Imidazo-pyrimidine derivatives as ligands for GABA receptors

专利摘要:
At the meta position of the phenyl ring, 3-phenyl which is directly bonded, optionally substituted by halo- and / or cyano-substituted aryl or heteroaryl groups, further substituted by one or two fluorine atoms in the phenyl ring Since the class of midazo [1,2-α] pyrimidine derivatives is a selective ligand for GABA A receptors, particularly with good affinity for the α2 and / or α3 and / or α5 subunits, it includes anxiety, convulsions and cognitive impairment. It is useful for treating and / or preventing side effects of the central nervous system.
公开号:KR20030083001A
申请号:KR10-2003-7012252
申请日:2002-03-19
公开日:2003-10-23
发明作者:챔버스마크스튜어트；굿에이커사이몬찰스；할렛데이비드제임스；제닝스앤드류；존스필립；루이스리차드토마스；무어케빈윌리암；스트리트레슬리조셉；체케리스헬렌제인
申请人:머크 샤프 앤드 돔 리미티드；
IPC主号:

专利说明:

Imidazo-pyrimidine derivatives as ligands for GABA receptors}
[1] The present invention relates to the class and treatment of substituted imidazo-pyrimidine derivatives. More specifically, the present invention relates to imidazo [1,2-α] pyrimidine analogs substituted at the 3-position by substituted phenyl rings. Since these compounds are ligands for the GABA _A receptor, they are useful for treating noxious mental states.
[2] Receptors for major inhibitory neurotransmitters, γ-aminobutyric acid (GABA), are divided into two main classes: (1) GAGA _A receptors, which are members of the upper class of ligand gate ion channels, and (2) G-protein coupled receptors. GABA _B receptors, which may be members of a higher class. By cloning the first cDNA encoding the individual GABA _A receptor subunits, known members of many mammalian classes include at least six α subunits, four β subunits, three γ subunits, and one δ subunit. , 1 Subunit and 2 Subunit.
[3] While knowledge of the diversity of the GABA _A receptor gene class represents an infinite step towards understanding such ligand gate ion channels, insight into the range of subtype diversity is still in its infancy. The α subunit, β subunit and γ subunit constitute the minimum requirement to form a fully functional GABA _A receptor expressed by transient infection of cDNA with cells. As indicated above, δ, ε, and ρ subunits also exist, but only in a minimal range in the GABA _A receptor group.
[4] Receptor size studies and visualization by electron microscopy have established that the native GABA _A receptor is in pentameric form, as is other members of the ligand gate ion channel class. Selection of at least one α, one β and one γ subunit from 17 receptors allows for the possible presence of more than 10,000 pentameric subunit combinations. Moreover, this calculation overlooked possible further substitutions when the arrangement of subunits around the ion channel is not forced (ie there may be 120 possible modifications for receptors of five different subunits).
[5] Receptor subtype assemblies that may be present include α1β2γ2, α2βγ1, α2β2 / 3γ2, α3βγ2 / 3, α4βδ, α5β3γ2 / 3, α6βγ2 and α6βδ, among many subtypes. Subform assemblies containing α1 subunits appear in most of the brain and are considered to be at least 40% of GABA _A receptors in rats. Subform assemblies containing α2 and α3 subunits, respectively, are considered to be about 25% and 17% of the GABA _A receptors in rats. Subform assemblies containing α5 subunits appear predominantly in the hippocampus and cortex and are considered to be about 4% of the GABA _A receptors in rats.
[6] The nature of all known GABA _A receptors is the presence of a number of regulatory sites, one of which is a benzodiazepine (BZ) binding site. The BZ binding site is a highly investigated GABA _A receptor regulatory site, and anxiolytic drugs such as diazepam and temazepam are sites that show their effect. Prior to the cloning of the GABA _A receptor gene class, the benzodiazepine binding site was historically subdivided into two subtypes BZ1 and BZ2 based on radiation binding studies. The BZ1 subform has been shown to be pharmacologically equivalent to the GABA _A receptor comprising the α1 subunit with βsubunit and γ2. It is the most abundant GABA _A receptor subform and is believed to represent nearly half of all GABA _A receptors in the brain.
[7] Two other major groups are the α2βγ2 and α3βγ2 / 3 subforms. Together they constitute about 35% of the additional GABA _A receptor list. Although the BZ2 subform may also include certain α5-containing subform assemblies, pharmacologically such a combination has already been shown to be equivalent to the BZ2 subform as defined by radioligand binding. The physiological role of these subforms is not clear so far because no sufficiently selective agonists or antagonists are known.
[8] It is believed that drugs that act as BZ agonists in the α1βγ2, α2βγ2 or α3βγ2 subforms will have the desired anxiety relief properties. Benzodiazepine compound control design of the binding site of the GABA _A receptor by acting as BZ agonists are referred to after the "GABA _A receptor agonists". α1 Selective GABA _A Receptor Agonists Alpidem and zolpidem are described clinically as hypnotic agents, and at least some of the sedation associated with known anxiolytic drugs acting at the BZ1 binding site is via a GABA _A receptor containing an α1 subunit. Indicates controlled. Thus, GABA _A receptor agonists that react more favorably with α2 and / or α3 subunits than α1 are believed to be effective in treating anxiety with a reduced tendency to cause sedation. Moreover, drugs that are inverse agonists of the α5 subunit are likewise effective for improving cognition in patients with dementia diseases (eg Alzheimer's disease). In addition, drugs that are antagonists or inverse agonists at α1 are used to reverse sedation or hypnosis caused by α1 agonists.
[9] Accordingly, the compounds of the invention, selective ligands for the GABA _A receptor, are useful for the treatment and / or prevention of various diseases of the central nervous system. Such disorders include anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without panic disorder history, animals and other phobias including social phobia, obsessive-compulsive disorder, posttraumatic treatment and acute stress disorders Stress disorders and general or substance-induced anxiety disorders, neuroses, cramps, migraine, depression or bipolar disorders such as single-episode or recurrent major depressive disorders, mood swings, bipolar I and bipolar II mood swings, and circulatory mood disorders, Psychosis including schizophrenia, neurodegeneration resulting from cerebral ischemia, attention deficit hyperactivity, speech disorders including stuttering and, for example, day cycle rhythm disorders in flight parallax or shift shift patients.
[10] Additional diseases for which selective redundancy to the GABA _A receptor may be beneficial include vomiting, including pain and pain, acute, delayed and anti-vomiting, especially vomiting, motion sickness, and post-surgical zones caused by chemotherapy or radiation and Dietary disorders, including vomiting, anorexia nervosa and pathological anorexia, premenstrual syndromes, such as hearing disorders including muscle spasms or stiffness, tinnitus and aging-related hearing impairment in patients with lower limbs, incontinence and alcohol withdrawal Substance abuse or dependence. Selective ligands for the GABA _A receptor may be effective for cognitive enhancement, for example, in patients with dementia disease (eg, Alzheimer's disease), and may be effective as preliminary medications before anesthesia or subprocedures, such as endoscopy including gastroscopy. Can be.
[11] In addition, the compounds according to the invention may be useful as radioligands in compound detection assays capable of binding to human GABA _A receptors.
[12] The present invention provides a class of imidazo-pyrimidine derivatives having the desired binding properties in various GABA _A receptor subforms. The compounds according to the invention have good affinity as ligands for the α2 and / or α3 and / or α5 subunits of the human GABA _A receptor. The compounds of the present invention may react more favorably on α2 and / or α3 subunits than on α1 subunits and / or react more favorably on α5 subunits than on α1 subunits.
[13] Compounds of the invention have a GABA with a binding affinity (K _i ) to α2 and / or α3 and / or α5 subunits of 200 nM or less, typically 100 nM or less, ideally 20 nM or less, as measured in the assays described below. _A receptor subform ligand. The compounds according to the invention may have a selective affinity for α2 and / or α3 and / or α5 subunits at least 2 times, suitably at least 5 times and advantageously at least 10 times relative to the α1 subunit. However, compounds that are not selective in terms of binding affinity for the α2 and / or α3 and / or α5 subunits relative to the α1 subunit are also included within the scope of the present invention, which compounds are preferably zero or less in the α1 subunit. Action selectivity in terms of weak (positive or negative) efficacy and (i) full or partial agonist profiles in the α2 and / or α3 subunits and / or (ii) inverse agonist profiles in the α5 subunits.
[14] The present invention provides a compound of formula (IA) or a pharmaceutically acceptable salt thereof.
[15]
[16] In Formula IIA above,
[17] X ¹¹ is fluoro,
[18] X ¹² is hydrogen or fluoro,
[19] Z is aryl or heteroaryl, which may be optionally substituted by one or more substituents selected from halogen and cyano,
[20] R ¹¹ is hydrogen, C _1-6 alkyl, halo (C _1-6 ) alkyl, dihalo (C _1-6 ) alkyl, hydroxy (C _1-6 ) alkyl, dihydroxy (C _1-6 ) alkyl , C _1-6 alkoxy (C _1-6 ) alkyl, di (C _1-6 ) alkoxy (C _1-6 ) alkyl, cyano (C _1-6 ) alkyl, C _2-6 alkoxycarbonyl (C _{1 6} ) alkyl, heteroaryl, C _1-6 alkyl-heteroaryl, heteroaryl (C _1-6 ) alkyl, halogen, cyano, trifluoromethyl, formyl, C _2-6 alkylcarbonyl, C _{2 -6} alkoxycarbonyl or -CR ⁵ = NOR ⁶ ,
[21] R ⁵ is hydrogen or C _1-6 alkyl,
[22] R ⁶ is hydrogen, C _1-6 alkyl, hydroxy (C _1-6 ) alkyl or di (C _1-6 ) alkylamino (C _1-6 ) alkyl.
[23] In addition, the present invention
[24] R ¹¹ is hydrogen, C _1-6 alkyl, halo (C _1-6 ) alkyl, dihalo (C _1-6 ) alkyl, hydroxy (C _1-6 ) alkyl, C _1-6 alkoxy (C _1-6 ) Alkyl, di (C _1-6 ) alkoxy (C _1-6 ) alkyl, heteroaryl, C _1-6 alkyl-heteroaryl, heteroaryl (C _1-6 ) alkyl, halogen, cyano, trifluoromethyl , Formyl, C _2-6 alkylcarbonyl, C _2-6 alkoxycarbonyl or —CR ⁵ = NOR ⁶ ,
[25] Z, X ¹¹ , X ¹² , R ⁵ and R ⁶ provide a compound of Formula IIA or a pharmaceutically acceptable salt thereof as defined above.
[26] For use as a medicament, the salt of the compound of formula IIA is a pharmaceutically acceptable salt. However, other salts may be useful for the preparation of the compounds according to the invention or pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts of the compounds of the present invention can be prepared by, for example, pharmaceutically acceptable acids such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, Acid addition salts which can be formed by mixing with a solution of succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, where the compounds of the present invention comprise acidic moieties, pharmaceutically acceptable suitable salts thereof are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts and suitable Salts formed using organic ligands, such as quaternary ammonium salts.
[27] Suitable alkyl groups include straight and branched chain alkyl groups having 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups and straight or branched propyl, butyl and pentyl groups. In particular, alkyl groups are methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl and 2,2-dimethylpropyl. Derived expressions such as "C _1-6 alkoxy", "C _1-6 alkylamino" and "C _1-6 alkylsulfonyl" are thus also constituted.
[28] Suitable aryl groups include phenyl and naphthyl, in particular phenyl.
[29] Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, Pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxdiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.
[30] The expression “heteroaryl (C _1-6 ) alkyl” as used herein refers to furylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl, oxazolylethyl, thiazolylmethyl, thiazolylethyl, imida Zolylmethyl, imidazolylethyl, oxadiazolylmethyl, oxdiazolylethyl, thidiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinyl Ethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl and isoquinolinylmethyl.
[31] The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine, in particular fluoro or chloro.
[32] If the compounds according to the invention have one or more asymmetric centers, they can therefore exist as enantiomers. If the compounds according to the invention have two or more asymmetric centers, they may additionally exist as diastereoisomers. All such isomers and mixtures thereof in any proportion are included within the scope of the present invention.
[33] In the compounds of formula (IA) the aryl or heteroaryl group Z may be unsubstituted or substituted by one or more substituents selected from halogen and cyano. Typically, group Z may be unsubstituted or substituted by one or two substituents. Suitably, group Z is unsubstituted or monosubstituted.
[34] Substituents Z include phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl, these groups May be optionally substituted by one or more substituents selected from halogen and cyano.
[35] Substituents Z each comprise phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, triazolyl and tetrazolyl, these groups being halogen And one or more substituents selected from cyano.
[36] Substituent Z typically includes phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, imidazolyl and triazolyl and these groups are selected by one or more substituents selected from halogen and cyano May be optionally substituted. Z is typically phenyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, and these groups may be optionally substituted by one or more substituents selected from halogen and cyano. In a preferred embodiment, Z is an optionally substituted phenyl group, in particular mono- or di-substituted phenyl. In another preferred embodiment Z is optionally substituted pyridinyl, in particular unsubstituted or monosubstituted pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.
[37] Examples of suitable substituents for group Z include fluoro, chloro and cyano. In particular, examples of substituents for group Z include fluoro and cyano, more particularly cyano.
[38] Z is specifically cyanophenyl, (cyano) (fluoro) phenyl, (chloro) (cyano) phenyl, pyridinyl, fluoro-pyridinyl, difluoro-pyridinyl, cyano-pyridinyl, pyri Dazinyl, pyrimidinyl, pyrazinyl, cyano-thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl and triazolyl.
[39] Z is suitably cyanophenyl, (cyano) (fluoro) phenyl, (chloro) (cyano) phenyl, pyridinyl, fluoro-pyridinyl, difluoro-pyridinyl, cyano-pyridinyl, Pyridazinyl, pyrimidinyl, pyrazinyl, cyano-thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl and triazolyl.
[40] Z is typically cyanophenyl, (cyano) (fluoro) phenyl, (chloro) (cyano) phenyl, pyridinyl, fluoro-pyridinyl, difluoro-pyridinyl, cyano-pyridinyl, Pyridazinyl, pyrimidinyl, pyrazinyl, cyano-thienyl, isothiazolyl, pyrrolyl and imidazolyl.
[41] Z is illustratively cyanophenyl, (cyano) (fluoro) phenyl, pyridinyl, fluoro-pyridinyl, cyano-pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, cyano-thienyl , Thiazolyl, imidazolyl and triazolyl. Z independently includes cyanophenyl, (cyano) (fluoro) phenyl, pyridinyl, fluoro-pyridinyl, cyano-pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.
[42] Z includes in particular 2-cyanophenyl, 2-cyano-4-fluorophenyl, pyridinyl-2-yl, pyridin-3-yl and 3-cyanopyridin-2-yl.
[43] In one embodiment, Z is 2-cyano-4-fluorophenyl.
[44] In other embodiments, Z is pyridin-3-yl.
[45] In a preferred embodiment, X ¹² is hydrogen. In other embodiments, X ¹² is fluoro.
[46] Suitably R ⁵ is hydrogen or methyl, in particular hydrogen.
[47] Suitably R ⁶ is hydrogen, methyl, ethyl, hydroxyethyl or dimethylaminoethyl. R ⁶ is especially hydrogen, hydroxyethyl and dimethylaminoethyl. Typically, R ⁶ is hydrogen or dimethylaminoethyl, especially hydrogen.
[48] When R ¹¹ is heteroaryl, this group is suitably pyridinyl, furyl, thienyl or oxazolyl.
[49] When R ¹¹ is C _1-6 alkyl-heteroaryl, this group is suitably methylthiazolyl (eg 2-methylthiazol-5-yl) or methyloxadiazolyl (eg 3-methyl [1, 2,4] oxadiazol-5-yl).
[50] When R ¹¹ is heteroaryl (C _1-6 ) alkyl, this group is suitably imidazolylmethyl or triazolylmethyl.
[51] R ¹¹ is independently hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (particularly 1-hydroxyethyl), fluoroethyl (particularly 1 -Fluoroethyl), difluoroethyl (particularly 1,1-difluoroethyl), dimethoxyethyl (particularly 1,1-dimethoxyethyl), isopropyl, hydroxypropyl (particularly 2-hydroxy Hydroxyprop-2-yl), dihydroxypropyl (particularly 1,2-dihydroxyprop-2-yl), fluoropropyl (particularly 2-fluoroprop-2-yl), cyano Propyl (particularly 2-cyanoprop-2-yl), methoxycarbonylpropyl (particularly 2-methoxycarbonylprop-2-yl), tert-butyl, hydroxybutyl (particularly 1- Hydroxy-2-methylprop-2-yl), pyridinyl, furyl, thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl, triazolylmethyl, chloro, cyano, trifluor Rommethyl, formyl, Cetyl, methoxycarbonyl and -CR ³ = NOR ⁴ include (wherein, R ³ and R ⁴ are the same as defined above).
[52] R ¹¹ is hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (particularly 1-hydroxyethyl), fluoroethyl (particularly 1-fluoro Roethyl), difluoroethyl (particularly 1,1-difluoroethyl), dimethoxyethyl (particularly 1,1-dimethoxyethyl), isopropyl, hydroxypropyl (particularly 2-hydroxyprop Pro-2-yl), fluoropropyl (particularly 2-fluoroprop-2-yl), tert-butyl, pyridinyl, furyl, thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl, already Dazolylmethyl, triazolylmethyl, chloro, cyano, trifluoromethyl, formyl, acetyl, methoxycarbonyl and -CR ³ = NOR ⁴ , where R ³ and R ⁴ are as defined above do.
[53] In one preferred embodiment, R ¹¹ is 2-hydroxyprop-2-yl. In another preferred embodiment, R ¹¹ is trifluoromethyl.
[54] The present invention advantageously provides a compound of formula (IA) or a pharmaceutically acceptable salt thereof, wherein Z is (cyano) (fluoro) phenyl or pyridinyl, and X ¹¹ , X ¹² and R ¹¹ are as defined above. .
[55] Representative examples of compounds of formula (IA) are compounds of formula (IIB) and pharmaceutically acceptable salts thereof.
[56]
[57] In Formula IIB above,
[58] X ¹¹ , X ¹² and R ¹¹ are as defined above,
[59] R ⁷ is hydrogen, fluoro or chloro.
[60] Suitably, R ⁷ is hydrogen or fluoro.
[61] In one embodiment, R ⁷ is hydrogen.
[62] In other embodiments, R ⁷ is fluoro.
[63] In further embodiments, R ⁷ is chloro.
[64] Other representative examples of compounds of formula (IA) are compounds of formula (IC) and pharmaceutically acceptable salts thereof.
[65]
[66] In the formula IIC above,
[67] X ¹¹ , X ¹² , R ¹¹ and R ⁷ are as defined above.
[68] Other representative examples of compounds of Formula IIA are compounds of Formula IID and pharmaceutically acceptable salts thereof.
[69]
[70] In the above formula IID,
[71] X ¹¹ , X ¹² and R ¹¹ are as defined above,
[72] R ⁸ is hydrogen, fluoro or cyano.
[73] Suitably R ⁸ is hydrogen or cyano, in particular hydrogen.
[74] In one embodiment, R ⁸ is hydrogen.
[75] In further embodiments, R ⁸ is fluoro.
[76] In other embodiments, R ⁸ is cyano.
[77] Other representative examples of compounds of formula (IIA) are compounds of formula (IIE) and pharmaceutically acceptable salts thereof.
[78]
[79] In the above formula IIE,
[80] X ¹¹ , X ¹² , R ¹¹ and R ⁸ are as defined above,
[81] R ⁹ is hydrogen or fluoro.
[82] Suitably, R ⁹ is hydrogen.
[83] In other embodiments, R ⁹ is fluoro.
[84] Certain compounds within the scope of the present invention
[85] 2'-fluoro-5 '-(imidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[86] 2'-fluoro-5 '-(7-methylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[87] 5 '-(7-acetylimidazo [1,2-α] pyrimidin-3-yl) -2'-fluorobiphenyl-2-carbonitrile,
[88] 2'-fluoro-5 '-(7-isopropylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[89] 2'-fluoro-5 '-(7-tert-butylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[90] 2'-fluoro-5 '-[7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[91] 2'-fluoro-5 '-[7- (1-fluoro-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[92] 2'-fluoro-5 '-(7-hydroxymethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[93] 2'-fluoro-5 '-[7- (1-hydroxyethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[94] 2'-fluoro-5 '-[7- (1-fluoroethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[95] 2'-fluoro-5 '-[7- (2-methylthiazol-5-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[96] 2'-fluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[97] 5 '-[7- (1,1-difluoroethyl) imidazo [1,2-α] pyrimidin-3-yl] -2'-fluorobiphenyl-2-carbonitrile,
[98] 5 '-(7-chloroimidazo [1,2-α] pyrimidin-3-yl) -2'-fluorobiphenyl-2-carbonitrile,
[99] 5 '-(7-difluoromethylimidazo [1,2-α] pyrimidin-3-yl) -2'-fluorobiphenyl-2-carbonitrile,
[100] 2'-fluoro-5 '-(7-methoxymethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[101] 3- (2'-cyano-6-fluorobiphenyl-3-yl) imidazo [1,2-α] pyrimidine-7-carbonitrile,
[102] 2'-fluoro-5 '-[7- (3-methyl- [1,2,4] oxadiazol-5-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl -2-carbonitrile,
[103] 2'-fluoro-5 '-[7- (oxazol-5-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[104] 2'-fluoro-5 '-[7- (hydroxyiminomethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[105] 5 '-{7- [1- (2-dimethylaminoethoxyimino) methyl] imidazo [1,2-α] pyrimidin-3-yl} -2'-fluorobiphenyl-2-carbonitrile,
[106] 3 '-(7-difluoromethylimidazo [1,2-α] pyrimidin-3-yl) -4'-fluorobiphenyl-2-carbonitrile,
[107] 2'-fluoro-5 '-(7-fluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[108] 2'-fluoro-5 '-[7- (furan-3-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[109] 2'-fluoro-5 '-[7- (thien-3-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[110] 2'-fluoro-5 '-[7- (pyridin-2-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[111] 7- (1,1-difluoroethyl) -3- [4-fluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine,
[112] 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[113] 3'-fluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[114] 3'-fluoro-5 '-(7-hydroxymethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[115] 2'-fluoro-3 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[116] 3- [4-fluoro-3- (pyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[117] 3- [4-fluoro-3- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[118] 2'-fluoro-5 '-[7-([1,2,4] triazol-1-ylmethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbo Nitrile,
[119] 2'-fluoro-5 '-[7- (imidazol-1-ylmethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[120] 2'-fluoro-5 '-[7-([1,2,3] triazol-1-ylmethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbo Nitrile,
[121] 2'-fluoro-5 '-[7-([1,2,3] triazol-2-ylmethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbo Nitrile,
[122] 3- [4-fluoro-3- (pyridin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[123] 3- [2,4-difluoro-3- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[124] 3- [2,4-difluoro-3- (pyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[125] 2- [3- (4-fluoro-3- (pyridin-4-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[126] 3- [2-fluoro-3- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[127] 2- [3- (2-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[128] 3- [2-fluoro-3- (pyridin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[129] 2- [3- (2-fluoro-3- (pyridin-4-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[130] 3- [2-fluoro-3- (pyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[131] 2- [3- (2-fluoro-3- (pyridin-2-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[132] 3- [4-fluoro-3- (pyridazin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[133] 2- [2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenyl] nicotinonitrile,
[134] 3- [4-fluoro-3- (pyridin-2-yl) phenyl] imidazo [1,2-α] pyrimidine,
[135] 3,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[136] 6,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[137] 5,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[138] 4,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[139] 2 ', 6'-difluoro-3'-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[140] 3- [4-fluoro-3- (pyrazin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[141] 3- [4-fluoro-3- (pyrimidin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[142] 3- [2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenyl-pyridine-2-carbonitrile,
[143] 3- [4-fluoro-3- (5-fluoropyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[144] 7- (1,1-difluoroethyl) -3- [4-fluoro-3- (pyridin-4-yl) phenyl] imidazo [1,2-α] pyrimidine,
[145] 7- (1,1-difluoroethyl) -3- [2,4-difluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine,
[146] 2- [3- (2,4-difluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -propan-2-ol,
[147] 1- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -ethanone,
[148] 3 '-[7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] -4,2', 6'-trifluorobiphenyl-2-carbo Nitrile,
[149] 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -propane-1,2-diol,
[150] 3- [2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl] phenyl] -thiophene-2-carbonitrile,
[151] 3- {2-fluoro-5- [7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] phenyl} thiophene-2-carbonitrile,
[152] 3- {2,6-difluoro-3- [7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] phenyl} thiophen-2- Carbon Nitrile,
[153] 3- [4-fluoro-3- (3-fluoropyridin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[154] 4-chloro-2'-fluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[155] 2- [3- (4-fluoro-3- (pyrazin-2-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[156] 2- [3- (4-fluoro-3- (5-fluoropyridin-2-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[157] 3- [4-fluoro-3- (3-fluoropyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[158] 2- [3- (4-fluoro-3- (3-fluoropyridin-2-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[159] 3- [3- (3,5-difluoropyridin-2-yl) -4-fluorophenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[160] 2- [3- (3- (3,5-difluoropyridin-2-yl) -4-fluorophenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol ,
[161] 3- [2,4-difluoro-3- (pyridin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[162] 2- [3- (2,4-difluoro-3- (pyridin-4-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[163] 4,2'-difluoro-5 '-[7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[164] 2'-fluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl] biphenyl-3-carbonitrile,
[165] 2'-fluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl] biphenyl-4-carbonitrile,
[166] 3- [2,4-difluoro-3- (pyridin-3-yl) phenyl] -7- (1-fluoro-1-methylethyl) imidazo [1,2-α] pyrimidine,
[167] 7- (1-fluoro-1-methylethyl) -3- [4-fluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine,
[168] 2- [3- (2,4-difluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -2-methylpropionic acid methyl ester,
[169] 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -2-methylpropionitrile,
[170] 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -2-methylpropan-1-ol,
[171] 3- [4-fluoro-3- (4-fluoropyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[172] 3- [4-fluoro-3- (pyrrole-1-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[173] 3- [4-fluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine,
[174] 3- [4-fluoro-3- (5-fluoropyridin-2-yl) phenyl] imidazo [1,2-α] pyrimidine,
[175] 3- [2,4-difluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine,
[176] 3- [5-fluoro-3- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[177] 3- [2-fluoro-5- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[178] 3- [4-fluoro-3- (pyridin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[179] 3- [4-fluoro-3- (imidazol-1-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[180] 3- [4-fluoro-3- (isothiazol-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[181] 3- [4-fluoro-3- (pyrimidin-5-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[182] 3- [4-fluoro-3- (thiazol-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[183] 2- {2-fluoro-5- [7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] phenyl} nicotinonitrile,
[184] 4- [2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenyl] nicotinonitrile,
[185] 4- {2-fluoro-5- [7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] phenyl} nicotinonitrile,
[186] 3- [2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenyl] isonicotinonitrile,
[187] 2- [3- (4-fluoro-3- (pyridazin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[188] 2- [3- (4-fluoro-3- (pyridazin-4-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[189] 3- [4-fluoro-3- (pyrazol-1-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[190] 2- [3- (4-fluoro-3- (pyrazol-1-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[191] 3- [4-fluoro-3-([1,2,4] triazol-1-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[192] 2- [3- (4-fluoro-3-([1,2,4] triazol-1-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2- All,
[193] 2- {3- [4-fluoro-3- (5-fluoropyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidin-7-yl} propan-2-ol and pharmaceuticals Acceptable salts thereof.
[194] In addition, the present invention provides a method for treating and / or preventing anxiety, comprising administering to a patient in need thereof an effective amount of a compound of Formula (IIA) or a pharmaceutically acceptable salt thereof or a prodrug thereof. Is provided.
[195] In addition, the present invention comprises administering an effective amount of a compound of Formula (IIA) or a pharmaceutically acceptable salt thereof or a prodrug thereof to a patient in need of treatment and / or prevention of convulsions (eg, patients with epilepsy or related diseases). , Methods of treating and / or preventing convulsions are provided.
[196] The binding affinity (K _i ) of the compounds according to the invention for the α3 subunit of the human GABA _A receptor is conveniently measured in the assay described below. The α3 subunit binding affinity (K _i ) of the anxiolytic compound of the present invention is ideally 50 nM or less, preferably 10 nM or less, and more preferably 5 nM or less.
[197] Anxiety alleviating compounds according to the invention ideally enhance the GABA EC ₂₀ response in at least 40%, preferably at least 50%, more preferably in stable infected recombinant cell lines expressing the α3 subunit of the human GABA _A receptor. More than 60%. Moreover, the compounds of the invention ideally enhance the GABA EC ₂₀ response up to 30%, preferably up to 20%, more preferably 10 in stable infected recombinant cell lines expressing the α1 subunit of the human GABA _A receptor. It can be derived below%.
[198] Enhancement of the GABA EC ₂₀ response in stably infected recombinant cell lines expressing the α3 and α1 subunits of the human GABA _A receptor is conveniently described in Wafford et al., Mol. Pharmacol., 1996, 50, 670-678 can be measured by a method similar to the method described. The method may suitably be carried out using a culture of stably infected eukaryotic cells, generally stably infected mouse Ltk-fibroblasts.
[199] The compounds according to the invention can exhibit anxiety relief activity and can be demonstrated by positive responses in the rising pulse maze and control suppression of drinking tests (Dawson et al., Psychopharmacology, 1995, 121, 109-117). . Moreover, the compounds of the present invention can likewise have a virtually non-soothing effect and can be confirmed by the appropriate results obtained from reaction sensitivity (chain-pooling) tests. Bayley et al., J. Psychopharmacol., 1996, 10, 206-213.
[200] Compounds according to the invention may exhibit anticonvulsant activity. This is described in Bristow et al., J. Pharmacol. Exp. Ther., 1996, 279, 492-501 can be demonstrated by the ability to block pentylenetetrazole-induced seizures in rats and mice according to methods analogous to those described.
[201] In another aspect, the invention includes administering an effective amount of a compound of Formula (IAA) or a pharmaceutically acceptable salt thereof to a patient in need of treatment and / or prevention of cognitive disorders, including dementia diseases such as Alzheimer's disease Provided are methods for treating and / or preventing disorders.
[202] Cognitive enhancement may be indicated by treating the compound in a Morris Water Maze, as reported by McNamara and Skelton, Psychobiology, 1993, 21, 101-108. Further details of related methodologies are described in WO 96/25948.
[203] Cognitive disorders that may benefit from the compounds of the present invention include cognitive deficits, seizures, Parkinson's disease and Down's syndrome, including aging-related memory deficits due to delirium, dementia, amnesia and trauma damage. These diseases may be due to substance abuse or withdrawal. Examples of dementia include early and late onset Alzheimer's dementia and vascular dementia, which are non-merging or dementia, delusional or depressed mood and dementia due to HIV disease, head trauma, Parkinson's disease or Creutzfeld-Jakob It may be accompanied by a disease.
[204] To induce these behavioral effects, the compounds of the present invention may ideally be brain penetrators. That is, these compounds may cross over the so-called "blood-brain block". Preferably, the compounds of the present invention can exert their beneficial therapeutic action upon administration by the oral route.
[205] The present invention also provides pharmaceutical compositions comprising one or more compounds of the present invention in combination with a pharmaceutically acceptable carrier. Preferably, these compositions are tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosols or liquids for oral, parenteral, nasal, sublingual or rectal administration or for administration by inhalation or aspiration. Unit dosage forms such as sprays, drops, ampoules, autoinjector devices or suppositories. To prepare a solid composition, for example a tablet, the main active ingredient is a pharmaceutical carrier, such as conventional tableting ingredients, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, It may be mixed with magnesium stearate, dicalcium phosphate or gum and other pharmaceutical diluents such as water to form a solid preformulation composition comprising a homogeneous mixture of a compound of the invention or a pharmaceutically acceptable salt thereof. have. When these preformulated compositions are referred to as homogeneous, it means that the active ingredients are uniformly dispersed throughout the composition so that the composition can be easily subdivided into the same effective unit dosage form, e.g. tablets, pills and capsules. do. Such solid preformulation compositions are subdivided into unit dosage forms of the above form containing from 0.1 to about 500 mg of the active compound of the present invention. Typical unit dosage forms contain 1 to 100 mg of active ingredient, for example 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg or 100 mg. Tablets or pills of the novel compositions may be coated or formulated to provide dosage forms that provide extended action benefits. For example, tablets or pills may comprise internal dose and external dose components, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which acts to disrupt the digestion of the stomach and to pass the internal components into the duodenum or to delay the release. Various materials can be used in such enteric layers or coatings, and such materials include a mixture of a plurality of polymeric acids and polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.
[206] Liquid forms in which the novel compositions of the present invention may be incorporated by oral administration or injection are, in combination with elixirs and similar pharmaceutical vehicles, aqueous solutions, suitably flavor syrups, aqueous or oil suspensions and edible oils, for example Flavor oils with cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents suitable for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl pyrrolidone or gelatin .
[207] In the treatment of neurological diseases, suitable dosage levels are about 0.01 to 250 mg / kg, preferably about 0.05 to 100 mg / kg, in particular about 0.05 to 5 mg / kg. The compound may be administered 1 to 4 times a day.
[208] The compounds according to the invention can be prepared by a process comprising reacting a compound of formula III with a compound of formula IV in the presence of a transition metal catalyst.
[209]
[210]
[211] In Formulas III and IV above,
[212] X ¹¹ , X ¹² , Z and R ¹¹ are as defined above,
[213] L ¹ is a suitable leaving group,
[214] M ¹ is a boronic acid residue —B (OH) ₂ or a cyclic ester thereof formed using an organic diol such as pinacol, 1,3-propanediol or neopentyl glycol, or —Sn (Alk) ₃ ( Where Alk is a C _1-6 alkyl group, typically n-butyl).
[215] Leaving group L ¹ is typically a halogen atom, for example bromo.
[216] The transition metal catalyst for use in the reaction of the compound of formula III with the compound of formula IV is suitably tetrakis (triphenylphosphine) palladium (O). The reaction is conveniently carried out at elevated temperatures in a solvent such as N, N-dimethylacetamide, 1,4-dioxane or tetrahydrofuran, advantageously of potassium phosphate, copper iodide, sodium carbonate or cesium carbonate. In the presence. Alternatively, the transition metal catalyst used is dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II), in which case the reaction is conveniently a solvent, for example N, N-dimethylform. In amides, it is advantageously carried out at elevated temperatures in the presence of potassium phosphate.
[217] In another method, the compound according to the invention reacts a compound of formula V with a compound of formula VI under conditions similar to those described for the reaction of a compound of formula III with a compound of formula IV in the presence of a transition metal catalyst. It can manufacture by the method to include.
[218]
[219]
[220] In Formulas V and VI above,
[221] X ¹¹ , X ¹² , Z, R ¹¹ , L ¹ and M ¹ are as defined above.
[222] In another method, the compound according to the invention reacts a compound of formula VII with a compound of formula VIII under conditions similar to those described for the reaction of a compound of formula III with a compound of formula IV in the presence of a transition metal catalyst. It can manufacture by the method to include.
[223]
[224] M ^1- Z
[225] In the above formulas VII and VIII,
[226] X ¹¹ , X ¹² , Z, R ¹¹ , L ¹ and M ¹ are as defined above.
[227] In compounds of formula (VII), leaving group L ¹ is typically trifluoromethanesulfonyloxy (triflyloxy) or a halogen atom, for example bromo.
[228] Or a compound according to the invention comprises reacting a compound of formula (IX) with a compound of formula (X) under conditions similar to those described for the reaction of a compound of formula (III) with a compound of formula (IV) in the presence of a transition metal catalyst It can manufacture by.
[229]
[230] L ^1- Z
[231] In the above formulas IX and X,
[232] X ¹¹ , X ¹² , Z, R ¹¹ , L ¹ and M ¹ are as defined above.
[233] In the intermediates of Formulas IV and IX, when M ¹ is a boronic acid residue -B (OH) ₂ or a cyclic ester thereof formed using pinacol or neopentyl glycol, the compound of formula IV or IX is bis (pinacole) Ito) diboron or bis (neopentyl glycolrato) diborane can be prepared by reacting with a compound of formula VIA or VIIA in the presence of a transition metal catalyst, respectively.
[234]
[235]
[236] In the above formulas VIA and VIIA,
[237] X ¹¹ , X ¹² , Z and R ¹¹ are as defined above,
[238] L ² is hydroxy or a suitable leaving group.
[239] When L ² is a leaving group, it is typically a triflyloxy or halogen atom, for example bromo.
[240] Transition metal catalysts used for the reaction of bis (pinacolato) diboron or bis (neopentyl glycolrayto) diborane with a compound of formula VIA or VIIA are suitably dichloro [1,1′-bis (diphenylforce). Pino) ferrocene] palladium (II). The reaction is conveniently carried out at elevated temperature, optionally in a solvent, such as 1,4-dioxane, in a mixture with dimethylsulfoxide, typically 1,1'-bis (diphenylphosphino) ferrocene and / or potassium acetate Perform in the presence of
[241] When L ¹ / L ² in the intermediate of formula (VII / VIIA) is trilyloxy, the compounds of formula (VII / VIIA) can be prepared by reacting a suitable compound of formula (XI) with triflic acid anhydride, typically in the presence of pyridine.
[242]
[243] In the above formula (XI),
[244] X ¹¹ , X ¹² and R ¹¹ are as defined above.
[245] Similar conditions can be used to convert intermediates of formula VIA in which L ² is hydroxy to the corresponding compounds of formula VI / VIA in which L ¹ / L ² is trityloxy.
[246] Intermediates of formula (XI) may suitably be prepared from a suitable methoxy substituted precursor of formula (XII) by treatment with hydrogen bromide under reflux, typically in acetic acid.
[247]
[248] In formula (XII) above,
[249] X ¹¹ , X ¹² and R ¹¹ are as defined above.
[250] Intermediates of formula (XII) may be prepared by reacting a compound of formula (III) with a suitable compound of formula (XIII) in the presence of a transition metal catalyst, under conditions similar to those described for the reaction of a compound of formula (III) with a compound of formula (IV).
[251]
[252] In formula (XIII) above,
[253] X ¹¹ , X ¹² and M ¹ are as defined above.
[254] In particular, the transition metal catalyst used in the reaction of the compound of formula III with the compound of formula XIII is suitably tetrakis (triphenylphosphine) palladium (O), in which case the reaction is conveniently carried out at elevated temperature, eg solvent For example, in aqueous 1,2-dimethoxyethane it is advantageously carried out in the presence of sodium carbonate.
[255] In the intermediate of formula (V), when M ¹ is -Sn (Alk) ₃ and Alk is as defined above, such a compound is a reagent of formula (Alk) ₃ Sn-Hal, wherein Hal is a halogen atom , Typically chloro). The reaction is conveniently carried out by treating the compound of formula III with isopropylmagnesium chloride, typically in a solvent, for example tetrahydrofuran, and adding stanyl reagent (Alk) ₃ Sn-Hal.
[256] When L ¹ is bromo in the intermediate of formula III, such compounds can be prepared by bromination of the corresponding compound of formula XIV, typically by treatment with bromine in the presence of sodium acetate and optionally potassium bromide in methanol.
[257]
[258] In Formula XIV above,
[259] R ¹¹ is as defined above.
[260] Intermediates of formula (XIV) may be prepared by reacting chloroacetaldehyde or bromoacetaldehyde or acetal derivatives thereof, such as dimethyl or diethyl acetal, with the essential compounds of formula (XV).
[261]
[262] In Formula XV above,
[263] R ¹¹ is as defined above.
[264] When chloroacetaldehyde or bromoacetaldehyde is used as one of the reactants, the reaction is conveniently carried out under basic conditions, in a suitable solvent such as lower alcohols such as sodium in methanol and / or ethanol. By heating at reflux of the solvent in methoxide or sodium bicarbonate. When acetal derivatives of chloroacetaldehyde or bromoacetaldehyde, for example their dimethyl or diethyl acetals, are used as one of the reactants, the reaction is conveniently carried out by reacting the reactants under acidic conditions with suitable solvents such as lower In aqueous hydrobromic acid in alcohols such as methanol and / or ethanol, this is typically done by heating at the reflux temperature of the solvent.
[265] In another method, the compounds according to the invention are prepared by reacting a compound of formula XV with a compound of formula XVI under conditions similar to those described for the reaction of chloroacetaldehyde or bromoacetaldehyde or an acetal derivative thereof with a compound of formula XV. It may be prepared by a method including the reaction.
[266]
[267] In Formula XVI above,
[268] X ¹¹ , X ¹² and Z are as defined above,
[269] L ³ is a suitable leaving group.
[270] Leaving group L ³ is suitably a halogen atom, for example bromo.
[271] Intermediates of formula (XIV) may be prepared by reacting a compound of formula (XVII) or (XVIII) with a compound of formula (XIX) or an acid addition salt thereof, such as a hemisulfate salt.
[272]
[273]
[274]
[275] In the above formulas XVII to XIX,
[276] R ¹¹ is as defined above,
[277] Alk ¹ is C _1-6 alkyl.
[278] Alk ¹ is typically methyl and ethyl.
[279] The reaction is conveniently carried out at the reflux temperature of the solvent, typically in a suitable solvent such as lower alkalol, such as methanol or ethanol, for example sodium methoxide or ethoxide, under basic conditions. Perform by heating.
[280] In another method, compounds according to the invention wherein R ¹¹ is a heteroaryl moiety can be prepared by a process comprising reacting a compound of formula XX with a compound of formula XXI in the presence of a transition metal catalyst.
[281] R ^1a -M ¹
[282]
[283] In the above formulas XX and XXI,
[284] Z and M ¹ are as defined above,
[285] R ^1a is a heteroaryl moiety,
[286] L ⁴ is a suitable leaving group.
[287] Leaving group L ⁴ is typically a halogen atom, for example chloro.
[288] The transition metal catalyst used in the reaction of the compound of formula (XX) with the compound of formula (XXI) is suitably tetrakis (triphenylphosphine) palladium (O), in which case the reaction is conveniently carried out at elevated temperatures, eg solvents, e.g. For example, it is performed in N, N-dimethylacetamide, typically in the presence of potassium phosphate or lithium chloride and copper iodide. Alternatively, the transition metal catalyst may suitably be tris (dibenzylideneacetone) dipalladium (O), in which case the reaction is typically at elevated temperature, typically in a solvent, for example 1,4-dioxane. It is carried out in the presence of tri-tert-butylphosphine and cesium carbonate.
[289] When L ⁴ is a halogen atom in the compound of formula XXI, these compounds correspond to compounds of formula IIA in which R ¹¹ is halogen and can be prepared by the methods described above for the preparation of compounds according to the invention.
[290] Compounds of the invention wherein Z is pyrrole-1-yl can be prepared by reacting a compound of Formula XXII with 2,5-dimethoxytetrahydrofuran.
[291]
[292] In the above formula XXII,
[293] X ¹¹ , X ¹² and R ¹¹ are as defined above.
[294] The reaction is conveniently carried out in a solvent such as acetic acid at elevated temperature.
[295] Intermediates of formula (XXII) can be prepared by reacting a compound of formula (III) with an appropriate compound of formula (XXIII) under conditions similar to those used for reaction of compounds of formula (III) with compounds of formula (XIII) in the presence of a transition metal catalyst.
[296]
[297] In the above formula XXIII,
[298] X ¹¹ , X ¹² and M ¹ are as defined above.
[299] The compound of formula XIX is commercially available from Sigma-Aldrich Company Ltd., Dorset, England.
[300] If they are not commercially available, the starting materials of the formulas VI, VIII, X, XIII, XV, XVI, XVII, XVIII, XX and XXIII are similar to those described in the Examples or are well known in the art. It may be prepared by standard methods.
[301] Compounds of formula (IA) initially obtained from the process may optionally be synthesized into other compounds of formula (IA) by techniques known in the art. For example, a compound of formula (IA) obtained initially wherein R ¹¹ is di (C _1-6 ) alkoxy (C _1-6 ) alkyl is hydrolyzed with an inorganic acid, typically aqueous hydrochloric acid so that R ¹¹ is C _2-6 Alkylcarbonyl which can be converted to the corresponding compound of formula (IA). Compounds in which R ¹¹ is formyl can be reduced to the corresponding compound in which R ¹¹ is hydroxymethyl using sodium triacetoxyborohydride. Compounds of formula (IIA) wherein R ¹¹ is hydroxymethyl can be treated with manganese dioxide to oxidize to the corresponding compounds of formula (IIA) where R ¹¹ is formyl. The formyl derivative thus obtained is condensed with a hydroxylamine derivative of formula H ₂ N-OR ⁶ to provide a compound of formula IIA wherein R ¹¹ is -CH = NOR ⁶ . In addition, compounds of formula (IIA) wherein R ¹¹ is —CH═NOH are treated with triethylamine in the presence of 1,1′-carbonyldiimidazole to provide the corresponding compounds of formula (IIA) wherein R ¹¹ is cyano. Or, R ¹¹ is a formyl compound of the formula IIA of the Grignard reagent and reacted with R ¹¹ is hydroxy (C _1-6) alkyl, provides a compound of formula IIA, and, R ¹¹ in these compounds with manganese dioxide Oxidized to the corresponding compound of formula (IIA) which is C _2-6 alkylcarbonyl. The latter compound is condensed with a hydroxylamine derivative of formula H ₂ N-OR ⁶ to provide a compound of formula IIA wherein R ¹¹ is -CR ⁵ = NOR ⁶ . Compounds of formula (IA) wherein R ¹¹ is hydroxy (C _1-6 ) alkyl are treated with (diethylamino) sulfur trifluoride (DAST) to provide a corresponding compound of formula (IIA) wherein R ¹¹ is fluoro (C _1-6 ) alkyl. It can be converted into a compound. Similarly, compounds of formula (IA) wherein R ¹¹ is C _2-6 alkylcarbonyl can be treated with DAST to convert to the corresponding compounds of formula (IA) wherein R ¹¹ is difluoro (C _1-6 ) alkyl. Compounds of formula (IA) wherein R ¹¹ is -COCH ₃ can be treated with thioacetamide in the presence of pyridinium tribromide to obtain the corresponding compounds of formula (IA) wherein R ¹¹ is 2-methylthiazol-5-yl. Moreover, the corresponding compound of formula IIA wherein R ¹¹ is oxazol-5-yl by treating a compound of formula IIA wherein R ¹¹ is formyl with (p-tolylsulfonyl) methyl isocyanide (TosMIC) in the presence of potassium carbonate Can be obtained. Treatment of a compound of formula (IIA) wherein R ¹¹ is hydroxymethyl with carbon tetrabromide and triphenylphosphine to give the corresponding compound of formula (IIA) wherein R ¹¹ is bromomethyl and (typically in situ) imidazole Or a compound of formula IIA wherein R ¹¹ is imidazol-1-ylmethyl or [1,2,4] triazol-1-ylmethyl by reacting with a sodium salt of 1H- [1,2,4] triazole, respectively Obtained, or reacted with the sodium salt of 1H- [1,2,3] triazole, wherein R ¹¹ is [1,2,3] triazol-1-ylmethyl and [1,2,3] triazole-2- A mixture of compounds of formula (IIA) can be obtained which is monomethyl.
[302] If a mixture of products is obtained from the process described in the preparation of the compounds according to the invention, the desired product can be prepared in conventional steps, for example silica and / or with a suitable solvent system, for example with preparative HPLC or a suitable solvent system. Or by column chromatography using alumina.
[303] If the methods described in the preparation of the compounds according to the invention give a mixture of stereoisomers, these isomers can be separated by conventional techniques, for example by preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared by enantio specific synthesis or cleavage. The novel compounds are, for example, standard techniques such as preparative HPLC or optically active acids such as (-)-di-p-toluyl-d-tartaric acid and / or (+)-di-p Salts with -toluoyl l-tartaric acid can be divided into these component enantiomers by formation of diastereomeric pairs by salt salting followed by fractional crystallization and regeneration of the free base. The novel compounds can be partitioned by diastereomeric ester or amide formation followed by chromatographic separation and removal of chiral aids.
[304] During the synthesis process, it may be necessary and / or desirable to protect selective or reactive groups with respect to the molecules involved. This is described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973 and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999). The protecting group can be removed at an appropriate subsequent step using methods known in the art.
[305] The following example illustrates the preparation of a compound according to the invention.
[306] The compounds according to the invention strongly potentiate the binding of [ ³ H] -flumazenyl to the benzodiazepine binding site of the human GABA _A receptor containing α2 and / or α3 and / or α5 subunits stably expressed in Ltk-cells. Suppress it.
[307] reagent
[308] Phosphate Buffered Saline (PBS)
[309] Assay buffer: 10 mM KH ₂ PO ₄ , 100 mM KCl, pH 7.4, room temperature
[310] [ ³ H] -flumazenyl (18 nM for α1β3γ2 cells, 18 nM for α2β3γ2 cells, 10 nM for α3β3γ2 cells, 10 nM for α5β3γ2 cells), in assay buffer
[311] Flunitrazepam 100 μM in assay buffer
[312] Resuspend cells in assay buffer (10 ml of one tray)
[313] Cell collection
[314] Supernatant is removed from the cells. PBS (about 20 ml) is added. The cells are scraped and placed in 50 ml centrifuge tubes. The method is repeated with 10 ml of PBS to remove most of the cells. Cells are pelleted by winsoming in a benchtop centrifuge at 3000 rpm for 20 minutes and optionally frozen. The pellet is resuspended with 10 ml of buffer per tray of cells (25 cm × 25 cm).
[315] analysis
[316] It can be performed in deep 96-well plates or tubes. Each tube contains 300 μl of assay buffer, 50 μl of [ ³ H] -flumazenyl (final concentration: 1.8 nM for α1β3γ2, α2β3γ2: 1.8 nM, α3β3γ2: 1.0 nM, α5β3γ2: 1.0 nM), compound 10% DMSO When dissolved in (whole), contain 50 μl of buffer or solvent carrier (eg 10% DMSO), test compound or flunitrazepam (to determine non-specific binding), 10 μM final concentration, 100 μl of cells.
[317] The analytes are incubated at 40 ° C. for 1 hour, filtered on a GF / B filter using a Tomtec or Brandel cell harvester and washed 3 × 3 ml with ice cold assay buffer. The filter is dried and counted by liquid scintillation counting. Expected values for total binding are 3000-4000dpm for full count when using liquid scintillation counting and less than 200dpm for non-particularly binding or 1500-2000dpm for full count when counting with Meltirex solid scintillation system. And less than 200 dpm for non-particularly binding. Binding parameters are determined by nonlinear least squares regression analysis, in which the inhibition constant K _i can be calculated for each test compound.
[318] The compounds of this example were tested in this assay, and all were found to have K _i values of less than 100 nM for the replacement of [ ³ H] -flumazenyl from the α2 and / or α3 and / or α5 subunits of the human GABA _A receptor. .
[319] Example 1
[320] 2'-fluoro-5 '-(imidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile
[321] 2-bromo-1-fluoro-4-nitrobenzene in 1,4-dioxane (900 ml, containing 18 ml dimethylsulfoxide) [Org. Proc. Res. Dev., 2000, 4 (1) (66 g, 300 mmol), potassium acetate (58.9 g, 600 mmol), bis (pinacolato) diboron (83.8 g, 330 mmol) and dichloro [1,1'-bis ( A mixture of diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (7.35 g, 9 mmol) is degassed with nitrogen for 1 hour and heated at 90 ° C. for 14 hours. The reaction is cooled to ambient temperature and concentrated in vacuo. The residue is stirred with 2N sodium hydroxide (1 L) for 10 minutes and filtered. The filtrate is extracted with diethyl ether (2x750 ml) and the organics are discarded. The aqueous component is cooled to 0 ° C. and treated dropwise with 36% hydrochloric acid (about 175 ml) over 15 minutes to pH 5. The resulting precipitate is left at 0 ° C. for 2 hours, filtered and washed with ice cold water. The sandy solid was dried with phosphorus pentoxide under vacuum (300 mmHg) to give 2- (2-fluoro-5-nitrophenyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane ( 76.1 g, 95%).
[322] δ _H (400 MHz, CDCl ₃ ) 1.38 (12H, s), 7.17 (1H, dd, J 9 and 9), 8.32 (1H, ddd, J 9, 5 and 3), 8.64 (1H, dd, J 5 and 3).
[323] 2-bromobenzonitrile (34.6 g, 190 mmol), 2- (2-fluoro-5-nitrophenyl) -4,4,5,5-tetramethyl- [1,3, in tetrahydrofuran (600 ml) 2] A mixture of dioxaborolane (76.1 g, 285 mmol) and potassium fluoride (36.4 g, 627 mmol) was degassed with nitrogen for 30 minutes and tris (dibenzylideneacetone) dipalladium (O) (1.74 g, 1.9 mmol) ), Followed by tri-tert-butylphosphine (38 ml of 0.1 M solution in 1,4-dioxane, 3.8 mmol), and the reaction was stirred at ambient temperature for 30 minutes and 50 ° C. for 1 hour. Heat the coupling to complete the coupling. The slurry type reaction mixture is diluted with water (3 L) and stirred at ambient temperature for 90 minutes. The resulting solids were collected by filtration, washed with water, then with isohexane and dried under vacuum with final phosphorus pentoxide to give 2'-fluoro-5'-nitrobiphenyl-2-carbonitrile as a beige solid (46 g). , 100%).
[324] δ _H (360 MHz, CDCl ₃ ) 7.37-7.42 (1H, m), 7.53 (1H, d, J 8), 7.59 (1H, td, J 8 and 1), 7.75 (1H, td, J 8 and 1) , 7.83 (1H, doublet of doublets, J 8 and 1), 8.35-8.39 (2H, m).
[325] A cooled (0 ° C.) suspension of 2'-fluoro-5'-nitrobiphenyl-2-carbonitrile (24.2 g, 100 mmol) in ethanol (150 ml) and tetrahydrofuran (150 ml) was diluted with tin (II) dihydrate. (67.7 g, 300 mmol) and the mixture is stirred at ambient temperature over 12 hours. The solvent is removed in vacuo and the residue is treated with ice cold 2N sodium hydroxide (750 ml). The resulting slurry is stirred for 60 minutes and extracted with dichloromethane (2x400 ml). The organics are combined, washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated to yield a red solid. Crystallization from toluene yields 5'-amino-2'-fluorobiphenyl-2-carbonitrile as a cream solid (16 g, 75%).
[326] δ _H (400 MHz, CDCl ₃ ) 3.65 (2H, br), 6.67-6.73 (2H, m), 7.00 (1H, t, J 9), 7.44-7.49 (2H, m), 7.64 (1H, td, J 9 and 2), 7.7 (1H, doublet of doublets, J 8 and 2).
[327] m / z (ES ⁺ ) 213 (M ⁺ + H).
[328] A solution of 5'-amino-2'-fluorobiphenyl-2-carbonitrile (7.85 g, 37 mmol) in 1,4-dioxane (25 ml) was treated with 48% hydrobromic acid (125 ml) and the resulting suspension was Stir and cool to 3 ° C. (internal temperature). A solution of sodium nitrite (5 ml) in water is added dropwise over 20 minutes while maintaining the internal temperature below 5 ° C. Stirring is continued for 2 hours below 5 ° C. and the reaction is poured into a fresh (5 ° C.) solution of freshly purified copper bromide (I) (6.37 g, 44 mmol) in 48% hydrobromic acid (50 ml). The resulting purple reaction mixture is stirred at 5 ° C. for 10 minutes and warmed to 50 ° C. for 20 minutes. The reaction is diluted with ice cold water (500 ml) and extracted with ethyl acetate (2x250 ml). The organics are combined, washed with 5% aqueous sodium sulfite, saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered and then pre-adsorbed onto silica. Purification by chromatography on silica eluting with isohexane (containing 1% methanol) to a gradient of ethyl acetate (2 to 10%) yielded a colorless oil which was crystallized on standing to crystallize 5'-bromo-2'-fluorine. Roviphenyl-2-carbonitrile is obtained as a white solid (6.5 g, 64%).
[329] δ _H (400 MHz, CDCl ₃ ) 7.09-7.14 (1H, m), 7.45-7.57 (4H, m), 7.66 (1H, td, J 8 and 2), 7.77 (1H, dd, J 8 and 2).
[330] A mixture of 5'-bromo-2'-fluorobiphenyl-2-carbonitrile (1.1 g, 4 mmol), potassium acetate (1.18 g, 12 mmol) and bis (pinacolato) diboron (1.17 g, 4.6 mmol) Is dissolved in 1,4-dioxane (15 ml) containing 1% v / v dimethylsulfoxide and the solution is degassed with nitrogen for 5 minutes. Dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (98 mg, 0.12 mmol) is added and the mixture is heated at 90 ° C. for 16 h. After cooling to ambient temperature, the reaction is partitioned between ethyl acetate and water. The organic phase is washed with brine, dried over anhydrous magnesium sulfate, filtered and presorbed on silica. Purification by chromatography on silica eluting with isohexane against a gradient of ethyl acetate (2 to 10%) gave a colorless oil, which was crystallized on standing to give 2'-fluoro-5 '-(4,4,5). , 5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) biphenyl-2-carbonitrile is obtained as a white solid (1.3 g, 100%).
[331] δ _H (400 MHz, CDCl ₃ ) 1.34 (12H, s), 7.21 (1H, dd, J 10 and 8), 7.45-7.52 (2H, m), 7.65 (1H, td, J 8 and 2), 7.74- 7.78 (1H, m), 7.83 (1H, doublet of doublets, J 8 and 2), 7.88 (1H, ddd, J 8, 5, and 2).
[332] A solution of 2-aminopyrimidine (0.5 g, 5.26 mmol), bromoacetaldehyde diethyl acetal (2.07 g, 10.5 mmol) and 48% aqueous hydrobromic acid (0.5 ml) in ethanol (5 ml) was refluxed for 18 hours. Heat. The reaction is cooled and presorbed directly on silica gel. Purification by flash chromatography eluting with dichloromethane (containing 1% concentrated ammonia) to a gradient of methanol (1-3%) yielded a solid, which was triturated with 5% diethyl ether in isohexane and imidazo [1 , 2-α] pyrimidine is obtained as a tan solid (0.51 g, 82%).
[333] δ _H (400 MHz, CDCl ₃ ) 6.92 (1H, dd, J 7 and 4), 7.59 (1H, d, J 1), 7.84 (1H, d, J 1), 8.49 (1H, dd, J 7 and 2 ), 8.58 (1H, doublet of doublets, J 7 and 2).
[334] Imidazo [1,2-α] pyrimidine (0.20 g, 1.68 mmol) and sodium acetate (207 mg, 2.52 mmol) are dissolved in methanol (2 ml) saturated with potassium bromide, and the mixture is cooled to -10 ° C. Bromine (269 mg, 1.68 mmol) is added dropwise over 5 minutes. After complete addition, the mixture was quenched by addition of 1 M sodium sulfite solution (2 ml) and the solvent was removed in vacuo. The residue is treated with water (15 ml) and saturated sodium bicarbonate solution (15 ml) and extracted with ethyl acetate (2x50 ml). The organics are combined, washed with brine (40 ml) and then dried over anhydrous sodium sulfate to evaporate to yield an off white solid. The solid was purified by silica gel chromatography, eluting with dichloromethane and 1% concentrated ammonia with a gradient of methanol (1-2%) to give 3-bromoimidazo [1,2-α] pyrimidine as a white solid ( 0.29 g, 87%).
[335] δ _H (400 MHz, CDCl ₃ ) 7.02 (1H, dd, J 7 and 4), 7.83 (1H, s), 8.43 (1H, dd, J 7 and 2), 8.59 (1H, dd, J 7 and 2) .
[336] 3-bromoimidazo [1,2-α] pyrimidine (198 mg, 1.00 mmol), potassium phosphate (425 mg, 2.00 mmol) and 3 ′-(4,4, in N, N-dimethylacetamide (3 ml) 5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) biphenyl-2-carbonitrile (581 mg, 1.80 mmol) is degassed with nitrogen for 15 minutes. Tetrakis (triphenylphosphine) palladium (O) (58 mg, 0.05 mmol) is added and the mixture is heated at 80 ° C. for 18 h. The mixture is cooled to ambient temperature, diluted with water (50 ml) and saturated sodium bicarbonate solution (20 ml) and extracted with ethyl acetate (2x75 ml). The combined organic fractions are washed with brine (40 ml), dried over anhydrous sodium sulfate and then evaporated to afford a black oil. The oil is purified by silica gel chromatography, eluting with dichloromethane (containing 1% concentrated ammonia) against a gradient of methanol (1-3%). The solid obtained is triturated with diethyl ether to give 2'-fluoro-5 '-(imidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile as off-white solid.
[337] δ _H (360 MHz, CDCl ₃ ) 6.96 (1H, dd, J 7 and 4), 7.41 (1H, t, J 9), 7.55 (1H, td, J 8 and 1), 7.59-7.65 (3H, m) , 7.71 (1H, td, J 8 and 1), 7.84 (1H, dd, J 8 and 1), 7.92 (1H, s). 8.61 (1 H, dd, J 7 and 2), 8.66 (1 H, d, J 7 and 2).
[338] m / z (ES ⁺ ) 315 (M ⁺ + H).
[339] Preparation Example A
[340] 7-methylimidazo [1,2-α] pyrimidine and 5-methylimidazo [1,2-α] pyrimidine
[341] Sodium methoxide (1.62 g, 30 mmol) is added to a stirred solution of 2-aminoimidazole hemisulfate (2.64 g, 20 mmol) and 1,1-dimethoxy-3-butanone (2 ml) in ethanol (25 ml). The mixture is heated under reflux for 8 hours, cooled to room temperature and then directly adsorbed on silica. Purified by silica gel chromatography, eluting with dichloromethane and 1% concentrated ammonia for a gradient of methanol (1-4%) to 7-methylimidazo [1,2-α] pyrimidine and 5-methylimida 95: 5 mixture of crude [1,2-α] pyrimidine is obtained as a white crystalline solid (1.68 g, 64%).
[342] δ _H (400 MHz, CDCl ₃ , 7-methyl isomer) 2.64 (3H, s), 6.74 (1H, d, J 7), 7.45 (1H, d, J 1), 7.73 (1H, d, J 1), 8.29 (1 H, d, J 7).
[343] Preparation Example B
[344] 3-bromo-7- (1,1-dimethoxyethyl) imidazo [1,2-α] pyrimidine
[345] Boron trifluoride etherate (17.03 g, 120.0 mmol) is added dropwise to a chilled (-40 ° C.) solution of triethyl orthoformate (14.82 g, 100.0 mmol) in dichloromethane (50 ml) over 15 minutes. Stirring is continued for 10 minutes, the solution is transferred to an ice-water bath and stirred at 0 ° C. for 20 minutes. The mixture was cooled to -78 ° C, 3,3-dimethoxy-2-butanone (6.61 g, 50.0 mmol) was added and N, N-diisopropylethylamine (19.39 g, 150.0 mmol) was added over 15 minutes. Add it down. Stirring continued for 1 hour and the solution was poured into a vigorously stirred mixture of saturated sodium bicarbonate solution (500 ml) and dichloromethane (200 ml). The organic phase was separated, washed with ice cold 1M sulfuric acid solution (2x500ml) and ice cold water (2x500ml), then dried over anhydrous sodium sulfate solution and evaporated to 1,1-dimethoxy-4,4-dimethoxypentan-3-one Is obtained as an orange oil (11.72 g, 100%).
[346] 1,1-diethoxy-4,4-dimethoxypentan-3-one is condensed with 2-aminoimidazole hemisulfate as described in Example A to give 7- (1,1-dimethoxyethyl) imidazo [1,2-α] pyrimidine is obtained as a white solid (6.61 g, 64%).
[347] δ _H (400 MHz, CDCl ₃ ) 1.70 (3H, s), 3.28 (6H, s), 7.30 (1H, d, J 7), 7.55 (1H, d, J 1), 7.84 (1H, d, J 1 ), 8.43 (1H, d, J 7).
[348] 7- (1,1-dimethoxyethyl) imidazo [1,2-α] pyrimidine (207 mg, 1.00 mmol) was brominated as described in Example 1 to give 3-bromo-7- (1,1 -Dimethoxyethyl) imidazo [1,2-α] pyrimidine is obtained as a white solid (197 mg, 69%).
[349] δ _H (360 MHz, CDCl ₃ ) 1.70 (3H, s), 3.28 (6H, s), 7.43 (1H, d, J 7), 7.82 (1H, s), 8.39 (1H, d, J 7).
[350] Preparation Example C
[351] 2'-cyano-2-fluorobiphenyl-3-boronic acid
[352] A mixture of 2-bromobenzonitrile (5.1 g, 28 mmol), 2-fluorobenzeneboronic acid (4.9 g, 35 mmol) and potassium fluoride (5.37 g, 92 mmol) in tetrahydrofuran (50 ml) was purged with nitrogen for 10 minutes. Degas. The mixture was treated with tris (dibenzylideneacetone) dipalladium (O) (510 mg, 0.56 mmol) and tri-tert-butylphosphine (5.6 ml of 0.2M solution in 1,4-dioxane, 1.12 mmol). After treatment, the reaction is stirred at ambient temperature for 15 minutes. The resulting slurry is heated at 50 ° C. for 30 minutes to consume residual starting material and to cool to ambient temperature. The reaction mixture is filtered and the filter cake is washed with tetrahydrofuran (50 ml). The filtrate is evaporated to dryness and the residue is partitioned between ethyl acetate and water. The organics are washed with brine, dried over anhydrous magnesium sulfate, filtered and presorbed on silica. Purification by chromatography on silica eluting with isohexane against a gradient of ethyl acetate (5 to 10%) affords 2'-Fluorobiphenyl-2-carbonitrile as a pale yellow solid (5.5 g, 100%). .
[353] δ _H (360 MHz, CDCl ₃ ) 7.19-7.29 (2H, m), 7.40-7.52 (4H, m), 7.65 (1H, ddd, J 8, 8 and 1), 7.79 (1H, dd, J 8 and 1 ).
[354] A cooled (-78 ° C) solution of n-butyllithium (11.7 ml of 2.5M solution in hexanes, 29.1 mmol) in tetrahydrofuran (100 ml) to 2,2,6,6-tetramethylpiperidine (5.16 ml) Treat and continue stirring at −78 ° C. for 15 minutes. The reaction is treated dropwise over 10 minutes with a cooled (0 ° C.) solution of 2′-fluorobiphenyl-2-carbonitrile (5.50 g) in tetrahydrofuran (15 ml). The mixture is stirred for 2 h at −78 ° C. and treated dropwise with trimethyl borate (6.30 ml) over 5 minutes. The reaction is stirred at −78 ° C. for 10 minutes and warmed to ambient temperature. 2N hydrochloric acid (5 ml) is added and the mixture is evaporated to dryness. The residue is stirred with 2N hydrochloric acid (95ml) for 30 minutes and extracted with diethyl ether (2x100ml). The organics are combined, extracted with 2N sodium hydroxide (100ml) and the organics are discarded. The aqueous is cooled to 0 ° C. and made acidic (pH 6) with 36% hydrochloric acid. After stirring for 1 hour at 0 ° C., the resulting solid is collected by filtration and dried. Crystallization from diethyl ether / isohexane gives 2'-cyano-2-fluorobiphenyl-3-boronic acid as a yellow solid (4.50 g, 67%).
[355] δ _H (360 MHz, CDCl ₃ ) 5.23 (1H, s), 5.25 (1H, s), 7.33 (1H, m), 7.42-7.56 (3H, m), 7.65 (1H, m), 7.77 (1H, m ), 7.93 (1 H, m).
[356] Preparation Example D
[357] 3-bromo-7- (1-methyl-1-triethylsilanyloxyethyl) imidazo [1,2-α] pyrimidine
[358] Triethylsilyl trifluoromethanesulfonate (4.85 ml, 21.5 mmol) was added 2- (3-bromoimidazo [1,2-α] pyrimidin-7-yl) in dichloromethane (150 ml) over 15 minutes. To the cooling (-50 ° C.) solution of propan-2-ol (5.0 g, 19.5 mmol) and N, N-diisopropylethylamine (4.76 ml, 27.5 mmol) was added dropwise. The mixture is stirred at −50 ° C. for 20 minutes and warmed to ambient temperature over 10 hours. The reaction mixture is diluted with dichloromethane (100 ml), washed with 1N hydrochloric acid (100 ml) and water (100 ml), then dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting red oil is purified by anhydrous flash column chromatography on silica, eluting with dichloromethane against a gradient of methanol (0-3%) to 3-bromo-7- (1-methyl-1- Triethylsilanyloxyethyl) imidazo [1,2-α] pyrimidine is obtained as a pale yellow solid (6.21 g, 86%).
[359] δ _H (400 MHz, CDCl ₃ ) 0.64 (6H, q, J 8), 0.97 (9H, t, J 8), 7.50 (1H, d, J 7), 7.72 (1H, s), 8.35 (1H, d , J 7), 10.36 (1H, d, J 7).
[360] m / z (ES ⁺ ) 358 (M ⁺ + H).
[361] Example 2
[362] 7- (1,1-difluoroethyl) -3- [4-fluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine
[363] 2-bromo-1-fluoro-4-nitrobenzene was dissolved in tetrahydrofuran (75 ml) and ethanol (75 ml), tin chloride (II) dihydrate was added, and the mixture was stirred at ambient temperature for 4 hours. do. The solvent is evaporated and the residue is treated with ice cold 2N sodium hydroxide solution (200 ml). The resulting slurry is stirred for 30 minutes and extracted with dichloromethane (3x200 ml). The combined organic phases were washed with water (200 ml) and brine (200 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to afford 3-bromo-4-fluorophenylamine as a yellow oil (7.92 g, 92%). Obtained as
[364] δ _H (360 MHz, CDCl ₃ ) 3.53 (2H, s), 6.53-6.57 (1H, m), 6.83-6.85 (1H, m), 6.90 (1H, dd, J 9 and 9).
[365] 3-bromo-4-fluorophenylamine (7.92 g, 41.7 mmol) in 1,2-dimethoxyethane (30 ml) and water (15 ml), diethyl (3-pyridyl) borane (6.74 g, 45.9 mmol ), A mixture of tetrakis (triphenylphosphine) palladium (O) (0.96 g, 0.83 mmol) and potassium carbonate (17.26 g, 125 mmol) is heated at 80 ° C. for 20 hours. After cooling to ambient temperature, the reaction is partitioned between ethyl acetate (500 ml) and water (500 ml). The organics are washed with brine (400 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane against a gradient of ethyl acetate (0-20%) to afford 4-fluoro-3- (pyridin-3-yl) phenylamine as a colorless oil (3.64). g, 46%) and solidify on standing to give a white solid.
[366] δ _H (360 MHz, CDCl ₃ ) 3.65 (2H, s), 6.65-6.72 (2H, m), 6.99 (1H, dd, J 9 and 9), 7.33-7.37 (1H, m), 7.84-7.86 (1H m), 8.58 (1 H, d, J 4), 8.76 (1 H, m).
[367] A warm solution of 4-fluoro-3- (pyridin-3-yl) phenylamine (3.64 g, 19.3 mmol) in 1,4-dioxane (10 ml) is treated with a solution of 48% aqueous hydrobromic acid (100 ml). . The resulting suspension is cooled to 0 ° C. and treated dropwise with a solution of sodium nitrite (1.53 g, 22.2 mmol) in water (4 ml) over 20 minutes. After stirring at 0 ° C. for 2 hours, a cooled (0 ° C.) solution of copper bromide (I) (8.31 g, 57.9 mmol) in 48% aqueous hydrobromic acid (30 ml) was added to the reaction and stirred at 0 ° C. for 10 minutes. And heat at 50 ° C. for 20 minutes. The reaction is cooled to ambient temperature, poured into ice-cold concentrated ammonia (500 ml) and the product is extracted with ethyl acetate (500 ml). The organics are washed with water (300 ml) and brine (300 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a dark oil. Purification by anhydrous flash column chromatography on silica eluting with isohexane against a gradient of ethyl acetate (10-30%) yielded 3- (5-bromo-2-fluorophenyl) pyridine as a white solid (3.1 g, 64%).
[368] δ _H (360 MHz, CDCl ₃ ) 7.09 (1H, dd, J 9 and 1), 7.37-7.40 (1H, m), 7.46-7.51 (1H, m), 7.56-7.59 (1H, m), 7.83-7.86 (1H, m), 8.63-8.65 (1H, m), 8.77-8.79 (1H, m).
[369] 3- (5-bromo-2-fluorophenyl) pyridine (3.1 g, 12.3 mmol), potassium acetate (3.62 g, 36.9 mmol) and bis (pinacolato) diboron (3.75 g, 14.8 mmol) Is dissolved in, 4-dioxane (40 ml) and dimethylsulfoxide (0.8 ml) and the mixture is degassed with N ₂ for 15 minutes. Dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (300 mg, 0.37 mmol) is added and the mixture is heated at 90 ° C. for 18 hours. The mixture is cooled to ambient temperature and partitioned between diethyl ether (200 ml) and 2N hydrochloric acid (50 ml). The organics are discarded and the aqueous phase is adjusted to pH 8 by addition of 4N sodium hydroxide solution and extracted with diethyl ether (2x500 ml). The organic layer is washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and presorbed on silica. 3- [2-fluoro-5- (4,4,5,5-tetramethyl- [1,3] which is crystallized upon standing by purification by flash column chromatography on silica, eluting with 25% ethyl acetate in isohexane. , 2] dioxaborolan-2-yl) phenyl] pyridine is obtained as a yellow oil (2.64 g, 72%).
[370] δ _H (360 MHz, CDCl ₃ ) 1.35 (12H, s), 7.20 (1H, dd, J 10 and 8), 7.35-7.39 (1H, m), 7.81-7.91 (3H, m), 8.61 (1H, dd , J 5 and 2), 8.82 (1 H, s).
[371] Oxalyl chloride (2.79, 22.0) in a cooled (0 ° C.) solution of 2,2-difluoropropionic acid (prepared according to the method described in US Pat. No. 5,859,051) (2.20 g, 20.0 mmol) in dichloromethane (15 ml). mmol) is added dropwise over 10 minutes. The mixture is stirred for 10 minutes at 0 ° C. and warmed to ambient temperature overnight. The mixture is cooled to −10 ° C. and added via cannula to a cooled (-10 ° C.) solution of ethyl vinyl ether (1.59 g, 22.0 mmol) and pyridine (1.74 g, 22.0 mmol) in dichloromethane (50 ml). The mixture is stirred at −10 ° C. for 10 minutes and at ambient temperature for 5 hours. The brown solution is diluted with dichloromethane (30 ml), washed with ice cold 1M sulfuric acid (2x50 ml) and ice cold water (2x50 ml), dried over anhydrous sodium sulfate and evaporated to give crude 1-ethoxy-4,4-difluoropent-. 1-en-3-one is obtained as an orange oil (3.28 g, 100%).
[372] δ _H (400 MHz, CDCl ₃ ) 1.38 (3H, t, J 7), 1.71 (3H, t, J 19), 4.05 (2H, q, J 7), 5.94 (1H, dt, J 12 and 1), 7.81 (1 H, d, J 12).
[373] 1-Ethoxy-4,4-difluoropent-1-en-3-one (3.28 g, 20.0 mmol) in ethanol (10 ml) was 2-aminoimidazole hemisulfate in ethanol (40 ml) over 10 minutes. (3.96 g, 30.0 mmol) and sodium methoxide (2.16 g, 40.0 mmol) are added dropwise to a warmed (60 ° C.) suspension. The mixture is heated at reflux for 18 hours, cooled to ambient temperature and presorbed directly onto silica. Purification by chromatography on silica gel, eluting with dichloromethane (containing 1% concentrated ammonia) to a gradient of methanol (1-3%), yielded 7- (1,1-difluoroethyl) imidazo [1,2 -α] pyrimidine is obtained as off-white solid (1.80 g, 49%).
[374] δ _H (400 MHz, CDCl ₃ ) 2.14 (3H, t, J 19), 7.26 (1H, d, J 7), 7.64 (1H, d, J 1), 7.92 (1H, d, J 1), 8.56 ( 1H, d, J 7).
[375] 7- (1,1-difluoroethyl) imidazo [1,2-α] pyrimidine (0.30 g, 1.64 mmol) was brominated as described in Example 1 to give 3-bromo-7- (1 , 1-difluoroethyl) imidazo [1,2-α] pyrimidine is obtained as a white solid (0.25 g, 59%).
[376] δ _H (400 MHz, CDCl ₃ ) 2.14 (3H, t, J 19), 7.39 (1H, d, J 7), 7.90 (1H, s), 8.53 (1H, d, J 7).
[377] 3-bromo-7- (1,1-difluoroethyl) imidazo [1,2-α] pyrimidine (113 mg, 0.43 mmol) was prepared as described in Example 1 with 3- [2-fluoro. -5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] pyridine, coupled with 7- (1,1-difluoroethyl) 3- [4-Fluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine is obtained as a white solid.
[378] δ _H (360 MHz, DMSO) 2.11 (3H, t, J 7), 7.36 (1H, d, J 7), 7.55-7.64 (2H, m), 7.83-7.87 (1H, m), 7 / 99-8.01 (1H, m), 8.11-8.13 (1H, m), 8.21 (1H, s), 8.66 (1H, dd, J 5 and 1), 8.91 (1H, s), 9.27 (1H, d, J 7) .
[379] Example 3
[380] 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol
[381] A solution of 3-hydroxy-3-methyl-2-butanone (10.75 ml, 100 mmol) and triethylamine (21 ml, 150 mmol) in dichloromethane (125 ml) was treated with acetic anhydride (11.8 ml, 125 mmol), 4 Treat with dimethylaminopyridine (610 mg, 5 mmol) and stir the reaction at ambient temperature for 14 hours. Methanol (10 ml) is added and stirring is continued for 30 minutes and the reaction is concentrated in vacuo. The residue was dissolved in ether (300 ml), washed with 0.5N hydrochloric acid (2x300 ml), water, saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to 1,1-dimethyl-2-oxo. Propyl ester is obtained as a yellow liquid (13.5 g, 94%).
[382] δ _H (400 MHz, CDCl ₃ ) 1.46 (6H, s), 2.09 (3H, s), 2.12 (3H, s).
[383] Acetic acid 1,1-dimethyl-2-oxopropyl ester was converted to acetic acid 4,4-diethoxy-1,1-dimethyl-2-oxobutyl ester as described in Example B, as in Example A Condensation with 2-aminoimidazole hemisulfate yields 2- (imidazo [1,2-α] pyrimidin-7-yl) propan-2-ol as an orange solid.
[384] δ _H (400 MHz, CDCl ₃ ) 1.60 (6H, s), 5.31 (1H, s), 7.10 (1H, d, J 7), 7.54 (1H, d, J 1), 7.72 (1H, d, J 1 ), 8.49 (1 H, d, J 7).
[385] 2- (imidazo [1,2-α] pyrimidin-7-yl) propan-2-ol was brominated as described in Example 1 to give 2- (3-bromoimidazo [1,2-α ] Pyrimidin-7-yl) propan-2-ol is obtained as off-white solid.
[386] δ _H (400 MHz, CDCl ₃ ) 1.62 (6H, s), 4.20 (1H, s), 7.17 (1H, d, J 7), 7.76 (1H, s), 8.40 (1H, d, J 7).
[387] 2- (3-bromoimidazo [1,2-α] pyrimidin-7-yl) propan-2-ol was prepared as described in Example 1 with 3- [2-fluoro-5- (4, Coupling with 4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] pyridine to yield 2- [3- (4-fluoro-3- (pyridine-3- I) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol as a white solid. Bis-hydrochloride salt (from ethyl acetate / ethanol).
[388] δ _H (400 MHz, DMSO) 1.56 (6H, s), 7.73 (1H, dd, J 11 and 9), 7.81-7.90 (3H, m), 8.09 (1H, dd, J 7 and 2), 8.42 (1H , dd, J 7 and 1), 8.55 (1H, s), 8.81 (1H, dd, J 5 and 1), 9.06 (1H, s), 9.39 (1H, d, J 7).
[389] Example 4
[390] 3- [4-fluoro-3- (pyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine
[391] 2-amino-4- (trifluoromethyl) pyrimidine in ethanol (10 ml) {produced according to Zanatta et al., J. Heterocyclic Chem., 1997, 34 (2), 509-513] (500 mg, 3.1 mmol) and a mixture of bromoacetaldehyde diethyl acetal (1.38 ml, 9.2 mmol) are treated with hydrobromic acid (0.5 ml of 48% aqueous solution) and heated at 70 ° C. for 12 hours. The reaction is cooled to ambient temperature and presorbed onto silica. Purification by chromatography on silica eluting with dichloromethane (containing 1% concentrated ammonia) to a gradient of methanol (1-5%) yielded 7-trifluoromethylimidazo [1,2-α] pyrimidine. Obtained as a cream solid (500 mg, 87%).
[392] δ _H (400 MHz, CDCl ₃ ) 7.22 (1H, d, J 7), 7.74 (1H, d, J 1), 8.03 (1H, d, J 1), 8.67 (1H, d, J 7).
[393] 7-trifluoromethylimidazo [1,2-α] pyrimidine (0.20 g, 1.07 mmol) was brominated as described in Example 1 to give 3-bromo-7-trifluoromethylimidazo [1,2-α] pyrimidine is obtained as a white solid (0.28 g, 98%).
[394] δ _H (400 MHz, CDCl ₃ ) 7.35 (1H, d, J 7), 8.02 (1H, s), 8.62 (1H, d, J 7).
[395] Isopropylmagnesium chloride in a cooled (-78 ° C) solution of 3-bromo-7-trifluoromethylimidazo [1,2-α] pyrimidine (1.0 g, 3.78 mmol) in tetrahydrofuran (20 ml) (2.08 ml 2M solution in tetrahydrofuran, 4.16 mmol) is added. After stirring for 5 minutes, tributyltin chloride (1.2 ml, 4.42 mmol) was added and the reaction stirred at −78 ° C. for 10 minutes and warmed to ambient temperature to 3-tri in tetrahydrofuran (about 0.15 M) A solution of butylstannyl-7-trifluoromethylimidazo [1,2-α] pyrimidine is obtained.
[396] m / z (ES ⁺ ) 474, 476, 478 (M ⁺ + H).
[397] 5-bromo-2-fluoronitrobenzene in 3-tributylstannyl-7-trifluoromethylimidazo [1,2-α] pyrimidine (73 ml of 0.13M solution in tetrahydrofuran, 9.44 mmol) (4.20 g, 19 mmol) is added followed by tetrakis (triphenylphosphine) palladium (O) (0.62 g). The resulting mixture is heated at reflux for 4 hours. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel eluting with 30% ethyl acetate in dichloromethane to give 3- (4-fluoro-3-nitrophenyl) -7-trifluoromethylimidazo [1 , 2-α] pyrimidine is obtained.
[398] δ _H (400 MHz, DMSO) 7.59 (1H, d, J 7), 7.83 (1H, dd, J 11 and 9), 8.18 (1H, m), 8.36 (1H, s), 8.53 (1H, dd, J 7 and 2), 9.36 (1 H, d, J 7).
[399] m / z (ES ⁺ ) 327 (M ⁺ + H).
[400] Anhydrous tin chloride in a suspension of 3- (4-fluoro-3-nitrophenyl) -7-trifluoromethylimidazo [1,2-α] pyrimidine (0.819 g, 2.51 mmol) in ethanol (10 ml) (II) (2.0 g) is added. After stirring for 2 hours at ambient temperature, the resulting solution is treated with 30% ammonium hydroxide (40 ml). The mixture is stirred for 10 minutes and concentrated under reduced pressure. The residue is treated with ethanol and evaporated to remove residual water. The residue is boiled with 10% methanol in dichloromethane and the insoluble material is filtered off. The filtrate is evaporated in vacuo, the residue is treated with a warm solution of 50% toluene in ethyl acetate and the insoluble material is filtered off. The filtrate is evaporated under reduced pressure and the residue is crystallized from warm toluene to give 2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenylamine .
[401] δ _H (400 MHz, DMSO) 5.42 (2H, br), 6.87 (1H, m), 7.07 (1H, dd, J 9 and 2), 7.20 (1H, dd, J 12 and 8), 7.50 (1H, d , J 7), 8.13 (1H, s), 9.18 (1H, d, J 7).
[402] m / z (ES ⁺ ) 297 (M ⁺ + H).
[403] To a cooled (4 ° C.) mixture of copper (II) bromide (0.285 g) in anhydrous acetonitrile (4 ml) was added tert-butyl nitrite (0.20 ml) and 2-fluoro-5- (in acetonitrile (8 ml) A solution of 7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenylamine (0.297 g, 1 mmol) was added dropwise over 5 minutes. The resulting mixture is stirred at ambient temperature for 16 hours. The reaction mixture was purified by chromatography on silica gel eluting with 10% ethyl acetate in dichloromethane to give 3- (3-bromo-4-fluorophenyl) -7-trifluoromethylimidazo [1,2 -α] pyrimidine is obtained.
[404] m / z (ES ⁺ ) 360, 362 (M ⁺ + H).
[405] 3- (3-bromo-4-fluorophenyl) -7-trifluoromethylimidazo [1,2-α] pyrimidine (0.190 g, 0.528 mmol in N, N-dimethylformamide (5 ml) 2-tri-n-butylstannylpyridine (0.265 g) was added to a solution of, followed by dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (0.187δ). Add. The mixture is heated at 100 ° C. for 9 hours. The solvent is evaporated under reduced pressure and the residue is chromatographed on silica gel, eluting with 4% methanol in dichloromethane. The residue is loaded into a cartridge of strong cation-exchange resin. Elution with methanol yields non-basic impurities. Further elution with 2M ammonia in methanol yields the crude product. Preparative thin layer chromatography on silica gel using 4% methanol in dichloromethane as eluent and the residue further purified by crystallization from toluene / isohexane to give 3- [4-fluoro-3- (pyridin-2-yl) Phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine is obtained as a yellow needle.
[406] δ _H (400 MHz, DMSO) 7.46 (1H, m), 7.53 (1H, d, J 7), 7.61 (1H, dd, J 11 and 9), 7.86-7.91 (2H, m), 7.95-7.99 (1H , m), 8.24 (1H, dd, J 7 and 2), 8.30 (1H, s), 8.74-8.76 (1H, m), 9.27 (1H, d, J 7).
[407] m / z (ES ⁺ ) 359 (M ⁺ + H).
[408] Example 5
[409] 3- [4-fluoro-3- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine
[410] 3- (3-bromo-4-fluorophenyl) -7-trifluoromethylimidazo [1,2-α] pyrimidine was described as 3-tri-n-butylstane as described in Example 4. Coupling with nilpyridine affords 3- [4-fluoro-3- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine.
[411] δ _H (400 MHz, DMSO) 7.51 (1H, d, J 7), 7.53-7.64 (2H, m), 7.85-7.89 (1H, m), 8.03 (1H, dd, J 7 and 2), 8.12 (1H , dd, J 8 and 2), 8.34 (1H, s), 8.66 (1H, dd, J 5 and 2), 8.90 (1H, t, J 2), 9.38 (1H, d, J 7).
[412] m / z (ES ⁺ ) 359 (M ⁺ + H).
[413] Example 6
[414] 3- [4-fluoro-3- (pyridin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine
[415] 3- (3-bromo-4-fluorophenyl) -7-trifluoromethylimidazo [1,2-α] pyrimidine (70 mg, 0.19 mmol) in N, N-dimethylacetamide (3 ml) And a solution of 4- (tri-n-butylstannyl) pyridine (107 mg, 0.29 mmol) is degassed with N ₂ . Tetrakis (triphenylphosphine) palladium (O) (30 mg, 0.026 mmol) and copper iodide (I) (15 mg, 0.079 mmol) are added and the mixture is heated at 80 ° C. for 6 hours. The solvent is evaporated in vacuo, the residue is partitioned between dichloromethane and water, separated and the aqueous phase is reextracted with dichloromethane. The combined organics are washed with brine, dried (MgSO ₄ ) and evaporated. The residue is purified by preparative thin layer chromatography on silica gel using 30% ethyl acetate / dichloromethane as eluent to afford a yellow solid. Further purification using preparative thin layer chromatography on silica gel, eluting with 2% methanol / dichloromethane, yields 3- [4-fluoro-3- (pyridin-4-yl) phenyl] -7-trifluoromethyl. Midazo [1,2-α] pyrimidine is obtained as a cream solid.
[416] δ _H (360 MHz, DMSO) 7.52 (1H, d, J 7), 7.63 (1H, dd, J 10 and 8), 7.71-7.73 (2H, m), 7.90 (1H, ddd, J 9, 5 and 2) ), 8.04 (1H, dd, J 7 and 2), 8.33 (1H, s), 8.72 (2H, m), 9.37 (1H, d, J 7).
[417] m / z (ES ⁺ ) 359 (M ⁺ + H).
[418] other way:
[419] 3-bromo-7-trifluoromethylimidazo [1,2-α] pyrimidine was prepared as described in Example 1, 4- [2-fluoro-5- (4,4,5,5 3- [4-fluoro-3- (pyridin-4-yl) by coupling with tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] pyridine (see Example 9). ) Phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine is obtained as a cream solid.
[420] Example 7
[421] 3- [2,4-difluoro-3- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine
[422] 3-bromo-2,4-difluorophenylamine in tetrahydrofuran (150 ml) and water (50 ml) [repared according to the method described in EP 0184384] (12.5 g, 60 mmol) , A mixture of diethyl (3-pyridyl) borane (10.6 g, 72 mmol) and potassium carbonate (16.6 g, 120 mmol) was degassed with nitrogen for 15 minutes. Tetrakis (triphenylphosphine) palladium (O) (2.1 g, 1.8 mmol) is added to the mixture and the reaction is heated at reflux for 4 days. The mixture is cooled to ambient temperature and most of the tetrahydrofuran is removed in a rotary evaporator. The residue is diluted with water (250 ml), extracted with ethyl acetate (300 ml) and the organics are washed with water, brine, dried over anhydrous magnesium sulfate, filtered and preadsorbed onto silica. Purification by chromatography on silica gel eluting with isohexane (containing 1% triethylamine) against a gradient of ethyl acetate (10-50%) to give 2,4-difluoro-3- (pyridin-3-yl ) Phenylamine is obtained as a cream solid (5.8 g, 47%).
[423] δ _H (400 MHz, CDCl ₃ ) 3.69 (2H, br), 6.72-6.88 (2H, m), 7.39 (1H, dd, J 8 and 5), 7.80 (1H, d, J 8), 8.62 (1H, dd, J 5 and 1), 8.72 (1H, s).
[424] 2,4-difluoro-3- (pyridin-3-yl) phenylamine was subjected to bromo-deaminedation as described in Example 2 to 3- (3-bromo-2,6-difluorophenyl ) Pyridine is obtained as a white solid.
[425] δ _H (400 MHz, CDCl ₃ ) 6.97 (1H, ddd, J 9, 9 and 2), 7.40-7.44 (1H, m), 7.55-7.60 (1H, m), 7.77-7.81 (1H, m), 8.66 (1H, doublet of doublets, J 5 and 2), 8.71 (1H, s).
[426] 3- (3-bromo-2,6-difluorophenyl) pyridine (2.97g, 11mmol), potassium acetate (2.16g, 22mmol) and bis (neopentylglycolto) in 1,4-dioxane (30ml) The mixture of diboron (2.86 g, 12.7 mmol) is heated to 90 ° C. for 16 h. The reaction is cooled and filtered (the filter cake is washed with a small amount of diethyl ether) and the filtrate is concentrated in vacuo. The residue is partitioned between diethyl ether (100 ml) and 1 M sodium hydroxide (100 ml) and the organics are discarded. The aqueous is washed with additional diethyl ether and cooled in an ice water bath. The pH is adjusted to about 6 with 36% hydrochloric acid and left for 1 hour. The resulting solid is collected by filtration and dried under vacuum to give 2,4-difluoro-3- (pyridin-3-yl) benzeneboronic acid as a gray solid (2.2 g, 85%).
[427] m / z (ES ⁺ ) 236 (M ⁺ + H).
[428] 3-bromo-7-trifluoromethylimidazo [1,2-α] pyrimidine was synthesized as described in Example 1, 2,4-difluoro-3- (pyridin-3-yl) benzene Coupling with boronic acid to form 3- [2,4-difluoro-3- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine as off-white solid To obtain. Bis-hydrochloride salt (from ethyl acetate / ethanol).
[429] δ _H (400 MHz, DMSO) 7.60-7.65 (2H, m), 7.90-7.96 (2H, m), 8.34 (1H, s), 8.47 (1H, d, J 8), 8.87 (1H, dd, J 5 And 1), 9.08 (1H, s), 9.32 (1H, dd, J 7 and 3).
[430] Example 8
[431] 3- [2,4-difluoro-3- (pyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine
[432] 3-bromo-2,4-difluorophenylamine (5.2 g, 25 mmol), 2-tri-n-butylstannylpyridine (11.0 g, 30 mmol), lithium chloride (10.6 g) in tetrahydrofuran (100 ml) , 250 mmol) and a mixture of copper iodide (I) (476 mg, 2.5 mmol) were degassed with nitrogen for 20 minutes and tetrakis (triphenylphosphine) palladium (O) was added. The reaction is heated at reflux for 5 days. The mixture is cooled to ambient temperature and partitioned between ethyl acetate and 10% ammonium hydroxide. The organics are washed with water, brine, dried over anhydrous magnesium sulfate, filtered and presorbed on silica. Purification by chromatography on silica eluting with isohexane (containing 0.5% triethylamine) for a gradient of ethyl acetate (20-50%) to give 2,4-difluoro-3- (pyridin-2-yl) Phenylamine is obtained as a brown oil (550 mg, 11%).
[433] δ _H (400 MHz, CDCl ₃ ) 3.65 (2H, br), 6.74-6.84 (2H, m), 7.31 (1H, ddd, J 7, 5 and 1), 7.46-7.51 (1H, m), 7.78 (1H , ddd, J 8, 8 and 2), 8.74-8.77 (1H, m).
[434] m / z (ES ⁺ ) 207 (M ⁺ + H).
[435] 2,4-difluoro-3- (pyridin-2-yl) phenylamine was subjected to bromo-deaminedation as described in Example 2 to 2- (3-bromo-2,6-difluorophenyl A 50:50 mixture of) pyridine and 2- (2,6-difluorophenyl) pyridine is obtained as a colorless oil and used without further purification.
[436] m / z (ES ⁺ ) 269/272 and 192 (M ⁺ + H).
[437] Crude 2- (3-bromo-2,6-difluorophenyl) pyridine (300 mg, 1.1 mmol), potassium acetate (220 mg, 2.2 mmol) and bis (pincolaito) in 1,4-dioxane (3 ml) The mixture of diboron (350 mg, 1.4 mmol) is heated to 90 ° C. for 14 hours. The reaction is cooled and filtered (the filter cake is washed with a small amount of diethyl ether) and the filtrate is concentrated in vacuo. The residue is stirred with 2N sodium hydroxide (20 ml) for 10 minutes and filtered. The filtrate is washed with diethyl ether (2x20ml) and the organics are discarded. The aqueous phase is cooled in an ice water bath, the pH is adjusted to about 8 with 5N hydrochloric acid and extracted with diethyl ether. The organics were dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to afford 2- [2,6-difluoro-3- (4,4,5,5-tetramethyl- [1,3,2] dioxabo Rolan-2-yl) phenyl] pyridine is obtained as a pale yellow solid (170 mg, 48%).
[438] m / z (ES ⁺ ) 318 (M ⁺ + H).
[439] 3-Bromo-7-trifluoromethylimidazo [1,2-α] pyrimidine was prepared as described in Example 1, 2- [2,6-difluoro-3- (4,4, Coupling with 5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] pyridine 3- [2,4-difluoro-3- (pyridin-2-yl) Phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine is obtained as a pale yellow solid. Bis-hydrochloride salt (from ethyl acetate / ethanol).
[440] δ _H (360 MHz, DMSO) 7.55 (1H, dd, J 9 and 9), 7.62-7.68 (2H, m), 7.86-7.96 (2H, m), 8.14 (1H, ddd, J 8, 8 and 2) , 8.38 (1H, s), 8.84 (1H, d, J 5), 9.30 (1H, dd, J 7 and 3).
[441] m / z (ES ⁺ ) 377 (M ⁺ + H).
[442] Example 9
[443] 2- [3- (4-fluoro-3- (pyridin-4-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol
[444] 2-bromo-1-fluoro-4-nitrobenzene (6.44 g, 29.3 mmol), 4-tri-n-butylstannylpyridine (14.0 g, 38.0 mmol) in N, N-dimethylacetamide (40 ml) , Tetrakis (triphenylphosphine) palladium (O) (1.69 g, 1.46 mmol) was added to a degassing solution of lithium chloride (12.4 g, 293 mmol) and copper iodide (I) (0.56 g, 2.93 mmol), and the reaction was carried out. Heat at 80 ° C. for 18 hours. After cooling to ambient temperature, the solvent is evaporated and the residue is diluted with dichloromethane (800 ml) and the mixture is stirred vigorously for 30 minutes and filtered. The organics are washed with water (500 ml) and brine (300 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to afford a black oil. The residue was purified by silica gel chromatography, eluting with isohexane (containing 1% methanol and 1% triethylamine) to a gradient of ethyl acetate (20-50%) to afford 4- (2-fluoro-5-nitro Phenyl) pyridine is obtained as off-white solid (5.60 g, 88%).
[445] δ _H (360 MHz, CDCl ₃ ) 7.38 (1H, t, J 9), 7.50-7.53 (2H, m), 8.30-8.35 (1H, m), 8.41-8.44 (1H, m), 8.76-8.78 (2H , m).
[446] To a solution of 4- (2-fluoro-5-nitrophenyl) pyridine (1.0 g, 5.58 mmol) in ethanol (30 ml) and ethyl acetate (10 ml) was added platinum (IV) oxide (52 mg) and the mixture was hydrogen ( 40 psi) for 35 minutes. The reaction is filtered through glass microfiber filter paper and the filtrate is evaporated to dryness to afford 4-fluoro-3- (pyridin-4-yl) phenylamine as a white solid (862 mg, 100%).
[447] δ _H (360 MHz, CDCl ₃ ) 3.49 (2H, s), 6.66-6.70 (1H, m), 6.71-6.76 (1H, m), 6.99 (1H, t, J 9), 7.44-7.46 (2H, m ), 8.66 (2H, doublet, J 5).
[448] 4-fluoro-3- (pyridin-4-yl) phenylamine (0.58 mg, 3.08 mmol) was subjected to bromo-deaminedation according to the method described in Example 2 to 4- (5-bromo-2-fluoro Rophenyl) pyridine is obtained as a colorless solid (464 mg, 60%).
[449] δ _H (360 MHz, CDCl ₃ ) 7.38 (1H, t, J 9), 7.59-7.62 (2H, m), 7.68-7.73 (1H, m), 7.84 (1H, dd, J 7 and 3), 8.68 ( 2H, d, J 5 and 3).
[450] 4- (5-bromo-2-fluorophenyl) pyridine (3.8g, 15.1mmol), potassium acetate (2.96g, 30.1mmol) in 1,4-dioxane (50ml) and dimethylsulfoxide (1ml) and A mixture of bis (pincollato) diboron (4.21 g, 16.6 mmol) is degassed with nitrogen for 1 hour. Dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (370 mg, 0.5 mmol) is added and the mixture is heated to 90 ° C. for 18 hours. The reaction is cooled to ambient temperature, filtered and the filter cake is washed with diethyl ether. The filtrate is evaporated to dryness and the residue is stirred with ice cold 2N sodium hydroxide (100 ml) for 20 minutes. The aqueous mixture is filtered and the filtrate is washed with diethyl ether (2x75 ml). The organics are discarded, the aqueous phase is cooled to 0 ° C. and 36% hydrochloric acid is added to lower the pH to 8. The resulting solid is collected by filtration and triturated with diethyl ether to give 4-fluoro-3- (pyridin-4-yl) benzeneboronic acid as a tan solid (1.51 g, 46%).
[451] δ _H (360 MHz, DMSO) 7.34 (1H, dd, J 11 and 8), 7.61 (2H, d, J 5), 7.88-7.92 (1H, m), 8.05 (1H, dd, J 8 and 1), 8.26 (2H, s), 8.70 (2H, d, J 5).
[452] m / z (ES ⁺ ) 218 (M ⁺ + H).
[453] The aqueous filtrate is extracted with diethyl ether. The organic phase is washed with water, brine, dried over anhydrous magnesium sulfate, filtered and evaporated to 4- [2-fluoro-5- (4,4,5,5-tetramethyl-) which solidifies upon standing for several days. [1,3,2] dioxaborolan-2-yl) phenyl] pyridine is obtained as dark oil (1.28 g, 29%).
[454] δ _H (360 MHz, CDCl ₃ ) 1.36 (12H, s), 7.19 (1H, dd, J 11 and 8), 7.50-7.53 (2H, m), 7.82-7.87 (1H, m), 7.93 (1H, dd) , J 8 and 1), 8.67 (2H, doublet of doublets, J 4 and 1).
[455] m / z (ES ⁺ ) 300 (M ⁺ + H).
[456] 2- (3-bromoimidazo [1,2-α] pyrimidin-7-yl) propan-2-ol was prepared as described in Example 1, 4-fluoro-3- (pyridin-4-yl 2- [3- (4-fluoro-3- (pyridin-4-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol by coupling with benzeneboronic acid Is obtained as a white solid (240 mg, 58%). Bis-hydrochloride salt (from ethyl acetate / ethanol).
[457] δ _H (360 MHz, DMSO) 1.56 (6H, s), 7.77 (1H, dd, J 11 and 9), 7.85 (1H, d, J 7), 7.94-7.98 (1H, m), 8.12-8.15 (3H m), 8.55 (1H, s), 8.95 (2H, d, J 6), 9.38 (1H, d, J 7).
[458] m / z (ES ⁺ ) 349 (M ⁺ + H).
[459] Example 10
[460] 3- [2-fluoro-3- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine
[461] 3-Bromopyridine and 2-fluorobenzeneboronic acid are coupled using the method described in Example 1 to give 3- (2-fluorophenyl) pyridine, which crystallizes upon standing, as a pale yellow oil.
[462] δ _H (360 MHz, DMSO) 7.33-7.40 (2H, s), 7.46-7.55 (2H, m), 7.61 (1H, ddd, J 8. 8 and 2), 7.96-8.01 (1H, m), 8.61 ( 1 H, dd, J 5 and 2), 8.77 (1 H, s).
[463] 3- (2-fluorophenyl) pyridine was lithiated as described in Example C and reacted with trimethyl borate to give 2-fluoro-3- (pyridin-3-yl) benzeneboronic acid as a white solid do.
[464] m / z (ES ⁺ ) 218 (M ⁺ + H).
[465] 3-bromo-7-trifluoromethylimidazo [1,2-α] pyrimidine is coupled with 2-fluoro-3- (pyridin-3-yl) benzeneboronic acid as described in Example 1 Ringing affords 3- [2-fluoro-3- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine as off-white solid. Bis-hydrochloride salt (from ethyl acetate / ethanol).
[466] δ _H (360 MHz, DMSO) 7.62 (2H, dd, J 7 and 7), 7.85-7.96 (3H, m), 8.36 (1H, s), 8.58 (1H, d, J 8), 8.86 (1H, dd , J 5 and 1), 9.14 (1H, s), 9.33 (1H, dd, J 7 and 3).
[467] m / z (ES ⁺ ) 359 (M ⁺ + H).
[468] Example 11
[469] 2- [3- (2-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol
[470] 2- (3-bromoimidazo [1,2-α] pyrimidin-7-yl) propan-2-ol was prepared as 2-fluoro-3- (pyridin-3-yl as described in Example 1 2- [3- (2-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol by coupling with benzeneboronic acid Is obtained as a white solid. Bis-hydrochloride salt (from ethyl acetate / ethanol).
[471] δ _H (360 MHz, DMSO) 1.56 (6H, s), 7.65 (1H, dd, J 8 and 8), 7.79-7.83 (1H, m), 7.85-7.87 (2H, m), 7.92-7.97 (1H, m), 8.48 (1H, d, J 7), 8.55 (1H, s), 8.83 (1H, dd, J 5 and 1), 9.10 (1H, s), 9.29 (1H, dd, J 7 and 3) .
[472] m / z (ES ⁺ ) 349 (M ⁺ + H).
[473] Example 12
[474] 3- [2-fluoro-3- (pyridin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine
[475] A mixture of 4-bromopyridine hydrochloride (7.5 g, 38.6 mmol) and 2-fluorobenzeneboronic acid (6.75 g, 48 mmol) in tetrahydrofuran (80 ml) and 2M sodium carbonate (58 ml) was degassed with nitrogen for 20 minutes Tetrakis (triphenylphosphine) palladium (O) (1.34 g, 1.2 mmol) is added and the reaction is heated at reflux for 24 h. The mixture is cooled to ambient temperature and partitioned between ethyl acetate and 10% sodium carbonate. The organics are washed with water, saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and preadsorbed onto silica. Purified by chromatography on silica, eluting with isohexane (containing 0.5% triethylamine) to a gradient of ethyl acetate (20 to 40%), yellowed 4- (2-difluorophenyl) pyridine, which crystallized on standing. Obtained as an oil (6.26 g, 94%).
[476] δ _H (400 MHz, CDCl ₃ ) 7.17-7.22 (1H, m), 7.26 (1H, ddd, J 8, 8 and 1), 7.38-7.44 (1H, m), 7.47-7.50 (3H, m), 8.68 (2H, d, J 4).
[477] m / z (ES ⁺ ) 174 (M ⁺ + H).
[478] 4- (2-fluorophenyl) pyridine was lithiated as described in Example C and reacted with trimethyl borate to give 2-fluoro-3- (pyridin-4-yl) benzeneboronic acid as a white solid do.
[479] m / z (ES ⁺ ) 218 (M ⁺ + H).
[480] 3-bromo-7-trifluoromethylimidazo [1,2-α] pyrimidine couples with 2-fluoro-3- (pyridin-4-yl) benzeneboronic acid as described in Example 1 Ringing affords 3- [2-fluoro-3- (pyridin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine as a white solid. Bis-hydrochloride salt (from ethyl acetate / ethanol).
[481] δ _H (400 MHz, DMSO) 7.64-7.70 (2H, m), 7.95-8.01 (2H, m), 8.37 (1H, s), 8.39 (2H, s), 9.05-9.07 (2H, m), 9.40 ( 1H, dd, J 7 and 3).
[482] m / z (ES ⁺ ) 359 (M ⁺ + H).
[483] Example 13
[484] 2- [3- (2-fluoro-3- (pyridin-4-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol
[485] 2- (3-bromoimidazo [1,2-α] pyrimidin-7-yl) propan-2-ol was prepared as described in Example 1 2-fluoro-3- (pyridin-4-yl 2- [3- (2-fluoro-3- (pyridin-4-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol by coupling with benzeneboronic acid Obtained as a white solid. Bis-hydrochloride salt (from ethyl acetate / ethanol).
[486] δ _H (360 MHz, DMSO) 1.56 (6H, s), 7.69 (1H, dd, J 8 and 8), 7.84-7.92 (2H, m), 7.99-8.04 (1H, m), 8.21 (2H, d, J 6), 8.53 (1H, s), 8.98 (2H, d, J 6), 9.30 (1H, dd, J 7 and 3).
[487] m / z (ES ⁺ ) 349 (M ⁺ + H).
[488] Example 14
[489] 3- [2-fluoro-3- (pyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine
[490] 2-Bromopyridine and 2-fluorobenzeneboronic acid are coupled using the method described in Example 12 to give 2- (2-fluorophenyl) pyridine which crystallizes upon standing as a pale yellow oil.
[491] δ _H (400 MHz, CDCl ₃ ) 7.13-7.19 (1H, m), 7.24-7.28 (2H, m), 7.35-7.41 (1H, m), 7.73-7.81 (2H, m), 7.97 (1H, ddd, J 8, 8 and 2), 8.72-8.74 (1H, m).
[492] m / z (ES ⁺ ) 174 (M ⁺ + H).
[493] 2- (2-fluorophenyl) pyridine was lithiated as described in Example C and reacted with trimethyl borate to give 2-fluoro-3- (pyridin-2-yl) benzeneboronic acid as a white solid do.
[494] m / z (ES ⁺ ) 218 (M ⁺ + H).
[495] 3-bromo-7-trifluoromethylimidazo [1,2-α] pyrimidine couples with 2-fluoro-3- (pyridin-2-yl) benzeneboronic acid as described in Example 1 Ringing affords 3- [2-fluoro-3- (pyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine as a white solid. Bis-hydrochloride salt (from ethyl acetate / ethanol).
[496] δ _H (360 MHz, DMSO) 7.61-7.71 (3H, m), 7.87-7.91 (1H, m), 8.07-8.11 (2H, m), 8.20-8.24 (1H, m), 8.42 (1H, s), 8.87 (1H, dd, J 5 and 1), 9.42 (1H, dd, J 7 and 3).
[497] m / z (ES ⁺ ) 359 (M ⁺ + H).
[498] Example 15
[499] 2- [3- (2-fluoro-3- (pyridin-2-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol
[500] 2- (3-bromoimidazo [1,2-α] pyrimidin-7-yl) propan-2-ol was prepared as described in Example 1 2-fluoro-3- (pyridin-2-yl 2- [3- (2-fluoro-3- (pyridin-2-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol by coupling with benzeneboronic acid Obtained as a white solid. Bis-hydrochloride salt (from ethyl acetate / ethanol).
[501] δ _H (360 MHz, DMSO) 1.57 (6H, s), 7.62 (1H, dd, J 7 and 5), 7.64 (1H, s), 7.80-7.85 (1H, m), 7.89 (1H, d, J 7 ), 8.03 (1H, s), 8.10-8.19 (2H, m), 8.62 (1H, s), 8.83 (1H, d, J 5), 9.35 (1H, dd, J 7 and 3).
[502] m / z (ES ⁺ ) 349 (M ⁺ + H).
[503] Example 16
[504] 3- [4-fluoro-3- (pyridin-2-yl) phenyl] imidazo [1,2-α] pyrimidine
[505] To a cooled (-78 ° C) solution of 3-bromoimidazo [1,2-α] pyrimidine (500 mg, 2.5 mmol) in tetrahydrofuran (20 ml) isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran 1.39 ml, 2.78 mmol) is added. After stirring for 5 minutes, tri-n-butyltin chloride (0.8 ml, 2.90 mmol) was added and the reaction stirred at -78 ° C for 10 minutes, warmed to ambient temperature, 3-tributylstane in tetrahydrofuran A solution of nilimidazo [1,2-α] pyrimidine is obtained.
[506] m / z (ES ⁺ ) 407, 409, 411 (M ⁺ + H).
[507] 2- (5-bromo-2-fluorophenyl) pyridine (100 mg, 0.4 mmol) and tetrakis (triphenylphosphine) palladium (O) (150 mg, 0.13 mmol) were added and the mixture was refluxed for 2 hours. Heat. The reaction is cooled to ambient temperature and the solvent is removed. Purification by chromatography on silica gel eluting with dichloromethane containing 4% methanol, crystallized from toluene / diethyl ether, 3- [4-fluoro-3- (pyridin-2-yl) phenyl] imidazo [1,2-α] pyrimidine is obtained as a white solid.
[508] δ _H (400 MHz, CDCl ₃ ) 8.73-8.75 (1H, m), 8.68 (1H, dd, J 7 and 2), 8.60 (1H, dd, J 4 and 2), 8.23 (1H, dd, J 7 and 2), 7.49 (1H, s), 7.87-7.90 (1H, m), 7.79-7.84 (1H, m), 7.53-7.58 (1H, m), 7.30-7.38 (2H, m), 6.94 (1H, dd, J 7 and 4).
[509] m / z (ES ⁺ ) 291 (M ⁺ + H).
[510] Example 17
[511] 3,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile
[512] A mixture of 2,6-difluorobenzonitrile (19.0 g, 137 mmol) and ethanol (200 ml) presaturated with ammonia gas is heated in an autoclave at 140 ° C. for 6 hours (terminal pressure 200 psi). The mixture is cooled to ambient temperature, evaporated to dryness and ground with water (200 ml). The solid is filtered and air dried to afford 2-amino-6-fluorobenzonitrile as off-white solid (18.0 g, 97%).
[513] δ _H (360 MHz, CDCl ₃ ) 4.53 (3H, s), 6.44-6.52 (2H, m), 7.24-7.30 (1H, m).
[514] 2-amino-6-fluorobenzonitrile (18.0 g, 132 mmol) is dissolved in warm 1,4-dioxane (20 ml), 48% hydrobromic acid (200 ml) is added and the mixture is cooled to 0 ° C. and water A solution of sodium nitrite (10.5 g, 152 mmol) in (20 ml) was added dropwise over 1.5 hours. The resulting mixture is stirred at 0 ° C. for 1.5 h and poured into a cold (0 ° C.) solution of copper bromide (56.8 g, 396 mmol) in 48% hydrobromic acid (50 ml). The solution is stirred at 0 ° C. for 15 minutes and heated at 50 ° C. for 20 minutes. The mixture is cooled to ambient temperature, diluted with water (1200 ml) and extracted with ethyl acetate (2x400 ml). The combined organics are washed with 10% aqueous ammonia solution (400 ml), water (400 ml) and brine (500 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to give an orange oil. Purification by chromatography on silica gel eluting with isohexane against a gradient of ethyl acetate (2-4%) yields 2-bromo-6-fluorobenzonitrile as a white solid (18.5 g, 70 A%). .
[515] δ _H (400 MHz, CDCl ₃ ) 7.17-7.23 (1H, ddd, J 8, 8 and 1), 7.44-7.52 (2H, m).
[516] 2-bromo-6-fluorobenzonitrile (2.50 g, 12.5 mmol), potassium fluoride (2.40 g, 41.3 mmol) and 2- (2-fluoro-5-nitrophenyl)-in tetrahydrofuran (50 ml)- A suspension of 4,4,5,5-tetramethyl- [1,3,2] dioxaborolane (4.67 g, 17.5 mmol) is degassed with nitrogen for 30 minutes. Tris (dibenzylideneacetone) dipalladium (O) and tri-tert-butylphosphine (0.2M solution in 1,4-dioxane, 3.7 ml) are added and the mixture is stirred at ambient temperature for 15 minutes, Stir at 50 ° C. for 18 hours. After cooling to ambient temperature, the resulting dark suspension is poured into 0.5 M sodium hydroxide solution (500 ml) and stirred vigorously for 2 hours. The dark solid was collected by filtration, washed with water (100 ml) and isohexane (50 ml) and air dried to afford 3,2'-difluoro-5'-nitrobiphenyl-2-carbonitrile as a brown / black solid (3.25). g, 100%).
[517] δ _H (360 MHz, CDCl ₃ ) 7.32-7.44 (3H, m), 7.71-7.77 (1H, m), 8.35-8.41 (2H, m).
[518] 3,2'-difluoro-5'-nitrobiphenyl-2-carbonitrile (3.25 g, 12.5 mmol) in tetrahydrofuran (20 ml) and ethanol (20 ml) was diluted with tin (II) dihydrate (9.86 g). , 43.8 mmol), and the mixture is stirred at ambient temperature for 18 hours. The solvent is evaporated and the residue is stirred with 2N sodium hydroxide solution (40 ml) for 2 hours. The resulting suspension is diluted with water (100 ml) and extracted with dichloromethane (3 × 200 ml). The combined organics were washed with water (200 ml) and brine (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated to afford 5'-amino-3,2'-difluorobiphenyl-2-carbonitrile as a brown solid (2.87). g, 100%).
[519] δ _H (360 MHz, CDCl ₃ ) 3.74 (2H, s), 6.66-6.75 (2H, m), 7.01 (1H, dd, J 9 and 9), 7.19-7.30 (2H, m), 7.59-7.65 (1H , m).
[520] 5'-amino-3,2'-difluorobiphenyl-2-carbonitrile (2.87 g, 12.5 mmol) is dissolved in warm 1,4-dioxane (4 ml) and 48% aqueous hydrobromic acid (40 ml) The mixture is cooled to 0 ° C. and sodium nitrite (0.86 g, 12.5 mmol) in water (1.5 ml) is added dropwise over 20 minutes. The resulting mixture is stirred for 1.5 h at 0 ° C. and poured into a cooled (0 ° C.) solution of copper (I) bromide (5.38 g, 37.5 mmol) in 48% hydrobromic acid (10 ml). The solution is stirred at 0 ° C. for 15 minutes and heated at 50 ° C. for 20 minutes. The mixture is cooled to ambient temperature, diluted with water (500 ml) and extracted with ethyl acetate (2x300 ml). The combined organics are washed with 10% aqueous ammonia solution (200 ml), water (200 ml) and brine (200 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to afford a dark solid. Purification by chromatography on silica gel, eluting with isohexane (containing 0.5% methanol) to a gradient of ethyl acetate (2-6%), afforded 5'-bromo-3,2'-difluorobiphenyl-2- Carboninitrile is obtained as a white solid (2.48 g, 68 A%).
[521] δ _H (400 MHz, CDCl ₃ ) 7.13 (1H, dd, J 9 and 9), 7.27-7.30 (2H, m), 7.53-7.59 (2H, m), 7.64-7.69 (1H, m).
[522] 5'-bromo-3,2'-difluorobiphenyl-2-carbonitrile (2.48 g, 8.43 mmol), potassium in 1,4-dioxane (40 ml) containing dimethyl sulfoxide (0.8 ml) A mixture of acetate (2.48 g, 25.3 mmol) and bis (neopentylglycolto) diboron (2.48 g, 11.0 mmol) is degassed with nitrogen for 20 minutes. Dichloro [1,1'-bis (diphenylphosphino) Ferrocene] palladium (II) dichloromethane adduct (200 mg, 0.25 mmol) is added and the reaction is heated at 90 ° C. for 24 h. The mixture is cooled to ambient temperature, partitioned between 2N sodium hydroxide (75 ml) and diethyl ether (100 ml) and the organics are discarded. The aqueous extract is acidified with 36% hydrochloric acid (pH 5) and extracted with diethyl ether (2x75ml). The organic extracts were washed with water (50 ml) and brine (75 ml), dried over anhydrous magnesium sulfate and evaporated to 5 '-(5,5-dimethyl- [1,3,2] dioxaborinane that crystallized upon standing. 2-yl) -3,2'-difluorobiphenyl-2-carbonitrile is obtained as a brown oil (2.5 g, 95%).
[523] δ _H (360 MHz, CDCl ₃ ) 1.03 (6H, s), 3.77 (4H, s), 7.17-7.25 (2H, m), 7.30 (1H, d, J 8), 7.59-7.65 (1H, m), 7.81-7.91 (2H, m).
[524] 3-Bromo-7-trifluoromethylimidazo [1,2-α] pyrimidine was reacted with 5 '-(5,5-dimethyl- [1,3,2] di as described in Example 1. Coupling with oxaborinan-2-yl) -3,2'-difluorobiphenyl-2-carbonitrile to give 3,2'-difluoro-5 '-(7-trifluoromethylimidazo [ 1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile is obtained as off-white solid.
[525] δ _H (360 MHz, CDCl ₃ ) 7.31 (2H, dd, J 7 and 3), 7.43-7.49 (2H, m), 7.64-7.75 (3H, m), 8.10 (1H, s), 9.04 (1H, d , J 7).
[526] m / z (ES ⁺ ) 401 (M ⁺ + H).
[527] Example 18
[528] 6,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile
[529] A mixture of 2,3-difluorobenzonitrile (19.0 g, 137 mmol) and ethanol (200 ml) presaturated with ammonia gas is heated in an autoclave for 8 hours (terminal pressure 200 psi) at 140 ° C. The mixture is cooled to ambient temperature and evaporated to dryness. The residue is dissolved in water (400 ml) and extracted with diethyl ether (2x300 ml). The combined organics are washed with water (300 ml) and brine (250 ml), dried over anhydrous magnesium sulfate, filtered and evaporated. Polishing with isohexane (150 ml) yields 2-amino-3-fluorobenzonitrile as off-white solid (9.8 g, 50%).
[530] δ _H (360 MHz, CDCl ₃ ) 4.47 (2H, s), 6.65-6.71 (1H, m), 7.14-7.20 (2H, m).
[531] 2-amino-3-fluorobenzonitrile (9.8 g, 71.9 mmol) was bromo-deamined as described in Example 17 to afford 2-bromo-3-fluorobenzonitrile as a pale brown solid.
[532] δ _H (360 MHz, CDCl ₃ ) 7.62-7.68 (1H, m), 7.74-7.85 (1H, ddd, J 9, 9 and 1), 7.74-7.85 (1H, ddd, J 8, 1 and 1).
[533] 2-Bromo-3-fluorobenzonitrile (2.50 g, 12.5 mmol) was prepared as described in Example 17, 2- (2-fluoro-5-nitrophenyl) -4,4,5,5-tetra Coupling with methyl- [1,3,2] dioxaborolane to afford 6,2'-difluoro-5'-nitrobiphenyl-2-carbonitrile as a black solid.
[534] δ _H (400 MHz, CDCl ₃ ) 7.40-7.44 (1H, m), 7.47-7.52 (1H, m), 7.59-7.67 (2H, m), 8.37-8.44 (2H, m).
[535] 6,2'-Difluoro-5'-nitrobiphenyl-2-carbonitrile (3.25 g, 12.5 mmol) was reduced using the method described in Example 17 to reduce the 5'-amino-6,2'- Difluorobiphenyl-2-carbonitrile is obtained as a brown oil.
[536] δ _H (360 MHz, CDCl ₃ ) 3.74 (2H, s), 6.68 (1H, m), 6.73-6.77 (1H, m), 7.02 (1H, dd, J 9 and 9), 7.37-7.49 (2H, m ), 7.59-7.65 (1 H, m).
[537] 5'-amino-6,2'-difluorobiphenyl-2-carbonitrile was bromo-deamined as described in Example 17 to give 5'-bromo-6,2'-difluorobiphenyl- 2-carbonitrile is obtained as a light brown solid.
[538] δ _H (360 MHz, CDCl ₃ ) 7.13 (1H, dd, J 9 and 9), 7.37-7.49 (2H, ddd, J 9, 9 and 1), 7.57-7.62 (4H, m).
[539] 5'-Bromo-6,2'-difluorobiphenyl-2-carbonitrile was treated with 6,2'-difluoro-5 '-(4,4,5) using the method described in Example 1. , 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) biphenyl-2-carbonitrile. This gives a brown oil which crystallizes upon standing.
[540] δ _H (360 MHz, CDCl ₃ ) 1.34 (12H, s), 7.21 (1H, dd, J 8 and 2), 7.38-7.51 (2H, m), 7.57-7.59 (1H, m), 7.85 (1H, dd , J 8 and 2), 7.90-7.94 (1 H, m).
[541] 3-bromo-7-trifluoromethylimidazo [1,2-α] pyrimidine was prepared as described in Example 1, 6,2'-difluoro-4 '-(4,4,5 6,2'-Difluoro-5 '-(7-trifluoro) by coupling with, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) biphenyl-2-carbonitrile Romethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile is obtained as off-white solid.
[542] δ _H (400 MHz, CDCl ₃ ) 7.29 (1H, d, J 7), 7.44-7.71 (6H, m), 8.11 (1H, s), 9.00 (1H, d, J 7).
[543] m / z (ES ⁺ ) 401 (M ⁺ + H).
[544] Example 19
[545] 5,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile
[546] 2-Bromo-4-fluorobenzonitrile was prepared in 2- (2-fluoro-5-nitrophenyl) -4,4,5,5-tetramethyl- [1,3, as described in Example 17. 2] coupling with dioxaborolane to give 5,2'-difluoro-5'-nitrobiphenyl-2-carbonitrile as a black solid.
[547] δ _H (360 MHz, CDCl ₃ ) 7.25-7.33 (2H, m), 7.40-7.44 (1H, m), 7.86 (1H, dd, J 9 and 6), 8.35-8.42 (2H, m).
[548] 5,2'-difluoro-5'-nitrobiphenyl-2-carbonitrile was reduced using the method described in Example 17 to give 5'-amino-5,2'-difluorobiphenyl-2- Carbonitrile is obtained.
[549] δ _H (360 MHz, CDCl ₃ ) 3.68 (2H, s), 6.67-6.76 (2H, m), 7.02 (1H, dd, J 9 and 9), 7.12-7.27 (2H, m), 7.78 (1H, dd) , J 9 and 6).
[550] 5'-Amino-5,2'-difluorobiphenyl-2-carbonitrile was bromo-deamined as described in Example 17 to give 5'-bromo-5,2'-difluorobiphenyl- 2-carbonitrile is obtained as a light brown solid.
[551] δ _H (400 MHz, CDCl ₃ ) 7.13 (1H, dd, J 9 and 9), 7.19-7.23 (2H, m), 7.52-7.60 (2H, m), 7.81 (1H, dd, J 8 and 5).
[552] 5'-Bromo-5,2'-difluorobiphenyl-2-carbonitrile was reacted with 5 '-(5,5-dimethyl- [1,3,2] dioxabori as described in Example 17. L-2-yl) -5,2'-difluorobiphenyl-2-carbonitrile. This gives a brown oil which crystallizes upon standing.
[553] δ _H (400 MHz, CDCl ₃ ) 1.03 (6H, s), 3.77 (4H, s), 7.15-7.24 (3H, m), 7.77 (1H, dd, J 9 and 6), 7.83 (1H, dd, J 8 and 2), 7.87-7.91 (1 H, m).
[554] 3-Bromo-7-trifluoromethylimidazo [1,2-α] pyrimidine was reacted with 5 '-(5,5-dimethyl- [1,3,2] di as described in Example 1. Coupling with oxaborinan-2-yl) -5,2'-difluorobiphenyl-2-carbonitrile to give 5,2'-difluoro-5 '-(7-trifluoromethylimidazo [ 1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile is obtained as off-white solid.
[555] δ _H (360 MHz, CDCl ₃ ) 7.25-7.31 (2H, m), 7.44-7.50 (1H, m), 7.67 (1H, ddd, J 9, 5 and 2), 7.67 (1H, s), 7.69 (1H , s), 7.88 (1H, dd, J 9 and 6), 8.11 (1H, s), 9.05 (1H, d, J 7).
[556] m / z (ES ⁺ ) 401 (M ⁺ + H).
[557] Example 20
[558] 4,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile
[559] 2-amino-5-fluorobenzonitrile was prepared as described in Example 17. 2- (2-fluoro-5-nitrophenyl) -4,4,5,5-tetramethyl- [1,3,2 ] Coupling with dioxaborolane yields 4,2'-difluoro-5'-nitrobiphenyl-2-carbonitrile as a black solid.
[560] δ _H (360 MHz, CDCl ₃ ) 7.38-7.56 (4H, m), 8.33-8.40 (2H, m).
[561] 4,2'-difluoro-5'-nitrobiphenyl-2-carbonitrile was reduced using the method described in Example 17 to give 5'-amino-4,2'-difluorobiphenyl-2- Carbonitrile is obtained.
[562] δ _H (360 MHz, CDCl ₃ ) 3.66 (2H, s), 6.66-6.70 (1H, m), 6.71-6.74 (1H, m), 7.00 (1H, dd, J 9 and 9), 7.33-7.38 (1H m), 7.44-7.49 (1 H, m).
[563] 5'-Amino-4,2'-difluorobiphenyl-2-carbonitrile was bromo-deamined as described in Example 17 to give 5'-bromo-4,2'-difluorobiphenyl- 2-carbonitrile is obtained as a light brown solid.
[564] δ _H (360 MHz, CDCl ₃ ) 7.11 (1H, dd, J 9 and 9), 7.37-7.58 (5H, m).
[565] 5 '-(5,5-dimethyl- [1,3,2] di was reacted with 5'-bromo-4,2'-difluorobiphenyl-2-carbonitrile using the method described in Example 17. Convert to oxaborinan-2-yl) -4,2'-difluorobiphenyl-2-carbonitrile. This gives a brown oil which crystallizes upon standing.
[566] δ _H (360 MHz, CDCl ₃ ) 1.03 (6H, s), 3.76 (4H, s), 7.20 (1H, dd, J 10 and 8), 7.33-7.38 (1H, m), 7.44-7.50 (2H, m ), 7.81 (1H, doublet of doublets, J 8 and 2), 7.85-7.90 (1H, m).
[567] 3-Bromo-7-trifluoromethylimidazo [1,2-α] pyrimidine was reacted with 5 '-(5,5-dimethyl- [1,3,2] di as described in Example 1. Coupling with oxaborinan-2-yl) -4,2'-difluorobiphenyl-2-carbonitrile to provide 4,2'-difluoro-5 '-(7-trifluoromethylimidazo [ 1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile is obtained as off-white solid.
[568] δ _H (400 MHz, CDCl ₃ ) 7.29 (1H, d, J 7), 7.42-7.48 (2H, m), 7.57 (1H, dd, J 8 and 3), 7.61-7.66 (3H, m), 8.10 ( 1 H, s), 9.02 (1 H, d, J 7).
[569] m / z (ES ⁺ ) 401 (M ⁺ + H).
[570] Example 21
[571] 7- (1,1-difluoroethyl) -3- [4-fluoro-3- (pyridin-4-yl) phenyl] imidazo [1,2-α] pyrimidine
[572] 3-bromo-7- (1,1-difluoroethyl) imidazo [1,2-α] pyrimidine was treated with 7- (1,1-difluoroethyl) according to the method described in Example 4. -3-tributylstannylimidazo [1,2-α] pyrimidine.
[573] m / z (ES ⁺ ) 470, 472, 474 (M ⁺ + H).
[574] 7- (1,1-difluoroethyl) -3-tributylstannylimidazo [1,2-α] pyrimidine was prepared in 4- (5-bromo-2 according to the method described in Example 4. -Fluorophenyl) pyridine to react with 7- (1,1-difluoroethyl) -3- [4-fluoro-3- (pyridin-4-yl) phenyl] imidazo [1,2-α] Pyrimidine is obtained as a white solid.
[575] δ _H (360 MHz, CDCl ₃ ) 2.16 (1H, t, J 19), 7.31 (1H, d, J 7), 7.43 (1H, dd, J 10 and 8), 7.54 (2H, dd, J 6 and 1 ), 7.57-7.66 (2H, m), 8.00 (1H, s), 8.67 (1H, d, J 7), 8.74 (2H, d, J 6).
[576] m / z (ES ⁺ ) 355 (M ⁺ + H).
[577] Example 22
[578] 7- (1,1-difluoroethyl) -3- [2,4-difluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine
[579] 3- (3-Bromo-2) according to the method described in Example 4 to 7- (1,1-difluoroethyl) -3-tributylstannylimidazo [1,2-α] pyrimidine Reacted with 6-difluorophenyl) pyridine to yield 7- (1,1-difluoroethyl) -3- [2,4-difluoro-3- (pyridin-3-yl) phenyl] imidazo [ 1,2-α] pyrimidine is obtained as a white solid.
[580] δ _H (360 MHz, CDCl ₃ ) 2.16 (1H, t, J 19), 7.22-7.78 (1H, m), 7.31 (1H, d, J 7), 7.59 (1H, ddd, J 8, 3, and 1) , 7.52-7.59 (1H, m), 7.85 (1H, dd, J 8 and 1), 8.03 (1H, s), 8.39 (1H, dd, J 7 and 3), 8.69 (1H, d, J 5 and 3), 8.78 (1 H, s).
[581] m / z (ES ⁺ ) 373 (M ⁺ + H).
[582] Example 23
[583] 2- [3- (2,4-difluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol
[584] 2- (3-bromoimidazo [1,2-α] pyrimidin-7-yl) propan-2-ol (256 mg) in tetrahydrofuran (3 ml) and sodium carbonate (1.25 ml 2M solution in water, 1.5 mmol) , 1.0 mmol) and a mixture of 2,4-difluoro-3- (pyridin-3-yl) benzeneboronic acid (352 mg, 1.5 mmol) are degassed with nitrogen for 10 minutes. Tetrakis (triphenylphosphine) palladium (O) (58 mg, 0.05 mmol) is added and the mixture is heated at 65 ° C. for 24 h. The reaction is cooled to ambient temperature and partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The organics are dried over anhydrous magnesium sulfate, filtered and presorbed on silica. 2- [3- (2,4-difluoro- solidified upon purification by chromatography on silica gel, eluting with dichloromethane (containing 1% concentrated ammonia) to a gradient of methanol (1-5%). 3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol is obtained as a pale yellow oil (200 mg, 44%). Bis-hydrochloride salt (from ethyl acetate / ethanol).
[585] δ _H (360 MHz, d ₆ -DMSO) 1.56 (6H, s), 7.62 (1H, t, J 9), 7.79-7.84 (1H, m), 7.86 (1H, s), 7.88 (1H, s), 8.32 (1H, d, J 8), 8.54 (1H, s), 8.80 (1H, d, J 5), 8.98 (1H, s), 9.27 (1H, dd, J 7 and 3).
[586] Example 24
[587] 1- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] ethanone
[588] 3-Bromo-7- (1,1-dimethoxyethyl) imidazo [1,2-α] pyrimidine is 4-fluoro-3- (pyridin-3-yl) as described in Example 23. Coupling with benzeneboronic acid gave 7- (1,1-dimethoxyethyl) -3- [4-fluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine in orange Obtained as a foam. It is dissolved in 2.5N hydrochloric acid and stirred at 50 ° C. for 15 hours. After cooling to ambient temperature, the reaction is neutralized by addition of solid sodium bicarbonate and the resulting solid is collected by filtration. The solid is dissolved in dichloromethane / methanol (1: 1) and presorbed on silica. Flash column chromatography on silica gel eluting with dichloromethane containing 1% ammonia and 5% methanol gave 1- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1, 2-α] pyrimidin-7-yl] ethanone is obtained as a yellow solid.
[589] δ _H (360 MHz, d ₆ -DMSO) 2.71 (3H, s), 7.54-7.63 (3H, m), 7.84-7.88 (1H, m), 8.01 (1H, dd, J 8 and 2), 8.10-8.13 (1H, m), 8.34 (1H, s), 8.66 (1H, dd, J 5 and 2), 8.90 (1H, s), 9.24 (1H, d, J 7).
[590] Example 25
[591] 3 '-[7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] -4,2', 6'-trifluorobiphenyl-2-carbo Nitrile
[592] A mixture of 2,6-difluorobromobenzene (125.5 g, 650 mmol) in 98% sulfuric acid (250 ml) was cooled in an ice water bath and the rate of 98% sulfuric acid and fuming nitric acid at a rate such that the internal temperature did not exceed 35 ° C. Treated dropwise with a 1: 1 mixture (100 ml). After complete addition, the reaction is stirred at ambient temperature for 3 hours and poured onto ice. The mixture was diluted with water (final volume 5 L) and the resulting solid collected by filtration, washed with water and dried under phosphorus pentoxide under vacuum to afford 2-bromo-1,3-difluoro-4-nitrobenzonitrile. Obtained as a cream solid (145 g, 94%).
[593] δ _H (360 MHz, CDCl ₃ ) 7.10-7.15 (1H, m), 8.09-8.16 (1H, m).
[594] A mixture of 2-bromo-1,3-difluoro-4-nitrobenzene (30 g, 130 mmol) and tin (II) chloride dihydrate in 36% hydrochloric acid (150 ml) is heated to 40 ° C. Diethyl ether (20 ml) was added slowly to form a solution. Once in solution, the reaction proceeds rapidly and the ether is boiled. After heating at 60 ° C. for 1 hour, the reaction is cooled and poured into ice water (1.5 L). The solution is made basic (pH 13) with 30% aqueous sodium hydroxide while maintaining the internal temperature below 20 ° C. The resulting gray slurry is disturbed with chloroform (2x500 ml), the organic extracts are combined, washed with water, then dried over anhydrous magnesium sulfate containing 2 g of bleached charcoal, filtered and evaporated to dryness. Polishing with isohexane gives 3-bromo-2,4-difluorophenylamine as a tan solid (23 g, 85%).
[595] δ _H (360 MHz, CDCl ₃ ) 3.51 (2H, br), 6.65-6.70 (1H, m), 6.75-6.80 (1H, m).
[596] 2-Bromo-5-fluorobenzonitrile was reacted with 5-fluoro-2- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane as described in Example 1. Conversion to 2-yl) benzonitrile yields a pale yellow solid.
[597] δ _H (360 MHz, CDCl ₃ ) 1.38 (12H, s), 7.27 (1H, ddd, J 8, 8 and 2), 7.39 (1H, dd, J 9 and 2), 7.90 (1H, dd, J 8 and 6).
[598] 3-bromo-2,4-difluorophenylamine (5.2 g, 25 mmol) and 5-fluoro-2- (4,4,5,5-tetra) in tetrahydrofuran (95 ml) and water (5 ml) A solution of methyl- [1,3,2] dioxaborolan-2-yl) benzonitrile (7.10 g, 28.8 mmol) was treated with potassium fluoride (4.8 g, 82.5 mmol) and the mixture was purged with nitrogen for 10 minutes. Degassing was added tris (dibenzylideneacetone) -dipalladium (O) (460 mg, 0.5 mmol) and tri-tert-butylphosphine (2.5 ml of 0.2 M solution in 1,4-dioxane, 0.5 mmol) do. The reaction is heated at 50 ° C. for 2 hours and cooled to ambient temperature. The mixture is poured into ice cold 0.5N sodium hydroxide (750 ml), stirred for 10 minutes, and the solids are collected by filtration. Polished with water and dried to give 3'-amino-4,2 ', 6'-trifluorobiphenyl-2-carbonitrile as a gray powder (6.6 g). Use without further purification.
[599] δ _H (360 MHz, CDCl ₃ ) 3.74 (2H, br), 6.79-6.89 (2H, m), 7.36-7.42 (1H, m), 7.45-7.51 (2H, m).
[600] 3'-amino-4,2 ', 6'-trifluorobiphenyl-2-carbonitrile was bromo-deamined as described in Example 1 to 3'-bromo-4,2', 6 ' Trifluorobiphenyl-2-carbonitrile is obtained as an orange solid.
[601] δ _H (360 MHz, CDCl ₃ ) 6.97-7.03 (1H, m), 7.39-7.54 (3H, m), 7.62-7.68 (1H, m).
[602] 3'-bromo-4,2 ', 6'-trifluorobiphenyl-2-carbonitrile was reacted with bis (pinacolato) diboron as described in Example 1 to 3'-(4,4 , 5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -4,2 ', 6'-trifluorobiphenyl-2-carbonitrile is obtained as a tan solid.
[603] m / z (ES ⁺ ) 360 (M ⁺ + H).
[604] 2- (3-bromoimidazo [1,2-α] pyrimidin-7-yl) propan-2-ol was prepared as 3 '-(4,4,5,5-tetra as described in Example 23. Coupling with methyl- [1,3,2] dioxaborolan-2-yl) -4,2 ', 6'-trifluorobiphenyl-2-carbonitrile 3'-[7- (1-hydro Roxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] -4,2 ', 6'-trifluorobiphenyl-2-carbonitrile is obtained as off-white solid.
[605] δ _H (400 MHz, d ₆ -DMSO) 1.51 (6H, s), 7.42 (1H, d, J 7), 7.54-7.58 (1H, m), 7.80-7.85 (1H, m), 7.89-7.96 (3H , m), 8.14 (1H, dd, J 9 and 2), 8.78 (1H, dd, J 7 and 3).
[606] Example 26
[607] 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propane-1,2-diol
[608] Inside a cooled (-10 ° C.) solution of methyl isopropenyl ketone (42 g, 500 mmol) in acetone (200 ml) with a solution of hydrogen peroxide (27.5 wt%, 61.9 g, 500 mmol) and aqueous sodium hydroxide (10 ml, 4N) Simultaneously but independently (without premixing) dropwise treatment at a rate such that the temperature does not exceed -5 ° C. After the addition is complete, the reaction is stirred at -10 ° C for 12 h. NMR indicates the reaction is about 50% complete, additional hydrogen peroxide (27.5 wt.%, 61.9 g) and aqueous sodium hydroxide (10 ml, 4N) are added and stirring is continued at -10 ° C. for 16 hours. The reaction is neutralized with 4N sulfuric acid (20 ml) and added dropwise to a flask containing manganese (IV) (10 g) over 15 minutes. The mixture is filtered through glass microfiber filter paper (GF / A) and acetone is distilled off at atmospheric pressure to give crude 1- (2-methyloxyranyl) ethanone as a colorless liquid. Use without further purification.
[609] δ _H (360 MHz, d ₆ -DMSO) 1.36 (3H, s), 1.97 (3H, s), 2.91 (1H, d, J 5), 3.12 (1H, d, J 5).
[610] The crude sample of 1- (2-methyloxyranyl) ethanone prepared above is diluted to 300 ml with water and treated with 70% perchloric acid (10 ml). The mixture is heated at reflux for 6 hours and cooled to ambient temperature. The mixture is filtered to remove the black solid and the filtrate is neutralized with solid sodium hydrogen carbonate. The aqueous filtrate is saturated with solid sodium chloride, filtered (excess removed) and extraction continued with dichloromethane for 3 days. The organic phase is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was purified by anhydrous flash chromatography, eluting with isohexane against a gradient of ether (20-100%) to give 3,4-dihydroxy-3-methylbutan-2-one as pale yellow oil (30 g, 51%). , Over two steps).
[611] δ _H (360 MHz, CDCl ₃ ) 1.29 (3H, s), 2.29 (3H, s), 2.50 (1H, br), 3.64 (1H, d, J 12), 3.85 (1H, d, J 12), 4.15 (1H, br).
[612] A mixture of 3,4-dihydroxy-3-methylbutan-2-one (4.13 g, 35 mmol), acetone (25 ml) and p-toluenesulfonic acid monohydrate (33 mg, 0.18 mmol) in isohexane (75 ml) Is heated in a Dean-Stark instrument for 10 hours. The solvent is distilled off at atmospheric pressure and the residue is purified by chromatography on silica gel. Elution with 50% ether in isohexane gives 1- (2,2,4-trimethyl- [1,3] dioxolan-4-yl) ethanone as a pale yellow liquid (5.1 g, 92%).
[613] δ _H (360 MHz, d ₆ -DMSO) 1.29 (3H, s), 1.34 (3H, s), 1.36 (3H, s), 2.20 (3H, s), 3.69 (1H, d, J 9), 4.18 ( 1H, d, J 9).
[614] 1- (2,2,4-trimethyl- [1,3] dioxolan-4-yl) ethanone was prepared in 3,3-diethoxy-1- (2,2,4- as described in Example B. Conversion to trimethyl- [1,3] dioxolan-4-yl) propan-1-one and condensation with 2-aminoimidazole sulfate as in Example A 1,3] dioxolan-4-yl) imidazo [1,2-α] pyrimidine is obtained as a pale orange solid (7.10 g, 96%).
[615] δ _H (360 MHz, d ₆ -DMSO) 1.31 (3H, s), 1.47 (3H, s), 1.57 (3H, s), 4.05 (1H, d, J 9), 4.49 (1H, d, J 9) , 7.27 (1H, d, J 7), 7.71 (1H, d, J 1), 7.92 (1H, d, J 1), 8.98 (1H, d, J 7).
[616] 7- (2,2,4-trimethyl- [1,3] dioxolan-4-yl) imidazo [1,2-α] pyrimidine was brominated as described in Example 1 to give 3-bromo -7- (2,2,4-trimethyl- [1,3] dioxolan-4-yl) imidazo [1,2-α] pyrimidine is obtained as off-white solid.
[617] δ _H (400 MHz, d ₆ -DMSO) 1.31 (3H, s), 1.47 (3H, s), 1.57 (3H, s), 4.06 (1H, d, J 9), 4.47 (1H, d, J 9) , 7.40 (1H, d, J 7), 7.88 (1H, s), 8.81 (1H, d, J 7).
[618] 3-bromo-7- (2,2,4-trimethyl- [1,3] dioxolan-4-yl) imidazo [1,2-α] pyrimidine was prepared as described in Example 23. 3- [4-fluoro by coupling with [2-fluoro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] pyridine -3- (pyridin-3-yl) phenyl] -7- (2,2,4-trimethyl- [1,3] dioxolan-4-yl) imidazo [1,2-α] pyrimidine orange oil Obtained as
[619] δ _H (400 MHz, d ₆ -DMSO) 1.33 (3H, s), 1.47 (3H, s), 1.59 (3H, s), 4.08 (1H, d, J 9), 4.49 (1H, d, J 9) , 7.31 (1H, d, J 7), 7.54-7.59 (2H, m), 7.77-7.81 (1H, m), 7.94 (1H, dd, J 7 and 2), 8.01 (1H, s), 8.09- 8.12 (1H, m), 8.65 (1H, doublet of doublets, J 5 and 2), 8.89 (1H, s), 9.08 (1H, d, J 7).
[620] 3- [4-fluoro-3- (pyridin-3-yl) phenyl] -7- (2,2,4-trimethyl- [1,3] dioxolan-4-yl) imidazo [1,2- α] pyrimidine (1.00 g, 2.47 mmol) is stirred with 2N hydrochloric acid (20 ml) at 70 ° C. for 10 minutes. The reaction mixture is cooled and loaded into a strong cation exchange cartridge. Non-basic impurities are removed by eluting with methanol. 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] which solidifies on elution with 10% ammonia in methanol Propane-1,2-diol is obtained as an oil (450 mg). Bis-hydrochloride salt (from ethyl acetate / ethanol).
[621] δ _H (360 MHz, d ₆ -DMSO) 1.50 (3H, s), 3.67 (2H, m), 7.74 (1H, dd, J 11 and 8), 7.89 (3H, m), 8.13 (1H, dd, J 7 and 2), 8.51 (1H, d, J 8), 8.58 (1H, s), 8.85 (1H, dd, J 5 and 1), 9.12 (1H, s), 9.40 (1H, d, J 7) .
[622] Example 27
[623] 3- [2,4-fluoro-3- (pyridin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine
[624] A suspension of 4-bromopyridine hydrochloride (6.81 g, 35 mmol) in tetrahydrofuran (100 ml) is treated with sodium hydroxide (8.75 ml 4N solution in water) and the mixture is stirred at ambient temperature for 5 minutes. 2,6-difluorobenzeneboronic acid (6.36 g, 40 mmol) and potassium fluoride (6.71 g, 116 mmol) were added, the mixture was degassed with nitrogen for 10 minutes and tris (dibenzylideneacetone) dipalladium (O) (640 mg, 0.7 mmol) and tri-tert-butylphosphine (7 ml of a 0.2 M solution in 1,4-dioxane, 1.4 mmol) are added. The mixture is stirred at ambient temperature for 15 minutes and heated at 50 ° C. for 30 minutes. The reaction mixture is diluted with dichloromethane and extracted with ice cold 1N sodium hydroxide solution (x2). The organics are dried over anhydrous magnesium sulfate, filtered and presorbed on silica. 4- (2,6-difluorophenyl) pyridine purified by chromatography on silica eluting with isohexane (containing 0.5% methanol and 0.5% triethylamine) for a gradient of ethyl acetate (20-30%). To a white solid (3.2 g, 48%).
[625] δ _H (400 MHz, CDCl ₃ ) 6.99-7.06 (2H, m), 7.32-7.39 (1H, m), 7.40-7.42 (2H, m), 8.71 (2H, d, J 6).
[626] 4- (2,6-difluorophenyl) pyridine is converted to 2,4-difluoro-3- (pyridin-4-yl) benzeneboronic acid using the method described in Example C.
[627] m / z (ES ⁺ ) 235 (M ⁺ + H).
[628] 3-bromo-7-trifluoromethylimidazo [1,2-α] pyrimidine was synthesized in 2,4-difluoro-3- (pyridin-4-yl) benzene as described in Example 23. Coupling with boronic acid to afford 3- [2,4-difluoro-3- (pyridin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine as a white solid To obtain. Bis-hydrochloride (from ethanol / ethyl acetate).
[629] δ _H (400 MHz, DMSO) 7.60-7.65 (2H, m), 7.96-8.01 (1H, m), 8.16 (2H, d, J 6), 8.34 (1H, s), 9.00-9.02 (2H, m) , 9.34 (1H, doublet of doublets, J 7 and 3).
[630] m / z (ES ⁺ ) 377 (M ⁺ + H).
[631] Example 28
[632] 2- [3- (2,4-difluoro-3- (pyridin-4-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol
[633] 2- (3-bromoimidazo [1,2-α] pyrimidin-7-yl) propan-2-ol was prepared as described in Example 23. 2,4-difluoro-3- (pyridine- 4-yl) benzeneboronic acid, coupled with 2- [3- (2,4-difluoro-3- (pyridin-4-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl ] Propan-2-ol is obtained as off-white solid. Bis-hydrochloride (from ethanol / ethyl acetate).
[634] δ _H (360 MHz, DMSO) 1.56 (6H, m), 7.62-7.67 (1H, m), 7.85 (1H, d, J 7), 7.88-7.94 (1H, m), 7.99 (2H, d, J 6 ), 8.50 (1H, s), 8.94 (2H, d, J 6), 9.26 (1H, dd, J 7 and 3).
[635] m / z (ES ⁺ ) 367 (M ⁺ + H).
[636] Example 29
[637] 4,2'-difluoro-5 '-[7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile
[638] 2- (3-bromoimidazo [1,2-α] pyrimidin-7-yl) propan-2-ol was reacted with 5 '-(5,5-dimethyl- [1, 3,2] dioxaborinan-2-yl) -4,2'-difluorobiphenyl-2-carbonitrile, coupled with 4,2'-difluoro-5 '-[7- (1- Hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile is obtained as a white solid.
[639] δ _H (400 MHz, CDCl ₃ ) 1.62 (6H, s), 4.47 (1H, s), 7.08 (1H, d, J 7), 7.39-7.46 (2H, m), 7.55 (1H, dd, J 8 and 3), 7.60-7.64 (3H, m), 7.85 (1H, s), 8.81 (1H, d, J 7).
[640] m / z (ES ⁺ ) 391 (M ⁺ + H).
[641] Example 30
[642] 3- [2,4-difluoro-3- (pyridin-3-yl) phenyl] -7- (1-fluoro-1-methylethyl) imidazo [1,2-α] pyrimidine
[643] 3-fluoro-3-methylbutan-2-one is described as 3-bromo-3-methylbutan-2-one as described in Fry and Migron, Tetrahedron Lett., 1979, 3357-3360. From 94.6 mixtures of the desired fluoro compound and 3-methyl-3-buten-2-one are obtained as colorless oil in 47% yield after distillation using a Vigreux column.
[644] Boiling Point: 74 to 76 ° C
[645] δ _H (360 MHz, CDCl ₃ ) 1.45 (6H, d, J 22), 2.28 (3H, d, J 5).
[646] 3-Fluoro-3-methylbutan-2-one was converted to 1,1-diethoxy-4-fluoro-4-methylpentan-3-one as described in Example B and in Example A Condensation with 2-aminoimidazole hemisulfate to yield 7- (1-fluoro-1-methylethyl) imidazo [1,2-α] pyrimidine, which crystallizes upon standing, as an orange oil.
[647] δ _H (400 MHz, CDCl ₃ ) 1.77 (6H, d, J 22), 7.21 (1H, dd, J 7 and 2), 7.54 (1H, d, J 1), 7.79 (1H, d, J 1), 8.45 (1 H, d, J 7).
[648] 7- (1-fluoro-1-methylethyl) imidazo [1,2-α] pyrimidine was brominated as described in Example 1 to give 3-bromo-7- (1-fluoro-1- Methylethyl) imidazo [1,2-α] pyrimidine is obtained as off-white solid.
[649] δ _H (360 MHz, CDCl ₃ ) 1.78 (6H, d, J 22), 7.35 (1H, d, J 7 and 2), 7.77 (1H, s), 8.42 (1H, d, J 7).
[650] 3-bromo-7- (1-fluoro-1-methylethyl) imidazo [1,2-α] pyrimidine was treated with 2,4-difluoro-3- (pyridine as described in Example 23. 3- [2,4-difluoro-3- (pyridin-3-yl) phenyl] -7- (1-fluoro-1-methylethyl) imidazo [coupling with -3-yl) phenylboronic acid 1,2-α] pyrimidine is obtained as a white solid.
[651] δ _H (360 MHz, CDCl ₃ ) 1.80 (6H, d, J 22), 7.21-7.29 (2H, m), 7.46 (1H, dd, J 8 and 5), 7.50-7.57 (1H, m), 7.85 ( 1H, d, J 8), 7.92 (1H, s), 8.31 (1H, dd, J 7 and 3), 8.70 (1H, dd, J 5 and 1), 8.79 (1H, s).
[652] m / z (ES ⁺ ) 369 (M ⁺ + H).
[653] Example 31
[654] 7- (1-fluoro-1-methylethyl) -3- [4-fluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine
[655] 3-Bromo-7- (1-fluoro-1-methylethyl) imidazo [1,2-α] pyrimidine was reacted with 3- [2-fluoro-5- (4 as described in Example 23. 7- (1-fluoro-) after crystallization from ethyl acetate / isohexane by coupling with, 4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] pyridine 1-methylethyl) -3- [4-fluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine is obtained as a white solid.
[656] δ _H (360 MHz, CDCl ₃ ) 1.74 (6H, d, J 22), 7.26 (1H, dd, J 7 and 2), 7.53-7.60 (2H, m), 7.80 (1H, ddd, J 8, 5 and 2), 7.94 (1H, dd, J 8 and 2), 8.05 (1H, s), 8.10 (1H, ddd, J 8, 4 and 2), 8.65 (1H, dd, J 5 and 1.5), 8.89 ( 1 H, s), 9.13 (1 H, d, J 7).
[657] m / z (ES ⁺ ) 351 (M ⁺ + H).
[658] Example 32
[659] 2- [3- (2,4-difluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -2-methylpropionic acid methyl ester
[660] Methyl 2,2-dimethylacetoacetate is converted to 5,5-diethoxy-2,2-dimethyl-3-oxopentanoic acid methyl ester as described in Example B and according to the method described in Example A Condensation with 2-aminoimidazole hemisulfate yields 2- (imidazo [1,2-α] pyrimidin-7-yl) -2-methylpropionic acid methyl ester as a brown oil.
[661] δ _H (360 MHz, CDCl ₃ ) 1.67 (6H, s), 3.70 (3H, s), 6.85 (1H, d, J 7), 7.48 (1H, d, J 1), 7.76 (1H, d, J 1 ), 8.34 (1H, d, J 7).
[662] 2- (imidazo [1,2-α] pyrimidin-7-yl) -2-methylpropionic acid methyl ester was brominated as described in Example 1 to give 2- (3-bromoimidazo [1,2 -α] pyrimidin-7-yl) -2-methylpropionic acid methyl ester is obtained as off-white solid.
[663] δ _H (400 MHz, CDCl ₃ ) 1.68 (6H, s), 3.69 (3H, s), 6.98 (1H, d, J 7), 7.75 (1H, s), 8.32 (1H, d, J 7).
[664] 2- (3-bromoimidazo [1,2-α] pyrimidin-7-yl) -2-methylpropionic acid methyl ester and 2,4-difluoro-3- (pyridin-3-yl) benzeneboron The acid was coupled in the same manner as described in Example 23 to give 2- [3- (2,4-difluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] Pyrimidin-7-yl) -2-methylpropionic acid methyl ester is obtained as a white solid.
[665] δ _H (360 MHz, CDCl ₃ ) 1.69 (6H, s), 3.70 (3H, s), 6.91 (1H, d, J 7), 7.20-7.25 (1H, m), 7.43-7.47 (1H, m), 7.50-7.57 (1H, m), 7.84-7.87 (1H, m), 7.89 (1H, s), 8.21 (1H, dd, J 7 and 3), 8.69 (1H, dd, J 5 and 2), 8.78 (1H, d, J 1).
[666] m / z (ES ⁺ ) 409 (M ⁺ + H).
[667] Example 33
[668] 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -2-methylpropionitrile
[669] 2,2-dimethyl-3-oxobutyronitrile is prepared from 3-methyl-2-butanone as described in Rasmussen, Synthesis, 1973, 682, distilled under reduced pressure, and then Nitrile is obtained as a colorless oil.
[670] Boiling Point: 74 to 76 ° C. (30 mmHg).
[671] δ _H (360 MHz, CDCl ₃ ) 1.51 (6H, s), 2.43 (3H, s).
[672] 2,2-dimethyl-3-oxobutyronitrile was converted to 5,5-diethoxy-2,2-dimethyl-3-oxopentannitrile as described in Example B, and Condensation with 2-aminoimidazole hemisulfate to give 2- (imidazo [1,2-α] pyrimidin-7-yl) -2-methylpropionitrile as a white solid.
[673] δ _H (400 MHz, CDCl ₃ ) 1.84 (6H, s), 7.27 (1H, d, J 7), 7.58 (1H, d, J 1), 7.84 (1H, d, J 1), 8.49 (1H, d , J 7).
[674] 2- (imidazo [1,2-α] pyrimidin-7-yl) -2-methylpropionitrile was brominated in the same manner as described in Example 1 to give 2- (3-bromoimidazo [ 1,2-α] pyrimidin-7-yl] -2-methylpropionitrile is obtained as off-white solid.
[675] δ _H (400 MHz, CDCl ₃ ) 1.84 (6H, s), 7.39 (1H, d, J 7), 7.82 (1H, s), 8.46 (1H, d, J 7).
[676] 2- (3-bromoimidazo [1,2-α] pyrimidin-7-yl] -2-methylpropionitrile and 4-fluoro-3- (pyridin-3-yl) benzeneboronic acid Coupling according to the method in Example 23, 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -2 -Methylpropionitrile is obtained as a white solid.
[677] δ _H (360 MHz, CDCl ₃ ) 1.86 (6H, s), 7.32 (1H, d, J 7), 7.38-7.45 (2H, m), 7.53-7.62 (2H, m), 7.86-7.97 (1H, m ), 7.91 (1H, d, J 3), 8.62 (1H, d, J 7), 8.67 (1H, dd, J 8 and 3), 8.84 (1H, s).
[678] m / z (ES ⁺ ) 358 (M ⁺ + H).
[679] Example 34
[680] 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -2-methylpropan-1-ol
[681] 4-hydroxy-3,3-dimethylbutan-2-one (prepared according to the method described in US Pat. No. 4,255,434) (5.00 g, 43.0 mmol) was protected as an acetate according to the method in Example 3, Conversion to diethyl acetal as described in Example B, followed by condensation with 2-aminoimidazole hemisulfate as described in Example A to yield 2- (imidazo [1,2-α] pyrimidine-7 -Yl) -2-methylpropan-1-ol is obtained as a white solid (1.43 g, 17%).
[682] δ _H (360 MHz, CDCl ₃ ) 1.37 (6H, s), 3.87 (2H, s), 5.29 (1H, s), 6.93 (1H, d, J 7), 7.47 (1H, d, J 1), 7.74 (1H, d, J 1), 8.37 (1H, d, J 7).
[683] 2- (imidazo [1,2-α] pyrimidin-7-yl] -2-methylpropan-1-ol was brominated as described in Example 1 to give 2- (3-bromoimidazo [1 , 2-α] pyrimidin-7-yl] -2-methylpropan-1-ol is obtained as off-white solid.
[684] δ _H (360 MHz, CDCl ₃ ) 1.38 (6H, s), 3.88 (2H, s), 7.07 (1H, d, J 7), 7.72 (1H, s), 8.35 (1H, d, J 7).
[685] 2- (3-bromoimidazo [1,2-α] pyrimidin-7-yl) -2-methylpropan-1-ol was prepared according to the method in Example D according to the method of 3-bromo-7- (1 Conversion to, 1-dimethyl-2-triethylsilanyloxyethyl) imidazo [1,2-α] pyrimidine yields a colorless oil that crystallizes upon standing.
[686] δ _H (360 MHz, CDCl ₃ ) 0.55 (6H, q, J 8), 0.88 (9H, t, J 8), 1.40 (6H, s), 3.77 (2H, s), 7.17 (1H, d, J 7 ), 7.71 (1 H, s), 8.27 (1 H, d, J 7).
[687] 3-Bromo-7- (1,1-dimethyl-2-triethylsilanyloxyethyl) imidazo [1,2-α] pyrimidine was subjected to 4-fluoro-3- according to the method in Example 23. Coupling with (pyridin-3-yl) benzeneboronic acid (323 mg, 1.28 mmol), dissolved in 3N hydrochloric acid, heated at 48 ° C. for 14 hours to deprotection to afford 2- [3- (4-fluoro-3 -(Pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -2-methylpropan-1-ol is obtained as a white powder.
[688] δ _H (360 MHz, CDCl ₃ ) 1.39 (6H, s), 3.54 (1H, t, J 7), 3.89 (1H, d, J 7), 6.99 (1H, d, J 7), 7.35-7.45 (2H , m), 7.51-7.60 (2H, m), 7.83 (1H, s), 7.90-7.94 (1H, m), 8.53 (1H, d, J 7), 8.68 (1H, dd, J 5 and 2) , 8.83 (1 H, s).
[689] m / z (ES ⁺ ) 363 (M ⁺ + H).
[690] Examples 35-38
[691] The following compounds are prepared using methods similar to those described above.
[692]
[693]
[694]
[695]
[696] Additional Example
[697] The following compounds are prepared by the methods described herein.
[698] 2'-fluoro-5 '-(7-methylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[699] 5 '-(7-acetylimidazo [1,2-α] pyrimidin-3-yl) -2'-fluorobiphenyl-2-carbonitrile,
[700] 2'-fluoro-5 '-(7-isopropylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[701] 2'-fluoro-5 '-(7-tert-butylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[702] 2'-fluoro-5 '-[7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[703] 2'-fluoro-5 '-[7- (1-fluoro-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[704] 2'-fluoro-5 '-(7-hydroxymethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[705] 2'-fluoro-5 '-[7- (1-hydroxyethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[706] 2'-fluoro-5 '-[7- (1-fluoroethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[707] 2'-fluoro-5 '-[7- (2-methylthiazol-5-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[708] 2'-fluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[709] 5 '-[7- (1,1-difluoroethyl) imidazo [1,2-α] pyrimidin-3-yl] -2'-fluorobiphenyl-2-carbonitrile,
[710] 5 '-(7-chloroimidazo [1,2-α] pyrimidin-3-yl) -2'-fluorobiphenyl-2-carbonitrile,
[711] 5 '-(7-difluoromethylimidazo [1,2-α] pyrimidin-3-yl) -2'-fluorobiphenyl-2-carbonitrile,
[712] 2'-fluoro-5 '-(7-methoxymethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[713] 3- (2'-cyano-6-fluorobiphenyl-3-yl) imidazo [1,2-α] pyrimidine-7-carbonitrile,
[714] 2'-fluoro-5 '-[7- (3-methyl- [1,2,4] oxadiazol-5-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl -2-carbonitrile,
[715] 2'-fluoro-5 '-[7- (oxazol-5-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[716] 2'-fluoro-5 '-[7- (hydroxyiminomethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[717] 5 '-{7- [1- (2-dimethylaminoethoxyimino) methyl] imidazo [1,2-α] pyrimidin-3-yl} -2'-fluorobiphenyl-2-carbonitrile,
[718] 3 '-(7-difluoromethylimidazo [1,2-α] pyrimidin-3-yl) -4'-fluorobiphenyl-2-carbonitrile,
[719] 2'-fluoro-5 '-(7-fluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[720] 2'-fluoro-5 '-[7- (furan-3-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[721] 2'-fluoro-5 '-[7- (thien-3-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[722] 2'-fluoro-5 '-[7- (pyridin-2-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[723] 3'-fluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[724] 3'-fluoro-5 '-(7-hydroxymethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[725] 2'-fluoro-3 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[726] 2'-fluoro-5 '-[7-([1,2,4] triazol-1-ylmethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbo Nitrile,
[727] 2'-fluoro-5 '-[7- (imidazol-1-ylmethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
[728] 2'-fluoro-5 '-[7-([1,2,3] triazol-1-ylmethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbo Nitrile,
[729] 2'-fluoro-5 '-[7-([1,2,3] triazol-2-ylmethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbo Nitrile,
[730] 3- [4-fluoro-3- (pyridazin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[731] 2- [2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenyl] nicotinonitrile,
[732] 2 ', 6'-difluoro-3'-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[733] 3- [4-fluoro-3- (pyrazin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[734] 3- [4-fluoro-3- (pyrimidin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[735] 3- [2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenyl] pyridine-2-carbonitrile,
[736] 3- [4-fluoro-3- (5-fluoropyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[737] 3- [2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenyl] thiophen-2-carbonitrile,
[738] 3- {2-fluoro-5- [7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] phenyl} thiophene-2-carbonitrile,
[739] 3- {2,6-difluoro-3- [7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] phenyl} thiophen-2- Carbon Nitrile,
[740] 3- [4-fluoro-3- (3-fluoropyridin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[741] 4-chloro-2'-fluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
[742] 2- [3- (4-fluoro-3- (pyrazin-2-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[743] 2- [3- (4-fluoro-3- (5-fluoropyridin-2-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[744] 3- [4-fluoro-3- (3-fluoropyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[745] 2- [3- (4-fluoro-3- (3-fluoropyridin-2-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[746] 3- [3- (3,5-difluoropyridin-2-yl) -4-fluorophenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[747] 2- [3- (3- (3,5-difluoropyridin-2-yl) -4-fluorophenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol ,
[748] 2'-fluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-3-carbonitrile,
[749] 2'-fluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-4-carbonitrile,
[750] 3- [4-fluoro-3- (4-fluoropyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[751] 3- [4-fluoro-3- (pyrrole-1-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[752] 3- [4-fluoro-3- (5-fluoropyridin-2-yl) phenyl] imidazo [1,2-α] pyrimidine,
[753] 3- [4-fluoro-3- (pyridazin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[754] 3- [4-fluoro-3- (imidazol-1-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[755] 3- [4-fluoro-3- (isothiazol-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[756] 3- [4-fluoro-3- (pyrimidin-5-yl) phenyl] -7-trifluoroimidazo [1,2-α] pyrimidine,
[757] 3- [4-fluoro-3- (thiazol-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[758] 2- {2-fluoro--5- [7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] phenyl} nicotinonitrile,
[759] 4- [2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenyl] nicotinonitrile,
[760] 4- {2-fluoro-5- [7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] phenyl} nicotinonitrile,
[761] 3- {2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenyl] isonicotinonitrile,
[762] 2- [3- (4-fluoro-3- (pyridazin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[763] 2- [3- (4-fluoro-3- (pyridazin-4-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[764] 3- [4-fluoro-3- (pyrazol-1-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[765] 2- [3- (4-fluoro-3- (pyrazol-1-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
[766] 3- [4-fluoro-3-([1,2,4] thiazol-1-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
[767] 2- [3- (4-fluoro-3-([1,2,4] triazol-1-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2- All,
[768] 2- {3- [4-fluoro-3- (5-fluoropyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidin-7-yl} propan-2-ol.

权利要求:
Claims (29)
[1" claim-type="Currently amended] A compound of formula (IA) or a pharmaceutically acceptable salt thereof.
Chemical Formula IIA

In Formula IIA above,
X ¹¹ is fluoro,
X ¹² is hydrogen or fluoro,
Z is aryl or heteroaryl, which may be optionally substituted by one or more substituents selected from halogen and cyano,
R ¹¹ is hydrogen, C _1-6 alkyl, halo (C _1-6 ) alkyl, dihalo (C _1-6 ) alkyl, hydroxy (C _1-6 ) alkyl, dihydroxy (C _1-6 ) alkyl , C _1-6 alkoxy (C _1-6 ) alkyl, di (C _1-6 ) alkoxy (C _1-6 ) alkyl, cyano (C _1-6 ) alkyl, C _2-6 alkoxycarbonyl (C _{1 -6)} alkyl, heteroaryl, C _1-6 alkyl-heteroaryl, heteroaryl (C _1-6) alkyl, halogen, cyano, trifluoromethyl, formyl, C _2-6 alkylcarbonyl, C _{2 -6} alkoxycarbonyl or -CR ⁵ = NOR ⁶ ,
R ⁵ is hydrogen or C _1-6 alkyl,
R ⁶ is hydrogen, C _1-6 alkyl, hydroxy (C _1-6 ) alkyl or di (C _1-6 ) alkylamino (C _1-6 ) alkyl.
[2" claim-type="Currently amended] The compound of formula (IIB) or a pharmaceutically acceptable salt thereof.
Formula IIB

In Formula IIB above,
X ¹¹ , X ¹² and R ¹¹ are as defined in claim 1,
R ⁷ is hydrogen, fluoro or chloro.
[3" claim-type="Currently amended] The compound of claim 2, wherein R ⁷ is fluoro.
[4" claim-type="Currently amended] The compound of claim 3, wherein R ¹¹ is trifluoromethyl.
[5" claim-type="Currently amended] The compound of formula IIC or a pharmaceutically acceptable salt thereof.
Chemical Formula IIC

In the formula IIC above,
X ¹¹ , X ¹² and R ¹¹ are as defined in claim 1,
R ⁷ is as defined in claim 2.
[6" claim-type="Currently amended] The compound of formula IID or a pharmaceutically acceptable salt thereof.
Chemical Formula IID

In the above formula IID,
X ¹¹ , X ¹² and R ¹¹ are as defined in claim 1,
R ⁸ is hydrogen, fluoro or chloro.
[7" claim-type="Currently amended] The compound of claim 6, wherein R ⁸ is hydrogen.
[8" claim-type="Currently amended] 8. Compounds according to claim 7, wherein R ¹¹ is 2-hydroxyprop-2-yl.
[9" claim-type="Currently amended] The compound of formula IIE or a pharmaceutically acceptable salt thereof.
Chemical Formula IIE

In the above formula IIE,
X ¹¹ , X ¹² and R ¹¹ are as defined in claim 1,
R ⁸ is as defined in claim 6,
R ⁹ is hydrogen or fluoro.
[10" claim-type="Currently amended] 10. The compound of any one of claims 2-9, wherein X ¹² is hydrogen.
[11" claim-type="Currently amended] 2'-fluoro-5 '-(imidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
2'-fluoro-5 '-(7-methylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
5 '-(7-acetylimidazo [1,2-α] pyrimidin-3-yl) -2'-fluorobiphenyl-2-carbonitrile,
2'-fluoro-5 '-(7-isopropylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
2'-fluoro-5 '-(7-tert-butylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
2'-fluoro-5 '-[7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
2'-fluoro-5 '-[7- (1-fluoro-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
2'-fluoro-5 '-(7-hydroxymethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
2'-fluoro-5 '-[7- (1-hydroxyethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
2'-fluoro-5 '-[7- (1-fluoroethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
2'-fluoro-5 '-[7- (2-methylthiazol-5-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
2'-fluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
5 '-[7- (1,1-difluoroethyl) imidazo [1,2-α] pyrimidin-3-yl] -2'-fluorobiphenyl-2-carbonitrile,
5 '-(7-chloroimidazo [1,2-α] pyrimidin-3-yl) -2'-fluorobiphenyl-2-carbonitrile,
5 '-(7-difluoromethylimidazo [1,2-α] pyrimidin-3-yl) -2'-fluorobiphenyl-2-carbonitrile,
2'-fluoro-5 '-(7-methoxymethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
3- (2'-cyano-6-fluorobiphenyl-3-yl) imidazo [1,2-α] pyrimidine-7-carbonitrile,
2'-fluoro-5 '-[7- (3-methyl- [1,2,4] oxadiazol-5-yl) imidazo [1,2-α] pyrimidin-3-yl) biphenyl -2-carbonitrile,
2'-fluoro-5 '-[7- (oxazol-5-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
2'-fluoro-5 '-[7- (hydroxyiminomethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
5 '-{7- [1- (2-dimethylaminoethoxyimino) methyl] imidazo [1,2-α] pyrimidin-3-yl} -2'-fluorobiphenyl-2-carbonitrile,
3 '-(7-difluoromethylimidazo [1,2-α] pyrimidin-3-yl) -4'-fluorobiphenyl-2-carbonitrile,
2'-fluoro-5 '-(7-fluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
2'-fluoro-5 '-[7- (furan-3-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
2'-fluoro-5 '-[7- (thien-3-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
2'-fluoro-5 '-[7- (pyridin-2-yl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
7- (1,1-difluoroethyl) -3- [4-fluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine,
2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
3'-fluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
3'-fluoro-5 '-(7-hydroxymethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
2'-fluoro-3 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
3- [4-fluoro-3- (pyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
3- [4-fluoro-3- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
2'-fluoro-5 '-[7-([1,2,4] triazol-1-ylmethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbo Nitrile,
2'-fluoro-5 '-[7- (imidazol-1-ylmethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
2'-fluoro-5 '-[7-([1,2,3] triazol-1-ylmethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbo Nitrile,
2'-fluoro-5 '-[7-([1,2,3] triazol-2-ylmethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbo Nitrile,
3- [4-fluoro-3- (pyridin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
3- [2,4-difluoro-3- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
3- [2,4-difluoro-3- (pyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
2- [3- (4-fluoro-3- (pyridin-4-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
3- [2-fluoro-3- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
2- [3- (2-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
3- [2-fluoro-3- (pyridin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
2- [3- (2-fluoro-3- (pyridin-4-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
3- [2-fluoro-3- (pyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
2- [3- (2-fluoro-3- (pyridin-2-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
3- [4-fluoro-3- (pyridazin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
2- [2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenyl] nicotinonitrile,
3- [4-fluoro-3- (pyridin-2-yl) phenyl] imidazo [1,2-α] pyrimidine,
3,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
6,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
5,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
4,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
2 ', 6'-difluoro-3'-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
3- [4-fluoro-3- (pyrazin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
3- [4-fluoro-3- (pyrimidin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
3- [2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenyl] -pyridine-2-carbonitrile,
3- [4-fluoro-3- (5-fluoropyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
7- (1,1-difluoroethyl) -3- [4-fluoro-3- (pyridin-4-yl) phenyl] imidazo [1,2-α] pyrimidine and
7- (1,1-difluoroethyl) -3- [2,4-difluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine and Pharmaceutically acceptable salts thereof.
[12" claim-type="Currently amended] 2- [3- (2,4-difluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -propan-2-ol,
1- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -ethanone,
3 '-[7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] -4,2', 6'-trifluorobiphenyl-2-carbo Nitrile,
2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -propane-1,2-diol,
3- [2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenyl] -thiophene-2-carbonitrile,
3- {2-fluoro-5- [7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] phenyl} thiophene-2-carbonitrile,
3- {2,6-difluoro-3- [7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] phenyl} thiophen-2- Carbon Nitrile,
3- [4-fluoro-3- (3-fluoropyridin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
4-chloro-2'-fluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile,
2- [3- (4-fluoro-3- (pyrazin-2-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
2- [3- (4-fluoro-3- (5-fluoropyridin-2-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
3- [4-fluoro-3- (3-fluoropyridin-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
2- [3- (4-fluoro-3- (3-fluoropyridin-2-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
3- [3- (3,5-difluoropyridin-2-yl) -4-fluorophenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
2- [3- (3- (3,5-difluoropyridin-2-yl) -4-fluorophenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol ,
3- [2,4-difluoro-3- (pyridin-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
2- [3- (2,4-difluoro-3- (pyridin-4-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
4,2'-difluoro-5 '-[7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] biphenyl-2-carbonitrile,
2'-fluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl] biphenyl-3-carbonitrile,
2'-fluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl] biphenyl-4-carbonitrile,
3- [2,4-difluoro-3- (pyridin-3-yl) phenyl] -7- (1-fluoro-1-methylethyl) imidazo [1,2-α] pyrimidine,
7- (1-fluoro-1-methylethyl) -3- [4-fluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine,
2- [3- (2,4-difluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -2-methylpropionic acid methyl ester,
2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -2-methylpropionitrile,
2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] -2-methylpropan-1-ol,
3- [4-fluoro-3- (4-fluoropyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
3- [4-fluoro-3- (pyrrole-1-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
3- [4-fluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine,
3- [4-fluoro-3- (5-fluoropyridin-2-yl) phenyl] imidazo [1,2-α] pyrimidine,
3- [2,4-difluoro-3- (pyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidine,
3- [5-fluoro-3- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
3- [2-fluoro-5- (pyridin-3-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
3- [4-fluoro-3- (pyridinzin-4-yl) phenyl]]-7-trifluoromethylimidazo [1,2-α] pyrimidine,
3- [4-fluoro-3- (imidazol-1-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
3- [4-fluoro-3- (isothiazol-4-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine and
3- [4-fluoro-3- (pyrimidin-5-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine and a pharmaceutically acceptable salt thereof .
[13" claim-type="Currently amended] 3- [4-fluoro-3- (thiazol-2-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
2- {2-fluoro-5- [7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] phenyl} nicotinonitrile,
4- [2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenyl] nicotinonitrile,
4- {2-fluoro-5- [7- (1-hydroxy-1-methylethyl) imidazo [1,2-α] pyrimidin-3-yl] phenyl} nicotinonitrile,
3- [2-fluoro-5- (7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) phenyl] isonicotinonitrile,
2- [3- (4-fluoro-3- (pyridazin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
2- [3- (4-fluoro-3- (pyridazin-4-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
3- [4-fluoro-3- (pyrazol-1-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
2- [3- (4-fluoro-3- (pyrazol-1-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol,
3- [4-fluoro-3-([1,2,4] triazol-1-yl) phenyl] -7-trifluoromethylimidazo [1,2-α] pyrimidine,
2- [3- (4-fluoro-3-([1,2,4] triazol-1-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2- Come and
2- {3- [4-fluoro-3- (5-fluoropyridin-3-yl) phenyl] imidazo [1,2-α] pyrimidin-7-yl} propan-2-ol And pharmaceutically acceptable salts thereof.
[14" claim-type="Currently amended] A pharmaceutical composition comprising a compound of formula (IA) according to claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
[15" claim-type="Currently amended] Use of a compound of formula (IA) according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and / or prophylaxis of harmful neurological diseases.
[16" claim-type="Currently amended] (A) reacting a compound of Formula III with a compound of Formula IV in the presence of a transition metal catalyst, or
(B) reacting a compound of Formula V with a compound of Formula VI in the presence of a transition metal catalyst, or
(C) reacting a compound of formula VII with a compound of formula VIII in the presence of a transition metal catalyst, or
(D) reacting a compound of Formula IX with a compound of Formula X in the presence of a transition metal catalyst, or
(E) reacting a compound of Formula XV with a compound of Formula XVI, or
(F) reacting a compound of formula XX with a compound of formula XXI in the presence of a transition metal catalyst, or
(G) reacting a compound of formula XXII with 2,5-dimethoxytetrahydrofuran,
(H) If desired, a process for preparing a compound of formula (IA) according to claim 1 comprising converting the initially obtained compound of formula (IA) to another compound of formula (IA) by standard methods.
Formula III

Formula IV

Formula V

Formula VI

Formula VII

Formula VIII
M ^1- Z
Formula IX

Formula X
L ^1- Z
Formula XV

Formula XVI

Formula XX
R ^1a -M ¹
Formula XXI

Formula XXII

In the above formulas III to XXII,
X ¹¹ , X ¹² , Z and R ¹¹ are as defined in claim 1,
L ¹ is a suitable leaving group,
M ¹ is boronic acid residue —B (OH) ₂ or a cyclic ester thereof formed with an organic diol, or —Sn (Alk) ₃ , wherein Alk is a C _1-6 alkyl group,
L ³ is a suitable leaving group,
R ^1a is an aryl or heteroaryl moiety,
L ⁴ is a suitable leaving group.
[17" claim-type="Currently amended] Treatment and / or prophylaxis of harmful neurological diseases comprising administering to a patient in need thereof an effective amount of a compound of formula (IIA) or a pharmaceutically acceptable salt thereof according to claim 1 Way.
[18" claim-type="Currently amended] 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol or a pharmaceutically acceptable thereof salt.
[19" claim-type="Currently amended] Bis-hydrochloride salt of 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol.
[20" claim-type="Currently amended] 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol or a pharmaceutically acceptable thereof A pharmaceutical composition comprising a salt with a pharmaceutically acceptable carrier.
[21" claim-type="Currently amended] Bis-hydrochloride salt of 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol A pharmaceutical composition comprising with a pharmaceutically acceptable carrier.
[22" claim-type="Currently amended] 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl for preparing a medicament for treating and / or preventing anxiety ] Propan-2-ol or a pharmaceutically acceptable salt thereof.
[23" claim-type="Currently amended] 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl for preparing a medicament for treating and / or preventing anxiety ] Use of bis-hydrochloride salt of propan-2-ol.
[24" claim-type="Currently amended] Effective amount of 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol or pharmaceutically acceptable A method of treating and / or preventing anxiety, comprising administering a salt thereof to a patient in need thereof.
[25" claim-type="Currently amended] Bis-hydrochloride of an effective amount of 2- [3- (4-fluoro-3- (pyridin-3-yl) phenyl) imidazo [1,2-α] pyrimidin-7-yl] propan-2-ol A method of treating and / or preventing anxiety, comprising administering a salt to a patient in need of treatment and / or prevention of anxiety.
[26" claim-type="Currently amended] 4,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile.
[27" claim-type="Currently amended] Pharmaceutically acceptable carrier of 4,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile A pharmaceutical composition comprising with.
[28" claim-type="Currently amended] 4,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) ratio for the manufacture of a medicament for the treatment and / or prevention of anxiety Use of Phenyl-2-carbonitrile.
[29" claim-type="Currently amended] An effective amount of 4,2'-difluoro-5 '-(7-trifluoromethylimidazo [1,2-α] pyrimidin-3-yl) biphenyl-2-carbonitrile is treated with anxiety and / Or administering to a patient in need thereof.

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JP4237497B2|2009-03-11|Pyrazolopyridines, their preparation and their use as therapeutic compounds

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同族专利:

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公开号 | 公开日

---

EA006234B1|2005-10-27|

---

TWI248936B|2006-02-11|

---

JP2004523584A|2004-08-05|

---

CN1294133C|2007-01-10|

---

JP4409174B2|2010-02-03|

---

WO2002074773A1|2002-09-26|

---

IL157641D0|2004-03-28|

---

EA200301037A1|2004-04-29|

---

PL363804A1|2004-11-29|

---

BG108166A|2004-09-30|

---

DE60205101T2|2006-05-24|

---

AU2002241138B2|2007-09-20|

---

SK11672003A3|2004-05-04|

---

EE200300455A|2003-12-15|

---

MXPA03008572A|2003-12-08|

---

CN1498218A|2004-05-19|

---

CZ20032539A3|2004-03-17|

---

NZ527901A|2005-09-30|

---

DE60205101D1|2005-08-25|

---

HU0303630A3|2005-06-28|

---

HU0303630A2|2004-03-01|

---

NO20034170D0|2003-09-19|

---

PE20020970A1|2002-11-01|

---

EP1381606A1|2004-01-21|

---

EP1381606B1|2005-07-20|

---

CA2461426C|2010-08-03|

---

ES2244752T3|2005-12-16|

---

WO2002074772A1|2002-09-26|

---

NO20034170L|2003-11-19|

---

CA2461426A1|2002-09-26|

---

BR0207994A|2004-03-02|

---

AT299882T|2005-08-15|

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:
2001-03-21|Priority to GB0107134A

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2001-03-21|Priority to GB0107134.9

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2001-11-21|Priority to GB0127938A

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2001-11-21|Priority to GB0127938.9

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2002-03-19|Application filed by 머크 샤프 앤드 돔 리미티드

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2002-03-19|Priority to PCT/GB2002/001351

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2003-10-23|Publication of KR20030083001A

优先权:

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申请号 | 申请日 | 专利标题

---

GB0107134A|GB0107134D0|2001-03-21|2001-03-21|Therapeutic agents|

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GB0107134.9|2001-03-21|

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GB0127938A|GB0127938D0|2001-11-21|2001-11-21|Therapeutic agents|

---

GB0127938.9|2001-11-21|

---

PCT/GB2002/001351|WO2002074772A1|2001-03-21|2002-03-19|Imidazo-pyrimidine derivatives as ligands for gaba receptors|