KR100470192B1 - Androgen Receptor Modulators Compounds and Methods - Google Patents

Abstract

The present invention relates to a nonsteroidal compound that is a poor agonist with high affinity and high selectivity for androgen receptors. The present invention also provides methods of using these compounds and compositions to treat patients in need of such pharmaceutical compositions, androgen receptor agonists, partial agonists or antagonist therapies, intermediates and androgen receptor modulators useful in the preparation of these compounds. The present invention relates to a method for preparing a compound.

Description

Androgen Receptor Modulator Compounds and Methods

The present invention relates to nonsteroidal compounds that are modulators (ie, agonists and antagonists) of androgen receptors and methods of making and using these compounds.

Intracellular receptors (IRs) form a class of structurally-related gene regulators that scientists call "ligand depen-dent transcription factors" [R.M. Evans, 240 Science, 889 (1988). Steroid receptors are recognized subsets of IRs, including progesterone receptors (PR), androgen receptors (AR), estrogen receptors (ER), glucocorticoid receptors (GR) and mineralocorticoid receptors (MR). Regulation of genes by these factors requires both IR itself and corresponding ligands having the ability to selectively bind to IR in a manner that affects gene transcription.

Ligands for IRs may include low molecular weight natural molecules such as hormone progesterone, estrogen and testosterone and synthetic derivative compounds such as hydroxyprogesterone acetate, diethylstilbestol and 19-nortestosterone. These ligands, when present in the pericellular fluid, pass through the outer cell membrane by passive diffusion to bind to specific IR proteins to form ligand / receptor complexes. These complexes are then translocated to the cell nucleus where they bind to a particular gene or genes present in the DNA of the cell. Once bound to DNA, the complex modulates the production of the protein encoded by the gene. In this regard, compounds that bind IR and mimic the effect of natural ligands are called "agonists", while compounds that inhibit the effect of natural ligands are called "antagonists".

Ligands for steroid receptors are known to play an important role in the health of both women and men. For example, female natural ligands progesterone, and synthetic analogues such as norgestrel (18-homo northysterone) and norethosterone (17 α-ethynyl-19-nortestosterone) are both PR and ER. As an effective modulator for, it is typically used in birth control agents in combination with the female hormone estrogen or synthetic estrogen analogues. Antagonists against PR, on the other hand, are potentially useful for treating chronic diseases such as certain hormone-dependent cancers of the breast, ovary, and uterus, and for treating non-malignant diseases that are the leading cause of female infertility, such as leiomyoma and endometriosis. Do. Likewise, AR antagonists such as cyproterone acetate and flutamide have been found useful in the treatment of prostatic hyperplasia and prostate cancer.

The effectiveness of known modulators of steroid receptors is sometimes mitigated due to their undesirable side effect profile, especially during prolonged administration. For example, the effectiveness of progesterone and estrogen agonists such as norgestrel and diethylstilbestol, respectively, as female birth control agents should be considered in comparison with the increased risk of carcinogenesis and heart disease in women taking such agents. Similarly, progesterone antagonist mifepristone (RU486), when administered to chronic indications such as leiomyoma, endometrial hyperplasia and certain hormone-dependent cancers, has been shown to balance imbalance of bioalways in patients due to its inherent cross-activity as a GR antagonist. Can cause. Thus, identifying compounds with good specificity for one or more steroid receptors and having low or no cross-activity for other steroids or intracellular receptors are of significant value in the treatment of male and female hormonal reactive diseases. will be.

Groups of adjacent polynuclear heterocyclic rings having substituents with nonionic properties or groups of quinolone analogs having adjacent polynuclear ring systems of the indene or fluorene series have been reported as photoconductors, stabilizers, laser dyes and antioxidants. US Patent No. 3,798,031; 3,830,647; 3,832,171; 3,928,686; 3,979,394; 4,943,502 and 5,147,844 and US Pat. 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. Prom-st., 97 (Moscow, 1967)]. In addition, quinolone derivative groups have recently been reported as modulators of steroid receptors [1996. 6. 27 published WO 96/19458.

Summary of the Invention

The present invention relates to compounds, pharmaceutical compositions, and methods for modulating processes mediated by androgen receptors (AR). More particularly, the present invention relates to nonsteroidal compounds and compositions that are high affinity and high specific agents for the androgen receptor, partial agonists (ie, partial activators and / or tissue-specific activators) and antagonists. The present invention also provides methods for preparing such compounds and pharmaceutical compositions, and important intermediates used in their synthesis.

These and other various advantages and novel features that characterize the invention are described in detail in the claims that form part of the invention as attached to the specification. However, in order to better understand the present invention, its advantages and the objects obtained by using the present invention, reference should be made to the description in which preferred embodiments of the present invention are described.

Definition and naming

As used herein, the following terms are defined to have the following meanings unless explicitly stated otherwise. In addition, the compounds described herein were named according to the following general criteria in an effort to maintain consistency in the naming of compounds having different but similar structures with substituents. A numbering system for the location of substituents on such compounds is also provided.

The terms alkyl, alkenyl, alkynyl and allyl include straight chain, branched, cyclic, saturated and / or unsaturated structures and combinations thereof.

The term aryl means an optionally substituted 6-membered aromatic ring including 2 to 4, more preferably 2 to 3, most preferably 2 rings, polyaromatic rings and polycyclic ring systems.

The term heteroaryl includes one or more selected from the group consisting of carbon, oxygen, nitrogen and sulfur, including polycyclic rings of two to four, more preferably two to three, most preferably two rings Carbon and nitrogen, including optionally substituted 5-membered heterocyclic rings containing heteroatoms, or polycyclic rings of 2 to 4, more preferably 2 to 3, most preferably 2 rings It means a 6-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of.

6a, 10-dihydro-pyrrolidino [1,2-a] quinoline is defined by the structure:

7a, 11-dihydro-2-pyridino [5,6-g] pyrrolidino [1,2a] quinoline is defined by the structure:

8-pyridono [5,6-g] quinoline is defined by the structure:

9-Pyridono [6,5-i] Julolidine is defined by the following structural formula:

1,10- [1,3-dihydro-3-oxo- (2,1-isoxazolyl)]-8-pyridono [5,6-g] quinoline is defined by the structure:

Detailed Description of the Invention

Compounds of the present invention are defined as compounds of the general formula (I), (II), (III), (IV) or (V):

In the above formula,

R ¹ is hydrogen, F, Cl, Br, I, NO ₂ , OR ²⁰ , NR ²¹ R ²² , SR ²⁰ , C ₁ -C ₄ alkyl or perhalo alkyl, or optionally substituted allyl, arylmethyl, alkynyl, Alkenyl, aryl or heteroaryl, where R ²¹ is hydrogen, C ₁ -C ₆ alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl or arylmethyl, SO ₂ R ²³ or S (O) R ²³ , R ²³ is hydrogen, C ₁ -C ₆ alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl or arylmethyl, R ²⁰ is hydrogen, C ₁ -C ₆ alkyl or perfluoro Alkyl, aryl, heteroaryl, optionally substituted allyl or arylmethyl, R ²² is hydrogen, C ₁ -C ₄ alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl or arylmethyl, OR ²⁰ or NHR ²¹ ;

R ² is hydrogen, F, Br, Cl, C ₁ -C ₄ alkyl or perhaloalkyl, aryl, heteroaryl, CF ₃ , CF ₂ H, CFH ₂ , CF ₂ OR ²⁰ , CH ₂ OR ²⁰ or OR ²⁰ , Wherein R ²⁰ is as defined above;

R ³ is hydrogen, C ₁ -C ₄ alkyl, F, Cl, Br, I, OR ²⁰ , NR ²¹ R ²² or SR ²⁰ , wherein R ²⁰ to R ²² are as defined above;

R ⁴ and R ⁵ are each independently hydrogen, C ₁ -C ₄ alkyl or perfluoroalkyl, heteroaryl, optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or optionally hydrogen, F, Cl, Br, Aryl substituted by OR ²⁰ or NR ²¹ R ²² , or R ⁴ and R ⁵ together form a 3- to 7-membered ring optionally substituted by hydrogen, F, Cl, Br, OR ²⁰ or NR ²¹ R ²² Wherein R ²⁰ to R ²² are as defined above;

R ⁶ and R ⁷ are each independently hydrogen, C ₁ -C ₄ alkyl or perfluoroalkyl, heteroaryl, optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or optionally hydrogen, F, Cl, Br, Aryl substituted by OR ²⁰ or NR ²¹ R ²² , or R ⁶ and R ⁷ together form a 3- to 7-membered ring optionally substituted by hydrogen, F, Cl, Br, OR ²⁰ or NR ²¹ R ²² Wherein R ²⁰ to R ²² are as defined above;

R ⁸ is hydrogen, C ₁ -C ₁₂ alkyl or perfluoroalkyl, hydroxymethyl, aryl, heteroaryl, or optionally substituted allyl, arylmethyl, alkynyl or alkenyl;

R ⁹ to R ¹⁸ are each independently hydrogen, C ₁ -C ₄ alkyl or perfluoroalkyl, heteroaryl, optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or optionally hydrogen, F, Cl, Br, or oR ²⁰ or aryl substituted by NR ²¹ R ^22, R ⁹ to R ¹⁸ are both together hydrogen, F, Cl, Br, oR 20 or NR ²¹ R ²² by a 3-to 7-membered ring optionally substituted in the , Wherein R ²⁰ to R ²² are as defined above;

R ¹⁹ is F, NO ₂ or SR ²⁰ , wherein R ²⁰ is as defined above;

R ²⁴ is hydrogen, C ₁ -C ₄ alkyl, F, Cl, Br, I, NO ₂ , OR ²⁰ , NR ²¹ R ²² or SR ²⁰ , wherein R ²⁰ to R ²² are as defined above;

R ²⁵ is hydrogen, C ₁ -C ₁₂ alkyl or perfluoroalkyl, hydroxymethyl, aryl, heteroaryl, or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or R ²⁵ and R ⁸ together May form a 3- to 7-membered ring optionally substituted with hydrogen, F, Cl, Br, OR ²⁰ or NR ²¹ R ²² , wherein R ²⁰ to R ²² are as defined above;

R ²⁶ is hydrogen, C ₁ -C ₆ alkyl or perfluoroalkyl, NO ₂ , OR ²⁰ , C (O) R ²⁰ , C (O) OR ²⁰ , C (O) NR ²¹ R ²² , or optionally substituted Aryl, heteroaryl, allyl or arylmethyl, wherein R ²⁰ to R ²² are as defined above;

R ²⁷ and R ²⁸ are each independently hydrogen, F, Cl, Br, I, OR ²⁰ , NR ²¹ R ²² , C ₁ -C ₄ alkyl or perfluoroalkyl, heteroaryl, optionally substituted allyl, arylmethyl, Alkynyl or alkenyl, or aryl, optionally substituted by hydrogen, F, Cl, Br, OR ²⁰ or NR ²¹ R ²² , or R ²⁷ and R ²⁸ together are hydrogen, F, Cl, Br, OR ²⁰ or NR ^May form a 3- to 7-membered ring optionally substituted with ²¹ R ²² , wherein R ²⁰ to R ²² are as defined above;

m is 0 or 1;

n is 0 or 1;

0 is 0 or 1;

Y is O or S;

Z is O, S, NH, NR ²² or NCOR ²² , wherein R ²² is as defined above;

Two of R ⁴ to R ⁸ , R ²⁵ and R ²⁸ together may form a 3- to 7-membered ring optionally substituted by hydrogen, F, Cl, Br, OR ²⁰ or NR ²¹ R ²² , wherein R ²⁰ to R ²² are as defined above.

In a preferred aspect, the present invention relates to the androgen receptor modulating compounds of the general formulas (I) to (V) shown above, wherein R ¹ to R ²⁸ , Y, Z, m, n and o all have the same definition as given above. Provided are pharmaceutical compositions containing an effective amount.

In another preferred aspect, the present invention relates to administering to a patient an effective amount of a compound of the general formulas (I) to (V) shown above, wherein R ¹ to R ²⁸ , Y and Z all have the same definition as given above. Characterized by modulating a process mediated by androgen receptors.

The compounds of the present invention can be synthesized as pharmaceutically acceptable salts for inclusion in various pharmaceutical compositions. Pharmaceutically acceptable salts as used herein include hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, citric acid, maleic acid, acetic acid, lactic acid, nicotinic acid, succinic acid, oxalic acid, phosphoric acid, malonic acid, salicylic acid, phenylacetic acid , Stearic acid, pyridine, ammonium, piperazine, diethylamine, nicotinamide, formic acid, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic acid, methylamino, methanesulfonic acid, picric acid, tartaric acid, triethyl Salts with amino, dimethylamino and tris (hydroxymethyl) aminomethane, including but not limited to these. Additional pharmaceutically acceptable salts are known to those skilled in the art.

AR agonists, partial agonists and antagonist compounds of the invention include, but are not limited to, acne, male baldness, androgen replacement therapy, hydroponics, hirsutism, hematopoiesis, hypogonadism, prostatic hyperplasia, prostate cancer and hydraulic pressure It is useful in the treatment of various hormone-dependent cancers and as anabolic agent.

While compounds of the present invention are typically applied as selective agonists, partial agonists or antagonists, it will be understood by those skilled in the art that compounds with mixed steroid receptor profiles may be desirable in some cases. For example, the use of PR agents (ie progestins) in female contraception often leads to side effects such as increased water retention and acne redness. In this case, compounds that preferentially act as PR agents but also exhibit some AR and MR modulatory activity would be useful. Specifically, the mixed MR effect is useful for adjusting the water balance in the body, and the AR effect can control any acne flare-up that appears.

It will also be appreciated by those skilled in the art that the compounds of the present invention, including pharmaceutical compositions and formulations containing the compounds of the present invention, can be used in a variety of combination therapies to treat the conditions and diseases described above. That is, the compounds of the present invention include chemotherapeutic agents such as cytostatic and cytotoxic agents, immunomodulators such as interferon, interleukin, growth hormone and other cytokines, hormone therapy, surgery and radiation therapy (except these It may be used in combination with other hormones and other therapies.

Representative AR modulator compounds (ie, agonists and antagonists) according to the present invention include (R / S) -6,7,7a, 11-tetrahydro-7a-methyl-4-trifluoromethyl-2-pyridono [ 5,6-g] pyrrolidino [1,2-a] quinoline; (R / S) -3-Fluoro-6,7,7a, 11-tetrahydro-7a-methyl-4-trifluoromethyl-2-pyridino [5,6-g] pyrrolidino [1, 2-a] quinoline; (R / S) -6,7,7a, 11-tetrahydro-1,7a-dimethyl-4-trifluoromethyl-2-pyridino [5,6-g] pyrrolidino [1,2-a ] Quinoline; (R / S) -3-fluoro-6,7,7a, 11-tetrahydro-1,7a-dimethyl-4-trifluoromethyl-2-pyridono [5,6-g] pyrrolidino [ 1,2-a] quinoline; 11- (trifluoromethyl) -9-pyridono [6,5-i] zoloridine; 8-methyl-11- (trifluoromethyl) -9-pyridono [6,5-i] zurolidine; 7-fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 6-difluoromethyl-7-fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-8-pyridono [5,6-g] quinoline; 7-fluoro-1,2,3,4-tetrahydro-2,2,9-trimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 6-difluoromethyl-7-fluoro-1,2,3,4-tetrahydro-2,2,9-trimethyl-8-pyridono [5,6-g] quinoline; 7-fluoro-1,2,3,4-tetrahydro-1,2,2,9-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 6-difluoromethyl-7-fluoro-1,2,3,4-tetrahydro-1,2,2,9-tetramethyl-8-pyridono [5,6-g] quinoline; 7-fluoro-1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 7-fluoro-1,2,3,4-tetrahydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 1,10- [1,3-dihydro-3-oxo- (2,1-isoxazolyl)]-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6 -Trifluoromethyl-8-pyridono [5,6-g] quinoline; 7-fluoro-1,2-dihydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 7-fluoro-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 7-fluoro-1,2,3,4-tetrahydro-2,2,4,9,10-pentamethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 7-fluoro-1,2,3,4-tetrahydro-1,2,2,4,10-pentamethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 1,2,3,4-tetrahydro-1-hydroxy-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 1,2,3,4-tetrahydro-1-hydroxy-2,2,9-trimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 2,2-diethyl-7-fluoro-1,2,3,4-tetrahydro-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; (R / S) -4-ethyl group-formyl-1,2,3,4-tetrahydro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline; (R / S) -4-ethyl-1,2,3,4-tetrahydro-1- (trifluoroacetyl) -6- (trifluoromethyl) -8-pyridono [5,6-g] Quinoline; (R / S) -1-acetyl-4-ethyl-1,2,3,4-tetrahydro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline; (R / S) -4-ethyl-1,2,3,4-tetrahydro-10-nitro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline; 1,2,3,4-tetrahydro-2,2-dimethyl-10-nitro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline; 1,2,3,4-tetrahydro-2,2-dimethyl-7,10-dinitro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline; And (R / S) -4-ethyl-1,2,3,4-tetrahydro-1-nitro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline .

Compounds of the present invention, including groups of heterocyclic nitrogen compounds and derivatives thereof, may be prepared by conventional chemical synthesis methods, for example by modifications of known heterocyclic nitrogen compounds or by a person skilled in the art. It can be obtained by a synthetic method.

The step-by-step reaction sequence for some general schemes for synthesizing the compounds of the present invention is shown below. In each scheme, the R groups (eg R ¹ , R ^2, etc.) correspond to the specific substitution patterns described in the examples. However, it will be understood by those skilled in the art that other functional groups described herein for that position in Formulas (I) to (V) are also included as possible substituents that may be present at corresponding positions in the structure in the scheme. Could be.

The method of Scheme I begins with an acetylide addition reaction to 5-chloro-2-pentanone (Compound 1), for example using ethynyl magnesium bromide. The alcohol is then esterified with the corresponding acetate (compound 2) using, for example, acetic anhydride in pyridine and 4-dimethylaminopyridine. Compound 4 is obtained by continuous propargylation / alkylation of compound 2 with aniline (compound 3) in the presence of a copper (I) or copper (II) salt such as copper (I) and a base such as triethylamine. See, Y. Imada, M. Yuasa, I. Nakamura and S.-I. Murahashi, "Copper (I) -Catalyzed Amination of Propargyl Esters. Selective Synthesis of Propargylamines, 1-Alken-3-yl-amines, and (Z) -Allylamines", J. Org. Chem. 1994, 59, 2282; The description of this document is incorporated herein by reference]. Compound 4 is then ring closed in the presence of a copper catalyst such as copper (I) to afford compound 5 [see N.R. Easton and D.R. Cassady, "A Novel Synthesis of Quinolines and Dihydroquinolines" J. Org. Chem. 1962, 27, 4713 and N.R. Easton and G.F. Hennion, "Metal Catalyst Process for Converting α-Amino-Acetylenes to Dihydroquinoline", US Pat. No. 3,331,846 (1967); The description of this document is incorporated herein by reference].

Orefin is reduced with hydrogen on, for example, a metal catalyst such as palladium on carbon to give compound 6. Compound 6 is nitrated with, for example, fuming nitric acid, followed by a small amount of geometric isomers (compound 7B) separated by reduction of the nitro group, for example, by hydrogen on a metal catalyst such as palladium on carbon. Obtain diamine (Compound 7A). Knorr ring closure of compound 7A with β-ketoesters or hydrated derivatives is carried out, for example, with zinc chloride, to give compound 8 [see, E.T. McBee, O.R. Pierce, H.W. Kilbourne and E.R Wilson, "The Preparation and Reactions of Fluorine-containing Acetoacetic Esters", J. Am. Chem. Soc. 1953, 75, 3152; The description of this document is incorporated herein by reference in connection with the preparation of fluorinated acetoacetate reagents]. The compound of formula 8 may be further modified to a compound of formula 9 by treating compound 8 with a base such as sodium hydride and an alkylating agent such as methyliodide.

The method of Scheme II begins with the nitration of tricyclic tetrahydroquinoline, such as Julolidine, of compound 10, followed by reduction of the nitro group to give aniline, like compound 11. Compound 11 is treated with a β-keto ester such as ethyl 4,4,4-trifluoroacetoacetate and Lewis acid such as zinc chloride (Knorr reaction) to give a tetracyclic quinolinone like compound 12. Quinoline is further functionalized, for example, by treatment with a base such as sodium hydride followed by alkylation of the amide nitrogen by addition of an alkylating agent such as iodomethane to give a compound like compound 13.

The process of Scheme III begins by esterifying propargyl alcohol (formula 14) with, for example, acetic anhydride and 4-dimethylaminopyridine in pyridine (getting compound of formula 15). Alkylation of acetate with aniline (Compound 3) in the presence of a copper (I) or copper (II) salt such as copper (I) and a base such as triethylamine affords the compound of formula (16). The compound of formula 16 is ring closed in the presence of a copper catalyst such as copper (I) to afford the compound of formula 17.

The olefin is reduced with hydrogen over a metal catalyst such as, for example, palladium on carbon to give the compound of formula 18. The compound of formula 18 is nitrated, for example with fuming nitric acid, and then the nitro group is reduced with hydrogen on a metal catalyst, for example palladium on carbon, to yield the compound of formula 19. The knor ring closure of the β-keto ester or hydrated derivative carried out by, for example, zinc chloride with the compound of formula 19 yields the compound of formula 20. The compound of formula 20 can be further transformed into a compound of formula 21 by treating the compound of formula 20 with a base such as sodium hydride and an alkylating agent such as methyliodide. The compound of formula 21 can be further modified, for example, by reductive alkylation with paraformaldehyde and sodium borohydride in acetic acid to yield the compound of formula 22.

The process of Scheme IV begins by acylation of 3-nitroaniline (formula 23) with an acylating agent, for example di-t-butyldicarbonate or trimethylacetylchloride, to afford the compound of formula 24. The nitro group is reduced with hydrogen on a metal catalyst, for example palladium on carbon, to give the corresponding aniline (formula 25). The compound of formula 25 is treated with a catalyst such as acetone and iodine in a method known as Skraup ring closure to give the compound of formula 26 [see R.H.F. Manske and M. Kulka, "The Skraup Synthesis of Quinolines", Organic Reactions 1953, 7, 59; The description of this document is incorporated herein by reference]. Deprotection with acid or base, and the corresponding aniline is then treated with β-keto ester (or corresponding hydrate) in the presence of Lewis acid such as zinc chloride to give the compound of formula 27 as main product. The ring closure of aniline as described above is known as the Knorre ring reaction (see G. Jones, "Pyridines and their Benzo Derivatives: (v) Synthesis"). In Comprehensive Heterocyclic Chemistry, Katritzky, A. R .; Rees, C.W., eds. Pergamon, New York, 1984, Vol 2, chap. 2.08, pp 421-426. The quinolinone nitrogen may then be alkylated by, for example, treatment with sodium hydride and then with iodomethane to give the compound of formula 28. Likewise, the compound of formula 29 can be obtained by alkylating the quinoline nitrogen with, for example, paraformaldehyde and sodium cyanoborohydride.

The method of Scheme V involves the reduction of C (3) -C (4) olefins of the compound of formula 27 to give tetrahydroquinoline of formula 30, which reaction is carried out, for example, using hydrogen on palladium on carbon. By hydrogenation or by cationic methods using, for example, trifluoroacetic acid and triethylsilane.

The method of Scheme VI includes oxidizing both the quinoline nitrogen and the C (10) alkyl group of the compound of formula 30 and then ring closing and removing water to yield the compound of formula 31. This reaction can be carried out by treating a compound of formula 30 (R ¹ = alkyl, preferably methyl) with an oxygen transfer agent such as hydrogen peroxide or a combination of oxygen transfer agents in the presence of peracetic acid to give the compound of formula 31 .

The method of Scheme VII includes alkylation of one or two nitrogen atoms of the compound of formula 30. The quinolinone nitrogen may be optionally alkylated by treatment with a base such as sodium hydride followed by an alkylating agent such as methyliodide to yield the compound of formula 32. Quinoline nitrogen can be selectively alkylated, for example, by reductive alkylation with paraformaldehyde in the presence of sodium cyanoborohydride and acetic acid to yield the compound of formula 33. Subsequently, the quinoline nitrogen of the compound of formula 32 may be reductively alkylated in a similar manner to converting compound 30 to compound 33, or the quinolinone nitrogen of the compound of formula 33 may be equivalent to converting compound 30 to compound 32. It can be alkylated in a similar manner. These methods yield the compound of formula 34.

The process of Scheme VIII begins with the reaction of the quinoline nitrogen atom of the compound of formula 20 with an oxygen transfer agent such as hydrogen peroxide or a mixture of oxygen transfer agents in the presence of peracetic acid to give the compound of formula 35. The quinolinone nitrogen can then be alkylated, for example by treatment with sodium hydride and methyliodide, to afford the compound of formula 36.

The process of Scheme IX begins with the reaction of aniline (formula 37) with an unsaturated acid, for example acrylic acid, followed by a ring closure reaction, for example mediated by polyphosphoric acid, to give 4-quinolinone. The nitrogen atom is then protected by treatment with a base, for example 4-dimethyl aminopyridine, and then an acylating agent such as di-t-butyldicarbonate is added to give a compound of formula 38. For example, an organomagnesium or organolithium reagent is added with ethylmagnesium bromide to obtain an alcohol. The alcohol is reduced, for example by hydrogen on palladium on carbon, followed by deprotection of nitrogen atoms to give the compound of formula 39. The compound of formula 39 is nitrated, for example by reacting nitric acid in the presence of sulfuric acid, and then the nitro group is reduced with, for example, hydrogen on palladium on carbon, to yield 7-amino-1,2,3,4 Tetrahydroquinoline is obtained. Knorr ring closure using, for example, β-keto esters carried out by zinc chloride, affords the compound of formula 41. The compound of formula 41 can be further modified to a compound of formula 42 by acylation of quinoline nitrogen, which can be carried out by one of two methods. The compound of formula 41 is treated with an acid chloride, for example acetyl chloride, followed by a base, for example potassium carbonate, to give a compound of formula 42. Alternatively, the compounds of formula 41 can be treated with anhydrides, for example trifluoroacetic anhydride, to likewise obtain compounds of formula 42.

The process of Scheme X involves the reaction of a compound of formula 43, for example with nitric acid, in the presence of sulfuric acid, to give compounds of structures 44, 45 and 46, for example.

Compounds of the invention also include racemates, geometric isomers, and mixtures of these compounds, including isotopically-labeled and radio-labelled compounds. These isomers can be separated by standard separation techniques including fractional crystallization and chiral column chromatography.

As mentioned above, the steroid modulator compounds of the present invention are useful in treating a biological condition or disease described herein in a mammal, more preferably a human patient, in combination with a pharmaceutically acceptable carrier. Pharmaceutical compositions may be provided. The particular carrier used in such pharmaceutical compositions may take various forms depending on the mode of administration desired, eg, intravenous, oral, topical, suppository or parenteral administration.

To prepare the compositions in oral liquid dosage forms (eg, suspending agents, elixirs and solutions), typical pharmaceutical media such as water, glycols, oils, alcohols, perfumes, preservatives, colorants and the like can be used. Likewise, when preparing oral solid dosage forms (eg powders, tablets and capsules), carriers such as starch, sugars, diluents, granulating agents, suspending agents, binders, disintegrating agents and the like may be used. Tablets and capsules are the most preferred oral dosage forms of the pharmaceutical compositions of the present invention because of their ease of administration.

For parenteral administration, other components that aid in dissolution or act as a preservative may include sterile water. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like are used.

For topical administration, the compounds of the present invention can be formulated using non-irritant, wettable bases such as ointments or creams. Examples of suitable ointments include petrolatum, a combination of petrolatum and volatile silicones, lanolin, and water in an oil emulsion such as Eucerin ^™ , Beiersdorf. Examples of suitable cream bases include Nivea ^TM Cream (Beiersdorf), Cold Cream (USP), Perpose Cream (Purpose Cream ^TM , Johnson & Johnson), Hydrophilic Ointment (USP) and Lubriderm ^TM , Warner- Lambert).

Pharmaceutical compositions and compounds of the invention generally range from about 1 μg to about 500 mg, more preferably from about 10 μg / kg to about 25 mg / kg, most preferably from about 20 μg / kg to about 100 mg / kg of body weight. It is administered in unit dosage form (eg tablets, capsules, etc.) at the dose of. As will be appreciated by those skilled in the art, the specific amount of the pharmaceutical composition according to the invention to be administered to a patient is not limited to these, including but not limited to the desired biological activity, the patient's condition and resistance to the drug. It depends on the factors.

The compounds of the invention also have utility as ligands for use in tests to determine the presence of AR in the cell background or extract when radio- or isotope-labeled. They are particularly useful because of their ability to selectively activate androgen receptors and thus can be used to determine the presence of such receptors in the presence of other steroid receptors or related intracellular receptors.

Due to the selective specificity of the compounds of the present invention for steroid receptors, these compounds can be used to purify samples of steroid receptors in vitro. This purification process involves mixing a sample containing a steroid receptor with one or more compounds of the invention to allow the compound to bind to the receptor of choice, followed by separation of the bound ligand / receptor combination by techniques known to those skilled in the art. By separation. These techniques include, among others, column separation, filtration, centrifugation, tagging and physical separation methods, and antibody complexation.

The compounds and pharmaceutical compositions of the present invention can advantageously be used in the treatment of the diseases and conditions described herein. In this regard, the compounds and compositions of the present invention include, but are not limited to, especially acne, male baldness, androgenic hormone therapy, myelopathy, hirsutism, hematopoiesis, hypogonadism, prostate hypertrophy, prostate cancer, and breast cancer It is useful as a modulator of male sex steroid-dependent diseases and conditions and as an anabolic agent for the treatment of various hormone-dependent cancers and the like.

The compounds and pharmaceutical compositions of the present invention have a number of advantages over previously known steroidal and nonsteroidal compounds.

In addition, the compounds and pharmaceutical compositions of the present invention have a number of advantages over previously known steroid modulator compounds. For example, the compounds of the present invention are preferably AR at a concentration of less than 100 nM, more preferably at a concentration of less than 50 nM, even more preferably at a concentration of less than 20 nM, most preferably at a concentration of 10 nM or less. It is a very potent AR activator showing 50% maximal activation of. In addition, selective compounds of the invention are generally found in compound mifepristone (RU486; Roussel Uclaf), a known PR antagonist that exhibits undesirable cross-reactivity to GR and AR, limiting its use for long-term chronic administration. Does not exhibit undesirable cross-reactivity with other steroid receptors, as is. In addition, since the compound of the present invention is a small organic molecular compound, it is easier to synthesize, provides greater stability, and can be more easily administered in oral dosage form than other known steroid compounds.

The invention is explained in more detail with reference to the following non-limiting examples.

Example 1

(R / S) -6,7,7a, 11-tetrahydro-7a-methyl-4-trifluoromethyl-2-pyridono [5,6-g] pyrrolidino [1,2-a] quinoline (Compound 101, structural formula 8 of Scheme I, R ^One If = H)

(R / S) -6-chloro-3-methylhex-1-yn-3-ylacetate (Compound 2)

In a 1 L three-necked round bottom flask equipped with an addition funnel, a solution of 5-chloro-2-pentanone (33.1 g, 274 mmol) in THF (140 mL) was added at -78 ° C. over 0.5 h at ethylmagnesium bromide 564 ml, 282 mmol, 1.03 equiv) of 0.5 M solution). The internal temperature rose to -30 ° C during the addition period. The mixture was warmed to 0 ° C. and stirred for 1 h and then poured into a cold mixture of ether (400 mL) and 1N NaHSO ₄ (400 mL). The aqueous layer was extracted with ether (2 × 200 mL), the combined organic layers washed with brine, dried (MgSO ₄ ), filtered and concentrated to give 42 g of brown oil. The product was transferred to a 250 ml round bottom flask, pyridine (27 ml) and acetic anhydride (36.4 g, 356 mmol, 1.3 equiv) were added and the flask was cooled to 0 ° C. DMAP (1.67 g, 13.7 mmol, 5%) was added and the solution was stirred for 2 days and then treated with MeOH (10 mL). After 1 hour, the solution was poured into a cold mixture of ether (250 mL) and 2N NaHSO ₄ (250 mL). The aqueous layer was extracted with ether (250 mL), the combined organic layers washed with brine (250 mL), dried (MgSO ₄ ), filtered and concentrated to give a brown oil. Distillation gave 30.5 g (58.8%) of compound 2 as a colorless oil at bp 79-8 ° C (@ 10 mmHg). Data for compound 2: ¹ H NMR (400 MHz, CDCl ₃ ) 3.52-3.65 (m, 2H), 2.57 (s, 1H), 1.85-2.15 (m, 4H), 2.04 (s, 3H), 1.71 (s , 3H).

(R / S) -2-ethynyl-2-methyl-1-phenylpyrrolidine (Compound 4)

Aniline (5.43 g, 58.3 mmol, 1.07 equiv), copper chloride (I) (0.528 g, 5.33 mmol, 0.098 equiv) in THF (110 mL) in a 250 mL three-neck round bottom flask equipped with a water cooled reflux condenser; A mixture of triethylamine (5.90 g, 58.3 mmol, 1.07 equiv) was added to 6-chloro-3-methylhex-1-yn-3-ylacetate (10.2 g, 54.3 mmol) in THF (10 mL) over 5 minutes. Treated with. The mixture was heated at reflux for 5 hours, cooled to room temperature and then poured into a mixture of EtOAc (100 mL) and saturated NH ₄ Cl (100 mL). The aqueous layer was extracted with EtOAc (100 mL). The extract was washed with brine (100 mL), dried (MgSO ₄ ) filtered and concentrated to give a brown oil. This was purified by flash chromatography (7 × 20 cm column, hexanes: EtOAc, 19: 1) to give 6.35 g (63%) of compound 4 as a pale golden oil. Data for compound 4: Rf 0.32 (19: 1 hexanes: EtOAc); ¹ H NMR (400 MHz, CDCl ₃ ) 7.20-7.28 (m, 2H), 6.95 (d, J = 8.1, 2H), 6.72 (t, J = 7.2, 1H), 3.43-3.52 (m, 1H), 3.35 -3.43 (m, 1H), 2.40-2.50 (m, 1H), 2.40 (s, 1H), 2.05-2.17 (m, 2H), 1.92-2.02 (m, 1H), 1.62 (s, 3H).

(R / S) -6a, 10-Dihydro-6a-methyl-pyrrolidino [1,2-a] quinoline (Compound 5)

In a 100 ml round bottom flask equipped with a water cooling condenser, a mixture of compound 4 (1.85 g, 10.0 mmol) and copper chloride (I) in THF (40 ml) was heated at reflux for 10 hours, and then cooled to room temperature. Pour into a mixture of EtOAc (75 mL) and saturated NH ₄ Cl (75 mL). The aqueous layer was extracted with EtOAc (75 mL). The extract was washed with brine (75 mL), dried (MgSO ₄ ) filtered and concentrated to give a brown oil. This was purified by flash chromatography (5 × 15 cm column, hexanes: EtOAc, 24: 1) to give 1.37 g (74%) of compound 5 as a light amber oil. Data for compound 5: Rf 0.37 (24: 1 hexanes: EtOAc); ¹ H NMR (400 MHz, CDCl ₃ ) 7.06 (td, J = 7.9, 1.0, 1H), 6.92 (dd, J = 7.3, 0.9, 1H), 6.55 (t, J = 7.3, 1H), 6.37 (d, J = 8.0, 1H), 6.27 (d, J = 9.6, 1H), 5.62 (d, J = 9.6, 1H), 3.40-3.50 (m, 1H), 3.28-3.38 (m, 1H), 1.85-2.05 (m, 4 H), 1.08 (s, 3 H).

5,6,6a, 10-tetrahydro-6a-methyl-pyrrolidino [1,2-a] quinoline (Compound 6)

Hydrogen gas was flowed through a mixture of compound 5 (1.37 g, 7.39 mmol) and 10% Pd / C (68 mg, 5%) in EtOAc (15 mL) in a 100 mL round bottom flask and placed under a hydrogen balloon. After 4 days the mixture was filtered through Celite and concentrated to yield 1.36 g (98.6%) of compound 6 as a colorless oil. Data for compound 6: ¹ H NMR (400 MHz, CDCl ₃ ) 7.07 (t, J = 7.7, 1H), 7.03 (d, J = 7.4, 1H), 6.55 (td, J = 7.3, 0.9, 1H), 6.41 (d, J = 8.0 Hz, 1H), 3.46 (td, J = 9.1, 2.1, 1H), 3.19 (q, J = 9.1 Hz, 1H), 2.86-2.96 (m, 1H), 2.72 (ddd, J = 16.5, 5.1, 1.9), 2.05-2.20 (m, 1H), 1.88-2.08 (m, 3H), 1.60 (td, J = 12.0, 7.8, 1H), 1.42 (td, J = 13.2, 5.1, 1H), 1.04 (s, 3H).

(R / S) -5,6,6a, 10-tetrahydro-6a-methyl-2-nitropyrrolidino [1,2-a] quinoline

A solution of compound 6 (1.21 g, 6.47 mmol) in concentrated sulfuric acid (12.9 mL) in a 25 mL round bottom flask was cooled to −5 ° C. and treated dropwise with fuming nitric acid (0.26 mL, 6.5 mmol) over 3 minutes. The red solution was stirred for 20 minutes and then carefully poured into a cold mixture of CH ₂ Cl ₂ (100 mL) and saturated K ₂ CO ₃ (100 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 100 mL), the combined organic layers washed with phosphate buffer (pH 7, 100 mL), dried (MgSO ₄ ), filtered and concentrated to give an orange oil. This was purified by flash chromatography (5 × 12 cm column, hexane: EtOAc, 9: 1) to give (R / S) -5,6,6a, 10-tetrahydro-6a-methyl-2-nitro- as an orange oil. 1.11 g (74%) of pyrrolidino [1,2-a] -quinoline were obtained. Data for (R / S) -5,6,6a, 10-Tetrahydro-6a-methyl-2-nitro-pyrrolidino [1,2-a] quinoline: Rf 0.39 (9: 1 hexanes: EtOAc) ; ¹ H NMR (400 MHz, CDCl ₃ ) 7.38 (dd, 8.1, 2.3, 1H), 7.18 (d, J = 2.3, 1H), 7.09 (d, J = 8.1, 1H), 3.52 (td, J = 9.2, 1.9, 1H), 3.25 (q, J = 9.2, 1H), 2.88-2.98 (m, 1H), 2.78-2.88 (m, 1H), 2.15-2.25 (m, 1H), 1.95-2.15 (m, 3H ), 1.64 (td, J = 12.1, 7.8, 1H), 1.41 (td, J = 13.2, 5.2, 1H), 1.07 (s, 3H).

(R / S) -2-Amino-5,6,6a, 10-tetrahydro-6a-methyl-pyrrolidino [1,2-a] quinoline (Compound 7)

(R / S) -5,6,6a, 10-tetrahydro-6a-methyl-2-nitro-pyrrolidino [1,2 in EtOAc (2.2 mL) and EtOH (2.2 mL) in a 25 mL round bottom flask. -a] Hydrogen gas was perfused with a mixture of quinoline (1.02 g, 4.37 mmol) and 10% Pd / C (51 mg, 5%) and then placed under hydrogen atmosphere. After 16 h the mixture was filtered through celite and concentrated to give a colorless oil. This was purified by flash chromatography (5 × 12 cm column, hexanes: EtOAc, 7: 3) to give 589 mg (67%) of the desired compound 7A as a colorless oil. In addition, 89 mg (10%) of the regioisomer compound 7B were also isolated as a colorless oil. Data for compound 7A: Rf 0.34 (7: 3 hexanes: EtOAc); ¹ H NMR (400 MHz, CDCl ₃ ) 6.81 (d, J = 7.7, 1H), 5.95 (dd, J = 7.7, 2.2, 1H), 5.79 (d, J = 2.1, 1H), 3.46 (broad s, 2H ), 3.40 (td, J = 9.1, 1.7, 1H), 3.16 (q, J = 8.9, 1H), 2.75-2.85 (m, 1H), 2.62 (dd, J = 16.1, 3.8, 1H), 2.06- 2.18 (m, 1H), 1.85-2.05 (m, 3H), 1.57 (td, J = 12.0, 7.9, 1H), 1.39 (td, J = 13.0, 5.1, 1H), 1.02 (s, 3H). Data for compound 7B: Rf 0.45 (7: 3 hexanes: EtOAc); ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.91 (t, J = 7.9, 1H), 6.04 (d, J = 7.8, 1H), 5.96 (d, J = 8.1, 1H), 3.50 (broad s, 2H) , 3.40 (td, J = 9.0, 2.2, 1H), 3.23 (q, J = 8.7, 1H), 2.4-2.6 (m, 2H), 1.75-2.15 (m, 4H), 1.55-1.65 (m, 1H ), 1.45 (td, J = 12.5, 6.7, 1H), 1.00 (s, 3H).

(R / S) -6,7,7a, 11-tetrahydro-7a-methyl-4-trifluoromethyl-2-pyridono [5,6-g] pyrrolidino [1,2-a] quinoline (Compound 101, structural formula 8 of Scheme I, R ^One If = H)

Compound 7 (512 mg, 2.56 mmol), ethyl 4,4,4-trifluoroacetoacetate (518 mg, 2.82 mmol, 1.1 equiv) and 4 angstrom molecular sieve (260 mgs, in benzene (25.6 mL) in a 100 mL round bottom flask 50%) suspension was treated with ZnCl ₂ (523 mg, 3.83 mmol, 1.5 equiv). The mixture was heated at reflux for 1 hour and then treated with benzene (15 mL) and isopropanol (5 mL) to disperse the precipitate and heated at reflux for 3 hours. The mixture was treated with p-TsOH (190 mg, 1.00 mmol, 0.39 equiv), heated at reflux for 2 h and then cooled to 0 ° C. and poured into a mixture of EtOAc (200 mL) and water (200 mL). The molecular sieves were filtered, the organic layer was washed with brine (100 mL), dried (MgSO ₄ ), filtered and concentrated to give a light brown solid. This was purified by flash chromatography (5 × 12 cm column, CH ₂ Cl ₂ : EtOAc, 3: 2) to yield 320 mg (39%) of impure compound 101 together with 130 mg (16%) of compound 101 as a yellow solid. . Data for Compound 101: Rf 0.15 (1: 1: 1 EtOAc: CH ₂ Cl ₂ : hexane): ¹ H NMR (400 MHz, Acetone-d ₆ ) 10.54 (s, 1H), 7.34 (s, 1H), 6.42 (s, 1H), 6.36 (s, 1H), 3.52 (t, J = 9.7, 1H), 3.28 (q, J = 9.6, 1H), 2.92-3.05 (m, 1H), 2.80-2.90 (m, 1H), 2.18-2.30 (m, 1H), 2.00-2.20 (m, 3H), 1.68 (td, J = 12.1, 7.9, 1H), 1.46 (td, J = 13.3, 5.1, 1H), 1.14 (s , 3H).

Example 2

(R / S) -3-Fluoro-6,7,7a, 11-tetrahydro-7a-methyl-4-trifluoromethyl-2-pyridino [5,6-g] pyrrolidino [1, 2-a] quinoline (Compound 102, formula 8 of Scheme I, R ^One If = F)

Ethyl 2,4,4,4-tetrafluoro-3,3-dihydroxybutanoate (Scheme I)

A suspension of ethyltrifluoroacetate (31.6 g, 223 mmol, 1.44 equiv) and NaH (60% mineral oil suspension 7.79 g, 195 mmol, 1.05 equiv, washed with 20 mL pentane) in a 100 mL round bottom flask at 6O < 0 > C for 6 hours Treated with ethylfluoroacetate over (16.4 g, 154 mmol). The addition was stopped when the release of H ₂ was no longer observed. The mixture was heated at 50 ° C. for 2 h and stirred at rt overnight then poured into a mixture of ice (100 g), concentrated H ₂ SO ₄ (19.5 mL) and ether (200 mL). The aqueous layer was extracted with ether (200 mL). The combined organic layers were washed with phosphate buffer (pH 7, 50 mL) and brine (50 mL), dried (MgSO ₄ ), filtered and concentrated to afford a two-phase oil. The lower layer was removed and distilled to give 15.1 g of a colorless liquid at bp 30-31 ° C. (@ 15 mmHg). The oil was crystallized at 0 ° C. to give 5.76 g (18%) of ethyl 2,4,4,4-tetrafluoro-3,3-dihydroxybutanoate as a white solid. Data for ethyl 2,4,4,4-tetrafluoro-3,3-dihydroxybutanoate: ¹ H NMR (400 MHz, CDCl ₃ ) 5.06 (d, J = 47.7, 1H), 4.80 (broad s, 1H), 4.40 (q, J = 7.2, 2H), 4.07 (broad s, 1H), 1.39 (t, J = 7.2, 3H).

Compound 7 (122 mg, 0.609 mmol), ethyl 2,4,4,4-tetrafluoro-3,3-dihydroxybutanoate in benzene (1.2 ml) in a 15 ml round bottom flask equipped with a water cooled condenser (147 mg, 0.670 mmol, 1.1 equiv) and a suspension of 4 Angstrom molecular sieves (120 mgs, 100%) were treated with ZnCl ₂ (124 mg, 0.913 mmol, 1.5 equiv). The mixture was heated at reflux for 6 hours and then treated with p-TsOH (23 mg, 0.12 mmol, 0.20 equiv) and EtOH (0.3 mL). After refluxing for 2 hours, the mixture was poured into a mixture of EtOAc (50 mL) and water (25 mL), filtered through celite and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and concentrated to give a light brown solid. This was purified by flash chromatography (3.5 × 15 cm column, CH ₂ Cl ₂ : MeOH, 23: 2) to yield 77 mg (37%) of compound 102 as a yellow solid. Data for compound 102: Rf 0.54 (CH ₂ Cl ₂ : MeOH, 23: 2); ¹ H NMR (400 MHz, CDCl ₃ ) 11.29 (s, 1H), 7.41 (s, 1H), 6.17 (s, 1H), 3.53 (t, J = 9.5, 1H), 3.30 (q, J = 9.2, 1H ), 2.95-3.05 (m, 1H), 2.77-2.86 (m, 1H), 2.15-2.25 (m, 1H), 2.03-2.15 (m, 2H), 2.00 (dd, J = 11.9, 6.8, 1H) , 1.60-1.70 (m, 1 H), 1.46 (td, J = 13.3, 4.9, 1 H), 1.10 (s, 3H).

Example 3

(R / S) -6,7,7a, 11-tetrahydro-1,7a-dimethyl-4-trifluoromethyl-2-pyridino [5,6-g] pyrrolidino [1,2-a ] Quinoline (Compound 103, structure 9 of Scheme I, R ^One If = H)

In a 25 ml round bottom flask a mixture of compound 101 (73 mg, 0.23 mmol) and NaH (60 mg mineral oil dispersion 36 mg, 0.91 mmol, 4 equiv) in THF (3.3 mL) was stirred for 0.5 h and then iodomethane (129 mg, 0.91 mmol, 4 equivalents). Phosphate buffer (pH 7, 20 mL) was added to the mixture to quench and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic worms were washed with brine (20 mL), dried (MgSO ₄ ), filtered and concentrated to give a yellow solid. This was purified by flash chromatography (3 × 15 cm column, CH ₂ Cl ₂ : EtOAc: hexane, 2: 1: 1) to give 31 mg (41%) of compound 103 as a yellow solid. Data for compound 103: Rf 0.52 (2: 1: 1 CH ₂ Cl ₂ : EtOAc: hexane); ¹ H NMR (400 MHz, CDCl ₃ ) 7.44 (s, 1H), 6.71 (s, 1H), 6.12 (s, 1H), 3.67 (s, 3H), 3.56 (t, J = 9.0, 1H), 3.30 ( q, J = 9.2, 1H), 2.95-3.05 (m, 1H), 2.80-2.90 (m, 1H), 2.20-2.32 (m, 1H), 2.08-2.20 (m, 2H), 2.03 (dd, J) = 11.9, 6.8, 1H), 1.68 (td, J = 12.2, 7.9, 1H), 1.48 (td, J = 13.3, 5.1, 1H), 1.13 (s, 3H).

Example 4

(R / S) -3-fluoro-6,7,7a, 11-tetrahydro-1,7a-dimethyl-4-trifluoromethyl-2-pyridono [5,6-g] pyrrolidino [ 1,2-a] quinoline (Compound 104, formula 9 of Scheme I, R ^One If = F)

This compound was prepared in the same manner as described for the preparation of Compound 103 (Example 3), by using Compound 102 (40 mg, 0.12 mmol), NaH (60% mineral oil dispersion 9.3 mg, 0.23 mmol, 2 equivalents) in THF (1.2 mL). ) And iodomethane (33 mg, 0.23 mmol, 2 equiv) to give 4.8 mg (12%) of compound 104 as a yellow solid after chromatography (CH ₂ Cl ₂ : EtOAc, 24: 1). Data for Compound 104: ¹ H NMR (400 MHz, CDCl ₃ ) 7.46 (s, 1 H), 6.11 (s, 1 H), 3.72 (s, 3 H), 3.54 (t, J = 8.8, 1 H), 3.31 (q , J = 9.1, 1H), 2.95-3.07 (m, 1H), 2.80-2.88 (m, 1H), 2.20-2.30 (m, 1H), 2.07-2.22 (m, 2H), 2.03 (dd, J = 12.0, 6.8, 1H), 1.68 (td, J = 12.2, 7.9, 1H), 1.47 (td, J = 13.4, 5.1, 1H), 1.12 (s, 3H).

Example 5

11- (trifluoromethyl) -9-pyridono [6,5-i] zoloridine (Compound 12 of Scheme II)

7-nitrozoloridine

Julolidine (2.12 g, 12.2 mmol) and concentrated sulfuric acid (14 mL) were introduced into a 250 mL round bottom flask. The reaction mixture was cooled to 0 ° C. and 90% nitric acid (0.55 mL, 12 mmol, 1.0 equiv) was added via syringe over a period of 10 minutes. The reaction mixture was stirred for an additional 10 minutes and then poured onto ice (100 g). The resulting suspension was neutralized by slowly adding potassium carbonate (40 g) in equal portions into four portions. The product was extracted with CH ₂ Cl ₂ (3 × 100 mL) and washed with saturated NaHCO ₃ (1 × 100 mL). The combined extracts were dried (MgSO ₄ ), filtered through a pad of celite and concentrated to give a yellow solid (2.68 g, 99%). Data for 7-nitrorulolidine: ¹ H NMR (400 MHz, CDCl ₃ ) 6.99 (d, J = 8.3, 1H), 6.82 (d, J = 8.3, 1H), 3.20 (q, J = 5.7, 4H ), 2.91 (t, J = 6.5, 2H), 2.77 (t, J = 6.4, 2H), 1.94 (m, 4H).

11- (trifluoromethyl) -9-pyridono [6,5-i] zoloridine (Compound 12 of Scheme II)

A solution of 7-nitrozoloridine (0.44 g, 2.0 mmol) in 1: 1 EtOH: EtOAc (20 mL) in a 100 mL round bottom flask was treated with 10% Pd / C (200 mg) and 4 under H ₂ atmosphere. Stir for hours. The reaction mixture was filtered and concentrated to give a red oil (0.37 g) which was dissolved in EtOH (30 mL) and ethyl 4,4,4-trifluoroacetoacetate (0.30 mL) and zinc chloride (0.30 g) Heated to reflux for 12 h. The reaction mixture was poured into H ₂ O (30 mL) and extracted with EtOAc (3 × 30 mL). The extract was washed with H ₂ O (2 × 30 mL) and brine (1 × 30 mL), combined to dryness (MgSO ₄ ), filtered and concentrated. This was purified by silica gel chromatography (CH ₂ Cl ₂ : MeOH, 12: 1) to give compound 12 (0.41 g, 66%) as a yellow solid. Data for compound 12: ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.5 (br s, 1 H), 7.16 (s, 1 H), 6.50 (s, 1 H), 3.40 (m, 4H), 2.99 (t, J = 6.2, 2H), 1.95 (m, 4H), 1.91 (m, 2H).

Example 6

8-methyl-11- (trifluoromethyl) -9-pyridono [6,5-i] zoloridine (Compound 13 of Scheme III)

A solution of compound 12 (32 mg, 0.10 mmol) in DMF (1 mL) was treated with 60% NaH (6 mg, 0.1 mmol, 1 equiv) in a 10 mL round bottom flask followed by MeI (7 mL, 0.1 mmol, 1 equiv) Treated with. The reaction mixture was stirred at room temperature for 6 hours and then poured into H ₂ O (5 mL) and extracted with EtOAc (3 × 6 mL). The extract was washed with H ₂ O (1 × 5 mL) and brine (1 × 6 mL), combined and dried (MgSO ₄ ), filtered and concentrated. The product was purified by silica gel chromatography (CH ₂ Cl ₂ : MeOH, 30: 1) to give compound 13 (3 mg, 10%) as a yellow solid. Data for Compound 13: ¹ H NMR (400 MHz, Acetone-d ₆ ) 7.14 (s, 1 H), 6.44 (s, 1 H), 3.60 (s, 3 H), 3.38 (m, 4 H), 2.98 (t, J = 6.2, 2H), 1.95 (m, 4H), 1.91 (m, 2H).

Example 7

7-Fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 105, Structural Formula 20 of Scheme III) , R ^One = R ² = Me, R ³ Trifluoromethyl, R ⁴ = F

2-methyl-3-butyn-2-yl (phenyl) amine (Scheme 16 of Scheme III, R ^One = R ² If = Me)

A solution of 2-methyl-3-butyn-2-ol (10.0 mL, 0.10 mol, 1.3 equiv) in CH ₂ Cl ₂ (100 mL) in a 500 mL round bottom flask was charged with Et ₃ N (15.0 mL, 0.107 mol, 1.4 Equivalent), acetic anhydride (11.6 mL, 0.12 mol, 1.5 equiv) and DMAP (0.61 g, 5.0 mmol, 5.0 mol%) in turn. The reaction mixture was stirred at room temperature for 2 hours and then poured into saturated NH ₄ Cl (60 mL). The layers were separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 100 mL). The organic layer was washed with 1N HCl (2 × 100 mL), combined dried (MgSO ₄ ), filtered through a pad of celite and distilled to remove volatiles (<45 ° C. distillate). The residue was dissolved in THF (100 mL) and slowly added aniline (7.00 mL, 77 mmol) via syringe followed by addition of CuCl (0.76 g, 10 mol%). The reaction mixture was heated at reflux for 3 hours. The resulting red solution was cooled to room temperature, most of the volatiles were removed in vacuo, and the residue was diluted with EtOAc (120 mL). The solution was washed with saturated NH ₄ Cl (2 × 100 mL) and brine (1 × 100 mL). The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated. The product was purified by silica gel chromatography (hexane: EtOAc, 16: 1) to give 10.5 g (87%) of 2-methyl-3-butyn-2-yl (phenyl) amine as a pale yellow liquid. Data for 2-methyl-3-butyn-2-yl (phenyl) amine: ¹ H NMR (400 MHz, CDCl ₃ ) 7.20 (t, J = 7.7, 2H), 6.95 (d, J = 7.7, 2H), 6.80 (t, J = 7.7, 1 H), 3.65 (br s, 1 H), 2.36 (s, 1 H), 1.61 (s, 6 H).

1,2-dihydro-2,2-dimethylquinoline (Formula 17 of Scheme III, where R ¹ = R ² = Me)

A solution of 2-methyl-3-butyn-2-yl (phenyl) amine (24.3 g, 152 mmol) in THF (200 mL) in a 1 L round bottom flask was treated with CuCl (1.70 g, 11 mol%) and refluxed for 14 h. Under heating. The reaction mixture was cooled to room temperature, filtered and most of THF was removed in vacuo. The residue was poured into saturated NH ₄ Cl (200 mL) and extracted with EtOAc (3 × 250 mL). The extract was washed with saturated NH ₄ Cl (1 × 200 mL) and brine (1 × 200 mL), combined, dried (MgSO ₄ ), filtered through a pad of celite and concentrated to give an orange oil. This was purified by silica gel chromatography (hexane: EtOAc, 40: 1) to give 18.0 g (74%) of quinoline as a pale yellow oil. Data for 1,2-dihydro-2,2-dimethylquinoline: ¹ H NMR (400 MHz, CDCl ₃ ) 6.95 (t, J = 7.7, 1H), 6.87 (d, J = 7.3, 1H), 6.57 ( t, J = 7.3, 1H), 6.40 (d, J = 7.7, 1H), 6.25 (d, J = 9.7, 1H), 5.46 (d, J = 9.7, 1H), 3.63 (br s, 1H), 1.31 (s, 6 H).

1,2,3,4-tetrahydro-2,2-dimethylquinoline (formula 18 in Scheme III, where R ¹ = R ² = methyl)

The resulting solution of dihydroquinoline (16.2 g) in 1: 1 EtOH: EtOAc (300 mL) in a 1 L round bottom flask was treated with 10% Pd / C (1.05 g) and stirred under hydrogen atmosphere. The reaction was monitored by ¹ H NMR and was complete after 4 hours. The reaction mixture was purged and filtered through a pad of celite, then the pad was washed with EtOAc (200 mL). The filtrate was concentrated to give 16.2 g (99%) of the desired tetrahydroquinoline as a pale yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) 6.98 (m, 2H), 6.60 (t, J = 7.3, 1H), 6.44 (d, J = 8.0, 1H), 2.77 (t, J = 6.7, 2H), 1.70 (t, J = 6.7, 2H), 1.21 (s, 6H).

1,2,3,4-tetrahydro-2,2-dimethyl-7-nitroquinoline

1,2,3,4-tetrahydro-2,2-dimethylquinoline (6.06 g) in H ₂ SO ₄ (40 mL) was cooled to -5 ° C in a 250 mL round bottom flask. 90% HNO ₃ (1.70 mL) was added dropwise to this slurry over a period of 15 minutes. The reaction mixture was stirred for an additional 15 minutes and poured onto ice (300 g). K ₂ CO ₃ (100 g) was added slowly with vigorous stirring. The residue was extracted with CH ₂ Cl ₂ (3 × 300 mL). The extract was washed with H ₂ O (1 × 200 mL) and saturated NaHCO ₃ (1 × 100 mL), combined and dried (MgSO ₄ ), filtered through a pad of celite and concentrated. The product was purified by silica gel chromatography (hexane: EtOAc, 40: 1 to 20: 1 gradient) to yield 4.40 g (57%) of the desired product as an orange solid. Data for 1,2,3,4-tetrahydro-2,2-dimethyl-7-nitroquinoline: ¹ H NMR (400 MHz, CDCl ₃ ) 7.39 (dd, J = 7.9, 2.2, 1H), 7.27 (d , J = 2.2, 1H), 7.04 (d, J = 7.9, 1H), 3.95 (bs, 1H), 2.81 (t, J = 6.7, 2H), 1.72 (t, J = 6.7, 2H), 1.21 ( s, 6H).

7-amino-1,2,3,4-tetrahydro-2,2-dimethylquinoline (Scheme 19, R in Scheme III) ^One = R ₂ If = Me)

In a 200 ml round bottom flask a solution of 1,2,3,4-tetrahydro-2,2-dimethyl-7-nitroquinoline (1.00 g, 4.84 mmol) in 1.1 EtOH: EtOAc (40 ml) was added with 10% Pd / Treated with C (0.20 g). The reaction mixture was degassed and a H ₂ balloon was attached. The reaction mixture was stirred for 6 hours, degassed, and filtered through a pad of celite. The pad was washed with EtOAc (300 mL). The filtrate was concentrated to give 0.85 g (99%) of crude aniline as a red oil. Data for 7-amino-1,2,3,4-tetrahydro-2,2-dimethylquinoline: ¹ H NMR (400 MHz, CDCl ₃ ) 6.77 (d, J = 7.9, 1H), 6.00 (dd, J = 7.9, 2.2, 1H), 5.81 (d, J = 2.2, 1H), 3.47 (bs, 1H), 3.40 (bs, 2H), 2.66 (t, J = 6.7, 2H), 1.65 (t, J = 6.7, 2H), 1.18 (s, 6H).

7-Fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 105, Structural Formula 20 of Scheme III) , R ^One = R ² = Me, R ³ Trifluoromethyl, R ⁴ If = F)

This compound was prepared in the same manner as described for compound 102 (Example 2), with 7-amino-1,2,3,4-tetrahydro-2,2-dimethylquinoline (269 mg, 1.53 in benzene (15 mL). mmol), ethyl 2,4,4,4-tetrafluoro-3,3-dihydroxybutanoate (370 mg, 1.68 mmol, 1.1 equiv) and ZnCl ₂ (313 mg, 2.30 mmol, 1.5 equiv) Then, p-TsOH (72.8 mg, 0.383 mmol, 0.25 equiv) was used to give 298 mg (62%) of compound 105 after chromatography (CH ₂ Cl ₂ : EtOAc, 5: 2). Data for compound 105: Rf 0.40 (5: 2 CH ₂ Cl ₂ : EtOAc); ¹ H NMR (400 MHz, CDCl ₃ ) 12.49 (s, 1H), 7.39 (s, 1H), 6.45 (s, 1H), 4.46 (s, 1H), 2.83 (t, J = 6.5, 2H), 1.69 ( t, J = 6.6, 2H, 1.20 (s, 6H); elemental calcd. for C ₁₅ H ₁₄ F ₄ N ₂ O: C 57.33, H 4.49, N 8.91; found: C 57.04, H 4.72, N 8.74.

Example 8

6-difluoromethyl-7-fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-8-pyridono [5,6-g] quinoline (Compound 106, structural formula 20 of Scheme III) , R ^One = R ² = Me, R ³ = Difluoromethyl, R ⁴ Jungwoo with = F)

This compound was prepared in the same manner as described for compound 102 (Example 2) with 7-amino-1,2,3,4-tetrahydro-2,2-dimethylquinoline (150 mg, 0.851) in benzene (9.5 mL). mmol), ethyl 2,4,4-trifluoroacetoacetate (172 mg, 0.936 mmol, 1.1 equiv) and 4 angstrom molecular sieve (75 mgs, 50%) and ZnCl ₂ (174 mg, 1.28 mmol, 1.5 equiv) 116 mg after recrystallization from chromatography (CH ₂ Cl ² : MeOH, 23: 2) and EtOAc, followed by preparation using p-TsOH (40.5 mg, 0.213 mmol, 0.25 equiv) and EtOH (0.8 mL) (46%) of compound 106 were obtained. Data for Compound 106: Rf 0.33 (23: 2 CH ₂ Cl ₂ : MeOH): ¹ H NMR (400 MHz, Acetone-d ₆ ) 10.93 (Broad s, 1H), 7.52 (s, 1H), 7.33 (t, J = 53.1, 1H), 6.48 (s, 1H), 5.85 (broad s, 1H), 2.8-2.9 (m, 2H), 1.73 (t, J = 6.7, 2H), 1.25 (s, 6H).

Example 9

7-fluoro-1,2,3,4-tetrahydro-2,2,9-trimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 107, of Scheme III Structural Formula 21, R ^One = R ² = Me, R ³ Trifluoromethyl, R ⁴ = F

This compound was prepared in a similar manner to that described for compound 103 (Example 3), compound 105 (20 mg, 0.064 mmol), NaH (3.6 mg, 0.088 mmol, 1.4 equiv) in THF (1.3 mL) and Preparation from iodomethane (13 mg, 0.089 mmol, 1.4 equiv) afforded 11 mg (51%) of compound 107 as a yellow solid after chromatography (CH ₂ Cl ₂ : EtOAc, 19: 1). The product was recrystallized from ethyl acetate to give 5.6 mg (27%) of a yellow solid. Data for compound 107: Rf 0.29 (CH ₂ Cl ₂ : EtOAc, 19: 1); ¹ H NMR (400 MHz, CDCl ₃ ) 7.44 (s, 1H), 6.32 (s, 1H), 4.32 (broad s, 1H), 3.66 (s, 3H), 2.87 (t, J = 6.6, 2H), 1.76 (t, J = 6.7, 2H), 1.28 (s, 6H).

Example 10

6-difluoromethyl-7-fluoro-1,2,3,4-tetrahydro-2,2,9-trimethyl-8-pyridono [5,6-g] quinoline (Compound 108, of Scheme III Structural Formula 21, R ^One = R ² = Me, R ³ = Difluoromethyl, R ⁴ If = F)

This compound was prepared in a similar manner to that described for compound 103 (Example 3), compound 106 (40 mg, 0.14 mmol), NaH (6.8 mg, 0.17 mmol, 1.4 equiv) in THF (2.6 mL) and Preparation from iodomethane (25 mg, 0.18 mmol, 1.4 equiv) afforded 40 mg (96%) of compound 108 as a yellow solid after chromatography (CH ₂ Cl ₂ : EtOAc, 19: 1). Data for compound 108: Rf 0.53 (CH ₂ Cl ₂ : MeOH, 23: 2); ¹ H NMR (400 MHz, Acetone-d ₆ ) 7.57 (s, 1 H), 7.35 (t, J = 53.0, 1 H), 6.58 (s, 1 H), 5.87 (broad s, 1 H), 3.59 (s, 3 H) 2.87 (t, J = 6.6, 2H), 1.75 (t, J = 6.6, 2H), 1.27 (s, 6H).

Example 11

7-fluoro-1,2,3,4-tetrahydro-1,2,2,9-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 109, Scheme 22, R in Scheme III ^One = R ² = Me, R ³ Trifluoromethyl, R ⁴ If = F)

A mixture of compound 107 (16 mg, 0.049 mmol) and paraformaldehyde (15 mg, 0.49 mmol, 10 equiv) in AcOH (3.0 mL) in a 10 mL round bottom flask was dissolved in sodium cyanoborohydride (15 mg, 0.24 mmol, 4.8 equiv. ). The resulting mixture was stirred at room temperature for 18 hours and then carefully poured into 25% aqueous NaOH (25 mL) and ice to make the mixture strongly alkaline (pH 11). The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 20 mL), the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give a yellow solid. This was purified by flash chromatography (CH ₂ Cl ₂ : EtOAc, 20: 1) to give 15.2 mg (91%) of compound 109 as a yellow solid. Data for compound 109: Rf 0.74 (12: 1 CH ₂ Cl ₂ : MeOH); ¹ H NMR (400 MHz, CDCl ₃ ) 7.39 (s, 1H), 6.28 (s, 1H), 3.74 (s, 3H), 2.95 (s, 3H), 2.82 (t, J = 6.4, 2H), 1.85 ( t, J = 6.4, 2H), 1.32 (s, 6H).

Example 12

6-difluoromethyl-7-fluoro-1,2,3,4-tetrahydro-1,2,2,9-tetramethyl-8-pyridono [5,6-g] quinoline (Compound 110, Scheme 22, R in Scheme III ^One = R ² = Me, R ³ = Difluoromethyl, R ⁴ If = F)

This compound was prepared in a similar manner to that described for Compound 109 (Example 11). Compound 108 (18.4 mg, 0.0590 mmol), paraformaldehyde (17.7 mg, 0,592 mmol, 10 equiv) and sodium in AcOH (3.0 mL) 11 mg (57%) as a yellow solid after purification by flash chromatography (CH ₂ Cl ₂ : EtOAc, 19: 1) by preparation using cyanoborohydride (17.9 mg, 0.286 mmol, 4.8 equiv) Compound 110 was obtained. Data for Compound 110: ¹ H NMR (400 MHz, Acetone-d ₆ ) 7.54 (s, 1H), 7.36 (t, J = 53.0, 1H), 6.48 (s, 1H), 3.71 (s, 3H), 3.02 (s, 3H), 2.75-2.85 (m, 2H), 1.87 (t, J = 6.4, 2H), 1.34 (s, 6H).

Example 13

7-Fluoro-1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 111, formula 27 in Scheme IV, R ^One = H, R ³ Trifluoromethyl, R ⁴ If = F)

1-t-butyloxycarbamoyl-3-nitrobenzene (Scheme 24 of Scheme IV, R ^One = H, R ² = t-BuO)

Di-t-butyldicarbonate (31.60) in a flame-dried 500 ml round-bottom flask containing 3-nitroaniline (formula 23 in Scheme IV, R ¹ = H) (20.0 g, 144.8 mmol) in 150 ml THF. g, 144.8 mmol, 1.00 equiv) was added and the mixture was cooled to 0 ° C. 4-N, N-dimethylaminopyridine (19.46 g, 159.3 mmol, 1.10 equiv) was added portionwise and the mixture was allowed to warm to room temperature overnight. Ethyl acetate (400 mL) was added and the mixture was washed with 1M NaHSO ₄ (aq) (2 × 200 mL) and brine (200 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, hexanes / ethyl acetate, 9: 1) to give 31.4 g (91%) of 1-t-butyloxycarbamoyl-3-nitrobenzene as a white solid. Data for 1-t-butyloxycarbamoyl-3-nitrobenzene: ¹ H NMR (400 MHz, CDCl ₃ ) 8.31 (dd, 1H, J = 2.2, 2.2, 2-H), 7.88 (dd, 1H, J = 7.9, 1.5, 4-H), 7.69 (br d, 1H, J Å 7.8, 6-H), 7.44 (dd, 1H, J = 8.3, 8.1, 5-H), 6.74 (br s, 1H, NH), 1.54 [s, 9H, (CH ₃ ) ₃ CO].

3-t-butyloxycarbamoylaniline (Scheme 25 of Scheme IV, R ^One = H, R ² = t-BuO)

In an oven-dried 1 L round-bottom flask containing 1-t-butyloxycarbamoyl-3-nitrobenzene (20.0 g, 83.9 mmol) in 500 mL of 1: 1 ethyl acetate / ethanol, 10% palladium on carbon (approx. 1 mol%) was added and the mixture was stirred for 6 hours under an atmosphere of H ₂ gas. The reaction mixture was then filtered and concentrated under reduced pressure to yield 17.4 g (quantitative) of 3-t-butyloxycarbamoylaniline as a white oily solid. Data for 3-t-butyloxycarbamoylaniline: ¹ H NMR (400 MHz, CDCl ₃ ) 7.04 (dd, 1H, J = 8.0, 8.0, 5-H), 6.98 (br s, 1H, NH), 6.53 (dd, 1H, J = 7.9, 1.8, 4-H), 6.36 (m, 2H, 6.2-H), 3.66 (br s, 2H, NH ₂ ), 1.51 [s, 9H, (CH ₃ ) ₃ CO ].

7- t-Butyloxycarbamoyl-1,2-dihydro-2,2,4-trimethylquinoline (wherein Scheme 26, R ¹ = H, R ² = t-BuO)

3-t-butyloxycarbamoylaniline (17.4 g, 83.5 mmol), MgSO ₄ (50 g, 5 equiv) and 4-t-butyl catechol (420 mg, 3 mol%) in 120 ml of acetone (approximately 0.75 M in aniline) Iodine (1.07 g, 5 mol%) was added into an oven-dried 1 L round bottom flask containing) and the mixture was heated at reflux for 8 hours. The crude reaction mixture is then cooled to room temperature and filtered through a bed of Celite ^™ on a fritted-glass funnel, which is washed with ethyl acetate and then dried (Na ₂ SO ₄ ) and depressurized Concentrated under. The product was purified by flash column chromatography (silica gel, hexane / ethyl acetate, gradient elution) to give 19.9 g of 7-t-butyloxycarbamoyl-1,2-dihydro-2,2,4-trimethylquinoline as a white solid. (82%) was obtained, which was recrystallized from acetonitrile and further purified to give white needle crystals. Data for 7-t-butyloxycarbamoyl-1,2-dihydro-2,2,4-trimethylquinoline: ¹ H NMR (400 MHz, CDCl ₃ ) 6.93 (d, 1H, J = 8.3, 5-H ), 6.81 (br s, 1H, HNBoc), 6.34 (m, 2H, 6,8-H), 5.21 (d, 1H, J = 0.9, 3-H), 3.71 (br s, 1H, NH), 1.94 (d, 3H, J = 1.0, 4-CH ₃ ), 1.50 [s, 9H, (CH ₃ ) ₃ CO], 1.24 [s, 6H, 2- (CH ₃ ) ₂ ].

7-amino-1,2-dihydro-2,2,4-trimethylquinoline

In an oven-dried 25 ml round bottom flask containing 7-t-butyloxycarbamoyl-1,2-dihydro-2,2,4-trimethylquinoline (400 mg, 1.38 mmol) in 2 ml of dichloromethane at 0 ° C. Trifluoroacetic acid (1.06 mL, 10 equiv) was added and the mixture was allowed to warm to room temperature. After 3 hours at room temperature, the reaction mixture was diluted with 5 mL of dichloromethane and transferred to a 125 mL Erlenmeyer flask and cooled to 0 ° C. before neutralization to pH 8 with saturated aqueous NaHCO ₃ . The above mixture was transferred to a separatory funnel, the layers were separated, the organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give a pale red oil. The crude material thus obtained had a purity of 98% or more according to ¹ H NMR, and the next step was carried out without further purification. The obtained 7-amino-quinoline decomposed to detectable within a few hours when left at room temperature, while the ethanol solution could be stored at -20 ° C for 2-3 days without any substantial side effects on subsequent reactions. Generally, however, the material was stored in bulk form as crystalline Boc-protected amines, and hydrolyzed partly if necessary. Data for 7-amino-1,2-dihydro-2,2,4-trimethylquinoline: ¹ H NMR (400 MHz, CDCl ₃ ) 6.86 (d, 1H, J = 8.2, 5-H), 5.99 (dd , 1H, J = 8.0, 2.3, 6-H), 5.79 (d, 1H, J = 2.0, 8-H), 5.12 (d, 1H, J = 1.4, 3-H), 3.53 (br s, 3H , NH ₂ , NH), 1.93 (d, 3H, J = 1.2, 4-CH ₃ ), 1.24 [s, 6H, 2- (CH ₃ ) ₂ ].

7-Fluoro-1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 111, formula 27 in Scheme IV, R ^One = H, R ³ Trifluoromethyl, R ⁴ If = F)

This compound was prepared in the same manner as described for compound 102 (Example 2) with 7-amino-1,2-dihydro-2,2,4-trimethylquinoline (174 mg, 0.924 mmol) in benzene (9.2 mL). , Ethyl 2,4,4,4-tetrafluoro-3,3-dihydroxybutanoate (205 mg, 1.02 mmol, 1.1 equiv), molecular sieve of 4 angstroms (90 mgs, 52%) and ZnCl ₂ (189 mg , 1.39 mmol, 1.5 equiv) followed by p-TsOH (44 mg, 0.23 mmol, 0.25 equiv) to give 235 mg (76%) after chromatography (CH ₂ Cl ₂ : MeOH, 23: 2) Compound 111 was obtained. Data for compound 111: Rf 0.30 (23: 2 CH ₂ Cl ₂ : MeOH); ¹ H NMR (400 MHz, CDCl ₃ ) 12.58 (broad s, 1H), 7.40 (broad s, 1H), 6.42 (s, 1H), 5.43 (s, 1H), 4.41 (broad s, 1H), 2.02 (d , J = 1.1, 3H), 1.31 (s, 6H).

Example 14

7-fluoro-1,2,3,4-tetrahydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 112, of Scheme V) Structural Formula 30, R ^One = H, R ³ Trifluoromethyl, R ⁴ If = F)

A solution of Compound 111 (4.0 mg, 0.012 mmol) in EtOH (0.49 mL) and EtOAc (0.49 mL) containing 10% Pd / C (1 mg, 25%) was stirred under H ₂ atmosphere for 12 hours. The reaction mixture was filtered through a pad of celite and purified by silica gel chromatography (CH ₂ Cl ₂ : EtOAc, 1: 1) to yield 1.1 mg (28%) of compound 112 as a yellow solid. Data for compound 112: Rf 0.44 (1: 1 CH ₂ Cl ₂ : EtOAc); ¹ H NMR (400 MHz, CDCl ₃ ) 11.94 (broad s, 1H), 7.56 (s, 1H), 6.38 (s, 1H), 4.38 (broad s, 1H), 2.90-3.00 (m, 1H), 1.80 ( dd, J = 12.6, 4.5, 1H), 1.35-1.45 (m, 1H), 1.39 (d, J = 6.7, 3H), 1.28 (s, 3H), 1.22 (s, 3H).

Example 15

1,10- [1,3-dihydro-3-oxo- (2,1-isoxazolyl)]-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6 -Trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 113, formula 31 in Scheme VI, R ³ Trifluoromethyl, R ⁴ If = H)

6-t-butyloxycarbamoyl-2-nitrotoluene (Scheme 24 of Scheme IV, R ^One = Me, R ² = t-BuO)

This compound is grayish white by preparing from 2-methyl-3-nitroaniline (5.00 g, 32.8 mmol) in a manner similar to that described for 1-t-butyloxycarbamoyl-3-nitrobenzene (Example 13). 7.44 g (90%) of the desired carbamate was obtained as a solid. Data for 6-t-butyloxycarbamoyl-2-nitrotoluene: ¹ H NMR (400 MHz, CDCl ₃ ) 7.98 (br d, 1H, JÅ 8.0 Hz, 5-H), 7.51 (br d, 1H, JÅ 8.1 Hz, 3-H), 7.28 (dd, 1H, J = 7.6, 3.4 Hz, 4-H), 6.58 (br s, 1H, NH), 2.34 (s, 3H, 1-CH ₃ ), 1.53 [ s, 9H, (CH ₃ ) ₃ CO].

2-amino-6-t-butyloxycarbamoyltoluene (Scheme 25 of Scheme IV, R ^One = Me, R ² = t-BuO)

This compound was prepared from 6-t-butyloxycarbamoyl-2-nitrotoluene (4.60 g, 18.2 mmol) in a manner similar to that described for 3-t-butyloxycarbamoylaniline (Example 13). This gave 4.00 g (99%) of the desired aniline as a colorless oil. Data for 2-amino-6-t-butyloxycarbamoyltoluene: ¹ H NMR (400 MHz, CDCl ₃ ) 7.04 and 6.81 (BR δ of ABq, 2H, J _AB = 8.0 Hz, J _A = OHz, J _B = 7.9 Hz, 4,5-H), 6.49 (d, 1H, J = 8.3 Hz, 3-H), 6.26 (br s, 1H, NH), 3.61 (br s, 2H, NH ₂ ), 2.02 ( s, 3H, 1-CH ₃ ), 1.51 [s, 9H, (CH ₃ ) ₃ CO].

7-t-butyloxycarbamoyl-1,2-dihydro-2,2,4,8-tetramethylquinoline (Scheme 26, R in Scheme IV) ^One l = Me, R ² = t-BuO)

This compound is 2-amino-6-t-butyl in a similar manner as described for 7-t-butyloxycarbamoyl-1,2-dihydro-2,2,4-trimethylquinoline (Example 13). Preparation from oxycarbamoyltoluene (4.00 g, 18.0 mmol) afforded 4.56 g (84%) of the desired dihydroquinoline as a white solid. Data for 7-t-butyloxycarbamoyl-1,2-dihydro-2,2,4,8-tetramethylquinoline: ¹ H NMR (400 MHz, CDCl ₃ ) 6.94 and 6.88 (br ABq, 2H, J _AB Å 8.3 Hz, 6,5-H), 6.16 (br s, 1 H, HNBoc), 5.27 (s, 1 H, 3-H), 3.61 [br s, 1 H, (CH ₃ ) ₂ CNH], 2.04 ( s, 3H, 8-CH ₃ ), 1.97 (s, 3H, 4-CH ₃ ), 1.50 [s, 9H, (CH ₃ ) ₃ CO], 1.28 [s, 6H, 2- (CH ₃ ) ₂ ] .

7-amino-1,2-dihydro-2,2,4,8-tetramethylquinoline

Removal of Boc protecting group from 7-t-butyloxycarbamoyl-1,2-dihydro-2,2,4,8-tetramethylquinoline (400 mg, 1.32 mmol) was performed with 7-amino-1,2- A similar procedure to that described for dihydro-2,2,4-trimethylquinoline (Example 13) was carried out to give 267 mg (quantitative) of the desired aniline as a pale red oil. Data for 7-amino-1,2-dihydro-2,2,4,8-tetramethylquinoline: ¹ H NMR (400 MHz, CDCl ₃ ) 6.82 (d, 1H, J = 8.2 Hz, 5-H) , 6.08 (d, 1H, J = 8.1 Hz, 6-H), 5.15 (d, 1H, J = 1.2 Hz, 3-H), 3.56 (br s, 3H, NH ₂ , NH), 1.95 (d, 3H, J = 1.2 Hz, 4-CH ₃ ), 1.91 (s, 3H, 8-CH ₃ ), 1.27 [s, 6H, 2- (CH ₃ ) ₂ ].

1.2-dihydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-f] quinoline (Scheme IV of Scheme IV, R ^One = Me, R ² Trifluoromethyl, R ⁴ If = H)

This compound was prepared in the same manner as described for compound 102 (Example 2), 7-amino-1,2-dihydro-2,2,4,8-tetramethylquinoline (100 mg, 0.49 mmol) and ethyl 4 75 mg (47%) of the desired 2-quinolone as a fluorescent yellow solid were obtained by preparing from 4,4-trifluoroacetoacetate (107 mL, 0.73 mmol, 1.5 equiv). Data for 1,2-dihydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-f] quinoline: ¹ H NMR (400 MHz, CDCl ₃ ) 9.23 (br s, 1H, CONH), 7.37 (s, 1H, 5-H), 6.67 (s, 1H, 7-H), 5.45 (s, 1H, 3-H), 4.14 [br s, 1H, (CH ₃ ) ₂ CNH], 2.12 (s, 3H, 10-CH ₃ ), 2.04 (d, 3H, J = 1.1 Hz, 4-CH ₃ ), 1.37 [3, 6H, 2- (CH ₃ ) ₂ ].

1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Scheme V of Scheme V, R ^One = Me, R ² = Trifluoromethyl, R4 = H)

1,2-dihydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-f] quinoline (421 mg, 1.31 in 5 ml of 1,2-dichloroethane) Triethylsilane (1.04 mL, 6.53 mmol, 5.0 equiv) and trifluoroacetic acid (0.50 mL, 6.53 mmol, 5.00 equiv) were added to a 50 mL round bottom flask containing mmol), and the mixture was refluxed using an oil bath. Heated. After 12 hours, the mixture was cooled to 0 ° C. and quenched by addition of saturated aqueous NaHCO ₃ . The resulting biphasic mixture was extracted with EtOAc (50 mL) and the organic solution was washed with 25 mL brine and then dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, hexanes / EtOAc, 2: 1) to give 398 mg (94%) of the desired 3,4-saturated analog as a light fluorescent yellow solid. It was. Data for 1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline: mp 239-40 ° C. ; ¹ H NMR (400 MHz, CDCl ₃ ) 9.70 (br s, 1 H, CONH), 7.50 (s, 1 H, 5-H), 6.68 (s, 1 H, 7-H), 4.13 [br s, 1 H, (CH) ₃ ) ₂ CNH], 3.00 (ddq, 1H, J = 12.9, 12.4, 6.3 Hz, 4-H), 2.15 (s, 3H, 10-CH ₃ ), 1.83 and 1.46 [dd, 2H, J _{AB of} ABq] = 13.0 Hz, J _A = 5.3, 1.6 Hz (3-H _eq ), J _B = 12.9, OHz (3-H _ax )] 1.40 (d, 3H, J = 6.6 Hz, 4-CH ₃ ), 1.36 and 1.25 [2s, 2 × 3H, 2- (CH ₃ ) ₂ ]; ¹³ C NMR (100MHs, CDCl ₃ ) δ 162.5, 144.9, 139.1, 137.1, 124.3, 122.7, 120.9, 113.8, 105.7, 101.6, 50.2, 43.5, 31.8, 28.9, 27.6, 20.1, 9.7: C ₁₇ H ₁₉ F ₃ Elemental Analysis Calcd for N ₂ O: C 62.95, H 5.90, N 8.64; Found: C 63.02, H 6.01, N 8.48.

1,10- [1,3-dihydro-3-oxo- (2,1-isoxazolyl)]-1,2,3,4-tetrahydro-2,2,4-trimethyl-6-trifluoro Romethyl-8-pyridono [5,6-g] quinoline (Compound 113)

1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (50.0 mg in 1.5 mL CH ₃ CN) , 0.15 mmol) was added with 0.8 ml of 30% aqueous H ₂ O ₂ and 0.5 ml of peracetic acid at room temperature. The mixture was stirred at rt for 24 h and then transferred to a separatory funnel containing 40 mL CH ₂ Cl ₂ , 20 mL 10% aqueous Na ₂ S ₂ O _{3 and} 20 mL saturated aqueous NaHCO ₃ . The layers were separated and the organic solution was washed with 20 mL brine and then dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by preparative TLC (silica gel, 500 mm, hexanes / EtOAc, 1: 1) to give 22.3 mg (41%) of oxo-isoxazolyl-derivative as a shiny purple solid. . Data for Compound 113: ¹ H NMR (400 MHz, CDCl ₃ ) 9.70 (br s, 1H, CONH), 7.15 (s, 1H, 5-H), 6.58 (s, 1H, 7-H), 3.08 (m) , 1H, 4-H), 2.13 and 2.07 [dd, 2H of ABq, J _AB = 13.0 Hz, J _A = 5.3, 1.6 Hz (3-H _eq ), J _B = 12.9, OHz (3-H _ax ) ], 1.61 and 1.59 [2 ×, 2 × 3 H, 2- (CH ₃ ) ₂ ], 1.46 (d, 3H, J = 6.6 Hz, 4-CH ₃ ).

Example 16

7-Fluoro-1,2-dihydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 114, structural formula of Scheme IV 27, R ^One = Me, R ³ Trifluoromethyl, R ⁴ If = F)

This compound was prepared from 7-amino-1,2-dihydro-2,2,4,8-tetramethylquinoline (242 mg, 1.19 mmol) in a manner similar to that described for compound 102 (Example 2). This gave compound 114 (206 mg, 51%) as a yellow solid. Data for Compound 114: ¹ H NMR (400 MHz, CDCl ₃ ) 9.78 (br s, 1 H, CONH), 7.40 (s, 1 H, 5-H), 5.46 (s, 1 H, 3-H), 4.10 [br] s, 1H, (CH ₃ ) ₂ CNH], 2.16 (s, 3H, 10-CH ₃ ), 2.04 (s, 3H, 4-CH ₃ ), 1.37 ppm [s, 6H, 2- (CH ₃ ) ₂ ].

Example 17

7-fluoro-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 115, Structural Formula 30 of Scheme V, R ^One = Me, R ³ Trifluoromethyl, R ⁴ If = F)

This compound was added to 1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Example 15). Compound 115 (57 mg, 68%) was obtained as a yellow solid by preparing from compound 114 (84 mg, 0.25 mmol) in a similar manner as described for. Data for Compound 115: ¹ H NMR (400 MHz, CDCl ₃ ) 10.21 (br s, 1 H, CONH), 7.52 (s, 1 H, 5-H), 4.06 [br s, 1 H, (CH ₃ ) ₂ CNH] , 3.00 (ddq, 1H, J = 12.9, 12.4, 6.3 Hz, 4-H), 2.19 (s, 3H, 10-CH ₃ ), 1.83 and 1.46 [dd, 2H, J _AB = 13.0 Hz, J of ABq] _A = 5.3, 1.6 Hz (3-H _eq ), J _B = 12.9, OHz (3-H _ax )], 1,39 (d, 3H, J = 6.6 Hz, 4-CH ₃ ), 1.36 and 1.24 [ 2s, 2 × 3H, 2- (CH ₃ ) ₂ ].

Example 18

7-fluoro-1,2,3,4-tetrahydro-2,2,4,9,10-pentamethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 116, scheme 32 of Scheme VII, R ^One = Me, R ³ Trifluoromethyl, R ⁴ If = F)

This compound is compound 7-fluoro-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6- in the manner described above for methylation of amide nitrogen (Example 3). Compound 116 (18 mg, 85%) was obtained as a yellow solid by making from trifluoromethyl-8-pyridono [5,6-g] quinoline (21 mg, 0.06 mmol). Data for Compound 116: ¹ H NMR (400 MHz, CDCl ₃ ) 7.67 (s, 1H, 5-H), 4.13 (s, 3H, 9-CH ₃ ), 3.98 [br s, 1H, (CH ₃ ) ₂ CNH], 3.00 (ddq, 1H, J = 12,9, 12.4, 6.3 Hz, 4-H), 2.41 (s, 3H, 10-CH ₃ ), 1.83 and 1.54 [dd, 2H, J _{AB of} ABq = 13.0 Hz, J _A = 5.3, 1.6 Hz (3-H _eq ), J _B = 12.9, OHz (3-H _ax )], 1.45 (d, 3H, J = 6.6 Hz, 4-CH ₃ ), 1.36 and 1.25 [2s, 2 × 3H, 2- (CH ₃ ) ₂ ].

Example 19

7-fluoro-1,2,3,4-tetrahydro-1,2,2,4,10-pentamethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 117, Scheme 33 in Scheme VII, R ^One = Me, R ³ Trifluoromethyl, R ⁴ If = F)

This compound was prepared in the manner described above for methylation of quinoline nitrogen (Example 11) 7-fluoro-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoro Compound 117 (17 mg, 91%) was obtained as a yellow solid by making from methyl-8-pyridono [5,6-g] quinoline (18 mg, 0.05 mmol). Data for Compound 117: ¹ H NMR (400 MHz, CDCl ₃ ) 10.34 (br s, 1H, CONH), 7.53 (s, 1H, 5-H), 3.62 (s, 3H, 1-CH ₃ ), 3.00 ( ddq, 1H, J = 12.9, 12.4, 6.3 Hz, 4-H), 2.21 (s, 3H, 10-CH ₃ ), 1.82 and 1.42 [dd, 2H, J _AB = 13.0 Hz of ABq, J _A = 5.3 , 1.6 Hz (3-H _eq ), J _B = 12.9, OHz (3-H _ax )], 1.45 (d, 3H, J = 6.6 Hz, 4-CH ₃ ), 1.33 and 1.25 [2s, 2 × 3H , 2- (CH ₃ ) ₂ ].

Example 20

1,2,3,4-tetrahydro-1-hydroxy-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 118, Scheme 35 in Scheme VIII , R ³ Trifluoromethyl, R ⁴ If = H)

1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Scheme 20, R in Scheme III) ³ Trifluoromethyl, R ⁴ = H)

A solution of 7-amino-1,2,3,4-tetrahydro-2,2-dimethylquinoline (Example 7) (0.85 g) in EtOH (10 mL) was placed in a 50 mL round bottom flask with ethyl 4,4, Treated with 4-trifluoroacetoacetate (0.70 mL, 4.8 mmol) and ZnCl ₂ (0.96 g, 7.0 mmol, 1.5 equiv) and heated at reflux for 18 h. Two main products were observed by TLC (30: 1 CH ₂ Cl ₂ : MeOH, Rf 0.85 and Rf 0.35). The reaction mixture was cooled to room temperature and most of the solvent was removed in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with H ₂ O (3 × 80 mL) and brine (1 × 100 mL). The export was extracted with EtOAc (2 × 100 mL). The combined organic layers were dried (MgSO ₄ ), filtered through a pad of celite and the pad was washed with EtOAc (200 mL). The filtrate was concentrated and purified by silica gel chromatography (CH ₂ Cl ₂ : MeOH, 60: 1 to 15: 1 gradient). 0.74 g (52%) of 1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline as a yellow powder as the lower main band Obtained. Data for 1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline: ¹ H NMR (400 MHz, DMSO d ₆ ) 11.70 (s, 1H), 7.18 (s, 1H), 6.85 (s, 1H), 6.35 (s, 1H), 2.65 (t, J = 6.6, 2H), 1.61 (t, J = 6.6, 2H), 1.17 (s, 6 H).

1,2,3,4-tetrahydro-1-hydroxy-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 118, Scheme 35 in Scheme VIII , R ^One = R ² = Me, R ³ Trifluoromethyl, R ⁴ If = H)

1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (40 mg, 0.13 mmol) in 1.0 mL of CH ₃ CN 0.5 ml of 30% aqueous H ₂ O ₂ and 0.3 ml of peracetic acid were added to a 10 ml round bottom flask. The mixture was stirred at rt for 24 h and then transferred to a separatory funnel containing 30 mL of CH ₂ Cl ₂ , 15 mL of 10% aqueous Na ₂ S ₂ O _{3 and} 15 mL of saturated aqueous NaHCO ₃ . The layers were separated and the organic solution was washed with 15 mL brine and then dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by preparative TLC (silica gel, 500 mm, hexanes / EtOAc, 1: 1) to give 27 mg (65%) of N-hydroxy-derivative as a shiny purple solid. Data for Compound 118: ¹ H NMR (400 MHz, CDCl ₃ ) 9.88 (br s, 1 H, CONH), 7.26 (s, 1 H, 5-H), 7.14 (s, 1 H, 7-H), 6.50 (s , 1H, 10-H), 2.96 (dd, 2H, J = 7.0, 6.1, 4-H), 2.23 (dd, 2H, J = 6.8, 6.8, 3-H), 1.32 [s, 6H, 2- (CH ₃ ) ₂ ].

Example 21

1,2,3,4-tetrahydro-1-hydroxy-2,2,9-trimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 119, of Scheme VIII Structural Formula 36, R ^One = R ² = Me, R ³ Trifluoromethyl, R ⁴ If = H)

This compound was prepared as described above (Example 2) 1,2,3,4-tetrahydro-1-hydroxy-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6- g] Preparation by methylation of quinoline (16 mg, 0.05 mmol) yielded 12 mg (73%) of methylated derivative as a shiny purple solid. Data for Compound 119: ¹ H NMR (400 MHz, CDCl ₃ ) 7.26 (s, 1H, 5-H), 7.18 (s, 1H, 7-H), 6.44 (s, 1H, 10-H), 3.97 ( s, 3H, 9-CH ₃ ), 2.90 (dd, 2H, J = 7.0, 6.1, 4-H), 2.21 (dd, 2H, J = 6.8, 6.8, 3-H), 1.58 [s, 6H, 2- (CH ₃ ) ₂ ].

Example 22

2,2-diethyl-7-fluoro-1,2,3,4-tetrahydro-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 120, structural formula of Scheme III 20, R ^One = R ² = Et, R ³ Trifluoromethyl, R ⁴ If = F)

3-ethylpent-1-yn-3-ylacetate (Scheme 14 of Scheme III, R ^One = R ² If = Et)

A solution of 3-ethyl-1-pentin-3-ol (11.5 g, 102 mmol) in pyridine (10.2 mL) was dissolved in 250 mL round bottom flask with Et ₃ N (15.0 mL, 0.107 mol, 1.4 equivalents), acetic anhydride (13.5 ML, 143 mmol, 1.4 equiv) followed by DMAP (1.25 g, 10.2 mmol, 10.0 mol%). The reaction mixture was stirred at room temperature for 5 days and then treated with MeOH (5 mL) and stirred for 1 hour. The mixture was partitioned between ether (100 mL) and water (100 mL) and the aqueous layer was extracted with ether (100 mL). The organic layer was washed successively with 2N NaHSO ₄ and brine (50 mL), dried (MgSO ₄ ), filtered and concentrated. Distillation under reduced pressure gave 11.8 g (58.8%) of 3-ethylpent-1-yn-3-ylacetate as a colorless oil at bp 38-39 ° C (@ 15 mmHg). Data for 3-ethylpent- ^1- yn-3-ylacetate: ¹ H NMR (400 MHz, CDCl ₃ ) 2.54 (s, 1H), 2.03 (s, 3H), 1.96-2.08 (m, 2H), 1.84 -1.95 (m, 2H), 0.97 (t, J = 7.4, 6H).

2-ethyl-1-pentyn-3-yl (phenyl) amine (Scheme 16 of Scheme III, R ^One = R ² If = Et)

This compound was prepared in a similar manner to that described for compound 4 (Example 1): aniline (4.10 g, 44.0 mmol, 1.1 equiv), CuCl (0.396 g, 4.00 mmol, 10 mol%), 3 in THF (100 mL), 3 Flash chromatography (hexane: EtOAc, 16: 1) by preparation using ethylpent-1-yn- _3- ylacetate (6.17 g, 40 mmol) and Et ₃ N (4.45 g, 44.0 mmol, 1.1 equiv) 5.11 g (68.2%) of 2-ethyl-1-pentyn-3-yl (phenyl) amine were obtained after the preparation. Data for 2-ethyl-1-pentyn-3-yl (phenyl) amine: Rf 0.28 (16: 1 hexanes: EtOAc); ¹ H NMR (400 MHz, CDCl ₃ ) 7.15-7.22 (m, 2H), 6.96 (dd, J = 8.5, 1.0, 2H), 6.78 (t, J = 7.4, 1H), 3.58 (broad s, 1H), 2.44 (s, 1H), 1.75-1.94 (m, 4H), 1.02 (t, J = 7.5, 6H).

2,2-diethyl-1,2-dihydroquinoline (Scheme 17, R in Scheme III) ^One = R ² If = Et)

This compound is 2-ethyl-1- in THF in a manner similar to that described for 1,2-dihydro-2,2-dimethylquinoline (formula 17 in Scheme III, R ¹ = R ² = Me). Flash chromatography (hexane: EtOAc, 16: 1) followed by 2,2-diethyl by preparation from pentin-3-yl (phenyl) amine (3.00g, 16.0mmol) and CuCl (0.190g, 1.92mmol) 1.51 g (50%) of -1,2-dihydroquinoline was obtained. Data for 2,2-diethyl-1,2-dihydroquinoline: Rf 0.44 (16: 1 hexanes: EtOAc); ¹ H NMR (400 MHz, CDCl ₃ ) 6.85-6.95 (m, 1H), 6.81 (d, J = 7.3, 1H), 6.48 (t, J = 7.3, 1H), 6.36 (d, J = 9.9, 1H) , 5.21 (d, J = 9.9, 1H), 3.39 (broad s, 1H), 1.35-1.55 (m, 4H), 0.93 (t, J = 7.5, 6H).

2,2-diethyl-1,2,3,4-tetrahydroquinoline (Scheme 18 of Scheme III, R ^One = R ² If = Et)

This compound was prepared in a manner similar to that described for 1,2,3,4-tetrahydro-2,2-dimethylquinoline (formula 18 in Scheme III, where R ¹ = R ² = Me), with EtOAc (18.7 mL). Flash chromatography (hexane: EtOAc, 97) by preparation from 2,2-diethyl-1,2-dihydroquinoline (1.46 g, 7.80 mmol) and 10% Pd / C (146 mg, 10 wt%) : 3), 1.04 g (70%) of 2,2-diethyl-1,2,3,4-tetrahydroquinoline was obtained. Data for 2,2-diethyl-1,2,3,4-tetrahydroquinoline: Rf 0.43 (24: 1 hexanes: ethyl acetate); ¹ H NMR (400 MHz, CDCl ₃ ) 6.90-7.00 (m, 2H), 6.57 (td, J = 7.3, 1.0, 1H), 6.46 (dd, J = 8.4, 1.0, 1H), 3.63 (broad s, 1H ), 2.72 (t, J = 6.7, 2H), 1.69 (t, J = 6.7, 2H), 1.38-1.53 (m, 4H), 0.86 (t, J = 7.4, 6H).

2,2-diethyl-1,2,3,4-tetrahydro-7-nitroquinoline

This compound was prepared in 2,2-diethyl in concentrated sulfuric acid (10 mL) in a manner similar to that described for 1,2,3,4-tetrahydro-2,2-dimethyl-7-nitroquinoline (Scheme III). Chromatography (hexane: EtOAc, 24: 1) followed by preparation from -1,2,3,4-tetrahydroquinoline (0.955 g, 5.04 mmol) and fuming HNO ₃ (0.32 g, 5.0 mmol) followed by 2, 0.811 g (69%) of 2-diethyl-1,2,3,4-tetrahydro-7-nitroquinoline were obtained. Data for 2,2-diethyl-1,2,3,4-tetrahydro-7-nitroquinoline: Rf 0.43 (24: 1 hexanes: ethyl acetate); ¹ H NMR (400 MHz, CDCl ₃ ) 7.38 (dd, J = 8.3, 2.3, 1H), 7.29 (d, J = 2.3, 1H), 7.04 (d, J = 8.3, 1H), 4.00 (broad s, 1H ), 2.78 (t, J = 6.7, 2H), 1.71 (t, J = 6.7, 2H), 1.38-1.58 (m, 4H), 0.88 (t, J = 7.4, 6H).

7-amino-2,2-diethyl-1,2,3,4-tetrahydroquinoline (Scheme 19, R in Scheme III) ^One = R ² If = Et)

This compound is prepared in a similar manner to that described for 7-amino-1,2,3,4-tetrahydro-2,2-dimethylquinoline (wherein Scheme 19, R ¹ = R ² = Me). 2,2-diethyl-1,2,3,4-tetrahydro-7-nitroquinoline (0.311 g, 1.33 mmol) and 10% Pd / C (31 mg, in EtOAc (4.0 mL) and EtOH (4.0 mL) 10 weight%) to give 255 mg (94%) of 7-amino-2,2-diethyl-1,2,3,4-tetrahydroquinoline. Data for 7-amino-2,2-diethyl-1,2,3,4-tetrahydroquinoline: Rf 0.26 (4: 1 hexanes: ethyl acetate); ¹ H NMR (400 MHz, CDCl ₃ ) 6.77 (d, J = 7.9, 1H), 6.12 (dd, J = 7.9, 1.9, 1H), 6.05 (d, J = 2.0, 1H), 4.68 (broad s, 3H ), 2.62 (t, J = 6.7, 2H), 1.67 (t, J = 6.7, 2H), 1.38-1.55 (m, 4H), 0.85 (t, J = 7.4, 6H).

2,2-diethyl-7-fluoro-1,2,3,4-tetrahydro-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Compound 120, structural formula of Scheme III 20, R ^One , R ² = Et, R ³ Trifluoromethyl, R ⁴ If = F)

This compound was prepared in a similar manner to that described for compound 102 (Example 2) with 7-amino-2,2-diethyl-1,2,3,4-tetrahydroquinoline (0.100 g) in benzene (4.9 mL). , 0.489 mmol), ethyl 2,4,4,4-tetrafluoro-3,3-dihydroxybutanoate (109 mg, 0.538 mmol, 1.1 equiv) and ZnCl ₂ (100 mg, 0.734 mmol, 1.5 equiv) Prepared using p-TsOH (23.2 mg, 0.122 mmol, 0.25 equiv) followed by flash chromatography (CH ₂ Cl ₂ : EtOAc, 5: 2) to give 98 mg (58%) of compound 120 . Data for compound 120: Rf 0.47 (5: 2 CH ₂ Cl ₂ : EtOAc); ¹ H NMR (400 MHz, CDCl ₃ ) 12.03 (broad s, 1H), 7.40 (s, 1H), 6.42 (s, 1H), 4.40 (s, 1H), 2.82 (t, J = 6.6, 2H), 1.74 (t, J = 6.6, 2H), 1.40-1.60 (m, 4H), 0.93 (t, J = 7.4, 6H).

Example 23

(R / S) -4-ethyl-1-formyl-1,2,3,4-tetrahydro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline (Compound 121 , Structural Formula 42 of Scheme IX, where R = H)

1,2,3,4-tetrahydro-4-quinolinone

Aniline (9.78 mL, 0.107 mol), acrylic acid (7.36 mL, 0.107 mol) and toluene (100 mL) were introduced into a 200 mL round bottom flask. The reaction mixture is stirred and heated at 100 ° C. for 16 hours and then cooled to room temperature and the solvent is removed in vacuo to yield 10.34 g (60%) of the desired intermediate carboxylic acid which is used directly without further purification for the next step. It was.

Acid (10.34 g, 0.064 mol) and polyphosphoric acid (200 mL) obtained were introduced into a 500 mL round bottom flask. The reaction mixture was stirred and heated at 100 ° C. for 16 hours. The reaction mixture was cooled to room temperature and poured into 700 mL of a 1: 1 mixture of ice / water and slowly neutralized with NaOH. The aqueous phase was extracted with ethyl acetate (3 × 200 mL), dried (Na ₂ SO ₄ ), and the solvent was removed in vacuo to give a solid residue, which was subjected to flash chromatography (silica gel, hexane / ethyl acetate, 6: 1) to give 6.97 g (76%) of 1,2,3,4-tetrahydro-4-quinolinone. Data for 1,2,3,4-tetrahydro-4-quinolinone: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84 (dd, J = 7.9, 1.1, 1H), 7.28 (ddd, J = 7.9 , 7.9, 1.2, 1H), 6.72 (ddd, J = 8.1, 8.1, 0.8, 1H), 6.66 (d, J = 8.1, 1H), 4.49 (s, 1H), 3.56 (t, J = 6.9, 2H ), 2.69 (t, J = 6.8, 2H).

1-t-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolinone (Scheme 38 of Scheme IX)

10 ml THF at 0 ° C. in a stirred solution of Boc ₂ O (10.05 g, 0.046 mol) and 1,2,3,4-tetrahydro-4-quinolinone (6.16 g, 0.042 mol) in THF (100 mL) DMAP (5.11 g, 0.042 mol) was added slowly. The reaction mixture was stirred overnight, then water (75 mL) was added, and the mixture was extracted with ethyl acetate (2 × 200 mL). The organic phase was dried (Na ₂ SO ₄ ), and the solvent was removed in vacuo to give a solid residue, which was subjected to flash chromatography (silica gel, hexane / ethyl acetate, 8: 2) to 1-t-butyloxycarbonyl- 8.5 g (82%) of 1,2,3,4-tetrahydro-4-quinolinone were obtained. Data for 1-t-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolinone: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (dd, J = 7.9, 1.7, 1H ), 7.76 (d, J = 8.4, 1H), 7.49 (ddd, J = 7.5, 7.5, 1.7, 1H), 7.15 (ddd, J = 8.0, 8.0, 0.9, 1H), 4.15 (t, J = 6.3 , 2H), 2.76 (t, J = 6.6, 2H), 1.55 (s, 9H).

(R / S) -1-t-Butyloxycarbonyl-4-ethyl-1,2,3,4-tetrahydro-4-hydroxyquinoline

1-t-butyloxy in Et ₂ O (4 mL) at -10 ° C. in a flame-dried 25 mL round bottom flask containing ethylmagnesium bromide (4.0 mL of 3.0 M solution in Et ₂ O, 12.0 mmol, 3.0 equiv) A solution of carbonyl-1,2,3,4-tetrahydro-4-quinolinone (1.0 g, 4.0 mmol) was added dropwise. The reaction mixture was stirred at −10 ° C. for 15 minutes and then warmed to room temperature over 10 minutes. Then 1.0M solution of NaHSO ₄ (10 mL) was added rapidly. The resulting biphasic mixture was extracted with EtOAc (3 × 10 mL), the combined organic extracts were dried (Na ₂ O ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexane / EtOAc, 4: 1) to give 800 mg (71%) of the desired product as a clear yellow oil (Rf 0.14, hexane / EtOAc, 4: 1). Data for 1-t-butyloxycarbonyl-4-ethyl-1,2,3,4-tetrahydro-4-hydroxyquinoline: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68 (d, 1H, J = 8.4, 8-H), 7.47 (dd, 1H, J = 7.9, 1.7, 5-H), 7.21 (ddd, 1H, J = 7.4, 7.4, 1.6, 6-H), 7.09 (ddd, 1H, J = 7.8, 7.8, 1.1, 7-H), 4.03 (ddd, 1H, J = 12.9, 7.1, 4.7, 2-H), 3.47 (ddd, 1H, J = 13.1, 8.6, 4.3, 2-H) , 2.11 (ddd, 1H, J = 13.5, 8.6, 4.8, 3-H), 1.86 (m, 3H, 3-H, CH ₂ CH ₃ ), 1.52 [s, 9H, C (CH ₃ ) ₃ ], 0.89 (t, 3H, J = 7.5, CH ₃ ).

(R / S) -4-ethyl-1,2,3,4-tetrahydroquinoline (Scheme 39 of Scheme IX)

Contain 1-t-butyloxycarbonyl-4-ethyl-1,2,3,4-tetrahydro-4-hydroxyquinoline (800 mg, 2.88 mmol) in a 1: 1 solution of EtOAc / EtOH (20 mL) To a flame-dried 100 mL round bottom flask was added 10% Pd / C (about 1 mol%) at room temperature. After evacuation and the vessel was perfused with nitrogen three times, one drop of trifluoroacetic acid was added, the vessel was evacuated once more and the mixture was stirred under hydrogen atmosphere for 16 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was transferred with CH ₂ Cl ₂ (3 mL) to a 25 mL round bottom flask and stirred at room temperature. TFA (1.2 mL) was added and the reaction was drained and stirred at rt for 2 h. A solution of saturated NaHCO ₃ (adjusted to pH 9 with 3.0M NaOH) was added until the aqueous phase was about pH 9. The resulting aqueous phase was extracted with CH ₂ Cl ₂ (3 × 10 mL), the combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 351 mg (71%) of a colorless oil, which was air Upon exposure to blue color (Rf 0.40, hexanes / EtOAc, 2: 1). Data for (R / S) -4-ethyl-1,2,3,4-tetrahydroquinoline: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.02 (d, 1H, J = 7.6, 8-H), 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-H), 6.47 (d, 1H, J = 7.9, 5- H), 3.83 (br s, 1H, CH ₂ NH), 3.31 (ddd, 1H, J = 11.3, 11.3, 3.6, 2-H), 3.25 (ddd, 1H, J = 9.7, 9.7, 4.8, 2- H), 2.65 (dddd, 1H, J = 10.1, 5.1, 5.1, 5.1, 4-H), 1.92 (dddd, 1H, J = 9.6, 4.7, 4.7, 4.7, 3-H), 1.82 (m, 1H , 3-H), 1.74 (m, 1H, CH ₂ CH ₃ ), 0.98 (t, 3H, J = 7.4, CH ₃ ).

(R / S) -7-amino-4-ethyl-1,2,3,4-tetrahydroquinoline (Scheme 40 of Scheme IX)

A 25 mL round bottom flask containing (R / S) -4-ethyl-1,2,3,4-tetrahydroquinoline (340 mg, 2.1 mmol) was cooled to -10 ° C and concentrated H ₂ SO ₄ (5 mL). ) Was added slowly. The resulting solution was allowed to warm to room temperature to completely dissolve quinoline, then cool to -10 ° C and stir vigorously. Fuming HNO ₃ (85 μl) was slowly added dropwise and the reaction mixture turned dark red. After 10 minutes the reaction mixture was poured onto crushed ice and diluted with water (5 mL). Saturated NaHCO ₃ (80 mL) was added and the pH was adjusted to pH 9 with 3.0 M NaOH. This aqueous phase was extracted with EtOAc (3 × 75 mL), the combined extracts were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give a dark red oil. This crude was placed in a 250 mL round bottom flask with 1: 1 EtOAc / EtOH (40 mL) and 10% palladium on carbon (about 1 mol%). The vessel was evacuated, perfused with nitrogen three times, stirred under hydrogen atmosphere for 16 hours, filtered, and concentrated under reduced pressure to yield a yellow oil, which was flash chromatography (silica gel, CH ₂ Cl ₂ / methanol, 9: 1). Purification by) yielded 210 mg (57%) of the desired product as a dark yellow oil. Data for (R / S) -7-amino-4-e-1,2,3,4-tetrahydroquinoline: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.81 (d, 1H, J = 8.1, 5 -H), 6.02 (dd, 1H, J = 8.0, 2.2, 6-H), 5.84 (d, 1H, J = 2.3, 8-H), 3.48 (s, 2H, NH ₂ ), 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-H), 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, 3-H), 1.72 (m, 2H, 3-H, CH ₂ CH ₃ ), 1.48 (m, 1H, CH ₂ CH ₃ ), 0.96 (t, 3H, J = 7.4, CH ₃ ).

(R / S) -4-ethyl-1,2,3,4-tetrahydro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline (Scheme 41 of Scheme IX)

Ethyl-4,4 at room temperature in a flame-dried 100 mL round bottom flask containing 7-amino-4-ethyl-1,2,3,4-tetrahydroquinoline (210 mg, 1.19 mmol) in ethanol (20 mL). , 4-trifluoroacetoacetate (190 μl, 1.31 mmol, 1.1 equiv) was added followed by ZnCl ₂ (244 mg, 1.79 mmol, 1.5 equiv). The reaction mixture was heated at reflux for 6 hours, at which time all starting material was consumed (by TLC analysis). The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Dichloromethane (20 mL) was added and the organic phase was washed with saturated NaHCO ₃ (2 × 10 mL) and brine (1 × 10 mL), then dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. This crude product was purified by flash chromatography (silica gel, CH ₂ Cl ₂ / MeOH, 15: 1) to give 24.4 mg (7%) of the desired product as a yellow solid. Data for (R / S) -4-ethyl-1,2,3,4-tetrahydro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline: Rf 0.37 (CH ₂ Cl ₂ / MeOH, 9: 1); ¹ H NMR (400 MHz, CD ₃ OD) δ 7.31 (s, 1H, 5-H), 6.47 (s, 1H, 7-H), 6.37 (s, 1H, 10-H), 3.34 (m, 2H, 2-H), 2.70 (m, 1H, 4-H), 1.88 (m, 2H, 3-H), 1.62 (m, 2H, CH ₂ CH ₃ ), 1.00 (t, 3H, J = 7.5, CH ₃ ).

(R / S) -4-ethyl-1-formyl-1,2,3,4-tetrahydro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline (Compound 121 , Structural Formula 42 of Scheme IX, where R = H)

(R / S) -4-ethyl-1,2,3,4-tetrahydro-6- (trifluoromethyl) -8- in formic acid (0.14 mL, 3.6 mmol, 40 equiv) in a 5 mL round bottom flask. A mixture of pyridono [5,6-g] quilin (27 mg, 0.091 mmol) was treated with acetic anhydride (30 μl, 0.32 mmol, 3.5 equiv) and the reaction mixture was stirred at rt overnight. The mixture was quenched with saturated aqueous NaHCO ₃ (25 mL). The aqueous layer was extracted with EtOAc (3 × 25 mL), the combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated to give 21 mg (70%) of compound 121 as a white solid. Data for compound 121: Rf 0.51 (11.5: 1 CH ₂ Cl ₂ : MeOH); ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.40 (s, 1H, C (O) NH), 8.98 (s, 1H, C (O) H), 7.63 (s, 1H, 5-H), 7.21 (s , 1H, 10-H), 7.01 (s, 1H, 7-H), 3.85-3.95 (m, 1H, 2-H), 3.75-3.85 (m, 1H, 2-H), 2.75-2.85 (m , 1H, 4-H), 1.90-2.05 (m, 2H, 2 × 3-H), 1.70-1.80 (m, 1H, CHCH ₃ ), 1.55-1.65 (m, 1H, CHCH ₃ ), 1.02 (t , J = 7.4 Hz, 3H, CH ₃ ).

Example 24

(R / S) -4-ethyl-1,2,3,4-tetrahydro-1- (trifluoroacetyl) -6- (trifluoromethyl) -8-pyridono [5,6-g] Quinoline (Compound 122, formula 42 of Scheme IX, R = CF ₃  If

(R / S) -4-ethyl-1,2,3,4-tetrahydro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline (11.3) in a 5.0 ml round bottom flask. mg, 0.038 mmol), a mixture of triethylamine (6.4 μl, 0.046 mmol) and CH ₂ Cl ₂ (2.0 mL) were treated with anhydrous trifluoroacetic acid (6.5 μl, 0.046 mmol) and stirred at room temperature for 24 hours. It was. Then the mixture was partitioned between H ₂ O (10 mL) and CH ₂ Cl ₂ (10 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 15 mL), the combined organic layers washed with brine, dried (Na ₂ SO ₄ ) filtered and concentrated to give a yellow solid. This was purified by flash chromatography (2 × 15 cm column, hexanes: EtOAc, 1: 1) to give 7.6 mg (50%) of compound 122 as a pale yellow solid. Data for compound 122: Rf 0.48 (11.5: 1 CH ₂ Cl ₂ : MeOH); ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.72 (Broad s, 1H, C (O) NH), 7.77 (Broad s, 1H, 10-H), 7.67 (s, 1H, 5-H), 7.08 (s , 1H, 7-H), 4.00-4.10 (m, 1H, 2-H), 3.72-3.82 (m, 1H, 2-H), 2.83-2.93 (m, 1H, 4-H), 2.19-2.29 (m, 1H, 3-H), 1.75-1.94 (m, 2H, 3-H, CHCH ₃ ), 1.58-1.67 (m, 1H, CHCH ₃ ), 1.00 (t, J = 7.4 Hz, 3H, CH ₃ ).

Example 25

(R / S) -1-acetyl-4-ethyl-1,2,3,4-tetrahydro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline (Compound 123, Scheme 42 in Scheme IX, where R = Me)

(R / S) -4-ethyl-1,2,3,4-tetrahydro-6- (trifluoromethyl) -8-pyridono [5, in dichloroethane (3.0 mL) in a 25 mL round bottom flask. A mixture of 6-g] quinoline (116 mg, 0.39 mmol, 1.0 equiv) and triethylamine (0.218 mL, 1.56 mmol, 4.0 equiv) was treated by dropwise addition of acetylchloride (0.111 mL, 1.56 mmol, 4.0 equiv), 7 Stir for hours. The mixture was partitioned between H ₂ O (25 mL) and CH ₂ Cl ₂ (25 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 25 mL), the extracts were combined, washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give a yellow solid. ^It was confirmed by ¹ H NMR spectrum that the starting material remained. The crude was treated with triethylamine (0.22 mL, 1.6 mmol, 4.0 equiv) and acetyl chloride (42 μl, 0.58 mmol, 1.5 equiv) in dichloroethane (7.0 mL). After 8 hours, the mixture was partitioned between H ₂ O (25 mL) and CH ₂ Cl ₂ (25 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 25 mL), the extracts were combined washed with brine and dried (Na ₂ SO ₄ ), filtered and concentrated to give a yellow solid. The crude (17.0 mg) was treated with K ₂ CO ₃ (6.9 mg, 0.050 mmol, 1.0 equiv) in MeOH for 15 minutes. The reaction mixture was partitioned with CH ₂ Cl ₂ (10 mL) and pH 7 phosphate buffer (10 mL), dried (Na ₂ SO ₄ ), filtered and concentrated to give a yellow solid. This was purified by semi-preparative HPLC (ODS reverse phase column, 3: 1 MeOH: water) to give 2.4 mg (14%) of compound 123 as a white solid. Data for compound 123: Rf 0.23 (1: 1 hexanes: EtOAc); ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.25 (broad s, 1H, C (O) NH), 7.60 (broad s, 1H, 10-H), 7.58 (s, 1H, 5-H), 6.99 (s , 1H, 7-H), 3.88-3.98 (m, 1H, 2-H), 3.70-3.80 (m, 1H, 2-H), 2.70-2.80 (m, 1H, 4-H), 2.36 (s , 3H, C (O) CH ₃ ), 2.05-2.12 (m, 1H, 3-H), 1.80-1.90 (m, 1H), 1.70-1.80 (m, 1H), 1.60-1.66 (m, 1H) , 1.01 (t, J = 7.4 Hz, 3H, CH ₃ ).

Example 26

(R / S) -4-ethyl-1,2,3,4-tetrahydro-10-nitro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline (Compound 124, Structural Formula 44, R of Scheme X ^One = Et, R ² If = H)

(R / S) -4-ethyl-1,2,3,4-tetrahydro-6- (trifluoromethyl) -8-pyridono in H ₂ SO ₄ (2.0 mL) in a 15 mL round bottom flask [ A mixture of 5,6-g] quinoline (64.7 mg, 0.22 mmol) was cooled to 0 ° C. Fuming HNO ₃ (20.0 μL, 0.44 mmol, 2 equiv) diluted in H ₂ SO ₄ (0.4 mL) was added over 1.2 minutes and warmed to room temperature over 10 minutes. The mixture was poured into a mixture of ice (25 g) and K ₂ CO ₃ (7.0 g). The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 25 mL), the combined organic layers washed with pH 7 phosphate buffer, dried (MgSO ₄ ), filtered and concentrated to give a yellow solid. This was purified by flash chromatography (2 × 15 cm column, CH ₂ Cl ₂ : EtOAc, 9: 1) to give 5.1 mg (6%) of compound 124 as an orange solid. Data for compound 124: Rf 0.29 (9: 1 CH ₂ Cl ₂ : EtOAc); ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.38 (broad s, 1H, C (O) NH), 9.82 (broad s, 1H, NH), 7.48 (s, 1H, 5-H), 6.84 (s, 1H , 7-H), 3.62-3.70 (m, 2H, 2 × 2-H), 2.75-2.84 (m, 1H, 4-H), 1.92-2.02 (m, 2H, 2 × 3-H), 1.59 -1.67 (m, 2H, CH ₂ CH ₃ ), 1.01 (t, J = 7.4 Hz, 3H, CH ₃ ).

Example 27

1,2,3,4-tetrahydro-2,2-dimethyl-10-nitro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline (Compound 125, structural formula of Scheme X 44, R ^One = H, R ² = Me) and 1,2,3,4-tetrahydro-2,2-dimethyl-7,10-dinitro-6- (trifluoromethyl) -8-pyridono [5,6-g] Quinoline (Compound 126, formula 45 of Scheme X, R ^One = H, R ² If = Me)

1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline (Scheme 20, R in Scheme III) ^One , R ² = Me, R ₃ Trifluoromethyl, R ⁴ If = H)

This compound was prepared in a similar manner to that described for Compound 102 (Example 2) with 7-amino-1,2,3,4-tetrahydro-2,2-dimethylquinoline (2.35 g, 12 mmol), ethyl 4, 1,2,3,4-tetrahydro-2,2-dimethyl by preparing from 4,4-trifluoroacetoacetate (2.15 g, 13 mmol, 1.1 equiv) and ZnCl ₂ (2.74 g, 20 mmol, 1.7 equiv) 1.91 g (48%) of -6-trifluoromethyl-8-pyridono [5,6-g] quinoline were obtained. Data for 1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.70 (s, 1H), 7.18 (s, 1H), 6.85 (s, 1H), 6.35 (s, 1H), 2.65 (t, J = 6.6Hz, 2H), 1.61 (t, J = 6.6Hz , 2H), 1.17 (s, 6H).

1,2,3,4-tetrahydro-2,2-dimethyl-10-nitro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline (Compound 125, structural formula of Scheme X 44, R ^One = H, R ² = Me) and 1,2,3,4-tetrahydro-2,2-dimethyl-7,10-dinitro-6- (trifluoromethyl) -8-pyridono [5,6-g] Quinoline (Compound 126, formula 45 of Scheme X, R ^One = H, R ² If = Me)

This compound was prepared in the same manner as described for compound 124 (Example 26) in 1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoro in concentrated H ₂ SO ₄ (1.4 mL). 18 mg (24%) of compound 125 as an orange solid by making from rommethyl-8-pyridono [5,6-g] quinoline (65 mg, 0.22 mmol) and fuming HNO ₃ (26 mL, 0.66 mmol, 3.0 equiv) And 19 mg (22%) of compound 126 as an orange solid. Data for compound 125: Rf 0.38 (11.5: 1 CH ₂ Cl ₂ : MeOH); ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.38 (broad s, 1H, C (O) NH), 9.67 (broad s, 1H, NH), 7.51 (s, 1H, 5-H), 6.83 (s, 1H , 7-H), 2.93 (t, J = 6.6 Hz, 2H, benzyl CH ₂ ), 1.84 (t, J = 6.6 Hz, 2H, 2 × 3-H), 1.44 (s, 6H, 2 × ( CH ₃ ) ₂ ). Data for compound 126: Rf 0.24 (2: 1 nucleic acid: EtOAc); ¹ H NMR (400 MHz, CDCl 3) δ 12.85 (broad s, 1H, C (O) NH), 9.83 (broad s, 1H, NH), 7.53 (s, 1H, 5-H), 2.96 (t, J = 6.7 Hz, 2H, benzyl CH ₂ ), 1.88 (t, J = 6.7 Hz, 2H, 2 × 3-H), 1.47 (s, 6H, 2 × (CH ₃ ) ₂ ).

Example 28

(R / S) -4-ethyl-1,2,3,4-tetrahydro-1-nitro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline (Compound 127, Scheme 46 of reaction Scheme x, R ^One = Et, R ² If = H)

(R / S) -4-ethyl-1,2,3,4-tetrahydro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline (50.0) in a 15 mL round bottom flask. mg, 0.17 mmol) and H ₂ SO ₄ (2.0 mL) were cooled to 2 ° C. Fuming HNO ₃ (15.0 μl, 0.33 mmol, 2 equiv) diluted in H ₂ SO ₄ (0.5 mL) was added over 2.0 min, stirred at 4 ° C. for 45 min, then ice (25 g) and K ₂ CO ₃ (6.0 g) was poured into a mixture. The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 25 mL), the combined organic layers washed with pH 7 phosphate buffer, dried (MgSO ₄ ), filtered and concentrated to give a yellow solid. This was purified by flash chromatography (2 × 15 cm column, CH ₂ Cl ₂ : EtOAc, 9: 1) to give 10.2 mg (18%) of Compound 127 as an orange solid and 8.1 mg (14%) of Compound 124 as an orange solid. Obtained. Data for compound 127: Rf 0.14 (9: 1 CH ₂ Cl ₂ : EtOAc); ¹ H NMR (4000 Hz, CDCl ₃ ) δ 12.32 (broad s, 1H, C (O) NH), 8.17 (s, 1H, 10-H), 7.66 (s, 1H, 5-H), 7.06 (s, 1H, 7-H), 4.09 (dt, J = 15.0, 4.9 Hz, 1H, 2-H), 3.71 (ddd, J = 15.5, 10.0, 6.1 Hz, 1H, 2-H), 2.85-2.92 (m , 1H, 4-H), 2.00-2.10 (m, 2H, 2 × 3-H), 1.63-1.72 (m, 1H, CHCH ₃ ), 1.53-1.61 (m, 1H, CHCH ₃ ), 1.02 (t , J = 7.4 Hz, 3H).

Steroid receptor activity

"Cis-trans" or "Cotran" described in Evans et al., Science, 240: 889-95 (May 13, 1988), the contents of which are incorporated herein by reference. Compounds of the present invention were tested using the "co-transfection" test method to confirm that AR possesses strong and specific activity as agonists, partial agonists and antagonists. This test method is described in detail in US Pat. Nos. 4,981,784 and 5,071,773, the contents of which are incorporated herein by reference.

The coatfection test method provides a method for identifying functional or partial agonists or antagonists that mimic the effects of natural hormones and for quantifying their activity on reactive IR proteins. Here, this courtesy test method mimics an in vivo system in a laboratory. Importantly, the activity in the coatfection test method is highly related to known in vivo activities, so that the coatfection test method serves as a qualitative and quantitative indicator of the in vivo pharmacology of the test compound. T. Berger et al., 41 J. Steroid Biochem. Molec. Biol. 773 (1992), the description of which is incorporated herein by reference.

In the cotfection test method, cDNA cloned to IR (e.g. human PR, AR or GR) under the control of a constitutive promoter (e.g. SV40 promoter) is substantially free of endogenous IRs. It is introduced by transfection into a background cell (a process that induces the cell to absorb a foreign gene). This introduced gene instructs the recipient cell to produce the desired IR protein. The second gene is also introduced (cotfected) into the same cell along with the IR gene. This second gene containing cDNA for a reporter protein, such as firefly luciferase (LUC), is regulated by an appropriate hormone responsive promoter containing a hormone response element (HRE). This reporter plasmid acts as a reporter on the transcriptional-regulatory activity of the target IR. Thus, the reporter acts as a surrogate for the product (mRNA and then protein) normally expressed by the gene under the control of the target receptor and its natural hormones.

Cortfection test methods can detect small molecule agonists or antagonists of target IRs. Exposure of the transfected cells to the agonist ligand compound increases reporter activity in the transfected cells. This activity can be conveniently measured, for example, by increasing luciferase production, which reflects a compound-dependent IR-mediated increase in reporter transcription. Coatfection assays for detecting antagonists are performed in the presence of a constant concentration of agents (eg progesterone for PR) known to induce defined reporter signals. Increasing the expected concentration of the antagonist decreases the reporter signal (eg luciferase production). Thus, the coatfection test method is useful for detecting both agonists and antagonists of specific IRs. In addition, the method does not only whether the compound interacts with a particular IR but also whether the interaction mimics (functionalizes) or blocks (antagonizes) the effect of natural regulatory molecules on target gene expression, and such interactions. The specificity and intensity of the action can be measured.

The activity of selected steroid receptor modulator compounds of the present invention was assessed using the coatfection test and standard IR binding test according to the specific examples below.

Example 29

Court Verification Exam

African green monkey kidney fibroblasts were cultured in the presence of Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% charcoal resin-stripped fetal bovine serum and then trans One day prior to speciation it was transferred to a 96-well microtiter plate.

To measure the AR agonist and antagonist activity of the compounds of the present invention, CV-1 cells were described in Berger et al., 41 J. Steroid Biochem. Mol. Biol., 733 (1992)], were transiently transfected by potassium phosphate co-precipitation with the following plasmids: pRShAR (5 ng / well), HTV-LUC reporter (100 ng / well), pRS β-Gal (50 ng / well) and filler DNA (pGEM; 45 ng / well). Receptor plasmid pRShAR is described in J.A Simental et al., "Transcriptional activation and nuclear targeting signals of the human androgen receptor", 266 J. Biol. Chem., 510 (1991), contains human AR under the structural control of the SV-40 promoter.

Receptor plasmid MTV-LUC contains cDNA for firefly luciferase (LUC) under the control of the long terminal repeat of mouse carcinoma virus (MTV), a conditional promoter containing an androgen response element. Berger et al., Supra. Also, this. PRS-β-Gal encoding the structural expression of E. coli β-galactosidase (β-Gal) was included as an internal control for the evaluation of transfection efficiency and compound toxicity.

After 6 hours of transfection, the medium was removed and the cells washed with phosphate-buffered saline (PBS). Control compound {ie progesterone as PR agonist, mifepristone ((11β, 17β) -11- [4- (dimethylamino) phenyl] -17-hydroxy-17- (1-propynyl) estra-4 as PR antagonist , 9-dien-3-one: RU486; Roussel Uclaf); Active metabolism of dihydrotestosterone (DHT; Sigma Chemical) as an AR agonist and 2-OH-flutamide (2-methyl-N- [4-nitro-3- (trifluoromethyl) phenyl] propanamide as an AR antagonist Products; Schering-Plough); Estradiol (Sigma) as ER agonist and ICI 164,384 (N-butyl-3,17-dihydroxy-N-methyl- (7α, 17β) -estra-1,3,5 (10) -triene as ER antagonist -7-undecamide; ICI Americas); Dexamethasone (Sigma) as GR agonist and RU486 as GR antagonist; And aldosterone (Sigma) as MR agonist and spironolactone (7α- [acetylthio] -17α-hydroxy-3-oxopreg-4-ene-21-carboxylic acid γ-lactone; Sigma) as MR antagonist; and / Alternatively, a medium containing the modulator compound of the present invention at a concentration ranging from 10 ⁻¹² to 10 ⁻⁵ M was added to the cells. Three to four replicates were used for each sample. Transfection and subsequent processing were performed at the Biomek 1000 automated laboratory work station.

After 40 hours, cells were washed with PBS, lysed with Triton X-100-based buffer and LUC and β-Gal activity were measured using a luminometer or spectrophotometer, respectively. The normalized response (NR) for each replicate was calculated as the LUC response / β-Gal rate (where β-Gal rate is β-Gal · 1 × 10 ⁻⁵ / β-Gal incubation time) .

The mean of NR and standard error of mean (SEM) were calculated. Data are shown as the response of the compound compared to the control over the range of dose-response curves. For agonist experiments, the effective concentration (EC ₅₀ ) representing 50% of the maximum response was quantified. Agent efficacy was a function (%) of LUC expression relative to maximal LUC production by the control agent for PR, AR, ER, GR or MR. Antagonist activity was determined by examining the amount of LUC expression at EC ₅₀ concentrations in the presence of fixed amounts of DHT as AR agonist and progesterone as PR agonist. Concentrations of test compounds that inhibited by 50% LUC expression induced by the control agent were quantified (IC ₅₀ ). In addition, the efficacy of the antagonist was measured as a function of maximal inhibition (%).

IR binding test

AR Binding: For whole cell binding assays, COS-1 cells in 96-well microtiter plates containing DMEM-10% FBS were transfected with the following plasmid DNA as described above: pRShAR (2 ng / well ), pRS-β-Gal (50 ng / well) and pGEM (48 ng / well). After 6 hours of transfection, the medium was removed, cells were washed with PBS and fresh medium was added. The next day, the medium was changed to DMEM without serum to remove endogenous ligands that could bind to intracellular receptors.

After 24 hours in serum-free medium, saturation assay to determine K _d for tritiated dihydrotestosterone ( ³ H-DHT) for human AR or competition of ³ H-DHT for AR Competitive binding tests were performed to assess the ability. For saturation analysis, medium containing ³ H-DHT (concentrations ranging from 12 nM to 0.24 nM) in the absence (total binding) or presence (nonspecific binding) of 100-fold molar excess of unlabeled DHT (DMEM-0.2% CA) -FBS) was added to the cells. For competitive binding testing, medium containing 1 nM ³ H-DHT and test compound at concentrations ranging from 10 ⁻¹⁰ to 10 ⁻⁶ M was added to the cells. Three replicates were used for each sample. After 3 hours at 37 ° C., an aliquot of the total binding medium at each concentration of ³ H-DHT was separated to determine the amount of free ³ H-DHT. Residual media was removed, cells were washed three times with PBS to remove unbound ligand and cells were lysed with Triton X-100-Basic Buffer. The lysate was tested for scintillation counter or spectrophotometer and the amount of bound ³ H-DHT and β-Gal activity, respectively.

For saturation analysis, the difference between total and nonspecific binding normalized by β-Gal rate was defined as specific binding. Specific binding was assessed by Scatchard analysis to determine K _d for ³ H-DHT [see, eg, D. Rodbard, "Mathematics and statistics of ligand assays: an illustrated guide" In: J. Langon and JJ Clapp, eds., Ligand Assay, Masson Publishing USA, Inc., New York, pp. 45-99 (1981); The description of this document is incorporated herein by reference]. For competitive testing, data is shown as the amount of ³ H-DHT remaining (% of control in the absence of test compound) over the range of dose-response curves for a given compound. The concentration of test compound that inhibits 50% of the amount of ³ H-DHT bound in the absence of a competitive ligand was quantified after log-logit transformation (IC ₅₀ ). K _i values were determined by substituting the IC ₅₀ values into the Cheng-Prusoff equation as follows:

After correction for nonspecific binding, IC ₅₀ values were determined. IC ₅₀ values are defined as the concentration of the competitive ligand required to reduce specific binding by 50%. IC ₅₀ values were determined on a graph from a log-logit plot of data. K _i values were determined by substituting the IC ₅₀ values, the concentrations of the labeled ligands, and the K _d of the labeled ligands in the Wise-Prusov equation.

The agonist, antagonist and binding activity test results of selected androgen receptor modulator compounds and standard control compounds for AR and cross-reactivity of selected compounds for PR, ER, MR and GR receptors are shown in Table 1-2 below. It was. Efficacy is expressed as the percentage of maximum response observed for each compound relative to the control agent and antagonist compounds mentioned above. Table 1-2 also reported for each compound its antagonist potency or IC ₅₀ (concentration (nM) necessary to reduce maximal response by 50%), its agonist potency or EC ₅₀ (nM).

As can be seen in the tables above, compounds 109 and 112 are highly selective AR antagonists, while compounds 105, 111 and 113 are mixed AR agonists / antagonists. Importantly, these AR compounds have little or no cross reactivity to other sex steroid receptors. In contrast, the known PR antagonist RU486 exhibits strong cross-reactivity to both GR and AR, showing nearly equal titers as both PR and GR antagonists and potent activity as AR antagonists.

Example 30

Mouse Kidney Ornithine Decarboxylase (ODC) Activity As an In Vivo Test to Measure Activity of AR Modulators

Ornithine decarboxylase (ODC) is the first rate limiting enzyme for polyamine synthesis and promotes the conversion of L-ornithine to putrescine while releasing CO ₂ . It is a constitutive enzyme present in all cells and tissues. ODC concentrations are very low in quiescent cells but increase severalfold within hours after exposure to trophic stimuli such as hormones, drugs and growth factors as part of the growth response (G. Scalabrino, et al., “ Polyamines and Mammalian Hormones ", Mol. Cell. Endocrinol. 77: 1-35, 1991.

This enzyme in mouse kidneys is specifically promoted by androgens, but not by estrogens, progesterone or glucocorticoids (see O.A. Janne, et al. "Ornithine Decarboxylase mRNA in Mouse Kidney: A Low Abundancy Gene Product Regulated by Androgens with Rapid kinetics", Ann New York Academy of Sciences 438: 72-84, 1984 and J.F. Catterall, et al. "Regulation of Gene Expression by Androgens in Murine Kidney", Rec. Prog. Hor. Res. 42: 71-109, 1986. Androgen induction of ODC activity and gene expression occurs rapidly and is maximally stimulated within 24 hours of a single dose of testosterone. Therefore, it has been used as an acute test to determine the androgen specific response of compounds including the compounds of the present invention in vivo.

In this test, castrated male ICR mice (˜30 g, 5-6 weeks old) were divided into 4 groups and treated for 1 or 3 days:

1) control vehicle

2) Testosterone Propionate (TP) (0.01-1.0 mg / mouse or 0.3-30 mg / kg subcutaneous)

3) TP (3 mg / kg, subcutaneous) and control compounds or compounds of the invention (30-90 mg / kg, oral / subcutaneous) to demonstrate antagonist activity, or

4) Compounds of the present invention (30-90 mg / kg, oral / subcutaneous) used alone to demonstrate AR agonist activity.

The animals were sacrificed 24 hours after the last dose and a pair of kidneys were harvested and homogenized. The homogenate was centrifuged to obtain a supernatant (cytosol), which was incubated with [ ³ H] ornithine for 1 hour. The activity of this enzyme was determined by titration analysis of [ ³ H] putrescine production rate. The results are expressed as femtomoles of [ ³ H] putrencine formed per hour, per mg of protein. See, R. Djurhuus "Ornithine Decarboxylase (EC4.1.1.17) Assay Based Upon the Retention of Putrescine by a Strong Cation-Exchange Paper ", Anal. Biochem. 113: 352-355, 1981.

AR agent mode:

Testosterone propionate (TP) induced ODC activity in a dose-dependent manner within a dose range of 0.01-1.0 mg / mouse. Even at the highest dose used (1 mg / mouse), the induced ODC activity was not saturated, which was a 700-fold increase compared to castrated controls. Testosterone also showed a similar stimulatory effect on ODC activity with less efficacy compared to TP (see Table 3). However, estradiol (0.02 mg / mouse) or progesterone (1 mg / mouse) did not show any stimulatory activity against this enzyme. The increase in ODC activity is accompanied by an increase in parallel seminal vesicle weight, albeit slightly less. For example, TP (1.0 mg / mouse / day) results in a 700-fold increase in ODC activity while sperm weight increases 4- to 5-fold.

AR antagonist mode:

When testosterone propionate (0.1 mg / mouse) was used to induce enzymatic activity, the control AR antagonists flutamide, cassodex and cyproterone acetate inhibited this induction. Compounds of the present invention showed AR antagonist activity in this test model as shown in Table 4.

Pharmacological and Other Applications

As will be appreciated by those skilled in the art, the androgen receptor modulator compounds of the present invention require AR antagonist or agonist activity and are readily available in pharmacological applications where it is desirable to minimize cross-reactivity with other steroid receptor related IRs. Can be. In vivo applications of the invention include administering the described compounds to a mammal, particularly a human.

The following examples provide specific pharmaceutical composition formulations.

Example 31

Hard gelatin capsules were prepared using the following ingredients:

                                  Volume (mg / capsule)

Compound 101 140

Dried Starch 100

Magnesium Stearate 10

                                     250mg total

The above ingredients were mixed and filled into hard gelatin capsules in an amount of 250 mg.

Tablets were made using the following ingredients:

                                  Volume (mg / tablet)

Compound 101 140

Microcrystalline Cellulose 200

Fumigation Silicon Dioxide 10

Stearic acid 10

                                     360mg total

The ingredients were combined and compressed into tablets weighing 360 mg each.

Tablets containing 60 mg of each active ingredient were prepared as follows:

                                  Volume (mg / tablet)

Compound 101 60

Starch 45

Microcrystalline Cellulose 35

Polyvinylpyrrolidone (PVP)

(With 10% solution in water) 4

Sodium Carboxymethyl Starch (SCMS) 4.5

Magnesium Stearate 0.5

Talc 1.0

                                     150mg total

The active ingredient, starch and cellulose are U.S. Pass the 45 sieve and mix thoroughly. The resulting powder was mixed with a solution of PVP and then U.S. Passed No. 14 body. The granules thus produced are dried at 50 ° C. and U.S. Passed No. 18. U.S. in advance on the granules. SCMS, magnesium stearate and talc passed through No. 60 were added, mixed, and then compressed into tablets to obtain tablets each weighing 150 mg.

Suppositories each containing 225 mg of the active ingredient can be prepared as follows:

       Compound 101 225 mg

       2,000mg saturated fatty acid glyceride

                                  2225 mg total

The active ingredient is U.S. Passed through No. 60 and suspended in pre-melted saturated fatty acid glycerides using the minimum heating required. The mixture was then poured into a standard 2 g volume of suppository mold and cooled.

Intravenous dosage forms can be prepared as follows:

       Compound 101 100mg

       Isotonic saline 1,000ml

       Glycerol 100ml

The compound was dissolved in glycerol and then the solution was slowly diluted with isotonic saline. The solution of the components was administered intravenously to the patient at a rate of 1 ml per minute.

Although descriptions of preferred embodiments and processing conditions are provided according to the condition of the patient, the scope of the invention is not limited thereto or by them. Those skilled in the art can variously modify and replace the present invention without departing from the scope and spirit of the present invention.

Accordingly, an understanding of the scope of the invention is made with reference to the following claims.

Claims (13)

A compound of formula (I), (II), (III), (IV) or (V) In the above formula, R ¹ is hydrogen, F, Cl, Br, or I; R ² is C ₁ -C ₄ alkyl or perhaloalkyl; R ³ is hydrogen; R ⁴ and R ⁵ are each independently hydrogen or C ₁ -C ₄ alkyl; R ⁶ and R ⁷ are each independently hydrogen; R ⁸ is hydrogen or C ₁ -C ₁₂ alkyl; R ⁹ to R ¹⁸ are each independently hydrogen; R ¹⁹ is hydrogen, F, or NO ₂ ; R ²⁴ is hydrogen, C ₁ -C ₄ alkyl, or NO ₂ ; R ²⁵ is hydrogen or C ₁ -C ₁₂ alkyl; R ²⁶ is hydrogen, C ₁ -C ₆ alkyl, NO ₂ , OR ²⁰ , or C (O) R ²⁰ , wherein R ²⁰ is hydrogen, C ₁ -C ₆ alkyl or perfluoroalkyl; R ²⁷ and R ²⁸ are each independently hydrogen or C ₁ -C ₄ alkyl; m is 0 or 1; n is 0 or 1; o is 0 or 1; Y is o or S; Z is NH or NR ²² , wherein R ²² is C ₁ -C ₄ alkyl. The compound of claim 1, which is an androgen receptor modulator. The compound of claim 2, which is an androgen receptor antagonist. The compound of claim 2, which is an androgen receptor agonist. 3. The compound of claim 2, which is an androgen receptor partial agonist. The compound according to claim 2, wherein (R / S) -6,7,7a, 11-tetrahydro-7a-methyl-4-trifluoromethyl-2-pyridino [5,6-g] pyrrolidino [1] , 2-a] quinoline; (R / S) -3-Fluoro-6,7,7a, 11-tetrahydro-7a-bucky-4-trifluoromethyl-2-pyridino [5,6-g] pyrrolidino [1, 2-a] quinoline; (R / S) -6,7,7a, 11-tetrahydro-1,7a-dimethyl-4-trifluoromethyl-2-pyridino [5,6-g] pyrrolidino [1,2-a ] Quinoline; (R / S) -3-fluoro-6,7,7a, 11-tetrahydro-1,7a-dimethyl-4-trifluoromethyl-2-pyridono [5,6-g] pyrrolidino [ 1,2-a] quinoline; 11- (trifluoromethyl) -9-pyridono [6,5-i] zoloridine; 8-methyl-11- (trifluoromethyl) -9-pyridono [6,5-i] zurolidine; 7-fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 6-difluoromethyl-7-fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-8-pyridono [5,6-g] quinoline; 7-fluoro-1,2,3,4-tetrahydro-2,2,9-trimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 6-difluoromethyl-7-fluoro-1,2,3,4-tetrahydro-2,2,9-trimethyl-8-pyridono [5,6-g [quinoline; 7-fluoro-1,2,3,4-tetrahydro-1,2,2,9-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 6-difluoromethyl-7-fluoro-1,2,3,4-tetrahydro-1,2, 2,9-tetramethyl-8-pyridono [5,6-g] quinoline; 7-fluoro-1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 7-fluoro-1,2,3,4-tetrahydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 1,10- [1,3-dihydro-3-oxo- (2,1-isoxazolyl)]-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6 -Trifluoromethyl-8-pyridono [5,6-g] quinoline; 7-fluoro-1,2-dihydro-2,2, 4,10-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 7-fluoro-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 7-fluoro-1,2,3,4-tetrahydro-2,2,4,9,10-pentamethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 7-fluoro-1,2,3,4-tetrahydro-1,2,2,4,10-pentamethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 1,2,3,4-tetrahydro-1-hydroxy-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 1,2,3,4-tetrahydro-1-hydroxy-2,2,9-trimethyl-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; 2,2-diethyl-7-fluoro-1,2,3,4-tetrahydro-6-trifluoromethyl-8-pyridono [5,6-g] quinoline; (R / S) -4-ethyl-1-formyl-1,2,3,4-tetrahydro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline; (R / S) -4-ethyl-1,2,3,4-tetrahydro-1- (trifluoroacetyl) -6- (trifluoromethyl) -8-pyridono [5,6-g] Quinoline; (R / S) -1-acetyl-4-ethyl-1,2,3,4-tetrahydro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline; (R / S) -4-ethyl-1,2,3,4-tetrahydro-10-nitro-6- (trifluoromethyl) -8-pyridono- [5,6-g] quinoline; 1,2,3,4-tetrahydro-2,2-dimethyl-10-nitro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline; 1,2,3,4-tetrahydro-2,2-dimethyl-7,10-dinitro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline; And (R / S) -4-ethyl-1,2,3,4-tetrahydro-1-nitro-6- (trifluoromethyl) -8-pyridono [5,6-g] quinoline Compound selected from among. Treat or control acne, masculine baldness, male hormone replacement therapy, hydroponics, hirsutism, hematopoiesis, hypogonadism, prostate hyperplasia, hormone-dependent cancer containing the compound of claim 1 and a pharmaceutically acceptable carrier Pharmaceutical compositions used as agents. 8. A pharmaceutical composition according to claim 7, formulated for oral, topical, intravenous, suppository or parenteral administration. The pharmaceutical composition of claim 7 wherein the compound is administered to the patient in a unit dose of 1 μg / kg body weight to 500 mg / kg body weight. The pharmaceutical composition of claim 7 wherein the compound is administered to the patient in a unit dose of 10 μg / kg body weight to 250 mg / kg body weight. The pharmaceutical composition of claim 7 wherein the compound is administered to the patient in a unit dose of 20 μg / kg body weight to 100 mg / kg body weight. It is characterized by administering the compound according to claim 1 in vivo in animals other than humans, acne, male baldness, male hormone replacement therapy, hydrocephalus, hirsutism, hematopoiesis, hypogonadism, prostatic hypertrophy, hormone-dependent cancer A method of treating or regulating and using as an assimilation agent. 8. The composition of claim 7, wherein the hormone-dependent cancer is prostate cancer or cancer cancer.