TW201206935A - Triazolo-and pyrazoloquinazoline derivatives as PDE10A enzyme inhibitor - Google Patents

Abstract

The invention relates to compounds of the formula and their use as pharmaceutical ingredients, in particular for the treatment of CNS related diseases.

Description

201206935 VI. Description of the Invention: [Technical Field of the Invention] The present invention provides a compound which is a PDE10A enzyme inhibitor, and is therefore suitable for the treatment of neurodegenerative disorders and psychiatric disorders. The invention also provides pharmaceutical compositions comprising a compound of the invention and methods of using the compounds of the invention to treat disorders. [Prior Art] Throughout this application, reference is made to various publications. The disclosure of these publications is hereby incorporated by reference in its entirety in its entirety in its entirety in the extent of the disclosure of the disclosure of the present disclosure. The cyclic nucleotide cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) act as intracellular second messengers that regulate a large number of processes in neurons. Intracellular CAMP and cGMP are produced by adenylate and guanylate cyclase and are degraded by cyclic nucleoside phosphodiesterase (PDE). The intracellular content of cAMp& cGMp is controlled by intracellular signaling, and the stimulation/inhibition of adenylate and guanylate cyclase in response to gpcr activation is a fully characterized means of controlling the concentration of cyclic nucleotides (Antoni, FA· 2000, W,

103-132). The cAMP and cGMP content in turn controls the activity of cAMP and cGMP-dependent kinases and other proteins containing cyclic nucleotide response elements, which regulate key neuronal functions, such as synaptic transmission, via subsequent phosphorylation of proteins and other processes. Neuronal differentiation and survival. Phosphodiesterase 10A (PDE10A) is a bispecific nucleotidyl diesterase that converts cAMP to AMP and cGMP to GMP (Loughney, K. et al. Gene 1999, 234, 109-117; Fujishige, K. Etc. left wr. 201206935 1999, 2 (56, 1118-1127 and Soderling, S. et al., : £: Natl. Acad. Sci. 1999, 96t Ί (ΠΪ-Ί0Ί6). PDE10A from the striatum Neurons, caudate nucleus, accumbens nucleus medium spiny neuron (MSN) and corresponding olfactory nodules (〇lfact〇ry tubercle) neurons in the south (Kotera, J Etc. 5/oc/zew· Less ί·

Comm. 1999, 2 (57, 55 1-557 and Seeger, T. F. et al. ίπ·« and uearc/z, 2003, P55, 113-126). These neurons form the core of the bottom node system. MSN plays a key role in the cortical-bottom-thalamic cortex, integrating convergent cortical/thalamic inputs' and sends this integration information back to the cortex. MSN exhibits two types of functional neurons: D®, which exhibits dopamine receptors, and D2, which exhibits 〇2 dopamine receptors. D-like neurons are part of the “direct” striatum output pathway, which is widely used to promote Behavioral response. D2 neurons are part of the "indirect" striatum output pathway that is used to suppress behavioral responses that compete with behavioral responses promoted by "direct" pathways. These competitive paths work like car brakes and accelerators. From the simplest point of view, the movement of Parkinson's disease is not caused by the excessive activity of the "indirect" path, whereas excessive exercise such as Huntington's disease indicates excessive activity of the direct path. PDE10A regulation of cAMP and/or cGMP signaling in the dendritic compartment of such neuronal trees may be associated with filtering the cortical/thalamic input to MSN. In addition, pDE1〇A is involved in the regulation of GABA release in the substantia nigra and globus pallidus (Seeger, Ding et al. i?eiyearc;/, 2003, 113-126). Dopamine D2 receptor antagonism is fully confirmed in the treatment of schizophrenia 201206935 疋. Since the 1950s, dopamine A receptor antagonism has been the backbone of psychiatric/desktop therapy and all effective antipsychotic drugs antagonize receptors. The effects may be mediated primarily by neurons in the striatum, n. accumbens, and olfactory nodules, as these regions receive the densest dopamine sputum projections and have the strongest D2 receptor expression (Konradi, C _ and Heckers, S.

Society of Biological Psychiatry, 2QQ1, 50, Ί29-Ί42). The dopamine D2 styptic effect leads to a decrease in cAMp content in the cells 'in cells, which is expressed by inhibition of adenylate cyclase, and this is a component of 〇2 signaling (Stoof, JC; Kebabian JW jVaiwre 1981, 366- 368 and Neve, Κ·Α· et al. J〇urnal of Recept〇rs and Signal 7>(10)... 2004, pp. 165-205). Conversely, the D2 receptor antagonism effectively increases the CAMP content, and this effect can be mimicked by inhibiting the degradation of cAMp nucleotide diesterase. Most of the 2L phosphodiesterase genes are widely expressed; therefore, inhibition may have side effects. Because in this case pDE1〇A has the required performance characteristics of high and relatively specific expression in neurons in the striatum, nucleus accumbens and olfactory tubercle, PDE1〇A inhibition may have similar to A receptor buck resistance. The role of action and therefore antipsychotic effect. Although PDE10A is expected to inhibit partial I receptor antagonism, it is expected to have different characteristics. The h receptor has a signal transduction other than cAMp, and the piece (Neve, KA専人〇yj illusion is as follows) 2004, 2( 165_2〇5), so inhibition of interfering cAMP via pDEi〇A may be adversely regulated via Receptor dopamine signaling rather than direct antagonism of dopamine signaling. This reduces the risk of extrapyramidal side effects seen with strong % antagonism 201206935. Conversely, PDE1〇A inhibition may have no effect under D2 receptor antagonism Some of the effects. pDEi〇A is also expressed in D, receptors in striatal neurons (Seeger, TF et al. (1)·hwwd, 2003, PM, U3-126). Because D丨 receptors activate The action leads to stimulation of adenylate cyclase and causes an increase in cAMp content, so PDE10A inhibition may also have a mimicking effect on Di receptor agonism. Finally, PDE10A inhibition will not only increase cAMp in cells, but also It is expected to increase cGMP content because PDE1〇A is a bispecific phosphodiesterase. cGMP activates many of the target proteins of cell t (such as cAMp) and also interacts with cAMP signaling pathways. In summary, pDE丨〇a inhibits possible moieties Simulating Da receptor antagonism and thus antipsychotic effects, but the characteristics may be different from those observed with typical receptor antagonists. PDE10A inhibitor papaverine has been shown to be active in several antipsychotic models. Papaverine enhances Da receptor The antagonist haloperidol (hal〇perid〇1) acts as a tonic in rats, but does not cause tonicity itself (w〇03/093499). Papaverine reduces the height induced by pcp in rats Activity, and amphetamine-induced decrease in activity is not significant (WO 03/093499). These models suggest that PDE1〇A inhibition has a typical antipsychotic potential' from a theoretical point of view that it would be desirable ^ W〇03/093499 further discloses the use of selective pDE1 〇 inhibitors for the treatment of related neurological and psychiatric disorders. In addition, PDEioa inhibits subchronic pcp induction of reversible attentional set-shifting in rats Sexual defects (Rodefer et al. Eur'丄NeUrosci· 2〇〇5, 4, 1070-1076). This model suggests that PDE1〇A inhibition may attenuate cognitive deficits associated with schizophrenia 201206935 The tissue distribution of PDE10A indicates that the PDE1〇a inhibitor can be used to increase the level of cAMp&/ or cGMP in cells expressing PDE10 enzymes, especially in neurons of the bottom node and thus the pDE1〇A inhibitor of the present invention will be suitable. It treats a variety of related neuropsychiatric conditions involving the bottom section, such as neurological and psychiatric disorders, schizophrenia, polarization abnormalities, obsessive-compulsive disorder and the like, and may have the benefit of having no undue side effects associated with current therapies on the market. In addition, the latest publication (W0 2005/1205 14, WO 2005012485,

Cantin et al., Bioorganic & Medicinal Chemistry Letters 17 (2007), 2869-2873) suggest that PDE10A inhibitors are useful in the treatment of obesity and non-insulin dependent diabetes. Regarding the inhibitor of PDE10A, EP 125 〇 923 reveals that the general selective PDE 10 : inhibitor and especially papaverine for the treatment of specific neurological and psychiatric disorders e. WO 09/152825 discloses as a PDE10A enzyme inhibitor, suitable for the treatment of various diseases (Phenyl p-mythracene derivatives including CNS-related diseases such as schizophrenia). Pyridodiazepine and its variants as inhibitors of PDE10 are disclosed in WO 05/03129 and W〇05/02579. They are used as a PDE10 inhibitor. The substituted quinazoline and Isoquinoline is disclosed in W〇〇5/82883. WO 06/11 040 discloses substituted quinazoline and isoquinoline compounds useful as inhibitors of PDE1. us 2〇〇5〇182〇79 disclosed a substituted quinazoline and an isoquinoline substituted tetrahydroisoquinolinyl derivative as an effective phosphodiacetate (PDE) inhibitor. In particular, us 2〇〇5〇182〇79 is related to such compounds, 201206935 It is a selective inhibitor of PDE 10. Similarly, us 20060019975 discloses a quinazoline and isoquinoline, which is not used as an effective phosphodiesterase (PDE) inhibitor, as a derivative. US 2 0060019975 also relates to PDE10. Compounds of selective inhibitors. WO 06/028957 discloses alpha octane derivatives as inhibitors of phosphodiesterase type 10 for the treatment of psychotic and neurological syndromes. However, these disclosures are not related to the present invention. a compound that is structurally unrelated to any known PDE10 inhibitor (Kehier, j People _"Cafes Γ/zer. Pwe heart 2〇〇7, 77, 147158) 〇 The following three compounds are known in the art: 1) N,N_dimethyl-2-[[2- Methyl[1,2,4]triazolo[l,5-c]oxazoline-5-yl)thio]methyl-1-propyl-1H-benzimidazole·5-sulfonamide (CAS Accession No.®1 147433-89-3 ), 2) 1-Butyl-2-[[2_indolyl[^,4]triazolo[15_c]quinazolin-5-yl)thio]methyl]- 1H-benzo flavor. Sit _5_sulfonamide (CAS accession number ® 1147384-60-8), 3) 5-[[[1-(difluoromethyl)_111_benzimidazole_2-yl]indolyl]thio] 2_Methyl-[1,2,4]triazolo[uc]quinazoline (CAS Accession No. 938929-10-3), but not used as a PDE10 inhibitor or as a pharmaceutical compound. This specific compound is not part of the invention. The compounds of the present invention have proven to be potent pDE1A enzyme inhibitors and thus may provide an alternative to current marketing therapies for neurodegenerative and/or psychiatric disorders that are not effective in all patients. Therefore, alternative methods of treatment are still needed. 201206935 [Inventive content] Agent 2 = t aims to provide as an alternative (4) PDE1GA enzyme to inhibit metabolic stability and compounding: the other is to provide this activity and have good (better improved) solubility compared to prior art σ, Or bioavailable compounds. EFFICIENCY Another object of the present invention is to provide a therapeutic, especially long-term treatment for a human patient without causing side effects typically associated with current therapies for nerves and:: disorders. Other objects of the present invention will become apparent after reading this specification. [Lrt λ 々 系 关于 因此 因此 因此 ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ ’

L--het R3 丫, N-R4 Formula ι - a compound of the invention wherein R1 - R4 are selected from the group consisting of: H; Ci (: 6 alkyl, such as methyl, #素, such as gas and gas; a base, such as a trifluoromethyl group; an aryl group such as a phenyl group; an alkoxy group such as a methoxy group, a dimethoxy group, an ethoxy group, a methoxy-ethoxy group, and an ethoxymethoxy group. And Ci_C6 hydroxyalkyl groups such as CH2CH2OH; and 6 9 201206935

Where het is selected from the group consisting of:

Wherein R5 and R6 are selected from the group consisting of: H; c丨·Q alkyl, such as methyl, ethyl, 1-propyl, 2-propylisobutyl-n-butyl second butyl or second butyl Base, C|-C6 alkyl (C3_C8) cycloalkyl, such as cyclopropyl bauxite, CrC6 hydroxyalkyl 'such as via ethyl; cation (3); cH2C(〇)NH2; Arylalkyl' such as benzyl and anal benzoquinone: and alkyl-heterocycloalkyl, such as tetrahydropyran-4-methyl and 2morpholine-4-yl-ethyl; R7-R11 is selected from the group consisting of: h such as methoxy; and a phytokine such as gas or fluorine; and c 1 -C6 alkoxy' wherein the other L is a linking group selected from the group consisting of _s_CH2- And in the CH2-S- and -Ch2_Ch2- groups, wherein Y is selected from the group consisting of CH, N in the specific example of the present invention het is selected from the group consisting of or C-CN. [A specific example of you, & column (specific examples of groups:

201206935 R6

-R10, R9: wherein R5 is selected from the group consisting of: H; Ci_. Alkyl such as methyl, ethyl, 1-propyl, 2-propyl, isobutyl, n-butyl, t-butyl or first butyl 'CVC: 6 alkyl (CrCs) cycloalkyl, such as Cyclopropylmethyl; hydroxyalkyl, such as hydroxyethyl; CH2CN; CH2C(0)NH2; arylalkyl, such as benzyl and 4-chlorophenylhydrazine; and Ci„C6 alkyl-based a group such as tetrahydropyran-4-yl-methyl and 2-morpholine-4-yl-ethyl; and R7Rn is selected from the group consisting of: H; Ci_C6 alkoxy, such as methoxy; and halogen , such as gas or fluorine. In a specific example (specific example III) of any of the prior embodiments of the present invention, the 'linking group L' is -CH2-CH2-. In any of the specific examples I to 本 of the present invention In one specific example (specific example IV), the linking group L is -CH2-CH2- and het is

Wherein R5 is selected from the group consisting of: H; Ci-C6 alkyl such as methyl, ethyl, 1-propyl, 2-propyl, isobutyl, n-butyl, t-butyl or tert-butyl Ci-c6 alkyl (c3-c8) cycloalkyl, such as cyclopropylmethyl; Ci_C6 alkyl, such as hydroxyethyl; CH2CN; CH2C(0)NH2; aryl burn 11 201206935 base 'such as benzene Methyl and 4_gas benzyl; and LG alkyl-heterocyclic, such as tetrahydropyran-4-yl-methyl and 2-morpholin-4ethyl. In the specific example of the invention! A specific example of any one of Ιπ (specific example V) towel attachment group (1) is -CH2-CH2- and het is ""

Wherein R6 is selected from the group consisting of: H; C1_C6 alkyl, such as methyl, ethyl, 1-propyl, 2-propyl, isobutyl, n-butyl, t-butyl or t-butyl; CrCs alkyl (C3-cs) cycloalkyl, such as cyclopropylmethyl; ci C6 hydroxyalkyl, such as hydroxyethyl; CH2CN; CH2C(〇)NH2; C|_C6 arylalkyl, such as alum 4-cycloalkyl; and q-C6 alkyl-heterocycloalkyl, such as tetrahydropyran-4-yl-methyl and 2 morpholine-4-yl-ethyl; and R7ru is selected from the following composition a group of: H; alkoxy, such as methoxy; and halogen, such as gas or fluorine. In a specific example of specific example I (specific example VI), the compound of the invention is selected from the group consisting of: 5_( Benzothiazole_2•ylmercaptosulfanyl)-9-bromo-2-methyl-[1,2,4]triazolo[15-4quinazoline;5_(1H benzimidazole-2- Methylsulfanyl)_9-bromo-2-indolyl-[1,2,4]triazolo[i,5-c]quinazoline; 5-(1Η-benzimidazole-2-ylmethyl) Benzylalkyl)_2-methyltriazolo[l,5-c]quinazoline; 2-mercapto-5-(1-indolyl-4-phenyl-1H-imidazol-2-ylmethyl Thioalkyl)-[1,2,4]triazolo[l,5-c]quinazoline ;5-(1Η-benzimidazole·2_ 12 201206935 ylmethylsulfanyl)-9-fluoro-2-indolyl-[1,2,4]triazolo[l,5-c] quinazoline ; 5-(1^1-benzimidazol-2-ylmethylsulfanyl)_8_gas_2-methyl-[1,2,4]triazolo[l,5-c]quinazoline ; 5-(benzoxazol-2-ylmercaptosulfanyl)_2-fluorenyl-[1,2,4]triazolo[l,5-c]quinazoline; 5-(imidazo[12] -a]pyrimidine-2-ylmethylsulfanyl)-2-methyl-[1,2,4]tri. Sit and [i,5-c]噎Salina; 2-methyl-5-(1-indolyl-1H-benzimidazol-2-ylmethylsulfanyl)_[ι,2,4] Oxazo[l,5-c]quinazoline; 2-methyl-5-(quinoline-2-ylmethylsulfanyl)-(^2,4]III. Sit and [l,5-c a quinazoline; 5-(imidazopyridine-2-ylsulfonylthio)-2-indolyl-[1,2,4]triazolo[i,5-c]quinazoline; 5- (Imidazo[i,2_b] ^明^2-ylmercaptosulfanyl)-2-indenyl-[ι,2,4]triazolo[i,5-c]quinazoline; 5-[ 4-(2-Gas-phenyl)-1-indenyl-1H-imidazol-2-ylmercaptosulfanyl]-2-indolyl-[1,2,4]triindole[l,5- c] quinazoline; 5-[4-(3-foxy-phenyl)-1_methyl-1H-imidin-2-ylmethylsulfanyl]-2-mercapto-[1, 2,4]triazolo[l,5-c]quinoxazine;5-[4-(4-decyloxy-phenyl)_1_indolyl-1H-imidazol-2-ylsulfonylsulfane 2-methyl-[1,2,4]triazolo[l,5-c]quinazoline; 5-[4-(2-fluoro-phenyl)-1-indolyl-1H- Imidazol-2-ylindenylthioalkyl]_2_mercapto-triazolo[l,5-c]quinazoline; 5-(imidazo[2,lb]thiazole..6-ylmercaptosulfane 2-methyl-[1,2,4]triazolo[l,5-c]quinazoline; 5-(imidazo[2,lb][l,3,4] σ a sigma-based 6-ylmethylthioalkyl)-2-methyl-[ι,2,4]tris-[i,5-c]°f0 porphyrin; 2-mercapto-5-(3H -thieno[3,4-d]imidazolium-2-ylsulfonylsulfanyl-[1,2,4]triazolo[l,5-c]quinazoline; 5-(imidazopyridinium) 2_Methylthiosulfanyl)-2-methyl-indole 嗤 坐 坐 ;; 2_ 曱 _5-(4_ 本-1H-Mimi. Sodium-2-ylthioalkyl) _ «7 is more than α[1,5_c]啥啥琳; 2_methyl-5-(quinolin-2-ylmethylsulfanyl)-oxazolo[15^]quinazoline; 5_(imidazole 201206935 and [l,2-a]. dimethyl-2-methylsulfanyl)_2_mercapto-indole[i,5-c]e quetiapine; 5-(1Η-benzo Imidazolyl-2-ylsulfonylsulfanyl)_2_fluorenyl-pyrazole quinone. Shenglin; 2-mercapto-5-(1_fluorenyl) 仏benzimidazole_2_ylmercaptosulfane Base)-咐<Saliva[l,5-c]quinazoline; 2-mercapto-5-(1-indolyl-4-phenyl-1H-imidazol-2-ylmercaptosulfanyl) -»Bizozolo[15^]quinazoline;5_[4-(3-methoxy-phenyl)-1-indolyl-1H-imidazol-2-ylmercaptosulfanyl]-2-indole -pyrazolo[l,5-c] 啥 琳 _1 _1-carbonitrile; 5-(imidazo[l,2-a]pyridin-2-ylmethylsulfanyl)-2-mercaptopyrene And [IS-c Quinazoline-1-carbonitrile; 2-methyl-5-(1-methyl-1H-benshim-2-ylmercaptothiol)_0 ratio. Sit and [i, 5_c] 0 Kui. sit.林_1_曱赌; 5_[4-(3-methoxy-phenyl)methyl-m_imidazole_2-ylmercaptosulfanyl]_2_methyl-pyrazolo[l,5-c a quinazoline; 5_[5_(3_decyloxy-phenyl)_1Himidazol-2-ylsulfanyl fluorenyl]_2_fluorenyl _. ratio. Sit and [i,5 c]喧Salina; 5_[5_(3_methoxy-phenyl)-1Η-imidazol-2-ylmethylsulfanyl]_2-methyl-pyrazolo[uc] Quinazoline; 2-mercapto-5-(quinolin-2-ylmethylsulfanyl)-pyrazolo[匕弘...quinazoline-1-carbonitrile; 2-methyl-5-(( 1-methyl_4_phenyl_1H-imidazolium-2-yl)methylthio)pyrazolo[l,5-c]quinazoline-1-carbonitrile; 2·methyl_5_((1( 2-(morpholinoethyl)-1Η·benzo[d]imidazol-2-yl)methylthio)β-pyrazolon,5-c]quinazoline]-carbonitrile; 4-(2-(2- ((2-indolyl.biazole and n,5_c]quinazoline-5-ylthio)methyl)-4-phenyl-1H-mimi.-1-yl)ethyl)morpholine; 2_ Methyl _5((1_(2 morpholinoethyl)-4-phenyl-1H-miso-2-yl)methylthio)D-pyrolo-n,5 c]indolin-1-ene Guess; 2-methyl-5-(1-methyl-4-phenyl-m-imidazole | ylsulfanylmethyl) 吼 并 并 n, 5-C] 啥 琳 琳; 9, nitrogen methyl _5_(1•methyl-4-phenyl-1H-mimi. sitting 2_ylsulfanylmethyl)_D than salino n,5_c]oxazoline; gas winter methyl-5-(1- Methyl-4n1Hn2_ylthioalkylmethyl p-pyrazole 14 201206935 [l,5-c]quinazoline; 7-chloro-2-methyl-5-(1-methyl-4-phenyl- 1H-imidazole -2-ylthioalkylmethyl)-pyrazole[l,5-c]quinazoline; 2,9-dimethyl-5-(1-indolyl-4-phenyl-1H-flavor唆-2-ylthiopyranylmethyl)_σ ratio. Sit and [i,5-c]〇|· α sitin; 2,7-dimethyl-5-(1-f-based-4-phenyl -1Η-imidazol-2-ylsulfanylmethyl)-pyrazolo[l,5-c]quinazoline; 8-methoxy-2-methyl-5-(1-methyl-4- Phenyl-1H-°m. sit-2-ylthioalkylmethyl)-. Compared with hydrazino[i,5-c]t-quino π-sallin; 7-methoxy-2-indolyl-5- (1-methyl-4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-pyrazolo[1,5-(;]quinazoline; 2-methyl-5-[2- (1-indolyl-4-phenyl-111-imidazol-2-yl)-ethyl]-pyrazolo[l,5-c]quinazoline; 9-chloro-2-indolyl-5-[ 2-(l-fluorenyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-pyrazolo[i,5-c]quinazoline; 7_gas_2曱yl-5-[2 -(l-methyl-4-phenyl-1H-imidazol-2-yl)-ethyl]_D-pyrazolo[丨'^...quinazoline; 2,9-dimethylmethyl-4-benzene Base_1H-imidazole_2_yl)-ethylidene]-pyrazoloindole, 5--quinazoline; 7-methoxy-2-indenyl_5_[2_(1_mercapto_ 4_V phenyl-1H-imidazol-2-yl)-ethylindole oxazolo[^^^ quinazoline;8·decyloxy-2-indole -5-[2-(1-methyl-tungylphenyl[l,5-c]quinazoline; 9-methoxy.2_methyl_5_[2_(1_methyl_4_phenyl) _ imidazol-2-yl)-ethyl]-pyrazolo[i,5_c] quinazoline is 0-fluorenyl...-i-yl, ethyl]diazoline, 2,7-didecyl-5 -[2-〇Methyl-4-phenyl-1H_imidazole_2-yl)·ethyl]-D is more than spit [l,5-c]quinoxaline. In a specific embodiment (specific example viii) of the specific example 1, the compound of the present invention is selected from the group consisting of '3 UH-benzazole-2-ylmethylsulfanyl)-2-mercapto-[1] , 2, 4] triterpene [1,5 <] 嗤 嗤;; 5_(" and [l,2-a]pyrimidin-2-ylmercaptosulfanyl)_2•methyl-[^4] three Oxazolo (1) 15 201206935 坐琳; 2_曱基·5_0.methyl·1Η·benzoimin. [2-ylmercaptothiol Hl,2,4] triterpenes, 5_situ; 2_Methyl_5_(嗜琳冬基methylthioalkyl)_[1,2,4]Trisporin n,5_eM(四); 比口定_2. 基曱基魏基)_2·Methyl_Π ,Μ]三Μ Π,5-shaped 嗤琳; 5-(°米唾和[1,2^°比定-2-ylmethylsulfanyl)-2-methyl-4-oxazolo[1,5_C ] 啥 (4) small carbonitrile; 2 _ methyl-5-U-methyl-m-benzopyrim. sit _2 _ methyl thiopyrazine than saliva (1) 5, saliva. Lin-ι-carbonitrile 1 (2.(2_((2_曱-Pyrylpyrazolo[1,5_C]〇t°坐琳-5-ylthio)methyl)-4-phenyl-1H♦ sityl ethyl)morpholine ;2·Indolyl-5-(0-(2-morpholinoethyl)-4·indolyl]η-imidazol-2-yl)phosphonium). Biwa and n,5_c]嗤嗤琳9 _Chloromethyl-5-[2-〇- Methyl-4-phenyl·1H_imi. 圭.2_基)ethyl]_吼. Sit and [ye]啥. sitt; and 2,9-dimethyl·5 cases of methyl phenyl phenyl*坐 _2 基 _2 _2 _2 _2 _2 _2 _2 _2 _2 U U U U 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本IX). In a specific example, to one of the specific examples, the compound of the present invention is used for treating 痳妯M k > ° spent neurodegenerative disorders or psychiatric disorders, especially (,, Example XI) For the treatment of schizophrenia, such as paranoia (- (four) (4) nf Zhang type, undifferentiated or residual type; schizophrenia mental disorders; schizoaffective mental disorders, such as delusions ... a) pear or melancholy; paranoia. The invention further provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a neurodegenerative disorder, a 4 λ disorder or a psychiatric disorder, in particular (specific examples) for the manufacture of a medicament for treatment Drugs for the following diseases 16 201206935 Agent: Schizophrenia, such as paranoid, disordered, stressed, undifferentiated or Residual type; schizophrenia-like mental disorder; schizoaffective disorder, such as delusional or melancholic; delusional. Further, the present invention provides a method of treating a patient suffering from a neurodegenerative disorder, which comprises administering to the patient A compound of any of the specific examples (specific example XIV). In a further aspect, the invention provides a method of treating a patient suffering from a psychiatric condition, comprising administering to the patient a specific example (4) 11 of the The compound of Example XV). In another embodiment (specific example XVI), the invention provides a method of treating a patient suffering from drug addiction (such as alcohol, amphetamine, cocaine, or opiate addiction), including administering to the patient A compound of any of the specific examples I-VIII (specific example χνπ) of the present month. Further, the present invention further provides a compound which is used as a pharmaceutical product, or a pharmaceutically acceptable acid addition salt thereof (specific example xvni). In another sad form, the present invention provides a A pharmaceutical composition comprising, as an example, a compound of the formula _νΐΙΙ, and a pharmaceutically acceptable carrier, diluent or excipient (example χιχ). [Embodiment] Unless otherwise specified, 'the compound of the present invention' refers to - or a plurality of compounds encompassed by the present invention (i.e., the compound of Formula 1). When tested in the PDE10A Enzyme Inhibition Assay, the compound has a 50 value between about 10 η Μ and 430 η ,, which makes it a compound suitable for inhibiting the activity of PDEl〇A enzyme. 17 201206935 Pharmaceutically acceptable salts The present invention also encompasses salts of the compounds of the invention, typically pharmaceutically acceptable salts, which include pharmaceutically acceptable acid addition salts. Including inorganic acids and salts of organic acids. 'Representative examples of suitable inorganic acids include hydrochloric acid, hydrogen desert acid, hydrogen stone acid, phosphoric acid, sulfuric acid, amine sulfonic acid, nitric acid and the like. Representatives of suitable organic acids Examples include citric acid, acetic acid, tri-glycolic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid 'citric acid, fumaric acid, glycolic acid, itaconic acid, lactic acid, decane sulfonic acid, cis Butenedioic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyroic acid, salicylic acid, succinic acid, decane sulfonic acid, ethane sulfonic acid, tartaric acid, ascorbic acid, bishydroxy Naphthoic acid, bis-indenyl salicylic acid, ethane disulfonic acid, gluconic acid, pyrocitrate 'aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, face acid Benzene acid, p-toluene acid, tea acetic acid and 8_i-theophylline (example) 8-Bromo-resin bases and analogs thereof. Other examples of pharmaceutically acceptable inorganic or organic acid addition salts include those listed by Berge, SM et al., 乂 5^. 1977' 66, 2. Pharmaceutically acceptable salts are incorporated herein by reference in their entirety. Further, 'the compounds of the invention may be formed in unsolvated as well as with pharmaceutically acceptable solvents such as water, ethanol and the like. The solvated form exists as usual. For the purposes of the present invention, the solvated form is considered to be equivalent to the unsolvated form. Pharmaceutical Composition The present invention provides a pharmaceutical composition comprising a separate present invention 18 201206935 :: a compound or a combination of a compound of the invention and another active ingredient, and a pharmaceutically acceptable carrier or diluent. The invention also provides a pharmaceutical composition, a compound comprising the compound of the invention and Pharmacologically, it can be used as a diluent or a thinner. In addition, the compound can be administered in a single or multiple doses in a single or multiple doses or in combination with a carrier, diluent or excipient. This hair

ReJgt0:::e hence and Practice 〇f pharmacy, 2nd edition, g_(10)

Mack Publishing ^5lj East〇nj pA> 2005 # / Formulated with a pharmaceutically acceptable carrier or diluent and any other known adjuvants and excipients. The pharmaceutical composition can be specifically formulated for administration by any suitable route such as oral, rectal, nasal, transpulmonary, topical (including frequency and sublingual), transdermal, intracranial, intraperitoneal Transvaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It should be understood that this route will depend on the general condition and age of the patient to be treated, the nature of the condition to be treated, and the active ingredient. The pharmaceutical composition for oral administration includes solid dosage forms such as capsules, troches, dragees, pills, buccal tablets, powders and granules. The composition may be prepared, if appropriate, to have a coating, such as an enteric coating, or it may be formulated according to methods well known in the art to provide controlled release of the active ingredient, such as sustained or extended release. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs. Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous solutions. 2012 20120 35 Injectable solutions, dispersions, suspensions or emulsions, and sterile powders to be reconstituted in a sterile injectable solution or dispersion before use. Other suitable forms of administration include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, and implants. A typical oral dose of a compound of the invention is in the range of from about 0_001 mg to about 100 mg per kilogram of body weight per day. Typical oral doses are also in the range of from about 0.01 mg to about 50 mg per kilogram of body weight. A typical oral dose of the compound of the present invention is additionally in the range of from about mg5 mg to about 1 曰 per kg body weight. Oral agents are usually administered in one or more daily doses, typically one to three doses. The exact dose will depend on the frequency and manner of administration, the sex, age, weight and general condition of the patient being treated, the nature and severity of the condition being treated, and any complications to be treated and those familiar with the art. Depending on other factors. The compositions may also be presented in unit dosage form by methods known to those skilled in the art. For illustrative purposes, typical unit dosage forms for oral administration may contain from about 0.01 mg to about 1000 mg, from about 5 to about 5 mg or from about 5 mg to about 200 mg of a compound of the invention. . The typical dose is about half of the dose for oral administration, in intrapulmonary, intralesional, intramuscular, and similar parenteral routes. The invention also provides a process for the preparation of a pharmaceutical composition comprising a compound of the invention alone or a combination of a compound of the invention and another: at least one pharmaceutically acceptable carrier or diluent. The compounds of the invention are generally utilized in the form of a free acceptable salt. 1 By its pleasure 20 201206935 For parenteral administration, the compound of the present invention can be used in a sterile aqueous bath, an aqueous solution of propylene glycol, an aqueous solution of vitamin E or a solution of sesame oil or peanut oil. If necessary, the aqueous solutions should be suitably buffered and the liquid diluent first rendered isotonic with sufficient physiological saline or glucose. Aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sigma of the present invention can be incorporated into known sterile aqueous media using standard techniques known to those skilled in the art. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions, and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, hard lye and cellulose. Examples of lower m liquid carriers include (but not Limited to) syrup, peanut oil, sassafras oil, canned fat, fatty acids, fatty acid amines, polyoxyethylene and water. The carrier, or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate alone, or mixtures thereof with wax. The pharmaceutical composition formed by combining the compound of the present invention with a pharmaceutically acceptable carrier is then readily administered in a variety of dosage forms suitable for the disclosed route of administration. The composition is preferably present in unit dosage form by methods known in the art of pharmacy. The compositions of the present invention suitable for oral administration can be presented in individual unit form, such as capsules or lozenges, each containing a predetermined amount of active ingredient and Depending on the composition of 'it % ❹ 赋 卜 卜 ' ' ' ' M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M . 21 201206935 Right, raw mouth is said to use a solid carrier, the preparation can be made into a tablet, placed in a hard gelatin capsule in the form of a powder = pellet or it can be a tablet (t (10) he) or a 3 button (ozenge) form. The amount of solid carrier will vary widely, but will be in the range of 彳 ft per dose. , "mg" to a range of about 1 g. If a liquid carrier is used, the preparation may be in the form of a sugar, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or nonaqueous liquid suspension or solution. The pharmaceutical composition of the present invention can be prepared by a conventional method of the present technology. For example, a tablet can be prepared by mixing an active ingredient with a common adjuvant and/or diluting f and then in a conventional ingot. Examples of a towel to compress the mixture to prepare a key to prepare a & agent or diluent include: corn house powder, horse age umbrella knife alpha stone, magnesium stearate, gelatin, lactose, gum and the like. Any other adjuvant or additive used for such purposes, such as a coloring agent, a flavoring agent, a preservative, etc., is considered to be compatible with the active ingredient. Treatment of the Condition As mentioned above, the present invention The compound is a PDE10 chymase inhibitor and is therefore suitable for the treatment of related neurological and psychiatric disorders. Accordingly, the present invention provides a compound of the present invention and a pharmaceutical composition containing the same for use in treating neurodegeneration in a patient A condition, a psychiatric disorder, or a drug addiction, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, and cranial Dementia associated with internal tumor or brain trauma, dementia associated with Huntington's disease or Parkinson's disease or AIDS-related dementia; sputum; amnesia; post-traumatic stress disorder; mental retardation; 22 201206935 learning disabilities, such as reading ' lack of power / hyperactivity disorder; and the annual barrier or written expression of the disorder; the injection is selected from the following:: Zhiyi retreat, and its Yin mental disorder, such as paranoia: J 3 induced psychosis, such as by alcohol He =, 妄4 syndrome; cause, hallucinogens, inhalants, hong dynasty, marijuana, cocaine paranoid personality disorder; and a "psychotic-induced mental illness; early obstruction, and guessing arsenic splitting addiction" Alcohol, An Feixian 4, and it makes the drug cocaine or W «cancer. The compound of the present month may be used for treating the itch of the compound of the present invention, which may be H. The combination of sputum and singularity, disease or condition, wherein the drugs are all female or more effective than the present invention. In addition, the compound of +Zhouyue can be used in combination with the side effects of the compound of the invention or /α:, prevention, control, and improvement. ", or other drugs that reduce their risk, U can be administered simultaneously or sequentially with the compound of the present month by its usual route and amount. Therefore, the pharmaceutical composition of the present invention includes a compound other than the present invention. . ^ ^ and other components. The combination can be used as one of the early active ingredients in one or the other active ingredient, or as a kit or treatment for the idiot, the case, in the set In the group or treatment regimen, one or the other drug is administered in a separate dosage form as part of the treatment regimen. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The method comprises administering to the patient a compound of the invention. The invention also provides a method of treating a patient suffering from a psychiatric condition, 23 201206935 The method comprising administering to the patient a compound of the invention. Examples of therapeutic psychiatric disorders include, but are not limited to, phlegm schizophrenia, such as paranoid, disordered, stressed, undifferentiated or residual; schizophrenia-like mental disorders; Splitting affective mental disorders, such as delusional or melancholic, paranoia; substance-induced mental disorders, such as those induced by alcohol, amphetamines, marijuana, cocaine, ecstasy, inhalants, opioids or phencyclidine Psychosis; paranoid personality disorder; and schizophrenic personality disorder; anxiety disorder selected from panic disorder; fear of snoring; specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; The compounds of the present invention may be administered in combination with at least one neuroleptic (which may be a typical or atypical antipsychotic) to provide an improved treatment of a psychiatric disorder, such as schizophrenia. Combinations, uses, and The method may also provide advantages in treating a patient who has not responded appropriately or is resistant to other known treatments. Accordingly, the present invention provides a method of treating a patient suffering from a psychiatric disorder, such as a mental knife disease, the method Including administering to the patient a compound of the invention alone or as a combination therapy with at least one neuroleptic The compound of the present invention. As used herein, the term "neur〇lepUc agent" refers to the recognition of antipsychotic drugs for reducing confusion, delusions, hallucinations and psychomotor agonism in psychotic patients. A drug that acts. Also known as Qiang Ning Shen and antipsychotics, mental stabilizers include (but are not limited to): typical antipsychotic drugs, including morphine, which is further divided into 24 201206935 aliphatic, b chen ° and mating, sparse r 1 . «Star (eg cisordinol), phenolic butyrate (eg fluorine), two-cylinder ammonia, ,, open, gas, (for example, loxapine), two Hydrogen t-ketone (eg, mGlind (me)), diphenylbutyl pyridin (eg, Phn〇zide); and atypical antipsychotics including benzisoxazole (eg, Risperidone (Hsperid〇ne), Sertind〇le, 〇lanzapine, quetiapine, oxazanetene and ziprasidone (ziprasid)尤其ne). Particularly preferred neuroleptics for use in the present invention are saponin, olanzapine, risperidone, thiophene thiophene, adipine (adpip_ie), gas, alcohol, gas nitrogen (el) -), ziprasidone and oxatanide. The present invention further provides a method for treating a patient suffering from a cognitive disorder, the method comprising The compound of the present invention is administered. The cognitive disorder which can be treated according to the present invention includes, but is not limited to, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other Drug-related dementia, dementia associated with intracranial tumor or brain trauma, dementia associated with Huntington's disease or Parkinson's disease or AIDS-related dementia; ||妄; amnesia; post-traumatic stress disorder mental retardation; learning disabilities, For example, dyslexia, mathematical disorders or written expression disorders... dysfunction/hyperactivity disorder; and age-related cognitive decline. The invention also provides a method of treating dyskinesia in a patient, the method comprising administering to the patient a compound of the invention Examples of dyskinesias treatable according to the present invention include, but are not limited to, Huntington's disease and exercise difficulties with dopamine agonist therapy (4). The present invention further provides a treatment selected from Parkinson's disease and Method for dyskinesia of leg restlessness syndrome, Bean 25 201206935, which comprises administering a compound of the invention to the patient. This January also provides a treatment for mood disorders. The method comprises administering to the patient a compound of the invention. The mood disorder treatable according to the invention: examples of emotional episodes include (but are not limited to) mild, " or severe dust episodes of depressive episodes, mania or Mixed mood episodes, mild manic episodes; depressive episodes with typical characteristics; depressive episodes with symptoms of anxiety; depressive episodes with symptoms of stiffness; emotional episodes of postpartum seizures; Major depression; low-grade emotional disorder; mild depression syndrome; • sputum disappointment's post-psychotic depression of April schizophrenia, syndrome, and mental disorder ^ severe depression such as paranoia or schizophrenia Bipolar anomalies such as type 1 19 abnormalities, type 11 polarization abnormalities; and cyclic affective disorders. It should be understood that emotional disorders are psychiatric disorders. The present invention further provides a method of treating a drug addiction (e.g., alcohol, amphetamine, cocaine, or opiate) in a patient, the method comprising administering to the patient a compound of the present invention in an amount effective to treat the drug addiction. As used herein, the term "drug addicti" refers to the abnormal need for drugs and the general characteristics are motivational disturbances, such as forced medications and strong drug cravings. Drug addiction is widely regarded as a pathological condition. Addictions involve the development of short-term drug use to the development of drug-seeking behavior, relapse of vulnerability, and reduced response to natural reward stimuli. For example, The Diagn〇stic and

Statistical Manual of Mental Disorders, Fourth Edition (DSM.IV) divides addiction into three phases: preemption/expectation, intemperance/poisoning, and withdrawal/negative 26 201206935 Impact. The characteristics of these stages are sustained cravings and preoccupation to obtain substances; use of more substances than necessary to experience the consequences of poisoning; and experience of tolerance, withdrawal symptoms and reduced motivation for normal life activities. The invention further provides a method of treating a patient's attention and/or a lack of awareness of a condition as a symptom, the method comprising administering to the patient an amount of a compound of the invention effective to treat the condition. Other conditions treatable in accordance with the present invention are obsessive-compulsive disorder, Tourette's syndrome, and other tic symptoms. As used herein, and unless otherwise indicated, otherwise "neurodegenerative dis〇rder 〇rc〇ndiu〇n" refers to dysfunction of neurons in the central nervous system and/or A condition or condition caused by death. Enhancement of the dysfunction or death of neurons in the risk of such conditions or conditions and/or by compensating for functional loss caused by dysfunction or death at risk An agent that damages or functions as a healthy neuron to promote the treatment of such conditions and conditions. As used herein, the term "neurtrophic agent" refers to a substance or agent that has some or all of these properties. Examples of neurodegenerative disorders and conditions treatable according to the present invention include (but are not limited to) Platinum's disease; Huntington's disease; dementia, such as Alzheimer's disease, multi-infarct dementia, AIDS-related dementia And the amount of cancer (Fr〇ntotemperal Dementia); neurodegeneration associated with brain trauma; neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarction; hypoglycemia 2 induced neurodegeneration; neurodegeneration associated with seizures; Neurodegeneration associated with neurotoxin poisoning; and multiple system atrophy. 27 201206935 In a specific embodiment of the invention, a neurodegenerative disorder or condition involves neurodegeneration of a striatum multi-spinal neuron in a patient. In another embodiment of the invention, the neurodegenerative disorder or condition is Huntington's disease. In another embodiment, the invention provides a method of treating a patient to reduce body fat or body weight or treating non-insulin demand diabetes (NIDDM), metabolic syndrome, or glucose intolerance, comprising administering to a patient in need thereof A compound of the invention. In some embodiments, the patient is overweight or obese and orally administered a compound of the invention. In another preferred embodiment, the method further comprises administering to the patient a second therapeutic agent, preferably an anti-obesity agent such as rim〇nabant, orlistat (〇rHMat). , sibutramine, bromocriptine (br〇m〇cripUne), ephedrine, leptin, pseudoephedrine or peptide YY3-36 or an analogue thereof. As used herein, the term "metab〇Uc syndrome" refers to a group of conditions that exposes humans to a high risk of coronary artery disease. These conditions include type 2 diabetes, obesity, hypertension, and undesirable lipids. They are high LDL ("bad") cholesterol, low HDL ("good") cholesterol, and high triglycerides. All of these conditions are associated with high blood insulin levels. The basic defect of metabolic syndrome is membrane resistance in adipose tissue and muscle. All references (including publications, patent applications, and patents) cited herein are hereby incorporated by reference in their entirety in their entirety in the extent of And the full text of the statement (to the maximum extent permitted by law). 28 201206935 The headings and subheadings used herein are for convenience only and are not to be construed as limiting the invention in any way. The use of any and all examples, or <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; The patent documents cited and incorporated herein are for convenience only and do not reflect any point of view of the validity, patentability, and/or legal enforceability of such patent documents. The present invention includes, as permitted by applicable law. All modifications and equivalents of the patient elements described in the appended claims are included. Experimental Part Preparation of Compounds of the Invention The compounds of formula I of the invention can be prepared as described in the following reaction schemes, unless otherwise indicated In the following reaction schemes and discussion, het, R1-R11, L and Y are as defined above. Compounds of formula I which are -CH2-S- can be made by formula II, III or Ilia as shown in Scheme 1. The nucleophile is prepared by coupling with an electrophile of formula IV wherein X is a leaving group such as CM, Br, I, methanesulfonyl, 4-toluenesulfonyl. Reaction between Ilia and IV In the use of IV to make Ilia sulphur Both the subalkylation and the ring closure to form the triazole ring are carried out under the same reaction conditions in a one-p〇t procedure. 29 X201206935

II

w +

IV

Het=S

III

+

IV

X

I M

IV Process wherein the compound of formula III (het=S) can be one of the following structures

30 201206935 This reaction is typically at about 〇. 〇 to a temperature range of about 20 CTC, in a solvent such as 1-propanol, toluene, DMF or acetonitrile, optionally in a carbonate base such as potassium carbonate or such as triethylamine or diisopropylethylamine (DIPEA) In the presence of a tertiary amine base, it is carried out under pressure in a closed vessel as appropriate. Other suitable solvents include benzene, gas, dioxane, ethyl acetate, 2-propanol and diphenylbenzene. Alternatively, a solvent mixture such as anthraquinone/2-propanol can be used. Compounds of formula II are commercially available or can be prepared as described in the literature, see for example Kjellin, G; Sandstrdm, J. dcia C/zem. Scizwi/. 1969, 23, 2879-2887; Laufer, SA et al. 2008, 253-266. Compounds of formula III are commercially available or can be prepared as described in the literature, see J. G. Brown et al. Aust. J. Chem. 1978, 31, 397-404; Yutilov et al./nw. Geier. 1988, 799-804 ; Wilde et al

Bioorg. Med. Chem. Lett. 1995, 5, 167-172; Kidwai A J. Ruler/C/zew. ^Soc. 2005, P, 2 8 8-291. The compound of formula Ilia can be prepared from the corresponding 1,2-diaminopyridine and thiocarbonyl group in a suitable solvent such as chloroform at a suitable temperature, such as room temperature or about 40 ° C, as described in WO 96/01826. Prepared by diimidazole reaction. The necessary 1,2-diaminopyridine is readily available from the corresponding commercially available 2-aminopyridines and such as hydrazine-based groups by a suitable solvent such as chloroform at a suitable temperature such as 0 ° C or room temperature. For the reaction of a sulfonyl)hydroxylamine suitable for the amide amidating reagent, see WO 96/01826 ° Formula 5, 5-chloromercapto-2-methyl-1H-[1,2,4]triindole [1, 5_(;] quinine. The porphyrin and 5-chloromethyl-2.methyl-1H-pyrazolo[uc]quinazoline can be prepared by methods known in the art (see, for example, Gerecke et al. 31 201206935 (1994), 39(2), 693-721 and DeStevens, G. et al. yowrAia/o/Orgamc (1963), 28 1336-9 and Makisumi, Y. Chemical &amp; Pharmaceutical Bulletin (1962), 10 620 -6 and Breuer, H. Tetrahedron Letters (1976), (23), 1935-8) o The compound of formula I wherein L is -S-CH2· can be used to render the nucleophile of formula V as shown in Scheme 2 Prepared by coupling with an electrophile of formula VI. HET—^ OH Via

HET-^ + X VI

R7 R8

Nh2 NH R9 VIII 1· H0CH2C02Me, base 2. Ester reduction N-amination

X = Cl, Br, I, OMs, OTs This reaction is typically at about 〇. 〇 to a temperature of about 2 〇 (in the temperature range of rc, in a solvent such as 1-propanol, toluene, DMF or acetonitrile, optionally in the case of potassium carbonate or such as triethylamine or diisopropyl In the presence of a tertiary amine of the amine (DIPEA), it is carried out under pressure in a closed vessel, as appropriate. Other suitable solvents include benzene's gas, dioxane, ethyl acetate, 2-propanol and xylene. 'A solvent mixture such as toluene/2-propanol can be used. 32 201206935 Some of the electrophiles of the formula νι are commercially available, and many other electrophiles are known in the art, see for example JP 59 1 76277. X An electrophile VI which is a leaving group (e.g., Cl, Br, I, methanesulfonyl, 4-nonylsulfonyl) can also be used to render a compound of formula VIa by methods known to chemists skilled in the art. The primary alcohol is converted to the leaving group. The methods may, for example, be selected from the group consisting of a suitable solvent such as dioxane or 1,2-diethane, and optionally, such as diethylamine, In the presence of monoisopropylethylamine or η than the bite test, the compound of the formula Via and sulphur sulphur gas, three gasification , three evolution scales, vermiculite gas or 4-methyl sapphire chlorine reaction. Alternatively, the pro-electron agent of the formula νι can be used at a suitable temperature such as room temperature or reflux, such as hydrazine, 2-two In a suitable solvent for methoxyethane or ethanol, a commercially available aromatic amine of the formula VII is reacted with 1,3 -di-propanone of the formula 例如 (for example, 1,3 -diacetone). Electrophilic agents are commercially available, and many other electrophiles are known in the art, see for example Tsuchiya, T_; Sashida, H. / CTzem.

Chem. Commun. 1980, 1 109-1110 ; Tsuchiya, T.; Sashida, H·

Konoshita, A. P/zarm. Bw//. 1983, 3/, 4568-4572. Further, the alcohol of the formula V can be obtained by subjecting an aromatic amine of the formula VII to a commercially available aldehyde such as hydrazine at a suitable temperature such as 〇c or room temperature in a suitable solvent such as a gas. The hydroxylamine is prepared by reaction with an iV-aminating agent, see w〇96/01826, to give a compound of formula VIII. The compound of the formula νιπ can be obtained by reacting with methyl hydroxyacetate, followed by a method known to the chemist skilled in the art, in a suitable solvent such as diethyl ether or tetrahydrofuran, using a suitable reducing agent such as lithium aluminum hydride. The ester is reduced to the essential alcohol and converted to the compound of formula V. 33 201206935 An electrophile of formula VI which is 2-haloindenyl-4-(aryl)-hydrazine-n-imidazole can be used, for example, by using a method well known to chemists skilled in the art, such as sulfinium chloride, A suitable reagent for vaporizing phosphorus or phosphorus tribromide is prepared by argonizing the corresponding 2-hydroxymethyl-4-(aryl)-1 Η-imidazole using a suitable solvent such as dioxane as appropriate. The necessary 2-hydroxymethyl-4-(aryl)_1Η-imidazole can be prepared by methods known in the art (see, for example, Magdolen, Ρ; Vasella, A. Helv. Chim. Acta 2005, 88, 2454). - 2469 ; Song, Z. et al. //. C/zem. 1999, &lt;54, 1859-1867). Compounds of formula V are commercially available or can be prepared as described in the literature, see, for example, Blank, J., European Journal of Organic Chemistry (2003), (1), 1 82-189 and Pfeiffer, W. et al. journal of /feierocyc/zc C/zewniir Less (1999), 36(5), 1327-1336 and Colotta, V. et al. journal of Medicinal Chemistry (\996), 39(15), 2915-2921. The compound of formula I wherein R5 and R6 are not hydrogen can be prepared by calcination of a compound of formula I wherein R5 and R6 are hydrogen, as shown in Scheme 3. 34 201206935

I (where R5 = H or R6 = H)

I (where R5 = H or R6 = H)

Process 3. The reaction is typically carried out at a temperature ranging from about 〇 ° C to about 1 oo ° C in a suitable solvent such as dimethyl decylamine, dimethyl acetamide or acetonitrile, such as a carbonate test (eg, carbonic acid). It is carried out in the presence of a suitable base such as unloading or a tertiary amine test such as triethylamine or diisopropylethylamine (DIPEA). The compound of formula I wherein L is -CH2-CH2- can be prepared by the reaction sequence shown in Scheme 4 exemplified by phenylimidazole as a specific het, and the compound of formula I having other types of het is prepared in a similar manner. 35 201206935

IV

(where -l-ch^qv and HET are as shown) R10

reduction

La (where -L- = -CH=CH- and HET as shown) Flow 4. Specifically, a hydrazine compound of the formula wherein L is -CH2-CH2 can be reduced by hydrogenation using a transition metal catalyst such as palladium metal and a hydrogen source such as hydrogen, ammonium hydrogencarbonate or cyclohexadiene to reduce Lg_CH=CH_ The formula of methene 2 was prepared. L is the equation of -CH=CH_! The olefin may be a scale salt of the formula XII and a formula χιπ in the presence of a suitable base such as 1,8-diazabicyclo[5 4 fluorene]undec-7_ene in a suitable solvent such as tetra:furan. The Wittig reaction between the aldehydes is prepared. The scale salt of the formula π is readily obtained by reacting a compound of the formula IV with the triphenylphosphine as described in the above Scheme 2, by methods known to chemists skilled in the art. An oxime of the formula ιππ is readily oxidized by an alcohol known to the chemist skilled in the art (see Scheme 2 above), for example by a suitable solvent such as di-methane or 1,2. The alcohol of the formula Via is reacted with a suitable oxidizing agent such as Dess-Martin periodinane. 36 201206935 The invention disclosed herein is illustrated by the steps. Preparation of intermediates The following non-limiting examples are presented. General Methods S himadzu Analytical LC-MS data was obtained using one of the following methods. Use a pE Sciex ΐ5〇Εχ instrument equipped with atmospheric pressure photoionization and LC-8A/SLC-10A LC system. Column: 4_6x3〇mm Waters ci8 column with a particle size of 3.5 μϊ; column temperature: 60t; solvent system, system: A = water/tri-acetic acid (ι〇〇: 〇·(6) and Β = water/acetonitrile/ Trifluoroacetic acid; method: linear gradient elution in 2.4 minutes. 5:95:0.035 and at a flow rate of 3.3 mL/min with eight upper = 9 〇: 1 〇 to 〇: 1 。. Preparative LC-MS purification on ionized PE Sciex Αρι 15〇Εχ instrument. Column: 5〇χ2〇mmYMCODS-A with a particle size of 5 μη; method: flow rate in 7 minutes and at 22 7 ml/min Linear gradient elution with A:B = 80:20 to 0:100. Fractional collection by shunt MS detection. Record 咕 NMR spectra at 500 13 MHz on a Bruker Avance AV500 instrument or on a Bruker Avance DPX250 instrument H NMR spectra were recorded at 250 13 MHz. TMS was used as an internal reference standard. Chemical shift values are expressed in ppm. The following abbreviations are used for the multiplicity of NMR signals: s = singlet, d = doublet, t = triple Peak, q = quadruple peak, 丨 丨 = five heavy peak, h = seven heavy peak, dd = double doublet, dt = double triplet, dq = double quadruple , u = three triplets, m = multiplet, br s = wide unimodal and br = wide signal. 37 201206935 Abbreviations according to ACS Style Guide: "The ACS Styleguide - A manual for authors and editors j Janet S. Dodd, 1997 edition, ISBN: 0841234620 ° Preparation of intermediate synthesis WX47_X02 Process 1

OMF-OMA -^

Method for preparing compound 2

The mixture of Compound 1 ((100 mL) was transferred under reflux for 2 hours. After that, the residue was washed with hexane (50 mL) (44.8 g, yield: 96%). *l (35g, 〇.2l2mol) #DMF-DMA for 2 hours. Excess excess dmF-DMF was removed under vacuum. Wash residue was dried under vacuum to give yield: 96%). A method that can be used to prepare compound 3

3 38 2 201206935 To a solution of compound 2 (20 g, 0·09 m〇1) in absolute ethanol (168 mL) was added H2NNH2 (4.3 g, 0.133 m 〇1). After the addition was completed, the mixture was mixed under reflux overnight. The resulting mixture was concentrated under vacuum. The residue was washed with EtOAc (EtOAc)EtOAc.咕NMR (CDC13 300MHz IMS): ^7.74-7.70 (m, 2H), 7.64-7.57 (-&gt; 2H), 7.50-7.45 (m, 1H), 6.53-6.51 (m, 1H), 6.11 (brs, 1H) Method for preparing compound 4

A mixture of compound 3 (25 g () i3 m〇i) and hydrazine (5 g, nmw/w) in MeOH (5 mL) was obtained overnight at room temperature under H2 (5 () psi). After (iv), the mixture was concentrated under vacuum to give compound 4 (17 </ s, yield: 81%) which was used in the next step without further purification. Method for preparing WX47_X02

Cs2l h2o 0 than bite

SH WX47._X〇2 Stir compound 4 (^ mouth qing h 1/ g, 0.U m〇l) under reflux with 87 mL CS2K 141.5 mL pyridine and 7 m]L water Τ ·&lt;-mixture Overnight. The reaction mixture was concentrated under EtOAc (EtOAc) (EtOAc:EtOAc. !H NMR (CDC13 300MHz TMS): &lt;510.78 (s, 1H), 8.20 (s, 1H), 7.90 (dd, J = 1.2 Hz and 7.8 Hz, 1H), 7.55-7.53 (m, 1H), 7.44 -7.40 (m,2H),7.03 (s,1H) » Synthetic WX47 X03 Process 2

Method for preparing compound 5

A mixture of Compound 1 (10 g, 〇 06 m〇i) and DMF-DMF (12.09 g, 〇_〇9 mol) was mixed for 3 hours under reflux. After the excess of DMF-DMF was removed in vacuo, the residue was washed with hexane (5 mL) and dried in vacuo to give compound 5 (14·04 g, yield: 83%) without further purification It can be used in the next step. 40 201206935 Method of preparing compound 6

To a solution of compound 5 (35 g, 0.15 mol) in dry ethanol (3 mL) was added H2NNH2. The mixture was sanded under reflux overnight. The solvent was removed under vacuum and the residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc : M2.76 (s, 1H) 7 72 (dd 5.6 Hz and 6·8 Hz, 2H), 7.64.7.61 (m, 1H)', 7 5〇7 46 (9) 1H), 6.26 (s, 1H) , 2.68 (s, 3H). Method for preparing compound 7

H2 (10% Pd/C MeOH

A mixture of compound 6 (15 g, 74 mm 〇 1) and Pd/C (4 g' 10 〇 / 〇 w/w) in Me 〇 H (5 〇〇 mL) at room temperature under H2 (5 GpSi) overnight. After filtration, the mash was concentrated under vacuum to give compound 7. Yield (86%) which was used in the next step without further purification. Method of preparing WX47-X03 乂 ”

CS2, Η^Ο

201206935 Compound 7 (8 g, 46 mm 〇 1) and 555 m were stirred under reflux at N2; a mixture of L CS2 in 05 mL of pyridine and 3 mL of water was overnight. The reaction mixture was concentrated under EtOAcqqqqqqlililililililililililililili Η NMR (DMSO-A 400MHz TMS): &lt;513.38 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.56-7.54 (m, 2H), 7.40-7.36 (m, 1H), 7.16 (s, 1H), 2.41 (s, 3H). Synthesis WX47_X〇4 Process 3

Method for preparing compound 9

·* W02005/303 A1 Add CH3CN ( 17.4 mL, 330.12 mmol) to a solution of _BuLi (132.6 mL '2.5 Μ hexane solution, 330.12 mmol) in 100 mL THF at -78 °C for 20 min. 210 mL of THF solution. The resulting mixture was stirred at -78 °C for 1 hour, then a solution of compound 8 (30 g, 165.06 mmol) in loo mL THF was added at -78 °C for 15 minutes 42 201206935. After stirring for 1 hour, the reaction mixture was allowed to warm to 451: and stirred for 2 hours. A saturated NH 4 Cl solution (50 mL) was added at 0 ° C, and the mixture was extracted with ethyl acetate (2 〇〇 mL X 2 ). The combined organic layers were dried with anhydrous sodium s The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Method of preparing compound 10

## je ·* US4900836 A1

To a solution of Compound 9 (7.0 g, 36.8 mmol) in 175 mL of CHCI3 was added dropwise a solution of DMF ( 7.35 g, 55.2 mmol) in 35 mL of CHC. The reaction mixture was spoiled overnight below _5 °C. After the solvent was removed, the residue was purifiedjjjjjjjjjjjjjjjj Method for preparing compound 11

10 To a solution of compound 10 ( 7.62 g, 29.4 mmol) in dry ethanol (200 mL) / EtOAc, H.sub.2H.sub.2. After the addition was completed, the mixture was stirred under reflux overnight. After the solvent was removed, the residue was purified by column chromatography (EtOAc / EtOAc EtOAc EtOAc) Method of preparing compound 12

References: W02004/106292 A1 Compounds u (61 26.8 mmol) and Pd/C (0.6 g, 1〇〇/0 w/w) at Me〇H (15〇) at 25 ° C under H2 (15 psi) The mixture in mL) was overnight. After filtration, the filtrate was concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Method for preparing WX47_X04

SH WX47 X04 A mixture of compound 12 (1.0 g, 5 mmol) and 5 · 5 mL of CS2 in 40 mL of 0 to D and 0.4 mL of water was stirred overnight under N2. The reaction mixture was concentrated under vacuum <RTI ID=0.0></RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 4 NMR (DMSO-A 400 MHz TMS): &lt;513.92 (brs, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.61 (d, J = 44 201206935

8.0 Hz, 1H), 7_56 (t, ·/ = 8.0 Hz, 1H), 2.50 (s, 3H). Synthesis WX47_X05A Process 4

Method of preparing compound 14

13 14 To a solution of compound 13 (140 g, 0.77 mol) in a mixture of DMF (2 mL) and CH.sub.2C12 ( 1400 mL), EtOAc (1 60 mL). After the addition was completed, EtOAc m m m m m m m m 45 201206935 Method of preparing compound 15

Add to a solution of (9, iV-dimethyl-amine (124 5 g, i 5 m〇l) and Et3N (313 mL ' 2.25 mol) in CH2Cl2 (15 mL) at 0 °C Compound 14 (150 g, 0.75 m 〇1). The mixture was stirred at room temperature overnight and quenched with water (500 mL). The mixture was adjusted to pH = 1 from concentrated HCI. (8 〇〇) and NaHCCh (800 mL), EtOAc (EtOAc m. Further purification can be used in the next step. Method for preparing compound 16.

Aibn (13.6 g '0.084 mol) was added to a solution of compound 15 (63 g, 0.28 mol) and NBS (150 g, 〇_844 mol) in CCU (1200 mL) under N2. The mixture was stirred at reflux overnight. The reaction mixture was quenched with water (1 〇〇〇 mL) and the organic layer was separated, and the aqueous layer was extracted with CH2C12 (500 ml &gt;3). The combined organic layer was dried over NadO4, dried and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) Add -BuLi (150 mL) to the saturated THF (250 mL) solution. After the addition was completed, the mixture was stirred at -78 °C for 1.5 hours, and a solution of compound 18 (25 g, 71 mmol) in THF ( igh mL) was added at -78 °C. After stirring at -78 ° C for 1.5 hours, the mixture was stirred at room temperature overnight. The resulting mixture was quenched with EtOAc (EtOAc) (EtOAc) The combined organic layers were dried with EtOAc EtOAc m. Synthesis WX47 Y03 Process 7

Method of preparing compound 27

^ ^ : J. Org. Chem. 1985, 50, 5022-5027 A round bottom flask equipped with a nitrogen inlet, a gas outlet to the bleach scrubber and a temperature probe was charged with DMSO (3000 mL) and compound 26 47 201206935 (5 0〇g ' 4.1 6 mo 1 ). The mixture was heated at 60 ° C, and an aqueous HBr solution (695 g, 48%, 4·16 mol) was slowly added via a feed funnel to maintain the internal temperature of the reaction at 60-68 °C. When dithizone is formed, it is removed using a nitrogen purge. After the addition of HBr was completed, the internal temperature was maintained at 65 C with external heating until TLC (petroleum ether / EtOAc = 5/1) indicated that the reaction was completed. After cooling to room temperature, the reaction mixture was taken up in water (5 mL) and extracted with ethyl acetate (2000 mL×3). The combined organic layers were washed with brine (2 mL EtOAc) EtOAcjjjjjjjjjjjjj One step. Method for preparing WX24_X〇3_2

WX24_X03, 2 References · WO2004/94395 Add acetic acid (1〇〇〇) to a mixture of compound 27 (633 g, 4.16 mol) 'ammonium acetate (124〇g, 16.68 mol) in methanol (3000 mL) mL) 'A solution of hydroxy-methoxy-acetic acid methyl ester (81 〇g, 8 34 mol) in methanol (1000 mL) was then added with stirring. After stirring for 8 hours, the reaction mixture was concentrated under vacuum. To the residue was added 0 5 N hydrochloric acid (5 br.), and the mixture was washed with ethyl acetate (2000 mL x 3). The aqueous layer was basified to pH = 9 and extracted with ethyl acetate (2 mL). The combined organic layers were washed with EtOAc EtOAc EtOAc m. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) /6 400MHz TMS): &lt;513.50 (s, 1R), 7.90 (s, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.37-7.35 (m, 2H), 7.24-7.20 (m, 1H) ), 3.85 (s, 3H). Method of preparing compound 28

References: US2004/122018 Adding Mel (1〇g, 〇〇75 m〇〇 and k2c〇3 (10 g) to WX24_X03-2 (1〇g, 〇〇5 m〇1) in DMF (100 mL) The mixture was stirred at 20 C for 4 h until TLC ( pet ether / EtOAc = 2:1).丨g, yield: 1 〇〇%), which was used in the next step without further purification.

XM ·&quot; J. Med. Chem., 1986, 29, 1065-1080 〇Add to THF (200 mL) bath of compound 28 ( l〇.7g, 〇·〇5 m〇l) at 〇C LiA1H4 (5.7 g, 〇·ΐ5 mol). The mixture was stirred at 0 °C for 4 hours until TLC (petroleum ether/Et 〇Ae = 2:1) indicated that compound 49 201206935 28 was almost completely consumed. The reaction mixture was quenched with 1% aqueous nh4C1 (20 mL) and 10% aqueous K:2 C3 (200 mL). The resulting mixture was extracted with B3 long-term @曰(200 mLx3). The combined organic layers were washed with EtOAcqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH It was used in the next step without further purification. Method for preparing WX47_Y03

SOCI2 ch2ci2

WX47 Y03 References: US5296493 A1 (1994/03/22) To a solution of compound 29 (9 g, 0.04 8 mol) in CH2C12 (1 mL) was added SOCl2 (100 mL), then the mixture was stirred at room temperature 4 hour. The reaction mixture was concentrated under reduced EtOAc. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Purification can be used in the next step. Synthesis WX47_Y04 Process 8

50 201206935 Method of preparing 30

LiAIH4 THF WX24_X〇3_2

30 Add THF (200 g of WX24_X〇3-2 (3 g, 14.8 with 〇1) to a mixture of uaih4 (1&gt;7 g, 45 mmol) in HF (1 mL) at 〇 °c mL) Solution 'The mixture was stirred at room temperature overnight. (Petroleum ether / EtOAc = 2:1) indicated that WX24_x 〇 3 2 was almost consumed. The mixture was quenched with h) 〇/〇nh4C1 aqueous solution (10 mL). The reaction mixture was filtered through celite.帛THF (3〇mLx5) washes the knees of the earth. The combined filtrates were dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH . Method for preparing WX47_Y〇4

SOCI2 -) ch2ci2 30

WX47wY 〇4 ^b^^30 (2.0 g, ll mmol) ^CH 2 Cl 2 (l 〇〇 mL) was added dropwise to a solution of S 〇 Cl 2 (5 () mL), followed by overnight at room temperature. The reaction mixture was concentrated with EtOAc EtOAc m. Dirty (DMSO-A 4〇〇MHz): After 15 (s, 1H), 7 Μ ?Μ ^ 2H), 51 201206935 7.52-7.40 (m, 3H), 5.05 (s, 2H). Synthesis WX47_Y〇6

A mixture of compound 31 (100 g, i_〇i mol) and 1,3-dichloro-propan-2-one (150 g, 1.2 mol) in 300 mL of DME was stirred overnight at room temperature. The DME was removed under reduced pressure and the residue was dissolved in 2500 mL EtOH. The resulting mixture was stirred under reflux for 3 hours. After concentrating under reduced pressure, the residue was partitioned between CH2C12 (1500 mL) and sat. NaHC.sub.3 (1000 mL). The organic layer was separated and washed with brine (" s mL), dried over Na2S04, filtered and under vacuum Concentration gave WX47_Y06 (9 1 g, yield: 60%) which was used directly in the next step.

#· # XM * Tetrahedron, 1995, 5 1, 9643-9656 5:1 Add 1,3-dichloro-propane-2 dropwise to 315 mL of DME solution of compound 32 (100 g, 1.05 mol) at room temperature a ketone (133.3 g, 1.05 mol) in 210 mL DME solution. The reaction mixture was stirred with EtOAc EtOAc (EtOAc m. . A small portion of the residue was purified by EtOAc EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: ^8.58 (dd, J = 4.0Hz, 2.0 Hz, 1H), 8.44 (dd, 6.8 Hz and 2.0 Hz, 1H), 7.63 (s, 1H), 6.91 (dd, / = 6.8 Hz and 4.0 Hz, 1H) , 4.82 (s, 2H). Synthesis WX47 Y09

1. H2/10°/〇 Pd/C

3 Dioxane, reflux WX47_Y09 Overnight Reference: US4910199 Stir compound 33 (5.0 g, 3 8.7 mmol) and i〇% pd/c (〇5 g) in ethanol at room temperature under H2 (1 atm) A mixture of 5 〇 mL) was taken overnight until TLC (EtOAc / petroleum ether = 1/1) indicated that Compound 33 was completely consumed. The mixture was obtained, and the filtrate was evaporated, mjjjjjjjjjjjj The desired product of the above reaction (3 g, 31.5 mm 〇1) and a mixture of compound 33A (4.8 g &apos; 37.9 mmol) in 1,4-dipyr (l 〇〇mL) were stirred overnight under reflux. Sodium acetate (1 29 g, 15 7 mmol) was added, and the obtained mixture was refluxed for further 4 hr. The reaction mixture was concentrated under EtOAc (EtOAc m.) 53 201206935 Synthesis WX47 ΥΙΟ Process 12

WX47_Y10 Method for preparing compound 35 ΧΧ&quot;°2 (^γΝ〇2

CI^^CI EtOH C|-^%AN^/0H 34 35 &quot; To a solution of compound 34 (10 g, 0.052 _) in ethanol (1 mL) was added 15.7 mL of 2-amino-ethanol. After the addition is completed, at 75_8 〇. . Mix the sandalwood for 164 hours. After cooling to room temperature, the reaction mixture was poured into mL 0.5N HCl. The solid formed was collected by filtration, washed with water (1 〇) and dried under vacuum to give a compound Μ &quot;. ? Factory production rate: 95%). Method of preparing compound 36

CI

35 N〇2N~. Η Η

SnCI2 md

NH2 36

OH 0.09 55 m]L of concentrated HCn was added dropwise to a solution of compound 3S (7 g, 0.03 m) and SnCl2 (17 g, mol) in water (95 mL) at 100C. 54 201206935 After the addition was completed, the mixture was stirred at 100 ° C for 3 hours. The reaction mixture was basified with EtOAc (50 mL &lt;&lt;&gt;&gt;&lt;6&gt;&gt; The combined organic layers were dried with EtOAc EtOAc (EtOAc) Method for preparing WX47_Y10

To a solution of Compound 36 (1.0 g, 5 mmol) in 1 mL of EtOAc EtOAc (EtOAc) The mixture was diluted with 5 mL water and extracted with EtOAc (30 mL EtOAc). The combined organic layers were concentrated in vacuo and purified <RTI ID=0.0></RTI> </ RTI> </ RTI> <RTIgt; Synthesis WX47_Y11 Process 13

55 201206935 Method of preparing compound 38

Compound 37A (20.3 g, 0.144 mol) was added to a mixture of compound 37 (10 g, 0.072 mol) and K2C03 (19.87 g, 0.144 mol) in 150 mL of THF at 0 ° C. The mixture was stirred for 12 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated and concentrated in vacuo to give a yield of 16.2 g of compound 38. Method of preparing compound 39

To a solution of compound 38 (20 g, 79.68 mmol) in a mixture of 2 50 mL of ethanol and 250 mL of water at <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> NaHS (44.62 g, 796.8 mmol) of a 250 mL aqueous solution. After the addition was completed, the mixture was stirred under reflux overnight. After removing the ethanol in vacuo, the residue was extracted with &lt;RTI ID=0.0&gt;&gt;&gt;&gt; Method for preparing WX47 Y11

56 201206935 To a solution of compound 39 (0_5 g, 2.26 mmol) in 5 mL THF was added K.sub.2.sub.3 ( 3.12 g, 22.6 mmol). Add 7.5 mL of acetic acid solution of 0.3 mL of gas-brewed chlorine to the bowl under the armpit. After mixing at 5 ° C for 3 minutes, a solution of p-acetic acid gas (0.125 mL) was added dropwise to a solution of 25 mL of acetamidine. After stirring at 5 ° C for 15 minutes, the resulting mixture was filtered and subjected to a reduction in a vacuum and a liquid. The residue was diluted with aq. aq. EtOAc (1 mL) andEtOAc. The combined organic layers were washed with brine (30 mL) dried over Na Nas The residue was dissolved in 5 mL of 0_4N HCl in dioxane and stirred at 9 (TC s. hr. After cooling to room temperature, the mixture was purified with saturated aqueous NaHCO:) (1 〇mL) Extracted with CH2C12 (20 mL) &lt;3&gt;. The combined organic layer was washed with brine (3 EtOAc). Obtained 0.2 g of WX47_Y11 in a yield of 32%. Synthesis of WX47_Y12 Scheme 14

57 201206935 Method of preparing compound 41

^ ^ Μ ·* J. Org. Chem., 1985, 50, 5022-5027 DMSO (300 mL) and compound 40 were placed in a round bottom flask equipped with a nitrogen inlet, a gas outlet to the bleach scrubber and a thermometer. (30 g, 200 mmol) 〇 The solution was heated to 6 〇t:, and aqueous HBr (37.5 g, 4%) was slowly added via an addition funnel to keep the internal temperature of the reaction from 6 〇 to 6 8 C. When dimethyl sulfide is formed, it is removed using a nitrogen purge. After the hb r addition was completed, the internal temperature was maintained at 65 ° C with external heating until ΤΙχ (petroleum ether / Et 〇 Ac = 5 / l) indicating completion of the reaction. After cooling to room temperature, the reaction mixture was taken in water (300 mL) andEtOAc. The combined organic layers were washed with EtOAc EtOAc m. It was used in the next step without further purification. Method of preparing compound 42

41

Wen Guang: J. C/2em., 1999, 1859-1867. To a mixture of 2-methyl-2-methoxyacetic acid methyl ester (38.7 g, ο υ m〇1), B 58 201206935 acid (0.64 mol) in methanol (450 mL), acetic acid (300) (mL), followed by the addition of a solution of compound 41 (40 g, 0.235 mmol) in methanol (3 mL) with stirring. After 1.5 hours, the reaction mixture was condensed under vacuum. The residue was diluted with 0.5 mL of EtOAc (EtOAc)EtOAc. The aqueous layer was basified to pH = 9 and extracted with ethyl acetate (3 mL mL). Under vacuum / agricultural shrinkage. The residue was purified by silica gel column chromatography (EtOAc / EtOAc / Method of preparing compound 43

Add a solution of compound 42 (7 〇g, 3〇17 in THF (200 mL) dropwise to a mixture of LiAlH4 (3. 44 g, 90.5 mmol) in THF (200 mL), then stir at room temperature. The mixture was stirred overnight until TLC (petroleum ether / EtOAc = 1/2), which indicated that compound 42 was almost depleted. The reaction mixture was quenched with 10% aqueous NH4C1 (40 mL) and filtered over a pad. 1 50 mL×5 ) Washed the diatomaceous earth. The combined filtrate was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 6 g of compound 43 in a yield of 97%. 59 201206935 Method for preparing WX47_Y12

43 SOCI2 -3 ch2ci2

WX47_Y12 To a solution of compound 43 (6.0 g, 29 mmol) in CH.sub.2Cl.sub.2 (.sub.5 mL) was added dropwise. The reaction mixture was concentrated under reduced pressure, and the residue was evaporated to ethyl ether (yield: EtOAc EtOAc EtOAc EtOAc

WX47.Y13 Method for preparing compound 44

To a mixture of compound 42 (11. 61 g, 50.07 mmol) and K2C03 (1 〇 36 g, 75.1 mmol) in DMF (100 mL) was added 峨 院 (1〇·6ό g '75·ι mmol), followed by 60 The mixture was stirred at ° C 2 60 201206935 until TLC (petroleum ether / EtOAc = 2/1) indicated the reaction was completed. The reaction mixture was quenched with brine (1 mL) andEtOAcEtOAc The combined organic layers were washed with brine (250 mL &lt;2&gt;&lt;2&gt;) and dried over anhydrous sodium sulfate <~~~~~~~~~~~~~~~~~~~~~~~~~~~~ , 9. g of compound 44, the yield is the method of preparing compound 45

A solution of compound 44 (9.0 g, 36.5 mmol) in THF (200 mL) was added dropwise to a mixture of EtOAc (250 mL) The mixture was stirred overnight until TL C.' (petrole ether /EtOAc - 2 / 1). Here. The reaction mixture was quenched with 10% aq. EtOAc (50 mL) and filtered over EtOAc. The diatomaceous earth was washed with THF (300 mL x 5 ). The combined filtrate was dried <RTI ID=0.0> Method for preparing WX47_Y13

61 201206935 : Compound 45 (2.4g' n匪.1) is called. "(10)(4) 4 was added dropwise l2 (56.4 mL), then the mixture was poured at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was washed with anhydrous ethyl acetate (2 〇^Lx2) to give 2 2 g WX47—γΐ3, yield 嶋 H NMR (methanol-A 300MHz): 38.05 (s,1Η), 7.55-7.44 (m,1Η), 7.32-7.24 (m, 2H), 7.14-7.06 (m, 1H), 5.12 (s, 2H), 4.03 (s, 3H), 3.90 (s, 3H). The following intermediate was prepared in a similar manner: 2-methylmethyl-indole_ethyl-4_phenyl_1H -imidazole 95% yield, iH NMR (4 〇〇 MHz, DMS 〇〇: deduction % (s, ih), 7.92-7.89 (m, 2H), 7.51-7.47 (m, 2H), 7.43.7.39 (m , 1H), 5.26 (s, 2H), 4.24 (q, "/= 7.2 Hz, 2H), 1.46 (t, "/= 7.2 Hz, 3H). 2_gasmethyl-1-isopropyl-4 -phenyl-1H-imidazole 100% yield, 4 NMR (400 MHz, DMSO-A): mp. 54 (s, 1H), 7.93 (d3 J = 7 &gt; 6 Hz, 2H), 7.52-7.29 (m , 3H), 5.28 (s, 2H), 4·84-4·75 (m, ih), 1·50 (d, ·/= 6.8Hz, 6H). 2-Gasyl-4-(2- Fluorophenyl)-1-indenyl-1H-imidazole 80 〇/〇 yield, NMR (400 MHz, DMSO-A): 38.06-8.02 (m, ^), 7.91 (d, 7 = 3.2 Hz, 1 H), 7.41-7.38 (m, 1H), 7.34-7.29 (m, 2H), 5.12 (s, 2H), 3.84 (s, 3H). 2-methylmethyl-4-(3-fluorophenyl) -1-Methyl-1H-imidazole 89% yield, iH NMR (400 MHz, methanol-methanol): (58.07 (s, 1H), 7-58-7.51 (m, 3H), 7.27-7.23 (m, 1H), 5.11 (s, 2H), 4.01 (s, 3H). 62 201206935 2-chloromethyl-4-(4-fluorophenyl)-1-methyl-1H-imidazole 74% yield, 'HNMR (400 MHz, DMSO-A): &lt;58.19 (s, 1H), 7.94-7.91 (m, 2H), 7.37-7.33 (m, 2H), 5.20 (s, 2H), 3.86 (s, 3H). 2- gas fluorenyl-4-(2-phenylphenyl)-1-indolyl-1H-imidazole 74% yield, iH NMR (400 MHz, DMSO-d6): (58.11 (s, 1H), 7.89 ( Dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.48-7.38 (m, 2H), 5.13 (s, 2H), 3_87 (s, 3H). Gas methyl 4-(3-chlorophenyl)-1-methyl-1H-imidazole 99% yield, 4 NMR (400 MHz, DMSO-A): 38.30 (s, 1H), 8.00-7.99 (m , 1H), 7.84 (m, 1H), 7.52-7.43 (m, 2H), 5.20 (s, 2H), 3.86 (s, 3H). 2-carboyl-4-(4-chlorophenyl)- 1-mercapto-1H-imidazole; 80% yield, 4 NMR (400 MHz, methanol-d4): &lt;58.00 (s, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 5.10 (s, 2H), 4.01 (s, 3H). 2-Chloromethyl-4-(2-methoxyphenyl)-1-methyl-1H-imidazole 93% Yield, 4 NMR (400 MHz, DMSO-i/6): 38.12 (s, 1H), 7.98 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.45-7.40 (m, 1H), 7.20 (d , J = 8.0 Hz, 1H), 7.13-7.06 (m, 1H), 5.27 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H). 2-chloroindol-4-(3- 90% yield of decyloxyphenyl)-1-indenyl-1H-imidazole, 4 NMR (300 MHz, decyl alcohol - ί/4): &lt;58.05 (s, 1H), 7.55-7.44 (m, 1H) ), 7.32- 7.24 (m, 2H), 7.14-7.06 (m, 1H), 63 201206935 5.12 (s, 2H), 4.03 (s, 3H), 3.90 (s, 3H). 2-Gasyl-4-(4-曱oxyphenyl)-1-indenyl-1H-imidazole 97% yield, iH NMR (400 MHz, DMSO-i/6): (58.10 (s, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 5.20 (s, 2H), 3.83 (s, 3H), 3.75 (s, 3H). 2- gas fluorenyl-4-phenyl-1H-imidazole 81% yield, 4 NMR (400 MHz, DMSO-A): (58.21 (s, 1H), 7.96-7.92 (m, 2H), 7.59-7.55 (m, 2H), 7.50-7.47 (m, 1H), 5.12 (s, 2H). Synthesis of WX47_Y15 Process 16

Method of preparing compound 46

64 201206935 A mixture of WX24_X03__2 (5 g, 25 mmol), compound 40A (6.9 g, 37 mmol) and K2C03 (5 g, 37 mm〇i) in dmf (200 mL) was added overnight at 70 C. The reaction mixture was filtered, and the sputum was concentrated in vacuo to give 8 g of compound s. Method of preparing compound 47

To a mixture of LiAlH4 (193 mg, 5 mmol) in THF (20 mL), EtOAc (20 mL). The reaction mixture was stirred at 0 &lt;0&gt;C for 2 h and quenched from saturated NH4CI (50 mL) EtOAc. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. Method for preparing WX47_Y15

To a mixture of compound 47 (5.8 g '〇.02 mol) in CH2C12 (1 mL), SOCl2 (40 n &lt; L) was added dropwise at 0 ° C. The mixture was then stirred at room temperature for 2 hours. Concentrate under reduced pressure. The residue was recrystallized from a mixture of MeOH/EtOAc (EtOAc) to afford 3 g of WX47-Y15' yield 65 201206935 49.2% 〇methyl_4_phenyl-1 jj- miso-2_a chain

o-viC0 in the Ar atmosphere to (1_methyl_4-phenyl-1H-imidazol-2-yl)-methanol (5〇.〇mg' Ο·266 _〇1) 1,2-two gas Ethyl (4.0 mL) solution, force, Dess Martin, two hard burns (1 24 mg '0.292 mmol), and the mixture was stirred at room temperature for 2 hours. A saturated NaHC 3 solution was added, the organic layer was separated and the aqueous layer was extracted with hexane, 2-hexane. The combined organic layers were dried over Na.sub.2.sub.4, and evaporated. The title compound (39 丨 mg, 79 〇 /.) was obtained as a white solid. Nmr

(500 MHz, DMSO-^6): S9.76 (s, 1H), 8.11 (s, 1H), 7.84 (d, J -7.7 Hz, 2H), 7.42 (t, j = j 6 Hz 2h), 7.30 (t, J = 7.4 Hz, 1H), 3_99 (s, 3H). Taste _1-collisive formic acid (2-imido·4,6·didecyl_2H_pyridyl) decylamine 66 201206935

A modification of the method described in WO 96/01826 was used for 15 minutes. Adding 7% by weight to a solution of 0-sulfonyl hydrazide hydroxamic acid (i 7g, 6 〇mmol) in 1,4-two-milling (1〇mL) cooled in an ice bath Pervaporate acid (7_5mL) to maintain the internal temperature below 15. 〇 Next, use ice water (i〇〇mL) to dilute the mixture to precipitate the product sulfonyl)hydroxylamine, filter it out, wash it thoroughly with water, and dissolve it immediately in the air while still moist (丨〇mL ). The organic layer was separated and the water was removed by stoppering a Na 2 S 4 in a sintered syringe. The thus obtained solution of 0-(physylsulfonyl)hydroxylamine was added dropwise to 2-amino-4,6-dimethylpyridine (〇6 u g, 5 mmol) cooled in an ice bath. In a gas imitation (10 mL) solution. The mixture was then warmed to room temperature and stirred for 2 hours to convert to intermediate. Next, a 1,1-sulfanyl group is added to the reaction mixture. Sit (1.16 g, 6.5 mmo 1) and mix the resulting mixture overnight at 40 °C. Volatile substances were evaporated and the residue was subjected to silica gel chromatography (graduated elution with heptane: acetic acid ethyl 100:0 - 0:100) to give imidazole-1-thiocarboxylic acid as a pale white solid (2_ Amino _4,6-dimercapto-2H_. Ratio 67 201206935 pyridine-1-yl)-decylamine (0.50 g, 40%) containing a small amount of residual imidazole jhnmr (500 MHz, DMSO-c/6): 57.88 (s, 1H), 7.64 (sv 5 i ri;, /.42 (br s, 2H), 6.93 (s, 1H), 6.69 (s, 1H), 6.67 (s, 1H), 2.28 (s, 3H) 2·27 (s, 3H). ' 'The following intermediate was prepared similarly' except that it was used for the preparation of the final compound without prior purification or characterization: savory-1 - thioformic acid (5 - desert _2 · 亚月安基_4•Methyl-2h “Bitter small base”-decylamine, salivary small thioformic acid (5-acting 2_imino- 4,6-dimethyl-2 core ratio Pyridin-1-yl)-nonylamine, imidazolium-1 -thiocarboxylic acid (5_gas_2•imino-3-3-methyl-2H-pyridine-i-yl)-decylamine, sulphonazole-1-sulfur Formic acid (5-cyano Iimino 2 Η 吼 · i i 酿 酿 酿 酿 酿 酿 酿 酿 。 。 。 。 曱 曱 曱 曱 曱 曱 曱 曱 曱 曱

KSCN HCI - HOAc

Modifications using the method reported by Kjellin and Sandstrdm, dcia C/zew. 1969, 23, 28*79-2887. Heating 2-mercaptoamino-1·phenyl-ethanone hydrochloride (〇754g, 4〇6 mni〇l) using a microwave synthesizer at 14〇&lt;&gt; (see, for example, Hyde et al. Am. Chem. Soc. 1928, 50, 2287-2292 ; Shang et al. c/zem. Qin · /. 2007, /3, 7780-7784 ) with thiocyanide unloading (0.434 g, 4.46 mm〇l) The mixture was diluted with water (50 mL) and cooled in an ice-bath to elute the product, which was collected by filtration, washed with water and dried in vacuo to give a pure white solid. Compound (0-365 g, 47%). 4 NMR (500 MHz, DMSO-c/6): 512.66 (br s, 1H), 7.65 (d, J = 7.6 Hz, 2H), 7.60 (s, 1H), 7.3 9 (t, J = 7.8 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H), 3.49 (s, 3H). The following intermediates were prepared analogously: 4-phenyl-1,3-dihydro-imidazole -2-thione 80% yield ' NMR (500 MHz, DMSO 〇: δ 12.53 (br s, 1H), 12.15 (br s, 1H), 7.69-7.65 (m, 2H), 7.41-7.35 (m , 3H) 7.27 (t,= 7.4 Hz,1H) 〇4-phenyl-1H-imiline-2 - road

Treating monohydrate phenylglyoxal (1〇2 g, 〇_67 mol) with glyoxal didecyl acetal (60%) with acetic acid recorded 8202 g, 2.61 mol) in methanol (i.il) solution A solution of the aqueous solution '232 mL, 1.54 mol) in decyl alcohol (1M) was stirred at room temperature for 6 hours. The volatiles were removed in vacuo and the residue was slurried in 2N EtOAc (1. (: heating for 30 minutes. The cooled solution was extracted with Et 〇Ac (2 〇〇 mL) and the separated aqueous layer was basified to pH 9 with 9 N NaOH solution. The solid was filtered, washed with water and dried in vacuo to give Heading 69 201206935 (97.2 g, 84%) as a light brown solid. LC-MS: w/z = 173.0 (MH+), iR = 0.66 min 〇 1-(2-hydroxypropyl)-4- phenyl-1H-imidazole-2-formaldehyde

Treatment of 4·phenyl_1H-imidazol-2-furaldehyde (200 mg, 1.16 mmol) and sodium carbonate (60 mg, 0.6 mm〇i) with propylene oxide (170, 2.4 mmol) in a closed vessel The syrup in ethanol (4 mL) was EtOAc (3 mL). %), which was used without further purification. LC-MS: m/z = 231.5 (MH+), = 〇. 4 1 min, Method A The following intermediates were prepared similarly, except that they were not previously purified or characterized. For the preparation of the final compound: (S)-l-(2·hydroxypropyl)-4·phenyl-1H-imidazol-2-furaldehyde, (R)-l-(2-hydroxypropyl)-4 phenyl-1H-imidazole-2-carboxaldehyde, 1-(2-hydroxy-2-methyl-propyl)-4-phenyl-1H-imidazol-2-carbaldehyde, from I-Ga-2-methyl- 2-propanol 2-methyl-imidazo[i,2-a]pyridine

70 201206935 Use the method of vaneile et al. (10) 1991, 〇, 5 173 5 184. Add 2-aminopyridine to a solution of 1,3-dichloro-2-propanone (2.69 g, 21 2 mm〇i) in u-dimethoxyethyl &amp; (5 mL) and stir the mixture at room temperature 2 hours. During this time, a thick precipitate formed and the precipitate was collected by filtration. The precipitate was refluxed in absolute ethanol for 2 hours, and then the volatiles were removed by evaporation. The residue was dissolved in water (3 〇 mL) and solid NaHC 〇 3 was added to neutralize the mixture. A white precipitate was formed and the residue was crystallised eluted eluted eluted eluted elution elution 1h NMr (5〇〇mHz, CDC13): 58.08 (d, /= 6.7 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.17-7.22 (m, 1H) , 6.80 (t, J = 6.8 Hz, 1H), 4.78 (s, 2H). The following intermediates were prepared analogously: 2·Gas methyl-8-fluorenyl-ρm salidi[1,2 - a]. 《 53% yield, NMR (500 MHz, CDC13): δ7.95 (d,·/= 6.9

Hz, 1H), 7.61 (s, 1H), 6.97 (dt, J= 7.0 Hz, 1.1 Hz, 1H), 6.70 (t, ·/= 6.8 Hz, 1H), 4.80 (s, 2H), 2.60 (s , 3H) » The following compounds are known in the art: 2-chloromethyl-1-phenyl-1H-benzimidazole (JP 59176277). Methyl-1,3-dihydro-benzimidazole-2-thione (Wilde et al. 仏oorg. Med. C/zem. 1995, 5, 167-172). 1-phenyl-1,3-dihydro-benzo-flavor σ sit·2-sulfur_ (Kidwai et al. J. J. C/jem. 2005, 4P, 288-291) ° [1,2,4]3 Sit and [l,5-a]° bite-2-sulfur_ (E5rov/n et al. 乂wsi.yi 71 201206935 C/z Hidden 1978, 37, 397-404) 〇1,3 -Dihydro-° The rice sits and [4,5-b] D is more than α-thione (Yutilov et al. Khim. Geter. Soedin. 19S8, Ί99-%04~). 0 to 0 sits and [1,5-a] 0 ratio. Ding-2-yl-sterol (Tsuchiya, T.; Sashida, J. Chem. Soc., Chem. Commun. 1980, 1 109-1 1101 Tsuchiya, T.;

Sashida, H; Konoshita, A. Chem. Pharm. Bull. 1983, 31, 4568-4572). Preparation of PDE10A Inhibitor Example 1: 5-(1Η-Benzimidazol-2-ylmethylsulfanyl)-2-methyl-[1,2,4]triazolo[l,5-c]quina Oxazoline (WX47_X03Yi)

Mix at 60 C. Mix a mixture of WX47_X03 (250 mg, 1 mmol) and DIPEA (3 87 mg &gt; 3 mmol) in DMF (5 mL) for 15 min, then add WX47_Y01 (183 mg at 60 °C) , 1_1 mmol). After stirring for an additional 1 hour at 6 (TC), the reaction mixture was quenched with water (1 mL). The solid was collected by filtration and purified by preparative HPLC to afford EtOAc (3) as a yellow solid. The yield was 32%. The following compounds were prepared in a similar manner: 5-(benzothiazol-2-ylsulfonylsulfanyl)9-bromo-2-methyl-[^斗]3. Sit and [l,5- c] quinazoline 72 201206935 5-(1 Η-benzimidazol-2-ylmethylsulfanyl)-9-bromo-2-indolyl-[1,2,4] tris-π[[, 5 - c ] 唆唆琳 2-mercapto-5-(1-methyl-4-phenyl-1 Η-imidazol-2-ylmercaptosulfanyl)-[1,2,4]triazolo[ 1,5-c]quinazoline 5-(111-benzimidazol-2-ylmercaptosulfanyl)-9-fluoro-2-indolyl-[1,2,4] tris([1,2,4] ,5 - c ]喧α坐琳 5-(1Η-benzoimidazol-2-ylmethylsulfanyl)-8-chloro-2-indolyl-[1,2,4] III. Sit and [1 ,5 - c ]喧°坐琳5-(Benzo 03⁄4° sit-2-ylmethylthioalkyl)-2-indolyl-[1,2,4] II. Sit and [1,5 - c啥α sits. Lin 5-(imidazo[1,2-a]pyrimidin-2-ylmethylsulfanyl)-2-mercapto-[1,2,4] tris-sigma[1,5 - c ]啥σ坐琳 2-mercapto-5-(1-methyl-1Η-benzimidazole-2- Methylsulfanyl)-[1,2,4]triazolo[l,5-c]quinazoline 2-methyl-5-(quinolin-2-ylmethylsulfanyl)-[ 1,2,4]triazolo[l,5-c] α奎嗤琳 5-(imidazo[l,2-a].pyridin-2-ylmercaptosulfanyl)-2-indenyl -[1,2,4] tri-α sits and [1,5 - c ]喧β坐琳 5-(imidazo[l,2-b]嗒耕_2_ylmethylsulfanyl)-2-曱基-[1,2,4] Three D sit and [1,5-〇]喧° sitin 5-[4-(2-chloro-phenyl)-1-indenyl-1H-imidazole-2- Mercaptosulfanyl]-2-mercapto-[1,2,4]triazolo[1,5-c]quinazoline 5-[4-(3-decyloxy-phenyl)-1 -mercapto-1H-imidazol-2-ylmercaptosulfanyl]-2-methyl-[1,2,4]triazolo[l,5-c]quinazoline 73 201206935 5-[4- (4-methoxy-phenyl)-indole_methyl_1H-imidazolium-2-ylmethylsulfanyl]-2-mercapto-[1,2,4]triazolo[lsc]quinazoline 5 -[4-(2-Fluoro-phenyl)·^methyl_1H-imidazol-2-ylmethylsulfanyl]_2_ decyl-[1,2,4]triazolo[i,5-c]quina Oxazoline 5-(taste. sit-[2,lb]thiazole-6-ylmethylsulfanyl)_2_indenyl^^, triazolo[l,5-c]quinazoline-5-(imidazole And [2,lb][l,3,4]thiadiazole_6-ylmercaptosulfanyl)-2-mercapto-[1,2,4]triazole [uc]quinazoline 2-methyl-5-(3H-thieno[3,4_d]imidazolium-2-ylmethylsulfanyl H1,2,4]triazolo-U,5-c]quinazole Porphyrin 5-(Imidazo[1,2-ap-pyridylsulfonylsulfanyl)2-methyl-indolozolo[1,5-&lt;:]啥11坐琳 2-methyl-5- (4-Phenyl-1H-imidazol-2-ylsulfanylmethylpyrazolo[l,5-c]啥 琳 甲基 甲基 5 5 5 5 比 比 比 [ 1,5_c] fluorene imidazo[1,2-a]pyrimidin-2-ylmethylsulfanyl)-2-methyl-. Bisazo[1 '5-c]喧σ sit I»林5-(1Η_笨和味° sit-2-ylmethylsulfanyl)-2-mercapto-oxazolo[1,5- c]啥α sit. 2-methyl-5-(1-indolyl-1Ηbenzimidazol-2-ylmethylsulfanyl)pyrazolo[l,5-c]quinazoline 2methyl-5-(1-曱_4•Phenyl-1H-imidazol-2-ylmethylsulfanyl)·pyrazolo[l,5-c]quinazoline 5 [4_(3-methoxy, phenyl)-1-pyrene keto-1H-imidazol-2-ylmercaptosulfane 74 201206935 yl]-2-methylbiszolo D,5&quot;]quinazolinecarbonitrile 5-(imidazo[l,2-a]pyridine_2 -ylmethylsulfanyl)_2_methyl_σ-biazo[1,5-c]啥. Selenium-1-carbonitrile 2-methyl-5-(1-methyl-1H-benzimidazol-2-ylsulfonylsulfanyl)-pyrazolo[l,5-c]quinazoline- 1-phthalonitrile 5-[4-(3-decyloxy-phenyl)methyl]imidazolium-2-ylmethylsulfanyl]-2-methyl-. Bisazo[l,5-c]quinazoline 5-[5-(3-methoxy-phenyl)_111_imidazol-2-ylmethylsulfanyl]_2-methyl-pyrazole [1,5-c]quinazoline 2-methyl-5-(quinolin-2-ylmethylsulfanylbisoxazoloquinazolin-1-indolecarbonitrile 2-mercapto-5-((1) -methyl_4-phenyl-1H-imidazol-2-yl)methylthio)pyrazolo[1,5-C]quinoxaline-1 -carbonitrile 2-methyl-5-((1- (2-morpholinylethyl)-111_benzo[(1]imidazol-2-yl)methylamyl)pyrazolo[l,5-c]quinazolininonitrile-4-(2-(2) -((2-indolylpyridinium[μ-ο]啥" sits _5_ylthio)methylΜ-phenyl-1Η-imidazole small group)ethyl)morpholine 2-mercapto-5 -(( 1-(2-morpholinoethyl)_4_phenyl-1Η-imidazol-2-yl)methanoyl)" 嗤 嗤 [1,5 · c ] 喧. sitting _ 1 - Formaldehyde: Example 2: 2-Mercapto-5-(4-phenyl-JH-imidazol-2-ylsulfanylmethyl)-indolozolo[1,5-c]pyrene 75 201206935

Stir 5-mercapto-2-methyl-pyrazolo[15^]quinazoline (173 mg, 0.9834 mm〇l) and DIPEA (379 mg, 2 94 〇1) in DMF at 60 ° C The solution in 5 mL) was used for 15 minutes. 4_Stupyl L3 dihydro-imidazole-2-thione (250 mg, 1 mmo〇) was added, and the mixture was stirred for another 4 hours at 6 ° C. After adding water (15 mL), solids were collected by filtration and Purification by preparative HPLC to give 2-mercapto-5-(4-phenyl-1-H-imidazol-2-ylsulfanylmethyl)-pyrazolo[l,5-c]quinazoline (113 mg , Yield: 31 6%). Example 3: Synthesis of 2-methyl-5-((1-methyl-4-phenyl-1 and -imidazol-2-ylthio)methyl)β-pyrazole And [l, 5_c] quinoline.

Heating 5-(gasmethyl)-2-methylpyrazolo[i,5-c]quinazoline (1 畠, 0.76 mmol), 1 methyl-4-phenylene-1,3 at 80 °C -Dihydro-m-methane-2-thione (1 equivalent of '0_76 mm〇i), decyldiisopropylamine (dip)Ea) (3 equivalents of ' 2.28 mmol) in anhydrous ch3CN (13 mL) The mixture was 3 hours. H2 hydrazine was added to the solution and extracted with CH2Cl2; the combined organic layers were dried and condensed. After purification by FC (petroleum ether / AcOEt 1:1, 2:8, AcOEt) and milling with a suitable solvent, the analytically pure product was isolated. 76 201206935 The following compounds were prepared in a similar manner: 9 - 2 ® fluorenyl _5-(1_methyl-4-phenyl-1 Η-imidazol-2-ylsulfanylmethyl)-° ratio嗤[1,5 is oxazoline, 8-chloro-2-methylindole, butyrate·5·(1-indolyl-4-phenyl-1Η-imidazol-2-ylsulfanylmethyl) _Roar. Sit and [He] quinazoline, 7-chloro-2-methyl^^τ丞'5-(1-indolyl-4-phenyl-1H-imidazol-2-ylsulfanyl)-pyrazole And [l,5-c]quinazoline, '_monomethyl-4-phenyl-1H-imidazol-2-ylsulfanyl fluorenyl)-. Bisazo[1,5^]quinazoline, fluorenyl 5-(1-indolyl-4-phenyl-1H-methane. sit-2-ylsulfanyl fluorenyl)_pyrazolopyrene, 5ι Quinazoline, 8-hydrazinyl-2-methyl_5_(1_fluorenyl-4phenyl_1H imidazolyl-2-ylsulfanylmethyl)·対[[,,,,,,,,, Methyl lactyl-2-methyl_5_(1_methyl_4_phenyl_1H 嗤 嗤 基 朴 ,, 5 外 # (4). Example 4 «成2_methyl|(2_(1_ Methyl _ heart phenyl heart is good _ azole azole · · base) B 0 than saliva [l,5-c] quinazoline 77 201206935

Under We will be helium methyl) 2 - methyl. More than saliva and ΠΧ] (4) leaching (1 equivalent of '0.95 _〇1) and triphenylphosphine (i equivalent, 〇95 _〇1) in π# [4mL) _ mixture heated for 5 hours Milling residue '_' and (iv) 'requires the desired gasification in the form of a white solid ((2 methyl hydrazine and hydrazine, 5·seat. _5_ yl) methyl) three stupid scales, which are not It can be used after characterization. Batching into a suspension of 60% NaH mineral, mountain, and f丄feed oil solution (1_1 equivalent, 0.88 〇1) in Qing (4mL) cooled to -5C Add the scale (1, quantity, ο.% touch and mix the obtained yellow solution at the same temperature for 3 〇 second field. Add 1-F-based 4-phenyl-丨^imidazole_2, 丄τ Acid (1 eq., 0.76 mmol) and the mixture was stirred at room temperature for 1.5 hours. The whole material was poured onto H20, extracted with &lt;RTI ID=0.0&gt; Ether/Ac〇Et 6:4, 1:1 ACUfit) Purified Residues' gave the pure product as a yellow solid. (6)_2_Methyl_5_(2(1_A) at 45 psi at room temperature Base 4 phenyl 78 201206935 -177-flavor-2-yl)vinyl)pyrazole The mixture of quinazoline (1 eq., 〇76 mmol) and 10% Pd/C (0.1 eq., 0.071 mmol) in THF (35 mL) was hydrogenated for 6 s. The suspension was filtered over Celite® and concentrated. (Petroleum ether / Ac〇Et 1:1, 2:8, AcOEt) Purified and ground with AcOEt, the analytically pure product was isolated. The following compounds were prepared in a similar manner: thiol-5-[2-(1_甲甲Phenyl-1H-imidazole-2-yl)-ethyl]-pyrazolo[l,5-c] quinazoline, 9-chloro-2-indolyl_5-[2-(1-methyl _4_Phenyl-.all-2-yl)-ethyl]-.Bizozolo[1,5-c]quinazoline, 7-chloro-2-methylmethyl_4'phenyl·1Η- _ ° sit -2 -yl)-ethyl]-° than saliva and [1,5 -c] 啥 saliva. Lin, 2,9-dimethyl_5_[2, (bu methyl-4_phenyl_1 】Xinmi ton_2_yl)·ethyl]-° than salivation [l,5-c]quinazoline, · 7_decyloxy-2-methyl_5_[2-(1-mercapto -4-phenyl-1H-imidazol-2-yl)-ethyl l·11-pyrazolo[l,5-c]quinazoline, 8_decyloxy-2-methyl_5-[2- (卜曱基_4-phenyl-1H-imidon-2-yl)-ethyl]pyrazolo[l,5-c]quinoxaline, 9-methoxy-2-indenyl_5_[2- (Bu methyl-4-phenyl_1Η·imidazol-2-yl)_ethyl ratio And [l,5-c]quinazoline, 8_gas-2_mercapto_5_[2 (]_-methyl-4-phenyl]1Η-口米嗤_2·yl)-ethyl] - Sit more than 0 and [l,5_c]嗤嗤, 2,7-dimethyl _4_phenyl-1Ιί-imidazole-2·yl)_ethyl]_pyrazolo[l,5-c Quinazoline. 79 201206935 Example 5: Analytical chemical data for exemplified compounds Table 1: Analysis of exemplified compounds Chemical characterization PDE10A Inhibitor number Chemical name Retention time UV-purity (%) ELSD-purity (%) MS M+H+ 1 5-( Benzothiazol-2-ylmercaptosulfanyl)-9-bromo-2-indolyl-[1,2,4]triazolo[1,5-c]quinazoline 1.83 98.41 100 441.97 2 5- (1Η-benzoimidazol-2-ylmethylsulfanyl)-9-indol-2-methyl-[1,2,4]triazolo[1,5-c]quinazoline 0.87 91.35 100 425.01 3 5-(1Η-Benzimidazol-2-ylmethylsulfanyl)-2-methyl-[1,2,4]triazolo[l,5-c]quinazoline 0.67 100 100 347.10 4 2-mercapto-5-(1-methyl-4-phenyl-1H-imidazol-2-ylmethylsulfanyl)-[1,2,4]triazolo[l,5-c]quina Zoline 0.81 96 100 387.13 5 5-(1 H-benzoimidazol-2-ylmethylsulfanyl)-9-fluoro-2-methyl-[1,2,4]triazolo[l,5 -c]quinazoline 0.75 99 100 365.09 6 5-(1Η-benzoimidazol-2-ylmethylsulfanyl)-8-gas-2-methyl-[1,2,4]triazolo[ l,5-c]quinazoline 0.82 91 100 381.06 7 5-(benzoxazol-2-ylmethylsulfanyl)-2-methyl-[1,2,4]triazolo[l, 5-c]quinazoline 0.79 100 100 348.08 8 5_(Imidazo[l,2-a]pyrimidin-2-ylmercaptosulfanyl)-2-methyl-[1,2,4]triazolo[l,5-c]quinazoline 0.41 100 100 348.10 9 2-Methyl-5-(1-methyl-1H-benzimidazol-2-ylmercaptosulfanyl)-[1,2,4]triazolo[1,5-c Quinazoline 0.71 96 98 361.12 10 2-methyl-5-(quinolin-2-ylmercaptosulfanyl)-[1,2,4]triazolo[l,5-c]quinazoline Porphyrin 1.04 100 100 358.10 11 5-(imidazo[1,2-a]pyridin-2-ylmercaptosulfanyl)-2-methyl-[1,2,4]triazolo[l,5- c] quinazoline 0.63 100 100 347.10 12 5-(imidazo[1,2-b]indolin-2-ylmercaptosulfanyl)-2-methyl-[1,2,4]triazole [1,5-c]quinazoline 0.84 100 100 348.10 13 5-[4-(2-Gas-phenyl)-1-methyl-1H-imidazol-2-ylmethylsulfanyl]-2- Mercapto-[1,2,4]triazole and 0.89 94 100 421.09 14 5-[4-(3-decyloxy-phenyl)-1-methyl-1H-imidazol-2-ylmethylsulfane 2-methyl-[I,2,4]triazolo[l,5-c]quine. Sitting on a 0.85 98 100 417.14 15 5-[4-(4-methoxy-phenyl)-1-methyl-1H-imidazol-2-ylmethylsulfanyl]-2-methyl-[1, 2,4] Triazolo[l,5-c]°t. Sitting Lin 0.83 92 100 417.14 16 5-[4-(2-Fluoro-phenyl)-1 -methyl-1H-imidazol-2-ylmethylsulfanyl]-2-methyl-[1,2, 4] Triazolo[l,5-c]喧峻琳0.86 97 100 405.12 80 201206935 17 5-(imidazo-p,1-b]thiazol-6-ylmethylsulfanyl)-2-methyl- [1,2,4]triazolo[l,5-c]quinazoline 2.565 100 99.5 353.06 18 5-(imidazo[2,1 -b] [ 1,3,4]thiadiazole-6- Mercaptosulfanyl)-2-methyl-[1,2,4]triazolo[l,5-c] °i. sit.林1.02 100 100 354.05 19 2-Methyl-5-(3H-thieno[3,4-d]mi. sit-2-ylmethylsulfanyl)-[1,2,4]triazolo[ l,5-c] quinazole 2.43 97.6 95.95 353.06 20 5-(imidazo[1,2-a]pyridin-2-ylmethylsulfanyl)-2-mercaptobiszolo[l,5- c] quinazoline 0.84 ΊΊ 99 346.10 21 2-methyl-5-(4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-° ratio °[1,5-c]喧° Sitting Lin 2.509 98 100 372.12 22 2-methyl-5-(quinolin-2-ylmercaptosulfanyl)-pyrazolo[1,5-c] quinazole.林2.793 100 100 357.11 23 5-(imidazo[1,2-a]pyrimidin-2-ylmethylsulfanyl)-2-mercapto-D is more than saliva [l,5-c]°t嗤琳2.704 100 100 347.10 24 5-(1Η-Benzimidazol-2-ylmercaptosulfanyl)-2-indenylpyranyl[l,5-c]〇i·»坐琳2.513 99.306 98.153 346.10 25 2-mercapto-5-(1-methyl-1H-benzimidazol-2-ylmethylsulfanyl)-pyrazole[l,5-c]quinazoline 2.61 97.889 100 360.12 26 2- Methyl-5-(1-indolyl-4-phenyl-1H-imidazol-2-ylmercaptosulfanyl)-pyrazolo[l,5-c]quinazoline 2.755 98.193 98.821 386.14 27 V 5 -[4-(3-methoxy-phenyl)-1-methyl-1H-imidazol-2-ylindenylthiophene]-2-indenyl-σ ratio σ sits together; [l,5- c] quinquin.坐琳-1-carbonitrile 2.775 98.904 100 441.14 28 5-(imidazo[1,2-a]acridin-2-ylmethylsulfane;:yl)-2-mercapto-pyrazolo[l, 5-c]quinazoline-1-indolecarbonitrile 2.839 99.164 98.296 371.10 29 2-mercapto-5-(1-indolyl-1H-benzimidazol-2-ylmethylsulfanyl)-pyrazole [1,5-c]quinazoline-1-carbonitrile 2.608 99.609 96.808 385.12 30 5-[4-(3-decyloxy-phenyl)-1-methyl-1H-imidazol-2-ylindenyl Sulfur-based]-2-mercapto-° ratio l[l,5-c]°t嗤琳 2.761 96.369 100 416.15 31 5-[5-(3-methoxy-phenyl)-1Η-imidazole- 2-ylsulfanylmethyl]-2-methylpyrazolo[l,5-c]quinazoline 2.559 100 100 402.13 32 5-[5-(3-decyloxy-phenyl)-1Η- Imidazol-2-ylmercaptosulfanyl]-2-methyl-pyrazolo[l,5-c]quinazoline 2.709 95.315 98.853 402.13 33 2-methyl-5-(quinolin-2-ylmethyl) Alkylthioalkyl)-&quot;Bizozolo[1,5-c]喧. '' 曱 曱 曱 0.9 0.92 99 100 382.10 34 2-methyl-5-((1-methyl-4-phenyl-1H-imidazol-2-yl) sulfoximine) ° carbazole [l ,5-c]quinazoline-1-indolecarbonitrile 2.71 99.25 95.22 411.13 35 2-methyl-5-((1-(2-morpholinoethyl)-1Η-benzo[d]imidazole-2- Base) methylthio). Bisazo[1,5-c]quinoxaline-1-indolonitrile 2.31 95.97 99.44 484.18 81 201206935 36 4-(2-(2-(2-mercaptopyrazolo[1,5-c]quina Oxazolin-5-ylthio)indolyl-4-phenyl-1H-imidazol-1-yl)ethyl)line 2.44 96.11 100 485.20 37 2-methyl-5-((1-(2- Morpholinylethyl)-4-phenyl-1H-imidazol-2-yl)methylthio)"pyrazolo[l,5-c]quinazoline-1-carbonitrile 2.51 96.74 100 510.20 38 2_ Methyl-5-(1-methylphenylphenyl-1H-pyrazole-2·ylsulfanylmethyl)-pyrazolo[l,5-c]quinazoline 1.1 97 100 386.14 39 9-chloro -2-methyl-5-(1-methyl-4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-pyrazolo[l,5-c]quinazoline 1.34 96.9 100 420.10 40 8-oxo-2-methyl-5-(1-methyl-4-phenyl-1H-imidazol-2-ylsulfanyl)-pyrazolo[l,5-c]quinazoline 1.3 95.6 100 420.10 41 7-Gas-2-methyl-5-(1-indolyl-4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-pyrazolo[l,5-c Quinazoline 1.18 99.2 100 420.10 42 2,9-Dimethyl-5-(1-indolyl-4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-pyrazolo[l, 5-c]quinazoline 1.23 99.1 100 400.15 43 2,7-Dimethyl-5-(1-indolyl-4-phenyl-1H-imidazole-2- Thioalkylmethyl)-pyrazolo[1,5-c]quinazoline 1.29 98.3 100 400.15 44 8-methoxy-2-indolyl-5-(1-methyl-4-phenyl-1H -Imidazolyl-2-ylsulfanyl fluorenyl)-&quot;Bizozolo[1,5-c]quine. sit. Lin 1.16 96.8 100 416.15 45 7-Methoxy-2-mercapto-5-(1-indolyl-4-phenyl-1H-imidazol-2-ylsulfanyl)-&gt; 1,5-c] quinine.圭琳1.06 99.3 100 416.15 46 2-Methyl-5-[2-(l-indolyl-4-phenyl-1H-imidazol-2-yl)-ethyl]--pyrazole[l,5- c] quinazoline 1.09 97.8 100 368.18 47 9-Ga-2-methyl-5-[2-(l-methyl-4-phenyl-1H-methane-2-yl-2-yl)-ethyl]- ° Sit and sit [l,5-c]嗤°. Lin 1.26 95.1 100 402.14 48 7-Gas-2-methyl-5-[2-(l-indolyl-4-phenyl-1H-methane-2-yl-2-yl)-ethyl] ratio. Sit and [l,5-c]°t° sitting 1.14 98.3 100 402.14 49 2,9-Dimethyl-5·[2-(1-methyl-4-phenyl-1H-咪0 sitting-2 -yl)-ethyl] ratio. Sit and sit [l,5-c]°t°. Lin 1.2 98.9 100 382.20 50 7-decyloxy-2-methyl-5-[2-(l-fluorenyl-4-phenyl-1H-imidazol-2-yl)-ethyl]- tt oxazole [l,5-c] quinine. sit. Lin 1.1 99.5 100 398.19 51 8-Methoxy-2-methyl-5-[2-(l-indolyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-. Bisazo[1,5-c]quine.坐琳 1.1 97.9 100 398.19 52 9-Methoxy-2-methyl-5-[2-(l-indolyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-. Bisazo[1,5-c]quine. Sitting leaching 1.3 98.3 100 398.19 53 8-gas-2-methyl-5-[2-(l-mercapto-4-phenyl-1H-methane. sit-2-yl)-ethyl] l,5-c]°|:° sitting 1.42 90.2 100 402.14 54 2,7-Dimethyl-5-[2-(l-methyl-4-phenyl-1H-imidazol-2-yl)- Ethyl]-β-pyrazolo[1,5-c]quine. Sitting Lin 1.4 99.5 100 382.20 82 201206935 Pharmacological Testing PDE10A Enzymes Active PDE1 0A enzymes can be prepared in a variety of ways for pde assays (Loughney, K. et al. Gene 1999, 234, 109-117; Fujishige, κ et al. Eur J Biochem. 1999, 266, 1118-1127 and Soderling, s. et al. Proc. Natl. Acad. Sci. 1999, 96, 7071-7076). PDE1〇a can be expressed as a full-length protein or a truncated protein as long as it exhibits a catalytic domain. PDE 10A can be prepared in different cell types, such as insect cells or E. coli. In the context of the present invention, a catalytically active PDE 1 〇A enzyme is prepared by amplifying the catalytic domain of human PDE10A from total human brain total rnA by standard RT-PCR (from accession number NP 006652) Amino acid 4:40-779) and colonized into the BamHl and XhO::vl sites of the pET28a vector (Novagen). Performance was performed in E. coli according to standard protocols. Briefly, the expression plasmid was transformed into the BL21(DE3) E. coli strain, and the 50 mL culture inoculated with the cells was allowed to grow to OD600 of 〇.4-〇.6, followed by induction of protein expression with 0.5 mM IPTG. After the induction, the cells were cultured overnight at room temperature, and then the cells were collected by centrifugation. The cells expressing PDE 10 A were resuspended in 12 mL (50 mM TRIS-HCl-pH 8.0, 1 mM MgCl2 and protease inhibitor). After dissolving the cells by sonication and dissolving all the cells, TritonXIOO was added according to the Novagen protocol. PDE10A was partially purified on Q Sepharose and the most active fraction was mixed. PDE10A inhibition assay in PDE10A and 83 201206935 containing enough to convert 20-25% 1〇 nM 3H-cAMP

PDE10A inhibition assay was performed in 60 pL assay buffer (50 mM HEPES (pH 7.6); 10 mM MgCl2; 0.02% Tween20) with different inhibitors. The reaction is initiated by the addition of a cyclic nucleotide. After incubation for t hours at room temperature, the reaction was stopped by the addition of 15 μί 8 mg/mL citrate SPA beads (Amersham), allowing the beads to settle in the dark for one hour, followed by a Wallac ICO Microbeta counter. Board count. The IC50 value was calculated using XLfit (IDBS) by non-linear regression. The experimental results show that the test compound of the present invention inhibits PDE i 〇A enzyme with an IC5q value of about 15 nM to 730 nM, see Table 2: Table 2: IC50 value of the exemplified compound of the present invention (ND· means "undetected" PDE10A Inhibitor No. 1 Chemical Name 5·(本和°°0坐-2-ylmethylthioalkyl)-9-Methyl-2-methyl-[1,2,4]三嗤和fi 5- Cl〇$· oxazoline, j PDE10A IC50 (nM) ND 2 5-(1 Η- 本 〇 。. sit-2-ylmercaptothiol)-9-bromo-2-methyl-[1, 2,4]三嗤养[l,5-c] quetialine 44 3 5-(1Η-benzimidazol-2-ylmethylsulfanyl)·2-mercapto-[1,2,4] Triazoloindole 1 5-cloxazoline* J £ 10 4 2-methyl-5-(1-methyl-4-phenyl_1H-m-[sodium-2-ylmethylsulfanyl) [ι,2,4]Trisporin [l,5-c]quinoxaline 130 5 5-(1Η-benzoimidazol-2-ylmethylsulfanyl)-9-fluoro-2-methyl- [1,2,41 =oxazolium [l,5-c:|quinazoline liter 130 6 5-(1Η-benzimidazolylmethylsulfanyl)-8-gas-2-methyl-[1 , 2,4]Three "Shen and [l,5-c]quinazoline 120 7 (benzoxazol-2-ylmethylsulfanyl)-2-methyl-oxime, 2,41 = azole And fl, 5-clazole. Also 84 8 5-(imidazo[1,2-a]pyrimidin-2-ylmethylsulfanyl)-2-methyl-[1,2,4]triazolo[l,5-c] Oxazoline 27 9 2-methyl-5-(1-methyl-1H-benzoimidazol-2-ylmethylsulfanyl)-[1,2,4]triazolo[l,5-c ]oxazoline 17 10 2-methyl-5-(quinolin-2-ylmethylsulfanyl)-[1,2,41 triazole and 1,1,5-cl quinazolyl 24 11 5-( Imidazo[1,2-a]pyridin-2-ylmercaptosulfanyl)-2-methyl-[1,2,4]triazolo[l,5-c]quinazoline 15 84 201206935 12 5-(imidazo[1,2-b]indole-2-ylmethylsulfanyl)-2-.methyl-[1,2,4]triazolo[1,5-(;]喧°坐琳44 13 5-[4-(2-Ga-phenyl)-1-indolyl-1H-imidazol-2-ylmethylsulfanyl]-2-methyl-[1,2,4] Trisporin [l,5-c]啥峻琳260 14 5-[4-(3-methoxy-phenyl)-1-indolyl-1H-imidazol-2-ylmethylsulfanyl]- 2-methyl-[1,2,4]triazolo[1,5-(:]quinazoline 100 15 5-[4-(4-methoxy-phenyl)-1-methyl-1H -imidazol-2-ylmethylsulfanyl]-2-methyl-[1,2,4]triazolo[1,5- quinazoline 82 16 5-[4-(2-l-benzene ))-1-methyl-1H-imidazol-2-ylmethylsulfanyl]-2-mercapto-[1,2,4] three-degree sitting[lj-c]'»!·'1 sit Lynn 9 9 17 5-(Imidazo[2,1-b]thiazol-6-ylmercaptosulfanyl)-2-mercapto-[1,2,4]triazolo[l,5-c]indole.坐琳130 18 5-(Imidazo[2,1-7][1,3,4]thiadiazol-6-ylmethylsulfanyl)-2-mercapto-[1,2,4]triterpenoid And [l,5-c]喧嗤琳210 19 2-methyl-5-(3H-thieno[3,4-d]imidazol-2-ylmercaptosulfanyl)-[1,2,4 Triazolo[1,5-〇]喧. Sit. Lin 100 20 5-(imidazo[l,2-a].pyridin-2-ylmethylsulfanyl)-2-methylpyrazole And [l,5-c] quinazoline 630 21 2-methyl-5-(4-phenyl-1H-imidazol-2-ylsulfanyl)-pyrazolo[l,5-c] Quinazoline 67 22 2-methyl-5-(quinolin-2-ylmercaptosulfanyl)-pyrazole[1,5-c]quinazoline 470 23 5-(imidazo[1, 2-a]pyrimidin-2-ylmethylsulfanyl)-2-methyl-oxazolo[1,5-c]quinazoline 750 24, 5-(1Η-benzimidazol-2-yl Methylsulfanyl)-2-mercapto-pyrazolo[1,5-c]quinazoline 370 25 2-methyl-5-(1-methyl-1H-benzimidazole-2-ylmethyl Pyrithione-pyrazolo[l,5-c]quine.坐琳440 26 2-Methyl-5-(1-methyl-4-phenyl-1H-imidazol-2-ylmercaptosulfanyl)-pyrazolo[1,5-c] 92 27 5- [4-(3-Methoxy-phenyl)-1-indolyl-1H-imidazol-2-ylmethylsulfanyl]-2-methyl ratio ° sit and [1,5-c] ° ° sit '#-1 -phthalonitrile 160 28 5-(imidazo[1,2-aptbpyridine-2-ylmercaptosulfanyl)-2-mercaptobiszolo[l,5-c] quinazole曱-1-曱carbonitrile 21 29 2-mercapto-5-(1-methyl-1H-benzimidazol-2-ylmethylsulfanyl)-&quot;Bizozolo[l,5-c]quina ° sitin-1-carbonitrile 28 30 5-[4-(3-methoxy-phenyl) benzhydryl-1H-imidazol-2-ylmethylsulfanyl]-2-methyl than α And [1,5-c]啥° sit 'lead 310 31 5-[5_(3-曱oxy-phenyl)-1Η-imidazol-2-ylsulfanylmethyl]-2-methylpyrazole And [l,5-c]嗤°坐琳 140 32 5-[5-(3-曱-oxy-phenyl)-1Η-imidazol-2-ylindenylsulfanyl]-2-indenyl-anthracene Oxazolo[1,5-〇]喧°坐琳90 33 2-mercapto-5-(quinolin-2-ylmercaptosulfanyl)-·&gt;biazolo[1,5-c]quina Oxaline-1 -carbonitrile ND 85 201206935 34 2 sit ^ base · 5- ((1-methyl-4-phenyl-1 Η- ° m "sit-2-yl) sulfhydryl)" than 嗤 [ i,5-c]〇^ 100 35 heart methyl·5_(( 1 -(2-? Benzyl)-1 Η-benzo[d]imidazol-2-yl)methylthio)pyrazoloindole,5-cl quinazoline_ι_carbonitrile 210 36 4-(2·(2- ((2-Mercapto-biazolo[l,5-c]quinazolin-5-ylthio)indolyl)-4-phenyl·ιη-carbazol-1-yl)ethyl)morpholine 7.9 37 2-Methyl-5-((1-(2-morphinylethyl)-4-phenyl-1Η-flavored salin-2-yl)methylthio)*»比嗤[l,5 -cl quinazolin-1-indene nitrile 16 38 2·fluorenyl·5-(1-methyl·4_phenyl-1H-imidazol-2-ylsulfanyl fluorenyl)-0-pyrazole[15_c ] °^. Sit 1^^· 45 39 9-Gas-2-methyl-5-(1-methyl-4-phenyl-1H-imidazol-2-ylsulfanyl)-pyrazolo[l,5 -cM 琳琳48 40 8-Ga-2-indyl-5-(1-methyl-4-phenyl-1H-imidazol-2-ylthioalkyl)-«Bizozolo[l,5 -cl quinones 110 41 7-gas-2-mercapto-5-(1-mercapto-4-phenyl-1 Η-° m. sit-2-ylthioalkyl thiol)-*» than wow And [l,5-cl〇|:嗤琳73 42 2,9-dimercapto-5-(1-methyl-4-phenyl-1H-mimi&quot; sit-2-ylthioalkyl sulfhydryl )-&quot; than saliva [l,5-cl quinazoline 76 43 2,7-dimercapto-5-(1-methyl-4-phenyl-1H-imidazol-2-ylsulfanyl) Base)··Bizozolo[l,5-cl quinazoline 160 44 8-methoxy-2-methyl-5-(1-methyl-4-phenyl-1Η-σ米. Sit-2 -ylthioxylmethyl)-β is 嗤[l,5_c]噎 噎 100 45 7-methoxy-2-mercapto-5-(1-methyl-4-phenyl-1H-imidazole -2-ylsulfanylmethyl)-. Butyrazole &lt; l,5-cl quinazoline 83 46 2·methyl·5·[2-(1-indolylphenyl-1H-imidazol-2-yl)-ethyl]-indoleazole [l,5-c]quinoline 50 47 9-gas-2-methyl-5-[2-(l-methyl-4-phenyl-1H.m..sup.2-yl)-ethyl] Sit and [l,5-cl quinazoline 16 48 7-gas-2-methyli-5-[2-(l-fluorenyl-4-phenyl-1H-imidazol-2-yl)-B ]]-pyrazolo[l,5-cMoxaline 52 49 2,9-monodecyl·5-[2·(1-methyl-4-phenyl-1H-W-sodium-2-yl) -ethyl]-° ratio °[1,5-cl quinazoline 16 50 7-methoxy-2-methyl-5-[2-(l-methyl-4-phenyl-1H- Imidazol-2-yl)-ethyl]-pyrazolo[l,5-cl quinazoline 37 51 8-methoxy-2-methyl-5-[2-(l-methyl-4-benzene) -1H-imidazol-2-yl)-ethyl]-pyrazolo[l,5-c quinazoline 31 52 9-methoxy-2-indolyl-5-[2-(l-methyl- 4-phenyl-1H-imidazol-2-yl)-ethyl]pyrazole[l,5-c]°°°Shen-Lin 430 53 8-Ga-2-methyl-5-[2-( L-Methyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-0-pyrazolo[l,5-c] quinazole.林50 54 2,7-Dimercapto-5-[2-(l-indolyl-4-phenyl-1H-imidazol-2-yl)-ethyl]-0-pyrazolo[l,5-c ]quinazoline 78 86 201206935 [Simple description of the diagram] No [Main component symbol description] No 87

Claims (1)

201206935 VII. Patent application scope: 1. A compound, Wherein R1 to R4 are selected from the group consisting of: H; cic6 alkyl, such as fluorenyl; halogen, such as gas and cyano; cyano; (6) is an alkyl group, such as trifluoromethyl; aryl 'such as phenyl; Alkoxy groups such as methoxy, dimethoxy, ethoxy, decyloxy-ethoxy and ethoxylated oxime and C1-C6 hydroxyalkyl, such as (: Η20ϋ2〇ίΙ; and wherein The oxime is selected from the group consisting of N, CH or C_CN; and wherein het is selected from the group consisting of: Wherein R5 and R6 are individually selected from the group consisting of C1_C6 88 201206935 alkyl such as decyl, ethyl, propyl, 2-propyl, isobutyl, n-butyl, t-butyl or tert-butyl H; C1C6 alkyl (c3_c8) cycloalkyl, such as cyclopropyl fluorenyl; C1. hydroxyalkyl, such as hydroxyethyl; CH2CN; CH2C(0)NH2; C1-C6 arylalkyl, such as benzene Methyl and 4-chlorobenzyl; and C1-C6 alkyl·heterocycloalkyl, such as tetrahydropyran-4-ylmethyl and 2-norlin-4-yl-ethyl; and wherein R7 -R11 is selected from the group consisting of H; ci_c6 alkoxy such as methoxy; and dentate such as chlorine or fluorine; and wherein L is a linking group selected from the group consisting of -CH2- CH2-, -S-CH2-, and -CH2-S-; and tautomers thereof and pharmaceutically acceptable acid addition salts. The compound of claim 1 wherein the linking group (L) is -CH2-CH2-. The compound of any one of clause 1 or 2, wherein the het is selected from the group consisting of: and _ 1 9 RR R8 • A compound according to claim 1 which is selected from the group consisting of 5-(benzothiazolyl-2-ylmethylsulfanyl)_9_bromo-2-methyl-triazole And [l,5-c]quinazoline; 5_(1H_benzimidazol-2-ylmethylsulfanyl)_9_bromomethyl-[1,2,4]diazoloquinazoline; 5_ (1H-benzimidazole 2 base 89 201206935 methylthioalkyl)-2 -methyl-[1,2,4]triazino[l,5-c]°i:.坐琳; 2-methyl-5-(1-methyl-4-phenyl-1H-imidazol-2-ylmercaptosulfanyl)-[1,2,4]triazolo[l,5- c] quinazoline; 5-(1Η-benzoimidazol-2-ylmethylsulfanyl)-9-fluoro-2-methyl-[1,2,4]triazolo[1,5-c Quinazoline; 5-(1Η-benzoimidazole-2-ylmercaptosulfanyl)-8-a-2-indolyl-[1,2,4]triazolo[l,5-c] Quinazoline; 5-(benzoxazol-2-ylmercaptosulfanyl)-2-indenyl-[1,2,4]triazolo[l,5-c]quinazoline; 5- (Imidazo[l,2-a]pyrimidin-2-ylmethylsulfanyl)-2-methyl-[1,2,4] triwax[l,5-c]quinazoline; 2- Mercapto-5-(1-indolyl-1H-benzimidazol-2-ylmercaptosulfanyl)-[1,2,4]triazolo[l,5-c]quinazoline; 2- Mercapto- 5-(quinoline-2-ylmercaptothiol)-[1,2,4]triazino[l,5-c]啥嗤琳; 5-(asthmatic sitting and [1, 2-&amp;]0 is determined by _2-ylmethylthioalkyl)_2-fluorenyl-[1,2,4]triazino[1,5-(:] 啥 porphyrin, 5-(imidazole And [l,2-b]morphin-2-ylmercaptosulfanyl)_2-methyl-[1,2,4]triazolo[l,5-c]quinazoline; 5-[4 -(2- gas-phenyl)_1_indenyl·ιη_imidazol-2-ylmethylsulfanyl]-2-mercapto-[1,2,4]triazolo[i , 5-c]quinazoline; 5-[4-(3-methoxy-phenyl)-1-methyl-1H-imidazol-2-ylsulfonylthiol]·2-methyl-[ I,2,4]triazolo[l,5-c]quinazoline; 5-[4-(4-decyloxy-phenyl)-1_methyl-1Η-imidazol-2-ylindenyl sulfide Alkyl]-2-methyltriazoloquinazoline; 5-[4-(2-fluoro-phenyl)-didecyl-1H-imidazolylsulfonyl]-2-methyl-[1, 2,4]triazolo[l,5-c]quinazoline; 5_(imidazo[2,]^] And [l,2-a]pyridin-2-ylmethylsulfanyl)_2-methyl-. Ratio _cj oxazoline; 5-(flavored salicillin [l,5-c] quinazole 201206935 porphyrin; 2-mercapto-5-(4-phenyl-1H-imidazol-2-yl sulane Methyl)-pyrazolo[l,5-c] quinazoline; 2·•indolyl-5-(quinolin-2-ylmethylthioalkyl)-pyrazolo[l,5-c Quinazoline; 5-(imidazo[l,2-a]pyrimidin-2-ylmercaptosulfanyl)-2-methylbisazoloquinazoline;5·(1Η_benzimidazole_2 _ylmethylsulfanyl)-2-methyl-η-pyrazolo[l,5-c]quinazoline; 2-methyl-5-(1-methyl-1Η-benzimidazole-2- Methylsulfanyl)-pyrazolo[i,5-c]quinazoline; 2-methyl-5-(1-methyl-4-phenyl-1H-imidazol-2-ylmethylsulfanyl )_pyrazolo[ij-c] 嗤.Shenlin; 5-[4-(3-methoxy-phenyl)-1-indenyl-1H-imidazole-2-ylmethylsulfanyl]- 2-methyl-pyrazolo[l,5-c]quinazoline-1·carbonitrile; 5-(imidazo[12-a]pyridin-2-ylmethylsulfanyl)_2-mercapto-pyridyl Zymbly n,5_c]quinazolinecarbonitrile; 2-methyl-5-(1-methyl-1H-benzimidazole-2-ylmethylsulfanyl)-pyrazolo[l,5-c Quinazoline-1-indene nitrile; 5-[4-(3-decyloxy-phenyl)_ι_indenyl-1H_imidazole-.2-ylmercaptosulfanyl]_2-methyl-pyrazole ,, ... oxazoline; 5-[5-(cyclomethoxy-phenyl)·ιη-imidazolylsulfanylmethyl]_2-fluorenyl-pyrazolo[l,5-c] quinazoline Porphyrin; 5-indole (3-methoxy-benzimidazole-2-ylsulfonylsulfanyl]-2-mercapto-pyrazolo[u-c]quinazoline; 2-methyl-5-(quinoline) _2_ mercaptosulfanyl)-pyrazolo[l,5-c]quinazolinonitrile nitrile; 2methylmercapto-4-phenyl]H-imidazolyl)methylthio)pyrazoloquinazoline ]_ 曱carbonitrile '2-methyl _5·((1_(2_morpholinoethyl)_1H benzo(4) oxazolyl) 曱 thiol 嗤[Uc] 喧嗤 小 small carbonitrile; 4 ( 2_(2_((2_methyl^and[l,5-c]quinazoline-5-ylthio)methyl)_4phenyl-ih imidazolyl)ethyl)morpholine; 2-methyl -5_((1·(2-morpholinoethyl)·4·phenyl_ih-s-zol-2-yl)methylthio) 吼 并[l,5_c]喧 琳 _ _ _ carbonitrile; 2_ Methyl _5-7-methyl-4-phenyl-1H-imidazolium-2-ylsulfanylmethyl)_d-pyrazolo[Myoxazoline^ 91 201206935 9-Ga-2-indole _5_( 1-mercapto_4_phenyl_m_imidazolyl-2-ylsulfanyl)-pyrazolo[1,5-&lt;:]quinazoline; 8-gas-2-mercapto-5- (1-methyl-4-phenyl-1H-methane-based thiolmethyl)-pyrazole [l,5-c]quinazoline; 7-gas-2-methyl-5-(1-methyl-4-phenyl_1H-imidazol-2-ylsulfanylalkyl)_D-pyrazole [i,5_c] 啥°坐琳, 2,9-dimethyl_5-(l-methyl-4-phenyl-1H-imidazol-2-ylsulfanyl)-pyrazole, n, 5_c] quinazoline; 2,7-dimethyl-5-(1-methyl-4-phenyl-1H-imidazolyl-2-ylsulfanylalkyl)-pyrazolo[i,5-c]quina Oxazoline; 8-methoxy-2-methyl-5-(1-methyl-4-phenyl-1-H-imidazol-2-ylsulfanylthiopyrazolo-U'5-c] quinazoline Porphyrin; 7·decyloxy_2_methyl_5_(1_fluorenyl_4_phenyl_1H imidazol-2-ylsulfanylmethyl)-pyrazoloquinazoline; 2_mercaptopurine 4-phenyl·ιΗ·imidazole_2_yl)-ethyl]-pyrazolo[匕^...quinazoline; 9_gas-2-.methyl-5-[2-(1-indenyl) _4-Phenyl-1 Η-imidazol-2-yl)-ethyl]-pyrazole, 5-0] quinazoline; 7-chloro-2-methyl-5-[2-(1-methyl 4-phenyl-1H-imidazole 2-yl)-ethyl]-pyrazolo[l,5-c]quinazoline; 2,9-dimethyl-5-[2-(1-methyl) 4-Bundle-1Η-imidazole_2_yl)-ethyl]-pyrazolo[丨,5_c]carbazole. 7; methoxy 2_indolyl 5-[2-(1-methyl-4(phenyl)-i-imidazol-2-yl)-ethyl]-α-pyrazolo[l,5-c a quinazoline; 8-methoxy-2-indolyl_5_[2(1_methyl_4_phenyl.ιη_imidazolylethyl)pyrazolo[l,5-c]quinazoline; 9-decyloxy-2-methyl-%[2-(l-nonylphenyl_1H-imidazol-2-yl)-ethyl]-pyrazolo[丨,5 c]quinazoline; 8- Gas-2-methyl_5·[2_(1_fluorenyl_4_phenyl_1H_imidazol-2-yl)-ethyl]-[p-azolo[l,5-c]quinazoline; , 7-Dimethyl-5-[2-(1- mercapto-4-phenylimidazol-2-yl)-ethyl]-pyrazolo[i,5-c]quinazoline. A compound of claim 1 which is selected from the group consisting of 5-(1Η-benzimidazole_2-ylmercaptosulfanyl)_2•indolyl_[12,4]triazole 92 201206935 and [l,5-c]quinazoline,·5_(imidazo[nj-a]pyrimidin-2-ylsulfonylsulfanyl)_2_indolyl-[1,2,4]triazolo[15-c] Quinazoline; 2._methyl_5 (lf-based _ih benzimidazol-2-ylmethylsulfanyl)-indole, 2,4]triazoloquinazoline; 2 methyl-5-( Quinoline-2-ylmethylsulfanyl H1,2,4]triazolo[^-^ quinazoline; 5-(imidazo[l,2-a]acridin-2-ylmethyl Alkyl)-2_methyl_π,2,4]triazolo[l,5-c]quinazoline; 5-(imidazo[l,2_a]pyridin-2-ylmethylsulfanyl) _2_Methyl-pyrazolon,5-C]quinazoline-indole-carbonitrile; 2-methyl_5_(1methyl-1H_benzimidazol-2-ylmethylsulfanyl)-pyrazole And fl,5_c]quinazoline_丨_carbonitrile; 4-(2-(2-(2-methylpyrazoloindole, 5-c)quinazoline·5-ylthio)methyl 4-phenyl-1H-imidazol-1-yl)ethyl)morpholine; 2-methyl_5_((Bu(2morpholinoethyl)-4-phenyl-1H-imidazol-2-yl) )methylthio)pyrazolon,5-c]quinazoline]-carbonitrile, 9-chloro-2-methyl-5-[2-(l-methyl_4_phenyl-1H-imidazole_2 _yl)-ethyl]-pyrazolo[l,5-c]quinazoline; and 2,9-dimethyl_5_[2_(1_methyl-4phenylimidazol-2-yl)- Ethyl]-oxazoloquinazoline. 6. A compound according to any one of claims 1 to 5, which is used as a pharmaceutical. 7. If the scope of patent application is from items 1 to 5 A compound according to any one of the compounds for use in the treatment of a neurodegenerative disorder or a psychiatric disorder, alone or in combination with one or more neuroleptics selected from the group consisting of: sertindole Olanzapine, rispeHd〇ne, quetiapine, aripiprazrazol, haloperidol, ci〇zapine , ziprasidone and osanetant, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimeris disease, multiple infarctions 93 201206935 dementia, alcohol Dementia caused by toxic dementia or other drug-related dementia, dementia associated with intracranial tumor or brain trauma, dementia associated with Huntingt〇nis disease or Parkinson's disease (Parkins〇n, s(1) “coffee” or a (d);谵妄; amnestic dis〇rder; post-traumatic stress disorder; mental retardation; learning disabilities such as dyslexia, mathematical disorders or written expression disorders;; lack of mind/hyperactivity; and age-related cognitive decline, and The psychotic disorder is selected from the group consisting of schizophrenia, such as paranoia: Pa (10). (4) type, confusion, tension type 'undifferentiated or residual type; schizophrenia mental disorder schizoaffective mental disorder, such as delusion (-a1) or depression type; delusion; polarization abnormality (bipolar d - Ο 'Example! Type of polarization abnormality, „type polarization abnormality and cyclic affective disorder; substance-induced mental disorder, such as alcohol, amphetamine, marijuana, cocaine (c〇caine), elucidation, inhalation Psychosis induced by opioids or benzophenones; paranoid personality disorder; and schizophrenic personality disorder. 8's use of compounds of the scope of items i to 5 of the patent scope, For the manufacture of a medicament for the treatment of a neurodegenerative disorder or a psychiatric disorder, wherein the neurodegenerative disorder is selected from the group consisting of: Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia Dementia associated with intracranial tumor or brain trauma, dementia associated with Huntington's disease or Parkinson's disease or AIDS-related dementia; sputum; amnesia; Post-stress... force retardation; learning disabilities such as dyslexia 'mathematical or written expression disorder; &amp; olfactory deficit/hyperactivity disorder; and age-related cognitive decline' and the psychotic disorder selected from the group consisting of: 94 94069035 w schizophrenia, such as paranoid type, sputum type; schizophrenia undifferentiated or imaginary or melancholic; delusional knife. Perceptual mental disorders, abnormalities, II35 polarization and abnormalities, For example, type 1 polarization and circulatory affective mental disorders, such as by 侑枰陬 , 物质 物质 物质 物质 物质 物质 物质 物质 物质 物质 物质 物质 物质 物质 、 吸入 吸入 吸入 吸入 吸入 吸入 吸入 吸入 吸入 吸入 四 四 四 四 四 四 四 四Induced psychosis; paranoid disease, and schizophrenic personality disorder. 9' species such as the application for patents and the use of other compounds - one of the items of the chemistry or the mental illness of the drug, the other two hearts Degenerative disease group: 。 哗, 皇 1 1 口 化 选自 选自 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇 皇Nitrogen 10, back zipperone and oxatanide, the disease is selected. Free to form the following rescue. τ &quot; Hai neurodegenerative alcohol toxic dementia bite 1 he / Alzheimer's disease, multi-infarct dementia, injury related Dementia:,:;:=:[Dementia, dementia with Gu's tumor or brain-creating sputum; Dementia or learning disorder related to second disease or Parkinson's disease such as ..., post-traumatic stress disorder; Intelligence Involuntary; lack of sound /: two obstacles, mathematical disorders or written expression disorders; attention deficit / hyperactivity disorder; and annual freedom ... into groups. Two: clothing retreat, and the mental illness selected tension 2 crack 'for example Paranoid, chaotic, dilated or residual; schizophrenia-like mental disorder; sub-sexual disorder, such as delusion or worry#; delusion; polarization, such as I open + k μ 1 polarization abnormality, sputum-type polarized heterosexual mental disorder; temporary temporary key eight "hanging and circumstantial emotional temptation to induce sacredness, such as alcohol, An Feixian, marijuana, cocaine, 抻他迷幻条, inhalation Agent, opioid or benzocyclohexaphen 95 2012069 35 = induced psychosis; paranoid personality disorder; and schizophrenic personality disorder 10. A method for treating a neurodegenerative disorder or a psychotic disorder, which causes the neurodegenerative disorder to be selected from the group consisting of: Infarct dementia, alcohol-toxic cancer or other drug-related dementia, dementia associated with intracranial or brain trauma, or Parkinson's disease, or s-related dementia; reading sputum; = post-injury house disease; mental retardation , learning disabilities, such as dyslexia, digital disorder or written expression disorder; attention deficit/hyperactivity disorder: cognitive decline' and the mental disorder is selected from the group consisting of schizophrenia, such as paranoid, chaotic , tension, undifferentiated or residual type. schizophrenia mental disorder; schizoaffective mental disorder, such as delusion; paranoia; polarization abnormalities, such as type 1 polarization abnormalities, J polarization abnormalities and circulation Affective mental disorder; substance-induced mental disorder: for example, alcohol induced by amphetamine, marijuana, cocaine, psychedelic rate, agent, and benzophenone Disease; paranoid personality and schizophrenic personality disorder; the method involves administering to the patient a combination of the two: the application of patent scope 1 to 5: -:: compound and one or A variety of groups of neuroleptics selected from the following (four): olanzapine, risperidone, thiophene thiophene, adi (tetra) sputum, gas nitrogen, ziprasidone and oxatanide. 1: Two pharmaceutical compositions comprising a compound according to the scope of the claims, a compound of the dilution, and one or more pharmaceutically acceptable %l diluents and excipients. 96