JP2005516901A - 1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid amide compound - Google Patents

Abstract

The present invention discloses 1H-pyrrolo [3,2-b] pyridine-3-carboxylic amide compounds that bind to the benzodiazepine site of the GABA _A receptor. These compounds can be used to modulate ligands that bind to GABA _A receptors in vivo and in vitro and are particularly useful for the treatment of various central nervous system (CNS) disorders in humans, domestic pets and livestock animals. is there.

Description

(Background of the Invention)
This application is filed with US provisional application S.D. N. No. 60 / 333,027 is claimed and the entire description of this application is incorporated herein by reference.
(Field of Invention)
The present invention relates to 1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid amide compounds that bind to the benzodiazepine site of the GABA _A receptor. The invention also relates to pharmaceutical compositions containing such compounds and their use in the treatment of central nervous system (CNS) diseases.

(Description of related technology)
The GABA _A receptor is classified as a major inhibitory neurotransmitter, γ-aminobutyric acid or GABA, one of the receptors that act via these receptors. Widely distributed throughout the mammalian brain, but distributed in a heterogeneous manner, GABA mediates many of its actions via a complex protein called the GABA _A receptor. This GABA _A receptor causes changes in chloride conduction and membrane polarization. In addition to being a site of neurotransmission, many medications, including anxiolytic and sedating benzodiazepine compounds, bind to this receptor. The GABA _A receptor generally, but not unchanged, includes a chloride channel that opens in response to GABA, thereby allowing the introduction of chloride into the cell. This then acts to slow neural activity by hyperpolarization of the cell membrane potential.

The GABA _A receptor is composed of five protein subunits. Many cDNAs related to these GABA _A receptor subunits have been cloned and their major structures have been determined. These subunits share the basic features of four membrane-spanning helics, but there are sufficient sequence differences in these subunits to classify them into several species. . To date, at least 6α, 3β, 3γ, 1ε, 1δ and 2ρ subunits have been identified. Natural GABA _A receptors are typically composed of 2α, 2β and 1γ. Various sets of evidence (eg, message distribution, gene location and biochemical study results) show that the major naturally occurring receptor combinations are α ₁ β ₂ γ ₂ , α ₂ β ₃ γ ₂ , α ₃ β ₃ γ ₂ , and It is suggested that it is α ₅ β ₃ γ ₂ (Mohler et al., Neuroch. Res. 1995; 20 (5): 631-36).

GABA _A receptor binding sites for GABA (2 per receptor complex) are formed by amino acids from the α and β subunits. The amino acids from the α and β subunits together form one benzodiazepine site for each receptor. Benzodiazepines exert their pharmacological effects by interacting with benzodiazepine binding sites associated with GABA _A receptors. In addition to the benzodiazepine site (this site is sometimes referred to as the benzodiazepine or BDZ receptor), the GABA _A receptor contains sites of interaction with several other groups of drugs. These include steroid binding sites, picrotoxin sites, and barbiturate sites. The benzodiazepine site of the GABA _A receptor is a different site on the receptor complex that does not overlap with another group of drugs that bind to the receptor or the interaction site for GABA (eg, Cooper et al., The Biological Basis of Neuropharmacology. 6th edition, 1991, pages 145-148, Oxford University Press, New York).

In the classical allosteric mechanism, drug binding to the benzodiazepine site increases the affinity of the GABA receptor for GABA. Benzodiazepine compounds and related medicaments that enhance the ability of GABA to open GABA _A receptor channels are known as agonists or partial agonists that respond to GABA potentiation levels. Another class of drugs that occupy the same site and negatively modulate the action of GABA, such as β-carboline derivatives, are called inverse agonists. The third class of compounds occupies the same sites as both agonists and inverse agonists and has little or no effect on GABA activity. However, these compounds block the action of agonists or inverse agonists. This is therefore referred to as a GABA _A receptor agonist.

  The important allosteric regulatory effect of medicinal action at the benzodiazepine site has been recognized since early, and the distribution of activity at different subtype receptors has been a region of strong pharmacological discovery. Agonists acting at the benzodiazepine site are known to exhibit anxiety, sedation, and hypnosis, while compounds acting as inverse agonists at this site are anxiety-generating, cognitive-enhancing, and proconvulsant Induces action. Benzodiazepine compounds have long been happily used as pharmaceuticals as anxiolytics, but these compounds are also known to exhibit many undesirable side effects. These side effects can include cognitive impairment, sedation, ataxia, enhanced ethanol action, and tolerance and drug dependence.

GABA _A selective ligands may also serve to enhance the action of certain other CNS active compounds. As an example, a selective serotonin reuptake inhibitor (SSRI) can exhibit greater antidepressant activity when used in combination with a GABA _A selective ligand compared to when used alone.

(Summary of the Invention)
The present invention is a with a high degree of affinity and high selectivity to the benzodiazepine site of GABA _A receptors, including humans GABA _A receptor is preferably bound 1H- pyrrolo [3,2-b] pyridine-3-carboxylic acid amide provide. The compounds according to the invention preferably bind to the GABA _A receptor with a high degree of selectivity and / or high affinity, thereby acting as agonists, antagonists or inverse agonists of such receptors. Thus, these compounds are useful for the treatment of various CNS disorders.
The present invention provides compounds of formula I (shown below) and pharmaceutical compositions containing compounds of formula I.

The present invention also provides a method of treating a patient suffering from a CNS disorder with an effective amount of a compound according to the present invention. The patient can be a human or other mammal. Treatment with an effective amount of a compound according to the invention for humans, domestic pets (pets) or livestock animals suffering from certain CNS disorders is encompassed by the present invention.
In another aspect, the present invention provides a method for enhancing the action of certain CNS active compounds. This method comprises administering an effective amount of a compound according to the invention in combination with another CNS active compound.
Furthermore, the present invention relates to the use of a compound of formula I as a probe for the localization of GABA _A receptors in tissue parts.

In a first aspect, the present invention provides compounds of formula I and pharmaceutically acceptable salts:

The present invention encompasses three groups of compounds of formula I, these groups of compounds being represented by Group 1, Group 2 and Group 3.
In all the compounds of these groups, group 1, group 2 and group 3, the substituents R ₁ , R ₂ and R ₃ have the same definition. That is, in each of Group 1, Group 2 and Group 3, R ₁ , R ₂ and R ₃ are independent and represent the following meanings:
A) hydrogen, halogen, halo (C ₁ -C ₆₎ alkyl, hydroxy, cyano, amino, alkyl, alkoxy, mono (C ₁ -C ₆₎ alkylamino, di - (C ₁ -C ₆₎ alkylamino, mono (C ₁ -C ₆₎ alkylamino (C ₁ -C ₆₎ alkyl, di - (C ₁ -C ₆₎ alkylamino (C ₁ -C _{6) alkyl, -C (= O) NR 10} R 11, - C (═O) OR ₁₀ , and —OC (═O) R ₁₀ , —C (═O) R ₁₀ (wherein R ₁₀ and R ₁₁ are independently hydrogen, C ₁ -C ₆ alkyl, phenyl, phenyl, (C ₁ -C ₆ ) alkyl, pyridyl, or pyridyl (C ₁ -C ₆ ) alkyl); or

B) haloalkoxy, alkenyl, alkynyl, _{hydroxyalkyl, -DR 20, -E-R 35} , -C 1 -C 4 alkyl -DR _20, -C ₁ -C ₄ alkyl -O-R _20, -E-R ₂₀ -GR ₃₀ , -E-L, -E-R ₂₀ -L, J, -C (= O) -L, or -C ₁ -C ₄ alkyl-J;
[Where _{D, -S (O) n -,} - S (O) n NH -, - S (O) n NH 2 -, - S (O) n NR 30 -, - NHC (= O) - , -NHC (= O) H, -NR 30 C (= O) -, - NR 30 C (= O) H, represents -NHS (O) n- and -NR ₃₀ S (O) n-;
E and G are independently —NH—, —N (C ₁ -C ₆ alkyl)-, S and O;

R ₂₀ and R ₃₀ are each independently (C ₁ -C ₈ ) linear, (C ₁ -C ₈ ) branched, (C ₃ -C ₈ ) cyclic alkyl, or (C ₃ -C _8). ) A cycloalkyl (C ₁ -C ₆ ) alkyl group, each of which contains 0, 1 or 2 or more double or triple bonds, and R ₂₀ and Each carbon atom present in the R ₃₀ group may be substituted by one or more substituents independently selected from group C), wherein group C) is oxo, hydroxy, halogen , cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C _{6 alkyl), - N (C 1 -C} 6 alkyl) (C ₁ -C ₆ alkyl), - NHC (= O) (C ₁ -C _{6 alkyl), - N (C 1 -C} 6 alkyl) C (= O) ( ₁ -C _{6 alkyl), - NHS (O) n} (C 1 -C 6 _{alkyl), - S (O) n} (C 1 -C 6 _{alkyl), - S (O) n} NH (C 1 -C 6 Alkyl), —S (O) _n N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), or L, n is 0, 1 or 2;

Each R ₃₅ is independently a (C ₁ -C ₈ ) linear, (C ₁ -C ₈ ) branched, (C ₃ -C ₈ ) cyclic alkyl or (C ₃ -C ₈ ) cycloalkyl ( C ₁ -C ₆ alkyl) groups, each of which contains 0, 1 or 2 or more double or triple bonds and is present in the R ₃₅ group. Each carbon atom may be substituted by one or more substituents independently selected from group C);
J and L, when present, are independently selected from saturated, partially unsaturated and aromatic rings having 4 to 7 ring atoms, in which 0, 1 or 2 of the ring atoms Are oxygen or nitrogen, and the remaining ring atoms are carbon, and these rings are unsubstituted or substituted by one or more substituents independently selected from the group below May be:

i) halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy or mono-, - or di - (C ₁ -C ₆₎ alkylamino; or ii) phenyl, pyridyl, respectively pyrimidyl or pyrazinyl (these groups are unsubstituted or one to three Halogen, hydroxy, amino, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and mono- or di- (C ₁ -C ₄ ) Optionally substituted by alkylamino); or R ₄ is hydrogen, halogen or hydroxyl.

In the case of group 1 compounds, at least one R ₁ , R ₂ and R ₃ is selected from B) and J is not phenyl or pyridyl.
“Ar” that can be varied has a different definition for each of Group 1, Group 2, and Group 3.
In the case of group 1 compounds and salts:
Ar represents an aryl, arylalkyl, heteroarylalkyl or heteroaryl group, each aryl or heteroaryl having one or two aromatic rings, each aromatic ring having 4 to 7 ring atoms And selected 0, 1 or 2 of the ring atoms are oxygen, nitrogen or sulfur, the remaining ring atoms are carbon, and each of these rings is 1 or 2 Optionally substituted by R ₄₀ above:

Wherein R ₄₀ , if present, is independently selected from hydroxy, halogen, cyano, nitro, amino, XR ₅₀ , C ₁ -C ₄ alkyl-XR ₅₀ , and Y;
X, when present, is a bond, —CH ₂ —, —CHR ₆₀ —, —O—, —C (═O) —, —C (═O) O—, —OC (═O) —, — S (O) _n —, —NH—, —NR ₆₀ —, —C (═O) NH—, —C (═O) NR ₆₀ —, —S (O) _n NH—, —S (O) _n Independently selected from the group consisting of: NR ₆₀ —, —NHC (═O) —, —NR ₆₀ C (═O) —, —NHS (O) _n — and —NR ₆₀ S (O) _n —; n Is 0, 1 or 2;

R ₅₀ and R ₆₀ , when present, are independently of hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl and (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkyl. The alkyl and cycloalkyl each contain zero, one or more double or triple bonds, and the carbon atoms of the alkyl, cycloalkyl or cycloalkylalkyl are each independently , one or more oxo, hydroxy, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C _{6 alkyl), - N (C 1 -C} 6 alkyl) (C ₁ -C ₆ Alkyl), —NHC (═O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (═O) (C ₁ -C ₆ alkyl), —NHS (O) _n (C ₁ -C ₆ alkyl), - S (O) _n (C ₁ -C ₆ alkyl), —S (O) _n NH (C ₁ -C ₆ alkyl), —S (O) _n N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), and Optionally substituted by Z, wherein n is 0, 1 or 2; and

Y and Z are selected from saturated, partially unsaturated or aromatic rings having 4 to 7 ring atoms, in which 0, 1 or 2 of the ring atoms are oxygen or nitrogen; the remaining ring atoms are carbon, and Y and Z are independently, be unsubstituted, or one or more halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy or mono-, - or di - (C ₁ -C ₆₎ alkylamino May be substituted.

For group 2 compounds and salts:
Ar represents heteroaryl or heteroaryl (C ₁ -C ₆ ) alkyl, which is quinolinyl, benzothienyl, indolyl, pyridazinyl, pyazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl , Pyrazolyl, oxazolyl, thienyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzoisoxolyl, dihydro-benzodioxinyl, furanyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, Imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, iso Romaniru, Kuromanoniru, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzofuran tetrahydrofuranyl,

Isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl Benzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromanyl, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinyl, dihydroisoxinyl Norinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinoni , Pyrrolyl N- oxide, pyrimidinyl N- oxide, pyridazinyl N- oxide, pyrazinyl N- oxide,

Quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, Thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide , Benzothiopyranyl S-oxide and benzothiopyranyl S, S-dioxide, Ar is also one or more R ₄₀ may be substituted.

For Group 2 compounds, each R ₄₀ is independently hydroxy, halogen, cyano, nitro, amino, XR ₅₀ , C ₁ -C ₄ alkyl-XR ₅₀ , or Y;
Here, each X is independently a bond, —CH ₂ —, —CHR ₆₀ —, —O—, —C (═O) —, —C (═O) O—, —OC (═O) —, —S (O) _n —, —NH—, —NR ₆₀ —, —C (═O) NH—, —C (═O) NR ₆₀ —, —S (O) _n NH—, —S (O) _{n NR 60 -, - NHC (} = O) -, - NR 60 C (= O) -, - NHS (O) n - and -NR ₆₀ S (O) _n - and is;

R ₅₀ and R ₆₀ , when present, are independently of hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, and (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkyl. The alkyl and cycloalkyl contain 0, 1 or 2 or more double or triple bonds, and the carbon atoms present in these alkyl, cycloalkyl or cycloalkylalkyl are each , one or more oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C _{6 alkyl), - N (C 1 -C} 6 alkyl) (C ₁ - C ₆ alkyl), —NHC (═O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (═O) (C ₁ -C ₆ alkyl), —NHS (O) _n (C ₁ -C ₆ alkyl), - S O) _n (C ₁ -C _{6 alkyl), - S (O) n} NH (C 1 -C 6 _{alkyl), - S (O) n} N (C 1 -C 6 alkyl) (C ₁ -C ₆ alkyl ), And optionally substituted with Z; where n is 0, 1 or 2; and

Y and Z, when present, are independently selected from saturated, partially unsaturated and aromatic rings having 4 to 7 ring atoms, in which 0, 1 or 2 of the ring atoms Is oxygen or nitrogen, the remaining ring atoms are carbon, and Y and Z are independently unsubstituted or one or more halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy or mono-, - or di - (C ₁ -C ₆₎ may be substituted by alkylamino.

For Group 3 compounds and salts:
Ar represents phenyl, pyridyl or pyrimidinyl, each of which may be substituted by one or more R ₄₀ ; each R ₄₀ is independently hydroxy, halogen, cyano, nitro Amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkanoyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl (C ₁ -C ₄ ) alkyl, C ₃ -C ₇ cycloalkyl -O-, C ₃ -C ₇ cycloalkyl (C ₁ -C ₄₎ alkoxy -, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkylthio -, halo (C ₁ -C ₆₎ alkyl Or halo (C ₁ -C ₆ ) alkoxy.
Furthermore, Ar is at least one _{-E-R 50 -G-R 60} , -E-R 50 -G-Y, C 1 -C 4 alkyl -XR ₅₀ present in the compound of Group 3 and Shiochu, Must be substituted by —NH—R ₆₀ —Y, — (NR ₅₀ ) R ₆₀ —Y or Y.

In this case, X, when present, is —O—, —C (═O) —, —C (═O) O—, —OC (═O) —, —S (O) _n —, —NH. _{-, - NR 60 -, -} C (= O) NH -, - C (= O) NR 60 -, - S (O) n NH -, - S (O) n NR 60 -, - NHC (= O )-, —NR ₆₀ C (═O) —, —NHS (O) _n — and —NR ₆₀ S (O) _n —; where n is 0, 1 or 2;

R ₅₀ and R ₆₀ , when present, are independently of hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, and (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkyl. Wherein the alkyl and cycloalkyl each contain 0, 1 or 2 or more double or triple bonds, and the carbon atoms present in the alkyl, cycloalkyl or cycloalkylalkyl are each one or two or more oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C _{6 alkyl), - N (C 1 -C} 6 alkyl) (C ₁ -C ₆ alkyl), - NHC (= O) (C 1 -C 6 _{alkyl), - N (C 1 -C} 6 alkyl) C (= O) (C 1 -C 6 alkyl), - NHS (O) _n (C ₁ -C ₆ alkyl) _{-S (O) n (C 1} -C 6 _{alkyl), - S (O) n} NH (C 1 -C 6 _{alkyl), - S (O) n} N (C 1 -C 6 alkyl) (C ₁ - C ₆ alkyl), and may be independently substituted from Z; and

Y and Z, if present, are each independently selected from saturated, partially unsaturated or aromatic rings having 4 to 7 ring atoms in each aromatic ring, in which the ring atoms 0 One, two or two are oxygen or nitrogen, the remaining ring atoms are carbon, and Y and Z are independently unsubstituted or one or more halogen, oxo, hydroxy , amino, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy or, It may be substituted by mono- or di- (C ₁ -C ₆ ) alkylamino.

(Detailed description of the invention)
Particular embodiments of the present invention include compounds and pharmaceutically acceptable salts in groups 1, 2 and 3 wherein R ₄ is hydrogen.
The present invention further relates to compounds and salts of group 1 in formula I wherein Ar represents the group , Pyrrolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, [1,3,4] thiadiazolyl, triazolyl, indolyl, quinolinyl, isoquinolinyl, benzodioxolyl, benzofuranyl, benzimidazolyl, benzoisoxolyl, and dihydro-benzodi It is selected from oxynyl and optionally substituted by one or more R ₄₀ , where R ₄₀ is as defined above. In the following description, such compounds are referred to as Group 1A compounds.

The present invention also includes compounds and pharmaceutically acceptable salts in group I of formula I wherein R ₁ is selected from B).
In this embodiment, R ₂ and R ₃ are hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and Independently selected from mono- or di- (C ₁ -C ₆ ) alkylamino; more preferably R ₂ and R ₃ are hydrogen, halogen, CF ₃ , CHF ₂ , OCF ₃ , hydroxy, cyano, C ₁ Independently selected from —C ₂ alkyl, C ₁ -C ₂ alkoxy, and mono- or di- (C ₁ -C ₂ ) alkylamino; or R ₂ and R ₃ are independently hydrogen, halogen, methyl and ethyl It can also be selected.

In this embodiment, R ₄ is preferably hydrogen; and Ar is as defined for group 1A compounds.
Furthermore, the present invention includes compounds of formula I of group 1A and pharmaceutically acceptable salts. The compounds and salts of formula I of group 1A are:
R ₁ is selected from B);
R ₂ and R ₃ are independently selected from hydrogen, halogen, methyl and ethyl;
R ₄ is preferably hydrogen; and when R ₄₀ is present, respectively, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, mono- or di- (C ₁ -C ₆ ) alkylamino Mono- or di- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, and (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆₎ independently selected from alkoxy;
A compound.

The present invention relates to Formula I of Group 1A:
With respect to embodiments that include compounds wherein R ₁ is selected from B) and pharmaceutically acceptable salts; in this embodiment, B) is —E—R ₃₅ , —C ₁ -C ₄ alkyl-O—R ₂₀ , — E—R ₂₀ —G—R ₃₀ , —E—L, —E—R ₂₀ —L, J, or —C ₁ -C ₄ alkyl-J; and in this embodiment, E and G are independently —NH—, —N—C ₁ -C ₆ alkyl-, or O.

In this embodiment, R ₂₀ , R ₃₀ and R ₃₅ , if present, are each independently selected from linear, branched, and cyclic alkyl groups, and (cycloalkyl) alkyl groups. , Branched and cyclic alkyl groups and (cycloalkyl) alkyl groups each have from 1 to 8 carbon atoms and contain 0, 1 or 2 double or triple bonds And 1 to 8 carbon atoms present in the R ₂₀ and R ₃₅ groups are each further substituted by one or more substituents independently selected from group C) And in R ₃₅ , at least one of the 1 to 8 carbon atoms is further substituted by one or more substituents independently selected from group C), wherein group C ) Oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C _{6 alkyl), - N (C 1 -C} 6 alkyl) (C ₁ -C ₆ alkyl), - NHC ( ═O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (═O) (C ₁ -C ₆ alkyl), —NHS (O) _n (C ₁ -C ₆ alkyl) , —S (O) _n (C ₁ -C ₆ alkyl), —S (O) _n NH (C ₁ -C ₆ alkyl), —S (O) _n N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), and a L.

J and L, if present, are each independently selected from saturated heterocyclic rings having 4 to 7 ring atoms, in which one or two of the ring atoms are nitrogen, and the rest ring atoms are carbon, the rings unsubstituted or where one or more halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, Independently selected from C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, and mono- or di- (C ₁ -C ₆ ) alkylamino Optionally substituted by the following substituents: where J is not unsubstituted or substituted phenyl or unsubstituted or substituted pyridyl.

In this embodiment, R ₂ and R ₃ are hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and Independently selected from mono- or di- (C ₁ -C ₆ ) alkylamino; more preferably R ₂ and R ₃ are hydrogen, halogen, CF ₃ , CHF ₂ , OCF ₃ , hydroxy, cyano, C ₁ Independently selected from —C ₂ alkyl, C ₁ -C ₂ alkoxy, and mono- or di- (C ₁ -C ₂ ) alkylamino; or R ₂ and R ₃ are independently hydrogen, halogen, methyl and ethyl Can also be selected;
R ₄ is preferably hydrogen; and R ₄₀ , if present, is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, mono- or di- (C ₁ -C ₆ ) alkylamino. Mono- or di- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, and (C ₁ -C ₆ ) alkoxy Independently selected from (C ₁ -C ₆ ) alkoxy.

The present invention also has a definition as defined for Group 1A compounds and salts in Formula I of Group 1 and when R ₄₀ is present, respectively, hydroxy, halogen, cyano, amino, —XR ₅₀ , C ₁ -C ₄ alkyl -XR _50, and independently from Y is selected;
When each X is present, from the bond, —CH ₂ —, —CHR ₆₀ —, —O—, —C (═O) —, —S (O) _n —, —NH—, and —NR ₆₀ —. Independently selected, where n is 0, 1 or 2;

R ₅₀ and R ₆₀ , if present, are independently selected from hydrogen and linear, branched, and cyclic alkyl groups, and (cycloalkyl) alkyl groups, wherein the linear, branched, Chain and cyclic alkyl groups and (cycloalkyl) alkyl groups each have from 1 to 8 carbon atoms and contain 0, 1 or 2 double bonds or triple bonds, each 8 carbon atoms present in the group, one or more oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C ₆ alkyl ), —N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), —NHC (═O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (═O ) (C ₁ -C ₆ alkyl), - NHS (O) _n C ₁ -C _{6 alkyl), - S (O) n} (C 1 -C 6 _{alkyl), - S (O) n} NH (C 1 -C 6 _{alkyl), - S (O) n} N (C 1 - C ₆ alkyl) (C ₁ -C ₆ alkyl), and optionally further substituted by a substituent independently selected from Z, wherein n is 0, 1 or 2; and

Y and Z, when present, are selected from saturated, partially unsaturated or aromatic rings having 4 to 7 ring atoms, in which 0, 1 or 2 of the ring atoms are oxygen Selected from and nitrogen, the remaining ring atoms are carbon, and Y and Z are unsubstituted or one or more halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, and mono- or di- (C ₁ -C ₆ ) May be substituted by a substituent independently selected from alkylamino:
Includes compounds and pharmaceutically acceptable salts. Such compounds are referred to as Group 1B compounds.

Another aspect of the invention relates to compounds of Group 1B and pharmaceutically acceptable salts:
R ₁ is selected from B);
R ₂ and R ₃ are independently selected from hydrogen, halogen, methyl and ethyl;
And R ₄ is preferably hydrogen;
It relates to compounds and pharmaceutically acceptable salts.

In another embodiment, the present invention relates to compounds of formula 2 and pharmaceutically acceptable salts of group 2. In this embodiment, Ar represents aryl, arylalkyl, heteroaryl or heteroarylalkyl, where aryl and heteroaryl are piperazinyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, [1,3,4] thiadiazolyl, Selected from triazolyl, indolyl, quinolinyl, isoquinolinyl, benzodioxolyl, benzofuranyl, benzimidazolyl, benzisoxolyl, and dihydro-benzodioxinyl, and may be substituted by one or more R ₄₀ Well; where R ₄₀ relates to the compounds of group 2 and has the definition given above. Such compounds are referred to as Group 2A compounds.

The invention also provides in Formula I of Group 2A:
R ₁ is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono- or di- (C ₁ -C ₆₎ is selected from alkylamino and B);
Includes compounds and pharmaceutically acceptable salts.
In this embodiment, R ₂ and R ₃ are hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and Independently selected from mono- or di- (C ₁ -C ₆ ) alkylamino; more preferably R ₂ and R ₃ are hydrogen, halogen, CF ₃ , CHF ₂ , OCF ₃ , hydroxy, cyano, C ₁ Independently selected from —C ₂ alkyl, C ₁ -C ₂ alkoxy, and mono- or di- (C ₁ -C ₂ ) alkylamino; or R ₂ and R ₃ are independently hydrogen, halogen, methyl and ethyl It can also be selected.

In the compounds of the formula I of group 2A, R ₄ is preferably hydrogen.
Another aspect of the present invention is a compound of Formula I in Group 2A and a pharmaceutically acceptable salt thereof,
R ₁ is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono- or di- (C ₁ -C ₆₎ is selected from alkylamino and B), and B) is _{-E-R 35, -C 1 -C} 4 alkyl _{-O-R 20, -E-R} 20 -G-R 30, -E -L, is -E-R ₂₀ -L, J or -C ₁ -C ₄ alkyl -J,;
It relates to compounds and pharmaceutically acceptable salts.

E and G are independently —NH—, —N—C ₁ -C ₆ alkyl-, or O;
R ₂ and R ₃ are independently selected from hydrogen, halogen, methyl and ethyl;
And R ₄ is hydrogen.
Another aspect of the invention is a compound of Formula 2A and a pharmaceutically acceptable salt thereof, wherein Ar is as defined for the compound of Group 2A, wherein one or more R _Optionally substituted by ₄₀ ;
It relates to compounds and pharmaceutically acceptable salts.
In this embodiment, each R ₄₀ , if present, is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, mono- or di- (C ₁ -C ₆ ) alkylamino, mono- or di- ( C ₁ -C ₆₎ alkylamino (C ₁ -C ₆₎ alkoxy, (C ₁ -C ₆₎ alkoxy (C ₁ -C ₆₎ alkyl, and (C ₁ -C ₆₎ alkoxy (C ₁ -C ₆₎ Independently selected from alkoxy.

In this embodiment, R ₁ in this embodiment is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, Selected from mono- or di- (C ₁ -C ₆ ) alkylamino and B).
In this embodiment, R ₂ and R ₃ are hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and Independently selected from mono- or di- (C ₁ -C ₆ ) alkylamino; or more preferably R ₂ and R ₃ are hydrogen, halogen, CF ₃ , CHF ₂ , OCF ₃ , hydroxy, cyano, C _1- C ₂ alkyl, C ₁ -C ₂ alkoxy, and mono- or di- (C ₁ -C ₂ ) alkylamino are independently selected; or R ₂ and R ₃ are from hydrogen, halogen, methyl and ethyl Independently selected.
In this embodiment, R ₄ is hydrogen

Another aspect of the invention is a compound of Formula 2A and a pharmaceutically acceptable salt thereof, wherein Ar is as defined for the compound of Group 2A, wherein one or more R _Relates to compounds optionally substituted by ₄₀ and pharmaceutically acceptable salts. In this embodiment, each R ₄₀ , if present, is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, mono- or di- (C ₁ -C ₆ ) alkylamino, mono- or di- ( C ₁ -C ₆₎ alkylamino (C ₁ -C ₆₎ alkoxy, (C ₁ -C ₆₎ alkoxy (C ₁ -C ₆₎ alkyl, and (C ₁ -C ₆₎ alkoxy (C ₁ -C ₆₎ Independently selected from alkoxy.

R ₁ is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono- or di- (C ₁ -C ₆ ) selected from alkylamino and B).
In this embodiment, B) is —R ₃₅ , —C ₁ -C ₄ alkyl-O—R ₂₀ , —E—R ₂₀ —G—R ₃₀ , —E—L, —E—R ₂₀ —L, J Or —C ₁ -C ₄ alkyl-J, wherein E and G are independently —NH—, —N—C ₁ -C ₆ alkyl-, or O.

In this embodiment, R ₂₀ , R ₃₀ and R ₃₅ , if present, are each independently selected from linear, branched, and cyclic alkyl groups, and (cycloalkyl) alkyl groups. , Branched, and cyclic alkyl groups and (cycloalkyl) alkyl groups each have from 1 to 8 carbon atoms and contain 0, 1 or 2 double or triple bonds And 1 to 8 carbon atoms present in the R ₂₀ and R ₃₅ groups may each be substituted by one or more substituents independently selected from group C) Well, and in R ₃₅ , at least one of the 1-8 carbon atoms is further substituted with one or more substituents independently selected from group C); wherein group C) Is oxo, Hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C _{6 alkyl), - N (C 1 -C} 6 alkyl) (C ₁ -C ₆ alkyl), - NHC (= O ) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (═O) (C ₁ -C ₆ alkyl), —NHS (O) _n (C ₁ -C ₆ alkyl), — S (O) _n (C ₁ -C ₆ alkyl), —S (O) _n NH (C ₁ -C ₆ alkyl), —S (O) _n N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), and L.

In this embodiment, J and L, if present, are each independently selected from saturated heterocycles having 4 to 7 ring atoms, in which one or two of the ring atoms is nitrogen; the remaining ring atoms are carbon, or these rings are unsubstituted, or one or more halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy Independently of C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, and mono- or di- (C ₁ -C ₆ ) alkylamino Optionally substituted by a selected substituent: where J is not phenyl or pyridyl.

In this embodiment, R ₂ and R ₃ are hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, And independently selected from mono- or di- (C ₁ -C ₆ ) alkylamino; or more preferably, R ₂ and R ₃ are hydrogen, halogen, CF ₃ , CHF ₂ , OCF ₃ , hydroxy, cyano, Independently selected from C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, and mono- or di- (C ₁ -C ₂ ) alkylamino; or R ₂ and R ₃ are hydrogen, halogen, methyl and ethyl Selected independently.
In this embodiment, R ₄ is preferably hydrogen.

The invention also encompasses compounds and pharmaceutically acceptable salts of formula I, wherein Ar is as defined for compounds of group 2A.
In this embodiment, R ₄₀ , if present, is independently selected from hydroxy, halogen, cyano, amino, XR ₅₀ , — (C ₁ -C ₄ ) alkyl-XR ₅₀ , and Y.
In this embodiment, X, when present, is a bond, —CH ₂ —, —CHR ₆₀ —, —O—, —C (═O) —, —S (O) _n —, —NH—, and — NR ₆₀ - independently selected from where n is 0, 1 or 2.

In this embodiment, R ₅₀ and R ₆₀ , if present, are independently selected from hydrogen and linear, branched, and cyclic alkyl groups, and (cycloalkyl) alkyl groups, , Branched, and cyclic alkyl groups and (cycloalkyl) alkyl groups each have from 1 to 8 carbon atoms and contain 0, 1 or 2 double or triple bonds 1 to 8 carbon atoms present in these groups are each one or more oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, —NH (C ₁ -C _{6 alkyl), - N (C 1 -C} 6 alkyl) (C ₁ -C ₆ alkyl), - NHC (= O) (C 1 -C 6 _{alkyl), - N (C 1 -C} 6 alkyl) _{C (= O) (C 1} -C 6 alkyl) _{-NHS (O) n (C 1} -C 6 _{alkyl), - S (O) n} (C 1 -C 6 _{alkyl), - S (O) n} NH (C 1 -C 6 alkyl), - S (O ) _n n (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), and it may be further substituted with substituents selected independently from Z, where n is 0, 1 or 2 is there.

In this embodiment, Y and Z, if present, are each independently selected from saturated, partially unsaturated or aromatic rings having 4 to 7 ring atoms, in which 0 of the ring atoms, One or two are selected from oxygen and nitrogen, the remaining ring atoms are carbon, and Y and Z are unsubstituted or one or more halogen, oxo, hydroxy, amino, cyano C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, and mono- or di - (C ₁ -C ₆₎ may be substituted with substituents independently selected from alkylamino. Such compounds are referred to as Group 2B compounds.

Another group of compounds of formula I and salts of group 2B included in the present invention are those wherein R ₁ is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, Selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono- or di- (C ₁ -C ₆ ) alkylamino and B);
R ₂ and R ₃ are independently selected from hydrogen, halogen, methyl or ethyl; and R ₄ is hydrogen;
Compounds and salts.

In the present invention, R ₁ is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono- or It relates to compounds of the formula I of group 3 selected from di- (C ₁ -C ₆ ) alkylamino and B) and pharmaceutically acceptable salts.
In this embodiment, R ₂ and R ₃ are hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, And independently selected from mono- or di- (C ₁ -C ₆ ) alkylamino; or preferably R ₂ and R ₃ are hydrogen, halogen, CF ₃ , CHF ₂ , OCF ₃ , hydroxy, cyano, C Independently selected from _1- C ₂ alkyl, C ₁ -C ₂ alkoxy, and mono- or di- (C ₁ -C ₂ ) alkylamino; and R ₄ is preferably hydrogen.

Another compound of formula I in group 3 is a compound wherein Ar is phenyl, pyridyl or pyrimidinyl and each of these groups may be substituted by one or more R ₄₀ . In this case, R ₄₀ is preferably each, if present, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo (C ₁ -C ₆ ) alkyl and halo (C ₁ -C ₆₎ independently selected from alkoxy.
In this embodiment, Ar is at least one -E-R ₅₀ -G-R ₆₀ , -E-R ₅₀ -G-Y, C ₁ -C ₄ alkyl-XR ₅₀ , -NH-R ₆₀ -Y,- (NR ₅₀ ) R ₆₀ —Y, and substituted by Y:
X, when present, is —O—, —C (═O) —, —C (═O) O—, —OC (═O) —, —S (O) _n —, —NH—, — Independently selected from NR ₆₀ —, —C (═O) NH—, —C (═O) NR ₆₀ —, —NHC (═O) — and NR ₆₀ C (═O) —;

R ₅₀ and R ₆₀ , if present, are independently selected from hydrogen and linear, branched, and cyclic alkyl groups, and (cycloalkyl) alkyl groups, wherein the linear, branched, Chain and cyclic alkyl groups and (cycloalkyl) alkyl groups each have from 1 to 8 carbon atoms and contain 0, 1 or 2 double or triple bonds; each 8 carbon atoms present in the group, one or more oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C ₆ alkyl ), —N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), —NHC (═O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (═O ) (C ₁ -C ₆ alkyl), and German from Z It may be further substituted by substituents selected.

In a preferred embodiment of the invention, R ₂ and R ₃ are hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and independently selected from mono- or di- (C ₁ -C ₆ ) alkylamino; or preferably R ₂ and R ₃ are hydrogen, halogen, CF ₃ , CHF ₂ , OCF ₃ , hydroxy, Independently selected from cyano, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, and mono- or di- (C ₁ -C ₂ ) alkylamino or from hydrogen, halogen, methyl and ethyl.
In this embodiment, R ₄ is preferably hydrogen.

Another preferred compound of formula I is that R ₁ is amino (C ₁ -C ₆ ) alkoxy, mono (C ₁ -C ₃ ) alkylamino (C ₁ -C ₆ ) alkoxy, di (C ₁ -C ₃ ) alkylamino (C ₁ -C ₆ ) alkoxy, pyridyl (C ₁ -C ₆ ) alkoxy, hydroxy (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₆ ) alkoxy, Piperazinyl (C ₁ -C ₆ ) alkoxy (where the piperazinyl group may be substituted by (C ₁ -C ₆ ) alkyl), morpholinyl (C ₁ -C ₆ ) alkoxy or thiomorpholinyl (C ₁ -C ₆₎ ) Alkoxy;
R ₂ and R ₃ are independently selected from H, (C ₁ -C ₆ ) alkyl, halogen or (C ₁ -C ₆ ) alkoxy;
Includes compounds.

Another class of compounds of formula I within this preferred embodiment are those in which both R ₂ and R ₃ are both hydrogen.
Further preferred compounds of formula I are
R ₁ is amino (C ₁ -C ₄ ) alkoxy, mono (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkoxy, di (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) Alkoxy, pyridyl (C ₁ -C ₄ ) alkoxy, hydroxy (C ₁ -C ₄ ) alkoxy, piperazinyl (C ₁ -C ₄ ) alkoxy (where the piperazinyl group is substituted by (C ₁ -C ₄ ) alkyl Or a compound that is morpholinyl (C ₁ -C ₆ ) alkoxy.
Another class of compounds of formula I within this preferred embodiment are those in which both R ₂ and R ₃ are both hydrogen.

Further preferred compounds of formula I are
R ₂ and R _3, H, (C ₁ -C ₄₎ alkyl, are independently selected from halogen or (C ₁ -C ₄₎ alkoxy, provided that at least one compound is H R ₂ and R ₃ Include.
Yet another preferred compound of formula I is
R ₁ is amino (C ₁ -C ₄ ) alkoxy, mono (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkoxy, di (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) Alkoxy, pyridyl (C ₁ -C ₄ ) alkoxy, hydroxy (C ₁ -C ₄ ) alkoxy, piperazinyl (C ₁ -C ₄ ) alkoxy (where the piperazinyl group is substituted by (C ₁ -C ₄ ) alkyl Or morpholinyl (C ₁ -C ₆ ) alkoxy;
R ₂ and R ₃ include H, (C ₁ -C ₄₎ alkyl or (C ₁ -C ₄₎ independently of the alkoxy is selected, provided that at least one of R ₂ and R ₃ are H compound To do.

Another preferred compound of formula I within this preferred embodiment is one in which both R ₂ and R ₃ are both hydrogen.
Yet another preferred compound of formula I is
R ₁ is amino (C ₁ -C ₄ ) alkoxy, mono (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkoxy, di (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) Alkoxy, pyridyl (C ₁ -C ₄ ) alkoxy, hydroxy (C ₁ -C ₄ ) alkoxy, piperazinyl (C ₁ -C ₄ ) alkoxy (where the piperazinyl group is substituted by (C ₁ -C ₄ ) alkyl Or morpholinyl (C ₁ -C ₄ ) alkoxy;
R ₂ and R ₃ are independently selected from H and (C ₁ -C ₄ ) alkyl, provided that at least one of R ₂ and R ₃ is H.

Another preferred compound of formula I within this preferred embodiment is one in which both R ₂ and R ₃ are both hydrogen.
Yet another preferred compound of formula I is
R ₁ is amino (C ₂ -C ₄ ) alkoxy, mono (C ₁ -C ₄ ) alkylamino (C ₂ -C ₄ ) alkoxy, di (C ₁ -C ₄ ) alkylamino (C ₂ -C ₄ ) Alkoxy, pyridyl (C ₂ -C ₄ ) alkoxy, hydroxy (C ₂ -C ₄ ) alkoxy, piperazinyl (C ₂ -C ₄ ) alkoxy (where the piperazinyl group is substituted by (C ₁ -C ₄ ) alkyl. Or morpholinyl (C ₂ -C ₄ ) alkoxy;
R ₂ is H or methyl; and R ₃ is H;
Includes compounds.
Another preferred compound of formula I within this preferred embodiment is one in which both R ₂ and R ₃ are both hydrogen.

  Representative compounds according to the present invention encompassed by Formula I include, but are not limited to, the compounds described in Examples 1, 2, and 3 and their pharmaceutically acceptable acid and base addition salts. When the compound according to the invention is obtained as an acid addition salt, the free base can be obtained by basifying the acid salt solution. Conversely, if the product is a free base, the free base is dissolved in a suitable organic solvent according to conventional methods for the preparation of acid addition salts from base compounds, and the solution is then treated with an acid. By doing so, an addition salt, particularly a pharmaceutically acceptable addition salt can be obtained.

Non-toxic pharmaceutical salts include hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfinic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanol silicates (e.g., _{acetic, HOOC- (CH 2) n -ACOOH} , where n is 0-4) include acid salts, such as. A wide variety of pharmaceutically acceptable addition salts are considered recognized by those skilled in the art.
The present invention also includes hydrates of the compounds of formula I.
The present invention includes compounds of formula I in all crystalline forms. Certain crystal forms may be preferred.

  The present invention also includes acylated prodrugs of the compounds of Formula I. Those skilled in the art will be able to recognize a variety of synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable salts and acylated prodrugs of the compounds encompassed by Formula I. The present invention also includes all enantiomers and diastereomers of the disclosed compounds. Those skilled in the art are considered to be already aware of how to redissolve a mixture of enantiomers and diastereomers. As used herein, the definition of Formula I includes possible isomers, such as tautomers and rotamers.

The present invention relates to 1H- pyrrolo [3,2-b] pyridine-3-carboxylic acid amide compound, its preferred examples binds with high affinity to the benzodiazepine site of GABA _A receptors, including humans GABA _A receptor. Suitable 1H- pyrrolo [3,2-b] pyridine-3-carboxylic acid amide compound binds with high selectivity to the benzodiazepine site of GABA _A receptors, including humans GABA _A receptor is also encompassed by the present invention. While not wishing to be bound by any particular theory, the interaction of the compounds of Formula I with the benzodiazepine moiety results in the utility of these compounds as pharmaceuticals.

The invention further encompasses a method of treating a patient in need of such treatment with an amount of a compound according to the invention sufficient to alter the symptoms of a CNS disorder. Compounds according to the invention that act as agonists at the α ₂ β ₃ γ ₂ and α ₃ β ₃ γ ₂ receptor subtypes are anxiety disorders such as panic disorder, obsessive compulsive disorder, and generalized anxiety disorder, stress disorder (post traumatic) Useful in the treatment of stress and acute stress disorders). The compounds according to the invention acting as agonists at the α ₂ β ₃ γ ₂ and α ₃ β ₃ β ₂ receptor subtypes are also useful in the treatment of depression or bipolar disorder and in the treatment of sleep disorders. The compounds according to the present invention acting as inverse agonists at the α ₅ β ₃ γ ₂ receptor subtype or the α ₁ β ₂ γ ₂ and α ₅ β ₃ γ ₂ receptor subtypes are used for Down syndrome syndrome, neurodegenerative diseases (eg Alzheimer's). Disease and Parkinson's disease), and the treatment of cognitive impairments, including diseases that develop from seizure-related dementia.

The compounds according to the invention acting as inverse agonists at α ₅ β ₃ γ ₂ are particularly useful for the treatment of cognitive impairment in memory-impaired patients, especially by enhancing short-term memory. The compounds according to the invention which act as agonists at the α ₁ β ₂ γ ₂ receptor subtype are useful for the treatment of convulsive disorders such as epilepsy. Compounds that act as antagonists at the benzodiazepine site are useful in reversing the effects of benzodiazepine overdose and treating pharmaceutical and alcohol dependence.
Diseases and / or disorders that can be treated using the compounds and compositions according to the present invention include the following diseases and disorders:

Depression , such as atypical depression, bipolar disorder, and bipolar disorder.
Anxiety , such as generalized anxiety disorder (GAD), agoraphobia, panic disorder +/- agoraphobia, social phobia, specific phobia, post-traumatic stress disorder, obsessive compulsive disorder (OCD), dysthymia, mood and Adaptation disorder with anxiety disorder, separation anxiety disorder, anticipatory anxiety, acute stress disorder, adaptation disorder, circulatory temperament.
Sleep disorders as secondary symptoms of sleep disorders such as insomnia, circadian rhythm sleep disorders, mood modulation NOS, parasomnia including nightmare disorder, night-surprise disorder, depression and / or anxiety, or another mental disorder , Substance-induced sleep disorders.

Cognitive impairment , such as cognitive impairment, memory impairment, short-term memory impairment, Alzheimer's disease, Parkinson's disease, moderate cognitive impairment (MCI), age-related cognitive decline (ARCD), seizures, traumatic brain injury, AIDS-related dementia, And dementia associated with depression, anxiety or psychosis.
Attention deficit disorders , such as attention deficit disorder (ADD), and attention deficit and hyperactivity disorder (ADHD).
Language disorders such as stuttering, including motor tics, chronic stuttering, dysfluency, speech blockage, dysarthria, Tourete syndrome or aphasia.

The present invention also relates to the treatment of disorders responsive to GABA _A receptor modulation comprising one or more compounds according to the present invention together with a pharmaceutically acceptable carrier or excipient, for example by GABA _A receptor modulation. Pharmaceutical compositions for the treatment of anxiety, depression, sleep disorders or cognitive disorders are provided. The pharmaceutical composition is described above and in instructions (eg, labels) indicating that the GABA _A receptor ligand in the container should be used in the treatment of disorders responsive to GABA _A receptor modulation in the patient. As such, it encompasses packaged compositions comprising a container holding a therapeutically effective amount of at least one GABA _A receptor modulator.

In another aspect, the present invention provides a method for assessing the action of another CNS active compound, comprising administering an effective amount of a compound according to the present invention in combination with another CNS active compound. Such CNS active compounds include, but are not limited to, the following compounds: serotonin receptors (eg, 5-HA _1A ) agonists and antagonists in the case of anxiety; neurokinins in the case of anxiety and depression Receptor antagonists or corticotropin releasing factor receptor (CRF ₁ ) antagonists; in the case of sleep disorders, melatonin receptor agonists; In particular, the present invention provides a method for enhancing the antidepressant activity of a selective serotonin reuptake inhibitor (SSRI), which method comprises administering an effective amount of a GABA agonist compound according to the present invention in combination with an SSRI.

Combined administration is by Da-Rocha et al. (J. Psychopharmacology (1997) 11 (3) 211-218); by Smith et al. (Am. J. Psychiatry (1998) 155 (10) 1339-45; or Le et al. ( Alcohol and Alcoholism (1996) 31 Suppl. 127-132) can be performed in a manner similar to that disclosed, and PCT International Application Nos. _A receptor ligand 3- (5-methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4 -A] Phthalidine, Nico Agonists, studies relating to the use in combination with muscarinic agonists and acetylcholinesterase inhibitors can be referred respectively. Also this regard, a group of GABA _A receptor ligands, 1,2,4-triazolo [4,3-b] Reference can be made to PCT International Application No. WO 99/37303 for studies relating to the use of pyridazine compounds in combination with SSRIs.

The present invention also provides benzodiazepine compounds for GABA _A receptor, relates to a method of inhibiting the binding of e.g. Ro15-1788 or GABA, that this method is a solution containing a compound according to the invention is contacted with a cell expressing GABA _A receptor Where the compound is present in vitro at a concentration sufficient to inhibit benzodiazepine binding or GABA binding to the GABA _A receptor. This method reduces the binding of a benzodiazepine compound to a GABA _A receptor in vivo, for example, in a patient given a sufficient amount of a benzodiazepine binding or GABA binding to a GABA _A receptor in vitro. Include. In one aspect, such methods are useful for the treatment of benzodiazepine drug overdose. GABA amount sufficient to inhibit the binding of benzodiazepine compounds for _A receptor may be readily determined by analysis according to GABA _A receptor binding assay, for example, Example 6. The GABA _A receptor used to measure in vitro binding can be obtained from a variety of sources, such as from rat cortical specimens or cells expressing cloned human GABA _A receptor.

The invention also relates to a method for altering signaling activity, in particular the chloride ion conductivity of GABA _A receptors, which comprises exposing cells expressing such receptors to an effective amount of a compound according to the invention. This method involves altering GABA _A receptor signaling activity in a patient given in vivo, eg, in vitro, a sufficient amount of a compound of formula I to alter GABA _A receptor signaling activity. GABA sufficient amount of the compound to change the signaling activity of _A receptor can be determined by analytical methods described in GABA _A receptor signal transduction assay, such as Example 7. Cells that express GABA _A receptors in vivo can be, but are not limited to, neural cells or brain cells. Such cells can be contacted with a compound according to the invention by contact with a body fluid containing the compound, for example by contact with cerebrospinal fluid. Changes in in vitro GABA _A receptor signaling activity are measured from the electrophysiological detectable changes of cells expressing GABA _A receptor when such cells are contacted with a compound according to the invention in the presence of GABA. be able to.

Intracellular recording or patch-clamp recording can be used to quantify changes in electrophysiology of cells. Reproducible changes in the behavior of animals given the compounds according to the invention can also be used to show electrophysiological changes in cells of animals expressing GABA _A receptors.
The GABA _A receptor ligands provided by the present invention and its labeled derivatives are also useful as standards and reagents in determining the potential of a drug to bind to the GABA _A receptor. Radiolabeled derivative GABA _A receptor ligands provided by the present invention are also for positron emission tomography (PET) imaging or single photon emission tomography (SPECT) Useful as a radioactive tracer.

More particularly, the compounds according to the invention can be used for determining the presence of GABA _A receptors in a cell or tissue sample. This measurement can be performed by preparing a plurality of matched cell or tissue samples, at least one of which is prepared as an experimental sample and at least one of which is prepared as a control sample. The experimental sample is not previously contacted with any of the compounds or salts according to the invention with an experimental solution containing a detectably labeled specimen of the selected compound or salt in the initially determined molar concentration It is prepared by contacting with at least one compatible cell or tissue sample (under conditions that allow binding of RO15-1788 to GABA _A receptor within the cell and tissue sample). The control sample is prepared by the same method as the experimental sample, but also contains a higher concentration of the same unlabeled specimen of the compound or salt according to the invention.

The experimental and control samples are then washed to separate unbound detectably labeled compound. The remaining bound detectably labeled compound is then measured and then compared to the amount of detectably labeled compound in the experimental and control samples. _A comparison showing a measurement of the amount of detectable label in the at least one washed experimental sample that is greater than the amount measured in any control sample demonstrates the presence of GABA _A receptor in the experimental sample.
The detectably labeled compound used in this method can be labeled with a radioactive label or a direct or indirect fluorescent label. When tissue fragments are used in this manner and the detectably labeled compound has a radioactive label, the bound labeled compound can be detected by autoradiography, which produces an autoradiogram. The amount of detectable label in the experimental or control sample can be determined by observing the autoradiogram and then comparing the exposure density of the autoradiogram.

Chemical Description and Terminology The compounds described herein can have one or more asymmetric centers or faces. Compounds according to the invention which contain atoms substituted in an asymmetric state can be isolated in optically active or racemic form. How to make optically active forms is well known in the art and can be made, for example, by resolution of racemic forms (racemates), by asymmetric synthesis, or by synthesis from optically active starting materials. . Racemic resolution can be achieved by conventional methods such as, for example, crystallization in the presence of a resolving agent or, for example, chromatography using a chiral HPLC column. Considerable geometric isomers such as olefins, C═N double bonds, etc. can also be present in the compounds described herein, and all such stable isomers are encompassed by the present invention. . Cis and trans geometric isomers of the compounds according to the invention are disclosed, which can be isolated as a mixture of isomers or in separated isomeric forms. All chiral (enantiomers and diastereomers) and racemic forms, as well as all geometric isomeric forms, are included unless a specific stereochemical or isomeric form is specifically indicated.

When any change occurs in one or more of any configuration or formula of a compound, its definition when present at each occurrence is independent of its definition when present at each other. Thus, as an example, is shown as being replaced by the group 0-3 R ^* (R ^* is either modifiable group, e.g. Ar, etc. _{R 1, R 2, R 3} ) This group may be substituted by up to 3 R ^* groups, each R ^* where present, is independently selected from the definition of R ^* . Also, combinations of substituents and / or alterable groups are permissible only if such combinations result in stable compounds.

A dash “-” that is not between two letters or symbols is used to indicate a point of attachment for a substituent. As an example, “—NH—R ₆₀ —Y” is bonded via a nitrogen atom.
As used herein, “alkyl” is intended to include both branched and straight chain aliphatic hydrocarbons having the specified number of carbon atoms. Alkyl groups having 2 or 3 or more carbon atoms can contain double or triple bonds. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl and s-pentyl. Preferred alkyl groups are C ₁ -C ₆ alkyl group. “C ₁ -C ₆ alkyl” refers to an alkyl group having from 1 to about 6 carbon atoms. Further preferred alkyl groups are methyl, ethyl and propyl.

As used herein, “alkoxy” represents an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, Includes neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. “C ₁ -C ₆ alkoxy” represents an alkoxy group having from 1 to about 6 carbon atoms. Preferred alkoxy groups are methoxy, ethoxy, propoxy, and butoxy groups.

“Alkenyl” is a hydrocarbon chain having a linear or branched arrangement containing one or more unsaturated carbon-carbon bonds that may be present at any stable point along the chain. For example, ethenyl and propenyl. Alkenyl groups typically have 2 to about 12 carbon atoms, more typically 2 to about 8 carbon atoms, preferably 2 to 6 carbon atoms.
“Alkynyl” is a hydrocarbon chain having a linear or branched arrangement containing one or more triple carbon-carbon bonds that may be present at any stable point along the chain; For example, it has the meaning including ethynyl and propynyl. Alkynyl groups typically have 2 to about 12 carbon atoms, more typically 2 to about 8 carbon atoms, preferably 2 to 6 carbon atoms.

“Aryl” refers to an aromatic group having one or more rings, wherein the members of the aromatic ring are carbon. Where indicated, such groups may be substituted. Such groups include optionally substituted phenyl and optionally substituted naphthyl.
The term “cycloalkyl” is meant to include saturated ring groups having the specified number of carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Cycloalkyl groups typically have from 3 to about 8 ring members.

In the terms “(cycloalkyl) alkyl” and “alkyl” as defined above, the point of attachment is via a carbon atom in the alkyl group. This term includes, but is not limited to, cyclopropylmethyl, cyclohexylmethyl, cyclohexylmethyl. In the term “cycloalkyl”, the point of attachment is via a ring carbon atom.
As used herein, “haloalkyl” is substituted by one or more halogen atoms (eg, —CvFw, where v = 1-3, and w = 1). It is meant to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (which is (2v + 1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

As used herein, “haloalkoxy” represents a haloalkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy and trichloromethoxy.
As used herein, the term “heteroaryl” refers to a bicyclic heterocycle containing a carbon atom and a heteroatom independently selected from the group consisting of 1 to 4 N, O and S. It has a meaning representing a cyclic aromatic ring. The total number of S and O atoms in this aromatic heterocycle is preferably not more than 1.

  Examples of heteroaryl groups include, but are not limited to, the following groups: pyrimidinyl, pyridyl, quinolinyl, benzothienyl, indolyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl , Oxazolyl, thienyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzoisoxolyl, dihydro-benzodioxinyl, furanyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyr Dinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochroma , Chromanonyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl , Phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl,

Dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromanyl, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroiso Quinolinyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N- Oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imida Ryl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide , Thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide and benzothiopyranyl S, S-dioxide.

Suitable heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and imidazolyl. Also included are spiro compounds and fused rings containing, for example, the above heterocycles.
The term “oxo” refers to an oxygen atom forming a carbonyl group. When an oxo group appears as a substituent, the possible valence of the substituted position is not exceeded. When an aryl or heteroaryl group is substituted with oxo, the aryl or heteroaryl group is converted to a partially saturated system. As an example, a pyridyl group substituted by oxo is pyridone.

  “Pharmaceutically acceptable” refers to a balanced responsive benefit / risk ratio within the scope of theoretical medical judgment, without toxicity, irritation, allergic reactions or other problems or complications. Thus, it is used to denote compounds, materials, compositions and / or dosage forms suitable for contact with human or animal tissue. As used herein, a “pharmaceutically acceptable salt” is a derivative of a disclosed compound wherein the parent compound is modified by its acid or base salt. Represents. Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues such as amine mineral acids or organic acid salts; acidic residues such as alkali or organic salts of carboxylic acids and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.

By way of example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid; and organic acids such as acetic acid, propionic acid, Succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, malefic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2- acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, _{isethionic, HOOC- (CH 2) n -COOH} ( wherein, n represents a is 0 to 4) are derived from such Salt. The pharmaceutically acceptable salts according to the present invention can be synthesized from the parent compound which contains a basic or acidic molecule by conventional chemical methods.

In general, such salts can be prepared by reacting the free acid or base form of the compound with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or mixtures thereof. . In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, page 1418 (1985).
The terms “trihaloalkyl” and “trihaloalkoxy” refer to haloalkyl and haloalkoxy groups containing a particular type of three halogen atoms, such as trichloromethyl, trifluoromethyl and trifluoromethoxy.

Pharmaceutical Compositions The compounds of general formula I can be administered orally, topically, parenterally, inhaled or sprayed as dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, auxiliaries and vehicles. Or can be administered rectally. Oral administration in the form of pills, capsules, elixirs, syrups, lozenges, troches and the like is preferred. As used herein, parenteral terms include subcutaneous injection, intradermal, intravascular (eg, intravenous), intramuscular, spinal cord, intrathecal injection or similar injection, or perfusion techniques. To do. Further provided is a pharmaceutical composition comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of the general formula I may contain one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or auxiliaries and optionally another type of activity. It can be present in combination with a compound. Pharmaceutical compositions containing a compound of general formula I are in a form suitable for oral use, such as tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs It can be in the form of

  Compositions intended for oral use can be prepared according to any of the methods known in the art for the manufacture of pharmaceutical compositions, such compositions comprising one or more sweeteners, flavoring agents. Auxiliaries selected from the group consisting of agents, colorants and preservatives can be included, thereby providing an elegant and palatable formulation as a medicament. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients include, for example, inert diluents (eg, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate); granulating agents and disintegrants (eg, corn starch or alginic acid); binders (eg, starch , Gelatin or acacia); and lubricants (eg, magnesium stearate, stearic acid or talc). The tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. As an example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used.

  Formulations for oral use are also as hard gelatin capsules (where the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin) or as soft gelatin capsules (where the active ingredient is water or An oily medium, such as peanut oil, liquid paraffin or olive oil).

  Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents (eg, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and acacia); dispersing or wetting agents such as naturally occurring phosphatides (eg, lecithin) Or a condensation product of an alkylene oxide and a fatty acid (eg, polyoxyethylene stearate), or a condensation product of an ethylene oxide and a long chain aliphatic alcohol (eg, heptadecaethyleneoxycetanol), or an ethylene oxide and a fatty acid And condensation products with partial esters derived from hexitol (eg, polyoxyethylene sorbitol monooleate) or ethylene oxide with fatty acids and Condensation products of ethylene oxide with partial esters derived from a hexitol (e.g., polyoxyethylene sorbitan monooleate) is. Aqueous suspensions also contain one or more preservatives (eg, ethyl or n-propyl p-hydroxybenzoate), one or more flavoring agents, and one or more sweetnesses. An agent (eg, sucrose or saccharin) can be included.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (eg, arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (eg, liquid paraffin). Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those mentioned above and flavor-imparting agents can be added to obtain a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water contain the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents can also be present.

  The pharmaceutical composition according to the invention can also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil (eg, olive oil or arachis oil), or a mineral oil (eg, liquid paraffin), or a mixture of these. Suitable emulsifiers include naturally occurring gums (eg, acacia or tragacanth gum), naturally occurring phosphatides (eg, esters or partial esters derived from soy, lecithin and fatty acids and anhydrous hexitol) and the partial esters and ethylene oxide. It can be a condensation product (eg, polyoxyethylene sorbitan monooleate). The emulsion can also contain sweetening and flavoring agents.

  Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents such as those mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are preferably used as the solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. Furthermore, the use of fatty acids such as oleic acid is found in injectable formulations.

The compounds of general formula I can also be administered in the form of suppositories, eg for rectal administration of the medicament. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ambient temperature but liquid at the rectal temperature, thereby melting in the rectum and releasing the drug. it can. Such materials include cocoa butter and polyethylene glycol.
The compounds of general formula I can be administered parenterally in a sterile medium. Depending on the medium and concentration used, the medicament can be suspended or dissolved in the medium. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the medium.

When administered to non-human animals, the composition can also be added to animal feed or drinking water. It is preferred that the compositions are prepared as these animal feeds and drinking water so that the animal takes the appropriate amount of the composition with its diet. It is also desirable to provide the composition as a premix for addition to feed or drinking water.
Dosage levels on the order of about 0.1 mg to about 140 mg / kg body weight are useful for the treatment of the symptoms (about 0.5 mg to about 7 g / patient / day). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.

The frequency of administration will also vary depending on the compound used and the particular disease being treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. When treating anxiety, depression or cognitive impairment, a dosage regimen of once or twice daily is particularly preferred. For treatment of sleep disorders, a single dose that readily reaches effective concentrations is desirable.
However, the particular dosage level involved in any particular patient will depend on the activity, age, weight, general health, sex, diet, frequency of administration, route of administration and excretion rate of the particular compound used, drug combination, As well as a variety of factors, including the particular disease to be treated.

Preferred compounds of the present invention have certain pharmacological properties. Such properties include, but are not limited to, high solubility in aqueous solutions (preferably 500 ng / ml or higher), oral bioavailability, low toxicity, low serum protein binding, clinical relative EKG Effects and desirable in vitro and in vivo half-lives are included. While compounds used in the treatment of CNS disorders require permeability to the blood-brain barrier, compounds used in the treatment of peripheral disorders are often preferred at low brain levels.
Analysis can be used to predict these desirable pharmacological properties. Analytical methods used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. To predict compound toxicity, toxicity to cultured hepatocytes can be used. The permeability of a compound to the blood-brain barrier in humans can be predicted from the brain level of the compound in laboratory animals administered the compound intravenously.

Serum protein binding can be predicted from an albumin binding assay. Such an analysis method is described in a paper by Oravcova et al. (Journal of Chromatography B (1996), volume 677, page 1-27).
Compound half-life is inversely proportional to the frequency of compound administration. The in vitro half-life of the compounds can be predicted from the microsomal half-life analysis disclosed by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998), 26, 1120-1127).

Example
Preparation of Compounds Representative synthetic routes for preparing compounds according to the present invention are outlined in the following reaction scheme. The reaction shown below shows a specific method for the synthesis of the compounds according to the invention. However, those skilled in the art will recognize that the reactants and reaction conditions can be varied to obtain additional specific end products. Furthermore, it is readily apparent that additional compounds that fall within the scope of Formula I but are not described in detail in this experimental part can be prepared in a similar manner. Protecting groups, and protection and deprotection methods, such as Protecting Groups in Organic Synthesis by T.M. The method described in Greene is well known and obvious in the art. Compounds and intermediates that require protection / deprotection are considered readily apparent to those skilled in the art.

Scheme I

  Scheme I illustrates the synthesis of 5-methyl-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid amide compounds of formula I. In step 1, a substituted pyridine compound such as 2-chloro-3-nitro-5-methylpyridine is reacted with the sodium salt of diethyl malonate to produce a condensation product, and in step 2, the product is lithium chloride. Deprotect by heating with to produce product III. Product III is readily converted to N, N-dimethylenamine IV by heating with dimethylformamide dimethyl acetal. Hydrogenation of product III provides cyclized product V. Depending on the choice of catalyst and conditions, hydrogenation also produces 1-hydroxy-6-methyl-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid ethyl ester. In this case, a subsequent additional hydrogenation in the presence of palladium (II) hydroxide was used and the 1-hydroxy-6-methyl-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid ethyl ester was converted to V Can be converted to Amination of V can be readily achieved by reaction with the corresponding amine derivative in the presence of trimethylaluminum, which gives the compound of formula VI.

Scheme II

  In Scheme II, the corresponding pyridine, such as 2-chloro-3-nitro-6-chloropyridine I, is reacted with sodium diethyl malonate to give a mixture of condensation products II with a small amount of product III. In Step 2, IV is obtained by decarboxylation of a mixture of II and III by heating with lithium chloride, followed by purification on silica gel. In step 3, product IV is reacted with sodium alkoxide to give the corresponding alkoxypyridine V. In step 4, alkoxypyridine V is heated with tert-butoxybis (dimethylamino) methane to give N, N-dimethylenamine VI. In Step 5, enamine VI is hydrogenated in the presence of Raney Nickel to clearly give 5-alkoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid ethyl ester VII. The amination in step 6 is advantageously accomplished by reaction with the corresponding amine derivative in the presence of trimethylammonium, thereby producing the compound of formula VIII.

The following examples are illustrative of the invention and are not limiting. In these examples, commercially available reactants are used without further purification. Purification by chromatography is performed on a pre-packed silica column from Biotag (Dyax Corp. Biotage Division, Charlottesville, Va.). Melting points (mp) are uncorrected using a Mettler Toledo FP62 melting point apparatus (Mettler-Toledo, Inc., Worthington, OH) at a temperature gradient rate of 10 ° C./min. Proton nuclear magnetic resonance ( ¹ H NMR) spectra are recorded in a tritiated solvent on a Varian INOVA 400 (400 MHz) spectrometer (Varian NMR System, Palo Alto, Calif.). Chemical shifts are recorded in parts per million (ppm, δ) relative to Me 4 Si (δ 0.00).

The proton NMR splitting pattern consists of singlet (s), doublet (d), triplet (t), quartered (q), quinted (quin), sexted (sex), septet (sep), multiplet (m), apparently ( certify as ap) and broad (br). Coupling constants are reported in hertz (Hz). Carbon-13 nuclear magnetic resonance response ( ¹³ C NMR) spectra are recorded on a Varian INOVA 400 (100 MHz). The chemical shifts are ppm (ppm of the center line of the 1: 1: 1 triplet of deuterochloroform (δ77.00), the centerline of dutron methanol (δ49.0) or the centerline of dutron dimethyl sulfoxide (δ39.7). δ). The number of reported carbon resonances may not match the actual number of carbons in some molecules due to magnetically and chemically equivalent carbon, and may exceed the actual number of carbons due to conformers Sometimes.

Mass spectra (MS) are obtained using a Waters ZMD mass spectrometer and using flow injection atmospheric pressure chemical ionization (APCI) (Waters Corporation, Milford, Mass). Gas chromatography with mass detection (GCMS) uses a Hewlett-Packard HP6890 series GC system equipped with a HP5973 mass selective detector and an HP-1 (crosslinked methylsiloxane) column (Agilent Technologies, Wilmington, DE). obtain. HPLC spectra are recorded on a Hewlett-Packard 1100 series HPLC system equipped with a Zorbax SB-C8, 5 μm, 4.6 × 150 mm column (Agilent Technologies, Wilmington, DE) using gradient elution at 25 ° C.

Solvent A is water, solvent B is acetonitrile, and solvent C is 1% trifluoroacetic acid in water. A linear gradient over 4 minutes starts with 80% A, 10% B, 10% C and ends with 0% A, 90% B, 10% C. The eluate remained at 0% A, 90% B, 10% C for 3 minutes. A linear gradient over 1 minute is used to bring the eluate back to 80% A, 10% B, 10% C and is held until an operating time equal to 10 minutes. Room temperature (RT) means 20-25 ° C. The abbreviations “h” and “hrs” stand for “time”.

２−クロロ−５−メチル−３−ニトロ−ピリジンは、Ｊ．Ｍｏｌ．Ｓｔｒｕｃｔ．（１９９１）２４８：１８９−２００に記載の方法に従い製造するか、またはＳＰＥＣＳおよびＢｉｏＳＰＥＣＳ Ｂ．Ｖ．，Ｆｌｅｍｉｎｇｌａａｎ Ｔｈｅ Ｎｅｔｈｅｒｌａｎｄｓから購入することができる。 Example 1
Preparation of 6-methyl-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid ethyl ester
A. Preparation of 2-chloro-5-methyl-3-nitro-pyridine

2-Chloro-5-methyl-3-nitro-pyridine is described in J. Am. Mol. Struct. (1991) 248: 189-200 or SPECS and BioSPECS B. V. , Fleminglanan The Netherlands.

B. Preparation of 2- (5-methyl-3-nitro-pyridin-2-yl) -malonic acid diethyl ester

A solution of diethyl malonate (72 g, 0.436 mol) in DME (200 ml) was stirred into a magnetically stirred suspension of NaH (23 g, 0.58 mol) in dry 1,2-dimethoxyethane (DME, 350 ml). Add dropwise to the liquid. The mixture is stirred at room temperature for 1 hour, then a solution of 2-chloro-5-methyl-3-nitro-pyridine (50 g, 0.290 mol) in DME (100 ml) is added to give a dark red solution. After 18 hours of stirring, the reaction mixture is poured into ice-cold water and then acidified to pH 3 with 6N HCl solution. This mixture is extracted with ethyl acetate. The organic phase is washed with water, brine, dried over Na ₂ SO ₄ and then concentrated. The excess diethyl malonate was separated under high vacuum at 50 ℃, 2- (5- methyl-3-nitro - pyridin-2-yl) - get the malonic acid diethyl ester i as a dark red concentrate residue; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.28 (t, J = 9 Hz, 6H), 4.26 (q, J = 9 Hz, 4H), 8.27 (s, 1H), 8.63 (s, 1H) .

C. Preparation of (5-methyl-3-nitro-pyridin-2-yl) -acetic acid ethyl ester

To a solution of 2- (5-methyl-3-nitro-pyridin-2-yl) -malonic acid diethyl ester (50 g, 0.168 mol) in DMSO (100 ml) containing water (12 g, 0.678 mol). Suspend LiCl (10.6 g, 0.252 mol) and then stir at 150 ° C. for 3 h. The reaction mixture is allowed to cool, diluted with water (200 ml) and then extracted with ethyl acetate. The organic phase is collected and then washed sequentially with saturated aqueous NaHCO ₃ , water, brine, dried over Na ₂ SO ₄ and then concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with 20% EtOAc-hexanes to give (5-methyl-3-nitro-pyridin-2-yl) -acetic acid ethyl ester as an oil: ¹ H NMR ( 300 MHz, CDCl ₃ ) δ 1.23 (t, J = 9 Hz, 3H), 4.15 (q, J = 9 Hz, 2H), 4.25 (s, 2H), 8.2 (s, 1H), 8 .58 (s, 1H).

D. Preparation of 3-dimethylamino-2- (5-methyl-3-nitro-pyridin-2-yl) -acrylic acid ethyl ester

  A solution of dimethylformamide dimethyl acetal (4 g, 0.033 mol) in dry DMF (10 ml) was added to (5-methyl-3-nitro-pyridin-2-yl) -acetic acid ethyl ester (5 g) in dry DMF (20 ml). , 0.022 mol) to obtain a red solution. The solution was heated under reduced pressure at 60 ° C. for 3 hours and DMF and other volatile components were evaporated under reduced pressure to give 3-dimethylamino-2- (5-methyl-3-nitro-pyridin-2-yl. ) -Acrylic acid ethyl ester is obtained as a viscous oil. This product was used without further purification.

E. Preparation of 1-hydroxy-6-methyl-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid ethyl ester

A solution of 3-dimethylamino-2- (5-methyl-3-nitro-pyridin-2-yl) -acrylic acid ethyl ester (6.2 g, 0.022 mol) in ethanol (50 ml) was added to 10% Pd- Hydrogenate over 50 hours at 50 psi over C. The catalyst is separated by filtration through a celite pad and the solvent is then evaporated under reduced pressure. The residue was chromatographed on a silica gel column eluted with 7% MeOH-DCM containing a few drops of NH ₄ OH to give 1-hydroxy-6-methyl-1H-pyrrolo [3,2- b] Obtaining pyridine-3-carboxylic acid ethyl ester; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.25 (t, J = 6.6 Hz, 3H), 4.21 (q, J = 6.6 Hz) , 2H), 7.59 (s, 1H), 8.15 (s, 1H), 8.29 (s, 1H); LRMS: calculated value 220.2;

F. Preparation of 6-methyl-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid ethyl ester

To a solution of 1-hydroxy-6-methyl-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid ethyl ester (1.2 g, 0.005 mol) in ethanol (20 ml), Pd (OH) ₂ (200 mg) is added followed by hydrogenation at 50 psi over 24 hours. The catalyst is separated by filtration through a celite pad and the solvent is then evaporated under reduced pressure. The residue was chromatographed on silica gel eluting with 5% MeOH-DCM containing a few drops of NH ₄ OH to give 6-methyl-1H-pyrrolo [3,2-b] pyridine-3- Carboxylic acid ethyl ester (550 mg, 50%) is obtained; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.28 (t, J = ₆ Hz, 3H), 2.38 (s, 3H), 4.24 ( q, J = 6.6 Hz, 2H), 7.62 (s, 1H), 8.17 (s, 1H), 8.31 (s, 1H); LRMS: calculated value 204.23; 15.

Example 2
Preparation of 5- (1-methyl-piperidin-4-yloxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide
A. Preparation of 2- (6-chloro-3-nitro-pyridin-2-yl) -malonic acid diethyl ester

  5- (1-Methyl-piperidin-4-yloxy) -1H-pyrrolo [3,2-b] pyridin-3-carboxylic acid pyridin-2-ylamide can be obtained from Robinson, R .; P. (J. Heterocyclic Chem. 1996, V33, p. 287) as a 2: 1 mixture of regioisomers II / III (Scheme I). Alternatively, the title compound can be prepared as a 4.6: 1 mixture of regioisomer II / III using the following reaction conditions: diethyl malonate (7.95 ml, 52.52 ml) in THF (20 ml). 3 mmol) is added dropwise to a mixture of NaH (4.35 g, 108.8 mmol) in THF (150 ml) over 35 min at room temperature. The resulting mixture is stirred at room temperature for 40 minutes and then allowed to cool until the internal temperature is −20 ° C. A solution of 2,6-dichloro-3-nitropyridine (10,0 g, 51.8 mmol) in THF (25 ml) is then added over 10 minutes while maintaining the internal temperature at -20.degree.

The reaction mixture is allowed to warm to room temperature over 3 hours and then stirred for an additional 30 minutes. A saturated solution of NH ₄ Cl (20 ml) is added over 10 minutes, followed by H ₂ O (20 ml) and brine (20 ml). The mixture is diluted with EtoAc (100 ml), the phases are separated and the aqueous phase is extracted with EtOAc (2 × 50 ml). The organic phase is collected and washed with 50% brine solution (100 ml) and then with brine (100 ml). The organic layer is dried over Na ₂ SO ₄ , the solid separated by filtration and then concentrated (vacuum) to give the title compound as a 4.6: 1 mixture of regioisomer II / III as a dark red oil ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42 (d, 1H, J = 8.7 Hz, major), 8.24 (d, J = 8.3 Hz, small amount), 7.69 (d , J = 8.3 Hz, small amount), 7.50 (d, 1H, J = 8.7 Hz, main amount), 5.44 (s, 1H, main amount), 4.96 (s, 0.22H, A small amount), 4.32-4.27 (m.4H), 1.30-1.23 (m, 6H): MS (CI) m / z 317.2 / 319.4 (M + 1).

B. Preparation of (6-chloro-3-nitro-pyridin-2-yl) -acetic acid ethyl ester

2- (6-Chloro-3-nitro-pyridin-2-yl) -malonic acid diethyl ester (32.45 g, 103 mmol), LiCl (16.18 g, 268 mmol), H ₂ O (10 ml), and dimethyl sulfoxide ( 50 ml) is stirred at 120 ° C. for 24 hours. The mixture is allowed to cool to room temperature and then diluted with H ₂ O (400 ml). 1N NCl (aq) is added until all of the solids are dissolved. The mixture is extracted with EtOAc (5 × 150 ml) and the organic extracts are collected, washed with H ₂ O (2 × 100 ml), then with brine (100 ml) and then dried over Na ₂ SO ₄ . The mixture is filtered, the solid separated, concentrated and then purified by flash chromatography on silica (eluting with 5% EtOAc in hexanes) to give the title compound as a yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (d, 1H, J = 8.7 Hz), 7.47 (d, 1H, J = 8.7 Hz), 4.28 (s, 2H), 4.19 (q , 2H, J = 7.1 Hz), 1.27 (t, 3H, J = 7.1 Hz); ¹³ C (100 MHz, CDCl ₃ ) δ 168.7, 166.8, 154.8, 151.4, 135 .9, 124.4, 61.7, 41.9, 14.3; MS (CI) m / z 255.2 (M + 1).

C. Preparation of [6- (1-methyl-piperidin-4-yloxy) -3-nitro-pyridin-2-yl] -acetic acid ethyl ester

To a solution of 4-hydroxy-1-methylpiperidine (4.72 g, 41 mmol) in THF (82 ml) is added sodium hydride (60%, 1.64 g, 41 mmol) at room temperature. The mixture is stirred for 30 minutes. A solution of (6-chloro-3-nitro-pyridin-2-yl) -acetic acid ethyl ester (5.0 g, 20.5 mmol) in TFH (10 ml) is then added. The resulting purple mixture is stirred at room temperature for 70 minutes. Additional NaH (410 mg, 10.3 mmol) is added. The resulting mixture is stirred at room temperature for 70 minutes, then a saturated solution of NaHCO ₃ (30 ml) is added slowly. The mixture is diluted with EtOAc (100 ml) and 1N NaOH (aq, 10 ml). The layers are separated and the aqueous layer is extracted with EtOAc (3 × 50 ml).

The organic extract is collected and washed with H ₂ O (50 ml) and brine (50 ml), then dried over Na ₂ SO ₄ . The mixture is filtered, the solid separated, concentrated and then purified by flash chromatography on silica (gradient elution: 5% EtOAc in hexanes to 2% MeOH / CHCl ₃ containing 0.1% NH ₄ OH. , 0.1% NH ₄ OH containing up to 4% MeOH / ChCl ₃ ), affording the title compound as a dark brown oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (d, 1H, J = 9. 1 Hz), 6.73 (d, 1H, J = 9.1 Hz), 4.18 (q, 2H, J = 7.1 Hz), 4.17 (s, 2H), 2.70-2.65 ( m, 2H), 2.35-2.27 (m.2H), 2.30 (s, 3H), 2.07-2.00 (m, 2H), 1.89-1.80 (m, 2H), 1.25 (t, 3H, J = 7.1 Hz); ¹³ C NMR (100 MHz , CDCl ₃ ) δ 169.5, 164.6, 150.6, 139.5, 136.9, 111.3, 72.5, 61.4, 53.0, 46.3, 44.0, 30. 9, 14.4; MS (CI) m / z 324.2 (M + 1).

D. Preparation of 3-dimethylamino-2- [6- (1-methyl-piperidin-4-yloxy) -3-nitro-pyridin-2-yl] -acrylic acid ethyl ester

[6- (1-Methyl-piperidin-4-yloxy) -3-nitro-pyridin-2-yl] -acetic acid ethyl ester (5.93 g, 18.3 mmol) and tert-butoxybis (dimethylamino) methane (5. 7 ml, 27.5 mmol) is heated to 65 ° C. for 6 hours. The mixture was allowed to cool to room temperature and then purified by flash chromatography on silica (gradient elution: 0.1% NH ₄ OH containing 4% MeOH / 0.1% from CHCl ₃ NH ₄ OH containing 4% MeOH / To CHCl ₃ ) to give the title compound as a dark orange oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, 1H, J = 9.1 Hz), 7.5 (s, 1H), 6.49 (d, 1H, J = 9.1 Hz), 5.00-4.96 (m, 1H), 3.97-3.82 (m.2H), 2.69 (brs, 6H) 2.60-2.50 (m, 2H), 2.20-2.10 (m, 2H), 2.16 (s, 3H), 1.92-1.85 (m, 2H), 1 .74-1.65 (m, 2H), 0.98 (t, 3H, J = 7.1 Hz); ¹³ C NM R (100 MHz, CDCl ₃ ) δ 167.7, 163.3, 151.7, 150.8, 141.8, 135.5, 109.3, 96.8, 71.7, 59.8, 52.9 46.3, 43.6, 31.4, 30.9, 14.4; MS (CI) m / z 379.3 (M + 1).

E. Preparation of 5- (1-methyl-piperidin-4-yloxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid ethyl ester

3-Dimethylamino-2- [6- (1-methyl-piperidin-4-yloxy) -3-nitro-pyridin-2-yl] -acrylic acid ethyl ester (3.69 g, 9.76 mmol), EtOH (100 ml The mixture of RANEY 2400 nickel (3,7 g, wet) in) is shaken under a hydrogen atmosphere (50 psi) for 7 hours at room temperature. During this period, the pressure is reduced to 20 psi. The reaction vessel is refilled with hydrogen (50 psi) and then shaken at room temperature for 17 hours. The reaction mixture is filtered through celite and washed with EtOH (300 ml) taking care that the filtrate can never be dried. The filtrate was concentrated and then purified by chromatography on silica (gradient elution: from 0.1% NH ₄ OH containing 10% MeOH / CHCl ₃ to 0.1% NH ₄ OH containing 14% MeOH / CHCl ₃ ) To give the title compound as a yellow solid;

Melting point = 231.9 ° C. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1 H), 7.64 (d, 1 H, J = 8.7 Hz), 6.51 (d, 1 H, J = 8.7 Hz), 5. 36-5.28 (m, 1H), 4.26 (q, 2H, J = 7.1 Hz), 3.15-3.06 (m.2H), 3.00-2.90 (m.2H) ), 2.61 (s, 3H), 2.30-2.20 (m, 2H), 2.18-2.08 (m, 2H), 1.30 (t, 3H, J = 7.1 Hz) ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.0, 159.3, 140.5, 133.7, 125.8, 123.7, 107.3, 106.6, 66.1, 60.0 51.6, 44.2, 28.5, 14.6; MS (CI) m / z 304.3 (M + 1).

F. Preparation of 5- (1-methyl-piperidin-4-yloxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide

To a solution of 2-aminopyridine (56 mg, 0.59 mmol, 2M in PhCH ₃ ) in toluene (1.0 ml) and 1,2-dichloroethane (1.0 ml) at room temperature was added AlMe ₃ (0.3 ml, 0 ml). .59 mmol) is added. The resulting solution is stirred for 30 minutes at room temperature. 5- (1-Methyl-piperidin-4-yloxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid ethyl ester (60 mg, 0.20 mmol) is then added. The resulting mixture is heated at 100 ° C. for 3 hours. The mixture is allowed to cool to room temperature and then Na ₂ SO ₄ .10H ₂ O (285 mg, 0.89 mmol) is added. The mixture is stirred for 30 minutes and then MeOH (5 ml) is added. The resulting mixture is filtered through a celite pad and then washed with MeOH ( ₃ × 5 ml) and CHCl ₃ ( ₃ × 5 ml).

The filtrate was concentrated and then purified by chromatography on silica (gradient elution: 0.1% NH ₄ OH containing 5% MeOH / CHCl ₃ from 0.1% NH ₄ OH containing 8% MeOH / CHCl _3, then 10% MeOH / CHCl _{3 with} 0.1% NH ₄ OH) to give the title compound as a pale yellow solid; (Compound No. 1) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.29-8.27 ( m, 2H), 8.01 (s, 1H), 7.73-7.69 (m, 2H), 7.03 (dd, 1H, J = 7.1, 5.4 Hz), 6.63 ( d, 1H, J = 8.7 Hz), 5.40-5.34 (m, 1H), 2.86-2.80 (m.2H), 2.57-2.52 (m.2H), 2.35 (s, 3H), 2.30-2.26 (m, 2H), 1.91-1.86 ^{m, 2H); 13 C NMR} (100MHz, CD 3 OD) δ163.9,159.5,152.4,148.1,139.1,138.2,131.6,125.1,124.1 119.5, 114.2, 109.3, 107.2, 70.8, 53.6, 45.7, 30.8; MS (CI) m / z 352.3 (M + 1).

Example 3
The compounds shown in Table I, Table II, and Table III are synthesized following essentially the methods described in the above schemes and examples.

In the following Table, X1 and X4 are each, represent the point of attachment of R ₁ and Ar on skeletal ring system.

Example 4
Production of radiolabeled probe compounds according to the invention The compounds according to the invention are produced as radiolabeled probes by synthesis using a precursor carrying at least one atom which is a radioisotope. The radioisotope is preferably selected from at least one carbon (preferably ¹⁴ C), hydrogen (preferably ³ H), sulfur (preferably ³⁵ S) or iodine (preferably ¹²⁵ I). Such radiolabeled probes are easily synthesized by radioisotope suppliers who are experts in routine synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, IL; Cambridge Isotop Laboratories, Inc. Andover, MA; SIR International, Menlo Park, CA; Wizard Laboratories, West Sacramento, CA; ChemSyn Laboratories, Lexena, KS; American Radiolabeled Chemicals. St. Louis, MO; and Moravek Biochemicals Inc. Brea, CA is included.

  Tritium-labeled probe compounds are also preferably prepared catalytically by platinum catalyzed exchange in tritiated acetic acid, acid catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous catalyzed exchange using tritium gas. Such a preparation is also preferably carried out as a routine radiolabeling by one of the suppliers listed in the previous section, using the compound according to the invention as a substrate. In addition, certain precursors can correspondingly be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide.

Example 5
Receptor Autoradiography Receptor Autoradiography (Receptor Mapping) uses a radiolabeled compound according to the present invention prepared as described in the previous examples, and uses Current Protocols in Pharmacology (1998) John Wiley & Sons, Performed in vitro as described by Kuhar in Sections 8.1.1-8.1.9 of New York.

Example 6
Binding Analysis The high affinity and high selectivity of the compounds according to the invention for the benzodazepine site of the GABA _A receptor is confirmed using the binding assay disclosed by Thomas and Tallman (J. Bio. Chem. 1981; 156). : 9838-9842 and J. Neurosci. 1983; 3: 433-440).

  Rat cortical tissue is minced and homogenized in 25 volumes (w / v) of buffer A [0.05 M Tris HCl buffer, pH 7.4 at 4 ° C.]. The tissue homogenate is centrifuged at 20,000 × g for 30 minutes when cold (4 ° C.). The supernatant is separated by decantation and the pellet is rehomogenized in the same volume of buffer and then centrifuged again at 20,000 × g. The supernatant of this centrifugation step is separated by decantation and the resulting pellet is stored at -20 ° C overnight. The pellet is then frozen and then resuspended in 25 volumes of buffer A (original, weight / volume), centrifuged at 20,000 × g, and the supernatant is then separated by decantation. This washing process is repeated once more. The pellet is finally resuspended in 50 volumes of buffer A.

Incubation contains 100 μl of tissue homogenate, 100 μl of radioligand (0.5 nM ³ H-Ro15-1788 [ ³ H-Flumazenil), specific activity 80 Ci / mmol), and test compound or control (see below). To a total volume of 500 μl with buffer A. Incubation is carried out at 4 ° C. for 30 minutes and then rapidly filtered through Whatman GFB filters to separate free and bound ligand. The filter is washed twice with fresh buffer A and counted with a liquid scintillation counter. Non-specific binding (control) is measured by displacement of 3H-Ro15-1788 by 10 μM Diazepam (Research Biochemicals International, Natick, NA). Data are collected by triplicate and averaged, then the percent inhibition of total specific binding (total specific binding = total-nonspecific) is calculated for each compound.

Competitive binding curves can be expanded up to 11 points in the compound concentration range from 10 ⁻¹² M to 10 ⁻⁵ M obtained from the curve by the method described above for measuring percent inhibition. Calculate the Ki value according to the Cheng-Prussof equation. Each of the compounds described in Example 3 was tested in this manner and each was found to have <4 μM. Preferred compounds according to the invention have a Ki value of less than 100 nm, and more preferred compounds have a Ki value of less than 10 nm.

Example 7
Electrophysiology When the compound according to the invention acts as an agonist, antagonist or inverse agonist at the benzodazepine site of the GABA _A receptor, the following analytical method is used for the measurement.
The analysis follows the methods disclosed by White and Gurley (Neuro Report 6: 1313-1316) and by White, Gurley, Hartnett, Stilling and Gregory (Receptors and Channels 3: 1-5, 1995), but modified. Do. Electrophysiological recording is performed using two electrode voltage-clamp techniques at a membrane holding potential of -70 mV. Xenopus laevis oocytes are isolated enzymatically and injected with non-polyadenylated cRNA mixed at a ratio of 4: 1: 4 for each of the α, β and γ subunits. Among the nine combinations of α, β and γ subunits described in the publication by White et al., Preferred combinations are α ₁ β ₂ γ ₂ , α ₂ β ₃ γ ₂ , α ₃ β ₃ γ _2. And α ₅ β ₃ γ ₂ .

All of the subunit cRNAs in each combination are preferably human clones or all are rat clones. The sequence of each of these cloned subunits can be obtained from GENBANK, eg, human α ₁ , GENBANK approval number no. X14766; human α ₂ , GENBANK approval number No. A28100; human α ₃ , GENBANK approval number No. A28102; human α ₅ , GENBANK approval number No. A28104; human β ₂ , GENBANK approval number No. NM021911; human β ₃ , GENBANK approval number No. M82919 and approval number no. Z20136; human γ ₂ , GENBANK approval number No. X15376; rat α ₁ , GENBANK approval number No. L08490; rat α ₂ , GENBANK approval number No. L08491; Rat α ₃ , GENBANK Approval No. L08492; Rat α ₅ , GENBANK Approval No. L08494; rat β ₂ , GENBANK approval number No. X15467; rat β ₃ , GENBANK approval number No. X15468; and rat γ ₂ , GENBANK approval number no. There is L08497. For each subunit combination, inject enough messages into each constituent subunit to obtain a current amplitude of> 10 nA when 1 μM GABA is applied.

Compounds are evaluated against GABA concentrations that elicit <10% of the highest elicited GABA current (eg, 1 μM-9 μM). Each oocyte is exposed to increasing concentrations of the evaluation compound (test compound) and the concentration / effect relationship is evaluated. Test compound potency is calculated as a percent-change in current amplitude: 100 ^* ((Ic / I) -1), where Ic is the GABA-induced current amplitude found in the presence of the test compound, and I Is the GABA-induced current amplitude found in the absence of the test compound.

The specificity of the test compound for the benzodiazepine site is measured according to the completion of the following concentration / effect curve. After the oocytes are thoroughly washed to remove previously applied test compound, the oocytes are exposed to GABA + 1 μM RO15-1788 and then to GABA + 1 μM RO15-1788 + test compound. The percent change due to compound addition is calculated as described above. Any percent change found in the presence of RO15-1788 is subtracted from the percent change in current amplitude found in the absence of 1 μM RO15-1788. These authentic values are used to calculate mean potency and EC ₅₀ values by standard methods. To assess average potency and EC ₅₀ values, concentration / effect data are averaged between cells and fit to a logical equation.

  It should be understood that the foregoing description is of preferred embodiments of the invention and that modifications can be made without departing from the scope of the invention as set forth in the claims.

Claims (55)

formula:

Or a pharmaceutically acceptable salt thereof:
Where
R ₁ , R ₂ and R ₃ are independently the following groups:
A) hydrogen, halogen, halo (C ₁ -C ₆₎ alkyl, hydroxy, cyano, amino, alkyl, alkoxy, mono- - or di - (C ₁ -C ₆₎ alkylamino, mono - or di - (C ₁ - C ₆₎ alkylamino (C ₁ -C _{6) alkyl, -C (= O) NR 10} R 11, -C (= O) oR 10, and _{-OC (= O) R 10,} -C (= O) R ₁₀ (where R ₁₀ and R ₁₁ are independently hydrogen, C ₁ -C ₆ alkyl, phenyl, phenyl (C ₁ -C ₆ ) alkyl, pyridyl, or pyridyl (C ₁ -C ₆ ) alkyl) ;
B) haloalkoxy, alkenyl, alkynyl, _{hydroxyalkyl, -D-R 20, -E-} R 35, -C 1 -C 4 alkyl _{-D-R 20, -C 1 -C} 4 alkyl -O-R _{20, -E-R 20 -G-R 30} , -E-L, -E-R 20 -L, J, -C (= O) -L or -C ₁ -C ₄ alkyl -J,;
[Where _{D, -S (O) n -,} - S (O) n NH -, - S (O) n NH 2 -, - S (O) n NR 30 -, - NHC (= O) - , -NHC (= O) H, -NR 30 C (= O), - NR 30 C (= O) H, -NHS (O) n - and -NR ₃₀ S (O) _n - and is;
E and G are independently —NH—, —N (C ₁ -C ₆ alkyl)-, S and O;
R ₂₀ and R ₃₀ are each independently a (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl or (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkyl group; The alkyl and cycloalkyl groups each contain 0, 1 or 2 or more double bonds or triple bonds, and each of the carbon atoms present in the R ₂₀ and R ₃₀ groups is 1 or It may be substituted by a substituent independently selected from two or more groups C), wherein C) is oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, —NH (C ₁ -C _{6 alkyl), - N (C 1 -C} 6 alkyl) (C ₁ -C ₆ alkyl), - NHC (= O) (C 1 -C 6 _{alkyl), - N (C 1 -C} 6 alkyl ) C (= O) (C 1 -C 6 alkyl), - NHS O) _n (C ₁ -C _{6 alkyl), - S (O) n} (C 1 -C 6 _{alkyl), - S (O) n} NH (C 1 -C 6 _{alkyl), - S (O) n} N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), or L, and n is 0, 1 or 2;
And R ₃₅ each independently, (C ₁ -C ₈₎ linear, (C ₁ -C ₈₎ branched chain, (C ₃ -C ₈₎ cycloalkyl or (C ₃ -C ₈₎ cycloalkyl ( C ₁ -C ₆ alkyl) groups, each of which contains 0, 1 or 2 or more double or triple bonds and is present in the R ₃₅ group. Each carbon atom may be independently substituted with one or more substituents selected from group C);
J and L are each independently selected from saturated, partially unsaturated and aromatic rings having from 4 to 7 ring atoms, in which 0, 1 or 2 of the ring atoms Is oxygen or nitrogen, and the remaining ring atoms are carbon, and these rings are unsubstituted or substituted by one or more substituents independently selected from the group below May be:
i) halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, and mono- - or di - (C ₁ -C ₆₎ alkylamino; and ii) phenyl, pyridyl, pyrimidyl and pyrazinyl (or these groups are each unsubstituted, or 1-3 Halogen, hydroxy, amino, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and mono- or di- (C ₁ -C ₄ ) Independently selected from alkylamino);
Where J is not phenyl or pyridyl];
Provided that at least one of R ₁ , R ₂ and R ₃ is selected from B);
R ₄ is hydrogen, halogen or hydroxyl;
Ar represents an aryl, arylalkyl, heteroarylalkyl or heteroaryl group, each aryl having 1 or 2 aromatic rings, each aromatic ring having 4 to 7 ring atoms And 0, 1 or 2 of the ring atoms are oxygen, nitrogen or sulfur, the remaining ring atoms are carbon, and these rings are each substituted by one or more R ₄₀ Wherein each R ₄₀ is independently hydroxy, halogen, cyano, nitro, amino, XR ₅₀ , C ₁ -C ₄ alkyl-XR ₅₀ , or Y;
X, when present, is a bond, —CH ₂ —, —CHR ₆₀ —, —O—, —C (═O) —, —C (═O) O—, —OC (═O) —, — S (O) _n —, —NH—, —NR ₆₀ —, —C (═O) NH—, —C (═O) NR ₆₀ —, —S (O) _n NH—, —S (O) _n Independently selected from the group consisting of: NR ₆₀ —, —NHC (═O) —, —NR ₆₀ C (═O) —, —NHS (O) _n — and —NR ₆₀ S (O) _n —;
R ₅₀ and R ₆₀ , when present, are independently of hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl and (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkyl. Selected, the alkyl and cycloalkyl each contain 0, 1 or 2 or more double or triple bonds, and the carbon atoms of the alkyl, cycloalkyl or cycloalkylalkyl are each 1 pieces or two or more of oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C _{6 alkyl), - N (C 1 -C} 6 alkyl) (C ₁ -C ₆ Alkyl), —NHC (═O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (═O) (C ₁ -C ₆ alkyl), —NHS (O) _n (C ₁ -C ₆ alkyl), - S ( ) _N (C ₁ -C _{6 alkyl), - S (O) n} NH (C 1 -C 6 _{alkyl), - S (O) n} N (C 1 -C 6 alkyl) (C ₁ -C ₆ alkyl) , And Z, where n is 0, 1 or 2; and Y and Z, if present, each have 4 to 7 ring atoms, saturated, partially unsaturated or aromatic Selected from group rings, in which 0, 1 or 2 of the ring atoms are selected from oxygen and nitrogen, the remaining ring atoms are carbon, and Y and Z are unsubstituted, or one or more halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ - C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, and mono- or di- Optionally substituted by a substituent independently selected from (C ₁ -C ₆ ) alkylamino: and n are each independently 0, 1 or 2. formula:

Or a pharmaceutically acceptable salt thereof:
Where
R ₁ , R ₂ and R ₃ are independently selected from the following groups:
A) hydrogen, halogen, halo (C ₁ -C ₆₎ alkyl, hydroxy, cyano, amino, alkyl, alkoxy, mono- - or di - (C ₁ -C ₆₎ alkylamino, mono - or di - (C ₁ - C ₆₎ alkylamino (C ₁ -C _{6) alkyl, -C (= O) NR 10} R 11, -C (= O) oR 10, and _{-OC (= O) R 10,} -C (= O) R ₁₀ (where R ₁₀ and R ₁₁ are independent and independent of hydrogen, C ₁ -C ₆ alkyl, phenyl, phenyl (C ₁ -C ₆ ) alkyl, pyridyl, and pyridyl (C ₁ -C ₆ ) alkyl) Selected);
B) haloalkoxy, alkenyl, alkynyl, _{hydroxyalkyl, -D-R 20, -E-} R 35, -C 1 -C 4 alkyl -DpR _20, -C ₁ -C ₄ alkyl -O-R _20, -E _{-R 20 -G-R 30, -E} -L, -E-R 20 -L, J, -C (= O) -L, and -C ₁ -C ₄ alkyl -J;
[Where _{D, -S (O) n -,} - S (O) n NH -, - S (O) n NH 2 -, - S (O) n NR 30 -, - NHC (= O) - , -NHC (= O) H, -NR 30 C (= O) -, - NR 30 C (= O) H, -NHS (O) n - and -NR ₃₀ S (O) _n - and is;
E and G are independently NH, N—C ₁ -C ₆ alkyl, S and O;
R ₂₀ , R ₃₀ and R ₃₅ , if present, are each independently selected from linear, branched, and cyclic alkyl groups, and (cycloalkyl) alkyl groups, wherein the linear, branched, Chain and cyclic alkyl groups and (cycloalkyl) alkyl groups each have from 1 to 8 carbon atoms and contain 0, 1 or 2 double bonds or triple bonds, Also, 1 to 8 carbon atoms present in the R ₂₀ and R ₃₅ groups may each be substituted by one or more substituents independently selected from group C), and R _{In 35} , at least one of the 1 to 8 carbon atoms is further substituted with a substituent independently selected from one or more groups C);
Here Group C) oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C _{6 alkyl), - N (C 1 -C} 6 alkyl) (C ₁ -C ₆ Alkyl), —NHC (═O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (═O) (C ₁ -C ₆ alkyl), —NHS (O) _n (C _1- C ₆ alkyl), —S (O) _n (C ₁ -C ₆ alkyl), —S (O) _n NH (C ₁ -C ₆ alkyl), —S (O) _n N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), and L;
J and L are each independently selected from saturated, partially unsaturated and aromatic rings having from 4 to 7 ring atoms, in which 0, 1 or 2 of the ring atoms Are selected from oxygen and nitrogen, and the remaining ring atoms are carbon, and these rings are unsubstituted or substituted by one or more substituents independently selected from the group below and may be: i) halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, and mono- - or di - (C ₁ -C ₆₎ alkylamino; and ii) phenyl, pyridyl, pyrimidyl and pyrazinyl (each of these groups, or is unsubstituted, Other 1-3 halogens, hydroxy, amino, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and mono- - or di - it may be substituted by (C ₁ -C ₄₎ substituted independently selected from alkylamino)];
R ₄ is hydrogen, halogen or hydroxyl;
Ar represents heteroaryl or heteroaryl (C ₁ -C ₆ ) alkyl, which is quinolinyl, benzothienyl, indolyl, pyridazinyl, piadinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, Oxazolyl, thienyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzoisooxolyl, dihydro-benzodioxinyl, furanyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl , Isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromane , Chromanonyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, Phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromanyl, Tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinyl, dihydroisoquinolino Dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, Indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, Indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-o Selected from xoxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide and benzothiopyranyl S, S-dioxide, Ar is also one or more R _Optionally substituted by ₄₀ ;
Where R ₄₀ , if present, is independently selected from hydroxy, halogen, cyano, nitro, amino, XR ₅₀ , C ₁ -C ₄ alkyl-XR ₅₀ and Y;
X, when present, is a bond, —CH ₂ —, —CHR ₆₀ —, —O—, —C (═O) —, —C (═O) O—, —OC (═O) —, — S (O) _n —, —NH—, —NR ₆₀ —, —C (═O) NH—, —C (═O) NR ₆₀ —, —S (O) _n NH—, —S (O) _n Independently selected from the group consisting of: NR ₆₀ —, —NHC (═O) —, —NR ₆₀ C (═O) —, —NHS (O) _n — and —NR ₆₀ S (O) _n —;
R ₅₀ and R ₆₀ , if present, are independently selected from hydrogen and linear, branched and cyclic alkyl groups, and (cycloalkyl) alkyl groups, wherein the linear, branched, and And cyclic alkyl groups and (cycloalkyl) alkyl groups contain 1 to 8 carbon atoms and contain 0, 1 or 2 double bonds or triple bonds, and these groups each one or two or more oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C _{6 alkyl), - N (C 1 -C} 6 alkyl) (C ₁ -C ₆ alkyl), - NHC (= O) (C 1 -C 6 _{alkyl), - N (C 1 -C} 6 alkyl) C (= O) (C 1 -C 6 alkyl), - NHS (O ) _N (C ₁ -C ₆ alkyl), —S (O) _n (C ₁ — C _{6 alkyl), - S (O) n} NH (C 1 -C 6 _{alkyl), - S (O) n} N (C 1 -C 6 alkyl) (C ₁ -C ₆ alkyl), and independent of the Z Optionally substituted by selected substituents;
Y and Z, when present, are selected from saturated, partially unsaturated and aromatic rings having 4 to 7 ring atoms, in which 0, 1 or 2 of the ring atoms are oxygen And the remaining ring atoms are carbon and Y and Z are unsubstituted or one or more halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, and mono- or di- (C ₁ -C ₆ ) May be substituted with a substituent independently selected from alkylamino]: and n, if present, is independently selected from 0, 1 and 2. formula:

Or a pharmaceutically acceptable salt thereof:
Where
R ₁ , R ₂ and R ₃ are independently selected from the following groups:
A) hydrogen, halogen, halo (C ₁ -C ₆₎ alkyl, hydroxy, cyano, amino, alkyl, alkoxy, mono- - or di - (C ₁ -C ₆₎ alkylamino, mono - or di - (C ₁ - C ₆₎ alkylamino (C ₁ -C _{6) alkyl, -C (= O) NR 10} R 11, -C (= O) oR 10, and _{-OC (= O) R 10,} -C (= O) R ₁₀ (where R ₁₀ and R ₁₁ are independently selected from hydrogen, C ₁ -C ₆ alkyl, phenyl, phenyl (C ₁ -C ₆ ) alkyl, pyridyl, or pyridyl (C ₁ -C ₆ ) alkyl. ;);
B) haloalkoxy, alkenyl, alkynyl, _{hydroxyalkyl, -D-R 20, -E-} R 35, -C 1 -C 4 alkyl _{-D-R 20, -C 1 -C} 4 alkyl -O-R _{20, -E-R 20 -G-R 30} , -E-L, -E-R 20 -L, J, -C (= O) -L, and -C ₁ -C ₄ alkyl -J;
[Where _{D, -S (O) n -,} - S (O) n NH -, - S (O) n NH 2 -, - S (O) n NR 30 -, - NHC (= O) - , -NHC (= O) H, -NR 30 C (= O) -, - NR 30 C (= O) H, -NHS (O) n - and -NR ₃₀ S (O) _n - and is;
E and G are independently —NH—, —N—C ₁ -C ₆ alkyl-, S and O;
R ₂₀ , R ₃₀ and R ₃₅ , if present, are each independently selected from linear, branched, and cyclic alkyl groups, and (cycloalkyl) alkyl groups, wherein the linear, branched, Chain and cyclic alkyl groups and (cycloalkyl) alkyl groups each have from 1 to 8 carbon atoms and contain 0, 1 or 2 double bonds or triple bonds, Also, 1 to 8 carbon atoms present in the R ₂₀ and R ₃₅ groups may each be substituted by one or more substituents independently selected from group C), and R _{In 35} , at least one of the 1-8 carbon atoms may be further substituted with one or more substituents independently selected from group C);
Here Group C) oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C _{6 alkyl), - N (C 1 -C} 6 alkyl) (C ₁ -C ₆ Alkyl), —NHC (═O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (═O) (C ₁ -C ₆ alkyl), —NHS (O) _n (C _1- C ₆ alkyl), —S (O) _n (C ₁ -C ₆ alkyl), —S (O) _n NH (C ₁ -C ₆ alkyl), —S (O) _n N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), and L;
J and L are each independently selected from saturated, partially unsaturated and aromatic rings having from 4 to 7 ring atoms, in which 0, 1 or 2 of the ring atoms Are selected from oxygen and nitrogen, and the remaining ring atoms are carbon, and these rings are unsubstituted or substituted by one or more substituents independently selected from the group below and may be: i) halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, and mono- - or di - (C ₁ -C ₆₎ alkylamino; and ii) phenyl, pyridyl, pyrimidyl and pyrazinyl (each of these groups, or is unsubstituted, Other 1-3 halogens, hydroxy, amino, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and mono- - or di - it may be substituted by (C ₁ -C ₄₎ alkylamino)];
R ₄ is hydrogen, halogen or hydroxyl;
Ar represents phenyl, pyridyl or pyrimidinyl, Ar may be substituted by one or more R ₄₀ , where R ₄₀ , if present, is hydroxy, halogen, cyano, nitro, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkanoyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl (C ₁ -C ₄₎ alkyl, C ₃ -C ₇ Cycloalkyl-O—, C ₃ -C ₇ cycloalkyl (C ₁ -C ₄ ) alkoxy-, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkylthio-, halo (C ₁ -C ₆ ) alkyl, and halo (C ₁ -C ₆ ) alkoxy independently selected and Ar is at least one of —E—R ₅₀ —G—R ₆₀ , —E—R ₅₀ —G—Y, C ₁ —C ₄ alkyl— _{XR 50, -NH-R 60 -Y} , - (NR ₅₀₎ substituted by R ₆₀ -Y, and Y;
X, when present, is —O—, —C (═O) —, —C (═O) O—, —OC (═O) —, —S (O) _n —, —NH—, — _{NR 60 -, - C (=} O) NH -, - C (= O) NR 60 -, - S (O) n NH -, - S (O) n NR 60 -, - NHC (= O) -, Independently selected from the group consisting of —NR ₆₀ C (═O) —, —NHS (O) _n — and —NR ₆₀ S (O) _n —;
Wherein R ₅₀ and R ₆₀ , if present, are independently selected from hydrogen and linear, branched, and cyclic alkyl groups, and (cycloalkyl) alkyl groups, Branched and cyclic alkyl groups and (cycloalkyl) alkyl groups each have 1 to 8 carbon atoms and contain 0, 1 or 2 double or triple bonds. 1 to 8 carbon atoms present in these groups are each one or more oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), —NHC (═O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C ( = O) (C ₁ -C ₆ alkyl), - NHS ( ) _N (C ₁ -C _{6 alkyl), - S (O) n} (C 1 -C 6 _{alkyl), - S (O) n} NH (C 1 -C 6 _{alkyl), - S (O) n} N ( C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), and optionally further substituted by a substituent independently selected from Z;
Y and Z, if present, are each selected from saturated, partially unsaturated or aromatic rings having 4 to 7 ring atoms, in which 0, 1 or 2 of the ring atoms are oxygen And the remaining ring atoms are carbon and Y and Z are unsubstituted or one or more halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, and mono- or di- (C ₁ -C ₆ ) May be substituted with a substituent independently selected from alkylamino]: and n, if present, is independently selected from 0, 1 or 2. Ar represents aryl, arylalkyl, heteroaryl or heteroarylalkyl, which is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, [1,3,4] Selected from thiadiazolyl, triazolyl, indolyl, quinolinyl, isoquinolinyl, benzodioxolyl, benzofuranyl, benzimidazolyl, benzisoxolyl, and dihydro-benzodioxinyl, and substituted by one or more R ₄₀ The compound or salt of claim 1, which may be 5. A compound or salt according to claim ₄ wherein R4 is hydrogen. R ₁ is selected from B);
R ₂ and R ₃ are hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and mono- or di - (C ₁ -C ₆₎ are independently selected from alkylamino; and R ₄ is hydrogen;
5. A compound or salt according to claim 4. R ₁ is selected from B);
R ₂ and R ₃ are hydrogen, halogen, CF ₃ , CHF ₂ , OCF ₃ , hydroxy, cyano, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, and mono- or di- (C ₁ -C ₂ ) Independently selected from alkylamino; and R ₄ is hydrogen;
The compound or salt according to claim 4. R ₁ is selected from B);
R ₂ and R ₃ are independently selected from hydrogen, halogen, methyl and ethyl;
R ₄ is hydrogen;
5. A compound or salt according to claim 4. Each R ₄₀ , if present, is independently selected from hydroxy, halogen, cyano, amino, XR ₅₀ , (C ₁ -C ₄ ) alkyl-XR ₅₀ , and Y;
X, when present, from the bond, —CH ₂ —, —CHR ₆₀ —, —O—, —C (═O) —, —S (O) _n —, —NH—, and —NR ₆₀ —. Independently selected;
R ₅₀ and R ₆₀ , if present, are independently selected from hydrogen and linear, branched, and cyclic alkyl groups, and (cycloalkyl) alkyl groups, wherein the linear, branched, Chain and cyclic alkyl groups and (cycloalkyl) alkyl groups each have from 1 to 8 carbon atoms and contain 0, 1 or 2 double bonds or triple bonds, each 8 carbon atoms present in the group, one or more oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C ₆ alkyl ), —N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), —NHC (═O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (═O ) (C ₁ -C ₆ alkyl), - NHS (O) _n C ₁ -C _{6 alkyl), - S (O) n} (C 1 -C 6 _{alkyl), - S (O) n} NH (C 1 -C 6 _{alkyl), - S (O) n} N (C 1 - C ₆ alkyl) (C ₁ -C ₆ alkyl), and optionally further substituted by a substituent independently selected from Z;
Y and Z, if present, are each selected from saturated, partially unsaturated or aromatic rings having 4 to 7 ring atoms, in which 0, 1 or 2 of the ring atoms are oxygen And the remaining ring atoms are carbon and Y and Z are unsubstituted or one or more halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, and mono- or di- (C ₁ -C ₆ ) Optionally substituted by a substituent independently selected from alkylamino: and n, if present, is independently selected from 0, 1 or 2;
The compound or salt according to claim 4. R ₁ is selected from B);
R ₂ and R ₃ are independently selected from hydrogen, halogen, methyl and ethyl; and R ₄ is hydrogen;
10. A compound or salt according to claim 9. R ₁ is selected from B);
R ₂ and R ₃ are independently selected from hydrogen, halogen, methyl and ethyl;
R ₄ is hydrogen; and when R ₄₀ is present, respectively, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, mono- or di- (C ₁ -C ₆ ) alkylamino, mono- Or di- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, and (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆₎ independently of the alkoxy is selected;
The compound or salt according to claim 4. R ₁ is selected from B);
B) is -ER ₃₅ , -C ₁ -C ₄ alkyl-O-R ₂₀ , -ER ₂₀ -GR ₃₀ , -E-L, -E-R ₂₀ -L, J, or be -C ₁ -C ₄ alkyl -J;
E and G are independently —NH—, —N—C ₁ -C ₆ alkyl-, or O;
R ₂₀ , R ₃₀ and R ₃₅ , if present, are each independently selected from linear, branched, and cyclic alkyl groups, and (cycloalkyl) alkyl groups, wherein the linear, branched, Chain and cyclic alkyl groups and (cycloalkyl) alkyl groups each have from 1 to 8 carbon atoms and contain 0, 1 or 2 double bonds or triple bonds, Also, 1 to 8 carbon atoms present in the R ₂₀ and R ₃₅ groups may each be substituted by one or more substituents independently selected from group C), and R _{In 35} , at least one of the 1 to 8 carbon atoms is further substituted with a substituent independently selected from one or more groups C);
Here Group C) oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C _{6 alkyl), - N (C 1 -C} 6 alkyl) (C ₁ -C ₆ Alkyl), —NHC (═O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (═O) (C ₁ -C ₆ alkyl), —NHS (O) _n (C _1- C ₆ alkyl), —S (O) _n (C ₁ -C ₆ alkyl), —S (O) _n NH (C ₁ -C ₆ alkyl), —S (O) _n N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), and L;
J and L, if present, are each independently selected from saturated heterocycles having from 4 to 7 ring atoms, in which one or two of the ring atoms are nitrogen, and the remaining rings atoms are carbon, or these rings are unsubstituted, or one or more halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ Independently selected from —C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, and mono- or di- (C ₁ -C ₆ ) alkylamino Optionally substituted by a substituent: where J is not phenyl or pyridyl;
R ₂ and R ₃ are independently selected from hydrogen, halogen, methyl and ethyl;
R ₄ is hydrogen; and R ₄₀ , if present, is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, mono- or di- (C ₁ -C ₆ ) alkylamino, mono- Or di- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, and (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆₎ independently of the alkoxy is selected;
The compound or salt according to claim 4. Ar represents an aryl, arylalkyl, heteroaryl or heteroarylalkyl group, wherein the aryl and heteroaryl are piperazinyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, [1,3,4] thiadiazolyl, triazolyl, indolyl , Quinolinyl, isoquinolinyl, benzodioxolyl, benzofuranyl, benzimidazolyl, benzoisoxolyl, and dihydro-benzodioxinyl, and may be substituted by one or more R ₄₀ ;
The compound or salt according to claim 2. R ₄ is hydrogen The compound or salt according to claim 13. R ₁ is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono- or di- (C ₁ -C ₆₎ is selected from alkylamino and B);
R ₂ and R ₃ are hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and mono- or di - (C ₁ -C ₆₎ are independently selected from alkylamino; and R ₄ is hydrogen;
14. A compound or salt according to claim 13. R ₁ is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono- or di- (C ₁ -C ₆₎ is selected from alkylamino and B);
R ₂ and R ₃ are hydrogen, halogen, CF ₃ , CHF ₂ , OCF ₃ , hydroxy, cyano, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, and mono- or di- (C ₁ -C ₂ ) Independently selected from alkylamino; and R ₄ is hydrogen;
14. A compound or salt according to claim 13. R ₁ is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono- or di- (C ₁ -C ₆₎ is selected from alkylamino and B);
B) is —E—R ₃₅ , —C ₁ -C ₄ alkyl-O—R ₂₀ , —E—R ₂₀ —G—R ₃₀ , —E—L, —E—R ₂₀ —L, J, or — C ₁ -C ₄ alkyl-J;
E and G are independently —NH—, —N—C ₁ -C ₆ alkyl, or O;
R ₂ and R ₃ are independently selected from hydrogen, halogen, methyl and ethyl;
R ₄ is hydrogen;
14. A compound or salt according to claim 13. R ₄₀ , if present, is independently selected from hydroxy, halogen, cyano, amino, XR ₅₀ , — (C ₁ -C ₄ ) alkyl-XR ₅₀ , and Y;
X, when present, from the bond, —CH ₂ —, —CHR ₆₀ —, —O—, —C (═O) —, —S (O) _n —, —NH—, and —NR ₆₀ —. Selected independently from the group;
R ₅₀ and R ₆₀ , if present, are independently selected from hydrogen and linear, branched, and cyclic alkyl groups, and (cycloalkyl) alkyl groups, wherein the linear, branched, Chain and cyclic alkyl groups and (cycloalkyl) alkyl groups each have from 1 to 8 carbon atoms and contain 0, 1 or 2 double bonds or triple bonds, each 8 carbon atoms present in the group, one or more oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C ₆ alkyl ), —N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), —NHC (═O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (═O ) (C ₁ -C ₆ alkyl), - NHS (O) _n C ₁ -C _{6 alkyl), - S (O) n} (C 1 -C 6 _{alkyl), - S (O) n} NH (C 1 -C 6 _{alkyl), - S (O) n} N (C 1 - C ₆ alkyl) (C ₁ -C ₆ alkyl), and optionally further substituted by a substituent independently selected from Z;
Y and Z, if present, are each selected from saturated, partially unsaturated or aromatic rings having 4 to 7 ring atoms, in which 0, 1 or 2 of the ring atoms are oxygen Selected from and nitrogen, the remaining ring atoms are carbon, and Y and Z are unsubstituted or one or more halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, and mono- or di- (C ₁ -C ₆ A) optionally substituted by a substituent independently selected from alkylamino: and n, if present, is independently selected from 0, 1 or 2;
14. A compound or salt according to claim 13. R ₁ is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono- or di- (C ₁ -C ₆₎ is selected from alkylamino and B);
R ₂ and R ₃ are independently selected from hydrogen, halogen, methyl and ethyl; and R ₄ is hydrogen;
19. A compound or salt according to claim 18. R ₁ is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono- or di- (C ₁ -C ₆₎ is selected from alkylamino and B);
R ₂ and R ₃ are independently selected from hydrogen, halogen, methyl and ethyl;
R ₄ is hydrogen; and R ₄₀ , when present, is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, mono- or di- (C ₁ -C ₆ ) alkylamino, mono- Or di- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, and (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆₎ independently of the alkoxy is selected;
14. A compound or salt according to claim 13. R ₁ is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono- or di- (C ₁ -C ₆₎ is selected from alkylamino and B);
B) is —E—R ₃₅ , —C ₁ -C ₄ alkyl-O—R ₂₀ , —E—R ₂₀ —G—R ₃₀ , —E—L, —E—R ₂₀ —L, J, or — C ₁ -C ₄ alkyl-J;
E and G are independently —NH—, —N—C ₁ -C ₆ alkyl, or O;
R ₂₀ , R ₃₀ and R ₃₅ , if present, are each independently selected from linear, branched, and cyclic alkyl groups, and (cycloalkyl) alkyl groups, wherein the linear, branched, Chain and cyclic alkyl groups and (cycloalkyl) alkyl groups each have from 1 to 8 carbon atoms and contain 0, 1 or 2 double bonds or triple bonds, Also, 1 to 8 carbon atoms present in the R ₂₀ and R ₃₅ groups may each be substituted by one or more substituents independently selected from group C), and R _{In 35} , at least one of the 1 to 8 carbon atoms is further substituted with a substituent independently selected from one or more groups C);
Here Group C) oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C _{6 alkyl), - N (C 1 -C} 6 alkyl) (C ₁ -C ₆ Alkyl), —NHC (═O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (═O) (C ₁ -C ₆ alkyl), —NHS (O) _n (C _1- C ₆ alkyl), —S (O) _n (C ₁ -C ₆ alkyl), —S (O) _n NH (C ₁ -C ₆ alkyl), —S (O) _n N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), and L;
J and L, if present, are each independently selected from saturated heterocyclic rings having from 4 to 7 ring atoms, in which one or two of the ring atoms are nitrogen and the remaining ring atoms are carbon, or these rings are unsubstituted, or one or more halogen, oxo, hydroxy, amino, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C _1- C ₆ alkoxy (C ₁ -C ₆ alkyl), C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, and mono- or di- (C ₁ -C ₆ ) alkylamino substituted Good: where J is not phenyl or pyridyl;
R ₂ and R ₃ are independently selected from hydrogen, halogen, methyl and ethyl;
R ₄ is hydrogen; and when R ₄₀ is present, respectively, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, mono- or di- (C ₁ -C ₆ ) alkylamino, mono- Or di- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, and (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆₎ independently of the alkoxy is selected;
14. A compound or salt according to claim 13. _4. A compound or salt according to claim 3 wherein R4 is hydrogen. R ₁ is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and mono- or di- (C ₁ -C ₆₎ is selected from alkylamino and B);
R ₂ and R ₃ are hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and mono- or di - (C ₁ -C ₆₎ are independently selected from alkylamino; and R ₄ is hydrogen;
The compound or salt according to claim 3. R ₁ is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and mono- or di- (C is selected from ₁ -C ₆₎ alkylamino;
R ₂ and R ₃ are hydrogen, halogen, CF ₃ , CHF ₂ , OCF ₃ , hydroxy, cyano, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, and mono- or di- (C ₁ -C ₂ ) Independently selected from alkylamino; and R ₄ is hydrogen;
The compound or salt according to claim 3. Ar may be substituted by one or more R ₄₀ ;
When R ₄₀ is present, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo (C ₁ -C ₆ ) alkyl, and halo (C ₁ -C ₆ ), respectively. Independently selected from alkoxy;
Ar is at least one _{-E-R 50 -G-R 60} -, - E-R 50 -G-Y, C 1 -C 4 alkyl _{-XR 50, -NH-R 60 -Y} , - (NR 50 ) R ₆₀ -Y, and substituted by Y:
When each X is present, —O—, —C (═O) —, —C (═O) O—, —OC (═O) —, —S (O) _n —, —NH—, — Independently selected from NR ₆₀ —, —C (═O) NH—, —C (═O) NR ₆₀ —, —NHC (═O) — and —NR ₆₀ C (═O);
R ₅₀ and R ₆₀ , if present, are independently selected from hydrogen and linear, branched, and cyclic alkyl groups, and (cycloalkyl) alkyl groups, wherein the linear, branched, Chain and cyclic alkyl groups and (cycloalkyl) alkyl groups each have from 1 to 8 carbon atoms and contain 0, 1 or 2 double bonds or triple bonds, each 8 carbon atoms present in the group, one or more oxo, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH (C ₁ -C ₆ alkyl ), —N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), —NHC (═O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (═O ) (C ₁ -C ₆ alkyl), and independent of Z It may be further substituted by substituents selected Te;
The compound or salt according to claim 3. R ₁ is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and mono- or di- (C is selected from ₁ -C ₆₎ alkylamino;
R ₂ and R ₃ are hydrogen, halogen, CF ₃ , CHF ₂ , OCF ₃ , hydroxy, cyano, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, and mono- or di- (C ₁ -C ₂ ) Independently selected from alkylamino; and R ₄ is hydrogen;
26. A compound or salt according to claim 25. R ₁ is hydrogen, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono- or di- (C ₁ -C ₆₎ is selected from alkylamino and B);
R ₂ and R ₃ are independently selected from hydrogen, halogen, methyl and ethyl; and R ₄ is hydrogen;
26. A compound or salt according to claim 25. 2. A compound or salt according to claim 1 selected from the following group:
5- (1-methyl-piperidin-4-yloxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (2-fluoro-phenyl) -amide;
1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
7-chloro-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (2-fluoro-phenyl) -amide;
6-methyl-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (4-methoxy-phenyl) -amide;
6-methyl-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (5-propoxy-pyridin-2-yl) -amide;
6-methyl-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-3-ylamide;
5-methoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (2-fluoro-phenyl) -amide;
5-methoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5-methoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (4-methoxy-phenyl) -amide;
5-ethylamino-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (4-methoxy-phenyl) -amide;
5-ethylamino-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (2-fluoro-phenyl) -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (2-fluoro-phenyl) -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (4-methoxy-phenyl) -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (5-chloro-pyridin-2-yl) -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (6-bromo-pyridin-3-yl) -amide;
5-isopropoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-fluoro-phenyl) -amide;
5-isopropoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-fluoro-4-methoxy-phenyl) -amide;
1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid quinolin-8-ylamide;
1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid [4- (3-methanesulfonylamino-propoxy) -phenyl] -amide;
1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-propyl- [1,2,4] thiadiazol-5-yl) -amide;
1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
6-methyl-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-propyl-1H-pyrazol-3-yl) -amide;
6-methyl-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyrazin-2-ylamide;
5-methoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid [6- (3-diethylamino-propoxy) -pyridin-3-yl] -amide;
5-methoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (pyridin-2-ylmethyl) -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid [6- (3-diethylamino-propoxy) -pyridin-3-yl] -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid [4- (2-ethoxy-ethoxy) -phenyl] -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid [6- (tetrahydro-furan-3-yloxy) -pyridin-3-yl] -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-methyl-isothiazol-5-yl) -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (5-methyl-1H-pyrazol-3-yl) -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-methyl-isoxazol-5-yl) -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (5-methyl-isoxazol-3-yl) -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-ethyl-1H-pyrazol-3-yl) -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid [4- (2-hydroxy-ethyl) -phenyl] -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid [4- (2-diethylamino-ethyl) -phenyl] -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-hydroxymethyl-phenyl) -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-pyrrolidin-1-ylmethyl-phenyl) -amide;
5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid [4- (2-pyrrolidin-1-yl-ethyl) -phenyl] -amide;
5-isopropoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-methyl-isothiazol-5-yl) -amide;
5-isopropoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-methyl-isoxazol-5-yl) -amide;
5-isopropoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (5-methyl-isoxazol-3-yl) -amide;
5-isopropoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (5-methyl-1H-pyrazol-3-yl) -amide;
5-isopropoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-ethyl-1H-pyrazol-3-yl) -amide;
5- (2-methoxy-ethoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (5-methyl-isoxazol-3-yl) -amide;
5- (2-methoxy-ethoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-methyl-isoxazol-5-yl) -amide;
5- (2-methoxy-ethoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-methyl-isothiazol-5-yl) -amide;
5- (2-methoxy-ethoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (5-methyl-1H-pyrazol-3-yl) -amide;
5- (1-methyl-piperidin-4-yloxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (5-methyl-isoxazol-3-yl) -amide;
5- (1-methyl-piperidin-4-yloxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (1-methyl-piperidin-4-yloxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
5- (1-methyl-piperidin-4-yloxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (6-methoxy-pyrazin-2-yl) -amide;
5- (1-methyl-piperidin-4-yloxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-4-ylamide;
5- (2-diethylamino-ethoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (5-methyl-isoxazol-3-yl) -amide;
5- (2-diethylamino-ethoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (2-diethylamino-ethoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
5- (2-pyrrolidin-1-yl-ethoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (5-methyl-isoxazol-3-yl) -amide;
5- (2-pyrrolidin-1-yl-ethoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (2-pyrrolidin-1-yl-ethoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
5- (1-methyl-pyrrolidin-3-yloxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (5-methyl-isoxazol-3-yl) -amide;
5- (1-methyl-pyrrolidin-3-yloxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (1-methyl-pyrrolidin-3-yloxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
5- (2-dimethylamino-ethoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (5-methyl-isoxazol-3-yl) -amide;
5- (2-dimethylamino-ethoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (2-dimethylamino-ethoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
5- (1-methyl-azetidin-3-yloxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
5- (3-dimethylamino-2,2-dimethyl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
5- (3-dimethylamino-2,2-dimethyl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (3-dimethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (6-methoxy-pyridin-3-yl) -amide;
5- (3-dimethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-fluoro-phenyl) -amide;
5- (3-dimethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-methyl-isothiazol-5-yl) -amide;
5- (3-dimethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyrimidin-2-ylamide;
5- (3-dimethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (5-methyl- [1,3,4] thiadiazol-2-yl) -amide;
5- (3-dimethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (6-methyl-pyridin-2-yl) -amide;
5- (3-dimethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (4,6-dimethyl-pyridin-2-yl) -amide;
5- (3-dimethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-methyl-isoxazol-5-yl) -amide;
5- (3-dimethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (3-dimethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
5- (3-dimethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-ethyl-1H-pyrazol-3-yl) -amide;
5- (3-dimethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-propyl-1H-pyrazol-3-yl) -amide;
5- (3-dimethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-butyl-1H-pyrazol-3-yl) -amide;
5- (3-diethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (6-ethyl-pyridin-2-yl) -amide;
5- (3-diethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (6-methyl-pyridin-2-yl) -amide;
5- (3-diethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
5- (3-diethylamino-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5-oxo-4,5-dihydro-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
5- (4-dimethylamino-butoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (3-piperidin-1-yl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
5- (3-piperidin-1-yl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (3-azetidin-1-yl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
5- (3-azetidin-1-yl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- [2- (1-Methyl-pyrrolidin-2-yl) -ethoxy] -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl)- An amide;
5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy] -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (3-pyrrol-1-yl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (3-pyrrol-1-yl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
5- [3- (3-Methyl-piperidin-1-yl) -propoxy] -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- [3- (3-Methyl-piperidin-1-yl) -propoxy] -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl)- An amide;
5- (3-hydroxy-3-methyl-butoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (4,6-dimethyl-pyridin-2-yl) -amide;
5- (3-hydroxy-3-methyl-butoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (6-methyl-pyridin-2-yl) -amide;
5- (3-hydroxy-3-methyl-butoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (4-hydroxy-4-methyl-pentyloxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- [3- (6-Aza-bicyclo [3.2.2] non-6-yl) -propoxy] -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H -Pyrazol-3-yl) -amide;
5- [3- (6-Aza-bicyclo [3.2.2] non-6-yl) -propoxy] -1H-pyrrolo [3,2-b] pyridin-3-carboxylic acid pyridin-2-ylamide;
5- (4-diethylamino-butoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (3-bilidin-2-yl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-methyl-isoxazol-5-yl) -amide;
5- (3-pyridin-2-yl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-ethyl-1H-pyrazol-3-yl) -amide;
5- (3-pyridin-2-yl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-butyl-1H-pyrazol-3-yl) -amide;
5- (3-pyridin-2-yl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-propyl-1H-pyrazol-3-yl) -amide;
5- (3-pyridin-2-yl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
5- (3-pyridin-2-yl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (4-hydroxy-butoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- [3- (4-Methyl-piperazin-1-yl) -propoxy] -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- [3- (4-Methyl-piperazin-1-yl) -propoxy] -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl)- An amide;
5- (3-morpholin-4-yl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (3-morpholin-4-yl-propoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;
5- [2- (4-methyl-piperazin-1-yl) -ethoxy] -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- [2- (4-Methyl-piperazin-1-yl) -ethoxy] -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl)- An amide;
5- (2-morpholin-4-yl-ethoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid pyridin-2-ylamide;
5- (2-morpholin-4-yl-ethoxy) -1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide; and its pharmaceuticals Acceptable salt.
Receptor binding compounds exhibit a Ki of 1 micromolar or less. 4. The compound or salt according to any one of claims 1 to 3, wherein the compound exhibits a Ki of 100 nanomolar or less in GABA _A receptor binding analysis. 4. The compound or salt according to any one of claims 1 to 3, wherein in the GABA _A receptor binding assay, the compound exhibits a Ki of 10 nanomolar or less.   A pharmaceutical composition comprising the compound or salt according to any one of claims 1 to 3 together with a pharmaceutically acceptable carrier or excipient.   32. The pharmaceutical composition according to claim 31, wherein the pharmaceutical composition is formulated as an injectable liquid, aerosol, cream, gel, pill, capsule, syrup or transdermal patch.   A method of treating anxiety, depression, sleep disorder, attention deficit disorder or Alzheimer's disease dementia, wherein a therapeutically effective amount of the compound or salt according to any one of claims 1 to 3 is treated with such treatment. The method of treatment comprising administering to a patient in need thereof.   A method for enhancing the therapeutic effect of a CNS agent, comprising administering the CNS agent and the compound or salt according to any one of claims 1 to 3 to a patient.   A method for improving short-term memory in a patient comprising administering to the patient a therapeutically effective amount of a compound or salt according to any of claims 1-3. _A method for measuring the presence or absence of a GABA _A receptor in a sample, comprising:
(A) contacting the sample with the compound or salt of any one of claims 1 to 3 under conditions that allow the compound to bind to the GABA _A receptor;
(B) not bound to GABA _A receptor compound or the salt separates; then (c) measuring the level of bound compound or salt in GABA _A receptor, thereby the presence or absence of GABA _A receptor in a sample Detect
A method as described above, comprising the steps.   38. The method of claim 36, wherein the presence or absence of bound compound is detected using autoradiography. _A method for altering the signal transduction activity of a GABA _A receptor, wherein said method is such that the cell expressing the GABA _A receptor is at a concentration sufficient to cause the cell to undergo an electrophysiologically detectable alteration. _A method as described above, comprising contacting with a solution containing a compound or salt according to any of -3, thereby altering GABA _A receptor signaling activity. A method for modifying the signaling activity of GABA _A receptors, the cells that the method of expressing a GABA _A receptor, a concentration sufficient to inhibit in vitro RO15-1788 binding to cells expressing human GABA _A receptor A method as described above, comprising exposing to a compound or salt according to any of claims 1-3.   40. The method of claim 38, wherein the electrophysiologically detectable change of the cell is a change in the chloride ion conductivity of the cell. 40. The method of claim 39, wherein the cell recombinantly expresses a heterologous GABA _A receptor and the electrophysiological alteration of the cell is detected by intracellular recording or patch clamp recording.   Claim 31. In a container or structure used in a composition for treating a patient suffering from anxiety, depression, sleep disorders, attention deficit disorder or Alzheimer's dementia or short-term memory loss. A packaged pharmaceutical formulation comprising a pharmaceutical composition of:   Use of a compound or salt according to any of claims 1 to 3 in the manufacture of a medicament for treating anxiety, depression, sleep disorders, attention deficit disorder or Alzheimer's dementia or short-term memory loss. formula:

Or a pharmaceutically acceptable salt thereof:
Where
R ₁ is amino (C ₁ -C ₆ ) alkoxy, mono (C ₁ -C ₃ ) alkylamino (C ₁ -C ₆ ) alkoxy, di (C ₁ -C ₃ ) alkylamino (C ₁ -C ₆ ) Alkoxy, pyridyl (C ₁ -C ₆ ) alkoxy, hydroxy (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₆ ) alkoxy, piperazinyl (C ₁ -C ₆ ) alkoxy (here Wherein the piperazinyl group is optionally substituted by (C ₁ -C ₆ ) alkyl), morpholinyl (C ₁ -C ₆ ) alkoxy, or thiomorpholinyl (C ₁ -C ₆ ) alkoxy;
R ₂ and R ₃ are independently selected from H, (C ₁ -C ₆ ) alkyl, halogen or (C ₁ -C ₆ ) alkoxy;
Ar is pyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrimidyl, or pyridazinyl, each of these groups being unsubstituted or one, two or three independent (C _1- It may be substituted by a group that is C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, halogen, OCF ₃ or CF ₃ . R ₁ is amino (C ₁ -C ₄ ) alkoxy, mono (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkoxy, di (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) Alkoxy, pyridyl (C ₁ -C ₄ ) alkoxy, hydroxy (C ₁ -C ₄ ) alkoxy, piperazinyl (C ₁ -C ₄ ) alkoxy (where the piperazinyl group is substituted by (C ₁ -C ₄ ) alkyl may be), or morpholinyl (C ₁ -C ₆₎ alkoxy, a compound according to claim 44. R ₂ and R ₃ are independently selected from H, (C ₁ -C ₄ ) alkyl, halogen or (C ₁ -C ₄ ) alkoxy, provided that at least one of R ₂ and R ₃ is H; and Ar is pyridyl, isoxazolyl, oxazolyl, pyrazolyl, pyrimidyl, or pyridazinyl, each of these groups being unsubstituted or one, two or three independent alkyl, alkoxy, halogen, OCF ₃ Or optionally substituted by a group that is CF ₃ ;
46. The compound of claim 45. R ₁ is amino (C ₁ -C ₄ ) alkoxy, mono (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkoxy, di (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) Alkoxy, pyridyl (C ₁ -C ₄ ) alkoxy, hydroxy (C ₁ -C ₄ ) alkoxy, piperazinyl (C ₁ -C ₄ ) alkoxy (where the piperazinyl group is substituted by (C ₁ -C ₄ ) alkyl Or morpholinyl (C ₁ -C ₆ ) alkoxy;
R ₂ and R ₃ are independently selected from H, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy, provided that at least one of R ₂ and R ₃ is H; and Ar is , Pyridyl, isoxazolyl, oxazol-5-yl, pyrazolyl, pyrimidyl, or pyridazinyl, each of these groups being unsubstituted or 1, 2, or 3 independent (C ₁ -C ₄ Optionally substituted by a group which is alkyl, (C ₁ -C ₄ ) alkoxy, halogen, OCF ₃ or CF ₃ ;
48. The compound of claim 46. R ₁ is amino (C ₁ -C ₄ ) alkoxy, mono (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkoxy, di (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) Alkoxy, pyridyl (C ₁ -C ₄ ) alkoxy, hydroxy (C ₁ -C ₄ ) alkoxy, piperazinyl (C ₁ -C ₄ ) alkoxy (where the piperazinyl group is substituted by (C ₁ -C ₄ ) alkyl Or morpholinyl (C ₁ -C ₄ ) alkoxy;
R ₂ and R ₃ are independently selected from H and (C ₁ -C ₄ ) alkyl, provided that at least one of R ₂ and R ₃ is H; and Ar is pyrid-2-yl, iso Oxazol-5-yl, oxazol-5-yl, pyrazol-3-yl, pyrimid-2-yl, or pyridazin-3-yl, each of these groups being unsubstituted or 1 or 2 Optionally substituted by a group which is an independent (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy or halogen;
48. The compound of claim 47. R ₁ is amino (C ₂ -C ₄ ) alkoxy, mono (C ₁ -C ₄ ) alkylamino (C ₂ -C ₄ ) alkoxy, di (C ₁ -C ₄ ) alkylamino (C ₂ -C ₄ ) Alkoxy, pyridyl (C ₂ -C ₄ ) alkoxy, hydroxy (C ₂ -C ₄ ) alkoxy, piperazinyl (C ₂ -C ₄ ) alkoxy (where the piperazinyl group is substituted by (C ₁ -C ₄ ) alkyl may be), or morpholinyl (C ₂ -C ₄₎ alkoxy;
R ₂ is H or methyl; and R ₃ is H;
45. The compound of claim 44. R ₁ is amino (C ₁ -C ₆ ) alkoxy, mono (C ₁ -C ₃ ) alkylamino (C ₁ -C ₆ ) alkoxy, di (C ₁ -C ₃ ) alkylamino (C ₁ -C ₆ ) Alkoxy, pyridyl (C ₁ -C ₆ ) alkoxy, hydroxy (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₆ ) alkoxy, piperazinyl (C ₁ -C ₆ ) alkoxy (here Wherein the piperazinyl group is optionally substituted by (C ₁ -C ₆ ) alkyl), morpholinyl (C ₁ -C ₆ ) alkoxy or thiomorpholinyl (C ₁ -C ₆ ) alkoxy;
R ₂ and R ₃ are independently selected from H, (C ₁ -C ₆ ) alkyl, halogen or (C ₁ -C ₆ ) alkoxy;
The compound of claim 1. R ₁ is amino (C ₁ -C ₄ ) alkoxy, mono (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkoxy, di (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) Alkoxy, pyridyl (C ₁ -C ₄ ) alkoxy, hydroxy (C ₁ -C ₄ ) alkoxy, piperazinyl (C ₁ -C ₄ ) alkoxy (where the piperazinyl group is substituted by (C ₁ -C ₄ ) alkyl Or morpholinyl (C ₁ -C ₆ ) alkoxy;
51. A compound according to claim 50. R ₁ is amino (C ₁ -C ₆ ) alkoxy, mono (C ₁ -C ₃ ) alkylamino (C ₁ -C ₆ ) alkoxy, di (C ₁ -C ₃ ) alkylamino (C ₁ -C ₆ ) Alkoxy, pyridyl (C ₁ -C ₆ ) alkoxy, hydroxy (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₆ ) alkoxy, piperazinyl (C ₁ -C ₆ ) alkoxy (here Wherein the piperazinyl group is optionally substituted by (C ₁ -C ₆ ) alkyl), morpholinyl (C ₁ -C ₆ ) alkoxy, or thiomorpholinyl (C ₁ -C ₆ ) alkoxy;
R ₂ and R ₃ are independently selected from H, (C ₁ -C ₆ ) alkyl, halogen or (C ₁ -C ₆ ) alkoxy;
The compound according to claim 2. R ₁ is amino (C ₁ -C ₄ ) alkoxy, mono (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkoxy, di (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) Alkoxy, pyridyl (C ₁ -C ₄ ) alkoxy, hydroxy (C ₁ -C ₄ ) alkoxy, piperazinyl (C ₁ -C ₄ ) alkoxy (where the piperazinyl group is substituted by (C ₁ -C ₄ ) alkyl Or morpholinyl (C ₁ -C ₆ ) alkoxy;
53. A compound according to claim 52. R ₁ is amino (C ₁ -C ₆ ) alkoxy, mono (C ₁ -C ₃ ) alkylamino (C ₁ -C ₆ ) alkoxy, di (C ₁ -C ₃ ) alkylamino (C ₁ -C ₆ ) Alkoxy, pyridyl (C ₁ -C ₆ ) alkoxy, hydroxy (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₆ ) alkoxy, piperazinyl (C ₁ -C ₆ ) alkoxy (here Wherein the piperazinyl group is optionally substituted by (C ₁ -C ₆ ) alkyl), morpholinyl (C ₁ -C ₆ ) alkoxy, or thiomorpholinyl (C ₁ -C ₆ ) alkoxy;
R ₂ and R ₃ are independently selected from H, (C ₁ -C ₆ ) alkyl, halogen or (C ₁ -C ₆ ) alkoxy;
The compound according to claim 3. R ₁ is amino (C ₁ -C ₄ ) alkoxy, mono (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkoxy, di (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) Alkoxy, pyridyl (C ₁ -C ₄ ) alkoxy, hydroxy (C ₁ -C ₄ ) alkoxy, piperazinyl (C ₁ -C ₄ ) alkoxy (where the piperazinyl group is substituted by (C ₁ -C ₄ ) alkyl Or morpholinyl (C ₁ -C ₆ ) alkoxy;
55. A compound according to claim 54.