CN100584830C - Y-aminobutyric acid energy regulator - Google Patents

Abstract

The present invention relates to the use of benzindazole derivative compounds, salts and solvates thereof in the preparation of medicines for regulating α2 subtype GABA A receptors. The present invention also relates to novel heterocyclic compounds and pharmaceutical compositions comprising said compounds. In addition, the present invention also relates to compounds of formula (I), salts and solvates thereof in the preparation of drugs for the treatment of depression, anxiety disorders, psychiatric disorders, learning or cognitive disorders, sleep disorders, convulsions or seizure disorders or pain the use of.

Description

GABAergic modulators

The present invention relates to the use of compounds for the preparation of medicaments for modulating _α2 subtype GABA _A receptors and for treating individuals afflicted with diseases which can be alleviated by modulating GABA _A receptors with heterocyclic compounds , more specifically, to substituted 7-aryl indazoles, 7-aryl-2H-pyrazolo[3,4-c]pyridines, 7-aryl-2H-pyrazolo[4,3- c] Pyridine and 7-aryl-2H-pyrazolo[4,3-b]pyridine compounds and salts thereof. The present invention also relates to novel heterocyclic compounds and pharmaceutical compositions comprising said compounds.

GABA (4-aminobutyric acid) is the main inhibitory transmitter in the brain, maintaining the balance between the excitation and inhibition of neurons. Three major classes of GABA receptors have been identified: GABA _A , GABA _B and GABA _C receptors. GABA _A and GABA _C receptors are ligand-gated ion channels (LGICs), whereas GABA _B receptors are G-protein coupled receptors. LGIC receptors are heteropentamers composed of α _1-6 , β _1-3 , γ _1-3 , ρ _1-3 , δ, ε, π and θ subunits. Each subunit contains four transmembrane domains. Its N-terminal domain and C-domain are located extracellularly, and the agonist/antagonist binding site is located at the N-terminus. An intracellular circuit exists between the 3rd and 4th transmembrane domains (M. Chabib and GAR Johnston, J. Med. Chem. 2000 43(8):1427-1447).

While several studies will continue to define the composition and anatomical distribution of GABA LGIC receptors, the dominant motif is known to be _2α2β1γ with various α subtypes. A subset of subtypes comprising the _α1 subunit is present in most brain regions and is thought to account for more than 40% of rat GABAA receptors. The set of subtypes comprising α ₂ β _2/3 γ ₂ and α ₃ β _n γ _2/3 oligomers is thought to account for approximately 18% and 17% of the rat GABAA receptors, respectively (RMMcKernan et al., Trend Neurosci 199619:139 -143). The set of subtypes comprising the _α5 subunit is predominantly expressed in the hippocampus and cortex, where it is thought to account for about 4% of rat GABAA receptors. The most common sets of receptor subtypes appear to be the 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 sets (H. Mohler et al., Neuroch. Res. 199520 (5): 631-636).

类物质-结合部位：BZ1和BZ2。已经表明BZ1亚型是包含α₁亚基以及β亚基和γ₂的GABAA受体的药理学等价物。这是最丰富的GABAA受体亚型。两种其它主要群体是α₂βγ₂和α₃β_2/3γ₂亚型。这些亚型一起占总GABAA受体全部数量的大约另外35％。在药理学上，α₂βγ₂和α₃β_2/3γ₂亚型似乎与BZ2亚型等价。迄今为止仍然不清楚这些亚型的生理学作用，因为还未获知具有充分选择性的激动剂或拮抗剂。All known GABAA receptors contain many different regulatory sites, one of which is the benzodiazepine (BZ) Binding site. Other regulatory sites include picrotoxin, barbiturates, neuroactive steroids, and allosteric sites of ethanol. The BZ binding site is the most studied GABAA receptor regulatory site and is the site through which anxiolytics such as diazepam act. Early radioligand-binding studies indicated the presence of two different benzodiazepines

Substance-like binding sites: BZ1 and BZ2. The BZ1 subtype has been shown to be the pharmacological equivalent of the GABAA receptor comprising the _α1 subunit as well as the β and _γ2 subunits. This is the most abundant GABAA receptor subtype. Two other major groups are the _α2βγ2 and _{α3β2 / 3γ2 subtypes} . Together these subtypes account for approximately another 35% of the total number of total GABA A receptors. Pharmacologically, the _α2βγ2 and _{α3β2 / 3γ2} subtypes appear to be _equivalent to the BZ2 subtype. The physiological role of these isoforms has so far remained unclear, since no sufficiently selective agonists or antagonists are known.

类物质是首先用于临床的GABAA受体调节剂，并且是最常见的被开具用于焦虑、抑郁和其它精神病学病症的药物和作为抗惊厥剂的药物。具有相对温和副作用的苯并二氮杂

类物质成为了副作用更强的巴比妥类物质的替代选择。不幸地是，许多早期的苯并二氮杂

类物质具有相对有限的亚型选择性，可导致镇静、依赖性、认知缺损、共济失调、乙醇作用的增强、耐受性和脱瘾性脑综合征。Barbiturates and benzodiazepines

GABAA receptor modulators were the first to be used clinically and are the most commonly prescribed drugs for anxiety, depression and other psychiatric conditions and as anticonvulsants. Benzodiazepines with relatively mild side effects

Barbiturates have become an alternative to barbiturates with stronger side effects. Unfortunately, many early benzodiazepines

Substances with relatively limited subtype selectivity can cause sedation, dependence, cognitive impairment, ataxia, enhanced ethanol effects, tolerance, and withdrawal brain syndrome.

Advances in genetics and molecular biology have provided finer receptor subtype-selective probes and offered promising prospects for the discovery of more selective substances. Receptors containing _α1 , _α2 , _α3 , or _α5 subunits have been classified as diazepam-sensitive receptors, whereas receptors containing _α4 or _α6 subunits are classified as diazepam-insensitive sex receptors. In particular the _α1 subtype has been linked to sedation, and _α1- selective ligands have potential as sedatives (RM McKernan et al., Nature Neurosci. 2000 3(6):587-592). Hypnotic/sedative compounds that bind preferentially to the _α1 subtype have been identified (DJ Sanger and H. Depoortere, CNS Drug Reviews, 1998 47(5):323-340). However, for anxiolytics, a sedative effect is undesirable.

部位结合但对GABA活性几乎没有或者没有影响、但是能阻断作用于这一部位的GABAA受体激动剂或反相激动剂的作用的第三类化合物被称为拮抗剂。作用于苯并二氮杂

部位的激动剂表现出抗焦虑、镇静和催眠作用，而作为反相激动剂作用于这一部位的化合物引起致焦虑(anxiogenic)、增强认知和促惊厥(proconvulsant)作用。optionally with benzodiazepines Compounds that bind to and enhance the ability of GABA to open a GABAA receptor channel at the site or other allosteric site are agonists (or positive allosteric modulators) of the GABA receptor. Compounds that interact with the allosteric site but negatively modulate the action of GABA are called inverse agonists (negative allosteric modulators). Inverse agonists reduce the ability of GABA to open receptor channels. optionally with benzodiazepines

A third class of compounds that bind at this site but have little or no effect on GABA activity, but block the action of agonists or inverse agonists of GABAA receptors acting at this site, are called antagonists. Acts on benzodiazepines

Agonists at this site exhibit anxiogenic, sedative and hypnotic effects, whereas compounds acting at this site as inverse agonists cause anxiogenic, cognitive enhancing and proconvulsant effects.

The α1 _- selective GABAA receptor agonists alpitant and zolpidem are clinically prescribed as hypnotic agents, further suggesting that at least some of the sedative effects associated with known anxiolytics are via GABAA containing the _α1 subunit receptor mediated. Thus, GABA _A receptor agonists that selectively interact with the _α2 and/or _α3 subunit more selectively than the _α1 subunit should retain anxiolytic activity with a reduced propensity to cause sedation. In addition, substances that are antagonists or inverse agonists for the _α1 subtype may antagonize the sedative or hypnotic effects of _α1 modulators.

等人，Science 2000 290：131-134)；但是，α₃-选择性反相激动剂似乎是致焦虑剂和促惊厥剂(I.J.Collins等人，WO 9855480)。因为α₂以及可能地α₃和α₅选择性配体具有调节(BZ2)部位同时不活化催眠镇静部位(BZ1)的可能性，所以它们可能提供一类新的非镇静性抗焦虑剂。其它非-BZ选择性α₂GABA调节剂可能也会表现出没有许多不希望的作用的抗焦虑性质。Selective _α2 and _α3 ligands are more difficult to identify, and there is often cross-reactivity between these receptors. Several compounds have been reported that are ten to a hundred times more selective for α2 _/3 than _α1 (see, eg, WR Carling et al., WO 0044752). Experiments with point-mutated mouse lines suggest that the _α2 , but not the _α3 , isoform is responsible for the anxiolytic activity (U. Rudolph et al., Trends Pharmacol. Sci. 2001 22(4): 188-194; K.

et al., Science 2000 290:131-134); however, α ₃ -selective inverse agonists appear to be anxiogenic and proconvulsant (IJ Collins et al., WO 9855480). Since _α2 and possibly _α3 and _α5 selective ligands have the potential to modulate the (BZ2) site while not activating the hypnotic-sedative site (BZ1), they may offer a new class of non-sedating anxiolytics. Other non-BZ selective [alpha] _2GABA modulators may also exhibit anxiolytic properties without many of the undesired effects.

The _α5 subtype is primarily located in the hippocampus and is thought to be involved in learning and cognition. Approximately 20% of hippocampal GABA receptors contain the _α5 subtype. The hippocampus is an area of the brain associated with learning and memory. Inverse _α5 agonists improve memory and cognition in animal behavioral models; however, the anxiogenic and convulsive effects of nonselective compounds limit their application. Selective _α5 inverse agonists may be very useful in the treatment of Alzheimer's disease and related dementias (MS Chambers et al., J. Med. Chem. 2003 46(11):2227-40).

Selective ligands for the GABA _A receptor of the present invention are useful in the treatment and/or prevention of anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, including social phobia phobias, obsessive-compulsive disorders, stress disorders including post-traumatic stress disorder (stress disorder) and acute stress disorder, and generalized anxiety disorder or psychoactive substance-induced anxiety disorders; depression or bipolar disorders such as Single or recurrent episodes of major depressive disorder, dysthymia, bipolar I and bipolar mania II; schizophrenia; learning and cognitive disorders such as Alzheimer's disease and ADHD; sleep disorders and circadian rhythm disorders, such as those of patients affected by jet lag or the effects of shift work; convulsive or seizure disorders, such as epilepsy and pain.

Other neurotransmitter systems have been studied and drugs that modulate serotonergic neurotransmission have shown promise in the treatment of anxiety-related disorders. Recently, drugs commonly used as antidepressants such as buspirone (a partial agonist of the 5HT1A receptor and a serotonin reuptake inhibitor) have been described. GABA _A selective ligands can potentiate the effects of certain other CNS active compounds. There is evidence that selective serotonin reuptake inhibitors (SSRIs) exhibit higher antidepressant activity when combined with GABA _A- selective ligands than when used alone.

Certain indazole compounds of the present invention have been disclosed as antagonists of the corticotropin releasing factor receptor in US Patent Application Serial No. 60/431,168, which is incorporated herein by reference in its entirety.

The present invention relates to pharmaceutical compositions and the use of compounds in the preparation of medicines for the prevention or treatment of diseases that can be relieved by positive allosteric modulators of _GABAA receptors, wherein the positive allosteric modulators of _GABAA receptors Constitutive modulators can selectively regulate the _α2 subtype in the presence of the _α1 subtype, said prevention or treatment comprising administering an effective amount of a compound of formula I, wherein:

R ¹ is -NR ^a R ^b , -CR ^c R ^d R ^e , CHR ^f R ^g , CO ₂ R ^a , -C(O)NR ^a R ^b , hydrogen, C _2-10 alkynyl, C _1-6 Haloalkyl, C _1-10 cycloalkenyl, halogen, cyano, -C(=Z)R ^o , -X ² C(=O)X ¹ R ^f , NR ^f SO ₂ R ^o , -N[C( =O)OR ^m ] ₂ , -N=CR ^f NR ^j R ^k , -S(O) _m R ^h , CONR ⁱ NHR ^o , aryl, heteroaryl, wherein each aryl or heteroaryl is optionally Substituted by one or more substituents independently selected from C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfonyl, halogen , C _1-6 haloalkyl, cyano, nitro, -C(O)NR ^a 'R ^b ' and -NR ^a 'R ^b ', wherein R ^a ' and R ^b ' are each independently selected from hydrogen, C _1-9 alkyl and _C1-9 alkylcarbonyl, or ^R is C in which 2 or 3 non-adjacent carbon atoms in the alkyl chain may be replaced by -O-, -S- or ^-NRf _1-10 alkyl;

R ² is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl; C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-3 alkoxycarbonyl -C _1-3 alkyl; C _1-6 alkylcarbonyl, C _1-6 alkylsulfonyl, aryl or aryl-C _1-6 alkyl, wherein the aryl or arylalkyl is any optionally substituted by one or more substituents independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and halogen;

R ³ is aryl or heteroaryl, each of which is optionally substituted by one or more substituents independently selected from C _1-6 alkyl, C _1-6 alkoxy, C _{1-6 6} alkylthio, C _1-6 alkylsulfonyl, aminosulfonyl, C _1-10 monoalkylaminosulfonyl, C _1-10 dialkylaminosulfonyl, halogen, C _1-6 haloalkyl, cyanide Base, nitro and -NR ^a "R ^b ", wherein R ^a "and R ^b " are each independently selected from hydrogen, C _1-9 alkyl and C _1-9 alkylcarbonyl;

R ⁴ is C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, cyano, nitro, halogen, -NR ^a "R ^b " and aryl, which is optionally replaced by C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkyl-S(O) _m - (where m is 0 to 2), aminosulfonyl, C _{1 -10} monoalkylaminosulfonyl, C _1-10 dialkylaminosulfonyl, halogen, C _1-6 haloalkyl, cyano, nitro and -NR ^a "R ^b ", wherein R ^a "and R ^b " each independently selected from hydrogen, C _1-9 alkyl and C _1-9 alkylcarbonyl;

R ^a and R ^b are each independently selected from hydrogen, C _1-9 alkyl, C _1-10 hydroxyalkyl, C _1-6 alkoxyalkyl, C _1-6 alkylthioalkyl, C _{1-6 10} carboxyalkyl, acyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, di-C _3-6 cycloalkyl C _1-3 alkyl, C _1-6 Heteroalkyl, C _1-10 aminoalkyl, C _1-10 aminocarbonylalkyl, C _1-6 cyanoalkyl, C _5-8 heterocyclyl, C _5-8 heterocyclyl-C _1-6 Alkyl, aryl, aryl-C _1-6 alkyl, heteroaryl, heteroaryl-C _1-6 alkyl, phenyl-C _1-6 alkyl, diphenyl-C _1-6 alkane and C _1-3 alkyl substituted by both C _3-6 cycloalkyl and phenyl, wherein said cycloalkyl, phenyl, aryl or heteroaryl are each optionally replaced by one or more independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, amino, C _1-10 alkylamino, C _1-10 dialkylamino, C _1-10 hydroxy Substituents of alkyl, cyano, acylamino, C _1-10 alkylsulfonyl, C _1-10 alkylsulfonyloxy and halogen, and each of said amino groups is optionally monosubstituted by alkyl or two substitutions; or

R ^a and R ^b together with the nitrogen to which they are attached form a compound selected from pyrrolidine, piperidine, homopiperidine, tetrahydropyridine, 1,2,3,4-tetrahydroquinoline, 1,2,3 , the heterocyclyl or heteroaryl ring of 4-tetrahydroisoquinoline, tetrahydropyrimidine, hexahydropyrimidine, pyrazolidine, piperazine, morpholine, imidazoline, pyrrole, pyrazole and imidazole, wherein said Each ring is optionally substituted by one or more substituents selected from the group consisting of hydroxy, oxo, alkyl, C _1-10 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkoxy Alkyl, C _1-10 aminoalkyl, acyl, acylamino, aminocarbonyl, C _1-10 aminocarbonylalkyl, aminocarbonylamino, aminosulfonyl, C _1-10 alkylsulfonylamino, aminosulfonyl Amino and phenyl, wherein each of said phenyl is optionally selected from one or more of C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, amino, C _{1 -10} alkylamino, C _1-10 dialkylamino and halogen groups are substituted, and each of said amino groups is optionally monosubstituted or disubstituted by alkyl, or contained in pyrrolidinyl, piperidinyl , morpholinyl or piperazinyl;

R ^c is hydrogen, hydroxyl, C _1-6 alkoxy or -NR ^a '"R ^b '";

R ^d and R ^e are each independently selected from hydrogen, C _1-9 alkyl, C _1-10 hydroxyalkyl, C _1-6 alkoxyalkyl, C _1-6 alkylthioalkyl, C _{1-6 6} Heteroalkyl, C _5-8 Heterocyclyl, C _5-8 Heterocyclyl-C _1-6 Alkyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkyl-C _1-3 Alkyl , Di-C _3-6 cycloalkyl-C _1-3 alkyl, aryl, aryl-C _1-6 alkyl, heteroaryl, heteroaryl-C _1-6 alkyl, phenyl-C _1-6 alkyl, diphenyl-C _1-3 alkyl and C _1-3 alkyl substituted by both C _3-6 cycloalkyl and phenyl, wherein the cycloalkyl, phenyl, Each of the aryl or heteroaryl is optionally replaced by one or more independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, amino, C _1-10 alkylamino , C _1-10 dialkylamino and halogen substituent substitution; or,

R ^c and R ^d together form a group selected from C _1-6 alkylene, C _1-6 heteroalkylene, C _3-6 cycloalkylene, C _3-6 cycloalkyl-alkylene, C _{3- 6} cycloalkyl-C _1-3 alkyl-alkylene, C _3-6 heterocyclylene, C _3-6 heterocyclyl-C _1-3 alkylene, C _3-6 heterocyclyl-C _1-6 alkyl-C _1-3 alkylene, aryl _- C 1-3 alkylene, aryl-C _1-3 alkyl-alkylene, heteroaryl-C _1-3 alkylene and a divalent group of heteroarylalkyl-C _1-3 alkylene, wherein each of said cycloalkyl, aryl or heteroaryl is optionally selected by one or more independently selected from C _1- Substituents of ₆ alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, amino, C _1-10 alkylamino, C _1-10 dialkylamino and halogen; or,

R and ^R together with the carbon to which they ^are attached form a _C3-8 cycloalkyl or heterocyclyl ring;

R ^f is hydrogen or C _1-10 alkyl;

R ^g is C _2-10 alkenyl, -NHNH ₂ , cyano, -OC(=O)R ^f , -S(O) _m R ^h or -X ² (C=O)X ¹ R ^f ;

R ^h is C _1-6 alkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, NR ^j R ^k or phenyl, which is optionally substituted by one or more substituents, said substituted The group is independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, amino, C _1-10 alkylamino, C _1-10 dialkylamino, C _1-10 Hydroxyalkyl, cyano, acylamino, C _1-10 alkylsulfonyl, C _1-10 alkylsulfonyloxy and halogen;

R ⁱ is R ^o , hydrogen, C _3-6 cycloalkyl or C _3-6 cycloalkyl-C _1-3 alkyl;

R ^j and R ^k (i) are independently hydrogen, C _1-6 alkyl, C _1-6 heteroalkyl, or (ii) together with the nitrogen atom to which they are attached, are C _4-6 alkylene or ( CH ₂ ) ₂ X ¹ (CH ₂ ) ₂ ;

R ^m is C _1-10 alkyl;

R ^o is C _1-6 alkyl, C _2-6 alkenyl or phenyl, which is optionally substituted by one or more substituents independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, amino, C _1-6 C _1-10 alkylamino, C _1-6 dialkylamino, C _1-10 hydroxyalkyl, cyano, acylamino , C _1-10 alkylsulfonyl, C _1-10 alkylsulfonyloxy and halogen;

^X1 and ^X2 are independently -O- or ^-NRf1- , where in each occurrence, ^Rf1 is an independently selected ^Rf group, or if ^Rf and ^Rf1 are attached to the same nitrogen atom , then R ^f and R ^f1 can also be C _4-6 alkylene or (CH ₂ ) ₂ X ¹ (CH ₂ ) ₂ together;

Z is O or NOR ^o ;

m is an integer from 0 to 2;

n is an integer from 0 to p, where p=3 minus the number of A1, A2 and A3 which are nitrogen;

R ^a '" and R ^b '" are each independently selected from hydrogen, C _1-9 alkyl, C _1-10 hydroxyalkyl, C _1-6 alkoxyalkyl, C _1-6 alkylthioalkyl , C _1-10 carboxyalkyl, acyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, di-C _3-6 cycloalkyl-C _1-3 alkyl , C _1-6 heteroalkyl, C _1-10 aminoalkyl, C _1-10 aminocarbonylalkyl, C _1-6 cyanoalkyl, C _5-8 heterocyclyl, C _5-8 heterocyclyl -C _1-6 alkyl, aryl, aryl _- C _1-6 alkyl, heteroaryl, heteroaryl-C 1-6 alkyl, phenyl-C _1-6 alkyl, diphenyl- C _1-3 alkyl and C _1-3 alkyl substituted by both C _3-6 cycloalkyl and phenyl, wherein said cycloalkyl, phenyl, aryl or heteroaryl are each optionally Substituted by one or more substituents independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, amino, C _1-10 alkylamino, C _1-10 dialkylamino, C _1-10 hydroxyalkyl, cyano, acylamino, C _1-10 alkylsulfonyl, C _1-10 alkylsulfonyloxy and halogen, and each of the amino groups optionally monosubstituted or disubstituted by C _1-10 alkyl; or,

R ^a '" and R ^b '" together with the nitrogen to which they are attached form a group selected from pyrrolidine, piperidine, homopiperidine, tetrahydropyridine, 1,2,3,4-tetrahydroquinoline, 1,2, Heterocyclic or heteroaryl rings of 3,4-tetrahydroisoquinoline, tetrahydropyrimidine, hexahydropyrimidine, pyrazolidine, piperazine, morpholine, imidazoline, pyrrole, pyrazole and imidazole, wherein Each ring of is optionally substituted by one or more substituents selected from the group consisting of hydroxyl, oxo, C _1-10 alkyl, C _1-10 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkoxyalkyl, C _1-10 aminoalkyl, acyl, acylamino, aminocarbonyl, C _1-10 aminocarbonylalkyl, aminocarbonylamino, aminosulfonyl, C _1-10 alkylsulfonyl Amino, aminosulfonylamino and phenyl, wherein each of said phenyl is optionally replaced by one or more independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy , amino, C _1-10 alkylamino, C _1-10 dialkylamino and halogen, and each of said amino groups is optionally monosubstituted or disubstituted by C _1-10 alkyl, or is substituted by Contained in pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl;

A ¹ , A ² and A ³ are independently C or N, provided that at least one of A ¹ , A ² and A ³ is CH or CR ⁴ ; and,

Individual isomers, racemic or non-racemic mixtures, solvates, hydrates or pharmaceutically acceptable salts thereof.

The present invention also relates to novel compounds of formula I useful for the prophylaxis or treatment of conditions which can be alleviated by positive allosteric modulators of GABA _A receptors, said prophylaxis or treatment comprising administering an effective amount of a compound of formula I.

In one embodiment of the present invention, there are provided compounds useful for the prevention or treatment of conditions that can be alleviated by administering positive allosteric modulators of _GABAA receptors, said compounds including compounds of formula I, wherein ^R is CHR ^f R ^g , C _2-10 alkynyl, C _1-6 haloalkyl, halogen, cyano, -C(=Z)R ^o , -X ² C(=O)X ¹ R ^f , NR ^f SO ² R ^o , -N[C(=O)OR ^m ] ₂ , -N=CR ^f NR ^j R ^k , -S(O) _m R ^h , CONR ⁱ NHR ^o or 2 or 3 in the alkyl chain C _1-10 alkyl whose non-adjacent carbon atoms may be replaced by -O-, -S- or -NR ^f ; R ² is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-3 alkoxycarbonyl-C _1-3 alkyl, C _1-6 haloalkyl or aryl-C _1-6 alkyl; and, R ³ , R ⁴ , R ^a ″, R ^b ″, R ^f , R ^f1 , R ^g , R ^h , R ⁱ , R ^j , R ^k , R ^m , R ^o , X ¹ , X ² , Z, A ¹ , A ² , A ³ , m, n are as defined above.

In another embodiment of the present invention, there are provided compounds useful for preventing or treating conditions that can be alleviated by administering positive allosteric modulators of _GABAA receptors, said compounds including compounds of formula I, wherein R ¹ is CHR ^f R ^g , C _2-10 alkynyl, C _1-6 haloalkyl, halogen, cyano, -C(=Z)R ^o , -NR ^f SO ₂ R ^o , -S(O) _m R ^o , CONR ⁱ NHR ^o or C _1-10 alkyl in which 2 or 3 non-adjacent carbon atoms in the alkyl chain may be replaced by -O-, -S- or -NR ^f ; R ² is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-3 alkoxycarbonyl-C _1-3 alkyl, C _1-6 Haloalkyl or aryl-C _1-6 alkyl; and, R ^a ", R ^b ", R ³ , R ⁴ , R ^f , R ^g , R ⁱ , R ^j , R ^m , R ^o , Z, A ¹ , A ² , A ³ , m, n are as defined above.

In another embodiment of the present invention, there are provided compounds useful for the prevention or treatment of conditions that can be alleviated by administration of positive allosteric modulators of _GABAA receptors, said compounds including compounds of formula I, wherein R ¹ is CHR ^f R ^g , C _2-10 alkynyl, C _1-6 haloalkyl, halogen; R ² is hydrogen, C _1-6 alkyl; R ³ is optionally substituted aryl; and, R ^4. R ^a ″, R ^b ″, R ^f , R ^h , R ^g , R ^j , R ^k , R ^m , R ^o , X ¹ , X ² , A ¹ , A ² , A ³ , m, n are as above defined in the text.

In another embodiment of the present invention, there are provided compounds useful for the prevention or treatment of conditions that can be alleviated by administration of positive allosteric modulators of _GABAA receptors, said compounds including compounds of formula I, wherein R ¹ is -X ² C(=O)X ¹ R ^f or -S(O) _m R ^h ; R ² is hydrogen or C _1-6 alkyl; R ³ is optionally substituted aryl; X ² is NR ^f1 ; m is 2; and, R ⁴ , R ^a ″, R ^b ″, R ^f , R ^f1 , R ^h , R ^j , R ^k , R ^o , X ¹ , A ¹ , A ² , A ³ , n are as defined above.

In another embodiment of the present invention, there are provided compounds useful for the prevention or treatment of conditions that can be alleviated by administration of positive allosteric modulators of _GABAA receptors, said compounds including compounds of formula I, wherein R ¹ is CHR ^f R ^g ; R ^g is -X ² C(=O)X ¹ R ^f ; R ² is hydrogen or C _1-6 alkyl; R ³ is optionally substituted aryl; and, R ^4. R ^a ", R ^b ", R ^f , R ^f1 , X ¹ , X ² , A ¹ , A ² , A ³ , n are as defined above.

In another embodiment of the present invention, there is provided the use of a compound of formula I in the preparation of a medicament for the prevention or treatment of a condition that can be alleviated by administering a positive allosteric modulator of _GABAA receptor, wherein in said formula In compound I, R ¹ , R ² , R ³ , R ⁴ , R ^a , R ^a ′, R a ″, R ^a ′″, R ^b , R ^b ′, R ^{b ″} , R ^b ′″, R ^c , R ^d , R ^e , R ^f , R ^f1 , R ^g , R ^h , R ⁱ , R ^j , R ^k , R ^m , R ^o , X ¹ , X ² , Z, A ¹ , A ² , A ³ , m, n are as defined above.

In another embodiment of the present invention, there is provided the use of a compound of formula I in the preparation of a medicament for the prevention or treatment of a condition that can be alleviated by administering a positive allosteric modulator of _GABAA receptor, wherein in said formula In compound I, R ¹ is -NR ^a R ^b , -CR ^c R ^{d Re} , CHR ^f R ^g , CO ₂ R ^a , -C(O)NR ^a R ^b ; hydrogen, C _2-10 alkynyl, C _1-6 haloalkyl, C _1-10 cycloalkenyl, halogen, cyano, -C(=Z)R ^o , -NR ^f SO ₂ R ^o , -S(O) _m R ^o , CONR ⁱ NHR ^o , aryl, heteroaryl, wherein each aryl or heteroaryl is optionally substituted by one or more substituents independently selected from C _1-6 alkyl, C _1-6 alkoxy , C _1-6 alkylthio, C _1-6 alkylsulfonyl, halogen, C _1-6 haloalkyl, cyano, nitro, -C(O)NR ^a 'R ^b 'and -NR ^a 'R ^b ', wherein R ^a ' and R ^b ' are each independently selected from hydrogen, C _1-9 alkyl and C _1-9 alkylcarbonyl, or R ¹ is wherein 2 or 3 of the alkyl chains are not adjacent C _1-10 alkyl whose carbon atoms may be replaced by -O-, -S- or -NR ^f ; R ² is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 ring Alkyl-C _1-3 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkylsulfonyl, aryl or aryl-C _1-6 alkyl, wherein the aryl or aryl alkane R is optionally substituted by one or more substituents independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and halogen; ^R is C _2-10 alkenyl and, R ³ , R ⁴ , R ^a , R ^a ′, R ^{a ″, R a ′} ″, R ^b , R ^{b ′} , R ^b ″, R ^b ′″, R ^c , R ^d , R ^e , R ^f , R ^f1 , R ⁱ , R ^o , Z, A ¹ , A ² , A ³ , m, n are as defined above.

In another embodiment of the present invention, there is provided the use of a compound of formula I in the preparation of a medicament for the prevention or treatment of a condition that can be alleviated by administering a positive allosteric modulator of _GABAA receptor, wherein in said formula In compound I, R ¹ is -NR ^a R ^b , -CR ^c R ^{d Re} , CHR ^f R ^g , CO ₂ R ^a , -C(O)NR ^a R ^b , hydrogen, C _2-10 alkynyl, C _1-6 haloalkyl, C _1-10 cycloalkenyl, halogen, cyano, -C(=Z)R ^o , -NR ^f SO ₂ R ^o , -S(O) _m R ^o , CONR ⁱ NHR ^o , or R ¹ is C _1-10 alkyl in which 2 or 3 non-adjacent carbon atoms in the alkyl chain may be replaced by -O-, -S- or -NR ^f ; R ^c is hydrogen, hydroxyl, C _1-6 alkoxy or -NR ^a '"R ^b '"; R ^d and R ^e are each independently selected from hydrogen, C _1-9 alkyl, C _1-10 hydroxyalkyl, C _1-6 alkane Oxyalkyl, C _1-6 alkylthioalkyl, C _3-6 cycloalkylC _1-3 alkyl; or R ^c and R ^d together form a group selected from C _1-6 alkylene, C _1- A divalent group of ₆ heteroalkylene, C _3-6 cycloalkylene, C _3-6 cycloalkyl-alkylene; or R ^d and R ^e together with the carbon to which they are attached form C _3-8 cycloalkyl or heterocyclyl ring; R ^g is C _2-10 alkenyl; and, R ² , R ³ , R ⁴ , R ^a , R ^a ″, R ^a ′″, R ^b , R ^b ″, R ^b '", R ^f , R ⁱ , R ^o , Z, A ¹ , A ² , A ³ , m, n are as defined above.

In another embodiment of the present invention, there is provided the use of a compound of formula I in the preparation of a medicament for the prevention or treatment of a condition that can be alleviated by administering a positive allosteric modulator of _GABAA receptor, wherein in said formula In compound I, R ¹ is -X ² C(=O)X ¹ R ^f or -S(O) _m R ^h ; R ² is hydrogen or C _1-6 alkyl; R ³ is optionally substituted Aryl; X ² is NR ^f1 ; m is 2; and, R ⁴ , R ^a ″, R ^b ″, R ^f , R ^f1 , Rh , R ^j , R ^k , ^{R o ,} X ¹ , A ¹ , A ² , A ³ , n are as defined above.

In another embodiment of the present invention, there is provided the use of a compound of formula I in the preparation of a medicament for the prevention or treatment of a condition that can be alleviated by administering a positive allosteric modulator of _GABAA receptor, wherein in said formula In compound I, R ¹ is CHR ^f R ^g ; R ^g is -X ² C(=O)X ¹ R ^f ; R ² is hydrogen or C _1-6 alkyl; R ³ is optionally substituted aryl and, R ⁴ , R ^a ″, R ^b ″, R ^f , R ^f1 , X ¹ , X ² , A ¹ , A ² , A ³ , n are as defined above.

In another embodiment of the present invention, the compound of formula _I is provided for preventing or treating depression, anxiety, bipolar manic disorder, schizophrenia, learning or Cognitive disorders, convulsions, seizures or pain in medicine, wherein in the compound of formula I, R ¹ , R ² , R ³ , R ⁴ , R ^a , R ^a ′, R ^a ″, R ^a ′″, R ^b , R ^b ′, R ^b ″, R ^b ′″, R ^c , R ^d , R ^e , R f , R ^f1 , R ^g , R ^h , R ⁱ , ^{R j ,} R ^k , R ^m , R ^o , X ¹ , X ² , Z, A ¹ , A ² , A ³ , m, n are as defined above.

In another embodiment of the present invention, there is provided a compound of formula I in the preparation of a positive allosteric modulator of the _GABAA receptor and a selective serotonin reuptake inhibitor, a corticotropin releasing factor antagonist or Use of phosphodiesterase IV inhibitors to prevent or treat depression, anxiety, bipolar mania, schizophrenia, learning or cognitive impairment, convulsions, seizures or pain, wherein the formula In compound I, R ¹ , R ² , R ³ , R ⁴ , R ^a , R ^a ′, R a ″, R ^a ′″, R ^b , R ^b ′, R ^{b ″} , R ^b ′″, R ^c , R ^d , R ^e , R ^f , R ^f1 , R ^g , R ^h , R ⁱ , R ^j , R ^k , R ^m , R ^o , X ¹ , X ² , Z, A ¹ , A ² , A ³ , m, n are as defined above.

In another embodiment of the present invention, it is provided that the compound of formula I can be inhibited by administering a selective positive allosteric modulator of the _α2 subtype of the GABA _A receptor relative to the _α1 subtype in the preparation of prophylaxis or treatment. Use in a medicament for a relieved condition, said medicament comprising wherein R ¹ , R ² , R ³ , R ⁴ , R ^a , R a ′, R ^a ″, R ^{a ′} ″, R ^b , R ^b ′, R ^b ″, R ^b ′″, R ^c , R ^d , R ^e , R ^f , R ^f1 , R ^g , R ^h , R ⁱ , R ^j , R ^k , R ^m , R ^o , X ¹ , X ² , Z, A ¹ , A ² , A ³ , m, n are as defined above for the compound of formula I.

In another embodiment of the present invention, there is provided a pharmaceutical composition for preventing or treating a condition alleviated by a positive allosteric modulator of _GABAA receptor, said composition comprising a therapeutically effective amount of a compound of formula I and At least one diluent, excipient or carrier mixed with it, in the compound of formula I, R ¹ is CHR ^f R ^g , C _2-10 alkynyl, C _1-6 haloalkyl, halogen, cyano radical, -C(=Z)R ^o , -X ² C(=O)X ¹ R ^f , NR ^f SO ₂ R ^o , -N[C(=O)OR ^m ] ₂ , -N=CR ^f NR ^j R ^k ; -S(O) _m R ^h , CONR ⁱ NHR ^o or C in which 2 or 3 non-adjacent carbon atoms in the alkyl chain may be replaced by -O-, -S- or -NR ^f _1-10 alkyl; R ² is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-3 alkoxycarbonyl- C _1-3 alkyl, C _1-6 haloalkyl or aryl-C _1-6 alkyl; and, R ³ , R ⁴ , R ^a ″, R ^b ″, R ^f , R ^f1 , R ^g , R ^h , R ⁱ , R ^j , R ^k , R ^m , R ^o , X ¹ , X ² , Z, A ¹ , A ² , A ³ , m, n are as defined above.

In another embodiment of the present invention, there is provided a pharmaceutical composition for preventing or treating a condition alleviated by a positive allosteric modulator of _GABAA receptor, said composition comprising a therapeutically effective amount of a compound of formula I and At least one diluent, excipient or carrier mixed with it, in the compound of formula I, R ¹ is CHR ^f R ^g , C _2-10 alkynyl, C _1-6 haloalkyl, halogen, cyano radical, -C(=Z)R ^o , -NR ^f SO ₂ R ^o , -S(O) _m R ^o , CONR ⁱ NHR ^o or wherein 2 or 3 non-adjacent carbon atoms in the alkyl chain can C _1-10 alkyl replaced by -O-, -S- or -NR ^f ; R ² is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-3 alkoxycarbonyl-C _1-3 alkyl; C _1-6 haloalkyl or aryl-C _1-6 alkyl; and, R ³ , R ⁴ , R ^a " , R ^b ", R ^f , R ^g , R ⁱ , R ^j , R ^m , R ^o , Z, A ¹ , A ² , A ³ , m, n are as defined above.

In another embodiment of the present invention, there is provided a pharmaceutical composition for preventing or treating a condition alleviated by a positive allosteric modulator of _GABAA receptor, said composition comprising a therapeutically effective amount of a compound of formula I and Selective serotonin reuptake inhibitor or corticotropin releasing factor antagonist or phosphodiesterase IV inhibitor, the combination is mixed with at least one diluent, excipient or carrier, in said formula I In the compound, R ¹ is CHR ^f R ^g , C _2-10 alkynyl, C _1-6 haloalkyl, halogen, cyano, -C(=Z)R ^o , -X ² C(=O)X ¹ R ^f , NR ^f SO ₂ R ^o , -N[C(=O)OR ^m ] ₂ , -N=CR ^f NR ^j R ^k ; -S(O) _m R ^h , CONR ⁱ NHR ^o or the alkyl chain C _1-10 alkyl in which 2 or 3 non-adjacent carbon atoms may be replaced by -O-, -S- or -NR ^f ; R ² is hydrogen, C _1-6 alkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _1-3 alkoxycarbonyl-C _1-3 alkyl; C _1-6 haloalkyl or aryl-C _1-6 alkane and, R ³ , R ⁴ , R ^a ″, R ^b ″, R ^f , R ^f1 , R ^g , R ^h , R i , R ^j , R ^k , R ^m , ^{R o ,} X ¹ , X ² , Z, A ¹ , A ² , A ³ , m, n are as defined above.

Unless otherwise indicated, the following terms used in this application, including the specification and claims, have the definitions given below.

As used herein, the phrase "a" entity refers to one or more entities; for example, a compound refers to one or more compounds or at least one compound. Accordingly, the terms "a", "one or more" and "at least one" are used interchangeably herein.

The phrase "as defined above" refers to the definition provided for the first time in the detailed description of the invention.

As used herein, unless otherwise specified, the term "alkyl" refers to an unbranched or branched saturated monovalent monovalent group consisting solely of carbon and hydrogen atoms having from 1 to 10 carbon atoms, inclusive. Hydrocarbyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, pentyl, n-hexyl and specifically disclosed in the Examples of those. The term "lower alkyl" lower alkyl refers to an alkyl group having 1 to 6 carbon atoms.

The term "alkenyl" as used herein denotes an unsubstituted hydrocarbon chain group having 2 to 10 carbon atoms and having one or two olefinic double bonds, preferably one olefinic double bond. As used herein, "C _2-10 alkenyl" refers to an alkenyl group consisting of 2 to 10 carbons. Examples thereof are vinyl, 1-propenyl, 2-propenyl (allyl) or 2-butenyl (crotyl).

As used herein, unless otherwise specified, the term "alkylene" refers to an unbranched or branched chain saturated divalent hydrocarbon radical consisting only of carbon and hydrogen atoms having 1 to 10 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, 2-methylethylene, 3-methylpropylene, 2-ethylethylene, pentylene, Hexyl and those specifically disclosed in the Examples.

The term "alkynyl" as used herein denotes an unbranched or branched group having 2 to 10 carbon atoms, preferably 2 to 4 carbon atoms, and having one or possibly two triple bonds, preferably one triple bond. chain of hydrocarbon chain groups. As used herein, "C _2-10 alkenyl" refers to an alkenyl group consisting of 2 to 10 carbons. Examples thereof are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl.

The term "alkoxy" as used herein refers to the group -OR, where R is lower alkyl as defined herein. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, isopropoxy, and those specifically disclosed in the Examples.

The terms "alkoxycarbonyl" and "aryloxycarbonyl" as used herein represent a group of formula -C(=O)OR, wherein R is alkyl or aryl, respectively, and alkyl and aryl are as defined herein.

The terms "alkylsulfonyl" and "arylsulfonyl" as used herein mean a group of formula -S(=O) _2R , wherein R is alkyl or aryl respectively and alkyl and aryl are as defined herein . The terms "alkylsulfonyloxy" and "arylsulfonyloxy" as used herein mean a group of formula -OS(=O) ₂ R, where R is alkyl or aryl respectively and alkyl and aryl as defined herein.

The term "acylamino" as used herein denotes a group of formula -NHC(=O)R, wherein R is hydrogen or lower alkyl as defined herein.

The terms "alkoxycarbonylalkyl" and "aryloxycarbonylalkyl" as used herein refer to the group R'R", wherein R' is alkoxycarbonyl or aryloxycarbonyl and R" is as defined herein Alkylene and the point of attachment of aryl(alkoxy)carbonylalkyl will be on the alkylene.

The term "alkylthio" or "sulfanyl" as used herein means an -S-alkyl group, wherein alkyl is as defined above, such as methylthio, ethylthio, n-propylthio, iso-propyl Thio, n-butylthio, hexylthio, including their isomers. "Lower alkylthio" or "lower sulfanyl" as used herein means alkylthio, wherein "lower alkyl" is as defined above. "C _1-10 alkylthio" as used herein refers to -S-alkyl wherein the alkyl is C _1-10 alkyl.

The term "alkylthioalkyl" as used herein denotes the group R'R", wherein R' is alkylthio, R" is alkylene as defined herein, and the point of attachment of the alkylthioalkyl will be at the on the alkyl.

_The term "aminosulfonyl" as used herein refers to the group -S(O) _2NH2 . The terms "alkylaminosulfonyl" and "dialkylaminosulfonyl" as used herein refer to the group -S(O) ₂ NR'R", wherein R' and R" are hydrogen and lower alkyl and R ' and R" are independently lower alkyl. Examples of alkylaminosulfonyl include, but are not limited to, methylaminosulfonyl, iso-propylaminosulfonyl. Examples of dialkylaminosulfonyl include, but are not limited to, dialkylaminosulfonyl Methylaminosulfonyl, iso-propylmethylaminosulfonyl.

As used herein, unless otherwise specified, the term "cycloalkyl" refers to a saturated group containing one or more rings and consisting only of carbon and hydrogen atoms, having from 3 to 8 carbon atoms, inclusive. Monovalent carbocyclic group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, and those specifically disclosed in the Examples.

The term "substituted cycloalkyl" as used herein refers to a cycloalkyl group as defined herein comprising 1 to 3 substituents such as hydroxy, cyano, lower alkyl, lower alkoxy, Sulfanyl, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl and sulfonylamino. Examples of cycloalkyl groups include, but are not limited to, 3-ethylcyclobutyl, 4-hydroxycyclohexyl, 3-chlorocyclopentyl, and those specifically disclosed in the Examples.

The term "cycloalkylalkyl" as used herein refers to the group -R'R", wherein R' is alkylene and R" is cycloalkyl or substituted cycloalkyl as defined herein. Examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl, and those specifically disclosed in the Examples.

As used herein, unless otherwise specified, the term "cycloalkenyl" refers to an unsaturated group containing one or more rings and consisting only of carbon and hydrogen atoms, having from 1 to 10 carbon atoms, inclusive. monovalent carbocyclic groups. Examples of cycloalkenyl include, but are not limited to, cyclobuten-1-yl, cyclopenten-1-yl, and those specifically disclosed in the Examples.

Unless otherwise stated, the term "substituted cycloalkenyl" as used herein refers to a cycloalkenyl group as defined herein comprising 1 to 3 substituents such as hydroxy, cyano, lower alkyl , lower alkoxy, sulfanyl, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl and sulfonyl Amino. Examples of substituted cycloalkenyl groups include, but are not limited to, 3-ethylcyclobuten-1-yl, 3-fluorocyclohepten-1-yl, and those specifically disclosed in the Examples.

As used herein, the term "cyano" refers to a carbon attached to nitrogen by a triple bond, ie -C≡N.

As used herein, the term "halogen" or "halo" refers to fluorine, bromine, chlorine or iodine and combinations thereof.

The term "haloalkyl" as used herein refers to lower alkyl as defined herein substituted at any position by one or more halogen atoms as defined herein. Examples of haloalkyl include, but are not limited to, 1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloro Ethyl groups and those specifically disclosed in the Examples.

As used herein, the term "aryl" or "aromatic" refers to a monocyclic or bicyclic group of 6 to 12 ring carbon atoms having at least one aromatic ring, it being understood that the point of attachment of the aryl group will be on the aromatic ring. Aryl is optionally substituted independently with one or more substituents selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, acyl, acylamino, amino, alkylamino, dialkyl Amino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonyloxy, -SO ₂ NR'R" (where R' and R" are independently hydrogen or alkyl), alkoxy , haloalkoxy, alkoxycarbonyl, carbamoyl, hydroxy, halogen, nitro, cyano, sulfur, methylenedioxy or ethylenedioxy. More specifically, the term aryl includes, but is not limited to, phenyl, naphthyl, tetrahydronaphthyl, 3,4-methylenedioxyphenyl, 1,2,3,4-tetrahydroquinoline- 7-yl, 1,2,3,4-tetrahydro-isoquinolin-7-yl and those specifically disclosed in the Examples.

The terms "heteroaryl" and "heteroaromatic" as used herein refer to a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic ring comprising 1, 2 or 3 ring heteroatoms selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon, it should be clear that the point of attachment for the heteroaryl will be on the aromatic ring. The heteroaryl ring is optionally substituted independently with one or more substituents selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, acyl, acylamino, amino, alkylamino, di Alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonyloxy, -SO ₂ NR'R" (where R' and R" are independently hydrogen or alkyl), alkane Oxy, haloalkoxy, alkoxycarbonyl, carbamoyl, hydroxy, halogen, nitro, cyano, sulfur, methylenedioxy or ethylenedioxy and those specifically disclosed in the examples. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 2 heteroatoms, examples of which include, but are not limited to, pyridyl, furyl, thienyl, thiazolyl, isothiazolyl , triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl and pyrimidinyl and derivatives thereof; and bicyclic aromatic moieties having 9 to 10 ring atoms, including 1 to 3 heteroatoms, It includes, but is not limited to, benzofuryl, tetrahydrobenzofuryl, isobenzofuryl, benzothiazolyl, benzodiathiazolyl, benzisothiazolyl, benzotriazolyl, indolyl, isoindolyl , benzoxazolyl, quinolinyl, 5,6,7,8-tetrahydroquinolyl, isoquinolyl, 5,6,7,8-tetrahydroisoquinolyl, benzimidazolyl, Benzisoxazolyl and benzothienyl and derivatives thereof and those specifically disclosed in the examples.

The term "heteroalkyl" as used herein refers to a group in which 1, 2 or 3 hydrogen atoms have been independently selected from -OR ^a , -NR ^b R ^c and -S(O) _n R ^d (wherein n is 0 Alkyl as defined herein substituted by a substituent of an integer from to 2), it should be understood that the point of attachment of heteroalkyl is through a carbon atom, where ^Ra is hydrogen, acyl, alkyl, cycloalkyl or cycloalkyl -C _1-3 alkyl; and R ^b and R ^c are independently selected from hydrogen, acyl, alkyl, cycloalkyl or cycloalkyl-C _1-3 alkyl; when n is 0, R ^d is hydrogen , alkyl, cycloalkyl and cycloalkyl-C _1-3 alkyl, when n is 1 or 2, R ^d is alkyl, cycloalkyl, cycloalkyl-C _1-3 alkyl, amino, Acylamino, monoalkylamino or dialkylamino. Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3 -Hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 2 -aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonyl-methyl, methylamino Sulfonylethyl, methylaminosulfonylpropyl and those specifically disclosed in the Examples.

The term "heterocyclyl" as used herein refers to a group in which one or two ring atoms are selected from the group consisting of NR', O or S(O) _n (wherein R' is alkyl, heteroalkyl or hydrogen, and n is an integer of 0 to 2) and a saturated or unsaturated non-aromatic monocyclic or bicyclic group of 3 to 10 ring atoms in which the remaining ring atoms are carbon. Heterocyclyl is optionally substituted with one or more substituents selected from hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, heteroalkyl and acyl. The term heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidino, tetrahydropyrimidin-5-yl, tetrahydropyrimidin-1-yl, N-methylpiperidin-3-yl, piperazinyl, N-methylpyrrolidin-3-yl, 3-pyrrolidinyl, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, pyrrole Linyl, imidazolinyl, tetrahydroquinolin-1-yl and tetrahydroisoquinolin-2-yl and those specifically disclosed in the Examples.

The term "arylalkyl" or "aralkyl" as used herein refers to the group -R'R", wherein R' is alkylene and R" is aryl as defined herein. Examples of arylalkyl include, but are not limited to, 4-fluorophenylmethyl, 3,4-dichlorophenylethyl, and those specifically disclosed in the Examples.

As used herein, the term "heteroarylalkyl" refers to the group -R'R", wherein R' is alkylene and R" is heteroaryl as defined herein. Examples of heteroarylalkyl groups include, but are not limited to, such as 3-pyridylmethyl, 4-chloropyrimidin-2-ylmethyl, 2-thiophen-2-ylethyl and those specifically disclosed in the Examples.

The term "heterocyclylalkyl" as used herein refers to the group -R'R", wherein R' is alkylene and R" is heterocyclyl as defined herein. Examples of heterocyclylalkyl include, but are not limited to, tetrahydropyran-2-ylmethyl, 2-piperidinylmethyl, 3-piperidinylmethyl, morpholin-1-ylpropyl and in Examples those specifically disclosed in.

The terms "amino", "alkylamino" and "dialkylamino" as used herein refer to _-NH2 , -NHR and _-NR2 respectively and R is alkyl as defined above. The two alkyl groups attached to the nitrogen in a dialkyl moiety may be the same or different. The terms "aminoalkyl", "alkylaminoalkyl" and "dialkylaminoalkyl" as used herein refer to NH ₂ (CH ₂ ) _n -, RHN(CH ₂ ) _n - and R ₂ N ( _CH2 ) _n- , wherein n is 1 to 6 and R is alkyl as defined above. "C _1-10 alkylamino" as used herein refers to -aminoalkyl in which the alkyl is a C _1-10 alkyl. Examples of alkylamino and dialkylamino include, but are not limited to, methylamino, ethylamino, cyclopropylmethylamino, dicyclopropylmethylamino, dimethylamino, methylethylamino, diethylamino Amylamino, bis(1-methylethyl)amino and those specifically disclosed in the Examples.

The term "acyl" refers to a formyl group of the formula -C(O)H or a carbonyl group of the formula -C(O)R', wherein R' is selected from C _1-18 alkyl, cycloalkyl, cycloalkylalkyl , haloalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, or NR'R", as defined herein, wherein R' and R" are the hydrogens of alkyl or R', R" and the nitrogen to which they are attached are pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl.

As defined herein, the term "alkylene" as used herein refers to the divalent group =CRR', wherein R and R' are independently alkyl or hydrogen. Examples of alkylene groups include, but are not limited to, ethylene, propylene, butylene, and those specifically disclosed in the Examples.

As defined herein, the term "cycloalkylene" as used herein refers to the divalent group =CRR', wherein R and R' together with the carbons to which they are attached form a divalent cycloalkyl group. Examples of cycloalkylene include, but are not limited to, cyclopentylene, 3-fluorocyclohexylene, and those specifically disclosed in the Examples.

As defined herein, the term "cycloalkyl-alkylene" as used herein refers to the divalent group =CRR', where R is alkyl or hydrogen, and R' is cycloalkyl. Examples of cycloalkyl-alkylene groups include, but are not limited to, cyclopropylmethylene, cyclohexylmethylene, 1-cyclopentylethylene, and those specifically disclosed in the Examples.

As defined herein, the term "cycloalkylalkyl-alkylene" as used herein refers to the divalent group =CRR', where R is alkyl or hydrogen, and R' is cycloalkylalkyl . Examples of cycloalkylalkyl-alkylene groups include, but are not limited to, 2-cyclopentylethylene, 1-cyclohexylpropylene-2-yl, and those specifically disclosed in the Examples.

As defined herein, the term "heteroalkylene" as used herein refers to the divalent group =CRR', where R is heteroalkyl, haloalkyl, alkyl, or hydrogen, and R' is heteroalkyl or haloalkyl. Examples of heteroalkylene include, but are not limited to, 3,3,3-trifluoropropylene, 2-hydroxybutylene, 3-aminopropylene, and those specifically disclosed in the Examples.

As defined herein, the term "heterocyclylene" as used herein refers to the divalent group =CRR', wherein R and R' together with the carbons to which they are attached form a divalent heterocyclyl. Examples of heterocyclylene include, but are not limited to, pyrrolidin-2-ylene, tetrahydropyran-4-ylene, piperidin-4-ylene and those specifically disclosed in the Examples.

As defined herein, the term "heterocyclyl-alkylene" as used herein refers to the divalent group =CRR', wherein R is alkyl or hydrogen, and R' is heterocyclyl. Examples of heterocyclyl-alkylene include, but are not limited to, 4-piperidinylmethylene, 4-methyl-1-piperazinylmethylene, and those specifically disclosed in the Examples.

As defined herein, the term "heterocyclylalkyl-alkylene" as used herein refers to the divalent group =CRR', where R is alkyl or hydrogen, and R' is heterocyclylalkyl . Examples of heterocyclylalkyl-alkylene groups include, but are not limited to, 2-(tetrahydropyran-4-yl)ethylene, 1-(piperidin-3-yl)propylene-2-yl, and in Those specifically disclosed in the Examples.

As defined herein, the term "arylalkylene" as used herein refers to the divalent group =CRR', where R is aryl, alkyl or hydrogen, and R' is aryl. Examples of arylalkylene include, but are not limited to, 4-chlorophenylmethylene, 6,7-dimethoxynaphthalen-2-ylmethylene, and those specifically disclosed in the Examples.

As used herein, the term "arylalkyl-alkylene" refers to the divalent group =CRR', where R is alkyl or hydrogen, and R' is arylalkyl, as defined herein. Examples of arylalkyl-alkylene groups include, but are not limited to, 2-(4-trifluoromethylphenyl)ethylene, 1-(3,4-dichlorophenyl)propylene-2-yl, and Those specifically disclosed in the Examples.

As defined herein, the term "heteroarylalkylene" as used herein refers to the divalent group =CRR', wherein R is alkyl or hydrogen, and R' is heteroaryl. Examples of heteroarylalkylene include, but are not limited to, 3-pyridylmethylene, 4-chloro-2-pyrimidinylmethylene, and those specifically disclosed in the Examples.

As defined herein, the term "heteroarylalkyl-alkylene" as used herein refers to the divalent group =CRR', where R is alkyl or hydrogen, and R' is heteroarylalkyl . Examples of heteroarylalkyl-alkylene groups include, but are not limited to, 2-(4-trifluoromethylpyrimidinyl)ethylene, 1-(thiophen-2-yl)propan-2-yl, and in Examples those specifically disclosed in.

The terms "hydroxyalkyl" and "alkoxyalkyl" as used herein refer to the group R'R", wherein R' is hydroxy or alkoxy, respectively, and R" is an alkylene group as defined herein, and hydroxy The point of attachment of the alkyl group is on the alkylene group.

It is envisioned that the definitions set forth herein may be appended to form chemically related combinations such as "heteroalkylaryl", "haloalkylheteroaryl", "arylalkylheterocyclyl", "alkylcarbonyl", "alk Oxyalkyl" and those specifically disclosed in the Examples.

As used herein, the term "optional" or "optionally" means that the subsequently described event or condition can occur but is not required to occur, and that the description includes instances where the event or condition occurs and instances where it does not. For example, "an optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds.

"Isomerism" refers to compounds that have the same molecular formula but differ in either the nature or sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of each other are termed "diastereomers", and those that are non-superimposable mirror images are termed "enantiomers", or sometimes optical isomers. A carbon atom bonded to four different substituents is called a "chiral center".

"Chiral isomer" refers to a compound having one chiral center. It has two enantiomeric forms of opposite chirality and can exist as a single enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of each enantiomeric form of opposite chirality is termed a "racemic mixture". Compounds with more than one chiral center have 2n ^-1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as individual diastereomers or as a mixture of diastereomers known as a "diastereomeric mixture". When a chiral center is present, stereoisomers can be described in terms of the absolute configuration (R or S) at that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are according to the Sequence Rule of Cahn, Ingold and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold J. Chem. Soc. (London) 1951, 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

"Geometric isomer" refers to diastereomers that exist due to hindered rotation about a double bond. The prefixes cis and trans or Z and E are used on their names to distinguish these configurations. According to the Cahn-Ingold-Prelog rule, the prefixes cis and trans or Z and E indicate that the group is located in the same position as the double bond in the molecule. side or side.

As used herein, the phrase "substantially pure" means that at least about 90 mole percent of the desired compound, enantiomer or stereoisomer is present compared to the other possible configurations.

The phrase "pharmaceutically acceptable" as used herein refers to pharmaceutical compositions which are generally safe, non-toxic and free from biologically or otherwise undesired properties, and include their use in veterinary and human acceptable for pharmaceutical use.

The phrase "pharmaceutically acceptable salt" of a compound as used herein refers to a salt, as defined herein, which is pharmaceutically acceptable and which possesses the desired pharmacological activity of the parent compound. Such salts include: (i) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, lemon acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, Acid addition salts of mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, etc.; or (ii ) Salts formed when the acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, alkaline earth metal ion or aluminum ion; or when coordinated with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

Preferred pharmaceutically acceptable salts are those formed from acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc and magnesium. It should be clear that all references to a pharmaceutically acceptable salt include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein of the same acid addition salt.

The term "crystalline form" or "polymorph" refers to a crystal structure in which a compound can crystallize in different crystalline packing arrangements, all having the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate.

As used herein, the term "solvate" refers to solvent addition forms that contain stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar proportion of solvent molecules in the crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with a substance in which the water retains its molecular state as _H2O , eg, a combination capable of forming one or more hydrates.

"Individual" refers to mammals and non-mammals. Mammal means any member of the class Mammalia, including but not limited to humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats and pigs; livestock such as Rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; etc. Examples of non-mammals include, but are not limited to, birds and the like. The term "individual" does not denote a particular age or gender.

"Disease state" refers to any disease, disorder, symptom or indication. Treatment of a disease state or treatment of a disease state includes: (i) prophylaxis of the disease state, i.e., causing the clinical symptoms of the disease state to occur when the disease state is likely to occur or predisposed to the disease state, but has not yet experienced or exhibited symptoms of the disease state Does not occur in an individual; (ii) inhibiting the disease state, ie arresting the development of the disease state or its clinical symptoms, or (iii) relieving the disease state, ie causing temporary or permanent regression of the disease state or its clinical symptoms.

"Mood disorder" or "affective disorder" refers to a psychopathological disorder in which a general disturbance of the mood constitutes the core manifestation. These terms include anxiety and related neuroses, especially depressive forms. Examples of "mood disorders" or "affective disorders" include, but are not limited to, depression, major depressive disorder, single episode depression, recurrent depression, childhood abuse-induced depression, postpartum depression, dysthemia, unipolar disorder, Bipolar disorder presenting with insomnia and eating disorders, dysthymia, double depression, morbid and clinical depression, mania and bipolar cycling temperament.

"Obsessive-compulsive disorder" is characterized by repetitive, unwanted, intrusive thoughts, images, or urges and a strong desire to do something to reduce the discomfort caused by these thoughts, images, or urges. "PTSD" occurs when a patient re-experiences a traumatic event that has already occurred. This re-experience causes intense fear, helplessness, fear and avoidance of trauma-related stimuli. Adjustment disorder with anxious mood is a type of anxiety disorder that, unlike PTSD, is caused by less severe stimuli, as opposed to PTSD. Emotional or behavioral symptoms are often a response to identifiable psychosocial stressors.

"Social anxiety disorder" and "social phobia" are characterized by anxiety caused by specific social situations or performance-based situations. Specific social phobia is a disorder in which patients avoid certain social situations. Social phobia may differ from social anxiety disorder in that the patient's anxiety may be due to specific social situations or performance-based situations rather than social or performance-based situations in general. For example, patients may develop untyped anxiety about public speaking.

A "specific phobia" is an excessive or irrational fear that has no apparent adjustment. In general, adults are aware that the fear is exaggerated or irrational, but children may not be aware of this. "Phobia" includes agoraphobia, specific phobia and social phobia. Agoraphobia is characterized by anxiety about places or situations that may be difficult to avoid or that may not be available for help during an embarrassing or panic attack. Agoraphobia can also occur in the absence of a history of panic attacks. "Specific phobias" are characterized by clinically significant anxiety caused by a feared object or situation. Specific phobias include the following subtypes: zoonotic, cued from animals or insects; natural environment, cued from objects in the natural environment, such as storms, heights, or water; blood-injection-injury, cued from seeing blood or injuries or is suggested by seeing or receiving injections or other invasive medical procedures; situational, which is suggested by specific situations such as public transportation, tunnels, bridges, elevators, flying, driving, or enclosed spaces; and which, where fear is suggested by other stimuli of. Specific phobias can also be called simple phobias.

The above disorders and disorders are well known to those skilled in the art. Diagnostic methods and descriptions of these disorders can be found in Diagnostic And Statistical Manual of Mental Disorders, 4th Edition, American Psychiatric Association, Washington, D.C., 1994.

Examples of compounds

The examples of representative compounds within the scope of the invention provided in Tables A-C describe representative compounds encompassed by the invention. These examples and the preparation methods provided below enable those skilled in the art to understand and practice the present invention more clearly. They should not be construed as limiting the scope of the invention, but merely illustrative and representative of the invention.

In general, the nomenclature used in this application was generated based on AUTONOM ^(TM) Version 4.0, a Beilstein Institute computerized system for generating IUPAC systematic nomenclature. The following numbering system for these ring systems is as follows:

The indazole compounds in Table A were prepared as described in Scheme 1. The 3-substituted indazoles in Table A were prepared by deprotonation of C-3 and quenching of the resulting carbanion with an alkyl halide, haloalkene, haloalkyne, or carbonyl compound from This leads directly to the compounds of the invention or to intermediates which are further transformed to prepare said compounds. Alternatively, direct electrophilic substitution at the C-3 position can be employed to prepare compounds of the invention (eg, 3-halo compounds). These methods are described in Schemes 2 and 4-7.

Compounds in Table B are derived from 2-methyl-7-phenyl-2H-indazole-3-carboxylic acid (12a: E=CO ₂ H) or 2-methyl-7-bromo-2H in Scheme 4 - Carboxylate esters and amides of indazole-3-carboxylic acid (12b: E= _CO2H ). The carboxylic acid is prepared by quenching the 3-lithium compound with carbon dioxide. When the indazole compound is a 7-halogenated compound (eg 11b), deprotonation of the 3-position is accomplished with LDA to avoid concomitant transmetalation.

The compounds in Table C were prepared from 2-methyl-7-phenyl-2H-indazol-3-ylamine as described in Scheme 9 (2-methyl-7-phenyl-2H -indazol-3-yl)-amine. Also in Table C is the [2-methyl-7-phenyl-2H-indazol-3-ylmethyl]-dimethyl-amine compound.

The compounds in Table D include sulfone and sulfonamide species and their precursors.

Table E illustrates representatives of 3-hydroxymethyl derivatives of compounds of the invention. The 3-hydroxymethylindazole compounds of the present invention are prepared by reacting 3-lithium-indazole with aldehydes or ketones as shown in Scheme 5. Alternatively, the 3-carboxy derivative can be reduced with an appropriate metal hydride to give the hydroxymethyl compound. Further transformation of the 3-hydroxymethyl compound by standard methods affords the ethers, esters, carbamates encompassed by the invention.

Preparation

The compounds of the present invention can be prepared by a variety of methods shown in the illustrative synthetic reaction schemes shown and described below. The starting materials and reagents used in the preparation of these compounds are generally available from suppliers such as Aldrich Chemical Co. or can use methods known to those skilled in the art according to references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, Vols 1-21; R.C. LaRock, Comprehensive Organic Transformations, 2nd Edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (eds.) Vols 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A.R. Katritzky and C.W. Rees (eds) Pergamon, Oxford 1984, vols 1-9; Comprehensive Heterocyclic Chemistry II, A.R. Katritzky and C.W. Rees (eds) Pergamon, Oxford 1996, vols 1-11; and Organic Reactions Prepared by the method described in Wiley & Sons: New York, 1991, vol. 1-40. The following synthetic reaction flow diagrams are only illustrations of some methods that can synthesize the compounds of the present invention, and various modifications can be made to these synthetic reaction flow diagrams. Those skilled in the art will obtain the relevant information after referring to the disclosure included in the application. Inspiration for these modifications.

The starting materials and intermediates in the synthetic reaction schemes can be isolated and purified, if necessary, by conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such substances can be characterized by conventional means including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein are preferably carried out under an inert atmosphere, atmospheric pressure, from about -78°C to about 150°C, more preferably from about 0°C to about 125°C, most preferably and conveniently at about room temperature (or ambient temperature) , eg at a reaction temperature of about 20°C.

Some of the compounds in the schemes below are depicted with generalized substituents; however, those skilled in the art will immediately recognize that the nature of the group R can be altered to yield the various compounds contemplated by the invention. Furthermore, the reaction conditions described are exemplary and alternative conditions are well known. The reaction procedures in the following examples are not intended to limit the scope of the invention described in the claims.

In particular, some of the indazole compounds of formula I (A ¹ , A ² and A ³ are CH or CR ⁴ ) can be prepared using 7-bromoindazole (3) as an intermediate, and the preparation method is shown in the flow chart 1 and described in Example 1. Compounds of formula I can be prepared from (3) by a three-step procedure comprising N-alkylation, palladium-catalyzed arylation at the 7-position and by electrophilic substitution or deprotonation and Substitution at the 3-position was quenched by the resulting 3-lithium indazole. There is considerable flexibility in the order of these three operations, which can be used to optimize the method for various situations. Thus, in procedure A, the arylation at the 7-position is carried out before the N-alkylation and the substituent at the 3-position is introduced in the last step (Scheme 1; Example 2). The best method for a particular compound will generally be apparent by inspection and minimal experimentation. In another approach (Scheme 1; Procedure B), N-alkylation and introduction of substituents at the 3-position precede the arylation step (see Example 3). Alternatively, N-alkylation and arylation can be performed prior to the introduction of substituents at the 3-position (Scheme 1; Step C).

Flowchart 1

Aryl coupling procedures which can be advantageously used are described in DW Knight Coupling Reactions Between sp ² Carbon Centers, Comprehensive Organic Synthesis, Vol. 3, G. Pattenden (ed.), Pergamon, Oxford 1991 pp. 481-520. The Suzuki is widely used in the preparation of the compounds described herein. The Suzuki reaction [equation (i)] is a palladium-catalyzed boronic acid (R = aryl or vinyl) with an aryl or vinyl halide or triflate (R' = aryl or vinyl; Y = halo or -OSO ₂ CF ₃ ) coupling. Typical catalysts include

Pd(PPh ₃ ) ₃ , Pd(OAc) ₂ and PdCl ₂ (dppf). Using _PdCl2 (dppf), primary alkylborane compounds can be coupled with aryl or vinyl halides or triflates without □-elimination. The reaction can be performed in various organic solvents including toluene, THF, dioxane, 1,2-dichloroethane, DMF, DMSO and acetonitrile, in aqueous solvents and under biphasic conditions. The reaction is generally carried out at about room temperature to about 150°C. Additives such as CsF, KF, TlOH, NaOEt, and KOH can often accelerate this coupling. Although there are many components in a Suzuki reaction (including palladium source, ligand, addition solvent, temperature, etc.), many protocols have been identified. Highly active catalysts have been identified (see, for example, JP Wolfe et al., J.Am.Chem.Soc. 1999121(41): 9550-9561 and AF Littke et al., J.Am.Chem.Soc. 2000 122(17): 4020-4028). Those skilled in the art will be able to determine a satisfactory protocol without undue experimentation.

Deprotonation of the 3-position of 7-aryl-2-alkyl-indazole (5) or 7-bromo-2-alkyl-indazole compound (6) was accomplished with LDA in THF at -78°C of (flow chart 1). Deprotonation of indazole species can also be accomplished with BuLi in THF at -78°C. The latter condition is acceptable for trialkylphenyl substituents; however, some 7-substituted phenylindazole species are prone to 7-aryl substituents when deprotonated with n-BuLi deprotonation or transmetallation. Those skilled in the art will readily be able to determine acceptable deprotonation conditions without undue experimentation.

Flowchart 2

Other embodiments of the invention can be prepared more efficiently by introducing a boronic acid derivative at the 7-position of the indazole and coupling 10 with an aryl halide (Example 2). Intermediates for aryl coupling have been prepared efficiently with the cross-coupling of aryl halides and aryl triflate and pinacol borane. (T.Ishiyama et al., Tetrahedron Lett. 1997 38:3447-3450; A.Wolan and M.Zaidlewicz, Org.Biomol.Chem.2003 1:3274-3276; M.Brimble and M.Y.H.Lai, Org.Biomol.Chem. 2003 1:2084-2095).

Flowchart 3

2H-pyrazolopyridines are prepared from pyridines substituted at adjacent positions by methyl and acetamido groups. 2-Chloro-3-nitro-4-picoline (28) is subjected to palladium-mediated coupling of arylboronic acids to afford the corresponding 2-arylpyridines (29). After reduction of the nitro group to the amine and acetylation, the acetamide is treated with isoamyl nitrite, potassium acetate and acetic anhydride. The intermediate N-nitroso compound is cyclized under reaction conditions to give acetylated pyrazolopyridine 31a, which is hydrolyzed to give 31b (P. Marakos et al., Synth Lett. 1997 561-62; D. Chapman and J. Hurst, J. Chem. Soc. Perk. I 1980 2398). N-alkylation of the 2-position and further manipulation of the 3-position were performed as described for the indazole species. Similar procedures can be adapted for other pyrazolopyridines.

Flowchart 4

Substitution at the three positions is accomplished by performing electrophilic substitution or by deprotonating the 3-position with a strong base. 3-Lithium-7-arylindazole 13 can be reacted with various electrophiles such as alkyl halides (e.g., MeI, E=Me; 2-methoxyethoxymethyl chloride, E= _CH2O ( CH ₂ ) ₂ OMe), haloalkenes (e.g., allyl bromide, E=allyl), haloalkynes (e.g., propyne bromide, E=propargyl), aldehydes (e.g., acetaldehyde, E=CH(OH)R), ketones (e.g., acetone, E=C(OH)R'R"), amides (e.g., MeC(=O)N(Me)OMe, E=C(=O)Me ; DMF, E=CHO), disulfides (eg, EtSSEt, E=SEt) and carbon dioxide (eg, E=COOH) react to generate 3-substituted indazoles.

Flowchart 5

R, ^Ra , ^Rb , ^Rc = H, alkyl; R' = alkyl; Ar = (substituted) aryl

(a) RC(=O)R'; (b) p-TsOH, PhCH ₃ ; (c) H ₂ , Pd/C

Embodiments of the invention include alkyl, alkenyl, alkynyl, and hydroxyalkyl substituents. Many of these groups can be introduced directly by reacting the desired substituent with a suitable leaving group on the carbon atom to be attached to the indazole with the lithiated indazole (Scheme 4). The 1-alkenyl substitution at the 3-position was introduced by a two-step procedure in which an aldehyde or ketone was reacted with 13 to give the carboxyl alcohol 14, which could be dehydrated to give the alkene. The dehydration generally produces a mixture of E and Z olefins; the invention includes both the pure E and Z isomers and mixtures thereof. The olefin can optionally be further converted to the corresponding paraffin 16a by catalytic hydrogenation.

Flowchart 6

Similarly, 3-alkyn-[n]-yl groups where n>2 can be introduced directly by reacting the alkynyl compound with a suitable leaving group. The 3-ethynyl group can be obtained by combining (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (19; S.Müller et al., Syn Lett. 1996(6):521-22) with 3-Formyl-7-arylindazole (17) is introduced by condensation. 3-Formyl-7-bromoindazole was prepared by condensation of 3-lithium-7-bromoindazole with DMF, followed by palladium-catalyzed introduction of the aryl substituent. Alkenes (e.g., 15: R ^a = H, R ^c = Alkyl) into acetylene. Alternatively, ethynyl compound 18 can be deprotonated and alkylated (J. March, supra, p. 481). 3-Hydroxymethyl-2-methyl-7-arylindazole (4: R ^a =R ^a = H) into the corresponding 3-cyano derivative.

3-halogenated indazoles can be obtained by direct electrophilic substitution of unsubstituted indazoles with brominating or chlorinating agents. The preparation method of the 3-halogenated compound is described in Scheme 7.

Flowchart 7

The invention also includes 3-alkoxycarbonyl-indazoles (34: X=OR) and 3-carbamoyl-indazoles prepared by the condensation of activated carboxylic acid derivatives with alcohols, ammonia, primary and secondary amines (22: X = _NH2 , NHR' or NR'R") compound (Table B). Carboxylic acid 34 was prepared by contacting 13 with _CO2 .

Flowchart 8

Y = Br or (substituted) aryl

X=OR, _NH2 , NHR', NR'R"

R, R', R" = alkyl, aralkyl, aryl, cycloalkyl

"Activated carboxylic acid derivative" or "activated 3-carboxy-indazole" refers to a stable reactive derivative (e.g., an acid chloride or bromide or (mixed) anhydride) or a transitionally reactive form of a carboxylic acid (e.g., by Dialkylisouronium (isouronium) salt formed by condensation with N,N'-dialkyldiimine), which makes the compound active in the desired reaction, where the initial compound has only moderate reactivity or no reactivity. Activation is achieved by forming derivatives or chemical species with higher free energy content intramolecularly aggregated than the original compound, which makes the activated form more susceptible to reaction with other reagents. Alcohols (J.March, Advanced Organic Chemistry, John Wiley & Sons, New York 1992392-398; J. Mulzer Synthesis of Esters, Activated Esters & Lactones, Comprehensive Organic Synthesis, edited by E. Winterfeldt, Vol. 6, PergamonPress, Oxford 1991, pp. 324-340) and amines (J. March, supra, pp. 417-425; HGBenz, Synthesis of Amides and Related Compounds, Comprehensive Organic Synthesis, edited by E. Winterfeldt, vol. 6, Pergamon Press, Oxford 1991 pp. 381 -411 pages) are reviewed. Alternatively, the carboxylate esters prepared as described above can be converted to amides by treatment with an appropriate amine. Amide formation can be accelerated by the presence of a Lewis acid (eg, _Me3Al ).

The present invention also includes 3-dialkylaminoindazoles (Table C). Nitration of 36a yielded a mixture of regioisomer nitroindazoles, from which 3-nitroindazole 36b could be easily isolated. The nitro substituent can be reduced to the corresponding primary amine 36c under standard conditions. Another route to 36c involves treating the carboxylic acid with Hoffmann or Curtius reaction conditions or variants thereof (J. March Advanced Organic Chemistry 4th Edition J Wiley & Sons: New York, 1991; pp. 1090-1095; T. Shioiri, Degradation Reactions, Comprehensive Organic Synthesis, Volume 6, E. Winterfeldt (ed.) Pergamon, Oxford 1991 pp. 795-825).

Flowchart 9

Amines such as 36c can be converted to amides by various methods (supra). Reduction of amide 37 with borane-THF complex or other reducing agents (J. March, supra, pp. 445-446; AGM Barrett, Reduction of carboxylic Acid Derivatives to Alcohols, Ethers and Amines, Comprehensive Organic Synthesis Vol. 8, I . Fleming (ed.) 1991 248-251), giving secondary amine 38 which can be further converted to tertiary amine 39 by reductive amination or by a second acylation and reduction procedure. This method allows the introduction of two different alkyl groups onto the amine. Reductive amination can be used when it is desired to obtain a tertiary amine with two identical alkyl groups (Scheme 8). Reductive amination is preferably achieved by combining the amine and the carbonyl compound in the presence of complex metal hydrides such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride or borane/pyridine. case, conveniently at a pH of 1-7, optionally in the presence of _a dehydrating agent such as molecular sieves or Ti(IV)(Oi-Pr) to aid in the formation of the imine intermediate, at ambient temperature phase mixing or with hydrogen in the presence of a hydrogenation catalyst, for example in the presence of palladium on carbon, at a hydrogen pressure of 1 to 5 bar, preferably at a temperature from 20° C. to the boiling point of the solvent used. During the reaction it may be advantageous if the reactive group is protected with a conventional protecting group, after which the protecting group is cleaved by conventional methods. Reductive amination methods have been reviewed: RM Hutchings and MK Hutchings, Reduction of C=N to CHNH by Metal Hydrides, Comprehensive Organic Synthesis, Vol. 8, I. Fleming (ed.) Pergamon, Oxford 1991 pp. 47-54.

Amines C3 and C4 are prepared by reduction of carboxamide compound 35 (X=NH-alkyl or N(alkyl) ₂ ) with a metal hydride. 3-Aminomethyl compounds can also be prepared from 3-formyl compounds by reductive amination. Acylation of 3-amino and 3-aminomethyl compounds can be accomplished as described above.

Carbamate 121 and urea 122 were synthesized by reacting 3-amino(40, R=H) or 3-aminomethyl compounds with alkoxy chloroformates, alkylaminocarbonyl chlorides, or related derivatives well known in the art. (120, n=1) was prepared by acylation. Acylation with an alkoxy chloroformate (eg, ethoxy chloroformate) or an aryloxy chloroformate produces a carbonate compound (3: Y=O-alkyl or -O-aryl). Carbonates are formally diesters of carbonic acid and can be obtained from phosgene or its equivalent. Usually, phosgene is introduced at low temperature into the reaction mixture containing alcohol and base. N,N-dialkylamines or quaternary ammonium salts can catalyze this reaction. The reaction can be terminated at the stage of an alkoxy chloroformate intermediate. This alkoxy chloroformate can then be used to prepare asymmetric carbonates. The condensation of alkoxy chloroformate can be carried out in solvents such as dichloromethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, optionally in the presence of inorganic Or in the case of an organic base (for example, triethylamine or pyridine), at a temperature of -20 to 200°C, preferably at a temperature of -10 to 80°C. Alternatives to the toxic gaseous phosgene include trichloromethyl chloroformate (diphosgene) and bis(trichloromethyl)carbonate (triphosgene) (H. Eckert and A. Nestl, Functions Containing acarbonyl Group and at least Chalcogen (but no Halogen), Comprehensive Organic Functional Group Transformations, B.Trost (Editor) Volume 6, E.Winterfeldt (Volume Editor) Pergamon Press Oxford, UK, 1995, pp. 460-462; J.March, Advanced Organic Chemistry, John Wiley & Sons, NY, 1992 p. 392). Acylation with alkylaminocarbonyl chlorides, (hetero)arylaminocarbonyl chlorides or with the corresponding isocyanates leads to carbamate compounds (H. Eckert and A. Nestl, supra, pp. 484-485).

Flowchart 10

3-Alkylthio-, 3-alkylsulfinyl- and 3-alkylsulfonyl-substituted indazoles are prepared by contacting 3-lithium-indazoles with disulfides to give 3-alkane Sulfur-based compounds 22. Oxidation with one or two equivalents of MCPBA or an equivalent oxidant leads to sulfoxide (23, n=1) or sulfone (23: n=2) respectively (Scheme 10). Sulfonyl chloride 123 was prepared by oxidation of thiobenzyl ether (22, R=Me, R'= _CH2Ph ) to sulfonyl chloride (Th. Zincke and H. Rose, Ann. 1914406:127,; RH Baker et al., J. Am. Chem. Soc. 194668:2636-2639). Alternatively, sulfonyl chlorides can be prepared by direct sulfonylation of indazole with trimethylsilyl chlorosulfonate and treatment of the resulting sulfonic acid with thionyl chloride and a catalytic amount of DMF. Sulfonamides are prepared by condensation of sulfonyl chlorides with (di)alkylamines. The unsubstituted sulfonamide (125, R ^j =R ^k =H) was prepared by reduction of the sulfonyl azide. 3-(Alkyl)aminosulfonamides (127) were prepared in a similar manner from 3-aminoindazoles (126).

Dosage and Administration

The compounds of the present invention can be formulated in a variety of dosage forms and carriers for oral administration. Pharmaceutically acceptable carriers can be solid or liquid. Oral administration can take the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, syrups or suspensions. The compounds of the invention are also effective when administered by other routes of administration, including continuous (intravenous infusion) topical parenteral administration, intramuscular administration, intravenous administration, subcutaneous administration , transdermal (which may include a penetration enhancer), buccal, nasal, inhalational, and suppository administrations. The preferred mode of administration is generally oral administration using a conventional daily dosage regimen which can be adjusted according to the extent of the disorder and the patient's response to the active ingredient.

The compounds of the present invention and their pharmaceutically acceptable salts can be prepared together with one or more conventional excipients, carriers or diluents in the form of pharmaceutical compositions and unit doses. Said pharmaceutical compositions and unit dosage forms may contain conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and unit dosage forms may contain any suitable effective amount of active ingredient. The pharmaceutical composition may be in the form of solids such as tablets or filled capsules, semi-solids, powders, sustained release formulations or liquids such as solutions, suspensions, emulsions, elixirs or filled capsules for oral use; or in the form of suppositories For rectal or vaginal administration; or for parenteral use in the form of an injectable sterile solution. A typical preparation will contain from about 5% to about 95% active compound(s) (w/w).

The term "excipient" as used herein refers to a compound useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and has no biological or other undesirable properties, including for veterinary use and A carrier acceptable for human pharmaceutical use. As used herein, the term "excipient" includes both one and more than one such excipient.

Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid, which is a mixture containing the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low Melting point wax, cocoa butter, etc. Liquid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active ingredient, coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickening agents , solubilizer, etc.

The term "preparation" or "dosage form" as used herein includes formulations of the active compound containing an encapsulating material as carrier, which provides a capsule into which the active ingredient, with or without a carrier, is associated. surrounded by. Similarly, cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be solid forms suitable for oral administration.

Liquid formulations are also suitable for oral administration and include emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions. Also included are solid form preparations which are to be converted, shortly before use, to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.

The compounds of the invention may be formulated for parenteral administration (e.g. by injection, e.g. bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, prefilled syringes, small volume infusions or Available in multi-dose containers with added preservatives. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol solution. Examples of oily or non-aqueous carriers, diluents, solvents or bases include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulation substances such as Preservatives, wetting agents, emulsifying or suspending agents, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution before use with a suitable vehicle, eg, sterile pyrogen-free water, obtained by aseptically dispensing sterile solids or by lyophilizing solutions.

The compounds of the invention may be formulated for topical application to the epidermis in ointments, creams or lotions, or in the form of a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and generally also contain one or more emulsifying, stabilizing, dispersing, suspending, thickening or coloring agents. Formulations suitable for topical administration in the mouth include lozenges containing the active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles; and mouthwashes containing the active ingredient in a suitable liquid carrier.

The compounds of the invention may be formulated for administration in the form of suppositories. First, a low-melting wax such as a mixture of fatty acid glycerides or cocoa butter is melted and the active ingredient is uniformly dispersed therein, for example by stirring. The molten homogeneous mixture is then poured into suitably sized molds and allowed to cool and solidify.

The compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, carriers known in the art to be suitable.

The compounds of the invention may be formulated for nasal administration. Solutions or suspensions may be applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. Formulations may be presented in single or multiple dose form. In the latter case of a dropper or pipette, this may be accomplished by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of nebulizers, this can be achieved, for example, by means of metered atomizing spray pumps.

The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract, and including intranasal administration. The compounds typically have a small particle size, eg, on the order of five (5) microns or less. The particle size can be obtained by methods known in the art, for example by micronization. The active ingredient is supplied in a pressurized pack containing a suitable propellant such as a chlorofluorocarbon (CFC), for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane or carbon dioxide or other suitable gas. Aerosols may also suitably contain surfactants such as lecithin. Drug dosage may be controlled by a metered valve. Alternatively, the active ingredient may be presented in dry powder form, for example as a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). The powder carrier will form a gel in the nasal cavity. Powder compositions may be presented in unit dosage form, eg, in the form of capsules or cartridges, eg gelatin capsules or cartridges, or blister packs, from which the powder may be administered by an inhaler.

酮(1-十二烷基氮杂-环庚-2-酮)组合使用。可通过手术或注射将缓释递送系统皮下插入皮下层。皮下植入物将化合物包囊在液体可溶性膜、例如硅橡胶或生物可降解的聚合物、例如聚乳酸中。Formulations can be prepared, if desired, with enteric coatings suitable for slow or controlled release administration of the active ingredient. For example, the compounds of the invention can be formulated into transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with the treatment regimen is critical. Compounds in transdermal delivery systems are often attached to a skin-adhesive solid carrier. Compounds of interest can also be combined with penetration enhancers such as lauryl nitrogen

A ketone (1-dodecylazepine-cycloheptan-2-one) was used in combination. Sustained release delivery systems can be inserted subcutaneously into the subcutaneous layer by surgery or injection. Subcutaneous implants encapsulate the compound in a liquid soluble membrane such as silicone rubber or a biodegradable polymer such as polylactic acid.

Suitable formulations, as well as pharmaceutically acceptable carriers, diluents, and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E.W. Martin, Mack Publishing Company, 19th ed., Easton, Pennsylvania. The skilled formulation scientist can modify formulations within the teachings of this specification to obtain a number of formulations for a particular route of administration without destabilizing the compositions of the invention or impairing their therapeutic activity.

Modification of the compounds of the present invention to make them more soluble in water or other matrices can be easily accomplished, for example, by minor modifications (salt formation, esterification, etc.), which are well within the capabilities of those of ordinary skill in the art. It is also well known to those of ordinary skill in the art that the route of administration and dosing regimen of a particular compound can be altered to manipulate the pharmacokinetics of the compounds of the invention to maximize their beneficial effect in the patient.

The term "therapeutically effective amount" as used herein refers to the amount required to alleviate the symptoms of a disease in an individual. Dosage adjustments will be made according to the individual needs in each particular case. The dosage can vary widely, depending on many factors, such as the severity of the disease being treated, the age and general health of the patient, other drugs being used by the patient being treated, the route and form of administration, and the medical practitioner involved preferences and experiences. For oral administration, a daily dosage of about 0.01 to about 100 mg/kg body weight/day should be suitable, in monotherapy or in combination therapy. A preferred daily dosage is from about 0.1 to about 500 mg/kg body weight/day, more preferably from 0.1 to about 100 mg/kg body weight/day, most preferably from 1.0 to about 10 mg/kg body weight/day. Thus, for administration to a 70 kg human, the dosage range would be about 7 mg to 0.7 g per day. The daily dose may be administered in a single dose or in divided doses, usually 1 to 5 doses per day. In general, treatment is initiated with smaller doses which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect for each patient is reached. Those of ordinary skill in the art of treating the diseases described herein will be able to determine, without undue experimentation, in reliance on personal knowledge, experience and the disclosure of this application, that for a given disease and patient a compound of the invention is therapeutically effective quantity.

The pharmaceutical formulations are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

The purpose of giving the pharmaceutical composition of Example 21 is to enable those skilled in the art to understand and implement the present invention more clearly. They should not be considered as limiting the scope of the invention, but merely as illustrations and representations of the invention.

Example 1

7-Bromo-2H-indazole

step 1

3-Bromo-2-nitrotoluene (Scheme 1; 1c) - A mixture of copper(II) bromide (3.52 g, 15.7 mol) in 20 mL of dry acetonitrile was heated to 65 °C under _N2 atmosphere. To this was added tert-butyl nitrite (2.35 mL, 2.03 g, 19.7 mmol) in one portion. To the above solution was added a solution of 3-methyl-2-nitroaniline (1b; 2.00 g, 13.1 mmol; J. Org Chem. 197641(21):3357) in 15 mL of acetonitrile at a rate sufficient to maintain a gentle reflux. After the addition, the mixture was heated at gentle reflux for an additional 15 minutes. The reaction mixture was cooled to room temperature and partitioned between 6N HCl solution (150 mL) and diethyl ether (150 mL). The ether solution was separated and washed with brine, then dried over _MgSO4 . Evaporation of the solvent gave 2.76 g of impure material which was flash chromatographed on _SiO and eluted with 10% acetone in hexane to give 1.62 g (57%) of 1c as a yellowish-green liquid .

step 2

垫过滤并将滤液在减压下蒸发。将残余物用Et₂O(约200mL)吸收，用盐水洗涤，然后用MgSO₄干燥。蒸发掉溶剂，得到2.66g(42％)深色液体形式的2a。 2-Bromo-6-methylaniline (2a) - A mixture of tellurium (21.6 g, 169.4 mmol) and _NaBH4 (15.0 g, 396 mmol) in 575 mL of anhydrous EtOH was heated at reflux under _N2 atmosphere for 1 h , then, allow to cool to room temperature. To this was added a solution of 3-bromo-2-nitrotoluene (1c; 7.32 g, 33.8 mmol) in 25 mL of EtOH in one portion and the mixture was stirred at room temperature for 2 hours. The reaction mixture was used

A pad was filtered and the filtrate was evaporated under reduced pressure. The residue was taken up in _Et2O (ca. 200 mL), washed with brine, and dried over _MgSO4 . Evaporation of the solvent afforded 2.66 g (42%) of 2a as a dark liquid.

step 3

(2-Bromo-6-methylphenylazo)-tert-butylsulfide (2b) - 2-Bromo-6-methylaniline (2a; 1.18g, 6.34mmol) and 3.4mL 6N HCl were dissolved in Heat in an oil bath at 60° for 30 minutes, then cool to 0°. A solution of NaNO ₂ (481 mg, 6.97 mmol) in 1.5 mL H ₂ O was added dropwise thereto, and then it was stirred for another 1 hour under this cooling condition. The pH of the reaction mixture was adjusted to 4-5 with saturated NaOAc solution, then it was added in one portion to an ice-cold solution of tert-butylmercaptan (0.80 mL, 629 mg, 6.97 mMol) in 14 mL EtOH. The mixture was allowed to warm to room temperature overnight. The reaction mixture was partitioned between EtOAc (50 mL) and _H2O (50 mL). The aqueous layer was back extracted with EtOAc (50 mL). The combined EtOAc extracts were washed with brine and dried over _MgSO4 . The solvent was evaporated to give 1.46 g (80%) of 2b.

step 4

7-Bromoindazole (3) - (2-Bromo-6-methylphenylazo)-tert-butyl sulfide (2b; 880 mg, 3.06 mmol) in 10 mL of dry DMSO under argon The solution was added dropwise to a solution of potassium tert-butoxide (3.44 g, 30.6 mmol) in 25 mL of dry DMSO. The reaction mixture was stirred at room temperature for 2 hours, then it was poured into 150 g of ice and 150 mL of 2N HCl solution. The mixture was extracted with ether (2 x 150 mL). The combined ether extracts were washed with brine and dried over _MgSO4 . Evaporation of the solvent afforded 581 mg (96%) of 3 as a beige solid.

Example 2

7-(2,4-Dichloro-phenyl)-2-methyl-2H-indazole

5: Ar=2,4-dichlorophenyl; R=Me

step 1

A solution of 7-bromo-1H-indazole (3; 1.01 g, 5.13 mmol) and tetrakis(triphenylphosphine) palladium (0) (0.176 g, 0.152 mmol) in 15 mL of ethylene glycol dimethyl ether was stirred for 30 minute. To this solution was added 2,4-dichlorophenylboronic acid (1.93 g, 10.1 _mmol ) and 2M aqueous _Na2CO3 (7.1 mL, 14.2 mmol). The orange-yellow mixture was stirred at 80°C for 19 hours, allowed to cool, then partitioned between 50 mL ethyl acetate and 50 mL water. The organic layer was dried over _MgSO4 , filtered and concentrated to give an orange oil. Column chromatography (0 → 10% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-1H-indazole (4; 1.12 g, 83% ).

step 2

A solution of 7-(2,4-dichloro-phenyl)-1H-indazole (4; 1.12g, 4.27mmol) and dimethyl sulfate (0.405mL, 4.28mmol) in 15mL toluene was heated at 110°C Stir for 17 hours, allow to cool, then cool at 0-5°C. The mixture was carefully washed with 15 mL of saturated aqueous NaHCO ₃ , dried over MgSO ₄ , filtered (rinsing with ether) and concentrated to give an orange oil. Column chromatography (0 → 33% EtOAc/hexanes) gave 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole (5; 0.92 g, 78%).

Step 3 - Hydrochloride

To a solution of 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole (5; 0.056 g, 0.20 mmol) in 2 mL of ether was added 0.2 mL of 2.0 M HCl in ether. The resulting mixture was stirred for 30 minutes and filtered to give 0.041 g (65%) of 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole; hydrochloride: m.p.133-147.

The following compound was prepared in a similar manner to 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole and purified by reverse phase HPLC:

7-(2,4-Dichloro-phenyl)-2-ethyl-2H-indazole; compound 2-benzyl-7-(2,4-dichloro-phenyl)-2 with trifluoroacetic acid -2H-Indazole, compound with trifluoroacetic acid; [7-(2,4-dichloro-phenyl)-indazol-2-yl]-ethyl acetate; compound with trifluoroacetic acid

Example 3

7-(2,4-Dichloro-phenyl)-2,3-dimethyl-2H-indazole; hydrochloride

step 1

A solution of 7-bromo-1H-indazole (3; 1.71 g, 8.67 mmol) and dimethyl sulfate (0.90 mL, 9.5 mmol) in 30 mL of toluene was stirred at 110 °C for 4 hours and then allowed to cool. The mixture was carefully washed with 30 mL of saturated aqueous NaHCO ₃ , dried over MgSO ₄ , filtered (rinsing with ether) and concentrated to give an orange oil. Column chromatography (0→50% EtOAc/hexanes) afforded 7-bromo-2-methyl-2H-indazole (6: R=Me; 1.33 g, 73%) as a beige solid.

step 2

To a solution of 7-bromo-2-methyl-2H-indazole (5.49 g, 26.0 mmol) in 100 mL THF at -78 °C was added 2.0 M lithium diisopropylamide in tetrahydrofuran/heptane/ethyl Solution in benzene (19.5 mL, 39.0 mmol). The resulting dark orange solution was stirred at 0-5°C for 15 minutes, then it was re-cooled at -78°C for 15 minutes. To this was added iodomethane (2.5 mL, 40 mmol), and the orange solution was slowly warmed to room temperature with stirring over 17 hours. Water (100 mL) was added thereto, and the mixture was extracted with 100 mL of ether. The organic layer was washed with 200 mL of saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated to give an orange solid. Column chromatography (0→50% EtOAc/Hexanes) afforded 7-bromo-2,3-dimethyl-2H-indazole (8: R=R″=Me ; 5.28 g, 90%) which was used without further purification.

step 3

A freshly ground Potassium phosphate (6.04g, 28.5mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (0.225g, 0.572mmol) and palladium(II) acetate (0.032g, 0.14 mmol) was evacuated and backfilled with nitrogen. Toluene (50 mL) was added and the yellow-orange mixture was stirred at 100° C. for 22 hours, then allowed to cool. Diethyl ether (200 mL) was added and the yellow solution was decanted from the dark granular solid. The organic layer was washed sequentially with 200 mL of 10% aqueous NaOH and 200 mL of saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated to give a pale yellow solid. Column chromatography (0 → 33% EtOAc/hexanes) afforded 2,3-dimethyl-7-(2,4,6-trimethyl-phenyl)-2H-indazole as an off-white solid (7: R=R'=Me, Ar=2,4,6-trimethylphenyl; 3.03 g, 79%; mp162-164).

In a similar manner to the preparation of 2,3-dimethyl-7-(2,4,6-trimethyl-phenyl)-2H-indazole from 7-bromo-2,3-dimethyl-2H- Indazole The following compounds were prepared (using the appropriate electrophile and/or phenylboronic acid). The compound named "Containing trifluoroacetic acid" was purified by reverse phase HPLC and isolated as the TFA salt:

7-(2,4-dichloro-phenyl)-2,3-dimethyl-2H-indazole; hydrochloride;

3-chloro-7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole;

7-(2,4-dichloro-phenyl)-3-(2-methoxyethoxymethyl)-2-methyl-2H-indazole;

7-(2,4-Dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methyl ester;

7-(2,4-Dichloro-phenyl)-2-ethyl-2H-indazole-3-carboxylic acid methyl ester (synthesized from 7-bromo-2-ethyl-3-methyl-2H-indazole );

1-[7-(2,4-dichloro-phenyl)-2-methyl-2H-indazol-3-yl]-ethanol;

7-(3-Methoxy-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methyl ester; compounds with trifluoroacetic acid;

7-(2-Phenoxy-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methyl ester; compounds with trifluoroacetic acid;

Methyl 2-methyl-7-m-tolyl-2H-indazole-3-carboxylate; compounds with trifluoroacetic acid;

7-(3,5-Dimethyl-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methyl ester; compounds with trifluoroacetic acid;

7-(6-Methoxy-2-methyl-pyridin-3-yl)-2-methyl-2H-indazole-3-carboxylic acid methyl ester; compounds with trifluoroacetic acid;

7-(2,5-Dimethoxy-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methyl ester; compounds with trifluoroacetic acid;

2-Methyl-7-(4-phenoxy-phenyl)-2H-indazole-3-carboxylic acid methyl ester; compounds with trifluoroacetic acid;

2-Methyl-7-thiophen-3-yl-2H-indazole-3-carboxylic acid methyl ester; compounds with trifluoroacetic acid;

7-furan-3-yl-2-methyl-2H-indazole-3-carboxylic acid methyl ester; compounds with trifluoroacetic acid;

7-(2,4-Dimethoxy-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methyl ester; compounds with trifluoroacetic acid;

7-(4-Isopropyl-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methyl ester; compounds with trifluoroacetic acid;

7-(2,5-Dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methyl ester; compounds with trifluoroacetic acid;

Example 4

7-(2,4-Dichloro-phenyl)-2-methyl-2H-pyrazolo[3,4-c]pyridine; hydrochloride

step 1

2-Chloro-4-methyl-3-nitropyridine (28; 1.08 g, 6.24 mmol), 2,4-dichlorophenylboronic acid (1.26 g, 6.62 mmol), (Ph ₃ P) ₄ Pd ( A mixture of 0) (0.405 g, 0.350 mmol), 40 mL DMF and 20 mL 2M aqueous K ₂ HPO ₄ was stirred at 70° C. for 40 hours. The mixture was partitioned between 200 mL ether and 200 mL water. The organic layer was washed successively with 200 mL of water and 200 mL of saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated to give a yellow oil mixed with a white solid. Column chromatography (0 → 20% EtOAc/hexanes) afforded 2-(2,4-dichloro-phenyl)-4-methyl-3-nitro- Pyridine (29; 1.19 g; 68%), which was used without further purification.

step 2

521过滤并将残余物垫用甲醇充分洗涤。浓缩滤液，将微红色-橙色的残余物在50mL乙酸乙酯和50mL饱和NaHCO₃水溶液之间进行分配。将有机层用50mL饱和NaCl水溶液洗涤，用MgSO₄干燥，过滤并浓缩，得到黄色油状物。向该油状物中加入10mL甲苯和乙酸酐(0.41mL，4.35mmol)，并将该黄色溶液在100℃下搅拌23小时，然后将其浓缩为深黄色的残余物。用柱色谱进行处理(50→66％EtOAc/己烷)，得到灰白色固体形式的N-[2-(2，4-二氯-苯基)-4-甲基-吡啶-3-基]-乙酰胺(30；0.815g；68％)。To 2-(2,4-dichloro-phenyl)-4-methyl-3-nitro-pyridine (29; 1.15 g, 4.05 mmol), 10 mL of ethanol, 2.5 mL of water and 0.5 mL of To the mixture of concentrated HCl solution was added iron powder (1.37 g, 24.6 mmol). The gray suspension was stirred for 1 hour, allowed to cool, and washed with

521 for filtration and the residue pad was washed well with methanol. The filtrate was concentrated and the reddish-orange residue was partitioned between 50 mL ethyl acetate and 50 mL saturated aqueous NaHCO ₃ . The organic layer was washed with 50 mL of saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated to give a yellow oil. To the oil was added 10 mL of toluene and acetic anhydride (0.41 mL, 4.35 mmol), and the yellow solution was stirred at 100 °C for 23 hours, then it was concentrated to a dark yellow residue. Column chromatography (50→66% EtOAc/hexanes) afforded N-[2-(2,4-dichloro-phenyl)-4-methyl-pyridin-3-yl]- Acetamide (30; 0.815 g; 68%).

step 3

To N-[2-(2,4-dichloro-phenyl)-4-methyl-pyridin-3-yl]-acetamide (30; 0.787g, 2.67mmol), 30mL benzene, To a mixture of acetic anhydride (0.780 mL, 8.27 mmol) and potassium acetate (0.330 g, 3.36 mmol) was added isoamyl nitrite (0.572 mL, 4.27 mmol), and the yellow mixture was stirred for 22 hours. After cooling, the mixture was filtered and concentrated to an orange oil. To this oil was added 21 mL of ethanol, 7 mL of water and lithium hydroxide monohydrate (0.339 g, 8.80 mmol). The orange mixture was stirred for 3 hours, then it was concentrated to remove ethanol. The orange residue was partitioned between 50 mL ether and 50 mL 10% aqueous NaOH, and the aqueous layer was extracted with 50 mL ether. The combined organic layers were washed with 100 mL of saturated aqueous NaCl, dried over _MgSO , filtered, loaded onto silica gel and concentrated. Column chromatography (0→20% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-1H-pyrazolo[3,4-c] as a foamy light yellow solid Pyridine (31; 0.484 g; 67%).

step 4

7-(2,4-Dichloro-phenyl)-1H-pyrazolo[3,4-c]pyridine (31; 0.107g; 0.405mmol), 4mL THF and 60% sodium hydride/mineral oil (0.020 g, 0.50 mmol sodium hydride) was stirred for 3 hours. To the green solution was added dimethyl sulfate (0.040 mL, 0.42 mmol). The resulting yellow cloudy solution was stirred for 30 minutes, then quenched with silica gel and concentrated. Column chromatography (0 → 50% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-2-methyl-2H-pyrazolo[3,4- c] Pyridine (32; 0.029 g; 26%).

To a solution of 7-(2,4-dichloro-phenyl)-2-methyl-2H-pyrazolo[3,4-c]pyridine (0.029 g, 0.10 mmol) in 1 mL of ether was added 0.100 mL 2M HCl in ether solution. The resulting white suspension was stirred for 15 minutes then concentrated to give 0.031 g of 7-(2,4-dichloro-phenyl)-2-methyl-2H-pyrazolo[3,4- c] Pyridine hydrochloride (32·HCl): m.p.191-196.

Example 5

7-(3,5-Dichloro-pyridin-2-yl)-2-methyl-2H-indazole; hydrochloride

step 1

Dimethylsulfoxide (5 mL) was degassed under nitrogen by three freeze-pump-thaw procedures. To this was added 7-bromo-2-methyl-2H-indazole (0.100 g, 0.474 mmol), bis(pinacolato) diboron (0.132 g, 0.520 mmol), potassium acetate (0.138 g, 1.41 mmol) and [1.1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (0.012 g, 0.015 mmol), and the mixture was subjected to another freeze-pump-thaw procedure. The mixture was stirred at 80° C. for 19 hours, allowed to cool, and 20 mL of water was added thereto. The mixture was extracted with three 5 mL portions of ethyl acetate. The combined organic layers were dried over _Na2SO4 , filtered and concentrated to give _a brown solid. Column chromatography (0 → 90% EtOAc/hexanes) gave slightly impure 2-methyl-7-(4,4,5,5-tetramethyl-[1,3,2]diox Borolan-2-yl)-2H-indazole, which was used without further purification (10; 0.062 g, 51%).

step 2

2-Methyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (0.040g, 0.15mmol), 2,3,5-trichloropyridine (0.274g, 1.50mmol), (Ph ₃ P) ₄ Pd (0) (0.019g, 0.017mmol), 2mL DMF and 2mL 2M K ₃ PO ₄ solution The mixture was stirred at 65°C for 16 hours, then allowed to cool. To this was added water (10 mL) and the mixture was extracted with three 5 mL portions of ethyl acetate. The combined organic layers were dried over _Na2SO4 , filtered and concentrated to give _a brown solid. Column chromatography (0 → 50% EtOAc/hexanes) afforded 7-(3,5-dichloro-pyridin-2-yl)-2-methyl-2H-indazole (7: R=Me; R' = H; Ar = 3,5-dichloro-pyridin-2-yl; 0.042 g; 93%).

To a solution of 7-(3,5-dichloro-pyridin-2-yl)-2-methyl-2H-indazole (0.042 g) in ether was added 2M HCl in ether. The mixture was filtered to obtain 0.039 g of 7-(3,5-dichloro-pyridin-2-yl)-2-methyl-2H-indazole hydrochloride in the form of a yellow solid.

2-Methyl-2H-indazole (for Suzuki couplings using the appropriate aryl halide) (those reporting compounds "with trifluoroacetic acid" were purified by reverse phase HPLC):

2-Methyl-7-phenyl-2H-indazole; compounds with trifluoroacetic acid

7-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-2-methyl-2H-indazole

2-(2-Methyl-2H-indazol-7-yl)-nicotinonitrile

3-Methyl-4-(2-methyl-2H-indazol-7-yl)-benzonitrile

Example 6

step 1

7-Bromo-2-methyl-2H-indazole (6: R=Me; 2.01 g, 9.53 mmol), 2,4,6-trimethylphenylboronic acid (1.70 g, 10.4 mmol), tetrakis( A mixture of triphenylphosphine)palladium(0) (0.657 g, 0.569 mmol), 70 mL of DMF and 33 mL of 2M aqueous _K2HPO4 was stirred at 69 ° _C for 6.5 days. The mixture was partitioned between 350 mL ether and 350 mL water. The organic layer was washed with 350 mL of saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated to give a pale yellow oil. Column chromatography (0 → 33% EtOAc/hexanes) gave impure 2-methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazole as a white solid (5: R=Me, Ar=2,4,6-trimethylphenyl; 1.44 g), which was used without further purification.

step 2

To a solution of the impure 2-methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazole (0.500 g) prepared above in 10 mL THF at -78 °C A 2.0 M solution of lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (1.2 mL, 2.4 mmol) was added. The yellow solution was stirred at 0-5°C for 15 minutes, and the resulting purple solution was recooled to -78°C for 15 minutes. To this was added acetaldehyde (0.14 mL, 2.5 mmol) and the resulting yellow solution was stirred for 90 minutes before it was quenched with silica gel and concentrated. Column chromatography (0 → 50% EtOAc/hexanes) afforded 1-[2-methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazole as a white solid -3-yl]-ethanol (12a: R=Me, R'=2,4,6-trimethylphenyl, E=CH(OH)Me; 0.280 g; 48%; m.p. 246).

The following compounds were prepared in a similar manner to the preparation of 1-[2-methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazol-3-yl]-ethanol (using the appropriate Electrophile):

1-[2-Methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazol-3-yl]-ethanone

3-Ethylthio-2-methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazole

Example 7

3-Bromo-7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole

To a solution of 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole (0.659 g, 2.38 mmol) in 2 mL of acetic acid was added bromine (0.122 mL, 2.38 mmol) dropwise. The yellow-orange solution was stirred for 15 minutes, during which time an orange solid precipitated. The mixture was concentrated to give a yellow solid which was partitioned between 20 mL of 10% aqueous NaOH and 20 mL of diethyl ether. The organic layer was washed with 20 mL of saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated to give a white solid interspersed with yellow. Column chromatography (0→10% EtOAc/hexanes) afforded 3-bromo-7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole (24 : Ar=2,4-dichlorophenyl; 0.525 g; 62%; mp137-139).

Example 8

3-chloro-7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole

step 1

To a solution of 7-bromo-2-methyl-2H-indazole (6: R=Me; 0.500 g, 2.37 mmol) in 5 mL of acetic acid was added sulfonyl chloride (0.29 mL, 3.6 mmol). The mixture was stirred for 5 hours, then 30 mL of 2M aqueous NaOH was added thereto. The mixture was extracted with three 30 mL portions of ethyl acetate, the combined organic layers were dried over _Na2SO4 , filtered and concentrated to give a white _solid . Column chromatography (0 → 15% EtOAc/hexanes) gave slightly impure 7-bromo-3-chloro-2-methyl-2H-indazole (25: R=Me; 0.530 g; 90% ), which was used without further purification.

step 2

7-Bromo-3-chloro-2-methyl-2H-indazole (0.079g, 0.32mmol), 2,4-dichlorophenylboronic acid (0.122g, 0.641mmol), 2mL ethylene glycol dimethyl ether , a mixture of 2 mL of 2M aqueous _Na2CO3 and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.010 mmol) was stirred at 88 ° _C overnight, then diluted with 10 mL of ethyl acetate. The mixture was washed with two 5 mL portions of saturated aqueous NaCl, dried, filtered and concentrated to give a yellow oil. Column chromatography (0 → 5% EtOAc/hexanes) afforded 3-chloro-7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole (26 : R=Me; Ar=2,4-dichlorophenyl; 0.063 g; 63%).

Example 10

2-Methyl-7-(2,4,6-trimethyl-phenyl)-3-vinyl-2H-indazole

1-[2-Methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazol-3-yl]-ethanol (0.263g, 0.893mmol) and 4-toluenesulfonic acid A solution of the hydrate (0.217 g, 1.14 mmol) in 10 mL of toluene was stirred at 103 °C for 16 hours, then allowed to cool. The yellow-orange solution was washed successively with 10 mL of 10% aqueous NaOH and 10 mL of saturated aqueous NaCl, dried over _MgSO4 , filtered and concentrated to give an orange oil. Column chromatography (20% EtOAc/hexanes) afforded 2-methyl-7-(2,4,6-trimethyl-phenyl)-3-vinyl-2H-indole as a light yellow solid Azole (15: Ra= ^Rb =H, Ar=2,4,6-trimethylphenyl; ^0.135g ; 55%; mp84.9-95.4).

Example 11

7-(2,4-Dichloro-phenyl)-2-methyl-3-((E)-1-propyl-but-1-enyl)-2H-indazole

step 1

To a solution of 7-bromo-2-methyl-2H-indazole (1.5 g, 7.1 mmol) in 18 mL THF at -78 °C was added 2M lithium diisopropylamide in heptane/ethylbenzene/ Solution in THF (5.3 mL, 11 mmol). The solution was stirred at 0-5°C for 10 minutes, then recooled to -78°C. To this was added 4-heptanone (1.49 mL, 10.6 mmol), and the solution was stirred overnight, allowing it to slowly warm to room temperature. To it was added saturated aqueous NaHCO ₃ (40 mL) and the mixture was extracted with three 30 mL portions of ethyl acetate. The combined organic layers were dried over _Na2SO4 , filtered and concentrated to give _a brown solid. Column chromatography (0→20% EtOAc/hexanes) afforded 4-(7-bromo-2-methyl-2H-indazol-3-yl)-heptan-4-ol (42; 1.80 g; 78%).

step 2

4-(7-Bromo-2-methyl-2H-indazol-3-yl)-heptan-4-ol (1.75g, 5.38mmol), 50mL of toluene and 4-toluenesulfonic acid (1.23g, 6.46mmol ) was stirred at 110°C for 20 hours and then allowed to cool. To it was added saturated aqueous NaHCO ₃ (50 mL) and the mixture was extracted with three 30 mL portions of ethyl acetate. The combined organic layers were dried over _MgSO4 , filtered and concentrated to give a brown oil. Column chromatography (0 → 8% EtOAc/hexanes) afforded 7-bromo-2-methyl-3-((E)-1-propyl-but-1-enyl)-2H-indazole (43; 1.47 g; 89%).

step 3

7-Bromo-2-methyl-3-((E)-1-propyl-but-1-enyl)-2H-indazole (1.47g, 4.79mmol), 2,4-dichlorophenyl A mixture of boronic acid (1.32 g, 6.94 mmol), 18 mL of ethylene glycol dimethyl ether, tetrakis(triphenylphosphine)palladium(0) (0.166 g, 0.143 mmol) and 20 mL of 2M _{aqueous Na2CO3} was stirred at 85 °C Leave overnight, then allow to cool. Ethyl acetate (50 mL) was added and the mixture was washed with two 40 mL portions of saturated aqueous NaCl. The combined aqueous layers were extracted with 20 mL of ethyl acetate. The combined organic layers were dried over _Na2SO4 , filtered _and concentrated to give a brown oil. Column chromatography (0 → 5% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-2-methyl-3-((E)-1-propane as a white solid (15a; 1.57 g; 88%).

Example 12

7-(2,4-Dichloro-phenyl)-3-ethynyl-2-methyl-2H-indazole

step 1

Under argon atmosphere, 2-methyl-7-bromoindazole (6: R=Me; 5.31 g, 25.16 mmol) in THF (100 mL) was cooled to -78 °C. To this was slowly added a solution of 2M LDA in heptane/THF/ethylbenzene (20 mL, 40 mmol). The mixture was then stirred at -78°C for 10 minutes and at 0°C for 20 minutes. The solution was recooled to -78°C and DMF (6 mL, 77.48 mmol) was added slowly via syringe. The mixture was stirred and allowed to warm to room temperature for 19 hours. The reaction was partitioned between EtOAc and _NH4Cl solution. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over _MgSO4 and concentrated to almost dryness. The resulting yellow solid (3.83 g) was collected by filtration and washed with 10% EtOAc in hexanes. The filtrate was concentrated and the residue was purified by _SiO2 chromatography eluting with EtOAc/hexanes (5→30%) during 30 minutes to afford another crop of 17a (0.46 g, 62% overall yield) as well as recovered Starting material (0.768 g, 14%).

step 2

A DME solution (100 mL) of 3-formyl-7-bromoindazole (17a; 3.83 g, 16.02 mmol), boronic acid (6.10 g, 31.97 mmol) and palladium catalyst (0.55 g, 0.47 mmol) was flushed with argon for 5 minute. To this _was added 2M _Na2CO3 solution (23 mL, 46 mmol). The mixture was stirred at 80°C under argon. _Na2CO3 precipitated out and _H2O (65 mL) was added to dissolve _the salt. The reaction mixture was stirred at 80 °C for 19 hours, then it was cooled to room temperature. The mixture was partitioned between EtOAc and water and the organic layer was dried over _MgSO4 . The solvent was removed to almost dryness, the solid 17b (Ar = 2,4,6-trimethylphenyl; 3.36 g) was collected by filtration, and a second crop of product was obtained from the filtrate (0.90 g, combined yield 86%; mp: 153.4-156.4°C).

step 3

Under nitrogen, 17b (Ar = 2,4,6-trimethylphenyl; 1.56 g, 5.11 mmol) and 1-(dimethoxy-phosphoryl)-2-oxo-propane-1-heavy A solution of diazonium (1.27 g, 6.13 mmol) in MeOH/THF (70 mL/55 mL) was treated with _K2CO3 ( _1.41 g, 10.20 mmol). The mixture was stirred for 6 hours and the reaction was monitored by thin layer chromatography until complete. The mixture was partitioned between EtOAc and water and the organic layer was dried over _MgSO4 . The solvent was removed and the residue was purified by SiO2 chromatography eluting with 8% EtOAc in hexanes to afford 18 (Ar = 2,4,6-trimethylphenyl) as an off-white solid (1.176 g, 76%; mp 129.9-130.9°C).

Example 13

7-(2,4-Dichloro-phenyl)-2-methyl-2H-indazole-3-carbonitrile

step 1

To a solution of 7-bromo-2-methyl-2H-indazole (6: R=Me; 0.578 g, 2.93 mmol) in 15 mL THF at -78 °C was added 2.0 M lithium diisopropylamide in Solution in tetrahydrofuran/heptane/ethylbenzene (1.8 mL, 3.6 mmol). The yellow-orange solution was stirred at 0-5°C for 15 minutes, then recooled to -78°C for 15 minutes. To this was added paraformaldehyde (0.92 g) and the orange mixture was stirred rapidly at -78°C for 75 minutes, then at room temperature for 100 minutes. The mixture was loaded onto silica gel and concentrated. Column chromatography (0→66% EtOAc/hexanes) afforded 0.662 g of impure (7-bromo-2-methyl-2H-indazol-3-yl)-methanol (14a).

step 2

Impure (7-bromo-2-methyl-2H-indazol-3-yl)-methanol (0.642g) and tetrakis(triphenylphosphine)palladium(0) (0.089g, 0.077mmol) were dissolved in 25mL The solution in ethylene glycol dimethyl ether was stirred for 30 minutes. To this solution was added 2,4-dichlorophenylboronic acid (1.00 g, 5.27 mmol), followed by _3.8 mL of 2M aqueous _Na2CO3 , and the yellow mixture was stirred at 78 °C for 15 hours. The mixture was partitioned between 50 mL ethyl acetate and 50 mL water. The organic layer was washed with 50 mL of saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated to give an orange oil. Column chromatography (0 → 50% EtOAc/hexanes) followed by crystallization from benzene gave 0.203 g ("25%") of 7-(2,4-dichloro-phenyl)-2-methyl-2H -Indazol-3-yl]-methanol (14b).

521过滤(用二氯甲烷进行清洗)并将其浓缩，得到黄色固体。用柱色谱进行处理(0→10％EtOAc/己烷)，得到白色固体形式的7-(2，4-二氯-苯基)-2-甲基-2H-吲唑-3-腈(20：R³＝2，4-二氯苯基；0.058g；39％；m.p.137-139)。To a solution of [7-(2,4-dichloro-phenyl)-2-methyl-2H-indazol-3-yl]-methanol (0.153 g) from step 2 in 2 mL of THF was added 2M Ammonia in IPA (1.0 mL, 2.0 mmol), _MgSO4 (0.910 g, 7.56 mmol), and 85% active _MnO2 (0.771 g, 7.54 mmol). The dark mixture was stirred for 2 days and then washed with

521 filtered (rinsing with dichloromethane) and concentrated to give a yellow solid. Column chromatography (0→10% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carbonitrile (20 : R ³ =2,4-dichlorophenyl; 0.058 g; 39%; mp137-139).

Example 14

3-Ethylsulfonyl-2-methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazole

To a solution of 3-ethylthio-2-methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazole (45; 0.034g, 0.11mmol) in 1mL of dichloromethane 3-Chloroperbenzoic acid (0.083 g of 57-86% pure material from Aldrich Chemical Company) was added. The colorless solution was stirred for 16 hours, then diluted with 5 mL of dichloromethane and washed with 5 mL of 10% aqueous NaOH. The aqueous solution was extracted with 5 mL of dichloromethane, the combined organic layers were dried over MgSO ₄ , filtered and concentrated to give a yellow oil. Column chromatography (0 → 20% EtOAc/hexanes) afforded 3-ethanesulfonyl-2-methyl-7-(2,4,6-trimethyl-phenyl)-2H as a white solid - Indazole (46; 0.017 g; 45%).

Example 15

7-(2,4-Dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylic acid cyclopropylmethyl-propyl-amide

step 1

To a solution of 7-bromo-2-methyl-2H-indazole (6: R=Me 1.50 g, 7.12 mmol) in 50 mL THE at -78 °C was added 2M lithium diisopropylamide in THF/ Solution in heptane/ethylbenzene (4.3 mL, 8.6 mmol). The solution was stirred at 0-5°C for 15 minutes, then recooled to -78°C. To this solution was added methyl chloroformate (0.66 mL, 8.5 mmol) in one portion, and the mixture was stirred while slowly warming to room temperature over 19 hours. The reaction was quenched with silica gel and concentrated. Column chromatography (0 → 20% EtOAc/hexanes) afforded methyl 7-bromo-2-methyl-2H-indazole-3-carboxylate (35a: 1.52 g; 79%; m.p.131-132).

step 2

35a (0.750 g, 2.79 mmol), 2,4-dichlorophenylboronic acid (1.06 g, 5.57 mmol), 10 mL of ethylene glycol dimethyl ether, tetrakis(triphenylphosphine)palladium(0) (0.097 g, 0.084 mmol) and 10 mL of 2M _{aqueous Na2CO3} was stirred at 85 °C overnight and then allowed to cool. To this was added ethyl acetate (50 mL) and the mixture was washed with 30 mL of saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated to give a yellow oil. Column chromatography (0 → 10% EtOAc/hexanes) afforded methyl 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylate as a white solid (35b: 0.582g; 62%; mp128-131).

step 3

To a solution of N-propylcyclopropanemethylamine (0.69 mL, 4.8 mmol) in 12 mL of benzene was slowly added 2M trimethylaluminum in heptane (2.4 mL, 4.8 mmol) and the solution was stirred for 75 minutes. This solution was transferred by pipette to a solution of 35b (0.200 g, 0.597 mmol) in 10 mL of benzene. The solution was heated to 79°C, stirred for 2 days, then cooled to 0-5°C. To this was slowly added 2M aqueous NaOH (20 mL), and the mixture was extracted with three 20 mL portions of dichloromethane. The combined organic layers were washed with 40 mL of saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated to give a brown oil. Column chromatography (0 → 20% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylic acid cyclopropane as an oil Dimethyl-propyl-amide (35c: 0.117 g; 47%).

Example 16

7-(2,4-Dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methylamide

A solution of 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methyl ester (35b; 0.050 g, 0.15 mmol) in 4 mL of 2M methylamine in methanol After stirring for 6 days, it was concentrated to give a white solid. Column chromatography (0 → 45% EtOAc/hexanes) gave 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methylamide (35d; 0.044 g; 88%).

Example 17

step 1

A mixture of 7-bromo-2-methyl-2H-indazole-3-carboxylic acid methyl ester (35a; 0.215 g, 0.799 mmol), 8 mL of 2M aqueous NaOH and 6 mL of ethanol was stirred at 55 °C overnight, then it was concentrated to Remove ethanol. The remaining aqueous layer was acidified with 10% aqueous HCl and extracted with three 20 mL portions of ethyl acetate. The combined organic layers were dried over _Na2SO4 , filtered and concentrated to give crude 7-bromo-2-methyl-2H _- indazole-3-carboxylic acid (35e; 0.193g; 94%) which was extracted without used with further purification.

step 2

To a mixture of 35e (0.075 g, 0.29 mmol) in 3 mL of chloroform was added thionyl chloride (0.058 mL, 0.79 mmol) and 1 drop of DMF. The mixture was stirred at reflux for 3 hours, then concentrated. To this was added chloroform (2.5 mL) followed by tert-butyl N'-cyclopropylmethyl-N-ethyl-hydrazinecarboxylate (0.062 g, 0.29 mmol) in 0.5 mL chloroform. The solution was stirred overnight, then diluted with 40 mL of dichloromethane, washed sequentially with 2M aqueous sodium hydroxide and saturated aqueous NaCl, dried over _Na2SO4 , filtered and concentrated to an oil _. Column chromatography (0 → 10% EtOAc) gave N-(7-bromo-2-methyl-2H-indazole-3-carbonyl)-N'-cyclopropylmethyl-N-ethyl- tert-Butyl carboxylate (35f: 0.025 g; 20%).

step 3

35f (0.025g, 0.055mmol), 2,4-dichlorophenylboronic acid (0.024g, 0.11mmol), tetrakis(triphenylphosphine)palladium(0) (0.002g, 0.002mmol), 1mL ethylene glycol A mixture of dimethyl ether and 1 mL of _2M aqueous _Na2CO3 was stirred overnight at 85 °C. Ethyl acetate ₍ 50 mL) was added and the mixture was washed with two 20 mL portions of saturated aqueous NaCl, dried over _Na2SO4 , filtered and concentrated to give a clear oil. Column chromatography (0 → 15% EtOAc/hexanes) afforded N-cyclopropylmethyl-N'-[7-(2,4-dichloro-phenyl)-2-methyl-2H- Indazole-3-carbonyl]-N-ethyl-hydrazinecarboxylate tert-butyl (35 g; 0.020 g; 70%).

step 4

Prepare a methanolic solution of HCl by slowly adding 1 mL of acetyl chloride to 4 mL of methanol. This solution was added to 35 g (0.020 g, 0.039 mmol) and the solution was stirred overnight, then it was concentrated to give 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole - Crude 3-carboxylic acid N-cyclopropylmethyl-N'-ethyl-hydrazide (35h), purified by reverse phase HPLC.

Example 18

N'-cyclopropylmethyl-N-ethyl-hydrazinecarboxylate tert-butyl

step 1

To a solution of ethylhydrazine oxalate (1.03 g, 0.686 mmol) and di-tert-butyl dicarbonate (1.05 g, 4.81 mmol) in 50 mL of methanol was added triethylamine (1.86 mL, 13.4 mmol). The solution was stirred for 1 hour, cyclopropanecarbaldehyde (0.425 mL, 5.69 mmol) was added, the solution was stirred for 2 hours, then concentrated. EtOAc (50 mL) was added and the mixture was washed sequentially with two portions of 2M aqueous NaOH (20 mL each) and 20 _mL of water, dried over _Na2SO4 , filtered and concentrated to a clear oil. Column chromatography (0→20% EtOAc/Hexanes) afforded N'-[1-cyclopropyl-methylene-(E)-yl]-N-ethyl-hydrazinecarboxylate tert-butyl ester (45 ; 0.780 g; 77%).

step 2

A mixture of sodium cyanoborohydride (0.276 g, 4.39 mmol), 5 mL of THF and TMSCl (0.56 mL, 4.4 mmol) was stirred for 10 minutes, then 45 (0.780 g, 3.67 mmol) in 10 mL of THF was added slowly thereto. The mixture was stirred for 1 hour, then 15 mL of 2M aqueous NaOH was added thereto. The mixture was extracted with 40 mL of ether, the organic layer was washed with two 20 mL portions of saturated aqueous NaCl, dried over _Na2SO4 , filtered and concentrated _. Column chromatography (0→20% EtOAc/hexanes) afforded tert-butyl N'-cyclopropylmethyl-N-ethyl-hydrazinecarboxylate (46; 0.323 g; 41%).

Example 19

[7-(2,4-Dichloro-phenyl)-2-methyl-2H-indazol-3-yl]-dipropyl-amine hydrochloride

step 1

7-(2,4-Dichlorophenyl)-2-methyl-indazole (5a; 0.293 g, 1.05 mmol) was dissolved in 3.0 mL of glacial HOAc and 0.3 mL of acetic anhydride, which was then placed in an ice bath cool down. To this was added 90% nitric acid (0.070 mL; 1.48 mmol) in one portion and stirred at room temperature for 1 hour, then it was heated in an oil bath at 50° for 2 hours. The reaction mixture was cooled to room temperature, then treated with ice (-10 g). The mixture was extracted with ether (2 x 40 mL). The combined ether extracts were washed with saturated NaHCO ₃ solution (2×50 mL), then dried over MgSO ₄ . Evaporation gave a mixture of 3 isomers which were separated by flash chromatography on silica gel (EtOAc:hexane, 1:9) to afford 37b (0.077 g; 22%).

step 2

Nitroindazole 37b and 10 mg of 10% palladium on carbon were combined in 7 mL of MeOH, which was then stirred overnight under nitrogen atmosphere (1 atm). The catalyst was filtered off and the solvent was evaporated to give 36c (0.070 g), which was used in the next step without further purification.

step 3

Under _N2 atmosphere, amine 36c (70 mg, 0.23 mmol) and TEA (0.037 mL, 26 mg, 0.26 mmol) were dissolved in dichloromethane (3 mL) and cooled in an ice bath. To this was added propionyl chloride (0.022 mL, 24 mg, 0.26 mmol), then allowed to warm to room temperature. When the reaction was complete, the mixture was evaporated and the residue was flash chromatographed (ethyl acetate:hexane, 1:1) to afford 48 (0.068 g; 82%).

step 4

Amide 48 (0.068 mg, 0.19 mmol) was dissolved in 5 mL of dry THF under _N2 atmosphere. To this was added 1M BH ₃ -THF solution (0.40 mL, 0.40 mmol) in one portion, the mixture was heated at reflux for 2 hours, cooled to room temperature and 1 mL of 6N HCl was carefully added, the mixture was reheated at reflux for 1 hour, Then it was cooled to room temperature. The mixture was made basic with 6N NaOH solution, then extracted with dichloromethane (2 x 25 mL). _The combined extracts were washed with brine and dried over _Na2SO4 . The solvent was evaporated to give 38 (0.071 g) as a light brown viscous liquid which was used without further purification.

step 5

Under nitrogen, amine 38 and propionaldehyde (0.032 mL, 26 mg, 0.44 mmol) were combined in 3 mL of DCE and stirred at room temperature for 10 minutes. To this was added Na(OAc) _3BH (102 mg, 0.48 mmol) in one portion and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with 20 mL of dichloromethane and washed with dilute _NH4OH solution. _{The CH2Cl2} solution was separated off and _dried ( _Na2SO4 ). Evaporation of the solvent gave a residue which was purified by flash chromatography (EtOAc:hexanes, 1:9) to afford 27.4 mg of the free base of 39 as a viscous liquid. The free base was dissolved in 1 mL of ether and treated with 0.1 mL of 2M HCl in ether to afford 39 as a white solid (0.022 g).

Example 20

3-allyl-7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole

step 1

To a mixture of 7-bromo-2-methyl-indazole (9, 0.200 g, 0.948 mmol) and dry THF (1.5 mL) cooled to -78 °C and maintained under N μL, 1.90 mmol, 2.0 M solution in heptane/THF/ethylbenzene). After complete addition, the reaction mixture was stirred for 10 minutes and allowed to warm to 0° C. for 10 minutes. The dark red solution was cooled to -78°C and allyl bromide (123.0 μL, 1.42 mmol) was added dropwise thereto. The solution was allowed to warm to room temperature and allowed to stir over weekend. The reaction was quenched by the addition of saturated _NH4Cl (10 mL) and the resulting solution was extracted twice with EtOAc. The combined extracts were dried ( _MgSO4 ), filtered and evaporated. The crude product was purified by flash chromatography on _SiO2 (linear gradient 0 to 40% EtOAc/heptane over 20 minutes) to afford 60 as a yellow solid (0.032 g). 0.078 g of starting material was also recovered from the column.

step 2

Into a round bottom flask was added 61 (0.032 g, 0.127 mmol), 2,4-dichlorophenylboronic acid (0.049 g, 0.254 mmol), Pd(PPh ₃ ) ₄ (0.0042 g, 0.0038 mmol), DME (30.0 μL ) and 2M Na ₂ CO ₃ (300.0 μL). The reaction mixture was heated to 80 °C overnight. The reaction mixture was cooled to room temperature and diluted with _H2O , extracted twice with EtOAc, the combined organic phases were dried ( _MgSO4 ), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on _SiO2 (linear gradient 0 to 10% EtOAc/heptane over 20 min) to afford 62 as a yellow oil (0.015 g).

Example 21

7-(2,4-Dichloro-phenyl)-3-methoxymethyl-2-methyl-2H-indazole

step 1

A solution of 7-bromo-2-methylindazole (9, 0.050 g, 0.24 mmol) and THF (1 mL) was cooled to -78 °C and LDA solution (0.17 μL, 2.0 M in THF/hept alkane/ethylbenzene solution). The reaction was stirred at -78°C for 15 minutes and 25 mL of chloromethyl methyl ether was added dropwise. After 10 minutes of addition, the reaction was allowed to warm to room temperature and the volatile solvents were removed in vacuo. The residue was partitioned between DCM (10 mL) and water. The organic solution was washed with brine, dried ( _MgSO4 ), filtered and evaporated. The crude product was purified by flash chromatography on _SiO2 (50% EtOAc/Hexanes) to afford 62 (0.052 g) contaminated with a small amount of starting material.

step 2

Towards 7-Bromo-3-methoxymethyl-2-methylindazole (62, 50 mg, 0.12 mmol), dichlorophenylboronic acid (46 mg, 0.12 mmol), _2M Na2CO ₃ in water (1 mL) and DME (1 mL). The tube was flooded with _N2 and Pd( _PPh3 ) ₄ (0.008 g, 0.007 mmol) was added and the tube was sealed. The reaction mixture was warmed to 85°C and stirred for 12 hours. The reaction mixture was cooled to room temperature and diluted with 5 mL of EtOAc, washed twice with brine, _dried ( _Na2SO4 ). The organic phase was filtered and evaporated in vacuo, and the crude product was purified by flash chromatography on _SiO2 (0 to 25% EtOAc/hexanes) to afford 63.

Example 22

7-(2,4-Dichloro-phenyl)-2-methyl-2H-indazol-3-ylmethyl carbamate

step 1

Aldehyde 64 (3.00 g, 9.83 mmol) was suspended in MeOH (50 mL) at 0 °C and to it was added solid _NaBH4 (0.41 g, 10.84 mmol) in portions over 10 min. The resulting mixture was stirred at 0°C for 30 minutes, then at room temperature for an additional 10 minutes. The reaction was quenched by adding ice. Methanol was removed by rotary evaporation. The residue was partitioned between EtOAc and _H2O . The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried ( _MgSO4 ), filtered and evaporated to give 14b (2.92g, 9.51mmol, 97%).

step 2

To a suspension of 14b (310 mg, 1.01 mmol) in benzene (2 mL) was added NaOCN (0.130 g, 2.00 mmol). Then TFA (0.16 mL, 2.08 mmol) was added slowly. The mixture was stirred overnight at room temperature and partitioned between EtOAc and water. The organic layer was dried ( _MgSO4 ) and concentrated in vacuo. The crude product was purified by flash chromatography on _SiO2 (linear gradient from 20 to 30% EtOAc/hexanes over 30 minutes) to afford 65 (0.94 g, 27% theory).

P113, ref: JOC, 1963, 3421.

Example 23

Dimethyl-carbamate 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazol-3-ylmethyl ester

To a solution of alcohol 14b (0.045 g, 0.146 mmol) and benzene (1 mL) was added NaH (10 mg, 0.25 mmol, 60% dispersion in mineral oil) and the reaction mixture was stirred for 10 min. Carbamoyl chloride (0.02 mL, 0.22 mmol) was added thereto, and the mixture was stirred at room temperature overnight. Analysis of the reaction indicated that the reaction did not go to completion. Carbamoyl chloride (0.02 mL, 0.22 mmol) was further added thereto and the mixture was stirred at 80° C. overnight. The reaction was cooled to room temperature and partitioned between EtOAc and _H2O . The organic layer was dried over _MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (2 mm thickness, 50% EtOAc/hexanes, 3 times elution) to afford 66 (0.023 g, 42% theory).

Example 24

3-Chloro-7-(3,5-dichloro-pyridin-2-yl)-2-methyl-2H-indazole

step 1

A solution of 6 (R=Me, 0.5 g, 2.4 mmol), HOAc (5 mL) and sulfonyl chloride (0.29 mL, 0.490 g, 3.6 mmol) was stirred under _N2 atmosphere for 4 h. The reaction mixture was added to 2M NaOH (30 mL) and extracted three times with EtOAc (30 mL). _The combined extracts were dried ( _Na2SO4 ), filtered and evaporated. The crude product was purified by flash chromatography on _SiO2 (0 to 15% EtOAc/hexanes) to afford 25 (R = Me, 530 mg; 90% of theory).

step 2

To DMSO (1.3 mL, degassed three times) maintained under _N atmosphere was added pinacol borane (0.056 g, 0.22 mmol), KOAc (0.059 g, 0.60 mmol), _PdCl (dppf) (0.005 g , 0.006mmol) and 25 (R=Me, 0.050g, 0.200mmol). The reaction mixture was heated to 85 °C for 1 hour, then allowed to cool to room temperature. To this was added _H2O (10 mL) and the solution was stirred for 1 min, extracted three times with EtOAc (5 mL). _The combined extracts were dried ( _Na2SO4 ), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on _SiO2 (0 to 30% EtOAc/hexanes) to afford impure 67 (0.065 g).

step 3

管中加入得自步骤2的67(65mg，0.23mmol)、2，3，5-三氯吡啶(420mg，0.2.3mmol)、2N K₂PO₄水溶液(2mL)和DMF(2mL)。将该管用N₂进行充溢并向其中加入Pd(PPh₃)₄(2.9mg，0.025mmol)，然后将该管密封。将反应混合物加温至65℃达16小时，冷却至室温并用H₂O(15mL)稀释。将该溶液用EtOAc(5mL)萃取三次并将合并的萃取物干燥(Na₂SO₄)，过滤并真空浓缩。将粗产物在SiO₂上用快速色谱进行纯化(0至20％EtOAc/己烷)，得到不纯的68(0.059g)，通过使用相同条件的第二次色谱处理将其进一步纯化。将产物溶解于Et₂O中并向其中加入2M HCl在Et₂O中的溶液，将沉淀出的盐酸盐滤出并真空干燥。Towards

67 (65 mg, 0.23 mmol) from step 2, 2,3,5-trichloropyridine (420 mg, 0.2.3 mmol), 2N _{aqueous K2PO4} (2 mL) and DMF (2 mL) were added to the tube. The tube was flooded with _N2 and Pd( _PPh3 ) ₄ (2.9 mg, 0.025 mmol) was added and the tube was sealed. The reaction mixture was warmed to 65 °C for 16 h, cooled to room temperature and diluted with _H2O (15 mL). The solution was extracted three times with EtOAc (5 mL) and the combined extracts were dried ( _Na2SO4 ), filtered and concentrated in vacuo _. The crude product was purified by flash chromatography on _SiO2 (0 to 20% EtOAc/hexanes) to give impure 68 (0.059 g), which was further purified by a second chromatography using the same conditions. The product was dissolved in _Et2O and to it was added 2M HCl in _Et2O , the precipitated hydrochloride was filtered off and dried in vacuo.

Example 25

3-Bromo-7-(3,5-dichloro-pyridin-2-yl)-2-methyl-2H-indazole

To a solution of 69 (131 mg, 0.47 mmol) and HOAc (5 mL) was added bromine (75 mg, 0.47 mmol) via syringe. The reaction was stirred for 1 h, the solution was concentrated in vacuo and diluted with _H2O (10 mL). The resulting solution was extracted twice with EtOAc (5 mL) and the combined extracts were dried (MgSO4), filtered and evaporated to give a brown oil. The crude product was purified by flash chromatography on _SiO2 (0 to 50% EtOAc/hexanes) to afford 70 (0.096 g).

Example 26

[7-(2,4-Dichloro-phenyl)-2-methyl-2H-indazol-3-yl]-acetonitrile

step 1

Alcohol 14b (257 mg, 0.836 mmol) was suspended in CHCl ₃ (5 mL) and cooled to 0° C., to which PBr ₃ (0.09 mL, 0.947 mmol) was slowly added. The mixture was stirred at 0 °C for 3.5 hours and quenched with ice water. The mixture was extracted twice with EtOAc and the combined extracts were washed with water, dried ( _MgSO4 ). The solvent was removed in vacuo to afford 71 (315 mg, 100% of theory), which was used in the next step without further purification.

step 2

Bromide 71 (0.315 g, 0.85 mmol) was dissolved in NMP (5 mL) and cooled to 0 °C. To this solution was added NaCN (0.210 g, 4.29 mmol) and the reaction was stirred for 2 hours, quenched with ice water. The mixture was extracted twice with EtOAc and the combined extracts were washed four times with brine, dried ( _MgSO4 ), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on _SiO2 (eluting with a linear gradient of 20 to 30% EtOAc/hexanes over 30 minutes) to afford 72 (0.096 g, 36% of theory).

Example 27

step 1

Into a flask was added 3-carboxy-7-(2,4-dichlorophenyl)-2-methylindazole (73, 1.386 g, 4.32 mmol), toluene (12.5 mL) and tert-butanol (12.5 mL). To the resulting solution was added TEA (1.80 mL, 12.95 mmol) and diphenylphosphoryl azide (2.79 mL, 12.95 mmol). The reaction mixture was heated at 100 °C for 22 hours, cooled and diluted with EtOAc (50 mL). The resulting solution was washed twice with water and once with brine (50 mL). The resulting organic phase was dried (MgSO ₄ ), filtered and evaporated to give a brown oil which was purified by flash chromatography on SiO ₂ (0-30% EtOAc/hexanes) to afford 74 (1.28 g, 70 % theoretical value).

step 2

A solution of 74 (0.5 g, 1.28 mmol), TFA (3 mL) and DCM (5 mL) was stirred at room temperature for 7 hours. To this solution was added 1M NaOH (10 mL) and 50% NaOH (5 mL). The resulting solution was extracted three times with DCM (20 mL), dried ( _MgSO4 ), filtered and evaporated to afford 75 (346.2 g, 93% of theory) as a white solid.

step 3

To a solution of 75 (0.100 g, 0.35 mmol) and DCM (2 mL) and pyridine (0.1 mL) was added methanesulfonyl chloride (0.43 g, 0.37 mmol). The reaction was stirred for 5 hours and quenched with _H2O (10 mL). The resulting solution was extracted twice with EtOAc (25 mL) and the combined extracts were dried ( _MgSO4 ), filtered and evaporated. The crude product was purified by flash chromatography on _SiO2 (0 to 50% EtOAc/Hexanes) to afford 76 (89 mg, 70% theory).

step 4

To a solution of 75 (0.100 g, 0.35 mmol) and dichloroethane (2 mL) was added via syringe (35 mg, 0.37 mmol). The reaction mixture was stirred overnight at room temperature and quenched by the addition of saturated NaHCO ₃ (10 mL). The resulting solution was extracted three times with EtOAc (30 mL), the combined extracts were dried ( _MgSO4 ), filtered and evaporated. The crude product was purified by flash chromatography on _SiO2 (0 to 50% EtOAc/hexanes) to afford 77.

Example 28

[7-(2,4-dichloro-phenyl)-2-methyl-2H-indazol-3-yl]-urea (75) and 3-[7-(2,4-dichloro-phenyl )-2-methyl-2H-indazol-3-yl]-1,1-dimethyl-urea (76)

A solution of 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazol-3-ylamine (0.050 g, 0.17 mmol) in DCM (5 mL) was dichloroisocyanate Acetyl ester (0.022 mL, 0.035 g, 0.188 mmol) was treated and the solution was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction mixture was concentrated under vacuum, the residue was dissolved in MeOH (5 mL), K ₂ CO ₃ (0.1 g, 0.72 mmol) was added thereto and the heterogeneous mixture was stirred at room temperature for 1 h. The solvent was evaporated, _H2O (30 mL) was added thereto, and the precipitated solid was filtered off and dried. Crystallization from MeOH/ _Et2O afforded 76 as a white solid (0.049 g, 49% of theory, mp > 300°C).

A suspension of 75 (0.100 g, 0.342 mmol) and 10 mL of toluene under nitrogen atmosphere was treated with AlMe3 (0.46 mL, 0.92 mmol, 2M in toluene) to slowly dissolve the solid to give a grayish green solution. After 10 minutes at room temperature, the mixture was treated with dimethylcarbamoyl chloride (0.085ml, 0.099g, 0.92mmol) and heated to 100°C for 8 hours. The reaction mixture was cooled to room temperature, treated with _H2O (50 mL) and saturated _NaHCO3 (25 mL) solution, extracted three times with EtOAc (25 mL). The combined extracts were washed with brine (50 mL), dried ( _MgSO4 ), filtered and evaporated to dryness. The residue was purified by flash chromatography on _SiO2 (acetone/ _CH2Cl2 , _15:85 ) to afford 77 as a brown solid (0.085 g, 60% yield, mp 123-126 °C).

Example 29

N-[7-(2,4-dichloro-phenyl)-2-methyl-2H-indazol-3-ylmethyl]-N-methyl-acetamide

Amine hydrochloride 78 (0.0254 g, 0.064 mmol) was dissolved in pyridine (1 mL), to which Ac ₂ O (0.2 mL, 2.12 mmol) was added. The mixture was stirred at room temperature for 72 hours and partitioned between EtOAc and 10% aqueous HCl. The organic phase was washed with _H2O , brine, dried ( _MgSO4 ) and concentrated in vacuo. The crude product was purified by flash chromatography on _SiO2 (eluting with 2% MeOH _{in CH2Cl2} containing 0.15% _NH4OH ) to afford 79 (0.023 g, 99% theory).

Example 30

Methyl [7-(2,4-dichloro-phenyl)-2-methyl-2H-indazol-3-ylmethyl]-carbamate; hydrochloride

step 1

Into a solution of 7-bromo-2-methyl-indazole (6, R=Me, 3.20 g, 15.16 mmol) and dry THF (50 mL) cooled to -78 °C and maintained under _N atmosphere was added dropwise Add LDA (12.0 mL, 22.74 mmol, 2.0 M solution in heptane/THF/ethylbenzene). After complete addition, the reaction mixture was stirred for 10 minutes and warmed to 0 °C for 20 minutes. The dark red solution was cooled to -78°C and DMF (3.0 mL, 45.48 mmol) was added dropwise thereto. The solution was allowed to warm to room temperature and allowed to stir overnight. The reaction was quenched by the addition of saturated _NH4Cl (50 mL), and the resulting solution was extracted twice with EtOAc. The combined extracts were dried ( _MgSO4 ), filtered and evaporated. The crude product was purified by flash chromatography on _SiO2 (linear gradient 0 to 40% EtOAc/heptane over 20 minutes) to afford 0.890 g of a solid as a mixture of starting material and desired product. The reaction was rechromatographed on _SiO2 (linear gradient 0 to 20% EtOAc/heptane over 20 minutes) to afford pure 80 as a solid (0.470 g). The second portion contained 1.22 g of a mixture of starting material and desired product.

step 2

Into a round bottom flask was charged 80 (1.36 g, 5.69 mmol), 2,4-dichlorophenylboronic acid (1.411 g, 7.40 mmol), Pd(PPh ₃ ) ₄ (0.1972 g, 0.17 mmol), DME (35.0 mL ) and 2M Na ₂ CO ₃ (8.0 mL). The reaction mixture was heated to 80 °C overnight. During the reaction, _{Na2CO3 solid} precipitated out, to which water was added as needed to obtain a homogeneous solution (23 mL). The reaction mixture was cooled to room temperature and diluted with EtOAc. The aqueous phase was extracted twice with EtOAc and the combined organic phases were dried ( _MgSO4 ), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on _SiO2 (linear gradient 0 to 20% EtOAc/heptane over 20 min) to afford 64 as a yellow solid (1.62 g).

step 3

64 (2.294g, 2.29mmol), ammonia (4.6mL, 9.18mmol, 2.0M solution in 2-propanol), _MgSO4 (4.14g, 34.4mmol) and _MnO2 (2.0g, 23.0mmol) The suspension was stirred overnight at room temperature. The crude product was purified by flash chromatography on _SiO2 (linear gradient 0 to 10% EtOAc/hexanes over 20 min) to afford 81 as a white solid (0.428 g).

step 4

To a vigorously stirred ice-cold solution of 81 (0.100 g, 0.331 mmol), CoCl ₂ .6H ₂ O (0.008 g, 0.033 mmol), THF (1.0 mL) and H ₂ O (0.5 mL) over a period of 5 minutes To the solution was added NaBH ₄ (0.275 g, 0.728 mmol) in portions. The reaction was brought to room temperature and allowed to stir for 2 hours. The suspended black solid was filtered off and the reaction mixture was concentrated in vacuo. The residual aqueous phase was extracted twice with EtOAc and the combined organic extracts were dried ( _MgSO4 ), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on _SiO2 (linear gradient from 0 to 100% EtOAc/hexanes over 10 min) to afford 82 as a white solid (0.073 g).

step 5

To a solution of 82 (0.073 g, 0.238 mmol) and _Et2O (1.5 mL) were added TEA (66.0 μL, 0.478 mmol) and methyl chloroformate (27.63 μL, 0.358 mmol) sequentially. The resulting mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with _H2O and extracted twice with EtOAc (25 mL). The combined extracts were dried ( _MgSO4 ), filtered and evaporated. The crude product was purified by flash chromatography on _SiO2 (linear gradient 0 to 50% EtOAc/heptane over 15 minutes) to afford 0.049 g of an impure white solid. The resulting solid was further purified by preparative TLC (50% EtOAc/hexanes). The oil recovered from the preparative plate was dissolved in warm THF and a 1.0M HCl/ _Et2O solution was added dropwise until the solution reached a nominal pH of about 1. The resulting mixture was stirred for 0.5 h and the white solid formed was collected by filtration to afford 83 (0.017 g, mp 146.3-148.6 °C).

Example 31

[7-(2,4-Dichloro-phenyl)-2-methyl-2H-indazol-3-ylmethyl]-hydrazine; hydrochloride

step 1

A solution of aldehyde 64 (0.700 g, 0.657 mmol), tert-butyl carbazate (0.087 g, 0.657 mmol), THF (5 mL) and MeOH (5 mL) was stirred at 65 °C overnight. After 20 hours, another aliquot of tert-butyl carbazate (0.092 g, 0.696 mmol) was added and stirring was continued for 24 hours. The reaction was concentrated to give a foamy orange solid which was purified by column chromatography (0 to 50% EtOAc/Hexanes) to give hydrazone (0.303 g) as a foamy pale yellow solid.

A mixture of _NaBH3CN (0.051 g, 0.81 mmol), THF (1 mL) and trimethylchlorosilane (0.100 mL, 0.788 mmol) was stirred for 10 minutes. The hydrazone from the previous step was dissolved in THF (4 mL) and added thereto. The pale yellow solution was stirred for 19 hours; the reaction did not go to completion. To the reaction was added a second aliquot of _NaBH3CN (0.073 g, 1.16 mmol), THF (1 mL) and trimethylchlorosilane (0.150 mL, 1.18 mmol). After 1.25 h, 10% aqueous NaOH (10 mL) was added slowly, and the resulting mixture was extracted with _Et2O (10 mL). The organic layer was washed with 10 mL of saturated aqueous NaCl, dried ( _MgSO4 ), filtered and concentrated to give a yellow oil. Column chromatography (0 to 50% EtOAc/hexanes) afforded 0.097 g (45%) of 84 as a slightly impure white solid.

step 2

Acetyl chloride (1 mL) was slowly added to MeOH (4 mL, EXOTHERMIC). The resulting solution was added to slightly impure 84 (0.097 g, 0.23 mmol), and the pale yellow solution was stirred for 17 hours, then concentrated to give a white solid. The solid was partitioned between _Et2O (5 mL) and 10% aqueous NaOH (5 mL). The aqueous layer was extracted with _Et2O (5 mL), the combined organic layers were washed with saturated brine (10 mL), dried ( _MgSO4 ), filtered and concentrated to give 0.050 g of a yellow oil. The oil was dissolved in _Et2O (3 mL) and to it was added 2.0 M HCl in _Et2O (0.2 mL). The resulting mixture was stirred for 30 minutes, then concentrated to give a pale yellow solid. The solid was triturated with 5 mL of hot THF. After cooling to room temperature, the solid was filtered off, washed well with _Et2O , air-dried and then vacuum-dried to afford 85 (0.036 g, 40%, mp 172.5-176.0) as a pale yellow solid.

Example 32

7-(2,4-Dichloro-phenyl)-2-methyl-2H-indazole-3-sulfonic acid amide

step 1

To a solution of 7-bromo-2-methylindazole (9, 3.330 g, 0.0158 mmol) and dry THF (50 mL) cooled to -78 °C was added dropwise LDA (11.50 mL 0.024 mmol, 2.0 M in heptan alkane/THF/ethylbenzene). The deep red solution was stirred at -78°C for 10 minutes, then at 0°C for an additional 20 minutes. The reaction mixture was recooled to -78°C, and a solution of dibenzylated disulfide (5.83 g, 0.24 mmol) in THF (10 mL) was added dropwise thereto. After complete addition, the reaction mixture was stirred overnight at room temperature. The reaction was quenched by adding 10% NaOH and the aqueous phase was extracted twice with _Et2O (25 mL). The combined extracts were washed with brine (25 mL), dried ( _MgSO4 ), filtered and evaporated. The crude product was purified by silica gel chromatography (0-15% during 20 min, then 15-25% during 10 min) to afford 86 as a light brown solid (3.07 g).

step 2

To a 100 mL flask was added 86 (1.00 g, 3.0 mmol), HOAc (25 mL) and _H2O (2.0 mL). The reaction was cooled in an ice bath and _Cl2 was bubbled through the reaction through a Subsurface Pasteur pipette for exactly 10 seconds. The ice- _water bath was removed and _the solution was stirred for 2 min, at which time the reaction _was quenched by the addition of 10% _Na2S2O3 solution (60 mL), and the aqueous phase was extracted twice with _CH2Cl2 (60 mL). _The combined extracts were washed with 10% NaOH (60 mL), dried ( _Na2SO4 ), filtered and concentrated in vacuo. The pale yellow solid was dried in vacuo and chromatographed on _SiO2 (linear gradient 0-5% EtOAc/hexanes over 20 min) to afford 87 (590 mg) as a white solid.

step 3

A solution of sulfonyl chloride 87 (0.725 g.2.34 mmol), sodium azide (0.152 g, 2.34 mmol), acetone (12 mL) and H ₂ O (12 mL) was stirred at 0° C. for 2.5 hours. Acetone was removed under vacuum and the resulting mixture was extracted twice with _Et2O . The combined organic extracts were dried ( _MgSO4 ), filtered and evaporated to afford 88 as a white solid (0.689g; mp 98.5-99.2°C), which was used in the next step without further purification.

To a solution of 88 (0.650 g, 2.05 mmol), NH ₄ Cl (0.2562 g, 4.79 mmol), EtOH (26 mL) and H ₂ O (9 mL) was added zinc metal (0.269 g, 4.112 mmol) and the reaction was Stir vigorously overnight at room temperature. TLC analysis indicated some sulfonyl azide was still present, to which additional zinc metal (0.1344 g, 2.06 mmol) and NH ₄ Cl (0.110 g, 2.06 mmol) were added and stirring continued for a further 24 hours, at which point no initiation was shown Raw material remaining. The reaction mixture was concentrated in vacuo. The residue was diluted with 5% _NH4Cl and extracted twice with EtOAc (25 mL). The combined extracts were washed with brine, dried ( _MgSO4 ), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on _SiO2 (linear gradient 0 to 30% EtOAc/hexanes over 15 min) to afford 89 as a white solid (0.461 g, mp 202.4-205.3 °C).

step 4

89 (0.293g, 1.01mmol), 2,4-dichloroboronic acid (0.3854g, 2.02mmol), Pd( _PPh3 ) ₄ (0.0351g, 0.030mmol), DME (9.0mL) and _{2M Na2CO3} (2·20 mL) of the solution was heated to 80 °C overnight. Another aliquot of _H2O (4.5 _mL ) was added to dissolve the _Na2CO3 precipitated from the solution. The reaction mixture was cooled and diluted with EtOAc, the aqueous layer was removed and washed twice with EtOAc. The combined organic extracts were washed with brine, dried ( _MgSO4 ) and concentrated in vacuo. The crude product was purified by flash chromatography on _SiO (linear gradient from 0 to 15% EtOAc/heptane during 30 minutes, followed by isocratic elution at 15%) to afford 1,2,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,3,3,4,3,3,3,4,3,3,3,3,3,3 Ac/heptane as a white solid as a white solid. 90 (0.410 g, mp 170.4-171.5°C).

Example 33

7-(2,4-Dichloro-phenyl)-2-methyl-2H-indazole-3-sulfonic acid (2-hydroxy-ethyl)-amide

step 1

Into a round bottom flask was charged 7-(2,4-dichlorophenyl)-2-methyl-indazole (5, 1.750 g, 6.0 mmol), trimethylsilyl chlorosulfonate (2.918 mL, 3.575 g, 19 mmol) and DCE (35 mL), which was fitted with a condenser and heated to 80° C. overnight with stirring. The reaction mixture was cooled to room temperature and concentrated in vacuo. The obtained orange oil was dissolved in SOCl ₂ (10 mL), DMF (500 μL) was added thereto, and the reaction mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography on SiO ₂ (linear gradient from 0 to 15% EtOAc/hexanes over 20 minutes) to afford 87 (0.365 g ).

step 2

To a solution _of sulfonyl chloride 87 (0.030 g, 0.080 mmol) and _CH2Cl2 (5 mL) was added ethanolamine (10.0 μL, 0.160 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography on _SiO (linear gradient 0 to 80% EtOAc/hexanes over 15 minutes) to afford 92 as a white solid (0.014 g , mp202.4-205.3°C). The product can be further purified by reverse phase preparative chromatography eluting with MeCN, _H2O and TFA.

The following compound was prepared in a similar manner from 77-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-sulfinyl chloride using 2-methoxyethylamine, di Methylamine, methylamine, morpholine, N-methylpiperazine, and diethanolamine replace ethanolamine.

7-(2,4-Dichloro-phenyl)-2-methyl-2H-indazole-3-sulfonic acid (2-methoxy-ethyl)-amide (D7)

7-(2,4-Dichloro-phenyl)-2-methyl-2H-indazole-3-sulfonic acid dimethylamide (D8)

7-(2,4-Dichloro-phenyl)-2-methyl-2H-indazole-3-sulfonic acid methylamide (D9)

7-(2,4-Dichloro-phenyl)-2-methyl-3-(morpholine-4-sulfonyl)-2H-indazole (D10)

7-(2,4-dichloro-phenyl)-2-methyl-3-(4-methyl-piperazine-1-sulfonyl)-2H-indazole D(11)

7-(2,4-Dichloro-phenyl)-2-methyl-2H-indazole-3-sulfonic acid bis-(2-hydroxy-ethyl)-amide D(12)

Example 34

7-(2,4-Dichloro-phenyl)-3-methanesulfonylmethyl-2-methyl-2H-indazole

step 1

To a solution of bromide 71 (0.370 g, 1.00 mmol) and NMP (5 mL) at room temperature was added NaSMe (0.210 g, 3.00 mmol), the resulting solution was stirred for 3 h and dissolved between EtOAc and _H2O to allocate between. The aqueous layer was extracted twice with EtOAc. The combined organic extracts were dried ( _MgSO4 ), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on _SiO2 (linear gradient from 15 to 20% EtOAc/hexanes over 30 minutes) to afford 93 as an oil (0.115 g, 34% theory).

step 2

To a solution of sulfide 93 (115 mg, 0.34 mmol) and _CH2Cl2 (2 mL) at room _temperature was added MCPBA (215 mg, <0.96 mmol, <77% assay) and the reaction mixture was stirred overnight. The mixture was partitioned between EtOAc and _NaHCO3 . The aqueous phase was extracted twice with EtOAc and the combined organic layers were dried ( _MgSO4 ), filtered and concentrated in vacuo. The residue was triturated with 20% EtOAc/hexanes and the resulting solid was filtered off and air dried to afford 94 (0.053 g, 42% of theory).

Example 35

step 1

Into a round bottom flask was charged 7-bromo-2,3-dimethylindazole (8, 2.290 g, 10.17 mmol), 2,4-dichlorophenylboronic acid (3.883 g, 20.35 mmol), Pd( _PPh ) ₄ (0.3525 g, 0.31 mmol), DME (25 mL) and 2M Na ₂ CO ₃ (25 mL). The reaction mixture was heated to 80 °C for 72 hours. The reaction mixture was cooled to room temperature, diluted with _H2O and extracted twice with EtOAc, the combined organic phases were dried ( _MgSO4 ), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on _SiO2 (linear gradient 0 to 20% EtOAc/heptane over 20 min) to afford 7 as a light brown oil (2.05 g).

step 2

A solution of fuming nitric acid (5.30 mL) and _Ac2O (1.8 mL) was stirred at 0 °C for 5 min. To this mixture was added 7 (0.627 g, 2.15 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 °C and carefully quenched with 50% NaOH, the aqueous layer was extracted twice with EtOAc, the combined organic phases were dried ( _MgSO4 ), filtered and concentrated in vacuo to afford 95 as a yellow solid ( 0.682g).

step 3

To a vigorously stirred mixture of 95 (0.100 g, 0.297 mmol) and tin (0.1624 g, 1.368 mmol) was added concentrated HCl in three equal portions. After the exothermic reaction subsided, EtOH (2.0 mL) was added and the reaction was heated at 80 °C for 1 h. The reaction mixture was concentrated under vacuum and the residue was carefully mixed with 2N NaOH, extracted twice with _Et2O . The combined organic phases were dried ( _MgSO4 ) and filtered.

To the _Et2O solution from the reduction reaction was added TEA (82.9 DL, 0.595 mmol) and methyl chloroformate (45.9 μL) sequentially. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with _NaHCO3 and the resulting aqueous phase was extracted twice with EtOAc, the combined organic phases were dried ( _MgSO4 ), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on _SiO2 (linear gradient 0 to 30% EtOAc/heptane over 20 minutes) to afford 0.021 g of a slightly impure yellow solid. The yellow solid was dissolved in _Et2O and 1.0M HCl/ _Et2O solution was added dropwise thereto. The resulting solid was collected by filtration to afford 96 (0.0107 g).

Example 36

7-(2,4-Dichloro-phenyl)-2-methyl-2H-pyrazolo[4,3-c]pyridine

step 1

To a solution of 4-amino-3-picoline (97, 10 g, 0.092 mmol) and HBr (50 mL) heated to 70 °C was added 15% _H2O2 (16 _mL ) over 1 h. The reaction mixture was stirred for another hour and poured into ice (100 g). The pH of the solution was adjusted to about 5 with 50% NaOH and the resulting red precipitate was filtered off. The pH was raised to about 9 and the resulting white precipitate was collected by filtration to afford 98 (13.5 g, 78% of theory)

step 2

A suspension of 98 and toluene (100 mL) was heated to 110 °C until the solids dissolved. To the warm solution was added TEA (30 mL, 0.216 mmol) and acetic anhydride (20.4 mL, 22.1 g, 0.216 mmol) and the reaction was heated for 3 hours. After 3 hours, another 30 mL of _Ac2O was added and another 30 mL of TEA was added after 6 hours. The solution was concentrated under vacuum and the residue was dissolved in EtOAc (500 mL), extracted twice with _H2O (200 mL). The aqueous extract was back extracted twice with EtOAc (200 mL), the combined EtOAc extracts were dried ( _MgSO4 ), filtered and evaporated to give a brown oil. The crude product was purified by flash chromatography on _SiO2 (0 to 20% EtOAc/hexanes) to give an impure yellow oil which was subjected to a second flash chromatography on _SiO2 (20 to 50% EtOAc/ hexanes) to afford 99 (12.1 g).

step 3

To a 100ml round bottom flask was added 99 (630mg, 2.3mmol), 2,4-dichlorophenylboronic acid (662mg, 3.5mmol), 2N _{aqueous Na2CO3} (15mL) and DME (15mL). The tube was flooded with N2 and Pd( _PPh3 ) ₄ (79mg, 0.07mmol) was added. The reaction mixture was warmed to 85 °C for 24 hours, cooled to room temperature and diluted with EtOAc (100 mL). The solution was washed twice with brine (20 mL), the organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on _SiO2 (0 to 50% EtOAc/hexanes) to afford pure 100 (0.154 g, 22% theory).

step 4

To a solution of 100 (1.5 g, 5.08 mmol) and benzene (100 mL) was added KOAc (1.4 g, 5.84 mmol) and _Ac2O (1.30 mL, 1.4 g, 13.73 mmol). The solution was warmed to 90 °C and isoamyl nitrite (1.37 mL, 10.16 mmol) was added via syringe. The reaction was heated for 5.5 hours, cooled to room temperature and the mixture was concentrated in vacuo. To the residue were added MeOH (15 mL) and LiOH (20.32 mmol) and the resulting mixture was heated to reflux for 1 h. The reaction was aged overnight at room temperature, then heated for an additional 1 hour. To this solution was added 5 g of silica gel and the solvent was evaporated. The crude product absorbed onto silica was loaded on top of a SiO2 column and purified by flash chromatography (0 to 50% EtOAc/hexanes) to afford indazole 101 (0.570 g, 42% theory).

step 5

To a solution of 101 (0.285 g, 21.08 mmol) and DMF (5 mL) was added NaH (0.060 g, 1.51 mmol, 60% in mineral oil). When gas evolution ceased, dimethyl sulfate (0.136 g, 1.08 mmol) was added and the reaction mixture was stirred for another 0.5 hours. The reaction was quenched by addition of _H2O (20 mL) and extracted three times with EtOAc (30 mL). The combined extracts were dried ( _MgSO4 ), filtered and evaporated to give a brown solid containing two isomers of the N-methyl compound. The crude product was purified by flash chromatography on _SiO2 (20-70% EtOAc/Hexanes). The first fraction contained the 1-methyl isomer and the second fraction contained the 2-methyl isomer. The second fraction was further purified with a second column to afford 102 (0.103 g).

Example 37

7-(2,4-Dichloro-phenyl)-2-methyl-2H-pyrazolo[4,3-b]pyridine

step 1

A mixture of _POCl3 (22 mL) and _PCl5 (15 g) was warmed to 70 °C and to it was added 4-hydroxy-3-nitropyridine (103, 10 g) in small portions. A white solid formed and gas evolved. After complete addition, the reaction was warmed to 140°C and allowed to stir for 5 hours. The reaction mixture was cooled and concentrated in vacuo. _H2O (50 mL) was carefully added to the residue and its pH was adjusted to _7.5 with solid _Na2CO3 . To this was added DCM and the biphasic mixture was stirred for 30 minutes. The phases were separated and the aqueous phase was washed twice with DCM (50 mL). The combined organic phases were dried ( _MgSO4 ), filtered and evaporated to give 104 (8.72 g, 77% of theory) which was pure enough to be used directly in the next step.

step 2

Into a 500 mL round bottom flask was added 104 (6.794 g, 42.9 mmol), 2,4-dichloroboronic acid (8.24 g, 43.2 mmol), Pd(PPh ₃ ) ₄ (2.897 g, 2.51 mmol), DMF (200 mL ) and 2M K ₂ HPO ₄ (128 mL) and the reaction mixture was warmed to 68° C. under N ₂ atmosphere for 21 h. The reaction mixture was diluted with _H2O (1 L) and the yellow precipitate was filtered off, air dried and dried under high vacuum to give 10.07 g of crude product which was purified by flash chromatography on _SiO2 (20% EtOAc/Hexane ), affording 6.002 g (52%) of slightly impure 105 as a yellow solid.

step 3

过滤并用MeOH充分洗涤滤垫。将滤液真空浓缩并在H₂O(20mL)和DCM(20mL)之间进行分配。将水相用DCM(20mL)萃取两次并将合并的有机层干燥(MgSO4)，过滤并蒸发，得到5.809g粗产物，其包含大量起始原料。用7.96g铁粉浓HCl(2mL)重复该过程。如前所述对反应进行后处理，得到橙色树脂形式的不纯的106(4.360g)83％。A solution of 105 (5.935 g, 22.06 mmol), EtOH (26 mL) and _H2O (11 mL) was heated to 90 °C, iron powder (1.85 g, 33.25 mmol) and concentrated HCl (0.4 mL) were added carefully. The reaction was stirred for 2 hours and quenched with 10% NaOH solution (10 mL), then stirred for an additional 10 minutes, then allowed to cool to room temperature. The reaction mixture was treated with CELITE

Filter and wash the pad well with MeOH. The filtrate was concentrated in vacuo and partitioned between _H2O (20 mL) and DCM (20 mL). The aqueous phase was extracted twice with DCM (20 mL) and the combined organic layers were dried (MgSO4), filtered and evaporated to give 5.809 g of crude product which contained a large amount of starting material. The process was repeated with 7.96 g iron powder concentrated HCl (2 mL). The reaction was worked up as previously described to afford impure 106 (4.360 g) 83% as an orange resin.

step 4

To a solution of 106 (2.178 g 9.11 mmol) and HOAc (20 mL) was added bromine (0.94 mL, 18 mmol) dropwise over 1 min. The reaction mixture was stirred at room temperature for 23 hours, then concentrated in vacuo. The crude product was purified by flash chromatography on _SiO2 (10% EtOAc/Hexanes) to afford 107 (0.959 g) (27%) as a yellow-orange solid.

step 5

A solution of 107 (0.050 g, 0.13 mmol), _Ac2O (0.5 mL) and methanesulfonic acid (1 drop) was heated at 130 °C overnight. The reaction mixture was concentrated in vacuo, dissolved in DCM (5 mL), washed with saturated NaHCO ₃ (5 mL), dried (MgSO ₄ ), filtered and evaporated to give 108 (0.072 g) as a yellow oil (“118 %"), which solidifies after standing.

step 6

垫过滤并用MeOH洗涤。在真空下除去溶剂并将粗产物在SiO₂上用快速色谱纯化(0至10％EtOAc/己烷)，得到白色固体形式的109(0.020g)(49％2-步)。A 35 mL three-necked flask was fitted with a stir bar, vacuum outlet and hydrogen filled balloon and added 108 (0.058 g, 0.121 mmol), THF (2 mL) and 10% Pd/C (0.062 g). The vessel was evacuated and filled with _H2 . After 4 h, the _H2 was evacuated and MeOH (1 mL) was added, then the vessel was evacuated and filled with _H2 . After another 4 hours, the reaction was stopped by removal of _H2 and the reaction was allowed to stand at room temperature overnight. The reaction mixture was treated with CELITE

Pad filter and wash with MeOH. The solvent was removed in vacuo and the crude product was purified by flash chromatography on _SiO2 (0 to 10% EtOAc/hexanes) to afford 109 (0.020 g) as a white solid (49% 2-step).

step 7

A solution of 109 (0.410 g, 1.02 mmol), EtOH (4 mL) and pyrrolidine (1 mL) was stirred for 15 min. The volatile solvents were removed in vacuo and the resulting yellow oil was purified by flash chromatography on _SiO2 (0 to 33% EtOAc/hexanes) to afford 110 (0.303 g) (83%) as a white solid.

Step 8

Equip a flask with a stir bar and condenser and add 110 (0.295 g, 0.819 mmol), dioxane (2.7 mL), H ₂ O (0.3 mL), K ₂ CO ₃ (0.395 g, 2.86 mmol ), PdCl ₂ (dppf) (0.068 g, 0.083 mmol), and trimethylboroxine (0.120 mL, 0.858 mmol). The reaction mixture was heated at 93 °C for 2.5 hours, cooled and the solution was partitioned between _H2O (10 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (10 mL), the combined extracts were dried ( _MgSO4 ), filtered and concentrated in vacuo. The crude yellow oil was purified by flash chromatography on _SiO2 (100% EtOAc/hexanes) to afford 111 (0.184 g, 76% theory) as a yellow oil.

step 9

Isoamyl _nitrite (0.13 mL, 0.971 mmol), the reaction mixture was stirred for 14.5 hours, then cooled to room temperature and concentrated in vacuo to give a yellow solid. The residue was taken up with _H2O (2 mL), EtOH (6 mL) and LiOH- _H2O (0.084 g, 2.00 mmol) and heated at 79 °C for 3 h. The mixture was cooled, concentrated in vacuo, and the residue was partitioned between _H2O (5 mL) and _Et2O (5 mL). The aqueous phase was extracted with _Et2O , the combined organic extracts were washed with brine (10 mL), filtered and evaporated. The resulting orange oil was purified by flash chromatography on _SiO2 (0 to 50% EtOAc/hexanes) to afford 112 (0.096 g) (60%) as a yellow foam.

Step 10

To an ice-cold solution of 112 (0.093 g, 0.352 mmol) and THF (4 mL) was added NaH (0.020 g, 0.50 mmol). The bubbling solution was stirred for 15 minutes, then dimethyl sulfate (0.033 mL, 0.35 mmol) was added and the reaction was removed from the ice bath and stirred for 0.5 hours. The reaction was quenched by addition of _SiO2 and concentrated in vacuo. Silica gel was placed on top of a flash column (0 to 66% EtOAc/hexanes) to give 113 (0.057 g, 21% theory) as a yellow solid after standing to solidify.

Example 38

7-(2,4-Dichloro-phenyl)-2-methyl-2H-pyrazolo[3,4-c]pyridine; hydrochloride

step 1

₂ -Chloro-4-methyl-3-nitro-pyridine (114, 1.08g, 6.24mmol), Pd(PPh ₃ ) ₄ (0.405g, 0.350mmol), 2,4- A solution of dichlorophenylboronic acid (1.264 g, 6.62 mmol), DMF (40 mL) and 2M K ₂ HPO ₄ (20 mL, 40 mmol) was heated at 70° C. for 41 hours. The reaction mixture was cooled to room temperature and partitioned between _H2O (200 mL) and _Et2O (200 mL). The organic phase was washed with _H2O (200 mL), brine (200 mL), dried ( _MgSO4 ), filtered and concentrated in vacuo. The resulting yellow oil was purified by flash chromatography on _SiO (0 to 20% EtOAc/hexanes) to afford 115 (1.193 g) (68%) as a yellow oil that was pure enough to be used directly in the following step.

step 2

A solution of 115 (1.148 g, 4.05 mmol), EtOH (10 mL), _H2O (2.5 mL) and cone. HCl (0.5 mL) was heated to 85 °C and iron powder (1.371 g, 24.55 mmol,) was added thereto. The reaction mixture was stirred with continued heating for 1 hour, cooled, and washed with filter. The filter pad was washed well with MeOH and the volatile solvents were removed in vacuo. The red residue was partitioned between EtOAc (50 mL) and saturated NaHCO ₃ (50 mL). The organic phase was washed with brine (50 mL), dried ( _MgSO4 ), filtered and evaporated. The residue was dissolved in toluene (10 mL) and acetic anhydride (0.41 mL) and heated at 100° C. for 22 hours. The reaction mixture was cooled and volatile solvents were removed under vacuum. The dark yellow residue was purified by flash chromatography on _SiO2 (50 to 66% EtOAc/Hexanes) to afford 116 as a white solid (0.815 g 68%).

step 3

A solution of 116 (0.787 g, 2.67 mmol), benzene (30 mL), _Ac2O (0.780 mL, 8.27 mmol) and HOAc (0.330 g, 3.36 mmol) was heated to 78 °C and to it was added isoamyl nitrite ( 0.572 mL, 4.27 mmol). The reaction mixture was heated for 22 hours, cooled, filtered and concentrated in vacuo. The resulting oil (1.063 g) was dissolved in EtOH (21 mL), to which _H2O (7 mL) and LiOH- _H2O (0.339 g, 8.08 mmol) were added. The reaction mixture was heated to 80 °C for 3 hours, cooled and concentrated in vacuo. The orange residue was partitioned between _Et2O (50 mL) and 10% NaOH (50 mL). The aqueous phase was extracted with _Et2O (50 mL), the combined organic extracts were washed with brine (100 mL), dried ( _MgSO4 ), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on _SiO2 (0 to 20% EtOAc/hexanes) to afford 117 (0.484 g, 69%) as a pale yellow foam.

step 4

To a solution of 117 (0.107 g, 0.405 mmol) and THF (4 mL) was added NaH (0.020 g, 0.50 mmol, 60% dispersion in mineral oil). After stirring for 3 hours, dimethyl sulfate (0.040 mL, 0.42 mmol) was added thereto, and the mixture was stirred for 0.5 hours. The reaction was quenched with _SiO2 and concentrated in vacuo. SiO2 was placed on a flash column (0 to 50% EtOAc/hexanes) to give 118 (0.029 g) (26%) as an opalescent film. This product was dissolved in _Et2O (1 mL) and 2.0M HCl/ _Et2O solution was added thereto. The resulting white suspension was stirred for 15 minutes, concentrated and dried in vacuo overnight to afford the hydrochloride salt of 118 (0.031 g) as an off-white solid.

Example 39

35S-TBPS binding assay

Said binding assay is based on that reported by K. Gee et al., Eur. J. Pharmacol. 1987 136:419-423.

Preparation of homogenate: Membrane preparation of HEK293 cells containing GABA _A α ₁ β ₂ γ ₂ or GABA _A α ₂ β ₃ γ ₂ constructs was performed according to a modification of the method previously described by Gee et al. (supra). Whole HEK 293 cells in D-PBS buffer (without calcium/magnesium) adjusted to pH 7.4 were centrifuged at 7,280 xg for 20 minutes. After discarding the supernatant, the pellet was resuspended in buffer and centrifuged at 1,820 x g for 10 min. Afterwards, the supernatant was discarded, and the pellet was resuspended in ice-cold preparation buffer (50 mM Tris HCl pH 7.4, 4 °C and 150 mM KCl), homogenized with a BrinkmannPolytron PT3000 (setting 6) for 30 seconds, at 4 Centrifuge at 48,000 xg for 30 minutes at °C. The centrifugation and homogenization were repeated two more times for a total of 3, and the membranes were then resuspended at a final protein concentration of 0.5 mg/mL. An aliquot (30 mL) of the final membrane preparation was then centrifuged at 48,000 xg for 30 minutes, and the resulting pellet was stored at -80°C until use. 35S-TBPS binding assay . Membrane pellets containing GABA _A α ₁ β ₂ γ ₂ or GABA _A α ₂ β ₃ γ ₂ constructs were thawed on ice and resuspended in 10 mL of 50 mM Tris HCl pH 7.4 at 4 °C and 150 mM KCl and centrifuged at 48,000 x g for 30 min at 4°C. After discarding the supernatant, the pellet was resuspended in 30 mL incubation buffer (50 mM Tris HCl pH 7.4, 25° C. and 150 mM KCl) at a protein concentration of approximately 0.5 mg/mL. In ³⁵ S-TBPS competition studies, HEK293 membranes were incubated with ³⁵ S-TBPS ( 5nM final concentration) and GABA (1μM) for 2 hours. Non-specific binding was determined with picrotoxin (100 [mu]M final concentration). Binding was terminated by vacuum filtration through GF/B filters pre-soaked in 0.1% polyethyleneimine followed by washing (3 x 1 mL) with ice-cold wash buffer (50 mM Tris HCl pH 7.4, 4°C and 150 mM KCl) reaction. Measurements of bound radioactivity were performed with a Packard Microplate 96-well topcount scintillation counter. Competition curve analysis and estimation of _pIC50 values of test compounds were performed with the software programs ActivityBase and/or Prism (version 3.0).

Example 40

Pharmaceutical compositions comprising the subject compounds for different routes of administration were prepared as described in this example.

Composition (A) for oral administration

The ingredients are mixed and dispensed into capsules, each containing approximately 100 mg; one capsule will approximately approximate a total daily dose.

Composition for oral administration (B)

The ingredients are combined and granulated with a solvent such as methanol. The preparation is then dried and formed into tablets (containing about 20 mg of active compound) using a suitable tablet machine.

Composition (C) for oral administration

The ingredients are mixed to form a suspension for oral administration.

Parenteral preparations (D)

The active ingredient is dissolved in a portion of water for injection. Then, enough sodium chloride was added with stirring to make the solution isotonic. The solution was adjusted to the prescribed weight with the remaining water for injection, filtered through a 0.2 micron membrane filter and packaged under aseptic conditions.

Suppository preparation (E)

The ingredients were melted and mixed together on a steam bath and poured into molds containing 2.5 g total weight.

Topical formulations (F)

The ingredients, except water, were combined and heated to about 60°C with stirring. Then, with vigorous stirring, sufficient water at about 60°C was added to emulsify the ingredients, followed by qs to about 100 g.

Nasal spray preparation (G)

Various aqueous suspensions containing about 0.025-0.5% active compound are prepared as nasal spray formulations. The formulations optionally contain inactive ingredients such as, for example, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose and the like. Hydrochloric acid can be added to adjust the pH. Nasal spray formulations can be delivered by nasal spray metered pumps, typically delivering about 500-100 microliters of formulation per spray. A typical dosing regimen is 2-4 sprays every 4-12 hours.

Although the invention has been described with reference to particular embodiments thereof, it will be apparent to those skilled in the art that a particular situation, compound, composition, method, method step or steps may be adapted to suit the objective objectives as defined by the claims. Subject and scope. Such adjustments may be made without departing from the true spirit and scope of the invention as determined by the following claims, along with the full range of equivalents to which such claims are entitled.

All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were individually indicated.

Claims (11)

1. A compound of formula I:

wherein:

R¹is CHR^fR^g、C_2-10Alkynyl, C_1-6Haloalkyl, halogen, cyano, -C (═ Z) R^o、-X²C(＝O)X¹R^f、-NR^fSO₂R^o、-N[C(＝O)OR^m]₂、-S(O)_mR^h、CONRⁱNHR^oOr in which 2 or 3 non-adjacent carbon atoms in the alkyl chain may be replaced by-O-, -S-or-NR^fSubstituted C_1-10An alkyl group;

R²is hydrogen, C_1-6Alkyl radical, C_1-6A haloalkyl group;

R³is aryl, optionally substituted with one or more substituents independently selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio, halogen, C_1-6Haloalkyl, cyano;

R⁴is-NR^a″R^b", wherein R^a"and R^bEach independently selected from hydrogen, C_1-9Alkyl and C_1-9An alkylcarbonyl group;

R^fis hydrogen or C_1-10An alkyl group;

R^gis C_2-10Alkenyl, -NHNH₂Cyano, -OC (═ O) R^f、-S(O)_mR^hor-X²(C＝O)X¹R^f；

R^hIs C_1-6Alkyl radical, C_1-6Heteroalkyl group, NR^jR^k；

RⁱIs C_3-6cycloalkyl-C_1-3An alkyl group;

R^jand R^k(i) Independently of each other is hydrogen, C_1-6Alkyl radical, C_1-6Heteroalkyl, or (ii) together is C_4-6Alkylene or (CH)₂)₂X¹(CH₂)₂；

R^mIs C_1-10An alkyl group;

R^ois C_1-6An alkyl group;

X¹and X²Independently is-O-or-NR^f1-, wherein at each occurrence, R^f1Is independently selected R^fA group, or if R^fAnd R^f1Attached to the same nitrogen atom, then R^fAnd R^f1May also be C together_4-6Alkylene or (CH)₂)₂X¹(CH₂)₂；

Z is O or NOR^o；

m is an integer of 0 to 2;

n is an integer of 0 to 3;

A¹、A²and A³Is C;

the aryl group is phenyl, naphthyl, tetrahydronaphthyl or 3, 4-methylenedioxyphenyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein:

R¹is CHR^fR^g、C_2-10Alkynyl, C_1-6Haloalkyl, halogen or C_1-10An alkyl group;

R²is hydrogen, C_1-6Alkyl or C_1-6A haloalkyl group;

R³is aryl, optionally substituted with one or more halogens;

R⁴is-NR^a″R^b", wherein R^a"and R^bEach independently selected from hydrogen, C_1-9Alkyl and C_1-9An alkylcarbonyl group;

R^fis hydrogen;

R^gis C_2-10An alkenyl group;

n is 0;

A¹、A²and A³Is C;

the aryl group is phenyl, naphthyl, tetrahydronaphthyl or 3, 4-methylenedioxyphenyl;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein R¹Is CHR^fR^g、C_2-10Alkynyl, C_1-6Haloalkyl or halogen; r²Is hydrogen or C_1-6An alkyl group; and R is³Is aryl, optionally substituted with one or more halogens, said aryl being phenyl.

4. A compound according to any one of claims 1 to 3, wherein the compound is selected from

7- (2, 4-dichloro-phenyl) -2, 3-dimethyl-2H-indazole hydrochloride,

2, 3-dimethyl-7- (2, 4, 6-trimethyl-phenyl) -2H-indazole hydrochloride,

7- (2, 4-dichloro-phenyl) -3-ethynyl-2-methyl-2H-indazole,

3-allyl-7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole,

1- [ 2-methyl-7- (2, 4, 6-trimethyl-phenyl) -2H-indazol-3-yl ] -ethanone,

3-chloro-2-methyl-7- (2, 4, 6-trimethyl-phenyl) -2H-indazole,

3-chloro-7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole,

3-bromo-2-methyl-7- (2, 4, 6-trimethyl-phenyl) -2H-indazole hydrochloride,

3-bromo-7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole,

[7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazol-3-yl ] -acetonitrile,

7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole-3-carbonitrile,

7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole-3-carboxylic acid N-cyclopropylmethyl-N' -ethyl-hydrazide trifluoroacetic acid,

[7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazol-3-ylmethyl ] -hydrazine hydrochloride,

[7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazol-3-ylmethyl ] -carbamic acid methyl ester hydrochloride,

dimethoxycarbonylamino- [ 2-methyl-7- (2, 4, 6-trimethyl-phenyl) -2H-indazol-3-yl ] -amine,

morpholine-4-carboxylic acid [7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazol-3-ylmethyl ] -amide,

[7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazol-3-yl ] -carbamic acid methyl ester,

3- [7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazol-3-ylmethyl ] -1, 1-dimethyl-urea,

3- [7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazol-3-yl ] -1, 1-dimethyl-urea,

3-ethylsulfonyl-2-methyl-7- (2, 4, 6-trimethyl-phenyl) -2H-indazole,

3-methanesulfonyl-2-methyl-7- (2, 4-dichloro-phenyl) -2H-indazole,

7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole-3-sulfonamide,

2- [7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole-3-sulfonyl ] -ethanol,

7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole-3-sulfonic acid (2-hydroxy-ethyl) -amide,

7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole-3-sulfonic acid (2-methoxy-ethyl) -amide,

7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole-3-sulfonic acid dimethylamide,

7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole-3-sulfonic acid methylamide,

7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole-3-sulfonic acid bis- (2-hydroxy-ethyl) -amide,

7- (2, 4-dichloro-phenyl) -3-methanesulfonylmethyl-2-methyl-2H-indazole,

7- (2, 4-dichloro-phenyl) -3-methanesulfinyl-2-methyl-2H-indazole,

n- [7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazol-3-yl ] -methanesulfonamide,

7- (2, 4-dichloro-phenyl) -3- (2-methoxy-ethoxymethyl) -2-methyl-2H-indazole,

acetic acid [7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazol-3-yl ] -methyl ester,

dimethyl-carbamic acid 7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazol-3-ylmethyl ester,

carbamic acid 7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazol-3-ylmethyl ester.

5. The compound of claim 4, wherein the compound is selected from the group consisting of:

7- (2, 4-dichloro-phenyl) -2, 3-dimethyl-2H-indazole hydrochloride,

7- (2, 4-dichloro-phenyl) -3-ethynyl-2-methyl-2H-indazole,

3-allyl-7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole,

3-chloro-7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole, and

3-bromo-7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole.

6. The compound of claim 5, wherein the compound is selected from the group consisting of:

7- (2, 4-dichloro-phenyl) -2, 3-dimethyl-2H-indazole hydrochloride, and

3-bromo-7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole.

7. The compounds 7- (2, 4-dichloro-phenyl) -2-methyl-3-vinyl-2H-indazole, 2-methyl-7- (2, 4, 6-trimethyl-phenyl) -3-vinyl-2H-indazole, 7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole-3-carbaldehyde O-methyl-oxime, 7- (3, 5-dichloro-pyridin-2-yl) -2, 3-dimethyl-2H-indazole, 3-chloro-7- (3, 5-dichloro-pyridin-2-yl) -2-methyl-2H-indazole, m, 3-bromo-7- (3, 5-dichloro-pyridin-2-yl) -2-methyl-2H-indazole or 7- (2, 4-dichloro-phenyl) -2-methyl-2H-indazole-3-carboxylic acid ethyl-propyl-amide trifluoroacetic acid.

8. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of diseases which can be mediated by GABA_AA disorder ameliorated by a positive allosteric modulator of a receptor.

9. The use of claim 8, wherein the disorder is depression, an anxiety disorder, a psychiatric disorder, a learning or cognitive disorder, a sleep disorder, a convulsive or seizure disorder or pain.

10. The use of claim 8, wherein said GABA is_APositive allosteric modulators of receptors vs. alpha₁Alpha for a subtype₂Selective modulators of subtypes.

11. For the prevention or treatment of diseases which can be mediated by GABA_AA pharmaceutical composition for the treatment of a condition alleviated by a positive allosteric modulator of a receptor, said composition comprising a therapeutically effective amount of a compound according to any one of claims 1-7 in admixture with at least one diluent, excipient or carrier.