

This compound was prepared by a four step procedure as depicted in Scheme XV. To a yellow solution of Compound 163 (EXAMPLE 63) (120 mg, 0.3 inmol) in THF (6 inL) at 78 0 C was added 0.3 mL, of n-BuLi (1.6 M in hexane, 0.48 mmol), and the resulting solution was stirred for 15 mini before a solution of di-t-butyl dicarbonate (150 mg, 0.7 inmol) in 2 ml of THF was introduced. The reaction mixture was allowed to warm up to rt and was stirred for 5 h. The mixture was quenched with water and was extracted with ethyl acetate (2 x 20 mL). Removal of solvent and chromatography of the crude mixture on a silica gel column using 10-30% mixture of ethyl acetate 'and hexane afforded 50 mng of the t- Boc protected quinoline (structure 49 of Scheme XV where R=4-chlorophenyl, R I=R 2

=H)

and 80 mng of Compound 163.

The t-Boc protected Compound 163 (structure 49 of Scheme XV where R= 4 -chlorophenyl, R I=R 2 (40 mg, 0.08 mmol) in TH-F (4 mL) was treated with 0.3 mL of BH3.THF M in THF, 0.3 mmol) at rt for 3 h and was then quenched with 0.2 ml, of KOH (3 M aqueous). To the above solution 0.2 mL of H202 (30% in water) was added and the midxture was stirred for 30 inin, then 5 mL of water was introduced. The mixture was extracted with EtOAc, washed with brine and concentrated. Chromatography of the crude mixture on a silica gel column (10-30% EtOAc/hexane gradient) afforded two major isomers. The first fraction (20 mg, 50%) was assigned as (R/S-31, 4u, 51)-I-tbutyloxycarbonyl-5-(4-chlorophenyl)- 1,,,-erhdo3hdrx-,,-rmtychromno[3,4-Ilquinoline (structure 50 of Scheme XV where R-4-chlorophenyl,

R

1

=R

2 The second fraction (12 ing, 30%) was assigned as (R/S-31, 4u, butyloxylcarbonyl-5-(4-chlorophenyl) 1234ttaydo3hdoy22,-rmty-H chromrreno[3,4-flquino lne (structure 51 of Scheme XV where R=4-chlorophenyl, R I =R 2 (R/S-31, 4u, 50- l-t-Butyloxylcarbony1..s.(4..chlorophel) 1 2 3 4 -tetrahydro-3..hydroxy- 2 2 4 -trimethyl-SH-chromeno[3,4-AJqunoline (structure 50 of Scheme XV where R=4chiorophenyl,

R'=R

2 (20 mg, 0.04 mnmol) was oxidized with PCC (100 mg, 0.46 mmol) in 5 mL of methylene chloride at rt for 60 mini to yield (R/S-41, (4-chiorophenyl)-

I,

2 3 4 -tetahydro224 th[S-H -chro e [3 -A -q i li n a a colorless oil after chromatography. This compound was then treated with 0.2 mL. of 'WA in 0.5 mL of methylene chloride for 30 mini and was quenched with 5 mL of KOH The reaction mixture was extracted with EtOAc, washed with brine and was concentrated.

Chromatography of the crude residue on a silica* gel colurm (10-30% EtOAc/hexane gradient) afforded 15 mg of Compound 234 as a white solid. Data for Compound 234: IH NMR (400 MHz, CDC13) 7.64 J 8.2, 2 7.18 J 8.6, 2 7.13

J

8.6, 2 7.05 J= 7.9, 1 6.96 J= 7.8, 1 6.84 J= 8.3, 1 6.76

J

7.9, 1 6.37 I 3.73 1 3.56 J 7.4, 1 1.44 3 1.26 3 H), 0. 87 J= 7.4, 3 H).

EXAMPLE 135 (R/S-41, 5-(4-Chlorophenyn- l 2 3 4 ttayr.2.timeth 1..SHchrMffenoF 34 f quinolirione (Compound 235 struture 53 of Scheme XV. where R= 4 -clorphtnvl (R/S-31, 4u, 5u)- l-t-Butyloxylcarbonylv5.(...horophenyl) l, 2 3 4 -tetrahydro..3.hydroxy- 2 2 4 -trimethyl-SH-chxomeno(3,4jAquinoline (structure 51 of Scheme XV where R=4chlorophenyl,

R

1

=R

2 (EXAMPLE 134) (12 mg, 0.024 mmol) was oxidized and deprotected by methods similar to that described for Compound 234 (EXAMPLE 134) to yield 8 mg of Compound 235 as a white solid. Data for Compound 235: 1 H NMR (400 MHz, CDC1 3 7.59 J 8.4, 1 7.57 J 8.0, 1 7.15 J 8.5, 2 7.06 J 8.5, 2 7.04 (in, 1 6.94 J 7.8, 1 6.85 J 7.6, 1 6.83 (d, J 8.3, 1 3.73 I 3.35 J 7.5, 1 1.50 J 7.5, 3MH), 1.46 3 H), 1. 17 3 H).

EXAMPLE 136 (R/S')-5-(4-Chlorophenyl)-I l 2 3 4 -t trahydro2.24.4AetA hlH.~oeo3 4 qIuinolinone (Compound 236. structure 54 of Scheme XV where R=4-chlorophenyl,

R=

2

H

To a solution of (R/S-41, 5u)- l-t-butyloxylcarbonyl-5-(4-chloropheny)- l, 2 ,3,4-tetrahydro- 2 2 4 -trimethyl-SH-chromeno[3,4-A-3.quinolinone (EXAMPLE 134) (5 mg, 0.01 mmol) in 2 mL of THF was added 10 mg of NaH (40% in mineral oil, 0.25 mmpol) and the resulting slurry was stirred at rt for 20 min before Mel 1 g, 0. 7 mmol) was introduced. Th e mixture was stirred at rt for 2 h and was then quenched with water (5 mL). The mixture was extracted with EtOAc and purified by silica gel chromatography to provide 1.5 mg of Compound 236 as a colorless oil Data fo r Compound 236: 1 H NMR (400 MHz, CDCI3) 7.59 J= 8.2, 1 7.56 J= 7.8, 1 7.13 J= 8.7, 2H), 7.09 J 2H), 7.01 J 7.9, 1 6.91 J 7.9, 1 6.85 I 6.83-6.78 (in, 2 3.83 I H), 1.63 3 1.38 3 1.33 3 1.28 3 H).

EXAMPLE 137 1.-iyro224 (Compoundrn 237. structure 57 of Scheme XVI. where R I=R 2

R

3 =methoxvlmethvl.

Z-O)

General Method 7: 1.

2 -Dihy-ro-2.2.4-trinethy1guiolines (Compounds of structure 57 or 67) fro Copunso structure 56 or 66): ambient pressure version In an r.b.

flask equipped with a reflux condensor, a solution of the aniline (a compound of structure 56 or 66) in acetone (0.05-0.20 M) was treated with iodine (5-20 mol%) and heated to reflux for 1-3 days. Addition of CeliteTM followed by concentration afforded a fluffy orange powder which was purified by silica gel chromatography to afford the desired dihydroquinoline (compound of structure 57 or 67).

1--iyr-24tiehl6mtoyehl8Mna[,: unln (Compound 237. structure 57 of Scheme XVI. where R=R 2

R

3 =methoxlmethyl. Z-O) This compound was prepared by General Method 7 from 7 -amino-4-methoxymethylcoumiarin (structure 56 of Scheme XVI, where R 1

=R

2

R

3 =inethoxymethyl) (1.0 g, 4.87 inmol) to afford 82 mg of Compound 237 as a light yellow solid in addition to 487 mng of 1,2dihdro2,24-amet yl 8-ethxymthy-6-yraono(6,-fluin lie.Data for Compound 237: Rf 0.23 (silca gel, hexanes/EtOAc, 2: Iff NMR (400 MHz, C61)6) 7.01 1 6.24 I 6.18 I 5.02 1 3.97 2 3.74 (br s, 1 2.92 3 1.78 J 3 0.98 6 H).

EXAMPLE 138 1.-iyi- -r 6 rmty--y (Compound 238. structure 57 of Scheme XVIM. where R=R 2 R=rluromethvI This compound was prepared as depicted in Scheme XVII and as described below.

O-Pivalovl-3-nitropbenol structu re 65 of Scheme VHI where R 1 I~ -uv.ZO

TO

300 mL of CH2CI2 was added 3 -nitrophenol (structure 64 of Scheme XVII, where R 1

=H,

Y=O) (15 g, 0. 11 mol), pyridine (20 mL) and DMAP (10 mg). To this cooled solution (00(2) was slowly added trimethylacetyl chloride (18 mL, 146 mmol1, 1.4 equiv). The solution was allowed to warm to rt and stirred for 3 h. To the amber colored solution was added sat'd NH4CI (300 mL). The organic layer was washed with 1IN HCl (2 x 150 mnL), CuSO4. 5 H20 (2 x 100 mL), and brine (2 x 100 mL). The extract was dried (Na2SO4) and concentrated in vacuc to give 22.5 g of O-pivaloyl-3-nitrophenol as a white solid. Data for O-pivaloyl-3-nitrophenol: Rf 0.55 (silica gel, hexanes/EtOAc, 3:1); IH NMR (400 MI-z, CDCl3) 8.11 (dd, J 4.2, 1.3, 1 7.96 J 2.2, 1 7.56 (dd, J 8.4, 8.2, 1 7.42 (dd, J 6.5, 1.3, 1 1.35 9 H).

O-Pivaloyl-3 am Dbpenol structure 66 of Scheme XVI. where RI=H Pt- u. 7--n% To 60 mL anhydrous CH2CI2 was added O-pivaloyl-3-nitrophenol (5.0 g, 22.4 mrnol) and a catalytic amount (50 mg) of 10% Pd on C. T'he flask was repeatedly evacuated and flushed with N2. The reaction flask was again evacuated and H2 was introduced by balloon.

After stirring under an atmosphere of H2 for 3 h, the reaction flask was flushed twice with N2. The suspension was then filtered through a bed of CeliteTm and concentrated to give 4.15 g of O-pivaloyl-3-aminophenol as a viscous amber oil. Data for O-pivaloyl.3aminophenol: Rf 0.21 (silica gel, hexanes/EtOAc, 3: 1H NMR (400 MHz, CDCI3) 7.12 (dd, J 8.0, 8.0, 1 6.52 (dd, J 7.8, 2.7, 1 6.44 (ddd, J 8.0, 2.4, 1.4, 1H), 6.38 J= 2.2, 114), 3.81 (br s, 2H), 1. 34 9 H).

General -Method8l- ihdr-L2. timthylguino lines oponds of strucur 5 o 67) from anilines (C onds of structr 56 or 66) pesur tuevr I[n a threaded resealable pressure tube, a solution of the aniline (a compound of structure 56 or 66) in acetone (0.05-0.20M) was treated with iodine (5-20 mol%) and heated to 100- 120 *C for 1- 3 days. The reaction vessel was allowed to cool to rt and transferred to a r.b. flask.

Addition of CeliteTM followed by concentration afforded a fluffy orange powder which was purified by silica gel chromatography to afford the desired dihydroquino line (Compound of structure 57 or 67).

1.

2 -Dihydro-2.2.4.trfrnthyL..7( 1.1.1- 'trethylcet x iunoljnA (srcurq7ofShm XVII. where R I H. P=t-btyL Z=O This compound was prepared by General Method 8 from O-pivaloyl-3-aminophenol (structure 66 of Schemne XVII, where R 1 P-butyl, Y=O) (1.26 g, 6.53 mmol) to afford 1.06 g of 1,-iyr-,,-bmty--111 trirethylacetoxy)quinoline as a light brown solid. Data for l, 2 -dihydro-2,2,4..rrimethyl.7- (1,1,-timethylacetoxy)quino line: Rf 0.23 (silica gel, hexanes/EtOAc, 'H NMR (400 MHz, CDCI3) 7.00 J 8.3, 1 6.28 (dd, I 5.2, 2.3, 1 5.25 I 3.69 1 1.96 J 1.2, 3 1.32 9 1.26 6 87).

eh unja To 70 mL 85% ethanol was added 1,2diyr-,,-inty--111tiehlctx~unln (1.03 g, 3.77 mmol) and NaOH(aq) (3 mL) to give a clear colorless solution. The reaction was followed by TLC (hexanes/EtOAc, 3: After 3 h the resulting purple solution was quenched with sat'd NH4CI (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (2 x 75 mnL), dried (Na2SO4), and concentrated in vacuo to give a dark purple oil. The oil was dissolved in a minimal amount of hexanes ethyl acetate and filtered though a plug of silica rinsing with a solution of hexanes I ethyl acetate The washes were concentrated in vacuo to afford 7 10 mg of l,2-dihydro-7hydroxy-2,2,4-trim.ethylquinoline as a dark yellow oil. Data for 1,2-dihydro-7-hydroxy- 2 2 4 -trimethylquinoline: Rf 0.30 (silica gel, hexanes/EtOAc, 3: IH NMR (400 MHz, DMSO-d6) 8.90 I 6.70 J 8.2, 1 5.89 J 2.3, 1 5.85 (dd, J 8.3, 2.4, 1 5.65 I 5,04(s, 1 1.8 J= 1. 1, 3 1. 14 (s,687M.

structure 57 of Scheme X:VII. where RR 2

F.R

3 =trffluooehlZO General Method Prepration ofCmonso tute5or7fom hnls To a solution of 1,-iyr--yrx-,,-rmtyqioln 1-0.5 M) in absolute EtOH was added a j3-keto ester (a compound of structure 68) (1-3 equiv) in a 4 x 13.5 cm pressure tube equipped with a magnetic stir bar and a threaded Teflon stopcock. To this solution was added ZnC12 (1-6 equiv). The sealed pressure tube was heated in a oil bath at 80-120 0 C for 6-72 h. The cooled solution was diluted with sat'd NH4C1 and extracted with eth yl acetate.

The combined organics were concentrated on CeiteTM under reduced pressure to. give a free flowing powder, which was purified by flash column chromatography (silica ge) hexanes ethyl acetate, 5: 1) to give the desired product. Further purification cOuild be effected by recrystallization from hexanes /toluene.

1.-iydo224tie 238.nno Ciinn 0 structure 55 of Scheme XVII. where Rl=R 2

R

3 =tifluoromethyl. Z0O) This compound was prepared by General Method 9 from I, 2 -dihydro-7-hydroxy..2,2,4.

triniethylquinollne (1.58 g, 8.5 mmol) and ethyl 4 4 4 -trifluoroacetoacetate (3.00 g, 16.8 mmol, 2.0 equiv) to afford 1.7 g of Compound 238 as a light yellow powder. Data for Compound 238: Rf 0.32 (silica gel, hexanes/EtOAc, IH NMR (400 MHz, C6136) 7.22 1 6.15 1H), 5.97 1 4.93 1 3.23 (hr s, I 1.66 J 1.1, 3 0.98 6 H).

EXAMPLE 139 1.

2 -Dihydro2.2.4.t iehl.0-iso 0u i Qr4.l uinoe Copud29 structure 57 of Scheme XVwhere RH 2 R=ez.Z

O

This compound was prepared by General Method 8 (EXAMPLE 138) from 7-amino-3,4benzocoumarmn (structure 56 of Scheme XVI, where R 1

R

2

=R

3 =benzo, 1=0O) (180 mg, 0.85 mmol) to afford 75 mg of Compound 239 along with 150 mg of 1,2dihydro- 2 ,2,4-tiethyl1loisocouaino[34fquline as yellow solids. Data for Compound 239: mp 246-248 OC; IH NMR (400 MHz, CDCI3) 8.18 J 7.6, 1 8.16 J 7.6, 1 7.80 I 7.78 J 7.6, 1 7.43 J 7.6, 1 6.39 I H), 5.45 (s1 2.11 3 1.33 6 13 C NMR (100 MHz, CDCI 3 162.2, 152.7, 146.1, 136.4, 134.9, 130.7, 129.1, 127.2, 126.5, 120.5, 119.4, 119.0, 117.8, 107.6, 99.8, 52.7, 31.8, 19.0; Anal. Calcd for C19Hl7NO 2 C, 78.33; H, 5.88; N, 4.8 1. Found: C, 77.99; H, 5.79; N, 4.72.

EXAMPLE 140 I 2 -Dihydro-2.2.4.triMethl. I1 uinolonor4 ~u oline(COmt 0 )und240. srcture 57 of Scheme IV.whr R=H R 2

R

3 ez I= 3 -Anno- 6 henantijjpe(tutr 6o ceeX I hr 1

H

R

2

=R

3 =benzo. mixture of 3 -nitro-6(S5f)-phenanthridinone (structure 55 of Scheme XVI, where R 1

R

2

=R

3 -benzo, (480 mg, 1.5 mniol) and 50 mg of Pd/C in 60 mL of DMF was stirred under an atomnsphere of H2 for 2 h. The midxture was filtered through a CeliteTM pad and the filtrate was concentrated to give 0.4 g of the crude .aniline as a yellow solid. This material was used without further purification.

1.2Dhdo224tr t I- l-isouinolono

F

4 3-guoie(Cmo d24.srtue5 of Schieme XVI. where

R

1

H.R

2 3 =benzo. Z-NH) This compound was prepared by General Method 8 (EXAMPLE 138) from 3-mn-(H-peatrdnne (0.4 iodine (150 mg, 0.6 mmol), acetone (16 mL) and DMF (14 mL) to afford 220 mg of Compound 240 as a yellow solid. Data for Compound 240: mp 30 1-302 OC; ER (KBr, crn- 1) 3300, 3010, 1670, 1450, 1300; Ijj NMR (400 MHz, CDC13) 8.28 J 7.6, 1 8.25 I 7.6, 1 7.90 1 7.70 J 7.6, 1 7.39 J 7.6, 1 6.48 1 H), 5.78 (br s, 1 5.42 I 2.13 3 1.33 6 13 C NMR (100 MI-z, acetoned6) 162.4, 147.1, 139.2, 137.0, 133.3, 129.2, 128.7, 128.6, 125.8, 125.0, 121.8, 118.9, 118.4 108.5, 98.1, 52.8, 31.6, 19.0.

EXAMPLE 141 1.-iyr-...1111- 2i~ioo[.-gqioln (Compound 41sucture 57 of Scheme XVI. wher RIEER 2 3 mehv.Z= This compound was prepared by General Method 8 (EXAMPLE 138) from Carbostyril 124 (structure 56 of Scheme XVI, where R I=R 2

R

3 =methyl, Z=N11) (500 mg, 2.8 mmol) to afford 175 mg of Compound 241 as a pale yellow solid. Data for Compound 241: mp 282-284 OC; IR (KBr, cm- 1 2966, 2918, 1658, 1641, 1425, 1257; IH NMR (400 MHz, CDC13) 7.24 1 6.34 I 6.23 1 5.37 I 2.41 3 2.04 3 H), 1.29 6 13 C NMR (100 MHz, CDC13) 165.0, 149.8, 146.5, 140.3, 129.2, 127.6, 119.1, 118.5, 114.9, 112.5, 97.2, 52.4, 31.8, 19.3, 18.9.

EXAMPLE 142 1 .2-Dihydro- L-hydroxy-2.2,4..rMethl-. FO-isochromenor4.3..glguinoline (Compound 242. structure 62 of Scheme XVI. where R=H. R 2

R

3 =benzo. Z-O) To a yellow solution of Compound 239 (EXAMPLE 139) (10 mg, 0.033 mmol) in 0.5 mL of toluene at -78 OC was added 0.050 mL of DIBALH (1.5 M in toluene 0.075 mmol), and the resulting solution was stirred at -50 10 OC for 20 min. The reaction was quenched with water (1 miL) and extracted with ethyl acetate (2 x 5 mnL). Removal of solvent and chromatography of the crude residue (silica gel, 20% ethyl ac'dtate/hexanes) afforded 6 mg of Compound 242 as a colorless oil. Data for Compound 242: lIH NMR (400 MHz, acetone-d6) 7.74 J 7.8, 1 7.52 1 7.37 J 7.8, 1 7.31 J 7.8, 1 7.19 J= 7.8, 1 6.26 J= 6.5, 1 6.17 I 5.97 J= 6.5, 1 5.40) (br s, I 5.29 1 2.05 3 1.27 6 H).

EXAMPLE 143 1. 2 Dh-dro 2 .2.4.6-tetra meth.8.prn3 I-'gin~n (CHon-23 tucue6 of Scheme XVI, where R=R 2

R

3 =met Al Z-O) 1.

2 -Dihydro-2.2.4.6-tetrarrethyI..8..pvanonor5.6..glquinoline structure 7 'F Sc-hemeXV where R=R 2 =metby- -ZO) To a solution of 7 -nitro- 4 -miethylcoumarin (structure of Scheme XVI, where R 1

=R

2

R

3 =methyl, (0.61 g, 1.75 mmol) was added mg of 10% Pd/C. The reaction mixture was stirred under an atmosphere of H2 for 2 h. The mixture was filtered through a pad of CeliteTm and the filtrate was concentrated to give 0.5 g of the crude amino compound as a yellow solid. This material was used without further purification, and was submitted to General Method 3 to afford 90 mg of 1,2-dihydro- 2,2,4,6-tetramethyl-8-pyranono[5,6-gquinoline as a yellow solid. Data for 1,2-dihydro- 2,2,4,6-tetramethyl-8-pyranono[5,6-g]quinoline: mp 258-260 oC; IR (KBr) 3300, 2955, 1720, 1630, 1505, 1390, 1250; 1H NMR (400 MHz, CDC13) 7.27 1 6.30 1 H), 6.12 (br s, 1 5.84 1 5.44 1 2.37 3 2.05 3 1.32 6 13

C

NMR (100 MHz, CDC1 3 161.9, 155.4, 153.1, 147.1, 128.8, 127.0, 119.2, 110.3, 109.0, 98.6, 52.6, 31.8, 18.6.

S2-Dihdr-2,24 6-tetr thnompound 243. structure 61 of Scheme XVI. where RI=R 2

R

3 =methyl, Z=O) To a solution of 1,2-dihydro- 2,2,4,6-tetramethyl-8-pyranono[5,6-gJquinoline (15 mg, 0.06 mmol) in 1 mL of toluene at 78 0 C was added DIBA1-H (0.5 M in toluene, 0.24 mL, 0.12 mmol) and the resulting mixture was allowed to stir at -50oC for 60 min, generating a clear brown solution. The reaction was quenched with water (1 mL) and was extracted with ethyl acetate (2 x 10 mL).

The organic extract was concentrated and was chromatographed (silica gel, 4:1 hexanes /ethyl acetate) to afford I mg of Compound 243 as a colorless oil Data for Compound 243: IH NMR (400 MHz, acetone-d6) 6.84 1 5.96 1 5.33 J 1 5.26 1 5.21 1 4.59 J 3.5, 2 1.96 3 1.93 3 H), 1.24 6 H).

EXAMPLE 144 2 3 4 -Tetrahydro-2,2.4-trimethyl-10-isoquinolonor4.3-gquinoline (Compound 244.

structure 63 of Scheme XVI, where R 1

R

2

=R

3 =benzo. Z=O) Hydrogenation of Compound 240 (550 mg, 1.9 mmol) over 10% Pd/C (200 mg) in 250 mL of ethyl acetate for 14 h at rt afforded 510 mg of Compound 244 as a yellow solid. Data for Compound 244: mp 263-264 oC; IR (KBr) 3304, 2960, 2928, 1658, 1606, 1467, 1267 cm- 1 IH NMR (400 MHz, CDC13) 9.67 (br s, 1 8.45 J 8.0, 1 8.11 J 8.0, 1 7.94

I

7.69 J 8.0, 1 7.41 J 8.0, 1 6.25 1 4.08 (br s, I 3.02

I

1.81 (dd, J= 12.8,5.2, 1 1.49 12.8, 1 1.46 6.7, 3 1.29 3 H) and 1.23 3 H).

EXAMqPLE 145 l.

2 Diydo-.24.trmehy..I -thioisoui n r 4 3-gunle (Cmon 24 srct ureg 58 of Schemie XVI, where R 1-H. R 2

=R

3 =benzo

ZO)

A mixture of Compound 240 (9 mg, 0.03 mrnol) and Lawesson's reagent (41 mg, 0. 1 MMOl) in 2 mL of TI-F was stirred at 80 0 C for 3 h, generating a bright yellow solution. Removal of the solvent and chromatography of the crude mixture (silica gel, 1: 1 ethyl acetate/hexanes) afforded 8.2 mg of Compound 245 as a yellow oil. Data for Compound 245: IH NMR (400 MHz, acetone-d6) 8.93 J 8. 1, 1 8.33 J 8. 1, 1 8.01 INF), 7.75 J= 8. 1, 1 7.44 J= 8. 1, 1 6.73 1 5.97 (br s, I 5.51 I 2.15 3HM, 1.35 6H).

EXAMPLE 146 1.

2 3 4 etrah ydro-2.24.-ety lOiouiooor. in ine opud26 structuire 63 of Scheme XVI. whr0,H R=~ez

Z--O)

This compound was prepared by a HPLC separation of the enantiomers of Compound 244 using a Chiracel OD-R column, using a 4:1 midxture of methanol and water as the mobile phase. The optical purity of Compound 246 was determined by HPLC to be 99% e.e.; (aI 2 0 D 106 (MeOB).

EXAMPLE 147 Mimet (Co pon247 structuare 57 of Scheme XVII where R =R 2

R

3 rifluometh I This compound was prepared as depicted in Scheme XVII and as described below.

l1-tert-Butyloxyc rbamovl13-.nitrobennene (tucur 65 ofScheme XVI whereR 1 4j P=tbutyloxvcarbonyl. Genral Method 10. N-Boc-Protecno^n of Ni roaniineM To a flame-dried 500 mL r.b. flask containing 3 -nitroaniline (structure 64 of Scheme

XVII,

where R I=H, Z=-NH) (20.0 g, 144.8 mmnol) in 150 mL THF was added di-tert-butyl dicarbonate (3 1 .60 g, 144.8 mmol, 1.00 equiv), and the midxture was cooled to 0 0 C. 4-Nfl- Dimethylaminopyrid ine (19.46 g, 159.3 rrunol, 1. 10 equiv) was added portion-wise, and the mixture was allowed to warm to r1 overnight. Ethyl acetate (400 mL) was added, and the mixture was washed with 1 M NaHSQ4(aq) (2 x 200 mL) and brine (200 mL), dried (Na2SO 4 and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 9: 1) afforded 31.4 g (91 of 1 -tertbutyloxycarbamoyl-3-nitro benzene as a white solid. Data for l-tert-butyloxycarbamoyl-3 nitrobenzene: IH NMR (400 MHz, CDC13) 8.31 (dd, 1H, J 2.2, 2.2, 1IH, 7.88 (dd, J 7.9, 1.5, 1H, 4-11), 7.69 (br d, J-7.8, IH, 7.44 (dd, J= 8.3, 8. 1, 111, 6.74 (br s, 1H, NH), 1.54 9H-, (C113)3C0)J.

3 -tert-Butvtoxycarbarn lanjji(srcue 6o chm VIihrR HPt butvloxv~carbonyl. ZNH) To an oven-dried I-L r.b. flask containing lWertbutyloxycarbamoyl.3- tobeuzene (20.0 g, 83.9 mmnol) in 500 mL 1: 1 ethyl acetate/ethanol at rt was added 10% Pd on C (approx I mol%), and the mixture was stirred under an atmosphere of H2 gas for 6 h. The reaction mixture was then filtered, and concentrated under diminished pressure to give 17.4 g (quant of 3 -tert-butyloxycarbamoylaniline as a white oily solid. Data for 3 -tert-butyloxycarbamoylaniline 1Hj NMR (400 MHz, CDC1 3 7.04 J 8.0, 8.0, IH, 6.98 (br s, iN, NH), 6.53 (dd, J 7.9, 1.8, 1IH, 6.36.

(in, 2H-, 3.66.(br s, 2H, NH2), 1.51 9H, (C113)3C0)].

7 -tert-Buy- vabmy l- ivdro-I2.4trnethy'guin-line (trce 67 of Scheme XVII. whrR=.P-uyo arboyl WZ=j QGral MethodAL 51&£aW cyiato oerBuyxyrbampyanljnes To an oven-dried 1 L r.b. flask containing 3-etbtlxcraolnln (17.4 g, 83.5 nol), MgSO4 (50 g, 5 equiv), and 4-tertbutylcatechol (420 mg, 3 mol%) in 120 mL acetone (approx 0.75 M in the aniline) was added iodine (1.07 g, 5 mol%), and the mixture was heated to reflux for 8 h. The crude reaction mixture was then cooled to rt, filtered through a bed of CeliteTM on a fitted-glass funnel, rinsing with ethyl acetate, dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, gradient elution) afforded 19.9 g of 7 -tert-butyloxycaiibamoyl12di.ydro-2,24trimethyiquinoline as a white solid, which was further purified by recrystallization from acetonitrile to give white needles. Data for 7 -tert-butyloxycarbamoyl- 1 ,2-dihydro-2,2,4trimethylquinoline: IH NMR (400 MHz, CDCI3) 6.93 J 8.3, 1H, 6.81 (hr s, I1-, HNBoc), 6.34 (in, 2H, 5.21 J 0.9, IH, 3.71 (br s, 111, NH), 1.94 (d, J 3H, 4-CH3), 1.50 9H, (CH3)3C0)], 1.24 6H, 2-(CH3) 2 1.

7-Amino- l.

2 -diIhydro-2.Z.4-trirnethyginoline Geea ehd1:Removal of Boc Protective Group from Compounds of structure 67 of Scheme XVII1. where P=tbut 'OXvCari onvl. Z=TN) To an oven-dried 25 mL r.b. flask containing 7-tertbuyoyabmy-,-iydo224tiehluna (400 mg, 1.38 inmol) in 2 mL dichioromethane at 0 0 C was added trifluoroacetic acid (1.06 miL, 10 equiv), and the midxture was allowed to warm to rt. After 3 h at rt, the reaction mixture was diluted with 50 mL dichioromethane, transferring to a 125 mL erlynmeyer flask, and cooled to 0 0 C before neutralization to PH 8 with sat'd aqueous NaHCO3. The biphasic: mixture was transferred to a separatory funnel, the layers were separated, and the organic phase was dried (Na2SO4), and concentrated under reduced pressure to afford a light reddish oil. The crude material thus obtained was of greater than 98% purity by I H NMR, and was carried on to the next step without further purification. While the 7 -amino-quinoline obtained decomposed appreciably within a few hours upon standing at it, ethanolic solutions could be stored at -20TC for 2-3 days without substantial adverse effect on the subsequent reaction outcome. Typically however, the material was stored in bulk as the crystalline Bocprotected amine, and portions were hydrolysed as needed. Data for 7 -amino- 1,2-dihydro.

2 2 4 -trimethylquinoline: IH NMR (400 MHz, CDC13) 6.86 J 8.2, IH, 5.99 (dd, J 8.0, 2.3, 1H, 5.79 J 2.0, 11H, 5.12 J 1.4, 1H, 3.53 (br s, 3H-, NH2, NH), 1.93 J 1.2, 3H, 4-CH3), 1.24 6H, 2-(Clf3)2].

1.

2 -Dihydro-2.2.4 iiethv6tluoont 0 nrs..qIoe (Cmpu. 2 4 structuare 57 of Scheme XVUI where R=R 2 =H R-rfuomtv ZNH Geea Mthod 3: Knorr C-clizatio of -amin -1.2-dihvdr-.2 2 4..rmtygiolnswt Ket Eter To an oven-dried 10 mL r.b. flask containing 7 -amidno-l,2-dhydro2,24 trimethyiquinoline (100 mng, 0.53 mmol) and ethyl 4 4 4 -trifluoroacetoacetate (85.4 m.L, 0.58 mmnol, 1. 1 equiv) in 2.5 mL absolute ethanol was added ZnCI2 (110 mg, 0.81 mmol, equiv) and the mixture was heated to reflux for 3 h. Upon cooling to it, the reaction mixture was diluted with 40 mL ethyl acetate, and the organic solution was washed with sat'd aqueous NH-4C1, dried (Na2SQ 4 and concentrated under reduced pressure.

Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, gradient elution) afforded 72 mg Of Compound 247 as a bright fluorescent-yellow solid, in addition to 70 mg Of Compound 248 (EXAMPLE 148) as a pale yellow crystalline solid, and 10.4 mg of Compound 249 (EXAMPLE 149) as a white solid. Data for Compound 247: IH NMR0(00 MHz, CDC13) 11.45 (br s, I H, CONH), 7.38 WI, 6.66 IN, 6.27 IH, 10-H), 5.42 IH, 4.35 [br s, IH, (CH3)2CNHI, 2.03 3H, 4-CH3), 1.33 6H, 2-(CH3)2].

EXAMPLE 148 8-Ethoxy-12-iyr-.4-im-hl-t+l--neh-82 dd9L-% gm (Compound 248. structure 71 of Schteme XWLI where

R

1 =R=H R=rfuomthv

R

5 =ethyL. Z=N' This compound was obtained along with Compounds 247 and 249 as described above (EXAMPLE 147). Data for Compound 248: IH NMR (400 MHz, CDCI3) 7.56 (d 1H, J 6.84 IN, 6.74 1H, 10-H), 5.52 1H, 3-H), 4.47 2H, J 7.0, CH3CII 2 4.12 [br s, 1H, (CN3)2CNMI, 2.09 3H, J 1.3, 4- CH3), 1.42 3H, J 7.0, CH3CH 2 1.34 6H, 2-(CFI3)2]. This product was readily converted to the 2 -quinolone isomer Compound 247 by heating neat with 10 equiv pchiorophenol at 1 80 0 C for 3 h, giving Compound 247 in >80% yield.

EXAMPLE 149 l.

2 6 7 -Tetrayrhyry24 etltfi

I

giuinoliri (Comnound 249.-rcue6 fShm VI hr 1 R H

R

3 =rifuormetyL _DH This compound was obtained along with Compounds 247 and 248 as described above (EXAMPLF, 147). Data for Compound 249: IH NMR (400 Mliz, DMSO-d6) 10.16 IN, CQNH), 7.09 IH, 6.61 1H, OH), 6.24 IH, 6.01 IH, (CH3)2CNHJ, 5.21 IH-, 2.80 and 2.72 (ABq, 2H, JAB 16.4, 7-H), 1. 86 3H, 4-CH3), 1.19 and 1. 17 [2s, 2 x 3H, 2-(CH3) 2 1. This product was readily converted to the 2-quinolone isomer Compound 247 by heating to 60'C in benzene or toluene with a catalytic amount of p-TsOH for 2 h, giving Compound 247 in >95% yield.

EXAMdPLE 150 (RIS)- l.

2 3 4 ,Tetrahdro.2.4Timty6tlpometh0ID 0aoflrslgunno~n (Comound 250. structure-63 of Scheme XVIII where- R 1

=R

2 -rJ R 3 =trifluoromethyl

Z=O)

(RIS)- 1.

2 .3.4-Tetrahydro-224- Tmthl-7.( 111-rmtvaeovunln srcue7 of Scheme XVII where R=.P-btlZO)In a dry r.b. flask equipped with a magnetic stir bar was suspended I,2-dihydro2,2,4.tithy17-( 1, 1trimethylacetoxy)quino line (structure 67 of Scheme XVII, where R 1 P=t-butyl,

Z=O;

EXAMPLE 138) (1.01 g, 3.37 mmol) and 10% Pd/C (200 mg) in CH2C12. The flask was charged with H2 gas and allowed to react for 12h with constant stirring. The suspension was filtered though a bed of CeliteTM, washed with EtOAc (2 x 50 mL) and concentrated in vacuo to afford 996 mng of IRS)1,2,3,4tetrahydro224ithyl 7 (ll1 trimethylacetoxy)quinoiine as a light brownish-red solid. Data for (RIS)- I, 2 ,3, 4 -tetrahydro.

2,,-rmty-7(,,-rintyaeoyqioe IH NMR (400 14Hz, CDCI 3 7.10 (dd,J= 8.5, 0.9, iN), 6.30 (dd,J= 8.4, 2.4, 1H), 6.13 2.2,1 H, 3.62 (br s, 11-), 2.87 (in, 1.71 (dd,JI= 13, 5.4, 1 1.41 (apparent t, J= 13, 1H), 1.31 1.22 3 1. 16 3 H).

(RIS- l.

2 3 4 Tetrahydro-7..hydrox224.-- etyginln This compound was prepared as described above for 1,-iyr--yrx-,24tintyqioln (EXAMPLE 138) from (RIS)-1,,,-erhdo22,Iity--111 trimethylacetoxy)quinoline (230 mg, 0.845 minol) to afford (R/S)-l,2,3,4-tetrahydro-7.

bydroxy-2,2,4r1tylquinolie, which was used in the following reaction without further purification.

(RIS)- 1.

2 3 ~erhdo2~h1filoothl

FS

6 g inoin (Compound 250 structure 63 of Scheme VI where R 2

R

3 tiuoroetv Za!) This compound was prepared by General Method 9 (EXAMPLE 138) firom crude (RIS)- l, 2 3 A-tetrahydro7hydroxy224trimnethyqunlin and ethyl 4,4,4trifluoroacetoacetate (3 10 mg, 1.69 inmol, 2 equiv) to afford 160 mg (6 1% overall) of Compound 250 as a yellow solid. Data for Compound 250: Rf 0.4 (hex/EtOAc, 3: 1

H

NMR (400 MHz, CDC1 3 7.41 I 6.37 I 6.33 1 4.46 I 2.92 (mn, 1 1.80 (dd, J 13, 5.0, 1 1.42 (dd, J 13, 13, 1 1.38 JI 6.0, 3 1.31 3 1.25 3 H).

EXAMPLE 151 1.

2 -Dihyvdro-22.4f1bethyh-6-ifluontv1..ti Panon r6.gluinn lie(omon 251, structure 58 of Scheme XVI. where R I=R 2 R 3 =trifluoromethyl, 1=0) In a dry pressure tube equipped with a magnetic stir bar was dissolved Compound 238 (EXAMPLE 138) (50 mg, 0. 159 mmol) and Lawesson's reagent (320 mg, 0.79 mmol, 5 equiv) in 15 mL toluene. The resulting solution was heated at 100 0 C for 20 h. The cooled solution was concentrated on Celite Tm to give a free flowing powder which was purified by flash column chromotography (silica gel, hexanes/EtOAc, 5:1) to give 40 mg of Compound 251 as a bright red solid. Data for Compo und 251: Rf 0.36 (silica gel, hex/EtOAc, 3: 1 H NMR (400 M4Hz, acetone-d6) 7.25 1 4.03 I 6.89 (br s, I 6.53 I 5.62 I 2.77 J =1.l1, 3H), 1.39 6H).

EXAMPLE 152 (RIS)- 1...-erhdo22 8ti n-r trctre76 of'Scheme IX. were R=R 2 0 3 tilooehl In a dry pressure tube equipped with a magnetic stir bar was dissolved Compound 250 (EXAMPLE 150) (26 mg, 0.0836 mmol) and Lawessori's reagent (60 mg, 0.41 mmol, equiv) in 15 mL toluene. The resulting solution was heated at 100'C for 20 h. The cooled solution was concentrated on CeliteTM to give a free flowing powder which was purified by flash column chromotography (silica gel, hexanes/EtOAc, 5: 1) to afford 19.2 mg (71 of Compound 252 as a bright orange solid. Data for Compound 252: Rf 0.37 (silica gel, hex/EtOAc, 1 H NMR (400 MHz, CDCI3) 7.43 I 7.16 1 6.45 I H), 4.59 (br s, 1 2.93 (in, I 1.82 (dd, J =13, 5. 1, 1 1.45 (app t, J= 13, 1 1.39 J= 6.6, 3 1. 34 3 1. 27 3 H).

EXAMVPLE 153 (Copoud 53.stuctre57 of Scheme WVIT whereR 1 R

R

3 =hloodfluroethl.Z=O) This compound was prepared by General Method 9 (EXAMPLE 138) from l, 2 -dihydro-7 hyrx-,,-iehlunh (EXAMPLE 138) (71 mg, 0.37 mmol) and methyl 4chloro- 4 4 -difluoroacetoacetate (150 mg, 1.62 mmol, 2.2 equiv) to afford 17.6 mg (15 of Compound 253 as a light yellow solid. Data for Compound 253: Rf 0.35 (hex/EtOAc, 3: 1H NMR (400 MHz, CDCl3) 7.40 1 6.33 1 6.31 1 5.41 1 H), 4.42 (br s, 1 2.02 3 1.36 6 H).

EXAMPLE 154 9Acetyl- 2- tilor h18 dn 6 mln (Compound 254. structure59 ofScheme XVI.where R-R-H. 3 rfluoromethl.

R

4 =acetyL ZN)m To an oven-dried 10-mL r.b. flask containing Compound 247 (15 mg, 0.049 mmol) in I miL dichioromethane at rt was added acetic anhydride 10 ML, 1. Immol.) and 4-NNdirnethylaminopyridine (6.5 mg, 0.054 mmol, 1. 1 equiv), and the mixture was stirred min. Dichloromethane (20 mL) was added, and the solution was washed with IM pH 7 potassium phosphate buffer, dried (Na2SQ 4 and concentrated under reduced pressure.

Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, gradient elution) afforded 16 mg of Compound 254 as a yellow oily solid. Data for Compound 254: 'H NMR (400 MHz, CDC13) 7.66 1H, 7.08 IH, 6.83 (s, 1H, 10-H), 5.63 1H, 4.31 [br s, 11-, (CH3)2CNH], 2.38 3H, CII3CON), 2.12 (s, 3H, 4-CH 3 1.48 6H, 2-(CH3) 2 EXAMPLE 155 I .2-Dillvdro-2.2.4.10 -tetramethv6t ilomth..

8 piono[5.6-glUmoline mon 255. structure 57 of Scheme XVI. where R =methyl.

R

2

R:

3 =triflu rmtbvl

Z--NH

6 -tert-Buvlovcr amo vl2n i pluene c65f Scheme II here =m thl.

P=t-bu yoxycar~~n IZ=N-l This intermed iate was prepared from 2 -methy1-3-nitro aniline (5.00 g, 32.8 mmol) by General Method 10 (EXAMPLE147), affording 7.44 g of 6tert-butyloxycarbamoyl-2nitrotoluene as an off-white solid. Data for 6-tertbutyloxycarbamoyI..2itrotoluene: IH NMR (400 MHz, CDCI3) 7.98 (br d, J 1H, 7.51 (br d, J 8. 1, 11-, 7.28 (dd, J 7.6, 3.4, 1H, 6.58 (br s, 18, NH), 2.34 3H4, 1-CH3), 1.53 9H, (CH3)3COyj.

2 -Amino- 6 -ter -t I vx carbamovltolee(trcue6 o ceeXVI hr Rl=methyl. P=t-ut lox carbonyl. =xm-I This compound was prepared from 6-tertbutyloxycarbamfoylp2.nitrotoluene (4.60 g, 18.2 mmol) in a manner similar to that described for 3 -tert-butyloxycarbamnoylaniline (EXAMPLE 147), affording 4.00 g of 2-amino- 6 -tert-butyloxycarbamoyltoluene as a colorless oil. Data for 2 -arnino-6-tertbutyloxycarbamoyltoluene: IH NMR (400 M.Hz, CDC1 3 7.04 (br d of ABq, JAB JA 0,

T

B 7.9, 2H, 6.49 J 8.3, 18. 6.26 (br s, 18H, NH), 3.61 (br s, 2H, NH2), 2.02 3H, 1-CH3), 1.51 9Hf, (CH3)3C0)J.

7 -tert-Butvl xycarbamov l.-iyr-....taethlquinoline (tructure 67 of Scheme XYYI where R=methyl. P=-butloxcarboni, Z--NH) This compound was prepared from 2 -amino- 6 -tert-butyloxycarIbamoyltoluene (4.00 g, 18.0 mmol) according to General Method I11 (EX-AMVPLE 147), affording 4.56 g of 7 -tert-butyloxycarbamoyll, 2 -dihydro-2,2,4,8-tetramethylquinoline as a white solid. Data for 7-tertbutyloxycarbamoyl- l, 2 .diIhydro-2,2,4,8-tetramethylquinoline: 1 H NMR (400 MHz, CDCI3) 6.94 and 6.88 (br ABq, JAB~ 8.3, 2H, 6.16 (br s, 1H, IfNBoc), 5.27 (s, 1II, 3.61 (br s, IH, (CH3)2CNH]) 2.04 3H, 8-CH3), 1.97 3H, 4-CH3), 1.50 (s, 9H, (C113)3C0)]), 1.28 6H, 2-(CH3)2).

7-Amno-l.

2 dihdro224.8-tetramethyjguinojine This compound was prepared by General Method 12 (EXAMPLE 147) from 7 -tert-butyloxycarbamoyl 12.dihyro-2 2,489 tetramethylquinoline (400 mg, 1.32 mmol) affording 267 mg (quant) of 7-amino-1,2dihydro-2,2,4,8-tetrame-thylquinoline as a light reddish oil. Data for 7-amidno-I ,2-diliydro- 2 2 4 8 -tetramrethylquinoline: 1II NMR (400 MI-z, CDCl3) 6.82 J 8.2, 1 H, 6.08 J 8. 1, 1 H, 5.15 J 1.2, 1IH, 3.56 (br s, 3H, NJI2, NH), 1.95 J 1.2, 3H, 4-CH3), 1.91 3H, 8-CH3), 1.27 6H, 2-(CH3)2].

I .2-Dihydro-2,2,4. IO-tetramth I- -tr fluoromethyl-8.yioorA ~n lie(omon 255. structure 57 of Scheme XVII. where R 1 =methvl. R 2

R

3 trifluoromet yl, Z-=NH) This compound was prepared by General Method 13 (EXAMPLE 147) from 7-amino- 1,2dihydro-2,2,4,8-tetramethylquin~oline (100 mg, 0.49 mmol) and ethyl 4,4,4trifluoroacetoacetate (107 mL, 0.73 mrnol, 1.5 equiv) affording 75 mg of Compound 255 as a fluorescent-yellow solid. Data for Compound 255: IH NMR (400 MHz, CDC13) 9.23 (br s, 1H, CONH), 7.37 IH, 6.67 IH, 5.45 IH, 4.14 [br s, 1H, (CH3)2CNH], 2.12 3H4, IO-CH3), 2.04 J 1. 1, 3H, 4-CH3), 1.37 6H, 2- (CH3)2].

EXAMPLE 156 I .2-Dihyvdro-2.2.-trirnethyl6( 1.1 2 2 et fuorethyvl)..8p-gnn- s6iuoln (Compound 256. structure: 57 of Scheme XVII. where R 1

=R

2 R=pentafluooethyl.

ZaO) This compound was prepared by General Method 9 (EXAMPLE 138) from 1,2dihydro-7-hydroxy -2,2,4..trimethylquino line (EXAMPLE 138) (67 mg, 0.35 mmol) and ethyl 4,4,5,5,5- pentafiuoropropionylacetate (179 mg, 0.76 rnol, 2.2 equiv) to afford 11. 8 mg (10 of Compound 256 as a light yellow solid. Data for Compound 256: IH NMR (400 MHz, CDCl3) 7.31 1 6.35 1 6.33 1 5.40 1 4.54 1 H), 1.99 J= 1. 1, 3H), 1.35 6H).

EXAMPLE 157 (R/S)-6-Chloro(djflu-or-oAthv. l 2 3 4 etayr224thlI-8.-panonos ZlIquinoline (Compound 257. structure 3 ofSceeX I.whrR 1 R=

R

3 =chlorodifluoromethyI. ZO) This compound was prepared by General Method 9 (EXAMPLE 138) from (RS-,,,-erhdo7hdoy224tiehlunln (EXAMVPLE 150) (57 mg, 0.29 mmol) and methyl 4 -chloro- 4 4 -difluoroacetoacetate (120 mg, 0.645 mmol, 2.2 equiv) to afford 35.6 mg (38 of Compound 257 as a fight yellow solid.Data for Compound 257: Rf 0.37 (hex/EtOAc, 3: 111 NMR (400 MHz, CDC13) 7.55 I 6.36 1 6.32 I 4.53 (hr s, 1 2.95 (in, I H 1. 80 (ddd, J 13, 5.1, 1.5, 1 1.45 (apparent t, J 13, 1 1.39 J= 6.7, 3 1.32 3 1.27 3

H).

EXAMPLE 158 7-Chlro thLLtnloorty--pTn-~ u~nln (Compound 258. structure 57 of Scheme XVII. where R I=H, R 2 R1 3 trifluoromethyl.

This compound was prepared by General Method 9 (EXAMPLE 138) from 1,2dihydro-7-hydroxy2,2,4imethyquinoline (EXAMPLE 138) (78 mg,. 0.41 mrnol) and ethyl 2 -chloro-4,4,4-trifluoroacetoacetate (195 mg, 0.898 inmol, 2.2 equiv) to afford 7.2 mg of Compound 258 as a red solid. Data for Compound 258: Ri 0.33 (hex/EtOAc, 3: IH NMR (400 Mz, CDC1 3 7.37 1 6.32 I 5.42 1 4.54 (br s, 1 2.01 J 1.0, 3 1.31 6 H).

EXAMPLE 159 (R/S)-7-Chloro- Il.

4 etrhydro2 .24utyb1oothy8 yann5 6 glc~~~uinoline~~ (Cmond 29.stucure 63 of Scheme XVIII. where R=H.R

C.

R

3 =trifluoromethyl. Z-O) This compound was prepared by General Method 9 (EXAMPLE 138) from (RIS)-1,,,-etayr-7hdoy-,, inethylquinoline (EXAMPLE 150) (57 mng 0.29 inmol) and ethyl 2 -chloro-4,4,4-trjfluoroacetoacetate (140 mg, 0.645 mrnol, 2.2 equiv) to afford 6.8 mng of Compound 259 as a yellow solid. Data for Compound 259: Rf 0.35 (hex/EtOAc, 3: IH NMR (400 MHz, CDC13) 7.53 1 EH), 6.32 I 4.51 (br s, I 2.93 (in, 1 1.81 (dd, J 13, 3.7, 1 1.44 (apparent t, J 13, 3 1.31 3H), 1.25 3 H).

EXAMPLE 160 (RIS-1234Ttayr-. 4-"ehl6tiloomty n qio (Compound 260. trtulr 63 of Scheme XVI. where R 1

=R

2

R

3 =trifluoromethvl.

(R/S-

7 -tert-Buty' xcaram0 1 1 2 3 4 ttayr.224rmtygioje(tutr Scheme XVII whre =H Pt-uyo caonlZ= H To an oven-dried 100 ml, round-bottomed flask containing 7-tert- butyloxycarbamoyl.1 ,2-dihydro-22,4 trirnethyiquino line (EXAMPLE 147) (200 mg, 0.69 mmol) in 50 mL 2:1 ethyl acetate/ethanol at rt was added 10% Pd on C (approx 1 mol%), and the mixture was stirred under an atmosphere of H2 for 4 h. The reaction mixture was then filtered, and concentrated under diminished pressure to give 201 mg (quant) of 7-tertbutyloxycarbamoyl. l, 2 3 4 -tetrahydro..2,2,4..trimethylquinolineasawieolsld.Dt for (R/.ST- 7 -tert.butyloxycarbamoyl. l, 2 3 4 -tetrahydro..2,2,4-trimiethylquino line: IH NMR (400 MHz, CDC13) 7.02 J 8.7, 1IH, 6.73 (br s, I1H, HNBoc), 6.39 (dd, J 8.3, 2.2, IH, 6.29 (Ibr s, 1H, 3.62 (br s, 1H, NH), 2.85 (ddq, J 12.5, 12.3, 6.4, IH, 1.70 and 1.39 [d of AIBq, JAB 12.8, JA =5.5 Hz (3-Hequiv), JB 12.6 Hz (3- Hax)2H], 1.49 9H-, (CH3)3C0)J, 1.29 J1= 6.7, 3H, 4-CH3), 1.21 3H, 2-CR 3 1-14 3H, 2-CH 3 )-..-etayr.2.2,4 Ltb~ethyjqUiflji= This compound was prepared by General Method 12 (EXAMPLE 147) from 7 -tert-butyloxycarbamoyl- 1,2,3,4tetrahydro..2,2,4- iethylquinoline (150 mg, 0.51 mmol) to afford 98 mg (quant) of (RIS)- 7-nio1234ttayro224tiehlunln as a light reddish oil. Data for 7amn-,,,-erhdo224tintyqioie lfl NMR (400 MHz, CDC13) 6.92 (dd, J 0.8, 1H-, 6.02 (dd, J 8.2, 2.3, 1W, 5.77 J 2.3, 1W, 3.39 (br s, 3H, NH2, NH), 2.81 (ddq, J 12.6, 12.3, 6.4, IH, 1.68 and 1.38 [d of ABq, JAB= 12.8, JA 5.5 Hz 3 -Hequiv). JB 12.5 Hz (3-HaxJ2H], 1.26 J 3H, 4-Clf3), 1. 19 3H, 2-CR 3 1.14 3H, 2-CR 3 (Copoud 60.stuctre63 of Scheme VIII where R-R 2 H. 3 trifluoomethvl.

Za~ffj This compound was prepared by General Method 13 (EXAMPLE 147) from (R/S)7amino ,2,3,4tetrahyo224-ethylqoln (98 mg, 0.5 1 mmol) and ethyl 4 4 ,4-trifluoroacetoacetate (82 mL, 0.56 mmol, 1.1 equiv) to afford 66 mg of Compound 260 as a fluorescent-.yellow solid. Data for Compound 260: IH NMR (400 MHz, CDCI 3 11.32 (br s, IH, CONU), 7.50 lH, 6.64 IH, 6.41 1W, 10-H), 4.55 [br s, 1H, (CH3)2CNH], 2.91 (ddq, J 12.6, 12.4, 6.3, IH, 1.76 and 1.41 [d of ABq, JAB 12.8, JA 5.5 Hz 3 -Hequiv), JB 12.4 Hz (3-Hax)2H], 1.37 J 6.8, 3H, 4-CH3), 1.22 3H, 2-CH 3 1.18 3H, 2-CH 3 EXAMPLE 161 l.2-Dihydro- 2 .2,4,9-tetramethyl-6-rifluorometh-8-vridono.6 uinoline (Compoun 261. structure 57 of Scheme XVVL where R 1=R 2

R

3 =trifluoromethyl. Z=NCI1) To an oven-dried 50-mL r.b. flask containing Compound 247 (500.0 mg, 1.62 mmol) in mL THF at 0 0 C was added portion-wise sodium hydride (71.4 mg of a 60% dispersion in mineral oil, 1.78 mmol, 1.10 equiv). After 30 min, iodomethane (101 mL, 1.62 mmol, 1.00 equiv) was added, and the mixture was allowed to warm to rt, and after 4 h, the reaction mixture was cooled to 0°C, and water (5 mL) was added. The reaction mixture was then diluted with 100 mL ethyl acetate, and the organic solution was washed with 50 mL brine, dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, gradient elution) afforded 497 mg of Compound 261 as a bright fluorescent-yellow solid. Data for Compound 261: 1 H NMR (400 MHz, CDC13) 7.41 J 1.7, 1H, 6.73 1H, 6.28 1H, 10-H), 5.42 1H, 4.36 [br s, 1H, (CH3)2CNH], 3.62 3H, NCH3), 2.04 J 1.2, 3H, 4- CH3), 1.33 6H, 2-(CH3)2].

EXAMPLE 162 1.2-Dihdr-22.4-rimethv--trifloromethvl-6-vridono5. inoline(Comound262 structure 70 of Scheme XVII, where RI=R 2 =H R 3 trfluormethyl, Z=NH) An alternative procedure for the Knorr reaction combined 7-amino-1,2-dihydro-2,2,4trimethylquinoline (EXAMPLE 147) (131 mg, 0.70 mmol) and ethyl 4,4,4trifluoroacetoacetate (154 mL, 1.05 mmol, 1.5 equiv) with 0.5 mL polyphosphoric acid (PPA) in a 10-mL r.b. flask and the mixture was heated to 100°C for 2 h. The cooled reaction mixture was diluted with 140 mL ethyl acetate, and the solution was washed with neutralized to pH 8 with 50 mL sat'd aqueous NaHCO3. The layers were separated, and the organic phase was washed with 50 mL brine, dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, gradient elution) afforded 79 mg of Compound 247 along with 8 mg of Compound 262 as a fluorescent-yellow solid. Data for Compound 262: IH NMR (400 MHz, CDCI 3 10.50 (hr s, 1H, C=CCF3NH), 7.33 IH, 6.62 IH, 6. 17 (s, 1H, 10-H), 5.33 1H, 4.21 [br s, LH, (CH3)2CNH], 2.04 3H, 4-CH3), 1.36 [s, 6H, 2-(CH3)2].

EXAMPLE 163 6-rDichloro(ethoxy~ehl. I -i r-B6mqig (Compound 263. structure 57 of Scheme XVII. where R=R 2

R

3 =dichloro ethxmethyl. This compound was prepared by General Method 9 (EXAMPLE 138) from 1,2-dihydro-7hydroxy-2,2,4-trirnethylquino line (EXAMPLE 138) (67 mg, 0.35 mnmol) and ethyl 4,4,4trichloroacetoacetate (179 mg, 0.77 mmol, 2.2 equiv) to afford 30 mg of Compound 263 as a light orange solid. Data for Compound 263: Rf 0.28 (hex/EtOAc, IH NMR (400 MHz, CDCI3) 7.97 1 6.51 1 6.32 1 4.42 J 2 2.92 I 1.79 (dd, J 13, 5. 1, 1 1.40 4 1.38 J 6.6, 3 1.30 3 H), 1.25 3 H).

EXAMPLE 164 5-(3-Furyl)- l.

2 dhydro- 2 .2.4-t ety-.prnnr6.luinoline (Compound 264.

structure 57 of Scheme XVII. where R=R 2 H. R 3 =3frl.Z O This compound was prepared by General Method 9 (EXAMPLE 138) from 1,2-dihydro-7hydroxy-2,2,4-nimxethylquinoline (EXAMPLE 138) (120 mg, 0.62 rnol) and ethyl B-oxo- 3 -furanpropionate (227 mg, 1.25 mrnol, 2 equiv) to afford 6.4 mg of Compound 264 as a light yellow solid. Data for Compound 264: Rf 0.30 (hex/EtOAc, IH NMR (400 MHz, CDC13) 7.76 I 7.76 (dd, J 3.5, 1.8, 1 7.34 1 6. 66 J 1.7, 1 6.35 1 6.06 1 5.36 I 4.34 I 1.95 J 1. 1, 3 1.34 6

H).

EXAMPLE 165 -1.2-Dihydro- 1, 2 2 4 -tetamethvI6t furmtv-.panonor.6g-giguino line (Copound 265 structure 60 of Scheme X 1. whe R =R 2 =g 5 =luoromethyl

Z-O)

In a dry r.b. flask equipped with a magnetic stir bar. was dissolved Compound 238 (50 mg, 0. 162 mmol) and paraformaldehyde (48 mg, 1.62 mmol, 10 equiv) in glacial acetic acid To this bright yellow solution was added NaCNBH 3 (50 mg, 0.81 mmol, 5 equiv).

The solution stirred for 18 h under an atmosphere of N2. In a separate flask was prepared a suspension of 100 g ice and 20 miL of 20% NaOFI(aq). The reaction mixture was slowly poured o ver the NaOH solution, extracted with EtOAc (3 x 50 mL), washed with brine, dried (Na2SO4) and concentrated in vacuo to afford 50.6 mg of Compound 265 as -a bright yellow solid. Data for Compound 265: Rf 0.39 (he4/EtQAc, 3: 1H NM4R (400 MHz, CDCI3) 7.20 J 11-1), 6.36 2 5.36 J 1.0, 1 2.88 3 H), 2.00 J .1, 3 HM, 1.39 (s6H).

EXAMPL E 166 l.

2 ~Diydroe .trinuromethl254etl~hi uinoline (Conmound 6A otructure57 of Scheme XVHI where

R=R

2

R

3 fuo etv 3 -AmioS..btlxcroy tiohenol (struture 6of ceme xVIInwhreR 1

H.

P=t-b AAtYQovcny Z S To a solution of 3 -aminothiophenol (500 mg, 4.0 mmol) and di-t-butyl dicarbonate (872 mg, 4.0 mmol) in 10 ml, of dry dichlorornethane at OTC was added dropwise, triethylamine (557 mL, 4.0 mmol). When the addition was complete, the reaction was allowed to warm to rt and the resulting mixture was stirred for 16 h. The reaction mixture was concentrated in vacuo and the residue was then diluted with 20 mL of ethyl acetate and washed with water (2x 10 mL), dried. (Na2SO 4 and concentrated in vacuo to an oil that was subjected to flash chromatography (silica gel, hexanes/ethyl acetate, 7:3) which gave 274 mg of 3 -an-dno-S-t..butyloxycarbonyl thiophenol as a clear oil. Data for 3 -amino-S-tbutyloxycarbonyl thiophenol: 1 H NMR (400 MHz, CDC1 3 7.12 (apparent t, J 8.2, 1lH), 6.90 J 8.2, 1fH), 6.84 J 2.2, 1ff), 6.68 (dd, J 8.2, 2.2, 1ff), 3.68 (br s, 2Hf), 1.56 9H).

110 h r 1 .Ptbtloyaljy ZS@ This compound was prepared by General Method 13 (EXAMPLE 147) from 3-fin---utlxcroy thiophenol (274 mg, 1.2 rnmol) to afford 148 mg of 7 -t-butyloxycarbonylthio. I,2-dihydro-2,2,4trimethyiqu ino line as' a yellowish oil. Data for 7 -t-butyloxycarbonylthio1,2dihyro 2 2 4 trimethyiquinoline: IH NMIR (400 MHz, CDC13) 7.02 J 7.9, 1IH), 6.74 (dd, J 7.9, 1.6, 1H), 6.57 J 1H), 5.31 IH), 3.73 (br s, IH), 1.95 3H), 1.50 9H), 1.26 6H).

.1.

2 -Dihyd-ro- 6 -trifluoromethvkl22-4-tmerhthi#'--nB- -8-F uinoine (Compound 266, structire 57r of Scheme VI hr 1 R=.R=trifluoornthvL Trifluoroacetic acid (744 mL, 0.0096 mol) was added all at once via a syringe to a solution of7tbtlxcroyti-12dhdo224arehlunln 14 g) in I mL of dry dichioromethane at 0 0C. After 10 midn the ice bath was removed and the mixture was allowed to stir at rt for 45 minutes. It was then cooled to 0 00 and neutralized with sat'd NaH-C03, extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with water (10 mL), dried (Na2SO 4 and concentrated in vacuo to a crude product (50 mg) that was used directly in the next step. A solution of the crude material obtained above (50 mg) and zinc chloride (100 mg, 0.724 mmol) in 0.5 mL of absolute ethanol was heated in a sealed tube for 16 h at 80 The reaction was quenched with sat'd NH4CI (2 mL) and extracted with ethyl acetate (2 x 5 mL), dried (Na2S 04) and concentrated in vacuc to an orange solid residue that was subjected to flash chromatography (silica gel, hexanes/ethyl acetate, follo wed by preparative TLC (500 Jltm, hexanes/ethyl acetate, 7:3) to afford 2.2 mg of Compound 266 as a yellow oil.

Data for Compound 266: IH NMR (400 MHz, CDC13) 7.54 I1-1), 6.62 I 6.43 (s, IH), 5.44 1H), 4.32 (br s, 1H), 2.03 3H1), 1.29 6H).

EXAMPLE 167 1 .2-Dihydrn- I I d th6- iuroty- yrds~ (Compound 267. structre 60 of Scee5I hr 1 R H R 3 =trfflornrmthvl.

ZaNzmethyl To a 25-mL r.b. flask containing Compound 247 (EXAMPLE 147) (125.8 mg, 0.41 mmol) in 5 mL DMF at rt was added 200 mg (approx 10 equiv) solid KOH. After 30 min, iodomethane (129 ML, 2.04 mmol, 5.0 equiv) was then added, and the mixture was allowed to stir at rt overnight. Ethyl acetate (50 mL) was then added, the biphasic: mixture was neutralized, to pH- 6 with sat'd aqueous NH4Cl, and the layers were separated. The organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, gradient elution) afforded I111 mg (8 of Compound 267 as a bright fluorescent-yellow solid. Data for Compound 267: IH NMR (400 MHz, CDCI 3 7.37 IH, 6.74 (s, IH, 6.21 lH, 10-H), 5.38 IH, 3.69 3H, CONCH31, 2.94 3H, (CH3)2CNCH 3 2.03 3H, 4-C113), 1.40 6H, 2-(C113)2].

to EXAMPLE 168 7-Chloro- 1.

2 -dihyd-ro 2 2 4 *ethvllooehIpioos&lun~ (Conmound-68 structure 57 o f-Sche me XVI.weeR=.R=I 3 tilooehl This compound was prepared by General Method 13 (EXAMPLE 147) from 7-amino-1,2dihydro-2,2,4-trirnethylquino line (EXAMPLE 147) (64 mg, 0.34 mmol) and ethyl 2-chloro- 4 4 4 -trifluoroacetoacetate (147 mg, 0.68 mrnol, 2.0 equiv) to afford 36 mg (31 of Compound 268 as a fluorescent-yellow solid. Data for Compound 268: IH NMR (400 MI-z, CDCI3) 7.52 IN, 6.31 IH, 10-H), 5.43 IH, 4.47 [br s, IH, (CH3)2CNHI, 2.03 3H, 4-CH3), 1.33 6H, 2-(CH3)2].

EXAMPLE 169 6 -Chloro(diluoro'mthyl-..

(Comound 29 structure 57 of Scheme VII. where R=R 2

=H,

R

3 =chiloro(difluoromethvl)Z_N-ffl This compound was prepared by General Method 13 (EXAMPLE 147) from 7-amidno- 1,2d hdo224timtyqioln (EXAMPLE 147) (60 mg, 0.33 mmol) and methyl 4chloro-4,4-difluoroacetoacetate (92 mg, 0.49 mmol, 1.5 equiv) to afford 17 mg of Compound 269 as a fluorescent-yellow solid. Data for Compound 269: 111 NMR (400 MHz, CDCI3) 12.50 (br s, 1H, CONK), 7.52 IN, 6.62 lH, 6.39 IN, 10- 5.42 I H, 4.48 [br s, INH, (CH3)2CNH], 2.04 J1 1.0, 3H, 4- CH3), 1.31 6H, 2-(CH3)2].

EXAMPLE 170 8-Cyano-1, 2 -dihydro- 4-rimethlindenor3.2-e inoline (Compound 270. structure 16 of Scheme IV, where R 2 4

R

6 H. R 5 =cvano, X=CH2) To a 25-mL r.b. flask equipped with a magnetic stir bar were added Compound 117 (104.7 mg, 0.40 mmol), DMF (1.5 mL), pyridine (0.16 mL), and copper cyanide (43.2 mg, 0.48 mmol). A reflux condenser was attached to the flask. The green cloudy mixture was.

stirred at reflux for 3 hours, and allowed to cool to room temperature. The reaction mixture was diluted with ether (30 mL) which formed a precipitate in the dark solution. The precipitate was gravity filtered through Celite. The filtrate was rinsed three times with ether (20 mL). The isolated solution was added to a separatory funnel The organic layer was washed with 2:1 mixture of water and ammonium hydroxide (20 mL) followed by saturated ammonium chloride solution (2 x 20 mL) and saturated sodium bicarbonate mL). The aqueous layers were extracted with ether (3 x 10 mL). The organic layers were combined, dried (Na2SO4), and concentrated. The product was purified by flash column chromatography (75 mL silica, hexane) to afford 30 mg (26 of Compound 270. Data for Compound 270: IH NMR (400 MHz, acetone-d6) 7.77 1H), 7.72 1 H), 7.61 2 6.72 1 5.54 1 5.39 1 3.79 2 2.08 3 1.29 (s, 6 H).

EXAMPLE 171 6 3 -Cvano-5-fluorophenyl)-

L

2 -dihdro-2.2.4trimethylquinoline (Compound 271.

structure 4 of Scheme II, where R l=3-cyano.5-fluoropheny1) 3 -Bromo-5-fluorobenzonitrile. To a I liter r.b. flask equipped with a magnetic stir bar, commercially available 1, 3 -dibromo-5-fluorobenzene (44.0 g, 173.3 mmol), DMF (268 mL), pyridine (28.0 mL), and copper cyanide (15.5 g, 173.3 mmol) were added under nitrogen.. A reflux condenser was attached to the flask. The green cloudy mixture was stirred at reflux for 3 h. The reaction progress was difficult to monitor by TLC, so once lower Rf impurities were observed the reaction was allowed to cool to rt. The reaction mixture was quenched with 200 mL ether which formed a precipitate in the dark solution.

The precipitate was gravity filtered through Celite. The filtrate was rinsed three times with ether (100 mL). The isolated solution was added to a separatory funnel. The organic layer was washed with 2 to 1 mixture of water and ammnonium hydroxide (200 mL) followed by saturated amnmonium chloride solution (2 x 200 mL) and saturated sodium bicarbonate (200 mL). The aqueous layers were extracted with ether (3 x 100 mL). The organic layers were combined and dried (Na2S 04). The product, 3 -bromo-5-fluorobenzonitrile, was purified by flash column chromatography (300 mL silica, hexane) followed by recrystallization from hexane to afford 22.3 g (65 of the product as white crystals. Data for fluorobenzonitrile: 1 H NMR (400 MHz, acetone-d6) 7.81 I Hl), 7.73 (dd, J 1.9, 1 7.65 (dd, J 8.5, 2.0, 1 6 3 -Cyano-5-fluorophenyl). 1.

2 -dihydro-2.2.4 T- eh~unlne(opud21 structure 4 of Scheme HI. where R=3-can.~~oohnl This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (46.3 mng, 0. 14 mniol) and 3 -bromo-5-fluorobenzonjtrjje (29.1 mg, 0. 14 mmol). The crude material was purified by recrystallization from hexane to afford 15.8 mg of Compound 271. Data for Compound 271: 1 H NMR (400 Mi1z, acetone-d6) 7.83 (app t, J 1 7.68 (dd, J 10.6, 4.0, 1 7.43 J 2.0, 1 7.41 (dd, I 2.2, 1.2 1W) 7.35 (dd, J 8.3, 2.2, 1 6.59 J 8.4, 1 5.35 (br s, 1 5.39 1 2.04 3 1.28 6 H).

EXAMPLE 172 6 3 -Cyano-4-fluorophenyl rl.-iyr22.trnehgui Co ond7 structure 4 of Scheme 11. whr -cn 4fluorhn) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (53.8 mg, 0. 17 inmoles) and 3 -bromo-6-fluoro-benzonitrile (33.9 mg, 0. 17 mmol). The crude material was purified by HPLC (reverse phase ODS column, methanol/water, 3.0 mLlmidn) to afford 3.3 mg of Compound 272. Data for Compound 272: 1H1 NMR (400 MHz, acetone-d6) 7.97 (dd, J 6.1, 2.2, 1 7.93 (in, 1 7.39 t, J =17.9, 9.0, 1 7.35 J 1.5, 1 7.27 (dd, J=8.3, 1.9, 1 6.58 J=8.3, 1 H), 5.38 I 5.34 1 2.08 3 1.28 6 H).

EXAMdPLE 173 6 -(-Cano6-luoopeny) 2 -ihdro 2.24nmeth u inoline Cmoud23 structure 4 of Scheme fl, where

-R'

1 -vn 11urohfv) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (70.0 mg, 0.22 mmol) and 3-rm--lorbnoifl (44.1 mg, 0.22 mmol). The crude material was purified by HPLC (reverse phase ODS column, methanol/water, 3.0 mL/min) to afford 3.3 mg of Compound 273. Data for Compound 273: 'H NMR (400 MHz, acetone-d 6 7.90 (dd, J 7.5, 2. 1, 1 7.67 (in, 1 7.36 (dd, J 10.9, 8.5, 1 7.28 1 M, 7.21 (in, 1 6.58 J 8.2, 1 5.48 (s, 1 5.37 1 2.04 3 1.29 6 H).

EXAMPLE 174 6 -rs-flugro-3-(trifluoro ithv)henv11 dwro2.2.4- rIim.ethylguinoijne ompound 274.~U sWutr 4o Scee1.w ere RI!Dhnl This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (42.8 mg, 0.13 mol) and 3 -bromo-5-fluorobenzotrifuoride (32.7 mg, 0.13 mmnol). The crude material was purified by HPLC (reverse phase ODS column, methanol/water, 3.0 mL~/min) to afford 3.1 mng of Compound 274. Data for Compound 274: 1H NMR (400 MHz, acetone-d6) 7.71 1 7.63 J1= 10.5. 1 H), 7.40 J= 2.2, 1 7.34 (dd, J1=8.1, 2.0, 1 7.29 J 8.6, 1 6.59 J= 8.3, 1 5.50 I 5.39 I 2.05 3 1.29 6 H).

EXAMPLE 175 1.2-r [rmeetylpheno)lin(Compund 275.

structuire 4 of Scheme LI. where -hoo2eh~hnl This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (70.0 mng, 0.22 inuol) and 2 -bromo-6-chlorotoluene (45.2 mng, 0.22 minol).

The crude material was purified by flash column chromatography (75 ml silica, hexane to ethyl acetate/hexane) to afford 63.1 mg of Compound 275. Data for Compound 275: 1H NMR (400 MHz, acetone-d 6 7.30 J 8.3, 1 7.16 (mn, 1 6.95 1 H), 6.87 J 10.2, 1 6.54 J 8.0, 1 M-1, 5.36 1 5.25 I 2.03 3 1.28 6 H).

EXAMPLE 176 1 2 -Dihvd-o2 2 4 'ethv1-(3nithelgunje (Cmon 27.-rcue4o Scheme IwheR 1 3ntphv) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (19.4 mg, 0.06 mmol) and 3 -nitrobromo benzene (12.3 mg, 0.06 mmol). The crude material was purified by flash column chromatography (75 ml silica, hexane to ethyl acetate/hexane). followed by reverse phase flash column chromatography (50 mL ODS, 80% methanol/water) to afford 2.9 mg of Compound 276. Data for Compound 276: 1 H NMR (400 MHz, acetone-d6) 8.35 (app t, J 4.1, 2.0, 1 8.05 J 8.0, 1 8.01 (dd, J 8.1, 6.5, 1 7.64 i 15.9, 8.0, 1 7.40 d, J= 2. 1, 1 7.34 (dcl, J 8.4, 2.3, 1 6.61 J 8.4, 1 5.40 J 1.4, 1 2.05 3 1.29 6 H).

EXAMPLE 177 6 4(3-Akcetylphenfl-

W.

2 dildo" trnithlung -Cm ound 277. strutue 4 t Schemne HI. where 3-cet I hnvl This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (66.2 mg, 0.21 mxnol) and 3 -bromnoacetophenone (41.4 mg, 0.21 mmol). The crude material was purified by flash column chromatography (30 ml silica, hexane to acetone/hexane) followed by reverse phase flash column chromatography (50 ruL ODS, methanol/water) and a second normal phase flash column chromatography (30 mL silica, hexane to 20% acetone/hexane) to afford 5.0 mg of Compound 277. Data for Compound 277: IH NMR (400 MHz, acetone-d6) 8.13 I 7.81 (in, 1 7.50

J

15.0, 7.8, 1 7.33 (in, 2 6.59 J1=8. 1, 1 5.38 1 5.32 I 2.62 3 2.08 3 1.28 6 H).

EXAMPLE 178 6 3 -cyano-2-methylp~henyl)-l.

2 -dihydro-2.2.4timehvgunoin (Cm ound 278.

structure4 f Schemeif.r wheR-cvn-mtvphnl 3 -Brmo--mehvlenznitileThis compound was prepared in a manner similar to that described for 3 -bromo-5-fluorobenzoniaile from commercially available 2,6dibromotoluene (1.80 g, 7.20 mrnol), DMF (I11 mL), pyridine (1.1I mL), and copper

(I)

cyanide (0.52 g, 5.76 mniol). The crude product was purified by flash column chromatography (100 mL silica, hexane) to afford 50 mg; (35 of 3-bromo-2methylbenzonitrile. Data for 3 -bromo-2-methylbenzonitrile: IH NMR (400 MHz, acetone-d6) 7.88 J 8.0, 1 7.73 J 8.0, 1 7.32 J 15.8, 7.9, 1 2.58 (s, 3H).

6 4 3 -cygno-2-methylphenyl)- 2 dih do-2 2.4- th I Uinolinf- (Copond 78 strctue ofSchmeIhr R'=3-cano-2.methvylphenv1) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (56.5 mg, 0. 18 mmoI) and 3 -bromo-2-methylbenzonitril (34.8 mg, 0.18 mmol). The crude material was purified by flash column chromatography (50 mld silica, hexane to 20% acetone/hexane) followed by a second flash column chromatography (75 mL silica, hexane to acetone/hexane) to afford 10.5 mg of Compound 278. Data for Compound 278: 1H NMR (400 MHz, acetone-d6) 7.59 (dd, J 7.7, 0.9, 1 7.48 (dd, J 7.8, 0.8, 1 7.36 J= 15.3, 7.7, 1 6.99 J 1. 8, 1 6.91 (dd, J 1.9, 1 6.58 (d,J 1 5.37 1 5.30 I 2.48 3 1.97 3 1.30 6 H).

EXAMPLE 179 1.-iyr hIhnIu o m o und 7 structure 4 Scheme 11. where R 1 =3-methlphenyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (99.5 mg, 0.31 mmol) and 3 -bromotoluene (53.5 mg, .31mmoles). The crude material was purified by HPLC (reverse phase, ODS column, 80% methanol/water, mnLlmin.) to afford 2.7 mg of Compound 279. Data for Compound 279: 1IH NMR (400 MHz, acetone-d6) 7.37 1 7.32 J 7.9, 1 7.28 J 2.0, 1 H), 7.21 (in, 2 7.02 J 7.3, 1 6.55 J 8.3, 1 5.36 I 5.22 I 2.34 3 2.03 3 1.27 6 H).

EXAMPL-E 180 6 -(5-Fluoro-3-nitrohenvlI. l.Aa~do2...rmtvgino eCompound 280. structure 4 of Scheme where R' H-floro-3-itphenvi) 5-Fluo)ro-3-niitroiodo bnzene To a 25 mL round-bottom flask equipped. with a magnetic stir bar 3 -iodo-5-nitroaniline (543.3 mng, 2.06 mmol) and methylene chloride (10 rnL) were added under nitrogen. Nitrogen was bubbled through the colorless solution for 15 mini. The solution was cooled to 0 0 C in an ice bath. At that point approximately 500 mg nitrosonium tetrafluoroborate was added in one portion making a cloudy precipitate. The reaction was allowed to continue stirring for 2 hours. The mixture was kept under nitrogen as 10 mL dry, deoxygenated ortho-dichlorolbp.zene was added. A distillation apparatus was fitted to the reaction flask. The flask was placed in an oil bath and was heated until the material had completely distilled over. The crude product was isolated by washing the residue through a short column (74 mL silica, hexane). Purification by silica gel chromatography (74 mL silica, hexane) afforded 279.4 mng (50 of 5-fluoro-3-ntroiodo benene. Data for 3 -nitroiodo benzene: 1 H NMR (400 MHz, acetone-d6) 8.36 I 8.00 (n,4 2 H).

6 -(-Fuor-3nitopeny) 2 divroi2.2 .I eh uin lin.(Cm ound 20. tructur 4 of Scheme ff. wer R 5-uro3.iopenyI) This compound was prepared according to General Method 2 (EXAMVPLE 9) from Compound 9 (140.2 mng, 0.44 mmnol) and fluoro-3-nitroiodobenzene (117.6 mg, 0.44 inmol). The crude material was purified by flash column chromatography (150 nil silica, hexane to 20% acetone/hexane) followed by a second flash column chromatography (100 mL silica, hexane to 20% acetone/hexane) to afford 95 mg of Compound 280. Data for Compound 280: Ifl NMR (400 MHz, acetone-d6) 8.22 (app t, J 3.0, 1.5, 1 7.78 (mn, I 7.43 J 2.2, 1 7.38 (dd, J 8.4, 2.3, 1 6.61 J= 8.3, 1 5.58 I 5.40 I 2.05 3 1.29 6

H).

EXAMPLE 181 VPey _..nehlu n (Com ound 281.

structuire 4 of Scheme here 3-Ethxyhev This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (79.1 mg, 0.25 mmol) and 3 -bromoanisole (46.5 mg, 0.25 mmol). The crude material was purified by flash column chromatography (75 mL silica, hexane to 10 %ethyl acetate/hexane) to afford 2.1 mg (3 of Compound 281. Data for Compound 281: 1

H

NMR (400 MHz, acetone-d6) 7.25 (mn, 2 7.11 J1 6.9, 1 7.07 (app t, J 4. 1, 2.2, 1 6.78 (dd, I 8.6, 2.2, 1 6.55 J 8.3, 1 5.36 1 5.26 I 3.82 3 2.03 3 1.27 6 H).

EXAM4PLE 182 (Compound= 282.yl struct ue 4 of Scheme E1. where 1 -vn3.prd) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (45.6 mg, 0.14 mmol) and 3 -cyano-5-bromopyridine (26.2 mig, 0.14 mniol).

The crude material was purified by flash column chromatography (100 mL silica, hexane) to afford 10.4 mg of Compound 282. Data for Compound 282: IH NMR (400 MHz, acetone-d6) 8.21 1.7,1 H),7.79(in,2H), 7.44(d,J=2.1, IH),7.39(dd,J= 8.4, 2.3, 1 6.61 J 1 5.59 1 5.40 1 2.05 3 1.29 6 H).

EXAMPLE 183 1.

2 )ihdr224..t.4 oh6(hI structure 4 of Scheme H. where R'2mthIr'.nitr henv1 This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (170.6 mg, 0.54 nimol) and 2 -bromo-6-nitrotoluene (115.8 mg, 0.54 mmol).

The crude material was purified by flash column chromatography (80 mlA silica, hexane to 20% acetone/hexane) followed by a second flash column chromatography (75 mL silica, hexane to 20% aCetone/hexane) to afford 68 mig (4 of Compound 283. Data for Compound 283: IH NMR (400 MHz, acetone-d6) 7.71 J 7.9, 1 7.49 (dd, J 7.4, 0.9, 1 7.41 J 15.6, 7.9, 1 6.99 J= 1.8, 1 6.91 (dd, J= 8.1, 1.9, 1 H), 6.57 J 1 5.37 I 5.32 I 2.35 3 1.97 3 1.29 6 H).

EXAMPLE 184Q 6 2 -Amn-.~iloohnl. 2dhdo224..-i~hvgioie(opud24 structure 4 fShm U hr '2-anino- 0-difluorophenyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (48.8 mg, 0. 15 inmol) and 2 -bromo-4,6-difluoroaniline (31.9 mg, 0. 15 mmol).

The crude material was purified by flash column chromatography (ODS reverse phase, methanol/water) to afford 15 mg of Compound 284. Data for Compound 284: 1

H

NMR (400 MHz, acetone-d6) 7. 10 Cd, J 2.0, 1 7.02 (dd, J 8.1, 2.0, 1 6.80 (mn, 1 6.69 (in, 1 H) 6.56 J 8. 1, 1 5.36 1 5.34 1 4.22 (br s, 2 1.97 Cs, 3 1.28 6H).

EXAMPLE 185 6 3 -Bromo-2-chloro-5-fluorohny1.. lZdhro224tieygux oine Comound 285. structure 4 of Scheme UI. where R 1 3 -bromo- This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (143.3 mg, 0.45 inmol) and 1l-chloro-2,6-dibromo-4fluoro bnzene (129.9 mg, 0.45 mmol). The crude material was purified by flash column chromatography (50 mL silica, hexane) followed by reverse phase preparatory TLC (1000 mL ODS, methanoVwater) to afford 4.3 mg of Compound 285. Data for Compound 285: 1

H

NMR (400 MHz, acetone-d6) 7.50 (dd, J 3.0, 1H), 7.19 (dd,JI= 9.2, 3.0, 1H), 7.10 J= 2.0, 1 7.03 (dd, J 8.1, 2.0, 1 6.55 J= 8.3, 1 5.61 1 5.37 I 1.97 3 1.29 6 M).

EXAMPLE 186 6 4( 3 ygno-5-fluorophenvl). 1.

2 -dihvdro-2 2 4-tr*rrethyl.3..uinolone (Compound 286.

structure 79 of Scheme XX whre R =0 3 =0=11. R 2 =cano. R 4 =fluoro, p=tbutoxycArbonyl) In a 100 mL r.b. flask, a solution of l.

2 -dihydro-6-3-cyano5fluorophenyl)224 trmty-I--uoyabnlunln (structure 77 of Scheme XX, where R I=0=R0=11,

R

2 =cyano, R 4 =fluoro. Pt-butoxycarbonyl, an intermediate from EXAMPLE 171) (134.8 mg, 0.34 inmol) in THF (17.2 mL) was treated with a 1.0 M THFf solution of BH3-THF (1.29 mL, 1.3 mmol, 3.9 equiv). The reaction mixture was stirred for 20 min, then poured into a cold (0 0 C) 10 M solution of NaOH (50 mL), ether (50 inL), and 30% hydrogen peroxide mL). The reaction midxture was stirred overnight (16 The reaction mixture was extracted with ether (3 x 20 mL). 'The extracts were combined, dried (Na2SO4), and concentrated. The crude material was dissolved in CI-2C12 (2 mL) and treated with PCC mg). The reaction mixture was stirred for I h, filtered through a pad of Celite, and concentrated. Purification by flash column chromatography (175 mL silica, hexane) afforded 1.3 mng of Compound 286 as a white solid. Data for Compound 286: IH NMR (400 M~z, acetone-d6) 7.90 11H), 7.75 J 10.6, 1 7.54 (mn, 2 7.48 (d, J 8.3, 1 6.95 J1=8.2, 1 5.52 1 3.61 (mn, I 1.49 J 7.05, 3 H), 1.33 3 1.23 3 H).

EXAMPL E 187 6 3 -Fluoro-2-methlphen) 2 -dihdr224-ineyguol Cmp nd87 structure 4 of'Scheme IT.I where R 1 =3-fluoro-2-methljp henvlI This compound was prepared by General Method 2 (EXAMPLE 9) from Compound 9 mng, 0.158 mmol) and 2 -bromo-6-fluorotoluene (60 mg, 0.3 15 inmol). Purification by flash chromatography on silica gel (20g) using 5% EtOAc:hexanes afforded 6 mg of Compound 287 as a yellow oil. Data for Compound 287: IH NMR (400 MHz, acetoned6) 7.20 (in, IN), 7.02 (mn, IM), 6.98 (mn, 2H), 6.91 (mn, 114), 6.56 J=8.0, IH), 5.37 (s, IN), 5.29 (br s, 111), 2.19 3H), 1.98 3H), 1.28 6H).

EXAMPLE 188 1.

2 -Dihydro-2.2.4-tr* th I[6-3-mrethylhohnl)unle(opud28 tutr of Scheme H1. where R=3-methlthiophenyl) This compound was prepared by General Method 2 (EXAMPLE 9) from Compound 9 mg, 0. 158 inmol) and 3 -bromothioanisole (64 mng, 0.3 15 minol). Purification by flash chromatography on silica gel (20 g) using 5% EtQAc:hexanes afforded 7 mng of Compound 288 as a yellow oil. Data for Compound 288: IH NMR (400 MHz, acetoned6) 7.43 I 7.32 (mn, 3H), 7.24 (in, 2H), 7.14 (in, IlH), 6.57 J=8. 1, 1lH), 5.37 (s, IN), 5.31 (br s, 11H), 2.53 1.28 6H).

EXAM4PLE 189 6 -S-hlr-2theyl l 2 dihydr -ietvluinoln (mpund 289 stutue4Of Schemep IT. whereD 5-hloro-2.thienvi) ThIS compound was prepared by General Method 2 (EXAMPLE 9) from Compound 9 mg, 0. 158 mmol) and 2 -bromo-5-chloroti1.jophefle (63 mg, 0.3 15 mmol). Purification by flash chromatography on silica gel (20 g) using 5% EtQAc:hexanes afforded 10 mg (22%) of Compound 289 as a yellow oil. Data for Compound 289: 1Hj NMR (400 MI-Iz, acetoned6) 7.21 J 2. 1, 18W, 7.1 (dd, J 8.1, 2.0, 1HT), 7.02 J 3.7, 6.93 J 3.7, 18), 6.51 8.3, 1Hi), 5.42 (br s, 18), 5.40 1H), 2.01 38), 1.27 6H).

EXMLE 190 1.-ivr-29At~akj<-h (COpound 290. stucture 4 o Schemne 11, where R3LmehYLL1Wmthenl) This compound was prepared by General Method 2 (EXAMvPLE 9) from Compound 9 mg, 0.158 rnmol) and 2 -bromo-3-nmethylthijophene (57 mg, 0.3 15 mmnol). Purification by flash chromatography on silica gel (20 g) using 5% EtOAc:hexanes afforded 5 mg of Compound 290 as a yellow oil. Data for Compound 290: 1Hj NMR (400 Mliz, acetone-d6) 7.18 J 5.2, 1H), 7.09 J 1.9, 1H), 7.03 (dd, J 8.1, 2.0, 1H), 6.88 5.1, 1IM, 6.54 J 8.1, 11-1), 5.38 18), 5.32 (hr s, 1H), 2.26 3H), 1.99 38), 1.29 6H).

EXAMAPLE 191 8-F uo o. l 2 ih dr 2. .4~e h y 3 n tr p h n y )qu in o m o u d 9 stru t r 83 of Sche-me XX wher

R=R

3 -7=R9=H

R

8 =fz) 4 ~mn.3.loo.'nto~hn1(tutr 2o cheme X where

RR

3 7

=H.

Geerl eho 1 :Su uk ouln ofa 4 Bn ilin wha AryLbronic Acid.

A

mixture of 3 -nitrobenzeneboropjc acid (0.70 g, 4.2 mmol), 4 -bromo-2..fluoroaniline (730 mg, 4.0 mmol), (PPh3)4Pd (93 mg, 0.08 mmol), and K2CQS (0.69 g, 5.0 mmol) in toluene (20 mL) and water (2 mL) was heated at 95 OC for 16 h and the mixture was diluted with EtOAc (20 miL). The mixture was washed with water (10 mL) and brine (10 mL), concentrated and purified by silica gel chromatography to afford the 4 -amino-3-fluoro-3! nitrobiphenyl (structure 82 of Scheme XXI, where R I =R 3 7=H, R 8 (0.4 g, 41 as a yellow solid.

8-Fluoro- 2 -dih~r%' 'Iro A 4 I- -3.nitro henylIguinoln (Cmon 9.rcture 83 of Scheme XXI. whr 'R =R9=H,

R

8 This compound was preprdb General Method 8 (EXAMPLE 138) from 4 -amino-3-fluoro-3'.nitrobiphenyI (0.4 g, 1.7 mmol to afford 10 1 mg of Compo und 291 as a red solid, in addition to 0. 8 g o f the starting aminobiphenyl. Data for Compound 291: ER (neat) 3400, 2968, 1531, 1506, 1346; 1 H NMR (400 MHz, CDC13) 8.35 I 2.0, 1 8. 10 (dd, J 7.8, 2.0, 1 7.80

J=

7.8, 1 7.54 J= 7.8, 18H), 7.14 (d,1J 11.7, 1 7.11 J= 1.8, 1 5.43 1 H), 4.07 (bs, 1 2.07 3 1.35 6 13 C NMR (100 MHz, CDC13) 150.4 J 237), 149.0, 142.6, 132.2, 132.1, 130.0, 129.8, 128.0, 126.2 J= 124.0, 121.2, 12 1. 1, 117.8, 113.0 J= 20), 52.1, 31.7, 19. 1.

EXAM4PLE 192 l.

2 -Dihydro-_64(3nitohnn2....tam h Iuino i e Comound 22.stucre 6 of SChieme XXII. whre-

RI=_R

3 5 =f 2 =nitro) 4 -Bromro-2-methylaniline (5.58 g, 30 mmol) was treated with iodine (0.2 g, 0.9 mmol) and acetone (150 niL) in a sealed tube at 80 OC for 24 h to provide 6-bromno- 1,2-dilydro-8 methyiquinoline (Compound 85 of Scheme XXII) in 9 yield as a yellow oil (0.70g).

Most of the aniline was recovered. A mixture of the 6-bromo- 1,2-dihydro-8..

methylquinoline (90 mg, 0.33 mmol), 3 -nitrobenzeneboronic acid (167 mg, 1.0 nimol), Pd(PPh 3 4 (24 mg, 0.02 mmol), K2C0 3 (190 mig, 1.38 mmol) in toluene (7 mQL and water (1.5 niL) was heated at 70 OC for 16 h. Standard work-up followed by chromatography afforded 23 mg of Compound 292 as a yellow oil. Data for Compound 292: ER (neat) 3412, 2966, 1602, 1530, 1348; 1H NMR (400 MHz, CDCI3) 8.38 J 2.0, 1 H), 8.08 (dd, J 7.8 and 2.0, 1 7.85 J 18H), 7.52 J1=7.8, 1 7.24 J1= 11.7, 11-H), 7.21 J= 1.9, 1 5.39 1 3.72 (bs, I 2.18 3 2.07 3 1.34 (s, 6 1 3 C NMR (100 MHz, CDCI 3 148.9, 143.7, 142.0, 132.2, 129.6, 128.8, 128.7, 128.6, 126.5, 121.3, 121.0, 120.7, 120.6, 120.3, 52.3, 31.9, 19.2, 17.3.

208 EXAM4PLE 193 6 4.5-13m-3priv) l.-ihdo-2.2..tmethyguroliie (Cmpound 29.srcure 4of Scheme where R 1 =5-bMo-3-pvrdyl) This compound was prepared by General Method 2 (EXAMPLE 9) from dibromopyridine (119 mg, 0.5 rnmol) and Compound 9 (50 mg, 0. 16 mmol) to afford 18 mg of Compound 293 as a yel low oil. Data for Compound 293: Iii NMR (400 MHz, CDC13) 8.69 I 8.52 I 7.93 J 1 7.21 J 1, 1 7.20 (dd, J 8.1, 2. 1, 1 6.50 J 8. 1, 1 5.37 1 3.88 (bs, 1 2.05 3 1.31 6

H).

EXAMPLE- 194 -di (Comp ound 294. structure 4 f Scheme where R 1 3 E-bromo-2-pyidvl) This compound was prepared by General Method 2 (EXAMPLE 9) from 2,6dibromopyridine (237 mg, 1.0 mmol) and Compound 9 (100 mg, 0.32 mmol) to afford 42 mg of Compound 294 as a yellow oil. Data for Compound 294: IR (neat) 3379, 2966, 1604, 1575, 1433, 1124; 111 NMR (400 MvIHz, CDCI3) 7.68 J= 1.9, 1 7.66 (dd, J= 8.1, 1.9, 1 7.54 J 1 7.49 J 1 7.23 J 1 H), 6.49 J1=8. 1, 1 5.35 1 3.93 (bs, 1 2.08 3 1.30 6 13 C NMR (100 M.Hz, CDC13) 159.3, 145.1, 142.1, 138.8, 128.7, 128.6, 127.7, 126.6, 124.6, 122.6, 121.5, 117.6, 113.1, 52.4, 31.6, 18.9.

EXAMPLE 195 u' 3 Boo2-hey) H.-iyr~..tieh~u n~ (Coon29 .srcue4f Schee U.whee R 1 3-bomozathenYl) This compound was prepared by General Method 2 from 2 ,5-dibromothiophene (242 mg, mrrol) and Compound 9 (50 mg, 0. 16 mmol) to afford 24 mg of Compound 295 as a yellow oil. Data for Compound 295: 1H NMR (400 MHz, CDCl3) 7.17 (bs, I H), 7.15 (dd, J 1.9, 1 6.95 1 6.86 (bs, 1 6.42 (bs, I 5.36 1 3.80 (bs, 1 2.01 (sj 3 1.29 6 H).

EXAMPLE 196 afur-:i~rd~D- (Cormehluiol mpound 296. structure 4 of Scheme where R2.3.56-tetrafluoro4.pvridivl) This compound was prepared by General Method 2 from 4-bromo-2,3,5,6tetrafluoropyridine (150 mg, 0.63 mmol) and Compound 9 (50 mg, 0.16 mmol) to afford 13.4 mg of Compound 296 as a white solid. Data for Compound 296: IH NMR (400 MHz, CDCI3) 7.23 1 7.20 J 7.9, 1 6.51 J 7.9, 1 5.38 1 H), 4.08 (bs, 1 2.00 3 1.33 6 13 C NMR (100 MHz, CDCI3) 145.4, 144.5 (dd, J1=2k0,16 139.3 (dd, J =256, 33), 130.7 J= 17.2), 129.0, 128.6, 125.7, 123.8, 12 1. 1, 113.8, 113.1, 112.6, 52.7, 32.1, 18.7.

EXAMPLE 197 5.8-Difluoro- l.

2 -dih-dro- 6 3 -n rphnvft.24.trimethylguinon (Compound 297.

structure 83 of Scheme XXI, where R 1

=R

3 5 =R7=R9=H. R 2 =nitro. R 6

=R

8 =fluoro) This compound was prepared by the same procedure as described in the synthesis of Compound 291 (EXAMAPLE 19 1) from 4 -bromo-2,5-difluoroaniie (32 mg, 0. 13 mmol) and 3nitro benzeneboronic acid (167 mg; 1.0 mmol) to afford 3 mg of Compound 297 as a colorless oil. Data for Compound 297: IH NMR (400 MHz, CDC1 3 8.33 J 1.6,'1 H), 8.14 (dd, J 8.0, 1.6, 1 7.78 J 8.0, 1 7.57 J 8.0, 1 6.94 (dd, J 10.8, 6.3, 1 5.37 1 4.16 (bs, I 2.17 (dd, J 7.0, 1.3, 3 1.34 6 H).

EXAMPLE 198 2 .4-Diethyl-8-fluoro- l.

2 -dihvdro-2-me3hyl-k-(2.nitrophenyl)guinoline ompouind 98.

structure 83 of Scheme XXI. where R=R 3 7

R

2 =nitro- 8 fluoro. R 9 =methl)

A

mixture of 2 -fluoro-4(3-nitrophenyl)aniline (100 mg, 0.43 rnmol), iodine (10 mg, 0.039 mrnol) and 2-butanone (5 mL) was heated at 100 TC in a sealed tube for 16 h. Removal of solvent and chromatography of the crude mixture on a silica gel column afforded 4 mg of Compound 298 as a yellow oil. Data for Compound 298: IH NMR (400 MHz, CDCI 3 8.33 J 1 8. 10 (dd, J 2.0, 1 7.81 J 1 7.54 (t,IJ= 7.8, 1 7.14 1 7.12 J 11.0, 1 5.30 I 3.96 (bs, I 2.47 J 7.5, 2 H), 1.57 J 2 1.31 3 1.21 J 3 0,95 J 3 H).

EXAMqPLE 199 4of Scheme I. where R' germphnj This compound was prepared by General Method 2 (EXAMP4LE 9) firom Compound 9 (100 mg, 0.32 mmol) and l, 3 -dibro mo benzene (0.20 miL, 1.60 mmol). The crude product was purified by prep TLC (5 x 20 cm, 2 50mm, 25% EtOAc:hexane) to afford 2.3 mg of Compound 299 as a white solid. Data for compound 299: Rf=6.43 (silica gel, EtOAc:hexane); IH NMR (400 MHz, acetone-d 6 7 7 2(s, I 7.56 J 8.5, 1 H), 7.38(d, J 8.5, 1 7.37 2 7.24 J 8.5, 1 6.58 J 8.5, 1 5.39 (br in, 2 2.04 3 1.29 6 H).

EXAMPLE 200 1.

2 -i rO..~ty& 5-i -o2thi n I uinnline Cmpun 3 0 structure 4 o ceeI.w eeR=Snto2tinr This compound was prepared by General Method 2 (EXAMPLE 9) from Compound 9 (50 mg, 0.16 mmol) and 2 -bromo-5-nitrothiophene (0.16 g, 0.79 mmol). The crude product was purified by prep TLC (20 x 20cm, lOO0nmm, 25% EtQAc:hexane) to afford mg (8 of Compound 300 as a purple solid. Data for compound 300: Rf=O0.40 (silica gel, 25% EtOAc:hex); ~IH NMR (400 MHz, CDC1 3 7.85 J 4.3, 1 7.27 (in, 2 H), 7.04 J=4.3, 1 6.43 J=8.5, 1 5.38 (brs, 1 M,4.13 (brs, I 2.03 3H), 1.32 6 H).

EXCAMPLE 201 1.

2 -DihvdTO..6A- 24 A jfjuor 0 IV) ioln ornnid structure 4 of Scee I heeR -trf ronyl This compound was prepared by General Method 2 (EXAMPLE 9) from compound 9 (50 mng, 0. 16 inmol) and 2 4 ,S-trifluorobromo benzene 10 mL, 0.79 mnmol). The crude product was purified by prep TLC (5 x 20cm, 250mm, 25% EtOAc:hexane) to afford 15 mg (3 of Compound 301 as a Yellow oil. Data for compound 301: Rf=O0.40 (Silica gel, EtOAc: hex); IH NMR (400 MHz, CDCl3) 7.21 (in, I 7.18 I 7.13 J= 8.5, 1 6.96 I 6.47 J 8.5, l1-I), 5.34 I 3.83 (brs, 1 2.01 3 1.31 (s, 6 H), EXAMPLE 202 6 3 -Bromo-5-flu ro hn I 1.

2 -ihvdo224r~eh~un~ii (Com')n 302.Ti structur of Scem IweeR -r lr Ie This compound was prepared by General Method 2 (EXAMPLE 9) from compound 9 mg, 0.16 mmol) and 1, 3 -dibromo5-fuoro benene (0.20 mL, 1.60 mmol). The crude product was purified by prep TLC (20 x 20cm, 500mm, 25% EtOAc:hexane) to afford mg of Compound 302 as a colorless oil. Data for compound 302: Rf=0.40 (silica gel, 25% EtOAc:hex); IH NMR(400 MHz, CDCl3) 7.44 1 7.21 to 7.09 (in, 4 H), 6.46 J 8.5, 1 5.35 1 3.80 (brs, lIi), 2.04 3 1.30 6 H).

EXAMPLE 203 6 4-(Sarboxa~eye3l~ey'. ihdo2 2 4- thylquinoline- (Compound 33., struct Ke 4 of Scheme 11. where R I= 3 -thienL-5-c boxaldghyde) This compound was prepared by General Method 2 (EXAMPLE 9) from compound 9 mg, 0. 16 mmnol) and 4 -bromo- 2 -thiophenecarboxaldehyde 15 g, 0.79 minol). The crude product was purified by prep TLC (20 x 20cm, 1000mm, 25% EtQAc:hexane) to afford 31 mng of Compound 303 as a yellow oil. Data for compound 303: Rf=0.44 (silica gel, EtQAc:hex); IH NMR(400 MHz, CDCI3) 9.95 1 7.96 I 7.66 1 M), 7.25 1 7.22 J 3.8, 1 6.47 J 8.5, 1 5.37 I 3.84 (brs, I 2.04 3 1.31 6 H).

EXAMPLE 204 1.-iyi-...-erfiehl nt hy nln (Comond3.A st curA 8 of Scheme XXI where i= 3 5 6 =8-9=H

R

2 =nitro. R 7 =methl) 4 -Amino-2- methyl-YL nitrobpev(srcue8ofShmXX.w reR R 3

=R

6

=R

8

R

2 =nito R 7 inth This compound was made according to the General Method 14 (EXAMPLE 191) from 3 -nitrobenzene boronic: acid (673.2 mg, 3.82 inmol) and 4 -bromo-3-methylanjline (710.2 mng, 3.82 inmol) to afford 540 mg of 4 -arnjno-2.

inethyl-3 .nitrobiphenyl (structure 82 of Scheme XXI, where RlI=R 3 -S=R6=R8=H,

R

2 =nitro,

R

7 =inethyl). Data for 4 -amino-2-methyl.3 t.nitrobiphenyl: 114 NMR (400 MHz, aceto ne-d6) 8.13 (dd, J= 7.5, 1. 1, 1 H0, 8.09 1.8, 18H), 7.73 (ddd, J 7.7, 1.6, 1.4, 11-H), 7.66 (dd, J1=8.0, 7.8, 114), 6.99 J1=8.0, LH), 6.60 (mn, I 4.73 (br s, 18), 2.18 3H).

of Scheme Y -XX wh re R =R 3 -5=g6=Z8-9 1

R~

2 ntro. -RZ=Methy This compound was Prepared according to General Method 8 (EXAMPLE 138) from 540 mng of 4 -amino-2 methyl-3! 'nitro biphenyl. Approximately 10% of the reaction mixture was worked up and purified to afford 1.5 mg of Compound 304. Data for Compound 304: 1H NMR (400 MHz, acetone-d 6 8.13 (mn, 2 7.76 (dcl, J 8.9, 1.2, 1 7.69 i 15.9, 8.0, 1 H), 6.93 I 6.43 I 5.32 I 2.14 3 El), 1.95 3 1.27 6 H).

EXAMJPLE 205.

tucur o ShmeF. wheR S-loo2mtoy-3n&rpen) This compound was prepared by General Method 2 (EXAMPLE 9) from compound 9 ing, 0. 19 inmol) and 2 -bromo-4fluoro6-itroaiole (37 mng, 0. 15 innol). The crude product was purified by silica gel chromatography (EtOAc/hexane, 10:1) to afford 5 mug of Compound 305 as a yellow oil. Data for compound 305: IH NMR (400 MHz,

CDCI

3 7.34 (dd, J 7.3, 3.3, 1 7.25 (mn, 38), 7.21 (dd, I 8.1, 2.0, 18H), 6.50

J

8.3, 18H), 5.37 IlH), 3.89 I1H), 3.55 3H4), 2.01 J= 1.4, lIl), 1.33 68).

EXAMPLE 206 6 ~(-Cloo~etaxphnyl)-.di L- (C mp und06.

strctre o Shem I here R 3 -chl 2- th x.Yhenl) This compound was prepared by General Method 2 (EXAMPLE 9) from compound 9 ing, 0. 19 n-mol) and 2 -broino-6-chloroanisole (33 mug, 0. 15 mmrol). The crude product was purified by silica gel chromatography (EtOAc/hexane, 10: 1) to afford 6 mg of Compound 306 as a yellow oil. Data for compound 306: IH NMR (400 MI-z, CDCI3) 7.30 2H), 7.20 Cm, 2H), 7.05 J= 8.0, 11-H), 6.51 (d,IJ= 8.3, 1 5.34 I 3.75 (s, IH), 3.52 3H), 2.01 3H1), 1.34 6H-).

EXAMPLE 207 l.

2 -Dihydro224tety.6.234trfurheIgin ln (Compound 307. tutr 4 of Scheme 1. where 2 3 4 -riu rophenyl) This compound was prepared by General Method 2 (EXAMPLE 9) from compound 9 mg, 0. 19 mmnol) and l-brorno- 2 ,3,4-tifuorobenzene 11 mL, 0.93 mmuol). The crude product was purified by silica gel chromatography (EtOAc/hexane, 10: 1) to afford 30 mg of Compound 307 as white crystals. Data for compound 307: IH NMR (400 M~iz, acetone-d6) 7.28 (in 111), 7.20 Cmr, 2H), 7.13 (dt, J= 8.2, 1.9, 111), 6.58 J 111), 5.43 (br s, 111), 5.39 IH), 2.00 Cd; J= 1.3, 3H), 1.30 611).

EXAMPLE 208 6 3 -BIromo-2-methylphenyl)-1 2 -dhdo 4rj ehygio jie(omond38 structure 4 of Scheme II where Rl1 3 -broo-2mthyphnyl) This compound was prepared by General Method 2 (EXAMPLE 9) from compound 9 mg, 0.16 mmnol) and 2 6 -dibromotoluene (0.16 g, 0.64 mmol). The crude product was purified by silica gel chromatography (EtOAc/hexane, 10: 1) to afford 27 mg of Comnpound 308 as a colorless glass. Data for compound 308: 'H NMR (400 MHz, CDCl3) 7.49 J 8.3, 111), 7.17 J 6.9, 111), 7.04 J 7.7, 111), 6.95 J 1.9, 111), 6.89 (dd, J 8.0, 1.9, 1 6.46 Cd, J 8.0, 11H), 5.35 I 3.77 (br s, 111), 1.97 J 311), 1.32 611).

EXAMPLE 209 7-Chloro- 1, 2 -dihydio-2.2. etYl-64n rpeylgioline (COmpud .sr cture 83 of Scheme XXI here 3 6 R-9 2 -0to 7 =ho -Cloo--aino3'.Ptrbihenv structure 82 of Scheme XXI where

R

3 5 R-4

R

2 =nitro. R=chloo). This compound was prepared by General Method 14 (EXAMPLE 191) from 3 nitro benzeneboro nic acid (0.25 g, 1.5 mmol), 4 -bromo-3-chloroanfline (0.21 g, 1 .0 mmol), and (PPh3)4Pd (35 mg, 0.030 mrnol) to afford 0.08 g of 2-chloro-4amino-3!-nitrobipheny1 as an orange solid. Data for 2 -chloro-4am-no3 nitrobip henyl: Iff NMR (400 MHz, acetone-d6) 8.29 (app t, J1=2.0, 1IN), 8.18 (dt, J 9.0, 1.2, 11-1), 7.76 (dd, J1=9.0, 1.2, 1 7.56 J= 8.0, 11-H), 7.14 J1=8.2, 1IH), 6.82 J1=2.2, 1I-H), 6.65 (dd, J 8.2, 2.2, 3.86 (br s, 2H-).

7-Chio.l.dhd024.t -eth I- .3.nitophenyhgingling (ompound 9. srure 83 of Scheme YY i. hr R'-0- 6 =08-9-H, 2 -nitro-.R=choro This compound was prepared by General Method 8 (EXAMPLE 138) from 2 -chloro..4..an-no..3'.nitrobiphenyI (0.08 g, 0.3 mmol) to afford 15 mg of Compound 309 as an orange solid, in addition to 2 mg of Compound 310 (EXAMPLE 210) as an orange solid. The structures of Compounds 309 and 310 were secured by n.O.e. experiments. Data for Compound 309: IH NMR (400 MHz, acetone-d 6 8.77 J 2.0, iH), 8.21 (dt, J 9.0, 1.2, 1 7.88 (dd, J 6.6, 1.6, 1H), 7.71 1 7. 10 1H), 6.67 iH), 5.43 1H), 1.99 3H), 1.32 6H).

EXAM]PLE210 ioro- I 2 .djh vdroI -224- .tj.illine nd..

83 of Scheme XXI. wher R=R 3 5 RD7-9-"

R

2 nto R 6 ho This compound (2 mg, was obtained along with Compound 309 (EXAMPLE 209) as described above. Data for Compound 310: IH NMR (400 MHz, acetone..d6) 8.21

I

1.4, 111), 8.20 (in, IH), 7.81 (dt, J 8.8, 1.4, INH), 7.70 (in, lH), 7.01 J 8. 1, 6.71 J1=8. 1, 1H1), 5.74 (br s, IH), 5.55 J iH), 2.31 J= 1.3, 3H), 1.28 6H).

EX AMPLE 211 -imtyl6-nitropnl')uwome (Co-mpoun 31.srcture 83 of Scheme X w er R=R 3 7 =R9HR=ir.R=hoo 3 -Chloro-4-amino-3 .nitro i hen I structure. 2 of Scdheme XX where R=R 3 7

=H.

R nio.R=h ro This compound was prepared by General Method 14 (EXAMPLE 191) from 3 -nitro benzene boronic acid (0.25 g, 1.5 minol), 4 -bromo-2-chboroaniline (0.21 g, mmol), and (PPh3)4Pd (35 mg, 0.030 mmol) to afford a crude material which was used directly in the next step.

8-Chloro- 2 -dihdro 224-" ti60nitrheI u6(3...onr 83 of Schemne XXI. where R l-R 3 7 =R9=H

R

2 nitro. R 8 =chloro). This compound was prepared by General Method 8 (EXAMPLE 138) from the crude biphenyl amine obtained above to afford 2 mg of Compound 311 as an orange solid. Data for Compound 311: 1H NMR (400 MHz, acetone-d6) 8.48 J 2.0, 1H), 8.11 (dd, J1 8.0, 2.0, 1li), 8.04 (dd, J 6.6, 1.6, 18), 7.67 J 8.0, 18), 7.55 J 18), 7.40 J 2.0, 111), 5.43 18), 1.99 3H), 1.29 68).

EXAMPLE 212 8-Ethyl-i (Cmfpound 2.stucur 83 of, Scheme XX where

R

1

=R

3 7 =R9=H

R

2 nitro. R=thvl) 4 -A nino-3-ethvl-1.nitroiphekvl rtum-re 2f cheme-XXI. where Rl-R 3 7

=H

R

2 =ito. 8 =thy).This compound was prepared by General Method 14 (EXA.MPLE 191) from 3 -nitrobenzeneboronic acid (0.47 g, 2.8 mmol), 4 -bromo-2-ethylanijline (432 mg, 2.16 minol), and (PPh3)4Pci (75 mg, 0.065 inmol) to afford 139 mg of 4-amidno-3ethyl-3 '-nitrobiphenyl. Data for 4 -arnino-3-ethyl-3 '-nitrobiphenyl: 1 H NMR (400 MHz, acetone-d6) 8.38 J 2. 1, 18), 8.08 (in, 18), 8.00 (mn, 18), 7.66 J 8.0, 18), 7.45 (d, J 18), 7.39 (dd, J= 8.3, 2.3, 18), 6.83 J= 8.3, 18), 4.68 (br s, 2H).

8-Et yl l. -di~ dro 2.24..1Th eth 1..6.(3.niro~ e in o m pund 3 12 .Ltructure 83 of Scheme XI whre

=R

3 -7R9=H8

R

2 =nitro

R

8 ethl). This compound was prepared by General Method 8 (EXAMPLE 138) from the crude biphenyl amine obtained above to afford 2 mg (1 of Compound 312 as an orag solid. Data for Compound 312: 1 H NMR (400 Mfiz, acetone-d6) 8.38 J 2. 1, 18H), 8.06 (mn, 28), 7.66 J 8.0, 18H), 7.34 (mn, 18H), 5.44 18H), 4.88 (br s, 18H), 2.60 J 7.5, 2M), 2.08 1. 34 6H), 1.23 J 7.5, 3H).

EXAMqPLE 213 9- hir- 2 dhvro 22.dm ethyu.sumanrj 4.lu oj~ mp und 313.

structure 88 of Scheme XXIII. where RI 2

=R

4 6 =R9=H R 7

=R

8 mtvRchp) 2 -Amidno-6choro3,,-enzocoun..rin (structure 87 of Scheme XXIII, where R 1 2

=R

4 6

R

3 -chloro, an intermediate from EXAMPLE 109) (100 mg, 0.407 mmol) and 1, 1-dimethyl propargyl acetate (52 mg, 0.41 mmol) were dissolved in TI-F (5 mL) and treated with triethylamidne (57 p1L, 0.41 mmol). The resulting solution was treated with CuCi (20 mg, 0.20 mrnol). The reaction midxture was heated at relux for 16 h. The reaction was quenched with 1% HOI (2 mL) and diluted with EtOAc (20 mL). The mixture was poured into a separatory funnel and the aqueous layer was extracted with EtOAc (2 x mL). The combined organics were washed with brine (I x 20 mL), dried (Na2SQ 4 filtered, and concentrated onto Celite. The material was purified by flash chromatography on silica gel (50 g) using 15% ErOAc:hexanes as eluent to afford 50 mg of the dim~ethyl propargyl amine intermediate. This material was dissolved in THIF and treated with CuCI (2 mg, 0.02 mmol) and heated at reflux for 16 h. The reaction was quenched with 1 (v/v) HCI (2 mL) and diluted with EtOAc and water. The reaction mixture was poured into a separatory funnel and the aqueous was extracted with EtOAc (2 x 20 mL). The combined organics were washed with brine (15 mL), dried (Na2SO 4 filtered, and concentrated onto Celite. The material was purified by flash chromatography on silica gel (20 g) using EtOAc:hexanes to afford 30 mg of Compound 313 as a yellow solid. Data for Compound 313: 1 H NMR (400 MHz, acetone-d6) 8.07 J1=2.4, 1 7.99 J 8.7, 1H), 7.91 J= 10.4, 1H), 7.38 (dd, J= 8.6, 2.4, 1H), 7.26 J= 8.7, III), 7.10

J

IH), 6.04 (br sIH), 5.74 (dd, J 10.4, 1.4, 1H), 1.36 6H).

EXAM4PLE 214 314. stucture 41 of SceeX.w eeR

R

2 =mthox) 2 .S-imetoxvheny~roi acid cture 37 of Scheme X. where R =H.

R

2 =mthoy).This compound was prepared in a manner similar to that of 5-fluoro-2methoxyphenylboronic acid (EXAMPLE 107) from 1-bromo-2,5-dinlethoxybenzene (2.00 mL, 13.3 mmol), n-BuLi (2.5 M in hexanes; 5.34 mL, 13.3 mmol), and trirnethylborate mL, 40 mmol) to afford 2.43 g of 2 ,5-dimethoxyphenylboronic acid which was used without further purification.

Met (nitro-2z hen xyja This compound was prepared in a manner similar to that of methyl 5'-fluoro-2'-methoxy-4-nitro- 2biphenylcarboxylate (EXAMPLE 107) from methyl 2 -bromo-5-nitrobenzoate (2.46 g, 9.46 mmol), (PPh3)4Pd (0.33 g, 0.28 mmol), and 2 5 -dimethoxyphenylboronic acid (2.42 g, 13.3 mmol) to afford 2.08 g of methyl (2',5dimethoxy-4-nitro-2-biphenylcarboxylate) as a white solid. Data for methyl (2'5'dimethoxy-4-nitro-2-biphenylcarboxylate): IH NMR (400 MHz, CDC13) 8.70 J 2.4, 1f), 8.37 (dd, J= 8.4, 2.5, 1f), 7.52 J 8.5, 1H), 6.92 (dd, J 8.8, 3.0, 1H), 6.84 1H), 3.82 3H), 3.75 3H), 3.67 3H).

2'5-Dimethoxy-4-nitro-2-bi henvicarbxylic acid. This compound was prepared in a manner similar to that of 5-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl 2',5-dimethoxy-4-nitro-2-biphenylcarboxylate (2.07 g) to afford 1.93 g of 2',5'-dimethoxy-4-nitro-2-biphenylcarboxylic acid as a white solid.

Data for 2 ',5-dimethoxy-4-nitro-2-biphenylcarboxylic acid: IH NMR (400 MHz, acetoned6) 8.64 J 2.5, 1H), 8.43 (dd, J 8.4, 2.6, 1H), 7.67 J 8.5, 1H), 6.94 2H), 3.80 3H), 3.68 3H).

6 -Methoxv-2-nitro-3.4-benzocumrin. This compound was prepared in a manner similar to that of 6-fluoro-2-nitro-3,4-benzocoumarin (EXAMPLE 107) from dimethoxy-4-nitro-2-biphenylcarboxylic acid (1.

9 6.36 nmol), SOC12 (0.47 mL, 6.4 mmol), and AIC13 (0.67 g, 5.0 mmol) to afford 1.71 g of 6-methoxy-2-nitro-3,4benzocoumarin as an orange powder. Data for 6 -methoxy-2-nitro-3,4-benzocoumarin: 1

H

NMR (400 MHz, acetone-d6) 9.04 J 2.4, 1f), 8.74 J 8.9, 1H), 8.69 (dd, J 8.9, 2.4, 1H), 7.92 J 2.9, 1H), 7.41 I 9.0, 1fH), 7.30 (dd, J 9.0, 2.9, 1H), 3.97 3H).

zocoumai (structure 40 of Scheme w

R

2 =methoxy). This compound was prepared in a manner similar to that of 2-amino-6fluoro-3,4-benzocoumarin (EXAMPLE 107) from 6 -methoxy-2-nitro-3,4-benzocoumarin (1.71 g, 6.3 mrnol) to afford 1.27 g of 2 -amidno-6-mehoxy3,4-enzocoumarjn as a white solid. Data for 2-mn--itoy-,-ezcuain: IH NMR (400 MHz, acetone-d6) 8.1 0 J= 8.7, 11-H), 7.60 J 1H), 7.55 J=2.5, 1 7 2 5 2H), 6.99 (dd, J1= 8.7, 2.8, 1lH), 3.90 3 H).

nto 224 t '..g34n~ LLn (Compound 314. structure 41o Schema I wre R'f.R=eh This compound was prepared in a manner similar to that of Compound 207 from 2-mn--ehx-,-ezcuai (1.27 g, 5.0 mmnol) to afford 0.25 g of Compound 314 as a yellow solid. Data for Compound 314: 1H NMR (400 MHz, CDCI3) 7.73 J 8.6, IN), 7.35 J 2.8, IN), 7.23 J 8.9, IR), 7.00 J 8.6, IN), 6.92 (dd, J 8.9, 2.8, IN), 5.57 114), 4.29 (br s, IH), 3.88 2.11 J= 1.1, 3H), 1.33 6H).

EXAMPLE 215 9-Fluoro- 2dihydo-2.24 ltermthylS u i[3.-lunin Cmon 315 structure 8 of Sc-heme XX V. whre R 2 4 R6=H. 3 =fluorp.

R

5

=R

7 9 =methyi) Methyl -furo-5 '-methoxy 5-meth-11 i'ijto.--2..bipenyat (structure 92 of Scheme XIV hr R.1 2 =0 4 =06" R 3 fluoro. 5 =methyl). This compound was prepared in a manner similar to that of methyl 5t.fluoro-2 -methoxy-4-nitro-2 biphenyicarboxylate (EXAMPLE 107) from methyl 2 (1.73 g, 6.31 mmol), (PPh3)4Pd (0.22 g, 0. 19 nimol.), and 5-fluoro-2-rnethoxyphenylboronic acid (EXAMPLE 107) (1.50 g, 8.8 mmoi) to afford 0.77 g of methyl methoxy- 6 -methy1-4-ni.tro2.bjlhenycarboxlte Data for 2-fluoro-5t'methoxy-6-methyl- 4 -nitro-2-biphenylcarboxylate:1 'NMR (400 MHz, acetone-cl 6 8.61 J 2.3, 1IH), 8.27 J 2.4, lH), 7.09 (mn, iN), 6.91 (dd, J 9.0, 4.3, IN), 6.73 (dcl, J 8.2, 3.0, IH), 3.70 3.69 3H), 2.19 3H).

2 uor~5~mthox~i-o-.2-bin henuh-nr^-1acid This compound was prepared in a manner similar to that of 5-fuo-2mtox2'..etrbihox4..roxyic ci (EXAMPLE 107) from methyl 2 Lfluoro5methoxy6methy4nitro2biphenaroylate 219 (0.77 g) to afford 0.73 g of 2 Lfluoro5'methoxy.4to2.biphenlcrbxyi. cda a white solid, which was used in the next step without further purfication.

LLk o uain This compound was prepared in a manner similar-to that of 6-fluoro-2-nitro.3,4-benocoumarin (EXAMPLE 107) from 2'-fluoro-5 methoxy-4-nitro-2biphenylcaibxylic acid (0.73 g, 2.4 mmol), SOC12 (0.18 mL, 2.4 nunol), and A1C13 (0.32 g, 2.4 minol) to afford 0.63 g of 6 -fluoro-4methyl-2.rtro- 3,4-benzocouni.rin as an orange powder. Data for 6 -fluoro-4-methy..2nitro.3,4benzocoumarin: IH NMR (400 MHz, acetone-d6) 8.99 J 2.5, INH), 8.63 J 18H), 8.29 (dd, J 10.9, 2.4, lH), 7.53 (mn, 287), 3.14 3H).

2 -Amno~~f~oromety134~ocu. strctireS7 of Scheme XXYV where Rl- 2

=R

4 =6=H 3 =fluro. 5 =methyl. This compound was prepared in a manner similar to that of 2 -amidno-6-fluoro-3,4-. ocoun rin (EXAMPLE 107) from 6-fluoro-4-nethyI2nitro- 3 ,4-benzocouari (0.61 g) to afford 0.54 g of 2 -aniino-6-fluoro4methylI3,..

benzocoumnarin as a white solid, which was used in the next step without further purification.

9-loo iyr-.1. I-tetaeh15omrn 3 4guole(opud 315 structare 88 of Scheme XXIV. here Rl1 2

=P

4 -v6- R 3 -fluoro

R

5

=R

7 9 1 -methyl).

T'his compound was prepared in a manner similar to that of Compound 207 from 2-amidno- 6-loo4nehl-,-ezcumi (0.54 g) to afford 0.29 g of Compqound 315 as a yellow solid. Data for Compound 315: IH NMR (400 MIHz, acetone-d6) 7.87 (dd, J 11.4, 2.9, IH), 7.32 (dd, J 9.0, 5. 1, 18), 7.28 (mn, 1H), 7.02 1ff, 5.52 J 1.2, 18), 2.76 3H), 2.01 3H), 1.30 68).

EXAMPLE 216 l.

2 -Dihydo~..4gttamthI.5.cuinF 4 flno U (Coon3 6.srcue4 of Sce nI. whrIR=-. 2 mehl 2 -Metoxv~5methIphny r nic cid strutre37 f SceeQ.wh r H RZ=methyL) This compound was prepared in a manner similar to that of 5-fluoro-2methoxyphenylboronic acid (EXAMPLE 107) from 2 -bromo-4-methylanisole (2.00 g, 9.94 mmol), n-BuLi (2.5 M in hexanes; 4.00 mL, 10 mmol), and trimethylborate (3.4 mL, mmol) to afford 1.60 g of 2 -methoxy-5-methylphenylboronic acid which was used without further purification.

Methyl 2 '-methoxy-5-'met yl-4-nitro bigenvicarboxvit. This compound was prepared m a manner similar to that of methyl 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylate (EXAMPLE 107) from methyl 2 -bromo-5-nitrobenzoate (1.80 g, 6.92 mmol), (PPh3)4Pd (0.33 g, 0.28 mmol), and 2 -methoxy-5-methylphenylboronic acid (1.58 g, 9.51 mmol) to afford 2.03 g of methyl 2 '-methoxy-5'-methyl-4-nitro-2-biphenylcarboxylate as a white solid. Data for methyl (2'-methoxy-5'-methyl-4-nitro-2-biphenylcarboxylate) 1H NMR (400 MHz, CDCl3) 8.69 J 2.5, 1H), 8.36 (dd, J 8.4, 2.5, 18), 7.51 J 18), 7.20 1H), 7.07 J 2.1, 6.81 J 8.4, 18), 3.75 3H), 3.69 3H), 2.35 3H).

2a-Methoxy-5'-methyl-4-nitro-2-biphenvicarboxlc acid. This compound was prepared in a manner similar to that of 5'-fluoro- 2 '-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl 2 '-methoxy-5'-methyl-4-nitro- 2 -biphenylcarboxylate (2.02 g) to afford 1.93 g of 2 '-iethoxy-5t-methyl-4-nitro-2-biphenylcarboxylic acid as a white solid. Data for 2 '-methoxy-5'-methyl-4-nitro-2-biphenylcarboxylic acid: 1H NMR (400 MHz, acetone-d6) 8.63 J 2.5, 1H), 8.42 (dd, J 8.5, 2.5, 1H), 7.63 J= 18), 7.19 1H), 7.14 J= 2.2, 6.93 J= 8.4, 1H), 3.70 3H), 2.32 3H).

6 -Methy-2-nitro-34-benzocoumi This compound was prepared in a manner similar to that of 6 -fluoro-2-nitro-3,4-benzocoumarin (EXAMPLE 107) from 2'-methoxy-5'-methyl-4nitro-2-biphenylcarboxylic acid (1.92 g, 6.68 mmol), SOC12 (0.49 mL, 6.7 mmol), and AIC13 (0.89 g, 6.7 mmol) to afford 1.65 g of 6 -methyl-2-nitro-3,4-benzocoumarin as an orange powder. Data for 6 -methyl-2-nitro-3,4-benzocoumarin: 1H NMR (400 MHz, acetone-d 6 9.04 J 2.5, 18), 8.69 2H), 8.26 1H), 7.53 J 8.6, 1H), 7.35 (d, J= 8.6, 18), 2.49 3H).

2 -Amino-6-methyv13.4..b noounain srcue4 of SchemeXI. whrR 1

R

2 =meth I This compound was prepared in a manner similar to that of 2 -amidno-6-fluoro- 3 ,4-benzocoumarin (EXAMPLE 107) from 6 -methyl-2-'nitro-3,4-,enzocoumarin (1.64 g) to afford 1.40 g of 2 -amidno-6-methyl-3,4-benzocoumarin as a white solid, which was used in the next step without further purification.

1.

2 -Dihydio- 2 2 4 .9-tetr me-thvl...omarnr.4.gin-n (opun 1. tutue4 of Scheme XI. where R I=H. R 2 =Metv. This compound was prepared in a manner similar to that of Compound 207 from 2 -amino-6-methyl-3,4-beuocoumarin (1.40 g) to afford 0.738 g of Compound 316 as a yellow solid. Data for Compound 316: IH NMR (400 MHz, acetone-d6) 7.96 J= 8.6, 18H), 7.89 I1-H), 7.19 J= 8.6, 1 7.18 18), 7.14 J1=8.4, IHI), 6.04 (br s, IH), 5.51 IM), 2.41 3H), 1.29 6H). The C(4) methyl is obscured by the acetone multiplet.

EXAMPLE 217 7-Chloro- l, 2 :dihtdIO_- 2 .2.4-tethyks-5coumarinof3.4..ngu ioline (Compound 317.

structure 88 of Scheme XXIV. here 1 =chloro. R 2 6

R

7 9 -methl 3 -Chloro-2-met-hoxviphenylboronic acid (structuire90 of Scheme XXIV. where Rl=chloro.

R

2 4 This compound was prepared in a manner similar to that of 5-fluoro-2methoxyphenylboroic acid (EXAMPLE 107) from 2 -bronio-6-chloroanisole (0.71 g, 3.2 mmol), n-BuLi (2.5 M in hexanes; 1.28 mL, 3.2 mmol), -and trin-ithylborate (1.09 mL, 9.6 mmnol) to afford 0.55 g of 3 -chloro-2-nmethoxyphen ylboropnjc acid which was used without further purification.

Methyl (3 tchlorqo 2 -mie hx ir2.iheycr, late). This compound was prepared in a manner similar to that of methyl (5 '-fluoro-2tmethoxy-4.ntro-2-.

biphenylcarboxylate) (EXAMPLE 107) from methyl 2 -bromo-5-nitrobenzoate (0.58 g, 2.2 mnmol), (PPh3)4Pd (77 mg, 0.066 mmol), and 5-chloro- 2 -methoxyphenylboronic acid (0.54 g, 2.9 ml) to afford 245 mg of methyl 3 '-chloro-2methoxy4nitro-2 biphenylcarboxylate) as a clear oil Data for methyl (3-hoo2-ehx--lto2 biphenylcarboxylate): IH NMR (400 MHz, CDC13) 8.79 J 2.4, 18), 8.40 (dd, J= 8.4, 2.4, 18H), 7.57 J= 8.5, 7.45 (in, I 7.15 2H), 3.75 38), 3.47 3H).

3 1-Chloro-2-methoxy-4-nit acid. This compound was prepared in a manner similar to that of 5'-fluoro-2m-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl (3-chloro- 2 'methoxy-4-nitro-2-biphenylcarboxylate) (230mg) to afford 0.21 g of 3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid as a white solid. Data for 3 -chloro-2'2methoxy-4-nitro-2-biphenylcarboxylic acid: I NMR (400 MHz, acetone-d6) 8.76 J 2.5, 1 8.50 (dd, J 8.4, 2.5, 11H), 7.74

J=

IH), 7.51 (dd, J= 7.9, 1.8, 1W), 7.31 (dd, J= 7.4, 1.8, 1H), 7.24 J 3.47 (s, 3H).

8 -Chloro2-nitro34enzocoumarin This compound was prepared in a manner similar to that of 6 -fluoro-2-nitro-3,4-benzocoumarin (EXAMPLE 107) from 3 t-chloro-2'-methoxy-4nitro-2-biphenylcarboxylic acid (0.20 g, 0.65 mmol), SOC12 (50 mL, 0.69 mmol), and AIC13 (85 mg, 0.65 mmol) to afford 0.18 g of 8 -chloro-2-nitro-3,4-benzocoumarin as yellow crystals. Data for 8-chloro-2-nitro-3,4-benzocoumarin: 1 H NMR (400 MHz, acetone-d6) 9.06 J= 1.4, 1H), 8.74 2H), 8.45 (dd, J= 8.0, 1.4, 11), 7.32 (dd, J= 1.2, 11), 7.51 J= 8.0, IH).

2 -Amino-8-,hloro3.4aenzocoumarin (Struture 7 f SceXXIV.whe R'choro.

R

2 6 This compound was prepared in a manner similar to that of 2 -amino-6-fluoro- 3,4-benzocoumarin (EXAiMPLE 107) from 8 -chloro-2-nitro-3,4-benzocoumarin (0.18 g, 0.65 mmol) to afford 0.10 g of 2 -amino-8-chloro-3,4-benzocoumarin as a white solid, which was used in the next step without further purification.

o in 3 4structre of hm v here R 1 -chloro R 2 6 =H R 7 9 methyl) This compound was prepared in a manner similar to that of Compound 207 from 2 -amino-9-chloro-3,4benzocoumarin (0.10 g) to afford 24 mg of Compound 317 as a yellow solid. Data for Compound 317: 1 H NMR (400 MHz, acetone-d6) 8.04 (dd, J= 8.1, 1.1, 1H), 7.98 (d, J 8.7, 1H), 7.48 (dd, J 9.0, 1.1, IH), 7.28 J= 8.8, 7.23 J= 8.6, 1W), 6.24 (br s, IH), 5.55 J= 1.2, 18), 2.08 3H), 1.31 6H).

EXAMdPLE 218 Fluoro benzyl)- l.

2 -dihyedro-224-timety5H. hoenr.4fqun ie(Cmond 318, structur-e 32 of -Scheme IX.,where R 3 -uobey) To a solution of Compound 225 (EXAMPLE 125) (10 mg, 0.03 mmol) in CH2C12 (5 ml) was added triethylsilane (0.05 ml, 0.3 rnmol) and trifluoroacetic acid (0.024 ml, 0.3 mmol) at rt. The reaction was monitored by TLC and was found to be complete after 15 hours.

The reaction mixture was quenched with an aqueous 10% NaOH solution (5mL) then extracted with EtOAc (10 mL). The organic layer was washed with brine (3 x 5 mL), dried (Na2SQ4), then concentrated in vacuo to afford a yellow oil. The crude product was purified by prep TLC (5 x 20cmk 250mm, 1: 1 CHf2CI2:hexane) to afford 1.0 mg. of Compound 318 as a yellow oil. Data for Compound 318: Rf=-0.26 (silica gel, EtOAc:hex); IH NMR (400 MHz, CDCI3) 7.66 J 8.5, 1 7.48( d, J= 8.5 1 7.23 (in, 2 7.03 (in, 1 6.89 (in, 3 6.61 1= 8.5, 1 6. 10 (nm, I El), 5.49 I H), 3.98 (brs, I 3. 10 (in, 1 2.73 (in, I 2.29 3 1. 29 3 1. 19 3 H).

EXMPLE 219 (R/S')-9-Chloro- 1.-iydo5mt eh15-ho o4fnini.

(Compound 319. stucur 4 !1:F1:17 of Scheme'I whereg F? 2 =choo. R 3 =methAL.

=O)

(R/S')-9-chloro-1.-ivr--yo -24 hI -hnAr (structure 46 f Sheme .where

=HR

2 =cloro ad clr -2-dxv.el.

1.2(structure 94 of SchemeylXXV.

where R- 2

=R

4 6

R

3 chlro.

R

7 9 =ethl). Compound 209 (EXAMPLE 109) (100 mg, 0.307 inmol) was dissolved in THF, cooled to -40 0 C, and treated with DIIBAL (614 pAL, 0.6 14 minol, I M in THF, Aldrich), warming to -20 0 C over 30 mmi. The reaction mixture was quenched with NH4CI (sat) (2 mE) and allowed to warm to rt. The reaction midxture was poured into a separatory funnel containing EtOAc and water. The aqueous was extracted with EtOAc (2 x 20 mL). The combined organics were washed with NaCl (sat) (I x 15 mE), dried (Na2SO4), filtered, and concentrated onto Celite. The material was purified by flash chromatography using 25% EtOAc:hexanes to afford 65 mg of chloro- 1,-iyr 5hdoy224tinty-Hcr meo3A unn (structure 46 of 224 Scheme XIV, where R I R 2 =chloro) and 20 mg of 6 -(5-chloro-2-hyclroxyphenyl)- 1,2dihydro -5hyro xymethy224imethylquino ln (structure 94 of Scheme XX V, where

RI-

2

=R

4 6 H, R 3 =chloro,

R

7 9 =mnethyl). Data for (R/S)-9chloro1,2-dihydro.5-hyroxy- 2 2 4 timethy..sH-chomeno[3,4-Afquinohne: lf NMR (400 MHz, acetone-d 6 7.71

J

1H), 7.55 J1= 8.4, IN), 7.11 (dd, J 8.5, 2.4, IH), 6.94 J 8.4, 6.84

J

5.9, 1IH), 6.78 (di, J 8.2, IN), 6.01 J 6.0, 18)D, 5.56 (bs, 18H), 5.52 I1H), 2.36 (s, 38), 1.31 3H), 1. 18 38). Data for 6 -(5-chloro-2..hyciroxyphenyl)- 1 hydroxymethy2,2,-rithylquinolie: IH NMR (400 MHz, acetone-ci 6 7.18 (dcl, J 3.0, 11-H), 7. 10 J 2.5, 1H), 6.92 J1= 8.6, 18), 6.75 (di, J 8.0, 18), 6.63 (di, J= 8. 1, IH), 5.46 18), 5.25 18), 4.55 (ABq, J =11.4, 28), 2.35 3H), 1.27 68).

iR/S')-9Chlyro. ')Af4-hAI ch e (Compound 319. strtur 47 of Scheme XIV. where R 1

R

2 _mhlor R=MetvL X O) (R/S)-9-chloro-l, 2 dihyro5hydroxy224nethlSHhroeo3-qunle mg, 0.092 mmol) was dissolved in methanol (3 ruL) and- treated with p-toluenesulfoijc acid mg). After 10 rmin the reaction was quenched with NaHCO3 (2 mL). The resulting mixture was diluted with water (2 ruL), poured into a separatory funnel, and extracted with EtOAc (3 x 20 ruL). The combined organics were washed with NaCI(sat) (1 x 20 ml.), dried (Na2SQ 4 filtered, and concentrated onto Celite. The material was purified by flash chromnatography on silica (20 g) using 10 EtOAc:hexanes as eluent to afford 20 mg of Compound 319 as an opaque oil. Data for Compound 319: IH NMR (400 MHz, acetone-ci6) 7.73 (di, J 2.4, 18), 7.56 (ci, J 8.3, 18), 7.17 (dci, J 8.2, 2.4, 18), 7.08 (ci, J 8.3, 18), 6.80 (ci, J 18), 6.37 I1H), 5.62 (br s,18) 5.54 1IM, 3.44 38), 2.27 3H), 1.32 3H), 1. 17 3M).

EXAM4PLE 220 9-Chior-- :~uyr~224.i~thyI..sH c hrmen r32 4 -lu n (C mond3 0 structure 3 o f Schem X XV. where

R-

2 4 -6Hr~ 3 =choro. R 7 9 =Mgth1) 6 -(5-Chloro-2-hyciroxyphenly) 1,-iyr--yrxmty-,,-iehlunln (EXAMPLE 219; structure 94 of Scheme XXV, where

R[-

2 =R4-6H

R

3 =chloro,

R

7 9 mg, 0.061 mmol) was dissolved in CH2Cl 2 and treated with thionyl chloride g~L, 0.067 mmol) and tllethylamine (9 4~L 0.067 mniol). After 2 h the reaction was quenched with water and poured into a separatory funnel *containing CH2CI2 (20 mL) and water (l0mL). The aqueous was extracted with CH2CI 2 (2 x. 20 mL). The combined organics were washed with NaCi (sat)(1 x 15 mL), dried (Na2S 04), filtered and concentrated. The resulting benzyl chloride intermediate was dissolved in 1,2dichioroethane (IlmL) and treated, with triethylamjjne (100 mL), then heated to reflux. After 1 h the reaction was quenched with water and poured into a separatory funnel. The pH- was adjusted to 6 (1 %vlv HCI) and the aqueous was extracted with CH2CI2 (2 x 20 mL) The combined organics were washed with NaCI(sat) (20 mL), dried (Na2SO 4 filtered, and concentrated onto Celite. The material was purified by flash chromatography on silica gel g) using 5% EtQAc:hexanes to afford 10 mg of Compound 320. Data for Compound 320: IH NMR (400 MEFz, acetone-d 6 7.60 J 2.4, 7.43 J1 8.4, 18), 7.08 (dd, J 8.5,2.4, lh), 6.89 J 8.5, 1H), 6.70 (di, J 8.4, 114), 5.56 (br s, 18H), 5.49 5.32 28), 2.11 38), 1.25 6H).

EXAMKPLE 221 (RMS-9-Chloro.. 3 4 -,gline (Comnound T1. utr 47 of Sche-me XWV where R=H

R

2 =chloro, 3 =oV X=0) (R/S)-9-Chloro-12dhdo--yrx-224 mthl5-honeo34 flquinoiine (EXAMPLE 219; structure 46 of Scheme XIV, where

R

1

R

2 =chloro) mg, 0.092 mmol) was dissolved in l-propaniol (3 mL) and treated with p-toluenesulfojnjc acid (10 mg). After 10 min the reaction was quenched with NaHCO 3 (2 mL). The resulting mixture was diluted with H20 (2 mL), poured into a separatory funnel, and extracted with EtOAc (3 x 20 miL). The combined organics were washed with NaCI(sat) (I x 20 mL), dried (Na2SO 4 filtered, and concentrated onto celite. The material was purified by flash chromatography on silica (20 g) using 10 EtOAc:hexanes as eluent to afford 22 mg: (61 of Compound 321 as an opaque oil. Data for Compound 321: 111 NMR (400 MHz, acetone-d6) 7.73 J= 2.4, 18H), 7.56 J= 8.5, 18H), 7.14 (dd, J= 8.3, 2.5, 18H), 7.03

J

8.5, 11-H), 6.80 J= 8.5, 18H), 6.46 18H), 5.60 (br s, I 5.53 18H), 3.81 (in, 1H), 3.59 (in, 18), 2.29 38), 1.46 (in, 28), 1.32 3H), 1. 17 3H), 0.75, (in, 3H4).

EXAMPLE 222 (R/S')-9-Fluoro-1.-iyr-L: o 24 I- -chomeno F4-fgino line (Compound 322., structure 47 ofShm .weeR=H.

R

2 fluoro.

R

3 =methv

X=O.

This compound was prepared in a manner similar to that described for Compound 319 (EXAMPLE 219) from Compound 207 (55 mg) to afford 34 mng of Compound 322 as a clear oil. Data for Compound 322: IH NMR (400 MHz, acetone-d6) 7.53 J 1 7.48 (dd, J= 9.9, 3.0, 1H), 7.05 (dd, J 4.9, 1 6.92 (n,4 I 6.80 J= 8.3, 1 6.34 ILH), 5.54 J 1.4, 1H), 3.44 3H), 2.28 J 1.4, 1.32 3Ff), 1. 16 3Hf).

EXAMPLE 223 (R/5)-9-Fluoro-l2dhrn) -t (Compounid 323. structure 47 o Scheme V. where .R=lpo

R

3 =r~yl. =S.

(RMS-9-Fluoro- 2 -dih dro-5hydroxv.2-.4-trimth15H..Jchromenor 3 4 .Iu-inline (structure 46 of Scheme XIV. where R=H. R 2 =fluoro). This compound was prepared in a manner similar to that of 9-chioro- 2 -dihydro..5.hydroxy.2,2,4..trimethyl.SH chroineno [3,4Aqio lie (EXAMPLE 219) from Compound 207 (0.16 g, 0.51 iniol) to afford 80 mng of 9-fluoro- l, 2 -dihydro5hydroxy224nethy5cmo[ 3 4 ulquinoiine as a white solid. Data for 9-fluoro-1,l 2 -dihydro-5hyroxy22,4-.imethyl15Hchromeno[3,4-Acquinoline: 1 f{ NMR (400 MHz, acetone-d 6 7.52 1 8.5, 1Ff), 7.46 (dd, J= 9.9, 2.9, 1Ff), 6.93 (mn, 1Ff), 6.86 (mn, 2Ff), 6.78 J 1Ff, 5-98 J 1Ff), 5.56 (be s, 1Ff), 5.52 J= 1. 1, IH), 2.37 J= 1.2,3Ff), 1.30 3H), 1. 18 3H).

(RS'-9F~op-l~d ivdo2.2.4rm tvlhorpxyHhon[ 4 g ine (Compound 323 structue 47 of Scheme Iv. hr I -Hf R 2 =fluoro. 3 poplS.

This compound was prepared in a manner similar to that of Compound 319 (EXAMPLE 219) from 9-fluoro-1,-iyr--yrx-224tinty-Hchoeo34Aunln (18 mg) to afford 21 mg of Compound 323 as a clear oil. Data for Compound 323: IHf NMR (400 MHz, acetone-d6) 7.48 J= 8.5, 1Ff), 7.45 (dd, J= 10.0, 1.7, 1Ff), 7.14 1I-H), 6.95 (mn, 2Ff), 6.73 J1= 8.5, 1Ff), 5.52 J 1. 3, 1IH), 2.76 (n-4 I 2.58 (dt, J 12.9, 7.4, 1 2.47 J= 1.2, 3H), 1.66 (mn 2H), 1.25 3H), 1.22 0.95 J 7.3, 3H).

EXAMPLE 224 (R/S)-9-Fluoro.. 1 -rmt 5 ox-H (COmpOund 324, structire 47 of Scheme IV. w-her

DR

1

R

2 =fluoro.

R,

3 HRopvl.

X=O).

This compound was prepared in a manner similar to that of Compound 319 (EXAMPLE 219) from 9-fluoro-1,-iyr--yrx-,,-rmehl5-hoeo34Aunln (EXAMPLE 223) (20 mg) to afford 21 mg of Compound 324 as a white solid. Data for Compound 324: IH NMR (400 MHz. acetone-d6) 7.53 J 8.4, LH), 7.47 (dd, J 9.9, 2.9, 1H), 7.02 (dd, J 8.8, 5.0, IM1, 6.95 (mn, 1I), 6.80 J 8.5, 5.53 J 1.5,11-1), 3.81 Wdt, J= 9.2, 6.7,18H), 3.58 (dt, J= 9.2, 6.7, 18M, 2.29 J= 1.5,3H), 1.46 (sext, J 1.32 3H), 1.16 3H), 0.75 J= 7.4, 3H).

EXAMPLE 225 r.-+dihv5r-chrom4toy3.4ctI Lnor 3 hnne (Copoud 25.stuctre42 of Scheme X. wh r)

R

2 =chloro. Rbutyl.

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 (38 mng, 0.12 mmol) and 2.5 M n-BuLi in hexanes (0.28 mL, 0.70 inmol) to afford 7 mng of Compound 325 as a clear oil. Data for Compound 325: 1 H NMR (400 Mz, acetone-d6) 7.72 J 2.4, IH), 7.58 J 8.5, 18), 7.12 (dd, J 8.3, 2.5, 18), 7.05 (d, J 8.5, 1 6.75 J 8.5, 18H), 5.53 18H), 4.82 J 8.0, 18H), 2.40 (mn, 28), 2.09 (s, 3H), 1.5-1.4 (mn, 6H), 1.25 (br s, 6H), 0.95 J 7.8, 3H).

EXA vPLE 226 vi Hh~uoD4- ob (Comoun 32 srucur42 of Sceme XI where R-K

R

2 =methox. butyl).

This compound (12 mng, 33%) was obtained as a by-product in the formation of Compound 355 (EXAMAPLE 255) as a colorless oil. Data for Compound 326: IH NMR (400 M~ffz, aceto ne-d 6 7.47 J 8.4, 18H), 7.20 J 18H), 6.80 J 8.5, 11-1), 6.69 (in, 28), 5.79 (dd,JI= 10.3, 3.2, 1H), 5.51 (d,JI= 1.2, lH), 3.80 3H), 2.24 J= 1.0. JH), 1.74 (rn, 1H), 1.5-1.3 (mn, 5H), 1.27 3H), 1. 18 3H), 0.84 J 3H).

EXAMPLE 227 (RS-9Furo .dhdo2.2.45ttran-yfhv1 SZU -romenq

F

3 4 -flqguinoline (Comp2ound 327. strcture 42 of Scheme XI. where RI-H. R=fluoroRnitv) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 (36 mng, 0.12 innol) and 1.4 M MeLi in ether (0.45 mL, 0.63 inmol) to afford 6 mg of Compound 327 as a clear oil. Data for Compound 327: IH NMR (4.00 Mhz, acetone-d6) 7.46 J 8.4, 18), 7.41 (dt, J 10.0, 1.5, 18H), 6.84 (in, 2H), 6.80 J 8.5, IH), 6.07 J 6.5, 18), 5.53 J 1.4, 18), 2.25 J 1.1, 38), 1.32 J 6.5, 3H), 1.26 38), 1.20 38).

EXAMPLE 228 (R/S')-9-Fluoro- l.

2 -dihvrro2.2.4thyl5Hi-omnor34I-un e (Comipoundj 32.srcue 2o cee VI. where R 1

R

2 fluoro) This compound was prepared in a manner similar to that described for Compound 202 (EXAMPLE 102) from 9-fluoro- 2 -dihydro-5-hydroxy..2,2,4-trimethy 1 5

H

chromeno[3,4-Afquinoline (EXAMPLE 223) (15 mg) to afford 14 mg of Compound 328 as a clear glass. Data for Compound 328: IH NMR (400 MHz, acetone-d6) 7.41

J

8.4,18H), 7.41 Wdt, J= 10.0, 1.5, IH), 6 8 4 2H), 6.70 J= 8.4, 18), 5.49 J= 1.2, IH), 5.29 28), 2.11 J= 1.6, 38), 1.26 68).

EXAMPLE 229 (RIS- 1.-rmtx-Hcrr~oIA+-,-l (Compound 29. utr 2o Schem Xl. whreD R 1 -6H. R 2 =metho Ilguinoln Msr ire 46o chemne XIV were H.R= etov This compound was prepared in a manner similar to that of9choo 1,-iyr--yrx-,,-iehl511 chrormno[3,4-.jquioijne (EXAMPLE 219) from Compound 314 (24 mng, 0.075 rnunol) to afford 15 mg of I, 2 -dihydro5hydroxy-9 methoxy-2,2,4-tiehISH chro meno [3,4..fquino line as a white solid, which was used directly in the next step.

(RIS)- 1 -5hdo9~ehxy.. etYsc~~o3 4-nuino~ (Copod 329. strtureAl 42 f Sch-m XI. where RI-R=H.

R

2 =e-thoxv) This compound was prepared in a manner similar to that described for Compound 202 *(EXAMPLE 102) from l, 2 dihydro5hydroxy9methoxy224imhylSH-crmn[,-lu line (15 mg) to afford 12 mg of Compound 329 as a clear glass. Data for Compound 329: ljj NMR (400 MHz, acetone-d6) 7.41 J 8.3, 1IH), 7.16 J 3.0, 18H), 6.81 J 8.6, 1 H), 6.68 (0-4 IH), 5.48 J1= 1.2, 18), 5.23 28), 3.80 3H), 2. 10 1.2, 38), 1.24 (s, 6H).

EXAM4PLE 230 WRS)- 0.Dhdo24.ttaeh5 structuret 42, ofScee where R

R

2 metvl) This compound was prepared in a manner similar to Compound 229 (EXAMPLE 229) from Compound 316 (34 mg, 0. 11 mmol) to afford 16 mg of Compound 330 as a clear oil Data for Compound 330: 1tH NMR (400 MHz, acetone-d6) 7.42 (in, 1H), 7.41 J 8.4, 18H), 6.90 (in, 18H), 6.76 J 8.0, 1IH), 6.64 J 8.4, 5.48 18H), 5.41 (br s, 18H), 5.25 2H), 2.30 3H), 2.11 J= 1.4, 3H), 1.24 68).

EXAMPLE 231 Y24ctimthno 34-nguinnpjn (Cmpun-31 structuire 93 of Schemne XXIfv. w hre

D

1 cl R 2

R

7 9 =Methyf This compound was prepared in a manner simailar to Compound 229 (EXAMPLE 229) from Compound 317 (20 mg, 0.061 inmol) to afford I1I mg of Compound 331 as a clear oil. Data for Compound 331: IH NMR (400 MI-z, acetone-d6) 7.57 (dd, J 7.9, 1.2, 18H), 7.42 J IH), 7.18 (dd, J=7.9, 1.2,18H), 6.98 J 18), 6.70 J 18H), 5.56 (bins, 18), 5.50 J= 1.2, IH), 5.40 28), 2.14 J= 1.3, 3H), 1.25 6H).

EXAMdPLE 232 (R/S)-9-hoo l 2 dhdo224Sermtv5cono rfldgilin(Cmpound 332. structure 42 of Schenge XI. Where R I=H. R 2 =clr.R-ehl This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 (40 mg, 0. 123 mmol) and methyllithium (438 jitl, 0.6 14 mmo 1, 1.4 M in ether, Aldrich) to afford 8 mg of Compound 332 as an opaque oil. Data for Compound 332: 1 H NMR (400 MI-z, acetone-d6) 7.65 J 2.5, 1Ih), 7.49 J 8.4, 11-H), 7.08 (dd, J 8.5, 2.4, IN), 6.85 J 8.5, 111), 6.70 J 8.5, lH), 6.09 1H), 5.52 iN), 2.25 1.32 J= 6.5, 3H), 1.26 3H), 1.20 3H-).

EXAMPLE 233 (R/S)-5-4-Bromopheny).9.chloro-. 2 -dih do-224rmety..5 HchoenoB, 4 figuinoline (Cmpounjd333. structure 42 of Scheme X. where R=4-bromohenvl.

R

1

=H.

g 2

=CI)

This compound was prepared by General Method 5 (EXAMPLE 60) frm Compound 209, mg, 0. 123 minol) and l, 4 -dibromobenzene (203 mg, 0.859 mmol) to afford I11 mg of Compound 333 as a pale cream colored oil. Data for Compound 333: 1 H NMR (400 MHz, acetone-d6) 7.59 J 2.4, IH), 7.58 J 6.3, MN, 7.42 J 8.5, 2H), 7.16 (d,IJ= 8.5, 2H), 6.94 (dd, J 4.2, INH), 6.92 (s,lIH), 6.84 J INH), 6.77

J

111), 5.68 (br s, IM), 5.48 1.98 31-1), 1.27 3H), 1.24 3H).

EXAMPLE 234 9 -Chloro..5.(3.cl r hen I)-l 2 ih dO2tI A-4-.5H1jmeo 3 figuinoline (Compound 334. structure 42 of Scheme X. where R 3-chloagphenL. !am-i

R=I

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 mg, 0. 123 mmol) and 3 -bro mochloro benzene (164 mg, 0.856 mmol) to afford 9 mg of Compound 334 as a pale yellow oil. Data for Compound 334: IH NMR (400 MHz, acetone-d6) 7.61 J 2.3, 1IH), 7.59 J 9.0, 1 7.25 (in, 4H), 6.95 (in, 2H), 6.85 J 8.3, IH), 6.83 J 7.3, IN), 5.72 (br s, IN), 5.50 IH), 2.00 3H), 1.28 3H), 1.26 3H).

EXAMPLE 235 (R/S)-.9-Chloro-1 2-i 224 flguinoline (Compound 335. structure 42 of Scheme XI. where R=3-methlphenvl.

R=H.

RL&CI)

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 mg, 0.061 mmol) and 3-bromotoluene (147 mg, 0.859 mxnol) to afford 10 mg of Compound 335 as a pale white oil. Data for Compound 335: IH NMR (400 MiHz, acetoned6) 7.59 J 2.4, IN), 7.58 J 9. 1, IH), 7.19 (mn, 2H), 6.95 (mn,3H), 6.83 J IH), 6.78 J 8.5, 5.64 (br s, IH), 5.81 IN), 2.20 3H1), 2.05 3H1), 1.27 (s, 3H), 1.24 3H).

EXAMPLE 236 9 -Chloro-5-(4..chloro..3.methy-penl' I 2 -dihdo-2 2 4.trimethyH chromenor3.4-fjpuino 'n CopoUnd 6. tutrZ2o ceeX.weeR-hoo 3-methylphenyL. R=H. R 2 =1) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 mg, 0.061 inmol) and 5-broino-2-chlorotoluene (177 mg, 0.859 inmol) to afford 9 mg of Compound 336 as a cream colored oil. Data for Compound 336: IH NMR (400 MHz, acetone-d6) 7.60 J 2.4, IN), 7.57 (dJ iH), 7.23 (mn, 2H), 7.00 (mn, 2H), 6.91 I1H), 6.84 (d,JI= 8.2, 1H), 6.79 8.5, 5.68 (br s, IH), 5.48 (ds, IH), 2.23 3H), 1.99 3H), 1.27 1.25 3H).

.EXAM1PLE 237 (R S)-9 Chlo o. l 2 ~di vdro 5.r3.(rrfluo o~th l~ph n 11 2 4 chromeno 3 4-f uinoline mpund 337. structure 42 f Scheme XI. where R= (tifuoomthl~hevLR'8.R 2

CI)

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 mg, 0. 123 mnmol) and 3 -bromobenzotrifluoride (276 mg, 1.23 mmol) to afford I11 mg of Compound 337 as a cream colored oil. Data for Compound 337: IH NMR (400 MHz, acetone-d 6 7.61 J1=2.3, 18H), 7.52 (in, 4H), 7.07 I 6.99 (dd, J= 8.5, 2.4, IH), 6.87 J 8.3, 1H), 6.84 J1=8., 18), 5.73 (br s, 18), 5.51 1H), 2.01 3H), 1.27 6H-).

EXAMPLE 238

(R/S)

9 -Choros.(3s..di chloropheny~-I 2 IhYro-2 2 4Jtrime C~o flguinoline (Compound 338. structure 42oAS7 m XT, where R= 3 R9 1

R

2 =Cfl This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 (40 mng, 0. 123 inmol) and I -bromo-3,5-dichloro bnzene (277 mg, 1.23 mrnol) using diethyl ether for the formation of the aryl lithium in the first step. The final step afforded I11 mg of Compound 338 as a pale yellow oil. Data for Compound 338: IH NMR (400 MHz, acetone-d6) 7.64 J1=2.3, 18), 7.61 J 8.5, 7.32 IN), 7.20 7.19 18), 7.03 (dd, J 8.9, 2.4, 6.91 IN), 6.89 J 6.7, 18), 6.88 J1 6.7, 18), 5.78 Obr s, 18), 5.53 IN), 2.03 3H), 1.28 38), 1.27 3H).

EXAMPLE 239 (R/S')-9Clo.

flguinoln (Cmon 3.s cture 42 of Sche-me YI. her- 4 -methoxyphenyl R' R 2 =C1) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 (40 mg, 0. 123 mmol) and 4 -bromoanisole (230 mg, 1.23 mmol) to afford I11 mg of Compound 339 as a pale yellow oil. Data for Compound 339: 1H NMR (400 MI-z, acetone-d6) 7.59 J 2.5, 1H), 7.56 J 8.5, 18), 7.11 J 8.7, 2H), 6.94 (dd, J 2.4, 18), 6.89 1H), 6.82 J 8.5, 18), 6.75 (in, 3H), 5.61 (br s, 18), 5.45 18), 3.69 38), 1.99 3H), 1.26 3H), 1.23 38).

EXAMPLE 240 (R/S)I).Chloro..5(fluoro4..htho hi) chromienor3.4.lpjuihn(Comond 340.Ui structur-e42 ofSchemeX.w eeR3fur.

L.ehxpey 1 8 2 Ci) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 mg, 0.061 inmol) and 4 -bromo-2-fluoroaisole (88 mng, 0.429 mmol) to afford 8 mg of Compound 340 as a pale yellow oil Data for Compound 340: IH NMR (400 MI-z, acetone-d6) 7.60 J1=2.4, 18H), 7.58 J1=-8.5, 1H), 7.02 (dd, J 10.2, 2.4, 181), 6.97 (dd, J= 8.5, 2.3,18H), 6.94 J= 8.5,18H), 6.90 18), 6 89 18H), 6.84 J 18H), 6.79 J= 8.5, 18), 5.68 (br s, 18H), 5.48 IH), 3.79 31H), 2.00 38), 1.27 (s, 38), 1.24 38).

EXAM4PLE 241 Ch~ro~44.f~u rop~ny l 2 -d hyd o2. 4j thl H -chrnm fnrz A t~quinolinedo~on 31stcur42 of Scheme X. wher R4-luopnl. R I=H.

This Compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 mg, 0. 123 mmol) and 4 -fluorophenyl magnesium bromide (1 Ml, 1.03 mmol, I M, Aldrich) to afford I1I mg of Compound 341 as a pale yellow oil. Data for Compound 341: IH NMR (400 MHz, acetone-d6) 7.60 J1=2.4, IR), 7.58 J1=7.3, 1IH), 7.24 (in, 2H), 6.96 (nm, 4H), 6.84 J= 8.3, 18), 5.67 (br s, IH), 5.48 18), 1.98 3H), 1.26 (s, 3H), 1.24 3H).

EXAMPLE 242 0h r-5-m..h~roieoxy xythlhl) At-dhdr.24rnet chro ienor3.iguinoline mon 4.srcue42 of Scheme- XI -hereR3-coro- 4 methNoxy-5-meth dphenyL R=Ha 2

C

This compound was prepared by General Method 5 (EXAMVPLE 60) from Compound 209 mg, 0.123 inm-ol) and 4 -bromo-2-chloro5-mthyanisole (181 mg, 0.770 mrnol) to afford 12 mng (21 of Compound 342 as a pale yellow oil. Data for Compound 342: 11 NMR (400 MHz, acetone-d6) 7.61 J1=2.4, 18H), 7.58 J 8.4, 18H), 7.03 (in, 18H), 6.99 (dd, J 8.5, 2.4, 28), 6.91 1H), 6.84 (dd, J 8.3, 3.8, 2H), 5.69 (br s, 18H), 5.49 (s, 3.70 38),'2.18 38), 2.01 38), 1.27 3H), 1.26 3H).

EXAMPLE 243 tlguinon (C mon 34-stu tre 42 of Scheme VT. whre R= 4 -fluor 3meth P-enI This compound was prepared by General Method 5 (EXANIpLE 60) from Comp ound 209 mng, 0.123 inmol) and 4 -fluoro-3-phenyl magnesium bromide (1 ml, 1.026 inmol,

IM,

Aldrich) to afford 8 mng of Compound 343 as a pale yellow oil. Data for Compound 343: 1 H NMR (400 MHz, acetone-d 6 7.59 J 2.6, 1 7.57 J 8.6, 18H), 7.12

J

235 8. 1, 1IH), 6.99 (in, I1-H), 6.96 (dd, J 8.2, 2.4, 1IH), 6.90 (mn, I1H), 6.84 J 8.3, 1 H), 6.77 J 8.5, 18), 5.68 (br s, 1141), 5.48 18), 2.14 3H), 1.25 3H), 1.24 3H-).

EXAMPLE 244 9 -Chloro-5-(3..fluorophqny1) l.~I t 2.24 thy..s..c& mnor 4 tiguinoline (Cmpound 344. sructure 42 of Scheme X. wlhe-re R=3-fluoropey 1

H

R

2

=CI

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 mg, 0. 123 inmol) and Il-bro mo-3-fluoro benzene (150 mg, 0.860 inmol) to afford I I mg of Compound 344 as a pale yellow oil Data for Compound 344: 1 H NMR (400 MHz, acetone-d6) 7.61 J= 2.4, 1IH),7.59 J= 8.4, 1 7.29 (in, IlH), 7.04 J= 7.9, 1 6.97 (mn, 4H), 6.85 J 8.5, 18H), 6.80 J 8.5, 1IH), 5.7 (br s, 18H), 5.50 I1H), 2.01 3H), 1.27 3H), 1.25 3H).

EXAMPLE 245 hydo224tieh- -mtycei hn154ih frjuino)line (Compound 345. struture 32 of Scheme IX. where R=3,4k(eleediO-xy)phenv This compound was prepared by the General Method 5 (EXAMvPLE 60) from 4-bromo- 1,2- (methylenedioxy) benzene (201 mg, 1.0 minol) and Compound 159 (15 mg, 0.05 nml) to afford 1.5 mg of Compound 345 as a colorless oil Data for Compound 345: 1H NMR (400 MHz, acetone-d6) 7.60 J 7.6, 1 7.55 J 8.4, 1 6.98 J 7.6, 1 6.88-6.60 (in, 6 5.98 1 5.91 2 5.51 (bs, 1 5.46 1 2.02 3 1.25 3 1.23 3 H).

EXAMPLE 246 (R/)-S(4~h~oo....mthypheny')1. 2 -dihydro-2 2 4-trmthlI-5H-chromnoF 3 .41 fguinoline (Comound 346. rcue3ofShme Xwhere

R=

4 -choro-lmethenvI This compound was prepared by the General Method 5 (EXAMPLE 60) from 5-bromo-2chlorotoluene (206 mng, 1.0 minol) and Compound 159 (10 mng, 0.03 inmol) to afford 8.0 mng of Compound 346 as a colorless oil. Data for Compound 346: IH NMR (400 MHz, acetone-d6) 7.60 J 1 7.55 J= 8.4, 1 H) 7.23-7.19 (in, 2 7.01 J= 9.9, 1 6.97 J= 7.7, 1 6.89 I 6.88-6.81 (in, 2 6.78 J= 8.0, 1 5.55 (bs, I 5.48 1 2.22 3 2.00 3 1.26 3 1.24 3 H).

EXAM4PLE 247 mo-3.prdl. ttavro.dmeh1 chromneno[344-qnine (Cmpound 34. -Structure 33 ofShm L.-where R=4- bro mo- This compound (1.8 mg, was obtained as a colorless oil along with Compound 197 as described above (EXAMPLE 97). Data for Compound 347: IH NMR (400 MHz, CDC1 3 8.22 J 5.2, 1 7.56-7.49 (mn, 2 7.34 I 7.12 J 6.5, 1 7.03 (td, J 7.4, 1.3, 1 6.92 (td,J 1.3, 1 6.86 (d,J 1 6.61 J 1 6.58 1 4.98 I 4.52 1 2.43 J= 14.5, 1 2.22 J= 14.5, 1 1.34 (s, 3 1. 17 3 H).

EXAMPLE 248 (RS)5-35-ifuroh jv)- 2 -dihdo-2.2.4 neI5Hcwoeo 34-ginln (Copoud 48.stuctre32 of Scheme Ix, where =5-difluorph n 1 This compound was prepared by the General Method 5 (EXAMPLE 60) from 1-brom-3,5difiuorobenzene (193 mng, 1.0 rniol) and Compound 159 (20 mng, 0.07 inmol) to afford 14 mng of Compound 348 as a colorless oil. Data for Compound 348: IH NMR (400 MHz, acetone-d6) 7.63 J 7.6, 1 7.58 J 8.4, 1 7.03 J 7.7, 1 6.95 (s, 1 6.94-6.83 (in, 6 5.62 (bs, I 5.11 I 2.04 3 1.27 3 1.26 3

H).

EXAMPLE 249 (ROS--(.Dihopenl A.-ivr -2.4meth -5HchromnoB F4-fluinoline This compound was prepared by the General Method 5 (EXAMPLE 60) from dichlorobenzene (226 mg, 1.0 inmol) and Compound 159 (15 mg, 0.05 inmol) to afford mng of Compound 349 as a colorless oil. Data for Compound 349: IR (neat) 3350, 2940, 1690, 1590, 1480, 1070; 1 H NMR (400 MHz, acetone-d6) 7.63 J 7.7, 1 7.58 J 8.4, 1 7.29 J1 1. 9, 1 7.20 J 1. 9, 2 7.03 J 7.7, 1 6.97 I H) 6.93-6.85 (mn, 3 5.63 (bs, .1 5.53 I 2.04 3 1.28 3 1.27 3 13 C NMR (100 MHz, acetone-d6) 151.0, 147.3, 145.7, 135.5, 135.1, 135.0, 129.0, 128.8, 128.6, 128.4, 127.8, 125.3, 124.6, 123.2, 123.0, 120.3, 119.7, 118.3, 116.4, 116.3, 74.9, 51.2, 24.0.

EXAMPLE 250 (R/S')-5-(3-Brcomo-5-methyllpheny). 1.

2 -d hco224tmeh~ hr menor 4.

flguinoline (Comound 350. structure 32 of Schemne IX. where methylphenvfl) This compound was prepared by the General Method 5 (EXAMPLE 60) from dibromotoluene (250 mng, 1.0 mrnol) and Compound 159 (10 mng, 0.03 inmol) to afford 6.1 mng of Compound 350 as a colorless oil. Data for Compound 350: lIH NMR (400 MI-z, acetone-d6) 7.61 J 7.7, 1 7.56 J 8.4, 1 7.17 I 7.14 I 7. 10 1 7.01 J1=7.7, 1 6.91 1 6.90-6.82 (mn, 3 5.58 (bs, 1 5.50 (s, I 2.21 3 2.02 3 1. 27 3 1.26 H).

EXAMPLE 251 (R/S-S-(3-Bromo-5-fluorophenyl). 2 -dihydro- 2 .2.4-triethl-5H-chromeno f3tlguinoline (Comnound 351. structure 32 of Scheme IX. here This compound was prepared by the General Method 5 (EXAMPLE 60) from 1 ,3-dibromo- (254 mg, 1.0 minol) and Compound 159 (10 mng, 0.03 minol) to afford 6.2 mg of Compound 351 as a white powder, along with 0.7 mg of Compound 352 (EXAMPLE 252). Data for Compound 351: mp 82-84 OC; ER (neat) 3367, 1699, 1595, 1581, 1469, 1435, 1251; IH NMR (400 MHz, acetone-d6) 7.63 J 7.7, 1 7.58 J 1 7.23 J 5.2, 1 7.20 1 7.08-7.02 (mn, 2 .6.97 I 6.94-6.85 (in, 3 5.64 (bs, I 5.53 I 2.04 3 1.28 3 1.27 3 14); 13 C NMR (100 MHz, acetone-d6) 163.4 J 250 Hz), 151.1, 147.3, 146.4 J 7.0 Hz), 135.0, 129.1, 128.8, 128.4, 128.3, 125.3, 124.6, 123.2, 123.0, 122.9, 120.4, 119.7, 119.2 J 24.8 Hz), 118.3, 116.4, 115.2 J 22.2 Hz), 74.9, 51.2, 29.4, 24.0.

238 EXAMPLE 252 (R/S)-5-(3-Bromo-5-fluorophenvI. -1 2 3 4 -tetrAhydron2.dmehI.4etvidn r3-4jflguino fine (Compound 352. structure 33 of Scheme IX, where R=3- The compound (0.7 mg, was obtained along with Compound 351 as described above (EXAMPLE 25 1) as a colorless oil. Data for Compound 352: 'H NMR (400 MFz, CDCI3) 7.54 J 7.7, 1 7.51 J 8.4, 1 7.24 J 5.5, 1 7.06-6.84 (in, 6.60 J 8.4, 1 6.57 1 4.96 I 4.56 I 4.01 (bs, I 2.42 J =12.3, 1 2.21 J= 12.3, 1 1.34 3 1. 15 3 H).

EXAMPLE 2531 4 uoro3(trifluoro thy)phnl .diyr224trimethyI5H.

chro meno B.4-tlpuino line (Comround 353. structure 32 of Sche-me lX. where R=4-fluoro- 3 -(Wrfluoromethyn~phenyl) This compound was prepared by the General Method 5 (EXAMvPLE 60) from 5-bromo-2fluorobenzotrifluoride (243 mg, 1.0 mrnol) and Compound 159 (10 mg, 0.03 inmol) to afford 3.5 mg of Compound 353 as a colorless oil. Data for Compound 353: IH NMR (400 MHz, acetone-d6) 7.62 J 7.7, 1 7.6 1-7.53 (in, 3 7.27 J 7.7, 1 7.04-6.82 (in, 5 5.62 Cbs, 1 5.51 1 2.02 3 1.26 6 H).

EXAMPLE 254 (R/S-9-Equoro-. 2 -dihy-dro2. 4 e hy1(~h~hn1S~ flguinoline (Compound 354 structue 42 of Scheme X. where R=3-methvlhenyvL

R

1 =H.i This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 (31 mg, 0.10 mmol) and 3 -broinotoluene (90 mL, 0.74 mmol) to afford 18 mg of Compound 354 as a colorless glas. Data for Compound 354: IH NMR (400 MHz, acetone-d6) 7.53 J 8.5, IH), 7.33 (dd, J 9.9, 2.9, 1H), 7.08 (mn, 2H), 6.98 J 6.7, 2H), 6.89 18H), 6.83 J= 8.5, 18H), 6.75 (in, 2H), 5.48 I1H), 2.20 3H), 1.99 (s, 3H), 1.27 3M), 1.25 3H).

239 EXAMPLE 255 tlauinoine WCnpud35 tutr 42of Scheme XI. where R=3-metyIphenvl- R 1

=H.

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 314 (32 mg, 0.10 mnioI) and 3 -bromotoluene (90 mL, 0.74 mmol) to afford 10 mg of Compound 355 as a colorless glass. Data for Compound 355: IH NMR (400 MHz, acetone-d6) 7.53 J= 8.5, 1W), 7.13 J= 2.8, IH), 7.08 (in, 2H), 6.99 (in, 2H), 6.83 (d, J 6.0, 1W), 6.80 I1H), 6.70 J 11H), 6.55 (dd, J 8.7, 2.8, 5.46 J 1.2, 1 3.72 3H), 2.24 3H), 1.98 3H), 1.26 3H), 1.24 3H).

EXAMPLE 256 9 FRuoro53fluoro4toxhevl l.-i o2.2.4.t.rithyl5Hchromenor3.4.-lguinoline(Copound 356. structure 42 of Scheme ,I where R=3-fluoro.

4 mtoyhnl 1

HR-'

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 (41 mg, 0. 12 minol) and 4 -bromo-3-fluoroanisole 13 mL, 1.0 minol) to afford I11 mg of Compound 356 as a yellow oil Data for Compound 356: IH NMR (400 MHz, acetone-d 6 7.55 J= 8.5, 1W), 7.35 (dd, J= 10.0, 2.8, 1W), 7.01 (dd, J1= 12.5, 1.9, 1H), 6.95 J 6.9, 11H), 6.87 (in, 3H), 6.74 (mn, 2H), 5.48 J 1. 2, 1WH), 3.79 3H), 1. 97 (s, 3H), 1.27 314), 1.24 3H).

EXAMPLE 257 (R/S')-9-Fluoro- I 2 .rdhvdr-2 2 4tr '1e1hyl 5371iifro h~ Choeo341un~ Compond 37 t tr 42 of Scheme XI. w ere R=3.

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 mg, 0. 12 minol) and 3 -bromobenzotrifluoride 14 mL, 1.0 minol) to afford 11 Img of Compound 357 as a yellow oil. Data for Compound 357: IH NMR (400 MHz, acetone-d6) 7.54 J 8.5, 1 7.35 (dd, J 9.9, 2.9, 1 7. 10 (in, 2H), 6.98 J 6.7, 6.89 1H), 6.85 8.5, I 6.75 (mn 5.48 lH), 1.99 3H), 1.27 (s, 3H), 1.25 3H).

EXAM4PLE 258

(RIS)

9 Fur...(.flo hen 1h-) l.~ivr~.4.rnehlHcihomenrL 3 4 flguinoline (Compound 158. strture~ 42r ofShem XI. where R 4 -fIuoro3-rethlhenZ

I,

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 (38 mg, 0. 12 inmol) and 1.0 M 4 -fluoro-3-miethylphenyl magnesium chloride in TF (Aldrich) to afford 25 mg of Compound 358 as a yellow oil. Data for Compound 358: 1 H NMR (400 MHz, acetone-d 6 7.54 Kd J 1N), 7.34 (dd, J 10.0, 2.8, lIH), 7.14 (mn, 7.00 (mn, 1H), 6.91 J= 9.6, IN), 6.88 114), 6.83 J= 8.4, 111), 6.79- 6.68 (in, 5.48 111), 2.13 3H1), 1.99 3H), 1.27 3H), 1.24 3H).

EXAMPLE 259 2 .4~Diluorobnzylidne).. ld ro22 4tinthy15H.c hromnr 4 (Copoud 59.stuctre45 of Scheme XIII. where R=R 2

R

3 2 4-difluorph 1v) This compound was prepared by General Method 6 (EXAMPLE 119) from 2,4difluorobenzyi bromide (0.27 ml, 2. 10 inmol) and compound 159 (20 mg, 0.07 rmol) to afford 16 mg of Compound 359 as a yellow oil. Data for Compound 359: Rf=O.44 (silica gel, 25% EtOAc: hex); IH NMR. (400 MHz, acetone-d 6 8.43 (in, I 7.86 J 1IH), 7.67 J= 8.5, INH), 7.20 (mn 2 7. 11 to 7.03 (mn, 3 6.86 J 1 5.88 I 5.55 I 2.11 3 1.29 (irs, 6 H).

EXAMPLE 260 (Z (3 i u ro e zy id n l. d h d o 2 2 4 r t v 5 c A -en r 3 4 f g n e (Copond36 trctre45 of Sche me II h r R =RH R =3 4diflurp 1nv) This compound was prepared by General Method 6 (EXAMPLE 119) from 3,4difluorobenzyl bromide (0.27 ml, 2.10 iniol) and Compound 159 (20 mg, 0.07 mrnol) to afford 20 mg of Compound 360 as a yellow oil. Data for Compound 360: Rf=-0-44 (silica gel, 25% EtOAc:hex); 1 H NMR (400 MHz, acetone-d6) 7.83 (rn, 2 7.66 J 1 7.55 1 7.31 (Mi I 7.24 2 7. 10 (in, I 6.85 J= 8.5, 1 H), 5.67 1 5.55 I 2.08 3 1.28 (brs, 6 H).

EXAMPLE 261 54 3 -Fluoro eZylidne.l. 7 terhdo224 eh~~l~m r 4 figuinoline (Compound 361).

A solution of Compound 159 (20 mg, 0.07 minol) in EtOAc (10 mld) was stirred over Pd/C (5 mg) at rt under an atmosphere of H2 (0 atm) for 15 h. The reaction mixture was filtered then concentrated in vacuo to afford 14 mg of the l, 2 ,3,4-tetrahydro.2,2,4- (3,4-elquino line as a yellow solid. According to General Method 6 (EXAMPLE 119), from 3-fluorobenzyl chloride 17 ml, 1.40 rmol) and 1,2,3,4tetrahydro 2 2 ,4trethysHcoumrino[34eqiolie (14 mng, 0.0 imol) was obtained 8.6 mg of Compound 361 as a yellow solid. Data for Compound 361: Rf=-0.38 (silica gel, 25% EtQAc:hex); 111 NMR (400 MHz, acetone;d06) 7.82 J 8.5, 1 6.69 (mn, I 7.62 J 8.5, 1 7.58 J 8.5, 1 7.40 (in, 1 7.22 (in, 2 7.08 (mn, 1 6.97 (in, I 6.74 J 8.5, 1 6.24 1 5.30 (brs, 1 3.76 (Mn I 1.97 (mn, 1 1.55 1 1.40 (d,J 6.6, 3 1.30 3 1.26 3 H).

EXAMPLE 262 2 6 -Difluorobenz lidene). -1~iyr~.24tyscoenr4lun (Comnound 362 structure 45 of Schem XIII. where R=R 2

EHR

3 2,-ifluorophnvl) This compound was prepared by General Method 6 (EXAMPLE 119) from a-bromo-2,3difluorotoluene (0.43 g, 2.1 iniol) and Compound 159 (20 mg, 0.07 inmol) to afford 4.4 mg of Compound 362 as a yellow oil. Data for Compound 362: Rf=0.45 (silica gel, EtQAc:hex); IH NMR (400 MHz, acetone-d6) 7.83(d, J 8.5, 1 7.68 J 1 7.35 I 7.15 1 7.04 3 4.90 J= 8.5 H, I 6.87 J 8.5, 1 5.61 I 5.57 I 2.23 3 1.32 (brs, 6 H).

EXAMPLE 263 Lylt2,nzliene-22,-trimety 5Hchromenor3Azfung o line (Copoud 63.stuctre45 ofScheme X11[Iwhere

RI=R

2

R

3 =2-methlphenyl) This compound was prepared by General Method 6 (EXAMPLE 119) from a-chloro-oxylene. (0.20 ml, 1.6 mmol) and Compound 159 (15 mg, 0.05 mmnol) to afford 15 mg (76%) of Compound 363 as a yellow oil. Data for Compound 363: Rf=-0.45 (silica gel, EtOAc: hex); IH NMR (400 MHz, acetone-d6) 8.22(d, J 8.5, 1 7.82 J 8.5, 1 H), 7.64 J 8.5, 1 7.26 to 7.04 (in, 6 6.83 J 8.5, 1 5.94 1 5.54 1 2.28 3 2.15 3 1.25 (brs, 6 H).

EXAMPLE 264 (71 2 Dihydro5 2.4.6 ethbenz id -24 2tvl~lr 3 fguinoline (ompoun 364d strctur 45oA ceeXI.weeR= 2 H 3 246 trimethylp~henvi) This compound was prepared by General Method 6 (EXAMPLE 119) from achloroisodurene (0.50 g, 3.0 inmol) and Compound 159 (30 mg, -0 10 inmol) to afford mng of Compound 364 as a yellow oil. Data for Compound 364: Rf=-0.40 (silica gel, EtOAc:hex); 1 H NMR (400 Mliz, CDC13) 7.65 J 8.5, 1 7.51 J 8.5, 1 7.15 J 8.5, 1 6.93 J 8.5, 1 M, 6.88 2 6.80 J 8.5, 1 6.65 (d, J 8.5, 1 5.69 1 5.50 I 3.73 (brs, 1 2.28 6 2.26 3 2.16 (s, 3 1.45 (brs, 6 H).

EXAMPLE 265 7 9 -Chloro-5-(25-difluorobenzylidene)l. 2 -dihyro2.2.4-tbnethli5Hchromeno 13.4flguinoljne (Compound 365. structure 45 of'Scheme XflI where RI=H. R 2 -CI. R 3 difluorophenyl) This compound was prepared by General Method 6 (EXAMPLE 119) firom Compound 209 mg, 0.123 rnmol) and a-bromo-2,5-difluorotoluene (414 mng, 2.0 inmol) to afford 10 mng of Compound 365 as a yellow oil. Data for Compound 365: 111 NMR (400 MHz, acetone-d6) 8.05 (mn, IH), 7.87 (s,I 7.72 J 8.5, 111), 7.26 (in, 1H), 7.19 (mn, 1H), 7.06 (mn, lH), 6.90 J= 8.5, IH), 5.94 I 5.57 111), 2.11 3H), 1.32 (br s, 6H1).

EXAMVPLE 266 (Z)-S-Benzvnofenejcuiorlin (Compound 36stutr45oScmeXIII where R I=H. R 2 =CI. gyphv) This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 209 mg, 0. 123 rnmol) and benzyl magnesium chloride (614 il-, 0.614 mniol, I M, Aldrich) to afford 10 mng of Compound 366 as a yellow oil. Data for Compound 366: IH NMR (400 MHz, acetone-d6) 7.83 J 1WH), 7.81 (rn, 2H), 7.67 J 8.4, 1 7.39 (mn, 2H), 7.21 (in, 3H), 6.84 J 8.5, 1H), 5.71 I 2. 10 3H), 1.34 (br s, 6M).

EXAMPLE 267 (Z--Chloro- l.

2 -diIdro2.2.4flethy1I-5-2-mthyben id H flauinoline (Compound 367 sructure 45 of Scheme XIII where R

R

2 =CI. R 3 =2methlphenyj) This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 209 ing, 0.154 inmol) and ct-chloro-o-xylene (345 mng, 2.46 inmol) to afford 14 mg of Compound 366 as a yellow oil. Data for Comnpound 366: IH NMR (400 Mliz, acetone-d6) 7.85 J 2.5, 1H), 7.66 J 8.5, 1W), 7.17 (mn, 211), 7.11 (mn, 2H), 6.80 J 8.5, 2H), 6.55 111), 5.73 1W),4.98 1W), 2.19 3H), 1.29 (br s, 3H), 1.21 3H).

EXAMPLE 268 (z)-5-enyiee9ho.1 t (Copoud 68.stuctr95 of Scheme XVI. whreR

-=R

4 6 =R9=H R 7 8 =rethyl.

RT

1 ::phenyl This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 313 mg, 0.080 inmol) and benzyl magnesium chloride (0.802 mL, 0.802 inmol, 1 M solution in ether, Aldrich) to afford 5 mng of Compound 368 as a yellow oil. Data for Compound 368: IH NMR (400 MHz, acetone-d6) 7.86 7. 1, 1WH), 7.79 J 2.2, 1WH), 7.63 J 8.5, 1 7.40 (in, 2H1), 7.20 (mn, 4H1), 6.89 J 8.6, 1WH), 6.78 J 8.4, 111), 5.99 11H), 5.70 J= 8.3, 1WH), 1.37 6H).

EXAMVPLE 269 9 -Choo5(-lurbnyiene) l 2 -dihydro-224trj-thv,-l5Hc1-oM9Bo[ 3 4flguinoline (C-omp-ound 369. structure 45 of Scheme XI ere R=H. R 2 -CI. R 3 =2 frop~henyl) This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 209 mg, 0. 123 mmol) and 2 -fluorobenzylbromide (160 mg, 0.860 mmol) to afford 9 mg of Compound 369 as a yellow oil. Data for Compound 369: IH NMR (400 MHz, acetone-d6) 8.32 1H), 7.84 1 1.7, 111), 7.69 J 8.5, IH), 7.26 (nm, 2H), 7.20 (d, J1=3.0, 111), 7.18 (in, 211), 6.87 J 8.5, 1H), 5.97 111), 5.57 1H1), 2.11 311), 1.33 (br s, 6H).

EXAMPL E 270 9 -Chloro-5-(3- Fluoro enfl.en) flguinoline (ompound 370. structure 4-5 of Scheme V1I10. where R 1

R

2 =Cl. R 3 =3fluorophenl This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 209 (38 mg, 0. 12 inmol) and 3 -fluorobenzyl chloride (0.23 mL, 1.9 inmol) to afford 20 mg of Compound 370 as a yellow oil. Data for Compound 370: IJ{ NMR (400 MHz, acetone-d6) 7.85 J 2.3, 111), 7.69 J 8.5, 111), 7.66 (mn, 1H1), 7.52 J 7.7, IH), 7.41 I 7.25 (mn, 211), 7.01 (mn, 111), 6.87 J= 8.4, 111), 5.73 Cs, 11H), 5.57 J= 1.2, 1iH), 1.45-1.35 Cbr d, 6H1). The C(4) methyl is obscured by the acetone inultiplet.

EXAMPLE 271 E/Z)-5 -Bez I in e uoo l 2 ih r- 2 t h1.5 h r omnoF 4 -fiuio*ie This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 207 (79 mg, 0.25 inmol) and* 1.0 M benzylmagnesiuin chloride in Et2O (Aldrich) to afford mng of Compound 371 as a yellow oil, as a 2:1 ZIE mixture. Data for Compound

CZ)-

371: IH NMR (400 MH z, acetone-d6) 7.80 J 7.7, 7.6 211), 7.39 J 7.8, 1H), 7.23 7.15 I 7.08 111), 6.95 I1H), 6.83 Cdd, J= 8.4, 2.8, 11H), .70 IH), 5.55 J= 1.2, IH), 2.10 1.35-1.25 (br d, 6H). The characteristic signals for (E)-371 are: 6.53 1H), 5.04 1.94 J 1.2, 3H), 1.33 3H), 1.00 3H).

EXAMjPLE 272 0Z')-S-Benzylidene.8..flApro..

(Compound 372- strture 45 of ScheMe XIII whe-reI R 1 -CD R H R 3 peVI) This compound was prepared by General Method 6 (EXAMVPLE 119) from Compound 208 mg, 0. 18 mmol) and 1.0 M benzylmagnesium chloride in Et2O (Aldrich) to afford 11I mg of Compound 372 as a yellow oil. Data for Compound 372: IH NMR (400 MHz, acetone-d 6 7.86 (dd, J= 8.7, 6.2, 1 7.80 J 2H), 7.61 J= 8.4, 1 H), 7.40 (app t, J 7.8, 2H), 7.20 (mn, IH), 7.05 (mn, 1W), 6.86 (in, 1Wf), 6.83 J 8.4, 1W), 5.71 5.55 J 1, 1H), 2.11 3H), 1.40 (br s, 6H).

JEXAMPLE27 (Compound 73. stutue45o Scheme II. whr 1 H 2 mtov

R

3 pen) This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 314 mng, 0. 18 mmol) and 1.0 M benzylinagnesium chloride in Et2O (Aldrich) to afford 11 mg of Compound 373 as a yellow oil. Data for Compound 373: 1Ij NMR (400 MHz, acetone-d 6 7.79 J 7.6, 2H), 7.53 J 8.5, 1WH), 7.4-7.2 (in, 6.84 (in, 2H), 5.67 IH), 5.55 1W), 3.82 3H), 2.11 3H), 1.35-1.30 (br s, 6H).

EXAM4PLE 274 (Z--lor. .3.4do-4.tiehl(2tl i tlguinoline mon 74 structure 45 o Schemne X III where R IR 2 =oo 3 This compound was prepared by General Method 6 (EXAMVPLE 119) from Compound 207 (34 mg, 0. 11 mmol) and freshly prepared 1.0 M 2 -mrethylbenzyl magnesium chloride in Et2O to afford 30 mg of Compound 374 as a yellow oil. Data for Compound 374: 1 HNMR (400 MHz, acetone-d6) 8.20 J 114), 7.64 1IH), 7.58 (dd,1J 10.0, 2.9, 18), 7.26 (appc, J I 7.19 1 7.4, IH), 7.14 (in, 2H), 6.94 (mi, IH), 6.84 J= 8.5, 5.95 lH), 5.55 J= 1.1, 1ff), 2.28 3H), 2.14 1= 1.1, 3M), 1.35-1.30 (br s, 6H).

~EXAMAPLE 275 (z)-8-For. dhdo 2 2tieh1.(2t~ VId)S flguinoline (Compound 375. sructure 45 of Sche-me XI.whr R=fluoro.

R

2

R

3 =2meth jphenvl) This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 208 (31 mg, 0. 10 nimol) and freshly prepared 1.0 M 2 -methylbenzyl magnesium chloride in Et2O to afford 32 mig of Compound 375 as a yellow oil. Data for Compound 375: 1 ff NMR (400 MHz, acetone-d6) 8.19 J 7.9, 18H), 7.86 (dd, J 8.8, 4.2, 18H), 7.61 (d, J 8.5, 18H), 7.28 (app t, J 18H), 7.20 J= 6.9, 1 7.15 (in, I 6.94 (dd, J1=9.6, 2.7,18H), 6.86 (mn, 2H), 5.97 1I), 5.55 J 1.2, 1H), 2.28 38), 2.14 38), 1.35 (br s, 614).

,EXAMPLE 276 aldee-5--rmeoB4 flguinofn (Ciad37 .srcure 45 of Sceme XI.heeR H.R meoXV.

R=-ehlhnl This compound was prepared by General Method 6 (EXAM~PLE 119) from Compound 314 mg, 0. 18 inmol) and 1.0 M benzylmagnesium chloride in Et2Q (Aldrich) to afford 11I mg of Compound 373 as a yellow oil. Data for Compound 373: 1 H NMR (400 MHz, acetone-d6) 8.23 J 7.8, 18H), 7.64 J 8.5, 1 7.37 (mn, 18H), 7.30 (in, 18H), 7.15 (in, 284), 7.04 J 8.6, 18H), 6.82 J 8.4, 18H), 6.77 (dd, J 8.6, 3. 0, 18H), 5.92 (s, 18H), 5.53 J 1. 2,18H), 3.82 3H), 2.27 384), 2.14 3H), 1. 35 (br s, 6M).

EXAMdPLE 277 (opud3 7 tutr 95 of Scheme XXVI where R 1 2

=RP

4 =R6 R 3 5

=R

7 9 =inethyl. R 10 phevl This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 315 (28 mg, 0.087 mmol) and 1.0 M benzylmagnesium chloride in Et20 (Aldrich) to afford 19 mg of Compound 377 as a yellow foam. Data for Compound 377: IH NMR (400 MHz, acetone-d6) 7.79 J 7.6, 2H), 6.63 (dd, J 11.4, 2.9, IH), 7.39 (app t, J 7.8, 2H), 7.25 2H), 6.97 IH), 6.68 IH), 5.74 IH), 5.52 J 1.2, 1H), 2.61 (s, 3H), 1.97 3H), 1.33 (br s, 6H).

EXAMPLE 278 -(4-Chlrophenl).

2 3 4 -etrhvdro-2.2-d ethvl-5Hhrcomen 4quinolinone (Compound 378 structure 97 of Scheme XXV where R4-chlorophenyl To a solution of Compound 164 (EXAMPLE 64) (220 mg, 0.6 mmol) in 6 mL of THF at 78 oc was added 1.6 M n-BuLi hexane solution (1 mL, 1.6 mmol), followed by di-t-butyl dicarbonate (0.7 g, 3.2 mmol) in 2 mL of THF. The reaction mixture was warmed to rt and stirred for 15 h, then was quenched with 2% NaOH aqueous solution. The mixture was extracted with EtOAc (2 x 30 mL) and was concentrated. Chromatography of the crude residue on a silica gel column using 10 EtOAc/hexane as solvent afforded the N-Boc Compound 164 (87 mg) in 30 yield in addition to 60 of the starting material (132 mg).

The N-Boc material (40 mg, 0.082 mmol) in methanol (20 mL) at -78 oc was treated with 03 for 3 min and then with methyl sulfide (0.5 mL) for 30 min. Removal of solvent and chromatography of the crude mixture afforded a colorless oil, which was treated with excess TFA (0.5 mL) in 1 mL of CH2C12 for 60 min. The reaction was quenched with 2% NaOH mL) and was extracted with EtOAc (2 x 30 mL). Removal of the solvent and chromatography again provided 15 mg of Compound 378 as a yellow oil. Data for Compound 378: 1H NMR (400 MHz, acetone-d6) 7.86 J= 8.8, 1 7.61 J 7.7, 1 7.40 1 7.04 J 7.7, 1 6.99 J 8.8, 1 6.90 J 7.7, 1 6.82 (d, J 7.7, 1 6.38 (bs, I 2.65 J 15.2, 1 2.44 J 15.2, 1 1.97 3 H), 1.37 3 1.27 3 H).

EXAMVPLE 279 R 5 C o r p h n y l. 3 -t tr a y d o 2 2 3 t e r a m t h l H c h ro m e n o 3 4 -4 guinolinone (Compound 379, structure 98 of Scheme XXVIwhrR 4 corhev R 1 =mth I' To a suspension of 40% NaH in mineral oil (10 mg, 0.25 mmol) in THF (I mL) was added a solution of (RIS)-1I(t-butoxycarbonyl).5.(4..chlorophenyI) I 2 3 4 -tetrahydro..2,2 m.no 4quinoLio ne'(structure 96 of Scheme XXVMf, where R=4chiorophenyl, R I=methyl) (10 mg, 0.02 mmol) and excess Mel 1 mL). The reaction was stirred at rt for 2 h and was quenched with water (I mL), and extracted with EtOAc (2 x mL). Removal of solvent provided the crude mixture, which was treated with TFA (0.2 mL) in dichloromethane (1 mL) for 60 min. Chromatography of the crude mixture on a silica gel column using 15 EtOAc/Hexane as solvent afforded 6.5 mg of Compound 379 as a colorless oil Data for Compound 379: If[ NMR (400 MHz, CDCl3) 7.73 J 8.7, 1 7.49 J= 7.7, 1 7.30 I 7.13 4 7.04 J= 7.7, 1 6.91 J =7.7, 1 6.83 J= 7.7, 1 6.71 J= 8.7, 1 M, 4.28 1 1.29 3 1.20 3 H), 1. 13 3 1.03 3 H).

EXAMPLE 280 (RS)-5-(4-Chlorophenyl)..l. 2 -dihviirn-,'2.2d--ImetylHc romn:no34nine (Compound 380- rtur IA f'Schemne XX=X where

R=

4 -chl orhenyl) To a solution of Compound 379 (EXAMPLE 279) (10 mg, 0.025 mmol) in toluene (I mL) at -78 OC was added 0.5 M DIBAL toluene solution 1 mL, 0.05 miol1) and the resulting mixture was warmed up to rt. The reaction mixture was quenched with water (1 mL) and was extracted with EtOAc (2 x 5 mL). Removal of solvent and chromatography of the mixture on a silica gel column afforded 6.8 mg of 5-(4-chlorophenyl).1,234 tetrahydro4hyroxy22.dmethyl5Hchr 3 4 -Aqunl as a colorless oil, which was treated in dichloromethane (1 mL) with a catalytic amount of TsOH for 3 h to provide 4.1 mg of Compound 380 as a colorless oil. Data for Compound 380: 1 H NMR (400 MHz, acetone-d6) 7.60 J 7.7, 1 7.52 J 8.5, 1 7.27 J 8.6, 2 H), 7 2 5 J 2H)7.01 J 1 6.89 J=7.7 Hz,lI 6.81 J 1 H), 6.67 J 1 6.57 I 6.33 J 10.0, 1 5.57 J 10.0, 1 5.55 (bs, I 1.32 3 1.30 3 H).

EXAM4PLE 281 4 1, 'IChorpen1 A-t..4teahdro-22 4-timethy15 ho 3.4fl 3 -guinolin one. (Compound 381. structure 53 of Scheme XV. where R=4-chloohenyl.

This compound (0.7 mg) was prepared by HPLC separation of the enantiomers of Compound 235 by a chiral column, Chiracel OD-R, using a 9:1 mixture of methanol and water as mobile phase. The optical purity of Compound 381 was determined by HPLC to be 90% [a] 20 D 101 (MeOH).

EXAMPL E 282 4 5tetrClhyoprn22)-Ith 15H-c rmnB.

4 1- 3 guinolinone (Compound 382. srcture 53 of Scheme XV. where R 4 -chorp eny1.

R 1

=R

2 =Mf This comfpound (1.5 mg)was prepared by HPLC separation of the enantiomers of Compound 235 by a chiral column, Chiracel OD-R, using a 9:1 mixture of methanol and water as mobile phase. The optical purity of Compound 382 was determined by HPLC to be 68% [a] 20 D =-63 (MeON).

EXAMPLE 283 (/)5-(4-Chloroph n ly. I 2 3 4 -tetrahvro.2 2-dieth .5Hc rmn 3 4 3 guinolinone (Compounid 383. structure 4A of Scheme XIX. whr R=4-chLorophenl) This compound (0.63 mg, was prepared in a manner similar to that described for Compound 234 (EXAMPLE 134) from Compound 380 (EX-AMPLE 280) as a colorless oil.

The major product (4 was Compound 378 (EXAMVPLE 278). Data for Compound 383: IH NMR (400 MHz, CDCI3) 7.62 J 8.3, 1 7.60 J 7.7, 1 7.17 J 8.6, 2 7.09 J 8.6, 2 7.06 J 7.7, 1 6.94 J 7.7, 1 6.83-6.80 2 H), 6.26 I 3.88 (bs, I 3.55 J= 20.0, 1 3.11 J= 10.0, 1 1.33 3 H), 1.32 3 H).

EXAMqPLE 284

(R/S)

3 urbur153furb ld 123 4 -tetrhd0 3vd~x 2 4 3 4 fgioln Cmpud34 tutr Ao ceex x where R 1=R2)=H R3--luorohe RAmel) (RIS)- I A 3 ~-Ttr IAh-d-o.2.4 t hylcoumarinor34-3.un~n stutr

A

Schee XX. were 1

=R

2 H).This compound was prepared by the same Bocproeto/yrbrto/xdtion/deprotcto procedure as described in the synthesis of Compound 234 (EXAMPLE 134) from Compound 159 (EXAMPLE 59) (440 mg, mmol) to afford 98 mg of(/)1234ttayr-,,-iehlomrn[,-] 3 -quinolinone as a yellowish oil. Data for RS1,3,-erhdo2,4 trmtycuaio3,-I3qioi e IH NMR (400 MHz, CDCI3) 7.95 (d,JI= 8.6, 2 7.38 J 8.2, 1 Ml, 7.3 1-7.24 (in, 2 7.16 J 8.5, 1 5.29 J 7.4, 1 H), 3.94 (bs, 1 1.56 3 1.48 J 7.4, 3 ),1.22 3 H).

(RS:k3F~ooez I )5(3f OLuoe li )l 2 3 erhdr L3..hvnU-22 2 4 tmethvsjjch--roen fo nnlie (Compound 384 su ue 8A ceeX where RI1 =R2=H.ID-* R 3 =-WiUoohen-yi) To a solution of (RIS)- I 2 3 ,4-tetrahydro-22,4 tdehlomrn[,---unlnn (3 mg, 0.01 minol) in ether (3 mL) at rt was added the freshly prepared a 0.5 M 3 -fluorobenzymagnisium chloride ether solution (0.5 mL, 0.25 mmol) and the resulting mixture was stirred at rt for 2 h, then was quenched with water mL). The mixture was extracted with EtOAc (2 x 5 mL) and was concentrated and purified by silica gel chromatography to afford the intermediate, which was treated with TsOH mg) in dichloromethane (I mL) for 60 rmin. The reaction was quenched with 2% NaOH mL) and was extracted with EtOAc: (2 x 5 mL). Removal of solvent and chromatography of the mixture afforded 3.0 rug of Compound 384 as a colorless oil. Data for Compound 384: IH NMR (400 MHz,

CDCI

3 7.71 J1 7.8, 1 7.63 J 11.0, 1 7.51 J 8.4, 1 7.40 J 7.8, 1 7.33 (td, J 7.8, 6.2, 1 7.28-7.18 (in, 3 7.13-6.92 (mn, 5 6.65 J 8.3, 1 5.89 I 3.73 J 6.8, 1 3.66

I

3.08 J 14.2, 1 2.97 J1 14.2, 1 2.79 I 1.33 3 1.29

J

6.8, 3 1. 18 3 H).

EXAM9PLE 285 LMS'- Di utv 1-1 2 4 -ttahdr.3.h rx v- 2 2 4~tiehlHh 34 flguine (Cmon 8.rcture 9A of Scheme XXXI. where

R=R

2

R

3 =nbtl To a solution of l, 2 3 4-tetra hyo-t24-ro22e hlcoraio34A--unl.

(EXAMVPLE 284) (4 mg, 0.01 mmol) in ether (3 mL) at it was added 1.6 M n-BuLi hexane solution (0.05 mL, 0.08 mmol) and the resulting midxture was stirred at rt for 2 h, then was quenched with water (5 mL). The mixture was extracted with EtOAc (2 x 5 mL) and was concentrated and purified by silica gel chromatography to afford the intermediate, which was treated with Et3SiH (0.05 mL) and TWA (0.05 mL) in dichloromethane (I ruL) for min. The reaction was quenched with 2% NaOH- (5 niL) and was extracted with EtOAc (2 x mL). Removal of solvent and chromatography of the mixture afforded 0.8 mg of Compound 385 as a colorless oil The relative stereochemistry of this compound was not determined. Data for Compound 385: Iii NMR (400 MHz,

CDC

3 7.61 J 7.8, 1 Hi), 7.44 J= 83Hz, I 7.14 J= 7.8, 1 Hf), 6.98 J= 7.8, 1 6.94 1 H), 6.53 J 8.3, 1 5.53 (dd, J 10.3, 3.5, 1 3.42 (bs, I 2.94 J 7.0, 1 H), 2.65 1 1.88-1.63 (m1, 2 1.53-1.22 (ri, 10 1.44 J1= 7.0, 3 1.33 3 1.08 3 0.94 J1=7.2, 3 0.87 J= 7.2, 3 H).

EXAMPLE 286 (RIt-5ButI lromen 4- uio2.4tn.olthyn 1 1 ne (Copoud 36.Strctue O-A or A of Scheme XX wH ere 1 2 3 To a solution of (RIS)- l-t-butoxycarbonyl-123 terhdo-,,- mehlomaio34 Al- 3 -4uinolinone (structure 6A of Scheme XXX, where R I=R 2 an intermediate from EXAMPLE 284) (4 mg, 0.012 minol) in ThF (1 mL) at -78 OC was added 1.6M n-BuLi hexane solution 0 16 mL, 0.024 minol) and the resulting mixture was warmed up slo wly to -20 OC, then was quenched with water (0.5 mL). Removal of solvent provided the crude product, which was treated with TFA (0.05 mL, 0.65 mmol) and Et3Si- 1 mL, 0.65 mmnol) in dichloromethane (I mL) for 60 min. The'reaction was quenched with 2% NaOH (2 mL) and was extracted with EtOAc (2 x 5 mL). Removal of solvent and chromatography of the residue afforded 0.7 mg of Compound 386 as a colorless oil. The relative stereochen-istry of Compound 386 was not determined. Data for Compound 386: 1

H

NMR (400 MI-.z, CDCI3) 7.63 J 7.7, 1 7.51 J 8.2, 1 7.16 J 7.7, 1 H), 7.01 J 1 6.96 (d,1J= 7.7, 1 6.74 1 5.32 (dd, J= 10.l1and 1 3.66 J 7.2, 1 1.98-1.90 (in, I 1.58-1.18 (in, 5 1.48 3 1.44

J

7.2, 3 1.20 3 0.89 J= 7.3, 3 HD.

EXAM4PLE 287 (R/S-4.5t)-l..34Ttnter% A o4 (Compound 87 tuctur 18A of Scheme XXXIII. where R H.R=hn) This compound, along with Compound 388 (EXAMPLE 288), was prepared by the same Boc-proteion/hydrobration/oxcdation/depoet procedure as described in the synthesis of Compound 234 (EXAMPLE 134) from Compound 161 (EXAMPLE 61) mg, 0. 11 minol). Compound 387 (4.0 mg, 10%) was obtained as a colorless oil. Data for Compound 387: IH NMR (400 MHz, CDC1 3 7.59 J 8.3, 1 7.57 1 1 H), 7.21-7.12 (mn, 5 7.05 J1=7.6, 1 6.92 J 1 6.86 J 1 6.83 J1=8.3, 1 6.37 I 3.72 (bs, I 3.41 J= 7.5, 1 1.50 J1=7.5, 3 H), 1.45 3 1. 17 3 H).

EXAM4PLE 288 (RIS-22Su) t 5 e (opud3 8 tutr 17A o F Scheme XXXI. where R =R 2 =14 R 3 phn) This compound, along with Compound 387 (EXAMPLE 287), was prepared by the same Bocproectiohydroraoo dation/dteto procedure as described in the synthesis of Compound 234 (EXAMPLE 134) from Compound 161 (EXAMPLE 61) mg, 0. 11 rmol). Compound 388 (7.3 mg, 18 was obtained as a white poweder. Data for Compound 388: mp 108-1 10 OC; ER (neat) 3358, 2972, 1720, 1473, 1292, 1213, 752;

IH

NMR (400 MHz, CDC13) 7.66 J 7.7, 1 7.64 J 8.2, 1 7.20 5 7.06 (t, J 7.7, 1 6.95 J 7.7, 1 6.83 J 8.2, 1 6.77 J 7.7, 1 6.39

I

3.72 (bs, I 3.58 1 1 1.44 3 1.23 3 0.80 J1=7.4, 3 H); 13 C NMR (100 MEHz, CDCI3) 214.4, 151.0, 143.2, 139.3, 131.1, 128.9, 128.8, 128.6, 128.5, 123.4, 122.7, 122.2, 122.1, 122.0, 118.3, 116.6, 75.4, 60.2, 43.9, 28.1, 27.3, 16.3.

Anal. (C25H23NO2-3/4H 2 0) C, H, N.

EXAM4PLE 289 (Z-(R/--3Fur 1ezldn) 2 3 4 -tetrAhvo2.24eh~~l,.mnr 4 3 -gu inofinonle (Compound 389. structure 19A of Scheme XXXrV, where R I-R 2

R

3 .3f luorophenvl) To a solution of (RIS)- I -t-butoxycarbonyi. 1,,,-erhdo224-rmtyeuaio34 f]- 3 -quinolinone (structure 6A of Scheme XXX, where R 1

=R

2 an intermediate from EXAMPLE 284) (10 mg, 0.025 mmol) in THF (1 mL) at -78 OC was added freshly prepared M 3 -fluorobenzylmagnesium bromide (0.06 mL, 0.06 mmol) and the reaction was slowly warmed up to rt and was quenched with water (1 niL). The mixture was extracted with EtOAc (2 x 5 mL) and was concentrated to provide the crude intermediate, which was treated with excess TFA (0.2 mL) in dichloromethane (1 mQL for 30 mini and then quenched with 5 NaGH (5 mL). The mixture was extracted with EtOAc (2 x 10 miL), concentrated and chromatographed to afford 6.0 mg of Compound 389 as a yellowish oil. Data for Compound 389: ]OR (neat) 3356, 1716, 1604, 1469, 1251; 1Hf NMR (400 M'Hz, CDCl 3 7.73 J 1 7.70 (d,1J 11. 1, 1 7.60 J 1 7.42 1 H), 7.31 (td, J =8.0Oand 6.2, 1 7.22 J1=8. 1, 1 7.18 J1=7.0, 1 7.08 J 1, 1 6.94 (td, J 8.4 and 2.4, 1 6.85 J 8.3, 1 5.87 I 4.33 J 7.3, 1 3.78 I 1.56 J 7.3, 3 1.51 3 1.24 3 13 C NMR (100 MHz, CDC1 3 2.14.0, 162.4 J1 244.0 Hz), 152.3, 147.0, 144.2, 137.2 J 8.1 Hz), 129.8 (d, J =8.8 Hz), 128.7, 128.0, 125.4, 124.2, 123.0, 122.6, 122.4, 121.9, 121.8, 118.1, 116.5, 115.8 J1=23.1 Hz), 114.1, 113.8 2 1.1 Hz), 60.1, 44.9, 27.7, 27.2, 17.4. A minor mg product was also isolated and identified as fluorobenzylidene)- 1,,,-erhdo224tiehl5-hoeo34A3qioioe 1Hj NMR (400 MHz, CDCI3) 7.78 J 7.9, 1 7.70 J 8.7, 1 7.67 J 10.2, 1 7.42 J 1 7.35-7.26 (in, 3 7.21 J= 8. 1, 1 7. 10 J= 8.2, 1 H), 6.97 (td, J 8.4 and 2.4, 1 5.80 1 4.28 J 7.3, 1 3.55 (bs, I 1.88 3 1.76 J 7.3, 3 1.33 3 H).

EXAM4PLE 290 (IMIZAI 224tie I- ch mga4-If-3guinoinone (Comod 30stuur23oF Scheme XXXV. where R 1 =hnD l.-ihydo-2 2 4trimeth 1 O-isocoumarino 34-1gunoijne (Compound 21lA Scheme XXXV) This compound was prepared by General Method 8 (EXAMPLE 138) from 7amino- 3 4 -benzocouniari to afford I,2-dihydro.2,2,4tainthyI.l1-isocoumiarino[3,4 flquinoline (150 mg, 0.52 mmol, 60%) as a yellow solid. Data for 1,2-dihydro-2,2,4triniethy-10.isocounirio(3,4.jlquino~e: mp 197-199 OC; ER (KBr) 3350, 2960, 1711, 1608, 1566, 1468 and 1311; 1H NMR (400 NMz, CDC13) 8.20 J 7.6, 1 Hl), 8. 10 J 7.6, 1 7.83 J 8.6, 1 7.77 J 7.6, 1H), 7.44 (tJ 7.6, 1lH), 6.64

J=

8.6, 1 5.88 (bs, 1 5.38 1I-H), 2.39 3 1.29 6 13 C NMR (100 Mliz, CDC13) 161.5, 149.6, 146.9, 136.6, 134.8, 130.4, 128.3, 126.6, 122.8, 120.8, 119.0, 111. 1, 109.6, 108.6, 51.7, 30.4, 23.6.

112-i 3 o22 -rmeh- -e IHishoxo.

4 -fiuinoline structure 22A f Schemne XV. where RL- =penvl) This compound was prepared by General Method (EXAMPLE 60) from 1,-iyr-,,4wrty-0iscuai3 4 -flquinoline (60 mg, 0.20 mmol) and bromobenzene (157 mg, 1.0 mmol) to afford 60 mg as a colorless oiL Data for 1,-iyr-,,-rmty--hnl-Hiohoeo34fqioln:I NMR (400 MHz, CDC13) 7.60 J 7.7, 1 7.44 J 8.3, 1 7.43-7.30 (in, 7 H), 7.10 J= 7.7, 1 6.73 J 1 M, 6.04 1 5.22 I 3.87 (bs, 1 2.11 3 1.26 3 1.23 3 Hl); 13 C NMR (100 MHz, CDC13) 152.0, 146.3, 145.2, 139.6, 132.9, 131.6, 129.3, 128.6, 128.4, 125.9, 125.6, 123.5, 121.2, 113.9, 111.2, 108.5, 80.1, 51.4, 30.3, 30.1, 23.5.

R/-16- Terdro22 4trthyl-APhenIShLih~gqjzz gunolinrone This compound was prepared by the same Bocprtcinhdooainoiaindpoeto procedure as described in the synthesis of Compound 234 (EXAMPLE 134) from l, 2 -dihydro..2,2,4..trimethy16-pheny1..5Hisochromeno[3,4..jjquinohne (30 mg, 0.085 mmcl). Compound 390 (2.2 mg, was obtained as a colorless oil, along with 4.4 mg of Compound 391 (EXAMvPLE 291).

255 Data for Compound 390: IH NMR (400 MHz, CDC1 3 7.65 J 1 7.49

J

8.4, 1 7.37 1 M,7.30 H)719(t 8 IX 6.89 J=7.8, 1 H), 6.38 J 1 6.14 1 3.83 J= 7.5, 1 3.67 (bs, I1-H), 1.41 3 1.39 (d,1J= 7.5, 3 1. 12 3 H).

EXAMPLE 291 (RIS-41.61234Ttrh--- d--mt,,1 gunoinne(Cmpun 31.structure 24A o heme XXXV. whr 1 enyl) Compound 391 (4.4 mg, 14%) was obtained as a colorless oil along with Compound 390 as described above (EXAMPLE 290). Data for Compound 391: IR (neat) 3358, 1716, 1614, 1471, 1439, 1030; IH NMR (400 MHz, CDC13) 7.66 1=7.7, 1 7.53 J 8.3, 1 7.35 5 7.34 J1=7.7, 1 7.15 J1=7.7, 1 6.79 J1=7.7, 1 6.12 (s, I 3.82 1 1 3.66 (bs, I 1.41 1.23 3 1. 14 J1= 7.3, 3 H).

EXAMPLE 292 1.23 -quinolinone (Comound 2.stucur 19A of Scheme XXXIV. where

P=R

2

=H.

RL--phnyl) To a solution of (RIS)- I -t-butoxycarbonyl. 1,,,-erhdo224-rmtycuaio3 fI-3-quinolinone (structure 6A of Scheme XXX, where

R

1

=R

2 an intermediate firomn EXAMPLE 284) (10 mg. 0.025 mmol) in THF (I mL) at -78 OC was added 1.0 M benzylmagnesiumn bromide (0.06 mL, 0.06 mniol) and the reaction was slowly warmed up to rt and was quenched with water (1 mL). The mixture was extracted with EtOAc (2 x mL) and was concentrated to provide the crude intermediate, which was treated with excess TFA (0.2 mL) in dichloromethane (I mL) for 30 min and then quenched with 5 NaOH mL). The mixture was extracted with EtOAc (2 x 10 mL), concentrated and chromatograpbhjed to afford 3.8 mg of Compound 392 as a colorless oil. Data for Compound 392: IR (neat) 3354, 1716, 1469, 1261, 1045; IH NMR (400 MHz, CDCI3) 7.81 J 7.3, 2 7.72 J 7.7, 1 7.59 J 8.4, 1 7.39 J 7.3, 2 H), 7.24-7.18 (in,4 2 7.17 J 7.7, 1 7.08 J 7.7, 1 6.83 J 8.4, 1 5.91 I 4.37 J 7.3, 1 3.76 I 1. 57 J1 7.3, 3 1. 51 3 1. 24 3 13 C NMR (100 MHz, CDCI3) 2.14.1, 152.7, 146.0, 144.2, 135.1, 129.5, 128.6, 128.5, 127.1, 124.2, 122.8, 122.4, 122.2, 121.8, 121.7, 117.8, 116.5, 115.4, 60.1, 44.9, 27.7, 27.2, 17.4.

EXAMPLE 293 fl.Su)-5-(3-Fluorophenvl)-.l. 2 3 4 -tetrah -r2 2 4trethy-Ushc~~o 3 guinolinone Co-mpound 393. srcure 17A of Scheme YXYYT. hr 'R 2 H 3 3 fluorophenyl) This compound, along with Compound 394 (EXAMPLE 294), was prepared by the same Boc-protetonhydroboration/oxidation/deprotecion procedure as described in the synthesis of Compound 234 (EXAMPLE 134) from Compound 191 (EXAMPLE 91) mg, 0.081 mmol). Compound 393 (6.9 mg, 22%) was obtained as a colorless oil. Data for Compound 393: ER (neat) 3356, 171 9, 1602, 1487, 1288, 1209, 1028; IH NMR (400 MHz, CDCI3) 7.66 J 7.7, 1 7.64 J= 8.3, 1 7.19 (td, J= 7.9, 5.8, 1 7.09- 6.86 (in, 5 6.85 J 1 6.78 J 1 6.38 I 3.72 (bs, I 3.58 J 7.4, 1 1.44 3 1.23 3 0.87 J 7.4, 3 13 C NMR (100 MHz, CDCI3) 214.1, 162.9 J =246.2), 150.7, 143.3, 141.8 J 130.4, 130.2, 130. 1, 128.6, 124.6, 123.3, 122.7, 122.4, 122.3 J= 22. 118.3, 116.9, 115.8 J= 21.4), 74.5, 60.2, 43.9, 28.1, 27.3, 14.4.

EXAMPLE 294 4 I5fl-5(3.F'uorophenyI)

I

2 3 4 tta d ri2eth -5 -c 0 nrz A- 3 guinolinone (Comound 394. rcue 18A of Schieme XXI1. whre R I=R 2

R

3 3fluorophenyn) This compound, along with Compound 393 (EXAMPLE 293), was prepared by the same Bo-rtcinhdooainoiaindpoeto procedure as described in the synthesis of Compound 234 (EXAMPLE 134) from Compound 191 (EXAMPLE 91) mng, 0.08 1 mmol). Compound 394 (5.0 mg, 16%) was obtained as a colorless oil. Data for Compound 394: ]OR (neat) 3356, 1719, 1608, 1473, 1288, 1209, 1039; IH NMR (400 MHz, CDC1 3 7.60 J 8.3, 1 7.58 J 7.7, 1 7.15 (td, I 7.9, 5.8, 1 7.09 J 1 6.97-80 (in, 6 6.34 I 3.73 I 3.38 J 7.3, 1 1.50 (d, J 7.3, 3 1.46 3 1. 19 3 13 C NMR (100 MHz, CDC13) 213.2, 162.9 J 247), 150.8, 142.7, 141.6 J 130.2, 130.1, 129.9, 128.5, 123.6, 122.8, 122.7, 122.4, 122.2, 118.3, 116.8, 115.5 J 21.6), 114.9 J 22.6 Hz), 74.2, 60.1, 43.0, 27.3, 26.6, 18.4.

EXAMPLE 295 (R/S-41,51)- l.

2 3 4 -Tetrahydro-2.24-trimethy[-543.(iuoromethv1)pheny115Hchromenor3.4-fl-3-guinolinone (Compound,395, srcture 18A of Schemne XXXMI. where

R

1

=R

2

R

3 =3(trifluoromethyl hen-1) This compound, along with Compound 396 (EXAMPLE 396), was prepared by the same Boc-protectionihydroboratiorfoxidatiorp/deprotection procedure as described in the synthesis of Compound 234 (EXAMPLE 134) from Compound 195 (EXAMPLE 95) mg, 0.049 mmol). Compound 395 (3.2 mg, 15%) was obtained as a colorless oil. Data for Compound 395: IR (neat) 3354, 2926, 1720, 1607, 1473, 1211, 1126, 1074; IH NMR IS- (400 MHz, CDCI3) 7.61 J 8.3, 1 7.57 J 7.7, 1 7.42 J 7.7, 1 7.39 I M, 7.38-7.30 (mn, 2 7.09 J 7.7, 1 6.95 1= 7.7, 1 6.91 J 8.4, 1 6.86 J 8.3, 1 6.39 1 3.77 1 3.37 J 7.3, 1 1.50 I 7.3, 3 1.48 3 1.20 3 13 C NMR (100 MHz, CDC13) 213.1, 150.7, 142.8, 13 1. 1, 129.4, 129.1, 128.6, 125.4, 124.6, 123.0, 122.7, 122.6, 122.5, 122.2, 118.3, 117.0, 74.0, 60.2, 43.1, 27.1, 26.5, 18.4.

EXAMPLE 296 (RIS-41.Su)-l l.

3 4 -Tetrahvdro- 2 .2.4-imethvi5[3.(fluoromethy~phenv1]5Hchromenor3.4-tl-3-guinolinone (Compound 396 structure 17A of Scheme XXXM-I where

R

1

=R

2

R

3 =3-(trifluormthl)phbenyl) This compound, along with Compound 395 (EXAMPLE 395), was prepared by the same Boc-protection/hydroboration/oxidation/deprotection procedure as described in the synthesis of Compound 234 (EXAMPLE 134) from Compound 195 (EXAMPLE 95) (20 mg, 0.049 inmol). Compound 396 (3.2 mng, 15%) was obtained as a colorless oil. Data for Compound 396: IR (neat) 3356, 2928, 1718, 1602, 1.330, 1126, 1074; IH NMR (400 MHz, CDCI3) 7.67 I 8.3, 1 7.65 J 7.7, 1 7.52 I 7.48 (in, 1 7.35-7.30 (in, 2 7.08 J 7.7, 1 6.98 J 1 6.88 J 8.3, 1 6.78 I 7.7, 1 6.43 I 3.75 I 3.57 J= 7.4, 1 1.45 3 1.24 3 0.86 (d, J1 7.4, 3 13 C NMR (100 MI-z, CDC13) 214.0, 150.5, 143.3, 140.3, 132.1, 131.2 J 31.7), 130.0, 129.1, 128.7, 125.7, 123.3, 122.7, 122.6, 122.5, 122.2, 118.3, 117.1, 74.3, 60.2, 43.8, 28.2, 27.3, 16.5.

EXAMPLE 297 (RIS-31.4u.Su1)-54 -Chloropheny). I tt chromeno13.4-Dquinoline (Compound 397, structure 26A-of Scheme XXXVI. where R '=R 2

R

3 -chlRhenvl.

R

4 =methyl) To a solution of 3

I,

4 u.Su)-5-(4.c1orophenyl)-.1, 2 3 4 -tetrahydro-3-hydroxy-2,2,4trirnethyl-5H-chromeno3,4..nqnoijne (structure 14A of Scheme XXXII, where

R

1

=R

2

R

3 =4-chlorophenyl, an intermediate from EXAMPLE 135) (8 mg, 0.016 inmol) in DMF (0.5 mL) and excess Mel (0.5 mL) was added 60% NaH in mineral oil (10 mg, 0.25 minol). The resulting white slurry was stirred at rt for 2 h and was quenched with water mL). The mixture was extracted with EtOAc (2 x 10 mL) and Was concentrated to give the crude product, which was treated with TFA (0.2 mL) in CH2C12 (1 mL) for 60 min and was quenched with 5 NaOH (5 mL). The mixture was extracted with EtOAc (2 x 10 mL), concentrated and was purified by silica gel chromatography to afford 5.0 mng of Compound 397 as a colorless oil. Data for Compound 397: IH NMR (400 MHz, CDCl3) 7.53 J 1 7.48 J= 8.4, 1 7.12 4 7.04 J 1 6.89 (t,J 7.7, 1 6.87 J 7.7, 1 6.63 J 8.4, 1 6.48 1 3.74 (bs, 1 3.26 (s, 3 3.08 J 3.8, 1 2.83 (qd, J 7.3, 3.8, 1 1.52 J1=7.3, 3 1.35 3 H), 1.50 3 H).

EXAMPLE 298

(R/S-

3 1- 4 u.5t)-S54-Chloropheny)-.l. 2 3 4 -tetrahydro)3.inethoxy..4.tethy1-5Hchro ienor3.4-fquinotine (Copud 398. tructure 25A of Scheme XXX VI. whr

R

1

=R=HR

3 4coopny.R meh) To a solution of 3 1, 4 u,SO-5-(4.c1oropheny)-.1 2 3 4 -tetraydro-3-hydroxy-2,2,4.

trimethy1-5Hchromeno[34.JquinoJjne (structure 13A of Scheme XXXIII, where

R

1

=R

2

R

3 =4-chlorophenyl, an intermediate from EXAMPLE 135) (8 mng, 0.0 16 mmol) in DMF (0.5 mL) and excess Mel (0.5 mL) was added 60% NaHl in mineral oil (10 mg, 0.25 mrnol). The resulting white slurry was stirred at rt for 2 h and was quenched with water ML). The ixture was extracted with EtOAc (2 x 10 mL) and was concentrated to give the crude product, which was treated with TFA (0.2 mL) in CH2I2 (1 mU) for 60 min and was quenched with 5 NaOH (5 mL). The midxture was extracted with EtOAc (2 x10 ml), concentrated and was purified by silica gel chromatography to afford 4.7 mg of Compound 398 as a colorless oil. Data for Compound 398: 1 H NMR (400 MHz, CDCI3) 7.55 J 7.7, 1 7.47 J= 8.4, 1 7.16 J 2 7.12 J1=8.7, 2 H), 6.97 J 7.7, 1 6.89 J 7.7, 1 6.73 J 7.7, 1 6.68 J 8.4, 1 6.34 I 3.65 (bs, I 3.53 3 3.03 I 3.02 (qd, J 7.0, 0.8, 1 1.30 3 1. 11 3 0. 88 J 3H).

EXAMPLE. 299

(RIS..

3 1.4u-5 4..Chl oro l...1erhdr.3poyoy24l ty chro enor3.4-flguinoline (Comp)ound 399. strture 5A of Scheme XXXVI. where R I=R 2 3 =4-chlorophenyl.R-r-opy) To a solution of (RIS- 3 l, 4 uS5.5(4..chlorophenyl)-1 2 ,34-tetrahydro.3.hyroxy2,2,4..

trimethy1.5H.chomeno[3,4Aquinoie (structure 13A of Scheme XXXII, where R 1

=R

2

R

3 =4-chlorophenyl, an intermediate from EXAMPLE 135) (7 mg, 0.0 14 mmol) in DMF (0.5 mU) and excess PrI (0.5 mL) was added 60% NaH in mineral oil (10 mg, 0.25 mmo The resulting white slurry was stirred at rt for 2 h and was quenched with water mL). The mixture was extracted with EtOAc (2 x 10 mU) and was concentrated to give the crude product, which was treated with TFA (0.2 mU) in CH2C12 (1 nL) for 60 min and was quenched with 5 NaOH (5 mL). The midxture was extracted with EtOAc (2 x 10 mU), concentrated and was purified by silica gel chromatography to afford 2.5 mg of Compound 399 as a colorless oil. Data for Compound 399: 1H NMR (400 MHz, CDC13) 7.57 J 7.7, 1 7.48 J= 8.4, 1 7.16 J 2 7.12 J= 8.6, 2 H), 6.99 1 7.7, 1 6.89 J 7.7, 1 6.73 J 7.7, 1 6.68 J 8.4, 1 6.33 I 3.65 (bs, I 3.58 (mn, 2 3. 11 J 5.8, 1 3.00 (qd, J 7.0, 5.8, 1 1.65-1.50 (mn, 2 1.30 3 1. 10 3 0.93 J= 7.4, 3 0.88 J1=7.0, 3 H).

EXAM4PLE 300 (R/S-3.4u-.5-.'4-hlorohenv1~ IA vl-5H-.,-3prploy12~ chromeno f3.1-Aqluino line (Comnpound 400. structure 26A of Scheme XXXVI. where To a solution of (R/S- 3 l.

4 uSu)-5-(4-clJorophenyI)-I 2 3 4 -tetrahydro-3hydroxy-2,2,4trixethyl-5Hchromeno[3,4lquinoie (structure 14A of Scheme XXXIII, where

R

1

=R

2

R

3 =4-chlorophenyl, an intermediate from EXAMPLE 135) (8 mg, 0.016 mmol) in DMF (0.5 mL) and excess Pr! (0.5 mL) was added 60% NaH- in mineral oil (10 mg, 0.25 mmol). The resulting white slurry was stirred at'rt for 2 h and was quenched with water mL). The mixture was extracted with EtOAc (2 x 10 mL) and was concentrated to give the crude product, which was treated with TFA (0.2 mL) in CH2CI2 (0 mL) for 60 mmd and was quenched with 5 NaOH (5 mL). The mixture was extracted with EtOAc (2 x 10 mL), concentrated and was purified by silica gel chromatography to afford 2.5 mng of Compound 400 as a colorless oil. Data for Compound 400: 1 H NMR (400 MHz, CDCI3) 7.54 J 1 7.48 J= 8.4, 1 7.12 J 2 7.09 J=8.6, 2 7.02 J 7.7, 1 6.89 J 7.7, 1 6.87 J 7.7, 1 6.62 J 8.4, 1 6.48 I 3.72 (bs, I 3.28 (in, 2 3.16 J 4.0, 1 2.78 (qd, J 7.2, 4.0, 1 M), 1.51 J 3 1.51-1.36 (in, 2 1.34 3 1. 14 3 0.80 J1=7.4, 3 H).

EXAMPLE 301 (R/S~l.Sf~3~Bezyliene.54.(4-.c forophnl 3 4 chromeor34npinojo (Cmond 401. sucture 27A f Scheme XX VII where

R

1 2

=H.R

3 =4chloophnyl. =n henvlI To a solution of Compound 234 (EXAMPLE 134) (35 mg, 0.086 minol) in THF (4 mL) was added a 1 OM ether solution of benzylniagnesium chloride (0.3 m.L, 0.3 inmol) and the reaction was stirred at rt for 2 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2 x 10 mL). Removal of solvent and chromatography of the crude residue afforded the adduct in 66% yield as a 8:1 midxture of two isomers. The adduct intermediate (8 mg, 0.0 16 mrnol) and Burgess reagent (15 mng, 0.063 mrnol) in benzene were heated at reflux for 2 h. Removal of solvent and purification of the midxture on a prep' TLC plate using a 25% mixture of EtOAc/Hexane as solvent afforded 0.5 mg of Compound 401 as a colorless oil. Data for Compound 401: IH NMR (40)0 M~z, CDCI 3 7.61 Kd J 7.7, 1 7.56 J 8.4, 1 7.43 J 7.5, 2 7.32 1 1 7.21 J 7.6, 2 7.16 J 8.6, 2 7.05-6.93 (nm, 2 6.96 J 8.6, 2 6.72

J

8.4, 1 6.68 J 7.7, 1 6.38 I 6.05 I 4.02 J 7.5, 1 3.55 (bs, I 1.52 3 1.41 3 0. 84 J1=7.5, 3 H).

EXAMPLE 302

(RI..

4 5u).5.4..lilropenyj l 2 3 4 trah n-drIo22-4-ehIH F.-13 53 of Scheme .w ere 1 H R 2 =fluooR 4 chlorophenyl) This compound (2.2 mg, was prepared in a manner similar to that described for the preparation of Compound 234 (EXAMPLE 134) from Compound 214 (EXAMPLE 114) mg, 0. 16 mrnol). In addition, 2.2 mg of Compound 403 (EXAMPLE 303) was also obtained as a clear-colorless oil. Data for compound 402: Rf=-0.38 (silica gel, EtOAc:hex); 1Hj NMR (400 MHz,

CDCI

3 7.51 J 8.5, 1 7.23 J 8.5, 1 H), 7.16 (d,IJ= 8.5, 2 7.04 J 2 6.84 1 6.78 (in, 2 6.30 Cs, 1 3.79 (brs, 1 3.33 J 1 1.49 (d,IJ= 7.5, 3 1.46 3 1.25 3H).

EXAMAPLE 303 ciioione (ompound 403 tutr 2 fShm V. where R=H R 2 =luoo chlorophenyl) This compound (2.2 mng, was obtained along with Compound 402 as described above (EXAMPLE 302). Data for compound 403: Rf=-0.38 (silica gel, 25% EtOAc:hex); I HNMR (400 MHz, CDCl3) 7.56 J 8.5, 1 7.31 J 8.5, 1 7.20 J 2 7. 10 J 8.5, 2 6.85 J 8.5, 1 6.74 (mn, 2 6.35 1 3.79 (brs,1 3.55 J1=7.5,1J= 7.5, 1 1.45 Cs, 3 1.26 Cs, 3 0.86 1 3 H).

EXAMPLE 304 (RIS- 1 .2.3.4-Tetrahydro- 1 2 2 4 -tetramethvl-A-trfflooeh18~nn 56-lunl (Compound 404. structure 28A of Scheme XXXV I. where R 1

=R

2

=R

5

=H.

R

3 =trifluoromethyl. Z=-O) In a flame dried r.b. flask was dissolved Compound 250 (EXAMPLE 150) (50 mg, 161 p mol1) in glacial acetic acid (10 mL). To the stirred solution was added para-formadehyde (51 mg, 1.61 mmol, 10 equiv). The cloudy yellow solution stirred for 10 min, then NaCNBH3 (50 mg,.805 jimol, 5 equiv) was added at once. Upon addition the solution emitted gas for approx. 5 min then turned a brilliant fluorescent yellow/green. After stirring at rt under a blanket of N2 for 20 h, the solution was slowly poured over ice and quenched with NaOH extracted with EtOAc (2 x 50 mL), washed with brine (2 x 25 mL), dried over Na2SO4 and concentrated in vacuo to give 51.3 mg (99 of Compound 404 as a yellow-green solid. Data for Compound 404: Rf 0.39 (hexanes/EtOAc; 3: 1H NMR (400 MHz, CDCI3) 7.31 (dd, J 1.5, 1.5, 1 6.44 1 6.35 1 2.90 3 H, N- CH3), 2.83 (in, partially obscured by Me, 1 H, C4-H), 1.84 (dd, J 4.2, 13.3, 1 H, C3-H),' 1.53 (dd, J 13.0, 13.0, 1 1.36 J 6.6, 3 H, C4-CH3), 1.35 3 H, C2-CH3), 1.29 3 H, C2-CH3).

EXAMPLE 305 (RIS-5-(3-F wrn.r (Comound 405.structure 63 of Scheme XVIII. where R 1

=R

2 R3= 3 -furyl., Z=o) In a oven dried pressure tube equipped with a magnetic stir bar was dissolved 1,2,3,4.

terhdo224tmthl7hdoyunln (EX-AMvLE 150) (50.8 mng, 292 pmol), ethyl 3 -keto-3-(3-furyl)propionate 10 mL, 642 p mol, 2.2 equiv) and ZnCl2 (119 mg, 876 pmol, 3 equiv) in absolute ethanol (6 mL). The solution was heated at 105 0 C for 1 *9 h. The cooled solution was concentrated on CeliteTM to give a firee flowing powder which was purified via silca gel flash column chromatography using a solvent system of hexanes/ethyl acetate to 14.6 mng (16% of Compound 405 as a yellow oil. Data for Compound 405: Rf 0.26 (hexanes/EtOAc; 3: 1 H NMR (400 MHz, CDC13) 7.76 1 7.58 (dd, J 1.4, 3.0, 1 7.48 1 6.66 I 6.37 I 6.06 I 4.37 (br s, 1 H, NH), 2.91 (mn, 1 H, C4-H), 1.7 8 dd, J 4.1, 13, 1 H, 1.44 (dd, J 13, 13, 1 H, C3-H), 1.33 J= 6.7, 3 H, C4- CH 3 1.31 3 H, C2- CH 3 1.23 3 H, C2- CH3).

EXAMPLE 306 2 4-tetrPmrth 056 -glquio lin (Com pound 406. structuire 60 of SchemeXVI were 111R1'

=R

2 =R5-R 3 3frlZ In a flame dried r.b. flask was dissolved Compound 264 (EXAMVPLE 164) (1.1 mg, 3.58 p rho]) in glacial acetic acid (3 ML). To the stirred solution was added para-formadeh,,de (1.2 mg, 36 pmol, 10 equiv). The cloudy yellow solution stirred for 10 mmd then NaCNB3H 3 (1.1I mg, 17 p mol, 5 equiv) was added at once. Upon addition the solution emitted gas for approx 5 mini then turned bright yellow. After stirring at rt under a blanket of N2 for 20 h the solution was slowly poured over ice and quenched with NaOH extracted with EtOAc (2 x 10 mL), washed with brine (2 x 10 mL), dried over Na2SO 4 and concentrated in vacuo to give a impure product that was further purified by preparatory plate chromatography (silica gel, 1000 pm) using a solvent system of 4:1 hexanes/EtOAc to afford 0.8 mg (70 of Compound 406 as a yellow-green solid. Data for Compound 406: Rf =0.25 (hexanes/EtOAc; 1 HNMR (400 MHz, CDCl3) 7.77 IH), 7.57 (d,J 1.7, 1 7.30 1H), 6.66 J 1.7, 1 6.40 1 6.07 1 5.33 I H, C3- 2.89 3 H, N-Ckl3), 1.95 J 1. 1, 3 H, C4-Qj 3 1.38 6 H, (CH3) 2 EXA MPLE 307 6 -triflunromethy[l I .2-ihd- l...~ermty~~iprnnr& ie fCom ,ound 7 t ct e 9ofShme XXIwhr

RR

2 _pSH In a dry r. b. flask was dissolved Compound 251 (EXAMPLE 151) (5.2 mg, 16.1 p mol) in glacial acetic acid (5 mL). To the stirred solution was added para-formadehyde (5.4 mg, 160 jimol, 10 equiv). The cloudy red solution stirred for 10 mini then NaCNBH 3 (5.1 mg, p mol, 5 equiv) was added at once. After stirring under a blanket of N2 for 12 h the solution was slowly poured over ice and quenched with NaOH extracted with EtOAc (2 x mL), washed with brine (2 x 20 ruL), dried over Na2SO 4 and concentrated in vacuo to give an impure product that was fuirther purified by prep TLC (silica gel, 1000 pm) using a solvent system of 4:1 hexanes/EtOAc to afford 3.2 mg of Compound 407 as a red solid. Data for Compound* 407: Rf 0.39 (hexanes/EtOAc; 3: 1 H NMR (400 MI-z, CDCI 3 7.21

J

1 7.16 1 6.51 1 5.42 I H, C3-I-1), 2.90 3 H, N-CH-3), 2.00

J

1, 3 H, C4-CH3), 1.41 6 H, (CH13)2).

EXA pLE 308 6-Chloro- -(.furv1) 1 .2-dih dro- 1224tta a.ln (Compound 408, structure-60 of Schemep XVI re R R2=chloro.

R

3 =trifluoromethyL

Z-O)

In a dry r.b. flask was dissolved Compound 258 (EXAMPLE 158) (5.9 mg, 17.2 pmol) in glacial acetic acid (5 mL). To the stirred solution was added para-formadehyde (5.5 mg, 172 pmnol, 10 equiv). The cloudy yellow solution stirred for 10 min then NaCNBH 3 (5.8 mg, 86 pmnol, 5 equiv) was added at once. After stirring under a blanket of N2 for 12 h the solution was slowly poured over ice and quenched with NaOH extracted with EtOAc (2 x 20 mL), washed with brine (2 x 20 mL), dried over Na2SO4 and concentrated in vacuo to give an impure product that was fuirther purified by 3 consecutive prep TLC's (silica gel, 1000 pmr) using a solvent system of 4:1 hexanes/EtOAc to afford 2.5 mg of Compound 408 as a orange/yellow solid. Data for Compound 408: Rf 0.36 (hexan es/EtOAc; 3: 1 H NMR (400 MHz, CDC13) 7.32 J1= 1.7, 1 6.33 1 H), 5.38 1 H, C3-H), 2.88 3 H, N-CH3), 1,99 J 1. 1, 3 H, C4-CH3), 1,39 6 H, (CH3)2).

EXAMPLE 309 1 2 3 .4-Tetrahydro224. )-er (Co pound 409. strucure-63 of ScheM XII whre=mehl 2

H

R

3 =trifUormethvLZ

H)

7 -trBuyovram 2i l...~erhdo22..8tetrame h I uino (trctre72o Sceex m hr 1 mthvL Pt-b txvZNH). This compound was prepared from 7 -tert-butyloxycarbamoylI l) 2 -dihydro2,2,4,8tetramethylqui 0 line (EXAMPLE 155) (4.50 g, 14.9 mrnol) according to the general hydrogenatio *n procedure previously described (EXAMPLE 160), affording 4.48 g of the desired tetrahydroquinoline as a white solid. Data for 7 -tert-butyloxycarbamoyl-,,,-erhdo2,48traihyunln e: IH NN4R (400 MHz, CDCl3) 7.03 1 H, J 8.3, 6.81 I H, J 8.2, 6.13 (br s, I H, BOCNHr), 3.43 (brs, 21-, NH2), 2.91 (ddq, I H,J= 19.0, 12.8, 6.6, 4-Ml, 1.96 3H-, 8-CU 3 1.73 and 1.40 (d of ABq, 2H-, JAB =12.8, JA 5 6 JB 12.6, 3-11), 1.31 3H, i 4-CH3), 1.28 and 1.16 ppmn [2s, 2 x 3H, 2-(CH3) 2 111 hl This co rnpound was prepared by General Method 12 (EXAMPLE 147) from 7 -rert-butyloxycarbamoyl. 1, 2 3 4 -tetrahydro. 2 2 4 ,8-tetramethyquinoie (4.48 g, 14.9 mmol) to afford 2.92 g of the desired aniline as a light reddish oil. Data for 7 -amino1,2.diydfro2248temehylqio IH NMR (400 MHz, CDC13) 6.89 IH, J= 8.1, 5-14), 6.14 II-I, J 8.2, 3.42 (br s, 3H, NH2, NH), 2.87 (ddq, IH, J 18.7, 12.7, 6.4,4-Hl), 1.90 3H, 8-CH3), 1.70 and 1.39 (d of Alq, 2H1, JAB 12.8, JA 5.6, J]3 12.5, 1.29 3H-, J 6.7, 4-CH3), 1.27 and 1. 16 ppm (2s, 2 x 3H, 2-(C113) 2 1.

1 2 3 4 -Tetrahyd-o.2 4 O- rmt ilormt_'n ioig This compound was prepared by General Method 13 (EXAMPLE 147) from 7 -amino- 1,,,-erhdo2248ttaehlunln (2.92 g, 14.3 mmnol) and ethyl 4,4,4trifluoroacetoacetate (3.13 mL, 21.4 mmoL, 1.5 equiv) to afford 2.04 g of Compound 409 as a pale fluorescent-yellow solid. Data for Compound 409: mnp 239-40 OC; 1H NMR (400 Mliz, CDC1 3 9.70 (br s, IH, CONII), 7.50 111, 5-H1), 6.68 111, 7-8H), 4.13 [br s, 18, (CH3)2CNHI, 3.00 (ddq, IH, J= 12.9, 12.4, 6.3, 2.15 3H1, 10-Cl- 3 1.83 and 1.46 [dd of ABq, 2H, JA 13.0, JA 1.6 Hz 3 -Hequiv), JB =12.9, 0 Hz (3-Hax)j, 1.40 314,1=6.6, 4-C113), 1.36 and 1.25 ppm [2s, 2 x 314, 2-(CH 3 2 J. 13 C NMR (100 MHz, CDC13) d 162.5, 144.9, 139.1, 137.1, 124.3, 122.7, 120.9, 113.8, 105.7, 101.6, 50.2, 43.5, 31.8, 28.9, 27.6, 20.1, 9.7 ppm Anal. Calcd for C17H19F 3

N

2 0: C, 62.95; H, 5.90; N, 8.64. Found: C. 63.02; H, 6.01;N, 8.48.

EXAMPL.E310 (omnnound 410. trcture 33A f Schene XL. where 3

=R

6 =H 4 _e

A.

R

5 riuomeh) 3 3 -Methoxyanilino)propionic acid. To a oven dried 500 mL rb flask equipped with a magnetic stir bar and a water cooled reflux condenser was dissolved anisidine (5 mL, 44.6 mmol) in toluene (70 mL). The stirred solution was heated to reflux and acrylic acid mL, 44.1 mmol, I equiv) was dripped in over a 10 min period to give a clear colorless solution. After heating at reflux for 3 h the dark red solution was cooled to rt and concentrated in vacuo to remove both the unreacted acrylic acid and toluene to give a 6.4 g of a 1:1 mixture of the desired amino acid and anisidine as a red viscous oil. Data for 3-(3- Methoxyanilino)proionic acid: Rf 0.1 (hexanes/EtOAc, 1H NMR (400 MHz, CDC13) 9.08 (br s, 1 H, NH), 7.28 J 4.3, 1 7.21 (dd, J 8.1, 8.1, 1 7.03 (dd, J 1.3, 7.9, 1 6.67 (dd, J 2.3, 8.4, 1 H).3.80 3 3.58 2 2.33 3 H).

1.

2 3 4 -Tetrahydro-7-methoxy-4-quinolone. To a oven dried 500 mL rb flask equipped with a magnetic stir bar and a N2 gas inlet, the material obtained above was dissolved in PPA (-150 mL). The resulting red viscous solution was heated at 100 0 C with constant stirring under a blanket of N2 for 12 h. The still warm solution was carefully poured over ice (1 L) and while vigorously stirring the iced solution with a metal stir rod the reaction was quenched by slow addition of a sat. K2C03 solution. The near neutral solution was extracted with CHC13 (5 x 150 mL), washed with brine (2 x 100 mL), dried over Na2SO4 and concentrated in vacuo to give an impure solid. The solid was purified by taking up in EtOAc and concentrating the liquor on CeliteTM to give a free flowing powder which was purified via flash column chromatography (silica gel, CH2C12 /MeOH, 95:5) to give 1.2 g of 1,2,3,4-tetrahydro-7-methoxy-4-quinolone as a yellow solid. Data for 1,2,3,4tetrahydro-7-methoxy-4-quinolone: Rf 0.43 (CH2Cl2/MeOH, 95:5); 1 H NMR (400 MHz, CDC13) 7.79 J 8.8, 1 6.31 (dd, J 2.0, 8.9, 1 6.08 J 2.0, 1 4.54 (br s, 1 H, NH), 3.78 3 H, OCH3), 3.54 (td, J 1.7, 8.0, 2 2.63 J 7.0, 2 H).

S-t-Butoxycarbonv l- 2 3 4 -tetrahydro-7-methoxy-4-quinolone (structure 31A of Scheme XL, where RI- 3 To a flame dried 250 mL rb flask equipped with a magnetic stir bar and a N2 gas inlet was dissolved 1,2,3,4-tetrahydro-7-methoxy-4-quinolone (1.18 g, 6.67 mmol) and BOC anhydride (2.03 g, 9.33 mmol, 1.33 equiv) in anhydrous THF (60 mL).

The solution was cooled to 0°C and N,N-dimethyl-4-aminopyridine (DMAP) (1.30 g, 10.7 mmol, 1.6 equiv) was added with constant stirring. After stirring over N2 for 16 h the reaction was carefully quenched with 10% NaHSO 4 solution (20 mL). The biphasic solution was extracted with EtOAc (3 x 50 mL), washed with brine (2 x 50 mL), dried over Na2SO4 and concentrated in vacuo to give 1.65 g of 1-t-butoxycarbonyl-1,2,3,4tetrahydro-7-methoxy-4-quinolone as an off white solid. Data for 1-t-butoxycarbonyl- 1, 2 3 4 -tetrahydro-7-methoxy-4-quinolone: Rf 0.31 (hexanes/EtOAc, 1 H NMR (400 MHz, CDC13) 7.27 J= 1.6, 1 7.06 J 8.5, 1 6.61 (dd, J 2.4, 8.5, 1 H), 3.78 3 3.71 J 6.0, 2 2.82 1 2.02 1 1.57 1 1.27 J= 3 H).

I -t-Butoxycarbonyl- 1.

2 3 4 -tetrahydro-4-hydroxv-4-methyl-7-methoxvquinolin. To a flame dried 250 mL 3-necked rb flask equipped with a magnetic stir bar was added Ce(II)C1.7 H20 (2.74 g, 7.35 mmol, 2 equiv). The flask was heated in a 140 0 C oil bath under reduced pressure 1 torr) for 2.5 h. The flask was cooled to rt and slowly filled with N2 g. The white powder was suspended in dry THF (30 mL), stirred at rt for 1 h and then cooled to -78 0 C. To the white suspension was added a 1.4 M solution of methyl lithium (MeLi) in Et20 (5.25 mL, 7.35 mmol, 2 equiv) by syringe. The dark yellow/brown solution stirred at -78 0 C for 1 h and then l-t-butoxycarbonyl-1, 2 ,3, 4 -tetrahydro-7-methoxy-4quinolone dissolved in 3 mL THF was added. The solution stirred at -78 °C for 3 h and was warmed to 0°C for 2 h. The reaction did not go to completion and starting material was observed by TLC (silica gel, hexane/EtOAc, The reaction was quenched with H20 (1 mL) and allowed to warm to rt. The solution was neutralized with sat NH4Cl solution mL), extracted with EtOAc (3 x 100 mL), washed with brine (1 x 100 mL), dried over Na2SO4 and concentrated in vacuo to give a mix of the desired alcohol and starting material. The mixture was taken up in EtOAc and concentrated on CeliteTM to give a free flowing powder which was purified via flash column chromatography (silica gel, hexanes/EtOAc, 3:1) to give 796 mg of the desired product as a vicious clear colorless oil. Data for 1-t-butoxycarbonyl-1,2,3, 4 -tetrahydro-4-hydroxy-4-methyl-7methoxy-quinoline: Rf 0.20 (hexanes/EtOAc, 1 H NMR (400 MHz, CDC13) 7.42 (d, J 8.7, 1 7.33 J 2.5, 1 6.66 (dd, J 2.5, 8.6, 1 3.98 1 3.79 3 H,

OCH

3 3.61 I 1.98 2 1.58 3 1.53 9 H).

(RIS)-l1-t-Butoxycearbonyl1234ttrhd4mtyl-7 eto i To a oven dried 250 mL rb flask equipped with a magnetic stir bar was dissolved I -tbutoxycarbonyl- 1, 2 3 4 -tetrahydro-.4-.hydroxy-4 ethyl.7-methoxy-quinoline (44 mg, 150 p mol) in EtOAc (15 mL). The flask was repeatedly evacuated and flushed with N2 then a catalytic amount of 10% Pd on C mg) was added. The flask was again evacuated and flushed with N2 several times and then H2 was introduced by balloon. The solution was stirred under H2 for 12 h. The flask was again evacuated and flushed with N2 several times to remove any residual H2 and the solution was filtered through a pad of CeliteTm and concentrated in vacuo to give the desired amine (37.0 mg, 133 pmol, 90% yield) as a clear colorless oil. Data for I -t-butoxycarbony1,

I

2 3 4 -tetrahydro4methy17.methoxyquinoline: Rf =0.59 (hexanes/EtOAc, 3: 'H NMR (400 Mliz, CDCI3) 7.28 J =2.3, 1 H, Ar-8), 7.07 J1=8.5, 1 H, Ar-5), 6.61 (dd, J 8.5, 1 H, Ar-6), 3.78 3 H, OMe), 3.71 (dd, J1=6.1, 12.2, 2 H, C2-H), 2,83 (in, 1 H, C4-H), 2.00 (in, 1 H, C3-H, 1.58 (mn, I H, 1.53, 9 H, (CH3)3), 1.27 J1=7.0 Hz. 3 H, C4-CH3).

fR/S)l.

2 .3.4Tetrahvdro-4-thl]-7.-mnthoxyguinoli-- To a oven dried 250 m.L r.b. flask equipped with a magnetic stir bar and a N2 gas inlet was dissolved l-t-butoxycarbonyl- 1,,,-erhdo4mthl7mtoyqioln (678 mng, 2.44 minol) in CH2CI2 mL). To the stirred solution was added trifluoroacetic acid (TFA) (2 mL) at rt. The solution stirred under N2 for 2 h and then quenched with sat NaHCO 3 solution (25 rnL), extracted with CH2C1 2 (3 x 20 mL), washed with brine (1 x 30 mL), dried over Na2SO4 and concentrated in vacuo to give 370 mg of the desired quino line as a clear colorless oil.

Data for l, 2 3 4 -tetrahydro4iethyl7.methoxyquinoie: Rf 0.32 (hexanes/EtOAc, 3: 1); 1 H NMR (400 MHz, CDCl3) 6.95 J1=8. 1, 1 H, Ar-5), 6.22 (dd, J1=2.5, 8.3, 1 H, Ar-6), 6.03 J1=2,6, 1 H, Ar-8), 3.86 (br s, I H, NHl), 3.73 3 H, 3.28 (mn, 2 H, C2-H), 2,85 (in, I H, C4-H), 1.95 (in, 1 H, C3-H), 1.64 (mn, 1 H, C3-H), 1.25 J 3H, C4- Me).

(RIS- l 2 3 4 Ttayr-7hcrx.4evguinoie. To a flame dried 25 ml, rb flask equipped with a magnetic stir bar and a N2 gas inlet was dissolved 1 2 3 ,4-tetraiydro-4.

methyl-7-methoxyquinoline (17.7 mg, 100 p mol) in CH2CI 2 (3 ML). The solution was cooled to 0 0 C under a blanket of N2 and then 250 pL of a 1.0 M solution of BBr3 in hexanes (250 p mol, 2.5 equiv) was added at once by syringe. The stirred solution was warmed to rt and allowed to react for 3 h. The reaction was quenched with H20 0I mL), neutralized with sat. NaHCO3 (4 mL) and extracted with CF12C1 2 (5 x 50 mL), dried over Na2SO4 and concentrated to give 12 mg of the desired phenolic quinoline as a light yellowoil. Data for l,234tetrahydro.7hydroxy.4ethylqotie Rf= 0.15 (hexanes/EtOAc, 3: 1 H NMR (400 MHz, CDC1 3 6.91 J 8.7, 1 6.12 (dd, J= 8.3, 1 5.97 J 2.5, 1 3.27 (mn, 2 H, C2-H), 2.84 (in, 1 H, C4-H), 1.95 (mn, 1 H, C3-H), 1.66 (mn, I H, C3-H), 1.25 J 6.9, 3 H, C4-CH3).

1--rfur (Copoud 10.stuctre33A F Scheme- Y. whre 1

-=R

6

R

4 =methvl.

R

5 =t ifluoromethyl) .In an oven dried pressure tube equipped with a magnetic stir bar was dissolved l 2 ,3,4tetrahydro-7hydroxy.4-methylquino lie (11.7 mg, 64.6 pmol) and ethyl trifluoroinethylacetoacetate (20 pL, 146 pmol, 2.2 equiv) and ZnCI2 (20 mg) in mL absolute ethanol. The light yellow solution was heated at 98 'C for 20 h and cooled to rt. The dark green solution was concentrated on CeliteTM to give a free flowing powder which was purified via silica gel flash column chromatography using a solvent system of hexafles/ethyl acetate to give 12.4 mng of Compound 410 as a yellow solid.

Data for Compound 410: Rf 0.19 (hexanes/EtOAc, 1H NMR (400 ivI~z, CDCI3) 7.29 1 6.36 (mn, 2 4.70 (br s, I H, NH), 3.43 (Mn 2 H, C2-H), 2.95 (mn, 1 H, C4- 1.97 (mn, I H, C3-H), 1.72 (mn, I H, C3-H), 1.31 J 7.0, 3 H, C4-CH3).

EXAM4PLE 311 l.kivdo22inehl.6..fluoromethyl an o 5-gquiin Co pon 4 1 structure 37A f Sc-heme XLI. rR 2 i 6 -H R 3 4 methL.. n 5 trfuooSt im O-Dihvdro..:I22i.xdz me6hf Sche11. Itr' ethvlac eto'lqunon Isrctr 36 of Scheme XLI.whee R 1

R

2 R =R 4 =ehy. P tb tyl X In a oven dried pressure tube equiipped with a magnetic stir bar was dissolved O-pivaloyl-3-aininophenol

(EXAMPLE

138) (4.8 g, 25.0 mmol, 1.5 equiv) and 3 -methy1-3-acetoxy..l.butyne (2.1 g, 16.7 mmol, 1 equiv) in dry THF mL). To the stirred solution was added CuCI (240 mg, 25 mmol, 0. 15 equiv). The sealed pressure tube was heated at 98 -C for 5 h, cooled to rt and concentrated on CeliteTM to give a free flowing powder which was purified via flash column chromatography (silica gel, hexanes/EtOAc, 5: 1) to give 1.2 g of the desired product as an off white solid. Data for I, 2 -dihydro-2,2dimethyl.7.(l1.1.

timethylacetoxy)quino line: Rf 0.80 (hexanes/EtOAc, 1H NMR (400 MHz, CDCl3) 6.83 J1 8.0, 1 6.23 (in, 2 6.12 J 2. 1, 1 5.42 J 9.7, 11-1), 3.67 (br s, 1 1.31 9 1.29 13 C NMR (100 MHz, CDCI3) 177, 151, 130, 127, 123, 117, 109, 105, 52, 49, 31, 27.

1.

2 -Dih~dro-7-hvtdrnxY..2...iftyquij.e To a oven dried rb flask was dissolved 1,2diyr-,-inty--I tiehlctx~unln (48 mng, 185 p mol) in absolute ethanol (5 mL) and H20 (I mL). To the stirred solution was added a catalytic amount of 20% aqueous NaOH solution mL). After 1.5 h the dark purple solution was diluted with H20 (10 mL), EtOAc (15 mL) and quenched with sat. NH4CI solution (5 mL). The biphasic solution was extracted with EtbAc (4 x 20 mL), washed with brine (2 x 30 mL), dried (Na2SO4) and concentrated in vacuo to give 31 mg of the desired phenolic amidne, which was used without further purification.

(Clieompund41 Structure 37A f SceeXLI. hr 2 RHR=methyL

R

5 tifluo etv K-=QJ. In a oven dried pressure tube equipped with a magnetic stir bar was dissolved 1,2diyr--yrx-,-iehlunln (31 mg, 177 pinol), ethyl (4,4,4trifluoroacetoacetate) (75 mg, 408 pmol, 2.2 equiv) and ZnCI2 (75 mg, 550 pinol, 3 equiv) in absolute EtOH. Upon addition of the ZnICI2 the solution went a dark brown. The sealed presur tbe was heated at 105 0 C for 16 h, cooled to rt and concentrated on CeliteTM to give a free flowing powder which was purified via flash column chromatography (silica gel, hexanes/EtOAc, 5:1) to give 2.3 mng of Compound 411 as a bright yellow solid.

Data for Compound 411: Rf 0.31 (hexanes/EtOAc, 3: 1H NMR (400 MHz, CDC1 3 7. 11 I 6.41 I 6.32 2 5.58 8.0, 1 4.39 (br s, 1 1.55 6

H).

EXAMPLE 312 U Compound 412. structure 40IA of cheme XLII. where

R-

2 =R6=H

R

3

R

4 -methvl.

R

5 =trffluoromethvl

X=O).

1, 2 3 4 -Tetrahydro..22..dI;.ehy7 .11-tiehyaetx uioin srutr 3 of Schemne XLII. wAr R 2 HRR eth d P=tbt1 X 0. To a oven dried 250 mL rb flask equipped with a magnetic stir bar and a N2 gas inlet was dissolved 1,2-dihydro-.

2 ,2-dimethyl.7.(1 1, 1l-rethylacetoxy)quino line (EXAMPLE 311) (47 mg, 192 p mol) in dry EtOAc (5 mL). The flask was repeatedly evacuated and flushed with N2 then a catalytic amount of 10% Pd on C (-10 mg) was added. The flask was again evacuated and flushed with N2 several times and then H2 was introduced by balloon. The solution was stirred under H2 for 13 h. The flask was again evacuated and flushed with N2 several times to remove any residual 82 and the solution was filtered through a pad of CeliteTm and concentrated in vacuc to give the desired amnine (38.0 mg, 154 jamol, 8 1% yield) as an off white solid. Data for l, 2 3 4 -tetrahydro22diethyl 7 (1,,l-timethylacetoxy)quinoline: Rf 0.54 (bexanes/EtOAc, 3: 18 NUR (400 Mz, CDC1 3 6.93 J1= 8. 1, 1 6.26 (dd, J 8. 1, 1 6.13 J 1, 1 3 .59 (br s, I 2.73 J 2 1.67

J

2 M, 1.32 9 1. 18 68H).

1.

2 3 4 4tavr7.yrx.22.iehlun~ To a oven dried rb flask was dissolved l, 2 3 4 -tetrahydro22dimethy 7 (,1-trimethylacetoxy)quinojin (38 mg, 154 pmol) in absolute ethanol (5 mL) and H20 (1 mL). To the stirred solution was added a catalytic amount of 20% aqueous NaOH solution mL) and stirred under N2 at rt. After 3 h the dark purple solution was diluted with H20 (10 mL), EtOAc (15 mL) and quenched with sat. NI14C solution (5 mL). The bi-phasic solution was extracted with EtOAc (4 x mL), washed with brine (2 x 30 ruL), dried (Na2SQ 4 and concentrated in vacuo to give mg of the desired phenolic amnine as a light yellow oil. Data for I 2 3 ,4-tetrahydro-7.

hyrx-,-iehlun ie Rf 0.22 (hexanes/EtOAc, 1H NMR (400 MHz, CDC1 3 6.82 J 8. 1, 1 6.09 (dd, J 2.6, 8.2, 1 5.93 J 2.4, 1 2.68 J 6.7, 2 1. 67 J= 6.7, 2 1. 19 6 H).

1,3 -rf linetv--nrnn r (Copun 412. structure 40A of Scheme XLII. where RI- 2

=R

6 =R8-H

R

3 =R -methyl

R

5 =trifluoroMthvl. In a oven dried pressure tube equipped with a magnetic stir bar was dissolved l, 2 3 4 -tetrahy7 hydroxy-2,2d ethl.noi (25.1 mg, 142 P mol), TFEEA (62 mg, 338 pmol, 2.2 equiv) and ZnCl2 (62 mg, 462 pmol, 3 equiv) in absolute EtOH. The sealed pressure tube was heated at 105 TC for 13 h, cooled to rt and concentrated on CeliteTM to give a free flowing powder which was purified via flash column chromatography (silica gel, hexanes/Etc)Ac, 5: 1) to 26.3 mg of Compound 412 as a bright yellow solid. Data for Compound 41.2: Rf 0.31 (hexanes/EtOAc, 3: 1 H NMR (400 MHz, CDCI 3 7.26 1 6.37 (in, 2 4.52 (br s, I H)m, 2.83 J 6.6, 2 H), 1.74 (t,J 2H), 1.28 61H).

EXAMPLE 313 l.

23 Ttrhvro.j-urome" vlSpraoos.g ine Cm d 4 3.

structure- 45A f Scem LII where

R

1 =H R 2 =trifluoromethvl 3 -Methoxv-rnsid oe Ixm Copu 43A. cheme XLIM*. To an oven dried 250 mL rb flask equipped with a magnetic stir bar, a N2 gas inlet and a water cooled reflux condenser was dissolved 7 -methoxyindanone (2.0 g, 12.3 mimol), Et3N (3.0 mL, 21.5 mmol, I equiv) and NH2OH.HCl (1,48 g, 21.5 mmol, I equiv) in MeOH (50 mL). The clear colorless solution was heated at reflux for 12 h, cooled to rt and partially concentrated under reduced pressure to half the original volume. The liquor was diluted with H20 (25 mL) and extracted with EtOAc (4 x 50 ML), washed with brine (3 x 25 mL), dried (Na2SO4) and concentrated in vacuo to afford 2.14 g of the desired adduct as a white solid. Data for 3 -methoxy-trans-indanone oxime: Rf =0.23 (hexanes/EtOAc, 3: 1 Jf NMR (400 MHz, CDC13) 8.01 (br s, I 7.47 J 2.4, 1 6.88 (dd, J 2.4, 8.3, 1 6.82

J

1 3.30 3 2.79 (in, 2 2.44 J 6.7, 2 H).

-1 2 3 4 -Tetrah dro.7.metho yuinoline (ompound 44A Schemne XLIUl. In a flame dried 100 m.L rb flask equipped with a magnetic stir bar, a N2 gas inlet and a water cooled reflux condenser was dissolved 3 -methoxy-trans indanone oxime (280 mng, 1. 10 mmol) in dry THF. Under a blanket of N2 the solution was cooled to 0 0 C -and a 1 .0 M solution of LAN in pentane (0.5 mrL, 5.0 mmol, 4.3 equiv) was added via syringe. The solution was then heated to reflux for 4.5 h. The solution was cooled to r1 and quenched with H20 (2 extracted with EtOAc (3 x 25 mL), washed with brine (50 niL, dried over Na2SO 4 and concentrated on CeiteTM to give a free flowing powder which was purified via flash column chromatography (silca gel, hexanes/EtOAc, 3: 1) to give 14 mg of the desired adduct as an off white solid. Data for 1,,,-erhdo7nehxqioie Rf 0.35 (hexanes/EtcjAc, 1HNMR (400 MHz, CDC1 3 6.84 J1=8.0, 1 6.19 (dd, J= 8.2, 1 6.03 J 2.5, 1 3.81 (br s, 1 3.73 3 3.27 (in, 2 2.69

J

6.4, 2 1.91 (mn, 2 H).

1 2 3 4 -tetrahydro- 7.hy droxyqumoline In a flame dried 100 mL rb flask equipped with a' magnetic stir bar and a N2 gas inlet was dissolved 1,,,-erhdo7-fehxqioln (14.0 mng, 85.8 pinol) in CH2CI2 mL). The solution was cooled to -78TC under a blanket of N2 and a 1.0 M solution of BBr3 in CN 2 Cl 2 (0.25 m.L, 250 pinol, 3 equiv) was added via syringe. The solution stirred at -78*C for lh, warmed to 0 0 C for I h and rt for 2 h.

The reaction was quenched with H20 (2 mL), extracted with CH2CI2 (3 x 20 mL), washed with brine. (2 x 20 mL), dried (Na2SO 4 and concentrated in vacuo to afford 12 mng (88%) of the desired adduct as a yellow oil Data for 1,,,-erhdo7-yrxqioie Rf= 0.21 (hexanes/EtOAc, 1HNMR (400 MHz, CDC1 3 6.79 J 1 6.12 (dd, J 8.0, 1 6.04 J1=2.3, 1 4.78 (br s, I 3.27 (n,4 2 2.67 (n-4 2 1.91 2H).

2 -ta r--rf rmt nn5-unln (Comnndi, 413.

structure 45AofScheme XLTHI whereR=N

R

2 =floomethl). In a oven dried pressure tube equipped with a magnetic stir bar was dissolved 1, 2 3 ,4-tetrahydro-7hydroxyquinoiLine (11.7 mng, 78.5 pmol), TFEEA (>10 fold excess) and ZnCI2 (>10 fold 274 excess) in absolute EtOH (3 mL). The sealed pressure tube was heated at I IlO'C for 16 h, cooled to r1 and concentrated on CeliteTM to give a free flowing powder which was purified via flash column chromatography (silica gel, hexanes/EtOAc, 4: 1) to give 8.6 mg, (41 of Compound 413 as a bright yellow solid. Data for Compound 413: Rf 0.31 (hexanes/EttJAc, 3: 1 H NMR (400 MHz,

CDCI

3 7.21 I 6.35 (in, 2 4.66 (br s, 1 3.40 (in, 2 2.80 J 6.3, 2 1.95 (in, 2 H).

EXAMAPLE 314 (R/SM l~~.~erhdo6- u romethv-8- anr6.gu e (Cmpund 414. tructure 33A of Sch eme XL. where, R 1 3

-DR

6 -L R 4 =ethvA.

R

5 triflu rnetv &MIS'- l--uoyabny.4.ty. l 2 3 4 etahvd4hydrox7nthxL-o lg.~ To a flame dried 250 mL r-b. flask equipped with a magnetic stir bar and a N2 gas inlet was dissolved l-t-Butoxycarbonyl-1,l 2 3 4 -terahydro7methoxy4quinolone (106 mg, 390 pmol) in dry THF (8 mL). The solution was cooled to 0 0 C under a blanket of N2 and a M solution of ethyl magnesium bromide (EtMgBr) in ethyl ether (1.3 mL, 1.36 mmol, 3.5 equiv)was added via syringe. The solution was stirred at 0 0 C for 2 h and at it for 3 h.

The reaction did not go to completion and starting material was observed by TLC (silica gel, hexane/EtijAc, 3: The reaction was quenched with H20 (2 mL), extracted with EtOAc (4 x 25 mL), washed with brine (40 mL), dried over Na2SO 4 and concentrated in vacuo to give 38 mg of the desired alcohol as a colorless oil. Data for (RIS)- I-tbutoxycarbonyl4ethyl. 1,,,-erhdo4hdrx--ehxqioie Rf 0. 14 (hexanes/EtOAc, 1 Jj NMR (400 MvHz, CDCl 3 7.36 J 8.7, 1 H, Ar-5N), 7.34 (d, J 2.5, 1 H, Ar-SN), 6.67 (dd, J 2.5, 8.5, 1 H, Ar-6H), 4.08 I 3.86 (br s, 1 H, OH), 3.79 3 H, OMe), 3.43 (mn, I 1.87 (mn, 3 14), 1.53 9 H, t-butyl), 0.859

J

7.4, 3 H, -CH3).

(RSI- tBtovabnl.ethyl- 4 trayo.7niehXvunle To an oven dried 250 mL r.b. flask equipped with a magnetic stir bar and a N2 gas inlet was dissolved

(RIS)-

l-t-butoxycarbonyl-4ethyl-123 ttayr--ydoy7mtoy'n~ (37.6 ing, 123 p inol) in dry EtOAc (8 mL). The flask was repeatedly evacuated and flushed with N2 then a catalytic amount of 10% Pd on C mng) was added. The flask was again evacuated and flushed with N2 several times and then H2 was introduced by balloon. The solution was stirred under 14~2 for 14 h. The flask was again evacuated and flushed with N2 several times to remove any residual H2 and the solution was filtered through a pad of CeliteTM and concentrated in vacuo to give 34 mg of the desired amine as a clear colorless oil Data for (RIS)- l-t-butoxycarbonyl4ethyl I 2 3 4 -tetaydro-7.

methoxyquino line: Rf 0.52 (hexanes/EtOAc, 3: 1 H NMR (400 MHz, CDC1 3 7.27 (d, J 2.3, 1 H, Ar-8H), 7.02 J 8.5, 1 H, Ar-5H), 6.59 (dd, J 2.7, 8.4, 1 H, Ar-6H), 3.78 3 H, OMe), 3.74 (in, partially obscured by OMe, I 3.58 (mn, 1 2,62 (mn, I 1.95 (mn, 1 1.72 (ri, 2 1.53 9 H, t-butyl), 1.48 (n,4 partially obscured by t-butyl, 1 H), 0.949 (t J 7.4, 3 H, -CH3).

(R/S 4-E hvl. l. 3 4etr hyd o~i etho ygu no~ In a oven dried 250 m L r.b. flask equipped with a magnetic stir bar and a N2 gas inlet was dissolved (RIS)-lI-tbutoxycarbony4ethy123tehdr 7 -rehxq oln (34.0 mg, 117 pinol) in dry CH2CI2 0I inL. To the stirred solution was added TFA (1.2 niL) at rt and was allowed to react for 2 h. The dark red solution was quenched with sat NaHCQ 3 solution (10 niL), extracted with CH2CI 2 (3 x 25 mL), washed with brine (50 niL), dried (Na2SO4) and concentrated in vacuo to afford 21 mg of the desired amine as a clear light yellow oil.

Data for (R/S)-4-ethyl. 1,,,-erhdo7-ehxqioi Rf 0. 1 (hexanes/EtOAc, 3: 1 H NMR (400 MHz, CDC1 3 6.92 J 8.5, 1 6.21 (dd, J 2.5, 8.2, 1 6.03 J=2.5, 1 3.73 3 3.27 (n,4 2 2.59 (nm, I1-H), 1. 86 (mi, I 1.75 (mn, 2 H), 1.48 I H) 0.968 (t,J =743

H).

(R/S)4-hylox 34u* hvdrihd rtre 3'A o f Sch-emne XL where

R

1 3

R

4 =ethfl. In a flame dried 100 niL rb flask equipped with a magnetic stir bar and a N2 gas inlet was dissolved (R/S)-4-ethyl-1,l 2 ,3,4-tetrahydro7methoxyquinoin (21 mg, 109.9 pmol) in CH2CI2 (4 niL). The solution was cooled to OTC and a 1.0 M solution of BBr3 in CH2Cl 2 (0.33 niL, 320 pmol, 2.75 equiv) was added slowly by syringe. The solution was warmed to it and stirred under a blanket. of N2 for 9 h. The reaction was quenched by addition of sat. NaI-C0 3 solution (5 mL), extracted with CH2CI2 (3 x 25 niL), washed with brine (2 x 20 inL), dried (Na2SO 4 and concentrated in vacuc to give 19 mig of the desired phenolic amnine as a clear yellow oil. Data for (R/S)-4-ethyl- 1,2,3,4tetrahydro-7..hydroxyqujino line: H NMIR (400 MI-z, CDC1 3 6.85 J 8. 1, 1 6.11 (dd, J= 2.4, 8.3, 1 H) 5.98 J=2.4, 1 3.25 (mn, 2H1), 2.57 (rn, I 1. 85 (mn, I H), 1.76 (mn, I 1.67 (mn, I 1.51 (mn, I 0.940 J= 7.4, 3 H).

fR/S)-4-Ott]- 414, structure 33A f Scheme XL. where R 3

=R

6 -H R 4 =ethylI

R

5 riluoromethyl,. In a oven dried pressure tube equipped with a magnetic stir bar was dissolved (R/S)-4-ethyll, 2 3 4 -tetrahydro-7-hydroxyquino line (19 mg, 109 jpmol) and TFEAA (excess) and ZnCl2 (excess) in absolute EtOH inL. The sealed pressure tube was heated at 101 0 C for 10 h, cooled to rt and concentrated on CeliteTM to give a free flowing powder which was purified via flash column chromatography (silica gel, hexanes/EtOAc, 3: 1) to give 3 mng of Compound 414 as a bright yellow solid. Data for Compound 414: Rf 0. 19 (hexanes/EtcjAc, 3: 1 H NMR (400 MHz, CDCI3) 7.25 1 6.38 1 6.36 1 4.70 (br s, I 3.40 (in, 2 2.70 (mn, I 1.89 (mn, 2 1.67 n(rn, I 1.55 (in, 1 0.95 J 7.4, 3 H).

EXAMPLE 315 (RIS'- 1 4 -7 era'1o. l.d~ehl8- vanono 5 6 pluinolim (ompound 415.r Structujre 34A f Schem XL where

R-

3

=R

6 R8=H

R

4 inethvl

R

5 rifluroinethvl) In a flame dried 100 mL rb flask equipped with a magnetic stir bar was dissolved Compound 410 (EXAMYLE 3 10) (10.0 mg, 35.6 p mot) in glacial acetic acid (4 inL. To the stirred solution was added para-formadehyde (12 mg, 356 p mol, 10 equiv). The cloudy yellow solution stirred for 10 min then NaCNBHi 3 (12 mng, 178 pinol, 5 equiv) was added at once. Upon addition the solution emitted gas for approx 5 mmd then turned bright yellow.

After stirring for 12 h the solution was slowly poured over ice and quenched with NaOH extracted with EtOAc (2 x 25 inL), washed with brine (50 inL), dried (Na2SO4) and concentrated in vacuo to give 8.9 mg of Compound 415 as a yellow-green solid.

Data for Compound 415: Rf =0.22 (hexanes/EtOAc; 3: 1 H NMR (400 MHz,

CDCI

3 7.25 I 6.42 I 6.35 I 3.42 (mn, 2 3.00 3 2.91 (in, I 2.00 (mn, 1 1.72 (mn, I 1.28 J 3 H).

EXAMPLE 316 (R/S)-4-Ethvl- 2 2 34-tetrah dr-1I-meth I- -praonor.gqm n (Cmp Id 416.

structure 34A of Scheme XL. where R1- 3

-R

6

=R

8 =H R 4 -=ethyl, R 5 =trifluorome h 1).

In a flame dried 100 mL rb flask equipped with a magnetic stir bar was dissolved Compound 414 (8.0 mg, 27.1 pimol) in glacial acetic acid (3 mL). To the stirred solution was added para-formadehyde (8.0 mg, 271 pmol, 10 equiv). The cloudy yellow solution stirred for 10 mini then NaCN13H 3 (8.0 mg, 135 pmol, 5 equiv) was added at once. Upon addition the solution emitted gas for approx. 5 mini then turned bright yellow. After stirring for 12 h the solution was slowly poured over ice and quenched with NaOH extracted with EtOAc (2 x 25 mL), washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuo to give 7.9 mg (94% yield) of Compound 416 as a bright yellow-green solid. Data for Compound 416: Rf 0.23 (hexanes/EtOAc; 3: 1HNMR (400 M14z, CDC13) 7. I 6.43 I 6.35 I 3.47 (in, 1 3.30 I 3.00 3 2.68 (in, 1 1. 89 (mn, 2 1.56 (mn 4 0.980 J= 7.4, 3 H).

EXAMPLE 317 2.2-Dinethyl. l.

2 3 4 -tetrahdo& flron hvlgSpyidonof5.,q lii(omon 417. structure 40A of Scheme XLHI where R 1 2

R

6

R

3

=R

4 mthyl,

R

5 =trifluoromethyL X-N 1.2-d hut o-2arb2 vl. et (sIctr 36An of- Scerne XLRI wh-re Rl=R 2 H, 3

=R

4 =methXI,. X=NH. To a flame-dried 200 mL r. b. flask containing 3 -tert-butylcarbamoylaniijne (EXAMPLE 147) (7.7 g, 0.037 mol) in 40 mL, of anhydrous THF was added CuCI (183 mg, 1.8 inmol), triethylamne (5.15 mL, 0.037 mol) and 3 -acetoxy-3-inethy[1..butyne (4.66 g, 0.037 mol). The reaction mixture was brought to reflux for 5 h then cooled to rt and filtered though a short pad of celite. Purification by flash column chromatography (silica gel, hexanesfethyl acetate, 7:3) afforded 6.83 g of the desired propargyl intermediate that was used directly for the next step. The propargyl amine (6.5 g, 0.0237 mol) was dissolved in 40 mL of anhydrous THF, CuCI (234 mg, 0.0024 mol) was added and the mixture was heated to reflux for 16 h. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with water and brine. The organic layer was dried (Na2SO 4 and concentrated in vacuo to an oil that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 9: 1) which afforded 2.24 g of 7 -tert-butyloxycarbamoy[- I 2 -dihydro-2,2-dimethylquinoline along with 4. Ig of the undesired regloisomer.

Data for 7-tert- butylo xycarbamnoyl- 1, 2 -d ihydro-2,2-dirnethylquino line: IH NMR (400 MHz, CDCI3) 6.80 (bs, lH), 6.77 J IH), 6.33 (bs, 6.31 18 J 9.7, 1IH), 5.37 J 9.7, 1iH), 3.70 (bs, IlH), 1.49 9H), 1. 27 6H).

7-Amino-i 2 3 4 -tetrahvdro-2'.2:dirmthv unoieAsouinf7-et butyloxycarbamoy-1,2.diyro2,2dimethylquino line (3.4 g, 0.012 mol) in 150 ml, of ethyl acetate was hydrogenated under an atmosphere of hydrogen with Pd-C 10% (340 mg) at rt for 7 h. Filtration over celite afforded 3.7 g (100%) of pure 7 -tert-butyloxycarbamoyll, 2 3 4 -tetrahydro-2,2..dimethylquinoline. The title compound was prepared by General Method 12 (EXAMPLE 147) from 7 -tert-butyloxycarbamoyl1,2,3,4tetrahydro-2, 2 dimethylquinoline (3.7 g, 0.0 12 mol) to afford 2.35 g (100%) of 7-amidno- 1,2,3,4tetrahydro-2,2-dimethylquinoijne as a light reddish oil. Data for 7-amino-I ,2,3,4tetrahydro-2,2-dimethylquinoijne: IH NMR (400 MHz, CDCI3) 6.77 J 7.9, 18), 6.00 (dd, J= 7.9, 2.2,18H), 5.81 J= 2.2, IH), 3.47 (bs, 18), 3.40 (bs, 2H), 2.66 J 6.7, 2H), 1.65 J 6.7, 2H), 1. 18 6H).

2.2-DimethyI do tr o nethyl8-pyidono[5. f~uioline (Compound 417. structure 40 A of Scheme XLH. where R 1 2

=R

6

R

3

=R

4 =methyl.

R

5 =trifluoromethyl. X=NH). This compound was prepared by General Method 13 (EXAMPLE 147). from 7 -amino- l, 2 ,3,4-tetrahydro-2, 2 -dimethylquinoline (2.35 g, 0.0 12 mol), ZnCI2 (2.74 g, 0.02 mol) and ethyl 4 4 4 -trifluoroacetoacetate (2.15 mL, 0.0 13 mol) to afford 1.91 g of Compound 417. Data for Compound 417: 18 NMR (400 MHz, DMSO d6) 11.70 18H), 7.18 18H), 6.85 I 6.35 18H), 2.65 J 6.6, 28), 1.61 J 2H), 1. 17 6H).

EXAMPLE 318 (ompond 4 8. sructre 4 A of Scheme XLIV. where R=R 2 -LH R 3 trifluoromethyl) pvrdoof.6.tguiolii (trctre 46A ofScheme XLIV. where

R=R

2

=U

R

3 =triflU-o-KQomet-hYl) To a suspension of NaH 60% in mineral oil (16 mg, 0.387 mmol) in I mL of anhydrous THF at 0 0 C, was added dropwise, a solution of Compound 247 (EXAMPLE 147) (100 mg, 0.32 mmol) and the resulting mixture was stirred at 0 0 C for min. A solution of t-Boc2O (78 mg, 0.355 mmol) in I mL of THF was added dropwise and the reaction mixture was stir-red at rt for I h. The reaction mixture was quenched with water (1 mL), extracted with ethyl acetate (2 x 5 mL) and concentrated in vacuo to give 148 mg (100%) of a yellow solid that was used directly for the next step. To a solution of 9-tertbutyloxycarbamoyl-1,l 2 -dihydro.224.1.ethy8pyrd[5, 6 nle(3 g

O.

3 2mmol) in 10 mL of anhydrous THP at -78*C was added n-BuLi 2.5 M in hexane (121 mL, 0.32 mmol) and the midxture stirred for 10 min. t-Boc2O (73 mg, 0.33 mmol) in I mL of THF was added and the reaction mixture stirred at -78*C for 6.5 h. The temperature was raised to 0 TC and the mixture quenched with water (3 mL), extracted with ethyl acetate (2 x 10 mL), dried (Na2SO 4 and concentrated in vacuo to give a solid residue. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 8:2) gave 79 mg of 1, 9 -di.tert-butyloxycarbamoyl-12dhdo2,,-rmtyl8prdn 56Aunln IH NMR (400 MHz, CDC13) 7.76 1H), 7.72 1H), 7.38 IN), 5.67 IH), 2.13 (s, 3H), 1.62 3H), 1.57 9H), 1.50 9H).

I -tert-btlxcabmy 3 tetra 3-h u..et -2 2 4- 'tet 2 J-pyrdognors,641um- A ouino -di-tert-butyoxycabaoyli 1 .2-dihydro-22,4 ftmty--yioo56Aunln (79 mg, 0. 155 mmol) in 2 rnL of anhydrous THF at rt was treated with 388 jil, of BH3.THF (1.0 M in THF, 0.388 mmol) for 3 h and was then quenched with 78 gL of NaH-C0 3 satd't followed by 30% H202 (78 jil,). The reaction mixture was stirred for 1 h, then 2 mL of water was added. The mixture was extracted with ethyl acetate (5 mL), dried (Na2SO4) and concentrated in vacuc to an oil that was subjected to flash columni chromatography (silica gel, hexanes/ethyl acetate, 7:3) to give 21 mg (32%) of l..tert..butyloxycarbamoyl-123 ttayr--hdoy224tiiety--yioo56 flquinoline. Data for 1 -tert-butyloxycarbamoyil1 2 3 4 .tetrahydro3hydroxy2,24.

ftmty--yion[,-qioie 1 H NMR (400 MHz,

CDCI

3 12.5 (bs, IH), 7.51 (s, 1H), 7.28 1I), 6.85 I1H), 3.19 (dd, J 5.2, IH), 2.91 (in, IN), 2.14(d, IH), 1.65 3H), 1.55 9H), 1.52 1.46 J 6. 1, IH).

(RIS)- L? 'Idtt~,A-ctilooehl224teth yidonor f3 nn (Compound 418, structure 47A of Scheme XLIV. where

R=R

2

R

3 =trifluorome- l To a suspension of PCC (50 mg, 0.23 mmol) in 2 mL of dichioromethane at rt was added

I-

tert-butyloxycarbamoyl-1234ttah.o3hdox--rfurofehl22,-iehl8 pyridono[5,6-fAquino line (16) (10 mg, 0.023 mmol) in I mL of dichioromethane. The reaction midxture was stirred at rt for 1.5 h, then it was filtered over celite and the solvent was removed in vacuo to give a dark oil that was subjected to flash colun chromatography (silica gel, hexanes/ethyl acetate, 6:4) to give 5.5 mg of I -tert-butyloxycarbam y1.

l, 2 3 4 tetrahydro6.trifluoromethy224-mn hyl8prdnIS-f--unl that was used directly for the next step. The title compound was prepared by General Method 12 (EXAMPLE 147) from l-ert-butyloxycarbamyl-1l2 3 4 -tetrahydro6-tifluoromethyl- 2,,-rmty--yioo56f--unlnn mg, 0.013 mmol) to afford 3 mg (71 of Compound 418. Data for Compound 418: IH NMR (400 MHz, CDCI3) 12.3 (bs, lH), 7.51 I14), 6 8 5 6.71 IH), 4.27 1H), 3.61 J IM-1, 1.55

J

6.3, 3H1), 1.40 3H1), 1.31i 311).

EXAMPLE 3119 rethylu7p~idonor56elindioli (C mond 419. tructure 49 A of Scheme XLV. hr R'trfloomthl

R=H)

6 -A inoindgline A solution of 6 -nitroindoline (1 g, 6.1 inmol) in 50 mL of ethyl acetate was hydrogenated under an atmosphere of hydrogen with Pd-C 10% (100 mg) at it for 3 h.

Filtration over celite afforded 1.0 g of 6 -amidnoindoline. Data for 6 -aminoindoline: IH NMR (400 MHz, CDC13) 7.40 J 7.4, I 6.05 J 2.0, 1 6.03 d, J 1H), 3.67 (bs I 3.49 J 2H), 3.48 (bs, 2.90 J 8.2, 2H).

S~Tifuoomthl~~io 6-se ino (C o un 49srctr L42A o f Schem XLV, h r 'tiloo ehR=H) This compound was prepared by General Method 13 (EXAMPLE 147) from 6 -aminoindoline (200 mg, 1.2 mmol), ZnCI2 (262 mg, 1.93 mmol) and ethyl 4 4 4 -trifluoroacetoacetate'(194 mL, 1.32 mmol) to afford .100 mg (32%) of Compound 419. Data for Compound 419: IH NMR (400 MHz, DMSO d6) 12.1 (s, I1-1), 7.31 IlH), 6.82 6.49 I 6.40 I 3.59 J 2H), 3.01

J

8.1, 2H).

EXAM4PLE 320 uor (ChompoundA__c 420.

structure 0A of Scheme XLV. where Rl=trifluromethyj

R

2 3 4-horpev To a solution of Compound 419 (EXAMPLE 319) (13 mg, 0.05 mmnol) in 2 mL, of anhydrous THF at -78 0 C was added n-BuLi 2.5 M in hexane (21 mL, 0.05 mrnol) and the resulting mixture was stirred for 15 min. Then 4 -chlorobenzoyl chloride (6.4 mL, 0.05 mmnol) was added and the reaction mixture was slowly brough to rt over a p eriod of 30 mini.

The reaction mixture was quenched with a saturated aqueous solution of NH4CI (1 m.L), extracted with ethyl acetate (5 mL) and concentrated in vacuo to an oil that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 8:2) which afforded 3 mg of Compound 420. Data for Compound 420: 1H NMR (400 MI~z, CDC13) 8.19 (d, J 8.6, 2H1), 7.77 11H), 7.51 J 8.6, 2H1), 7.25 I 6.99 I 4.45 3.77 J 8.0, 2H), 3.28 J1= 8.0, 2H1).

EXAMPLE 321 0Tiety- 4 ttahyrilurmtlpid r5.6guinlie (opud4 1 tutr 40A of Scheme XLHI w eeR=R 3 R etvR-R- 7 -tert-Butylxyaam l. l 2 dhro2 28-trinmethvlguiio (ructure 36A Schem XLII. where

RR

3 R4=mthyl.

R

2 H. Pt-uov X=H. To a flame-dried 10 mL r. b.

flask containing 3-etbtlxcramy--ehlnln (EXAMvPLE 155) (490 mg, 0.0022 mol) in 3 mL of anhydrous THF was added CuCI (I1I mg, 0. 1 mmol), triethylamine (307 mL, 0.0022 mol) and 3-ctx--ehllbtn (278 mg, 0.0022 mol). The reaction mixture was brought to reflux for 5 h then cooled to rt and filtered through a short pad of celite. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 7:3) afforded 290 mg of the desired propargyl intermediate that was used directly for the next step. The propargyl amine (290 mg, 0.001 mol) was dissolved in 5 mL of anhydrous THF, CuCI (5 mg, 0.05 mmol) was added and the mixture was heated to reflux for 16 h. The reaction mixture was diluted with ethyl acetate (10 mL), and washed with water then brine. The organic layer was dried (Na2SO4) and concentrated in vacuc to an oil that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 9: 1) which afforded 114 mg of 7- tert- butylo xycarbamoy.. hdo228 tiehlu ie Data for 7 -tert-butyloxycarbamoyl-12dhdo228bittyqioie I H NMR (400 MHz, CDCI3) 6.85 Kd J 7.4, 1 6.75 J 7.4, 18H), 6.23 J 9.5, 1 6.18 (bs, 18H), 5.42 J1=9.5, I 3.57 (bs, I 1. 92 3H), 1. 45 9H)j, 1. 29 6H).

7-Ai- terhdo..8.tfrehgunie A solution of 7-tertbuyoyabfiy-,-iydo228tiehlunln (114 mg, 0.39 mmol) in 4 mL of ethyl acetate was hydrogenated under an atmosphere of hydrogen with Pd-C 10% (11 mg) at rt for 7 h. Filtration over Celite afforded 60 mg of 7 -tert-butyloxycarbamoyl- 1,,,-erhdo22,-rmtyqioie The title compound was prepared by General Method 12 (EXAMPLE 147) from 7 -tert-butyloxycarbamoyl-1 2 3 4 -tetrahydro-2,2,8trimethylquinoline (60 mg, 0.206 mmol) to afford 30 mg of 7-amino-i 1,2,3,4terhdo228biehlunln as a light reddish oil. Data for 7-amino-1,2,3,4.

terhdo228hmtyqioie lH NMR (400 MHz, CDC13) 6.70 J 7.9, liH), 6.09 J 7.9, 1H), 3.30 (bs, 3H), 2.71 J 6.7, 2H), 1.89 3H), 1.65 J 6.7, 28), 1.21 6H).

2.2. 1 O-Trimethyl- 1.

2 3 4 -tetrahydoro- tVPld- oS~line (Como und 42 1. structure 40A of Sch eme XLII. whereR R4 etvR=R

H

R

5 =trifluoromethyl X=NH). This compound was prepared by General Method 13 (EXAMPLE 147) from 7 -amino-123,4tetrahydro22,8-tethylquinoline (30 mg, 0. 159 mmol), ZnCI2 (35 mg, 0.255 mmol) and ethyl 4 4 4 -trifluoroacetoacetate (26 mL, 0. 175 mmol) to afford 21 mg of Compound 421. Data for Compound 421: 18 NMR (400 MHz, CDC13) 9.13 1H), 7.34 IH), 6.67 18), 4. 10 18), 2.88 J 6.7, 2H), 2. 10 3H), 1.75 J 6.7, 2H), 1.30 6Mf.

EXAMPLE 322 11 (Compounh r hd 22.

structure 53A of Scheme XLVI where R- 3

=R

5

R

4 =ifluormitl) 7-Nitro- W~ 1,4ttahdoumln l 2 3 4-Tetrahydroquino ie (5 g, 0.0375 mo I) was dissolved in 16 ML of sulfuric acid and the temperature lowered to O 0 C, then 90%. fuming nitric acid (1.67 mL, 0.0375 mol) was added slowly and the mixture strirred at 0 0 C for mun. It was then poured onto 100 g of ice and extracted with dichloromethane (2 x 100 mL). The organic phase was washed with saturated aqueous solution of NaHCO 3 (75 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 8:2) which afforded 4.1 g (61 of 7-nitro- 1,2,3,4tetrahydroquinoline Data for 7-nitro- l, 2 3 4tetrahydroquinoie: 1H NMR (400 MfHz,

CDCI

3 7.39 (dd,J1= 8.3, 2.2, lH), 7.26 (d,JI= 3.5, IH), 7.01 (d,JI= 8.3,18), 4.16 (bs, 1IH), 3.35 J 5.0, 2H), 2.8 J 2H), 1. 95 (quintet, J 6.1, 2H).

7- 4n (structure q2)A f Scheme- XLVI. weeR 3

A

solution of 7-ir-1234terhdounln (396 mg, 0.0022 mol) in 4 mL of ethyl acetate was hydrogenated under an atmosphere of hydrogen with PdC 10% (40 mg) at rt for 2 h. Filtration over celite afforded 330 mg (100%) of 7 -amino..l,2,3,4.tetrahydroquinoie.

Data for 7 -amidno1,2,3,4tetrahydroqiolie: 1H NMR (400 NMz, CDC13) 6.72 J 7.9, 1W), 6.00 (dd, J= 7.9, 2.3, 5.84 J1=2.3, 1H), 3.67 (bs, 1W), 3.42 (bs, 2H), 3.24 J1=5.0, 2H), 2.65 J1=6.4, 2H), 1.91 (quintet, J 6.0 Hz. 2H).

l~ 3 4 Tta~r6 r methy pidnrfl~, (C mp-n 422 strctur 53Aof chme LVIwh re Rl 3

R

4 =triflooehl This compound was prepared by General Method 13 (EXAMPLE 147) from 7-arrnino-1,2,3,4tetrahydroquinoline (330 mg, 0.0022 mol), ZnCI2 (452 mg, 0.0033 mol) and ethyl 4,4,4trifluoroacetoacetate (356 mL, 0.0024 mol) to afford 70 mg (11I%) of Compound 422. Data for Compound 422: 1 H NMR (400 MHz, DMSO d 6 11 .7 (bs, I1W), 7.11 I1W), 6.92 (s, IH), 6.35 2H), 3.22 (bs, 2H), 2.71 J 2H), 1. 93 (quintet, J 6 2H).

EXAMPLE 323

I.

2 -Dihdro~r~urot4- 1.

2 2 4-tetr m th 8-~dnr..~un~ C m on 423. tructure 60 fSheeX I where R 1 2

=R.

5

R

3 =#uooetv 7=N-) To a stirred solution of Compound 247 (EXAMPLE 147) (100 mg, 0.323 mmol) and paraformaldehyde (98 mg, 3.23 mmol) in 3 mL of acetic acid at rt was added portionwise sodium cyanoborohydride (102 mg, 1.61 mm-ol). The resulting mixture was stirred at for 29 h then carefully poured into 20% aqueous NaOH (10 mL) and ice 10 g and the pH adjusted to The mixture was extracted with dichloromethane (25mbL), dried (Na2SO 4 and concentrated in vacuo to a fluorescent yellow solid that was subjected to flash colun chromatography (silica gel, hexanes/ethyl acetate, 8:2) to give 92 mg (71 of Compound 423. Data for Compound 423: Ifl NMR (400 MHz, CDCI3) 11.21 (bs, I1H), 7.33 I H), 6.67 IH), 6.23 lIH), 5.39 IH), 2.92 3H), 2.02 314), 1.38 6H).

EXAMPLE 324 id n5.-lnnlin (ompound 424. struture57A of Schaete LVII. where R=methl

R

2 H.R tifurneh) o (nrstrutrailn cture 55A o Scheme XLVHI whe

R

1 =metghvl R =H To a suspension of NaH 60% dispersion in oil (97 mg, 0.0023 mol) in 2 mL of anhydirous THF at 0 0 C was added 2 -bromo-5-nitroaniline (500 mg, 0.0023 mol) in 2 niL of TEIF dropwise, the temperature was raised to rt to complete deprotonation then lowered to 0 3 -bromo-2-miethylpropene (232 mL, 0.0023 mol) was added very slowly and the reaction mixture was stirred at 0 0 C for 3 hi then neutralized with water (5 niL). The midxture was extracted with ethyl acetate (2 x 10 mL), dried (Na2SQ4) and concentrated in vacuo to an oil that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 8:2) to give 200 mg of 2-rm--2mty--roey)5ntonln (structure 55A of Schemne XLVII, where

R

1 ~methyl,

R

2 Data for 2-bromo-N-(2.

mehl2poey)--iraiie IH NMR (400 MHz, CDC13) 7.55 J 8.5, IH), 7.40 (dd, J= 8.5, 2.8, 7.39 J= 2.8, 4.96 2H),.4.95 (bs, 3.82 J= 5.9, 2H), 1.81 3H).

3 3 -imetvI6.~tro ne (stucture 56A of -Schemne XLVI where R =methvl

R

2 A solution of 2 -bromo-N(2..methyI2-propenl) 5 -nitroan (100 mg, 0.369 mmol), Pd(OAc)2 (2 mg, 0.0073 mol), Bu4NBr (119 mg, 0.369 mmol) and triethylamine (129 mL, 0.922 mmol) in 1 iL. of dry DMF under argon atmospere was heated at 80 *C for I h. Then sodium formate (25 mg, 0.369 mmol) was added to the reaction mixture with continued heating at 80 0 C for 20 h. Water (2 mL) was added arnd the mixture was extracted with ethyl acetate (2 x 5 mL), dried (Na2S 04) and concentrated in vacuo to an oil that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 8:2) to give mg of 3 3 -dimethy-6-nitroindo line Data for 3 3 -dinethyl.6.nitroindo line: IH NMR (400 MHz, CDCI3) 7.60 (dd, 1= 8.2, 2.0, 11-H), 7.35 J 2.0, 1 7.08 J 8.2, 18), 3.98 (bs, lH), 3.41 2ff), 1.33 611).

6- io33ietyjdln A solution of 3 3 -dimethy-6-nitoind line (60 mg, 0.31 mniol) in 3 mL of ethyl acetate was hydrogenated under an atmosphere of hydrogen with Pd-C 10% (10 mg) at rt for 3 h. Filtration over celite afforded 45 mg of 6-amino-3,3dimethylindoline. Data for 6 -amino-3,3-dimethylindolie: IH NMR (400 MHz, CDC1 3 )6.80 J= 7.8, 18), 6.08 (dd,J 7.8, 2.1, 1ff), 6.01 J= 2.1, 18), 3.60 (bs, 18), 3.50 (bs, 2H1), 3.26 2H), 1.25 6ff).

do of Schgeme XT VII. whr -=ethvl R 2 =R 4 =H R 3 =trifuqrm~th 1)Thscmon was prepared by General Method 13 (EXAMPLE 147) from 6 -amino-3,3-dimethylindoline mg, 0.277 mITol), ZnCI2 (57 mg, 0.416 mmol) and ethyl 4 4 4 -trifluoroacetoacetate mL, 0.305 mmnol) to afford 7.3 mg of33dtehl5tflormty--yioo56 elindoline 18 NMR (400 MHz,

CDCI

3 12.4 (bs, 18), 7.32 lIH), 6.73 1H), 6.52 1H), 4.33 18), 3.45 1.36 3Hf).

EXAM4PLE 325 (RIS)- 1.

2 3 4 Tetrh r-me- t16u r m th 1 -8 (Cormnound 42 trct 62A of Sceheme XLVII where 1 3 6 R 4 =methyl.

g 5 =triqgLuomethyl).

1.

2 3 4 -Tetrahvro4-inone (structre5Ao SceeXVII where

R

3 hIa 200 mL r.b. flask was introduced aniline (9.78 mL, 0. 107 mol), acrylic acid (7.36 mL, 0. 107 mol) and toluene (100 mL). The reaction mixture was stirred anid heated at 100' C for 16 h, cooled to rt and the solvent was removed in vacuo to give 10.34 g of the desired intermediate carboxylic acid .that was used directly without further purification for the next step. In a 500 mL. r.b. flask Was introduced the acid (10.34 g, 0.064 mol) and Polyphosphoric acid (200 The reaction mixture was stirred and heated at 1000 C for 16 h. The reaction mixture was cooled to rt, poured onto 700 mL. of a 1: 1 mixture of ice/water and neutralized slowly with NaOH.. The aqueous phase was extracted with ethyl acetate (3 x 200 mQ., dried (Na2SO 4 and the solvent was removed in vacuc to give a solid residue that was subjected to flash chromatography (silica gel, hexanes/ethyl acetate, 6: 1) to afford 6.97 g of 1,,,-erhdo4qioioe Data for 1, 2 3 ,4-tetrahydro.4quinolinone: 1 H NMR (400 MHz,

CDCI

3 7.84 (dd, J 7.9, 1. 1, 1HM, 7.28 (ddd, J 7.9, 7.9, 1.2, 1Ff), 6.72 (ddd, J 8.1, 8.1, 0.8, 1IH), 6.66 J= 8. 1, 1Ff), 4.49 1ff), 3.56 (4,J= 6.9, 2H), 2.69 J 6.8, 2ff).

I -ter-Buvoy~oy. l...-erhdo Quooe To a stirred solution of Boc2O (10.05 g, 0.046 mol) and 1,,,-erhdr--unlnn (6.16 g, 0.042 mol) in 'lHF (100 mL.) at 00 C was added slowly DMAI' (5.11 g, 0.042 mol) in 100 mL. of TIHEF The reaction mixture was stirred overnight, then water (75 mL.) was added and the mixture was extracted with ethyl acetate (2 x 200 The organic phase was dried (Na2SO 4 and the solvent was removed in vacuo to give a solid residue that was subjected to flash chromatography (silica gel, hexanes/ethyl acetate, 8:2) which afforded 8.5 g of 1-tertbutyloxycarbonyl. 34-erhdr--unoioe Data for I -tert-butyloxycarlbonyl- 1,,,-erhdo4qioioe 1 H NMR (400 MHz,

CDCI

3 7.98 (dd, J 7.9, 1.7, 1HI), 7.76 J 8.4, IH), 7.49 (ddd, J 7.5, 7.5, 1.7, 1ff), 7.15 (ddd, J= 8.0, 8.0, 0.9, lI-), 4.15 J1=6.3, 2ff), 2.76 J1=6.6, 2fH), 1.55 9H).

1-4me~y~qiaQjM.To a solution of 1-etbtlxcroy-,,,-erhdo4qionn (170 mg, 0.687 mmol) in THF mL.) at 00 C was added 3.0 M methylmagnesium bromide in ether (688 mL., 2.1 mmol).

The reaction mixture was stirred at 00 C for I h then quenched with water (2 ml., extracted with ethyl acetate (2 x 10 ml., dried (Na2SO 4 and the solvent was removed in vacuo to give an oil that was subjected to flash chromatography (silica gel, hexanes/ethyl acetate, 7:3) to afford 120 mg of I tr-uyoyabnl ,,,-erhdo4hdoy4 methylquinone. Data for l-tert-butyloxycarbonyil1 2 3 4 tetrahydro-4hydroxy.4 methyiquino line: IH NMR (400 MI-z, DMSO-d 6 7.54 J 7.7, IH), 7.50 (dd, J =7.7, 1H), 7.14 (ddd, J 7.3,7.3,1.7, IM), 7.04 (ddd, J 7.9, 7.9, 1 IH), 5.14 1H), 3.69 1.87 J1=6.5, 1.46 9M-1, 1.37 3H).

1 -tr- tl vabnl l 2 3 4 ttavr4t gino-line. A solution of 1 -tertbutylo xycarbonyl 234tetradohydroxhyr 4 ehylq oln (109 mg, 0.41 minol) in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C mg) and a trace of conc. H2S 04 at rt for 7 h. Filtration over Celiterm afforded 93 mng of Il-tert-butyoxycaronljj1,23,4-ttayro4..yqunln Data for I1-tertbuyoyabnl 111,-erhyr--ehlqioln:I NMR (400 MI-z, CDC1 3 7.62 J 8.1, IH), 7.16 J 7.8, IH), 7.11 (ddd, J=7.8,7.8, 1.6, IH), 7.01 (ddd,JI= 7.7, 7.5, 1.0, 1 3.71 (mn, 2H), 2.87 (ddq, J 6.8, 6.8, 6.8, 1IH), 2.04 (dddd, 7.4, 7.4, 7.4,6.1, 1H), 1.61 (mn, IM), 1.51 9H), 1.3 J= 6.8,3H).

1, 2 3 4 ttAhvr~ehlunl (srcu60A of Scheme XLVIIH. where R 1- 3

=H.

R±--:ethvD This compound was prepared by General Method 12 (EXAMPLE 147) from 1 -tert-butyloxycarbonyI ,,,-ttayro4mtylunln (93 mng, 0.353 inmol) to afford 55 mng of 1,,,-erhdo--ehlunln as an oil which was used directly without purification for the next step.

7-Nitr- l...-erhyr.4tylgingline- 1,,,-erhdo--ehlunl mng, 0.337 inmol) was dissolved in sulfuric acid (0.5 mL) and the temperature was lowered to 0' C. To this solution 90% fuming nitric acid (15 niL, 0.337 mmnol) was added slowly and the mixture stirred at 0' C for I h, then warmed to rL The reaction mixture was poured onto I g of ice and extracted with dichloromethane (2 x 5 mL). The organic phase was washed with sat. NaHCO3 (I x 3 mL) and concentrated in vacuc to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 8:2) which afforded 36 mng of 7 -nitro- 1,,,-erhdo4mtyqioie Data for 7-nitro- 1,2,3,4tetrahydro-4-nethylquinoline: IH NMR (400 MHz, CDC13) 7.41 (dd, J 8.3, 2.2, 1 H), 7.27 (d,1J 2.3, 1IH), 7.11 J 8.3, 1lH), 4.21 I 3.35 2H), 2 9 5 IH), 1. 96 (mn, 1.

7 2 (mn IN), 1.3 J 7.0, 3H).

l.

2 3 A~etrahvdo~meh luoromethyl8p~ioosgg~~ Cmon 425). A solution of 7-nito-l1, 2 3 4 -tetrahyclro-4..methylqu ino line (36 mg, 0. 172 mmol) in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (4 mg) at rt for 2 h. Filtration over CeliteTM4 afforded 26 mg of 7-amnio- 1,2,3,4tetrahydro-4-methylquino line (structure 61A of Scheme XLVIII, where RI- 3

=H,

R

4 =methyl) that was used without further purificati on for the next step. The title compound was prepared by General Method 13 (EXAMPLE 147) from 7 -amino-1,2,3,4-tetrahydro-4.

methylquinoline (26 mg, 0. 145 mmol), ZnCl2 (30 mg, 0.2 18 mmol) and ethyl 4,4,4trifluoroacetoacetate (21 mnL, 0. 145 mol) to afford 0.8 mg of 1, 2 ,3,4-tetrahydro.4mehl6tilooity-8prdn[,-lunln (Compound 425). Data for Compound 425: 1 H NMR (400 MHz, DMSO-d6) 11.65 (bs, IH), 7.20 LH), 6.96 (s, 1ff), 6.37 2H), 3.25 (in, 2ff), 2.90 (in, 1Hf), 1.84 (ri, 1ff), 1.59 (in, 1H), 1.20 J= 6.9, 3Hf).

EXAMPLE 326 1.2D(Compoundtrmet

I

426. tructure 57 of Scheme XVI. were R=R 2

R

3 methoxymehyL Z-Ni To a flame-dried 25-mL rb flask at it was added ethanol (10 mL) and 7 -amino-1,2-dihydro.

2 2 4 -Utrmethylquinoline (EXAMPLE 147)(600 mg, 3.5 inunol), and the midxture stirred at it until the amnine had completely dissolved. Methyl-4-methoxyacetoacett (680 p L, 5.3 mniol, 1.5 equiv) was then added, followed by ZnC12 (960 mg, 7.0 inmol, 2.0 equiv). The reaction was stirred at rt under N2 for 24 h. The solvent was removed under reduced pressure, and the solid residue was dissolved in EtOAc (10 mL). The organic phase was washed with sat'd. NaHCO3 (adjusted to pH 9 with 3.0 M NaOH) (3 x 5 mL), dried (Na2SO 4 and concentrated under reduced pressure. Purification by flash chromat 'ography (silica gel, CH2Cl2 MeOff, 9: afforded 65 mg of Compound.426 as a dark yellow powder. Data for Compound 426: Rf 0.42 (CH2Cl2:MeOH, 9: IH NMR (400 MHz, DMSO-d 6 11.24 1fH, 7.12 IlH, 6.63 1fH, 6.26 1ff, 6.04 I H, 3-H 5.35 IfH, (CH3)2CNH 4.56 2H, C112), 3.37 3H, OCH3), 1.93 3H, 4-CHi3), 1.21 6H, C(C11 3 2 1.

289 EXAMVPLE 327 1 2 2 .Trreh- ro6 rmty-- (COmpound 427. tucture A oA f Scheme XLHI where

R

2

R

6 R8H

R

3 4 =methvI.

R

5 =triflqoroMethy.X=) This compound was prepared in the manner similar to that described for Compound 416 (EXAMPLE 316) from Compound 412 (EXAMPLE 312) (5 mg) to give Compound 427 (4.2 mg, 93% yield) as a bright yellow solid. Data for Compound 427: 1 H NMR (400 MHz, CDC1 3 7.19 I1-H), 6.49 I 6.36 1 2.91 3 2.7 8 J= 6.5, 2 H), 1.84 J 6.5, 2 1.31 6 H).

EXAMPLE 328 rRIS)- lluoro eTe r-8- anonr5 uinoline (Cmoud42 .stutue33A fShmgL hr 1 3 6 =H R-n-rpl R L-tMiN uoromet h l~tert~ B toxycar onyI-hy .oxynth This com pound was prepared in a manner similar to that described for l-tert-butoxycarbony14ethy-4hydrxy- 7 -methoxyquinoline (EXAMPvILE 314) from I-tert-butoxycarbony.. l 2 3 4 -tetrahydro7.

methoxy-4..quinolinone (100 mg) to give the desired quinoline (51.2 mg, 40% yield) as an off-white solid. Data for I tr-uoyabnl4hdoy7mtoy4poy-un ie IH NMR (400 MHz, CDCI3) 7.37 J 8.7, 1 7.30 J 2.5, 1 6.66 (dd, J 8.9, 2.8, 1 4.08 (in, I 3.86 3 .3.42 1 2.04 (mn, 1 1.89 (mn, 1 1.81 (in, 2 1.53 9 1.26 (mn, 2 0.90 J 7.3, 3 H).

This compound was prepared in a manner similar to that described for I -tert- butoxycarbonyI.4-ethyl. 1 2 3 4 -tetrahydro.7inethoxyquinoline (EXAMPLE 314) from l-tert-butoxycarbonyl-1, 2 3 ,4-tetrahyciro.4hydroxy-7-methoxy4propyquinoie mg) to give the desired quinoline (44.3 mg, 94% yield) as a colorless oil. Data for Il-tert- buto xycarbony1-7.methoxy 4 -pr l linline:1 NMR (400 Ml-z, CDCI3) 7.27 J 2.5, 1 7.01 J 8.6, 1 6.59 (dd, J 1 3.78 3 3.73 (mn, 1 3.58 (mn, I 2.70 (in, I 1.94 (i,1H,1.71 (mn, 1 1.63 (mn, I1-H), 1.53 9H), 1.40 (mn, 3 0. 93 J1=7.2, 3 H) 3

R

4 -propy). T'his compound was prepared in a manner similar to that described for 4-ethyl- 1,,,-erhdo7mtoyunln (EXAMPLE 314) from We-tebutoxycarbonyl-1234-erhdr--etoy4propylquinolin (44 mg) to give the desired quinoline (28 mg, 98%) as a colorless oil. Data for 1, 2 3 4-tetrahydro7methoxy- 4 propyiquinoline: 1 H NMR (400 MHz, CDC1 3 6.90 J 8.2, 1 6.20 (dd, J 8.4, 2.6, 1 6.03 J1=2.5, 1 3.83 (br s, 1 M, 3.72 3 3.28 (mn, 2 2.68 (mn, 1 1.89 l.

23 4 TetahdrohycroYA=Q.RYIqop This compound was prepared in a mannier similar to that described for 4-ty-1234 erhdo7hdoyunln (EXAMPLE 314) from 1,,,-erhdo7mtoy4poyqioln (28 ing) to give the desired quinoline as a colorless oil, which was used without further purification in the following reaction. Data for 1,,,-erhdo7hdoy4poyqioie 1H NMR (400 MvHz, CDC1 3 6.84 J= 8.2, 1 6. 10 (dd, J= 8.2, 2.3, 1 5.97 J= 2.2, 1 H), 3.78 (br s, I 3.29 (mn I 3.21 (n-4 1 2.66 (mn I 1.87 (Mn I 1.75 (in, I H), 1.60 (mn, 1 1.45 (n4 3 0.933 J= 7.2, 3 H).

4 -Propyl-~~~.6 l. A e r h drmvon t y1 p a o o S C m n "428 This compound was prepared in a manner similar to that described for Compound 414 (EXAMPLE 314) from

P

2 3 4 tetahydro7hyoxy4prop h.uioln (23 mg) to give the Compound 428 (28.4 mg, 61%) as a yellow solid. Data for Compound 428: 1 H NMR (400 NMz, CDC1 3 7.23 1 6.37 I 6.36 1 4.70 (br s, I 3.40 (in, 2 2.81 (in, 1 1.88 2H), 1.

4 7 3H) 0963 (tJ =.2,3H) EXAMPLE 329 (Compound 429. srcure 65A of Scheme XLIX. where R 2 R7-H R 5 meth 1 To a solution of Compound 266 (EXAMPLE 166) (50 mg, 0. 15 mmol) in dichioromethane (7 mL was added triethylsilane (0.23 mL,l1.5 mmol) and TFA (0.25 mL at rt. After h, the reaction was complete according to TLC. The reaction mixture was quenched with a saturated NaHCO3 solution (10 mL). This solution was extracted with EtOAc (20 mL).

The organic layer was washed with water and brine (3 x 5 niL each), dried (Na2SO 4 and concentrated in vacuo to afford the crude product as an orange solid. The crude product was purified by prep TLC (20 x 20cm, 1 O0jgnm, 1: 1 CH2CI2:Hex.) to afford 49 mg (99%) of Compound 429 as a yellow solid. Data for Compound 429: Rf 0.44 (silica gel, EtOAc:Hex); 1 H NMR(400 MHz, CDCI 3 7.70 1 6.62 I 6.46 1 4.41 (brs, I 2.95 (ddq, J= 12.9, 6. 1, 1 1. 81 (dd, J= 12.9, 1. 1, 1 1.48 J= 6. 1, INH), 1.41 J= 6.1, 3 1.31 3 1.24 3 ER (film, NaC1) 1134, 1177, 1200, 1235, 1269, 1368, 1365, 1420, 1451, 1476, 1520, 1634, 3351.

EXAMPLE 330 I .2-Dihydro ir l 2 2 4 tea thk. ttif1-9-ome an-l o Com oun 4 3 s ruc ure6 0 f S hem X V w ereR 1 2 R 5 =H R =trifluoro rethyl.

To a stirred solution of Compound 266 (EXAMPLE 166) (100 mg, 0.30 mmol) and paraformalciehyde (93 mg, 3.0 mmol) in acetic acid (3 mL) at rt was added portionwise sodium cyanoborohydride (100 mg, 1.50 mmcl). The resulting mixture was stirred at rt for 16 hi, then carefully poured into 20% aqueous NaOH (10 mL) and ice (10 g) and the pH adjusted to The mixture was extracted with dichloromnethane (25 mL), dried (Na2SQ 4 and concentrated in vacuo to a fluorescent yellow solid that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 9: 1) to give 90 mig of Compound 430 as a fluorescent yellow solid. Data for Compound 430: IH NMR (400 MHz, CDCI 3 7.48 I 6.62 I 6.45 I 5.40 I 2.89 3 2. 10 3 1.39 6

H).

EXAMPLE 331 1 2 3 4-Terrahdro- 2 -rmh--rfurmt i (Compound 431. structure 41A oF Shm XI.whr 1 2

RRHR

4 meh1

R

5 =trifluoromethYl

=NH.

To a stirred solution of Compound 417 (EXAMPLE 317) (21 mg, 0.07 mnmol) and paraformaldehyde (22 mg, 0.70 mmol) in acetic acid (1 mL) at rt was added portionwise sodium cyanoborohydride (22 mg, 0.35 mmol). The resulting mixture was stirred at rt for 16 h then carefully poured into 20% aqueous NaQH (2 mnL) and ice (10 g) and the pH adjusted to T~he mixture was extracted with dichloromethane (2 x lOmL), dried .(Na2SO4) and concentrated in vacuo to a fluorescent yellow solid that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 7:3) to give 16 mg of Compound 431 as a fluorescent yellow solid. Data for Compound 431: IH NMR (400 Mlz, CDC1 3 10.83 (bs, 1 7.31 1 6.66 1 6.29 I 2.93 3 2.80 J= 6.1, 21-1), 1. 83 J= 6.5, 2 1. 30 6 H).

EXAMPLE 332 I 2 .3.4-Tetrahydro-l-ehl41rnl6till~^--,I 0 (COmpound 432 structure 34A of Scheme .weeR-= 6 8 H R 4 ropv-.

RLWtifuorometh This compound was prepared in a manner similar to that described for Compound 415 (EXAMPLE 315) from Compound 428 (EXAMPLE 328) (8.0 mg) to afford 7.9 mg (99%) of Compound 432 as a bright yellow solid. Data for Compound 432: 1 H NMR (400 MHz, CDCI3) 7.18 I 6.43 I 6.35 1 3.46 (in, I 3.33 (n,4 I 3.00 3 1.92 (mn, 1 1.87 (in, I 1.49 (in, 4 0.95 J 7.3, 3 H).

EXAMPLE 333 I 2 3 .4-erhcr. Ohdovntv24mty~pfurtl. 4iflin (omou433. tructUre 67AiofQScheme L where R 2

=R=H.R

3 To an oven-dried 5O-mL round-bottom flask containing Compound 409 (EXAMPLE 309) (125 mg, 0.39 mmol) in 1,4-dioxane (7 mL) was added selenium dioxide (107 mg, 0.96 mmol, 2.50 equiv), and the mixture was heated to reflux for 18 h. Upon cooling to rt, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate, 4:1 to 0: 1 gradient), affording 15.6 mg of Compound 433 as a fluorescent yellow solid. Data for Compound 433: 1 H NMR (400 MI-z, CDCI3) 9.32 (br s, 1 H, CON~H, 7.44 I H, 6.74 1 H, 5.32 [br s, I H, (CH3)2CNHI, 4.57 I H, J 9.7, OH), 5.02 and 4.93 (ABq, 2 H, JAB~ 14.0, CH2OH), 2.85 (ddq. I H, 1 12.9, 12.4, 5.5, 1.84 and 1.54 [d of ABq, 2H, JA 13. 1, JA 4.3, 3 -Heq), JB 0 1.41 3H, J 5.5 Hz, 4-CH3), 1.39 and 1.26 [2s, 2 x 3H, 2-(C113)21.

EXAMPLE 334 I 2 .3.4-Tetrah do- l 2 2 4 -t taehy-6- u rmh I- thiop 58o r6- lu nlne (Compound 434, structure 28A of Scheme XXXVIHI where R I- 2

=R

5

-HA

R

3 =trifluoromthyL

Z&)

To a solution of Compound 429 (EXAMPLE 329) (10 mg, 0..03 mmol) in acetic acid (5 mL was added paraformaldehyde (10 mg, 0.3 mmol) and sodium cyanoborohydride (10 mg, 0. 15 mrnol) under nitrogen with stirring at rt. After 15 h, the reaction was complete according to IH NMR. The reaction was quenched with saturated NaHCO 3 (10 mL). This solution was extracted with EtOAc (20 mL). The organic layer was washed with water and brine (3 x 5 mL each), dried (Na2SO4), and concentrated in vacuo to afford the crude product. The product was purified by prep TLC (5 x 20cm, 250pgm, 1: 1 CH2CI2: hexanes) to afford 4.5 mg of Compound 434 as a yellow solid, Data for compound 434: IH NMR(400 MHz, CDCI3) 7.59 1 6.60 1 6.53 I 2.89 3 2.85 (in, I 1.83 (dd, J 13.2, 4.2, 1 1.53 J 13.2, 1 1.36 J 6.6, 3 1.33 3 H), 1.23 3H); ER (filrn, NaCi) 1022, 1066, 1094, 1113, 1134, 1271, 1368, 1464, 1512, 1593, 2926.

EXAM4PLE 335 (COmpound 435. rctre RdA ofShme LVI. where- I =R5- 6

R

2 3 =methvl.

In a 25-mL a solution Of Compound 417 (165 mg, 0.557 mrnol) in THF (4 mL) was cooled to 0' C and treated with 60% NaH in mineral oil (23 mg, 0.58 mrnol, 1.0 equiv).

The reaction mixture was stirred 10 mini. To this slurry, iodomethane (35 mL, 0.56 mrnol, equiv) was added via syringe. The reaction midxture was stirred 12 h, diluted with mL), and extracted with ethyl acetate (3 x 20 mL). The extracts were washed with brine (1 x 20 mnL), combined, dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (CH2CI2:MeOH, 50:1) afforded 1 3 4 mg of Compound 435 as a pale yellow powder. Data for Compound 435: 1 H NMR (400 MHz, acetone-d 6 7.35 (s, 1 6.56 1 6.51 I 6.09 (br s, 11-) 3.53 3 2.87 J 6.7, 2 1.76 J 6.7, 2 1.29 6 H).

EXAM4PLE 336 (RIS)- 1..,-Tar (Cormound 6. stutr 2 fShem XVT.whee

R

2 R R HR= ehl R tifuo mome hyl)- 1 -ertBut~oyc~onv l..

3 4 -terhmeo.th t..4UIin(srcue6 Af Schemie L. whr R 1 2 -11 R 3 methy-). To a solution of I tr-uyoyaroy-1234 tetrahyro4quioin 0 n (structure 68A of Scheme LI, where

RI-

2 (EXAMVPLE 325) (500 mg, 0.002 mol) in THF (5 mL) at -780 C was added 2.0 M LDA in TI{F (1.01 mL, 0.002 mol). The reaction mixture was stirred at -780 C for 15 mini and iodomethane (126 mL, 0.002 mol) was added all at once. The temperature was raised to 0' C and the resul, ting mixture stirred for 4 h. The reaction was then quenched with sat'd NH4CI (5mL), extracted with ethyl acetate (2 x 10 rnL), dried (Na2SO 4 and concentrated in vacuo to a solid residue that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 95:5) to give 117 mg of l-ter-butyloxycarbony1234ttrdo 3 -reh-4qione (structure 69A of Scheme LI, where R I 2

R

3 =methyl), 128 mg (23 of I -tertbutyloxycarbonylp 1,,,-erhdo33dmty--unlnn (structure 70A of Scheme LIU, where

RI-

2

R

3 4 -methyl) and 2 00 mg of recovered starting material. Data for 1 -tert-butyloxycarbonyl-l, 2 3 4 -tetrahydro3nethy[-4quino linone: IH NMR (400 MI-z, CDCI3) 7.99 (dd, J=7.9, 1.7, 18H), 7.77 J= 8.4, 1 7.48 (ddd, J=7.3, 7.3, 1.7, I 7.13 (dd, J 7.4, 1.0, 1 4.32 (dd, J 13.4, 4.4, 1 3.69 (dd, J 13.3, 9.8, 1 H), 2.76 (ddq, J 7.0, 4.4, 1 1.56 9 1.24 J 7.0, 3 H).

I -tert-tlycrnv l 2 3 4 tetrah Iro -meth I u' oline. To a solution of I -tertbutyloxycarbonyl-I, 2 3 4 -tetrahydro.3.methyl4quinoion (117 mg, 0.45 mmol) in methanol (2 mL) at 00 C was added portionwise sodium borohydride (17 mg, 0.45 mrnol) and the reaction mixture was stirred at 00 C for 3 h. The reaction was quenched with of sat'd NH4C1 (2 mL), extracted with ethyl acetate (2 x 5 ml), dried (Na2SO4) and concentrated in vacuo to give 116 mg of the alcohol that was used directly without purification for the next step. A solution of the alcohol intermediate (116 mg, 0.44 mmol) in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C mg) and a trace of conc. H2S0 4 at rt for 16 h. Filtration over Celiterm afforded 104 mg 1 5 9 5 o 1 te r -b tyl xy arb n y -1 ,3 4 e tr y d ro 3 m e th y lq u no li e D a ta fo r W- e rtbutyloxycarbonyl,2,34tetrydro3methylqo liIR NMR (400 MHz, CDC13) 7.65 J 8.3, 1 7.11 (dd, J 7.7, 7.7,1 7.04 J1=7.2, 1 6.96 (dd, J1=7.4, 7.4, 1 3.97 (ddd, J= 12.7, 4.2, 1.0, 1 3.09 (dd, J= 11. 8, 9.8, 1 2.86 (dd, J= 16.2, 5.3, 1 2.40 (dd, J 16.1, 9.6, 1lH), 2.03 1 1.

5 2 9H), 1.05 J=6.7, 3H).

1.

2 3 dtavr.3.~tvgioine (tructure MIA of Sh eLIw erRb

R

4

-H.

R

3 =me hyl) This compound was prepared by General Method 12 (EXAMPLE 147) from 1-etbtlxcroy-,,,-erhdo3nehlunln (104 mg, 0.42 mmol) to afford 51 mg of 1,,,-erhdo--ehlunln as an oil which was used directly without purification for the next step.

7-Nitro.. l.

2 3 4 1,2,t,4-ydrr..yd.m3-ththyuquino in(51.

mg, 0.35 mmol) was dissolved in sulfuric acid (0.5 mL) and the temperature lowered to 00 C. To this solution 90% fumdig nitric acid (15 mL, 0.35 mmol).was added slowly and the mixture stirred at 0' C for 1 h, then warmed to rt. The reaction mixture was then poured onto I g of ice and extracted with dichloromethane (2 x 5 mL). The organic phase was washed with saturated aqueous NaH-C0 3 (3 mL) and concentrated in vaCUO to a reddish residue that was subjected to choaogah (silica gel, nexanes/letnyl acetate, 85:15) which afforded 8.2 mg of 7 -nitro 1234tetrhdro3rehlun lie.Dtaf*r7 niro 1,,,-erhdo3-ehl 1 oie H NMR (400 NMz, CDCI3) 7.39 (dd, J 8.25, 2.2, 1 7.27 (d,J 1 7.01 J= 8.3, 1 4.19 I 3.33 (Mn I H), 2.94 (dd, J= 10. 1, 10. 1, 1 2.86 (ddd, J= 13.8, 4.7, 1.7, 1 2.46 (dd J= 16.6, 10.0, 1 2.05 (mn, I 1.06 J 6.7, 3 H).

t( -i 436). A solution of 7 nitro-1,2,34etrhydro-3.methylqinline (8.2 mg, 0.042 mniol) in ethyl acetate (1 m[L) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (4 mg) at rt for 2 h. Filtration over CeliteTm afforded 6.2 mg. of 7-amidno-I ,2,3,4tetrahydro-3..methylquinojjne (structure 61A of Scheme XLVMI, where

RI-

2

-R

4

-H,

R

3 =methyl) that was used without further purification for the next step. Compound 436 was prepared by General Method 13 (EXAMPLE 147) from 7 -amidno- 1,2,3,4-tetrahydro-3 methyiquinoline (6.2 mg, 0.038 mmol), ZnCI2 (8.0 mg, 0.057 mol) and ethyl 4,4,4trifluoroacetoacetate (5.5 mL, 0.03 8 mol) to afford 5.8 mng of Compound 436 as a yellow solid. Data for Compound 436: IH NMR (400 MHz, DMSO-d 6 11.80 (bs, 1 H), 7. 11 I 6.95 I 6.37 2 3.26 (mn, I 2.83 (in, 2 2.51 (dd, J 15.7, ZO 10. 3, 1 1. 88 1 0. 97 J1 6.6, 3 H).

EXAMvPLE 337 1..3 n Copond 437. structure 7A f Sc~hem LIr where R'-1 =R 5 -R=H R 3 4 eh g6=trithvLO th 1.

1 -tert-utoycrnl. I 2 3 4tta~vr~.~imeth 1-4 u*lion (trctre7-o Scheme L19 whre

P

2

R

3 -4meth I This compound was obtained along with 1-.

tert-butyloxycarbonyI- 1,,,-erhdo3mty--unlnn as described above (EXAMPLE 336). Data for I -ter:..butyloxycarbonyl- l, 2 3 4 -tetrahydro.3,3dimnethy14quinolinone: IH NMR (400 MHz, CDCI 3 8.01 (dd, J 7.9, 1.6, 1 7.78 J 1 7.49 (ddd, J 7.6, 7.6, 1.7, 1 7.14 (ddd, J 7.8, 7.8, 1.6, 1 3.86 2 1.56 (s, 9 1.20 6 H).

I -ter-Butyloxycarbonyl- 1.

2 .,3 4 -terahydro. 3dimnethyluine. To a solution of 1-tertbutyloxycarbonyl-1,2,3,4-tetrahydro-3, 3 -dimethyl-4-quinolinone (128 mg, 0.47 mmol) in methanol (2 mL) at 00 C was added portionwise sodium borohydride (18 mg, 0.47 mmol) and the reaction mixture was stirred at 00 C for 3 h. The reaction mixture was then quenched with sat'd NH4CI (2 mL), extracted with ethyl acetate (2 x 5 mL), dried (Na2SO4) and concentrated. A solution of this crude material in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (20 mg) and a trace of conc.

H2SO 4 at rt for 16 h. Filtration over CeliterM afforded 100 mg of 1-tertbutyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethylquinoline. Data for 1-tertbutyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethylquinoline:

I

H NMR (400 MHz, CDC1 3 7.68 8.3, 1 7.12 (ddd, J= 8.8, 8.8, 1.5, 1 7.02 J= 7.0, 1 6.97 (ddd, J= 7.4, 7.4, 1.0, 1 3.46 2 2.58 2 1.51 9 1.01 6 H).

1, 2 3 4 -tetrahydro-3.3-dimethYluinoline structure 71A of Scheme LIL where R 1 2=R 5 =H R 3 4 =methyl). This compound was prepared by General Method 12 (EXAMPLE 147) from 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethylquinoline (100 mg, 0.38 mmol) to afford 51 mg of 1,2,3,4-tetrahydro-3,3-dimethylquinoline as an oil which was used directly without purification for the next step.

7-Nitro- 1,2.

3 4 -tetrahydro-3 3-dimethuino lin. 1,2, 3 ,4-Tetrahydro-3,3dimethylquinoline (51 mg, 0.32 mmol) was dissolved in sulfuric acid (0.5 mL) and the temperature lowered to 00 C. To this solution 90% fuming nitric acid (14 mL, 0.32 mmol) was added slowly and the mixture stirred at 0° C for I h, then warmed to rt. The reaction mixture was then poured onto 1 g of ice and extracted with dichloromethane (2 x 5 mL).

The organic phase was washed with saturated aqueous NaHCO3 (3 riL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 85:15) which afforded 39 mg of 7 -nitro-1,2,3,4-tetrahydro-3,3dimethylquinoline. Data for 7-nitro-1,2,3,4-tetrahydro-3,3-dimethylquinoline: 1H NMR 298 (400 MHz, CDCI3) 7.40 (dd, J 8.3, 2. 1, 1 7.29 J 1.8, 1 7.01 J 8.3 H, 1 4.25 1 2.98 2 2.54 2 1 .0 1 6 H).

1.

2 3 -erhdo.3diehl6trillurmty~ 0 glguinoline (Comp-ound 437). A solution of 7 -nitro- 1,2,3,4-tetrahydro.3, 3 -din'mthylquino line (39 mg, 0. 187 mmol) in ethyl acetate (2 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (4 mg) at rt for 2 h. Filtration over CeliteTm afforded 30 mg (91 of 7-amino- 1,2,3,4tetrahydro-3,3-dimethylquinoie (structure 72A of Scheme LII, where RI- 2

-R

5 H, R 3 4 =methyl) that was used without fuirther purification in the next step. Compound 437 was prepared by General Method 13 (EXAMPLE 147) from 7 -amino- 1,2,3,4-tetrahydro.3,3.

dirnethyiquinoline (30 mg, 0. 17 mmol), ZnCI2 (34 mg, 025 mmol) and ethyl 4,4,4trifluoroacetoacetate (25 nil, 0.17 mol) to afford 13 mg of Compound 437 as a yellow solid. Data for Compound 437: IH NMR (400 MHz, DMSO-d 6 11.71 Cbs, 1 H), 7.11 I 7.01 Cs, 1 6.40 1 6.37 1 2.89 2 2.51 Cs, 2 0.93 6 158).

EXAMPLE 338 (RIS) 1...-erhy-o22 (Compound 438 structure 79A of Scheme LI. where R=R 5

=R

7 2 4 =methvl.

R= Muormhl.

1 -tert-Butoxycarbonyl- .234t (srcth 76A o Schemre LI. where

R

1

R

2 3 =methyl). A solution of aniline (19 mL, 0.20 mol), 3acetoxy..3.methyl4.butyne (26 g, 0.20 mol), CuCI (1.0 g, 10 mxnol) and Et3N (28 mL, 0.20 mol1) in THF (120 mL was heated at reflux for 5 h and was filtered through a pad of CeliteTM. Removal of solvent and chromatography of the crude mixture (silica gel, EtOAc/hexane, 3/7) afforded 21 g of 3-ty--hnlnin--uye Treatment of the. amnino butyne with CuCI (0.70 mg, .7.0 mmol) in THF (200 mL at 700 C for 16 h followed by chromatography (silica gel, EtOAc/hexane, 3/7) afforded 13 g of 1,2dihydro..2,2direthylquinolie (structure 75A of Scheme LII, where R 1

R

2 3 =methyl).

Treatment of the quinoline with di-tert-butyl dicarbonate (22 g, 0. 10 mol) and DMAP (12 g, 0. 10 mot) in THF (100 nL for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) afforded 15 g (7 of l-tert-butoxycabonyll2..dihyro 2 2 dinlethylquino line. 1 -tert-Butoxycarbonyl. l, 2 -dihydro-2,2-dimethylquino line (3.0 g, I1I rnmol) in THF (30 mL was treated with 1 .0 M BH3-TH-F in TI-F (29 mL, 29 mmol) at it for 3 h and was quenched with 3 M KOH (20 mnL). To the above solution 30% H202 mL) was added and the midxture was stirred for 60 mini, then 5 mL of water was introduced.

The mixture was extracted, washed with brine and concentrated. Chromatography of the crude mixture on a silica gel column using a 10-30% mixture of EtOAc/Hexane as eluents afforded a 2A1 mixture of two isomers (0.87 g, 3.1 mmol), which was oxidized with PCC g, I11 mmol) in 60 mL of methylene chloride at rt for 60 mini. Removal of solvent and chromatography of the black oil on a silica gel column using a 20% mixture of EtOAc and hexane as solvent afforded 0.58 g of 1-tert-butoxycabonyl1,2,3,4tetrhydro- 2 2 dimethyl-4-quinolinone as a white solid. Data for l-tert-butoxycarbony-1I,2,3,4-tetrahydro 2 2 dimethyl-4-quinoiunone: IH NMR (400 MIHz, CDCI 3 7.93 J 7.8, 1 7.42 J 7.8, 1 7.31 J 1 7.02 J 1 2.73 2H), 1.56 9H), 1.49 (s, 6 H).

l.

2 3 4 -tetrabydro-2,2.3ti,.ethlguinolin structre 77A f Schem LI.whr

R

1

=R

5 2 =ety. To a solution of l-tert-butoxycaxbonyl-1 ,2,3A.-tetrahydro-2,2.

duiethyl-4-quinolinone (0.10 g, 0.36 mmol) and iodomethane (0.50 mL, 8.0 mmol) in DMF (4 mL) was added NaH (60 in mineral oil, 20 mg, 0.50 mmol) and the resulting mixture was stirred at rt for 2 h. The reaction was quenched with water (5 mL) and was extracted with EtOAc (2 x 15 mL). Removal of solvent and chromatography of the crude residue on a silica gel column using a 10% mixture of EtOAc and hexane as solvents afforded 90 mg of l-tert-butoxycarbony1,2,3,4tetrahyro2 2 3 triethyl 4 quinolinone as a colorless oil. The oil (90 mg, 0.32 mmol) was treated with NaBH4 mg, 1.3 mnmol) in methanol (5 mL for I h and the reaction mixture was concentrated.

Filtration from the inorganic material through a silica gel pad provided a colorless oil, which was then subjected to hydrogenation over 10 Pd/C (10 mg) in EtOAc (5 mL) under a hydrogen balloon for 15 h. Filtration firom the catalyst thr ough a CeliteTM pad followed by removal of solvent gave 70 mg of 1-tert-butoxycarbony[123,4 tetrahydro..2,2,3-atrnethylquno line as a colorless oil. The crude oil (70 mg, 0.26 mmol) was treated with TFA (0.50 mL, 6.5 mnmol) in CH2CI 2 for 30 mmd. and was quenched with NaOH (6 mL). The mixture was extracted with EtOAc (2 x 15 mL) and was concentrated. Chromatography on silica gel using a 10% mixture of EtOAc and hexane afforded l, 2 3 4 tetrahydo2,2,3-timethylqu ino line as a colorless oil (40 mg, Data for 1,,,-erhdo223wmtyqioie IH NMR (400 MHz, CDCI3) 7.00-6.91 (in, 2 6.60 J 7.3, 1 6.45 J 7.3, 1 3.61 (br s, 1 2.74 (dd, J 16.6, 5.3, 1 2.47 (dd, J 16.6, 10.3, 1 1.82 (in, 1 1.20 3 1.05 3 0.97

J

3 H).

(RIS) 2 3 4 -Tetrahydro2.2.3- imethj-trfin-t%- 81 ion (Compound 438, structure The quinoline (20 mg, 0. 11 mmol) was converted to Compound 438 according to the nitration-hydrogenatonKnor procedure described above for Compound 436 (EXAMPLE 336) in a 12% yield as a yellow solid (4 mg). Data for Compound 436: IH NMR (400 MHz, CDC13) 11.46 I 7.35 1 6.66 1 M), 6.31 I 4.40 I 2.83 (dd, J 16.6, 4.8, 1 2.57 (dd, J 16.6, 10.3, 1 1.83 EXAMPLE-339 (R/S-21.4u)- l.

2 3 4 -Tetrahyro2n D id F.-guinline (Co mund 439. structure 62A of Scheme XVII whre

=R

3

=R

6 H.i R 2

R

4 =methvl.

R

5 =trifuorom hyl I -tert-Btxcroy. l 2 3 4 trado..ethvlgunone. A mixture of aniline g, 32 minol) and crotonic acid (2.0 g, 23 inmol) in toluene (20 mL was heated at reflux. for 18 h. Removal of solvent and chromatography (silica gel, EtOAc/hexane, 9/1) of the crude material afforded 2.5 g (61 of 3 -phenylamidnobutanoic acid. The acid was treated with PPA (20 mL at 100 C for 6 h and the reaction midxture was poured into ice water (50 mL) and then was neutralized with Na2CO 3 to pH 7. Extraction with EtOAc (3 x inL) followed by chromatography (silica gel, EtOAc/hexane, 4/6) afforded 1.0 g (44%) of 1,,,-erhdo2mty--unlnn (structure 59A of Scheme XLVII, where

R

1

=R

3

R

2 =methyl) as a yellow solid. The quinolinone was treated with di-tert-butyl dicarbonate (2.2 g, 10 mmol) and DMAP (0.84 g, 6.8 inmol) in TI-F (15 mL) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) to afford 1. 1 g of Il-tertbutoxycarbony-1,2,3,4tetrahydro.2ethy..4.quinoaone as a yellow oil. Data for l-tertbutoxycarbonyl-1I, 2 3 4 -tetrahydro-2-methy1.4-quinolinone: IH NMR (400 MHz, CDCI3) 7.99 (d,IJ= 7.5, 1 7.78 J 1 7.50 J 1 7.12 (t,J 1 5. (in, I 3.04 (dd, J= 17.3, 5.8, 1 2.57 (dd, J= 17.3, 1.7, 1 1.56 9 1.22 J 6.9, 3H).

(R/S-21.4u)-

L.

2 3 4 -T =rahYdro 4dimethvlhyuoroinethi8P uinrs in.

(Compound 439) To a solution of a 3.0 M ether solution of MeMgBr (1.0 ML, 3.0 mrnol) was added 1-tert-butoxycarbonyI-1,2,3,4-tetrhydro-2-methy14quinolione 13 mng, 0.50 mmol) in THF (6 mL) and the reaction was allowed to stir at r1 for 3 h, then was quenched with water (10 mL). Extraction with EtOAc (2 x 30 mL) followed by chromatography (silica gel, EtOAc/hexane, 3/7) afforded 50 mg of the adduct ,which was treated with Pd/C (10 mg) and one drop of H2S04 in EtOAc (15 mL) under a hydrogen atmosphere for 16 h. Filtration from the catalyst through CeliteTm afforded the crude Itert-butoxycarbonyl-123 ttaydo24dmtyl4qioie which was treated with TFA (0.4 mL) in methylene chloride (1 mL) for 30 mmd. The reaction was neutralized with NaOH to pH 10 and was extracted with EtOAc (2 x 20 mL). Chromatography (silica gel, EtOAc/hexane, 1/9) afforded 20 mg of (R/S-21-4u)- l,2,3,4-tetrahydro-2,4.

dimethyl-4-quinoline (structure 60A of Scheme LI,' where R 1

=R

3

R

2

=R

4 =methyl) as a colorless oil. The quinoline was converted to the title compound according to the general ntation- hydrogenatjo n-Knorr procedure described above for Compound 436 (EXAMPLE 336) in 14% three step yield as a yellow solid. Data for Compound 439: IH NMR (400 M.Hz, CDCl3) 11.75 1 7.47 1 6.65 1 6.33 1 4.41 1 3.59 (mn, I 2.92 (in, 1 1.94 (mn, 1 1.38 J 6.8, 3 1.24 (in, I 1.22 J 6.4, 3 H).

EXAMPLE-340 (R/S-21.4u)- i-Ethl. 1.

2 3 4 -tetrahydro2-et hv[6-tfuoromethvyI8-p anonof.

6 giquinoline (Copound 440 structure 33A of Scheme XL. where RI 2

=R

6 =14_

R

3 amethyl. R 4 =ethyl R 5 =trifluoom thyi).

(RIS- 1.

2 4 -etrhvdo-7-ethxv-metyI~uin~on This compound was prepared in a manner similar to that described for 1,,,-erhdo--ehx--un lone (EXAMPLE 310) from anisidine and crotonic acid to afford the quinolinone as a brown oil.

Data for 1,,,-erhdo7mtox--ehl4qioioe IHNMR (400 M'Hz, CDCI3) 7.78 J 8.7, 1 6.33 (dd, J 6.2, 2.2, 1 6.08 J 2. 1, 1 4.27 (hr s, 1 H4), 3.80 3 2.59 (dd, J 16, 3.7, 2 2.42 (dd, J 13, 12, 2 H), (RISW-1-tert-Butoxycarbonyl-I l 2 3 4 -te rahvro7-mpto2ethv.4gipgn (ructure 31A of Scheme XL. where RI- 2

R

3 =ethyl). This compound was prepared in a manner similar to that described for i-tert-butoxycarbonyl-1,2,3,4.ttrahyro7methoxy-4 quinolone (EXAMPLE 310) from 1,,,-erhdo7mtoy2mty--unlnn (3.26 mg) to give 961 mg of the desired quinolone as an off-white solid. Data for Itert-butoxycarbonyl- l, 2 3 4 -tetrahydro-7-methoxy-2..methy14.quinolone: IH NMR (400 MHz, CDCI3) 7.94 J 8.9, 1 7.35 J 2.4, 1 6.67 (dd, J 8.7, 2.4, 1 5.08 (in, 1 3.86 3 2.99 (dd, J= 17, 5.8, 1 2.48 (dd, J= 17, 1.7, 1 1.57 9 H), 1. 24 J= 6.9, 3 H).

(RIS)- 1 -tert-Butoxygarbony...thi. l...-etay -7-.methox-2-methylquino line (structure 32A of Schemne XL. where R! 2

R

3 =methl, R 4 =ethyl). This compound was prepared in a manner simiflar to that described for l-tert-butoxycarbonyl-4.ethyl. 1,2,3,4tetrahydro-7-methoxy.4.quinolone (EXAMPLE 314) from 1-tert-butoxycarbonyl-1,2,3,4.

tetrahydro-7-m-ethoxy-2-methylk4quinolone (100 mg) to give the desired quinoline (34 mng, as a mixture of diastereomers. Data for l-tert-butoxycarbony[-4ethyl- 1,2,3,4tetrahydro-7-methoxy-2-miethylquinoline: 1 H NMR (400 MHz, CDCI 3 7.05 J 8.6, 1 6.97 J 2.5, 1 6.66 (dd, J 8.5, 2.5, 1 4.38 (mn, 1 3.78 3 2.39 (mn, I 2.28 (in, 1 2.04 (mn, 2 1.55 (in, I 1.49 9 1. 14 J 3 1.08 J 7.4, 3 H).

(R/S)-4-EthyL- l 2 3 4 -tetrahydro-7-hydroxy2 methyI u ino lie. This compound was prepared in a manner similar to that described for 4-ethyl-i 2 ,3,4-tetrahydro -7hydroxyquinoline (EXAMPLE 314) from 1 -tert- butoxycarbonyl-4-ethyl 1 ,2,3,4-tetrahydro- 7 methoxy-2-methylqu io line (34 mg) to give the desired quinoline as'a colorless oil, which was used without fuirther purification in the following reaction.

(RS-/4u4Ety 123 -tetrahydro2methv1.6..flin--,--I 8-2yethl 8 Qiunln Cmon This compound was prepared in a manner similar to that described for Compound 414 (EXAMPLE 314) to give the desired compound as a midx of diastereomers. Recrystallization of the diastereomeric mixture afforded a sample of Compound 440. Data for Compound 440: 1 Hl NMR (400 MHz, CDC13) 7.38 I H), 6.37 I 6.35 1 4.43 (br s, I 3.57 (mn, I 2.79 (in, I 2.04 (in, 2 H), 1. 61 1 1. 28 J= 6.4, 3 M, 1.00 J= 7.3, 3 H).

EXAMPLE 341 (R/S-21.3u)- Ttai-r-oo -u (Co mound 441. tructure 62A of Scheme XLI.wer

R=R

4

=R

6

R

2 3 =methvl RS4flooeh) To a solution of I -tert-butoxycarbonyl-l) 2 3 4 tetrahydro2miethy4quinolione (EXAMPLE 339) (0.13 mg, 0.50 mmol) and iodoine&thane (0.50 inL, 8.0 mrnol) in DMF (6 mL) was added NaH in a 60% mineral oil (40 mng, 1.0 inrol). The reaction mixture was stirred at rt for 16 h and was quenched by water (10 mL). Extraction of the mixture with EtOAc (2 x 30 nL followed by chromatography (silica gel, EtOAc/hexane, 1/9) afforded a mixture of three alkylated products (125 mg, The above mixture was treated with NaBH 4 (38 mng, 1.0 inmol) in methanol (15 mL for I h and the alcohol intermediates were purified by chromatography (silica gel, EtOAc/hexane, 3/7) to afford a mixture of three alcohols (120 mng, The mixture of alcohol intermediates (120 mng, 0.43 inmol) was treated with 10% Pd/C (20 mg) and one drop of H2S0 4 in EtOAc (15 mL) under H2 for 18 h. Filtration through a CeliteTM pad provided the reduced products, which were directly treated with TFA (0.5 mrL) in methiylene chloride (1.0 in) for I h. The reaction was quenched with 5% NaOH, brought to pH 10, and was extracted with EtOAc (2 x 20 inL).

*Chromatography (silica gel, EtOAc/hexane, 2/8) afforded a mixture of three products mg, containing (RIS-21,3u)-1,,,-erhdo23dtehln lin (structure of Scheme LI, where R' R 4

R

2 3 =inethyl); (R/S-21,30)- l 2 3 ,4-tetrahydro-2,3.

dirnethylquino line (structure 60A of Scheme LI, where R I =R 4

R

2 3 =methyl), and (Rig)- I, 2 3 4 -tetrah~dro-2,3,3-timethylquino line (structure 71A of Scheme LU, where R I =R 5

R

2 4 =methyl). The mixture of the quinolines (30 mg, 0. 18 mrnol) was subjected to the nitration-hydrogenation- Knorr procedure described above for Compound 436 (EXAMPLE 336) to afford a midxture of Compound 441, 442, and 443, which was purified by HPLC (10 mmn x 25 cm ODC column, 80% MeOHI20% H20, 3.0 mL /min.).

Data for Compound 441: IJJ NMR (400 MHz, acetone-d6) 10.68 1 7.25 1 H), 6.48 1 6.41 I 6.09 1 3.13 (in, I 2.80 (dd, J= 15.9, 4.3, 1 2.53 (dd, J= 15.9, 12.0, 1 1.61 (in, I1H), 1.24 J 3H), 1.04 J 3H).

EXAMPLE 342 (R/S-21.2t)-l234 etayr-.:dimethMtilooehl8pioo56,l nln (Compound 442 struture 62A o~f Schem XLII hr 1

=R

6 2 3 =methyl.

R

5 =trifluoromehl)~ Compound 442 was obtained along with Compounds 441 and 443 as described above (EXAMPLE 341). Data for Compound 442: IH NMR (400 MHz, acetone-d6) 10.80 1 7.28 I 6.49 1 6.48 1 6.15 I 3.62 (in, 1 2.91 (in, I H), 2.62 (dd, J 16.3, 6.5, 1 2.07 (in, 1 1. 15 J 6.5, 3 0.93 J 6.8, 3 H).

EXAMPLE 343 (RIS)3.- e h o)I--nthl8prdn 6 (Comound 443. structure 73A of Scheme LUI hr -R 1

=RR

7

.R

2 =eh.

R

6 =trcRi=Ruor gm-thethy.

Compound 443 was obtained along with Compounds 441 and 442 as described above (EXAMPLE 341). Data for Compound 443: IH NMR (400 MHz, acetone-d6) 10.58 1 7.23 I 6.50 1 6.41 1 6.08 I 3.28 (in, I 2.65 J 15.8, 1 2.53 J =15.8, 1 1. 15 J1=6.6, 3 1.03 3 0.84 3 H).

305 EXAMPLE 344 (RIS)-1 erhdo2mty--ril~ai -2idn[ he (Comound 444, structure 53A of SchemY XLVI.weeR-= 5 =.R=ehl

R

4 =trifluoroniethyl) 1 2 3 4 -tetrahydro-2-methylquino line 15 g, 1.0 mmo 1) was converted to Compound 444 according to the riration-hydrogenation- Knorr procedure described for Compound 436 (EXAMPLE 336) to afford 35 mg of Compound 444 as a yellow solid. Data for Compound 444: 1 H NMR (400 MHz, acetone-d6) 10.83 1 7.29 1 6.55 I 6.50 I 6.17 1 3.57 (mn 1 2.91-2.82 (in 2 2.03 (in, I 1.54 (rr, 1 1.25 J 3 H).

EXAMPLE 345 (R/S)-4-Ethy- 1...-erh-r--rfur nr.-lunln (Compound 445. structure 62A of Scheme XLVII. where, R 1 3

=R

6

R

4 =ethyl. R 5 =tro loromethvfl (RIS)- 1 -tert-Butyloxvcarbonyl-4-ethyl- 2 3 4 -terravdro-4- hvdroxyguino line. To a flamedried 25-mi, rb flask containing ethyhniagnesium bromide (4.0 ml, of a 3.0 M solution in Et2O, 12.0 minol, 3.0 equiv), at -10' C was added dropwise a solution of W-ertbutyloxycarbonyl-1,2,3,4..tetrahydro-4-quinolone (1.0 g, 4.0 minol) in Et2O (4 mL). The reaction mixture was stirred at -10' C for 15 mini, then allowed to warm to rt over 10 mini.

A 1.0 M solution of NaHSQ4 (10 mL) was then rapidly added. The resulting biphasic mixture was extracted with EtOAc (3 x 10 mL), and the combined organic extracts were dried (Na2SQ4) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes EtOAc, 4: affording 800 mg (71 of the desired product as a clear yellow oil (Rf 0. 14, hexanes EtOAc, 4: Data for 1-tertbutoxycarbonyl.4ethyl- 1 2 3 4 -tetrahydro-4-hydroxyquinoie: IH NMR (4.00 MHz,

CDCI

3 7.68 IH, J= 8.4, 7.47 (dd, IlH, J= 7.9, 1.7, 7.21 (ddd, I1H, J= 7.4, 7.4, 1.6, 7.09 (ddd, I H, J 7.8, 7.8, 1.1, 4.03 (ddd, IlH, J 12.9, 7.1, 4.7, 3.47 (ddd, I1H, J 13.1, 8.6, 4.3, 2. 11 (ddd, I1H, J 13.5, 8.6, 4.8, 1. 86 3H, 3-H, CH2CH3), 1.52 9H, C(CH3)3], 0.89 3H, J 7.5, CH3).

306 (R/S)-4-Ethyl- 1.

2 3 4 -tetrahvdroquinoline (structure 60A of Scheme XLVII. where R 1 3

R

4 =ethyl). To a flame-dried 100-mL rb flask containing 1-tert-butyloxycarbonyl-4ethyl-1,2, 3 4 -tetrahydro-4-hydroxyquinoline (800 mg, 2.88 mmol) in a 1:1 solution of EtOAc EtOH (20 mL) at rt was added 10% Pd/C (approx. 1 mol After evacuation and flushing of the vessel three times with nitrogen, one drop of trifluoroacetic acid was added, the vessel evacuated once more, and the mixture stirred under an atmosphere of hydrogen for 16 h. The reaction mixture was then filtered, and concentrated under reduced pressure.

The residue was transferred to a 25-mL rb flask with CH2C12 (3 mL) and stirred at rt. TFA (1.2 mL) was added and the reaction was vented and stirred for 2 h at rt. A solution of sat'd. NaHCO3 (adjusted to pH 9 with 3.0 M NaOH) was added until the aqueous phase was approximately pH 9. The resulting aqueous phase was extracted with CH2CI 2 (3 x mL), and the combined organic extracts were dried (Na2SO4), and concentrated under reduced pressure to yield 351 mg of a colorless oil, which turned blue on exposure to air (Rf 0.40, hexanes EtOAc, Data for (R/S)-4-ethyl-1,2,3,4-tetrahydroquinoline: 1

H

NMR (400 MHz, CDC13) 7.02 1H, J=7.6, 6.96 (ddd, IH, J=7.7, 7.7, 1.3, 7-H), 6.61 (ddd, IH, J 8.2, 8.2, 1.0, 6.47 IH, J 7.9, 3.83 (br s, 1H, CH2NH), 3.31 (ddd, 1H, J 11.3, 11.3, 3.6, 3.25 (ddd, IH, J 9.7, 9.7, 4.8, 2.65 (dddd, IH, J 10.1, 5.1, 5.1, 5.1, 1.92 (dddd, IH, J 9.6, 4.7, 4.7, 4.7, 3- 1.82 IH, 1.74 1H, CH2CH3), 0.98 3H, J 7.4, CH3).

(R/-7-Amino-4-ethyl-1.

2 3 4-tetrahvdroouinoline (structure 61A of Scheme XLVIII where RI- 3

R

4 =ethyl). A 25-mL rb flask containing (R/S)-4-ethyl-l,2,3,4tetrahydroquinoline (340 mg, 2.1 mmol) was cooled to -10° C, and conc. H2SO4 (5 mL) was added slowly. The resulting solution was warmed to rt to effect complete dissolution of the quinoline, then cooled again to -10° C and stirred vigorously. Fuming HNO3 (85 p L) was added dropwise, slowly, and the reaction mixture turned dark red. After 10 min, the reaction mixture was poured onto cracked ice and diluted with water (5 mL). Sat'd NaHCO 3 (80 mL) was added, and the pH was adjusted to pH 9 with 3.0 M NaOH. This aqueous phase was extracted with EtOAc (3 x 75 mL), and the combined extracts were dried (Na2SO4),and concentrated under reduced pressure to yield a dark red oil. This crude material was placed into a 250-mL rb flask with 1:1 EtOAc EtOH (40 mL) and 10% Pd on C (approx. I mol The vessel was evacuated and flushed with nitrogen three times, then stirred under an atmosphere of hydrogen for 16 h, filtered, and concentrated under reduced pressure to yield a yellow oil, which was purified by flash chromatography (silica gel, CH2CI2 methanol, 9: affording 2 10 mg (57 of the desired product as a dark yellow oil(Rf 0.50, CI-2C12/IMeOf, Data for (RIS)-7-amino4ethy11l2,34.

tetrahydroquinoline: 1 H NMR (400 MI-z, CDCl3) 6.81 I H, J 8.1, 6.02 (dd, I1H, J 8.0, 2.2, 5.84 1FH, J 2.3, 3.48 2H, NH2), 3.27 (ddd, ILH, J 11.1, 11.1,3.5,2-H), 3.20 (ddd, IH,J= 9.8, 5.3, 2.55 (dddd, IH,J= 10.2, 5.2, 5.2, 5.2, 4H), 1.90 (dddd, 1H, J 9.6, 9.6, 9.6, 4.7, 1.72 (min 2Hf, 3-H, CHf2CH3), 1.48 (in, IlH, CH2CH3), 0.96 3H, J 7.4, CH3).

(R/S)-4-Eth j- 1.

2 3 4 -te rahydra-6- ooeh18p~ioos..~uinoieC pud 445). To a flame-dried 100-mL rb flask containing 7-amino-4-ethyl,2,3,4tetrahydroquinoline (210 mg, 1.19 mmol), in ethanol (20 mL), at mt was added ethyl-4,4,4trifluoroacetoacetate (190 PL, 1.31 mrnol, 1.1 equiv) followed by ZnCI2 (244 mg, 1.79 mmol, 1.5 equiv). The reaction midxture was heated to reflux for 6 h, at which point all starting material had been consumed (by TLC analysis). The reaction mixture was cooled to Mt and the solvent removed under reduced pressure. Dichloro methane (20 mL) was added and the organic phase washed with sat'd NAHCO3 (2 x 10 rL) and brine (I x mL), then dried (Na2SO4), and concentrated under reduced presure. This crude product was purified by flash chromatography (silica gel, CH2C12 MeOHf, 15:1), affording 24.4 mg of the desired product as a yellow solid. Data for Compound 445: Rf 0.37, (CH2C1 2 MeOH, 9: IH NMR (400 MHz, CD3OD) 7.31 1Ff, 6.47 I H, 7- 6.37 1Hf, 10-H), 3.34 (in, 2H, 2.70 (mn, 1H, 1.88 (mn, 2Ff, 1.62 (mn, 2H, CII2CH3), 1.00 3Hf, J 7.5, CH3 EXAMPLE 346 (R/S-21. 2 -rmty--1 giguinoline (Copomnd 446 structure 81A of Scheme LIU. where Rl=R 4

=R

6

-R

8

R

2 3 =methyl. R 5 =trifluoromethyl) 308' To a solution of Compound 441 (3.5 mg, 0.012 mmol) and iodomethane (0.10 alI L, 1.6 mmol) in THF (2.0 mL) was added Nail as a 60% in mineral oil (10 mg, 0.25 mmol) and the reaction was stirred at rt for I h, then, was quenched by water (10 mL Extraction with EtOAc (2 x 15 ml) and chromatography (silica gel, EtOAc/hexane, 1/1) afforded 3.0 mg (8 of Comipound 446 as a yellowish solid. Data for Compound 446: Ifl NMR (400 MHz, CDC13) 7.36 I 6.72 I 6.32 I 4.40 I 3.61 3 3.14 (in, I 2.83 (dd, J 16.0, 4.4, 1 2.54 (dd, J 16.0, 11 1 1.63 (in, I 1.26 J= 6.3 31-H), 1.06 J 6.6, 3 H).

EXAMPLE 347 (RIS)- I.

2 3 4 etrahdr4pov1 -furmtv.8-j23aidonors6 gguQinoline (Compound 447. structure 62A of Scheme XLVMI. where R I 3

=R

6 H. R 4 =-propvi.

R

5 =trfuoromethvl' I -tert-Butyloxycarbony1 2 3 4 -tetrah do-4-hydox This compound was prepared from 1 -tert-butyloxycarbamoyl- 1, 2 3 4 -tetrahydro-4-quino tone (1.00 g, 4.00 inmol) in the manner previously described for l-tert-butyloxycarbonyl4ethyl- 1,2,3,4tetrahydro-4-hydroxyquino line (EXAMPLE 345), affording 567 mg of the tertiary alcohol as a yellow oil (Rf 0.22, hexanes EtOAc, 4: Data for l-tert-butyloxycarbonyl- 1,,,-erhdo4hdoy4poyqioie 1jH NMR (400 MHz, CDC13) 7.67 (d, IH, J 8-M, 7.48 (dd, IH, J 7.9, 1.7, 7.20 (ddd, IH, J 8.6, 8.6, 1.4, 6-H), 7.08 (ddd, 1Hl, J 7.6, 7.6, 1.1, 4.03 (ddd, 1H, J 12.8, 7.1, 4.8, 3.46 (ddd, 1H, J 13.0, 8.5,4.4, 2.11 (ddd, IH, J1= 13.5, 8.5,4.8, 1.89 (ddd, IH, J1= 13.6,7.2, 4.4, 1.78 (mn, 2H, CH2C2HS), 1.52 9H, C(Cff3) 3 1.32 (in, 2H, CH2CHi2CH3), 0.90 0t, 3H, J 7.3, CH2CH3).

MI/S)-l..ATtavcr.4.rpI uinoline trcture 6iA -f Shm L II hr ~ILPHanprop2A). This compound was prepared from 1 -tert-butyloxycarbonyl 1,2,3,4-.

tetrahydro-4hydroxy-4propylquinoline (550 mg, 1.89 mmol) in the manner previously described for 4 -ethy-1,2,3,4-tetrahydroquinoie (EXAMPLE 345), affording 229 mng of the desired tetrahydroquinoline as a yellow oil (Rf 0. 10, hexanes EtOAc, 2: 1).

Data for (RIS)- I, 2 3 4 tetrahydro-4-propylquinoline: IH NMR (400 MHz, CDC13) 7.07 I1H, J= 7.6, 7.02 (ddd, I1H, J 7.9, 1.1, 6.77 (dd, I H, J 7.4, 6-H), 6.67 1H, J= 7.9, 6.25 (br s, 1H, NHl), 3.37 (ddd, 1H, J= 11.5, 11.5,3.5, 2-H), 3.30 (in, I H, 2.78 (dddd, I H, J 10.0, 5.0, 5.0, 5.0, 1.99 and 1.84 (2 x Mn. 2 x IH, 1. 68 (mn, IlH, CH2CH2CH 3 1.47 (in, 3H,.CH2CJJ2CH 3 0.95 3H, J 7.3, CH3).

(R/S-7-Amidno- 1 2 3 4 -tetrahvdro-4-p)ropvgI 'oline (structure 61A of Scheme XLVIII.

where R 1 3

R

4 =n-propyl). This compound was prepared from (RIS)-l, 2 ,3,4-tetrahyjro.

4 -propylquinoine (220 mg, 0.78 minol) in the manner previously described for 7-amino-4ethyl- 1, 2 3 4 -tetrahydroquinoline (EXAMPLE 345), affording 114 mng of the product as a colorless oil (Rf 0. 10, hexanes EtOAc, 2: Data for (R/S)-7-arnino- 1,2,3,4tetrahydro4propylqunolie: IH NMR (400 MHz, CDCI3) 6.80 1H, J 8.0, 6.01 (dd, I1H, J 2.3, 5.83 I1H, J= 2 3.74 (br s, I1H, NH), 3.41 (br s, 2H, NH2), 3.28 (ddd, 18, J= 11.0, 11.0, 3.3, 3.19 (ddd, 1H, J 4.7, 4.7, 2-H), 2.65 (dddd, 18, J 5.1, 5.1, 5.1, 5.1, 4-1-1, 1.89 (dddd, 1H, J 9.7, 9.7, 9.7, 4.5, 1.73 (dddd, 18,1J= 8.6, 8.6, 4.8, 4.8, 1.61 (mn 1H, CH2CH2CH3), 1.40 (in, 3H-, CH2CH2CH 3 0.93 3H, J 7.0, CH3).

(RIS-123 -Ttayr--rpl6tilooehl8 io (Compound 447) This compound was prepared from 7 -amino- 1,2,3,4-tetrahyro-4 propyiquinoline (1 10 mg, 0.58 mrnol) in the manner previously described for Compound 445 (EXAMPLE 345), affording 8.9 mg of the desired product as a yellow powder (RI 0.44, CH2C12 MeOH, IH NMR (400 MHz, CDC13) 7.34 1H, 6.65 18, 6.40 18, 10-H), 4.65 (br s, 18, (CH3)2CNII)], 3.42 (ddd, 18,1J= 11.2, 11.2, 3.34 (ddd, 1H, J 7.9, 3.8, 3.8, 2.82 (in, 18, 1.88 (mn 2H, 1.52 (n4 4H, CH2CH2CH 3 0.96 3H,1J 7. 1, CH3).

EXAMPLE 348 (R/S-3-thy- l 2 3 4 -ttraydro-2.2-diimethy[-6 fioroethy8-y~idono r5,6-glQuinoline (opud4 8 tutr 79A of Scheme LII. where R =R 5

R

7

R

2 3 =methvI.

R

4 =ethA_. 6 =trluroineh 1) (R/S')-3-Ethyl- 1.

2 3 4 -tetrahydro-2- dimethvlgqu nie (srcue7 fShme

LIUI

where R 1

R=-.R

3 mty 4 ehl.To a Solution of Il-tert-butoxycarbonyl 234 tetrahydro..2,2-dimethyl-4quinolinone (EXAMPLE 325) 10 g, 0.36 mmol) and iodoethane (0.50 mnL, 6.3 mmol) in DMF (5 mL) was added NaH (60 in mineral oil, mg, 1.0 mmol) and the resulting mixture was stirred at rt for 15 h. The reaction was quenched with water (5 mL) and was extracted with EtOAc: (2 x 15 mL Removal of solvent and chromatography of the crude residue on a silica gel colunm using a mixture of EtOAc and hexane as solvents afforded a midxture of products, which was treated with TFA (0.50 mL) in methylene chloride (1.0 mL) for 3 h. The reaction was neutralized to pH 10 by 5 NaOH and was extracted with EtOAc: (2 x 20 nL Chromatography (silica gel, EtOAc/bexane, 3/7) afforded 30 mg (41 of (R/S)-3-ethyl- l, 2 3 ,4-tetrahydro.

2 2 -dimethyl-4-quinolinone (30 mg, 0. 15 mmol) as a colorless oil. The quinolinone (30 mg, 0. 15 mmoi) was treated with Et3SiH (1.0 mL and BF3-OEt 2 (0.05 mL, 0.4 mmol) in CH2Cl2 (1.0 mL) at 1000 C for 15 h in a sealed tube. Purification of the crude product by chromatography (silica gel, EtOAc/hexane, 1/9) afforded 20 mg (7 of (R/S)-3-ethyl- 1,23 ttayr-,2dmtyqioie Data for (R/S)-3-ethyl-.1 2 ,3,4-tetrahydro-2,2dirnethyiquinoline: IfH NMR (400 MHz, CDC13) 6.98 J 7.5, 1 6.96 J 7.5, 1 6.61 J 7.5, 1 6.44 J 7.5, 1 3.60 1 2.90 (dd, J 16.7, 5.2, 1 H), 2.41 (dd, J= 16.7, 10.7, 1 1.68 (in, I 1.52 (in, 1 1.23 (mn, 1 1.22 3 H), 1.05 3H).

(R/S')-3-Ethyl- h--*ur o (Compound 448). The quinoline prepared above (20 mg) was converted to Compound 448 according to the nitration-hydrogenation Korr procedure described for Compound 436 (EXAMPLE 336) to afford 2.0 mg of Compound 448 asa yellow solid. Data for Compound 448: 1Hj NMR (400 MHz, acetone-d 6 10.65 1 7.31 I 6.47

I

6.41 I 6.06 I 3.01 (dd, J= 16.6, 4.8, 1 2.53 (dd, J= 16.6, 11.0, 1 H), 1.72 (mn, 1 1.53 (in, 1 1.30 1 1. 12 3 1. 10- 1.00 (in, 4 H).

EXAMPLE 349 (RIS)- l.

2 3 4 Tetrhdro? 2dIneth-I tilootvIPovgd glguinoline (Compound 4-4-9structure 79A of SchemeLI.whrR 1 R R 7

R

3 =methvl. R 4 -propyI 6tfooehy) (RIS)- l.

2 3 4 -Tetrahvdro-2.2..dimthyl-4-propvylguino line (structure 77A of Scheme LIII.

where R I=R 5 2 3 =methyl.

R

4 ==n-propyl). T7his compound was prepared in a manner similar to that described for (R/.S)-3-ethyl- 1,,,-erhdo-,-intyqino line (EXAMPLE 348) but using iodopropane in place of iodoethane. (RIS)-l1, 2 3 4 -Tetrahydro.

2 2 -dimnethyI-4-propylquino.jne was obtained in 16% overall yield as a colorless oil. Data for (RI5 -1,2,3,4-tetrahydro-2,2-im etyl- 4 propylquinoline: IH NMR (400 MHz, CDCI3) 6.98 J 7.4, 1 6.96 J 7.4, 1 6.61 J 7.4, 1 6.45 J 7.4, 1 3.60 (brs, 1 2.87 (dd, J= 16.6, 5.2, 1 2.42 (dd, J= 16.6, 10.7, 1 1.66-1.49 (in, 3 H), 1.40-1.25 2 1.21 3 1.05 3 0.92 J =7.1 3 H).

(RIS)- 2 3 4 Tetrahdro 2-dim imethv16.jfthlo-ropty8 1 3 tJ 6 glquinoline (Compound 449). Compound 449 was prepared in manner similar to that described for Compound 448 (EXAMPLE 348), to afford Compound 449 in a 32% overall yield. Data for Compound 449: 1H NMR (400 MHz, CDCI3) 11.00 1 7.32 I H), 6.61 I 6.42 1 4.60 (brs, 1 2.90 (dd, J 16.6, 4.4, 1 2.45 (dd, J 16.6, 11.3, 1 M, 1.70-1.42 (mn, 3 1.

36 -1.24 2 1. 18 3 1.02 3 0.93 J= 6.7, 3 H).

EXAMPLE 350 I Mty--rfurmtyL7pdoo5 idln (Compoun 40 srctue- AlA t Scheme LV. where R 1 3

=R

5

R

4 =trifluoronethyl,

R

6 m-ethl Compound 419 (10 mg, 0.0393 iniol) and paraformaldehyde (11I mg, 0.0393 mmrol) were dissolved in glacial acetic acid (2.5 inL) and stirred for 10 min at rt. NaBH3CN (13 mg, 0. 197 iniol) was added in one portion and allowed to sir at rt for 15 h. The reaction mixture was poured over ice and made basic with 10% NaOH. The aqueous layer was extracted with EtOAc (3 x 50 mQL, dried (Na2SO4), filtered, and concentrated. The crude material was dissolved in 5% MeOHICHCI 3 (0.5 mQL and loaded onto a 1000 Pm reverse phase TLC plate (Whatman PLKC18F Silica Gel 150 The plate was eluted with 312 MeOHIH2O to afford 5.8 mg of Compound,450 as a light yellow solid. Data for Compound 450: IH NMR (400 Mffz, acetone-d6) 7.29 J 1. 6, 1 6.54 1 6. 1 3.50 J 8.1, 2 3.01 J 8.0, 2 2.83 3 H).

EAPE31 6-(5-Cyano-2-thienvl)-1 2 -dihydro-2.2,4-trimethvlquinolinie (Compound 451. stucture 4 of Scheme UI. where R 1 =5-cyano-2-thienfl).

To a solution of I -tert-butyloxycarbonyl16-(5formy12-thienyl) 1 ,2-dihydro-2,2,4trimethylquino line (12 mg, 0.03 mmnol) in acetonitrile/water (10 mld/O.5 ml) was added hydroxylamidne-O-sulphonic acid (5 mg, 0.04 mmol). The reaction mixture was heated to 650 C for I h. The reaction was quenched with 10% NaOH (5 mL) and extracted with EtOAc (10 rnL. The organic layer was washed with water and brine (3 x 5 mL each), dried (Na2S 04), and concentrated in vacua to afford the crude product as a yellow oil. The crude product was purified by prep. TLC (20 x 20cm,4 250pgm, 25% EtOAc:hexane) to afford 5 mg of 1-etbtlxcroy--5can--hey)12dhdo224 trimethyiquinoline as a yellow oil. This product was dissolved in CH2Cl2 (5 mL) and treated with TFA 1 mld) at rt with stirring. After 2 h, the reaction was quenched with NaOH (5 mL). The organic layei was washed with water and brine (3 x 5 ml, each), dried (Na2SQ4) and concentrated in vacuo to afford the crude product as a yellow oil. The crude product was purified by prep. TLC (20 x 20cm, 250pnm. 25% EtOAc:hexane) to afford 2 mg of Compound 451 as a yellow oil. Data for Compound 451: Rf 0.3 (silica gel, EtOAc:Hex); 'H NMR(400 MHz, CDC13) 7.52 J 4.0, 1 7.23 1 7.22 J 7.4, 1 7.07 J 4.0, 1 6.43 J 7.4, 1 5.38 1 2.02 3 1.31 (s, 6 H).

EXAMPLE 352 6-4Cyn--hey)l2dhdr-..- ~hlunln (Compound 452 stucture 4 of Scheme where R=4-cyano-3-thienyl).

4 -B~romo- 2 -9yanothiophene. To a solution of 4 -bromo-2-thiophenecarboxaldehyde (1.0 g, 5.2 mmol, Aldrich) in acetonitrile/water (20 mLt2 mL) was added hyroxylamiine-O-sulfonic acid (2.4 g, 21.2 mmol, Aldrich). The dark solution was heated to 650 C with stirring. After 8 h, the reaction was quenched with 10% NaOH (10 mL). The solution was extracted with EtOAc (30 rnL). The organic layer was washed with water and brine (3 x 10 mL each), dried (Na2S 04), and concentrated in vacuo to afford the crude product as a tan solid. The crude product was purified by silica flash chromatography (5-25% EtOAc:hexane) to afford 0.50 g (51 of 4 -bromo-2-cyanothiophene as a white solid. Data for 4-bromo-2cyanothiophene: Rf 0.49 (silica, 25% EtQAc:hex.); IH NMR(400 MHz, CDCJ 3 7.54 1 7.50 1 H).

6 -(4-Cyano-3-thienyl)- l.

2 -dihvdro-2.2.4 trlinthylquinoline (Compo-und 452). This compound was prepared by General Method 2 from compound 9 (200 mg, 0.63 mmol) and 4 -bromo-2-cyanothiophene (0.50 g, 2.65 mmol). The crude product was purified by prep.

TLC (20 x 20cm, 1000pm, 25% ETOAc:Hexane) to afford 160 mg of Compound 452 as a yellow oil Data for Compound 452: Rf 0.50 (silica gel, 25% EtOAc:hex);

IH

NMR(400 MHz, CDCI 3 ).7.79 1 7.46 1 7.20 I 7.16 J 8.3, 1 H), 6.46 J= 8.3, 1 5.37 I 2.03 3 1.31 6 IR (film, NaCi) 1159, 138 1, 1402, 1449, 1476, 1499, 1609, 1653, 2216, 2915, 3294, 3584.

EXAMPLE 353 6 3 -Formylpheny 1,2diydro2.2.4±,etygunoe(Cmpud 53 trctr 4o Scheme where R=3-ormvphenvl) This compound was prepared by General Method 2 from Compound 9 (50 mg, 0. 158 mmol) and 2 3 -bromopheny)- 1,3-dioxolane (171 mg, 0.788 mmnol). Purification by flash chromatography on silica gel (20 g) using 5% EtOAc:hexanes; afforded 21 mg of Compound 453 as a yellow oil. Data for Compound 453: IH NMR (400 MHz, acetoned6) 10.09 1 8.11 J 1.4, 1 7.90 J 1 7.77 J= 7.5, 1 7.59 J= 7.6, 1 7.40 J 1 7.33 (dd, J 2.2, 1 6.61 J= 8.2, 1 H), 5.40 1 5.38 (bs, 1 1.29 9 H).

EXAMPLE 354 1 2 -Dihydr o-2.2.4-trimth.1-6-. ~meth IsufonyIh-nyl-g~~ (opon 4 4 structure 4 of Scheme 1. where R=3-(methlsufonynphenyI_) 3 -Brmopenv~mehvlsuloneIn a 50 rnL r.b flask, m-CPBA (623 mg, 2.166 mniol, was suspended in CH2CI2 (20 mL) and cooled to -201 C. 3 -Bromothioanisole (200 mg, 0.985 mmol) in CH2CI2 (1 rnL was added to the slurry and allowed to warm to rt for 2 hi. The reaction was quenched with H20 and the aqueous layer was extracted with C82C12 (3 x 50 mnL). The combined organics were washed with brine (25 mL), dried (Na2SO 4 filtered, and concentrated onto CefiteTm. The material was purified by flash chromatography on silica gel (40 g) using 30% EtOAc/hexanes as eluent to afford 229 mg (99 of the sulfone as a tan solid. Data for 3 -bromophenyl(methyl)sulfone: 1 H~ NMR (400 MHz, CDCL3) 8. 10 J 1.6, 1 I),7.88 J 7.9, 1 7.79 J 8.0, 1 7.46 7.9, 1 3.07 3 M).

l* 2 -Dihydro-2.2.4-tri ~thl6-r3(MthUlsulfonyI henyqunle ICmon 454).'g This compound was prepared by a modification of General Method 2 as follows. A flask was charged with Compound 9 (123 mg, 0.388 mmol), the sulfone (83 mg, 0.353 mmol), Pd(OAc)2 (4 mg, 0.018 mmol), triphenylphosphine (18.5 mg, 0.071 mnmol), and K3P0 4 (112.4 mg, 0.530 mm-ol). The flask was flushed with N2 for 5 min and then 5 mL of DMF (anhydrous) was added. The resulting reaction m-ixture was heated to 1000'C for 15 h. The reaction was allowed to cool to rt and was quenched with H20 (20 mL). The aqueous layer was extracted with EtOAc (3x100 mL). The combined organics were washed with (3x50 mL) and brine (30 mL), dried (Na2SO 4 filtered and concentrated. The resulting material was dissolved in diniethylsulfide (0.5 and cooled to 00 C. This solution was treated with trifluoroacetic acid (0.5 mL) and allowed to stir at 00 C for 1h. The reaction was quenched with H20 (2 mL) followed by a slow addition of NaHCQ 3 (sat) until neutralized. The aqueous was extracted with EtOAc (2 x 30 mL). The combined organics were washed with brine (10 mL), dried (Na2SO 4 filtered and concentrated onto CeliteTM.

The material was purified by flash chromatography on silica gel (30 g) using EtOAc/hexanes as eluent to give 15 mg (12% overall) of Compound 454 as a fight yellow' film. Data for Compound 454: 1Hl NMR (400 MHz, acetone-d6) 8.08 J 1.8, 1 7.91 (dd, J 1.5, 1 7.78 (dd,J 1.6, 1 Ml, 7.64 J 1 7.39 J 1 7.33 (dd, 1 8.12.0, 1 6.61 J =8.l1, 1 5.43 (bs, 1 5.41 I 3.16 3 2.09 3 1.3 6 H).

EXAMPLE 355 6 -(3.Cyano-5.fluorophenvlI.- l 2 3 4 -Terhdo224iehlun~n Cmon 455. structure 5 of Scheme 1. where R =3-cano--Luoroahenyl) A 25 mL r.b. flask was charged with Compound 271 (EXAMVPLE 171) (145.0 mg, 0.50 mmol), ethyl acetate (I mL) and 10% Pd/C (10 mg). The flask was fitted with a septum and the system was flushed with nitrogen. A balloon filled with hydrogen gas was inserted into the reaction flask and the reaction was allowed to progress at rt for 2 h. The crude reaction midxture was filtered through a plug of CeliteTM. The crude mixture was purified by reverse phase semid-preparatory HPLC (70 methanol/water-with trace triethyl amine; retention time 29 min.) yielding 50.0 mg of Compound 455. Data for Compound 455: 1H NMR (400 MHz, acetone-d6) 7. 81 (dt, J 2.9, 1.5, 1 7.65 (ddt, J1= 8.9, 3.7, 2.3, 1 7.55 1 7.37 (dd, J=9.7, 1. 1, 1 7.32 (dd,J 1.2, 1 6.59

J

8.4, 1 5.25 (br s, I 2.95 (in, 1 1. 80 (ddd, J1= 8.0, 5.4, 1.5, 1 1.40 (mn, 4 H), 1. 25 3 1. 19 3 H).

EXAMPLE 356 (RIS')-9-Chloro-1.-i ro22'0 34 trctre42 of Scheme Xl. where R-phnv

R

1 H.R Cl) This compound was prepared by General Method 5 (Example 60) from Compound 209 mg, 0.230 minol) and phenyl magnesium bromide (1.84 mL, 1.84 minol) to afford 61 mg (68 of Compound 456 as a clear film. Data for Compound 456: IH NMR (400 MHz, acetone-d6) 7.58 J 2.3, 1 7.56 1 7.22 (mn, 4 7.19 (in, 1 6.94 (dd, J 2.5, 2 6.83 J 8.5, 1 6.76 J 8.5, 1 5.63 (br s, 1 5.46 J 1 1.98 3 1.26 3 1.24 3 H).

EXAMPLE 357 2 -dihydro-2,2.4.9..tetrainethvl..SH-thrnmentor3I- Iguiiolin Compndm 457, s ue4 of SceeXI. whee R=n-btl. IR={ R=methl).

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 316 (EXAMPLE 216) (44 mg, 0.14 inmol) and n-BuLi (2.5 M in hexanes, 0.30 mL, 0.75 minol, 5.2 equiv) to afford 12 mg of Compound 457 as a pale yellow glass. Data for Compound 457: 1 H NMR (400 MHz, acetone-d6): 7.48 1 7.45 J= 8.2, 1 H), 6.91 J 6.6, 1 6.76 J 8.0, 1 6.67 J 8.2, 1H), 5.80 (dd, J= 7.9, 3.3, 1 5.51 1 5.36 (br s, 1 2.81 3 2.78 3 1. 75 1 1.55-1.35 (m, 3 1.30-1.20 2 1.27 3 1.18 3 0.84 J 7.3, 3 H).

Steroid Receptor Activity Utilizing the "cis-trans" or "co-transfection" assay described by Evans et al., Science, 24Q:889-95 (May 13, 1988), the disclosure of which is herein incorporated by reference, the compounds of the present invention were tested and found to have strong, specific activity as both agonists, partial agonists and antagonists of PR, AR, ER, GR and MR. 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.

The co-transfection assay provides a method for identifying functional agonists and partial agonists which mimic, or antagonists which inhibit, the effect of native 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 cotransfection assay correlates very well with known in vivo activity, such that the cotransfection assay functions as a qualitative and quantitative predictor of a tested compoundsina v pharmacology. See, te., T. Berger et al. 41 J. Steroid Biochem. Molec.

JioL 773 (1992), the disclosure of which is herein incorporated by reference.

In the co-transfection assay, a cloned cDNA for an IR human PR, AR or GR) under the control of a constitutive promoter 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), 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.

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, 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 progesterone for PR) known to induce a defined reporter signal Increasing concentrations of a suspected antagonist will decrease the reporter signal 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.

The activity of selected steroid receptor modulator compounds of the present invention were evaluated utilizing the co-transfection assay, and in standard IR binding assays, according to the following illustrative Examples.

EXAMPLE 358 Co-transfection assay CV- I1 cells (African green monkey kidney fribroblasts) were cultured in the presence of Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% charcoal resinstripped fetal bovine serum then transferred to 96 -well microtiter plates one day prior to transfection.

To determine PR agonist and antagonist activity of the compounds of the present invention, the CV- 1 cells were transiently transfected by calcium phosphate coprecipitation according to the procedure of Berger et al., 41 J. Steroid Biochem. Mol. Biol., 733 (1992) with the following plasmids: pSVhPR-B (5 ng/well), MTV-LUC reporter (100 ng/well), pRS-8-Gal (50 ng/well) and filler DNA (pGEM; 45 ng/well). The receptor plasmid, pSVhPR-B, contains the human PR-B under constitutive control of the SV-40 promoter, and is more fully described in E. Vegeto et aL, "The mechanism of RU 486 antagonism is dependent on the conformation of the carboxy-terminal tail of the human progesterone receptor", 69 Cell, 703 (1992), the disclosure of which is herein incorporated by reference.

Similarly, the AR, ER, GR and MR agonist and antagonist activity of the compounds of the present invention were determined according to the same procedure described herein, except that the plasmids pRShAR, pRShER, pRShGR and pRShMR were substituted for the plasmid pSVhPR-B described above. Each of these plasmids are more fully described in J.A. Simental et al., 'Transcriptional activation and nuclear targeting signals of the human androgen receptor", 266 J. Biol. Chem., 510 (1991) (pRShAR), M.T. Tzukerman et aL, "Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions", 8 Mol.

Endocrinol., 21 (1994) (pRShER), V. Giguere et al., "Functional domains of the human glucocorticoid receptor", 46 Cell, 645 (1986) (pRShGR), and J.L. Arriza et al., "Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with glucocorticoid receptor", 237 Science, 268 (1987) (pRShMR), the disclosures of which are herein incorporated by reference.

The reporter plasmid, MTV-LUC, contains the cDNA for firefly luciferase

(LUC)

under control of the mouse mammary tumor virus (MTV) long terminal repeat, a conditional promoter containing a progesterone response element. This plasmid is more fully described in Berger et al spra. In addition, for ER agonist and antagonist determinations, the reporter plasmid MTV-ERE5-LUC, which contains LUC under control of the mouse mammary tumor virus (MTV) long terminal repeat in which the glucocorticoid response elements have been deleted and replaced with five copies of a 33-base pair ERE as described in Tzukerman et al., spra, was substituted for the MTV-LUC plasmid described herein. pRS-8-Gal, coding for constitutive expression of E. coli 8-galactosidase (8-Gal), was included as an internal control for evaluation of transfection efficiency and compound toxicity.

Six hours after transfection, media was removed and the cells were washed with phosphate-buffered saline (PBS). Media containing reference compounds (Le. progesterone as a PR agonist, mifepristone lbeta,17beta)-1 l-[ 4 -(dimethylamino)phenyl]-17-hydroxy- 1 7 -(l-propynyl)estra-4,9-dien-3-one: RU486; Roussel Uclaf) as a PR antagonist; dihydrotestosterone (DHT; Sigma Chemical) as an AR agonist and 2 -OH-flutamide (the active metabolite of 2 -methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]pronanamide; Schering- Plough) as an AR antagonist; estradiol (Sigma) as an ER agonist and ICI 164,384 (N-butyl- 3,1 7 -dihydroxy-N-methyl-(7-alpha,1 7 -beta)-estra-l,3,5(10)-triene-7-undecanamide;

ICI

Americas) as an ER antagonist; dexamethasone (Sigma) as a GR agonist and RU486 as a GR antagonist; and aldosterone (Sigma) as a MR agonist and spirolactone ((7-alpha- (acetylthio]-1 7 -alpha-hydroxy-3-oxopregn-4-ene-21-carboxylic acid gamma-lactone; Sigma) as an MR antagonist) and/or the modulator compounds of the present invention in concentrations ranging from 10-12 to 10-5 M were added to the cells. Three to four replicates were used for each sample. Transfections and subsequent procedures were performed on a Biomek 1000 automated laboratory work station.

After 40 hours, the cells were washed with PBS, lysed with a Triton X-100-based buffer and assayed for LUC and B-Gal activities using a luminometer or spectrophotometer, respectively. For each replicate, the normalized response (NR) was calculated as: LUC response/B-Gal rate where B-Gal rate B-Gal*1xl0-5/8-Gal incubation time.

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 PR, AR, ER, GR or MR. Antagonist activity was determined by testing the amount of LUC expression in the presence of a fixed amount of progesterone as a PR agonist, DHT as an AR agonist, estradiol as an ER agonist, dexamethasone as a GR agonist, or aldosterone as an MR 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.

320 IR Binding assay PR and GR Binding: In addition, the binding of the compounds of the present invention to the steroid receptors was also investigated according to the following methodology for PR and GR. PR and GR proteins were prepared from Baculovirus extracts by incorporating the appropriate cDNAs for human progesterone receptor A form (PR-A; P.

Kastner et al., 9 EMBO, 1603 (1990), the disclosure of which is herein incorporated by reference) and human glucocorticoid receptor alpha (GRa) into appropriate baculovirus the expression plasmids as described in E.A. Allegretto et al., 268 J. Biol. Chem., 26625 (1993); G. Srinivasan and B. Thompson, 4 Mol. 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, NY, pp. 139-179 (1992), the disclosures of which are herein incorporated by reference.

Assay buffers consisted of the following: PR, 10% glycerol, 10 mM Tris, 1 mM EDTA, 12 mM monothioglycerol (MTG) and ImM PMSF, pH 7.5 40C; GR, 10% glycerol, mM sodium phosphate, 10 mM KF, 2mM DTT, 0.25 mM CHAPS, and 20 mM sodium molybdate, pH The PR and GR steroid receptor binding assays were performed in the same manner.

The final assay volume was 500 pL for PR and 250 ptL for GR, and contained -5 gg of extract protein for PR and -50 mg for GR, as well as 2-4 nM of the appropriate 3 H] steroid [3H] progesterone and [3H] dexamethasone, respectively) and varying concentrations of competing ligand at concentrations that ranged from 0 10-5 M. Incubations were carried out at 4 0 C for 16 hours.

Non-specific binding was defined as that binding remaining in the presence of 500 nM of the appropriate unlabelled steroid. At the end of the incubation period, bound from free ligand were separated by either charcoal (PR) or hydroxylapatite The amount of bound tritiated hormone was determined by liquid scintillation counting of an aliquot (700 mL) of the supernatant fluid or the hydroxylapatite pellet.

AR Bindinf: For the whole cell binding assay, COS- 1 cells in 9 6-well microtiter plates containing DMEM-10% FBS were transfected as described above with the following plasmid DNA: pRShAR (2 ng/well), pRS-6-Gal (50 ng/well) and pGEM (48 ng/well). Six hours after transfection, media was removed, the cells were washed with PBS and fresh media was added. The next day, the media was changed to DMEM-serum free to remove any endogenous ligand that might be complexed with the receptor in the cells.

After 24 hours in serum-free media, either a saturation analysis to determine the Kd for tritiated dihydrotestosterone 3 H-DHT) on human AR or a competitive binding assay to evaluate the ability of test compounds to compete with 3 H-DHT for AR was performed.

For the saturation analysis, media (DMEM-0.2% CA-FBS) containing 3 H-DHT (in concentrations ranging from 12 nM to 0.24 nM) in the absence (total binding) or presence (non-specific binding) of a 100-fold molar excess of unlabeled DHT were added to the cells. For the competitive binding assay, media containing 1 nM 3 H-DHT and test compounds in concentrations ranging from 10-10 to 10-6 M were added to the cells. Three replicates were used for each sample. After three hours at 37 0 C, an aliquot of the total binding media at each concentration of 3 H-DHT was removed to estimate the amount of free 3 H-DHT. The remaining media was removed, the cells were washed three times with PBS to remove unbound ligand, and cells were lysed with a Triton X-100-based buffer. The lysates were assayed for amount of bound 3 H-DHT and B-Gal activity using a scintillation counter or spectrophotometer, respectively.

For the saturation analyses, the difference between the total binding and the nonspecific binding, normalized by the 8-Gal rate, was defined as specific binding. The specific binding was evaluated by Scatchard analysis to determine the Kd for 3 H-DHT.. See eg., D. Rodbard, "Mathematics and statistics of ligand assays: an illustrated guide" In: J.

Langon and JJ. Clapp, eds., Ligand Assay, Masson Publishing Inc., New York, pp.

45-99, (1981), the disclosure of which is herein incorporated by reference. For the competition studies, the data was plotted as the amount of 3 H-DHT of control in the absence of test compound) remaining over the range of the dose-response curve for a given compound. The concentration of test compound that inhibited 50% of the amount of 3

H-

DHT bound in the absence of competing ligand was quantified (IC50) after log-logit transformation. The Ki values were determined by application of the Cheng-Prusoff equation to the IC 5 0 values, where: Ki 3 H-DHT])/Kd for 3

H-DHT

To date, binding assays have not been performed utilizing ER or MR proteins.

After correcting for non-specific binding, IC50 values were determined. The value is defined as the concentration of competing ligand needed to reduce specific binding by 50%. The IC50 value was determined graphically from a log-logit plot of the data. The Ki values were determined by application of the Cheng-Prusoff equation to the IC50 values, the labeled ligand concentration and the Kd of the labeled ligand.

The agonist, antagonist and binding activity assay results of selected steroid receptor modulator compounds of present invention and the standard reference compounds on PR, AR, ER, GR and MR, as well as the cross-reactivity of selected compounds on all of these receptors, are shown in Tables 1-5 below. Efficacy is reported as the percent maximal response observed for each compound relative to the reference agonist and antagonist compounds indicated above. Also reported in Tables 1-5 for each compound is its antagonist potency or ICso (which is the concentration required to reduce the maximal response by its agonist potency or ECso PR, AR and GR protein binding activity (KI in nM) is shown in Tables 1-2 and 4.

Table 1: Agonist, antagonist and binding activity of selected steroid receptor modulator compounds of present invention and the reference agonist compound, Progesterone (Prog), and reference antagonist compound, mifepristone (RU486), on PR.

PR Agonist PR Antagonist

PR

Cm d CV-1 Cells CV-1 Cells Bindin Efficacy Potency Efficacy Potency

K,

N o (nM (nM) (nM) 103 na na 91 780 372 104 39 2,750 71 120 82 109 na na 87 138 23 116 nt nt 85 549_9 38 117 na na 68 462 na 124 74 1,600 36 10 4 126 124 2,400 58 145 11 132 22 6,400- 76 80 31 150 24 3,200 91 24 17 152 na na 82 130-- 53 161 47 203 75 209- 3 163 77 15 45 3,617"- 1 PR Agonist PR Antagonist

PR

Cmpd CV-1 Cells CV-1 Cells Binding Efficacy Potency Efficacy Potency Ki No. (nM) (nM) (nM) 191 26 9 74 150 1 195 89 13 na na 3 210 72 16 na na 3 220 147 33 na na 1 221 105 117 na na 4 228 114 40 na na 3 271 na na 78 32 286 na na 84 155 61 291 na na 79 46 4 310 na na 70 260 7 313 26 300 94 140 87 328 86 2200 65 26 7 331 na na 88 210 273 332 138 3 na na 0.4 368 183 43 na na 4 374 231 4 na na 377 101 550 na na 379 na na 87 350 381 81 58 na na 18 385 27 82 45 2300 31 389 133 17 na na 4 391 na na 65 120 187 400 na na 68 370 14 401 43 600 na na 150 452 119 2400 70 24 17 455 na na 76 35 Prog 100 4 na na 3 RU486 na na 96 0.1 0.8 na not active efficacy of <20 and potency of >10,000) nt not tested Table 2: Agonist, antagonist and binding activity of selected steroid receptor modulator compounds of present invention and the reference agonist compound, dihydrotestosterone (DHT), and reference antagonist compound, 2-hydroxyflutamide (Flut), on AR.

na not active efficacy of <20 and potency of >10,000) profiles as an AR antagonist in vivo Table 3: Agonist, antagonist and binding activity of selected steroid receptor modulator compounds of present invention and the reference agonist compound, Estrogen (Estr), and reference antagonist compound,

ICI

164,384 (ICI 164), on ER.

ER Agonist ER Antagonist Cmpd CV-1 Cells CV-. Cells Efficacy Potency Efficacy Potency No. (nM) nM 161 nt nt 86 505 170 nt nt 78 580 191 nt nt 93 330 192 na na 80 195 194 nt nt 94 390 195 90 1900 68 4406 Estr 100 7 na na ICI 164 na na 99 43 na not active efficacy of <20 and potency of >10,000) nt not tested [rest of page left purposely blank] 326 Table 4: Antagonist and binding activity of selected steroid receptor modulator compounds of present invention and the reference antagonist compounds, RU486 and Spironolactone (Spir), on GR and MR, respectively.

GR Antagonist MR Antagonist Cmnpd CV-1 Cells CVI Cells Efficacy Potency Efficacy Potency No. (nM) I(nM) 161 97 600 58 1000 167 96 855 61 2000- 170 94 1550 84 410 192 81 280 70 132 195 96 590 47 1900 R _48 100 1 77 1100 Spir 80 2000 96 250 nt not tested

GR

Bindine

K,

(nM) 137 21 47 214 26 -0.4 nt Table 5: Overall agonist and antagonist potency of selected steroid receptor modulator compounds of present invention and the reference agonist and antagonist compounds shown in Tables 1-4 on PR, AR, ER, GR and MR.

Cmpd PR Potency AR Potncy Agon Antag Agon Antag No. (nM) (nM) (nM) 12 -100 10 nt 1500 150 3200 24 nt 140 163 15 3617 -nt 1550 170 73 145 nt 290 191 9 150- nt 520 192 na 8-9 nt 79 195 1 13 na nt 470 255 na 3050 na 25 IC g 16 4n na na00 na Sir nt 268 ER Poenc Agon Antag nt na na 2150 nt 580 nt 330 nt 19 1900 4406 na na nt nt na na na 1500 1700 na na na 7 na na 160 na n GR MR Potency Potency Antag Antag (nM1L (nM) na na 2700 1900 1330 1450 1550 410 nt nt 280 320 590 1900 na na -nt nt na nt 0.7 1100 na nt na na na Nt na na 2000O na=not active efficacy of 20 and potency of >10,000) nt=not tested As can be seen in the Tables, Compounds 163, 191, 332 and 374 are highly selective PR agonists, while Compounds 124, 150, 328 and 455 are highly selective PR antagonists.

Importantly, these PR antagonist Compounds show very little or no cross reactivity on GR, or any of the other tested steroid receptors. In contrast, the known PR antagonist, RU486, shows strong cross reactivity on both GR and AR, showing essentially equal potency as both a PR and GR antagonist. Thus RU486 may not be generally useful for long-term, chronic administration due to this undesirable GR cross reactivity. Furthermore, Compounds 255, 260, 417 and 437 of the present invention shown equal or better activity as AR antagonists than the known antagonist compound 2 -OH-flutamide.

EXAMPLE 359 The effectiveness of selected compounds of the present invention as PR agonists was investigated in the well recognized uterine wet weight assay, as described in G.J.

Marcus, "Mitosis in the rat uterus during the estrous cycle, early pregnancy and early pseudopregnancy", 10 Biol. Reprod., 447 (1974), S. Sakamoto et al., "Effects of estrogen and progesterone on thymidine kinase activity in the immature rat uterus", 145 Am. J.

Obstet. Gynecol., 711 (1983), and C.W. Emmens and R.I. Dorfman, "Estrogens" (Ch. 2) and "Antiestrogens" (Ch. in Methods in Hormone Research, ed. R.I. Dorfman, Academic Press, New York, New York, ppll01-130 (1969), the disclosures of which are herein incorporated by reference. Four to five week old, ovariectomized, Sprague-Dawely rats (Harlan-Sprague-Dawely, Indianapolis, IN) were obtained 1 week after surgery and allowed to acclimate for an additional week after shipment. Compound 163, Compound 210, medroxyprogesterone acetate (MPA) (Sigma, St. Louis, MO) a synthetic progesterone agonist, and estrone (El) (Sigma, St. Louis, MO) a synthetic estrogen agonist, were fully dissolved in purified sesame oil (Croda, Parsippany,NJ). Animals were randomized into treatment groups (4 rats/group) and administered Compound 163, Compound 210, or MPA 1.0 or 3.0 mg/rat, 0.5 mL volumes, oral, once a day for three days in the presence of estrone (10 pg/day, subcutaneous). Additional control groups of rats were administered estrone or vehicle (Le. sesame oil) alone. Animals were sacrificed on the fourth day of the experiment. Upon necropsy, uterine wet weights were obtained, and are reported in Table 6 below.

Table 6: Mean uterine wet weights in presence of estrone (10 gg), MPA, a recognized PR agonist, and Compounds 163 and 210 of the present invention.

Group Control 1 2 3 4 6 7 8 El MPA Cmpd 163 El (U0

MPA

(mg) Cmpd 163

(MLY)

mi)( none 10 10 10 10 10 10 10 10 none none 0.3 1.0 3.0 none none none none none none none none none 3.0 none none none Cmpd 210 Mean Uterine (mg) Wet Weight (mg) none none 205 none 140 none 130 none 130 none 125 0.3 110 1.0 100 3.0 100 As can be seen in Table 6, estrone alone increased uterine wet weight 4-fold over control treated animals. MPA co-administered with estrone significantly decreased the uterine wet weight at doses of 0.3 mg, 1.0 mg, and 3.0 mg/rat. Compound 163 at a dosage of 3 mg/rat, decreased by approximately half, the mean uterine wet weight, as did Compound 210 at doses of 0.3 mg, 1.0 mg, and 3.0 mg/rat.

EXAMPLE 360 The activity of Compound 150 of the present invention as a PR antagonist was measured via an implantation assay, a recognized test of antiprogestin activity, as described in F.H.Bronson, et al., "Reproduction", In Biology of the Laboratory Mouse, 2nd ed., pp 329 187-204, McGraw Hill, New York, NY (1966), the disclosure of which is herein incorporated by reference. Virgin female mice (ICR strain) were caged with fertile males of the same strain overnight and examined the next morning for vaginal plugs (Day 1 of pregnancy). Mating was assumed to have taken place at 02.00 h, time 0.

The animals were treated orally with a known amount of the antiprogestin, mifepristone (RU486) or Compound 150 daily between days 2 and 4 of pregnancy.

Compound 150 was dissolved in sesame oil (50 mg/mL) and kept at room temperature before use. RU486 was first dissolved in 100% ethanol and diluted to a concentration of mg/mL with sesame oil. Control animals received an equivalent volume of the control vehicle, sesame oil, alone.

The animals were sacrificed, and autopsies were carried out at Day 8 of pregnancy, and numbers of implantation sites counted and recorded, and are shown in Table 7 below.

Each group consisted of between 5 and 7 animals.

Table 7: Percent pregnancy rate in mice in the presence of RU486 (mifepristone) a recognized PR antagonist, and Compound 150 of the present invention.

RU486 Cmpd 150 Percent GroupL (mg/day) (m g/da) Pregnancy Rate Control none none I00 1 1.0 none 0 2 none 2.5 3 none 5.0 0 As can be seen from Table 7, the control group of mice exhibited a pregnancy rate of one hundred. Administration of 1.0 mg/day of RU486 resulted in a pregnancy rate of zero, while administration of Compound 150 at 2.5 mg/day and 5.0 mg/day resulted in pregnancy rates of 50 and 0, respectively. In addition, the above noted effect on pregnancy rate of Compound 150 was reversed to the control level by the simultaneous injection of the known PR agonist Compound R5020 (promegestone; (17! 3 )-17-methyl-17-(l-oxopropyl) estra-4,9dien-3-one; New England Nuclear, Boston, MA) at a dose of 1.0 mg per day.

EXAMPLE 361 The activity of selected compounds of the present invention as AR antagonists was investigated in an immature castrated male rat model, a recognized test of the antiandrogen activity of a given compound, as described in L.G. Hershberger et al., 83 Proc. Soc. Exptl.

Biol. Med., 175 (1953); P.C. Walsh and R.F. Gittes, "Inhibition of extratesticular stimuli to prostatic growth in the castrated rat by antiandrogens", 86 Endocrinology, 624 (1970); and BJ. Furr et al., "ICI 176,334: A novel non-steroidal, peripherally selective antiandrogen", 113 J. Endocrinol., R7-9 (1987), the disclosures of which are herein incorporated by reference.

The basis of this assay is the fact that the male sexual accessory organs, such as the prostate and seminal vesicles, play an important role in reproductive function. These glands are stimulated to grow and are maintained in size and secretory function by the continued presence of serum testosterone which is the major serum androgen produced by the Leydig cells in the testis under the control of the pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH). Testosterone is converted to the more active form, dihydrotestosterone (DHT), within the prostate by 5ac-reductase. Adrenal androgens also contribute about 20% of total DHT in the rat prostate, and about 40% of that in 6 5 -year-old men. F. Labrie et al. 16 Clin. Invest. Med., 475-492 (1993). However, this is not a major pathway, since in both animals and humans, castration leads to almost complete involution of the prostate and seminal vesicles without concomitant adrenalectomy. Therefore, under normal conditions, the adrenals do not support significant growth of prostatic tissue. M.C.

Luke and D.S. Coffey, "The Physiology of Reproduction" ed. by E. Knobil and J.D. Neill, 1, 1435-1487 (1994). Since the male sex organs are the tissues most responsive to modulation of androgen activity, this model is used to determine the androgen-dependent growth of the sex accessory organs in immature castrated rats.

Male immature rats (60-70 g, 23 -25-day-old, Sprague-Dawley, Harlan) were castrated under metofane anesthesia. Five days after surgery, animals groups were dosed for 3 days as follows: control vehicle Testosterone Propionate (TP)(0.1 mg/rat/day, sub cutaneous) TP plus flutamide, a recognized antiandrogen, as a reference 331 compound, and/or a compound of the present invention (different doses, oral administration, daily) to demonstrate antagonist activity, or a compound of the present invention alone (different doses, oral administration daily) to demonstrate agonist activity At the end of the 3-day treatment, the animals were sacrificed, and the ventral prostates (VP) and seminal vesicles (SV) were collected and weighed. To compare data from different experiments, the sexual organ weights were first standardized as mg per 100 g of body weight, and the increase in organ weight induced by TP was considered as the maximum increase Super-anova (one factor) was used for statistical analysis.

The gain and loss of sexual organ weights reflect the changes of cell number (DNA content) and cell mass (protein content), depending upon the serum androgen concentration.

See Y. Okuda et aL, 145 J Urol., 188-191 (1991), the disclosure of which is herein incorporated by reference.. Therefore, measurement of organ wet weights is sufficient to indicate the bioactivity of androgens and androgen antagonists. In immature castrated rats, replacement of exogenous androgens increased the weights of the ventral prostate (VP) and the seminal vesicles (SV) in a dose-dependent manner as shown in Table 8.

Table 8: TP-Induced Ventral Prostate and Seminal Vesicle Growth in castrated immature rats, with oral dosing once daily, for 3 days.

Treatment VP %VP SV

%SV

(mg TP) (wet wt) growth (wet wt) growth 0 10.5±1.0 100 7.5±0.6 100 0.01 15.4±0.6 146.5 12.3±0.8 165.1 0.03 23.5±1.3 224.1 27.5±0.8 369.5 0.1 35.3±2.1 337.0 42.0±2.0 563.8 0.3 43.6±1.1 415.9 45.9±1.9 616.1 1 44.8±3.7 427.4 51.0±5.4 684.6 The maximum increase in organ wet weights was 4 to 5-fold when dosing 3 mg/rat/day of testosterone or I mg/rat/day of testosterone propionate (TP) for 3 days.

332 The EC50 of T and TP were about I mg and 0.03 mg, respectively. The increase in the weights of VP and SV also correlated with the increase in the serum T and DHT concentrations. Although administration of T showed 5-times higher serum concentrations of T and DHT at 2 hours after subcutaneous injection than that of TP, thereafter, these high levels declined very rapidly. In contrast, the serum concentrations of T and DHT in TPtreated animals were fairly consistent during the 24 hours, and therefore, TP showed about 10-30-fold higher potency than free T.

In this immature castrated rat model, a known AR antagonist (flutamide) was also administered simultaneously with 0.1 mg of TP (ED80), inhibiting the testosteronemediated increases in the weights of VP and SV in a dose-dependent manner as shown in Table 9. The antagonist effects were similar when dosing orally or subcutaneously.

Compounds 255 and 261 also exhibited AR antagonist activity by suppressing the testosterone-mediated increases in the weights of the VP and SV, as summarized in Table 9.

Table 9: Inhibition of TP-InducedVentral Prostate and Seminal Vesicle Growth in castrated immature rats at oral dosing, once daily, for 3 days of flutamide (flut), Compound 255 or Compound 261.

VP wt SV wt VP of TP SV of TP Treatment (wet wt) control) (wet wt) control) Control 9.8±1.2 36.2 9.9±0.9 21.7 TP 25.5±1.2 100 33.6±4.0 100 TP+ flut 12.4±1.1 49.9 8.5±0.6 30.3 TP+ flut 9.5 ±0.4 37.4 9.8±0.5 29.3 TP+ 255 22.1±0.7 86.4 29.8±2.5 88.7 TP+ 255 20.0±4.5 78.2 24.8±9.0 73.9 TP+ 255 17.3±1.2 67.7 20.4±1.2 60.6 TP+ 261 21.011.7 84.4 23.8±1.8 85.0 TP+ 261 16.7±1.0 67.1 20.8±1.3 74.2 Pharmacological and Other Applications As will be discernible to those skilled in the art, the non-steroid modulator compounds of the present invention can be readily utilized in pharmacological applications where PR, AR, ER, GR and/or MR antagonist or agonist activity is desired, and where it is desired to minimize cross reactivities with other steroid receptor related IRs. In vivo applications of the invention include administration of the disclosed compounds to mammalian subjects, and in particular to humans.

The following Example provides illustrative pharmaceutical composition formulations: EXAMPLE 362 Hard gelatin capsules are prepared using the following ingredients: Quantity (me/caPsule) COMPOUND 191 140 Starch, dried 100 Magnesium stearate I0 Total 250 mg The above ingredients are mixed and filled into hard gelatin capsules in 250 mg quantities.

A tablet is prepared using the ingredients below: Quantity (mv/tablet) COMPOUND 191 140 Cellulose, microcrystalline 200 Silicon dioxide, fumed Stearic acid I0 Total 360 mg The components are blended and compressed to form tablets each weighing 665 mg.

Tablets, each containing 60 mg of active ingredient, are made as follows: Quantity COMPOUND 191 Starch Cellulose, microcrystalline 3545 Polyvinylpyrrolidone

(PVP)

(as 10% solution in water) 4 Sodium carboxymethyl starch (SCMS) Magnesium stearate Talc 0 Total 150 mg The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S.

sieve and mixed thoroughly. The solution of PVP is mixed with the resultant powders, which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 500 C and passed through a No. 18 mesh U.S. sieve. The SCMS, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, and then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

Suppositories, each containing 225 mg of active ingredient, may be made as follows: COMPOUND 191 225 mg Saturated fatty acid glycerides 2.000 mg Total 2,225 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary.

The mixture is then poured into a suppository mold of normal 2g capacity and allowed to cool.

An intravenous formulation may be prepared as follows: COMPOUND 191 l0mg Isotohic saline 1,000 mL Glycerol 100 mL The compound is dissolved in the glycerol and then the solution is slowly diluted with isotonic saline. The solution of the above ingredients is then administered intravenously at a rate of I mL per minute to a patient.

335 While in accordance with the patent statutes, description of the preferred embodiments and processing conditions have been provided, the scope of the invention is not to be limited thereto or thereby. Various modifications and alterations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention.

Consequently, for an understanding of the scope of the present invention, reference is made to the following claims.

Claims

2. A compound according to claim 1, wherein the compounds of formulae I through XVIII comprise steroid receptor modulator compounds.
3. A compound according to claim 2, wherein the compounds of formulae I, II, III, IV, X and XI comprise PR antagonists.
4. A compound according to claim 2, wherein the compounds of formulae V and VI comprise PR modulators. A compound according to claim 2, wherein the compounds of formulae VII, VIII, XII, XIII, XIV, XV and XVI comprise PR agonists.
6. A compound according to claim 2, wherein the compounds of formulae IX, XVII and XVII comprise AR modulators.
7. A compound according to claim 6, wherein the compounds of formulae IX and XVII comprise AR antagonists.
8. A PR antagonist compound according to claim 3 selected from the group consisting of 1,2,3,4-Tetrahydro-2,2,4-timethyl-6-phenylquinoline (Compound 100); 1,2- Dihydro-2,2,4-trimethyl-6-(1, 2 3 -thiadiazol-5-yl)quinoline (Compound 101); 1,2-Dihydro- 2 2 ,4-trimethyl-6-(1, 3 -oxazol-5-yl)quinoline (Compound 102); 6 4 ,5-Dichloroimidazol- 1- yl)-1,2-dihydro-2,2,4-trimnethylquinoine (Compound 103); 6-(4-Bromo- 1 -methylpyrazol-3- yl)-1, 2 -dihydro-2,2,4-rimethylquinoline (Compound 104); 1,2-Dihydro-2,2,4-uimethyl-6-(3- pyridyl)quinoline (Compound 105); 6 4 -Fluorophenyl)-1, 2 -dihydro-2,2,4-trimethylquinoline (Compound 106); 1,2-Dihydro-6-(3-trifluoromethylphenyl)-2,2,4-timethylquinoline (Compound 107); 1,2-Dihydro-2,2,4-trimethyl-6-(4-nitrophenyl)quinoline (Compound 108); 6 2 3 -Dichlorophenyl)- 1, 2 -dihydro-2,2,4-trimethylquinoline (Compound 109); 1,2-Dihydro- 6-( 2 -hydroxycarbonyl-4-nitrophenyl)-2,2,4-timethylquinoline (Compound I10); 6-(3,4- Dichlorophenyl)- 1, 2 -dihydro-2,2,4-triethylquinoline (Compound 111); 4-Ethyl-1,2- dihydro-2,2-dimethyl-6-phenylquinoline (Compound 112); 1, 2 -Dihydro-2,2-dimethyl-6- phenyl-4-propylquinoline (Compound 113); 6-(2-Chlorophenyl)-1,2-dihydro-2,2,4- trimethyiquino lne (Compound 114); 6 3 ,S-Difluoropheny). 1 2 3 4 -tetrahydro22,4 trimethylquinoline (Compound 143); 6 3 -Chlorophenyl). I,2-dihydro-2,2,4- trimethyiquinoline (Compound 146); 6 3 ,5-Difluorophenyly 1 ,2-dihydro-2,2,4- tfrmethylqupnoh~ (Compound 147); 6 3 -Fluorophenyl). I,2-dilhydro-2,2,4 trinmethylquinoline (Compound 148); 1,-iyr-,,-rmtyl6(-yiy~unln (Compound 149); 6 3 -Cyanophenyl). l 2 -dihydro-2,2,4- iethylquin~oline (Compound 150; 6(3,-Dihloopeny)-12-dhydo-22,-tiethlqunolne(Compound 151); 6-(2,3- Difluorophenyl). l, 2 -dihydro..2,2,4trijthylqunoline (Compound 152); 1 ,2-Dihydro-2,2,4- trimnethyI.. 6 -(pentafluorophenl)quinolin (Compound 153); 1,2-Dihydro-2,2,4-timthy.6- 4 (trifluoroacetyl)pheny1]quinoin (Compound 154); 1, 2 -Dihydro-2,2,4.trimethy16-(1,3- (Compound 155); 6 3 -Cyanophenyl). I 2 3 4 -tetrahycdro.224. tnmethylquino line (Compound 156); 5,8-Difluoro.1 2 -dihydro-2,2,4-.tr1thylindeno [1,2- giquinoline (Compound 157); 7, lO-Difluoro- 2 -dihydro..2,2,4..trimthyideno[2,1- flquinoline (Compound 158); 8-Cyano-1,-iyr-,,-rrehyidn[,-~unln (Compound 270); 6 3 -Cyano-5-fluorophenyl). l 2 -dihydro..2,2,4trirmthylquinoline (Compound 271); 6 3 -Cyano-4-fluorophenyl). dhdr-,,-tntyqunln (Compound 272); 6 3 -Cyano-6-fluorophenyl). dhyr-,24timtyqunln (Compound 273); 6 -[5-fluoro-3..(trifluoromethyl)phenyll I ,2-dihydro-2,2,4- trimnethyiquinoline (Compound 274); 6 3 -chloro-2.metlylphenyl). I,2-dihydro-2,2,4- trmthylquinoline (Compound 275); 1,-iyr-,,-rmhl6(-irpey~unln (Compound 276); 6-(3-Acetylphenyl)-1,l2 -dihydro-2,2,4- ithylquino~ne (Compound 277); 6 3 -cyano-2-miethylphenyl). l 2 -dihydro-2,2,4iPthyquinioiie (Compound 278); 1,-iyr-,,-rmty--3mtypey~un~n (Compound 279); 6 -(5-Fluoro-3- nutrophenyl)- 1,-iyr-,,-rmhlunln (Compound 280); 1 ,2-Dihydro-6-(3. rmthoxyphenyl).2,2,4-triethylquijfl]jf (Compound 28 6 -(5-Cyano-3-py-idyl)- 1,2- dihydro..2,2,4-trinithyqunojjjne (Compound 282); l, 2 -Dihydro2,2,4ti~thy16-(2-n.thyI- 3 -nitrophenyl)quinoline (Compound 283); 6 2 -Arrino-35-difluorophenyl) I ,2-dihydro- 2,,-imthiunln (Compound 284); 6 3 -Bromo..2.chloro5fluorophenyl)- 1,2- dihydro-2,2,4-trinithyquinoine (Compound 285); 6 3 -Cyano-5-fluorophenyl) I ,2-dihycfro- 2 2 4 -ftrinethy1-3..quinolone (Compound 286); 6 3 -Fluoro.2methylphenyl) I ,2-dihydro- 2 2 4 -trimnethylquinofine (Compound 287); l, 2 -Dihydro-2,2,4tpiethy16-(3. methylthiophenyl)qunofine (Compound 288); 6 -(5-Chloro-2-tiienyly. I,2-dihydro-2,2,4. trimethyiquinoline (Compound 289); 1, 2 -Dihydro-2,2,4-Jnthy6(3.methy-2- thienyl)quino line (Compound 290); 8-Fluoro- l, 2 -dihydro2,2,4.timethyl-6(3. nitrophenyl)quinoline (Compound 291); l? 2 -Dihydro-6-(3..nitrophenyl)..2,2, 4 8 tetramethyiquinoline (Compound 292); 6 -(5-Bromo-3-pyidyl). I,2-dihydro-2,2,4- trimethyiquinoline (Compound 293); 6 -(3-Bromfo-2-pyridyl) I ,2-dihydro-2,2,4. timethyiquino line (Compound 294); 6 -(3-Bromo-2-thienyl) I ,2-dihydro-2,2,4- trimethylquinoline (Compound 295); I, 2 -Dihydro6(2,3,5,6.tetrafuoro4.py!idy) 2 2 4 trimethylquinoline (Compound 296); 5,8-Difluoro- l, 2 -dihydro-6-(3-nitrophenyl)..2,2,4. trimethyiquinoline (Compound 297); 2 4 -Diethyl-8-fluoro. I,2-dihydro-2-methy..6(3-. nitrophenyl)quinoline (Compound 298); 6 3 -Bromophenyl) I ,2-dihydro-2,2,4- trimthyiquinollne (Compound 299); 1,-iyr-,,-rity--5nto2 thienyl)quinoline (Compound 300); 1,-iyr--245trfurpey)224 trimethylquinoline (Compound 301); 6 3 -Bromo-5-fluorophenyl).1 ,2-dihydro-2,2,4- trimethyiquinoline (Compound 302); 6 -(5-Carboxaldehyde.3thienyl) 1 ,2-dihydro-2,2,4- trimethyiquinoline (Compound 303); lP 2 -Dihydro-2,2,4,7-tetamthy..6(3. nitrophenyl)quinoline (Compound 304); 6 -(5-Fluoro-2-methoxy3-nIitropheny) I ,2-dihydro- 2 2 4 -ftimethylquinoline (Compound 305); 6 3 -Chloro-2-miethoxyphenyl) 1 ,2-dihydro- 2 2 4 -trimethylquinoline (Compound 306); l,2-Dihydro-2,2,4htyl- 6 2 3 4 trifluorophenyl)quinoline (Compound 307); 6 3 -Brorm-2-methylphenyl).1 ,2-dihydro-2,2,4- trimethylquinoline (Compound 308); 7-Chioro- 1 2-dihydro-2,2,4ithy6(3- nitrophenyl)quinoline (Compound 309); 5-Chloro- l, 2 -dihydro-2,2,4-hgnmthy6.(3. nitrophenyl)quino line (Compound 310); 8-Chloro- l, 2 -dihydro-2,2,4..tri.ethyI.6-(3. nitrophenyl)quinoline (Compound 311); 8-Ethyl- l,2-dihydro2,2,4hnithy16-(3. nitrophenyl)quinoline (Compound 312); 9-Chioro- l, 2 -dihydro-2,2-dirmthyl-5. coumarino[3,4-fAqujinoline (Compound 313); lt 2 -Dihydro9-mthoxy22,4-triethyl1S coumanino[3,4-]quinolie (Compound 314); 9-Fluoro- I ,2-dihydro-2,2,4, I1 coumarino[3,4-jlquinoline (Compound 315); l, 2 -Dihydro-2,2,4,9-tetramethy15- coumarino[3,4-Aquinoline (Compound 316); 7-Chloro- l, 2 -dihydro-2,2,4-trimethyl.5. coumarino[3,4-f]quinoline (Compound 317); (R/S}.9-Chloro-1, 2-dihydro-5-methoxy-2,2,4. triinethyl-SII -chromfeno[3,4-flquinoline (Compound 319); (R/S)-9-Fluoro. I,2,-dihydro- 2 2 4 -trimthyl-SH-chromeno 3 4 -fjquinoline (Compound 328); 6 -(5-Cyano-2-thienyl)-.1,2- dihydro-2,2,4..trimnethylquinoline (Compound 45 6 -(5-Cyano-3-thienyl)- I ,2-dihydro-2,2,4. trimerhylquinoline (Compound 452); 6 3 -Formylphenyl)- 1,2-dihydro-2,2,4. trimethyiquinoline (Compound 453); 1 2 -Dihydro-2,2,4-rimthyl643. (miethylsulfonyl)phenyllquinoline (Compound 454); (R/S)-6-(3-Cyano-5-fluoropheny). l, 2 3 4 -Tetrahydro-2,2,4-timethylquiotine (Compound 455) and (RIS)-9-Chloro- 1,2- (Compound 456).
9. A PR modulator compound according to claim 4 selected from the group consisting of (R/S)-5-Butyl-1,-iyr-,,-tiehl5-hoen[,-lunln (Compound 160); (Compound 161); (RIS)-1,,,-erhdo22dnehy--ityiee5pey-H chromeno[3,4-Ilquinoline (Compound 162); (R/S)-5-(4-Chlorophenyl). 1 ,2-dihydro-2,2,4- trimethyl-5H-chromeno[3,4.fquinoline (C 'ompound 163); (R/S)-5-(4-Chlorophenyly. 1,2,3,4- terhdo22dmty--ehldee5-honn[,-~unln (Compound 164); (R/S)-5-(4-Fluorophenyl). (Compound 165); (R/S)-5-(4-Acetylphenyl). l 2 -dihydro-2,2,4ifethyI5-chromno[3,4 I]quinoline (Compound 166); (RIS)- lI 2 -Dihydro-2,2,4tnethy-5-(4-metylphenyl)-5H- chromeno[3,4-f~quinoline (Compound 167); (RIS)- 1 2 -Dihydro.5-(4-methoxyphenyl)..224 trimthyI-5H-chromeno[3,4ifquinoine (Compound 168); (RIS)- 1,2-Dihydro-2,2,4- (Compound 169); (RIS)- l, 2 -Dihydro- 2 ,2,4-triffethy15-(tiophen3-y1>5H..chr.omeno[3,4-]quinoijne (Compound 170); (-)-1,-iyr-,,-rmehl5(-fehlhey)5-hoeo34 ]]quinoline (Compound 171); (-)-5-(4-Chlorophenyl)- l, 2 -dihydro-2,2,4-trimethyl.5H. chromeno[3,4-flquinoljne (Compound 172); (RIS)-1I, 2 -Dihydro-2,2,4-njnethy15..(3- mehlhnl-Hcroeo34Aunln (Comound 173); Chiorophenyl)-1,,,-etayr-224 nethyl-5f-Ichromeno[34fquinolie (Compound 174); 51)-5-(4-Chlorophenyl)-1,,,- rhdo-,,-iehl5Hcroeo34 flquinoiine (Compound 175); (R/S- 4 ,Su)-5-(4-Chloropheny1)-1,2,3 ,4-tetrahydro-2,2,4- arnethyl-5H-chromenor3,4flquinoline (Compound 176); (R/S)-5-(3-Chiorophenyl). 1,2- (Compound 177); Chiorophenyl)-1,,,-erhdo22dieh (Compound 178); (R/S)-5-(4-Bromophenyl). I 2 -dihydro-2,2,4- mthyl-5H-chromeno [3,4- J]quinoline (Compound 179); (R/S)-5-(4-Bromophenyl-1234-erhyr-,2dmthl4 3 4 -fiquinolie (Compound 180); (R/S)-5-(3-Bromophenyl)-.1,2- diyr-,,-rmty-Hcrmn[,-lunln (Compound 18 Bromophenyl)- 1,,,-erhdo22diehl4fieh~ee5-hoeo34Aunln (Compound 182); (R/S)-5-(3,4-dichlorophenyl). I,2-dihydro-2,24tuimety.5H- chromeno[3,4-fjquinoline (Compound 183); (R/S)-5-(3-Bromo.2pyridy).1 ,2-dihydro-2,2,4. trimethyl-5H-chromeno[3,4-fquinoline (Compound 184); (R/S)-l 1 (Compound 185); (RIS)- 1 ,2-Dihydro-2,2,4- trmhl5nitoy5-hoeo34fqioie(Compound 186); (R/S)-1,2-Dihydro. 2,,-iehl5p'px-Hcrmn[,-lunln (Compound 187); l, 2 -dihydro-2,2,4triethy[-5Hchromno[ 3 4 -flquinoline (Compound 188); (RIS)- 1,2- Diyr-,,-ity--rpl5-hoeo34Aunln (Compound 189); (RIS)- 1,2- (Compound 190); (R/S)-5-(3-Fluorophenyl')1,2dhdo22 trmty-Hcrmeo34Auntn (Compound 191); (R/S)-5-(3-Fluorophenyl). 34ttrhdo22difehl4nityiee 5H-chromieno[3,4-flquinoie (Compound 192); (RiS)- l, 2 -Dihydro2,2,4triethyI5- propylthio-5H-chroneno[3,4jflquinoline (Compound 193); (RIS)- 1,2-Dihydro-5.(3. mehxpey)224umty-Hcrmn[,-lunln (Compound 194); (RIS) 1,2- Diyr-,,-rmty--3(rfurmty~hnl-Hcrmn[,-lunln (Compound 195); 3 -Fluoro-4methylphenyl) l,2-dihydro-2,2,4uirmthy1..5H- chromeno[3,4-f]quinoie (Compound 196); (R/S)-5-(4-Bromo3pyidy')-1 ,2-dihydro-2,2,4- timthyI-5ff-chromeno(3,4.f~quinoline (Compound 197); (RIS)- I ,2-Dihydro-2,2,4- uity--3prdl-Hcrn&o34Aunln (Compound 198); (R/S)-5-(4-Chloro. 3 (Compound 199); (RIS)-1,-iydo224,-er [y-Hchoeo 3 4 -flquinoline (Compound 200); ilquinoline (Compound 175); (RI 4 li 5 u)-5-(4Clorophenyl) tetrahydro-2,2,4- timethyI-5H-chromeno[3,4.jlqumolie (Compound 176); (R/S)-5-(3-Chloropheny).1,2- diyr-,,-it~-Hcrmn(,-lunln (Compound 177); Chiorophenyl)- 1,,,-erhdo22dnehl4mtydn-Hcrmn 34fqiofn (Compound 178); (R/ST-5-(4-Bromophenyly.. l 2 -dihydro-2,2,4-tr~thyl-5H-chrormno[3,4- j]quinoline (Compounmd 179); (R/S)-5..(4..Bromfophenyl-1234. rhyr-,2dmthl4 methyldeneHchoeno34quiofe (Compound 180); (R/S)-5-(3-Bromopheny)-.1,2- diyr-,,-~tty-H-hoeo34Aunln (Compound 181); Bromophenyl)- 1,,,-erhdo22dnehl4fiehhee5-hoeo34Aunl (Compound 182); (R/S)-5-(3,4..diclorophenyl) l, 2 -dihydro2,2,4-imty..SH- chromfeno[3,4-jlqunoline (Compound 183); (R/S)5-(3-Broff 2 -pyridyl) 1 ,2-dihydro-2,2,4. trmhl5-homo34Aunln (Compound 184); (RIS)- l, 2 2 2 4 inthylsHchroneno[34]qunoline (Compound 185); (RIS)- 1,2-Dihydro-224- 5ethoxy Hclono[ 3 4 qoln (Compound 186); (RIS)- 1,2-Dihydro- 2,,-iehl5pooy5-hoin[,-lunln (Compound 187); 1,-iyr-,,-iehl5-hoeo34Aunln (Compound 188); (RIS)- 1,2- Diyr-,,-iity--rpy-Hcrmn[,-qion (Compound 189); (RIS)- 1,2- Dihydro224me thy5(2pyrdyl)- Hcf 3 4 -qunle (Compound 190); (RfS)-5-(3-Fluoropheny). (Compound 191); (R/S)-5-(3-Fluorophenyl). 234ttrhdo22diity--mtyiee 5H-chromeno[3,4-qinoiie (Compound 192); (RIS)- l. 2 -Dihydro.2,2,4fiffthy15- prplho5-hoeo34Aunln (Compound 193); (RIS)- 1 ,2-Dihydro-5-(3.. nfthoxypheny)2,4rethy5Hcofin[ 3 4 qin. (Compound 194); (RIS) 1,2- (Compound 195); (R/S)-5-(3-Fluoro..4-niethylpheny1) l, 2 -dihydro2,2,4.eirthyl.5H- chromeno[3,4..flquinofine (Compound 196); (R/S 4 -Bromo-3.-pyridyly 1 ,2-dihydr-o-2,2,4- triffethYl-5H-chromeno[3,4-Aquinoline (Compound 197); (RIS)-1I,2-Dihydro-2,2,4- trmty--3prdl-Hcrmn[,-qion (Compound 198); (R/S)-5-(4-Chloro. 3-lurphny)1,-dhdr-,24-rm'Yo homeno[3,41]q u oline (Compound 199); (RIS)- 2 -Dihydro2,2,4,5-tetr thy-5Hchromeno[34flnoin (Compound 200); Dihydro-5-hey ,,-rmty-H-hoeo34Aunln (Compound 201); 1,-iyr-,,-rmty-5-hoeo34Auntn (Compound 202); (RIS)- 1,2- Diyr--3mtybtl-,,-imty-Hcrneo34Aunln (Compound 203); (RIST-5-(4-Chiorobutyl). 1,-iyr-,,-rmty-Hcrmn[,-lunln (Compound 204); (R/S)-5-Benzyl- l, 2 -dihydro-2,2,4-rrjrethyl.5H..chomeno r 3 ,-fjquinoline (Comound 205); (R/S)-5-(4-Bromo butyl)- l, 2 -dihydro-2,2,4-tithyl-5H..chromeno[j3,4- fiquinoine (Compound 206); (R/S)-5-Butyl-9.fluoro-1,l 2 -dihycro-2,2,4ithy1-5H- chromeno[3,4.flquin~oine (Compound 210); (R/S}-5-Butyl-8..fluoro. I,2-dillydro-2,2,4- inthyl-5H-chrorneno[3,4flqunoline 1 (Compound 21 (R/S)-5-(3-Chlorophenyl).9- fluoro-1,-iyr-,,- ity-Hcrfieo34Aunln (Compound 212); 4 -Chloro-3-methylphenyl).9-fluoro-1, 2 -dihydro-2,24ritriethy15Hchomeno[ 3 4 IAquinoiine (Compound 213); (R/S)-5-(4-Chloropheny).9-fluoro I ,2-dihydro-2,2,4. trimethyl-5Hchromeno3,4flquinolie (Compound 214); (R/S)-9-Fluoro-1I,2-dihydro-5-(4. iethoxphey)22h rnfl2 u5H-crmn,4-qunoin Cooud Fluoro-1, jyr--itoyl224umty-Hchoeo34Aunln (Compound 216); (R/S)-5-(4..Chlorophenyly.8-fluoro-12d do22,-ifehl5Hcrmn[,- ulquinoline (Compound 217); and (R/S).O-Chloro..5-(4-chioropheny1) I ,2-dihydro-2,2,4- trimethyl-5H-chromeno[3,4jqunoline (Compound 218); 9-Chloro- I ,2-dihydro-2,2,4. trirnethyl-5H-chrorneno[3,4..ilquinoline (Comound 320); (RIS)-9-Fluoro-1I,2-dihydro-5- methoxy- 2 2,4imehyl5Hcl1omeno[34Aquinoj 1 (Compound 322); (R/S)-9-Fluoro- 1,-iyr-,,-iity--horoix-Hcrmn[,-]unln (Compound 323); (R/S)-9-Fluoro-12dhdo224amehl5pooy5-hrmn[,-qion (Compound 324); (RIS)-1,-iyr--fehx-,,4amhl5-hoeo34 fjquinoline (Compound 329); (RIS)- l) 2 -Dihydro-2249temety1Hco[ 3 4 ]]quinoline (Compound 330); (R/S)-7-Chloro-l, 2 -dihydro-2,2,4iethy5Hcromeno[ 3 4 flquinoline (Comound 331); (R/S)-5-(4-Bromo-3..pyrdyl) 1234ttrhdo22-iehl4 imthy~idene-5H-chroffino[3,4-AIquino~ie (Comrpound 347); (R/S)-5-(3,5-Difluorophenyl)- 1,-iyr-,,-rmty-5-hofeo34Aunln (Comound 348); (RIS) l 2 3 4 tetahydro 22d thy 1.nithyidenHcreHo 3 4 tAquinoline (Compound 352); (Z)-1,,Dhdo5(,46tirtybnzfdn)224 triTet hyl-5H-chrome&no[3,4..flquinoine (Compound 364); PZ-5- Benzylidene-9-fluoro- 1,2- dihydro-2,2,4,1 ttaehl5Hcrmn 34fqioln (Compound 377); Chiorophenyl)- 1,,,-ttayro22dmehl5-crmn[ 3 4 4 -quinolinone (Compound 378); (R/S)-5-(4-Chlorophenyl). I 2 3 ,4-tetrahydro-2,2,3 chromeno[3,4-fl-4-quinolinone (Compound 379); (R/S)-5-(4-Chlorophenyy 1 ,2-dihydro- 2 2 -dimethyl-5H-:chromeho[3 4 /]-quinoline (Compound 380); Chiorophenyl)- 1, 2 3 4 -tetrahydro-2,2,4-U nethyl-5H-chronmeno 3 4 t]- 3 -quinolinone (Compound 381); (--R-1,1--4Choohnl1 2 3 4 -tetrahydro-.2,2,4tinJethyl15H- chromneno[3,4-I1-3-quinolinone (Compound 382); (R/S)-5-(4-Chlorophenyl)-.1,2,3,4- terhdo22dnehl5-hrreo341--unlnn (Compound 383); Flooezl--3-lurbnyiee ,,,4ttay~o3hdox-,,-rmty-H chromeno[3,4-fquinoline (Compound 384); (R/S)-3,5-Dibutyl- l, 2 ,3,4-tetraiydro-3- hydroxy 2 ,2,4Utirnthy1.Hchomeno[34-Aqujnoline (Compound 385); 1,,,-erhdo224umhl-Hcrmn[,---unlnn (Compound 386); (R/S-4!,St)-1,,,-erhdo224t ehl5phnl5-hoeo341--unln (Compound 387); (R/S-41,Su)-1,,,-erhdo224-imhl5pey-H chromeno[3,4-f]-3quinolinone (Compound 388); (RIS-41,6u)-1I,2,3,4-Tetrahydro-2,2,4 (Compound 390); (R/S-41,61)- 1,,,-erhdo224tiehl6pey-Hiohoeo34f--unlnn (Compound 391); (R/S- 3 I,4u,Su)-5-(4-Chlorophenyl1) 2 3 ,4-tetrahydro-3-meho xy22,4 trmthy1-5H-chromeno[3,41!quinoline (Compound 397); (R/S-31,4u,SO-5-(4. Chiorophenyl)- 1,,,-erhdo3nehx-,,-iehl5-hoin[,-~unln (Compound 398); (R/S-3l.4u,5)-5-(4-Chloropheny)-.1 2 3 4-tetrahydro-3propyloxy2,2,4- trimthyl-5H-chromeno[3,4..Aquinolie (Compound 399); (R/S-31,4u,5u)-5-(4. Chiorophenyl)-1,, ',-erhdo3poyoy224amty-Hcrnin(,-lunln (Compound 400); and (R/S- 4 3 -Benzyiidene..5.(4-chlorophenyl) 1 ,2,3,4-tetrahydro- 2 2 4 -trimethyl-5H-chromeno[3,4.flquinoline (Compound 401). A PR agonist compound according to claim 5 selected from the group consisting of (Z)-5-Butylidene- 2 -dihydro-2,2,4-trimethy1-5H..chomelo[3,4flquinoline (Compound 219), (Z)-5-Benzylidene- l, 2 -dihydro-2,2,4-t thyl-5H-chronieno[3 ,4- f~quinoline (Compound 220); 4 -Fluorobenzylidene)-1,l 2 -dihydro-2,2,4-timethyl-5H. chromeno[3,4-flquinoline (Compound 22 4 -Bromobenzyfidene)- 1 ,2-dihydro-2,2,4- 3 4 -j]quinoline (Compound 222); (Z)-5-(3-Bromobenzylidene). 1,2- dihydro- 2 2 4 xniethyl[5H-chromeno[3,4.flquinolie (Compound 223); Chlorobenzylidene)- l 2 -dihydro-2,2,4-tithyl-5H-chromeno[3,4-fqino~ine (Compound 224); (Z)-5-(3-Fluorobenzyhidene).. hdr-,,-tmty-5-hofxo34f~unln (Compound 225); (Z)-5-(2-Chloro benzylidene)- 1 2 -dihydro-2,2,4-trinethyl15H. chromeno[3,4-Aquinoline (Compound 226); 2 -Bromobenzylidene)-1 ,2-dihydro-2,2,4- trimethyl-5H-chromeno[3,4-.fquinoline (Compound 227); (Z)-5-(2-Fluorobenzylideney. 1,2- dihydro- 2 2 4 -iffethylsHcromfeno[3,4-Jquinoline (Compound 228); Difluorobenzyidene). l 2 -dihydro- 2 ,2,4-t thyl-5H-chromfeno[34-lquinoline (Compound 229); (Z)-5-(2,5-Difluorobenzyidene). dhdo-,,-iety-Hcroeo34 flquinoline (Compound 230); 9 -Fluoro-5-(3-fluorobenzylidene) I ,2-dihydro-2,2,4- niethyl-5H-chromneno[3,4..pqiinoie (Compound 231); (Z)-9-Fluoro-5-(3- mthoxybenzylideney. l, 2 -dihydro-2,2,4-trimethyl.5Hchromeno 3 ,4-Jjquinoline (Compound 232); 8 -Fluoro-5-(3..fluorobenzylidene) l,2-dhydro-2,2,4mthy-5Hchroffno[ 3 4 ijquinoline (Compound 233); (RIS- 4 .Su)-5-(4-Chlorophenyl). 2 3 ,4-tetrahydro-!2,2,4- trimethyl-5H-chromeno[3,4-fy3.quinolinone (Compound 234); (R/S-414S0-(4- Chiorophenyl)- 1,,,-erhdo224tmty-5-hoeo34f--unlnn (Compound 235); and (R/S)-5-(4-Chlorophenyly. ,,-etayr-,244ttamty-H chromeno[3,4..fy3quinolinone (Compound 236); 5-( 3 -Pluorobenzyl- 1,2-dihydro-2,2,4- trimnethy;5Hchromeno[3,4-jquinoline (Compound 318); (R/S)-9-Chloro- 1,2-dihydro- 2 2 4 -timethy1.5-propyoxysH.chromeno[3,4-Aquinoline (Compound 321); 9-hlr-12-iydo2,,4timh-H-homeno,4--jjq inolne (Compound 325); (RIS)- 1,-iyr--fehx-,,-rmty-Hcrmn[,-~unln (Compound 326); (R/S)-9-Fluoro- I, 2 -dilydro2,2,4,5tetramthy15Hchromno [3,4-flquino line (Compound 327); (R/S)-9-Chloro-1,-iyr-,,,-eraehl5-hoeo34 flquinotine (Compound 332); (RS--(-rmpI l--clr-,2-dihyclro-2,2,4 trimethyl-5H-chromeno[3,4.jjquinojjne (Compound 333); Chloro-5-(3- chiorophenyl)-1,-iydo22,-rmthy-5H-chromeno[34uno (Compound 334); (R/S)-9-Chloro.. 1,-iyr-,,-rmty--3ffehlhnl-Hcrneo3 flquinoline (Compound 335); (RS--hlr--4-hoo3-I yphnl-,2-dihyciro- 2,,-ifehl5-hrneo34Aunln (Compound 336); (R/S)-9-Cliloro. I,2-dihydro- 5-3(rfurrehlpeyl224trnty-Hcrfin[,-~unln (Compound 337); 9 -Chloro.5-(3,5dichJorophenyl) l, 2 dihydro2,24ixthyl-5Hchomel 0 3 4 Aquinoline (Compound 338); (R/S)-9-Chloro- 2 -dihydro-5(4-mthoxyphefl)y224- trimethyl-5H-chromfeno[3,4-quijfline~ (Compound 339); (R/S)-9-Choro5S(3..fluoro-4 methoxyphenyl)-12dhdo2,,. ztyl5-hoxo[,-qion (Compound 340); 9 -Chloro.5(4-fluorophenyl) 12dhdo224tiety-Hcrneo34 .f]quinoiine (Compound 341); (RI5 9 -Chloro.5.(3.Choro4mthox--mthylhey)12 diyr-,,-tfmhl5Hcrneo34Aunln (Compound 342); 4 -fluoro-3-methylphenyl).. 1,-iyr-,,-iehl5-hoin 34jqioln (Compound 343); 9 Choro..5.(3-fluorophenyl) l, 2 -dihydro..2,2,4timethy1-5H. chromeno[3,4..~quiojne (Compound 344); (RIS)-1I,2-Dihydro-2,2 .4-trimethyl-5..[(3,4 omeno[ 3 4 jioln (Compound 345); (R/S)-5-(4-Chloro. 3 -methylphenyl). 1,-iyr-,,-rmty-5-hoeo34Aunln (Compound 346); (R/S)-5-(3,5-Dichlorophenyl)-1,l 2 dihydro2,24iethy1-5H-chomeno[ 3 4 fAquinobie (Compound 349); (RIS)-S..(3..Bromo..5..Ithylphenyl)-1 ,2-dihydro-2,2,4- aiithyI-5H-.chrorneno[3,4..flquinoijne (Compound 350); (RIS)-5-(3-Bromo.5 fluorophenyl)- l, 2 -dihydro-2,2,4- ithyl-5H..chromeno[34..,cqiiinojine (Compound 35 1); Alquinoline (Compound 353); (R/S) 9 .Fluoro1,2dyro224tithylS( 3 mehlhnl-Hcrfin[,-qion (Compound 354); (RIS)-1I,2-Dihydro-9- methoxy. 2 ,2,4mtethy5(3nithylphenyl)5Hcrmn[,-qion (Compound 355); 9 Fuoro5(3fluoro4thoxhny) l 2 -dihydro..2,2,4..ri.thy1..5H- chromeno[3,4..Aquinoae (Compound 356); (R/S)-9-Fluoro-1,l 2 -dihydro-2,2,4-timethy15- 3 -(trifluoroethyI)phen y1]5-hroneo[ 3 4 j.ol (Compound 357); Fluoro-5-(4-fluoro3methylphenyl)- I, 2 -dihydro-2,2,4 tinithyI-5H-chromeno[3,4- flquinoiine (Compound 358); 2 ,4-Difluoro benzylidene). I 2 -dihydro-2,2,4-.nimethy1- 5H-chromeno[3,411quinio~ie (Compound 359); (Z)-5-(3,4Dffuorobenzyidene)-1,2- diyr-,,-Umty-Hcrmn 34fqioln (Compound 360); Fluorobenzylidene)- 1, 2 3 4 -tetraro22d-ro22eth I5-hroe[ 3 ,4Aunln (Compound 361); 2 ,6-Difluorobenzyidene) l, 2 -dihydro2,2,4i-mthyl-5H. chromeno[3,4jjquinolin (Compound 362); yr--2fithlezldh)224 tnmethyI-5Hchomeno[34qiolie (Compound 363); (Z)-9-Chloro..5.(2,5 difuoobezyidee)1,2diydr-22Y-rmtC l-hroeno[ ,4 quinoine (Compound 365); (Z)-5-Benzylidene-9ctdr-,2dhdo-,,- 0 mty-H-hoino34 qunln (Compound 366); (Z)-9-Chioro-12dhdo224-rmty -2mthlez~ee-H chromeno[3,4..Aquinoie (Compound 367); (Z)-5-Benzylidene-9..choro I ,2-dihydro..2,2 (Compound 368); (Z)-9-Chloro-5.(2-. fluorobenzylidene) 1, 2 -dihydro-2,2,4 uiethyl-5H-chromeno 3 4 -flquinoline (Compound 369); (Z--hoo5(-looezy ee-,-iyr-,,-tiehl5-hoeo34 fjquinoline (Compound 370); (E/Z)-5-Benzylidene.9-fluoro- I 2 -dilhydro-2,2,4-iethyl15H- chromeno[3,4-Aquinoline (Compound 371); (Z)-5-Benzylidene-8fluoro-1 ,2-dihydro-22,4 triehl5-hoeo34Aunln (Compound 372); (Z)-5-Benzylidene-.1 ,2-dihydro-9. mehx-,,-rrehl5-hoeo34Aunln (Compound 373); 9 -Fluoro- 1,2- !0 diyr-,,-iity--2mtybnzldn)5-hoeo34Aunln (Compound 374); (Z)-8-Fluoro-1,-iyr-,,-r hl5(-etybnydn)5-hoeo34 flquinoiine (Compound 375); (Z)-1,-iyr--mtoy224-ity--2 methylbenzydene)H.chomeno3-quinolin (Compound 376); Fluorobenzylidene). 34ttahdo224trmty-Hcrofeo34A--unlnn (Compound 389); (Z)-(RfS)-5-(Benzylidene) 1234ttayr-224tmty-H choeo34A--unlnn (Compound 392); (R/S41,Su)-5-(3.Ruoropheny)-1,2,3,4- terhdo224thty-Hchofn[,---unlnn (Compound 393); (R/S-41,sO)- 3 -Fluorophenyl) 1234ttayr-,,4tiehl5-hofen[,---unfnn (Compound 394); (RIS-41,s01,234Terhdr-,,-tiehy--3 (trfluoromiethyl)pheny I5chm o[ 3 4 3 -unloe (Compound 395); (RIS-41,Su)- quinolinone (Compound 396); (R/S- 4 l,5u)-5-(4-Cfforophenyl)1).I 2 3 4 -tetrahycdro..224 3 4 -fJ- 3 -quinolinone (Compound 402); (R/S-41,sr)-5.(4- Chiorophenyl)- 1,,,-erhdo224tiehl-Hcrmn[,---unlnn (Compound 403); and (R/S)-5-Butyl-1,-iyr-,,,-ermehl5-hofeo34 flquinoline (Compound 457). It. An AR modulator compound according to claim 6 selected from the group consisting of 1, 2 -Dihydro-2,2,4..timethyl.6methoxy !1thy!8-pyraon[561gqinl (Compound 237); 1,-iyr-,,-iehl6tiloo-thl8prnn[,-lunln Cmon 238); l, 2 -Dihydro-2,2,4-trhnethy.l- 0isocoumarino[4, 3 -glquinoline (Compound 239); 1,2- Dihydro-2,2,4rimey10-sqiooo ,-~unlieCmon 240); 1 ,2-Dihydro- 2,,,-erfity--prdn[,-lunln (Compound 241); 1 ,2-Dihydro- IO-hydroxy- 2 2 ,4-trirnethyl. lOH isochromeno[4,3.g]quinoline (Compound 242); 1, 2-Dihydro-2,2,4,6- tetrmethy-8H-pao 3 2 -glquinoline (Compound 243); (RIS)-lI, 2 3 4-Tetrahydro224 trixnthyl- lO-isoquinolono[4,3-gjquinoline (Compound 244); l, 2 -Dihydro2,2,4timthylI lO-thioisoquinolono[4,3..glquinoljne (Compound 245); 2 3 ,4-Tetrahydro-224 trimethyl- lO-isoquinolono(4,3-glquinone (Compound 246); l,2-Dihydro2,2,4tithy16- trifluoromethy-8pyidono[5,6.glquinolin (Compound 247); (RIS)- 1 2 3,4-Tetrahydro- 2,,-ity--rfurmtyl8prnn[,-lunln (Compound 250); 1,2- Diyr-,,-rrehl6tfloofxhl8tiprnio56gqion (Compound 251); (RIS)- 1,,,-erhdo224hmty--rfurfity--hoyaoo56gqion (Compound 252); 6 -Chloro(difluoro)mfethyl-l, 2 -dihydro-2,2,4ithy.8-pyanono[, 6 giquinoline (Compound 253); 9-Acetyl-1,-iyr-,, imthl6twooehl8 pyridono[5,6-glquinoline (Compound 254); l, 2 -Dihydro-2,2,4,10-tetraIthy..6 ufluoromiethyl-8-pyridono5,6gjquinoie (Compound 255); l,2-Dihydro-2,2,4..tjthylI 1,1 2 2 2 -pentafluoroethy)8pyranono [5, 6 -glquinoline (Compound 256); (RIS)-6- Chloro(dfuoro)methyl. 1,,,-erhdo224tiehl8prnn[,-~unln (Compound 257); 7-Ch~oro-1,-iyr-,, inehl6tilooety--yaoo56 glquinoline (Compound 258); (R/S)-7-Chloro. l, 2 3 4 -tetrahydro224tithy16- trifluoromethyl-8-pyranono 15,6-g]quinoline (Compound 259); 1 ,2,3,4-Tetrahydro-2,2,4- trimthyI-6-trifluoromethy-8-pyridono [5,6-g~quino lie (Compound 260); 1 ,2-Dihydro- 2 2 4 9 -tetramethy-6-trifluoromethy-8-pyridono[,6-gquinoine (Compound 26 1,2- Dihydro- 2 ,2,4-n-iimthyl-8-trifluoromethy1-6-pyridono[5,6gquin~oame (Compound 262); 6- [Dichloro(ethoxy)methyl]- 1, 2 -dihydro- 2 2 4 -trimnethyl- 8-pyrano no [5,6g~quino ine (Compound 263); 5-(3-Furyl)- 1, 2 -dihydro-2,2,4-trimethyl-8-pyranono [5,6-giquinoline (Compound 264); 1 ,2-Dihydro- 1, 2 2 4 -tetramethyl-6-trifluoromethyl-8-pyranono[5,6- glquinoline (Compound 265); 1, 2 -Dihydro-6-trifiuoromethy1-2,2,4-trimethyl-9-tiopyran.8 ono[5,6-gI quinoline (Compound 266); 1 ,2-Dihydro- 1,2,2,4,9-pentamnethyl-6- trifluoromexthyl-8-pyridono[5,6-g]quinoline (Compound 267); 7-Chloro- I ,2-dihydro-2,2,4- trimthyl-6-trifluoromethyl-8-pyridono[5,6-glquinoline (Compound 268); and 6- Chloro(difluoro)mfethyl- l, 2 -dihydro- 2 2 4 -trimethy-8-pyridono[5,6-giquinoline (Compound 269); (RIS)- 1,2,3,4-Tetrahydro-1 2 2 4 -tetramethyl-6-trifluoromethyl-8-pyranono [5,6- giquinoline (Compound 404); (R/S)-5-(3-Furyl)- 1 2 ,3,4-tetrahydro-2,2,4-trimthy-8- pyranono[5,6-glquinoline (Compound 405); 5-(3-Furyl)-1I,2-dihydro- 1,2,2,4-tetramethyl-8- pyranono [5,6-giquinoline (Compound 406); 5-(3-Furyl)- 1 ,2-dihydro- 1 ,2,2,4-tetramthyl-8- thiopyranono [5,6-g]quinoline (Compound 407); 6-Chloro-5-(3-fulryl)- 1,2-dihydro- 1,2,2,4- tetramethyl-8-pyranono[5,6-g]quino~ine (Compound 408); 1 ,2,3,4-Tetrahydro-2,2,4, termty--rfurmtyl8prdn[,-lunln (Compound 409); (RIS)- 1,2,3,4- Terhdo4mty--rfurmehl8prnn[,-lunln (Compound 410); 1,2- Diyr-,-iehl6tiloofxhl8prnn[,-~unln (Compound 411); 1 2 3 ,iTetrahydro-2,2-dimethy-6-ifluoroethy8pyranono[6gqo~ne (Compound 412); 1, 2 3 4 Tetahydro-6-trifluoromethyl-8-pyranono[5,6-giquinoline (Compound 413); (R/S)-4-Ethyl-1I 2 3 4 -tetrahydro-6-trifluoromethyl-8-pyranono[5,6-glquinoine (Compound 414); (RIS)- 1,2,3,4-Tetrahydro- 1, 4 -dimethyl-8-pyranono[5,6-g]quinoline (Compound 415); (RIS)-4-Ethyl- 1,2,3,4-tetrahydro- 1 -nmethyl-8-pyranono[5,6-g]quinoline (Compound 416); 2,2-Dimethyl- 1 p 2 3 -tetrahydro-6-trifloromthyl-8-pyridono(5,6-.fquinoline (Compound 417); (RIS)-1I,2,3,4-tetrahydro-6-tfluoromethy-2,24iethy-8pyridono[5,6-j.3- quinolinone (Compound 418); 5-Trifluoromfethyl-7-pyridono[5,6-e]indoline (Compound 419); 8 4 -Chlorobenzoyl)-5-tfluoromethyl-7-pyridono[5,6-e]indoine (Compound 420); 7- tert-Butyloxycarbamoyl. 1, 2 -dihydro..2,2,8-. trimthylquino line (Compound 42 1,2,3,4- Tetrahydro 6 tffuoromethy8pyidono (56-Aquno lie (Compound 422); 1 .2-Dihydro-6- trifluoromey-12,-eramet hy -yidn(,-Aunln (Compound 423); 3,3.. Dimhl5tilO~ehl--yioo56eidln (Compound 424); 1,2,3,4- Tetrahydro.4methy6(t.jfmeluorometyi) 8 p[ 5 6 jqunln (Compound 425); (RIS)- 1,,,-erhdo4nehl6(rfuooehl--yioo56gqion (Compound 426); 1 2 2 ,-TrimethyI-1,,,-erhdo--r uoehl--yaoo56 glquinoline (Compound 427); 1,,,-erhdo4popl6tflooehl8 pyranono[5,6-glquinoline (Compound 428); I, 2 3 4 -Tetrahydro224iithy16- uilooehl9tipra--n[,-lunln (Compound 429); 1 ,2-Dihydro- 1,2,2,4- terr~ty--rfurmty--hoya--n[,-~unln (Compound 430); 1,2,3,4- Tetrahydro- l, 2 2 tithyl- 6 -trfluoromethyl-pyridono 5 6 ]inn (Compound 431); 1 2 3 ,4-Tetrahydro- I -methy--rl--triloryonhl8roo [5,6yl lpu[S 6 ]n (Compound 432); 1 2 3 ,4-Tetrahydro-10hdoy-ty 224unehl6-rfurrehl 8 -pyridono[5,6-glquinoljne (Compound 433); 1 2 3 4 -Tetrahydro- I, 2 2 4 -tetramethy1-6- trfurmty--hoya--n[,-junln (Compound 434); i 2 3 ,4-Tetrahydro. 2,,-ifehl6tilooithl8prdn[,-lunln (Compound 435); (RIS)- 1, 2 3 4 -Tetahydro3methy 1..6.ifuorothl. 8 idn[5,-~un (Compound 436); 1,,,-erhdo33dmty--rfurnehl8prdnf,-~unln (Compound 437); (RIS)1,,,-erhdo223tifity--rfurnehl8 pyridono[5,6-g]quinoline (Compound 438); (RIS-21,4u)- l, 2 3 4 -Tetrahydro..2,4..dirmthy-6- tfluoromethy1.8pyidono[,6gjquinolie (Compound 439); (R/S-21,4u)-4-Ethyl-1,2,3,4- tetrahydro.2mel6thy1uorothy 8 pano[ 6 ].uno (Compound 440); (RIS- 21,3u)- 1,,,-erhdo23dnehl6tilooehl8prdn[,-~unln (Compound 441); rhdo23dnety--rfurnehl8 pyridono[5,6..glquinojie (Compound 442); (RIS)- l, 2 3 4 -Tetrahydro2,3,3tthy-6- tifluoromethy18pyridono[,6gjquino 0 in (Compound 443); (RIS)- I 2 ,3,4-Tetrahydro-2- methyl-6..trifluoromethyl.8.pyridono [5, 6 -gjquinoline (Compound 444); Ethyl- 1,,,-erhdo6tflooehl8prdn[,-junln (Compound 445); (R/S-21, 3u)- 1,,,-erhdo239tiehl6tilooehl8prdn[,-luntn (Compound 446); (R/S)-1,2,3,4-Tetrahydro-4-propyl-6-trifluoromethyl-8-pyridono[5,6- g]quinoline (Compound 447); (R/S)-3-Ethyl-1,2,3, 4 -tetrahydro-2,2-dimethyl-6- trifluoromethyl-8-pyridono[5,6-g]quinoline (Compound 448); (R/S)-1,2,3,4-Tetrahydro-2,2- dimethyl-6-trifluoromethyl-3-propyl-8-pyridono[5,6-g]quinoline (Compound 449); and 1- Methyl-5-trifluoromethyl-7-pyridono[5,6-f]indoline (Compound 450).
12. A compound according to claim 2, wherein the compound comprises an estrogen receptor agonist or antagonist.
13. A compound according to claim 2, wherein the compound comprises a glucocorticoid receptor agonist or antagonist.
14. A compound according to claim 2, wherein the compound comprises a mineralocorticoid receptor agonist or antagonist. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
16. A pharmaceutical composition according to claim 15, wherein the composition is formulated for oral, topical, intravenous, suppository or parental administration.
17. A pharmaceutical composition according to claim 15, wherein the compound is administered to a patient as a dosage unit at from about lp.g/kg of body weight to about 500 mg/kg of body weight.
18. A pharmaceutical composition according to claim 15, wherein the compound is administered to a patient as a dosage unit at from about 10Pg/kg of body weight to about 250 mg/kg of body weight.
19. A pharmaceutical composition according to claim 15, wherein the compound is administered to a patient as a dosage unit at from about 20.g/kg of body weight to about 100 mg/kg of body weight. A pharmaceutical composition according to claim 15, wherein the composition is effective in treating and/or modulating human fertility, female hormone replacement, dysfunctional uterine bleeding, endometriosis, leiomyomas, acne, male-pattern baldness, osteoporosis, prostatic hyperplasia, cancer of the breast, cancer of the ovaries, endometrial cancer, prostate cancer, carbohydrate, protein and lipid metabolism, electrolyte and water balance, and functioning of the cardiovascular, kidney, central nervous, immune and skeletal muscle systems.
21. Use of compound according to claim I for the preparation of an agent for affecting steroid receptor activity.
22. Use of composition according to claim 15 for the preparation of an agent for affecting steroid receptor activity.
23. Use of compound according to claim 1 for the preparation of an agent for modulating a process mediated by steroid receptors.
24. Use of composition according to claim 15 for the preparation of an agent for modulating a process mediated by steroid receptors. A pharmaceutical composition comprising an effective amount of a steroid receptor modulator compound of the formula: R1 R 9 R1 0 R 9 R' R2 zRi R zRR 2 R4 OR R 4 OR R 4 wherein: R 1 through R each independently are hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl; R 4 is hydrogen, a Cl C6 alkyl, or R 5 C=O, OR 6 or NR 6 R 7 where R 5 is hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, and wherein R 6 and R each independently are hydrogen, a C1 C6 alkyl, optionally substituted allyl, arylmethyl, aryl, or heteroaryl; R 9 through R1 0 each independently are hydrogen, a C1 C6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl; R 1 1 is hydrogen, a Cl C6 alkyl, OR 6 or optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, where R 6 has the same definition given above, or R 1 and R 2 R 2 and R 3 R I and R R 10 and R 1 R 1 and RI 0 and/or R 11 and R 2 when taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, !0 OR 6 or NR R 7 where R through R 7 have the definitions given above, provided, however, that R R 2 R 10 and R 11 cannot form more than two three- to seven-membered rings at a time; Y is 0, CHR or NR where R 6 has the same definition given above; and Z is an aryl or heteroaryl group, including mono- and poly-cyclic structures, optionally substituted at one or more positions with hydrogen, a C 1 -C 6 alkyl, optionally substituted allyl, arylmnethyl, alkynyl, alkenyl, aryl, heteroaryl, F, Cl, Br, I, CN, R 5 C=O, R 6 R 7 NC=O, R 6 OC=O, perfluoroalcyl, haloalkyl, a C 1 I C 6 straight-chain hydroxy alkyl, HOCR 5 R 8 nitro, R 6 OCH2, R 6 0, NH2, or R 6 R 7 N, where R 5 through R 7 have the definitions given above and where R 8 is hydrogen, a Ci C6 alkyl or optionally substituted allyl, arylmthyL, alkynyl, alkenyl, aryl, or heteroaryl; and a pharmaceutically acceptable carrier. [rest of page left purposely blank]
26. A pharmaceutical composition according to claim 25, wherein Z is selected from the group consisting of: 0^ N^T os^ C 1_11- N C S N0 0 N O, a 0 NN
27. A pharmaceutical composition according to claim 25, wherein the composition is effective in treating and/or modulating human fertility, female hormone replacement, dysfunctional uterine bleeding, endometriosis, leiomyomas, acne, male-pattern baldness, osteoporosis, prostatic hyperplasia, cancer of the breast, cancer of the ovaries, endometrial cancer, prostate cancer, carbohydrate, protein and lipid metabolism, electrolyte and water balance, and functioning of the cardiovascular, kidney, central nervous, immune -and skeletal muscle systems.
28. Use of a compound listed below for the preparation of a medicament for treating a patient requiring steroid receptor therapy, wherein said compound has the following formula: 2, N 2 a 2 4 OR R4 OR R wherein: R I through R 3 each independently are hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl; R 4 is hydrogen, a Ci C6 alkyl, or R 5 C=O, OR 6 or NR 6 R 7 where R 5 is hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, and wherein R 6 and R each independently are hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, aryl, or heteroaryl; R 9 through R 10 each independently are hydrogen, a C1 C6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl; R 1 1 is hydrogen, a Cl C6 alkyl, OR 6 or optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, where R has the same definition given above, or R 1 and R 2 R 2 and R 3 R 1 and R 9 R 10 and R R 1 and R 0 and/or R 11 and R 2 when taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, OR 6 or NR 6R 7 where R 6 through R 7 have the definitions given above, provided, however, that R R R1 0 and R 11 cannot form more than two three- to seven-membered rings at a time; Y is 0, CHR or NR where R has the same definition given above; and Z is an aryl or heteroaryl group, including mono- and poly-cyclic structures, optionally substituted at one or more positions with hydrogen, a Ci -C6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, heteroaryl, F, Cl, Br, I, CN, R 5 C=O, R 6 R 7 NC=O, R 6 0C=O, perfluoroalkyl, haloalkyl, a Ci C6 straight-chain hydroxy alkyl, HOCR 5 R 8 nitro, R 6 OCH2, R 6 0, NH2, or R 6 R 7 N, where R 5 through R 7 have the definitions given above and where R 8 is hydrogen, a Cl C6 alkyl or optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl.
29. Use according to claim 28, wherein the compound is effective in treating and/or modulating human fertility, female hormone replacement, dysfunctional uterine bleeding, endometriosis, leiomyomas, acne, male-pattern baldness, osteoporosis, prostatic hyperplasia, cancer of the breast, cancer of the ovaries, endometrial cancer, prostate cancer, carbohydrate, protein and lipid metabolism, electrolyte and water balance, and functioning of the cardiovascular, kidney, central nervous, immune and skeletal muscle systems. A pharmaceutical composition comprising an effective amount of a steroid receptor modulating compound of the formulae: R 4 R 3 R I IR R6 H OR R 1 2 R 13 R 4 R 3 R14 R R 10 RS H (II) (1ll) 19 (Iv) (VI) (VUJ) 365 (VIMu (DC) (XJ) (KUI) R 12 0 R 11 R R 5 N 9 1 R 6 HR OR pall) R 12 Rb N OFgJ R 6 HR9 OR (XIV) R1 4 R 16 R' 120R3R2N RI 1 R 3 R 2 H R 1 41 Ro 13 R 9 V 12 4 R' N "9 RA 6 H R OR (XVT) p2R 26 R21 3 3 3 CVII) OR R3 R 24 R 26 R21 R 3 N R 27 R22A221 (XVMI) wherein: R is a heteroaryl optionally substituted with a C 1 C 4 alkyl, F, Cl, Br, NO 2 CO 2 H, C0 2 R 2, CHO, CN, CF 3 CH 2 0H or GOGH 3 where R 2is hydrogen, a C 1 C 4 alkyl or perfluoroalcyl, aryl, heteroaryl or optionally substituted allyl, aryirnthyl, alkynyl or alkenyl, and where said R Iheteroaryl is attached to compounds of formulas I and X through a carbon or nitrogen atom R 3is hydrogen, a C 1 C 4 alkyl or perfluoroalkyl, hydroxymethyl, aryl, heteroaryl or optionally substituted allyL, aryimethyl, alkynyl or alkenyl; Rthrough Reach independently axe hydrogen, F, CL, Br, 1, N0 2 CO 2 H, C0 2 R 2 2 2 2 2 2 COR CN, CF 3 CH 2 OH, a CI-C 4 alkyl or perfluoroalkyl, OR SR S(O)R S0 2 R SO 3 H, S(NR 2R7 )R 2, S(O)(NR 2R 7)R 2, NR 2 R 7 aryl, heteroaryl. or optionally substituted allyl, arylmethyl, alcynyl or alIkenyl, where R2 has the definition given above, R 7is hydrogen, a C 1 C 4 alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl or arylmethyl, OR 8or NHR 8, where R 8is hydrogen, a C 1 C 6 alkyl. or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, S0 2 R 2or S(O)R2 R 9and R 10each independently are hydrogen, a C 1 C 6 alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or R 9 and R 10 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, 2 2 7 2 7 OR or NR R where R and R have the definitions given above; I 1 15 2 R through R each independently are hydrogen, F, Cl, Br, 1, NO 2 CO 2 H, C0 2 R 22 2 2 COR ,CN, CF 3 CH 2 OH, a C 1 -C 4 alkyl or perfluoroalcyl, OR SR S(O)R S 2 27 27 2702 S0 3 S(NR2 R 7)R 2, S(O)(NR2 R 7)R 2, NR 2R 7, aryl, heteroaryl. or optionally substituted allyl, arylmnethyl, alkynyl or alkenyl, where R R and R have the definitions given above; W is 0, NHl, NR 7 CH 2 CHOH, C=O, OC=O, O=CO, NR 7 C=O, NHC=O, 7 -77 O.=CNR O=CNH, SC=O, O=CS, or CHOCOR where R7 has the definition given above; is CH 2 0, S or NR 7 where k7has the definition given above; 16 17 17 2 7 R is hydrogen, OH, OR SR NR R optionally substituted allyL, arylmethyl, alkynyl, alkenyl, aryl, heteroaryl or CI CI 0 alkyl, where R 17 is a C 1 CI 0 alkyl or perfluoroalcyl, or is an optionally substituted allyl, arylmethyL, aryl or heteroaryl, and where R2and R 7 have the definitions given above; R 18and R 19each independently are hydrogen, a C 1 C 6 alkyl or perfluoroalky, aryl, heteroaryl or optionally substituted allyl, arylmthyl, alkynyl. or alkenyl, or R 18 and R1 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, OR or NR R where R R' and R' have the definitions given above; a CI C 6 alkyl or an optionally substituted allyl, aryl-ethyl, alkenyl, aryl or heteroaryl; SR21 is hydrogen, a C 1 C 4 alkyl or optionally substituted allyl, arylmethyl, aryl or heteroaryl; R 2 is hydrogen, a C 1 C 4 alkyl, F, CL Br, 1, OR 2 NR 2 R 7 or SR where R 2 and R have the definitions given above; R 23is hydrogen, Cl, Br, OR 8 NR 2 R 7 a C 1 C 4 alkyl or perhaloalkyl, or is an optionally substituted allyl, arylniethyl, alkynyl, alkenyl, aryl or heteroaryl, where R R. and R 8have the definitions given above; 369 R24 is hydrogen, F, Br, Cl, a CI C 4 alkyl or perhaloalkyl, aryl, heteroaryl, CF3, CF 2 OR 25 CH2OR 2 5 or OR 25 where R 25 is a CI C4 alkyl; R 26 is hydrogen, a CI C4 alkyl, F, C, Br, I, OR 2 N2R or SR 2 where R 2 and R have the definitions given above; R 27 and R 2 8 each independently are hydrogen, a C 1 C 4 alkyl or perfluoroalkyl, heteroaryl, optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or an aryl optionally substituted with hydrogen, F, Cl, Br, OR or NR R or R 27 and R 2 8 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR 2 2 7 2 7 or NR R where R and R have the definitions given above; R 29 is hydrogen, a C 1 C 6 alkyl or an optionally substituted allyl, arylmethyl, aryl or heteroaryl; R 30 and R 3 1 each independently are hydrogen, a CI C 6 alkyl or an optionally substituted allyl, arylmethyl, aryl or heteroaryl, or R 30 and R 3 1 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, OR 2 or NR2R 7 where R 2 and R have the definitions given above; 32 33 R and R each independently are hydrogen, a CI C 4 alkyl or an aryl optionally substituted with hydrogen, F, Cl, Br, OR 2 or NR R or R 32 and R 33 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR 2 or NR 2R where R 2 and R 7 have the definitions given above; n is 0 or 1; YisOorS; Z is 0, S, NH, NR 2 or NCOR 2 where R 2 has the same definition given above; the wavy line in the compounds of formulas VII, XII, XIII and XVI represent an olefin bond in either the cis or trans configuration; the dotted lines in the structures depict optional double bonds; and a pharmaceutically acceptable carrier.
31. A composition according to claim 30, wherein the compounds of formulae I through XVIII comprise steroid receptor modulator compounds.
32. A composition according to claim 31, wherein the compounds of formulae I, II, II, IV, X and XI comprise PR antagonists.
33. A composition according to claim 31, wherein the compounds of formulae V and VI comprise PR modulators.
34. A composition according to claim 31, wherein the compounds of formulae VII, VIII, XII, XIII, XIV, XV and XVI comprise PR agonists. A composition according to claim 31, wherein the compounds of formulae IX, XVII and XVIII comprise AR modulators.
36. A composition according to claim 35, wherein the compounds of formulae IX and XVII comprise AR antagonists.
37. A composition according to claim 30, wherein the compound comprises an estrogen receptor agonist or antagonist..
38. A composition according to claim 30, wherein the.compound comprises a glucocorticoid receptor agonist or antagonist.
39. A composition according to claim 30, wherein the compound comprises a mineralocorticoid receptor agonist or antagonist. A composition according to claim 30, wherein the composition is formulated for oral, topical, intravenous, suppository or parental administration.
41. A composition according to claim 30, wherein the compound is administered to a patient as a dosage unit at from about lgg/kg of body weight to about 500 mg/kg of body weight.
42. A composition according to claim 30, wherein the compound is administered to a patient as a dosage unit at from about lOg/kg of body weight to about 250 mg/kg of body weight.
43. A composition according to claim 30, wherein the compound is administered to a patient as a dosage unit at from about 20gg/kg of body weight to about 100 mg/kg of body weight.
44. A composition according to claim 30, wherein the composition is effective in treating and/or modulating human fertility, female hormone replacement, dysfunctional uterine bleeding, endometriosis, leiomyomas, acne, male-pattern baldness, osteoporosis, prostatic hyperplasia, cancer of the breast, cancer of the ovaries, endometrial cancer, prostate cancer, carbohydrate, protein and lipid metabolism, electrolyte and water balance, and functioning of the cardiovascular, kidney, central nervous, immune and skeletal muscle systems. Use of a compound having the formulae listed below, for the preparation of a medicament for treating patients requiring steroid receptor therapy, wherein said compounds have the following formulae: -Rio (II) R 0 (V (VI) (VUI) (Vri) ax) MXID (XIIII) (XIV) 375 R 6 HR (XV) OR R 1 4 R13 1 R16 R O R R20 1 R21 R3R 2 R12 R1 R° R 6 H R (XVI) OR 23 R24 R26 21R3 32 R R R 33 2 R27 R 22 R 2 9 (XVH) OR R 24 R 2 6 R21R3 R23 ~R 7 (XVUI) wherein: R is a heteroaryl optionally substituted with a Cl C 4 alkyl, F, Cl, Br, NO 2 CO 2 H, CO 2 R 2 CHO, CN, CF3, CH 2 0H or COCH 3 where R 2 is hydrogen, a CI C 4 alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, and where said RI heteroaryl is attached to compounds of formulas I and X through a carbon or nitrogen atom; R 3is hydrogen, a C 1 C 4 alkyl or perfluoroatkyl, hydroxymethyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl; 46 2 Rthrough R each independently are hydrogen, F, Cl, Br, 1, NO 2 CO 2 H, C0 2 R 2 2 2 2 2 COR CN, CF 3 CH 2 OH, a C I-C 4 alkyl or perfluoroalkyl, OR SR S(O)R S0 2 R, SO 3 H, S(NR 2 R 7 )R 2 S(O)(NR 2 R 7 )R 2 NR 2 R 7 aryl, heteroaryl or optionally substituted allyl, arylmthyl, alkynyl or alkenyl, where R 2has the definition given above, R 7is hydrogen, a C 1 C24 alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl or arylmaethyl, OR 8or NHR 8, where R 8is hydrogen, a C 1 C 6 alkyl or perfiucroalkyl, aryl, 2 2 heteroaryl or optionally substituted allyl, arylmethyl, SO 2 R2 or S(O)R; R 9and R 10each independently are hydrogen, a C 1 C 6 alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmnethyl, alkynyl or alkenyl, or R 9 and R 10 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, 2 2 7 2 7 OR or NR R where R and R have the definitions given above; R IIthrough R 15each independently are hydrogen, F, Cl, Br, 1, NO 2 CO 2 H, C0 2 R2 22 2 2 COR CN, CF 3 CH 2 OH, a C I-C 4 alkyl or perfluoroalkyl, OR 2 SR 2 S(O)R S0 2 R SQ 3 H, S(NR 2 R 7 )R 2 S(O)(NR 2 R 7 )R 2 NR 2 R 7 aryl, heteroaryl. or optionally substituted allyl, arylinethyl, alkynyl or alkenyl, where R2, R 7and R' have the definitions given above; W is 0, NH, NR 7 CH 2 CHOH, C=O, OC=O, O=CO, NR 7 C=O, NHC=O, 7 7 7 O=CNR O=CNH, SC=O, O=CS, or CHOCOR where R has the definition given above; X is CH 2 0, S or NR 7 where R 7 has the definition given above; R is hydrogen, OH, OR SR NR R optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, heteroaryl or C 1 CIO alkyl, where R 17 is a C 1 CIO alkyl or perfluoroalkyl, or is an optionally substituted allyl, arylmethyl, aryl or heteroaryl, and where R 2 and R 7 have the definitions given above; R 18 and R each independently are hydrogen, a C 1 C 6 alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or R 18 and R 19 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, OR 2 or NR7R 8 where R 2 R 7 and R 8 have the definitions given above; R 20 is a C 1 C 6 alkyl or an optionally substituted allyl, arylmethyl, alkenyl, aryl or heteroaryl; R is hydrogen, a C 1 C 4 alkyl or optionally substituted allyl, arylmethyl, aryl or heteroaryl; R is hydrogen, a.Ci C4 alkyl, F, C, Br, I, OR 2 N2R or SR 2 where R 2 and R 7 have the definitions given above; R 23 is hydrogen, CL Br, OR 8 NR2R a C 1 C 4 alkyl or perhaloalkyl, or is an optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl or heteroaryl, where R 2 R 7 and 8 R have the definitions given above; R 24 is hydrogen, F, Br, Cl, a C 1 C 4 alkyl or perhaloalkyl, aryl, heteroaryl, CF 3 CF 2 0R 25 CH 2 0R 25 or OR 25 where R 25 is a C1 C4 alkyl; R 26 is hydrogen, a C 1 C 4 alkyl, F, CI, Br, I, OR 2 NR 2 R 7 or SR 2 where R 2 and R 7 have the definitions given above; R 27 and R 28 each independently are hydrogen, a C 1 C 4 alkyl or perfluoroalkyl, heteroaryl, optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or an aryl optionally substituted with hydrogen, F, Cl, Br, OR 2 or NR2R or R 27 and R 28 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR 2 or N R 2R 7 where R 2 and R 7 have the definitions given above; R29 is hydrogen, a CI C 6 alkyl or an optionally substituted allyl, arylmethyl, aryl or heteroaryl; R 30 and R 31 each independently are hydrogen, a CI C 6 alkyl or an optionally substituted allyl, arylmethyl, aryl or heteroaryl, or R 30 and R 3 1 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, OR 2 or NR2R 7 where R 2 and R have the definitions given above; R 32 and R 33 each independently are hydrogen, a Ci C 4 alkyl or an aryl optionally substituted with hydrogen, F, Cl, Br, OR 2 or NR2R 7 or R 32 and R 33 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR 2 2 7 2 7 or NR R where R and R have the definitions given above; nis0 or 1; Y is O or S; Z is 0, S, NH, NR 2 or NCOR 2 where R 2 has the same definition given above; the wavy line in the compounds of formulas VII, XII, XIII and XVI represent an olefin bond in either the cis or trans configuration; and the dotted lines in the structures depict optional double bonds.
46. Use according to claim 45, wherein the compound is effective in treating and/or modulating human fertility, female hormone replacement, dysfunctional uterine .0 bleeding, endometriosis, leiomyomas, acne, male-pattern baldness, osteoporosis, prostatic hyperplasia, cancer of the breast, cancer of the ovaries, endometrial cancer, prostate cancer, carbohydrate, protein and lipid metabolism, electrolyte and water balance, and functioning of the cardiovascular, kidney, central nervous, immune and skeletal muscle systems.
47. A compound having the formulae: 379 OR(I R13 R R 7 R 82 R 2 ON N R H R 1 R 1 7 RO R 8' 00 NR OR() R 6 R 7 14 R R N 9 wherein: (IV) Z is 0, S, or NRI, where RI is hydrogen, R 2 C=O, R 2 C=S, R 3 OC=O, R 3 SC=O,. R 3 OC=S, R 3 SC=S or R 3 R 4 NC=O, where R 2 is hydrogen, a Ci C6 alkyl or perfluoroalkyl, optionally substituted allyl or aryl methyl alkenyl, alkynyl, aryl or heteroaryl, and where R 3 and R 4 each independently are hydrogen, a Ci C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl; .R 5 is hydrogen, R 2 C=O, R 2 C=S, R 3 OC=O, R 3 SC=O, R 3 OC=S, R 3 SC=S, or R 3 R 4 NC=O, where R 2 R 3 and R 4 have the same definitions as given above;, R 6 is hydrogen, a Ci C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, alkynyl, aryl, heteroaryl, R 3 0, HOCH2, R 3 OCH2, F, Cl, Br, I, cyano, R 3 R 4 N or perfluoroalkyl, where R 3 and R 4 have the same definitions as given above; R 7 through R 9 each independently are hydrogen, a Ci C6 alkyl, allyl or optionally substituted allyl, arylmethyl, alkynyl, ailkenyl, aryl, or heteroaryl, or R 8 and R 9 taken together form a three- to seven-membered carbocylic or heterocyclic ring; RIO is hydrogen, a Ci C6 alkyl, optionally substituted ally!, arylmethyl, aryl, or heteroaryl, R 2 C=Q, R 2 C=S, R 3 OC=O, R 3 SC=O, R 3 OC=S, R 3 SC=S or R 3 R 4 NC=O, where R 2through R4 have the same definitions as given above; RI 1 and R 12 each independently represent hydrogen, a C I C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, alkynyl, aryl, heteroaryl, R 3 0, HOCH2, R 3 OCH2, F, Cl, Br, 1, cyano, R 3 R 4 N or perfluoroalkyl, where R3and R have the same definitions as given above; R 13 is hydrogen, a CI C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, alkynyl, aryl, heteroaryl, R 3 0, FIOCH2, R 3 OCH2, R 3 R 4 N, C1720, CF2OR 3 or perfluoroalkyl, where R 3and-R have the same definitions as given above; R 14 is hydrogen, 'a C I C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, ZO alkynyl, aryl, heteroaryl, R 3 0, HOCH2, R 3 OCH2, F, CL, Br, I, cyano, R 3 R 4 N or perfluoroalkyl where R 3and R have the same definitions as given above; and R 15 is F, Cl, Br, 1, B(OR1 6 SnRl 7 Rl 8 R 19 or 0S02R 20 where R 16 is hydrogen or a C I C6 alkyl, R 17 through R 19 each independently represent a C I C6 alkyl, R 2 0 or heteroaryl, R 2 0 is a C I C6 alkyl, perfluoroalcyl, aryl, or heteroaryl, and R 2 has the same definition as given above.
48. A compound according to claim 45 selected from the group consisting of 1, 2 -Dihydro-2,2,4-trimthyl-5-coumarino[3,4..J]quinoline; 9-Fluoro- 1,2-dihydro-2,2,4- trimethyl-5-coumarino[3,4-fAquinoline;, 8-Fluoro-1I, 2 -dihydro-2,2,4-rinthyl.5 coumiarinot3,4-j]quinoline; 9-Chioro- l, 2 -dihydro-2,2,4trimethyps5counwino[3,4- J]quinoline; 8-Ethoxy- 1, 2 -dihydro- 2 2 4-imethyl6tifuoromethyl8pyridof5,6 giquinoline; and 1,,,-erhdo6hdoy224tiehl6tilooehl8 pyrido no[(5,6-glquino line.
49. A method for producing a 6-substituted-l1,2-dihydro N- I protected quinoline comprising: in a one-pot reaction, exchanging a 6-halo-i ,2-dihydro N- I protected quinoline of the formula: RA 6 RW X N- R 5 R N 2 R' R in the presence of an alkyflithium, followed by addition of an organo borate and acid treatment to yield the corresponding 6-boro- 1 ,2-dihydro N- I protected quinoline; coupling the 6-boro-i1,2-diiydro N- I protected quinoline with a coupling partner of the formula R 9Y in the presence of a palladium catalyst and base to yield a 6- substituted-i ,2-dihydro N- I protected quinoline of the formula: R 2 R P.3 wherein R is. hydrogen, a C 1 C 4 alkyl, aryl or heteroaryl; R 2and R 3each independently are a C 1 C 4 alkyl, aryl Or heteroaryl; R 4through R 6 each independently are hydrogen, a C I C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, alkynyl, aryl, heteroaryl, R 7 0, HOCH2, R 7 OCH2, F, CI, Br, 1, cyano, R 7 R 8 N or perfluoroalkyl, where R 7 and R 8 each independently are hydrogen, a C I C6 alkyl, optionally substituted aflyl, arylinethyl, aryl or heteroaryl; R 9is an aryl or heteroaryl; X is Br, Cl or 1; Y is Cl, Br, I or OSO 2 CF 3 and P is hydrogen, a Ci C6 alkyl, optionally substituted ailyl, arylmethyl, aryl or heteroaryl, RIOC=Q, RIOC=S, RI 1 0OC=O, RI ISC=O, RI 1 0C=S, R 1 ISC=S or RI 1 R 12 NC=O, where RIO is hydrogen, a C I C6 alkyl or perfluoroalkyl, optionally substituted allyl or aryl methyl alkenyl, alkynyl, aryl or heteroaryl, and where RI I and R1 2 each independently are hydrogen, a C 1 C6 ailkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl.
50. A method for producing a 6 -substituted- 1,2.dihydro N- I protected quinoline according to claim 49, further comprising, deprotecting the 6-substituted-I ,2-dihydro N- I protected quinoline to yield the corresponding 6-substituted-i ,2-dihydroquinoline.
51. A method for producing a 6 -substituted- 1,2-dihydro N- I protected quinoline comprising: in a one-pot reaction, exchanging a 6 -halo-1,2-dihydro N-I protected quinoline of the formula: R 6 R'1 RXN3 R in the presence of a reactive metal, followed by addition of an organoborate and acid treatment to yield the corresponding 6-boro- I ,2-dihydro N- I protected quinoline; coupling the 6-boro- 1 ,2-dihydro N- I protected quinoline with a coupling partner of the formula R 9Y in the presence of a palladium catalyst and base to yield a 6- substituted-i,2-dihydro N- I protected quinoline of the formula: R 6 R 1 R 2 R P wherein R is hydrogen, a C 1 C 4 alkyl, aryl or heteroaryl; R 2 and R 3 each independently are a C 1 C 4 alkyl, aryl or heteroaryl; R 4 through R 6 each independently are hydrogen, a Cl C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, alkynyl, aryl, heteroaryl, R 7 0, HOCH2, R 7 0CH2, F, Cl, Br, I, cyano, R 7 R 8 N or perfluoroalkyil, where R 7 and R 8 each independently are hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl; R 9 is an aryl or heteroaryl; X is Br, Cl or I; Y is Cl, Br, I or OSO 2 CF 3 and P is hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl, R 10 C=O, R 10 C=S, R 11 0C=O, RI ISC=O, R 1 1O C=S, R 1 1 SC=S or R I IR 12 NC=O, where R 10 is hydrogen, a Cl C6 alkyl or perfluoroalkyl, optionally substituted allyl or aryl methyl alkenyl, alkynyl, aryl or heteroaryl, and where R 1 1 and R 12 each independently are hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl.
52. A method for producing a 6-substituted- 1,2-dihydro N-1 protected quinoline according to claim 51, further comprising, deprotecting the 6-substituted-1,2-dihydro N-1 protected quinoline to yield the corresponding 6-substituted-1,2-dihydroquinoline.
53. A method for producing a 6-substituted-1,2-dihydro N-1 protected quinoline according to claim 51, wherein the reactive metal is selected from the group consisting of magnesium, zinc, and combinations thereof.
54. A method for producing a 6-substituted- 1,2-dihydro N- 1 protected quinoline comprising: in a one-pot reaction, exchanging a 6-halo-1,2-dihydro N-1 protected quinoline of the formula: in the presence of an alkyllithiurn, followed by addition of an organotin species to yield the corresponding 6-siannyl- I ,2-dihydro N- I protected quinoline; coupling the G-stannyl-l,2-dihydro N- I protected quinoline with a coupling partner of the formula R 9Y in the presence of a palladium catalyst to yield a 6-substituted- I ,2-dihydro N- I protected quino line of the formula: R9 R R 5 N R P wherein R Iis hydrogen, a C 1 C 4 alkyl, aryl or heteroaryl; R 2and R 3each independently are a C 1 C 4 alkyl, aryl. or heteroaryl; R4 through R 6each independently are hydrogen, a CI C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, alkynyl, aryL. heteroaryl, R 7 0, HOCH2, R 7 OCH2, F, CL Br, 1, cyano, R 7 R 8 N or perfluoroalkyl, where R 7 and R 8 each independently are hydrogen, a C1 C26 alkyl, optionally substituted allyL, arylmnethyl, aryl or heteroaryl; R 9is an aryl. or heteroaryl; X is Br, Cl or 1; Y is CL, Br, I or OSO 2 CF 3 and P is hydrogen, a C I C6 alkyl, optionally substituted allyl arylinethyl, aryl or heteroaryl, RIOC=O, RIOC=S, RI I0C=O, RI ISC=O, RI I0C=S, RI ISC=S or RI I 1 2 NC=O, where RIO is hydrogen, a CI C6 alkyl or perfluoroalkyl, optionally substituted allyl or aryl. methyl alkenyl, alkynyl, aryl or heteroaryl, and where R I and R 12 each indepe ndently are hydrogen, a C I C6 ailkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl. A method for producing a 6-substituted- 1,2-dihydro N- I protected quinoline according to claim 54, further comprising, deprotecting the 6-substituted- 1,2-dihydro N-1 protected quinoline to yield the corresponding 6 -substituted-1,2-dihydroquinoline.
56. A method for producing a 6-substituted-1,2-dihydro N-I protected quinoline comprising: in a one-pot reaction, exchanging a 6-halo-1,2-dihydro N-1 protected quinoline of the formula: R 6 R 1 R2 RN 3 R P in the presence of a reactive metal, followed by addition of an organotin species to yield the corresponding 6 -stannyl-1,2-dihydro N- protected quinoline; coupling the 6 -stannyl-1,2-dihydro N-1 protected quinoline with a coupling partner of the formula R Y in the presence of a palladium catalyst and base to yield a 6- substituted- 1,2-dihydro N- protected quinoline of the formula: R 6 R 1 R 9 R 2 R 4 P wherein R 1 is hydrogen, a C 1 C 4 alkyl, aryl or heteroaryl; R 2 and R 3 each independently are a C 1 C 4 alkyl, aryl or heteroaryl; R 4 through R 6 each independently are hydrogen, a Cl C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, alkynyl, aryl, heteroaryl. R 7 0, HOCH2, R70CH2, F, Cl, Br, I, cyano, R 7 R 8 N or perfluoroalkyl, where R 7 and R 8 each independently are hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl; R is an aryl or heteroaryl; X is Br, CI or I; Y is Cl, Br, I or OSO 2 CF 3 and P is hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl, 386 R 10 C=O, R10C=S, RI 1OC=0, RllSC=0, R 1 1 OC=S, R 1 ISC=S or R 1 1 R 12 NC=O, where R 10 is hydrogen, a Cl C6 alkyl or perfluoroalkyl, optionally substituted allyl or aryl methyl alkenyl, alkynyl, aryl or heteroaryl, and where R 1 1 and R 12 each independently are hydrogen, a CI C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl.
57. A method for producing a 6 -substituted-1,2-dihydro N-1 protected quinoline according to claim 56, further comprising, deprotecting the 6-substituted-1,2-dihydro N-1 protected quinoline to yield the corresponding 6-substituted-1,2-dihydroquinoline.
58. A method for producing a 6-substituted-1,2-dihydro N-I protected quinoline according to claim 56, wherein the reactive metal is selected from the group consisting of magnesium, zinc, and combinations thereof.
59. A method for producing a 6 -substituted-1,2-dihydro N-1 protected quinoline comprising: coupling the 6-halo-1,2-dihydro N-1 protected quinoline with a coupling partner of the formula R Y in the presence of a palladium catalyst and base to yield a 6- substituted-1,2-dihydro N-1 protected quinoline of the formula: Z0 R 6 R 1 R 9 R R P R wherein R 1 is hydrogen, a C 1 C 4 alkyl, aryl or heteroaryl; R 2 and R 3 each independently. are a C 1 C 4 alkyl, aryl or heteroaryl; R 4 through R 6 each independently are hydrogen, a Cl C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, alkynyl, aryl, heteroaryl, R 7 0, HOCH2, R 7 0CH2, F, Cl, Br, I, cyano, R 7 R 8 N or perfluoroalkyl, where R 7 and R 8 each independently are hydrogen, a C I C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl; R 9is an aryl or heteroaryl; X is Br, Cl, I Or OSO 2 CF 3 Y is B(OR 10)2 Or SnR IIR 1 2 where R0is hydrogen or a C 1 I C 4 alkyl, and where RIIthrough R 3each independently are a C 1 C 4 alkyl; and P is hydrogen, a Ci C6 alkyl, optionally substituted allyl, aryimethyl, aryl or heteroaryl, R 14 C=O, R 14 C=S, R 15 OC=O, R 15 SC=O, R' 5 0C=S, R 15 SC=S or R 15 Rl 6 NC=O, where R1 4 is hydrogen, a Cl C6 alkyl. or perfluoroalcyl, optionally substituted allyl or aryl, mnethyl. alkenyl, alkynyL, aryl or heteroaryl and where R 1 and R 16 each independently are hydrogen, a Ci C6 alkyl, optionally substituted allyl, arylmethyl aryl or heteroaryl. A method for producing a 6-substituted-i ,2-dihydro N- I protected quinoline according to claim 59, Further comprising, deprotecting the 6-substituted-I ,2-dihydro N- I protected quinoline to yield the corresponding 6-substituted-i ,2-dihydroquinoline.
61. A method for producing a nitro benzocoumarin comprising: coupling a 2-haio-5-nitrobenzoic acid derivative with a 2-methoxyphenyl boronic acid of the formula: R 2 ~OCH 3 II R 3 t~ ,B(OH) 2 M in the presence of a palladium catalyst and base to yield a biaryl carboxylate of the formula: 2 R' CH 3 RCo R 3 in a one-pot reaction, sequentially cyclizing the biaryl carboxylate to the corresponding nitrobenzocoumarin by deprotecting the biaryl carboxylate to afford the biaryl carboxylic acid, converting the biaryl carboxylic acid to the corresponding biaryl acid chloride, followed by cyclizing the biaryl acid chloride in the presence of a Lewis acid to yield a nitrobenzocoumarin of the formula: R 1 R2" O O R 3 0 R 4 R 5 NO 2 R 6 wherein R through R 6 each independently are hydrogen, F, Cl, Br, CN, CF3, a C 1 C 4 alkyl, or OR 7 where R 7 is hydrogen or a Ci C4 alkyl; and X is OR 8 or NR R 9 where R 8 and R 9 each independently are hydrogen, a C 1 C 4 alkyl or optionally substituted allyl, aryl methyl, aryl or heteroaryL
62. A method according to claim 61, further comprising, reducing the nitrobenzocournarin to the corresponding aminobenzocoumarin.
63. A method according to claim 62, further comprising, adding an optionally substituted allyl of the formula: S R1 2 to the aminobenzocoumarin to yield a coumarino[3,4-]quinoline of the formula: 389 R f N 12 wherein RI through R 9 have the same definitions as given in claim 67, and wherein R 10 is hydrogen, a C 1 C 4 alkyl, aryl or heteroaryl, and R 11 and R 12 each independently are a C 1 C 4 alkyl, aryl or heteroaryL
64. A method according to claim 63, further comprising, sequentially adding an organometallic to the coumarino[3,4-fjquinoline, followed by reduction to a chromeno[3,4-fjquinoline of the formula: R 1 R 2 n R,13 R N R12 R6 H wherein R 1 through R 12 have the same definitions as given in claim 69, and wherein R 13 is hydrogen, a Ci C 12 alkyl, OH, OR 4 or SR 14 where R 1 4 is a CI C 10 alkyl, CF 3 a five- membered heteroaryl optionally substituted with F, Cl, Br, CH 3 or CF3, a six-membered heteroaryl optionally substituted with F, Cl, Br or CH 3 or an aryl optionally substituted with hydrogen, F, Cl, Br, OR 15 or NR 2 15, where R 15 is hydrogen or a CI C 4 alkyl. A method for producing a 5H-chromeno [3,4-flquio line comprising sequentially adding an organometallic to a co umarino (3,4-flquino fine, followed by dehydration to yield a 5H-chromeno[3,4-flquinoline of the formula: R I R 1 Fl 0 R R R4 R F 1 1 F 6 HR 1 6 wherein R through R each independently are hydrogen, F, CI, Br, CN, CF 3 a CI C 4 alkyl 7 7 8 8 9 8 9 or OR where R is hydrogen ora CIC~4 alkyl; X isO or NR R where R and R each independently are hydrogen, a C 1 C 4 alkyl or optionally substituted allyl, aryl methyl, aryl or heteroaryl; R 10is hydrogen, a C 1 C 4 alkyl, aryl or heteroaryl; R IIand R 12each independently are a C 1 C 4 alkyl, aryl or heteroaryl; R 13is hydrogen, a Cj C 12 alkyl, OH, OR 14or SR 1, where R 14is a CI CIO alkyl, CF 3 a five-membered heteroaryl optionally substituted with F, Cl, Br, CH 3 or CF 3 a six-membered heteroaryl optionally substituted with F, Cl, Br or CH 3 or an aryl optionally substituted with hydrogen, F, Cl, Br, OR 15or NR 2 1, where R 15is hydrogen or a C 1 I C 4 ailkyl; and- the wavy line in the structure at R 13represents an olefin bond in either the cis or trans configuration.
66. A method of producing a linear tricyclic 1 ,2-dihydroquinoljne comprising: acylating a 3-nitroaryl of the formula: R 1 HZ NO 2 with an acylating agent of the formula: with an acylating agent of the formula: 0 P X to yield the corresponding 5-protected 3-nitroaryl; reducing the 5-protected 3-nitroaryl to the corresponding 5-protected 3- aminoaryl; adding an optionally substituted allyl of the formula: to yield a 5-protected 1,2-dihydroquinoline of the formula: R 1 R 3 0 p Al., cyclizing the 5-protected 1,2-dihydroquinoline by first deprotecting the Z group and then cyclizing in the presence of a P-keto ester of the formula: 0 0 OR'6 and Lewis acid to yield a linear tricyclic I, 2 -dihydroquinoline selected from the group consisting of: R 9 R 1 3 I R 4 R 02 R2NHRP Z N and R1 1 3 RR Z N 5 4 R9 Z N 1R 2 H an R 9 H 1 2 wherein R and R each independently are hydrogen, a C 1 C 4 alkyl, a hydroxy methyl, F, Cl, Br, I or CN; R 3is hydrogen, a C 1 C 4 alkyl, aryl or heteroaryl; R4 and R independently are a C 1 C 4 alkyl, aryl or heteroaryl; R 6 is hydrogen, a C 1 C 4 alkyL, CF 3 a five-membered heteroaryl. optionally substituted with F, Cl, Br, GB 3 or CF 3 a six-membered heteroaryl optionally substituted with F, Cl, Br or CH 3 or an aryl optionally substituted with 7 78 7 8 hydrogen, F, Cl, Br, OR7 or NR R where R and R8 each independently are hydrogen or a C 1 C 4 alkyl; R 9is hydrogen, a C 1 C 4 alkyl, CF 3 perhaloalkyl, CF 2 0R 1 0 CH 2 0R'0, or OR 0, where R 10is a C 1 C 4 alkyl; R IIand R 12 each independently represent hydrogen o r 6 6 a 1-C ly;Zi ,No ;Xi ,CB,1 No R, where R has the same meaning as above; and P is hydrogen, a Ci C6 alkyl, optionally substituted allyl, arylmethyl, aryl, or heteroaryl, R 13 C=O, R 13 C=S, R 14 0C=O, R 14 SC=O, R 14 0C=S, R 14 SC=S or R 14 R I 5 NC=O, where R 13 is hydrogen, a C I C6 alkyl or perfluoroalkyl, optionally substituted allyl or aryl methyl alkenyl, alkynyl, aryl or heteroaryl, and where R 14 and R 1 each independently are hydrogen, a Ci C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl.
67. A method of producing a linear tricyclic 1 2 -dihydroquinoline comprising: acylatine a 3-amino aryl of the formula: RI HZ9 NH 2 2 with an acylating agent of the formula: 0 P X in the presence of base to yield the corresponding 5-protected 3 -amidnoaryl; adding an optionally substituted allyl of the formula: RA 3 to yield a 5-protected I 2 -dihydroquino fine of the formula: P- cyclizing the 5-protected 1,2-dihydroquinoline by first deprotecting the Z group and then cyclizing in the presence of a 13-keto ester of the formula: 0 0 R OR 1 1 R 6 and Lewis acid to yield a linear tricyclic 1,2-dihydroquinoline selected from the group consisting of: wherein R and R 2 each independently are hydrogen, a CI C 4 alkyl, a hydroxy methyl, F,. Cl, Br, I or CN; R 3 is hydrogen, a C 1 C 4 alkyl, aryl or heteroaryl; R 4 and R 5 each independently are a C 1 C 4 alkyl, aryl or heteroaryl; R 6 is hydrogen, a C 1 C 4 alkyl, CF 3 a five-membered heteroaryl optionally substituted with F, CI, Br, CH 3 or CF 3 a six-membered heteroaryl optionally substituted with F, Cl, Br or CH 3 or an aryl optionally substituted with hydrogen, F, Cl, Br, OR 7 or NR R where R and R each independently are hydrogen or a C 1 C 4 alkyl; R 9 is hydrogen, a CI C 4 alkyl, CF 3 perhaloalkyl, CF 2 OR 10 CH 2 OR 10 or OR 10 where R 10 is a C 1 C 4 alkyl; R 11 and R 12 each independently represent hydrogen or a CI C4 alkyl; Z is 0, N or S; X is F, Cl, Br, I, CN or OR 6 where R 6 has the same meaning as above; and P is hydrogen, a C1 C6 alkyl, optionally substituted allyl, arylmethyl, aryl, or heteroaryl, R 13 C=O, R 13 C=S, R1 4 0C=0, R 14 SC=0, R1 4 0C=S, R 14 SC=S or R14Rl5NC=O, where R 13 is hydrogen, a C1 C6 alkyl or perfluoroalkyl, optionally substituted allyl or aryl methyl alkenyl, alkynyl, aryl or heteroaryl, and where R 14 and R 1 each independently are hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryL
68. A method for determining the presence of one or more steroid receptors in a sample comprising combining a compound according to claim 1 with the sample containing one or more unknown steroid receptors and determining whether said compound binds to a receptor in the sample.
69. A ligand-steroid receptor complex formed by the binding of a compound 0 according to claim 1 to a steroid receptor. A method of purifying steroid receptors comprising combining a compound according to claim 1 with a sample containing steroid receptors, allowing said compound to bind said steroid receptors, and separating out the bound combination of said compound and said steroid receptors. A method of purifying steroid receptors comprising combining a compound according to claim I with a sample containing steroid receptors, allowing said compound to bind said steroid receptors, and separating out the bound combination of said compound and said steroid receptors. Dated this 26th day of September 2003 LIGAND PHARMACEUTICALS INCORPORATED By their Patent Attorneys GRIFFITH HACK Fellows Institute of Patent and Trade Mark Attorneys of Australia