NL1025527C2 - Triazole compounds that are useful in therapy. - Google Patents

Description

5 10

TRIAZLE COMPOUNDS THAT ARE USEFUL IN THERAPY

This invention relates to novel compounds useful in therapy and methods for the preparation of intermediates used in the preparation of compositions containing such derivatives, and their use.

Japanese Patent Application No. 09328484 describes triazole quinoxalines useful as anti-allergic and inflammatory agents. Japanese patent application No. 09132576 describes triazole quinoxalines that are useful as anti-allergic and inflammatory agents. Japanese patent application No. 06135965 describes triazole quinoxalines that are useful for curing and preventing allergies, inflammation, and PAF-related diseases. Japanese Patent Application No. 06128262 describes triazole quinoxalines that are useful for drug intermediates and agrochemicals.

The compounds of the present invention have been found to have useful pharmaceutical properties. These can be used to treat aggression, Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder, asthma, atherosclerosis, autism, cardiovascular disease (including angina, atherosclerosis, hypertension, cardiac insufficiency, edema, hypernatremia), cataract, disease of the central nervous system, cerebrovascular ischemia, cirrhosis, cognitive impairment, CUS disease- 1025527

2 I

depression, diabetes mellitus, dysmenorrhea (primary I

and secondary), emesis (including motion sickness), endo-I

metriosis, gastrointestinal disease, glaucoma, gynecolo-I

logical disease, heart disease, internal retardation I

Uterus growth, inflammation (including rheumatoid I

arthritis), ischemia, ischemic heart disease, lung tumor, I

micturition disorder, mittelschmerz., neoplasm, nephrotoxicity,. I

non-insulin dependent diabetes, obesity, obesity

severe / compulsive disorder, ocular hypertension, pre-I

10 clampsia, early ejaculation, premature (early-term I

g) contractions, pulmonary disease, Raynaud's disease, kidney disease

te, renal insufficiency, male or female sexual I

dysfunction, septic shock, sleep disorder, injury to the I

spinal cord, thrombosis, urinary tract infection or uroli

Thiasis. I

Of particular interest are the following diseases or disorders:

anxiety, cardiovascular disease (including angina, I

atherosclerosis, hypertension, heart failure, edema, I

Hypernatremia), dysmenorrhea (primary and secondary), and I

dometriosis, emesis (including motion sickness), delay I

of internal growth in the uterus, inflammation (including I

rheumatoid arthritis), mittelschmerz, preclampsia, early I

timely ejaculation, premature (early) contractions and I

25 Raynaud's disease. I

In particular, these antagonistic actions show

vasopressin and can be used in I

the treatment of dysmenorrhea (primary and secondary). I

There is a major, unforeseen need in the field

30 offer of menstrual disorders. It is estimated that up to 90% I

of all menstruating women due to this to some extent through I

is affected. Up to 42% of women are absent

at work or as a result of other activities I

of menstrual pain, and it has been estimated that as a result United States 600 million working hours per

years (which is approximately $ 2 billion in pro- I

production loss). I

1025527 I

3

Menstrual pain in the lower abdomen is caused by myometric hyperactivity and reduced blood flow to the uterus. These pathophysiological changes result in pain in the abdomen radiating to the back and legs. This can cause women to feel nauseous, have a headache and suffer from insomnia. This condition is called dysmenorrhea and can be classified as primary or secondary dysmenorrhea.

The diagnosis is primary dysmenorrhea if no abnormality is identified that causes the condition. This affects up to 50% of the female population. When a fundamental gynecological disorder is present, such as endometriosis, pelvic inflammatory disease (PID), fibroids or cancers, secondary dysmenorrhea will be the diagnosis. Secondary dysmenorrhea is diagnosed in only about 25% of women who suffer from dysmenorrhea. Dysmenorrhea can occur with menorrhagia, which. about 12% of the referrals to gynecological clinics.

Today, women suffering from primary dysmenorrhea are treated with non-steroidal anti-inflammatory drugs (NSAIDs) or the oral contraceptive pill. With secondary dysmenorrhea, surgery can be performed to correct the fundamental gynecological disorder.

Women suffering from dysmenorrhea have circulating vasopressin level that are larger than those observed in healthy women at the same time in the menstrual cycle. Inhibition of the pharmacological effects of vasopressin on the vasopressin receptor in the uterus may prevent dysmenorrhea.

According to the present invention, there is provided a compound of formula (I), 1 025527

N-N I

X-N / A \ I I

.ΛνΛ y 1i w,

! I

X 4 γ 1

(I). . I

10 I

or a pharmaceutically acceptable derivative thereof, wherein I

V represents - (CH 2) d (O) e-, -CO- or -CH (C 1-6 alkyl) -, I

W is -0-, -S (0) a- or -N (R1) -, I

R 1 represents H, C 1-6 alkyl, (CH 2) b CO 2, CO (CH 2) b NR 2 R 3, I

SO2R2, (CH2) cOR2, (CH2) cNR2R3 or (CH2) bhetl, I

het1 represents a saturated or unsaturated hetero-I

ring with 3 to 8 atoms containing one or more heteroatoms I

which are selected from 0, N or S, and optionally substituted

is C 1-6 alkyl

X and Y independently represent H, C 1-6 alkyl, halo

none, OH, CF3, OCF3, OR4, I

Z represents - (CH 2) f (O) g-, -CO- or -CH (C 1-6 alkyl) -, I

Ring A represents a 4-7-membered, saturated hetero-I

ring containing N, optionally substituted with OH, and I

Wherein optionally at least one ring-N is substituted I

with 0, I

Ring B represents a phenyl or a 4-7-long indefinite

saturated heterocycle containing N, optionally substituted I

with OH, halogen, CN, CO NH 2, CF 3, CF 3, and wherein optionally I

At least one ring -N is substituted with 0.1

R2 and R3 independently represent H, C1-6 alkyl [even-I

optionally substituted with OH, halogen, N (C 1-6 alkyl) 2 or I

C1-6 alkyloxy], C1-6 alkyloxy, N (C1-6 alkyl) 2 or [C3-8 cycloalkyl]

alkyl], I

35 or R 2 and R 3, together with the nitrogen atom to which de-I

they are bound, independently represent a heterocycle I

1 025527 I

5 with 3 to 8 atoms, optionally substituted with C 1-6 alkyl, R 4 represents straight or branched C 1-6 alkyl, a and c independently represent 0, 1 or 2, 5 b, e narrowly represent 0 or 1, d and f independently 1 or 2 proposals.

In the above definitions, halogen, fluorine, chlorine, bromine or iodine means. Alkyl groups containing the required number of carbon atoms may have a branched or branched chain except where indicated. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of alkyloxy include methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, sec-butyloxy and t-butyloxy.

Restorations included in the definition of "heterocycle" include pyrrolyl, imidazolyl, triazolyl, thie-myl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazo-lyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indoleyl, isoindyl , quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl and quinoxalanyl, together with partially or fully saturated versions thereof, as well as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxazepanyl and morpholiyl.

Preferred groups of compounds are those in which one. or more of the following may apply: (I) W is NR 1, (ii) R 1 is C 1-6 alkyl. and more preferably methyl, i-propyl or n-butyl, (iii) R1 is H, (iv) R1 is (CH2) bhet1, (v) het1 is pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, oxazepanyl, pyrimidinyl, pyridinyl , thiazolyl or imidazolyl (optionally substituted with C 1-6 alkyl), 1025527

(vi) R 1 is CO (CH 2) b NR 2 R 3, I

(vii) R 2 is morpholinyl or pyrimidinyl (optionally I

substituted with C 1-6 alkyl [optionally

substituent with OH, halogen, N (C 1-6 alkyl) 2 I

5 or C 1-6 alkyloxy] or NMe 2), I

(viii) R2 and R3 represent, together with the stitching I

substance to which they are bound, morphol

nyl, pyrrolidinyl, piperazinyl, azetidinyl,

tetrahydropyranyl, pyrimidinyl or piperidine

Nyl (optionally substituted with C 1-6 I

alkyl). I

(ix) V is - (CH 2) <j (O) e-, I

(x) Z is - (CH 2) f (0) g-, I

(xi) d is 1.1

15 (xii) e is 0.1

(xiii) f is 1

(xiv) g is 0.1

(xvj X is H, (xvi) Y is in the 4 position of the phenyl

Loan ring (according to the numbering of formula I

(I)) to which it is bound, I

(xvii) Y is halogen, and preferably chlorine, I

(xviii) Y is alkyloxy, preferably methoxy, I

(xix) Y is alkyl, and preferably methyl, I

(Xx) Y is CF 3 or OCF 3, I

(xxi) Z is (CH 2) d (0) e -1

(xxii) e is 0. I

(xxiii) d is 1, I

(xxiv) ring A is bound to ring B via a stitching

30 dust atom in ring A, I

(xxv) ring A is piperidinyl (optionally substituted)

with OH, and at least one N is l

substituted with O), I

(xxvi) ring B is pyridinyl (optionally substituted

35 honored with one or more groups being I

selected from OH, halogen, CN, CONH 2, CF 3, I

0 CF 3, and at least one ring -N is substituted

v025527 I

7.

O), and preferably this is 2-pyridinyl, (xxvii) ring is B pyrimidinyl (optionally substituted with one or more groups selected from OH, halogen, CN, CONH2, CF3, OCF3, and optionally a ring -N is substituted with 0), and preferably it is 2-pyrimidinyl, (xxviii) n is 1, 10 (xxix) n is 2.

Preferred compounds of the present invention are: (1) 8-Chloro-5-methyl-1- (3,4,5,6-tetrahydro-2H- [1,21] bi-pyridinyl-4-yl) -5, 6-dihydro-4H-2,3,5,10b-tetraazabenzo [e] -azule trihydrochloride, 8-chloro-5-isopropyl-1- (3,4,5,6-tetrahydro-2H- [1,2 '] -bipyridinyl-4-yl) -5,6-dihydro-4H-2,3,5,10b-tetraazabenzo [e] azuline trihydrochloride, 20 1- [8-chloro-1- (3,4,5,6-) tetrahydro-2H- (1,2-bipyridinyl-4-yl) -4H-6H-2,3,5,10b-tetraazabenzo [e] -azulene-5-yl] -ethanone dihydrochloride, 8-chloro- 5-methanesulfonyl-1- (3,4,5,6-tetrahydro-2H- [1,2 ') bipyridinyl-4-yl) -5,6-dihydro-4H-2,3,5,10b-tetra- Azabenzo (e) azulene, (5) 8-Chloro-5-methyl-1- (1-pyrimidin-2-ylpiperidin-4-yl) -5,6-dihydro-4H-2,3,5,10b- tetraazabenzo [ejazulene, 8-chloro-5-methanesulfonyl-1- (1-pyrimidin-2-yl-piperidin-4-yl) -5,6-dihydro-4H-2,3,5,10b-tetraazabenzo-30 [ e] azulene, 13-Chloro-8-methyl-3- (3,4,5,6-tetrahydro-2H- [1,2 '] bi-pyridinyl-4-yl) -2,4,5,8- tetraazatricyclo [9.4.0.0 * 2.6 *] - pentadeca-1 (11), 3,5,12,14-pentaene, 13-chloro-3- (3, 4,5,6-tetrahydro-2H- [1,2 '] bipyri-35-vinyl-4-yl) -8-oxa-2,4,5-triazatricyclo [9.4.0.0 * 2.6 * ] - pentadeca-1 (11), 3,5,12,14-pentaene, 1025527

8 I

1- [8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyri]

dinyl-4-yl) -4H, 6H-2,3,5,10b-tetraazabenzo [e] azulene-5-yl] -1

2-dimethylaminoethanone, I

5 (10) [8-Chloro-1- (3,4,5,6-tetrahydro-2 H- [1,2 '] bipyri]

dinyl-4-yl) -4H, 6H-2,3,5,10b-tetraazabenzo [e] azulene-5-yl] -1

morpholin-4-ylmethanone, (+) - or. (-) - 8-Chloro-5- (4-methylmorpholin-2-ylmethyl)

thyl) -1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -1

5,5-dihydro-4H-2,3,5,10b-tetraazabenzo [e] azulene,

8-Chloro-5-pyrimidin-2-yl-1- (3,4,5,6-tetrahydro-2 H -1)

[1,2 "] bipyridinyl-4-yl) -5,6-dihydro-4 H -2,3,5,10b-tetra-1

azabenzo [e] azulene, I

8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-1

4-yl) -4H, 6H-2,3,5,10b-tetraazabenzo [e] azulene-5-sulfone-1

acid dimethylamide, I

8-1- Chloro-1- (1-pyrimidin-2-yl-piperidin-4-yl) -4.H, 6H-1

2,3,5,10b-tetraazabenzo [e] azulene-5-sulfonic acid I

dimethylamide, I

20 (15) 13-Chloro-9-methyl-3- (3,4,5,6-tetrahydro-2H- (1,2 ') -1

bipyridinyl-4-yl) -2,4,5,9-tetraazatricyclo [9.4.0.0 * 2.6 *] -1

pentadeca-1 (11), 3,5,12,14-pentaene and I

(16) 13-Chloro-8-methyl-3- (1-pyriraidin-2-ylpiperidine-4-)

yl) -2,4,5,8-tetraazatricyclo [9.4.0.0 * 2.6 *] pentadecial

25 1 (11), 3,5,12,14-pentaene.

Alternatively, a connection with

formula (I *), I

30 n-N 1

y— ^ I

^ aT n w |

(b | Λρ (cH2) n I

* Y I

35

o *) I

1 02552? I

9 wherein WO, S or NR 1 is, R 1 represents H, C 1-6 alkyl, - (CH 2) a - [C 3-8 cycloalkyl], phenyl, benzyl, pyridyl, pyrimidyl, -COR 2, -C 2 R 2, -CO- ( CH 2) α-NR 2 R 3, -SO 2 R 2, - (CH 2.) B-OR 2, - (CH 2) b R NR 2 R 3, or a saturated heterocycle with 3 to 8 atoms containing one or more. contains heteroatoms selected from O, N and S, X and Y independently represent H, halogen, OH, CF 3,. OCF 3, R 4, - (CH 2) d-CONR 4 R 5, - (CH 2) d-CN, (-CH 2) d-SO 2 NR 4 R 5, - (CH 2) dNR 4 SO 2 Me, - (CH 2) d-COR 4, - (CH 2) d-OCOR 4 ,. - (CH2) d-NHCOR4, - (CH2) d-NR4 COR5, - (CH2) d-OR6. or - (CH 2) d -CO 2 R 6,

Ring A represents a piperidinyl, piperazinyl, pyrrolidinyl or azetidinyl group, Ring B represents a phenyl, pyridinyl or pyrimidinyl group (optionally substituted with one or more groups independently selected from halogen, CN, CONH2, CF 3, OCF 3, R 1 and - (CH 2) OR 8), R 2, R 3, R 4, R 5 and R 7 independently represent H, straight or branched C 1-6 alkyl, - (CH 2) c- [C 3-7 cycloalkyl], phenyl, benzyl, pyridyl or pyrimidyl, or R2 and R3 or R4 and R5, together with the nitrogen atom to which they are attached, independently represent a heterocycle with 3 to 8 atoms, R6 and Re independently represent H, straight or branched C1-6 alkyl, - ( CH2) c- [C3-8 cycloalkyl], - (CH2) e-NR4 R5, - (CH2) e-OR4, phenyl, benzyl, pyridyl or pyrimidyl, n = 0, 1 or 2, a, c, d and f all are independently selected from 0, 1, 2 or 3, b and e are independently selected from 2 or 3. Pharmaceutically acceptable derivatives of the compounds of formula (I) of the present invention include salts, solvates, complexes, polymorphs, prodrugs, stereoisomers, geometric isomers, tautomeric forms and isotopic variations of compounds of formula (I). Preferably, pharmaceutically acceptable include 1 02552 7

10 I

derivatives of compounds of formula (I) salts, solva-I

, esters and amides of the compounds of formula (I). I

More preferably, pharmaceutically acceptable derivatives of I

compounds of formula (I) salts and solvates. I

The pharmaceutically acceptable salts of the compound

things of formula (I) include the acid addition and base I

salts thereof. I

Suitable acid addition salts are formed with acids I

which form non-toxic salts. Examples include the I

Acetate, aspartate, benzoate, besylate, bicarbonate

carbonate, bisulfate, borate, camsylate, citrate, I

edisylate, esylate, formate, fumarate, glucose, I

gluconate, glucuronate, hexafluorophosphate, hibenzate, I

hydrochloride / chloride, hydrobromide / bromide, hydrojo

Dide / iodide, isethionate, D and L lactate, malate, I

maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-rapesylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, diwa

terstate phosphate / saccharate, stearate, succinate, sulphite

20 fate, D and L tartrate, tosylate and trifluoroacetate salts

. A particularly suitable salt is the besylate derivative I

of the compounds of the present invention. I

Suitable base salts are formed from bases that I

form non-toxic salts. Examples include the al

Minium, arginine,. benzathine, calcium, choline, I

diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

: For an overview of suitable salts, see: Stahl and I

30 Wermuth, Handbook of Pharmaceutical Salts: Properties, Se-I

lection and Use, Wiley-VCH, Weinheim, Germany (2002). I

A pharmaceutically acceptable salt of a compound

Formula (I) can be easily prepared by I

mixing the solution and the compound with formal

35 formula (I) and the desired salt or base, to I

whichever applies. The salt can be removed from the I

precipitate the solution and are collected by filtration or I

1025527 I

11 are recovered by evaporation of the solvent. The degree of ionization in the salt can vary from fully ionized to substantially non-ionized.

The compounds of the present invention can exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the present invention and one or more pharmaceutically acceptable dissolving molecules, e.g., ethanol. The term "hydrate" is used when the solvent is water.

Included within the scope of the present invention are complexes such as clathrates, so-called host-drug-inclusion complexes in which, unlike the aforementioned solvates, the drug and recipient are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug that contain two or more organic and / or inorganic components that may be present in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized or non-ionized. For an overview of such complexes, see J. Pharm. Sci., 64 (8), 1269-1288, by Haleblian (August 1975).

Hereinafter, all references to compounds of formula (I 1 and pharmaceutically acceptable derivatives include references to salts, solvates and complexes thereof, and to solvates and complexes or salts thereof. The compounds of the present invention include compounds of formula (I) as previously defined, polymprints, prodrugs and isomers thereof (including optical, geometric, and tautomeric isomers) as defined below and isotope-labeled compounds of formula (I).

As noted, the present invention includes all polymorphs of the compounds of formula (I) as hereinbefore defined.

1 025527

12 I

Also within the scope of the present invention

invention, so-called "prodrugs" fall from the compounds

of formula (I). Certain derivatives of compounds with I

formula (I) which itself may have little or no pharmacology

Have a chemical activity, when they are in or on the I

be administered to the body, thus being converted into

things of formula (I) with the desired activity, e.g.

for example by hydrolytic cleavage. Such derivatives

are referred to as "prodrugs". Further information I

10 on the use of prodrugs can be found in I

"Pro-drugs as Novel Delivery Systems, vol. 14, ACS Symp-I

. sium Series (T. Higuchi and W. Stella) and "Bioreversible I

Carriers in Drug Design ", Pergamon Press, 1987 (ed. E.B. I

Roche, American Pharmaceutical Association). I

Prodrugs in accordance with the present invention

The invention can be produced, for example, by Compound

capture 'of suitable functions included in the compounds with I

formula (I) are present by certain residues, which for I

those skilled in the art are known as "pro-residues" such as, for example

20 image are described in. "Design of Prodrugs" by Η. I

Bundgaard (Elsevier, 1985). I

Some examples of prodrugs in accordance with I

with the present invention include: I

(I) when the compound of formula (I) is an I

25 contains carboxylic acid function (-COOH), an ester thereof, for example

example by replacing the hydrogen with (Ci-I

C6 alkyl, I

(ii) when the compound of formula (I) is an I

contains alcohol function (-OH), an ether thereof, for example

Image by replacing the hydrogen with (C * -. I

C 1-6 alkanoyloxymethyl and I

(iii) when the compound of formula (I) is an I

primary or secondary amino function (-NH2 or -NHR where R I

H) contains one. amide thereof, for example by replacement I

35 of one or both hydrogens by (C 1 -C 10) alkanoyl. I

Further examples of replacement groups in I

accord with the preceding examples, and examples I

1025527-1

13 of other prodrug types can be found in the aforementioned references.

Finally, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

Also within the scope of the present invention are the metabolites of the compounds of formula (I) when formed in vivo.

Compounds of formula (I) containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. When a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible and, for example, when the compound has a keto or oxime or an aromatics moiety tautomeric isomerism ("tautomerism") may occur. It goes without saying that a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including. compounds that exhibit more than one type of isomerism, and mixture of one or more thereof. Also included are acid addition or base salts in which the counter ion is optically active, for example D-lactate or L-lysine, or is racemic, for example DL-tartrate or DL-arginine.

Cis / trans isomers can be separated by conventional techniques known to those skilled in the art, for example fractional crystallization and chromatography. Conventional techniques for preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically, pure precursor or separation of the racemate (or the racemate of a salt or derivative) using, for example, chiral HPLC. Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active. compound, for example an alcohol, or, in the case of 02552 /

14 I

wherein the compounds of formula (I) are an acid or basic

chemical residue, an acid or base such as tartaric acid I

or 1-phenylethylamine. The resulting diastereomeric mixture I

can be separated by chromatography and / or fractional

5 crystallized crystallization and one or both diastereomers can

can be converted into the corresponding pure I

enantiomer (s) by means suitable for an expert I

be famous. Chiral compounds of the present invention

invention (and chiral precursors thereof) can be advanced

10 were enriched in enantiomeric form with the aid of chromium

matography, typically HPLC, on an asymmetry

synthetic resin with a mobile phase consisting of an I

hydrocarbon, in a typical heptane or hexane, which is 0 to I

50% isopropanol, typically 2 to 20%, and 0 l

15 to 5% of an alkylamine, typically 0.1% I

diethylamine. Concentration of the eluate yields the I

enriched mixture. I

Stereoisomeric conglomerates can be separated I

by means of conventional techniques used for expertise

20 are known - see, for example, "Stereochemistry of I

Organic Compounds ". By E. L. Eliel (Wiley, New York, I

1994). I

The present invention also includes all pharmaceuticals

Iotically acceptable isotopic yariations of a compound

A compound of the formula (I) in which one or more atoms are replaced

are by atoms with the same atomic number, but with I

an atomic mass or mass number that resp. that is different from I

the atomic mass or mass number that is usually found in nature I

is found. I

Examples of isotopes suitable for incorporation

. in the compounds of the present invention

contain isotopes of hydrogen such as 2H and 3H, carbon, etc.

as UC, 13C and UC, nitrogen such as 13N and 15N, oxygen such

as 150, 170 and 180, phosphorus such as 32 P, sulfur such as 35 S, flu

35 or such as 18F, iodine such as 123I and 12SI, and chlorine such as 36C1. I

Certain isotope-labeled compounds I

of formula (I), for example those in which a radioactive I

1025527-1

• isotope is included, are useful in distribution studies of drug and / or substrate tissue. The radioactive isotope tritium, i.e. 3H, and carbon-14, that. that is, 14C, are particularly useful for this purpose in view of the ease of their recording and the easy method of detection.

Substitution with heavier isotopes such as deuterium, i.e., 2H, can provide certain therapeutic benefits that result from greater metabolic stability, e.g., increased in vivo half-life or lower dosage requirements, and may therefore be preferred in some cases.

Substitution with isotopes emitting positrons, such as UC, 18F, 150 and 13N, may be useful with. Positron 15 Emission Topography (PET) studies for research into the occupation of a substrate receptor.

Compounds of formula (I) provided with an isotope label can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying examples and preparations, wherein instead of unlabelled reagents that were previously used now that suitable reagents with an isotope label 25 are used.

Pharmaceutically acceptable solvates in accordance with the present invention include those in which the crystallization solvent may be isotopically substituted, e.g., D2O, d6-acetone and d2-DMSO.

According to the present invention there is provided a process for the production of a compound of formula (I), which comprises: a) reacting a compound of formula (II) with an acid catalyst 1025527-

16 I

N-N I

5 · ί ~ \ Ά v 'I

° w'z \ __ Y I

H2N \ I

(ίο x I

10 I

wherein the rings λ and B and the groups V, W, X, Y, Z and η

have the meaning given above, I

b) reacting a compound with formula

15 le (III) I

N-N I

h / "\ JL v I

H N A Y ^ N V 1 I

20. ΙτΓ'1 I

X Y I

(in) I

25 I

with a compound of formula (IV) I

(B 2 "I

30's

(IV) I

35 wherein the rings A and B and the groups V, W, X, Y, Z and η I

have the meaning given above and Z 'has a departure I

specific group such as halogen, I

102552 - I

C) when W in compound (I) represents NR 1, reacting a compound of formula (V) 5 N-N /

Yes) n nh / (b [Γι'2 10 (V) with a compound of formula (VI) 15 -j ': <Y0 wherein the rings A and B and the groups Ra> V, X, Y, Z and n have the meaning given above and Z "has a starting group, such as halogen, or d) when W in compound (I) represents NR1, reacting a compound of formula (V) Χγ" (V) with a compound of formula (VII) 35 R 10 (VII) · ..

/ f 1025527-

18 I

wherein the rings A and B and the groups R1, V, X, Y, Z and η I

have the meaning given above,

e) reacting a compound of formula I

le (XIII) I

5 I

o I

VV ^ NH I

NH? I

10. I

(XIII) I

with a compound of formula (XXIV) I

I

S I

V I

HN \ 1 w |

20 I

- Y I

(XXIV) I

Wherein the rings A and B and the groups V, W, X, Y and Z de I

have the meaning given above, I

f) reacting a compound of formula I

le (xiii) I

o I

30 I

NHj

(XIII) I

35 I

1025527-1

. 19 with a compound of formula (XXV) 5 N

W

• Qrz '; x v (XXV) wherein the rings A and B and the groups V, W, X, Y and Z have the meaning given above.

Unless otherwise stated herein: 15, WSCDI means 1- (3- (dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, DCC Ν, Ν'-dicyclohexylcarbodiimide, HOAT means 1-hydroxy-7-azabenzotriazole, HOBT means 1-hydroxybenzotriazole hydrate, 20 PyBOP® means benzotriazole-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate, means "PyBrOP® bromo-trispyrrolidinophosphoni'umhexa-fluorophosphate, means HBTU O-benzotfiazol-1-yl-Ν, Ν, Νf-orff-orffon-hef-hefon-orff-phonium-phosphorate" , Mukaiyama reagent means 2-chloro-1-methylpyridinium iodide, KHMDS means potassium bis (trimethylsilyl) amide, Hünig's base means N-ethyldiisopropylamine, Et3N means triethylamine means NMM N-methylmorpholine, means HMDS hexamethyldisalazane'2,2.2-azalazane'2Disaprazole -bis (diphenylphosphino) -1,1'-binaphthyl, Dba means dibenzylidene acetone, Boe means tert-butoxycarbonyl, CBz means benzyloxycarbonyl, 1 0 25 52 7

20 I

p-TSA means p-toluenesulfonic acid, I

TBAF means tetrabutylammonium fluoride, I

MeOH means methanol, EtOH ethanol and EtOAc I

ethyl acetate, I

5, THF means tetrahydrofuran, DMSO dimethyl sulfoxide I

and DCM dichloromethane, DMF Ν, Ν-dimethylformamide, NMP N-1

methyl 2-pyrrolidinone,

AcOH means acetic acid, TFA trifluoroacetic acid, I

Me means methyl, Et ethyl, I

10 means Cl means chlorine and OH means hydroxy.

The following schemes illustrate the preparation of

compounds of the formula (I) in which everywhere the rings A I

and B and the groups V, W, X, Y and n the I given above

Have meaning unless otherwise stated. (I ') I

represents (I) when W is NR1. I

N-N 11

20 "^ -jTyV-v" I

f Υ-Ά Λ I. u \ ^ x I A \ N \ I

(b w — z _ !! _>. ΛλΛΝ i w I

^ ^ I

00 W'x, (I) I

25 Schémai.1 I

Step (a): the oxadiazole (II) is reacted I

with an acid catalyst, which is the compound of formula I

30 le (I). In a typical case, the. response

carried out by heating the starting materials until I

elevated temperatures, such as 50-150 ° C, for 1 to 48

hour with a suitable acid catalyst such as β-TSA, tri-l

fluoroacetic acid or a Lewis acid as a catalyst, such as

Magnesium chloride, optionally with a solvent such as xyl

lene, toluene or tetrahydrofuran. I

The preferred conditions are: I

1025 527-1

21 amine (II) and cat. p-TSA, in xylene at 14 ° C for 48 hours or amine (II), trifluoroacetic acid in tetrahydrofuran at. . 60 ° C for 24 hours.

5 When W = NR1, then:

N-N

/ ^ Λ> -v Ύ A ΪΌ \ 10 ”VvY · ψ-θχ - (Η) a / 15

N-N

N-N / ~ \ JL

i a T n y R. (q 1. nr1; (bJC ^ Λ. / η (vo vjy. · Γ7-2

. b (Π * V

20 M!

Scheme 1.2 «25 Z 'is OH or halogen, typically Cl.

The compounds suitable for use as compound (VI) are commercially available or known in the literature.

Step (b): The reaction of amine (V) with compound (VI) can be carried out by standard methods.

When R 1 - (CH 2) b COR 2, CO (CH 2) b NR 2 R 3, SO 2 R 2, the coupling can typically be carried out by using: (I) an acyl sulfonyl chloride (VI) + amine (V) with an excess of one acid acceptor, in a suitable solvent, or 1025527-

22 I

(ii) an acid (VI) with a usual coupling I

agent + amine (V), optionally in the presence of an I

catalyst, with an excess of an acid acceptor in an I

suitable solvent and I

(Iii) when R 1 represents an aryl group, an I

aryl halide (VI) + amine (V), optionally in the presence I

of a catalyst, with an excess of an acid acceptor I

in a suitable solvent. I

The conditions are typically as follows: I

10 I

Acylerin / sulfonylerin, Z1 - Cl. I

(I) An excess of acyl / sulfonyl chloride (VI) (in I

generated), 1 eq. of amine (V), optionally with an I

excess of a 3 ° amine such as Et 3 N, Hünig's base or NMM, I

15 in DCM or THF, without heating for 1 to 24 hours. I

The preferred conditions are: I

Amine (V), 1.1-3.0 eq. acid / sulfonyl chloride (VI), I

1.5-3 eq. NMM, Et 3 N or pyridine in DCM at room temperature

for 1-16 hours. I

20 I

Formation of amide bond, Z '= OH I

(ii) Excess acid (VI), WSCDI / DCC and HOBT / HOAT, 1 I

eq. of amine (V), with an excess of NMM, Et 3 N, Hünig's I

base in THF, DCM or EtOAc, at room temperature during I

25 4 to 48 hours or I

excess acid (VI), PyBOP® / PyBrOP® / Mukaiyama-I

reagent / HBTU, 1 eq. amine (V), with an excess of NMM, I

Et 3 N, Hünig's base in THF, DCM or EtOAc, at room temperature

for 4 to 24 hours. I

30. The preferred conditions are: I

Amine (V), 2 eq. HBTU, 2 eq. acid (R ^ H) in DCM. at I

room temperature for 18 hours I

or I

amine (V), HOBT, WSCDI, Et3 N, in DCM at room temperature

35 hours for 18 hours. I

Arylerinq (R1 = aryl, heteroaryl), Z '= halogen I

1025527-1

(Iii) Arylation of compound (V) can be carried out by a palladium-catalyzed cross-coupling reaction with a suitable base (t-BuONa), a catalyst. amount of a suitable additive such as 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl and a suitable palladium catalyst in toluene at an elevated temperature for 1 to 24 hours under an inert atmosphere, meaning compound (I *> gives. Alternatively, compound (I ') can be prepared by reacting the' amine (V) with compound (VI) by heating, to an elevated temperature, such as 50-140 ° C, in a suitable solvent such as DMF, NMP or 1,4-dioxane for about 1-48 hours with a base such as potassium carbonate, sodium hydrogen carbonate or Hü-.

. nig's base.

The preferred conditions are: 1-2.5 eq. halide (VI), 1-2 eq. potassium carbonate in N, N-dimethylformamide at 50-95 ° C for 4-18 hours or 1-2.5 eq. halide (VI), 2-3 eq. Hünig's base in 1,4-dioxane or NMP under reflux for 18-48 hours 20 or 1 eq. halide (VI), 3.5 eq. NaOt-Bu, 0.08 eq. BI-NAP, 0.4 eq. Pd (dba) 2, in toluene for 8 hours at 70 ° C.

Alkylerinq (R1 = substituted alkyl), Z '= haloqene, preferably Br or Cl

Alkylation of compound (V) can be carried out by reaction with a suitable alkylating agent, F 2 Z ', in the presence of a suitable tertiary amine (NMM, Et 3 N or Hünig's base) or an alkali metal base (K 2 CO 3, CS 2 CO 3) in a suitable solvent (MeCN, DMF) at about room temperature.

The preferred conditions are: amine (V) 1, Z 2, excess K 2 CO 3 or Hünig's base in DMF for 18 hours at room temperature.

1025527

24 I

Alternatively, the compounds (I) may become I

prepared by the route shown below I

in schedule 1.3. I

5 I

N "N N-N I

/ ^ \ Λ 3 -v r * o% _v I

A Y · N \ / A Υ> Γ V \ I

(b yxy i (vu) / b y \ y r v I

•. w

10 (V) x v (ir x V 1

Schedule.3 I

Compounds suitable for use as a compound

binding (Vil) are commercially available or known in I

the literature. I

Step (c): Amine (V) is reacted with an I

20 oversize of aldehyde / ketone (VII) in the presence of an I

reducing agent, such as sodium triacetoxyborohydride or na

cyanoborohydride or sodium cyanoborohydride, which I

gives the compound of formula (I1). This reaction can I

are carried out by: I

Stirring the starting materials at temperatures so

as from 20-80 ° C for 1 to 48 hours in a suitable solution

release agent such as dichloromethane or I

heating amine (V) with an excess of compound I

compound (VII) with a suitable Lewis acid as a catalyst, such as I

As titanium tetrachloride or titanium tetraisopropoxide, at I

L temperatures such as from 50-100 ° C in a suitable solvent

such as dichloromethane or ethanol for 1-18 hours, I

followed by reduction of the intermediate, and imine-I

/ iminium compound, with a suitable reducing agent, such as I

Sodium borohydride, or hydrogenolysis over a suitable I

catalyst, such as platinum oxide or palladium-on-carbon. I

The preferred conditions are: I

102552? I

Amine (V), 1-1.5 eq. aldehyde / ketone (VII), 1-2.0 eq. sodium triacetoxyborohydride in dichloromethane, optionally in the presence of AcOH at room temperature for 2 hours.

When ring B is attached to ring A via an N atom, and W represents O or S, then: · '00. . .-- 0¾ (VIII). (IX) • i.

15 | d · iTny i w. (W) "00 A, ** 10"; 11. Q ~ z

2C X γ - "x V

(I) (H1);

Schedule 2.1 25

Prot. represents a suitable protecting group for nitrogen, for example Boe, CBz or allyl carbamate. The standard methodology for protecting groups for nitrogen is used, such as that found in textbooks (eg "Protecting Groups in Organic Synthesis" by T. W. Greene and P. Wuts). Z "represents a leaving group such as halogen.

Compounds suitable for use as compound (IV) are commercially available or known in the literature.

1025527

26 I

Arylation of compound (III) can be performed. I

as described in the above step (b). I

The preferred conditions are: I

1-2.5 eq. halide (IV), 1-2 eq. potassium carbonate in I

5 Ν, Ν-diinethylformamide at 50 ° C for 4-18 hours or I

1-2.5 eq. halide (IV), 2-3 eq. Hünig's base in I

1,4-dioxane or NMP under reflux for 18-48 hours I

or I

1 eq. halide (IV), 3.5 eq. NaOt-Bu, 0.08 eq. BI-I

10 NAP, 0.4 eq. Pd (dba) 2, in toluene for 8 hours at I

70 ° C. I

Step (d): Deprotection of compound (IX) is under investigation I

with the aid of standard methodology, as is used

15 wrote in "Protecting Groups in Organic Synthesis" by I

T.W. Greene and P. Wuts. I

When Prot is Boe, the preferred methods are: I

hydrogen chloride in a suitable solvent such as I

1,4-dioxane at room temperature for 1-16 hours or I

20 a solution of trifluoroacetic acid in dichloromethane

thane for 1-2 hours. I

When Prot is CBz, the preferred method is hydro-I

genolysis with a suitable palladium catalyst in an op

release agent such as ethanol. I

When Prot is an allyl carbamate, preferred I

conditions thiobenzoic acid and a suitable palladium catalyst

such as Pd 2 (dba) -3 with a suitable phosphine additive such

as 1,4-bis (diphenylphosphino) butane in tetrahydrofuran

lasting 20 minutes I

When ring B is bound to ring A via an N atom I

is, and W represents NR1, then: I

1Q25527-1

27 ΚΙ-Ν Ν-Ν - S; : - ^ κ · '-: W. '(ΝΠΙΓ) ν'χ. I γ I.

.

-. . R ^ ° / ^ m / c b (vi) ..-- 1 in Ν-Ν Ν-Ν i ~ ~ R ’ρ« * - ν · Λ / A .n-R1 O * 2 · O-2.

icY \ x V (»n.: X dd U" ..; · '.. Xv. · - V-vCK' οΛΚ; rV2 '' - -Ο-2 i 20 x *% 6 .xyj in.; ·, "··" <»: -. ./.

Scheme 2.2 Prbt represents a suitable protecting group for nitrogen, for example Boe, CBz or allyl carbamate. The standard methodology for protecting groups for nitrogen is used, such as that found in textbooks (e.g., "Protecting Groups in Orgahic. Synthesis" by T. W. Greene and P, Wuts).

Z 'represents a leaving group (typically Cl or OH). Z "represents halogen (in a typical case Cl).

Compounds suitable for use as compound 35. Binding (IV) are commercially available or known in the literature.

1025527-

28 I

Compound (IX ") can typically be I

Prepare from compound (IX ') using methodology I

which is described in the above step (b) and step I

(c). "I

Compound (III ') can be used in a typical case

Prepare from compound (IX ") using methodology I

which is described in the above step (d). I

The compounds (I ') can typically be I

. prepared by arylation of the compounds (III ') with I

10 using the methodology described in the BO

step (b) below. I

Compounds suitable as compounds (II) I

and (VIII) are known in the literature or may be

prepared as shown in schemes below I

15. 3.1, 3.2 and 3.3. I

N-1 * H-W-Z γ I

20 Γγθ * 0 * * 'V-Ö * I

^ w (X,) I

1 x 25.

N-N I

:: I

^ Η ^ χ I

y w. x I

30 I

35 VG represents a leaving group, typically I

Halogen, and preferably chlorine or bromine. I

1 025527. ' I

29

Schedule 3.1

When the rings A. and B are bonded via an N atom, then: '5 • N-N H' · w — ζ · ''.

10 (xii) · (xi): N * N-N. · • —N Λ JT O. \

Prot ^ Nv_y W — z. - ÖI 7. (VIII): VG is a leaving group, typically halogen, and preferably chlorine or bromine. Scheme 3.2.

Compounds suitable for use as the compounds (XI) are known in the literature or may be. prepared using standard methodology, for example reduction of benzoic acids (see preparation 7 below) or benzonitriles (see preparation 10 below) or nitrobenzenert (preparations 57 and 58).

When W represents NR1:.

Step (e): Compound (X) / (XII) is reacted. with an excess of compound (XI), reassembly resp.

35 gives compound (II) / (VIII), optionally in the presence of. an excess of a base such as triethylamine, Hünig's base or NMM or potassium carbonate as proton acceptor, 1025527

30 I

optionally in the presence of a catalyst (e.g. Nal) I

in a suitable high-boiling solvent such as THF, toluene I

or DMF at temperatures of 50 to 100 ° C for 1 to I

48 hours. I

The preferred conditions are: I

2.5 eq. compound (XI) in THF at 50 ° C for 48 l

hour or I

1.1 eq. compound (XI), 1.1 eq. NMM or K 2 CO 3, 0.5 eq.

Nal in THF at 50 ° C. I

10 When W represents O or S: I

Step (e): Compound (X) / (XII) is reacted I

with an excess of compound (XI) in the presence of I

a base such as sodium hydride, potassium hexamethyldisilazide, I

N-butyl lithium or isopropyl magnesium chloride, in a gel

suitable solvent such as THF, toluene or NMP at temperature

0 ° C to 50 ° C for 1 to 24 hours, which I

resp. compound (II) / (VIII). I

The preferred conditions are: I

1.1-3 eq. compound (XI) and 1.1-2.5 eq. NaH in THF I

at 20 ° C for 2 hours. I

When W = NR1 and Z = CO, then: I

25 ^ I

-V A, 0 I

0 h I

w \ i b .x 0 dl) QT I

30 * '' · I

n-n L · J / vyi. /. I

VH, "/ I

(XX) I

35 Schedule 3.3 I

1025527-1

31

Step (I): Amine (XX) can be prepared by amination of compound (X) with the amine RXNH 2 in a solvent such as ethanol or tetrahydrofgran at 25-75 ° C for 5-72 hours. Preferred conditions are:

Compound (X), excess R11 in ethanol and THF at room temperature for about 72 hours.

Compound (II) can be prepared by coupling the amine (XX) with the acid (XXI) according to the procedure previously described in step (b).

Compounds suitable as the compounds (X) and (XII) are known in the literature or can be prepared as shown in schemes 4.1 and 4.2.

>> Xv °; 1 ___ (A N "NH * + f ·!.

H vv 20 (XIII) ^ χ.

: Ai ° VvG.

^ aPn'nh.

9 (XV) N-N.

A JT O V <3 (X). ! Scheme 4.1 35 X 'represents OH or halogen, and preferably represents Cl. VG represents a leaving group, typically halogen, and preferably chlorine or bromine.

102552?

32 I

When rings A and B are bonded via an N atom I

are, then: I

5 I

VG

I

. (XIII *). <X, V) I

• P I

Prot * 'N ^ y HI

15 g I

^ (XV)

N-N I

/ ^ 0H, I

from · I

(XII)! I

20 |

Schedule 4.2

X 'represents OH or halogen, and I preferably represents

this Cl for. VG is a leaving group, in a typical I

halogen, and preferably chlorine or bromine. . I

Compound (XIV) is commercially available or available

in the literature. I

30 I

Step (f): The reaction of the hydrazide (XIII / XXII ') with I

compound (XIV) can be carried out by means of I

standard methods. I

Linking can be performed by using: I

(I) an acyl chloride (XIV) + hydrazide (XIII / XIII ') I

with an excess of an acid acceptor and a suitable solution

release agent or I

1025527 I

33. (ii) an acid (XIV) with. a conventional co-ordinating agent + hydrazide (XIII / XIII '), optionally in the presence of a catalyst, with an excess of an acid acceptor in a suitable solvent.

In a typical case, the conditions are as follows: (I) an acid chloride (XIV) (generated in situ), an excess of hydrazide (XIII / XIII1), optionally with an excess of a 3 ° amine such as EtaN, Hünig's base or NMM , in DCM or THF, without heating for 1 to 24 hours or (ii) an acid (XIV), WSCDI / DCC and HOBT / HOAT, an excess of hydrazide (XIII / XIII ') / with an excess of NMM, EtaN, Hünig's base or THF, DCM or EtOAc, at room temperature for 4 to 48 hours or (iii) 'an acid (XIV), PyBOP® / PyBr.OP® / Mukaiyama reagent, an excess of hydrazide (XIII / XIII'), with an excess of NMM, EtaN, Hünig's base in THF, DCM or EtOAc, at room temperature for 4 to 24 hours.

The preferred conditions are:

Hydrazide (XIII / XIII '), 1.5 eq. chloroacetyl chloride 20 (XIV), 1.5 eq. NMM in DCM at room temperature for 16 hours.

Step (g): The ring closure of compound (XV / XV ') is carried out under suitable conditions for dehydration. 25 at elevated temperatures up to 18 hours. In a typical case, dehydrants such as polyphosphoric acid, phosphorus oxychloride, trifluoromethanesulfonic anhydride are used at temperatures of 20 to 120 ° C for 5 minutes to 12 hours. Optionally, the reaction can be carried out in the presence of a base such as pyridine and suitable solvents such as dichloromethane and acetonitrile. Alternatively, the oxadiazole (XII / X) can be prepared according to the method of Rigo et al., Synth. Commun., 16 (13), 1665, 1986.

The preferred conditions are: 1 025527 -

34 I

Phosphorus oxychloride at 100 ° C for 8 hours, or 2.5 l

eq. trifluoromethanesulfonic anhydride in acetonitrile at I

20 ° C for 5 hours. I

Compounds suitable for use as the I

Compounds (XIII / XIIX ') are known in the literature or I

can be prepared as shown in schemes I

5.1 and 5.2. I

10 0_ © _f © - · (ΕΜΞΚ ^ I

•. f I

(XVI) (XVII) I

15 l

0- © - ^^ I

20. . O

: ·. ραία I

Schedule 5.1 I

When A and B are bonded via an N atom, then: I

^^ Η Η I

O Η ΛΛ I

/ Λ // HJM ^ Prot "PrDt" - NV A ΓΊ \ Prot "· |

• Prot * —N A) - \ η I

V_J OH: ^ I

30 (xvi ·) (xvii ·) I

, _ ^ Η I

N-ΝΗ2

Prot * —N A | —ti I

35 I

(Χΐ'Γ) I

Schedule $ .2 I

1 025527-1

The compounds (XVI / XV ') and the protected hydrazine are commercially available or known from the standard methodology, such as the hydrolysis of the corresponding. ester. .

A carboxylic acid (XVI / XVI ') and a protected hydrazine, in which prot * in a typical case is Boe, can be coupled to give compound (XVH / XVH1), respectively, using the conditions described above before the preparation of (XV / XV '), and then prot * is removed using standard methodology as described in the above step (d) to give (XX-II / XIII').

Alternative routes to compound (XXXX / XXXX ') are shown below in schemes 6.1 and 6.2: 20 dHZH1' ': «"> "" R1 is a typical case of C1-2 alkyl

Schedule 6.1

If rings A and B are bonded via an N atom, then: 3.5 1025527

36 I

IW-Ai HjN "NHj / -" JJ-NH. I

OR --- »- Prot. ^ I

W) h (XI ,,., ° I

10 I

I

R is typically C1-2 alkyl I

Scheme 6.2 I

Step (h): The ester (XVIII / XVIII ') can be reacted I

brought with hydrazine in a suitable solvent such as I

methanol, at an elevated temperature, which

drazide (XVII / XVII '). I

Preferred conditions: I

25 3 eq. hydrazine, in methanol, refluxed

for 18 hours. I

Alternatively, the compounds of formula I

(I) are prepared according to scheme 7.0 I below

30 I

35 I

1025527-1

.37 · s 5 ^ M HI'J \ HN, - \ ·. : jy:

X Y. x Y X Y

fWM \ (XXIV).

(XX * 1) (xxni) / 10. ". . "! .

. "nh,".

15 n-n & <»> 3-y WW" V J x>

Xr1 / · Q-r. · YQel i X γ

. (!). ; (XXV) I

20; R = H or C 1-4 alkyl, typically tert-butyl, methyl or ethyl

Schedule 7.0

When R = H, compounds of formula (XXIII) can be prepared by an intramolecular coupling of the amino acid 30 (XXII), according to the procedure previously described in step (b). Preferably, the compound (XXII) is treated with 1.4 eq. HBTU, 4.5 eq. NMM in DCM at room temperature for approximately 18 hours.

When R = C 1 -C 7 alkyl, compounds of formula (XXIII) can be prepared by base-catalyzed ring closure of the amino ester (XXII) which in a typical case of ka 102552?

38 I

temperature or lower is carried out for 1-5 l

o'clock. In a typical case, bases such as potassium tert-I

butoxide, sodium ethoxide or isopropyl magnesium chloride I

used at 20 ° C or lower in a suitable solvent

5 as tetrahydrofuran or ethanol for 1.5 hours. At I

the compound (XXII) is preferably treated with 1.1 eq. I

potassium tert-butoxide in THF at 20 ° C for about 2 liters

o'clock. I

Step (j): Formation of thioamide I

Thionation of the amide (XXIII) with a suitable I

thionation agent (used by Lawesson reagent, P4S10) and I

optionally in the presence of a base (e.g., Na 2 CO 3) in an I

suitable solvent (e.g. THF) between 0 ° C and room temperature

15 rature. I

The preferred conditions are: I

1 eq. P4S10, 1 eq. Na 2 CO 3, 1 eq. amide (XXIII) in THF I

between 3-25 ° C for 18-72 hours. I

Step (k): Formation of thioimidate I

Treatment of the thioamide (XXIV) with a strong.

base such as KO-t-Bu or LDA, in a suitable solvent

as THF or ether, followed by termination of the reaction of I

the anion formed by a suitable methyl source I

25 (e.g. Mei, Me-p-tosylate), gives the thioimidate (XXV). I

The preferred conditions are: I

1 eq. thioamide (XXIV) treated with 1 eq. KO-t-Bu, 11

eq. Me-p-tosylate in THF. I

30. Triazole formation: I

Step (1): The thioimidate (XXV) is treated with the I

hydrazide (XIII) in a suitable solvent, in a type I

ethanol at an elevated temperature, which I

the compound of formula (I), optionally in present

35 of an acid catalyst, such as TFA, p-TSA. I

The preferred conditions are: I

1025527-1

39 1 eq. thioimidate (XXV), 1 eq. hydrazide (XIII), in ethanol under reflux for 2 hours.

Step (m): The thioamide (XXIV) is treated with the hydrazide (XIII) in a suitable solvent, typically n-butan-1-ol at an elevated temperature, giving the compound of formula (I) optionally in the presence of an acid catalyst such as TFA, p-TSA.

The preferred conditions are: .10 1 eq. thioamide (XXIV), 1 eq. hydrazide (XIII), in n-butan-1-ol under reflux for 18 hours.

Compounds suitable for use as the compounds (XXII) are known in the literature or can be prepared by standard methodology, see for example C. Apfel et al., J. Med. Chem., 44 (12), 1847-1852, 2001; C.P. Lang et al., WO 2002008228; F. Ishi-kawa, J. Med. Chem., 28 (10), 1387-93, 1985, or Uskokovic, M. et al., Journal of Organic Chemistry, (1965), 30 (9), 3111-14.

It will be apparent to those skilled in the art that sensitive functional groups protect and deprotect during the. may require synthesis of a compound of formula (I). This can be realized by conventional techniques, such as described, for example, in "Protective Groups in Organic Synthesis" by T.W. Greene and P.G.M. Wuts, John Wiley and Sons Ine., 1991, for which examples 42-49 and 55-58 are given.

Certain compounds of formula (I) can be converted into alternative compounds of formula (I) using standard chemical conversions. Examples of this are explained below.

Amination (e.g., examples 40 & 41)

When R1 contains a leaving group, such as a chlorine substituent, it can react with a suitable amine HNR2 R3 in the presence of a suitable tertiary amine as base (EtaN, NMM or Hünig's base) or an alkali metal 1025527-

I 40 I

I base (K 2 CO 3, CS 2 CO 3) in a suitable solvent (e.g. I

I DMF, MeCN), optionally at elevated temperature. For I

The chlorine compound is preferably treated with an excess of I

1 HNR 2 R 3, in the presence of excess K 2 CO 3 in DMF at 70 ° C. I

Reduction (e.g. examples 50-54, 64 & 65) I

Compounds containing a carbonyl function can be I

I are reduced with the help of a suitable reduction I

Agent such as DIBAL or borane in a suitable solvent

I such as ether or THF at room temperature or between room I

Temperature and the reflux temperature of the reaction

I mixture. The amide compound is preferably treated

Id with 10 eq. borane in refluxing THF, which I

I is followed by an excess of HG1 under reflux. I

Reductive amine (e.g. Examples 69-81 & 84-90) I

Compounds of formula (I) that have a reactive N atom I

I can react with an aldehyde or ketone, vol

According to methods described in step (c). At I

Preferably, the amine of formula (I) is treated with an I

Excess aldehyde / ketone and 2 eq. Na (0Ac) 3BH in DCM, optionally I

In the presence of excess Et3 N and acetic acid, i.e.

Ran for up to 18 hours at room temperature. I 1

1025527 I

Oxidation (e.g. when W = S) I

Compounds of formula (I) that have a sulfur atom

I can be oxidized with the aid of an I

I suitable oxidizing agent such as hydrogen peroxide or meta-I

Chloroperbenzoic acid in a suitable solvent such as I

I trifluoroacetic acid or 1,1,1,3,3,3-hexafluoropropan-2-ol I

I between 0 and. 25 ° C. "I

When is oxidized to the sulfoxide (W. = I

S (O) i), the sulfide of formula (I) is preferably I

traded with 1-1.2 eq. 30% hydrogen peroxide in water in I

1,1,1,3,3,3-hexafluoropropan-2-ol for up to 1 hour at I

35 room temperature. I

When is oxidized to the sulfone (W = S (0) 2), I

the sulfide of formula (I) is preferably treated I

41 with 2-3. eq. 30% aqueous hydrogen peroxide in trifluoroacetic acid for up to 1 hour.

(Alternatively, the above sulfoxide (W = S (O) i) can be oxidized to the sulfone (W = S (0) 2) with 1-2 equivalent of 30% hydrogen peroxide in water in trifluoroacetic acid for up to 1 hour).

In addition, in accordance with the present invention, there is provided an intermediate of formula (II): 10

N-N

T 0 / B / 2 · 15 (II) H »N-Ox; 20 an intermediate product of formula (III): j

N-N

h-n lw 25. -z • ·> ''. (H1) 30 an intermediate of formula (X) 1025527-

42 I

N-N I

r \ JL y- \ I

"0 / g I

(X). · I

5 an intermediate of formula (XV): I

O I

Γ V’G |

(δ V ^ ki NH

10 fTyW. Η. · I

• (XV) I

I

an intermediate of formula (XXIV): I

S I

^ —V I

20. HN · \ I

A. w I

: I

(XXIV) I

25 I

and an intermediate of formula (XXV): I

/ I

s

V I

30. NT \

i W i

Y.

(XXV) I

35

102552? " I

43 wherein V, W, X, Y, Z, the rings A and B, VG and n have the meaning given above.

The compounds of the present invention are useful because these pharmacological activity are in animals. In particular, these are useful in the treatment of a number of conditions / including aggression, Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder, asthma, atherosclerosis, autism, cardiovascular disease (including angina, atherosclerosis, hypertension, cardiac insufficiency, edema, hypernatremia), cataract, disease of the central nervous system, cerebrovascular ischemia, cirrhosis, cognitive impairment, "Cushing's disease, depression, diabetes mellitus, dysmenorrhea (primary and secondary), emesis (including motion sickness), endometriosis, gastrointestinal disease, glaucoma, gynecological disease, heart disease, retardation of internal growth in the uterus, inflammation (including rheumatoid arthritis), ischemia, ischemic heart disease, lung tumor, mictation disorder, mittel-schmerz, neoplasm, nephrotoxicity, non-insulin-dependent diabetes , obesity, obsessive / compulsive disorder, ocular hypertension, preclampsia, premature ejaculation, premature other contractions, pulmonary disease, Raynaud's disease, kidney disease, kidney failure, male or female sexual dysfunction, septic shock, sleep disorder, spinal cord injury, thrombosis, urinary tract infection or urolithiasis. Of particular interest is dysmenorrhea (primary or secondary) and more particularly primary dysmenorrhea.

Thus, in another aspect of the present invention, there is provided a method of treatment for dysmenorrhea which comprises administering a therapeutically effective amount of a compound of the present invention to a patient suffering from anxiety, cardiovascular disease (including angina, atherosclerosis, hypertension, cardiac insufficiency, edema, hypernatremia), dysmenorrhea (primary and secondary), endometriosis, emesis (including motion sickness), slowing of the internal 1 025.52.7-

I 44 I

I growth in the uterus, inflammation (including rheumatoid I

I arthritis), mittelschmerz, preclampsia, premature ejacu

I lation, premature (early) contractions or Ray's disease

I naud. Use is also made of the connection I

As a medicine and the use of the compounds

I gene of the present invention in the manufacture of I

I a medicine for the treatment of anxiety, cardiovas I

Icular disease (including angina, atherosclerosis, hyper-I

Idension, cardiac insufficiency, edema, hypernatremia), dys-I

Menorrhea (primary and secondary), endometriosis, emesis I

I (including motion sickness), delay of the internal I

Uterine growth, inflammation (including rheumatoid I

I arthritis), mittelschmerz, preclampsia, premature ejacu

I lation, premature (early) contractions or Ray's disease

Naud, in particular dysmenorrhea. I

The compounds of the present invention which are i

Intended for pharmaceutical use can be used

I serve as crystalline or amorphous products. These can I

I are obtained, for example, as solid layers, powders or I

I films by methods such as precipitation, crystal I

Iization, freeze drying, spray drying or drying by means of I

I from evaporation. Drying can be carried out for this purpose with

I help from micro or radio waves. I

These can be administered alone, or in combination

With one or more other compounds of the present I

Invention, or in combination with one or more other gen

I drugs (or as a combination thereof). The connection I

For example, things of the present invention can be I

I are administered in combination with an oral contraceptive

I tivum. They can also be administered in combination with I

I a PDE5 inhibitor. They can also be administered in I

I combination with an NO donor. Alternatively, these I

I are administered in combination with L-arginine, or as an I

Arginate salt. The compounds of the present invention

I can also be used in combination with a COX-I

I inhibitor. I

1 025527-1

45%. Generally, this will be administered as a preparation with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any component other than the compound (s) of the present invention. The choice of the excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the release of compounds of the present invention and methods of their preparation will be apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in "Re-mington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).

Thus, according to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

The compounds of the present invention can be administered orally. Oral administration may involve ingestion, so that the compound enters the gastrointestinal tract. 25 or buccal or sublingual administration can be used, whereby the compound enters the blood stream directly through the mouth.

Preparations suitable for oral administration. include solid preparations such as tablets, capsules containing solid particles, liquids or powders, pastilles (including liquid-filled), chewable tablets, preparations consisting of many or very fine solid particles, gels, solutions of solids, liposomes, films (including muco -adhesive), ovules, sprays and liquid preparations,

Liquid preparations include suspensions, solutions, syrups and elixirs. Such compositions may be 102552.

46 I

used as fillers in soft or hard capsules I

and typically include a carrier, for example I

water, ethanol, polyethylene glycol, propylene glycol, me

methyl cellulose, or a suitable oil, and one or more emulsion

Gators and / or suspending agents. Liquid preparations I

can also be prepared by reconstituting I

a solid, for example from a sachet. I

The compounds of the present invention can be I

also be used in fast dissolving, fast disintegration

Dosage forms such as those described in I

Expert Opinion in Therapeutic Patents, 11 (6), 981-986, I

by Liang and Chen (2001). I

For tablet dosage forms, the drug may depend

depending on the dose, 1 to 80% by weight of the dosage form and I

15 in a more typical case of 5 to 60% by weight of the do-I

form. In addition to the drug, the I

tablets in general one. disintegrant. For I

images of disintegrants include sodium starch I

glycolate, sodium carboxymethylcellulose, calcium carboxy-I

Methylcellulose, croscarmellose sodium, crospovidone, pol

lyvinyl pyrrolidone, methyl cellulose, microcrystalline cell I

lulose, lower alkyl substituted hydroxypropyl cell I

lulose, starch, pregelatinized starch and sodium algae

naat. In general, the disintegrant will be 1 to 25 l

25 wt% and preferably 5 to 20 wt% of the dosage form

to grasp. I

Binders are generally used for cohesion

. give its tablet properties equivalent properties. I

Suitable binders include microcrystalline cellulose

30 se, gelatin, sugars, polyethylene glycol, natural and I

synthetic gums, polyvinylpyrrolidone, pregelatinised I

starch, hydroxypropyl cellulose and hydroxypropyl methyl cell I

lulose. Tablets also contain diluents such as I

lactose (monohydrate, spray dried monohydrate, aqueous I

Free and the like), mannito.1, xylitol, dextrose, saccha

rosé, sorbitol, microcrystalline cellulose, starch and I

dibasic calcium phosphate dihydrate. I

1025527-1

47

Tablets may optionally also contain surfactants such as hatrium lauryl sulfate and polysorbate 80, and lubricants such as silica and talc. When present, the surfactants may be 2 to 5 wt. % of the tablet, and lubricants may comprise 0.2 to 1% by weight of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise from 0.25 to 10% by weight and preferably from 0.5 to 3% by weight of the tablet.

Other possible ingredients include antioxidants, colorants, fragrances and flavors, preservatives, and taste masking agents.

For example, tablets contain up to about 80% drug, about 10 to about 90% binder, about 0 to about 85% diluent, about 2. to about 10% disintegrant, and about 0.25 to about 10 wt% lubricant.

Tablet blends can be compressed directly or by means of a roller to form tablets. Tablet blends or portions of blends may alternatively be granulated wet, dry or melted, solidified from a melt, or extruded prior to tableting. The final composition may comprise one or more layers and may or may not be coated; it can even be encapsulated.

The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets, vol. 1" by H.

Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., USA, 1980 (ISBN 0-8247-6918-X).

Solid compositions for oral administration can be formulated for immediate and / or modified release. Modified-release preparations include those. for delayed, uninterrupted, pulsed, controlled, targeted and programmed delivery.

1'025527-

48 I

Suitable modified release preparations for I

the objects of the present invention are achieved, I

described in U.S. Patent No. 6,106,864. BijI

details of other suitable delivery technologies, such as I

5 as high-energy dispersions and osmotic and coated I

particles are found in: Pharmaceutical Technology-I

gy On-line, Verma et al., 25 (2), 1-14 (2001). The use I

of chewing gum for controlled release I

described in WO 00/35298. I

The compounds of the present invention can be I

administered directly into the blood stream, in the I

muscles or in an internal organ. Suitable modes of I

parenteral administration include intravenous, intra-I

arterial, intraperitoneal, intrathecal, intraventricular I

Laire, intra-uretral, intrasternal, intracranial, in- I

tramuscular and subcutaneous administration. Suitable means I

for parenteral administration. including needle (including mi

needle) injectors, injectors without needle and infusion I

techniques. I

Parenteral compositions are typical solutions in I

water containing excipients such as salts, carbohydrates and buffer

formers (preferably up to a pH of 3 to 9)

but for some applications they can become better

formulated as sterile non-aqueous solutions or I

25 as a dried form used with a suitable I

vehicle such as sterile, pyrogen-free water. The preparation I

of parenteral preparations under sterile conditions, I

for example by freeze drying, can be easily cleaned

realized using standard pharmaceutical technology

30 that are known to those skilled in the art. I

The solubility of the compounds of formula (I) I

used in the preparation of parenteral solution

releases can be increased by a suitable operation

for example through the use of high energy I

Spray-dried dispersions (see WO 01/47495) and / or by I

the use of suitable formulation techniques, such as I

the use of agents that increase solubility. I

1025527 · I

49 '

Preparations for parenteral administration can be formulated for immediate and / or modified release. Modified-release preparations include the. delayed, uninterrupted, pulsed, controlled, targeted and programmed delivery. The compounds of the present invention can thus be formulated as a solid, a semi-solid or as a thixotropic liquid for administration as an implanted depot that provides for the modified release of the active compound. Examples of such compositions include drug-coated stents and PGLA microspheres.

The compounds of the present invention can also be applied topically to the skin or mucous membranes, dermally or transdermally. Typical compositions for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, lubricants, foams, etc. films, skin patches, waffles, implants, sponges, fibers, dressings and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum ,. white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers can also be included - see, for example, J. Pharm. Sci., (10), 955-958, by Finnin and Morgan (Oct. 25, 1999).

Other modes of topical administration include delivery by iontophoresis, electroporation, phonophoresis, sonophoresis, and injection using a micro needle or without a needle (e.g., Powderject ™, Bioject ™, etc.).

Preparations for topical administration can be formulated for immediate and / or modified release. Modified-release preparations include delayed, continuous, pulsed, controlled, targeted, and programmed release.

The compounds of the present invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (al. 1025527).

50 I

as a mixture, for example in a dry mixture I

with lactose, or as particles containing mixed ingredients

for example mixed with phospholipids, such as phosphol

fatidylcholine) from a dry powder inhaler or I

5 as an aerosol spray from a pressurized container, I

pump, spray, nebulizer (preferably a nebuliser that I

forms a fine mist with the aid of electrohydrodynamics), I

with or without the use of a suitable propellant such as I

1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-1

Propane. I

For intranasal use, the powder may be a bioadhesive

contain a selective agent, for example chitosan or cyclodex-I

trine. I

The pressurized container, pump, spray or spray

15 contains a solution or suspension of the compound

of the present invention which, for example, I

ethanol, aqueous ethanol or a suitable alternative medium

for dispersing, solubilizing or renewing

the release of the active agent, the propellant gas (s) I

20 as a solvent and an optional surfactant I

such as sorbitan trioleate, oleic acid or an oligomilk

acid. I

Prior to use in a dry powder or I

The suspension preparation reduces the drug product I

25 to a size suitable for delivery by inhalation

(typically less than 5 microns). This can be I

be realized by means of a suitable reduction

method, such as grinding with a screw

radius, grinding with a swirl layer radius, working I

Supercritical liquid, which is nanoparticles I

forms, high pressure homogenization or spray drying. I

Capsules (which are for example from gelatin or HPMC I

made), blister packs and cartridges for use in I

an inhaler or insufflator can be shaped in such a way

35 that it is a powder mixture of the compound of the present invention, a suitable powder raw material,

such as lactose or starch, and a performance modifier such as

1025527-1

51 as 1-leucine, mannitol or magnesium stearate. The lactose can be anhydrous or in the form of the monohydrate, but preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution as a preparation for use in a nebulizer with the aid of electrodynamics to form a fine mist can contain 1 pg to 2 mg of the compound of the present invention per stroke, 10. and the stroke volume can range from 1 μΐ to 100 μΐ. A typical preparation may include a compound of formula (I), propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used in place of propylene glycol include gycerol and polyethylene glycol.

Suitable fragrances and flavors, such as menthol and vomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those compositions of the present invention that. intended for inhaled / intranasal administration.

Preparations for inhaled / intranasal administration may be formulated for immediate and / or modified release with, for example, poly-DL milk coglycolic acid (PGLA). Modifications for modified release include delayed, continuous, pulsed, controlled, targeted, and programmed release.

The compounds of the present invention can be administered rectally or vaginally, for example in the form of a suppository, pessary or clysma. Cocoa butter is a traditional raw material for a suppository, but various alternatives can be used as needed.

Preparations for rectal / vaginal administration can be formulated for immediate and / or modified delivery. Compositions for modified release. delayed, uninterrupted, pulsed, controlled, targeted and programmed release.

1025527-

52 I

The compounds of the present invention can be I

also be applied directly to the eye or ear I

serving, typically in the form of drops of I

a very fine suspension or isotonic solution, I

5 sterile saline with an adjusted pH value. Ande I

other preparations that are suitable for ocular and oral. I

administration include ointments, biodegradable (e.g. I

absorbable gel sponges, collagen) and non-organic I

degradable (e.g. silicone) implants, waffles, lenses I

10 and particulate or vesicle systems, such as

niosomes or liposomes. A polymer such as cross-linked polya

crylic acid, polyvinyl alcohol, hyaluronic acid, a cellulose pol

polymer, for example hydroxypropyl methylcellulose, hydrogen

hydroxyethylcellulose or methylcellulose, or a heteropoly

Saccharide polymer, for example, as the case may be, together with I

a preservative such as benzalkonium chloride, I

Such compositions may also be dispensed

by iontophoresis. I

Preparations for ocular / oral administration may be used

20 formulated for immediate and / or modified I

issue. Modified-release preparations include I

delayed, continuous, pulsed, controlled, I

targeted or programmed release. I

The compounds of the present invention can

Be combined with soluble macromolecular entity

such as cyclodextrin, or polymers containing polyethylene I

glycol for the improvement of their solubility

ity, dissolution rate, masking the taste, the biological

availability and / or stability, for the

Use of one of the aforementioned methods of administration. I

Complexes of drug-cyclodextrin were found to be I

example generally useful for most dosage forms

men and administration routes. Both inclusion and non-I

containment complexes can be used. As an all-I

35 alternative to direct complexation with the medicine I

the cyclodextrin may be used as an auxiliary additive

used, i.e. as a carrier, diluent I

102552 - I

53 or solubilizer. The most frequently used for this purpose are alpha, beta and ganvma cyclodextrins, examples of which can be found in International Patent Application No. WO 91/11172, WO 94/02518 and WO 98/55148.

Since it may be desirable to administer a combination of active compounds, for example for the purpose of treating a particular disease or condition, this is within the scope of the present invention that two or more pharmaceutical compositions, of which at least contains at least one compound in accordance with the present invention, it may be combined in the form of a kit suitable for co-administration of the compositions.

The kit of the present invention thus comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) in accordance with the present invention, and means for keeping such compositions separate, such as a container, a bottle with subdivision or a subdivided foil-20 package. An example of such a kit is the well-known blister pack used for packaging tablets, capsules and the like.

The kit of the present invention is particularly suitable for administering different dosage forms, for example oral and parenteral, for administering the separate compositions at different dosing intervals, or for titrating the separate compositions against each other. In order to facilitate this, the kit typically contains instructions for administration and administration. it can be provided with a so-called memory support.

For administration to human patients, the total daily dose of the compounds of the present invention will typically be in the range of about 0.01 to about 15 mg / kg of body weight, which depends on the mode of administration. The total daily dose can be administered as a single? 025 52? .....

t

54 I

multiple dose or divided doses during the day. This I

dosages are based on an average human patient

client. with a weight of approximately 65 to 70 kg. The doctor I

will easily be able to determine doses I

5 for patients whose weight falls outside this range, I

such as children and the elderly. I

As used herein, the terms are used

gene "treatment" and "treating" intended to relieve I

of symptoms, the removal of the cause, temporary

10 or permanent basis, or the prevention or delay of the I

appearance of symptoms. The term "treat I

"includes the lighting, the elimination of the cause I

(on a temporary or permanent basis) or the occurrence of I

symptoms and disorders associated with primary I

. And / or secondary dysmenorrhea. The treatment can be either an I

pre-treatment as well as treatment at the start of

the symptoms are. I

The compounds of the present invention can be I

be tested in the studies below

20: I

1.0 Cia filter binding assay

1.1 Merobrane preparation I

Receptor binding assays were performed on cell mem I

branes prepared from CHO cells containing the human I

V1A receptor, (CHO-hVuJ-) brought stable expression. I

The CHO hViA cell line was licensed

kindly provided by Mare Thibonnier, Dept. or Medi

30 cine, Case Western Reserve University School of Medicine, I

Cleveland, Ohio, USA / The CHO hViv cells became routine I

measure at 37 ° C in a humidified atmosphere

with 5% CO2 in DMEM / Hams F12 feed mix that was I

supplemented with 10% fetal bovine serum, 2 mM L-glutamine, I

35 15 mM HEPES and 400 pg / ml G418. For large-scale products

Cell pellets were attached to CHO-hViA cells

grows to a co-growth of 90-100% in roller bottles I

1 025527-1

.55 with an area of 850 cm 2 containing a medium of DMEM / Hams F12 feed mixture supplemented with 10% fetal bovine serum, 2 mM L-glutamine and 15 mM HEPES. . Concentrated CHO hViA cells were washed with phosphate buffered saline (PBS) harvested in ice cold PBS. and centrifuged at 1000 rpm. The cell pellets were stored at -80 ° C until use. The cell pellets were thawed in ice and homogenized in membrane preparation buffer consisting of 50 mM Tris-HCl with pH 7.4, 5 mM MgCl 2, and supplemented with a protease inhibitor cocktail (Roche). The cell homogenate was centrifuged for 10 minutes at 1000 rpm and 4 ° C, the supernatant removed and stored in ice. The remaining pellet was homogenized and centrifuged as before. The super 15 natants were pooled and centrifuged for 30 minutes at 25,000 x g and 4 ° C. The pellet was resuspended in freezing buffer consisting of 50 mM Tris-HCl with pH 7.4, 5 mm MgCl 2 and 20% glycerol, and stored in small volumes at -80 ° C until use. The protein concentration was determined using Bradford reagent and BSA as standard.

1.2 ViA filter binding. .

The linearity of the protein followed by studies on binding saturation were turned off. lined on each new batch of the membrane. The membrane concentration was chosen such that it gave specific binding to the linear portion of the curve. Binding saturation studies were then performed with various concentrations of [3 H] arginine vasopressin, [3 H.] - AVP (0.05 nM - 100 nM), and the Ka and ΒΜχ were determined.

The compounds were tested for their effects on the binding of [3 H] AVP to CHO-hVur membranes, (3 H-AVP; specific activity 65.5 Ci / mmol; NEN Life Sciences). The compounds were solubilized in dimethyl sulfoxide (DMSO) and diluted to a working concentration of 10% DMSO

1 025527 -

56 I

with assay buffer containing 50 mM Tris-HCl with pH 7.4, 5 mM Mg-1

Cl2 and 0.05% BSA. 25 μΐ compound and 25 μΐ [3H] -. I

AVP (final concentration at or below the Kd that for each I

lot membrane was calculated, in a typical case 0.5 nM I

5 - 0.6 nM) were added to a polypropylene plate with I

96 wells with round bottom. The binding reaction was started I

by the addition of 200 μΐ membrane and the plates I

gently shaken for 60 minutes at room temperature. I

The reaction was terminated by rapid filtration with an I

Filtermate cell harvester (Packard Instruments) through a GF / B 'I

UniFilter 96-well plate previously soaked I

in 0.5% polyethylene protein to stick the peptide

appearance. The filters were washed three times with 1 ml

ice cold wash buffer containing 50 mM Tris-HCl with pH = 7.4 and 5 mM I

15 MgCl 2. The plates were dried and attached to each well I

50 μΐ Microsint-0 (Packard Instruments) was added. I

The plates were closed and counted in a TopCount mi

crop plate scintillation counter (Packard Instruments). The I

non-specific binding (NSB) was determined using I

20 1 μΜ unlabeled d (CH2) 5 Tyr (Me) AVP ([β-mercapto-p, β- I

. cyclopentamethylenepropionyl-O-Me-Tyr2, Arg8] vasopressin) I

(pMCPVP), (Sigma). The binding data of the grade

dioligand were analyzed using a logarit I

economic comparison with four parameters where the mini I

25 minutes at 0%. The slope angle was calculated and I

fell between -0.75 and -1.25 for valid curves. The speci I

specific binding was calculated by the mean NSB cpm in I

deduct from the average total cpm. For I

test compounds, the amount of ligand added to the

Receptor was bound expressed as a percentage bound = I

(sample cpm - mean NSB cpm) / specific binding cpm I

x 100. The percentage of binding was plotted against the conc

concentration of the test compound and an s-shaped curve I

was obtained. The constant for the brake dissociation (Ki) I

35 was calculated with the Cheng-Prusoff equation: Ki = I

IC50 / (1 + [L] / K <i), wherein [L] is the concentration of ligand I

present in the well and Kd the dissociation constant I

1025527-1

57 of the radioligand is obtained from analysis of the Scatchard graph.

2.0 functional ViA ~ assay; inhibition of AVP / Vir ~ R promoted mobilization of Ca2 + by FLIPR (Fluorescent Ima-5 went Plate Reader) (Molecular Devices)

The intracellular release of calcium was measured in CHO-hViA cells using FLIPR, which allows the rapid detection of calcium from the receptor after activation. The CHO hViA cell line was inserted. in the context of a permit granted benevolently by Mare Thibonnier, Dept. Of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. The CHO-ViA cells were maintained as a routine measure at 37 ° C in a humidified atmosphere with 5% CO 2 in DMEM / HAMS F12 feed mix supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 15 mM HEPES and 400 pg / ml G418. On the afternoon prior to the assay, the cells were placed as a plate at a density of 20,000 cells per well in black sterile plates. 96 wells of which the bottoms were clear, so that the cells could be inspected and fluorescence measurements made from the bottom of each well. Wash buffer containing Dulbecco's phosphate buffered saline (DPBS) and 2.5 mM probenic acid and dye consisting of cell culture medium containing 4 μΜ Fluo-3-AM (dissolved in DMSO and pluronic acid) (Mole-cular Probes) and 2 5 mM probenecid were freshly prepared on the day of the assay. The compounds were solubilized in DMSO and diluted in assay buffer consisting of DPBS containing 1% DMSO, 0.1% BSA and 2.5 mM probenecid. The cells were washed with 100 μΐ of dye per well for. 1 hour at. 37 ° C incubated in a humidified atmosphere with 5% CO2. After applying the colorant. the cells were washed three times in 100 μΐ wash buffer, using a Denley plate washer. 100 μΐ wash buffer remained in each well-35. The intracellular fluorescence was measured by FLIPR. The fluorescence readings were taken at 2 second intervals.

1 0255.27-

58 I

obtained with 50 μΐ of the test compound which after 30 sec. I

was added. A further 155 measurements were taken with an interval of 1

zxen of 2 sec done to any agonistic activity I

of the connection. Then 50 μΐ ar-I

5: ginin vasopressin (AVP) added so that the end I

assay volume was 200 μΐ. More readings from the fluid

orescence were observed for 120 seconds. collected with I

1 second intervals The responses were measured as I

peak fluorescence intensity (FI). For pharmacological I

After identification, a basic F1 value was deducted

on each fluorescence response. For dose I

response curves of AVP, each response was expressed as I

percentage of the response to the highest concentration of I

. AVP in that series. For determinations of the IC 50 values, I

15 each response expressed as a percentage of the response to I

AVP. The IC 50 values were converted to a modified I

Kb value using the Cheng-I equation

Prusoff, which takes into account the concentration of the I

agonist, [A], the EC 50 value of the agonist and the slope: I

20 Kb = IC50 / (2+ [A] / A50] n) 1 / n-1, where [A] is the concentration of I

AVP, A50 is the EC 50 value of AVP from the dose-response curve and n = the slope of the dose

AVP response curve. H

The compounds of the present invention can be I

Have the advantage that they are more powerful, a longer I

have a duration of activity, have a wider activity range, I

are more stable, have fewer side effects or are more selective

or have other properties that are more useful I

than the prior art compounds. I

Thus, the present invention provides: I

(i) a compound of formula (I) or a formula

pharmaceutically acceptable derivative thereof, I

(ii) a process for the preparation of an I

compound of formula (I) or a pharmaceutical I

35 a pharmaceutically acceptable derivative thereof, I

(iii) a pharmaceutical composition comprising a compound I

formula (I) or a pharmaceutical I

1025527-1

59.

acceptable derivative thereof, together with a pharmaceutically acceptable excipient, diluent or carrier, (iv) a compound of formula (I) or a pharmaceutically acceptable derivative or composition thereof, for the use as a medicine, (v) the use of a compound of formula (I) or of a pharmaceutically acceptable derivative or preparation thereof, for the manufacture of a medicament for the treatment, aggression, Alzhei disease. EIA, anorexia nervosa, anxiety, anxiety disorder, asthma, atherosclerosis, autism, car-diovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia), cataract, central nervous system disease, cerebrovascular ischemia , cirrhosis, cognitive impairment, Cushing's disease, depression, diabetes mellitus, dysmenorrhea (primary and secondary), emesis (including motion sickness), endometriosis, gastrointestinal disease, glaucoma, gynecological disease, heart disease, delay in internal uterine growth, inflammation (including rheumatoid arthritis), ischemia, ischemic heart disease, lung tumor, micturition disorder, mit counters, neoplasm, nephrotoxicity, non-insulin dependent diabetes, obesity, obsessive / compulsive disorder, ocular hypertension, preclampsia, early ejaculation ,. premature (premature) contractions, pulmonary disease, Raynaud's disease, kidney disease, renal failure, male or female sexual dysfunction, septic shock, sleep disorder, injury 1025527-

60 I

of the spinal cord, thrombosis, infection of I

the urinary tract or urolithiasis, I

(vi) use as in (v), wherein the disease or I

disorder is anxiety, cardiovascular disease I

5 (including angina, atherosclerosis, hyper-I

retention, cardiac insufficiency, edema, hyper-I

natremiej, dysmenorrhoea (primary and secondary)

. daire), endometriosis, emesis (including be I

weighing disease), delay of the internal I

Uterus growth, inflammation (including I

rheumatoid arthritis), mittelschmerz, pre-I

clampsia, early ejaculation, premature I

re (early) contractions or Ray-I disease

naud, I

(Vii) use as in (v), wherein the disease or I

disorder is dysmenorrhea (primary and secondary)

daire), I

(viii) a method of treatment for a mammalian I

of aggression, Alzheimer's disease, I

20 anorexia nervosa, anxiety, anxiety disorder, I

asthma, atherosclerosis, autism, cardiovas I

cellular disease (including angina, I

atherosclerosis, hypertension, heart failure

ention, edema, hypernatremia), cataract, I

25 disease of the central nervous system, cereal

brovascular ischemia, cirrhosis, cognitive

disorder, Cushing's disease, depression, I

diabetes mellitus, dysmenorrhea (primary and I

secondary), emesis (including movement I

Disease), endometriosis, gastrointestinal I

disease, glaucoma, gynecological disease,

heart disease, internal delay I

uterine growth, inflammation (including I

rheumatoid arthritis), ischemia, ischemic I

35 heart disease, lung tumor, micturition disorder,

telschmerz, neoplasm, nephrotoxicity, I

non-insulin dependent diabetes, I

1025527-1

61 obesity, obsessive / compulsive disorder, ocular hypertension, preclampsia, premature ejaculation, premature labor, pulmonary disease, Raynaud's disease, kidney disease, renal insufficiency, male or female sexual dysfunction, septic shock, sleep disorder, injury of the spinal cord, thrombosis, urinary tract infection or urolithiasis, including treating the mammal with an effective amount of a compound of formula (I) or with a pharmaceutically acceptable derivative or preparation thereof, (ix) a method as in (vii) ",. wherein the disease or disorder is anxiety, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia), dysmenorrhea (primary and secondary), endometriosis, emesis (including motion sickness), delay of the disease internal growth in the uterus, inflammation (including rheumatoid arthritis), mittel-schmerz, preclampsia, premature ejaculation, premature contractions or Raynaud's disease, (x) a method as in (vii), where the disease or disorder is dysmenorrhea (primary and secondary), (xi) intermediates of formulas (II), (ll), (X), (XV), (XXIV) and (XXV), (xii). use of a combination of formula (I) with an oral contraceptive for the treatment of dysmenorrhea (primary or secondary, secondary). 35 (xiii) use of a combination of a compound of formula (I) with a PDEs inhibitor 1025527-

62 I

for the treatment of dysmenorrhea (primary I

primary and / or secondary), I

(xiv) use of a combination of a compound

of formula (I) with an NO donor for I

Treating dysmenorrhea (primary I

and / or secondary).

(xv) use of a combination of a connection

of formula (I) with L-arginine for I

treating dysmenorrhea (primary I

10 and / or secondary), I

(xvi) use of a combination of a compound

of formula (I) with a COX inhibitor I

for the treatment of dysmenorrhea (primary I

primary and / or secondary). I

I

The present invention is illustrated by the I

following preparations and examples: I

Preparation 1: 3,4,5,6-Tetrahydro-2H- [1,2 '] bipyridinyl-4-I

Carboxylic acid hydrazide I

/ -. o I

25 WN 'VV Λ | NH, I

3,4,5,6-Tetrahydro-2H- [1,2'-bipyridinyl-4-carboxylic acid ethyl]

lester (1 g, 4.3 mmol) (see reference: Farmaco, 1993, I

48 (10), 1439) was dissolved in methanol (20 ml) which hydra-l

zine hydrate (620 μΐ, 20 mmol), and it lasted for 1 hour

heated for 18 hours under reflux. The mixture was left I

35 cooled to room temperature and it was evaporated under

reduced pressure. The solid formed was crushed I

1,02552 - I

63.

with propan-2-ol to give the title compound as a white solid (493 mg).

APCI-MS: m / z 221 [M + H] +. .

Preparation 1b: 3,4,5,6-Tetrahydro-2H- [1,2 '] bipyridinyl-4-carboxylic acid ethyl ester o 10

Potassium carbonate (52.5 g, 0.399 mol) was added to a stirred solution of 2-bromopyridine (60 g, 0.399 mol) and ethylisonipecotate (59.7 g, 0.399 mol) at an ambient temperature before heating for 24 hours up to 120 ° C. The mixture was allowed to cool to room temperature and propane-2-ol was added to the solution. The reaction mixture was then filtered and used for preparation 1c.

25

Preparation 1c: 3,5,5,6-tetrahydro-2H- [1,2 ') bipyridinyl-4-carboxylic acid hydrazide

. rWH

\ == N '-. N - NH 2 - 35 1025527 "

64 I

Hydrazine hydrate (61.4 ml, 1,265 mol) was added I

to a solution of 3,4,5,6-tetrahydro-2 H- [1,2'-bipyri]

dinyl 4-carboxylic acid ethyl ester (0.253 mol, 5 ml / g) (see above)

reference: Farmaco, 1993, 48 (10), 1439) in propan-2-ol

5 before being refluxed for 18 hours. I

The mixture was allowed to cool to room temperature and cooled

up to 10 ° C, and the product, a white solid, I

was collected by filtration (44.5 g). I

APCI-MS :. m / z = 221 [M + H] +. I

10 I

Preparation 2: 1-Pyrimidin-2-ylpiperidine-4-carboxylic acid I

hydrazide I

15 jT \ - / ~~ Λ /? I

\ = / v_y n-nh2 I

20 I

The title compound was obtained from 1-pyrimidine-2-L

ylpipidine-4-carboxylic acid ethyl ester (see Farmaco, 1993, 48 I

(10), 1439), in 91%. yield by following the procedure

25 gene described in preparation 1. I

APCI-MS: m / z = 222 [M + H] 1

Preparation 3: 3,4,5,6-Tetrahydro-2H- [1,2 '] bipyridinyl-4-I

carboxylic acid N '- (2-chloroacetyl) hydrazide I

30 I

(VO ^ "Va I

35 I

1025527-1

65

The hydrazide of preparation 1 (23.6 g, 0.11 mol) was suspended in dichloromethane (500 ml) and 4-methylmorpholine (17.7 ml, 0.16 mol) added. The mixture was cooled with the aid of an ice bath and chloroacetyl chloride (12.8 ml, 0.16 mol) added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The solid formed was isolated by filtration, washed with dichloromethane and diethyl ether and dried under vacuum to give the title compound (20.4 g).

LCMS: m / z, ES + '= 297 [M + H) +

Preparation 3b: 3,4,5,6-Tetrahydro-2H- [1,2 '] bipyridinyl-4-carboxylic acid N' - (2-chloroacetyl) hydrazide

. P

20. : Q

The hydrazide of preparation 1c (5.0 g, .23 mmol) was suspended in dichloromethane (100 mL) and 4-methyl-morpholine (3.75 mL, 34 mmol) added. The mixture was cooled with the aid of an ice bath and chloroacetyl chloride (1.9 ml, 24 mmol) added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The formed solid was isolated by filtration, washed with dichloromethane and dried under vacuum to give the title compound (2.2 g).

LCMS: m / z, ES + = 297 [M + H] + 35

Preparation. 4: 1-Pyrimidin-2-ylpiperidine-4-carboxylic acid N '- (2-chloroacetyl) hydrazide 1025527-

66 I

0 I

5 rrCr * ° I

///. o I

The title compound was prepared from the hydrazide of I

preparation 2 and chloroacetyl chloride, in 96% yield, I

using the procedure described in preparation

thing 3. I

APCI-MS: m / z = 298 [M + H] 1

I

Preparation 5: 4- (5-Chloromethyl [1,3,4] oxadiazol-2-yl) -1

3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl I

20 I

25 I

The hydrazide of preparation 3 (20.4 g, 69 mmol) became I

suspended in phosphorus oxychloride (150 ml) and for 4 l

heated to 100 ° C for one hour. The mixture was allowed to cool and the I

The solvent was evaporated under reduced pressure. The re- I

sidu was dissolved in ethyl acetate and added to water

ter. The water layer was made basic by adding I

solid sodium hydrogen carbonate and the phases were washed

divorce. The aqueous phase was extracted with ethyl acetate I

35 (x 2) and the combined organic layers were dried

on magnesium sulfate and evaporated under reduced pressure. I

The isolated material was triturated with diethyl

1025527-1

67 lether to give the title compound as a beige solid (15 g).

1 H NMR (400 MHz, CD3 OD): δ = 1.91 (m, 2 H), 2.19 (m, 2 H), '3.14 (m, 2 H), 3.30 (m, 1 H), 4 29 (m, 2H), 4.86 (s, 2H), 5.69. (m, 1H), 6.89 (d, 1H), 7.58 (m, 1H) ,. .8.08 (d, 1 H).

Preparation 5b: 4- (5-Chloromethyl [1,3,4] oxadiazol-2-yl) - 3,4,5,6-tetrahydro-2H- [1,2 '] pyridyridinyl

0 '<^ SV ^ CI

The hydrazide of preparation 3 (50.0 g, 169 mmol) was suspended in acetonitrile (250 ml) and cooled using an ice bath. Trifluoromethanesulfonic anhydride (29.9 ml, 177 mmol) was added dropwise at T <15 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was cooled using an ice bath and a solution of sodium hydrogen carbonate (29.8 g, 354 mmol) in water (250 ml) was added dropwise. Dichloromethane (250 ml) was added and the phases were separated. The organic phase containing the product was used in preparation 14b.

1 H-NMR (400 MHz, CD3 OD): δ = 1.91 (m, 2H), 2.19 (m, 2H), 3.14 (m, 2H), 3.30 (m, 1H), 4 29 (m, 2H), 4.86 (s, 2H), 6.69. (M, 1H), 6.89 (d, 1H), 7.58 (m, 1H), 8.08 (d 1 H).

Preparation 6: 2- [4r (5-Chloromethyl [1,3,4] oxadiazol-2-yl) piperidin-1-yl] pyrimidine 1025527-

68 I

*; : ..CKDHPLa I

The title compound was prepared from the hydrazide of I

preparation 4, in 84% yield, using the procedure I

re described in preparation 5. I

APCI-MS: m / z = 280 [M + H] + I

1 H NMR (400 MHz, CDCl 3): δ * 1.91 (m, 2H), 2.19 (m, 2H), 1

15 3.14 (m, 3H), 4.65 (s, 2H), 4.86 (m, 2H), 6.49 (m, 1H), I

6.89 (d, 1H), 8.35 '(d, 1H). I

Preparation 7: (2-Amino-5-methoxyphenyl) methanol I

20 I

OH 1

25 I

2-Amino-5-methoxybenzoic acid (2.0 g, 12 inmol) in te

trahydrofuran (20 ml) was added dropwise to I

30 an ice-cooled 1 niolar solution of lithium aluminum

umhydride (14.4 ml) in tetrahydrofuran and for 2 hours I

stirred at 5 ° C. Water (0.5 ml) was added dropwise

followed by a 2 molar solution of sodium hydrogen

aqueous hydroxide (0.5 ml). The resulting emulsion was treated

35 dried over magnesium sulfate, then filtered and

evaporated under reduced pressure to give the title compound I

as a yellow solid (766 mg). I

1025527-1

69 APCI-MS: m / z = 154 [M + H] +.

1 H NMR (400 MHz> CD3 OD): δ = 3.70 (s, 3H), 4.55 (s, 2H), 6.65-6.78 (m, 3H).

Preparation 8: (2-Amino-6-chlorophenyl) methanol tfH 2

10 UL

The title compound was prepared from 2-amino-6-chlorobenzoic acid. in 69% yield, as an off-white solid, by following the procedure described in Preparation 7.

APCI-MS: m / z = 158 [M + H] + 20 X H-NMR (400 MHz, CDCl 3): δ = 4.85 (s, 2H), 6.60 (d, 1H), 6.80 ( d, 1 H), 7.00 (t, 1 H).

Preparation 9: (2-Amino-4-chlorophenyl) methanol 25 ^ 30

The title connection. was prepared from 2-amino-4-.35 chlorobenzoic acid, in 48% yield, as an off-white solid, by following the procedure described in Preparation 7.

102552?

70 I

APCI-MS: m / z = 170 [MNa] + I

1 H NMR (400 MHz, CD3 OD): δ - 4.55 (s, 2H), 6.60 (d, 1H), I

6.70 (d, 1 H), 7.00 (d, 1 H). I

Preparation 10: 2-Aminomethyl-4-chlorophenylamine I

nh2 I

10 c nh 2 I

2-Amino-5-chlorobenzonitrile (9.0 g, 59 mmol) in te

Trahydrofuran (100 ml) was added dropwise to I

an ice-cooled 1 molar solution of lithium aluminum

umhydride (100 ml) in tetrahydrofuran and the reaction mixture

stirred at room temperature for 18 hours. Water I

(10 ml) was added dropwise. The resulting emulsion

20 g was dried over magnesium sulfate, filtered and filtered

evaporated under reduced pressure to give the title compound I

as a white solid (4.56 g). I

1 H NMR (400 MHz, CDCl 3):. δ = 3.85 (s, 2H), 4.50 (s, 2H), I

6.60 (d, 1 H), 7.05 (m, 2 H). I

25 I

Preparation 11: Acetic acid 2- (2-acetylamino-5-chlorophenyl) -1

ethyl ester I

Hi

3 ° I

. I

35 I

"" 2552f_ ~ I

71

A solution of chlorine in glacial acetic acid (0.98 M, 30 ml) was added dropwise to a solution of N- [2- (2-hydroxyethyl) phenyl] acetamide (5.0 g, 27.9 mmol) (see reference : Biochemistry, 1979, 18 (5), 860) in glacial acetic acid 5 (50 ml) and the mixture stirred at room temperature for 20 hours. The glacial acetic acid was removed under reduced pressure. The resulting oil was triturated with diethyl ether to give the title compound (3.3 g) as a pale yellow solid after filtration.

APCI-MS: m / z 256 [M + H] +, 278 [MNa] + 1 H-NMR (400 MHz, CDCl3): δ = 2.13 (s, 3H), 2.26 (s, 3H) , 2.87 (t, 2H), 4.13 (t, 2H), 7.11 (d, 1H), 7.23 (dd, 1H), 8.05 (d, 1H), 8.27 (s, 1 H).

Preparation 12: 2- (2-Amino-5-chlorophenyl) ethanol 20 The compound from preparation 11 was suspended in 2 molar hydrochloric acid (20 ml) and heated to 100 ° C for 4 hours. The solution was allowed to cool, made basic (pH = 9) with ammonia (s.d. = 0.880) and partitioned with ethyl acetate (50 ml). The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. The solution was filtered and then evaporated under reduced pressure. The residue was purified by chromatography on silica gel with methanol and ammonium hydroxide in dichloromethane as eluent 35 (5: 0.5: 95) to give the title compound as a brown oil (0.43 g).

APCI-MS: m / z = 172 [MH] + 1025527

72 I

1 H NMR (400 MHz, CD3 OD): δ = 2.64 (t, 2H), 3. 69 (t, 2H), I

6.61 (d, 1 H), 6.87 (dd, 1 H), 6.93 (d, 1 H). I

Preparation 13: 2 - ({[5- (3,4,5,6-Tetrahydro-2 H- [1,2 '] - I

5. bipyridinyl-4-yl) [1,3,4] oxadiazole-2-l

ylmethyl] amino} methyl) phenylamine I

"" I

A solution of 2-aminomethylphenylamine (2.2 g, 1

17.9 mmol) in tetrahydrofuran (50 ml) was added to I

a solution of the oxadiazole of preparation 5 (2.0 g, I

7.18 mmol) in tetrahydrofuran (50 ml) and the mixture is diluted

Heated to 50 ° C for 18 hours. The reaction mixture was in

evaporated under reduced pressure and the residue purified

by chromatography on silica gel with methanol and ammonium

umhydroxide in dichloromethane as eluant (5: 0.5: 95), I

giving the title compound as a pale yellow gum (2.6 g)

25 gave. I

APCI-MS: m / z = 365 [M + H] +, 387 [MNa] + I

1 H NMR (400 MHz, CDCl 3): δ = 1.94 (m, 2H), 2.18 (m, 2H), I

3.14 (m, 3H), 3.88 (s, 2H), 4.00 (s, 2H), 4.31 (m, 2H), I

6.60-6.75 (m, 4H), 7.02 (d, 1H), 7.12 (t, 1H), 7.48 (t, I

30 (1 H), 8.20 (d, 1 H). I

Preparation 14: 4-Chloro-2 - ({[5- (3,4,5,6-tetrahydro-2 H -1)

[1,2 '] bipyridinyl-4-yl [1,3,4] oxadiazole-2-l

ylmethyl] amino) methyl) phenylamine I

35 I

102552? I

73 ci; s 10

A solution of the amine of preparation 10 (6.4 g, 41 iranol) in tetrahydrofuran (50 ml) was added to a solution of the oxadiazole of preparation 5 (4.56 g, 16 mmol) in tetrahydrofuran (50 ml and the mixture was heated to 50 ° C for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue purified by chromatography on silica gel with methanol in.

dichloromethane as eluant (5:95) to give the title compound as a white solid (4.65 g).

APCI-MS: m / z = 399 [M + H] + 1 H-NMR (400 MHz, CDCl 3): δ 1.95 (m, 2H), 2.20 (m, 2H). 3.10 (m, 2H), 3.20. (m, 1 H), 3.80. (s, 2H), 4.00 (s, 2H),. 4.30 (m, 2H), 6.60 (m, 1H), 6.65 (t, 1H), 6.70 (d, 1H), 7.00 (s, 1H), 7.05 (d , 1 H), 7.50 (t, 1 H), 8.20 (d, 1 H).

25

Preparation 14b: 4-Chloro-2 - ({[5- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) [1,3,4] oxadiazole-2 -ylmethyl] amino) methyl) phenylamine; .35 1 0255.2? -

74 I

The acetonitrile / dichloromethane solution of the I

oxadiazole from preparation 5b was distilled, the residue I

in acetonitrile, and then for 5 l

heated under reflux for 1 hour with sodium hydrogencarbon

5 nate (14.9 g, 177 mmol) and the amine from preparation 10 l

(39.7 g, 253 mmol). The mixture was cooled and water (250 l

ml) and dichloromethane (1500 ml) were added. The fa

were separated and the organic phase was distilled

and replaced with ethyl acetate. The resultant I

The stroke was isolated by filtration, which is the. title I

binding as a yellow solid (32.8 g). I

APCI-MS: m / z = 280 [M + H] + I

1 H NMR (400 MHz, CDCl 3): $ 1 1.91 (m, 2H), 2.19 (m, 2H), I

3.14 (m, 3H), 4.65 (s, 2H), 4.86 (m, 2H), 6.49 (m, 1H), I

15 6.89 (d, 1 H), 8.35 (d, 1 H). I

Preparation 15: 4-Chloro-2 - ({[5- (1-pyrimidin-2-yl piperyl)

dine-4-yl) [1,3,4] oxadiazool-2-ylmethyl] -1

aminomethyl) phenylamine I

20 I

ci I

25 I

A solution of the amine from preparation 10 (4.12 g, I

26 mmol) in tetrahydrofuran (50 ml) was added to I

a solution of the oxadiazole of preparation 6 (2.95 g, I

11 mmol) in tetrahydrofuran (50 ml) and for 18 hours I

heated to 50 ° C. The reaction mixture was evaporated under I

35 reduced pressure and the residue purified by chromatography

on silica gel with ethyl acetate as eluant, the

02552 - I

75 did not give the title compound as an off-white solid (2/34 g).

APCI-MS: m / z = 400 [MH] + 1 H-NMR (400 MHz, CDCl3): δ = 1.80 (m, 2H), 2.20 (m, 2H), 3.20 (m, 3 H), 3.80 (s, 2 H), 4.00 (s, 2 H), 4.75 (m, 2 H), 6.50 (t, 1 H), 6.60 (d, 1 H), 7, 00 (d, 1H), 7.05 (d, 1H), 8.35 (d, 2H).

Preparation 16: 2- [5- (3,4,5,6-Tetrahydro-2 H- [1,2 '] bipyrididin-4-yl) [1,3,4] oxadiazol-2-ylmethoxy-methyl ] is phenylamine. 5__. nh2 1 1025527 20

A solution of (2-aminophenyl) methanol (996 mg, 8 mmol) in tetrahydrofuran (5 ml) was added dropwise to an ice-cooled suspension of sodium hydride. .25 (60% in mineral oil, 324 mg, 8.1 mmol) in tetrahydrofuran (5 ml) and stirred for 0.5 hours. A solution of the oxadiazole of preparation 5 (750 mg, 2.69 mmol) in tetrahydrofuran (5 ml) was added dropwise and the mixture stirred at room temperature for 3 hours. Ethyl acetate (50 ml) was added and the solution extracted with water (25 ml). The aqueous solution was washed with ethyl acetate (2 x 20 mL). The combined organ. The technical layers were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel with a gradient of ethyl acetate in pentane as eluant (2: 1 to 100: 0),

76 I

giving the title compound (300 mg) as a white, solid I

gave substance. I

APCI-MS: m / z - 366 [MH] + I

1 H NMR (400 MHz, CDCl 3): δ = 1.90 (m, 2H), 2.20 (m, 2H), I

5 3.10 (m, 2H), 3.20 (m, 1H), 4.20 (s, 2H), 4.35 (m, 2H), I

4.64 (s, 2H), 4.66 (s, 2H), 6.65 (m, 4H), 7.05 (d, 1H), I

7.15 (t, 1H), 7.50 (t, 1H), 8.20 (d, 1H). I

Preparation 17: 3-Chloro-2- [5- (3,4,5,6-tetrahydro-2 H -1)

[1,2 '] bipyridinyl-4-yl) [1,3,4] oxadiazole-2-l

ylmethoxymethyl] phenylamine I

15 or 11

NH1

20 I

The title compound was prepared from the alcohol of BE

preparation 8 and the oxadiazole of preparation 5, in 55%

brehgst, using the procedure described I

25 in preparation 16.

APCI-MS: m / z = 400 [MH] + I

1 H NMR (400 MHz, CDCl 3): δ = 1.95 (m, 2H), 2.20 (m, 2H), 1

3.05 (m, 2H), 3.20 (m, 1H), 4.30 (m, 2H), 4.40 (s, 2H), I

4.70 (s, 2HJ, 4.90 (s, 2H), 6.55 (d, 1H), 6.60 (m, 1H), I

6.70 (d, 1H), 6.75 (d, 1H), 7.00 (t, 1H), 7.15 (t, 1H), I

7.45 (t, 1H), 8.20 (d, 1H). I

Preparation 18: 5-Chloro-2- [5- (3,4,5,6-tetrahydro-2 H -1)

[1,2 '] bipyridinyl-4-yl) [1,3,4] oxadiazole-2-l

35 ylmethoxymethyl] phenylamine I

1025527 I

77 NH 2 to 10

The title compound was prepared from the alcohol of preparation 9 and the oxadiazole of preparation 5, in 42% yield, using the procedure described in preparation 16.

APCI-MS: m / z = 400 [MH] +, 422 [MNa] + 1 H-NMR (400 MHz, CDCl3): δ = 1.90 (m, 2H), 2.20 (m, 2H), 3.10 (m, 3H), 4.30 (m, 4H), 4.60 (s, 2H), 4.65 (s, 2H), 6.75 (m, 4H), 7.00 (d 1 H), 7.45 (t, 1 H), 8.20 (d, 1 H).

Preparation 19: 4-Methoxy-2- [5- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) [1,3,4] oxadiazol-2-ylmethoxymethyl ] phenylamine /

25 'N - N

CrCr1 ^^ ... NH2 .30

The title compound was prepared from the alcohol from preparation 7 and the oxadiazole from preparation 5, in 53% yield, using the procedure described.

35 in preparation 16.

APCI-MS: m / z = 396 [MH] +, 418 [MNa] + 1025527 ·

78 I

1 H NMR (400 MHz, CDCl 3): δ = 1.95 (m, 2H), 2.20 (m, 2H), I

3.10 (m, 3H), 3.75 (s, 3H), 4.60 (s, 2H), 4.65 (s, 2H), I

6.70 (m, 5H), 7.45 (t, 1H), 8.20 (d, 1H). I

Preparation 20: 4-Chloro-2- [5- (3,4,5,6-tetrahydro-2 H -1)

[1,2 '] bipyridinyl-4-yl) [1,3,4] oxadiazole-2-l

ylmethoxymethyl] phenylamine I

ci I

10 N - N.

nh2

I

The title compound was prepared from (2-amino-5

chlorophenyl) methanol and the oxadiazole of preparation 5 in I

61% Yield, using the procedure that was used I

20 described in preparation 16. I

APCI-MS: m / z = 400 [MH] + I

X H NMR (400 MHz, CDCl 3): δ = 1.95 (m, 2H), 2.20 (m, 2H), I

3.10 (m, 2H), 3.20 (m, 1H), 4.20 (s, 2H), 4.35 (m, 2H), I

4.60 (s, 2H), 4.70 (s, 2H), 6.60 (m, 2H), 6.70 (d, 1H), I

Δ 7.10 (m, 2H), 7.45 (t, 1H), 8.20 (d, 1H). I

Preparation 21: 2- {2- [5- (3,5,5,6-tetrahydro-2H- [1> 2 '] bi-I

pyridinyl-4-yl) [1,3,4] oxadiazol-2-yl-

methoxy} ethyl} phenylamine I

30 I

. Hain I

35 I

1025521 - I

79

The title compound was prepared from 2- (2-amino-phenyl) ethanol and the oxadiazole of preparation 5, in 66% yield, using the procedure described in preparation 16.

APCI-MS: m / z = 380 [MH] + 1 H-NMR (400 MHz, CDCl3): δ = 1.95 (m, 2H), 2.15 <m, 2H), 2.80 (t, 2H), 3.10 (m, 3H), 3.80 (m, 4H), 4.30 (m, 2H), 4.65 (s, 2H), 6.70 (m, 4H), 7.00 ( m, 2H), 7.50 (t, 1H), 8.20 (d, 1H).

10

Preparation 22: 4-Chloro-2- {2- [5- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) [1,3,4] oxadiazole-2 -methylmethoxy] ethyl} phenylamine> 5 ^ Cl -

The title compound was prepared from the alcohol of be-25. preparation 12 and the oxadiazole of preparation 5. 52% yield, using the procedure described in Preparation 16.

APCI-MS: m / z = 414 [MH] + 1 H-NMR (400 MHz, CDCl3) 6 = 1.92 (m, 2H), 2.15 (m, 2H), 2.77 {t, 2H ), 3.10 (m, 3H), 3.79 (t, 2H), 4.28 (m, 2H), 4.66 (s, 2H), 6.58 (d, 1H), 6.62 (d (1 H), 6.71 (d, 1 H), 6.97 (m, 2 H), 7.49 (t, 1 H), 8.20 (d, 1 H).

Preparation 23: 4-Chloro-2- [5- (1-pyrimidin-2-ylpiperidin-4-yl) [1,3,4] oxadiazol-2-ylmethoxymethyl] phenylamine 1025527-

80 I

I Cl. I

I NH 2 I

10 I

I A solution of (2-amino-5-chlorophenyl) methanol I

I (850 mg, 5.4 mmol) in tetrahydrofuran (10 ml) was added dropwise

I peeled to an ice-cooled suspension

I of sodium hydride (60% in mineral oil, 215 mg, 5.4 I

15 mmol) in tetrahydrofuran (5 ml) and stored for 1 hour

I stirred. A solution of the oxadiazole of preparation 6 I

I (500 mg, 1.79 mmol) in tetrahydrofuran (5 ml) was added dropwise

I was added peeled and the mixture was stirred for 1 hour

I stirred at room temperature. Dichloromethane (50 ml) was I

I was added and the solution extracted with water (25 ml). I

The aqueous solution was washed with dichloromethane

I (2x20 ml). The combined organic layers were added

I dried over magnesium sulfate and evaporated under reduced I

I busy. The residue was purified by chromatography on I

Silica gel with diethyl ether followed by ethyl acetate as I

I eluent, which, after trituration with diethyl ether, the I

I gave the title compound (320 mg) as a white solid.

APCI-MS: 11 / z = 401 [MH] + I

1 H NMR (400 MHz, CDCl 3): δ = 1.92 (m, 2H), 2.19 (m, 2H), I

3.24 (m, 3H), 4.60 (s, 2H), 4.68 (s, 2H), 4.75 (m, 2H), I

I 6.57 (m, 1H), 6.63 (d, 1H), 7.08 (m, 2H), 8.37 (d, 2H). I

Preparation 24: 2- (2- [5- (1-Pyrimidin-2-yl-piperidin-4-yl) -1

I [1,3,4] oxadiazol-2-ylmethoxy] ethyl} -1

Phenylamine I

1025527-1

81 N - N. The title compound was prepared from 2- (2-aminophenyl) ethanol and the oxadiazole of preparation 6, in 54% yield, using the procedure described in preparation 23.

APCI-MS: m / z = 381 [MH] + 15 1 H-NMR (400 MHz, CDCl 3): δ = 1.85 (m, 2H), 2.15 (m, 2H), 2.88 (m, 2 H), 3.18 (m, 3 H), 1 H), 3.80 (t, 2 H), 4.68 (s, 2 H), 4.74 (m, 2 H), 6.51 (m, 1 H) , 6.80 (m, 2H), 7.08 (m, 2H), 8.37 (d, 2H).

. 2.0 Preparation 25: 4- [N'- (2-Chloroacetyl) hydrazinocarbonyl] -piperidine-1-carboxylic acid tert-butyl ester butyl ester (see reference WO 9703986 A1 19970206) (25 g, 103 mmol) was dissolved in dichloromethane (300 ml) and 4- methyl methylphenol (12.5 ml, 113 mmol) added. The mixture was cooled with an ice bath and chloroacetyl chloride (8.2 ml, 103 mmol) added dropwise. It was allowed to do 1 025527

82

I reaction mixture was warmed to room temperature and 4 l

Stirred for 1 hour. The reaction mixture was partitioned with sodium I

I aqueous hydrogen carbonate solution, dried over magnesium

Ium sulfate, filtered and the filtrate evaporated, yielding I

The title compound as an off-white solid

I (29.6 g). I

APCI-MS: m / z - 318 [M-H] + 1

Found: C, 48.41; H, 6.91; N, 12.85; I

I for C 13 H 22 N 3 O 4 Cl. 0.3 H 2 O is required; I

10 ° C, 48.32; H, 7.01; N, 12.92%. I

Preparation 26: 4- (5-Chloromethyl [1,3,4] oxadiazol-2-yl) -1

I piperidine-1-carboxylic acid tert-butyl ester I

I 15 I

I * ^ 1 I

20 I

The hydrazide of preparation 25 (5.0 g, 15.6 mmol). I

I was suspended in dichloromethane (200 ml) and pyridine I

I (6.4 ml, 78 mmol) was added before the mixture was I

I cooled to 10 ° C. Trifluoroacetic anhydride (6.6 ml, 39 l

1 mmol) was added dropwise over 15 minutes and then continued

The mixture was stirred at room temperature for 3 hours. I

The reaction mixture was partitioned with water (50 ml) and the I

Organic layer dried over magnesium sulfate. The mixture I

I was filtered and the filtrate evaporated under reduction

I third edition. The residue was purified by chromatography I

I on silica gel with methanol in dichloromethane as the course

I agent (2:98), which gives the title compound as a white, I

I gave solid (2.95 g). I

I 1025527-I

83 1 H NMR (400 MHz, CD 3 OD): δ = 1.45 (s, 9H), 1.74 (m, 2H), 2.19 (m, 2H), 3.04 (m, 2H), 3.24 (m, 1 H), 4.09 (m, 2 H), 4.85. (s, 2H).

Preparation 27: 4- [5- (2-Amino-5-chlorobenzyloxymethyl) - [1,3,4] oxadiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester 10 o 1 V. . . . ° Ovjy NH 2 15

A solution of (2-amino-5-chlorophenyl) methanol (1 g, 6.4 mmol) in tetrahydrofuran (10 ml) was added dropwise to an ice-cooled suspension of sodium hydride (60% in mineral oil) , 215 mg, 5.4 mmol) in tetrahydrofuran (5 ml) and stirred for 1 hour. A solution of the oxadiazole of preparation 26 (1 g, 5.3 mmol) in tetrahydrofuran (5 ml) was added dropwise and the mixture stirred at room temperature for 2 hours. The reaction mixture was partitioned between dichloromethane (50 ml) and sodium hydrogen carbonate solution (25 ml). The aqueous solution was washed with dichloromethane (2 x 20 ml). The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on. silica gel with methanol in dichloromethane (5:95) as eluant, which gave the title compound (1.3 g) as a yellow solid.

APCI-MS: m / z = 423 [MH] +, 323 [M-Boc) + 1 H-NMR (400 MHz, CDCl3): δ = 1.47 (s, 9H), 1.81 (m, -) 2 H), 2.07 (m, 2 H), 2.96 (m, 2 H), 3.08 (m, 1 H), 4.12 (m, 2 H), 1025527-

84 I

4.23 (s, 2H), 4.58 (s, 2H), 4.68 (s, 2H), 6.62 (d, 1H), I

7.07 (s, 1H), 7.12 (d, 1H). I

Preparation 28: 4- (8-Chloro-4H, 6H-5-oxa-2,3, 10b-triaza)

Benzo [e] azulene-1-yl) piperidine-1-carbon-1

acid tert-butyl ester I

11 I

σ. I

I

Toluene-4-sulfonic acid (80 mg, 0.46 inmol) was added

added to a solution of the oxadiazole of preparation I

27 (1.28 g, 3.0 inmol) in xylene and there was added for 18 l

Heated for 20 hours at 140 ° C. The xylene was removed under I

reduced pressure. The residue was partitioned between dichloromethane

thane (100 ml) and sodium hydrogen carbonate solution (25 l

ml). The aqueous solution was washed with dichloromethane

thane (2 x 20 ml). The combined organic layers were I

Dried over magnesium sulfate and evaporated under reduction

the pressure. The residue was purified by chromatography I

on silica gel with methanol and ammonium hydroxide in I

dichloromethane (5: 0.5: 95) as eluant, which is the titr

compound (730 mg) as a pale yellow foam. I

APCI-MS: m / z = 405 [MH] + 305 [M-Boc) + I

1 H NMR (400 MHz, CDCl 3): δ = 1.43 (s, 9H), 1.85 (m, 2H), 1

1.96 (m, 2 H), 2.92 (m, 2 H), 3.08 (m, 1 H), 4.18 (m,. 2 H), I

4.40 (s, 2H), 4.66 (s, 2H), 7.36 (d, 1H), 7.58 (m, 2H). I

Found: C, 57.98; H, 6.17; N, 13.40; I

35 is required for C 20 H 25 N 4 O 3 Cl 0.5 H 2 O; I

C, 58.04; H, 6.33; N, 13.54%. I

1025527-1

85

Preparation 29: 8-Chloro-1-piperidin-4-yl-4H, 6H-5-oxa.

2,3,10-triazabenzo [e] azulene 5 η α 10

The triazole of preparation 28 (700 mg, 1.73 in mol) was dissolved in 1,4-dioxane (6 ml) and hydrogen chloride (4M in 1,4-dioxane, 12 ml) added. The reaction mixture was stirred at room temperature for 4 hours. The 1,4-dioxane was removed under reduced pressure. The. residue was partitioned between dichloromethane (100 ml) and sodium hydrogen carbonate solution (25 ml). The aqueous solution was washed with dichloromethane (2 x 20 ml). The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure to give the title compound (410 mg) as a pale yellow foam.

APCI-MS: m / z = 305 [MH] + 25 1 H-NMR (400 MHz, CD3 OD): δ = 1.83 (m, 4H), 2.65 (t, 2H), 3.09 (m, 2 H), 3.24 (m, 1 H), 4.41 (s, 2 H), 4.58 (s, 2 H), 7.58 (m, 3 H).

Preparation 30: (2-Amino-5-fluorophenyl) methanol 30 nH 2

F

35 10 25 52?

86 I

The title compound was prepared from 2-amino-5-L

fluorobenzoic acid, in 81% yield, as a broken-I

white solid by following the procedure described in I

described in preparation 7. I

APCI-MS: m / z = 142 [M + H] + I

1 H NMR (400 MHz, CDCl3): δ = 4.60 (s, 2H), 6.60 (dd, 1H), I

6.77-6.86 (m, ^ 2H). . I

Preparation 31: 4-Fluoro-2- [5- (3,4,5,6-tetrahydro-2 H- [1.2 *] - 1

Bipyridinyl-4-yl) [1,3,4] oxadiazol-2-yl-1

methoxymethyl] phenylamine I

CJTH · I

is rr °. ° "- \ I

Cr I

20 I

The title compound was prepared from the alcohol of BE

preparation 30 and the oxadiazole of preparation 5, in 60%

yield, using the procedure described I

. in preparation 16. I

APCI-MS: m / z = 384 [M + H] + I

X H NMR (400 MHz, CDCl 3): δ = 1.95 (dk, 2H), 2.18 (d, 2H), I

3.06-3.21 (m, 3H), 4.33 (td, 2H), 4.60 (s, 2H), 4.70 (s, I

2 H), 6.58-6, 67 (m, 2 H), 6.73 (d, 1 H), 6.80-6, 90 (m, 2 H), I

7.52 (t, 1H), 8.19 (d, 1H). I

30 I

Preparation 32: (2-Amino-4,5-difluorophenyl) methanol I

NH 2

35 s ** OH I

F

1025527-1

87

The title connection. was prepared from 2-amino-4,5-difluorobenzoic acid, in 86% yield, as a yellow solid, following the procedure described in Preparation 7.

APCI-MS: m / z = 142 [M + H-H2 O] +, 160 [M + H] + X H NMR (400 MHz, CDCl3): δ = 4.10 (bs, 2H), 4.58 (s, 2H), 6.48 (dd, 1H), 6, S2 (dd, 1H).

Preparation 33: 4,5-Difluoro-2- [5- (3,4,5,6-tetrahydro-2H-[1,2 '] bipyridinyl-4-yl) [1,3,4] oxadiazole-2 - ylmethoxymethyl] phenylamine fV-λ, '

15 .Λ-ο P

20

The title compound was prepared from the alcohol from preparation 32 and the oxadiazole from preparation 5, 50% by weight. 25 yield, using the procedure described in preparation 16.

APCI-MS: m / z = 402 [M + H] + 1 H-NMR (400 MHz, CDCl 3): δ = 1.94 (dk, 2H), 2.09 (bd, 1H),.

3.09 (bt, 2H), 3.18 (m, 1H), 4.20 (bs, 2H), 4.33 (td, 2H), 4.54 (s, 2H), 4.68 ( s, 2H), 6.47 (dd, 1H), 6.64 (t, 1H), 6.72 (d, 1H), 6.92 (dd, 1H), 7.52 (t, 1H) , 8.19 (d, 1H).

Preparation 34: 2-Amino-5-trifluoromethoxybenzoic acid 35 1025527-

88 I

. / NH 2

5>

> /> OH 0

10 I

5-Trifinoinethoxy-1H-indole-2,3-dione (3.48 g, 15.0 l)

in mol) was dissolved in 2N aqueous sodium hydroxide (90 l

ml) and cooling to 17 ° C before 30% hydrogen per liter

aqueous oxide solution (2.75 ml, 27 mmol) in 20 minutes. I

15 was added dropwise. The mixture was stirred for 1

Stirred at room temperature for 1 hour before concentrated I

hydrochloric acid (7 µl) was added. The resulting brown n £ er- I

Stroke was filtered off and in vacuum at I for 66 hours

Dried at 50 ° C to give the title compound (1.83 g) as an I

20 gave a brown solid. I

APCI-MS: m / z = 220 [M + H) + I

1 H NMR (400 MHz, DMSO): δ = 6.80 (d, 1 H), 7.24 (dd, 1 H), I

7.53 (d, 1 H). I

Preparation 35: (2-Amino-5-trifluoromethoxyphenyl) methanol I

f reef I

30 I

OH I

35 I

The title compound was prepared from the acid of I

line 34, in 62% yield, as a white solid I

1025521-1

89 by following the procedure described in Preparation 7.

APCI-MS: m / z = 206 [M + H] + 1 H-NMR (400 MHz, CDCl 3): δ = 4.85 (s, 2H), 6.67 (d, 1H), 5 6.92 - 7.00 (m, 2 H).

Preparation 36: 2- [5- (3, 4,5, 6-Tetrahydro-2H- [1, 2-yl] pyridinyl-4-yl) [1, 3, 4] oxadiazol-2-ylmethoxy-methyl3-4 trifluoromethoxyphenylamine 10 f-N ·.

O

Cf ·. ’··; f 20

The title compound was prepared from the alcohol of preparation 35 and the oxadiazole of preparation 5, in 28% yield, using the procedure described in preparation 16. * APCI-MS: m / z = 450 [M + H] +1 H-NMR (400 MHz, CDCl3): δ = 1.94 (dk, 2H), 2.16 (bd, 1H), 3.09 (t, 2H), 3.17 (m, 1H), 4 , 37 (bd, 2H), 4.60 (s, 2H) ,.

4.67 (s, 2H), 6.60-6.66 (m, 2H), 6.70 (d, 1H), 6.95-7.07 (ία, 2H), 7.49 (t 1 H), 8.19 (d, 1 H).

Preparation 37: 4-Methyl-2- [5- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) [1,3,4] oxadiazol-2-ylmethoxymethyl] phenylamine 35 1025527 "

90 I

κ, ___ Ν I

· I

- 0 I 'I

5. y__ ... I

Η? Ν “—γ \ —CHs I

10 I

The title compound was prepared from (2-amino-5-L

methylphenyl) methanol (see Arch. Pharm., (1929), 583) and I

the oxadiazole of preparation 5, in 38% yield, with i

help from the procedure described in preparation 16. I

APCI-MS: m / z = 380 [M + H] + I

1 H NMR (400 MHz, CDCl 3): δ 1.92 (dk, 2H), 2.16 (bd, 2H), 1

2.19 (s, 3H), 3.09 (t, 2H), 3.17 (m, 1H), 4.37 (bd, 2H), I

4.60 (s, 2H), 4.67 (s, 2H), 6.64 (m, 2H), 6.85 (m, 3H), I

7.58 (t, 1H), 8.09 (d, 1H). I

20 I

Preparation 38: N- [2- (2-Acetylaminoethyl) phenyl] acetamide I

25 I

HN \ / - I

V / I

30 I

A solution of acetic anhydride (9.6 ml, 101 l

mmol) in dichloromethane (50 ml) was added dropwise

added to a solution of 2- (2-aminoethyl) phenylamine I

35 (see JACS, 9θ, (1977), 5716) (8.0 g, 46 mmol) and triethylla I

mine (8.4 ml, 60 mmol). dichloromethane (200 ml). The I

The mixture was stirred at room temperature for 18 hours

1025527-1

91 before it was partitioned with water (100 ml). The organic layer was washed with a saturated saline solution (50 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel with methanol and ammonium hydroxide in dichloromethane (5: 0.5: 95) as eluant to give the title compound (4.1 g) as an off-white solid.

APCI-MS: m / z = 221 [M + H] + 10 H NMR (400 MHz, CDCl 3): δ = 2.04 (s, 3H), 2.33 (s, 3H), 2.81 ( t, 2H), 3.28 (m, 2H), 6.19 (bs, 1H), 7.03 (bt, 1H), 7.07 (d, 1H), 7.22 (m, 1H), 8.11 (d, 1H), 8.88 (bs, 1H) - Found: C, 65.18%; H, 7.27%; N, 12.70%; for C12 H16 N2 O2 requires: .15 C, 65.43%; H, 7.32%; N, 12.72%.

Preparation 39: N- [2- (2-Acetylaminoethyl) -4-chlorophenyl] acetamide 20

H J

A solution of chlorine in glacial acetic acid (1.22 M, 29 ml) was added dropwise to a solution of the acetamide of preparation 38 (7.78 g, 35 mmol) in glacial acetic acid (70 ml) and stirred at room temperature for 2 hours. The glacial acetic acid was removed under reduced pressure. The resulting solid was triturated with a mixture of ethyl acetate. and propane-2-ol (7: 3, 20 ml), which gives the titanium

92 I

compound (4.83 g) after filtration as a pale yellow solid.

ESI-MS: m / z - 277 [M + Na] + I

1 H NMR (400 MHz, CDCl 3): δ = 2.03 (s, 3H), 2.33 (s, 3H), I

5 2.79 (m, 2H), 3.22 (m, 2H), 6.28 (bs, 1H), 7.05 (s, 1H), I

7.20 (dd, 1H), 8.14 (d, 1H), 9.09 (bs, 1H). I

Preparation 40: 2- (2-Aminoethyl) -4-chlorophenylamine dihydro

chloride

10 I

nh2 I

15 \ L = / ~ \ I

. "NH, CI. i

20 I

The compound from preparation 39 (4.83 g, 19 mmol) became I

suspended in 2 molar hydrochloric acid (50 ml) and for 18 l

heated to 100 ° C for one hour. Evaporation under reduced pressure gave a red solid, which was triturated with propane-2.

25 ol (15 ml), which is the title compound after filtration as I

a pale pink solid (3.5 g). I

ESI-MS: m / z = 171 [M + H] + I

1 H NMR (400 MHz, DMSO-d 6): δ = 3.00 (t, 2H), 3.12 (m, 2H), 1

. 7.38 (dd, 1H), 7.40 (d, 1H), 7.46 (d, IR), 8.15 (bs, 3H). I

Found: C, 39.29%; H, 5.45%; N, 11.46%; I

CeHuN2.2HCl requires: I

C, 39.45%; H, 5.38%; N, 11.50%. I

Preparation 41: 4-Chloro-2- (2 - {[5- (3, 4,5,6-tetrahydro-2 H -1)

35 [1,2 "] bipyridinyl-4-yl) [1,3,4] oxadiazol-2-yl-1

methyl] amino) ethyl) phenylamine I

1025527-1

0 93 n-n 5 Ν ~ λ y = \ α; ^ ίο

A solution of the amine of preparation 40 (3.5 g, 14.4 mmol) in tetrahydrofuran (50 ml) was added to a solution of the oxadiazole of preparation 5 (4.0 g, 14.4 mmol) and triethylamine (7.0 ml, 50 mmol) in tetrahydrofuran (50 ml) and it was heated to 50 ° C for 4 hours. The reaction mixture was evaporated under reduced pressure and the residue purified by chromatography on silica gel with ethyl acetate as eluent, followed by methanol and ammonium hydroxide in dichloromethane (5: 0.5: 95) to give the title compound as a brown oil (1 35 g).

APCI-MS: m / z = 413 [M + H] + 1 H-NMR (400 MHz, CDCl 3): δ 1.92 (dk, 2H), 2.15 (bdd, 2H),.

2.68 (t, 2H), 2.93 (t, 2H), 3.07 (dt, 2H), 3.14 (m, 1H), 4.01 (s, 2H), 4.31 (btd (2H), 6.57 (d, 1H), 6.62 (dd, 1H), 6.70 (d, 1H), 6.95-7.02 (m, 2H), 7.27 (t, 1 H), 8.19 (d, 1 H).

.30

Preparation 42: Morpholine-2,4-dicarboxylic acid 4-tert-butyl ester, 2-ethyl ester 1025527-

94 I

o o I

5 ° γ ^ Ύ I

r I

CHS CH * I

10 I

A mixture of 4-phenylmethyl-2-morpholinecarboxylic acid I

ethyl ester (J. Med. Chem., 1993, 36 (6), 683-9), (8.4 g, I

32.4 mmol), di-tert-butyl dicarbonate (8.47 g, 38.9 mmol), I

15 1-methyl-1,4-cyclohexadiene (12.37 ml, 110 mmol) and 10% I

palladium on charcoal (900 mg) in ethanol (330 ml) was I

heated to 88 ° C for 22 hours. TLC analysis showed I

that starting material remained, so that the reaction mixture

was cooled and additional 1-methyl-1,4-cyclohexadiene (2.37 L

20 ml, 21 mmol) and 10% palladium on charcoal (900 mg)

and the reaction mixture was added for another 12 hours

was heated to 88 ° C. The cooled mixture was filtered

Arbocel® and the filtrate evaporated under evaporation

reduced pressure. The remaining brown oil was purified

25 by column chromatography on silica gel with an elution grade

service of dichloromethane: methanol (100: 0 to 95: 5), the

did not give the title compound as a pale yellow oil; 5.97

g- I

1 H NMR (400 MHz, CDCl 3): δ * 1.30 (t, 3H), 1.43 (s, 9H), I

3.10 (m, 2H), 3.50-3.70 (m, 2H), 4.01 (m, 1H), 4.25 (k, 1).

2H). I

Preparation 43: Morpholine-2,4-dicarboxylic acid 4-tert-butyl ester

35 I

102552 - I

95 <ry <0 y OH. H 3 C CH 10

Lithium hydroxide (28 ml, 1M in water, 28 mmol) was added to a solution of the ester from preparation 42 (2.85 g, 11 mmol) in tetrahydrofuran (30 ml) and the reaction mixture stirred at room temperature for 19 hours . The mixture was acidified to pH = 3 with 2M hydrochloric acid and then extracted with dichloromethane (2 x 70 ml); The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure to give the title compound as a yellow solid; 2.36 g.

1 H NMR. (400 MHz, CDCl 3): δ = 1.47 (s, 9H), 3.03-3.11 (m, 3H), 3.60 (m, 1H), 3.77-3.86 (m, 1 H), 4.02 (m, 1 H), 4.15 - 4.23 (m, 1 H).

'25

Preparation 44: 6-Methylene [1,4] oxazepane-4-carboxylic acid tert-butyl ester CH1.

96 I

Sodium hydride (992.6 mg, 60% in mineral oil, 24.8 l

inmol) was added portionwise to a solution of I

5 (2-hydroxyethyl) carbamic acid tert-butyl ester (2 g, 12.4 l

mmol) in 1-methyl-2-pyrrolidinone (20 ml) at -2 ° C every 1

maintain a temperature below 5 ° C. The mixture was I

then stirred for 30 minutes, cooled to -5 ° C and I

a solution of 3-chloro-2-chloromethyl-1-propene (1.44 l

.10 ml, 12.4 mmol) of 1-methyl-2-pyrrolidinone (10 ml) of drops

added peeled to keep the temperature below 3 ° C

to maintain. Once the addition was complete, it was left I

warm the reaction mixture to room temperature and was diluted

stirred for another 18 hours. The reaction mixture was diluted I

15 with water and extracted with ether (2 x 50 ml). The combined I

Organic extracts were dried over magnesium l

sulfate and evaporated under reduced pressure. The remaining I

oil was purified by column chromatography on silica-I

gel with ethyl acetate: pentane (10:90), giving the title I

Gave the compound as a clear oil; 713 mg. I

^ -NMR (400 MHz, CDCl 3): δ = 1.46 (s, 9H), 3.51 (d, 2H), I

3.72 (d, 2H), 4.00-4.20 (m, 4H), 4.95 (s, 1H), 5.04 (s, I

1H). I

APCI: m / z = 236 [MNa] + I

25 I

Preparation 45: 6-0xo [1,4-oxazepane-4-carboxylic acid tert-butyl]

ester I

30 V. I

V-Nv 'P I

HjC // \ - / I

35 I

102552 - I

97

Sodium periodate (1/0 g, 4.69 in mol), followed by ammonium tetroxide (0.15 ml, 2.5% by weight solution in tert-butanol, 0.014 mmol), was added to a suspension. of the olefin from preparation 44 (500 mg, 2.34 mmol) in di-oxane (10 ml) and water (10 ml) and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with water (50 ml), concentrated saline was added and the mixture extracted. with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure to give the title polymer compound as a brown oil; 567 mg.

1 H NMR (400 MHz, CDCl 3): δ = 1.47 (s, 9H), 3.68 (m, 2H), 3.91 (br m, 2H), 4.06 (br m, 2H), 4.11 (s, 2H).

APCI: m / z = 233 [M + NH <] + '

Preparation 46: 2- (2-Methylaminoethyl) phenylamine 20 nh 2 · [j 2 CH> 25

A mixture of N-methyl-N- (2- (2-nitrophenyl) ethyl) -amine (WO 9803473, p. 100) (3 g, 16.65 mmol) and Rahey® nickel (500 mg) in ethanol (50 ml was hydrogenated for 2 hours at 60 psi and room temperature. The mixture was filtered through Celite® and the filtrate evaporated under reduced pressure to give the title compound as an oil.

APCI-MS: m / z = 152 [MH] +

Preparation 47: 2- (1-Methylaminoethyl) phenylamine 1025527-

98 I

J ** hn ^ ch »I

CH, I

10 I

Acetic acid (10 drops) was added to a solution

release of methylamine (10 g) in dichloomethane (150 ml) I

15 which was cooled to 5 ° C, followed by o-amino acetophenone I

(3.5 g, 25.9 mmol) and the solution was l for 10 minutes

stirred. Sodium triacetoxyborohydride (1.5 g, 38.8 mmol) I

was added and the reaction mixture was added for 72 hours

stirred at room temperature. The reaction mixture was l

20 diluted with water, the layers were separated and the organ

solution evaporated under reduced pressure, which is I

gave the title compound as a yellow oil. I

1 H NMR (400 MHz, CDCl 3): δ = 1.44 (s, 3H), 2.36 (s, 3H), I

4.77-5.08 (br s, 1H), 6.56-6.78 (m, 2H), 7.02 (m, 2H). I

25 I

Preparation 48: N- {2- [2- (Acetylmethylamino) ethyl) phenyl} -1

acetamide I

V S ** I

30, H, c. I

35 I

1025527-1

99 4-Methyl morpholine (4.45 g, 44 mmol) and acetic anhydride (4.49 g, 44 mmol) were added to an ice-cooled solution of the ainine from preparation 4 6 (2.2 g, 14, 67 mmol). dichloromethane (50 ml). . 4-Pyrrolidinopyridine (100 mg, 0.7 mmol) was then added and it. reaction mixture stirred for 2 hours at room temperature. The reaction mixture was then washed with dilute hydrochloric acid (2x), sodium carbonate solution (2x) and concentrated saline (2x). It was dried over magnesium sulfate and evaporated under reduced pressure to give the title compound as an oil.

1 H NMR (400 MHz, CDCl 3):. δ = 2.16 (s, 3H), 2.36 (s, 3H), 2.80 (m, 2H), 3.14 (s, 3H), 3.36 (m, 2H), 7.01 (m, 1 H), 7.18 (m, 1 H), 7.22 (m, 1 H), 8.22 (d, 1 H), 9.22 (s, 1 H). APCI: m / z = 235 [MH] +

Preparation 49: N- (2- [1- (Acetylmethylamino) ethyl] phenyl} - 20 acetamide: ΛίΛ.: 25 30

The title compound was obtained as an oil, from the amine from preparation 47 and acetic anhydride, followed by a procedure similar to that described in preparation 48, except that no 4-35 pyrrolidinopyridine was added.

10 2 5 52 ^ -1

100 I

1 H NMR (400 MHz, CDCl 3): δ = 1.55 (d, 3H), 2.16 (s, 3H), 1

2.20 (s, 3H), - 2.78 (s, 3H), 6.02 (k, 1H), 7.09 (m, 2H), I

7.36 (m, 2H), 8.25 (d, 1H), 9.40 (br s, 1H). I

APCI-MS: m / z - 257 [MNa] + I

Preparation 50: N- {2- [2- (Acetylmethylamino) ethyl] -4- I

chlorophenyl Jacetamide I

o I

/ k ° <s ^ ch3 I

10 hn ^ ch, y

CHS I

Cl I

I

Chlorine (7.3 g) was passed into acetic acid (102 g). An I

portion of this solution (15 g) was added to an I

ice-cooled solution of the compound from preparation I

48 (3.3 g, 14.1 mmol) in acetic acid (50 ml), and the reaction

The mixture was stirred at room temperature for 20 hours

time. The mixture was concentrated under reduced I

pressure and the residue dissolved in ethyl acetate. This solution I

was washed with saturated sodium carbonate solution

25 and concentrated saline. Then the I

they were dried over magnesium sulfate and evaporated under reduction

third edition, which gives the title compound as a brown,

solid; 2.7 g. I

^ -NMR (400 MHz, CDCl3): δ = 2.16 (s, 3H), 2.30 (s, 3H), I

30 2.78 (m, 2H), 3.12 (s, 3H), 3.30 (m, 2H), 7.05 (s, 1H), I

7.19 (d, 1H), 8.20 (d, 1H), 9.38 (s, 1H). I

APCI-MS: m / z = 291 [MNa] + I

Preparation 51: N- (2- [1- (Acetylmethylamino) ethyl] -4-chloro-I

Phenyl-acetamide I

102552 / I

101.0 HSC ^; 5 - 4 / NH, CH 3 and CH.

Cr; ch, 10

Chlorine. (1.88 g) was fed into a solution of the compound from Preparation 49. (6.4 g, 26.6 inmol) in acetic acid (30 ml) and the reaction mixture stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure and the residue suspended in ethyl acetate. The solution was then washed with sodium bicarbonate solution and concentrated saline before being dried over magnesium sulfate and evaporated under reduced pressure. The product was recrystallized from isopropyl ether and methanol to give the title compound; 3.5 g.

1 H-NMR (400 MHz, CDCl 3): δ = 1.60 (d, 3H), 2.16 (s, 3H), 2.20 (s, 3H), 2.79 (s, 3H), 6 .00 (k, 1H), 7.24 (m, 1H), 8.25 (d, 1H), 9.39 (s, 1H).

APCI-MS: m / z = 291 [MH] + 30 Preparation 52: 4-Chloro-2- (2-methylaminoethyl) phenylamine nh? ci Nchs 35 1025527-

102 I

A solution of the compound from preparation 50 (2.6 l

g, 9.68 ramol) in 2 N hydrochloric acid (100 ml) was l for 1 hour

stirred at 80 ° C and for an additional 72 hours at room temperature. TLC-I

The analysis showed that starting material remained, so that I

additional 12 N hydrochloric acid (50 ml) was added and the reaction I

The mixture was stirred for an additional 3 hours at 90 ° C. The af I

cooled mixture was made basic with ammonia (s.d. = I

0.88) and then extracted with ethyl acetate (3x). The I

10 combined organic extracts were washed with I

formaldehyde solution (3x) and concentrated saline I

(2x) before being dried over magnesium sulfate. and ing. I vaporizes under reduced pressure to give the title compound I

as an oil; 1.29 g. I

1 H NMR (400 MHz, CDCl 3): δ = 2.42 (s, 3H), 2.65 (t, 2H), 1

2.83 (t, 2H), 6.59 (d, 1H), 6.99 (m, 2H). I

Preparation 53: 4-Chloro-2 (1-methylaminoethyl) phenylamine I

20 I

Nh2 I

/ Ifi I

/ ^ nh I

a h3c I

25 I

A solution of the compound from preparation 49 l

(3.40 g, 12.65 mmol) in 12 N hydrochloric acid (150 ml) was diluted

stirred for 24 hours at 100 ° C. The cooled solution I

30 was carefully treated with ammonia (s.d. = 0.88) and I

extracted with dichloromethane (3x). The combined I

organic extracts were dried per magnesium sulfate I

and evaporated under reduced pressure to give an oil; I

2.24 g. I

35 1 H NMR (400 MHz, CDCl 3): δ = 1.42 (d, 3H), 2.38 (s, 3H), I

3.76 (k, 1 H), 6.50 (d, 1 H), 6.99 (m, 2 H). I

APCI-MZ: m / z = 185 [MH] + I

1025527-1

103.

Preparation 54: 2- (5-Chloro-2-nitrophenoxy) ethanol 5 NO 2.

10 Cl \> H

Sodium hydride (125 mg, 60% dispersion in mineral oil, 3.13 mmol) was added to a mixture of 4-chloro-2-fluoronitrobenzene (500 mg, 2.85 mmol) and ethylene glycol (0.18 ml) , 3.13 mmol) in 1-methyl-2-pyrrolidinone (5 ml) and. the reaction mixture was stirred for 18 hours at 80 ° C. TLC analysis showed that starting material remained, so that additional sodium hydride (114 mg, 60% dispersion in mineral oil, 2.85 mmol) and ethylene glycol (0.82 mL, 14.25 mmol) were added and the reaction mixture was added for an additional Stirred at 110 ° C for 18 hours. The cooled mixture was partitioned between water and dichloromethane, and the layers were separated. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate: pentane. 30 (50:50) as eluant, yielding the title compound as a solid; 290 mg.

1 H-NMR (400 MHz, CDCl 3): δ = 4.00 (t, 2H), 4.22 (t, 2H), 7.04 (d, 1H), 7.10 (s, 1H), 7 , 85 (d, 1 H).

Preparation 55: 3 - [(5-Chloro-2-nitrobenzyl) amino] propionic methyl ester: 025527-

104 I

NOj I

y j i

10 I

A mixture of powdered 4 A molecular sieves (16.9 g) and I

Lithium hydroxide monohydrate (1.80 g, 43 mmol) in Ν, Ν-I

dimethylformamide (100 ml) was stirred for 20 minutes I

at room temperature. β-Alanine methyl ester, hydrochloride I

(5.0 g, 35.8 mmol) was added and the mixture lasted

stirred for an additional 45 minutes. 2- (Bromomethyl) -4-chloro-11

Nitrobenzene (J. Het. Chem., 1972; 9 (1), 119-22) (8.98 g, I

35.8 mmol) was added and the reaction mixture during I

Stirred at room temperature for 16 hours. The mixture was l

filtered, the filtrate diluted with ethyl acetate (150 ml) I

then washed with concentrated saline I

25 (3x150 ml) and extracted with 2N hydrochloric acid (2x75 ml). The I

combined acid extracts were made basic with I

sodium carbonate and then extracted with ethyl acetate

tate. The combined organic extracts were added

dried over magnesium sulfate and evaporated under reduced I

30, yielding the title compound; 1.29 g. I

^ -NMR (400 MHz, CDCl 3): 6 * 2.56 (t, 2H), 2.90 (t, 2H), 1

3.69 (s, 3H), 4.05 (s, 2H), 7.38 (dd, 1H), 7.72 (d, 1H), I

7.94 (d, 1 H). I

APCI-MS: m / z = 272 [M-H] + I

35 I

Preparation 56: 3 - [(5-Chloro-2-nitrobenzyl) methylamino] -1

propionic acid methyl ester I

10255.27

105 NOj.

5, HSC 1.

. / Η, Ο

Cl 10

Formaldehyde (37% aq. Solution, 1.2 g, 26 nutiol), followed by sodium triacetoxyborohydride (7.7 g, 36.4 inmol) and formic acid (30% aq., 3.1 g, 104 mmol) were added - to a solution of the amine from preparation 55 (7.1 g, 26 mmol) in dichloromethane (70 ml), and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, the residue diluted with ethyl acetate and the solution washed with 1N sodium hydroxide and concentrated saline. The solution was concentrated under reduced pressure and the crude product purified by column chromatography on silica gel with an elution gradient of. pentane: ethyl acetate (100: 0 to 95: 5) to give the title compound; 6 g.

X H NMR (400 MHz, CDCl 3): δ 2.20 (s, 3H), 2.44 (t, 2H),. 2.72 (t, 2H), 3.64 (s, 3H), 3.78 (s, 2H), 7.35 (dd, 1H), 7.63 (s, 1H), 7.80 ( d, 1 H).

Preparation 57: 2- (2-Amino-5-chlorophenoxy) ethanol NH 4

106

A mixture of the compound from preparation 56 (280 I

1 mg, 1/29 mmol) and platinum oxide (80 mg). ethanol (25 mg) I

I was hydrogenated at 60 psi and room for 5 hours

I temperature. The mixture was filtered, washed through I

I with more ethanol and the filtrate evaporated under reduction

I third edition. The crude product was purified by ko

Chromatography on silica gel with dichloromethane

Thane: methanol: ammonia (s.d. ** 0.88) (95: 5: 0.5), which is I

I the title compound as an off-white solid.

I delivered; 195 mg. I

1 H-NMR (400 MHz, CDCl 3): 6-3.98 (t, 2H), 4.16 (t, 2H), I

I 6.75 (d, 1 H), 6.82 (m, 2 H). I

APCI-MS: m / z = 188 [MH] + I

Preparation 58: 3 - [(2-Amino-5-chlorobenzyl) methylamino] -1

Propionic acid methyl ester

20 I

NH 2

I

25 I

A mixture of the compound from preparation 56 (6.01

g, 22.0 mmol) and platinum oxide (500 mg) in ethanol (100 ml) I

30 was hydrogenated at 60 psi and room for 1 hour

temperature. The mixture was filtered through Celite®, and I

the filtrate evaporated under reduced pressure. The impure I

Each product was purified by column chromatography on I

silica gel with dichloromethane: methanol: ammonia (s.d. = I

35, 88) (90: 10: 1), yielding the title compound. I

1025527-1

107 1 H NMR (400 MHz, CDCl 3): δ = 2 '(s' 3H), 2'50 (t »2H), 2.72 (t, 2H), 3.44 (s, 2H), 3 63 (s, 3H), 4.62 (br s, 2H), 6.56 (d, 1H), 6.98 (s, 1H), 7.01 (dd, 1H).

Preparation 59: 3 - [(2-Amino-5-chlorobenzyl) methylamino] propionic acid dihydrochloride 2. .

10 /? 2 HCl.

/ HSC 4 OH Cl 15

A mixture of the ester from preparation 58 (1.1 g, 4.3 mmol) in tetrahydrofuran (10 ml), water (1.4 ml) and hydrogen chloride in dioxane (4M, 10 ml) was stirred for 2 hours at room temperature, and then for an additional 8 hours at 90 ° C. The cooled solution was concentrated under reduced pressure and the residue azeotroped from ethyl acetate and toluene to give the title compound.

1 H NMR (400 MHz, DMS0d6): δ = 2.62 (s, 3H), 2.8.1 (t, 2H), 3.30 (t, 2H), 4.22 (s, 2H) , 6.78 (m, 1H), 7.18 (d, 1H), 7.39 (s, 1H).

APCI-MS: m / z = 243 [MH) +

Preparation 60: Methyl [5- (3,4,5,6-tetrahydro-2 H- [1,2 '] bipyridinyl-4-yl) [1,3,4] oxadiazol-2-ylmethyl) amine —N 35 · ... "N *.

1025521.-

108 I

Methylamine (2/23 ml, 33% solution in ethanol (17.9 l

5 mmol) was added to a solution of the chloride I

from preparation 5 (1 g, 3.59 mmol) in tetrahydrofuran (20 L

ml) and the solution was stirred at room temperature for 18 hours

temperature. Extra methylamine (10 ml, 33% solution I

in ethanol), was added and the reaction mixture was still 72 l

Stirred for 10 hours. The reaction mixture was evaporated, evaporated

reduced pressure, the solid triturated with ethyl acetate I

and the precipitate removed by filtration. The filtrate I

was concentrated under reduced pressure and the residue I

azotropically evaporated from dichloromethane to give the titr

15 as a crystalline solid. I

1 H NMR (400 MHz, CDCl 3): δ = 1.98 (m, 2H), 2.17 (br d, 2H), I

2.48 (s, 3H), 3.18 (t, 2H), 3.35 (m, 1H), 3.95 (s, 2H), I

4.58 (br d, 2H), 6.62 (dd, 1H), 6.68 (d, 1H), 7.46 (dd, I

1H), 8.18 (d, 1Ή). I

APCI: m / z = 274 [MH] + I

Preparation 61: 4-Chloro-2- {2 - [5- (3,4,5,6-tetrahydro-2 H -1)

[1,2 '] bipyridinyl-4-yl) [1,3,4] oxadiazole-2-l

ylmethoxy] ethoxyphenyl amine I

25 I

o— ^

Qf Hp-y-a

Sodium hydride (60% dispersion in mineral oil, 45 l

mg, 1.1 mmol) was added to an ice-cooled solution

release of the alcohol from preparation 57 (190 mg, 1 mmol)

1,025,527;

109. in tetrahydrofuran (10 ml), and the solution for 30 minutes. stirred. A solution of the chloride from preparation 5 (310 mg, 1.1 mmol) in tetrahydrofuran (6 ml) was added and the reaction mixture stirred at room temperature for 18 hours. The reaction was stopped by the addition. addition of water (1 ml) and the mixture then partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The layers were separated, the organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with an elution gradient of ethyl acetate unethanol (96: 4 to 95: 5) to give the title compound as a pale orange oil; 280 mg.

1 H NMR (400 MHz, CDCl 3): δ = 1.99 (m, 2H), 2.20 (m, 2H), 3.18 (m, 3H), 2.96 (m, 2H), 4 18 (m, 2H), 4.30 (m, 2H), 4.80 (s, 2H), 6.60-6.80 (m, 5H), 7.55 (m, 1H), 8, 20 (m, 1 H).

APCI-MS: m / z = 452 [MNa] + 20 '

Preparation 62: 2-Amino-5-chloro-N-methyl-N- [5- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) - [1,3 4) oxa-diazol-2-ylmethyl] benzamide 25

° A

HSC O 5-chloroanthranilic acid (314 mg, 1.83 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (350 mg, 1.83 mmol) and N-methylmorpholine (0.4 ml, 3.64 mmol) were added to a solution of the amine from be. 102552?

lio I

preparation 60 (500 mg, 1.83 mmol) in dichloromethane (20 ml) I

and the reaction mixture was stirred at room temperature for 3 hours

temperature. The reaction mixture was washed with 10% I

citric acid solution, saturated sodium bicarbonate solution

5 s.ing and concentrated saline, then dried

on magnesium sulfate and evaporated under reduced pressure. I

The combined water phases were extracted with I

dichloromethane (2 x 25 ml) and the combined extracts in I

dichloromethane evaporated under reduced pressure. The ge I

10 combined crude products were purified by kor I

chromatography on silica gel with ethyl acetate as

eluent, and the product azeotroped from I

dichloromethane and ether, which gives the title compound as I

yielded a white solid; 278 mg. I

1 H NMR (400 MHz, CDCl 3): 8 - 1.92 (m, 2H), 2.16 (d, 2H), 1

3.02-3.22 (m, 6H), 4.32 (d, 2H), 4.85 (br s, 2H), 6.63 (m, I

2H), 6.70 (d, 1H), 7.14 (m, 2H), 7.50 (dd, 1H), 8.20 (d, 1H)

1H). I

APCI-MS: m / z = 427 [MH] + I

20 I

Preparation 63: 4-Chloro-2- (2- {methyl [5- (1-pyrimidine-4- I

ylpiperidin-4-yl) [1,3,4] oxadiazole-2-l

ylmethyl] amino) ethyl) phenylamine I

25 I

N - N H 2 N »I

hJ I

30 I

A mixture of the amine from preparation 52 (1.1 g, I

35, 96 mmol), the chloride from preparation 6 (1.51 g, 5.42 l

mmol), N-methylmorpholine (0.60 g, 5.96 mmol) and sodium jol

dide (400 mg, 2.66 mmol) in tetrahydrofuran (50 ml)

! 025527

111 for 18 hours. stirred at 50 ° C. The reaction mixture was concentrated under reduced pressure and the residue dissolved in ethyl acetate. The solution was washed with water. (3x) and concentrated saline, then dried. 5 on magnesium sulfate and evaporated under reduced pressure to give the title compound as a yellow oil; 1.77 g. APCI-MS: m / z = 428 [MH) +

Preparation 64: 4-Chloro-2- (1 - {[4- (4-chlorophenyl) -5- (Ι- ΙΟ 'pyrimidin-2-yl-piperidin-4-yl) -4H- [1,2,4] - triazol-3-ylmethyl] methylamino} ethyl) phenylamine ci

Jl ·

XsSiN. Λ NS HjC CHS

C11

A mixture of the chloride from preparation 6 (1.37 g, 4.92 mmol), the amine from preparation 53 (1.0 g, 5.41 mmol) and potassium carbonate (0.75 g, 5.41 mmol) in tetrahydrofuran (50 ml) was stirred at room temperature for 18 hours. Sodium iodide (40 mg, 2.67 mmol) was added and the reaction mixture stirred for an additional 24 hours. The reaction mixture was concentrated under reduced pressure, the residue dissolved in ethyl acetate and the solution washed with concentrated saline. The solution was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel with dichloromethane: methanol (99: 1) to give the title compound as an oil; 1.30 9 · 1025527-

112 I

1 H-NMR (400 MHz, CDCl 3): 6 - 1.45 (d, 3H), 1.86 (m, 2H), 1

2.18 (m, 2H), 2.35 (s, 3H), 3.20 (m, 3H), 3.78 (m, 2H), I

3.88 (d, 1H), 4.74 (m, 2H), 6.50 (dd, 1H), 6.58 (d, 1H)., I

7.00 (m, 2H), 8.32. (s, 2H). I

APCI-MS: m / z = 428 [MH] + I

Preparation 65: 3- [8-Chloro-1- (3,4,5,6-tetrahydro-2 H -1)

[1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3,5,10b -1

Tetraazabenzo [e] azulene-5-carbonyl] pyrrile

dihe-1-carboxylic acid tert-butyl ester I

n-n. I

15 G I

Cl. I I

20 I

1-Hydroxybenzotriazole hydrate (426 mg, 3.16 mmol), 1- I

(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride I

(658 mg, 3.42 mmol), triethylamine (0.91 mL, 6.58 mmol) and I

1-tert-butyl-1,3-pyrrolidinedicarboxylate (J. Med. Chem., I

44; 1; 2001; 94-1004) (900 mg, 3.95 mmol) were added

added to a suspension of the amine from Example 4 (1 L

g, 2.63 mmol) in dichloromethane (20 mL) and the reaction I

The mixture was stirred at room temperature for 3 hours

TLC analysis showed that starting material remained, so

that additional 1-hydroxybenzotriazole hydrate (355 mg, 2.63 L

mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

chloride (506 mg, 2.63 mmol) and 1-tert-butyl-1,3

pyrrolidine dicarboxylate (600 mg, 2.63 mmol) was added

35 and the reaction mixture was added for another 18 hours

stirred. The mixture was partitioned between 2 N sodium hydrogen

hydroxide solution and dichloromethane and the layers were added

102552 - I

113 divorce. The organic solution was evaporated under reduced pressure and the residue purified by column chromatography on silica gel with dichloromethane: methanol (95: 5) as eluant, yielding the title compound as an off-white foam; 690 mg.

1 H NMR (400 MHz, CDCl 3): δ 1.41 (s, 9H), 1.68-2.30 (m, 6H), 2. 81-3.18 (m, 3H), 3.20 -3.81. (m, 5H), 3.83-5.36 (m, 6H), 6.60 (dd, 1H), 6.66 (d, 1H), 7.38-7.62 (m, 4H), 8.18 (m, 1 H).

APCI-MS: m / z = 578 [MH] +

Preparations £ 6 to 72:

The following preparations of general formula: 20 'to 25 were prepared from the amine. Example 4 and the correct acid by following a procedure similar to that described in Preparation 65.

102552?

114 I

Η

Ber. ηο. "" Ö1 löp bringslj Geaëifêfis' Ί I

"66" "7 _ch," 4if ". ^ H-NMR (400MHz, CDCl3): δ = I

? | T1 H3 * 1.06-1.58 (m, 11 H) t 1.78-2.40 I

. > * S ^ NN S :. (m, 6H), 2.80-3.20 (m, 3H), I

. '-' 3.40-3.77 (m, 3H). 4.19-4.62 I

(m, 4H), -5.02 = -5.60 (m, 2H), I

6.58-6.72 (m, 2H), 7.37-7.66, 1

(m, 4H), 8.18 I

APCPMS; / n / * 577 [M-H] * I

67. "" N 9h3 "" 79 1 H NMR (400MHz, CDCIS): δ * I

? | "Vu" white *, T; 06-1 ^ 58 (mt 11H), 1.78-2.40

X "vΛ Dust (m, 6H), 2.80-3.20 (m, 3H), I

3.40-3.77 (m, 3H), 4.19-4 £ 2 l

(m, 4H), 5.02-5.60 (m, 2H), I

6.58-6.72 (m, 2H), 7.37-7.66 I

"(M, .4H), 8.18 (m, 1H). I

". APCI-MS; m = 577 [M-H] * I

68 "1 · T '~ 85 APCI-MS: / 7T / 2 = 591 [M-H]"' I

/ ° yCH3 I

\ / ~ \ / chj I

V— <> H »c I

cr '- ^ I

1025527-1

.115 ~ 69 ΓΤ o O "·; · I 58 | .APCPMS! M / 2 = 592 ΜΗ] * I.

ji. 1 5: rj h, c ^, foam 7Ö: o ° \ ~ ~ 58 "APCHMSs / 77/2 * 592 [MH] +" J! V ° v 3 - ·.

-N / CH 3 white 10 / n »C; . foam 7? -o ou ". 55" APC (-MS; m / z * 594 [MH] + "~ ll >> - O.« “j '« RV /. gebrokfen · • \ - n / Cl ^ white ƒ \ HSC foam

15 · \ J

• '72 ~ ^ ~ "r ~ ° T ~ 69 APOMS: m / 2 £ 16 [MNaf Γ Λ VCHs' O ^ Y) hscAch * O - f *! 20 L ·. ^ · - ·, ·· ^ - - - - - - - - - - - 4- (tert-butoxycarbonyl) morpholine-2-carboxylic acid (WO.

03035077, example 6, step 1, page 88) was used as the starting acid.

30 Y

1 02552t “

116 I

Preparation 73: 3- [8-Chloro-1- (3,4,5,6-tetrahydro-2 H -1)

[1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3,5,10b-tetra-1

azabenzo [e] azulene-5-yl] azetidin-1-carboxylic acid I

tert-butyl ester I

5 I

N-N H r I

Jl v \, «. . I

a, oJ \ I

ff ___ CHs I

10 I

α I

3-Oxoazetidine-1-carboxylic acid tert-butyl ester (JP I

2002/255932, p. 6) (562 mg # 3.16 nunol) and sodium triacet

Toxic borohydride (1.12 g, 5.26 ramol) were added to I

a suspension of the amine from example 4 (1 g, 2.63 l

mmol) in dichloromethane (50 ml), and the reaction mixture I

20 was stirred at room temperature for 72 hours. The I

mixture was partitioned between 2N batrium hydroxide and I

dichloromethane, the layers were separated and the organ

phase was evaporated under reduced pressure. The remainder I

The resulting yellow oil was purified by column chromatography I

25 over silica gel with dichloromethane: methanol: ammonia (s.d. I

= 0.88) (95: 5: 0.5) as eluant, which is the title compound

as a white foam.

1 H NMR (400 MHz, CDCl 3): δ = 1.42 (s, 9H), 1.60-2.46 (m, 1

4H), 2.90-3.00 (m, 2H), 3.12 (m, 1H), 3.50 (ra, 2H), 3.79-1

3.90 (m, 3H), 3.99-4.60 (m, 6H), 6.60 (m, 1H), 6.60 (d, I)

1 H), 7.28 (d, 1 H), 7.42-7.56 (m, 2 H), 7.58 (dd, 1 H), 8.18 I

(m, 1 H). I

APCI-MS: m / z = 558 [MNa] + I

35 '

1025527-1

117

Preparation 74 :. 3- [8-Chloro-1- (3 / 4,5,6-tetrahydro-2H- [1,2 ') bipyridinyl-4-yl) -4H, 6H-2,3,5,10b-tetraazabenzo [e] azulene-5-yl] pyrrolidiner 1-carboxylic acid tert-butyl ester 5 N-NO;

__N

f l ·} - \ - j J <CH> 10.

ci

The title compound was obtained as an off-white solid, in 53% yield from the axnin. Example 4 and 3-oxopyrrolidine-1-carboxylic acid tert-butyl ester by following a procedure similar to that described in Preparation 73, except that acetic acid (3 drops) was also added to the reaction mixture.

1 H - N.MR (400 MHz, · CDCl 3): δ = 1.44 (s, 9H), 1.50-1.70 (m, 2H), 1.75-2.55 (m, 5H) , 2.80-3.90 (m, 11H), 4.20-4.45 (m, .2H), 6.60 (dd, 1H), 6.66 (d, 1H), 7.35 ( d, 1 H), 7.41-7.57 (m, 3 H), 8.18. (d, 1 H) APCI-MS: m / z = 572 [MNa] +

Preparation 75: 4- [8-Chloro-1- (3,4,5, 6-tetrahydro-2H- [1,21] bipyridinyl-4-yl) -4H, 6H-2,3,5,10b- tetraazabenzo [e] azulene-5-yl] piperidin-1-30 carboxylic acid tert-butyl ester N-N wr '// \\' X / "* f ΓγΛ /" Λ J-Λ

Jf ___J - \ / N — V Wi 35

Cl 1025527-

118

I-tert-Butyl-4-oxopiperidine carboxylate (628 mg, 3.16 I

1 mmol) and sodium triacetoxyborohydride (1/12 g, 5.26 inmol) I

I were added to a suspension of the amine from I

Example 4 (1 g, 2.63 mmol) in dichloromethane (50 ml), I

I and the reaction mixture was stirred at I for 72 hours

I room temperature. TLC analysis showed starting material

Material remained, so that additional tert-butyl 4-oxopiperyl

I dinecarboxylate (628 mg, 3.16 mmol) and sodium triacetoxy-I

1 borohydride (1.12 g, 5.26 mmol) was added, and it

The reaction mixture was stirred for an additional 5 hours. The mixing I

I became. divided between 2 N sodium hydroxide (100 ml) and I

1 dichloromethane (100 ml), and the layers were separated. I

The organic phase was washed with concentrated salt

I solution (100 ml), dried over magnesium sulfate and in

I vapors under reduced pressure, giving the title compound I

I as a colorless gum. I

1 H-NMR (400 MHz, CDCl 3): δ = 1.42 (s, 9H), 1.72-2.20 (m, I

18 H), 2.40 (m, 2 H), 2.61-2.78 (m, 1 H), 2. 92-3.20 (m, 2 H), I

I 3.40-3.60 (m, 1H), 3.70 (m, 2H), 3.82 (m, 2H), 4.04-4.19 I

I 20 (m, 2 H), 4.34 (m, 2 H), 6.60 (m, 1 H), 6.66 (d, 1 H), 7.32 I

I (d, 1 H), 7.42-56 (m, 3 H), 8.18 (m, 1 H). I

Preparation 76: 6- [8-Chloro-1- (3,4,5,6-tetrahydro-2 H -1)

I [1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3,5,10b-I

Tetrazabenzo [e] azulene-5-yl] [1,4] -1

I oxazepane 4-carboxylic acid I

_I Ι ° Λ I

I \ / I

I 30 J \ _ I

CT (T I

I HSC ch3 I

35 I

102552 - I

119

A solution of the ketone from Preparation 45 (286 mg, 1.33 µmol) in dichloromethane (5 ml), followed by sodium triacetoxy borohydride (281.5 mg, 1.33 ramol) was added to a suspension of the amine From Example 4 (500 mg, 1.31 mmol) in dichloromethane (20 ml), and the reaction mixture was stirred at room temperature for 18 hours. TLC analysis showed that starting material remained, so that additional ketone (250 mg, 1.16 mmol) was added and the reaction mixture was stirred for an additional 70 hours. Saturated sodium bicarbonate solution (15 ml) was added and the mixture stirred at room temperature for 30 minutes. The layers were separated and the organic phase was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The remaining brown oil was purified by column chromatography on silica gel with dichloromethane: methanol (95: 5) as eluant, yielding the title compound; 189 mg.

APCI-MS: m / z = 580 [MH] + 20

Preparation 77: 1- [8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl] -4H, 6H-2,3,5,10b-tetraazabenzo [e] azulene-5-yl] 2-dimethylaminoethanone • 25.

N - N

30 '

Cl 35 1-hydroxybenzotriazole hydrate (107 mg, 0.79 mmol), 1-. (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (184 mg, 0.86 mmol), triethylamine (0.23 ml, 1.65 mmol) and 02552f-.

120 I

Ν, Ν-dimethylglycine (71.2 mg, 0.69 mmol) were added I

to a suspension of the amine from Example 4 (250 mg, I

0.66 mmol) in dichloromethane (10 ml) and the reaction mixture

The mixture was stirred for 18 hours at room temperature. I

The reaction mixture was partitioned between 2 N sodium hydroxide

the solution (10 ml) and dichloromethane (10 ml), the layers I

were separated and the aqueous phase was extracted with I

more dichloromethane (10 ml). The combined organic I

solutions were washed with concentrated salt

10 solution (20 ml), dried over magnesium sulphate and dissolved

evaporates under reduced pressure. The remaining gum was l

purified by column chromatography on silica gel with I

dichloromethane: methanol: ammonia (s.d. = 0.88) (95: 5: 0.5), I

which gave the title compound as a white foam; 220 mg.

1 H NMR (400 MHz, CDCl 3): δ = 1.58-1.88 (m, 4H), 2.20-2.40 I

(2xs, 6H), 2.60-4.60 (m, 9H), 5.28-5.60 (m, 2H), 6.60 (m, I

1 H), 6.66 (d, 1 H), 7.40 (dd, 1 H), 7.46 (m, 1 H); 7.57 (m, I

1 H), 7.60 (d, 1 H), 8.18 (m, 1 H). I

APCI-MS: m / z = 466 [MH] + I

2 ° I

Preparation 78: 8-Chloro-5-methyl-3,4,5,6-tetrahydro-1H-1

benzo [b] [1,5] diazocin-2-one

! S 't I

cQ

Cf 'CH, I

30 I

A mixture of the compound from preparation 59 (1.35 L

g, 4.3 mmol), N-methyl morpholine (2.2 ml, 19.3 mmol) and O-I

benzotriazol-1-yl-Ν, Ν, Ν ', N'-tetramethyluronium hexafluoro-I

35 phosphate (2.3 g, 6 mmol) in dichloromethane (100 ml) became I

stirred at room temperature for 18 hours. The reac I

. The mixture was washed with 1M sodium hydroxide solution I

1,02552

121 (3x), water and concentrated saline, then dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with ethyl acetate and the resulting solid was filtered off and dried, yielding the title compound. The filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel with dichloromethane: methanol (100: 0 to 95: 5) to give more title compound as a white solid (550 mg in total). .

1 H NMR (400 MHz, CDCl3): δ = 2.30 (m, 2H), 2.45 (s, 3H) 1, 2.98 (m, 2H), 3.60 (s, 2H) , 7.04 (d, 1H), 7.25 (d, 1H), 7.38 (s, 1H), 7.78 (br s, 1H). .

APCI-MS: m / z = 255 [MH] + 15

Preparation 79: 8-Chloro-5-methyl-3,4,5,6-tetrahydro-1H-benzofb] [1,5] diazocine-2-thione. ·; s 20/7) 25

Sodium carbonate (254 mg, 2.4 mmol) was added to a solution of phosphorus pentasulfide (1.07 g, 2.4 mmol) in tetrahydrofuran (5.5 mL) at 5 ° C. The solution was cooled to 3 ° C and the compound from preparation 78 (.540 mg, 2.4 mol) was added. Water (83 μΐ, 4.6 mmol) was added dropwise and the resulting mixture stirred at room temperature for 18 hours. The reaction mixture was diluted with ammonia (s.d. = 0.88) and extracted with dichloromethane (2x). The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated under reduced 1025527

122 I

pressure. The residue was adsorbed on silica gel and purified

by column chromatography on silica gel with dichloro-I

methane: methanol: ammonia (s.d. = 0.88) (100: 0: 0 to I

90: 10: 1) to give the title compound (0.23 g). I

5 1 H NMR (400 MHz., CDCl 3): 5 = 2.42 (s, .3H), 2.78 (m, 2H), 1

3.12 (m, 2H), 3.60 (s, 2H), 7.10 (d, 1H), 7.33 (d, 1H), I

7.40 (s, 1H), 9.50 (br s, 1H). I

APCI-MS: m / z - 241 [MH] + I

Preparation 80: 8-Chloro-5-methyl-2-methylsulfanyl-3,4,5,6-1

tetrahydrobenzo [b] [1,5] diazocine I

- I

vch3 I

20 I

Potassium tert-butoxide (0.55 ml, 1 M in tetrahydrofuran, I

0.55 mmole) was added dropwise to a solution

of the compound from preparation 79 (131 mg, 0.55 L

mmol). tetrahydrofuran (2 ml) and the solution was washed

Stirred for 30 minutes. p- I

Methyl toluene sulfonate (102.4 mg, 0.55 mmol) was added

and the reaction mixture stirred at I for 3 hours

room temperature. The mixture was concentrated under I

reduced pressure and the residue partitioned between dichloromethane. I

Thane and water, and the layers were separated. The organization I

phase was washed with concentrated saline, I

dried over magnesium sulfate and concentrated in vacuo

reduced pressure to give the title compound (152 mg).

APCI-MS: m / z = 255 [MH] + I

35 I

Preparation 81: (2-Amino-5-chlorobenzylamino) acetic acid I

tert-butyl ester I

1025527 I

123 nh 2 o 1 5 Cl

Chloroacetic acid tert-butyl ester (500 mg., 3.34 in mol). 10 was added to a solution of the amine from Preparation 10 (1.04 g, 6.65 mmol) in THF (20 mL) and the reaction mixture was heated to 65 ° C for 20 hours. The mixture was allowed to cool and filtered. The filtrate was evaporated under reduced pressure and the resulting. 15 gummy residue purified by column chromatography on silica gel with ethyl acetate as eluant to give the title compound (726 mg) as a white, crystalline solid.

X H NMR (400 MHz, CD3 OD): δ = 1.50 (s, 9H), 3.28 (s, 2H), 3.67 (s, 2H), 6.68 (d, 1H), 7.00 (d, 1 H), 7.02 (s, 1 H).

. APCI-MS: m / z = 271 [MH] \ 293 [MNa] +

Preparation 82: 7-Chloro-1,3,4,5-tetrahydrobenzo [e] [1,4] -.

diazepine-2-one 25 H.

30. To a degassed solution of the ester of preparation 81 (49.2 g, 181.7 mmol) in THF (500 mL) was added potassium terbutyl 35 (20.38 g, 181.6 mmol) and the mixture was stirred at room temperature for 2 hours. A second addition of potassium tert-butoxide (2.04 g, 18.2 1025527)

124 I

iranol) and stirring was continued for 15 minutes

continued before a saturated solution of ammonium I

chloride was added (150 ml). The resulting mixture I

was extracted with ethyl acetate (4 dm 3). The organic I

5 extracts were dried (MgSO 4) and filtered. The fil I

strat was evaporated under reduced pressure, yielding an I

gave a yellow solid that was triturated twice with I

pentane (150 ml) and filtered. This gave the title connection

as an off-white, crystalline solid I

10 (31.1 g). I

X H NMR (400 MHz, CD3 OD): δ = 3.54 (s, 2H), 3.92 (s, 2H), I

7.02 (d, 1 H), 7.25 (d, 1 H), 7.27 (s, 1 H). I

Preparation 83: 7-Chloro-4-methyl-1,3,4,5-tetrahydrobenzo

[E] [1,4] diazepine-2-one I

H_> ° I

20 v. I

Formaldehyde (37% w / v in water, 5 ml, 60 mmol) I

25 was added to a suspension of the amine of preparation 82 ($, 4 g, 42.7 mmol) in dichloromethane (140 mL) and

acetic acid (1 ml.) The mixture was washed for 0.25 hours

stirred at room temperature before sodium triacetoxy boron

hydride (14 g, 64.1 mmol) was added portionwise, and I

It was stirred for an additional 30 minutes. The reaction mixture I

was partitioned between 2 N hydrochloric acid (50 ml) and dichloromethane

thane (200 ml). The organic layer became I a second time

extracted with 2N hydrochloric acid (50 ml) before it was removed

lined. The combined acidic layers were basified

35 makes with 2N NaOH, which did a pale yellow solid

precipitate which was filtered off. The filtrate became double

extracted several times with dichloromethane (2 x 100 ml) and added

1025527-1

• 125 added to a solution of the pale yellow solid filter cake dissolved in dichloromethane (500 ml). The combined dichloromethane layers were dried (MgSO 4 filtered and the filtrate evaporated under reduced pressure to give a yellow solid. Trituration with diethyl ether gave the title compound as a pale yellow solid (7.1 g).

1 H NMR (400 MHz, CDCl 3): δ »2.54 (s, 3H), 3.42 (s, 2H), 3.77 (s> 2H), 6.94 (d, 1H), 7, 24 (m, 2H), 8.58 (s, 1H).

APCI-MS: m / z = 211 [MH] +, 233 [MNa] +

Preparation 84: 7-Chloro-4-methyl-1,3,4,5-tetrahydrobenzo, [e] [1,4] diazepine-2-thione

H ^ a, S

20

Sodium carbonate (1.06 g, 10 mmol) was added to a suspension of phosphorus pentasulfide (4.45, g, 10 mmol) in tetrahydrofuran (25 mL) at 5 ° C. The solution was cooled to 3 ° C and the compound from preparation 83 (2.11 g, 10 mmol) added. Water (1 ml) was added dropwise and the resulting mixture stirred at room temperature for 18 hours. The reaction mixture was diluted with ammonia (s.d. = 0.88) (50 ml) and extracted with dichloromethane (2 x 200 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate as an aid to give the title compound as a yellow solid (2.11 g).

1 025527-

126 I

1 H NMR (400 MHz, CDCl 3): δ = 2.62 (s, 3H), 3.61 (s, 2H), I

3.67 (s, 2H), 7.00 (d, 1H), 7.34 (m, 2H), 10.1 (s, 1H). I

APCI-MS: m / z = 227 [MH] + I

Preparation 85: (5-Chloro-2-nitrobenzylsulfanyl) acetic acid I

V. I

10 CS ^ s ^ y ° I

Cl · I

Mercaptoacetic acid (1.39 ml, 20 mmol) was dissolved in I

a 3.3 molar solution of sodium hydroxide in water (12 l

ml, 40 mmol) and cooled in an ice bath before a solution

2-bromomethyl-4-chloro-1-nitrobenzene (T.J. Mc-I

Cord et al., J. Het. Chem., 1972, 119-122) (5 g, 20 mmol) I

20 in acetone (50 ml) was added slowly. The resulting I

The solution was stirred at room temperature for 20 minutes

before being diluted with water (50 ml) and extracted

with dichloromethane (25 ml). The aqueous phase became acid I

made with acetic acid and extracted with dichloromethane I

25 (2 x 25 ml). The combined organic liquids were I

washed with concentrated saline, dried (Mg-1

SO4), filtered and evaporated to the title product. I

as an off-white foam (3.65 g). I

1 H NMR (400 MHz, CDCl 3): δ = 3.15 (s, 2H), 4.20 (s, 2H), I

7.40 (d, 1 H),. 7.50 (s, 1H), 8.00 (d, 1H), 11.85 (br s, I

1H). I

APCI-MS: m / z = 260 [MH] + I

Preparation 86: 2-Chloro-5,9-dihydro-8-thia-5-azabenzo

35 cyciohepten-6-one I

1025527-1

127 10

Platinum oxide (1 g) was added to a solution of the nitro compound of preparation 85 (2.59 g, 9.9 iranol) in ethanol (100 ml). The mixture was added for 1 hour. hydrogenated under a pressure of 40 psi and room temperature. The reaction mixture was allowed to cool before being filtered through a layer of Arbocel®. The filtrate was evaporated and the residue suspended in xylene (50 µl) before being heated to 150 ° C for 20 hours. The mixture was allowed to cool and was purified by column chromatography on silica gel with dichloromethane as eluent, followed by ethyl acetate to give a chamois solid which was triturated with diethyl ether; this afforded the title compound as a white solid (850 mg).

25. 1 H NMR (400 MHz, CDCl 3): δ = 3.05 (s, 2H), 3.80 (s, 2H), 7.00. (d, 1 H), 7.30. (dd, 1 H),. 7.35 (s, 1 H), 7.90 (s, 1 H). APCI-MS: m / z = 212 [MH] +

Preparation 87: 2-Chloro-5,9-dihydro-8-thia-5-azabenzo-cyclohepten-6-thione 35 1025527-

128 I

5 H // I

C | / X / \ s I

10 I

Sodium caiborate (394 mg, 3.7 mmol) was added

to a suspension of phosphorus pentasulfide (1.65 g, 3.7 l

mmol) in tetrahydrofuran (20 ml) at 5 ° C. The solution I

15 was cooled to 3 ° C and the compound from preparation 86 l

(750 mg, 3.5 mmol) added. Water (4 drops) became I

added dropwise and the resulting mixture for 1 hour

stirred at room temperature for 18 hours. The reaction mixture I

was diluted with ammonia (s.d. = 0.880) (75 ml) and diluted

20 extracted with dichloromethane (2 x 35 ml). The combined I

organic extracts were washed with concentrated I

brine, dried over magnesium sulfate and evaporated. I

under reduced pressure, giving the title compound as an I

white solid (603 mg).

1 H-NMR (400 MHz, CDCl 3): δ = 3.55 (s, 2H), 3.85 (s, 2H), 1

7.00 (dd, 1H), 7.35 (m, 2H), 9.20 (br s, 1H). I

APCI-MS: m / z - 230 [MH] + I

Preparation 88: 2-Amino-5-chloro-N-methylbenzamide I

NH 2 O 1

ci I

35 I

102552 - I

129 ·

To a solution of 5-chloroisatoic anhydride (10.0 g, 51 mmol) in tetrahydrofuran. (100 ml) a 40 wt% / wt. At ambient temperature. aqueous solution of methylamlamine (19.80 g, 255 mmol) dropwise. added. The mixture was stirred at ambient temperature for 1 hour. Ethyl acetate. (100 ml) and water (100 ml) were added and the phases separated. The aqueous layer was back extracted with ethyl acetate (100 ml) and the combined organic liquids were evaporated under reduced pressure to give a white solid which was recrystallized from toluene (60 ml); this gave the title compound as a white solid (8.15 g). 15 on.

^ -NMR (400 MHz, CDCl3); 6-2.86 (s., 3H), 6.71-6.73 (d, 1H), 7.11-7.14. (m, 1 H), 7.41 (s, 1 H).

Preparation 89: (2-Amino-5-chlorobenzyl) methylamine 20, CH 2.

- Cl

To a suspension of 2-amino-5-chloro-N-methyl-benzamide (20.08 g, 109 mmol) and sodium borohydride (12.37 g, 327 mmol) in tetrahydrofuran (200 ml), boron trifluoride diethyl etherate was added dropwise at T <15 ° C. The mixture was stirred at ambient temperature for 1 hour before refluxing for 6 hours. The reaction mixture was cooled in an ice water bath and a solution of piperazine (75.08 g, 872 mmol) in water (530 ml) added dropwise. The 102552?

130 I

The mixture was then heated under 16 hours

backflow. The mixture was allowed to cool to ambient

temperature and ethyl acetate (100 ml) was added. The .1

phases were separated and the aqueous layer was back extracted

5 with ethyl acetate (40 ml). The combined organ

The phases were washed with water (3 x 80 ml) and introduced

evaporates under reduced pressure, yielding an orange oil I

(17.58 g, 103 mmol). The oil was dissolved in I

. ethyl acetate (175 ml) and benzenesulfonic acid (16.29 g, 103 l

10 mmol) was added and then stirred for 2 hours

at ambient temperature. The white precipitate was collected

reported by filtration, which is the benzene sulfonate salt I

(24.12 g). The white solid was partitioned. I

between dichloromethane (240 ml) and 2M sodium hydroxide I

15 (240 ml) and the phases were separated. The organic phase

was evaporated under reduced pressure to give the title I

compound as a colorless oil (10.78 g). I

1 H-NMR (400 MHz, CDCl 3): δ = 2.42 (s, 3H), -3.72 (s, 2H), 1

6.55-6.57 (d, 1H), 7.00-7.04 (m, 2H) .. I

20 I

Preparation 90: (2-Amino-5-chlorobenzyl) methyl {[5- (1- I

pyridin-2-yl-piperidin-4-yl) -1,3,4-. I

oxadiazol-2-yl] methyl} amine I

25 o I

rUtv I

0 I

30 I

The oxadiazole of preparation 5b (2.77 g, 9.93 mmol) I

35 was heated with reflux for 5 hours

amine from preparation 89 (2.53 g, 14.9 mmol) and sodium wax

dust carbonate (0.8 -8 g, 10.43 mmol) in acetonitrile. The I

1025527-1

The mixture was cooled and water (20 ml) and dichloromethane (20 ml) were added. The phases were separated and the organic phase was evaporated under reduced pressure to give the title compound as an oil (4.8 g).

<1> H NMR (400 MHz, CDCl3): [delta] 1.91-2.01 (m, 2H), 2.16-2.20 (m, 2H), 2.33 (s, 3H), 3, 07-3.21 (m, 3H), 3.57 (s, 2H), 3.79 (s, 2H), 4.29-4.33 (m, 2H) ·, 6.55-6.57 (d, 1H), 6.62-6.65 (m,: 1H), 6.69-6.71 (d, 1H), 6.98 (m, 1H), 7.03-7.05 ( m, 1 H), 7.47-7.51 (m, 1 H), 8.19-8.20 (m, 1 H).

10

Preparation 91: 8-Chloro-5-methyl-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipididinyl-4-yl) -5,6-dihydro-4H-2 3.5 lb-tetraazabenzo [e] azulene dibesylate 15 nm

Cr ^ cricy · '"20 Cl.

To a suspension of 8-chloro-5-methyl-1- (3,4,5,6-25 tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -5,6-dihydro-4H-2 3.5 lb-tetraazabenzo [e] azulene (25.3 g, 64 mmol) in methanol (250 ml), benzenesulfonic acid (20.3 g, 128 mmol) was added. The. The yellow solution was heated to 60 ° C for 1 hour, then allowed to cool to ambient temperature and stirred for 16 hours. The mixture was | cooled in ice water for 1 hour before being filtered under vacuum to yield a white, granular solid which, after being dried under vacuum at 50 ° C for 16 hours, yielded the title compound (41.3 g).

1 H NMR (400 MHz, D 2 O): δ = 1.62-1.82 (m, 2H), 2.04-2.20 (m, 1H), 2.31-2.43 (m, 1H) 1.98 (s, 3H), 3.08-3.23 (m, 1H), 0.25527-

132 I

3.30-3.43 (m, 1H), 3.44-3.54 (m, 1H), 3.84-4.02 (in, 2H), I

4.02-4.13 (m, 1H), 4.13-4.27 (m, 1H), 4.27-4.40 (m, 1H), I

6.81-6.90 (m, 1H), 7.17-7.19 (d, 1H), 7.40-7.54 (m, 6H), I

7.62-7.73 (m, 5H), 7.73-7.82 (m, 3H), 7.82-7.94 (m, 1H); I

Found: C, 55.6; H, 5.0; N, 11.8%; I

C33 H35 ClN6 O6 S2 requires: I

C, 55.7; H, 5.0; N, 11.8%. I

Example 1: 1- (3,4,5,6-Tetrahydro-2H- [1,2 '] bipyridinyl-1

4-ylj-5,6-dihydro-4H-2,3,5,10b-tetraaza-1

benzo [e] azulene I

n-n I

15 yl y— \ 1

U U-I

20 I

Toluene-4-sulfonic acid (100 mg, 0.58 mmol) was added

added to a solution of the oxadiazole of preparation I

13 (2.45 g, 6.8 mmol) and heated for 18 hours

25 to 150 ° C. The mixture was cooled and purified by I

chromatography on silica gel with methanol and ammonium hydrogen

hydroxide in dichloromethane (5: 0.5: 95) as eluant, given

followed by chromatography on silica gel with methanol and I

ammonium hydroxide in ethyl acetate (10: 1: 90), followed by I

Methanol and ammonium hydroxide in dichloromethane (7: 1: 93)

as eluant, which, after trituration with ethyl acetate, I

gave the title compound (770 mg) as a brown solid.

APCI-MS: m / z = 347 [MH] + I

1 H NMR (400 MHz, CDCl 3): δ = 1.80-2.40 (m, 4H), 2.95 (m, 1

35 2H), 3.20 (m, 1H), 3.73 (s, 2H), 3.88 (s, 2H), 4.33 (m / l)

2 H), 6.57 (m, 1 H), 6.68 (d, 1 H), 7.37 (d, 1 H), 7.50 (m, I

4H), 8.17 (d, 1H). I

102552 / - I

133

Example: 5-Methyl-1- (3,4f5,6 "tetrahydro-2H- [1,2] bipyridinyl-4-yl) -5,6-dihydro-4H-2,3,5,10b-5 Tetraazabenzo [ejazulene: Formuladehyde (37 wt.% / vol. in water, 1 ml, 81 mmol) was added to a solution of the amine of Example 1 (100 mg, 0.28 mmol) in dichloromethane (20 ml).

The mixture was stirred at room temperature for 0.25 hours before sodium triacetoxyborohydride (500 mg, 2.4 mmol) was added. The reaction mixture was stirred for an additional 0.25 hours. The dichloromethane was removed under reduced pressure. The residue was partitioned between 2N aqueous sodium hydroxide solution (50 ml) and ethyl acetate (50 ml). The organic layer was washed with saturated saline and dried on. magnesium sulfate before filtering and the filtrate was evaporated under reduced pressure to give the title compound as a pale yellow foam (75 mg).

. APCI-MS: m / z = 361 [MH] +, 384 [MNa] +. 1 H NMR (400 MHz, CDCl 3): δ = 2.08 (m, 4H), 2.52 (s, 3H), 3.00 (m, 2H), 3.21 (m, 2H), 3.40 (s, 2H), 3.70 (s, 2H), 4.36 (m, 2H), 6.60 (m, 1H), 6.68 (d, 1H), 7.40 (d 1 H), 7.50 (m, 4 H), 8.18 (d, 1 H).

Example 3: 1- [1- (3,4,5,6-Tetrahydro-2H-1,2,2-bipyridinyl-4-yl) -4H, 6H-2,3,5,10b-tetraazabenzo [ e] azulene-5-yl] ethanone 1025527-

I 134 I

I N "^ '. I

I ^ ~ λ J · I

I I

I 10 I

Acetyl chloride (22 mg, 0.29 inmol) was added to I

I an ice-cooled solution of the amine of Example I.

I. 15 l (100 mg, 0.29 mmol) in dichloromethane (50 ml and I

I stirred at room temperature for 2 hours. The dichloro-I

Methane was evaporated under reduced pressure and the residue

Idu purified by chromatography on silica gel with metha

Iol and ammonium hydroxide in dichloromethane (5: 0.5: 95) as I

Eluent, which gives the title compound as a brown I

I gave foam (102 mg). I

APCI-MS: m / z = 389 [MH] +, 412 [MNa] + I

I (400 MHz, CDCl3): δ * 1.50-2.28 (m, 7H, rotamers), I

I 3.01 (brs, 2H), 3.10 (m, 1H)., 4.00-5.00 (m, 6H, rotam I)

I 25), 6.61 (m, 1 H), 6.68 (m, 1 H), 7.50 (m, 3 H), 7.61 (m, 1 H)

I 2 H), 8.18 (m, 1 H). I

Example 4: 8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] -1

I bipyridinyl-4-yl) -5,6-dihydro-4 H -2,3,5,10b -1

Tetraazabenzo [e] azulene I

I I

^ I

σ v

1025527-1

135.

Toluene-4-sulfonic acid (100 mg, 0.58 mmol) was added to a solution of the oxadiazole of preparation 5 (4.65 g, 12 mmol) and. heating to 140 ° C for 18 hours. The mixture was cooled and purified by chromatography on silica gel with methanol and ammonium hydroxide in dichloromethane (5: 0 * 5: 95) as eluant to give the title compound (2.0 g) as an off-white solid.

APCI-MS: m / z = 381 [MH] +, 403 [MNa] + 1 H-NMR (400 MHz, CDCl3): δ = 1.80-2.20 (m, 4H), 2.95 (m, 2 H), 3.14 (m, 1 H), 3.68 (s, 2 H), 3.92 (s, 2 H), 4.36 (m, 2 H), 6.60 (m, 1 H), 6, 67 (d, 1H), 7.35 (d, 1H), 7.50 (m, 3H), 8.17 (d, 1H),

Found: C, 59.90; H, 5.48; N, 20.50;

For C20 H21 N6 Cl. 0.33CH2 Cl2 requires: C, 59.72; H, 5.34; N, 20.55%.

20

Example 4b: 8-Chloro-1r (3,4,5,6-tetrahydro-2H- [1,2 '] - bpyridinyl-4-yl) -5,6-dihydro-4H-2,3,5,10b tetraazabenzo [e] azulene

25 N

rw «Η

Cr "J V

Cl

Trifluoroacetic acid (2.9 ml, 38 mmol) was added to a solution of the oxadiazole of preparation 14b (10 g, .25 mmol) in tetrahydrofuran and heated to 65-67 ° C for 6 hours. The reaction mixture was cooled and 1025527-

136 I

the pH was adjusted to 7 with sodium hydroxide (5M) before the I

ethyl acetate was distilled off in vacuo. The pH of the I

reaction mixture was then adjusted to 10 with more na

triium hydroxide (5M), followed by cooling for 1 hour I

5 at 10 ° C. The product was isolated by filtration and I

then another slurry of water was added in water

before it was filtered off again. The product, I

a white solid, was dried under vacuum (7.75 L

9) · I

APCI-MS: m / z = 381 [MH] +, 403 [MNa] + I

1 H NMR (400 MHz, CDCl 3): δ = 1.80-2.20 (m, 4H), 2.95 (m, I

2H), 3.14 (m, 1H), 3.68 (s, 2H), 3.92 (s, 2H), 4.36 (τη, I

2 H), 6.60 (m, 1 H), 6.67 (d, 1 H), 7.35 (d, 1 H), 7.50 (m, 1

. 3 H), 8.17 (d, 1 H). I

15 Found:

C, 59.90; H, 5.48; N, 20.50; I

for C 20 H 21 N 6 Cl. 0.33 CH 2 Cl 2 requires: I

C, 59.72; H, 5.34; N, 20.55%. I

Example 5: 8-Chloro-5-methyl-1- (3,4,5,6-tetrahydro-2 H -1)

[1,2 '] bipyridinyl-4-yl) -5,6-dihydro-4 H -1

2,3,5,10b-tetraazabenzo [e] azuletrihydro-I

chloride I

25 I

vV ^ V I

O Λ. I

Formaldehyde (37% w / v in water, 0.1 ml, 1.2 l

35 mmol) was added to a solution of the amine of I

Example 4 (200 mg, 0.53 mmol) in dichloromethane (5 ml). I

The mixture was stirred at room temperature for 0.25 hours

1,02552 / I

. 137.

. before sodium triacetoxyborohydride (500 mg, 2.4 mmol) was added, and the reaction mixture was stirred for an additional 18 hours. The reaction mixture was partitioned between 2N aqueous sodium hydroxide solution (10 ml) and 5 dichloromethane (10 ml). evaporated under reduced pressure and purified by chromatography on silica gel with methanol in dichloromethane (5:95) as eluant The residue was dissolved in dichloromethane (2 ml) and hydrochloric acid (1M in diethyl ether, 2 ml) added. solvent was evaporated under reduced pressure to give the title compound as a brown foam (96 mg).

APCI-MS: m / z = 395 [MH] \ 417 [MNa] + 1 H-NMR (400 MHz, CD3 OD): δ> 2.00 (m, 2H), 2.27 (m, 1H), 2 58 (m, 1H), 3.11 (s, 3H), 3.36 (m, 1H), 3.62 (m, 2H), 4.21 (m, 4H), 4.40 (m, 1 H), 4.55 (m, 1 H), 7.00 (t, 1 H), 7.44 (d, 1 H), 7.88 (m, 2 H), 7.92 (m, 2 H), 8, 06 (t, 1H).

Found: C, 44.30; H, 5.52; N, 14.65; C21 H23 N6 Cl • 0.33 CH2 Cl2 .3HCl.2.5H2 O requires: "C, 44.37; H, 5.53; N, 14.53%.

Example 5b: 8-Chloro-5-methyl-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -5,6-dihydro-4H-25, 3,5,1b-tetraazabenzo [e] azulene. i

Cl 35

To a solution of the thioamide of preparation 84 (80 mg, 0.35 mmol) in butan-1-ol was added the hydrazide of 1025527

138 I

Preparation 1 (78 mg, 0.35 mmol) was added and the mixture I

was heated to 100 ° C for 20 hours. The reaction mixture I

was evaporated under reduced pressure and the residue was purified

diluted by column chromatography on silica gel with dichloro-I

Methane: methanol: ammonia (s.d. = 0.880) (90: 10: 1) as I

eluant, which gives the title compound as a brown I

foam (90 mg).

1 H NMR (400 MHz, CDCl 3): δ 2.00 (m, 4H), 2.45 (s, 3H), 1

3.96 (t, 2H), 3.15 (m, 1H), 3.36 (m, 1H), 3.64 (m, 2H), I

10.4.36 (m, 2H), 6.58 (m, 1H), 6.65 (d, 1H), 7.32 (d, 1H), I

7.46 (t, 1H), 7.52 (m, 2H), 8.18 (t, 1H). I

APCI-MS: m / z * 395 [ΜΗ] V 417 [MNa) + I

Example 5c: 8-Chloro-5-methyl-1- (3,4,5,6-tetrahydro-2 H -1)

[1,2,2] bipyridinyl-4-yl) -5,6-dihydro-4 H -1

2,3,5,10b-tetraazabenzo [e] azuletrihydro-I

chloride I

! I

20 Nw ^ · · I

j I

^ 'λ xj' I

Cl I

25 I

Acetic acid (3 ml, 52 mmol). was added to an op I

release of the amine from Example 4b (10 g, 26 mmol) in I

Dichloromethane (100 ml), followed by formaldehyde (37 l

% by weight / vol. in water, 3.2 ml, 39 mmol). In a separate vessel I

sodium triacetoxyborohydride (6.7 g, 31 mmol) in I

dichloromethane slurried and cooled to I

. <10 ° C. The imine solution was then taken in 15 l

Added dropwise to the cold slurry for 35 minutes. The I

The reaction mixture was stirred at room temperature for 0.5 hours

temperature, after which it was partitioned between 2N sodium hydrogen

1025527-1

139 aqueous hydroxide solution and dichloromethane. The organic phase was then washed three times with 50% aqueous sodium metabisulphite solution, and finally washed with water. The solution in dichloromethane was evaporated to half the volume before EtOAc was added and the whole was further distilled off to remove the residual dichloromethane. EtOAc was added and the reaction mixture heated for an additional 0.5 hours before cooling to 10 ° C and the product 10 isolated as a white solid. The solid was dried under vacuum at 50 ° C for 16 hours to give the title compound (7.48 g).

APCI-MS: m / z = 395 [MH] +, 417 [MNa] + 1 H-NMR (400 MHz, CD3 OD): δ = 2.00 (m, 2H), 2.27 (m, 1H), 15 2.58 (m, 1H), 3.11 (s, 3H), 3.36 (m, 1H), 3.62 (m, 2H), 4.21 (m, 4H), 4.40 (m (1 H), 4.55 (m, 1 H), 7.00 (t, 1 H), 7.44 (d, 1 H), 7.88 (m, 2 H), 7.92 (m, 2 H), 8.06 (t, 1 H). Found: C, 44.30; H, 5.52; N, 14.65; 20 for C 21 H 23 N 6 Cl. 0.33 CH 2 Cl 2. 3HCl. 2.5H 2 O requires: C, 44.37; H, 5.53; N, 14.53

Example 6: 8-Chloro-5-isopropyl-1- (3,4,5,6-tetrahydro-2 H- [1,2 '] bipyridinyl-4-yl) -5,6-dihydro-4 H -25, 3,5,10b-tetraazabenzo [e] azuline trihydrochloride 3 °. N yy ·.

O 1 35 1025527-

140 I

Acetone (0.1 ml, 1.36 mmuU was added to one

solution of the amine of example 4 (200 mg, 0.53 l

mmol} in dichloromethane (5 ml). The mixture was lasted

stirred for 0.25 hours at room temperature before sodium I

Triacetoxyborohydride (500 mg, 2.4 mmol) was added, I

and the reaction mixture was stirred for an additional 18 hours. I

The reaction mixture was partitioned between 2 N sodium hydroxide

the aqueous solution (10 ml) and dichloromethane (10 ml). I

The organic layer was evaporated under reduced pressure and purified by chromatography on silica gel with methane

nol in dichloromethane (5:95) as eluant. The residue I

was dissolved in dichloromethane (2 ml) and hydrogen chloride (1M in diethyl ether, 2 ml) added. The solvent was evaporated under reduced pressure to give the title compound as a brown foam (161 mg).

APCI-MS: m / z = 423 [MH] +, 445 [MNa] + I

1 H NMR (400 MHz, CD3 OD): δ 1.57 (m, 6H), 2.00 (m, 2H), 1

2.24 (m, 1 H), 2.58 (m, 1 H), 3.38 (m, 1 H), 3.58 (m, 1 H), I

3.70 (m, 1 H), 3.86 (m, 1 H), 4.23 (m, 3 H), 4.40 (m, 1 H), I

20 4.62 (m, 1 H), 5.00 (m, 1 H), 7.00 (m, 1 H), 7.43 (m, 1 H), I

7.80-8.06 (m, 5H). I

Found: I

C, 46.51; H, 5.98; N, 13.96; I

for C23 H27 N6 Cl. 0.28 CH 2 Cl 2. 3HCl. 2.5H 2 O is required: I

25 C, 46.51; H, 5.96; N, 13.98%. I

Example 7: 8-Chloro-1- (3,4,5,6-tetrahydro-2 H - [1,2 '] -1

bipyridinyl-4-yl) -5- (tetrahydropyran-4-yl) -1

5,6-dihydro-4H-2,3,5,10b-tetraazabenzo [e] -1

Azulene I

◦ I

1025527-1

141.

Tetrahydropyran-4-one (68 mg, 0.68 in mol) was added to a solution of the amine of Example 4 (130 mg, 0.34 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 0.25 hours before sodium triacetoxyborohydride (217 mg, 1.0 mmol) was added, and the reaction mixture was stirred for an additional 18 hours. More tetrahydropyran-4-one (68 mg, 0.68 mmol) and sodium triacetoxyborohydride (217 mg, 1.0 mmol) were added and the reaction mixture was heated to 40 ° C for 24 hours. The reaction mixture was partitioned between 2N aqueous sodium carbonate solution (10 ml) and ethyl acetate. 15 t (50 ml). The organic layer was washed three times. with 2N aqueous sodium carbonate solution (10 ml), once with saturated aqueous salt solution and then dried over magnesium sulfate before filtration and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography on silica gel with a gradient of ethyl acetate in pentane (0 to 30%) as eluant, followed by chromatography on silica gel with a gradient of methanol in dichloromethane (0 to 5%) as eluant, using the title compound a brown foam (80 mg).

APCI-MS: m / z = 465 [MH] +, 487 [MNa] + X H-NMR (400 MHz, CDCl3): δ = 1.57-1.75 (m, 4H) 1.75-2.20 (m, 6H), 2.72. (m, 1H), 2.98 (t, 2H), 3.16 (m, 1H), 3.39 (t, 2H), 3.40-3, 60 (m, .2H), 3.60 -4.10 (m, 2H), 4.02 (d, 2H), 4.34 (d, 2H), 6.61 (dd, 1H), 6.69 (d, 1H), 7.33 (d, 1H), 7.45-7.59 (m, 3H), 8.17 (d, 1H).

Example 8: 1- [8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3,5,10b- Tetraazabenzo [e] azulene-5-yl] ethanone dihydrochloride 1025527-

142 I

r. — N / -— \ N- ^ I

5 LbC ^ X I

a I

10 I

Acetyl chloride (0.1 ml, 1.4 mmol) was added to I

15 an ice-cooled solution of the amine of Example 1

4 (200 mg, 0.53 mmol) in dichloromethane (5 ml), and there I

was stirred at room temperature for 20 hours. The I

dichloromethane was evaporated under reduced pressure and I

the residue purified by chromatography on silica gel

20 with methanol in dichloromethane (5:95) as eluant. The I

residue was dissolved in dichloromethane (2 ml) and water

dust chloride (1M in diethyl ether, 2 ml). The op I

release agents were evaporated under reduced pressure, the

. gave the title compound as a brown foam (110 mg). I

ESI-MS: m / z = 423 [MH] + I

1 H-NMR (400 MHz, CD3 OD): δ = 1.95-2.40 (m, 7H, rotamers), I

3.40-3.55 (m, 2H), 3.80 (m, 1H), 4.20-4.90 (m, 4H, rotam I)

. ren), 4.82 (s, 2H), 7.02 (t, 1H), 7.46 (d, 1H), 7.80 (m, I)

1 H), 7.91 (t, 1 H), 7.95-8.00 (m, 2 H), 8.07 (t, 1 H). I

Found: I

C, 45.94%; H, 5.77%; N, 14.35%; I

for C22H23CIN6O. 2HCl. 0.4 OCH 2 Cl 2. 3.07H2O is required: I

C, 45.98%; H, 5.50%; N, 14.36%

Example 9: [8-Chloro-1- (3,4,5,6-tetrahydro-2 H- [1,2 '] -1

bipyridinyl-4-yl) -4H, 6H-2,3,5, 10b-tetra-1

1025527-1

143 azabenzo [e] azulene-5-yl] cyclopropylmethanone dihydrochloride 5

1 - N Γ V // "N

r yd) - C JL

The title compound was prepared from cyclopropanecarbonyl chloride and the amine of Example 4, in 50% yield, using the procedure described in Example 8.

ESI-MS: m / z - 449 [MH] + 20 1 H-NMR (400 MHz, CD 3 OD): 6 - 0.83-1.00 (m, 4H), 1.80-2.50 (m, 4H (rotamers), 3, 40-3, 60 (m, 2H), 3.89 (bt, 1H), 4.20-5.0 (m, 3H, rotamers), 4.86 (s, 2H), 7.04 (t, 1H), 7.26 (d, 1H), 7.82. (bd, 1H), 7.90-8.00 (m, 3H), 8.08 (t, 1H).

25 "

Example 10: 1- [8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -4H, 5H-2,3,5,10b- tetraazabenzo [e] azulene-2, 2-dimethyl-propane-1-dihydrochloride

30 / \ // ^ N

\ "X

102552 - 35 ^

144 I

The title compound was prepared from 2,2-dimethyl-I

propionyl chloride and the amine of Example 4, in 54% I

5 yield, using the procedure described I

in example 8. I

APCI-MS: m / z = 465 [MH] + I

1 H NMR (400 MHz, CD3 OD): δ - 1.40 (s, 9H), 1.80-2.60 (m, I

4H, rotamers), 3.40-3.60 (m, 2H), 3.88 (bt, 1H), 4.10 -1

10 5.00 (m, 4H, rotamers), 4/85 (s, 2H), 7.04 (t, 1H), 7.47 I

(d, 1H), 7.80-7.86 (m, 2H), 7.94 (d, 1H), 7.99 (d, 1H), I

8.08 (t, 1 H). I

Example 11: 8-Chloro-5-methanesulfonyl-1- (3,4,5,6-

Tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -5,6-I

dihydro-4H-2,3,5,10b-tetraazabenzo [e] -1

azulene I

20 O ^ OXX I

a I

25

Methanesulfonyl chloride (0.1 ml, 1.29 mmol) was added

added to an ice-cooled solution of the amine I.

Of Example 4 (200 mg, 0.53 mmol) in dichloromethane (5 l

ml) and stirred at room temperature for 20 hours

time. The dichloromethane was evaporated under reduced I

pressure and the residue purified by chromatography on silica

licagel with methanol in dichloromethane (5:95) as the course I

35, which gives the title compound as a brown foam I

(71 mg). I

APCI-MS: m / z = 459 [MH] +, 481 [M + Na] I

102552 - I

'145

Found: C, 52.98%; H, 5.05%; N, 17.20%; . for C21 H23 ClN6 O2 S. 0.25 CH 2 Cl 2 requires: C, 53.15%; H, 4.93%; N, 17.50%.

5

Example 12: 8-Chloro-1- (1-pyrimidin-2-yl-piperidin-4-yl) -5,6-dihydro-4H-2,3,5,10b-tetraazabenzo [ejazulene: <\ - \

/ NH

15 Cl

Toluene-4-sulfonic acid (5 mg, 0.03 mmol) was added to a solution of the oxadiazole of preparation 15 (2.34 g, 5.9 mmol), and heated to 140 ° for 18 hours C. The mixture was cooled and purified by chromatography on silica gel with methanol and ammonium hydroxide in dichloromethane (5: 0.5: 95) as eluant, the title compound (1.12 g) as an off-white solid dust.

ESI-MS: m / z = 382 [MH] + 1 H-NMR (400 MHz, CDCl 3): δ «1.60-2.20 (m, 4H), 2.95 (bt, 2H), 3.10 (m, 1H), 3.63 (s, 2H), 3.70-4.00 (m, 2H), 4.75 (d, 2H), 6.43 (t, 1H), 7.26 (d, 1 H), 7.40-7.52 (m, 2 H),. 8.22. (d / 2H).

Found: C, 57.24%; H, 5.31%; N, 24.10%; for C19 H20 ClN7. 0.25 CH2 Cl2 requires: • 35. C, 57.36%; H, 5.13%; N, 24.32%.

10,255.27; »

146 I

Example 13: 8-Chloro-5-methyl-1- (1-pyrimidin-2-yl-1)

piperidin-4-yl) -5,6-dihydro-4 H -2,3,5,10b -1

tetraazabenzo [e] azulene I

5 I

\ ^) I

10 I

O I

I

Formaldehyde (37% w / v in water, 0.1 ml, 1.2

mmol) was added to a solution of the amine of I

Example 12 (100 mg, 0.26 mmol) in dichloromethane (5

20 ml). The mixture was stirred at room temperature for 0.25 hours

temperature before sodium triacetoxyborohydride (111 l

mg, 0.53 mmol) was added, and the reaction mixture became I

stirred for an additional 18 hours. The mixture was partitioned I

between 2N aqueous sodium hydroxide solution (10 ml) and I

Dichloromethane (10 ml). The organic layer was evaporated

under reduced pressure and purified by chromatography I

on silica gel with methanol in dichloromethane (5:95) as eluant, giving the title compound as a brown

foam (66 mg). I

ESI-MS: m / z = 382 [MNa] + I

1 H NMR (400 MHz, CDCl 3): δ = 1.50-2.20 (m, 4H), 2.45 (s, I

3 H), 2.98 (bt, 2 H), 3.10 (bt, 1 H), 3.20-3.90 (m, 3 H), 4.77 I

(s, 2H), 6.45 (s, 1H), 7.32 (d, 1H), 7.46-7.53 (m, 2H), I

8.26 (d, 2H). I

Found: I

C, 59.12%; H, 5.50%; N, 24.00% / l

for C20 H22 ClN7. 0.15 CH 2 Cl 2 is required: I

1025527-1

147 C, 59.23%; Η 5.66%; N, 23.99%.

Example 14: 8-Chloro-5-isopropyl-1- (1-pyrimidin-2-yl-piperidin-4-yl) -5,6-dihydro-4H-2,3,5,10b-5-tetraazabenzo [e] azulene 10 α 15

The title compound was prepared from acetone and the amine of Example 12, in 65% yield, using the procedure described in Example 13.

ESI-MS: ici / z - 382 [M + H] + 20 1 H-NMR (400 MHz, CDCl 3): δ = 1.20 (d, 6H), 1.60-2.10 · (m, 4H) , 2.90-3.07 (m, 3H), 3.18 (t, 1H), 3.30-4.00 (m, 4H), 4.78 (d, 2H), 6.47 (t 1 H), 7.29 (d, 1 H), 7.48-7.58 (m, 2 H), 8.30 (d, 2 H).

Found it: .

. C, 60.55%; H, 6.24%; N, 21.73%; for C22H26CIN7. 0.22 CH 2 Cl 2 requires: C, 60.17%; H, 6.03%; N, 22.11%.

Example 15: 8-Chloro-5-methanesulfonyl-1- (1-pyrimidin-2-yl-piperidin-4-yl) -5,6-dihydro-4H-2,3,5,10b-tetraazabenzo [e] azulene

"Λ-N \ f ~ \ / ^ N

^ y — N y— ^ J [·

Cl 1025527-

148 I

The title compound was prepared from the amine of I

Example 12, in 69% yield, using the procedure

duration described in Example 11. I

APCI-MS: m / z = 460 [M + H] +, 482 [M + Na] + I

X H NMR (400 MHz, CDCl 3): δ = 1.40-2.40 (m, 6H), 2.95 (s, I)

10 H), 2.90-4.20 (m, 5H), 4.40-5.30 (m, 4H), 6.52 (t, 1H), I

7.40 (d, 1H), 7.60-7.70 (m, 2H), 8.32 (d, 2H). I

Example 16: [8-Chloro-1- (1-pyrimidin-2-ylpiperidine-4- I

yl) -4H, 6H-2,3.5, 10b-tetraazabenzo [e] -1

Azulene-5-yl] cyclopropylmethanone I

/ r ~ K / - \ .n — M I

(ry_NO) _ ^ yr I

c ^ ~~ ^ ^ I

25. I

The title compound was prepared as an off-white I

foam from cyclopropane carbonyl chloride and the amine of

Example 12, in 69% yield, using the procedure

duration described in Example 3. I

APCI-MS: m / z 472 [M + Na] + I

1 H NMR (400 MHz, CDCl 3): δ = 0.86 (m, 2H), 1.04 (m, 2H), 1

1.40-2.40 (m, 6H), 2.70-3.20 (m, 3H), 4.40-5.80 (m, 5H), I

6.61 (t, 1H), 7.39 (d, 1H), 7.52-7.65 (m, 2H), 8.32 (d, 1H)

2H). I

35 I

102552? I

14 9

Example 17: 1- [8-Chloro-1- (1-pyrimidin-2-yl-piperidin-4-yl) -4H, 6H-2,3,5,10b-tetraazabenzo [e] azulene-5-yl ] -2,2-dimethylpropane-1-one 5

/ r-N ./-V

10.

Cl · 15

The title compound was prepared from 2,2-dimethylpropionyl chloride and the amine of Example 12, in 42% yield, using the procedure described in Example 3.

APCI-MS: m / z = 466 [M + H] + 1 H-NMR (400 MHz, CDCl 3): δ = 1.38 (s, 9H), 1.40-2.40 (m, 7H), 2 , 90-3.10 (m,> 2H), 3.17 (m, 1H), 4.60-5.00 (m, 2H), 5.27 (s, 2H), 6.58 (t, 1 H), 7.35 (d, 1 H), 7.54-7.68 (m, 2 H), 8.29 (d, 1 H).

Example 18: 1- [8-Chloro-1- (1-pyrimidin-2-ylpiperidin-4-yl) -4H, 6H-2,3,5,110b-tetraazabenzo [e] azulene-5-yl ] ethanone

30 - "/" V_ ΓΛ // "K

\ == N '-'.

CνΎ 35 ci 1025527-

150 I

The title compound was prepared from acetyl chloride and I

the amine of example 12, in 37% yield, using I

5 of the procedure described in Example 3. I

APCI-MS: m / z «424 [M + H} + I

1 H NMR (400 MHz, CDCl 3): δ = 1.40-2.50 (m, 10H), 2.70-3.30

(m, 4H), 4.70-4.90 (m, 2H), 6.52 (t, 1H), 7.38 (d, 1H), I

7.54-7.64 (m, 2H), 8.33 (d, 2H). I

10 I

Example 19: 8-Chloro-1- (6'-trifluoromethyl-3,4,5,6-l

tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -1

4H, 6Hr5-oxa-2,3,10b-triazabenzo [e] azulene I

I

.I I

F ° I

20 I

a I

2-Chloro-6-trifluoromethylpyridine (55 mg, 0.30 mmol) I

And potassium carbonate (41 mg, 0.30 mmol) were added

to a solution of the amine of preparation 29 (45 mg, I

0.15 mmol) in N, N-dimethylformamide (2 ml). The mixture I

was heated to 100 ° C for 18 hours before starting

evaporates under reduced pressure. The residue was purified

30 by chromatography on silica gel with methanol and ammonium

ammonium hydroxide in dichloromethane (5: 0.5: 95) as eluant, I

which is the title compound (30 mg) as a brown foam I

yielded. I

APCI-MS: m / z = 450 [M + H] +, 472 [M + Na] + I

35 1 H NMR (400 MHz, CD 3 OD): δ = 1.88-2.06 (m, 4H), 3.01 (bt, 1

2H), 3.40 (m, 1H), 4.44 (bs, 2H), 4.51 (d, 2H), 4.59 (s, I

1025527 I

151. 2 H), 6.94 (d, 1 H), 7.02 (d, 1 H), 7.68 (t, 1 H), 7.74-7.78.

(m, 4.H). Example 20: 4- (8-Chloro-4H, 6H-5-oxa-2,3,10b-triaza-benzo [e] azulene-1-yl) -3,4,5,6-tetrahydro - 2H- [1,2 '] bipyridinyl-6'-carbonitrile

Cl

The title compound was prepared from 6-chloropyridine-2-carbonitrile and the amine from preparation 29, in 61% yield, using the procedure described in Example 19.

APCI-MS: m / z = 407 [M + H] +, 429 [M + Na] + 1 H-NMR (400 MHz, CD3 OD): δ = 1.86-2.08 (m, 4H), 3, O 3 (bt, 2 H), 3.44 (m, 1 H), 4.4 6 (m, 4 H), 4.59 (s, 2 H), 7.03 (d, 1 H), 7.11 (d, 1 H), 7.62 (dd, 1 H), 7.72-7.78 (, 3 H).

Found: C, 61.31%; H, 4.73%; N, 20.38%; for C 21 H 19 ClN 60. 0.25H 2 O requires: C, 61.31%; H, 4.78%; N, 20.43%.

Example 21: 4- (8-Chloro-4H, 6H-5-oxa-2,3,10b-triaza-benzo [e] azulene-1-yl) -3,4,5,6-tetrahydro-2H- [1,2 '] bi-pyridinyl-6' -carboxylic acid amide 1025527-

152 I

1> ^ ό I

Cl I

5 I

Powdered potassium hydroxide (46 mg, 81 mmol) was added

added to a solution of the carbonitrile from before I

image 20 (110 mg, 0.27 mmol) in 2-methylpropan-2-ol (6 L

ml). The mixture was heated to 100 ° C for 18 hours

10 before being evaporated under reduced pressure. The residue I

was purified by chromatography on silica gel with Me

thanol and ammonium hydroxide in dichloromethane (5: 0.5: 95)

as eluant, which gives the title compound (62 mg) as an I

off-white solid. I

APCI-MS: m / z = 425 [M + H] + 447 (M + Na] + I

X H NMR (400 MHz, CD 3 OD): δ = 1.89-2.07 (m, 4H), 3.01 (bt, I

2H), 3.42 (m, 1H), 4.45 (s, 2H), 4.52 (bd, 2H), 4.60 (s, I

2H), 7.02 (d, 1H), 7.38 (d, 1H), 7.67 (dd, 1H), 7.72-7.78 I

(m, 4 H) ... I

20 I

Example 22: 13-Chloro-3- (3,4,5,6-tetrahydro-2 H- [1,2 ') -1

bipyridinyl-4-yl) -2,4,5,8-tetraazatricyclo-

[9.4.0.0 * 2.6 *] pentadeca-1 (11), 3,5,12,14-1

pentaene I

25 I

K1 ^ N I

II ^ nn

NH I

jy "v / I

3 ° Vs? I

Cl I

Toluene-4-sulfonic acid (50 mg, 0.3 mmol) was added

was added to a solution of the oxadiazole of preparation 41 (1.35 g, 3.3 mmol), and heating was carried out for 2 hours

102552 - I

153 to 140 ° C. The mixture was cooled and purified by chromatography on silica gel with ethyl acetate, followed by methanol and ammonium hydroxide in dichloromethane (5: 0.5: 95) as eluant to give the title compound (273 5 mg) as an off-white solid.

APCI-MS: m / z - 398 [M + H] + 1 H-NMR (400 MHz, CDCl 3): δ = 1.42 (bd, 1H), 1.65 (dk, 1H), 2.05 (dt 1 H), 2.16 (bd, 1 H), 2.32 (dk, 1 H), 2.63-2.77 (m, 2 H), 2.79-2.94 (m, 2 H), 2, 95 (m, 1H), 3.10 (d, 1H), 3.46 (dt, 1H), 4.18 (bd, 1H), 4.38 (bd, 1H), 4.41 (d, 1 H), 6.59 (dd, 1 H), 6.65 (d, 1 H), 7.18 (d, 1 H), 7.38-7.42 (m, 2 H), 7.57 (t, 1 H ), 8.17 (d, 1 H).

Found: C, 62.41%; H, 5.98%; N, 20.45%; 15 for C21 H23 ClN6. 0.12 CH 2 Cl 2 requires: C, 62.72%; H, 5.78%; N, 20.75% ..

Example 23: 1- [13-Chloro-3- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -2,4,5,8-tetraaza-20 tricyclo [9.4.0.0 * 2.6 *) pentadeca-1 (11), 3, 5.12, 14 pentaen-^ 8-yl] ethanone

X V-A

Cl 30

Acetic anhydride (35 ml, 0.37 mmol) was added to a solution of the amine of Example 22 (120 mg, 0.30 mmol) and triethylamine in dichloromethane (5 ml), and stirred at room temperature for 2 hours . The dichloromethane was evaporated under reduced pressure and the residue purified by chromatography on silica gel 102552.

154 I

with methanol and ammonium hydroxide in dichloromethane I

(5: 0.5: 95) as eluant, giving the title compound as I

a white solid (120 mg). I

APCI-MS: m / z = 437 [M + H] \ 459 [M + Na] * I

5 1 H NMR (400 MHz, CDCl 3): δ - 1.44 (bd, 1H), 1.63 (m, 1H), I

2.16 (m, 2H), 2.10-2.22 (m, 2H), 2.28 (dt, 1H), 2.44 (s, I

3 H), 2.63-2.80 (m, 2 H), 2.83-3.05 (m, 3 H), 3.66 (d, 1 H), I

4.15 (bd, 1H), 4.41 (bd, 1H), 4.94 (dd, 1H), 5.06 (d, 1H), I

.6.59 (t, 1H), 6.63 (d, 1H), 7.17 (d, 1H), 7.38-7.50 (m, I

10 3 H), 8.14 (d, 1 H). I

Found: I

C, 61.92%; ft, 5.93%; N, 18.38%; "I

for C21 H23 ClN6. 0, 6OH 2 O is required: I

C, 61.70%; H, 5.90%; N, 18.77%; I

I

Example 24: 13-Chloro-8-methyl-3- (3, 4,5, 6-tetrahydro-1)

2H- [1,2 '] bipyridinyl-4-yl) -2,4,5,8-tetra-1

azatricyclo [9.4.0.0 * 2.6 *] pentadeca-1 (11), I

3,5,12,14-pentaene I

20 I

w-N I

: I

25 IV

c ?. v 1 α

The title compound was prepared from the amine of I

Example 22, in 78% yield, using the procedure

duration described in Example 2. I

APCI-MS: m / z = 409 [M + H] \ 431 [M + Na] + I

1 H NMR (400 MHz, CDCl 3): δ = 1.41 (bd, 1H), 1.62 (dk, 1H), 1

35 2.14 (bd, 1H), 2.23-2.32 (m, 2H), 2.37 (s, 3H), 2.55 (dd, I)

1 H), 2.66-2.78 (m, 2 H), 2.88 (m, 1 H), 2.96 (dt, 1 H), 3.20 l

(d, 1H), 3.26 (dd, 1H), 4.15 (d, 2H), 4.35 (bd, 1H), 6.55 I

1025527-1

155 (dd, 1H), 6.62 (d, 1H), 7.14 (d, 1H), 7.32-7.39 (m, 2H), 7.41 (t, 1H), 8.12 (d, 1 H).

5

Example 25: 3- (1-Pyrimidin-2-yl-piperidin-4-yl) -8-oxa-2,4,5-triazatricyclo [9.4.0.0 * 2.6 *] penta-deca-1 (11), 3 , 5,12,14-pentaene 10

Cr "^ (y

The title compound was prepared from the oxadiazole of preparation 24, in 50% yield, using the procedure described in Example 22.

ESI-MS: m / z = 364 [M + H] + 1 H-NMR (400 MHz, CDCl 3): δ = 1.48 (bd, 1H), 1/65. (dk, 1H), 2.20 (bd, 1H), 2.31 (dk, 1H), 2.44 (m, 1H), 2.83-2.95 (m, 2H), 3.01 (m, 1H), 3.11 (dt, 1H), 3.50 (k, 1H), 3.92 (d, 1H), 4.26 (m, 1H), 4.60 (d, 1H) , 4.92 (d, 1H), 5.08 (d, 1H), 6.50 (t, 1H), 7.24 (t, 1H), 7.40 (t, 1H) ·, 7.46 (d, 1 H), 7.53. (t, 1 H), 8.32. (d, 2 H).

Example 26: 8-Chloro-1- (1-pyrimidin-2-yl-piperidin-4-yl) -4H, 6H-5-oxa-2,3,10b-triazabenzo [e] azulene 3525

156 I

Cr '# I

5 ci I

The title compound was prepared from the oxadiazole of I

preparation 23, in 70% yield, using the process

expensive that was described in Example 22. I

ESI-MS: m / z = 383 [M + H] + I

10 H NMR (400 MHz, CDCl 3): δ = 1.92-2.13 (m, 4H), 3.07 (t, 1

2H), 3.12 (m, 1H), 4.39 (s, 2H), 4.66 (s, 2H), 4.82 (m, I

2H), 6.53 (t, 1H), 7.39 (d, 1H), 7.57-7.63 (m, 2H), 8.33 I

(d, 2 H). I

15 'Example 27: 13-Chloro-3- (3,4,5,6-tetrahydro-2 H- [1,2'] -1

bipyridinyl-4-yl) -8-oxa-2,4,5-triazatal

cyclo [9.4.0.0 * 2.6 *] pentadeca-1 (11), 3.5.12, I

14-pentaene I

20 I

cr ° ^ J

25 'CI

The title compound was prepared from the oxadiazole of I

Preparation 22, in 40% yield, using the process

expensive that was described in Example 22. I

APCI-MS: m / z = 396 [M + H] + I

1 H NMR (400 MHz, CDCl 3): δ = 1.44 (bd, 1H), 1.66 (dk, 1H), 1

2.17 (bd, 1H), 2.36 (dk, 1H), 2.43 (m, 1H), 2.72-2.85 (m, I

35 2H), 2.89-3.03 (m, 2H), 3.55 (t, 1H), 3.97 (d, 1H), 4.14-1

4.26 (m, 2H), 4.40 (bd, 1H), 5.07 (d, 1H), 6.59 (dd, 1H), I

102552 - I

157 6.64 (d, 1H), 7.19 (d, 1H), 7.38-7.48 (m, 3H), 8.15 (d, 1H).

Found it: .

C, 62.84%; H, 5.54%; N, 17.34%; 5 for C21 H22 ClN5 O. 0.08 CH 2 Cl 2 requires: C, 62.88%; H, 5.55%; N, 17.39%.

Example 28: 3- (3,4,5,6-Tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -8-oxa-2,4,5-triazatricyclo [9.4.0.

10 * 2.6 *] pentadeca-1 (11), 3,5,12,14-pentaene dihydrochloride / T'i \ f ~ \ // ^ n

15 x / ~ N / J J

20

The title compound was prepared from the oxadiazole of preparation 21, in 4% yield, using the procedure described in Example 22. The dihydrochloride salt was prepared using the procedure described in Example 8.

APCI-MS: m / z = 362 [M + H] + 1 H-NMR (400 MHz, CD3 OD): δ = 1.67-1.8.1 (m, 2H), - 2.32 (dk, 1H), 2.47-2.57 (m, 2H), 3.11 (dd, 1H), 3.25 (dt, 1H), 3.33. (m, 2H), 3.45-3, 62 (m, 3H), 4.07-4.16 (m, 2H), 4.30 (m, 1H), 4.40 (bd, 1H) .05.07 (d, 1H), 7.00 (t, 1H), 7.40 (d, 1H), 7.60-7.66 (m, 2H), 7.69-7.78 ( m, 2H), 7.96 (d, 1H), 8.06 (t, 1H).

Example 29: 8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bi-pyridinyl-4-yl.) -4H, 6H-5-oxa-2, 3,110-triaza-benzo [e] azulene 1025521- "

158 I

/ r * i / \ Jh * I I

<0 ^ ° I

α I

The title compound was prepared from the oxadiazole of I

preparation 20, in 60% yield, using the process

10 which was described in Example 22. I

APCI-MS: m / z = 382 [M + H] + I

1 H NMR (400 MHz, CDCl 3): δ = 1.97 (bd, 2H), 2.09 (m, 2H), I

2.98 (dt, 2H), 3.17 (m, 1H), 4.32-4.40. (m, 4H), 4.64 (s, I

2H), 6.59 (dd, 1H), 6.64 (d, 1H), 7.39 (d, 1H), 7.45 (t, I

1 H), 7.56-7.61 (m, 2 H), 8.17 (d, 1 H). I

Found: I

C, 60.19% / H, 5.17%; N, 17.31% / l

for C21H22CIN5O. 0.27 CH 2 Cl 2 is required: I

C, 60.14%; H, 5.11% / N, 17.30%. I

20 I

Example 30: 7-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bi-I

pyridinyl-4-yl) -4H, 6H-5-oxa-2,3, 10b-triaza-1

benzo [e] azulene dihydrochloride I

25 I

. I

30 I

The title compound was prepared from the oxadiazole of I

35 preparation 17, in 21% yield, using the process

duration described in Example 22. The dihydrochloro-I

1,02552 - I

The ride salt was prepared using the procedure that was used. described in Example 8.

. APCI-MS: m / z = 382 [M + H] + 1 H-NMR (400 MHz, CD3 OD): δ «2.10 (m, 2H), 2.30 (m, 2H), .5. 3.50 (bt, 2H), 3.74 (m, 1H), 4.32 (m, 2H), 4.93 (s, 2H), 7.00 (t, 1H), 7.46 (d 1 H), 7.77-7.95 (m, 3 H), 8.00 (dd, 1 H), 8.09 (t, 1 H).

Example 31: 1- (3,4,5,6-Tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -4H, 6H-5-oxa-2,3,110-triazabenzo [e] azulene 15 w.

20

The title compound was prepared from the oxadiazole of preparation 16, in 41% yield, using the procedure described in Example 22.

APCI-MS: m / z = 348 [M + H] + 25 α H-NMR (400 MHz, CDCl3): δ = 1.98 (bd, 2H), 2.12 (m, 2H),> 2.97 (t, 2H), 3.24 (m, 1H), 4.35 (d, 2H), 4.45 (s, 2H), 4.65 (s, 2H), 6.59 (dd, 1H) , 6.69 (d, 1H), 7.38-7.49 (m, 2H), 7.53-7.65 (m, 3H), 8.18 (d, 1H).

Found: 30 C, 64.55%; H, 5.84%; N, 17.92%; for C20 H21 N5 O. 0.40 CH 2 Cl 2. 0.08 C8 H10 requires: C, 64.82%; H, 5.84%; N, 17.96%.

Example 32: 8-Methoxy-1- (3,4,5,6-tetrahydro-2H- [1,2 '] -bipyridinyl-4-yl) -4H, 6H-5-oxa-2,3,10b - triazabenzo [e] azulene dihydrochloride 1025527-

160 I

Λ — IΝ / —TV N ^ w I

- * \ I

<Μ ^ ° I

·; —Ο I

The title compound was prepared from the oxadiazole of I

Preparation 19, in 68% yield, using the process

duration described in Example 22. The dihydrochloro-I

ride salt was prepared using the procedure that was I

described in Example 8. I

ESI-MS: m / z ', 379 [M + H] + I

15? -NMR (400 MHz, CD3OD): § = 2.08 (bk, 2H), 2.30 (bd, 2H), I

3.49 (t, 2H), 3.85 (m, 1H), 3.95 (s, 3H), 4.32 (bd, 2H), I

4.59 (s, 2H), 4.68 (s, 2H), 7.03 (t, 1H), 7.31-7.35 (m, 1

2H), 7.45 (d, 1H), 7.80 (d, 1H), 7.97 (d, 1H), 8.08 (t, I

1H). I

20 I

Example 33: 8-Fluoro-1- (3, 4,5, 6-tetrahydro-2H- [1,2 ''] bi-I

pyridinyl-4-yl) -4H, 6H-5-oxa-2,3, 10b-triaza-1

benzo [e] azulene I

25 I

/ T ~ N, J— \ I

: I

I \ ~ / ° I

30 I

The title compound was prepared from the oxadiazole of I

35 preparation 31, in 62% yield, using the process

expensive that was described in Example 22. I

APCI-MS: m / z = 366 [M + H] + I

1025527-1

161 1 H NMR (400 MHz, CDCl 3): δ = 1.90-2.16 (m, 4H), 2.97 (dt, 2H), 3.16 (m, 1H), 4.28-4 , 40 (m, 4H), 4.63 (s, 2H), 6.58 (dd, 1H), 6.66 (d, 1H), 7.24-7.35 (m, 2H), 7, 40-7.52 (m, 2H), 8.15 (d, 1H). .

Found: C, 64.47%; H, 5.56%; N, 18.50%; for C 20 H 20 FN 5 O. 0.07 CH 2 Cl 2. 0.07 EtOAc is required: C, 64.74%; H, 5.53%; N, 18.55%.

Example 34: 8,9-Difluoro-1- (3,4,5,6-tetrahydro-2H-[1,2 '] bipyridinyl-4-yl) -4H, 6H-5-oxa-2,3, 10-triazabenzo [e] azulene dihydrochloride 15. Ö-'CHX '20. F. :

The title compound was prepared from the oxadiazole of preparation 33, in 44% yield, using the procedure described in Example 22. The dihydrochloride salt was prepared using the procedure described in Example 8.

APCI-MS: m / z = 384 [M + H] + 30 H NMR (400 MHz, CD3 OD): δ = 2.00-2.13 (m, 2H), 2.18-2.37 (m (2H), 3.52 (dt, 2H), 4.33 (bd, 2H), 4.58 (s, .2H), 4.68 (s, 2H), 7.02 (t, 1H), 7.47 (d, 1H), 7.81 (dd, 1H), 7.94 - 8.02 (m, 1H), 8.06 (t, 1H).

Found: 35 C, 49.58%; H, 5.01%; N, 14.25%; for C 20 H 19 F 2 N 5 O. 2HCl. 0.30 CH 2 Cl 2. 0.58H 2 O requires: C, 49.53%; H .; 4.66%; N, 14.23%.

1,02552?

162 I

Example 35: 9-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] -1

bipyridinyl-4-yl) -4H, 6H-5-oxa-2,3,110-tri-1

azabenzo [e] azulene dihydrochloride I

5 I

Ö-ΟΛλ I

α— (!) - ^

I

The title compound was prepared from the oxadiazole of I

preparation 18, in 54% yield, using the process

duration described in Example 22. The dihydrochloro-I

Ride salt was prepared using the procedure that was I

described in Example 8. I

APCI-MS: m / z = 383 [M + H} + I

^ -NMR (400 MHz, CD3OD): δ = 2.10 (m, 2H), 2.35 (m, 2H), I

3.55 (dt, 2H), 4.00 (bd, 1H), 4.35 (ift, 2H), 4.65 (s, 2H), I

25 4.80 (s, 2H), 7.02 (m, 1H), 7.45 (m, 1H), 7.81 (s, 2H), I

8.00 (m, 3 H). I

Example 36: 1- (3,4,5,6-Tetrahydro-2H- (1,2 ') bipyridinyl-1

4-yl) -8-trifluoromethoxy-4H, 6H-5-oxal

2,3,10b-triazabenzo [e) azulene I

^ I

/ v_ / ° I

\ r.

fH ° I

102552 - I

163

The title compound was prepared from the oxadiazole of preparation 36, in 44% yield, using the procedure described in Example 22.

APCI-MS: m / z = 432 [M + H] + ^ -NMR (400 MHz, CDCl 3): 6 = 1.99 (m, 2H), 2.13 (m, 2H), 3.00 (dt (2H), 3.17 (m, 1H), 4.37 (d, 2H), 4.42 (s, 2H), 4.66 (s, 2H), 6.60 (dd, 1H), 6.68 (d, 1H), 7.40-7.52 (m, 4H), 8.16 (d> 1H).

Found: C, 58.16%; H, 4.77%; N, 15.84%; for C 2 H 20 F 3 N 5 O 2 requires: C, 58.47%; H, 4.67%; N, 16.23%.

Example 37: 8-Methyl-1- (3,4,5,6-tetrahydro-2H- [1,2 '] - bipyridinyl-4-yl) -4H, 6H-5-oxa-2,3,10b- triazabenzo [e] azulene O-OXX: 25 ° C The title compound was prepared from the oxadiazole of preparation 37. in 48% yield, using the procedure described in Example 22.

APCI-MS: m / z = 362 [M + H] + - NMR (400 MHz, CDCl 3): δ = 1.99 (m, 4H), 2.43 (m, 3H), 2.96. (dt, 2H), 3.41 (m, 1H), 4.34 (d, 2H), 4.42. (s, 2H), 4.66 (brs, 2H), 6.62 (dd, 1H), 6.83 (d, 1H), 7.44-7.60 (m, 3H), 7.63 ( d, 1 H), 8.06 (d, 1 H).

1025527 -

164 I

Example 38: 1- [8-Chloro-1- (3,4,5,6-tetrahydro-2 H -1)

[1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3,5,10b -1

triazabenzo [e] azulene-5-yl] -2-dimethyl-1

Aminoethanone I

r. — N y of n

\ / ~ N) - \ O I

10 \ = / λ- / I

. I

Cl N \ I

I

A solution of HBTü (152 mg, 0.38 mmol) in Ν, Ν-I

dimethylacetamide (1.9 ml) was added to a solution of the amine of Example 4 (97 mg, 0.26 mmol), triethylamine (1.5 μΐ, cat.) and dimethylaminoacetic acid (36

mg, 0.26 mmol) in N, N-dimethylacetamide (2.5 ml) and er

was heated to 50 ° C for 2 hours. The mixture was cooled and the solvent evaporated under reduced pressure.

The residue was partitioned between dichloromethane (10 ml) and I

2M aqueous sodium hydroxide solution (10 ml). The organization I

phase was dried over magnesium sulfate before it

was evaporated under reduced pressure and purified by I

chromatography on silica gel with methanol and ammonium hydrogen

Droxide in dichloromethane (7: 1: 93) as eluant, the

none the title compound (70 mg) as a brown foam

verde. I

APCI-MS: m / z = 466 [M + H] + I

Found: I

35 C, 60.14%; H, 5.93%; N, 20.29%; I

for C24H28 CIN7O. 2HCl. 0.20CH2 Cl2 requires: I

C, 60.18%; H, 5.93%; N, 20.30%. I

1025527-1

165

Example 39: 2-Chloro-1- [8-chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3, 5,10b-triazabenzo [e] azulene-5-yl] ethanone 5

N - N

(Γ, V'nn ___ J \: n-1 10 \ j. RV7 ° α 15

Triethylamine (1.37 ml, 9.81 iranol) and chloroacetyl chloride (0.35 ml, 4.35 mmol) were added to a solution of the amine from Example 4 (1.5 g, 3.95 nutiol) in dichloromethane (50 ml), and the reaction mixture was stirred at room temperature for 2 hours. TLC analysis showed that starting material remained, so that additional chloroacetyl chloride (0.35 ml, 4.35 mmol) was added and the reaction mixture was stirred for an additional 1.5 hours. The mixture was partitioned between dichloromethane and 2N sodium hydroxide solution and the layers were separated. The aqueous phase was extracted with more dichloromethane and the combined organic solutions were washed with concentrated saline (50 ml), dried over magnesium sulfate and evaporated under reduced pressure. The remaining foam was purified by column chromatography on silica gel with dichloromethane: methanol: ammonia (s.d. = 0.88) (95: 5: 0.5) to give the title compound as a foam; 1.12 g.

.351 H NMR (400 MHz, CDCl3): δ = 1.30-2.60 (m, 4H), 2.84-3.20 (m, 3H), 3.40-4.80 (m, 8 H), 6.62 (m, 1 H), 6.70 (m, 1 H), 7.40 (m, 1 H), 7.50 (m, 1 H), 7.61 (m, 2 H), 8, 18 (m, 1 H).

1025527-

166 I

APCI-MS: m / z = 457 [MH] + I

Microanalysis found: C, 55.13; H, 4.81; N, 17.19. I

for C22 H22 Cl2 N6 O. 0.33 CH 2 Cl 2 is required: I

C, 55.26; H, 4.71; N, 17.31%. I

5 I

Example 40: 2-Azetidin-1-yl-1- [8-chloro-1- (3,4,5,6-I

tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -1

10H, 6H-2,3,5,10b-tetraazabenzo [e] azulene-5-l

yl] ethanone I

. N-n I

I

Cl 1

20 I

Potassium carbonate (227 mg, 1.65 mmole) and azetidine I

(0.06 ml, 0.82 mmol) were added to a solution I

of the chlorine compound from Example 39 (250 mg, 0.55 L

25 mol) in N, N-dimethylformamide (5 ml), and the reaction mixture

The mixture was stirred at 70 ° C for 18 hours. The reaction I

mixture was concentrated under reduced pressure and it

residue partitioned between water (10 ml) and ethyl acetate (10 L

ml), and the layers were separated. The water phase was started

Extracted with ethyl acetate (2 x 10 ml). The combined I

organic solutions were washed with water (20 ml) I

and concentrated saline (10 ml), then added

dried over magnesium sulfate and evaporated under reduced I

pressure. The crude product was purified by column chromatography

35 matography on silica gel with dichloromethyl

thane-methanol: ammonia (s.d. = 0.88) (95: 5: 0.5), which is I

the title compound yielded as a white foam; 55 mg. I

1 02552.7-1

167 1 H NMR (400 MHz, CDCl 3): δ = 1.68-2.30 (m, 6H), 2.80-3.90 (m, 11H), 4.10-4.50 (m, 2H ), 5.10-5.55 (m, 2H), 6.60 (dd, 1H), 6.66 (d, 1H), 7.40 (dd, 1H), 7.45 (m, 1H) , 7.58 (m, 2H), 8.18 (d, 1H).

APCI-MS: m / z = 478 [MH] +

Microanalysis, found: C, 60.26; H, 5.83; N, 19.55; for C 25 H 28 ClN 7 O; 0.33 CH 2 Cl 2 requires: C, 60.12; H, 5.71; N, 19.38%.

10

Example 41: 1- [8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3,5,10b- tetraazabenzo [e] azulene-5-yl] -2-pyrrolidine-1-ylethanone 15 N-N. y r "vQi 20 K *}. ry 0 egg 25

The title compound was obtained as a pale yellow foam from the chlorine compound of Example 39 and pyrrolidine by following the procedure described in Example 40.

3Ö. 1 H NMR (400 MHz, CDCl 3): δ = 1.54-2.01 (m, 8H), 2.05-4.00 (m, 11H), 4.20-4.45 (m, 2H) , 5.10-5.58 (m, 2H), 6.60 (m, 1H), 6.66 (d, 1H), 7.40 (dd, 1H), 7.44 (m, 1H), 7.56-7.74 (m, 2H), 8.18 (d, 1H).

APCI-MS: m / z = 492 [MH] + 35

Example 42: [8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3,5,10b-tetraaza - 1.025527-

168 I

benzo [e] azulene-5-yl] pyrrolidin-3-yl-1

raethanontrihydrochloride I

5 I

N / - 3 HC I

ΤΤ) 1 "I

10 7 I

Cl I

I

A solution of hydrogen chloride in dioxane (2.98 l

ml, 4M) was added to a solution of the be

Protected amine from preparation 65 (690 mg, 1.10 mmol) in I

dichloromethane (5 ml), and the reaction mixture was diluted

stirred for 1 hour at room temperature. The mixture was

evaporated under reduced pressure to give the title compound

. as a white solid (744 mg). I

1 H-NMR (400 MHz, CD3OD): δ - 2.00-2.22 (m, 3H), 2.56 (m, I

1 H), 3.38-4.01 (m, 14 H), 4.24-4.41 (m, 2 H), 7.02 (m, 1 H), I

7.45 (d, 1H), 7.80 (m, 1H), 7.90-8.00 (m, 2H), 8.00-8.10 I

(m, 2 H). I

APCI-MS: m / z = 478 [MH] + I

30 I

Examples 43 to 49: I

The following compounds with the general structure: I

35 I

1025527 I

169 Ν — Ν ΐ.

5 7 ^. 3Hd.

Cl were prepared quantitatively from the appropriate protected amines by following the procedure described in Example 42.

Ex. no,! "" "Form Data V 43 * ^ H solid. 1 H NMR (400MHz. CD3OD): 5 *" solid 1.88-2.70 (m, 8H), 3.38-3.83 (m, 6H), 4.50-5.63 (m, 6H), 7.02 (dd, 1H), 7.45 (d, 1H), 7.81 (fn, 2H). 7.90 (m, 1 H), 7.98 (d, 1 H), 8.07 (rh, 1 ', 1 H).

APCHV / S: m ^ 478 [MHf ^% JT "solid" H-NMR (400 MHz, CD3 OD): Ss / st 1.80-2.80 (m, 8H), 3.22-3.78 (m, 6H) , 3.82-5.12 (m, 6H), 7.01 (m.

1 H), 7.42 (d, 1 H), 7.80 (m, 2 H), 7.98 (d, 1 H), 8.05 (m, 1 H).

; APCHMS: mk478 [MHJ * 45 ~ 7; · H ”fixed APO-MSm / s-OI [MH] 7" 7 V / V · dust 46 0 H white NM NMR (400MHz, CD3OD): 6 * 1.40-y, m \ / £ 60 ( m, 10 H), 3.38-3.83 (m, 6 H).

3) 90-5.60 (m, 6H), 7.02 (m, 1H), 7.45 (m, 1H), 7.79-8.18 (m, 5H). APCI-MS: m / 2 »491 [M-H]" 1025527-

170 I

Γ 47 Ö Η ~ white, ’H-NMR (400MHz, CD3OD): δ * 1.40- I

5 / Itofe 2.70 (m'10H> AM-V5 (m, 12H), I

3.00 (m, 1H), 7.46 (m, 1H), 7.80-1

8.18 (m, 5H). I

APCI-MS: m / M91 [M-H] "I

10. 48 'o H' white, V H NMR (400 MHz, CD3 QD): δ-. I

y ~ y λ solid 196-2.37 (m, 3H), 2.62 (m, 1H), I

r \ _ / dust

0 3.36-3.70 (m, 7H), 3.79-3.98 (m, I

2 H), 4.08 (m, 1 H), 4.20-4.66 (m, I

4H), 5.04-5.62 (m, 2H), 7.02 (dd, I

15 '(1 H), 7.48 (d, 1 H), 7.82 (m, 1 H),! I

7.98 (m, 2H), 8.06 (m, 1H), 8.18 I

(m, 1 H). I

APCI-M $: m / * 494 [MHf I

49 ^ T __} j white, 1 H NMR (400MHz, QD3OD): δ * I

r {J> 1.40-2.40 (m, 4H), 3.20-3.78 (m. I

° 0 S ° 10H), 3.96-5.41 (m, 6H), 7.00 (m, I

1 H), 7.41 (d, 1 H), 7.74-7.80 (m, I

2 H), 7.95 (d, 1 H), 8.02 (m, 1 H). I

APCI-MSim / & 516 [MNa] * I

1025527-1

171

Example 50: 8-Chloro-5-pyrrolidine- (2S) -2-ylmethyl-1- (3,4,5,6-tetrahydro-2H- (1,2 ') bipyridinyl-4-yl) -5.6 dihydro-4H-2,3,5,10b-tetraazabenzo [ejazulene 5

N - N

Cl.

Borane (1M solution in tetrahydrofuran, 7.25 ml, 7.25 inmol) was added to a suspension of the amide from Example 43 (398 mg, 0.725 mmol) in tetrahydrofuran (10 ml), and the mixture was kept for 2 heated under reflux for 1 hour. Hydrochloric acid (6M) was added until no more gas developed, and the reaction mixture was heated under reflux for a further 3 hours. The cooled mixture was made basic with 2N sodium hydroxide solution and then extracted with ethyl acetate (x2). The combined organic extracts were washed with concentrated saline, dried over magnesium sulfate and evaporated under reduced pressure. The colorless gum was purified by column chromatography on silica gel with dichloromethane: methanol: ammonia (s.d. = 0.88) (80: 20: 3) as eluant, yielding the title compound as white foam; 98 mg.

1 H NMR (400 MHz, CDCl 3): δ = 1.39 (m, 1H), 1.59-2.18 (m, 7H), 2.58 (m, 2H), 2.80-3.76 (m, 10H), 4.23 (m, 2H), 6.50 (dd, 1H), 6.58 (d, 1H), 7.22 (d, 1H), 7.36-7.58 ( m, 3 H), 8.04 (d, 1 H).

APCI-MS: m / z = 464 [MH] + 1025527-

172

Examples 51 to 54 I

The following compounds with the general structure: I

I ^ r \ I

I *. I

10 α I

I were prepared from the appropriate amides by the procedure

I "15 described in Example 50. I

102552 - I

173

Ex. no. ^ Yield Data (%) / Required YES '56' H-NMR (400MHz, CPCl3): 6 * 1.05 - white: 2.23 (m, 10H), 2.40 -2.70 (m, 3H), J foam - 2.96 (m, 2H), 3.12 (m, 2H), 3.27-3.90 (m, 5H), 4.34 ( m, 2H), 6.58 (dd, 1H), 6.66 (d | 1H), 7.33 (d, 1H), 7.45 (m. 3H), 8.18 (m, 1H). APOMS; m / fc478 [MH] + ------—- - - - - - - - - - - 52. .53 1 H-NMR (400MHz, CDCl3): 6 * 1.05 - ·

O11, 2.05 (m, 10H), 2.40-2.70 (m, -3H), 1; scnoma 2.97 (m, 2H), 3.10 (m, 2H), 3.10-4.40 (m, 7H), 6.60 (dd, 1H), 6.66 (d, 1H), 7.35 (d, 1 H), 7.50 (m, 3 H), 8.18 (d, 1 H).

APChMS: m / a478 [MHf 53 24 "1 H NMR (400MHz, CDCl3): δ = 1.42-

^ NH

White 2.40 (m, 12H), 2.60 (m, 1H), 2.80-.

foam 3 ^ 10 (m, 4H), 3.18-3.65 (m, 5H), 4.22 (m, 2H), 6.50 (dd, 1H), 6.59 (d,, 1H) ), 7.18 (s, 1H), 7.21 (d, 1H), 7.39. (m, 2H), 8.06 (m, 1H).

. APCUMS: m / & 478 [MH] + 54 37 1 H NMR (400 MHz, ODCl 3): 6 * 1.82-IJ white 2.22 (m, 4H), 2.40-3.00 (m, 9H), foam '3.10 (m, 1H), 3.38-3.90 (m, 6H),' 4.36 (m, 2H), 6.60 (dd, 1H), 6.66 (d, 1 H), 7.33 (d, 1 H), 7.42-7.58 (m,.

3 H), 8.18 (d, 1 H).

APCHVIS.m / 2'502 [MNa] * 102552? -

174 I

Example 55: 5-Azetidin-3-yl-8-chloro-1- (3,4,5,6-I

tetrahydro-2H- [1,2] bipyridinyl-4-yl) -5,6-I

dihydro-4H-2,3,5,10b-tetraazabenzo [e] -1

azulene I

5 I

N-N I

(VO ^ Qh ^.; I

10 I

<ci I

Hydrogen chloride in dioxane (5.6 ml, 4M) was added

added to a solution of the protected amine from BE

preparation 73 (1.2 g, 2.24 mmol) in dichloromethane (10 ml),

and the solution was stirred at room I for 18 hours

temperature. The mixture was partitioned between 2N sodium I

Hydroxide and dichloromethane and the layers were separated

Pine tree. The aqueous phase was extracted with dichloromethane

(x2) and the combined organic solutions were added

washing with concentrated saline, dried on magnet

sulfate and evaporated under reduced pressure

Yellow solid was purified by column chromatography

silica gel with dichloromethane

thane: methanol: ammonia (s.d. = 0.88) (95: 5: 0.5 to 1)

93: 7: 1), representing the title compound as a white foam

(300 mg). I

30 X H NMR (400 MHz, CDCl 3): 6. = 1.60-2.20 (m, 4H), 2.82-3.77 I

(m, 10H), 4.35 (m, 4H), 6> 60 (d, 1H), 6.66 (d, 1H), 7.36

(d, 1 H), 7.42-7.59 (m, 3 H), 8.18 (m, 1 H). I

APCI-MS: m / z = 458 [MNa] + I

Example 56: 8-Chloro-5-pyrrolidin-3-yl-1- (3,4,5,6-I

tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -5,6-I

102552 - I

175 dihydro-4H-2,3,5,10b-tetraazabenzo [e] -azulene

n — "N

5 / NTSvn // A

"Cl.

10 ·

Hydrogen chloride in dioxane (1.5 ml, 4 M) was added. to a suspension of the protected amine from preparation 74 (767 mg, 1.39 mmol) in dioxane (30 ml), and the reaction mixture was stirred at room temperature for 18 hours. TLC analysis showed that starting material remained, so that additional hydrogen chloride in dioxane (1.5 ml, 4 M) was added and the reaction mixture was stirred for an additional 5 hours. The mixture was evaporated under. reduced pressure and the residue purified by column chromatography on silica gel with dichloromethane: methanol: ammonia (s.d. .. = 0.88) (90: 10: 1). The residue was azeotropically evaporated from ether to give the title compound as a brown foam; 404.6 mg.

1 H NMR (400 MHz, CDCl 3): δ = 1.57-2.39 (m, 9H), 2.78-3.57 (m, 9H), 4.33 (m, 2H), 6, 59 (dd, 1H), 6.66 (d, 1H), 7.32 (d, 1H), 7.44 (m, 1H), 7.52 (m, 2H), '8.18 (d, 1H).

APCI-MS: m / z = 472 [MNa] + 30

Example 57: 8-Chloro-5-piperidin-4-yl-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -5,6-dihydro-4H -2.3.5, 10b-tetraazabenzo [e] -azulene 35.

I02552t

176 I

N-N I

α ° Χχ> ι

3 HCl. I

Cl. I

10. I

Hydrogen chloride in dioxane (8.44 ml, 4M) was added

added to a solution of the protected amine from BE

75 (1.9 g, 3.37 mmol) in dichloromethane (50 ml), I

and the reaction mixture was stirred at I for 18 hours

room temperature. The mixture was evaporated under reduction

third edition, giving the title compound as a pale pink, I

solid. I

1 H-NMR (400 MHz, CD3 OD): δ = 1.70-2.35 (m, 6H), 2.55-2.65 I

(ra, 2H), 3.03-3.40 (m, 7H), 3.60-3.96. (m, 2H), 4.20-5.08

(m, 4H), 7.01 (dd, 1H), 7.43 (d, 1H), 7.90 (s, 2H), 7.98. I

(dd, 1H), 8.04 (m, 2H). I

APCI-MS: m / z = 464 [MH] + I

25 I

Example 58: 8-Chloro-5- [1,4] oxazepan-6-yl-1- (3,4,5,6-I

tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -5,6-I

dihydro-4H-2,3,5,10b-tetraazabenzo [e] -1

azuline trihydrochloride I

30 I

3 HCl

35 cl

1025527-1

177

Hydrogen chloride in dioxane (1 ml, 4 M) was added to a solution of the protected amine from preparation 76 (180 mg, 0.31 mmol) in dioxane (5 ml) and the reaction mixture was stirred for 18 hours at room temperature. The mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel with dichloromethane: methanol: ammonia (s.d. = 10.88) (95: 5: 0.5) as eluant. The product was dissolved in dichloromethane and the solution treated with hydrogen chloride in ether. (1 M) . The solution was evaporated under reduced pressure to provide the title compound.

15 H 1 NMR (400 MHz, CD 3 OD): δ = 2.00-2.60 (m, 4H), 3.36-3.62 (m, 7H), 3.70-4.00 (m, 7H ), 4.12-4.40 (m, 4H), 7.01 (dd, 1H), 7.43 (d, 1H), 7.78 (dd, 1H), 7.81 (m, 1H) , 7.90 (s, 1H), 7.98 (d, 1H), 8.05 (m, 1H).

APCI-MS: m / z = 480 [MH] + 20

Example 59: [8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3,5,10b-tetra -azabenzo [e] azulene-5-yl] morpholin-4-yl-methanone 25

. N - N

/ N - o

Cl 35. A mixture of the amine from Example 4 (150 mg, 0.42 mmol), morpholine carbonyl chloride (0.15 ml, 1.26 mmol) and triethylamine (0.18 ml, 1.26 mmol) in dichloromethane 102552;

178 I

(10 ml) was stirred at room temperature for 18 hours

time. The reaction mixture was evaporated under reduced I

pressure and the residue purified by column chromatography over I

silica gel with dichloromethane, methanol: ammonia (s.d. = I

5, 0.88) (95: 5: 0.5), giving the title compound as a solid I

substance (130 mg). I

1 H NMR (400 MHz, CDCl 3): δ - 1.56-1.85 (m, 4H), 2.85-3.38

(m, 7H), 3.60-3.98 (m, 6H), 4.22-4.54 (m, 3H), 4.78-4.97 I

(m, 1H), 6.61 (dd, 1H), 6.68 (d, 1H), 7.38 (d, 1H), 7.50 I

10 (m, 1H), 7.58 (m, 2H), 8.18 (m, 1H). I

APCI-MS: m / z = 516 [MNa] + I

Examples 60 to 63 l

The following compounds with the general structure: I

I

n-n; I

20 V Cr 'I

Cl I

25 were prepared from the amine from Example 4 and the suitability

acid chlorides by following the procedure that was used

written in example 59. I

1025527 I

179 R1 "" Yield Data no · (%) / form.

iÖ: ° <s ^ 0χ:: ~ 83. 1 H-NMR (4QMH "2, CDCl 3): δ = 1.56- / Schs white → 2.38 (m, 4H), 2.80-3.18 (m, 3H), solid stDf 3.5β- 3.98 (m, 5H), 4.18-4.46 (m, 2H), 4.79-5.40 (m, 2H), 6.60 (dd, 1H), 6.64 (d 1 H), 7.38 (d, 1 H), 7.42 (m, 1 H), 7.50-7.61 (m, 2 H), 8.17 (m, 1 H). MNaf 6.O. ~ 92 92 H NMR (400MHz, CDOI3): 6 = 1.60- / ~~ NV white, 1.95 (m, 2H), 2.05-2.19 (m, 2H CHS; solid 2.83-3.03 (m, 8H), 3.17 (m, 1H), substance 3.70-4.05 (m, 2H), 4.19-4.55 (m (3H), 4.70-5.94 (m, 1H), 6.62 (m, 1H), 6.69 (d, .1H), 7.38 (d, 1H), 7.46 (m 1 H), 7.58 (m, 2 H), 8.18 (d, 1 H).

APCHMSim / 2,452 [MHf V ": * 93 V H NMR (400MHz, CDCl3): δ * 1.58-L | white, 2.39 (m, 7H), 2.84-3.02 (m, 2H) ,

ItlT 3.16 (m, 1H), 3.40 (m, 4H), 3.65-4.00 (m, 2H), 4.20-4.62 (m, 4H), 4.80-5 , O 2 (m, 1 H), 6.60 (dd, 1 H), 6.66 (d, 1 H), 7.38 (d, 1 H); 7.42-7.60 (m, 3H), 8.18 (m, 1H). APCI-MS: m / z * 478 [MH] + 102552 -

180 I

5 I

! Wm. 9λ / -y ~ T 69 ’. H NMR (400 MHz. CDCU): δ, 1.59. I

10 / N / n "~ ch 3 · white, 1.95 (m, 3H), 2.18-2.60 (m, 7H), I

substance 2.82-3.02 (m, 2H), 3.15 (m, 1H),

3.39 (m, 4H), 3.72-4.02 (m, 2H), I

4.20-4.52 (m, 3H). 4.78-4.96 (m, I

1 H), 6.60 (dd, 1 K), 6.68 (d, 1 H), I

7.38 (d, 1H), 7.45 (dd, 1H), 7.58 l

(d, 2H), 8.18 (d, 1H). I

APCI-MS / n / 2su507 [MHf. I

20

α-isolated without column chromatography I

102552 - I

181

Example 64: (2- [8-Chloro-1- (3,4,5, Ê-tetrahydro-H-tl, 2 '] bipyridinyl-4-yl) -4H, 6H-2, 3, 5,10h- tetraazabenzo [e] azulene-5-yl] ethyl} di-methylamine trihydrochloride 5.

· '· ·' N — N

3hci

CHS

Cl 2 Borane (1M solution in tetrahydrofuran, 4 .3 ml, .4.3 mmol) was added to a suspension of the amide from Example 61 (398 mg, -0.43 mmol) in tetrahydrofuran (10 ml. and the mixture was refluxed for 2 hours. Hydrochloric acid (6M) was added until no more gas was developed and the reaction mixture was then refluxed for an additional 3 hours. The cooled mixture was made basic with 2N sodium hydroxide solution; and then extracted. with dichloromethane (3x20 · ml). The combined organic extracts were washed. 25 with. concentrated saline (20 ml), dried over magnesium sulfate and evaporated under reduced pressure. The colorless gum was purified by column chromatography on silica gel with dichloromethane: methanol: ammonia, (sd = 0.88) (93: 7: 1) as eluant, yielding a colorless gum. This gum was treated with hydrogen chloride in ether which gave the title compound (194 mg).

1 H NMR (400: MHz, CD3 OD): .5 = 2.00-2.19 (m, 4H), 3.00 (m, 6H), 3.18 (m, 2H),. 3.42-4.46 (m, 11 H),. 7.00 (dd, 1H), 7.42 (d, 1H), 7.79 (dd, 1H)> 7.63 (m, 2H), 7.97 (m, 1H), 8.03 ( m, 1 H).

APCI-MS: m / z «452 [MH] + 1025527-

182 I

Example 65: 8-Chloro-5- (2-pyrrolidine-1-ylethyl) -1-I

(3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-I

yl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-1

benzo [e] azuline trihydrochloride I

5 I

N-N I

// N'A 3 HCl

, cr

α I

The title compound was obtained in 15% yield I

from the amide from Example 62 by following a procedure

gene similar to that described in I

Example 64. I

1 H NMR (400 MHz, CD3 OD): δ 2.03-2.23 (m, 8H), 3.00-3.83 l

20 (m, 13H), 4.00-4.80 (m, 4H), 7.00 (m, 1H), 7.43 (d, 1H), I

7.80-8.08 (m, 5H). I

APCI-MS: m / z = 478 [MH] + I

Example 66: [8-Chloro-1- (3,4,5,6-tetrahydro-2 H- [1.2 *] -1)

Bipyridinyl-4-yl) -4H, 6H-2,3,5,10b-tetra-1

azabenzo [e] azulene-5-yl] acetic acid methyl-I

ester I

Qq I

30 - "": H> I

u (V. I

α I

35 I

1025527-1

183

A mixture of the amine from Example 4 (500 mg, 1.31 mmol), methyl bropmacetate (260 mg, 1.70 mmol) and potassium carbonate (220 mg, 1.59 mmol) in N, N-dimethylformamide (15 ml ) was stirred at room temperature for 72 hours. The mixture was evaporated under reduced pressure and the residue purified directly by column chromatography on silica gel. dichloromethane: methanol (93: 7) as eluant, yielding the title compound.

X H NMR (400 MHz, CDCl 3): δ = 1.42-2.40 (m, 4H), 3.00-3.22 (m, 3H), 3.39-3.98 (m, 9H ), 4.38 (m, 2 H), 6.63 (m, 1 H), 6.74 (m, 1 H), 7.36 (d, 1 H), 7.57 (m, 3 H), 8.18 (d, 1 H). APCI-MS: m / z - 453 [MH] +

Example 67: 1- [8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3,5,10b - 1 tetraazabenzo [e] azulene-5-yl] -3-methoxy-propan-1-one Nr N '/ 20' o-ch 8; oJ3r (O <: a) 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (116 mg, 0.6 mmol) was followed by Ι-ΙΟ hydroxybenzo triazole hydrate (81 mg, 0.6 mmol) and triethylamine (84 μΐ, 0.6 mmol), added to a solution of 3-methoxypropionic acid (63 mg, 0.6 mmol) in dichloromethane (10 ml) and the solution was stirred for 10 minutes The amine from Example 4 (150 mg, 0.4 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours.The reaction mixture was washed with saturated sodium bicarbonate solution, dried 1025527

184 I

on magnesium sulfate and evaporated under reduced pressure. I

The residue was purified by column chromatography on I

silica gel with dichloromethane: methanol: ammonia (s.d. = I

0.88) (95: 5: 0.5), giving the title compound as a white I

5 te, solid (166 mg). I

X H NMR (400 MHz, CDCl 3): δ = 1.57-2.38 (m, 4H), 2.63-3.03

(m, 4H), 3.14 (m, 1H), 3.26 (s, 3H), 3.78-3.98 (m, 3H), I

4.23-4.43 (m, 3H), 4.75-4.92 (d, 1H), 5.44-5.62 (m, 1H), I

6.61 (dd, 1H), 6.68 (d, 1H), 7.40 (dd, 1H), 7.46 (m, 1H), I

10 7.58 (m, 2H), 8.18 (d, 1H). I

APCI-MS: m / z = 489 [MNa] + I

Example 68: 1- [8-Chloro-1- (3,4,5,6-tetrahydro-2 H -1)

[1,2 '] bipyridinyl-4-yl] -4H, 6H-2,3,5,10b -1

Tetraazabenzo [e] azulene-5-yl] -3-dimethyl-H

aminopropan-1-one H

'fXjry ^ L · ^ I

2 ° V / I

Cl

'I

O · ^ · (1H-Benzotriazol-1-yl) -N, N, N ', N'-tetramethyl-1

uronium hexafluorophosphate (200 mg, 0.52 mmol) was added H

added to a solution of 3-dimethylaminopropion-I

Acid hydrochloride (80 mg, 0.52 mmol) in dichloromethane (5 L

ml), and the solution was stirred for 15 minutes. The I

amine from Example 4 (100 mg, 0.26 mmol) was added H

and the reaction mixture stirred at room H for 18 hours

temperature. The mixture was partitioned between dichloromethane. I

Thane and aqueous sodium bicarbonate solution, and the layers I

were separated. The organic phase was dried on I

magnesium sulfate and evaporated under reduced pressure. The

1025527-1

The crude product was purified by column chromatography on silica gel with dichloromethane: methanol: ammonia (s.d. = 0.88) (90: 10: 1) to give the title compound as a white solid (110 mg).

<1> H NMR (400 MHz, CDCl3): δ <1.60-2.00 (m, 2H), 2.20 (m, 3H), 2.38-2.42 (2xs, 6H), 2, 62 (m, 1H), 2.75-3.00 (m, 4H), 3.14 (m, 1H), 3.97-4.80 (m, 4H), 5.05-5.66 ( m, 2H), 6.60 (dd, 1H), 6.66 (d, 1H), 7.40 (m, 1H), 7.46 (m, 1H), 7.59 (m, 2H), 8.18 (d, 1H). ..

APCI-MS: m / z = 480 [MH] +

Example 69: 8-Chloro-5- (1-methylpyrrolidine- (2S) -2-ylmethyl) -1- (3,4,5,6-tetrahydro-2H- [1,21] -bipyridinyl-4- yl) -5,6-dihydro-4H-2,3,5,10b-15 tetraazabenzo [e] azuline trihydrochloride XV-1; V / CH * 20 'Q) 3 HCl' 25

Formaldehyde (0.1 ml, 33% by weight aqueous solution) and sodium triacetoxyborohydride (64 mg, 0.30 mmol) were added to. a suspension of the amine from Example 50 (70 mg, 0.15 mmol) in dichloromethane (5 ml), and the reaction mixture was stirred at room temperature for 2 hours. The. The mixture was partitioned between dichloromethane and 2N sodium hydroxide solution and the phases were separated. The organic solution was evaporated under reduced pressure and the residue was purified by column chromatography. silica gel with dichloromethane: methanol: ammonia (s.d. = 0.88) (93: 7: 1) as a running agent. The product was treated with hydrochloric acid in 10255.27-

186 I

ether and the solution evaporated under reduced pressure, I

to give the title compound (35 mg). I

1 H NMR (400 MHz, CD 3 OD): δ «1.78-2.98 (m, 9H), 2.96-3.38

(m, 8H), 3.40-4.38 (m, 8H), 7.01 (dd, 1H), 7.43 (d, 1H), I

Δ 7.80 (m, 1H), 7.89 (m, 2H), 7.98 (d, 1H), 8.06 (dd, '1H)'. I

APCI-MS: m / z - 502 [MH] + I

Examples 70 to 72: I

The following compounds with the general structure: I

10 I

20 were prepared from the appropriate amines and formaldehyde by I

follow a procedure similar to that well-being I

ke was described in example 69.

.25 I

30 I

I 025527- I

187 5 _ · _.

Ex. no. Yield Data (%) / form 708-~ 67 ^ H-NMR (400MHz, COCl 3): δ & V6 (m, ΔN v ± 2H), 1.57 (m, 2H), 1 , 70-2.47 (m, 10H), 10? / · 2-, 80 - (m, 2H), 3.96 (m, 2H), 3,, 12 (m, 1H), 3, 27-3.80 (m, 6H), 4.36 (m, 2H), 6.58 (dd, 1H), 6.62 (d, 1H), 7.31 (d, 1H), 7.44 (m, 3H), 8.18 (m, 1H). APCHV1S: m / 2fe492 [MHf 15 718 7] -. 70 ^ 11 H NMR (400 MHz, CDCl3): δ, 26 (m, white 2H), 1.58 (m, 2H), 1.70-2.45 (m, 10H), γ foam 2.79 -3.00 (m, 4H). 3.12 (m, ΊΗ), 3.24-3.81 (m, 6H), 4.36 (m, 2H), 6.59 (dd, j20.1H), 6.62 (d, 1H) 7.31 (dj 1H), 7.41 (j, 7.56 (m, 3H), 8.18 (m, 1H).

. APCI-MS; 7V ^ 492 [MH] + "'7'2'" 57 7''H-NMR (400MHz, CD3OD): 6 = 4.83- "1. h \ white 2.62 (m, 8 H), 2.81-3.02 (m, 6 H), 3.22 - foam 3.97 (^ 7 ^ .4-4-4.98 (111.6 ^ 7.00 (dd, 1H) 7.45 (d, 1H), 7.90 (s, 2H), δ 7.98 (d, 1H), 8.02 (m, 2H).

APCWMSim / 2492 [MH] * 30 α-isolated as the free base 1025527 -

188 I

Examples 73 and 74: (+) - and (-) - 8-chloro-5- (4-methyl-1)

morpho-line-2-ylmethyl) -1- (3,4,5,6-I

tetrahydro-2H- [1,2 '] bipyridinyl-4-I

5 yl) -5,6-dihydro-4H-2,3,5,10b -1

tetraazabenzo [e] azulene I

n-n

3.0 years ~ I

^ fl / \ I

J: W I

a I

I

Formaldehyde (0.1 ml, 37% by weight aqueous solution) and I

sodium triacetoxyborohydride (55 mg, 0.26 mmol) were I

added to a suspension of the amine from example I.

54 (60 mg, 0.12 mmol) in dichloromethane (5 ml), and the I

reaction mixture was stirred at room temperature for 2 hours

perature. The mixture was partitioned between dichloromethane I

and 2N sodium hydroxide solution and the phases were added

. separation · The organic solution was evaporated under I

25 reduced pressure and the residue purified by column chromatography

silica gel with dichloromethane: metha I

nol: ammonia (s.d. = 0.88) (93: 7: 1) as eluant. The product was then purified by HPLC with

a 250 x 20 mm Chiracel OD column and methanol as the loop I

30, which is the title compound of example 73: I

1 H NMR (400 MHz, CDCl 3): δ = 1.60-2.30 (m, 9H), 2.55-2.81 I

(m, 4H), 2.96 (m, 2H), 3.13 (m, 1H), 3.38-3.98 (m, 7H), I

4.37 (m, 2H), 6.60 (dd, 1H), 6.66 (d, 1H), 7.32 (d, 1H), I

7.42-7.59 (m, 3H), 8.18 (m, 1H), I

APCI-MS: m / z = 516 [MNa] +, I

[α] D = -1.20 ° (c = 0.33, methanol), I

and the title compound of example 74:

1025527-1

189 X H NMR (400 MHz, CDCl 3): δ = 1.60-2.20 (m, 6H), 2.30 (s, 3H), 2.50-2.79 (m, 4H), 2, 96 (m, 2 H); 3.13 (m, 1H), 3.20-3.79 (m, 6H), 3.92. (m, 1 H), 4.37 (m, 2 H), 6.60 (dd, 1 H), 6.65. (d, 1H), 7.32 (d, 1H), 7.42-7.59 (m, 3H), 8.18 (m, 5H), APCI-MS: m / z = 516 [MNa ] +, [a] D = + 3.43 ° (c = 0.23, methanol).

Example 75: [8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3,5,10b- tetraazabenzo [e] azulene-5-yl] - ((2S) -1-methyl-pyrrolidin-2-yl) methanone

ic N — N

5-20 Cl. :

Formaldehyde (37% by weight in water, 0.1 ml), triethylami. ne (0.5 ml), acetic acid {0.5 ml) and sodium triacetoxyborohydride (135 mg, 0.63 mmol) were added to a suspension of the amine from Example 43 (175 mg, 0.32 mmol) in dichloromethane (10 ml), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was partitioned between dichloromethane (50 ml) and 2 N sodium hydroxide solution (50 ml), and the phases were separated. The organic solution was evaporated under reduced pressure and the residue purified by column chromatography on silica gel with dichloromethane: methanol: ammonia (sd = 0.88) (95: 5: 0.5) as eluant, yielding the title compound as a white foam (103 mg).

1 H NMR (400 MHz, CDCl 3): δ = 1.60-2.04 (m, 6H), 2.20-2.52 (m, 5H), 2.84-3.23 (m, 6H) , 3.60-4.46 (m, 4H), 5.50-5.85 1025527-

190 I

(m, 2H), 6.60 (dd, 1H), 6.66 (d, 1H), 7.38-7.48 (m, 2H), I

7.58-7.63 (m, 2H), 8.18 (m, 1H). I

APCI-MS: m / z = 492 [ΜΗ] 4 I

Examples 76 to 81: I

The following compounds with the general structure: I

N-n I

rvCCl rR11

KJ (Y I

Cl I

15. I

were prepared from the appropriate gminen and formaldehyde with I

using a procedure similar to that I

which was described in Example 75. I

1025527-1

191

"A f" I

Ex. no. · Yield Data (%) / form 76 9 | CHS 57 '1 H-NMR (400 MHz, CDCl 3): 6 = 1.56 - γν · .. white 2.40 (m, 11H), 2.83-3.28 (m, 6H), UV foam 3, 61-3.91 (m, 2H), 4.23-4.42 (m, -2H), 5.46-5 * 86 (m, 2H), 6.60 (dd, 1H), 6.66 (d, 1H), 7.37-7.50 (m, 2H), 7.57-7.63 (m, 2H), 8.18 (d, 1H). APCI-MS: m / fcs492 [MHf Microanalysis], found: C, 61.34; H, 6.23; N, 18.93 for C26 H30 ClN7.

0.25 CH 2 Cl 2 requires: C, 61.43; H, 5.99; N, 19.10.

77 * 77 29 · 1HNMR (400MHz, CDCl 3): δ * 1.58- / 1.19 (m, 2H), 2.03-2.38 (m, 4H),: 2j38-2, 60 (m, 4H), 2.70-3.19 (m, 4H), 3.20-3.45 (m, 1H), 3.63-4.98 (m, 6H), 5.00- 5.62 (m, 2H), 6.60 (0d, 1H), 6.66 (d, 1H), 7.38-7.56 (m, 2H), 7.59 (m, 2H). 8.18 (m, 1 H). i. APCI-MS: m / 2 + 492 [MH] +. T85 "Γ", 1 H NMR (400 MHz, CD 3 OD): δ * 1.64-2.02 (m, 8H), 2.25 (m, 2H), 2.58 (m, 1H), 2.85 (m, 4H), 3.18-3.60 (m, 3H), 3.80 (m, 1H), 3.98-4.70- (m, 4H), 4.82-5.78 ( m, 2H), 7.01 (m, 1H), 7.43 (d, 1H), 7.80 -. 7.95 (m, 3H), 7.98 (d, 1H), 8.04 (m, 1H), 8.20 (br s, 1H). · APCHMSm / 3506 [ΜΗΓ · 1025527-

192 I

5 79 59 59 PH NMR (400 MHz, CDCl 3): 6 * 1.42-1

2.38 (m, 11 H), 2.61 (m, 1 H), 2.77-1

7 ^ 3.18 (m, 5H), 3.14-4.82 (m, 6H), I

5.18-5.60 (m, 1H), 6.80 (dd, 1H), 1

6.60 (d, 1 H), 7. 38-7.52. (01, 2H), I

10. 7.58 (m, 2H), 8.18 (d ^ 1H). I

APChMS: m / 2 = 506 [MHf I

'.80 ~ Ö. : 54 54 1 H NMR (400 MHz, CDCl 3): δ * 1.58-1

I 2.42 (m, 7 H), 2.61-2.76 (m, 1 H), I

2.81-3.19 (m, 5H), 3.44-4.52 (m, I

15 H), 4.99-5.60 (m, 2H), 6.60 (dd, I

1 H), 6.60 (d, 1 H), 7.39 (dd, 1 H), I

7.45 (dd, 1H), 7.58 (m, 2H), 8.18 I

(m.1 H). . | I

APCHMS: m / 2 ≤ 508 [MHf I

81®, δ <j: Hs ", 62 ~", H-NMR (400MHz, CDCl3): δ = 1.62.

2.42 (m, 8H), 2.79-3.20 (m, 4H), I

J 3.35 (m, 1H), 3.59-3.97 (m, 6H), I

4.20-4.42 (m, 2H), 5.00-5.70 (m, I

2H), 6.59 (dd, 1H), 6.63 (d, 1H), I

7.36-7.45 (m, 2H), 7.58 (m, 2H), 1

8.16 (m, 1 H). I

ΑΡΟ-Μ £ ηι / ζ * 608 [MHf I

30 I

α reaction mixture stirred for 24 hours at karaoke temperature

nature. I

b-product treated with HCl in ether, which is the trihyd

hydrochloride salt.

35 I

102552 - I

193

Example 82: 8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2,3-bipyridinyl-4-yl) -4H, 6H-2,3,5flOb-tetraazabenzo [ e] azulene-5-yl] (tetrahydropyran-4-yl) -ethanone 5 - (- 1-Benzotriazol-1-yl) - (1 H-Benzotriazol-1-yl) - Ν, Ν, Ν ', N'-tetramethyluronium hexafluorophosphate (243 mg, 0.64 mmol) was added to a solution of tetrahydro-4-pyrancarboxylic acid (J. Med. Chem., 37 (26), 4549, 1994) (82 mg, 0.64 mmol) in dichloromethane (10 mL), and the solution was stirred for 30 minutes The amine from Example 4 (120 mg, 0.32 mmol) was added and the reaction mixture was added for 18 stirred for 1 hour at room temperature TLC analysis showed that starting material remained, so that additional 0 - (1H-benzotriazol-1-yl) -N, N, N ', N1-tetramethyluronium hexafluoro-phosphate (122 mg, 0.32) mmol) and tetrahydro-4-pyran-carboxylic acid (41 mg, 0.32 mmol) were added, and the reaction mixture was stirred for a further 24 hours.The mixture was partitioned between dichloromethane and saturated sodium bicarbonate aqueous solution, and the layers were separated. The organic phase was dried over magnesium sulfate and. evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel with difchloromethane: methanol: ammonia (s.d. = 0.88) (95: 5: 0.5) as eluant. to give the title compound as a white solid (105 mg).

X H NMR (400 MHz, CDCl 3): δ = 1.58-2.42 (m, 10H), 2.81 (m, 1H), 2.98-3.22 (m, 4H), 3.50 (m, 2H), 3.97-4.17 (m, 2H), 1025 52?

194 I

4.22-4.50 (m, 2H), 5.08-5.46 (m, 1H), 6.60-6.78 (m, 2H), I

7.40 (d, 1 H), 7.50-7.65 (m, 3 H), 8.20 (d, 1 H). I

APCI-MS: m / z = 493 [MH] + I

Example 83: [8-Chloro-1- (3,4,5,6-tetrahydro-2 H- [1,2 '] -1)

bipyridinyl-4-yl) -4H, 6H-2,3,5, 10b-tetra-1

azabenzo [e] azulene-5-yl] (1-methyl piperyl)

din-4-yl) methanone I

10 I

/ tx / “λ_ / τϊ ^ s * I

V I

. Cl I

O- (ΙΗ-Benzotriazol-1-yl) -N ^ / N '^ N'-tetramethyluro

Numhexafluorophosphate (395 mg, 1.04 mmol) was added I

to a solution of 1-methylpiperidine-4-carboxylic acid I

hydrochloride (210 mg, 1.04 mmol) in dichloromethane (10 L

ml) and the solution was stirred for 30 minutes. The I

amine from Example 4 (200 mg, 0.52 mmol) was added, I

25 and the reaction mixture was stirred at I for 18 hours

room temperature. The mixture was washed with sodium I

aqueous carbonate solution and the organic solution

dried on magnesium sulfate. The solution was evaporated I

purified under reduced pressure and the crude product I

30 by column chromatography on silica gel with ethyl acetate

tate: methanol: ammonia (s.d. = 0.88) (90: 10: 1) as eluant

del, yielding the title compound as a white solid (195 mg).

APCI-MS: m / z = 506 [MH] + I

35 I

1025527-1

.., 195

Example 84: [8-Chloro-5- (1-methylazetidin-3-yl] -1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -5.6 dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene 5 N-N.

cl Formaldehyde (37% in water, 0.1 ral), triethylamine (0.5 ml), acetic acid (0.5 ml) and sodium triacetoxyborohydride (75 mg, 0.36 mmol) were added to a suspension of the amine from Example 55 (77 mg, 0.18 mmol) in dichloromethane (10 ml), and the reaction mixture was stirred at room temperature for 3 hours. The mixture was partitioned between dichloromethane and 2N sodium hydroxide solution and the phases were separated. The aqueous layer was extracted with more dichloromethane and the combined organic solutions were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with dichloromethane: methanol: ammonia (sd = 0.88) (95: 5: 0.5) as eluant to give the title compound as a white foam (72 mg), 1 H- NMR (400 MHz, CDCl3): δ = 1.79-2.21 (m, 4H), 2.40 (s, 3H), 2.83-3.78 (m, 12H), 4.34 ( m, 2H), 6.60 (dd, 1H), 6.66 (d, 1H), 7.34 (d, 1H), 7.42-7.58 (m, 3H), 8.18 (d 1 H). APCI-MS: m / z = 450 [MH] + 35 1025527-

196 I

Examples 85 to 88: I

The following compounds with the general structure:

5 n-N I

(Γ \ N — R1 I

W I

10 ° I

were prepared from the appropriate amines and aldehydes or ketones

by following a similar procedure I

to that described in Example 84. I

I

| ex. no. | R ’I Proceeds! "Data Ί I

(%) / form I

85 "^ 62" 1 H NMR (400 MHz, CDCl 3): 6 * 0.95 L

White (d, 6H), 1.78-2.40 (r11, 5H), 2.86-1

Ch3, I

foam 3/60 (m, 12H), 4.36 (m, 2H), 6.60 I

(dd, 1H), 6.65 (d, 1H), 7.34 (d, 1H), I

. 7.44 (m, 2H), 7.53 (d, 1H). 8.18 (d, I

1H). I

APChMS: m / 478 [MH] + I

86 ^ 1 29 1 H-NMR (400 MHz, CDCl 3): 5 * 1760-1

2.08 (m, 8 H), 2.25 (s, 3 H), 2.51 (m, 1)

1 H), 2.80-3.01 (m, 4 H), 3.17 (m, I

1 H), 3.40-3.96 (m, 6 H), 4.36 (m, I

2H). 6.60 (m, 1 H), 6.66 (d, 1 H), I

7/30 (d, 1 H), 7.41-7.58 (m, 3 H), I

8.18 (d, 1H). I

APCI-MSvm / * 478 [MHf I

102552? I

197

87 / - 32 N NMR (400 MHz, CDCl 3): 6-1.10 (t, I

3 H), 1.54-2.10 (m.8 H). 2.40 (k, 2H), 2/54 (m, 1H), 2.76-3.03 (m, 6M), 3.17 (m, 1H), 3.42-4.96 (m, 4H) , 4.36 (m, 2H), 6.60 (m, 1H),> 6.66 (d, 1H), 7.30 (d, 1H), 7.41-7.58 (m, 3H) , 8.18 (d, 1H). APCHV! S * "/ 7Vfc492 [MHf 88" ^ "H". 30'H NMR (400MHz, CDCl3): 5-1.10. H (d, 6H), 1.72-2.38 (m, 8H), 2.58 (m, 1H); 2.78-3.03 (m, 7H), 3.14 (m, 1H), 3.38-4.00 (m, 4H), 4.36 (m.

2 H), 6.60 (m, 1 H), 6.66 (d, 1 H), 7.30 (d, 1 H), 7.41-7.58 (m, 3 H), 8.18 (d, 1 H) ).

APCHVIS: m / z * 628 [MNaf 1025527-

198 I

Example 89: 8-Chloro-5- (1-methylpyrrolidin-3-yl) -1-I

(3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-I

yl) -5,6-dihydro-4H-2,3,5,10b tetrazabenzo

5 [e] azulene I

N-N I

n λ AVCH8 I

α I

I

Formaldehyde (18 μΐ, 37% by weight aqueous solution, 0.22 l

mmol) and sodium triacetoxyborohydride (47 mg, .0.22 mmol) I

were added to a solution of the amine from I

Example 56 (100 mg, 0.22 mmol) in dichloromethane (5 L

20 ml), and the reaction mixture was stirred for 30 minutes

at room temperature. Saturated sodium bicarbonate

aqueous solution (10 ml) was added, the mixing

The mixture was vigorously stirred for 10 minutes and the layers were washed

separated. The organic layer was evaporated under evaporation

25 pressure and the residue purified by column chromatography

graph over silica gel with dichloromethane. methanol: ammonia I

(s.d. = 0.88) (95: 5: 0.5) as eluant. The product was

azeotropically evaporated from ether to give the title compound

(60 mg). I

1 H-NMR (400 MHz, CDCl 3): δ = 1.74-2.30 (m, 8H), 2.34 (s, I

3 H), 2.45 (s, 1 H), 2.5.7 (d, 1 H), 2.66 (d, 1 H), 2.80 (t,

1 H), 2.93 (s, 2 H), 3.12 (t, 1 H), 3.23 (t, 1 H), 3.48 (s, I

2H), 4.33 (s, 2H), 6.60 (t, 1H), 6.64 (d, 1H), 7.32 (d, I

1 H), 7.45 (t, 1 H), 7.52 (m, 2 H), 8.15 (d, 1 H). I

APCI-MS: m / z = 564 [MH] + I

r 025 52 Ti ~ I

199

Example 90: 8-Chloro-5- (1-isopropylpyrrolidin-3-yl) -1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -5,6 -dihydro-4H-2,3,5,10b-tetraazabenzo [e] azuline trihydrochloride 5 '

Qr ^ AJ ^ j

II

,. . 3 HCl

Acetone (0.1 ml) and sodium triacetoxyborohydride (47 mg, 0.22 mmol) were added to a solution of the amine from Example 56 (100 mg, 0.22 mmol) in dichloromethane (5 ml). ), and the reaction mixture was stirred at room temperature for 16 hours. Saturated sodium bicarbonate aqueous solution (10 ml) was added, the mixture stirred vigorously for 10 minutes, and the layers were separated. The organic layer was evaporated under reduced pressure and the residue purified by column chromatography on silica gel with dichloromethane: methanol: ammonia (s.d. = 0.88) (95: 5: 0.5) as a loosening agent. The product was treated with hydrochloric acid in ether to give the title compound. .

1 H NMR (400 MHz, CD3 OD): δ = 1.43 (d, 6H), 1.85-2.70 (m, 4H), 3.35-4.85 (m, 17H), 7.02 (t, 1H), 7.47 (d, 1H.), 7.80-30 7.92 (m, 2H), 7.97 (d, 2H), 8.06 (t, 1H).

APCI-MS: m / z = 492 [MH] +

Example 91: 2- [8-Chloro-1- (1-pyrimidin-2-yl-piperidin-4-yl) -4H, 6H-2,3,5,110b-tetraazabenzo-35 [e] azulene-5- yl] ethanol 1025527-

200 I

10 Ν, Ν-Diisopropylethylamine (80 μΐ, 0.62 iranol), I

followed by 2-chloroethanol (52 μΐ, 0.78 mmol), added

added to a solution of the amine from Example 12

(200 mg, 0.52 ml) in N, N-dimethylformamide (6 ml), and I

the reaction mixture was stirred at room temperature for 18 hours

15 mt temperature. The mixture was concentrated under v

reduced pressure and the residue purified by column chromatography

graph over silica gel with ethyl acetate: methanol: ammonia

(s.d. = 0.88) (90: 10: 1) as eluant, which is the title I

compound as an off-white solid (120 mg) I

20 gave. I

1 H NMR (400 MHz, CDCl 3): δ -1, 62-2.22 (m, 3H), 2.62 (m, 1

1 H), 2.84 (m, 2 H), 3.00 (m, 2 H), 3.18 (m, 1 H), 3.38-3.90 I

(m, 6H), 4.80 (m, 2H), 6.46 (m, 1H), 7.38 (d, 1H), 7.58 I

(m, 2H), 8.30 (s, 2H). I

APCI-MS: m / z = 462 [MH] + I

Example 92: 8-Chloro-5- (2-methoxyethyl) -1- (1-pyrimi)

dine-2-yl-piperidin-4-yl) -5,6-dihydro-4 H -1

2,3,5,10b-tetraazabenzo [e] azulene

30 I

35. "I

1025527-1

201 Ν, Ν-Diisopropylethylamine (80 μΐ, 0.62 nmole), followed by 2-bromomethoxyethane (0.2 ml, 0.62 mmol), were added to a solution of the amine from Example 12 (200 mg, 0.52 mmol) in N, N-dimethylformamide (6 ml) and the reaction mixture was kept for. Stirred for 18 hours at 80 ° C. The mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel with ethyl acetate: methanol: ammonia (sd = 0.88) (95: 5: 0.5) to give the title compound as a gum (76 mg) .

1 H NMR (400 MHz, CDCl 3): δ 1.84-2.16 (m, 4H), 2.78-3.20 (m, 5H), 3.20-4.50 (m, 9H) , 4.80 (m, 2H), 6.48 (dd, 1H), 7.32 (d, 1H), 7.58 (m, 2H), 8.30 (d, 2H).

APCI-MS: m / z = 462 [MNa] +

Example 93: 8-Chloro-5-pyrimidin-2-yl-1- (3,4,5,6-tetrahydro-2H- [-1,2 '' ') bipyridinyl-4-yl) -5,6- dihydro-4H-2,3,5,10b-tetraazabenzo [e] -20 azulene

n — N

α · 30

A mixture of the amine from Example 4 (200 mg, 0.53 mmol), 2-chloropyrimidine (66 mg, 0.58 mmol) and potassium carbonate (72 mg, 0.53 mmol) in N, N-dimethylformamide (5 ml) was stirred at room temperature for 18 hours. TLC analysis showed that starting materials remained, so that additional 2-chloropyrimidine (66 mg, 0.58 mmol) was added and the reaction mixture was kept for an additional 72 hours.

202 I

stirred at 80 ° C. The cooled mixture was evaporated

of the reduced pressure, the residue partitioned between ethyl acetate

tate and concentrated saline and the layers were l

separated. The organic layer was washed with water, I

5 washed with ammonium chloride solution, dried on magnet

sulphate and then evaporated under reduced I

pressure. The remaining yellow oil was purified by column I

chromatography on silica gel with dichloromethane: methanol I

(95: 5) as eluant, which gives the title compound as an I

10 yellow oil (117 mg). I

1 H NMR (400 MHz, CDCl 3): δ = 1.61-2.40 (m, 4H), 2.82-3.19 I

(m, 3H), 3.63-4.48 (m, 4H), 5.60-5.84 (m, 2H), - 6.60 (m, I

2H), 6.66 (d, 1Hj, 7.40 (d, 1H), 7.43 (m, 1H), 7.52 (m, I

1 H), 7.60 (s, 1 H), 8.16 (m, 1 H), 8.38 (d, 2 H). I

APCI-MS: m / z = 459 [MH] + I

Example 94: 8-Chloro-5-pyrimidin-4-yl-1- (3,4,5,6-I

tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -5,6-I

dihydro-4H-2,3,5,10b-tetraazabenzo [e] -1

Azulene

N-N I

l / / n == \ I

α I

30 I

A mixture of the amine from Example 4 (500 mg, I

1.3 mmol), potassium carbonate (480 mg, 3.5 mmol) and 4- I

chloropyrimidine (300 mg, 2.6 mmol) was I for 18 hours

stirred at 95 ° C. The cooled reaction mixture was diluted I

35 with ethyl acetate and the solution washed with concentrate

salt solution (5x), then dried on magnet

sodium sulfate and concentrated under reduced pressure. The I

1 0255.2 - I

203 crude product was purified by column chromatography on silica gel with dichloromethane: methanol (100: 0 to 95: 5) as eluant and the product, triturated with diethyl ether to give the title compound (80 mg) - 5 th.

1 H NMR (4.00 MHz, CDCl 3): δ - 1.80-2.24 (m, 4H), 2.97 (m, 2H), 3.18 (m, 1H), 3.90-4, 43 (m, 4H), 5.20-5.80 (m, 2H) :, 6.56 (d, 1H), 6.60 (m, 1H), 6.66 (d, 1H), 7.42 ( m, 2H), 7.57 (d, 1H), 7.62 (s, 1H), 8.18 (m, 1H), 8.32 (d, 1H), 8.70 (s, 1H).

APCI-MS: m / z = 459 [MH] +

Example 95: 8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3,5,10b-tetra- Azabenzo [e] azulene-5-carbaldehyde

n — N

c \ 25

A solution of the amine from Example 4 (300 mg, 0.79 mmol) in formic acid (15 ml) was stirred at 80 ° C for 3 hours. The cooled mixture was concentrated under reduced pressure. and the residue partitioned between ethyl acetate and sodium bicarbonate solution. The layers were. and the organic phase was evaporated under reduced pressure to give the title compound.

1 H-NMR (400 MHz, CDCl 3): δ 1.60-2.42 (m, 4H), 2.98-3.24 (m, 3H), 3.78-4.58 (m, 5H ), 5.43 (m, 1 H), 6.62 (m, 1 H), 6.75 (m, 1 H), 7.40 (m, 1 H), 7.55 (m, 1 H), 7, 60 (d, 1H), 8.18 (m, 1H), 8.21 (d, 1H).

APCI-MS: m / z - 409 [MH] + 1025527-

204 I

Example 96: 8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] -1

bipyridinyl-4-yl) -4H, 6H-2,3,5, 10b-tetra-1

azabenzo [e] azulene-5-sulfonic acid dimethyl-I

5 amide I

N-N I

CH "I"

i °. xX B 'ch, I

α I

I

Dimethylsulfamoyl chloride (0.12 ml, 1.08 mmol) became I

added to a solution of the amine from Example 4 I.

(140 mg, 0.36 mmol) and pyridine (90 μΐ, 1.08 mmol) in I

dichloromethane (8 ml), and the reaction mixture was diluted

Stirred at room temperature for 18 hours. TLC analysis I

showed that starting material remained, so that additional di

methyl sulfamoyl chloride (0.08 ml, 0.72 mmol) was added

and the mixture was stirred for an additional 24 hours. I

The mixture was washed with saturated sodium bicarbonate

25 aqueous solution, dried over magnesium sulfate and I

evaporated under reduced pressure. The crude product I

was purified by column chromatography on silica gel with I

dichloromethane / methanol: ammonia (s.d. = 0.88) (95: 5: 0.5) I

as eluant, giving the title compound as a bleaching agent

Yielded yellow gum (120 mg). I

1 H NMR (400 MHz, CDCl 3): δ «1.58-1.94 (m, 2H), 2.10-2.40 I

(m, 2H), 2.78-3.02 (m, 8H), 3.15 (m, 1H), 3.62-4.00 (m, I

2H), 4.21-4.97 (m, 4H), 6.60 (dd, 1H), 6.67 (d, 1H), 7.39 I

(d, 1H), 7.47 (dd, 1H), 7.59 (d, 1H), 7.62 (s, 1H), 8.19 I

35 (d, 1 H). I

APCI-MS: m / z - 488 [MH) + I

1025527-1

.205

Example 97: 8-Chloro-5-pyridine-2-ylniethyl-1- (1-pyrimidin-2-ylpiperidin-4-yl) -5,6-dihydro-4H-2,3,5,10b-tetraazabenzo [e ] -5 azulene 10-15

Sodium triacetoxyborohydride (277 mg, 1.31 mmol) was added to a mixture of the amine from Example 12 (250 mg, 0.65 mmol), 2-pyridinecarboxaldehyde (105 mg, 0.98 mmol) and acetic acid (3 drops) in dichloromethane (5 ml), cooled to 5 ° C and the reaction mixture then for 18 hours. stirred at room temperature. Ammonia (s.d. = 0.88) was added to the reaction mixture, the phases were separated, the organic layer was dried over magnesium sulfate and evaporated under reduced pressure.

The crude product was purified by column chromatography on silica gel with dichloromethane imethanol (95: 5) as eluant to give the title compound (167 mg). verde.

X H NMR (400 MHz, CDCl 3): δ - 1.78-2.26 (m, 4H), 3.00, 3.18 (2xm, 4H), 3.35-3.60, 3.80 -3.98 (2xm, 5H), 4.80 (m, 2H), 6.48 (dd, 1H), 7.22 (m, 1H), 7.37 (d, 1H), 7.53 ( m, 3 H) ,.

7.75 (m, 1 H), 8.30 (s, 2 H), 8.60 (d, 1 H).

APCI-MS: m / z = 473 [MH] +? 0255.27- "" - · ". . . "i

206 I

Examples 98 and 99: I

The following compounds with the general structure: I

C ^ v ^ X. I

10 Cl

were prepared from the appropriate amines by a procedure I

to follow that was similar to that. which was I

15 wrote in example 97. I

Ex. no. R1 "1 Data ~" "I

g 8 "1 H-NMR (4 -0MH 2, CDCl 3): $ F1 * 79-2, j2 (m, 4H), 1

2Q h - 3.00 (m, 2H), 3.18 (m, 1H), 3.26-3.64 (m, 3H), I

4.06 (m, 3H), 4.65-5.00 (m, 3H), '6.45 (s, 1 Η). I

7.36 (m, 3H), 7.50 (s, 1H), 7, §8 (d, 1H), 8.28 (d, I

2H). I

APCPMS / rafe479 [MH] + I

- 1Γ ’H-NMR (400MHz, CDCU): 6 * 1.75-2.25 (m. 4H), I

2.99 (m, 2H), 3.18 (m, 1H), 3.20-4.06 (m, 6H),. I

4.79 (m. 2H), 6.33 (s, 1H), 6.45 (m, 1H), 7.35 (d, I

1 H), 7.52 (m, 3 H), 8.26 (m, 2 H). I

APCPMSm / z ^ [MHf I

..... 11. 11 i - '' ^ 1— i | i i i | | ii i <............ · *

1 025527-1

207

Example 100: 8-Chloro-1- (1-pyrimidin-1-piperidin-1-yl) -H, 6H-2,3,5,10b-tetraazabenzo [e] azulene-S-sulfonic acid dimethylamide 5, N, y N - / Γ ~ \ / **% 10 / ° CH,

Cl 15 N, N-Diisopropylethylamine (77 μΐ, 0.44 mmol), followed by dimethylsulfamoyl chloride (50 μΐ, 0.44 rumol), was added to an ice-cooled solution of the amine from Example 12 (150 mg, 0 , 4 mmol) in dichloromethane (10 ml) and the reaction mixture was stirred at room temperature for 4 hours. TLC analysis showed that starting material remained, so that additional dimethylsulfamoyl chloride (91 μΐ, 0.8 mmol) and N, N-diisopropylethylamine (140 μΐ, 0.8 mmol) were added, and the mixture was stirred for a further 18 hours at room temperature . The mixture was evaporated under reduced pressure, the residue partitioned between dichloromethane and aqueous sodium bicarbonate solution, the layers were separated and the organic phase was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel with dichloromethane: methanol: ammonia (s.d. = 0.88) (95: 5: 0.5).

as eluant, yielding the title compound as an off-white solid (135 mg).

X H NMR (400 MHz / CDCl 3): δ = 1.58-1.89 (m, 2H), 2.16-2.35 (m, 2H), 2.83-3.19 (m, 9H 3.63-3.99 (m, 2H), 4.59-4.97. 35 (m, 4H), 6.50 (dd, 1H), 7.38 (d, 1H), 7.59 (d, 1H), 7.63 (s, 1H), 8.30 (d, 2H) ).

APCI-MS: m / z = 489 [MH] +. .

1025527-

208 I

Example 101: 8-Chloro-5-methyl-1- (3,4,5,6-tetrahydro-2H-1

[1,2 '] bipyridinyl-4-yl) -4,5-dihydro-1

2,3,5,10b-tetraazabenzote] azulene-6-one I

fi - N r - v I

X_j ^^ V_Z— ^ JL I

10) = / ^ I

α

Acetic acid (2 drops) was added to a solution of the amine from preparation 62 (250 mg, 0.59 inmol) in toluene (6 ml), and the reaction mixture was kept for 3 hours

stirred under reflux. The cooled mixture was I

purified directly by column chromatography on silica

cagel with ethyl acetate: dichloromethane: methanol (100: 0: 0 I

20 to 0: 95: 5) as eluant. The product became azeotropic I

evaporated from dichloromethane (2x10 ml) and ether (4x10 l

ml), giving the title compound as a white foam (151 l

mg). I

1 H NMR (400 MHz, DMS0d6): δ = 1.45 (m, 2H), 1.92 (m, 2H), I

25 2.74 (m, 1H), 2.85-3.35 (m, 5H), 4.10, (m, 1H), 4.32-4.60 I

(m, 3H), 6.51 (m, 1H), 6.74 (d, 1H), 7.42 (m, 1H), 7.61-1

7.84 (m, 3H), 8.00 (s, 1H). I

APCI-MS: m / z = 409 [MH) + I

Example 102: 13-Chloro-9-methyl-3- (3,4,5,6-tetrahydro-1)

2H- [1,2 '] bipyridinyl-4-yl) -2,4,5,9-tetra-1

azatricyclo [9.4.0.0 * 2.6 *] pentadeca-1 (11), I

3,5,12,14-pentaene I

35 I

1025527 I

209 A mixture of the compound from preparation 80 (140 mg, 0.55 mmol) and the hydrazide from preparation 1 (121 mg, 0.55 mmol) in ethanol (2 ml) was heated under reflux for 23 hours and then allowed to cool. The mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel with an elution gradient of dichloromethane: methanol: ammonia (s.d. «0.88) (100: 0: 0 to 90: 10: 1). The product was dissolved in dichloromethane (6 ml), the solution treated with polymer-bound isocyanate (0.6 g, 1.5 mmol / g) and the mixture stirred for 1 hour. The mixture was filtered and the filtrate evaporated under reduced pressure to give the title compound (57 mg).

X H NMR (400 MHz, CDCl 3): δ = 1.42 (m, 1 H), 1.63 (m, 1 H), 2.18 (m, 1 H), 2.30 (m, 2 H), 2 , 42 (s, 3H), 2.78 (m, 2H), 2.83-3.05 (m, 3H), 3.18 (m, 2H), 3.61 (d, 1H), 4, 18 (m, 1 H), 4.39 (m, 1 H), 6.58 (m, 1 H), 6.62 (d, 1 H)> 7.19 (d, 1 H), 7.42 (m, 2 H), 7.52 (s, 1 H), 8.14 (m, 1 H).

APCI-MS: m / z = 409 [MH] + 30

Example 103: 13-Chloro-8-methyl-3- (1-pyrimidin-2-yl-piperidin-4-yl) -2,4,5,8-tetraazatricyclo- [9.4.0.0 * 2.6 *] pentadeca -1 (11)., 3,5,12,14-pentaene 35 1025527-

210 I

/ 7 ~~ \ r --- ν Ν I

(2Υλ ~} - <3. I

5 I

CT I

10 I

Trifluoroacetic acid (1.5 ml) was added to one. I

solution of the compound from preparation 63 (1.60 g, 3.72 l

mmol) in toluene (100 ml) and the mixture was added for 24 l

stirred at 60 ° C. The cooled mixture was concentrated

15 under reduced pressure and the residue partitioned between I

dichloromethane and sodium bicarbonate solution. The la-I

were separated, the organic layer was dried on I

magnesium sulfate and evaporated under reduced pressure. The I

residual oil was purified by column chromatography I

20 over silica gel with dichloromethane: methanol (95: 5) as I

eluent. The product was suspended in dichloromethane

thane (100 ml) and treated with activated carbon. The I

mixture was filtered, the filtrate evaporated under I

reduced pressure and the residue purified by column chromatography

25 about photography. silica gel with dichloromethane: methanol I

(96: 4) as eluant, it does not have the title compound as an I

oil (469 mg). I

1 H NMR (400 MHz, CDCl 3): δ = 1.42 (m, 1H), 1.62 (m, 1H), 1

2.18 (m, 1 H), 2.25 (m, 2 H), 2.42 (s, 3 H), 2.60 (m, 1 H), I

30 2.80 (m, 2H), 2.93-3.01 (m, 2H), 3.28 (m, 2H), 4.20 (d, I

1 H), 4.60 (m, 1 H), 4.86 (m, 1 H), 6.45 (dd, 1 H), 7.18 (d, I

1 H), 7.40 (d, 2 H), 8.27 (d, 2 H). . I

APCI-MS: m / z = 410 '[MH] + I

Example 104: 8-Chloro-5,6-dimethyl-1- (1-pyrimidin-2-yl-1)

piperidin-4-yl) -5,6-dihydro-4 H -2,3,5,10b -1

tetraazabenzo [e] azulene I

1025527-1

21.1 ...

5 CHa α

Trifluoroacetic acid (0.5 ml) was added to a solution of the compound from preparation 64 (0.9 g, 2.10 inmol) in toluene (10 ml), and the reaction mixture was stirred at 100 ° C for 18 hours. The cooled mixture was washed with sodium bicarbonate solution and concentrated saline and then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with dichloromethane: methanol (95: 5) as eluant to give the title compound as a white foam (530 mg).

X H NMR (400 MHz, C 2 D 2 Cl 4, at 373K): δ = 1.23 (d, 3H), 1.82 (m, 2H), 2.03 (m, 2H), 2.40 (s, 3H ), 3.01-3.19 (m, 3H), 3.29 (m, 1H), 3.49 (m, 1H), 3.63 (m, 1H), 4.64 (m, 1H) , 4.78 (m, 1 H), 6.42 (m, 1 H), 7.24 (d, 1 H), 7.50 (m, 2 H), 8.26 (d, 2 H).

APCI-MS: m / z = 432 [MNa] + 25

Example 105: 1- (3-, 4,5,6-Tetrahydro-2H- [1,2'-pyridin-4-yl) -8-trifluoromethyl-4H, 6H-5-oxa-2,3,10b-triazabenzo (e) azulene 30 '.35 1025527-

212 I

Sodium hydride (81 mg, 60% dispersion in mineral I

oil, 2.03 mmol) was added to an ice-cooled I

solution of 2-amino-5-trifluoromethylphenylmethanol (WO I

99/05147, p. 60) (350 mg, 1.8 mmol) in tetrahydrofuran I

5 (20 ml), and the solution was stirred for 30 minutes

at 0 ° C. A solution of the chloride from preparation 5 l

(560 mg, 2.0 mmol) in tetrahydrofuran (10 ml) was added dropwise

added one by one and as soon as the addition was complete I

The reaction mixture was stirred at room temperature for 5 hours

10 temperature. The reaction was quenched with water (2 ml) I

and the mixture partitioned between dichloromethane and sodium I

bicarbonate solution. The layers were separated, the organ

The technical phase was dried over magnesium sulfate and evaporated

under reduced pressure. The crude product was purified

Diluted by column chromatography on silica gel with dichloro-I

methane: methanol: ammonia (s.d. = 0.88) (95: 5: 0.5) as I

eluent, yielding white solid (560 mg). I

A mixture of this solid in xylene (20 ml) and p-l

toluene sulfonic acid (40 mg) was stirred for 18 hours I

20 at 140 ° C. The cooled solution was evaporated under evaporation

reduced pressure and the residue purified by column chromatography

graph over silica gel with ethyl acetate: methanol: ammonia I

(s.d. = 0.88) (97: 3: 0.3 to 90: 10: 1) as eluant, i.e.

none the title compound as a pale yellow solid (210 L

25 mg). I

1 H NMR (400 MHz, MeOD): δ = 1.98 (m, 4H), 2.98 (m, 2H), I

3.41 (m, 1H), 4.37 (m, 2H), 4.57 (s, 2H), 4.61 (s, 2H), I

6.64 (m, 1H), 6.63 (d, 1H), 7.58 (m, 1H), 7.98 (d, 1H), I

8.03 (m, 3 H). I

APCI-MS: m / z = 416 [MH] + I

Example 106: 10-Chloro-1- (3,4,5,6-tetrahydro-2 H - [1.21] -1

bipyridinyl-4-yl) -6,7-dihydro-4H-5,8-dioxa-1

2,3,12b-triazabenzo [a] cyclopenta [c] cycloil

35 noneen I

102552 - I

213 °.

A mixture of the compound from preparation 61 (250 mg, 0.58 mmol) and p-toluenesulfonic acid (cat.) In xylene (75 ml) was stirred for 24 hours at 140 ° C. The cooled mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel with dichloromethane: methanol: ammonia. (sd = 0.88) (95: 5: 0.5) as eluant, and again purified with ethyl acetate: methanol: ammonia (sd = 0.88) (95: 5: 0.5 to 90: 10: 1) ) as eluant, yielding the title compound as a whitened foam (42 mg).

1 H NMR (400 MHz, MeOD): δ 1.30 (m, 2H), 2.04 (m, 2H), 2.74-2.98 (m, 3H), 3.70 (m, 1 H), 3.81 (m, 1 H), 4.19 (m, 3 H), 4.37 (m, 1 H), 4.50 (m, 1 H), 4.78 (m, 1 H), 6, 62 (m, 1H), 6.82 (d, 1H), 7.36 (m, 1H), 7.48 (m, 2H), 7.58 (m, 1H.), 8.02 (m, 1H).

APCI-MS: m / z = 412 [MH] +

Example 107: 8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2'-bipyridinyl-4-yl) -4H, 6H-5-thia-2,3,10b -triazabenzo [e] azulene 30 · ν-λ__ II / \ tr $.

Cl 102552?

214 I

To a solution of the thioamide of preparation 87 l

(581 mg, 2.53 inmol) in butan-1-ol (20 ml) became the hydra-l

1 of preparation 1 (557 mg, 2.53 inmol) was added, and I

the mixture was heated to 100 ° C for 20 hours. The I

The reaction mixture was evaporated under reduced pressure and I

the residue purified by silica gel column chromatography

gel with dichloromethane: methanol (95: 5) as eluant, I

which is the title compound as an off-white foam I

(825 mg). I

10 1 H NMR (40 6 MHz, CDCl 3): δ = 1.60 (m, 1 H), 1.65 (m, 1 H), 1

2.20 (m, 1 H), 2.40 (m, 1 H), 2.80 (m, 1 H), 3.00 (m, 2 H), I

3.40 (d, 1H), 3.60 (m, 2H), 4.00 (d, 1H), 4.20 (d, 1H), I

4.40 (d, 1H), 6.60 (dd, 1H), 6.65 (d, 1H), 7.25 (d, 1H), I

7.45 (m, 3 H), 8.20 (d, 1 H). I

APCI-MS: m / z ≤ 398 [MH] + I

Example 108: 8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] -1

bipyridinyl-4-yl) -4H, 6H-5-thia-2,3,10b -1

triazabenzo [e] azulene-5-oxide I

20 I

^ I

25 '

Cl I

To a solution of the sulfide of Example 107 I

(150 mg, 0.38 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol I

(5 ml) was added to a 30% solution of hydrogen peroxide

water (0.09 ml) added. The resulting reaction mixture I

was stirred at room temperature for 1 hour before I

It was partitioned with sodium sulfite in water. The organization I

layer was washed with concentrated saline, I

dried (MgSO 4), filtered and evaporated. The result I

1025527-. I

215 residue was purified by column chromatography on silica gel with dichloromethane: methanol ammonia (sd = 0.88) (95: 5: 0.5) as eluant, yielding the title compound as an off-white foam (6.4 mg) .

5. 1 H NMR (400 MHz, CDCl 3): δ - 1.55 (m, 1 H), 1.75 (m, 1 H), 2.20 (m, 1 H), 2.30 (m, 1 H), 2.82 (m, 1H), 3.03 (m, 2H), 3.18 (d, 1H), 3.28 (d, 1H), 3.90 (d, 1H), 4.22 (m (1 H), 4.42 (m, 1 H), 5.02 (d, 1 H), 6.60 (dd, 1 H), 6.65 (d, 1 H), 7.40 (d, 1 H), 7 45 (t, 1H), 7.60 (m, 2H), 8.18 (d, 1H).

10 'APCI-MS: m / z = 436 [MH] +

Example 109: 8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] - bipyridinyl-4-yl) -4H, 6H-5-thia-2,3,10b- triazabenzo [e] azulene-5,5-dioxide 15

k. * - N

20

Cl To a solution of the sulfide of Example 107 (150 mg, 0.38 mmol) in 1,1,1-trifluoroacetic acid (5 mL) was added a 30% aqueous hydrogen peroxide (0.09 mL) solution. The resulting reaction mixture was stirred at room temperature for 1 hour before being diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (2 x, 50 ml). The organic layer was washed with brine, dried (MgSO 4), filtered and evaporated to give the title compound as an off-white solid (108 mg).

1 H NMR (400 MHz, CDCl 3): δ = 1.80 (m, 1 H), 2.20 (m, 1 H), 2.30 (m, 1 H), 2.82 (m, 1 H), 3, 03 (m, 2H), 3.95 (d, 1H), .1025527-

216 I

4.10 (m, 2H), 4.25 (m, 1H), 4.40 (m, 1H), 4.80 (dd, 1H), I

6.65 (m, 2H), 7.405 (m, 2H), 7.70 (m, 2H), 8.20 (d, 1H). I

APCI-MS: m / z = 452 [MH] + I

Example 110: I

Examples of specific compounds that were I

tested in study 1.0 (ViA filter binding assay) as hereinafter

described above are given as explanations in the chapter

the table below. I

10

Example no. Ki (nM) __ I

5, 4.66

_6__2.37_. I

8 2.47

11__0.68 I

13_ 13.86_I

15 4.71

_24_ 1.00_ I

27_ 1.25_I

38 ___ 4.63 __ I

_59_ 1.32_I

73 & 74 6.84 & 6.02 I

. 93 I, 2.33, I

96_ 0.24 I

100_ 0.77_ I

102 _4.16 _ I

103. 2.02 I

1025527-1

Claims (20)

A compound of formula (I), c. NN rvd) * η ar ^ \ - / W x 20 (I) or a pharmaceutically acceptable derivative thereof, wherein V represents - (CH 2) d (0) e ~ , -CO- or -CH (C 1-6 alkyl) -, W is -0-, -S (O) a- or -N (R1) -, R1 represents H, O6-6 alkyl, (CH2) bCOR2, CO (CH2) bNR2R3, SO2R2, (CH2) cOR2, ( CH2) cNR2R3 or (CH4bhet1), it represents a saturated or unsaturated, hetero ring with 3 to 8 atoms containing one or more heteroatoms selected from 0, N or S and optionally substituted with C1-6 alkyl , X and Y independently represent H, C 1-6 alkyl, halogen, OH, CF 3, OCF 3, OR 4, Z represents - (CH 2) f (O) g-, -CO- or -CH (C 1-6 alkyl) -, Ring A represents a 4-7-membered, saturated hetero ring containing N, optionally substituted with OH, and 1025527 Η 218 where optionally at least one ring-N is substituted with O, Ring B represents a phenyl or a 4-7-unsaturated heterocycle containing N, optionally substituted with OH, halogen, CN, CONH2, CF3 , OCF 3, and in which optionally I at least one ring-N is substituted with O, R 2 and R 3 independently represent H, C 1-6 alkyl [optionally substituted with OH, halogen, N (C 1-6 alkyl) 2 or C 1-6 16 alkyloxy], C 1-6 alkyloxy, N (C 1-6 alkyl) 2 or [C 3-6 cycloalkyl], I or R 2 and R 3, together with the nitrogen atom to which they are attached, independently represent a heterocycle I with 3 to 8 atoms, optionally substituted with C 1-6 alkyl, I A compound according to claim 1, wherein W represents NR1. I A compound according to claim 1 or claim 2, wherein R 1 represents H, C 1-6 alkyl, - (CH 2) b COR 2 or SO 2 R 2. I A compound according to any one of claims 1-3, wherein R 1 is methyl. I 5 I X Y I (V) I A compound according to claim 1 or claim 2, wherein R 2 is morpholinyl or pyrimidinyl (optionally substituted with C 1-6 alkyl [optionally substituted with OH, halogen, N (C 1-6 alkyl) 2 or C 1-6 alkyloxy] or NMe 2). I A compound according to any preceding claim, wherein X is H. I A compound according to any preceding claim, wherein Y is in the 4 position of the phenylene ring (according to the I numbering of formula (I)) to which it is bound I. I 8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3,5,110-tetraazabenzo [e] azulene -5-sulfonic acid dimethylamide, 1- 8-chloro-1- (1-pyrimidin-2-yl-piperidin-4-yl) -4 H, 6 H -1,3,5, 10b-tetraazabenzo [e] azulene-5 -sulfonic acid-dimethylamide, I (15) 13-Chloro-9-methyl-3- (3,4,5,6-tetrahydro-2H- [1,2 '] -1-bipyridinyl-4-yl) -2, 4,5,9-tetraazatricyclo [9.4.0.0 * 2.6 *] - 35 pentadeca-1 (11), 3,5,12,14-pentaene and I (16) 13-Chloro-8 -methyl-3- (1-pyrimidin-2-yl-piperidin-4-yl) -2,4,5,8-tetraazatricyclo [9, 4.0.0 * 2.6 *] pentadeca-102552; 11 (11), 3,5,12,14-pentaene, or pharmaceutically acceptable derivatives thereof. 8-Chloro-5-pyrimidin-2-yl-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -5,6-dihydro-4H-2 3,5-10b-tetra-azabenzo [e] azulene, I 8-Chloro-5-methanesulfonyl-1- (1-pyrimidin-2-yl-piperidin-4-yl) -5,6-dihydro-4H-2,3,5,10b-tetraazabenzo [e] azulene , I 8-Chloro-5-methanesulfonyl-1- (3,4,5,6-tetrahydro-2H-1 [1,2 '] bipyridinyl-4-yl) -5,6-dihydro-4H-2, 3.5 10b-tetra-azabenzo [e] azulene, I (5) 8-Chloro-5-methyl-1- (1-pyrimidin-2-yl-piperidin-4-5-yl) -5,6-dihydro-4H- 2,3,5,10b-tetraazabenzo [e] azulene, I A compound according to claim 7, wherein Y is chloro. I 1025527 A compound according to any preceding claim, wherein ring A is attached to ring B via a nitrogen atom in ring λ. I with a compound of formula (VII) I R 10 (VU). Wherein the rings Ά and B and the groups R1, X, Y and n have the meaning given in claim 1. I A method of making a compound of formula (I) according to claim 1, or a pharmaceutically acceptable derivative thereof, comprising: reacting a compound of formula I (XIII) I 25. I nh, i (XIII) I with a compound of formula (XXIV) s, Ayr. x V. (XXIV) wherein the rings A and B and the groups V, W, X, Y and Z have the meaning given in claim 1. A method of making a compound of formula (I) according to claim 1, or a pharmaceutically acceptable derivative thereof, comprising: reacting a compound of formula (XIII) or 10 I N-N I · I 15 (II) I In which the rings A and B and the groups W, X, Y and n have the meaning given above. 23. A method of making a compound of formula (I) according to claim 1, or a pharmaceutically acceptable derivative thereof, comprising: reacting a compound of formula I (III) I N-N I 30. I χΧγ I (III) I With a compound of formula (IV) GK 5 <IV> wherein the rings A and B and the groups W, X, Y and n have the meaning given in claim 1 and Z 'is a starting point group such as halogen. The method of making a compound of formula (I) according to claim 1, wherein W represents NR 1, or a pharmaceutically acceptable derivative thereof, comprising: reacting a compound of formula (V) • N-N; (Ty 2 Z) 4 / NH 4 - (V) 25 with a compound of formula (VI) 2: (vi). Wherein the rings A and B and the groups R1, X, Y and n have the meaning given in claim 1 and Z "represents a leaving group such as halogen. 25. A method of making a compound of formula (I) according to claim 1, wherein W represents NR 1, or a pharmaceutically acceptable derivative thereof, comprising: 1025527 224 I reacting a compound of formula (V) I. .N-NI A compound according to any preceding claim, wherein ring A represents piperidinyl (optionally substituted with OH, and optionally at least one N is substituted with 0). 11. A compound according to any preceding claim, wherein ring B represents pyridinyl or pyrimidinyl (optionally substituted with OH, halogen, CN, CO NH 2, CF 3, OCF 3, and optionally at least one ring N is substituted with 0). The compound of claim 11, wherein ring B represents pyridinyl. 13-Chloro-3- (3,4,5,6-tetrahydro-2H- [1,2'-bipyridinyl-4-yl) -8-oxa-2,4,5-triazatricyclo [9.4, 0.0 * 2.6 *) - 1 pentadeca-1 (11), 3,5,12,14-pentaene, 1 15- [8-Chloro-1- (3,4,5,6-tetrahydro-) 2H- [1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3,5,10b-tetraazabenzo [e] azulene-5-yl] -1,2-dimethylaminoethanone, I (10) [8-Chloro-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3,5,10b-tetraazabenzo [ e] azulene-5-yl] - 1 morpholin-4-ylmethanone, I (+) - or {-) - 8-Chloro-5- (4-methylmorpholin-2-ylmethyl) -1- (3 4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -1,5,6-dihydro-4H-2,3,5,10b-tetraazabenzo [e] azulene, I 13-Chloro-8-methyl-3- (3,4,5, 6-tetrahydro-2H- [1,2 '] bi-pyridinyl-4-yl) -2,4,5,8-tetraazatricyclo [ 9.4.0.0 * 2.6 *] - 1 pentadeca-1 (11), 3,5,12,14-pentaene, I A compound according to any preceding claim, wherein V represents -CH 2 -. A compound according to any preceding claim, wherein Z represents -CH 2 -. 15. A compound according to an. of claims 1-3, wherein when R 2 and R 3 together with the nitrogen to which they are attached represent a heterocycle, the heterocycle is selected from piperazinyl, pyrrolidinyl, piperidinyl, pyrimidinyl, tetrahydropyranyl or morpholinyl, and optionally substituted with C 1-6 alkyl. R 4 represents straight or branched C 1-6 alkyl, I a and c independently represent 0, 1 or 2, b, e and g independently represent 0 or 1 and I d and f independently represent 1 or 2. I A compound according to claim 1, selected from: (1) 8-Chloro-5-methyl-1- (3,4,5,6-tetrahydro-2H- [1,2] bi-pyridinyl-4- yl) -5,6-dihydro-4H-2,3,5,10b-tetraazabenzo [e] -azule trihydrochloride, 8-chloro-5-isopropyl-1- (3,4,5,6-tetrahydro-2H-) [1,2 '] bipyridinyl-4-yl) -5,6-dihydro-4H-2,3,5,10b-tetraazabenzo [e] azuline trihydrochloride, 1- [8-Chloro-1- (3,4 5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -4H, 6H-2,3,5,10b-tetraazabenzo [e] -azulene-5-35 yl] ethanone dihydrochloride, 102552? 220 I Use of a compound according to any of claims 1-16 as a medicine. 18. Use of a compound according to any of claims 1-16 in the manufacture of a medicament for the treatment of anxiety, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia), dysmenorrhea (primary and secondary), endometriosis, emesis (including motion sickness), retardation of internal growth in the uterus, inflammation (including rheumatoid arthritis), mittelschmerz, preclampsia, premature ejaculation, premature (premature). contractions or Raynaud's disease. Use according to claim 18, for the treatment of dysmenorrhea (primary or secondary). 20. A pharmaceutical composition comprising a compound according to any one of claims 1-16, together with a pharmaceutically acceptable excipient, diluent or carrier. 21. Intermediates of the formulas (II), (III), (X) and (XV): N-N 25 N-N ^ -V. ΟΙ). x Y ("') 30 N-N /? ° V ^ vs ^ πyy ^, 0 (- U v G Cb H (X). (XV), 1025 52 7.35 222 I wherein W, X, Y, Z, the rings λ and B and n have the meaning given in claim 1 I and VG represents a suitable leaving I group. I A method of making a compound of formula (I) according to claim 1, or a pharmaceutically acceptable derivative thereof, comprising: reacting a compound of formula I (II) with an acid catalyst I V (XIH) 25 S, N, S, N with a compound of formula (XXV) W Qrz ...?% 30 (XXV) wherein rings A and B and groups V, W, X, Y and Z have the meaning given in claim 1. 28. 8-Chloro-5-methyl-1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridihyl-4-yl) -5,6-dihydro-4H-2,3 5, 10b-tetraaza-benzo [e] azulene dibesylate. 1025527