KR20030061459A - Carbazole derivatives and their use as neuropeptide y5 receptor ligands - Google Patents

Abstract

The present invention relates to compounds of formula (I) The present invention further relates to a process for its preparation and its use as NPY 5 inhibitors.

Formula I

Description

Carbazole derivatives and their use as neuropeptide Ｙ5 receptor ligands {CARBAZOLE DERIVATIVES AND THEIR USE AS NEUROPEPTIDE Y5 RECEPTOR LIGANDS}

NPY is a 36 amino acid polypeptide that is a member of the pancreatic polypeptide class of regulatory peptides that are widely distributed throughout the mammalian community. NPY is the most abundant neuropeptide in the central and peripheral nervous system and has a powerful complex effect on diet, anxiety, circadian rhythm, reproduction, pituitary-adrenal cortex function, memory retention, seizures, temperature regulation and cardiovascular and gastrointestinal function appear. NPY interacts with a heterogeneous population of six or more receptor subtypes Y ₁ -Y ₆ that activate adenylated cyclase through the G-protein. For reviews of NPY, see CRC Critical Reviews in Neurobiology (1988) 4, 97-135; Regulatory Peptides (1996) 62, 1-11.

One of the most striking effects of NPY is dietary induction of various herbivore species. Direct injection of NPY into the hypothalamus of satiety rats can increase food intake up to 10-fold over 4 hours, and NPY is the only known peptide that can cause animals to eat until they become obese. Recent studies on NPY have focused on the identification of NPY receptors that contribute to dietary regulation. NPY-5 receptor was identified as the receptor that most closely matches the presented appetite receptor. The functional role of this receptor has been addressed in receptor blocking studies. Intraventricular injection of NPY-5 receptor antisense oligodeoxynucleotides prevented hypothalamic NPY levels during food deficiency and inhibited rat food intake due to fasting [Schaffhauser et al (1997) Diabets 46, 1792-1798. ]. Thus, NPY-5 receptors are potential pharmacological targets in the regulation of eating disorders such as obesity. For a review of the relationship between NPY and diet, see Zimanyi et al (1998) Current Pharm Des 4, 349-66; Heinrichs et al (1998) Vitamins and Hormones 54, 51-66.

Obesity is a large and growing problem in affluent societies, reaching epidemic proportions. According to the American Medical Institute, 59% of Americans are clinically obese, or 20% more than their ideal weight. Obesity is associated with susceptibility to many other conditions, such as non-insulin dependent diabetes, hypertension, dyslipidemia and coronary heart disease. This condition leads to reduced life expectancy and reduced quality of life. While it is difficult to quantify the overall financial burden of obesity, it is estimated to be 6-8% of the total health care costs in the United States.

Thus, there is a need for pharmaceutical agents that are efficacious in the treatment of appetite disorders such as obesity, anorexia nervosa, abnormal appetite and related disorders. Examples of “related disorders” are obesity, dyslipidemia, hypertension and sleep disorders, especially diabetes.

Modulation of NPY activity through antagonism at the NPY-5 receptor provides one potential target for pharmacological intervention in this condition.

WO 00/63171 discloses tricyclic compounds that are NPY inhibitors. Surprisingly, the inventors have found that certain classes of such compounds are potent NPY5 inhibitors and also have beneficial toxicological profiles that make them particularly suitable for administration to warm-blooded animals such as humans.

The present invention relates to compounds that antagonize the interaction between neuropeptide Y (NPY) and neuropeptide Y5 (NPY-5) receptor subtypes. The present invention also relates to methods of preparing NPY-5 receptor antagonists or agonists, pharmaceutically acceptable salts thereof, and novel pharmaceutical compositions of NPY-5 receptor antagonists or agonists.

Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof:

Where

R ¹ is C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfamoyl Is selected from; Wherein R ¹ may be optionally substituted on carbon with one or more R ⁷ ;

R ² and R ³ are both methyl or R ² and R ³ together form — (CH ₂ ) ₄ — or — (CH) ₄ —; Wherein-(CH ₂ ) ₄ -or-(CH) ₄ -may be optionally substituted with R ⁸ ;

R ⁴ is C _1-4 alkyl;

R ⁵ is —C (O) NR ⁹ R ¹⁰ , —C (O) R ⁹ or —C (O) C (O) R ⁹ ;

R ⁶ and R ⁸ are independently halo, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-4 alkyl, N- (C _1-4 alkyl) amino, N, N- (C _{1 -4} alkyl) ₂ amino and C _1-4 alkoxy;

R ⁷ is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _a Wherein a is 0 to 2, C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl, N, N- (C _1-4 alkyl) ₂ sulfamoyl, C _{1- 4} alkylsulfonylamino, carbocyclyl or heterocyclyl;

R ⁹ and R ¹⁰ are independently hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-4 alkoxy, carbocyclyl or heterocyclyl; Wherein R ⁹ and R ¹⁰ can be optionally substituted independently with one or more R ¹¹ on carbon; Wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by R ¹² ;

Or R ⁹ and R ¹⁰ together with the nitrogen attached thereto form a heterocycle optionally substituted with one or more R ¹³ on carbon; Wherein if said heterocycle contains an —NH— moiety that nitrogen may be optionally substituted by R ¹⁴ ;

R ¹¹ and R ¹³ are independently halo, hydroxy, cyano, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl oil, C _1-4 alkanoyloxy, C _1-4 alkanoylamino, C _2-6 alkenyloxycarbonyl, C _1-4 alkoxycar Carbonyl, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _1-4 alkoxycarbonylamino, C _1-4 alkoxycarbonyl-N- (C _{1- 4} alkyl) amino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _a (where a is 0 to 2), N- (C _1-4 alkyl) sulfamoyl, N, N- (C _1-4 alkyl) ₂ sulfamoyl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocycle Arylcarbonylamino, heterocyclylthio, carbocyclyl, carbocyclyloxy, carbocyclylcarbonyl, carbocyclylcarbonylamino, carbocyclyloxyca Carbonyl, and thio and carbocyclyl; Wherein R ¹¹ and R ¹³ can be optionally substituted independently on carbon with one or more R ¹⁵ ; Wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by R ¹⁶ ;

R ¹² , R ¹⁴ and R ¹⁶ are independently C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, sulfamoyl, N- (C _1-4 alkyl) sulfamoyl, N, N -(C _1-4 alkyl) ₂ sulfamoyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbo Barmoyl, carbocyclyl, carbocyclylC _1-4 alkyl, carbocyclylcarbonyl, carbocyclylsulfonyl, heterocyclyl, heterocyclylC _1-4 alkyl, heterocyclylcarbonyl, heterocyclylsul Ponyl; Wherein R ¹² , R ¹⁴ and R ¹⁶ can be optionally substituted independently with one or more R ¹⁷ on carbon;

R ¹⁵ is halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _{2- 4} Alkynyl, C _1-4 Alkoxy, C _1-4 Alkanoyl Oil, C _1-4 Alkanoyloxy, C _1-4 Alkanoylamino, C _2-6 Alkenyloxycarbonyl, C _1-4 Alkoxycarbonyl , N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _1-4 alkoxycarbonylamino, C _1-4 alkoxycarbonyl-N- (C _1-4 Alkyl) amino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _a (where a is 0 2), N- (C _1-4 alkyl) sulfamoyl, N, N- (C _1-4 alkyl) ₂ sulfamoyl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclyl Methyloxy, heterocyclyloxycarbonyl, carbocyclyl, carbocyclyloxy, carbocyclylcarbonyl, carbocyclylmethyloxy and carbocyclyloxycarbonyl .; Wherein R ¹⁵ may be optionally substituted on carbon with one or more R ¹⁸ ;

R ¹⁷ and R ¹⁸ are halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl , Methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N, N -Dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl;

m is 0 to 2, wherein the value of R ⁶ may be the same or different.

As used herein, the term "alkyl" includes both straight and branched chain alkyl groups, but is only specified linearly with respect to the individual alkyl groups such as "propyl" and branched with respect to the individual branched chain alkyl groups such as "isopropyl". Only specific. Similar conventions apply to other radicals, such as "phenylC _1-4 alkyl" will include phenylC _1-4 alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term "halo" means fluoro, chloro, bromo and iodo.

When any substituent is selected from "one or more" groups, it is to be understood to include all substituents selected from one of the specific groups or substituents selected from two or more of the particular groups.

"Heterocyclyl" refers to a saturated, partially saturated or unsaturated, monocyclic or bicyclic ring in which one or more atoms contain 3 to 12 atoms selected from nitrogen, sulfur or oxygen and which may be carbon or nitrogen linked unless otherwise indicated Wherein the —CH ₂ — group may be optionally substituted with —C (O) — or the ring sulfur atom may be optionally oxidized to form an S-oxide. Preferably, “heterocyclyl” contains 5 or 6 atoms of at least one atom selected from nitrogen, sulfur or oxygen, and unless otherwise stated, saturated, partially saturated or unsaturated, monocyclic which may be carbon or nitrogen linked. Or a bicyclic ring, wherein the —CH ₂ — group may be optionally substituted with —C (O) — or the ring sulfur atom may be optionally oxidized to form an S-oxide. Examples and suitable values of the term “heterocyclyl” include thiazolidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidoneyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinoneyl, 1,1- Dioxotetrahydrothienyl, 2,4-dioxyimidazolidinyl, 2-oxo-1,3,4- (4-triazolinyl), 2-oxazolidinoneyl, 5,6-dihydrouracil 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo [2.2.1] heptyl, 4-thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, tetra Hydrofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl, 1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino, 1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyyl, thiadiazolyl, isothiazolyl , 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl, indole , Pyrimidyl, thiazolyl, a pyrazinyl, pyridazinyl, pyridyl, 4-pyridyl donil, quinolyl and 1-isopropyl nolil quinolone days. Preferably, the term “heterocyclyl” refers to piperidinyl, tetrahydrofuran, morpholino, piperazinyl, 1,1-dioxotetrahydrothienyl, triazolyl, 2-pyrrolidinone, tetrahydropyran And pyridyl.

"Carbocyclyl" is a saturated, partially saturated or unsaturated monocyclic or bicyclic carbon ring containing 3 to 12 atoms, wherein the -CH ₂ -group may be optionally substituted with -C (O)-. Preferably, "carbocyclyl" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for "carbocyclyl" include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1 -There is a single oxo. In particular, "carbocyclyl" is cyclohexyl.

An example of “C _1-4 alkanoyloxy” is acetoxy. Examples of "C _1-4 alkoxycarbonyl" are methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of "C _1-4 alkoxy" are methoxy, ethoxy and propoxy. Examples of “C _1-4 alkanoylamino” include formamido, acetamido and propionylamino. Examples of “C _1-4 alkylS (O) _{a wherein} a is 0 to 2) include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl and ethylsulfonyl. Examples of "C _1-4 alkylsulfonyl" are mesyl and ethylsulfonyl. Examples of "C _1-4 alkylsulfonylamino" are mesylamino and ethylsulfonylamino. Examples of "C _1-4 alkanoyl" are propionyl and acetyl. Examples of "N- (C _1-4 alkyl) amino" are methylamino and ethylamino. Examples of “N, N- (C _1-4 alkyl) ₂ amino” are di-N-methylamino, di- (N-ethyl) amino and N-ethyl-N-methylamino. Examples of "C _2-10 alkenyl" and "C _2-4 alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C _2-10 alkynyl" and "C _2-4 alkynyl" include ethynyl, 1-propynyl and 2-propynyl. Examples of "N- (C _1-4 alkyl) sulfamoyl" include N- (methyl) sulfamoyl and N- (ethyl) sulfamoyl. Examples of "N, N- (C _1-4 alkyl) ₂ sulfamoyl" include N, N- (dimethyl) sulfamoyl and N- (methyl) -N- (ethyl) sulfamoyl. Examples of "N- (C _1-4 alkyl) carbamoyl" are methylaminocarbonyl and ethylaminocarbonyl. Examples of “N, N- (C _1-4 alkyl) ₂ carbamoyl” are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of "C _2-6 alkenyloxycarbonyl" are allyloxycarbonyl and 2-butenyloxycarbonyl. Examples of “C _1-4 alkoxycarbonylamino” are methoxycarbonylamino, ethoxycarbonylamino, n- and t-butoxycarbonylamino. Examples of "C _1-4 alkoxycarbonyl-N- (C _1-4 alkyl) amino" include methoxycarbonyl-N-methylamino, ethoxycarbonyl-Nethylamino, n- and t-butoxycarb Carbonyl-N-methylamino. Examples of "heterocyclyloxy" are pyridyloxy and thiazolyloxy. Examples of "heterocyclylcarbonyl" include pyrimidylcarbonyl and morpholinocarbonyl. Examples of "heterocyclyloxycarbonyl" include pyrrolidinyloxycarbonyl and pyranyloxycarbonyl. Examples of "carbonylcyclyloxy" are phenoxy and cyclopropyloxy. Examples of "carbocyclylcarbonyl" are benzoyl and cyclohexylcarbonyl. Examples of "carbocyclyloxycarbonyl" include phenoxycarbonyl and indanyloxycarbonyl. Examples of "heterocyclylcarbonylamino" include morpholinocarbonylamino, pyridylcarbonylamino and thienylcarbonylamino. Examples of "heterocyclylthio" include pyridylthio, pyranylthio and pyrrolinylthio. Examples of "carbocyclylcarbonylamino" include benzoylamino and cyclopropylcarbonylamino. Examples of "carbocyclylthio" are phenylthio and cyclohexylthio. Examples of "heterocyclylmethyloxy" include pyridylmethyloxy and piperidylmethyloxy. Examples of "carbocyclylmethyloxy" are benzyloxy and cyclopentylmethyloxy. Examples of “carbocyclylC _1-4 alkyl” are phenethyl, benzyl and cyclopropylmethyl. Examples of "carbocyclylsulfonyl" are phenylsulfonyl and cyclohexylsulfonyl. Examples of “heterocyclylC _1-4 alkyl” include pyridylmethyl and pyrrolidinoneylethyl. Examples of "heterocyclylsulfonyl" include pyrazinylsulfonyl and morpholinosulfonyl.

Examples of pharmaceutically acceptable salts of compounds of formula (I) are acid addition salts of the compounds of the invention which are sufficiently basic, for example inorganic acids or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid or male Acid addition salts with acids. In addition, suitable pharmaceutically acceptable salts of the compounds of the invention that are sufficiently acidic provide alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts or physiologically acceptable cations. Salts with organic bases such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris (2-hydroxyethyl) amine.

The compounds of formula (I) may be administered in the form of prodrugs that are degraded in the human or animal body to provide the compounds of formula (I). Examples of prodrugs are in vivo hydrolyzable esters of compounds of formula (I).

Various forms of prodrugs are known in the art. As examples of such prodrug derivatives, reference may be made to the following documents:

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

b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", H. Bundgaard, p. 113-191 (1991);

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

d) H. Bundgaard, et al., Journal of pharmaceutical Sciences, 77, 285 (1988); And

e) N. Kakeya, et al., Chem Pharm Bulll, 32, 692 (1984).

Examples of hydrolyzable esters in vivo of the compounds of formula (I) containing carboxy or hydroxy groups are pharmaceutically acceptable esters which hydrolyze in human or animal bodies to give the parent acid or the parent alcohol. Suitable pharmaceutically acceptable esters for carboxy include C _1-6 alkoxymethyl esters such as methoxymethyl; C _1-6 alkanoyloxymethyl esters such as pivaloyloxymethyl, phthalidyl esters; C _3-8 cycloalkoxycarbonyloxyC _1-6 alkyl esters such as 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters such as 5-methyl-1,3-dioxolen-2-onylmethyl; And C _1-6 alkoxycarbonyloxyethyl esters such as 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of the present invention.

In vivo hydrolyzable esters of compounds of formula (I) containing hydroxy groups include inorganic esters such as phosphate esters (including phosphoamide-based ring esters) and in vivo hydrolysis results of α-acyloxyalkyl ether and ester degradation As related compounds which provide the mohydroxy group (s). Examples of α-acyloxyalkyl ethers are acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. Examples of in vivo hydrolyzable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl And substituted benzoyl and phenylacetyl, alkoxycarbonyl (provides alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl) -N-alkylcarbamoyl (provides carbamate), di Alkylaminoacetyl and carboxyacetyl. Examples of substituents for benzoyl include morpholino and piperazino, which are linked from the ring nitrogen atom to the 3 or 4 position of the benzoyl ring by a methylene group.

As long as some of the compounds of formula (I) as defined above may be present in optically active or racemic form by one or more asymmetric carbon atoms, the present invention provides any such optical activity with the properties of an agonist or antagonist at the neuropeptide Y5 receptor. Or understand that the racemic form is included in the definition. Synthesis of optically active forms can be accomplished by standard techniques of organic chemistry well known in the art, such as synthesis from optically active starting materials, or by decomposing racemic forms. Similarly, binding to neuropeptide Y5 receptors can be assessed using standard laboratory techniques described below.

The present invention also relates to any and all tautomeric forms of the compounds of formula (I) having neuropeptide Y5 receptor agonist or antagonist activity.

It is also to be understood that certain compounds of the present invention may exist in the form of solvates, such as hydrates, as well as non-solvates. It is to be understood that the present invention includes all such solvate forms having properties that interact with the neuropeptide Y5 receptor.

Preferred values of the variable group are as follows. Such values may be used suitably with any of the definitions, claims, or embodiments defined above or below.

Preferably, R ¹ is selected from C _1-4 alkyl optionally substituted with one or more R ⁷ on which R ⁷ is C _1-4 alkoxy.

More preferably, R ¹ is selected from ethyl, isopropyl or 2-methoxy-1-methylethyl.

In one embodiment of the invention, in particular R ¹ is ethyl.

In another embodiment of the invention, in particular, R ¹ is isopropyl.

In one embodiment of the invention, it is preferred that R ² and R ³ are both methyl.

In another aspect of the invention, it is preferred that R ² and R ³ together form-(CH ₂ ) ₄ -optionally substituted with R ⁸ .

In another embodiment of the invention, it is preferred that R ² and R ³ together form-(CH) ₄ -optionally substituted with R ⁸ .

Preferably, R ² and R ³ form-(CH ₂ ) ₄ -or-(CH) ₄ -optionally substituted with R ⁸ ; Wherein R ⁸ is selected from halo or C _1-4 alkyl.

Preferably, R ² and R ³ together form-(CH ₂ ) ₄ -or-(CH) ₄ -optionally substituted with R ⁸ ; Wherein R ⁸ is selected from fluoro, bromo or methyl.

Preferably, R ⁴ is methyl or isopropyl.

In one embodiment of the invention, R ⁴ is more preferably methyl.

In another embodiment of the invention, R ⁴ is more preferably isopropyl.

In one embodiment of the invention, R ⁵ is preferably —C (O) NR ⁹ R ¹⁰ .

In another embodiment of the invention, R ⁵ is preferably -C (O) R ⁹ .

In another embodiment of the invention, R ⁵ is preferably -C (O) C (O) R ⁹ .

Preferably, R ⁵ is —C (O) NR ⁹ R ¹⁰ , —C (O) R ⁹ or —C (O) C (O) R ⁹ ; here

R ⁹ and R ¹⁰ are independently C _1-10 alkyl, C _1-4 alkoxy or heterocyclyl; Wherein R ⁹ and R ¹⁰ may be optionally substituted independently with one or more R ¹¹ on carbon; Wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by R ¹² ;

Or R ⁹ and R ¹⁰ together with the nitrogen to which they are attached form a heterocycle optionally substituted with one or more R ¹³ on carbon; Wherein if said heterocycle contains an —NH— moiety that nitrogen may be optionally substituted by R ¹⁴ ;

R ¹¹ and R ¹³ are independently selected from halo, hydroxy, carbamoyl, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxycarbonylamino, heterocyclyl, carbocyclyl ; Wherein R ¹¹ and R ¹³ can be optionally substituted independently with one or more R ¹⁵ on carbon;

R ¹² and R ¹⁴ are independently selected from C _1-4 alkyl, heterocyclyl;

R ¹⁵ is selected from hydroxy, amino, C _1-4 alkoxycarbonylamino.

More preferably, R ⁵ is —C (O) NR ⁹ R ¹⁰ , —C (O) R ⁹ or —C (O) C (O) R ⁹ ; here

R ⁹ and R ¹⁰ are independently C _1-4 alkyl, C _1-4 alkoxy, piperidinyl or tetrahydrofuran; Wherein R ⁹ and R ¹⁰ may be optionally substituted independently with one or more R ¹¹ on carbon; Wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by R ¹² ;

Or R ⁹ and R ¹⁰ together with the nitrogen to which they are attached form morpholino, piperidin-1-yl, piperazin-1-yl, optionally substituted with one or more R ¹³ on carbon; Wherein 1-piperazin-1-yl may be optionally substituted with R ¹⁴ on nitrogen;

R ¹¹ and R ¹³ are independently chloro, hydroxy, carbamoyl, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxycarbonylamino, 1,1-dioxotetrahydrothienyl , Triazole, 2-pyrrolidinone, tetrahydropyran, pyridyl, cyclohexyl; Wherein R ¹¹ and R ¹³ can be optionally substituted independently with one or more R ¹⁵ on carbon;

R ¹² and R ¹⁴ are independently selected from C _1-4 alkyl, pyridyl;

R ¹⁵ is selected from hydroxy, amino, C _1-4 alkoxycarbonylamino.

In particular, R ⁵ is t-butoxycarbonyl, morpholino, tetrahydrofuran-3-ylcarbonyl, 2- (1,1-dioxotetrahydrothien-3-yl) acetyl, 3-carbamoyl Piperidin-1-ylcarbonyl, 2,2,2-trichloroacetyl, 4- (pyrid-2-yl) piperazin-1-ylcarbonyl, 3- (pyrid-4-yl) propion 1, N- [2- (pyrid-4-yl) ethyl] -N-methylaminocarbonyl, N- (pyrid-3-ylmethyl) -N-methylaminocarbonyl, N- (1-methyl Piperid-4-yl) -N-methylaminocarbonyl, 4-hydroxymethylpiperid-1-ylcarbonyl, 4- (pyrid-4-yl) piperid-1-ylcarbonyl, 4- Hydroxyethylpiperid-1-ylcarbonyl, 3-methoxy-2- (t-butoxycarbonylamino) propionyl, 2- (1,2,4-triazol-1-yl) acetyl, 2 -(2-pyrrolidinone-1-yl) acetyl, tetrahydropyran-4-ylcarbonyl, 2- [3- (t-butoxycarbonylamino) cyclohexyl] acetyl, 3-methoxy-2- Aminopropionyl, 2- (3-aminocyclohexyl) acetyl, 4- Lead-4-ylpiperidin-1-yloxalyl, 4-pyrid-2-ylpiperazin-1-yloxalyl, 4-hydroxypiperidin-1-yl, 2-hydroxyethylaminocarbonyl and N-methoxy-N-methylaminocarbonyl.

In particular, R ⁵ is t-butoxycarbonyl, morpholinocarbonyl, tetrahydrofuran-3-ylcarbonyl, 2- (1,1-dioxotetrahydrothien-3-yl) acetyl, 3-car Bamoylpiperidin-1-ylcarbonyl, 2,2,2-trichloroacetyl, 4- (pyrid-2-yl) piperazin-1-ylcarbonyl, 3- (pyrid-4-yl Propionyl, N- [2- (pyrid-4-yl) ethyl] -N-methylaminocarbonyl, N- (pyrid-3-ylmethyl) -N-methylaminocarbonyl, N- (1 -Methylpiperid-4-yl) -N-methylaminocarbonyl, 4-hydroxymethylpiperid-1-ylcarbonyl, 4- (pyrid-4-yl) piperid-1-ylcarbonyl, 4-hydroxyethylpiperid-1-ylcarbonyl, 3-methoxy-2- (t-butoxycarbonylamino) propionyl, 2- (1,2,4-triazol-1-yl) acetyl , 2- (2-pyrrolidinone-1-yl) acetyl, tetrahydropyran-4-ylcarbonyl, 2- [3- (t-butoxycarbonylamino) cyclohexyl] acetyl, 3-methoxy- 2-aminopropionyl, 2- (3-aminocyclohexyl) a Cetyl, 4-pyrid-4-ylpiperidin-1-yloxalyl, 4-pyrid-2-ylpiperazin-1-yloxalyl, 4-hydroxypiperidin-1-yl, 2-hydroxy Ethylaminocarbonyl and N-methoxy-N-methylaminocarbonyl.

In another aspect of the invention, preferably R ⁵ is —C (O) NR ⁹ R ¹⁰ or —C (O) R ⁹ ;

R ⁹ and R ¹⁰ are independently hydrogen, C _1-10 alkyl, carbocyclyl or heterocyclyl; Wherein R ⁹ and R ¹⁰ may be optionally substituted independently with one or more R ¹¹ on carbon; Wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by R ¹² ;

Or R ⁹ and R ¹⁰ together with the nitrogen to which they are attached form a heterocycle optionally substituted with one or more R ¹³ on carbon; Wherein if said heterocycle contains an —NH— moiety that nitrogen may be optionally substituted by R ¹⁴ ;

R ¹¹ and R ¹³ are independently halo, hydroxy, carbamoyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkanoylamino, C _1-4 alkoxycarbonyl, N- (C _{1 -4} alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _1-4 alkoxycarbonylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _{1- 4} alkyl) ₂ carbamoyl, C _1-4 alkyl S (O) _{a wherein} a is 0 or 2, heterocyclyl, heterocyclyloxy or carbocyclyl; Wherein R ¹¹ and R ¹³ can be optionally substituted independently with one or more R ¹⁵ on carbon;

R ¹² and R ¹⁴ are independently C _1-4 alkyl, C _1-4 alkanoyl, carbamoyl, C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl and carbocyclylC _1-4 alkyl;

R ¹⁵ is selected from hydroxy, C _1-4 alkoxy, N, N- (C _1-4 alkyl) ₂ amino, heterocyclyl.

In another aspect of the invention, more preferably, R ⁵ is —C (O) NR ⁹ R ¹⁰ or —C (O) R ⁹ ;

R ⁹ and R ¹⁰ are independently hydrogen, C _1-6 alkyl, cyclopropyl, 2-H-5,6-dihydroxypyranyl, 4-H-5,6-dihydropyranyl, 2-oxotetra Hydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, 2-oxopyrrolidinyl, pyrazinyl, 1,2,5,6-tetrahydropyridinyl, isoxazolyl, 1,2,4-triazolyl, tetra Hydrothienyl, tetrahydropyranyl or piperidinyl; Wherein R ⁹ and R ¹⁰ may be optionally substituted independently with one or more R ¹¹ on carbon; Wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by R ¹² ;

Or R ⁹ and R ¹⁰ together with the nitrogen to which they are attached piperidinyl, pyrrolidinyl, homopiperazinyl, 4-oxohomopiperazinyl, morpholino, 2 optionally substituted with one or more R ¹³ on carbon with carbon to which they are attached; Oxopiperazinyl or piperazinyl; Wherein if said heterocycle contains an —NH— moiety that nitrogen may be optionally substituted by R ¹⁴ ;

R ¹¹ and R ¹³ are independently halo, hydroxy, carboxy, carbamoyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkanoylamino, C _1-4 alkoxycarbonyl, N- ( C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _1-4 alkoxycarbonylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkyl S (O) _a (where a is 0 or 2), piperidinyl, 2,4-dioxoimidazolidinyl, tetrahydrofuran One, tetrahydrofuranyloxy, 4-oxo-1,4-dihydropyridinyl, pyrazinyl, cyclohexyl or phenyl; Wherein R ¹¹ and R ¹³ can be optionally substituted independently with one or more R ¹⁵ on carbon;

R ¹² and R ¹⁴ are independently C _1-4 alkyl, C _1-4 alkanoyl, carbamoyl, C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl and benzyl;

R ¹⁵ is selected from hydroxy, C _1-4 alkoxy, N, N- (C _1-4 alkyl) ₂ amino, pyrrolidinyl.

In another embodiment of the invention, R ⁵ is 3-ethoxycarbonylpiperidin-1-ylcarbonyl, 3-hydroxymethylpiperidin-1-ylcarbonyl, 4-carbamoylpiperidine- 1-ylcarbonyl, 4-ethoxycarbonylpiperidin-1-ylcarbonyl, 1-acetylpiperidin-4-ylcarbonyl, 1-N, N-dimethylcarbamoylpiperidine-3 -Ylcarbonyl, 1-acetylpiperidin-3-ylcarbonyl, 3-methoxycarbonylpyrrolidin-1-ylcarbonyl, 1-N-methylcarbamoylpiperidin-3-ylcarbon Carbonyl, 1-carbamoylpiperidin-3-ylcarbonyl, 3-N, N-dimethylcarbamoylpyrrolidin-1-ylcarbonyl, 1-carbamoylpiperidin-4-ylcar Bonyl, 1-N, N-dimethylcarbamoylpiperidin-4-ylcarbonyl, 1-acetylpyrrolidin-3-ylcarbonyl, 1-N, N-dimethylcarbamoylpyrrolidine-3 -Ylcarbonyl, 1-N-methylcarbamoylpyrrolidin-3-ylcarbonyl, 1-hydroxy-3-methylpent-2-ylaminocarbonyl, 3-hydroxy-3-phenylprop -2-Japanese Army Nocarbonyl, (1-hydroxycyclohex-1-yl) methylaminocarbonyl, N-methyl-N- (3-phenyl-3-hydroxyprop-2-yl) aminocarbonyl, 2-hydroxy Hydroxymethylpiperidin-1-ylcarbonyl, 2-hydroxymethylpyrrolidin-1-ylcarbonyl, 3-hydroxypiperidin-1-ylcarbonyl, 3-cyclohexyl-1-hydroxy Prop-2-ylaminocarbonyl, 3-hydroxyprop-2-ylaminocarbonyl, 3-hydroxypyrrolidin-1-ylcarbonyl, 4-N, N-dimethylcarbamoylpiperi Din-1-ylcarbonyl, 4-N-methylcarbamoylpiperidin-1-ylcarbonyl, 3-hydroxypent-3-ylcarbonylamino, N, N-dimethylaminoacetyl, methoxyacetyl , Ethoxyacetyl, 2-hydroxybut-2-ylcarbonyl, N-methylpyrrolidin-2-ylcarbonyl, 2-oxotetrahydrofuran-5-ylcarbonyl, tetrahydrofuran-2-yl Carbonyl, 2-hydroxy-1-acetamidoethyl, 3-methoxypropionyl, 2-methoxyethoxyacetyl, 3-e Cypropionyl, 3-methylthiopropionyl, 2-trifluoromethyl-2-hydroxypropionyl, 2-phenyl-2-methoxypropionyl, piperidin-1-ylacetyl, tetrahydrofuran- 3-yloxyacetyl, tetrahydrothien-2-ylcarbonyl, 3-hydroxypropionyl, (3-hydroxymethyltetrahydropyran-3-yl) carbonyl, (1-carbamoylcycloprop- 1-yl) carbonyl, 3-acetamidopropionyl, 2-H-5,6-dihydropyran-3-ylcarbonyl, 3-ethylthioprop-2-ylcarbonyl, 2,3- 4-H-dihydrpyran-2-ylcarbonyl, 1-hydroxy-3-methylbutylcarbonyl, 3-N, N-dimethylaminopyrrolidin-1-ylcarbonyl, 2-methyl-2- Hydroxypropionyl, N-methyl-N- (2-hydroxyethyl) aminocarbonyl, N, N-di (2-hydroxyethyl) aminocarbonyl, tetrahydrofuran-2-ylmethylaminocarbonyl, 2,6-dimethylpiperazin-4-ylcarbonyl, 4-hydroxypiperidin-1-ylcarbonyl, N-methyl-N- ( N-methylpiperidin-4-yl) aminocarbonyl, 2-methoxyprop-2-ylaminocarbonyl, 2-hydroxypropylaminocarbonyl, 2-methoxyethylaminocarbonyl, 2-meth Methoxymethylpyrrolidin-1-ylcarbonyl, 2- (pyrrolidin-1-ylmethyl) pyrrolidin-1-ylcarbonyl, 3-hydroxypiperidin-1-ylcarbonyl, N- Methyl-N- (3-N, N-dimethylaminopropyl) aminocarbonyl, N, N-di (2-methoxyethyl) aminocarbonyl, 1-acetylpiperazin-4-ylcarbonyl, 3-acet Amidopyrrolidin-1-ylcarbonyl, 3-t-butoxycarbonylaminopyrrolidin-1-ylcarbonyl, N-methyl-N- (N-methylpyrrolidin-3-yl) aminocarbon Carbonyl, N-methylhompiperazin-4-ylcarbonyl, 1-hydroxy-3-methylbut-2-ylaminocarbonyl, 1-hydroxyprop-2-ylaminocarbonyl, 2,6- Dimethylmorpholinocarbonyl, N-methyl-N- (2-methoxyethyl) aminocarbonyl, N-methyl-N- (N-benzylpyrrolidin-3-yl) aminocarbonyl, 2-jade Homopiperazin-4-ylcarbonyl, 3-mesylpyrrolidin-1-ylcarbonyl, 2- (N, N-dimethylaminomethyl) piperidin-1-yl, N-acetylhomopiperazine-4 -Ylcarbonyl, N-methyl-N- (2,3-dihydroxypropyl) aminocarbonyl, homopiperazin-1-ylcarbonyl, 2- (N-methylamino) ethylaminocarbonyl, 2- Hydroxymethylpyrrolidin-1-ylcarbonyl, 3-N, N-dimethylaminopyrrolidin-1-ylcarbonyl, N-methyl-N- (3-N, N-dimethylaminoethyl) aminocarba Bonyl, 2,4-dioxoimidazolidine-5-ylacetyl, 2-oxopyrrolidin-5-ylcarbonyl, pyrazin-2-ylcarbonyl, N, N-dimethylaminoacetyl, 2-acetyl Amidopropionyl, 3- (N, N-dimethylcarbamoyl) propionyl, mesylacetyl, N-methyl-1,2,5,6-pyridylcarbonyl, 5-methylisoxazol-4-ylcar Bonyl, 3-hydroxypropionyl, 3,5-dimethyl-1,2,4-triazol-1-ylacetyl, tetrahydrofuran-3-yloxyacetyl, 4-oxo-1,4-dihydropy De-1-ylacetyl, 3-pyrazin-2-ylpropionyl, 4-carboxypiperidin-1-ylcarbonyl, piperidin-4-ylcarbonyl, piperidin-3-ylcarbonyl, 1-t-butoxycarbonylpyrrolidin-3-ylcarbonyl and pyrrolidin-3-ylcarbonyl.

In another embodiment of the invention, preferably R ⁵ is —C (O) NR ⁹ R ¹⁰ , —C (O) R ⁹ or —C (O) C (O) R ⁹ ; here

R ⁹ and R ¹⁰ are independently hydrogen, C _1-10 alkyl, C _1-4 alkoxy, carbocyclyl or heterocyclyl; Wherein R ⁹ and R ¹⁰ may be optionally substituted independently with one or more R ¹¹ on carbon; Wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by R ¹² ;

Or R ⁹ and R ¹⁰ together with the nitrogen to which they are attached form a heterocycle optionally substituted with one or more R ¹³ on carbon; Wherein if said heterocycle contains an —NH— moiety that nitrogen may be optionally substituted by R ¹⁴ ;

R ¹¹ and R ¹³ are independently halo, hydroxy, carbamoyl, amino, carboxy, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkanoylamino, C _1-4 alkoxycarbonyl, N -(C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _1-4 alkoxycarbonylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _{a wherein} a is 0 or 2, heterocyclyl, heterocyclyloxy or carbocyclyl; Wherein R ¹¹ and R ¹³ can be optionally substituted independently with one or more R ¹⁵ on carbon;

R ¹² and R ¹⁴ are independently C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, heterocyclyl and carbocyclylC _1-4 alkyl;

R ¹⁵ is selected from hydroxy, amino, C _1-4 alkoxycarbonylamino, C _1-4 alkoxy, N, N- (C _1-4 alkyl) ₂ amino, heterocyclyl.

In another aspect of the invention, more preferably R ⁵ is —C (O) NR ⁹ R ¹⁰ , —C (O) R ⁹ or —C (O) C (O) R ⁹ ; here

R ⁹ and R ¹⁰ are independently hydrogen, C _1-6 alkyl, C _1-4 alkoxy, cyclopropyl, 2-H-5,6-dihydropyranyl, 4-H-5,6-dihydropyranyl , 2-oxotetrahydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, 2-oxopyrrolidinyl, pyrazinyl, 1,2,5,6-tetrahydropyridinyl, isoxazolyl, 1,2,4 -Triazolyl, tetrahydrothienyl, tetrahydropyranyl or piperidinyl; Wherein R ⁹ and R ¹⁰ may be optionally substituted independently with one or more R ¹¹ on carbon; Wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by R ¹² ;

Or R ⁹ and R ¹⁰ together with the nitrogen to which they are attached piperidinyl, pyrrolidinyl, homopiperazinyl, 4-oxohomopiperazinyl, morpholino, 2 optionally substituted with one or more R ¹³ on carbon with carbon to which they are attached; Oxopiperazinyl or piperazinyl; Wherein if said heterocycle contains an —NH— moiety that nitrogen may be optionally substituted by R ¹⁴ ;

R ¹¹ and R ¹³ are independently halo, hydroxy, carboxy, carbamoyl, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkanoylamino, C _1-4 alkoxycarbonyl, N -(C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _1-4 alkoxycarbonylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkyl S (O) _a , wherein a is 0 or 2, 1,1-dioxotetrahydrothienyl, triazolyl, 2- Pyrrolidinone, tetrahydropyran, pyridyl, piperidinyl, 2,4-dioxoimidazolidinyl, tetrahydrofuranyl, tetrahydrofuranyloxy, 4-oxo-1,4-dihydropyridinyl, Pyrazinyl, cyclohexyl or phenyl; Wherein R ¹¹ and R ¹³ can be optionally substituted independently with one or more R ¹⁵ on carbon;

R ¹² and R ¹⁴ are independently C _1-4 alkyl, C _1-4 alkanoyl, carbamoyl, C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, pyridyl and benzyl;

R ¹⁵ is selected from hydroxy, C _1-4 alkoxy, amino, C _1-4 alkoxycarbonylamino, N, N- (C _1-4 alkyl) ₂ amino and pyrrolinyl.

In another embodiment of the invention, R ⁵ is 3-ethoxycarbonylpiperidin-1-ylcarbonyl, 3-hydroxymethylpiperidin-1-ylcarbonyl, 4-carbamoylpiperidine -1-ylcarbonyl, 4-ethoxycarbonylpiperidin-1-ylcarbonyl, 1-acetylpiperidin-4-ylcarbonyl, 1-N, N-dimethylcarbamoylpiperidine- 3-ylcarbonyl, 1-acetylpiperidin-3-ylcarbonyl, 3-methoxycarbonylpyrrolidin-1-ylcarbonyl, 1-N-methylcarbamoylpiperidin-3-yl Carbonyl, 1-Carbamoylpiperidin-3-ylcarbonyl, 3-N, N-dimethylcarbamoylpyrrolidin-1-ylcarbonyl, 1-carbamoylpiperidin-4-yl Carbonyl, 1-N, N-dimethylcarbamoylpiperidin-4-ylcarbonyl, 1-acetylpyrrolidin-3-ylcarbonyl, 1-N, N-dimethylcarbamoylpyrrolidine- 3-ylcarbonyl, 1-N-methylcarbamoylpyrrolidin-3-ylcarbonyl, 1-hydroxy-3-methylpent-2-ylaminocarbonyl, 3-hydroxy-3-phenylprop Ph-2-yl Minocarbonyl, (1-hydroxycyclohex-1-yl) methylaminocarbonyl, N-methyl-N- (3-phenyl-3-hydroxyprop-2-yl) aminocarbonyl, 2-hydroxy Hydroxymethylpiperidin-1-ylcarbonyl, 2-hydroxymethylpyrrolidin-1-ylcarbonyl, 3-hydroxypiperidin-1-ylcarbonyl, 3-cyclohexyl-1-hydroxy Prop-2-ylaminocarbonyl, 3-hydroxyprop-2-ylaminocarbonyl, 3-hydroxypyrrolidin-1-ylcarbonyl, 4-N, N-dimethylcarbamoylpiperi Din-1-ylcarbonyl, 4-N-methylcarbamoylpiperidin-1-ylcarbonyl, 3-hydroxypent-3-ylcarbonylamino, N, N-dimethylaminoacetyl, methoxyacetyl , Ethoxyacetyl, 2-hydroxybut-2-ylcarbonyl, N-methylpyrrolidin-2-ylcarbonyl, 2-oxotetrahydrofuran-5-ylcarbonyl, tetrahydrofuran-2-yl Carbonyl, 2-hydroxy-1-acetamidoethyl, 3-methoxypropionyl, 2-methoxyethoxyacetyl, 3- Oxypropionyl, 3-methylthiopropionyl, 2-trifluoromethyl-2-hydroxypropionyl, 2-phenyl-2-methoxypropionyl, piperidin-1-ylacetyl, tetrahydrofuran-3 -Yloxyacetyl, tetrahydrothien-2-ylcarbonyl, 3-hydroxypropionyl, (3-hydroxymethyltetrahydropyran-3-yl) carbonyl, (1-carbamoylcycloprop-1 -Yl) carbonyl, 3-acetamidopropionyl, 2-H-5,6-dihydropyran-3-ylcarbonyl, 3-ethylthioprop-2-ylcarbonyl, 2,3-4 -H-dihydropyran-2-ylcarbonyl, 1-hydroxy-3-methylbutylcarbonyl, 3-N, N-dimethylaminopyrrolidin-1-ylcarbonyl, 2-methyl-2-hydrate Hydroxypropionyl, N-methyl-N- (2-hydroxyethyl) aminocarbonyl, N, N-di (2-hydroxyethyl) aminocarbonyl, tetrahydrofuran-2-ylmethylaminocarbonyl, 2 , 6-dimethylpiperazin-4-ylcarbonyl, 4-hydroxypiperidin-1-ylcarbonyl, N-methyl- N- (N-methylpiperidin-4-yl) aminocarbonyl, 2-methoxyprop-2-ylaminocarbonyl, 2-hydroxypropylaminocarbonyl, 2-methoxyethylaminocarbonyl, 2-methoxymethylpyrrolidin-1-ylcarbonyl, 2- (pyrrolidin-1-ylmethyl) pyrrolidin-1-ylcarbonyl, 3-hydroxypiperidin-1-ylcarbonyl , N-methyl-N- (3-N, N-dimethylaminopropyl) aminocarbonyl, N, N-di (2-methoxyethyl) aminocarbonyl, 1-acetylpiperazin-4-ylcarbonyl, 3-acetamidopyrrolidin-1-ylcarbonyl, 3-t-butoxycarbonylaminopyrrolidin-1-ylcarbonyl, N-methyl-N- (N-methylpyrrolidin-3-yl ) Aminocarbonyl, N-methyl homopiperazin-4-ylcarbonyl, 1-hydroxy-3-methylbut-2-ylaminocarbonyl, 1-hydroxyprop-2-ylaminocarbonyl, 2 , 6-dimethylmorpholinocarbonyl, N-methyl-N- (2-methoxyethyl) aminocarbonyl, N-methyl-N- (N-benzylpyrrolidin-3-yl) aminocarbonyl, 2 - Sohopiperazin-4-ylcarbonyl, 3-mesylpyrrolidin-1-ylcarbonyl, 2- (N, N-dimethylaminomethyl) piperidin-1-yl, N-acetylhomopiperazine- 4-ylcarbonyl, N-methyl-N- (2,3-dihydroxypropyl) aminocarbonyl, homopiperazin-1-ylcarbonyl, 2- (N-methylamino) ethylaminocarbonyl, 2 -Hydroxymethylpyrrolidin-1-ylcarbonyl, 3-N, N-dimethylaminopyrrolidin-1-ylcarbonyl, N-methyl-N- (3-N, N-dimethylaminoethyl) amino Carbonyl, 2,4-dioxoimidazolidine-5-ylacetyl, 2-oxopyrrolidin-5-ylcarbonyl, pyrazin-2-ylcarbonyl, N, N-dimethylaminoacetyl, 2- Acetamidopropionyl, 3- (N, N-dimethylcarbamoyl) propionyl, mesylacetyl, N-methyl-1,2,5,6-pyridylcarbonyl, 5-methylisoxazol-4-yl Carbonyl, 3-hydroxypropionyl, 3,5-dimethyl-1,2,4-triazol-1-ylacetyl, tetrahydrofuran-3-yloxyacetyl, 4-oxo-1,4-dihydro Lead-1-ylacetyl, 3-pyrazin-2-ylpropionyl, 4-carboxypiperidin-1-ylcarbonyl, piperidin-4-ylcarbonyl, piperidin-3-ylcarbonyl, 1-t-butoxycarbonylpyrrolidin-3-ylcarbonyl, pyrrolidin-3-ylcarbonyl, t-butoxycarbonyl, morpholinocarbonyl, tetrahydrofuran-3-ylcarbonyl , 2- (1,1-dioxotetrahydrothien-3-yl) acetyl, 3-carbamoylpiperidin-1-ylcarbonyl, 2,2,2-trichloroacetyl, 4- (pyrid -2-yl) piperazin-1-ylcarbonyl, 3- (pyrid-4-yl) propionyl, N- [2- (pyrid-4-yl) ethyl] -N-methylaminocarbonyl, N- (pyrid-3-ylmethyl) -N-methylaminocarbonyl, N- (1-methylpiperid-4-yl) -N-methylaminocarbonyl, 4-hydroxymethylpiperid-1- Ilcarbonyl, 4- (pyrid-4-yl) piperid-1-ylcarbonyl, 4-hydroxyethylpiperid-1-ylcarbonyl, 3-methoxy-2- (t-butoxycarbon Bonylamino) propionyl, 2- (1,2,4-tria Zol-1-yl) acetyl, 2- (2-pyrrolidinone-1-yl) acetyl, tetrahydropyran-4-ylcarbonyl, 2- [3- (t-butoxycarbonylamino) cyclohexyl] Acetyl, 3-methoxy-2-aminopropionyl, 2- (3-aminocyclohexyl) acetyl, 4-pyrid-4-ylpiperidin-1-yloxalyl, 4-pyrid-2-ylpiperazine -1-yloxalyl, 4-hydroxypiperidin-1-yl, 2-hydroxyethylaminocarbonyl and N-methoxy-N-methylaminocarbonyl.

In another embodiment of the invention, R ⁵ is 3-ethoxycarbonylpiperidin-1-ylcarbonyl, 3-hydroxymethylpiperidin-1-ylcarbonyl, 4-carbamoylpiperidine -1-ylcarbonyl, 4-ethoxycarbonylpiperidin-1-ylcarbonyl, 1-acetylpiperidin-4-ylcarbonyl, 1-N, N-dimethylcarbamoylpiperidine- 3-ylcarbonyl, 1-acetylpiperidin-3-ylcarbonyl, 3-methoxycarbonylpyrrolidin-1-ylcarbonyl, 1-N-methylcarbamoylpiperidin-3-yl Carbonyl, 1-Carbamoylpiperidin-3-ylcarbonyl, 3-N, N-dimethylcarbamoylpyrrolidin-1-ylcarbonyl, 1-carbamoylpiperidin-4-yl Carbonyl, 1-N, N-dimethylcarbamoylpiperidin-4-ylcarbonyl, 1-acetylpyrrolidin-3-ylcarbonyl, 1-N, N-dimethylcarbamoylpyrrolidine- 3-ylcarbonyl, 1-N-methylcarbamoylpyrrolidin-3-ylcarbonyl, 1-hydroxy-3-methylpent-2-ylaminocarbonyl, 3-hydroxy-3-phenylprop Ph-2-yl Minocarbonyl, (1-hydroxycyclohex-1-yl) methylaminocarbonyl, N-methyl-N- (3-phenyl-3-hydroxyprop-2-yl) aminocarbonyl, 2-hydroxy Hydroxymethylpiperidin-1-ylcarbonyl, 2-hydroxymethylpyrrolidin-1-ylcarbonyl, 3-hydroxypiperidin-1-ylcarbonyl, 3-cyclohexyl-1-hydroxy Prop-2-ylaminocarbonyl, 3-hydroxyprop-2-ylaminocarbonyl, 3-hydroxypyrrolidin-1-ylcarbonyl, 4-N, N-dimethylcarbamoylpiperi Din-1-ylcarbonyl, 4-N-methylcarbamoylpiperidin-1-ylcarbonyl, 3-hydroxypent-3-ylcarbonylamino, N, N-dimethylaminoacetyl, methoxyacetyl , Ethoxyacetyl, 2-hydroxybut-2-ylcarbonyl, N-methylpyrrolidin-2-ylcarbonyl, 2-oxotetrahydrofuran-5-ylcarbonyl, tetrahydrofuran-2-yl Carbonyl, 2-hydroxy-1-acetamidoethyl, 3-methoxypropionyl, 2-methoxyethoxyacetyl, 3- Ethoxypropionyl, 3-methylthiopropionyl, 2-trifluoromethyl-2-hydroxypropionyl, 2-phenyl-2-methoxypropionyl, piperidin-1-ylacetyl, tetrahydrofuran- 3-yloxyacetyl, tetrahydrothien-2-ylcarbonyl, 3-hydroxypropionyl, (3-hydroxymethyltetrahydropyran-3-yl) carbonyl, (1-carbamoylcycloprop- 1-yl) carbonyl, 3-acetamidopropionyl, 2-H-5,6-dihydropyran-3-ylcarbonyl, 3-ethylthioprop-2-ylcarbonyl, 2,3- 4-H-dihydrpyran-2-ylcarbonyl, 1-hydroxy-3-methylbutylcarbonyl, 3-N, N-dimethylaminopyrrolidin-1-ylcarbonyl, 2-methyl-2- Hydroxypropionyl, N-methyl-N- (2-hydroxyethyl) aminocarbonyl, N, N-di (2-hydroxyethyl) aminocarbonyl, tetrahydrofuran-2-ylmethylaminocarbonyl, 2,6-dimethylpiperazin-4-ylcarbonyl, 4-hydroxypiperidin-1-ylcarbonyl, N-methyl -N- (N-methylpiperidin-4-yl) aminocarbonyl, 2-methoxyprop-2-ylaminocarbonyl, 2-hydroxypropylaminocarbonyl, 2-methoxyethylaminocarbonyl , 2-methoxymethylpyrrolidin-1-ylcarbonyl, 2- (pyrrolidin-1-ylmethyl) pyrrolidin-1-ylcarbonyl, 3-hydroxypiperidin-1-ylcarbon Bonyl, N-methyl-N- (3-N, N-dimethylaminopropyl) aminocarbonyl, N, N-di (2-methoxyethyl) aminocarbonyl, 1-acetylpiperazin-4-ylcarbonyl , 3-acetamidopyrrolidin-1-ylcarbonyl, 3-t-butoxycarbonylaminopyrrolidin-1-ylcarbonyl, N-methyl-N- (N-methylpyrrolidine-3- 1) aminocarbonyl, N-methyl homopiperazin-4-ylcarbonyl, 1-hydroxy-3-methylbut-2-ylaminocarbonyl, 1-hydroxyprop-2-ylaminocarbonyl, 2,6-dimethylmorpholinocarbonyl, N-methyl-N- (2-methoxyethyl) aminocarbonyl, N-methyl-N- (N-benzylpyrrolidin-3-yl) aminocarbonyl, 2- Oxohomopiperazin-4-ylcarbonyl, 3-mesylpyrrolidin-1-ylcarbonyl, 2- (N, N-dimethylaminomethyl) piperidin-1-yl, N-acetylhomopiperazine- 4-ylcarbonyl, N-methyl-N- (2,3-dihydroxypropyl) aminocarbonyl, homopiperazin-1-ylcarbonyl, 2- (N-methylamino) ethylaminocarbonyl, 2 -Hydroxymethylpyrrolidin-1-ylcarbonyl, 3-N, N-dimethylaminopyrrolidin-1-ylcarbonyl, N-methyl-N- (3-N, N-dimethylaminoethyl) amino Carbonyl, 2,4-dioxoimidazolidine-5-ylacetyl, 2-oxopyrrolidin-5-ylcarbonyl, pyrazin-2-ylcarbonyl, N, N-dimethylaminoacetyl, 2- Acetamidopropionyl, 3- (N, N-dimethylcarbamoyl) propionyl, mesylacetyl, N-methyl-1,2,5,6-pyridylcarbonyl, 5-methylisoxazol-4-yl Carbonyl, 3-hydroxypropionyl, 3,5-dimethyl-1,2,4-triazol-1-ylacetyl, tetrahydrofuran-3-yloxyacetyl, 4-oxo-1,4-dihydro Pyrid-1-ylacetyl, 3-pyrazin-2-ylpropionyl, 4-carboxypiperidin-1-ylcarbonyl, piperidin-4-ylcarbonyl, piperidin-3-ylcarbonyl , 1-t-butoxycarbonylpyrrolidin-3-ylcarbonyl, pyrrolidin-3-ylcarbonyl, t-butoxycarbonyl, morpholinocarbonyl, tetrahydrofuran-3-ylcar Bonyl, 2- (1,1-dioxotetrahydrothien-3-yl) acetyl, 3-carbamoylpiperidin-1-ylcarbonyl, 2,2,2-trichloroacetyl, 4- (pi Lead-2-yl) piperazin-1-ylcarbonyl, 3- (pyrid-4-yl) propionyl, N- [2- (pyrid-4-yl) ethyl] -N-methylaminocarbonyl , N- (pyrid-3-ylmethyl) -N-methylaminocarbonyl, N- (1-methylpiperid-4-yl) -N-methylaminocarbonyl, 4-hydroxymethylpiperid-1 -Ylcarbonyl, 4- (pyrid-4-yl) piperid-1-ylcarbonyl, 4-hydroxyethylpiperid-1-ylcarbonyl, 3-methoxy-2- (t-butoxy Carbonylamino) propionyl, 2- (1,2,4-tri Zol-1-yl) acetyl, 2- (2-pyrrolidinone-1-yl) acetyl, tetrahydropyran-4-ylcarbonyl, 2- [3- (t-butoxycarbonylamino) cyclohexyl] Acetyl, 3-methoxy-2-aminopropionyl, 2- (3-aminocyclohexyl) acetyl, 4-pyrid-4-ylpiperidin-1-yloxalyl, 4-pyrid-2-ylpiperazine -1-yloxalyl, 4-hydroxypiperidin-1-yl, 2-hydroxyethylaminocarbonyl, N-methoxy-N-methylaminocarbonyl, 3-N, N-dimethylcarbamoylpi Ferridin-1-ylcarbonyl, 3-N-methylcarbamoylpiperidin-1-ylcarbonyl and 3-carboxypiperidin-1-ylcarbonyl.

Preferably, R ⁶ and R ⁸ are independently selected from halo or C _1-4 alkyl.

More preferably, R ⁶ and R ⁸ are selected from fluoro, chloro, bromo or methyl.

Preferably, R ⁶ is 2-methyl.

Preferably, R ⁶ is 2-methyl and R ⁴ is methyl.

In one embodiment of the invention, preferably m is zero.

In another embodiment of the invention, preferably m is 1.

Preferably, m is 0 or 1.

When m is 1, the substituent R ⁶ is preferably at position 2, that is, at the ortho position relative to the —NHR ⁵ substituent.

Therefore, in a preferred embodiment of the invention, there is provided a compound of formula I (shown above) or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:

R ¹ is selected from C _1-4 alkyl optionally substituted with one or more R ⁷ on carbon; Wherein R ⁷ is C _1-4 alkoxy;

R ² and R ³ together form-(CH ₂ ) ₄ -or-(CH) ₄ -optionally substituted with R ⁸ ; Wherein R ⁸ is selected from halo or C _1-4 alkyl;

R ² and R ³ together form-(CH ₂ ) ₄ -or-(CH) ₄ -optionally substituted with R ⁸ ; Wherein R ⁸ is selected from fluoro, bromo or methyl;

R ⁴ is methyl or isopropyl;

R ⁵ is —C (O) NR ⁹ R ¹⁰ , —C (O) R ⁹ or —C (O) C (O) R ⁹ ; here

R ⁹ and R ¹⁰ are independently C _1-10 alkyl, C _1-4 alkoxy or heterocyclyl; Wherein R ⁹ and R ¹⁰ may be optionally substituted independently with one or more R ¹¹ on carbon; Wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by R ¹² ;

Or R ⁹ and R ¹⁰ together with the nitrogen to which they are attached form at least one substituted heterocycle on the carbon with R ¹³ ; Wherein if said heterocycle contains an —NH— moiety that nitrogen may be optionally substituted by R ¹⁴ ;

R ¹¹ and R ¹³ are independently selected from halo, hydroxy, carbamoyl, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxycarbonylamino, heterocyclyl, carbocyclyl ; Wherein R ¹¹ and R ¹³ can be optionally substituted independently with one or more R ¹⁵ on carbon;

R ¹² and R ¹⁴ are independently selected from C _1-4 alkyl, heterocyclyl;

R ¹⁵ is selected from hydroxy, amino, C _1-4 alkoxycarbonylamino;

R ⁶ and R ⁸ are independently selected from halo or C _1-4 alkyl.

Therefore, in a preferred embodiment of the invention, there is provided a compound of formula I (shown above) or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:

R ¹ is selected from C _1-4 alkyl optionally substituted with one or more R ⁷ on carbon; Wherein R ⁷ is C _1-4 alkoxy;

R ² and R ³ together form-(CH ₂ ) ₄ -or-(CH) ₄ -optionally substituted with R ⁸ ; Wherein R ⁸ is selected from fluoro, bromo or methyl;

R ⁴ is methyl or isopropyl;

R ⁵ is —C (O) NR ⁹ R ¹⁰ , —C (O) R ⁹ or —C (O) C (O) R ⁹ ; here

R ⁹ and R ¹⁰ are independently C _1-10 alkyl, C _1-4 alkoxy or heterocyclyl; Wherein R ⁹ and R ¹⁰ may be optionally substituted independently with one or more R ¹¹ on carbon; Wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by R ¹² ;

Or R ⁹ and R ¹⁰ together with the nitrogen to which they are attached form a heterocycle optionally substituted with one or more R ¹³ on carbon; Wherein if said heterocycle contains an —NH— moiety that nitrogen may be optionally substituted by R ¹⁴ ;

R ¹¹ and R ¹³ are independently selected from halo, hydroxy, carbamoyl, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxycarbonylamino, heterocyclyl, carbocyclyl ; Wherein R ¹¹ and R ¹³ can be optionally substituted independently with one or more R ¹⁵ on carbon;

R ¹² and R ¹⁴ are independently selected from C _1-4 alkyl, heterocyclyl;

R ¹⁵ is selected from hydroxy, amino, C _1-4 alkoxycarbonylamino;

R ⁶ and R ⁸ are independently selected from halo or alkyl;

m is 0 or 1;

Therefore, in another preferred embodiment of the invention, there is provided a compound of formula I (shown above) or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:

R ¹ is selected from C _1-4 alkyl optionally substituted with one or more R ⁷ on carbon; Wherein R ⁷ is C _1-4 alkoxy;

R ² and R ³ together form-(CH ₂ ) ₄ -or-(CH) ₄ -optionally substituted with R ⁸ ; Wherein R ⁸ is selected from halo or C _1-4 alkyl;

R ⁴ is methyl or isopropyl;

R ⁵ is —C (O) NR ⁹ R ¹⁰ , —C (O) R ⁹ or —C (O) C (O) R ⁹ ; here

R ⁹ and R ¹⁰ are independently C _1-10 alkyl, C _1-4 alkoxy or heterocyclyl; Wherein R ⁹ and R ¹⁰ may be optionally substituted independently with one or more R ¹¹ on carbon; Wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by R ¹² ;

Or R ⁹ and R ¹⁰ together with the nitrogen to which they are attached form a heterocycle optionally substituted with one or more R ¹³ on carbon; Wherein if said heterocycle contains an —NH— moiety that nitrogen may be optionally substituted by R ¹⁴ ;

R ¹¹ and R ¹³ are independently halo, hydroxy, carbamoyl, amino, carboxy, carbamoyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkanoylamino, C _1-4 alkoxy Carbonyl, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _1-4 alkoxycarbonylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkyl S (O) _a , wherein a is 0 or 2, heterocyclyl, heterocyclyloxy or carbocyclyl Is selected from; Wherein R ¹¹ and R ¹³ can be optionally substituted independently with one or more R ¹⁵ on carbon;

R ¹² and R ¹⁴ are independently C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, heterocyclyl and carbocyclylC _1-4 alkyl;

R ¹⁵ is selected from hydroxy, amino, C _1-4 alkoxycarbonylamino, C _1-4 alkoxy, N, N- (C _1-4 alkyl) ₂ amino, heterocyclyl;

R ⁶ is 2-methyl;

m is 0 or 1;

In another aspect of the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof, selected from:

3- (morpholinocarbonylamino) -4-methyl-9-isopropyl-9H-carbazole;

3- (3-carbamoylpiperidin-1-ylcarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole;

3- (1,1-dioxotetrahydrothien-3-ylmethylcarbonylamino) -4-methyl-9-isopropyl-9H-carbazole;

3- (morpholinocarbonylamino) -4-methyl-6-fluoro-9-isopropyl-9H-carbazole;

3- (3-carbamoylpiperidin-1-ylcarbonylamino) -4-methyl-9-isopropyl-9H-carbazole;

3- (4-hydroxypiperidin-1-ylcarbonylamino) -4-methyl-6-fluoro-9-isopropyl-9H-carbazole;

3- [3- (N-methylcarbamoyl) piperidin-1-ylcarbonylamino] -2,4-dimethyl-9-isopropyl-9H-carbazole;

3- [1- (N, N-dimethylcarbamoyl) piperidin-4-ylcarbonylamino] -2,4-dimethyl-9-isopropyl-9H-carbazole;

3- [1- (N, N-dimethylcarbamoyl) pyrrolidin-3-ylcarbonylamino] -2,4-dimethyl-9-isopropyl-9H-carbazole; And

3- [4-hydroxypiperidin-1-ylcarbonylamino] -2-methyl-9-isopropyl-9H-carbazole.

Preferred embodiments of the invention relate to compounds of formula (I) or pharmaceutically acceptable salts thereof.

Another aspect of the invention provides for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug or solvate thereof, consisting of the following process (unless otherwise stated, the variable groups are as defined in formula (I)): Provide a way:

Process a) for a compound of Formula I wherein R ⁵ is —C (O) R ⁹ ; Reacting an amine of formula II with an acid of formula III or an activated derivative thereof: or

Step b) for a compound of Formula I wherein R ⁵ is -C (O) NR ⁹ R ¹⁰ ; Reacting a compound of formula IV with an amine of formula V:

(Wherein L is a substitutable group)

Process c) for a compound of Formula I wherein R ⁵ is —C (O) NR ⁹ R ¹⁰ ; Reacting a compound of formula II with a compound of formula VI:

Step d) for a compound of Formula I wherein R ⁵ is -C (O) NR ⁹ R ¹⁰ and one of R ⁹ and R ¹⁰ is hydrogen; Reacting a compound of formula II with an isocyanate of formula VII:

Wherein R ^a is R ⁹ or R ¹⁰ but not hydrogen)

Step e) reacting a compound of formula VIII with a compound of formula IX:

(Wherein Z is a substitutable group or when R ¹ is C _1-4 alkanoyl, Z may be hydroxy)

Step f) if R ⁵ is a compound of Formula I wherein -C (O) NR ⁹ R ¹⁰ ; Reacting a compound of formula X with an amine of formula V;

And thereafter, as needed

i) converting the compound of formula I to another compound of formula I;

ii) removing any protecting groups;

iii) forming a pharmaceutically acceptable salt or prodrug or solvate thereof.

L is a substitutable group. Suitable values for L include phenols such as p-nitrophenol or pentafluorophenol.

Y is a substitutable group. Suitable values for Y include halo such as chloro, bromo or trifluoromethylsulfonyloxy.

Specific reaction conditions for the reaction are as follows.

Process a) The amine of formula II and the acid of formula III can be coupled together in the presence of a suitable coupling reagent. Standard peptide coupling reagents known in the art can be used as suitable coupling reagents or, for example, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally a base such as triethylamine, pyridine or 2 Carbonyldiimidazole and dicyclohexylcarbodiimide can be used in the presence of, 6-dialkylpyridine, such as 2,6-lutidine or 2,6-di-t-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide. The coupling reaction can be easily carried out at a temperature in the range of -40 to 40 ° C.

Suitable activated acid derivatives include acid halides such as acid chlorides and active esters such as pentafluorophenyl esters. The reaction of these types of compounds with amines is well known in the art, for example they can be reacted in the presence of a base as described above, in a solvent as described above. The reaction can be easily carried out at a temperature in the range of -40 to 40 ° C.

Amines of formula (II) and acids of formula (III) are commercially available, or they are known compounds, or they can be prepared by methods known in the art, for example in the examples for the preparation of compounds of formula (II). See the described method.

In addition, compounds of formula II may be prepared by the following schemes 1 and 2:

Wherein Y is a leaving group as defined above and step ii) in the final step in Scheme 2 is required when a compound of formula II is required in which R ² and R ³ together form-(CH ₂ ) _4- It is omitted.

As one skilled in the art, Scheme 2 can be adopted by starting with substituted cyclohexane, i.e., to provide R ⁸ , and wherein R ² and R ³ are both methyl using 2-oxo-3-chlorobutyl as starting material It will be appreciated that the compounds of II may be provided. Furthermore, in Scheme 2, compound (IId) has R ⁴ , which is hydrogen, so that the R ⁴ group can be introduced at a later stage in the synthesis, for example by the route illustrated in Scheme 1.

For compounds of Formula II wherein R ⁶ is 1-methyl and R ⁴ is methyl:

Wherein Y is a leaving group as defined above.

Those skilled in the art can employ Scheme 3 to provide different values of R ⁴ and R ⁶ , but as long as R ⁶ is in position 1 and equal to R ⁴ , two possible products are produced from the first stage of the synthesis. It will be recognized, and separation will be needed.

Wherein Y is a leaving group as defined above and step ii) in the final step in Scheme 4 is required when a compound of formula II is required in which R ² and R ³ together form-(CH ₂ ) _4- It is omitted.

Those skilled in the art can employ compounds of formula II wherein Scheme 2 starts with substituted cyclohexanes, i.e., to provide R ⁸ , and wherein both R ² and R ³ are methyl using 2-oxobutyl as starting material. It will be appreciated that it can be provided.

Compounds of formula (IIa), (IIc), (IId), (IIf), (IIg) and (IIj) are commercially available or they are known compounds or are prepared by methods known in the art.

Process b) The compound of formula IV and the amine of formula V together form a suitable base such as triethylamine, pyridine or 2,6-dialkylpyridines such as 2,6-lutidine or 2,6-di-t The reaction can be carried out in the presence of -butylpyridine or in the presence of excess compound (V) in a suitable solvent such as dichloromethane, ethyl acetate or tetrahydrofuran. The reaction can be easily carried out at a temperature in the range from -40 to 50 ° C.

Compounds of formula IV can be prepared from amines of formula II by methods known in the art. Compounds of formula (V) are commercially available, or they are known compounds, or they can be prepared by methods known in the art.

Process c) The compound of formula II and the compound of formula VI can be reacted in the presence of a base as described above in the presence of a suitable solvent such as dichloromethane, toluene or tetrahydrofuran. The reaction can be easily carried out at a temperature in the range of -40 to 100 ° C.

Compounds of formula (V) are commercially available, or they are known compounds, or they can be prepared by methods known in the art.

Process d) The compound of formula II and the compound of formula VII can be reacted in the presence of a suitable solvent such as toluene, dichloromethane or tetrahydrofuran.

Compounds of formula (VII) are commercially available, or they are known compounds, or they can be prepared by methods known in the art.

Process e) Compounds of formula (VIII) and compounds of formula (IX) are suitable bases such as sodium hydride, potassium hexamethyldisilazane, triethylamine, pyridine, or 2,6-dialkylpyridines, such as 2,6- The reaction may be carried out in a suitable solvent such as dichloromethane, ethyl acetate or tetrahydrofuran in the presence of lutidine or 2,6-di-t-butylpyridine. The reaction can be easily carried out at a temperature in the range of 25 ° C. to reflux temperature. When R ¹ is C _1-4 alkanol and Z is hydroxy, the compound of formula VIII and the compound of formula IX can be reacted together under the conditions as described in step a) above.

Compounds of formula (VIII) may be prepared by the procedures described for the preparation of compounds of formula (I), wherein R ¹ is hydrogen. Those skilled in the art will also recognize when a protecting group for this nitrogen is required. Therefore, compounds of formula (VIII) may also be prepared by deprotecting compounds of formula (I) in which R ¹ is a nitrogen protecting group.

Compounds of formula (IX) are commercially available, or they are known compounds, or they can be prepared by methods known in the art.

Process f) The compound of formula X and the amine of formula V can be reacted together under conditions similar to those described in process d).

Compounds of formula (X) can be prepared according to Scheme 5:

The compounds of formula (Xa) are commercially available, or they are known compounds, or they may be prepared by methods known in the art, for example reference may be made to the methods described in the Examples.

Some of the various ring substituents in the compounds of the present invention are introduced by standard aromatic substitution reactions or by conventional functional group modifications either before or after the processes described above, and are themselves included in the production embodiments of the present invention. Examples of such reactions and modifications include introduction of substituents by aromatic substitution reactions, reduction of substituents, alkylation of substituents and oxidation of substituents. Reagents and reaction conditions for such procedures are well known in the chemical art. Specific examples of aromatic substitution reactions include the introduction of nitro groups using concentrated nitric acid, under Friedel Kraft conditions, such as the introduction of acyl groups using acyl halides and Lewis acids (eg, aluminum trichloride), under Friedel Kraft conditions. There are methods for introducing alkyl groups using alkyl halides and Lewis acids (eg, aluminum trichloride) and reactions for introducing halo groups. Specific examples of denaturation include, for example, catalytic hydrogenation with a nickel catalyst or the treatment of iron in the presence of hydrochloric acid while heating to reduce the nitro group to an amino group, and oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl. General guidelines regarding reaction conditions and reagents can be found in Advanced Organic Chemistry, 4th edition, Jerry March, published by John wiley & Sons, 1992.

In addition, it should be appreciated that some of the reactions mentioned herein may need / desir to protect any sensitive groups in the compound. Where protection is required or desired and suitable methods of protection are known to those skilled in the art. Conventional protecting groups can be used in accordance with standard practice (for description see T.W. Green, protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, where the reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect such groups in some of the reactions mentioned herein.

Examples of suitable protecting groups for amino or alkylamino groups are acyl groups such as alkanoyl groups such as acetyl, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl groups, arylmethoxycarbonyl groups For example benzyloxycarbonyl or aroyl groups such as benzoyl. The deprotection conditions for such protecting groups necessarily depend on the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or alkoxycarbonyl groups or aroyl groups can be removed, for example, by hydrolysis with an appropriate base such as alkali metal hydrates such as lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as t-butoxycarbonyl groups can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups, for example For example, it may be removed by hydrogenation on a catalyst such as palladium on carbon or by treatment with Lewis acid, for example, boron tris (trifluoroacetate). Examples of suitable alternative protecting groups for primary amino groups are phthaloyl groups, which can be removed by treatment with alkylamines such as dimethylaminopropylamine or with hydrazine.

Examples of suitable protecting groups for hydroxy groups are acyl groups such as alkanoyl groups, such as acetyl, aroyl groups such as benzyl groups, or arylmethyl groups such as benzyl. Deprotection conditions for such protecting groups will necessarily depend on the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or aroyl group can be removed by hydrolysis with an appropriate base such as alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide. Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation, for example on a catalyst such as palladium on carbon.

Examples of suitable protecting groups for carboxyl groups include, for example, esterification groups that can be removed by hydrolysis with a base such as sodium hydroxide, such as methyl or ethyl groups, or by treatment with an organic acid such as an acid, for example trifluoroacetic acid. T-butyl groups, or benzyl groups, which can be removed by hydrogenation on a catalyst such as palladium on carbon.

Protecting groups can be removed at any easy step during synthesis using conventional techniques well known in the chemical art.

Biological analysis

The activity of the compounds of the present invention was measured in the following neuropeptide Y5 receptor binding assays. In addition, compounds were tested in binding assays for neuropeptide Y ₁ and neuropeptide Y ₂ receptors. Activity against these two receptors is contraindicated for neuropeptide Y5 antagonists.

a) High 5 ^TM Expression of Human Neuropeptide Y5 Receptor in Insect Cells

High 5 ^™ insect cells were obtained from Invitrogen (catalog number B855-02) and stored in liquid nitrogen. Cells are resuscitated from liquid nitrogen storage and stirred at 140 rpm with an Innova 4330 orbital shaker (New Brunswick Scientific) at 28 ° C. in a 100 ml ExCell 405 (JRH Biosciences) serum-free medium in a 250 ml conical flask (Corning). Grown in. Cultures were passaged routinely every 3 to 4 days.

High 5 ^TM insect cells were transfected with human NPY5 receptors as follows. PCR primers were selected from the huNPY5 receptor sequence [Genbank Accession No. U56079; Gerald et. al. (1996) Nature 382, 168-171, but expressed a protein with 10 amino residues shorter at the amino terminus starting from base 56 to base 1393 [Borowsky et. al. (1998) Regulatory Peptides 75-76, 45-53. These primers were used to amplify the huNPY5 receptor from human placental genomic DNA by PCR. This was then subcloned into pZERO2 (obtained from Invitron) for sequencing and recloned to pFASTBAC1 (obtained from Gibco BRL Life Technologies) for expression. Human NPYr was isolated from pZERO2 on the BamHI fragment and subcloned into pFastbac1 on the BamHI restriction site. The sequence of the junction was determined to allow correction before expression.

The baculovirus containing pFASTBAC1 was then transferred to the Bac-to-Bac ^™ baculovirus expression system [Anderson et. al. (1996) FASEB Journal 10 (6), 727-726 (obtained from Gib BRL Life Technologies) was generated using the protocol that Gibco BRL Life Technologies provided with this expression system.

High 5 ^TM insect cells were infected with baculovirus to transfect cells with the human neuropeptide Y5 receptor as follows: The batch was a 7 L bioreactor (FT-Applikon with 1.75 x 10 ⁹ medium logarithmic multiplier High 5 ^TM cells). The cells were grown for membrane preparation by inoculating 5 liters of ExCell 405 ^™ medium in. After 2 to 3 days of growth at 28 ° C., the medium logarithmic cultures were grown to 1.0. Infected with baculovirus expressing the human NPY5 receptor at an infection fold (MOI) of cells (typically 1 × ^{10 10} ), harvested 48 hours after infection by centrifugation, flashed with liquid nitrogen for storage at −80 ° C. Frozen.

b) membrane manufacturing procedures

The following buffer was prepared daily and stored at 4 ° C. 50 mM Tris HCl pH 7.4, 5 mM EDTA and 10% wv sucrose. Protease inhibitor cocktails (Möllinger Mannheim) were added to both buffers according to the manufacturer's instructions. The cells are thawed rapidly in three times the volume of their filled cells (3: 1 mixture of water and buffer) and 5 Vibra Cell sonicators (Sonics and Materials Incorporated) per second for High 5 ^TM insect cells. Graded) was used to routinely dissolve on ice. The cell lysate (typically 10-15 ml) was carefully loaded into a 10 ml 41% sucrose cushion filled with lysis buffer and used at a Beckman Optima LE-80K ultracentrifuge at 150,000 g at 4 ° C. for 1 hour. Rotated. Membrane fractions were carefully removed from phase to phase and diluted more than four times with lysis buffer. Membrane pellets were recovered by centrifugation at 150,000 g for 20 minutes at 4 ° C. with a Beckman Optima LE-80K ultracentrifuge and resuspended at 5 × 10 ⁷ cell equivalents / ml. The resuspended membrane was typically divided into 1 ml into working aliquots, flash frozen with liquid nitrogen and stored frozen at -80 ° C until use.

Prior to use, 1 ml High 5 ^TM membrane was thawed and resuspended in 8 ml binding buffer (see below). The membrane was used at approximately 7 μg / ml of protein per incubator.

c) Neuropeptide Y5 Receptor Binding Assay

The following reagents were used:

Binding buffer: 50 mM HEPES, 2.5 mM CaCl ₂ , 1 mM MgCl ₂ , 0.5% BSA, pH = 7.4

Binding wash buffer: 50 mM HEPES, 2.5 CaCl ₂ , 1 mM MgCl ₂ , 0.5 M NaCl, 0.5% BSA, pH = 7.4

Unifilter GFC Filter Plate: 50 μl of 0.5% Polyethylenimine was added to each well and left to equilibrate for 4 hours prior to use.

Incubated plate: 96 well polypropylene plate (silicone treated before use)

Test Compound: Compound was dissolved at a concentration of 1 mM in DMSO. The final concentration of DMSO in the assay did not exceed 1%.

Peptide PYY (Pancreatic Polypeptide Y): 10 μΜ stock in binding buffer.

¹²⁵ I PYY: 10 μCi / ml stock diluted at 1:10 dilution with binding buffer.

Assays were performed with 96 well microtiter plates. 10 μl of diluted test compound was added to each well of the plate, followed by 80 μl of membrane and radiolabeled ¹²⁵ I PYY (0.01 μCi per well). Global and nonspecific binding controls were included in each plate. Nonspecific binding wells received 10 μl of peptide PYY from 10 μM stock, while total binding wells received 10 μl of binding buffer. In each assay, a double dose response of peptide PYY was included, with a peak concentration of 1 μM.

The plates were incubated for 2 hours at room temperature with mixing and then filtered through pretreated filter plates. The incubation plates were washed twice with 150 μl of cold binding wash buffer per well, and then the filter plates were further washed with approximately 2.5 ml per well. The filter plate was dried overnight at room temperature, the bottom was sealed and 20 μl of scintillation agent (Microscint 40, Canberra Packard) was added to each well. The top of the plate was sealed and the plate was counted for 1 minute on a protocol instrument against ¹²⁵ I on a 96 well plate liquid scintillation counter (Top Count, Canberra Packard).

Compounds were considered active if they inhibited binding above 50% at a concentration of 10 μM. Dose responses were performed for all compounds found to be active (two 8 point curves).

Although the pharmacological properties of the compounds of formula (I) depend on the structural changes as expected, the compounds of formula (I) generally had IC ₅₀ in the test, for example in the range of 0.0002 to 200 μM.

In order to utilize a compound of formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment (including prophylactic treatment) of mammals, including humans, it can usually be formulated as a pharmaceutical composition according to standard pharmaceutical practice.

The compositions of the present invention may be used orally (eg, tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical (eg creams, ointments, gels or aqueous). Or oily solutions or suspensions), sterile aqueous or oily solutions for aeration (eg, fine powders or liquid aerosols), for inhalational administration (eg, fine powders) or for parenteral administration (eg, for intravenous, intramuscular or intramuscular administration). Or suppositories for enteral administration).

The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavors and / or preservatives.

Examples of pharmaceutically acceptable excipients suitable for tablet formulations include inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; Granulating and disintegrating agents such as corn starch or alginic acid; Binders such as starch; Lubricants such as magnesium stearate, stearic acid or talc; Preservatives such as ethyl or propyl p-hydroxybenzoate; And antioxidants such as ascorbic acid. Tablet formulations may or may not be coated using conventional coatings and procedures, which are well known in the art, in any case to modify the disruption and subsequent absorption of the active ingredients in the gastrointestinal tract, or to improve their stability and / or appearance. You may not.

Oral compositions may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as a soft capsule in which the active ingredient is mixed with water or oil such as peanut oil, liquid paraffin or olive oil. It may be in the form.

In general, the aqueous suspension comprises one or more suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, tragacanth gum and acacia gum; Dispersing or wetting agents, such as the condensation products of lecithin or alkylene oxides with fatty acids (eg polyoxyethylene stearate), or the condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, or ethylene oxide The active ingredient in fine powder form together with the condensation product of fatty acids and partial esters derived from hexitol, such as polyoxyethylene sorbitol monooleate, or ethylene oxide, and the condensation product of partial esters derived from fatty acids and hexitol anhydride It contains. In addition, the aqueous suspension may contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate), antioxidants (such as ascorbic acid), colorants, flavors and / or sweeteners (such as sucrose, saccharin or aspart). Tom).

Oily suspensions can be prepared by suspending the active ingredient in vegetable oils (eg, arachis oil, olive oil, sesame oil or coconut oil) or mineral oils (eg liquid paraffin). Oily suspensions may also contain thickening agents such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents such as those described above may be added to provide a delicious oral formulation. Such compositions can be preserved by adding antioxidants such as ascorbic acid.

In general, dispersible powders and granules suitable for the preparation of an aqueous suspension by addition of water contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents include those already mentioned above. Additional excipients may also be present, such as sweetening, flavoring and coloring agents.

In addition, the pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include natural gums such as acacia gum or tragacanth gum, natural phospholipids such as soybeans, esters or partial esters derived from lecithin, fatty acids and hexitol anhydrides (eg sorbitan monooleate), and the partial esters Condensation products of ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening, flavoring and preservatives.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, polypropylene glycol, sorbitol, aspartame or sucrose, and may also contain analgesics, preservatives, flavors and / or colorants.

In addition, the pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions or oily suspensions, which may be prepared according to known procedures using one or more suitable dispersing or wetting agents and suspending agents. In addition, the sterile injectable preparation may be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.

Suppositories can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at the intestinal temperature and will therefore melt in the intestine to release the drug. Examples of suitable excipients are cocoa butter and polyethylene glycols.

Generally, topical preparations such as creams, ointments, gels and aqueous or oily solutions or suspensions can be obtained by formulating the active ingredients with conventional topically acceptable vehicles or diluents using conventional procedures well known in the art.

The composition for aeration may be in the form of a fine powder containing particles having an average diameter of, for example, 30 μm or less, the powder itself consisting of the active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose. Consists of the active ingredient. The breathable powder is then usually kept in a capsule containing 1 to 50 mg of the active ingredient for use in a turbo inhaler device, for example as used in the aeration of the conventional formulation sodium chromoglycate.

Compositions for inhalation administration may be in the form of conventional pressurized aerosols arranged to dispense the active ingredient as an aerosol containing finely divided solids or droplets. Conventional aerosol propellants such as fluorohydrocarbons or hydrocarbons can be used, and the aerosol device is readily arranged to dispense a metered amount of active ingredient.

For further information regarding formulations, see Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, formulations for oral administration to humans generally contain from 0.5 mg to 2 g of active ingredient in a suitable and easy amount of excipient, which may be from about 5 to about 98% by weight of the total composition. Generally, unit dosage forms contain about 1 mg to 500 mg of active ingredient. For further information regarding the route of administration and administration regimen, see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

The size of the dosage for therapeutic or prophylactic purposes of the compound of formula (I) will depend essentially on the nature and severity of the condition of the animal or patient, on age and sex, and on the route of administration, according to well-known medical principles.

In using the compounds of formula (I) for therapeutic or prophylactic purposes, administrations are generally administered to accommodate daily dosages, such as in the range of 0.5 mg to 75 mg / kg body weight, if a divided dose is required. Generally, lower doses are administered when using the parenteral route. Thus, for intravenous administration, for example, dosages ranging from 0.5 mg to 30 mg / kg body weight are generally used. Similarly, for aeration administration, for example, dosages in the range of 0.5 mg to 25 mg / kg body weight are used. However, oral administration, especially in tablet form, is preferred. Typically, unit dosage forms contain about 1 mg to 500 mg of a compound of the present invention.

The compounds of the present invention can be used in combination with other drugs and therapeutic agents used in the treatment of disease states that benefit from antagonism at the neuropeptide Y5 receptor. For example, the compounds of formula (I) can be used in combination with drugs and therapeutic agents used in the treatment of eating disorders.

When formulated as a fixed dosage, such combination products use a compound of the invention within the dosage ranges described herein and other pharmaceutically active agents within the approved dosage ranges. If a combination formulation is inappropriate, continuous use may be considered.

While compounds of formula (I) are of major value as therapeutics for warm-blooded animals such as humans, they are also useful if it is desired to antagonize binding at the neuropeptide Y5 receptor. Thus, they are useful as pharmacological standards for the development of new biological tests and for the study of new pharmacological agents.

According to another aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof together with a pharmaceutically acceptable diluent or carrier.

According to one aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof as a medicament.

According to another aspect of the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate for use in a method of treating warm blooded animals by therapy.

According to another aspect of the invention, there is provided a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt, prodrug or solvate thereof for such treatment in a warm blooded animal in need of treatment of a disorder mediated by the neuropeptide Y5 receptor. Pharmaceutically compositions comprising an acceptable diluent or carrier are provided.

An example of a "disorder mediated by the neuropeptide Y5 receptor" is a dietary disorder. Examples of eating disorders include obesity, abnormal appetite or anorexia nervosa. Examples of “related disorders” are diabetes, dyslipidemia, hypertension and sleep disorders. Preferably, "associated disorder" means diabetes.

According to another aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof, in combination with a pharmaceutically acceptable diluent or carrier, for the treatment of a dietary disorder in a warm blooded animal Pharmaceutical compositions are provided.

According to another aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof, for use in promoting weight loss, together with a pharmaceutically acceptable diluent or carrier A pharmaceutical composition is provided.

Preferably, promoting weight loss means promoting weight loss in warm-blooded animals. Warm-blooded animals are preferably human.

According to another aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof in the manufacture of a medicament for the treatment of a dietary disorder in a warm blooded animal.

According to another aspect of the present invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof in the manufacture of a medicament for promoting weight loss.

The use of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof in the manufacture of a medicament for the treatment of a eating disorder in a warm blooded animal is provided.

The use of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof in the manufacture of a medicament for promoting weight loss is provided.

According to another aspect of the invention, there is provided a method of treating a dietary disorder in a warm blooded animal comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof Is provided.

According to another aspect of the present invention there is provided a method of promoting weight loss, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof.

The invention is now illustrated by the following non-limiting examples, unless otherwise indicated:

(i) the temperature is given in degrees Celsius (° C.); The operation was carried out at room temperature or at room temperature, ie in the range of 18-25 ° C .;

(ii) the organic solution is dried over anhydrous magnesium sulfate unless otherwise indicated; Evaporation of the solvent was carried out using a rotary evaporator at a bath temperature of up to 60 ° C. under reduced pressure (600 to 4000 Pascal; 4.5 to 30 mmHg);

(iii) chromatography means flash chromatography on silica gel (Merk Keiselgel ART 9385); Thin layer chromatography (TLC) was performed on silica gel plates; When referring to the "Bond Elut" column here, this means a column containing 20 g of silica, which is contained in a 70 ml disposable syringe, supported by a 54 micropore sized porous disk, under the trade name "ISOLUTE". Obtained from International Sovent Technology; "ISOLUTE" is a registered trademark; If a Biotage cartridge is mentioned, it contains KP-SIL ^™ silica, 60 Hz, particle size 32-63 mM commercially available from Biotage of Diax Corporation, Avon Street Extended 1500, 22902, Charlotteville, VA. A cartridge;

(iv) generally, TLC is performed after the reaction proceeds and reaction time is provided for illustration only;

(v) the final product had satisfactory proton nuclear magnetic resonance (NMR) spectra and / or mass spectral data;

(vi) yields are provided for illustrative purposes only and are not necessarily obtainable by elaborate process development; The preparation was repeated when more material was needed;

(vii) When NMR data is provided, this is the main diagnosis for tetramethylsalan (TMS) as an internal standard, measured at 300 MHz using perduterio dimethyl sulfoxide (DMSO-d ₆ ) as solvent, unless otherwise stated. In the form of delta values (ppm) of protons; s, single peak; d, double peaks; dd, double double peak; t, triple peak; tt, triple triple peak; q, quadruple peak; tq, triple quadruple peak; sep, seven-peak peak; m, multiple peaks; br, broad peak;

(viii) chemical symbols have the usual meaning; SI units and symbols are used;

(ix) solvent ratios are given in volume: volume (v / v);

(x) mass spectra were performed with electron energy of 70 electron volts in chemical ionization (CI) mode using a direct exposure probe; Wherein the indicated ionization was carried out by electron collision (EI), fast atom bombardment (FAB) or electron spray (ES); providing a value for m / z; In general, only ions indicating the parental mass are reported; Unless stated otherwise, values for (M + H) + are cited;

(xi) unless otherwise stated, compounds containing asymmetric substituted carbon and / or sulfur atoms did not decompose;

(xii) when the synthesis is described as similar to that described in the previous examples, the amount used is the same millimolar ratio as used in the previous examples;

(xvi) The following abbreviations were used:

DMFN, N-dimethylformamide;

EDAC1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride;

DDQ3,3-dichloro-5,6-dicyano-1,4-benzoquinone;

EtOHethanol;

MeOH methanol;

EtOAc ethyl acetate; And

DCM dichloromethane

Example 1

2,4-dimethyl-3-morpholinecarbonylamino-9-isopropyl-9H-carbazole

To a solution of 3-amino-2,4-dimethyl-9-isopropyl-9H-carbazole (method 14; 308 mg, 1.22 mmol) and triethylamine (170 μl, 1.22 mmol) in DCM (10 mL) was added 4 Morpholine carbonyl chloride (142 μl, 1.22 mmol) was added slowly and the mixture was stirred at room temperature under argon atmosphere. After 16 and 18 hours respectively additional 4-morpholine carbonyl chloride (142 μl, 1.22 mmol) and triethylamine (170 μl, 1.22 mmol) were added. The reaction mixture was further heated at reflux for 64 h and then purified by chromatography (eluent-50% EtOAc / isohexane-75% EtOAc / isohexane) on a bond ilut cartridge to give the product as a white solid. Rf (50% EtOAc / isohexane) 0.10;

NMR (CDCl ₃ ) 8.18 (d, 1H), 8.52 (d, 1H), 7.40 (d, 1H), 7.20 (m, 2H), 5.90 (s, 1H), 4.96 (sep, 1H), 3.75 (m , 4H), 3.50 (m, 4H), 2.76 (s, 3H), 2.44 (s, 3H), 1.70 (d, 6H); m / z 366.76.

Examples 2-12

Using the appropriate starting materials, the following compounds were prepared following the procedure of Example 1.

Example 13

3- (3-carbamoylpiperidin-1-ylcarbonylamino) -4-methyl-9-isopropyl-9H-carbazole

To a solution of 3- (2,2,2-trichloroacetamido) -4-methyl-9-isopropyl-9H-carbazole (Example 26; 0.86 g, 2.13 mmol) in EtOAc (30 mL) -(Dimethylamino) pyridine (26 mg, 0.21 mmol) was added slowly. After stirring for 10 minutes, nifecottamide (300 mg, 2.34 mmol) was added in portions over 20 minutes. The reaction mixture was stirred for 2 hours, preabsorbed into silica and loaded onto a suction column. The column was eluted first with EtOAc, then eluted with 10% MeOH / EtOAc. The required fractions were combined, dried and concentrated in vacuo to afford the title compound (0.77 g, 93%).

NMR 8.15-8.20 (m, 2H), 7.7 (d, 1H), 7.3-7.5 (m, 3H), 7.15-7.20 (m, 2H), 6.8 (brs, 1H), 5.1 (sep, 1H), 4.0 -4.20 (m, 2H), 2.75-2.95 (m, 2H), 2.6 (s, 3H), 2.2-2.4 (m, 1H), 1.9-1.95 (m, 1H), 1.35-1.70 (m, 9H) .

Example 14

3- (3-carbamoylpiperidin-1-ylcarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole

3- (2,2,2-trichloroacetamido) -2,4-dimethyl-9-isopropyl-9H-carbazole (Example 24; 0.200 g, 0.5 mmol), Nicopecotamide (0.0966 g , 0.75 mmol) and sodium carbonate (0.32 g, 3.02 mmol) were placed in DMSO (5 mL) and stirred at 80 ° C. overnight. After cooling, the mixture was added all at once to water and then extracted with EtOAc. The organic layers were combined, dried and evaporated to give a viscous yellow solid. It was purified by column chromatography (100% EtOAc-1% MeOH in EtOAc) to give a viscous white solid, triturated with diethyl ether to give a creamy solid (0.142 g, 69.5%).

NMR 1.40-1.50 (m, 1H), 1.60 (m, 8H), 1.85-1.95 (m, 1H), 2.30 (m, 4H), 2.60 (s, 3H), 2.70-2.95 (m, 2H), 4.10 -4.20 (m, 2H), 5.00-5.15 (m, 1H), 6.80 (brs, 1H), 7.10 (t, 1H), 7.30-7.40 (m, 3H), 7.65 (d, 1H), 7.90 (s , 1H), 8.10 (d, 1H); m / z 405 (M ⁻ H) ⁻ .

Examples 15-21

Using 2- (2,2,2-trichloroacetamido) -2,4-dimethyl-9-isopropyl-9H-carbazole (Example 24) and a suitable amine, following the procedure of Example 14 The following compounds were prepared.

Example 22

3-pivaloylamino-4-methyl-9-ethyl-9H-carbazole

A solution of 3-pivaloylamino-9-ethyl-9H-carbazole (1.18 g, 4.0 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to -30 ° C under argon stream. To the stirred solution was added 1.7 M t-butyllithium in pentane (5.15 mL, 8.8 mmol) carefully over 10 minutes and the mixture was warmed to 0 ° C. over 30 minutes and recooled to −30 ° C. . Iodomethane (596 mg, 4.2 mmol) was added slowly, stirred at room temperature for 3 hours, and then reduced under vacuum. The residue was purified by chromatography using 1: 3 EtOAc in isohexane as eluent to afford the title compound (214 mg).

NMR 8.94 (s, 1H), 8.05 (d, 1H), 7.84 (s, 1H), 7.54 (d, 1H), 7.43 (s, 1H), 7.38 (t, 1H), 7.12 (t, 1H), 4.38 (q, 2 H), 2.31 (s, 3 H), 1.27 (m, 12 H); m / z 309.

Example 23

3-pivaloylamino-2,4-dimethyl-9-isopropyl-9H-carbazole

3-amino-2,4-dimethyl-9-isopropyl-9H-carbazole (method 14; 117 mg, 0.46 mmol) and triethylamine (66 μl in DCM (10 mL) stirred at 0 ° C. under argon atmosphere Pivaloyl chloride (58 μl, 0.47 mmol) was added slowly to the solution. The reaction mixture was allowed to warm to rt, stirred for 1 h, then extracted with DCM and washed with water. The organic layer was dried and the solvent was removed under vacuum to give a gray solid (154 mg; 100%). Rf (diethyl ether) 0.60.

NMR 8.87 (s, 1H), 8.12 (d, 1H), 7.66 (d, 1H), 7.38 (m, 2H), 7.15 (t, 1H), 5.10 (sep, 1H), 2.58 (s, 3H), 2.30 (s, 3H), 1.63 (d, 6H), 1.30 (s, 9H); m / z 337.44.

Examples 24-26

The following compounds were prepared using the appropriate starting material and following the procedure of Example 23.

Example 27

3- (tetrahydrofuran-3-ylcarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole

3-amino-2,4-dimethyl-9-isosolofil-9H-carbazole (method 14; 0.25 g, 0.99 mmol), dimethylaminopyridine (0.3394 g, 2.77 mmol) and tetrahydro-3-furoic acid ( 0.115 g, 0.99 mmol) was taken up in DCM (15 mL) and DMF (1 mL). To the stirred solution was added EDAC (0.2853 g, 1.48 mmol) and the reaction was stirred at rt overnight. The solvent was removed under vacuum, the residue was taken up in EtOAc and washed thoroughly with water. The solution was dried and the solvent removed under vacuum. The resulting golden oil was purified by column chromatography (50% to 80% EtOAc in hexanes) to give a white solid (0.249 g, 72%).

NMR 1.60 (d, 6H), 2.15 (q, IH), 2.30 (s, 3H), 2.60 (s, 3H), 3.25 (m, 2H), 3.70-3.80 (m, 3H), 4.00 (t, 1H ), 5.20 (m, 1H), 7.15 (t, 1H), 7.25-7.4 (m, 2H), 7.70 (d, 1H), 8.10 (d, 1H), 9.35 (s, 1H); m / z 349 (M ⁻ H) ⁻ .

Examples 28-36

The following compounds were prepared following the procedure of Example 27 using a suitable starting material (commercially available unless otherwise noted).

Example 37

3- (3-carbamoylpiperidin-1-yloxalylamino) -4-methyl-9-isopropyl-9H-carbazole

3-trichloroacetamido-4-dimethyl-9-isopropyl-9H-carbazole (Example 26; 400 mg, 1.03 mmol), nifecottamide (119.2 mg, 1.56 mmol) in DMSO (10 mL) And sodium carbonate (659.9 mg, 6.22 mmol) and the reaction mixture was heated to 80 ° C. overnight. After cooling, the reaction mixture was added all at once to water and then extracted with EtOAc. The organic layers were combined, dried and evaporated to afford dark brown oil. It was purified by column chromatography (50% EtOAc in hexane) to give a dark yellow solid (272.2 mg).

NMR 1.35-1.60 (m, 2H), 1.60 (d, 6H), 1.75 (m, 1H), 2.20-2.40 (m, 1H), 2.65 (m, 3H), 2.70-2.85 (m, 2H), 3.10 -3.20 (m, 1H), 3.80-3.90 (m, 1H), 4.20-4.40 (m, 1H), 5.05-5.15 (m, 1H), 6.90 (brs, 1H), 7.20 (t, 1H), 7.25 -7.30 (m, 1H), 7.35-7.45 (m, 3H), 7.55 (d, 1H), 7.70 (m, 1H), 8.20 (d, 1H); m / z ESP 421.

Examples 38 and 39

The following compounds were prepared following the procedure of Example 37 using Example 26 and a suitable starting material.

Example 40

3- (3-methoxy-2-aminopropionamido) -4-methyl-9-isopropyl-9H-carbazole

3- [3-methoxy-2- (t-butoxycarbonylamino) propionamido] -4-methyl-9-isopropyl-9H-carbazole in DCM (10 mL) (Example 30; 270.9 mg) , 0.62 mmol) was dissolved and cooled to 0 ° C. Trifluoroacetic acid (0.5 mL, 6.5 mmol) was added dropwise and the mixture was warmed to room temperature and stirred for 12 h under argon. Water (20 mL) was added to the reaction mixture, which was then basified with aqueous potassium carbonate solution. The aqueous mixture was extracted with DCM (3 x 20 mL). The combined organic extracts were dried and concentrated in vacuo to afford the title compound (0.2016 g, 96%).

NMR 8.20 (d, 1H), 7.70 (d, 1H), 7.50 (d, 1H), 7.35-7.45 (m, 2H), 7.18 (t, 1H), 5.0-5.20 (m, 1H), 3.50-3.62 (m, 3H), 3.35 (s, 3H), 2.65 (s, 3H), 1.6 (d, 6H); m / z 340.59.

Example 41

3- [2- (3-aminocyclohexyl) acetamido] -4-methyl-9-isopropyl-9H-carbazole

The title compound was prepared according to the procedure of Example 40 using 3- {2- [3- (t-butoxycarbonylamino) cyclohexyl] acetamido} -4-methyl-9-isopropyl-9H-carbazole ( From Example 34).

NMR 9.40 (s, 1H), 8.19 (d, 1H), 7.70 (d, 1H), 7.50 (d, 1H), 7.40 (t, 1H), 7.10-7.25 (m, 2H), 5.10 (sep, 1H ), 3.30 (brs, 2H), 3.00-3.05 (m, 1H), 2.65 (s, 3H), 2.20-2.30 (m, 2H), 1.701.95 (m, 2H), 1.65 (d, 6H), 1.10-1.50 (m, 6H), 0.9-1.0 (m, 1H); m / z 378.65.

Example 42

3- (4-hydroxypiperidin-1-ylcarbonylamino) -4-methyl-6-fluoro-9-isopropyl-9H-carbazole

To a stirred solution of triphosphene (115 mg, 0.35 mmol) in DCM (5 mL) containing diisopropylethylamine (197 μl, 1.1 mmol) was 3-amino-4-methyl- over 30 minutes under argon. 6-Fluoro-9-isopropyl-9H-carbazole (method 17; 256 mg, 1 mmol) solution is added, the solution is stirred for an additional 5 minutes, 2.5 ml drops are removed and diiso under argon To a stirred solution of 4-hydroxypiperidine (30 mg, 0.3 mmol) in DCM (2 mL) containing propylethylamine (47 μl, 0.27 μmol) was added and stirred overnight. The solution was diluted with EtOAc (20 mL), washed with water (10 mL), 3M citric acid (10 mL), water (10 mL) and saturated brine (10 mL), dried and evaporated to dryness. Trituration with diethyl ether and filtration gave the title compound as a white solid (92 mg).

NMR (CDCl ₃ ) 1.5 (m, 2H), 1.6 (d, 6H), 1.9 (m, 2H), 2.7 (s, 3H), 3.2 (m, 2H), 3.9 (m, 3H), 4.9 (m , 1H), 6.3 (s, 1H), 7.2 (t, 1H), 7.3 (s, 1H), 7.4 (d, 1H), 7.9 (d, 1H) ,: m / z 384 (M ⁺ ).

Examples 43-45

The following compound was prepared following the procedure of Example 42 using 3-amino-4-methyl-6-fluoro-9-isopropyl-9H-carbazole (Method 17) and a suitable amine.

Examples 46-99

3- (phenoxycarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole (method 48; 100 mg, 0.28 mmol) is a suitable amine (0.28 mmol) in anhydrous tetrahydrofuran (2 mL). ) And triethylamine (0.28 mmol) at 55 ° C. for 64 h. After cooling to room temperature, water (6 mL) was added and the resulting precipitate was filtered off, washed with 2M sodium hydroxide solution (2 × 2 mL) and then with water (2 mL).

3- (phenoxycarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole (method 48) or 3- (phenoxycarbonylamino) -4-methyl-9-isopropyl-9H Using carbazole (Method 49), the following compounds were prepared following the procedure above.

Examples 100-103

4- (4-nitrophenoxycarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole (method 50; 300 mg, 0.72 mmol) in ethyl acetate (15 mL) Dimethylamino) pyridine (9 mg, 0.074 mmol) was added and stirred at room temperature for 10 minutes. Relevant amine (0.792 mmol) was added and the reaction mixture was stirred for 3 hours. Ethyl acetate (10 mL) was added and the mixture was washed with potassium carbonate solution (3 x 20 mL). Ethyl acetate was concentrated in vacuo and the crude material was dissolved in dichloromethane (10 mL) to which TBD-methyl polystyrene (0.72 mmol) was added. It was stirred for 12 hours, filtered, dried and concentrated in vacuo to afford the required product.

Example 104

3- (4-carboxypiperidin-1-ylcarbonylamino) -4-methyl-9-isopropyl-9H-carbazole

3- (4-Ethoxycarbonyl-piperidin-1-ylcarbonylamino) -4-methyl-9-isopropyl-9H-carbazole in ethanol (50 mL) (Example 87; 1.6 g, 3.8 mmol) was added 2 M NaOH solution (30 mL). The mixture was stirred at room temperature for a total of 2 hours 40 minutes, then acidified with 2M HCl solution, then extracted with EtOAc (2 × 200 mL) and washed with water (2 × 200 mL). Drying and solvent removal gave the product as a brown gum (1.47 g, 98%).

NMR 1.54 (m, 2H), 1.62 (d, 6H), 1.84 (m, 2H), 2.60 (s, 3H), 2.93 (m, 2H), 3.29 (m, 1H), 4.03 (m, 4H), 5.09 (sept, 1 H), 7.17 (m, 2 H), 7.41 (m, 2 H), 7.67 (d, 1 H), 8.17 (m, 2H); m / z 394.30.

Example 105

3- [3- (N, N-dimethylcarbamoyl) piperidin-1-ylcarbonylamino] -4-methyl-9-isopropyl-9H-carbazole

3- (3-carboxypiperidin-1-ylcarbonylamino) -4-methyl-9-isopropyl-9H-carbazole (Example 104; 200 mg, 0.51 mmol) was EDAC (108 mg, 0.56 mmol) ) And 4-dimethylaminopyridine (10 mg) in anhydrous THF (4 mL). Dimethylamine (2M solution in THF, 280 μl) was added and the mixture was stirred at rt for 16 h. The reaction mixture was extracted with EtOAc (2 × 200 mL) and washed with water (2 × 200 mL). The solvent was removed and the product was obtained by chromatography (eluent-MeOH / EtOAc 1: 9) as a white solid (65 mg, 30%).

NMR 1.50 (m, 2H), 1.62 (d, 6H), 1.67 (m, 1H), 2.60 (s, 3H), 2.83 (s, 3H), 2.90 (m, 4H), 3.05 (s, 3H), 4.15 (m, 2H), 5.09 (sept, 1H), 7.17 (m, 2H), 7.41 (m, 2H), 7.67 (d, 1H), 8.17 (m, 2H); m / z 421.33.

Example 106

3- [3- (N-methylcarbamoyl) piperidin-1-ylcarbonylamino] -4-methyl-9-isopropyl-9H-carbazole

3- (3-carboxypiperidin-1-ylcarbonylamino) -4-methyl-9-isopropyl-9H-carbazole (Example 104; 177 mg, 0.45 mmol) was treated with triethylamine (70 And 0.5 mmol) in anhydrous THF. Ethylchloroformate (48 μl, 0.5 mmol) was added slowly and stirred for 1 hour. Methylamine (1 mL of 2M solution in THF) was added and the mixture was stirred at rt for 3 h. The reaction mixture was extracted with EtOAc (2 × 200 mL) and washed with saturated potassium carbonate solution. The organic layer was then back washed with 2 M HCl solution and then dried over sodium sulfate. Solvent was removed to give the product as a light brown solid (77 mg, 42%).

NMR 1.50 (m, 2H), 1.62 (d, 6H), 1.68 (m, 2H), 2.32 (m, 1H), 2.59 (m, 6H), 2.80 (m, 2H), 4.12 (m, 2H), 5.09 (sept, 1 H), 7.17 (m, 2 H), 7.41 (m, 2 H), 7.67 (d, 1 H), 8.17 (m, 2H); m / z 407.29.

Example 107

3- (3-carboxypyrrolidin-1-ylcarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole

3- (3-methoxycarbonylpyrrolidin-1-ylcarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole (Example 103) was purified according to the procedure of Example 104. Digested.

NMR 1.62 (d, 6H), 2.0-2.25 (m, 3H), 2.36 (s, 3H), 2.65 (s, 3H), 3.05-3.22 (m, 1H), 3.26-3.72 (m, 5H), 5.10 (sept, 1H), 7.16 (t, 1H), 7.3-7.5 (m, 2H), 7.82 (s, 1H), 7.66 (d, 1H), 8.15 (d, 1H); m / z 394.24.

Example 108

3- [3- (N, N-dimethylcarbamoyl) pyrrolidin-1-ylcarbonylamino] -2,4-dimethyl-9-isopropyl-9H-carbazole

Couple 3- (3-carboxypyrrolidin-1-ylcarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole (Example 107) and dimethylamine according to the procedure of Example 105. Ring.

NMR (CDCl ₃ ) 1.70 (d, 6H), 2.10-2.22 (m, 1H), 2.25-2.42 (m, 1H), 2.46 (s, 3H), 2.80 (s, 3H), 3.0 (s, 3H) , 3.10 (s, 3H), 3.25-3.42 (m, 1H), 3.47-3.6 (m, 1H), 3.66-3.87 (m, 3H), 5.0 (sept, 1H), 5.72 (s, 1H), 7.19 (t, 1H), 7.23 (s, 1H), 7.4 (t, 1H), 7.5 (d, 1EI), 8.2 (d, 1H); m / z 421.24.

Example 109

3- (piperidin-4-ylcarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole

3-amino-2,4-dimethyl-9-isopropylcarbazole (Method 14; 1.44 g, 5.73 mmol) was treated with EDAC (1.208, 6.30 mmol), 4-dimethylaminopyridine (70 mg, 0.57 mmol) at room temperature and Stir for 19 h in anhydrous THF (30 mL) with 1-t-butyl-oxycarbonyl-piperidine-4-carboxylic acid (1.312 g, 5.73 mmol). The mixture was extracted with DCM, washed with water, the organics dried and the solvent removed. The residue was dissolved in DCM (30 mL) and trifluoroacetic acid (6 mL) was added. The reaction mixture was stirred at rt for 3.5 h and then basified with saturated potassium carbonate solution. After extraction with EtOAc, washed with water, then dried over sodium sulfate, and the solvent was removed to give the title compound as a brown gum (1.599 g, 77%). M / z 364.44.

Examples 110-112

The following compound was prepared using the procedure of Example 109. In Example 111, the hydrolysis step of t-butyl-oxycarbonyl was omitted.

Example 113

3- (1-Carbamoylpiperidin-4-ylcarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole

3- (piperidin-4-ylcarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole (Example 109; 647 mg, 1.82 mmol) potassium cyanate for 16 hours under reflux (534 mg, 6.594 mmol) was stirred in water / ethanol (30 mL / 30 mL). The reaction mixture was cooled down, diluted with water and then diluted with 2 M HCl solution. The aqueous mixture was extracted with DCM and EtOAc, then the organics were collected, dried over sodium sulfate and the solution was removed. Chromatography (eluent-EtOAc to EtOAc / MeOH 7: 3) was carried out to give the title compound as a brown gum (255 mg, 35%).

NMR (CDCl ₃ ) 1.58 (d, 6H), 1.74 (m, 6H), 2.22 (s, 3H), 2.41 (m, 1H), 2.50 (s, 3H), 2.76 (m, 2H), 3.90 (m , 1H), 4.72 (m, 1H), 4.86 (sept, 1H), 7.09 (m, 3H), 7.28 (m, 1H), 7.41 (m, 1H), 8.00 (m, 1H); m / z 405.40.

Examples 114 and 115

The following compound was prepared using the procedure of Example 113.

Example 116

3- [1- (N, N-dimethylcarbamoyl) piperidin-4-ylcarbonylamino] -2,4-dimethyl-9-isopropyl-9H-carbazole

3- (piperidin-4-ylcarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole (Example 109; 411 mg, 1.132 mmol) and pyridine (1.6 mL) were DCM ( 12 ml). Dimethylcarbamoylchloride (125 μl, 1.358 mmol) was added to the reaction mixture and stirred for 16 hours. 2 M HCl solution was added and the mixture was extracted with DCM / MeOH (19: 1). The organics were dried over sodium sulfate and the solvent was removed. Chromatography (eluent-EtOAc to EtOAc / MeOH 9: 1) gave the title compound as a yellow solid (115 mg, 23%).

NMR (CDCl ₃ ) 1.68 (d, 6H), 1.74 (m, 1H), 1.95 (m, 2H), 2.07 (m, 2H), 2.22 (s, 3H), 2.41 (s, 3H), 2.72 (s , 3H), 2.82 (m, 2H), 2.87 (s, 6H), 3.78 (m, 2H), 4.96 (sept, 1H), 6.84 (br s, 3H), 7.19 (t, 1H), 7.27 (s , 1H), 7.41 (t, 1H), 7.54 (d, 1H), 8.17 (d, 1H); m / z 435.30.

Examples 117 and 118

The following compound was prepared using the procedure of Example 116.

Example 119

3- [1- (N-methylcarbamoyl) piperidin-3-ylcarbonylamino] -2,4-dimethyl-9-isopropyl-9H-carbazole

Phosgene (0.8 mL, 1.55 mmol, 20% solution in toluene) was stirred in anhydrous THF (3 mL) under argon and cooled in an ice bath. A solution of N- (3-carboxypiperidine) -3-amino-2,4-dimethyl-9-isopropylcarbazole (Example 110; 511 mg, 1.41 mmol) in anhydrous THF (3 mL) was added dropwise, Triethylamine (0.2 mL, 1.1 mmol) was then added dropwise. After stirring for 1 hour, methylamine (1.41 mL, 2.82 mmol, 2M solution in THF) was added and the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was extracted with DCM and washed with saturated potassium carbonate solution and water. The organics were dried over sodium sulfate and the solvent was removed. Chromatography (eluent-DCM to DCM / MeOH 19: 1) on a Biotage system gave the title compound as a white solid (112 mg, 19%).

NMR (CDCl ₃ ) 1.62 (m, 3H), 1.70 (d, 6H), 2.00 (m, 1H), 2.14 (m, 1H), 2.38 (s, 3H), 2.70 (s, 3H), 2.79 (d , 3H), 3.29 (m, 1H), 3.44 (m, 1H), 3.75 (d, 2H), 4.80 (m, 1H), 4.96 (sept, 1H), 7.19 (t, 1H), 7.25 (s, 1H), 7.40 (t, 1H), 7.53 (d, 1H), 7.73 (s, 1H), 8.16 (d, 1H); m / z 421.29.

Example 120

The following compound was prepared using the procedure of Example 119.

Example 121

3- (1-acetylpyrrolidin-3-ylcarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole

3- [1- (t-butoxycarbonyl) pyrrolidin-3-ylcarbonylamino] -2,4-dimethyl-9-isopropyl-9H-carbazole in glacial acetic acid (2.2 mL) (Example 111) Acetic anhydride (239 mg, 2.34 mmol) was added to 500 mg) of the stirring solution. The mixture was heated to 120 ° C. for 5 hours. The mixture was concentrated under vacuum and the residue was chromatographed (eluent i; ethyl acetate, eluent ii: 5% methanol / dichloromethane) to afford the title compound (150 mg, 35%).

NMR (CDCl ₃ ) 1.60-1.75 (m, 6H), 2.08-2.22 (m, 1H), 2.28-2.38 (m, 3H), 2.39-2.48 (m, 1H), 2.52-2.62 (m, 3H), 3.70-3.80 (m, 1H), 2.92-3.18 (m, 1H), 3.25-3.95 (m, 4H), 4.85-5.05 (m, 1H), 7.06-7.6 (m, 4H), 8.02-8.15 (m , 1H); m / z 390.30.

Example 122

3- (1-acetylpiperidin-4-ylcarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole

3-amino-2,4-dimethyl-9-isopropylcarbazole (Method 14; 250 mg, 0.99 mmol) in anhydrous DMF (15 mL) was dissolved and stirred at room temperature for 10 minutes. To the solution o- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (437 mg, 0.987 mmol), N, N-diiso Propylethylamine (255 mg, 1.974 mmol) and 1-acetylpiperidine-4-carboxylic acid (169 mg, 0.987 mmol) were added and the reaction mixture was stirred at rt for 6 h. The mixture was then concentrated under vacuum and water (150 mL) was added. It was extracted with chloroform (3 × 100 mL), dried and concentrated in vacuo to give a light brown solid (348 mg, 87%).

NMR 1.43-1.77 (m, 8H), 1.80-1.98 (m, 2H), 2.02 (s, 3H), 2.30 (s, 3H), 2.58 (s, 3H), 3.03-3.19 (m, 1H), 3.82 -3.95 (m, 1H), 4.35-4.45 (m, 1H), 5.10 (sept, 1H), 7.15 (t, 1H), 7.32-7.43 (m, 2H), 7.66 (d, 1H), 8.12 (d , 1H), 9.20 (s, 1H); m / z 406.30.

Example 123

The following compound was prepared using the procedure of Example 122.

Examples 124-164

O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (6.34 g, 16.67 mmol) and N, N in DMF (95.4 mL) Diisopropylethylamine (5.3 mL, 30.43 mmol) was dissolved to give solution A. Solution B was obtained by dissolving 3-amino-4-methyl-9-isopropylcarbazole (Method 21: 5.5 g, 23.11 mmol) in DMF (40 mL). Solution A (2.65 mL) was added to a suitable acid and the mixture was stirred at room temperature for 15 minutes. To this mixture was added Solution B (0.74 mL) and the reaction mixture was stirred at rt for 40 h. 1 ml of each reaction was taken and purified using a preparative LC / MS-HPLC apparatus to afford the required compound.

In Examples 150-164, an equivalent amount of 3-amino-2,4-dimethyl-9-isopropylcarbazole (method 14) was used as solution B.

Example 165

5-methyl-6-morpholinecarbonylamino-9-isopropyl-9H-1,2,3,4-tetrahydrocarbazole

The title compound was prepared from 9-isopropyl-1,2,3,4-tetrahydro-5-methyl-6-aminocarbazole (method 53) in a similar manner to Example 1.

NMR (300 MHz); 7.94 (s, 1H), 7.17 (d, 1H), 6.73 (d, 1H), 4.59 (m, 1H), 3.60 (m, 4H), 3.40 (m, 4H), 2.92 (m, 2H), 2.72 (m, 2H), 2.34 (s, 3H), 1.75 (m, 4H), 1.48 (d, 6H); m / z 356.5.

Example 166

3- (3-carboxypiperidin-1-ylcarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole

3- [3- (ethoxycarbonyl) piperidin-1-ylcarbonylamino] -2,4-dimethyl-9-isopropyl-9H-carbazole (Example 100) was described in Example 104. Hydrolysis was carried out in a similar manner to the title compound.

NMR (300 MHz; CDCl ₃ ) 1.3-1.85 (m, 4H), 1.60 (d, 6H), 1.80 (m, 3H), 2.29 (s, 3H), 2.4 (1H, m), 2.62 (s, 3H) , 3.1-3.7 (m, 4H), 4.90 (sep, 1H), 5.3 (1H, brs), 6.00 (brs, 1H), 7.10 (t, 1H), 7.18 (s, 1H), 7.30 (t, 1H ), 7.42 (d, 1 H), 8.05 (d, 1 H); m / z 408.24.

Example 167

3- [3- (N, N-dimethylcarbamoyl) piperidin-1-ylcarbonylamino] -2,4-dimethyl-9-isopropyl-9H-carbazole

The title compound was subjected to 3- (3-carboxypiperidin-1-ylcarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole in a similar manner to that described in Example 105. Example 166).

NMR (300 MHz; CDCl ₃ ) 1.62 (d, 6H), 1.80 (m, 3H), 2.38 (s, 3H), 2.69 (s, 3H), 2.73-3.05 (m, 4H), 2.88 (s, 3H) , 3.01 (s, 3H), 3.87 (m, 1H), 4.15 (m, 1H), 4.90 (sep, 1H), 6.00 (brs, 1H), 7.10 (t, 1H), 7.16 (s, 1H), 7.32 (t, 1 H), 7.44 (d, 1 H), 8.10 (d, 1 H); m / z 435.40.

Example 168

3- [3- (N-methylcarbamoyl) piperidin-1-ylcarbonylamino] -2,4-dimethyl-9-isopropyl-9H-carbazole

The title compound was prepared in a manner similar to that described in Example 105 except for using methylamine 3- (3-carboxypiperidin-1-ylcarbonylamino) -2,4-dimethyl-9-iso Prepared from propyl-9H-carbazole (Example 166).

NMR (300 MHz; CDCl ₃ ) 1.63 (d, 6H), 1.65 (m, 3H), 2.03 (m, 1H), 2.30 (m, 1H), 2.36 (s, 3H), 2.64 (s, 3H), 2.66 (s, 3H), 3.40 (m, 2H), 3.52 (m, 1H), 3.73 (m, 1H), 4.90 (sep, 1H), 6.10 (brs, 1H), 6.63 (brs, 1H), 7.13 ( t, 1H), 7.19 (s, 1H), 7.34 (t, 1H), 7.46 (d, 1H), 8.09 (d, 1H); m / z 421.30.

Preparation of Starting Material

The starting materials of this example are either commercially available or can be readily prepared using standard methods from known materials. For example, non-limiting examples for preparing some of the starting materials used in the above reactions are illustrated below.

Method 1

1,2,3,4-tetrahydro-5,7-dimethylcarbazole

To a reflux solution of 3,5-dimethylaniline (15 mL, 120.8 mmol) in EtOH (40 mL) was added slowly a solution of 2-chlorocyclohexanone (6.9 mL, 60.4 mmol) in EtOH (40 mL). The reaction mixture was stirred at reflux for 20 h, concentrated and dissolved in diethyl ether / water (50/50). The aqueous layer was washed with diethyl ether and the combined organic layers were washed with 5M hydrochloric acid, water and sodium bicarbonate solution, respectively. Dry and remove solvent to afford the title compound as a brown solid. Rf (diethyl ether) 0.82.

NMR 10.31 (s, 1H), 6.80 (s, 1H), 6.44 (s, 1H), 2.88 (m, 2H), 2.63 (m, 2H), 2.50 (s, 3H), 2.28 (s, 3H), 1.77 (m, 4 H).

Method 2

1,2,3,4-tetrahydro-5,7-dimethyl-6-nitrocarbazole

To a stirred solution of 1,2,3,4-tetrahydro-5,7-dimethylcarbazole (method 1; 8.24 g, 41.4 mmol) in concentrated sulfuric acid (100 mL) was added potassium nitrate (4.19 g, 41.4 at 0 ° C.). mmol) was added in part. The reaction mixture was stirred for 2 hours and then added all at once to ice / water. The yellow precipitate was filtered off, washed with 10% aqueous ammonia, water and dissolved in EtOAc. After drying, purification by chromatography (eluent-DCM) afforded the title compound as an orange solid. Yield 5.193 g (51%); Rf (DCM) 0.55.

¹ H NMR 10.96 (s, 1H), 7.03 (s, 1H), 2.98 (m, 2H), 2.67 (m, 2H), 2.45 (s, 3H), 2.25 (s, 3H), 1.77 (m, 4H ); m / z 243.63.

Method 3 and 4

The following compounds were prepared using the appropriate starting material and following the procedure of Method 2.

Method 5

2,4-dimethyl-3-nitro-9H-carbazole

To a stirred solution of 1,2,3,4-tetrahydro-5,7-dimethyl-6-nitrocarbazole (Method 2; 14 g, 57.4 mmol) in 1,4-dioxane (200 mL) at room temperature DDQ (26 g, 114.8 mmol) was partially added. The reaction mixture was stirred at 100 ° C. for 4 hours and then concentrated in vacuo. Chromatography (eluent-20% EtOAc / isohexane-50% EtOAc / isohexane) gave the title compound as an orange solid. Yield 6.62 g (48%). Rf (20% EtOAc / Isohexane) 0.24.

NMR 11.75 (s, 1H), 8.17 (d, 1H), 7.56 (d, 1H), 7.46 (t, 1H), 7.34 (s, 1H), 7.24 (t, 1H), 2.74 (s, 3H), 2.42 (s, 3 H); m / z 239.59.

Method 6 and 7

The following compounds were prepared using the appropriate starting material and following the procedure of Method 5.

Method 8

2,4-dimethyl-9-isopropyl-3-nitro-9H-carbazole

2,4-dimethyl-3-nitrocarbazole (Method 5; 6.62 g, 27.6 mmol) and cesium carbonate (18 g, 55.2 mmol) were stirred in an argon atmosphere at room temperature and anhydrous DMF (100 mL). 2-iodopropane (5.51 mL, 55.2 mmol) was added to the reaction mixture and then heated to 85 ° C. Additional cesium carbonate (9 g, 27.6 mmol) and 2-iodopropane (2.76 mL, 27.6 mmol) were added after 3.5 and 5.5 hours. The reaction solvent was removed under vacuum and the residue was extracted with EtOAc and washed with water and brine. The organic layer was dried and the solvent removed under vacuum. Chromatography (eluent-10% EtOAc / isohexane-20% EtOAc / isohexane) gave the title compound as a yellow solid. Yield 6.18 g (79%). Rf (50% EtOAc / Isohexane) 0.65.

NMR 8.20 (d, 1H), 7.78 (d, 1H), 7.62 (brs, 1H), 7.48 (t, 1H), 7.25 (t, 1H), 5.17 (sep, 1H), 2.72 (s, 3H), 2.42 (s, 3 H).

Method 9 to 13

The following compounds were prepared using the appropriate starting material and using the procedure of Method 8.

Method 14

3-amino-2,4-dimethyl-9-isopropyl-9H-carbazole

To a stirred solution of 2,4-dimethyl-9-isopropyl-3-nitrocarbazole (Method 8; 6.18 g, 21.9 mmol) in EtOAc (200 mL) under argon atmosphere was added 10% palladium on carbon (800 mg). Added. The reaction mixture was stirred at room temperature under hydrogen atmosphere. Additional 10% palladium on carbon (800 mg) was added after 64 hours and after 88 hours. The catalyst was filtered off through diatomaceous earth and washed with EtOAc. The filtrate was concentrated and chromatographed (eluent-20% EtOAc / isohexane-50% EtOAc / isohexane) to give the title compound as a white / yellow solid (5.294 g, 96%). Rf (20% EtOAc / isohexane) 0.19.

NMR (CDCl ₃ ) 8.24 (d, 1H), 7.48 (d, 1H), 7.36 (t, 1H), 7.16 (m, 2H), 4.95 (sep, 1H), 2.76 (brs, 3H), 2.42 (brs , 3H), 1.68 (d, 6H); m / z 253.74.

Method 15 to 19

The following compounds were prepared using the appropriate starting material and following the procedure of Method 14.

Method 20

3-amino-4,9-diisopropyl-9H-carbazole

3-nitro-4,9-diisopropyl-9H-carbazole (Method 25; 0.55 g, 1.86 mM) in EtOH (20 mL) at room temperature under atmospheric hydrogen was hydrogenated on 10% palladium on carbon (100 mg). . The catalyst was filtered off through diatomaceous earth and the filtrate was concentrated. Chromatography (eluent gradient from hexane to DCM) afforded the title compound as a light brown foam (0.55 g). R f (Et ₂ O) 0.41.

NMR (CDCl ₃ ) 8.29 (d, 1H), 7. 53 (d, 1H), 7.41 (t, 1H), 7.27 (d, 1H), 7.16 (t, 1H), 6.90 (d, 1H), 4.98 (sep, 1H), 4.43 (br m, 1H), 1.71 (d, 6H), 1.63 (d, 6H); m / z 267.14.

Method 21

Using the appropriate starting material and following the procedure of Method 20, the product was purified by chromatography (eluant-50% EtOAc / isohexane) to afford the following compound.

Method 22

Benzophenone (2-chloro-5-methylphenyl) hydrazone

3-bromo-4-chlorotoluene (6.45 mL, 48.7 mmol), benzophenone hydrazone (9.54 g, 48.7 mmol), palladium acetate (112 mg, 0.5 mmol) in room temperature and anhydrous toluene (25 mL) under argon and (S)-(-)-2,2'-bis (diphenyl-phosphino) -1,1'-binafthyl (311 mg, 0.5 mmol) was stirred together. Sodium t-butoxide (6.55 g, 68.2 mmol) was added in part, followed by additional anhydrous toluene (25 mL). The reaction mixture was heated at 80 ° C. for 24 h, then cooled to rt and diluted with diethyl ether. The precipitate was filtered off, washed with diethyl ether and the filtrate solvent removed under vacuum. Chromatography (eluent-10% EtOAc / isohexane) gave the title compound as an orange / yellow solid. Rf (10% EtOAc / Isohexane) 0.53.

NMR 7.89 (s, 1 H), 7.68-7.09 (m, 12 H), 6.63 (dd, 1 H), 2.29 (s, 3H); m / z 321.44.

Method 23

1,2,3,4-tetrahydro-8-chloro-5-methylcarbazole

Benzophenone (2-chloro-5-methylphenyl) hydrazone (method 22; 48.7 mmol), p-toluenesulfonic acid monohydrate (19 g, 0.1 mmol) and cyclohexanone (7.55 mL, in EtOH (250 mL) under reflux 73 mmol) was stirred for 40 hours. After removal of EtOH under vacuum, the residue was diluted with EtOAc, washed with saturated sodium bicarbonate solution, water and brine respectively and then dried over potassium carbonate. The solvent was removed under vacuum and chromatographed (eluent-isohexane-20% DCM / isohexane) to give the title compound as an oil (8.19 g, 77%). Rf (20% DCM / isohexane) 0.39.

NMR 10.80 (brs, 1H), 6.85 (d, 1H), 6.62 (d, 1H), 2.86 (m, 2H), 2.69 (m, 2H), 2.51 (s, 3H), 1.75 (m, 4H).

Method 24

3-Amino-1-chloro-4-methyl-9-isopropylcarbazole hydrochloride salt

To a stirred solution of 1-chloro-9-isopropyl-4-methyl-3-nitrocarbazole (method 6; 123 mg, 0.41 mmol) in EtOH (10 mL) and water (5 mL) was added sodium hydrosulfite ( 428 mg, 2.46 mmol) was added. The reaction mixture was heated at reflux for 2 hours. After removal of EtOH under vacuum, the residue was extracted with EtOAc, washed with water and dried. After removing the solvent under vacuum, chromatography (eluent-20% EtOAc / isohexane) was performed to give a gum. The title compound was treated with hydrogen chloride (2M solution in diethyl ether) and then filtered off. Rf (50% EtOAc / Isohexane) 0.47.

NMR 10.15 (brs, 2H), 8.30 (d, 1H), 7.90 (d, 1H), 7.58 (s, 1H), 7.55 (t, 1H), 7.30 (t, 1H), 6.10 (sep, 1H), 2.75 (s, 3 H), 1.69 (d, 6 H); m / z 273.67.

Method 25

3-nitro-4,9-diisopropyl-9H-carbazole

Isopropylmagnesium chloride (2 M solution in tetrahydrofuran) in 3-nitro-9-isopropyl-9H-carbazole (Method 31; 1.13 g, 4.45 mM) in tetrahydrofuran (20 mL) at -15 ° C. (2.23 mL, 4.46 mM) was added. After 1 hour, DDQ (2.22 g, 9.79 mM) was added and then warmed to room temperature for 18 hours. The mixture was diluted with DCM, washed with aqueous potassium carbonate solution, dried over sodium sulphate and concentrated. Chromatography (eluent gradient from hexane to DCM) afforded the title compound as a yellow solid (0.56 g; 46%). Rf (DCM: hexane (2: 3)) 0.29.

NMR (CDCl ₃ ) 8.20 (d, 1H), 7.67 (d, 1H), 7.57 (d, 1H), 7.45 (t, 1H), 7.32 (d, 1H), 7.24 (t, 1H), 4.97 (sep , 1H), 4.16 (sep, 1H), 1.66 (d, 6H), 1.56 (d, 6H); m / z 297.18.

Method 26-30

The following compounds were prepared using the appropriate starting material and following the procedure of Method 25.

Method 31

3-nitro-9-isopropyl-9H-carbazole

3-nitro-9H-carbazole (Synth. Commun., 24 (1994), 1; 0.99 g, 4.68 mM) in NaH (60% in oil; 281 mg, 7.02 mM) in DMF (35 mL) at room temperature under an inert atmosphere. ), Then isopropyl bromide (0.66 mL, 7.02 mM) was added and heated to 60 ° C. for 18 h. Immediately after cooling to room temperature, the mixture was diluted with DCM, washed with water, dried over sodium sulfate and concentrated. Chromatography (eluent gradient from hexane to DCM) afforded the title compound (0.98 g, 79%). Rf (70% DCM / isohexane) 0.24.

NMR (CDCl ₃ ) 9.16 (d, 1H), 8.40 (d, 1H), 8.28 (dd, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.54 (t, 1H), 7.30 (t , 1H), 5.20 (sept, 1H), 1.62 (d, 6H).

Method 32

6-bromo-1,4-dimethyl-9-isopropyl-9H-carbazole

To a solution of 18-crown-6 (0.4 g) in DMF (25 mL) was added potassium bis (trimethylsilyl) amide (2.8 g, 14 mmol). The mixture was stirred at rt for 10 min. 6-bromo-1,4-dimethylcarbazole (Chem. Pharm. Bull., 1987, 35 (1), 425-8; 3.5 g, 13 mmol) was added in portions over 10 minutes, and the mixture was then allowed to come to room temperature. Stirred for 30 min. 2-iodopropane (1.4 mL, 14 mmol) was added in a single portion and the mixture was heated to 90 ° C. for 18 hours. The solvent was removed under vacuum and the residue was partitioned between DCM (50 mL) and 1 M HCl (50 mL). The organic layer was separated, washed with brine (50 mL), dried and evaporated under vacuum to afford a red oil. The crude product was purified by flash chromatography (using a 5: 1 mixture of isohexane: EtOAc as eluent) to afford the product as a colorless solid (1.0 g).

NMR (CDCl ₃ ) 8.2 (d, 1H), 7.4 (d, 1H), 7.3 (dd, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 5.4 (m, 1H), 2.7 (s , 3H), 2.65 (s, 3H), 1.6 (d, 6H).

Method 33

6-bromo-1,4-dimethyl-9-isopropyl-3-nitro-9H-carbazole

6-Bromo-1,4-dimethyl-9-isopropyl-9H-carbazole (Method 32; 1.0 g, 3.2 mmol) in glacial acetic acid (20 mL) was dissolved and the resulting solution was cooled in an ice bath. Concentrated nitric acid (d = 1.42, 0.4 mL) was added dropwise over 5 minutes and the mixture was stirred in an ice bath for 1 hour. The mixture was added all at once to water (50 mL) and filtered to collect the solid. The solid was washed with water (2 x 25 mL) and MeOH (2 x 25 mL). The product was dried in air to give a yellow solid.

NMR (CDCl ₃ ) 8.35 (d, 1H), 7.8 (s, 1H), 7.55 (d, 1H), 7.5 (dd, 1H), 5.4 (m, 1H), 2.95 (s, 3H), 2.75 (s , 3H), 1.7 (d, 6H).

Method 34 and 35

The following compounds were prepared using the appropriate starting material and following the procedure of Method 33.

Method 36

3-amino-1,4-dimethyl-9-isopropyl-9H-carbazole

Method 37

3-amino-6-bromo-1,4-dimethyl-9-isopropyl-9H-carbazole

Palladium on carbon (10% wt) in a solution of 6-bromo-1,4-dimethyl-9-isopropyl-3-nitro-9H-carbazole (method 33; 0.49 g, 1.4 mmol) in EtOAc (25 mL) / wt, 0.4 g) was added. The resulting mixture was stirred for 72 h under hydrogen atmosphere at room temperature. The mixture was filtered through diatomaceous earth and the residue was washed with DCM (2 × 25 mL). The solvent was evaporated under vacuum and the residue was purified by preparative HPLC using 30-95% MeCN in water (0.1% TFA) as eluent to give the primary eluent (i) 3-amino as a colorless solid (95 mg). -1,4-dimethyl-9-isopropyl-9H-carbazole; NMR 10.15 (brs, 3H), 8.25 (d, 1H), 7.8 (d, 1H), 7.45 (m, 1H), 7.25 (m, 2H), 5.5 (m, 1H), 2.8 (s, 3H), 2.75 (s, 3 H), 1.65 (d, 6 H); m / z 253; And secondary eluate (ii) 3-amino-6-bromo-1,4-dimethyl-9-isopropyl-9H-carbazole as colorless solid (33 mg); NMR (CDCl ₃ ) 8.25 (s, 1H), 7.4 (d, 1H), 7.35 (d, 1H), 5.35 (m, 1H), 2.65 (s, 3H), 2.55 (s, 3H), 1.6 (d , 6H).

Method 38

3-nitro-9- (2-methoxy-1-methylethyl) -4-methyl-9H-carbazole

To a stirred solution of 4-methyl-3-nitro-9H-carbazole (method 29; 450 mg, 1.99 mM) in DMF (6 mL) is added cesium carbonate (1.3 g, 3.98 mM), followed by toluene-4 Sulfonic acid 2-methoxy-1-methyl-ethyl ester (method 39; 550 mg, 2.39 mM) was added. The resulting suspension was heated to 85 ° C. and stirred for 5 days. The mixture was then added all at once to cold water (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with saturated NaHCO ₃ (3 × 50 mL), 1 M HCl, brine (2 × 50 mL), dried and concentrated under reduced pressure. The resulting brown oil was chromatographed using DCM as eluent on a 10 g Bond Elute column to give the title compound (305 mg, 1.0 mmol) as a yellow solid.

NMR 1.6 (d, 3H), 3.0 (s, 1H), 3.75 (m, 1H), 4.05 (m, 1H), 5.25 (m, 1H), 7.3 (t, 1H), 7.55 (t, 1H), 7.75 (d, 1 H), 7.85 (d, 1 H), 8.0 (d, 1 H), 8.3 (d, 1 H); m / z 299.

Method 39

Toluene-4-sulfonic acid 2-methoxy-1-methylethyl ester

Tosyl chloride (6.94 g, 36.4 mmol) was partially added over 5 minutes to a stirred solution of 1-methoxy-2-propanol (3.91 mL, 40 mmol) in pyridine (25 mL). The reaction was stirred at rt for 24 h, then added together in 1 M HCl (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with 1 M HCl (3 x 75 mL), saturated NaHCO ₃ (2 x 50 mL), brine (2 x 50 mL), dried and concentrated under reduced pressure to yield the title compound (7.2 g) as a white solid. , 31 mmol) was obtained.

NMR 1.2 (d, 3H), 2.35 (s, 3H), 3.15 (s, 3H), 2.3 (m, 2H), 4.6 (m, 1H), 7.25 (d, 2H), 7.7 (d, 2H).

Method 40

4-fluoro-2-methyl-phenyl hydrazine hydrochloride

The title compound is described in J. Het. Chem v. 32 p. 5 (1995)], but 4-fluoro-2-methyl-aniline was used in place of o-toluidine.

NMR 2.2 (s, 3H), 7.0 (m, 3H), 7.7 (s, 1H), 10.15 (s, 3H).

Method 41

6-fluoro-8-methyl-1,2,3,4-tetrahydrocarbazole

To a solution of 4-fluoro-2-methyl-phenyl hydrazine hydrochloride (method 40; 10.75 g, 50 mmol) in EtOH (160 mL) was added cyclohexanone (4.9 g, 50 mmol) and the resulting mixture was refluxed. Under heating overnight. The slurry was evaporated to dryness, the residue taken up in EtOAc, washed with water then saturated brine, dried, evaporated to dryness and purified by vacuum flash chromatography on to Merck 60H silica using toluene as eluent 7.2 g of the title compound. Got.

NMR (CDCl ₃ ) 1.9 (m, 4H), 2.3 (s, 3H), 2.7 (m, 2H), 2.8 (m, 2H), 6.7 (d, 1H), 7.0 (d, 1H), 7.5 (s , 1H),

Method 42

1-methyl-3-fluoro-9H-carbazole

The title compound is described in J. Med. Chem. 1973 v.16 n.4 p.427, but with 6-fluoro-8-methyl-1,2, instead of 6-fluoro-1,2,3,4-tetrahydrocarbazole. Prepared using 3,4-tetrahydrocarbazole (method 41).

NMR (300MHz, CDCl ₃ ) 2.6 (s, 3H), 7.0 (d, 1H), 7.2 (t, 1H), 7.4 (m, 2H), 7.6 (d, 1H), 7.9 (s, 1H), 8.0 (d, 1H).

Method 43

3-Amino-4-methyl-9-methylsulfonyl-9H-carbazole

A solution of 4-methyl-9-methylsulfonyl-3-nitro-9H-carbazole (Method 44; 245 mg, 0.80 mmol) in EtOAc (10 mL) with 10% palladium on carbon (138 g) under hydrogen atmosphere Stir for 2 hours. The reaction mixture was filtered and the filtrate was distilled to dry to give a nearly colorless gum (183 mg).

NMR (CDCl ₃ ) 8.18 (d, 1H), 8.15 (d, 1H), 7.84 (d, 1H), 7.45 (dd, 1H), 7.38 (dd, 1H), 2.83 (s, 3H), 2.62 (s , 1H); m / z 275.35

Method 44

4-methyl-9-methylsulfonyl-3-nitro-9H-carbazole

To a stirred solution of 4-methyl-3-nitro-9H-carbazole (Method 29; 165 mg, 0.73 mmol) in anhydrous DMF (4 mL) was added sodium hydride (32 mg of 60% dispersion in mineral oil, 0.80 mmol). It was. The dark red mixture was stirred for 30 minutes, then a stirred solution of methanesulfonyl chloride (63 μL, 0.80 mmol) in anhydrous DMF (4 mL) was added dropwise. The mixture was stirred for 1 hour and partitioned between EtOAc and water. The EtOAc solution was washed with brine, dried and evaporated to give a yellow solid (245 mg) which was used without purification.

NMR 8.38 (d, 1H), 8.16 (d, 1H), 8.10 (s, 2H), 7.66 (dd, 1H), 7.54 (dd, 1H), 3.45 (s, 3H), 2.94 (s, 3H).

Method 45

Cis-1-amino-3- (ethoxycarbonylmethyl) cyclohexane

1-amino-3- (ethoxycarbonylmethyl) phenyl) (Collect.Czech.Chem.Comm., 60 (1995) 4, 659-66; 21 g), glacial acetic acid (500 mL), Adams catalyst (2 g ) Was heated at 35-40 ° C. and 25 psi for 4 hours. The solvent was removed under vacuum and the residue was partitioned between saturated aqueous sodium carbonate solution (30 mL) and EtOAc (100 mL). The aqueous phase was extracted with additional EtOAc (3 x 100 mL). The organic extracts were combined, washed with brine (30 mL) and evaporated to dryness to afford the title compound as an oil (6.02 g).

Method 46

Cis-1- (t-butoxycarbonylamino) -3- (ethoxycarbonylmethyl) cyclohexane

To a solution of cis-1-amino-3- (ethoxycarbonylmethyl) cyclohexane (method 45; 6.07 g) in toluene (10 mL) di-t-butyl dicarbonate (6.43 g) in toluene (15 mL) The solution was added dropwise. If the reaction weakened, the clear solution was heated in a steam bath for 1 hour. The solution was then evaporated to dryness to give a colorless oil. It was distilled under vacuum (11 ° C., 0.5 mmHg), liquid triturated with 40/60 petrol and cooled to give a white solid (2.58 g).

Elemental analysis of C ₁₅ H ₂₇ NO ₄ ;

Theoretical: C, 63.2%; H, 9.5%; N, 4.9%

Found: C, 63.5%; H, 9.7%; N, 4.8%

Method 47

Cis-1- (t-butoxycarbonylamino) -3- (carboxymethyl) cyclohexane

Cis-1- (t-butoxycarbonylamino) -3- (ethoxycarbonylmethyl) cyclohexane (method 46; 4.47 g), MeOH (100 mL) and sodium hydroxide (2M, 16 mL) were at room temperature Let it stand overnight. The solvent was removed under vacuum and the resulting aqueous solution diluted with water (15 mL) and washed with ether. The aqueous layer was then acidified with concentrated hydrochloric acid (up to pH 3) and extracted with EtOAc (2 × 30 mL). The organic phases were combined, washed with brine, dried and evaporated to dryness to give a colorless oil. The colorless oil was dissolved in ether (20 mL) and triturated with 40/60 petrol. The solution was cooled in a freezer, the resulting white crystals were filtered and air dried to afford the title compound (2.82 g).

Elemental analysis of C ₁₃ H ₂₃ NO ₄ ;

Theoretical: C, 60.7%, H, 8.9%; N, 5.4%

Found: C, 61.0%; H, 9.2%; N, 5.4%

Method 48

3- (phenoxycarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole

3-amino-2,4-dimethyl-9-isopropylcarbazole (method 14) in anhydrous tetrahydrofuran (25 mL) in a solution of phenyl chloroformate (1.254 mL, 10 mmol) in anhydrous tetrahydrofuran (25 mL) 2.52 g, 10 mmol) was added. A solution of triethylamine (1.394 mL, 10 mmol) in anhydrous tetrahydrofuran (5 mL) was added slowly and the reaction mixture was stirred for 40 minutes at room temperature under argon atmosphere. The white precipitate was filtered off and washed with ethyl acetate. The filtrate solvent was removed under vacuum to afford the title compound as a brown oil (3.651 g, 98%). Rf 0.3 (1: 4; ethyl acetate: isohexane).

NMR 1.62 (d, 6H), 2.47 (s, 3H), 2. 73 (s, 3H), 5.10 (sept, 1H), 7.21 (m, 4H), 7.43 (m, 4H), 7.71 (d, 1H ), 8.18 (d, 1 H), 9.32 (s, 1 H); m / z 373.29.

Method 49

3- (phenoxycarbonylamino) -4-methyl-9-isopropyl-9H-carbazole

The title compound was prepared from 3-amino-4-methyl-9-isopropylcarbazole (Method 21) using the procedure of Method 48.

NMR 1.63 (d, 6H), 2.75 (s, 3H), 5.15 (sept, 1H), 7.24 (m, 4H), 7.42 (m, 4H), 7.57 (d, 1H), 7.73 (d, 1H), 8.22 (d, 1H), 9.60 (s, 1H); m / z 359.33.

Method 50

3- (4-nitrophenoxycarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole

3-amino-2,4-dimethyl-9-isopropylcarbazole in a suspension of potassium carbonate (1.37 g, 9.91 mmol) and 4-nitrophenyl chloroformate (2.0 g, 9.92 mmol) in ethyl acetate (100 mL) (Method 14; 2.27 g, 9.01 mmol) was partially added. After the addition was complete, the reaction mixture was vigorously stirred for 30 minutes. Ethyl acetate (50 mL) was added to the reaction mixture, which was then washed with water (3 x 200 mL). Ethyl acetate was dried and concentrated in vacuo to give a yellow solid. The yellow solid was preabsorbed on silica and loaded on a column, 1) isohexane 2) 10% diethyl ether / isohexane 3) 50% diethyl ether / isohexane 4) 50% ethyl acetate / isohexane Eluted. The required fractions were collected and concentrated in vacuo to yield 1.6 g of the title compound (10% unidentified impurities identified by NMR).

NMR 1.62 (d, 6H), 2.73 (s, 3H), 5.10 (sept, 1H), 7.18 (t, 1H), 7.4 (t, 1H), 7.7 (d, 1H), 8.05-8.35 (m, 3H ).

Method 51

9-isopropyl-1,2,3,4-tetrahydro-6-nitrocarbazole

9-isopropyl-1,2,3,4-tetrahydrocarbazole (JCS Perkin 1 573-80, 1993) was nitrified in a similar manner as described in Method 2.

NMR (300 MHz, CDCl ₃ ) 8.40 (d, 1H), 8.00 (dd, 1H), 7.39 (d, 1H), 4.64 (m, 1H), 2.75 (m, 4H), 1.97 (m, 2H), 1.88 (m, 2H), 1.60 (d, 6H), 0.88 (m, 1H); m / z 259.7.

Method 52

9-isopropyl-1,2,3,4-tetrahydro-5-methyl-6-nitrocarbazole

The title compound was prepared from 9-isopropyl-1,2,3,4-tetrahydro-6-nitrocarbazole (method 51) using methyl magnesium bromide and in a similar manner as described in Method 25.

NMR (300 MHz) 7.58 (d, 1H), 7.48 (d, 1H), 4.70 (m, 1H), 2.96 (m, 2H), 2.85 (m, 2H), 2.84 (s, 3H), 1.78 (m, 4H), 1.50 (d, 6H); m / z 272.

Method 53

9-isopropyl-1,2,3,4-tetrahydro-5-methyl-6-aminocarbazole hydrochloride

The title compound was prepared from 9-isopropyl-1,2,3,4-tetrahydro-5-methyl-6-nitrocarbazole (method 52) in a similar manner as described in Method 14.

NMR (300 MHz) 10.0 (br, 3H), 7.38 (d, 1H), 7.08 (d, 1H), 4.64 (m, 1H), 2.93 (m, 2H), 2.73 (m, 2H), 2.53 (s, 3H), 1.77 (m, 4H), 1.48 (d, 6H); m / z 243.4.

Example 165

Exemplary pharmaceutical formulations exemplified below contain a compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof (hereinafter referred to as compound X) and are used for therapeutic or prophylactic use in humans :

(a) Tablet I

mg / tablet

Compound X100

Lactose (European Pharmacopoeia)

Croscarmellose Sodium 12.0

Corn Starch Paste (5% w / v Paste) 2.25

Magnesium Stearate 3.0

(b) tablets II

mg / tablet

Compound X 50

Lactose (European Pharmacopoeia)

Croscarmellose Sodium 6.0

Corn Starch 15.0

Polyvinylpyrrolidone (5% w / v paste) 2.25

Magnesium Stearate 3.0

(c) tablets III

mg / tablet

Compound X 1.0

Lactose (European Pharmacopoeia) 93.25

Croscarmellose Sodium 4.0

Corn Starch Paste (5% w / v Paste) 0.75

Magnesium Stearate 1.0

(d) capsules

mg / capsules

Compound x 10

Lactose (European Pharmacopoeia)

Magnesium Stearate 1.5

(e) Injection I

(50 mg / ml)

Compound X 5.0% w / v

1 M sodium hydroxide solution 15.0% v / v

0.1 M hydrochloric acid (pH 7.6 adjustment)

Polyethylene glycol 400 4.5% w / v

Up to 100% water for injection

(f) water for injection II

10 mg / ml

Compound X 1.0% w / v

Sodium Phosphate BP 3.6% w / v

0.1 M sodium hydroxide solution 15.0% v / v

Up to 100% water for injection

(g) Water for Injection III

(1 mg / ml, buffered at pH 6)

Compound X0.1% w / v

Sodium Phosphate BP2.26% w / v

Citric Acid 0.38% w / v

Polyethylene glycol 4003.5% w / v

Up to 100% water for injection

week:

The formulations can be obtained by conventional methods well known in the pharmaceutical art. The tablets (a) to (c) may be enteric coated in a conventional manner, for example to provide a coating of cellulose acetate phthalate.

Claims (15)

A compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof: Formula I Where R ¹ is C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfamoyl Is selected from; Wherein R ¹ may be optionally substituted on carbon with one or more R ⁷ ; R ² and R ³ are both methyl or R ² and R ³ together form — (CH ₂ ) ₄ — or — (CH) ₄ —; Wherein-(CH ₂ ) ₄ -or-(CH) ₄ -may be optionally substituted with R ⁸ ; R ⁴ is C _1-4 alkyl; R ⁵ is —C (O) NR ⁹ R ¹⁰ , —C (O) R ⁹ or —C (O) C (O) R ⁹ ; R ⁶ and R ⁸ are independently halo, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-4 alkyl, N- (C _1-4 alkyl) amino, N, N- (C _{1 -4} alkyl) ₂ amino and C _1-4 alkoxy; R ⁷ is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _a Wherein a is 0 to 2, C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl, N, N- (C _1-4 alkyl) ₂ sulfamoyl, C _{1- 4} alkylsulfonylamino, carbocyclyl or heterocyclyl; R ⁹ and R ¹⁰ are independently hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-4 alkoxy, carbocyclyl or heterocyclyl; Wherein R ⁹ and R ¹⁰ can be optionally substituted independently with one or more R ¹¹ on carbon; Wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by R ¹² ; Or R ⁹ and R ¹⁰ together with the nitrogen attached thereto form a heterocycle optionally substituted with one or more R ¹³ on carbon; Wherein if said heterocycle contains an —NH— moiety that nitrogen may be optionally substituted by R ¹⁴ ; R ¹¹ and R ¹³ are independently halo, hydroxy, cyano, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl oil, C _1-4 alkanoyloxy, C _1-4 alkanoylamino, C _2-6 alkenyloxycarbonyl, C _1-4 alkoxycar Carbonyl, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _1-4 alkoxycarbonylamino, C _1-4 alkoxycarbonyl-N- (C _{1- 4} alkyl) amino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _a (where a is 0 to 2), N- (C _1-4 alkyl) sulfamoyl, N, N- (C _1-4 alkyl) ₂ sulfamoyl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocycle Arylcarbonylamino, heterocyclylthio, carbocyclyl, carbocyclyloxy, carbocyclylcarbonyl, carbocyclylcarbonylamino, carbocyclyloxyca Carbonyl, and thio and carbocyclyl; Wherein R ¹¹ and R ¹³ can be optionally substituted independently on carbon with one or more R ¹⁵ ; Wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by R ¹⁶ ; R ¹² , R ¹⁴ and R ¹⁶ are independently C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, sulfamoyl, N- (C _1-4 alkyl) sulfamoyl, N, N -(C _1-4 alkyl) ₂ sulfamoyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbo Barmoyl, carbocyclyl, carbocyclylC _1-4 alkyl, carbocyclylcarbonyl, carbocyclylsulfonyl, heterocyclyl, heterocyclylC _1-4 alkyl, heterocyclylcarbonyl, heterocyclylsul Ponyl; Wherein R ¹² , R ¹⁴ and R ¹⁶ can be optionally substituted independently with one or more R ¹⁷ on carbon; R ¹⁵ is halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _{2- 4} Alkynyl, C _1-4 Alkoxy, C _1-4 Alkanoyl Oil, C _1-4 Alkanoyloxy, C _1-4 Alkanoylamino, C _2-6 Alkenyloxycarbonyl, C _1-4 Alkoxycarbonyl , N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _1-4 alkoxycarbonylamino, C _1-4 alkoxycarbonyl-N- (C _1-4 Alkyl) amino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _a (where a is 0 2), N- (C _1-4 alkyl) sulfamoyl, N, N- (C _1-4 alkyl) ₂ sulfamoyl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclyl Methyloxy, heterocyclyloxycarbonyl, carbocyclyl, carbocyclyloxy, carbocyclylcarbonyl, carbocyclylmethyloxy and carbocyclyloxycarbonyl .; Wherein R ¹⁵ may be optionally substituted on carbon with one or more R ¹⁸ ; R ¹⁷ and R ¹⁸ are halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl , Methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N, N -Dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl; m is 0 to 2, wherein the value of R ⁶ may be the same or different. The compound of formula (I) or a pharmaceutically acceptable thereof, according to claim 1, wherein R ¹ is selected from C _1-4 alkyl optionally substituted with one or more R ⁷ on carbon, wherein R ⁷ is C _1-4 alkoxy Salts, prodrugs or solvates. ^{3. The} compound of claim 1, wherein R ² and R ³ together form — (CH ₂ ) ₄ — or — (CH) ₄ — optionally substituted with R ⁸ , wherein R ⁸ is halo or C _{1- 4} or a pharmaceutically acceptable salt, prodrug or solvate thereof. The compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 1 to 3, wherein R ⁴ is methyl or isopropyl. The method according to any one of claims 1 to 4, R ⁵ is —C (O) NR ⁹ R ¹⁰ , —C (O) R ⁹ or —C (O) C (O) R ⁹ ; here R ⁹ and R ¹⁰ are independently hydrogen, C _1-10 alkyl, C _1-4 alkoxy, carbocyclyl or heterocyclyl; Wherein R ⁹ and R ¹⁰ may be optionally substituted independently with one or more R ¹¹ on carbon; Wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by R ¹² ; Or R ⁹ and R ¹⁰ together with the nitrogen to which they are attached form a heterocycle optionally substituted with one or more R ¹³ on carbon; Wherein if said heterocycle contains an —NH— moiety that nitrogen may be optionally substituted by R ¹⁴ ; R ¹¹ and R ¹³ are independently halo, hydroxy, carbamoyl, amino, carboxy, carbamoyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkanoylamino, C _1-4 alkoxy Carbonyl, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _1-4 alkoxycarbonylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkyl S (O) _a , wherein a is 0 or 2, heterocyclyl, heterocyclyloxy or carbocyclyl Is selected from; Wherein R ¹¹ and R ¹³ may be optionally substituted independently with one or more R ¹⁵ on carbon; R ¹² and R ¹⁴ are independently C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, heterocyclyl and carbocyclylC _1-4 alkyl; R ¹⁵ is selected from hydroxy, amino, C _1-4 alkoxycarbonylamino, C _1-4 alkoxy, N, N- (C _1-4 alkyl) ₂ amino, heterocyclyl A compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof. The compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 1 to 5, wherein R ⁶ is 2-methyl. 7. The compound of formula I according to claim 1, wherein m is 0 or m is 1 and R ⁶ is ortho to the —NHR ⁵ substituent. The method of claim 1, R ¹ is selected from C _1-4 alkyl optionally substituted with one or more R ⁷ on carbon; Wherein R ⁷ is C _1-4 alkoxy; R ² and R ³ together form-(CH ₂ ) ₄ -or-(CH) ₄ -optionally substituted with R ⁸ ; Wherein R ⁸ is selected from halo or C _1-4 alkyl; R ⁴ is methyl or isopropyl; R ⁵ is —C (O) NR ⁹ R ¹⁰ , —C (O) R ⁹ or —C (O) C (O) R ⁹ ; here R ⁹ and R ¹⁰ are independently hydrogen, C _1-10 alkyl, C _1-4 alkoxy, carbocyclyl or heterocyclyl; Wherein R ⁹ and R ¹⁰ may be optionally substituted independently with one or more R ¹¹ on carbon; Wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by R ¹² ; Or R ⁹ and R ¹⁰ together with the nitrogen to which they are attached form a heterocycle optionally substituted with one or more R ¹³ on carbon; Wherein if said heterocycle contains an —NH— moiety that nitrogen may be optionally substituted by R ¹⁴ ; R ¹¹ and R ¹³ are independently halo, hydroxy, carbamoyl, amino, carboxy, carbamoyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkanoylamino, C _1-4 alkoxy Carbonyl, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _1-4 alkoxycarbonylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkyl S (O) _a , wherein a is 0 or 2, heterocyclyl, heterocyclyloxy or carbocyclyl Is selected from; Wherein R ¹¹ and R ¹³ can be optionally substituted independently with one or more R ¹⁵ on carbon; R ¹² and R ¹⁴ are independently C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, heterocyclyl and carbocyclylC _1-4 alkyl; R ¹⁵ is selected from hydroxy, amino, C _1-4 alkoxycarbonylamino, C _1-4 alkoxy, N, N- (C _1-4 alkyl) ₂ amino, heterocyclyl; R ⁶ is 2-methyl; m is 0 or 1 A compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof. The method of claim 1, 3- (morpholinocarbonylamino) -4-methyl-9-isopropyl-9H-carbazole; 3- (3-carbamoylpiperidin-1-ylcarbonylamino) -2,4-dimethyl-9-isopropyl-9H-carbazole; 3- (1,1-dioxotetrahydrothien-3-ylmethylcarbonylamino) -4-methyl-9-isopropyl-9H-carbazole; 3- (morpholinocarbonylamino) -4-methyl-6-fluoro-9-isopropyl-9H-carbazole; 3- (3-carbamoylpiperidin-1-ylcarbonylamino) -4-methyl-9-isopropyl-9H-carbazole; 3- (4-hydroxypiperidin-1-ylcarbonylamino) -4-methyl-6-fluoro-9-isopropyl-9H-carbazole; 3- [3- (N-methylcarbamoyl) piperidin-1-ylcarbonylamino] -2,4-dimethyl-9-isopropyl-9H-carbazole; 3- [1- (N, N-dimethylcarbamoyl) piperidin-4-ylcarbonylamino] -2,4-dimethyl-9-isopropyl-9H-carbazole; 3- [1- (N, N-dimethylcarbamoyl) pyrrolidin-3-ylcarbonylamino] -2,4-dimethyl-9-isopropyl-9H-carbazole; And 3- [4-hydroxypiperidin-1-ylcarbonylamino] -2-methyl-9-isopropyl-9H-carbazole Or a pharmaceutically acceptable salt, prodrug or solvate thereof. Process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug or solvate thereof, consisting of the following process (unless otherwise indicated, the variable groups are as defined in claim 1): Process a) for a compound of Formula I wherein R ⁵ is —C (O) R ⁹ ; Reacting an amine of formula II with an acid of formula III or an activated derivative thereof: or Formula II Formula III Step b) for a compound of Formula I wherein R ⁵ is -C (O) NR ⁹ R ¹⁰ ; Reacting a compound of formula IV with an amine of formula V: Formula IV (Wherein L is a substitutable group) Formula V Process c) for a compound of Formula I wherein R ⁵ is —C (O) NR ⁹ R ¹⁰ ; Reacting a compound of formula II with a compound of formula VI: Formula VI Step d) for a compound of Formula I wherein R ⁵ is -C (O) NR ⁹ R ¹⁰ and one of R ⁹ and R ¹⁰ is hydrogen; Reacting a compound of formula II with an isocyanate of formula VII: Formula VII Wherein R ^a is R ⁹ or R ¹⁰ but not hydrogen) Step e) reacting a compound of formula VIII with a compound of formula IX: Formula VIII Formula IX (Wherein Z is a substitutable group or when R ¹ is C _1-4 alkanoyl, Z may be hydroxy) Step f) if R ⁵ is a compound of Formula I wherein -C (O) NR ⁹ R ¹⁰ ; Reacting a compound of formula X with an amine of formula V; Formula X And thereafter, as needed i) converting the compound of formula I to another compound of formula I; ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt or prodrug or solvate thereof. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof of any one of claims 1 to 9 together with a pharmaceutically acceptable diluent or carrier. Use of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof of any one of claims 1 to 9 as a medicament. 10. Treatment of an eating disorder in a warm blooded animal comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 1 to 9. Way. 10. A compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate of any one of claims 1 to 9 in the manufacture of a medicament for treating an eating disorder in a warm blooded animal. Use of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof of any one of claims 1 to 9 for the treatment of a dietary disorder in a warm blooded animal.