CZ469699A3 - Inhibitors of farnesyl protein transferase - Google Patents

Abstract

Quinoline and benzapine derivatives are disclosed inhibit phamesyl protein transferase (Ftasu) afamesylation of oncogenic protein res. Thus, these compounds are effective as anticancer agents. The compounds are also

Description

Technical field

The present invention relates to compounds that inhibit farnesyl protein transferase and ras protein farnesylation, making them useful against cancer. These compounds are also useful in the treatment of diseases other than cancer, which are associated with ras signaling transduction pathways and which are associated with non-ras CAAX-containing proteins, which are also post-translationally modified with farnesyl protein transferase enzyme. These compounds also function as inhibitors of other prenyltransferases and are therefore effective in the treatment of diseases associated with other prenyl modifications of proteins.

SUMMARY OF THE INVENTION

The group of mammalian ras genes comprises three genes: H-ras, K-ras and N-ras. Ras proteins are a family of hydrolyzing and GTP binding proteins that regulate cell growth and differentiation.

Overproduction of normal ras proteins or mutations that inhibit their GTPase activity may lead to uncontrolled cell division.

in

The transforming activity of ras is dependent on protein localization on plasma membranes. This membrane binding is accomplished through a series of post-translational modifications of cytosolic ras proteins. The first and mandatory step of this sequence is the farnesylation of these proteins. The reaction is catalyzed by the enzyme farnesyl protein transferase (FPT) and the enzyme farnesyl pyrophosphatase (FPP), which serves as a farnesyl group donor in this reaction. The C-terminus of the ras contains a sequence motif labeled "Cys-Aaai-Aaa ₂ -Xaa box (CAAX box) in which Cys is cysteine, Aaa is aliphatic amino acid, and Xaa is serine or methionine. Farnesylation occurs at the cysteinyl residue of the CAAX box (Cys-186), thereby attaching a prenyl group to the protein via a thioether bond.

Broader description of the invention

According to the invention, a compound of formulas I, II

Rg, Rio

Up

(ii) their enantiomers and diastereoisomers and their pharmaceutically acceptable salts, prodrugs and solvates inhibit

S-farnesyl protein transferase, an enzyme involved in ras oncogenic function. In the general formulas I and II and throughout the description, 9 9 99 99

99 9 9 9 9 «· · 9 9 9

9 99 99 9

9 9 9 9 9 9 «9 9999 9 · 99 Unless otherwise stated, symbols are defined as follows:

1, m, r, s and t are 0 or 1; n is 0, 1 or 2;

Y is selected from the group consisting of CHR ¹² , SO 2, CO, CO 2, O, NR ¹³ , SO ² NR ¹⁴ , CONR ¹⁵ , C (NCN), C (NCN) NR ¹⁶ , nr ¹⁷ co, nr ¹⁸ so2, CONR ¹⁹ NR ²⁰ , SO 2 NR ²¹ NR ²² , S (O) (NR ²³ ), S (NR ²⁴ ) (NR ²⁵ ), or is without Y;

Z is selected from the group consisting of CR ¹² , S, SO, SO 2, SO 3, CO, CO 2, O, NR ¹³ , SO ² NR ¹⁴ , CONR ¹⁵ , NR ²⁵ NR ²⁷ , ONR ²⁸ , NR ²⁹ O, NR ³⁰ SO2NR ³¹ , NR ³² SO2, NR ³³ C (NCN), NR ³⁴ C (NCN) NR ³⁵ , nr ³⁶ co, nr ³⁷ conr ³⁸ , NR ³⁹ CO ₂ , OCONR ⁴⁰ , S (O) (NR ⁴¹ ), S (NR ⁴² ) (NR ⁴³ ) or CHR ¹² or without

OF;

R ⁷ , R ⁸ are selected from the group consisting of hydrogen, halogen, nitro, cyano and UR ⁴⁴ ;

U is selected from the group consisting of sulfur atom, oxygen atom, NR ⁴⁵ , CO, SO, SO 2, CO 2, NR ⁴⁶ CO 2, NR ⁴⁷ CONR ⁴⁸ , NR ⁴⁹ SO ₂ ,

NR ⁵⁰ Sat ₂ nr ⁵¹ , Sat ₂ nr ⁵² , NR ⁵³ CO, CONR ⁵⁴ , PO2R ⁵⁵ and PO3R ^! R ⁹ , R ¹⁰ , R ¹² , R ¹³ pl4 pl5 pl® p1 7 _R 18 p2Q ft \ ff \ f Γ \ fi \ fr \ f £ \ f R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ _p 42 _p 43 _y 45 _y 46 _y 47 _y 48 _y 49 R ⁵³ , R ⁵⁴ , r55 R ⁵⁷ , R ⁵⁸ and R ⁵⁹ are selected from

R

R ³⁵ , R ³⁶ , R ³⁷ , p ⁵⁰ R ⁵² 'v ¥ is composed of hydrogen, lower alkyl, aryl, heterocycles, substituted alkyl, aryl or substituted heterocycles; R ¹¹ and R ⁴⁴ are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl , heterocycle, substituted heterocycle, cyano, carboxy, carbamyl (e.g.

CONH ₂ ), a substituted carbamyl group (wherein the nitrogen atom may be substituted with groups selected from hydrogen, alkyl, substituted alkyl, aryl or aralkyl, substituted aryl, heterocycle, substituted heterocycle), alkoxycarbonyl; any two of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ may combine to form a cycloalkyl group; any two of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 taken} together may be oxo, except that when the carbon atom bearing the substituent is part of a double bond;

R, S and T are selected from the group consisting of CH ₂ , CO and

CH (CH ₂ ) _p Q, o. where Q denotes NR ⁵⁷ R ⁵⁸ , OR ⁵⁹ or CN; and p indicates 0, 1 or Z t B, and C, indicates carbon atom, atom oxygen, atom open or atom nitrogen; D indicates carbon atom, atom oxygen, atom open or atom

nitrogen, or is free of D, provided that

1. When l and m are both 0, n is not 0,

2. R ¹¹ may denote a hydrogen atom except that when

Z represents SO, or when Z is oxygen, NR ¹³ or or sulfur atom and carbon atom to which it is attached is part of a double bond or when Y is SO2, CO2, NR ¹⁸ SO 2, S (0) (NR ²³⁾ or S (NR ²⁴ ) (NR ²⁵ ),

3. R ⁴⁴ may be hydrogen, except when U is * SO, SO ₂ , NR ⁴⁶ CO 2 or NR ⁴⁹ SO 2.

Detailed description of the invention

Definitions

The following are definitions of various terms used to describe this invention. These definitions refer to terms as used in this specification unless otherwise limited by special cases, either individually or as part of a larger group.

ΦΦ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

The term "alkyl" refers to straight or branched chain unsubstituted hydrocarbon groups having 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms.

The term "lower alkyl" refers to unsubstituted C 1 -C 4 alkyl groups.

The term "substituted alkyl" refers to an alkyl group which is substituted, for example, with one to four substituents, such as halogen, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, alkyl, aryloxy, aryloxy, aryloxy, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfo nyl, sulfonamido (e.g. SO2NH2), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH2), substituted carbamyl (e.g. CONHalkyl, CONH-aryl, CONH-uralkyl or cases where two substituents are selected on the nitrogen atom alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocycles such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. As mentioned above, where the substituent is further substituted, the substituent is an alkyl group, an alkoxy group, an aryl group, an aralkyl group or a halogen atom.

The term "halogen" refers to a fluorine, chlorine, bromine and iodine atom.

The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring moiety, such as phenyl, naphthyl, biphenyl or biphenyl, each of which may be substituted.

The term "aralkyl" refers to an aryl group attached directly through an alkyl group such as benzyl.

The term "substituted aryl" refers to an aryl group that is substituted, for example, with one to four substituents, such as alkyl; halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyklothioskupina, ureido, nitro, cyano, carboxy , carboxyalkyl, carbamyl, αTkoxycarbonyl, alkylthion, arylthion, alkylsulfonyl, sulfonamide, aryloxy and the like. The substituents may be further substituted with a halogen atom, a hydroxy group, an alkyl group, an alkoxy group, an aryl group,

0 0>

substituted aryl, substituted alkyl or aralkyl.

The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms having one to four double bonds.

The term "substituted alkenyl" refers to alkenyl groups substituted with, for example, one or two substituents such as halogen, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dilakylamino, alkanoylamino, thiol, alkyl, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.

The term "alkynyl" refers to a straight or branched chain hydrocarbon group having one to four triple bonds and containing 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms.

The term "substituted alkynyl" refers to an alkynyl group substituted with a substituent such as halogen, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthio, alkylthion, sulfonyl, thionyl, sulfonyl, sulfonyl, sulfonyl, sulfonyl, sulfonyl, sulfonyl, sulfonyl, sulfonyl; nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocycle, for example imidazolyl, φ · φ · φ φ φ φ φ φ furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.

The term "cycloalkyl" refers to optionally substituted saturated cyclic hydrocarbon ring systems which preferably contain 1 to 3 rings and 3 to 7 carbon atoms in each ring and which may be further condensed with an unsaturated carbocyclic ring of 3 to 7 carbon atoms. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl. Exemplary substituents include one or more of the alkyl groups described above or one or more of the groups described above as alkyl substituents.

The terms "heterocycle," heterocyclic and "heterocyclo" refer to an optionally substituted fully saturated or unsaturated aromatic or non-aromatic cyclic group, for example a monocyclic ring system having 4 to 7 members, a bicyclic ring system having 7 to 11 members, or a tricyclic ring system having 10 to 15 members, wherein the ring system contains at least one heteroatom in the ring containing at least one carbon atom. Each ring of a heteroatom-containing heterocyclic group may have 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxethanyl, pyrazolinyl, imidazolyl, imidazolyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidl, isothiazolinyl, isothiazolinyl, isothiazolinyl, isothiazolinyl, isothiazolinyl , piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, piridyl, N-oxopyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranylsulfone, thiomorpholinyl thiomorpholinyl, thiomorpholinyl thiomorpholinyl, morpholinyl thiomorpholinyl, morpholinyl , 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thiethanyl, thiiranyl, triazinyl and triazolyl and the like.

Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolyl, quinolyl-N-oxide, tetrahydroisoquinolyl, isoquinolyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumaryl, pyrrolidinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl furo [2,3c] pyridyl, furo [3,1b] pyridyl or furo [2,3-b] pyridyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxoquinazolinyl), benzisothiazolyl, benzisoxazolyl, bezodiazinyl, benzofurazanyl , benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, thiindolinyl, pyridinyl, pyridinyl, phthalazinyl, piperazinyl, piperazinyl, piperazinyl, phthalazinyl, piperazine

Exemplary substituents include one or more of the alkyl groups described above or one or more of the groups described above as alkyl substitunets. Also included are smaller heterocycles such as epoxides and aziridines.

9 * 9

9 · 9 9 9

9

9999999 9 · 99.9999

The term heteroatoms includes an oxygen atom, a sulfur atom, and a nitrogen atom.

The ABCD fused ring may be monocyclic or bicyclic, for example of naphthyl or quinolyl.

The compounds of formulas I and II form salts which are also part of the invention. Preferred are pharmaceutically acceptable salts (i.e., non-toxic, physiologically acceptable), although other salts are useful, for example, in the isolation and purification of the compounds of the invention.

The compounds of formulas I and II may form alkali metal salts such as sodium, potassium and lithium, alkaline earth metals such as calcium or magnesium with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as for example, arginine, lysine, and the like. These salts can be obtained, for example, by exchange of carboxylic acid protons, if in the compounds of formulas I and II they contain a carboxylic acid, for the desired ion, in a salt-precipitating medium or in an aqueous medium and subsequent evaporation. Other salts may be formed, as is known to the person skilled in the art.

The compounds of formulas I and II form salts with a variety of organic and inorganic acids. Such salts include salts formed with hydrochloric acid, hydrobromic acid, methanesulfonic acid, hydroxyethanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and a number of others (eg nitrates, phosphates, borates, tartrates, citrates). , succinates, benzoates, ascorbates, salicylates and the like). Such salts can be formed by reacting compounds of formulas I and II in an equivalent amount of acid in a salt-precipitating medium or in an aqueous medium and subsequent evaporation.

·· · · · · · · · · · · ·

In addition, they may be formed by zwitterions (inner salts).

The compounds of formulas I and II may also be in the form of a prodrug. Any compound that in vivo conversion provides a bioactive agent (i.e., a compound of Formula I 'or II) is a prodrug within the scope and spirit of the invention.

For example, a carboxylic acid ester, which is usually formed by esterification of any carboxylic acid functional group, is found on said ring structure (s).

Many forms of drug precursors are well known in the art. As examples of such prodrugs, see:

a) Design of Prodrugs, edited by H. Bundgaard, Elsevier (1985) and Methods in Enzymology, Vol. 42, 309-396, edited by K. Widder et al., Academic Press (1985);

b) Textbook of Drug Design and Development, ed.

Krosgaard-Larsen and H. Bundgaard, Chapter 5, Design and Application of Prodrugs, H. Bundgaard, 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews 8, 1-38 (1992);

d) H. Bundgaard et al., Journal of Pharmaceutical Sciences TT, 285 (1985); and

e) N. Kakeya et al., Chem. Phar. Bull. 32, 692 (1984).

4 * ·· ·· • * 4 4 4 4 4 4

4 * 4 4 4 4 4

4444 44 44

It is further understood that solvates (e.g., hydrates) of the compounds of Formulas I and II are also within the scope of this invention. Solvation methods are generally known in the art.

* Convenient parts

The following parts are preferred for the compounds of this invention:

In compounds of formulas I and II, η 1 or 2.

More preferred are compounds of formulas I and II in which n, is 1 or 2 and "ABCD is a hydrocarbon ring, for example a benzo ring.

Use and utility

The compounds of formulas I and II are inhibitors

S-farnesyl protein transferases. Thus, they are useful in the treatment of various cancers, including, but not limited to, for example:

cancer including bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, and skin cancer; including squamous cell carcinoma;

lymphoid lineage hematopoietic tumors including leukemia, acute lymphatic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkitt's lymphoma;

hematopoietic tumors of the myeloid lineage including acute and chronic myeloid leukemia and promyelocytic leukemia;

tumors of mesenchymal origin including fibrosarcoma and rhabdomyosarcoma;

··········

I · 4 · · <

Other tumors including melanoma, seminoma, teratocarcinoma, neuroblastoma and glioma;

tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma and schwanoma;

tumors of mesenchymal origin including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma;

other tumors including melanoma, xeroderma pigmentosum, keratoacanthoma, seminoma, follicular thyroid carcinoma, and teratocarcinoma.

The compounds of formulas I and II are particularly useful in the treatment of tumors having a high incidence of ras involvement, such as colon, lung and pancreatic tumors. Administration of formulations comprising one (or combination) compound of the invention reduces the development of tumors in mammalian hosts.

The compounds of formulas I and II are also useful in the treatment of non-cancer diseases that are associated with signal transduction pathways operating through the ras gene, such as neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis after angioplasty or chirurugugic cure surgery, hypertrophic scar and endotoxic shock.

The compounds of formulas I and II are also useful as antifungal agents.

The compounds of formulas I and II are also useful in the treatment of diseases associated with non-ras substrates of farnesyltransferase (e.g. nuclear lamin and transducin), which are also post-translationally modified by the enzyme farnesyl protein transferase.

 ·

• 0

00 ·· ··

0 0 0 · · 0 ·

0 · · · 0 · ··· 0 0 0 0 0 0 0 0 · · · ·

0 »00» 0000

The compounds of formulas I and II also act as inhibitors of other prenyltransferases (e.g., geranylgeranyltransferases I and II) and may thus be effective in treating diseases associated with other prenyl modifications (e.g., geranylgeranylation) of proteins (e.g., rap, rab, rac and rho gene products). and so). For example, they may find use as drugs against hepatitis delta virus (HDV) infections, as suggested in recent findings that geranylgeranylation of large HDV delta isoforms is required for productive viral infection (JS Glen et al., Science 256, 1331 (1992)) .

The compounds of formulas I and II also induce or inhibit apoptosis, a physiological process of cell death that is critical to normal development and homeostasis. Alteration of apoptotic pathways contributes to the pathogenesis of various human diseases. Compounds of formulas I and II, as modulators of apoptosis, are useful in the treatment of various human diseases with apoptosis aberration, including cancer (particularly follicular lymphomas, p53 mutation cancers, hormone-dependent breast, prostate and ovarian tumors and precancerous lesions such as but not limited to familial adenomatous polyposis), viral infections (including but not limited to herpesvirus, poxvirus, Epstein-Barr virus, Sindibis virus and adenovirus), autoimmune diseases (including systemic lupus erythematosus, immune-mediated glomerulonephritis, rheumatoid arthritis) , but not limited to, psoriasis, inflammatory bowel disease and autoimmune diabetes mellitus, neurodegenerative diseases (including Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa) , but not limited to spinal muscular atrophy and cerebellar atrophy), AIDS, myelodysplastic syndromes, aplastic anemia, associated ischemic damage

4 4449

4 4

4

44

4 4 4

9 4

4 4 4 4

4 4

4444 • 9 44 • 4 ·

4 4 4 • «0« • · · ·

44 myocardial infarction, cerebrovascular accident and reperfusion, arrhythmia, atherosclerosis, toxin or alcohol-induced liver disease, haematological diseases (including, but not limited to, chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including osteoporosis) and arthritis, but not limited to), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.

The compounds of this invention are also useful in combination with known antitumor and cytotoxic agents, for example topoisomerase I and II inhibitors, antimetabolites, microtubule-affecting agents, agents that bind or integrate into DNA, angiogenesis interfering agents, DNA alkylating agents, hormonal agents, protein kinase inhibitors, ribonuclease reductase inhibitors, mitochondrial respiratory inhibitors, agents affecting the Golgi apparatus, telomerase inhibitors, prenyltransferase inhibitors, cell membrane interacting agents, and treatment including radiation. When formulated as a fixed dose, such combination produces the use of the compounds of the invention within the dosage range described below and other pharmaceutically active agents within its agreed dosage range. The compounds of formulas I and II may be used sequentially with known antitumor and cytotoxic agents and treatment involving radiation when the combination formulation is inappropriate.

Farnesyltransferase assays were performed as described in V. Manne et al., Drug Development Research 34, 121 137 (1995). The compounds of Examples 1 to 13 inhibited farnesyltransferase at IC ₅₀ values between 1 nM and 100 µΜ.

The compounds of the invention may be formulated with a pharmaceutical vehicle or diluent for oral, intravenous or subcutaneous administration. The pharmaceutical preparations may be prepared in a conventional manner using solid or liquid carriers, diluents and excipients suitable for the desired mode of administration. Orally, the compounds may be administered in the form of tablets, capsules, granules, powders, and the like. The compounds are administered in a dosage range of about 0.05 to 200 mg / kg per day, preferably less than 100 mg / kg per day in single or 2-4 divided doses.

Preparation method

Compounds of formulas I and II are prepared according to the following schemes.

* <t ·

Step 1

In Scheme 1, compound 1 is suitably protected with, for example, a tert-butyloxycarbonyl group or an alkylsulfonyl group. The reaction is carried out in an inert organic solvent such as THF at a temperature ranging from -78 ° C to about room temperature in the presence of a base such as sodium hexamethyldisilazide.

Step 2

Compound 2 is reduced by hydrogenation in the presence of a catalyst such as platinum oxide. The reaction is carried out in the presence of an alcohol such as ethanol at about room temperature.

Compound 3 in which R 1 is a halogen atom, such as bromine, can be prepared from compound 3 in which R 1 is a hydrogen atom by reaction with a halogenating agent, such as tetrabutylammonium tribromide, in an inert solvent such as chloroform at about room temperature.

Step 3

Thereafter, the various products undergo reductive alkylation in the presence of an acid, for example acetic acid, a reducing agent, for example NaBH (OAc) ₃ , in an inert organic solvent, for example dichloroethane, at a temperature of about room temperature to 60 ° C. Reductive alkylation can also be carried out using hydrogen and a catalyst such as palladium on carbon in a solvent such as ethanol in the presence of an acid such as acetic acid at about room temperature.

Step 4

In step 4 of Scheme 1, the amine protecting group is removed (for example, Boc using an acid such as TFA in an organic solvent such as methylene chloride).

Step 5

In Step 5 of Scheme 1, the resulting compound is reacted, under standard conditions, with various active alkylating or sulfonylating agents (such as acids under carbodiimide conditions or acid chlorides to form amides; sulfonyl chlorides to form sulfonamides) to form the claimed compound 7, wherein R ₃ denotes a hydrogen atom. Alternatively, compound 5 reacts under standard reductive amination conditions with aldehydes as described in Step 3 of Scheme 1 to give compound 6 wherein R ₃ is not hydrogen. The resulting compound is reacted under standard conditions with various active-acylating or sulfonylating agents as described above to form the claimed compound 7.

00 0 0 0

0 0 0

0 0 ·

0 0 ·

0 0 0

Compound 1 of Scheme 2 can be obtained by the procedure for Compound 3 of Scheme 1. The amine protecting group is removed (for example, Boc using an acid such as TFA in an organic solvent such as ⁷ methylene chloride). The resulting compound 2 reacts under standard conditions with various active acylating and sulfonating agents

-r ', as described in step 5 of Scheme 1, to give compound <3. If compound 2 is treated with an optically active acyl group such as mandelic acid, the resulting diastereomer may be separated by standard purification methods such as e.g. silica gel chromatography. Removal of the acyl group under standard conditions, such as sulfuric acid treatment, may afford a homochiral compound 2. If PG in compound 1 denotes ZR ₂ , then compound 4 may be obtained directly from compound 1. It may then react under standard reductive amination conditions. as described in step 3 of Scheme 1. The imidazole of compound 4 is optionally protected and the resulting compound can be reacted with R ₄ -L in an inert solvent such as DMF, THF or methylene chloride in the presence of a base such as sodium hydride, at 0 to 100 ° C when L is a leaving group such as chloride, bromide, mesylate, tosylate or trifluoromethanesulfonate and R ₄ represents a substituted alkyl, substituted aryl or substituted heterocyclic group. Alternatively, protected compound 4 may be treated with an alcohol under the conditions of the Mitsunobu reaction, for example in the presence of triphenylphosphine and diethyl azodicarboxylate. Then, the protecting group is removed from the product, for example in the presence of trifluoroacetic acid, to give the claimed compound 5.

9 · <<<<<φ φ φ φ

Φ «« · · 9 9 • 9 9

9 9 · * ρ «

Scheme 3

Compound 1 of Scheme 3 wherein R _x is CN can be prepared from Compound 3 of Scheme 2 wherein R _x is a halogen atom by CuCN replacement at elevated temperature and in an inert solvent such as NMP or by replacement with Zn (CN) 2 in the presence of a catalyst such as tetrakistriphenylphosphine palladium. Compound 1 of Scheme 3 can be alkylated as described in Step 3 of Scheme 2. It then reacts under standard reductive amination conditions as described in Step 3 of Scheme 1 to yield the claimed compound.

r ₃

Step 1

In a first step, the sulfonyl chloride is combined with the amino acid ester hydrochloride salt in an organic solvent in the presence of a base such as a tertiary amine at room temperature to give compound 2.

Step 2

Compound 2 is reacted with compound 3, such as benzyl alcohol, under standard Mitsunobu reaction conditions (triphenylphosphine, diisopropylazodicarboxylate, THF as solvent) at room temperature to give compound 4.

··

Compound 3 in which R 1 is aryl can be prepared from compound 3 in which R 1 is bromine, iodine or trifluoromethanesulfonyl by condensation of an aryl or heteroaryl metalloid derivative such as phenylboronic acid using a catalyst such as palladium acetate or tetrakis (triphenylphosphine) palladium, in a mixed solvent such as water / acetone, in the presence of a base such as sodium carbonate, at a temperature ranging from room temperature to 90 ° C.

Step 3

Then, the product is saponified under basic conditions such as lithium hydroxide in a solvent such as water / THF to give compound 5.

Step 4

Then, compound 5 is converted to the acid chloride by treatment with thionyl chloride in an organic solvent such as methylene chloride in the presence of a catalytic amount of pyridine and at a temperature of 35 ° C. The resulting acid chloride is cyclized by the Fridel-Craft type cyclization in the presence of a Lewis acid such as aluminum chloride in an organic solvent such as methylene chloride to give compound 6.

Step 5

Then, compound 6 is reduced to compound 7 by treatment with a reducing agent such as sodium borohydride at room temperature in a protic solvent such as ethanol.

«· · · ♦

Φ · * φ φ φ φ φ φ φ φ φ φ φ φ φ

Step 6

Then compound 7 is converted to compound 8 by treatment with an azide compound such as diphenylphosphoryl azide in the presence of a base such as DBU in an organic solvent such as toluene at 0 ° C.

Step 7

Then, compound 8 is converted to compound 9 by treatment with a reducing agent, such as lithium aluminum hydride, in an organic solvent, such as THF.

Step 8

Thereafter, the various products may undergo reductive alkylation in the presence of an acid such as acetic acid, a reducing agent such as sodium triacethoxyborohydride and an aldehyde such as formylimidazole in an inert organic solvent such as dichloromethane at a temperature ranging from rt to 50 ° C to give compound 10.

φ «« «« · · · · · · · φ φ φ

Scheme 5

Η

AlkylOOC1N4P.G.

i ^R '

P.G.

Ph / S ^ - (ch ₂ ) 'cho v

Z t

r ₂ ^P pV

'of

X

R _from f 3 3 $

"in

Z - OO, SO 3, SO 2 NR 6 R 8, etc., can be reduced to alcohol (X = OH) using a reducing agent such as lithium borohydride by methods known in the art. The alcohol group may then be converted to a halogen such as bromine by methods known in the art, for example by treatment with carbon tetrabromide, in the presence of triphenylphosphine. If desired, the protecting group PG may be removed, for example, the Boc group may be removed by treatment with hydrogen chloride in dioxane. The free amine can be converted to the sulfonamide (Z = SO ₂ ) by treatment with various sulfonyl chlorides, such as benzenesulfonyl chloride. Then, compound 3 can be converted to a phosphonium ylide by treatment with triaryl or trialkylphosphines, such as triphenylphosphine. Thereafter, the ylide 4 can be treated with various substituted imidazolaldehydes, such as 1-trityl-4-formyl imidazole, in the presence of a strong base, such as, for example, 1-trityl-4-formyl imidazole.

· • · · · · · ·

Lithium hexamethyldisilazane to give compound 5 containing a cis or trans double bond. Then, compound 5 can be alkylated on a nitrogen atom by treatment with variously substituted 2-bromotoluenes that contain a leaving group on a methyl group, such as 4-bromo-3 (bromoethyl) benzonitrile, in the presence of a base such as potassium hexamethyldisilazane, thereby then compound 6 can be cyclized in the presence of a catalyst such as palladium acetate in the presence of a base such as triethylamine to give compound 7. When a protecting group R ₃ such as triphenylmethane, for example, is used, this group is removed by treatment with an acid such as trifluoroacetic acid.

Protecting groups as used herein can be used in the above procedures with amines having reactive functional groups such as hydroxyl, carboxyl, amino, mercapto, guanidine, imidazolyl, indolyl, and the like. The individual protecting groups used for amino acid residues depend on the other groups to be protected and are generally known in the art. Exemplary protecting groups include acetyl, benzoyl, benzyl, tert-butyl and the like for hydroxyl; cyclohexyl, benzyl, methyl, ethyl, tert-butyl and the like for carboxyl; benzyl, 4-methylbenzyl, 4-methoxybenzyl, acetyl, acetamidomethyl, triphenylmethyl (trityl) and the like for mercapto; tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), N - [(9H-fluoren-9-ylmethoxy) carbonyl] (Fmoc), phthalolyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl, 2- (trimethylsilyl) ethoxycarbonyl (Teoc) and the like for amino;

2,4-dinitrophenyl, benzyloxymethyl, Tos, Boc, trityl and the like for imidazolyl; formyl, Cbz, Teoc, 2,2,2-trichloroethylcarbamate (TROC) and the like for indolyl; and tosyl, nitro,

4 ·

«4 4

4 · 4 · 44 · 4 · 4 · 4 · 44

4 bis (1-adamantyloxycarbonyl) and the like for guanidine.

Protecting groups may be removed, if desired, for example by treatment with one or more deprotecting agents in an inert solvent or solvent mixture. For examples of protecting groups and suitable deprotecting agents, see M. Bodansky and A. Bodansky, The Practice of Peptide Synthesis Springer Verlag, Inc. (1984); and T.W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, New York (1991).

Following! the Examples and Preparations describe the method and process of preparing and utilizing preferred embodiments of the invention and are illustrative rather than limiting. It is to be understood that there may be other embodiments that fall within the scope and spirit of the invention as defined by the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -1-naphthalenesulfonamide dihydrochloride

HCl • φ φ

ΦΦ II ** ·· • · φ · φ * · φ φ. φ · · φ φ φ φ φ φ φ φ φ φ φ · · · · · φ φ φ φ · · · φ φ

The title compound is prepared as follows.

A) 3-quinolylcarbamic acid 1,1-dimethyl ester,

To a solution of 3-aminoquinoline (1.44 g; 10 mmol) in tetrahydrofuran (30 mL) under argon was added sodium hexamethyldisilazide (1 molar in tetrahydrofuran; 21 mL;

mmol). To the resulting dark brown mixture was added Boc anhydride (2.4 g; 11 mmol). After 1 hour, water (10 mL) and 1N hydrochloric acid (15 mL) were added to the mixture. The aqueous layer was separated and extracted with ethyl acetate (25 mL). The combined organic layer was washed with brine (15 mL), dried with magnesium sulfate (MgSO ₄ ) and evaporated to give practically pure compound A (2.5 g; 100%).

Mass Spectrum: (M + H) ⁺ = 245.

B) (1,2,3,4-tetrahydro-3-quinolyl) carbamic acid 1,1-dimethylethyl ester

To a solution of compound A (1.0 g; 4.1 mmol) in methanol (25 mL) was added acetic acid (3 mL) and platinum oxide (100 mg). The mixture is subjected to hydrogenation under a pressure of 50 psi. After 18 hours, the mixture was filtered and the filtrate was evaporated in vacuo.

The residue was dissolved in chloroform (30 mL) and washed with saturated aqueous sodium bicarbonate (NaHCO ₃ ) (30 mL). The organic layer was dried with magnesium sulfate (MgSO ₄ ) and evaporated. Purification by silica gel flash column chromatography eluting with 30% ethyl acetate in hexanes gave Compound B (460 mg; 4.66%) as a pale yellow solid. Mass Spectrum: (MH) ~ = 247.

(C) (6-bromo-1,2,3,4-tetrahydro-3-quinolyl) carbamic acid 1,1-dimethylethyl ester;

0 0 0 0

0 0 0 0 0 · 0 0 0

0000 00 ··

0 0 0 0 0 · 1 ·

0 0 0 * ♦ • 0000 «» ·

0 0 · · · · · ·

Κ of a solution of compound Β (90 mg; 0.37 mmol) in tetrahydrofuran (2 mL) was added dropwise a solution of pyridinium tribromide (128 mL; 0.41 mmol) in tetrahydrofuran (2 mL). After 15 minutes, water (5 mL) and ether (5 mL) were added. The organic layer was separated and washed with water (10 mL). The combined aqueous layer was extracted with ethyl acetate (10 mL). The organic layers were combined, dried with MgSO4 and evaporated. Purification by silica gel flash column chromatography eluting with 30% ethyl acetate in hexanes gave Compound C (90 mg;

%) as a solid.

Mass Spectrum: (M + H) ⁺ = 327.1 Br sample.

D) [6-Bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -carbamic acid 1,1-dimethyl ester

To a solution of compound C (200 mg; 0.61 mmol) in dichloromethane (3 mL) was added 4-formylimidazole (96 mg; 1 mmol), acetic acid (0.5 mL), and 3A sieves. After 15 minutes, sodium triacethoxyborohydride (212 mg; 1 mmol) was added and the mixture was stirred vigorously. After three hours the mixture was filtered through celite and the filtrate was treated with aqueous ammonia (10N; 20 mL) and chloroform (15 mL). After 1 hour, the organic layer was separated, dried with magnesium sulfate (MgSO ₄ ) and evaporated. The residue was purified by silica gel flash column chromatography eluting with 0.5% methanol in chloroform to afford compound D (208 mg; 93%) as a solid.

Mass Spectrum: (M + H) ⁺ - 407, 409, 1 Br sample.

E) 6-Bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolinamine trihydrochloride

To a solution of compound D (200 mg; 0.49 mmol) in chloroform (3 mL) was added trifluoroacetic acid (1.5 mL). Two

• · · · · · · · · φ · · · · · · · • · • · φ · φ · hodinách · hodinách · · · · φ · hodinách · hodinách · hodinách · hodinách · hodinách · hodinách · under vacuum. The residue was dissolved in chloroform (20 mL) and washed with 0.5 N sodium hydroxide solution (10 mL). The organic layer was separated, dried and evaporated to give the desired product (35 mg). The aqueous layer was evaporated in vacuo and the residue triturated with methanol (2 x 10 mL). The methanol extracts were combined with the product previously obtained and the mixture evaporated to give a solid (600 mg) which was dissolved in methanol (5 mL) and treated with 1 N hydrochloric acid in ether (20 mL). The ether was evaporated on a rotary evaporator and the remaining solution was filtered. The filtrate by evaporation gave compound E (190 mg; 93%) as a yellow powder.

Mass Spectrum: (M + H) ⁺ = 307 ⁺ , 309 ⁺ , 1 Br sample.

F) N- [6-Bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -1-naphthalenesulfonamide dihydrochloride

To a suspension of compound E (50 mg; 0.12 mmol) in dichloromethane (3 mL) was added diisopropylethylamine (0.5 mL) and 1-naphthalenesulfonyl chloride (58 mg; 0.26 mmol). After 18 hours, chloroform (15 mL) and saturated aqueous sodium bicarbonate (NaHCO 3) (15 mL) were added to the mixture. The organic layer was separated, dried and evaporated. Purification by silica gel flash column chromatography eluting with 10% methanol in chloroform gave the bis-sulfonylated product which was dissolved in methanol (0.5 mL) and 1N sodium hydroxide solution (0.3 mL) was added. After 1 hour, water (2 mL) was added and the mixture was extracted with chloroform (5 mL). The organic layer was dried with potassium carbonate (K 2 CO 3) and evaporated. Purification of the residue by silica gel flash column chromatography eluting with 0.5% methanol in chloroform gave the free base of the title compound (28 mg; 47%). To this solid was added 1 N hydrochloric acid in ether (2 mL) and the mixture was dried in vacuo to give the title compound (30 mg).

 · 9 * ··

99-9 9 9 9 • 9 9 9 9 9 9

9999999 9 9

9 9 9 9 9 .9 99 9999

99

9 9 9

9 9 9

9 9 9

9 9 9

99

Mass spectrum: (M + H) ⁺ = 497, 499. Rf 0.33 (10% methanol in chloroform).

Example 2

N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -1-naphthalenecarboxamide dihydrochloride

HCl

To a solution of 6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolinamine (30 mg; 0.072 mmol) in dimethylformamide (1 mL) was gradually added 1-hydroxyazabenzotriazole (19 mL). mg; 0.15 mmol), 1-naphthoic acid (25 mg; 0.15 mmol), diisopropylethylamine (0.7 mL; 0.4 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (28 mg; 0.15 mmol). After 18 h, the mixture was diluted with chloroform (10 mL) and washed with saturated sodium bicarbonate (NaHCO ₃ ) (10 mL). The organic layer was separated, dried and evaporated. Purification by silica gel flash column chromatography eluting with 50% ethyl acetate in hexanes followed by methanol in chloroform 1: 9 gave 2 fractions. More polar fraction 2 (14 mg) is the desired product and less polar fraction 1 (35 mg) is the diacylated product. Part 1 was dissolved in methanol (1 mL) and treated with 1 N sodium hydroxide solution (0.2 mL). After 30 minutes, the mixture was evaporated and mixed with fraction 2 obtained above. The resulting mixture was dissolved in chloroform (10 mL) and washed with water (10 mL). The organic layer was dried with magnesium sulfate

• 5 · ·

4 44 44 44

4 4 4 4 4 4

4 4 4 4 4 5

4,444 44 4

4 4 4 4 4 5

4444 44 44 (MgSO ₄ ), evaporated and purified by silica gel flash column chromatography eluting with 5% methanol in chloroform to give the free base of the title compound (20 mg; 60%). The solid was dissolved in chloroform and hydrogen chloride gas was bubbled through the mixture for 30 seconds. Then the mixture was evaporated in vacuo to give the title compound (23 mg).

Mass Spectrum: (M + H) ⁺ = 461, 463 (1: 1 ratio), 1 Br sample.

IR: 1638, 1499 cm ^-1 .

Example 3

N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N- (phenylmethyl) methanesulfonamide dihydrochloride &

HCl

The title compound is prepared as follows.

A) 6-Bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N (phenylmethyl) -3-quinolinamine

To a solution of 6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolinamine (184 mg; 0.45 mmol) in methanol (2 mL) and chloroform (2 mL) benzaldehyde (0.45 mL, 0.45 mmol), acetic acid (0.5 mL) and anhydrous magnesium sulfate (1 g) were added at room temperature. After 15 minutes, sodium triacethoxyborohydride (110 mg; 0.5 mmol) was added. After 1 hour and after

• φ · φ 'φ'

Sodium triacethoxyborohydride (215 mg and 110 mg) was added over a period of hours. After 6 hours, the mixture was filtered and evaporated. The residue was diluted with chloroform (20 mL) and stirred vigorously with ammonium hydroxide (20 mL). After 1 h, the aqueous layer was separated and extracted with chloroform (15 mL). The combined organic layer was dried with potassium carbonate (K ₂ CO ₃ ) and evaporated in vacuo to give compound A (120 mg; 67%) as an oil.

Mass Spectrum: (M + H) ⁺ = 397.

B) N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N- (phenylmethyl) methanesulfonamide dihydrochloride

Compound A (40 mg; 0.1 mmol) was converted to compound B in a manner similar to that described in Step F of Example 1 except that the residue obtained from the treated reaction mixture was treated with 50% trifluoroacetic acid in dichloromethane (1 mL). ). After 2 hours, the mixture was evaporated and purified by RP HPLC eluting with 40-90% aqueous methanol containing 0.1% trifluoroacetic acid. Appropriate fractions were collected, evaporated and treated with 4N hydrogen chloride in dioxane (1 mL) and evaporated in vacuo. The last procedure was repeated twice and finally the residue was dissolved in water and lyophilized to give the title compound (10 mg; 18%).

Mass Spectrum: (M + H) ⁺ = 475.1 Br sample.

Example 4

N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] benzenesulfonamide dihydrochloride

HCl

0 • 0 9 • 0900

The title compound was prepared in a manner similar to Step F of Example 1. 6-Bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolinamine (42 mg; 0.1 mmol) in dimethylformamide (0.2 mL) was treated with triethylamine (0.3 mL; 2.1 mmol), dimethylaminopyridine (10 mg) and benzenesulfonyl chloride (0.014 mL; 0.11 mmol) to give a solid (17 mg;

%).

Mass spectrum: (M + H) ⁺ = 447.1 Br sample.

Example .5

N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N- (phenylmethyl) acetamide dihydrochloride &amp;

HCl

To a solution of the compound of Example 3 (50 mg; 0.12 mmol) in pyridine (0.4 mL) at room temperature was added dimethylaminopyridine (10 mg) and acetic anhydride (0.3 mL). After 18 hours, chloroform (15 mL) and phosphate buffer solution, pH 4 (10 mL) were added to the mixture. The organic layer was separated, washed with water (10 mL), dried with potassium carbonate (K 2 CO 3) and evaporated in vacuo. The residue was purified by reverse phase (RP) HPLC eluting with 40-90% aqueous methanol containing 0.1% trifluoroacetic acid. Appropriate fractions were collected, evaporated and treated with 1N hydrochloric acid (1 ml) and methanol (1 ml) and then evaporated in vacuo. The last procedure was repeated twice and the residue was finally added

9

99 ·· 99

9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 99 99 9

9 9 9 9 9

9 9 99 9999 9 9 99 dissolved in water and lyophilization gave the title compound (10 mg; 20%).

Mass Spectrum: (M + H) ⁺ = 439, 441, 1 Br sample.

Example 6

N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N- (4-methoxyphenyl) methylmethanesulfonamide dihydrochloride

HCl

The title compound is prepared as follows.

A) 6-Bromo-1,2,3,4-tetrahydro-3-quinolinamine

To a solution of (6-bromo-1,2,3,4-tetrahydro-3-quinolyl) -carbamic acid 1,1-dimethylethyl ester (652 mg; 2 mmol) in dichloromethane at room temperature under argon was added trifluoroacetic acid (1 mL). Chloroform (10 mL) was added and evaporation in vacuo gave the title compound (1 g) as an oil which was used without further purification.

Mass Spectrum: (M + H) ⁺ = 227.

Β) N- (6-Bromo-1,2,3,4-tetrahydro-3-quinolyl) methanesulfonamide

The title compound (400 mg; 66% over two steps) was obtained from compound A (2 mmol crude) as an off-white solid in a manner similar to Step B of Example 3.

Tt tt tt tt tt tt tt tt tt tt tt tt tt tt tt tt tt tt · Tttttttt

Mass Spectrum: (M + H) ⁺ = 305, 307, 1 Br sample.

C) N- [6-Bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] methanesulfonamide

The title compound was prepared in a manner similar to Step D of Example 1 to give a solid (320 mg; 69%). Mass spectrum: (M + H) ⁺ = 385, 387, 1 Br sample.

D) N- [6-Bromo-1,2,3,4-tetrahydro-1 - [(1- (triphenylmethyl) -1Himidazol-4-yl) methyl] -3-quinolyl] methanesulfonamide

To a solution of compound C (280 mg; 0.78 mmol) in acetonitrile (4 mL) at room temperature under argon was added diisopropylethylamine (0.18 mL; 1 mmol) and trityl chloride (223 mg; 0.8 mmol). The mixture was stirred overnight (16 hours) and evaporated in vacuo. The residue was dissolved in chloroform (20 mL) and washed with saturated sodium bicarbonate solution (20 mL).

The organic layer was dried with MgSO4 and evaporated to give crude compound D (500 mg; 105%), which was used without further purification.

Mass Spectrum: (M + H) ⁺ = 627; (MH +) = 625.

E) N- [6-Bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N- (4-methoxy-phenyl) -methyl-methanesulfonamide monohydrochloride

To a solution of compound D (63 mg; 0.1 mmol) in tetrahydrofuran (1 mL) was added triphenylphosphine (52 mg; 0.2 mmol), diisopropylazodicarboxylate (26 μΐ; 0.13 mmol) and 4-methoxybenzenemethanol (18 mg; 0.13 mmol). After 18 hours, an additional equivalent of triphenylphosphine, diisopropylazodicarboxylate and 4-methoxybenzenemethanol was added. After 5 hours the mixture was evaporated in vacuo. 9 9 9 9 φ · <· · · '9 99' 9 9 9 9 9 9 9 9 9 9 9 And the residue was purified by silica gel flash column chromatography eluting with 50% ethyl acetate in hexanes to give the impure product. The impure product was dissolved in dichloromethane (2 mL) and treated with trifluoroacetic acid (1 mL). After 2 hours the mixture was evaporated and the residue was purified by RP HPLC eluting with 35% to 90% aqueous methanol containing 0.1% trifluoroacetic acid. The appropriate fractions were collected, evaporated and the residue dissolved in 1N hydrochloric acid and re-evaporated. After repeating the last step twice, the residue thus obtained was dissolved in water and lyophilized to give the title compound (14 mg; 26%).

Mass Spectrum: (M + H) ⁺ = 505, 507 1: 1.

Example 7

N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(4-methylphenyl) methyl] methanesulfonamide monohydrochloride

The title compound is prepared as follows.

A) N- [6-Bromo-1,2,3,4-tetrahydro-1 - [(1- (triphenylmethyl) -1Himidazol-4-yl) methyl] -3-quinolyl] -N - [(4-methylphenyl) (Methyl) methanesulfonamide

To a stirred solution of Compound D from Example 6 (0.1 g; 0.16; 4 9 9 9 0 0 0 0 0

9 0 0 · · · 0-0 0 0

0 0000 00 0 e 00 00 0

9 9 9 9 9

Sodium hydride (60% dispersion in oil; 7 mg; 0.17 mmol) was added under argon atmosphere in dimethylformamide (1 mL). After stirring for 30 minutes, methylbenzyl bromide (0.035 g; 0.191 mmol) was added and stirred overnight. After 16 h, the mixture was diluted with water (5 mL) and ethyl acetate (20 mL). The layers were separated. The aqueous layer was re-extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with water (2 x 5 mL), dried with magnesium sulfate (MgSO ₄ ), filtered and evaporated. The brown oil was purified by silica gel flash column chromatography eluting with ethyl acetate and the appropriate fractions by evaporation to afford the title compound (60 mg; 52%) as a white foam.

HPLC: Rt. 4.41 min, 10-90% aqueous methanol with 0.2% H ₃ PO ₄ buffer, 4 minute gradient, 4 mL / min, 220 nm, YMC S5 ODS column.

B) N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(4-methylphenyl) methyl] methanesulfonamide monohydrochloride

To a solution of compound A (60 mg; 0.081 mmol) in anhydrous methylene chloride (0.5 mL) was added trifluoroacetic acid (0.5 mL) under argon. After 3 hours, the reaction mixture was evaporated, chloroform (3 mL) was added and evaporated again. The residue was purified by silica gel flash chromatography, eluting with chloroform and methanol (19: 1). The appropriate fractions were evaporated and the residue was treated with 1N aqueous hydrochloric acid and methanol and evaporated. This procedure was repeated twice, the final residue was dissolved in water and lyophilized to give the title compound (17 mg; 43%) as a light tan solid.

Mass Spectrum: (M + H) ⁺ = 489.

Φ Φ Φ · · · φ φ φ φ φ φ φ φ φ φ φ · · · · · · ·

Example 8

Ν- [6-Cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(3-methylphenyl) methyl] benzenesulfonamide monohydrochloride

The title compound is prepared as follows.

A) N- (6-Bromo-1,2,3,4-tetrahydro-3-quinolyl) benzenesulfonamide

The title compound (680 mg; 56%; white solid) was prepared from 6-bromo-1,2,3,4-tetrahydro-3-quinolinamine in a manner similar to Step B of Example 3.

Mass Spectrum: (M + H) ⁺ = 366, 368, 1: 1 ratio.

Alternatively, compound A can be prepared from N- (1,2,3,4-tetrahydro-3-quinolyl) benzenesulfonamide using the procedure described in this step. N- (1,2,3,4-Tetrahydro-3-quinolyl) benzenesulfonamide was prepared as described below in Step C and D.

Β) N- (6-Cyan-1,2,3,4-tetrahydro-3-quinolyl) benzenesulfonamide

A solution of Compound A (443 mg; 1.2 mmol) in dimethylformamide (4 mL) was bubbled through the solution for 4 minutes for 9 minutes. argon. Zinc cyanide (135 mg; 1.15 mmol) was added and the mixture was deoxygenated. Tetrakistriphenylphosphine palladium (105 mg; 0.09 mmol) was added and the mixture was deoxygenated. The mixture was then heated at 90 ° C for 4 hours. The mixture was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (20 mL). The combined organic layer was dried over magnesium sulfate (MgSO 4), filtered and evaporated in vacuo. Dichloromethane (4 mL) was added to the residue and compound B (300 mg; 81%) precipitated on standing as a white crystalline solid.

Mass Spectrum: (M + H) ⁺ = 314.

C) N- (3-Quinolyl) benzenesulfonamide

To a solution of 3-aminoquinoline (7.2 g; 50 mmol) in acetonitrile (150 mL) was added pyridine (25 mL) and the resulting mixture was cooled to 0 ° C. A solution of benzenesulfonyl chloride (7 mL; 55 mmol) in acetonitrile (20 mL) was added dropwise over 30 minutes. The mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with ethyl acetate (100 mL) and washed successively with IN hydrochloric acid, brine and saturated copper sulfate (CuSOJ, dried over magnesium sulfate (MgSO ₄₎ and evaporated in vacuo to give an oil. Purification by flash chromatography on silica gel eluting with 30% ethyl acetate in hexanes afforded compound C (13.6 g; 95%) as a white solid.

Mass Spectrum: (M + H) ⁺ = 285.

D) N- (1,2,3,4-Tetrahydro-3-quinolyl) benzenesulfonamide

To a solution of compound C (13.6 g; 4.78 mmol) in a mixture of methanol and ethyl acetate (6 and 8 mL) was added 20% palladium hydroxide on carbon (1.2 g) and the mixture was subjected to hydrogenation. 9

9 9 9

9 9 9 9 999 9 9 9

9 9 9 9 «· · ·· ·« at atmospheric pressure. After 24 h, the mixture was filtered and the filtrate evaporated in vacuo to give compound B (13.6 g;

99.8%) as a white solid.

Mass Spectrum: (M + H) ⁺ = 289.

E) N- (6-Cyano-1,2,3,4-tetrahydro-3-quinolyl) -N - [(3-methylphenyl) methyl] benzenesulfonamide

Compound B (65 mg; 0.26 mmol) was converted to the title compound (34 mg; 32%) as a clear oil by a method similar to the preparation of Compound A from Example 7 except that 3-methylbenzyl bromide (0.041 mL; 0.31 mmol).

HPLC: Rt. 4.3 min., 10 to 90% aqueous methanol with 0.2% H ₃ PO ₄ buffer, 4 minute gradient, 4 mL / min, 220 nm, YMC S5 ODS column.

F) N- [6-Cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(3-methylphenyl) methyl] benzenesulfonamide monohydrochloride

A mixture of compound F (34 mg; 0.081 mmol), 4-formylimidazole (0.31 g; 0.325 mmol) and 3A molecular sieves in dichloroethane (0.5 mL) and acetic acid (0.5 mL) under an argon atmosphere was warmed to temperature 50 ° C. After 2 hours, sodium triacethoxyborohydride (0.017 g; 0.479 mmol) was added. After one hour intervals, the equivalent of sodium triacethoxyborohydride is added twice. Then the mixture was cooled to room temperature and stirred overnight. Additional borohydride and aldehyde were added and the mixture was heated to 50 ° C. After 24 hours, the reaction mixture was diluted with ammonium hydroxide (NH ₄ OH) (2 mL) and chloroform (5 mL) and after stirring for 20 minutes the layers were separated. The aqueous layer was reextracted with chloroform (2 x 10 mL). The combined organic layer was washed with sodium bicarbonate (NaHCO ₃ ) (5 mL), dried with sulfate

magnesium (MgSO ₄ ), filtered and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate followed by chloroform / methanol (19: 1). The appropriate fractions were evaporated, treated with 1N aqueous hydrochloric acid and methanol and then evaporated. This procedure was repeated twice, the residue was dissolved in water and lyophilized to give the title compound (18 mg; 45%) as a pale yellow solid.

Mass Spectrum: (M + H) ⁺ = 498.

Example 9

N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-yl) -3-quinolyl] -N - [(2-methylphenyl) methyl] benzenesulfonamide monohydrochloride

Ni

HCl

The title compound was prepared from N- (6-cyano-1,2,3,4-tetrahydro-3-quinolyl) -benzenesulfonamide using the procedure described in steps F and G of Example 8 to give a pale yellow solid (39 mg; 66%). ).

Mass Spectrum: (M + H) ⁺ = 498.

• · · φ · φ · φ · φ ·

Example 10

N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-yl) -3-quinolyl] -N- (phenylethyl) benzenesulfonamide monohydrochloride

HCl

The title compound is prepared as follows.

A) N- (6-Cyano-1,2,3,4-tetrahydro-3-quinolyl) -N (phenylethyl) benzenesulfonamide

A solution of N- (6-cyano-1,2,3,4-tetrahydro-3-quinolyl) benzenesulfonamide (50 mg; 0.2 mmol) in anhydrous tetrahydrofuran (2 mL) was stirred under argon.

Triphenylphosphine (0.156 g; 0.596 mmol), phenethyl alcohol (0.023 mL; 0.2 mmol) and diethyl azodicarboxylate (0.077 mL; 0.5 mmol) were added sequentially. After 16 hours, an additional equivalent of phenethyl alcohol was added. After 48 hours, the reaction mixture was evaporated. The crude product from another reaction (obtained from the reaction mixture of 0.24 mmol of compound B of Example 8) was mixed with this crude product and purified on a silica gel column eluting with hexane / ethyl acetate (3: 1; 2: 1; 1: 1) . Appropriate fractions by evaporation gave impure Compound A (0.1 g; 25%; only 50% pure). Mass Spectrum: (M-H) = 416 ', LC / Mass Spectrum:

(M + H) &lt; + & gt ^; = 418.

B) N- [6-Cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N- (phenylethyl) benzenesulfonamide monohydrochloride

· Φ φ • • •

A mixture of compound A (50 mg; 0.119 mmol), 4-formylimidazole (37 mg; 0.4 mmol) and triethylsilane (0.35 mL; 2.19 mmol) in trifluoroacetic acid (0.7 mL) and methylene chloride (0, 7 ml) was stirred under argon. After 2 hours the mixture was evaporated. The residue was purified by silica gel flash column chromatography eluting with ethyl acetate followed by chloroform / methanol (19: 1). The appropriate fractions were evaporated. The residue was treated with 1N aqueous hydrochloric acid and methanol and then evaporated. This procedure is repeated twice. The final residue was dissolved in water and lyophilized to give the title compound (12 mg; 20%) as a pale yellow solid.

Mass Spectrum: (M + H) ⁺ = 498.

Example 11

2,3,4,5-tetrahydro-5 - [(1H-imidazol-4-ylmethyl) amino] -2- (1-naphthylsulphonyl) -8-methoxy-1H-2-benzazepine dihydrochloride

HCl

The title compound is prepared as follows.

A) N- (1-Naphthylsulfonyl) -β-alanine methyl ester

To a stirred suspension of β-alanine methyl ester hydrochloride (6.0 g; 43 mmol) in anhydrous methylene chloride (30 mL) was added triethylamine (6 mL) followed by 1-naphthalenesulfonyl chloride (10 g; 44 mmol). After 3 hours, the solution is washed with water.

saturated aqueous sodium hydrogencarbonate solution followed by a 1 molar aqueous potassium hydrogensulfate solution and brine. The organic layer was dried with magnesium sulfate (MgSO ₄ ) and evaporated in vacuo to give compound A (6.3 g; 86%) as a white solid.

Mass Spectrum: (M + H) ⁺ = 294.

B) 3-N- (3-methoxybenzyl) -N- (1-naphthylsulphonyl) -alanine methyl ester

M-Methoxybenzyl alcohol (422 mg; 3.1 mmol), Compound A (0.9 g; 3.1 mmol) and triphenylphosphine (0.8 g; 3.1 mmol) were combined in anhydrous tetrahydrofuran (10 mL). . The solution was stirred under a nitrogen atmosphere while diisopropyldiazocarboxylate (620 mg; 3.1 mmol) in tetrahydrofuran (1 mL) was added dropwise over 1 minute. The solution was stirred for 2 hours and then evaporated. The residue was purified by silica gel flash column chromatography eluting with ethyl acetate / hexanes (1:10 to 10: 0). Appropriate fractions were collected and evaporated to give compound B (1.2 g; 94%) as a white solid.

Mass Spectrum: (M + NH ₄ ) ⁺ - 431.

C) 3-N- (1-Naphthylenesulfonyl) -3-N- (3-methoxybenzyl) aminopropionic acid

Compound B (1.1 g; 2.4 mmol) was treated with methanol (20 mL) and aqueous lithium hydroxide (6 mL; 1 molar). After 16 hours, the solution was evaporated in vacuo. Water (30 mL) and ethyl ether (30 mL) were added to the residue and the layers were separated. Wash the aqueous layer with ethyl ether / hexanes. The aqueous layer was acidified to pH = 2 with 5N hydrochloric acid (aqueous) and the product was extracted with ethyl acetate. The ethyl acetate layer was dried with magnesium sulfate (MgSO ₄ ) and evaporated to give compound C

• · · 0 0 · 0 0 · 0 ·

0 0 0 0 0 0

0000 0 0 0 0 0 0 0 0 0 0

0 00 0000 (960 mg; 99%) as a white solid. Mass Spectrum: (M + NH ₄ ) ⁺ = 417.

D) 2,3,4,5, -Tetrahydro-8-methoxy-2- (1-naphthylsulfonyl) -2-benzazepin-5-one

To a solution of compound C (600 mg; 1.5 mmol) in methylene chloride (5 mL) was added thionyl chloride (0.3 mL; 4 mmol) and pyridine (0.001 mL) and the solution was stirred at 35 ° C for 1 hour. . The solution was evaporated and the residue was dissolved in methylene chloride (10 mL). After cooling the mixture to 0 ° C, aluminum chloride (220 mg; 1.7 mmol) was added. After 15 minutes, the mixture was poured into aqueous 2N hydrochloric acid / ice (80 mL) along with methylene chloride (30 mL). The organic layer was separated, evaporated, dissolved in ethyl acetate (60 mL), washed with saturated aqueous sodium bicarbonate, dried with magnesium sulfate (MgSO ₄ ), filtered and evaporated under high vacuum to give compound D (530 mg; 92%). ) as whitish crystals.

Mass Spectrum: (M + NH ₄ ) ⁺ = 417.

E) 2,3,4,5, -Tetrahydro-8-methoxy-2- (1-naphthylsulfonyl) -1H-2-benzazepin-5-ol (

To a solution of compound D (225 mg; 0.59 mmol) in ethanol (15 mL) was slowly added sodium borohydride (111 mg; 3 mmol). After 1 hour, ethyl acetate (60 mL) and water (60 mL) were added and the layers were separated. The aqueous layer was washed with ethyl acetate, the organic layers were combined, dried with magnesium sulfate (MgSO ₄ ), filtered and evaporated to give compound E (228 mg; 99%) as a glassy material.

Mass Spectrum: (M + H) ⁺ = 384.

φ φ

Φ Φ φ · φ • • • • •

• φ · φφ φφφφ

F) 2,3,4,5, -Tetrahydro-8-methoxy-2- (1-naphthylsulfonyl) -1Η-2-benzazepine-5-azide

Κ a solution of compound E (200 mg; 0.52 mmol) and diphenylphosphoryl azide (0.14 mL; 0.62 mmol) in anhydrous toluene (1 mL) cooled to 0 ° C was added DBU (0.93 mL; 63 mmol). The solution was stirred for 2 hours at 0 ° C and for 16 hours at room temperature. Water (20 ml), 1N aqueous hydrochloric acid (5 ml) and ethyl acetate (20 ml) were added and the layers were separated. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified by flash chromatography eluting with ethyl acetate / hexanes (1: 3 to 1: 1). Product containing fractions were combined and evaporated to give compound F (150 mg; 70%) as a white solid.

Mass Spectrum: (M + H) ⁺ = 409.

G) 2,3,4,5, -Tetrahydro-8-methoxy-2- (1-naphthylsulfonyl) -1H-2-benzazepin-5-amine

Compound F (50 mg; 0.12 mmol) was treated with lithium aluminum hydride (1 molar in tetrahydrofuran; 1 mL; 1 mmol) in tetrahydrofuran (1 mL). After 0.5 h, water (20 mL), 1 N aqueous sodium hydroxide solution (10 mL) and ethyl ether (30 mL) were added. The organic layer was separated. The aqueous layer was extracted with ethyl ether, and the combined organic layer was dried with magnesium sulfate (MgSO ₄ ), filtered and evaporated to give compound G (40 mg; 85%) as a glass.

Mass Spectrum: (M + H) ⁺ = 383.

H) 2,3,4,5-Tetrahydro-5 - [(1H-imidazol-4-ylmethyl) amino] -2- (1-naphthylsulfonyl) -8-methoxy-1H-2-benzazepine dihydrochloride

A solution of compound G (30 mg; 0.78 mmol) of 4-formylimidazole.

4 9 9 9 9 4 9 9 9 9 • 4999 4 44 949 94 94 (7.5 mg; 0.78 mmol) 1 2-dichloroethane (5 mL) and acetic acid (5 mL) was stirred at room temperature for 30 minutes, followed by the addition of triacethoxyborohydride (16 mg; 0.78 mmol). After ¹⁸ hours, the mixture was diluted with ethyl acetate (20 mL) and hydroxide. The mixture was extracted with ethyl acetate (2 x 25 mL) and the combined organic extracts were washed with aqueous sodium bicarbonate solution (25 mL) followed by aqueous ammonium chloride (25 mL), dried with sodium sulfate. (Na ₂ SO 4) and evaporated in vacuo to a semi-solid, which was purified by reverse phase HPLC, the product containing fractions were combined and evaporated to dryness, dissolved in aqueous 2N hydrochloric acid and evaporated to dryness. to give the title compound (8 mg) as a white solid.

Mass Spectrum: (M + H) ⁺ = 463.

Example 12

2,3,4,5-tetrahydro-5 - [(1H-imidazol-4-ylmethyl) amino] -2- (1-naphthylsulfonyl) -8-phenyl-1H-2-benzazepine dihydrochloride

HCl

The compound was prepared as follows.

A) m-Phenylbenzyl alcohol

To a solution of m-bromobenzyl alcohol (5.0 g; 27 mmol), phenylboronic acid (3.3 g; 27 mmol) and potassium carbonate (9.2 g; 67.4).

44

4 · 4 · · ·

4445 44 4 4 4 4 4

4,444 44 4 4 44 44 4

4 4 4 44

Palladium acetate (12 mg; 0.53 mmol) in degassed acetone (14 mL) was added in a mixture of degassed acetone (50 mL) and degassed water (45 mL) under a nitrogen atmosphere. The solution was heated at 65 ° C for 16 hours under a nitrogen atmosphere.

Ethyl ether (120 mL) was added to cool and the layers were separated. The aqueous layer was washed with ethyl ether. The combined ether layer was washed with brine, dried with magnesium sulfate (MgSO ₄ ), filtered and evaporated. The residue was purified by flash chromatography eluting with ethyl acetate / hexanes (1:10 to 1: 1). Product containing fractions were combined and evaporated to give compound A (4.9 g) as a white solid.

/ ^{C 4} Mass Spectrometry: (M + H) = 185.

B) 3- (m-Phenylbenzyl) -N- (1-naphthylsulphonyl) -β-alanine methyl ester

The title compound (267 mg; 65%) was prepared by reacting Compound A with N- (1-naphthylsulfonyl) -β-alanine methyl ester in a manner similar to the preparation of Compound B from Example 11. Mass Spectrometry: (M + H) ⁺ = 428.

C) 2,3,4,5-tetrahydro-5 - [(1H-imidazol-4-ylmethyl) amino] -2- (1-naphthylsulfonyl) -8-phenyl-1H-2-benzazepine dihydrochloride

The title compound (10 mg; white solid) was prepared from Compound B using the same synthesis procedure as described in the preparation of Example 11.

Mass Spectrum: (M + H) ⁺ - 509.

Example 13

2,3,4,5-tetrahydro-5 - [(1H-imidazol-2-ylmethyl) amino] -2- (1-naphthylsulfonyl) -8-phenyl-1H-2-benzazepine dihydrochloride

00 • 0 0 · 0 0 0 0 «0 · 00 ·· · 0 · 0 0 0000 · 0 0 0 · 0 00 0 • 0 0 00 0 0 0 0

0 00 0000 00 00

HCl

The title compound (4 mg; white solid) was prepared from 2,3,4,5-tetrahydro-8-phenyl-2- (1-naphthylsulfonyl) -2-benzazepin-5-amine in the synthesis of Example 12 using as described in Step H of Example 11 except that 2-formylimidazole was used in place of 4-formylimidazole.

Mass Spectrum: (M + H) ⁺ = 509.

Example 14

N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(2-ethoxyphenyl) methyl] benzenesulfonamide monohydrochloride

The title compound is prepared as follows.

A) Polymer-bound N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -benzenesulfonamide ·· φ

ΦΦ 9 · ·· ΦΦ · · · Φ · Φ ·

- _Λ φφφφφ □ □ □ · · · □ □ □ □ □ □ □ □ □ φ □ φ

Κ a solution of compound F of Example 8 (250 mg; 0.64 mmol) in DMF (3 mL) was added diisopropylethylamine (0.17 mL; 1 mol) and 2-chlorotrityl chloride resin (0.2 g; 0.147-0.074 mm;

1% DVB; 1 mmol / g charge) and the mixture is shaken for 24 hours. The solvent was removed in vacuo and the residue was washed with 10% triethylamine in dichloromethane. After drying in vacuo, a resin (360 mg) was obtained.

B) N- [6-Cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(2-ethoxyphenyl) methyl] benzenesulfonamide monohydrochloride

To a suspension of compound A (30 mg; 0.03 mmol) in anhydrous tetrahydrofuran (1 mL) was added triphenylphosphine (0.26 g; 0.1 mmol), o-ethoxybenzyl alcohol (0.014 mL; 0.1 mmol), and diisopropylazodicarboxylate ( 0.015 ml (0.1 mmol) was added and the mixture was shaken. After 62 hours, the solvent was stripped off. Tetrahydrofuran (1 mL) and another equivalent of three reagents were added. After 24 hours the solvent was removed and the resin was washed with dichloromethane. The resin was then shaken with a 1: 1 mixture of dichloromethane and trifluoroacetic acid and triethylsilane (1 mL). The crude product from the other reaction (obtained from the reaction to the same extent and using diamide instead of diisopropylazodicarboxylate) was mixed with the product and purified by RP HPLC eluting with aqueous methanol containing 0.1% trifluoroacetic acid. Appropriate fractions by evaporation afforded compound A (6 mg; 15%).

LC / mass spectrum: (M + H) ⁺ = 528.

Example 15

N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N- (phenylmethyl) benzenesulfonamide monohydrochloride

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 9

9,999,999

9 99 9900 99 99

The title compound is prepared as follows.

A) N- [6-Cyano-1,2,3,4-tetrahydro-1 - [[1- (triphenylmethyl) -1Himidazol-4-yl] methyl] -3-quinolyl] benzenesulfonamide

The title compound (2.5 g; 75%) was obtained from N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N- (phenylmethyl) benzenesulfonamide (2.68 g; 5.3 mmol) in a manner similar to the preparation of N- [6-bromo-1,2,3,4-tetrahydro-1- (trifluoromethyl) -1H-imidazol-4-yl] (methyl) -3-quinolyl] methanesulfonamide, except that dimethylformamide is used as the solvent instead of acetonitrile. The solid was used without further purification.

B) N- [6-Cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N- (phenylmethyl) benzenesulfonamide monohydrochloride

The title compound was prepared in a similar manner to Example E, except that the reaction mixture was refluxed for 6 hours in the first portion. A white lyophilisate (39 mg; 83%) was obtained.

Mass Spectrum: (M + H) ⁺ = 484.

44

4 4 4

4 4 4

4 4 4 4

4 4 4

44

4 • · 4

4 4 4 • 4444

4 4

4 ··

4 4 4

4 4

4 4 4

4 4

4444

The following examples were prepared from N- [6-cyano-1,2,3,4-tetrahydro-1 - [(1- (triphenylmethyl) -1H-imidazol-4-yl) methyl] -3-quinolyl] benzenesulfonamide in a manner similar to that in Example 15 .

Example 16

N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(2,3-dimethoxyphenyl) methyl] benzenesulfonamide monohydrochloride

Example 17

N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(3,5-dimethylphenyl) methyl] benzenesulfonamide monohydrochloride

Example 18

N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(1-naphthalenyl) methyl] benzenesulfonamide monohydrochloride

Example 19

N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(2-thiophene) methyl] benzenesulfonamide monohydrochloride

Example 20

N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(2,5-dimethylphenyl) methyl] benzenesulfonamide monohydrochloride

Example 21

N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(3-thiophene) methyl] benzenesulfonamide monohydrochloride

9 · Φ

Φ 9 9 9 • 9999

9 9

9

9 9 9

9 9

9 9 9

9 9

9999

98 • 9 9 9

9 9 9

9 9 9 9

Example 22

N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(3-chlorophenyl) methyl] benzenesulfonamide monohydrochloride

Example 23

N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(2-fluorophenyl) methyl] benzenesulfonamide monohydrochloride

Example 24

N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-quinolyl] -N - [(3-pyridyl) methyl] benzenesulfonamide monohydrochloride

Example 25

N- [6-cyano-1,2,3,4-tetrahydro-1 - [(1- (methyl) 1H-imidazol-5-yl) methyl] -3-quinolyl] -N- (phenylmethyl) benzenesulfonamide monohydrochloride

The title compound is prepared as follows.

A) N- [6-Cyano-1,2,3,4-tetrahydro-1 - [(1- (triphenylmethyl) -1Himidazol-5-yl) methyl] -3-quinolyl] -N- (phenylmethyl) benzenesulfonamide • ·

• · · · · ·

Example 15 is converted to the title compound in a manner similar to Example A of Example 15. ‘

B) N- [6-Cyano-1,2,3,4-tetrahydro-1 - [(1 (methyl) -1H-imidazol-5-yl) methyl] -3-quinolyl] -N (phenylmethyl) benzenesulfonamide monohydrochloride

Compound A (362 mg; 0.5 mmol) was dissolved in THF (5 mL) and cooled to -78 ° C. To this solution was added methyl trifluoromethanesulfonate (90.2 mg; 0.55 mmol). The mixture was stirred at -78 ° C for 0.5 h and then stirred at 0 ° C for 2 h. Water (1 mL) and acetic acid (1 mL) were added and the solution was refluxed for 2 hours. The reaction mixture was cooled to room temperature and neutralized with 1N sodium hydroxide solution. The product was extracted with dichloromethane (3 x 20 mL) and the combined organic extract was dried over sodium sulfate (Na ₂ SO ₄ ) and evaporated. The residue was triturated with hexanes (2 x 10 mL) and purified by silica gel flash chromatography, eluting with CH ₂ Cl ₂ / MeOH / NH ₄ OH (95: 5: 0.1) to give the desired product. Dissolve the compound in 1 N hydrochloric acid (1 mL) and water (10 mL) and lyophilize to afford the title compound (210 mg; 79%) as a colorless lyophilisate.

Mass Spectrum: (M + H) ⁺ = 498.

Example 26

N- [6-cyano-1,2,3,4-tetrahydro-1 - [(1- (methyl) -1H-imidazol-5-yl) methyl] -3-quinolyl] -N - [(3-thiophenomethyl) monohydrochloride of benzenesulfonamide

Ni

Me

A • »»

AND

The title compound was prepared from Example 21 using the same synthesis procedure as described for Example 25.

Example 27

N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N- (phenylmethyl) methanesulfonamide monohydrochloride

The title compound is prepared as follows.

A) N- (6-Bromo-1,2,3,4-tetrahydro-3-quinolyl) methanesulfonamide

The title compound was prepared from 3-aminoquinoline using the synthesis procedure from step C to step E of Example 8. Mass spectrum: (M + H) ⁺ = 305.

Β) N- (6-Bromo-1,2,3,4-tetrahydro-3-quinolyl) -N- (phenylmethyl) methanesulfonamide

The title compound was prepared using the procedure described for Step A of Example 7. Yield 600 mg (76%), white solid.

Mass Spectrum: (M + H) ⁺ - 396.

C) N- (6-Cyano-1,2,3,4-tetrahydro-3-quinolyl) -N- (phenylmethyl) methanesulfonamide

The title compound was prepared using the procedure described for Step B of Example 8. Yield 430-mg (66%), white solid.

Mass Spectrum: (M + H) ⁺ = 342.

 · 9

D) N- [6-Cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N- (phenylmethyl) methanesulfonamide monohydrochloride

The title compound was prepared using the procedure described for Step B of Example 10. Yield 30 mg (66%). Mass Spectrum: (M + H) ⁺ = 422.

Example 28

N- [6-kan-1,2,3,4-tetrahydro-1 - [(1- (methyl) -1Himidazol-5-yl) methyl] -3-quinolyl] -N- (phenylmethyl) methanesulfonamide monohydrochloride

The title compound was prepared from Example 27 in a manner similar to that described in Step G of Example 29. Yield 35 mg (80%).

Mass Spectrum: (M + H) ⁺ = 436.

Example 29

(R) -N- [6-Cyano-1,2,3,4-tetrahydro-1 - [(1 (methyl) -1H-imidazol-5-yl) methyl] -3-quinolyl] -N- ( phenylmethyl) benzenesulfonamide

A) [6-Cyano-1,2,3,4-tetrahydro-3-quinolyl) carbamic acid 1,1-dimethyl ester

The title compound was prepared from 1,1-dimethyl ester.

000 9 0 «9 90 ·

0 0999 99 9 0 09 00 9 0 090 000 0 0 0000 00 9 4 (6-bromo-1,2,3,4-tetrahydro-3-quinolyl) carbamic acid, using the procedure described in step B of Example 8. Yield 140 mg (67%).

Mass Spectrum: (M + H) ⁺ = 273.

B) 6-Cyano-1,2,3,4-tetrahydro-3-quinolinamine hydrochloride

To a solution of compound A (546 mg; 2 mmol) in methylene chloride (5 mL) at room temperature was added hydrochloric acid in dioxane (4 molar; 2 mL; 8 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was evaporated and the residue triturated with diethyl ether (20 mL). The solid was collected, washed with diethyl ether (20 mL) and dried to give compound B (420 mg; 100%) as a solid.

LC / mass spectrometry: (M + H) &lt; + & gt ^; = 174.

C) N- (6-Cyano-1,2,3,4-tetrahydro-3-quinolyl) -α-hydroxybenzeneacetamide

A mixture of compound B (209 mg; 1 mmol) and N-methylmorpholine (0.5 mL) in DMF (5 mL) was stirred at room temperature. After 10 minutes, (S) - (+) - mandelic acid (185 mg; 1.2 mmol), HOBt (153 mg; 1 mmol) and EDAC x HCl (230 mg; 1.2 mmol) were added sequentially. The mixture was stirred at room temperature overnight, diluted with ethyl acetate (20 mL) and washed with water (2 x 20 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ) and evaporated. The residue was purified by silica gel flash column chromatography eluting with EtOAc / hexanes (2: 1) to give the faster moving isomer 1 (120 mg; 39%) as a foam and the slower moving isomer 2 (100 mg; 33%) as a solid. substance. Isomer 2 is recrystallized in acetone and analyzed by single crystal X-ray analysis and the structure is determined as the (S, S) -configuration.

• tt. ♦ • · · 9 tt

<* 9 9 9 9 • 9 9

Isomer 1: [S- (R, R *)] - N- (6-Cyano-1,2,3,4-tetrahydro-3-quinolyl) α-hydroxybenzeneacetamide [O] _D = + 54 ° (c = 1) 70 (MeOH).

₁ H NMR (CD ₃ OD) 7.23 (m, 2H); 7.14 (m, 3H); 7.03 (m, 2 H); 6.37 (d, 1H, J = 7.6Hz); 4.83 (s, 1 H); 4.04 (m, IH); 3.19 (m, IH); 3.04 (m, IH); 2.74 (m, IH); 2.64 (m, IH).

Isomer 2: [S- (R *, S *)] - N- (6-Cyano-1,2,3,4-tetrahydro-3-quinolyl) α-hydroxybenzeneacetamide [α] _D - + 99 ° (c = 1.70 (MeOH); mp 151-157 ° C.

1 H NMR (CD 3 OD) 7.29 (m, 7H); 6.57 (d, 1H, J = 7.6Hz); 4.98 (s, 1 H); 4.12 (m, IH); 3.43 (m, IH); 3.28 (m, IH); 2.94 (m, IH); 2.80 (m, IH).

D) (R) -6-Cyano-1,2,3,4-tetrahydro-3-quinolinamine

A solution of isomer A (120 mg; 0.39 mmol) in ethanol (1 mL) and 15% sulfuric acid (1 mL) was stirred at reflux temperature for 16 hours. The mixture was cooled to room temperature and the volatiles removed in vacuo. Water (2 mL) was added and the solution was washed once with methylene chloride. The aqueous solution was basified with 4N sodium hydroxide solution to pH 10 and extracted with methylene chloride (3 x 5 mL). The extracts were combined, dried with sodium sulfate (Na 2 SO ₄ ) and evaporated to give compound D (48 mg; 72%) as a solid.

LC / mass spectrum: (M + H) ⁺ = 174.

E) (R) -6-Cyano-1,2,3,4-tetrahydro-N- (phenylmethyl) -3-quinolinamine

A mixture of compound D (48 mg; 0.28 mmol) and benzaldehyde (29 mg; 0.28 mmol) in acetic acid (1 mL) was stirred at

The solution was stirred for 15 minutes and NaBH (OAc) ₃ (58 mg; 0.28 mmol) was added. Equal amounts of benzaldehyde and NaBH (OAc) ₃ were added over 0.5 hours. A third portion of the same amount of benzaldehyde (29 mg) and NaBH (OAc) ₃ (58 mg) was added for another 0.5 h. The reaction mixture was neutralized with 1N sodium hydroxide solution and extracted with methylene chloride (3 x 10 mL). The combined extract was dried over sodium sulfate (Na ₂ SO ₄ ) and evaporated. The residue was purified by silica gel flash column chromatography eluting with ethyl acetate to give the title compound (55 mg; 75%) as a gel. LC / mass spectrum: (M + H) ⁺ = 264.

F) (R) -N- (6-Cyano-1,2,3,4-tetrahydro-3-quinolyl) -N (phenylmethyl) benzenesulfonamide

A mixture of compound E (55 mg; 0.21 mmol), benzenesulfonyl chloride (55 mg; 0.33 mmol), triethylamine (50 mg; 0.5 mmol) and DMAP (20 mg) in methylene chloride (1 mL) was stirred at The mixture was stirred at room temperature for 3 hours and then diluted with methylene chloride (10 mL). The resulting mixture was washed with water, dried with magnesium sulfate (MgSO ₄ ) and evaporated. The residue was purified by silica gel flash column chromatography eluting with EtOAc / hexanes (1: 2) to give the title compound (61 mg; 72%) as a foam.

LC / mass spectrum: (M + H) ⁺ = 404.

G) (R) -N- [6-Cyano-1,2,3,4-tetrahydro-1 - [(1 (methyl) -1H-imidazol-5-yl) methyl] -3-quinolyl] -N monohydrochloride - (phenylmethyl) benzenesulfonamide

A mixture of compound F (58 mg; 0.14 mmol) and 1-methyl-5-formylimidazole (20 mg; 0.18 mmol) in 1,2-dichloroethane (0.5 mmol) and TFA (0.2 mL) at RT The mixture was stirred at room temperature for 5 minutes and triethylsilane (0.05 ml) was added. The mixture was stirred at room temperature for 2 hours and evaporated. The residue is purified and

<1 ♦ · ♦ 9 9 9 9 9

9 9 9 9 9

9 9 9 9 99 99 reverse phase HPLC (column: YMC S5 ODS 20 x 100 mm; linear gradient from 10 to 90% MeOH in water containing 0.1% TFA in 15 min at 20 mL / min; UV 220 nm) . The fractions containing the desired product were combined and evaporated. The residue was dissolved in 1N hydrochloric acid (0.5 mL) and water (1 mL) and lyophilized to give the title compound (42 mg; 79%) as a colorless lyophilisate.

Mass Spectrum: (M + H) ⁺ = 498.

[α] _D = + 33.2 ° (c = 0.83, MeOH).

Example 30

(R, E) -8-Cyano-2,3,4,5-tetrahydro-3 (phenylmethyl) -2- (phenylsulfonyl) -5 - [(1H-imidazol-4-yl) methylene] ΙΗ-2- monohydrochloride benzazepine

The title compound is prepared as follows.

(A) (R) - [3-Hydroxy-1 (phenylmethyl) propyl] carbamic acid 1,1-dimethylethyl ester

To a solution of (R) -β - [[(1,1-dimethylethoxy) carbonyl] amino] benzenebutyrate (1.5 mg; 5.1 mmol; J. Med. Chem. 28, 434 (1985)) in THF (10 ml) lithium borohydride (218 mg; 10 mmol) was added dropwise followed by ethanol (10 ml). After stirring at room temperature for 18 hours, additional lithium borohydride (218 mg; 10 mmol) was added and stirring was continued for 6 hours.

^U1 «9 9 9 9 · 9

The reaction mixture was ice-cooled and adjusted to pH 4 by addition of 10% citric acid solution. The organic solvents were removed and the resulting cloudy aqueous solution was extracted with dichloromethane. The extracts were combined, dried over magnesium sulfate (MgSO ₄₎ and evaporated in vacuo yielding a clear colorless oily residue which was purified by flash chromatography on silica eluting with 30% ethyl acetate in hexanes to give the title compound (1.2 g; 89%) as a clear colorless oil.

Mass Spectrum: (M + H) ⁺ = 266.

B) (R) - [3-Bromo-1 (phenylmethyl) propyl] carbamic acid 1,1-dimethylethyl ester

To a solution of compound A (1.14 g; 4.8 mmol) and carbon bromide (7.9 g; 9.24 mmol) in methylene chloride (50 mL) was added triphenylphosphine (2 mL) in portions over 0.5 h. , 5 g (9.6 mmol). The mixture was evaporated in vacuo and the residue was purified by silica gel flash chromatography. Elution with 10% ethyl acetate in hexane gave the title compound (1.3 g;

%) as a white solid.

Mass Spectrum: (M + H) ⁺ - 328.

C) (R) -N- [3-Bromo-1- (phenylmethyl) propyl] benzenesulfonamide

A solution of compound B (1.3 g; 4 mmol) in 4N hydrochloric acid in dioxane (30 mL) was stirred for 3 hours.

A white precipitate is obtained. The mixture was evaporated to dryness and the residue was washed with ether and dried in vacuo to give 1.0 g of a white solid. To a solution of this solid and triethylamine (1.7 mL; 12 mmol) in methylene chloride (30 mL) was added dropwise benzenesulfonyl chloride (0.56 mL; 4.4 mmol). After 3 hours, the solution was flash chromatographed on silica gel. Elution with 3% ethyl acetate in chloroform gave the title compound

φ · · φ φ 1,3 (1.33 g; 90%) as a colorless oil.

Mass Spectrum: (M + H) ⁺ = 367.1 Br sample.

D) (R) -Triphenyl- [4-phenyl-3 - [(phenylsulfonyl) amino] butyl] phosphonium bromide

A solution of compound C (1.0 g; 2.7 mmol) and triphenylphosphine (0.78 g; 3 mmol) in acetonitrile (10 mL) was heated to 125 ° C in a pressure vessel. After 20 hours, the mixture was cooled to room temperature and added dropwise to 250 mL of vigorously stirred ether. A white precipitate is obtained. Filtration under a nitrogen atmosphere gave the title compound (1.4 g; 82%) as a white powder.

E) (R) -N- [1- (Phenylmethyl) -4- [1- (triphenylmethyl) -1H-imidazol-4-yl] -3-butenyl] benzenesulfonamide

A solution of Compound D (400 mg; 0.63 mmol) and 1-trityl-4-formylimidazole (320 mg; 0.94 mmol) in methylene chloride was dried with magnesium sulfate (MgSO ₄ ). The solids were filtered and the filtrate was evaporated to dryness. The white foam residue was diluted with THF (24 mL) and 3A molecular sieves were added. After 1 hour, a solution of lithium bis (trimethylsilyl) amide (1.4 mL; 1 molar) in THF was added dropwise. After 1 hour, the mixture was filtered and the filtrate was evaporated in vacuo. The residue was diluted with ethyl acetate and the solution was washed with brine, dried with magnesium sulfate (MgSO ₄ ) and evaporated. The resulting residue was purified by silica gel flash chromatography. Elution with 40% ethyl acetate in hexane gave the title compound (108 mg) and the Z-isomer (149 mg) (combined yield 67%).

Mass Spectrum: (M + H) ⁺ = 610.

• 9 99 99

F) 4-Bromo-3- (bromomethyl) benzonitrile

To a solution of 4-bromo-3-methylbenzonitrile (1.0 g; 5.0 mmol) in carbon tetrachloride (7.5 mL) was added N-bromosuccinimide (1.0 g;

5.6 mmol) followed by benzoyl peroxide (50 mg; 0.2 mmol) and the mixture was refluxed. After 10 hours, cool the reaction to room temperature, filter and wash the filtrate with 10% sodium bisulfite (NaHSO ₃ ) (5 mL) followed by water (5 mL).

Dry the organic layer with sodium sulfate (Na ₂ SO ₄ ), filter, remove the volatiles and purify the residue by flash chromatography on silica gel. Elution with 10% ethyl acetate in hexanes gave the title compound (0.5 g; 36%) as a white solid.

¹ H NMR (270 MHz, CDCl ₃ ) δ 4.55 (s, 2H); 7.38-7.42 (m, IH);

7.65-7.77 (m, 2 H).

G) (R, E) -N - [(2-Bromo-5-cyanophenyl) methyl] -N- [1- (phenylmethyl) -4 H- (triphenylmethyl) -1 H -imidazol-4-yl] -3-butenyl benzenesulfonamide

To a solution of compound E (279 mg; 0.45 mmol) in THF (4 mL) was added a 0.5 molar solution of potassium bis (trimethylsilyl) amide (1 mL) in toluene dropwise at room temperature under nitrogen. After stirring for 15 minutes, a solution of compound F (151 mg; 0.55 mmol) in THF (1 mL) was added. After 18 hours, the mixture was diluted with ethyl acetate, washed twice with brine, dried over magnesium sulfate (MgSO ₄ ), filtered and evaporated. The residue is flash chromatographed on silica gel. Elution with 10% ethyl acetate in hexane gave the title compound (185 mg;

%) as white foam. Obtained compound F (118 mg; 43%). Mass Spectrum: (M + H) ⁺ = 803.

H) (R, EN) -8-Cyano-2,3,4,5-tetrahydro-3- (phenylmethyl) -2 (phenylsulfonyl) -5 - [[1- (triphenylmethyl) -1H-imidazol-4-yl] methylene] 1 H-2-benzazepine

A solution of compound G (30 mg; 0.37 mmol), palladium acetate (0.4 mg; 0.002 mmol), triphenylphosphine (2 mg; 0.008 mmol), and triethylamine (11 μΐ) in acetonitrile (0.5 mL) was stirred at room temperature. The 80 ° C was heated for 6 hours. Then an additional amount of palladium acetate (1 mg) and triphenylphosphine (4 mg) were added. After 18 hours the volatiles were removed and the residue was subjected to flash chromatography on silica gel. Elution with 35% ethyl acetate in hexane gave the title compound (20 mg; 75%) as a pale yellow foam.

Mass Spectrum: (M + H) ⁺ = 723.

(I) (R, E) -8-Cyano-2,3,4,5-tetrahydro-3 (phenylmethyl) -2- (phenylsulfonyl) -5 - [(1H-imidazol-4-yl) methylene] monohydrochloride] - 2-benzazepine

To a solution of compound H (20 mg; 0.027 mmol) in dichloromethane (0.5 mL) was added triethylsilane (0.25 mL) and trifluoroacetic acid (0.1 mL). After 3 hours at room temperature, the volatiles were removed in vacuo. The residue as a white solid was diluted with ethyl acetate, a small amount of saturated sodium bicarbonate (NaHCO ₃ ) was added and the mixture was stirred vigorously. The mixture was dried with magnesium sulfate (MgSO ₄ ) and evaporated to give a gummy residue. This material was subjected to flash chromatography on silica gel. Elution with 3% methanol in chloroform gave the free base of the title compound as a white solid, which was dissolved in ethyl acetate and 1 molar hydrogen chloride in ether (30 μΐ) was added. The resulting precipitate was filtered and dried in vacuo to give the title compound (6.5 mg; 47%) as a white solid.

Claims (18)

Compound of formula I or II (I) 77, 88 in which 1, m, r, s and t are 0 or 1; n is 0, 1 or 2; Y is selected from the group consisting of CHR ¹² , SO 2, SO 3, CO, CO 2, O, NR ¹³ , SO ² NR ¹⁴ , CONR ¹⁵ , C (NCN), C (NCN) NR ¹⁶ , NR ¹⁷ CO, nr ¹⁸ SO 2, CONR ¹⁹ NR ²⁰ , SO 2 NR ²¹ NR ²² , S (O) (NR ²³ ), S (NR ²⁴ ) (NR ²⁵ ), or is without Y; Z is selected from the group consisting of CR ¹² , S, SO, SO 2, SO 3, CO, CO 2, O, NR ¹³ , SO ² NR ¹⁴ , CONR ¹⁵ , NR ²⁶ NR ²⁷ , ONR ²⁸ , NR ²⁹ O, NR ³⁰ SO2NR ³¹ , NR ³² SO2, NR ³³ C (NCN), NR ³⁴ C (NCN) NR ³⁵ , NR ³⁶ CO, NR ³⁷ CONR ³⁸ , NR ³⁹ CO ₂ , OCONR ⁴⁰ , S (O) (NR ⁴¹ ), S (NR ⁴² ) (NR ⁴³ ) or CHR ¹² ; or is without Z; R ⁷ , R ⁸ are selected from the group consisting of w 1 hydrogen, halogen, nitro, cyano and UR ⁴⁴ ; U is selected from the group consisting of sulfur atom, oxygen atom, NR ⁴⁵ , CO, SO, SO 2, CO 2, NR ⁴⁶ CO 2, NR ⁴⁷ CONR ⁴⁸ , NR ⁴⁹ SO 2, NR ⁵⁰ SO ² NR ⁵¹ , SO ² NR ⁵² , NR ⁵³ CO, CONR ⁵⁴ , PO2R ⁵⁵ and PO ₃ R ⁵⁶ or is free of U; R ⁹ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ R ¹⁹ , R ²⁰ , R ²² , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² R ³³ , R ³⁴ R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ / R ⁴² , R ⁴³ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ R ⁴⁸ , R ⁴⁹ R ⁵⁰ , R ⁵¹ , R ⁵² , R ⁵³ , R ⁵⁴ , R ⁵⁵ , R ⁵⁶ , R ⁵⁷ , R ⁵⁸ and R ⁵⁹ are selected that groups, which v is composed of hydrogen, lower alkyl, aryl, heterocycle, substituted alkyl or aryl; R ¹¹ and R ⁴⁴ are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle; R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl , heterocycle, substituted heterocycle, cyano, alkoxycarbonyl, carboxyl, carbamyl, substituted carbamyl, wherein the substituents on the nitrogen-substituted carbamyl group are selected from hydrogen, alkyl, substituted alkyl, aryl or aralkyl, substituted aryl, heterocycle, substituted heterocycle ; any two of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ may combine to form a cycloalkyl group; any two of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 taken} together may be oxo, except that when the carbon atom bearing the substituent is part of a double bond; R, S and T are selected from the group consisting of CH ₂ , CO and CH _{(CH2) p} Q, 9th where Q denotes NR ⁵⁷ R ⁵⁸ , OR ⁵⁹ or CN; and P indicates 0, 1 or 4- r A, B, and C indicates carbon atom, atom oxygen, atom open or atom nitrogen; D indicates carbon atom, atom oxygen, atom open or atom • · Or is free of D; its enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and solvates thereof; provided that when l and m are both 0, n is not 0, * 11 o R may be hydrogen, except when Z is SO or when Z is oxygen, NR ¹³ or sulfur and the carbon atom to which it is attached forms a double bond or when Y is SO ₂ , CO ₂ , NR ¹⁸ SO ₂ , S (O) (NR ²³ ) or S (NR ²⁴ ) (NR ²⁵ ); and * R ⁴⁴ can be hydrogen, except when U is SO, SO ₂ , NR ⁴⁶ CO 2 or NR ⁴⁹ SO ₂ . A compound according to claim 1, wherein 1, m, r, s and t are 0 or 1; n is 1 or 2; Y is CHR ¹² , SO 2, SO 3, CO, CO 2, SO ² NR ¹⁴ , CONR ¹⁵ or is without Y; and Z is CR ¹² , SO 2, SO ₃ , CO, CO ₂ , NR ¹³ , SO ₂ NR ¹⁴ , CONR ¹⁵ , NR ³⁰ SO ₂ NR ³¹ , NR ³² SO 2, NR ³⁶ CO, NR ³⁷ CONR ³⁸ , NR ³⁹ CO 2 . A compound of formula I according to claim 2, wherein 1, r, s and t are 0; m is 1; n is 1 or 2; Y is CHR ¹² , SO 2, CO, SO ² NR ¹⁴ or CONR ¹⁵ or is without Y; and Z is CR ¹² , SO 2, SO ₃ , CO, CO ₂ , SO ₂ NR ¹⁴ , CONR ¹⁵ , NR ³⁰ SO ₂ NR ³¹ , NR ³² SO ₂ , NR ³⁶ CO, NR ³⁷ CONR ³⁸ , NR ³⁹ CO 2 OF. A compound of formula II according to claim 2, wherein r, s, mat is 0; 1 is 1; n is 1 or 2; Y is CHR ¹² , SO 2, SO 3, CO, CO 2, SO ² NR ¹⁴ , CONR ¹⁵ or is without Y; and Z is CR ¹² , NR ¹³ , SO ² NR ¹⁴ , CONR ¹⁵ , NR ³⁹ CO ₂ or is Z free. A compound according to claim 3 or 4, wherein R ⁷ , R ⁸ represents an atom. Φ halogen, nitro, cyano or UR ⁴⁴ , where U is sulfur, oxygen, NR ⁴⁶ CO ₂ , NR ⁴⁷ CONR ⁴⁸ , R ⁴⁴ denotes hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocycle or substituted heterocycle; R ⁴⁶ and R ⁴⁷ denote hydrogen, lower alkyl, aryl, substituted. alkyl or aryl and A, B, C, D are carbon or nitrogen. The compound of claim 1, wherein the salt is from an organic or inorganic acid. A compound according to claim 6 which is a salt of hydrochloric acid, hydrobromic acid, methanesulfonic acid, hydroxyethanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid, nitric acid, phosphoric acid, boric acid, acids tartaric acid, citric acid, succinic acid, benzoic acid, ascorbic acid or salicylic acid. ^{7 * * * * * * * * * * * *} The compound of claim 1 which is: N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -1-naphthalenesulfonamide dihydrochloride; N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -1-naphthalenecarboxamide dihydrochloride; N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N- (phenylmethyl) methanesulfonamide dihydrochloride; N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -benzenesulfonamide dihydrochloride; N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N- (phenylmethyl) acetamide dihydrochloride; > 0 00 • · 0 · * ··· · 0 0 0 0 0 0 0 0 0 0 0 0 0 N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(4-methoxyphenyl) methyl] methanesulfonamide monohydrochloride; N- [6-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(4-methylphenyl) methyl] methanesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-yl) -3-quinolyl] -N - [(3-methylphenyl) methyl] benzenesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-yl) -3-quinolyl] -N - [(2-methylphenyl) methyl] benzenesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-yl) -3-quinolyl] -N- (phenylethyl) benzenesulfonamide monohydrochloride; 2,3,4,5-tetrahydro-5 - [(1H-imidazol-4-ylmethyl) amino] -2- (1-naphthylsulfonyl) -8-methoxy-1H-2-benzazepine dihydrochloride; 2,3,4,5-tetrahydro-5 - [(1H-imidazol-4-ylmethyl) amino] -2- (1-naphthylsulfonylsulfonyl) -8-phenyl-1H-2-benzazepine dihydrochloride; 2,3,4,5-tetrahydro-5 - [(1H-imidazol-2-ylmethyl) amino] -2- (1-naphthylsulfonyl) -8-phenyl-1H-2-benzazepine dihydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(2-ethoxyphenyl) methyl] benzenesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N- (phenylmethyl) benzenesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(2,3-dimethoxyphenyl) methyl] benzenesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(3,5-dimethylphenyl) methyl] benzenesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(1-naphthalenyl) methyl] benzenesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(2-thiophene) methyl] benzenesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(2,5-dimethylphenyl) methyl] benzenesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(3-thiophene) methyl] benzenesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(3-chlorophenyl) methyl] benzenesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(2-fluorophenyl) methyl] benzenesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N - [(3-pyridyl) methyl] benzenesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1 - [(1 (methyl) -1H-imidazol-5-yl) methyl] -3-quinolyl] -N (phenylmethyl) benzenesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1 - [(1 (methyl) -1H-imidazol-5-yl) methyl] -3-quinolyl] -N - [(3-thiophenomethyl) benzenesulfonamide monohydrochloride ; N- [6-cyano-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-quinolyl] -N- (phenylmethyl) methanesulfonamide monohydrochloride; N- [6-cyano-1,2,3,4-tetrahydro-1 - [(1 (methyl) -1H-imidazol-5-yl) methyl] -3-quinolyl] -N (phenylmethyl) methanesulfonamide monohydrochloride; 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0000000 0 0 «« _t '00 0000 (R) -N- [6-Cyano-1,2,3,4-tetrahydro-1 - [(1 (methyl) -1H-imidazol-5-yl) methyl] -3-quinolyl] -N- ( phenylmethyl) benzenesulfonamide; and (R, E) -8-Cyano-2,3,4,5-tetrahydro-3 (phenylmethyl) -2- (phenylsulfonyl) -5 - [(1H-imidazol-4-yl) methylene] ΙΗ-2- monohydrochloride benzazepine. 9. A method of inhibiting farnesyl protein transferase comprising administering to a mammalian subject an effective amount of a compound of claim 1 which inhibits farnesyl protein transferase. 10. A method of inhibiting prenyltransferase comprising administering to a mammalian subject an effective amount of a compound of claim 1 inhibiting prenyltransferase. 11. A method of inhibiting tumors comprising administering to a mammalian subject an effective amount of a tumor inhibiting compound of claim 1. 12. A method of treating diseases associated with ras signaling transduction pathways, comprising administering to a mammalian subject an effective amount of a compound of claim 1. 13. A method of treating diseases associated with proteins that are post-translationally modified with a farnesyl protein transferase enzyme comprising administering an effective amount of a compound of claim 1 to a mammalian subject. 14. A method for treating diseases associated with proteins that are post-translationally modified with geranylgeranyl protein transferase, the method comprising administering to a mammalian subject an effective amount of a compound of claim 1. φφ φφφφ 15. A method of treating autoimmune diseases comprising administering to a mammalian subject an effective amount of a compound of claim 1. 16. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1. fa 17. A pharmaceutical composition comprising a compound according to claim 1 in combination with known anticancer and cytotoxic agents and a pharmaceutical carrier. 18. A method of inhibiting tumors comprising administering to a mammalian subject an effective amount of a tumor inhibiting compound of claim 17.