AU2776100A - Steroid receptor modulator compounds and methods - Google Patents

Description

r r

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): 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 me/us: DOCKET NO.

016-0014A.WO 1 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.

Back2round 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, 15 889 (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.

20 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." H.\PriyanLka\K-p\specM5977-96.STEROD RECEPTOR.doc 17/01/00 DOCKET NO.

016-0014A.WO 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 (17ct-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 10 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.

HoPri\anka\,=pPcCM597796.sEROID RECEPTORdoc 17/01/00 DOCKET NO.

016-00 14A.WO 3 Prom-st., 97 (Moscow, 1967). However, no biological activity of any kind has been ascribed to these compounds.

H-.Priyanka\Kfep\specM5977-96.SThRO[D RECEPTIfR-dOC 17/01/00 DOCKET NO.

016-0014A.WO 4 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 10 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 Smatter, in which there is illustrated and described preferred embodiments of the invention.

*oo *w ii H,.Pranka\Ko-p\specM597796.STEROID RECEPTORdoc 17/01/00 DOCKET NO.

016-0014A.WO 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, 10 including polyaromatic rings.

The term heteroaryl refers to an optionally substituted five-membered heterocyclic V-0 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 15 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 4 8 3 9 N 2 1 H:\Priyaa\Kp\spcS597796.STROID RECEPIORdoc 17/01/00 DOCKET NO.

016-0014A.WO 6 An indeno[2,1-Jlquinoline is defined by the fol-lowing structure. Compounds of structure 17 herein are named as indeno 1 -Aquino lines.

8 ~54 N 2 11 1 C C

CC

A ben zof b]furano[3,2-glquinofine is defined by the fol-lowing structure.

Compounds of structure 16 herein are named as benzo furano[3,2-g] quino lines.

7 6 11 1 See.

S

A ben zo~b]fu rano[2,3.fl quinoline is defined by the following structure.

Compounds of structure 17 herein are named as benzo[b]furano[2,3-flquinolines.

11 1 An indolo[3,2-glquinoline is defined by the following structure. Compounds of structure 16 herein are named as indo lo [3,2-g]quino lines.

HI\Prnyanka\Kemp~specM\5977-96.SThROIfl RECEPTOfR4doe 17/01/00 DOCKET NO.

016-0014A.WO 7 6 ty 2 H 1 An indololl2,3-flquinoline is defined by the following structure. Compounds of structures 17 and 29 herein are named as indolo [2,3-JAquino lines.

S

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

12 1 A SH-chromenoll3,4-JAquinoline is defined by the following structure. Compounds of structures 34, 35, 42, 45 to 54, 93, 95, 97 to 99, IA, 4A, 7A to 11A, 17A to 19A and to 27A herein are named as 5H-chro meno [3,4-Jlquino lines.

7 6 12 1 H\Priyanka\Coop\specMS4977-96.STER OID RECEPTORdoc 17/01/00 DOCKET NO.

016-00 14A.WO 8 An 8-pyranono[5,6-glquinoiine is defined by the following structure. Compounds of structures 57 60 63 69 73 28A 33A, 34A, 37A 38A 40A 41A 45A, 65A and 67A herein are named as 8-p yranono quino lines.

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

.Compounds of structures 57 (R 2

=R

3 =benzo, 60 (R 2

=R

3 =benzo, and 63 2

=R

3 =benzo, Z=0) herein are named as lO-isocoumarino[4,3-glquinolines.

7 6 44 0 0N 1 A lO-isoquinolinoll4,3-g]quinoline is defined by the following structure.

Poe. Compounds of structures 57 (R 2

=R

3 =benzo, Z=NH), 60 (R 2

=R

3 =benzo, Z=NH), and 63 *Go:

(R

2

=R

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

7 8 N6

N

0 NN 11 H 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 H.\riyaL\-p~pet\497796.TERIDRECEPTOR.doc 17/01/00 DOCKET NO.

016-0014A.WO 9 70A, 72A, 74A, 79A, 80A, 81A and 84A herein are named as 8-pyridono[5,6g]quinolines.

6 5 4 82 0 N N 9H 10 1 A 1OH-isochromneno[4,3-gjquinoline is defined by the following structure. Compounds of structures 61 (R 2

=R

3 =benzo, Z=0) and 62 (R 2

=R

3 =benzo, Z=O) herein are named as I1OHisoc hromeno [4,3-g]quinolines.

54 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 8H-pyrano[3,2-g]quinolines.

6 5 4 9 10 1 A lO-thioisoquinolino[4,3-glquinoline is defined by the folowing 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-thio isoquinotlino [4,3 quinotlines.

7 9 3.

2 12 1 H:\Priyanka\Keep'.specMS4977-96.SlhROID RECEPTOR.doc 17/01/00 DOCKET NO.

016-0014A.WO A 9-pyrido[3,2-g]quinoline is defined by the following structure. Compounds of structures 71 and 75 herein are named as 9-pyrido3,2-g]quinolines.

6 5 4 7QQ 8 N.

9 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 quinolines.

ed* 9 6 5 4 73 SrO)CnN 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]quinolines.

o 5 4 6 8 /N 2 N 2 .99.

*N N 9 H 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-o no quino lines.

6 5 4 73 8 2 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-]indolines.

H:\Priyanka\KepspecMS\977-96.STEROID RECEP1TOR.doc 17/01/00 DOCKET NO.

016-00 14A.WO it 6 5 4 3 7 2 An 5H-isochromneno[3,4-jjquinoline is defined by the following structure.

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

7 6 8 0 9 3* 12 1 H:\Pn\Kop\pceM977-96.S'MROID RRCEPIORdoc 17/01/00 DOCKET NO.

016-0014A.WO 12 Detailed Description of Embodiments of the Invention Compounds of the present invention are defined as those having the formulae: R 4 R 3

S'

to to00 13

R

R14 (111) '9

(IV)

H.IPniya~da\K~p\pcM5977-96.sTEROrD RECEPTOR-doc 17/01/00 DOCKET NO.

0 16-0014A.WO 13

R

R12 1 RH

R

R 6 H R

(V)

OR

R13R140R6 R XN 0 1 12 I 18 R 11 R H 10 a..R R 5

N

6 R R.

(VI)

OR

R 14 R 13 R R 3 R NRR R12 *1 R lo;0

(VUL)

OR

I RRm R R 6 HR9

(VIII)

OR

R24 R26 R3 R23 RR 27~ Y Z N 28

R

22 A 9

(IX)

OR

H.Vanka\Kp\spcMS97-96.STEROD RECEPTflR~do 17/01/00 DOCKET NO.

016-00 14A.WO 14 R 4 R21 R3 R x I R 10

H

1 2

A

6

HR(X)

R 21 3 R 1 RR 09:R 14N x1 .0R15 R N 5R W 0000(XI) *0 OR 1l4 13

RR

R 0I RR 21 000R12 R w

R

5 R R(XII)

OR

00*0 a 14 X R

R

12 -o R N% R R11 R 6 N

OR(XIII)

R13 R4 0 R 1 6 3 2 R RNR3 12 11 I 10

(XIV)

OR

H:,\Priyanka\Koep\spccM5977-96.S'rERO[D PECEP'IOR.doc 17/01/00 DOCKET NO.

016-0014A.WO

A

.Rio

(XV)

*SSS

S.

(XVI)

(XVIII)

x

(XVIII)

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

C

4 alkyl, F, Cl, Br, NO 2

CO

2

H,

2 2 C0 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 Iheteroaryl is attached to compounds of formulas I and X through a carbon or nitrogen atom- HAPriaa\Kep\speci\59Th-96.SmROD PECEP'IOR.doc 17/01/00 DOCKET NO.

016-0014A.WO 16

R

3 is hydrogen, a C 1

C

4 alkyl or perfluoroalkyl, hydroxymethyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl; 4 6 2 R through R each independently are hydrogen, F, Cl, Br, I, NO 2

CO

2 H, CO 2

R

2

COR

2 CN, CF 3 CH20H, a C 1

-C

4 alkyl or perfluoroalkyl, OR 2

SR

2

S(O)R

2

SO

2

R

2

SO

3 H, S(NR2R7)R2, S(O)(NR2R7)R 2 N2R 7 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 e 8 8 8 arylmethyl, OR or NHR where R is hydrogen, a C 1

C

6 alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl or arylmethyl, SO 2 R or S(O)R2; 9 10 R and R10 each independently are hydrogen, a C1 Cg alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or R9 and R1 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, OR 2 or NR2R 7 where R 2 and R 7 have the definitions given above; 15 R through R 15 each independently are hydrogen, F, Cl, Br, I, NO 2

CO

2

H,

CO

2 R COR CN, CF 3 CH20H, a Ci-C 4 alkyl or perfluoroalkyl, OR SR 2

S(O)R

2

SO

2

R

2

SO

3 H, S(NR2R )R 2 S(O)(NR2R )R2, NR2R aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, where R 2 R and R have the definitions given above; W is O, NH, NR 7 CH2, CHOH, C=O, OC=0, O=CO, NR 7 C=O, NHC=O,

O=CNR

7 O=CNH, SC=O, O=CS, or CHOCOR 7 where R 7 has the definition given above, except that when W is NH, CH 2 or O in the compounds of formula III, then R 11 through

R

14 and R 4 cannot all be hydrogen when R 3

R

9 and R1 0 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 O or NH in the compounds of H:\Pnyanka\Kqp\spccM 5977-96.STEROID RECEPTOR.doc 17/01/00 DOCKET NO.

016-0014A.WO 17 formula IV, then R through R and R 1 through R 14 cannot all be hydrogen when R 3

R

and R 10 are all CH 3 7 7 X is CH 2 O, S or NR where R has the definition given above;

R

16 is hydrogen, OH, OR 17 SR NR2R 7 optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, heteroaryl or Cl C 10 alkyl, where R 17 is a C 1

C

10 alkyl or perfluoroalkyl, or is an optionally substituted allyl, arylmethyl, aryl or heteroaryl, and where .i R 2 and R 7 have the definitions given above; 18 19 R and R each independently are hydrogen, a C 1

C

6 alkyl or perfluoroalkyl, 18 aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or R 8 and S19

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 have the definitions given above; R is a C 1

C

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

R

21 is hydrogen, a C 1

C

4 alkyl or optionally substituted allyl, arylmethyl, aryl or 15 heteroaryl;

R

22 is hydrogen, a C1 C 4 alkyl, F, C1, Br, I, OR N2R 7 or SR 2 where R 2 and R have the definitions given above;

R

23 is hydrogen, Cl, Br, F, OR 8 NR2R 7 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 R 8 have the definitions given above;

R

24 is hydrogen, F, Br, Cl, a C 1

C

4 alkyl or perhaloalkyl, aryl, heteroaryl, CF3,

CF

2 0R 25

CH

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

C

4 alkyl, except that R 24 cannot be CH3 when Z is 0, R 2

R

23

R

2 and R 29 are all hydrogen and R 3

R

27 and R 2 8 all are CH 3

R

26 is hydrogen, a C1 C 4 alkyl, F, C1, Br, I, OR 2 N2R 7 or SR 2 where R 2 and R 7 have the definitions given above; H\Priyanka\K-ep\spccM5977-96.S'hROID RECEPTORdoc 17/01/00 DOCKET NO.

016-0014A.WO 18

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 2 27 27 28 substituted with hydrogen, F, C1, Br, OR or NR2R 7 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 NR2R 7 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; 30 31

R

30 and R 31 each independently are hydrogen, a C1 C6 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; 32 33 R and R 33 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 3 3 taken together can g form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR 2 2 7 2 7 15 or NR2R 7 where R and R have the definitions given above; n is 0 or 1; Y is O or S; 2 2 2 Z is 0, S, NH, NR or NCOR where R 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

C

4 double bond in the nitrogen bearing ring of compounds of formula II, then

R

1 through R cannot all be hydrogen and R 3 R and R 10 cannot all be methyl, and further except when R 2 is an aryl, R 22

R

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

NR

2 then R 2 cannot be a C 1

C

4 alkyl.

Hw\Priyana\Kfep\.pec45-96.STEROD RECEPTOR.doc 17/01/00 DOCKET NO.

016-0014A.WO 19 Preferably, the compounds of formulae I, II, III, 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.

The present invention also provides a pharmaceutical composition comprising an effective amount of steroid receptor modulating compounds of the formulae: 9.

R

1

R

9

R

1

R

9

R

R 2 z

R"

N R.3 N 3

R

2 10 R 4 OR R 4 OR R 4 .oo wherein: 93

:R

3

R

1 through R each independently are hydrogen, a C1 C6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl; 15 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 C1 C6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, and wherein R 6 and R 7 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

1 1 is hydrogen, a C1 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 and R 3

R

1 and R 9

R

10 and R 11

R

1 and R 10 and/or R 11 and R 2 when taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, OR or NR6R 7 where R through R have the definitions given above, provided, however, HEPrianka\Kp\pc\5977-96STEROD RECEPTOR.doc 17/01/00 DOCKET NO.

016-0014A.WO that R R 2

R

0 and R 1 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=0,

R

6

R

7 NC=0, R60C=0, perfluoroalkyl, haloalkyl, 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 Cl C6 alkyl or optionally substituted 10 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] H.Uiyaa"\Kfep\specM5977-96.STEROID RECEPT1fR.doc 17/01/00 C..f C CC C C C C 91N DOCKET NO.

016-0014A.WO O N

'N

S I Sl 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

9

R

1 N R 3

R

4 wherein R 1 through R 1 1 and Z have the same definitions as given above.

H:\Priyanka\Keep\specM5977-96.STERO[D RECEPTOR.doc 17/01/00 DOCKET NO.

0 16-0014A.WO In a preferred aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a steroid receptor modulating compound of the formulae:

RH

4 R 3 -R114 3 R R Rio

(III)

(IV)

H,.Priyak\Kmep\pcM597796.STPROD RECEPTflR.doc 17/01/00O DOCKET

NO.

016-00 14A.WO 24

RH

13 R 1 0R 1 R121 H R1 R

OR

13 R 14 1 6 R FRI R19 R12 R 1 R W R 1 11i 10

RH

6

(VI)

.9..OR 14 20 13 N 9

H

1 Ne. 1 ORi 14

H

13 H 16 R 21 R3 R12 x H e N H HR -6 H R 9 OR (ViII) R24 R26R3 R23 H Z N N8 N 2 A 27 OR

~(X

H\Prynka\ep\spcl\5977-96.SmROID RECEPTORAdo 17/01/00 DOCKET NO.

016-0014A.WO R 4 R 218R3 R N 9

RH

6 H R

(X)

OR

13 R11 4 21 3 R 1 0 R14 x 1

R

R 6 H R

OR

13 4 .:1321 RR R

RH

12 x 11

R

NN

OR

R 13

R

1 0 3 21 a..12 O-o SRR RR C R 1 11 I 1 R6

HR

(XIII)

OR

R H3R 14 0R16 32

H

12 0 11 I

(XIV)

OR

H:.\Pniyanka\K-p\'..M5977-96.STEROID RECEPTOR-do 17/01/00 DOCKET NO.

016-0014A.WO R 10

(XV)

(XVI)

(XVII)

(XVIII)

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

C

4 alkyl, F, Cl, Br, N0 2

CO

2

H,

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 Iheteroaryl is attached to compounds of formulas I and X through a carbon or nitrogen atom-; H:.\Pranka\Kcp\spcM597796STmROID RECEPTOR-doc 17/01/00 DOCKET NO.

016-0014A.WO 27 R3 is hydrogen, a C1 C 4 alkyl or perfluoroalkyl, hydroxymethyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl; 4 6 2 R through R each independently are hydrogen, F, Cl, Br, I, NO 2

CO

2 H, CO 2

R

2 2 2 2 2 COR2, CN, CF 3 CH20H, a C 1

-C

4 alkyl or perfluoroalkyl, OR 2, SR S(O)R, SO 2

R

2 72 2 72 2 7

SO

3 H, S(NR2R )R2, S(O)(NR2R7 NR R aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, where R2 has the definition given above, R7 is hydrogen, a C 1

C

4 alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl or 8 8 8 arylmethyl, OR or NHR where R is hydrogen, a C 1

C

6 alkyl or perfluoroalkyl, aryl, 10 heteroaryl or optionally substituted allyl, arylmethyl, SO 2 R2 or S(O)R2 R and R10 each independently are hydrogen, a C 1

C

6 alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alynyl or alkenyl, or R 9 and R 10 taken together can form a three- to seven-membered ring optionally substituted with 2 2 7 2 7 hydrogen, F, OR, or NR2R7, where R and R have the definitions given above; 11 R through R each independently are hydrogen, F, Cl, Br, I, NO 2

CO

2

H,

CO

2 R2 COR2 CN, CF 3

CH

2 OH, a C 1

-C

4 alkyl or perfluoroalkyl, OR2, SR2 S(O)R2 SOR2, SO3H, S(NR2R7 )R2, S(O)(NR 2 R 7

)R

2

N

2 R7, aryl, heteroaryl or optionally 2 7 8 substituted allyl, arylmethyl, alkynyl or alkenyl, where R2, R and R have the definitions given above; W is O, NH, NR 7

CH

2 CHOH, C=O, OC=O, O=CO, NR 7 C=O, NHC=O,

O=CNR

7 O=CNH, SC=O, O=CS, or CHOCOR 7 where R 7 has the definition given above; X is CH 2 O, S or NR where R 7 has the definition given above; 16 17 17 2 7 R16 is hydrogen, OH, OR 7, SR7, NR R optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, heteroaryl or C 1

C

10 alkyl, where R17 is a C 1

C

10 alkyl or perfluoroalkyl, or is an optionally substituted allyl, arylmethyl, aryl or heteroaryl, and where R2 and R7 have the definitions given above; H1Priyank2alKeeppecM4977-96.STEROID RECEPTOR.doc 17/01/00 DOCKET NO.

016-0014A.WO 28

R

18 and R 19 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 or NR7R where R 2

R

7 and R 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

2 1 is hydrogen, a C 1

C

4 alkyl or optionally substituted allyl, arylmethyl, aryl or heteroaryl; 22 2 27 2 2 7 R is hydrogen, a C 1 C4 alkyl, F, Cl, Br, I, OR N2R or SR 2 where R 2 and R 7 10 have the definitions given above;

R

23 is hydrogen, C, Br, OR NR R a C 1

C

4 alkyl or perhaloalkyl, or is an 9. optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl or heteroaryl, where R 2

R

7 and R have the definitions given above; 24 R is hydrogen, F, Br, Cl, a C 1

C

4 alkyl or perhaloalkyl, aryl, heteroaryl, CF 3 25 25 25 25

CF

2 0R 2 5

CH

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

C

4 alkyl;

R

26 is hydrogen, a C1 C4 alkyl, F, C, Br, I, OR 2 N2R 7 or SR 2 where R 2 and R 7 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, C1, Br, OR 2 or NR2R, 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 N2R 7 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; H:\PRiyaaka\Kp\specM4597796STROID RECEPTfR.do 17/01/00 DOCKET NO.

016-0014A.WO 29

R

30 and R 31 each independently are hydrogen, a C 1

C

6 alkyl or an optionally substituted allyl, arylmethyl, aryl or heteroaryl, or R30 and R31 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 7 have the definitions given above;

R

32 and R 33 each independently are hydrogen, a C 1

C

4 alkyl or an aryl optionally substituted with hydrogen, F, C1, Br, OR 2 or NR2R 7 or R 32 and R 3 3 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, C1, Br, OR 2 2 7 2 7 or NR R 7 where R and R have the definitions given above; n is 0 or 1; 10 Y is O or S; 2 2 2 Z is O, S, NH, NR or NCOR where R 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, III, 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 o 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 35 R through R 35 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 HPraoa\Kep\p scM5977-96.S2RO[D RECEPTORdoc 17/01/00 DOCKET NO.

016-0014A.WO 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 S 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 H.\Priyakam\Kop\.pocM5977-96.SThROID RECEPTOR.doo 17/01/00 DOCKET NO.

016-0014A.WO 31 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 0*0 •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-l-methylpyrazol-3-yl)-1,2-dihydro- H:\Prianka\vp\pc M977-96.STEROID RECEPTfR.doc 17/01/00 DOCKET NO.

016-0014A.WO 32 2 ,2, 4 -timethylquino line (Compound 104); 1 ,2-Dihydro-2,2,4-timethyl-6-(3p yridyl)quino line (Compound 105); 6-(4-Fluorophenyl)- 1,2,-dihydro-2,2,4trimethyiquinofine (Compound 106); 1 ,2-Dihydro-6- (3-trifluoromethylphenyl)-2,2,4trimethyiquino line (Compound 107); 1 2 -Dihydro-2,2,4-trirethyl-6-(4nitrophe nyl)quino line (Compound 108); 6-(2,3-Dichlorophenyl)- 1,2-dihydro-2,2,4trimethyiquino line (Compound 109); 1 2 -Dihydro-6-(2-hydroxycarbony14-nitrophenyl)> 2 2 4 -trimethylquinoiline (Compound 110); 6 -(3,4-Dichlorophenyl)- 1 ,2-dihydro-2,2,4trimethyiquino line (Compound 111); 4-Ethyl-i 1, 2 -dihydro-2,2-dimethyl-6-p henylquino line (Compound 112); l, 2 -Dihydo- 2 2 -dimethy-6-phenyl.4-propylquino line (Compound 113); 6- (2-Chlorophenyl)- 1, 2 -dihydro-2,2,4-trimethylquino line (Compound 114); 1 ,2-Dihydro- 400000 2 ,2,4-trimethylindeno 1,2-glquino line (Compound 115); 1 ,2-Dihydro-2,2,4tr m t yin e o 2 1tooi oi e o po n 1 r m 2 d h d o 2 2 4 trimethylindeno [21 quinoltine (Compound 117); 1 ,-Drm--ihydro-2,2,4- :trimethylbenzo[b]furano[32g]quinoline (Compound 118); 1,2-Dihydro-2,2,4trirnethylbenzo [bifurano [2,3-J]quinoline (Compound 119); 6-Fluoro- 1,2-dihydro-2,2,4trimethylindeno (2,1 -flquinoline (Compound 120); 9-Fluoro- 1,2-dihydro-2,2,4- 0 trimethylindeno 1, 2 quino line (Compound 121); 1 ,2-Dihydro-9-hydroxylmethy-2,2,4-.

trimethylindeno [1,2-gj quino line (Compound 122); 8-Chioro- 1,2-dihydro-2,2,4trimethylindeno 1,2-g] quino line (Compound 123); 8-Fluoro- 1,2-dihydro-2,2,4trimethylindeno 1, 2 -glquino line (Compound 124); 8-Acetyl- 1,2-dihydro-2,2,4trimethylindeno [1 2 -gjquinoline (Compound 125); 6-Fluoro- 1,2-dihydro-2,2,4- *trimethylindeno 2-g] quino line (Compound 126); 7-Bromo-1,2-dihydro-2,2,4trimethylindeno [2,1 -Jquinoline (Compound 127); 1 ,2-Dihydro-2,2,4-trimethylp7nitroindeno 1 -fl quino line (Compound 128); 1 ,2-Dihydro-2,2,4-trimethy-8.

nitroindeno [I 2 quino line (Compound 129); 6,9-Difluoro- 1,2-dihydro-2,2,4trimethylindeno 1, 2 -glquino line (Compound 130); 7-Fluoro- 1,2-dihydro-2,2,4-trirnethyl- 11 (thiomethyl) indeno 1 -]quinoline (Compound 131); 5,8-Difluoro- 1,2-dihydro- hydroxy-2,2,4-trimethylindeno [1 2 -g]quinoline (Compound 132); 7,9-Difluoro- 1,2-dihydro- 1 O-hydroxy-2,2,4-trimethylindeno 1, 2 quino line (Compound 133); 7, 10-Difluoro- 1,2diyr-,,-rmty--xidn[,-lunln (Compound 134); 7,9-Difluoro- 1,2dihydro-2,2,4-trimethyl-.10-oxoindeno[ 1, 2 -glquinoline (Compound 135); 8-Fluoro- 1,2dihydro- 1 O-hydroxy-2,2,4-trimnethylindeno 1 2 -gllquino line (Compound 136); 8-Fluoro- 1,2- H.\P~aap\,p 597796.STROD RECEPTORAdo 17/01/00 DOCKET NO.

016-0014A.WO 33 dihydro- 2,2,4-trimethyl- 1 0- oxo indeno 1 quino line (Compound 137); 7-Fluoro- 1,2d ihydro -2,2,4-trimethyl- 8-nitro indeno 1, 2 quinoline (Compound 138); 5-Chioro- 1,2dihydro 1 0-hydro xy- 2,2,4-trimnethylindeno 1, 2-g] quiio line (Compound 139); 6-Fluoro- 1,2d ihydro-2,2,4-trimethyl- 1 0- oxoindeno 1 quino line (Compound 140); 6-Fluoro- 1,2dihydro- 1 0-hydroxy-2,2,4-trimnethylindeno 1 ,2-gjquino line (Compound 141); 5,8-Difluoro- 1 ,2-dihydro-2,2,4-trimethyl- 10- (trifluoroacetoxy)indeno 1,2-g]quino line (Compound 142); 6- (3,5-Difluorophenyl)- 1 2 3 4 -tetrahydro-2,2,4-trimethylquino line (Compound 143); 1,2- Dihydro-2,2,4-trimethylindo lo [3, 2 quino line (Compound 144); 5-Ethyl-i ,2-dihydro- 2,2,4-trimethylindo lo [2,3-fj quino line (Compound 145); 6- (3-Chiorophenyl)- 1,2-dihydro- 2,2,4-trirnethyiquino line (Compound 146); 6-(3,5-Difluorophenyl)-1,2-dihydro-2,2,4trimethyiquino line (Compound 147); 6-(3-Fluorophenyl)- 1,2-dihydro-2,2,4- *trimethyiquinoline (Compound 148); 1, 2 -Dihydro-2,2,4- trimethyl-6- (4-p yrid yl)quino line (Compound 149); 6-(3-Cyanophenyl)- 1, 2 -dihydro-2,2,4-trimethylquinoline (Compound 150); 6- (3 ,5-Dichlorophenyl) 1, 2 -dihydro -2,2,4-trimnethylquino line (Compound 151); 6- (2,3-Difluorophenyl)- 1, 2 -dihydro-2,2,4-trimethylquinoline (Compound 152); 1 ,2-Dihydro- 2 2 4 -trimnethyl-6-(pentafluorophenyl)quinoline (Compound 153); 1 ,2-Dihydro-2,2,4trimethyl-6- (trffluoroacetyl)p henyl] quino line (Compound 154); 1 ,2-Dihydro-2,2,4trimethyl-6- (1,3-pyrimid-5-yl)quino line (Compound 155); 6-(3-Cyanophenyl)-1,2,3,4tetrahydro-2,2,4-trirnethylquino line (Compound 156); 5 ,8-Difluoro- 1,2-dihydro-2,2,4trimethylindeno [1 ,2-g]quinoline (Compound 157); 7,1 0-Difluoro- 1,2-dihydro-2,2,4trimnethylindeno [2,1 -f]quinoline (Compound 158); 8-Cyano- 1,2-dihydro-2,2,4trimethylindeno [3 quino line (Compound 270); 6-(3-Cyano-5-fluorophenyl)- 1,2d ihydro-2,2,4-trimethylquino line (Compound 271); 6-(3-Cyano-4-fluorophenyl)- 1,2dihydro-2,2,4-trimethylquino line (Compound 272); 6-(3-Cyano-6-fluorophenyl)- 1,2d ihydro-2,2,4-trimethylquino line (Compound 273); 6- [5-fluoro-3-(trifluoromethyl)phenyl]- 1 2 -dihydro-2,2,4-trirnethylquinoline (Compound 274); 6-(3-chloro-2-methylphenyl)- 1,2dihydro-2,2,4-trimethylquino line (Compound 275); 1 ,2-Dihydro-2,2,4-trimethyl-6-(3nitrophenyl)quino line (Compound 276); 6-(3-Acetylphenyl)- 1,2-dihydro-2,2,4trimethyiqui-no line (Compound 277); 6 -(3-cyano-2-methylphenyl)- 1 ,2-dihydro-2,2,4trimethyiquino line (Compound 278); 1 2 -Dihydro-2,2,4-trimethyl-6-(3- H.Prnka\Kop\peciM5977-96.STEROD RECEPTOR~ow 17/01/00 DOCKET NO.

0 16-0014A.WO 34 methylp henyl)quino line (Compound 279); 6 -(5-Fluoro-3-nitrophenyl)- 1 ,2-dihydro-2,2,4trimethyiquino line (Compound 280); 1 ,2-Dihydro-6-(3-methoxyphenyl)22,4 trimethyiquino line (Compound 28 6-(5-Cyano-3-pyridyl)- 1 ,2-dihydro-2,2,4trimethyiquino line (Compound 282); 1 2 -Dihydro-2,2,4-trimethyl-6-(2-methyb3nitrophenyl)quino 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-trimnethylquino line (Compound 285); 6-(3-Cyano-5-fluorophenyl)- 1,2d ih ydro trimethyl-3-quino lone (Compound 286); 6-(3-Fluoro-2-methylphenyl)- 1,2dihydro-2,2,4-trimethylquino line (Compound 287); l,2-Dihydro-2,2,4-trimethyl-6-(3- 10 (opud, methylthiophenyl)quino line (Cmon 28) 6-5Clr-.tiey)12-dihydro-2,2,4trimethyiquinoline (Compound 289); 1 ,2-Dihydro-2,2,4-trn-ethyl-6-(3-methylp2 thienyl)quinoline (Compound 290); 8-Fluoro- 1,2-dihydro-2,2,4-trimethyl-6-(3nitrophenyl)quino line (Compound 291); 1 2 -Dihydro-6-(3-nitrophenyl)-2,2,4, 8tetramethyiquinoline (Compound 292); 6- (5-Bromo-3-pyridyl)- 1,2-dihydro-2,2,4trmtyqioln Cmon*9) -(-rm--yiy)12dhdo22 line (Compound 293); 6 -(3-Bromo-2-pyidyl)-1,2-dihydro-2,2,4triniethyiquino line (Compound 295); 1 ,2-Dihydro-6-(2,3 ,5,6-tetrafluoro-4-pyridyl)-2,2,4trimethyiquino line (Compound 296); 5, 8-Difluoro- 1,2-dihydro-6-(3-nitrophenyl)-2,2,4trimethyiquinoline (Compound 297); 2,4-Diethyl-8-fluoro- 1,2-dihydro-2-methyl-6-(3- 0.0. 20 nitrophenyl)quino line (Compound 298); 6-(3-Bromophenyl)- 1,2-dihydro-2,2,4- 0 0 trimethyiquino line (Compound 299); 1 ,2-Dihydro2,2,4-nethylp&(5-nitro-2 thienyl)quino line (Compound 300); 1 2 -Dihydro-6-(2,4,5-trifluorophenyl)..22,4 trimethyiquinoline (Compound 301); 6 3 -Bromo-5-fluorophenyl)- 1,2-dihydro-2,2,4trimethyiquino line (Compound 302); 6-(5-Carboxaldehyde-3-thienyl)-1 ,2-dihydro-2,2,4trimethyiquinoline (Compound 303); 1 2 -Dihydro-2,2,4,7-tetramethyl.6-(3nitrophenyl)quino line (Compound 304); 6 -(5-Fluoro-2-methoxy-3-nitrophenyl> 1,2dihydro-2,2,4-trimethylquino line (Compound 305); 6 3 -Chloro-2-methoxyphenyl)- 1,2dihydro-2,2,4-trirnethylquino line (Compound 306); 1 ,2-Dihydro-2,2,4-trimnethyl-6-(2,3,4-, trifluorophenyl)quino line (Compound 307); 6 3 -Bromo-2-methylphenyl)- 1 ,2-dihydro- 2,2,4-trimethyiquino line (Compound 308); 7-Chloro- 1,2-dihydro-2,2,4-timethyl-6-(3nitrophenyl)quinoline (Compound 309); 5-Chloro- 1,2-dihydro-2,2,4-trimethyl-6-(3- H:-\Piak\K~op\,pecM\597796.S'hROD RECEPTIORdoc 17/01/00 DOCKET

NO.

0 16-0014A.WO nitrophenyl)quino line (Compound 310); 8-Chioro- 1,2-dihydro-2,2,4-methyl-6-(3nitrophenyl)quino line (Compound 311); 8-Ethyl- 1,2-dihydro-2,2,4-timethyl-6-(3nitrophenyl)quino line (Compound 312); 9-Chioro- 1,2-dihydro-2,2-dirnethyl-5co umarino [3,4-flquino line (Compound 313); 1 2 -Dihydro-9-methoxy-2,2,4-trimethyls5 coumnarino [3,4-Jlquino line (Compound 314); 9-Fluoro- 1,2-dihydro-2,2,4,1 coumnarino quino line (Compound 315); 1 2 -Dihydro-2,2,4,9-tetramethyl-5co umarino quino line (Compound 316); 7-Chloro- 1 2 -dihydro-2,2,4-trimethy[-5coumnarino [3,4-flquino line (Compound 317); (R/S)-9-Chloro- 1,2-dihydro-5-methoxy-2,2,4quino line (Compound 319); (RIS)-9-Fluoro- 1,2-dihydro- 10 2 2 4 -trimethyl-5H-chro meno [3,4f] quino line (Compound 328); 6-(5-Cyano-2-thienyl)-1,2dihydro-2,2,4-timethylquinoljne (Compound 45 6-(5-Cyano-3-thienyl)- 1 ,2-dihydro- 2 2 4 -trimethylquinoline (Compound 452); 6 -(3-Formylphenyl)- 1,2-dihydro-2,2,4trimethyiquino line (Compound 453); 1 ,2-Dihydro-2,2,4-trmethylb6-.[3- (methylsulfo nyl)p henyl~quino lne (Compound 454); (R/S)-6-(3-Cyano-5-fluorophenyl..

1 2 3 4 -Tetrahydro-2,2,4-trimethylquinoijne (Compound 455); and (R/S)-9-Chloro- 1,2d ihydro-2,2,4-timethyl-5-pheny1.5H..cho meno [3,4-flquino line (Compound 456).

Representative PR modulator compounds agonists and antagonists) according to the present invention include: (R/S)-5-Buty-1,2-dihydro2,2,4.jmethylSHchromeno 3 4 -Jlquino line (Compound 160); (RIS)- 1 2 -Dihiydro-2,2,4-trimethy1-5-pheny1- 5H-chromeno 3 4 -Jlquinoline (Compound 161); (RIS)- 1, 2 ,3,4-Tetrahydro-2,2-dimethyl-4.

eo[,-lqioln (Compound 162); Chiorophenyl)- l, 2 -dihydro-2,2,4-trimethyl-5H-chro meno [3,4-flquino line (Compound 163); (R/S)-5-(4-Chlorophenyl)- l, 2 3 4 -tetrahydro-2,2-dimethyb4methylidene-5Hchro meno [3 4 quino line (Compound 164); (4-Fluorophenyl)- 1,2-dihydro-2,2,4trimethyl-SH-c-womeno [3 ,4-flquino line (Compound 165); (R/S)-5-(4-Acetylphenyl)- 1,2d ihydro -2,2,4-trimethyl5Hc .romeno [3,4-fAquino line (Compound 166); (RIS)- 1,2-Dihydro- 2 2 4 -trimethyl-5-(4-methylphenyl)SH-chromeno [3,4-flquinoline (Compound 167); (RIS)l, 2 -Dihydro-5-(4methoxypheny)2,2,4trimethyl.sH-chomel 0 [3 ,4-fjquino lne (Compound 168); (RIS)- 1, 2 -Dihydro-2,2,4-trmethyl 5- 4 chro meno [3, 4 -fl quino line (Compound 169); (RIS)- 1,2-Dihydro-2,2,4-trimethyl-5- (thiophen- 3 -yl)-SH-chromeno [3,4-Jlquino line (Compound 170); 1,2-Dihydro-2,2,4-a-imethyl-5-(4methylp henyl)-SH-chro meno [3, 4 -fj quino line (Compound 171); (-)-5-(4-Chlorophenyl)- 1,2- H'riyak\Kt\peM5977g6.S'ROD RECEPTOR4OC 17/01/00 DOCKET NO.

0 16-0014A.WO 36 dihydro-2,2,4-trimethyl-5H-chromeno [3 ,4-f]quinoline (Compound 172); (RIS)- 1,2-Dihydro- 2,2,4-trimethyl-5-(3-methylphenyl)-5H-chromeno [3 ,4-flquinoline (Compound 173); (41,51)-5-(4-Chlorophenyl)- 1,2,3 4 -tetrahydro-2,2,4-trirnethyl-5H-chromeno [3 ,4-flquino line (Compound 174); (-)-(41,51)-5-(4-Chlorophenyl)- 1 2,3,4-tetrahydro-2,2,4-trimethyl-SHchromeno [3,4-Jl quino line (Compound 175); (R/S-41,5u)-5-(4-Chlorophenyl)- 1,2,3,4tetrahydro- 2,2,4-trimethyl-5H-chromeno [3 ,4-fl quino line (Compound 176); (3- Chlorophenyl)- 1 2 -dihydro-2,2,4-trimethyl-SH-cliro meno [3 ,4-fjquino line (Compound 177); (R/S)-5-(3-Chlorophenyl)- 1,2,3 4 -tetrahydro-2,2-dimethyl-4-methylidene.sHchromeno [3,4-fAquino line (Compound 178); (R/S)-5-(4-Bromophenyl)- 1,2-dihydro-2,2,4- 10 trimtethyl-SH-chromeno [3,4-fl quino line (Compound 179); (R/S)-5-(4-Bromophenyl)- 1 2 3 4 -tetrahydro-2,2-dimethyl-4- methylidene5H-c romeno [3 ,4-flquino line (Compound 0 180); (R/S)-5-(3-Bromophenyl)- 1, 2 -dihydro-2,2,4-trimethyl-SH-c hromeno [3,4-fiquino line :(Compound 181); (R/S)-5-(3-Bromophenyl)- 1,2,3,4-tetrahydro-2,2-dimethyl-4- [3 ,4-fjquinoline (Compound 182); ,4-Dichlorophenyl)- 15 1, 2 -dihydro-2,2,4-trimethyl-5H-chromeno[3,4.jAquinoljne (Compound 183); Bromo-2-pyridyl)- 1, 2 -dihydro-2,2,4-trimethyl-SH-chromeno [3 ,4-fjquinoline (Compound 184); (RIS)- 1, 2 -Dihydro-5- hydroxy-2,2,4-trimethy1-SH-chromeno, [3 ,4-Jlquino line 0 (Compound 185); (RIS)- 1, 2 -Dihydro-2,2,4-trimethyl-5-methoxy5H-chromeno [3,4f]quinoline (Compound 186); (RIS)- 1, 2 -Dihydro-2,2,4-trimethyl-5-propoxy-5Hc hro meno [3 quino line (Compound 187); (RIS)-5-Aflyl- 1,2-dihydro-2,2,4-trimethyl-SH- 0 .m n l u i o i e o p u d 1 8 R S i y r 2 4 a m t y r p l 5chromeno [3 ,4-fquino line (Compound 18); 1,2-Dihydro-2,2,4-trimethyl-5-pypyridyl)-SH-chromeno [3 ,4-fAquinoline (Compound 190); (R/S)-5-(3-Fluorophenyl)- 1,2dihydro-2,2,4-trimethyl-5H-cliiomeno [3,4-fjquinoline (Compound 191); (RIS)-5-(3- Fluorophenyl)- 1, 2 3 4 -tetrahydro- 2 2 -dimethyl-4-methylidene5H-chromeno [3,4-JAquino line (Compound 192); (RIS)- 1 2 -Dihydro- 2 2 ,4-trirethy1-5-propylthio-SH-chromeno [3,4- Jlquinoline (Compound 193); (RIS)- 1, 2 -Dihydro-5-(3-methoxyphenyl)2,2,4-trimethylsHchro meno quino line (Compound 194); (RIS) 1 ,2-Dihydro-2,2,4-trimethyl-5-[3- (trifluoromethyl)phenyl] -5H-chromeno [3,4-f]quino line (Compound 195); Fluoro-4-methylphenyl)- 1 2 -dihydro-2,2,4-trimethyl-5H-chromeno [3 ,4-fAquinoline (Compound 196); (RIS)-5-(4-Bromo-3-pyridyl)- 1,2-dihydro-2,2,4-trimethyl-SHchro meno[3,4-fj quino line (Compound 197); (RIS)- 1,2-Dihydro-2,2,4-timethyl-5-(3- H.VPrianka\Kccp\spec\5977-96.STEROID RECEPTORdoc 19/01/00 DOCKET NO.

0 16-0014A.WO 37 p yrid yl)-SH-c hromeno [3,4-fj quino line (Compound 198); (R/S)-5-(4-Chloro-3fluorophenyl)- 1 ,2-dihydro-2,2,4-trimethyl-SH-chro meno [3 ,4-flquino line (Compound 199); (RIS)- 1, 2 -Dih ydro-2,2,4,5-tetramethyl- 5H-chromeno [3 ,4-fjquino line (Compound 200); (RIS)- 1, 2 -Dihydro-5-hexyl-2 2 4 -arimethyl-5H-chromeno [3,4-Jlquinoline (Compound 201); 1 2 -Dihydro-2,2,4-trimethyl-5H-chromeno[3 ,4-fjquinoline (Compound 202); (RIS)- 1,2- Dihydro-5-(3-methylbuty1)-2,2,4-trimethy1-5Hchromeno [3 ,4-fjquinoline (Compound 203); (R/S)-5-(4-Chlorobutyl)- 1 2 -dihydro-2,2,4.-trimnethyl-5H-chromeno [3 ,4-fjquino line (Compound 204); (RIS)-5-Benzyl- 1 2 -dihydro-2,2,4- trimethyl-5H-c hro meno 3 4 -JAquino line (Compound 205); (R/S)-5-(4-Bromobutyl)- 1, 2 -dihydro-2,2,4-trimethyl-5H-chromeno [3,4- 10 jlquinoline (Compound 206); (R/S)-5-Butyl-9-fluoro- 1,2-dihydro-2,2,4-timethyl-5chro meno [3 ,4-A quino ine (Compound 210); (R/S)-5-Butyl-8-fluoro- 1,2-dihydro-2,2,4trimethyl-5H-chromeno [3,4-JAquinoline (Compound 211); (R/S)-5-(3-Chlorophenyl)-9- *:fluoro 1 2 -dihydro- 2,2,4-timethyl-5H-c hromeno, [3,4-fAquino line (Compound 212); 4 -Chloro-3-methylphenyl)-9-fluoro- 1, 2 -dihydro-2,2,4-trimethyl-5H-chromeno [3,4- 1: 5 fjquinoline (Compound 213); (R/S)-5-(4-Chlorophenyl)-9-fluoro- 1,2-dihydro-2,2,4trimethyl-5H-chromeno 3 4 quino line (Compound 214); (R/S)-9-Fluoro- 1,2-dihydro-5-(4methoxypheny1)- 2,2,4-tiimethy1-sH-chromeno [3,4-JAquino line (Compound 215); (RIS)-8- Fluoro- 1 2 -dihydro-5-methoxy-2,2,4-trimethy1-5Hchomeno [3 ,4-fAquino line (Compound 216); (R/S)-5-(4-Chlorophenyl)- 8-fluoro- 1, 2 -dihydro-2 ,2 ,4-trimethyl-5H-chromeno [3,4- 1] quinoline (Compound 217); and (R/S)-9-Chloro-5-(4-chloropheny)- 1,2-dihydro-2,2,4trimethyl-SH-chromeno [3 quino line (Compound 218); 9-Chioro-1I,2-dihydro-2,2,4quino line (Compound 320); (R/S)-9-Fluoro- 1,2-dihydro-5methoxy- 2 ,2,4-trimethyl-5H-chro meno [3,4-flquino line (Compound 322); (R/S)-9-Fluorol, 2 -dihydro- 2 ,2,4-trimethy1-5-thiopropoxy.sHchro meno [3,4-flquino line (Compound 323); (RIS)-9-Fluoro- l, 2 -dihydro-2,2,4-timethy1-5-propoxy5H-chromeno [3 ,4-J~quinoline (Compound 324); (RIS)- 1, 2 -Dihydro-9-methoxy-2,2,4-trimethyl-5H-chomeno [3,4- JAquinoline (Compound 329); (RIS)- 1, 2 -Dihydro-2,2,4,9-tetramethy-5Hchomeno [3,4fAquinoline (Compound 330); (R/S)-7-Chloro- 1,2-dihydro-2,2,4-tiethyl-5Hchro meno [3,4-Alquinoltine (Compound 331); (R/S)-5-(4-Bromo-3-pyridyl)- 1,2,3,4tetrahydro-2,2-dirnethyl-4 methyidene5Hc homeno [3 ,4-fjquino line (Compound 347); -(3,5-Difluorophenyl)- 1 2 -dihydro-2,2,4-trimethy- 5Hcho meno [3,4-fAquino line ana\Kp\.c.\4577-6.SEROD ECEPTORdoc 19/01/00 DOCKET

NO.

o 16-0014A.WO 38 (Compound 348); (R/S)-5-(3-Bromo-5-fluoropheny1> 1 2 3 4 -tetrahydro-2,2-dimethyp4methylidene- 5H-c hro meno [3,4-A quinoijne (Compound 352); 1,2,-Dihydro-5-(2,4,6trimethylbenzylidene)224-tethylSH-chromeno quino line (Compound 364); 5-Benzylidene-9-fluoro-1 ,2-dihydro-2,2,4, 11 -tetramethyl-5H-chro meno [3 ,4-flquino line (Compound 377); (R/S)-5-(4-Chlorophenyl)-1,2,3 4 -tetrahydro-2,2-dimethyl15Hchromeno 3 4 -fl-4-quinotinone (Compound 378); (RIS)-5-(4-Chlorophenyl)- 1,2,3,4tetrahydro-2,2,3,3-tetramethyl15H..cro meno [3 4 -fj-4-quino linone (Compound 379); (RIS)- 5-(4-Chlorophenyl)- l, 2 -dihydro-2,2-dimethyl5H-chiiomeno [3,4-flquino line (Compound 380); (+)-.(R*-4l,S1)-.5-.(4-.Chlorophenyl) 1,2,3 4 -tetrahydro-2,2,4-tri-methy1-5Hchromeno[3,4-JJ-3-quinolinone (Compound 38 4 l,S1)-.5-(4-.Chlorophenyl). 1,2,3,4tetrahydro-2,2,4-trimethy15Hchomeno 3 4 -fj-3-quinolinone (Compound 382); Chiorophenyl)- l, 2 3 4 -tetrahydro-.2,2-dimethypsH-chromno[3 4 -f]-3-quinolinone (Compound 383); 3 -Fluorobenzy1)-.5-.(3-fluorobenzylidene> 1 ,2,3,4-tetrahydro-3hydroxy-2,2,4-trimethyl5Hchomeno [3 ,4-fjquinoline (Compound 384); 15 mty-Hcrmn[3,4-f~quinoline (Compound 385); (R/S)-5-Butyl- 1,2,3 4 -tetrahydro-2,2,4-.trimethyl15H..chomeno 3 4 -fj-3-quinolinone (Compound 386); (R/S-41,5l)- l, 2 3 4 -Tetrahydro-2,2,4-timethy5phenylk5H chromeno [3 4 3 -quinolino ne (Compound 387); (R/S-41,5u)- 1,2,3,4-Tetrahydro-2,2,4meno 3 4 -fl-3-quinolinone (Compound 388); (R/S-41,6u)- 1,,,-erhdo224tiety -hnl5-scrmn[, 4 -fJ-3-quinolinone **(Compound 390); (R/S-41,61)-1,,,-erhdr-,,-tmthl6pey-H isochromeno [3 4 -fI-3-quinolinone (Compound 391); (R/S- 3 l, 4 u,5u)-.5-(4Chlorophenyl)> 1,,,-erhdo3mtoy224timty-Hcrmn 34fqioln (Compound 397); (R/S- 3 l, 4 u,5f)-5-(4-.Chlorophenyl) 1,2,3 4 -tetrahydro-3-methoxy224trimethylp5Hchro meno [3,4-Aiquino line (Compound 398); (R/S- 3 l, 4 u,51)-5-(4-Chlorophenyly 1,2,3,4terhdo3-rpl y224tiety-5-homn 34fqioln (Compound 399);

(R/S-

3 1,4u,5u)-.5-(4-.Chlorophenyl)> 1,,,-erhdo3poyoy224umty-H chro meno [3,4-A quino line (Compound 400); and (R/S- 4 1,51)-3-Benzylidene5(4.

chiorophenyl)- l, 2 3 4 -tetrahydro-2,2,4-trimnethy1-5Hchomeno [3 4 -flquino line (Compound 401).

Representative PR agonists according to the present invention include: l, 2 -dihydro 2 2 ,4-trimethy5Hchro meno [3,4jlquin 0 ofln (Compound 219); H:\Priynb\K-ep\sp~cM\597h96.STROD RECPPTOR4O 19/01/00 DOCKET NO.

016-00 14A.WO 39 1,2-dihydro-2,2,4-trimethyl-5H-chromeno [3,4-Jlquino line (Compound 220); (4-Fluorobenzylidene)- 1, 2 -dihydro-2,2,4-timethyl-5H-chromeno[3,4-j]qujnoline (Compound 221); (Z)-5-(4-Bromobenzylidene)- 1,2-dihydro-2,2,4-trimethyl-5Hchro meno [3,4-Ajquino line (Compound 222); (Z)-5-(3-Bromobenzylidene)- 1,2-dihydro- 2,2,4-trirnethyl-5H-chro meno quino line (Compound 223); Chloro benzylidene)- 1 2 -dihydro-2,2,4-trimethyl-SH-chromeno [3,4-flquino line (Compound 224); (Z)-5-(3-Fluorobenzylidene)- 1,2-dihydro-2,2,4-trimethyl-5H-chromeno [3,4f~quino line (Compound 225); (Z)-5-(2-Chlorobenzylidene)- 1,2-dihydro-2,2,4-trimethyl-5Hchro meno, [3,4-fJquino line (Compound 226); (Z)-5-(2-Bromobenzylidene)-1 ,2-dihydro- 2,2,4-trimethyl-SH-chro meno [3,4-flquino line (Compound 227); Fluoro benzylidene)- 1, 2-dihydro-2,2,4-trimethyl-SH-c hromeno [3 ,4-fAquino line (Compound 228); (Z)-5-(2,3-Difluorobenzylidene)- 1,2-dihydro-2,2,4-trimethyl-5H-chromeno [3,4f]quinotine (Compound 229); (Z)-5-(2,5-Difluorobenzylidene)- 1,2-dihydro-2,2,4-trimethyl- SH-chromeno [3 ,4-flquino line (Compound 230); (Z)-9-Fluoro-5-(3-fluorobenzylidene)- 1,2- 15 dihydro-2,2,4-timethyl-SH-chromeno [3,4-Jlquinoline (Compound 231); (Z)-9-Pluoro-5-(3methoxybenzylidene)- 1 ,2-dihydro-2,2,4-trimethyl-SH-chromeno [3,4-JAquinoline (Compound 232); (Z)-8-Fluoro.-5-(3-fluororbenzylidene)-1 ,2-dihydro-2,2,4-trimethyl-SH- ~chromeno [3,4-fAquinoline (Compound 233); (R/S-41, 5u)-5- (4-Chiorophenyl)- 1,2,3,4tetrahydro-2,2,4-trimethyl-SH-chromeno [3,4-J]-3-quinolino ne (Compound 234); (R/S-41, 5 /)-5-(4-Chlorophenyl)- 1 ,2,3,4-tetrahydro-2,2,4-trimethyl-SH-chro meno 4 quinolinone (Compound 235); and (R/S)-5-(4-Chlorophenyl)- 1,2,3,4-tetrahydro-2,2,4,4tetramethyl-SH-chromeno -3-quinolinone (Compound 236); 5-(3-Fluorobenzyl)- 1,2dihydro-2,2,4-trimethyl-5H-chromeno [3 ,4-Jlquinoline (Compound 318); (R/S)-9-Chloro- 1 2 -dihydro-2,2,4-trimethyl-5-propyloxy-5H-chromeno [3 ,4-JAquinoline (Compound 321); (R/S)-5-Butyl-9-chloro- 1, 2-dihydro-2,2,4-trimethyl- 5H-chromeno [3 ,4-Jlquino line (Compound 325); (R/S)-5-Butyl- 1, 2 -dihydro-9-methoxy-2,2,4-trimethyl-5H-chromeno[3,4- J] quinoline (Compound 326); (R/S)-9-Fluoro- 1,2-dihydro-2,2,4,5-tetramethyl-5Hchro meno [3,4-A quino line (Compound 327); (R/S)-9-Chloro- 1,2-dihydro-2,2,4,5tetramethyl- 5H-c hro meno [3 ,4-A quino line (Compound 332); (R/S)-5-(4-Bromophenyl)-9chioro- 1,2-dihydro-2,2,4-trimethyl-5H-chromeno [3,4-Jlquinoline (Compound 333); Chloro-5-(3-chlorophenyl)- 1 2 -d ih ydro-2,2,4-trimethyl-5H-chro meno [3 ,4-flquino line H. ,an"Kmpspei\497796.TERID ECEPTRAdQ 19/01/00 DOCKET NO.

016-0014A.WO (Compound 334); (R/S)-9-Chloro- 1,2-dihydro-2,2,4-trimethyl-5-(3-methylphenyl)-5Hchro meno [3 ,4-fjquino line (Compound 335); (R/S)-9-Chloro-5-(4-chloro-3-methylphenyl)- 1 ,2-dihydro- 2,2,4-trimethyl- 5H-c hromeno [3,4-Jl quino line (Compound 336); Chioro- 1 ,2-dihydro-5-1j3-(trifluoromethyl)phenyl] -2,2,4-trimethyl-5H-chromeno [3,4flquinoline (Compound 337); (R/S)-9-Chloro-5-(3,5-dichlorophenyl)- 1,2-dihydro-2,2,4- [3,4-jlquino line (Compound 338); (R/S)-9-Chloro- 1,2-dihydro-5-(4methoxyphenyl)-2,2,4-trimethyl- 5H-c hro meno [3 ,4-flquino line (Compound 339); (RIS)-9- Chloro-5-(3-fluoro-4-methoxyphenyl)- 1,2-dihydro-2,2,4-trimethyl-5H-chromeno [3,4fjquinoline (Compound 340); (R/S)-9-Chloro-5-(4-fluorophenyl)- 1,2-dihydro-2,2,4trimethyl-5H-chromeno [3,4-flquinoline(Compound 341); (R/S)-9-Chloro-5-(3-chloro-4- 1,2 -dihydro-2 ,2 ,4-trimethyl-5H-chromeno [3,4-fjquino line :*too.

(Compound 342); (R/S)-9-Chloro-5-(4-fluoro-3-methylphenyl)- 1,2-dihydro-2,2,4-trimethyl- [3 ,4-J]quino line (Compound 343); (R/S)-9-Chloro-5-(3-fluorophenyl)- 1,2dihydro-2,2,4-trimethyl-5H-chromeno [3,4-J]quinoline (Compound 344); (RIS)-t1,2-Dihydro- Oct*~* 15 2,2,4-trimethyl-5- [(3,4-methylenedioxy)phenyl] -5H-chromeno [3,4-flquinoline (Compound *.0 345); (R/S)-5-(4-Chloro-3-methylphenyl)- 1,2 -dihydro-2 ,2 ,4-trirnethyl-5H-chromeno [3,4f.Jquinoline (Compound 346); (R/S)-5-(3,5-Dichlorophenyl)- 1,2-dihydro-2,2,4-tin-ethyl-5Hchromeno quino line (Compound 349); (R/S)-5-(3-Bromo-5-methylphenyl)- 1,2dihydro-2,2,4-trimethyl-5H-chromeno [3 ,4-J]quinoline (Compound 350); (R/S)-5-(3-Bromo- 5-fluorophenyl)- 1,2-dihydro-2,2,4-trimethyl-5H-chromeno [3,4-flquino line (Compound 351); [4-Fluoro-3-(trifluoromethyl)phenyl] -1 ,2-dihydro-2,2,4-trimethyl-5Hchro meno [3,4-fl quino line (Compound 353); (R/S)-9-Fluoro- 1,2-dihydro-2,2,4-trimethyl-5- [3,4-fAquino line (Compound 354); (RIS)- 1,2-Dihydro-9methoxy- 2,2,4-trimethyl- 5- (3-methylp henyl)-5H-ch-ro meno [3 ,4-flquino line (Compound 355); (R/S)-9-Fluoro-5-(3-fluoro-4-methoxyphenyl)- 1,2-dihydro-2,2,4-trimethyl-5Hchro meno [3 ,4-A quino line (Compound 356); (R/S)-9-Fluoro- 1,2-dihydro-2,2,4-trimethyl-5- [3 (trifluoromethyl)phenyl] -5H-chro meno [3 ,4-A quino line (Compound 357); (RIS)-9- Fluoro-5-(4-fluoro-3-methylphenyl)- 1 ,2-dihydro-2,2,4-trimethyl-5H-chromeno [3,4- Jlquinoline (Compound 358); (Z)-5-.(2,4-Difluorobenzylidene)- 1,2-dihydro-2,2,4-trimethylI- 5H-chromeno [3 ,4-Jl quino line (Compound 359); (Z)-5-(3,4-Difluorobenzylidene)- 1,2dihydro-2,2,4-trimethyl-5H-chromeno [3,4-fquino line (Compound 360); H.VPynka\Kep,pcM597796.ST2OID RECEPTOR-doc 19/01/00 DOCKET NO.

016-0014A.WO 41 Fluoro benzylidene)- 1,2,3 4 -tetrahydro-2,2,4-trimethy5Hc homeno [3 ,4-fAquino line (Compound 36 (Z)-5-(2,6-Difluorobenzylidene)- 1 ,2-dihydro-2,2,4-trimethyl-5Hchro meno [3,4-JAquino line (Compound 362); 1, 2 ,-Dihydro-5-(2-methylbenzylidene)- 2 2 4 -timethy-5H-chro meno [3,4A quino ie (Compound 363); (Z)-9-Chloro-5-(2,5difluoro benzylidene)- l, 2 -dilhydro- 2 ,2,4-tr tethyl-5H-chromeno [3,4-J]quinoline (Compound 365); -5-Benzylidene- 9-chloro. 1, 2 -dihydro trmethy1-5H-c hromeno [3 ,4-JAquino line (Compound 366); (Z)-9-Chloro- l, 2 -dihydro- 2 ,2,4-trimethyl.5-(2-methylbenzylidene)-5Hchromeno [3,4-flquino line (Compound 367); (Z)-5-Benzylidene-9-chloro-1 ,2-dihydro-2,2meno [3,4-flquino line (Compound 368); (Z)-9-Chloro-5-(2- 10 fluorobenzylidene)- l, 2 -dihydro-2,2,4-trimethy1-5H-chromeno [3,4-fAquino line (Compound 369); 9 -Chloro-5-(3-fluorobenzylidene) l, 2 -dihydro-2,2,4-tiethy-5H-chromeno [3,4flquinoline (Compound 370); (E/Z)-5-Benzylidene-9-fluoro-.1 ,2-dihydro-2,2,4-trimethyl- [3 ,4-fj quino line (Compound 371); (Z)-5-Benzylidene-8-fluoro 1 ,2-dihydro- 2 2 4 -trimethyl-5H-chromeno [3 4 -flquinoline (Compound 372); (Z)-5-Benzylidene- 1,2dihydro- 9 -methoxy-2,2,4-trimethyl.5H..chromeno [3, 4 -f]quino line (Compound 373); Fluoro- l, 2 -dihydro-2,2,4trimethy15-(2-methylbenzylidene)-5H-chromeno [3,4-fjquinoline (Compound 374); (Z)-8-Fluoro-1,-iyr-,,-tiehl5(-ehybnyiee-H *chro meno 3 4 -A quino line (Compound 375); 1 2 -Dihydro-9-methoxy-2,2,4trimethy15- 2 -methylbenzylidene)-5H-chromeno [3 ,4-fjquinoline (Compound 376); 20 Fluoro benzylidene)- 1,2,3 4 -tetrahydro-2,2,4-trimethyl-5H-c 1 omen 0 [3 ,4-fl-3-quinolino ne (Compound 389); (Z)-(R/S)-5-(Benzylidene> 1 2 3 4 -tetrahydro-2,2,4-trimethyl5Hchromeno 3 -quinolinone (Compound 392); (R/S-41,5u)-5-(3-Fluorophenyl). 1,2,3,4tetrahydro-2,2,4-trimethylp5H-chromeno 3 4 3 -quinolinone (Compound 393); (R/S-41,Sl)- (3-Fluorophenyl)- l, 2 3 4 -tetrahydro-2,2,4-t inethyl-5H-chromeno [3, 4 -fj-3-quinolinone (Compound 394); (R/S-41,51)- 1 2 3 4 -Tetrahydro-2,2,4-trirnethyl15-.[3- [3 ,4-fJ-3-quino limo ne (Compound 395); (RIS-41,5u)- 1,,,-erhdo224tiehy -3(rfurmty~hnl-5H-chro meno [3 quinolino ne (Compound 396); (R/S- 4 1,5u)-5-(4-Chlorophenyl)-1,2,3 ,4-tetrahydro-2,2,4- [3 4 -fl-3-quinolinone (Compound 402); (R/S-41,51)-5-(4- Chiorophenyl)- l, 2 3 4 -tetrahydro-2,2,4-trimethy15H-chro meno[3 4 -f]-3-quinolinone H:'\PriYana\Kep\sP cM5977-96.STRO[D RECEPTORdoc 19/01/00 DOCKET

NO.

0 16-0014A.WO 42 (Compound 403); and (R/S)-5-Butyl-1 ,2-dihydro-2,2,4, 9 -tetramethyl-Sflchromeno [3,4- J~quinoline (Compound 457).

Representative AR modulator compounds agonists and antagonists) according to the present invention include: l, 2 -Dihydro-2,2,4trimethyl6methoxymethyl-8pyrano no quino line (Compound 237); l, 2 -Dihydro-2,2,4-trimethyp6-tifluoromethyl 8 -pyranono [5,6-g]quino line (Compound 238); 1 2 -Dihydro-2,2,4-trimethyl-10isocoumnarino 4 ,3 quino line (Compound 239); 1 2 -Dihydro-2,2,4-rimethy...10isoquinolono 4 3 -glquinoline(Compound 240); 1 2 -Dihydro-2,2,4,6-tetramethyl 8pyridono quino line (Compound 241); 1 ,2-Dihydro- lO-hydroxy-2,2,4-trimethyl 1OH- 10 isochromeno[4,3-glquinoline (Compound 242); 1, 2 -Dihydro-2,2,4,6-tetramethyl.8Hpyrano [3 2 -g]quino line (Compound 243); (RIS)- 1,2,3 4 -Tetrahydro-2,2,4.trimethyl-10isoquino lono 4 quino line (Compound 244); 1 2 -Dihydro-2,2,4-trimethyl- thio isoquino lo no 4 quino line (Compound 245); 1,2,3 4 -Tetrahydro-2,2,4-trimethylp 1 0-isoquinolono 4 3 -g]quinoline (Compound 246); 1 2 -Dihydro-2,2,4-trimethyp6- 15 trifluoromethyl-8-pyridono [5, 6 -g]quinoline (Compound 247); (RIS)-l1,2,3,4-Tetrahydro- 2 2 4 -timethyl-6-trifluoromethyl8pyanono [5,6-g]quino line (Compound 250); 1,2- Dihydro 2 ,2,4-trimethyb6.trifluoromethy18 thiopyrano no [5,6-gj quino line (Compound 251); rhdo22,-rmty--tfuroehl8tiprnn[5,6glquinoline (Compound 252); 6 -Chloro(difluoro)methyl-1 2 -dihydro-2,2,4-trimethyl-8 20 pyranono [5,6-g]quinoline (Compound 253); 9-Acetyl- 1 2 -dihydro-2,2,4-trimethy.6trifluoromethyl-8-pyridono [5, 6 -g]quinoline (Compound 254); 1 ,2-Dihydro-2,2,4, tetramethyl-6-trifluoromethy18-pyridono [5, 6 -glquinoline (Compound 255); 1 ,2-Dihydro- 2 ,2,4-trimethyl-6-( 1,1 2 2 2 -pentafluoroethyl)-8-pyranono [5,6-glquino line (Compound 256); (R/S)-6-Chloro(difluoro)methyl-.1,2,3 4 -tetrahydro-2,2,4-trimethy-8-pyranono [5,6glquinoline (Compound 257); 7-Chioro- l, 2 -dihydro- 2 ,2,4-rmethyl6trifluoromethyl-8 p yrano no quino line (Compound 258); (R/S)-7-Chloro- 1, 2 ,3,4-tetrahydro-2,2,4trimethyl-6-trifiuoromethyl8pyranono [5,6-glquinoline (Compound 259); 1,2,3,4- Tetrahydro-2,2,4trimethyI6triffuoromethyl 8-pyrido no [5, 6 quino line (Compound 260); 1, 2 Dihydro-22,4,9tetramethy6trifluoro methyl18 pyridono [5,6-gjquino line (Compound 261); 1, 2 -Dihydro -2,2,4-trimethyb8 trifluoromethyl 6-pyridono [5,6-glquino line (Compound 262); 6- [Dichloro (ethoxy)methyl] -1 2 -dihydro-2,2,4-t-imethyl 8-pyranono [5,6glquinoline (Compound 263); 5-(3-Furyl)- l, 2 -dihydro-2,2,4-trimethyl-8pyranono [5,6- H.:\Pranka\Xwp\spec\97796.hROID RECEPTOR-doc 19/01/00 DOCKET NO.

016-0014A.WO 43 glquinoline (Compound 264); 1 ,2-Dihydro- 1,2,2,4-tetramethyl-6-trifluoromethyl- 8pyranono [5,6-glquino line (Compound 265); 1 ,2-Dihydro-6-trifluoromethyl-2,2,4-4rjmethyl- 9-thiopyran- 8-ono [5,6-gl quinoline (Compound 266); 1 ,2-Dihydro- 1, 2 ,2,4,9-pentamethyl-6trifluoro methyl- 8-p yridono [5 quino line (Compound 267); 7-Chioro- 1,2-dihydro-2,2,4trimethyl-6-trifluoromethyl-8-pyridono [5,6-g]quino line (Compound 268); and 6- Chloro(difluoro)mnethyl- 1 ,2-dihydro-2,2,4-trimethyl- 8-pyridono [5,6-giquino line (Compound 269); (RIS)- 1,2,3,4-Tetrahydro- 1, 2 2 4 -tetramethyl-6-trifluoromethyl- 8p yranono quino line (Compound 404); (R/S)-5-(3-Furyl)- 1,2,3 ,4-tetrahydro-2,2,4trimethyl- 8-p yrano no quino line (Compound 405); 5-(3-Furyl)- 1,2-diihydro- 1,2,2,4- 10 tetramethyl- 8-pyranono quinohlne (Compound 406); 5-(3-Furyl)- 1 ,2-dihydro- 1,2,2,4- 00: tetramethyl- 8-thiopyranono [5,6-gj quino line (Compound 407); 6-Chloro-5-(3-furyl)- 1,2d ihydro- 1 ,2,2,4-tetramethyl- 8-pyranono quino line (Compound 408); 1,2,3,4- Tetrahydro-2,2,4, 1 O-tetramethyl-6-trifluoromethyp8-pyridono [5,6-giquino line (Compound 409); (RIS)- 1 2 3 4 -Tetrahydro -4-methyk6-trifluoromethyps8pyranono [5 ,6-gljquino line (Compound 410); 1 2 -Dihydro- 2 2 -dimethy1-6-trifluoromethy1-8-pyranono [5 ,6-glquino line (Compound 411); 1 2 3 4 -Tetrahydro-2,2-dimethy-6-trifluoromethy-8-pyranono [5,6glquinoline (Compound 412); 1,2,3 4 -Tetrahydro-6-trifluoromethyl-8-pyranono [5,6giquinoline (Compound 413); (R/S)-4-Ethyl- 1, 2 ,3, 4 -tetrahydro-6-trifluoromethyl-8pyrano no quino line (Compound 414); (RIS)- 1,2,3,4-Tetrahydro- 1,4-dimethyl-8pyranono quinotline (Compound 415); (R/S)-4-Ethyl- 1,2,3,4-tetrahydro- 1-methyl- 8p pyranono quino line (Compound 416); 2,2-Dimethyl- 1,2,3,4-tetrahydro-6trifloromethyl-8-pyridono [5,6-fAquino line (Compound 417); (RIS)-1 ,2,3,4-tetrahydro-6trifiuoromethyl-2,2,4-t-irnethyl-8-pyridono -3-quinolinone (Compound 418); Trifluoromethyl-7-p yrido no indo line (Compound 419); 8-(4-Chlorobenzoyl)-5trifluoromethyl-7-pyridono [5,6-ejindo line (Compound 420); 7-tert-Butyloxycarbamoyl- 1,2d ihydro -2,2,8 -trimethyiquino line (Compound 42 1 2 ,3,4-Tetrahydro-6-trifluoromethyl-8p yridono [5,6-f]jquino line (Compound 422); 1 ,2-Dihydro-6-trifluoromethyl- 1,2,2,4tetramethyl- 8-p yridono [5,6-J quino line (Compound 423); 3,3-Dimethyl-5-trifluoromethYl- 7-pyridono [5,6-elindo line (Compound 424); (RIS)- 1,2,3,4-Tetrahydro-4-methyl-6- (ftifluoromethyl)- 8-pyridono quino line (Compound 425); (RIS)- 1,2,3,4-Tetrahydro-4methyl-6-(trifluoromethyl)-8-pyridono [5,6-g]quino line (Compound 426); 1 ,2,2,-Trimethyl- H.NPriyank\Kmp\spccM5977-96.STERO[D RECEPTIORAdO 19/01/00 DOCKET

NO.

016-00 14A.WO 44 I ,2,3,4-tetrahydro-6-trifluromethyl- 8-pyranono [5,6-gjquino line (Compound 427); (RIS)- 1 2 ,34-Tetrahydro-4-propyl-6-trifluoromethyl 8-pyranono [5,6-gjquino line (Compound 428); 1,234Terhdr-,,4tiethyl-6-trifluoromethyb9-thiopyran8ono [5,6glquinoline (Compound 429); 1 ,2-Dihydro- 1 2 2 4 -tetramethy-6-trifluoromethy19thiopyran- 8-ono quino line (Compound 430); 1 ,2,3,4-Tetrahydro- 1,2,2-trimethyl-6trifluoromethyl-8-pyridono [5,6-giquinoline (Compound 431); 1,2,3 ,4-Tetrahydro- 1-methyl- 4 -propyl-6-trifluoro methyl- 8-pyranono quino line (Compound 432); 1,2,3,4- Tetrahydro- 1 -hydroxymethyl- 2 ,2,4-trimethyl6-trffuoromethyl-8-pyridono [5,6giquinoline (Compound 433); 1 ,2,3,4-Tetrahydro- 1 2 2 4 -tetramethyl-6-trifluoromethyl-9thiopyran- 8-ono quino line (Compound 434); l, 2 ,3,4-Tetrahydro-2,2,9-trimethyl-6trifluoromethyl- 8-pyridono [5,6-glquinoline (Compound 435); (RIS)-l1,2,3,4-Tetrahydro-3methyl-6-trifluoromethyl-8-pyridono [5,6-glquinoline (Compound 436); 1 ,2,3,4-Tetrahydro- 3 3 -dimethyl- 6-trifluoro methyl- 8-p yridono quino line (Compound 437); (RIS) 1,2,3,4- Tetrahydro -2,2,3-trimethyl-6-trifluoromethylp 8 -pyridono quino line (Compound 438); (R/S-21,4u)- 1,,,-erhdo24dmtyl6tilooehl8prdn [5,6-giquinoline (Compound 439); (R/S-2/,4u)-4-Ethyl- 1 2 3 4 -tetrahydro-2-methy1-6-trifluoromethy1-8p yranono quino line (Compound 440); (RIS-21,3u)- 1,2,3,4-Tetrahydro-2,3-dimethyl-6trifluoromethyl-8-pyridono [5,6-g]quinoline (Compound 441); (R/S-21,31)- 1,2,3,4- Tetrahydro-2,3-dimethy1-6trifluoromethy-8-pyridono [5,6-giquino line (Compound 442); (RIS)- l, 2 3 4 -Tetrahydro-2,3,3-trimethyl-6-tifluoromethyl-8-pyridono [5,6-g]quinoline (Compound 443); (RIS)- 1,234Ttayr--ehl6trfurmty--yioo56 giquinoline (Compound 444); (R/S)-4-Ethyl- 1,2,3 4 -tetrahydro-6-trifluoromethyl-8pyridono quino line (Compound 445); (R/S-21, 3u)- 1, 2 ,3,4-Tetrahydro-2,3,9-trimethyl- 6 -trifiuoromethyl-8-pyridono [5,6-gllquino line (Compound 446); (RIS)- 1,2,3 ,4-Tetrahydro-4propyl- 6 -trifluoromethyb8-pyridono [5,6-glquino line (Compound 447); (R/S)-3-Ethyl- 1,,,-erhdo22dmty-6tilooehl -yion quino line (Compound 448); (RIS)- l, 2 3 4 -Tetrahydro-2,2-dimethyb&trifluoromethy3propy-8-pyridono [5,6g]quinoline (Compound 449); and I -Methyl- 5-trifluoro methyl7pyridono [5,6-fJindo line (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 HW\P~kaKPPCS97796.SEROID RECEPTORAdo 19/01/00 DOCKET NO.

016-0014A.WO 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 1

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

HN

0 3

H

2 S0 4

R

1 N H 2 Pd/C R N0 2 NH 1 2 3

CH

3 CH 3 .acetone, 12 H 2 Pd/C R

-OH

3 CH 3 S4 H 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 15 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.

HN'riyank\Kp\.spccM597796.ST'ROID RECEPTOR.doc 19/01/00 DOCKET

NO.

0l6-Ool4A.WO Scheme I[ Br

NH

2 6 acetone,

L

1) n -BuLi 2) di-t -butyldicarbonate 7

H

Br 1) t -BuLi (HO) 2 B 'N 'N N OH3 2) trimethylborate I OH 3 8 t -B o/ H 3 9 N CH 3 t B u01- 0

R

1 Br, Pd(PPh,),

K

2 C0 3 toluene, EtCH

TFA

t -BuO/1--

I

4

H

1) SeO 2 dioxane 2) NaBH 4 Me/H/

OH

R1 N Ph 3 P, OBr 4

C~H

3 OH 1I O

H

3 t -BuO/ 0 1) R 2 MgBr, Oul 13 ether 01 2) TFA t -BuO/ 0 13

H

The process of Scheme II begins with the conversion of 4-bromoaniline (Compound 6) to 6-bromo- 1, 2 -dihydro-2,2,4-trirnethylquino 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 H:-\Priyanka\Koep\speci\45977-96.S'rEROD RECEPTORAdo 19/01/00 DOCKET NO.

016-0014A.WO 47 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.

10 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 S. 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, S' trifluoroacetic acid affords the 4,6-disubstituted-1, 2 -dihydro-2,2,-dimethylquinoline (structure 13).

HAPriyaa\Kp\sccM59T-96.STE ROID RECEPThR.doo 19/01W00 DOCKET NO.

016-0014A.WO Scheme III t -BuO

O

R

1 Pd(PPh 3 4 3 3 ft^-- K2C0 3 toluene, EtOH

CH

3 R CH 3 H CH 3

CH

3

ROCH

3 10 t N

C

H

3 t-BuO 0O

TFA

a *ae a o o o The process of Scheme m 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 R3

R

2

H

2 Pd/C 5 1

R

s

R'

6

R

6 X NH 2

"NO

2 acetone, 12 H

R

16 17 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 H:\Priyanka\Kep\pecM5977-96.STEROID RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 49 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

DIBAI-H

H3

CH

3 HO CH 3 HO 5 N CH3

H

999999 99 9 9999 *9 9 r 9.

0999 99 9 9e 94 The process of Scheme V involves the reduction of an ester such as Compound 18 10 to the corresponding methyl alcohol (Compound 122) with a metal hydride reagent, for example, diisobutylaluminum hydride or lithium aluminum hydride.

Scheme VI

R

4

R

3 R4 3

R

4

R

2

CH

3 a R 3

R

2

CH

3

R

5 DIBAI-H

R

C H I I- I -I CHi 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.

H,\Priyanka\Kop\spcMi\5977-96.S7TROD RECEPOR.doo 19/01/00 DOCKET NO.

016-0014A.WO Scheme VII Br F CO 2 Me 21

F

70 1) Cu, 190 C, 2 h 2) 10% aq. NaOH THF, A 1) SOCI 2 PhH, A F 2) CF 3

SO

3 H, CH 2

CI

2 -78 °C L 0* 6 *66*

U

*fl.

90%HNO 3 "O v -NO 2 0 F CH 3 1) acetone, 12 F C H L CH3 2) DIBAI-H" HO N CH 3 132

H

2 5% Pd/C 57% HI, P(red)

CH

3

CO

2

H

F

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, "Modern 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 H:\Priyanka\Kmeppeci45977-96.STEROiD RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 51 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.

10 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.

9**9 99 Scheme VIII o*o

R

6 6 RR5 Rs RR R 4 NH CH 3 7 4 ,R 7 CH3 R NaH, RX R4 3 1 H CH 3 R 1 R C H 3 28 29 The process of Scheme VIII 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.

HN\R~ka\Kp\spcc'1597796.STROID RECEPTOR.doe 19/01/00 DOCKET NO.

016-0014A.WO 52 Scheme IX C0 2 H 1)HN0 3 acetone, 1 2 2) DMA, heat 3) Pd/C, H 2

NH

2 115 C 31 O O t i 1) RMet N CH H

CH

3 32 N "CH 3 2) CF 3

CO

2 H, Et 3 SiH N oO

R

H CH 3 or •..*159 159

BF

3 -OEt 2 Et 3 SiH

CH

3 H CH 3 33 The process of Scheme IX begins with the nitration of 2-biphenylcarboxylic acid 5 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.

H*Priyaiuka\Kp\specM\5977-96-SThROID RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO Scheme X

H

2 Pd/C

OCH

3

H

3 Vo a0 The process of Scheme X involves the reduction of a dihydroquino line (structure 5 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] H.Nriy~kaK-psp.,\497796.TER(DRECEPTORAdo 19/01/00 DOCKET

NO.

016-0014A.WO Scheme XI R\ OCH3 R2 B r 36

I

1) n -BuLi, THF, -78 °C Ri OCH3 R23B(OH) 2 37 2) B(OCH 3 3 3) H 3

O

37, 2.0 M Na 2

CO

3

DME

(Ph 3

P)

4 Pd (cat) 6* *6* 6 r

NO

2 1) KOH, EtOH, HaO, THF acetone, 12 120 OC 2) SOCI 2 3) AIC13 4) Pd/C, H 2 1) RMet

CH

3 2) BF 3 -Et 2 O, Et 3 SiH

-CH

3 -Hs 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.

H.riyan\Kcppspeci145977-96.STEROIDRECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 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 *5* 1 O 3 CO 2

H

B CH 3 Br 2.0 M Na 2

CO

3

DME

B(OH)

2 NO 2 (Ph 3

P)

4 Pd (cat) 37 43 R I,

OCH

3 1) SOCI 2 RO O S2) AICI 3 R2

HO

2 C

NO

2 3) Pd/C,

H

2 44

NH

2

S

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.

H.Priyanka\Ktcp\$p0ci\59Th96.SThROID RECEPTORdoc 19/01/00 DOCKET NO.

0 16-0014A.WO Scheme XII .5

S

*SSS

5*

S.

Ni U 0 OH 3 1) R 3

CH

2 MgX or R 3

CH

2 Li R 1 0 OH 3 R 2 N 0H 3 2) p-TSA, CH 2 C1 2 R OH 3 H OH 3 NlOH 41H

H

5 The process of Scheme XIIII involves the addition of an organometallic reagent, for example an organomagnesium or organolithium 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 R

DIBAI-H

2.

S

5.*

S

SSSS**

S S R 3 XH, p-TSA_

R

5 SiR 3 R 6 TMSOTf

-CH

3 H-'Prnka\KIpec 5977h96.STROD RECEPTOR~oc 19/01/00 DOCKET NO.

016-0014A.WO 57 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 O 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 a a 1) n-BuLi

-CH

3 2) BOCO2 Ri O R CH3

CH

3

N

N

CH

3 49

BOC

1) BH 3

-THF

2) H 2 0 2 R OR RIR CH 3

R

2

~OH

RH

3 N

CH

3 as BOC 1) PCC 2) TFA 1) PCC 2) TFA 52 53 1) PCC or 51 1 2) NaH, CH31 3) TFA

-CH

3

CH

3 HSriyam\KcappclcM5977-96.STEROID RECEPIOR.doc 19/01/00 DOCKET

NO.

016-0014A.WO 58 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 10 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] H.\"kanaK p\,pocM5977-96.STEROID RECEPTRdoc 19/01/00 DOCKET NO.

016-0014A.WO Scheme XVI

H

2 Pd/C acetone, 12

A

Lawesson's reagent base, R 4

X

-CH

3

H

2 Pd/C

"IDIBAI-H

R3 CH 3 1

OH

3 HO Z N 62R1H OH 3

*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-methoxyphenyly 1 3 -dithia-2,4-diphosphetane24-disulfhde]. See B. S. Pedersen, S.

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

XXII. The Dimer of p-Methoxyphenylthionophos..phine sulfide as Thiation Reagent. A H:\PriankNK~p\,peci\S977-96.STEROD RECEPIORdoc 19/01/00 DOCKET NO.

016-0014A.WO 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(1) 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, 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 10 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 Swhich is herein incorporated by reference.

0 Alternatively, the C(8) ester group of a compound of structure 57 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).

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016-0014A.WO Scheme XVII HZ

NO

2

R

1 64

O

P X

H

2 Pd/C acetone, 12

A

0 P 'Z

-NH

2 *e 9 9*e* 9 99** O 0 R a ROR 4 R 68 Lewis acid de-protect 0 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 H:\Priyanka\K p\Ispeci45977-96.STEROlD RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 62 structure 67. Deprotection by either acid or base, followed by treatment of the corresponding aniline or phenol with a P-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 10 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] [rest of page left purposely blank] H:Priyanka\Keep\pecM\-5977-96.STEROID RECEPTOR.do 19/01/00 DOCKET NO.

016-0014A.WO Scheme XVIII

CH

3

H

2 Pd/C 00 R3 O R4 de-protect

R

2 68 Lewis acid Lewis acid 0 *e 0 0 0** 0* 0* 0 r 0* 6 6*00

R

3

CH

3 CH3 0 z N

O

1 H

CH

3 63

S

R

3 OH CH 3

CH

3 O Z N 1 H C H 3 73 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 P-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 H:\Priyank-\Kop\spccM5977-96.STeRO[ RECEPTfR.do 19/01/00 DOCKET NO.

016-0014A.WO Scheme XIX O CH 3 Lawesson's reagent S ZN C3H RI H CH 3 6 z H CH 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)- 1, 3 -dithia-2,4-diphosphetane-2,4-disulfide].

Scheme XX 1) BH 3

-THF

2) H 2 0 2

OH

1) PCC D o CH3

R

4 2) CF 3

CO

2 H R R 5, CH 3 H CH 3 79 The process of Scheme XX begins with a protected 6-aryl-1,2-dihydro-2,2,4trimethylquinoline (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 -hydroxyltetrahydroquinoline (structure 78). Oxidation of the alcohol with a typical oxidant, for example pyridinium chlorochromate, and deprotection with a strong acid such as trifluoroacetic acid affords a compound of structure 79.

H:N\"ank\Koep\spccM5977-96.STEROID RECEPTORdoc 19/01/00 DOCKET NO.

016-00 14A.WO Scheme XXI (Ph 3

P)

4 Pd, base heat

B(OH)

2

NH

2

R

8 81 RjR' 6 R 3 R R 9 O H 3 I R 5 R7R R7 NH 2 1 2 heat R7 N R8R 8 H OH 3 82 83 5 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)palladium as the catalyst, to afford a substituted 4-aminobiphenyl (a compound of structure 82). A Skraup reaction using an alkyl methyl ketone, for example acetone or 2-butanone, affords a compound of structure 83.

Scheme XXII B r__NH 2

OH

3 acetone, 12, heat

CH

3 B r

OH

3

N

OH H

OH

3 (Ph 3

P)

4 Pd, base heat

OH

3 H:.\Priyanka\Kc-p\spcMS 977-96.ST2ROID RECEPTORdoc 19/01/00 DOCKET NO.

016-0014A.WO 66 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 R AcO R 7

R

0 2.

0 0 R R 2 00 R

H

3 R R3 4 CuX, heat 7 R5 NH 2 R

SR

6 R 6 HR 8 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.

S.Cassady, "A Novel Synthesis of Quinolines and Dihydroquinolines.", J. Org. Chem. 1962, 15 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.

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NO.

0 16-0014A.WO Scheme XXIV R 2 OCH 3 R 3 Br 89 1) n -BuLi, THF, -7800C 2) B(OCH 3 3 3) H 3 0+

'B(OH)

2 55..

S

*5 C0 2

CH

3 Br R 5 N0 R 6 90, 2.0 M Na 2 C0 3

DME

(Ph 3

P)

4 Pd (cat) 92 R6 1) KOH, EtOH, FH 2 0, THF 2) SOC1 2 3) AIC1 3 4) Pd/C, H 2 acetone, 12 12000C

'NH

2 1) DIBAL-H 8 2) BF 3 -OEt 2 Et 3 SiH~

,R

R 8 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, H:Prak\Ke p\pcM5977-96.S'ROID RECEPTOR-doc 1 9/01/00 DOCKET NO.

016-0014A.WO 68 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 O O R ROHOHR 9 .3

DIBAL-H

%R 47 4 *R 5 R7 4 .R 6 H R R R H 88 94

R'

RR

H

R

8 R 4 R R

R

6 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.

H.\Piyaaa\Kp\specM5977-96.SThROID RECEPTORdoc 19/01/00 DOCKET NO.

016-0014A.WO Scheme XXVI 1) R 3

CH

2 MgX or R 3

CH

2 Li 2) p-TSA, CH2CI

-R

7

R

8 *r 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 0 R SI1) n-BuLi

SCH

3 2) t-Boc 2 0

N

CHH

3 3) 03 33 0 RO 0 RO TFA 0 N CH3 I

H

I CH3

CH

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.

H.\Priyana\Kp\sp MS97-96.S1ROID RECEPIUR.doc 19/01/00 DOCKET NO.

016-0014A.WO Scheme XXVII

CHOH+

R NH

)TF

1) base RI 8 H K +3 NH CH3 srcue96 Bitoor eapsoimhdideo ihu diorplmd olwdb or a n-xueo oo n iakldpout.Sbeun eoHa 3 fth rtetn gopwthe porocxpess o fl eme XXVforegis ithther derttone bof compound of structures 98 and 99.

Scheme XXIX NaBH 4 I1) n -BuLi

OH

3 2) p-TSA N H 2) t -Boc 2

O

H OH 3 H OH 3 97 1A

N

0 R 0 R 1) BH-THF 0 N C32) H 2 0 2 N H O H 3 O, H 3 2A Boo 3) Cr0 3 3A Boo

N

0

R

TFA

N

OH

3

N

H OH 3 4A H-\ranka\p\pM977-96.S7EROID RECEPTOR 4O 19/01/00 DOCKET NO.

016-0014A.WO 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 1A 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 10 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 1) n-BuLi 2) t-Boc 2 0 3) BH 3

-THF

4) H 2 0 2 R CH3 N CHs 5A Boc CrO 3 I R 2

N'

6A

B(

1) R 3

CH

2 MgX or R 3

CH

2 Li 2) p-TSA, CH 2

CI

2

TFA

-CH

3 ,H3 H.,PriyaakaKcepbpccM5977-96.STEROID RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 72 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 10 the intermediate hemiketal with, for example, para-toluenesulfonic acid, affords a compound of structure 8A.

Scheme

XXXI

R O O R CH O 1) R 3 MgX or R 3 i H OH

R

2

R

2 R3 SI CH N 2) TFA, Et 3 SiH N CH 3 H CH 3 H 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 ORH 3 o 1 CH3 Ri CH 3 CH 3 SCH3

OCH

3 1) R3MgX or R3Li 10AH 3 N C 2) TFA, Et 3 SiH 3 I CH3 RI R 6A Boc CH 3 R2

O

SCH

3 H CH 3 11A H:-riyanka\Kcp\speclM5977-96.STEROID RECEPTOR.doc 19/01/00 DOCKET NO.

o 16-0014A.WO 73 The process of Scheme XXXII begins with the addition of an organolithium or organomagnesium 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 10A and I A.

Scheme XXXIII 1) n -BuLi 1) BH 3

-THF

2) H 2 02 13A Boc Cr0 3 Cr0 3

-CH

3 1

STFA

17A I.18A H.Nriyanka\Ke~p\speci\49Th-96.SmEROlD RECEPTORAdo 1 9/01/00 DOCKET NO.

016-0014A.WO 74 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 0 0 0 R O O R /0

CH

3 1) R 3

CH

2 MgX or R 3

CH

2 Li

CH

3 RN0 R 2 1 C H 3 2 TFA

CH

3 N 2)TFA N

CH

3 H CH 3 6A Boc 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] H:\Priyanka\Kemp'spcM5977-96.SThROID RECEPTR.doc 19/01/00 DOCKET NO.

016-0014A.WO Scheme XXXV O O Sacetone, 12 H 3 heat I

CH

3

NH

2 N H CH 3 21A

R

1 S3 1) n -BuLi 1 1i 0 CH 3 2) t-BOc 2

O

1) R'MgX or R Li 2) t-Boc20 )r N3) BH,-THF i J LCH 3 2) TFA, Et 3 SiH N 4) H 2 0 2 H CH3 S22A 5) CrO 3 2: 6) TFA

R

1

R

1 0 CH 3 O CH 3 0

CH

3 CH 3 H CH 3 H CHa 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.

H\PRiyanka\Koep\pecM5977-96.STO'ROiD RECEPTORdoe 19/01/00 DOCKET NO.

016-0014A.WO Scheme XXXVI RI 0 R 3 R RH3

R

2

OH

CH

3 I CH 3 11,A Boc 1) NaH, R 4

X

2) TFA 26A 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 1) R 4

CH

2 MgX or R 4

CH

2 Li O

-CH

3

CH

3 27A The process of Scheme XXXVII 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.

H:\PriyaLnka\Kep\rpecM5977-96.STEROID RECEPTOR.do 19/01/00 DOCKET NO.

016-0014A.WO 77 Scheme XXXVIII R CH 3

R

3

CH

3 R 2 base, R 5

CH

2 X R2

CH

3 I CH 3 0 HZ 1 N CH 3 or R 5 CHO, NaCNBH 3 O Z R CH3 63 63 28A The process of Scheme XXXVIII involves the alkylation of N(1) 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 *Sa* R CH 3 R3 CH 3 N base, RsCH 2 X R

OH

3

CH

3 S Z N S Z N CH3 R H CH 3 or R5CHO, NaCNBH 3 RS CH 3 58 29A R The process of Scheme XXXIX involves the alkylation of N(1) 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.

HN"-Lka\K-P\-pep~spc \45977-TER OID RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO Scheme XL

CO

2

H

R3 heat

NH

2 2) PPA 3) t-Boc 2 O, DMAP

CH

3 1) R4Met 2) Pd/C, H 2 3) TFA 31A

*S.

R

1

R

4

CH

3 aON R 3

R

2 32A 1) BBr 3

R

5

R

1

R

4

R

6 O00 N R 3

R

2 H ZnCI 2 33A R CH 2 X, base R 8 0 N R 3 or R CHO, NaCNBHs R2

R

8 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 3-keto ester effected by, for example, zinc chloride, affords a compound of structure HN.riyanka\K-p\'pecM 977-96.STEROID RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 79 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 O OAc R4 P X NH2 P X N 3 R Ri HR 35A 36A 5 R 2 1) deprotect R R R R 2) O R4

R

5 C0 2

R

7 O X NR

R

6 ZnCI 2 37A

R

5

R

2 R CH 2 X, base R 6 or R 8 CHO, NaCNBH 3 O X R3

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 O or S) or Knorr cyclization (X NH) with a 0-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 HPriyanka\K-ep\sppccM5977-96.SIhROID RECEPTR.doc 19/01/00 DOCKET NO.

016-0014A.WO 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 Pd/C,

H

2

ON.

S

e 36A 39A 1) deprotect 2) 0 Rs CO 2

R

7

R

6 ZnCl2 R5 R 2 RR R

R

I 4

/R

H

R

R

8

CH

2 X, base R

R

4 or R 8 CHO, NaCNBH 3 O

R

R

8 41A The process of Scheme XLII 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 O or S) or Knorr cyclization (X NH) with a P-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 H'riyankalEKeep\specM5977-96.STEROID RECEPTOR.doe 19/01/00 DOCKET NO.

016-00 14A.WO 81 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 ri~~r~\H 2

NOH-HCI

CH

3 ONcq 0 42A

CH

3 0OC 43A

N-.OH

LiAIH 4 ep..

*5 S

S.

S

CH

3 0

H

44A 1) deprotect 2) 0 R'"U C0 2

R

3 R 2 ZnC1 2 The process of Scheme XLIII begins with 6 -methoxy-1-tetralone (Compound 42A) which is treated with hydroxylamine hydrochloride to afford the corresponding oxirne, Compound 43A. A reductive Beckman rearrangement effected by, for example, lithium alumidnum hydride, affords Compound 44A. Demethylation of the methyl ether with, for example, boron tribromnide, followed by a Pechman cyclization with a f3-keto ester effected by, for example, zinc chloride, affords a compound of structure H'\Pyaa\K-~P\sp.iMs97796.S'hROID RECEPTOR~doc 19/01/00 DOCKET NO.

016-0014A.WO Scheme XLIV 1) base 2) t-Boc 2

O

3) base 4) t -Boc20

R

3

CH

3

CH

3 0 N

N

Boc R 1 BHoc 46A a 1) BH 3 -THF 2 0 2) H 2 0 2 CH O N N 3) PCC H CH 3 4) TFA

R

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] H:\Pranka\KUepsccp5977-96.STROID RECEPTR.doc 19101/00 DOCKET NO.

016-0014A.WO Scheme XLV 1) Pd/C, H 2 02N N 2) O

HI

48A R R C0 2

R

3 Ri 2 ZnCI 2 49A 4r 9 9 4 9* 9* 9 1) base 2) R 4

COCI

Ri R 2 0 N

N

H

0 "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 P-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 1) HNO 3 2) Pd/C, H 2

H

2

N

51A 52A 0 C0 2

R

6 R 5 ZnC1 2

R

4

R

1 RO I3R 2 H HR 53A H\PRiank\Kcp\pecM5977-96.STROID RECEPTORdoc 19101/00 DOCKET NO.

016-0014A.WO 84 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 3-keto ester effected by, for example, zinc chloride, affords a compound of structure 53A.

0@ a a *baa Scheme XLVII 2N VBr 0 2 N NH 2 NaH, X R'l or, Na(OAc)3BH, 54A R1

H

Pd(ll), base, NaO 2

CH

56A 1) Pd/C, H 2 R3 H 1- R4 R1 2) O

R

3 COR O N N

R

4 ZnCl 2 H H 57A The process of Scheme XLVII begins with the alkylation of (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 ca,3-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 H.Priyanka\KecpspecM5977-96.STEROID RECEPTOR.doc 19/01/00 DOCKET NO.

016-00 14A.WO with, for example, hydrogen over palladium on carbon, affords the aniline, and a Knorr cyclization with a f3-keto ester effected by, for example, zinc chloride, affords a compound of structure 57A.

Scheme XLVIII

NH

2 R C0 2

H

1) toluene, A

S

S S

S.

SSSS

S

*5 S

PS

S.

PPm 2) PPA 58A 1) Boc 2 O, DMAP 2) R 4 Met 3) H 2 Pd/C 4) TFA 59A 1) HNO 3

H

2 S0 4 R 2)

H

2 Pd/C

H

2

N

ZnC 2 EtOH 61A R 5 R4 7 R 6 R R 3 o N N R 2 H R 1

H

62A R5 R o) N N R 2 H

R

1

K

8 63A

R

8

CH

2 X, base or R 8 CHO, NaCNBH 3 HN~nkaKmpspei\497796.TERIDRECEPTOR-d 19/01/00 DOCKET NO.

016-0014A.WO 86 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 P-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 15 by alkylation of the nitrogen atom, which can be accomplished in one of two ways.

0.0. 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.

0** Scheme XLIX

R

6

R

1

R

5

R

6

R

1

R

R 4 Et 3 SiH/TFA

R

7 4

R

2 H R 2 H R4 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 l:\Piyanka\Kp\pccM 5977-96.STROID RECEPTORdoc 19/01/00 DOCKET NO.

016-0014A.WO Scheme L SeO 2

A

ON-

66A 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 R2,, CO2H 1) toluene, A 2) PPA 3) BocgO, DMAP 68A base, R 3

X

30- 1) R4Met 2) H H 2 Pd/C 3) TFA

R

4

R

2

NR

R

H

69A 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 H-l\Priyanka\Kep\specM597796-STROID RECEPTORAoc 19/01/00 DOCKET

NO.

01 6 -0014A.WO 88 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 69A R base, R4X

R

L

R

7( 4

-R

3 1) HNO 3

H

2 S0 4 2 2 R 2 2) H2, Pd/C

)A

1) R 5 Met 2) H H 2 Pd/C 3) TFA 00 RR4 R 6 y OR8

R

3

R

7

E

N R 2 ZnCI 2 EtOH H 2

N

72A

R

9

CH

2 X, base or R 9 CHO, NaCNBH 3 1

R

73A The process of Scheme LI 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 H.N RaaP&\Kecp\'pcM5977-96.SlhROID RECEPTIR.do 19/01100 DOCKET

NO.

016-0014A.WO 89 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-l,2,3,4-tetrahydroquinoline of structure 72A. A Knorr cyclization with a 13-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] [rest of page left purposely blank] H.Riymka"\KfCP\.pecM5977.gSThROID RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO Scheme LIII R NH 2

R

1 58A

R

2

R

3 1) CuCI, Et 3 NAco 2) CCI, 2) CuCl, A 1) Boc 2 O, DMAP 2) BH 3 -THF, then Hg2, 3) PCC 75A 1) base, R 4

X

R

3 2) RMet 2 3) H 2 Pd/C 4) TFA 1) HNO 3

H

2

SO

4 2) H 2 Pd/C 76A 77A ZnCI 2 EtOH 78A 79A

R

8

CH

2 X, base or R CHO, NaCNBH 3 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 H:Priyanka\Keep\pcciM5977-96.STEROD RECEPTOR.do 19/01/00 DOCKET NO.

016-0014A.WO 91 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 3-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

5

R

4

R

5

R

4 R8CH 2 X, base R R N R 0 N N R 2 H 1 H 8 H R8R0 R

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.

H.?Priyanka\Keep\pecMS4977-96.STEROID RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 92 Scheme LV Rs 4 3 R2

R

4

R

3 S R 1 R CH 2 X, base R 5 R R O N NR' H H O N N R or R 6 CHO, Na(CN)BH 3 H Ri R6 82A 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 10 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 5 6

R

4

R

1

R

4

R

1 RO 3R~ RCHg x base R R2 RH H R

HR

R ,J S 15 53A 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.

H.kPrpnka\Kpsc\459Th96.SThROID RECEPTORdoc 19/01/00 DOCKET NO.

016-0014A.WO 93 Process 1 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-butyllithium, sodium hydride, potassium hydride) at -100 0 C to 100 0 C, followed by reaction with di-t-butyldicarbonate at -100 0 C to 100 0 C to afford the 6-substituted-1,2-dihydro N-1 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 9* either iodine or ethylene dibromide in an inert solvent (typical solvents include ether, THF, pentane) at -20 0 C to 2000C. The organolithium or organomagnesium intermediate is then allowed to react with a trialkylborate (for example, trimethylborate, triisopropylborate) at -100 0 C to 100 0 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-l,2-dihydro N-1 protected quinoline: Compound 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, H.NPranmp\Kppcc5977-96.STEROID RECEPTOR4oc 19/01/00 DOCKET NO.

016-0014A.WO 94 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 a 6-substituted-1,2-dihydro N-1 protected quinoline (structure 10). Deprotection of a compound of structure 10, for example, with acid (for example, trifluoroacetic acid) at -80 0 C to 200 0 C, affords the corresponding 6-substituted-l,2-dihydroquinoline structure 4).

Process 2 is depicted in Scheme III and involves the treatment of a solution (typical solvents include toluene, DME, DMF) of 6-halo-1,2-dihydro N-1 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)palladium, 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 6- 15 substituted-1,2-dihydro N-l protected quinoline (structure 10). Deprotection of a compound of structure 10 with acid (for example, trifluoroacetic acid) at -80 0 C to 200 0

C

S* 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 20 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 0 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 0 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, H.\"ankP\Kep\ sppSo5977-96STPROID REC0PTORoc 19/01/00 DOCKET NO.

016-0014A.WO 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 0 C to 200 0 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 0 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, PtO2), affords the desired aminobenzocoumarin (structure o** Treatment of compounds of structure 40 with acetone and a catalyst such as iodine affords the coumarino[3,4-flquinoline (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 .o 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 0 C to 200 0 C, to afford a 5H-chromeno[3,4-f]quinoline (Compound of structure 42).

Process 4 is depicted in Scheme XII 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, para- HPriyanka\Xep\spccM59Th96sTEROID RECEPTOR~oc 19/01/00 DOCKET NO.

016-0014A.WO 96 toluenesulphonic 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 0 C to 200 0 C, to afford the protected 3-nitroaryl compound of structure 65. Reduction of the nitro group with, for 10 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, 15 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 0-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 20 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°C to 100°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 H:\Riyanka\Kcp\specM5977-96STEROID RECEPTOR-doc 19/01/00 DOCKET NO.

016-0014A.WO 97 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, LII, 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 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 (3-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 LII, 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

SR

R

5 Z N 9

R

11

R

10

R

OR(I)

OR

H.Priyanb\Kp\,pccM597-96.STEROID RECEPTORdoc 19/01/00 DOCKET NO.

016-00 14A.WO a

(III)

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, ailcynyl, aryl or heteroaryl, and where R 3 and R 4 each independently are hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl;

R

5 is hydrogen, R 2 C=0, R 2 C=S, R 3 OC=0, R 3 SC=0, R 3 OC=S, R 3 SC=S, or

R

3

R

4 NC=0, where R 2

R

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

R

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

ailcynyl, aryl, heteroaryl, R 3 0, HOCH2, R 3 OCH2, 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; H Priyaaka\Kmep'.pecM5977-96.STEROID RECEPTORdoc 19/01/00 DOCKET

NO.

016-0014A.WO 99

R

7 through R 9 each independently are hydrogen, a Ci C6 alkyl, allyl or optionally substituted allyl, arylmethyl, alkynyl, alkenyl, 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 allyl, arylmethyl, aryl, or heteroaryl,

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 2through R 4have the same definitions as given above; RI 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 OCH2, F, Cl, Br, 1, cyano, R 3

R

4 N or perfluoroalkyl, where R 3and R 4have the same definitions as 10 given above; R1 3 is hydrogen, a Ci C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, alkynyl, aryl, heteroaryl,

R

3 0, HOCH2, R 3 OCH2, R 3

R

4 N, CF2Cl, CF2OR 3 or perfluoroalkyl, where R 3 and Rhave the same definitions as given above;

R

14 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, 1, cyano, R 3

R

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

R

15 is F, Cl, Br, 1, B(0R 16 2 SnR 17

RI

8

RI

9 or 0S02R 2 0 where R1 6 is hydrogen or a Ci C6 alkyl, R 1 7 through

R

19 each independently represent a Ci C6 alkyl, R 2 0 or heteroaryl,

R

20 is a Cl C6 alkyl, perfluoroalcyl, 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-trimethyls5 co umarino [3 ,4-fJquino line (Compound 159); 9-Fluoro- 1, 2 -dihydro-2,2,4-trimethyl-5cournarino 3 4 -fj quino line (Compound 207); 8-Fluoro- 1 2 -dihydro-2,2,4-trimethyl-s..

co umarino 3 4 -J quino line (Compound 208); 9-Chioro- 1, 2 -dihydro-2,2,4-timethyl-5.

co umarino 3 4 -fl quino line (Compound 209); 8-Ethoxy- 1, 2 -dihydro-2,2,4-trimethyl-6 H'Tiyaaa\KftP\PcM\597796SIhROID RECEPTORdoc 19/01/00 DOCKET NO.

016-0014A.WO 100 6 -g]quinoline (Compound 248); and 1,2,6,7-Tetrahydro-6hydroxy-2,2,4-trimethyl-6-trifluoromethyl-8-pyridono[5, 6 -g]quinoline (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 10 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.

SIn 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 S 20 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 (Beiersdorf). Examples of suitable cream bases are Nivea T M Cream (Beiersdorf), cold cream (USP), Purpose Cream T (Johnson Johnson) hydrophilic ointment (USP), and Lubriderm T M (Warner-Lambert).

H.'\Paninaea\Kp\spccM597.96S'ROID RECEPTORoc 19/01/00 EDITORIAL NOTE APPLICATION NUMBER 27761/00 This specification does not contain pages 101 to 110.

DOCKET NO.

0 16-001 4A.WO 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)-2,2,4trimethylquino line. N-tert-butylo xycarbonyl- 1,2-dihydro-6-(2-hydroxycarbonyl-4nitrophenyl)-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, 0cc). 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.

10 Data for Compound 110: 1 H NMR (400 MHz, acetone-d6) 8.43 J 2.4, 1H), 8.33 (dd, J 8, 2.4, 1H), 7.72 J 8, 111), 7.08 J 2, lH), 7.02 (dd, J 8, 2, 1H), 6.57 J 1 5.62 (br s, 1lH), 5.41 I1H), 1. 96 J 2.4, 3H), 1. 28 611).

EXAMPLE 12 :*15 6-(3.4-Dichlorophenyl)- 1 2-dihydro-2.2,4-trimethylquinoline (compound 111. structure 4 of Scheme where R 1 =3,4-dichlorophenvl) This compound was prepared according to General Method 2 (EXAMPLE From Compound 9 (78.4 mg, 0.25 mmcl) and commercially available 3,4-dichloro bromo benzene (56.7 mg, 0.25 mmcl, Lancaster) was obtained a crude product which was isolated and purifed by preparative thin layer chromatography (PTLC) (1000 ptm. 10% ethyl acetate/hexane) to afford 22 mg of Compound 111. Data for Compound Il1: IH NMR (400 MHz, acetone-d6) 7.73 1H), 7.52 J 1.2, 2H), 7.32 J 2, 1H), 7.26 (dd, J 2, 1H), 6.57 J 8, l14), 5.42 (br s, 1H), 5.37 1H), 2.03 J 1.2, 3H), 1.27 6H).

EXAMPLE 13 4-Ethyl- 1 .2-dihydro-2,2-dimethyl-6-phenylq "uinoline (Compound 112, structure 13 of Scheme H. where Rl=phenyl, R 2 =methyl) N-tert-Butyloxycarbonyl- 1 .2-dihydro-2,2-dimethyl-4-hydroxymethyl-6-phenvl quinoline (structure 11, where R 1 2henyl):. 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 -mcl) and H.'Priyanka\Keep\,pcM\5977-96.STBRO[D RECEPTORdoc 19/01/00 DOCKET NO.

016-0014A.WO 112 selenium dioxide (345 mg, 3.11 mmol) 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 dichloromethane, dried (MgSO4), and the organic phase was concentrated in vacuo.

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

R

1 =phenyl. The aldehyde was treated with sodium borohydride in 25 mL of methanol at 0°C. After 1 h at 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, 10 1 H NMR (acetone d6) 7.68 J= 9, 2H), 7.61 J 1.8, 1H), 7.47 (dd, J 6.2, 1.8, 1H), 7.41 J= 6.4, 2H), 7.29 5.80 1H), 4.51 J 6.8, 2H), 4.12 J 6.8,1H), 1.52 (br s, N-tert-Butyloxycarbonyl-4-bromomethyl- 1,2-dihydro-2.2-dimethyl-6-phenyl quinoline S 15 (structure 12, where Rl=phenyl): To a solution of N-tert-butyloxycarbonyl-1,2-dihydro- 2,2-dimethyl-4-hydroxymethyl-6-phenylquinoline (structure 11, where R 1 phenyl) (230 mg, 0.630 mmol) and carbon tetrabromide (220 mg, 0.662 mmol) in 5 mL of dichloromethane at 0 C was added triphenylphosphine (174 mg, 0.662 mmol) in 2 mL of dichloromethane. The reaction mixture was allowed to warm to rt and stirred for 1 h. The 20 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%).

1 H NMR (acetone d6) 7.67 3H), 7.52 (dd, J 8.7, 2.1, 1H), 7.45 2H), 7.32 (m, 2H), 6.07 1H), 4.60 2H), 1.55 6H), 1.53 9H).

4-Ethyl-1,2-dihydro-2,2-dimethyl-6-henvlquinoline (Compound 112, structure 13 of Scheme II where R =phenvyl R2=methyl): To a solution of N-tert-butyloxycarbonyl-4bromomethyl-1, 2 -dihydro-2,2-dimethyl-6-phenylquinoline (structure 12, where R 1 =phenyl) mg, 0.047 mmol) and copper iodide (4 mg, 0.02 mmol) in 1 mL of anhydrous ether at 0°C was added MeMgBr (0.060 mL, 3 M in ether). After 30 min of stirring at 0°C, the H.\Pryanka\KrseP\CMS9T-96SThROID RECEPIOR~oc 19/01/00 DOCKET

NO.

0 16 -0014A.WO 113 reaction mixture was quenched with saturated NH4C1 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-2,2-dimethyl-6-phenylquinoline (16 mg,

IH

NMR (acetone-d6) 7.65 J 8.7, 2H), 7.51 (dd, J 8.0, 1.7, 1H), 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 10 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: 1 H NMR (acetone-d6) 7.55 J 8.6, 2H), 7.37 3H), 7.23 (m, 2H), 6.59 J 8.26, 1H), 5.38 3.76 1H), 2.48 J 7.4, 2H), 1.29 6H), 15 1.17 J= 7.4, 3H).

EXAMPLE 14 S1,2-Dihydro-2.2-dimethyl-6-phenyl-4-proplquinoline (Compound 113. structure 13 of Scheme I, where R 1 =phenvl. R 2 =ethyl) 20 To a solution of N-tert-butyloxycarbonyl-4-bromomethyl-1,2-dihydro-2,2-dimethyl-6phenyl quinoline (structure 12, where R1=phenyl) (20 mg, 0.047 mmol) and copper (I) iodide (4 mg, 0.019 mmol) in 1 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 NH4C1 and extracted with ethyl acetate. The organic layers were combined, dried (Na2SO4), 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 (Na2SO4) and concentrated in vacuo to provide an oil that was chromatographed (silica gel, hexane/ethyl acetate, 7:3) to give Compound 113 (9

H

9 .iyaax~ka\Kep~sp~cM5977.96.STROID RHCEPTORdoc 19/01/00 DOCKET

NO.

016-0014A.WO 114 mg, 61 Data for Compound 113: 1 H NMR (acetone-d6) 7.53 (in, 2H), 7.40 (in, 3H), 7.24 (mn, 2H), 6.58 J 8.14, lH), 5.38 1H), 3.76 1H), 2.45 J 7.40, 2H), 1.60 (sx, J 7.39, 2H), 1.29 6H), 0.99 J =7.27, 3H).

EXAMWPLE 6- Chlorophenyl). 2 -d-iydro- 2.2,4-trinethylguino line (Compound 114. structure 4 of Schem-e RI where- I =2-chlorophenyl) This compound was prepared according to General Method 2 (EXAMPLE From Compound 9 (48.5 mg, 0.15 minol) and commercially available 2 -chlorobromo benzene 0: 10 (17.8 mL, 0. 15 mmol, Lancaster) 15 mg of Compound 114 was isolated. Data for 0 00 .Compound 114: 1 H NMR (400 MHz, acetone-d6) 7.45 (dd, J 8,1.2, 1H), 7.36 (dd, J 8, 2, 1 7.3 3 (ddd, J 16, 8, 1.2, 1 H, 7.3(d, J= 1,8 1, H,7 1(,J=2 :7.03 (dd, J 8, 2, 1 6.53 J 8, 11H), 5.35 1IH), 5.31 (br s, IRH), 1. 97 J 1. 6, 3H), 1.28 6H).

EXAMPLE 16 2 Dihydro-2.24.trimethylindeno f 2. 1 -tlquinmoline (Compound 116. structure 17 of Scheme IV, where R I X=C 2) GeneralMethod 3: 2 -dihydroquino line formation frm an aniline: To a dry 500-mL 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 UV, the product appearing as a bright blue spot). After cooling to room temperature, Celitem (2.0 g) was added and the mixture 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 mixture of isomers of structures 16 and 17.

l.

2 -Dihydro-2,2.4-trimethylindeno[2 I -flquinoline (Compound 116, structure 17 of Scheme IV where R 1 6 =H X=CH2) This compound was prepared according to General Method 3 from structure 15 (where R 1 6 X=CH2) (5.0 g, 27 inmol) to afford a mixture of H.%Piynka\K-p\spccM597-96.STEROID RBCHPTORAdo 19101/00 DOCKET NO.

016-0014A.WO 115 Compound 115 (structure 16 of Scheme IV, where R1- 6 X=CH2)(1.64 g, 22.7%) and Compound 116 (336 mg, 4.65 in an 85:15 ratio (as determined by 1 H NMR). Data for Compound 116: Rf= 0.57 (silica gel, hexane/EtOAc, 1 H NMR (400 MHz, C6D6) 7.62 J 8.0, 1H), 7.45 J 8.0, 1H), 7.28 J 7.3, 1 6,31 J 8.0, 1H), 5.19 1 3.74 2 3.28 (br s, 1 1.98 J 1.2, 3 1.08 6 H).

EXAMPLE 17 8-Bromo-1, 2 -dihydro-2,2,4-trimethvlindeno[l.2-glquinoline (Compound 117. structure 16 of Scheme IV, where R 2 4

R

6 R5=Br, X=CH2 S 10 This compound was prepared according to General Method 3 (EXAMPLE 16) from structure 15 (where R-4, R 6 R5=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, 1 H NMR (400 MHz, C6D6) 7.38 3H), 6.17 1H), 5.15 1 3.34 2 3.27 (br s, 1 1.93 J 15 1.0, 3 1.08 6 H).

EXAMPLE 18 7-Bromo-1.

2 -dihydro-2,2,4-trimethylindenor2,1-flquinoline (Compound 127, structure 17 I of Scheme IV, where R 1 4

R

6 R5=Br. X=CH2) This compound was prepared according to General Method 3 (EXAMPLE 16) from structure 15 (where R 1

R

6 R5=Br, X=CH2) (2.0 g, 7.7 mmol) 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, 1 H NMR (400 MHz, C6D6) 7.38 J 8.3, 1 7.31 1 7.29 J 8.0, 1 7.19 J 8.0, 1 H), 6.25 J 8.1, 1 5.16 1 3.52 2 3.32 (br s, 1 1.91 J 1.4, 3 H), 1.05 6 H).

H:\iyanka\omp\specM 5977-96s7ROID RECEPToRdoc 19/01/00 DOCKET

NO.

016-00 14A.WO 116 EXAMPLE 19 1 2 -Dihvdro-2,2.4-trimethylbenzo[Wi furano [3 2 -Qguino line (Compound 118, structure 16 of Scheme TV where. R 2 6

XO)

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, IH NMR (400MHz, C6D)6) 7.61 J 6.9, 1H), 7.56 1 7.41 J 8.0, 1H), 7.13 (in, 2 6.38 1 5.12 1 H), 3.28 (br s, 1 1.91 3 1.05 6 H).

10 EXAMPLE .C 2 -Dihydro-2,2,4-trimethylbenzo rb] furano 2 ,3-tlg uino line (Compound 119. structure 17 of Schemne IV, where R 1 6 =H X=O =H This compound was prepared according to General Method 3 (EXAMPLE 16) from structure 15 (where R 1 6 X=O) to afford Compound 118 (264 mg, 1.00 mmol, 18.4%) 15 as a yellow solid and Compound 119 (936 mg, 3.55 mimol, 65. as a clear colorless oi.

Data for Compound 119: Rf=- 0.44 (silca gel, hexane/EtOAc, 3: 1H NMR (400 MHz, C6D6) 7.63 (dd, J 7.4, 1.5, 1 7.41 J 8.2, 1 7.35 J 1 7. 11 (in, C2 6.19 J 8.4, 1 5.11 1 3.38 (hr s, 1 2.49 J 1.2, 3 1.06 6

H).

20 EXAMPLE 21 6-Fluoro- Il.

2 -dihydro-2,2,4-trimethylindeno[r2 41uino line (Compound 120 structure 17 of Scheme IV. where

RI-

5

R

6 X-CH42 This compound was prepared according to General Method 3 (EXAMPLE 16) from structure 15 (where RI- 5

R

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

Data for Compound 120: Rf 0.70 (hexane/ EtOAc 3: IH NMR (400 MHz, 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 (hr s, 1 1.88 J 1.2, 3 H) 1.05 6 H).

H-Vriyank\K=eP\,pecM\5977-96.STEROID RECEPTORAdo 19/01/00 DOCKET NO.

o 16-0014A.WO 117 EXAMPLE22 9-Fluoro- 1 .2-dihydro-2,2,4-trimethyl inden0 E1 2 -glguino line (Compound 121. structure 16 of Scheme IV. 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: 1 H NMR (400 MHz, C6D6) 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 1 5.15 1 3.63 2 3.28, (br s, 1H), 1.93 J 1.2, 3 H) 1.09 6 H).

1.-Ihdo 9hdoyehl2,4tiEAMLnEn 231,.

2 g]guino line (Compound 122.

Scheme V).

:Methyl 1,.

2 -d ihydro-2.2,4-trimethyliadeno Fl 1.

2 -glguino line- 9-carboxylate (structure 16 of Scheme IV where R 2 5

R

6 =CO?,CH3 X=CH): This compound was prepared 15 according to General Process 1 from methyl 2 -aminofluoreno-8-carboxylate to afford 872- S...mg of methyl l, 2 -dihydro-2,2,4-trirnethylindeno 1, 2 quino line- 8-carboxylate (structure 16 of Scheme IV where R 2 5

R

6 =CO2CH3, X=CH2) as an off white solid.

see* *0S Data for methyll1, 2 -dihydro-2,2,4-trimethyindeno[ 1,2-g] quinoline-9-carboxylate: 1 H1 NMR (400 mHz, C6136) 8.03 J 7.8, 1 7.56 J 7.4, 1 7.50 1 7.20 20 (dd, J 15, 7.5, 1 6.32 1 5.17 1 4.28 2H), 3.55 3H), 1.97 J= 1. 3, 3 1. 10 611).

l.

2 -Dihydro- 9 -hydroxylmethyl2,2,4-imethylnden 0 fl 2 -glq -uinoline (Compound 122.

Scheme In a r.b. flask equipped with a magnetic stirring bar was dissolved methyl 1,2diyr-,,-rmtyidnf,-~untn--abxlt (23 mg, 72.1 p.mol) in 10 mnL dry THF. The solution was stirred at -78'C for 10 min and DIBA1-H (1.0 M in hexanes; 0.43 mL, 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 11, 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 H.Vryanka\Kep\specN497796STEROID RECEPTORdOC 19/01/00 DOCKET NO.

016-0014A.WO 118 in vacuo to give 10 mg of Compound 122 as a white solid. Data for Compound 122: Rf 0.23 (silica gel, hexane/EtOAc, 1 H NMR (400 MHz, acetone-d6) 7.55 J 7.4, 1H), 7.50 1H); 7.26 (dd, J 15, 7.5, 1H); 7.18 J 7.4, 1H); 6.73 1H); 5.36 1H); 5.21 1H); 4.72 J 5.8, 2H); 4.06 (dd, J 11.4, 5.7, 1H); 3.20 2H); 2.78 3H); 1.28 6H).

EXAMPLE 24 8-Chloro-1, 2 -dihydro-2.2.4-trimethylindeno 1.2-glquinoline (Compound 123. structure 16, Scheme IV. where R 2 4

,R

6 =H R 5 =C1, X=CH2) 2 -Amino-7-chlorofluorene (structure 15. Scheme IV. where R 1 -4R 6

R

5 =C1, X=CH2.

10 A 100 mL round-bottom flask was charged with structure 14 (where, R 2 4

,R

6

R

5 =C1, X=CH2) (496 mg, 2.02 mmol) and methylene chloride (20 mL) and 10% Pd/C (0.5g) was i 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 15 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 R 1 4,R 6

R

5 =C1, X=CH2)(400 mg, was used in the next step without purification.

20 8-Chloro-l, 2 -dihvdro-2.2.4-trimethylindeno1,.2-g quinoline (Compound 123. structure 16.

Scheme IV, where R 2 -4R 6

R

5 =CL X=CH2). This compound was prepared according to General Method 3 (EXAMPLE 16) from structure 15 (where R 1 4

,R

6

R

5 =C1, X=CH2)(400 mg, 1.85 mmol) and acetone (60 mL, Aldrich reagent grade) to afford Compound 123 and structure 17, where R 2 4

,R

6

R

5 =C1, X=CH2. Purification by PTLC (reverse phase, 80% methanoVwater) provided 1.8 mg of Compound 123.

Data for Compound 123: 1H NMR: (400 MHz, acetone-d6) 7.59 J 8, 1H), 7.46 (s, IH), 7.39 J 2, 1H), 7.24 (dd, J 8, 2, 1H), 6.67 1H), 5.35 1H), 5.26 (br s, 1H), 3.71 2H), 1.98 3H), 1.24 6H).

H.Vmianka\K-ppspcc,\45-96STEROID RECEPTIR.do 19/01/00 DOCKET

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01 6 -0014A.WO 119 EXAMPLE 8-Fluoro-l, 2 -dihydro-2,2,4-trimethylindeno[.

2 -gquinoline (Compound 124. structure 16.

Scheme IV, where R2-4,R 6

R

5 X=CH2) This compound was prepared according to General Method 3 (EXAMPLE 16) from 2amino-7-fluorofluorene (structure 15, where R1- 4

,R

6

R

5 X=CH2) (100 mg, 500 pmol) to afford 43 mg of a mixture of Compound 124 and structure 17, where R 1 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 (C-18, 20 x 20 cm, 1000 pm, MeOH H20, 5:1) to give Compound 124 as a brown solid. Data for Compound 124: Rf 0.59 10 (silca gel, hexane/EtOAc, 1 H NMR (400 MHz, C6D6) 7.43 1 7.24 1 H), 6.96 2 6.21 1 5.18 1 3.38 2 1.96 3 1.11 6 H).

EXAMPLE 26 8-Acetyl-1,2-dihydro-2,2,4-trimethylindenor1, 2 -glquinoline (Compound 125, structure 16, Scheme IV. where R 2 -4R 6

R

5 =COCH3n X= In a r.b. flask equipped with a magnetic stir bar was dissolved Compound 115 (EXAMPLE 16) (54 mg, 0.021 mmol) in CH2C12 (3 mL). To this solution was added freshly distilled S..acetyl chloride (20 pL, 1.3 equiv). The reaction mixture was stirred for 10 min, and A1C13 (=30 mg) was added. The reaction was followed by TLC (hexane/EtOAc, 3:1, visualized by 20 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 Celite

M

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, 1

H

NMR (400 MHz, C6D6) 8.06 1 7.94 J 8.0, 1 7.53 1 7.46 J 1 6.22 1 5.16 1 3.50 2 2.28 3 1.94 J 1.4, 3H), 1.10 6 H).

H.NManka\K~psspeci\45977-96.S'MRID RECEPTORQc 19/01/00 DOCKET NO.

016-0014A.WO 120 EXAMPLE 27 6-Fluoro- 1 2-dihydro-2.2.4-trimethylindeno[F 1 2 -glguino line (compound 126. structure 16.

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

R

3 X=CH2) (360 mg, 1.72 mmol) 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,4 1 7.02 J 10, 1 H) 6.73 1 H), 5.39 1H), 3.81 2 H) 2.87 3 1.28 6 H).

:::.EXAMPLE 28 1, 2 Dihydro -2.2.4-trimethylp7-ntroinde--n [2,.11 qfluino line (Compound 128. structure 17.

Scheme IV, where R 1 4

,R

6

R

5 =N09. X-CH2) This compound was prepared according to General Method 3 (EXAMPLE 16) from 2- 15 amino-7-nitrofluorene (100 mg, 0.44 inmol) 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 *MHz, 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 1 3.88 2 2. 10 3 1.31 6 H).

EXAMPLE 29 l.

2 -Dihydro-2,2.4-trimethy-8-nitroindenor[1. 2 -glguinoline (Compound 129. structure 16.

Scheme TV. where R 2 4

.R

6

R

5 =NO2 -X=CH 2 This compound was prepared according to General Method 1 from 2 -amino-7-nitrofluorene (100 mg, 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 1 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 1 4.26 2 2.30 3 1.31 6 H).

H?.Priynka\Kmp\spc\5977-96S7ROD RECEPTOR.doc 19101/00 DOCKET NO.

016-0014A.WO 121 6.9-Difluoro- 1 2 -dihydro- 2,2,4-trimnethylindeno r 1 .2-g lguino line (Compound 130. structure 16, Scheme IV, where R 2

,R

4 5

R

3

.R

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

,R

4 5

R

3

,R

6 X=CH2) (460 mg, 2.03 mmol) to afford 94 mg of Compound 130 as a light brown solid. Data for Compound 130: Rf 0.56 (silica gel, hexane/EtOAc, IH NMR (400 MHz, C6D6) 7.92 1 6.68 (ddd, J 9.1, 6.3, 3.6, 1 6.49 (ddd, J 8.5, 6.0, 3.5, 1 6.07 1 5.09 1 3.55 2 1.88 J 1.1, 1 1.06 6 H).

EXAMPLE 31 7-Fluoro- 1 .2-dihydro-2,2,4-trimethyl- 11I -(thiomethyl)indeno r2. 1 -flguino line (Compound 131. structure 17 of Scheme IV, where. R 1 =SCH3.R 2 4

R

6

R

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

R

6

R

5

=F)

(250 mg, 1.17 mmol) to afford 29 mg of Compound 131 as a white solid. Data for compound 131: Rf 0.55 (silica gel, hexane/EtOAc, 3: IH NMR (400 mHz, C6D6) 7.78 1 7.19 (in,4 1 6.90 1 6.88 1H), 5.44 1 5.22 1 3.54 (s, 2H), 2.05 3H), 1.92 J 1.2, 3 1.68 6 H).

EXAMPLE32 8-Difluoro- 1 2-dihydro- 1 -hydroxy-2,2.4-trirnethylindeno rl1.

2 -glgquinoline (Compound 132, Scheme VUI).

3,2'-Difluoro-2-biph'enic acid Compouind 231Shm I) A flame-dried 50 mL r.b. flask fitted with an air-cooled condenser containing methyl 2 -bro mo-5-fluoro benzo ate (Compound 21, Scheme VII) (4.00 g, 17.16 mmol) and 2-iodofluoro benzene (Compound 22, Scheme VII) (19.05 g, 85.82 mmol, 5.00 equiv) was heated to 176'C, at which time unactivated copper powder (15.0 g, 236 mmol, 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 ii and was filtered through a bed of CeliteTM on a fittedglass funnel, rinsing with 250 mL ethyl acetate. Concentration under reduced pressure H:\Praa\Kmp\pecM\5977-96-SThRO[D RECEPTOR~do 19/01/00 DOCKET

NO.

01 6 -0014A.WO 122 afforded an oil which was shown by 1 H 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 N aqueous HC1. 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: 1H NMR (400 MHz, CDC13) 7.76 (dd, J 9.1, 2.2, 1H), 7.32 3H), 7.26 (ddd, J 9.5, 7.8, 1.8, 1H), 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 To a flame-dried 100 mL flask containing 3 2 '-difluoro-2-biphenic acid (Compound 23, Scheme VII) (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 CH2C12 (5 mL) were then sequentially added and 20 removed by distillation. Anhydrous CH2C12 (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 0 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.]).

H,\Priyanka'\Kmpcsp=M5977.96.sTTeROID RECEPlR.doc 19/01/ O DOCKET

NO.

016-0014A.WO 123 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 fuming nitric acid at 0°C in a 5 mL round-bottomed flask. The ice bath was removed and the reaction mixture was gently heated to 50 0 C for 2 min 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 0 C, literature mp 207-208 0 C which was carried on to the next step without further purification.

2 -Amino- 4 ,7-difluorofluorenone (Compound 132, Scheme VII): 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 min, 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 0 C Data for Compound 132 1 H NMR (400 MHz, CDC13) 7.46 (dd, J 8.1, 4.5, 1H), 7.29 J 1.5, 1H), 7.11 (dd, J :i 8.5, 6.0, 1H), 6.79 J 1.9, 1H), 6.42 dd, J 10.9, 1.9, 1H), 3.99 (br s, 2H).

5,8-Difluoro-1, 2 -dihydro-2,2.4-trimethyl 10-oxoindeno[1.2-glquinoline (structure 19 of SScheme VI, where R 2

R

5 R3-4 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- 1, 2 -dihydro-2,2,4-trimethyl- 10-oxoindeno [1, 2 -g]quinoline (structure 19 of Scheme VI, where R 2

R

5

R

3 4

R

6 Data for 5,8-difluoro-1,2-dihydro-2,2,4-trimethyl-10oxoindeno[l,2-g]quinoline: Rf 0.49 (silca gel, hexane/EtOAc, 1 H NMR (400 MHz, acetone-d6) 7.50 (dd, J= 8.1, 4.6, 1 7.27 2 6.73 1 6.03 (br s, 1 5.47 1 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 hydroxy-2,2.4-trimethylindenor 1 2 quinoline (structure 20 of Scheme V: To a flame dried 25-mL r.b. flask equipped with a magnetic stir bar was added structure 19 dissolved in H\Paka\Kmp\pecM\S97796.ShROID RECEPTOR.do 191/00 DOCKET NO.

016-0014A.WO 124 anhydrous CH2C12 (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 S04-10 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-dihydro- 10-hydroxyl-22.4-trimethylindeno r 1.

2 -gquinoline (Compound 132, Scheme VII): 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 DIBA1-H (1.0 M in hexane, 0.5 mL, 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) 15 7.54 (dd, J 8.3, 5.0, 1 7.24 (dd, J 8.6, 2.3, 1 7.06 (ddd, J 11.3, 9.3, 2.5, 1 H), 6.68 1H), 5.63 (br s, 1 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-Difluoro-1.

2 -dihydro-2.2,4-trimethvl 10-oxoindeno [1,2-luinoline (Compound 135 structure 19. Scheme VI, where R 2 -3,R 5 =H R 4

,R

6

=F)

This compound was prepared according to General Method 3 (EXAMPLE 16) from 2amino- 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, 1 H NMR (400 MHz, acetone-d6) 7.46 1 7.22 (dd, J 8.5, 1.9, 1 6.76 1 6.68 (ddd, J 9.6, 5.8, 2.3, 1 5.89 (br s, 1 5.52 1 2.06 3 1.30 6

H).

H*\Priyanka\Kep\spec5977.96SThROD RECEPUTRdoR 1901/00 DOCKET NO.

016-0014A.WO 125 EXAMPLE 34 7.9-Difluoro- 1,2-dihydro- 10-hydroxv-2,2.4-trimethylindeno 1,2-g]quinoline (Compound 133, structure 20, Scheme VI, where R 2 -3,R 5 R4,R 6

=F)

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 CH2C12. The solution was cooled to -78 0 C and then DIBALH (0.5 mL, 1.0 M in hexanes) was added. The solution was stirred for 30 min, 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 mg of Compound 133 as an off-white solid.

Data for Compound 133: 1 H NMR (400 MHz, C6D6) 7.40 1 7.09 (dd, J 8.7, 2.1, 1 6.84 1 6.55 (ddd, J 10, 5.7, 2.0, 1 5.65 1 5.31 1 4.54 J 8.5, 1 2.00 J 1.0, 3 1.28 3 1.26 3 H).

EXAMPLE 7,10-Difluoro-1.

2 -dihydro-2.2.4-trimethyl-5-oxoindeno[2 1-flquinoline (Compound 134, structure 17 of Scheme IV, where R 2

R

5

R

1

R

2

R

6

X=C=O)

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 mmol) to afford 22 mg of Compound 134 as a purple solid. Data for Compound 134: Rf 048 20 (silica gel, hexane/EtOAc, 1 H NMR (400 MHz, acetone-d6) 7.47 1 7.24 2 6.52 J 11, 1H), 6.12 (br s, 1 5.66 1 2.25 J= 1.5, 3 1.27 6 H).

EXAMPLE 36 8-Fluoro- 1,2-dihydro-2.2.4-trimethyl- 10-oxoindenor[ ,2-g]quinoline (Compound 137, structure 16 of Scheme IV, where R 2 4

R

6

R

5

X=C=O)

To a dry 250-mL 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 mmol), along with iodine 15 mg) and mesityl oxide (20 mL, 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 H.Priyanka\Kcep\specM5977-96.ST0ROID RECEPTORdoc 19/01/00 DOCKET NO.

016-0014A.Wo 126 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 (in, 1 7.3 6 I1H), 7.21 (dd, J 10, 8, 1 7.16 (dd, J 10, 8, 1 6.7 8 I1H), 5.66 (br s, 1H), 5.51 1H), 2.04 3H), 1.29 6H).

EXAMPLE 37 8-Fluoro- 1 2-dihydro- 1 -hydroxy-2,2,4-trimethylindeno[ 1 2-glguinolie (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 gim silica, 19/1 hexanelEA) 0.9 mg of Compound 136 as a white solid. Data for Compound 136: IH NMR (400 MHz, acetone-d6) 7.52 (mn, 1IH), 7.37 7.21 (dd, J 8, 2.4, 1H), 7.02 (ddd, J 16, 8, 2.4, 1H), 6,77 1H), 5.38 J =12, 1H), 5.37 5.31 (br s, 1H), 4.59 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 rl1 2-gig-uinoline (Compound 138.

20 structure 16, Scheme IV, where R 2 3

R

6

R

4 =F R 5 N0.X=CH2) This compound was prepared according to General Method 3 (EXAMPLE 16) from 2amidno-6-fluoro-7-nitrofluorene (1.00 g, 4.00 inmol) to afford 98 mng of Compound 138 as a bright purple solid. Data for Compound 138: Rf 0.23 (silica gel, hexane/EtOAc, 3: 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).

H:.\Piynka\Kcp\pcM5977.96.SEROD RECEPTORdOC 19/01/00 DOCKET

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016-0014A.WO 127 EXAMPLE 39 1 .2-dihydro- 1 O-hydroxy-2,2.4-trimethylindeno 1 2-giguino line (Compound 139.

structure 20. Scheme VI. where R 2 =Cl. R 3 6 A solution of 2 -amidno-4-chloro-9-fluorenol (300 mg, 1.30 mmol), 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 H NMR (400 MHz, acetone- 10 d6) 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 1 4.59 J 8.5, 1 2.35 (s, :*go 3 1.32 3 H) and 1.21 3 H).

0g* i copud6-Freae fo -luoro- 1.-iyr-,.4tinty -oxideof[1u 2 -rgno (Co mo)nd to.& steps in the manner previously described for Compound 123 (EXAMPLE 24), affording 0*000.74 g (6 of Compound 140 as a dark purple solid. Data for Compound 140: 1 H NMR 20 (400 MHz, CDCI3) 7.33 1H), 7.26 3H), 6.75 1H), 5.45 1H), 3.96 (br s, 1H), 2.05 J 1.5, 3 1.31 6H).

EXAMPLE 41 6-Fluoro- 1 .2-dihydro- 1 0-hydroxy-2,2,4-trirnethylinde~no r 1 .2-glguino line (Compound 141.

structure 20, Scheme V 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 mmol) to afford 0.25 g of Compound 141 as a pale reddish-purple solid. Data for Compound 141: 1 H NMR (400 MHz, CDCl3) 7.49 1H), 7.32 J 7.3, 1 7.12 (dt, J 7.8, 4.8, 1 7. 00 (dd, J 9.8, 8.3, 1 6.71 I1H), 5.47 1 5.37 J 1. 2, 1 3.8 8 (br s, 1 2.06 J 1. 2, 3 1. 31 3 1. 30 3 H).

Hr.\"nk\Kep\specM597796S-hROD RECEPTOR~do 19/01/00 DOCKET NO.

016-0014A.WO 128 EXAMPLE 42 5,8-Difluoro- 1 2 -dihydro-2,2,4-trimethvl-10-(trifluoroacetoxv)indeno 2 -glquinoline (Compound 142, structure 16, Scheme IV, where R 2

,R

5 =F R 3

,R

4

R

6

X=CHOCOCF

3 To a flame-dried 25 mL r.b. flask containing 5,8-difluoro-1,2-dihydro-10-hydroxy-2,2,4trimethylindeno[1,2-g]quinoline, Compound 132, EXAMPLE 32, (15.0 mg, 0.048 mmol) in 2 mL dichloromethane at 0°C was added trifluoroacetic anhydride (10 mL, 0.071 mmol, equiv) and 4 -N,N-dimethylaminopyridine (18.0 mg, 0.147 mmol, 3.0 equiv), and the mixture was allowed to stir for 10 min. The reaction mixture was then transferred to a separatory funnel with ethyl acetate (20 mL), pH 7 potassium phosphate buffer (10 mL) 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, hexanes/ethyl acetate, gradient elution) afforded 14.1 mg of Compound 142 as a light yellow oily solid. Data for Compound 142: 1 H NMR (400 MHz, CDC1 3 7.59 (dd, J 8.4, 5.0, 1H), 7.15 (dd, J 8.2, 2.4, 1H), 7.09 (dt, J 8.8, 2.5, 1H), 6.64 (s, S 15 1H), 6.47 1H), 2.19 (dd, J 6.7, 1.2, 3H), 1.29 3 1.28 3 H).

EXAMPLE 43 6-(3,5-Difluorophenyl)- 12.3,4-tetrahydro-2,24-trimethylquinoline (Comound 143, structure 5 of Scheme I where R 1 20 A dry 10 mL r.b. flask was charged with Compound 147 (EXAMPLE 47) (17.4 mg, 0.06 mmol) and 0.3 mL ethyl acetate. To this solution was added 10% Pd/C (20 mg). 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 Celite T M to remove the solids, rinsed with ethyl acetate (50 mL) and concentrated. The crude material was purified by HPLC (reverse phase, ODS semi-preparatory column, 85% methanol/water, 3.0 mL/min).

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

Data for Compound 143: 1 H NMR (400 MHz, methanol-d4) 7.38 J 2.3, 1H); 7.20 (dd, J 8.5, 1.6, 1H); 7.09 2H); 6.72 1H); 6.56 J 8.2, 1H); 2.96 1H); 1.79 (dd, J 12.9, 5.8, 1H); 1.39 4H); 1.24 3H); 1.17 3H).

H:\Priyanka\Kmcp\pcc5977-96STEROID RECEPTORdoc 19/01/00 DOCKET

NO.

016-00 14A.WO 129 EXAMPLE 44 1 .2-Diihydro- 2,2,4-trimethylindo lo [3 2 -glgquino line (Compound 144. structure 16 of Scheme IV, where RI- 6

X=NH)

2-Aminocarbazole (structure 15 of Schieme IV, where RI- 6 X=NH): 2-Nitrocarbazole [Mendenhail, G. Smnith, P. A. S. Org. Syn. Coil. Vol. 5 1973, 829, the disclosure of which is herein incorporated by reference] (structure 14 of Scheme IV, where R 1 6

=H,

X=NTJ) (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 -aminocarbazole: 1 H NMR (400 NMz, CDCl3) 7.94 J 9.0, 1H), 7.83 J 8.0, 114), 7.80 (br s, 114), 7.35 (in, 2H), 7.15 (dd, J 8.2, 1 6.6 (d 1 1 H,65(d 1.8 1 3.7 (b s 2H).

1, l 2 -Dihydro-2,2,4-trimethylindolo 32-gluino line f~mon.144, structure 16 of Scheme IV, where RI- 6 XNH); A solution of 2 -amidnocarbazole (structure 15 of Scheme IV, where R 1 6 X=NH) (840 mg, 4.7 inmol) in 10 mL of acetone and one crystal (10 mng) 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-2,2,4- *trirnethylindolo [2,3.flquinoline (structure 17 of Scheme IV, where R 1 6 X=NH) (71 20 combined yield). Data for Compound 144: 1 H NMR (400 MHz, CDCl3) 7.90 J 11H); 7.80 (br s, 114), 7.66 (br s, 1H), 7.23 (br s, 2H), 7.12 (in, 1H), 6.30 (br s, 114), 5.32 (br s, 114), 3.75 (br s, 114), 2.13 314), 1.39 114).

EXAMPLE 5-Ethyl- 1, 2 -d ihydro-2,2,4-tinethylindo lo 2 3 -flguino line (Compound 145. structure 29 of Schem-e VUI. whre Rl 6

R

7 =Et) To a suspension of sodium hydride (60% in mineral oil, 16 mg, 0.405 mmol) in 1 mL of THF at 0 0 C was slowly added 1 2 -dihydro-2,2,4-trimethylindolo[2,3-f] quinoline (structure 28 of Scheme VIII, where R 1 6 (30 mng, 0. 116 inmol) in 1 mL of T14F and the resulting midxture was stirred at 0 0 C for 30 minutes. lodoethane (9.3 m-L, 0. 116 inmol) was added MHPri~anka\Kosp\spcM5977-96.STEROD RECEPORdoc 19/01100 DOCKET NO.

016-0014A.WO 130 dropwise via a microsyringe 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 vacuo to a residue that was purified by flash chromatography (silica gel, hexane/ethyl acetate, 9:1) which gave 27 mg of Compound 145. Data for Compound 145: 1 H NMR (400 MHz, CDC13) 7.81 (d, J 7.1, 1H), 7.63 J 8.1; 1H); 7.34 J 8.0, 1H); 7.25 (br s, 1H); 7.12 (apparent t, J 7.4, 1H); 6.51 (br s, 1H); 5.38 (br s, 1H); 4.25 J 7.0, 2H); 4.22 (br s, 1H); 2.16 (s, 3H); 1.26 6H); 0.91 J 7.0, 3H).

.09 10 EXAMPLE 46 26-(3-Chlorophenl)- 1, 2 -dihvdro-2,2,4-trimethylquinoline (Compound 146. structure 4 of Scheme II where R 1 =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 15 crude product was isolated and purified by silica gel chromatography (50 mL silica, ethyl acetate/hexane) and PTLC (reverse phase, 1000 p.m plate, 95% methanol/water) to :io. yield 54 mg of Compound 146. Data for Compound 146: 1 H NMR (400 MHz, acetone-d6) 7.56 J 4.0, 1H); 7.50 J 8.0, 1H); 7.34 (apparent t, J 8.0, 1H); 7.31 o° J 4.0, 1H); 7.24 (dd, J 8.0, 4.0, 1H); 7.23 (dd, J 8.0, 4.0, 1H); 6.57 J S 20 1H); 5.60 1H); 2.03 3H); 1.27 6H).

EXAMPLE 47 6-(3,5-Difluorophenvl)-1, 2 -dihydro-2.2,4-trimethylquinoline (Compound 147. structure 4 of Scheme II. where R 1 This compound was prepared according to General Method 2 (EXAMPLE From Compound 9 (59.7 mg, 0.19 mmol) and l-bromo-3,5-difluorobenzene (21.6 mL, 0.19 mmol, Lancaster) a crude reaction mixture was isolated and purified by HPLC (reverse phase, semi-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, acetone-d6) 7.34 J 2.2, 1H); 7.28 (dd, J 8.4, 2.3, 1H); H:\Priyank\Kp\pe \5977-96.STRO(D RECEPTORdoc 19/01/00 DOCKET

NO.

0 16-0014A.WO 131 7.19 (in, 2H); 6.80 (in, 114); 6.57 J 8.3, 114); 5.47 1H); 5.38 1H); 2.04 3H4); 1.28 6H).

EXAM NPLE 48 6 3 -Fluoropheny)12dihydro22.4-timethylinmo line (Compound 148. structure 4 of Scheme where R=3-flnnrnphe-nyI) 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 (in, 2H4); 7.26 (dd, J= 7.7, 2.2, 1H); 7. 10 J= 2.0, 114); 7.03 (dd, J= 8.1, 2.0, 1IH); 6.54 J 8.2, 114); 5.35 1H4); 5.29 114); 1.97 314); 1.28 6H).

EXAMPLE 49 l,-jyr-.,:rjehl6 lin (Copound 149. structure 4 of Scheme UI. where R =4-pridyl) a....This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (23.8 mng, 0.07 inmol) and 4 -bromopyridine hydrochloride (14.5 mng, 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/C142C1 2 then Et2O) to afford 7.3 mg of Compound 149. Data for Compound 149: 1 H NMR (400 MHz, acetone-d6) 8.59 J 6.0, 214); 7.55 (in, 214); 7.45 J 2.2, 114); 7.40 (dd, J 8.3, 2. 1, 114); 6.60 J 8.2, 114); 5.40 114); 2.06 314); 1.30 6H4).

EXAMPLE 6 -(3-Cyanophenyl)- l, 2 dihydro-2,2,4-trimethylguinoline (Copound 150 structure 4 of SchemeUl. where R=-canohevl H.'Pr~ana\-P'pci\597-9.STERIDRECEPTORdoc 19101/00 DOCKET NO.

016-0014A.WO 132 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 of Compound 150 as pale yellow crystals. Data for Compound 150: 1 H NMR (400 MHz, acetone-d6) 7.94 J 1.1, 1H); 7.88 1H); 7.56 2H); 7.38 J 2.2, 7.31 (dd, J 8.3, 2.2, 2H); 6.59 J 8.3, 1H); 5.42 1H); 5.38 1H); 2.01 3H); 1.28 6H).

EXAMPLE 51 10 6-(3,5-Dichlorophenyl)- 12-dihydro-2.2.4-trimethylquinoline (Compound 151. structure 4 of Scheme II, where R 1 This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (40.4 mg, 0.13 mmol) and 1-bromo-3,5-dichlorobenzene (28.7 mg, 0.13 15 mmol, Aldrich). The crude product was isolated and purified by silica gel chromatography (75 mL silica, 5% ethyl acetate/hexane) to afford 32 mg of Compound 151. Data for Compound 151: 1 H NMR (400 MHz, acetone-d6) 7.53 J 1.8, 2H); 7.34 J 1.8, 1H); 7.27 2H); 6.57 J 8.3, 1H); 5.38 1H); 2.04 3H); 1.28 6H).

EXAMPLE 52 S" 6-(2,3-DifluorophenyDl-1 2-dihydro-2.2.4-trimethylquinoline (Compound 152, structure 4 of Scheme II, where R 1 =2.3-difluorophenyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (28.7 mg, 0.09 mmol) 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: 1 H NMR (400 MHz, acetone-d6) 7.21 5H); 6.57 J 8.3, 1 H); 5.37 1H); 1.99 3H); 1.28 6H).

H:\Piyaka\Kap\speci5977-96.STEROID RECEPTORdoc 19/01/00 DOCKET NO.

0 16-001 4A.WO 133 EXAMPLE 53 1 2 -Dihydro-2.2,4-trimethyl-6-(pentafluorophenylqguino line (Compound 153. structure 4 of Scheme U. where RI=pentafluorophenyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (55.3 mg, 0. 17 mmol) and Il-bromopentafluorobenzene (21.7 mL, 0. 17 mmol, 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: 1 H NMR (400 MHz, acetone-d6) 7.11 J 1.2, 1H); 7.03 (dd, J :0 1.6, 1H); 6.60 J 8.3, 1H); 5.57 lH); 1.95 3H); 1.29 6H).

15 EXAMPLE 54 1 .2-Dihydro-2,2,4-trimethyl-6- 4 (trifluoroacetyl)phenyl guino line (Compound 154.

structure 4 of Scheme U, where R 1 =4-(trifluoroacetyl)p2henyl) a This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (49.1 mg, 0. 15 mmol) and 4 Thbromo-2,2,2-trifluoroacetophenone (23.5 p.L, 0. 15 nimol, 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 (in, 2H); 5.41 lH); 4.97 1H); 2.04 3H); 1.27 6H).

1 2-Dihydro -2,2,4-trimethyl-6- (1 .3-pyrimid-5- yl)g~uino line (Compound 155, structure 4 of Scheme H, where R 1 H?.\Pnyanka\Kcep'.pecM\5977-96.S7hROID RECEPTOR.Oc 19/01/00 DOCKET NO.

016-0014A.WO 134 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 mmol, Aldrich).

The crude product was isolated and purified by recrystallization (Et20/hexanes) to afford 2.1 mg of Compound 155. Data for Compound 155: 1 H NMR (400 MHz, acetoned6) 8.97 1H); 8.94 2H); 7.39 J 1.9, 1H); 7.32 (dd, J 8.4, 2.2, 1H); 6.63 J 8.3, 1H); 5.39 1H); 2.05 3H); 1.29 6H).

EXAMPLE 56 10 6-(3-Cyanophenyl)-l2, 3 4 -tetrahvdro-2,2,4-trimethvlquinoline (Compound 156, structure of Scheme I where RI=3-cvanophenyl) A dry 10 mL r.b. flask was charged with Compound 150 (EXAMPLE 50) (16.7 mg, 0.06 mmol) and 0.5 mL ethyl acetate. To this solution 10% Pd/C (20 mg) was added. The flask 15 was stirred under an atmosphere of hydrogen for 1 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 semipreparatory column, 85% methanol/water, 3.0 mL/min). The major peak was isolated and 20 identified as Compound 156 (1.8 mg, 11%) byNMR. Data for Compound 156: 1 H NMR (400 MHz, acetone-d6) 7.93 J 1.3, 1H); 7.88 1H); 7.55 2H); 7.51 J 1.4, 1H); 7.28 (dd, J= 8.7, 1.4, 1H); 6.59 J= 8.4, 1H); 2.95 1H); 1.80 (dd, J= 12.8, 5.4, 1H); 1.39 4H); 1.25 3H); 1.19 3H).

EXAMPLE 57 5,8-Difluoro-l, 2 -dihydro-2,2,4-trimethylindeno 2 -Lgquinoline (Compound 157. structure 16 of Scheme IV, where R 2

=R

5

R

3

=R

4

=R

6 X=CH2) 4, 7 -Difluoro-2-fluorenamine (Namkung, M. Fletcher,T. Wetzel, W. H. Derivatives of Fluorene. XX. Fluorofluorenes. V. New Difluoro-2-acetamidofluorenes for the Study of H:\Priyanka\Keepbpc\45977-96.STEROID RECEPTOR.do 19/01/00 DOCKET NO.

016-0014A.WO 135 Carcinogenic Mechanisms. J. Med. Chem. 1965, 8, 551-554, 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 mmol, 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% NH40H (20 mL), a white precipitate formed, and was filtered, washed with water, and dried under vacuum to afford 127 mg of 4 7 -difluoro-2-fluorenamine as a white solid, mp 119-120 0 C (lit. mp 119.5-121 0 Data for 4 ,7-difluoro-2-fluorenamine: 10 tH NMR (400 MHz, CDC1 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, 2.0,1 6.63 1 6.39 (dd, J= 11.6, 1.7, 1 3.83 2 3.80 *o (br s, 2 H).

15 5,8-Difluoro-1, 2 -dihvdro-2.2.4-trimethvlindeno [1,2-gquinoline (Compound 157, structure 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-fluorenamine (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 20 oil, along with 63 mg of the more polar Compound 157 as a white solid. Data for Compound 157: 1H NMR (400 MHz, CDC1 3 7.68 J 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 1 H, 11-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 7,10-Difluoro-l, 2 -dihydro-2.2.4-trimethvlindenor2,1 -fquinoline (Compound 158. structure 17 of Scheme IV, where R 2

=R

5

R

3

=R

4

=R

6 X=CH2) Compound 158 was obtained along with Compound 157 as described above (EXAMPLE 57). Data for Compound 158: 1 H NMR (400 MHz, CDCl 3 7.69 (dd, J 8.3, 5.3, 1 H, 6- H\PriyankalKccp\spccM5977-96.STBROID RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 136 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-trimethvl-5-coumarino 3.4-flquinoline (Compound 159, Scheme IX) The intermediate 2 -nitro-3,4-benzocoumarin was prepared by a modified literature 10 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 15 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 20 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; IR (KBr) H:\Priyanka\KceepspcciM5977-96.STEROID RECPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 137 3352, 2966, 2924, 1712, 1626, 1450, 1356, 1251, 1205; 1 H NMR (400 MHz, CDC1 3 7.90 J 7.8, 1 7.78 (d,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 C 1 9H 17 N0 2 C, 78.33; H, 5.88; N, 4.81. Found: C, 78.19; H, 6.12; N, 4.52.

EXAMPLE 10 IR/S)-5-Butyl- 1, 2 -dihydro-2,2.4-trimethvl-5Hchromenor3,4-flquinoline (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 15 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 -780C until the anion was formed. A yellow solution (0.2-0.5 M) of Compound 159 in THF was 20 cannulated into the above solution and the resulting dark red mixture was slowly allowed to O* *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 H.Panak.\Kp\,ocM5977.96.STmROID RECEPTORAo 19/01/00 DOCKET

NO.

016-0014A.WO 138 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.

10 (R/S)-5-Butvl- ,2-dihvdro-2,24-trimethvl-5H-chromeno [3.4-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- 1 1 H NMR (400 MHz, 15 CDC13) 7.62 J= 7.8, 1 7.44 J= 8.3, 1 7.14 J= 7.8, 1 6.98 J= 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).

20 EXAMPLE 61 (RIS)- 1, 2 -Dihydro-2,2,4-trimethyl-5-phenyl-5H-chromenof[34-flquinoline (Compound 161 structure 32 of Scheme IX, where R=phenvl) 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: 1 H 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).

H:\Priyank\Keep\pec5977-96.STEROID RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 139 EXAMPLE 62 (RIS)- l.

2 3 4 -Tetrahydro22dimethy[4methyidene5pheny1Sychromeno[3 4flginoine(Copound 162,,structure 33 of Scheme IX where R=phnl This compound (6 mg, 10%) was obtained along with Compound 161 as described above (EXAMPLE 6 Data for Compound 162: IH NMR (400 MHz, CDC1 3 7.53 J 7.3, 1 7.51 J 8.4, 1 7.24-7.12 (in, 5 6.97 J 7.3, 1 6.87 J 7.3, 1 6.80 J 7.3, 1 6.64 1 6.59 J 8.4, 1 4.93 1 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-Chlorophenyl) 122, 3fino line 1,-ivr -tiety5H-homnL*4fq .(Compound 163, structure 32 of Scheme TV. where R=4-chlorophenyl) This compound was prepared by General Method 5 (EXAMPLE 60) from 4bromochloro benzene (1.4 g, 7 rnmol) and Compound 159 (0.5 g, 1.7 mmol) to afford 0.27 g of Compound 163 as a white solid, in addition to 60 mg of Compound 164 (EXAMPLE 64). Data for Compound 163: mp 139-140 OC; ]OR (KBr) 3371, 2964, 1593, 1469, 1435 cm- 1 IH NMR (400 MHz, acetone-d 6 7.59 J 7.8, 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), S 20 6.86 J 7.8, 1 6.83 J 8.4, 1 6.77 J 7.8, 1 5.54 (br s, 1 5.48 I 1.99 3 1.26 3 1.24 3 H).

EXAMPLE 64 (4-ChlIorophenyl)- 1.2.3 4 -tetrahydro-2,2-dimethy-4-methylidene-5Hchrome o[3 4-fluinoline- Cmond14 trcue33o cem heeR4 chlorophenyl) This compound (60 mg, was obtained along with Compound 163 as described above (EXAMPLE 63). Data for Compound 164: IH NMR (400 MHz, CDC1 3 7.53 J 1 7.51 J= 8.3, 1 7.18 J= 8.7, 2 7.15 J= 8.7, 2 6.99 (t,J 7.7, 1 6.90 J 7.7, 1 6.79 J 7.7, 1 6.59 1 6.58 J 8.3, 1 H), 4.93 1 4.59 1 4.09 (br s, 1 2.43 J 12.3, 1 2.18 J 12.3, 1 H), 1.34 3 H) 1. 13 3 H).

HAPan-ka\KePsPeCM597796.S-EROID RECEP'IORAo 19/01/00) DOCKET

NO.

0 l 6 -0014A.WO 140 EXAMPLE 4 -Fl orophenyl)-1 -iyro224timty H-hoeo3 4 -flguinoline (Comnpound 165. structure 32 ofLScheme IX where R,=4-fluorphenyl) This compound was prepared by General Method 5 (EXAMPLE 60) from 4fluorophenylmagnesium bromide (1.0 M in THF, 1 mL) and Compound 159 (30 mg, 0. 1 mrmol) to afford 15 mg of Compound 165 as a colorless oil. Data for Compound 165: IIR(KBr) 3360,2962, 1707, 1601, 1506, 1469, 1221, 1157 cm- 1 1 H 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=

*0600: 10 8.3, 1 6.76 J 7.8, 1 5.54 (br s, 1 5.47 1 1.99 3 1.26 3 H), 0 *1.24 3 H).

EXAMPLE 66 9@ (R/&S)-5-(4-Acetylpheny) l1 2 -dihydro-2,2,4trimethylpsH..chomeno [3 4 -fluino ie (Compound 166, tructure 32 f Schemeffl whreR=4actvlhevl 'se# This compound was prepared by General Method 5 (EXAMPLE 60) from 2-(4bromophenyl)-2-methyl,3dioxafl (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 Sao* 166: IH NMR (400 MHz, acetone-d 6 7.83 J 8.3, 2 7.60 J 7.6, 1 7.57 6:0 20 J 8.4, 1 7.36 J 8.3, 2 6.99 1 6.98 J 7.6, 1 6.89-6.79 (in, ,goo s 3 5.56 (br s, 1 5.50 1 2.49 3 2.00 3 1.28 3 1.25 3 H).

EXAMPLE67 (RIS- 1, 2 -Dih do-2,2.4..trimethyl.5-f4-methylp henyl)-5H-chro meno [3 .4-flguino line This compound was prepared by General Method 5 (EXAMPLE 60) from 4 -bromotoluene (171 mg, 1.0 mmol) and Compound 159 (20 mg, 0.07 mmol) to afford 15 mg of Compound 167 as a colorless oil. Data for Compound 167: IXR (KiBr) 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 J 8.5, 1 7. 10 J 8.0, 2 7.00 J 8.0, 2 6.97 J 7.9, 1 H-."an\K-~spc \597-96SIEOIDRECEPTORAde 19/01/00 DOCKET No.

0 16-0014A.WO 141 6.89 1 6.84 J 7.9, 1 6.81 J 8.5, 1 6.75 J 7.9, 1 5.47 (bs, 1 5.45 1 2.19 3 1.99 3 1.25 3 1.23 3 H).

EXAMPLE 68 (RIS)- 1.-iyr--4mtoyhnl-,.-rmty-Hcrmn 3 4 -flguino line (COmpound- 168, structuire 32 of Scheme L. where R= 4 -methoxyphenvl) This compound was prepared by General Method 5 (EXAMPLE 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: 1 H 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, :0 0. 1 6.87 1 6.86 J 7.7, 1 6.81 J 8.4, 1 6.75 J 8.7, 2 H), 0 0 06.74 J 7.7, 1 5.47 (br s, I 5.45 1 3.69 3 1.99 3 1.25 3 oooo 1.23 3 H).

010. *.0 EXAMPLE 69 (RIS- l.

2 -Dih o224trethyl54(tr .uoroth)hyLSH-cr [eo34 (trifluoromethyl)phenyl) 0000 This compound was prepared by General Method 5 (EXAMPLE 60) from 4bromobenzotrifluoride (130 mg, 1.0 nimol) and Compound 159 (20 mg, 0.07 mmol) to afford 10 mig of Compound 169 as a colorless oil. Data for Compound 169: IH NMR (400 MHz, acetone-d 6 7.61-7.56 (mn, 4 7.45 J 8.3, 2 7.01 1 6.97 J 7.7, 1 6.86 J 7.7, 1 6.85 J 8.4, 1 6.81 J 7.7, 1 5.57 (br s, I 5.49 1 1. 99 3 H 1. 27 3 1. 25 3 H).

EXAMPLE (RIS)- 1, 2 -Dihydro224trimnethyl-5-f(thiophen-3 y) SH-hromn .4 tluino line (Compound 170 structure 32 of Scheme IX. eeR thipe--l This compound was prepared by General Method 5 (EXAMPLE 60) from 3bromothiophene (163 mg, 1.0 nimol) and Compound 159 (8 mig, 0.03 nimol) to afford 1.1 mg (11I%) of Compound 170 as a colorless oil. Data for Compound 170: IH NMR (400 H-*&akap\pct\97796SROD RECEPTOR.doc i9)01/0 DOCKET

NO.

016-0014A.WO 142 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 J 7.3, 1 6.88 J 3.0, 1 6.79 J 8.1, 2 5.48 (br s, 1 2.06 3 1.25 3 1.24 3 H).

EXAMPLE 71 l.

2 -Dihydro-224-qiMethylp5( 4 -methyllphenyl)-5H-homeno [3 4 -tlguinoline (Copoud 11, trutue 32 of Scheme IX. wher =-ehlhnl This compound was prepared by optical resolution of Compound 167 via HPLC 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% [cz] 2 0 D =-246 (MeGH).

EXAMPLE 72 4 -ChlorophenYl). -iydo-, -timt 1-H 3 4 meo -flguinoline (Compound 7.ITutr 32 of Scheme IX. where4chrohn) 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.; [a] 2 0 D =-254 (MeOH).

EXAMPLE 73 (RIS)- l.

2 -Dihydro- 2,2,4-trimethYI-5(3- methYphel) Hchro [3n QA-flguino line (Copoud 73.stuctr32 of Scheme X whe 3 -Methlh Iyl This compound was prepared by General Method 5 (EXAMPLE 60) from 3bromotoluene (171 mg, 1.0 inmol) and Compound 159 (15 mng, 0.05 inmol) to afford 3.6 mg of Compound 173 as a colorless oil. Data for Compound 173: 111 NMR (400 MHz, 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 J 8.4, 1 6.77 J 8.0, 1 5.49 (br s, 1 5.46 1 2.19 3 2.00 3 1.26 3 1.24 3 H).

H"\rnka\K=P\,PecM\5977-96.STROID RECEPTORdoc 19/01/00 DOCKET

NO.

016-00 14A.WO 143 EXAMPLE 74 4 4 l.51)-5-(4-Chlorophenyl) l.

2 3 4 -tetrahydro-2,2,4trmethl5Hch men[34.

flguinoline (Compound17.srcue3ofSemX.w reR-hrpen) Hydrogenation of Compound 163 (15 mg, 0.04 mmol) in the presence of 10% Pd/C afforded 12 mg of 4 /,51)..5.(4.chlorophenyl> l, 2 3 4 -tetrahydro-2,2,4tr~ethyl- SH-chromeno [3,4..fl quino 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,5l)-5-(4..chlorophenyI)y 1,,,-erhdr-,,-iehy Hcrmn[ 3 4 -Jlquinoline 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 4 1,51).5.(4chloropheny)1123,4 :erhyr -224tiehl5-hoeo[,-qioln afforded 3.1 mg of the first eluting, :0 enantiomer (Compound 174) (24 min), and 3.0 mg of the second eluting, enantiomer (Compound 175, EXAMPLE 75) (30 min). The optical purity of Compound 174 was *:determined by HPLC to be >99% e.e. Data for Compound 174: mp 158-159 OC; IH NMR (400 MHz, acetone-d 6 7.63 J 7.8, 1 7.53 J 8.5, 1 7.24 4 6.94 J 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, 1 3.25 (in, 1 1. 89 (dd, 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, CDC1 3 0000.*..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. [cL] 20 D 287 (MeOH).

EXAMPLE 4 1.Sl)-5-4-Chlorophenyl)- 1.

2 3 4 -tetrahydro22,4-rethyl-Hchromeno [3,4tlgu ioline (Copound 175 tructure- 34 of Scheme X.where

R=

4 chorphevl This compound was prepared by resolution of (R/S- 4 l,5I)-5-(4-chlorophenyl)- 1,,,-erhdo224--mty Hcrmn[ 3 ,4-flquinoline 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 95% [ctII 20 D =-260 (MeOH).

H.\riynk&K~pspei\497796.TERIDRECEPTDRAdO 19/01/00 DOCKET NO.

016-0014A.Wo 144 EXAMPLE 76 (R/S-41.5u)-5- 4 -Chlorop~henyl> l.

2 3 4 -tetrahydro-224trmeth 1-5H-chro meno [3.4flgin lie Comoud 76 structure 35 of Scheme I. where R=-cLoropenv This compound (1.1 mg, was obtained along with chlorophenyl). 1,,,-erhdo224umty-Hcrmn 3 4 -fjlquino line 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 J 1 6.59 J 8.4, 1 6.47 1 H), 3.73 (br s, 1 2.82 (in, 1 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, CDC1 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.

.:EXAMPLE 77 (R/S)-5-(3-Chlorophenyl)m. -1~dhvo224tfnehy5H-chro meno 3 4 -tlguino line ~(Compound 177 structure 32 f SceeI hr 3 -chloropenyl) This compound was prepared by General Method 5 (EXAMPLE 60) from 3bromochloro bnzene (195 mg, 1.0 inmol) and Compound 159 (20 mg, 0.07 mmol) to afford 14 mg of Compound 177 as a colorless oil, along with 2.3 mng of Compound 20 178 (EXAMPLE 78) as a colorless oil. Data for Compound 177: IH NMR (400 MHz, acetone-d 6 7.61 J 7.8, 1 7.57 J 8.4, 1 7.28-7.18 (in, 4 7.00

J

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

EXAMPLE 78 (R/S)-5-(3-Chlorophenyl)- 1..,-erhdo22dtntv--ehldnchromenor3.44lgI--olI;e (Comound 178 structure 33 of Scheme X whre R=3chlorophenyl) This compound (2.3 mg, was obtained along with Compound 177 as described above (EXAMPLE 77). Data for Compound 178: 1 H NMR (400 MHz, acetone-d 6 7.61 J 6.7, 1 7.59 J 8.6, 1 7.29-7.20 (in, 4 6.98 J 6.7, 1 6.88 J 6.7, 1 H*\"nka\Kp\pcM,5977-96.S'ROrD RECEPTORAdO 19/()1/00 DOCKET

NO.

016-0014A.WO 145 6.79 J 1 6.77 J 1 6.62 1 4.99 1 4.59 1 H), 2.41 J 12.2, 1 2.27 J 12.2, 1 1.35 3 1. 13 3 H).

EXAMPLE 79 (RIS)-5- (4-Bromophenyl)-.

2 -dihydro-2,2,4-trimethy..SH-chio meno [3,4-figuino line (Compound 179. structure 32 of Scem Xwhr R= -mophenyl This compound was prepared by General Method 5 (EXAMPLE 60) from l, 4 -dibro mo 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: IH 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 J 8.5, 2 6.98 J 7.8, 1 6.90 (s, 1 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 1 1.99 3 1.26 3 1.23 3 H).

EXAMPLE (/S')-54-(4Bromophenyl). 1,2.3 4 -tetrahydro-2.2dimethy14methylidene-5Hchromeno 34-ngioie(opud10 tutr 3o ceeL.weeR4 bromophenyl) This compound (2.5 mg, was obtained along with Compound 179 as described above (EXAMPLE 79). Data for Compound 180: 1 H NMR (400 MHz, acetoned6) 7.61 J 6.3, 1 7.59 J= 8.7, 1 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 2.26 J 12.2, 1 1.34 3 1. 11 3

H).

EXAMPLE 81 (R/S')-5-(3-Bromoph~enyl) 2 -d ihdro-224trimethyl..5H-cro meno [3.4-figuino line Compound 181. structure 32 of Scheme IX here R=3-bromohenvl) This compound was prepared by General Method 5 (EXAMPLE 60) from 1 3 -dibromo benzene (250 mg, mmol) and Compound 159 (15 mg, 0.05 mmol) to afford 13 mg 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 eaml; 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 H',riynkaKmpsccM97796.TERIDRECEPTOR4OC 19/01/00 DOCKET NO.

016-0014A.WO 146 1 7.26 J 6.6, 1 7.19 J 1 7.00 J 8.3, 1 6.98 1 H), 6.81-6.90 (in, 3 5.60 (br s, 1 5.50 1 2.01 3 1.27 3 1.25 3 H).

EXAMPLE 82 (R/S)-5-(3-Bromophenyl). l.

2 3 4 -tetrahydro-2,2-dimethyl4methylidene-5Hchro meno [3.4-flguino line (Compound 182. structure 33 of Scheme LX hr =3bromophenyl) This compound (2.0 mg, was obtained along with Compound 181 as described above (EXAMPLE 81). Data for Compound 182: IH NMR (400 MHz, CDCJ 3 7.55 J 7.9, 1 7.51 J 8.4, 1 7.28 J 8.0,1 7.12 J 7.9, 1 H), 0: 10 7.05 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 1 4.58 1 2.43 J 12.3, 1 2.19 J 12.3, 1 1. 32 3 1. 14 3 H).

EXAMPLE 83 (R/S)-5-(3.4-Dichlorophenyl) l.

2 -dihdro-22.4-iethyl-~5H-chromeno [3.4-fig~uinoline (Compound 183, structure 32 of 'Scheme IX, where R=34-dichlorophenyl) This compound was prepared by General Method 5 (EXAMPLE 60) from 1-bromo-3,4dichlorobenzene (226 mg, 1.0 inmol) and Compound 159 (20 mg, 0.07 mmol) to afford 8.7 mg of Compound 183 as a colorless oil. Data for Compound 183: 1 H NMR (400 MHz, CDC1 3 7.53 J 7.8, 1 7.50 J 8.3, 1 7.28-7.22 (in, 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 3 1.30 3 1.26 3 H).

EXAMPLE 84 (R/S)-5-(3-Bromo-2-pyridyl)-. l 2 -dihydro-2 2 4-trfrnethyl..5H..chomeno [3 .4-flguino line Compound 184. structure 32 of SceeL.weeR bromo-2-rdl This compound was prepared by General Method 5 (EXAMPLE 60) from 2 6 -dibromopyridine (237 mg, mmol) and Compound 159 (20 mg, 0.07 mrnol) to afford 20 mg of Compound 184 as a colorless oil. Data for Compound 184: IH NMR (400 MHz, acetone-d6) 7.63 (dd, J 7.8, 1.5, 1 7.54 J 8.5, 1 7.52 J 7.8, 1 7.3 9 J 7.9, 1 7.13 J 7.6, 1 7.03 J 7.6, 1 6.92-6. 80 (mn, 4 5.52 1 5.48 1 2.03 3 1.25 3 1.24 3 H).

H--"aaa\Kp\p..\457796.-MRIDRECEPTORAo 19,'01/00 DOCKET

NO.

016-0014A.WO 147 EXAMPLE (RIS)- 1,2-Dihydro-5-hydroxy-2,2,4-trimethyl-5H-chro meno 3, 4 -flquinoline (Compound 185. structure 46 of Scheme XIV, where RI=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 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 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 S 10 as eluents provided 6 mg of Compound 185 as a colorless oil. Data for Compound 185: 1 H NMR (400 MHz, CDC1 3 7.71 J 7.5, 1 7.53 J 8.4, 1 7.19 J= 7.5, 1 7.08 J 7.5, 1 7.07 J 8.4, 1 6.85 J 5.8, 1 6.70 J= 7.5, 1 5.52 1 3.92 (br s, 1 2.94 J 5.8, 1 2.37 3 1.32 3 H), S" 1.20 3 H).

EXAMPLE 86 1,2-Dihydro-2,2,4-trimethyl-5-methoxy-5H-chromenor 3 .4-flquinoline (Compound 186, structure 47 of Scheme XIV where R 1

=R

2 X=O R 3 =methyl To a solution of Compound 185 (25 mg, 0.085 mmol) in MeOH (7 mL) was added a 20 catalytic amount ofp-toluenesulphonic acid (-0.25 mg) and the solution was allowed to stir at rt for 5 min. The reaction mixture was quenched with a 10% NaOH solution (0.1 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 1 mL) then dried (Na 2 SO4) and concentrated in vacuo The crude product was purified on a 20 x 20 cm, 250 irm. 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); 1

H

NMR (400 MHz, CDC13) 7.69 J 7.7, 1 7.48 J 8.3, 1 7.15 J 7.7, 1 7.05 2 6.65 J 8.3, 1 6.35 1 5.50 1 3.90 (br s, 1 3.49 3 2.28 3 1.33 3 1.28 3 H).

H',"au"\K-P\.P~rp\45977-6.S7EROID RECEPTOR.d 19/01/00 DOCKET

NO.

016-00 14A.WO 148 EXAMPLE 87 (RIS)- l.

2 -Dihydro-2.2.4-timethyl..5-propoxy5Hcho meno 3 4 -tlguino line (Compound 187, structure 47 of Scheme XIV. where

R

1

=R

2 =H4 X=O. v 3 =-ropyl) This compound was prepared in a manner similar to that of Compound 186 (EXAMPLE 86) from Compound 185 (12 mg) 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); 1

H

NMR (400 MHz, CDC13) 7.68 J 7.7, 1 7.49 J 8.3, 1 7.17 (t J 7.6, 1 7.05 (in, 2 6.65 J 8.4, 1 6.42 1 5.50 1 3.90 (br s, 1 3.84 (dt, J 9.2, 6.7, 1 3.54 (dt, J 9.3, 6.8, 1 2.28 3 1.49 (in, 2 1.33 3 1. 18 3 0.77 J= 7.4, 3 H).

000. EXAMPLE 88 1, 2 -dihydro-2,2.4.trimethy1..5H..chomeno f 3 4 -flguino line (Compound 188.

00 .srcue4ofShmXIV. where R=R 2

=R

4 =R5-R6H To a solution of Compound 186 (12 mg, 0.04 inmol) in dichioromethane (1.5 mL) at 00 C 0.00 was added allyltrimethylsilane (0.005 mL, 0.062 inmol) and TMSOTf (0.01 niL, 0.057 nimol) under nitrogen. The reaction was stirred 5 h at rt. The reaction mixture was concentrated in vacuo and purified on a 5x20 cm, 250 j.IM, TLC plate, eluting with 25 00.0 EtOAc in hexane to afford 2.3 mig of Compound 188 as a colorless oil. Data for Compound 188: Rf 0.50 (silica gel, 25% EtOAc: Hexane); IH NMR (400 MHz, acetone- 0 d6) 7.67 J 7.4, 1 7.49 J 8.3, 1 7.12 J 7.4, 1 6.98 J 7.4, 1 6.87 J 7.4, 1 6.70 J 8.3, 1 5 .96-5 .85 (mn, 2 5.52 I 5.04 (s, 1 5.00 J 8.6, 1 2.54 (in, 1 2.25 (in, 4 1.27 3 1. 18 3 H).

EXAM PLE 89 (RIS)-I l.

2 Dihydro-2,2,4..timethyl.5.pro~ylSHchromn [.-tuinoline (Compound 189.

structure 2. ofScee X where Rn-rpl This compound was prepared by General Method 5 (EXAMPLE 60) from a 2.0 M solution of allylmagnesium chloride (0.2 niL, 0.4 nimol) in THF and Compound 159 (25 mg, 0.086 nimol) 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 MHz, CDCl3) 7.59 J 7.7, H:\riaka\Ko p\pel, 497796S7hROD RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 149 1 7.43 J 8.4, 1 7.13 J 7.7, 1 6.98 J 7.7, 1 6.91 J 7.7, 1 6.57 J 8.4, 1 5.89 J 10.4, 1 5.49 1 3.90 (br s, 1 2.25 (s, 3 1.84 2 1.49-1.35 2 1.29 3 1.20 3 0.89 J 7.4, 3 H).

EXAMPLE 2-Dihdro-2,24-trimethyl-2-idl) hroenoinoline (Copoun 190. structure 32 of Scheme IX. where R=2-pyridl) To a solution of Compound 184 (10 mg, 0.023 mmol) in 1 mL of THF at 78 OC was added a 1.0 M hexane solution ofn-BuLi (0.05 mL, 0.07 mmol), giving rise to a yellow then dark red solution. The mixture was allowed to stir for 15 min and was quenched with water (1 The mixture was extracted with ethyl acetate (2 x 10 mL) and the combined extracts .were concentrated. Chromatography of the crude mixture on a silica gel column using 30% ethyl acetate hexane as eluents afforded 7 mg of Compound 190 as a colorless oil. Data for Compound 190: 1 H NMR (400 MHz, acetone-d 6 8.48 (dd, J 5.4, 1.8, 1 7.61 (dd, J= 7.8, 1.6, 1 7.57 (td, J= 7.8, 1.8, 1 7.54 8.3, 1 7.16- 7.13 2 6.99 (td, J= 7.8, 1.6, 1 6.93 1 6.88 (td, J= 7.9, 1.0, 1 6.80 J= 8.5, 1 6.77 (dd, J= 7.9, 1.1, 1 5.48 (bs, 1 5.44 1 1.98 3 H), 1.23 3 1.22 3 H).

oo* be** EXAMPLE 91 (R/S)-5-(3-Fluorophenyl)- 1,2-dihdro-2,2.4-trimethyl-5H-chromeno[3,4-flouinoline oCo pound 191 structure 32 of Scheme IX where R=3-fluoropheny1 This 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 mmol) to afford 12 mg 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, 1 5.49 1 2.02 3 1.27 3 1.25 3 H).

H.Viyanka\Kssp\specL597T1-96.STROID RECEPrTR.AO 19/01/00 DOCKET

NO.

016-001 4A. WO 150 EXAMPLE 92 (R/S)-5-(3-Fluorophenyl)-. 2,3 4 -tetrahydro22dethy-4-methylidene-5Hchromeo34.~unn (Copound 192. srcue33 of Scheme LweeR3 fluorophenyi) This compound (1.5 mg, was obtained along with Compound 191 as described above (EXAMPLE 91). Data for Compound 192: IH NMR (400 MHz, CDCl 3 7.54 J 1 7.51 J 8.5, 1 7.15 (td, J 7.9, 5.9, 1 7.06-6.81 (in, 6 6.61 1 H), 6.59 J= 8.0, 1 4.94 1 4.61 I 2.43 J =12.3, 1 2.19 J 12.3, 1 1.34 3 1. 14 3 H).

*EXAMPLE 93 RIS)- l.

2 -Dih ydro- 2.2,4.trimethypsp:rop ylthio-SHchromeno 3 4 -tlquino line (Compound 193, structure 47 f Scheme IV, weeR= 2 H =.R=-rpl To a solution of Compound 185 (12 mg, 0.04 inmol) in a 1:1 midxture of 1- 15 propanethiol and methylene chloride (2 mL) 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

SO

4 Removal of solvent in vacuo followed by purification on a 5x.20 cmn, 250 pin-4 TLC plate, eluting with 20 EtOAc:hexane, afforded 14 mg 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 1 7.49 J 8.4, 1 7.16 (t J 7.6, 1 7.05 J 7.6, 1 6.93 J 7.6, 1 6.72 J 8.4, 1 5.51 I 2.79-2.73 (in, 1 2.62- 2.57 (in, 1 2.47 3 1.70 (in, 2 1.25 3 1.20 3 0.99 J 7.3, 3

H).

EXAMPLE 94 (RIS)-12Dhdo5L-ehxhey)2.4 imtyl5-c [me34-flquinoline (COmpound 194 structre 32 of Scheme X where R=3-ethox phnl) This compound was prepared by General Method 5 (EXAMPLE 60) from 3-bromoanisole (187 mg, 1.0 iniol) and Compound 159 (20 mg, 0.07 inmol) to afford 2.6 mg of H-."nk\Kpi\,P 597796SEROD RECEPTOR-doc 19/01/00 DOCKET

NO.

016-0014A.WO 151 Compound 194 as a colorless oil. Data for Compound 194: IH NMR (400 MHz, acetoned 6 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 1 6.88-6.7 1 (in, 6 5.52 (br s, 1 5.47 1 3.67 3 2.03 3 1.26 3 1.25 3 H).

EXAMPLE (RIS) 1 2 -Dihvdro-2,2,4-trimethyli. (trifluoromethyl)phenylys5Hchomeno [3,4flguinoline (Compound-195. structure 32 of Scheme X. where R=3I- (trifluoromethyl)phenyl) This compound was prepared by General Method 5 (EXAMPLE 60) from 3bromobenzotrifluoride (225 mng, 1.0 inmol) and Compound 159 (20 mg, 0.07 mmol) to afford 10 mng of Compound 195 as a colorless oil. Data for Compound 195: IH NMR (400 MHz, acetone-d 6 7.61 J 7.6, 1 7.60 J 1 7.56-7.45 (in, 4 7.04 1 6.98 J 1 6.89-6.83 (in, 3 5.60 1 5.55 1 2.02 15 3 1.27 6H).

EXAMPLE 96 3 -Fuoro-4iethyIphen-hlp l-yr-.,~rmtvS~~mn 34 tlguin line Compound 196. stutrL2-fShm1I.weeR= loo4 20 methylphenyl) This compound was prepared by General MethodS5 (EXAMPLE 60) from 4-bromo-2fluorotoluene (189 mg, 1.0 mnmol) and Compound 159 (20 mg, 0.07 inmol) to afford 15 mng of Compound 196 as a colorless oil. Data for Compound 196: 1 H 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, 1 5.48 (s, I 2.12 3 2.01 3 1.26 3 1.24 3 H).

EXAMPLE 97 (R/S)-5-(4-Bromo-3-pyr dyl)-. 2 -dihydro-2,2 4-triethyl-H-chromeno [3,4-flguino line (Cmon-97,tutr 32 f Scheme where R=4-bromo-3-vridyl) This compound was prepared by General Method 5 (EXAMPLE 60) from dibromopyridine (237 mg, 1.0 inmol) and Compound 159 (20 mng, 0.07 inmol) to afford 7 HVryp~\p\pcM59796.SROD PECEPTOR. 19/01/00 DOCKET

NO.

0l6-0014A.Wo 152 mg of Compound 197 as a colorless oil. Data for Compound 197: IH NMR (400 MHz, acetone-d 6 8.24 J 1 7.62 (dd, J 8.0, 1.3, 1 7.57 J 8.4, 1 7.34 1 7.27 J 1 7.06 (td, J 7.4, 1.3, 1 6.97 1 6.94-6.8 8 (in, 1 6.86 J 8.4, 1 5.68 (br s, 1 5.55 1 2.06 3 1.29 3 H), 1.28 3 H).

EXAMPLE 98 (RIS)- 1. 2 Dihydro- 2 .2,4-timethyl..543-p yid yl).sH.cro meno [3.4-flguino line (Compound 10 198, structure 32 of Scheme IX. where R=3-p ,y"v 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-d 6 8.42 (in, 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, 15 1 6.95 1 6.89-6.83 (mn, 3 5.61 (br s, 1 5.52 1 2.03 3 1.28 (s, 3 1.26 3 H).

EXAMPLE 99 (R/S)-5-(4-Chloro-3-fluorohenyl)-. l 2 ihydro-2,2,4~ tiethl-5H-~chromeno [3.4fl~quinaline (Compound 199. structure 32 of Schemne IX where R=4-chloro-3-fluorophenyl) This compound was prepared by General Method 5 (EXAMPLE 60) from bromofluoro benzene (209 mng, 1.0 mmol) and Compound 159 (15 mg, 0.05 inmol) to afford 13 mg of Compound 199 as a colorless oil. Data for Compound 199: IH NMR (400 MHz, acetone-d 6 7.61 (dd, J 7.7, 1.4, 1 7.57 J 8.3, 1 7.38 i 7.9, 1 H), 7.13 (dd, J 10. 3, 1.8, 1 7.05 J 7.8, 1 7.00 (dd, J 7.7, 1.3, 1 6.93 1 6.91-6.81 (in, 3 5.62 (br s, 1 5.50 1 2.02 3 1.27 3 1.25 3

H).

EXAMPLE 100 (RIS)- l.

2 -Dihydro-2,2,4,5-tetrameth 1-5H-c o no 3 ,4-tlgupingoline Compound 200.

structure 32 of Scheme X. where mtl) H-Piao\-specM5977.96.STROID RECEPTOR.o 19/01/00 DOCKET NO.

016-0014A.WO 153 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); 1H NMR (400 MHz, CDC13) 7.60 J 7.8, 1 7.43 8.4, 1 7.15 8.0, 1 7.00 J= 8.0, 1 6.91 8.1, 1 6.57 J 8.1, 1 6.60 J 6.1, 1 5.49 1 3.85 (br s, 1 2.26 3 1.38 J 6.6, 3 1.27 3 1.22 3 H).

EXAMPLE 101 12-Dihydro-5-hexyl-2,24-trimethyl-5H-chromeno 3, 4 -flquinoline (Compound 201 10 structure 32 of Scheme IX where 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, CDC13) 7.59 J 7.8, 1 7.43 J 8.3, 1 7.12 J 7.6, 1 6.98 J 15 7.4, 1 6.91 J= 7.7, 1 6.56 J= 8.1, 1 5.86 J= 7.4, 1 5.49 1 2.25 3 1.83 2 1.41 3 1.28 3 1.20 3 0.84 J 6.7, 3 H).

EXAMPLE 102 20 1,2-Dihydro-2,2,4-trimethvl-5H-chromeno 4finoline Compound 202, struct 32 o (Compound 202, structure 32 of Scheme IX, where R=H) To a solution of Compound 185 (EXAMPLE 85) (9.5 mg, 0.03 mmol) in methylene 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 1 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 10/1 hexane/EtOAc) afforded 4.6 mg of Compound 202. Data for Compound 202: Rf 0.36 (silica gel, 25% EtOAc: Hexane); 1 H NMR (400 MHz, CDC13) 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 1 5.32 2 H), 3.90 (br s, 1 H 2.10 3 1.27 6 H).

HPrianka\KepMspecl97.96s'MROD RECEPTOR.doc 19/01/00 DOCKET

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016-00 14A.WO 154 EXAMPLE 103 LBOS- 1.-iyo5(-ehybtl- ,-rmethl-5H-chromeno [3.4-tf1guino line (Comound203.strutur 32 of Scheme IX- where R=3-methlb utyl This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 159 (13 mg) and l-bromo-3-methylbutane to afford 1 mg of Compound 203 as a yellow oil. Data for Compound 203: TLC: Rf 0.29 (silica gel, 25% EtOAc: hexane); 1 H NMR (400 MHz, CDCI3) 7.58 J 8.0, 1 7.43 J 8.3, 1 7.17 J 8. 1, 1 H), 6.98 J 8. 1, 1 6.91 J 7.9, 1 6.58 d, J 8.0, 1 5.81 J 8.9, 1 H), 5.49 1 3.90 (br s, 1 2.24 3 1.80 (mn, 1 1.44 (in, 2 1.28 (mn, 5 H), 10 1.21 3 0.79 J 6.2, 3 0.70 J 6.2, 3 H).

EXAMPLE 104 (RIS)-5-(4-Chlorobutyl). 1, 2 -dihydro -2.2.4-trinethyl.5H-c ro meno r3.4-flguino line (Compound 204, structure 32 fShm XweeR4-chlorobutyl) 15 This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 159 (8.3 mng) and I- bro mo-4-chloro butane to afford 2.2 mng of Compound 204 as a yellow oil. Data for Compound 204: Rf 0.38 (silica gel, 25% EtOAc: Hexane); 1 H NMR (400 MHz, CDCl3) 7.59 J 8.0, 1 7.43 J 8.3, 1 7.13 J 7.7, 1 7.00 (t, J 8.4, 1 6.91 J 7.8, 1 6.57 J 8.3, 1 5.86 J =10.4, 1 5.49 1 3.90 (br s, 1 2.25 3 1.83 (in, 2 1.41 (in,4 4 1.29 3 1.20 3 0. 84 J= 7.3, 2H).

EXAMPLE 105 (R/S)-5-Benzyl-12dhdo22ztieyl5- hr mn r3.4-flguio lie (Compound 205.

structure 12 of Scheme IN, where R=tgnzyl) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 159 (16.8 mng) and benzylmagnesiuin chloride to afford 2.6 mng of Compound 205 as a yellow oil. Data for Compound 205: TLC: Rf 0.20 (silica gel, 25% EtOAc: Hexane); 1 H NMR (400 MHz, CDCI3) 7.66 J 7.8, 1 7.48 J 8.4, 1 7.30-7.15 (in, 6 7. 10 J 7.8, 1 6.89 J 8.4, 1 6.61 J 8.4, 1 6.13 (dd, J 10.2, H:Pa\K=,\,pcM597796s.S7ftOID RBCEPTlRdoc 19/01/00 DOCKET NO.

0 16-0014A.WO 155 3.4, 1 5.49 1 3.92 (br s, I 3.11 (dd, J 14.6, 10.2, 1 2.73 (dd, J 14.6, 3.4, 1 2.31 3 1.54 3 1.29 3 H).

EXAMPLE 106 (4-Bromo butyl)- L.

2 -dihydro-2.2,4-trimethyl..5H..chomeno[3 4 -flguino line (Compound 206.. structure 32 of Schm IX hr =-rmobutvl) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 159 (13.7 mg) and l, 4 -dibro mo butane to afford 6.0 mg of Compound 206 as a yellow oil.

Data for Compound 206: Rf 0.22 (silica gel, 1: 1 CH2Cl2/hexane); IH NMR (400 MHz, 10 CDC13) 7.59 J 8.0, 1 7.44 J 8.3, 1 7.12 J 7.7, 1 6.98 J 8.0, 1 6.93 J 8.0, 1 6.57 J 8.3, 1 5.85 J 10.4, 1 5.49 1 3.90 1 2.25 3 1.83 (in, 2 1.41 (n,4 4 1.29 3 1.20 3 H), 0.84 J= 7.3, 2H).

15 EXAMPLE 107 *9-Fluoro-1.-iyr [3.

4 -tfmty--ouain uino line (Compound 207, structure 41 of Scheme XI, where 1

R

2

=F)

S5-Fluoro-2-methoxyphenylboroni acid (structure 37 of Scheme XI. where R=H. R 2

=F)

In a 200-inL flask, a solution of 2 -bromo-4-fluoroanisole (Aldrich: 4.00 mL, 30.8 inmol) in THF (50 mL) was cooled to -78 0 C (COZ'IPA). To this solution n-BuLi (Aldrich: 2.5 M in hexanes; 12.4 mL, 31 inmol, 1.0 equiv) was added dropwise over a 30 min period. The reaction midxture was stirred at -78TC for 60 min 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 TC (ice/H20). The solution was treated with HCI until the pH reached 6. The reaction mixture was poured into sat'd NH4Cl (80 mL) and extracted with CH2Cl2 (3 x 100 mL). The extracts were washed with sat d NH4Cl (1 x mL), combined, dried (MgSO4), filtered through a pad of CeliterM, and concentrated to afford 4.90 g of a white semid-solid. Data for 5-fluoro- 2 -methoxyphenylboronic acid: 1 H NMR (400 MHz, acetone-d 6 7.47 (dd, J 8.8, 3.3, 1 7.17 (in, 1 7.05 (dd, J 9.0, 3.9, 1 3.93 3 H).

H.\Mka\KP\PeMS977-96.SIROID RBEPTOR.doc 19/01/00 DOCKET

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016-0014A.WO 156 Methyl (5'-fluoro-2'-methoxy-4-nitro-2 hen arboxvate (structure 39 of Scheme X where R=H, R 2 In a 250-mL flask, a solution of methyl 2 (Compound 38, Scheme XI) (Aldrich: 5.00 g, 19.2 mmol) in DME (60 mL) was treated with tetrakis(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 mmol, 1.5 equiv) in EtOH (8 mL) was added, followed by 2.0 M Na2CO3 (29 mL, 58 mmol, 3 equiv). The reaction mixture was heated to 80 OC for 6 h, cooled to rt, poured into 2.0 M Na2CO3 (100 mL), and extracted with EtOAc (3 x 100 mL). The extracts were washed with brine (1 x 100 mL), combined, dried 10 (MgSO4), filtered, and concentrated to an orange oil. Purification by SGC (hexane/EtOAc, 10/1) afforded 4.25 g of methyl (5'-fluoro-2'-methoxy-4-nitro-2-biphenyl)carboxylate as a yellow-orange solid. Data for methyl (5'-fluoro-2'-methoxy-4-nitro-2biphenyl)carboxylate: 1 H NMR (400 MHz, CDCI3) 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 15 6.85 (dd, J 8.9, 3.2, 1 3.76 3 3.70 3 H).

5'-Fluoro-2'-methoxy-4-nitro-2-biphenylcarboxvlic acid In a 2 00-mL flask, a solution of methyl (5'-fluoro-2'-methoxy-4-nitro-2-biphenyl)carboxylate (4.24 g, 13.9 mmol) in THF (50 mL) was cooled to 0 OC (ice/H20) 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 pH10 (pH paper) with 10% HC, and extracted with EtOAc (3 x 75 mL). The extracts were washed with brine (1 x 80 mL), combined, dried (MgS04), filtered, and concentrated to afford 3.68 g of5'-fluoro-2 '-methoxy-4-nitro-2-biphenylcarboxylic acid as a yellow solid. Data for 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid: 1 H NMR (400 MHz, acetone-ds): 8.68 J 2.6, 1 8.46 (dd, J 8.5, 2.6, 1 7.68 J 8.5, 1 7.16 2 7.05 (dd, J 8.8, 4.4, 1 3.73 3 H).

6 -Fluoro-2-nitro-3.4-benzocoumarin In a 250-mt flask, a suspension of 5'-fluoro-2'methoxy-4-nitro-2-biphenylcarboxylic acid (3.60 g, 12.3 mmol) in dichloroethane (30 mL) was treated with SOC12 (0.92 mL, 12.6 mmol, 1.0 equiv) and heated to a gentle reflux for 90 min. The reaction vessel was cooled to 0 OC (ice/H20) and AIC13 (0.91 g, 6.8 mmol, 0.55 equiv) was added portion-wise. The reaction mixture was allowed to slowly warm H.riyanaKep\pccM5977.96.SEROID RECEPTOR.doc 19/01/00 DOCKET

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016-00 14A.WO 157 to rt, stirred 5 h, and quenched with 5% HCI (100 mL). The crude product was extracted with EtOAc (4 x 150 mL). The extracts were washed with sat'd NI{4C1 (1 x 100 mL), combined, dried (MgSO4), filtered, and concentrated to afford 3.19 g (quant) of 6-fluoro-2nitro- 3,4- benzocournarin as a yellow solid. Data for 6 -fluoro- 2 -nitro-3,4-benzocoumarin: 1 H NMR (400 MHz, DMSO-d 6 8.84 J 2.3, 1 8.67 (in, 2 8.40 J 9.2, 1 7.55 (mn, 2 H).

2 -Anmino- 6 -fluoro-3,4benzocoumarin (structure 40 of Scheme X1. where R I=H. R 2 In a 500-mL flask, a suspension of 6 -fluoro- 2 -nitro-3,4-benzocoumarin (3.18 g, 12.2 inm-ol) in 0906..

10 EtOAc (300 mL) was treated with 10% Pd/C (2.0 g) and AcOH (0.2 mL), and stirred under an atmosphere of H2 for 1 h. The reaction mixture was filtered and the solids rinsed with acetone (200 mnL). Concentration of the fitrate afforded 2.19 g of 2 -amidno-6-fluoro- *9 3 4 -benzocoumarin as a yellow solid. Data for 2-mn--loo34bnoomrn 1

H

NMR (400 MHz, acetone-d 6 8.09 J 8.6, 1 7.86 (dd, J 9.8, 3.0, 1 7.55 (d, 15 J 2.6, 1 7.33 (dd, J 9.2, 4.9, 1 7.28 (dd, J 9.2, 2.6, 1 7.17 (dt, J 9.0,1 H).

9-Fluoro- l.

2 -dihydro-2.2.4-trimethyl.5-i socoumaino 3.4-flquino line (Compound 207.

structure 41 of Scheme JI. where R=H. R 2 In a 200-mL resealable pressure tube, a suspension of 2 -amino- 6 -fluoro3,4-benocoumarin (1.10 g) in acetone (100 mL) was 9 ~treated with iodine (Aldrich: 0.50 g) and heated to 110 0 C for 32 h. The reaction mixture was cooled to rt, concentrated to remove the bulk of the acetone, and dissolved in CH2Cl2 (200 mL). The organic layer was washed with 0.5 N Na2S2O 3 (2 x 200 m-fL) and sat'd NaHCO3 (1 x 100 mL). The aqueous layers were extracted with CH2Cl2 (2 x 100 mL).

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: 1 H NMR (400 MHz, acetone-cl 6 7.96 J 8.6, 1 7.83 (dd, J 10.0, 2.9, 1 7.30 (dd, J 9.0, 4.9, 1 7.22 J 8.6, 1 7.17 (mn, 1 6.25 (br s, 1 5.54 1 1.30 6 The acetone multiplet obscures the C(4) methyl group.

H:\riaa\Kep\,p-cM5977-96.s'hROD RECEPTDRdOC 19/01/00 DOCKET NO.

016-0014A.WO 158 EXAMPLE 108 8 -Fluoro- 1, 2 -dihydro-2, 2.4-trimethyl5coumarino 3.4-flquinoline (Compound 208 structure 41 of Scheme XI, where R 1

R

2

=H)

2 -Bromo-5-fluoroanisole (structure 36 of Scheme 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 mmol, 1.2 equiv), potassium carbonate (8 and water (1 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 mixture was extracted with EtOAc (3 x 120 mL); the 10 extracts were washed with brine (1 x 80 mL), combined, dried (K2C03), filtered, and concentrated to a clear oil. Bulb-to-bulb distillation (60-65 OC, 0.7 Torr) afforded 13.22 g (quant) of 2 -bromo-5-fluoroanisole as a colorless liquid. Data for 2 I1H NMR (400 MHz, CDC13): 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-methoxyphenylboronic acid (structure 37 of Scheme XI, where R 1

R

2

=H)

In a 100 mL 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 0 C (CO2/IPA) and n-BuLi (2.5 M in hexanes; 10.7 mL, 27 mmol, 1.0 equiv) was added via syringe over a 15 min period. The reaction mixture was 20 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 The reaction mixture was brought to pH6 with HC1, poured into sat'd NH4C1 (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 further purification.

7 -Fluoro-2-nitro-3,4-benzocoumarin 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 4- H:\riyanlka\Kep\pccM5977.96.STERO[D RECEPTOR.doc 19/01/00 DOCKET

NO.

016-0014A.WO 159 fluoro-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 mL). The reaction mixture was heated to 80 0 C for 6 h, cooled to rt, poured into 5% HC1 (100 mL), and extracted with EtoAc (3 x 100 mL). The extracts were washed with sat'd NH4C1 (1 x 100 mL) and brine (1 x 100 mL), combined, dried (MgS04), filtered, and concentrated to an orange solid. This crude material, consisting of impure 4 '-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid (structure 44 of Scheme XII, where RI=F, R 2 was suspended in 1, 2 -dichloroethane (80 mL), treated with thionyl chloride (1.2 mL), and heated at reflux for 90 min. The reaction mixture was cooled to rt, treated with aluminum trichloride (0.4 and allowed to react overnight (11 h).

The reaction mixture was poured into 20% KOH (80 mL) and extracted with methylene chloride (3 x 80 mL). The extracts were combined, dried (MgSO4), filtered, and concentrated to an orange oil. The crude material was dissolved in methylene chloride mL), 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 mL of 2:1 hexane:EtOAc, which was discarded, and then 400 mL of 1:1 hexane:EtOAc. The filtrate was concentrated to afford 2.08 g of 7-fluoro-2nitro-3,4-benzocoumarin as an orange solid. Data for 7 -fluoro- 2 -nitro-3,4-benzocoumarin: 1 H NMR (400 MHz, acetone-d 6 9.02 J 2.4, 1 8.71 (dd, J= 8.8, 2.4, 1 8.65 8.8, 1 8.53 (dd, J= 9.6, 6.1, 1 7 .34 2H).

2 -Amino-7-fluoro-34-henzooumarin (structure 40 of Scheme XII where R 1=F R 2

=H

In a 250-mL flask, a suspension of 7 -fluoro-2-nitro-3, 4 -benzocoumarin (2.04 g, 7.9 mmol) in EtOAc (150 mL) was treated with 10% Pd/C (1.2 g) and AcOH (0.2 mL), and stirred under an atmosphere of H2 for 1 h. The reaction mixture was filtered and the solids rinsed with acetone (200 mL). Concentration of the filtrate afforded 1.61 g of 2-amino-7fluoro-3,4-benzocoumarin as a yellow solid. Data for 2 -amino-7-fluoro-3,4benzocoumarin: 1 H NMR (400 MHz, acetone-d 6 8.15 (dd, J 9.6, 6.1, 1 8.05

J=

8.6, 1 7.55 J 2.5, 1 7.28 (dd, J 8.6, 2.5, 1 7.14 1 7.12 J 9.6, 1 5.4 (br s, 2 H).

8-Fluoro-l 2 -dihydro-2,2,4trimethyl-5-couarino[3,4-flquin line (Compound 208 structure 39 of Scheme XI, where RI=F, R 2 In a 200-mL resealable pressure tube, a H:\W\ana\Kcp\peM977-96STROfD RECEPTOR.doc 19/01/00 DOCKET

NO.

0 16 -0014A.WO 160 suspension of 2-amino-7-fluoro-3,4-benzocoumarin (1.61 g) in acetone (100 mL) was treated with iodine (Aldrich: 0.50 g) and heated to 110 0 C for 32 h. The reaction mixture was cooled to rt, concentrated to remove the bulk of the acetone, and dissolved in CH2C1 2 (200 mL). The organic layer was washed with 0.5 N Na2S203 (2 x 200 mL) and sat'd NaHC03 (1 x 100 mL). The aqueous layers were extracted with CH2C12 (2 x 100 mL).

The combined organic layers were dried (K2C03), filtered, and concentrated to afford an orange solid. Purification by SGC (hexane/EtOAc, 5/1) afforded 0.46 g of Compound 208 as a bright yellow solid. Data for Compound 208: 1 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 2 6.1 (br s, 1 5.53 J= 1.2, 1 1.29 6 The acetone multiplet obscures the C(4) methyl group.

EXAMPLE 109 9-Chloro- 1,2-dihydro-2,2,4-trimethyl-5-coumarino f3,4-fquinoline (Compound 209 structure 41 of Scheme XI, where R=H R 2

=C)

2 -Bromo-4-chloroanisole (structure 36 of Scheme XI, where R 1

R

2 =C1) In a 250 mL r.b. flask, a solution of 2 -bromo-4-chlorophenol (Lancaster: 16.94 g, 81.6 mmol, 1.0 equiv) in acetone (160 mL) was treated sequentially with iodomethane (6.10 mL, 98 mmol, 1.2 equiv), potassium carbonate (12 and water (4 mL). The reaction mixture was heated at reflux for 3 h, cooled to rt, 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 mL). The extracts were washed with brine (1 x 100 mL), combined, dried (K2C03), filtered through a pad of CeliteTM, and concentrated to a clear oil. Short-path distillation (80-85 oC, 1 Torr) afforded 17.74 g of 2 -bromo-4-chloroanisole as a clear liquid. Data for 2 -bromo-4-chloroanisole: 1 H NMR (400 MHz, acetone-d 6 7.53 J= 1 7.24 (dd, J 9.7, 2.5, 1 6.81 J 9.7, 1 3.88 3 H).

5-Chloro-2-methoxyphenylboronic acid (structure 37 of Scheme XI, where RI=H. R 2

=C)

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, mmol, 1.0 equiv), n-BuLi (2.5 M in hexanes; 3.62 mL, 9.0 mmol, 1.0 equiv), and HN'\"-Ko-kA\Kcmp~e g5h96.STRCOID RECEPTOR.doc 19/01/00 DOCKET NO.

0 l6-0014A.WO 161 trimethylborate (3.0 mL, 26 mrnol, 2.9 equiv) to afford 1.30 g of crude 5-chloro-2-.

rnethoxyphenylboronic 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-hiphenyl)caIrboxylate(srcue3ofShmXI wLhere R 1

R

2 =CI) This compound was prepared in a manner similar to that of methylfluoro-2 '-methoxy-4-nitro..2.bipheny1)carboxylate (EXAMPLE 107) from methyl 2bro mo-5-nitro benzo ate (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 minol, 1.5 equiv) to afford 0.85 g of mnethyl-5'chloro2'methoxy4 nitro- 2 -biphenylcarboxylate as a yellow-orange solid. Data for methyl 5'-chloro-2'- :::.methoxy- 4 -nitro.2-biphenylcarboxylate: IH NMR (400 MHz, CDCl3): 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

15 1 6.85 J 8.7, 1 3.76 3 3.70 3 H).

5-Clo9-!-acid This compound was prepared in a manner similar to that of 5 '-fluoro-2 '..methoxy-4-nitro2.biphenylcarboxylic acid (EXAMPLE 107) from methyl 5Lchloro-2 -methoxy4nitro-2-biphenylcarboxylate (0.83 g, 2.6 mmol) to afford 0.75 g of 5'.chloro-2 .methoxy4nitro-2biphenylcarboxylic acid as a yellow solid. Data for (5S-chloro-2'-methoxy4nitro-2-biphenyl)carboxylic acid: IH NMR (400 MHz, acetone-d 6 8.69 J 2.5, 1 8.46 (dd, J 8.3, 2.6, 1 7.68

J

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).

6 -Chloro-2-nitro3,4-enzocoumarin This compound was prepared in a manner similar to that of 6 -fluoro-2- nitro benzocoumnarin (EXAMPLE 107) from 5 -chloro-2'-methoxy-4 nitro- 2 -biphenylcarboxylic acid (0.74 g, 2.3 mmol), SOC12 (0.17 rnL, 2.3 mmol), and AIC13 (0.30 g, 2.5 mmol) to afford 0.64 g (quant) of 6 -chloro nitro-3,4- benzocoun'arin as a yellow solid. Data for 6-hoo2nto34bnoomrn IH NMR (400 MHz, acetoned 6 9.04 J 2.3, 1 8.73 (mn, 2 8.51 J 2.4, 1 7.72 (dd, J 8.6, 2.4, 1 7.50 J 8.7, 1 H).

H""-a\Kp'-~c.4597-96S7EOIDRECEPTOR4OC 19101100 DOCKET No.

0l6-0014A.WO 162 2 -Amino- 6 -chloro-3.4-benzocoumarin (structure.,40 of Scheme XI. where R 1

R

2 ==Cl) This compound was prepared in manner similar to that of 2 -amino-6-fluoro34 benzocoumnarin from 6 -chloro-2nitro3,4.ibenzocouain (0.64 g, 2.3 mmol) to afford 0.50 g of 2 -am-ino-6-choro3,4benzocounuain as a yellow solid. Data for 2 -amino-6chloro-3,4-benzocoumarin: IH NMR (400 MHz, acetone-d 6 8.11 (in, 2 7.55

J=

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

9-Chioro-1,-iyr-,2,4tiehl5cuaio A-lqiol(Com-pound 209.

strctue 4 ofSchme"I. where R 1

R

2 =C1) This compound was prepared in a manner similar to that of Compound 207 from 2 -amino-6-chloro-3, 4 -benzocoumarin (0.50 g) to afford 0. 14 g (21 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 HI); 8.00 J 8.7, 1 7.39 (dcl, J 8.7, 2.3, 1 7.26 J 8.8, 1 7.23 J 8.6, 1 5.55 1 1.30 (s, 6 The acetone multiplet obscures the C(4) methyl group.

EXAMPLE 110 kR/S')-5-Butyl-9-fluoro-l2 ih-r- 2 3 guiolin (Comp~ound 210 structure 42 of Scheme XI. where R=n-butyl. R=H.

R

2

=F)

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 (0.53 g, 1.7 mmol) and n-BuLi (2.5 M in hexanes, 2.7 mL, 6.8 mmol, 4.0 equiv) to afr 0.34 g of Compound 210 as a yellow foamn. Data for Compound 210: IH NMR (400 MHz, acetone-d 6 7.54 J 8.5, 1 7.49 (dd, J 10.2, 2.9, 1 7.03 (dd, J= 8.8, 4.9, 1 6.88 (dt, J 2.9, 8.8, 1 6.75 J 8.5, 1 5.80 (br 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 (br s, 8H); 0. 93 J 7.4, 3 H).

EXAMPLE Il1 l 2 dihydro-2,2.4-trethy-H-chomno 3 ,4-flguino line (opud21stct 42 of Scheme XI wher R=n-but I I R 1 F R 2

-H

H" ka\K-P\,PecM597796.SEROD RECEPTORAdo 19J01/oo DOCKET NO.

016-0014A.WO 163 This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 208 (29 mg, 0.09 mmol) and n-BuLi (2.5 M in hexanes, 0.16 mL, 0.40 mmol) to afford 6.5 mg of Compound 211 as a yellow foam. Data for Compound 211: 1H NMR (400 MHz, acetone-d6): 7.77 (dd, J= 8.7, 6.3, 1 7.51 J 8.5, 1 6.85 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 3 -Chlorophenyl)-9-fluoro 1,.2-dihvdro-2,2,4trimethvl-H-chromeno[34.

flquinoline (Compound 212, structure 42 of Scheme XI, where R=3-chlorophenl,

R

1

=H

R

2

=F)

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 (50 mg, 0.16 mmol) and 3 -bromochlorobenzene (120 mL) to afford 46 mg of Compound 212 as a colorless solid. Data for Compound 212: 1 H NMR (400 MHz, acetone-d 6 7.56 J 8.4, 1 7.36 (dd, J 9.8, 2.9, 1 7.25 4 6.95 1 6.85 J= 8.5, 1 6.81 1 6.74 (td, J 8.5, 2.9, 1 5.51 1 2.00 (d, J 1.0, 3 1.28 3 1.26 3 H).

EXAMPLE 113 LRS)5(4-Chlr-3-meth hen)-ur 2dihdr-2 -ieth-5H-chr n 4- ^fluinoline Compound 213 structure 42 of Scheme XI where R=4-chloro-3methylphenyvl R=H,

R

2

=F)

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 mg, 0.16 mmol) and 5-bromo-2-chlorotoluene (0.21 g) to afford 42 mg of Compound 213 as a colorless solid. Data for Compound 213: 1 H NMR (400 MHz, acetone-d 6 7.55 J 8.4, 1 7.34 (dd, J 10.0, 2.8, 1 7.22 2 7.00 (br d, J 10.3, 1 6.89 1 6.84 J 8.4, 1 6.75 2 5.49 1 2.24 3 H); 1.99 J 1.2, 3 1.27 3 1.25 3 H).

HIPryanka\K-P\-Fc.\4597-.STEROID RECEP'ORAo, 19/01/00 DOCKET

NO.

016-0014A.WO 164 EXAMPLE 114 (R/S)-5-(4-Chlorophenyl)-9fluoro. l.

2 -dihvdro-2,.4-trimethylp5H-chomen 0 r3 4flguinoline (Compound 214. structure 42. of Scheme XL. where R=4-chorohenl. 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 bromochloro benzene 19 g) to afford 33 mg of Compound 214 as a pale yellow oil. Data for Compound 214: 1 H NMR (400 MHz, acetone-d 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 2 6.92 1 6.84 J 8.5, 1 6.75 (in, 2 5.60 (br s, 1 5.48 .0000: J 1.3, 1 1.99 J 1.3, 3 1.27 3 1.24 3 H).

EXAMPLE 115 :(R/S)-9-Fluoro- 1.-ivdo5 (4mtoyhnl-H,-rmty-Hcr me 34- 15 flguinoline (Compound 215. structure 42 of Scheme XI, where R=4-methoxyphenyl.

Rl=H. R 2

=F)

a 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-d 6 7.53 J 1 7.34 (dd, J 10.0, 2.8, 1 7. 11 J 8.8, 2 6.86 1 6.82 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-. l 2 -dihyd-ro-5methxy224-timethyl-5H-chro meno3 r34-flguinoline (Compound 216 structure 47 of Scheme XIYwee 1 Fr 2 R-ety.X 0 (R/S)-8-Fluoro- 1,2dhyr--vdoy224tiety-Hcr n [3,4-flguinoline (structure 46 of Scheme IV. where R=F. R 2 This compound was prepared in a manner similar to that of Compound 185 (EXAMPLE 85) from Compound 208 (170 mg) and DIBALH (1.0 M in hexane; 1.25 mL) to afford 27 mng of (R/S)-8-fluoro-1,2d iyr--yrxl ,,-rmty5Hcr en 3,4-fjjquino line as a white solid. Data for H:\Priyanka\Kvep'specM5977-96.STEROID RECEPTORdoe 19/01/0O DOCKET

NO.

0 16-0014A.WO 165 (RIS)- 8-fluoro- l, 2 -dihydro-5hydroxy2,24- tmethyl..5H-chro meno [3 ,4-fjquino line: IH NMR (400 MHz, acetone-d 6 7.74 (dd, J 8.6, 6.3, 1 7.50 J 8.4, 1 6.85 1 6.79 (in, 2 6.72 (dd, J 9.9, 2.7, 1 5.51 J 1.2, 1 2.82 3 1.30 (s, 3 1. 17 3 H).

LR/SV8-Fluoro- 1, 2 -dihydro-5methox224trimethylSH-chromen 3 4 -flguino line (COmpound 216, structuire 47 of Sche-me Xirv where Rl=F.R H R mehlX0)Ti compound was prepared in a manner similar to that Of Compound 186 (EXAMPLE 86) from (R/S)-8-fluoro- l, 2 dihydro5hydroxy224 ethy1..S-h chre[ 3 4 Au ln (24 mg) to afford 25 mg (quant) of Compound 216 as a white solid. Data for Compound 216: 1 H NMR (400 MHz, acetone-d 6 7.74 (dd, J 8.5, 6.2, 1 7.50 J 8.4, 1 H); 6.85 (mn, 2 6.79 J 8.4, 1 6.38 1 5.52 J 1.0, 1 3.46 3 2.26 15 EXAMPLE 117 ,(R/S)-5-(4-ChlorOphenyl)..8-fluioro- 2 -dihydro-2,2,4frniethyl-5H-ciromeno 34- (qioln Compound 27-rhe XwhereAR=

R

2

=H)

.too.. This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 208 4 2 mg, 0. 13 inmol) and 4 -bromochloro benzene 19 g) to afford 10 mg of Compound 217 as a pale yellow oil. Data for Compound 217: 1 H NMR (400 MHz, acetone-d 6 7.62 (dd, J 8.6, 6.3, 1 7.53 J 8.4, 1 7.27 J 8.7, 2 7.23 J 8.7, 2 6.96 I 6.83 J 8.2, 1 6.67 (in, 1 6.58 (dd, J= 8.7, 2.5, 1 5.48 J 1.3, 1 1.99 J 1.2, 3 1.26 3 1.23 3 H).

EXAM P LE 118 (R/S)-2-Chloro..5.(4chlorophenyl)- 2 -dihvdro224trimethyl5Hchromeno (3.4fIgu ioline (Copound -218. strctre 2 of Scheme X where R=4-chlorphnylI R =H.

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 mg, 0. 12 inmol) and 4 broinochloro benzene 19 g) to afford 23 mg of HN~kaW-Ppc6\977-96.SMROID RECEPTOR.doc 19/1110 DOCKET

NO.

01 6 -0014A.WO 166 Compound 218 as an off-white oil. Data for Compound 218: 1 H 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 1,2-dihydro-2,24triethyl-5H-chromeno 3 ,4-fluinoline (Compound 219. structure 45 of Scheme XII where RI=R 2

R

3 =npropl General Method 6: Preparation of compounds of structure 45 from Compound 159 o compounds ofstructure 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 15 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 color 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.

H:ank"a-o\ep\pcS97796.TROID RECEPTORA.o 19/01/00 DOCKET No.

016-00 14A.WO 167 l.

2 -dihydro-2,2,4-tri ethyl-.5H..chro meno [3.4-flguino line (Compound srcue4ofShme XL1I, where R 1

=R

2 3 nprpl This compound was prepared by General Method 6 from 1.6 M hexane solution of n-butyllithium (0.2 rnL, 0.32 inmol) and Compound 159 (20 ing, 0.07 inmol) to afford 4.8 mng (21 of Compound 219 as a bright yellow oil. Data for Compound 219: Rf 0.62 (silica gel, 25% EtOAc: hexane); IH NMR (400 MHz, acetone-d 6 7.74 J 1 7.54 J 8.4, 1 H), 7.14 (t J 7.5, 1 7.03-6.98 (in, 2 6.74 J 1 5.48 1 4.81 J= 1 2.40-2.35 (in, 2 2.09 3 1.49-1.44 (in, 2 1.27 (br s, 6 0.93 J= 7.3, 3 H).

EXAMPLE 120 'Ld-5-Benzyidcene-12 yr-.,-riehl5-hoeo-3.-lunln (Compound This compound was prepared by General Method 6 (EXAMPLE 119) from benzyl bromide (171 mg, 1.0 inmol) and Compound 159 (20 ing, 0.07 inmol) to afford 6.3 mng of 15 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, 1 7.38 (t J 7.6, 2 7.24-7.20 (mn, 3 (7.09-7.06) (in,4 1 6.84 J 8.4, 1 5.68 1 5.55 (s 1 2.11 3 1.29 (br s, 6 H).

EXAMPLE 121 4 -Fluorobenzylidene)-,-iyr-,.4tiehl5- omeo3 4 -flguinoline (Compound 221 structure 45 of Scheme XII. whr 1 R=.R =4-fumpenjl) This compound was prepared by General Method 6 (EXAMPLE 119) from 4-fluorobenzyl chloride (145 ing, 1.0 nirol) and Compound 159 (20 ing, 0.07 mrnol) to afford 17 mng 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

8.4, 1 7.22-7.05 (n,4 5 6.82 J 8.4, 1 5.68 1 5.54 1 2. 10 (s, 3 1.32 (br s, 6H).

EXAMPLE 122 4 -Bromobenzylidenev. l.

2 -dihydro-2.2.4trimethyls5Hchromen r4- luinoline (Cmond2 2Lsrcue 45 fShem XII hr 1 R= .=4-broihenyl) H:\-rnka\Kep\SPecM\597h96STEROID RECEPTORdoc 19/01/00 DOCKET NO.

016-0014A.WO 168 This compound was prepared by General Method 6 (EXAMPLE 119) from 4 -bromobenzyl bromide (250 mg, 1.0 mmol) and Compound 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 8.4, 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 (mn, 1 6.84 J 8.3, 1 5.66 1 5.55 1 2.09 3 1.34 (br s, 6 H).

EXAMPLE 123 (Z)-5-(3-Bromobenzylideney. l.

2 -dihydro-2,2.4-trimethypsHchomeno r3,4flguinoline (Compound 223. structure 45 of Scheme XIII. where R 1

=R

2

R

3 =3bromophenyl) 9 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 mmol) to afford 22 mg of Compound 223 as a bright yellow oil. Data for Compound 223: 1H NMR (400 MHz, acetone-d6) 8.03 1 7.85 J 7.9, 1 7.78 J 7.9, 1 H), 15 7.66 J 8.4, 1 7.41-7.17 (mn, 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).

0 EXAMPLE 124 (Z)-5-(3-Chlorobenzylidene). l 2 -dihydro-2.2,4-trimethvls5H-chroenof~ 4fRguinoline (Compound224. structure 45 of Scheme XIII. where R=R 2

R

3 =3chlorophenyl) This compound was prepared by General Method 6 (EXAMPLE 119) from 3chlorobenzyl chloride (161 mng, 1.0 mmol) and Compound 159 (10 mng, 0.035 mmol) 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); 1 H NMR (400 MHz, acetone-d6) 7.88-7.85 (mn, 2 7.72 J 8.0, 1 7.67 J 8.4, 1 7.40 J 8.0, 1 7.26-7.20 (in, 3 H), 7.12-7.08 (in, 1 6.85 J 8.4, 1 5.68 1 5.56 1 2. 10 3 1.29 (br s, 6 H).

EXAMPLE 125 (Z)-5-(3-Fluoro benzy-idene)- 1 2 -dihydro-2,24-timethy-5Hchoenor3 .4-tjguinoline (Compound 225. structure 45 of Scheme XII where R 1

R

2 H 1 -1 uroheyl H\Prnke\Kp~svM597796STROID RECVTOR4O 19/01/00 DOCKET

NO.

Ol6-0014A.WO 169 This compound was prepared by General Method 6 (EXAMPLE 119) from 3-fluorobenzyl bromide (189 mg, 1.0 mmol) 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-d6) 7.85 J 1 7.66 (d, J 8.6, 2 7.52 J 7.9, 1 7.43-7.38 (in, 1 7 2 5- 7 .23(m, 2 7.11-7.07 (mn, 1 7.02-6.97 (n,4 1 6.85 J 8.6, 1 5.70 1 5.55 I 2. 10 3 H), 1.29 (br s, 6 H).

EXAMPLE 126 2 -Chlorobenzylidene)- .2dh m 3 4 fgioie (Copoud 26.strctr 45 of Scheme XII where R 1

=R

2

R

3 =2-chLoohenyl) This compound was prepared by General Method 6 (EXAMPLE 119) from 2 -chlorobenzyi chloride (161 mg, 1.0 inmol) and Compound 159 (20 ing, 0.07 rnmol) 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 H NMR (400 MHz, acetone-d6) 8.44 J 7.9, 1 7.85 (d, J 7.9, 1 7.67 J= 8.5, 1 7.45-7.37 (in, 2 7 2 5-7.21 3 7 2 0-7.11 1 6.86 J 8.5, 1 6.20 1 5.55 1 2.15 3 1.29 (br s, 6 H).

EXAMPLE 127 2 -Bronobenzylidne. Y -224tiehl5-hoeo3.4- lgufioline (Comnpound 227 structure 45 of Scheme XII where R=R 2 =H R 3 2bonpey)Ti compound was peedb General Meho (EXAMPLE 11)from 2-rmbny bromide (250 mg, 1.0 mmol) and Compound 159 20 ing, 0.07 minol) to afford 2.8 mg of Compound 227 as a bright yellow oil. Data for Compound 227: Rf 0.44 (silica gel, 25% EtOAc: hexane); 1 H NMR (400 MHz, 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 (mn, 4 6.87 J 1 6.19 1 5.55 1 2.15 3 1.29 (br s, 6 H).

H' CecpKt\pc 5977h96.SROD RECEPTORdoV 19101100 DOCKET

NO.

0l6-0014A.WO 170 EXAMPLE 128 (Z)-5-(2-Fluoro benzylidene)- l.

2 -dihydro-2,2,4-trmethyl-5H-chromeno [3 4 -flguinoline (Compound 228, structure 45 of Scheme XIII. where R I=R 2

R

3 -2-fluoro henyl') 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 mm-ol) to afford 2.1 mg of Compound 228 as a bright yellow oil. Data for Compound 228: 1 H NMR (400 MHz, acetone-d6) 8.39 (n4 1 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 1 5.90 1 5.55 1 2.13 3 H), 1.32 (br s, 6 H).

EXAMPLE 129 Dilo en zyAidene)- 1,2dhdo224tieh.5-hoeo34-f iquinoline (Compound229. structuire 45 of Scheme XI.whr 1 H 23-ifluorpenyl) This compound was prepared by General Method 6 (EXAMPLE 119) from 2,3- 15 difluorobenzyl bromide (207 mng, 1.0 mmol) and Compound 159 (10 mg, 0.034 inmol) to afford 4.8 mg of Compound 229 as a bright yellow oil. Data for Compound 229: IH NMR (400 MHz, acetone-.d6) 8.18 (dd, J 8.0, 6.6, 1 7.87 J 7.5, 1 7.69 J 1 7.30-7.08 (mn, 5 6.89 J= 8.4, 1 5.94 1 5.57 1 2.12 (s, 3 1.31 (br s, 6 H).

EXAMPLE 130 2 ,5-Difluorobenzylidene)- 1,-iyr-,,-rehl5-hoeo34fqioln (CQompound 230 sructure 45 of Scheme XIUI where R I =R 2 =H R 3 .=ifurphn, This compound was prepared by General Method 6 (EXAMPLE 119) from difluorobenzyl bromidde (207 mg, 1.0 inmol) and Compound 159 (15 mg, 0.05 mmol) 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, 1 7.88 J 8.3, 1 7.69 J 8.5, 1 H), 7.30-7.00 (in, 5 6.89 J 8.4, 1 5.93 1 5.94 1 5.56 1 2.11 (s, 3 1.32 (br s, 6 H).

H' "nka\-PN$-cM577-9.S ROI ECEPTOR. 19/01/00 DOCKET NO.

0 16-00 14A.WO 171 EXAMPLE 131 (Z)-9-Fluoro-5-(3-fluoro benzylidene)- 1 2 -dihydro-2,2,4-tirethyl-5H-chro meno [3.4tlguinoline (Compound 231, structure 45 of Scheme XIII. where R 1

R

2

R

3 fluorophenyl) 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: 1 H NMR (400 MHz, acetone-d6) 7.65 J 8.4, 1 7.64 (mi, 1 7.60 (dd, J 10.0, 3.0, 1 7.52 J 7.6, 1 7.40 (in, 1 H); 7.26 (dd, J 8.9, 4.8, 1 7.00 (in, 2 6.86 J 8.3, 1 5.72 1 5.57 J 0: 1.2, 1 2.10 3 1.40 (br s, 6 H).

EXAMPLE 132 (Z)-9-Fluoro-5-(3-methoxybenzylidene) 1 .2-dihydro-2.2,4-trimethyl-5H-chromeno [3.4- 15 flguinoline (Compound 232, structure 45 of Scheme XIII. where Rl=H. R 2

R

3 =3methoxyiphenyl) This compound was prepared by General Method 6 (EXAMPLE 119) from 3methoxylbenzyl chloride 18 g) and Compound 207 (31 mng) to afford 11 mg of Compound 232 as a yellow oil. Data for Compound 232: 1 H NMR (400 MHz, acetone- S 20 d6) 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 (n-4 1 6.98 (in,4 1 6.83 J 9.6, 1 6.82 (in, 1 5.68 1 5.56 (s, 1 3.86 3 2.10 3 1.35 (br s, 6 H).

EXAMPLE 133 (Z)-8-Fluoro-5- (3-fluororbenzvlidene)- 1 2 -dihydro-2,2,4-trimethyl-5lichromeno [3.4- [iguinoline (Compound 233. 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 208 (31 mg) to afford 7.5 mg of Compound 233 as a yellow oil. Data for Compound 233: 1 H NMR (400 MHz, acetoned6) 7.88 (dd, J 9.7, 6.2, 1 7.63 J 8.5, 1 7.58 (in, 2 7.42 (dd, J H:\Priyanka\Keep\specM\5977-96.S'hROID RECEPTORAoc 19/01/00 DOCKET NO.

016-0014A.WO 172 6.4, 1 7.09 (dd, J 9.5, 2.7, 1 7.00 1 6.92 1 6.85 J= 8.2, 1 H); 5.73 1 5.63 1 2.10 3 1.35 (br s, 6 H).

EXAMPLE 134 (R/S-41, 5u)-5-(4-Chlorophenyl)-1,2 3 4 -tetrahydro-2.2.4-trimethyl-5H-chromenof3,4-f-3quinolinone (Compound 234, structure 52 of Scheme XV, where R=4-chlorophenv, R =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 mmol) in THF (6 mL) 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 min before a solution of di-t-butyl dicarbonate (150 mg, 0.7 mmol) 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 15 column using 10-30% mixture of ethyl acetate and hexane afforded 50 mg of the t- Boc protected quinoline (structure 49 of Scheme XV where R=4-chlorophenyl,

R

1

=R

2

=H)

and 80 mg of Compound 163.

The t-Boc protected Compound 163 (structure 49 of Scheme XV where R=4-chlorophenyl, S 20 R 1

=R

2 (40 mg, 0.08 mmol) in THF (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 mixture was stirred for 30 min, 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, butyloxycarbonyl-5-(4-chlorophenyl)- 1,2,3, 4 -tetrahydro-3-hydroxy-2,2,4-trimethyl-5Hchromeno[3,4-f]quinoline (structure 50 of Scheme XV where R=4-chlorophenyl,

R

1

=R

2 The second fraction (12 mg, 30%) was assigned as (R/S-31, 4u, 5u)-1-tbutyloxylcarbonyl-5-(4-chlorophenyl)- 1,2,3,4-tetrahydro-3-hydroxy-2,2,4-trimethyl-5H HN\riyanka\Kecp'spcl\5977.96.sIhROD RECEPTORdoc 19/01/00 DOCKE-T NO.

016-0014A.Wo 173 chromeno [3,4-fquino line (structure 51 of Scheme XV where R=4-chlorophenyl,

R

1

=R

2 (R/S-31, 4u, 51i-t-Butyloxylcarbonyl-5-(4-chlorophenyl)- 1,2,3 4 -tetrahydro-3-hydroxy- 2 2 4 -trimethyl-5Hchromeno [3,4fjquno ie (structure 50 of Scheme XV where R=4chiorophenyl,

R

1

=R

2 (20 mg, 0.04 rnmol) was oxidized with PCC (100 mg, 0.46 mmnol) in 5 mL of methylene chloride at rt for 60 min to yield (R/S-41, 5u)- (4-chiorophenyl)- l, 2 3 4 -tetrahydro-224 trimethl5H -chrom n[ un h o ea colorless oil after chromatography. This compound was then treated with 0.2 ml of TFA in 0.5 ml of methylene chloride for 30 mmd and was quenched with 5 mL of KOH The reaction mixture was extracted with EtOAc, washed with brine and was concentrated.

Goes*..

Chromatography of the crude residue on a silica gel column (10-30% EtOAc/hexane gradient) afforded 15 mg of Compound 234 as a white solid. Data for Compound 234: IH NMR (400 MHz, CDCl3) 7.64 J 8.2, 2 7.18 J 8.6, 2 7.13

J

O 15 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 1 3.73 1 3.56 J 7.4, 1 1.44 3 1.26 3 H), 0. 87 (d,fJ= 7.4, 3 H).

EXAMPLE 135 O 20 (RIS-41. -5-4-Chlrnphnvl).. 1..I 4 ttaydro-2.24trimethyl-5H-chromeno[ .41f-3qunolione Compund35 sructure 53' of Scheme VAT where R=4-chlorohenvl.

R

1

=R

2

=H)

(R/S-31, 4u, 5u)- l-t-Butyloxylcarbonyl-5.(4-chlorophenyl) 1 2 3 4 -tetrahydro-3-hydroxy- 2,,-rmty-Hcr mn 34jqioln (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, CDC13) 7.59 J 8.4, 1 7.57 J 8.0, 1 7.15 J 8.5, 2 H), 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 1 3.35 J 7.5, 1 1.50 J 7.5, 3 1.46 3 H), 1. 17 3 H).

H:\rianka\Keop\speci\597-96.S-hROD RECEPTOfRAoc 19/01/00 DOCKET NO.

0 16-0014A.WO 174 EXAMPLE 136 (R/S)-5-(4-Chlorophenyl)- 1,2,3 4 -tetrahydro-2,2,4,4-tetramethyl-5H-chromeno r3 4-/1-3guinolinone (Compound 236. structure 54 of Scheme XV where R=4-chlorophenyl.

R I=R 2

=H)

To a solution of (R/S-41, 5u)-l1-t-butylo xylcarbonyl-5-(4-chlorophenyl)- 1,2,3 ,4-tetrahydro- 2 2 4 -trimethyl-5H-chromeno[3,4-f]-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 mmol) and the resulting slurry was stirred at rt for 20 min before Mel 1 g, 0.7 mmol) was introduced. The 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 for Compound 236: 1 H NMR (400 MHz, CDCl3) J 1 7.56 J 1 7.13 J 8.7, 2 7.09 J 8.7, 2 H), 7.01 J 1 6.91 J 7.9, 1 6.85 1 6.83-6.78 (in-4 2 3.83 1 H), 1.63 3 1.38 3 1.33 3 1.28 3 H).

0. EXAMPLE 137 *l.-Dihydro- 2 2 4 -trimethyl-6-methoxymethy18-pyiranono [5,6-giq uino line (Compound 237, structure 57 of Scheme XV1, where R 1

=R

2

R

3 =methoxvlmethyl, Z=OQ) General Method 7: l.

2 -Dihydro-2,2.4-timethylquino lines (Compounds of structure 57 or 67) from anilines (Compounds of 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).

l.

2 -Dihydro- 2 2 4 -trimethyl6-m thoxymethyl 8pyanono r5,6- g /quino line (Compoun 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-am-ino-4-methoxymethylcoumnarin (structure 56 of Scheme XVI, where R 1

=R

2

R

3 =methoxymethyl) (1.0 g, 4.87 mmol) to afford 82 mg of Compound 237 as a light yellow solid in addition to 487 mg of H-\riyanka\K-ppvMS4977-96.STEROID RECEPTORdo 19/01/00 DOCKET NO.

016-0014A.Wo 175 l, 2 -dihydro-2,2,4trimethyb8-methoxymethyl.6-pyranono 6 ,5-Jlquino line, Data for Compound 237: Rf 0.23 (silca gel, hexanes/EtOAc, 2: 1 H NMR (400 MHz, C6D6) 7.01 1 6.24 1 6.18 1 5.02 1 3.97 2 3.74 (br s, 1 2.92 3 1.78 J 1.0, 3 0.98 6 H).

EXAMPLE 138 l.

2 -Dihydro-2,2,4-trimethyl.6.trifluoromethyl 8-pyranono [5.6-g lguinoline (Compound 238, structure 57 of Scheme XVII. where R 1

=R

2

R

3 =rifluoromethyl. Z=O) This compound was prepared as depicted in Scheme XVII and as described below.

1 OPvaloyl3ntrpeol (structure 65 of Schm VI hr 1 H ~-uv.ZO To 300 mL of CH2Cl2 was added 3-nitrophenol (structure 64 of Scheme XVII, where R 1

=H,

(15 g, 0. 11 mol), pyridine (20 mL) and DMAP (10 mg). To this cooled solution *(0 0 C) was slowly added trimethylacetyl chloride (18 mL, 146 mm-ol, 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 IN HCl (2 x 150 m-L), CuS 04. 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 MHz, CDCl3) 8.11 (dd, J 4.2, 1.3, 1 7.96 J 2.2, 1 7.56 (dd, S 20 J 8.4, 8.2, 1 7.42 (dd, J 6.5, 1.3, 1 1.35 9 H).

O-Pivalovl-3-ann enol rcue6-fShm VI where R=H, P=t-butl, Z=0) To 60 mL anhydirous CH2Cl2 was added O-pivaloyl-3-nitrophenol (5.0 g, 22.4 mmol) and a catalytic amount (50 mg) of 10% Pd on C. The 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-3am-inophenol: Rf 0.21 (silica gel, hexanes/EtOAc, 1 H NMR (400 MHz, CDCl3) 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, lH), 6.38 J 2.2, 1 3.81 (br s, 2 1.34 9 H).

H.."akap\spM 597796.STROD RECEPTOR4 0 oc 19/01/00 DOCKET

NO.

0 1 6-0014A.WO 176 General. Method 8. 1, 2 -Dihydro-2,2,4-trimethylguino lines (Compounds of structure 57 or 67) from anilines (Compounds of structure 56 or.66), pressure tube version In 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 TC 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 dihydroquinoine (Compound of structure 57 or 67).

9. 10 1.-iyrI 2,-rmty--I 1, 1 -tulheyaceoxy)qunoie (structure 67 of Scheme XVIEL where R=H. P=-butyl. Z=O This compound was prepared by General Method 8 from O-pivaloyl-3-am-inophenol (structure 66 of Scheme XVII1, where R 1 Pt-butyl, aY=O) (1.26 g, 6.53 mmol) to afford 1.06 g of 1, 2 -dihydro-2,2,4trimethyl7(1,1,1 *5 trimethylacetoxy)quino line as a light brown solid. Data for l, 2 -dihydro-2,2,4-tirethylp7 1-trimethylacetoxy)quino ie: Rf 0.23 (silica gel, hexanes/EtOAc, 1H NMR (400 .555 MHz, CDC13) 7.00 J 8.3, 1 6.28 (dd, J 5.2, 2.3, 1 5.25 1 3.69 1 1.96 J 3 1.32 9 1.26 6 H).

1,-i do7hdoy2,.-rmtygioieTo 70 mL 85% ethanol was added 1,2- 20 dihydro-2,2,4-timethyl7-(1,1,1 -trimethylacetoxy)quinoline (1.03 g, 3.77 mmol) and S NaOH(aq) (3 mL) to give a clear colorless solution. The reaction was followed by TLC (hexanes/EtOAc, After 3 h the resulting purple solution was quenched with sat'd NH4Cl (200 mnL) and extracted with ethyl acetate (2 x 100 mL)Q. The combined organic layers were washed with brine (2 x 75 mL), dried (Na2SO4), and concentrated in vacuc to give a dark purple oil. The oil was dissolved in a minimal amount of hexanes ethyl acetate and ifitered 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 1 ,2-dihydro-7hydroxy-2,2,4trimethylquin line as a dark yellow oil. Data for l, 2 -dihydro-7-hydroxy- 2 2 4 -trimethylquino line: Rf 0.30 (silica gel, hexanes/EtOAc, 3: 1 H NMR (400 MHz, DMSO-d6) 8.90 1 6.70 J 8.2, 1 5.89 J 2.3, 1 5.85 (dd, J 8.3, 2.4, 1 5.65 1 5,04 1 1. 8 J= 1. 1, 3 1. 14 6 H).

HNnk\Kep\spcM97796.STROD RECEPTOR. 19/01/00 DOCKET

NO.

0 l1 6 -0Ol4A.WO 177 l.

2 -Dihydro.224trmethy16-trifluioromethyl8p=anono[5 6 -g]quinoline(Co mpound 238.

structure 57 of Scheme XVII wer R 1

=R

2

R

3 =trifluorMeth.Z=O General Method 9: Preparation -Of Compounds of structure 56 or 57 from phenols. To a solution of 1,-iyr--yrx-,24tintyqioln 1-0.5 M) in absolute EtOH was added a 1-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 ZnCl2 (1-6 equiv). The sealed pressure tube was heated in a oil bath at 80-120 'C for 6-72 h. The cooled solution was diluted with sat'd NH4CI and extracted with ethyl acetate.

10 The combined organics were concentrated on CeliteTM under reduced pressure to give a free 9flowing powder, which was purified by flash column chromatography (silica gel hexanes ethyl acetate, 5: 1) to give the desired product. Further purification could be effected by recrystallization from hexanes toluene.

2 -Dihydro-224.trmethyl6trfuoromethyl8-.panono56gIunle(opnd28 9*99structure 55 of Scheme XVII. where R=R 2

R

3 =trifluoromethvlI Z-O) This compound was prepared by General Method 9 from l,2-dihydro-7-hydroxy.2,2,4.

trmtyln lie(15 g, 8.5 mmol) and ethyl -t,,4-t-uniuoroacetoacetate (3.00 g, 1.

mmol, 2.0 equiv) to afford 1.7 g of Compound 238 as a light yellow powder. Data *99 20 for Compound 238: Rf 0.32 (silica gel, hexanes,'EtOAc, 3: 1 H NMR (400 MHz, C6D6) 7.22 1 6.15 lH), 5.97 1 4.93 1 3.23 (br s, 1 1.66 J 1.1, 3 0.98 6 H).

EXAMPLE 139 1, 2 -Dihydro-2,2,4.trimethyl. I -isocouimarino r4,3:glguino line (Cmpound 239 structure 57 of Schleme XVI. where R 1 H4. R 2 3

Z=O)

This compound was prepared by General Method 8 (EXAMPLE 138) from 7-amidno-3,4benzocoumnarin (structure 56 of Scheme XVI, where R I=H, R 2

=R

3 =benzo, Z=O) (180 m g, 0.85 mmol) to afford 75 mg of Compound 239 along with 150 mg of 1,2diyr-,,-rmty-1-iscuaio[,-qioln as yellow solids. Data for Compound 239: mp 246-248 OC; IH NMR (400 MHz, CDCI3) 8.18 J 7.6, 1 8.16 H:\Pra\KPcMe\59796SROID RECBPTOR.&c I 9/01Voo DOCKET

NO.

016-0014A.Wo 178 J 7.6, 1 7.80 I 7.78 1 7.6, 1 7.43 J 7.6, 1 6.39 1 H), 5.45 1 2.11 3 1.33 6 13 C NMR (100 MHz, CDC13) 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 C19H1 7 N0 2 C, 78.33; H, 5.88; N, 4.81. Found: C, 77.99; H, 5.79; N, 4.72.

EXAMPLE 140 1 2 -Dihydro-2,2,4-trimethylp 1 -isog-uinolono r 4 3 -glgquinoline(Compound 240. structure 57 of Scheme XV where R I=H. R 2 R 3 =benzo.Z=NH) 10 3-ndgLh-~eatrdnn (structure 56 of Scheme XVI. where 1

H

R

2

=R

3 =benzo. Z=NH-) A midxture of 3 -nitro-6(SI1)-phenanthridinone (structure 55 of Scheme XVI, where R 1

R

2

=R

3 =benzo, Z=NH) (480 mg, 1.5 mmol) 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 CehiteTM pad and the filtrate was concentrated to give 0.4 g of the crude 15 aniline as a yellow solid. This material was used without further purification.

1 2 -Dihydro-2.2.4-trirnethyl- 10 Oisoq uino lo n 4 3 -gLguino line (Compound 240. structure 57 of Scheme XVI. where Rl=. IR 2

=R

3 =benzo. Z--NH) This compound was prepared by General Method 8 (EXAMPLE 138) from 3 -amino-6(51f)-phenanthridinone (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; 1IR (KBr, cml) 3300, 3010, 1670, 1450, 1300; 1H NMR (400 MHz, CDC13) 8.28 J 7.6, 1 8.25 J 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 1 2.13 3 1.33 6 13 C NMR (100 MHz, 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,-iydo224[-ermehS8.ioo56-glguinoline-Compound 241 structure 57 of Scheme XVI where 3 mehy.Z=

H

H.NPnka\K-vepCM5977.96S-ROID RECEPTORAdo 19/01/00 DOCKET NO.

016-0014A.WO 179 This compound was prepared by General Method 8 (EXAMPLE 138) from Carbostyril 124 (structure 56 of Scheme XVI, where R 1

=R

2

R

3 =methyl, Z=NH) (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; 1 H NMR (400 MHz, CDC13) 7.24 1 6.34 1 6.23 1 5.37 1 2.41 3 2.04 3 H), 1.29 6 1 3 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 10 -1,2-Dihydro-10-hydroxy-2,2,4-trimethyl- 10H-isochromeno [r43-_lquinoline (Compoun 242, structure 62 of Scheme XVI, where R1=H. R 2

=R

3 =benzo. Z=0) 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 15 with water (1 mL) and extracted with ethyl acetate (2 x 5 mL). Removal of solvent and chromatography of the crude residue (silica gel, 20% ethyl acetate/hexanes) afforded 6 mg of Compound 242 as a colorless oil. Data for Compound 242: 1 H 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 1 5.97 J= 6.5, 1 5.40 20 (br s, 1 5.29 1 2.05 3 1.27 6 H).

EXAMPLE 143 1, 2 -Dihydro-2.2,4,6-tetramethyl- 8 H-pvrano3.

2 -glquinoline (Compound 243. structure 61 of Scheme XVI, where R 1

=R

2 R3=methyl, Z=0) 1, 2 -Dihydro-2,2,4,6-tetramethyl- 8 -pvranono 6 -glquinoline (structure 57 of Scheme XVI where R=R 2

R

3 =methyl, Z=0) To a solution of 7 -nitro-4-methylcoumarin (structure of Scheme XVI, where RI=R 2

R

3 =methyl, Z=0) (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- H\Priyanka\K< p\spcci45977-96.STEROID RECEPTOR.doc 19/01/00 DOCKET

NO.

016-0014A.WO 180 2 2 4 6 -tetramethyl-8-pyranono[5,6-g]quinoline as a yellow solid. Data for 1,2-dihydro- 2,2,4,6-tetramethyl-8-pyranono[5,6-gquinoline: mp 258-260 oC; IR (KBr) 3300, 2955, 1720, 1630, 1505, 1390, 1250; 1 H 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 1 3

C

NMR (100 MHz, CDC13) 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.

1, 2 -Dihydro-22,4,6-tetramethyl-8H-pyrano 3, 2 -glquinoline (Compound 243 structure 61 of Scheme XVI. where R 1

=R

2 =H R 3 =methyl, Z=O) To a solution of 1,2-dihydro- 10 2,2,4,6-tetramethyl-8-pyranono[5,6-g]quinoline (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 -50 0 C 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 15 /ethyl acetate) to afford 1 mg of Compound 243 as a colorless oil. Data for Compound 243: 1 H NMR (400 MHz, acetone-d6) 6.84 1 5.96 1 5.33 J 3.5, 1 5.26 1 5.21 1 4.59 J 3.5, 2 1.96 3 1.93 3 H), 1.24 6 H).

20 EXAMPLE 144 RS)- 1,2,3, 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, 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; 1 H NMR (400 MHz, CDC13) 9.67 (br s, 1 8.45 J 8.0, 1 8.11 J 8.0, 1 7.94 1 7.69 J 8.0, 1 7.41 J 8.0, 1 6.25 1 4.08 (br s, 1 3.02 1 1.81 (dd, J 12.8, 5.2, 1 1.49 J= 12.8, 1 1.46 J 6.7, 3 1.29 3 H) and 1.23 3 H).

H*\Priaanka\Kmp\spee\4597796STEROID RECEPMOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 181 EXAMPLE 145 l.

2 -Dihydro-2,24-trimethyl. 1 O-thioisoguinolono 4 3 -glgquino line (Compound 245. structure of Scem =V.wer 1 H, R 2

=R

3 =benzo, Z=0O) A midxture of Compound 2 4 0 (9 mg, 0.03 mmol) and Lawesson's reagent (41 mg, 0. 1 mmol) in 2 m.L of THF 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: 1H NMR (400 MHz, acetone-d6) 8.93 J 8. 1, 1 8.33 J 8. 1, 1 8.01 1 7.75 J 8. 1, 1 7.44 J 8. 1, 1 6.73 1 5.97 (br s, 1 10 5.51 1 2.15 3 1.35 6H).

0 EXAMPLE 146 -Ttrhy* 22,-tmehl--isoguinolonor4,3- lguinoline (Compound 246.

structure 63 of Scheme XVI. whieeR'H0

R=

3 =enoij0 9 15 This compound was prepared by a HPLC separation of the enantiomners of Compound 244 using a Chiracel OD-R column, using a 4:1 mixture of methanol and water as the mobile 0% phase. The optical purity of Compound 246 was determined by HPLC to be 99% e.e.; [cX]i 2 0 D =+106 (MeOH).

EXAMPLE 147 1,-iyr-,.-rmty-6tilooehl8Mdn

[S.

6 -glguino line (Compound 247.

structure 57 of Scheme W111, where R 1 =R=.R=rfurmtv Z-NH) This compound was prepared as depicted in Scheme XVII and as described below.

l-tert-Butvloxycarbamov3ntrbnee(tutr65o ScmeX I.w rR 1 P=tbutyloxycarbonyl General Method 10. -Boc-Protection of Nitroanilines To a flame-dried 500 mL r.b. flask containing 3 -nitroaniline (structure 64 of Scheme

XVII,

where R 1 Z=NH) (20.0 g, 144.8 mm-ol) in 150 mL THF was added di-tert-butyl dicarbonate (31.60 g, 144.8 mimol, 1.00 equiv), and the mixture was cooled to 0 0 C. 4-NN- Dimethylaminopyridine (19.46 g, 159.3 mmol, 1. 10 equiv) was added portion-wise, and the mixture was allowed to warm to rt overnight. Ethyl acetate (400 mL) was added, and the mixture was washed with IM NaHSO4(aq) (2 x 200 m.L) and brine (200 mL), dried H'\"nkA\-P'aec-577-9.ST ROI RCEPTORAdO 19/01/00 DOCKET

NO.

0l6-0014A.WO 182 (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 9:1) afforded 31.4 g (91 of 1 -tertbuyoxcraol3 ir ezn as a white solid. Data for l-tert-butyloxycarbamoyl-3 nitrobenzene: IH NMR (400 MHz, CDCl3) 8.31 (dd, 18, J 2.2, 2.2, 1H, 7.88 (dd, J 7.9, 1.5, 18, 7.69 (br d, J 7.8, 18, 7.44 (dd, J1 8.3, 8. 1, 18, 6.74 (br s, 1H, NH), 1.54 9H, (CH3)3C0)].

3 -tert-Butvloxycarbamnovlnl (tutr- 6o-cem V~hr~HPt butyloxycarbonyl. Z=NH) To an oven-dried 1-L r.b. flask containing W-ertbutyloxycarbamo yl-3-nitro benzene (20.0 g, 83.9 mmol) in 500 mL 1: 1 ethyl acetate/ethanol at rt was added 10% Pd on C (approx 1 mol%), and the mixture was stirred under an 9. 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-etbtlxcraolnln as a white oily solid. Data for 3 -tert-butyloxycarbamoylaniline: 1 H NMR (400 MHz, CDC13) 7.04 J 8.0, 8.0, 1H, 6.98 (br s, 18, NH), 6.53 (dd, J 7.9, 1.8, 1H, 6.36, (in, 2H, 3.66 (br s, 2H, NH2), 1.51 98, (CH3)3C0)].

7 -tert-Butylo xycarbamo yl- 2 -dihydro224trimethylguino lin (structure 67 of Scheme XVII. whereR P=t-butyloxycarbonyl Z=NH) General Method 11: Skraup Cydlization of te -utyloxycarbamoylanilines To an oven-dried 1 L r.b. flask containing 3 -tert-butyloxycarbamoylaniline (17.4 g, 83.5 mmol), 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 refiux 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 colurm chromatography (silica gel, hexanes/ethyl acetate, gradient elution) afforded 19.9 g of 7 -tert-butyloxycarbamoy12dihydro-22,.

trimethylquinoline 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, CDC13) 6.93 J 8.3, 18, 6.81 (br s, HpVia\Kmv~spc9796.SROID RECEPTOR~c, 19/OIAoO DOCKET NO.

016-0014A.WO 183 1H, HNBoc), 6.34 2H, 5.21 J 0.9, 1H, 3.71 (br s, 1H, NH), 1.94 (d, J 1.0, 3H, 4-CH3), 1.50 9H, (CH3)3CO)], 1.24 6H, 2-(CH3)2].

7-Amino- 1, 2 -dihydro-2,2,4-trimethylquinoline General Method 12: Removal of Boc Protective Group from Compounds of structure 67 of Scheme XVII, where P=tbutyloxycarbonyl, Z=NH) To an oven-dried 25 mL r.b. flask containing 7-tertbutyloxycarbamoyl-l,2-dihydro-2,2,4-trimethylquinoline (400 mg, 1.38 mmol) in 2 mL dichloromethane at 0°C was added trifluoroacetic acid (1.06 mL, 10 equiv), and the mixture was allowed to warm to rt. After 3 h at rt, the reaction mixture was diluted with 50 mL dichloromethane, transferring to a 125 mL erlynmeyer flask, and cooled to 0°C before 10 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 (Na2S04), and concentrated under reduced pressure to afford a light reddish oil. The crude material thus obtained was of greater than 98% purity by 1 H NMR, and was carried on to the next step without further purification. While the 7 -amino-quinoline obtained 15 decomposed appreciably within a few hours upon standing at rt, ethanolic solutions could be stored at -20°C for 2-3 days without substantial adverse effect on the subsequent reaction outcome. Typically however, the material was stored in bulk as the crystalline Boc- •protected amine, and portions were hydrolysed as needed. Data for 7-amino-1,2-dihydro- 2 2 4 -trimethylquinoline: 1H NMR (400 MHz, CDC13) 6.86 J 8.2, 1H, 5.99 (dd, J 8.0, 2.3, 1H, 5.79 J 2.0, 1H, 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-(CH3)2].

1,2-Dihvdro-2.2,4-trimethyl-6-trifluoromethl-8-pvridono f56-g1quinoline (Compound 247, structure 57 of Scheme XVI, where RI=R 2

R

3 =trifluoromethl, Z=NH) General Method 13 Knorr Cyclization of 7-amino- .2-dihydro-2,2.4-trimethylquinolines wth a Keto Ester To an oven-dried 10 mL r.b. flask containing 7-amino-l,2-dihydro-2,2,4trimethylquinoline (100 mg, 0.53 mmol) and ethyl 4 4 4 -trifluoroacetoacetate (85.4 mL, 0.58 mmol, 1.1 equiv) in 2.5 mL absolute ethanol was added ZnC12 (110 mg, 0.81 mmol, equiv) and the mixture was heated to reflux for 3 h. Upon cooling to rt, the reaction mixture was diluted with 40 mL ethyl acetate, and the organic solution was washed with sat'd aqueous NH4C1, dried (Na2SO4), and concentrated under reduced pressure.

H*\"anka\Ktp\sPCeM597796SIMROID RECEPTORmoc 19/ol/oo DOCKET

NO.

016-0014A.WO 184 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: 1 H NMR (400 MHz, CDC13) 11.45 (br s, lH, CONH), 7.38 114, 6.66 lH, 6.27 114, 10-H), 5.42 lH, 4.35 [br s, 114, (CH3)2CNHJ, 2.03 314, 4-CH3), 1.33 614, 2-(CH3)2].

EXAMPLE 148 10 8-Ethoxy- 1, 2 -dihydro-2.2,4-t ethvl-6-tifuoromethyl-pvridonof r6-gluinoline- (Comound 248 structure 71 of Scheme XVII, where R=R 2

R

3 =trffluooehl am uormetyl

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, CDCl3) 7.56 114, J 6.84 1H, 7-H4), 6.74 114, 10-H), 5.52 114, 3-H), 4.47 214, J 7.0, CH3CH2O), 4.12 [br s, 114, (C143)2CNH], 2.09 3H, J 1.3, 4- 0% 0 converted to the 2 -quinolone isomer Compound 247 by heating neat with 10 equiv p- S chiorophenol at 180'C for 3 h, giving Compound 247 in >80% yield.

20 EXAMPLE 149 (RS)-l l 2 6 7 -Tetrah dro6hydrox-224triethyl tffuoro nethl8idoo6gquino e Compound 9 tutr 6 fShm VI.weeRO 2

H

R

3 =rifuormetyl.Z=N This compound was obtained along with Compud 4 n 248 as described above (EXAMPLE 147). Data for Compound 249: IH NMR (400 MHz, DMSO-d6) 10.16 114, CONI!), 7.09 114, 6.61 114, 01H), 6.24 1H, 6.01 114, (CH3)2CNH], 5.21 114, 3-H4), 2.80 and 2.72 (ABq, 214, JAB~ 16.4, 7-H), 1. 86 314, 4-CH3), 1.19 and 1. 17 [2s, 2 x 314, 2-(CH3)2]. 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.

HJVMnkcp c97796S MROD RECEPTOR. ig/ljoo DOCKET

NO.

0 1 6-0014A.WO 185 EXAMPLE 150 (RIS- 1, 2 3 4 -Tetrahydro -2,2,4-timethylI 6-trfl u oro methy-8-P 3alo no [5 6 -glq uino line (Compound 250, structure 63 of Scheme XVIRI where R 1

=R

2

R

3 =trfuoo tyl.

Z=O)

1 2 3 4 -Tetrahydro-2,2,4-trimethyp7- (I 1 .1 -trimethylacetoxy)quino line (structure 72 of Scheme XVIII. where R 1 P t-butil, Z=O) In a dry r.b. flask equipped with a magnetic stir bar was suspended l, 2 -dihydro-2,2,4- iethyl-7-( 1,1,1 trimethylacetoxy)quino line (structure 67 of Scheme XVIII, where Rl=H, P~t-butyl,

Z=O;

EXAMPLE 138) (1.01 g, 3.37 mmol) and 10% Pd/C (200 mg) in CH2Cl2. The flask was 10 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 :0vacuo to afford 996 mg offI) ,,,-erhdo224tiehl7(,1 *:trimethylacetoxy)quino line as a light brownish-red solid. Data for (R/S)-l,2,3,4-tetrahyrotiehlctx~un ie IH NMR (400 MHz, CDC13) 7.10 (dd, J= 8.5, 0.9, 1H), 6.30 (dd, J= 8.4, 2.4, 1H), 6.13 J= 2.2,1 H, 3.62 (br s, 1H), CC** 2.87 (ni,1H), 1.71 (dd, J= 13, 5.4, 1 1.41 (apparent t, J= 13, 1H), 1.31 (in,10 H), 1. 22 3 1. 16 3 H).

too* (RIS)- l., 2 3 4 -Tetrahydo-7..hydroxy22A-trimethylq uino line This compound was 20 prepared as described above for 1,-iyr--yrx-,,-rmtyqioln (EXAMPLE 138) from (RS-,,,-erhdr-,,-rmty -11.

trimethylacetoxy)quino line (230 mg, 0.845 mmol) to afford (R/S)-l,2,3,4-tetrahydro.7hydroxy-2,2,4-thnethylquinoline, which was used in the following reaction without further purification.

(RIS)- l.

2 3 4 -Tetrahydro224trimethy16trflu oromethyl1 8 -pyin [5 6-glquino line (Compound 250 structure 63 of Sche-me XVIRI where R =R 2

R

3 trifluoromethyl, Z=Q) This compound was prepared by General Method 9 (EXAMPLE 138) from crude (RIS)- l, 2 3 4 tetrahydro7hydroxy224trimethylqo in and ethyl 4,4,4trifluoroacetoacetate (310 mg, 1. 69 mmol1, 2 equiv) to afford 160 mg (61 overall) of Compound 250 as a yellow solid. Data for Compound 250: Rf 0.4 (hex/EtOAc, 3: 1

H

NMR (400 MHz, CDCI3) 7.41 1 6.37 1 6.33 1 4.46 I 2.92 1 H-\ankKmP\~cI9796-STROID RECEPTORAOC 19/01/00 DOCKET NO.

016-0014A.WO 186 1.80 (dd, J 13, 5.0, 1 1.42 (dd, J 13, 13, 1 1.38 (d,J 6.0, 3 1.31 3 1.25 3 H).

EXAMPLE 151 1, 2 -Dihvdro-2.2,4-trimethyl-6-trifluoromethvl-8-thiopvranono r5.

6 -glauino line (Compound 251, structure 58 of Scheme XVI, where R 1

=R

2

R

3 =trifluoromethyl, Z=O) 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 10 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 Compound 251: Rf 0.36 (silica gel, hex/EtOAc, 1H NMR (400 MHz, acetone-d6) 7.25 1 4.03 1 6.89 (br s, 1 6.53 1 5.62 1 2.77 J 1.1, 3 1.39 6 H).

EXAMPLE 152 IS)- 1,2,3,4-Tetrahydro-2,24-trimethvl-6-trifluoromethl- 8-thiopvranono r5,6-glquinoline (Compound 252. structure 76 of Scheme XIX, where R=R 2

R

3 =trifluoromethvl. Z=) In a dry pressure tube equipped with a magnetic stir bar was dissolved Compound 250 20 (EXAMPLE 150) (26 mg, 0.0836 mmol) and Lawesson's reagent (60 mg, 0.41 mmol, 6 0 equiv) in 15 mL toluene. The resulting solution was heated at 100°C for 20 h. The cooled solution was concentrated on Celite T M to give a free flowing powder which was purified by flash column chromotography (silica gel, hexanes/EtOAc, 5:1) to afford 19.2 mg of Compound 252 as a bright orange solid. Data for Compound 252: Rf 0.37 (silica gel, hex/EtOAc, 1 H NMR (400 MHz, CDC13) 7.43 1 7.16 1 6.45 1 H), 4.59 (br s, 1 2.93 1 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).

H:\Priyaaa\Kmpopec\e597796smoiD RECEPTORdc 19/01/00 DOCKET NO.

016-0014A.WO 187 EXAMPLE 153 6-Chioro (difluoro)methyl- 1 2 -dihydro-2,2,4-trimethyl- 8 -pyranono [5 .6-glguinoline (Comound253.strutur 57 of Scheme XVII. where R l=R 2

=H

R

3 =chlorodifluoromethyl.

Z=O)

This compound was prepared by General Method 9 (EXAMPLE 138) from 1,2-dihydro-7hydroxy- 2 ,2,4-trimethylquinoline (EXAMPLE 138) (71 mg, 0.37 mimol) and methyl 4chloro- 4 4 -djfluoroacetoacetate (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: IH NMR (400 MHz, CDCI3) 7.40 1 6.33 1 6.31 1 5.41 1 H), .0 10 4.42 (br s, 1 2.02 3 1.36 6 H).

EXAMPLE 154 Acetyl- l.

2 -dihydro -2.2.4-trimethy1&_6trifluoromethyl 8- pyridono [5, 6 -91 quino line (Comp~ound 254. structuire 59( of Shm V.weeR- 2 H 3 tilooehl

R

4 =acetyl. Z=N) To an oven-dried 10-mi. r.b. flask containing Compound 247 (15 mg, 0.049 mmol) in 1 ML dichloromethane at rt was added acetic anhydride 10 ML, 1. lrnmol) and 4-NN- .dimethylaminopyridine (6.5 mg, 0.054 mmol, 1. 1 equiv), and the mnixture was stirred min. Dichloromethane (20 mi.) was added, and the solution was washed with IM pH 7 potassium phosphate buffer, dried (Na2S 04), 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: IH NMR (400 MHz, CDC13) 7.66 lH, 7.08 JH, 6.83 (s, lH, 10-H), 5.63 lH, 4.31 [br s, 1H, (CH3)2CNH-], 2.38 3H, CH3CON), 2.12 (s, 3H, 4-C113), 1.48 6H, 2-(CH3)2].

EXAMPLE 155 1 .2-Dihydro-2,2A4 1 0-tetramethyl-6-trifluoromethyl 8-Vyridono r5,6- giguino line (Compound 255 structure 57 of Sche-me XVIE[ where R=methylI

R

2 =H R 3 =trilooehy.Z N 6 -tert-Butvloxycarbamol2nitrotoluene (structure 65 of Scheme XVII. where Rlmethvl.

P=t-butyloxycrn.n Z=NHP) This intermediate was prepared from 2 -methyl-3-nitro aniline H.IPr~nk\Kcp\specM5977-96.SIROD RECEPTOR-doe 19/01/00 DOCKET

NO.

0 16-00 14A.WO 188 (5.00 g, 32.8 mrnol) by General Method 10 (EXAMPLE 147), affording 7.44 g of 6tert-butyloxycarbamoyp2-nitrotoluene as an off-white solid. Data for 6-tertbutyloxycarbamoyl-2-nitrotoluene: 1 H NMR (400 MHz, CDCl3) 7.98 (br d, J 8.0, 1H, 7.51 (br d, J 8. 1, lH, 7.28 (dd, J 7.6, 3.4, 1H, 6.58 (br s, 1H, NH), 2.34 3H, I1-CH3), 1.53 9H, (CH3)3C0)].

2 -Amiino- 6 -tert-butvloxycarbamoyltoluene (sructure 66 of Scheme XVII. where Rl=methyl. P=t-butyloxycarbonyl, Z=NH) This compound was prepared from 6-tertbutyloxycarbamoyl-2nitrotoluene (4.60 g, 18.2 mmol) in a manner similar to that described for 3 -tert-butyloxycarbamoylaniline (EXAMPLE 147), affording 4.00 g of 2-amino- 6 -tert-butyloxycarbamoyltoluene as a colorless oil. Data for 2 -amidno-6-tertbutyloxycarbamoyltoluene: IH NMR (400 MHz, CDCl3) 7.04 (br d of ABq, JAB~ JA= 0, .JB 7.9, 2H, 6.49 J 8.3, 1H. 6.26 (br s, 1 H, NH), 3.61 (br s, 2H, NH2), 2.02 3H, 1-CH3), 1.51 9H, (CH3)3C0)].

7 -tert-Butyloxycarbamo yl- l.

2 -dihydro-2.2,4 8-tetramethylquinoinje structure 67 of Scheme XVII. where R=methvl, P=t-butyjoxcarbonI. Z=NH) This compound was prepared from 2 -ami no- 6 -tert-butyloxycarbamoyltoluene (4.00 g, 18.0 mmol) according to General Method 11I (EXAMPLE 147), affording 4.56 g of 7 -tert-butyloxycarbamoylb 20 l, 2 -dihydro- 2 ,2,4,8-tetramethylquinoline as a white solid. Data for 7-tertbutylo xycarbamo yl- 1 ,2-dihydro-2,2,4, 8 -tetramethylquino line: 1 H NMR (400 MHz, CDCI3) 6.94 and 6.88 (br ABq, JABi 8.3, 2H, 6.16 (br s, IH, HNBoc), 5.27 (s, lH, 3.61 (br s, 1H, (CH3)2CNII]) 2.04 3H, 8-CH3), 1.97 3H, 4-CH3), 1.50 (s, 9H, (CH3)3C0)j, 1.28 6H, 2-(CH3)2).

7- Amino- 1, 2 -dihvdro-2.2,4,8-tetramethy~guinoline This compound was prepared by General Method 12 (EXAMPLE 147) from 7 -tert-butyloxycarbamoyl. 1 ,2-dihydro-2,2,4, 8tetramethylquino line (400 mg, 1.32 mmol) affording 267 mg (quant) of 7-amino-1,2d ihydro-2,2,4,8-tetramethylquino line as a light reddish oil. Data for 7-amino- 1 ,2-dihydro- 2 2 4 8 -tetramethylquino line: IH NMR (400 MHz, CDCI3) 6.82 J 8.2, 1H, HN\"nka'Kop'pcm5977-96.STROID RECEPTORdoc 19/01/00 DOCKET NO.

0 16-0014A.WO 189 6.08 J= 8. 1, 1H, 5.15 J= 1.2, 1H, 3.56 (br s, 3H, NH2, NH), 1.95 J 1.2, 3H, 4-CH3), 1.91 3H, 8-CH3), 1.27 6H, 2-(CH3)2].

1 .2-Dihydro-2,2,4. 1 O-tetramethvl-6-trifluoromethyl- 8-pyridonof [56-giguino tine (Compound 255, structure 57 of Scheme XVII. where Rl=methvl, R 2

R

3 =trifluoromethyl, Z=NH) This compound was prepared by General Method 13 (EXAMPLE 147) from 7-amino-1,2dihydro -2,2,4,8-tetramethylquino line (100 mg, 0.49 mrnol) and ethyl 4,4,4trifluoroacetoacetate (107 mL, 0.73 mmol, 1.5 equiv) affording 75 mg of Compound 255 as a fluorescent-yellow solid. Data for Compound 255: 1H NMR (400 MHz, CDCl3) 10 9.23 (br s, 1H, CONH), 7.37 1H, 6.67 1H, 5.45 lH, 4.14 [br s, 1H, (CH3)2CNH], 2.12 3H, l0-CH3), 2.04 J= 1.1, 3H, 4-CH3), 1.37 Es, 6H, 2- (CH3)21.EXAMPLE 1 .2-Dihydro-2,2.4-trirnethyl-6-( 1.1 2 2 2 -12entafluoroethyl)-8-pyranono [5.6-giguino line 15 (Comound 256, structure 57 of Scheme XVII. where R 1

=R

2

R

3 =p2entafluoroethvl.

Z=O) This compound was prepared by General Method 9 (EXAMPLE 138) from 1,2- 0% 0 dihydro-7- hydroxy-2,2,4-trimethylquino line (EXAMPLE 138) (67 mg, 0.35 mmol) and 99999ethyl 4,4,5,5,5- pentafluoropropionylacetate (179 mg, 0.76 mmol, 2.2 equiv) to afford 11.8 mg (10 of Compound 256 as a light yellow solid. Data for Compound 256: 1 H NMR 20 (400 MHz, CDC13) 7.31 1 6.35 1 6.33 1 5.40 1 4.54 1 H), 1.99 J 1. 1, 3 1.35 6 H).

EXAMPLE 157 (R/S)-6-Chloro(difluoro)methyl- 1 2 3 4 -tetrahydro-2.2.4-trirethyl-8-pyranono [5.6glguinoline (Compound 257. structure 63 of Scheme XVIII. where R=R 2

=H.

R

3 =chlorodifluoromethyl, Z=O) This compound was prepared by General Method 9 (EXAMPLE 138) from (RIS)- 1,2,3 4 -tetrahydro-7-hydroxy-2,2,4- trimethylquinoijne (EXAMPLE 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 light yellow solid.Data for Compound 257: Rf 0.37 (hex/EtOAc, 3: IH NMR (400 MHz, CDC13) H:*\Pnka\K~p\spvMS977-96.SrROD RECEPTflR.doc 19/01/00 DOCKET NO.

0 16-00 14A.WO 190 7.55 1 6.36 1 6.32 1 4.53 (br s, 1 2.95 (in, 1 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-Chioro- 1 2 -dihydro 2 ,24-trimethyl16-trifluoromethyl 8-p yrano no [5,6-glgquino line (Compound 258. -structure 57 of Scheme XVII. where R 1 I R 2 =Cl. R 3 =trifluoromethyl, Z=O) This compound was prepared by General Method 9 (EXAMPLE 138) from 1,2dihydro -7-hydroxy- 2,2,4-timethylquino line (EXAMPLE 138) (78 mng, 0.41 inmol) and ethyl 2 -chloro- 4 ,4,4-trifluoroaceto acetate (195 mg, 0.898 inmol, 2.2 equiv) to afford 7.2 mg 10 of Compound 258 as a red solid. Data for Compound 258: Rf 0.33 (hex/EtOAc, 3: IH NMR (400 MHz, CDC13) 7.37 1 6.32 1 5.42 1 4.54 (br s, 1 2.01 J 1.0, 3 1.31 6 H).

EXAMPLE 159 15 (RLS-7-Chloro1 [34ttayr-,.4tiehl6tilormty--vao 5.6glguinoline (Compound 259. structure 63 of Scheme XVIRI where R 1

R

2 =Cl.

R

3 =trifluoromethyl, Z=O) This compound was prepared by General Method 9 (EXAMPLE *138) from (RIS) -1,2,3 4 -tetrahydro-7-hydroxy-2,2,4-tri ethylquinoline (EXAMPLE 150) (57 mg 0.29 inm-ol) and ethyl 2 -chloro- 4 ,4,4-trifiuoroacetoacetate (140 mg, 0.645 inmol, 2.2 equiv) to afford 6.8 mg of Compound 259 as a yellow solid. Data for Compound 259: Rf 0.35 (hex/EtOAc, 3: 1 H NMR (400 MHz, CDC13) 7.53 1 6.32 1 4.51 (br s, 1 2.93 1 1.81 (dd, J 13, 3.7, 1 1.44 (apparent t, J 13, 3 1.31 3 1.25 3 H).

EXAMPLE 160 1, 2 3 4 -Tetrahydro-22.4trmiethyl6trfuoromethy8ppidono g] uino line (Comnpound 260. structure 63 of Scheme XVIII. where R=R 2

R

3 =trifluoronethyl, Z=NI1) 7 -tert-Butyloxycarbamo yl- 1. 23.

4 -tetrahydro-2 trimethylguino line (structure 72 of Scheme XVII where R=H. P=t-butloxcarbonyl, Z=NII) To an oven-dried 100 mL round-bottomed flask containing 7 -tert-butyloxycarbamoyl- 1,2-dihydro-2,2,4- H:Prik\KooppecM97796.SnROD RECEPTORdoc 19/01/00 DOCKET NO.

0 16-001 4A.WO 191 trimethylquino 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 H12 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-22,4trimethylquino line as a white oily solid. Data for (RIS)-7-tert-butylo xycarbamoyl- l, 2 3 4 -tetrahydro-2,2,4..timethylquino line: IH NMR (400 MHz, CDC13) 7.02 J 8.7, 1H, 6.73 (br s, 1H, HNBoc), 6.39 (dd, J 8.3, 2.2, 1H, 6.29 (br s, 1H, 3.62 (br s, 1H, NH), 2.85 (ddq, J 12.5, 12.3, 6.4, 1H, 1.70 and 1.39 [d of ABq, JAB 12.8, JA 5.5 Hz 3 -Hequiv),

JI

3 12.6 Hz (3- 10 Hax)2H], 1.49 9H, (CH3)3C0)], 1.29 J 6.7, 3H, 4-CH3), 1.21 3H, 2-CHA) 1-14 3H, 2-CH 3 R/S')-7-Amino- 1 l 2 3 4 -tetrah ydro-2 .4trimeth yjquino line This compound was prepared by General Method 12 (EXAMPLE 147) from 7 -tert-butyloxycarbamoyl23,4- 15 tetrahydro-2,2,4t.rnethylquinoline (150 mg, 0.51 mmol) to afford 98 mg (quant) of (RIS)- 7 -amino- 1,2,3,4tetrahyro-224t.imethylquinoline as a light reddish oil. Data for 7amino-1l 2 ,3,4tetrahydro224timethylquino~ lie H NMR (400 MHz, CDC13) 6.92 (dd, J 8.0, 0.8, IH, 6.02 (dd, J 8.2, 2.3, 1H, 5.77 J 2.3, 1H, 3.39 (br s, 3H, NH2, NHl), 2.81 (ddq, J 12.6, 12.3, 6.4, IH, 1.68 and 1.38 [d of ABq, JAB 20 12.8, JA 5.5 Hz 3 -Hequiv), JB 12.5 Hz (3-Hax)2H], 1.26 J 6.7, 3H, 4-CH3), 1. 19 3H, 2-CHA) 1.14 3H, 2-CH 3 1.

2 3 4 -Tetrahydro2 24.mthYItrifleth1mthyl- 8 3idn r56-gjquino line (Copoud 2 0, trutue 63 of Scheme XVIUI where _R 2 HR-rfurm Z=NHj This compound was prepared by General Method 13 (EXAMPLE 147) from (R/S)-7-amino- l, 2 3 4 -tetrahydro-2,2,4-trimethylquino line (98 mg, 0.51 mmol) and ethyl 4 4 ,4-trifluoroaceto acetate (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, CDC13) 11.32 (br s, 1H, CONH), 7.50 1H, 6.64 1H, 6.41 1H, 10-H), 4.55 [br s, 1H, (CH3)2CNH], 2.91 (ddq, J 12.6, 12.4, 6.3, 1H, 1.76 and 1.41 H:'\PriYanka\Kcp\pcM\597-7.96.SThROID RECEPTOR.do, 19/01/00 DOCKET NO.

016-0014A.WO 192 [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 .1,2-Dihydro-2,2,4, 9 -tetramethyl-6-trifluoromethvl-8-pridono 5.6-gquinoline (Compound 261, structure 57 of Scheme XVI. where Rl=R 2

R

3 =trifluoromethvl.

Z=NCH

3 To an oven-dried 50-mL r.b. flask containing Compound 247 (500.0 mg, 1.62 mmol) in mL THF at 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 10 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 15 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)21.

20 EXAMPLE 162 2 -Dihydro-2,2,4-trimethyl-8-trifluoromethyl-6-pyridono[5,6-glquinoline (Compound 262, structure 70 of Scheme XVII, where R 1

=R

2

R

3 =trifluoromethyl, 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 HNan"\K-P\3pwM597796.SER)O RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 193 Compound 262 as a fluorescent- yellow solid. Data for Compound 262: 1H NMR (400 MHz, CDC13) 10.50 (br s, 1H, C=CCF3N~H, 7.33 1H, 6.62 1H, 6.17 (s, 1H, 10-H), 5.33 1H, 4.21 [br s, 1H, (CH3)2CNH], 2.04 3H, 4-CH3), 1.36 [s, 6H, 2-(CH3)2].

EXAMPLE 163 6- [Dichloro (ethoxy)methyl]- -1.

2 -dihydro-2,2.4-trimethyl-8-pyranono r5,6-glguino line (Compound,263. structure 57 of Scheme XvII. whr- 1

R

2

H

R

3 =dichloro(ethoxy)methyl,

Z=O)

10 This compound was prepared by General Method 9 (EXAMPLE 138) from 1,2-dihydro-7hydroxy-2,2,4-trim-ethylquinoline (EXAMPLE 138) (67 mg, 0.35 mmol) and ethyl 4,4,4trichioroaceto acetate (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, 3: IH NMR (400 MHz, CDC13) 7.97 1 6.51 1 6.32 1 4.42 J 7.2, 2 2.92 (in, 1 1.79 (dd, J= 13, 5. 1,1 1.40 (in,4 4 1.38 J= 6.6, 3 1.30 3 H), 1.25 3 H).

EXAMPLE 164 9 ~5-(3-Furyl- l.-dihydro- 2 .2,4-trirnethyl-8pyranono [5,6-giguno ~e (Com-poud24 20 structure 57 of Scheme XVII. whra 1 R=H 3 3 ryl, Z=O) This compound was prepared by General Method 9 (EXAMPLE 138) from 1 ,2-dihydro-7hydroxy- 2,2,4-trinethylquino line (EXAMPLE 138) (120 mng, 0.62 inmol) and ethyl B-oxo- 3 -furanpropionate (227 mg, 1.25 minol, 2 equiv) to afford 6.4 mg of Compound 264 as a light yellow solid. Data for Compound 264: Rf 0.30 (hex/EtOAc, 3: IH NMR (400 MHz, CDCI3) 7.76 1 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 1 4.34 1 1.95 J 1. 1, 3 1.34 6

H).

EXAMPLE 165 1 .2-Dihydro- 1.

2 2 4 -tetramethyl-6-trifluoromethy1 8-pyanono 5s 6-giinlne Comon 265. structure 60 of Scheme XVI. whre R=R 2

=R

5

R

3 =trifluoromethvl.

Z=O)

ka\KepNp~ci49796.STROID RECEPTOR4OC 19/01/00 DOCKET

NO.

01 6 -0014A.WO 194 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 mL). To this bright yellow solution was added NaCNBH3 (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 mL of 20% NaOH(aq). The reaction mixture was slowly poured over 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 (hex/EtOAc, 1H NMR (400 MHz, CDC13) 7.20 J 1.8, 1 6.36 2 5.36 J 1.0, 1 2.88 3 H), 10 2.00 J= 1.1, 3 1.39 6 H).

EXAMPLE 166 ,2-Dihvdro--trifluorometh ,2,4-trimetl--thiopvrn-8-onof5,6-g1 quinoline (Compound 266, structure 57 of Scheme XVII where RI=R 2

R

3 =trifluoromethvl 3 -Amino-S-t-butvloxvcarbonyl thiophenol (structure 66 of Scheme XVII, where R=H, .:P=t-butyloxycarbonyl 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 dichloromethane at 0 0 C was added dropwise, triethylamine (557 mL, 4.0 mmol). When the addition was complete, the 20 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 (2x10 mL), dried (Na2SO4) 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 -amino-S-t-butyloxycarbonyl thiophenol as a clear oil. Data for 3 -amino-S-t-butyloxycarbonyl thiophenol: 1 H NMR (400 MHz, CDC13) 7.12 (apparent t, J 8.2, 1H), 6.90 J 8.2, 1H), 6.84 J 2.2, 1H), 6.68 (dd, J 8.2, 2.2, 1H), 3.68 (br s, 2H), 1.56 9H).

7 -t-Butyloxycarbonylthio_ 1 2 -dihydro2,2,4trimethylquinoine (structure 67 of Scheme XVII where RI=H. P=t-butyloxycarbonyl Z=S) This compound was prepared by General Method 13 (EXAMPLE 147) from 3 -amino-S-t-butyloxycarbonyl thiophenol (274 mg, 1.2 H.VM'nka\Ko-P\specM59Th9 6 STEROID RECEP~FR.c 19/01/00 DOCKET

NO.

016-0014A.WO 195 mmol) to afford 148 mg of 7 -t-butyloxycarbonylthio-1,2-dihydro-2,2,4trimethylquinoline as a yellowish oil. Data for 7 -t-butyloxycarbonylthio-1,2-dihydro-2,2,4trimethylquinoline: 1 H NMR (400 MHz, CDC13) 7.02 J 7.9, 1H), 6.74 (dd, J 7.9, 1.6, 1H), 6.57 J 1.6, 1iH), 5.31 1H), 3.73 (br s, 1H), 1.95 3H), 1.50 9H), 1.26 6H).

I 2-Dihydro-6-trifluoromethyl -2,2,4-tri iopan-8-ono r5.6-g quinoline (Compound 266. structure 57 of Scheme XVII. where R 1

=R

2 =H R 3 =trifluoromethyl, Z=S) Trifluoroacetic acid (744 mL, 0.0096 mol) was added all at once via a syringe to a 10 solution of 7-t-butyloxycarbonylthio-1,2-dihydro-2,2,4-trimethylquinoline (0.14 g) in 1 mL *of dry dichloromethane at 0 After 10 min the ice bath was removed and the mixture was allowed to stir at rt for 45 minutes. It was then cooled to 0 OC and neutralized with sat'd NaHCO3, extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with water (10 mL), dried (Na2SO4) 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 I ethanol was heated in a sealed tube for 16 h at 80 The reaction was quenched with sat'd NH4C1 (2 mL) and extracted with ethyl acetate (2 x 5 mL), dried (Na2SO4) and concentrated in vacuo to an orange solid residue that was subjected to flash 20 chromatography (silica gel, hexanes/ethyl acetate, followed by preparative TLC (500 hexanes/ethyl acetate, 7:3) to afford 2.2 mg of Compound 266 as a yellow oil.

Data for Compound 266: 1 H NMR (400 MHz, CDC13) 7.54 1H), 6.62 1H), 6.43 (s, 1H), 5.44 1H), 4.32 (br s, 1H), 2.03 3H), 1.29 6H).

EXAMPLE 167 S2-Dihydro-l,2,2, 4 9 -pentamethyl-6trifluoromethyl-8-pyridonor56-glquinoline (Copound 267. structure 60 of Scheme XVI, where R 1

=R

2

=R

5

R

3 =trifluoromethvL Z=N-methyl) 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 H:.%Piyanka ep\prcM597796STROID RECEPTOR.do 19/I1/00 DOCKET

NO.

016-0014A.WO 196 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 NII4C1, 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 111 mg (8 of Compound 267 as a bright fluorescent-yellow solid. Data for Compound 267: 1 H NMR (400 MHz, CDCl3) 7.37 lH, 6.74 (s, lH, 6.21 lH, 10-H), 5.38 LH, 3.69 3H, CONCH3], 2.94 3H, (CH3)2CNCH3], 2.03 3H, 4-CH3), 1.40 6H, 2-(CH3)2].

000.0: 10 EXAMPLE 168 7-Chioro- 1.2dhdo224tiehl6tilooehl pjdn [5,6-glquino line 9999 (Compound 268, structure 57 of Scheme XVII. where R I R 2 =Cl. R 3 =trifluoromethyl.

This compound was prepared by General Method 13 (EXAMPLE 147) from 7-amino-1,2dihydro-2,2,4-triniethylquino line (EXAMPLE 147) (64 mg, 0.34 mmol) and ethyl 2-chioro- 4 4 4 -trffluoroacetoacetate (147 mg, 0.68 mmol, 2.0 equiv) to afford 36 mg (3 of Compound 268 as a fluorescent-yellow solid. Data for Compound 268: 1H NMR (400 9 MHz, CDCl3) 7.52 1H, 6.31 1H, 10-H), 5.43 IH, 4.47 [br s, 1H, (CH3)2CNH], 2.03 3H, 4-CH3), 1.33 6H, 2-(CH3)2].

0 EXAMPLE 169 6 -Chloro(difluoro)methyl- 1, 2 -dihydro-2,2,4-trimethyp8-pyridono [5.6-giquino line (Compound 269, structure 57 of Scheme XVII. where R 1

=R

2

=H,

R

3 =chloro(difluoromethyl). Z-7H) This compound was prepared by General Method 13 (EXAMPLE 147) from 7-amino-l1,2dihydro -2,2,4-trirnethylquino line (EXAMPLE 147) (60 mg, 0.33 mm-ol) and methyl 4chloro- 4 4 -djfluoroacetoacetate (92 mg, 0.49 mmol, 1.5 equiv) to afford 17 mg of Compound 269 as a fluorescent- yellow solid. Data for Compound 269: 1 H NMR (400 MHz, CDCI3) 12.50 (br s, 1H, CONK'), 7.52 1H, 6.62 1H, 6.39 1H, 10-H), 5.42 1H, 4.48 [br s, IH, (CH3)2CNIHj, 2.04 J 3H, 4-CH3), 1.31 6H, 2-(CH3)2].

H'.PriYank\K=ep\sPecM5977-96.STERorD RECEPTOR.&~c 19101foo DOCKET NO.

016-0014A.WO 197 EXAMPLE 170 8-Cvano-1, 2 -dihydro-2,2,4-trimethylindeno[3.2-elquinoline (Compound 270. structure 16 of Scheme IV. where R 2 4

R

6 H. R 5 =cvano. X=CH) 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 10 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 Ssaturated 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 15 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: 1 H NMR (400 MHz, acetone-d6) 7.77 J 7.9, 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)- 1.

2 -dihydro-2.2,4-trimethylquinoline (Compound 271.

structure 4 of Scheme II, where R 1 To a 1 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 HPrtyank\Kp\pcM497796.SThROID RECEPOR.doc 19/01/00 DOCKET

NO.

016-0014A.WO 198 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 ammonium hydroxide (200 mL) followed by saturated ammonium 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 (Na2SO4). 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 1 7.73 (dd, J 8.4, 1.9, 1 7.65 (dd, J 8.5, 2.0, 1 H).

6 3 -Cyano-5-fluorophenyl)- 1, 2 -dihydro-2,2,4-trimethylquinoline (Compound 271 structure 4 of Scheme II, where Rl=3-cvano-5-fluorophenyl. This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (46.3 mg, 0.14 S mmol) and 3 -bromo-5-fluorobenzonitrile (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 MHz, acetone-d6) 7.83 (app t, J 1.3, 1 7.68 (dd, J 10.6, 4.0, 1 7.43 J 2.0, 1 7.41 (dd, J 2.2, 1.2 1H) 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 -Cvano-4-fluorophenvl)- 1, 2 -dihvdro-2.2.4-trimethylquinoline (Compound 272 structure 4 of Scheme II, where R 1 3 -cvano-4-fluorophenyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (53.8 mg, 0.17 mmoles) 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 mL/min) to afford 3.3 mg of Compound 272. Data for Compound 272: 1 H NMR (400 MHz, acetone-d6) 7.97 (dd, J 6.1, 2.2, 1 7.93 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 1 5.34 1 2.08 3 1.28 6 H).

H\anka\K-P\.speo\M597g6SThROID RECEPTORdoc 19/01/00 DOCKET NO.

016-0014A.WO 199 EXAMPLE 173 6 3 -Cyano-6-fluorophen-yl)-1l.

2 -dihydro-2,2,4.trimethylu ino line (Compound 273.

structure 4 of Scheme LI. wher R 1 =3-cano-r-fluornphen1 This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (70.0 mg, 0.22 mmol) and 3 -bromo-4-fluorobenzonitrile (44.1 mg, 0.22 mmol). The crude material was purified by HPLC (reverse phase ODS column, methanol/water, 3.0 rnL/midn) to afford 3.3 mg of Compound 273. Data for Compound 273: IH NMR (400 MHz, acetone-d6) 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 7.21 (mn, 1 6.58 J 8.2, 1 5.48 (s, 10 1 5.37 1 2.04 3 1.29 6 H).

.:EXAMPLE 174 6- [5-fluoro- 3 (trifluoromethyl)12heny!L -1 2 -dihydro-2,2.4-timethylguino line (Compound 274.strctue 4of chee where R'=5-fluoro-3(trifluoromethl)p2henyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (42.8 mg, 0. 13 mmol) and 3 -bromo-5-fluorobenzotijfluoride (32.7 mng, 0. 13 mmol). The crude material was purified by HPLC (reverse phase ODS column, methanol/water, 3.0 miL/min) to afford 3.1 mg of Compound 274. Data for Compound 274: 1 H NMR (400 MHz, acetone-d6) 7.71 1 7.63 J 10.5. 1 H), 7.40 J 2.2, 1 7.34 (dd, J 8.1, 2.0, 1 7.29 J 8.6, 1 6.59 J 8.3, 1 5.50 1 5.39 I 2.05 3 1.29 6 H).

EXAMPLE 175 6 3 -chloro-2-inethylphenyl)- 2 -dihydro-224triethluinouline Cofpound 275.

structure 4 f Scheme I.where R=-cloro-2-methYlphenyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (70.0 ing, 0.22 mrnol) and 2 -broino-6-chlorotoluene (45.2 mg, 0.22 rnrol).

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: IH NMR (400 MHz, acetone-d6) 7.30 (d,J 8.3, 1 7.16 (mn, 1 6.95 1 H), H.\ankA\Kcp\pc'\59h96.STEROID RECEPTORdoc 19/01/00 DOCKET NO.

016-0014A.WO 200 6.87 J 10.2, 1 6.54 J 8.0, 1 5.36 1 5.25 1 2.03 3 1.28 6 H).

EXAMPLE 176 2 -Dihydro-2,2,4-trimethvl-6-(3-nitrophenvl)quinoline (Compound 276. structure 4 of Scheme II, where R 1 =3-nitrophenvl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (19.4 mg, 0.06 mmol) and 3 -nitrobromobenzene (12.3 mg, 0.06 mmol). The crude material was purified by flash column chromatography (75 ml silica, hexane to 10 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 J 15.9, 8.0, 1 7.40 J 2.1, 1 7.34 (dd, 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 -(3-Acetvlphenv)- 2 -dihydro-2.2,4-trimethvlquinoline (Compound 277. structure 4 of Scheme I, where R 1 =3-acetylphenvl This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (66.2 mg, 0.21 mmol) and 3-bromoacetophenone (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 mL 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: 1 H NMR (400 MHz, acetone-d6) 8.13 1 7.81 1 7.50 J= 15.0, 7.8, 1 7.33 2 6.59 J= 8.1, 1 5.38 1 5.32 1 2.62 3 2.08 3 1.28 6 H).

EXAMPLE 178 6 3 -cyano-2-methylphenvl) -1.

2 -dihvdro-2.2,4-trimethvlquinoline (Compound 278.

structure 4 of Scheme II, where R=3-cvano-2-methylphenyl) HIriyanLka\K-p\spoM5977.96.SEROID RECEPTOR.doc 19/01/00 DOCKET NO.

016-00 14A.WO 201 3 -Bromo-2-methylbenzonitrile. This compound was prepared in a manner similar to that described for 3 -bromo-5-fluorobenzonitrile from commercially available 2,6dibromotoluene (1 .80 g, 7.20 mmol), DMF (11 mL), pyridine (1.1I mL), and copper (1) cyanide (0.52 g, 5.76 mrnol). The crude product was purified by flash column chromatography (100 rnL silica, hexane) to afford 50 mg (35 of 3-bromo-2methylbenzonitrile. Data for 3 -bromo-2-methylbenzonitrile: 1 H NMR (400 MHz, acetone-d6) 7.88 J 1 7.73 J 8.0, 1 7.32 J 15.8, 7.9, 1 2.58 (s, 3H).

10 6 3 -cyano-2-methylphenyl) l.

2 -dihdro-224-triMethylguinoline (Compound 278.

str-ucture 4, of Scheme where R 1 =3-cano-2-methvlphenyl. This compound was 0 prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (56.5 mg, 0. 18 mmol) and 3 -bromo-2-methylbenzonitrile (34.8 mg, 0. 18 mmol). The crude material was purified by flash column chromatography (50 ml silica, hexane to 20% acetone/hexane) followed by a second flash column chromatography (75 mL silica, hexane to 0% 0 acetone/hexane) to afford 10.5 mg of Compound 278. Data for Compound 278: 1

H

NMR (400 MHz, acetone-d6) 7.59 (dd, J1=7.7, 0.9, 1 7.48 (dd, J1=7.8, 0.8, 1 7.36 J 15.3, 7.7, 1 6.99 J 1. 8, 1 6.91 (dd, J 8.1, 1.9, 1 6.58 J 1, 1 5.37 1 5.30 1 2.48 3 1.97 3 1.30 6 H).

EXAMPLE 179 1,2Dhyr-.24trmt(l 3 -methylphenyl)guinoline (Copound 279 structure 4 of Scheme 11, where R=3-metylpenyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (99.5 mg, 0.31 mrnol) and 3 -bromotoluene (53.5 mg, 0.3 lmroles). The crude material was purified by HPLC (reverse phase, ODS column, 80% methanol/water, mL/niin.) to afford 2.7 mg of Compound 279. Data for Compound 279: 1 11 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 1 5.22 1 2.34 3 2.03 3 1.27 6 H).

H:'\Pria\Kftp\spccM5977-96STROD RECEPTURdoc 19/01/00o DOCKET

NO.

01 6 -0014A.WO 202 EXAMPLE 180 6-(5-Fluoro-3-nitrophenvl)- 1 2 -dihydro-2,2,4trimethylquinoline (Compound 280 structure 4 of Scheme II, where Rl=5-fluoro-3-nitrophenl) 5-Fluoro-3-nitroiodobenzene To a 25 mL round-bottom flask equipped with a magnetic stir bar 3 -iodo-5-nitroaniline (543.3 mg, 2.06 mmol) and methylene chloride (10 mL) were added under nitrogen. Nitrogen was bubbled through the colorless solution for 15 min. The solution was cooled to 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, 10 deoxygenated ortho-dichlorobenzene 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 9silica, hexane) afforded 279.4 mg (50 of 5-fluoro-3-nitroiodobenzene. Data for 3 -nitroiodobenzene: 1H NMR (400 MHz, acetone-d6) 8.36 1 8.00 2 H).

S

6 -(S-Fluoro-3-nitophenl)-1, 2 -dihydro-2.2,4-trimethylquin line (Compound 280. structure 4fScheme II, where R =5-fluoro3nitrohen This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (140.2 mg, 0.44 mmol) and fluoro-3-nitroiodobenzene (117.6 mg, 0.44 mmol). The crude material was purified by flash column chromatography (150 ml 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: 1 H NMR (400 MHz, acetone-d6) 8.22 (app t, J= 3.0, 1.5, 1 7.78 1 7.43 J 2.2, 1 7.38 (dd, J 8.4, 2.3, 1 6.61 J= 8.3, 1 5.58 1 5.40 1 2.05 3 1.29 6

H).

EXAMPLE 181 12-Dihdr-6-3-methoxhentrimethluinoline (Compound 281 structure 4 of Scheme I where R=3-methox henl) H:\Prianka\Koep\specM5977-9 6 -SRO[D RECEPTOR.d 0 0 19/01/00 DOCKET NO.

016-0014A.WO 203 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: 1H NMR (400 MHz, acetone-d6) 7.25 2 7.11 J= 6.9, 1 7.07 (app t, J= 4.1, 2.2, 1 6.78 (dd, J 8.6, 2.2, 1 6.55 J 8.3, 1 5.36 1 5.26 1 3.82 3 2.03 3 1.27 6 H).

EXAMPLE 182 10 6-(5-Cvano-3-pyridyl)-1 2-dihdro-2.2.4-trimthvlquinoline (Compound 282 structure 4 of Scheme II. where Rl=5-cyano-3-pyridvl) to 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 mg, 0.14 mmol).

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: 1H NMR (400 MHz, acetone-d6) 8.21 J= 1.7, 1 7.79 2 7.44 J= 2.1, 1 7.39 (dd, J= 8.4, 2.3, 1 6.61 J 8.2, 1 5.59 1 5.40 1 2.05 3 1.29 6 H).

EXAMPLE 183 .12-Dihydro-2,2,4-trimethyl-6-(2-methyl-3-nitrophenyluinoline (Compound 283 structure 4 of Scheme II where R 1 =2-methyl-3-nitrophenvl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (170.6 mg, 0.54 mmol) and 2 -bromo-6-nitrotoluene (115.8 mg, 0.54 mmol).

The crude material was purified by flash column chromatography (80 ml silica, hexane to 20% acetone/hexane) followed by a second flash column chromatography (75 mL silica, hexane to 20% acetone/hexane) to afford 68 mg of Compound 283. Data for Compound 283: 1H 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= 8.2, 1 5.37 1 5.32 1 2.35 3 1.97 3 1.29 6 H).

H',Panka\1p\spccM597796.S-ROI RECEPTOR.oc 19/01/00 DOCKET NO.

016-00 14A.WO 204 EXAMPLE 184 6-( 2 -An-ino-3,5-difluorophenyl)-.1 2 -d ihydro-2,2,4-trirnethylg uino line (Comnpound 284.

structure 4 of Scheme II. where R I=2-amino-3,5-diflporophenvl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (48.8 mg, 0. 15 mmol) and 2 -bromo-4,6-difluoro aniline (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 J= 2.0, 1 7.02 (dd, J= 8.1, 2.0, 1 6.80 (in, 1 6.69 (in, 1 H) 6.56 Kd J 8. 1, 1 5.36 1 5.34 1 4.22 (br s, 2 1.97 (s, 10 3 1.28 6 H).

EXAMPLE 185 6 3 -Bromo-2-chloro-5-fluorohenyl.. 1 2 -dihydro-2,2,4-trimethylguino line (Compound structure 4 of Scheme where. R I 3-bromo-2-chloro-5-fluorophenyl) This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (143.3 mg, 0.45 mmol) and Il-chloro-2,6-dibromo-4-fluoro benzene (129.9 mg, 0.45 mm-ol). The crude material was purified by flash colum n chromatography (50 mL silica, hexane) followed by reverse phase preparatory TLC (1000 mL ODS, methanol/water) to afford 4.3 mng of Compound 285. Data for Compound 285: 1

H

0. 20 NMR (400 MHz, acetone-d6) 7.50 (dd, J 7.8, 3.0, 1 7.19 (dd, J 9.2, 3.0, 1 7. J 2.0, 1 7.03 (dd, J 8.1, 2.0, 1 6.55 J 8.3, 1 5.61 1 5.37 1 1.97 3H), 1.29 6H).

EXAMPLE 186 6 3 -Cyano-5-fluorophenyl)- 1 2 -dihydro-2,2,4-trirethyl3guinolo ne (Compound 286.

structure 79 of Scheme XX. where R=R 3

=R

5

R

2 =cyano, R 4 =fluoro, P=tbutoxycarbonyl) In a 100 mL r.b. flask, a solution of l, 2 -dihydro-6-(3-cyano-5-fluorophenyl>22,4 trimethyl- I t-butoxycarbonylquinoline (structure 77 of Scheme XX, where R 1

=R

3

=R

5

=H,

R

2 =cyano, R 4 =fluoro, P=t-butoxycarbonyl, an intermediate from EXAMPLE 171) (134.8 mg, 0.34 mmol) in THE (17.2 mL) was treated with a 1.0 M THE solution of BH3-THF (1.29 ML, 1.3 H- n"en\-p~ci597796.s'ROID RECEPTORAdo 19/01/00 DOCKET NO.

016-0014A.WO 205 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 mL), and 30% hydrogen peroxide mL). The reaction mixture 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 CH2C12 (2 mL) and treated with PCC mg). The reaction mixture was stirred for 1 h, filtered through a pad of Celite, and concentrated. Purification by flash column chromatography (175 mL silica, hexane) afforded 1.3 mg of Compound 286 as a white solid. Data for Compound 286: 1

H

NMR (400 MHz, acetone-d6) 7.90 1 7.75 J 10.6, 1 7.54 2 7.48 (d, 10 J= 8.3, 1 6.95 J= 8.2, 1 5.52 1 3.61 1 1.49 J= 7.05, 3 H), 1.33 3 1.23 3 H).

*0oo EXAMPLE 187 6 3 -Fluoro-2-methylphenyl) -1 2 -dihydro-2.2.4-trimethylquinoline (Compound 287 15 structure 4 of Scheme II. where R 1 3 -fluoro-2-methvlphenvl) This compound was prepared by General Method 2 (EXAMPLE 9) from Compound 9 mg, 0.158 mmol) and 2 -bromo-6-fluorotoluene (60 mg, 0.315 mmol). 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: 1 H NMR (400 MHz, acetone- 20 d6) 7.20 1H), 7.02 1H), 6.98 2H), 6.91 1H), 6.56 J=8.0, 1H), 5.37 (s, 1H), 5.29 (br s, 1H), 2.19 3H), 1.98 3H), 1.28 6H).

EXAMPLE 188 12-Dihvdro-2,2,4-trimethl-6-methlthiophen uinoline (Compound 288, structure 4 of Scheme II, where R 1 =3-methylthiophenl This compound was prepared by General Method 2 (EXAMPLE 9) from Compound 9 mg, 0.158 mmol) and 3 -bromothioanisole (64 mg, 0.315 mmol). Purification by flash chromatography on silica gel (20 g) using 5% EtOAc:hexanes afforded 7 mg of Compound 288 as a yellow oil. Data for Compound 288: 1 H NMR (400 MHz, acetoned6) 7.43 1H), 7.32 3H), 7.24 2H), 7.14 1H), 6.57 J=8.1, 1H), 5.37 (s, 1H), 5.31 (br s, 1H), 2.53 3H), 1.28 6H).

H.\Pranka\wp\sc459Thg6-STROID RECEPTORdoc 19/01/00 DOCKET

NO.

016-0014A.WO 206 EXAMNPLE 189 6 -(5-Chloro-2-thienyl) l.

2 -dihdro-22,4-trimethyIguinoli-ne (Compun 28.stutre4o Schee II whre R=5-hloro-2-thienvl) This compound was prepared by General Method 2 (EXAMPLE 9) from Compound 9 mg, 0. 158 mmol) and 2 -bromo-5-chlorotffiophene (63 mg, 0.3 15 rnm-ol). Purification by flash chromatography on silica gel (20 g) using 5% EtOAc:hexanes afforded 10 mg (22%) of Compound 289 as a yellow oil. Data for Compound 289: 1H1 NMR (400 MHz, acetoned6) 7.21 J 2. 1, 1H), 7.1 (dd, J 8.1, 2.0, lH), 7.02 J 3.7, 6.93 J 3.7, 111), 6.51 8.3, 1H), 5.42 (br s, lH), 5.40 1H1), 2.01 3H), 1.27 6H).

EXAMPLE 190 1,-iyr-,,-tiehl6(-ehy -hey~unline Compound290. structure 4 of Schem-e I. where R!=-eHv12.thenl This compound was prepared by General Method 2 (EXAMPLE 9) from Compound 9 mg, 0.158 mmol) and 2 -bromo-3-methylthiophene (57 mg, 0.315 mmol). 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: 1H NMR (400 MHz, acetone-d6) 7.18 J 5.2, 111), 7.09 J1 1.9, 1H), 7.03 (dd, J 8.1, 2.0, 1H), 6.88 5. 1, 1H), 0 20 6.54 J 8. 1, 111), 5.38 IH), 5.32 (br s, 1H), 2.26 3H), 1.99 3H), 1.29 6H).

EXAMPLE 191 8 -Fluoro- 1,-iyr 224tiehl6-Q- tohnlgioln (Copound 291 structure 83 of Scheme- XX. whre

R=R

3 7 =R9HfR 8

-F)

4 -Amino-3 -fluoro.3 t-nitro bip hen yl (structure 82 of Scheme XXI where R=R 3 7

=H.

R

8

=F)

Gaenera Method 14: Suzuki Copling of a 4 -Bromoaniline with an Arylboronic Acid.

A

mixture of 3 -nitro benzeneboro ic acid (0.70 g, 4.2 mmol), 4 bromo-2-fluoro aniline (730 mg, 4.0 mmol), (PPh3)4Pd (93 mg, 0.08 mmol), and K2C03 (0.69 g, 5.0 mmol) in toluene (20 m.L) and water (2 mL) was heated at 95 OC for 16 h and the mixture was diluted with EtOAc (20 mL). The mixture was washed with water (10 m.L) and brine (10 mL), H.\rynaKc~pet4979.TRI RECEPTORdoc 19/01/00 DOCKET

NO.

0 l 6 -0014A.xvO 207 concentrated and purified by silica gel chromatography to afford the 4 -amiino-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.

8Fluro-1.2diydr-2,,4-riethl-6(3-itrphnylquiolie.(Compound 291. structure 83 of Scheme XXI. where R=R 3 7 =R9-aH R-F. This compound was prepared by General Method 8 (EXAMPLE 138) from 4 -amino- 3 -fluoro-3'..nitrobiphenyl (0.4 g, 1.7 mmol) to afford 101 mg of Compound 291 as a red solid, in addition to 0.8 g of the starting aminobiphenyl. Data for Compound 291: ER (neat) 3400, 2968, 1531, 1506, 1346; 10 1H NMR (400 MHz, CDCJ3) 8.35 J 2.0, 1 8. 10 (dd, J 7.8, 2.0, 1 7.80

J=

7.8, 1 7.54 J 1 7.14 J= 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 NNM (100 MHz, CDCl3) 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.

EXAMPL E 192 l.

2 -Dihydro-6-(3itropheny)22,4 8 -tetrametyluinoline (Compound 292. structure 86 4 -Bromo-2-methylaniline (5.58 g, 30 mmol) was treated with iodine (0.2 g, 0.9 nimol) and 20 acetone (150 niL) in a sealed tube at 80 OC for 24 h to provide 6 -bromo-1,2-dihyciro-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-dihycjro-8 methylquinoline (90 mg, 0.33 nimol), 3 -nitrobenzeneboronic acid (167 mg, 1.0 nimol), Pd(PPh3) 4 (24 mg, 0.02 nimol), K2C0 3 (190 mg, 1.38 nimol) in toluene (7 niL) and water (1.5 niL) was heated at 70 OC for 16 h. Standard work-up followed by chromatography afforded 23 mig of Compound 292 as a yellow oil. Data for Compound 292: ER (neat) 3412, 2966, 1602, 1530, 1348; 'H NMR (400 MHz, CDCJ3) 8.38 J 2.0, 1 8.08 (dd, J 7.8 and 2.0, 1 7.85 J 7.8, 1 7.52 J 1 7.24 J 11.7, 1 7.21 J 1.9, 1 5.39 1 3.72 (bs, 1 2.18 3 2.07 3 1.34 (s, 6 1 3 C NMR (100 MHz, CDCI3) 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.

HW\Priynka\Kop\specvM5977-96.SThROfD RECEPTR.d1oc 19/01/00 DOCKET

NO.

016-00 14A.WO 208 EXAMPLE 193 6 -(S-Bromo-3-pyiv) l.-di ro-22.-trinethylguinoline (Compound 293. structure 4 of Scheme where R 1 =5ibromo-3-pvridyl) This compound was prepared by General Method 2 (EXAMPLE 9) from dibromopyridine (119 mg, 0.5 mmol) and Compound 9 (50 mg, 0. 16 mrnol) to afford 18 mg of Compound 293 as a yellow oil. Data for Compound 293: IH NMR (400 MHz, CDC13) 8.69 1 8.52 1 7.93 J 2.0, 1 7.21 J 2. 1, 1 7.20 (dd, J 2. 1, 1 6.50 J= 8. 1, 1 5.37 1 3.8 8 (bs, 1 2.05 3 1. 31 6 10 H).

EXAMPLE 194 0. 6 3 -Bromo-2-pyridyl)- l., 2 -dihydro-2,2,4-trmethvlguinoline (Compound 294, structure 4 of Scheme where R 1 3 omo-2-pyid 11 15 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: JR (neat) 3379, 2966, 1604, 1575, 1433, 1124; IH NMR (400 MHz, CDC13) 7.68 1 1.9, 1 7.66 (dd, J 8.1, 1.9, 1 7.54 J 7.8, 1 7.49 J 7.8, 1 7.23 J 7.8, 1 H), 0 0 20 6.49 J 8. 1, 1 5.3 5 1 3.93 (bs, 1 2.0 8 3 1. 30 6 3

NM

(100 MHz, 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 6 -(3-Bromo-2-thienyl)- Il.

2 -dihydro-2,2,4-trimrethylg uino line (Compound 295. structure 4 of Scheme H. where R 1 =-rmo2thenn This compound was prepared by General Method 2 from 2 ,5-dibromothiophene (242 mg,.

mmol) and Compound 9 (50 mg, 0. 16 mmol) to afford 24 mg of Compound 295 as a yellow oil. Data for Compound 295: IH NMR (400 MHz, CDCl3) 7.17 (bs, 1 H), 7.15 (dd, J= 8.1, 1.9, 1 6.95 J= 3.7, 1 6.86 (bs, 1 6.42 (bs, 1 5.36 1 3.80 (bs, 1 2.01 3 1.29 6 H).

H:\Priyanka\Kep\pec597796S'MROI RECEPTORdoc 19/01/00 DOCKET NO.

016-001 4A.WO 209 EXAMPLE 196 1,-Dhyr--(.,,-erfur--yiy)224tiehl~ioln (Compound 296. structure 4 of Scheme UI. where Rl=2.3.5.6-tetrafluoro-4-pvridvl) 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 mmcl) to afford 13.4 mg of Compound 296 as a white solid. Data for Compound 296: 1 H NMR (400 MHz, CDCl3) 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, CDCl3) 145.4, 144.5 (dd, 10 J 230, 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-Dffluoro-1I 2 -dihydro- 6 3 -nitrophenyl)-2,2,4-trimethylguino line (Compound 297.

15 structure 83 of Scheme XXI. where R=R 3 5

=R

7

=R

9 .0nto 6 8 fur) This compound was prepared by the same procedure as described in the synthesis of Compound 291 (EXAMPLE 19 1) from 4 -bromo-2,5-difluoroanjline (32 mg, 0. 13 mmcl) and 3a...nitro 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), 20 8.14 (dd, J= 8.0, 1.6, 1 7.7 8 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, 1 2.17 (dd, J 7.0, 1.3, 3 1.34 6 H).

EXAMPLE 198 2,4-Diethyl-8-fluoro- 1 2 -dihydro-2-methyl-6-(3-nitrop~henyl)guinoijne (Compound 298.

structure 83 of Scheme XXI. where R=R 3 7

R

2 =nitro, R 8 =fluoro, R 9 =methvll A mixture of 2 -fluoro-4- (3 -nitrophenyl) aniline (100 mg, 0.43 mmcl), iodine (10 mg, 0.039 mmcl) 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 (3 of Compound 298 as a yellow oil. Data for Compound 298: IH NMR (400 MHz, CDC1 3 8.33 J 2.0, 1 8.10 (dd, J 7.8, 2.0, 1 7.81 J 7.8, 1 7.54 J 7.8, 1 H:\Priyanka\K~ep\specM5977-96-STEROID RECEPTORAdo 19101100 DOCKET

NO.

0l6-0014A.WO 210 7.14 1 7.12 J= 11.0, 1 5.30 1 3.96 (bs, I 2.47 J 7.5, 2 H), 1.57 J 7.5, 2 1.31 3 1.21 J 7.5, 3 0. 95 J 7.5, 3 H).

EXAMPLE 199 6 (3-Bromophenyl)- A 2 -dihydro- 22.4-triinethylq uino line (Compound 299. structure 4 of Scheme H, wyhere R 1 3 -bromophenyl-) This compound was prepared by General Method 2 (EXAMPLE 9) from Compound 9 (100 mg, 0.32 mmol) and l, 3 -dibromo benzene (0.20 mL, 1.60 mmol). The crude product was purified by prep TLC (5 x 20 cmy, 2 50mm, 25% EtOAc:hexane) to afford 2.3 mg of Compound 299 as a white solid. Data for compound 299: Rf=-0.43 (silica gel, EtOAc:hexane); IH NMR (400 MHz, acetone-d6) 7.72(s, 1 7.56 J 8.5, 1 H), 7.38(d, J 8.5, 1 7.37 (in, 2 7.24 J 8.5, 1 6.58 J 8.5, 1 5.39 (br m, S S*.2 2.04 3 1.29 6 H).

EXAMPLE 200 J.-iyr-,,-tmty--(-ii--hey)gioln (Compound 300.

structure 4 of Scheme I.where

R

1 =.-nitro-2-thienyl) This compound was prepared by General Method 2 (EXAMPLE 9) from Compound 9 (50 mng, 0.16 mmol) and 2 -bromo-5-nitrothiophene (0.16 g, 0.79 minol). The crude 20 product was purified by prep TLC (20 x 20cm, lOOOmm,4 25% EtOAc:hexane) to afford mg of Compound 300 as a purple solid. Data for compound 300: Rf=0.40 (silica gel, 25% EtOAc:hex); IH NMR (400 MHz, CDC13) 7.85 J 4.3, 1 M, 7.27 (mn, 2 H), 7.04 J 4.3, 1 6.43 J 8.5, 1 5.38 (brs, I 4.13 (brs, 1 2.03 3 H), 1.32 6 H).

EXAMPLE 201 64,, rmtyqioln (Compound 301.

structure 4 of Scheme 1. where R= 2 4 trifluorophenyl) This compound was prepared by General Method 2 (EXAMPLE 9) from compound 9 (50 mg, 0.16 mmol) and 2 4 ,5-trifluorobromo benzene (0.10 mL, 0.79 mmol). The crude product was purified by prep TLC (5 x 2 0cm, 250mm, 25% EtOAc:hexane) to afford 15 mng nkaK-P P-c4597-96STEOIDRECEPTOR.dO. 19/01/oo DOCKET

NO.

016-0014A.WO 211 of Compound 301 as a yellow oil. Data for compound 301: Rf--0.40 (silica gel, EtOAc:hex); 1 H NMR (400 MHz, CDCl3) 7.21 (in, 1 7.18 1 7.13 J 8.5, 1 6.96 (in, 1 6.47 J= 8.5, 1 5.34 1 3.83 (brs, 1 2.01 3 1.31 (s, 6 H).

EXAMPLE 202 6- 3 -Bromo-5-fluorophenyl)-. l 2 -dihydro-2,2,4-trimethylguino line (Compound 302.

structure 4 of Scheme II.where Rl= 3 This compound was prepared by General Method 2 (EXAMPLE 9) from compound 9 :.10 mg, 0.16 mmol) and l, 3 -dibromo-5-fluoro benzene (0.20 mL, 1.60 minol). 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, CDC13) 7.44 1 7.21 to 7.09 (in, 4 H), 6.46 J 8.5, 1 5.35 1 3.80 (brs, 1H), 2.04 3 1.30 6 H).

EXAMPLE 203 6 -(5-Carboxaldehyde-3-thienyl)-1 2 -dihydro-224-trimethylguinoline (Compound 303.

structure 4 of Scheme 11, where R 1 3 This compound was prepared by General Method 2 (EXAMPLE 9) from compound 9 20 mg, 0. 16 minol) and 4 -bromo-2-thiophenecarboxaldehyde 15 g, 0.79 minol). The crude product was purified by prep TLC (20 x 20cm, lOO0mm, 25% EtOAc:hexane) to afford 31 mg of Compound 303 as a yellow oil. Data for compound 303: Rf=-0.44 (silica gel, EtOAc:hex); IH NMR(400 MHz, CDCl3) 9.95 1 7.96 1 7.66 1 H), 7.25 1 7.22 J 3.8, 1 6.47 J 8.5, 1 5.37 I 3.84 (brs, 1 2.04 3 1.31 6 H).

EXAMPLE 204 l.

2 -Dihydro-2.24.7tetramethvl-6(3-nitrophenyl)guflinel (Compound 304. structure 83 of Scheme XXI, where R=R 3

-=R

6 =R8-9=H R 2 =nitro, R 7 =methl) 4 -Amino-2-methyl-3 Initrobi heny strcture 82? of Scem XXI whreR 1

=R

6

=R

8 =H R 2 =nitro R 7 =methyl). This compound was made according to the General H.\Priank\Keepspeci\5977-96.S7hROfD RECEP'10R4 0 19/01/00 DOCKET No.

016-0014A.WO 212 Method 14 (EXAMPLE 191) from 3 -nitrobenzene boronic acid (673.2 mg, 3.82 mmol) and 4 -bromo-3-methylaniline (710.2 mg, 3.82 mmol) to afford 540 mg of 4 -amino-2methyl-3'!.nitro biphenyl (structure 82 of Scheme XXI, where Rl=R 3 -5=R6=R8=H,

R

2 =nitro,

R

7 =methyl). Data for 4 -amino-2-methylp3 '-nitrobiphenyl: IH NMR (400 MHz, acetone-d6) 8.13 (dd, J 7.5, 1. 1, lH), 8.09 (dd, J= 3.9, 1.8, 1 7.73 (ddd, J 7.7, 1.6, 1. 4, 1 7.66 (dd, J 8.0, 7.8, 1 6.99 J 8. 0, 1 6.60 (in, 1IH), 4.73 (br s, I1H), 2.18 3H).

l* 2 -Dihydro-2 -4.tetramethyl.6.(3.nitrophen yl)uinoline Lo on 0,srcue8 of Schieme XXI- whe-re- RlI=R 3 -5=R6=R8-9=H,

R

2 =itr. 7 methv.Thscmon 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 mng of Compound 304. Data for Compound 304: IH NMR (400 MHz, acetone-d6) 8.13 (in, 2 7.76 (dd, J 8.9, 1.2, 1 7.69 J 15.9, 8.0, 1 H), 15 6.93 1 6.43 1 5.32 1 2.14 3 1.95 3 1.27 6 H).

EXAMPLE 205.

h-(5-Fluoro-2-methoxy3nitro hen y1,2ddo224fiehyqioln Cmon 0:0.305 structure 4 of Scheme where Rl= -fluoro-2-met _xy3nitrphenyl) 0:000: 20 This compound was prepared by General Method 2 (EXAMPLE 9) from compound 9 mg, 0. 19 inmol) and 2-rm--loo6ntonsl (37 mg, 0. 15 mmol). The crude product was purified by silica gel chromatography (EtOAc/hexane, 10:1) to afford 5 mg of Compound 305 as a yellow oil. Data for compound 305: lfl NMR (400 MHz, CDC13) 7.34 (dd, J 7.3, 3.3, 1H), 7.25 (in, 3H), 7.21 (dd, J 8.1, 2.0, 1H), 6.50

J

8.3, 1H), 5.37 lH), 3.89 1H), 3.55 3H), 2.01 J= 1.4, lH), 1.33 6H).

EXAMWPLE 206 6 3 -Chloro-2-inethoxyp~henyl)-l2dhdo224trimt lqin (Cn ompound 306.

s tructure 4 f Scheme 11 where Rl= 3 -hlorn-'2-inetoxyphenyl) This compound was prepared by General Method 2 (EXAMPLE 9) from compound 9 mng, 0. 19 inmol) and 2 -bromo-6-chloroanisole (33 mg, 0. 15 inmol). The crude product was H-'\i~ana\KP\3pcM577-9.sT ROI RCEPTOR~od; 19/01/00 DOCKET

NO.

01 6 -0014A.WO 213 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 MHz, CDCI3) 7.30 (in, 2H), 7.20 (in, 2H1), 7.05 J= 8.0, 11H), 6.51 J= 8.3, 1lH), 5.34 IlH), 3.75 (s, 111), 3.52 311), 2.01 3H), 1.34 6H).

EXAMPLE 207 1,-iyr-.24tiehl6-234tiloohnlqun line (Compound 307, structure 4 of Scheme JU. where R 1 2 3 4 -trifluorophenyl) This compound was prepared by General Method 2 (EXAMPLE 9) from compound 9 mg, 0.19 inmol) and I- bro mo-2,3,4-trifluoro bnzene (0.11 mL, 0.93 mmol). 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 MHz, acetone-d6) 7.28 (mn, 1H), 7.20 (in, 211), 7.13 (dt, J= 8.2, 1.9, 111), 6.58 J= 8.3, 1H1), 5.43 (br s, 1H), 5.39 111), 2.00 J 1.3, 311), 1.30 6H).

0 EXAMPLE 208 6 3 -Bromo-2-methylphenyl) 1 .2-iyd2,,-t.u rimeylguino lie structure 4 of Scheme H, where Rl= 3 -bromo-2-methylphenyl) This compound was prepared by General Method 2 (EXAMPLE 9) from compound 9 9 20 mg, 0. 16 inmol) and 2 6 -dibromotoluene 16 g, 0.64 inmol). The crude product was purified by silica gel chromatography (EtOAc/hexane, 10: 1) to afford 27 mg of Compound 308 as a colorless glass. Data for compound 308: 1 H NMR (400 MHz, CDCl3) 7.49 J 8.3, 1H), 7.17 J 6.9, IH), 7.04 J 7.7, 111), 6.95 J 1.9, 111), 6.89 (dd, J 8.0, 1.9, 111), 6.46 J 8.0, 111), 5.35 3.77 (br s, 111), 1.97 J 311), 1.32 6H).

EXAMPLE 209 7-Chloro- 1.-iy tiehl -3-ir hnlqioln (Compound 309. tutr 83 of Scheme XXI where R=R 3 -5=R 6 =R8-9=1 R 2 =nitro. 7 =chloro) 2 -Chloro-4-aniino-3'..nitrobipheny (structure 82 of Scheme XXI where R=R 3 5

=R

7

R

2 =nitro R 6 =chloro). This compound was prepared by General Method 14 (EXAMPLE H:N k\P K p\sp~i\S9-96.STROD RECEPTORAdo 19/01/00 DOCKET

NO.

o 16-0014A.WO 214 191) from 3 -nitro benzene boro nic acid (0.25 g, 1.5 mmol), 4 bromo-3 -chloro aniline (0.21 g, mmol), and (PPh3)4Pd (35 mg, 0.030 mrnol) to afford 0.08 g of 2-chloro-4amino-3 'nitrobiphenyl as an orange solid. Data for 2 -chloro -4-arnino -3 nitro bip henyl:

IH

NMR (400 MHz, acetone-d6) 8.29 (app t, J 2.0, 1H), 8.18 (dt, J 9.0, 1.2, 1H), 7.76 (dd, J 9.0, 1.2, 111), 7.56 J 8.0, 1H), 7.14 J 1H), 6.82 J 2.2, 111), 6.65 (dd, J 8.2, 2.2, 111), 3.86 (br s, 211).

7-Chioro-12dhdo224tieyl6 Q irpeylqioln (Compound 09. structure 83 of Scheme XXI. where R I R 3 6 R8-9 H R 2 =nto R 7 clr) This compound was to 10 prepared by General Method 8 (EXAMPLE 138) from 2 -chloro-4-amidno-3'..nitrobiphenyI (00 g, 0.3 mol) to afford 15 mg of Compound 309 as an orange solid, in addition 0***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: 1 H NMR (400 MHz, acetone-d6) 8.77 J 2.0, 111), 8.21 (dt, J 9.0, 1.2, 111), 7.88 (dd, *~e15 J 6.6, 1.6, 1H1), 7.71 J 7.9, 111), 7. 10 111), 6.67 111), 5.43 111), 1.99 311), 1.32 6H).

EXAMPLE 210 l.

2 -dihydro224trimethy6(3nitrophnfl).inoe(opud30 tutr This compound (2 mg, was obtained along with Compound 309 (EXAMPLE 209) as described above. Data for Compound 310: 1Hl NMR (400 MHz, acetone-d6) 8.21 J 1.4, 111), 8.20 111), 7.81 (dt, J 8.8, 1.4, 1H), 7.70 (in, IH), 7.01 J 8. 1, 111), 6.71 J 1, 111), 5.74 (br s, 111), 5.55 J 1.3, 111), 2.31 J 1.3, 3H), 1.28 6H).

EXAMPLE 211 8-Chloro-1 l 2 -dihydro-2.2.4-trirngthyl1..&(3- n itrophenyl)q uino line (Compound 311., structure 83 o Sceme XIwhee

R=R

3 7 -R9:H, R 2 =nitro R 8 =chloro) 3 -Chloro-4-amiino-3 nitrobinhenyI (srctur 82 of SchemeX I hr 1

R

7

H

R

2 =nitro. R 8 =chloro). This compound was prepared by General Method 14 (EXAMPLE 191) from 3 -nitrobenzeneboronic acid (0.25 g, 1.5 mmol), 4 -bromo-2-chloroaniline (0.21 g, H.APriyauka\Kmp\spec597-96S7hgOD RECEPTIORdoc 19/01/00 DOCKET

NO.

0l 6 -0014A.WO 215 1 .0 mmo and (PPh3)4Pd (35 mg, 0.030 mmol) to afford a crude material which was used directly in the next step.

8-Chloro- 1 2 -dihydro-2,2.4-trimethyl-6 3 -nitrophenyl'guino line (Compound 311. structure 83 of Scheme XXI, where R 1

=R

3 7

=R

9

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: 1 H NMR (400 MHz, acetone-d6) 8.48 J 2.0, 1H), 8.11 (dd, J 8.0, 2.0, lH), 8.04 (dd, J 6.6, 1.6, 1H), 7.67 J 8.0, lH), 7.55 J 2.0, 1H), 7.40 J 2.0, 1H), 5.43 10 1H), 1.99 3H), 1.29 6H).

EXAMPLE 212 8-Ethyl- 1, 2-~hdo22.-inty--3ntohnlqioln(Compound 312. structure R2ntrR8ehy) This compound was prepared by General Method 14 (EXAMPLE 191) from 3 -nitrobenzeneboronic acid (0.47 g, 2.8 nin-ol), 4 -bromo-2-ethylanjlne (432 mg, 2.16 mmol), and (PPh3)4Pd (75 mg, 0.065 mmol) to afford 139 mg of 4-amino-3ethyl-31-nitrobiphenyL Data for 4 -amino-3-ethyl-3' nitro biphenyl: 1 H NMR (400 MHz, acetone-d6) 8.38 J 2. 1, 114), 8.08 (in, 114), 8.00 (in, 114), 7.66 J 8.0, 1H), 7.45 (d, J 2.3, 1H), 7.39 (dd, J 8.3, 2.3, 1H), 6.83 J 8.3, 114), 4.68 (br s, 2H1).

8-Etv- ,-iyr-,,-rmthyl- 3nirphnl~un line (Cmound 312 structure 83 of Scheme XI. wher-e

R=R

3 7 =R9.H R 2 =nitro R 8 =ethvl). This compound was prepared by General Method 8 (EXAMPLE 138) from the crude biphenyl amine obtained above to afford 2 mg of Compound 312 as an orange solid. Data for Compound 312: IH NMR (400 MHz, acetone-d6) 8.38 J 2. 1, 8.06 (mn, 2H), 7.66 J 8.0, 114), 7.34 (mn, 1H), 5.44 lH), 4.88 (br s, lH), 2.60 J 7.5, 2H), 2.08 3H), 1.34 614), 1.23 J 7.5, 3H4).

H:\Piana\KcpspcM5977.96SnROD RECEPTOR. 19/01/00o DOCKET

NO.

0l6-0014A.WO 216 EXAMPLE 213 9- Chioro-.

2 -dihydro-2,2-dimethy1 5counirino 3 4 -fjq uino line (Compound 313.

structure 88 of Schemie XXfL where R 2 =R 4 6 =pR 9

R

7

=R

8 HMethy1 R=cloo 2 -Aniino-6-chloro34nzocoumarin (structure 87 of Scheme XXIII, where R 1 4-=H

R

3 =chloro, an intermediate from EXAMPLE 109) (100 mg, 0.407 mmnol) and 1, 1-dirnethyl propargyl. acetate (52 mg, 0.41 mrnol) were dissolved in THF (5 mL) and treated with triethylamidne (57 iL, 0.41 mmo The resulting solution was treated with CuCi (20 mg, 0.20 mmol). The reaction mixture was heated at relux for 16 h. The reaction was quenched with I% (vlv) HCl (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 00 20 mL). The combined organics were washed with brine (1 x 20 mL), dried (Na2SO4), *fee6 filtered, and concentrated onto Celite. The material was purified by flash chromatography 0. a 0. on silica gel (50 g) using 15% EtOAc:hexanes as eluent to afford 50 mg of the dimethyl 006. propargyl amine intermediate. This material was dissolved in THF 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 00:: separatory funnel and the aqueous was extracted with EtOAc (2 x 20 mL). The combined *00 **00organics were washed with brine (15 mL), dried (Na2S 04), filtered, and concentrated onto t* Celite. The material was purified by flash chromatography on silica gel (20 g) using 14000: 20 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 J 2.4, 1H), 7.99 J 8.7, 1H), 7.91 J 10.4, 1H), 7.38 (dd, J 8.6, 2.4, 1H), 7.26 J1 8.7, 1H), 7. 10 J 1 6.04 (br s, IH), 5.74 (dd, J 10.4, 1.4, 1 1. 36 6H).

EXAMPLE 214 2 -Dihvdro9methoxy 224trimethyls5coumaino 3 4 -tlq uino line (Compound 314 stucure41of chme X where R I-H R 2 =methoxy) 2 S-Dimethoxyphenylboroni acid (structure 37 of Scheme XI, where R 1

=H.

R

2 =methoxy). This compound was prepared in a manner similar to that of 5-fluoro-2methoxyphenylboronic acid (EXAMPLE 107) from l-bromo- 2 ,5-dimethoxybenzene (2.00 mL, 13.3 mmol), n-BuLi (2.5 M in hexanes; 5.34 mL, 13.3 mmol), and trimethylborate H:\Priyanka\ICmppecM'59T-96S.ERO[D RECEPTOR~do 19/01/00 DOCKET

NO.

016-0014A.WO 217 mL, 40 mmol) to afford 2.43 g of 2 ,5-dimethoxyphenylboronic acid which was used without further purification.

Methyl 2 .S'-dimethoxy-4-nitro2-biphenylcarboxlate). This compound was prepared in a manner sirnilar to that of methyl 5 '-fluoro-2 '-methoxy-4-nitro-2biphenylcarboxylate (EXAMPLE 107) from methyl 2 bro mo-5- nitro benzo ate (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 -dimethoxy-4-nitro-2-biphenylcarboxylate) as a white solid. Data for methyl 2 ',5'-dimethoxy-4-nitro-2-biphenylcarboxylate): IH NMR 0 10 (400 MHz, CDCl3) 8.70 J 2.4, 111), 8.37 (dd, J 8.4, 2.5, 111), 7.52 J 8.5, 1H), 6.92 (dd, J 8.8, 3.0, 1H), 6.84 (in, 1H), 3.82 3H), 3.75 3H), 3.67 3H).

V too :2 '5 '-Dimethoxy-4-nitro-2-biphenyitcarboxyic acid. This compound was prepared in a manner simidlar to that of 5'-fluoro- 2 '..methoxy4nitro.2-biphenylcarboxylic acid 15 (EXAMPLE 107) from methyl 2 ',5Ldimethoxy4nitro2biphenylcarboxylate (2.07 g) to .too afford 1.93 g of 2 ',S'-dimethoxy-4-nitro-2.biphenylcarboxylic acid as a white solid:' 0: 0. Data for 2' -uu11eLoxy-4-itro2-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, 111), 6.94 (in, 211), 3.80 3H), 3.68 3H1).

.00* 6 -Methoxy-2-nitro-3.4-benzocounma in. This compound was prepared in a manner s i m i l a r t o t h a t o f 6 -l o o 2 n t o 3 e z c u a i E X A M P L E 1 0 7 f r o m 2 5 dirnethoxy-4-nitro-2-biphenylcarboxylic acid (l.93.g, 6.36 imol), SOC12 (0.47 mL, 6.4 inmol), and A13 (0.67 g, 5.0 inmol) to afford 1.71 g of 6 -methoxy-2-nitro-3,4benzocoumarin as an orange powder. Data for 6 -methoxy-2-nitro-3,4-benzocoun-rin: 1

H

NMR (400 MHz, acetone-d6) 9.04 J 2.4, 111), 8.74 J 8.9, 1H), 8.69 (dd, J 8.9, 2.4, 1lH), 7.92 J 2.9, 1 7.41 J 9. 0, 111), 7.30 (dd, J 9.0, 2.9, 1 3.97 3 H).

2 -Amino- 6 -mthox -3 4bn7ocn~n(rucue4ifShm I hr 'II

R

2 =methoxy). This compound was prepared in a manner similar to that of 2-amino-6fluoro-3,4-benzocoumarin (EXAMPLE 107) from 6-ehx--ir-,-ezcuai H.,Priank\K-~sccM97796.'MRIDRECFPTORAdo 19/01/00 DOCKET NO.

016-0014A.WO 218 (1.71 g, 6.3 mmol) to afford 1.27 g of 2 -amnino-6-methoxy3,4-enzocoun-arin as a white solid. Data for 2-ndo6mtoy34bnoomrn 1 H NMR (400 MHz, acetone-d6) 8. 10 J 8.7, 1H), 7.60 J 2.8, 1H), 7.55 J 2.5, 1H), 7.25 (in, 2H), 6.99 (dd, J 8.7, 2.8, 1iH), 3.90 3H).

1,-iyr--ehx-..4tiehl5cimrn BA-fluino line (Compound 314, structure 41 of Scheme X. where R 1 R=mthxy. This compound was prepared in a manner similar to that of Compound 207 from 2 -amiino- 6 -methoxy3,4benzocoumari (1.27 g, 5.0 minol) to afford 0.25 g of Compound 314 as a yellow solid. Data for .10 Compound 314: 1H NMR (400 MHz, CDC13) 7.73 J 8.6, 114), 7.35 J 2.8, 1 H), 7.23 J 8.9, 1 7. 00 J 8.6, 114), 6.92 (dd, J 8.9, 2.8, 114), 5.57 1lH), 4.29 (br s, I1H), 3.88 3H), 2. 11 J1= 1. 1, 314), 1.33 6H4).

EXAMPLE 215 9-Fluoro- 11.-dihydro-2,2,4. 11 -tetraMethy-5-couiaino r3.4-tlguino line (Compound 315, strucure 88 f Scheme XXIV. hr R- 2

=R

4

=R

6

R

3 =fluoro, R 5

=R

7 9 =methyl) Methyl 2 -fluoro-5 '-meth-oxy-6-methyk4-nitro2biphenycarboxylate (structure 92 of Scheme XXIV. where R- 2

=R

4

-R

6 H 1R 3 =fluoro.

R

5 =methyl). This compound was prepared in a manner similar to that of meth yl 5 '-fluoro-2 '-methoxy-4-nitro..2.

biphenylcarboxylate (EXAMPLE 107) from methyl 2-boo3mty--ir ez t (1.73 g, 6.31 mmol), (PPh3)4Pd (0.22 g, 0. 19 mmol), and 5-fluoro- 2 -methoxyphenylboronic acid (EXAMPLE 107) (1.50 g, 8.8 minol) to afford 0.77 g of methyl mehx--ehl4nto2bpeycroyae Data for 2 'fluoro-5 '-methoxy-6-methyl.

4 -nitro-2-biphenylcarboxylate: 1HNMR (400 MHz, acetone-d 6 8.61 J 2.3, 114), 8.27 J 2.4, 114), 7.09 (in,4 114), 6.91 (dd, J 9.0, 4.3, 114), 6.73 (dd, J 8.2, 3.0, 1H4), 3.70 3H4), 3.69 3H4), 2.19 3H).

2 '-Fluoro-5 '-methoxy- 4 -nitro-2-biphenylcarboxylic acid. This compound was prepared in a manner similar to that of 5!fur-!mtoy4nto2bpeycroyi acid (EXAMOPLE 107) from methyl 2 '-fluoro-5'-methoxy-6-methylk4.nitro-2-biphenylcarboxylate H:,\PniakaKpspcM5977_96.STROID RECEPTORdo 19101100 DOCKET

NO.

016-0014A.Wo 219 (0.77 g) to afford 0.73 g of 2 '-fluoro-5'..methoxy-4nitro.2-biphenylcarboxylicacds a white solid, which was used in the next step without further purfication.

6 -Fluoro4methyl2nitro34nzocoumain. This compound was prepared in a manner similar to that of 6-fluoro-2-nitro-3,4-benzocoum'arin (EXAMPLE 107) from 2' methoxy- 4 -nitro2biphenylcarboxylic acid (0.73 g, 2.4 mmol), SOC12 (0.18 mL, 2.4 mmol), and AlC13 (0.32 g, 2.4 mmol) to afford 0.63 g of 6 -fluoro-4-methyl2nitro- 3 4 -benzocoumarin as an orange powder. Data for 6 -fluoro-4-methyl-2nitro.3,4 benzocoumarin: 1H NMR (400 MHz, acetone-d6) 8.99 J 2.5, IH), 8.63 J 1 8.29 (dd, J= 10. 9, 2.4, 1 7.53 2H), 3.14 3H).

2 -A ino- 6 -fluoro-4methv1.34 bnzoomrn(tutr 7o ceeX I.wee *a.

2

=R

4

=R

6 H =fluoro. R=methvl'. This compound was prepared in a manner similar to *a..that of 2 -ami no-6-fluoro-3,4benzocounrin (EXAMPLE 107) from 6 -fluoro-4-methyl-2 nitro-3,Lk-benzocoumarin (0.61 g) to afford 0.54 g of 2 -an-dno-6-fluoro-4methy13,4benzocoumnarin as a white solid, which was used in the next step without further purification.

9 -Fluoro- 1 .2-dihydro-2.2.4.1 zetramethy1-5counirino 3 4 -flguino line (Compound 315.

*structure 88 of Scheme XXIV. where R 2

=R

4 p 6

R

3 =fluoro.

R

5

=R

9 =m-ethvl)- 20 This compound was prepared in a manner similar to that of Compound 207 from 2-amino- 6 -fluoro-4-methyl-3,4benzocoumarin (0.54 g) to afford 0.29 g of Compound 315 as a yellow solid. Data for Compound 315: IH NMR (400 MHz, acetone-d6) 7.87 (dd, J 11.4, 2.9, 1H), 7.32 (dd, J= 9.0, 5. 1, 1H), 7.28 (in, 1H), 7.02 1H), 5.52 J= 1.2, 1H1), 2.76 3H), 2.01 3H), 1.30 6H).

EXAMPLE 216 1, 2 -Dihydro-2.24,9-tetramethvI5-couinarino r3 4 -flg~uino line Co mpo und 316. structure 41 of Sch eme XI where R =0 R 2 =methl)

R

2 =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 H.,"a\Kp\4 pM9796STROD RECEPTORAoc 19/01/00 DOCKET NO.

016-00 14A.WO 220 mmol), n-BuLl (2.5 M in hexanes; 4.00 mL, 10 mmol), and trirnethylborate (3.4 mL, mmol) to afford 1.60 g of 2 -methoxy-5-methylphenylboronic acid which was used without further purification.

Methy 2- 'methoxy-5! 'methyl- 4 nitro bip henylcarboxylate. This compound was prepared in 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 10 white solid. Data for methyl 2 '-methoxy-5'-methyl-4nitro2biphenylcarboxylate)

:I

NMR (400 MHz, CDCl3) 8.69 J 2.5, 111), 8.36 (dd, J 8.4, 2.5, lH), 7.51 J 7.20 (in, 1H), 7.07 J 1, 1H), 6.81 J1=8.4, 1H), 3.75 3H), 3.69 3H), :2.35 3H).

15 2 '-Methoxy-5'-methyl-4-nitro-2biphenylcarboxylic acd. This compound was prepared in a manner similar to that of 5 '-fluoro-2 -ehx--ir--bpeycroyi acid (EXAMPLE 107) from methyl 2 -methoxy-5!-methy[-4nitro-.2-biphenylcarboxylate (2.02 g) to afford 1.93 g of 2 mtoy5-ehl4nto2bpeycroyi acid as a white solid. Data for 2 '-methoxy-5'-methy1-4nitro2biphenylcarboxylic acid: 1 H NMR (400 MHz, acetone-d6) 8.63 J 2.5, 1 8.42 (dd, J 8.5, 2.5, 1 7.63 J IH), 7.19 (mn, I1H), 7.14 J 1 6.93 J1=8.4, 1FH), 3.70 3H), 2.32 3H).

6 -Methyl-2-nitro-3,4-benzocoumarin. 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 minol), SOC12 (0.49 mL, 6.7 inmol), and AIC13 (0.89 g, 6.7 inmol) to afford 1.65 g of 6 -inethyl-2-nitro-3,4-benzocoumarin as an orange powder. Data for 6-ehl2 ir 3,-ezcu-rn 1 H NMR (400 MHz, acetone-d6) 9.04 J 2.5, 1H), 8.69 (in, 2H), 8.26 1H), 7.53 J 8.6, 1H), 7.35 (d, J 8.6, lH), 2.49 3H).

H:.\Pka\Kq,\spci\5977.96.mROrD RECEPTORdoc 19/01/00 DOCKET NO.

016-0014A.WO 221 2-Am-ino-6-methyl-3 4 -benzocoumarin (structure 40 of Scheme XI, where Rl

R

2 =methyl). This compound was prepared in a manner similar to that of 2 -am-ino-6-fluoro- 3 ,4-benzocoumarin (EXAMPLE 107) from 6-methyl-2-nitro-3 ,4-benzocoumarin (1.64 g) to afford 1.40 g of 2-ndo6mty-,-ezcuai as a white solid, which was used in the next step without further purification.

1 2 -Dihydro-2,2.4,9-tetramethy15-coumaino 3 4 -flg~uinoline. (Compound 316. structure 41 of Scheme XI, where R 1

R

2 =-methyl This compound was prepared in a manner similar to that of Compound 207 from 2 -amidno-6-methy1-3,4-benzocouniain (1.40 g) to 10 afford 0.738 g of Compound 316 as a yellow solid. Data for Compound 316: IH NMR (400 MIHz, acetone-d6) 7.96 J= 8.6, 1H), 7.89 1H), 7.19 J= 8.6, 1H), 7.18 I1H), 7.14 J 8.4, 1 6.04 (br s, I1H), 5.51 IlH), 2.41 3H), 1. 29 6H). The methyl. is obscured by the acetone multiplet.

EXAMPLE 217 000*00 15 7-Chloro- l.

2 -dihvdro-2.2.4-timrethylb5..coumarino r3 4-flguino line (Compound 317.

structure 88 of Scheme XXIV whre R I=chloro, R 2 6

H.R

9 mtv 00.0 3 -Chloro-2-methoxyphenylboronic acid (structure 90 of Scheme XXIV. where R=chloro.

R

2 4 This compound was prepared in a manner similar to that of 5-fluoro-2methoxyphenylboronic: acid (EXAMPLE 107) from 2 -bromo-6-chloroanisole (0.71 g, 3.2 20 mmol), n-BuLi (2.5 M in hexanes; 1.28 mL, 3.2 mmol), and trimethylborate (1.09 mL, 9.6 mmol) to afford 0.55 g (91 of 3 -chloro-2-methoxyphenylboronic acid which was used without further purification.

Methyl (3 '-chloro--2 '-methoxy- 4 -nitro-2-biphenylcarboxylate). This compound was prepared in a manner similar to that of methyl (5'-fluoro-2!-methoxy-4nitro.2biphenylcarboxylate) (EXAMPLE 107) from methyl 2 -bromo-5-nitrobenzoate (0.58 g, 2.2 mmol), (PPh3)4Pd (77 mg, 0.066 mmol), and 5-chloro-2-methoxyphenylboronic acid (0.54 g, 2.9 mrnol) to afford 245 mg of methyl 3 '-chloro-2'-methoxy-4-nitro-2biphenylcarboxylate) as a clear oil. Data for methyl Q 3 '-chloro-2 methoxy-4-nitro-2biphenylcarboxylate): IH NMR (400 MHz, CDCl3) 8.79 J 2.4, lH), 8.40 (dd, J= 8.4, 2.4, lH), 7.57 J= 8.5, lH), 7.45 (in, IH), 7.15 (in, 2H), 3.75 3.47 3H).

H.M'n\Kp\pcS497796STROID RECEPTORAo 19/01/00 DOCKET NO.

016-O0l4A.WO 222 3 '-Chloro-2'-methoxy4nitro-2biphenycarboxylic acid. This compound was prepared in a manner similar to that of 5'-fluoro-2'..methoxy4nitro-2biphenylcarboxylic acid (EXAMPLE 107) from methyl (3 'chloro-2 '-methoxy-4-nitro-2-biphenylcarboxylate) 2 30mg) to afford 0.21 g of 3'clr- mtoy4nto2bpeycroyi acid as a white solid. Data for 3 !-chlor mtxynro-'-m enylox42. aid I NMR (400 MHz, acetone-d6) 8.76 J 2.5, 1FH), 8.50 (dd, J 8.4, 2.5, 1FH), 7.74 J= 1 7.51 (dd, J 7.9, 1.8, 1 7.31 (dd, J 7.4, 1.8, 1FH), 7.24 J 3.47 (s, 3H).

8 -Chloro-2-itro-3,4-enzocoumarin. This compound was prepared in a manner similar to that of 6 -fluoro-2-nitro-3,4-benzocoumarin (EXAMPLE 107) from 3 .chloro-2'-methoxy-4 nitro- 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-nitro3,4bnzocounrin as yellow crystals. Data for 8 -chloro-2nitro34nzocounmrin: 1H NMR (400 MHz, acetone-d6) 9.06 J 1F), 8.74 2F), 8.45 (dd, J 1.4, lH), 7.32 (dd, J 1.2, lH), 7.51 J= 8.0, 1ff).

2 -Ami 8c~r.34-benzocoumqrin (tuctur 7o cem XV hreR=hoo 20 R 2 6 This compound was prepared in a manner similar to that of 2 -amino-6-fluoro- 3 4 -benzocoumarin (EXAMPLE 107) from 8 -chloro-2-nitro-3,4-benzocounrin 18 g, 0.65 mm-ol) to afford 0.10 g of 2 -anmino-8-chloro-3, 4 -benzocoumarin as a white solid, which was used in the next step without further purification.

7-Chloro- 1,-iyr-,,-rmt 3 .comrioB4-flguino ine (Compound 317, structure 8 of Schem XXIV where 1 clro 2 6 9 =methyl). This compound was prepared in a manner similar to that of Compound 207 from 2 -amino-9-chloro-3,4benzocoumarmn (0.10 g) to afford 24 mg of Compound 317 as a yellow solid. Data for Compound 317: IH NMR (400 MHz, acetone-d6) 8.04 (dd, J= 8. 1, 1. 1, 7.98 (d, J 8.7, 1lH), 7.48 (dd, J 9. 0, 1. 1, 1 7.28 J 8.8, 1Ff), 7.23 J 8.6, 1Ff), 6.24 (br s, ILH), 5.55 J 1.2, 1Ff), 2.08 3Hf), 1.31 6H).

H:\Pianc\Kmp\spcM597796STROfD RECEPTORdOC 19/01/00 DOCKET NO.

016-0014A.W0 223 EXAMPLE 218 (3-Fluoro benzyl)- l.

2 -dihydro- 2 fimethyl-5H-chromeno D3 flquino fine (Compound 318, structure 32 of Sche-me IX. where R 3 -flugrobauDl To a solution of Compound 225 (EXAMPLE 125) (10 mg, 0.03 mmol) in CH2Cl2 (5 ml) was added triethylsilane (0.05 ml, 0.3 nimol) and trifluoroacetic acid (0.024 ml, 0.3 nimol) 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% NaGH solution (SniL) then extracted with EtOAc (10 mL). The organic layer was washed with brine (3 x 5 miL), dried 10 (Na2SO4), then concentrated in vacuo to afford a yellow oil. The crude product was purified by prep TLC (5 x 20cm, 250mm, 1: 1 CH2Cl2:hexane) to afford 1.0 mg. of Compound 318 as a yellow oil. Data for Compound 318: Rf=-0.26 (silica gel, 0 EtOAc:hex); IH NMR (400 MHz, CDC1 3 7.66 J 8.5, 1 7.48 d, J= 8.5 1 7.23 (in, 2 7.03 (in, 1 6.8 9 (in, 3 6.61 J= 8.5, 1 6. 10 (in, 1 5.49 1 H), 15 3.98 (brs, 1 3.10 (mn, 1 2.73 (in, 1 2.29 3 1.29 3 1.19 3 H).

0 EXAMPLE 219 .00 (R/S')-9-.Chloro- l.

2 -dihydro-5methoxy224trimethyj..5Hchromeno 3 ,4-flquinoline 0. (Compound 319 structure 47 of Schieme IV, where R=H. R 2 =chloro. 3 =methyl. X=0) 20 (R/S)-9-chloro- 1.-iyr--yrxy224tiehl5Hchromeno r 3 4 -Ilquino line (structure 46 of Scheme XIV. where R I=H. R 2 =chloro) and 6 -S-chloro-2-hdroxphenvlI..

1,-iyr--vrx ehl224tiehlunln (structure 94 of Scheme XXV, where R I 2

=R

4 6

R

3 =chloro.

R

7 9 =mehl. Compound 209 (EXAMPLE 109) (100 mg, 0.307 nimol) was dissolved in THF, cooled to -40 0 C, and treated with DIBAL (614 g.L, 0.614 rnrol, 1 M in THF, Aldrich), warm-ing to -20 0 C over 30 min. The reaction mixture was quenched with NH4Cl (sat) (2 niL) and allowed to warm to rt. The reaction mixture was poured into a separatory funnel containing EtOAc and water. The aqueous was extracted with EtOAc (2 x 20 niL). The combined organics were washed with NaCi (sat) (1 x 15 niL), dried (Na2S 04), filtered, and concentrated onto Celite. The material was purified by flash chromatography using 25% EtOAc:hexanes to afford 65 mg of chloro-12dhdo5hdoy224tieyl 5H-chro meno [3,4-fjquino line (structure 46 of H-.\PakKp\pecM5977-96STROID RECRP'IORAdo 19/01/00 DOCKET NO.

0O 16 -0014A.WO 224 Scheme XIV, where R I=H, R 2 =chloro) and 20 mg of 6 -(5-chloro-2-hydroxyphenyl>. 1,2diyr--yr yehl2,,-rmtyqioln (structure 94 of Scheme XXV, where

R

1 2

=R

4 6

R

3 =chloro,

R

7 9 =methyl). Data for (R/S)-9-chloro- l, 2 2,,-riehl 5Hcr 1 un ie H NMR (400 MHz, acetone-d 6 7.71

J

2.4, 1 7.55 J 8.4, 1 7.11 (dd, J 8.5, 2.4, 1 6.94 J 8.4, 1 6.84 J 5.9, 1H), 6.78 J 8.2, IH), 6.01 J 6.0, 1H), 5.56 (bs, lH), 5.52 LH), 2.36 (s, 3H), 1.31 3H), 1. 18 3H). Data for 6 -(5-chloro-2hydroxypheny 1l2diJhyo 5 hydro xymethylb2,2,4-tritethylquinline:l~ IH NMR (400 MI-z, acetone-d6) 7.18 (dd, J 3. 0, 1 7. 10 J 2.5, 1IH), 6.92 J 8.6, 11-H), 6./75 J 8.U, 1 6.63 (di, J= 10 8. 1, 1 5.46 1H), 5.25 1 4.55 (ABq, J= 11.4, 2H), 2.35 3H), 1.27 6H).

(R/S)-9-Chloro- 1,-ivr--ehx-,,-rmty5Hcoen r 3 4 -flquino line *(R/S)-9-chloro-1,-iyr -5hdoy224tiehl5-homn 3 4 -fjquino line 15 mg, 0.092 nrnol) was dissolved in methanol (3 mL) and treated with p-toluenesulfonic acid mg). After 10 min the reaction was quenched with NaHCO3 (2 mL). The resulting mixture was diluted with water (2 mL), poured into a separatory funnel, and extracted with EtOAc (3 x 20 mL). The combined organics were washed with NaC1(sat) (1 x 20 mL), dried (Na2S 04), filtered, and concentrated onto Celite. The material was purified by flash S 20 chromatography 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-d6) 7.73 J 2.4, 1H), 7.56 J 8.3, lH), 7.17 (dd, J 8.2, 2.4, 1H), 7.08

J

8.3, IH), 6.80 J= 8.3, 1H), 6.37 1H), 5.62 (br s,lIH), 5.54 1H), 3.44 3H), 2.27 3H), 1.32 3H), 1. 17 3H).

EXAMPLE 220 9-Chloro-. l 2 -dih ydro224trimethyl H hromeno [3 .4-iq uino line (Compound 320.

structure 93 of Schem XXV where R 1 2

=R

4 6 =H R 3 =chloro

R

7 9 =methyl) 6 -(5-Chloro-2..hydroxyphenyl)> 1,-iyr--yrxmty-,,-rtehlunln (EXAMPLE 219; structure 94 of Scheme XXV, where R 1

I-

2

=R

4 6

R

3 =chloro, R 7 9 mg, 0.061 mmol) was dissolved in CH2Cl 2 and treated with thionyl chloride H:\"an\Kep,pcM597796.M.RID RECEPTflR.doc 19/01/00 DOCKET

NO.

01 6 -0014A.WO 225 gL, 0.067 mmol) and triethylamine (9 g L 0.067 mmol). After 2 h the reaction was quenched with water and poured into a separatory funnel containing CH2C12 (20 mL) and water (lOmL). The aqueous was extracted with CH2C12 (2 x 20 mL). The combined organics were washed with NaCI (sat)(1 x 15 mL), dried (Na2SO 4 filtered and concentrated. The resulting benzyl chloride intermediate was dissolved in 1,2dichloroethane (1mL) and treated with triethylamine (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 (l%v/v HC1) and the aqueous was extracted with CH2C12 (2 x 20 mL) The combined organics were washed with NaCl(sat) (20 mL), dried (Na2SO4), filtered, and 10 concentrated onto Celite. The material was purified by flash chromatography on silica gel g) using 5% EtOAc:hexanes to afford 10 mg of Compound 320. Data for Compound 320: 1H NMR (400 MHz, acetone-d6) 7.60 J 2.4, 1H), 7.43 J= 8.4, 1H), 7.08 (dd, J 8.5,2.4, lh), 6.89 J 8.5, 1H), 6.70 J 8.4, 1H), 5.56 (br s, 1H), S..5.49 1H), 5.32 2H), 2.11 3H), 1.25 6H).

.:EXAMPLE 221 (R/S)-9-Chor .2-dihydr-22-triethy--pr pyxlo -5H-chrmn34-tquinine (Compound 321, structure 47 of Scheme XIV where RI=H, R 2 =chloro

R

3 pop

X=

(R/S)-9-Chloro-1,2-dihydro-5-hydroxy-2,2,4-trimethyl-5H-chromeno[34- 20 fAquinoline (EXAMPLE 219; structure 46 of Scheme XIV, where

R

1

R

2 =chloro) mg, 0.092 mmol) was dissolved in 1-propanol (3 mL) and treated with p-toluenesulfonic 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 mL). The combined organics were washed with NaCI(sat) (1 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 of Compound 321 as an opaque oil. Data for Compound 321: 1H NMR (400 MHz, acetone-d6) 7.73 J 2.4, 1H), 7.56 J 8.5, 1H), 7.14 (dd, J 8.3, 2.5, 1H), 7.03

J

8.5, 1H), 6.80 J 8.5, 1H), 6.46 1H), 5.60 (br s, 1H), 5.53 1H), 3.81 1H), 3.59 1H), 2.29 3H), 1.46 2H), 1.32 3H), 1.17 3H), 0.75, 3H).

H-'J'rjanka\K-Ppspcc\45977-96. ROID RECEPTOR.doc 19/oIoo DOCKET

NO.

0 16-0014A.WO 226 EXAMPLE 222 R/S)-9-Fluoro- 1, 2 -dihydro-5-methoxv22.4trimethyl SHchrko meno [3 .4-tlguino line (Compound 322, structure 47 of Scheme XIV. where R 1

R

2 =fluoro.

R

3 ,=methvl.

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 3 4 mg of Compound 322 as a clear oil. Data for Compound 322: 111 NMR (400 MHz, acetone-d6) 7.53 J 1 7.48 (dd, J 9.9, 3.0, 1H), 7.05 (dd, J 8.7, 4.9, 1H), 6.92 (in4 1H), 6.80 J 8.3, 1 6.34 1H), 5.54 J 111), 3.44 3H1), 2.28 J 1.4, 3H), 1.32 3H1), 1. 16 3H-).

00 EXAMPLE 223 *e RMJ-9-Fluoro-12dh o. -2uJ 2 uhietyl..J.thiopropoxy5H-cro meno [3 flguino line (Compound 323- trcture47 of Scheme XIV. where R=H. R 2 =fluor. 3 prplXS) 9-Fluoro 1, 2 -dihvdro- 5-hydro xy..4trimethyl 5Hchromeno 3 4 -flguino line (srcue4KfShm IV. where R=H R 2 -or) This compound was prepared in a manner similar to that of 9-chioro- l, 2 -dihydro-5hydroxy2,2,4iethyISHchro meno [3,4-AIquino ie (EXAMPLE 219) from Compound 207 (0.16 g, 0.51 inmol) to *seeafford 80 mg of 9-fluoro-1,- yr--ydoy224tiety Hcrmn[3,4- .:gfiquinoline as a white solid. Data for 9 -fluoro12dihydro5hydroxy224trimethylSH- 20 chroineno[3,4-Aquinoline: 1 H NMR (400 MHz, acetone-d6) 7.52 J 8.5, 1H), 7.46 (dd, J 9.9, 2.9, 111), 6.93 (mn, iIH), 6.86 (in, 211), 6.78 J 8.5, 1H1), 5.98 J 111), 5.56 (br s, 1H), 5.52 J= 1. 1, 1H), 2.37 J= 1.2, 3H), 1.30 311), 1. 18 3H).

(R/S)-9-Fluoro- 1,-iyr-,,-rmty-itiprpx-Hcrmn 4fqioln (Compound trutr 47 of Scheme XIV where R=H

R

2 =fluoro,

T

3 pov.X

S)

This compound was prepared in a manner similar to that of Compound 319 (EXAMPLE 219) from 9- fluoro- 1,-iyr--yrx-,,4tiehl5-homn [1,4-fjquino line (18 mg) to afford 21 mg of Compound 323 as a clear oil. Data for Compound 323: IH NMR (400 MHz, acetone-d6) 7.48 J 8.5, 1 7.45 (dd, J 10.0, 1.7, 111), 7.14 6.95 (mn, 2H), 6.73 J= 8.5, 1I), 5.52 J= 1.3, 111), 2.76 (mn, 1H), 2.58 (dt, J H-'PrianA\KP~s-c\4577-6.TERIDRECEPTORdoc 19/01/00 DOCKET

NO.

016-0014A.WO 227 12.9, 7.4, 1 2.47 J 1.2, 311), 1. 66 (mr, 2H), 1.25 3H1), 1.22 3H), 0.95

J=

7.3, 311).

EXAMWPLE 224 (R/S)-9-Fluoro- 2 -dihydro-224-trimethyl5propoxy-5H-chromeno [3 4 -flguinoline (Compound 324. structure 47 of ScheeXV hr 1 =1 2 fur.R=rpl This compound was prepared in a manner similar to that of Compound 319 (EXAMPLE 219) from 9-fluoro- l, 2 -dihydro -5hy droxy-2 24trieh et5-h15Hcho[ 3 ,4 l ln (EXAMPLE 223) (20 mg) to afford 21 mg of Compound 324 as a white solid. Data for Compound 324: 1 H NMR (400 MHz, acetone-d6) 7.53 J 1H), 7.47 (dd, J= 9.9, 2.9, 1H), 7.02 (dd, J 5.0, 111), 6.95(in, 111), 6.80 (d,JI= 8.5, 111), 5.53 (d,JI= .5 IH: 3.81 (dt, J= 9.2, 6.7, 111), 3.58 (dt, J= 9.2, 6.7, 111), 2.29 J= 1.5, 3H), 1.46 (sext, J 6.9, 2H), 1.32 3H), 1. 16 3H1), 0.75 J 7.4, 3H).

EXAMPLE 225 R/S)-5-Butyl-9chloro. 1,-iyr-224timty-5-hoe 3 .4-flguino line S Comoun 32. srucure42 of Sche.me XI. where nRI=H. R 2 =chloro Rbutyl).

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 mng, 0.12 mmol) and 2.5 M n-BuLi in hexanes (0.28 mL, 0.70 mm-ol) to afford 7 mg of Compound 325 as a clear oil. Data for Compound 325: 1H NMR (400 MHz, acetone-d6) 7.72 J 2.4, 1H1), 7.58 J 8.5, 1H1), 7.12 (dd, J 8.3, 2.5, 111), 7.05 (d, J 8.5, 111), 6.75 J 8.5, 111), 5.53 1H1), 4.82 J 8.0, 1H), 2.40 (mn, 211), 2.09 (s, 3H), 1.5-1.4 (in, 6H), 1.25 (br s, 611), 0.95 J1=7.8, 3H).

EXAMPLE 226 2 dihydro-9-methoxy2,2,4trimethyl-5h-chromn [3 4-flguino line (Copoud 3 6. trutur 42 of Scheme XI wher

-R

1 2 mtoy ,uy) This compound (12 mg, 33%) was obtained as a by-product in the formation of Compound 355 (EXAMPLE 255) as a colorless oil. Data for Compound 326: IH NMR (400 MHz, acetone-d 6 7.47 J 8.4, 111), 7.20 J 2.8, 111), 6.80 J 8.5, 1H), 6.69 (in, 2H), H-'\aak\K-P$PeM597-96STEOIDRECEPTOR. 19/01/00 DOCKET

NO.

Ol6-0014A.WO 228 5.79 (dd, J 10.3, 3.2, 1H), 5.51 J 1H), 3.80 3H), 2.24 J 1.0, 114), 1.74 (rn, 114), 1.5-1.3 (in, 514), 1.27 3H), 1. 18 3H), 0.84 J 3H).

EXAMPLE 227 R/S)-9-Fluoro- 1 2 dihydro-2,2,45.tetramethyl15H-chomen[3 4 -flguinoline (Compouind 217 strctue 42 of Scheme XI. where Rl=H.

R

2 =fluoro R1mehvl) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 (36 mng, 0. 12 inmol) 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 (400 MHz, acetone-d6) 7.46 J= 8.4, 1H), 7.41 (dt, J 10.0, 1.5, 1H), 6.84 (in, 2H4), ~6.80 J 8.5, 1H), 6.07 J 6.5, 1H), 5.53 J 1.4, IH), 2.25 J 1. 1, 3H), 1.32 J 6.5, 3H), 1.26 3H), 1.20 3H-).

EXAMPLE 228 R/S)-9-Fluoro. 2 -dihvdro-2,2,4-timethy1..5Hchromenof3 4 -flguinoline (Compondr 328 strctue 42 of Scheme XI, where R=R=H.

R

2 =floro).

*00 This compound was prepared in a manner sinmillar to that described for Compound 202 (EXAMPLE 102) from 9-fluoro-1,-iyr--hdoy224-rmty-H 6 chro meno [3,4-.fquino ie (EXAMPLE 223) (15 mg) to afford 14 mg of Compound 328 as a clear glass. Data for Compound 328: 1 H NMR (400 MHz, acetone-d6) 7.41

J

8.4, 11H), 7.41 (dt, J 10.0, 1.5, 1H), 6.84 (in, 2H), 6.70 J 8.4, 1H), 5.49 J 1.2, 1H), 5.29 214), 2. 11 J= 1.6, 3H), 1.26 614).

EXAMPLE29 LR/S- 2 -Diydro9methoxy224rethlHcrmn 3 4 -luino line (Copoud 29,stuctr42 f Scheme VF. where R =R=H

R

2 =mtoxy).

(RIS)- l.

2 -Dihyoydrodroxyetoine,4thxy2thlSHc [e34flginhn (trutue 6 f Schem.XIV where =H R 2 methoxv). This compound was prepared in a manner similar to that of 9-chloro- l, 2 -dihydro-5-hydroxy224trimethylsHchromeno[3,4flquinoie (EXAMPLE 219) from Compound 314 (24 mng, 0.075 mxnol) to H:,\Priy-V\Keep\sp~cM\597796STROID RECEPTOR.doc 19/01/00 DOCKET

NO.

0 l 6 -0014A.WO 229 afford 15 mg of l,2-dihydro5hydroxy9 -methoxy2,2,4fimethyl-5Hchro meno [3,4-Aquino line as a white solid, which was used directly in the next step.

(RIS)- l.

2 -Dihydro9methoxy224imethyl5Hcroe[ 3 4 -flguinoline (Comp ound 329. structure-' 42F of Sheme XI. where

R

1

R

2 =mtov This compound was prepared in a manner similar to that described for Compound 202 (EXAMPLE 102) from 1,-iyr--yrx--ehxy224t~ty-Hcrmn 3 ,4-fjquino line (15 mg) to afford 12 mg of Compound 329 as a clear glass. Data for Compound 329: 1 H NMR (400 MHz, acetone-d6) 7.41 J= 8.3, 1H), 7.16 J= 3.0, 1H), 6.81 J 1H), 6.68 (in, 1H), 5.48 J 1.2, 1H), 5.23 2H), 3.80 3H), 2.10 J 3Ff), 1.24 (s, 6H-).

(RIS)-l1.2-Dihydro-2,2,49 -tetramethyl-5H-chomeno r 3 4 -nginoline (Cmpound 330.

structure 42 of Scrheme XLwee R=R=Ff

R

2 mthvI) 15 This compound was prepared in a manner similar to Compound 229 (EXAMPLE 229) from C.:.Compound 316 3 4 mg, 0. 11 mmol) to afford 16 mg of Compound 330 as a clear oil.

Data for Compound 330: IH NMR (400 MHz, acetone-d6) 7.42 (in, 1Ff), 7.41 J 8.4, 1FfH), 6.90 (in, 1FH), 6.76 J1=8.0, 1Ff), 6.64 J 8.4, 5.48 1Ff, 5.41 (br s, 1H), 5.25 2Ff), 2.30 3H), 2. 11 J= 1.4, 3H), 1.24 6Ff).

EXAMPLE 231 (R/S)-7-Chloro -dihydro22, 4trmethl5-hro l5H34tqunlne(op.n 3 structure 93 of Scheme XV where R=chloro

R

2 6 =Hf R 7 9 =ethl) This compound was prepared in a manner similar to Compound 229 (EXAMPLE 229) from Compound 317 (20 mg, 0.061 mmol) to afford 11I mg of Compound 331 as a clear oil. Data for Compound 331: IH NMR (400 MHz, acetone-d6) 7.57 (dd, J 7.9, 1.2, 1Ff), 7.42 J 8.4, 1Ff), 7.18 (dd, J 1.2, 1Ff), 6.98 J= 7.9, 1Ff), 6.70 J= 8.4, 1Ff), 5.56 (br s, 1Ff), 5.50 J= 1.2, 1Ff), 5.40 2Ff), 2.14 J= 1.3, 3Ff), 1.25 6Ff).

H.'\ak\Kcep\,~spe49Th96.STROfD RECEP1OR.d. 19/01/00 DOCKET NO.

0 16-0014A.WO 230 EXAMPLE 232 fR/S)-9-Chloro- l.

2 -dihydro-2,2,4,5-tetramethy15N..chromeno 3 4 -flguinoline (Compound 332. structure 42 of Sche-me XI. where R I=H, R 2 =chlo ro, R=methyl) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 (40 mg, 0.123 mmol) and methyllithium (438 gtl, 0.6 14 mmol, 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 MHz, acetone-d6) 7.65 J 2.5, 1lh), 7.49 J 8.4, 1lH), 7.08 (dd, J 8.5, 2.4, IlH), 6.85 J 8.5, 1 6.70 J 8.5, 1 6.09 I1H), 5.52 I1H), 2.25 3H), 1. 32 J 3H), 1.26 3H), 1.20 3H).

EXAMPLE 233 .0 .:R/S)-5-(4-Bromophenvl).9-chloro- ~ty-Hcrmn[3.4t~lQuinln (Cmonu33 cture 42 of Scheme XI, where R=4-bromophenyl.

R

1

=H.

R

2 =Cl) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209, mg, 0. 123 mrnol) and l, 4 -dibro mo benzene (203 mg, 0. 859 mmol) to afford 11 mg of Compound 333 as a pale cream colored oil. Data for Compound 333: 1H NMR (400 MHz, acetone-d6) 7.59 J 2.4, 1H), 7.58 J 6.3, LH), 7.42 J 8.5, 2H), 7.16 J 2H), 6.94 (dd, J 1 6.92 6.84 1 6.77 J 1H), 5.68 (br s, lH), 5.48 1H), 1.98 3H), 1.27 3H), 1.24 3H).

EXAMPLE 234 9 -Chloro-5(3-chlorophenyl) l.

2 -dihdro-2.2.4-triethyl-5H-chromeno [3.4flguinoline (Compound 334 stucture 42 of Scheme XI. whereR=3-chlorophenvl.R 1 l.H.

R

2

=CI)

H. Priana\Kp~pcc59'7.6.TERIDRECEPTORdoc 19/01/00 DOCKET

NO.

0 16-0014A.Wo 231 This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 mg, 0. 123 mm-ol) and 3 -bromochloro 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, IR), 7.59 J 9.0, 1H), 7.25 (in, 4H), 6.95 (in, 2H), 6.85 J 8.3, 1H), 6.83 J 7.3, 1H), 5.72 (br s, 1H), 5.50 1H), 2.00 3H), 1.28 3H), 1.26 3H).

EXAMPLE 235 (R/S')-9-Chloro- .2-iyr-,,4t ehl5-3mtypenl Hcrmeno [3,4- 10 tlguinoline (Compound 335. structure 42 of Scheme XI. where R=3-methylphenyl, Rl=H,

R

2 =Cl) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 mg, 0.061 inmol) and 3 -bromotoluene (147 mg, 0.859 mmol) to afford 10 mg of Compound 335 as a pale white oil. Data for Compound 335: IH NMR (400 MHz, acetoned6) 7.59 J 2.4, 1H), 7.58 J 1, 1H), 7.19 (n,4 2H), 6.95 6.83 J= 1H), 6.78 J= 8.5, 1H), 5.64 (br s, 1H), 5.81 1H), 2.20 3H), 2.05 3H), 1.27 (s, 3H), 1.24 3H).

EXAMPLE 236 9 -Chloro-5-4.chloro.3methypheny). 1 2 -dihydro-2.2.4-trmethylI5Hchromeno 3 4-fginn (Comoun 336 structure 42 of Scheme where R=4-chloro- 3-inethylphenyl, R=H, R 2 =Cl) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 mng, 0.061 mmol) and 5-broino-2-chlorotoluene (177 mg, 0.859 rrirol) 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, 1H), 7.57 (dJ 8.5, 1H), 7.23 (mn, 2H), 7.00 (mn, 2H), H-\riana\-P~pel\597-9.SERIDRECEPTORAO 1910110 DOCKET

NO.

o 1 6-0014A.WO 232 6.91 I1H), 6.84 J= 8.2, 1H), 6.79 J1=8.5, 1H), 5.68 (br s, IlH), 5.48 (ds, JH), 2.23 3H), 1.99 3H), 1.27 3H), 1.25 3H).

EXA WPLE 237 R/S)-9-Chloro- 1 .2-dihydro-5-[3(rfurmty hnyl224tinty-H chroeno[.4ilujnoIne(Co"mpound 337. stuctre 42 -Of Scheme X1. where R=3- (trifluoromethyl)Vhenyl.

R

1

R

2

=C)

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 a 10 of Compound 337 as a cream colored oil. Data for Compound 337: IH NMR (400 MHz, acetone-d6) 7.61 J= 2.3, 1HM, 7.52 4H), 7.07 I1H), 6.99 (dd, J= 8.5, 2.4, IH±, 6.87 (di, J 8.3, 1H), 6.84 J 1H), 5.73 (br s, 1H), 5.51 1H), 2.01 3H), 1.27 6H).

15 EXAMPLE 238 LRL)-9Chlro5-(,5-iclorpheyD1. 2 -dihydro-2.2,4.tx~rethyI5Hchomenor34 tlguinoline omound 338 stucture 42 of Scheme XI where R3

R

1

R

2

=C)

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 *a 20 (40 mg, 0.123 mmol) and Il-bromo-3,5-dichloro bnzene (277 mg, 1.23 mmol) using diethyl ether for the formation of the aryl lithium in the first step. The final step afforded 11I mg of Compound 338 as a pale yellow oil. Data for Compound 338: IH NMR (400 MJ-z, acetone-d6) 7.64 J 1H), 7.61 J 8.5, 7.32 lH), 7.20 (s,1IH), 7.19 lIH), 7.03 (dd, J 8.9, 2.4, 11-1), 6.91 lH), 6.89 J 6.7, 1H), 6.88 J 6.7, lH), 5.78 (br s, IH), 5.53 1H), 2.03 314I), 1.28 3H), 1.27 3H).

H-''r~nk\K-~spcl4597-9.S-ERIDRECEPT0R.do 19/01/00 DOCKET

NO.

016-00 14A.WO 233 EXAMPLE 239 (R/S)-9-Chloro-1,- yr--4-ehxpey r,,-rmtyl5-hoeo3 .4tluinoline (omoun 339 stucur 42 of SceeX.wee 4 mto hnl.

Rl=H, R 2 =Cl) 4**~*eThis 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 (21 of Compound 339 as a pale yellow oil. Data for Compound 339: 1H NMR (400 MHz, acetone-d6) 7.59 J 2.5, 7.56 J 8.5, 1H), 7.11 J 8.7, 2H), 6.94 (dd, J= 2.4, 1H), 6.89 IH), 6.82 J 8.5, 1H), 6.75 (in, 3H), 5.61 (br s, 1H), 5.45 1H), 3.69 3H), 1.99 3H), 1.26 3H), 1.23 3H).

EXAMPLE 240

R/S)

9 Chloro5(3-fluoro-4methoxyphenyl) 2 -dihydro,-2,2.4trimethyl.5Hchromenor34..nguino ie (Compound 340 structure 42 of Scheme XI, where R=3-fluoro- 4 -methoxyphenyl R-H. R 2

=C)

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 mg, 0.061 mmol) and 4 -bromo-2-fluoroanisole (88 mg, 0.429 mmol) to afford 8 mg of Compound 340 as a pale yellow oil. Data for Compound 340: 1H NMR (400 MHz, acetone-d6) 7.60 J 2.4, IH), 7.58 J 8.5, 1Ff), 7.02 (dd, J 10.2, 2.4, lH), 6.97 (dd, J 8.5, 2.3, 1 6.94 J 8.5, 1FH), 6.90 I1H), 6.8 9 (in,4 IH), 6.84 J 1FH), 6.79 J 8.5, lH), 5.68 (br s, 1Ff), 5.48 1Ff), 3.79 3H), 2.00 3Hf), 1.27 (s, 1.24 3Ff).

Hx',ana\-spcc\9796SROD RECEPTOR.d 0 c 19/01/00 DOCKET

NO.

016-00 14A.WO 234 EXAMPLE 241 (R/S)-9-Chloro-5-4-fluorophenyl)- 1,-iyr- .2-rmtv-Hcrm [3.4.

flgUinln~o ud31 strcture 42 of Scheme XI. where R=4-fluorophenvl.

R

1

=H.

R

2 =C1) 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, 1 M, Aldrich) to afford 11I mg of Compound 341 as a pale yellow oil. Data for Compound 341: 1 H NMR (400 MHz, acetone-d6) 7.60 J 2.4, 1H), 7.58 J 7.3, 11-1), 7.24 (in, 2H), 6.96 (in, 48), 6.84 J 8.3, 1H), 5.67 (br s, 1H), 5.48 18), 1.98 3H), 1.26 (s, 3H), 1.24 3H).

EXAMPLE 242

(R/S)

9 Chloro-(3chloro4methox5methyhnl)- 2 -dihydro-224-trimnethyl-5H chro ienoBA.4flguinoline (Compound 342. utr 2o chm&I hr =3-chloro- 4 -methoxy- s-methylphenyl, R-H. R 2 This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 mg, 0.123 inmol) and 4 -bromo-2-chloro-5methylanisole (181 mng, 0.770n mol) to afford 12 mg of Compound 342 as a pale yellow oil. Data for Compound 342: IH NMR (400 MHz, acetone-d6) 7.61 J 2.4, 18), 7.58 J 8.4, 18H), 7.03 (in, 18H), 6.99 (dd, J 8.5, 2.4, 28), 6.91 18), 6.84 (dd, J 8.3, 3.8, 28), 5.69 (br s,1IH), 5.49 (s, 18), 3.70 38), 2.18 38), 2.01 38), 1.27 38), 1.26 38).

EXAMPLE 243 fRS) 9-hoo--(-loo.-ehl e b 2 -dih vdro-2.2,4- trethyl-H-cromeno r3.4f unln Cmon 43 structure 42 of Scheme XI. where R= 4 -fluorg3mehyphnv

R'=HR

2 Cl) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 209 mng, 0. 123 mmol) and 4 -fluoro--3-phenyl magnesium bromide (1 ml, 1.026 inmol, IM, Aldrich) to afford 8 mg of Compound 343 as a pale yellow oil. Data for Compound 343: IH NMR (400 MHz, acetone-d6) 7.59 J 2.6, 18), 7.57 J 8.6, 18), 7.12

J

H:\ryak\KeP\$PccM977-96.S'ROID RECEPTOR.d. 19/01/00 DOCKET

NO.

0 16-0014A.WO 235 8. 1, 1 6.99 (mn, I1H), 6.96 (dd, J 8.2, 2.4, 1 6.90 (in, 1 6.84 J 8.3, 1Ff), 6.77 J= 8.5, 1Ff), 5.68 (br s, 1ff), 5.48 1Ff), 2.14 3FH), 1.25 3Hf), 1.24 3H).

EXAMPLE 244 (R/S)-9-Chloro-5-(3-fluorophenyl)- l.

2 -dihydro-2,2,4-trimethy1-5H-chomenor3 .4flguinoline (Compound 344, structure 42 ofSche-me XI. where R=3-fluorophenvlI R=14f

R

2 =C1) 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 11 Img 10 of Compound 344 as a pale yellow oil. Data for Compound 344: IH NMR (400 M~fz, acetone-d6) 7.61 J 1Ff),7.59 J 8.4, 1Ff), 7.29 (in, 1Ff), 7.04 J 7.9, 1Ff), 6.97 (mn, 4Ff), 6.85 J 1Ff), 6.80 J 8.5, 1Ff), 5.7 (br s, 1Ff), 5.50 1Ff), 2.01 3Ff), 1.27 3Ff), 1.25 3Ff).

EXAMPLE 245 RIS)- l.

2 -Dihydro-2.2,4-t-imnty-534-methleedoy. eyl-H-hrm [o3.41fquino!LneCompound 345, structure 32 of Scheme IX. where R=3,4- (methylenedioxy)phenyl This compound was prepared by the General Method 5 (EXAMPLE 60) from 4-bromo-1,2- (methylenedioxy) benzene (201 mg, 1.0 inmol) and Compound 159 (15 mg, 0.05 inmol) to afford 1.5 mg of Compound 345 as a colorless oil. Data for Compound 345: 1

H

NMR (400 MHz, acetone-d6) 7.60 J 7.6, 1 Hf), 7.55 J 8.4, 1 6.98 J 7.6, 1 Hf), 6.88-6.60 (in, 6 5.98 1 Hf), 5.91 2 Hf), 5.51 (bs, 1 Hf), 5.46 I Hf), 2.02 3 Hf), 1.25 3 1.23 3 H).

EXAMPLE 246 (R/S')-5-(4-Chloro..3.methylphenyiy. l.

2 -dihydro-22.4tri~ethyls5H-cI omeno [3,41fgufioiie (Cmpoud 3 6 structure 32 of Schemge IX. where R-c--horo-3-methlphenyl) This compound was prepared by the General Method 5 (EXAMPLE 60) from 5-bromo-2chiorotoluene (206 mg, 1.0 inmol) and Compound 159 (10 mg, 0.03 inmol) to afford 8.0 ing of Compound 346 as a colorless oil. Data for Compound 346: IH NMR (400 MHz, H',r -a\Kp~s-Q\597-96STECIDRECRPTOR4OC 19/01/00 DOCKET NO.

016-00 14A.WO 236 acetone-d6) 7.60 J= 7.6, 1 7.55 J= 8.4, 1 7.23-7.19 (in, 2 7.01 J= 9.9, 1 6.97 J= 7.7, 1 6.89 1 6.88-6.8 1 (in,4 2 6.78 J 8.0, 1 5.55 (bs, 1 5.48 1 2.22 3 2.00 3 1.26 3 1.24 3 H).

EXAMPLE 247 (4-Bromo-3-pvridyl)- 1.2,3 4 -tetrahydro-2,2-dimethy-4methylidene-5Hchro meno[r3,4-flguino line (Compound 347, structure 33 of Scheme IX. where R=4-bromo- 3-pyridyl).

This compound (1.8 mg, was obtained as a colorless oil along with Compound 197 as 10 described above (EXAMPLE 97). Data for Compound 347: 1H NMR (400 MHz, CDCl3) 8.22 J 5.2, 1 7.56-7.49 (mn, 2 7.34 1 7.12 J 6.5, 1 7.03 (td, J= 7.4, 1.3, 1 6.92 (td, J 7.4, 1.3, 1 6.86 J 7.5, 1 6.61 J 8.2, 1 6.58 1 4.98 1 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 (R/S')-5-(3,5-Difluoropheny). l.

2 -dihydro-2,2,4-trimethyl.5H..chro meno [3.-figuino line (Comnpound 348, structure 32 of Scheme IX, where This compound was prepared by the General Method 5 (EXAMPLE 60) from 1-bromo-3,5difluorobenzene (193 mng, 1.0 inmol) and Compound 159 (20 mng, 0.07 inmol) to afford 14 mg 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, I 6.94-6.83 (in, 6 5.62 (bs, 1 5.11 1 2.04 3 1.27 3 1.26 3

H).

EXAMPLE 249 (R/S)-5-(3,5-DichlorophenyD) 2 -dihydro-224timeth yl5H..c homeno [3,4-flg~uino line (Compound 349. stucture 2 of Scheme IX. where This compound was prepared by the General Method 5 (EXAMPLE 60) from dichlorobenzene (226 ing, 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, H.-Priank\Kp~seci4597-6.S7ERIDRECEPTORAdO 19/01/00 DOCKET NO.

0 16-00 14A.WO 237 2940, 1690, 1590, 1480, 1070; IH NMR (400 MHz, acetone-d6) 7.63 J 7.7, 1 7.58 J 8.4, 1 7.29 J 1.9, 1 7.20 J 1.9, 2 7.03 J 7.7, 1 6.97 1 6.93-6.85 (in, 3 5.63 (bs, 1 5.53 1 2.04 3 1.28 3 1.27 3 1 3 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.

-0000:EXAMPLE 250 R/S)-5-(3-Bromo-5-methvlphenyl). 1, 2 -dihydroI2.2.-trimeth 15Hchomeno [3.4- 10 flguinoline (Compound 350. structure 32 of Scheme IX where methyllphenyl) This compound was prepared by the General Method 5 (EXAMPLE 60) from dibromotoluene (250 mg, 1.0 mmol) and Compound 159 (10 mg, 0.03 mmol) to afford 6.1 mg(6)of Copud350 as a colorless oil. Data for Compound 350: IH NMR (400 MHz, acetone-d6) 7.61 J1=7.7, 1 7.56 J1=8.4, 1 7.17 1 7.14 1 7. 10 1 7.01 J 7.7, 1 6.91 1 6.90-6.82 (in, 3 5.58 (bs, 1 5.50 (s, 1 2.21 3 2.02 3 1.27 3 1.26 3 H).

EXAMPLE 251 (R/S)-5-(3-Bromo-5-fluorophenyl)-.l. 2 -dihydro-2,2,4-trimTethyl..5Hchromeno [3.4flguinoline (Compound 351, structure 32 of Scheme IX, where This compound was prepared by the General Method 5 (EXAMPLE 60) from 1 ,3-dibromo- (254 mg, 1.0 mmol) and Compound 159 (10 mg, 0.03 mmol) 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; IIR (neat) 3367, 1699, 1595, 1581, 1469, 1435, 125 1; 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 (in, 2 H),.6.97 1 6.94-6.85 (in, 3 5.64 (bs, 1 5.53 1 2.04 3 1.28 3 1.27 3 1 3 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 (d,IJ= 22.2 Hz), 74.9, 51.2, 29.4, 24.0.

H.nka\K p\pcc597796.S-hROID RECEPTORAdO 19101100 DOCKET

NO.

016-0014A.WO 238 EXAMPLE 252 (R/S)-5-(3-Bromo-5-fluorophenyl)- 1, 2 3 4 -tetrahydro-2,2-dinmethy14-methylidene SII-chromeno[3,4-ngquinohlne (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: IH NMR (400 MHz, CDCl3) 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 1 4.56 1 4.01 (bs, 1 2.42 J 1 2.21 J= 12.3, 1 1.34 3 1. 15 3 H).

EXAMPLE 253 [4-Fluoro-3- (trifluoromethyl)phenyllL 2 -dihydro--2 24-trimnethyl-5Hchromienor3.4.flguino ie (Compound 3535. struc-ture 2 of Scheme IX where R=4-fluoro- 3 -(trifluoromethybphenyl) 15 This compound was prepared by the General Method 5 (EXAMPLE 60) from 5-bromo-2fluorobenzotrjfluoride (243 mg, 1.0 mmol) and Compound 159 (10 mg, 0.03 mmol) to *0e~ 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 7.61-7.53 (in, 3 7.27 J 7.7, 1 7.04-6.82 (in, 5 5.62 (bs, 1 5.51 1 2.02 3 1.26 6 H).

EXAMPLE 254 (R/S)-9-Fluoro-1,-iyr- .4fiehl5 [-ehlhnl)5-hoeo34flgquioline (Compound 354. structure 42 of Scheme XI. where R=3-metvlphenvl, RI=H4.

R

2

=F)

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 (31 mg, 0. 10 inmol) and 3 -bromotoluene (90 mL, 0.74 inmol) to afford 18 mg of Compound 354 as a colorless glass. Data for Compound 354: 1 H NMR (400 MHz, acetone-d6) 7.53 J 8.5, 1H), 7.33 (dd, J 9.9, 2.9, JH), 7.08 (mn, 2H), 6.98 J 6.7, 2H), 6.89 1H), 6.83 J= 8.5, 1H), 6.75 (in, 2H), 5.48 1H), 2.20 3H), 1.99 (s, 3H), 1.27 3H), 1.25 31-).

H:,\Prn\K~p.M5977h96.S'hROID RECEPTORAdv 19/01/00 DOCKET

NO.

016-.0014A.WO 239 EXAM PLE 255 215h) 1, 2 -Dihydro9meth x22,4imethyl5(3methlphenl)SHcho [o3.4-

R

2 =methoxy) This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 314 (32 mg, 0.10 mmol) and 3 -bromotoluene (90 mL, 0.74 mmol) to afford 10 mg of Compound 355 as a colorless glass. Data for Compound 355: 1 H NMR (400 MHz, acetone-d6) 7.53 J 8.5, 1H), 7.13 J 2.8, IR), 7.08 (in, 2H1), 6.99 (in, 2H), 6.83 (d, 6.0, 1 6.80 I1H), 6.70 J 1 6.55 (dd, J 8.7, 2.8, 1ff), 5.46 J 1.2, 1H), 3.72 3H), 2.24 3H), 1.98 3H), 1.26 3H1), 1.24 3H).

EXAMPLE 256 9 -Fluoro5(3.fluoro-4methoxyhenyl) l 2 -dihydro-2.2,4-trimethyl-5Hchrom-enor341unln (Comoun 35.srcure 42 of Scheme XIwhr R=3-fluoro- 4 -methoxyphenyl, Rl-H, R 2

=F)

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 (41 mg, 0. 12 mmol) and 4 -bromo-3-fluoroanisole 13 mL, 1.0 mmol) to afford I11 mg of Compound 356 as a yellow oil. Data for Compound 356: 1 H NMR (400 MHz, S acetone-d6) 7.55 J 8.5, 111), 7.35 (dd, J 10.0, 2.8, 111), 7.01 (dd, J 12.5, 1.9, 111), 6.95 J 6.9, 111), 6.87 (in, 3H), 6.74 (mn, 211), 5.48 J 1.2, 1H), 3.79 311), 1.97 (s, 3H), 1.27 3H), 1.24 3H).

EXAMPLE 257 (R/S)-9-Fluoro 1.

2 dihydro-2.2.4trimethyl-s..[3(trmuoronethyl)phenlJ

H-

lhoeo344unjn Compound 357 structure 42of Scheme XI, where R=3- (trifluoroinethyl)phenyl R=H. R 2

=F)

This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 mg, 0. 12 inmol) and 3 -bromobenzotrifluoride 14 mL, 1.0 inmol) to afford 11I mg of Compound 357 as a yellow oil. Data for Compound 357: IH NMR (400 MHz, acetone-d6) 7.54 J= 8.5, 1H), 7.35 (dd, J= 9.9, 2.9, 111), 7. 10 (mn, 211), 6.98 J= 6.7, H:\Priyanka\Kcq\pcc59796STER[f RPCEPTOR. 19/01/00 DOCKET

NO.

016-0014A.WO 240 2H), 6.89 I1H), 6.85 J= 8.5, 1WH), 6.75 (in, 2H), 5.48 1H), 1.99 3H), 1.27 (s, 3H), 1.25 3H).

EXAMWPLE 258 9 -Fluoro5(4-fluoro-3methylphenyl)- l.

2 -dihydro-224nethyl-5Hchomeno r3,4flgu iolineCmon35.srcue4ofSh eXIwhrR=-uoo3mtvpnl R I=HL R 2 This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 207 (38 mg, 0. 12 mmol) and 1.0 M 4 -fluoro-3-methylphenyl magnesium chloride in TWF 10 (Aldrich) to afford 25 mg (51 of Compound 358 as a yellow oil. Data for Compound too* 358: 1 H NMR (400 MHz, acetone-d6) 7.54 J 8.4, 1W), 7.34 (dd, J =10.0, 2.8, 1W), 7.14 (in, I1H), 7. 00 (in, 1WH), 6.91 J= 9.6, 1WH), 6.8 8 IlH), 6.8 3 J= 8.4, 1WH), 6.7 9- 6.68 (in, 2H), 5.48 1W), 2.13 3H), 1.99 3H), 1.27 3H), 1.24 3H).

EXAMPLE 259 2 .4Difluorobenzyidene) 2 dihydro-22.4trimethyl.sHcffQmefl 0 3 4 -f'lguinoline (Comp~ound 359 structure 45 of Scheme XIUI where R=

R

3 ilorpen) This compound was prepared by General Method 6 (EXAMPLE 119) from 2,4difluorobenzyl bromide (0.27 ml, 2.10 mrnol) and compound 159 (20 mg, 0.07 mmol) to afford 16 mg of Compound 359 as a yellow oil. Data for Compound 359: Rf=0.44 (silica gel, 25% EtOAc:hex); 1 H NMR (400 M~z, acetone-d6) 8.43 (in, 1W), 7.86 J 1 7.67 J 8.5, 1 7.20 2 7. 11 to 7.03 (in, 3 6.86 J 8.5, 1 H), 5.88 1 5.55 1 2.11 3WH), 1.29 (brs, 6WH).

EXAMPL E 260 0Z-5-(34-Difluoro benzylidene)- 1,-i do224umty-Hcrmn [3 .4-fguinotine (Copoud 3 0. trutur 45 of Scheme XI-I where R= .R=.-iloohnl This compound was prepared by General Method 6 (EXAMPLE 119) from 3,4difluorobenzyl bromidde (0.27 ml, 2.10 inmol) and Compound 159 (20 mg, 0.07 mmol) to afford 20 mg of Compound 360 as a yellow oil. Data for Compound 360: Rf=-0-44 (silica gel, 25% EtOAc:hex); IH NMR (400 MHz, acetone-d6) 7.83 (in, 2 7.66 J H-'P~iana\KP~sec\4577-6.TERIDRECEPTORdoc 19/01/00 DOCKET NO.

0 16-0014A.WO 241 1 7.55 1 7.31 1 7.24 (in,4 2 7. 10 (in, 1 6.85 J 8.5, 1 H), 5.67 1 5.55 1 2.08 3 1.28 (brs, 6 H).

EXAMPLE 261 (Z)-5-(3-Fluoro benzylidene). 1, 2 3 4 -tetrahydro-22 4trjmethl5Hchromeno [3,4tiguinoline (Compound 361).

A solution of Compound 159 (20 mg, 0.07 inmol) in EtOAc (10 mnl) was stirred over Pd/C (5 mg) at rt under an atmosphere of H2 (1 atm) for 15 h. The reaction midxture was filtered then concentrated in vacuo to afford 14 mg of the 1 2 ,3,4-tetrahydro.2,2,4- *:triiethy1-5H-cournarino [3,4-ejquino line as a yellow solid. According to General Method 6 (EXAMPLE 119), from 3-fluoroberizyl chloride 17 ml, 1.40 inmol) and 1,2,3,4terhdo224trmty Hcuain[,-~unln (14 mig, 0.05 mmol) was obtained 8.6 mng of Compound 361 as a yellow solid. Data for Compound 361: Rf=-0.38 (silica gel, 25% EtOAc:hex); 1 H NMR (400 MHz, acetone-d6) 7.82 J 8.5, 1 6.69 (in, 1 7.62 J 8.5, 1 7.58 J 8.5, 1 7.40 (mn, 1 7.22 (in, 2 7.08 (-4 1 6.97 1 6.74 J1= 8.5, 1 6.24 1 5.30 (brs, 1 3.76 1 1.97 (in, 1 1.55 1 1.40 J 6.6, 3 1.30 3 1.26 3 H).

EXAMPLE 262 2 6-Difluorobenzylidene): 2 -dihydro-2.,2,4-tri ethyl-5Hc oieno [3, 4 -fjlguinl (Compound 362 stucturet 45; of Shm II hr 1 R= 3 ilooh This compound was prepared by General Method 6 (EXAMPLE 119) from ac-bromo-2,3difluorotoluene (0.43 g, 2.1 minol) and Compound 159 (20 mg, 0.07 inmol) to afford 4.4 mng of Compound 362 as a yellow oil. Data for Compound 362: Rf=0.45 (silica gel, EtOAc:hex); IH NMR (400 MHz, acetone-d6) 7.83(d, J 8.5, 1 7.68 J 1 7.35 (in, 1 7.15 (in, 1 7.04 (in, 3 6.90 J= 8.5 H, 1 6.87 J 8.5, 1 5.61 1 5.57 1 2.23 3 1.32 (brs, 6 H).

H' nk\Kep\pcM59Th-96SROID RECEPTORdoc 19/01/00 DOCKET NO.

016-0014A.WO 242 EXAMPLE 263 (Comound363.strutur 45 of Scheme XIUI where R I=R 2

R

3 =2-methvlphen vl) This compound was prepared by General Method 6 (EXAMPLE 119) from aX-chloro-oxylene (0.20 ml, 1.6 mmol) and Compound 159 (15 mg, 0.05 mmol) 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 l.

2 Dihydro-5-(2.4,6-tr rrethylbenzylidene-22.4-tethyl-5H-chromeno r3,4fg~uinoline (Compound 364. structure 5o cee II hreR= 2 H R 3 =2 4 6trimethylphenyl) This compound was prepared by General Method 6 (EXAMPLE 119) from axchloroisodurene (0.50 g, 3.0 mmol) and Compound 159 (30 mg,. 0..10 mmol) to afford 0 mg of Compound 364 as a yellow oil. Data for Compound 364: Rf=0.40 (silica gel, o: o.25% EtOAc:hex); IH NMR (400 MHz, CDC13) 7.65 J 8.5, 1 7.51 J 8.5, 1 7.15 J 1 6.93 J 8.5, 1 6.88 2 6.80 J 8.5, 1 6.65 (d, J 8.5, 1 5.69 1 5.50 1 3.73 (brs, 1 2.28 6 2.26 3 2.16 (s, 3 1.45 (brs, 6 H).

EXAMPLE 265 9 -Chloro-5-(2.sdifuorobenzylidene) 2 -dihydro-2,2.4-trmethl-5H-chromeno 13.4flguinoline (Compnound 365 structure 45 of Scheme XIII. where R=H, R 2 =Cl. R 3 difluorophenyl) This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 209 mg, 0. 123 mmol) and a-bromo-2,5-difluorotoluene (414 mg, 2.0 mmol) to afford 10 mg of Compound 365 as a yellow oil. Data for Compound 365: IH NMR (400 MHz, acetone-d6) 8.05 (in, I1H), 7.87 (s,1IH), 7.72 J= 8.5, 1 7.26 (mn, IlH), 7.19 (mn, I1H), 7.06 (mn, 1H), 6.90 J= 8.5, 1H), 5.94 1H), 5.57 lH), 2.11 3H), 1.32 (br s, 6H).

H".Pria~k\K-~s-CM97796.TERIDRECEPTORdoc 19/01/00 DOCKET

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016-0014A.WO 243 EXAMPLE 266 (Z)-5-Benzlidene9chLoro-l. 2 -dihydro-2,24-trimethy1..5H..chomeno Ii 4 -flguinolijn This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 209 mg, 0. 123 mmol) and benzyl magnesium chloride (614 pt,, 0.6 14 rnmol, I M, Aldrich) to afford 10 mg of Compound 366 as a yellow oil. Data for Compound 366: 1H NMR (400 MHz, acetone-d6) 7.83 J 111), 7.81 (in, 211), 7.67 J 8.4, 1H), 7.39 2H), 7.21 (in, 3H), 6.84 J1=8.5, 1 5.71 11H), 2. 10 3H), 1. 34 (bn s, 6H-).

EXAMPLE 267 (Z)-9-Chloro- 1,-iyr-,,-rm~hl5(2mtybnviee-H rmnr3 .4flguinoline opud37 structure 45 of Seme XII. where 1

R

2 =Cl. R 3 =2methylphenyl.) This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 209 mg, 0. 154 inmol) and ax-chloro-o-xylene (345 mg, 2.46 inmol) to afford 14 mg of Compound 366 as a yellow oil. Data for Compound 366: 1H NMR (400 MHz, acetone-d6) 7.8 111 7.66 J 8.5, 111), 7.17 (in, 2H1), 7.11 (mn, 2H1), 68 d 6.55 111), 5.73 1H),4.98 1H), 2.19 311), 1.29 (br s, 3H), 1.21 311).

EXAMPLE 268 fZ)-5-Benzylidene9chloro- 1,-iyr-,-imty-Hcrmn r-flguinoline (Compound 368 structure 95 of Scheme XXVI. where R 1 2

=R

4 6

=R

9 11 R 7

R

8 =methyl.

R

1 0 =phenyl) This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 313 mng, 0.080 mm-ol) and benzyl magnesium chloride (0.802 mL, 0.802 mmol, 1 M solution in ether, Aldrich) to afford 5 mng of Compound 368 as a yellow oil. Data for Compound 368: 'H NMR (400 MHz, acetone-d6) 7.86 J= 7. 1, 111), 7.79 J= 2.2, 111), 7.63 J 8.5, 111), 7.40 (in, 211), 7.20 (in, 411), 6.8 9 J 8.6, 111), 6.7 8 J 8.4, 111), 5.99 111), 5.70 J 8.3, 111), 1.37 6H1).

H*\PY'n\K-~sP-1\597-96STEOIDRECEPTOfR.d-~ 19/01/00 DOCKET

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0l6-0014A.WO 244 EXAMPLE 269 9 -Chloro-5-(2-fluorobenzylidene)r 1, 2 -dihydro-2.2,4-trirnethy15Hchomeno [3,4tiguin lie(opud39 tutr 5o ceeXI.weeR=.R=I 3 =2fluorophenyl) 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: 1 H NMR (400 MHz, acetone-d6) 8.32 (in, 1H), 7.84 J 1.7, 1H), 7.69 J 8.5, 1IH), 7.26 (in, 211), 7.20 (d, 10 J 3.0, 111), 7.18 (mn, 2H), 6.87 J= 8.5, 1H), 5.97 1H), 5.57 1H), 2. 11 3H), 1.33 (br s, 6H1).

EXAMPLE 270 9 -C lo o -5 (3 fl u rob nz lid ne 1, 2 -dihydro-22 4-trim ethv1-H chr o en o3, 4 fluorophenyl) S 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 iniol) to afford 2 0 mg of Compound 370 as a yellow oil. Data for Compound 370: 1 H NMR (400 MHz, acetone-d6) 7.85 J 2.3, 111), 7.69 J 8.5, 111), 7.66 (n,4 111), 7.52 J 7.7, 1H1), 7.41 (in, IlH), 7.25 (in, 2H1), 7.01 (in, 11H), 6.87 J 8.4, 1lH), 5.73 11H), 5.57 J= 1.2, 111), 1.45-1.35 (br d, 611). The C(4) methyl is obscured by the acetone inultiplet.

EXAMPLE 271 LE/Z)-5-Benzyjidene.9-fluoro- h [3o224tiety-Hcrmn BA-flguino line (Cmpun 3 1.stu tr 45 of Scheme xII, heeR 1

H.R

2 F R=penl This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 207 (79 mg, 0.25 inmol) and 1.0 M benzylmagnesium chloride in Et2O (Aldrich) to afford mg of Compound 371 as a yellow oil, as a 2:1 ZIE midxture. Data for Compound 371: IH NMR (400 MHz, acetone-d6) 7.80 J 7.7, 111), 7.6 (in, 2H), 7.39 J 7.8, 111), 7.23 (in, 211), 7.15 (in, 111), 7.08 (Mn 111), 6.95 (in, 111), 6.83 (dd, J= 8.4, 2.8, 1 H), H.*Priank\Km~sccM97796.TERIDRECEPTORAdo 19/01/00 DOCKET

NO.

0 l 6 -0014A.WO 245 5.70 1H), 5.55 J= 1.2, 1H), 2. 10 3H), 1.35-1.25 (br d, 6H). The characteristic signals for (E)-371 are: 6.53 5.04 1H), 1.94 J 1.2, 3H), 1.33 3H), 1.00 3H-).

EXAMqPLE 272 (Z-5-Benzylidene-8.fluoro- 1 2 dihydro-2 2.4-t ethl.SH-chromeno [3 4 -flguino line (Compound 721 stucture 45C of Scheme XIUI where R=F.

R

2 =H.R penl This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 208 mg, 0. 18 mrnol) and 1.0 M benzylmagnesium chloride in Et2O (Aldrich) to afford 11 mg of Compound 372 as a yellow oil. Data for Compound 372: IH NMR (400 acetone-d6) 7.86 (dd, J 8.7, 6.2, 1lH), 7.80 J 7.6, 2H), 7.61 J 8.4, 1iH), 7.40 (app t, J 2H), 7.20(in, 7.05 lT), 6.86 (in, IH), 6.83 J 1H), 5.71 1 5.55 J= 1. 1, lEH), 2.11 3H), 1. 40 (br s, 6H).

EXAMPLE 273 2 -dihydro9methoxy224trmethy1-5 -crmn[, 4 fluinoline (Copond373 srutue 45 of Scheme XII where R I=H. Rmto

R

3 phnv) This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 314 mg, 0. 18 inmol) and 1.0 M benzylmagnesium chloride in Et2O (Aldrich) to afford 11I mg of Compound 373 as a yellow oil. Data for Compound 373: IH NMR (400 MHz, acetone-d 6 7.79 J 2H), 7.53 J 8.5, 1H), 7.4-7.2 (in, S5H), 6.84 (mn, 2H-), 5.67 lET), 5.55 lH), 3.82 3H), 2.11 3H), 1.35-1.30 (br s, 6H).

EXAM PLE 274 (Z)-9-Fluoro. 1,-iyr:.,-rme [-2mtlezlien)5-hoe34flgunolie (ompond 74 structure 45 of Scheme XIUI where R =H R 2 =fluoro R methyiphenyl) This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 207 (34 mg, 0. 11 inmol) and freshly prepared 1.0 M 2 -inethylbenzyl magnesium chloride in Et2O to afford 30 mg of Compound 374 as a yellow oil. Data for Compound 374: IH NMR (400 MHz, acetone-d6) 8.20 J 7.9, 1H), 7.64 J 8.5, lET), 7.58 (dd, J H"'ak\KP\ PeCMS97796STROD RECEP13R. 19/01/00 DOCKET

NO.

0l6-0014A.WO 246 10.0, 2.9, 1H), 7.26 (app t, J 7.6, 1I), 7.19 J 7.4, 1H), 7.14 (in, 2H), 6.94 (in, 1H), 6.84 J= 8.5, 1 5.95 I1H), 5.55 J= 1. 1, 1lH), 2.28 3H), 2.14 J= 1. 1, 3H), 1.35-1.30 (br s, 6H).

EXAMPLE 275 8-Fluoro- 1, 2 -dihydro 2 24trimethyl.5(2methbnylieneyi)5Hch [o34- Igu iotine (Compound 175. structure 45 ofShm XIII where R=fluoro.

R

2 -H R 3 =2methylphenyl-) This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 208 S 10 (31 mg, 0. 10 inmol) and freshly prepared 1.0 M 2 -inethylbenzyl magnesium chloride in Et2O to afford 32 mng of Compound 375 as a yellow oil. Data for Compound 375: H NMR (400 MHz, acetone-d6) 8.19 J 7.9, 1 7.86 (dd, J 8.8, 4.2, 1 7.61 (d, J 8.5, 1 7.28 (app t, J 7.6, l1-H), 7.20 J= 6.9, 1 7.15 (mn, I1H), 6.94 (dd, J 9.6, U 2.7, 1H), 6.86 (in, 2H), 5.97 1H), 5.55 J 1.2, 1H), 2.28 3H), 2.14 3H), 1.35 (br s, 6H).

EXAMPLE 276 h a L i gu i n o li n e C o m p o n d 7 .s t u t r 4 f S h e eX I I h r R .R m t o y

R

3 =2-methyl henyl) This compound was prepared by General Method 6 (EXAMPLE 119) from Compound 314 mng, 0. 18 inmol) and 1.0 M benzylmagnesiurn chloride in Et2O (Aldrich) to afford 11I mng of Compound 373 as a yellow oil. Data for Compound 373: 1H NMR (400 MHz, acetone-d6) 8.23 J 7.8, 11H), 7.64 J 8.5, 1 7.37 (mn, I1H), 7.30 (mn, I1H), 7.15 (in, 2H), 7.04 J 8.6, 1lH), 6.82 J= 8.4, 1 6.77 (dd, J= 8.6, 3. 0, 1lH), 5.92 (s, lH), 5.53 J 1H), 3.82 3H), 2.27 3H), 2.14 3H), 1.35 (br s, 6H).

EXAMPLE 277 (Z)-5-Benzylidene9fluoro- I 2-dihydro.2,2,4 11 -tetrainethyl-5H-chro meno [3,4-fig uino line (opud3 7 tutr 95 of Scheme XXVI where R 2

=R

4

=R

6

R

3 =F R 5

=R

7 9 -methyl.

R

1 0 =phenyl) H'.\anhKccpspcM597-96sTEOIDRECEPMhR.doc 19/01/00 DOCKET NO.

016-0014A.WO 247 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: 1 H NMR (400 MHz, acetone-d6) 7.79 J 7.6, 2H), 6.63 (dd, J= 11.4, 2.9, 1H), 7.39 (app t, J 7.8, 2H), 7.25 2H), 6.97 1H), 6.68 1H), 5.74 1H), 5.52 J 1.2, 1H), 2.61 (s, 3H), 1.97 3H), 1.33 (br s, 6H).

EXAMPLE 278 R/S)-5-(4-Chloropheny- l ,2,3, 4 -tetrahydro-2, 2 -dimethvl-5H-chromenof3,4-f1-4- 10 quinolinone (Compound 378, structure 97 of Scheme XXVI, where R=4-chlorophenl) 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 i 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 CH2Cl2 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: 1 H 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, 1 2.65 J 15.2, 1 2.44 J 15.2, 1 1.97 3 H), 1.37 3 1.27 3 H).

H. "~nka\Keep\speci\4597'7-96.SeRRECEPTOR.-d 19/01/00 DOCKET

NO.

016-00 14A.WO 248 EXAMPLE 279 R/S)-5-(4-Chlorophenyly. 1.2.3 4 -tetrahydro-2,2,3,3-tetramethylp5H-chromeno [3,4-fjj-4quinolinone (Compound379. stuctre 98 of Scheme xxvIII, whereR4chrpenl R 1 =methyl) To a suspension of 40% NaH in mineral oil (10 mg, 0.25 mmol) in THF (1 mL) was added a solution of (RIS)- l-(t-butoxycarbonyly5-(4-chlorophenyl) 1,2,3 ,4-tetrahydro-2,2- 4 -quinolino ne (structure 96 of Scheme XX VII, where R:=4chlorophenyl,

R

1 =methyl) (10 mg, 0.02 mmol) and excess Mel 1 The reaction was stirred at r1 for 2 h and was quenched with water (1 mL), and extracted with EtOAc (2 x 10 mL). Removal of solvent provided the crude mixture, which was treated with TFA (0.2 mL) in dichioromethane (1 mL) for 60 min. Chromatography of the crude midxture on a silica gel 4* colun using 15 EtOAc/Hexane as solvent afforded 6.5 mg of Compound 379 as a colorless oil. Data for Compound 379: IH NMR (400 MHz, CDCl3) 7.73 J 8.7, 1 7.49 J 7.7, 1 7.30 1 7.13 4 7.04 J 7.7, 1 6.91 J 7.7, 15 1 6.83 J= 7.7, 1 6.71 J= 8.7, 1 4.28 1 1.29 3 1.20 3 H), 1. 13 3 1.03 3 H).

EXAMPLE 280 (R/S)-S-(4-Chlorophenyl)- 2 -dihydro22dimethyl5H-chromeno [3.4zfl-quino line *4 20 (Compndr 380 structue IA of Scheme XXIX. hr- =-hoohnl To a solution of Compound 379 (EXAMPLE 279) (10 mg, 0.025 mmol) in toluene (1 mL) at -78 OC was added 0.5 M DIBAL toluene solution (0.1 mL, 0.05 mmol) 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-1234 terhyr [4hdoy22dmthl5-homn 3 ,4-fjquino line as a colorless oil, which was treated in dichloromethane (I 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: IH NMR (400 MHz, acetone-d6) 7.60 J 7.7, 1 7.52 J 8.5, 1 7.27 J 8.6, 2 H), 7.25 J 8.6, 2 7.01 J 7.7, 1 6.89 J 7.7 Hz,1I 6.81 J 7.7, 1 H), H-\r"a\Kmp\op MS9796.S-ROD RECEPTOR.dov 19101100 DOCKET

NO.

0 16-0014A.WO 249 6.67 J 8.5, 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).

EXA WPLE 281 +)-(R*-41.5)-5-(4-Chorohenyl)- L2 -3,tetrahdro-2,2,4-trimethl-5H-chromno 3.4-t 3-q rolinone, (Comound. 381, structure 13 nff 1-he-n vA7 where R=4-chlm ghgvl R =R 2HH This compound (0.7 mg) was prepared by HPLC separation of the enantiomers of .:...iCompound 235 by a chiral column, Chiracel OD-R, using a 9:1 mixture of methanol and 10 water as mobile phase. The optical purity of Compound 381 was determined by HPLC to be 90% [a]20D 101 (MeOH).

EXAMPLE 282 Chlorohenl)-11,2,3,4-tetrahdro-2 ,24-trimethl- 5H-chromenor34-f 3u iolinone 2phgn 32 tutue5_fSceeX. hr =-clr ne :i R=R2=H) This compound (1.5 mg)was prepared by HPLC separation of the enantiomers of :i Compound 235 by a chiral column, Chiracel OD-R, using a 9:1 mixture of methanol and iwater as mobile phase. The optical purity of Compound 382 was determined by HPLC to be 68% [a]20D 63 (MeOH).

EXAM LE 283 (4-ChloroDhenl)- 1,2,-3,.tetrah ydro-2 2-diethl-H-chro meno[34-fl-3 in lin n Cmon 83 tutr Go ceeXM hr ~clorophenyl This compound (0.63 mg, was prepared in a manner similar to that described for Compound 234 (EXAMPLE 134) from Compound 380 (EXAMPLE 280) as a colorless oil.

The major product was Compound 378 (EXAMPLE 278). Data for Compound 383: IH NMR (400 MHz, CDC13) 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 0.0, 1 1.33 3 H), 1.32 3 H).

H*\Priyanh\Kftppspccl\5977-96.STERIf RECEPTORx 19/01/00 DOCKET

NO.

0 16-0014A.Wo 250 EXAPLE 284 (R/S)-3-(3-Fluoro benzyl)-5..(3-fluorob2enzylidene)- 1.2,3 4 -tetrahydro..3.hycfoxy22 4 trimethvl14-mch,,omeno[3,4.jlg inolin (Compond 384.R structure 8A of Scheme

XXX,

where R I=R2=Hj R3=3-fluorophenvl) MRS)- 1.2.3 4 -Tetrahydro22,4-timethylcoumarin 0 f 3 4 -fI-3-gu inolino ne structure 7A of Scheme XXX. whr I =R 2 This compound was prepared by the same Bocprotection/hydroboration/oxidation/deprote etio procedure as described in the synthesis of Compound 234 (EXAMPLE 134) from Compound 159 (EXAMPLE 59) (440 mg, rrml to afford 98 mg of(/)1234ttayr-,,-rmtycuaio34A *00 10 3 -quinolinone as a yellowish oil. Data for (R/S)-l,2,3,4-tetrahyro22,4 trimethylcoumarino[34f-3-quinlinone: IH NMR (400 MHz, CDC13) 7.95 J 8.6, 2 7.38 J 1 7.31-7.24 (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).

2 -3-(-F~orobnzy)-5-3-fuoronzyiden)I..2.3 4 -tetrahydro-3hvdroxy-2.2.4- (Comoun 384 structuren 8A of Scheme

XXX.

0000 where R.i=R2=H. 3 =3-fluorophenvl) To a solution of (RIS)-l1 2 3 4 -tetrahydro-2,2,4 trimethylcoumarino[343-quinolinon (3 mg, 0.01 mmol) in ether (3 mL) at rt was added 0000 the freshly prepared a 0.5 M 3 -fluorobenzylmagnisium 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 (1 mL) for 60 mmi. 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 mg of Compound 384 as a colorless oil. Data for Compound 384: 1H NMR (400 MHz, CDC13) 7.71 J 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 (in, 5 6.65 J= 8.3, 1 5.89 1 3.73 J= 6.8, 1 3.66 1 3.08 J= 14.2, 1 2.97 J =14.2, 1 2.79 1 1.33 3 1.29

J

6.8, 3 1. 18 3 H).

H:\Pankae~p~sPecM\597l96.STROID RECEPTORdoc 19/01/00 DOCKET NO.

01 6 -0014A.WO 251 EXAMPLE 285 R/S)-3,5-Dibutl-1 2 3 4-tetrahy-3-hvdro3 hyrox-224-trime. thvl 5Hchromeno[34uinoline (Com und 385 structure 9A of Scheme XXXI where

R

1

=R

2 =H R 3 =n-butyI To a solution of (R/S)-,2,3,4-tetrahydro-2,2,4-trimethylcoumarino[3,4--3-quinolinone (EXAMPLE 284) 4 mg, 0.01 mmol) in ether (3 mL) at rt was added 1.6 M n-BuLi hexane solution (0.05 mL, 0.08 mmol) and the resulting mixture 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 TFA (0.05 mL) in dichloromethane (1 mL) for min. The reaction was quenched with 2% NaOH (5 mL) and was extracted with EtOAc (2 x .0.o 5 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: IH NMR (400 MHz, CDC13) 7.61 J= 7.8, 1 H), 7.44 J= 8.3Hz, 1 7.14 J= 7.8, 1 6.98 J= 7.8, 1 6.94 J= 7.8, 1 H), 6.53 J= 8.3, 1 5.53 (dd, J 10.3, 3.5, 1 3.42 (bs, 1 2.94 J 7.0, 1 H), 2.65 1 1.88-1.63 2 1.53-1.22 10 1.44 J= 7.0, 3 1.33 3 H), 1.08 3 0.94 J=7.2, 3 0.87 7.2, 3 H).

EXAMPLE 286 20 LR/S)-5-Butvl-,2,3,4_tetrahydro_2,2,4 timethl-5H-chromenol34- in -20 3 4 -f-3-quino linone (Co nd 386. struure OA or 1A of Scheme XXXII where R 1

=R

2 =H R3=n-but

I

To a solution of -t-butoxycarbonyl-1,2,3,4-tetrahydro-2, 2 ,4trimethylcoumarino[3,4fJ- 3 -quinolinone (structure 6A of Scheme XXX, where

R

1

=R

2 an intermediate from EXAMPLE 284) (4 mg, 0.012 mmol) in THF (1 mL) at -78 oC was added 1.6M n-BuLi hexane solution (0.016 mL, 0.024 mmol) and the resulting mixture was warmed up slowly 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 Et3SiH (0.1 mL, 0.65 mmol) in dichloromethane (1 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 stereochemistry of Compound 386 was not determined. Data for Compound 386: 1

H

H-\Prank,\K-p\1pcMS9796.7hROID RECEPTORA. 19/01/oo DOCKET

NO.

016-0014A.WO 252 NMR (400 MHz, CDC13) 7.63 J 1 7.51 J 8.2, 1 7.16 J 7.7, 1 H), 7.01 J 1 6.96 J 1 6.74 1 5.32 (dd, J =10. 1 and 1 3.66 J 7.2, 1 1.98-1.90 (in, 1 1.58-1.18 (in, 5 1.48 3 1.44

J

7.2, 3 1.20 3 0.89 J 7.3, 3 H).

EXAMNPLE 287 (R/S-41,sI)- l.

2 3 4 -Tetrahydro.2,2.4trimethyl5phenyl 5H-chromeno r 3 4 -1-3-guinolinon (Compound 87, strcture I18A of Scheme XXIII. where R I=R 2 3 =heyl 006 10 This compound, along with Compound 388 (EXAMPLE 288), was prepared by the same 10 Boc-protectionhyoboratiooxidatio d.tcto procedure as described in the synthesis of Compound 234 (EXAMPLE 134) from Compound 161 (EXAMPLE 61) img, 0.11 nimol). Compound 387 (4.0 mg, 10%) was obtained as a colorless oil. Data for Compound 387: IH NMR (400 MHz, CDC13) 7.59 J 8.3, 1 7.57 J 7.6, 1 H), 7.21-7.12 (mn, 5 7.05 J 7.6, 1 6.92 J 7.6, 1 6.86 J 7.6, 1 6.83 15 J 8.3, 1 6.37 1 3.72 (bs, 1 3.41 J 7.5, 1 1.50 J 7.5, 3 H), 1.45 3 1. 17 3 H).

EXAMPLE 288 (R/S-41.Su)- 1,,,zerhyr- 3 4 -f-3-guinolinone *S 20 (Cmon 8 .srcue 17A of Scheme XXXII, whe

=R

2 =H R=henyI) This compound, along with Compound 387 (EXAMPLE 287), was prepared by the same Bocprotectionhyoboratio/oxidatio d.tcto procedure as described in the synthesis of Compound 234 (EXAMPLE 134) from Compound 161 (EXAMPLE 61) mg, 0. 11 inmol). Compound 388 (7.3 mg, 18 was obtained as a white poweder. Data for Compound 388: mp 108-110 OC; JIR (neat) 3358, 2972, 1720, 1473, 1292, 1213, 752; 1

H

NMR (400 MHz, CDCl 3 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, 1 3.58 J 7.4, 1 1.44 3 1.23 3 0.80 J 7.4, 3 H); 13 C NMR (100 MHz, 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. (C25H23N0 2 3/4H 2 0) C, H, N.

H:,Piy\KppeciS97796S7ROID RECEPTOR4OC 19/01/00 DOCKET

NO.

016-0014A.WO 253 EXAMPLE 289 (Z)-(R/S)-5-(3-Fluoro benzylidene)-1 l 2 3 4 -tetrahydro-2,2,4-timethyl-5H-chromeno [3.4-fl 3 -gu nolinone (Compouind 389. st-ructure 19A of SceeXXV.weeR=R2

R

3 fluorophenyl) To a solution of (RIS)- 1-t-butoxycarbonyl-l, 2 3 4 -tetrahydro-2,2,4trimethyoumarino[3, 4

J]-

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 niL, 0.06 rumol) and the reaction was *gt 10 slowly warmed up to rt and was quenched with water (1 mL). The mixture was extracted with EtOAc (2 x 5 niL) and was concentrated to provide the crude intermediate, which was S. treated with excess TFA (0.2 mL) in dichioromethane (1 niL) for 30 mini and then quenched with 5 NaOH (5 mL). The mixture was extracted with EtOAc (2 x 10 niL), concentrated and chromatographed to afford 6.0 mig of Compound 389 as a yellowish oil. Data for 15 Compound 389: ]OR (neat) 3356, 1716, 1604, 1469, 1251; IH NMR (400 MHz, CDCl3) 7.73 J 7.8, 1 7.70 1 =11. 1, 1 7.60 J 8.3, 1 7.42 J 7.8, 1 H), .657.31 (td, J= 8.0 and 6.2, 1 7.22 J= 8. 1, 1 7.18 J= 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 1 4.33 J 7.3, 1 **too 3.78 I 1.56 J 7.3, 3 1.51 3 1.24 3 1 3 C NMR (100 MHz, CDCl3) 2.14.0, 162.4 J 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 J =23. 1 Hz), 114.1, 113.8 J 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,,,-erhdo224-rmty Hcrmn[ 3 4 -fi-3-quinolinone; 1H NMR (400 MHz, CDC13) 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, 1 1.88 3 1.76 J= 7.3, 3 1.33 3 H).

Y*\"alkaKeep\speccM5977-96.ST2ROID RECEPTORdoc 19/01/00) DOCKET

NO.

016-0014A.WO 254 EXAMPLE 290 (R/S-41,6u) l.

2 3 4 -Tetrahydro224imethl6helylHchom [o3 4-f1-3guinolinne. (Compound- 390, structure 23A of Scheme XXXV. whereg

R

1 =ph1v)) l.

2 -Dihydro-2,2,4trimethyl. lO-isocoumarino[3 '4jigquinoline (Compound 21A, Scheme XXXV) This compound was prepared by General Method 8 (EXAMPLE 138) from 7amino- 3,4- benzoco un-rin to afford l, 2 -dihydro-2,2,4-trimethy110-isocoum-arino [3,4fjquinoline (150 mg, 0.52 mmol, 60%) as a yellow solid. Data for 1,2-dihydro-2,2,4trimethyl- I10-isocoun1rino [34jfquino fine: mp 197-199 OC; JIR (KBr) 3350, 2960, 1711, see*: 1608, 1566, 1468 and 1311; 1HI NMR (400 MHz, CDC13) 8.20 J 7.6, 1 8. 10

J

o* 10 1 7.83 J 8.6, 1 7.77 J 7.6, 1 7.44 J 7.6, 1 6.64

J=

feet.. 8.6, 1 5.88 (bs, 1 5.38 1 2.39 3 1.29 6 13 C NMR (100 MHz, 0: 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, 0000 109.6, 108.6, 51.7, 30.4, 23.6.

0 g 1,-iyr-,24tiehl--2ey-Hio rmn [3 4 -tluino line (structure 22A of Schem XtXXV. hre 1 =heyl This compound was prepared by General Method 0 (EXAMPLE 60) from 1, 2 -dihydro-.2,2,4-nirmethyl- IO-isocounlarino[(3,4-]quino line (60 mg, 0.20 nimol) and bromobenzene (157 mg, 1.0 nimol) to afford 60 mg as a colorless oil. Data for l, 2 -dihydro-.2,2,4..trimethy1.6.pheyly5H-ioc ro en [3 4 -flquino line: 1

H

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 7.7, 1 6.04 1 5.22 1 3.87 (bs, 1 2.11 3 1.26 3 1.23 3 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/S-41.6u)- 1.2,3 4 Tetrahydro-2 24triethylp6-pheny1 H-isochromeno [3.4-fl-3guinolinone 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-timethy-6-pheny..5Hisochromeno [3,4.Jlquino line (30 mng, 0.085 inmol). Compound 390 (2.2 mg, was obtained as a colorless oil, along with 4.4 mng of Compound 391 (EXAMPLE 291).

H.\nka\Km~poMS97796S7ROD RECEPTORAdo 19/01/O0 DOCKET

NO.

O

16 -0014A.WO 255 Data for Compound 390: IH NMR (400 MHz, CDC1 3 7.65 J 7.8, 1 7.49

J

8.4, 1 7.37 J 7.8, 1 7.30 5 7.19 J 7.8, 1 6.89 J1 7.8, 1 H), 6.38 J1=8.4, 1 6.14 1 3.83 J 7.5, 1 3.67 (bs, I 1.41 3 1.39 J1=7.5, 3 1. 12 3 H).

EXAMPLE 291 (R/S-41. 61)-i.

2 3 4 Tetrahydro224trimethy6 he lHi~ m[o34-tJ-3quinolinnei (ompond- 391. structure 24A of Scheme XXXV. where R=he-nyl) 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, CDCl3) 7.66 J 7.7, 1 7.53 J 8.3, 1 7.35 5 7.34 J= 7.7, 1 7.15 J= 7.7, 1 6.79 J= 7.7, 1 6.12 (s, 3.82 J 1 3.66 (bs, 1 1.41 3 1.23 3 1. 14 J 3 H).

EXAMPLE 292 (Z)-(R/S)$(Benzvlidene) 12,3 4 -tetrahvdrt2imethyl H-chrmo [34f-3ouinolinone Cmon 392 structure 19A of Schem XXIV. where

R=

2

H

R

3 =p~heyl) To a solution of ER/S)-l1-t-butoxycarbonyl-. l 2 3 4 -tetrahydro-2,2,4- imethylcoumarino [3,4- 20 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 1.0 M benzylmagnesiurn bromide (0.06 mL, 0.06 mmol) and the reaction was slowly warmed up to rt and was quenched with water (1 mL). The mixture was extracted with EtOAc (2 x m.L) and was concentrated to provide the crude intermediate, which was treated with excess TFA (0.2 mL) in dichloromethane (I1 mL) for 30 min and then quenched with 5 NaOH mL). The midxture was extracted with EtOAc (2 x 10 mL), concentrated and chrornatographied to afford 3.8 mg of Compound 392 as a colorless oil. Data for Compound 392: ER (neat) 3354, 1716, 1469, 1261, 1045; 1 H NMR (400 MHz,

CDCL

3 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, 2 7.17 J1=7.7, 1 7.08 J 7.7, 1 6.83 J 8.4, 1 5.91 1 4.37 J 7.3, 1 3.76 1 1.57 J 7.3, 3 1.51 3 1.24 3 H:Pianp~specis 996.STROfD RECEPTORAdO 19/01/00 DOCKET NO.

016-0014A.WO 256 13 C NMR (100 MHz, CDC13) 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 R/S-41,5u)-5-(3-Fluorophenyl)- 1,2,3, 4 -tetrahydro-2,24-trimethyl-5H-chromeno[3,4-f-3 quinolinone (Compound 393. structure 17A of Scheme XXXIII, where R 1

=R

2

R

3 =3fluorophenyl) This compound, along with Compound 394 (EXAMPLE 294), was prepared by the same o. 10 Boc-protection/hydroboration/oxidation/deprotection 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: IR (neat) 3356, 1719, 1602, 1487, 1288, 1209, 1028; 1 H NMR (400 MHz, CDC13) 7.66 J= 7.7, 1 7.64 J 8.3, 1 7.19 (td, J 7.9, 5.8, 1 7.09- S 15 6.86 5 6.85 J= 8.3, 1 6.78 J= 7.7, 1 6.38 1 3.72 (bs, 1 3.58 J 7.4, 1 1.44 3 1.23 3 0.87 J 7.4, 3 13 C NMR (100 MHz, CDC13) 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= 22.1), 118.3, 116.9, 115.8 21.4), 74.5, 60.2, 43.9, 28.1, 27.3, 14.4.

EXAMPLE 294

(R/S-

4 1)-5-(3-Fluorophenyl)- 1.2,3, 4 -tetrahydro-2.24-trimethyl-5H-chromeno [3.4-f-3 quinolinone (Compound 394. structure 18A of Scheme XXXII, where RI=R 2

R

3 =3fluorophenyl) This compound, along with Compound 393 (EXAMPLE 293), was prepared by the same Boc-protection/hydroboration/oxidation/deprotection procedure as described in the synthesis of Compound 234 (EXAMPLE 134) from Compound 191 (EXAMPLE 91) mg, 0.081 mmol). Compound 394 (5.0 mg, 16%) was obtained as a colorless oil. Data for Compound 394: IR (neat) 3356, 1719, 1608, 1473, 1288, 1209, 1039; 1 H NMR (400 MHz, CDC13) 7.60 J= 8.3, 1 7.58 J 1 7.15 (td, J= 7.9, 5.8, 1 7.09 J 7.7, 1 6.97-80 6 6.34 1 3.73 1 3.38 J 7.3, 1 1.50 (d, H\"Piyanka\Kcep\spccM\5977-96.STEROID RECEPTOR.doc 19/01/00 DOCKET NO.

016-00 14A.WO 257 J 7.3, 3 1.46 3 1. 19 3 1 3 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 1 .2,34-Tetrahydro-2,2.4-trimethylb5-[3-(trifluoromethyl)p2henyll chromeno[3.4-fl-3-guinolinone (Compound 395. structure 18A of Scheme XXXULI where

R

1

=R

2

R

3 =3-(trifluoromethyl)phenyl) This compound, along with Compound 396 (EXAMPLE 396), was prepared by the same Boc-protectionlhydroboratioriloxidation,'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 (400 MHz, CDCL3) 7.61 J 8.3, 1 7.57 J 7.7, 1 7.42 J 7.7, 1 7.39 1 7.38-7.30 (in, 2 7.09 J 7.7, 1 6.95 J 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 J 7.3, 1.48 3 1.20 3 1 3 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, 00.

60.2, 43.1, 27.1, 26.5, 18.4.

EXAMPLE 296 (R/S-4.5u)-1,,,-erhdo_,24aiehl5r-tilooe I 1chromeno[3,4-nl3-guinolinone Compound 396. structure 17A of Scheme XXXIII where Rl=R 2

R

3 =3-(trifluoromethyl)phenyl) 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 mmol). Compound 396 (3.2 mg, 15%) was obtained as a colorless oil. Data for Compound 396: IR (neat) 3356, 2928, 1718, 1602, 1330, 1126, 1074; 1 H NMR (400 MHz, CDCI3) 7.67 J 8.3, 1 7.65 J 7.7, 1 7.52 I 7.48 (n,4 1 7.35-7.30 H',Priyanka\Kmep\pecM5977-96SMROID RECEPTOR.doc 19/0l1/00 DOCKET

NO.

016-0014A.WO 258 (in-4 2 7.08 J 1 6.98 J 7.7, 1 6.88 J 8.3, 1 6.78 J 7.7, 1 6.43 1 3.75 1 3.57 J 7.4, 1 1.45 3 1.24 3 0.86 (d, J 7.4, 3 1 3 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, 2 8.2, 27.3, 16.5.

EXAMPLE 297

(RIS-

3 l.

4 u,.5u)-5-(4..Chlorophenyl). 12.3 4 -tetrahydro3methoxy224tlrethyl15H chromeno[3,4-flquino line Compoundl 397, stucur 26 o cheme XXXVI, where R =R 2

R

3 -4-chlorophenyl.

R

4 =methl) To a solution of (R/S- 3 l, 4 u,5u)-5-(4..chlorophenyl)-.1 2 3 4 -tetrahydro-3-hydroxy2,2,4- [3,4.flquino line (structure 14A of Scheme XXXIII, where

R

1

=R

2

R

3 =4-chlorophenyl, an intermediate from EXAMPLE 135) (8 mg, 0.0 16 inmol) :in DMF (0.5 mL) and excess Mel (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 15 mL). The mixture was extracted with EtOAc (2 x 10 mL) and was concentrated to give the S crude product, which was treated with TFA (0.2 mL) in CH2Cl2 (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, CDC13) 7.53 J 7.7, 1 7.48 J 8.4, 1 7.12 4 7.04 J 7.7, 1 6.89 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 J 7.3, 3 1.35 3 H), 1.50 3 H).

EXAMPLE 298

(R/S-

3 l.

4 u,.51--4Choohenyl). l- 2 3 4 -tetrahdro3methoxy-22 4-t chromeno 3 4- luinoline Compuind3strutr 25AQ ofShM X X .w ere

R

1

=R

2 -H R 3 =4-chlorophenyl.

R

4 =methyl) To a solution of (R/S- 3 l, 4 u,51)-5-(4..chlorophenyl> 1 2 ,3,4-tetrahydro-3-hydroxy224 [3,4-.Jquino lie (structure 13A of Scheme XXXIII, where

R

1

=R

2

R

3 -4-chlorophenyl, an intermediate from EXAMPLE 135) (8 mng, 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 H"P~aa\K-~spci\597-96STEOIDRECEPTORAdo 19101100 DOCKET NO.

0O16-0014A.WO 259 mmol). The resulting white slurry was stirred at II 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 CH2CI 2 (1 niL) for 60 min and was quenched with 5 NaGH (5 mL). The mixture was extracted with EtOAc (2 x 10 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: 1H NMR (400 MHz, CDCl3) 7.55 J 7.7, 1 7.47 J= 8.4, 1 7.16 J= 8.7, 2 7.12 J 8.7, 2 H), 6.97 J 1 6.89 J 7.7, 1 6.73 J 7.7, 1 6.68 J 8.4, 1 6.34 1 3.65 (bs, 1 3.53 3 3.03 1 3.02 (qd, J 7.0, 0.8, 1 1.30 3 1. 11 3 0.88 J= 7.0, 3 H).

EXAMPLE 299

R/S..

3 l.

4 u.51)-5-(4-Chlorophenyl)- 1,234ttavr--rplx-,,-rmty-H chro menor34qtluino re (Compound 399, structure 25A of Scheme XXXVI. where 15 Rl=R 2

R

3 =4-chlorophenyl.

R

4 =propyl) S...To a solution of (RIS- 3 l, 4 u,S1)-5-(4-chlorophenyl> 1,2,3 4 -tetrahydro-3hydroxy22,4 trietyl-H-hroen [34-lqJuinoA.Aline (structure 13A of Scheme XXXIII, where

R

3 =4-chlorophenyl, an intermediate from EXAMVPLE 135) (7 mg, 0.0 14 inmol) in DMF (0.5 mL) and excess PrI (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 niL). The mixture was extracted with EtOAc (2 x 10 niL) and was concentrated to give the crude product, which was treated with TFA (0.2 niL) in CH2C12 (1 niL) for 60 min and was quenched with 5 NaOH (5 The midxture was extracted with EtOAc (2 x 10 niL), concentrated and was purified by silica gel chromatography to afford 2.5 mng of Compound 399 as a colorless oil. Data for Compound 399: 1 H NMR (400 MHz, CDC13) 7.57 1 7.48 J= 8.4, 1 7.16 J 2 7.12 J 2 H), 6.99 J 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, 1 3.58 (in, 2 3. 11 J 5.8, 1 3.00 (qd, J 7.0, 5.8, 1 H), 1.65-1.50 (mn, 2 1.30 3 1. 10 3 0.93 (t,IJ= 7.4, 3 0.88 J 7.0, 3 H).

H.'\aaaK-Psp-M597-96STEo[DRECEPTORAQ 19/01/00o DOCKET

NO.

016-0014A.Wcj 260 EXAMPLE 300

(R/S-

3 /.4u,.Su)..4Chlorophenyl). l.

2 3 4 -tetrahdro3.proploxy224trimethyl5Hchromeno 3 4-lquinojjne (Compound 400. structure 26A of Scheme XXXVI, where

R

1

=R

2

R

3 =4-chlorophenyl.

R

4 =propyl) To a solution of (R/S- 3

I,

4 u,5u)-5-(4chlorophenyl)-1,2,3 4 -tetrahydro-3-hydroxy-2,2,4- [3 ,4-fjquino line (structure 1 4A 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 PrH (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 midxture 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 NaGH (5 mL). The mixture was extracted with EtOAc (2 x 10 mL), concentrated and was purified by silica gel chromatography to afford 2.5 mg of Compound 400 as a colorless oil. Data for Compound 400: 1 H NMR (400 MHz, CDC13) 7.54 J 1 7.48 J 8.4, 1 7.12 J 8.6, 2 7.09 J 8.6, 2 H), *.a.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 1 3.72 (bs, 1 3.28 (in, 2 3.16 J 4.0, 1 2.78 (qd, J 7.2, 4.0, 11 H), 51 J 7.2, 3 1. 51-1.3 6 (mn, 2 1. 34 3 1. 14 3 0. 80 Jf= 7.4, 3 H).

EXAMPL E 301

R/S-

4 _/.5)-3Benzlidene5(4-hlorophenvl) 12.3 4 -tetrahydro-224-tiethyl-5Hchromeno[3 4- ~uinoie (Comound 401 structure 27A of Scheme XXXVII. where

R

1

-R

2 -H R 3 =4-chlorophenyl.

R

4 =phenyl) To a solution of Compound 234 (EXAMPLE 134) (35 mg, 0.086 nirol) in THF (4 niL) was added a I OM ether solution of benzylmagnesium chloride (0.3 niL, 0.3 rnmol) and the reaction was stirred at it for 2 h. The reaction mixture was quenched with water (5 niL) 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 mixture of two isomers. The adduct intermediate (8 mg, 0.0 16 nimol) and Burgess reagent (15 mg, 0.063 nimol) in benzene were heated at reflux for 2 h. Removal of solvent and purification of the mrixture on a prep TLC plate using a 25% mixture of EtOAc/Hexane as solvent afforded 0.5 mg of H:\PTJ*\ep\spcM,597796SEROD RECEPTOR. 19,V/oo DOCKET

NO.

0 l 6 -0014A.WO 261 Compound 401 as a colorless oil. Data for Compound 401: 1 H NMR (400 MHz, CDCI3) 7.61 J 7.7, 1 7.56 J 8.4, 1 7.43 J 7.5, 2 7.32 J 7.7, 1 7.21 J 7.6, 2 7.16 J 8.6, 2 7.05-6.93 (in-4 2 6.96 J 8.6, 2 6.72

J

1 6.68 J 7.7, 1 6.38 1 6.05 1 4.02 J 7.5, 1 3.55 (bs, 1 1.52 3 1.41 3 0. 84 J= 7.5, 3 H).

EXAMPLE 302 fR/S- 4 l.5u-5-(4-Chlorophenyl)- 1 2 3 4 -tetrahydro224-trethyl5Hchrmeo [34--3guinolinone (onmond 402.j structure 53 of Scheme XV. where R=H.

R

2 =fluoro, R=4chlorophenyl) 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) (50 mg, 0. 16 nirol). 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, 15 EtOAc:hex); IHj NMR (400 MHz, CDC1 3 7.51 J 8.5, 1 7.23 J 8.5, 1 H), a..7.16 J1=8.5, 2 7.04 J1=8.5, 2 6.84 J 8.5, 1 6.78 (in,4 2 6.30 1 3.79 (brs, 1 3.33 J 7.5, J 7.5, 1 1.49 J 7.5, 3 1.46 3 1.25 3H).

EXAMWPLE 303 4 -15)-5-4Chlorophenyl)-,,,-erydo2,4getl5Hcoen 344-3guinolinone moun403. structure 52 of Scheme XV where R=H

R

2 =fluoro R=4chlorophenyl) 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); IHNMR (400 MHz, CDCl 3 7.56 J 8.5, 1 7.31 J 8.5, 1 7.20 J 2 7. 10 J1 8.5, 2 6.85 J 8.5, 1 6.74 (n,4 2 6.35 1 3.79 (brs, 1 3.55 J 1 1.45 3 1.26 3 0.86 J= 7.5, 3 H).

A\K-P\sp.M59776.sTROD RECEPTORAdo I 9/01/Uo DOCKET NO.

016-0014A.WO 262 EXAMPLE 304 1,2,3,4-Tetrahydro- 1,22, 4 -tetramethyl-6-trifluoromethyl-8-pyranono 5.6-glquinoline (Compound 404. structure 28A of Scheme XXXVIII, where R=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 mol) 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 pmol, 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 10 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; 1H NMR (400 MHz, CDC13) 7.31 (dd, J 1.5, 1.5, 1 6.44 1 6.35 1 2.90 3 H, N- 15 CH3), 2.83 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 (R/S)-5-(3-Furyl)- 1.2.3.

4 -tetrahvdro-2.2.4-trimethyl- 8-pyvranono r5.6-gquino line (Compound 405, structure 63 of Scheme XVIII. where R 1

=R

2 R3= 3 -furvl, Z=0) In a oven dried pressure tube equipped with a magnetic stir bar was dissolved tetrahydro-2,2,4-trimethyl-7-hydroxyquinoline (EXAMPLE 150) (50.8 mg, 292 pmol), ethyl 3 -keto- 3 -(3-furyl)propionate (0.10 mL, 642 pmol, 2.2 equiv) and ZnC12 (119 mg, 876 pmol, 3 equiv) in absolute ethanol (6 mL). The solution was heated at 105 0 C for 19 h. The cooled 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 hexanes/ethyl acetate to 14.6 mg (16% of Compound 405 as a yellow oil. Data for Compound 405: Rf= 0.26 (hexanes/EtOAc; IH NMR (400 MHz, CDC13) 7.76 1 7.58 (dd, J 1.4, 3.0, 1 7.48 1 6.66 1 6.37 1 6.06 1 4.37 (br s, 1 H, NH), 2.91 1 H, C4-H), 1.78 (dd, J 4.1, 13, 1 H, C3-H), 1.44 (dd, J= 13, H.\Priyanka\Ke'p\KpcM597796.STROID RECEPTORdoc 19MI/00 DOCKET

NO.

016-0014A.WO 263 13, 1 H, C3-H), 1.33 J= 6.7, 3 H, C4- CH3), 1.31 3 H, C2- CH3), 1.23 3 H, C2- CH3).

EXAMPLE 306 6 -(3-Furyl)- 1,2-dihydro-

L.

2 2 4 -tetramethyl 8- panono 5.

6 -lguinoline Co ound 406 structure 60 of Scheme XVI where RI=R 2 =R5=H R 3 Z=7 In a flame dried r.b. flask was dissolved Compound 264 (EXAMPLE 164) (1.1 mg, 3.58 pmol) in glacial acetic acid (3 mL). To the stirred solution was added para-formadehyde (1.2 mg, 36 pmol, 10 equiv). The cloudy yellow solution stirred for 10 min then NaCNBH 3 (1.1 mg, 17 pmol, 5 equiv) was added at once. Upon addition the solution emitted gas for 10 approx 5 min 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 Na2SO4 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 S 15 afford 0.8 mg (70 of Compound 406 as a yellow-green solid. Data for Compound 406: Rf= 0.25 (hexanes/EtOAc; 1H NMR (400 MHz, CDC13) 7.77 1 7.57

J=

1.7, 1 7.30 1H), 6.66 J 1.7, 1 6.40 1 6.07 1 5.33 1 H, C3- 2.89 3 H, N-CH3), 1.95 J 1.1, 3 H, C4-CH 3 1.38 6 H, (CH3)2).

EXAMPLE 307 20 6 -trifluoromethl 1.2-dihdro- ,224tetramethy8thiopanouinolne (Compound 407. structure 29A of Scheme XXIX where R=R 2

R

3 =trifluoromethyl,

Z=O)

In a dry r.b. flask was dissolved Compound 251 (EXAMPLE 151) (5.2 mg, 16.1 pmol) in glacial acetic acid (5 mL). To the stirred solution was added para-formadehyde (5.4 mg, 160 pmol, 10 equiv). The cloudy red solution stirred for 10 min then NaCNBH 3 (5.1 mg, pmol, 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 mL), dried over Na2SO 4 and concentrated in vacuo to give an impure product that was further 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 H:\ianka\Kpspec5977-96S'ROfD RECEPTOR.doc 19/01/00 DOCKET

NO.

016-0014A.WO 264 Compound 407: Rf 0.39 (hexanes/EtOAc; 3: 1HNMR (400 MHz, CDCI 3 7.21

J

1.7, 1 7.16 1 6.51 1 5.42 1 H, C3-H), 2.90 3 H, N-CH3), 2.00

J

1. 1, 3 H, C4-CH3), 1.41 6 H, (CH3)2).

EXAMPLE 308 6 -Chloro-5-(3-furyl)-. 1 .2-dihydro- 1, 2 2 4 -tetramethylb8.pyranono [5 .6-glguino line (Comp~ound 48 tutr 0o ceeX I hr 1 R-.R-hoo

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, :.10 172 pmol, 10 equiv). The cloudy yellow solution stirred for 10 mini then NaCNBH 3 (5.8 9999mg, 86 pmol, 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 .9 EtOAc (2 x 20 mL), washed with brine (2 x 20 mL), dried over Na2SO4 and concentrated ivacuo to give an impure product that was further purified by 3 consecutive prep TLC's 15 (silica gel, 1000 pmn) 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 (hexanes/EtOAc* HNMR (400 MHz, CDCl3) 7.32 J 1H), 6.33 (s,l1H), 5.3 8 1 H, C3-H), 2.8 8 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-Tetrahydro-2,2,4. lO-tetramethyl-6-trifluoromethyl-8-pyridono5 [S6-glquinoline (Compound 409 structure 63 of Scheme XVII. whre I?=mety1

R

2 -r.

R

3 =trifluoromethyl

Z--NH)

7 -tert-Butylo xycarbamo yl- 1. 2 3 4 -tetrahyvdro-2.2,4, 8 tetrameth ylguino line (structure 72 of Scheme VI wr 1 thl D -uov This compound was prepared from 7 -tert-butyloxycarbamoyl- l, 2 -dihydro-2,2,4,8-tetramethylquino line (EXAMPLE 155) (4.50 g, 14.9 mmol) according to the general hydrogenation procedure previously described (EXAMPLE 160), affording 4.48 g of the desired tetrahydroquino line as a white solid. Data for 7 -tert-butyloxycarbamoyl-1,2,3 ,4-tetrahydro-2,2,4, 8 -tetramethylquinolie: 1H NMR (400 MHz, CDCl3) 7.03 IlH, J 8.3, 6.81 IlH, J 8.2, 6.13 (br H-\PrYaK lp-l\49l96SROD RECEPTOR.doc 19/01/00O DOCKET

NO.

O16-0014A.Wo 265 s, 1H, BOCNH) 3.43 (br s, 2H-, NH2), 2.91 (ddq, 1H, J 19.0, 12.8, 6.6, 1.96 3H1, 8-CH3), 1.73 and 1.40 (d of ABq, 2H1, JAB 12.8, JA JB 12.6, 1.31 3H1, J 6.7, 4-CH3), 1.28 and 1.16 ppm [2s, 2 x 3H1, 2-(CH3) 2 7 Amino- 1 2dihy -io-2,2,4,8tetIramethylguno line. This compound was prepared by General Method 12 (EXAMPLE 147) from 7 -tertbutyoxycarbamoy123 4 tahdo 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 -amiino1,2dihydro2248teamthlino IH NMR (400 MHz, CDCJ3) 6.89 I1H, J 8.1, 6.14 111, J 8.2, 6-H1), 3.42 (br so6. 10 s, 3H, NH2, NH), 2.87 (ddq, 111,1J=18.7, 12.7, 6.4,4-H1), 1.90 3H1, 8-CH 3 1.70 and 9999 1.39 (d of ABq, 211, JAB 12.8, JA 5.6, JB 12.5, 3-H1), 1.29 3H,J 6.7, 4-CH3), 1.27 and 1. 16 ppm [2s, 2 x 311, 2-(CH3) 2 _1, 2 3 4 -Tetrahydro22A -Otetramethyl14trfliuoromethyl 8 idon [5 6 -glqguino line.

15 This compound was prepared by General Method 13 (EXAMPLE 147) from 7 -amino- 1,,,-erhdo2248ttaehlunln (2.92 g, 14.3 mmol) 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-yehlow solid. Data for Compound 409: mp 239-40 IH NMR (400 MHz,

CDCI

3 9.70 (br s, 111, CONY'), 7.50 111, 5-H1), 6.68 111, 4.13 [br s, 20 111, (C113)2CNH], 3.00 (ddq, 1,1J= 12.9, 12.4,6.3, 2.15 311, 10-C1 3 1.83 and 1.46 [dd of ABq, 211, JAB 13.0, JA 1.6 Hz 3 -Hequiv), JB =12.9, 0 Hz 3 -Hax)], 1.40 3H, J1= 6.6, 4-CH3), 1.36 and 1.25 ppm [2s, 2 x 311, 2-(CIJ 3 2 13 C NMR (100 MHz, CDCI3) d 162.5, 144.9, 13 9.1, 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 C17Hl9F 3

N

2 0: C, 62.95;H1, 5.90; N, 8.64. Found: C, 63.02; H, 6.01;N, 8.48.

EXAMPLE 310 rhdo4mty--rfior~ehl8pinn[,:gqioi (Compound 410. structure 33A of Scheme XL. where

R

3

=R

6 =H R 4 meth

I

R

5 =trifluoromethyl) ank'K-\-Pci'597-9657EOIDRECEPTORAdo DOCKET NO.

016-0014A.WO 266 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, 1 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 S::v 10 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 15 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 20 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 (CH2C12/MeOH, 95:5); 1H 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-Butoxycarbonyl- ,2, 3 4 -tetrahydro-7-methoxy-4-quinolone (structure 31A of Scheme XL, where R 1 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, HAPriyanka\Keep\pecM5977-96.STERO[D RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 267 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% NaHS04 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 l-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, 1H 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 7.0, 3 H).

10 (RIS)-I-t-Butoxycarbonyl-1.

2 3 4 -tetrahydro-4-hydroxy-4-methyl-7-methoxyquin ine. To a flame dried 250 mL 3-necked rb flask equipped with a magnetic stir bar was added Ce(III)Cl-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 15 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 20 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 NH4C1 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, 1H 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 1 1.98 2 1.58 3 1.53 9 H).

HM',riYanka\Kp\tpccM5977-96.ST ROID RECEPTOR.e 19/01/00 DOCKET NO.

016-0014A.WO 268 -t-Butoxycarbonyl-1,2.3,4-tetrahydro-4-methyl-7-methoxy-quinoline To a oven dried 250 mL rb flask equipped with a magnetic stir bar was dissolved 1-tbutoxycarbonyl- ,2,3,4-tetrahydro-4-hydroxy-4-methyl-7-methoxy-quinoline (44 mg, 150 pmol) 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 10 colorless oil. Data for 1-t-butoxycarbonyl-1,2,3,4-tetrahydro-4-methyl-7-methoxyquinoline: Rf= 0.59 (hexanes/EtOAc, 1 H NMR (400 MHz, CDC13) 7.28 J =2.3, 1 H, Ar-8), 7.07 J 1 H, Ar-5), 6.61 (dd, J 8.5, 1 H, Ar-6), 3.78 3 H, OMe), 3.71 (dd, J=6.1, 12.2, 2 H, C2-H), 2,83 1 H, C4-H), 2.00 1 H, C3-H), 1.58 1 H, C3-H), 1.53, 9 H, (CH3)3), 1.27 J =7.0 Hz. 3 H, C4-CH3).

/-l2,34-Tetrahydro-4-methyl-7-methoxqinine. To a oven dried 250 mL r.b. flask equipped with a magnetic stir bar and a N2 gas inlet was dissolved 1-t-butoxycarbonyl- S1,2,3,4-tetrahydro-4-methyl-7-methoxy-quinoline (678 mg, 2.44 mmol) in CH2C12 mL). To the stirred solution was added trifluoroacetic acid (TFA) (2 mL) at rt. The solution 20 stirred under N2 for 2 h and then quenched with sat NaHCO3 solution (25 mL), extracted with CH2C12 (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 quinoline as a clear colorless oil.

Data for 1,2,3,4-tetrahydro-4-methyl-7-methoxyquinoline: Rf 0.32 (hexanes/EtOAc, 3:1); 1H NMR (400 MHz, CDC13) 6.95 J 1 H, Ar-5), 6.22 (dd, J 8.3, 1 H, Ar-6), 6.03 J 1 H, Ar-8), 3.86 (br s, 1 H, NH), 3.73 3 H, OMe), 3.28 2 H, C2-H), 2,85 1 H, C4-H), 1.95 1 H, C3-H), 1.64 1 H, C3-H), 1.25 J 3H, C4- Me).

()-,2,34-Tetrahydro-7hydroxy_4-meth lquinoline. 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-tetrahydro-4- H:PYanka\Kep\spc, 4597-96.TROID RECEPIOR.doc 19/01/00 DOCKET

NO.

016-0014A.WO 269 methyl-7-methoxyquino line (17.7 mg, 100 pmol) in CH2C2 (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 pmol, 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 (1 mL), neutralized with sat. NaHCO 3 (4 mL) and extracted with CH2CI2 (5 x 50 mL), dried over Na2SO 4 and concentrated to give 12 mg of the desired phenolic quinoline as a fight yellow oil. Data for (RIS)- 1,,,-erhdo7hdrx--ehlun ie Rf =0.15 (hexanes/EtOAc, 3: 1 H NMR (400 MHz, CDCl3) 6.91 J 8.7, 1 6.12 (dd, J 8.3, 1 5.97 J 2.5, 1 3.27 (in, 2 H, C2-H), 2.84 (in, 1 H, C4-H), 1.95 (in, 1 *10 H, C3-H), 1.66 (n,4 1 H, C3-H), 1.25 J 6.9, 3 H, C4-CH3).

(RIS)-1 ,.-erhyr--ehl6-rfurmthl8 6 -glquinoline (Compound 40 trcurl3 of SchemeXL. where R- 3

=R

6

R

4 =methvlI .In an oven dried pressure tube equipped with a magnetic stir bar was 15 dissolved (RS-1234ttayr--hdoy4mtyqioln (11.7 mg, 64.6 p mol) and ethyl trfurmtyaeoctt (20 pL, 146 pmol, 2.2 equiv) and ZnCl2 (20 mng) in mL absolute ethanol. The light yellow solution was heated at 98 TC for 20 h and cooled to rt. The dark green solution was concentrated on CeliterM to give a free flowing powder which was purified via silica gel flash column chromatography using a solvent system of hexanes/ethyl acetate 1) to give 12.4 mng of Compound 410 as a yellow solid.

Data for Compound 410: Rf 0.19 (hexanes/EtOAc, 1H NMR (400 MHz, CDCl3) 7.29 1 6.36 (in 2 4.70 (br s, 1 H, NHI), 3.43 (in, 2 H, C2-H), 2.95 (in, 1 H, C4- 1.97 (in, 1 H, C3-H), 1.72 (in, I H, C3-H), 1.31 J 7.0, 3 H, C4-CH3).

EXAM PLE 311 1, 2 -Dihydro-2,2-dimethvl-6trifluormethyl.8..pyranono

[S.

6 -gjquinoline (Cmpound 411.

structre 7A F Shm XL where R 2 R 6 -Y4 R 3

R

4 =methvl,

R

5 =trffluoronethyl..

X=O)

L.

2 -Dihydro22dimethyl.7-(, I.1.1 -trimeth ylacetoxy)quino lie (structre 36A of Schemne XLI where

R=R

2 =H R 3

=R

4 =methy. P=t-butyl In a oven dried pressure tube equiipped with a magnetic stir bar was dissolved O-pivaloyl-3-anophenol

(EXAMPLE

H"P~anm\KP~P-c\457796.TERIDRECEPTORdOC 19/01/00 DOCKET

NO.

016-0014A.WO 270 138) (4.8 g, 25.0 mmol, 1.5 equiv) and 3 -methyl-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 oC 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 1, 2 -dihydro-2,2-dimethyl-7-(1,1,1trimethylacetoxy)quinoline: Rf 0.80 (hexanes/EtOAc, 1H NMR (400 MHz, CDC13) 6.83 J= 8.0, 1 6.23 2 6.12 J= 2.1, 1 5.42 J= 9.7, 1 3.67 (br s, 1 1.31 9 1.29 6H). 13 C NMR (100 MHz, CDC13) 177, 151, 130, 127, 123, 10 117, 109, 105, 52, 49, 31, 27.

0° .0 S1,2-Dihdro-hdrox-22-dimeth uinolin. To a oven dried rb flask was dissolved 1,2dihydro-2,2-dimethyl-7(1,1,1 -trimethylacetoxy)quinoline (48 mg, 185 pmol) in absolute ethanol (5 mL) and H20 (1 mL). To the stirred solution was added a catalytic amount of 15 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. NH4C1 solution (5 mL). The biphasic solution was extracted with EtOAc (4 x 20 mL), washed with brine (2 x 30 mL), dried (Na2SO 4 and concentrated in vacuo to give 31 mg of the desired phenolic amine, which was used without further purification.

.0 1,2-Dihydro-2,2-dimethyl-6-trifluoromethyl-8-vranono[5, 6 quinoline (Corpound 411.

structre 37A of Scheme XLI, where R1- 2

=R

6 =H R 3

=R

4 =methyl, R=trifluoromethyl In a oven dried pressure tube equipped with a magnetic stir bar was dissolved 1,2dihydro-7-hydroxy-2,2-dimethylquinoline (31 mg, 177 pmol), ethyl (4,4,4trifluoroacetoacetate) (75 mg, 408 pmol, 2.2 equiv) and ZnC12 (75 mg, 550 pmol, 3 equiv) in absolute EtOH. Upon addition of the ZnC12 the solution went a dark brown. The sealed pressure tube was heated at 105 °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 mg of Compound 411 as a bright yellow solid.

Data for Compound 411: Rf= 0.31 (hexanes/EtOAc, 1H NMR (400 MHz, CDC1 3 H-'\"xak-'\K-p\,pcIMS97796.STEROID RECEPTORdoc 19/01/00 DOCKET No.

Ol 6 -0014A.WO 271 7-11 1 6.41 1 6.32 2 5.58 J 8.0, 1 4.39 (br s, 1 1.55 6

H).

EXAMPLE 312 1- 2 3 4 -Tetrahydro 2,2dihethyl1.6- trifluorometh l 8 31n r 5,6- gquino line (Compound 42.strctre 0Aof chme L1. wher R-=R 6

R

3

=R

4 =methvl.

R

5 =trifluoromethyl.

X=O).

-1234Ttayr-22dmty -L~-trimethyIacetoxy)gu ino line (structure 39A of Scheme XLI. whr

R

1

=R

2

R

3

=R

4 -Met+l APt-butylI To a oven dried 250 ML rb flask equipped with a magnetic stir bar and a N2 gas inlet was dissolved I ,2-dihydro- 2 2 -dimethyl7(1, 1, 1 imethylacetoxy)quino ln (EXAMPLE 311) (47 mg, 192 pmol) 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 H2 and the solution was filtered through a pad of CeliteTm and concentrated in vacuc to give the desired amnine (38.0 mg, 154 pmol, 81% yield) as an off white solid. Data for l, 2 3 4 -tetrahydro2,2dimethyl-7.( 1,1, l-trinethylacetoxy)quinoline: Rf 0.54 (hexanes/EtOAc, 3: 1H NMR (400 MHz, CDCl 3 6.93 J 8. 1, l1-H), 6.26 (dd, J 2.3, 8. 1, 1 6.13 J 2. 1, 1 3.5 9 (br s, 1 2.73 J 6.7, 2 1. 67 J 2 1.32 9 1. 18 6 H).

1,3-erhdo hdo 22dmtyg ioie To a oven dried rb flask was dissolved 1,2,3 4 -tetrahydro2,2dimethyl7-(1, 1, 1 -trimethylacetoxy)quino~ (3n Q8 mg, 154 p mol) 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 rnL) and quenched with sat. NTI4Cl solution (5 mL). The bi-phasic solution was extracted with EtOAc (4 x mL), washed with brine (2 x 30 mL), dried (Na2SO 4 and concentrated in vacuo to give mg of the desired phenolic amine as a light yellow oil. Data for 1, 2 3 ,4-tetrahydro-7hyr y22dmehlun ie Rf 0.22 (hexanes/EtOAc, 3: 1 H NMR (400 MHz, H-'P"-*'\KP\'P-MS97796-S R 0 CEPTOR.doc 19/01/00 DOCKET

NO.

0 1 6-0014A.WO 272 CDCl3) 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[STeguahidro-2l2-dimethinetrifluoromet (Comound 2 structure 40A of Scheme XLI. where R1- 2

=R

6 =R8=H, R3=R 4 =methl.

R

5 =trifluoromethyl, In a oven dried pressure tube equipped with a magnetic stir bar was dissolved 1,2,3,4-tetrahydro-7-hydroxy-2,2-diethylquino line(25.1 mg, 142 pmol), 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 OC for 13 h, cooled to rt and concentrated 10 on CeliteTM to give a free flowing powder which was purified via flash column chromatography (silica gel, hexanes/EtOAc, 5:1) to 26.3 mg of Compound 412 as a bright yellow solid. Data for Compound 412: Rf= 0.31 (hexanes/EtOAc, 1H NMR *,(400 MHz, CDC13) 7.26 1 6.37 2 4.52 (br s, 1 H)m, 2.83 J= 6.6, 2 H), 1.74 J= 6.6, 2 1.28 6 H).

EXAMPLE 313 1..,34-Tetrahydro-6-trifluorometh yl- 8413.anono r56-gjuinoline (Co ou 413 structure 45A of Scheme XLIII where R 1

R

2 trifluorometh 3 -Methxy-trns indanone oxime Comound 43A Scheme XLI). To an oven dried 250 20 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 mmol), Et3N (3.0 mL, 21.5 mmol, 1 equiv) and NH2OH.HC (1,48 g, 21.5 mmol, 1 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, H NMR (400 MHz, CDC13) 8.01 (br s, 1 7.47 J= 2.4, 1 6.88 (dd, J= 2.4, 8.3, 1 6.82

J

8.3, 1 3.30 3 2.79 2 2.44 J 6.7, 2 H).

H:\riyank\K-p\pct\4597796STROID RECEPTOR4oc 19/01/00 DOCKET NO.

016-0014A.WO 273 2 4 -Tetrahdro-7-methoxquinoline (Compound 44A. Scheme XLIIIT. In a flame dried 100 mL 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 mg, 1.10 mmol) in dry THF. Under a blanket of N2 the solution was cooled to 0 C and a 1.0 M solution of LAH in pentane (0.5 mL, 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 rt and quenched with H20 (2 mL), extracted with EtOAc (3 x 25 mL), washed with brine (50 mL), dried over Na2SO4 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 14 mg of the desired adduct i 10 as an off white solid. Data for 1,2,3,4-tetrahydro-7-methoxyquinoline: Rf= 0.35 (hexanes/EtOAc, H NMR (400 MHz, CDC13) 6.84 J= 8.0, 1 6.19 (dd, J= 2.5, 8.2, 1 6.03 J 2.5, 1 3.81 (br s, 1 3.73 3 3.27 2 2.69 J 6.4, 2 1.91 2 H).

15 12 3 4 -tetrahydro-7-hvdroxyquinoline. In a flame dried 100 mL rb flask equipped with a magnetic stir bar and a N2 gas inlet was dissolved 1,2,3,4-tetrahydro-7-methoxyquinoline (14.0 mg, 85.8 pmol) in CH2C12 mL). The solution was cooled to -78 0 C under a blanket of N2 and a 1.0 M solution of BBr3 in CH2C12 (0.25 mL, 250 pmol, 3 equiv) was added via syringe. The solution stirred at -78 0 C for lh, warmed to 0 C for 1 h and rt for 2 h.

20 The reaction was quenched with H20 (2 mL), extracted with CH2C12 (3 x 20 mL), washed with brine (2 x 20 mL), dried (Na2SO4) and concentrated in vacuo to afford 12 mg (88%) of the desired adduct as a yellow oil. Data for 1,2,3,4-tetrahydro-7-hydroxyquinoline: Rf 0.21 (hexanes/EtOAc, 1H NMR (400 MHz, CDC13) 6.79 J 8.2, 1 6.12 (dd, J 2.4, 8.0, 1 6.04 J= 2.3, 1 4.78 (br s, 1 3.27 2 2.67 2 1.91 2 H).

1,2,3,4-Tetrahydro-6-trifluoromethyl-8-pyranono[5,6-glquinoline (Compound 413, structure 45A of Scheme XLIII where R=H. R 2 =trifluoromethvl). In a oven dried pressure tube equipped with a magnetic stir bar was dissolved 1,2, 3 ,4-tetrahydro-7hydroxyquinoline (11.7 mg, 78.5 pmol), TFEEA (>10 fold excess) and ZnC12 (>10 fold H-Vianka\Kep\sp-cMS4977-96STEROID RECEPTOR.o. 19/01/00 DOCKET

NO.

0l6-0014A.WO 274 excess) in absolute EtOH (3 mL). The sealed pressure tube was heated at 1 I10 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, 4: 1) to give 8.6 mg, (41 of Compound 413 as a bright yellow solid. Data for Compound 413: Rf 0.31 (hexanes/EtOAc, 3: 1HNMR (400 MHz, CDCI3) 7.21 1 6.35 (in. 2 4.66 (br s, 1 3.40 (mn, 2 2.80 J 6.3, 2 1.95 (n,4 2 H).

EXAMPLE 314 (RS'-4-Ethyl- l.

2 3 4 -tetrahydro6trifluoromethyl8-pyanonoL rs6-glquinoline (Compound 414, structure 33'A f Sc-hem XL. where

R-

3

=R

6

R

4 ethvl. R 5 =trifluoromethvl) 10 (RIS)- 1 -t-Butoxycarbonyl-4ethylp

L.

2 3 4 -tetrahydro-4-hydoxy.7-methoxyquino line, To a flame dried 250 mL r.b. flask equipped with a magnetic stir bar and a N2 gas inlet was dissolved (RIS)-l1-t-Butoxycarbonyl-1234ttahdo7mtox--unlne (106 mng, *5 390 pinol) 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 nimol, 3.5 equiv)was added via syringe. The solution was stirred at OTC for 2 h and at rt for 3 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 (2 mL), extracted with EtOAc (4 x 25 inL), 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)- 1-tbutoxycarbonyl4ethyl- 1,,,-erhdo4hdrx--ehxqioi Rf 0. 14 (hexanes/EtOAc, 3: 1HNMR (400 MHz, CDCI3) 7.36 J 8.7, 1 H, Ar-5H), 7.34 (d, J 2.5, 1 H, Ar-8H), 6.67 (dd, J 2.5, 8.5, 1 H, Ar-6H), 4.08 (mn, 1 3.86 (br s, 1 H, OH), 3.79 3 H, OMe), 3.43 (in, 1 1.87 (in, 3 1.53 9 H, t-butyl), 0.859

J

7.4, 3 H, -CH3).

(RIS)- l-t-Bultoxycarbonyl-4ethyl1, 3 4 -tetrah ydro-7methoxYq u ino line To an oven dried 250 mL r.b. flask equipped with a magnetic stir bar and a N2 gas inlet was dissolved

(RIS)-

1 t- butoxycarbonyl4ethyl- 1, 2 3 4 tetrahydro4hydro xy7-methoxyqun line (37.6 mg, 123 pinol) in dry EtOAc (8 inL). The flask was repeatedly evacuated and flushed with N2 then a catalytic amount of 10% Pd on C ing) was added. The flask was again evacuated and flushed with N2 several times and then H2 was introduced by balloon. The H'p'--K-P\poM5977-96 STEROID RECEPTOR.doc i9/ol/oo DOCKET

NO.

01 6 -0014A.WO 275 solution was stirred under

H

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 CeliterM and concentrated in vacuo to give 34 mg of the desired amine as a clear colorless oil. Data for -t-butoxycarbonyl-4-ethyl- 1,2,3, 4 -tetrahydro-7methoxyquinoline: Rf 0.52 (hexanes/EtOAc, 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 partially obscured by OMe, 1 3.58 1 2,62 1 1.95 1 1.72 2 1.53 9 H, t-butyl), 1.48 partially obscured by t-butyl, 1 H), 0.949 J= 7.4, 3 H, -CH3).

l t tr. In a oven dried 250 mL r.b. flask equipped with a magnetic stir bar and a N2 gas inlet was dissolved Sbutoxycarbonyl-4-ethyl- 1,2,3,4-tetrahydro-7-methoxyquinoline (34.0 mg, 117 pmol) in dry CH2C1 2 (1 mL). To the stirred solution was added TFA (1.2 mL) at rt and was allowed to S 15 react for 2 h. The dark red solution was quenched with sat NaHCO 3 solution (10 mL), extracted with CH2C12 (3 x 25 mL), washed with brine (50 mL), dried (Na2SO 4 and concentrated in vacuo to afford 21 mg of the desired amine as a clear light yellow oil.

Data for (R/S)-4-ethyl-1,2,3,4-tetrahydro-7methoxyquinoline: Rf 0.1 (hexanes/EtOAc, 1H NMR (400 MHz, CDC13) 6.92 J 8.5, 1 6.21 (dd, J 2.5, 8.2, 1 6.03 20 J 2.5, 1 3.73 3 3.27 2 2.59 1 1.

8 6 1 1.75 2 H), 1.48 1 0.968 J= 7.4, 3 H).

(R/S)-4-thvlu (structure 32A of Scheme XL where R1- 3 =H R 4 =ethyl). In a flame dried 100 mL rb flask equipped with a magnetic stir bar and a N2 gas inlet was dissolved (R/S)-4-ethyl-1,2,3,4-tetrahydro-7-methoxyuinoline (21 mg, 109.9 pmol) in CH2C1 2 (4 mL). The solution was cooled to 0 0 C and a 1.0 M solution of BBr3 in CH2C1 2 (0.33 mL, 320 pmol, 2.75 equiv) was added slowly by syringe. The solution was warmed to rt and stirred under a blanket of N2 for 9 h. The reaction was quenched by addition of sat. NaHCO 3 solution (5 mL), extracted with CH2C12 (3 x 25 mL), washed with brine (2 x 20 mL), dried (Na2SO 4 and concentrated in vacuo to give 19 mg of the desired phenolic amine as a clear yellow oil. Data for (R/S)-4-ethyl- 1,2,3,4- H:\Priyan\Kep\p. 5977- 96 .STEROID RECEPTORA.d 19/01/00 DOCKET

NO.

O16-0014A.WO 276 tetrahydro-7-hydroxyquino line: H NMR (400 MHz, CDCJ3) 6.85 J 1, 1 6.11 (dd, J 2.4, 8.3, 1 5.98 J 2.4, 1 3.25 (in, 2 2.57 (in, 1 1. 85 (in, I H), l.

7 6 1 1.67 I 1.51 (mn, 1 H) 0.940 (t,J7.4, 3

H).

(R/S)-4-Ethvl- l.

2 3 4 -tetrahydro-6-trifluoromethy18pya no [5,6-glquino line (Compound 414, structure 11A of Scheme (L where RI- 3

-R

6

R

4 =ethvlI

R

5 =trfjuoroinet'yl). In a oven dried pressure tube equipped with a magnetic stir bar was dissolved (R/S)-4-ethyl- 1,234ttayr--yrxqioln (19 mg, 109 pinol) and TFEAA (excess) and ZnC12 (excess) in absolute EtOH mL). The sealed pressure tube was heated at 101TC for 10 h, 10 cooled to rt and concentrated on CeliteM to give a free flowing powder which was purified 64.6* via flash colum-n chromatography (silica gel, hexanes/EtOAc, 3: 1) to give 3 mg of Compound 414 as a bright yellow solid. Data for Compound 414: Rf 0. 19 *.:(hexanes/EtOAc, 1 H NMR (400 MHz, CDC13) 7.25 1 6.38 1 6.36 1 4.70 (br s, 1 3.40 (n,4 2 2.70 (mn, 1 1.89 (in, 2 1.67 n(in, I 1.55 (n,4 1 H) 0.95 (t,J 74,3H).

EXAMPL E 315 (RIS)

I.

2 3 4 -Tetrahydo-, 4 -dinethyl-8pvanono r5, 6 -glquinoline (Compound 415, ~structure.4A f Scheme XL. where RI 3

R

6 =R8=H

R

4 methy

R

5 =trifuriNetv In a flame dried 100 ml rb flask equipped with a magnetic stir bar was dissolved Compound 410 (EXAMPLE 310) (10.0 mg, 35.6 pmol) in glacial acetic acid (4 inL). To the stirred solution was added para-formadehyde (12 mg, 356 pinol, 10 equiv). The cloudy yellow solution stirred for 10 mini then NaCNBH 3 (12 mg, 178 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 inL), washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuc to give 8.9 mng of Compound 415 as a yellow-green solid.

Data for Compound 415: Rf 0.22 (hexanes/EtOAc; 3: 1H NMR (400 MHz, CDCl3) 7.25 1 6.42 1 6.35 1 3.42 (in4 2 3.00 3 2.91 (in, 1 2.00 (rn, 1 1.72 (in, 1 1.28 J 6.8, 3 H).

n\K'pcM\597796.sTROD RBEPTORAd 0 19/01/00 DOCKET NO.

016-0014A.WO 277 EXAMPLE 316 (R/S)-4-Ethyl- 1 2 ,34-tetrahvdro- 1 -methyl- 8-pyranono f 5.6:glQuino line (Compound 416.

structure3AofShmXLwhrR 1 3

R

6 R-.R-tvR trfurehy.

In a flame dried 100 mL rb flask equipped with a magnetic stir bar was dissolved Compound 414 (8.0 mg, 27.1 pmol) 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 min then NaCNBH 3 (8.0 mg, 135 p.mol, 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 mL), washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuc 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 MHz, CDCl3) 7. 1 6.43 1 6.35 1 3.47 1 3.30 (in-4 I 3.00 3 2.68 (i4 1 1.89 (mn, 2 1.56 (mn, 4 0.980 J= 7.4, 3 H).

EXAMPLE 317 2 .22-Diinethyl-I l 2 3 4 _tetrnhvriron6A romtyl.-yrd [56fgioe(opud 417 stucure40 ofSceme XLI where R- 2

=R

6

R

3

=R

4 =methyl,

R

5 =trifluoromethyl,

X-N-)

7 -tert-Butyloxycarbamoyl- 2 -dihydro22-dimethyIquinoline structure 36A of Scheme XLII. where R=R 2

R

3

R

4 =methvl, X=NH). To a flame-dried 200 mL r.b. flask containing 3 -tert-butylcarbamoylaniline (EXAMPLE 147) (7.7 g, 0.037 inol) in 40 mL of anhydrous THF was added CuCI (183 ing, 1.8 inmol), triethylainine (5.15 mL, 0.037 inol) and 3 -acetoxy-3-methy1..-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, hexanes/ethyl 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 inol) was dissolved in 40 mL of anhydrous THF, CuCl (234 mng, 0.0024 mol) was added and the mixture was heated to reflux for 16 h. The reaction mixture was diluted with ethyl acetate (200 inL), and washed with water and brine. The organic layer was dried (Na2S 04) and concentrated in vacuo to an oil that was subjected to chromatography (silica H\Pa\Kp\pccm597.96STROID RFCEPTORAdO 19/01/00 DOCKET NO.

016-0014A.WO 278 gel, hexanes/ethyl acetate, 9: 1) which afforded 2.24 g of 7 -tert-butyloxycarbamoyl- 1 2 -dihydro-2,2-dimethylquinoline along with 4. ig of the undesired regloisomer.

Data for 7-tert-butyloxycarbamoyl- 1, 2 -dihydro- 2,2-dimethylquino line: IH NMR (400 MHz, CDCI3) 6.80 (bs, 1Ff), 6.77 J= 7.4, 1Ff), 6.33 (bs, 1Ff), 6.31 (bd, J=7.4, 1H),.6.18 J 9.7, lH), 5.37 J 9.7, 1Ff), 3.70 (bs, 1Ff), 1.49 9H), 1.27 6H).

7-Amino 1, 2 3 4 -tetrahvdro -2,2-dimethvlguino line. A solution of 7-tertbuyoxcraoy-12dhdo22dmtyqioln (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-butyloxycarbamoyl- 1,,,-erhdo22dmtyqioe The title compound was prepared by General Method 12 (EXAMPLE 147) from 7 -tert-butyloxycarbamoyl-1 ,2,3,4-tetrahydro-2,2dimethylquino line (3.7 g, 0.0 12 mol) to afford 2.35 g (100%) of 7-amino- 1,2,3,4tetrahydro-2,2-dimethylquinoline as a light reddish oil. Data for 7-amiino-l,2,3,4tetrahydro-2,2-dimethylquinoline: IH NMR (400 MHz, CDC13) 6.77 J 7.9, 1Ff), 6.00 (dd, J 7.9, 2.2, 1H), 5.81 J 2.2, 1Ff), 3.47 (bs, 1Ff), 3.40 (bs, 2H), 2.66 1 6.7, 2Ff), 1. 65 J 6.7, 2H), 1. 18 6Ff).

C'....2,2-Dimethyl1 2 3 4 -tetrahydro-6-trfforomethyp8-p~pdoo [5,6-flg~ujno line (Compound 20 417. structure 40A of Scheme XLII. where P 1 6 H R 3 R= hL

R

5 =trifluoromethyl, X=NI). This compound was prepared by General Method 13 (EXAMPLE 147) from 7 -amino- l, 2 3 ,4-tetrahydro 2, 2 -dimnethylquino line (2.35 g, 0.0 12 mol), ZnC12 (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: 1 H NMR (400 MHz, DMSO d6) 11.70 1Ff), 7.18 1H), 6.85 1Ff), 6.35 1Ff), 2.65 J 6.6, 2H), 1.61 J1=6.6, 2H), 1. 17 6Hf).

EXAMPLE 318 (RIS)- 1, 2 3 4 -tetrahvdro-6-trifluromethy224trimethv18-p3Tidono r5,6-f-3-guinolino ne (opud4 8 tutr 47A of Scheme, VLI V. whr R R 2

HR

3 t luoromethvl) HN'rianka\K-p~specM5977.96.SIhROD RECEPTORAdo 19/01/00 DOCKET

NO.

0 l 6 -0OL4A.Wo 279 1 9 -di-tert-Butylo xycarbamoyl-. l 2 -dihydro6trifluoromethl224-imethyl-8p-ylidno56fqioieSrctr4A of S-em XLV where R I=R 2

=H,

R

3 =trifluorometvl To a suspension of NaH 60% in mineral oil (16 mg, 0.387 rnmol) in 1 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 '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 stirred at rt for 1 h. The reaction mixture was quenched with water (1 mL), extracted with ethyl acetate (2 x 5 mL) and concentrated in vacuc to give 148 mg (100%) of a yellow solid that was used directly for the next step. To a solution of 9-tertbutyloxycarbamoyl-12dhdo224-rmty.-yion[,-lunn 1(1 3 0 mg,

O.

3 2 mmol) in 10 mL of anhydirous THF 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 1 ml, 0. 0.of TFIF was added and the reaction mixture stirred at -78 0 C for 6.5 h. The temperature was raised to 0 'C and the mixture quenched with water (3 mL), extracted with ethyl acetate (2 x 15 10 mL), dried (Na2SO 4 and concentrated in vacuo to give a solid residue. Purification by *555flash colunm chromatography (silica gel, hexanes/ethyl acetate, 8:2) gave 79 mg of l, 9 -di-tert- butylo xycarbamo yl- 1,-iyr 224tiehl -yioo[,-q oln 1) 106INMR (400J M~,CD IH) 7.2s, IH,73 IH,5.67 (s H,2.13 (s, *SSS 3H), 1.62 3H), 1.57 9H), 1.50 9H).

0:00 l1-tert-butyloxycarbamoyp-.,,-erhdo3hdox--rfurmty-,, trmth 8 -Vyiidono r5, 6 4flquino line. A solution of 1, 9 -di-tert-butyloxycarbamoyl1 1 ,2-dihydro-2,2,4 trmty-8prdn 56Aun ie(79 mg, 0.155 mmol) in 2 rnL of anhydrous THF at rt was treated with 388 4.L of BH3.THF (1.0 M in TFIF, 0.388 mmol) for 3 h and was then quenched with 78 p.L of NaHCO3 satd't followed by 30% H202 (78 PLL). The reaction mixture was stirred for 1 h, then 2 nml, of water was added. The mixture was extracted with ethyl acetate (5 niL), dried (Na2SO4) and concentrated in vacuo to an oil that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 7:3) to give 21 mg (32%) of l-tert-butyloxycarbamoyl-.1,2,3,4ttayr-3hdoy22,- reh18-pyridono [5,6fiquinoline. Data for 1 -tert-butyloxycarbamoyp 1,2,3 4 -tetrahydro-3hydroxy224 trmty--yion[,-qioie IH NMR (400 MHz, CDCl 3 12.5 (bs, IH), 7.51 (s, H'PiabKpscM979.TRI RECEPTORdoc 19/01/00 DOCKET

NO.

016-O0l4A.WO 280 1W), 7.28 1H), 6.85 1W), 3.19 (dd, J 5.2, 1W), 2.91 (in, 1H), 2.14 J= 1.65 3H), 1.55 9H), 1.52 3H), 1.46 J= 6. 1, 1W).

(RIS)- 1, 2 3 4 -tetrahdro6trifluoromethy224trimethy1 8 -pyridono [5, 6 -fJ- 3 -guinolinone (Compouind 418.srutr 47A of Scheme XL.IV. wthere

R

1

=R

2

R

3 =trflorMetihyl To a suspension of PCC (50 mg, 0.23 inmol) in 2 mL of dichioromethane at ii was added 1tert-butyloxycarbamoyl- 1,,,-erhdo3hdoy6trfurmty ,,-rehl8pyridono [5,6-fjquino line (16) (10 mg, 0.023 mrnol) in 1 mL of dichioromethane. The reaction mixture 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 column chromatography (silica gel, hexanes/ethyl acetate, 6:4) to give 5.5 mg of l-tert-butyloxycarbamoyl- 1,,,-erhdo--rfurmtyl224tiehl 8 -pyridono [5, 6 3 -quinolino ne that :0.:was used directly for the next step. The title compound was prepared by General Method (EXAMPLE 147) from 1 -tert-butyloxycarbamoy1,234ttayr-6tilooehl 2,,-iehl8prdno56f--unlnn mg, 0.0 13 inm-ol) to afford 3 mg (71 of Compound 418. Data for Compound 418: IH NMVR (400 MHz, CDC13) 12.3 (bs, 7.51 1W), 6.85 1W), 6.71 1W), 4.27 1W), 3.61 J= 6.3, 1H), 1.55

J=

6.3, 3H), 1.40 3H), 1.31 3W).

EXAMPLE 319 6 -Aminoindo line. A solution of 6 -nitroindoline (1 g, 6.1 mmol) in 50 m-L of ethyl acetate was hydrogenated under an atmosphere of hydrogen with Pd-C 10% (100 mng) at rt for 3 h.

Filtration over celite afforded 1.0 g of 6 -amidno indo line. Data for 6 -amino indo line: IH NMR (400 MHz, CDCl3) 7.40 (d,JI= 7.4, 1W), 6.05 J 1W), 6.03 J= 1WH), 3.67 (bs 1WH), 3.49 J 2W), 3.48 (bs, 2W), 2.90 J1=8.2, 2W).

5-TrflnnrnmthI7pidon [S6eiili opound 419 structure 49A of Scheme XLV where R =trifluoromethyl,

R

2 hscmon a rprdb General Method 13 (EXAMPLE 147) from 6 -aminoindoljne (200 mg, 1.2 inmol), ZnCI2 (262 mg, 1.93 H\ Ms9aKp~pci49796.SROID RECEPTOR.do,1 9101/00 DOCKET NO.

o 16-0014A.WO 281 mmol) and ethyl 4 4 4 -trifluoro aceto acetate (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, 1H), 7.31 111), 6.82 111), 6.49 iIH), 6.40 111), 3.59 J 8.1, 2H), 3.01

J

8.1, 2H).

EXAMPLE 320 8-(4-Chloro benzoyl)-5tr fuoromehyl7p3idono [5.6-elindoline (Compound 420.

structure Ao ceeXV hr 1 tilrmtv 2 H 3 4clrpev) To a solution of Compound 419 (EXAMPLE 319) (13 mg, 0.05 mmol) in 2 mL of anhydrous THF at -78 0 C was added n-BuLi 2.5 M in hexane (21 mL, 0.05 mnmol) and the resulting mixture was stirred for 15 min. Then 4 -chlorobenzoyl chloride (6.4 mL, 0.05 S.mmol) was added and the reaction mixture was slowly brough to Ai over a period of 30 mmi.

05..The reaction midxture was quenched with a saturated aqueous solution of NH4CL (1 mL), e* extracted with ethyl acetate (5 mL) and concentrated in vacuc to an oil that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 8:2) which afforded 3 mg 15 of Compound 420. Data for Compound 420: 1 H NMR (400 MHz, CDCl3) 8.19 (d, J 8.6, 2H), 7.77 1I1M, 7.51 J 8.6, 2H), 7.25 I 6.99 111), 4.45 I1H), 3.77 J 8.0, 211), 3.28 J 8.0, 2H1).

EXAMPLE 321 1 0-Trimethyl- 1.2.3 4 -tetrahydro6trffluioromethyl8p~ idono [S.6-flguinoline (Compouind trcture 40A of Scheme XLII. where R 1 =R 3 R-4et 1 R 2 =R 6

=H.

R

5 =triftuoromethylX=Ij).

7 -tert-Butyloxycarbamo yl- 1 2-dihydro-2,2. 8 -trimethylquinoline (structure 36A Scheme XLII where R =R 3 =R4=methyl

R

2 =H P=t-butoxy. X=NH). To a flame-dried 10 mL r. b.

flask containing 3-etbtlxcramy--ehlnln (EXAMPLE 155) (490 mg, 0.0022 mol) in 3 nil, of anhydrous THF was added CuCI (11I mg, 0. 1 mmol), triethylamine (307 mL, 0.0022 mol) and 3 -acetoxy-3-methyl1..butyne (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 mng of the desired propargyl intermediate that was used directly for the next step. The propargyl amine (290 mg, 0.00 1 mol) was dissolved in 5 mL of anhydrous THF, CuCl (5 mg, 0.05 mmol) was added and the mixture was heated to reflux for 16 h. The reaction m-ixture was diluted with ethyl acetate (10 mnL), and washed H:\PEa\Kp\pcceM5977-96.STROfD RECEPTORdoc 19/01/00 DOCKET NO.

016-00 14A.WO 282 with water then brine. The organic layer was dried (Na2SO4) and concentrated in vacuo to an oil that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 9: 1) which afforded 114 mg of7 et uyoxcraol ,2-iyr 228tiehlun ie Data for 7 -tert-butyloxycarbamoyl- l, 2 -dihydro-2,2,8-trimethylquinoline: 1 H NMR (400 MHz, CDCl3) 6.85 J= 7.4, 1H), 6.75 J= 7.4, 1H), 6.23 J 1H), 6.18 (bs, lH), 5.42 J 9.5, 1H), 3.57 (bs, 1H), 1.92 3H), 1.45 9H), 1.29 6H).

7-Amino- 1,2.3.4-tetrahydro-2,2. 8 -trimethvlguino line. A solution of 7-tertbuyoxcrb..-12diyr-228-*ehyqinln (114 mg, 0.39 mmol) in 4 mL of 10 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, 2 ,3,4-tetrahydro-2,2,8 -trimethylquino line. The title compound was prepared by General Method 12 (EXAMPLE 147) from 7 -tert-butyloxycarbamoyl- 1 2 ,3,4-tetrahydro-2,2, 8trimethyiquino line (60 mg, 0.206 mmol) to afford 30 mg of 7-arnino-1,2,3,4- 15 tetrahydro-2,2,8-trimethylquinolin as a light reddish oil. Data for 7-aniino-1,2,3,4tetrahydro-2,2,8-trfrnethylquinoline: 1 H NMR (400 MHz, CDCl3) 6.70 J 7.9, 1H), 6.09 J 7.9, 1H), 3.30 (bs, 3H), 2.71 J 6.7, 2H), 1.89 3H), 1.65 J 6.7, 2H), 1.21 6H).

2.2, 1 0-Trimethyl- 1.2.3,4ttayr--rfooehl 8-2idn ,-qioln (Compound 421 stutr 0Ao cee XLI where R=R 3 4 =methvL. R 2

=R

6

=H.

R

5 =trifluoromethyl, X=NH). This compound was prepared by General Method 13 (EXAMPLE 147) from 7-ndo ,,,-erhdo ,,-rmtyqioln (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: IH NMR (400 MHz, CDCI3) 9.13 IlH), 7.34 ILH), 6.67 IlH), 4. 10 IlH), 2.8 8 J= 6.7, 2H), 2. 10 3H), 1.75 J 6.7, 2H), 1.30 6H).

EXAMPLE 322 l.

2 3 4 -Tetrahydro-6-trifluoromethyl -8-pyidono[ [6-flguinoline (Compound 422.

structure 51A fSche-m XLVI where R 3

=R

5 =H R 4 =trfloromethyl) H:'\Prianka\Ke-P\sPcM597796STEROfD RECEPTOR.doc 19/01/00 DOCKET NO.

0 l1 6 -0014A.Wo 283 7 -Nitro- .2.4tetrahydroqLuinoline. 1,234Ttayrqioln (5 g, 0.0375 mol) was dissolved in 16 mL of sulfuric acid and the temperature lowered to 0 0 C, then 90% fumidng nitric acid (1.67 mL, 0.0375 mol) was added slowly and the mixture strirred at 0 0 C for min. 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 vacuc to a reddish residue that was subjected to chromatography (silica *.gel, hexanes/ethyl acetate, 8:2) which afforded 4. 1 g (6 of 7-nitro- 1,2,3,4tetrahydroquino ie. Data for 7-nitro- l, 2 3 4 -tetrahydroquinoline: IH NMR (400 MHz, CDC13) 7.39 (dd, J 8.3, 2.2, 1H1), 7.26 J 3.5, 1H1), 7.01 J 1H1), 4.16 (bs, 10 11H), 3.35 J 2H), 2.8 J1=6.3, 2H), 1. 95 (quintet, J 6.1, 2H).

.0007-Aminn- 1.2?.3 4 -etadroguinolinge (strctu- r2A of Scheme XLVI. where R 1 3

A

solution of 7 -nitro- 1, 2,3,4-tetrahydroquino lin (396 mg, 0.0022 mol) in 4 mL of ethyl 0% 0 acetate was hydrogenated under an atmosphere of hydrogen with PdC 10% (40 mg) at rt for 15 2 h. Filtration over celite afforded 330 mg (100%) of 7 -anmino..l,2,3,4-tetrahydroquinoline Data for 7-mn-1234ttrhdoun ie 1 H NMR (400 MHz, CDC13) 6.72

J=

P: 0. 7.9, 11H), 6. 00 (dd, J 7.9, 2.3, I 5.84 J 2.3, 1 3.67 (bs, I1-H), 3.42 (bs, 2H), 3.24 J 5.0, 2H), 2.65 J 6.4, 2H), 1.91 (quintet, J 6.0 Hz. 2H1).

1.

2 3 4 -Tetrahydro..6.trfluoromethy1p8- [Sdno.

6 -flq uino line (Copound 422. structure 53A ofScrheme Y VI. where

RI

3 =R5=H

R

4 =trflorfmethvl) This compound was prepared by General Method 13 (EXAMPLE 147) from 7-am-ino-1,2,3,4tetrahydroquno ie (330 mg, 0.0022 MOD), ZnC12 (452 mg, 0.0033 mol) and ethyl 4,4,4trifluoroacetoacetate (356 mL, 0.0024 mol) to afford 70 mg (11 of Compound 422. Data for Compound 422: 1 H NMR (400 MHz, DMSO d6) 11.7 (bs, 1H), 7.11 IH), 6.92 (s, 1H), 6.35 211), 3.22 (bs, 2H), 2.71 J= 5.1, 2H), 1.93 (quintet, J 6.1, 2H).

EXA MPLE 323 1, 2 -Dihydro-6-tifliuoromethyJl-1 2 .4-tetramethyl8pyidono [5,6-tlquino line (Compound 423. strcurer 0 o -f Scheme XV whre 1 2

-DR

5

R

3 =trifluoromet

Z=NH)B.

H'-P~~a~a\ecPSpcM97796SI'R~EIRECEPTOR.doc 19/01/00Q DOCKET

NO.

016-0014A.WO 284 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 mmol). The resulting mixture was stirred at 25 0

C

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 (25mL), dried (Na2SO4) and concentrated in vacuo to a fluorescent yellow solid that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 8:2) to give 92 mg of Compound 423. Data for Compound 423: 1 H NMR (400 MHz, CDCI3) 11.21 (bs, 1H), 7.33 1H), .6.67 1H), 6.23 1H), 5.39 IH), 2.92 3H), 2.02 3H), 1.38 6H).

EXAMPLE 324 3.

3 -Dimethvl-5-trifluorgmethl-7-p idono [5,6-ejindo line (Compound 424. structure 57A of Scheme XLTVI where R=methvl

R

2

=R

4

R

3 =trifluoromethyl).

2-bro mo-N- pth l-II-5_it (structure 55A of Scheme LVII where R=methyl

R

2 To a suspension of NaH 60% dispersion in oil (97 mg, 0.0023 mol) in 2 mL of anhydrous THF at OoC was added 2 -bromo-5-nitroaniline (500 mg, 0.0023 mol) in 2 mL of THF dropwise, the temperature was raised to rt to complete deprotonation then lowered to 0 OC. 3 -bromo-2-methylpropene (232 mL, 0.0023 mol) was added very slowly and the reaction mixture was stirred at 0 0 C for 3 h then neutralized with water (5 mL). The mixture was extracted with ethyl acetate (2 x 10 mL), dried (Na2SO4) 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-bromo-N-(2-methyl-2-propenyl)-5-nitroaniline (structure 55A of Scheme XLVII, where R 1 =methyl,

R

2 Data for 2-bromo-N-(2- 1 H NMR (400 MHz, CDC13) 7.55 J= 8.5, 1H), 7.40 (dd, J 8.5, 2.8, 1H), 7.39 J 2.8, 1H), 4.96 2H), 4.95 (bs, 1H), 3.82 J= 5.9, 2H), 1.81 3H).

3 -Dimethvlnitoindolie structure 56A of Schm XL VII, where Rl=methvl,

R

2 A solution of 2-bromo-N-(2-methyl-2-propenyl)-5-nitroaniline (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 mL of dry DMF under argon atmospere was heated at 80 OC for 1 h. Then sodium formate (25 mg, 0.369 mmol) was added to the reaction mixture with continued H:-*\Pranb\K-p'SP-597796STROID RECEPTOR.do~ 19/01/00 DOCKET

NO.

0l6-0014A.WO 285 heating at 80 0 C for 20 h. Water (2 mL) was added and the mixture was extracted with ethyl acetate (2 x 5 mL), dried (Na2SO4) and concentrated in vacuc to an oil that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 8:2) to give mg of 3 3 -dimethyl-6- nitroindo line Data for 3 3 -dimethyl-6-nitroindo lie: 1

II

NMR (400 MHz, CDCl3) 7.60 (dd, J= 8.2, 2.0, 1Ff), 7.35 J 2.0, 1Ff), 7.08 J 8.2, 1Ff), 3.98 1Ff), 3.41 2H), 1.33 6H4).

6 -Amiino-3,3-dimethylindolie. A solution of 3 3 -dimethyl-6-ntroindo line (60 mg, 0.31 *mmol) 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-d imethylindo ine: IH NMR (400 MHz,

~'.CDC

3 )6.80 J 7.8, 1Ff), 6.08 (dd, J 7.8, 2. 1, 1Ff), 6.01 J 2. 1, 1Ff), 3.60 (bs, I1H), 3.50 (bs, 2H), 3.26 2Ff), 1.25 6Ff).

3 -iehv--rfurmty--yion [5, 6 -elindoine (Compound 424. structure 57A of Sch eme LVI where- DRI methvl.

R

2

=R

4 =Ff R 3 =triluoromethvl) This compound P....was prepared by General Method 13 (EXAMPLE 147) from 6 -amino-3,3-dimethyidoijne mg, 0.277 mmol), ZnC12 (57 mg, 0.416 mmol) and ethyl 4 4 4 -trifluoroacetoacetate mL, 0.305 mmol) to afford 7.3 mg of 3,-inty--rfurmty--yioo56 elindoline IH NMR (400 MHz, CDCl3) 12.4 (bs, 1Ff), 7.32 1Ff), 6.73 1Ff), 6.52 1Ff), 4.33 1Ff), 3.45 2H), 1.36 3H).

EXAMPLE 325 (RIS)- yr--ehl6(rfurmty)8pid 6 -gluino lne (Compnounfd 5.stucur 62A of Scheme XLVII where

R

3

=R

6 =Hf R 4 =metvl.

R

5 =trifluoromethyl).

1.

2 3 4 -Tetrahvdro..4nlnn-e (structure 59A fSheme XLVI, where

R

1 3 In a 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 and heated at 1000 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 H-Piak\m~pci4979.TRI RECEPTOR.djoc 19/01/00 DOCKET

NO.

Ol 6 -0014A.WO 286 step. In a 500 mL r.b. flask was introduced the acid (10.34 g, 0.064 mol) and polyphosphoric acid (200 mL). 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 mL), 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, 2 3 4 -tetrahydro4quinohnone. Data for 1, 2 3 4 -tetrahydro-4 quinolinone: 1 H NMR (400 MHz, CDCl 3 7.84 (dd, J 1. 1, Ii), 7.28 (ddd, J 7.9, 7.9, 1.2, 11H), 6.72 (ddd, J= 8.1, 8.1, 0.8, 1lH), 6.66 J 8. 1, 1 4.49 I1H), 3.56

J

10 6.9, 2H), 2.69 J 6.8, 2H).

I -tert-Butyloxycarbonyl-12 3 4 -tetrahydro-4-quiio inone. To a stirred solution of (10.05 g, 0.046 mol) and 1,,,-erhdo4qionn (6.16 g, 0.042 mol) in THF (100 m-L) at 0' C was added slowly DMAP (5.11 g, 0.042 mol) in 100 mL of THF. The reaction mixture was stirred overnight, then water (75 mL) was added and the mixture was extracted with ethyl acetate (2 x 200 mL). The organic phase was dried (Na2S 04) 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 l-tertbutyloxycarbonyl-1234ttayro4qioioe Data for 1 -tert-butyloxycarbonyl- 1,,,-erhdo4qioioe IH NMR (400 MHz, CDCl3) 7.98 (dd, J1 7.9, 1.7, IH), 7.76 J= 8.4, lH), 7.49 (ddd, J= 7.5, 7.5, 1.7, 1H), 7.15 (ddd, J= 8.0, 8.0, 0.9, 1H), 4.15 J 6.3, 2H), 2.76 J1= 6.6, 2H), 1.55 9H).

I -tert-B ityloxygarbony 1 2 3 4 -tyr-hydro4tylunol. Taouto 1-tert-butyloxycarbonyl-l, 2 3 4 -tetrahydro4quinolinone (170 mg, 0.687 mmo I) in THF mL) at 00 C was added 3.0 M methylmagnesiumn bromide in ether (688 m-L, 2.1 mmol).

The reaction mixture was stirred at 00 C for 1 h then quenched with water (2 mnL), extracted with ethyl acetate (2 x 10 mU), dried (Na2SO 4 and the solvent was removed in vacuc to give an oil that was subjected to flash chromatography (silica gel, hexanes/eth yl acetate, 7:3) to afford 120 mg of I -tert-butyloxycarbonyl- 1,,,-erhdo4hdoy4 methyiquinoline .Data for I-.tert-butyloxycarbonyl1 1,2,3 4 -tetrahydro-4hydroxy-4 H:\P"aakA\KP\-p-cM5977-96.STPROID RECEPTIOR dc 19/01/00 DOCKET

NO.

0l6-0014A.WO 287 methyiquinoline: 1 H NMR (400 MHz, DMSO-d 6 7.54 J 114), 7.50 (dd, J1 7.7, 1H), 7.14 (ddd, J 7.3, 7.3,1.7, 114), 7.04 (ddd, J 7.9, 7.9, 1.0, 114), 5.14 111), 3.69 (in, 21H), 1.87 J 6.5, 21H), 1.46 9H4), 1.37 314).

1 -tert-Butylo xycarbonyl- l.

2 3 4 -tetrahvclro-4-methylguino line. A solution of 1 -tertbutylo xycarbo nyli. 1,,,-erhdo--ydoy4mtyqioln (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. H2S04 at rt for 7 h. Filtration over Celiterm afforded 93 mg of 1 -tert-butyloxycarbonyl- 1,,,-erhdo4mtyqioie Data for 1 -tertbuyoyabn 1 1234ttayr--ehlun ie H NMR (400 MHz, CDCl3) 7.62 J 1 H),7.16 1 7.11 (ddd, J =7.87.8, 1.6, 1 7. 01 (ddd, J "0.00 7.7, 7.5, 1.0, 114), 3.71 (in, 214), 2.87 (ddq, J 6.8, 6.8, 6.8, 114), 2.04 (dddd, J 7.4, 7.4, 7.4, 6. 1, 114), 1. 61 (in, 114), 1. 51 914), 1. 3 J= 6.8, 3H).

l.

2 3 4 -te-trahvdqrn-A-.inhvI uinoline structure 60A f Scheme XL VIII. where

R-

3

-H.

R

4 =methyl). This compound was prepared by General Method 12 (EXAMPLE 147) from 1-etbtlxcabnl1234-erhdo4mehlunln (93 mg, 0.353 nimol) to afford 55 mg of 1,,,-erhdo4mtyqioln as an oil which was used directly without purification for the next step.

7-Nitro- 1, 2 3 4 -tetrahydro4methylguinoj~ lie ,,,-erhdr--ehlunl mg, 0.337 inmol) was dissolved in sulfuric acid (0.5 mL) and the temperature was lowered to 00 C. To this solution 90% fuming nitric acid (15 mL, 0.337 inmol) was added slowly and the mixture stirred at 0' C for 1 h, then warmed to rt. The reaction mixture was poured onto 1 g of ice and extracted with dichloromethane (2 x 5 nifL). The organic phase was washed with sat. NaHACO3 (1 x 3 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 8:2) which afforded 36 mig of 7-nitro-1,,,-erayr--ehyqioie Data for 7-nitro- 1,2,3,4tetrahydro-4-methylquinoine: ljj NMR (400 MHz, CDCl3) 7.41 (dd, J 8.3, 2.2, IH), 7.27 J= 2.3, 114), 7.11 J 8.3, 1 4.21 114), 3.35 (in, 214), 2 9 5 IlH), 1. 96 (mn, 1H), 1.72 (in,4 114), 1.3 J 7.0, 3H).

H\ianka\K-pypcMt\5977- 9 6 STEOID RECEPTflR4O 19/01/00 DOCKET NO.

016-00 14A.WO 288 2 3 4 -Tetrahydro-4meh6trifluoromethy18- idono 5s.-iunln Cmon 425). A solution of 7 -nitro-1, 2 3 4 -tetrahydro-4-methylquino line (36 mg, 0. 172 rnmol) 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 CeliteTM afforded 2 6 mg of 7-amino- 1,2,3,4tetrahydro-4-methylquino line (structure 61A of Scheme XLVIII, where RI- 3

=H,

R

4 =methyl) that was used without further purification for the next step. The title compound was prepared by General Method 13 (EXAMPLE 147) from 7 -amino- 1,2,3,4-tetrahydro4 methylquinoline (26 mg, 0. 145 mmol), ZnCI2 (30 mg, 0.218 mmol) and ethyl 4,4,4trifluoroaceto acetate (21 mL, 0.145 mol) to afford 0.8 mg of l,2,3,4-tetrahydro-4methyl-6-trifluoromethy8pyridon 0 [5, 6 -g]quinoline (Compound 425). Data for Compound 425: IH NMR (400 MHz, DMSO-d 6 11.65 (bs, lH), 7.20 111), 6.96 (s, 1H), 6.37 2H), 3.25 (in,4 2H), 2.90 (in, 1H), 1.84 (in, 1H), 1.59 (mn, 1H), 1.20 J 6.9, 3H).

EXAMPLE 326 1.-iyr-.,4tinty-- [hxmty--yioo5,6-giguinoline (Compound 426, structure 57 of Scheme XVII., where R=R 2

R

3 =nethoxymethyI,.

Z=NH)

To a flame-dried 25-mL rb flask at rt was added ethanol (10 mL) and 7-amino-1,2-dihydro- 2 2 4 -trimethylquinoline (EXAMPLE 147)(600 mg, 3.5 mmol), and the mixture stirred at rt until the amrine had completely dissolved. Methyl-4-methoxyacetoacetate (680 pL, 5.3 mmol, 1.5 equiv) was then added, followed by ZnCl2 (960 mg, 7.0 mmol, 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 m 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 chromatography (silica gel, CH2Cl2 MeOH, 9: afforded 65 mg of Compound 426 as a dark yellow powder. Data for Compound 426: Rf 0.42 (CH2Cl2:MeOH, 1H NMR (400 MHz, DMSO-d 6 11.24 1H, 7.12 lH, 6.63 1H, 6.26 lH, 6.04 I1H, 3-H 5.35 I1H, (CH3)2CNH 3, 4.56 2H, CH2), 3.37 3H, OCH3), 1.93 3H, 4-CHi3), 1.21 6H, C(CH3)2].

HriaDkK~p\.pcM597796S7ROID RECEPTOR.doe 19/1/0 DOCKET

NO.

0l6-0014A.WO 289 EXAMPLE 327 .1 2 2 -Trirnethyl- l.

2 3 4 -tetrahvdro-6-tifluro methyl- 8 -2ya nonno gliino line (Compound 42-7 strucrture. AlA of Scheme XLII where

RI-

2

=R

6 -R8=H

R

3 4 =mgethvI

R.

5 =trifluoromethyl.

X=O).

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 9*(4.2 mg, 93% yield) as a bright yellow solid. Data for Compound 427: 1 H NMR (400 :MHz, CDCl 3 7.19 1 6.49 1 6.36 1 2.91 3 2.78 J= 6.5, 2 H), 1.84 J =6.5i,2H), 1.31 61H).

EXAILE32 *R S era y r -r p l 6 9il o o eh l 8 M n n f -l u n l n 7 -methoxyquiEX A M PLE 328PE 3 4 ro -e tb t xy a b n l 1 2 3, -e r h d o of-whie soid. ata or I-t P- btrifluronethydrox--pyranoo S.-glguolin ie Itert-Butoxycarbonyk4..m hy~x..oxy-4p proquio ine T i opudws rprdi rpre namanner similar to that described for I tert butoxycarbony..4ethyl4..,34ter hy-7 7 -ethoxyquino ie (EXAMPLE 314) from 1 -tert-butoxycarbonyl1 2 3 4 -tetrahydro47..

hdo--methoxy-pryquino line (100 ig) to give the desired quinoline (51.2 mg, 409ed)asa ld of-wit s olored Data for 1-et uoyabnl7mtoy4poyqioln:1 H0 NMR (400 MHz, CDCI3) 7.7 J 1 7.0 J 1 6.6 (dd, 8., HllPaaa\Keq,\pcM597796SIER 0 1 RECEPTORAoc 19/1/0 DOCKET

NO.

0 l 6 -0014A.Wcj 290 1 3.78 3 3.73 (in, 1 3.58 (mn, 1 2.70 (in, 1 1.94 (i,1 1.71 (mn, 1 1.63 (in, 1 1.53 9H), 1.40 (in, 3 0.93 J= 7.2, 3 H) 1,,,-ft~hiin7mtl-, 4s-ctr 32A of Schemen XL.whreR 3

R

4 =n-prop2Yl). This compound was prepared in a manner similar to that described for 4-ethyl- l, 2 3 4 -tetrahydro -7iethoxyquino line (EXAMPLE 314) from 1 -tertk y ar onli1 2 ,4 te ra y -m t y -4 -pru pylu in in e (44 m to gi ethe desired quinoline (28 mg, 98%) as a colorless oil. Data for 1, 2 3 4 -tetrahydro-7-methoxy4 propyiquinoline: H NMR (400 MHz, CDC1 3 6.90 J= 8.2, 1 6.20 (dd, J 8.4, 2.6, 1 6.03 J 2.5, 1 3.83 (br s, 1 3.72 3 3.28 (in, 2 2.68 (mn, 1 1.89 (in, 1 1.75 (in, 1 1.60 (in, 1 1.46 (mn, 3 0.94 J 7.1, 3 H) 2 3 4 -Tetrahydro7hydroxy4prpvlguinoline. hscmon a rprdi manner similar to that described for 4-ethyl-i, 2, 3 4 tetrahydro7hydroxyquino line (EXAMPLE 314) from 1,,,-erhcio7mtoy4poyqioln (28 mg) to give the ::..desired quinoline as a colorless oil, which was used without further purification in the following reaction. Data for 1,,,-erhdo7hyrx--rplun lie:

NMR

(400 MHz, CDCl 3 6.84 J 8.2, 1 6. 10 (dd, J 8.2, 2.3, 1 5.97 J1 2.2, 1 H), 3.78 (br s, 1 3.29 (m I 3.21 (in, I 2.66 (in,4 1 1.87 (in, 1 1.75 (in, 1 H), 1.60 (in, 1 1.45 (n,4 3 0.933 J= 7.2, 3 H).

4-Popy-.1,23,-terahdr-6-riuro ty--pranono[5 6-glguinoline (Compound 428).

This compound was prepared in a manner similar to that described for Compound 414 (EXAMPLE 314) from 1,,,-erhdo7hdoy4poyqioln (23 mg) to give the Compound 428 (28.4 mg, 61 as a yellow solid. Data for Compound 428: 1 H NMR (400 MHz, CDC1 3 7.23 1 6.37 1 6.36 1 4.70 (br s, I 3.40 (in, 2 2.81 (in, 1 1. 88 (mn, 2 1. 47 (in, 3 0. 963 J1=7.2, 3 H) H-'r -K-P-Pc.\497796.TERIDRECEPTOfR. 19/01/00 DOCKET

NO.

016-0014A.WO 291 EXAMPLE 329 1 2 .34-Tetrahydro-2,2,4-trimethl-trifluoromethl 9-thi an- no 6 -gquinoline DCompound 429, structure 65A of Scheme XLIX where R 2 =R7=H

R

3 R6=trifluoromethyl,

X=S).

To a solution of Compound 266 (EXAMPLE 166) (50 mg, 0.15 mmol) in dichloromethane (7 mL) was added triethylsilane (0.23 mL, 1.5 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 NaHCO 3 solution (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 as an orange solid. The crude product was purified by prep TLC (20 x 20cm, 1000m, 1:1 CH2C2: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, CDC13) 7.70 1 6.62 1 6.46 1 4.41 (brs, 1 2.95 (ddq, J= 12.9, 6.1, 1 1.81 (dd, J= 12.9, 1.1, 1 1.48 J= 6.1, 1 H), 1.41 J= 6.1, 3 1.31 3 1.24 3 IR (film, NaCI) 1134, 1177, 1200, 1235, 1269, 1368, 1365, 1420, 1451, 1476, 1520, 1634, 3351.

Poo.

EXAMPLE 330 1

L

2-Dihydro- 1,2,2,4-tetrametth trfluo eth iopan 8ono uinolin (Compound 430, structure 60 of Scheme XVI, where R1- 2

=R

5

R

3 =trifluoromethyl S-i-S).

To a stirred solution of Compound 266 (EXAMPLE 166) (100 mg, 0.30 mmol) and paraformaldehyde (93 mg, 3.0 mmol) in acetic acid (3 mL) at rt was added portionwise sodium cyanoborohydride (100 mg, 1.50 mmol). The resulting mixture was stirred at rt for 16 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 (25 mL), dried (Na2SO 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 mg of Compound 430 as a fluorescent yellow solid. Data for Compound 430: 1 H NMR (400 MHz, CDC13) 7.48 1 6.62 1 6.45 1 5.40 1 2.89 3 2.10 3 1.39 6

H).

H.\PrjaankV\eep\sp.,:M5977-96slEol RECEPTORdoc 19/01/00 DOCKET

NO.

016-0014A.WO 292 EXAMPLE 331 1.

2 .3.4-Tetrahydro- 1,22tiehl6t-fur ehl pyion 56 ]qiotn (Compound 431. srcture 41A Of Scheme XLI[[. where R 1 2

=R

6

=R

8

R

3 4 =methyl.

R

5 =trifluoromethyl.

X=NH).

To a stirred solution of Compound 417 (EXAMPLE 317) (21 mg, 0.07 mmol) and paraformaldehyde (22 mg, 0.70 mmol) in acetic acid (1 mL) at rt was added portionwise 9* sodium cyanoborohydride (22 mg, 0.35 mmol). The resulting mixture was stirred at rt for 16 h then carefully poured into 20% aqueous NaOH (2 mL) and ice (10 g) and the pH adjusted to The mixture was extracted with dichioromethane (2 x 1 OmL), dried 0. 10 (Na2SO4) and concentrated in vacuc 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: 1 H NMR (400 MHz, CDC13) 10.83 (bs, 1 7.31 1 6.66 1 6.29 1 2.93 3 2.80 J= 6.1, 2 1. 83 J= 6.5, 2 1. 30 6 H).

EXAMPLE 332 1 2 .3,4-Tetrahydro-.l-methyl- 4 -prpyb6t ifluoromethyI-8-p yanono r5.6- glguilo line (Comp-cound 432. structure 34A of Scheme WL whre R 1 3 =R 6 =R 8

R

4 =n-ropvl.

R

5 =trifluoromethyl).

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: 1H NMR (400 MHz, CDCl3) 7.18 1 6.43 1 6.35 1 3.46 (in, 1 3.33 (in-4 1 3.00 3 1. 92 (in, 1 1. 87 (mn, 1 1. 49 (mn, 4 0. 95 J 7.3, 3 H).

EXAMPLE 333 1 2 3 4 zTetrahydro- 0-yrxnty-,,-rmthl6tilooehl8pro5.6-.

giqinoine(Copoud33. structure 67-A off Schem w eeR 2

.R

-methyl

R

6 =trifluoro methyl X=N-B.

H*.P~iana\Kpl-~c 4577-6. MRIDRECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 293 To an oven-dried 50-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 MHz, CDC13) 9.32 (br s, 1 H, CONH), 7.44 1 H, 6.74 1 H, 5.32 [br s, 1 H, (CH3)2CNH], 4.57 1 H, J 9.7, OH), 5.02 and 4.93 (ABq, 2 H, JAB 14.0, CH20H), 2.85 (ddq, 1 H, J= 12.9, 12.4, 5.5, 1.84 and 1.54 [d of ABq, 2H, JAB 10 13.1, JA 4.3, 3 -Heq), JB 0 3 1.41 3H, J 5.5 Hz, 4-CH3), 1.39 and 1.26 [2s, 2 x 3H, 2-(CH3)2].

EXAMPLE 334 1 ,2,3, 4 -Tetrahydro-12.

2 .4 tetramethyl-6-trifluoromethyl-9 thiopran-8-onor5 6 -lquinoline (Compound 434, structure 28A of Scheme XXXVIII. where R 1 2

=R

5

=H

i R 3 =trifluoromethyl,

Z=S)

*:mo 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 mmol) under nitrogen with stirring at rt. After 15 h, the reaction was complete according to 1 H NMR. The reaction was quenched with saturated NaHCO3 (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, 2 50tm, 1:1 CH2Cl2:hexanes) to afford 4.5 mg of Compound 434 as a yellow solid. Data for compound 434: 1

H

NMR(400 MHz, CDC13) 7.59 1 6.60 1 6.53 1 2.89 3 2.85 1 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); IR (film, NaCI) 1022, 1066, 1094, 1113, 1134, 1271, 1368, 1464, 1512, 1593, 2926.

HPriyanka\Kecp\spccM5977-96.STEROID RECEPTOR.doc 19/01/00 DOCKET

NO.

016-0014A.WO 294 EXAMWPLE 335 l.

2 3 4 Tetrahydro229trimet hytLfluriothl 8 -,yidoo 6 -glguinoline (Compound 435; stucur 8A of Scheme LVI. where

R

1

=R

5 6 -H R 2 3 =methv

R

4 =trifluoromethyl).

In a 25-mL a solution of Compound 417 (165 mg, 0.557 mmol) in THF (4 rnL) was cooled to 00 C and treated with 60% NaHl in mineral oil (23 mg, 0.58 mmol, 1.0 equiv).

The reaction mixture was stirred 10 min. To this slurry, iodomethane (35 mL, 0.56 mrnol, equiv) was added via syringe. The reaction mixture was stirred 12 h, diluted with mL), and extracted with ethyl acetate (3 x 20 mL). The extracts were washed with brine 10 (1 x 20 mL), combined, dried (MgON), filtered, and concentrated. Purification by silica gel chromatography (CH2CI2:MeOH, 50:1) afforded 134 mg of Compound 435 as a pale yellow powder. Data for Compound 435: 1 H NMR (400 MHz, acetone-d6): 7.35 (s, 1 6.56 1 6.51 1 6.09 (br s, 1 FH), 3.53 3 2.87 J 6.7, 2 1.76 J 2H), 1.29 6 H).

EXAMPLE 336 (RIS- l.

2 4 Tetrahyd o-3methyl.6..tifuromethy 18 I~don[5 6 -gquinoline (Componnd436. trctue 62A of Scheme VIIIyr. where

R

2

=R

4 =R6=H

R

3 =methv

R

5 =trifluoromethyl).

1 -tert-Butylo xycarbonyl- l.

2 3 4 -tetrahydro3.methyl4guinolione structure 69A of Scheme LI. hr 1 2 H. R 3 =meth l. To a solution of Il-tert-butyloxycarbony-1,234tetrahydro-4quinolinon (structure 68A of Scheme LI, where

RI-

2 (EXAMPLE 325) (500 mg, 0.002 mol) in THF (5 mL) at -78' C was added 2.0 M LDA in THF (1.01 mL, 0.002 mol). The reaction mixture was stirred at -78' C for 15 min and iodomnethane (126 mL, 0.002 mol) was added all at once. The temperature was raised to 0' C and the resulting mixture stirred for 4 h. The reaction was then quenched with sat'd NI-4CI extracted with ethy acetate (2 x 10 mL), dried (Na2S 04) 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 1-etbtlxcroy-,,,-erhdo3mty--unlnn (structure 69A of Scheme LI, where

R

1 2

R

3 =methyl), 128 mg of l-tertbutyloxycarbonyl-1, 2 3 4 -tetrahydro33dinethyl4qulion (structure 70A of Scheme H.'Pancp\KsP \9779&SBROID RECEPTflRAdo 19/01/00 DOCKET

NO.

0 16 -0014A.WO 295 LII, where

R

1 2

R

3 -4=methyl) and 200 mg of recovered starting material. Data for 1-tert-butyloxycarbonyl-l,2,3, 4 -tetrahydro-3-methyl-4-quinolinone: 1 H NMR (400 MHz, CDC13) 7.99 (dd, J 1.7, 1 7.77 J= 8.4, 1 7.48 (ddd, J=7.3, 7.3, 1.7, 1 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= 9.8, 7.0, 4.4, 1 1.56 9 1.24 J= 7.0, 3 H).

-tert-Butloxycarbonyl-1.

2 3 4 -tetrahvdrometh inoline To a solution of -trt- :butyloxycarbonyl-,2,3,4-tetrahydro-3-methyl--quinolinone (117 mg, 0.45 mmol) in methanol (2 mL) at 00 C was added portionwise sodium borohydride (17 mg, 0.45 mmol) and the reaction mixture was stirred at 0° C for 3 h. The reaction was quenched with of sat'd NH4CI (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 (20 mg) and a trace of conc. H2S04 at rt for 16 h. Filtration over Celite'M afforded 104 mg of l-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3-methylquinoline. Data for 1-tertbutyl o xycarbonyl-1,2,3,4-tetrahydro-3-methylquinoline: 1 H NMR (400 MHz, CDC13) 7.65 J= 8.3, 1 7.11 (dd, J= 7.7, 7.7,1 7.04 J 7.2, 1 6.96 (dd, J 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, 1 2.03 1 1.52 9 1.05 J 6.7, 3 H).

1 2 3 4 -tetrahdro-3-methlunoline structure 60A of Schme LI where R 1 2

=R

4

=H

R

3 =methyl). This compound was prepared by General Method 12 (EXAMPLE 147) from l-tert-butyloxycarbonyl- ,2,3,4-tetrahydro-3-methylquinoline (104 mg, 0.42 mmol) to afford 51 mg of 1,2,3,4-tetrahydro-3-methylquinoline as an oil which was used directly without purification for the next step.

7-Nitro-1234-tetrahdro-3-methluinol 1,2,3, 4 -Tetrahydro-3-methylquinoline (51 mg, 0.35 mmol) was dissolved in sulfuric acid (0.5 mL) and the temperature lowered to 0° C. To this solution 90% fuming nitric acid (15 mL, 0.35 mmol) was added slowly and the mixture stirred at 00 C for 1 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 r-ai.p\sp_1\4597796S'hROID RECEPTOR.do 19/01/00 DOCKET

NO.

016-0014A.WO 296 washed with saturated aqueous NaHCO 3 (3 rnL) and concentrated in vacuc to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 85:15) which afforded 8.2 mg of 7-ir-1234ttayr--ehlun ie Data for 7nitro- 1,2,3,4tetrahydro3methylquinoae: IH NMR (400 MHz,

CDCI

3 7.39 (dd, J 8.25, 2.2, 1 7.27 J= 2.3, 1 7.01 J= 8.3, 1 4.19 1 3.33 1 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 (n-4 1 1.06 J= 6.7, 3 H).

l.

2 3 4 -Tetrahydro3methy6trifluoromth 8 yidon [S 6 -glquino line (Compound 436). A solution of 7 -nitro-1,2,3,4-tetrahydro.3-methylquinolie (8.2 mg, 0.042 mmol) in ethyl acetate (1 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (4 mg) at 11 for 2 h. Filtration over CeliteTM afforded 6.2 mng of 7-amino- 1,2,3,4tetrahydro..3.methylquinoline (structure 61A of Scheme XLVIII, where

RI-

2

=R

4

=H,

R

3 =methyl) that was used without further purification for the next step. Compound 436 15 was prepared by General Method 13 (EXAMPLE 147) from 7 -amino-l1,2,3,4-tetrahydro-3 inethylquinoline (6.2 ing, 0.038 mmol), ZnC12 (8.0 mg, 0.057 mmol) and ethyl 4,4,4trifluoroacetoacetate (5.5 mL, 0.03 8 mol) to afford 5.8 mg of Compound 436 as a yellow solid. Data for Compound 436: IH NMR (400 MHz, DMSO-d 6 11.80 (bs, 1 H), 11 1 6.95 1 6.37 2 3.26 (ri, 1 2.8 3 2 2.51 (dd, J 15.7, 10. 3, 1 1. 88 1 0. 97 J 6.6, 3 H).

EXAMPLE 337 1,,,-erhdoa3dmeh 6tilooeh 8 -pvridono

[S.

6 -glquinoline (Copound 437 structure A fScheme 1I. where R R =RH. 3 4 methvl

R

6 =trifluoromethyl).

1 -tert-Butyloxycarbonyl-. 3,-erhdo33dmty---inlnn (structure 70A of Scheme I.1hre R 2 =H R 3 4 =methl). This compound was obtained along with 1tert..butyloxycarbonyl-1,2,3,4ttayr--ety--unlnn as described above (EXAMPLE 336). Data for 1 -tert-butyloxycarbonyl. l, 2 3 4 -tetrahydro.3,3dimethyl-4 quinolinone: IH NMR (400 MHz, CDC13) 8.01 (dd, J 7.9, 1.6, 1 7.78 J 8.4, 1 H'\Panp\K-P'-cM59796STROD RECEPTORdO 19/01/00 DOCKET

NO.

016-0014A.WO 297 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).

1 -tert-Butyloxvcarbonvl- 1.2,3.

4 -tetrah ydro.33-direthylquinoline 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 NH4Cl (2 mL), extracted with ethyl acetate (2 x 5 mL), dried (Na2SO04) 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.

H2S04 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-terti butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethylquinoline: 1 H NMR (400 MHz, CDC3) 3 7.68 J= 8.3, 1 7.12 (ddd, J= 8.8, 8.8, 1.5, 1 7.02 J= 7.0, 1 6.97 (ddd, J= 15 7.4, 7.4, 1.0, 1 3.46 2 2.58 2 1.51 9 1.01 6 H).

1.

2 3 4 -tetrahvdro-3.3-dimethylquinoline (structure 71A of Scheme LII where R 1 2 R H R 3 4 =methyl). This compound was prepared by General Method 12 (EXAMPLE 147) from 1 -tert-butyloxycarbonyl- 1,2,3, 4 -tetrahydro-3,3dimethylquinoline (100 mg, 0.38 20 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-tetrahdro-3.3-dimeth uio line. 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 00 C for 1 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 mL) 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-dimethylquino line: 1 H NMR H.\Riaanka\Kap\spci\459796STROID RECEPTOR.doc 19/01/00 DOCKET

NO.

016-0014A.WO 298 (400 MHz, CDCJ3) 7.40 (dd, J= 8.3, 2. 1, 1 7.29 J= 1.8, 1 7.01 J 8.3 H,1 4.25 I 2.98 2 2.54 2 1.01 6 H).

1, 2 3 4 -Tetrahydro33dimethyl-6-trifluoromethyl 8-p yidono [5.6-glgquino line (Compound 437). A solution of 7 -nitro-l1,2,3,4-tetrahydro -3, 3 -dimethylquino 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-amidno-l1,2,3,4tetrahydro -3,3..dimethylquino line (structure 72A of Scheme LII, where R 1 2

=R

5

R

3 4 =methyl) that was used without further purification in the next step. Compound 437 was prepared by General Method 13 (EXAMPLE 147) from 7-amino- l, 2 ,3, 4 -tetrahydro-3,3dimethylquino line (30 mg, 0. 17 mmol), ZnCJ2 (34 mg, 025 mmol) and ethyl 4,4,4trifluoroacetoacetate (25 mL, 0. 17 mol) to afford 13 mg of Compound 437 as a yellow solid. Data for Compound 437: IH NMR (400 MHz, DMSO-d6) 11.71 (bs, 1 H), 7.11 1 7.01 1 6.40 1 6.37 1 2.89 2 2.51 2 0.93 6

H).

EXAMPLE 338 f RIS) 1,,,-erh o-,,-nmehl6tilooehl p yidono glquino line (Comnpound 4381, struture 9A of Scheme L 1, wh-re R=R 5

=R

7

R

2 4 =methyl.

R

6 =trifluoromethyl).

1I -tert-Butoxycarbonyl 1.2,3 4 .tetrahydro22dimethy14-guinolinon (structure 76A of Scheme LII where Rl=H, R 2 3 awmthyl. A solution of aniline (19 mL, 0.20 mol), 3acetoxy..3.methyll-butyne (26 g, 02 o)Cu (1.0 g10mmol) adEt3N (28 m,0.20 mol) 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 -methyl-3-phenylano-l -butyne. Treatment of the, aminobutyne with CuCl (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 1,2d ihydro..2,2..dimethylquino line (structure 75A of Scheme LII, where

R

2 3 =methyl).

Treatment of the quinoline with di-tert-butyl dicarbonate (22 g, 0. 10 mol) and DMAP (12 g, 0. 10 mol1) in THF (100 mL for 16 h folIlo wed by c hro mato graphy (silica gel, H:\Priyaanb\Kmcp\specM\5977.96.SThRO[D RECEPTORAdo 19/01/00 DOCKET NO.

016-0014A.WO 299 EtOAc/hexane, 2/8) afforded 15 g of l-tert-butoxycarbonyl-1,2-dihydro-2,2dimethylquinoline. 1-tert-Butoxycarbonyl- 1, 2 -dihydro-2,2-dimethylquinoline (3.0 g, 11 mmol) in THF (30 mL) was treated with 1.0 M BH3-THF in THF (29 mL, 29 mmol) at rt for 3 h and was quenched with 3 M KOH (20 mL). To the above solution 30% H202 mL) was added and the mixture was stirred for 60 min, 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 2:1 mixture of two isomers (0.87 g, 3.1 mmol), which was oxidized with PCC g, 11 mmol) in 60 mL of methylene chloride at rt for 60 min. 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 l-tert-butoxycarbonyl-l,2,3,4-tetrahydro-2,2dimethyl-4-quinolinone as a white solid. Data for 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro- 2 2 -dimethyl-4-quinolinone: 1 H NMR (400 MHz, CDC13) 7.93 J 7.8, 1 7.42 J 7.8, 1 7.31 J 7.8, 1 7.02 J= 7.8, 1 2.73 2 1.56 9 1.49 (s, 15 6 H).

1.

2 3 4 -tetrahvdro-2,2.3trimethvlquinolie (structure 77A of Scheme LII where

RL=R

5

R

2 4 =methyl). To a solution of l-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2dimethyl-4-quinolinone (0.10 g, 0.36 mmol) and iodomethane (0.50 mL, 8.0 mmol) in S 20 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 1-tert-butoxycarbonyl-1,2,3, 4 -tetrahydro-2,2,3-trimethyl-4quinolinone as a colorless oil. The oil (90 mg, 0.32 mmol) was treated with NaBH4 mg, 1.3 mmol) in methanol (5 m for 1 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 from the catalyst through a CeliteTM pad followed by removal of solvent gave 70 mg of 1-tert-butoxycarbonyl-1,2,3,4tetrahydro-2,2,3-trimethylquinoline as a colorless oil. The crude oil (70 mg, 0.26 mmol) was treated with TFA (0.50 mL, 6.5 mmol) in CH2C12 for 30 min. and was quenched with H:\Priyanka\Keep\pecM\5977-96.STEROID RECEPTOR.doc 19/01/00 DOCKET

NO.

016-00 14A.WO 300 NaOH (6 mL). The mixture was extracted with EtOAc (2 x 15 rnL) and was concentrated. Chromatography on silica gel using a 10% midxture of EtOAc and hexane afforded ,,-erhd22-tr imhylqum o line as a colorless oil (40 mg, Data for l, 2 3 4 -tetrahydro-2,2,3..trmiethylquinoaie: IH NMR (400 MHz, CDC13) 7.00-6.9 1 (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

7.2, 3 H).

(RIS) l.

2 3 4 -Tetrahydro2.3.trimethl6triuoromthy 8-yidono [5.

6 -glguino line (Compound 438, structure The quinoline (20 mng, 0. 11 inmol) was converted to Compound 438 according to the nirto-yrgeain nr procedure described above for Compound 436 (EXAMPLE 336) in a 12% yield as a yellow solid (4 mng). Data for Compound 436: 1Hj NMR (400 MHz, CDC1 3 11.46 1 7.35 1 6.66 1 H), 6.31 1 4.40 1 2.83 (dd, J =16.6, 4.8, 1 2.57 (dd, J 16.6, 10.3, 1 1.83 (in, 1 1.25 3 1. 10 3 0.99 J= 6.9, 3 H).

EXAMPLE 339 1,34ltayr-,-int 6 -,gjguino line ~(Comnpound 439 structure 62A of.Scheme XLVII where

R=R

3

=R

6 =H R 2 R=ehl

R

5 =tifluoromethyl) 1 -tert-Butoxycarbonyl-1234Ltayr--ehl4nioio A mixture of aniline g, 32 inmol) 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 -phenylaminobutanoic acid. The acid was treated with PPA (20 mL at 100 C for 6 h and the reaction mixture was poured into ice water (50 mL) and then was neutralized with Na2CO 3 to pH 7. Extraction with EtOAc (3 x mL) followed by chromatography (silica gel, EtOAc/hexane, 4/6) afforded 1.0 g (44%) of 1,,,-erhyr--ehl -unlnne (structure 59A of Scheme XLVIII, 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 inmol) and DMAP (0.84 g, 6.8 minol) in THF (15 mL) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) to afford 1.1 g of l-tert- H:'\Priaaka\KeePxspecM5977-96.S7ROID RECEPTX)Rdocw 19/0)00 DOCKET NO.

016-00 14A.WO 301 butoxycarbonyl- 1 2 3 4 -tetrahydro-2-methy[-4quinolino ne as a yellow oil. Data for 1 -tertbutoxycarbonyl- l, 2 3 4 -tetrahydro-2-methyl4quinolinone: 1 H NMR (400 MHz, CDCJ3) 7.99 J 7.5, 1 7.7 8 J 7.5, 1 7.50 J 7.5, 1 7.12 J 7.5, 1 5. (in4 1 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)- 1..2,3 4 -Tetrahydro..24.dimethy6trifluoroinethyIZ8 pyridono

[S.

6 -giguino line (Compound 439) To a solution of a 3.0 M ether solution of MeMgBr (1.0 mL, 3.0 inmol) was added 1 -tert-butoxycarbony[l1 2 3 4 -tetrahydro-2-methyh4-quinolino ne (0.13 mg, 0.50 mmol) in THF (6 mL) and the reaction was allowed to stir at rt 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 Celite Tm afforded the crude 1 tert-butoxycarbonyl-1,2,3 4 -tetrahydro..2,4.dimethyp4-quinoline, which was treated with TFA (0.4 mL) in methylene chloride (1 mL) for 30 min. The reaction was neutralized with NaOH to pH 10 and was extracted with EtOAc (2 x 20 mL). Choaorphy (silica gel, EtOAc/hexane, 1/9) afforded 20 mg of (R/S- 2 1-4u)- 1,2,3,4-tetrahydro.2,4.

dimethyl-4-quinoljne (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 nitration- hydrogenation Korr procedure described above for Compound 436 (EXAMPLE 9999 336) in 14% three step yield as a yellow solid. Data for Compound 439: IH NMR (400 MHz, CDCl3) 11.75 1 7.47 1 6.65 1 6.33 1 4.41 1 3.59 (in, 1 2.92 1 1.94 (mn, 1 1.38 J 6.8, 3 1.24 (mn, 1 1.22 J= 6.4, 3 H).

EXAMPLE 340 R/S-21.4u)-4-Ethy- l., 2 3 4 -tetrahydro.2-methyl-6trifluoroinethyl8-pyanono rs .6giqinoine(Copoud 4 0. trutur 33 ofSchme L where R I 2

=H.

R

3 =methyl. R 4 =ethyL R 5 =trifluoromethyl).

H' "nkaK-p-p-M597-96STEOIDRECEPTOR.dO 19/01/00 DOCKET NO.

016-0014A.Wo 302 (RIS)- 4 -Tetrahydro- 7 -methox-2methyl-4-uinolinone. This compound was prepared in a manner similar to that described for 1 2 3 4 -tetrahydro-7-methoxy-4-quinolone (EXAMPLE 310) from anisidine and crotonic acid to afford the quinolinone as a brown oil.

Data for 1 2 3 4 -tetrahydro- 7 -methoxy-2-methy..4.quinolinone: I HNMR (400 MHz, CDCI3) 7.78 J 8.7, 1 6.33 (dd, J 6.2, 2.2, 1 6.08 J 2. 1, 1 4.27 (br s, 1 3.80 3 2.59 (dd, J 16, 3.7, 2 2.42 (dd, J 13, 12, 2 H), (RIS)- 1-tert-Butoxycarbonyl- 1 2 3 4 -tetrahydro-7-methoxy2methylb4-guio lone (structure 31A of Scheme XL. where R 1 2

R

3 =methyl). This compound was prepared in a manner similar to that described for l-tert-butoxycarbonyl-1,2,3,4tetrahyro7-methoxy-4 quino lone (EXAMvPLE 310) from 1,2,3 4 -tetrahydro-7-methoxy2methy4quinoione (3.26 mg) to give 961 mg of the desired quinolone as an off-white solid. Data for 1tert-butoxycarbonyl- 1,2,3 4 -tetrahydro-7 -methoxy-2-methy14-quino lone: I 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 :*fe* (in,4 1 3.86 3 2.99 (dd, J= 17, 5.8, 1 2.48 (dd, J= 17, 1.7, 1 1.57 9 H), *981. 24 J 3 H).

(RIS)- 1-tert-Butoxycarbonyl-4-ethyi. l.

2 3 4 -tetrahydro-7-methoxy2-mthylquino line (structure 32A of Scheme XL. where R- 2

R

3 =methvl. R 4 =ethyl). This compound was prepared in a manner similar to that described for l-tert-butoxycarbonyl-4-ethyl-1,2,3,4- -foetetrahydro-7-methoxy-4-quinolone (EXAMPLE 314) from 1 -tert-butoxycarbonyl- 1,2,3,4tetrahydro-7-methoxy-2methyI4-quinolone (100 mng) to give the desired quinoline (34 mg, as a mixture of diastereomers. Data for l-tert-butoxycarbonyl-4-ethyl-1,2,3,4tetrahydro-7-methoxy-2- methylquino line: I H NMR (400 MHz, CDC13) 7.05 J 8.6, 1 6.97 J1 2.5, 1 6.66 (dd, J 8.5, 2.5, 1 4.38 (mn, 1 3.78 3 2.39 (in, 1 2.28 (mn, 1 2.04 (in, 2 1.55 (mn, 1 1.49 9 1. 14 J1=6.2, 3 1.08 J 7.4, 3 H).

RIS)-4-Ethyl- 1, 2 3 4 -tetrahydro-7-hydroxy2- ethylquino line. This compound was prepared in a manner similar to that described for 4 -ethyl- 1,2,3,4-tetrahydro-7.

hydroxyquino line (EXAMPLE 314) from 1 -tert- butoxycarbonyl-4-ethyl- 1,2,3,4-tetrahydro- H:\Priyanka\Kep\spc597796.SEROjD RECEPTORdoc 19/01/00 DOCKET NO.

016-0014A.WO 303 7 -methoxy-2-methylquinoline (34 mg) to give the desired quinoline asa colorless oil, which was used without further purification in the following reaction.

RS-214u)-4-Ethyl- 1 2 3, 4 -tetrahydro-2-meth-6truoromethyl 8 56 uinoline (Compound440). This compound was prepared in a manner similar to that described for Compound 414 (EXAMPLE 314) to give the desired compound as a mix of diastereomers. Recrystallization of the diastereomeric mixture afforded a sample of Compound 440. Data for Compound 440: 1H NMR (400 MHz, CDC13) 7.38 1 H), 6.37 1 6.35 1 4.43 (br s, 1 3.57 1 2.79 1 2.04 2 H), 1.61 1 1.28 J= 6.4, 3 1.00 J= 7.3, 3 H).

EXAMPLE 341 (R/S-21,3u)-1.2,3,4-Tetrahydro_2.3dimethyl_6trifluoromethyl 8-pridono 6 -gquinoline (Compound 441 structure 62A of Scheme XLV where R=R 4

=R

6 =H R2-3=methy.

15

R

5 =trifluoromethyl).

To a solution of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinone (EXAMPLE 339) (0.13 mg, 0.50 mmol) and iodomethane (0.50 mL, 8.0 mmol) in DMF (6 S. mL) was added NaH in a 60% mineral oil (40 mg, 1.0 mmol). The reaction mixture was stirred at rt for 16 h and was quenched by water (10 mL). Extraction of the mixture with S 20 EtOAc (2 x 30 mL) followed by chromatography (silica gel, EtOAc/hexane, 1/9) afforded a mixture of three alkylated products (125 mg, The above mixture was treated with NaBH4 (38 mg, 1.0 mmol) in methanol (15 mL) for 1 h and the alcohol intermediates were purified by chromatography (silica gel, EtOAc/hexane, 3/7) to afford a mixture of three alcohols (120 mg, The mixture of alcohol intermediates (120 mg, 0.43 mmol) was S 25 treated with 10% Pd/C (20 mg) and one drop of H2SO4 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 mL) in methylene chloride (1.0 m) for 1 h. The reaction was quenched with 5% NaOH, brought to pH 10, and was extracted with EtOAc (2 x 20 mL).

Chromatography (silica gel, EtOAc/hexane, 2/8) afforded a mixture of three products mg, containing (R/S-21,3u)-1,2,3,4-tetrahydro-2,3-dimethylquinoline (structure of Scheme LI, where

RI=R

4

R

2 -3=methyl); (R/S-21,31)-1, 2 3 4 -tetrahydro-2,3- HnParm\Ksep\pov597796SThROID RECEPTOR.doc 19/01/00 DOCKET NO.

0 16-0014A.WO 304 dirnethyiquino line (structure 60A of Scheme LI, where R 1

=R

4

R

2 3 =methyl), and (RIS)- l, 2 3 4 -tetrahydro -2,3,3-trimethylquino line (structure 71A of Scheme LIE, where R I=R 5

R

2 -4=methyl). The midxture of the quinolines (30 mg, 0. 18 mmol) was subjected to the nitration-hydrogenation- Knorr procedure described above for Compound 436 (EXAMPLE 336) to afford a mixture of Compound 441, 442, and 443, which was purified by HPLC (10 mmn x 25 cm ODC column, 80% MeOH/20% H20, 3.0 mL /min.).

Data for Compound 441: 1 H NMR (400 MHz, acetone-d6) 10.68 1 7.25 1 H), 6.48 1 6.41 1 6.09 1 3.13 (in, 1 2.80 (dd, J 15.9, 4.3, 1 2.53 (dd, J 15.9, 12.0, 1 1.61 (mn, 1 1.24 J 6.3, 3 1.04 J 6.5, 3 H).

EXAMPLE 342 (R/S-21.31)- l.

2 3 4 -Tetrahydro-23dimethy16trifluoromethl8-p~gdono [5.6-glguino line (Compound 442. structure 62A of Scheme XLVII. whre RR R 6 H R 2 3 =methy.

R

5 =trifluoromethi1) 15 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 1 3.62 (mn, 1 2.91 (in, 1 H), *2.62 (dd, J 16.3, 6.5, 1 2.07 (mn, 1 1. 15 J= 6.5, 3 0.93 J 6.8, 3 H).

20 EXAMPLE 343 (RIS)-12 l 2 3 4 -Tetrahydro-2,3,3-aiethy-6trifluoromethyl-8-pyidono [5,6-giquino tine (Compound 443. strture 3A ceeLI hr r 1

R=

7 H R 2 4 =nethvl.

R

6 =trifluoromethyl1).

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 1 3.28 (in, 1 2.65 J =15.8, 1 2.53 J 15.8, 1 1. 15 J 6.6, 3 1.03 3 0.84 3 H).

H*\Piyaaa\Kp~spcM577-9.ST RH RCEPTOR~do 19/01/00 DOCKET NO.

016-0014A.WO 305 EXAMPLE 344 1 2 3 4 -Tetrahydro-2-methyl6.trifluoroiethyl8-Midono [5.

6 -glguinotine (COmpound 444, structure 53A of Scheme XLVI. where R I 2

=R

5

R

3 =methyl.

R

4 =trifluoromethyl) l, 2 3 4 -tetrahydro-2-methylquinotline 15 g, 1.0 inmol) was converted to Compound 444 according to the nitration- hydro genatio n- Knorr procedure described for Compound 436 (EXAMPLE 336) to afford 35 mng of Compound 444 as a yellow solid. Data for Compound 444: IH NMR (400 MHz, acetone-d6) 10.83 1 7.29 1 6.55 1 6.50 1 6.17 1 3.57 (mn, 1 2.91-2.82 (mn, 2 2.03 (i 1 1.54 (in, 1 1.25 J 3H).

EXAMPLE 345 (R/S)-4-Ethyl- 1 2 3 4 -tetrahydro-6-trifluoroinethyp- 8-pyidono [5.6-giguino line (Compound 445, structure 62A of Scheme XL VIII. where R 3

=R

6

R

4 =ethyl, R 5 =trifluoromethyl) 15 (RIS)- 1 -tert-Butyloxycarbonyl-4-ethy1- 12.3 4 -tetrahydro-4-hydroxyguino line. To a flamedried 25-mL rb flask containing ethylmagnesium bromide (4.0 m L of a 3.0 M solution in Et2O, 12.0 inmol, 3.0 equiv), at 10' C was added dropwise a solution of W-ert- :butylo xycarbonyl- 1, 2,3,4tetrahydro-4quino lone (1.0 g, 4.0 inmol) in Et2O (4 mL). The reactio n mixture was stirred at 10' C for 15 min, then allo wed to warm to rt over 10 min.

20 A 1.0 M solution of NaHSO4 (10 inL) was then rapidly added. The resulting biphasic mixture was extracted with EtOAc (3 x 10 inL), and the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes EtOAc, 4: affording 800 mng (71 of the desired product as a clear yellow oil (Rf 0. 14, hexanes EtOAc, 4: Data for 1-tert- 25 butoxycarbonyl-4-ethyl- 1 2 3 4 -tetrahydro-4-hydroxyquinoline: IH NMR (400 MHz, CDC3) 7.68 1H, J 8.4, 7.47 (dd, I1H, J 7.9, 1.7, 7.21 (ddd, I1H, J 7.4, 7.4, 1.6, 7.09 (ddd, I1H, J 7.8, 1.1, 4.03 (ddd, 1 H, J= 12.9, 7.1, 4.7, 2-H), 3.47 (ddd, IlH, J= 13.1, 8.6, 4.3, 2.11 (ddd, I1H, J= 13.5, 8.6, 4.8, 1. 86 (in, 3H, 3-H, CH2CH3), 1.52 9H, C(CH3)3], 0.89 3H, J 7.5, CH3).

H'\JCOk-\K-pOifcM597796STROID RECEPOR.dOC 19/01/o0 DOCKET NO.

016-0014A.WO 306 (R/S)-4-Ethyl-1,2.3, 4 -tetrahydroquinoline (structure 60A of Scheme XLVII, where R1 3

R

4 =ethyl). To a flame-dried 100-mL rb flask containing 1-tert-butyloxycarbonyl-4ethyl-l, 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 CH2C12 (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 (Rf0.40, hexanes EtOAc, Data for 4 -ethyl-1,2,3,4-tetrahydroquinoline: 1

H

15 NMR (400 MHz, CDC13) 7.02 H, J 7.6, 6.96 (ddd, 1H, J 7.7, 7.7, 1.3, 7-H), ~6.61 (ddd, 1H, J= 8.2, 8.2, 1.0, 6.47 1H, J= 7.9, 3.83 (br s, 1H, CH2NH), 3.31 (ddd, 1H, J= 11.3, 11.3, 3.6, 3.25 (ddd, 1H, J= 9.7, 9.7, 4.8, 2.65 (dddd, 1H, J= 10.1, 5.1, 5.1, 5.1, 1.92 (dddd, 1H, J 9.6, 4.7, 4.7, 4.7, 3- 1.82 1H, 1.74 1H, CH2CH3), 0.98 3H, J= 7.4, CH3).

(R/S)-7-Amino-4-ethyl-1,2, 3 4 -tetrahydroquinoine (structure 61A of Scheme XLVIII where R- 3 =H R 4 =ethy). A 25-mL rb flask containing (R/S)-4-ethyl-1,2,3,4tetrahydroquinoline (340 mg, 2.1 mmol) was cooled to -100 C, and conc. H2S04 (5 mL) was added slowly. The resulting solution was warmed to rt to effect complete dissolution of 25 the quinoline, then cooled again to -100 C and stirred vigorously. Fuming HNO3 (85 pL) 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 NaHCO3 (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 H:\Priyanka\Keep\spcMm5977-96.STEROID RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 307 C (approx. 1 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, CH2Cl 2 methanol, affording 210 mg (57 of the desired product as a dark yellow oil (Rf 0.50, CH2Cl2 /MeOH, Data for (R/S)-7-amino-4-ethyl-1,2,3,4tetrahydroquinoline: 1 H NMR (400 MHz, CDC13) 6.81 1H, J= 8.1, 6.02 (dd, 1H, J= 8.0, 2.2, 5.84 1H, J= 2.3, 3.48 2H, NH2), 3.27 (ddd, 1H, J= 11.1, 11.1,3.5,2-H), 3.20 (ddd, 1H, J=9.8, 5.3, 4.5, 2.55 (dddd, 1H,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 (mn, 2H, 3-H, CH2CH3), 1.48 1H, CH2CH3), 0.96 3H, J= 7.4, CH3).

R/S)-4-Ethy-l-l tra8-pyridonor5.6-g1quinoline (Comound 445). To a flame-dried 100-mL rb flask containing 7 -amino-4-ethyl-1,2,3,4tetrahydroquinoline (210 mg, 1.19 mmol), in ethanol (20 miL), at rt, was added ethyl-4,4,4- S 15 trifluoroacetoacetate (190 pL, 1.31 mmol, 1.1 equiv) followed by ZnC12 (244 mg, 1.79 mimol, 1.5 equiv). The reaction mixture 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 rt, and the solvent removed under reduced pressure. Dichloromethane (20 mL) was added and the organic phase washed with sat'd NaHCO3 (2 x 10 mL) and brine (1 x mL), then dried (Na2SO4), and concentrated under reduced presure. This crude product was purified by flash chromatography (silica gel, CH2C12 MeOH, 15:1), affording 24.4 mg of the desired product as a yellow solid. Data for Compound 445: Rf 0.37, (CH2C2 MeOH, 1 H NMR (400 MHz, CD30D) 7.31 1H, 6.47 1H, 7- 6.37 1H, 10-H), 3.34 2H, 2.70 (m 1H, 1.88 2H, 1.62 (im, 25 2H, CH2CH3), 1.00 3H, J 7.5, CH3).

EXAMPLE 346 (RS-21. 3u- 2 3 4 Tetrahydro-2,3,9-trimethyl-6-trifluoromethyl-8- dono56guinoline (Compound 446. structure 81A of Scheme L where RI=R 4

=R

6

=R

8

R

2 =methyl. R=trifuoromethyl H-.\Priyank-\K-rp~p clCr1 7-96.S R OID RECEPTOR.doc 19/01/00 DOCKET NO.

016-00 14A.WO 308 To a solution of Compound 441 (3.5 mg, 0.0 12 mmol1) and iodomethane 10 mL, 1.6 mmol) in THF (2.0 mL) was added NaH as a 60% in mineral oil (10 mg, 0.25 mmol) and the reaction was stirred at rt for 1 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 Compound 446 as a yellowish solid. Data for Compound 446: IH NMR (400 MHz, CDC13) 7.36 1 6.72 I 6.32 1 4.40 1 3.61 3 3.14 (in, 1 2.83 (dd, J 16.0, 4.4, 1 2.54 (dd, J 16.0, 11.0, 1 1.63 (in, I 1.26 J 6.3 3 1.06 J 6.6, 3 H).

EXAMPLE 347 1, 2 3 4 -Tetrahydro-4-p2ropy16-trifuoromethyl- 8-pyidono giquino line (COmpound 447. structure 62A of Scheme XLVII where 1 3

=R

6

R

4 =n-propvl.

R

5 =trifluoromethyl 1 -tert-Butyloxycarbonyl.1.2,3 4 -tetrahydro..4.hydroxy.4propylquinolin This compound 15 was prepared from 1 tr-uyoyabm l ,,,-erhdo4qioln (1.00 g, 4.00 9 imol) in the manner previously described for 1 -tert-butyloxycarbonyl4ethylp 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,,,-erhdo4hyrx--rplun lie H NMR (400 MHz, CDC13) 7.67 (d, 20 1 H, J 8.2, 7.48 (dd, I1H, J 1.7, 7.20 (ddd, I1H, J 8.6, 8.6, 1.4, 6-H), 7.08 (ddd, I1H, J 7.6, 1.1, 4.03 (ddd, I1H, J1= 12.8, 7.1, 4.8, 3.46 (ddd, I1H, j 13.0, 8.5, 4.4, 2. 11 (ddd, 1 H, J=l1 3 8.5, 4.8, 1. 89 (ddd, 1 H, J 13.6, 7.2, 4.4, 1.78 (in, 2H, CH2C2H5), 1.52 9H, C(CH3)3], 1.32 (in, 2H, CH2CH2CH3), 0.90 3H, J 7.3, CH2CH3).

PO* (RIS)-l l 2 3 4 -Tetrahydro..4-propvlpuino line (structure WA of Scheme XL VII. where R 1 3

R

4 n-propyl). This compound was prepared from l-tert-butyloxycarbonyl,2,3,4tetrahydro-4hydroxy-4propyquinoline (550 mng, 1.89 minol) in the manner previously described for 4 -ethyl-l, 2 ,3,4..tetrahydroquino ie (EXAMPLE 345), affording 229 mng of the desired tetrahydroquino line as a yellow oil (Rf 0. 10, hexanes EtOAc, 2: 1).

Data for (RIS)- l, 2 3 4 -tetrahydro -4-propylquinolin: 1 H NMR (400 MHz, CDCI3) 7.07 1H.\riynka~reep\speeMS977.96.STEROD RECEPTOR.doe 19/01/00 DOCKET NO.

0 16-00 14A.WO 309 IlH, J= 7.6, 7.02 (ddd, 1 H, J 7.9, 1.1, 6.77 (dd, I1H, J 7.4, 6-H), 6.67 I1H, J 7.9, 6.25 (br s, I1H, NH), 3.37 (ddd, I1H, J 11.5, 11.5, 3.5, 2-H), 3.30 (in, I H, 2.78 (dddd, I1H, J= 10.0, 5.0, 5.0, 5.0, 1. 99 and 1. 84 (2 x M 2 x 1H, 1.68 (in, 1H, CH2CH2CH 3 1.47 (in, 3H, CH2CH2CH3), 0.95 3H, J 7.3, CH3).

(R/S)-7-Ainino- l.

2 3 4 -tetrahydro-4-propguoie stuctur 6AoScee

XLVIIEL

where RI- 3 R=n-propyl). This compound was prepared from 1,2,3,4-tetrahydro.

4 -propylquino line (220 mg, 0.78 inmol) in the manner previously described for 7-amino-4ethyl-l, 2 3 4 -tetrahydroquino ie (EXAMPLE 345), affording 114 mng of the product as a colorless oil (Rf 0. 10, hexanes EtOAc, 2: Data for (R/S)-7-ainino- 1,2,3,4tetrahydro-4-propylquino line: IH NMR (400 MHz, CDC13) 6.80 1H, J 8.0, 6.01 (dd, LH, J 8.0, 2.3, 5.83 1H, J 2.2, 3.74 (br s, 1H, NH), 3.41 (br s, 2H, NH2), 3.28 (ddd, 1H, J 11.0, 11.0, 3.3, 3.19 (ddd, 1H, J 4.7, 4.7, 2-H), 15 2.65 (dddd, I1H, J 5. 1, 5.1, 5.1, 1.89 (dddd, 1H, J 9.7, 9.7, 9.7, 4.5, 1.73 (dddd, 1H, J 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)- l.

2 3 4 -Tetrahydro -4-propyb-6.trifluoroinethyl 8pyidono rS.6-glqguino line 20 (Comapd447) This compound was prepared from 7 -amfino-1,2,3,4-tetrahydro.4propyiquinoline (110 ing, 0.58 inmol) 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, 9: 1 H NMR (400 MHz, CDCl3) 7.34 I1H, 6.65 I1H, 6.40 1H, 10-H), 4.65 [br s, lH, (CH3)2CNH)], 3.42 (ddd, 1H, J 11.2, 11.2, 25 3.34 (ddd, 1H, J 7.9, 3.8, 3.8, 2.82 (in, 1H, 1.88 (in, 2H, 1.52 (in, 4H, CH2CH2CH 3 0.96 3H, J 7. 1, CH3).

EXAMPLE 348 3-Ethyl- 1,2.3 4 -tetrahydro-2,2-dmethl-6-trifluoronethyl 8- yido no g] uino line (opud48stutr79ofSemLIIwhere

R=R

5

=R

7

R

2 3 =ethyl,

R

4 =ethyl R 6 =trifluoronethyl) H:\Pr~anka\Keep~spec\497796STROrD RECEPTORdoc 19/01/00 DOCKET

NO.

016-O0l4A.WO 310 (R/S)-3-Ethyvl, l 2 3 4 -tetrahydo-22d' ethylquino ie (structure, 77A of Scheme LIU,.

where R 1

=R

5

=H,-R

2 3 =methyl,

R

4 =ethvl1). To a solution of l-tert-butoxycarbonyl2,3,4 tetrahydro-2,2-dimethyp4-quinoljnone (EXAMPLE 325) 10 g, 0.36 rnmol) and iodoethane (0.50 mL, 6.3 mnmol) in DMF (5 rnL) was added NaH- (60 in mineral oil, mg, 1.0 mniol) 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 column using a mixture of EtOAc and hexane as solvents afforded a mixture 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 mL Chromatography (silica gel, EtOAc/hexane, 3/7) afforded 30 mg (41 of (R/S)-3-ethyl- 1 2 ,3,4-tetrahydro- 2 2 -dimethyl-4-quinolinone (30 mg, 0.15 mmol) as a colorless oil. The quinolinone (30 mg, 0. 15 mmol) was treated with Et3SiH (1.0 mL and BF3-OEt2 (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 of (R/S)-3-ethyl- 1,,,4ttrhdo-,-dmtylunoie Data for (R/S)-3-ethyl- 1, 2 ,3,4-tetrahydro-2,2dimethylquinoline: Ill NMR (400 MHz, CDC13) 6.98 J 7.5, 1 FH), 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 (mn, 1 1.23 (n,4 1 1.22 3 H), 20 1.05 3H).

(Comp~ound 448). The quinoline prepared above (20 mg) was converted to Compound 448 according to the nitration-hydro genatio n-Knorr procedure described for Compound 436 (EXAMPLE 336) to afford 2.0 mg of Compound 448 as a yellow solid. Data for Compound 448: 1 H NMR (400 MHz, acetone-d6) 10.65 1 7.31 1 6.47 1 6.41 1 6.06 1 3.01 (dd, J= 16.6, 4.8, 1 2.53 (dd, J= 16.6, 11.0, 1 H), 1.72 (n,4 1 1.53 (in, 1 1.30 1 1.12 3 1.10-1.00 (in, 4 H).

H'*r'ykg\-P'~cl\497796.IERIDRECEPTORdO 19/01/00 DOCKET NO.

016-0014A.WO 311 EXAMPLE 349 (RIS)-1, ,-erhdo22diehl6tilooehy -rpl8prdn[5,6glqu ioline (Compound 449.' structure 79A of Scheme LIMT. where R I=R 5

=R

7

R

2 3 =methyl, R 4 =n-propyl,

R

6 =trifluoromethyl),) (RIS)-1 l 2 3 4 -Tetrahvdro-2.2-diniethl4-propylg uino line (structure 77A of Scheme LIIE[.

where R I=R 5

R

2 3 =methyl,

R

4 =n-propyl). This compound was prepared in a manner similar to that described for (R/S)-3-ethyl- 1,,,-erhdo22dmtyqioln (EXAMPLE 348) but using iodopropane in place of iodoethane. (RIS)- 1 2 ,3,4-Tetrahydro- 2 2 -dimethyl-4-propylquino line was obtained in 16% overall yield as a colorless oil. Data for (RIS)- l, 2 3 4 -tetrahydro-2,2-dimethyk4-propylquinoline: IH NMR (400 MHz, CDCl3) 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 (in, 2 1.21 3 1.05 3 0.92 J= 7.1 3 H).

(RIS)- l.

2 3 4 Tetrahydro-2 2 -dimethl-6-trifluoromethyl3propyl-8-pidon[56- 15 giguinoline (Comound 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: 1 H NMR (400 MHz, CDCl3) 11.00 1 7.32 1 H), 6.61 1 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 1.70-1.42 (in, 3 1.36-1.24 (in, 2 1. 18 3 1.02 3 0.93 J 20 6.7, 3 H).

EXAMPLE 350 l-Mehyl5-t~oroethy~p~donos6.indoline ompound 450. structure 83A of Scheme LV. where Rl 3

=R

5

R

4 =tifluroetvl 6 =etyl) 55*5 25 Compound 419 (10 mg, 0.0393 inmol) and paraformaldehyde (I11 mg, 0.0393 inmol) were a dissolved in glacial acetic acid (2.5 mnL) and stirred for 10 min at rt. NaBH3CN (13 mg, 0. 197 inmol) was added in one portion and allowed to stir at it 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 mL), dried (Na2SO4), filtered, and concentrated. The crude material was dissolved in 5% MeOH/CHCl 3 (0.5 mL) and loaded onto a 1000 pm reverse phase TLC plate (Whatman PLKC18F Silica Gel 150 The plate was eluted with H-A~iy~ka\mp'pec\4577-6.S ROI RCEPTOR4oc 19/01/00 DOCKET

NO.

0 16-0014A.WO 312 to afford 5.8 mg (55 of Compound 450 as a light yellow solid. Data for Compound 450: IH NMR (400 MHz, 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).

EXAMPLE 351 6-(5-Cyano-2-thienyl)- 1 2 -dihydro-2.2.4-trimethylq-uinoline (Compound 451. stucture 4 of Scheme where R 1 =5-cyano-2-thienyl).

To a solution of I -tert-butyloxycarbonyl-6(5..formyl2thienyl) 1 ,2-dihydro-2,2,4trimethyiquino line (12 mg, 0.03 rnrol) in acetonitrile/water (10 mId/0.5 m-l) was added hydroxylamine-O-sulphonic acid (5 mg, 0.04 mmol). The reaction mixture was heated to 650 C for 1 h. The reaction was quenched with 10% NaOH (5 mL) and extracted with EtOAc (10 mL). The organic layer was washed with water and brine (3 x 5 mL each), dried (Na2SO4), and concentrated in vacuc to afford the crude product as a yellow oil. The crude product was purified by prep. TLC (20 x 20cm, 250 pm, 25% EtOAc:hexane) to 15 afford 5 mg of 1-etbtlxcroy--5can--hey)12dhdo224 trimethyiquinoline as a yellow oil. This product was dissolved in CH2C12 (5 mL) and treated with TEA 1 ml) at rt with stirring. After 2 h, the reaction was quenched with NaOH (5 mL). The organic layer was washed with water and brine (3 x 5 mL each), dried (Na2S 04) and concentrated in vacuc to afford the crude product as a yellow oil. The crude product was purified by prep. TLC (20 x 20cm, 2 50g~m, 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); 1 H NMR(400 MHz, CDCl3) 7.52 J 4.0, 1 7.23 1 7.22 J 1 7.07 J 1 6.43 J 7.4, 1 5.38 1 2.02 3 1.31 (s, 6 H).

EXAMPLE 352 6 4 -Cyano-3-thienyl)- 1 2 -dihydro-2,2,4-t rimethylquino line (Compound 452. stucture 4 of Scheme I, where R=4-cano-3-thienyl).

4 -Bromo-2-cyanothiophene. To a solution of 4 -bromo-2-thiophenecarboxaldehyde (1.0 g, 5.2 mmol, Aldrich) in acetonitrile/water (20 mL/2 mL) was added hyroxylamine-O-sulfonic acid (2.4 g, 21.2 mmol, Aldrich). The dark solution was heated to 650 C with stirring. After H.VPaa\Kcp'pcMl5977-96.STEROro RECEP'IORAdo 19/01/00 DOCKET No.

016-00 14A.WO 313 8 h, the reaction was quenched with 10% NaGH (10 mL). The solution was extracted with EtOAc (30 mL). The organic layer was washed with water and brine (3 x 10 miL 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 of 4 -bromo-2-cyanothiophene as a white solid. Data for 4-bromo-2cyanothiophene: Rf 0.49 (silica, 25% EtOAc:hex.); IH NMR(400 MHz, CDCI3) 7.54 1 7.50 1 H).

6 4 -Cyano-3-thienyly. l.

2 -diiydro-22 4-tri-ethylQuino line (Compound 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 mm-ol). The crude product was purified by prep.

TLC (20 x 20cm 1 000ptnm, 25% ETOAc:Hexane) to afford 160 mg (91 of Compound 452 as a yellow oil. Data for Compound 452: Rf 0.50 (silica gel, 25% EtOAc:hex);

IH

NMR(400 MHz, CDCl3).7.79 1 7.46 1 7.20 1 7.16 J 8.3, 1 H), 0*0 15 6.46 J= 8.3, 1 5.37 1 2.03 3 1.31 6 IR (film, NaCi) 1159, 138 1, t. 00 1402, 1449, 1476, 1499, 1609, 1653, 2216, 2915, 3294, 3584.

EXAMPLE 353 6 3 -Formylphenyl)- l.

2 -dihydro-2,2,4-trimethlquinoie (CoMound 453 structure 4of 20 Schemne H, where 1 =-foMAVlpen S...This compound was prepared by General Method 2 from Compound 9 (50 mg, 0. 158 mmol) and 2 3 -bromopheny1)-1,3-dioxolane (171 mg, 0.788 mmol). Purification by flash S...*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, acetone- *to 25 d6) 10.09 1 8.11 J= 1.4, 1 7.90 J= 7.2, 1 7.77 J= 7.5, 1 7.59 J 7.6, 1 7.40 J 2.2, 1 7.33 (dd, J 8.4, 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 -DihydroI2.,2,4-trimethy-6. 3 -(methylsu Wonyl~phenylIquino line (Comound 454.

structure 4 of Scheme where ethylsUlfonvljpheyl) HN,\riaka\KCp\spccMS977.96.SIEROID RECEPTORdoc 19/01/00 DOCKET

NO.

01 6 -0014A.WO 314 3 -Bromophenyl(methyl)sulfone In a 50 mL r.b flask, m-CPBA (623 mg, 2.166 mmol, was suspended in CH2C12 (20 mL) and cooled to -20° C. 3 -Bromothioanisole (200 mg, 0.985 mmol) in CH2C12 (1 mL) was added to the slurry and allowed to warm to rt for 2 h. The reaction was quenched with H20 and the aqueous layer was extracted with CH2C12 (3 x 50 mL). The combined organics were washed with brine (25 mL), dried (Na2SO 4 filtered, and concentrated onto CeliteTM. 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, CDC13) 8.10 J 1.6, 1 7.88 J 7.9, 1 7.79 J 8.0, 1 7.46 J= 7.9, 1 3.07 3 H).

l 2 -Dihydro-2,2,4-triethyl6- 3 -(methylsulfonyl)phenylluinoline (Compound 454). This compound was prepared by a modification of General Method 2 as follows. A flask was Scharged with Compound 9 (123 mg, 0.388 mmol), the sulfone (83 mg, 0.353 mmol), 15 Pd(OAc) 2 (4 mg, 0.018 mmol), triphenylphosphine (18.5 mg, 0.071 mmol), and K3P0 4 (112.4 mg, 0.530 mmol). The flask was flushed with N2 for 5 min and then 5 mL of DMF S"(anhydrous) was added. The resulting reaction mixture 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 20 (3x50 mL) and brine (30 mL), dried (Na2SO 4 filtered and concentrated. The resulting material was dissolved in dimethylsulfide (0.5 mL), and cooled to 00 C. This solution was treated with trifluoroacetic acid (0.5 mL) and allowed to stir at 00 C for lh. The reaction was quenched with H20 (2 mL) followed by a slow addition of NaHCO 3 (sat) until i neutralized. The aqueous was extracted with EtOAc (2 x 30 mL). The combined organics S 25 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 light yellow film. Data for Compound 454: 1 H NMR (400 MHz, acetone-d6) 8.08 J= 1.8, 1 7.91 (dd, J= 6.7, 1.5, 1 7.78 (dd, J=6.5, 1.6, 1 7.64 J=7.8, 1 7.39(d, J= 2.1, 1 7.33 (dd, J= 8.1, 2.0, 1 6.61 J= 8.1, 1 5.43 (bs, 1 5.41 1 3.16 3 2.09 3 1.3 6 H).

H.*\PRiy-nka\K-p\spe\45977-96.ST D RECEPTOR.doc 19/01/00 DOCKET

NO.

0l6-0014A.WO 315 EXAMPLE 355 (R/S)-6-(3-Cyano-5fluiorophenyl). 1- 2 3 4 -Tetrahyd-ro-2.2,4-rimethylguino line (Compo und 455, structure 5 of Scheme I. where R I 3 A 25 ML r-b. flask was charged with Compound 271 (EXAMPLE 171) (145.0 mg, 0.50 mmol), ethyl acetate (1 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 mixture was filtered through a plug of CeliteTM. The crude mixture was purified by reverse phase semi-preparatory HPLC (70 methano Iwater- with trace triethyl. amine; retention time 29 min.) yielding 50.0 mg of Compound 455. Data for Compound 455: 1 H 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 8.6, 1.2, 1 6.59

J

8.4, 1 5.25 (br s, 1 2.95 (in, 1 1.80 (ddd, J 8.0, 5.4, 1.5, 1 1.40 (in, 4 H), 1. 25 3 1. 19 3 H).

EXAMPLE 356 (R/S)-9-Chloro- l.

2 -dihydro-224trimethyl5phenylpsH chromeno [3 4-flguinoline This compound was prepared by General Method 5 (Example 60) from Compound 209 C mg, 0.230 inmol) and phenyl magnesium bromide (1.84 mL, 1.84 mmol) to afford 61 mg (68 of Compound 456 as a clear film. Data for Compound 456: 1 H 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.e 25 1 1.98 3 1.26 3 1.24 3 H).

EXAMPLE 357 (R/S)-5-Butyl-12dhdo2249termtv-Hcrmn [3 .4-flguino line (Compound This compound was prepared by General Method 5 (EXAMPLE 60) from Compound 316 (EXAMPLE 216) (44 mg, 0. 14 rnmol) and n-BuLi (2.5 M in hexanes, 0.30 inL, 0.75 mmol, H:\Ia\.,PvcM97-96SROD RECEP'IORAd 0 19/01/00) DOCKET

NO.

0 16 -0014A.WO 316 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, 240:889-95 (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 15 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 ivo 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 20 compounds in vivo pharmacology. See, T. Berger et al. 41 J. Steroid Biochem. Molec.

Biol. 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 25 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 H\Priank\Kecp\spcM597796STROID RECEPTOR.doc 19/01/00 DOCKET

NO.

016-0014A.WO 317 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 5 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 Sassays, according to the following illustrative Examples.

20 EXAMPLE 358 Co-transfection assay CV-1 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-1-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 HPriyan-n\Kscp\spc-1\45977- MOID RECEPTOR.dc 19/01/00 DOCKET NO.

016-0014A.WO 318 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 S 15 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 S 20 fully described in Berger et al. supra. 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., supra, was substituted for the MTV-LUC plasmid described herein. pRS-1-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 progesterone as a PR agonist, mifepristone lbeta,17beta)-l l-[ 4 -(dimethylamino)phenyl]-17-hydroxy- 17-(1-propynyl)estra-4,9-dien-3-one: RU486; Roussel Uclaf) as a PR antagonist; HPriyanlka\Kep\speci\M5977-96.STBROID RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 319 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- 1,3,5(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-Gallxl10-5/B-Gal incubation time.

20 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 25 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.

H\Pliy-r\K-pcM-59796.SROID RECEPTOR.dvc 19/01/oo DOCKET NO.

016-0014A.WO 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 15 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 iL for GR, and contained -5 pg 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 3 H] dexamethasone, respectively) and varying concentrations 20 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 25 bound tritiated hormone was determined by liquid scintillation counting of an aliquot (700 mL) of the supernatant fluid or the hydroxylapatite pellet.

AR Binding: 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-8-Gal (50 ng/well) and pGEM (48 ng/well). Six hours after transfection, media was removed, the cells were washed with PBS and fresh H:\Pr\iankaKc p\%pcM59796.SThEROID RECEPTOR.doc 19100 DOCKET NO.

016-0014A.WO 321 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 15 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 B-Gal rate, was defined as specific binding. The specific binding was evaluated by Scatchard analysis to determine the Kd for 3 H-DHT. See S 20 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 S 25 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 IC50 values, where: ICT fo Ki (I+[3H-DHT])/Kd for 3H-DHT HWiyanka\Ktp\s c597796sThRO[D RECEPTfR.doc 19/01/00 DOCKET NO.

01 6 -0014A.WO 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 IC5o (which is the concentration required to reduce the maximal 15 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.

a.

PR Agonist Cm d CV-1 Cells Efficacy Potency No. (nM) 103 na na 104 39 2,750 109 na na 116 nt nt 117 na na 124 74 1,600 126 124 2,400 132 22 6,400 150 24 3,200 152 na na 161 47 203 163 77 15 PR Antagonist

PR

CV-1 Cells Binding Efficacy Potency Ki (nM) (nM) 91 780 372 71 120 82 87 138 23 85 549 38 68 462 na 36 10 4 58 145 11 76 80 31 91 24 17 82 130 53 75 209 3 45 3,617 1 H:\Priyanka\Kaep\pcM5977-96.STEROID RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 323 PR Agonist PR An Effcac Pt ency Efccy Effcac CV t ells Efccy No. (nM) tagonist j PR Cells Bi ndin' 191 195 26 89 -9 13 74 210 220 I 72 147 16 221 228 271 286 291 310 313 328 331 332 368 374 377 379 381 385 389 391 400 401 452 455 Prog RU486 33 105 114 na na na na 26 86 na 138 183 231 101 na 81 27 133 na na 43 119 na 100 na 117 40 na -na na na 300 2200 na 3 43 4 550 na 58 82 17 na na 600 240 0 na 4 na na na na na 78 84 84 79 70 94 65 88 na na na na 87 na 45 6a 65 68 70 70 76 na Potency (n M) 150 na na na na na 32 155 46 260 140 26 210 na na na na 350 na 2300 na 120 370 na 24 35 na 0.1 Ki 1 3 3 1 4 3 61 4 7 87 7 273 0.4 4 18 31 -4 187 14 150 17 3 ft

S.

S..

S S .55 96 0.8 na not active efficacy of <20 and potency of >10,000) nt not tested H'-Pr~nKmpcM97-96.SIROD RECEPTORAdo 19/01/00 DOCKET NO.

0l6-0014A.WO 324 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.

AR Agonist AR Antagonist

AR

Cmpdj ~f CV-1 Cells cv-I Cells Bindina Efficacy Potency Efficacy Potency Ki No. I (nM) M% (nM) 238@ 96 10 na na 44 247 23 2,400 69 34 864 255 na na 82 25 675 256 na na 91 624,0 260 na na 53 2443 265 na na 78562 420 40 210 80 2010 41 29**.74466 9 na not active efficacy of <20 and potency of >10,000) profiles as an AR antagonist in vivo H'.P"Cvo\-P\BcM1597796SIhROlD RECEPTOR.do, 19/01/00 DOCKET

NO.

016-0014A.WO 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.

na not active (i.e.

nt not tested *c '9 [rest of page left purposely blank] a

S..

S

.555 H.Vrianka\K~p\3pec \45-96STERO[D RECEPTOR.d 00 19/01/00 DOCKET NO.

016-0014A.WO 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.

Cmpd No. j GR Antagonist CV-1 Cells Efficacy jPotency (nM) MR Antagonist CV-1 Cells Efficacy Potency

GR

Binding 161 167 170 192 195 RU486 Svir 94 81 96 100 80 I (riM) 600 855 1550 280 590 2000 58 61 84 70 47 77 1000 137 2000 21 410 47 320 214 1900 26 1100 0.4 25 nt 96 nt not tested AOOeSW

S.

S. 0*S@

S.

.SSO

0

S.

*5*O 0e 0*

S.

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 No.

PR Ptency

AR

Agon Antag Agor (nM) (nM) (nM Potency aAntag ER Potency Agon JAntag (nM) I (nM) LGR

MR

Potency Potency Antag Antag 124 150 163 170 191 192 195 255 260 Prog RU486

DHT

Flut Estr ICI 164 1600 3200 15 73 9 na 13 na na 4 na na na nt Ena nt (riM) 10 24 3617 145 150 89 na 3050 2-30 na 0.1 1800 1900 nt na 268 nt nt nt nt nt -nt na na 1300 na 6 I 1500 140 1550 290 520 79 470 25 24 na 12 na 2100 nt na nt nt nt 1900 na (nM) (nM) na na 2150 580 330 195 4406 na na 2700 1330 F1550 280 590 na na 1900 1450 410 nt 320 1900 nt na na na nt 17a 150 0.n10 1700 I na T n~ I nt 4 J.

I

na na na 26 na na na 7 na na na 160 na na na na Nt na Ski-r~t nt n a 20 H-\na\sp' pe977-96STROID RECEPTOR.doe 19/01/00 DOCKET NO.

016-0014A.WO 327 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, ppl01-130 (1969), the disclosures of which are S 25 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 H\Priyanka-ps~pcl597796.STWROID RECEPTRdoc 19/01/00 DOCKET NO.

016-0014A.WO 328 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 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.

o S* El MPA Cmpd 163 Cmpd 210 Mean Uterine Group (mg) (mg) (mg) Wet Weight (mg) Control none none none none 1 10 none none none 205 2 10 0.3 none none 140 3 10 1.0 none none 130 4 10 3.0 none none 130 5 10 none 3.0 none 125 6 10 none none 0.3 110 7 10 none none 1.0 100 8 10 none none 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 H\Prianka\xeep'spcS97n96SmEROID RECEPTORdoc 19/01/00 DOCKET NO.

016-0014A.WO 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.

15 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 Grou (mg/day) (mg/day) Pregnancy Rate Control none none 100 11 .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 S 20 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; (173)-17-methyl-17-(1-oxopropyl) estra-4,9dien-3-one; New England Nuclear, Boston, MA) at a dose of 1.0 mg per day.

HP\jaaL\Kmp~sp~cc\45977.96.SROID RECEPTOR4o 19/O1MO DOCKET

NO.

0 16-0014A.WO 330 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 B.J. 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 15 follicle stimulating hormone (FSH). Testosterone is converted to the more active form, dihydrotestosterone (DHT), within the prostate by 5a-reductase. Adrenal androgens also contribute about 20% of total DHT in the rat prostate, and about 40% of that in 6 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 20 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, 2 3 -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 H-Priy-ka\Kftp\rps FLLS977-96.STR RECEPTR.doc 19/01/00 DOCKET NO.

016-0014A.WO 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 15 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 nimmature 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 1 mg/rat/day of testosterone propionate (TP) for 3 days.

H4anka\Kcp\,pc597796-S'hROID RECEPTORdoc 19/01/00 DOCKET NO.

016-0014A.WO 332 The EC50 of T and TP were about 1 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.

15 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.

S

Seas *5*5

S

S

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 22.110.7 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 21.0±1.7 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 HPrianka\Kp\spOcMS977-96.ST2ROD RECEPTORAoc 19/01/00 DOCKET NO.

016-0014A.WO 333 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 S. Starch, dried 100 15 Magnesium stearate 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: 20 20 Quantity (me/tablet) SCOMPOUND 191 140 Cellulose, microcrystalline 200 Silicon dioxide, fumed Stearic acid 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: H*\Riyaaka\Krrp\spci\4577-96.S TER RECEPTOR.doc 19/01/00 DOCKET NO.

016-0014A.WO 334 Quantity (mg/tablet) COMPOUND 191 Starch Cellulose, microcrystalline Polyvinylpyrrolidone

(PVP)

(as 10% solution in water) 4 Sodium carboxymethyl starch (SCMS) Magnesium stearate 0.5 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 2000 m Total 2,225 mg 25 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 Isotonic saline 100 mg Glycerol 100 mL 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 1 mL per minute to a patient.

H \,Pka\K-p\spscM5977m96SThROiD RECEPTOR.d 19/01/(om DOCKET NO.

016-0014A.WO 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.

V

V.

anka\Keep\pecS977-96.STEROID RECEPTORdoc 19/01100

Claims (4)

1. A compound having the formulae: S a S. R 1 2 (1JI) R 13 R1 ,R1 0 (IV) DOCKET NO. 0I 6 -0014A.WO 337 R13 0R16 1OR3 812 R N 9 R6 HR OR (V) R13 R 4 0 R 16 I X R19 R12 R N 18 RN 9 H R 12 .R 13 814 82 (VI) R 14 812 N

5.1. 11 p 6 H 9 (V1I 81 6 N R R6 HR OR (VilI) 8 248R268R3 R23 1 R 27 Y Z Nr,28 (IX) DOCKET NO.

016-0014A.WO 338 OR iR 4 R21 R3 R' 6N RX IH 5 OR OR1 R 1 3 R 1 R H4 X I OR 14 2 H1 3 S.R R~*1 1 0 R 6 1H .:oo OR po...R R oF3 R R H 1 3 NN H6 H4 H OR(XIII) 13 R' 4 R16 R' ~n H DOCKET NO. 0l6-0014A.WO 339 (XIV) OR R 14 R 16 (XV) 9 9* 9* 9 9

999. (XVI) (XVII) (XVIII) wherein: R1is 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 COCH 3 where R 2is hydrogen, a C 1 C 4 ailkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, DOCKET NO. 0 16-0014A.WO 340 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 Ci C 4 alkyl or perfluoroalkyl, hydroxymethyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl; 4 6 R through R 6 each independently are hydrogen, F, Cl, Br, I, NO 2 CO2H, C0 2 R 2 COR 2 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 SO3H, S(NR2R7)R2, S(O)(NR2R7)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 C 1 C 4 alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl or S 10 arylmethyl, OR 8 or NHR 8 where R is hydrogen, a C 1 C 6 alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, S0 2 R or S(O)R R 9 and R 10 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 hydrogen, F, 15 OR 2 or NR2R 7 where R 2 and R have the definitions given above; R 11 through R 15 each independently are hydrogen, F, Cl, Br, I, NO 2 CO 2 H, C0 2 R 2 COR CN, CF 3 CH20H, a CI-C 4 alkyl or perfluoroalkyl, OR 2 SR 2 S(O)R 2 S 2 R 2 SO 3 H, S(NR2R7)R 2 S(O)(NR 2 R 7 )R 2 NR2R 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 O, NH, NR CH 2 CHOH, C=O, OC=O, O=CO, NR C=O, NHC=O, O=CNR O=CNH, SC=O, O=CS, or CHOCOR where R has the definition given above; X is CH 2 O, S or NR 7 where R 7 has the definition given above; DOCKET NO. 016-0014A.WO 341 R 16 is hydrogen, OH, OR 17 SR 1 7 NR 2 R, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, heteroaryl or C 1 C 10 alkyl, where R 17 is a C 1 C 10 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 19 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 NR R 8 where R 2 R 7 and R have the definitions given above; R is a C 1 C 6 alkyl or an optionally substituted allyl, arylmethyl, alkenyl, aryl or 10 heteroaryl; 21 R is hydrogen, a C 1 C 4 alkyl or optionally substituted allyl, arylmethyl, aryl or heteroaryl; 22 2 27 2 2 7 R 22 is hydrogen, a C1 C4 alkyl, F, C1, Br, I, OR 2 N2R7 or SR2, where R 2 and R 7 have the definitions given above; R 23 is hydrogen, Cl, Br, OR 8 NR2R 7 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 R8 have the definitions given above; 24 SR is hydrogen, F, Br, C1, a C 1 C 4 alkyl or perhaloalkyl, aryl, heteroaryl, CF 3 CF 2 0R 25 CH 2 0R 25 or OR 2 5 where R 2 5 is a C 1 C 4 alkyl; 26 2 27 2 R 2 is hydrogen, a CI C 4 alkyl, F, C1, Br, I, OR 2 N2R or SR where R 2 and R 7 have the definitions given above; 27 28 R 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 2 or NR2R or R 27 and R 2 8 taken together can DOCKET NO. 016-0014A.WO 342 form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR 2 2 7 2 7 or NR2R 7 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 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 7 where R 2 and R have the definitions given above; 32 33 R and R each independently are hydrogen, a C 1 C 4 alkyl or an aryl optionally 10 substituted with hydrogen, F, Cl, Br, OR 2 or NR 2 R 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 or NR2R 7 where R 2 and R 7 have the definitions given above; o n is or 1; Y is O or S; 2 2 2 15 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; S the dotted lines in the structures depict optional double bonds, except that when there is a C 3 -C 4 double bond in the nitrogen bearing ring of compounds of formula II, then R 1 through R' 5 cannot all be hydrogen and R 3 R 9 and R 1 0 cannot all be methyl, and further except when R 23 is an aryl, R 22 R 24 and R 29 and all hydrogen, R 3 is CH 3 and Z is NR 2 then R 2 cannot be a CI-C 4 alkyl. 2. A compound according to claim 1, wherein the compounds of formulae I through XVIII comprise steroid receptor modulator compounds. DOCKET NO. o 16-O0l4A.WO 343 3. A compound according to claim 2, wherein the compounds of formulae 1, I1, 11I, 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 XVIII comprise AR modulators. *see to* @*of 7 Aosstn copon 1234Ttacdord2,tin to clm6wherequie ompound f 0) fomuaeX pyriy8. A PR antagom onist10compound aordihng o la-,-i 3 selec4tfrm th grioupn cnitnof (Compound 100); 1,2-Dhdo6(-rfurmtypey)224ritylinie Dihy,3dico2,rhetyl( 1dhy, 2 3 -thiaiazo1- y)quinolie (Compound 10); 1 ,2-Dihydro- 6(-yrxcroy4-irpey) 2 2 ,4-trimethyl--1 -oal5ylquinotine (Compound 102); 6 4 -iclromdao- 1 lrheyl)- 1 2 -dihydro-2,2,4-trinethylquinoline (Compound 031); 6-4rm -ethylpyrao-3 yl- 2 dihydro-2,2 4-timethyhe quinolijne (Compound 10); 1 ,2-Dihydro-2,2-rimethyl6( pyridyl4pyquinoli e (Compound 1 6 -(-Fluorop heny- l -h iydr,,-ehyquno- n DOCKET NO. 016-0014A.WO 344 trimethyiquino line (Compound 114); 6- (3 ,5-Difluorophenyl).1,2,3 ,4-tetrahydro-2,2,4 trimethyiquinoline (Compound 143); 6 -(3-Chlorophenyl)- 1,2-dihydro-2,2,4- trimnethylquinoline (Compound 146); 6-(3 ,S-Difluoropheny11,2-dihydro-2,2,4- trimethylquinoline (Compound 147); 6 3 Fluorophenyl)-1I,2-dihydro-2,2,4- trimethyiquino line (Compound 148); l, 2 -Dihydro-2,2,4-trimethylI6-( 4 -pyridyl)quinoine (Compound 149); 6 3 -Cyanophenyl)- l, 2 -dihydro-2,2,4-timethylquinoijne (Compound 150); 6 3 ,5-Dichlorophenyl). 1 l 2 -dihydro-2,2,4-trimethyqurjo line Cmon 5) -23 Difluorophenyl) -l1, 2 -dihydro-2,2,4-trimethylquino line (Compound 152); 1 ,2-Dihydro-2,2,4- trimethyl-.6-(pentafluoropheny)qunolin (Compound 153); 1 2 -Dihydro-2,2,4-trimethy16- 4 -(trifluoroacetyl)phenyllquinoline (Compound 154); l, 2 -Dihydro-2,2,4trirmethy16-(1,3- (Compound 155); 6 3 -Cyanophenyl)-1I 2 ,3, 4 -tetrahydro-2,2,4- trimethyiquino line (Compound 156); 5,8-Difluoro- l, 2 -dihydro-2,2,4-.trimrethyideno [1,2- giquinoline (Compound 157); 7,1 0-Difluoro-1,l 2 -dihydro-2,2,4-triethylindeno [2,1 fiquinoline (Compound 158); 8 -Cyano- 1,-iyr-,,-rrehlneo[,-lqioln (Compound 270); 6- 3 -Cyano-5-fluorophenyly l, 2 -dihydro-2,2,4-trimnethylquinoie (Compound 271); 6 3 -Cyano-4-fluorophenyl). l 2 -dihydro-2,2,4-trimethylquinoline (Compound 272); 6 3 -Cyano-6-fluorophenyl). l, 2 -dihydro-2,2,4-trirnethylquinoline (Compound 273); 6- [5-fluoro-3- (trifluoromethyl)phenyl] -1 ,2-dihydro-2,2,4- trimethylquinojline (Compound 274); 6- 3 -chloro-2-methylphenyl).1 ,2-dihydro-2,2,4- trimethyiquinoline (Compound 275); l, 2 -Dihydro-.2,2,4-trimethy16-(3-ntrophenyl)quinoine (Compound 276); 6 -(3-Acetylphenyl)-1,l 2 -dihydro-.2,2,4-trimethylquinoijne (Compound 277); 6 3 -cyano-2-methylphenyl). l, 2 -dihydro-2,2,4-t knethylquinoline (Compound 278); l, 2 -Dihydro-.2,2,4-.trimethy1-6-( 3 -methylpheny1)quinoline (Compound 279); 6- (5-Fluoro-3- nitrophenyl)- l, 2 -dihydro-.2,2,4-trimethylquinoline (Compound 280); 1 ,2-Dihydro-6-(3- methoxypheny>22,4trimethylquinolin (Compound 28 6 -(5-Cyano-3-pyridyl)y 1,2- dihydro-224tthuioln (Compound 282); 1,myuion 2 -Dihydro-2,24-trimethy16(2-methylI 3 nitrophenyl)quino line (Compound 283); 6 2 Amino- 3,5-difluorophenyl) -1,2-dihydro- 2 2 4 -trimethylquinoline (Compound 284); 6- 3 -Bromo-2-chloro-.Sfluorophenyl)-1,2- dihydro-.2,24trimethylquinoline (Compound 285); 6 3 -Cyano-5-fluorophenyl> 1 ,2-dihydro- 2 2 4 -trimethy1-3-.qujnolone (Compound 286); 6- 3 -Fluoro-2-.methylphenyl)-1 ,2-dihydro- DOCKET NO. 016-0014A.WO 345 2 2 4 -trimethylquinoline (Compound 287); l, 2 -Dihydro..2,2,4..trjmethyl.6-(3- methylthiophenyl)quino line (Compound 288); 6 -(5-Chloro-2-thienyl)-.1 ,2-dihydro-2,2,4. trimnethyiquinoline (Compound 289); l, 2 -Dihydro.2,2,4.tiethy16-(3-methy-2- thienyl)quinoiline (Compound 290); 8-Fluoro- l, 2 -dihydro-2,2,4-trisnethy-6-(3- nitrophenyl)quino lne (Compound 291); l, 2 -Dihydro-6-(3..nitrophenyl)y2,2,4, 8- tetramethyiquinoline (Compound 292); 6 -(5-Bromo-3-pyridyl).1 ,2-dihydro-2, 2,4- trimethylquinoline (Compound 293); 6 -(3-Bromo-2-pyridyl).1 ,2-dihydro-2,2,4- trimethylquino line (Compound 294); 6 3 -Bromo-2..thienyl> 1 ,2-dihydro-2,2,4- trimethyiquino line (Compound 295); l, 2 -Dihydro.6(2,3,,6tetrafluoro4pyidy)22,4 trimethyiquinoline (Compound 296); 5,8-Difluoro- 1, 2 -dihydro-6-(3..nitrophenyl>2,2,4- trirnethyiquinoline, (Compound 297); 2 4 -Diethyl-8-fluoro-1 ,2-dihydro-2-methyi6-(3- nitrophenyl)quinoline (Compound 298); 6 3 -Bromophenyl)- 1,2-dihydro-2,2,4- trimethylquinoline (Compound 299); 1 2 -Dihydro-2,2,4.triethy6(5-nitro-2 thienyl)quinoline (Compound 300); l, 2 -Dihydro..6.(245trifluorophenyl>22,4 trimethyiquinoline (Compound 301); 6- 3 -Bromo..5.fluorophenyl> 1 ,2-dihydro-2,2,4- trimethylquinoline (Compound 302); 6 -(5-Carboxaldehyde3thienyl> 1 ,2-dihydro-2,2,4- trimethyiquinoline (Compound 303); l, 2 -Dihydro-2,2,4,7..tetramthy6.(3. nitrophenyl)quinoline (Compound 304); 6- (5-Fluoro-2-methoxy-3-itrophenyl) 1 ,2-dihydro- 2 2 4 -trimethylquinoline (Compound 305); 6 3 -Chloro-2-methoxyphenyl). I,2-dihydro- 2 2 4 -trimethylquinoline (Compound 306); l, 2 -Dihydro-2,24-trmethy16-(2,3,4- trifluorophenyl)quinoline (Compound 307); 6 3 -Bromo-2-methylphenyly 1 ,2-dihydro-2,2,4- trimethyiquinoline (Compound 308); 7-Chioro- l, 2 -dihydro-2,2,4-tnimethy16-(3. nitrophenyl)quinoline (Compound 309); 5-Chioro- l, 2 -dihydro-2,2,4-trimnethylb6(3. nitrophenyl)quino line (Compound 310); 8-Chloro- l, 2 -dihydro-2,2,4-trimnethyl16-(3- nitrophenyl)qui-no line (Compound 311); 8-Ethyl- l, 2 -dihydro-2,2,4timethyI6-(3- nitrophenyl)quinoline (Compound 312); 9-Chloro- l, 2 -dihydro-2,2-dinethy..5- Scounarino [3 4 -fjquinoline (Compound 313); l, 2 -Dihydro..9.methoxy2,2,4trirethy15- coumnarino [3 4 -J]quinoline (Compound 314); 9-Fluoro- 1 ,2-dihydro-2,2,4, COUmiarino [3 4 -J]quinoline (Compound 315); l, 2 -Dihydro-2,2,4,9-tetramethy1-5 coumnarino [3,4-jjquino line (Compound 316); 7-Chloro- l, 2 -dihydro-2,2,4-trimethylI5- DOCKET NO. 016-00 14A.WO 346 co umarino [3,4-11 quino line (Compound 317); (R/S)-9-Chloro- 1 2 -dihydro-5-methoxy-2,2,4- chromenoli3,4-fjquinoline (Compound 319); (R/S)-9-Fluoro- 1 ,2,-dihydro- 2 2 4 -trimethyl-511-chro meno [3 ,4-fj quino line (Compound 328); 6- (5-Cyano-2-thienyl)- 1,2- dihydro-2,2,4-trinethylquino line (Compound 451); 6 -(5-Cyano-3-thienyl)- 1,2-dihydro-2,2,4- trirnethylquinoline (Compound 452); 6- (3-Formyiphenyl)- 1,2-dihydro-2,2,4- trimethyiquino line (Compound 453); 1 2 -Dihydro-2,2,4-trinethy16{3. (methylsulfonyl)phenyllquinoline (Compound 454); (R/S)-6-(3-Cyano-5-fluoropheny1>- 1 2 3 4 -Tetrahydro-2,2,4-trimethylquinoline (Compound 455) and (RIS)-9-Chloro- 1,2- dihydro- 2 2 ,4-triethyl-5phenylpsH-.chomen 0 3 ,4-Jlquinoline (Compound 456). 9. A PR modulator compound according to claim 4 selected from the group consisting of (RIS)-5-Butyl- l, 2 -dihydro- 2 ,2,4-trimethyl-5H.chromeno [3,4-fjquinoline (Compound 160); (RIS)- l, 2 -Dilhydro- 2 2 ,4-triethyl-5-phenylsft-chromeno [3,4 Jquinoline (Compound 161); (RIS)- 1,2,3 4 -Tetrahydro-2,2-dimethy14.methylidene5-phenyI-5H- chromeno[3,4-Ilquinoline (Compound 162); (R/S)-5-(4-Chlorophenyl)- 1,2-dihydro-2,2,4- trimethyl-5H-chromeno [3,4-Jlquinoline (Compound 163); (RIS)-5-(4-Chlorophenyl)-1,2,3,4- tetrahydro- 2 ,2-dimethy14methylidene.5Hchomeno 3 4 -J]quinoline (Compound 164); :0(R/S)-5-(4-Fluoropheny)- l, 2 -dihydro-2,2,4-trinethyl.5H-chromeno [3,4-flquinoline (Compound 165); (RIS)-5-(4-Acetylphenyl)- l, 2 -dihydro-2,2,4-trin-ethy5Hchomeno[3,4.. fjquinoline (Compound 166); (RIS)- l, 2 -Dihydro-2,2,4.trimethy..5-(4-methylphenyl)>5H- o chromeno [3 ,4-fJquino line (Compound 167); (RIS)- 1, 2 -Dihydro-5-(4-methoxyphenyl).2,2,4 trimnethyl-5H-chromeno[3,4Jilquinolie (Compound 168); (RIS)- l,2-Dihydro-2,2,4- ~trimethyl-5- (trifluoromethyl)phenyl]-SH-chro meno quino line (Compound 169); (RIS)- 1 2 -Dihydro-2,2,4-trimethyls -(thiophen-3-yl)-5H-chromeno [3 ,4-flquinoline (Compound 170); l, 2 -Dihydro- 2 2 ,4..trimnethy15-(4-methylphenyl) SH-chromeno [3,4- f] quinoline (Compound 171); (-)-5-(4-Chlorophenyl)- 1 2 -dihydro-2,2,4-trirethybsm chromeno[3,4-fjquinoline (Compound 172); (RIS)-1I, 2 -Dihydro-2,2,4-trimethyls5(3- [3, 4 -flquinoline (Comound 173); (4- Chiorophenyl)- 1 2 3 4 tetrahydro-2,2,4trimnethy15H-chromeno [3 ,4-A quino line (Compound 174); 5l)-5-(4-Chlorophenyl)- 1,2,3 4 -tetrahydro-2,2,4-triniethyl-5H-chromeno [3,4- DOCKET NO. o 16-0014A.WO 347 fjquinoiine (Compound 175); (R/S- 4 l,5u)-5-(4-Chorophenyl)-1 ,2,3,4-tetrahydro-22,4 [3 4 -Jlquinoline (Compound 176); (R/S)-5-(3-Chlorophenyl> 1,2- dihydro-2,2,4iethyl5H-chomeno 3 4 -fjquino line (Compound 177); Chlorophenyl>. 1,2,3 4 -tetrahydro- 2 2 -dimethy14-methylidene SH-chromeno [3 4 -f~quinoline (Compound 178); (R/S)-5-(4-Bromophenyl> ,-ihdo22,-rmehl5-crmn[3,4- fjquinoline (Compound 179); (RIS)-5- 4 -Bromophenyl- 1 2 3 4 -tetrahydro-2,2-dimethy14- met hylidene- 5H-chro meno 3 4 -Jl quino line (Compound 180); (R/S)-5-(3-Bromopheny1> 1,2- dihydro- 2 ,2,4-trimethy15Hchomeno [3, 4 -fjlquirioline (Compound 18 Bromophenyl)- l, 2 3 4 -tetrahydro2,2dimethy14-methylidene-5H-chromeno 3 4 -f~quinoline (Compound 182); ,4-dichlorophenyl)- l, 2 -dihydro-2,2,4-trirnethylk5H. chromeno[3,4-flquinoline (Compound 183); (RS--3Boo2prdy)12dhdo224 3 4 -fjquinoline (Compound 184); (RIS)- 1,2-Dihydro-5-hydroxy- 2 2 4 -trin-ethy-5H-chromeno 3 ,4-fjquinoline (Compound 185); (RIS)- 1,2-Dihydro-2,2,4- Hcrmn[ 3 4 -Jlquinoline (Compound 186); (RIS)- 1,2-Dihydro- 2 2 4 -trimethy-5-prpoxy5Hchomeno 3 4 -fjquinoline (Compound 187); 0. 0 :12dhdo224tiehy-Hcrmn[,-lunln (Compound 188); (RIS)- 1,2- Diyr-,,-rmtyl5poy-Hcrmn[3 4 -fjquinoline (Compound 189); (RIS)- 1,2- Dihydro-2,2,4- rimety)- -ridy V111I-1omn [3 4 -fiquino line (Compound 190); (RIS)-5-(3-.Fluoropheny1> l, 2 -dihydro-2,2,4-trfrethy15Hchomeno[3 ,4-fJquinoline (Compound 191); (R/S)-5-(3-Fluorophenyl)1,234ttayro22d ehl--ehhee S 5H-chromeno 3 ,4-flquinoline (Compound 192); (RIS)- l, 2 -Dihydro-2,2,4-trimethyl15. 3 4 -Jlquinoline (Compound 193); (RIS)- 1,2-Dihydro-5-(3- mehxpey)224trmty Hcrmn[ 3 ,4-fjquinoline (Compound 194); (RIS) 1,2- hnl-Hcrmn[ 3 ,4-fjquinoline (Compound 195); 3 -Fuoro4methylphenyl> l, 2 -dihydro-2,2,4-trimethyl.5H- chromeno[3,4-flquinoline (Compound 196); (R/S)-5-(4-Bromo-3pyidy1> 1 ,2-dihydro-2,2,4- [3 4 -fjquinoline (Compound 197); (RIS)- 1,2-Dihydro-2,2,4- trimethy1-5(3pyridy)>sH-chrmen 0 3 4 -Ilquinoline (Compound 198); (R/S)-5-(4-Chloro- 3 -fluorophenyl)-1,-iyr-,24tiehl Hcrmn[ 3 4 -fjquinoline (Compound 199); (RIS)-1,-iyr-,245ttaehy Hcrmn[ 3 4 -flquinoline (Compound 200); DOCKET NO. 016-00 14A.WO 347 fjquinoline (Compound 175); (R/S -(4/,5u)-5-(4-Chorophenyl) 1 2 ,3,4-tetrahydro-2,2,4- [3 4 -flquinoline (Compound 176); (R/S)-5-(3-Cmloropheny>. 1,2- diyr-,,4tiehl Hcrmn[3 4 -fjquinoline (Compound 177); Chiorophenyl)- 1,,,-erhdo2,-iehl4mty dn-Hcrmn[3 4 -Jlquino line (Compound 178); (R/S)-5-(4-Bromophenyly l, 2 -dihydro-2,2,4trimethyl-5H-chromeno [3,4- fjquinoline (Compo iid 179); (R/S)-5-(4-Bromophenyl-. l 2 3 4 -tetrahydro22dimethy14- 0 meno[ 3 4 -flquinoline (Compound 180); (R/S)-5-(3-Bromopheny1> 1,2- dihydro-2,2,4-trimethy1.5H-chromeno 3 4 -J]quinoline (Compound 181); (RIS)-5-(3- Bromophenyl).. 1,,,-erhdo2,-ieh 4mtyldn-Hcrm 3 4 -fjquinoline (Compound 182); (RIS)-5-(3,4..dichlorophenyl> l, 2 -dihydro-2,2,4trimethyl15H- chromeno 3 4 -fjquinoiine (Compound 183); (R/S)..5.(3..Bromo2-pyridyly 1 ,2-dihydro-2,2,4- 3 4 -fjquinoline (Compound 184); (RIS)- l, 2 2,,-rrehl5-hoeo34Aunln (Compound 185); (RIS)- 1,2-Dihydro-2,2,4- trimethy1..5.methoxy.5H-chromeno 3 4 -JAquinoline (Compound 186); (RIS> 1 ,2-Dihydro- 2 2 4 -timethy-5.propoxy5H-chromeno[3 4 -fjquinoline (Compound 187); l 2 -dihydro-2,2,4timethyp5H-chromeno 3 4 -jlquinoline (Compound 188); (RIS> 1,2- Diyr-,,-rinty -rpy-Hcrmn[34~unln (Compound 189); (RIS)- 1,2- Ve..Dihydro-2,2,4-trimethy5-2prdl5Hcomn[,fquoie (Compound 190); :(R/S)-5..(3-Pluorophenyl)1,2dhdo-,,-riehl5Hcrmn[ 3 4 -fiquinoline (Compound 191); (R/S)-5..(3..Fluorophenyl> l, 2 3 4 -tetrahydro22dimethy14-methylidene- 3 4 -flquinoiine (Compound 192); (RIS)- l, 2 -Dihydro-2,2,4.trimethy1..s. propylthio-5Hchromeno[3,4fquinoie (Compound 193); (RIS)- 1,2-Dihydro-5-(3- mehxpey)224trmty Hcrmn[ 3 4 -flquinoline (Compound 194); (RIS) 1,2- Dihydro..2,2,4.trianethyl.s..[ 3 -(trifiuoromethyl)phenyl] -SH-chromeno[3,4jjlquinoline (Compound 195); (R/S)-5-(3-Fluoro.4-methylphenyl) l, 2 -dihydro-2,24trimethyl15H- cnromeno 3 4 -flquinoline (Compound 196); (R/S)-5-(4-Bromo.3pynidyl) 1 ,2-dihydro-2,2,4- trunethyl-5H-chromeno 3 4 -fjquinoline (Compound 197); (RIS)- 1,2-Dihydro-2,2,4- 3 4 -fjquinoiine (Compound 198); (R/S)-5-(4-Chloro- 3 -fluorophenyly. -dhdo-,,-tiety 1111en[,4jqinln (Compound 199); (RIS)- l, 2 -Dihydro.2245tetramethyl5H-chromn[,-lunln Cmon 0) DOCKET NO. 016-0014A.Wo 348 1, 2-Dhdo5 ey-,,-rmty- chromeno 3 4 -jlquino line (Compound 201); l, 2 -Dihydro-2,2,4-trfrnethyl5H-chromeno [3 4 -Jlquinoline (Compound 202); (RIS)- 1,2- Diyr--Q-ehluy) ,,-tiehl5-homn [3 4 quino line (Compound 203); (R/S)-5-(4-Chlorobutyl). 1,-iyr 224trmty-Hcrm [3 4 -flquino tine (Compound 204); (R/S)-5-Benzyl- l, 2 -dihydro-2,2,4- trinethyl..sH-chijomeno [3 4 fl quino line (Como und 205); (R/S)-5-(4-Bromo butyl)- l, 2 -dihydro-2,2,4-trinethyl.5H..c!homeno [3,4- flquinoline (Compound 206); (R/S)-5-Butyl-9-fluoro-1, 2 -dihydro-2,2,4-trimnethyl15H- chromeno[3,4jflquinoie (Compound 210); (R/S)-5-Butyl-8-fluoro-.1 ,2-dihydro-2,2,4- trimethyl- 5H-chromeno 3 ,4-fjquino line (Compound 211); (R/S)-5-(3-Chiorophenyl)y9- fluoro- l, 2 -dihydro-2,2, 4 -trmtethyl-5H-chromeno 3 4 -J]quinoline (Compound 212); 4 -Chloro-3-methylphenyl>9-fluoro-l, 2 -dihydro-2,2,4-trmethy1..5H-chromeno [3,4- fAquinoline (Compound 213); 4 -Chlorophenyl)>9.fluoro 1 ,2-dihydro-2,2,4- [3 4 -flquinoline (Compound 214); (R/S)-9-iFluoro- 1,2-dihydro-5-(4- mehxpey)224trmty Hcrmn[ 3 4 -J]quinoline (Comnound 215); (RIS)- 8- Fluoro-1,-iyro5mtoyl224trmtySH-chromeno[3 ,4-flquinoline (Compound 216); (R/S)-5-(4-Choropheny>8-fluoro-l, 2 -dihydro-2,2,4-trimethyl-5H-chromeno flquinoline (Compound 217); and (R/S)-O-Chloro-5-(4-c~oropheny).1 ,2-dihydro-2,2,4- trimethyl-5H-chromeno [3 4 -JAquinoline (Compound 218); 9-Chloro- 1,2-dihydro-2,2,4- trimethyl- 5H-chromeno 3 4 quino line (Comound 320) (R/S)-9-Fluoro- 1,2-dihydro-5. 20 methoxy- 2 ,2,4-trimnethy1-5H-chromeno 3 4 -JAquinolie (Compound 322); (R/S)-9-Fluoro- 12dhdo224tinty5-horpx-Hcomo[ 3 4 -fjquinoline (Compound 323); (R/S)-9-Fluoro- l, 2 -dihydro-2,2,4-t imethyl-5-propoxy-5H-chromeno [3 4 -flquinoline (Compound 324); (RIS)- l, 2 -Dihydro-9methoxy22,4trimethyl SN chromeno [3,4- flquinoline (Compound 329); (RIS)- l, 2 -Dihydro-2,2,4,9tetramethyl15H-chromeno [3,4- Jlquinoline (Compound 330); (R/S)-7-Chloro. l, 2 -dihydro-2,2,4-timethyl-5H-chromeno [3,4- flquinoline (Comound 331) (R/S)-5-(4-Bromo-3pyrdyl) l, 2 3 4 -tetrahydro-2,2dimethy14- 3 4 -fjquinoline (Compound 347); (R/S)-5-(3,5-DifluorophenyI>- l, 2 -dihydro-2,2,4-trimethyl15H-chromeno 3 4 -fjquinoiine (Comound 348); (RIS) Bromo-5-fluorophenyI123,-erayr-22drnty 4mtySdn-H-chromeno [3,4- flquinoline (Compound 352); (Z)-1,,Dhdo5(,,-rmehlezldn)224 DOCKET NO. 016-00 14A.WO 349 [3,4-fiquinoline (Compound 364); (Z)-5-Benzylidene-9-fiuoro-1,2- dihydro-2,2,4, 11 -tetramethyl-5-H-chromeno [3 4 quino line (Compound 377); Chiorophenyl)> l, 2 3 4 -tetrahydro-2,2-dirnethyl-5H-chromeno [3,4-fl -4-quinolinone (Compound 378); (R/S)-5-(4-Chlorophenyl)- l, 2 3 4 -tetrahydro-2,2,3,3-tetramethy1-5H- chromeno 4 -quinolinone (Compound 379); (RIS)-5-(4-Chlorophenyl)- 1,2-dihydro- 2 2 -dirnethyl-5H-chromeho -quinoline (Compound 380); Chlorophenyl)- 1,2,3 4 -tetrahydro-2,2,4-trimethyl15H-chromeno -3-quinolinone (Compound 381); (--R-15)5(4Clrpey)1 2 3 4 -tetrahydro-2,2,4-trimethyl15H- chromeno 3 -quinolinone (Compound 382); (R/S)-5-(4-Chlorophenyly. 1,2,3,4- tetrahydro-2,2-dimnethyl-5H-chromeno -3-quinolinone (Compound 383); Fluorobenzyl)-5-(3-fluorobenzylidene)- 1,2,3 4 -tetrahydro-3-hydroxy2,2,4-trimethyl15H- chromeno [3,4-fAquinoline (Compound 384); ,5-Dibutyl- 1,2,3 ,4-tetrahydro-3- hydroxy-2,2,4-tinethylp5H-chomen 0 [3 4 -flquinoline (Compound 385); 1,2,3 4 -tetrahydro-2,2,4-trimethy15H-chromeno 3 -quinolinone (Compound 386); (R/S-41,51)-1,,,-erhdr-,,-rmthl5pey Hchromeno[3 4 -f]-3-quinolinone (Compound 387); (R/S-41,Su)- l, 2 3 4 -Tetrahydro-2,2,4trimethy15-pheny1-5H- chromeno -3-quinolinone (Compound 388); (R/S-41,6u)- 1,2,3 ,4-Tetrahydro-2,2,4- trimethyl-6-pheny15H-isochromeno [3 4 -f]-3-quinolinone (Compound 390); (R/S-41,61)- l, 2 3 4 -Tetrahydro-2,2,4trimethy6phenyl15H-isochromeno [3 4 -fj-3-quinolinone (Compound 391); (RIS- 3 l,4u,5u)-5-(4-Chlorophenyl)1, 2 3 ,4-tetrahydro-3-methoxy-2,2,4 trmethyl-5H-chomeno[3,4.jjquinolie (Compound 397); (R/S-31,4u,S1)-5-(4- Chiorphenyl- 1,2,3 4 -tetrahydro- 3 methoxy224-triethy1..5H-chromeno [3,4-fiquinole (Compound 398); (RIS-3l,4u,51)-5-(4-Chlorophenyl> 1,2,3 4 -tetrahydro-3-propyloxy-2,2,4. 3 ,4-flquinoline (Compound 399); (RIS-31,4u,5u)-5- (4- Chlorophenyly. l, 2 3 4 -tetrahydro3propyoxy2,24trimethyl 5H-chromeno [3 ,4-fAquinoline (Compound 400); and (RIS- 4 I,5)- 3 -Benzylidene5(4clorophenyl) 1 ,2,3,4-tetrahydro- 2 2 4 -triethy-H-chromeno [34jjquino ie (Compound 401). DOCKET NO. o 16-0014A.WO 350 A PR agonist compound according to claim 5 selected from the group consisting of (Z)-5-Butylidene- l, 2 -dihydro-2,2,4-trimethy1-5Hchomeno [3 ,4-fjquinoli-ne (Compound 219); (Z)-.5-Benzylidene- l, 2 -dihydro-2,2,4-trimethyl15H..chromeno [3,4- fjquinoline (Compound 220); (Z)-5-(4-Fluorobenzylidene)-1 2 -dihydro-2,2,4-trimethyl5H- chromeno [3,4-fjquinoline (Compound 22 (Z)-5-(4-Bromobenzyjjdene)- 1 ,2-dihydro-2,2,4- 3 4 -fJlquino line (Compound 222); (3-Bromo benzylidene)- 1,2- dihydro-2,2,4-trimnethyl5H-chromeno [3, 4 -fAquinoline (Compound 223); Chloro benzylidene)- l, 2 -dihydro -2,2,4-trimethylpsH-chomeno 3 ,4-JI quino line (Compound 224); (Z)-5-(3-Fluorobenzylidene). 2 -dihydro- 2 ,2,4-trimethy1..5H-cfiomeno 3 4 -fjquinoline (Compound 225); (Z)-5-(2-Chloro benzylidene)- 1 2 -dihydro-2,2,4-trimethy5H- chromeno 3 4 quino line (Compound 226); (Z)-5-(2-Bromobenzylidene> 1 ,2-dihydro-2,2,4- [3,4-fjquinoline (Compound 227); (Z)-5-(2-Fluorobenzylidene>. 1,2- dihydro-2,2,4-trirethyl5H-chromeno [3 4 -Jlquinoline (Compound 228); Difluoro benzylidene). l, 2 -dihydro-2,2,4-tri ethyl-5H-chromeno 3 4 -A quino line (Compound 229); 2 ,S-Difluorobenzylidene)- l, 2 -dihydro-2,2,4-triethylb5H-chromeno [3,4- fjquinoline (opud230); (Z--loo5(-looezldn)12dhdo224 trimethyl-5H-chromeno [3 4 -fjquinoline (Compound 231); (Z)-9-Fluoro-5-(3- methoxybenzylidene)-. 2 -dihydro- 2 ,2,4-t methyl-5H-.chromeno 3 4 -J]quinoline (Compound 232); 8 -Fluoro-5-(3-fluorobenzylideney l, 2 -dihydro-2,2,4-trimnethyl15H..chromeno [3,4- 20 flquinoline (Compound 233); (RIS- 4 I,Su)-5-(4-Chloropheny1> 1 ,2,3,4-tetrahydro-2,2,4- trimethyl-5H-chrorneno[3,4.fp3-quinolinone (Compound 234); (RIS-41,5l)-(4- Chiorophenyl)- l, 2 3 4 -tetrahydro-2,2,4-trimethyl-5H-chromeno 3 4 -f]-3-quinoiinone (Compound 235); and (R/S)-5-(4-Chborophenyl)1l 2 3 4 -tetrahydro-2,2,4,4tetramethy1-5H- chromeno[3,4-fl-3-quinolinone (Compound 236); 5-(3-F'Iuorobenzyl- 1,2-dihydro-2,2,4- trin-ethyl;-5H-chromeno [3 4 -Jl quino line (Compound 318); (R/S)-.9-Chloro- 1,2-dihydro- 2, 2 4 -trimethy-5-propyloxyspI..chromeno [3 4 -fjquinoline (Compound 321); *9-chloro- 1, 2 -dihydro-2,2,4-trimethy1..5H-chro meno 3 4 -fj quino line (Compound 325); (RIS)- 5-Butyl-1,-iyr--etoy224tiety Hcrmn[3 ,4-fjquinoline (Compound 326); (R/S)-9-Fluoro- l, 2 -dihydro-2,2,4,5-tetramethyl.5H-chromeno [3 ,4-f]quinollne (Compound 327); (RIS)-9-Chloro- l, 2 -dihydro- 2 ,2,4,5-tetramethy15Hchromeno[3,4 DOCKET NO. 0l6-0014A.WO 351 flquinoline (Compound 332); (R/S)-5-(4-Bromophenyl)y9-choro-1 ,2-dihydro-2,2,4- trimethyl- 5H-chromeno 3 4 -fl quino line (Compound 333); Chloro-5- (3- chiorophenyl)- 1, dhdo224tinty-5-hoeo[,-lqioln (Compound 334); (R/S)-9-Chjoro- l, 2 -dihydro- 2 ,2,4-trbnethy5(3-methylpheny)S5Hchomen[3,4- fJquinoline (Compound 335); (RIS)- 9-Chloro-5- 4 -chloro-3-methylpheny1> 1 ,2-dihydro- 2 2 4 -trimnethyl-5H-chro meno [3 4 -fJquino line (Compound 336); (R/S)-9-Chloro-1I,2-dihydro- 3 -(trifluoromethyl)pheny1]-22,4-tprethy15Hchroe[ 3 4 -fjquinoline (Compound 337); 9 -Ch~oro-5-(3,5dichlorophenl1,2dhdo-,,-riehl5Hcrm [3,4- JAquinoline (Compound 338); (R/S)-9-Chloro- l, 2 -dihydro-5-(4-methoxypheny)>224- trimethyl-5H-chromeno [3 4 -Jlquinoline (Compound 339); (R/S)-9-Choro5-(3fluoro-4 methoxyphenyl> ,-ihdo22,-rmehl5-cr n[ 3 4 -J]quinoline (Compound 340); 9 -Chloro-5-(4-fluorophenyl1) dhdo-,,-riehl5Hcrmn[3,4- fiquinoline (Compound 341); 9 -Choro5(3-Chloro..4.methoxy-5methylpheny1) 1,2- diyr-,,4tieh -Hcrmn[ 3 4 -Jlquinoline (Compound 342); 4 -fluoro-3-methylphenyl 1,2dhdo224 trmty-Hcrmno[,-lqioln (Compound 343); 9 -Choro-5(3-fluoropheny1,2dhdo224-rmty)H chromeno [3,4jflquiio line (Compound 344); (RIS)- 1,2-Dihydro-2,2,A-trimethyl-5-[(3,4-. methylenedioxy)phenyl] -5H-chromeno [3 4 -J]quinoline (Compound 345); Choro- 3 -methylphenyl). l, 2 -dihydro-2,2,4-timethyl-5H-chromeno 3 4 -fjquinoiine (Compound 20 346); (R/S)-5-(3,5-Dic1Iorophenyl)1,2dhdo-,,- iehl5Hcrmn[3,4- fjquinoline (Compound 349); (R/S)-5-(3-Bromo-5methylpheny1> 1 ,2-dihydro-2,2,4- ****trimethy1-5H-chromeno 3 4 -fjquinoline (Compound 350); (R/S)-5-(3-Bromo-5- fluorophenyl)- 1,-iyr-,,-rmty-Hcrmn 3 4 -flquinolfine (Compound 351); (R/S)-5-[4-Fuoro-3-(trifluoromethyl)phenyly- 1,-iyr-,24tiehl Hcrm [3,4- flquinoline (Compound 353); (R/S)-9-Fluoro- l, 2 -dihydro-2,2,4.trimnethyI5-(3- methylpheny)>sHcjhj 0 men 3 ,4-fjquino line (Compound 354); (RIS)-1I,2-Dihydro-9- methoxy- 2 24trimethy5(3mypehyl)-Hhny1)5 3 4 -Aqi ie(Cmon 355); (R/S)-9-Fluoro-5-.( 3 -fluoro-4-methoxyphenyl). l 2 -dihydro-2,2,4-trimethyp-5H. chromeno [3 4 -Ilquinoiine (Compound 356); (R/S)-9-Fluoro- l, 2 -dihydro-2,2,4-trimethy15- 3 -(trifluoromethyl)>phenyl-5H-cJh 0 ome 0 [3 4 -J]quinoline (Compound 357); DOCKET NO. 016-0014A.WO 352 Fluoro-5-(4-fluoro-3.methylphenyl)- l, 2 dihydro-2,2,4-trimethyI-5H..cjromeno [3,4- flquinoline (Compound 358); 2 4 -Difluoro benzylidene) l, 2 -dihydro-2,2,4-tr.imethylp 5H-chromeno[3,4-Aquinoline (Compound 359); (Z)-5-(3,4-Difluorobenzylidene) 1,2- diydo 2,,-tiehl5-hom 3 4 -Ajquino line (Compound 360); (3- Fluorobenzylidene)- 1,2,3,4ttayr -224 rmty-Hcroeo[,-q oln (Compound 361); 2 ,6-Difluorobenzyjdene)-1,l 2 -dihydro-2,2,4-trinmethy1-5H- chromeno 3 4 -fjquinoline (Compound 362); 2 -Dihydro-5-(2-methylbenzylidene-22,4 3 4 -fjquino line (Compound 363); (Z)-.9-Chloro-5- difluoro benzylidene) 1 l 2 -dihydro2,2,4trimethyl15H-chromeno [3 4 -JAquino line (Compound 365); (Z)-5-Benzylidene-9c~oro l, 2 -dihydro-2,2,4-trim-ethy-5H-chromeno 3 4 -fAquinoline (Compound 366); (Z)-9-Chloro-1,-iyr-,,-t chromeno [3 4 -JAquinoline (Compound 367); (Z)-5-Benzylidene-9.choro-1 ,2-dihydro-2,2. 3 4 -Ajquino line (Compound 368); (Z)-9-Chloro-5-(2- fluoro benzylideney l, 2 -dihydro-2,2,4trimethylpsH-chromeno 3 4 -flquinoline (Compound 369); 9 -Choro5(3-fluorobnzylidene) l, 2 -dihydro-2,2,4-tiethyl-5H1-chromeno [3,4- fjquinoline (Compound 370); (E/Z)-5-Benzyidene.9.fluoro-l, 2 -dihydro-2,2,4imethyl15H- chromeno 3 4 -fiquinoline (Compound 371); (Z)-5-Benzylidene8fluoro-1 ,2-dihydro-2,2,4- 3 4 quino line (Compound 372); (Z)-5-Benzylidene-1 ,2-dihydro-9- mehx-,,4tiehl Hcrmn[ 3 4 -JAquinoline (Compound 373); (Z)-9-Fluoro- 1,2- Uuhyro-z,24-tmethy5(2methyenzylid)5Hhrom 3 4 -flquinoline (Compound 374 Z) 8 -lu ro 1 -d hy ro ,2 4 -ri et yl 5 -2 e jyb n ien ej-5-c ho m e n o [3 4 &too Afquinoline (Compound 375); l, 2 -Dihydro-9methoxy224tiethylS5( 2 methylbenzylidene)- H-chromeno 3 4 -flquino line (Compound 376); (3- Fluorobenzylidene> 1,2,3 4 -tetrahydro-2,2,4-timethyl-5H-.chromeno [3, 4 -fi-3-quinolinone 25 (Compound 389); (Z)-(R/S)-5-.(Benzyljdene)-1,2,3 4 -tetrahydo224tlrjethyJ5H chromeno 3 4 -fI-3-quinolinone (Compound 392); (R/S- 4 ,Su)-5-(3.Fluorophenyl)-1,2,3,4- terhdo224timty Hcrmn[ 3 4 -fJ-3-quinolinone (Compound 393); (RIS-41,SI)- S-( 3 -Fluorophenyl). 1,2,3 4 tetrahydro-2,2,4rimethy5chreomeno[A 3 qun 3 .no (Compound 394); (R/S-41,51)- 1,2,3 4 -Tetrahydro-2,2,4trimethylI5-[3- (tilooehlphnl Hcrmn[ 3 4 ,-fI-3-quinolinone (Compound 395); (R/S-41,5u)- DOCKET NO. 016-00 14A.WO 353 1,,,-erhdo224tiehl5[-tffurmty~hnl-Hcrmn[,-l3 quinolinone (Compound 396); (R/S- 4 l,5u)-5-(4-Chorophenyl> I 2 3 ,4-tetrahydro-2,2,4- [3 4 3 -quinolinone (Compound 402); (RIS-41,51)-5- (4- Chlorophenyl)- 1,2,3 4 -tetrahydro.2,2,4trimethy15Hchomeno -3-quinolinone (Compound 403); and (R/S)-5-Butyl- l, 2 -dihydro..2,2,4,9..tetramethy1-5H-.chomeno (3,4. Jlquinoline (Compound 457). 11. An AR modulator compound according to claim 6 selected from the group consisting of l, 2 -Dihydro..2,2,4.trimethy6methoxymethy18pyanono [S,6-glquino line (Compound 237); 1, 2 -Dihydro.2,2,4trimethyl6t1.ifluoromethy18pyann[5, 6 -g]quinoline (Compound 238); 1, 2 -Dihydro-2,2,4-trimethyl-. l-isocoumarino[4,3..g]quinoline (Compound 239); 1,2- Dihydro-2,2,4.trimethyl. lO.isoquinolono[4,3.g]quinolie(Compould 240); 1 ,2-Dihydro- 2,,,-ermty--yrdn[,-junln (Compound 241); 1 ,2-Dihydro- .fe:224trmty-O-iohoeo4,-~unln (Compound 242); 1, 2-Dihydro-2,2,4,6- .15 tetramethylv8H-pyrano[3 2 -glquinoline (Compound 243); (RIS)- 1, 2 ,3,4-Tetrahydro-22,4 trimethyl-1 O-isoquinolono 4 3 -gjquinoiine (Compound 244); l, 2 -Dihydro-2,2,4-trimethyl1 1 O-thioisoquinolono 4 3 -g]quinoline (Compound 245); 1 2 3,4-Tetrahydro-2,2,4- **trimethyl-1 O-isoq-uinolono 4 3 -g]quinoline (Compound 246); l, 2 -Dihydro-2,2,4-trimethyp6- trifluoromethyl8pyridono [5, 6 -glquinoline (Compound 247); (RIS)- 1, 2 ,3,4-Tetrahydro- 20 2,,-rmty--rfurmthl8prnn[,-junln (Compound 250); 1,2- Diyro22,-trmthl6-rfloo ehy- 8 -thiopyrano fo [5, 6 -g]quino line (Compound 251); (RIS)- 1,,,-erhdo224tintyl6tflooeh 8tiprnn[5,6-g]quinoline (Compound 252); 6-Chloro (difluoro)methyl-l, 2 dihydro.2,2,4trimethy8pyanon 0 [5,6- gS...oin (Cmon 5) -ctl1 2 -dihydro..2,2,4..trirnethy16-trffluoromethyl-8 25 pyridono [5, 6 -glquinoline (Compound 254); 1 ,2-Dihydro-2,2,4,1 O-tetramethyl-6- trifluoro methyl8 pyidono [5, 6 -gj quino line (Compound 255); 1 2 -Dihydro-2,2,4-trimethyl- 1,1 2 2 2 -pentafluoroethyl8pyranono [5, 6 -gjquinoline (Compound 256); Chioro (difluoro)methyl- l, 2 3 4 -tetrahydro.2,2,4trimethy1-8pyanono [5,6-gjquinoline (Compound 257); 7-Chloro-1,-iyr-,,-rinty--rfuroehl8prnn[5,6- glquinoline (Compound 258); (RIS)-7-Chloro- l, 2 3 4 -tetrahydro..2,2,4..trimethy16- DOCKET NO. 016-0014A.WO 354 trifluoromethyl- 8-pyrano no [5,6-gl quino line (Compound 259); 1 ,2,3,4-Tetrahydro-2,2,4- trimethyl-6-trifluoromethyl-8-pyridono quinoline (Compound 260); 1 ,2-Dihydro- 2,2,4,9-tetramethyl- 6-trifluoromethyl- 8-pyridono [5 quino line (Compound 261); 1,2- Dihydro-2,2,4-trimethyi- 8-trifluoromethyl-6-pyridono [5 ,6-glquinoline (Compound 262); 6- [Dichloro(ethoxy)methyl] 2-dihydro -2,2,4-trimethyl- 8-pyranono quino line (Compound 263); 5-(3-Furyl)- 1, 2 -dihydro-2,2,4-trimethyl-8-pyranono [5,6-g]quinoline (Compound 264); 1 ,2-Dihydro- 1 2 2 4 -tetramethy1-6-trifluoromethy1-8-pyranono [5,6- g] quinoline (Compound 265); 1 2 -Dihydro-6-trifluoromethy1-2,2,4-trimethy-9thiopyran-8 ono quinoline (Compound 266); 1 ,2-Dihydro- 1,2,2,4,9-pentamethyl-6- trifluoromethyl-8-pyridono [5,6-giquinoline (Compound 267); 7-Chloro- 1,2-dihydro-2,2,4- trimethyl-6-trifluoromethyl-8-pyridono [5,6-glquinoline (Compound 268); and 6- Chloro(difluoro)methyl- 1, 2 -dihydro-2,2,4-trimethyl-8-pyridono [5,6-g]quinoline (Compound 269); (RIS)- 1,2,3,4-Tetrahydro- 1, 2 2 4 -tetramethyl-6-trifluoromethyl-8-pyranono [5,6- g]quinoline (Compound 404); (3-Furyl)- 1,2,3,4-tetrahydro-2,2,4-trimethyl-8- 15 pyranono[5,6-g]quinoline (Compound 405); 5-( 3 -Furyl)-1,2-dihydro-1,2,2,4-tetramethyl-8- 9 pyranono [5,6-glquinoline (Compound 406); 5-(3-Furyl)- 1 ,2-dihydro- 1 ,2,2,4-tetramethyl-8- thiopyranono [5,6-glquinoline (Compound 407); 6-Chloro-5-(3-furyl)- 1,2-dihydro- 1,2,2,4- tetramethyl-8-pyranono [5,6-g]quinoline (Compound 408); 1 ,2,3,4-Tetrahydro-2,2,4, tetramethyl-6-trifluoromethyl-8-pyridono [5,6-gjquinoline (Compound 409); (RIS)- 1,2,3,4- 20 Tetrahydro-4-methyl-6-trifluoromethyl-8-pyranono [5,6-giquinoline (Compound 410); 1,2- Dihydro-2,2-dimethyl-6-trifluoromethyk8-pyranono [5,6-g]quinoline (Compound 411); 1,2,3 4 -Tetrahydro-2,2-dimethy-6-trifluoromethyl. 8-pyranono[5,6-glquino line (Compound 412); 1 2 3 4 -Tetrahydro-6-trifluoromethyl-8-pyranono [5,6-glquinoline (Compound 413); (R/S)-4-Ethyl- 1 2 3 4 -tetrahydro-6-trifluoromethyl- 8pyranono [5,6-gl quino line (Compound 25 414); (RIS)- 1 ,2,3,4-Tetrahydro- 1 4 -dimethyl-8-pyranono[5,6-glquinoline (Compound 415); (R/S)-4-Ethyl- 1,2,3 ,4-tetrahydro- 1-methyl-8-pyranono [5,6-g]quinoline (Compound 416); 2,2-Dimethyl. 1 2 ,3, 4 -tetrahydro-6-trifloromethyl- 8 pyrido no [5,6-A quino line (Compound 417); (RIS)- 1, 2 3 4 -tetrahydro-6-trifluoromethyl-2,2,4trimethyt8pyridono[5,6-4p3 quinolinone (Compound 418); 5-Trifluoromethyl-7-pyrido no [5 indo line (Compound 419); 8 4 -Chlorobenzoyl)-5-trifluoromethyl-7-pyridono [5 ,6-e]indoline (Compound 420); 7- DOCKET NO. Ol 6 -0014A.WO 355 tert-Butyloxycarbamoylp l, 2 -dihydro-2,2,8 -trinethylquino tine (Compound 42 1,2,3,4- Tetrahydro-6-trifluoromethy-8-pyrdolo [5, 6 -fAquinolie (Compound 422); 1 ,2-Dihydro-6- trifluoromethyl-1,,,-ermthl8prdn[56Aunln (Compound 423); 3,3- Dimethyl-5-trifluoromethy17pyidono 6-e]indoline (Compound 424); (RIS)- 1,2,3,4- Terhdo4mty--tifurmty)8prdn[5, 6 -g]quinoline (Compound 425); (RIS)- l, 2 3 4 -Tetrahydro-4-methyl&. (trifluoromethyl)- 8-pyridono [5, 6 -gjquinoline (Compound 426); 1 2 2 ,-Trimethyl- l, 2 3 4 -tetrahydro-6-trfluromethyl- 8-pyranono [5,6- glquinoline (Compound 427); (RIS)- 1,,,-erhdo4popl6t looehl8- pyranono [5, 6 -g]quinoline (Compound 428); l, 2 3 4 -Tetrahycdro-2,2,4trimnethy16- trifluoromethyl-9-thiopyran-8-ono [5, 6 -glquinoline (Compound 429); 1 ,2-Dihydro- 1,2,2,4- tetramethyl-6-trifluoromethyl19-th~iopyran-8 -on0 [5, 6 quino line (Compound 430); 1,2,3,4- Tetrahydro- l, 2 2 -trimethy-6trifluoronethy18-pyridono [5, 6 quino line (Compound 431); 1,2,3 ,4-Tetrahydro-.l-methyl-4-propylk6-trifluoromethy18-pyranono 6 -g~quinoline (Compound 432); 1,2,3 ,4-Tetrahydro- lO-hydroxymethy2,2,4tiethy.6trfluoromethyl1 15 8-pyridono [5, 6 -glquinoline (Compound 433); 1,2,3 ,4-Tetrahydro- 1, 2 2 4 -tetramethyl-6- trifluoromethyl-9topyran8ono [5, 6 -glquinoline (Compound 434); 1,2,3 ,4-Tetrahydro- 2,,-rinty 6ti*ormty..*rdno56gqunln (Compournd 435); (RIS)- *1,2,3,4Ttayr--ety--rfurmehl8prdn[5,6-glquinoline (Compound 436J);1234Tayr-, 3 Juimeth1y--trfluorometh8rdon[5, 6 -g]quinoline 20 (Compound 437); (RIS)1,,,-erhdo-,,-rmty--tilooehl8 pyridono [5, 6 -g]quinoline (Compound 438); (R/S-21,4u)- l, 2 3 4 -Tetrahydro-2,4dimethy16- trifluoromethy-8-pyridono [5,6-g]quinoline (Compound 439); (R/S-21,4u)-4-Ethy1 1,2,3,4- tetrahyctro-2methy6trfluoromethy18-pyranono [5, 6 -gllquinoline (Compound 440); (RIS- 21,u)-,2,,4-etahydro-2,3-uieLyitrfluoromethy-I8 pyridono [5, 6 -gl quino line 2 (Compound 44) (R/-21 3 i)l1,2,3 4 -etrahyro23dethy6turmthyl 8 pyridono [5, 6 -glquinoline (Compound 442); (RIS)- 1 2 3 ,4-Tetrahydro-2,3 ,3-trimnethyl-6- trifluoromethylk8-pyridono [5, 6 -gj quino line (Compound 443); (RIS)- 1, 2 ,3,4-Tetrahydro-2- methyI-6-trifluoromethy18-pridono [5, 6 -glquinoline (Compound 444); (R/S)-4-Ethyl- 1,2,3 4 -tetrahydro-6-triffuoromethy1-8-pyridono [5, 6 -g]quinoline (Compound 445); (R/S-21, 3u)- 1 2 3 4 -Tetrahydro-2,3 9 -trimethyl-6-trifluoromethyl18-pyridono [5, 6 -gjquinoline DOCKET NO. 016-0014A.WO 356 (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-l,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. a 16. A pharmaceutical composition according to claim 15, wherein the composition is 20 formulated for oral, topical, intravenous, suppository or parental administration. S:i" 17. A pharmaceutical composition according to claim 15, wherein the compound is administered to a patient as a dosage unit at from about lI g/kg of body weight to about 500 mg/kg of body weight. DOCKET NO. 016-0014A.WO 357 18. A pharmaceutical composition according to claim 15, wherein the compound is administered to a patient as a dosage unit at from about 10gg/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 20gg/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 15 muscle systems. 21. Use of compound according to claim 1 for the preparation of an agent for affecting steroid receptor activity. 20 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. DOCKET NO. 016-0014A.WO 358 A pharmaceutical composition comprising an effective amount of a steroid receptor modulator compound of the formula: R R 9 R 10 R9 R zR 2N R Z 2 I4 R IR 1 4 R 3 R 4 OR R OR R wherein: R 1 through R 3 each independently are hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl; 10 R 4 is hydrogen, a Ci C6 alkyl, or R 5 C=0, OR 6 or NR 6 R 7 where R 5 is hydrogen, a C1 C6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, 7 and wherein R 6 and R each independently are hydrogen, a C1 C6 alkyl, optionally substituted allyl, arylmethyl, aryl, or heteroaryl; R 9 through R 1 0 each independently are hydrogen, a C1 C6 alkyl, optionally 15 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 1 and R 9 R 10 and R 11 R 1 and RIO and/or R 11 and R 2 when taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, OR or NR6R where R through R have the definitions given above, provided, however, that R R 2 R 1 and R 1 cannot form more than two three- to seven-membered rings at a time; Y is O, CHR or NR where R has the same definition given above; and DOCKET NO. 016-0014A.WO 359 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, R60C=O, perfluoroalkyl, haloalkyl, a Cl 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. [rest of page left purposely blank] o DOCKET NO. 016-0014A.WO 360 26. A pharmaceutical composition according to claim 25, wherein Z is selected from the group consisting of: C' 0Z C, 0 NC S a. Qc DOCKET NO. 016-0014A.WO 361 I I 0 N N s N N O oN 0 N e..N N 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: DOCKET NO. 016-0014A.WO 362 R 1 R 9 R 1 10 R9 R 1 11 z R 2 z R z 2 cc R 2 R1 2 N NR3 R2 N R 2 A4 R 14R 3 1 4 R 4 OR R 4 OR 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 C1 C6 alkyl, or R 5 C=O, OR 6 or NR 6 R 7 where R 5 is hydrogen, a C1 C6 alkyl, optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, and wherein R 6 and R 7 each independently are hydrogen, a C1 C6 alkyl, optionally substituted allyl, arylmethyl, aryl, or heteroaryl; 10 R 9 through R10 each independently are hydrogen, a C1 C6 alkyl, optionally S substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl; *t R 1 1 is hydrogen, a C1 C6 alkyl, OR 6 or optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, or heteroaryl, where R has the same definition given above, or R and 2 2 3 1 9 10 11 1 10 11 2 *R R and R, R and R R 1 and R R and R and/or R and R when taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, OR 6 or NR6R 7 where R 6 through R 7 have the definitions given above, provided, however, 1 2 10 11 that R R R 10 and R 1 1 cannot form more than two three- to seven-membered rings at a time; ooio Y is O, 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=0, R 6 R 7 NC=0, R 6 0C=0, perfluoroalkyl, haloalkyl, a C 1 C 6 straight-chain hydroxy alkyl, DOCKET NO. 016-0014A.WO 363 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: c. R R R 4 R 3 R 6 R o 5 •R 5 R N 9 15 R 6 HR OR (I) OR R'12 R13 R SR 4 R3 1 R14 R Rs N 9 R 6 HR OR(II) OR DOCKET NO. 016-0014A.WO 364 OR r14 R 13 Rl R12 I w R (TV) OR R12 R 11 i 5 N H 6 HR H. OR R14 R. RR 12 N. R9 18 R R R 159 ,6 R O R 123 6 HR 9 DOCKET NO. 0 l 6 0 0 14A.WO 365 1' 3 A 16 R N 9x R6 H R OR (Vill) OR (X R 2 RA OR N X9' R 12 A' 3 R R'21 3 R x R 15 R 1 0 RA6 riR9 (XI) (XII) DOCKET NO. Ol6-0014A.WO 366 8 3 R14 0 HR 20 13 R R213 R 5 R 9 OR6 HR9 OR (XIII) H'- 2 31 ~N R 8 H R OR (XIV) R14 R16 R813 R 2 812 R X R11 5 R8 OR (XV) 13 16 R821 8R3R82 812 N R11 FR 155 OR(XVI) (XVII) DOCKET NO. 016-0014A.WO 367 OR R 2 4 R26R 2 1 R3 R23X R 2 7 Y Z N 28 R22 A 2 9 9 (XVIII) wherein: R is a heteroaryl optionally substituted with a C 1 C 4 alkyl, F, Cl, Br, NO 2 CO 2 H, CO 2 R 2 CHO, CN, CF3, CH20H or COCH 3 where R 2 is hydrogen, a Cl 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; 3 R is hydrogen, a C 1 C 4 alkyl or perfluoroalkyl, hydroxymethyl, aryl, heteroaryl or o optionally substituted allyl, arylmethyl, alkynyl or alkenyl; 4 6 2 R through R each independently are hydrogen, F, Cl, Br, I, NO 2 CO 2 H, CO 2 R 2 S 15 COR 2 CN, CF 3 CH20H, a C 1 -C 4 alkyl or perfluoroalkyl, OR 2 SR 2 S(O)R 2 SO 2 R 2 SO 3 H, S(NR2R7)R 2 S(O)(NR2R7)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 C 1 C 4 alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl or arylmethyl, OR or NHR8, where R is hydrogen, a C 1 C 6 alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, SO 2 R 2 or S(O)R2; R 9 and R 10 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 hydrogen, F, OR 2 NR2 R 7 where R2 and R 7 have the definitions given above; OR or NR R where R and R have the definitions given above; DOCKET NO. 0 16-0014A.WO 368 R through R 1 each independently are hydrogen, F, Cl, Br, I, NO 2 CO 2 H, C0 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(NR2R7)R 2 S(O)(NR2R7)R 2 NR2R 7 aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, where R 2 R and R 8 have the definitions given above; W is O, NH, NR 7 CH 2 CHOH, C=O, OC=O, O=CO, NR7C=O, NHC=O, O=CNR 7 O=CNH, SC=O, O=CS, or CHOCOR 7 where R has the definition given above; X is CH 2 O, S or NR 7 where R 7 has the definition given above; R 16 is hydrogen, OH, OR 17 SR 17 NR2R optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, heteroaryl or C 1 C 10 alkyl, where R 17 is a C 1 C 10 alkyl or 10 perfluoroalkyl, or is an optionally substituted allyl, arylmethyl, aryl or heteroaryl, and where 2 7 R and R have the definitions given above; o 18 19 R 8 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 where R 2 R 7 and R 8 have the definitions given above; S R20 is a C 1 C 6 alkyl or an optionally substituted allyl, arylmethyl, alkenyl, aryl or heteroaryl; R21 is hydrogen, a C 1 C 4 alkyl or optionally substituted allyl, arylmethyl, aryl or heteroaryl; R 22 is hydrogen, a C 1 C 4 alkyl, F, Cl, Br, OR 2 N2R or SR, where R 2 and R 7 have the definitions given above; R 23 is hydrogen, Cl, Br, OR 8 NR2R 7 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 R 8 have the definitions given above; DOCKET NO. 016-0014A.WO 369 R24 is hydrogen, F, Br, Cl, a C 1 C 4 alkyl or perhaloalkyl, aryl, heteroaryl, CF 3 25 CH2R 2 5 or OR 25 where R 25 is a Cl C 4 alkyl; R 26 is hydrogen, a CI C4 alkyl, F, Cl, Br, I, OR 2 N2R or SR, where R 2 and R 7 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, C1, 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, C1, Br, OR 2 2 7 2 7 or NR2R where R and R have the definitions given above; 10 R is hydrogen, a Cl 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 2 7 15 where R and R have the definitions given above; 32 33 R 32 and R 33each independently are hydrogen, a Ci C 4 alkyl or an aryl optionally substituted with hydrogen, F, Cl, Br, OR 2 or NR2R or R 3 2 and R 33 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR 2 or NR2R 7 where R 2 and R 7 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; DOCKET NO. 016-0014A.WO 370 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, III, 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. DOCKET NO. 016-0014A.WO 371 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 ltg/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 10pg/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 20g/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, 20 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: DOCKET NO. 016-00 14A.WO 372 OR R OR R 12R 1 R 4 R 13 IN 1 H R9 r- 14 W 11 R. 0 ORR RN RA 6 H R 9 (IV) 14 9.*R 13 16 I R3 R 1 2 1 1 1 %RNN R 6 H crD (V DOCKET NO. 0 16-0014A.WO 373 R13R140R6 X R 1 R12 R1 R Rl 1 R 6 HR9 OR (VI) R14 R2 R13 0 R 3 RR R 14 R 0R R' RO o 9R so* OR (II R 24 R 26 R 3 I 2R 27 *0*022 A299 RR OR (IX) I R 5 N 9 R 6 HRW OR DOCKET NO. 016-0014A.Wo 374 R 12 R 13 R 11 4 R 4 R R 21 R 3 1 R R 4 R H (XI) OR R14 R R2 1 x1 R R N 9X RA 6 HR (XII) OR 142 R R R13 0 R RN 3 o* 0 R R R* 5 N R N 0* 4 -6 4HR' OR R14 R 3 16 so&*2 N R 3 R 2 1 31 12 R GC eo 11 10 R 6 HR (XIV) DOCKET NO. 016-0014A.WO (XV) (XVI) *0. .0* *..00 *00 (XVII) (XVIII) wherein: R Iis a heteroaryl optionally substituted with a C 1 C 4 alkyl, F, C1, Br, NO 2 CO 2 H, C0 2 R 2, CHO, CN, CF 3 CH 2 0H or COCH 3 where R 2is hydrogen, a C 1 C 4 ailkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, ailkynyl or alkenyl, and where said R Iheteroaryl is attached to compounds of formulas I and X through a carbon or nitrogen atom; DOCKET NO. 016-0014A.WO 376 R 3 is hydrogen, a C 1 C 4 alkyl or perfluoroalkyl, hydroxymethyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl; R 4 through R each independently are hydrogen, F, Cl, Br, I, NO 2 CO 2 H, CO 2 R 2 COR 2 CN, CF 3 CH20H, a C 1 -C 4 alkyl or perfluoroalkyl, OR 2 SR 2 S(O)R 2 SO 2 R 2 SO 3 H, S(NR2R7)R 2 S(O)(NR2R7)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 8 or NHR 8 where R 8 is hydrogen, a C 1 C 6 alkyl or perfluoroalkyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, SO 2 R 2 or S(O)R2; 10 R 9 and R 10 each independently are hydrogen, a Cl 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, i OR 2 or NR2R where R and R have the definitions given above; R1 through R15 each independently are hydrogen, F, Cl, Br, I, NO 2 CO 2 H, CO 2 R 2 COR2, CN, CF 3 CH20H, a C 1 -C 4 alkyl or perfluoroalkyl, OR 2 SR 2 S(O)R 2 SO 2 R 2 S0 3 H, S(NR2R7)R 2 S(O)(NR2R )R2, NR2R 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 O, NH, NR 7 CH 2 CHOH, C=O, OC=O, O=CO, NR C=O, NHC=O, O=CNR 7 O=CNH, SC=O, O=CS, or CHOCOR 7 where R 7 has the definition given above; X is CH 2 O, S or NR where R 7 has the definition given above; R 16 is hydrogen, OH, OR 17 SR 17 N2R 7 optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl, heteroaryl or C 1 C 10 alkyl, where R 17 is a C 1 C 10 alkyl or DOCKET NO. 016-0014A.WO 377 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 19 each independently are hydrogen, a Cl 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 where R 2 R 7 and R have the definitions given above; is a C 1 C 6 alkyl or an optionally substituted allyl, arylmethyl, alkenyl, aryl or heteroaryl; R21 is hydrogen, a C 1 C 4 alkyl or optionally substituted allyl, arylmethyl, aryl or heteroaryl; R 22 is hydrogen, a C 1 C 4 alkyl, F, Cl, Br, I, OR 2 N2R 7 or SR 2 where R 2 and R have the definitions given above; R 23 is hydrogen, Cl, Br, OR 8 N2R 7 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 S 15 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 25 25 25 i.CF 2 0R 2 CH 2 0R 2 or OR 2 where R 25 is a C 1 C 4 alkyl; R 26 is hydrogen, a C 1 C4 alkyl, F, C1, Br, I, OR 2 N2R 7 or SR 2 where R 2 and R 7 have the definitions given above; 27 28 R 27 and R 28 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 NR2R7, 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 or NR2R 7 where R2 and R7 have the definitions given above; or NR R where R and R have the definitions given above; DOCKET NO. 016-0014A.WO 378 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 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, C1, OR 2 or NR2R 7 where R 2 and R 7 have the definitions given above; R 32 and R 33 each independently are hydrogen, a C 1 C 4 alkyl or an aryl optionally substituted with hydrogen, F, Cl, Br, OR 2 or NR2R or R 3 2 and R 33 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR 2 10 or NR2R 7 where R 2 and R 7 have the definitions given above; n is 0 or 1; YisOorS; 2 2 2 Z is O, 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 S 15 olefin bond in either the cis or trans configuration; and o 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 20 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: DOCKET NO. 0 16-00 14A.WO 379 R 5 Z R 8 R 9 S S 5.55 S.. U (111) (IV) wherein: 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 ClI 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 Cl C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl; DOCKET NO. 016-0014A.WO 380 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, ailkynyl, aryl, heteroaryl, R 3 0, HOCH2, R 3 OCH2, 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 Ci C6 ailkyl, allyl or optionally substituted allyl, arylmnethyl, alkynyl, alkenyl, aryl, or heteroaryl, or R 8 and R 9 taken together form a three- to seven-membered carbocylic, or heterocyclic ring; R 10 is hydrogen, a Ci C6 alkyl, optionally substituted allyl, arylmethyl, aryl, or heteroaryl, 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 2through R have the same definitions as given above; RI 1 and R 12 each independently represent hydrogen, a Cl C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, alkynyl, aryl, heteroaryl, R 3 0, HOCH2, R 3 0CH2, F, Cl, Br, 1, cyano, R 3 R 4 N or perfluoroalkyl, where R 3and R4 have the same definitions as .4 R1 5 gvesboe hydrogen, a Ci C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, alkynyl, aryl, heteroaryl, R 3 0, HOCH2, R 3 OCH2, R 3 R 4 N, CF2Cl, CF2OR 3 or 3 perfluoroalkyl, where R and R4 have the same definitions as given above; R 14 is hydrogen, a ClI C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, 20 alkynyl, aryl, heteroaryl, R 3 0, HOCH2, R 3 OCH2, F, Cl, Br, 1, 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(0R 1 6 SnRl 7 Rl 8 RI 9 or 0S02R 2 0 where R 16 is hydrogen or a Ci C6 alkyl, R 17 through R 19 each independently represent a Cl C6 alkyl, R 2 0 or heteroaryl, R 2 0 is a Cl 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-trimethylb%.coumarino 3 4 -flquinoline; 9-Fluoro- 1,2-dihydro-2,2,4- trimethyl-5-coumarino[3 ,4-Jlquinoline; 8-Fluoro- 1,2-dihydro-2,2,4-trimethyl-5- DOCKET NO. 016-0014A.WO 381 coumarino [3,4-f]quinoline; 9-Chloro-1, 2 -dihydro-2,2,4-trimethyl-5-coumarino[3,4- flquinoline; 8-Ethoxy-1, 2 -dihydro- 2 ,2,4-tri methytrifluoromethyl-8-pyrido[5,6- g]quinoline; and 1,2,6,7-Tetrahydro-6-hydroxy-2,2,4-trimethyl-6-trifluoromethyl-8- pyridono[5,6-g] quinoline. 49. 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: R 6 R 1 6 6* *r .6. in the presence of an alkyllithium, followed by addition of an organoborate and acid treatment to yield the corresponding 6-boro-1,2-dihydro N-1 protected quinoline; coupling the 6-boro-1,2-dihydro N-1 protected quinoline with a coupling partner of the formula R9Y in the presence of a palladium catalyst and base to yield a 6- substituted-1,2-dihydro N-1 protected quinoline of the formula: R 6 R 1 RKAA 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, DOCKET NO. 016-0014A.WO 382 HOCH2, R 7 0CH2, F, C1, Br, I, cyano, R 7 R 8 N or perfluoroalkyl, where R 7 and R 8 each independently are hydrogen, a C1 C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl; R 9 is an aryl or heteroaryl; X is Br, Cl or I; Y is C1, Br, I or OSO 2 CF 3 and P is hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl, R10C=0, R 10 C=S, R 1 1 OC=O, RllSC=O, R 1 1O C=S, R 1 ISC=S or R 1 1 R 12 NC=O, where R 10 is hydrogen, a C1 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. 50. A method for producing a 6 -substituted-1,2-dihydro N-l protected quinoline according to claim 49, further comprising, deprotecting the 6-substituted-l,2-dihydro N-l protected quinoline to yield the corresponding 6-substituted-1,2-dihydroquinoline. 51. A method for producing a 6-substituted-1,2-dihydro N-l protected quinoline 15 comprising: in a one-pot reaction, exchanging a 6 -halo-1,2-dihydro N-l protected quinoline of the formula: .R 6 R 1 5 r R2 R" N 3 S4 p R in the presence of a reactive metal, followed by addition of an organoborate and acid l. 20 treatment to yield the corresponding 6-boro-1,2-dihydro N-1 protected quinoline; coupling the 6-boro-1,2-dihydro N-l protected quinoline with a coupling partner of the formula R9Y in the presence of a palladium catalyst and base to yield a 6- substituted-1,2-dihydro N-1 protected quinoline of the formula: DOCKET NO. 016-0014A.WO 383 R 6 R 1 R 1 R 2 R 4 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 Ci C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, alkynyl, aryl, heteroaryl, R 7 0, HOCH2, R 7 0CH2, F, CI, 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 9 is an aryl or heteroaryl; X is Br, C1 or I; Y is Cl, Br, I or OSO 2 CF 3 and P is hydrogen, a C1 C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl, 10 R 10 C=O, R 10 C=S, RO 1 C=O, R 1 1 SC=O, R 1 1 0C=S, R 1 1 SC=S or R 11 R 12 NC=O, where R 10 is hydrogen, a C1 C6 alkyl or perfluoroalkyl, optionally substituted allyl or aryl methyl S"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. 15 52. A method for producing a 6-substituted- 1,2-dihydro N-l 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-i protected quinoline 20 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: DOCKET NO. 016-0014A.WO 384 R 6 R 1 X RsI i R 2 R R 2 HP in the presence of an alkyllithium, followed by addition of an organotin species to yield the corresponding 6-stannyl-1,2-dihydro N-l 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 to yield a 6-substituted- 1,2-dihydro N-l protected quinoline of the formula: R 6 R 1 :R R 2 S 10P 4 .heteroaryl; R9 is an aryl or heteroaryl; X is Br, C or Y is C, Br, I or OSCF3; and P is 1 wherein R is hydrogen, a C 1 C 4 alkyl, aryl or heteroaryl; R and R 3 each independently 2 are a Cl C 4 alkyl, aryl or heteroaryl; R through R 6 each independently are hydrogen, a Cl S- C6 alkyl, optionally substituted allyl, aryl methyl, alkenyl, alkynyl, aryl, heteroaryl, R 7 0, "HOCH2, R 7 OCH2, 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 .o heteroaryl; R is an aryl or heteroaryl; X is Br, Cl or I; Y is Cl, Br, I or OSO 2 CF 3 and P is *O hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl, R 10 C=O, R 10 C=S, R 1 1 0C=O, R 1 1 SC=O, R 1 1 OC=S, R 1 1 SC=S or RllR 12 NC=0, 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. DOCKET NO. 016-0014A.WO 385 A method for producing a 6-substituted-1,2-dihydro N-1 protected quinoline according to claim 54, further comprising, deprotecting the 6-substituted-1,2-dihydro N-l protected quinoline to yield the corresponding 6-substituted-1,2-dihydroquinoline. 56. 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: R 6 R 1 X V I L R 2 N 2 R 4 R 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-1 protected quinoline; o 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- 15 substituted- 1,2-dihydro N-l protected quinoline of the formula: R 6 R 1 R 9 1 pI. I R 2 R T N R3 R P wherein R is hydrogen, a Ci 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 C1 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 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, DOCKET NO. 016-0014A.WO 386 R 10 C=O, R 10 C=S, R 1 1 OC=O, R 1 1 SC=, R110C=S, R 1 1 SC=S orR 1 1 R 12 NC=O, where R 10 is hydrogen, a C1 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 C1 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-l protected quinoline to yield the corresponding 6-substituted-1,2-dihydroquinoline. 58. A method for producing a 6-substituted-1,2-dihydro N-1 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-l protected quinoline comprising: coupling the 6-halo-1,2-dihydro N-1 protected quinoline with a coupling 9 partner of the formula R Y in the presence of a palladium catalyst and base to yield a 6- substituted-1,2-dihydro N-l protected quinoline of the formula: SR 6 R1 2 R N 3 R 4 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 DOCKET NO. 016-0014A.WO 387 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, I or OS0 2 CF 3 Y is B(OR10)2 or SnR R 1 R 1 3 where R1 0 is hydrogen or a C 1 C 4 alkyl, and where R 1 1 through R 13 each independently are a C 1 C 4 alkyl; and P is hydrogen, a C1 C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl, R1 4 C=O, R 14 C=S, R 15 0C=O, R 15 SC=O, R 15 0C=S, R 15 SC=S or R 15 R 16 NC=0, where R 14 is hydrogen, a Cl C6 alkyl or perfluoroalkyl, optionally substituted allyl or aryl, methyl, alkenyl, alkynyl, aryl or heteroaryl, and where R 1 and R 16 each independently are hydrogen, a Cl C6 alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl. A method for producing a 6-substituted-1,2-dihydro N-1 protected quinoline according to claim 59, further comprising, deprotecting the 6-substituted-1,2-dihydro N-1 protected quinoline to yield the corresponding 6-substituted-1,2-dihydroquinoline. S 15 61. A method for producing a nitrobenzocoumarin comprising: coupling a 2-halo-5-nitrobenzoic acid derivative with a 2-methoxyphenyl S boronic acid of the formula: R 1 R 2 OCH 3 R3 B(OH) 2 R 4 20 in the presence of a palladium catalyst and base to yield a biaryl carboxylate of the formula: DOCKET NO. 016-0014A.WO 388 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 NO 2 R 3o R N02 p .r ft 4*P*# wherein R 1 through R 6 each independently are hydrogen, F, Cl, Br, CN, CF3, a C 1 C 4 10 alkyl, or OR where R is hydrogen or a C1 C4 alkyl; and X is OR or NR R 9 where R and R 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 nitrobenzocoumarin to the corresponding aminobenzocoumarin. 63. A method according to claim 62, further comprising, adding an optionally substituted allyl of the formula: to the aminobenzocoumarin to yield a coumarino[3,4-f]quinoline of the formula: DOCKET NO. 016-0014A.WO 389 1 1 12 wherein R 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 1 1 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-f]quinoline, followed by reduction to a chromeno[3,4-flquinoline of the formula: S *c S S 5*S SS 9* S 9* S *S e S ~b 9@ wherein R 1 through R 12 have the same definitions as given in claim 69, and wherein R 13 is hydrogen, a Cl C 12 alkyl, OH, OR 14 or SR 14 where R 14 is a C 1 C 10 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 15 or NR 2 15, where R 15 is hydrogen or a CI C 4 alkyl. DOCKET NO. 016-0014A.WO 390 A method for producing a 5H-chromeno[3,4-f]quinoline comprising sequentially adding an organometallic to a coumarino[3,4-f]quinoline, followed by dehydration to yield a 5H-chromeno[3,4-f]quinoline of the formula: R 1 R 1 3 R R13 R2 O 0RO RR R3 R 11 4 R R N 0 12 R 6 HR wherein R through R each independently are hydrogen, F, C1, Br, CN, CF 3 a C 1 C 4 alkyl 7 7 8 89 8 9 or OR where R is hydrogen or a C1 C4 alkyl; X is OR or NR8R 9 where R and R 9 each independently are hydrogen, a C 1 C 4 alkyl or optionally substituted allyl, aryl methyl, 10 aryl or heteroaryl; R 10 is hydrogen, a C 1 C 4 alkyl, aryl or heteroaryl; R 1 1 and R 12 each t*1 independently are a C 1 C 4 alkyl, aryl or heteroaryl; R 13 is hydrogen, a C 1 C 12 alkyl, OH, OR14 or SR 14 where R14 is a C 1 C10 alkyl, CF3, 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, 0 115 15 OR5 or NR 2 15, where R is hydrogen or a C 1 C 4 alkyl; and the wavy line in the structure at R 13 represents an olefin bond in either the cis or trans configuration. 0 66. A method of producing a linear tricyclic 1,2-dihydroquinoline comprising: acylating a 3-nitroaryl of the formula: DOCKET NO. 016-0014A.WO NO 2 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: R 3 R 4 to yield a 5-protected 1,2-dihydroquinoline of the formula: and cyclizing the 5-protected 1,2-dihydroquinoline by first deprotecting the Z group and then cyclizing in the presence of a (3-keto ester of the formula: DOCKET NO. 016-0014A.WO 392 0 0 R9 OR 1 1 R 6 and Lewis acid to yield a linear tricyclic 1, 2 -dihydroquinoline selected from the group consisting of: 6 R 9 R R 3 R HR 1 R 3 R 6 R R4 0 5 R 4 O Z N Rs O Z N R 2 H R2 H S R R 3 0 R 1 R 3 R 6 R6 1 R R 1 R R R N 5 and RN R 2 HZ 2 H R wherein R 1 and R 2 each independently are hydrogen, a C 1 C 4 alkyl, a hydroxy methyl, F, C1, Br, I or CN; R 3 is hydrogen, a C 1 C 4 alkyl, aryl or heteroaryl; R 4 and R 5 each 10 independently are a Cl C 4 alkyl, aryl or heteroaryl; R 6 is hydrogen, a Ci C 4 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 S• hydrogen, F, Cl, Br, OR or NR R where R and R 8 each independently are hydrogen or a C 1 C 4 alkyl; R 9 is hydrogen, a C 1 C 4 alkyl, CF3, perhaloalkyl, CF 2 OR 10 CH 2 OR 10 or OR 10 where R 10 is a C 1 C 4 alkyl; R 1 1 and R 12 each independently represent hydrogen or a Cl C4 alkyl; Z is O, 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, DOCKET NO. 0l6-0014A.W'O 393 aryl, or heteroaryl, R 13 C=O, R 13 C=S, R 14 OC=O, R 14 SC=O, R 14 OC=S, R 14 SC=S or R 14 R I 5 NC=O, where R 13 is hydrogen, a C 1 C6 alkyl or perfluoroalkyl, optionally su bstituted allyl or aryl methyl alkenyl, alkynyl, aryl or hetero aryl, and where R 14 and R 1 each independently are hydrogen, a Ci C6 alkyl, optionally substituted allyl, arylmethyl, 5 aryl or heteroaryl. 67. A method of producing a linear tricyclec 1 ,2-dihydroquinoline comprising: acylatine a 3-aminoaryl of the formula: HZI NH 2 m with an acylating agent of the formula: 0 P -kX 15 in the presence of base to yield the corresponding 5-protected 3-am-inoaryl; adding an optionally substituted allyl of the formula: to yield a 5-protected 1 2 -dihydroquino line of the formula: DOCKET NO. 016-0014A.WO cyclizing the 5-protected 1, 2 -dihydroquinoline by first deprotecting the Z group and then cyclizing in the presence of a 3-keto ester of the formula: 0 0 R 9 OR 1 1 oo oo 10 and Lewis acid to yield a linear tricyclic 1,2-dihydroquinoline selected from the group consisting of: wherein R 1 and R 2 each independently are hydrogen, a C 1 C 4 alkyl, a hydroxy methyl, F, Cl, Br, I or CN; R 3 is hydrogen, a Ci 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, CF3, a DOCKET NO. 016-0014A.WO 395 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 7 or NR7R where R 7 and R each independently are hydrogen or a C 1 C 4 alkyl; R 9 is hydrogen, a C 1 C 4 alkyl, CF3, perhaloalkyl, CF20R 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 C 4 alkyl; Z is O, 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, R1 3 C=0, R 13 C=S, R 14 0C=0, R 14 SC=O, R140C=S, R 14 SC=S or R 14 R 1 5 NC=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 15 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 according to claim 1 to a steroid receptor. 70. 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. DOCKET NO. 016-0014A.WO 396 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. Dated this 1 4 th of April 2000 LIGAND PHARMACEUTICALS INCORPORATED By their Patent Atorneys GRIFFITH HACK Fellows Intitute of Patent and Trade Mark Attorneys of Australia o 6 4 .4