KR20050018945A - 7,8,9,10-TETRAHYDRO-6H-AZEPINO, 6,7,8,9-TETRAHYDRO-PYRIDO AND 2,3-DIHYDRO-2H-PYRROLO[2,1-b]-QUINAZOLINONE DERIVATIVES - Google Patents

Abstract

The present invention formula (I) novel 7,8,9,10-tetrahydro -6 H in - azepin Pino, 6,7,8,9-tetrahydro-pyrido and 2, 3-dihydro -2 H -Pyrrolo [2,1-b] quinazolinone derivatives and their use as active ingredients in the manufacture of pharmaceutical compositions. The present invention also relates to related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and in particular their use as orexin receptor antagonists.

Description

7,8.9,10-tetrahydro-6H-azino, 6,7,8,9-tetrahydro-pyrido and 2,3-dihydro-2H-pyrrolo [2,1-VII] -quinazolinone Derivatives {7,8,9,10-TETRAHYDRO-6H-AZEPINO, 6,7,8,9-TETRAHYDRO-PYRIDO AND 2,3-DIHYDRO-2H-PYRROLO [2,1-b] -QUINAZOLINONE DERIVATIVES}

The present invention provides novel 7,8,9,10-tetrahydro-6H-azino, 6,7,8,9-tetrahydro-pyrido and 2,3-dihydro- 2H of formula (I). -Pyrrolo [2,1-b] quinazolinone derivatives and their pharmaceutical uses. The present invention also relates to related aspects including the process for preparing this compound, pharmaceutical compositions containing one or more compounds of formula I and especially their use as orexin receptor antagonists.

Orexin (hypocretins) contains two neuropeptides produced in the hypothalamus. : Orexin A (OX-A) (33 amino acid peptide) and orexin B (OX-B) (28 amino acid peptide) (Sakurai T. et al., Cell, 1998,92, 573-585). Orexin has been shown to promote food consumption in rats, which deduces the physiological role of these peptides as mediators in central feedback mechanisms that control feeding behavior. (Sakurai T. et al., Cell, 1998, 92,573-585). On the other hand, orexin has also been proposed to regulate sleep and wakefulness conditions, opening up new therapeutic approaches for potentially narcoleptic patients. (Chemelli RM et AL., Cell, 1999, 98, 437-451). Two orexin receptors have been cloned and specified in mammals. They belong to the superfamily of G-protein coupled receptors. (Sakurai T. et AL., Cell, 1998,92, 573-585): Orexin-1 receptor (OX ₁ ) is selective for OX-A and Orexin-2 receptor (OX ₂ ) is OX-B as well as OX- Can also be coupled to A.

Orexin receptors are found in mammalian hosts and are responsible for many biological functions such as, but not limited to, pathologies including them. : depression; unrest; Addiction; Obsessive compulsive disease; Emotional disorder neurosis; Depressive neurosis; Anxiety neurosis; Dysthymic disorders; Behavioral disorders; Mood disorders; Erectile dysfunction; Psychological impotence; Sexual diseases; Schizophrenia; Mood swings; Delerium; dementia ; Severe mental retardation, and motor disorders such as Huntington's disease and Tourette's syndrome; Nutrition-related diseases such as anorexia, bulimia, cachexia and obesity; diabetes; Appetite / taste disorders; Vomiting / nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome / disease; Basophil adenoma; Prolactinoma; Hyperprolactinemia; Pituitary hypoplasia; Pituitary tumor / adenomas; Hypothalamic disease; Inflammatory bowel disease; Gastric dyskinesia; Stomach ulcers; Froehlich's syndrome; Adrenohypophysis disease; Pituitary Disease; Pituitary growth hormone; Anterior pituitary dysfunction; Anterior pituitary hyperfunction; Hypothalamic hypogonadism; Kalman syndrome (loss of smell, loss of smell); Functional or psychogenic amenorrhea; Pituitary hypoplasia; Hypothalamic hypothyroidism; Hypothalamic-adrenal disorders; Idiopathic hyperprolactinemia; Hypothalamic disease of growth hormone deficiency; Idiopathic growth deficiency; Certification; Certification; Acromegaly; Biological and circadian rhythm hunting; Sleep disorders associated with diseases such as neurological disease, neuropathic pain and restless leg syndrome; Heart and lung diseases, acute and congestive heart failure; Hypotension; High blood pressure; Urinary tract; osteoporosis; angina pectoris; Myocardial infarction; Ischemic or hemorrhagic stroke; Subarachnoid hemorrhage; ulcer; allergy; Benign prostatic hyperplasia; Chronic renal failure; Kidney disease; Impaired glucose tolerance; migraine; Hyperalgesia; ache; Enhanced or exaggerated sensitivity to pain such as pain, burning pain, and allodynia; Acute pain; Burning pain; Atypical facial pain; Neurotic pain; Back pain; Complex site pain syndromes I and II; Joint pain; Exercise injury pain; Infections such as HIV-related pain, pain after chemotherapy; Pain after a stroke; Pain after surgery; neuralgia; Symptoms associated with visceral pain such as irritability syndrome, migraine and angina pectoris; Urinary incontinence, for example, urge incontinence; Resistance to drugs or withdrawal symptoms; Sleep disease; Sleep apnea; Narcolepsy; insomnia; Event sleep; Parallax syndrome; And degenerative neurological disorders, including taxonomic entities such as deinhibition-dementia-Parkinson's-proximal complications; Palido-ponto-nigral degeneration (PPND) epilepsy; Seizure diseases and other orexin-related diseases.

The present invention provides 7, 8, 9, 10-tetrahydro-6H-azino, 6,7, 8, 9-tetrahydro-pyrido and 2, 3-dihydro-2H, which are non-peptide antagonists of human orexin receptors. -Pyrrolo [2,1-b] quinazolinone derivatives are provided. In particular, these compounds can be used for the treatment of obesity and / or sleep diseases.

International patent applications W0099 / 09024, W0099 / 58533, WO00 / 47577, WO00 / 47580 as orexin antagonists disclose phenyl urea derivatives and WO00 / 47576 disclose quinolinyl cinnamids.

Moreover, WO 0196302 has been disclosed where the piperidine derivatives have been disclosed as OX ₁ and OX ₂ antagonists, WO 0185693 has been disclosed where the N-acyltetrahydroisoquinoline derivatives have been disclosed as selective OX ₂ antagonists. WO 0244172 also discloses morpholine derivatives as antagonists of orexin receptors.

The novel compounds of the present invention belong to an entirely different class of low molecular weight compounds as compared to all prior art orexin receptor antagonists published to date.

The present invention provides novel 7,8,9,10-tetrahydro-6H-azepino, 6,7,8,9-tetrahydro-pyrido and 2,3-dihydro-2H- of general formula (I). Related to pyrrolo [2,1-b] quinazolinone derivatives.

Structural Formula (I)

here:

X is O or S;

n is an integer of 1,2, or 3;

m is an integer 0,1, 2, 3;

R ¹ , R ² , R ³ , R ⁴ are independently cyano, nitro, halogen, hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, trifluoromethyl, trifluoromethoxy , Cycloalkyloxy, aryloxy, aralkyloxy, heterocyclyloxy, heterocyclylalkyloxy, R ⁸ CO-, NR ⁹ R ¹⁰ CO-, R ⁹ R ¹⁰ N-, R ⁸ OOC-, R ⁸ S0 ₂ NH-, R ¹¹ -CO-NH- or R ² and R ³ together or R ¹ and R ² together or R ³ and R ⁴ together with a phenyl ring one or two separated by one or more carbon atoms To form 5, 6 or 7-membered rings containing at least oxygen atoms;

R ⁵ represents aryl, aralkyl, lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl;

R ⁶ is hydrogen, lower alkyl, trifluoromethyl,-(CH ₂ ) _m -OH,-(CH ₂ ) _m -O-lower alkyl,-(CH ₂ ) _m -CO ₂ H,-(CH ₂ ) _m -CO ₂ - lower alkyl, - (CH _{2) m} CONH _2, - (CH _{2) m} -CONH- lower alkyl, or - (CH _{2) m} -CON- (lower alkyl) _2, or - (CH ₂ ) _m -N- (lower alkyl) ₂ ;

R ⁷ represents aryl, aralkyl, lower alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl;

R ⁸ represents lower alkyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl;

R ⁹ and R ¹⁰ independently represent hydrogen, alkyl, cycloalkyl, cycloalkyl-lower alkyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl;

R ¹¹ represents lower alkyl, aryl, cycloalkyl, heterocyclyl, R ⁹ R ¹⁰ N- or R ⁸ O-.

Compounds of formula I may contain one or more asymmetric centers and are optically pure enantiomers, eg mixtures of enantiomers such as racemates, optically pure diastereomers, mixtures of diastereomers, diastereomers Isomer racemates, diastereomeric racemate mixtures, or meso forms and pharmaceutically acceptable salts thereof.

As used herein, the term "lower alkyl", alone or in combination, refers to a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms, preferably 1-5. By straight or pulverized alkyl groups having carbon atoms is meant. Examples of straight or milled C ₁ -C ₈ alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isobutyl, tert-butyl Isomeric pentyl, isomeric hexyl, isomeric heptyl and isomeric octyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, tert-butyl and n-pentyl .

The term "lower alkenyl", alone or in combination, refers to a straight-chain or ground alkenyl group having 2 to 5 carbon atoms, preferably allyl and vinyl.

The term "lower alkoxy", alone or in combination, refers to a group of the structural alkyl-O-. The term "alkyl" here refers to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, preferably methoxy and ethoxy Has the meaning given above.

Lower alkenyloxy groups are preferably vinyloxy and allyloxy.

The term "cycloalkyl", alone or in combination, means a cycloalkyl ring having 3 to 8 carbon atoms, and preferably a cycloalkyl ring having 3 to 6 carbon atoms.

Examples of C ₃ -C ₈ cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl, cyclohexyl or lower alkyl substituted cycloalkyl, which is preferably methyl Substituted with lower alkyl such as cyclopropyl, dimethyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, methyl-cyclohexyl, dimethyl-cyclohexyl.

The term "aryl", alone or in combination, refers to a phenyl or naphthyl group, which optionally has one or more substituents, preferably one or two substituents, each independently phenyl, p-tolyl Cyano, halogen, hydroxy, such as 4-methoxyphenyl, 4-tert-butoxyphenyl, 4-fluorophenyl, 2-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl and 2-naphthyl , Lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, nitro, trifluoromethyl, trifluoromethoxy, amino, carboxy, alkoxycarbonyl and the like. Preference is given to carboxyphenyl, lower alkoxy-phenyl, hydroxyphenyl and especially phenyl.

The term "aralkyl", alone or in combination, refers to an alkyl or cycloalkyl group as defined above, wherein one hydrogen atom is replaced by an aryl group as defined above. Preference is given to benzyl and benzyl in which the phenyl ring is substituted with hydroxy, lower alkyl, lower alkoxy or halogen, preferably fluorine. Especially preferred is benzyl.

In the terms "heterocycleyl" and "heterocyclyl-lower alkyl", the heterocyclyl group is preferably a 5- to 10-membered monocyclic or bicyclic ring, which is saturated or partially unsaturated Or aromatics containing one, two, or three heteroelements selected from, for example, the same or different, oxygen, nitrogen, sulfur. Examples of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thienyl, thiazolyl , Isothiazolyl, furyl, imidazolyl, pyrazolyl, pyrrolyyl, indazolyl, indolyl, isoindoleyl, isoxazolyl, oxazolyl, quinoxalinyl, phthalazinyl, cynolinyl, dihydropyrroyl , Pyrrolidinyl, isobenzofuranyl, tetrahydrofuranyl, dihydropyranyl. The heterocyclyl group may have up to 5, preferably 1,2 or 3 optional substituents. Suitable substituents include halogen, lower alkyl, amino, nitro, cyano, hydroxy, lower alkoxy, carboxy and lower alkyloxy-carbonyl.

The term "halogen" means fluorine, chlorine, bromine or iodine and preferably chlorine and fluorine, and in particular fluorine.

The term "carboxy", alone or in combination, refers to a -COOH group.

Preferred compounds are those where n is an integer of 1 or 2, m is an integer of 0,1 or 2, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the meaning given in the above formula (I) X is a compound of formula I, which represents oxygen.

Examples of preferred compounds are:

1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -3- (2- N-propyl-phenyl) -urea;

3-biphenyl-2-yl- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl ) -Urea;

3-naphthalen-1-yl-1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl- Ethyl) -urea;

3- (2-ethyl-phenyl) -1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1- Phenyl-ethyl) -urea;

3- (2-ethoxy-phenyl) -1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1 Phenyl-ethyl) -urea;

3- (2-ethyl-phenyl) -1- (6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl)- 1- (1-phenyl-ethyl) -urea;

3-biphenyl-2-yl-1- (6-fluoro-9-oxo-1, 2, 3, 9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1 -(1-phenyl-ethyl) -urea;

1- (6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl)- 3- (2-n-propyl-phenyl) -urea;

1- (6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl)- 3- (2-trifluoromethoxy-phenyl) -urea;

1- (6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-isopropyl-phenyl) -1- (1-phenyl-ethyl) -urea;

1- (6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3-naphthalen-1-yl-1 ( 1-phenyl-ethyl) -urea;

1- (7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) -3- (2-n-propyl-phenyl) -urea;

1- (7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) -3- (2-trifluoromethoxy-phenyl) -urea;

3-biphenyl-2-yl-1- (7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1 (1-phenyl-ethyl) -urea;

3- (2-ethyl-phenyl) -1- (7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl)- 1- (1-phenyl-ethyl) -urea;

1- (6-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) -3- ( 2-n-propyl-phenyl) -urea;

1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-ethyl-phenyl) -1 -(1-phenyl-ethyl) -urea;

1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3-naphthalen-1-yl-1 (1 Phenyl-ethyl) -urea;

1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-isopropyl-phenyl)- 1- (1-phenyl-ethyl) -urea;

1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -3 -(2-n-propyl-phenyl) -urea;

1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) -3- ( 2-trifluoromethoxy-phenyl) -urea;

3-biphenyl-2-yl-1- (7-chloro-9-oxo-1, 2, 3, 9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -urea;

1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -3 -(2-n-propyl-phenyl) -urea;

1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-ethyl-phenyl) -1 -(1-phenyl-ethyl) -urea;

1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -3 -(2-trifluoromethoxy-phenyl) -urea;

1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3-naphthalen-1-yl-1 (1 Phenyl-ethyl) -urea;

3-biphenyl-2-yl-1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -urea;

1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-isopropyl-phenyl)- 1- (1-phenyl-ethyl) -urea;

3-biphenyl-2-yl-1- (6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl ) -1- (1-phenyl-ethyl) -urea;

1- (6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) 3- (2-trifluoromethoxy-phenyl) -urea;

1- (6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl- Ethyl) -3- (2-n-propyl-phenyl) -urea;

1- (6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-ethyl- Phenyl) -1- (1-phenyl-ethyl) -urea;

3-biphenyl-2-yl-1-butyl-1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -urea;

1-Butyl-1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-n-propyl-phenyl) Urea;

1-benzyl-3-biphenyl-2-yl-1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -urea;

1-benzyl-3- (2-ethoxy-phenyl) -1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl)- Urea;

1-benzyl-1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3 yl) -3- (2-n-propyl-phenyl)- Urea;

3-biphenyl-2-yl-1- (11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (l Phenyl-ethyl) -urea;

1- (11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (l-phenyl-ethyl) -3- ( 2-n-propyl-phenyl) -urea;

3- (2-ethyl-phenyl) -1- (11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- ( 1-phenyl-ethyl) -urea;

3- (2-ethoxy-phenyl) -1- (11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl) -urea;

3-naphthalen-1-yl-1- l-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl -Ethyl) -urea;

3-biphenyl-2-yl-2- (2,3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6 -Yl) -1- (1-phenyl-ethyl) -urea;

1- (2,3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1- Phenyl-ethyl) -3- (2-n-propyl-phenyl) -urea;

1- (2,3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -3- (2- Ethyl-phenyl) -1- (1-phenyl-ethyl) -urea;

1- (2,3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -3- (2- Ethoxy-phenyl) -1- (1-phenyl-ethyl) -urea;

3-biphenyl-2-yl-1- (3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H pyrido [2,1-b] quinazolin-6-yl)- 1- (1-phenyl-ethyl) -urea;

1- (3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl ) -3- (2-n-propyl-phenyl) -urea;

3- (2-ethoxy-phenyl) -1- (3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [1,2-b] quinazolin-6- Yl) -1- (1-phenyl-ethyl) -urea;

3- (2-ethyl-phenyl) -1- (3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl ) -1- (1-phenyl-ethyl) -urea;

1- (2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl ) -3- (2-n-propyl-phenyl) -urea;

3- (2-ethyl-phenyl) -1- (2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl ) -1- (1-phenyl-ethyl) -urea;

1- (2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (l-phenyl-ethyl ) -3- (2-trifluoromethoxy-phenyl) -urea;

3- (2-ethoxy-phenyl) -1- (2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazoline-6- Yl) -1- (1-phenyl-ethyl) -urea;

3-biphenyl-2-yl-1- (2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl) -urea;

1- (2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -3-naphthalen-1-yl- 1- (1-phenyl-ethyl) -urea.

Particularly preferred compounds are those where n is an integer of 1 or 2, m is an integer of 0, R ⁵ is methyl, R ⁶ is phenyl, R ¹ , R ² , R ³ , R ⁴ , and R ⁷ is given in Formula I above X is a compound of formula I having meaning and representing oxygen.

Examples of particularly preferred compounds are:

3-biphenyl-2-yl- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl ) -Urea;

3- (2-ethyl-phenyl) -1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1- Phenyl-ethyl) -urea;

3- (2-ethoxy-phenyl) -1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1 Phenyl-ethyl) -urea;

3-biphenyl-2-yl-1- (6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1 -(1-phenyl-ethyl) -urea;

1- (6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl)- 3- (2-n-propyl-phenyl) -urea;

1- (6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl)- 3- (2-trifluoromethoxy-phenyl) -urea;

3- (2-ethyl-phenyl) -1- (6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl)- 1- (1-phenyl-ethyl) -urea;

1- (7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) -3- (2-n-propyl-phenyl) -urea;

1- (6-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) -3- ( 2-n-propyl-phenyl) -urea;

1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-isopropyl-phenyl)- 1- (1-phenyl-ethyl) -urea;

1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -3 -(2-n-propyl-phenyl) -urea;

1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-ethyl-phenyl) -1 -(1-phenyl-ethyl) -urea;

1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -3 -(2-n-propyl-phenyl) -urea;

1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-ethyl-phenyl) -1 -(1-phenyl-ethyl) -urea;

1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -3 -(2-trifluoromethoxy-phenyl) -urea;

3-biphenyl-2-yl-1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -urea;

1- (6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl- Ethyl) -3- (2-n-propyl-phenyl) -urea;

1- (6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-ethyl- Phenyl) -1- (1-phenyl-ethyl) -urea;

1- (11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl) -3- ( 2-n-propyl-phenyl) -urea;

1- (3-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl ) -3- (2-n-propyl-phenyl) -urea;

3- (2-ethyl-phenyl) -1- (3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl ) -1- (1-phenyl-ethyl) -urea;

1- (2,3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1- Phenyl-ethyl) -3- (2-n-propyl-phenyl) -urea;

1- (2,3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -3- (2- Ethyl-phenyl) -1- (1-phenyl-ethyl) -urea;

1- (2,3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -3- (2- Ethoxy-phenyl) -1- (1-phenyl-ethyl) -urea;

1- (2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl ) -3- (2-n-propyl-phenyl) -urea;

3- (2-ethyl-phenyl) -1- (2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl ) -1- (1-phenyl-ethyl) -urea;

3- (2-ethoxy-phenyl) -1- (2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6- Yl) -1- (1-phenyl-ethyl) -urea;

1- (5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1-((S) -1-phenyl -Ethyl) -3- (2-n-propyl-phenyl) -urea;

3-biphenyl-2-yl-1- (5-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1 -((S) -1-phenyl-ethyl) -urea;

1- (5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1-((S) -1-phenyl -Ethyl) -3- (2-trifluoromethoxy-phenyl) -urea;

1- (9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1-((S) -1 Phenyl-ethyl) -3- (2-trifluoromethoxy-phenyl) -urea;

1- (9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1-((S) -1 Phenyl-ethyl) -3- (2-n-propyl-phenyl) -urea;

3- (2-ethyl-phenyl) -1- (9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl ) -1-((S) -1-phenyl-ethyl) -urea;

3-biphenyl-1- (9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- ( (S) -1-phenyl-ethyl) -urea.

Examples of physiologically usable or pharmaceutically acceptable salts of the compounds of formula (I) include inorganic acids such as physiologically compatible hydrochloric acid, sulfuric acid or phosphoric acid; Or salts with organic acids such as methanesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. Compounds of formula (I) having free acid groups can also form salts with physiologically compatible bases. Examples of such salts are alkali metal, alkaline earth metal, ammonium and alkyl ammonium salts such as Na, K, Ca or tetraalkylammonium salts. Compounds of formula (I) may also exist in the form of zwitterions.

Compounds of formula (I) may contain several asymmetric centers and are optically pure enantiomers, for example mixtures of enantiomers such as racemates, optically pure diastereomers, mixtures of diastereomers, portions Stereoisomeric racemates or mixtures of diastereomeric racemates and in meso-forms.

Preferred compounds mentioned above have IC ₅₀ values of less than 500 nM. ; Particularly preferred compounds have an IC ₅₀ value of less than 100 nM, which is measured by the Fluorometric Imaging Plates Reader (FLIPR) method described earlier in the experimental section.

Compounds of formula (I) and their pharmaceutically usable salts include obesity, diabetes, prolactinoma, cardiovascular disease, cancer, pain, narcolepsy, sleep disorders such as insomnia, sleep apnea, sleep disorders, depression, anxiety, addiction, It can be used for the treatment of diseases or disorders that require antagonists of human orexin receptors, such as schizophrenia, neurodegenerative diseases and dementia.

The compounds of formula (I) and their pharmaceutically usable salts are particularly useful for the treatment of obesity and sleep diseases.

The compounds of formula I may also be used for the treatment or prevention of one or more other therapeutically useful substances such as other orexin receptor antagonists, lipid lowering agents, appetite suppressants, sleep inducers, antidepressants, or obesity or sleep diseases. Can be used in combination with other useful drugs.

The compounds of formula (I) and their pharmaceutically usable salts can be used as medicaments. (Eg in the form of pharmaceutical preparations). The pharmaceutical preparations may be in oral form (e.g. tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions) in the intestine, nasal (e.g. in the form of nasal sprays) or rectally. (For example in the form of suppositories). However, administration can also be effected parenterally (eg in the form of injection solutions), such as intramuscularly or intravenously.

The compounds of formula (I) and their pharmaceutically usable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the manufacture of tablets, coated tablets, dragees, and hard and soft gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof and the like can be used, for example, as such adjuvants in tablets, dragees, and hard gelatin capsules.

Suitable supplements for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid materials and liquid polyols.

Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose and the like.

Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

Moreover, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing agents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for the control of osmotic cancer, buffers, blockers or antioxidants. They may also contain other therapeutically valuable substances.

The invention also relates to a process for the preparation of the compounds of formula I.

Compounds of formula (I) of the present invention are prepared according to the general sequence of reactions summarized in the scheme below, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ are As defined in formula (I). When a compound having one or more optically active carbon atoms is obtained, it is known in essence by pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates and meso-forms in an essentially known manner. Will be analyzed.

The resulting compounds will also be converted to their pharmaceutically acceptable salts in an essentially known manner.

Compounds of formula (I) will be prepared by treatment with POCl ₃ from the corresponding 2-amino benzoic acid derivatives and the required lactams. (KARIMOV A. et al Chemistry of Natural Compound 1982, 18, 4,466-472; Bhardwaj V. et al Indian JOURNAL OF HETEROCYCLIC CHEMISTRY 1999, 8, 173-176). Radical bromination followed by substitution with the corresponding primary amine (Kamal A. et al J. Org. CHEM. 2001,66, 997-1001) provides secondary amine intermediates, which are then required urea or cheo Conversion to a urea compound by reaction with commercially available or synthesized isocyanates or isothiocyanates. (March J. Advanced Organic CHEMISTRY-REACTIONS, MECHANISMS and Structure 1992, page 418, 4th edition, John Wiley & Sons)

Scheme 1

2-amino benzoic acid derivatives, wherein R ¹ and R ⁴ are hydrogen, which were not commercially available and were prepared from benzoic acid derivatives using standard procedures as shown in Scheme 2. (Giencke A. et al LIEBIGS ANN. CHEM. 1990,569-579; Follope M.-P. et al Eur. J. MED. Chem. 1992,27, 291-295)

Scheme 2

In addition, 2-amino benzoic acid derivatives are also prepared by reacting aniline derivatives with chloral hydrate in the presence of hydroxylamine hydrochloride and yielding isatin intermediates by acid treatment. This was converted to the corresponding anthranilic acid derivative by reaction with hydrogen peroxide under basic conditions. (Scheme 3) (Neal Bramson H. et al J. MED. CHEFN. 2001, 44, 4339-4358; Deady LW et al J. MED. CHERN. 1997, 40, 2040-2046; Rowley M. et AL JMED CHEM 1993,36, 3386-3396; Hughes P. et al J. Heterocyclic Chem. 1990,27, 2151-2163).

Isatin Derivatives

Scheme 3

Experimental part

1.OX _One  And OX ₂  Biological Measurement of Receptor Antagonist Activity

The OX ₁ and OX ₂ receptor antagonist activity of the compound of formula (I) was measured according to the following experimental method.

Experiment method:

Intracellular Calcium Measurement

Chinese hamster ovary (CHO) cells expressing human orexin-1 receptor or human orexin-2 receptor were expressed in 300 μg / ml G418, 100 U / ml penicillin, 100 μg / ML streptomycin and 10% inactivated calf fetal serum. Cultured in medium containing L-glutamine and Ham F-12).

Cells were seeded in 96-well black clear bottom sterile plates (Costar) precoated with 1% gelatin in Hanks' Balanced Salt Solution (HBSS) at 80,000 cells / well. All reagents were obtained from Gibco BRL.

Inoculated plates were incubated overnight at 37 ° C., 5% CO ₂ .

As an agonist human orexin-A was prepared in a 1 mM stock solution in methanol: water (1: 1) and containing 0.1% bovine serum albumin (BSA) and 2 mM HEPES to a final concentration of 10 nM for use in the assay. Diluted with HBSS.

Antagonists were prepared with 10 mM stock solutions in DMSO and then diluted in 96-well plates first with DMSO and then with HBSS containing 0.1% bovine serum albumin (BSA) and 2 mM HEPES.

On assay day, 100 μl of loading medium (1% FCS, 2 mM HEPES, 5 mM probeneside (Sigma) and 3 μM of fluorescent calcium indicator fluo-3 AM (10% Pluronic Acid and DMSO 1 mM stock solution (HBSS) containing Molecular Probes) was added to each well.

This 96-well plate was incubated at 37 ° C., 5% CO ₂ for 60 minutes. The loading solution was then aspirated and the cells washed three times with 200 μl HBSS containing 2.5 mM probenside, 0.1% BSA, 2 mM HEPES. 100 μl of the same buffer was left in each well.

In Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices), the antagonist was added to the plate in a volume of 50 μl, incubated for 20 minutes and finally 100 μl of agonist. Fluorescence was measured at 1 second intervals in each well and the height of each fluorescence peak was compared with the height of the fluorescence peak induced by buffer and 10 nM orexin-A instead of antagonist. For each antagonist, an IC ₅₀ value (the concentration of compound needed to inhibit 50% of the efficacy response) was measured. IC ₅₀ values of selected compounds are provided in Table 1.

TABLE 1

IC ₅₀ (nM)

OX _One OX ₂

Example 3 115 79

Example 7 2400 27

Example 28 153 17

Example 30 261 16

Example 33 127 18

Example 40 37 14

Example 41 52 14

Example 44 67 27

Example 49 12 16

Example 50 14 18

Example 51 28 21

II. chemistry

The following examples illustrate the preparation of pharmacologically active compounds of the invention in detail, but do not limit the scope of the invention. All temperatures are given in degrees Celsius.

All hydrochloride salts were prepared by dissolving the free-base in dichloromethane and treating with excess etheric HCl (2M).

A. Abbreviations

AIBN 2,2'-azobisisobutyronitrile

BSA Bovine Serum Albumin

CHO Chinese Hamster Ovary

DMF Dimethylformamide

eq equivalent

ES electron injection

EtOH Ethanol

FC Flash Chromatography

FCS Calf Fetal Serum

FLIPR Fluorescent imaging plate reader

HBSS Hank's balanced salt solution

HEPES 4- (2-hydroxyethyl) -piperazine-1-ethanesulfonic acid

m multiplet (NMR)

MeCN acetonitrile

MeOH Methanol

MS Mass spectroscopy

NBS N-bromine succinimide

NMR nuclear magnetic resonance

LC Liquid Chromatography

q quartet (NMR)

R _t retention time

rt room temperature

s singlelet (NMR)

t triplet (NMR)

TEA triethylamine

THF tetrahydrofuran

B. 2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one derivatives

General procedure:

To the mixture of 2-aminobenzoic acid derivative (1 g), 2-pyrrolidone (1.5 eq), POCl ₃ (2.5 mL) was carefully added. The resulting mixture was stirred under nitrogen at 100 ° C. for 1 hour. After cooling, the reaction mixture was poured into ice water and saturated. Basicized with NAHCO ₃ and extracted with CH ₂ Cl ₂ (3 × 100 mL). The combined extracts were dried (anhydrous MgSO ₄ ), filtered and concentrated to give crude brown-yellow viscous oil. FC (CH ₂ Cl ₂ / MeOH: 9/1) provided the title compound as a solid.

1) 2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (CH ₂ Cl ₂ / MeOH: 9/1) provided the title compound as a yellow solid. (0.97 g, 71%).

2) 5-fluoro-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (CH ₂ Cl ₂ / MeOH: 9/1) provided the title compound as a brown solid. (0.92 g, 70%).

3) 6-fluoro-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (CH ₂ Cl ₂ / MeOH: 9/1) provided the title compound as yellow crystals. (0.79 g, 60%).

4) 7-fluoro-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (CH ₂ Cl ₂ / MeOH: 9/1) provided the title compound as yellow crystals. (0.97 g, 74%).

5) 6,7-difluoro-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (CH ₂ Cl ₂ / MeOH: 9/1) provided the title compound as orange crystals. (0.86 g, 67%).

6) 6-chloro-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (CH ₂ Cl ₂ / MeOH: 9/1) provided the title compound as yellow crystals. (1. 11 g, 86%).

7) 7-chloro-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (CH ₂ Cl ₂ / MeOH: 9/1) provided the title compound as yellow crystals. (1.14 g, 89%).

8) 8-chloro-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (CH ₂ Cl ₂ / MeOH: 9/1) provided the title compound as yellow crystals. (0.97 g, 75%).

9) 8-trifluoromethyl-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

A mixture of 2-amino-6-trifluoromethyl-benzoic acid (0.97 g), 2-methoxypyrroline (0.703 g, 1.5 eq) in dry toluene (12 mL) was stirred at reflux for 3 hours. This orange solution was then evaporated to dryness to afford an unpurified orange solid.

FC (CH ₂ Cl ₂ / MeOH: 9/1) provided the title compound as a yellow powder. (0.89 g, 74%).

C. 3-Bromo-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one derivative

General procedure:

2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one derivative (1 eq), NBS (1 eq), AIBN (0.085 eq) in dry CHCl ₃ (20 mL / g) The mixture was stirred under nitrogen at reflux for 20 hours. After cooling, the mixture was concentrated under reduced pressure and the resulting crude solid was purified by FC (AcOEt / heptane: 7/3) to afford the title compound.

1) 3-bromo-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (AcOEt / heptane: 7/3) provided the title compound as brown crystals. (40%).

2) 3-bromo-5-fluoro-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one FC (AcOEt / heptane: 7/3) is an orange solid The title compound was provided. (35%).

3) 3-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (AcOEt / heptane: 7/3) provided the title compound as an orange solid. (52%).

4) 3-bromo-7-fluoro-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (AcOEt / heptane: 7/3) provided the title compound as a reddish solid. (53%).

5) 3-bromo-6, 7-difluoro-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (AcOEt / heptane: 7/3) provided the title compound as a red solid. (69%).

6) 3-bromo-6-chloro-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (AcOEt / heptane: 7/3) provided the title compound as a reddish solid. (42%).

7) 3-bromo-7-chloro-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (AcOEt / heptane: 7/3) provided the title compound as a pink solid. (49%).

8) 3-bromo-8-chloro-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (AcOEt / heptane: 7/3) provided the title compound as a purple powder. (38%).

9) 3-bromo-8-trifluoromethyl-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (AcOEt / heptane: 7/3) provided the title compound as a red solid. (36%).

C. 3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one derivative

General procedure

3-Bromo-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one derivative in dry EtOH (10 mL) (0.56 g, 2.11 mmol), (D, L) A mixture of α-methylbenzylamine (1 eq), TEA (1.5 eq) was stirred under nitrogen for 20 hours at reflux. After cooling, the reaction mixture was combined with CH ₂ Cl ₂ / water and the aqueous phase was extracted with CH ₂ Cl ₂ . The combined extracts were dried (anhydrous MgSO ₄ ), filtered and concentrated to give a dark green residue as a mixture of diastereomers.

1) 3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (AcOEt / heptane: 7/3) provided the title compound as a dark green solid. (69%).

LC-MS (MeCN / H ₂ O: 1/1): R _t = 3.00 min. m / z = 306 (M + 1).

2) 6-fluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (AcOEt / heptane: 7/3) provided the title compound as a thick oil. (56%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 3.18 min. m / z = 324 (M + 1).

3) 7-fluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (AcOEt / heptane: 7/3) provided the title compound as a dark brown oil. (62%).

LC-MS (MeCN / H ₂ O: 1/1): R _t = 3.06 min. m / z = 324 (M + 1).

4) 6,7-difluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2, 1-B] quinazolin-9-one

FC (AcOEt / heptane: 7/3) provided the title compound as a dark green oil. (42%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 3.31 min. m / z = 342 (M + 1).

5) 6-chloro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (AcOEt / heptane: 7/3) provided the title compound as a dark green oil. (50%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 3.40 min. m / z = 340 (M + 1).

6) 7-chloro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (AcOEt / heptane: 7/3) provided the title compound as a dark brown oil. (54%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 3.34 min. m / z = 340 (M + 1).

7) 8-chloro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

FC (AcOEt / heptane: 7/3) provided the title compound as a dark brown oil. (71%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 3.21 min. m / z = 340 (M + 1).

8) 3-((S) -1-phenyl-ethylamino) -8-trifluoromethyl-2,3-dihydro-1H-pyrrolo [2, 1-B] quinazolin-9-one

Reaction with (S) -α-methylbenzylamine

FC (AcOEt) provided the title compound as a dark brown oil. (68%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 3.63 min. m / z = 374 (M + 1).

9) 5-Fluoro-3-((S) -1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one

Reaction with (S) -α-methylbenzylamine

FC (AcOEt) provided the title compound as a dark green oil. (58%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 3.36 min. m / z = 324 (M + 1).

D. 6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one derivatives

General procedure

To the suspension of 2-aminobenzoic acid derivative (1 eq) in dry CHCl ₃ (20 mL / g) was slowly added POCl ₃ (1.3 eq) with stirring under nitrogen at room temperature for 15 minutes. Δ-Valerolactam (1.1 eq) was then added in portions (portion wis) for 10 minutes and the reaction mixture was stirred for 3 hours under nitrogen at reflux. Aqueous HCl 5% participated in the reaction mixture and the aqueous phase was separated. (This operation was repeated three times). The combined aqueous extracts were clarified by the addition of active charcoal and filtered through celite. The resulting light yellow solution was basified with concentrated aqueous ammonia and extracted with CH ₂ Cl ₂ (3 times). The combined organic extracts were washed with water, dried (anhydrous Na ₂ SO ₄ ) and concentrated under reduced pressure to give a solid which was used without further purification in the next step.

1) 6,7, 8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one

Bright orange crystals (41%)

2) 3-fluoro-6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one yellow crystals (44%)

3) 2-fluoro-6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one yellow solid (56%)

4) 2,3-difluoro-6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one

Yellow crystals (45%)

E. 6-Bromo-6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one derivative

These compounds were prepared as described for 3-bromo-2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one derivatives.

1) 6-bromo-6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one

Light yellow crystals (55%).

2) 6-bromo-3-fluoro-6,7, 8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one

Light yellow crystals (65%).

3) 6-bromo-2-fluoro-6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one

White solid (69%).

4) 6-bromo-2,3-difluoro-6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one

White solid (55%).

F. 6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one derivative

These compounds were prepared as described for 3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one derivative. (Mixture of diastereomers).

1) 6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one

Light yellow solid (72%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 2.98 and 3.19 min. m / z = 320 (M + 1).

2) 3-fluoro-6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one

Yellow solid (40%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 3.18 min. m / z = 338 (M + 1).

3) 2-fluoro-6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one

Yellow solid (26%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 3.14 min. m / z = 338 (M + 1).

4) 2, 3-difluoro-6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2, 1-B] quinazolin-11-one yellow solid ( 40%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 3.15 min. m / z = 356 (M + 1).

Example 1

1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -3- (2- N-propyl-phenyl) -urea (mixture of diastereomers)

3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (50 mg, 0.163) in dry CH ₂ Cl ₂ (1 mL) mmol) to the solution, 2-n-propylphenyl isocyanate (26.3 mg, 0.163 mmol) was added. The resulting reaction mixture was stirred for 20 hours under nitrogen at room temperature. The reaction mixture was then concentrated under reduced pressure and the residue was purified by FC (AcOEt / heptane: 7/3) to give the title compound as white foam. (45%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 3.00 min. m / z = 467 (M + 1).

Example 2

3-biphenyl-2-yl-1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl -Ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 2-biphenyl isocyanate (1 eq) was used.

FC (AcOEt / heptane: 7/3) provided the title compound as a white foam (63%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.89 and 5.49 min. m / z = 500 (M).

Example 3

3- (2-ethoxy-phenyl) -1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1 Phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 2-ethoxyphenyl isocyanate (1 eq) was used. FC (AcOEt / heptane: 7/3) provided the title compound as a white foam. (55%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.60 and 5.23 min. m / z = 468 (M).

Example 4

3- (2-ethyl-phenyl) -1- (6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl)- 1- (1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 6-fluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq ) And 2-ethylphenyl isocyanate (1 eq) were used.

FC (AcOEt / heptane: 7/3) provided the title compound as a white foam. (62%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.76 and 5.33 min. m / z = 470 (M).

Example 5

3-biphenyl-2-yl-1- (6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1 -(1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 6-fluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq ) And 2-biphenylisocyanate (1 eq) were used.

FC (AcOEt / heptane: 7/3) provided the title compound as a white foam. (82%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.01 and 5.61 min. m / z = 518 (M).

Example 6

1- (6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl)- 3- (2-n-propyl-phenyl) -urea (mixture of diastereomers)

Similar to Example 1, 6-fluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq ) And 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige powder. (61%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.06 and 5.61 min. m / z = 484 (M).

Example 7

1- (6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl)- 3- (2-Trifluoromethoxy-phenyl) -urea (mixture of diastereomers)

Similar to Example 1, 6-fluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq ) And 2-trifluoromethoxyphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a white solid. (72%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.92 and 5.61 min. m / z = 526 (M).

Example 8

1- (6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-isopropyl-phenyl) -1- (1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 6-fluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq ) And 2-isopropylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a white foam. (70%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.98 and 5. 48 min. m / z = 484 (M).

Example 9

1- (6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3-naphthalen-1-yl-1 ( 1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 6-fluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H pyrrolo [2,1-b] quinazolin-9-one (1 eq) And 1-naphthyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a brown oil. (77%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.72 and 5.28 min. m / z = 492 (M).

Example 10

1- (7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) -3- (2-propyl-phenyl) -urea (mixture of diastereomers)

Similar to Example 1, 7-fluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq ) And 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as an orange oil. (75%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.99 and 5.53 min. m / z = 484 (M).

Example 11

1- (7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) -3- (2-Trifluoromethoxy-phenyl) -urea (mixture of diastereomers)

Similar to Example 1, 7-fluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq ) And 2-trifluoromethoxyphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a brown oil. (83%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.85 and 5.52 min. m / z = 526 (M + 1).

Example 12

3-biphenyl-2-yl-1- (7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1 -(1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 7-fluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq ) And 2-biphenylisocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a yellow brown oil. (70%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.02 and 5.59 min. m / z = 518 (M).

Example 13

3- (2-ethyl-phenyl) -1- (7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl)- 1- (1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 7-fluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H pyrrolo [2,1-b] quinazolin-9-one (1 eq) And 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige foam. (70%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.77 and 5.32 min. m / z = 470 (M).

Example 14

3-biphenyl-2-yl-1- (6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl ) -1- (1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 6, 7-difluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) and 2-biphenylisocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a light gray foam. (56%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.27 and 5.84 min. m / z = 536 (M).

Example 15

1- (6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) -3- (2-trifluoromethoxy-phenyl) -urea (mixture of diastereomers)

Similar to Example 1, 6, 7-difluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) and 2-trifluoromethoxyphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a brown foam. (61%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.07 and 5.74 min. m / z = 544 (M).

Example 16

1- (6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl- Ethyl) -3- (2-n-propyl-phenyl) -urea (mixture of diastereomers)

Similar to Example 1, 6, 7-difluoro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a brown foam. (67%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.22 and 5.74 min. 714 / Z = 502 (M).

Example 17

1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-ethyl-phenyl) -1 -(1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 7-chloro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) And 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a light beige foam. (66%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.09 and 5.73 min. m / z = 487 (M).

Example 18

1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3-naphthalen-1-yl-1 (1 -Phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 7-chloro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H pyrrolo [2,1-b] quinazolin-9-one (1 eq) and Using 1-naphthyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige solid. (47%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.99 and 5.61 min. m / z = 509 (M).

Example 19

1- (7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-isopropyl-phenyl)- 1- (1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 7-chloro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) And 2-isopropylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a gray solid. (87%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.30 and 5. 81 min. m / z = 501 (M).

Example 20

1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -3 -(2-n-propyl-phenyl) -urea (mixture of diastereomers)

Similar to Example 1, 7-chloro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) And 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a white foam. (58%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.34 and 5.92 min. m / z = 501 (M).

Example 21

1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) -3- ( 2-trifluoromethoxy-phenyl) -urea (mixture of diastereomers)

Similar to Example 1, 7-chloro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) And 2-trifluoromethoxyphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a light brown foam. (74%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.18 and 5.92 min. m / z = 542 (M).

Example 22

3-biphenyl-2-yl-1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 7-chloro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) And 2-biphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a white foam. (72%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.36 and 5.99 min. m / z = 535 (M).

Example 23

3-biphenyl-2-yl-1- (11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1 Phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2, 1-B] quinazolin-11-one (1 eq) and 2 Using biphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a yellow oil. (22%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.99 and 5.80 min. m / z = 515 (M + 1).

Example 24

1- (11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl) -3- ( 2-n-propyl-phenyl) -urea (mixture of diastereomers)

Similar to Example 1, 6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2, 1-B] quinazolin-11-one (1 eq) and 2 using -n-propylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige foam. (53%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.18 and 5.86 min. m / z = 481 (M + 1).

Example 25

3- (2-ethyl-phenyl) -1- (11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- ( 1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2, 1-B] quinazolin-11-one (1 eq) and 2 Using ethylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a yellow oil. (72%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.87 and 5.54 min. m / z = 467 (M + 1).

Example 26

3- (2-ethoxy-phenyl) -1- (11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 6- (1-phenyl-ethylamino) -6, 7, 8, 9-tetrahydro-pyrido [2, 1-B] quinazolin-11-one (1 eq) and 2 Use of ethoxyphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige solid. (41%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.81 and 5.67 min. m / z = 483 (M + 1).

Example 27

3-naphthalen-1-yl-1- (11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1- Phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2, 1-B] quinazolin-11-one (1 eq) and 1 Using naphthyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige solid. (28%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.87 and 5.51 min. m / z = 489 (M + 1).

Example 28

1- (2, 3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1- Phenyl-ethyl) -3- (2-n-propyl-phenyl) -urea (mixture of diastereomers)

Similar to Example 1, 2, 3-difluoro-6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11 Using -one (1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige foam. (80%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 6.13 min. m / z = 517 (M + 1).

Example 29

3-biphenyl-2-yl-1- (2, 3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2, 1-B] quinazolin-6 -Yl) -1- (1-phenylethyl) -urea (mixture of diastereomers)

Similar to Example 1, 2, 3-difluoro-6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2,1-b] quinazoline-11 Using -one (1 eq) and 2-biphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige foam. (48%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.57 and 6.22 min. m / z = 551 (M + 1).

Example 30

1- (2,3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -3- (2- Ethyl-phenyl) -1- (1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 2, 3-difluoro-6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2,1-b] quinazoline-11 Using -one (1 eq) and 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige foam. (97%).

LC-MS (MeCN / H 2 O: 1/1): R _t = 5.35 and 5.92 min. m / z = 503 (M + 1).

Example 31

1- (2, 3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -3- (2- Ethoxy-phenyl) -1- (1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 2, 3-difluoro-6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2,1-b] quinazoline-11 Using -one (1 eq) and 2-ethoxyphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige foam. (60%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.22 and 6.07 min. m / z = 519 (M + 1).

Example 32

3-biphenyl-2-yl-1- (3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenylethyl) -urea (mixture of diastereomers)

Similar to Example 1, 3-fluoro-6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one ( 1 eq) and 2-biphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige foam. (42%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5. 38 and 6.10 min. m / z = 533 (M + 1).

Example 33

1- (3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl ) -3- (2-n-propyl-phenyl) -urea (mixture of diastereomers)

Similar to Example 1, 3-fluoro-6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one ( 1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige foam. (98%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.29 and 5.96 min. m / z = 499 (M + 1).

Example 34

3- (2-ethoxy-phenyl) -1- (3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazoline-6- Yl) -1- (1-phenylethyl) -urea (mixture of diastereomers)

Similar to Example 1, 3-fluoro-6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one ( 1 eq) and 2-ethoxyphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a foam. (88%).

LC-MS (: MeCN / H ₂ 0: 1/1): R _t = 5.03 and 5.93 min. m / z = 501 (M + 1).

Example 35

3- (2-ethyl-phenyl) -1- (3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl ) -1- (1-phenylethyl) -urea (mixture of diastereomers)

Similar to Example 1, 3-fluoro-6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one ( 1 eq) and 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a foam. (47%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.07 and 5.74 min. m / z = 485 (M + 1).

Example 36

3-biphenyl-2-yl-1- (2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenylethyl) -urea (mixture of diastereomers)

Similar to Example 1, 2-fluoro-6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one ( 1 eq) and 2-biphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as. Yellow powder (43%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.38 and 6.07 min. m / z = 533 (M + 1).

Example 37

1- (2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl ) -3- (2-n-propyl-phenyl) -urea (mixture of diastereomers)

Similar to Example 1, 2-fluoro-6- (1-phenyl-ethylamino) -6, 7, 8, 9-tetrahydro-pyrido [2,1-b] quinazolin-11-one ( 1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as an orange-brown powder. (53%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.29 and 5.94 min. m / z = 499 (M + 1).

Example 38

3- (2-ethoxy-phenyl) -1- (2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2, 1-b] quinazoline-6- Yl) -1- (1-phenylethyl) -urea (mixture of diastereomers)

Similar to Example 1, 2-fluoro-6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one ( 1 eq) and 2-ethoxyphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a yellow powder. (44%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.03 and 5.86 min. m / z = 501 (M + 1).

Example 39

3- (2-ethyl-phenyl) -1- (2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl ) -1- (1-phenylethyl) -urea (mixture of diastereomers)

Similar to Example 1, 2-fluoro-6- (1-phenyl-ethylamino) -6,7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one ( 1 eq) and 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a yellow powder. (54%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.07 and 5.72 min. m / z = 485 (M + 1).

Example 40

1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) -3- ( 2-trifluoromethoxy-phenyl) -urea (mixture of diastereomers)

Similar to Example 1, 8-chloro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) And 2-trifluoromethoxyphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a white foam. (74%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.97 and 5.74 min. m / z = 542 (M).

Example 41

3-biphenyl-2-yl-1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 8-chloro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) And 2-biphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a yellow foam. (70%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.16 and 5. 80 min. m / z = 535 (M).

Example 42

1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-isopropyl-phenyl)- 1- (1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 8-chloro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) And 2-isopropylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige foam. (70%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.11 and 5.67 min. m / z = 501 (M).

Example 43

1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3-naphthalen-1-yl-1 (1 -Phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 8-chloro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) And 1-naphthyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige foam. (57%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.83 and 5.46 min. m / z = 509 (M).

Example 44

1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -3 -(2-n-propyl-phenyl) -urea (mixture of diastereomers)

Similar to Example 1, 8-chloro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H pyrrolo [2,1-b] quinazolin-9-one (1 eq) and Using 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige foam. (64%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.11 and 5.74 min. m / z = 501 (M).

Example 45

1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-ethyl-phenyl) -1 -(1-phenyl-ethyl) -urea (mixture of diastereomers)

Similar to Example 1, 8-chloro-3- (1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) And 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a light beige foam. (83%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 4.86 and 5.53 min. m / z = 486 (M).

Example 46

1- (5-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1-((S) -1-phenyl Ethyl) -3- (2-n-propyl-phenyl) -urea

Similar to Example 1, 5-fluoro-3-((S) 1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a light beige foam. (57%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.27 and 5.74 min. m / z = 485 (M + 1).

Example 47

3-biphenyl-2-yl-1- (5-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1 -((S) -1-phenyl-ethyl) -urea

Similar to Example 1, 5-fluoro-3-((S) 1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) and 2-biphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a green foam. (73%).

LC-MS (MeCN / HAO: 1/1): R _t = 5.39 and 5.94 min. m / z = 519 (M + 1).

Example 48

1- (5-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1-((S) -1-phenyl Ethyl) -3- (2-trifluoromethoxy-phenyl) -urea

Similar to Example 1, 5-Fluoro-3-((S) 1-phenyl-ethylamino) -2,3-dihydro-1H-pyrrolo [2,1-b] quinazolin-9-one (1 eq) and 2-trifluoromethoxyphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a light green solid. (62%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.13 and 5.72 min. m / z = 527 (M + 1).

Example 49

1- (9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1-((S) -1 -Phenyl-ethyl) -3- (2-trifluoromethoxy-phenyl) -urea

Similar to Example 1, 3-((S) -1-phenyl-ethylamino) -8-trifluoromethyl-2,3-dihydro-1H-pyrrolo [2,1-b] quinazoline- Using 9-one (1 eq) and 2-trifluoromethoxyphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige foam. (68%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.39 and 6.14 min. m / z = 577 (M + 1).

Example 50

1- (9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1-((S) -1 -Phenyl-ethyl) -3- (2-n-propyl-phenyl) -urea

Similar to Example 1, 3-((S) -1-phenyl-ethylamino) -8-trifluoromethyl-2,3-dihydro-1H-pyrrolo [2,1-b] quinazoline- Using 9-one (1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige foam. (54%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5. 54 and 6.13 minutes. m / z = 535 (M + 1).

Example 51

3- (2-ethyl-phenyl) -1- (9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl ) -1-((S) -1-phenyl-ethyl) -urea

Similar to Example 1, 3-((S) -1-phenyl-ethylamino) -8-trifluoromethyl-2,3-dihydro-1H-pyrrolo [2,1-b] quinazoline- Using 9-one (1 eq) and 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige foam. (62%).

LC-MS (MeCN / H 2 O: 1/1): R _t = 5.34 and 5.96 min. m / z = 521 (M + 1).

Example 52

3-biphenyl-1- (9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- ( (S) -1-phenyl-ethyl) -urea

Similar to Example 1, 3-((S) -1-phenyl-ethylamino) -8-trifluoromethyl-2,3-dihydro-1H-pyrrolo [2,1-b] quinazoline- Using 9-one (1 eq) and 2-biphenyl isocyanate (1 eq).

FC (AcOEt / heptane: 7/3) provided the title compound as a beige foam. (72%).

LC-MS (MeCN / H ₂ 0: 1/1): R _t = 5.64 and 6.22 min. m / z = 569 (M + 1).

Claims (11)

Of compounds of formula (I) and optically pure enantiomers, mixtures of enantiomers, racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, diastereomeric racemates Mixtures, or mesoforms, and pharmaceutically acceptable salts thereof. Structural Formula (I) here: X is O or S; n is an integer of 1,2, or 3; m is an integer 0, 1, 2, 3; R ¹ , R ² , R ³ , R ⁴ are independently cyano, nitro, halogen, hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, trifluoromethyl, trifluoromethoxy , Cycloalkyloxy, aryloxy, aralkyloxy, heterocyclyloxy, heterocyclylalkyloxy, R ⁸ CO-, NR ⁹ R ¹⁰ CO-, R ⁹ R ¹⁰ N-, R ⁸ OOC-, R ⁸ S0 ₂ NH-, R ¹¹ -CO-NH- or R ² and R ³ together or R ¹ and R ² together or R ³ and R ⁴ together with a phenyl ring one or two separated by one or more carbon atoms To form 5, 6 or 7-membered rings containing at least oxygen atoms. ; R ⁵ represents aryl, aralkyl, lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl; R ⁶ is hydrogen, lower alkyl, trifluoromethyl,-(CH ₂ ) _m -OH,-(CH ₂ ) _m -O-lower alkyl,-(CH ₂ ) _m -CO ₂ H,-(CH ₂ ) _m -CO ₂ - lower alkyl, - (CH _{2) m} CONH _2, - (CH _{2) m} -CONH- lower alkyl, or - (CH _{2) m} -CON- (lower alkyl) _2, or - (CH ₂ ) _m -N- (lower alkyl) ₂ ; R ⁷ represents aryl, aralkyl, lower alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl; R ⁸ represents lower alkyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl; R ⁹ and R ¹⁰ independently represent hydrogen, alkyl, cycloalkyl, cycloalkyl-lower alkyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl; R ¹¹ represents lower alkyl, aryl, cycloalkyl, heterocyclyl, R ⁹ R ¹⁰ N- or R ⁸ O-. n is an integer 1 or 2, m is an integer 0,1 or 2, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the meaning given in Formula I above and X is oxygen A compound of formula I represented. n is an integer of 1 or 2, m is an integer of 0, R ⁵ is methyl, R ⁶ is phenyl, R ¹ , R ² , R ³ , R ⁴ , and R ⁷ have the meaning given in the above formula (I) and X Is a compound of formula I wherein oxygen. A compound according to any one of claims 1 to 3 selected from the group consisting of: 1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (l-phenyl-ethyl) -3- (2- n-propyl-phenyl) -urea; 3-biphenyl-2-yl- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl ) -Urea; 3- (2-ethoxy-phenyl) -1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1 Phenyl-ethyl) -urea; 3- (2-ethyl-phenyl) -1- (6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl)- 1- (1-phenyl-ethyl) -urea; 3-naphthalen-1-yl-1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl- Ethyl) -urea; 3- (2-ethyl-phenyl) -1- (6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl)- 1- (1-phenyl-ethyl) -urea; 3-biphenyl-2-yl-1- (6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1 -(1-phenyl-ethyl) -urea; 1- (6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl)- 3- (2-propyl-phenyl) -urea; 1- (6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl)- 3- (2-trifluoromethoxy-phenyl) -urea; 1- (6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-isopropyl-phenyl) -1- (1-phenyl-ethyl) -urea; 1- (6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3-naphthalen-1-yl-1 ( 1-phenyl-ethyl) -urea; 1- (7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) -3- (2-n-propyl-phenyl) -urea; 1- (7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) -3- (2-trifluoromethoxy-phenyl) -urea; 3-biphenyl-2-yl-1- (7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1 -(1-phenyl-ethyl) -urea; 3- (2-ethyl-phenyl) -1- (7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl)- 1- (1-phenyl-ethyl) -urea; 1- (6-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) -3- ( 2-n-propyl-phenyl) -urea; 1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-ethyl-phenyl) -1 -(1-phenyl-ethyl) -urea; 1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3-naphthalen-1-yl-1 (1 Phenyl-ethyl) -urea; 1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-isopropyl-phenyl)- 1- (1-phenyl-ethyl) -urea; 1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -3 -(2-n-propyl-phenyl) -urea; 1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) -3- ( 2-trifluoromethoxy-phenyl) -urea; 3-biphenyl-2-yl-1- (7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -urea; 1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -3 -(2-n-propyl-phenyl) -urea; 1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-ethyl-phenyl) -1 -(1-phenyl-ethyl) -urea; 1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -3 -(2-trifluoromethoxy-phenyl) -urea; 3-biphenyl-2-yl-1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl-ethyl) -urea; 1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-isopropyl-phenyl)- 1- (1-phenyl-ethyl) -urea; 1- (8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3-naphthalen-1-yl-1 (1 Phenyl-ethyl) -urea; 3-biphenyl-2-yl-1- (6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl ) -1- (1-phenyl-ethyl) -urea; 1- (6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (phenyl-ethyl) 3- (2-trifluoromethoxy-phenyl) -urea; 1- (6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- (1-phenyl- Ethyl) -3- (2-n-propyl-phenyl) -urea; 1- (6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-ethyl- Phenyl) -1- (1-phenyl-ethyl) -urea; 3-biphenyl-2-yl-1-butyl-1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -urea; 1-Butyl-1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -3- (2-n-propyl-phenyl) Urea; 1-benzyl-3-biphenyl-2-yl-1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -urea; 1-benzyl-3- (2-ethoxy-phenyl) -1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl)- Urea; 1-benzyl-1- (9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3 yl) -3- (2-n-propyl-phenyl)- Urea; 3-biphenyl-2-yl-1- (11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1 Phenyl-ethyl) -urea; 1- (11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl) -3- ( 2-N-propyl-phenyl) -urea; 3- (2-ethyl-phenyl) -1- (11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- ( l-phenyl-ethyl) -urea; 3- (2-ethoxy-phenyl) -l- (11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl) -urea; 3-naphthalen-1-yl-1- (11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1- Phenyl-ethyl) -urea; 3-biphenyl-2-yl-1- (2, 3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H pyrido [2,1-b] quinazolin-6- Yl) -1- (1-phenyl-ethyl) -urea; 1- (2,3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1- Phenyl-ethyl) -3- (2-n-propyl-phenyl) -urea; 1- (2,3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -3- (2- Ethyl-phenyl) -1- (1-phenyl-ethyl) -urea; 1- (2,3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -3- (2- Ethoxy-phenyl) -1- (1-phenyl-ethyl) -urea; 3-biphenyl-2-yl-1- (3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl) -urea; 1- (3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl) 3- (2-n-propyl-phenyl) -urea; 3- (2-ethoxy-phenyl) -1- (3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazoline-6- Yl) -1- (1-phenyl-ethyl) -urea; 3- (2-ethyl-phenyl) -1- (3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl ) -1- (1-phenyl-ethyl) -urea; 1- (2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl ) -3- (2-n-propyl-phenyl) -urea; 3- (2-ethyl-phenyl) -1- (2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl ) -1- (1-phenyl-ethyl) -urea; 1- (2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl ) -3- (2-trifluoromethoxy-phenyl) -urea; 3- (2-ethoxy-phenyl) -1- (2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6- Yl) -1- (1-phenyl-ethyl) -urea; 3-biphenyl-2-yl-1- (2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -1- (1-phenyl-ethyl) -urea; 1- (2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido [2,1-b] quinazolin-6-yl) -3-naphthalen-1-yl- 1- (1-phenyl-ethyl) -urea; 1- (5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1-((S) -1-phenyl -Ethyl) -3- (2-n-propyl-phenyl) -urea; 3-biphenyl-2-yl-1- (5-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1 -((S) -1-phenyl-ethyl) -urea; 1- (5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1-((S) -1-phenyl -Ethyl) -3- (2-trifluoromethoxy-phenyl) -urea; 1- (9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1-((S) -1 Phenyl-ethyl) -3- (2-trifluoromethoxy-phenyl) -urea; 1- (9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- ((S) -1 Phenyl-ethyl) -3- (2-n-propyl-phenyl) -urea; 3- (2-ethyl-phenyl) -1- (9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl ) -1-((S) -1-phenyl-ethyl) -urea; 3-biphenyl-1- (9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-3-yl) -1- ( (S) -1-phenyl-ethyl) -urea. A disease associated with the role of orexin, in particular obesity and sleep, containing one or more compounds according to any one of claims 1 to 4, or their pharmaceutically acceptable salts, and useful carrier materials and adjuvant Pharmaceutical compositions for the treatment of diseases such as diseases. The method according to any one of claims 1 to 4, used as a drug for the treatment of diseases related to the role of orexin, in particular obesity, sleep diseases, cardiovascular diseases, cancer, pain, depression, schizophrenia or neurodegenerative diseases Compounds, or pharmaceutically acceptable salts thereof. Treating or preventing a disease or condition wherein an antagonist of the human orexin receptor is desired, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof. Way. A compound according to any one of claims 1 to 4, or a medicament thereof, as an active ingredient comprising mixing one or more active ingredients or ingredients with pharmaceutically acceptable additives and adjuvant in an essentially known manner. Process for the preparation of a pharmaceutical composition for the treatment of diseases related to orexin, in particular obesity, sleep disease, cardiovascular disease, cancer, pain, depression, schizophrenia or degenerative neurological disease, containing one or more compounds of a pharmaceutically acceptable salt . Other pharmacologically active agents, including other orexin receptor antagonists, lipid lowering agents, anorexia, sleep inducers, antidepressants or other beneficial drugs for the prevention or treatment of a disease given in any one of claims 6-8. One or more compounds according to any one of claims 1 to 4 used in combination with the compounds. The compound described in any of Examples 1-63 as a final-product. The invention disclosed herein.