TW201026672A - Spiroaminooxazoline analogues as alpha2C adrenergic receptor modulators - Google Patents

Abstract

In its many embodiments, the present invention provides a novel class of spiroaminooxazoline analogues as modulators of α2C adrenergic receptor, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more conditions associated with the α2C adrenergic receptors using such compounds or pharmaceutical compositions.

Description

201026672 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a spiroamine 11 oxazoline analog suitable for use as a-2C (or "cx2C") adrenergic receptor modulator, and the manufacture of such compounds A method, a pharmaceutical composition comprising the same, and a method of treating and preventing a disease condition associated with a-2C receptor modulation using the compounds and compositions, such as hyperemia (including nasal congestion) , migraine, congestive heart failure, cardiac ischemia, glaucoma, stress-induced urinary incontinence, Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder , pain and psychiatric conditions (such as depression and schizophrenia). This application claims the benefit of US Provisional Application Serial No. 61/103,385, filed on Jan. 7, 2008, which is hereby incorporated by reference. The bodies were originally classified into the alpha family and the beta family (Ahlquist RP, "A Study of the Adrenergic, Receptors" Am, J. Physiol. 153:586-600 (1948)). The alpha adrenergic receptor is functionally associated with most excitatory functions (vasoconstriction, uterine stimulation, and pupillary enlargement). Beta adrenergic receptors are involved in vasodilation, bronchodilation, and myocardial stimulation (Lands et al., "Differentiation of Receptor Systems Activated by Sympathomimetic, amines" Nature 214:597-598 (1967)). Due to this early study, alpha adrenergic receptors have been subdivided into adrenergic receptors and a2 adrenergic receptors. a kidney 143636.doc 201026672 The selection and performance of adrenergic receptors have confirmed the presence of α1 (α1Α, alB, alD) adrenergic receptors and various subtypes of a2 (a2A, a2B, a2C) adrenergic receptors (Michel Et al., "Classification of a! - Adrenoceptor Subtypes", Naunyn-Schmiedeberg's Arch. Pharmacol, 352: 1-10 (1995); Macdonald et al., "Gene Targeting--Homing in on a2-Adrenoceptor-Sub type Function", TIPS, 18:211-219 (1997)). The current therapeutic use of a-2 adrenergic receptor drugs includes their ability to mediate a variety of physiological effects of endogenous catecholamines. There are a variety of drugs that act on these receptors to control hypertension, intraocular pressure, redness of the eyes, and nasal congestion and induce analgesia and anesthesia. The a2 adrenergic receptor can be found in the ventrolateral nucleus of the cerebral ventricle and is known to respond to the neurotransmitter norepinephrine and the antihypertensive drug clonidine to reduce sympathetic outflow and reduce arteries. Blood pressure (Bousquet et al., "Role of the Ventral Surface of the Brain Stem in the Hypothesive Action of Clonidine", Eur. J. Pharmacol, 34: 151-156 (1975); Bousquet et al., "Imidazoline Receptors: From Basic Concepts to Recent Developments, 26: S1-S6 (1995)). Clonidine and other flavors are also associated with imidazoline receptors (formerly known as imidazoline-guanidinium acceptor sites or IGRS) (Bousquet et al., "Imidazoline Receptors: From Basic Concepts to Recent Developments", 26: S1_S6 (1995)). Some researchers have speculated that ° meters. The role of siting as a hypotensive agent in the middle and periphery may be related to the feeding of β-lin receptors (Bousquet et al., “Imidazoline 143636.doc 201026672”

Receptors: From Basic Concepts to Recent Developments, 26: S1-S6 (1995); Reis et al., "The Imidazoline Receptor:

Pharmacology, Functions, Ligands, and Relevance to Biology and Medicine", Ann. N. Y. Acad. Sci., 763: 1-703 (1995)). Compounds having epinephrine activity are well known in the art and are described in numerous patent and scientific publications. Adrenaline activity is generally known to be useful in the treatment of mammalian species, including humans, to cure or alleviate the symptoms and conditions of more than one disease and condition. In other words, a pharmaceutical composition which is generally considered to have an adrenaline compound as an active ingredient in the art is particularly suitable for the treatment of glaucoma, chronic pain, migraine, heart failure and psychosis (e.g., schizophrenia). For example, the published PCT application WO 02/076950 discloses a compound having an alpha 2 agonist activity in a ruthenium form:

Other publications which disclose similar compounds include WO 01/00586, WC) 99/28300, US 6,841,684 B2 and US 2003/0023098 Al. Another class of compounds having the properties of an alpha 2 agonist is disclosed in U.S. Patent No. 5,658,938 and having The following formula:

143636.doc 201026672 wherein n=1-2, R^-R3 represents hydrogen, halohydroxy, alkyl or alkoxy, and R5 is hydrogen or alkyl. Another class of compounds reported to have affinity for the alpha 2 receptor include the following two compounds (Bagley et al, Met/. C/zem. and 1994, 4: 346-364):

Compounds with epinephrine activity, such as alpha 2 agonists, are also known to be associated with undesirable side effects. Examples of such side effects include high blood pressure and hypotension, sedation, locomotor activity, and psychotic conditions (e.g., schizophrenia). Another class of compounds reported to have affinity for the alpha 2 receptor include the following two compounds (Miller et al, J_ Mei C/zew. 1994, 37: 2328-23 33; J. Med. Chem. 1996, 39: 3001-3013 J. Med. Chem. 1997, 37:3014-3024):

Another class of indane and tetrahydronaphthalene type compounds having the properties of an α2 agonist is disclosed in 卩 (: 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。

143636.doc 201026672 wherein η=0-1, X is 1 or 2 carbon units, R4 is Η, OH, alkyl or alkoxy, R5 can form a carbonyl group with R4, and R6-R8=H, OH , SH, alkyl, dilute, cycloalkyl, alkoxy, decyl, thiol, thiol, halo, CF3, N〇2 or alkylamine. This class includes, inter alia, MPV-2426C fadolmidine and its prodrug vinegar:

❹ wherein R is optionally substituted lower alkyl, aryl, cycloalkyl, heteroaryl, lower alkylamino, and saturated 5 or 6 membered heterocyclic containing 1 or 2 N atoms. In addition, other classes of compounds that exhibit functional selectivity to the a2C receptor have been discovered. A porphyrin compound having this activity is disclosed in USSN 11/508,458, filed on Aug. 23, 2006, the disclosure of which application Serial No. . CIP applications for these applications have been filed; serial numbers 11/705, 673 and 11/705, 683, both applied on February 13, 2009. Other applications by Schering-Plough and disclose a2C receptor agonists include application WO 2008/100480 (PCT/US2008/001808); WO 2008/100459 (PCT/US2008/001770) and WO 2008/100456 (PCT) /US2008/001765). Compounds that act as antagonists of the a2C receptor are also known in the art. Hoeglund et al. describe an allegedly effective and selective a2C antagonist and is said to be suitable for the treatment of "some psychiatric disorders such as depression and schizophrenia" 143636.doc 201026672 (Hoeglund et al., J Med. Chem 49: 6351-6363 (2006)). WO 2001/64645 to Orion Corp. is also described as a salivary derivative of the a-2C receptor antagonist and is indicated for use in the treatment of conditions in the peripheral or CNS system, including treatment of depression, anxiety, post-traumatic stress Symptoms, schizophrenia, Parkinson's disease and other motor disorders, and dementia (eg Alzheimer's disease). Also disclosed in WO 2003/082825 to Orion Corp., a-2C receptor antagonists are useful for treating conditions of conditions and conditions with sensorimotor-gating defects. Selliner et al. pointed out that η丫 bit-9-yl-[4-(4-indolylpyrheptyl-1-yl)-phenyl]amine is a south selective a-2C adrenergic receptor antagonist and can be applied to Treatment of neuropsychiatric disorders (Salliner et al, British J. Pharmacol. 150: 391-402 (2007)) ° Compounds known to have epinephrine activity, such as alpha 2 agonists, may be associated with undesirable side effects. Examples of such side effects include high blood pressure and hypotension, sedation, voluntary activity, and hyperthermia. The benzospiroene heterocyclic compound of the following formula is described in U.S. Patent Nos. 5,436,261, 5,486,532 and 5,648,374.

It is said to be suitable as an alpha 2 adrenergic agonist; in the compounds described therein, the definition of X includes -(ch2)2-, -〇-, -o-ch2- and -S-CH2-; 143636.doc 201026672 The definition includes -ο-, -S- and -N(R6)-; and the definition of R5 includes hydrogen or an amine group. Cordi et al., "/. Med. C/zew. 1994, 38: 4056-4069, also reveals [1,3-diazacyclopent-1-ene) 5,2'-(Γ, 2', 3 ',4·-tetrahydronaphthyl) or a spiro-imidazole compound, such as

As an alpha adrenergic agonist. W〇 2006/080890 discloses that this compound can be used in combination with other agents to prevent biofouling of the organism. U.S. Patent 6,673,337 describes and claims an ophthalmic composition comprising an a-2C agonist component and a component which increases solubility in addition to the cyclodextrin. This patent does not specifically describe the a-2C receptor agonist.

The compounds of the invention have been found to act as modulators of the a2C receptor (i.e., they act as a_2C receptor agonists or as a-2C receptor antagonists) and are useful for the treatment of a-2C receptor modulation according to the invention. Illness. There is a need for novel compounds, formulations, treatments and therapies for the treatment of diseases and conditions associated with a2C adrenergic receptors. In addition, there is a need for a-2C receptor modulators that minimize undesirable side effects such as adverse side effects associated with the a_2A receptor subtype, i.e., blood pressure or sedation. Accordingly, it is an object of the present invention to provide compounds which are useful in the treatment or prevention or amelioration of such diseases and conditions. SUMMARY OF THE INVENTION The present invention, in its many embodiments, provides a novel class of heterocyclic compounds as a2c kidney 143636.doc 201026672 adenosine modulators, or metabolites thereof, stereoisomers, dishes, solvents Or a polymorph, a method of preparing such a compound, a pharmaceutical composition of such a compound, or a method of preparing a pharmaceutical formulation comprising one or more of such compounds, and the use of such a compound or A method of treating, preventing, inhibiting or ameliorating one or more conditions associated with an a2C receptor. In one aspect, the application discloses a compound, or a pharmaceutically acceptable salt or metabolite, solvate, prodrug or polymorph of the compound, which compound has the general structure shown by the formula :

I wherein: J1, J2, J3 and J4 are independently -N-, -N(O)- or -C(R2)-; X is -C(R6)(R6')-, -N(R6') -, ·〇_ or _S·; W is -N(R15)-, -Ο- or -S-; Z is independently selected from the group consisting of η, -〇H, halo, -CN, -N〇2 > -S(0)pR7 ' -NR7Rr ^ -[C(Ra)(Rb)]qYR7' . -[C(Ra)(Rb)]qN<R7)YRr,-[C(Ra )(Rb)])=qOYR7' and -(CH2)q〇N=CR7R7·, and a pyridyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl group , aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclic 143636.doc •10· 201026672 alkyl, such groups optionally as at least one (preferably 丨Up to 5, more preferably 1 to 3) R5 substitution; wherein is a single bond or a double bond, the restriction is that when W is _〇_ or -s-, the double bond exists between the N and 2_ positions, And when w is -N(R15)-, the double bond exists between the ^^ and 2_ positions or the hip and the 孓 position 'but not 2 adjacent double bonds, · R1 is selected from the group consisting of: [C(Ra)(Rb)]qYR7,, _[c(Ra) (R )]qN(R7)YR7 . -[C(Ra)(Rb)]qNR7R7' . -[C(Ra)(Rb) ]q〇YR7' -[C(Ra)(Rb)]qN(Y R7)(YR7') , -[C(Ra)(Rb)]qON=CR7R7' and _[C(Ra)(Rb)]qCN ; y is selected from the group consisting of: _c(=0)_, _c(=〇)nr7_, _c(=G〇(>, -C(=0)-[C(Ra)(Rb)]n-〇_C(=〇)- > -C(=〇) N(Rc)-〇___C(=NR7)-, -C(=NOR7)-, -C(=NR7)NR7-, -C(=NR7)NR7〇-, -C(=N-CN)- , _s(0)p-, -S02NR7· and -C(=S)NR7-; wherein R and Rb are independently selected from the group consisting of alkyl, alkoxy and halo groups, and

Re is a hydrazine or a decyl group; R is absent or independently selected from the group consisting of Η, 〇Η, 卤, halo, CN, N〇2, -S(0)pR7, _nr7r7, and alkyl , alkoxy, alkenyl, diloxy, alkynyl, cycloserpine, nonyloxy, aryl, heteroarylalkyl and heterocyclylalkyl, such groups optionally being at least one of Preferably, i to 5, more preferably 1 to 3, R5 is substituted; R3 is independently selected from the group consisting of H, halo, _CN and (=〇), and alkyl, alkanoyl, alkenyl , alkenyloxy, alkynyl, cycloalkyl, 143636.doc -11· 201026672 cycloalkoxy, aryl, aryloxy, arylalkyl, heteroarylheteroarylalkyl, heterocyclyl and hetero a cycloalkyl group, which groups are optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) R5, with the proviso that when evaluated as 3, no more than 2 R3 groups are available. (=〇); R4 is independently selected from the group consisting of Η, D, _〇H, dentate, -CN, -S(0)pR7, -NR7R7', and -S(0)pNR7R7'' And alkyl, deuterated alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aromatic The group, the aryloxy group, the arylalkyl group, the heteroaryl group, the heteroarylalkyl group, the heterocyclic group and the heterocyclylalkyl group, wherein the groups are at least one (preferably 丄 to 5) Preferably, 1 to 3) R5 is substituted; R4' is independently selected from the group consisting of hydrazine, d, dentate, OH and alkyl, decyl and alkoxy; or R4 and R4 may be formed together ( = 〇), which is limited to the presence of no more than one (=〇) group when m>1; R5 is independently selected from the group consisting of hydrazine, halo, 〇H, _CN, -N〇 2, -NR7R7' and -S(0)pR7, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkane a base, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group and a heterocyclic alkyl group, each of which is optionally at least one (preferably 1 to 5, more preferably 1 to 3) from the group, OH, -CN, -N02, -NR7R7' and -S(0)pR7 substituents and/or Bugo 2 (=0) substitutions, R6 is selected from the group consisting of hydrazine, -OH, halo, _CN, -N02, -S(0)pR7, _NR7R7', -S(0)pNR7R7., -C(0)-R1(), -C(0)-OR]° and -c(o)-n (r7)rm, Alkyl, alkoxy, alkenyl, alkenyloxy, alkyne 143636.doc •12- 201026672 base, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, hetero An arylalkyl group, a heterocyclic group and a heterocyclic alkyl group, each of which is optionally at least one (preferably 1 to 5, more preferably 1 to 3) halo, -OH, -CN, -N 〇2, -NR7R7' and -S(0)pR7 substituents and/or 1 or 2 (=〇) groups and _C(=0)R7, -C(=0)〇R7, -C(= 0) NR7R7', -so2r7 and -so2nr7r7, substituted; R6 is selected from the group consisting of Η, -S(0)pR7, -S(0)pNR7R7·, -C(0)-R1(), _c (0)-〇R1(), _c(〇)-N(R7)R1G and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryl An oxy group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group, and a heterocyclic group, each of which is optionally at least one (preferably 1 to 5, more preferably 1 to 3) i), -OH, -CN, -N〇2, -NR7R7' and -S(0)pR7 substituents and/or 1 or 2 (= 〇) group substituents and _c(=〇) R7, _c(=〇)〇r7, -c(=o)nr7r7', _s〇2R7 and -so2nr7r7' are substituted; or R6 and R6 ' can be formed together (=〇); R7 is independently selected from the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl , aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heterocycloalkenyl, heterocycloalkenylalkyl, heteroaryl and heteroarylalkyl, each of which is optionally substituted by Ru One or more times (preferably 1 to 5 times, more preferably 1 to 3 times); R is independently selected from the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkane , cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heterocycloalkenyl, heterocycloalkenylalkylheteroaryl and heteroarylalkyl Each of them may be replaced by R!2 as a 143636.doc _ 13· 201026672 or multiple times (1 to 5 times better, preferably 1 to 3 times); or a) contemporary number is -NR7R7', - [C(Ra)(Rb)]qYR7,, _c[(Ra) (R )]qNR R, -[C(Ra)(Rb)]q〇YR7, -(cH2)qNR7R7·, -C(0) When NR7R7· or -s〇2:nr7r7', R7 and r7' independently form a 3- to 8-membered heterocyclic group, heterocycloalkenyl group or heteroaryl ring together with the nitrogen atom to which they are attached, In addition to the N atom, there are also 1 or 2 additional heteroatoms independently selected from the group consisting of ruthenium, n, _N(R9)- and s, wherein the cyclical conditions are up to 5 independently selected R5 moieties and / or 1 or 2 (=〇) replacement, or

b) When the 畲 code is -(CH2)qON=CR7R7, or -[c(Ra)(Rb)]q〇N=CR7R7, R7 and R7_ independently form a 3 to 8 member ring together with the carbon atom to which they are attached Alkyl, cycloalkenyl, aryl, heterocyclyl, heterocycloalkenyl or heteroaryl, wherein the heterocyclyl, heterocycloalkenyl or heteroaryl ring has from 1 to 3 pendants selected from a hetero atom of a group consisting of 〇, N, _N(R9)_&S, wherein the cyclical condition is substituted by 1 to 5 independently selected R5 moieties and/or 1 or 2 sin (=〇);

The R system is independently selected from the group consisting of hydrazine, _c(〇)_rio, _c(〇)_〇Rio and -S(0)p-〇R10, and alkyl, alkenyl, alkynyl, cycloalkyl aryl a base, an arylalkyl group, a heteroaryl group, and a heteroarylalkyl group, each of which is optionally at least one (preferably 1 to 5, more preferably 1 to 3) halo, 〇H, _CN, _n〇2, _n(r11)2 and a substituent and/or 1 or 2 (=〇) substitutions; R1() is independently selected from the group consisting of oxime, alkyl, alkenyl, alkynyl, cyclized I, an aryl group, an arylalkyl group, a heteroaryl group and a heteroaryl group, each of which is optionally at least one (preferably up to 5, more preferably up to a) basis ΟΗ

• CN-N02, -N(Rn)2&_s(〇)pRu substituents and 143636.doc •14· 201026672 or 2 (=〇) substitutions; are independently selected from the group consisting of: Alkyl, burnt, dilute, dilute, fast, benzyl, oxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroaryl, heterocyclic, and hetero Cycloalkyl, each of which is optionally substituted with at least one (preferably 1 to 5, more preferably i • 3) substituents selected from the group consisting of: _ group, -OH , -CN, -N〇2, -N(Rn')2&_s(〇)pRii. Substituents and, or i or 2 (=〇); ❹ . R is independently selected from the group consisting of ^ j, alkyl, alkoxy, alkenyl, alkenyl 'alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, Heterocyclyl and heterocyclylalkyl; R is independently selected from the group consisting of H, halo, _〇h, _CN, -N〇2 '-N(Rn)2 '-C(0)- 0R14 ' -N(R14)-C(〇)-R14 > -N(R14)-C(0)2-R14, -C(0)-N(R 丨丨)2, -N(R 丨4 )-S(0)2-R",_s(〇)2_n(rh)2 φ _S(0)pr11 and/or 1 or 2 (=〇} groups, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkenyl, cycloalkoxy, Aryl, aryloxy, arylalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heterocyclyl, heterocycloalkenyl, heterocyclenyloxy, heterocyclylalkyl, hetero a cycloalkyl group, an aryl alkoxy group, a heteroaralkyloxy group, a heterocyclic alkoxy group, and a heterocycloalkenyloxy group, each of which is optionally selected from the group consisting of the following: Substituted at least once (preferably 1 to 5 times, more preferably 1 to 3 times): anthracene, alkyl, haloalkyl, halo, -hydrazine, optionally substituted alkoxy, optionally substituted Alkoxy, optionally substituted cycloalkoxy, heteroaryloxy substituted by 143636.doc •15· 201026672, heterocyclic alkenyloxy substituted, _cN, N〇2, -N (R)2 and -S(0)PR" and or 2 groups, wherein the substituted alkoxy group, aryloxy group, optionally substituted cycloalkoxy group, as the case may be substituted Heteroaryloxy and heterocyclenyloxy groups are substituted by R11 when substituted One or more history (preferably up to 5 times, more preferably up to 3 times) R is independently a ruthenium, a ruthenium or an aryl group; R is absent (ie, nitrogen forms a _N=c with a carbon atom at the 2_ position) Z) _ key) or independently selected from the group consisting of: H, _C(〇)_R〗 0, _c(〇)_〇r10, -〇(〇)七(1^(^) and 3(〇) ?1丨0,8〇2卞尺7117, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, aryl group And a heteroaryl group, a heteroaryl group, a heterocyclic group and a heterocyclic alkyl group, each of which has at least one (preferably 1 to 5, more preferably 1 to 3) cleavage groups depending on the inert state, OH, -CN, -N〇2, -NR7R7j_s(〇)pR7 and or 2 (=0) group substituents and a C(=〇)r7, _c(=〇)〇r7, _c(=〇) Nr7r7,, -so2r7 and _s〇2NR7R7' are a single generation; n is independently a tutor of 〇_2; m is independently an integer of 1 _3; p is independently a tutor of 〇_2; and w is 0- An integer of 3; the constraint is that when R1 is - and u_s (〇v, p cannot be 〇. The compound of formula I is useful as (X2C adrenergic receptor modulator and J) for the treatment or prevention of one or more conditions associated with the a2C receptor by administering at least one compound of formula j to a mammal in need of treatment. Can be borrowed: Beer field regulation 143636.doc -16- 201026672 a2C receptor to treat the condition including ia ^ ^ ^ arrogant rhinitis, congestion (including the following related ▲: perennial allergic rhinitis, seasonal Allergic rhinitis, non-allergic rhinitis, vasomotor sinusitis or chronic sinusitis, 丄=1, acute heart-shaped or hyperemia caused by the common cold), pain (such as neuropathy, inflammation, arthritis or Diabetes), abdomen: glaucoma, congestive heart failure, chronic heart failure, heart area, blood mania, depression, anxiety, migraine, stress-induced urine

Incontinence, neuronal damage caused by ischemia, schizophrenia, hypopetic hyperactivity disorder, diabetes symptoms, post-traumatic stress disorder, Parkinson's disease: or dementia (eg Alzheimer's disease). Another embodiment of the present invention is the treatment or prevention of one or more diseases associated with a2c receptors by administering at least one compound of formula I to a mammal in need of treatment by selectively modulating a mammalian a2c adrenergic receptor. shape. Another embodiment of the present invention is to administer an effective amount to a mammal of the type (4)! The compounds are used to treat or prevent - or a variety of conditions associated with alpha 受体 receptors without altering blood pressure at therapeutic doses. Another embodiment of the invention is a method of selectively modulating a2C adrenergic receptors in a cell of a mammal in need thereof, comprising: constituting the cell with a therapeutically effective amount of at least one compound of the formula or a pharmaceutically acceptable compound thereof Contact with salt, vinegar, prodrug or salt. Another embodiment of the invention is a method of treating a blood donor in a mammal in need thereof without altering the blood house at a therapeutic dose, comprising administering to the mammal an effective amount of at least one compound having epinephrine activity, wherein This compound is a selective agonist of the a2C receptor. 143636.doc •17· 201026672 [Embodiment] In one embodiment, the invention discloses certain spiroamino oxazoline derivatives represented by structural formula I, or a pharmaceutically acceptable salt or solvate thereof , each part is as described above. In another embodiment, j1, j2, and Θ are each _C(R2)_. In another embodiment, j2, j3, and β are each _CH_. In another embodiment, J2 and J3 are _CH- and J丨 is _N_. In another embodiment, 'J1 and J3 are -CH- and J2 is _N_. In another embodiment, J1, J2, and J3 are independently _CR2_ or _N_. In another embodiment, J1 and j2 are _CH_ and j3 is -N_. In another embodiment, J1 and J2 are _CH- and J3a_n_. In another embodiment, n is one. In another embodiment, n is 2. In another embodiment, n is 〇. In another embodiment, ρ is an integer of 〇_2. In another embodiment, X is _CH2-. In another embodiment, X is -NH-. In another embodiment, X is _〇_. In another embodiment, X is _S-. In another embodiment, X is _N(r6,). In another embodiment, Ri is tied to the knot; J2, j3, and j4 are _CH; and χ is -CH2- 0. In another embodiment, R1 is constructed with j丨; J2; -NH-. 143636.doc 201026672

In another embodiment -O- 〇 in another embodiment is -S- 〇 in another embodiment is -CH2-. In another embodiment it is -NH-. In another embodiment it is -0-. In another embodiment it is -S-. In another embodiment it is -CH2-. In another embodiment it is -NH-. In another embodiment it is -0- in another embodiment -S-. In another embodiment it is -CH2-. In another embodiment it is -NH-. R1 is bonded to J1; J R1 is bonded to J1; J R1 is bonded to J4; J R1 is bonded to J4; J R1 is bonded to J4; J R1 is bonded to J4; J R1 is J1 bonding; J: R1 is bonded to J2; J1 R1 is bonded to J2; J] R1 is bonded to J2; J] R1 is bonded to J3; J1 R1 is bonded to J3; J1

J3 and J4 are -CH-; and X J3 and J4 are -CH-; and X J2 and J3 are -CH-; and X J2 and J3 are -CH-; and X J2 and J3 are -CH-; and X J2 and J3 are -CH-; and X J3 and J4 are -CH-; and X J3 and J4 are -CH-; and X J3 and J4 are -CH-; and X J3 and J4 are -CH-; and X J2 and J4 are -CH-; and X J2 and J4 are -CH-; and X 143636.doc -19- 201026672 In another embodiment, R1 is bonded to J3; j, j2 and; -0-. In another embodiment, the 'R1 line is bonded to J3; Ji, J2, and j4 are ·CH_; and are again -S-. In another embodiment, Z is -NR7R7', wherein R7 and R7 are independently H, alkyl, R12-aryl and R12-cycloalkyl. And R. Or haloalkyl. In another embodiment, m is 1 and W is -〇-. In another embodiment, m is 1 and W is -S-. In another embodiment, the spiral ring is:

In another embodiment

a substituted cycloalkyl group (e.g., cyclopropyl, cyclopentyl or cyclohexyl) or, as appropriate, -20-143636.doc 201026672, substituted aryl (e.g., phenyl), wherein the substituent is optionally present Halo, hydroxy, amine, alkylamino, dialkylamino, nitro or cyano. In another embodiment, z is an amine group, an alkylamino group or a dialkylamine group. In another embodiment, R15 is deuterium or alkyl. In another embodiment, R1 is -[C(Ra)(Rb)]qYR7_, _[C(Ra)(Rb)]qN(R7)YR7', and -[C(Ra)(Rb)]qCN, Where q is 0 or 1; Y is --C(=0)-, -C(=〇)NR7·, -C(=0)0-, -S(0)p-, and -S02NR7·. In another embodiment, R7 and R7. are independently R12-alkyl (eg, methyl, ethyl, propyl, optionally substituted with halo, cyano or alkoxy (eg, decyloxy); And R12-aryl (for example, phenyl optionally substituted by alkyl, haloalkyl, cyano, nitro, amine, alkylamino, dialkylamino, hydroxy or alkoxy). In another embodiment, the invention discloses a compound represented by Structural Formula II-V, or a pharmaceutically acceptable salt, solvate or ester thereof, wherein each definition is as defined above for Formula I:

Formula III 143636.doc 201026672

Formula IV Formula V Formula II-V is a compound wherein: R1 is -[C(Ra)(Rb)]qYR7, -[C(Ra)(Rb)]qN(R7)YR7,,_ [C(Ra) (Rb)]qOYRr and -[C(Ra)(Rb)]qCN, where q is 〇 or 1; Υ φ is --C(=0)-, _C(=0)NR7-, -C(=0)0-, -C(=NOR7)-, -S(0)p- and -so2nr7-; R7 and R7 are independently H, R12-alkyl (for example, halo, cyanide, as appropriate) a methyl or ethyl group substituted with an alkoxy group (e.g., methoxy); and a ri2_ aryl group (e.g., optionally via an alkyl group, a haloalkyl group, a nitro group, an amine group, an amine group) A phenyl group substituted with a dialkylamino group, a hydroxyl group or an alkoxy group; X is CH2 or hydrazine; and R15 is absent or is a hydrazine or an alkyl group (e.g., methyl or ethyl). An example of a compound of formula I is a compound of the formula:

VI or its pharmaceutically acceptable salt' is defined as the definition of Formula 1 143636.doc •22· 201026672. Another example of a compound of the formula νι is a compound wherein: R1 is -[C(Ra)(Rb)]qYR7', _[C(Ra)(Rb)]qN(R7)YR7', _[C( Ra) (Rb)]qOYR7' and -[C(Ra)(Rb)]qCN, , R4 is Η, D, alkyl or deuterated alkyl (eg _CH2d, CHD2 or CD3); R4 is Η, D , alkyl or deuterated alkyl (eg _ch2D, CHD2 or CD3); 9 Y is a bond, a C(=0)-, -C(=0)NR7-, -C(=0)0_,- C(=NOR7), -s(o)p- and -S02NR7-; q is 0 or 1; and R7 and R7 are independently fluorene, R12-alkyl (for example, halo, cyano or oxynitride, as appropriate) a methyl group, an ethyl group, a propyl group, and a Ri2. aryl group substituted by a group (for example, an oxiranyl group) (for example, an alkyl group, a dentyl group, a cyano group, a nitro group, an amine group, an alkylamino group, and a second compound). Amino, a trans- or alkoxy-substituted stupid base, φ or a pharmaceutically acceptable salt thereof. Another embodiment of a compound of formula I

VII or a pharmaceutically acceptable salt thereof, wherein the definition is the same as the definition of Formula I 143636.doc • 23· 201026672. Another example of a compound of formula VII is a compound wherein: R1 is -[C(Ra)(Rb)]qYR7', _[C(Ra)(Rb)]qN(R7)YR7', _[C( Ra) (Rb)]qOYR7' and -[C(Ra)(Rb)]qCN, R4 is Η, D, alkyl or deuterated alkyl (eg -CH2D, CHD2 or cd3); R4' is Η, D , alkyl or deuterated alkyl (eg -CH2D, CHD2 or cd3); Y is a bond, --C(=0)-, -C(=0)NR7-, -C(=0)0-, -C(=NOR7), -s(o)p-, and -S02NR7-; q is 0 or 1; and R7 and R7' are independently hydrazine, R12-alkyl (eg, i-based, cyano, or Alkoxy (eg methoxy) substituted fluorenyl, ethyl, propyl) and R12-aryl (eg, optionally, an alkyl group, a halogen group, a cyano group, a decyl group, an amine group, an acryl group, a phenyl group substituted with a dialkylamino group, a hydroxyl group or an alkoxy group, or a pharmaceutically acceptable salt thereof. Another example of a compound of formula VIII is a compound of the formula: nh2

143636.doc •24- 201026672 or a pharmaceutically acceptable salt thereof, wherein the definition is the same as the definition of the formula [. Another example of a compound of formula VIII is a compound wherein: R1 is -[C(Ra)(Rb)]qYR7', _[c(Ra)(Rb)]qN(R7)YRr, _[c(Ra ), (Rb)]q〇YR7' and -[C(Ra)(Rb)]qCN, r4 is H, D, alkyl or deuterated alkyl (eg -CH2D, CHD2 or CD3); r4 is H, D, alkyl or deuterated alkyl (for example -CHzD, CHD2 or cd3); Y is a bond, --C(=0)-, -C(=0)NR7·, -C(=0)0- , -C(=N〇R7), -S(0)p- and -S02NR7-; q is 0 or 1; and R7 and R7' are independently fluorene, R12-alkyl (eg, halo, as appropriate) a cyano or alkoxy group (e.g., a decyloxy group substituted with a methyl group, an ethyl group, a propyl group) and an R12-aryl group (e.g., optionally an alkyl group, a haloalkyl group, a cyano group, a nitro group, an amine group, an alkyl group) Alkyl, dialkylamino, hydroxy or alkoxy substituted phenyl), or a pharmaceutically acceptable salt thereof. Another example of a compound of formula I is a compound of the formula:

R4 R4' IX or a pharmaceutically acceptable salt thereof, wherein the definition is the same as the definition of Formula I 143636.doc -25- 201026672. Another example of a compound of the formula ι is a compound wherein: R1 is -[C(Ra)(Rb)]qYR7, -[C(Ra)(Rb)]qN(R7)YR7,,KRa) (Rb )]qOYR7' and -[C(Ra)(Rb)]qCN, R4 is Η, D, alkyl or deuterated alkyl (eg -CH2D, CHD2 or CD3); R4' is deuterium, D, alkyl or Deuterated alkyl (eg -CH2D, CHD2 or CD3); Y is a bond, --C(=0)-, -C(=0)NR7-, -C(=0)0-, -C(= NOR7) 10, -s(〇)P- and -so2nr7-; q is 0 or 1; and 7, R and han 7 are independently hydrazine, R12-alkyl (for example, halo, cyano or An alkoxy group (e.g., an oxiranyl group substituted with an alkyl group, an ethyl group, a propyl group) and a sulfonyl 12-aryl group (e.g., optionally an alkyl group, an alkyl group, a cyano group, a nitro group, an amine group, or an alkylamino group) a phenyl group substituted with a dialkylamine, a hydroxyl group or an alkoxy group, or a pharmaceutically acceptable salt thereof. In the category I

One of the compounds within the group is the compound shown below:

143636.doc 26- 201026672

Or a pharmaceutically acceptable salt of each of these compounds. Another group of compounds in the scope of Formula I are the compounds shown below:

And the pharmaceutically acceptable salts of each of these compounds. In another embodiment, the compound of Formula I, or a pharmaceutically acceptable salt, solvate or ester thereof, is present in isolated and purified form. An embodiment of the invention is a compound that acts as an agonist of the a2c receptor. a-2C steroid agonist can be used to treat or prevent allergic rhinitis, congestion (including but not limited to nasal congestion), migraine, congestive heart failure, chronic heart failure, cardiac ischemia, glaucoma, stress Induced urinary incontinence, impotence hyperactivity disorder, neuronal damage caused by ischemia and mental: syndrome. In addition, receptor agonists can be used to treat pain (chronic and acute 143636.doc *27- 201026672 =,: two inflammations, neuropathy, arthritis (including osteoarthritis and, = arthritis), diabetes ( For example, pain caused by diabetes or diabetes insipidus or pain of unknown cause. Examples of parasitic neuropathic pain may include, but are not limited to, diabetic neuropathy, any pathogen (eg, after cancer treatment, three nerves) Neuropathic pain, chemotherapy-induced neuropathy, back pain caused by neuropathy (eg sciatica), any pathogenic traumatic peripheral nerve injury, central pain (eg post-stroke, thalamus, spinal nerve injury). The treatable pain is nociceptive pain and visceral cause (4) pain, or pain secondary to inflammation or nerve damage in other diseases or causes unknown diseases. In addition, α 2 steroid agonist can be used to treat diabetes symptoms. Examples may include, but are not limited to, hyperglycemia, hypertriglyceridemia, high blood insulin levels, and hyperlipidemia. The compound has an efficacy of the a2C receptor of 23% Emax (GTPyS assay), and this compound is defined as an agonist of the a-2C receptor. Another embodiment of the present invention is the following: it takes precedence over the α2Α receptor sub Type-selective and preferably even specific as an agonist of the 〇12 (: or 0126/〇12€: (hereinafter referred to as a2C or a2B/2C) receptor subtype, and prioritizes the function of the α2Α receptor subtype Selectively acting as an agonist of the a2c or a2B/a2C receptor subtype, which has the desired therapeutic properties associated with adrenergic receptors without one or more undesirable side effects, such as blood pressure changes or sedation. The object of the invention 'if the effect of the compound on the a2C receptor> 30% EmaJGTPyS assay) and its pair (the efficacy of the X2A receptor is $35% Emax (GTPyS assay), then the compound is defined as the a2C receptor subtype is preferred over α2Α Receptor subtype specificity 143636.doc -28- 201026672 or at least a functional selective agonist. In another embodiment of the invention, the compound acts as an antagonist of the a-2C receptor. a-2C receptor antagonism Agents can be used to treat or prevent such as depression, schizophrenia, and trauma Diseases of stress, Parkinson's disease, dementia (eg, Azheimer's disease), and neuropathic disorders. If the compound is effective against the a2C receptor < 30% Emax (GTPyS assay) and for the a2C receptor Binding inhibition (Κ〇 < 500 nM, preferably < 200 nM, and optimal < 20 nM, the compound is defined as an antagonist of the a-2C receptor. In another embodiment of the invention, The a2C receptor subtype antagonist has the desired therapeutic properties associated with the a2C adrenergic receptor without one or more undesirable side effects associated with a2A agonism. For the purposes of the present invention, a compound which acts as an antagonist of the a2C receptor subtype preferably does not have an effect on the a2A receptor of 35% Emax or 35% Emax or more (GTPYS assay). Alternatively, the invention provides a method of treating hyperemia in a mammal in need thereof, comprising administering to the mammal an effective amount of at least one compound having renal adrenergic activity, wherein the compound is an a2C receptor or a2C/aB A functional selective agonist of the adrenergic receptor. - A further embodiment of the invention is a method of treating hyperemia in a mammal in need thereof, comprising administering to the mammal an effective amount of at least one compound having adrenergic activity, wherein the compound is a2C receptor or a2C/ a functionally selective agonist of the aB adrenergic receptor, wherein the selective agonist of the a2C receptor or the a2C/aB adrenergic receptor has an efficacy greater than or equal to 35% Emax in the GTPYS assay and its effect on a2A Receptor efficacy $35% Emax (GTP7S assay). 143636.doc -29- 201026672 As used above and throughout the disclosure, the following terms are understood to have the following meanings unless otherwise stated: "Patient" includes both humans and animals. "Mammal" means humans and other mammals. "(X-2C Modulator) or "a2C Modulator" means a compound that has a biological response (ie, an agonistic or antagonistic response) to α2 (the receptor has affinity (or binds to the a2C receptor)." The a-2C receptor agonist or the ra2c receptor agonist is an endogenous ligand (eg, neurotransmitter) that has affinity for α2 (the receptor and triggers the simulation to bind to the same receptor) a compound that reacts with the biological response of the reaction. a 2C antagonist or "a2c receptor antagonist" has affinity for the a2c receptor and initiates blockade or attenuation. A compound that reacts with a biological response caused by an endogenous ligand (such as a neurotransmitter). "Hybridation" refers to all types of hyperemia, including but not limited to perennial allergic rhinitis, seasonal allergic rhinitis , non-allergic rhinitis, vasomotor rhinitis, drug rhinitis, sinusitis, acute sinusitis or chronic sinusitis-related congestion or polyps caused by polyps or associated with the common cold. "burning" means direct linear Or branching chain The chain contains an aliphatic hydrocarbon group of from about 1 to about 20 carbon atoms. Preferably, the alkyl group contains from about 1 to about 12 carbon atoms in the chain. More preferably, the alkyl group contains from about 1 to about 6 carbon atoms in the chain. Branched chain means that one or more lower alkyl groups (such as methyl, ethyl or propyl) are attached to a linear alkyl chain. "Lower alkyl" means a chain which may be a straight or branched chain 143636 .doc 30- 201026672 A group having from about 1 to about 6 carbon atoms. The term "substituted alkyl" means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being Independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amine, _NH(alkyl), -NH (cycloalkyl And -N (alkyl group, carboxyl group and _c(〇)〇-alkyl group. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, t-butyl." "Deuterated alkyl" means an alkyl group in which at least one hydrogen of an aliphatic hydrocarbon group is replaced by a halogen atom. Examples of the alkylene group include, for example, _CDH3, _Cd2H, _Cd3, -CH2CD3, etc. Alkenyl" An aliphatic hydrocarbon group having one carbon-carbon double bond and which may be a straight or branched chain and comprising from about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have from about 2 to about 12 carbon atoms in the chain; More preferably, it has from about 2 to about 6 carbon atoms in the chain. Branched chains mean that one or more lower alkyl groups (such as decyl, ethyl or propyl) are attached to a linear alkenyl chain. "Base" means about 2 to about 6 carbon atoms in a chain which may be a straight or branched chain. "Amidino" may be unsubstituted or optionally substituted with one or more substituents which may be the same or different. Each substituent is independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, silk, and -8 (household). Non-limiting examples of suitable dilute groups include ethylene Base, propyl, n-butenyl, 3-methylbut-2-indolyl, n-pentenyl, octenyl and decenyl. "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon reference and which may be straight or branched and comprising from about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have from about 2 to about 12 carbon atoms in the chain; and more preferably from about 2 143636.doc • 31 to 201026672 to about 4 carbon atoms in the chain. Branched chain means that one or more lower alkyl groups (such as methyl, ethyl or propyl) are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-indenyl. The term "substituted alkynyl" means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of an alkyl group, an aryl group and a ring-based group. "Aryl" means an aromatic monocyclic or polycyclic ring system containing from about 6 to about 14 carbon atoms, preferably from about 6 to about 1 carbon atoms, wherein at least one of the polycyclic rings is an _aryl ring. The aryl group may optionally be substituted with one or more "ring system substituents" which may be the same or different and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. Non-limiting examples of aryl polycyclic systems include: αί or @ or 〇3?. "Heteroaryl" means about 5 to about 14 ring atoms, preferably about 5 to about 1 ring atoms (wherein - or more ring atoms are elements other than carbon, such as nitrogen or sulfur, early An aromatic monocyclic or polycyclic ring system, either alone or in combination, wherein at least one of the polycyclic rings is an aromatic ring. Preferred heteroaryl groups contain from about 5 to about 6 ring atoms. "Heteroaryl" may be optionally substituted with one or more substituents which may be the same or different and which are referred to herein as an anthracene ring system. The first aza, oxa or thia in the heteroaryl means that at least one nitrogen exists as a ring atom, respectively. The nitrogen of the chowder is considered to be the corresponding N-oxide. 143636.doc -32- 201026672 Non-limiting examples of suitable perovskite include pyridyl, pyrazinyl, furyl, thiacyl A, pyrimidinyl, isoxazolyl, isothia:yl: decyl, oxime... Base, sulfhydryl-based base... 2 — ° sit-based, % azine, base, 啥 琳, hand [, _a] pyridyl, imidazolium [2, 1-b] thiazolyl, benzoyl , n 引 Beer, , 丨木基Iheteroquinone, benzimidazolyl, benzoheptene, 喧琳基, σ米吨美,攻,# t里塞塞幷pyridyl, quin Oxazolinyl,

Thiophenepyrimidinyl, oxime, glutamic acid, mercaptopyridinyl, isoquinolyl, benzazepine, 1 2 4 _ , , 4-diazinyl, benzothiazolyl and Non-limiting examples of heteroaryl polycyclic systems include:

"基基" ""arylalkyl" means an aryl group and a hospital base such as the previously V aryl group. Preferred aryl groups comprise a low carbon alkyl group. Non-limiting examples of suitable aryl groups include benzyl, phenethyl and naphthylmethyl. Bonded to the parent part via the base. "Alkylaryl" means alkyl and aryl as defined previously. The alkyl-aromatic-preferably aryl aryl group comprises a low charcoal. A non-limiting example of a suitable alkyl aryl group is a tolyl group. Bonded to the parent moiety via an aryl group. "Cycloalkyl" means a non-aromatic monocyclic or polycyclic ring system comprising from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms. Preferably, the cycloalkyl ring contains from about 5 to about 7 ring atoms. The cycloalkyl group may be optionally substituted with one or more "ring system substituents" which may be the same or different from 143636.doc -33.201026672 and as defined above. Non-limiting examples of suitable monocyclic cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable polycyclic cycloalkyl groups include, for example, decahydronaphthyl, norfolk, adamantyl and the like. "Halogen" and "halo" mean that fluorine, chlorine, bromine or iodine is preferably fluorine, chlorine or bromine and more preferably fluorine and gas. "Ring system substituent" means, for example, a substituent attached to an aromatic or non-aromatic ring system, such as a substituent available for hydrogen on the ring system. Ring system substituents can be the same

Or different, each independently selected from the group consisting of aryl, heteroaryl, aralkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, hydroxy, aryl &oxy , aryloxy, aryloxy, aryl, aryl, yl, decyl, cyano, aryl, alkoxy, aryloxy, aryloxy, carbyl, Aryl (10), heteroaryl, thiol, arylthio, heteroarylthio, arylthio, heteroarylthio, cycloalkyl, heterocyclyl 'υιΥ2Ν·, YiY2NH, YiY2NC ( 〇) 4 y] y2Ns〇2_, wherein m2 may be the same or different and independently selected from the group consisting of ruthenium, alkyl, aryl and aryl. "Heterocyclyl" means a non-aromatic and monocyclic or polycyclic ring system comprising from about 3 to about 1 ring atom, preferably from about 5 to a rigid ring atom, wherein - or a plurality of atoms of the ring system are carbon Elements such as nitrogen, oxygen or sulfur, single 3 or in combination. No adjacent oxygen and/or sulfur atoms are present in the ring system. Preferred heterocyclic groups contain from about 5 to about 6 ring atoms. The p-hetero, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or ... exists, respectively. Any (10) in the heterocyclyl ring may be present in a protected form such as -n(b〇c), _N(CBz), _N(Tos) groups and the like, such as 243636.doc-34-201026672; The protected portion is also considered to be part of the invention. "Heterocyclyl" may be optionally substituted by one or more "ring system substituents" which may be the same or different and are as defined herein. The nitrogen or sulfur atom of the heterocyclic group may be oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide as the case may be. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidinyl, pyrrolidinyl, acenaphthyl, pyrazolidine, piperazinyl, morpholinyl, thiomorpholinyl, thiazole

A butyl group, a 1,4-dioxanyl group, a tetrahydrofuranyl group, a tetrahydrothiophenyl group, and the like. The compounds of formula I and their salts, esters, solvates and prodrugs may exist in their tautomeric form (for example in the form of a guanamine or an imine ether). All such tautomeric forms are contemplated herein as part of the present invention. Non-limiting examples of tautomeric forms that are part of the invention are as follows:

It should be noted that in the saturated heterocyclic group-containing system of the present invention, a trans group, an amine group or a sulfhydryl group is not present on a carbon atom adjacent to an n, hydrazine or § atom. So, for example, in the following ring: 143636.doc -35- 201026672

There is no direct connection to the carbons labeled 2 and 5. [β should also note that this definition does not exclude (=〇), (=s) or on C atoms adjacent to N, 〇 or S. (-N) substitution, or its tautomeric form. Thus, for example, in the above ring '(=〇) substitution on carbon 5 or its imine ether tautomer is allowed. Non-limiting examples illustrating the invention are as follows:

The following non-limiting examples are intended to identify groups not covered by the present invention:

SH OH

"Alkynyl" means alkynyl-alkyl-, wherein alkynyl and alkyl are as described in the prior art. Preferred alkynyl groups contain a lower alkynyl group and a lower carbon group. It is bonded to the parent part through the base. Non-limiting examples of suitable alkynylalkyl groups include propargyl fluorenyl. "Heteroaralkyl" means a heteroaryl-alkyl group wherein the heteroaryl group and the alkyl group are as previously described. Preferred heteroaralkyl groups contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridyl indenyl and quinoline-3-ylindenyl. The bond to the parent moiety is via alkane 143636.doc -36- 201026672.杂 辰 基 炫 基 基 基 § § § § § § § § § § § § § § § § § § § § § § § Preferred heterocyclic alkyl groups contain a low carbon alkyl group. Non-limiting examples of suitable heterocyclylalkyl groups include piperidinyl fluorenyl, π carbyl ethyl, pyrrolidinylmethyl, morpholinylpropyl, piperazinylethyl, azindylmethy, azetidin Alkylethyl, oxiranylpropyl and the like. It is bonded to the parent moiety via an alkyl group. φ "Heterocyclenyl or heteroCycloaikeneyi" means a non-aromatic monocyclic or polycyclic ring system comprising from about 3 to about 1 ring atom, preferably from about 5 to about 1 ring atom, wherein the ring system One or more of the atoms are elements other than carbon, such as nitrogen, oxygen or sulfur atoms (alone or in combination and contain at least one carbon-carbon double bond or carbon-nitrogen double bond. No phase exists in the ring system Oxygen and/or sulfur atom. Preferably, the heterocyclenyl ring contains from about 5 to about 6 ring atoms. The first aza, oxa or thia before the heterocyclenyl root name means that at least one nitrogen is present, The oxygen or sulfur atom is substituted as a ring atom. The heterocyclic ring may be substituted with a plurality of ring (10) substituents, wherein the "ring-purified soil" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl group may be oxidized to r = Oxide, 4 compound or S, S• dioxide. Non-limiting examples of suitable monocyclic aza (tetra) groups include a tetrahydro(tetra)yl group, a dihydrogen 0 base group, and a 1,4-dihydroindole ratio. Bite beauty,] 2 ^ & therefore hydrogen · X 1 疋 base 1 and 3, 6 - four heart bite base, M, 5, 6 four saliva Γ V Viloline, 3-约°琳基基, 2·味撒琳基, 2_° than heterozygous ~ sinoyl, 2 thiazolinyl and the like. Non-limiting examples of suitable oxydiyl groups include 3,4_2 Chlorine, dihydrogenite bite, south base and the like. Suitable non-epoxy heterocyclenyl 143636.doc -37-201026672 A non-limiting example is 7-oxabicyclo[221]heptenyl. Non-limiting examples of suitable monocyclic thiene heterocycles include dihydrothiophenyl, dihydrothiopiperine, and the like. "Heterocyclenylalkyl" means heterocyclenyl and alkyl. A heterocycloalkenyl-alkyl group as previously described. "Carbogenated" means an alkyl group as defined previously as HO-alkyl. Preferably, the alkyl group contains a lower alkyl group. Suitable hydroxyalkyl groups Non-limiting examples include hydroxyindenyl and 2-hydroxyethyl. "Rowry" means an organic acid group in which the OH group -OH is substituted with another substituent. Suitable non-limiting examples include H_c(〇)_, an alkane a group of -C(O)-, cycloalkyl-C(O)-, heterocyclyl-c(〇)_, and heteroaryl*_c(〇)., wherein the various groups are as previously described. The carbonyl group is bonded to the parent moiety. Preferably, the thiol group is contained. Non-limiting examples of suitable sulfhydryl groups include methyl ketone, ethyl ketone and propyl aryl. "Aromatic aryl" means aryl as defined above for the aryl _c(o)- group. Non-limiting examples of suitable groups include a benzyl group and a 1-naphthyl group. "Alkoxy" means an alkyl group such as alkyl-oxime as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. Bonded to the parent moiety via ether oxygen. "Aryloxy" An aryl group is an aryl-fluorene group as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthyloxy. Bonded to the parent moiety via ether oxygen. "Aromatic alkoxy" or "aryloxyalkyl" means an arylalkyl-o- group as described in 143636. doc-38-201026672. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1-naphthylmethoxy or 2-naphthyloxy. It is bonded to the parent moiety via ether oxygen. "Heteroaralkyloxy" means a heteroarylalkyl group as described above for a heteroarylalkyl group-- group. "Heterocyclylalkoxy" means a heterocyclylalkyl group as described above for a heterocyclylalkyl-0- group. "Heterocycledylalkoxy" means a heterocycloalkenylalkyl group as described above for a heterocycloalkenylalkyl-0- group. "Alkylthio" means an alkyl group as described above for the alkyl-S- group. Non-limiting examples of suitable alkylthio groups include sulfonylthio and ethylthio. Bonded to the t-part moiety via sulfur. "Arylthio" means an aryl group as aryl-S- group as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. Bonded to the parent moiety via sulfur. "Aralkylthio" means an aralkyl group as described above for an aralkyl-S- group. A non-limiting example of a suitable aralkylthio group is a benzylthio group. Bonded to the parent moiety via sulfur. "Alkoxycarbonyl" means an alkyl-0-C0- group. Non-limiting examples of suitable alkoxycarbonyl groups include anthracenyloxycarbonyl and ethoxycarbonyl. It is bonded to the parent moiety via a carbonyl group. "Aryloxycarbonyl" means an aryl-o-c(o)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthyloxycarbonyl. It is bonded to the parent moiety via a carbonyl group. 143636.doc •39- 201026672 "Aralkyloxycarbonyl" is an aralkyl-o-c(o)- group. A non-limiting embodiment of a suitable aralkoxycarbonyl group is a benzyloxycarbonyl group. Bonded to the parent moiety via a carbonyl group. "Alkylsulfonyl" means an alkyl-s(o2)- group. Preferred groups are those wherein the alkyl group is a lower alkyl group. Bonded to the parent moiety via a sulfonyl group. "Arylsulfonyl" means an aryl-s(o2)- group. It is bonded to the parent moiety via a sulfonyl group. The term "substituted" means that one or more hydrogens on a given atom are replaced by a member selected from the specified group, the regimen being such that it does not exceed the normal valence of the specified atom in the prior case, and the substitution produces a stable compound. Combinations of substituents and/or code numbers are only permitted if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a structure that is sufficiently robust to survive the separation from the reaction mixture to the appropriate purity and formulation as an effective therapeutic. Note that the carbon of formula I can be replaced by 1-3 helium atoms with the proviso that all valence requirements are met. The term "substituted as appropriate" means to be replaced by a specified group or part as the case may be. Straight line - as a mixture generally represents a mixture of possible isomers or any of them, non-limiting f examples include (R)-stereochemistry and (S)-stereochemistry. For example,

Η means both Η and Η 143636.doc -40- 201026672 The dotted line () indicates the key that exists as the case may be. Extend into the ring system _ line, such as:

Indicates that the specified line (key) can be connected to any of the original atoms. The four (4) systemic examples include carbon, nitrogen and sulfur ring atoms.

As is well known in the art, unless otherwise extended (wherein the bond ... (d) from the special atom π! bond & no part specified) indicates that the methyl group is bonded to the atom via the bond. For example:

It should also be noted that any heteroatom having an unsaturated valence in the text, scheme, examples and tables herein has a hydrogen species to saturate the valence of the valence. When the functional group in the compound is referred to as "protected", This means that the group is modified to avoid improper side reactions of the protected site when the compound is subjected to the reaction. Suitable protecting groups will be identified by familiarity with this technique and by reference to W. Greene f a > Protective Groups, please contact Peru (1991), Wiley, New Y〇rk). Any code of S (e.g., aryl, heterocycle, r2, etc.) appears in any composition or formula - more than one time. Unless otherwise defined, all definitions of the code are in accordance with the following convention: 143636.doc -41· 201026672 The right group forms a point of attachment to the molecule; if defined as an arylalkyl group, this means an alkyl group as defined. Part of the connection to the molecule. In addition, all binary codes are connected from left to right. For example, when R1 is _[C(Ra)(Rb)]qN(R7)YR7' and Y is -C(=0)-, -C(=0)0- or -C(=0)NR7 When R1 forms a group -[C(ita)(Rb)]qN(R7)-C(=0)-R7', -[C(Ra)(Rb)]qN(R7)-C( = 0) 0-Rr or -[C(Ra)(Rb)]qN(R7)- c(=o)n(r7)(r7'). In the present application, unless otherwise specified, whenever a structural formula (such as the structural formula of Formula I to Formula IX) is provided, this text is intended to encompass all forms of the compound, such as any solvate, hydrazine hydrate, stereoisomerism. Body, tautomer, etc. As used herein, the term "composition" is intended to cover a product comprising a specified amount of the specified ingredients, as well as any product which is produced directly or indirectly from a combination of the specified ingredients. Prodrugs and solvates of the compounds of the invention are also contemplated herein. As used herein, the term "prodrug" means a compound that is a precursor to a drug which, upon administration to an individual, undergoes chemical conversion by metabolic first chemical processes to produce a compound of formula I or a salt and/or solvate thereof. In T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987), ACS Symposium Series·^ % 14^ ^ 3. Bioreversible Carriers in Drug Design, (1987) Edited by Edward B. Roche, American Pharmaceutical Association and A discussion of prodrugs is provided in Pergamon Press, both of which are incorporated herein by reference. For example, if a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate of 143636.doc • 42· 201026672 contains a carboxylic acid functional group, the prodrug may be included by, for example, a vinegar formed by replacing a hydrogen atom of an acid group: (q-C8)alkyl, (Cz-C!2) alkoxymethyl, 1-(compressed base) having 4 to 9 carbon atoms Ethyl), iota-methyl_ι_(alkylhydrargyloxy)-ethyl having 5 to 1 碳 carbon atoms, alkoxycarbonyloxymethyl group having 3 to 6 carbon atoms, having 4 1-(alkoxycarbonyloxy)ethyl group having 7 carbon atoms, 1-mercapto-1-(alkoxycarbonyloxy)ethyl group having 5 to 8 carbon atoms, having 3 to 9 N-(calcined carbonyl)aminomethyl group of carbon atom, 1-(N-(oxygenoxy)amino)ethyl group having 4 to 1 carbon atoms, 3-bristyl group, 4-crotonic acid Lactone group, γ-butyrolactone-4-yl, bis-N'N-CC^CJ alkylamino (c2-C3) alkyl (such as β-dimethylaminoethyl), amine carbenyl-( CVC2) alkyl, anthracene, fluorenyl-di(C-C2)alkylaminecarbamyl-((^-(^) and (N-Bud.)-(c2-c3)alkyl, (N- . (C2-C3)alkyl or (N-morpholinyl)(C2_C3)alkyl, and the like. Similarly, if the compound of formula I contains an alcohol functional group, the prodrug may be A group such as the following replaces a hydrogen atom of an alcohol group to form: (Ci_c6) alkanomethoxymethyl, 1-GCVC6)alkylnonyloxy)ethyl, iota-yl-(i_((Cl_c6))alkylene Oxy)ethyl, (CkC6) alkoxycarbonyloxyindenyl, alkoxycarbonylaminemethyl, butadienyl, ((^-(:6) alkanoyl, a-amine (CrCJ) a aryl group, an aryl fluorenyl group and an α-amino fluorenyl group or an α-amino fluorenyl-α-amino fluorenyl group, wherein each α-amine fluorenyl group is independently selected from a naturally occurring L-amino acid, -ρ(〇) (ΟΗ) 2, -卩(9)(9)··)alkyl)2 or a glycosyl group (a group obtained by removing a hydroxyl group of a hemiacetal form of a carbohydrate) and the like. A compound of the formula I has a -NH- Functional groups, such as in primary or secondary amines 143636.doc -43- 201026672

In or in a nitrogen-containing heterocycle such as an imidazole ring or a pyrazine ring, the prodrug may be formed by replacing a hydrogen atom in the amine group with a group such as the following: R_carbonyl, RO-s, NRR And a carbonyl group, wherein R and R are each independently (Ci_Ci〇)alkyl, (CVC:7)cycloalkyl, benzyl' or R•carbonyl is scorpionamine or natural α-amine醯Base, _c(OH)c(〇)〇Yi, where γι is Ή, (Ci_C6)alkyl or benzyl, _C(OY2)Y3, where Y2 is (Ci_C4) alkane and Y3 is (C!-C6 An alkyl group, a carboxyl group (Cl_Cd alkyl group, an amine group (c-c4), an alkyl group or a mono-N_ or a di-N,N-(Cl-C6)alkylaminoalkyl group, -C(Y4)Y5, wherein Y4 is Η or methyl and Υ5 is mono-Ν- or di-N,N-(C-C0)alkylamino (indolyl), piperidin-1-yl or pyrrolidine-1-yl and the like .

One or more compounds of the invention may exist in unsolvated forms and in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the invention is intended to include both solvated forms and unsolvated forms. The terms 'mixture s' mean a physical association of a compound of the invention with one or more solvent molecules. This collection involves ionic bonding and covalent bonding of no (four) degrees: including hydrogen bonding. In some cases, such as when one or more solvents are incorporated into the crystal lattice of the crystalline solid, the solvate will be capable of separation. "Solvate" encompasses both the solution phase and the separable solvate. Non-limiting examples of illustrative solvates include ethanolates, methanolates, and the like. The "hydrate" is a solvate in which the solvent molecule is h2?. One or more compounds of the invention may optionally be converted to a solvate. - Preparation of solvates is generally known. Thus, for example, M. (10) et al. w. sakika α/fine., 93(3), (6) xian (鸠怀述 in ethyl acetate and from water to prepare antifungal fluconwa (flu (10) solvent 143636. Doc •44· 201026672 conjugate.EC van Tonder笙a . . no n7 Finder, AAPS PharmSciTech·, 5(1) Item 12 (2004); and A. L Bingham Stem λ ingham Specialist 'c/zew.Cowww /^· 603-604 (2001) describes a similar preparation of solvate #, hemisolvate, hydrate, and the like. A typical non-limiting method involves higher than

The compound of the present invention is dissolved in a desired amount of the desired solvent (organic solvent or water or a mixture thereof) under ambient/diagonal conditions, and the solution is cooled at a rate sufficient to form crystals, followed by separation of the crystal by standard methods. Analytical techniques such as ir. spectroscopy show the presence of a solvent (or water) in a crystal in the form of a solvate (or hydrate). Metabolic conjugates that can be reversibly converted to a compound of the formula, such as glucuronide and sulfate, are contemplated in the present invention. "Effective amount" or "therapeutically effective amount" is intended to describe the amount of a compound or composition of the invention effective to produce the desired therapeutic, ameliorating, inhibiting or prophylactic effect. As used herein, the terms "purification", "in purified form" or "in isolated and purified form" with respect to a compound mean the physical state of the compound after separation from a synthetic process (eg, from a reaction mixture) or its natural source or combination. status. Thus, the terms "purified," "in purified form," or "in isolated and purified form" with respect to a compound means that the compound is purified by methods well known to those skilled in the art (eg, chromatography, recrystallization, and The physical state obtained after its method), which is of sufficient purity, can be characterized by standard analytical techniques as described herein or familiar to those skilled in the art. "Capsules" are intended to describe a particular 143636.doc •45· 201026672 container or enclosure made of thioglycol, polyethylene or denaturing gelatin or starch to preserve or contain the active ingredient. Hard shell capsules are typically made from a blend of relatively high gel strength bone and pig skin gelatin. The capsule itself may contain small amounts of dyes, light-slit agents, plasticizers and preservatives. "Patch" is intended to describe a compressed or molded solid dosage form containing the active ingredient with a suitable diluent. Tablets can be prepared by compressing the mixture or granules (by granulation, dry granulation or by compaction). Oral ketamine is intended to describe the active ingredient dispersed or dissolved in a hydrophilic semi-solid matrix. Group with powder" means containing suspended in water or juice

Powder Blend of a Part and Suitable Diluent "Diluent" means a substance which typically constitutes a major part of the composition or dosage form. Suitable diluents include sugars such as lactose, co-, mannitol and xylitol u wheat, corn, rice and horseshoe powder; and fibrin' such as microcrystalline cellulose. The amount of diluent in the composition may range from about 10 weights on the total composition to ^^ 〇 / , 'reset / 〇' preferably from about 25% by weight to about 75 % by weight 'better about 3 〇 weight 〇 / 5

bamboo grove. To about 60% by weight, even more preferably from about 12% by weight to about 60% by weight. / within the scope of ❶. "Penticide" means adding to 6 and being privately owned. In order to help it split up (disintegration and release of the material of the music. People, Wengshan in.. σ 朋 解 包括 包括 包括 包括 包括 ; ; ; ; ; ; ; ; ; ; 改 改 改 改 改 改 改 改 改 改 改 改 改 改 改 改 改, ,. carboxylate-based sodium sulphate; natural rubber and synthetic rubber, such as 槐 胶 、, 梧 梧 胶 、, 壬 ^ ^ ^ Verne, tragacanth and agar; cellulose bio-blocking such as 曱 纤维 fiber 辛Alginic acid = acid: strontium cellulose; alginate, ", clay, such as bentonite; and foaming 143636.doc • 46 - 201026672 The amount of disintegrant in the group 5 may be between the composition From about 2% by weight to about 15% by weight, more preferably from about 4% by weight to about 1% by weight. "Binder" means that the powder is glued or "glued" together and formed by granules. Therefore, the substance binder acting as the "adhesive" of the formulation increases the bonding strength obtained in the diluent or the accumulating agent. Suitable binders include sugars such as Yan sugar; origins from wheat, corn, rice and Ma Feng Potato starch; natural gums such as acacia, gelatin and xanthine; gum; seaweed derivatives, Such as alginic acid, sodium alginate and calcium ammonium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganic substances such as citric acid The amount of binder in the composition may range from about 2% to about 20% by weight of the composition, more preferably from about 3% to about 1% by weight, even more preferably from about 3% to about 6% by weight. Within the scope of .. Lubricant is intended to describe the substance that is added to the dosage form to allow the tablet, granules, etc., to be released from the mold or mold with reduced friction or loss after compression. Suitable lubricants include metal stearin Acid salt, such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point wax; and water soluble lubricants; • such as sodium carbonate, sodium benzoate, sodium acetate, sodium oleate , polyethylene glycol and d'l-leucine. Lubricants are usually added in the last step before compression because they must be present on the surface of the particles and between the particles and the parts of the tablet machine. The amount may range from about 2% by weight to about 5% by weight of the composition. Preferably, it is from about 0.5 weight% to about 2% by weight, more preferably from about 3% by weight to about 1.5% by weight. "Sliding agent" means preventing particle agglomeration and improving particle flow characteristics to make 143636 .doc -47- 201026672 The liquid slippery and the average of the poplar. Suitable slip agents, including the amount of β-activator in the dioxide and slipper, may be between about 0.1% by weight of the total composition. Ρ Ρ 〇 〇 〇 〇 〇 5 5 5 5 5 。 。 。 。 。 。 。 。 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向 指向Food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as a viscous & alumina. The amount of the toner may range from about 0 to 1 weight per ounce to about 5% by weight of the composition, preferably about 〇 . Within 1% by weight to about 1% by weight. Γ"" 生物1 Bioavailability refers to the rate at which the active pharmaceutical ingredient or treatment component is absorbed into the systemic circulation from the administered dosage form as compared to the standard or control. A known method for preparing a tablet is known. Such methods include dry processes such as compression and compression of pellets produced by compaction, or wet or other special procedures. Conventional methods of making other forms of salvage, such as capsules, suppositories, and the like, are also well known. Cultural S-formed salts 'These salts are also within the scope of the invention unless otherwise specified, and the term "complexes" is understood to include reference to malate. As used herein, the term " "Salt" means an acid salt formed with an inorganic acid and/or an organic acid, and an alkali salt formed with an inorganic base and/or an organic base. Further, when the compound of formula I contains a basic moiety such as, but not limited to, pyridyl imidazole, and an acidic moiety such as, but not limited to, a carboxylic acid, a zwitterion ("internal salt") can be formed and It is included in the term "salt" as used herein. Although other salts are also suitable, pharmaceutically acceptable (i.e., non-Qin, physiologically acceptable) salts are preferred. Salts of formula I or compounds can be exemplified by reacting a formula with an amount (such as an equivalent) of an acid or base in a medium 143636.doc -48- 201026672 (such as a medium for salt precipitation) or in an aqueous medium. It is then lyophilized to form. Exemplary acid addition salts include acetate, ascorbate, benzoate, besylate, hydrogen sulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, counter-butyl Oxalates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, Propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate and the like. In addition, for example, S. Berge et al., Jowrwa/〇/Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and JTze 5 (Food & Drug Administration, Washington, DC, on its website) are generally considered to be suitable for the medicinal application of alkaline pharmaceutical compounds. The acid of the salt. Such disclosures are incorporated herein by reference. Exemplary salts include money salts, metal salts (such as sodium salts, salt and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts), and organic bases (such as organic amines) such as dicyclohexylamine. The salt formed by the third butylamine) and the salt formed with an amino acid such as arginine, lysine and the like. For example, lower alkyl halides (such as methyl, ethyl and butyl vapors, bromides and iodides), dialkyl sulfates (such as dinonyl sulfate, diethyl sulfate and dibutyl sulfate) can be used. Long chain halides (eg, sulfhydryl, lauryl, and stearyl sulfonate chlorides, bromides, and iodides), aralkyl i compounds (eg, benzyl 143636.doc -49- 201026672 and phenethyl) The reagents and other reagents of the read compound quaternize the basic nitrogen-containing groups. All such salts and salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid salts and salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention. All stereoisomers (9) such as geometric isomers, optical isoforms of the compounds of the invention (including salts, solvates and prodrugs of the compounds and salts and solvates of the prodrugs) are encompassed within the scope of the invention. Constructs and analogs thereof, such as stereoisomers which may exist due to asymmetric carbon or sulfur on various substituents, including apo-isomerization 4>, which can even be asymmetrically It exists in the presence of carbon, _ geometrically isomeric forms, stagnation isomers and diastereomeric forms. By way of example, if the compound of formula I has a double bond or (d), then the cis, trans and mixtures are intended to be within the scope of the invention. The individual = isomers of the compounds of the invention may be substantially free of other isomers, or may be, for example, racemic or in combination with all other or other selected stereoisomers. The palm center may have an S or R configuration as defined by the 1974 standard. The terms "salt", "solvate", "prodrug" and the like are intended to apply equally to the enantiomers, stereoisomers, oxime isomers, tautomers of the compounds of the invention. Salts, solvates and prodrugs of the body, racemate or prodrug. Diastereomeric complexes can be separated into eight individual non-absorpomers based on their physicochemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. The enantiomers can be separated by the following procedure with a suitable optically active compound (for example, a palmitic adjuvant such as 143636.doc -50- 201026672 for palmitol or Mosher's acid chloride). The reaction thus converts the enantiomeric mixture to a diastereomeric mixture, separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Furthermore, some of the compounds of formula I may be the atropisomers (for example, the two groups of the 'substituent substitutions) and are considered to be part of the invention. Enantiomers can also be separated by using a palmitic HPLC column. Polymorphic forms of the salts of the compounds of formula I and the salts, solvates and prodrugs of the compounds of formula I are intended to be included in the present invention. The invention also encompasses compounds of the invention which are labeled isotopes, which are identical to the compounds described herein except that one or more atoms are atomically replaced by atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and gas, such as 2H, 3H, 3C, 丨4C, 丨5N, 1«〇, 17〇, 3丨p, 32p, 35s, 18, α. Certain labeled isotope formulas (eg, labeled with a gentleman's compound) are suitable for compound and/or substrate distribution assays. Gasification (i.e., 3H) and carbon 14 (i.e., % isotope are particularly preferred because of their ease of preparation and measurability. In addition, some of the heavier isotopes such as ruthenium (i.e., 2h) can be used to obtain some Therapeutic advantages resulting from large metabolic stability (eg, long half-life in vivo 7 or reduced dosage requirements) and therefore may be preferred in some cases. Compounds of formula I labeled isotopes are generally available by the following schemes and/or examples below A similar procedure as disclosed in the above is prepared by substituting an unlabeled isotope reagent with a reagent of the labeled isotope. The compound of the present invention has pharmacological properties; in detail, the formula can be 143636.doc -51 · 201026672 A2C adrenergic receptor agonist. The preferred dose is about 1 mg to 5 mg of S! compound per kg body weight per day. Especially preferred dosage is about 1 mg to 25 mgsj per kg body weight per day. Or a pharmaceutically acceptable salt or solvate of the compound. The compounds of the invention may also be used in combination with one or more therapeutic agents (administered together or sequentially) 'the one or more therapeutic agents' Such as glucocorticosteroids, PDE-4 inhibitors, antimuscarinic agents, sodium cromoglycate, % receptor antagonists, 5-HTi agonists, NSAIDs, _sk contractile invertase inhibitors, angiotensin II Agonists, β-blockers, β-agonists (both long-acting and short-acting), leukotriene antagonists, diuretics, aldosterone antagonists, ionotropic agents, natriuretic peptides, pain Epileptic control/analgesics, anti-anxiety agents, anti-migraine agents, and therapeutic agents for the treatment of heart disease, psychotic disorders, and glaucoma. Suitable steroids include prednisolone, fluticasone (including all esters) , such as propionate or phthalate), triamcinolone, beclomethasone, mometasone (including any ester form, such as mometasone furoate) ), budasamine, ciclesonide betamethasone, dexamethasone, prednisone, flunisolide, and cortisone 〇 Suitable PDE-4 inhibitors include Luo Roflumilast, theophylline, rolipram, piclamilast, eilomilast, and CDP-840. 143636.doc -52- 201026672 Drug tests include ipratropium bromide and tiatropium bromide.

Suitable anti-reagents include astemizole, azatadine, azelastine, acristatine, brompheniramine Cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine ), descarboethoxyloratidine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine , efletirizeine, fexofenadine, hydroxyzine, ketotifen, loratidine, levocabastine, merle 0 Qin (meclizine), fexofenadine, 0-methyl, ketotifen, loratadine, levabastatin, meclizine, mesozine ?丁(mizolastine),美唾他call (mequitazine ), Mianserin, Norberts; Ding

I (noberastine), norastemizole, picumast, pyrilamine, promethazine, terfenadine, ko Tripelennamine, temelastine, trimeprazine or triprolidine 〇 suitable anti-inflammatory agents including aspirin, difenfenic acid H3636.doc -53- 201026672 (diclofenac), diflunisal, etodolac, flurbiprofen, ituprofen, indomethacin, ketoprofen , each acid (ketorolac), nabumetone, naproxen, oxaprozin, piroxicam, sulindac, and tolmetine Tolmetin). Suitable aldosterone antagonists include spironolactone. Suitable ion shifters include digitalaJis. Suitable angiotensin II receptor agonists include irbesartan and losartan. Suitable diuretics include spironolactone, methyl chlorothiazide, bumetanide, torsemide, hydrofluoroquinone 0, trioxazine, hydrogen hydrazine, amine benzene π industry triamterene , ethacrynic acid, 曱 gas ° ° ° Qin, hydrogen sputum, benzamidine, hydrogen chloride ° ° Qin, quinethyl quinone (quinethazone), hydrogen call, gas ketone, bite Toluidine, ° indapamide, hydrogen oxime, amine benzoquinone, trichlorothiazide, hydrogen thiazide, amine chloride hydrochloride. Compared with hydrazine, amine hydrazine hydrochloride, metolazone, trichlorin-11, benzyl fluoride, D, chlorohydrazine, hydrazine, hydroquinone, hydrofluoride, Chlorose ketone and 矣托拉宗. Suitable pain control/analgesics include Celecoxib, amitriptyline, ibuprofen, chapicide, gabapentin, tramadol, rofecoxib, and hydrochloric acid Oxycodone HC1, acetaminophenoxycodone HC1, carbamazepine, 143636.doc -54- 201026672 Amitriptyline, difenfen, diphenoate , relying on acid, fenoprofen calcium, flurbiprofen, ibuprofen, D-mesine, ketoprofen, ketorolac tromethamine, mefenamic acid , meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetine, valdecoxib, difenfen/miso Prostaglandol (misoprostol), oxycontin, vicodin, darvocet, percocet, morphine sulfate, dioxin (dilaudid) ), cyclosporine, stadol, dihydrofuran NS, acetaminophen With codeine, acetaminophen phenol and codeine #4, Lidoderm® patch, ziconotide, duloxetine, roboxetine, gabapentin and pupp Pregabalin. Suitable beta-blockers include acebutolol, atenolol, atenolol/gas ketone, betaxolol, bisoprolol Fumarate), bisoprolol/HCTZ, labetolol, metoprolol tartrate, nadolol, pindolol, propranolol , propranolol / HCTZ, sotalol (sotalol) and timolol (timolol). Suitable β-agonists include dobutamine, ritodrine, salbutamol, levalbuterol, metaproternol, formoterol ( Formoterol), fenoterol, bambuterol, brocaterol, crochet 143636.doc -55· 201026672 (clenbuterol), terbutaline, tertu Tulobuterol, adrenaline, isoprenalin and hexoproline. Suitable leucotriene antagonists include levamisole. Suitable anti-migraine agents include rovatriptan succinate, naratriptan HC1, rizatriptan benzoate, sumatriptan succinate , zolmitriptan, almotriptan malate, methysergide maleate, dihydroergotamine mesylate, tartar tartrate Ergotamine tartrate, ergotamine tartrate / coffee test, Fioricet®, Fiorninal®, Depakene® and Depakote® ° Suitable anti-anxiety agents and antidepressants including amitriptyline hydrochloride and bupropion HC1 , citalopram hydrobromide, clomipramine HC1, desipramine, fluoxetine, fluvoxamine maleate , macrotiline hydrochloride (maprotiline HCM), mirtazapine, nefazodone HC1, nortriptyline, paroxetine hydrochloride paroxetine HC1), protriptyline hydrochloride (protriptyline HC1), sertraline hydrochloride (sertraline HC1), doxepin (doxepin) dilute acid and butadiene trimipramine (trimipramine maleate). 143636.doc -56- 201026672 Suitable blood-tubulin contractivase inhibitors include Captopril, enalapril, enalapril/HCTZ, lisinopril, Lai Nopley/HCTZ and Aceon®. The pharmacological properties of the compounds of the invention can be determined by a number of pharmacological assays. The compounds of the present invention and salts thereof have been subjected to exemplary pharmacological assays described later. The invention also relates to a pharmaceutical composition comprising at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of the compound, and at least one pharmaceutically acceptable carrier. For the preparation of pharmaceutical compositions from the compounds described herein, the pharmaceutically acceptable inert carrier can be either solid or liquid. Solid form preparations include powders, lozenges, dispersible granules, capsules, cachets, and suppositories. Powders and lozenges can contain from about 5% to about 95% active ingredient. Suitable solid carriers are known in the art, such as magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of making various compositions can be found in A. Gennaro (ed.), iiewkgiow’j·

Sciewces, 18th ed., (1990), Mack Publishing Co., Easton, Pennsylvania ° Liquid form preparations include solutions, suspensions, and emulsions. When preparing a liquid formulation, one or more components that increase solubility are excluded. For example, U.S. 6,673,337, column 2, line 50 to column 3, line 17, and column 6, line 49 to line 31, the composition for increasing solubility is described; US 6,673,337 is expressly incorporated herein by reference. The specific increase in the exclusion of liquid form preparations 143636.doc -57- 201026672 The reagents for the resolution include metal methacrylate, metal hydrazine methyl, ethyl ketone β, and other compounds derived from propyl fluorenyl cellulose. And cyclodextrin. An example which may be mentioned is water or water-propylene glycol solution for non-salt injections or oral solutions, suspensions and emulsions, sweeteners and opacifiers. Liquid preparations may also be included for intranasal administration. Solution or suspension. One aspect of the invention is that the pharmaceutical composition is in a solid dosage form comprising a compound of formula I or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof and at least one pharmaceutically acceptable carrier Agent, adjuvant or vehicle.另一 Another aspect of the invention is a liquid, aqueous pharmaceutical composition comprising a mouthwash or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof and at least one pharmaceutically acceptable carrier, The agent or vehicle, with the proviso that the composition is not increased, the component of the degree of gluten, such as the composition described in US 6,673,337 (discussed above). A further aspect of the invention is a liquid, aqueous pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof and at least one pharmaceutically acceptable carrier, adjuvant Or vehicle 'where it is a cyclodextrin if there is a component that increases the solubility of ©. Another aspect of the invention is a pharmaceutical formulation which is a nasal spray wherein the pH is equal to or less than about 65, more preferably between about 6 and 62. In another aspect of the invention, the formulation is a nasal spray, wherein the adjuvant comprises a suspending agent (eg, AVICEL (such as AVICIL RC-581, RC-591, and CL-611), which is microcrystalline cellulose and Sodium carboxymethyl cellulose; hydroxypropyl decyl cellulose, methyl cellulose; polyvinyl alcohol; or CARBOPOL) and 143636.doc -58· 201026672 aerosol (eg glycerol, triose) sterol; Or right-handed sputum floats and lotions. For example, water injection may be mentioned, or an oral solution or suspension. The liquid form may also include a carrier for intranasal administration including a solution and a powder in the form of a powder (such as an inert compressed gas,

Liquid form preparations include solutions, or water-propylene glycol solutions for parenteral and emulsion addition of sweetening and opacifying agents with solutions or suspensions. An aerosol formulation suitable for inhalation, which can be combined with a pharmaceutically acceptable, e.g., nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral or parenteral administration. These liquid forms include solutions, suspensions and emulsions. The compounds of the invention may also be delivered transdermally. Such transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and may be included in a matrix or reservoir type percutaneous as is conventional in the art for this purpose. In the patch. The compounds of the invention may also be delivered subcutaneously. Preferably, the compound is administered orally. • The J. drug formulation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses appropriate to the appropriate amount (e.g., effective amount to achieve the desired purpose) of the active ingredient. The amount of active compound in a unit dosage formulation may vary or be adjusted from about 1 mg to about 1 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, depending on the particular application. 143636.doc -59- 201026672 The actual dose used may vary depending on the needs of the patient and the severity of the condition being treated. The appropriate dosing regimen to determine a particular situation is within the skill of the art. For convenience, the total daily dose can be divided into several parts as needed and administered in portions during the day. The amount and frequency of administration of the compound of the present invention and/or its pharmaceutically acceptable salt will be adjusted based on the judgment of the attending physician regarding factors such as the age, condition and size of the patient and the severity of the condition to be treated. A typical recommended dosage regimen for oral administration may range from about 1 mg/day to about 5 mg/day, preferably from 1 g/day to 200 mg/day, divided into two to four doses. A further aspect of the invention is a kit comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate of the compound, and a pharmaceutically acceptable carrier Agent, vehicle or diluent. A further aspect of the present invention is a kit comprising a quantity of at least one compound of formula I or a pharmaceutically acceptable salt or solvate of the compound, and a quantity of at least one of the above listed treatments Agents, wherein the amounts of two or more of the ingredients produce the desired therapeutic effect. In general, the compounds of the present invention can be made by a variety of methods known to those skilled in the art and by known methods analogous thereto. The invention disclosed herein is to be construed as illustrative and not restrictive. Alternative mechanical paths and similar structures will be apparent to those skilled in the art. Those skilled in the art are not limited to this. Those skilled in the art will recognize that one approach will be optimized based on the choice of additional substituents 143636.doc -60· 201026672. Additionally, those skilled in the art will recognize that in some cases it may be necessary to control the sequence of steps to avoid functional group incompatibility. The composition and purity of the prepared compounds can be analyzed and characterized by standard analytical techniques such as elemental analysis, NMR, mass spectrometry and IR spectroscopy.

Those skilled in the art will recognize that the reagents and solvents actually employed may be selected from a number of reagents and solvents known in the art to be effective equivalents. Thus, when referring to a particular solvent or reagent, it is meant to be an illustrative example of the particular reaction scheme and the conditions required in the preparations and examples below. When presenting NMR data, the 1Η spectrum is at Varian VXR-400 (400 MHz, 'Η) 'Varian Gemini-300 (300 MHz) 'Varian Mercury VX-400 (400 MHz) or Bruker-Biospin AV-500 (500 MHz) Obtained and reported chemical shifts in ppm, with the number of protons and multiplicities noted. When LC/MS data was presented, the analysis was performed using an Applied Biosystems API-100 mass spectrometer with a C18 column and a gradient of 10-95% CH3CN-H20 (with 0.05% TFA). The parent ion observed is given. The following solvents and reagents can be mentioned by the abbreviations in parentheses:

Me = mercapto; Et = ethyl; Pr = propyl; Bu = butyl; t-Bu = third butyl; Ph = phenyl, and Ac = ethyl thiol μ1 = microliter

AcOEt or EtOAc = ethyl acetate AcOH or HOAc = acetic acid ACN = acetonitrile aq = aqueous solution atm = atmospheric pressure 143636.doc -61 - 201026672

Bn = benzyl

Boc or BOC = third butoxycarbonyl BINAP = 2,2'-bis(diphenylphosphino)-1,1'-bisnaphthyl

Bz = benzoinyl cat = catalyst or catalytic

Cbz=benzoquinoneoxycarbonyl DEA=diethylamine DEAD=diethyl azodicarboxylate DCM or CH2C12: dichloromethane DMAP=4-dimethylaminopyridine DIBAL=diisobutylaluminum hydride DIPEA=diisopropyl Ethylethylamine DME=1,2-dimethoxyethane DMF=dimethylformamide DMS=dimethyl sulfide DMSO=disulfoxide sulfoxide Dppf=l,l'-bis(diphenylphosphino) Ferrocene EDCI or DEC = l-(3-dimethylaminopropyl)-3 -ethylcarbodiimide Eq = equivalent g = g or h = hr = hour HATU = 0 - (7-azabenzone) Triazol-1-yl)-oxime, anthracene, Ν', Ν'-tetrahydrohexafluorophosphate HOBt=l-hydroxybenzotriazole 143636.doc -62- 201026672 IPA=isopropyl alcohol Im=p meter Saliva LAH = lithium aluminum hydride LDA = lithium diisopropylamide. LCMS = liquid chromatography mass spectrometry analysis M = molar concentration mCPBA = m-chloroperoxybenzoic acid min = minutes mg = milligrams mL = milliliters mmol = milli Mole MeOH: methanol MS = mass spectrometry N = equivalent concentration NBS = N-bromobutaneimine NMO = N-methylmorphine N-oxide NMR = nuclear magnetic resonance spectroscopy. PG = protecting group

Pyr=0 is 0 or 0 (±) = racemic mixture or enantiomer RT or rt = room temperature (ambient, about 25 ° C) sat = saturated SFC = supercritical fluid chromatography SM = starting material 143636.doc -63- 201026672 TBSC1=Third butyl dimethyl decane chloride TBS=Ter Butyl dimethyl decyl TEA=Triethylamine (Et3N) TEMPO=2,2,6,6-tetradecyl Piperidine-1-oxygen TFA = trifluoroacetic acid THF = tetrahydro 0 Fennan TLC = thin layer chromatography TMS = tridecyl decyl

Tos or Ts=p-phenylenesulfonyl

Tol=toluene

TosMIC = acesulfonylmethyl hydrazine TPAP = tetrapropylammonium perrhenate Tr = triphenyl fluorenyl Example The compounds of the present invention can be prepared by the general methods outlined in the following schemes. These processes are provided to illustrate the invention. Although the process designates J1-.!4 as -CH-, where hydrogen can be replaced by A, this is for illustrative purposes only and those skilled in the art will be able to use the skilled artisan by modifying such processes. Other procedures are known for preparing compounds containing other definitions of J1-!!4. To assist in this, those skilled in the art will have a flow from Scheme 1 showing S1 (X=-CH2- and n=0-2; or X=-0-, -NH- or substituted N and n=l-2) is converted to B by reaction with ammonium carbonate and a cyanide source such as KCN, NaCN or TMSCN; or related conditions such as C02/NH40H/NaCN/ 143636.doc-64-201026672 H2〇2 The method of guanidine urea S2. Subsequent hydrolysis with a base (LiOH, NaOH, Ba(OH)2 or the like) to the amino acid S3a, followed by conversion to the amino ester S3b and reduction to the alcohol S4 (using reagents such as DIBAL, NaBH4, borane or LAH) ). Or the amino acid S3a is directly reduced to S4. In various embodiments, the amino alcohol (S4) is then cyclized to provide the following moiety: - Substituted 2-aminooxazoline S5a (Z = NHC(0)R), with isothiocyanate (such as phenyl guanidinium isothiocyanate). 2-amino oxazoline S5b (Z=NH2, via treatment with, for example, cyanogen bromide in the presence or absence of a base such as diisopropylethylamine, or by thioisocyanate (such as Et02C) NCS or BzNCS) treatment, followed by treatment with a base or an acid or a catalyst such as Hg(O), Hg(OAc)2 or 2-gas-3-ethylbenzoxazol tetrafluoroborate, and LiOH hydrolysis); - oxazoline S5c (Z = H, by treatment with, for example, methyl decanoate / DAST, trialkoxy phthalate, dimethylformamide decyl acetal or other similar reagent) - carbazole ketone (S5d, Z = OH), by treatment with reagents known in the literature (such as carbonyl diimidazole, triphosgene or related carbonate or carbative ester); (S5e, Z=SH, by treatment with a known reagent such as EtOCS2H, Im2CS, CS2, C12CS, NaSCH or MeSC(S)0Et, etc.; and - oxazoline S5f having a carbon bond at Z (by Numerous literature methods, such as treatment with RC (=NH)Oet, RCN/ZnCl2, RC02H, anhydride, RCHO and appropriate oximation agents, or other methods.) 143636.doc -65· 201026672 2-Aminooxazoline S5b ( Z=NH2) can also S5a (Z=NHC(0)R) is obtained by treatment with a hydroxide source such as LiOH. The oxazolidinethione S5e (Z=SH) may also be from 5d (Z=OH) by a sulfur reagent ( Obtained by treatment such as Lawesson's reagent. $ Sodium ketone (S5d, Z = OH) or oxazolidine (S5e 'Z = SH) can be alkylated or known by the literature. Further chemical substitution (to Z = OR or Z = SR, respectively). Alkylation of oxazolidine (S5e, Z = SR, where R = alkyl or its analog) is optionally oxidized to provide Z = S(0)pR (where p=i or 2). In various embodiments, the group A can be derived from a precursor group at various stages of the procedure (such as A = _, optionally protected alcohol) , nitro or, as the case may be, the protected amine) g is defined as various definitions of R. Alternatively, the functionalized A group may be present in the starting material "or its precursor. In the case of eight = halogen or alcohol Underneath, functionalization can occur in metal catalyzed or metal promoted processes (using copper, epigenetic or other metals).

To functionalize. Process 1

143636.doc -66 - 201026672

S5a, Z=NHC(0)R S5b, Z = NH2

S5c, Z = H

S5d, Z = OH or OR

S5e, Z=SH, SR*S(0)R S5f, Z = bond broken substituents According to another embodiment (Scheme 2), the compound SI is destroyed by the Strecker reaction (cyanide) The amine, such as NH4C1/KCN or alkylamine/NaCN, is converted to S6. The nitrile reduction (using LAH or similar reagent) is S7, which can be cyclized to provide S8 or S9. In another embodiment, the % of the compound is converted to the amino acid S3a by hydrolysis (Scheme 1). Process 2

According to another embodiment (Scheme 3) 'Compound S5d or S5e is converted to S1〇 (via gasification with s〇Cl2, P〇ci3, PCl3, Pcl5, Cl2 or the like). In various embodiments, 'intermediate S10 is replaced by an amine, oxygen or carbon nucleophile or in a metal catalyzed or metal promoted process such as palladium catalyzed Suzuki or Steele coupling to provide SS (where Z is Bonding a carbon, oxygen or gas substituent). Process 3

143636.doc -67- 201026672

Scheme 4 shows that the amino alcohol S4 is reacted with an acid under standard coupling conditions (using reagents such as EDCI, HOBt, etc.) or with an acid hydride to provide the indoleamine S11 (wherein R is defined as z in formula I or may be A method of converting to a group of Z). In one embodiment, the compound sil is then treated with a sulfur reagent such as a Lavesson reagent, p2S5 or Deoxy-Fluor to achieve and have S accompanied by cyclization to S12. Or 'S4 can be converted to thioguanamine or thiourea S13 (by reaction with thioester, thioacid or thioisocyanate) and then cyclized to S12 (under eve conditions) including HC1, SOCI2, Deoxy -Fluor, DAST, Hg(O), Hg(OAc)2 or 2-chloro-3-ethylbenzoxazole rust tetrafluoroborate or other reagents). In another embodiment, sn is first converted to S13 (either by treatment with a sulfur reagent such as a Lavesson's reagent, DAST or the like) and then cyclized to S12 in a stepwise manner. Process 4

S13

According to another embodiment (Scheme 5), the amino ester S3b (optionally protected) is treated with a human quinone organometallic 5 agent such as RMgBr, Grignard reagent (GHg (10) rd gent) or fluorenyl clock compound Ru to give a ketone. ..., followed by reduction to give S17 (wherein R is defined as the group of the formula r4 or a group convertible to r4), the i-substituted amino alcohol S17 is then cyclized to the substituted 143636.doc as previously described - 68- 201026672 ❿ oxazoline S18. Alternatively, this general method can be carried out with amino nitrile S6 or Weinreb decylamine S14 (p-amine coupling from amino acid S3a with HN(Me)OMe or reaction from amino ester S3b with HN(Me)OMe/AlMe3 And obtained) as the starting material. In another embodiment, S3b, S6 or S14 is reduced (or reduced/oxidized) to aldehyde S16, which is then subsequently reacted with an organometallic reagent to provide S17. The reduction of the ketone S15 can be carried out in a stereoselective manner to give preference to a stereoisomeric alcohol S17. Agents for stereoselective reduction are well known in the art and include, but are not limited to, CBS-carbazole boridine/borane reagent, LAH/N-methylephedrine, BINAL-H, Ipc2Ba, DIBAL- H, side chain, NaBHVCeCh and enzymatic catalyst. Process 5

S16 A 'R4 R2

R3 HNT(PG)- '卞R.AR R2

S3b, R' = C(0)0R S6, R' = CN S14, R' = C(0)-N(Me)0Me R2 A R3-H"(S VR3 S18 according to another embodiment (flow 6) Ketone S15 (protected as appropriate) undergoes deuteration (Wittig, Horner-Emmons, Tebbe reaction, etc.)-hydroboration procedure to provide alcohol S20 ( Wherein R is defined as R4 in formula I or a group convertible to R4), followed by cyclization to S21. Scheme 6

(PG) S15 S19 A Rs HN^(PG)

S20

S21 143636.doc -69- 201026672 According to another embodiment (Scheme 7), _s (as appropriate) undergoes thinning (Wittig, Horner-Emmons, etc.) to obtain hydrazine, 2_disubstituted olefin . Hydrogenation of the s22 butterfly (wherein R and R, independently defined as r4 or a group convertible to R4) provides the alcohol S23' followed by cyclization to S24. Process 7

According to another embodiment (Scheme 8), the alcohol S2(R) (as protected) is sequentially oxidized and treated with an organometallic reagent to provide S23 (wherein r and ri are independently defined as R4 in Formula I or can be converted to R4 Group). Compound S23 is then cyclized to provide S24. Process 8

According to another embodiment (Scheme 9), the palmitic alcohol S28 is prepared by adding an anion of the palmitic sub-S7 to the ketone S26. The intramolecular Sn2 reaction provides the epoxide S29' using a nitrogen nucleophile such as ammonia or by adding a νη2 precursor such as azide, phthalimide, benzylamine or benzhydrylamine. The oxide S29 is ring-opened to obtain an aldehyde S3 (the alcohols S31 and S32 are prepared by adding an organometallic compound such as organomagnesium) and removing the protecting group from the amine. 143636.doc •70- 201026672 Scheme 9

In another embodiment (Scheme 10), the palmitic subunit S33 contains an alkyl group R'. The epoxide ring opening provides the ketone S36 following a procedure analogous to that of Scheme 9. The alcohols S31 and S32 are obtained by a known method such as treatment with NaBH4 to reduce the ketone and to remove the amine from the protecting group. Alternatively, the ketone is reduced in an asymmetric manner using a palmitic reduction process known to those skilled in the art, such as CBS reduction. Process 10

S26 S33 S34

According to another embodiment (Scheme 11), compound S1 is treated with a palmitic amine such as (i〇-phenylglycine or other pair of palmitic amines) followed by a cyanide source (such as KCN, NaCN or TMSCN) Treatment to provide conversion to S6 in pure enantiomer or enantiomerically enriched form. Nitrile reduction, solution to palmitic cleavage 143636.doc-71 - 201026672, and cyclization provided as previously Said imidazoline S8. Alternatively, S6 is converted to S3b by hydrolysis (using MeOH/HCl or other methods) and cleavage of the palmitic aid.

According to another embodiment (Scheme 12), the ester S3b is converted to the guanamine S3c (by treatment with ammonia or an amine) and then reduced (with LAH, BH3 or similar reagent) to the diamine S38, which can be cyclized to Provided: -S39a, treated with a guanidine reagent such as formazan, acetamidine or benzamidine; -S39b, treated with diphenyl cyanocarbonimidate; -S39c, treated with cyanogen bromide And -S39d, by treatment with carbonyldiimidazole, triphosgene or related carbonate or chloroformate. Process 12 is difficult to find 1 R2

S3b, R = ΟΜβ or Ο-alkyl S38 S3c, R = NH2 or NHR

S39a, Z = H, alkyl, aryl S39b, Z = NHCN S39c, Z = NH2 S39d, Z = OH 143636.doc -72- 201026672 According to another embodiment (Scheme 13), the functionalized terpene benzene 40b (R=LG, such as Br, synthesized from S40a with NBS or its analogs) and N-protected glycinate (such as N-(diphenylmethylene)glycolate or N-Benzene Ethyl diglycolate is condensed to provide S41 which is further refined to S42. The enantioselectivity in the condensation is enhanced by the use of a palmitic N-protected glycinate or the use of a palmitic phase transfer catalyst with a non-preferable N-protected glycinate. Alternatively, S40b is condensed with a malonate such as dimethyl malonate to provide S43. A selective enzymatic hydrolysis of the ester (by esterase or similar enzyme) provides S44, which is converted to S45 by Curtuis rearrangement and then further refined to S42. Process 13

A

S40a, R = Η S40b, R = LG

R2 ^N(aux), C02Me R2 S41

A

R S45 The starting materials for the preparation of the compounds (including compounds SI, S26 and S40) and reagents are available from commercial suppliers such as Aldrich Chemical Co. (Wisconsin, USA) and Acros Organics Co. (New Jersey, USA). Or prepared by a literature method known to those skilled in the art. When not available from commercial suppliers, compound S1 (substituted by R2 and R3, or substituted with substituents converted to R2 and R3) is from S46, S47, S48, S49 or other starting materials according to the literature. The method is known for synthesis. 143636.doc -73- 201026672

Compounds of the formulae S5, S8, S9, S10, S12, S18, S21, S24, S39, S42 and S45 can be prepared by the general methods outlined above. Exemplary compounds are prepared as described in the Examples below or starting materials known in the art. These examples are provided to further illustrate the invention. It is for illustrative purposes only; the scope of the invention should not be construed as being limited in any way. Preparation example 1

Step 1 Heat 8-bromo-2-tetralone (5.0 g, 22.2 mmol), (NH4)2C〇3 (15.0 g, 156 mmol) and KCN (2.16 g, 3) at 85 ° C in a sealed tube. A mixture of 3.3 mmol) in 1:1 EtOH-H 2 O (50 mL) was taken overnight. The reaction was then cooled to room temperature, diluted with water (ca. 400 mL) and stirred 2 min 143636.doc -74 - 201026672. The precipitate was filtered and dried overnight in vacuo to afford EtOAc (5·95 g, 91%). LCMS m/z 295/297 (MH+). Step 2-3 A mixture of 1A (4.46 g, 15.1 mmol) and EtOAc (EtOAc) The reaction was then cooled to 0 ° C, acidified with 12 N EtOAc, LCMS m/z 270 (MH+). Thionine chloride (9 mL) was cautiously added to MeOH (300 mL) at EtOAc. The reaction was heated to reflux overnight and then cooled and concentrated. The residue was dissolved in saturated aqueous NaHCO3 (EtOAc) (EtOAc) The combined organic layers were dried over Na 2 SO 4 and concentrated. Chromatography (0-50% EtOAc/hex) afforded 1B as a red oil. LCMS m/z 284/286 (MH+). Step 4-5 Compound 1B (8.16 g, 28.7 mmol) was dissolved in anhydrous MeOH and then treated with Na.sub.2H.sub.4 (2.72 g. A second portion of NaBH4 (2.72 g, 71.8 mmol) was added after 15 min. The reaction was concentrated after TLC indicated 1B was consumed (about 15 min). THF (100 mL) was added to the residue and then removed in vacuo to afford a yellow foam 1C which was used in the next step without purification or aqueous. LCMS m/z 256/258 (MH+). The crude amino alcohol 1C (ca. 28. 7 mmol) was dissolved in dry THF (250 mL) and purified eluting After stirring at room temperature for 20 minutes, benzamidine isothiocyanate (4.3 mL, 32 143636.doc -75 - 201026672 mmol) was added. The reaction was concentrated after TLC and MS indicated 1 C to dryness (~ 20 min <><RTIID=0.0>>>> % EtOAc / hex) to provide 1D in the form of a yellow foam. LCMS m/z 385 / 387 (MH+). Step 6: 1D (approx. 38~7 mmol) and LiOH-H2 〇 (6.03 g, 144 mmol) in 1:1 The MeOH-H.sub.2 O.sub.2.sub.sub.sub.sub.sub.sub. To give the desired product 1E (white solid, 2.49 g, ca. 38% (3 steps), LCMS m/z 281/283 MH+) and a minor by-product of step 5 (ig, LCMS m/z 298/300 MH+) .

(士)-lG Step 7 Heat compound 1:E, EtNH2 (2.0 N/THF, 3 equivalents), Cul (0.5 equivalents), K3P〇4 (2 amount) and N at 100 ° C in a sealed tube. A mixture of N,-dimercapto-(1R,2R)-cyclohexanediamine (1.6 eq.) in DMF was taken overnight. The mixture was cooled, diluted with water and extracted with DCM (3). The combined organic layers were washed with brine, dried EtOAc EtOAc Chromatography (NH3-MeOH in DCM) afforded IF. Step 8 143636.doc -76- 201026672 A mixture of ethyl aniline IF in DCM was treated with ClC02Me (1.1 eq.) and DIPEA (2 eq.). The reaction was stirred at room temperature overnight, concentrated, and then purified to afford title (+)-1. Substituting Steps 4-6 Compound 1B was dissolved in anhydrous MeOH and then treated with NaBH4 (3 eq.). A second portion of NaBH4 (3 equivalents) was added after 15 minutes. The reaction was concentrated after TLC indicated 1B was consumed and then purified directly by flash chromatography to afford purified 1C.

The mixture of 1 C and cyanogen bromide (1.1 eq.) in DCM was stirred at room temperature over 4 hours and concentrated. Chromatography provided Compound 1E and the recovered starting material 1C. The racemic mixture of 1E or 1 (or its CBz protected derivative) is isolated on a preparative Chiralpak AD column with isopropanol-hexane to provide the pure enantiomer. In a manner similar to that described above, 1F (protected CBz as appropriate) is reacted with the specified reagent and, if protected, hydrogenated to provide the following compounds: Compound number reagent compound (±)-1Η MeNCO, HW (± )-11 Me0CH2C02H/EDCI/H0Bt or MeOCH2COCl όο° 143636.doc -77- 201026672 (±)-lJ methanesulfonic anhydride/TEA (earth), 1K Me2NS〇2Cl/pyr in a manner similar to that described above 1E was reacted in turn with CuI/MeNH2 and ClC02Me to provide the compound (±)-lL.

Preparation example 2

Rh

Step 1 A mixture of compound IE, CbzCl (2.5 eq.), hydrazine (2.5 eq.) and DMAP (0.2 eq.) in DCM was stirred at room temperature for 30 min. Add extra portions of CbzCl and TEA as necessary. The reaction was concentrated, taken up in water and EtOAc (EtOAc) The organic layer was dried over Na2SO4, filtered, evaporated Step 2 Treatment of a mixture of compound 2A, Pd2(OAc)2 (0.1 eq.), hydrazine (0.15 eq.) and Cs2CO3 (2.0 eq.) in toluene (20 mL) with benzophenone imine (1.5 eq.) And then stirred at 100 ° C overnight. After cooling to room temperature, the precipitate was filtered and washed with DCM. The combined filtrates were concentrated and chromatographed to afford 2B.

Step 3 A mixture of 2B, NaOAc (5 eq.) and NH20H-HC1 (3 eq.) in MeOH was stirred overnight. The reaction was then treated with aqueous NaOH (1 N) and extracted with DCM (2). The combined organic extracts were dried over Na2SO4, filtered andEtOAc Step 4-5 Compound 2C was treated with ClC02Me to provide 2D in a similar manner as described in Example 1 (Step 8). Compound 2D was hydrogenated (with Pd/C and H.sub.2) (40 psi, EtOAc, EtOAc). Preparation Example 3

1) NaBH4 2) pTsoH ΒΓΌ〇 3Α

1) 0s04/NM0 2) pTsOH

Example 1 3B 143636.doc -79- 201026672

Preparation of 6-bromo-3-chromanone 3B from 6-bromo-4-chromanone as described in Synthesis, 1980, 621: NaBH4 (1.2 eq, MeOH-DCM, 0 ° C to room Temperature, 2 hours) reduction, elimination with pTsOH (catalyst, benzene, reflux, 3 hours, 90% (2 steps)), deuteration (catalyst 〇S〇4, 1 equivalent NMO, water-acetone-tBuOH, room temperature , overnight) and finally treated with pTsOH (catalyst, toluene, reflux, 15 minutes, 86% (2 steps)). The compound (±)-3 was prepared from the compound 3B in substantially the same procedure as described in Example 1. Alternatively, compound 3C is reacted with 1.2 equivalents of cyanogen bromide (4 hours, room temperature, EtOH) and the reaction is concentrated and purified to provide a yield of dry. About 40% of the 〇(士)-3D (LCMS m/z 283/285, MH+) is the 3C of the starting material of It.

Alternatively, compound (±)-3 was prepared from 6-nitro-3-chromanone (prepared from 6-nitro-4-chromanone) in a similar manner as described in Example 4. Preparation Example 4

〇2N

Examples 1 and 2

SnCl2

143636.doc -80- 201026672 CIC02Me

MeO

4C

Etl

MeO

CBz

H2, Pd/C

(±H Step 1-2 Conversion of 7-nitro-2-tetralone to CBz protected compound 4A in a similar manner as described in Examples 1 and 2. Treatment of compound with SnCl2-2H20 (4 equivalents) The reaction mixture was stirred at <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Compound 5B was treated with ClC02Me (ll eq.) and DIPEA (2 eq.). The mixture was stirred at room temperature overnight and then concentrated. The obtained compound 4C was dissolved in acetone and taken to Cs2C03 (6 eq.) and Et. The reaction mixture was stirred at 50 ° C and cooled to room temperature. The mixture was diluted with DCM, filtered through a pad of Celite and concentrated in vacuo to afford 4D. Hydrogenation of compound 4D (with Pd/C and H2) (40 psi, overnight, MeOH), followed by chromatography (NH3-MeOH/DCM) to afford title (s)-4 〇 Preparation Example 5 143636.doc -81 - 201026672

(±)-5 Step 1

5A Adding carbonic acid to a sealed solution of 8-decyloxy-2-tetralone (600 mg, 3. 4 mmol) in a solution of 0.001-112 〇 (1:1, 12 1111 一) Ammonium (2.28 g, 23.8 mmol) of KCN (420 mg, 6-8 mmol). The mixture was heated at 80 ° C for 12 hours, then cooled to room temperature. Water (20 mL) was added to precipitate product 5A. The light grey solid was collected by filtration and washed with water and dried in air (835 mg, 100%, LCMS m/z 247, MH+). Step 2-3

A suspension of 5A (200 mg, 0.813 mmol) and Ba(OH) 2 (460 mg, 3.25 mmol) in water (2 mL) was heated in a sealed tube at 120 ° C for 36 hours. The mixture was acidified with 6N H2SO4 and filtered and washed with MeOH. The combined filtrate was concentrated under reduced pressure to give the crude acid as a white solid solid 143636.doc - 82 - 201026672. The crude product was added to a mixture of EtOAc ( 145 mg, 1.. The mixture was stirred for 3 hours under reflux, cooled to room temperature and concentrated under reduced pressure. The methyl ester hydrochloride was suspended in EtOAc (20 mL) and neutralized with saturated NaHC. The aqueous phase was extracted with EtOAc (2×10 mL). The combined organic layers were dried (Na2SO4) The residue was purified by EtOAc EtOAc EtOAc (EtOAc) ❿ Step 4

5B 5C LiAlH4 (1.02 g, 27 mmol) was added in small portions to a stirred solution of 5B (3.17 g, 13.5 mmol) in THF (50 mL). The mixture was stirred overnight at room temperature and quenched by slowly adding water (1 mL), 1 N NaOH (3 mL) and water (1 mL). The grey suspension was filtered and dried (Na.sub.2) (EtOAc). Step 5

1. BBr3 2. Boc20 5C

5D

NHBoc OH 143636.doc -83- 201026672 BBr3 (1 MDCM solution, 32.5 mL) was added to a stirred solution of 5C (2.79 g, 13.5 mmol) in DCM (25 mL). The bright yellow solution was stirred at this temperature for 3 hours and the reaction was stopped by adding saturated NaHC03 until the pH reached 7. The mixture was concentrated under reduced pressure to give an off-white solid. Boc20 (5.9 g, 27 mmol) and NaHC03 (1.7 g, 20.25 mmol) were added to a solution of the crude succinium-H2 (1:25). The mixture was stirred with EtOAc (4×60 mL). The combined organic layers were washed with EtOAc EtOAc m. Residual yang was purified by column chromatography (50% EtOAc / hexanes) to afford compound 5D (2.555 g, 64%, LCMS m/z 294, MH+). Step 6

To a solution of 5D (30 mg, 0.102 mmol) in DCM (1 mL), phenyl acid (37.3 mg, 0.306 mmol), Cu(OAc) 2 (18.5 mg, 0.102 mmol). The dark green suspension was disrupted overnight at room temperature and concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj Step 7-8 143636.doc -84- 201026672

(±)-5

5E

To a solution of 5E (30.1 mg, 0 - 816 mmol) in DCM (1 mL) was added TFA (0.5 mL). After stirring for 1 hour, the mixture was concentrated under reduced pressure and used for the next step. The crude material was suspended in DCM (0.6 mL) and then BrCN (3 M DCM solution, 0.033 mL, 0.098 mmol). The mixture was stirred at room temperature for 3 hours and purified by HPLC (0-50% CH3CN/H20) to yield Compound (+)-5 (6.4 mg, 27%, LCMS m/z 295 MH+) 5E (15 mg, 50%) recovered. The following compounds were synthesized in a similar manner as described above: Compound No. Compound LCMS (MH+) (±)-5F c'XjL nh2 329

Preparation Example 6 NH,

Zn(CN)2 Pd(dppf)CI2

Compound 3D (28 mg, 0.10 mmol), cyanide (35 mg, 143636.doc -85 - 201026672 0.30 mmol) was heated at 120 ° C based on the literature procedure (J. Med. Chem. 2007, 50, 1958). , a mixture of zinc powder (19 mg, 0.30 mmol) and Pd(dppf)Cl2 (20 mg, 0.024 mmol) in DMF (3 mL) overnight. The mixture was cooled, diluted with water (10 mL) and extracted with DCM ι (3 times). The combined organic layers were washed with brine, dried over Na2ssssssssssssssssssssssssssssssssssss /z 230 MH+). Preparation Example 7

Compound 3D (30 mg, 0.11 mmol), acetamide (32 mg, 0.53 mmol), N,N,-didecyl-(1R, 2R)-cyclohexane was heated in a sealed tube at 1 °C. Mixture of diamine (27 μΙ, 0.17 mmol), K3P〇4 (135 mg, 0.64 mmol) and Cul (24 mg, 0.13 mmol) in DiMF (3.2 mL) overnight. Cool the mixture to water (1 mL) The mixture was extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. (0-10% NH3-MeOH in DCM EtOAc) /z 262 (MH+). Synthesize the compound (±)-7A by the following procedure in a similar manner:

143636.doc -86 · 201026672 Add Cul (49 mg, 0.256 mmol) to a solution of 1E (60 mg, 0.214 mmol) and acetamide (18.9 mg '0.32 mmol) in DMF (2 mL). N,N'-Dimethyl-(1R,2R)·cyclohexanediamine (0.051 mL, 0.32 mmol) and K3P04 (54.3 mg, 0.256 mmol). The mixture was heated at 100 °C for 12 hours and treated with water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic phases were dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) φ LCMS m/z 260 (MH+). Preparation Example 8

1E (±)-8 To a solution of compound 1E (45 mg, 0.16 mmol) in DMF (1 mL), EtOAc (2) (2. The mixture was heated at 150 ° C for 24 hours and then cooled to room temperature. The mixture was treated with EtOAc and filtered thru a pad. After concentrating, the residue was purified by EtOAcjjjjjjjj LCMS m/z 228 (MH+) » Preparation Example 9

143636.doc • 87 · 201026672

9A 9B The 5-bromo-2-tetralone was converted to the amino alcohol 9B in a similar manner as previously described (Example 1, Steps 1-4). Step 2

9B 9C To a stirred solution of 9B (380 mg, 1.48 mmol) in THF (7 mL), EtOCONCS (0.168 g, 1.48 mmol). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in EtOH (10 mL) and H.sub.2 (O.sub.2) (471.6 mg, 1.48 mmol). After 1 hour, the mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc EtOAc EtOAc)

(soil)-9C

Co2h (±)-^D (±)-9 143636.doc -88- 201026672 (±)-9C (305 mg, 0.864 mmol) in THF (4 mL) at -78 °C

n-BuLi (2.9 M hexane solution, 0.745 mL, 2.16 mmol) was added to the stirred solution. The pale yellow solution was stirred at this temperature for 15 minutes and then dry ice was added. The white suspension was stirred at this temperature for 30 minutes and then warmed to room temperature. The mixture was quenched by the addition of saturated NH4C1 and extracted with EtOAc. The combined organic layers were washed with EtOAc EtOAc m. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: LiOH (10 equivalents) was added to a mixture of crude (±)-9D in MeOH / water (1:1). The mixture was refluxed for 2 hours and concentrated to remove most of MeOH. The mixture was extracted with EtOAc (EtOAc)EtOAc. The crude product was purified by preparative EtOAc (EtOAc) LCMS m/z 347 MH+. In a similar manner to that described above, the compound (±)-9C was treated with nBuLi and then quenched with ClC02Me to provide (±)-9E, followed by selective removal of the protecting group with LiOH to give (±)-9F. LCMS m/z 261 (MH+)

(±)-9C

(±)-9E

Preparation Example 10

(±)-9 (±)-10A (±)-10 143636.doc -89- 201026672 Add HATU (12.6 mg) to a solution of (±)-9 (7 mg, 0.022 mmol) in DMF (20 mL) , 0_033 mmol) and MeNH2 (2 M THF solution, 0.022 mL, 0.044 mmol) » The solution was allowed to stand overnight at room temperature and treated with Et0Ac/H20. The organic layer was dried and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) (±)-10A was deprotected with LiOH in a similar manner to that described in Example 9 to give (±)-1 呈 as a white solid. LCMS m/z 260 (MH+). The following compounds were synthesized from (±)-9 in a similar manner as described above:

Preparation Example 11

143636.doc -90- 201026672 Step 1 NHC02Et

(士)-9C (±)-11Α NHC02Et

The compound (±)-9C was treated with nBuLi in a similar manner as described in Example 9 (Step 3) and then quenched with DMF to provide (±)-11 Α. LCMS m/z 303 (MH+) Step 2-3

To a solution of (±)-llA (32 mg, 0.106 mmol) in Et.sub.2 (2 mL), EtOAc (EtOAc (EtOAc) After 2 hours the mixture became a white suspension and was concentrated under reduced pressure. The white solid was hydrolyzed with LiOH to give compound (s)-11 (11.6 mg, 46%) as a white solid. LCMS m/z 246 (MH+). In a similar manner, the compound (±)-11 处理 was treated with methoxyamine and then the protecting group was removed to provide (±)-11 Β. (LCMS m/z 260, MH+). 143636.doc -91 - 201026672

(±)-11A NHC02Et

1. NH2OMe-HCI, NaOH

0Me (±)·11Β Preparation Example 12

(±)-12 Compound (soil)-12 (LCMS m/z 281/283, MH+) was synthesized from 6-bromo-2-tetralone in a similar manner as previously described. Synthesis of compound (earth)-12A from (±)-12 by the following procedure:

(soil)·12 (±)-12A Add Zn(CN)2 (125 mg, 1.07 mmol), Zn powder to a solution of (±)-12 (100 mg, 0.36 mmol) in DMF (10 mL) ( 70 mg, 1.07 mmol) and hydrazine, hydrazine-bis(diphenylphosphino)ferrocene (73 mg, 0.09 mmol). The reaction mixture was stirred in a sealed tube at 120 ° C for 12 hours. The reaction mixture was then diluted with H20 and the organic layer was extracted multiple times with CH2C12. The combined organic layers were dried (MgSO4). The residue was purified by preparative EtOAc (EtOAc:EtOAc:EtOAc LCMS m/z 228 (MH+). 143636.doc -92- 201026672

Synthesis of compound (±)-12C from (±)-12 by the following procedure

(±)-12 (±)-12B (±)-12C Add ethylamine (3.0 M THF solution, 2.14) to a solution of (±)-12 (300 mg, 1.07 mmol) in DMF (30 mL) mL, 6.43 mmol), Κ3ΡΟ4 (680 mg, 3.21 mmol), Cul (203 mg, 1.07 mmol) and 2-ethyi-1-cyclohexanone (243 mg, 1.71 mmol). The reaction mixture was stirred in a sealed tube at 100 ° C for 12 hours. The reaction mixture was diluted with H20 and the organic layer was extracted with CH2C12. The organic layer was washed three times with H20 then dried (MgSO4), filtered and evaporated. The residue was purified by preparative EtOAc (EtOAc: EtOAc (EtOAc) MeNCO (15 mg, 0.257 mmol) was added to a solution of aniline (±)-12B (21 mg, 0.086 mmol) in DCM (3 mL). The mixture was spoiled at room temperature for 30 minutes. MeOH (1 mL) was added and the mixture was concentrated under reduced pressure. The residue was purified by preparative EtOAc (EtOAc:EtOAc) LCMS m/z 303 (MH+) Compound (±)-12D was synthesized from (±)-12 by:

(士)-12D (士),12 143636.doc -93· 201026672 Add acetamide (189 mg) to a solution of (±)_12 (3 00 mg, 1 · 07 mmol) in DMF (30 mL) , 5.34 mmol), K3P〇4 (1.36 g, 6.41 mmol), Cul (244 mg, 1.28 mmol) and (1R, 2R)-N1, N2-dimethyl 3 hexyl-1,2-diamine (243 Mg, 1.71 mmol). The reaction mixture was stirred in a sealed tube at 100 ° C for 12 hours. The reaction mixture was then diluted with H20 and the organic layer was extracted with CH2C12. The organic layer was washed three times with H.sub.2, then dried (MgSO4), filtered and evaporated. The residue was purified by preparative TLC (EtOAc/EtOAc/EtOAc) LCMS m/z 260 (MH+) Compound (±)-12E was synthesized from (±)-12B by:

(±)-12B (soil)-12E To a solution of 12B (15 mg, 0.06 mmol) in CH2CI2, DIPEA (30 <RTIgt; The reaction mixture was stirred at tempo until the starting material was consumed and then quenched with NaHC03 (sat.). The mixture was extracted with CH2C12. The CMgS04) organic extract was then dried, filtered and concentrated under reduced pressure. The residue was purified by preparative EtOAc (EtOAc:EtOAc) LCMS m/z 330 [MH+]. 143S36.doc -94- 201026672 Alternatively, the protection (e.g., as CBzCl) (±)-12, is reacted in the coupling reaction described above and then the protecting group (e.g., Pd-C, H2) is removed to provide the final compound. Preparation Example 13

13A 13B

(NH4)2C〇3 KCN

13C (±)-13

1) LiOH

2) SOCI2, MeOH

3) NaBH4 Step 1-2 2-Indanone was treated with (NH4)2C〇3 and KCN in a similar manner as described in Example 1 (Step 1) to provide the carbendazim 13A. Ethylcarbazide is brominated (HBr/Br2) as described in WO 004/082602 to provide 13B. Step 3-6 Compound 13B was treated in a similar manner as described in Example 1 (Step 2-4) with LiOH, SOCI2-MeOH and NaBH4 to afford 13C. Compound 13C was cyclized with cyanogen bromide to provide (±)-13 in a similar manner as described in Example 3. The following compounds were prepared from (±)-13 in a similar manner as previously described:

(±)-13D

(±)-13F

(±)-13E 143636.doc -95- 201026672

C±)-13G

TNtx&gt;cr YOocr (±)-13K (±)-13L

(±)-13J

(t)-13MΥχ»^ΝΗ2 (t&gt;13P

NH2 /N-N

NC^C〇CT

(±)-13N (±)-130 Preparation Example 14

Br

(NH4)2C〇3

A ° KCN Br

14A

〇 2) SOCi2, MeOH NH 1) LiOH Br

NH2 Ο

C02Me 14B

NaBH and

〇H 1)PhC(0)NCS Br 2) LiOH 14C

(±)-14 Preparation of compound (±)-14 from 7-bromo-2-tetralone in a similar manner as described in J 1 : Formation of carbendazim with (NH4)2C03/KCN LiOH is hydrolyzed, oxime ester is formed with SOCl2 / MeOH, reduced with NaBH4, cyclized with phenyl thiocyanate and hydrolyzed with LiOH to provide (±)-14 (LCMS m/z 281/283, ΜΉ+) . -96- 143636.doc 201026672

14E 14G

The racemic mixture (±)-14B was isolated on a preparative Chiralpak AD column (SFC chromatography with 20% MeOH-O.2% DEA) to afford the pure enantiomers 14D and 14E (&gt;99%) Ee), which was separately converted to provide compound 14F (LCMS m/z 281/283, MH+) and compound 14G (LCMS m/z 281/283, MH+). Alternatively, compound 14E was prepared as described in Example 15. Preparation Example 15

14E

2.0 M LDA (0.62 mL, 1.14 mmol) was added dropwise to the hydrazine 15A (J. Org. Chem. 1989, ·54,3130; 0.197 g, 1.039 mmol) in anhydrous THF under nitrogen at -75 °C. In a solution (4 mL). The mixture was stirred for 10 minutes and a solution of 7-bromo-2-tetralone (242 mg, 143636.doc -97 - 201026672 1.044 mmol) in anhydrous THF (2 mL) was added dropwise over 3 min. The resulting mixture was stirred at -75 °C for 30 minutes and then TFA (0.40 mL) was added. The mixture was warmed to room temperature, diluted with water and extracted with DCM. The combined organic phases were dried and the solvent was evaporated in vacuo to yield Et20 was added and the title compound 15B was precipitated as a white solid (205 mg, 47%, 3:1 mixture of diastereomers). Step 2

To a solution of the diastereomeric alcohol mixture 15B (120 mg, 0.29 mmol) in a 1:1 mixture (20 mL) of anhydrous EtOAc. The resulting mixture was stirred for 1.5 hours and KOtBu (13 mg, 0.12 mmol) was added. The mixture was then repelled for 30 minutes and the solvent was evaporated. The mixture was extracted with DCM in water. The combined organic phases were dried <RTI ID=0.0></RTI> to <RTI ID=0.0> 1 04 mg, 95%, consider separating 1 6 mg of secondary epoxide). Step 3

Ph

ΒΓκ_ \/~~^A^S(0)T0\

15C 143636.doc -9 8 · 201026672 Diphenylamine oxime (0.185 mL, 1.06 mmol) was added to a solution of epoxide 15C (80 mg, 0.212 mmol) in IPA (3 mL). The resulting mixture was heated at 9 (TC) for 17 h then cooled at rt. solvent was evaporated and residue was purified by column chromatography (1% to 10% AcOEt:hexane) to give the title of pale brown glass. Compound 15D (38 mg, 43%). Step 4

A solution of KOH (136 mg, 2.17 mmol) in dry MeOH (2 mL). The resulting mixture was added to a solution of aldehyde 15D (57 mg, 0.136 mmol) in MeOH (3 mL). The mixture was stirred for φ for 25 minutes, and the reaction was quenched with saturated aqueous Na.sub.2SO.sub.3 and extracted with DCM. The combined organic phases were dried <RTI ID=0.0> Title Compound 15E (37 mg, 61%)

15E 14E Step 5 143636.doc -99- 201026672 Heating the diphenylmethyl-protected aminoester 15E (37 mg, 0.082 mmol) in trifluoroacetic acid (3 mL) at 90 ° C in a 15 mL sealed tube The solution in the solution lasted 1 hour and 20 minutes. The mixture was cooled to room temperature, the solvent was removed and the residue was quenched with MeOH EtOAc (0.4 N). The solvent was evaporated and the residue was purifiedjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Preparation Example 16

5-methoxy-2-tetrazinthene was treated with ammonium carbonate and KCN in a similar manner as described in Example 1 (Step 1). A solution of the resulting carbendazim (7.02 g, 28.5 mmol) in DMF (80 mL) was obtained eluting with EtOAc. The mixture was stirred for 30 minutes and poured into water (200 mL). The mixture is smeared and washed with water. The beige solid was dried in air to give 16A (quant. yield). Compound 16A was converted to (±)-16B using the procedure described in Example 1. Compound (±)-16B was then coupled with CuI/EtNH2 in a similar manner as described in Examples 1 and 3, reacted with ClC02Me and the protecting group was removed with LiOH to afford the title compound (±)-16. Preparation Example 17 143636.doc -100- 201026672

Compound 5A was brominated (as described in Example 16) to provide 17A which was further converted to compound 17C in a similar manner as previously described. To a stirred solution of 17 C (1.53 g, 5.33 mmol) in THF (20 mL), EtOCONCS (0.7 g, The mixture was stirred at room temperature for 2 hr and concentrated under reduced pressure. The residue was dissolved in EtOH (40 mL) and then taken to a portion of Hg (OAc) 2 (1.698 g, 5.33 mmol). After stirring for 2 hours, the dark suspension was filtered through a pad of Celite and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc EtOAc (EtOAc) MH+) and 17E (LCMS m/z 383/385, MH+) (total 1.02 g, 50%). Compounds 17D and 17E were then individually converted to 17 and 17F in a manner similar to that previously described. Preparation Example 18

NH2 Br 18A Br nh2

Br 18B NH2 (QO^0 dance

Br 18C 143636.doc • 101 - 201026672 The 5-bromo-2-tetralone was converted to the aminoester (±)-18A in a similar manner as previously described (Example 1, Steps 1-4). The racemic mixture was then separated on a preparative Chiralpak OD column (30% EtOH-hexanes with 0.2% DEA) to afford pure enantiomers 18B and 18C (&gt;95% ee). Alternatively, 18B and 18C are synthesized by the asymmetric method outlined below: Step 1

OH

18D gave 5-bromo-2-tetralone (2.0 g, 8.89 mmol), (i〇-phenylglycine) (1.22 g, 8.89 mmol, 1.0 eq.) and 4 A molecular sieves in CHC13 (50 mL) The mixture was refluxed until the starting material disappeared (monitored by 1H NMR). After filtration of molecular sieves, solvent was removed under reduced pressure and residue 18D was used in the next step without further purification.

TMSCN (1.67 mL, 13.34 mmol, 1.5 eq.), MeOH (3.5 143636.doc -102 - 201026672 mL) was sequentially added to a solution of 18D in 10 mL of CH2C12. The cooling bath was removed and the reaction mixture was stirred at room temperature for 24 hours. The solution was concentrated under reduced pressure and residue 18E was used without further purification. Step 3

OTMS OH OH Ph,,J Ph', J Ph„.&quot; ψ^) (ik \(R) MeOH JC7cn o r^PC〇2Me + τ HCI(9) T Br Br Br 18E 18F 18G

The oily residue 18E was dissolved in 10 mL MeOH and cooled in an ice-water bath. Anhydrous HCl (g) was bubbled through the solution until saturation. After stirring for 1 hour, MeOH was evaporated and the residue was diluted with EtOAc EtOAc. The organic layer was washed with aq. After removal of the solvent, the amino ester was purified by SFC chromatography to yield 18F (1.75 g) and 18G (0.43 g). Step 4

Lead tetraacetate (362 mg, 0.82 mmol, 1.0 eq.) was added to a solution of 18F (330 mg, 0.82 mmol) in DCM (3.5 mL) and MeOH (1. After stirring the resulting mixture for 30 minutes, 10 0 143636.doc -103 - 201026672 mL of phosphate buffer (pH 7) was added to terminate the reaction. The mixture was filtered through celite, and the organic layer was separated, washed with water and concentrated to dry. The residual oil was purified by flash chromatography (1% MeOH / CH.sub.2) to yield 111 mg of &lt The individual enantiomers 18B and 18C were converted to the following compounds in a similar manner as previously described:

Preparation Example 19

step 1

MeO

143636.doc -104- 201026672 In a sealed tube, 8-methane-2-tetralone (600 mg, 3.4 mmol) in £1〇&gt;1-1120 (1:1,12]111〇 An aliquot of the solution was added (2.28 g, 23.8 mmol) and KCN (420 mg, 6.8 mmol). The mixture was heated at 80 ° C for 12 hours, then cooled to room temperature. Water (20 mL) was added The product 19 A was precipitated by passing through a sputum, collecting a light gray solid and washing with water and drying in air (835 mg '1 〇〇 ° / 〇 ' LCMS m / z 247, MH + ) ° Step 2-3

A suspension of 19A (200 mg '〇·813 mmo1) and Ba(OH) 2 (460 mg, 3.25 mmol) in water (2 mL) was heated in a sealed tube at 13 ° C for 36 hours. The mixture was acidified with 6 1 ^ 1123 〇 4 and filtered and the filter pad was washed repeatedly with ] 6 〇 11 . The combined mash was shrunk under reduced pressure to produce an amino acid in the form of an off-white solid. The crude product was added to a mixture of EtOAc (145 mg &lt;RTI ID=0.0&gt;&gt; The mixture was stirred for 3 hours under reflux, cooled to room temperature and concentrated under reduced pressure. Methylamine hydrochloride was suspended in EtOAc (20 mL) and neutralized with saturated NaHC. The aqueous phase was extracted with EtOAc (2×1 mL). The combined (NaaSCU) organic layer was filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Step 4 143636.doc •105· 201026672

19B 19C LiA1H4 (1.02 g, 27 mmol) was added in small portions to a stirred solution of 19B (3_17 g, 13.5 mmol) in THF (50 mL). The mixture was stirred overnight at room temperature and quenched by slowly adding water (1 mL), 1 N NaOH (3 mL) and water (1 mL). The grey suspension was filtered and dried (Na2EtOAc) filtered elute elute Step 5 rvr'u

19C

Compound 19C was treated with Boc20 in a similar manner as described in Example 5 (Step 5). Dess-Martin periodate (3·66 g, 8.634 mmol) was added to a solution of the obtained product (1.767 g, 5.756 mmol) in CH2C12 (30 mL). The mixture was stirred for 1 hour and NaS2〇5 solution (1 Μ, 20 mL) was added to terminate the reaction. The organic layer was separated and washed with a saturated NaHC03 solution and brine. The organic phase was dried (Na2SO4) filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc Step 6 143636.doc -106- 201026672 r\rn_i

19D 19E To a solution of compound 19D (1.673 g, 5.485 mmol) in CH.sub.2.sub.2 (30 mL). The mixture was stirred at this temperature for 1 hour and quenched by the addition of saturated aqueous NH4CI (20 mL) and EtOAc (80 mL). The organic layer was separated, washed with brine, dried w... The crude material (white solid, 1.756 g, 97%) was taken from &lt;EMI ID=9.1&gt;&gt; Step 7

19E

Compound 19E was cyclized and brominated to provide 19G in a similar manner as described in Examples 9 and 16. Compound 19G was converted to the title compound to provide (±)-19 in a similar manner as previously described (e.g., Example 2). Preparation Example 20

〇 (±)-20 143636.doc -107- 201026672 Step 1-3

20A 20B Heated 5-dehydronaphthone (5.5 g, 24.4 mmol) and "Bilo bite (2.6 g, 36.6 mmol) in toluene (100 g) under reflux with a Dean Stark trap The mixture in mL) lasted for 48 hours. The reaction was then concentrated to give 20A as a dark foam. LCMS m/z 278/280 (MH+). The enamine 20A was dissolved in 1 mL of 1,4-dioxane, treated with 15 mL of Mel and heated under reflux overnight. The reaction was cooled in an ice bath and then treated with 40 mL H20 and 1.5 mL AcOH. After heating for 3 hours under reflux, the reaction was concentrated and purified (EtOAc EtOAc) Step 4-10

20B 20C (士)-20D Compound 20B was converted to (±)-20D (LCMS m/z 295/297, MH+) in a similar manner as described in Example 1. (±) -2 〇D was converted to the title compound (±)-20 in a manner similar to that previously described. 143636.doc -108- 201026672 Preparation Example 21

18A was reduced with NaBD4 and cyclized with PhC(0)NCS in a manner similar to that described in Example 1. The S-enantiomer 21C was provided for palm separation (OD column, 25% EtOH-hexane) and hydrolysis with LiOH. LCMS m/z 283/285 (MH+). Compound 21C was then converted to 21 as previously described. Similarly, the R-enantiomer 21D was also synthesized. LCMS m/z 283/285 (MH+). Compound 21D was then converted to 21E as previously described.

Preparation Example 22

143636.doc -109- 201026672

A solution of compound 18A (0.92 g, 3 - 24 mmol) in THF (15 mL). The reaction was cooled in an ice bath and quenched with saturated aqueous NH4CI, and stirred for 30 min. The mixture was then treated with 1.0 M NaOH (ca. 10 mL) and then extracted with DCM (3×), dried over Na.sub.2.sub.4, and concentrated to afford 22A (0.92 g) as a brown foam. 22A was cyclized with PhC(0)NCS/Hg(OAc)2 in a similar manner as described in Example 17, and hydrolyzed to provide (±)-22C. LCMS m/z 309/311 (MH+). Compound (±)-22C was converted to (±)-22 as previously described. Preparation Example 23 1) (CH20) 2 1) DPPA ΓΎΎ0 f^OH 2) CH2=CHCN 2) HCI Br 3) NaOH Br Br

143636.doc -110- 201026672 Step 1-5 Preparation of 8-bromodecane-3-one 23B from 2-bromophenol in a manner similar to that described in the literature (J. Med. Chem., 1988, 689):

2-Bromophenol was reacted with trimeric furfural (MgCl2, NEt3, THF, 75 ° C, 4 hours), followed by treatment with acrylonitrile (pure, Dabco, 95 ° C, 18 hours) and hydrolyzed with 10% NaOH ( 23A was obtained at 100 ° C for 4 hours. Compound 23A was reacted with DPPA (NEt3, toluene, 110% (:, 2 hours), followed by 6N HCl (85 ° C, 2 λ|,) to give 8-bromodecane-3-one 23B. Step 6 -11 Preparation of compound 23D from 23 hydrazine in a similar manner as described in Example 1 : formation of carbendazim with (NH 4 ) 2 CO 3 /KCN, hydrolysis with LiOH, formation of oxime esters with SOCl 2 / MeOH, and reduction with NaBH 4 . Reaction with cyanogen bromide provided 23E (THF, rt, 3 hr). mp.

Me

0 (±)-24 Step 1 丫 丫0 KCN, NH4CI V1- Br Br

24A 143636.doc -111 - 201026672 Treatment of 5-di--2-tetralone (1.5 g, KCN (1.3 g, 19.99 mmo, 3·0 eq.) and NH4C1 (1.78 g, 33.3 mmol, 5.0 eq.) A solution of 6.66 mmol) in a 1:1 mixture of EtOH/H.sub.2 (50 mL). The reaction mixture was heated to 60 ° C for 16 hours and then cooled to room temperature. Saturated NaHCO.sub.3 (40 mL) EtOAc (EtOAc)EtOAc. 2

24A 24B A solution of the crude amino nitrile 24A in HCO2H (20 mL) was cooled to 0 &lt;0&gt;C and sat. After 10 minutes, the tannic acid was evaporated and the residue was dissolved in acetone (25 mL). The white solid was filtered to give compound 24B (1.25 g). Step 3-4

24B (±) _24C To a suspension of compound 24B (500 mg, 1.86 mmol) in EtOAc (EtOAc) Slow 143636.doc -112- 201026672 Ethyl chloride (0.16 mL, 2.23 mmol, 1.2 eq.) was added and the reaction was stirred at room temperature overnight. After the reaction was completed, a NaHCO 3 aqueous solution (15 mL) was added. Extracted with CH2C12 (2.times.2 mL), dried EtOAc (EtOAc) 24C (525 mg). LCMS m/z 293/295 (MH+). Compound (±)-24C was converted to (±)-24 in a similar manner as described in Example 12.制备 Preparation Example 25

A solution of 24B (100 mg, 0.37 mmol) and trimethyl sulfonate (0.049 mL, 0.44 mmol, 1.2 eq.) in 1 mL of DMF was microwaved at 140 ° C for 40 min. After cooling, H20 (5 mL) was evaporated and evaporated. The crude product was purified by flash chromatography eluting with 2-4% MeOH / CH.sub.2.sub.2 to afford 30 mg. LCMS m/z 279/281. (MH+). Convert (±)·25 to (±)-25Α in a manner similar to that described in Example 2.

(±)-25Α 143636.doc -113- 201026672 Preparation Example 26

Compound 23E was treated in DMF with cyanide, zinc powder and Pd(dppf)Cl2 in a similar manner as described in Example 6 and heated overnight at 120 °C to provide (±)-26. Preparation Example 27

The compound 14C solution was treated with Et0C (0) NCS (1.2 eq.) in THF, and stirred at room temperature for 3 hours, and then concentrated to afford 27A. The crude compound 27A was dissolved in CH3CN, cooled in ice-broil, and portion-wisely treated with 2-chloro-3-ethylbenzoxazolium tetrafluoroborate (1.2 eq.). The reaction was stirred for 1.5 hours and then the reaction was quenched with TEA and water. The mixture was extracted with DCM (2 times) and concentrated to afford 27B. Compound 27B was then deprotected with LiOH in a manner similar to that previously described. 143636.doc -114- 201026672 protecting group to provide (s)-14 ° Preparation Example 28

step 1

AlCl3 (41 6 g, u.j j mol) was fed into a 3-necked round vessel equipped with Condensation II and then heated to 75 °C. Ip_cage and sow Λ / bamboo 1 ring-opening heptanone (20 g, (M3 mol) is added dropwise to the hot A1C13. Xiang;;; different origin Ap, 丄3 Dingmen 仵 brown paste Add Br2 dropwise (24

g. ' 0.15 m〇1). The reaction mixture was stirred for 5 minutes and then cooled to 〇 °C. The reaction mixture was quenched with borneol. Slowly add concentrated hydrochloric acid under stirring to dissolve the mixture. The mixture was diluted with HA and the organic layer was extracted (2 times). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give a mixture of 6-bromocycloheptan-1-indole 28A and 8-bromocycloheptane ", μβ (1:2 ratio) Step 2

143636.doc 115- 201026672 NaBH4 was added to a 1:2 mixture of 28A and 28B in MeOH (20 mL) and THF (40 mL) at EtOAc. The reaction mixture was stirred at room temperature for 1 hour, then neutralized with &lt The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (5-10%EtOAc /EtOAc) toield And cycloheptane 28D (19.7 g) ° Step 3

HO Br

28C 28E To a solution of 28C (4.4 g, 0.02 mol) in toluene (50 mL) was added molecular sieves and p-toluenesulfonic acid monohydrate (347 mg, 1.82 mmol). The reaction mixture was refluxed for 3 hours, cooled to rt. The combined organic layers were dried (MgSO4), filtered and evaporated. Step 4

mCPBA (4_4 g, 143636.doc • 116- 201026672 0.03 mol) was added to 3 parts of 28E benzene solution (50 mL). The reaction mixture was stirred at room temperature for 1 hour, and then quenched with aqueous sodium sulfate (10%). The organic layer was washed with 1 N NaOH, dried (MgSO4), filtered and concentrated under reduced pressure to afford succinate 28F (for the next step). Step 5

Znl2 (7.31 g, 0.02 mol) was added to a 28 F benzene solution (50 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1.5 hours and diluted with H20. The mixture was extracted with CH2C12. The combined organic layers were dried (MgSO4) filtered and evaporated. Flash chromatography (EtOAc / hexanes, 1 : 9) gave the desired product 28 g (2.3 g, 53%). Step 6-10

〇 NH?

(±)-28H In a similar manner as previously described (e.g., Example 1), Compound 28G was subjected to the following procedure: Formation of carbendazole with (NH4)2C03/KCN, hydrolysis with LiOH, formation of SOCl2/MeOH The ester was reduced with NaBH4 and cyclized with BrCN to afford (+) -28H (LCMS m/z 295/297, MH+). Compound (±)-28H was converted to 143636.doc-117-201026672 as the title compound (±)-28 in a similar manner as described in Example 12. Compound 281 and (±)-28K (LCMS m/z 295/297, MH+) were synthesized from 28D in a similar manner. Compound (±)-28K was converted to the title compound (±)-28L in a similar manner as described in Example 12.

Preparation Example 29 N=\

NH Ο (土)-29 Step 1-2

5-Bromo-2-tetralone (2.00 g, 8.88 mmol) was dissolved in EtOH (40.0 mL, 685 mmol) and water (33.0 mL, 1830 mmol). KCN (1.157 g, 17.77 mmol) and NH4C1 (1.901 g, 35·54 mmol) were added in that order. The reaction was heated to 60 ° C and stirred overnight. The mixture was diluted with 143636.doc -118- 201026672 DCM and saturated NaHC03. The two phase solution was separated and the aqueous layer was extracted with three portions of DCM. The combined organic phases were dried with anhydrous sodium s A solution of 29 Α (2·20 g, 8.76 • mmol) in THF (20.0 mL, 246 mmol) was obtained from EtOAc (EtOAc) The reaction was cooled in an ice/water bath and the reaction was quenched slowly with water (drops) and 10% NaOH. The mixture was warmed to room temperature and stirred for 3 hours. The material was filtered through EtOAc (EtOAc)EtOAcEtOAcEtOAcEtOAc Step 3-4

A mixture of 29B (200 mg, 0. 78 mmol) and methylene acetate (106 mg, 1.02 mmol) in EtOH (10 mL, 171 mmol) was stirred at room temperature for 1 hour. The mixture was diluted with DCM and saturated sodium bicarbonate. The two phase solution was separated and the aqueous layer was extracted with three portions of DCM. The combined organic phases were dried over anhydrous sodium s LCMS m/z 265/267 (MH+). Compound (±)-29C was converted to the title compound (±)-29 in a similar manner as described in Example 12. Step 5-6 143636.doc -119- 201026672 or synthesize compound 29B from 18 A by the following two-step procedure:

18A

29D 29B A solution of 18A (190 mg, 0.67 mmol) in NH3-MeOH (7 N, 12 mL). The reaction mixture was concentrated to afford 29D (191 mg, 106%). A solution of compound 29D (180 mg, 0.67 mmol) in THF (10 mL) was slowly taken from &lt;RTI ID=0.0&gt;&gt; The reaction mixture was heated to 105 ° C for 2 hours, then cooled to 0 ° C in an ice/water bath and quenched with EtOH, K2CO3. The mixture was warmed to room temperature and stirred for 2 hours. The material was filtered through celite, washed with three portions of EtOH and concentrated. The crude mixture was diluted with DCM and saturated sodium bicarbonate. The two phase solution was separated and the aqueous layer was extracted with three portions of DCM. The combined organic phases were dried <RTI ID=0.0> Preparation Example 30

A solution of 29B (200 mg, 0.78 mmol) in THF (10 mL) was then taken from &lt;RTI ID=0.0&gt;0&gt; The mixture was diluted with DCM and saturated sodium bicarbonate. 143636.doc -120- 201026672 From the two phase solution and extract the aqueous layer in triplicate DCM. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to afford (+) -30A (228 mg &apos; 95%). LCMS m/z 305/307 (MH+). Compound (±)-30A was converted to the title compound (±)-30 in a similar manner as described in Example 12. Preparation Example 31 nh2 nh2

Π 29Β (士)-31Α (±)-31 A solution of 29B (200 mg, 0·78 mmol) in THF (10 mL) was then taken from BrCN (5 M/MeCN, 204 μM) and then stirred at room temperature. 1 hour. The mixture was diluted with DCM and saturated sodium bicarbonate. The two phase solution was separated and the aqueous layer was extracted with three portions of DCM. The combined organic phases were dried <RTI ID=0.0> LCMS m/z 280/282 (MH+). Compound (±)-31A was converted to the title compound (±)-30 in a similar manner as described in Example 12. Preparation Example 32

29B (±)-32A (±)-32 143636.doc • 121 - 201026672 Compound 29B was reacted with acetamidine hydrochloride (EtOH, room temperature, 2 centuries) in a manner similar to that described in Example 29 ( ±) -32A. LCMS m/z 279/281 (MH+). Compound (士)-32A was converted to the title compound (±)-32 in a similar manner as described in Example 12. Preparation Example 33

NH

(±)-33 In a similar manner to that described in Example 29, Compound 18A was reacted sequentially with methylamine (2M / MeOH, 105 ° C overnight in a sealed tube), BH3-SMe2 and yttrium acetate to afford (±)-33C. LCMS m/z 279/281 (MH+). Compound (±)-33C was converted to the title compound (±)-33 in a manner similar to that described in Example 12. Similarly, 18A is reacted with ethylamine, followed by reduction with BH3-SMe2 to provide 33E, respectively, with a formazan acetate ring to provide (±)-33F and cyclization with ethyl hydrazine hydrochloride to provide (earth)-33G (LCMS nx /z 307/309, MH+). Compound (±)-33F was converted to (±)-33H in a similar manner as previously described (e.g., Example 12). Similarly, the compound (±)-33G was converted to (±)-331. 143636.doc 122- 201026672

Convert 4-bromo-1-indanone to 4-bromo-2-indanone (34A) and then further to (±)-34F (LCMS) in a similar manner as previously described (eg, Example 1) m/z 267/269, MH+). Compound (±)-34F was converted to the title compound (±)-34 in a similar manner as described in Example 12. The alternative transformations of 34A to 34B are described below: 143636.doc -123 - 201026672

Potassium persulfate Br

Br 〇

Br Ο

34A

34G

To a solution of compound 34A (0.047 mol, from 10 g of 4-bromo-1-indanone) in EtOAc/water (220 mL / 220 mL), NaHC03 (19.7 g, 0.23) 5 mol) and acetone (34.5 mL, 0.47 mol). A solution of potassium persulfate (57.8 g, 0.094 mol) in water (220 mL) was added dropwise to the above mixture over 1 hour. The reaction mixture was stirred vigorously overnight and then the layers were separated. The organic phase was washed with brine (20 mL) dry To a solution of crude 34G in THF / CH.sub.2Cl.sub.2 (65 mL / 130 mL槚: The suspension was mixed for 2 hours and filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure and purified with EtOAc EtOAcjjjjjjjjjjj After four steps)) Another alternative conversion of 34A to 34B is described below: Sodium bicarbonate (2S.) is added in portions to an ice-cold mixture of 34A (crude, 22 g, 0.113 mol) in DCM (360 mL). 5 g, 0.339 mol), mCPBA (3 5.4 g, 0.16 mol). The reaction was slowly warmed to room temperature and stirred vigorously for 4 hours. The mixture was quenched with a 10% aqueous solution of sodium sulfite and the mixture was washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness afforded <RTIgt; The crude epoxide 143636.doc -124-201026672 34G (0.113 mol) was dissolved in benzene (360 mL) t in a dry round bottom flask under a nitrogen atmosphere. The flask was cooled to 0 ° C in an ice/water bath and anhydrous zinc diiodide (43.4 g, 0.136 mol) was gradually added. The resulting mixture was stirred at 〇 ° C for 10 minutes, then allowed to warm to room temperature and stirred for 4 hours. The mixture was washed with two portions of water and then finally washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to afford &lt Another alternative preparation of 34E is described below:

A mixture of 3-bromo-o-xylene (20 g, 0.108 mol) in CC 14 (200 mL) was obtained eluted with NBS (38.5 g, 2.0 eq.) and benzoic acid (263 mg, 0.01 eq.) and refluxed overnight. . The reaction was then cooled to o ° c and filtered. The filtrate was concentrated and purified (EtOAc, hexanes) toield of EtOAc (EtOAc) Treatment with NaHMDS (1.0 N/THF, 1.1 mL, 1.1 eq.) at -78 ° C in a similar manner as described in the literature (Tetrahedon, 1999, 55, 14281 and Tetrahedron ® Letters, 1992, 33, 1565) A mixture of N-(diphenylarylene)-glycine ethyl acetate (267 mg, 1 mmol) in THF and stirred for 30 min. Compound 34H (343 mg) in THF was added and the mixture was stirred at -78 °C for one hour and then at room temperature for 2 hours. The mixture was again cooled to -78.degree. C. and treated with NaHM EtOAc (EtOAc. The reaction was slowly warmed to rt and stirred overnight. EtOAc EtOAc m. The organic phase was dried over anhydrous sulphuric acid 143636.doc -125 · 201026672 and concentrated. The residue was dissolved in diethyl ether, taken to EtOAc (EtOAc) and EtOAc. The benzophenone by-product was removed from the reaction mixture by extraction with diethyl ether. The product was isolated by cooling the aqueous layer in an ice bath, neutralizing with 1 N NaOH and ethyl ether. The ether extract was concentrated to provide 341. Compound 341 was reduced with NaBH4 to provide 34E in a similar manner as previously described (e.g., Example 1). Preparation Example 35

°T Step 1-2 A mixture of 9 Β (1·0 g, 3.9 mmol) in THF-water (1:1, 40 mL) was treated with Boc20 (1 _ 28 g, 1.5 eq.) and Na2C03 (491 mg, 1.5 eq.). Stir at room temperature and then extract with EtOAc. The organic layers were combined and concentrated to give the product as a white solid (1.25 g, 90%). A mixture of Boc-protected alcohol (660 mg, 1.85 mmol) in DCM (20 mL) was obtained eluted with EtOAc (EtOAc) The reaction was then diluted with hexane (20 mL), stirred 1 min and filtered. The filtrate was concentrated and purified by silica gel chromatography to afford 35A (490 mg). 143636.doc •126- 201026672 Step 3-4 Cool down a solution of 35A (430 mg ' 1.21 mmol) in THF (15 mL) to -78 ° C with MeMgBr (3.0 N/THF, 0.93 mL, 2.3 eq. ) suitable for drop treatment. The mixture was allowed to warm slowly to room temperature and then quenched with saturated aqueous NH4CI in 0 °C. The reaction was extracted with DCM. The combined organic extracts were dried over Na 2 SO 4 , concentrated and purified to afford a mixture of &lt Compound 35C was converted to 35B by the following procedure: a mixture of 35C (145 mg, 0.5 mmol) and Ba(OH)2 in two calories-water (1:1 - 30 mL) at i〇〇 °c Until the LCMS analysis indicates that the SM is exhausted. The mixture was cold mash and diluted with EtOAc and water. The organic layer was separated, dried over Na 2 EtOAc (m.), EtOAc EtOAc (EtOAc) g, 9_8 mmol) </ br> </ br> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The reaction was quenched with saturated aqueous NH.sub.1 C. EtOAc (EtOAc m. 6 At room temperature, mix the amines 35B (100 mg, 0.37 mmol) and BrCN (5.0 N/MeCN, 0.09 mL) in EtOH (7 mL) for 4 hours. Concentrate the mixture and pass the tube Column chromatography (7N NH3-Me:H in DCM) was purified to afford (+)-35D. 143636.doc -127· 201026672 Compound (±)-35D was converted in a similar manner as described in Example 12. The title compound (±)-35. Preparation Example 36

Β〇〇2〇

Br 36A

34D, R = C02Me 34E, R = CH2OH, NHBoc oxidation

36C 1) TFA 2) EtOC(0)NCS; Hg (OAc)2

(±)-36D, R = C02Et (±)-36E, R = H

MeMgBr DCM

Compound 34E was protected by R Boc20 in the same manner as described in Example 35, oxidized with TPAP/NMO or Dess-Martin reagent, and R MeMgBr (in DCM, -78 ° C to room temperature overnight, or Treatment in THF, 1 hour, -78 °C) to afford 36C. In a similar manner to that previously described, 36C was deprotected with TFA, and was hydrolyzed with LiOH using Et0C(0) NCS/Hg(0Ac)2 ring to afford (s)-36E. Compound (±)-36E was converted to the title compound (±)-36 in a similar manner as described in Example 12. The enantiomers of compound 34D and 36A were separated by SFC (OD column, 10% MeOH and AD, with 201⁄4 MeOH). Separation of the diastereomers of the alcohol (36F and · 36G) by oxidation: oxime chromatography (2-25% EtOAc / hexanes)

143636.doc -128- 201026672 Preparation Example 37

To 9B (93 mg, 0.360 mmol) and DIPEA (78 pL, 0.432 mmol)

Tridecyl orthoacetate (55 pL, 0.432 mmol) was added to a mixture of DMF (3 mL). The mixture was stirred at 115 ° C for 16 hours. The mixture was diluted with H.sub.2 (5 mL). The combined organic layers were washed with brine (10 mL) dried over anhydrous The residue was purified (EtOAc, EtOAc EtOAc) elute LCMS m/z 280/282, (MH+). Compound (±)-37A was converted to the title compound (±)-37 in a similar manner as described in Example 12. Preparation Example 38

step 1

143636.doc -129- 201026672 Add 2_5 of hexane solution containing n-BuLi (260 pL, 0.650 mmol) to bromo 4b methyltriphenyl scale (211 mg, 0·600 mmol) in THF (3 mL) In the suspension. The mixture turned into an orange suspension. After stirring at room temperature for 30 minutes, a solution of EtOAc (EtOAc, EtOAc) The resulting mixture was kept at room temperature for 1 hour and a white smear was formed. The mixture was diluted with aq. EtOAc (EtOAc) The combined organics were washed with brine (10 mL EtOAc The residue was purified (EtOAc EtOAc EtOAc) LCMS m/z 352/354 (MH+). Step 2

Br 38B Br 38A A solution of 38A in THF (1 mL) EtOAc (EtOAc) The reaction was treated with 1 N NaOH [1.5 mL] followed by H2O2 (30%). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The reaction was extracted with EtOAc (2×10 mL). The combined organics were washed with H.sub.2 O (10 mL). The residue was purified (EtOAc EtOAc EtOAc) LCMS m/z 370/372 (MH+). Step 3: 143636.doc -130-

201026672 OH OH

To a solution of compound 38B (120 mg, 0.324 mmol) in CH.sub.2Cl.sub.2 (2 mL). The reaction was stirred at room temperature for 2 hours. The mixture was diluted with CH.sub.2Cl.sub.2 (10 mL) and basified with 50% NH4OH (v/v, 6 mL). The aqueous layer was extracted once more with CH2C12 (10 mL). The combined organics were dried with EtOAc EtOAc (EtOAc) LCMS m/z 270/272 (MH+). Step 4-5

A solution of 38C (67 mg, 0.248 mmol) in EtOAc (1 mL) was then taken from &lt;RTIgt;&lt;/RTI&gt; The mixture was concentrated, diluted with CH2C12 (10 mL) The aqueous layer was extracted once more with CH2C12 (10 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated. Purification (PTLC, EtOAc (MeOH) (EtOAc) (EtOAc) In a similar manner to that described in Example 12, the compound (±)-38C was converted to 143636.doc-131 - 201026672.

Boc9V

2) Et0C(0)NCS; Hg (OAc)2 3) LiOH

Vinyl magnesium bromide was added to compound 36B in a similar manner to that described in Example 35. The resulting product 39A was deprotected, cyclized and hydrolyzed to give (±)-39B in a similar manner as previously described. Odor and oxygen were bubbled through a mixture of compound (±)-39B in DCM at -78 °C for 30 minutes. Then the air was blown in for 10 minutes. The reaction was treated with dimethyl sulphate (10 eq.), warmed to room temperature, concentrated and purified by flash chromatography to afford (+)-39C. Compound (±)-39C was reduced with NaBH4 in a similar manner as previously described (e.g., Example 1). The DCM solution of the obtained alcohol was treated with Deoxy-Fluor (F3S-N(CH2CH2OMe)2) to reflux until the starting material was consumed. The reaction was cooled to rt. The organic layer was dried over Na.sub.2SO.sub.sub.sub. Alternatively, DAST (F3S-NEt2) is used as the fluorinating reagent. Compound (±)-39D was converted to the title compound (士)-3 in a similar manner as described in Example 12. Preparation Example 40 143636.doc •132- 201026672

NHBoc CD3MgBr HN-Boc DCM V OH Br Br d3c 36Β 40A 1) TFA 2) Et0C(0)NCS; Hg (OAc)2

3) LiOH 4) BrCN

Compound φ 36B was treated as CD3MgBr (prepared from CD3Br, see J. Am. Chem. Soc_1989, 111, 3897) and then converted to (±)-40B in a manner similar to that described in Example 35. Compound (±)-40B was converted to the title compound (±)-40 in a similar manner as described in Example 12. Preparation Example 41

1) TFA 2) EtOC(0)NCS; Hg (OAch

MeMgBr DCM

3) LiOH 4) BrCN

The 34D THF solution was treated with LiAlD4 for 1 hour at room temperature to afford 41A which was further processed to (+)-41 in a similar manner as outlined in Example 36. Preparation Example 42

143636.doc -133- 201026672 Step 1 3-Bromo-o-xylene (80 g, 432 mmol), NBS (154 g, 864 mmol) and AIBN (2,2,_ azo only (2-methylpropane) The suspension of nitrile), 2.0 g, 12.3 mmol) in anhydrous CC 14 (400 mL) was gradually warmed to boiling and then refluxed for 2 hr. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and filtered through a pad of EtOAc (EtOAc)EtOAc. The resulting product was concentrated, cooled in a freezer and then triturated with cold hexane to afford 42A (110 g). An extravagic product can be obtained from the mother liquor. Step 2-3 Cool NaHMDS (1.0 M / THF, 200 mL, 1.05 eq.) in THF to -78 ° C and ethyl N-(diphenylmethylene)glycolate (50.68 g, 1.0 eq.) The THF solution was treated dropwise. The reaction was stirred at -78 °C for 30 min and then treated dropwise with tribromide 42A (65 g, 1.0 eq.) in THF. The reaction was slowly warmed to room temperature overnight. The mixture was then cooled to -78 ° C and treated dropwise with NaHMDS (1.0 M / THF, 209 mL, 1.1 eq.). The reaction was again slowly warmed to room temperature overnight. The mixture was quenched with ice and extracted with Et20. The organic layer was treated with HCl (2N, 1 L) and stirred vigorously until analysis indicated that the intermediate imine was completely converted to 42B. The layers were then separated and the organic layer was discarded. The aqueous layer was cooled in an ice bath and neutralized with &lt;RTI ID=0.0&gt;&gt; The DCM layer was dried <RTI ID=0.0></RTI> to <RTI ID=0.0> Step 4-5 Treatment with Boc20 as previously described: Compound 42B. The resulting protected 143636.doc-134-201026672 amino ester (〇. 14 g, 0.364 mmol) was dissolved in anhydrous pentane (3 mL) and taken at 0 ° C with TMS-methyllithium (1.0 Μ / Pentane, 1.1 mL, 3.0 eq.). The reaction was stirred at 0&lt;0&gt;C for 2.5 h then quenched with MeOH (1 mL). The mixture was diluted with water and extracted with diethyl ether (3×50 mL). The ether layer was dried over Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub. Alternatively, as described in Example 66, (5> 2-mercapto-CBS-carbazole borane/borane or (7〇-2-fluorenyl-hydrazine CBS-carbazole boropyridine/borane) The method was to reduce 42C. Preparation Example 43

A solution of compound 43A (995 mg, 2.79 mmol, prepared from 36G as described in Example 36) in ® DCM (25 mL) was treated with a Dess-Martin periodin reagent (1.78 g, 4.19 mmol) at room temperature. Stir under 3 hours. The reaction was then quenched with aqueous Na2S203 and stirred at room temperature. The organic layer was separated and washed with aqueous Na.sub.2SO.sub.3. The aqueous layer was further extracted with EtOAc. The combined organic layers of the knees were washed with a saturated NaHC03 aqueous solution (2 times), brine, and water. The organic layer was dried with EtOAc (EtOAc m. LCMS m/z 352/354 (MH+). Stir BH3-DMS (2.54 mL 2·0 N THF solution) and (*S)-143636.doc -135- 201026672 2-mercapto-CBS-carbazole boridine (5.08 mL 2.0 N THF solution) at room temperature The mixture in THF (30 min) lasted 10 min. The reaction was cooled to EtOAc then EtOAc (EtOAc)EtOAc. The reaction was allowed to slowly warm to room temperature, stirred overnight, quenched with water and stirred for 2 hr. The mixture was extracted with EtOAc EtOAc (EtOAc)EtOAc. LCMS m/z 356/358 (MH+). Preparation Example 44

Step 1 Treatment of a mixture of 3-bromo-6-fluoro-o-xylene (25.37 g, 432 mmol) in anhydrous CC14 (250 mL) with NBS (44.5 g, 864 mmol) and benzammonium peroxide (310 mg) And heated under reflux overnight. The mixture was cooled to 0 ° C and filtered and washed with hexane. The filtrate was concentrated and EtOAc (EtOAc) elute elute Step 2-4 in a manner similar to that previously described in Example 42, Step 2-3 and Example 1, Step 4, followed by N-(diphenylhydrazinyl)glycolate, HC1 and NaBH4 at 143636 .doc -136- 201026672 Compound 44A to provide 44C. A mixture of the amino alcohol 44C (671 mg, 2.6 mmol) in dry EtOAc (EtOAc) (EtOAc) The reaction was stirred at room temperature for 18 hours and then quenched with aqueous ammonia and extracted with DCM. The organic extract was concentrated to give 44D (730 mg) as a white crystalline solid.

44D was converted to (±)-44 in a manner similar to that previously described in Example 6. In a manner similar to that described above, from an appropriately substituted nitro-2-tetraxanthene, schlossyl-1-tetrachloropyrene, odorous-2 -tetrazole, -1--1-tetrazide The following compounds were synthesized starting from caffeone, nitro-2-chromanone, nitro-1 -chromanone, bromo-2-chromanone or bromo-1 -chromanone: Compound numbering compound (±)- 100 Η 1 (±)-101 /〇人/ (±)-102 ΛΝΗ Η Ν 1 Ν^Λ 0C^° 143636.doc -137- 201026672 (±)-103 0C^° (±)-104 \ and nh2 〇to° (土)-105 Humanity NH. Yarn (士)-106 / 丫 xxf. (士)-107 H, "NH2 (士)-108 /〇IKXX) nh2 fj〇 (±)-109 'yx1 nh2 (±)-110 NH〇, 财. Η 143636.doc -138- 201026672

(士)-111 ςο /〇γΝ 0丨ΝΗο (±)-112 νη2 Hpcf° J 丫, 0 1 (±)-1131 NH〇/0 丫ΝΗ 〇(±)-114 Η, “叫/ 丫ιχκ ( ±)-115 νη2 (±)-116 νη2 Η Η η^\ Ύχχκ (±)-117 ΝΗ〇NCXXK (±)-118 NC^〇νη2 143636.doc -139- 201026672

The assay z is determined by the following general procedure detailed by Umland et al. ("Receptor reserve analysis of the human a2c-adrenoceptor using [35S] GTPyS and cAMP functional assays j European Journal of Pharmacology 2001, 411, 2 11-221). Efficacy agonist activity values for a2A and a2C (Emax, GTPYS assay). For the purposes of the present invention, if the compound is 30% Emax (GTPyS assay) for the efficacy of the a2C receptor, then the compound is defined as a2C a subtype of activity agonist. For the purposes of the present invention, if the compound has an efficacy of 230% Emax on the a2C receptor (GTPYS assay) and its effect on the α2Α receptor is $35% Emax (GTPYS assay), then the compound Is defined as a specific or at least a functionally selective agonist of the a2C receptor subtype. In addition, for the purposes of the present invention 'if the effect of the compound on the a2C receptor&lt;30% EmMGTPyS assay&gt; and on the a2C receptor subunit Type Ki&lt;5〇〇nM, preferably &lt;200 nM, and optimal &lt;20 nM 'the compound is defined as an antagonist of the a2C receptor subtype. Based on the definition previously defined, the following compounds were evaluated as a2C receptor subtype Sexual or functional selective agonist: (earth)·8, (士)·10, (土)-10®, 143636.doc • 140- 201026672 (±)-ll, (±)-11Β and (±) _12c. Based on the previously defined definition (Ki&lt;200 nM), the following compounds were evaluated as antagonists of the a2C receptor subtype: (±)-5 and (±)-9. Although specific implementations have been described above The present invention has been described, but it will be apparent to those skilled in the art that

143636.doc -141 -

Claims (1)

201026672 VII. Patent application scope: 1. A compound represented by formula I Or a pharmaceutically acceptable salt thereof: wherein J1, J2, J3 and J4 are independently -N-, -N(O)- or -C(R2)-; X is -C(R6)(R6') -, _n(R6')-, -Ο- or -S_; W is -N(R15)·, -〇_ or -S-; Z is independently selected from the group consisting of: η, -OH, halogen Base, -CN, -N02, _S(0)pR7 ' _NR7R7', -[C(Ra)(Rb)]qYR7', _[C(Ra) (Rb)]qN(R7)YRr . -[C( Ra)(Rb)]q=OYR7, A-(CH2)qON=CR7R7' &gt; and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl An aryloxy group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group and a heterocyclic group, the groups being optionally substituted with at least one R5; Where ------ is a single bond or a double bond, or -S-, is between -N(R15), and the constraint is when W is -〇- 143636.doc 201026672 R1 is selected from the following Group: _[C(Ra)(Rb)]qYR7·, _[C(Ra)(Rb)]qN(R7)YR7·, -[C(Ra)(Rb)]qNR7R7,,-[C(Ra ) (Rb)]q〇YR7,, _[C(Ra)(Rb)]qN(YR7)(YR7') , -[C(Ra)(Rb)]qON= CR7R7' and -[C(Ra) (Rb)]qCN ; Y is selected from the group consisting of _C(=〇)---C(=0)NR7---〇(=0)0-, -C(=〇HC(Ra)( Rb)]n-〇-C(=〇)-, -C(=0)N(Rc)-0-, -C(=NR7)-, -C(=NOR7)_, -C(=NR7) NR7-, -C(=NR7) NR70-, -C(=N-CN)-, -S(0)p-, -S02NR7- and -C(=S)NR7-; wherein R and R are independently A group consisting of H, a pyridyl group, an alkoxy group and a halogen group, and a RegH or an alkyl group; R2 is absent or independently selected from the group consisting of Η, 〇H, i group, CN, - No2, -S(0)pR7, _nr7r7, ' and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryloxy, arylalkyl, heteroarylalkyl and a heterocyclylalkyl group, wherein such groups are optionally substituted with at least one R 5 ; R 3 is independently selected from the group consisting of Groups: H, dentate, _CN and (= 〇), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, aryl Alkyl, heteroaryl, heteroarylalkyl, benzyl and heterocyclyl alkane & 'These groups are optionally substituted with at least one R5, with the proviso that when 〜3, no more than 2 The group may be (=0); the R4 system is independently selected from the group consisting of Η, D, yl, -CN, -S(0)PR7, Ν^, 〇)ρΝκ7κ7·, -OH, halogen And alkyl, 143636.doc •1· 201026672 alkyl, alkoxy, alkenyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl a heteroaryl group, a heteroarylalkyl group, a heterocyclic group and a heterocyclic group, the groups being optionally substituted with at least one R5; the R4 group is independently selected from the group consisting of ruthenium, D, halo , -ΟΗ ' and alkyl, deuterated alkyl and alkoxy; or R4 and R4' may form together (=〇), with the constraint that when m &gt; i, there is no more than 1 (=0) group R5 is independently selected from the group consisting of hydrazine, halo , -OH, -CN, -N02, -NR7R7' and -S(0)PR7, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl , aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, each optionally via at least one dentate group, _〇H, -CN, -N〇2 , -NR7R7' and -S(0)pR7 substituents and/or 1 or 2 (=〇) substitutions, R6 is selected from the group consisting of H, -OH, halo, -CN, -N02, - S(0)pR7, -NR7R7', -S(0)pNR7R7', -C(0)-R1Q, -C(〇)-〇R10 and -C(0)-N(R7)RiQ, and an alkyl group , alkoxy, alkenyl, alkenyloxy, fast radical, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and a heterocyclylalkyl group, optionally with at least one halo, -OH, -CN, -N02, _NR7R7' and -S (C〇pR7 substituent and/or 1 or 2 (=〇) groups, and _C(=〇)r7, _c(=〇)〇R7, -c(=o)nr7r7, -S02R7 and -S〇2NR7R7' are substituted; R6 is selected from the group consisting of Η, _S(0)pR7 , _S(0)PNR7R7,, -C(0)-R1(), _C(〇)-〇R丨❶, and alkyl, alkane 143 636.doc 201026672 oxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle And heterocyclylalkyl' are optionally substituted with at least one halo, 〇H, -CN, -N02, -NR7R7 and -S(0)PR7 and/or! Or 2 (=〇) group substituents, and -c(=o)r7, -C(=0)〇R7, _c(=0)NR7R7', -so2r7 and -so2nr7r7' substituted; or R6 and R6 ' can be formed together (=〇); R7 is independently selected from the group consisting of hydrazine and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl , aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heterocycloalkenyl, heterocycloalkenylalkyl, heteroaryl and heteroarylalkyl, each optionally substituted by R! Or multiple times; R is independently selected from the group consisting of hydrazine and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryl Alkyl, heterocyclyl, heterocyclylalkyl, heterocycloalkenyl, heterocycloalkenylalkyl, heteroaryl and heteroarylalkyl, each optionally substituted by RU - or multiple times; or a) When a variable is -NR7R7, _[c(RaKRb)]qYR7., _c[(Ra) (Rb)]qNR7R7, -[C(Ra)(Rb)]qOYR7., _(CH2)qNR7R7,, - When C(〇)NR7R7' or -S〇2NR7R7', r7 and R7 independently form a 3- to 8-membered heterocyclic group or a heterocycloalkenyl group together with the nitrogen atom to which they are attached. An aryl ring having, in addition to the N atom, or two heteroatoms independently selected from the group consisting of ruthenium, N, -N(R9)-, and S, wherein the cyclical conditions are from 1 to 5 R5 parts and/or ones (=〇) 143636.doc -4· 201026672 are replaced independently, or ▲ a variable is _(CH2)q〇N=CR7R7. or _[c(Ra) (Rb)] When q〇N=CRV., a 3 to 8 membered cycloalkyl, cycloaliphatic, aryl, heterocyclic, heterocyclic or heteroaryl ring is independently formed together with the carbon atom to which it is attached. The heterocyclyl ring, heterocyclic ring or heteroaryl ring has U independently selected from 〇, N, _N 岭 and s The heteroatoms of the group consisting of wherein the loops are substituted by 1 to 5 independently selected r5 moieties and/or 1 or 2 (=〇), and the R9 moieties are independently selected from the group consisting of: H, _c ( 〇)_Ri〇, -C(〇W and _s(0)p_Rl〇, and affiliary, alkenyl, fast-radical, ring-based, aryl, arylalkyl, heteroaryl and heteroaryl , depending on the situation, J _ base, ·0Η, -CN, -N02, -N(Ru)2 and -S(〇)pR&quot; substituents and/or 4 2 (=〇) substitutions; R10 is independent Is selected from the group consisting of H, anthracenyl, dilute, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each optionally having at least one _〇H, _CN, _n〇2, _n (r1, and -scc^pR11 substituents and/or hydrazine or (d)) (7) substituted; R11 is a moiety independently selected from the group consisting of alkyl, alkoxy , a dilute group, a base group, an alkynyl group, a (tetra)yl group, an oxy group, an aryl group, an aryloxy group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group and a heterocyclic alkyl group, each Substituting at least one substituent independently selected from the group consisting of: lS group, -OH, -CN, -N02, -N(Ru,)2 and S(0)pR substituents and/or 1 or 2 (=〇); R is independently selected from the group consisting of: Anthracene, alkyl 'alkoxyl I43636.doc 201026672 base, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroaryl An alkyl group, a heterocyclic group and a heterocyclic alkyl group; R12 is independently selected from the group consisting of hydrazine, halo, 〇h, -CN, -N02, -N(Ru)2, _C(0 )_0Ri4, _n(r14) c(〇) r14 ' -N(R14)-C(0)2.R14 . -c(〇)-N(Rn)2 ^ -N(R14)-S(0)2 .R11 , -S(0)2-N(Rn)2&amp;-S(0)pR&quot; and/or 1 or 2 (=〇)yl 15, and alkyl, alkoxy, alkenyl, olefinic oxygen , alkynyl, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heterocyclyl, hetero Cycloalkenyl, heterocycloalkenyloxy, heterocyclylalkyl, heterocycloalkenylalkyl, arylalkoxy, heteroaralkyloxy, heterocyclylalkoxy and heterocycloalkenyl alkoxy And optionally replacing at least one with a substituent selected from the group consisting of :H, alkyl, _alkyl, functional, -OH, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted cycloalkoxy, optionally substituted An aryloxy group, optionally substituted heterocyclenyloxy group, —CN, —NOS, —N(RU) 2 and —S(0)pRn and/or 1 or 2 (=〇) groups, wherein Substituting one or more of alkoxy, aryloxy, optionally substituted cycloalkoxy, optionally substituted heteroaryloxy and heterocyclenyloxy, as the case may be substituted R14 is independently hydrazine, alkyl or aryl; R15 is absent or independently selected from the group consisting of hydrazine, -C(0)-R10, -¢:(0)-0111°, -C (0)-N(R7)(R7')' and _s(〇)p_R]. , s〇2_nr7r7' ' and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, naphthenic 143636.doc -6 - 201026672 oxy, aryl, aryloxy, arylalkane a base, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group, and a heterocyclic alkyl group, each optionally having at least one halo group, -OH, -CN, -N〇2, -NR7R7', and -S(0) ) pR7 and/or 1 or 2 (=〇) group substituents, and -C(=0) R7, -C(=0)0R7, -C(=〇)NR7R7·, -S02R7 and _s〇 2NR7R7'substituted; . "" is an integer of 0-2; m is independently an integer of 1_3; P is independently an integer of 0-2; and Ww is an integer of 〇_3; the constraint is when Ri is - When [C(Ra)(Rb)]qYRr and Y is -S(0)p-, p cannot be 0 ° 2. The compound of claim 1, wherein Z is Η, -OH, halogen, -CN, - N〇2 or NR7R7·; R1 is selected from the group consisting of _[C(Ra)(Rb)]qYR7, _[c(Ra) φ (Rb)]qN(R7)YR7', _[C (Ra)(Rb)]qNR7R7', _[C(Ra)(Rb)]q〇YR7' and -[C(Ra)(Rb)]qCN; • Y is selected from the group consisting of: -C(=0)-, -C(=〇)N_R7- • , _C(=0)0_, -C(=0HC(Ra)(Rb)]n-0-C(=0)- , -C(=〇)N(Rc)-0-, -c(=nr7)_, -c(=nor7)_, _c(=nr7)nr7-, -c(=nr7)nr7o-, -C (=N-CN)-, -S(〇)p-, _S〇2NR7j_C(=s)NR7_ ; wherein Ra and Rb are independently selected from the group consisting of alkyl, alkoxy and halo, and 1 ^ is "[or alkyl; 143636.doc 201026672 R is independently selected from the group consisting of Η, 〇h, halo, -CN, -n〇2, -S(0)pR7, _NR7R7', And alkane and alkoxy groups, which are optionally substituted by at least one R5; R3 is independently selected from the group consisting of hydrazine, halo and (=〇), and alkyl, alkoxy, alkene , alkenyloxy, alkynyl, cycloalkyl 'cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, The groups are optionally substituted with at least one R, with the proviso that when 〜3, no more than 2 groups may be (=〇); R4 is independently selected from the group consisting of H, halo, _〇H, halo and -CN, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl a heteroaryl group, a heteroarylalkyl group, a heterocyclic group and a heterocyclylalkyl group, wherein the groups are optionally substituted with at least one R5; R4 is independently selected from the group consisting of: a halo group and an alkyl group; R5 is independently selected from the group consisting of H, halo, 〇H, CN, -N02, -NR7R7' and -S(0)PR7, and a group, alkoxy, alkenyl, alkenyloxy , alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heteroalkylalkyl, each optionally at least a leucoyl, hydrazine, _CN, -N02, -NR7R7, and -S(0)pR7 substituent and/or 1 or 2 (=〇) substitutions; R6 is selected from the group consisting of H and halo And alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy 1, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,环环基和杂 143636.doc 201026672 环基院基, • depending on the situation at least - halo, _〇h, loss, _n〇2 ... NR7R7 ^ 'S (0) PR7 substituents and / or 1 or 2 (=0), and C(〇)R, _c(=0)0r7, -C(=〇)NR7R7., -so2r7, and -so 2nr7r7_substituted; R7 is independently selected from the group consisting of: alkenyl, alkenyl, ., fast-acting, cycloalkyl, cycloalkyl, cycloalkenyl, cycloalkyl, aryl aryl a base, a heterocyclic group, a heterocyclylalkyl group, a heterocycloalkenyl group, a heterocyclic arylalkylidene group, and a heteroarylalkyl group, each optionally substituted by R12 or a plurality of times; R is independently selected from a group consisting of anthracene and alkyl, alkenyl, fast-radical, cycloalkyl, (iv) base, cycloalkenyl, cycloalkenyl, arylaryl, heterocyclyl, heterocyclyl a heterocyclic, a heterocyclic, a heteroaryl, and a heterofluorenyl, each optionally substituted by r12 - or a plurality of times; R11 is independently selected from the group consisting of H and alkyl, alkane Oxygen, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and hetero a cycloalkyl group, each optionally substituted with at least one substituent selected independently from the group consisting of: a group, _〇H, _CN, _n〇2, _N€R11,l and -S(0) pR substituents and / or 1 or 2 R is independently selected from the group consisting of: η, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, Arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; 143636.doc • 9· 201026672 R12 is independently selected from the group consisting of H, halo, -〇 H, -CN, -N02, -N(R&quot;)2&amp;_s(〇)pR&quot; and / or u^(=〇), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, Cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heterocyclyl, heterocycloalkenyl, hetero Cycloalkenyloxy, heterocyclylalkyl, heterocycloalkenylalkyl, arylalkoxy, heteroaralkyloxy, heterocyclylalkoxy and heterocycloalkenyl alkoxy, each optionally Substituted at least once with a substituent of the group consisting of H, alkyl, haloalkyl, halo, -OH, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted Cycloalkoxy, optionally substituted heteroaryloxy a heterocyclic alkenyloxy group, -CN, _N02, _N(R&quot;)2 and _S(〇)pRn and/or j or 2 (=0), as the case may be substituted Alkoxy, aryloxy, optionally substituted cycloalkoxy, optionally substituted heteroaryloxy and heterocyclenyloxy, substituted by R1! one or more times; R14 Is independently selected from the group consisting of H, alkyl, halo, -CN, and alkoxy; and R15 is absent or selected from the group consisting of hydrazine and alkyl, cycloalkyl, aryl, Arylalkyl, heteroaryl and heteroarylalkyl, each optionally via at least one dentate, _OH, _CN, _N〇2, _n (r1, and _s(〇)p Rl1 and/or 1 or 2 Substituting (=〇); or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 2, which has the formula 143636.doc •10· 201026672 (R3)w or a pharmaceutically acceptable salt thereof. 4. The compound of claim 3, wherein R1 is -[C(Ra)(Rb)]qYR7', _[c(Ra)(Rb)]qN(R7)YR7', _[C(Ra) (Rb )]q〇YR7· and _[C(Ra)(Rb)]qCN, where tq is . Or i; γ is -C(=〇)-, -C(=〇)NR7-, -C(=0)〇-, -C(=NOR7)-, -S(0)p- and -S02NR7- ; r7 and R7' are independently H, R12-alkyl or R12-aryl; R15 is absent or is H or alkyl, or a pharmaceutically acceptable salt thereof. 5. The compound of claim 2 which has the formula: R1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. 6. The compound of claim 5, wherein R1 is -[C(Ra)(Rb)]qYR7', _[c(Ra)(Rb)]qN(R7)YR7', _[C(Ra) (Rb )]q〇YR7' and -[C(Ra)(Rb)]qCN, where q is 〇 or 1; γ 143636.doc 201026672 is __c(=0)_, &lt;(=0)^7...c (=〇)〇, _c(= and -so2nr'; R7 and R7' are independently hydrazine, R12-alkyl or R12-aryl; R is absent or is fluorene or sulphonyl, or it is pharmaceutically acceptable a salt, solvate, ester or prodrug. 7. A compound according to claim 1 which is selected from the group consisting of Or each of these compounds is pharmaceutically acceptable. A pharmaceutical composition comprising at least one such as a requestant' or a pharmaceutically acceptable salt thereof and at least one, a carrier, an adjuvant or a vehicle, and the limitation is when the group: the ligand, the aqueous In the case of the composition, one or more of the components of the liquid cyclodextrin excluding "X" are excluded, 9. The pharmaceutical composition of claim 8, i is further a therapeutic agent. The invention comprises: or a plurality of other or a plurality of pharmaceutical compositions thereof as claimed in claim 9, further comprising a therapeutic agent thereof, wherein the other therapeutic agents are selected from the group consisting of : steroids, glucocorticosteroids, PDE_4 inhibitors, anti-drugs, muscle relaxants, sodium cromoglycate, Ηι receptor antagonists, 5_ΗΤι agonists, NSAIDs, angiotensin-invertase inhibitors, Vascular 'Shrinkin 11 receptor agonist, P-blocker, long-acting and short-acting β-agonist, agent, white diene antagonist, diuretic, aldosterone antagonist, ionotropic agents , natriuretic peptides, pain control/analgesics, anti-φ anxiety agents, anti-migraine agents, sedatives, NMDA receptor antagonists, α_adrenergic agents (excluding cardiac 1 receptor antagonists), anticonvulsants (antiC0nvulsants) , tachykinin (ΝΚ) antagonist, c〇X 2 inhibitor, neuroinhibitor (neur〇leptics), vanillin (vaniU〇id) receptor agonist or antagonist, β-adrenergic agent, topical Anesthetics, corticosteroids, A serotonin receptor agonist or antagonist, a PDEV inhibitor, an alpha 2 - delta ligand, canabinoids, and a therapeutic agent suitable for the treatment of heart disease, psychiatric disorders or glaucoma. U. A method of treating one or more conditions associated with a2C adrenergic receptors&apos; which comprises administering to a mammal in need of such treatment a compound as claimed or a pharmaceutically acceptable salt thereof. 12. The method of claim 11, wherein the condition is selected from the group consisting of: allergic rhinitis, congestion, pain, diarrhea, glaucoma, congestive heart failure, chronic heart failure, cardiac ischemia , manic disorders, depression, anxiety, migraine, stress-induced urinary incontinence, neuronal damage caused by ischemia, schizophrenia, hyperactivity disorder and diabetes. 13. The method of claim 12, wherein the condition is hyperemia. n: 13 method 'where the congestion is associated with perennial allergic nasal. Ml ant steep rhinitis, vasomotor rhinitis rhinitis, Baoyan, acute nasal inflammation or chronic nasal inflammation. 15. Request item 13 Method, related to colds. 16. The method of claim 11, wherein the method of claim 16 is related to arthritis or diabetes, wherein the congestion is caused by a polyp or is common to the condition in which the condition is pain. Wherein the pain and neuropathy, inflammation, 18. The method of claim 11, wherein the condition is Alzheimer's disease, depression, anxiety or Parkinson's disease. 143636.doc -14- 201026672 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature: 143636.doc