Benzazole derivatives and their use as JNK modulators

专利摘要:
The present invention relates to compounds of formula I Wherein, X is O, S, or R 0 is H or unsubstituted or substituted C 1 -C 6 alkyl and NR 0; G is an unsubstituted or substituted pyrimidyl group; As well as their use as pharmacologically active ingredients, as well as pharmacological formulations comprising such benzazole derivatives. The above-mentioned benzazole derivatives are effective modulators of the JNK pathway, and they are effective or selective inhibitors of JNK 2 and / or 3 in particular.
公开号:KR20020072282A
申请号:KR1020027007971
申请日:2000-12-20
公开日:2002-09-14
发明作者:할라지세르게；데니스 쳐치；몬트세랏트 캠프스；파스칼레 가일라드；진-피에르 갓텔랜드
申请人:어플라이드 리서치 시스템스 에이알에스 홀딩 엔.브이.；
IPC主号:

专利说明:

Benzazole derivatives and their use as JNK modulators BACKGROUND OF THE INVENTION < RTI ID = 0.0 > [0002] <
[2] Apoptosis is a complex anomaly in the cell membrane and intracellular organs when the cell undergoes a programmed cell death process. During this process, a unique suicide program is activated and organically destroys itself. The following sequence is observed:
[3] Blisters begin to form on the surface of the cell and display an electrical signal. Whole poppy cells then fractionate into membrane bound follicles, which are quickly and cleanly placed by the phytoplankton, giving minimal damage to surrounding tissue.
[4] Then the cell is separated from its neighbors.
[5] The nucleus also undergoes a morphological change in specific patterns and is specifically isolated from the DNA fraction when it is genetic suicide, chromatin fusion.
[6] Neurons play an important role in the normal development of the nervous system. The death of a growth neuron depends on the size of the target they deactivate: it appears that cells with fewer synaptic partners die more easily than those with multiple synapses. This reflects the process, balancing the relative number of presynaptic neurons to post-synaptic neurons in the growth nervous system. Although neuronal cell death is presumed to be an apoptotic event, it has recently been shown that neurons in the brains of growing rodents undergo apoptosis comprehensively when classified by morphology and DNA fractionation. It can be seen that cell growth in growth is not a pathological process, so the cell substantially stops its survival. Neuronal cell death occurs after traumatic nerve injury or through neurodegenerative diseases such as apoptotic or necrotic processes. Various factors come to mind as the main actors in the role of the programmed cell death of neurons. Of these factors, neurogenic apoptosis is a factor in SAPK / JNK, a subset of MAP kinases (MAPKs).
[7] MAPKs (motigen-activated protein kinase) are serine / threonine kinases activated by double phosphorylation on threonine and tyrosine residues. In mammalian cells, there is at least three separate but equilibrium pathways for information generated by extracellular stimulation sources for MAPKs. The pathway consists of ERKs (extracellular control kinase), JNKs (c-Jun n-terminal kinase), and kinase branches leading to activation of p38 / CSBP kinase. The JNK and p38 pathways are involved in relaying stress-extracellular signals, and the ERK pathway is primarily responsible for transferring the mitotic promoting / differentiating signal to the nucleus.
[8] The SAPK branch represents a subgenus of the mitogen-active protein kinase and is activated by other external stimuli including UV radiation, DNA damage by TNF-a, IL-1b, ceramide, cell stress and reactive oxygen species, Specificity. Signal transduction via MKK4 / JNK of MKK3 / p38 phosphorylates the inducible transcription factor, c-zune and ATF2, acting as heterodimers as well as homodimers in initiating transcription of the downstream effector.
[9] c-Zune forms homodimers and heterodimers (e. g., c-Fos) to produce the transactivation complex AP-1, which is required for the activation of many genes involved in inflammatory response (e. g., matrix metalloproteinases) 1 is a protein that produces. JNKs have been found when several other stimuli such as UV light and TNF-alpha have been found to stimulate the phosphorylation of c-quinone on the specific serine residue at the N-terminus of the protein.
[10] In a recent publication of Cheng X et al. ( Structure 1998 , 6 (8) ; 983-991), superiore or cervical ganglia (SCG) sympathetic nerve cells and NGF induced in rat PC- It has been suggested that activation of the stressful signal transduction in neurophysis is required. Inhibition of certain kinases, namely MAP kinase kinase 3 (MKK3) and MAP kinase kinase 4 (MKK4), or c-quasi (part of the MKK-4 branch) may be sufficient to block apoptosis (see also Kumagae Y et al, in Brain Res Mol Brain Res , 1999 , 67 (1) , 10-17 and Yang DD et al in Nature , 1997 , 389 (6653) ; 865-870). Within a few hours of NGF depletion in the SCG neurons, the c-quadrant is highly phosphorylated and increases the level of the protein. Similarly, rat PC-12 cells in which NGF, JNK and p38 have been depleted are delayed in activation and ERKs are inhibited. JNK3 KO mice that are in harmony with this are resistant to apoptosis-induced apoptosis in the hippocampus and, more importantly, they significantly reduce liver disease such as sensitization attacks to excretion cytotoxicity compared to normal animals ( Nature 1997 , 389 , 865-870).
[11] More recently, JNK signaling pathway is involved in cell proliferation and the autoimmune disease is interposed by T- cell activation and proliferation (Immunity, 1998, 9, 575-585 ; Current Biology, 1999, 3, 116-125) Can play an important role.
[12] Naive CD4 ⁺ helper T (Th) cells recognize specific MHC-peptide complexes on antigen-presenting cells (APC) via a T-cell receptor (TCR) complex. In addition to the TCT-mediated signal, a co-stimulatory signal is provided at least in part by ligation of CD28 expressed in T-cells with B7 proteins on APCs. The combination of these two signals leads to T-cell knockdown expression.
[13] After 4-5 days of proliferation, the precursors of CD4 ⁺ T cells differentiate into effector Th cells that regulate the function of the immune system. Substantial reprogramming of genetic expression occurs during the differentiation process.
[14] Two subset subsets of effector Th cells are defined by their distinct cytokine secretion pattern and their immunomodulatory effect: Th1 cells produce IFNg and LT (TNF-b), which are involved in cell-mediated inflammatory responses cell-mediated inflammatory response s); Th2 cells secrete IL-4, IL-5, IL-6, IL-10 and IL-13, which regulate B cell activation and differentiation. These cells play a central role in immune response. The JNK MAP kinase pathway is triggered by Th1 effector cells, not Th2 effector cells, with antigen stimulation. Moreover, differentiation of precursor CD4 ⁺ T cells in effector Th1, rather than Th2, is impaired in JNKl and JNK2-deficient mice. Thus, in recent years it has been recognized that the JNK kinase pathway plays an important role in balancing Th1 and Th2 immune responses through JNK1 and JNK2.
[15] For the purpose of inhibiting the JNK kinase pathway, WO / 9849188 is a biological product and discloses the use of a deposited human polypeptide, JNK-interacting protein 1 (JIP-1), to overcome apoptosis-associated aliases .
[16] Although these human polypeptides have been shown to have an inhibitory effect on the JNK kinase pathway, their use has various disadvantages:
[17] Active bio-peptides or bio-proteins are obtained only through more comprehensive and expensive biosynthetic means, and consequently this product is quite costly.
[18] The preparation of peptides or proteins is very expensive,
[19] Peptides or proteins exhibit poor membrane permeability and can not pass through the blood brain membrane.
[20] ㆍ Oral administration of peptides or proteins can not be used as a degradation by hydrolysis by the above acid medium.
[21] Peptides or proteins cause autoimmune reactions.
[22] It is therefore an object of the present invention to provide a relatively small molecule which eliminates all the above-mentioned absolute drawbacks arising from the use of bio-peptides or bio-proteins and which is suitable for the treatment of various diseases, in particular neuronal or autoimmune system related diseases . It is a particular object of the present invention to provide a method of treating a subject suffering from a disease, disorder or condition which is preferably capable of modulating the JNK (Jun kinase) pathway, preferably down-regulating or inhibiting, To provide a chemical compound of a small molecule. Furthermore, it is an object of the present invention to provide a method for producing the above-mentioned small molecule chemical compound. Furthermore, it is an object of the present invention to provide a new class of pharmaceutical formulations for the treatment of major diseases. A final object of the present invention is to provide a method for the treatment of diseases caused by autoimmune and / or nervous system disorders.
[1] The present invention relates to pharmaceutical active compounds, as well as benzazole derivatives and tautomers thereof, as well as pharmacological formulations comprising such benzazole derivatives. In particular, the present invention relates to benzazoles derivatives which are particularly effective in the treatment of autoimmune and neurological diseases, respectively, which show a substantial modulating factor, JNK (c-Jun-N-terminal Kinase) pathway inhibitory activity respectively. Furthermore, the present invention relates to novel benzazole derivatives, as well as processes for their preparation and pharmaceutical compositions containing them.
[23] The foregoing objects are fulfilled according to the independent claim. The preferred embodiment is set as a dependent term incorporated herein.
[24] The following provides limitations of various chemical terms for the purpose of uniform application in understanding the compounds according to the invention and throughout the specification and claims, provided that the limitations do not constitute broad limits.
[25] &Quot; C ₁ -C ₆ -alkyl " refers to monovalent alkyl groups having 1 to 6 carbon atoms. The term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and the like.
[26] &Quot; Aryl " refers to an unsaturated aromatic carboxyl group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensation rings (e.g., naphthyl). Preferably, aryl includes phenyl, naphthyl, phenanthrenyl, and the like.
[27] &Quot; C ₁ -C ₆ -alkylaryl " refers to a C ₁ -C ₆ -alkyl group having an aryl substituent including benzyl, phenethyl, and the like.
[28] &Quot; Heteroaryl " refers to a monocyclic heteroaromatic, or bicyclic or tricyclic fused ring heteroaromatic group. Specific examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, Thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazoyl, 1,2,4-triazoyl, 1,2,3-oxa Thiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-, 1,2,3-triazinyl, benzo Benzyloxycarbonyl, furyl, [2,3-dihydro] benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H- indolyl, benzimidazolyl, imidazo [ 3,4-b] pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido [3,4- b] Pyridyl, pyrido [3,2-b] pyridyl, pyrido [4,3-b] Tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, phthalidinyl, carbazolyl, quinolyl, quinolyl, isoquinolyl, tetrazolyl, Lt; RTI ID = 0.0 > benzenquinolyl. ≪ / RTI >
[29] "C ₁ -C ₆ -alkylheteroaryl" refers to a C ₁ -C ₆ -alkyl group having a heteroaryl substituent including 2-furylmethyl, 2-thienylmethyl, 2- (1H-indol- Alkyl "
[30] &Quot; Alkenyl " refers to an alkenyl group preferably having from 2 to 6 carbon atoms and having at least one or two sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (-CH = CH ₂ ), n-2-propenyl (allyl, -CH ₂ CH = CH ₂ ), and the like.
[31] "Alkynyl" is preferably at least 2 to 6 refer to alkynyl groups having 1 or 2 sites of alkynyl unsaturation having a carbon atoms, ethynyl, preferred alkynyl groups (-CCH), propargyl (-CH ₂ CCH ) And the like.
[32] &Quot; Acyl " refers to the group C (O) R where R comprises C ₁ -C ₆ -alkyl, aryl, heteroaryl, C ₁ -C ₆ -alkylaryl or C ₁ -C ₆ -alkylheteroaryl.
[33] &Quot; Acyloxy " refers to an OC (O) R group wherein R comprises C ₁ -C ₆ -alkyl, aryl, heteroaryl, C ₁ -C ₆ -alkylaryl or C ₁ -C ₆ -alkylheteroaryl .
[34] &Quot; Alkoxy " refers to an OR group wherein R comprises C ₁ -C ₆ -alkyl or aryl or heteroaryl or C ₁ -C ₆ -alkylaryl or C ₁ -C ₆ -alkylheteroaryl. Preferred alkoxy groups include, by way of example, methoxy, ethoxy, phenoxy, and the like.
[35] &Quot; Alkoxycarbonyl " refers to a C (O) OR group wherein R comprises C ₁ -C ₆ -alkyl or aryl or heteroaryl or C ₁ -C ₆ -alkylaryl or C ₁ -C ₆ -alkylheteroaryl do.
[36] "Aminocarbonyl" is C (O) NRR 'group refers to wherein R, R' are independently hydrogen or C ₁ -C ₆ - alkyl or aryl or heteroaryl or C ₁ -C ₆ - alkyl, aryl or C ₁ - C ₆ -alkylheteroaryl.
[37] &Quot; Acylamino " refers to the group NR (CO) R 'where R, R' are independently hydrogen or C ₁ -C ₆ -alkyl or aryl or heteroaryl or C ₁ -C ₆ -alkylaryl or C ₁ -C ₆ -alkylheteroaryl.
[38] &Quot; Halogen " refers to fluoro, chloro, bromo, and iodo atoms.
[39] "Sulfonyl" refers to wherein R is a group SO2-R is H, aryl, heteroaryl, C ₁ -C ₆ - alkyl, for, for example, a halogen-substituted with _{SO 2 -CF 3 C 1 -C 6} - alkyl, C ₁ -C ₆ - is selected from alkyl, heteroaryl-alkyl, aryl or C ₁ -C _6.
[40] "Sulfoxides" is S (O) -R, and refers to the group wherein R is H, C ₁ -C ₆ - alkyl, halogen, for example SO ₂ -CF ₃ group a substituted C ₁ -C ₆ - alkyl, aryl, heteroaryl, Aryl, C ₁ -C ₆ -alkylaryl or C ₁ -C ₆ -alkylheteroaryl.
[41] &Quot; Thioalkoxy " refers to the group SR where R comprises C ₁ -C ₆ -alkyl or aryl or heteroaryl or C ₁ -C ₆ -alkylaryl or C ₁ -C ₆ -alkylheteroaryl, the preferred thioalkoxy The group includes thiomethoxy, thioethoxy, and the like.
[42] "Substituted or unsubstituted": Unless limited by the definition of the individual substituent, the above set is a group such as alkyl, alkenyl, alkynyl, aryl and heteroaryl, a group C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkyl aryl, C ₁ -C ₆ - alkyl-heteroaryl, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, first class, second class, or tertiary amino groups or quarter Aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, mercapto, nitro, sulfoxy, sulfonyl, alkoxy, alkoxy, Thioalkoxy, trihalomethyl, and the like. The term " alkyl " Also, the substituents are markedly examples of efforts to form a lactam, lactone, cyclic anhydride and obtain a protecting group, including situations in which neighboring substituents are ring closed when vicinal functional substituents are involved Acetal, thioacetal, and aminal formed by ring closure also form.
[43] &Quot; Pharmaceutically acceptable salt or complex " refers to a salt or complex of the following particular compounds of formula I possessing the desired biological activity. Examples of such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like, and organic acids such as acetic, oxalic, tartaric, succinic, malic, , Salts formed with organic acids such as carbonic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid and polygalacturonic acid. The compound may also be administered in the form of a pharmaceutically acceptable pharmacologically acceptable pharmacologically acceptable salt thereof, in particular a quaternary ammonium salt of the formula NR, R, R + Z- wherein R, R ', R "is independently hydrogen, alkyl, or benzyl, and Z is chlorine, bromine, iodine, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (benzoate, Such as succinate, acetate, glycolate, maleate, maleate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandelate, and diphenylacetate . Sample-based addition salts include quaternary ammonium hydroxides, such as, for example, tetramethylammonium hydroxide, sodium, potassium and ammonium.
[44] A " pharmaceutically active derivative " refers to a compound that is capable of providing, directly or indirectly, the activity disclosed herein by administration to a receptor.
[45] &Quot; Enantiomeric excess (ee) " refers essentially to the product obtained by synthesis, including enantiomeric synthesis or enantioselective steps, whereby at least 52% ee An excess of anti-omers is obtained. In the absence of enantiomeric synthesis, the racemic product is usually obtained, but the invention allows the activity as a crude kinase inhibitor.
[46] It has been found that the benzazole derivatives according to formula I are suitable pharmacologically active agents by modulating, particularly inhibiting, the activity of JNKs, notably JNK 2 and / or 3.
[47] The compounds according to the invention are of formula I.
[48]
[49] In compounds according to formula I
[50] X is O, S, or R ⁰ is H or unsubstituted or substituted C ₁ -C ₆ alkyl, NR ^0, X = S is the most preferably.
[51] G is an unsubstituted or substituted or fused pyrimidyl group.
[52] R ¹ is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ -alkoxy, unsubstituted or substituted C ₁ -C ₆ -thioalkoxy, unsubstituted or substituted C ₁ -C ₆ -alkyl, Unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alkynyl, primary, secondary or tertiary amino groups, aminoacyl, aminocarbonyl, the or substituted C ₁ -C ₆ alkoxycarbonyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, cyano, halogen, hydroxy, nitro, sulfoxide, sulfonyl, sulfone Amide, unsubstituted or substituted hydrazide.
[53] Most preferably the substituent R ¹ is hydrogen, halogen, C ₁ -C ₆ - alkyl and C ₁ -C ₆ alkoxy group.
[54] R ² is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alkynyl, Unsubstituted or substituted C ₁ -C ₆ -alkyl-aryl, unsubstituted or substituted aryl or heteroaryl, unsubstituted or substituted C ₁ -C ₆ -alkyl-heteroaryl, -C (O) -OR ³ , -C (O) -R ³ , -C (O) -NR ³ R ^{3 '} , - (SO ₂ ) R ³ , wherein
[55] R ³ and R ^{3 '} are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ Alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C ₁ -C ₆ -alkylaryl, unsubstituted or substituted C ₁ -C ₆ -alkylheteroaryl ≪ / RTI >
[56] The present invention also relates to the use of the compounds of formula I as well as the mutual variants according to structural formula I, geometric isomers thereof, optically active forms, enantiomers, diastereomers as well as their racemates, As well as pharmaceutically active derivatives thereof.
[57] Preferably, substituent R ² is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkylaryl or C ₁ -C ₆ alkylheteroaryl, -C (O ) - R ³ , -C (O) -NR ³ R ^{3 '} , - (SO ₂ ) R ³ , wherein R ³ and R ^3' are as described above. More preferably the substituents R ² are hydrogen and C ₁ -C ₆ - alkyl group and, where R ² = H, it is the embodiment most preferably.
[58] Preferably R ³ and R ^{3 '} are hydrogen, C ₁ -C ₆ alkyl, aryl, heteroaryl, C ₁ -C ₆ -alkylaryl, C ₁ -C ₆ -alkylheteroaryl and the like. Most preferably, R ³ and R ^{3 '} are hydrogen or C ₁ -C ₆ alkyl.
[59] Such that the transition cross-mentioned here only the R ² and / or R ⁰ are hydrogen seongcheeun These structural formula II, and more characteristically the formula IIa and IIb. The mutual variants are modified in solution and the equilibrium between structural formulas Ia and Ib is achieved with structural formulas IIa and IIb.
[60]
[61] Such interconversions are included in the present application.
[62] Basically, all the above-mentioned aryl or heteroaryl substituents are substituted or unsubstituted C ₁ -C ₆ -alkyl such as trihalomethyl, substituted or unsubstituted C ₁ -C ₆ -alkoxy, acetoxy, Substituted or unsubstituted C ₂ -C ₆ -alkenyl, substituted or unsubstituted C ₂ -C ₆ -alkynyl, amino, aminoacyl, aminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aryl Which may be optionally further substituted by at least one group selected from halogen, hydroxy, nitro, sulfonyl, sulfoxy, C ₁ -C ₆ -thioalkoxy, carboxyl, cyano, halogen. Preferably, the aryl or heteroaryl group may be optionally further substituted by at least one group selected from halogen, hydroxy, nitro, sulfonyl, i.e., a trifluoromethylsulfonyl group.
[63] Particularly preferably, the benzazole derivative is an unsubstituted or substituted pyrimidyl group in which G is linked to the benzazole acetato backbone through the 4-position.
[64]
[65] Wherein L is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkoxy, unsubstituted or substituted C ₁ -C ₆ thioalkoxy, A substituted or unsubstituted C ₂ -C ₆ alkenyl, an unsubstituted or substituted C ₂ -C ₆ alkynyl, a primary, secondary or tertiary amino group, an aminoacyl, an aminocarbonyl, an amino- (C ₁ - C ₁₀₎ alkyl, amino-unsubstituted or substituted cyclic (C ₁ -C ₁₀₎ - alkyl-aryl, amino-unsubstituted or a substituted cyclic (C ₁ -C ₁₀₎ alkyl-heteroaryl, unsubstituted or substituted Substituted or unsubstituted aryl, unsubstituted or substituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, carboxyl, cyano, halogen, S, unsubstituted or substituted 3-8 membered cycloalkyl optionally containing at least one heteroatom selected from S, and a group consisting of or consisting of an unsubstituted or substituted hydrazide group Standing is selected.
[66] Particularly preferred benzazole derivatives are those wherein L is a substituted or unsubstituted (C ₁ -C ₁₀ ) -alkyl group.
[67] Furthermore, particularly preferred benzazole derivatives are those wherein L is -N (R ^a , R ^b ) or -OR ^a where R ^a and R ^b are each independently H, unsubstituted or substituted (C ₁ - C ₁₀₎ - alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl-aryl, unsubstituted or substituted C ₁ -C ₆ - alkyl-heteroaryl, unsubstituted or ring substituted aryl or heteroaryl and Beach Substituted or unsubstituted 4-8 membered saturated or unsaturated cycloalkyl.
[68] According to a particularly preferred embodiment according to structural formula I, L is selected from the following.
[69]
[70] Wherein n is 1 to 10, preferably 1 to 6, X is preferably S, R ¹ is H, and R ² is H.
[71] R ⁵ and R ^{5 '} are each independently H, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted C ₁ -C ₆ alkyl-aryl And substituted or unsubstituted C ₁ -C ₆ -alkyl-heteroaryl. Most preferably R < ⁵ > is unsubstituted or substituted imidazolyl.
[72] Most preferably, the benzazole derivatives according to formula I are the benzothiazole acetonitrile derivatives of formula IIb with formula Ib and / or their mutants.
[73]
[74] Wherein X is S, R ¹ is H or C ₁ -C ₆ alkyl, R ² is H, and G is a pyrimidyl group of the structure:
[75]
[76] Where L is the following.
[77] or
[78] Wherein n is 0, 1 or 2 and R ⁵ is aryl or heteroaryl, especially substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted imidazolyl.
[79] Specific examples of compounds of formula I include the following:
[80] Benzothiazol-2-yl (2-chloro-4-pyrimidyl) acetonitrile
[81] 1,3-benzothiazol-2-yl (2,6-dimethoxy-4-pyrimidyl) acetonitrile
[82] Benzothiazol-2-yl (2-chloro-6-methyl-4-pyrimidyl) acetonitrile
[83] Benzothiazol-2-yl [2- (methylsulfanyl) -4-pyrimidyl] acetonitrile
[84] Benzothiazol-2-yl {6-chloro-5-nitro-4-pyrimidyl} acetonitrile
[85] 1,3-benzothiazol-2-yl (hydroxy-4-pyrimidyl) acetonitrile
[86] Benzothiazol-2-yl (2-phenyl-4-quinazolinyl) acetonitrile
[87] (2- chloropyrimidin-4-yl) [5- (trifluoromethyl) -1,3-benzothiazol-2-yl] acetonitrile
[88] (3-methyl-1,3-benzothiazol-2 (3H) -ylidene) ethanenitrile
[89] (2 - {[2- (1H-imidazol-5-yl) ethyl] amino} -4-pyrimidyl) acetonitrile
[90] Benzothiazol-2-yl [2- (1-piperazinyl) -4-pyrimidyl] acetonitrile
[91] Benzothiazol-2-yl [2- (4-benzyl-1-piperidinyl) -4-pyrimidyl] acetonitrile
[92] Benzothiazol-2-yl [2- (4-methyl-1-piperazinyl) -4-pyrimidyl] acetonitrile
[93] Benzothiazol-2-yl [2- (4-morpholinyl) -4-pyrimidyl] acetonitrile
[94] Benzothiazol-2-yl [2- (methylamino) -4-pyrimidyl] acetonitrile
[95] Benzothiazol-2-yl (2- {4- [2- (4-morpholinyl) ethyl] -1-piperazinyl} -4-pyrimidyl) -acetonitrile
[96] Benzothiazol-2-yl {2- [4- (benzyloxy) -1-piperidinyl] -4-pyrimidyl} acetonitrile
[97] Benzothiazol-2-yl [2- (4-hydroxy-1-piperidinyl) -4-pyrimidyl] acetonitrile
[98] 1,3-benzothiazol-2-yl (2-hydrazino-4-pyrimidyl) acetonitrile
[99] Benzothiazol-2-yl (2- {[2- (dimethylamino) ethyl] amino} -4-pyrimidyl) acetonitrile
[100] Benzothiazol-2-yl [2- (dimethylamino) -4-pyrimidyl] acetonitrile
[101] Benzothiazol-2-yl {2 - [(2-methoxyethyl) amino] -4-pyrimidyl} acetonitrile
[102] Benzothiazol-2-yl {2 - [(2-hydroxyethyl) amino] -4-pyrimidyl} acetonitrile
[103] 1,3-benzothiazol-2-yl [2- (propylamino) -4-pyrimidyl] acetonitrile
[104] (2 - {[3- (1H-imidazol-1-yl) propyl] amino} -4-pyrimidyl) acetonitrile
[105] Benzothiazol-2-yl [2- (1-pyrrolidinyl) -4-pyrimidyl] acetonitrile
[106] Benzothiazol-2-yl {2 - [(2-phenylethyl) amino] -4-pyrimidyl} acetonitrile
[107] Benzothiazol-2-yl (2- {[2- (2-pyridinyl) ethyl] amino} -4-pyrimidyl) acetonitrile
[108] Benzothiazol-2-yl {2 - [(2-pyridinylmethyl) amino] -4-pyrimidyl} acetonitrile
[109] Benzothiazol-1-yl) -1-piperidinyl] -4-pyrimidyl} acetonitrile < / RTI >
[110] Benzothiazol-2-yl {2- [4- (2-pyrazinyl) -1-piperazinyl] -4-pyrimidyl} acetonitrile
[111] Benzothiazol-2-yl {2- [4- (2-pyrimidyl) -1-piperazinyl] -4-pyrimidyl} acetonitrile
[112] Benzothiazol-2-yl (2- {[2- (3-pyridinyl) ethyl] amino} -4-pyrimidyl) acetonitrile
[113] (5-bromo-2 - {[2- (dimethylamino) ethyl] amino} -4-pyrimidyl) -acetonitrile
[114] Benzothiazol-2-yl {2- [(2-morpholin-4-ylethyl) amino] pyrimidin-4- yl} acetonitrile
[115] Synthesis of 1,3-benzothiazol-2-yl [2- (4- {3 - [(trifluoromethyl) sulfonyl] anilino} piperidin- 1 -yl) pyrimidin-
[116] (2 - {[3- (2-oxopyrrolidin- 1 -yl) propyl] amino} pyrimidin-4-yl) -acetonitrile
[117] 2-yl (2- {methyl [3- (methylamino) propyl] amino} pyrimidin-4-yl) acetonitrile
[118] (2 - {[3- (4-methylpiperazin-1-yl) propyl] amino} pyrimidin-4-yl) -acetonitrile
[119] Benzothiazol-2-yl {2 - [(3-morpholin-4-ylpropyl) amino] pyrimidin-4- yl} acetonitrile
[120] (2 - {[2- (1-methyl-1H-imidazol-4-yl) ethyl] amino} pyrimidin-4-yl) acetonitrile
[121] (2 - {[2- (1H-indol-3-yl) ethyl] amino} pyrimidin-4-yl) acetonitrile
[122] (2 - {[2- (4-hydroxyphenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
[123] ({4- [1,3-benzothiazol-2-yl (cyano) methyl] pyrimidin-2- yl} amino) acetate
[124] Amino] pyrimidin-4-yl} (1,3-benzothiazol-2-yl) acetonitrile
[125] (2-aminoethyl) amino] pyrimidin-4-yl} (1,3-benzothiazol-2-yl) acetonitrile
[126] Benzothiazol-2-yl (2- {[3- (dimethylamino) propyl] amino} pyrimidin-4-yl) acetonitrile
[127] Benzothiazol-2-yl {2 - [(2-piperidin-1 -ylethyl) amino] pyrimidin-4- yl} acetonitrile
[128] (2 - {[2- (1-methyl-1H-imidazol-5-yl) ethyl] amino} pyrimidin-4-yl) acetonitrile
[129] Benzothiazol-2-yl [2- (benzylamino) pyrimidin-4-yl] acetonitrile
[130] Isopropyl 3 - ({4- [1,3-benzothiazol-2-yl (cyano) methyl] pyrimidin-2- yl} amino) propanoate
[131] Benzothiazol-2-yl {2- [(3-hydroxypropyl) amino] pyrimidin-4- yl} acetonitrile
[132] Benzothiazol-2-yl {2- [(pyridin-3-ylmethyl) amino] pyrimidin-4- yl} acetonitrile
[133] (2-aminopyrimidin-4-yl) (1,3-benzothiazol-2-yl) acetonitrile
[134] Benzothiazol-2-yl {2- [(pyridin-4-ylmethyl) amino] pyrimidin-4- yl} acetonitrile
[135] 2-yl} amino) -ethyl] phenylcarbamate < / RTI >
[136] (2 - {[2- (4-aminophenyl) ethyl] amino} pyrimidin-4-yl) (1,3-benzothiazol-
[137] (2 - {[2- (3,4-dimethoxyphenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
[138] (2 - {[2- (3-methoxyphenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
[139] (2 - {[2- (2-fluorophenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
[140] Benzothiazol-2-yl [2- ({2- [3- (trifluoromethyl) phenyl] ethyl} amino) pyrimidin-4-yl] acetonitrile
[141] Benzothiazol-2-yl {2- [(2-hydroxy-2-phenylethyl) amino] pyrimidin-4- yl} acetonitrile
[142] 2-yl] amino} ethyl) amino] - pyrimidin-4-yl} acetonitrile
[143] (2 - {[2- (3-chlorophenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
[144] Synthesis of 1,3-benzothiazol-2-yl (2 - {[2- (3,4-dichlorophenyl) ethyl] amino} pyrimidin-
[145] (2 - {[2- (4-methoxyphenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
[146] Synthesis of 1,3-benzothiazol-2-yl (2 - {[2- (4-methylphenyl) ethyl] amino} pyrimidin-
[147] (2 - {[2- (3-fluorophenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
[148] (2 - {[2- (4-phenoxyphenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
[149] (2 - {[2- (2-phenoxyphenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
[150] (2 - {[2- (4-bromophenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
[151] (2 - {[2- (4-fluorophenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
[152] Benzothiazol-2-yl {2 - [(2- [1,1'-biphenyl] -4-ylethyl) amino] pyrimidin-4- yl} acetonitrile
[153] Amino} phenyl} ethyl) amino] pyrimidin-4-yl} acetonitrile < / RTI >
[154] (2 - {[2- (1H-1,2,4-triazol-1-yl) ethyl] amino} pyrimidin-4-yl) acetonitrile
[155] (2 - {[3- (1H-pyrazol-1-yl) propyl] amino} pyrimidin-4-yl) acetonitrile
[156] Methyl} pyrimidin-2-yl} amino) ethyl] benzenesulfonamide < / RTI >
[157] Yl} [5- (trifluoromethyl) -1,3-benzothiazol-2-yl] acetonitrile < / RTI >
[158] Benzothiazol-2-yl {2- [(lH-tetrazol-5-ylmethyl) amino] pyrimidin-4- yl} acetonitrile
[159] Benzothiazol-2-yl [2- (benzyloxy) pyrimidin-4-yl] acetonitrile
[160] Benzothiazol-2-yl {2- [(4-pyridin-3-ylbenzyl) oxy] pyrimidin-4- yl} acetonitrile
[161] Benzothiazol-2-yl [2- (pyridin-4-ylmethoxy) pyrimidin-4-yl] acetonitrile
[162] Benzothiazol-2-yl [2- (pyridin-2-ylmethoxy) pyrimidin-4-yl] acetonitrile
[163] 2-yl [2- (3-pyridin-2-ylpropoxy) pyrimidin-4-yl] acetonitrile
[164] Benzothiazol-2-yl {2 - [(4-methoxybenzyl) oxy] pyrimidin-4- yl} acetonitrile
[165] Benzothiazol-2-yl [2- (pyridin-3-ylmethoxy) pyrimidin-4-yl] acetonitrile
[166] Benzothiazol-2-yl {2- [2- (4-methoxyphenyl) ethoxy] pyrimidin-4- yl} acetonitrile
[167] Benzothiazol-2-yl [2- ([1,1'-biphenyl] -3-ylmethoxy) pyrimidin-4- yl] acetonitrile
[168] Benzothiazol-2-yl {2 - [(3,4,5-trimethoxybenzyl) oxy] pyrimidin-4- yl} acetonitrile
[169] Benzothiazol-2-yl {2 - [(3,4-dichlorobenzyl) oxy] pyrimidin-4- yl} acetonitrile
[170] Benzothiazol-2-yl [2- ({3 - [(dimethylamino) methyl] benzyl} oxy) pyrimidin-4-yl] acetonitrile
[171] Benzothiazol-2-yl {2 - [(1-oxydopyridin-3-yl) methoxy] pyrimidin-4- yl} acetonitrile
[172] Benzothiazol-2-yl (2 - {[4- (morpholin-4-ylmethyl) benzyl] oxy} pyrimidin-4-yl) acetonitrile
[173] Benzothiazol-2-yl {2- [(4-pyridin-2-ylbenzyl) oxy] pyrimidin-4- yl} acetonitrile
[174] Benzothiazol-2-yl (2 - {[4- (piperidin-1-ylmethyl) benzyl] oxy} pyrimidin-4-yl) acetonitrile
[175] Benzothiazol-2-yl [2- (4-methoxyphenoxy) pyrimidin-4-yl] acetonitrile
[176] Benzothiazol-2-yl [2- (4-butoxyphenoxy) pyrimidin-4-yl] acetonitrile
[177] Yl} (1, 3-benzothiazol-2-yl) acetonitrile < / RTI >
[178] [2- (4-methoxyphenoxy) pyrimidin-4-yl] [5- (trifluoromethyl) -1,3-benzothiazol-2-yl] acetonitrile
[179] 1,3-benzothiazol-2-yl (pyrimidin-4-yl) acetonitrile
[180] Methyl} pyrimidin-2-yl} amino) ethyl] -4-chlorobenzamide < / RTI >
[181] Benzothiazol-2-yl (2-methoxy-4-pyrimidyl) acetonitrile
[182] Of these, the most preferred compounds are selected from the group consisting of:
[183] Benzothiazol-2-yl (2-chloro-4-pyrimidyl) acetonitrile
[184] Benzothiazol-2-yl [2- (methylsulfanyl) -4-pyrimidyl] acetonitrile
[185] (2 - {[2- (1H-imidazol-5-yl) ethyl] amino} -4-pyrimidyl) acetonitrile
[186] Benzothiazol-2-yl [2- (methylamino) -4-pyrimidyl] acetonitrile
[187] Benzothiazol-2-yl {2 - [(2-hydroxyethyl) amino] -4-pyrimidyl} acetonitrile
[188] Benzothiazol-2-yl [2- (benzyloxy) pyrimidin-4-yl] acetonitrile
[189] Benzothiazol-2-yl [2- (4-methoxyphenoxy) pyrimidin-4-yl] acetonitrile
[190] Benzothiazol-2-yl (2-methoxy-4-pyrimidyl) acetonitrile
[191] Benzothiazol-2-yl (2- {[2- (3-pyridinyl) ethyl] amino} -4-pyrimidyl) acetonitrile
[192] A total of 12 compounds of Structures I and II are disclosed in the catalog of the May Bridge plc company. In the above three compounds X is S, R ¹ and R ² are H, and G is:
[193]
[194] In three other compounds of the Maybridge, X is NH, R ¹ and R ² are H, and G is the following pyrimidines:
[195]
[196] Finally, the make-bridge compounds of the six X is N-CH _3, R ¹ and R ² is H and G is the following pyrimidine dinryu:
[197]
[198] A further aspect of the present invention is the use of a pharmaceutical composition for the preparation of a medicament for the controlled-markedly inhibition of diseases associated with the JNK pathway, in particular neurological diseases and / or immune disorders, And the use of the composition itself. Preferred JNK pathways are JNK2 and / or JNK3.
[199] As indicated above, the compounds of formula I are suitable for use as therapeutic agents. Thus, here we report that the compounds of formula I and their mutants can be used suitably in the treatment of various diseases. Such diseases include vertebrate animals, predominantly human autoimmune and neurological diseases. In particular, it is useful in the treatment of or prevention of diseases associated with the modulation of the JNK pathway, in particular in the form of a compound according to structural formula I or a pharmaceutical composition, in particular JNK, an abnormally expressed or activity of JNK2 and 3. Such abnormal expression or activity of JNK can be triggered by a variety of stimuli (e.g., stress, septic shock, oxidative stress, cytokinase) and may be caused by autoimmune diseases, including myriad diseases or diseases, It may become impossible to control the sheath. Thus, compounds according to formula I can be used in the treatment of diseases by modulating the JNK pathway. The modulation of the JNK function or pathway may include activation thereof, but preferably involves inhibition of the JNK pathway, notably JNK2 and / or JNK3. Compounds according to formula I can be employed on their own or in combination with additional < RTI ID = 0.0 >
[200] In particular, compounds according to formula I are useful for the treatment of epilepsy; Neurodegenerative diseases including Alzheimer's disease, Huntington's disease, Parkinson's disease; Retinal disease; Spinal cord injury; Various sclerosis, inflammatory bowel disease (IBD), head trauma including rheumatoid arthritis, autoimmune disease; asthma; Septic shock; Rejection of transplants; The inhibition of JNK2 or JNK3, such as cardiovascular disease, including breast, colon, rectum, stomach cancer and stroke, brain ischemia, arteriosclerosis, myocardial infarction, myocardial reperfusion injury, Or for the treatment and / or prevention of neurological diseases or pathological conditions.
[201] Surprisingly, it has been found that compounds according to formula I exhibit significant activity as inhibitors of JNK2 and 3. According to a preferred embodiment, the compounds according to the invention are essentially inert in terms of two additional MAP kinases, i.e. p38 and / or ERK2, belonging to the same lineage as JNK2 and 3. Thus, the compounds according to the invention offer the possibility of selectively modulating in the treatment of diseases associated with the JNK pathway, in particular the JNK pathway, and are not necessarily effective with respect to other targets such as p38 and ERK2, have. Since these related enzymes are generally involved in other diseases, this is of critical importance and it is desirable to employ the corresponding selective therapeutic agents in the treatment of distinct diseases.
[202] Another object of the present invention is a process for producing novel benzothiazole derivatives according to structural formula I. A general synthesis method for compounds according to formula I is as follows:
[203]
[204] Intermediate compound IV 'is modified as follows:
[205]
[206] Starting material III then reacts with the electrophilic compound G-Y, where Y is a suitable leaving group. The choice of Y, Y ', the reaction method, the reaction conditions, the solvent and the catalyst depend on the nature of G and can be selected accordingly according to the knowledge of the person skilled in the art. The method also involves some modification of G with the condensation of G-Y to Compound III.
[207] Preferred compounds of formula I and II are those wherein G is a pyrimidinyl group having the structure:
[208]
[209] Where L is as described above. Such compounds are preferably obtained according to Schematic I-III:
[210] Schematic I
[211]
[212] Schematic II
[213]
[214] Schematic III
[215]
[216] The benzothiazole derivatives can be prepared from readily available starting materials according to the following general procedures and procedures. Given the typical or preferred experimental conditions (i.e., reaction temperature, time, moles of reagent, solvent, etc.), other experimental conditions may also be used unless otherwise stated. Optimum reaction conditions include, But these conditions can be determined by an optimization process routinely performed by those skilled in the art.
[217] In the above Schemes I to III, R^One, R²And X are as described above.
[218] In the schematic diagram I, the compound of formula (III) with a base, such as starting compounds as sodium hydride, potassium hydride, Chabaka LM (in a dry inert atmosphere of about -78 ℃ to 25 ℃ in a polar solvent such as DMF or THF et al, Pol. J . Chem. 1994, 1317-1326), dropwise addition of the formula V of unsubstituted or substituted halogenated pyrimidyl ring derivative as described above in a solvent such as DMF or THF and then treated for one hour, and the temperature in the range of And then gradually converting the mixture to a compound of formula IV by heating at a temperature of about 25 ° C to 70 ° C for 1 to 18 hours to obtain a compound of formula IV.
[219] The benzazoles of formula III can be prepared commercially from commercially available compounds as well as commercially available as commercially available from Maybridge Chemicals, wherein R ¹ and X are as described above Most preferably H and S, respectively.
[220] Unsubstituted or substituted halogenated heteroaryl of formula V is not only commercially available, such as from Aldrich, Pruca, Sigma, etc., but can also be prepared from the known compounds by conventional procedures. Preferably, the halogenated heteroaryl as the starting material includes 2,4-dichloropyrimidine, 2-chloropyridine and the like.
[221] In Scheme II, compounds of formula VI, wherein R ¹ , R ² and X are as described above, are converted to compounds of formula I "by treatment with a group of L types as described above. Most preferably, Lt; RTI ID = 0.0 > amines, < / RTI >
[222] This reaction is DMF, NMP, DMSO, or, for example EtOH, in MeOH or iPrOH, is decided in the alcohol, and most preferably EtOH, Et ₃ N, under the organic salt, and most preferably Et ₃ N exist such as DIPEA, 25 To 80 < 0 > C. In a preferred method, the starting compounds are heated in a solution of EtOH, in 70 ℃ in the presence of Et ₃ N.
[223] Amines are not only commercially available but can be prepared from the known compounds by conventional procedures known to those skilled in the art. Preferably, the amine as a starting material includes methylamine, N, N-dimethylaminoethylamine, morpholine histamine, and the like.
[224] Alcohols or thioalcohols are not only commercially available but can also be prepared from the known compounds by conventional procedures known to those skilled in the art. Preferably, the alcohol or thioalcohol as the starting material includes MeOH, MeSH, and the like.
[225] In Scheme III, a compound of formula I 'wherein R ² is hydrogen and R ¹ and X are as described above, most preferably H and S, is a compound of formula I, wherein R ² is not hydrogen, or benzyl halides and acyl chlorides at the electro filter (electrophile) Y'-R temperature in the range from 25 ℃ to 80 ℃ ^2, such, such as the presence of a base such as potassium carbonate, sodium hydroxide, sodium hydride, DMSO, DMF or acetone In an anhydrous inert atmosphere in a solvent. In a preferred manner, the starting compound is stirred in a DMSO solution at 25 < 0 > C in the presence of potassium carbonate.
[226] Electrophiles are not only commercially available, but can also be prepared from the known compounds by conventional procedures known to those skilled in the art. Preferably, the electropyl as the starting material comprises methyl iodide and acetyl chloride.
[227] If the above general synthetic method is not applicable to the preparation of compounds of formula I, then the appropriate preparation methods known to those skilled in the art are used.
[228] A final aspect of the present invention relates to the use of a compound according to formula I for the modulation of the JNK pathway, to the use of said compound for the preparation of a pharmaceutical composition for the modulation of the JNK pathway as well as to the preparation of a formulation containing the active compound according to formula I All. JNK is thought to be involved in a variety of disease states. Thus, modulation of the levels of JNK, notably JNK2 and / or JNK3, Neurodegenerative diseases including Alzheimer's disease, Huntington's disease, Parkinson's disease; Retinal disease; Spinal cord injury; Various sclerosis, inflammatory bowel disease (IBD), head trauma including rheumatoid arthritis, autoimmune disease; asthma; Septic shock; Rejection of transplants; Including cardiovascular diseases including breast, colon, rectum, stomach cancer and stroke, brain ischemia, arteriosclerosis, myocardial infections, myocardial reperfusion injury,
[229] As used herein, " treatment " refers to inhibiting or inhibiting the development of a disease, disorder or condition and / or causing a decline or degradation of symptoms of a disease, disorder or condition. It is understood by those of ordinary skill in the art that various methodologies and analyzes are used to analyze the development of a disease, disorder or condition, and similarly, various methodologies and analyzes are used to analyze the decay or degradation of symptoms of a disease, disorder or condition .
[230] The term " prevention of disease symptoms considered by JNK " as used herein means preventing a disease, illness or condition that is at risk of disease but has no symptoms yet. The general practitioner in this field can be used to determine that various methods are at risk for disease and whether the subject is at risk for the disease depends on the patient's genetic makeup, age, weight, sex, diet, general physical and mental health, , Exposure to environmental conditions, and the like, which are well known to those skilled in the art.
[231] When employed pharmaceutically, the benzazole derivatives of the present invention are typically administered in the form of a pharmaceutical composition. Accordingly, pharmaceutical compositions comprising compounds of formula I and pharmaceutically acceptable carriers, diluents or adjuvants are also within the scope of the present invention. A person skilled in the art is aware of various carriers, diluents or adjuvant compounds suitable for formulating pharmaceutical compositions. The present invention also provides compounds for use as therapeutic agents. In particular, the present invention provides the use of a compound of formula I as a JNK, notably a JNK2 and JNK3 inhibitor, in the treatment of vertebrate animals, notably human immunity as well as neurological disorders, alone or in combination with other therapeutic agents .
[232] The compounds of the present invention are in the form of pharmaceutical compositions and unit dosage forms thereof, together with commonly employed adjuvants, carriers, diluents or excipients, and the forms may be solid, such as tablets or filled capsules, or solutions, suspensions, emulsions, Elixir, or capsules filled with the same, all oral, or topical (including subcutaneous) sterile injectable solutions. Such pharmaceutical compositions and unit dosage forms may comprise the components in a conventional ratio, with or without additional active ingredients or themes, and such unit dosage forms may contain suitable effective amounts of the active ingredients, corresponding to the intended dosage range employed do.
[233] When used as a medicament, the benzazole derivatives of the present invention are typically administered in the form of a pharmaceutical composition. Such compositions are prepared by methods well known in the art of pharmacy and comprise at least one active ingredient. Generally, a compound of the present invention is administered a pharmaceutically effective amount. The amount of the substantially administered compound is determined by a physician in light of the therapeutic condition, the route of administration, the actual compound administered, the age, the weight, the relevant environment including the response of the individual patient, and the severity of the patient's symptoms.
[234] The pharmaceutical composition of the present invention may be administered via various routes such as orally, rectally, topically, subcutaneously, intravenously, intramuscularly, and nasally. Depending on the intended delivery route, the compound is preferably formulated with an injectable, topical or oral composition. Compositions for oral administration may be in the form of a stock solution, a liquid solution or suspension, or an undiluted powder. However, universally take a unit dosage form that facilitates an accurate dose. The term " unit dosage form " refers to a physically distinct unit suitable for unit administration to human and vertebrate animals, wherein a predetermined amount of active material contained in each unit is combined with a suitable pharmaceutical excipient to provide the desired therapeutic effect . Typical unit dosage forms include pills, tablets, capsules, and the like in the case of pre-filled, pre-calculated ampoules or syringes or solid compositions of liquid compositions. In such a composition, the benzazole compound is typically formulated as a mixture of small constituents (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight, preferably from about 1 to about 40% by weight), with the balance being the various carriers and having the remainder to make the adjuvants useful for formulation in the desired dosage form %)to be.
[235] Suitable liquid forms for oral administration may include aqueous or nonaqueous carriers with buffer, suspensions and dispersions, colorants, fragrances, and the like. Solid forms can include, for example, one or more of the following ingredients, or compounds of similar properties: binders such as microcrystalline cellulose, gum tragacanth or gelatin; Excipients such as starch or lactose, disintegrating agents such as alginic acid, pre-Mosel, or konstach; Lubricants such as magnesium stearate; Such as corundum silicon dioxide; Sweeteners such as sucrose or saccharin; Or flavoring such as peppermint, methyl salicylate, or orange flavor.
[236] The injectable compositions are typically described in injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. As noted above, the benzazole compounds of formula I of such compositions typically range in the range of 0.05 to 10% by weight, with the remainder being typically small, sometimes in the form of injectable carriers and the like.
[237] The above-mentioned compositions for oral administration or injectable compositions are merely representative examples. Another material as well as manufacturing techniques, such as is described in "Part 8 of Remington's Pharmaceutical Sciences , 17 th Edition, 1985, Marck Publishing, Easton, Pennsylvania", is referred to here.
[238] The compounds of the present invention may also be administered in a sustained-release or sustained-release delivery system. Representative wastewater materials can also be found in the materials described in " Remington ' s Pharmaceutical Sciences ".
[239] Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited thereto. The compounds described herein are indicated in accordance with structural formula IIb and the compounds of structural formula Ib are mutual variants.
[240] The present invention will now be described in detail by way of practice, but is not construed to limit the scope of the present invention.
[241] HPLC, NMR and MS data provided in the examples described below were obtained as follows: HPLC: column Waters Symmetry C8 50 x 4.6 mm, conditions: a- MeCN / H ₂ O 0.09% TFA, 0 to 100% (10 min); b-MeCN / H ₂ O0.09% TFA, 0 to 100% (20 min); c-MeCN / H ₂ O 0.09% TFA, 5 to 100% (10 min), max plot 230-400 nm; d-MeCN / H ₂ O, 5 to 100% (10 min), max plot 230-400 nm; Mass spectrum: Perkin Elmer API 150 EX (APCI); ≪ ¹ > H-NMR: Brucker DPX-300 MHz.
[242] Example 1: Preparation of 1,3-benzothiazol-2-yl (2-chloro-4-pyrimidyl) -acetonitrile (One) Manufacturing
[243] To a stirred suspension of NaH (60% in oil, 9.2 g, 0.23 mol) in dry THF (200 ml) was added 1,3-benzothiazol-2-yl-acetonitrile (20 g, 0.15 mol) is added dropwise under an inert atmosphere. After stirring at room temperature for 1 hour and 30 minutes, a solution of 2,4-dichloropyrimidine (17.1 g, 0.15 mol) in dry THF (200 ml) is added dropwise. The reaction mixture is left under an inert atmosphere at room temperature until the starting material completely disappears. This reaction is terminated with the addition of water and the THF is distilled. Water is added and the suspension is slowly acidified with aqueous HCl 1M. The obtained precipitate is filtered and completely washed with water until it becomes neutral, and then washed with nucleic acid to remove the oil. The crude solid was stirred at 40 < 0 > C under vacuum to give 28 g (84%) of the title compound as a pale brown powder: mp 246 [deg.] C dec .; MS: 286.8 (M + 1); HPLC (Conditions a, 268 nm) 97%, rt 5.66 min; ^{1 HNMR (DMSO- d 6) d} 13.25 (br s, 1H, exchangeable), 8.09 (d, J = 4.14 Hz, 1H), 7.90 (d, J = 7.53 Hz, 1H), 7.61 (d, J = 7.92 Hz, 1 H), 7.39-7.34 (m, 1 H), 7.20-7.15 (m, 1 H), 6.96 (br d, 1 H).
[244] CHN analysis: C ₁₃ H ₇ ClN ₄ S: Calcd .: C, 54.19%, H 2.48%, N 19.45%; Discovery: C 53.35%, H 2.77%, N 17.62%
[245] Using the procedures described above in Example 1 and the appropriate starting materials and reagents, the following benzothiazole derivatives of formula I can be obtained.
[246] Benzothiazol-2-yl (2,6-dimethoxy-4-pyrimidyl) acetonitrile (2)
[247] Y = 11.3%; MS: 313.0 (M + 1); HPLC (Conditions b, 372 nm): 97%, rt. 13.90 min
[248] ¹ H NMR (DMSO- d 6) 12.78 (br s, 1H, exchangeable), 7.85 (d, J = 7.73 Hz, 1H), 7.55 (d, J = 7.97 Hz, 1H), 7.42-7.37 ), 7.25-7.20 (m, IH), 6.19 (s, IH), 4.07 (s, 3H), 3.86 (s, 3H).
[249] Benzothiazol-2-yl (2-chloro-6-methyl-4-pyrimidyl) acetonitrile (3)
[250] Y = 42.8%; MS: 300.8 (M + 1); HPLC (Conditions b, 254 nm): 92%; rt. 13.91 min.
[251] ^{1 HNMR (DMSO- d 6) d} 13.22 (br s, 1H, exchangeable), 7.96 (d, J = 7.79 Hz, 1H), 7.63 (d, J = 8.17 Hz, 1H), 7.48-7.42 (m, 1H ), 7.30-7.25 (m, 1 H), 7.07 (s, 1 H), 2.39 (s, 3 H).
[252] Benzothiazol-2-yl [2- (methylsulfanyl) -4-pyrimidyl] acetonitrile (4)
[253] Y = 73.5%; MS: 298.8 (M + 1); HPLC (Conditions a, 254 nm): 99%, rt. 4.64 min
[254] ^{1 HNMR (DMSO- d 6) d} 13.01 (br s, 1H, exchangeable), 8.10 (br d, 1H), 7.93 (d, J = 7.75 Hz, 1H), 7.66 (d, J = 8.01 Hz, 1H) , 7.45-7.40 (m, IH), 7.29-7.23 (m, IH), 6.84 (br d, IH), 2.71 (s, 3H).
[255] (6-chloro-5-nitro-4-pyrimidyl) acetonitrile (5)
[256] Y = 7.3%; MS: 332.0 (M + 1); HPLC (Conditions a, 270 nm): 86%, rt. 6.10 min
[257] ^{1 HNMR (DMSO- d 6) d} 8.80 (s, 1H), 8.00 (d, J = 7.91 Hz, 1H), 7.77 (d, J = 8.29 Hz, 1H), 7.53-7.47 (m, 1H), 7.38 -7.32 (m, 1 H).
[258] (2-oxo-2,3-dihydro-4-pyridinyl) acetonitrile (6)
[259] Y = 36.2%; MS: 269.0 (M + 1); HPLC (Conditions a, 271 nm): 90%, rt. 525 min
[260] ^{1 HNMR (DMSO- d 6) d} 12.86 (br s, 1H, exchangeable), 11.82 (br s, 1H, exchangeable), 8.06 (d, J = 8 Hz, 1H), 7.89 (d, J = 8.04 Hz, 1H), 7.58 (d, J = 7.28 Hz, 1H), 7.53-7.48 (m, 1H), 7.40-7.35 (m, 1H), 6.11 (d, J = 7.31 Hz, 1H).
[261] Benzothiazol-2-yl (2-phenyl-4-quinazolinyl) acetonitrile (7)
[262] Y = 83.6%; MS: 379.0 (M + 1); HPLC (Conditions a, 248 nm): 86%, rt. 7.09 min
[263] ^One≪ 1 > H NMR (DMSO-d6) d 12.86 (br s, 1H, exchangeable), 9.03 (d,J= 8.29 Hz, 1H), 8.43-8.34 (m, 2H), 7.99 (d,J= 7.91 Hz, 1 H), 7.87 (d,J =7.91 Hz, 1H), 7.83-7.67 (m, 5H), 7.60-7.53 (m, 1H), 7.47-7.42 (m, 1H), 7.33-7.28 (m, 1H).
[264] Yl] acetonitrile (8) [ 0156] To a solution of (2-chloropyrimidin-4-yl )
[265] Y = 58.6%; MS: 352.6 (M-1); HPLC (Conditions c, max plot): 99.8%, rt. 5.96 min
[266] ^One≪ 1 > H NMR (DMSO-d6) d 8.37 (d,J= 5.66 Hz, 1 H), 8.21 (d,J= 8.29 Hz, 1 H), 7.87 (s, 1 H), 7.60 (d,J= 7.91 Hz, 1 H), 7.23-7.19 (m, 1 H).
[267] (3-methyl-1,3-benzothiazol-2 (3H) -ylidene) ethanenitrile (9)
[268] Dry K ₂ CO ₃ and methyl iodide are added to a solution of 1 (0.1 g, 0.35 mmol) in dry DMSO and the suspension is stirred at room temperature for 2 days. The precipitate formed by the addition of water is filtered and then washed with water until neutral pH is reached. The crude residue was stirred at 40 < 0 > C under vacuum and titrated with warm acetonitrile, yielding 5.6 mg (5%) of the title compound as a yellow powder.
[269] MS: 623 (2M + Na); HPLC (Conditions a, 388 nm): 99%, rt. 5.31 min
[270] ^{1 H NMR (DMSO- d6):} d 8.01 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 7.4 Hz, 1H), 7.45-7.40 ( (d, J = 7.4 Hz, 1 H), 3.67 (s, 3H)
[271] Example 2: Synthesis of 1,3-benzothiazol-2-yl (2 - {[2- (1H-imidazol-4-yl) ethyl] amino} -4-pyrimidyl) acetonitrile (10) Manufacturing
[272] Et ₃ N (0.05 ml, 0.35 mmol) and histamine (0.078 g, 0.70 mmol) are added to a suspension of 1 (0.1 g, 0.35 mmol) in dry EtOH (3 ml). After sonication, the yellow solution is stirred at 70 < 0 > C for 3 days. The resulting yellow precipitate was filtered and washed with H2O (2X) and then with EtOH (3X) and dried under vacuum at 40 ° C to give 47 mg (37%) of the title compound as a light yellow powder: mp 257-258 [deg.] C ,
[273] 10 is taken in a mixture of DCM / TFA. The yellow needles formed by the addition of ether were filtered off, washed with ether (3X) and then dried under vacuum at 40 [deg.] C to give 36 mg (29%) of the title compound as a yellow powder: mp 247-249 [ , MS: 362.0 (M + 1); HPLC (Conditions a, 265 nm): 98%, rt. 2.87 min; ¹ H NMR (DMSO- d6 ): d 14.25 (br s, 2H, exchangeable), 11.05 (br s, 1H, exchangeable), 9.03 (s, 1H), 7.94-7.87 (m, 2H), 7.57-7.52 ( m, 2H), 7.42-7.37 (m, 1H), 7.24-7.19 (m, 1H), 6.40 (d, J = 7.1Hz, 1H), 3.97-3.55 (m , 3H), 3.11-3.05 (m, 2H).
[274] CHN analysis: C18H15N7S. 2 TFA: Calcd: C 44.83%, H 2.91%, N 16.63%; Discovery: C 44.59%, H 3.18%, N 16.43%
[275] By using the procedures described above in Example 2 and the appropriate starting materials and reagents, the following benzothiazole derivatives of the additional structural formula II can be obtained.
[276] Benzothiazol-2-yl [2- (1-piperazinyl) -4-pyrimidyl] acetonitrile (2 TFA) (11)
[277] Y = 37%; MS: 337.2 (M + 1); HPLC (Conditions a, 271 nm): 96%, rt. 2.58 min
[278] ^{1 H NMR (DMSO- d6):} d 9.13 (br s, 2H, exchangeable), 7.96 (br d, 1H), 7.90 (d, J = 7.74 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1H), 7.45-7.40 (m, 1H), 7.29-7.24 (m, 1H), 6.58 (d, J = 6.0 Hz, 1H), 4.70-3.60 .
[279] (4-benzyl-1-piperidinyl) -4-pyrimidyl] acetonitrile (TFA) (12)
[280] Y = 52%; MS: 426.0 (M + 1); HPLC (Conditions a, 394 nm): 99%, rt. 5.42 min
[281] ¹ H NMR (DMSO- d6 ): d 7.94 (d, J = 7.78 Hz, 1H), 7.72-7.69 (m, 2H), 7.46-7.41 (m, 1H), 7.32-7.24 7.21-7.18 (m, 3H), 6.50 (d, J = 6.2 Hz, 1H), 4.55-4.51 (m, 2H), 4.35-3.45 (m, 1H), 3.16-3.04 (m, 2H), 2.56 ( d, J = 7.0Hz, 2H), 2.00-1.85 (m, 1H), 1.81-1.72 (m, 2H), 1.34-1.21 (m, 2H).
[282] 2-yl [2- (4-methyl-1-piperazinyl) -4-pyrimidyl] acetonitrile (2 TFA) (13)
[283] Y = 30%; MS: 351.0 (M + 1); HPLC (Conditions a, 271 nm): 99%, rt. 2.54 min
[284] ^{1 H NMR (DMSO- d6):} d 10.10 (br s, 2H, exchangeable), 8,05 (br d, 1H), 7.88 (d, J = 7.8 Hz, 1 H), 7.63 (d, J = 8.0 (M, 2H), 4.42-3.68 (m, 2H), 6.60 (d, J = 1H), 3.67-3.50 (m, 2H), 3.48-3.31 (m, 2H), 3.26-3.05 (m, 2H), 2.86 (s, 3H).
[285] Yl] [2- (4-morpholinyl) -4-pyrimidyl] acetonitrile (TFA) (14)
[286] Y = 55%; MS: 338.0 (M + 1); HPLC (Conditions a, 270 nm): 99%, rt. 3.51 min
[287] ^{1 H NMR (DMSO- d6):} d 7.94 (d, J = 7.8 Hz, 1 H), 7.79 (br d, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.45-7.40 (m, 1H ), 7.30-7.25 (m, 1H), 6.54 (d, J = 6.3Hz, 1H), 4.40-3.65
[288] Benzothiazol-2-yl [2- (methylamino) -4-pyrimidyl] acetonitrile (TFA salt )(15)
[289] Y = 11%; MS: 282.0 (M + 1); HPLC (Conditions a, 270 nm): 97%, rt. 3.39 min
[290] ^{1 H NMR (DMSO- d6):} d 11.70 (v br s, 1 H, exchangeable) 8.15-7.90 (m, 2H [1 + 1 exchangeable]), 7.85-7.55 (m, 2H), 7.46-7.41 (m (M, 1H), 7.30-7.25 (m, 1H), 6.43 (d, J = 6.0 Hz, 1H), 4.81-3.78
[291] 1,3-benzothiazol-2-yl (2- {4- [2- (4-morpholinyl) ethyl] -1-piperazinyl} -4-pyrimidyl) -acetonitrile (3 TFA) ( 16)
[292] Y = 78%; MS: 450.2 (M + 1); HPLC (Conditions a, 270 nm): 99%, rt. 2.67 min
[293] ^{1 HNMR (DMSO- d 6) d} 7.91 (br d, 1H), 7.86 (d, J = 7.73 Hz, 1H), 7.66 (d, J = 8.01 Hz, 1H), 7.45-7.40 (m, 1H), 7.29-7.24 (m, 1H), 6.56 (d, J = 5.94 Hz, 1H), 4.10-3.93 (m, 4H), 3.85-3.42 (m, 5H), 3.32-3.23 (m, 4H), 3.18- 3.04 (m, 8 H)
[294] (17) < RTI ID = 0.0 > 1-benzothiazol-
[295] Y = 76.2%; MS: 442.2 (M + 1); HPLC (Conditions a, 268 nm): 99%, rt. 5.00 min
[296] ^{1 HNMR (DMSO- d 6):} d 7.92 (d, J = 7.94 Hz, 1H), 7.70 (d, J = 8.08 Hz, 1H), 7.65 (br d, 1H), 7.43-7.35 (m, 5H) , 7.32-7.22 (m, 2H), 6.46 (d, J = 6.6 Hz, 1H), 4.59 (s, 2H), 4.20-4.06 (m, 2H), 3.81-3.72 (m, 1H), 3.70-3.59 (m, 2H), 3.57-3.20 (m, 1H), 2.09-1.96 (m, 2H), 1.77-1.61
[297] (4-hydroxy-1-piperidinyl) -4-pyrimidyl] acetonitrile (TFA) (18)
[298] Y = 14%; MS: (M + 1); HPLC (Conditions a, 271 nm): 97%, rt. 3.21 min ¹
[299] ^{1 HNMR (DMSO- d 6):} d 7.95 (d, J = 7.79 Hz, 1H), 7.72-7.65 (m, 2H), 7.45-7.40 (m, 1H), 7.28-7.23 (m, 1H), 6.48 (, d, J = 6.07 Hz , 1H), 4.60-3.75 (m, 5H), 3.58-3.51 (m, 2H), 1.95-1.82 (m, 2H), 1.55-1.42 (m, 2H)
[300] Benzothiazol-2-yl (2-hydrazino-4-pyrimidyl) acetonitrile (TFA) (19)
[301] Y = 60%; MS: 283.0 (M + 1); HPLC (271 nm): 98%, rt. 3.17 min
[302] ¹ H NMR (DMSO- d6 ): d 9.78 (br s, 1H, exchangeable), 7.89-7.75 (m, 4H), 7.48-7.43 (m, 1H), 7.32-7.27 d, 1 H), 4.25 - 3.40 (m, 1 H).
[303] (2 - {[2- (dimethylamino) ethyl] amino} -4-pyrimidyl) acetonitrile (2 TFA )
[304] Y = 30%; MS: 339.0 (M + 1); HPLC (Conditions a, 270 nm): 99%, rt. 2.69 min
[305] ^{1 H NMR (DMSO- d6):} d 11.85 (v br s, 1H, exchangeable), 9.59 (br s, 1H), 7.90 (br d, 2H), 7.73 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 6.8 Hz, 1 H), 4.25-3.70 (m, 3H), 3.51-3.41 (br d, 1H), 7.43-7.38 m, 2 H), 2.87 (s, 6 H).
[306] Benzothiazol-2-yl [2- (dimethylamino) -4-pyrimidyl] acetonitrile (21)
[307] Y = 12%; MS: 295.8 (M + 1); HPLC (Conditions a, 270 nm): 99%, rt. 3.50 min
[308] ^{1 H NMR (DMSO- d6):} d 11.20, (br s, 1 H), 7.88 (d, J = 7.76 Hz 1H), 7.69 (d, J = 8 Hz 1H), 7.46 (br d, 1H), 7.38-7.33 (m, 1H), 7.20-7.16 (m, 1H), 6.38 (d, J = 6.9 Hz, 1H), 3.26 (s, 6H).
[309] Benzothiazol-2-yl {2- [(2-methoxyethyl) amino] -4-pyrimidyl} acetonitrile (22)
[310] Y = 54%; MS: 326.0 (M + 1); HPLC (Conditions a, 273 nm): 99%, rt. 3.66 min
[311] ^{1 HNMR (DMSO- d 6):} d 10.83 (s, 1H), 7.85 (d, J = 7.54 Hz, 1H), 7.72 (d, J = 7.91 Hz, 1H), 7.60 (br s, 1H), 7.44 (d, J = 6.78 Hz, 1H), 7.38-7.33 (m, 1H), 7.22-7.16 (m, 1H), 6.33 (d, J = 7.16 Hz, 1H), 3.82-3.74 (m, 2H), 3.62 (t, J = 5.27 Hz, 2H), 3.31 (s, 3H)
[312] Benzothiazol-2-yl {2- [(2-hydroxyethyl) amino] -4-pyrimidyl} acetonitrile (23)
[313] Y = 80%; MS: 312.2 (M + 1); HPLC (Conditions a, 273 nm): 99%, rt. 3.16 min
[314] ^{1 HNMR (DMSO- d 6):} d 10.85 (s, 1H), 7.86 (d, J = 7.91 Hz, 1H), 7.71 (d, J = 7.91 Hz, 1H), 7.57 (br s, 1H), 7.44 (d, J = 7.16 Hz, 1H), 7.38-7.32 (m, 1H), 7.21-7.16 (m, 1H), 6.32 (d, J = 7.16 Hz, 1H), 4.92 (br s, 1H), 3.68 (br s, 4H)
[315] Benzothiazol-2-yl [2- (propylamino) -4-pyrimidyl] acetonitrile (24)
[316] Y = 81%; MS: 310.0 (M + 1); HPLC (Conditions a, 273 nm): 95%, rt. 4.04 min
[317] ^{1 HNMR (DMSO- d 6):} d 10.91 (br s, 1H), 7.84 (d, J = 7.54 Hz, 1H), 7.71 (d, J = 8.29 Hz, 1H), 7.62 (br s, 1H), 7.42 (d, J = 6.78 Hz , 1H), 7.38-7.32 (m, 1H), 7.21-7.16 (m, 1H), 6.31 (d, J = 7.53 Hz, 1H), 3.42-3.33 (m, 2H) , 1.71-1.64 (m, 2H), 1.02-0.97 (m, 3H)
[318] Propyl] amino} -4-pyrimidyl) acetonitrile (TFA) (25) was obtained in the same manner as in Example 1,
[319] Y = 57%, MS: 376.0 (M + 1); HPLC (Conditions a, 270 nm): 98%, rt. 2.80 min
[320] ^{1 H NMR (DMSO- d6):} d 14.40 (br s, 1 H, exchangeable), 11.60 (br s, 1 H, exchangeable), 9.18 (s, 1H), 8.13 (br d, 1H), 7.92-7.85 (m, 2H), 7.74-7.59 ( m, 3H), 7.43-7.39 (m, 1H), 7.28-7.23 (m, 1H), 6.40 (d, J = 7.2 Hz, 1H), 4.35 (t, J 2H), 3.70-3.45 (m, 2H), 5.05-4.20 (m, 1H), 2.35-2.10
[321] Benzothiazol-2-yl [2- (1-pyrrolidinyl) -4-pyrimidyl] acetonitrile (26)
[322] Y = 27%, mp = 270-272 [deg.] C, MS: 322.0 (M + 1); HPLC (Conditions a, 372 nm): 98%, rt. 3.90 min
[323] ^{1 H NMR (DMSO- d6):} d 11.30 (v br s, 1 H, exchangeable), 7.86 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 6.8 Hz, 1H), 7.35-7.30 (m, 1H), 7.17-7.12 (m, 1H), 6.33 (d, J = 6.8 Hz, 1H), 3.90-3.45 (m, 4H).
[324] Benzothiazol-2-yl {2- [(2-phenylethyl) amino] -4-pyrimidyl} acetonitrile (27)
[325] Y = 46.1%; mp = 256 [deg.] C dec., MS: 371.8 (M + 1); HPLC (Conditions a, 270 nm): 99%, rt. 4.64 min
[326] ^{1 HNMR (DMSO- d 6):} d 11.04 (br s, 1H), 7.71 (d, J = 8.29 Hz, 1H), 7.64-7.61 (m, 2H), 7.45 (d, J = 7.16 Hz, 1H) , 7.37-7.32 (m, 5H), 7.29-7.26 (m, 1H), 7.20-7.16 (m, 1H), 6.33 (d, J = 7.17 Hz, 1H), 3.94-3.81 (m, 2H), 2.99 (t, J = 7.54 Hz, 2H)
[327] (2 - {[2- (2-pyridinyl) ethyl] amino} -4-pyrimidyl) acetonitrile (2 TFA )
[328] Y = 80%; mp = 247 [deg.] C dec., MS: 373.2 (M + 1); HPLC (Conditions a, 266 nm): 99%, rt. 2.85 min
[329] ^{1 HNMR (DMSO- d 6) d} 8.70 (d, J = 5.28 Hz, 1H), 8.15-8.10 (m, 1H), 7.88 (br s, 1H), 7.75-7.72 (m, 2H), 7.67 (d , J = 7.91 Hz, 1H) , 7.61-7.50 (m, 2H), 7.44-7.39 (m, 1H), 7.28-7.23 (m, 1H), 6.44 (d, J = 7.14 Hz, 1H), 4.65- 3.60 (m, 3 H), 3.32 - 3.28 (m, 2 H)
[330] CHN analysis: C20H16N6S. 2 TFA: Calcd .: C 47.29%, H 3.14%, N 13.79%; Discovery: C 47.47%, H 3.21%, N 13.71%
[331] (2-pyridinylmethyl) amino] -4-pyrimidyl} acetonitrile (2 TFA) (29)
[332] Y = 52%; mp = 250 [deg.] C dec., MS: 359.0 (M + 1); HPLC (Conditions a, 266 nm): 99%, rt. 2.84 min
[333] ^{1 HNMR (DMSO- d 6):} d 8.66 (d, J = 4.9 Hz, 1H), 8.38 (br s, 1H), 7.99-7.94 (m, 1H), 7.82 (d, J = 7.91 Hz, 1H) , 7.71-7.69 (m, 2H), 7.64 (d, J = 7.91 Hz, 1H), 7.45-7.38 (m, 2H), 7.28-7.23 (m, 1H), 6.48 (d, J = 6.78 Hz, 1H ), 5.00 (br s, 2H), 5.15-4.05 (m, 2H).
[334] CHN analysis: C19H14N6S. 2 TFA: Calcd .: C 47.10%, H 2.75%, N 14.33%; Discovery: C 46.93%, H 2.96%, N 14.24%
[335] Benzothiazol-1-yl) -1-piperidinyl] -4-pyrimidyl} acetonitrile ( TFA) 30
[336] Y = 65%; MS: 453.2 (M + 1); HPLC (Conditions a, 254 nm): 90%, rt. 4.39 min
[337] ^{1 HNMR (DMSO- d 6):} d 8.06 (d, J = 8.29 Hz, 1H), 8.01 (d, J = 8.67 hz, 1H), 7.91 (d, J = 7.91 Hz, 1H), 7.80 (br d , 7.70 (d, J = 8.29 Hz, 1H), 7.60-7.55 (m, 1H), 7.44-7.39 (m, 1H), 7.27-7.22 (m, 1H), 8.01-7.22 2H), 4.90-3.90 (m, 1H), 3.57-3.50 (m, 2H), 6.56 (d, J = 6.42 Hz, 1H), 5.40-5.33 (m, ), 2.37-2.27 (m, 4H)
[338] (31) < RTI ID = 0.0 > 1-benzothiazol-
[339] Y = 88%; MS: 415.2 (M + 1); HPLC (Conditions a, 254 nm): 99%, rt. 3.74 min
[340] ^{1 HNMR (DMSO- d 6):} d 8.39 (br d, 1H), 8.13 (dd, J = 2.64, 1.51 Hz, 1H), 7.97 (d, J = 7.91 Hz, 1H), 7.88 (d, J = 1H), 7.31-7.26 (m, 1H), 8.13-7.26 (d, J = 7.91 Hz, (m, 1H), 6.53 (d, J = 6.78 Hz, 1H), 4.06-3.96 (m, 4H), 3.87-3.77 (m, 4H), 4.60-3.65
[341] (2-pyrimidyl) -1-piperazinyl] -4-pyrimidyl} acetonitrile (TFA )
[342] Y = 85%; MS: 415.2 (M + 1); HPLC (Conditions a, 254 nm): 99%, rt. 3.81 min
[343] ^{1 HNMR (DMSO- d 6):} d 8.44 (d, J = 4.52 Hz, 2H), 8.03 (d, J = 7.91 Hz, 1H), 7.83 (br d, 1H), 7.78 (d, J = 7.91 Hz , 1H), 7.48-7.43 (m, 1H), 7.32-7.27 (m, 1H), 8.44-7.27 (very br m, 1H), 6.71-6.68 (m, 1H), 6.56 (d, J = 6.4 Hz , 5.15-4.10 (m, 1 H), 3.98 (s, 8 H)
[344] (3-pyridinyl) ethyl] amino} -4-pyrimidyl) acetonitrile (2 TFA) (33)
[345] Y = 74%; MS: 373.0 (M + 1); HPLC (Conditions a, 263 nm): 99%, rt. 2.92 min
[346] ^{1 HNMR (DMSO- d 6):} d 8.81 (d, J = 1.13 Hz, 1H), 8.71 (dd, J = 5.27 Hz, J = 1.13 Hz, 1H), 8.31 (d, J = 7.91 Hz, 1H) , 7.94 (br s, 1H) , 7.85-7.73 (m, 3H), 7.60 (br d, 1H), 7.45-7.40 (m, 1H), 7.29-7.24 (m, 1H), 6.43 (d, J = 1H), 6.00-4.40 (m, 2H), 4.05-3.87 (m, 2H), 3.19-3.15
[347] 1,3-benzothiazol-2-yl (5-bromo-2 - {[2- (dimethylamino) ethyl] amino} -4-pyrimidyl) -acetonitrile 34
[348] Y = 2%; MS: 419.0 (M + 1); HPLC (Conditions a, 285 nm): 88%, rt. 8.00 min
[349] ^{1 H NMR (DMSO- d6):} d 11.30 (v br s, 1 H, exchangeable), 7.76 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.8 Hz, 2H), 3.15-2.95 (m, 2H), 2.64 (s, 1H), 7.26-7.21 , 6H).
[350] 4-yl} acetonitrile (di TFA) (35) was obtained in the same manner as in Example 1 except that 1-benzothiazol-2-
[351] Y = 53%; MS: 381.0 (M + 1); HPLC (Conditions a, 254 nm): 99.5%, rt. 2.80 min
[352] ¹ H NMR (DMSO- d6 ): d 10.9 (v br s, 1 H, exchangeable), 8.00-7.98 (m, 2H), 7.73 (d, J = 7.9 Hz, , 7.42-7.37 (m, 1H), 7.27-7.22 (m, 1H), 6.55 (d, J = 7.15, 1H), 4.24-3.18 (m, 12H).
[353] ^{1 H NMR (D2O): d} 7.59 (d, J = 7.9 Hz, 1H), 7.39-7.29 (m, 2H), 7.20-7.15 (m, 2H), 6.20 (d, J = 6.8, 1H), 3.89 -3.82 (m, 6H), 3.45-3.32 (m, 6H)
[354] Synthesis of 1,3-benzothiazol-2-yl [2- (4- {3 - [(trifluoromethyl) sulfonyl] anilino} piperidin- 1 -yl) pyrimidin- (TFA) 36,
[355] Y = 69%; MS: 559.2 (M + 1); HPLC (Conditions a, 254 nm): 96%, rt. 5.60 min
[356] ^{1 H NMR (DMSO- d6):} d 7.94 (d, J = 7.54 Hz, 1H), 7.61-7.59 (m, 2H), 7.56-7.49 (m, 1H), 7.45-7.38 (m, 1H), 7.27 (M, 2H), 1.52-1.48 (m, 2H), 7.13-7.16 (m, 4H), 6.72-6.59 (m, 2H).
[357] Yl) acetonitrile (TFA) (37) The title compound was prepared in accordance with the general method of example 1, step (b)
[358] Y = 65%; MS: 3.93 (M + 1); HPLC (Conditions a, 254 nm): 98%, rt. 3.52 min
[359] ^{1 H NMR (DMSO- d6):} d 11.50 (v br s, 1H, exchangeable), 8.15-8.02 (br s, 1H), 7.95-7.60 (m, 4H), 7.46-7.41 (m, 1H), 7.31 (M, 2H), 1.92-1.84 (m, 4H), 7.25-7.25 (m, ).
[360] CHN analysis: C ₂₀ H ₂₀ N ₆ O ₁ S calculated: C, 51.80%, H 4.23%, N 16.47%; Discovery: C 51.59%, H 4.26%, N 16.16%
[361] Yl) acetonitrile (di TFA) (38) was obtained in the same manner as in Example 1,
[362] Y = 11%; MS: 353.2 (M + 1); HPLC (Conditions a, 272 nm): 96%, rt. 2.88 min
[363] ^{1 H NMR (DMSO- d6):} d 11.30 (v br s, 1H, exchangeable), 8.50-8.25 (br s, 2H), 7.92 (d, J = 7.91 Hz, 1H), 7.72-7.68 (m, 2H ), 7.43-7.37 (m, 1 H), 7.27-7.21 (m, 1 H), 6.46 (d, J = 6.8 Hz, 1 H), 4.00 -3.65 3.10-2.85 (m, 2H), 2.63-2.51 (m, 3H), 2.10-1.80 (m, 2H).
[364] Yl) acetonitrile (tri TFA salt) (39) The title compound was prepared in analogy to the procedure described in Example < RTI ID = 0.0 >
[365] Y = 65.2%; MS: 408.0 (M + 1); HPLC (Conditions a, 272 nm): 99.2%, rt. 2.67 min
[366] ^One≪ 1 > H NMR (DMSO-d6) d 7.94-7.91 (m, 2H), 7.74 (d,J(M, 1H), 6.40 (d, 1H), 7.46-7.38J= 7.17 Hz, 1H), 4.95-4.05 (m, 1H), 3.71-3.60 (m, 2H), 3.54-3.15 (m, 4H), 3.02-2.86 2.03-1.91 (m, 2H).
[367] Yl} acetonitrile (di TFA salt) (40) The title compound was prepared in analogy to example 1 ,
[368] Y = 73.9%; MS: 408.2 (M + 1); HPLC (Conditions a, 272 nm): 99.6%, rt. 2.77 min
[369] ^One≪ 1 > H NMR (DMSO-d6) d 9.66 (br s, 1 H), 7.94 (d,J= 7.91 Hz, 1 H), 7.86 (br s, 1 H), 7.73 (d,J= 7.91 Hz, 1 H) 7.55 (br d, 1 H), 7.43-7.38 (m, 1 H), 7.27-7.22J2H), 3.16-3.00 (m, 2H), 2.15-7.17 (m, 2H), 4.15-3.52 2.01 (m, 2H).
[370] Ethyl] amino} pyrimidin-4-yl) acetonitrile (41) was obtained in the same manner as in Example 1,
[371] Y = 58.8%; MS: 376.0 (M + 1); HPLC (Conditions a, 272 nm): 99.3%, rt. 3.09 min
[372] ^One≪ 1 > H NMR (DMSO-d6) d 2H), 7.43-7.38 (m, 1 H), 7.90-7.70 (m, 3H) , 7.27-7.22 (m, 1 H), 6.41 (d,J= 7.17 Hz, 1H), 4.60-4.10 (m, 1H), 3.93-3.85 (m, 2H), 3.83 (s, 3H), 3.11-3.02 (m, 2H).
[373] Yl) amino] pyrimidin-4-yl) acetonitrile (42) was obtained in the same manner as in Example 1,
[374] Y = 60.6%; MS: 411.0 (M + 1); HPLC (Conditions a, 272 nm): 99.9%, rt. 4.94 min
[375] ^One≪ 1 > H NMR (DMSO-d6) d (M, 1H), 7.71 (d, < RTI ID = 0.0 >J1H), 7.21-7.16 (m, 1H), 7.10-7.05 (m, 1H), 7.42-7.37 (m, , 6.97 - 6.92 (m, 1H), 6.44 (d,J= m 7.17 Hz, 1 H), 4.60-3.70 (m, 3H [2 + 1]), 3.12 (t,J= 7.15 Hz, 2H).
[376] Ethyl] amino} pyrimidin-4-yl) acetonitrile (43) was obtained in the same manner as in Example 1,
[377] Y = 76%; m.p. 258-261 C; MS: 388.0 (M + 1); HPLC (Conditions a, 272 nm): 98.8%, rt. 4.00 min
[378] ^One≪ 1 > H NMR (DMSO-d6) d 1H), 7.29-7.24 (m, 1H), 7.12 (d, 1H), 7.75-7.69J= 8.29 Hz, 1 H), 6.74 (d,J= 8.29 Hz, 1 H) 6.43 (d,J= 6.78 Hz, 1 H), 3.89-3.71 (m, 2H), 2.90-2.85 (m, 2H)
[379] Methyl} pyrimidin-2-yl} amino) acetate (TFA salt) (44) was reacted with tert-
[380] Y = 72%; MS: 382.0 (M + 1); HPLC (Conditions a, 272 nm): 98.2%, rt. 4.37 min
[381] ^One≪ 1 > H NMR (DMSO-d6) d 1H, exchangeable), 7.92 (br s, 1H, exchangeable), 7.82 (d,J= 7.54 Hz, 1 H), 7.75 (d,J= 8.23 Hz, IH), 7.61 (br d, IH), 7.46-7.39 (m, IH), 7.32-7.26J= 6.78 Hz, 1H), 4.50-3.80 (m, 2H), 1.40 (s, 9H)
[382] (Di-TFA) (45) To a solution of (2-amino-3-
[383] Y = 62%; MS: 325.0 (M + 1); HPLC (Conditions a, 382 nm): 90.0%, rt. 2.67 min
[384] ^One≪ 1 > H NMR (DMSO-d6) d 1H, exchangeable), 7.90 (br s, 1H, exchangeable), 7.90 (d,J= 7.92 Hz, IH), 7.75-7.49 (m, 3H), 7.44-7.37 (m, IH), 7.27-7.22J= 7.16 Hz, 1H), 5.50-4.00 (m, 3H, exchangeable), 3.80-3.5 (m, 2H), 3.00-2.80 (m, 2H), 2.10-1.80 (m, 2H).
[385] (Di-TFA) (46) To a solution of (2-aminoethyl) amino] pyrimidin-
[386] Y = 86%; MS: 311.0 (M + 1); HPLC (Conditions a, 382 nm): 95%, rt. 2.64 min
[387] ^One≪ 1 > H NMR (DMSO-d6) d 11.60 (v br s, 1H, exchangeable), 7.95-7.86 (m, 3H), 7.73 (d,J= 7.91 Hz, IH), 7.59 (br d, IH), 7.43-7.37 (m, IH), 7.28-7.22J= 7.16 Hz, 1 H), 5.50-4.00 (m, 3H, exchangeable), 3.90-3.70 (m, 2H), 3.25-3.10 (m, 2H).
[388] (47) was obtained in the same manner as in Example 1, except that 1, 3-benzothiazol-2-yl (2- {[3- (dimethylamino) propyl] amino} pyrimidin-
[389] Y = 54%; m.p. 204-205 DEG C; MS: 353.0 (M + 1); HPLC (Conditions a, 272 nm): 98%, rt. 2.75 min
[390] ^One≪ 1 > H NMR (DMSO-d6) d 11.4 (v br s, 1 H), 9.43 (s, 1 H), 7.94 (d, J = 7.91 Hz, 1 H). 7.90 (br s, 1 H), 7.73 (d,J= 7.91 Hz, IH), 7.55 (br d, IH), 7.43-7.37 (m, IH), 7.27-7.22J= 7.14 Hz, 1 H), 4.80-4.00 (m, 1H), 3.71-3.60 (m, 2H), 3.24-3.13J= 4.14 Hz, 6H), 2.11-1.99 (m, 2H)
[391] Yl} acetonitrile (di TFA salt) (48) The title compound was prepared in accordance with the general method of example 1, step (b)
[392] Y = 12%; m.p. 228-230 캜; MS: 379.0 (M + 1); HPLC (Conditions a, 270 nm): 99.9%, rt. 2.84 min
[393] ^One≪ 1 > H NMR (DMSO-d6) d 9.18 (br s, 1 H), 7.89-7.87 (m, 2 H), 7.74 (d,J= 7.91 Hz, 1 H), 7.62 (br s, 1 H), 7.44-7.39 (m, 1 H), 7.29-7.24J= 7.17 Hz, 1 H), 5.25-4.30 (m, 1H), 4.05-3.93 (m, 2H), 3.63-3.50 (m, 2H), 3.48-3.37 ), 1.90-1.30 (m, 6H)
[394] Yl) ethyl] amino} pyrimidin-4-yl) acetonitrile (di TFA salt) (49)
[395] Y = 46%; m.p. 219-220 C; MS: 376.0 (M + 1); HPLC (Conditions a, 270 nm) 99.8%, rt. 2.73 min
[396] ^One≪ 1 > H NMR (DMSO-d6) d 1H), 7.41-7.36 (m, 1H), 7.24 (brs, 1H), 7.83-7.64 -7.18 < / RTI > (m, 1H), 6.41 (d,J= 7.14 Hz, 1 H), 4.50-3.88 (m, 3H), 3.78 (s, 3H), 3.10-3.05
[397] Benzothiazol-2-yl [2- (benzylamino) pyrimidin-4-yl] acetonitrile (50)
[398] Y = 78%; MS: 358.0 (M + 1); HPLC (Conditions a, 254 nm): 99.2%, rt. 4.40 min
[399] ^One≪ 1 > H NMR (DMSO-d6) d 8.30 (br t, 1 H), 7.84 (d,J= 7.53 Hz, 1 H), 7.71 (d,J= 7.91 Hz, 1 H), 7.65 (br d, 1 H), 7.46-7.34 (m, 5H), 7.28-7.22J= 7.14 Hz, IH), 5.2-4.5 (m, IH), 4.86 (br d, 2H).
[400] Methyl} pyrimidin-2-yl} amino) propanoate (51) was obtained in the same manner as in Example 1 ,
[401] Y = 5%; MS: 382.0 (M + 1); HPLC (Conditions a, 254 nm): 98%, rt. 5.66 min
[402] ^{1 H NMR (DMSO- d 6)} d 8.56 (br d, 1H), 7.97 (d, J = 7.16 Hz, 1H), 7.91 (d, J = 6.40 Hz, 1H), 7.81 (d, J = 7.91 Hz 1H), 7.46-7.40 (m, IH), 7.33-7.26 (m, IH), 5.03-4.94 (m, IH), 4.68-4.64 (d, J = 6.40 Hz, 6H).
[403] ({2 - [(3-hydroxypropyl) amino] pyrimidin-4-yl} acetonitrile (52)
[404] Y = 44%; MS: 326.0 (M + 1); HPLC (Conditions c, max plot): 99%, rt. 3.26 min
[405] ^One≪ 1 > H NMR (DMSO-d6) d 10.81 (br s, 1H, exchangeable), 7.84 (d,J= 7.54 Hz, 1 H), 7.71 (d,J2H), 7.21-7.15 (m, 1H), 6.32 (d, 2H)J= 7.20 Hz, 1H), 4.65-4.50 (br s, 1H, exchangeable), 3.80-3.50 (m, 4H), 1.90-170
[406] Amino} pyrimidin-4-yl} acetonitrile (di TFA salt) (53)
[407] Y = 46%; MS: 359.0 (M + 1); HPLC (Conditions c, max plot): 99.7%, rt. 2.56 min
[408] ^One≪ 1 > H NMR (DMSO-d6) d 8.87 (s, 1 H), 8.64 (d,J1H), 6.46 (d, 1H), 7.25-7.20 (m,J= 7.16 Hz, 1 H), 4.97 (br d, 2 H).
[409] (2-aminopyrimidin-4-yl) (1,3-benzothiazol-2-yl) acetonitrile (54)
[410] A suspension of 1 (0.1 g, 0.35 mmol) in a 2M solution of ammonia in ethanol (10 ml) is heated to 150 < 0 > C for 3 hours in a Parr bezel. The solution is cooled to room temperature and the yellow precipitate formed is filtered off and then completely washed with ethanol / water 1: 1 and water. The precipitate was dried under vacuum at 40 < 0 > C to yield 48 mg (51%) of the title compound as a yellow powder.
[411] MS: 268.0 (M + 1); HPLC (Conditions c, max plot): 95%, rt. 3.20 min
[412] ^One≪ 1 > H NMR (DMSO-d6) d 10.92 (br s, 1H, exchangeable), 7.79 (d,J= 7.16 Hz, 1 H), 7.70 (d,J= 7.01 Hz, 1 H), 7.42-7.15 (m, 5 H), 6.34 (d,J= 7.54 Hz, 1 H)
[413] Yl} acetonitrile (di TFA salt) (55) was obtained in the same manner as in (1 ) except that 1-benzothiazol-
[414] Y = 46.5%; MS: 359.0 (M + 1); HPLC (Conditions c, max plot) 99%, rt. 2.55 min
[415] ^One≪ 1 > H NMR (DMSO-d6) d 8.77 (d,J= 6.4 Hz, 1 H), 8.33 (br t, 1 H), 7.95-7.93 (br d,J= 7.54 Hz, 1 H), 7.69-7.62 (m, 2H), 7.39-7.34 (m, 1 H), 7.24-7.19J= 7.17 Hz, IH), 5.05 (br d, 2H), 5.6-4.4 (br s, IH).
[416] yl} amino) ethyl] - phenylcarbamate (56) was obtained in the same manner as in Example 1, except that tert-butyl 4- [2-
[417] Y = 75%; MS: 487.2 (M + 1); HPLC (Conditions d, max plot): 98%, rt. 6.30 min.
[418] ^One≪ 1 > H NMR (DMSO-d6) d 10.86 (s, 1H), 9.28 (s, 1H), 7.72 (d,J= 7.91 Hz, 1 H), 7.68 (d,J= 7.54 Hz, 1 H), 7.51 (br t, 1 H), 7.44-7.34 (m, 4H), 7.22-7.15J= 7.53 Hz, 1H), 3.88-3.78 (m, 2H), 2.94-2.89 (m, 2H), 1.47 (s, 9H).
[419] (Di TFA) (57) To a solution of (2 - {[2- (4-aminophenyl) ethyl] amino} pyrimidin-
[420] Y = 73%. (salt); MS: 387.2 (M + 1); HPLC (Conditions c, max plot): 98.3%, rt 3.02 min
[421] ^One≪ 1 > H NMR (DMSO-d6) d (M, 3H), 6.40 (d, 1H), 7.93 (br d, 1H), 7.75-7.66J= 7.16 Hz, 1 H), 4.9-4.2 (v br s, 1 H), 3.94-3.82 (m, 2H), 2.99J= 7.16 Hz, 2H).
[422] Ethyl] amino} pyrimidin-4-yl) acetonitrile (58) was obtained in the same manner as in (1)
[423] Y = 75%; MS: 432.0 (M + 1); HPLC (Conditions c, max plot): 99%, rt. 4.26 min
[424] ^One≪ 1 > H NMR (DMSO-d6) d (M, 2H), 6.84-6.81 (m, 1H), 7.85-7.68 (m, 1H), < / RTI > 6.47 (d,J2H), 3.73 (s, 3H), 3.67 (s, 3H), 2.93 (t,J= 7.16 Hz, 2H).
[425] (3-methoxyphenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile (59)
[426] Y = 76%; MS: 402.0 (M + 1); HPLC (Conditions c, max plot): 99.9%, rt. 4.59 min
[427] ^One≪ 1 > H NMR (DMSO-d6) d 2H), 7.62-7.69 (m, 2H), 7.62 (br d, 1H), 7.45-7.40 (m, 1H), 7.30-7.24 ), 6.45 (d,J= 7.16 Hz, 1 H), 4.2-3.65 (m, 3 H), 3.72 (s, 3 H), 2.97J= 7.16 Hz, 2H).
[428] Ethyl] amino} pyrimidin-4-yl) acetonitrile (60) was obtained in the same manner as in (1)
[429] Y = 76%; MS: 390.2 (M + 1); HPLC (Conditions c, max plot): 99.7%, rt. 4.41 min
[430] ^One≪ 1 > H NMR (DMSO-d6) d 2H), 7.45-7.40 (m, 2H), 7.33-7.16 (m, 4H), 6.44 (d,J= 7.17 Hz, 1 H), 4.20-3.60 (m, 3 H), 3.04 (t,J= 7.14 Hz, 2H).
[431] (Trifluoromethyl) phenyl] ethyl} amino) pyrimidin-4-yl] acetonitrile (61)
[432] Y = 84%; MS: 440.0 (M + 1); HPLC (Conditions c, max plot): 99.3%, rt. 4.79 min
[433] ^One≪ 1 > H NMR (DMSO-d6) d (M, 1H), 7.45 (br, 1H), 7.75-7.54 (m, 7H), 7.46-7.41J= 7.14 Hz, 1 H), 4.45-3.70 (m, 3 H), 3.11 (t,J= 6.78 Hz, 2H).
[434] (2-hydroxy-2-phenylethyl) amino] pyrimidin-4-yl} acetonitrile (TFA )
[435] Y = 47% (salt); MS: 386.0 (M-1); HPLC (Conditions c, max plot): 99%, rt. 3.87 min
[436] ^One≪ 1 > H NMR (DMSO-d6) d 7.83 (br t, 1H), 7.75-7.57 (m, 3H), 7.50-7.24 8 m, 9H), 6.42 (d,J= 7.14 Hz, IH), 4.90 (br t, IH), 4.48-3.75 (m, IH), 3.68-3.53
[437] 2-yl] amino} ethyl) amino] pyrimidin-4-yl} acetonitrile (prepared from 63)
[438] Y = 89%; MS: 456.2 (M + 1); HPLC (Conditions c, max plot): 97.8%, rt. 3.78 min
[439] ^One≪ 1 > H NMR (DMSO-d6) d 8.29-8.19 (m, 1 H), 8.00 (br t, 1 H), 7.87 (d,J(M, 2H), 6.50 (d, 2H), 7.50 (d,J= 6.78 Hz, 1 H), 4.65-3.60 (m, 5 H).
[440] Ethyl] amino} pyrimidin-4-yl) acetonitrile (TFA) (64)
[441] Y = 70% (salt); MS: 406.0 (M + 1); HPLC (Conditions c, max plot): 99.7%, rt. 4.91 min
[442] ^One≪ 1 > H NMR (DMSO-d6) d (M, 3H), 7.60 (br d, 1H), 7.41-7.24 (m, 7H), 6.44J= 7.17 Hz, 1 H), 3.98-3.50 (m, 3H), 3.04-2.99 (m, 2H).
[443] Ethyl] amino} pyrimidin-4-yl) acetonitrile (TFA) (65) was obtained in the same manner as in Example 1,
[444] Y = 56% (salt); MS: 440.0 (M + 1); HPLC (Conditions c, max plot): 99.6%, rt. 5.15 min
[445] ^One≪ 1 > H NMR (DMSO-d6) d 2H), 6.44 (d, 1H), 7.75-7.73 (m, 3H), 7.62-7.58J= 7.17 Hz, 1 H), 4.20-3.60 (m, 3 H), 3.01 (t,J= 6.78 Hz, 2H).
[446] Ethyl] amino} pyrimidin-4-yl) acetonitrile (TFA) (66) was obtained in the same manner as in Example 1,
[447] Y = 69% (salt); MS: 402.0 (M + 1); HPLC (Conditions c, max plot) 99.6%, rt. 4.33 min
[448] ^One≪ 1 > H NMR (DMSO-d6) d 1H), 7.40-7.35 (m, 1H), 7.24-7.17 (m, 3H), 6.86 (d,J= 8.28 Hz, 2H), 6.38 (d,J= 7.16 Hz, 1 H), 4.15-3.65 (m, 3H), 3.69 (s, 3H), 2.9-2.85 (m, 2H).
[449] Ethyl) amino} pyrimidin-4-yl) acetonitrile (TFA) (67)
[450] Y = 72% (salt); MS: 386.0 (M + 1); HPLC (Conditions c, max plot): 100% rt. 4.66 min
[451] ^One≪ 1 > H NMR (DMSO-d6) d 1H), 7.27-7.14 (m, 4H), 6.47 (d, 1H), 7.87-7.67 (m, 3H), 7.47-7.42J= 7.14 Hz, 1 H), 4.20-3.55 (m, 3H), 2.98-2.93 (m, 2H), 2.30 (s, 3H).
[452] Ethyl] amino} pyrimidin-4-yl) acetonitrile (TFA) (68) was obtained in the same manner as in Example 1,
[453] Y = 34% (salt); MS: 390.0 (M + 1); HPLC (Conditions c, max plot): 98.4%, rt. 4.72 min
[454] ^One≪ 1 > H NMR (DMSO-d6) d 2H), 7.27-7.16 (m, 3H), 7.12-7.06 (m, 1H), 6.42 (d,J= 7.14 Hz, 1 H), 4.50-3.70 (m, 3H), 3.05-3.00 (m, 2H).
[455] Ethyl] amino} pyrimidin-4-yl) acetonitrile (69) was obtained in the same manner as in Example 1,
[456] Y = 71%; MS: 464.2 (M + 1); HPLC (Conditions c, max plot): 98%, rt. 5.34 min
[457] ^One≪ 1 > H NMR (DMSO-d6) d (M, 1H), 7.15-7.10 (m, 1H), 6.99-6.95 (m, 1H), 7.44-7.33 4H), < / RTI > 6.43 (d,J= 6.78 Hz, 1H), 4.0-3.40 (m, 3H), 2.99 (t,J= 6.78 Hz, 2H).
[458] Ethyl] amino} pyrimidin-4-yl) acetonitrile (70) was obtained in the same manner as in Example 1,
[459] Y = 55%; MS: 464.2 (M + 1); HPLC (Conditions c, max plot): 98%, rt. 5.29 min
[460] ^One≪ 1 > H NMR (DMSO-d6) d 7.88 (br t, 1 H), 7.73 (d,J2H), 7.32-7.17 (m, 5H), 7.06-6.91 (m, IH), 7.69 (br d, 6.88 - 6.85 (m, 3 H), 6.42 (d,J= 6.78 Hz, 1 H), 4.22-3.60 (m, 3 H), 3.01 (t,J= 6.78 Hz, 2H).
[461] Ethyl] amino} pyrimidin-4-yl) acetonitrile (71) was obtained in the same manner as in (1)
[462] Y = 96%; MS: 450.0 (M + 1); HPLC (Conditions c, max plot): 99.6%, rt. 5.01 min
[463] ^One≪ 1 > H NMR (DMSO-d6) d 7.81-7.68 (m, 3H), 7.60 (br d, 1 H), 7.53 (d,J= 8.28 Hz, 2H), 7.45-7.40 (m, 1H), 7.30-7.25 (m, 3H), 6.43J= 7.16 Hz, IH), 4.12-3.55 (m, 3H), 3.01-2.96 (m, 2H).
[464] Ethyl] amino} pyrimidin-4-yl) acetonitrile (72) was obtained in the same manner as in Example 1,
[465] Y = 73%; MS: 389.8 (M + 1); HPLC (Conditions c, max plot): 99.6%, rt. 4.72 min
[466] ^One≪ 1 > H NMR (DMSO-d6) d (M, 2H), 6.43 (d, 1H), 7.45-7.34 (m, 3H)J= 7.17 Hz, 1 H), 4.32-3.65 (m, 3H [2 + 1]), 2.99 (t,J= 7.16 Hz, 2H).
[467] Amino} pyrimidin-4-yl} acetonitrile (73) was obtained in the same manner as in (1)
[468] Y = 24%; MS: 448.2 (M + 1); HPLC (Conditions c, max plot): 97.8%, rt. 5.08 min
[469] ^One≪ 1 > H NMR (DMSO-d6) d 7H), 7.49-7.33 (m, 6H), 7.26-7.21 (m, 1H), 6.44 (d,J= 6.78 Hz, 1 H), 4.15-3.40 (m, 3H [2 + 1]), 3.20-3.08 (m, 2H).
[470] Amino] phenyl} ethyl) amino] pyrimidin-4-yl} acetonitrile (74)
[471] Y = 33.8%; MS: 417.2 (M + 1); HPLC (Conditions c, max plot): 98.7%, rt. 4.21 min
[472] ^One≪ 1 > H NMR (DMSO-d6) d (D, J = 8.66 Hz, 2H), 7.54 (br d, 1H), 7.42 2H), 3.55-3.10 (m, IH), 3.18-3.14 (m, IH) (m, 2H).
[473] Yl) ethyl] amino} pyrimidin-4-yl) acetonitrile (75) was obtained in the same manner as in (1)
[474] Y = 77.6%; MS: 361.2 (M-1); HPLC (Conditions c, max plot): 99.4%, rt. 2.79 min
[475] ^One≪ 1 > H NMR (DMSO-d6) d 8.59 (s, 1 H), 8.09 (s, 1 H), 7.93 (d,J= 7.54 Hz, 1 H), 7.75 (d,J= 7.91 Hz, 1 H), 7.67 (br d, 1 H), 7.48-7.43 (m, 1 H), 7.33-7.28J= 7.16 Hz, 1 H), 5.05-4.25 (m, 3H [2 + 1]), 4.10-3.98 (m, 2H).
[476] Propyl] amino} pyrimidin-4-yl) acetonitrile (76) was prepared in accordance with the general method of example 1,
[477] Y = 70%; MS: 374.0 (M-1); HPLC (Conditions c, max plot): 94.8%, rt. 3.40 min
[478] ^One≪ 1 > H NMR (DMSO-d6) d 7.95 (d,J2H), 7.31-7.26 (m, 1H), 6.45 (d, 1H)J= 7.17 Hz, 1 H), 6.22 (s, 1 H), 4.30-3.85 (m, 3H), 3.62-3.48 (m, 2H), 2.21-2.06 (m, 2H).
[479] Yl} amino) ethyl] benzenesulfonamide (77) The title compound was prepared from 4-
[480] Y = 80%; MS: 449.0 (M-1); HPLC (Conditions c, max plot): 99%, rt. 3.28 min
[481] ^One≪ 1 > H NMR (DMSO-d6) d (M, 3H), 7.44-7.22 (m, 4H), 6.43 (d, 1H), 7.20-7.65J= 6.78 Hz, 1H), 4.10-3.80 (m, 2H), 3.20-3.00 (m, 2H).
[482] Diethyl] amino} pyrimidin-4-yl} [5- (trifluoromethyl) -1,3-benzothiazol-2-yl] acetonitrile (di TFA) (78)
[483] Y = 30%; MS: 441.2 (M + 1); HPLC (Conditions c, max plot): 96%, rt. 3.39 min
[484] ^One≪ 1 > H NMR (DMSO-d6) d 11.20 (v br s, 1H, exchangeable), 8.77 (d,J= 1.88 Hz, 1 H), 8.70-8.67 (m, 1 H), 8.24 (d,J= 7.91 Hz, 1H), 8.02-7.94 (m, 2H), 7.81-7.75 (m, 2H), 7.52-7.48J= 7.14 Hz, 1 H), 4.10-3.85 (m, 2H), 3.30-3.00 (m, 2H).
[485] Amino} pyrimidin-4-yl} acetonitrile (TFA) (79) To a solution of 1-
[486] Y = 31%; MS: 447.8 (M-1); HPLC (Conditions c, max plot): 99%, rt. 2.60 min
[487] ^{1 H NMR (DMSO- d 6)} d 8.40-8.29 (br d, 1H, exchangeable), 7.78-7.60 (m, 4H), 7.41-7.36 (m, 1H), 7.27-7.21 (m, 1H), 6.47 (d, J = 6.78 Hz, 1H), 5.25-5.05 (m, 2H).
[488] Example 3: Preparation of 1,3-benzothiazol-2-yl [2- (benzyloxy) pyrimidin-4-yl] acetonitrile (80) Manufacturing
[489] A solution of benzyl alcohol (0.07 ml, 0.7 mmol) in dry DMA (1 ml) was added to a suspension of NaH (60% in oil, 0.056 g, 1.4 mmol) in dry DMA (1 ml) Lt; / RTI > A solution of 1 in DMA (1 ml) is added dropwise and the suspension is heated under inert atmosphere ON with stirring to 100 DEG C. The reaction is terminated by the addition of a saturated aqueous solution of water + NaCl (up to a final volume of 15 ml). After 2 hours at 4 [deg.] C, the precipitate formed is filtered and washed with water until neutral pH is reached. The solid obtained is yellowed in acetonitrile, cooled to room temperature and then filtered and washed with acetonitrile (3X). The residue was dried under vacuum at 40 캜 ON to give 0.082 g (33%) of the title compound as a yellow powder: mp 196-198 캜, MS: 359.0 (M + 1); HPLC (Conditions a, 262 nm): 99%, rt. 4.99 min. ^{1 HNMR (DMSO- d 6) d} 12.74 (br s, 1H, exchangeable) 7.95 (d, J = 7.53 Hz, 1H), 7.76-7.72 (m, 2H), 7.62-7.54 (m, 2H), 7.50- (S, 2H), 7.32 (m, 4H), 7.29-7.19 (m,
[490] Using the procedures described above in Example 3 and the appropriate starting materials and reagents, the following additional benzothiazole derivatives of structure III can be obtained.
[491] Benzothiazol-2-yl {2- [(4-pyridin-3-ylbenzyl) oxy] pyrimidin-4- yl} acetonitrile (81)
[492] Y = 20%; MS: 436.0 (M + 1); HPLC (Conditions c, max plot): 97%, rt. 3.43 min
[493] ^One≪ 1 > H NMR (DMSO-d6) d 9.05 (d,J= 1.9 Hz, 1H), 8.71-8.68 (br d, 1H), 8.42-8.38 (m, 1H), 7.98-7.84 (m, 4H), 7.75-7.70 (m, 4H), 7.45-7.39 1H), 7.29-7.23 (m, 1H), 6.71 (br d, 1H), 5.77 (s, 2H), 5.15-3.50 (m, 1H).
[494] Yl] acetonitrile (TFA) (82) The title compound was prepared in accordance with the general method of < RTI ID = 0.0 & gt ;
[495] Y = 20%; MS: 360.2 (M + 1); HPLC (Conditions c, max plot): 97.9%, rt. 2.91 min
[496] ^One≪ 1 > H NMR (DMSO-d6) d 8.77 (dd,J= 6.41 Hz, 1.51 Hz, 2H), 8.01 (br d, 1H), 7.94 (d,J= 7.91 Hz, 1 H), 7.86 (d,J= 6.41 Hz, 2H), 7.70 (d,J= 7.91 Hz, 1H), 7.46-7.40 (m, 1H), 7.30-7.25 (m, 1H), 6.79 (br d, 1H), 5.85 (s, 2H), 5.15-3.80 (m, 1H).
[497] 4-yl] acetonitrile (TFA) (83) was obtained in the same manner as in [
[498] Y = 42% (salt); MS: 360.0 (M + 1); HPLC (Conditions c, 254 nm): 96%, rt. 3.30 min
[499] ^One≪ 1 > H NMR (DMSO-d6) d 8.66 (d,J2H), 7.28-7.23 (m, 1H), 6.74 (d, 2H), 7.97-7.88 (m,J= 6.03 Hz, 1 H), 5.76 (s, 2 H).
[500] Yl] acetonitrile (TFA) (84) To a stirred solution of < RTI ID = 0.0 >
[501] Y = 33% (salt); MS: 386.0 (M-1); HPLC (Conditions c, max plot) 88%, rt. 2.93 min
[502] ^One≪ 1 > H NMR (DMSO-d6) d 8.98 (d,J= 5.27 Hz, 1 H), 8.20-8.15 (m, 1 H), 7.91 (d,J1H), 7.66-7.74 (m, 3H), 7.62-7.58 (m, 1H), 7.45-7.38J= 6.41 Hz, 1 H), 4.69 (t,J= 6.03 Hz, 2H), 3.12 (t,J= 7.54 Hz, 2H), 2.35-2.27 (m, 2H).
[503] Benzothiazol-2-yl {2- [(4-methoxybenzyl) oxy] pyrimidin-4- yl} acetonitrile (85)
[504] Y = 61%; MS: 387.0 (M-1); HPLC (Conditions d, max plot): 98%, rt. 5.74 min
[505] ^One≪ 1 > H NMR (DMSO-d6) d 12.69 (br s, 1H, exchangeable), 7.92 (d,J= 7.54 Hz, 1 H), 7.77-7.70 (m, 2H), 7.50 (d,J= 8.66 Hz, 2H), 7.41-7.55 (m, 1H), 7.24-7.18 (m,J= 8.67 Hz, 2H), 6.63 (d,J= 6.4 Hz, 1 H), 5.60 (s, 2 H), 3.76 (s, 3 H).
[506] Pyrimidin-4-yl] acetonitrile (TFA) (86) was obtained in the same manner as in [
[507] Y = 65% (salt); MS: 357.8 (M-1); HPLC (Conditions c, max plot): 99%, rt. 2.86 min
[508] ^One≪ 1 > H NMR (DMSO-d6) d 8.91 (d,J= 1.51 Hz, 1 H), 8.71-8.68 (m, 1 H), 8.23 (d,J1H), 7.75-7.93 (m, 2H), 7.74-7.65 (m, 2H), 7.45-7.40J= 6.39 Hz, IH), 5.76 (s, 3H), 5.9-5. 0 (very brs, 1H).
[509] Yl} acetonitrile (87) The title compound was prepared in analogy to the procedure described in Example < RTI ID = 0.0 & gt ;
[510] Y = 27%; MS: 400.8 (M-1); HPLC (Conditions d, max plot): 95%, rt. 5.79 min
[511] ^One≪ 1 > H NMR (DMSO-d6) d (M, 3H), 6.90 (d, 1H), 7.60-7.70 (m,J= 8.28 Hz, 2H), 6.60 (d,J= 6.4 Hz, 1H), 4.85-4.80 (m, 2H), 3.73 (s, 3H), 3.12-3.07 (m, 2H).
[512] Yl] acetonitrile (88) was obtained in the same manner as in [1, < RTI ID = 0.0 &
[513] Y = 40%; MS: 433.0 (M-1); HPLC (Conditions c, max plot): 98%, rt. 7.12 min
[514] ^One≪ 1 > H NMR (DMSO-d6) d (M, 2H), 7.75-7.67 (m, 4H), 7.56-7.37 (m, 6H), 7.26-7.21 ), 5.77 (s, 2H).
[515] Benzothiazol-2-yl {2 - [(3,4,5-tri methoxybenzyl) oxy] pyrimidin-4- yl} acetonitrile (89)
[516] Y = 18%; MS: 447.0 (M-1); HPLC (Conditions c, max plot): 92%, rt. 5.24 min
[517] ^One≪ 1 > H NMR (DMSO-d6) d 12.71 (br s, 1 H), 7.95 (d,J1H), 6.94 (s, 2H), 6.67 (br d, 1H), 5.59 (m, 2H), 7.90-7.72 (s, 2 H), 3.77 (s, 6 H), 3.65 (s, 3 H).
[518] Benzothiazol-2-yl {2 - [(3,4-dichlorobenzyl) oxy] pyrimidin-4- yl} acetonitrile (90)
[519] Y = 5%; MS: 424.8 (M-1); HPLC (Conditions c, max plot): 98%, rt. 6.79 min
[520] ^{1 H NMR (DMSO- d 6)} d 7.82-7.72 (m, 3H), 7.64 (d, J = 7.91 Hz, 1H), 7.50-7.46 (m, 2H), 7.24-7.21 (m, 1H),) , 7.01-6.96 (m, 1 H), 6.53-6.50 (br d, 1 H), 5.51 (s, 2 H).
[521] Benzyl} oxy) pyrimidin-4-yl] acetonitrile (TFA) (91) was obtained in the same manner as in [
[522] Y = 28%; MS: 416.2 (M + 1); HPLC (Conditions c, max plot): 98%, rt. 2.96 min
[523] ^One≪ 1 > H NMR (DMSO-d6) d 1H), 7.73-7.90 (m, 2H), 7.74-7.39 (m, 7H), 7.29-7.23J2H), 2.72 (s, 6H), 3.40 (s, 2H)
[524] Yl} acetonitrile (92) 12149 < / RTI >< RTI ID = 0.0 >
[525] Y = 16%; MS: 3.74.0 (M-1); HPLC (Conditions c, max plot): 90%, rt. 2.78 min
[526] ^One≪ 1 > H NMR (DMSO-d6) d (M, 2H), 7.45-7.39 (m, 1H), 7.29-7.23 (m, 1H), 6.72 , 5.73 (s, 2H), 4.35 (s, 2H), 4.05-3.00 (m, 8H)
[527] Benzyl] oxy} pyrimidin-4-yl) acetonitrile (TFA) (93)
[528] Y = 20%; MS: 458.2 (M + 1); HPLC (Conditions c, max plot): 99%, rt. 2.80 min
[529] ^One≪ 1 > H NMR (DMSO-d6) d 8.47 (s, 1 H), 8.22 (d,J= 6.03 Hz, 1 H), 7.98-7.94 (m, 2H), 7.31 (d,J= 8.28 Hz, 1 H), 7.62-7.33 (m, 3H), 7.30-7.26 (m, 1H), 6.82-6.68 (br d, 1H), 5.64 (s, 2H).
[530] Yl} acetonitrile (TFA) (94) The title compound was obtained as a colorless oil from < RTI ID = 0.0 & gt ;
[531] Y = 34%; MS: 435.0 (M + 1); HPLC (Conditions c, max plot): 99%, rt. 3.22 min
[532] ^{1 H NMR (DMSO- d 6)} d 8.80 (d, J = 4.14 Hz, 1H), 8.24 -7.79 (m, 10H), 7.55-7.49 (m, 2H), 7.39-7.33 (m, 1H), 6.82 (br d, 1 H), 5.89 (s, 2 H).
[533] Benzyl] oxy} pyrimidin-4-yl) acetonitrile (TFA) (95)
[534] Y = 15%; MS: 456.2 (M + 1); HPLC (Conditions c, max plot): 97%, rt. 3.00 min
[535] ^One≪ 1 > H NMR (DMSO-d6) d 1H), 5.73 (s, 2H), 4.28 (d, 2H), 7.27-7.29 (m,J= 4.9 Hz, 1H), 3.80-3.20 (m, 2H), 2.90-2.78 (m, 2H), 1.79-1.27 (m, 6H).
[536] Example 4: Synthesis of 1,3-benzothiazol-2-yl [2- (4-methoxyphenoxy) pyrimidin-4-yl] acetonitrile (96) Manufacturing
[537] 4-methoxyphenol (0.261 g, 2.1 mmol) and cesium carbonate (1.7 g, 5.25 mmol) were added to a solution of 1 (0.300 g, 1.05 mmol) in DMSO (7 ml) . After cooling to room temperature, the suspension is poured into ice / water and the product is extracted with AcOEt. The organic phase is washed with water, then brine, dried over MgSO ₄ and dried. The residue was titrated with hot EtOH, then filtered and dried at 50 < 0 > C under vacuum overnight to yield 202 mg (51%) of the title compound.
[538] MS: 375.0 (M + 1); HPLC (Conditions c, max plot): 99%, rt. 5.21 min
[539] ^One≪ 1 > H NMR (DMSO-d6) d 8.16 (br d, 1 H), 7.60 (d,J= 8.29 Hz, 1H), 7.45-7.37 (m, 2H), 7.28-7.23 (m, 3H), 7.11-7.08 (m, 2H), 6.83 (br d, 1H), 3.86 (s,
[540] By using the procedures described above in Example 4 and the appropriate starting materials and reagents the following additional benzothiazole derivatives of structure III can be obtained.
[541] 2-yl [2- (4-butoxyphenoxy) pyrimidin-4-yl] acetonitrile (97)
[542] Y = 42%; MS: 415.0 (M-1); HPLC (Conditions c, max plot): 90%, rt. 6.16 min
[543] ^One≪ 1 > H NMR (DMSO-d6) d 2H), 7.22-7.16 (m, 3H), 7.10-7.05 (br d, 1H) 7.05 (m, 2 H), 6.79 (d,J= 5.65 Hz, IH), 4.03 (m, 2H), 1.75 (m, 2H), 1.50 (m, 2H), 0.97 (m, 3H).
[544] Yl} (1,3-benzothiazol-2-yl) acetonitrile (98) was prepared in accordance with the general method of example 1 from 2- {4- [
[545] Y = 8.5%; MS: 469.2 (M-1); HPLC (Conditions c, max plot): 94.8%, rt. 4.10 min
[546] ^One≪ 1 > H NMR (DMSO-d6) d (M, 2H), 7.41-7.36 (m, 1H), 7.28-7.10 (m, 5H), 6.83 (br d, 1H), 3.23-3.17 4H), 2.07 (s, 3H).
[547] Yl] acetonitrile (99) was obtained in the same manner as in [2- (4-methoxyphenoxy) pyrimidin-4-yl]
[548] Y = 33%; MS: 443.2 (M + 1); HPLC (Conditions c, max plot): 99%, rt. 6.09 min
[549] ^One≪ 1 > H NMR (DMSO-d6) d 8.04-7.89 (m, 2H), 7.61-7.53 (m, 2H), 7.32 (d,J= 9.05 Hz, 2H), 7.12 (d,J= 9.05 Hz, 2 H), 6.83 (d,J= 6.40 Hz, 1 H), 3.87 (s, 3 H).
[550] Example 5: Preparation of 1,3-benzothiazol-2-yl (pyrimidin-4-yl) acetonitrile (100)
[551] Sodium acetate (29 mg, 0.35 mmol) and palladium on charcoal (20 mg) are added to a solution of 1 (0.1 g, 0.35 mmol) in acetic acid. The suspension is heated to 70 DEG C under 3.5 bar of hydrogen for 3 hours. After cooling to room temperature, the suspension is filtered through celite and the acetic acid is distilled. The light yellow powder is taken up in 10% aqueous solution of ethyl acetate and sodium hydroxide. After three times extraction, the organic phase is washed thoroughly with brine, dried over MgSO ₄ and dried. After purification by HPLC and drying in vacuo at 50 < 0 > C, 12 mg (13%) of the title compound are obtained as a yellow powder.
[552] MS: 253.2 (M + 1); HPLC (Conditions c, max plot): 98%, rt. 3.35 min
[553] ^One≪ 1 > H NMR (DMSO-d6) d 1H), 6.87 (s, 3H), 8.00-7.73 (m, 3H), 7.44-7.39 (m, 1H), 7.29-7.23 (m,
[554] Example 6: Synthesis of N- [2 - ({4- [1,3-benzothiazol-2-yl (cyano) methyl] pyrimidin- salt) (101)
[555] P -Chlorobenzyl chloride (0.056 g, 0.32 mmol) and triethylamine (0.09 ml, 0.64 mmol) were added to a solution of 46 (0.1 g, 0.32 mmol) in DCM / DMF 3/1 (4 ml) 0.0 > 40 C < / RTI > for 3 hours. The precipitate formed after cooling to room temperature is filtered, washed with DCM and then with water. After recrystallization in acetonitrile 98 mg (68%) of the title compound (base) is obtained as a yellow powder.
[556] This product is taken up in a mixture of DCM / TFA. The yellow needles formed by the addition of ether were filtered and washed with ether (3X) and then dried under vacuum at 40 < 0 > C to afford 105 mg of the title compound as a yellow powder:
[557] MS: 449.2 (M + 1); HPLC (Conditions c, max plot): 95%, rt. 3.99 min
[558] ^One≪ 1 > H NMR (DMSO-d6) d (M, 1H), 6.47 (d, 1H), 7.80-7.30 (m,J= 6.78, 1H), 4.50-3.30 (m, 5H).
[559] Example 7: Preparation of 1,3-benzothiazol-2-yl (2-methoxy-4-pyrimidyl) -acetonitrile (102) Manufacturing
[560] Dry MeOH (3 ml) in a suspension of 1 (0.1g, 0.35 mmol) MeONa ( 0.08 g, 1.4 mmol) and _{Et 3 N (0.05ml, 0.35 mmol} ) is added and the suspension is between dewe to 60 ℃ 6 il Loses. The remaining solid is filtered and the filtrate is dried. The resulting solid residue was washed with water until neutral pH was then dried at 40 ° C under vacuum to give 44 mg (45%) of the title compound as yellow powder: mp 234 ° C dec., MS: 283 M + 1); HPLC (Conditions a, 262 nm): 97%, rt. 3.40 min;
[561] ^{1 HNMR (DMSO- d 6) d} 7.79 (d, J = 4.52 Hz, 1H), 7.78 (d, J = 7.91 Hz, 1H), 7.55 (d, J = 7.91 Hz, 1H), 7.29-7.23 (m , 7.07-7.02 (m, 1 H), 6.53 (br d, 1 H), 4.02 (s, 3H)
[562] Example 8: Preparation of pharmaceutical formulations
[563] The following formulation examples illustrate representative pharmaceutical compositions according to the present invention, but are not limited thereto.
[564] Formulation 1 - Tablet
[565] The benzazole compound of Formula I is mixed with the dry gelatin binder in a dry weight ratio of about 1: 2 by weight. A small amount of magnesium stearate is added as a lubricant. This mixture is tablet pressed with 240-270 mg tablet (80-90 mg active benzazole compound per tablet).
[566] Formulation 2 - Capsule
[567] The benzazole compound of formula I is mixed with starch diluent in dry powder at about 1: 1 weight ratio. This mixture is filled in 250 mg capsules (125 mg active benzazole compound per capsule).
[568] Formulation 3 - Solution
[569] The benzazole compound (1250 mg), sucrose (1.75 g) and xanthan gum (4 mg) of the structural formula I were mixed. 10 mesh U.S. After passing through a sieve, it is mixed with a pre-prepared solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water is then added to make a total volume of 5 mL.
[570] Formulation 4 - Tablet
[571] The benzazole compound of Formula I is mixed with the dry gelatin binder in a dry weight ratio of about 1: 2 by weight. A small amount of magnesium stearate is added as a lubricant. This mixture is tablet pressed with 450-900 mg tablet (150-300 mg active benzazole compound per tablet).
[572] Formulation 5 - Injection
[573] The benzazole compound of formula I is dissolved in an injectable aqueous medium which is buffered sterile saline at a concentration of about 5 mg / mL.
[574] Example 9: Biological assay
[575] One of ordinary skill in the art can readily identify the various assays that can be used to analyze the activity of the benzazole compounds of the invention. The analysis specified below is cited as an example for analyzing the suitability of the benzazole compounds of the present invention to modulate JNK and thereby apoptosis accordingly.
[576] JNK 2 and 3 enzyme assays: JNK3 and / or 2 assays In a 96-well MTT plate, 0.5 mg of recombinant gene, GST-JNK3 or GST-JNK2 preactivated with 1 mg of recombinant gene, biotinylated GST- Jun and 2 mM ³³ g-ATP (2 nCi / ml) in 50 mM Tris-HCl, pH 8.0, in the presence or absence of one or more benzazoleze inhibitors; 10 mM MgCl _2; It is performed by cultivating at 1 mM dithiothreitol, and 50 ml of reaction volume containing 100 mM NaVO _4. The cultivation was carried out at room temperature for 120 minutes and 200 μl of a solution containing 250 mg of streptavidin-coated SPA beads (Amersham, Inc.) ^* , 5 mM EDTA, 0.1% Triton X-100 and 50 mM ATP in phosphate saline buffer Lt; / RTI > solution. After 60 min of incubation at room temperature, the beads were resuspended in 200 μl of PBS containing 5 mM EDTA, 0.1% Triton X-100 and 50 mM ATP by centrifugation at 1500 xg for 5 min and the beads precipitated Radioactivity is measured with post scintillation beta counter. By GST-c Jun with biotinylated GST- ₁ ATF ₂ substituted or unsubstituted Erin basic protein this assay may be used to respectively measure the inhibition of ERK and p38 MAP kinase activation in advance.
[577] Representative values for compounds of some embodiments are given in the table below:
[578] compound No. JNK3 IC ₅₀ (nM) JNK2 IC ₅₀ (nM) p38 IC ₅₀ (nM) ERK2 IC ₅₀ (nM) One290500> 30000> 30000 4350970> 30000> 30000 1070210> 30000> 30000 159502300> 30000> 30000 235101800> 30000> 30000 8060250> 30000> 30000 9630300> 30000> 30000 102105450> 30000> 30000
[579] The values indicated for JNK2 and 3, p38 and ERK2 represent the IC ₅₀ ([mu] m), i.e. the amount required to achieve a 50% inhibition rate of the target (i.e., JNK2 or 3). The compound number indicates the test compound as shown by the number in the above example. From the above table it can be concluded that the test compound has a sufficient effect on both JNK2 and more particularly JNK3, but has virtually no effect on p38 and ERK2, indicating a highly selective inhibitory effect.
[580] The test compound according to formula I exhibits an inhibition (IC ₅₀ ) for JNK3 of 10 μM, more preferably of 0.1 μM or less.
[581] In the following, test compounds according to the present invention show their JNK inhibition And in vivo and in vivo assays which may be subject to confirmatory apatosis control (i.
[582] A. Neurons Culture and Survival Assay of the Sympathetic Nervous System (In Vitro)
[583] The neurons of the sympathetic nervous system were removed from the ganglion ganglion (SCG) of the newborn rat (p4) and transplanted into a 48-well MTT plate coated with rattail collagen at a density of 10 ⁴ cells / cm ² to prepare 5% mL < / RTI > NGF 7S (Boehringer Mannheim Corp., Indianapolis, IN) and 10 ⁵ M of arabinosin. Cells were cultured at 4 days post-transplantation on a medium containing 10 mg / mL anti-NGF anti-body (Boehringer Mannheim Corp., Indianapolis, IN.) And no NGF or arabinosine in the presence or absence of benzazole azo inhibitor Lt; / RTI > After 24 hours of cell death induction, the cell viability was determined by incubating the cells with 0.5 mg / mL 3- (4,5-dimethylthiazol-2-yl) 2,5 diphenyltetrazolium bromide (MTT) ≪ / RTI > After incubation in MTT, cells are resuspended in DMSO, transferred to 96 MTT plates, and viability of the cells is measured at 590 nm. This analysis demonstrates that the compounds of structural formula I (ie, compounds (1), (25), (90) ) yield neurons from cell death (up to 80% neuron ratio)
[584] B. Il-2 Release Assay (in vitro)
[585] Jurkat cells, a human T cell leukemia cell line (American Type Culture Collection # TIB 152), are cultured in RPMI 1640 medium (Gibco, BRL) supplemented with 10% heat-activated FCS, glutamine and penstrept. The cell suspension of the medium is diluted to 2.10 ⁶ cells / mL. Cells were transplanted (2.10 ⁵ cells / well) onto 96-well plates containing different concentrations of test compound (final concentration of compound, 10, 3, 1, 0.3, 0.1 mu m). The mixture is incubated at 37 ^° C in a humidified CO ₂ atmosphere for 30 min. All wells except subcontrol are then treated with 10ul PMA + ionomycin (final concentration of 0.1 mu m and 1 mu m). In the compound-free wells, 10 μl of RPMI 2% DMSO (= final 0.1%) is added. Cells are cultured for 24 h at 37 ^° C and then harvested at the top prior to performing the IL-2 ELISA test at the top (if not used at the same time, at -20 ^° C).
[586] B1. IL-2 ELISA assay (in vitro)
[587] IL-2 release is assayed by ELISA in media with PMA + iono-stimulated Juirkocell in the presence or absence of the test compound. The following procedure is described in detail.
[588] solution:
[589] Wash buffer: PBS-Tween 0.05%
[590] Diluent: PBS-Tween 0.05%
[591] Substrate solution: Citric acid 0.1 M / Na ₂ HPO ₄ 0.1 M
[592] Final solution: H ₂ SO ₄ 20%
[593] Matched Antibody Pair / Standard:
[594] From the R & D system
[595] B2. Monoclonal anti-human IL-2 anti-body (MAB602) (capture)
[596] Biotinylated Anti-Human IL-2 Antibody (BAF202) (Detection)
[597] Recombinant human IL-2 (202-IL-010) (standard)
[598] Plate preparation
[599] 100 [mu] L of captured anti-body diluted in PBS to 5 [mu] g / mL is transferred to a 96 well ELISA plate and incubated overnight at room temperature.
[600] Gas is removed from each well and rinsed three times with wash buffer. After the final wash, platelets are wetted.
[601] 1. Saturated with 200 μl PBS-10% FCS. Incubate at room temperature for 1 hour.
[602] 2. Washing step 2. Repeat
[603] Assay procedure
[604] 1. Add 100 μl samples or standards (2000, 1000, 500, 250, 125, 62.5, 31.25 pg / ml) and incubate for 2 hours at room temperature.
[605] 2. Washing 3 times.
[606] 3. 100 μl of biotinylated anti-human IL-2 addition at 12.5 ng / mL. Incubate at room temperature for 2 hours.
[607] 4. Washing 3 times.
[608] 5. Add 100 μl of streptavidin-HRP (Zymed # 43-4323) at 1: 10'000. Incubate at room temperature for 30 min.
[609] 6. Washing 3 times.
[610] 7. 100 μl of substrate solution (citric acid / Na ₂ HPO ₄ (1: 1) + H ₂ O ₂ 1: 2000 + OPD). Incubate at room temperature for 20-30 minutes.
[611] 8. Add 50 [mu] l of final solution to each well.
[612] 9. Determine the luminous intensity using a microtiter plate reader set at 450 nm corrected to 570 nm.
[613] According to this analysis, the compounds of formula I (ie, compounds (1), (10), (83) ) reduce the production of IL-2 by more than 30% at 3 μM. Thus, the reduction of the level of inflammatory cytokinins is achieved by using compounds of formula I.
[614] C. C-Jun Reporter Assay (In Vitro)
[615] Cell culture
[616] Hlr c-Jun HeLa cells are cultured in DMEM High Glc packed with 10% FCS (Sigma), 2 mM glutamine (Gibco), P / S, 100 μg / ml hygromycin b and 250 μg / ml G418.
[617] Cell culture preparation
[618] Cell bank
[619] Cells are frozen in cryotubes and stored under liquefied nitrogen in a 1.8 mL volume of cell suspension in culture medium containing 10% dimethylsulfoxide.
[620] Cells do not maintain more than 20 passages in culture.
[621] Cell culture thawing
[622] If necessary, cell freezing vials are rapidly thawed until semi-complete thawing with gentle shaking in a 37 ° C water bath. The cell suspension is then added to 10 mL of the culture medium. The cell suspension is then centrifuged at 1200 rpm for 5 minutes, the supernatant is removed and the cell pellet is reconstituted into the medium and added to a 175 cm ² flask containing 25 mL medium. The flask is incubated at 37 ° C in an atmosphere of 5% CO ₂ .
[623] Cell passage
[624] The cells are successively subcultured until an 80% confluent monolayer is obtained. The culture medium of each flask is removed and the monolayer is washed with 10-15 mL of phosphate buffered saline (PBS). A trypsin-EDTA solution is added to the cell monolayer, incubated at 37 ° C, and patted at intervals to move the cells. The complete deviation and dispersion of the cell monolayer is confirmed by a preliminary examination. Then resuspended in 10 mL of complete medium and centrifuged at 1200 rpm for 5 min. The supernatant is discarded and the cells resuspended in the culture medium and diluted 1/5 in a 175 cm ² flask.
[625] 0 morning
[626] Cell preparation for transfection
[627] The cells are dislodged and dispersed by treatment with trypsin as described above from the flask of the muscle-mixed culture. The cells are resuspended in the medium and counted. The cell suspension is diluted to a volume of about 3.5 x ¹⁰ cells / mL and 1 mL of the cell suspension is placed in a 2 10 cm culture dish containing 9 mL of the culture medium. Plate is incubated at 37 ℃ under a humid atmosphere of 5% CO ₂ in air.
[628] 0 day evening
[629] Transfection
[630] Control: 0.2 p pTK Renilla, 5.8 p p Blue Script KS, 500 OP OPTIMEM (GIBCO), 18 Fusen 6
[631] Induction: 0.1 p pMEKK1, 0.2 p pTK Renilla, 5.7 p p Blue Script KS, 500 OP OPTIMEM (GIBCO), 18 Fuzen 6 30'RT
[632] The transfection mixture is added to the transfected cells. The plate is incubated overnight at 37 ° C in a humidified atmosphere of 5% CO ₂ in air.
[633] 1 day
[634] A 96-well plate containing 100 [mu] l of culture medium per well is prepared.
[635] Negative control (carrier): added to 100 쨉 l of 2 쨉 l of DMSO (in triplicate).
[636] Compound: 2 [mu] l of Hit compound storage diluent is added to 100 [mu] l (in triplicate)
[637] The transformed cells are trypsinized and resuspended in 12 mL of culture medium.
[638] 100 [mu] l of diluent is added to each 96-well plate.
[639] The plate is incubated overnight at 37 ° C in a humidified atmosphere of 5% CO ₂ in air.
[640] Hit compound dilution
[641] The Hit compound storage concentration is as follows:
[642] 3, 1 and 0.1 mM in 100% DMSO.
[643] 2 days
[644] Test procedure
[645] Dual-Luciferase ^™ Reporter Assay System (Promega)
[646] The medium is removed from the plate and the cells are washed twice with 100 μl PBS. Remove the wash solution safely before applying the PLB reagent. 1X PLB of each culture well is dispensed. The culture plate is gently shaken or stirred to place it in a locking flute groove or orbital shaker to cover and complete the cell monolayer with 1X PLB. The culture plate is shaken for 15 minutes at room temperature. Transfer 20 [mu] l of lysate into a white opaque 96 well plate. Read the luminometer.
[647] -50 [mu] l of luciferase reagent II injection 5 " Wait, 10 " read
[648] -50 ㎕ end & Glo ^ⓡ Reagent injection 5 "wait, 10" read
[649] RLU Lucifer / RLU Renilla ^* 1000 Check
[650] This assay inhibits JNK activity by more than 50% at 10 μM (ie, compounds (33), (93), (95) ). Thus, this analysis demonstrates the suitability of compounds according to formula I for down-regulated apatosis.
[651] D. LPS-Induced Endotoxin Shock in Mice (In Vitro)
[652] The efficacy of the JNK inhibitors described in Scheme I, which significantly lowers the level of inflammatory cytokines induced by LPS challenge, can be assessed by the following protocol:
[653] LPS (S. abortus-Galanos Lab.-) induced endotoxin shock by injecting male C57BL / 6 (200 mg / kg, iv) and compound (0.1, 1, 10 mg / kg) or NaCl And intravenously (10 mL / kg) 15 minutes before the challenge. Heparinized blood was obtained from orbital sinus at different time points after LPS challenge and the blood was centrifuged at 4 ° C for 10 min at 9'000 rpm and incubated with mouse ELISA kit such as IFN gamma (Duoset R & D Ref. DY485) Collect supernatant for measurement of tokynin production.
[654] Global Ischemia in E. Gerbil (In Vitro)
[655] The efficacy of the JNK inhibitors described in Scheme I to prevent cell death between strokes can be evaluated using the following protocol:
[656] -1-Method
[657] * Operation
[658] - Anesthesia: halothane or isoprourane (0.5-4%).
[659] - Esophageal clipping and skin incision.
[660] - Separation from the tissues of the common carotid artery (left and right).
[661] - Disinfection of the surgical site (Betadine ^ⓡ ) and skin suture (Autoclip ^ⓡ or
[662] Michel's hooks).
[663] - stabilize the animal under the heating lamp until it wakes up.
[664] - stabilization of animals in individual animals of animals.
[665] * Animal sacrifice
[666] - Seven days after Ischemia (taking Hyosu or pentobarbital).
[667] - Sampling of the brain.
[668] * Military variable
[669] - freezing of the brain in isopentane (-20 ° C)
[670] - incision of the hippocampus using a cryo-microtome (20 μm).
[671] - staining with cresyl violet and / or TUNEL method
[672] - Assessment of damage (in the lower area CA1 / CA2 of the hippocampus)
[673] - modified Gerhard & Boast score or
[674] - Cell counting in CA1 / CA2
[675] * Biochemical variables
[676] - Fine decomposition of the cerebral structure
[677] - Determined variables: DNA segment , lactate, calcium permeation.
[678] - Analysis method: ELISA , color measurement method, enzyme method, radiation measurement method
[679] -2-treatment
[680] - Administration of test substance or carrier: 15 minutes after re-circulation (5-10 minutes after recovery of anesthesia).
[681] - Standard protocol
[682] 50 animals: 10 dogs (group A: control group, group B-D: test substance 3 and E
[683] Group: Comparative compound (3x120 mg / kg of ketamine, ip or 3x300 mg / kg of ip , or ip ).

权利要求:
Claims (30)
[1" claim-type="Currently amended] The following structural formula I

Diastereomers and racemates thereof as well as their optically active forms as enantiomers as well as their pharmaceutically acceptable salts as well as their stereoisomers, Their salts.
Wherein, X is O, S, or R ⁰ is H or unsubstituted or substituted C ₁ -C ₆ alkyl and NR ^0;
G is an unsubstituted or substituted pyrimidyl group;
R ¹ is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ -alkoxy, unsubstituted or substituted C ₁ -C ₆ -thioalkoxy, unsubstituted or substituted C ₁ -C ₆ -alkyl, Unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alkynyl, primary, secondary or tertiary amino groups, aminoacyl, aminocarbonyl, the or substituted C ₁ -C ₆ alkoxycarbonyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, cyano, halogen, hydroxy, nitro, sulfoxide, sulfonyl, sulfone Amide, unsubstituted or substituted hydrazide;
R ² is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alkynyl, Unsubstituted or substituted C ₁ -C ₆ -alkyl-aryl, unsubstituted or substituted aryl or heteroaryl, unsubstituted or substituted C ₁ -C ₆ -alkyl-heteroaryl, -C (O) -OR ³ , -C (O) -R ³ , -C (O) -NR ³ R ^{3 '} , - (SO ₂ ) R ³ , wherein
R ³ and R ^{3 '} are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ Alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C ₁ -C ₆ -alkylaryl, unsubstituted or substituted C ₁ -C ₆ -alkylheteroaryl ≪ / RTI >
With the proviso that if X is S and R < ¹ > and R < ² > are H, then G is not the following pyrimidines;

Furthermore, when X is NH and R < ¹ > and R < ² > are H, then G is not the following pyrimidines;

As a last clue, if X is N-CH ₃ and R ¹ and R ² are H then G is not the next pyrimidine.

[2" claim-type="Currently amended] The following structural formula I

Diastereomers and racemates thereof as well as their optically active forms as enantiomers as well as their pharmaceutically acceptable salts as well as their stereoisomers, Therapeutics that become their salts.
Wherein, X is O, S, or R ⁰ is H or unsubstituted or substituted C ₁ -C ₆ alkyl and NR ^0;
G is an unsubstituted or substituted pyrimidyl group;
R ¹ is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ -alkoxy, unsubstituted or substituted C ₁ -C ₆ -thioalkoxy, unsubstituted or substituted C ₁ -C ₆ -alkyl, Unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alkynyl, primary, secondary or tertiary amino groups, aminoacyl, aminocarbonyl, the or substituted C ₁ -C ₆ alkoxycarbonyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, cyano, halogen, hydroxy, nitro, sulfoxide, sulfonyl, sulfone Amide, unsubstituted or substituted hydrazide;
R ² is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alkynyl, Unsubstituted or substituted C ₁ -C ₆ -alkyl-aryl, unsubstituted or substituted aryl or heteroaryl, unsubstituted or substituted C ₁ -C ₆ -alkyl-heteroaryl, -C (O) -OR ³ , -C (O) -R ³ , -C (O) -NR ³ R ^{3 '} , - (SO ₂ ) R ³ , wherein
R ³ and R ^{3 '} are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ Alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C ₁ -C ₆ -alkylaryl, unsubstituted or substituted C ₁ -C ₆ -alkylheteroaryl Selected from the group consisting of
[3" claim-type="Currently amended] 3. The mutant variant according to claim 1 or 2, as well as a benzazole derivative of the following structural formula I, as well as the following structural formula II.

here,
G is an unsubstituted or substituted pyrimidyl group;
R ¹ is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ -alkoxy, unsubstituted or substituted C ₁ -C ₆ -thioalkoxy, unsubstituted or substituted C ₁ -C ₆ -alkyl, Unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alkynyl, primary, secondary or tertiary amino groups, aminoacyl, aminocarbonyl, the or substituted C ₁ -C ₆ alkoxycarbonyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, cyano, halogen, hydroxy, nitro, sulfoxide, sulfonyl, sulfone Amide, unsubstituted or substituted hydrazide;
Provided that if R < ¹ > is H then G is not the next pyrimidine;

[4" claim-type="Currently amended] The process of any of the preceding claims, R ² is hydrogen, unsubstituted or substituted cyclic C ₁ -C ₆ - alkyl, unsubstituted or ring substituted with C ₁ -C ₆ - alkyl, aryl or C ₁ -C ₆ - (O) -OR ³ , -C (O) -NR ³ R ^{3 '} , - (SO ₂ ) R ³ wherein R ³ and R ^3' are as defined above for a benzazole derivative .
[5" claim-type="Currently amended] 5. The benzazole derivative of claim 4 wherein R < ² > is hydrogen and X and G are as described above.
[6" claim-type="Currently amended] _{6. A} benzazole derivative according to any one of claims 1 to 5, wherein R ¹ is selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy.
[7" claim-type="Currently amended] 5. Compounds according to claim 4, wherein R ³ and R ^{3 '} are selected from the group consisting of hydrogen, C ₁ -C ₆ -alkyl, aryl, heteroaryl, C ₁ -C ₆ -alkylaryl and C ₁ -C ₆ -alkylheteroaryl Benzazoles < / RTI >
[8" claim-type="Currently amended] The method of claim 7 wherein, R ³ and R ^{3 'is} hydrogen or C ₁ -C ₆ - alkyl benzamide azole derivatives.
[9" claim-type="Currently amended] 9. A compound according to any one of claims 1 to 8, wherein said aryl or heteroaryl group is substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -alkoxy, Or unsubstituted C ₂ -C ₆ -alkenyl, substituted or unsubstituted C ₂ -C ₆ -alkynyl, amino, aminoacyl, aminocarbonyl, substituted or unsubstituted C ₁ -C ₆ -alkoxy At least one selected from carbonyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, carboxyl, cyano, halogen, hydroxy, nitro, sulfonyl, sulfoxy and C ₁ -C ₆ -thioalkoxy Benzazole derivatives substituted with one substituent.
[10" claim-type="Currently amended] 10. A benzazole derivative according to any one of claims 1 to 9, wherein G is a pyrimidyl group.

Wherein L is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ alkoxy, unsubstituted or substituted C ₁ -C ₆ thioalkoxy, A substituted or unsubstituted C ₂ -C ₆ alkenyl, an unsubstituted or substituted C ₂ -C ₆ alkynyl, a primary, secondary or tertiary amino group, an aminoacyl, an aminocarbonyl, an amino- (C ₁ - C ₁₀₎ alkyl, amino-unsubstituted or substituted cyclic (C ₁ -C ₁₀₎ - alkyl-aryl, amino-unsubstituted or a substituted cyclic (C ₁ -C ₁₀₎ alkyl-heteroaryl, unsubstituted or substituted Substituted or unsubstituted aryl, unsubstituted or substituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, carboxyl, cyano, halogen, S, unsubstituted or substituted 3-8 membered cycloalkyl optionally containing at least one heteroatom selected from S, and a group consisting of or consisting of an unsubstituted or substituted hydrazide group Selected books.
[11" claim-type="Currently amended] 11. Compounds according to claim 10, wherein L is -N (R ^a , R ^b ) or -OR ^a where R ^a and R ^b are each independently H, unsubstituted or substituted (C ₁ -C ₁₀ ) Alkyl, unsubstituted or substituted C ₁ -C ₆ alkyl-aryl, unsubstituted or substituted C ₁ -C ₆ -alkyl-heteroaryl, unsubstituted or substituted aryl or heteroaryl, and unsubstituted or substituted Lt; / RTI > unsaturated or unsubstituted 4-8 membered saturated or unsaturated cycloalkyl.
[12" claim-type="Currently amended] 12. A benzazole derivative according to claim 11, wherein L is selected from:

Wherein n is from 1 to 10, preferably from 1 to 6,
R ⁵ and R ^{5 '} are each independently H, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted C ₁ -C ₆ alkyl-aryl And a substituted or unsubstituted C ₁ -C ₆ -alkyl-heteroaryl.
[13" claim-type="Currently amended] 13. A benzazole derivative according to claim 12 wherein X is S, R < ¹ > is H and R < ² >
[14" claim-type="Currently amended] 14. A benzazole derivative according to any one of claims 1 to 13, wherein X is S, R ¹ and R ² are H or C ₁ -C ₆ -alkyl and G is a pyrimidyl group of the structure:

Where L is
or
, Wherein n is 0, 1 or 2 and R < ⁵ > is aryl or heteroaryl.
[15" claim-type="Currently amended] 15. A benzazole derivative according to claim 14, wherein R < ⁵ > is phenyl, pyridyl or imidazolyl.
[16" claim-type="Currently amended] 16. A compound according to any one of claims 1 to 15, selected from the group consisting of benzazole derivatives:
Benzothiazol-2-yl (2-chloro-4-pyrimidyl) acetonitrile
1,3-benzothiazol-2-yl (2,6-dimethoxy-4-pyrimidyl) acetonitrile
Benzothiazol-2-yl (2-chloro-6-methyl-4-pyrimidyl) acetonitrile
Benzothiazol-2-yl [2- (methylsulfanyl) -4-pyrimidyl] acetonitrile
Benzothiazol-2-yl {6-chloro-5-nitro-4-pyrimidyl} acetonitrile
1,3-benzothiazol-2-yl (hydroxy-4-pyrimidyl) acetonitrile
Benzothiazol-2-yl (2-phenyl-4-quinazolinyl) acetonitrile
(2- chloropyrimidin-4-yl) [5- (trifluoromethyl) -1,3-benzothiazol-2-yl] acetonitrile
(3-methyl-1,3-benzothiazol-2 (3H) -ylidene) ethanenitrile
(2 - {[2- (1H-imidazol-5-yl) ethyl] amino} -4-pyrimidyl) acetonitrile
Benzothiazol-2-yl [2- (1-piperazinyl) -4-pyrimidyl] acetonitrile
Benzothiazol-2-yl [2- (4-benzyl-1-piperidinyl) -4-pyrimidyl] acetonitrile
Benzothiazol-2-yl [2- (4-methyl-1-piperazinyl) -4-pyrimidyl] acetonitrile
Benzothiazol-2-yl [2- (4-morpholinyl) -4-pyrimidyl] acetonitrile
Benzothiazol-2-yl [2- (methylamino) -4-pyrimidyl] acetonitrile
Benzothiazol-2-yl (2- {4- [2- (4-morpholinyl) ethyl] -1-piperazinyl} -4-pyrimidyl) -acetonitrile
Benzothiazol-2-yl {2- [4- (benzyloxy) -1-piperidinyl] -4-pyrimidyl} acetonitrile
Benzothiazol-2-yl [2- (4-hydroxy-1-piperidinyl) -4-pyrimidyl] acetonitrile
1,3-benzothiazol-2-yl (2-hydrazino-4-pyrimidyl) acetonitrile
Benzothiazol-2-yl (2- {[2- (dimethylamino) ethyl] amino} -4-pyrimidyl) acetonitrile
Benzothiazol-2-yl [2- (dimethylamino) -4-pyrimidyl] acetonitrile
Benzothiazol-2-yl {2 - [(2-methoxyethyl) amino] -4-pyrimidyl} acetonitrile
Benzothiazol-2-yl {2 - [(2-hydroxyethyl) amino] -4-pyrimidyl} acetonitrile
1,3-benzothiazol-2-yl [2- (propylamino) -4-pyrimidyl] acetonitrile
(2 - {[3- (1H-imidazol-1-yl) propyl] amino} -4-pyrimidyl) acetonitrile
Benzothiazol-2-yl [2- (1-pyrrolidinyl) -4-pyrimidyl] acetonitrile
Benzothiazol-2-yl {2 - [(2-phenylethyl) amino] -4-pyrimidyl} acetonitrile
Benzothiazol-2-yl (2- {[2- (2-pyridinyl) ethyl] amino} -4-pyrimidyl) acetonitrile
Benzothiazol-2-yl {2 - [(2-pyridinylmethyl) amino] -4-pyrimidyl} acetonitrile
Benzothiazol-1-yl) -1-piperidinyl] -4-pyrimidyl} acetonitrile < / RTI >
Benzothiazol-2-yl {2- [4- (2-pyrazinyl) -1-piperazinyl] -4-pyrimidyl} acetonitrile
Benzothiazol-2-yl {2- [4- (2-pyrimidyl) -1-piperazinyl] -4-pyrimidyl} acetonitrile
Benzothiazol-2-yl (2- {[2- (3-pyridinyl) ethyl] amino} -4-pyrimidyl) acetonitrile
(5-bromo-2 - {[2- (dimethylamino) ethyl] amino} -4-pyrimidyl) -acetonitrile
Benzothiazol-2-yl {2- [(2-morpholin-4-ylethyl) amino] pyrimidin-4- yl} acetonitrile
Synthesis of 1,3-benzothiazol-2-yl [2- (4- {3 - [(trifluoromethyl) sulfonyl] anilino} piperidin- 1 -yl) pyrimidin-
(2 - {[3- (2-oxopyrrolidin- 1 -yl) propyl] amino} pyrimidin-4-yl) -acetonitrile
2-yl (2- {methyl [3- (methylamino) propyl] amino} pyrimidin-4-yl) acetonitrile
(2 - {[3- (4-methylpiperazin-1-yl) propyl] amino} pyrimidin-4-yl) -acetonitrile
Benzothiazol-2-yl {2 - [(3-morpholin-4-ylpropyl) amino] pyrimidin-4- yl} acetonitrile
(2 - {[2- (1-methyl-1H-imidazol-4-yl) ethyl] amino} pyrimidin-4-yl) acetonitrile
(2 - {[2- (1H-indol-3-yl) ethyl] amino} pyrimidin-4-yl) acetonitrile
(2 - {[2- (4-hydroxyphenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
({4- [1,3-benzothiazol-2-yl (cyano) methyl] pyrimidin-2- yl} amino) acetate
Amino] pyrimidin-4-yl} (1,3-benzothiazol-2-yl) acetonitrile
(2-aminoethyl) amino] pyrimidin-4-yl} (1,3-benzothiazol-2-yl) acetonitrile
Benzothiazol-2-yl (2- {[3- (dimethylamino) propyl] amino} pyrimidin-4-yl) acetonitrile
Benzothiazol-2-yl {2 - [(2-piperidin-1 -ylethyl) amino] pyrimidin-4- yl} acetonitrile
(2 - {[2- (1-methyl-1H-imidazol-5-yl) ethyl] amino} pyrimidin-4-yl) acetonitrile
Benzothiazol-2-yl [2- (benzylamino) pyrimidin-4-yl] acetonitrile
Isopropyl 3 - ({4- [1,3-benzothiazol-2-yl (cyano) methyl] pyrimidin-2- yl} amino) propanoate
Benzothiazol-2-yl {2- [(3-hydroxypropyl) amino] pyrimidin-4- yl} acetonitrile
Benzothiazol-2-yl {2- [(pyridin-3-ylmethyl) amino] pyrimidin-4- yl} acetonitrile
(2-aminopyrimidin-4-yl) (1,3-benzothiazol-2-yl) acetonitrile
Benzothiazol-2-yl {2- [(pyridin-4-ylmethyl) amino] pyrimidin-4- yl} acetonitrile
2-yl} amino) -ethyl] phenylcarbamate < / RTI >
(2 - {[2- (4-aminophenyl) ethyl] amino} pyrimidin-4-yl) (1,3-benzothiazol-
(2 - {[2- (3,4-dimethoxyphenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
(2 - {[2- (3-methoxyphenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
(2 - {[2- (2-fluorophenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
Benzothiazol-2-yl [2- ({2- [3- (trifluoromethyl) phenyl] ethyl} amino) pyrimidin-4-yl] acetonitrile
Benzothiazol-2-yl {2- [(2-hydroxy-2-phenylethyl) amino] pyrimidin-4- yl} acetonitrile
2-yl] amino} ethyl) amino] - pyrimidin-4-yl} acetonitrile
(2 - {[2- (3-chlorophenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
Synthesis of 1,3-benzothiazol-2-yl (2 - {[2- (3,4-dichlorophenyl) ethyl] amino} pyrimidin-
(2 - {[2- (4-methoxyphenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
Synthesis of 1,3-benzothiazol-2-yl (2 - {[2- (4-methylphenyl) ethyl] amino} pyrimidin-
(2 - {[2- (3-fluorophenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
(2 - {[2- (4-phenoxyphenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
(2 - {[2- (2-phenoxyphenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
(2 - {[2- (4-bromophenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
(2 - {[2- (4-fluorophenyl) ethyl] amino} pyrimidin-4-yl) acetonitrile
Benzothiazol-2-yl {2 - [(2- [1,1'-biphenyl] -4-ylethyl) amino] pyrimidin-4- yl} acetonitrile
Amino} phenyl} ethyl) amino] pyrimidin-4-yl} acetonitrile < / RTI >
(2 - {[2- (1H-1,2,4-triazol-1-yl) ethyl] amino} pyrimidin-4-yl) acetonitrile
(2 - {[3- (1H-pyrazol-1-yl) propyl] amino} pyrimidin-4-yl) acetonitrile
Methyl} pyrimidin-2-yl} amino) ethyl] benzenesulfonamide < / RTI >
Yl} [5- (trifluoromethyl) -1,3-benzothiazol-2-yl] acetonitrile < / RTI >
Benzothiazol-2-yl {2- [(lH-tetrazol-5-ylmethyl) amino] pyrimidin-4- yl} acetonitrile
Benzothiazol-2-yl [2- (benzyloxy) pyrimidin-4-yl] acetonitrile
Benzothiazol-2-yl {2- [(4-pyridin-3-ylbenzyl) oxy] pyrimidin-4- yl} acetonitrile
Benzothiazol-2-yl [2- (pyridin-4-ylmethoxy) pyrimidin-4-yl] acetonitrile
Benzothiazol-2-yl [2- (pyridin-2-ylmethoxy) pyrimidin-4-yl] acetonitrile
2-yl [2- (3-pyridin-2-ylpropoxy) pyrimidin-4-yl] acetonitrile
Benzothiazol-2-yl {2 - [(4-methoxybenzyl) oxy] pyrimidin-4- yl} acetonitrile
Benzothiazol-2-yl [2- (pyridin-3-ylmethoxy) pyrimidin-4-yl] acetonitrile
Benzothiazol-2-yl {2- [2- (4-methoxyphenyl) ethoxy] pyrimidin-4- yl} acetonitrile
Benzothiazol-2-yl [2- ([1,1'-biphenyl] -3-ylmethoxy) pyrimidin-4- yl] acetonitrile
Benzothiazol-2-yl {2 - [(3,4,5-trimethoxybenzyl) oxy] pyrimidin-4- yl} acetonitrile
Benzothiazol-2-yl {2 - [(3,4-dichlorobenzyl) oxy] pyrimidin-4- yl} acetonitrile
Benzothiazol-2-yl [2- ({3 - [(dimethylamino) methyl] benzyl} oxy) pyrimidin-4-yl] acetonitrile
Benzothiazol-2-yl {2 - [(1-oxydopyridin-3-yl) methoxy] pyrimidin-4- yl} acetonitrile
Benzothiazol-2-yl (2 - {[4- (morpholin-4-ylmethyl) benzyl] oxy} pyrimidin-4-yl) acetonitrile
Benzothiazol-2-yl {2- [(4-pyridin-2-ylbenzyl) oxy] pyrimidin-4- yl} acetonitrile
Benzothiazol-2-yl (2 - {[4- (piperidin-1-ylmethyl) benzyl] oxy} pyrimidin-4-yl) acetonitrile
Benzothiazol-2-yl [2- (4-methoxyphenoxy) pyrimidin-4-yl] acetonitrile
Benzothiazol-2-yl [2- (4-butoxyphenoxy) pyrimidin-4-yl] acetonitrile
Yl} (1, 3-benzothiazol-2-yl) acetonitrile < / RTI >
[2- (4-methoxyphenoxy) pyrimidin-4-yl] [5- (trifluoromethyl) -1,3-benzothiazol-2-yl] acetonitrile
1,3-benzothiazol-2-yl (pyrimidin-4-yl) acetonitrile
Methyl} pyrimidin-2-yl} amino) ethyl] -4-chlorobenzamide < / RTI >
Benzothiazol-2-yl (2-methoxy-4-pyrimidyl) acetonitrile
[17" claim-type="Currently amended] 17. The method of claim 16, wherein the benzazole derivative selected from the group:
Benzothiazol-2-yl (2-chloro-4-pyrimidyl) acetonitrile
Benzothiazol-2-yl [2- (methylsulfanyl) -4-pyrimidyl] acetonitrile
(2 - {[2- (1H-imidazol-5-yl) ethyl] amino} -4-pyrimidyl) acetonitrile
Benzothiazol-2-yl [2- (methylamino) -4-pyrimidyl] acetonitrile
Benzothiazol-2-yl {2 - [(2-hydroxyethyl) amino] -4-pyrimidyl} acetonitrile
Benzothiazol-2-yl [2- (benzyloxy) pyrimidin-4-yl] acetonitrile
Benzothiazol-2-yl [2- (4-methoxyphenoxy) pyrimidin-4-yl] acetonitrile
Benzothiazol-2-yl (2-methoxy-4-pyrimidyl) acetonitrile
Benzothiazol-2-yl (2- {[2- (3-pyridinyl) ethyl] amino} -4-pyrimidyl) acetonitrile
[18" claim-type="Currently amended] In the preparation of a pharmaceutical composition for the modulation of the JNK pathway,

Diastereomers and racemates thereof as well as their optically active forms as enantiomers as well as their pharmaceutically acceptable salts as well as their stereoisomers, Use of their salts.
Wherein, X is O, S, or R ⁰ is H or unsubstituted or substituted C ₁ -C ₆ alkyl and NR ^0;
G is an unsubstituted or substituted pyrimidyl group;
R ¹ is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ -alkoxy, unsubstituted or substituted C ₁ -C ₆ -thioalkoxy, unsubstituted or substituted C ₁ -C ₆ -alkyl, Unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alkynyl, primary, secondary or tertiary amino groups, aminoacyl, aminocarbonyl, the or substituted C ₁ -C ₆ alkoxycarbonyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, cyano, halogen, hydroxy, nitro, sulfoxide, sulfonyl, sulfone Amide, unsubstituted or substituted hydrazide;
R ² is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alkynyl, Unsubstituted or substituted C ₁ -C ₆ -alkyl-aryl, unsubstituted or substituted aryl or heteroaryl, unsubstituted or substituted C ₁ -C ₆ -alkyl-heteroaryl, -C (O) -OR ³ , -C (O) -R ³ , -C (O) -NR ³ R ^{3 '} , - (SO ₂ ) R ³ , wherein
R ³ and R ^{3 '} are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ Alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C ₁ -C ₆ -alkylaryl, unsubstituted or substituted C ₁ -C ₆ -alkylheteroaryl Selected from the group consisting of
[19" claim-type="Currently amended] 19. Use according to claim 18 for the treatment or prevention of diseases associated with abnormal expression or activity of JNK.
[20" claim-type="Currently amended] 19. Use according to claim 18 for the treatment or prevention of diseases associated with abnormal expression or activity of JNK2 and / or 3.
[21" claim-type="Currently amended] Use of any one of the benzazole derivatives according to any one of claims 1 to 17 for the manufacture of a pharmaceutical composition for the treatment of neurological disorders including epilepsy, Alzheimer's disease, Huntington's disease, Parkinson's disease, retinal disease, spinal cord injury, head trauma.
[22" claim-type="Currently amended] A pharmaceutical composition for the treatment of autoimmune diseases including various sclerosis, inflammatory bowel disease (IBD), rheumatoid arthritis, asthma, septic shock, graft rejection, Use of a benzazole derivative.
[23" claim-type="Currently amended] Use of any one of the benzazole derivatives according to claims 1 to 17 for the manufacture of a pharmaceutical composition for the treatment of cancer, including breast, colon rectum and stomach cancer.
[24" claim-type="Currently amended] A pharmaceutical composition for the treatment of cardiovascular diseases, including stroke, arteriosclerosis, myocardial infraction, myocardial reperfusion injury, and any one of the benzazoles according to claims 1 to 17 Use of derivatives.
[25" claim-type="Currently amended] Use of a benzazole according to any one of claims 21 to 24 for the treatment or prevention of diseases associated with abnormal expression or activity of JNK.
[26" claim-type="Currently amended] A method for inhibiting the expression and / or activity of JNK comprising contacting cells expressing JNK with at least one benzazole derivative according to claims 1-17.
[27" claim-type="Currently amended] A method for treating a disease as contemplated by JNK, comprising administering to the patient an amount of any one of the pharmaceutically active ingredients according to claims 1-17.
[28" claim-type="Currently amended] A pharmaceutical composition comprising at least one benzazole derivative according to claims 1 to 17 and a pharmaceutically acceptable carrier, diluent or excipient thereof.
[29" claim-type="Currently amended] A process for preparing a benzazole derivative according to any one of claims 1 to 17, wherein the following reaction is carried out.

Where X and G are as described above and Y, Y 'is a suitable leaving group such as halogen.
[30" claim-type="Currently amended] 30. The method of claim 29, wherein the benzazole azole derivative is prepared by the following reaction.


Here, R ¹ , R ² , Y and X are as described above.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1999-12-24|Priority to EP99811207A

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1999-12-24|Priority to EP99811207.2

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2000-12-20|Application filed by 어플라이드 리서치 시스템스 에이알에스 홀딩 엔.브이.

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2002-09-14|Publication of KR20020072282A

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2007-07-06|Application granted

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2007-07-06|Publication of KR100736012B1

优先权:

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申请号 | 申请日 | 专利标题

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EP99811207A|EP1110957A1|1999-12-24|1999-12-24|Benzazole derivatives and their use as JNK modulators|

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EP99811207.2|1999-12-24|