HK1127037A

HK1127037A - Novel 2-amino-imidazole-4-one compounds and their use in the manufacture of a medicament to be used in the treatment of cognitive impairment, alzheimer's disease, neurodegeneration and dementia.

Info

Publication number: HK1127037A
Application number: HK09106140.7A
Authority: HK
Inventors: Stefan Berg; Jeremy Burrows; Gianni Chessari; Miles Stuart Congreve; Johan HEDSTRÖM; Sven Hellberg; Katharina HÖGDIN; Jacob KIHLSTRÖM; Karin Kolmodin; Johan LINDSTRÖM; Christopher Murray; Sahil Patel
Original assignee: 阿斯利康(瑞典)有限公司; 阿斯特克斯医疗公司
Priority date: 2005-11-21
Filing date: 2006-11-20
Publication date: 2009-09-18

Description

Novel 2-amino-imidazol-4-one compounds and their use in the manufacture of medicaments for the treatment of cognitive impairment, alzheimer's disease, neurodegeneration and dementia

Technical Field

The present invention relates to novel compounds and pharmaceutical compositions thereof. Furthermore, the present invention relates to a therapeutic method for the treatment and/or prevention of: a β -related pathologies (a β -related pathology), such as down syndrome (down syndrome) and β -amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as, but not limited to, MCI ("mild cognitive impairment"), Alzheimer Disease (Alzheimer Disease), memory loss, attention deficit symptoms associated with Alzheimer Disease, neurodegeneration associated with diseases such as Alzheimer Disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's Disease, progressive supranuclear palsy or cortical basal degeneration.

Background

Several groups have identified and isolated aspartic proteases with β -secretase activity (Hussain et al, 1999, Lin et al, 2000, Yan et al, 1999, Sinha et al, 1999 and Vassar et al, 1999). Beta-secretase is also known in the relevant literature as Asp2(Yan et al, 1999), beta-site APP-cleaving enzyme (BACE) (Vassar et al, 1999) or memapsin-2(Lin et al, 2000). Identification of BACE has employed a variety of experimental approaches, such as EST database analysis (Hussain et al 1999), expression cloning (Vassar et al, 1999), identification of human homologs from public databases of predicted c.elegans proteins (Yan et al 1999) and eventual use of inhibitors to purify proteins derived from human brain (Sinha et al 1999). Thus, five groups used three different experimental approaches to identify the same enzyme, and thus it was firmly believed that BACE is a β -secretase. The following patent documents are also mentioned: WO96/40885, EP871720, U.S. Pat. Nos. 5,942,400 and 5,744,346, EP855444, US6,319,689, WO99/64587, WO99/31236, EP1037977, WO00/17369, WO01/23533, WO0047618, WO00/58479, WO00/69262, WO01/00663, WO01/00665 and US6,313,268.

It was found that BACE is a pepsin-like aspartic protease, a mature enzyme consisting of an N-terminal catalytic domain, a transmembrane domain and a small cytoplasmic domain. BACE has optimal activity at pH 4.0-5.0 (Vassar et al, 1999) and is slightly inhibited by standard pepsin inhibitors (e.g., pepstatin). It has been shown that the catalytic domain, minus the transmembrane and cytoplasmic domains, is active on the substrate peptide (Lin et al, 2000). BACE is a membrane-bound type 1 protein that is synthesized as a partially active zymogen and is abundantly expressed in brain tissue. It is thought to represent the major beta-secretase activity and is considered to be the rate-limiting step in the production of amyloid-beta-protein (a β). Thus, BACE is of particular interest in the pathology of alzheimer's disease and in the development of drugs for the treatment of alzheimer's disease.

A β or amyloid- β -protein is the major component of brain plaques, which are characteristic of Alzheimer's disease (De Strooper et al, 1999). A β is a 39-42 residue peptide formed by the specific cleavage of a class I transmembrane protein (called APP or amyloid precursor protein). The a β -secretase activity cleaves this protein between residues Met671 and Asp672 (numbering the 770aa isoform of APP), forming the N-terminus of a β. Secondary cleavage of the peptide is associated with gamma-secretase, thereby forming the C-terminus of the a β peptide.

Alzheimer's Disease (AD) is estimated to afflict more than twenty million people in the world and is believed to be the most prevalent form of dementia. Alzheimer's disease is a progressive dementia in which large deposits, i.e., amyloid plaques and neurofibrillary tangles, formed from accumulated protein breakdown products accumulate in the brain. Amyloid plaques are thought to be responsible for the decline in intelligence found in alzheimer's patients.

The probability of developing alzheimer's disease increases with age, and as the aging population of developed countries increases, this disease becomes an increasingly serious problem. In addition to this, there is a familial association with alzheimer's disease, and therefore any individual with a double mutation of APP (known as the Swedish mutation, where the mutated APP constitutes a rather improved substrate for BACE) is much more likely to develop AD, and at a young age is also much more likely to develop AD (see also US 6,245,964 and US 5,877,399 relating to transgenic rodents including APP-Swedish). Therefore, there is also a strong need to develop compounds that can be used in these individuals in a prophylactic manner.

The gene encoding APP is found on chromosome 21, which is also found as an extra copy in down syndrome. Patients with down syndrome tend to have alzheimer's disease at a young age, and patients with down syndrome over 40 years of age almost all show alzheimer-type pathology (Oyama et al, 1994). This is thought to be due to the extra copy of the APP gene found in these patients, which causes overexpression of APP, thus increasing APP β levels, leading to a high incidence of alzheimer's disease in this population. Thus, inhibitors of BACE are useful for reducing alzheimer-type pathology in patients with down's syndrome.

Thus, drugs that reduce or block BACE activity should be able to reduce A β levels and levels of fragments of A β in the brain or elsewhere where A β or fragments thereof are deposited, thus slowing the formation of amyloid plaques and the progression of AD or other patients involving the deposition of A β or fragments thereof (Yankner, 1996; Desstrooper and Konig, 1999). Therefore, BACE is an important candidate target for the development of drugs for the treatment and/or prevention of the following diseases: a β -related pathologies such as down's syndrome and β -amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as, but not limited to, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with diseases such as alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

Thus, by inhibiting BACE with inhibitors (e.g., the compounds provided herein), it is useful to inhibit the deposition of a β and portions thereof.

The therapeutic potential to inhibit a β deposition has prompted many research groups to isolate and characterize secretases and to identify their potential inhibitors (see, for example, WO01/23533a2, EP0855444, WO00/17369, WO00/58479, WO00/47618, WO00/77030, WO01/00665, WO01/00663, WO01/29563, WO02/25276, US5,942,400, US6,245,884, US6,221,667, US6,211,235, WO02/02505, WO02/02506, WO02/02512, WO 02/518, WO02/02520, WO 02/0264, WO05/058311, WO05/097767 and US/2005 0282826).

Disclosure of Invention

The compounds of the invention exhibit improved properties, such as improved hERG selectivity, compared to potential inhibitors known in the art.

The present application provides novel compounds of formula I, as a free base, or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof:

wherein

R¹Selected from hydrogen, C_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, C_3-6Cycloalkyl radical, C_5-7Cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C_1-6Alkyl radical C_3-6Cycloalkyl, -C_1-6Alkylaryl, -C_1-6Alkyl heteroaryl or-C_1-6Alkyl heterocyclic group, wherein said C_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, C_3-6Cycloalkyl radical, C_5-7Cycloalkenyl, aryl, heteroaryl, heterocyclyl, C_1-6Alkyl radical C_3-6Cycloalkyl radical, C_1-6Alkylaryl group, C _1-6Alkyl heteroaryl or C_1-6The alkyl heterocyclyl is optionally substituted with one, two or three a;

R²selected from hydrogen, nitro, cyano, -Q-C_1-6Alkyl, -Q-C_2-6Alkenyl, -Q-C_2-6Alkynyl, -Q-C_3-6Cycloalkyl, -Q-C_5-7Cycloalkenyl radical, -Q-C_1-6Alkyl radical C_3-6Cycloalkyl, -Q-aryl, -Q-heteroaryl,-Q-C_1-6Alkylaryl, -Q-C_1-6Alkylheteroaryl, -Q-heterocyclyl or-Q-C_1-6Alkylheterocyclyl, wherein said-Q-C_1-6Alkyl, -Q-C_2-6Alkenyl, -Q-C_2-6Alkynyl, -Q-C_3-6Cycloalkyl, -Q-C_5-7Cycloalkenyl radical, -Q-C_1-6Alkyl radical C_3-6Cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C_1-6Alkylaryl, -Q-C_1-6Alkylheteroaryl, -Q-heterocyclyl or-Q-C_1-6The alkyl heterocyclyl is optionally substituted with one, two or three R⁷Substitution;

-Q-is a direct bond, -CONH-, -CO-, -CON (C)_1-6Alkyl) -, -CON (C)_3-6Cycloalkyl) -, -SO₂-、-SO₂NH-、-SO₂N(C_1-6Alkyl) -, -SO₂N(C_3-6Cycloalkyl) -, -NHSO₂-、-N(C_1-6Alkyl) SO₂-、-NHCO-、-N(C_1-6Alkyl) CO-, -N (C)_3-6Cycloalkyl) CO-or-N (C)_3-6Cycloalkyl) SO₂-；

R³Is- (C (R)⁴)(R⁵))_nR⁶、-C_2-4Alkenyl radical R⁶、-C_2-4Alkynyl radical R⁶、-C_5-7Cycloalkenyl radicals R⁶Nitro or cyano, and if n > 1, each C (R)⁴)(R⁵) Independently of each other;

R⁴and R⁵Independently selected from hydrogen, C_1-6Alkyl, cyano, halogen or nitro; or R⁴And R⁵Together form oxo, C_3-6Cycloalkyl or heterocyclyl;

R⁶selected from methyl and C_3-6Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said methyl, C _3-6Cycloalkyl, heterocyclyl, aryl or heteroaryl each optionally substituted with 1-4R⁷And wherein any of the individual aryl or heteroaryl groups may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein said bicyclic ring system is optionally substituted with 1-4A, with the proviso that said bicyclic ring is not indane, benzo [1, 3 ]]Dioxoles or 2, 3-dihydrobenzo [1, 4 ]]-a dioxin ring system;

R⁷selected from halogen, nitro, CHO, -C_0-6Alkyl CN, -OC_1-6Alkyl CN, -C_0-6Alkyl OR⁸、-OC_2-6Alkyl OR⁸Fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -C_0-6Alkyl radical NR⁸R⁹、-OC_2-6Alkyl radical NR⁸R⁹、-OC_2-6Alkyl OC_2-6Alkyl radical NR⁸R⁹、-NR⁸OR⁹、-C_0-6Alkyl group CO₂R⁸、-OC_1-6Alkyl group CO₂R⁸、-C_0-6Alkyl CONR⁸R⁹、-OC_1-6Alkyl CONR⁸R⁹、-OC_2-6Alkyl radical NR⁸(CO)R⁹、-C_0-6Alkyl radical NR⁸(CO)R⁹、-O(CO)NR⁸R⁹、-NR⁸(CO)OR⁹、-NR⁸(CO)NR⁸R⁹、-O(CO)OR⁸、-O(CO)R⁸、-C_0-6Alkyl group COR⁸、-OC_1-6Alkyl group COR⁸、-NR⁸(CO)(CO)R⁸、-NR⁸(CO)(CO)NR⁸R⁹、-C_0-6Alkyl SR⁸、-C_0-6Alkyl (SO)₂)NR⁸R⁹、-OC_1-6Alkyl radical NR⁸(SO₂)R⁹、-OC_0-6Alkyl (SO)₂)NR⁸R⁹、-C_0-6Alkyl (SO) NR⁸R⁹、-OC_1-6Alkyl (SO) NR⁸R⁹、-OSO₂R⁸、-SO₃R⁸、-C_0-6Alkyl radical NR⁸(SO₂)NR⁸R⁹、-C_0-6Alkyl radical NR⁸(SO)R⁹、-OC_2-6Alkyl radical NR⁸(SO)R⁸、-OC_1-6Alkyl SO₂R⁸、-C_1-6Alkyl SO₂R⁸、-C_0-6Alkyl SOR⁸、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6Alkylheterocyclic group and-OC_2-6Alkyl heterocyclic group, wherein any C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_0-6Alkyl radical C_3-6Cycloalkyl radical, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl, C _0-6Alkylheterocyclic group and OC_2-6The alkyl heterocyclic group may be optionally substituted with one or more R¹⁴And wherein any of the individual aryl or heteroaryl groups may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-4A, with the proviso that the bicyclic ring system is not indane, benzo [1, 3 ] or heterocyclyl]Dioxoles or 2, 3-dihydrobenzo [1, 4 ]]-a dioxin ring system;

R¹⁴selected from halogen, nitro, CHO, -C_0-6Alkyl CN, -OC_1-6Alkyl CN, -C_0-6Alkyl OR⁸、-OC_1-6Alkyl OR⁸Fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -C_0-6Alkyl radical NR⁸R⁹、-OC_2-6Alkyl radical NR⁸R⁹、-OC_2-6Alkyl OC_2-6Alkyl radical NR⁸R⁹、-NR⁸OR⁹、-C_0-6Alkyl group CO₂R⁸、-OC_1-6Alkyl group CO₂R⁸、-C_0-6Alkyl CONR⁸R⁹、-OC_1-6Alkyl CONR⁸R⁹、-OC_2-6Alkyl radical NR⁸(CO)R⁹、-C_0-6Alkyl radical NR⁸(CO)R⁹、-O(CO)NR⁸R⁹、-NR⁸(CO)OR⁹、-NR⁸(CO)NR⁸R⁹、-OR⁸、-O(CO)OR⁸、-O(CO)R⁸、-C_0-6Alkyl group COR⁸、-OC_1-6Alkyl group COR⁸、-NR⁸(CO)(CO)R⁸、-NR⁸(CO)(CO)NR⁸R⁹、-C_0-6Alkyl SR⁸、-C_0-6Alkyl (SO)₂)NR⁸R⁹、-OC_2-6Alkyl radical NR⁸(SO₂)R⁹、-OC_0-6Alkyl (SO)₂)NR⁸R⁹、-C_0-6Alkyl (SO) NR⁸R⁹、-OC_1-6Alkyl (SO) NR⁸R⁹、-OSO₂R⁸、-OSO₂R⁸R⁹、-SO₃R⁸、-C_0-6Alkyl radical NR⁸(SO₂)NR⁸R⁹、-C_0-6Alkyl radical NR⁸(SO)R⁹、-OC_2-6Alkyl radical NR⁸(SO)R⁸、-OC_1-6Alkyl SO₂R⁸、-C_1-6Alkyl SO₂R⁸、-C_0-6Alkyl SOR⁸、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6Alkylheterocyclic group and-OC_2-6Alkyl heterocyclic group, wherein any C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_0-6Alkyl radical C_3-6Cycloalkyl radical, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl, C _0-6Alkylheterocyclic group and OC_2-6The alkyl heterocyclyl may be optionally substituted with 1-4A;

R⁸and R⁹Independently selected from hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6Alkyl heterocyclic radical and-C_0-6Alkyl radical NR¹⁰R¹¹Wherein said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_0-6Alkyl radical C_3-6Cycloalkyl radical, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl or C_0-6Alkyl heterocyclyl is optionally substituted with a; or

R⁸And R⁹May together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said 4 to 6 membered heterocyclic ring being optionally substituted by a; when two R are⁸(ii) when present in said structure, then they may optionally together form a 5 or 6 membered heterocyclic ring, said 5 or 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, and being optionally substituted by A;

R¹⁰and R¹¹Independently selected from hydrogen, C_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylaryl, -C_0-6Alkyl heterocyclic radical and-C_0-6Alkyl heteroaryl, wherein said C_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, C_0-6Alkyl radical C_3-6Cycloalkyl radical, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl or C_0-6Alkyl heterocyclyl is optionally substituted with a; or

R¹⁰And R¹¹May together form a 4 to 6 membered heterocyclic ring, said 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S and being optionally substituted by A;

n is 0, 1, 2 or 3;

a is selected from oxo, halogen, nitro, CN, -OR¹²、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylheterocyclyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -OC_2-6Alkyl radical NR¹²R¹³、-NR¹²R¹³、-CONR¹²R¹³、-NR¹²(CO)R¹³、-O(CO)C_1-6Alkyl, - (CO) OC_1-6Alkyl, -COR¹²、-(SO₂)NR¹²R¹³、-NSO₂R¹²、-SO₂R¹²、-SOR¹²、-(CO)C_1-6Alkyl radical NR¹²R¹³、-(SO₂)C_1-6Alkyl radical NR¹²R¹³、-OSO₂R¹²and-SO₃R¹²Wherein said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl, C_0-6Alkyl heterocyclic radical and C_0-6Alkyl radical C_3-6Cycloalkyl optionally substituted by halogen, -OSO₂R¹²、-SO₃R¹²Nitro, cyano, -OR¹²、C_1-6Alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy and trifluoromethoxy;

R¹²and R¹³Independently selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein said C is_1-6Alkyl radical, C_3-6The cycloalkyl, aryl, heteroaryl or heterocyclyl group is optionally substituted with one, two or three of the following groups: hydroxy, cyano, halogen or C_1-3An alkyloxy group; or

R¹²And R¹³May together form a 4-to 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O or S and optionally substituted by hydroxy, C _1-3Alkyloxy, cyano or halogen substitution;

with the proviso that R¹、R²Or R³Wherein any of the aryl or heteroaryl groups is substituted with-OSO₂R⁸、-SO₃R⁸、-OSO₂R¹²or-SO₃R¹²(ii) a Or

With the proviso that R¹、R²Or R³Any of the individual aryl or heteroaryl groups in (a) is fused with a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-4A, with the proviso that the bicyclic ring isIs not indane, benzo [1, 3 ]]Dioxoles or 2, 3-dihydrobenzo [1, 4 ]]-a dioxin ring system; or

With the proviso that R¹Is C_3-6Alkynyl or C_5-7Cycloalkenyl optionally substituted with one, two or three a; or

With the proviso that Q is selected from-NHSO₂-、-N(C_1-6Alkyl) SO₂-、-SO₂NH-、-SO₂N(C_1-6Alkyl) -or-SO₂N(C_3-6Cycloalkyl) -, -SO₂-or-N (C)_3-6Cycloalkyl) SO₂-; or

With the proviso that R³Is selected from-C_2-4Alkenyl radical R⁶、-C_2-4Alkynyl radical R⁶、-C_5-7Cycloalkenyl radicals R⁶Nitro or cyano; or

With the proviso that R²Selected from nitro, cyano, C_2-6Alkynyl, C_5-7Cycloalkenyl or C_2-6Alkenyl, wherein said C_2-6Alkynyl, C_5-7Cycloalkenyl or C_2-6Alkenyl is optionally substituted by one, two or three R⁷And (4) substitution.

The present invention also provides a composition comprising a compound of formula I and at least one pharmaceutically acceptable carrier, diluent or excipient.

The present invention also provides methods of modulating the activity of BACE comprising contacting BACE with a compound of formula I.

The present invention also provides a method of treating or preventing an a β -related pathology in a patient, comprising administering to said patient a therapeutically effective amount of a compound of formula I.

The invention also provides a compound as described herein for use as a medicament.

The invention also provides a compound as described herein for use in the preparation of a medicament.

One aspect of the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, in free base form, wherein

R¹Is selected from C_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, C_3-6Cycloalkyl radical, C_5-7Cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C_1-6Alkyl radical C_3-6Cycloalkyl, -C_1-6Alkylaryl, -C_1-6Alkyl heteroaryl or-C_1-6Alkyl heterocyclic group, wherein said C_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, C_3-6Cycloalkyl radical, C_5-7Cycloalkenyl, aryl, heteroaryl, heterocyclyl, C_1-6Alkyl radical C_3-6Cycloalkyl radical, C_1-6Alkylaryl group, C_1-6Alkyl heteroaryl or C_1-6The alkyl heterocyclyl is optionally substituted with one or two a;

R²selected from hydrogen, cyano, -Q-C_1-6Alkyl, -Q-C_2-6Alkenyl, -Q-C_2-6Alkynyl, -Q-C_3-6Cycloalkyl, -Q-C_5-7Cycloalkenyl radical, -Q-C_1-6Alkyl radical C_3-6Cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C_1-6Alkylaryl, -Q-C_1-6Alkylheteroaryl, -Q-heterocyclyl or-Q-C_1-6Alkylheterocyclyl, wherein said-Q-C _1-6Alkyl, -Q-C_2-6Alkenyl, -Q-C_2-6Alkynyl, -Q-C_3-6Cycloalkyl, -Q-C_5-7Cycloalkenyl radical, -Q-C_1-6Alkyl radical C_3-6Cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C_1-6Alkylaryl, -Q-C_1-6Alkylheteroaryl, -Q-heterocyclyl or-Q-C_1-6The alkyl heterocyclyl is optionally substituted with one, two or three R⁷Substitution;

-Q-is a direct bond, -CONH-, -CO-, -CON (C)_1-6Alkyl) -, -CON (C)_3-6Cycloalkyl) -, -NHCO-, -N (C)_1-6Alkyl) CO-or-N (C)_3-6Cycloalkyl) CO-;

R³is- (C (R)⁴)(R⁵))_nR⁶、-C_2-4Alkenyl radical R⁶、-C_2-4Alkynyl radical R⁶or-C_5-7Cycloalkenyl radicals R⁶And if n > 1, then each C (R)⁴)(R⁵) Independently of each other;

R⁴and R⁵Independently selected from hydrogen, C_1-6Alkyl, cyano or halogen; or R⁴And R⁵Together form oxo, C_3-6Cycloalkyl or heterocyclyl;

R⁶selected from methyl and C_3-6Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said methyl, C_3-6Cycloalkyl, heterocyclyl, aryl or heteroaryl each optionally substituted with 1-4R⁷And wherein any of the individual aryl or heteroaryl groups may be optionally fused with a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-3A, with the proviso that the bicyclic ring is not indane, benzo [1, 3 ] or heterocyclyl]Dioxoles or 2, 3-dihydrobenzo [1, 4 ]]-a dioxin ring system;

R⁷Selected from halogen, nitro, -C_0-6Alkyl CN, -OC_1-6Alkyl CN, -C_0-6Alkyl OR⁸、-OC_2-6Alkyl OR⁸Fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -C_0-6Alkyl radical NR⁸R⁹、-OC_2-6Alkyl radical NR⁸R⁹、-OC_2-6Alkyl OC_2-6Alkyl radical NR⁸R⁹、-NR⁸OR⁹、-C_0-6Alkyl group CO₂R⁸、-OC_1-6Alkyl group CO₂R⁸、-C_0-6Alkyl CONR⁸R⁹、-OC_1-6Alkyl CONR⁸R⁹、-OC_2-6Alkyl radical NR⁸(CO)R⁹、-C_0-6Alkyl radical NR⁸(CO)R⁹、-O(CO)NR⁸R⁹、-NR⁸(CO)OR⁹、-NR⁸(CO)NR⁸R⁹、-O(CO)R⁸、-C_0-6Alkyl group COR⁸、-OC_1-6Alkyl group COR⁸、-NR⁸(CO)(CO)R⁸、-NR⁸(CO)(CO)NR⁸R⁹、-C_0-6Alkyl SR⁸、-C_0-6Alkyl (SO)₂)NR⁸R⁹、-OC_1-6Alkyl radical NR⁸(SO₂)R⁹、-OC_0-6Alkyl (SO)₂)NR⁸R⁹、-C_0-6Alkyl (SO) NR⁸R⁹、-OC_1-6Alkyl (SO) NR⁸R⁹、-OSO₂R⁸、-SO₃R⁸、-C_0-6Alkyl radical NR⁸(SO₂)NR⁸R⁹、-C_0-6Alkyl radical NR⁸(SO)R⁹、-OC_2-6Alkyl radical NR⁸(SO)R⁸、-OC_1-6Alkyl SO₂R⁸、-C_1-6Alkyl SO₂R⁸、-C_0-6Alkyl SOR⁸、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6Alkylheterocyclic group and-OC_2-6Alkyl heterocyclic group, wherein any C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_0-6Alkyl radical C_3-6Cycloalkyl radical, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl, C_0-6Alkylheterocyclic group and OC_2-6The alkyl heterocyclic group may be optionally substituted with one or more R¹⁴And wherein any of the individual aryl or heteroaryl groups may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein said bicyclic ring system is optionally substituted with 1-3A, with the proviso that said bicyclic ring system is not indane, benzo [1, 3 ] or heterocyclyl]Dioxoles or 2, 3-dihydrobenzo [1, 4 ]]-a dioxin ring system;

R¹⁴Selected from halogen, nitro, -C_0-6Alkyl CN, -OC_1-6Alkyl CN, -C_0-6Alkyl OR⁸、-OC_1-6Alkyl OR⁸Fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -C_0-6Alkyl radical NR⁸R⁹、-OC_2-6Alkyl radical NR⁸R⁹、-OC_2-6Alkyl OC_2-6Alkyl radical NR⁸R⁹、-NR⁸OR⁹、-C_0-6Alkyl group CO₂R⁸、-OC_1-6Alkyl group CO₂R⁸、-C_0-6Alkyl CONR⁸R⁹、-OC_1-6Alkyl CONR⁸R⁹、-OC_2-6Alkyl radical NR⁸(CO)R⁹、-C_0-6Alkyl radical NR⁸(CO)R⁹、-O(CO)NR⁸R⁹、-NR⁸(CO)OR⁹、-NR⁸(CO)NR⁸R⁹、-OR⁸、-O(CO)R⁸、-C_0-6Alkyl group COR⁸、-OC_1-6Alkyl group COR⁸、-NR⁸(CO)(CO)R⁸、-NR⁸(CO)(CO)NR⁸R⁹、-C_0-6Alkyl SR⁸、-C_0-6Alkyl (SO)₂)NR⁸R⁹、-OC_2-6Alkyl radical NR⁸(SO₂)R⁹、-OC_0-6Alkyl (SO)₂)NR⁸R⁹、-C_0-6Alkyl (SO) NR⁸R⁹、-OC_1-6Alkyl (SO) NR⁸R⁹、-OSO₂R⁸、-OSO₂R⁸R⁹、-SO₃R⁸、-C_0-6Alkyl radical NR⁸(SO₂)NR⁸R⁹、-C_0-6Alkyl radical NR⁸(SO)R⁹、-OC_2-6Alkyl radical NR⁸(SO)R⁸、-OC_1-6Alkyl SO₂R⁸、-C_1-6Alkyl SO₂R⁸、-C_0-6Alkyl SOR⁸、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6Alkylheterocyclic group and-OC_2-6Alkyl heterocyclic group, wherein any C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_0-6Alkyl radical C_3-6Cycloalkyl radical, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl, C_0-6Alkylheterocyclic group and OC_2-6The alkyl heterocyclyl may be optionally substituted with 1-3A;

R⁸and R⁹Independently selected from hydrogen, C_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6alkylheterocyclyl-C_0-6Alkyl radical NR¹⁰R¹¹and-C_1-6Alkyl radical NR¹⁰R¹¹Wherein said C is_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, C_0-6Alkyl radical C_3-6Cycloalkyl radical, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl or C _0-6Alkyl heterocyclyl is optionally substituted with a; or

R⁸And R⁹May together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said 4 to 6 membered heterocyclic ring being optionally substituted by a; when two R are⁸When present in the structure, then they may together form a 5 or 6 membered heterocyclic ring, said 5 or 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, and being optionally substituted with A;

n is 0, 1 or 2;

a is selected from oxo, halogen, nitro, CN, -OR¹²、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylheterocyclyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -OC _2-6Alkyl radical NR¹²R¹³、-NR¹²R¹³、-CONR¹²R¹³、-NR¹²(CO)R¹³、-O(CO)C_1-6Alkyl, - (CO) OC_1-6Alkyl, -COR¹²、-(SO₂)NR¹²R¹³、-NSO₂R¹²、-SO₂R¹²、-SOR¹²、-(CO)C_1-6Alkyl radical NR¹²R¹³、-(SO₂)C_1-6Alkyl radical NR¹²R¹³、-OSO₂R¹²and-SO₃R¹²Wherein said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl, C_0-6Alkyl heterocyclic radical and C_0-6Alkyl radical C_3-6Cycloalkyl optionally substituted by halogen, -OSO₂R¹²、-SO₃R¹²Nitro, cyano, -OR¹²、C_1-6Alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy and trifluoromethoxy;

R¹²and R¹³Independently selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein said C is_1-6Alkyl radical, C_3-6The cycloalkyl, aryl, heteroaryl or heterocyclyl group is optionally substituted with one or two of the following groups: hydroxy, cyano, halogen or C_1-3An alkyloxy group; or

R¹²And R¹³May together form a 4-to 6-membered heterocyclic ring, said 4-to 6-membered heterocyclic ring containing one or moreA heteroatom selected from N, O or S and optionally substituted by hydroxy, cyano, C_1-3Alkyloxy or halogen.

Another aspect of the invention provides a compound of formula I, or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, in free base form, wherein

R¹Is selected from C_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, C_3-6Cycloalkyl radical, C_5-7Cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C_1-6Alkyl radical C_3-6Cycloalkyl, -C_1-6Alkylaryl, -C _1-6Alkyl heteroaryl or-C_1-6Alkyl heterocyclic group, wherein said C_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, C_3-6Cycloalkyl radical, C_5-7Cycloalkenyl, aryl, heteroaryl, heterocyclyl, C_1-6Alkyl radical C_3-6Cycloalkyl radical, C_1-6Alkylaryl group, C_1-6Alkyl heteroaryl or C_1-6The alkyl heterocyclyl is optionally substituted with one or two a;

R²selected from-Q-aryl and-Q-heteroaryl, wherein said-Q-aryl or-Q-heteroaryl is optionally substituted with one, two or three R⁷Substitution;

R³is- (C (R)⁴)(R⁵))_nR⁶；

R⁶Selected from aryl or heteroaryl, wherein said aryl or heteroaryl is each optionally substituted with 1-4R⁷And wherein any of the individual aryl or heteroaryl groups may be optionally fused with a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-3A, with the proviso that the bicyclic ring is not indane, benzo [1, 3 ] or heterocyclyl]Dioxoles or 2, 3-dihydrobenzo [1, 4 ]]-a dioxin ring system;

R⁷selected from halogen, nitro, -C_0-6Alkyl CN, -OC_1-6Alkyl CN, -C_0-6Alkyl OR⁸、-OC_2-6Alkyl OR⁸Fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -OSO ₂R⁸、-C_0-6Alkylaryl and-C_0-6Alkyl heteroaryl, wherein any C_0-6Alkylaryl or C_0-6The alkylheteroaryl group may be optionally substituted with one or more R¹⁴And wherein any of the individual aryl or heteroaryl groups may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein said bicyclic ring system is optionally substituted with 1-3A, with the proviso that said bicyclic ring system is not indane, benzo [1, 3 ] or heterocyclyl]Dioxoles or 2, 3-dihydrobenzo [1, 4 ]]-a dioxin ring system;

R¹⁴selected from halogen, nitro, -C_0-6Alkyl CN, -OC_1-6Alkyl CN, -C_0-6Alkyl OR⁸、-OC_1-6Alkyl OR⁸Fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -C_0-6Alkyl group CO₂R⁸、-C_0-6Alkyl radical NR⁸(CO)R⁹、-OR⁸、-O(CO)R⁸、-C_0-6Alkyl group COR⁸、-OSO₂R⁸and-OSO₂R⁸R⁹C_1-6An alkyl group;

R⁸and R⁹Independently selected from hydrogen, C_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6alkylheterocyclyl-C_0-6Alkyl radical NR¹⁰R¹¹and-C_1-6Alkyl radical NR¹⁰R¹¹Wherein said C is_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, C_0-6Alkyl radical C_3-6Cycloalkyl radical, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl or C_0-6Alkyl heterocyclyl is optionally substituted with a; or

R⁸And R⁹May together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said 4 to 6 membered heterocyclic ring being optionally substituted by a; when two R are ⁸When present in the structure, then they may together form a 5 or 6 membered heterocyclic ring, said 5 or 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, and being optionally substituted with A;

R¹⁰and R¹¹Independently selected from hydrogen or C_1-6An alkyl group; or

n is 0;

a is selected from oxo, halogen, nitro, CN, -OR¹²、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylheterocyclyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy and-COR¹²；

R¹²And R¹³Independently selected from hydrogen and C_1-6An alkyl group.

Another aspect of the invention provides compounds of formula I, wherein R¹Is C_1-6An alkyl group.

Another aspect of the invention provides compounds of formula I, wherein R²wherein-Q-represents a direct bond.

Another aspect of the invention provides compounds of formula I, wherein R²is-Q-aryl, said aryl being optionally substituted with R⁷。

Another aspect of the invention provides compounds of formula I, wherein R²is-Q-heteroaryl, said heteroaryl being optionally substituted with one, two or three R⁷And (4) substitution.

Another aspect of the invention provides compounds of formula I, wherein R⁷Is selected from-OSO₂R⁸and-C_0-6Alkylaryl radical, wherein said C_0-6The alkylaryl group may optionally be substituted with one or more R¹⁴And wherein any one of the aryl groups may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl, 5, 6 or 7 membered cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-3A.

Another aspect of the invention provides compounds of formula I, wherein R⁷Selected from halogen, nitro, -C_0-6Alkyl CN, -OC_2-6Alkyl OR⁸Trifluoromethyl, fluoromethoxy, trifluoromethoxy, -OSO₂R⁸、-C_0-6Alkylaryl and-C_0-6Alkyl heteroaryl, wherein any C_0-6Alkylaryl or C_0-6The alkylheteroaryl group may be optionally substituted with one or more R¹⁴And wherein any of the individual aryl or heteroaryl groups may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-3A. An embodiment of the present invention provides compounds of formula I, wherein C_0-6Alkylaryl represents phenyl.

Another aspect of the invention provides compounds of formula I, wherein R is¹⁴represents-C_0-6Alkyl OR⁸or-OSO₂R⁸。

Another aspect of the invention provides compounds of formula I, wherein R is ¹⁴Selected from halogen, nitro, -C_0-6Alkyl CN, -C_0-6Alkyl OR⁸Fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -C_0-6Alkyl group CO₂R⁸、-C_0-6Alkyl radical NR⁸(CO)R⁹、-OR⁸、-O(CO)R⁸、-C_0-6Alkyl group COR⁸、-OSO₂R⁸and-OSO₂R⁸R⁹C_1-6An alkyl group.

Another aspect of the invention provides compounds of formula I, wherein R is⁸Is represented by C_1-6Alkyl or trifluoromethyl.

Another aspect of the invention provides compounds of formula I, wherein R is⁸And R⁹Independently selected from hydrogen, C_1-6Alkyl, trifluoromethyl, -C_0-6Alkylaryl and-C_0-6Alkyl radical NR¹⁰R¹¹Wherein said C is_1-6Alkyl radical, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl or C_0-6Alkyl heterocyclyl is optionally substituted with a; or

R⁸And R⁹May together form a 4-to 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O or S.

Another aspect of the invention provides compounds of formula I, wherein n is 0.

Another aspect of the invention provides compounds of formula I, wherein A is selected from-OR¹²、-C_1-6Alkyl and-COR¹²(ii) a And R is¹²Is C_1-6An alkyl group.

Another aspect of the invention provides compounds of formula I, wherein R⁶Is aryl, wherein said aryl is optionally substituted with 1-4R⁷And wherein said aryl group may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl, 5, 6 or 7 membered cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein said bicyclic ring system is optionally substituted with 1-3A.

Another aspect of the invention provides compounds of formula I, wherein R⁷Is selected from-OSO₂R⁸and-C_0-6Alkylaryl, and wherein said C is_0-6The alkylaryl group may optionally be substituted with one or more R¹⁴And (4) substitution.

In another aspect of the invention there is providedI compound, wherein said R¹⁴represents-C_0-6Alkyl OR⁸or-OSO₂R⁸。

Another aspect of the invention provides compounds of formula I wherein the aryl group may be optionally fused to a 5 or 6 membered heterocyclyl to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-3 a.

Another aspect of the invention provides a compound of formula I, wherein A is-COR¹²And R is¹²Is C_1-6An alkyl group.

Another aspect of the invention provides compounds of formula I, wherein R⁶Selected from aryl or heteroaryl, wherein said aryl or heteroaryl is each optionally substituted with 1-4R⁷And wherein any of the individual aryl or heteroaryl groups may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-3A.

Another aspect of the invention provides compounds of formula I, wherein R⁷Selected from halogen, nitro, -C_0-6Alkyl CN, -OC_2-6Alkyl OR⁸Trifluoromethyl, fluoromethoxy, trifluoromethoxy, -OSO₂R⁸、-C_0-6Alkylaryl and-C_0-6Alkyl heteroaryl, wherein any C _0-6Alkylaryl or C_0-6The alkylheteroaryl group may be optionally substituted with one or more R¹⁴And wherein any of the individual aryl or heteroaryl groups may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-3A.

Another aspect of the invention provides compounds of formula I, wherein R¹⁴Selected from halogen, nitro, -C_0-6Alkyl CN, -C_0-6Alkyl OR⁸Fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -C_0-6Alkyl group CO₂R⁸、-C_0-6Alkyl radical NR⁸(CO)R⁹、-OR⁸、-C_0-6Alkyl group COR⁸、-OSO₂R⁸and-OSO₂R⁸R⁹C_1-6An alkyl group.

Another aspect of the invention provides compounds of formula I, wherein R⁸And R⁹Independently selected from hydrogen, C_1-6Alkyl, trifluoromethyl, -C_0-6Alkylaryl and-C_0-6Alkyl radical NR¹⁰R¹¹Wherein said C is_1-6Alkyl or C_0-6Alkylaryl optionally substituted with a; or

Another aspect of the invention provides compounds of formula I, wherein R¹⁰And R¹¹Independently selected from hydrogen or C_1-6An alkyl group; or

R¹⁰And R¹¹May together form a 4-to 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O or S.

Another aspect of the invention provides compounds of formula I, wherein A is selected from-OR ¹²、C_1-6Alkyl and-COR¹²。

Another aspect of the invention provides compounds of formula I, wherein R¹²Is C_1-6An alkyl group.

Another embodiment of the present invention provides a compound of formula I, as a free base, or a pharmaceutically acceptable salt, solvate, or solvate of a salt thereof, including the following:

2-amino-5- (3-bromophenyl) -3-methyl-5-phenyl-3, 5-dihydro-imidazol-4-one;

5- [3- (2-acetyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one;

5- [3- (2-acetyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride;

5- [3- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one;

5- [3- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride;

2-amino-5- [3- (2, 3-dihydro-1-benzofuran-6-yl) phenyl ] -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- [3- (2, 3-dihydro-1-benzofuran-6-yl) phenyl ] -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride;

4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate hydrochloride;

4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate;

4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate hydrochloride;

2-amino-5- (3' -hydroxybiphenyl-3-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one;

trifluoromethanesulfonic acid 3' - (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) biphenyl-3-yl ester hydrochloride;

2-amino-5- (2 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one;

3' - (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-2-carboxylate trifluoromethanesulfonate hydrochloride;

3- (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) phenyl methanesulfonate hydrochloride;

2-amino-5- (3-hydroxyphenyl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one;

3- (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) phenyl trifluoromethanesulfonate hydrochloride;

2-amino-5- (3-bromo-4-hydroxyphenyl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (6-hydroxy-3' -methoxybiphenyl-3-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one;

trifluoromethanesulfonic acid 5- (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) -3' -methoxybiphenyl-2-ester;

3- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate hydrochloride;

3- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate hydrochloride;

2-amino-5- [3- (2, 3-dihydro-1-benzofuran-5-yl) phenyl ] -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- [3- (2, 3-dihydro-1-benzofuran-5-yl) phenyl ] -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride;

2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride;

(R) -4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate hydrochloride;

(S) -4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate hydrochloride;

2-amino-3-methyl-5- [3- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) phenyl ] -5-phenyl-3, 5-dihydro-4H-imidazol-4-one;

2-amino-3-methyl-5- [3- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) phenyl ] -5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride;

5- [3- (2-acetyl-1, 2, 3, 4-tetrahydroisoquinolin-5-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one;

5- [3- (2-acetyl-1, 2, 3, 4-tetrahydroisoquinolin-5-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride;

(R) -4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate hydrochloride;

(S) -4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate hydrochloride;

2-amino-3-methyl-5- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) -5-phenyl-3, 5-dihydro-4H-imidazol-4-one acetate;

2-amino-3-methyl-5-phenyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3, 5-dihydro-4H-imidazol-4-one hydrochloride;

5- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride;

5- [3- (1-acetyl-2, 3-dihydro-1H-indol-4-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride;

2-amino-5- [3- (3, 4-dihydro-2H-chromen-8-yl) phenyl ] -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one acetate;

methanesulfonic acid 3' - (2-amino-1-methyl-5-oxo-4-pyridin-4-yl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-3-yl ester;

methanesulfonic acid 3' - (2-amino-1-methyl-5-oxo-4-pyridin-2-yl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-3-yl ester;

methanesulfonic acid 3' - [ 2-amino-1-methyl-5-oxo-4- (1, 3-thiazol-5-yl) -4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester;

methanesulfonic acid 3' - [ 2-amino-1-methyl-5-oxo-4- (1, 3-thiazol-4-yl) -4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester;

4- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

Methanesulfonic acid 4- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester 0.25 acetate;

2-methoxyethanesulfonic acid 4- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

4- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

methanesulfonic acid 4- [ 2-amino-4- (5 '-chloro-2' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester 0.25 acetate;

4- [ 2-amino-4- (5 '-fluoro-2' -methylbiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

3' - (2-amino-1-methyl-4- {4- [ (methylsulfonyl) oxy ] phenyl } -5-oxo-4, 5-dihydro-1H-imidazol-4-yl) biphenyl-3-carboxylic acid methyl ester;

4- { 2-amino-4- [3- (1, 3-benzodioxol-5-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

methanesulfonic acid 4- { 2-amino-4- [3- (1H-indol-5-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester 0.25 acetate;

4- [ 2-amino-4- (3' -cyanobiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

4- { 2-amino-1-methyl-5-oxo-4- [ 3' - (trifluoromethoxy) biphenyl-3-yl ] -4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

4- { 2-amino-4- [3- (2-formyl-3-thienyl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

4- { 2-amino-4- [3- (5-formyl-2-thienyl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

4- { 2-amino-4- [3- (2-chloropyridin-4-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

4- {4- [ 3' - (acetylamino) biphenyl-3-yl ] -2-amino-1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate 0.25 acetate;

4- [ 2-amino-1-methyl-4- (3' -nitrobiphenyl-3-yl) -5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

4- [ 2-amino-4- (3' -cyanobiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

4- [ 2-amino-4- (2 ', 5' -dimethoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

4- [ 2-amino-4- (3' -ethoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

4- [ 2-amino-4- (2 '-fluoro-3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

4- [ 2-amino-4- (2 '-fluoro-5' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

4- [ 2-amino-4- (2 ', 6 ' -difluoro-3 ' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

4- [ 2-amino-4- (3 '-cyano-4' -fluorobiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

4- [ 2-amino-4- (5 '-cyano-2' -fluorobiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

4- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

4- { 2-amino-4- [3- (2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-1-sulfonate;

4- { 2-amino-4- [3- (5-chloro-2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-1-sulfonate;

4- { 2-amino-4- [3- (6-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-1-sulfonate;

4- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-5-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

4- { 2-amino-4- [3- (2-fluoropyridin-4-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-1-sulfonate;

4- { 2-amino-4- [3- (2-chloro-3-fluoropyridin-4-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-1-sulfonate;

4- { 2-amino-4- [3- (2-chloro-5-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-1-sulfonate;

4- { 2-amino-4- [3- (2, 6-difluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-1-sulfonate;

2-methoxyethanesulfonic acid 4- [ 2-amino-1-methyl-4- (3' -nitrobiphenyl-3-yl) -5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

2-methoxyethanesulfonic acid 4- [ 2-amino-4- (3' -cyanobiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

2-methoxyethanesulfonic acid 4- [ 2-amino-4- (2 ', 5' -dimethoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

2-methoxyethanesulfonic acid 4- [ 2-amino-4- (3' -ethoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

2-methoxyethanesulfonic acid 4- [ 2-amino-4- (2 '-fluoro-3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

2-methoxyethanesulfonic acid 4- [ 2-amino-4- (2 '-fluoro-5' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

2-methoxyethanesulfonic acid 4- [ 2-amino-4- (2 ', 6 ' -difluoro-3 ' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

2-methoxyethanesulfonic acid 4- [ 2-amino-4- (3 '-cyano-4' -fluorobiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

2-methoxyethanesulfonic acid 4- [ 2-amino-4- (5 '-cyano-2' -fluorobiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

2-methoxyethanesulfonic acid 4- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

4- { 2-amino-4- [3- (2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl 2-methoxyethanesulfonate;

2-methoxyethanesulfonic acid 4- { 2-amino-4- [3- (5-chloro-2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester;

4- { 2-amino-4- [3- (6-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl 2-methoxyethanesulfonate;

2-methoxyethanesulfonic acid 4- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-5-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

2-methoxyethanesulfonic acid 4- { 2-amino-4- [3- (2-chloro-3-fluoropyridin-4-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester;

2-methoxyethanesulfonic acid 4- { 2-amino-4- [3- (2-chloro-5-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester;

4- { 2-amino-4- [3- (2, 6-difluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl 2-methoxyethanesulfonate;

5- (4-hydroxyphenyl) -3-methyl-5- (3-phenoxyphenyl) -2-thioimidazolidin-4-one;

propane-1-sulfonic acid 4- (2-amino-4- {3 '-methoxy-5' - [ (methylsulfonyl) oxy ] biphenyl-3-yl } -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl) phenyl ester;

4- { 2-amino-4- [3- (5-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-1-sulfonate;

4- [ 2-amino-4- (4 '-fluoro-3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

4- { 2-amino-4- [3- (5-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl 2-methoxyethanesulfonate;

2-methoxyethanesulfonic acid 4- [ 2-amino-4- (4 '-fluoro-3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

2-Methoxyethanesulfonic acid 4- [ 2-amino-1-methyl-5-oxo-4- (3-pyrazin-2-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester 0.25 acetate;

propane-1-sulfonic acid 4- [ 2-amino-1-methyl-5-oxo-4- (3-pyrazin-2-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester 0.25 acetate;

(R) -4- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

(S) -4- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

methanesulfonic acid 3' - (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-3-yl ester hydrochloride;

3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

2-methoxyethanesulfonic acid 3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl propane-1-sulfonate;

3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl propane-2-sulfonate;

3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-2-sulfonate;

3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl cyclopropanesulfonate;

3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl cyclopropanesulfonate;

3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioxoimidazolidin-4-yl ] phenyl dimethylaminosulfonate;

3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl dimethylaminosulfonate;

morpholine-4-sulfonic acid 3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester;

morpholine-4-sulfonic acid 3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioxoimidazolidin-4-yl ] phenyl ethanesulfonate;

3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ethanesulfonate;

2-amino-5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

3- { 2-amino-4- [3- (5-methoxypyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ethanesulfonate 0.75 acetate;

4- { 2-amino-4- [3- (5-methoxypyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate acetate;

2-amino-5- [3- (2-fluoropyridin-3-yl) phenyl ] -5- (3-hydroxyphenyl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (3-hydroxyphenyl) -3-methyl-5- (3-pyrimidin-5-ylphenyl) -3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (3-hydroxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (3-hydroxyphenyl) -5- [3- (5-methoxypyridin-3-yl) phenyl ] -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

3- { 2-amino-4- [3- (2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl trifluoromethanesulfonate hydrochloride;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-5-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate hydrochloride;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate hydrochloride;

3- { 2-amino-4- [3- (5-methoxypyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl trifluoromethanesulfonate hydrochloride;

methanesulfonic acid (R) -3' - (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-3-yl ester hydrochloride;

(S) -3' - (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-3-yl methanesulfonate hydrochloride;

4- [ 2-amino-4- (3 ', 5' -dichlorobiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate hydrochloride;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

3- { 2-amino-4- [3- (6-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

3- { 2-amino-4- [3- (2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

3- { 2-amino-4- [3- (5-chloro-2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-5-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

3- { 2-amino-4- [3- (6-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-1-sulfonate;

3- { 2-amino-4- [3- (2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-1-sulfonate;

3- { 2-amino-4- [3- (5-chloro-2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-1-sulfonate;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-5-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-2-sulfonate;

3- { 2-amino-4- [3- (6-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-2-sulfonate;

3- { 2-amino-4- [3- (2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-2-sulfonate;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-5-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-2-sulfonate;

2-methoxyethanesulfonic acid 3- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

2-methoxyethanesulfonic acid 3- { 2-amino-4- [3- (6-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester;

2-methoxyethanesulfonic acid 3- { 2-amino-4- [3- (2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester;

2-methoxyethanesulfonic acid 3- { 2-amino-4- [3- (5-chloro-2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester acetate;

2-methoxyethanesulfonic acid 3- { 2-amino-4- [3- (5-chloro-2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl dimethylaminosulfonate;

3- { 2-amino-4- [3- (6-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl dimethylaminosulfonate;

3- { 2-amino-4- [3- (5-chloro-2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl dimethylaminosulfonate;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-5-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl dimethylaminosulfonate;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl cyclopropanesulfonate;

3- { 2-amino-4- [3- (6-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl cyclopropanesulfonate;

3- { 2-amino-4- [3- (2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl cyclopropanesulfonate;

3- { 2-amino-4- [3- (5-chloro-2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl cyclopropanesulfonate;

2-methoxyethanesulfonic acid 3- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-5-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester acetate;

morpholine-4-sulfonic acid 3- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

morpholine-4-sulfonic acid 3- { 2-amino-4- [3- (6-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester;

morpholine-4-sulfonic acid 3- { 2-amino-4- [3- (2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester;

morpholine-4-sulfonic acid 3- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-5-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

3- { 2-amino-4- [3- (5-methoxypyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-2-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

3- { 2-amino-4- [3- (5-methoxypyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-1-sulfonate;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-2-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate;

3- { 2-amino-4- [3- (5-methoxypyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-2-sulfonate;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-2-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-2-sulfonate;

2-methoxyethanesulfonic acid 3- { 2-amino-4- [3- (5-methoxypyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester;

3- { 2-amino-4- [3- (5-methoxypyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl dimethylaminosulfonate;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-2-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl dimethylaminosulfonate;

3- { 2-amino-4- [3- (5-methoxypyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl cyclopropanesulfonate;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-2-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl cyclopropanesulfonate;

3-methoxypropan-1-sulfonic acid 3- [ 2-amino-4- (4-methoxyphenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride;

3- [ 2-amino-4- (4-methoxyphenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate hydrochloride;

2-ethoxyethanesulfonic acid 3- [ 2-amino-4- (4-methoxyphenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride;

2-methoxyethanesulfonic acid 3- [ 2-amino-4- (4-methoxyphenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride;

4- [ 2-amino-1-methyl-5-oxo-4- (3-phenoxyphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate hydrochloride;

propane-1-sulfonic acid 4- [ 2-amino-1-methyl-5-oxo-4- (3-phenoxyphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride;

4- { 2-amino-4- [3- (3-methoxyphenoxy) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate hydrochloride;

3- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-2-sulfonate hydrochloride;

2-amino-5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one;

trifluoromethanesulfonic acid 3' - (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-3-yl ester hydrochloride;

4- { 2-amino-4- [3- (5-methoxypyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl propane-1-sulfonate hydrochloride;

2-amino-5- (3-bromophenyl) -5- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

5- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -2-amino-5- (3-bromophenyl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (3-bromophenyl) -3-methyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) imidazolidin-4-one;

2-amino-5- (3-bromophenyl) -5- (2, 3-dihydro-1H-inden-5-yl) -3-methylimidazolidin-4-one;

2-amino-5- (3' -methoxybiphenyl-3-yl) -5- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- (2 '-fluoro-5' -methoxybiphenyl-3-yl) -5- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

5- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -2-amino-5- (3' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

5- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -2-amino-5- (2 ', 5' -dimethoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

3' - [4- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -2-amino-1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] biphenyl-3-carbonitrile;

3' - [4- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -2-amino-1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -4-fluorobiphenyl-3-carbonitrile;

5- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -2-amino-5- (2 '-fluoro-5' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

5- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -2-amino-3-methyl-5- (3' -nitrobiphenyl-3-yl) -3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

5- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -2-amino-5- (2 '-fluoro-3' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

5- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -2-amino-5- [3- (3-furyl) phenyl ] -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (3' -methoxybiphenyl-3-yl) -3-methyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3, 5-dihydro-4H-imidazol-4-one;

3' - [ 2-amino-1-methyl-5-oxo-4- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -4, 5-dihydro-1H-imidazol-4-yl ] -6-fluorobiphenyl-3-carbonitrile;

2-amino-5- (2 ', 5' -dimethoxybiphenyl-3-yl) -3-methyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- [3- (1, 3-benzodioxol-5-yl) phenyl ] -3-methyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- (3' -ethoxybiphenyl-3-yl) -3-methyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3, 5-dihydro-4H-imidazol-4-one;

3' - [ 2-amino-1-methyl-5-oxo-4- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -4, 5-dihydro-1H-imidazol-4-yl ] biphenyl-3-carbonitrile;

3' - [ 2-amino-1-methyl-5-oxo-4- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -4, 5-dihydro-1H-imidazol-4-yl ] -4-fluorobiphenyl-3-carbonitrile;

2-amino-5- (2 '-fluoro-5' -methoxybiphenyl-3-yl) -3-methyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3, 5-dihydro-4H-imidazol-4-one;

2-amino-3-methyl-5- (3' -nitrobiphenyl-3-yl) -5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (2 '-fluoro-3' -methoxybiphenyl-3-yl) -3-methyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- [3- (3-furyl) phenyl ] -3-methyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (2, 3-dihydro-1H-inden-5-yl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

methanesulfonic acid 3' - [ 2-amino-4- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester;

Methanesulfonic acid 3' - [4- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -2-amino-1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester;

methanesulfonic acid 3' - [ 2-amino-1-methyl-5-oxo-4- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester;

methanesulfonic acid 3' - [ 2-amino-4- (2, 3-dihydro-1H-inden-5-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester;

2-amino-5- (3-bromophenyl) -5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (3-bromophenyl) -5- (3, 4-dihydro-2H-chromen-6-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride;

5- [3- (2-acetyl-2, 3-dihydro-1H-isoindol-4-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one acetate;

2-amino-5- (3-bromophenyl) -5- (3, 4-dihydro-1H-isochromen-7-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -5- (3' -ethoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -5- (2 ', 5' -dimethoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- [3- (1, 3-benzodioxol-5-yl) phenyl ] -5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -5- (2 '-fluoro-5' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -5- (2 '-fluoro-3' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

3' - [ 2-amino-4- (2, 3-dihydro-1-benzofuran-5-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -6-fluorobiphenyl-3-carbonitrile 0.25 acetate;

2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-5- (3' -nitrobiphenyl-3-yl) -3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -5- [3- (3-furyl) phenyl ] -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- [3- (1-benzofuran-2-yl) phenyl ] -5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-5- [ 3' - (trifluoromethoxy) biphenyl-3-yl ] -3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- (3' -chlorobiphenyl-3-yl) -5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- (3, 4-dihydro-2H-chromen-6-yl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- (3, 4-dihydro-2H-chromen-6-yl) -5- (3' -ethoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (3, 4-dihydro-2H-chromen-6-yl) -5- (2 ', 5' -dimethoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- [3- (1, 3-benzodioxol-5-yl) phenyl ] -5- (3, 4-dihydro-2H-chromen-6-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- (3, 4-dihydro-2H-chromen-6-yl) -5- (2 '-fluoro-5' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (3, 4-dihydro-2H-chromen-6-yl) -5- (2 '-fluoro-3' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

3' - [ 2-amino-4- (3, 4-dihydro-2H-chromen-6-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -4-fluorobiphenyl-3-carbonitrile;

3' - [ 2-amino-4- (3, 4-dihydro-2H-chromen-6-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -6-fluorobiphenyl-3-carbonitrile 0.25 acetate;

2-amino-5- (3, 4-dihydro-2H-chromen-6-yl) -3-methyl-5- (3' -nitrobiphenyl-3-yl) -3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- (3, 4-dihydro-2H-chromen-6-yl) -5- [3- (3-furyl) phenyl ] -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- [3- (1-benzofuran-2-yl) phenyl ] -5- (3, 4-dihydro-2H-chromen-6-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (3, 4-dihydro-2H-chromen-6-yl) -3-methyl-5- [ 3' - (trifluoromethoxy) biphenyl-3-yl ] -3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

2-amino-5- (3' -chlorobiphenyl-3-yl) -5- (3, 4-dihydro-2H-chromen-6-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

2-amino-5- (3, 4-dihydro-1H-isochromen-7-yl) -5- (2 '-fluoro-5' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

3' - [ 2-amino-4- (3, 4-dihydro-1H-isochromen-7-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -6-fluorobiphenyl-3-carbonitrile 0.25 acetate;

2-amino-5- (3, 4-dihydro-1H-isochromen-7-yl) -5- [3- (3-furyl) phenyl ] -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate;

methanesulfonic acid 3' - [ 2-amino-4- (2, 3-dihydro-1-benzofuran-5-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester 0.25 acetate;

methanesulfonic acid 3' - [ 2-amino-4- (3, 4-dihydro-2H-chromen-6-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester 0.25 acetate;

methanesulfonic acid 3' - [ 2-amino-4- (3, 4-dihydro-1H-isochromen-7-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester;

4- [ 2-amino-4- (3-bromo-4-fluorophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

4- [ 2-amino-4- (3' -cyano-6-fluorobiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

4- [ 2-amino-4- (3' -cyano-6-fluorobiphenyl-3-yl) -5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

4- [ 2-amino-4- (2 ', 6-difluoro-3' -methoxybiphenyl-3-yl) -5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

4- [ 2-amino-4- (2 ', 6-difluoro-5' -methoxybiphenyl-3-yl) -5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

4- [ 2-amino-4- (3 '-cyano-4', 6-difluorobiphenyl-3-yl) -5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

4- [ 2-amino-4- (5 '-cyano-2', 6-difluorobiphenyl-3-yl) -5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

4- [ 2-amino-4- (4-fluoro-3-pyridin-3-ylphenyl) -5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

4- { 2-amino-4- [ 4-fluoro-3- (2-fluoropyridin-3-yl) phenyl ] -5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

4- { 2-amino-4- [3- (5-chloro-2-fluoropyridin-3-yl) -4-fluorophenyl ] -5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

4- { 2-amino-4- [ 4-fluoro-3- (6-fluoropyridin-3-yl) phenyl ] -5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

4- { 2-amino-4- [ 4-fluoro-3- (2-fluoropyridin-4-yl) phenyl ] -5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

4- { 2-amino-4- [3- (2-chloro-3-fluoropyridin-4-yl) -4-fluorophenyl ] -5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

4- { 2-amino-4- [3- (2-chloro-5-fluoropyridin-3-yl) -4-fluorophenyl ] -5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

4- { 2-amino-4- [3- (2, 6-difluoropyridin-3-yl) -4-fluorophenyl ] -5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

4- { 2-amino-4- [ 6-fluoro-3' - (trifluoromethoxy) biphenyl-3-yl ] -5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

4- [ 2-amino-4- (3' -chloro-6-fluorobiphenyl-3-yl) -5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

4- { 2-amino-4- [3- (1, 3-benzodioxol-5-yl) -4-fluorophenyl ] -5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

4- [ 2-amino-4- (4-fluoro-3-pyridin-4-ylphenyl) -5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

4- [ 2-amino-4- (4-fluoro-3-pyrimidin-5-ylphenyl) -5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

4- { 2-amino-4- [3- (2-chloro-5-methoxypyridin-3-yl) -4-fluorophenyl ] -5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

methanesulfonic acid 4- (2-amino-4- { 6-fluoro-3 '-methoxy-5' - [ (methylsulfonyl) oxy ] biphenyl-3-yl } -5-oxo-4, 5-dihydro-1H-imidazol-4-yl) phenyl ester;

4- { 2-amino-4- [ 4-fluoro-3- (5-fluoropyridin-3-yl) phenyl ] -5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate;

4- [ 2-amino-4- (4-fluoro-3-pyrazin-2-ylphenyl) -5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate;

2-amino-5- (4-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one;

4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate hydrochloride;

4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-2-sulfonate hydrochloride;

4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl dimethylaminosulfonate hydrochloride;

morpholine-4-sulfonic acid 4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester; and

2-Methoxyethanesulfonic acid 4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride.

Some of the compounds of formula I may have stereogenic and/or geometric isomeric centres (E and Z isomers), and it is to be understood that the present invention includes all such optical, enantiomeric, diastereomeric, atropisomers and geometric isomers.

The present invention relates to the use of compounds of formula I as defined above and salts thereof. Salts for use in pharmaceutical compositions may be pharmaceutically acceptable salts, but other salts may be useful in the preparation of compounds of formula I.

It is to be understood that the present invention relates to any and all tautomeric forms of the compounds of formula I.

The compounds of the invention are useful as medicaments. In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, for use as a medicament. In some embodiments, the present invention provides a compound described herein for use as a medicament for treating or preventing an a β -related pathology. In other embodiments, the a β -related pathology is downs syndrome, a β -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), alzheimer disease, memory loss, attention deficit symptoms associated with alzheimer disease, neurodegeneration associated with alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

In another embodiment, the compounds of the invention are represented by formula (I) or a pharmaceutically acceptable salt thereof as described herein, for use as a medicament.

In another embodiment, the compounds of the invention are represented by formula (I) or a pharmaceutically acceptable salt thereof as described herein for the preparation of a medicament for the treatment or prevention of a β -related pathologies such as down's syndrome and β -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with diseases such as alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear or cortical basal degeneration, Parkinson's disease, Frontotemporal dementia of Parkinson's Type (Frontotemporal dementia Parkinson's Type), Parkinson's dementia complex of Guam, HIV dementia, diseases associated with neurofibrillary tangle pathologies, dementia pugilistica, amyotrophic lateral sclerosis, cortical matrix degeneration, Down's syndrome, Huntington's chorea, post-encephalitic parkinsonism, progressive supranuclear palsy, Pick's Disease, Niemann-Pick's Disease, stroke, head trauma and other chronic neurodegenerative diseases, bipolar disorders, affective disorders, depression, anxiety, schizophrenia, cognitive disorders, hair loss, contraceptive therapy, pre-dementia states, age-related memory impairment, age-related cognitive decline, non-dementia type cognitive impairment, mild cognitive decline, mild neurocognitive decline, late-life amnesia, memory impairment and cognitive impairment, post-life amnesia, post-stroke amnesia, post-prandial dementia, vascular dementia, Lewy body dementia (dementias with Lewy bodies), frontotemporal dementia and androgenic alopecia.

In another embodiment, the compounds of the present invention are represented by methods of treating a β -related pathologies such as down's syndrome and β -amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as, but not limited to, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with diseases such as alzheimer's disease or dementia including mixed vascular and degenerative origins, pre-senile dementia, senile dementia and dementia associated with parkinson's disease, progressive supranuclear or cortical basal degeneration, parkinson's disease, frontotemporal dementia of parkinson's type, parkinsonian dementia syndrome, HIV dementia, diseases associated with neurofibrillary tangle pathology, Dementia pugilistica, amyotrophic lateral sclerosis, cortical basal degeneration, down syndrome, huntington's chorea, postencephalitic parkinsonism, progressive supranuclear palsy, pick's disease, niemann-pick disease, stroke, head trauma and other chronic neurodegenerative disorders, bipolar disorders, affective disorders, depression, anxiety, schizophrenia, cognitive disorders, hair loss, contraceptive therapy, pre-dementia states, age-related memory impairment, age-related cognitive decline, non-dementia-type cognitive impairment, mild cognitive decline, mild neurocognitive decline, late-life forgetfulness, memory and cognitive impairment, vascular dementia, lewy body dementia, frontotemporal dementia and androgenic alopecia, comprising administering to a human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein.

In another embodiment, the compounds of the invention are represented by methods of preventing a β -related pathologies such as down's syndrome and β -amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as, but not limited to, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with diseases such as alzheimer's disease or dementia including mixed vascular and degenerative origins, pre-senile dementia, senile dementia and dementia associated with parkinson's disease, progressive supranuclear or cortical basal degeneration, parkinson's disease, frontotemporal dementia of parkinson's type, parkinsonian dementia syndrome, HIV dementia, diseases associated with neurofibrillary tangle pathology, Dementia pugilistica, amyotrophic lateral sclerosis, cortical basal degeneration, down syndrome, huntington's chorea, postencephalitic parkinsonism, progressive supranuclear palsy, pick's disease, niemann-pick disease, stroke, head trauma and other chronic neurodegenerative disorders, bipolar disorders, affective disorders, depression, anxiety, schizophrenia, cognitive disorders, hair loss, contraceptive therapy, pre-dementia states, age-related memory impairment, age-related cognitive decline, non-dementia-type cognitive impairment, mild cognitive decline, mild neurocognitive decline, late-life forgetfulness, memory and cognitive impairment, vascular dementia, lewy body dementia, frontotemporal dementia and androgenic alopecia, comprising administering to a human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein.

In another embodiment, the compounds of the present invention are represented by methods of treating a β -related pathologies such as down's syndrome and β -amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as, but not limited to, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with diseases such as alzheimer's disease or dementia including mixed vascular and degenerative origins, pre-senile dementia, senile dementia and dementia associated with parkinson's disease, progressive supranuclear or cortical basal degeneration, parkinson's disease, frontotemporal dementia of parkinson's type, parkinsonian dementia syndrome, HIV dementia, diseases associated with neurofibrillary tangle pathology, Dementia pugilistica, amyotrophic lateral sclerosis, cortical basal degeneration, Down syndrome, Huntington chorea, postencephalitic parkinsonism, progressive supranuclear palsy, pick's disease, niemann-pick disease, stroke, head trauma and other chronic neurodegenerative disorders, bipolar disorders, affective disorders, depression, anxiety disorders, schizophrenia, cognitive disorders, hair loss, contraceptive therapy, pre-dementia states, age-related memory impairment, age-related cognitive decline, non-dementia-type cognitive impairment, mild cognitive decline, mild neurocognitive decline, late-life forgetfulness, memory and cognitive impairment, vascular dementia, Lewy body dementia, frontotemporal dementia and androgenic alopecia, the method comprises administering to a human a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof and a cognitive and/or memory enhancing drug.

In another embodiment, the compounds of the present invention are represented by methods of treating a β -related pathologies such as down's syndrome and β -amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as, but not limited to, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with diseases such as alzheimer's disease or dementia including mixed vascular and degenerative origins, pre-senile dementia, senile dementia and dementia associated with parkinson's disease, progressive supranuclear or cortical basal degeneration, parkinson's disease, frontotemporal dementia of parkinson's type, parkinsonian dementia syndrome, HIV dementia, diseases associated with neurofibrillary tangle pathology, Dementia pugilistica, amyotrophic lateral sclerosis, cortical basal degeneration, Down syndrome, Huntington chorea, postencephalitic parkinsonism, progressive supranuclear palsy, pick's disease, niemann-pick disease, stroke, head trauma and other chronic neurodegenerative disorders, bipolar disorders, affective disorders, depression, anxiety disorders, schizophrenia, cognitive disorders, hair loss, contraceptive therapy, pre-dementia states, age-related memory impairment, age-related cognitive decline, non-dementia-type cognitive impairment, mild cognitive decline, mild neurocognitive decline, late-life forgetfulness, memory and cognitive impairment, vascular dementia, Lewy body dementia, frontotemporal dementia and androgenic alopecia, the method comprises administering to a human a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof and a cholinesterase inhibitor or an anti-inflammatory agent.

In another embodiment, the invention provides methods of treating or preventing A β -related pathologies, such as Down's syndrome and beta-amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as, but not limited to, MCI ("Mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementias including dementias of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear or cortical basal degeneration or any other disease, disorder or condition described herein, the methods comprise administering to a mammal (including a human) a compound of the present invention and an atypical antipsychotic. Atypical antipsychotics include, but are not limited to, Olanzapine (Olanzapine) (commercially available as Zyprexa), Aripiprazole (Aripiprazole) (commercially available as Abilify), Risperidone (Risperidone) (commercially available as Risperdal), Quetiapine (Quetiapine) (commercially available as seroque), Clozapine (Clozapine) (commercially available as Clozaril), Ziprasidone (Ziprasidone) (commercially available as Geodon), and Olanzapine/Fluoxetine (Olanzapine/Fluoxetine) (commercially available as symbax).

In another embodiment, the invention relates to a mammal or human being treated with a compound of the invention that has been diagnosed with a particular disease or disorder, such as those described herein. In these cases, the mammal or human being treated is in need of such treatment. However, the diagnosis need not be done previously.

The anti-dementia treatment as defined herein may be applied as a sole therapy or may involve conventional chemotherapy in addition to the compounds of the present invention. Such chemotherapy may include one or more of the following classes of drugs: acetylcholinesterase inhibitors, anti-inflammatory drugs, cognition and/or memory enhancing drugs or atypical antipsychotics.

Such combination therapy may be carried out by the simultaneous, sequential or separate administration of the individual therapeutic ingredients. These combinations use the compounds of the present invention.

Cognition enhancing drugs, memory enhancing drugs, and cholinesterase inhibitors include, but are not limited to, donepezil (Aricept), galantamine (remininyl or Razadyne), rivastigmine (rivastigmine), tacrine (Cognex), and memantine (memantine) (Namenda, Axura, or Ebixa).

Schizophrenia and other psychotic disorders include, but are not limited to: 1) psychotic Disorder, schizophreniform Disorder, schizoaffective Disorder, delusional Disorder, brief Psychotic Disorder, shared Psychotic Disorder, and Psychotic Disorder in general (Psychotic Disorder Dual to a general medical Condition); 2) dementia and other cognitive disorders; 3) anxiety disorders including, but not limited to, phobic disorders without agoraphobia, phobic disorders with agoraphobia, history of agoraphobia without phobic disorder, specific phobias, social phobias, obsessive-compulsive disorders, stress-related disorders, post-traumatic stress disorders, acute stress disorders, generalized anxiety disorders, and generalized anxiety disorders caused by general illnesses; 4) affective disorders including, but not limited to, a) depression (including, but not limited to, major and dysthymic Disorder), b) Bipolar depression and/or Bipolar mania (including, but not limited to, Bipolar I with manic, depressive, or mixed episodes) and Bipolar II), c) cyclothymic Disorder (cyclothymic's Disorder) and d) affective Disorder due to general condition; 5) sleep disorders; 6) disorders usually first diagnosed in infancy, childhood, or adolescence, including, but not limited to, mental retardation, down's syndrome, learning disorders, motor skills disorders, communication disorders, comprehensive mental development disorders, attention deficit disorders, and disruptive behavior disorders, feeding and eating disorders in infancy or early childhood, tic disorders, and excretory disorders; 7) drug-related disorders including, but not limited to, drug dependence, drug abuse, drug intoxication, withdrawal response, alcohol-related disorders, amphetamine (or amphetamine-like) related disorders, caffeine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen-related disorders, inhalant-related disorders, nicotine-related disorders, opiate-related disorders, phencyclidine (or phencyclidine-like) related disorders and sedative, hypnotic or anxiolytic related disorders; 8) attention deficit disorder and disruptive behavior disorder; 9) eating disorders; 10) personality disorders including, but not limited to, obsessive-compulsive personality disorder; 11) impulse control disorders.

Neurodegenerative diseases include, but are not limited to, alzheimer's Disease, mild cognitive impairment, dementia, age-related memory impairment, age-related cognitive decline, disorders associated with neurofibrillary tangles, dementia caused by alzheimer's Disease, dementia caused by schizophrenia, dementia caused by parkinson's Disease, dementia caused by Creutzfeld-Jacob Disease, dementia caused by huntington's chorea, dementia caused by pick's Disease, stroke, head trauma, spinal injury, multiple sclerosis, migraine, pain, general pain, localized pain, nociceptive pain, neuropathic pain, urinary incontinence, sexual dysfunction, premature ejaculation, movement disorders, endocrine disorders, gastrointestinal disorders, and vasospasm.

A number of the above conditions and disorders are described, for example, in the American Psychiatric Association: the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, TextRevision, Washington, DC, American Psychiatric Association, 2000.

The invention also includes pharmaceutical compositions comprising, as an active ingredient, one or more compounds of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient.

The definitions set forth herein are intended to clarify the terminology used throughout this application. The term "present application" refers to the entire application.

The term "optionally substituted" as used herein means that the substitution is optional and thus may be unsubstituted with respect to the designated atom or group. Where substitution is desired, such substitution means that any number of hydrogens on the designated atom or group is replaced with a selection from the designated group, provided that the designated atom or group's normal valency is not exceeded, and that the result of the substitution is a stable compound. For example, when the substituent is methyl (i.e. CH)₃) In this case, 3 hydrogens on the carbon atom may be replaced. Examples of such substituents include, but are not limited to: halogen, CN, NH₂、OH、SO、SO₂、COOH、OC_1-6Alkyl radical, CH₂OH、SO₂H、C_1-6Alkyl, OC_1-6Alkyl, C (═ O) C_1-6Alkyl, C (═ O) OC_1-6Alkyl, C (═ O) NH₂、C(＝O)NHC_1-6Alkyl, C (═ O) N (C)_1-6Alkyl radical)₂、SO₂C_1-6Alkyl, SO₂NHC_1-6Alkyl, SO₂N(C_1-6Alkyl radical)₂、NH(C_1-6Alkyl group), N (C)_1-6Alkyl radical)₂、NHC(＝O)C_1-6Alkyl, NC (═ O) (C)_1-6Alkyl radical)₂、C_5-6Aryl, OC_5-6Aryl, C (═ O) C_5-6Aryl, C (═ O) OC_5-6Aryl, C (═ O) NHC_5-6Aryl, C (═ O) N (C)_5-6Aryl radical)₂、SO₂C_5-6Aryl, SO₂NHC_5-6Aryl, SO₂N(C_5-6Aryl radical)₂、NH(C_5-6Aryl group), N (C)_5-6Aryl radical)₂、NC(＝O)C_5-6Aryl, NC (═ O) (C)_5-6Aryl radical)₂、C_5-6Heterocyclic group, OC _5-6Heterocyclyl, C (═ O) C_5-6Heterocyclyl group, C (═ O) OC_5-6Heterocyclyl, C (═ O) NHC_5-6Heterocyclyl, C (═ O) N (C)_5-6Heterocyclic radical)₂、SO₂C_5-6Heterocyclic radical, SO₂NHC_5-6Heterocyclic radical, SO₂N(C_5-6Heterocyclic radical)₂、NH(C_5-6Heterocyclic group), N (C)_5-6Heterocyclic radical)₂、NC(＝O)C_5-6Heterocyclyl or NC (═ O) (C)_5-6Heterocyclic radical)₂。

The various compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention includes all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) -isomers, (L) -isomers, racemic mixtures thereof, and other mixtures thereof, which are encompassed within the scope of the present invention. Additional asymmetric carbon atoms may be present in a substituent (e.g., alkyl). All such isomers and mixtures thereof are intended to be included in the present invention. The compounds described herein may have asymmetric centers. The compounds of the invention containing asymmetrically substituted atoms may be isolated in optically active or racemic forms. How to prepare optically active forms is well known in the art, for example by resolution of racemic forms, or by synthesis from optically active starting materials. Separation of the racemic material can be achieved by methods known in the art, if desired. Multiple geometric isomers of olefins, C ═ N double bonds, and the like, may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the invention are described and may be separated into a mixture of isomers or into separate isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended to be included in the invention, unless the specific stereochemistry or isomeric form is specifically indicated.

When a bond connecting substituents is shown to intersect a bond connecting two atoms in a ring, the substituent may be attached to any atom on the ring. When a substituent is listed without indicating through which atom the substituent is attached to the rest of the compound of a given structure, the substituent may be attached through any atom in the substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

"alkyl" or "alkylene" used herein alone or as a suffix or prefix is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms (or, if a specific number of carbon atoms is provided, that specific number). For example, "C_1-6Alkyl "denotes an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. It should be understood that as used herein, "C" is_1-3Alkyl groups "(whether terminal substituents or alkylene groups linking two substituents) specifically include straight and branched methyl, ethyl and propyl groups.

"alkenyl", used herein alone or as a suffix or prefix, is intended to include both branched and straight chain alkene-containing aliphatic hydrocarbon radicals having from 2 to 12 carbon atoms (or, if a specific number of carbon atoms is provided, that specific number). For example, "C_2-6Alkenyl "means alkenyl having 2, 3, 4, 5, or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-buteneA base, a 3-butenyl group, a 2-methylbut-2-enyl group, a 3-methylbut-1-enyl group, a 1-pentenyl group, a 3-pentenyl group and a 4-hexenyl group.

"alkynyl", used herein alone or as a suffix or prefix, is intended to include both branched and straight chain alkyne-containing aliphatic hydrocarbon radicals having from 2 to 12 carbon atoms (or, if a specific number of carbon atoms is provided, that specific number). For example, "C_2-6Alkynyl "refers to alkynyl groups having 2, 3, 4, 5, or 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, -pentynyl, hexynyl, and 1-methylpent-2-ynyl.

As used herein, "aromatic" refers to a hydrocarbon group having one or more unsaturated carbocyclic rings with aromatic character (e.g., 4n +2 delocalized electrons) and comprising up to about 14 carbon atoms. In addition, "heteroaromatic" refers to a group having one or more unsaturated carbocyclic rings containing carbon atoms and one or more heteroatoms (e.g., nitrogen, oxygen, or sulfur) with aromatic character (e.g., 4n +2 delocalized electrons).

The term "aryl" as used herein refers to an aromatic ring structure of 5 to 14 carbon atoms. The ring structure containing 5, 6, 7 and 8 carbon atoms may be a monocyclic aromatic group, such as phenyl. The ring structure containing 8, 9, 10, 11, 12, 13 or 14 carbon atoms may be polycyclic, for example naphthyl. The aromatic ring may be substituted with the substituents described above at one or more ring positions. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic and the other cyclic rings can be, for example, cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls. The terms "ortho", "meta" and "para" apply to 1, 2-, 1, 3-and 1, 4-disubstituted benzenes, respectively. For example, the names "1, 2-dimethylbenzene" and "o-dimethylbenzene" have the same meaning.

The term "cycloalkyl" as used herein is intended to include saturated cyclic groups having the specified number of carbon atoms. These ring radicals may includeIncluding fused or bridged polycyclic ring systems. Preferred cycloalkyl groups have 3 to 10 carbon atoms in their ring structure, more preferably 3, 4, 5 and 6 carbons in the ring structure. For example, "C _3-6Cycloalkyl "represents a group such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

As used herein, "cycloalkenyl" refers to a cyclic-containing hydrocarbon group having at least one carbon-carbon double bond in the ring and 3 to 12 carbon atoms.

As used herein, "cycloalkynyl" refers to a ring-containing hydrocarbon group having at least one carbon-carbon triple bond in the ring and from 7 to 12 carbon atoms.

As used herein, "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine. "counter ion" is used to denote small negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, tosylate, benzenesulfonate, and the like.

The term "heterocyclyl" or "heterocyclic" or "heterocycle" as used herein refers to a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring (unless otherwise specified) containing 3 to 20 atoms, wherein 1, 2, 3, 4 or 5 ring atoms are selected from nitrogen, sulfur or oxygen, and, unless otherwise specified, the heterocycle may be carbon or nitrogen-attached, wherein-CH₂-optionally substituted by-c (o) -and wherein, unless otherwise stated to the contrary, the ring nitrogen atom or the ring sulfur atom is optionally oxidized to N-oxide or S-oxide, or the ring nitrogen atom is optionally quaternized, wherein the ring-NH is optionally substituted by acetyl, formyl, methyl or methylsulfonyl, and the ring is optionally substituted by one or more halogens. It is understood that when the total number of S and O atoms in the heterocyclic group exceeds 1, these heteroatoms cannot be adjacent to each other. If the heterocyclyl is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclic group is monocyclic, it is not necessarily aromatic. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidine -yl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl and 2, 5-dioxoimidazolidinyl.

As used herein, "heteroaryl" refers to a heteroaromatic heterocycle having at least one ring heteroatom (e.g., sulfur, oxygen, or nitrogen). Heteroaryl groups include monocyclic ring systems and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1, 2, 4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, heteroaryl groups have from 1 to about 20 carbon atoms, and in other embodiments from about 3 to about 20 carbon atoms. In some embodiments, heteroaryl groups contain 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, heteroaryl groups have 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heteroaryl group has 1 heteroatom.

As used herein, "alkoxy" or "alkyloxy" refers to an alkyl group as defined above having the specified number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy, cyclopropylmethoxy, allyloxy, and propargyloxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above having the specified number of carbon atoms attached through a sulfur bridge.

The phrase "protecting group" as used herein refers to a temporary substituent, which is protectedA potentially reactive functional group such that it does not undergo an undesirable chemical transformation. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and the corresponding acetals and ketals of aldehydes and ketones. A review of the field of protecting group chemistry has been made (Greene, T.W.; Wuts, P.G.M.protective Groups in organic Synthesis, 3)^rd ed.；Wiley：New York，1999)。

As used herein, "pharmaceutically acceptable" refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines), inorganic or organic base salts of acidic residues (e.g., carboxylic acids), and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, which are prepared, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids (e.g., hydrochloric acid, phosphoric acid, etc.) and salts prepared from organic acids (e.g., lactic acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, etc.).

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, these salts can be prepared by the following method: reacting the free acid form or free base form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both; usually, nonaqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used.

As used herein, "in vivo hydrolysable precursor" refers to an in vivo hydrolysable (or cleavable) ester of a compound of formula I containing a carboxyl or hydroxyl group, e.g. an amino acid ester, C _1-6Alkoxymethyl esters (e.g. methoxymethyl ester), C_1-6Alkanoyloxymethyl esters (e.g. pivaloyloxymethyl ester), C_3-8Cycloalkoxy-carbonyloxy C_1-6Alkyl esters (e.g. 1-cyclohexylcarbonyloxyethyl ester), acetoxymethoxy ester or phosphoramide.

As used herein, "tautomer" refers to other structural isomers that exist in equilibrium due to hydrogen atom migration, such as keto-enol tautomerism, wherein the resulting compound has the properties of a ketone and an unsaturated alcohol.

As used herein, "stable compound" and "stable structure" refer to a compound that is sufficiently stable to survive isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

The compounds of the present invention also include hydrates and solvates.

The invention also includes isotopically-labeled compounds of the invention. An "isotopically labeled" or "radiolabeled" compound is a compound of the invention having the following characteristics: wherein one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in the compounds of the present invention include, but are not limited to ²H (also written as D, representing deuterium),³H (also written as T, representing tritium),¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、¹⁸F、³⁵S、³⁶Cl、⁸²Br、⁷⁵Br、⁷⁶Br、⁷⁷Br、¹²³I、¹²⁴I、¹²⁵I and¹³¹I. the radionuclide that is incorporated into these radiolabeled compounds depends on the particular application of the radiolabeled compound. For example, for in vitro receptor labeling and competition assays, binding is provided³H、¹⁴C、⁸²Br、¹²⁵I、¹³¹I or³⁵The compounds of S are generally most useful. Just put inFor the application of the radiographic imaging,¹¹C、¹⁸F、¹²⁵I、¹²³I、¹²⁴I、¹³¹I、⁷⁵Br、⁷⁶br or⁷⁷Br is generally most useful.

It is to be understood that a "radiolabeled compound" is a compound to which at least one radionuclide is bound. In some embodiments, the radionuclide is selected from³H、¹⁴C、¹²⁵I、³⁵S and⁸²Br。

the anti-dementia treatment as defined herein may be applied as a sole therapy or as a conventional chemotherapy including the compounds of the present invention. Such chemotherapy may include one or more of the following classes of drugs: acetylcholinesterase inhibitors, anti-inflammatory drugs, cognition and/or memory enhancing drugs or atypical antipsychotics.

The compounds of the invention may be administered as follows: oral, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingual, intramuscular, subcutaneous, topical, intranasal, intraperitoneal, intrathoracic, intravenous, epidural, intrathecal, intracerebroventricular, and injection into the joints.

When determining the most appropriate individual dosage regimen and dosage level for a particular patient, the dosage will depend upon the route of administration, the severity of the disease, the age and weight of the patient and other factors normally considered by the attending physician.

An effective amount of a compound of the present invention for treating dementia is an amount sufficient to symptomatically alleviate symptoms of dementia in a warm-blooded animal, particularly a human, slow the progression of dementia, or reduce the risk of worsening in a patient with symptoms of dementia.

For preparing pharmaceutical compositions from the compounds of the present invention, inert pharmaceutically acceptable carriers can be either solid or liquid. Solid formulations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents, and may also be an encapsulating material.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

To prepare suppository compositions, a low melting wax (e.g., a mixture of fatty acid glycerides and cocoa butter) is first melted and the active ingredient is then dispersed therein, e.g., by stirring. The molten homogeneous mixture is then poured into a suitably sized mold, which is then allowed to cool and solidify.

Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sucrose, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.

Some of the compounds of the present invention are capable of forming salts with various inorganic and organic acids and bases, and such salts are also within the scope of the present invention. For example, such conventional non-toxic salts include those derived from inorganic acids (e.g., hydrochloric acid, phosphoric acid, etc.) and salts prepared from organic acids (e.g., lactic acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, trifluoroacetic acid, etc.).

In some embodiments, the present invention provides a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, for use in the therapeutic treatment (including prophylactic treatment) of mammals, including humans, formulated into pharmaceutical compositions, generally in accordance with standard pharmaceutical practice.

In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may also contain, or be combined (administered simultaneously or sequentially) with one or more pharmacological ingredients having therapeutic value for one or more of the conditions described herein.

The term "composition" is intended to include a formulation of an active ingredient or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. For example, the present invention can be formulated into the following forms by methods known in the art: for example tablets, capsules, aqueous or oily solutions, suspensions, emulsions, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation and sterile aqueous or oily solutions or suspensions or sterile emulsions for parenteral use, including intravenous, intramuscular or infusion.

Liquid compositions include solutions, suspensions, and emulsions. As examples of liquid preparations suitable for parenteral administration, mention may be made of sterile aqueous solutions or sterile water-propylene glycol solutions of the active compounds. Liquid compositions may also be formulated as aqueous polyethylene glycol solutions. Aqueous solutions for oral administration can be prepared by the following method: the active ingredient is dissolved in water and suitable colorants, flavors, stabilizers, and thickeners are added as desired. Aqueous suspensions for oral use can be prepared by the following process: finely divided active ingredient is dispersed in water together with a viscous substance such as natural/synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other suspending agents known in the pharmaceutical art.

The pharmaceutical composition may be in unit dosage form. In this form, the composition is divided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, the package containing discrete quantities of the preparation, for example, tablets, capsules, and powders packaged in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or can be the appropriate number of any of these packaged forms.

The compositions may be formulated for any suitable route and method of administration. Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for administration of: oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. For convenience, the formulations may be in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

For solid compositions, conventional non-toxic solid carriers can be used, including, for example, pharmaceutical grades of mannitol, lactose, cellulose derivatives, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like. Liquid compositions useful for administration can be prepared, for example, by the following method: the active compounds as defined above and optional pharmaceutical excipients are dissolved, dispersed, etc. in a carrier, such as water, saline, aqueous dextrose, glycerol, ethanol, etc., thereby forming a solution or suspension. If desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and the like. The actual methods of preparing these dosage forms are known to, or will be apparent to, those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack publishing company, Easton, Pennsylvania, 15th Edition, 1975.

The compounds of the present invention may be derivatized in a variety of ways. As used herein, "derivatives" of a compound include salts (e.g., pharmaceutically acceptable salts), any complexes (e.g., inclusion complexes or chelates with compounds such as cyclodextrins, etc.), or with compounds such as Mn²⁺And Zn²⁺A complex formed by a plasma metal ion), an ester (e.g. an in vivo hydrolysable ester), a free acid or base, a polymorph of a compound, a solvate (e.g. hydrate), a prodrug or lipid, a coupling partner (coupling partner) and a protecting group. For example, "prodrug" refers to any compound that can be converted in vivo to a biologically active compound.

Salts of the compounds of the present invention are preferably physiologically well tolerated and non-toxic salts. Many examples of salts are known to those skilled in the art. All such salts are within the scope of the present invention and reference to the compounds includes the salt forms of the compounds.

Compounds having acidic groups (e.g., carboxylate, phosphate, or sulfate) can form salts with alkali or alkaline earth metals (e.g., Na, K, Mg, and Ca) or organic amines (e.g., triethylamine and tris (2-hydroxyethyl) amine). Compounds having basic groups, such as amines, can form salts with inorganic acids, such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids, such as acetic acid, citric acid, benzoic acid, fumaric acid or tartaric acid. Compounds having both acidic and basic groups can form internal salts.

Acid addition salts can be prepared with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with the following acids: hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propionic acid, butyric acid, malonic acid, glucuronic acid and lactobionic acid.

If the compounds are anionic or have functional groups which form anions (for example COOH can form COO)^-) Salts can then be prepared with the appropriate cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions (e.g., Na)⁺And K⁺) Alkaline earth metal cations (e.g. Ca)²⁺And Mg²⁺) And other cations (e.g., Al)³⁺). Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH)₄ ⁺) And substituted ammonium ions (e.g. NH)₃R⁺、NH₂R²⁺、NHR³⁺Or NR⁴⁺). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylaminePhenylbenzylamine, choline, meglumine and tromethamine and amino acids (e.g. lysine and arginine). An example of a common quaternary ammonium ion is N (CH) ₃)₄ ⁺。

Where the compounds contain amine functional groups, these compounds may form quaternary ammonium salts, for example, by the following method: the compound is reacted with an alkylating agent according to methods well known to the skilled person. These quaternary ammonium compounds are within the scope of the present invention.

The compounds comprising amine functionality may also form N-oxides. The compounds comprising amine functional groups to which the present application relates also include N-oxides.

In the case where the compound comprises several amine functional groups, one or more nitrogen atoms may be oxidized to the N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles.

The N-oxide can be prepared by the following method: the corresponding amines are treated with an oxidizing agent, such as hydrogen peroxide or a peracid, such as peroxycarboxylic acid, see for example Advanced Organic Chemistry, by JerryMarch, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the method of l.w. destination (syn.comm.1977, 7, 509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

Esters can be prepared between the hydroxyl or carboxyl group of a compound and a suitable carboxylic acid or alcohol reaction partner (interaction partner) using techniques well known in the art. Examples of esters are compounds comprising a group-C (═ O) OR, where R is an ester substituent, e.g. C _1-7Alkyl radical, C_3-20Heterocyclyl or C_5-20Aryl, preferably C_1-7An alkyl group. Specific examples of ester groups include, but are not limited to, -C (═ O) OCH₃、-C(＝O)OCH₂CH₃、-C(＝O)OC(CH₃)₃and-C (═ O) OPh. Examples of acyloxy (trans esters) are represented by-OC (═ O) R, where R is acyloxy substitutedRadicals, e.g. C_1-7Alkyl radical, C_3-20Heterocyclyl or C_5-20Aryl, preferably C_1-7An alkyl group. Specific examples of acyloxy include, but are not limited to, -OC (═ O) CH₃(acetoxy), -OC (═ O) CH₂CH₃、-OC(＝O)C(CH₃)₃-OC (═ O) Ph and-OC (═ O) CH₂Ph。

Derivatives that are prodrugs of a compound may be converted in vivo or in vitro to one of the parent compounds. Typically, at least one biological activity of a compound is reduced in a prodrug form of the compound and can be activated by converting the prodrug, thereby releasing the compound or a metabolite thereof. Some prodrugs are esters (e.g., physiologically acceptable metabolically labile esters) of the active compound. During metabolism, the ester group (-C (═ O) OR) is cleaved, giving the active drug. These esters can be prepared, for example, by esterification of any carboxyl group (-C (═ O) OH) of the parent compound, if necessary, protection of any other reactive group of the parent compound in advance, followed by deprotection as necessary.

Examples of such metabolically labile esters include those represented by the formula-C (═ O) OR, where R is C _1-7Alkyl (e.g. -Me (methyl), -Et (ethyl), -nPr (n-propyl), -iPr (isopropyl), -nBu (n-butyl), -sBu (sec-butyl), -iBu (isobutyl), -tBu (tert-butyl)), C_1-7Aminoalkyl radicals (e.g. aminoethyl, 2- (N, N-diethylamino) ethyl, 2- (4-morpholino) ethyl) and acyloxy-C_1-7Alkyl (e.g., acyloxymethyl, acyloxyethyl, pivaloyloxymethyl, acetoxymethyl, 1-acetoxyethyl, 1- (1-methoxy-1-methyl) ethyl-carbonyloxyethyl, 1- (benzoyloxy) ethyl, isopropoxy-carbonyloxymethyl, 1-isopropoxy-carbonyloxyethyl, cyclohexyl-carbonyloxymethyl, 1-cyclohexyl-carbonyloxyethyl, cyclohexyloxy-carbonyloxymethyl, 1-cyclohexyloxy-carbonyloxyethyl, (4-tetrahydropyranyloxy) carbonyloxymethyl, 1- (4-tetrahydropyranyloxy) carbonyloxyethyl, (4-tetrahydropyranyl) carbonyloxymethyl and 1- (4-tetrahydropyranyl) carbonyloxyethyl).

In addition, some prodrugs are activated by enzymes to give the active compound or compounds which give the active compound after further chemical reaction (e.g. in ADEPT, GDEPT, LIDEPT etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

Other derivatives include coupling partners for compounds wherein the compound is attached to the coupling partner, for example by chemical coupling or physical association with the compound. Examples of coupling partners include a marker molecule or reporter molecule, a carrier substance, carrier or transport molecule, an effector, a drug, an antibody or an inhibitor. The coupling partner may be covalently attached to the compounds of the invention through a suitable functional group of the compound, such as a hydroxyl, carboxyl or amino group. Other derivatives include formulating the compound with liposomes.

In the case where the compound contains a chiral center, various optical forms of the compound (e.g., enantiomers, epimers, and diastereomers, as well as racemic mixtures) are within the scope of the present invention.

The compounds may exist in a number of different geometric and tautomeric forms and reference to a compound includes all such forms. For the avoidance of doubt, where a compound may exist in one of several geometric or tautomeric forms and only one form is specifically described or shown, all other forms are still included within the scope of the invention.

The amount of the compound administered will vary with the patient being treated, and will range from about 100ng/kg to 100mg/kg body weight per day, preferably from 10ng/kg to 10mg/kg per day. For example, the dosage can be readily determined by one skilled in the art based on the disclosure herein and the knowledge in the art. Thus, the skilled person is readily able to determine the amount of the compound and optional additives, vehicles and/or carriers in the composition, and also the amount administered in the method of the invention.

The compounds of the present invention have been shown to inhibit β -secretase (including BACE) activity in vitro. It has been shown that inhibitors of beta-secretase can be used to block the formation or accumulation of a beta peptide and therefore have beneficial effects in the treatment of alzheimer's disease and other neurodegenerative diseases associated with elevated levels of a beta peptide and/or deposition of a beta peptide. Thus, it is believed that the compounds of the present invention are useful in the treatment of alzheimer's disease and dementia-related disorders. Thus, the compounds of the present invention and their salts are expected to have activity against age-related diseases such as alzheimer's disease and other a β -related pathologies such as down's syndrome and β -amyloid angiopathy. It is expected that the compounds of the present invention are most likely to be used in combination with a wide variety of cognitive deficit enhancing agents, but may also be used as single agents.

Various compounds of the present invention are useful as intermediates in the preparation of compounds of formula I. These compounds include, but are not limited to:

2-acetyl-7-bromo-1, 2, 3, 4-tetrahydroisoquinoline;

2-acetyl-7- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;

5- (3-bromo-phenyl) -3-methyl-5-phenyl-2-thioxo-imidazolidin-4-one;

1-acetyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline;

6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1-benzofuran;

(4- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) [2- (3' -methoxybiphenyl-3-yl) -1, 3-dithiane-2-yl ] methanol;

1- (4- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) -2- (3' -methoxybiphenyl-3-yl) ethane-1, 2-dione;

5- (4-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one;

4- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl methanesulfonate;

4- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioxoimidazolidin-4-yl ] phenyl trifluoromethanesulfonate;

4-methoxy-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol;

1- (3-hydroxyphenyl) -2-phenylethane-1, 2-dione;

5- (3-hydroxyphenyl) -3-methyl-5-phenyl-2-thioimidazolidin-4-one;

methyl-5-oxo-4-phenyl-2-thioxoimidazolidin-4-yl) phenylmethanesulfonate;

3-bromo-4- { [ tert-butyl (diphenyl) silyl ] oxy } benzaldehyde;

3-bromo-4- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) (2-phenyl-1, 3-dithian-2-yl) methanol;

1- (3-bromo-4- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) -2-phenylethane-1, 2-dione;

5- (3-bromo-4-hydroxyphenyl) -3-methyl-5-phenyl-2-thioimidazolidin-4-one;

2- (3' -methoxybiphenyl-3-yl) -1, 3-dithiane;

(3- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) [2- (3' -methoxybiphenyl-3-yl) -1, 3-dithiane-2-yl ] methanol;

1- (3- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) -2- (3' -methoxybiphenyl-3-yl) ethane-1, 2-dione;

5- (3-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one;

3- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioxoimidazolidin-4-yl ] phenyl trifluoromethanesulfonate;

3- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl methanesulfonate;

5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1-benzofuran;

2, 3-dihydro-1-benzofuran-5-yl (2-phenyl-1, 3-dithian-2-yl) methanol;

1- (2, 3-dihydro-1-benzofuran-5-yl) -2-phenylethane-1, 2-dione;

5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-5-phenyl-2-thioimidazolidin-4-one;

2-acetyl-5-chloro-1, 2, 3, 4-tetrahydroisoquinoline;

2-acetyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;

(4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) (2-phenyl-1, 3-dithian-2-yl) methanol;

1- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) -2-phenylethane-1, 2-dione;

3-methyl-5- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) -5-phenyl-2-thioxoimidazolidin-4-one;

6-iodo-1, 2, 3, 4-tetrahydronaphthalene;

6- (phenylethynyl) -1, 2, 3, 4-tetrahydronaphthalene;

1-phenyl-2- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) ethane-1, 2-dione;

3-methyl-5-phenyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -2-thioimidazolidin-4-one;

1-acetyl-5-iodoindoline;

1-acetyl-5- (phenylethynyl) indoline;

1- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) -2-phenylethane-1, 2-dione;

5- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) -3-methyl-5-phenyl-2-thioimidazolidin-4-one;

1-acetyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline;

8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) chroman;

3-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol;

3 '-hydroxy-5' -methoxybiphenyl-3-carbaldehyde;

3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-carbaldehyde;

tert-butyl { [ 3' - (1, 3-dithian-2-yl) -5-methoxybiphenyl-3-yl ] oxy } diphenylsilane;

[2- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl ] (pyridin-4-yl) methanol;

1- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -2-pyridin-4-ylethyl-1, 2-dione;

5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5-pyridin-4-yl-2-thioimidazolidin-4-one;

Methanesulfonic acid 5-methoxy-3' - (1-methyl-5-oxo-4-pyridin-4-yl-2-thioimidazolidin-4-yl) biphenyl-3-yl ester;

[2- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl ] (pyridin-2-yl) methanol;

1- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -2-pyridin-2-ylethyl-1, 2-dione;

5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5-pyridin-2-yl-2-thioimidazolidin-4-one;

methanesulfonic acid 5-methoxy-3' - (1-methyl-5-oxo-4-pyridin-2-yl-2-thioimidazolidin-4-yl) biphenyl-3-yl ester;

[2- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl ] (3-furyl) methanol;

1- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -2- (3-furyl) ethane-1, 2-dione;

5- (3-furyl) -5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one;

methanesulfonic acid 3' - [4- (3-furyl) -1-methyl-5-oxo-2-thioxoimidazolidin-4-yl ] -5-methoxybiphenyl-3-yl ester;

methanesulfonic acid 3' - [ 2-amino-4- (3-furyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester;

[2- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl ] (1, 3-thiazol-5-yl) methanol;

1- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -2- (1, 3-thiazol-5-yl) ethane-1, 2-dione;

5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5- (1, 3-thiazol-5-yl) -2-thioimidazolidin-4-one;

methanesulfonic acid 5-methoxy-3' - [ 1-methyl-5-oxo-4- (1, 3-thiazol-5-yl) -2-thioimidazolidin-4-yl ] biphenyl-3-yl ester;

[2- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl ] (1, 3-thiazol-4-yl) methanol;

1- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -2- (1, 3-thiazol-4-yl) ethane-1, 2-dione;

5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5- (1, 3-thiazol-4-yl) -2-thioimidazolidin-4-one;

methanesulfonic acid 5-methoxy-3' - [ 1-methyl-5-oxo-4- (1, 3-thiazol-4-yl) -2-thioimidazolidin-4-yl ] biphenyl-3-yl ester;

4-bromo-1-fluoro-2-methoxybenzene;

2- (4-fluoro-3-methoxyphenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane;

4- [ (3-bromophenyl) ethynyl ] phenol;

1- (3-bromophenyl) -2- (4-hydroxyphenyl) ethane-1, 2-dione;

5- (3-bromophenyl) -5- (4-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one;

4- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl methanesulfonate;

2-methoxyethanesulfonic acid 4- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester;

4- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl propane-1-sulfonate;

3-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl methanesulfonate;

3- [ (3-bromophenyl) ethynyl ] phenol;

1- (3-bromophenyl) -2- (3-hydroxyphenyl) ethane-1, 2-dione;

5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one;

3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl methanesulfonate;

2-methoxyethanesulfonic acid 3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester;

2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine;

1-ethynyl-3- (3-methoxyphenoxy) benzene;

3- [ (4-methoxyphenyl) ethynyl ] phenol;

4- { [3- (3-methoxyphenoxy) phenyl ] ethynyl } phenol;

1- (3-hydroxyphenyl) -2- (4-methoxyphenyl) ethane-1, 2-dione;

5- (3-hydroxyphenyl) -5- (4-methoxyphenyl) -3-methyl-2-thioimidazolidin-4-one;

1- (4-hydroxyphenyl) -2- [3- (3-methoxyphenoxy) phenyl ] ethane-1, 2-dione;

5- (4-hydroxyphenyl) -5- [3- (3-methoxyphenoxy) phenyl ] -3-methyl-2-thioimidazolidin-4-one;

1- (4-methoxyphenyl) -2- (3-phenoxyphenyl) ethane-1, 2-dione;

5- (4-methoxyphenyl) -3-methyl-5- (3-phenoxyphenyl) -2-thioimidazolidin-4-one;

3-methoxypropan-1-sulfonyl chloride;

3- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioxoimidazolidin-4-yl ] phenyl propane-2-sulfonate;

morpholine-4-sulfonic acid 3- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioxoimidazolidin-4-yl ] phenyl ester;

morpholine-4-sulfonic acid 3- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride;

6-iodo-1, 2, 3, 4-tetrahydronaphthalene;

6- [ (3-bromophenyl) ethynyl ] -1, 2, 3, 4-tetrahydronaphthalene;

1- (3-bromophenyl) -2- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) ethane-1, 2-dione;

5- (3-bromophenyl) -3-methyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -2-thioimidazolidin-4-one;

6-bromo-1, 2, 3, 4-tetrahydronaphthalen-2-ylmethyl ether;

[ (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) ethynyl ] (trimethyl) silane;

6-ethynyl-1, 2, 3, 4-tetrahydronaphthalen-2-ylmethyl ether;

6- [ (3-bromophenyl) ethynyl ] -1, 2, 3, 4-tetrahydronaphthalen-2-ylmethyl ether;

1- (3-bromophenyl) -2- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) ethane-1, 2-dione;

5- (3-bromophenyl) -5- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3-methyl-2-thioimidazolidin-4-one;

1-acetyl-6-iodo-1, 2, 3, 4-tetrahydroquinoline;

1-acetyl-6- [ (3-bromophenyl) ethynyl ] -1, 2, 3, 4-tetrahydroquinoline;

1- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -2- (3-bromophenyl) ethane-1, 2-dione;

5- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -5- (3-bromophenyl) -3-methyl-2-thioimidazolidin-4-one;

5- [ (3-bromophenyl) ethynyl ] indan;

1- (3-bromophenyl) -2- (2, 3-dihydro-1H-inden-5-yl) ethane-1, 2-dione;

5- (3-bromophenyl) -5- (2, 3-dihydro-1H-inden-5-yl) -3-methyl-2-thioimidazolidin-4-one;

2, 3-dihydro-1-benzofuran-5-yl [2- (3' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl ] methanol;

1- (2, 3-dihydro-1-benzofuran-5-yl) -2- (3' -methoxybiphenyl-3-yl) ethane-1, 2-dione;

5- (2, 3-dihydro-1-benzofuran-5-yl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one;

2-acetyl-4-chloroisoindoline;

5- [ (3-bromophenyl) ethynyl ] -2, 3-dihydro-1-benzofuran;

1- (3-bromophenyl) -2- (2, 3-dihydro-1-benzofuran-5-yl) ethane-1, 2-dione;

5- (3-bromophenyl) -5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-2-thioimidazolidin-4-one;

6- [ (3-bromophenyl) ethynyl ] chromane;

1- (3-bromophenyl) -2- (3, 4-dihydro-2H-chromen-6-yl) ethane-1, 2-dione;

5- (3-bromophenyl) -5- (3, 4-dihydro-2H-chromen-6-yl) -3-methyl-2-thioimidazolidin-4-one;

(3, 4-dihydro-1H-isochromen-7-ylethynyl) (trimethyl) silane;

7-ethynyl-3, 4-dihydro-1H-isochromene;

7- [ (3-bromophenyl) ethynyl ] -3, 4-dihydro-1H-isochromene;

1- (3-bromophenyl) -2- (3, 4-dihydro-1H-isochromen-7-yl) ethane-1, 2-dione;

5- (3-bromophenyl) -5- (3, 4-dihydro-1H-isochromen-7-yl) -3-methyl-2-thioimidazolidin-4-one;

4- { [ tert-butyl (diphenyl) silyl ] oxy } benzaldehyde;

tert-butyl [4- (1, 3-dithian-2-yl) phenoxy ] diphenylsilane;

(3-bromo-4-fluorophenyl) [2- (4- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) -1, 3-dithian-2-yl ] methanol;

1- (3-bromo-4-fluorophenyl) -2- (4- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) ethane-1, 2-dione;

5- (3-bromo-4-fluorophenyl) -5- (4-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one; and

methanesulfonic acid 4- [4- (3-bromo-4-fluorophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester.

Preparation method

The invention also relates to a process for the preparation of a compound of formula I in free base form or a pharmaceutically acceptable salt thereof. In the following description of these processes, it will be understood that, if desired, suitable protecting groups may be added to the various reactants and intermediates and subsequently removed therefrom in a manner readily understood by those skilled in the art of organic synthesis. Conventional methods for using such protecting Groups and examples of suitable protecting Groups are described, for example, in "Protective Groups in Organic Synthesis", T.W.Greene, P.G.M Wutz, Wiley-Interscience, New York, 1999. It should be understood that microwaves may be used to heat the reaction mixture.

Preparation of intermediates

This process (wherein R is, unless otherwise specified¹、R²、R³、R⁷、R⁸And R¹⁴As defined above) includes:

(i) acylating the compound of formula II to give a compound of formula III, wherein P represents a 4, 5, 6 or 7 membered nitrogen containing heterocyclyl, "halogen" represents halogen (e.g. iodine, bromine or chlorine) and R ¹⁵Is, for example, alkyl, cyclicA group such as an alkyl group, a heterocyclic group, an aryl group or a heteroaryl group,

the acylation may be carried out by the following method: the compound of formula II is reacted with a suitable acylating agent such as an anhydride (e.g. acetic anhydride) or an acid chloride (e.g. acetyl chloride) in a suitable solvent (e.g. dichloromethane, chloroform, toluene or acetonitrile) at-20 ℃ to reflux temperature. The reaction is preferably carried out in the presence of a base. Suitable bases may be organic amines (e.g. pyridine, 2, 6-lutidine, collidine, triethylamine, morpholine, N-methylmorpholine, diazabicyclo [5.4.0] undec-7-ene or tetramethylguanidine) or alkali or alkaline earth metal carbonates or hydroxides (e.g. sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide). The presence of 4-dimethylaminopyridine may assist the reaction. Alternatively, activated carboxylic acid esters can be used using standard amide coupling conditions.

(ii) Silylating the compound of formula IV to provide a compound of formula V, wherein "halogen" represents halogen (e.g., iodine, bromine, or chlorine), and R¹⁶Is an alkyl group or an aryl group,

(IV) (V)

the silylation can be carried out under the following conditions: the reaction is carried out in a suitable solvent (e.g. dichloromethane, tetrahydrofuran or dimethylformamide) at from 0 ℃ to 100 ℃ in the presence of a suitable base, for example an organic amine (e.g. imidazole, pyridine, 2, 6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine, diazabicyclo [5.4.0] undec-7-ene or tetramethylguanidine) or an alkali metal hydride (e.g. sodium hydride), with a suitable reagent, for example a trialkylchlorosilane (e.g. tert-butyldiphenylchlorosilane, trimethylchlorosilane or triisopropylchlorosilane) or a trialkylsilyl trifluoromethanesulfonate (e.g. triethylsilyl trifluoromethanesulfonate). 4-dimethylaminopyridine may assist in the reaction.

(iii) Converting the compound of formula VIa or VIb to give a compound of formula VIIa or VIIb, wherein R is¹⁷And R¹⁸Are each as exactly as above for R²And R³As defined, or in a protected variation thereof,

the transformation can be carried out by the following method: the compound of formula VIa or VIb is reacted with a suitable reagent, such as 1, 3-propanedithiol, in a suitable solvent, such as dichloromethane, acetonitrile, chloroform, toluene or diethyl ether, in the presence of an acid, such as hydrochloric acid or p-toluenesulfonic acid, or a Lewis acid, such as boron trifluoride or titanium tetrachloride, at temperatures from-78 ℃ to reflux temperature.

(iv) Reacting a compound of formula VIa or VIb with a compound of formula VIIb or VIIa to provide a compound of formula VIIIa or VIIIb, wherein R is¹⁷And R¹⁸As defined above in (iii),

the reaction can be carried out by the following method: treatment of VII with a suitable base such as an alkyllithium reagent (e.g. n-butyllithium or t-butyllithium) is followed by addition of VI. The reaction can be carried out under the following conditions: the reaction is carried out in a solvent such as tetrahydrofuran or diethyl ether or a mixture of either with hexane at-100 ℃ to 0 ℃. The presence of a reagent such as hexamethylphosphoric triamide (hexamethylphosphoric triamide) or N, N, N ', N' -tetramethyl-1, 2-ethylenediamine can assist the reaction.

(v) Oxidative deprotection of a compound of formula VIIIa or VIIIb to give a compound of formula IX, wherein R¹⁷And R¹⁸As defined above in (iii),

the oxidative deprotection can be carried out by:

a) a compound of formula VIIIa or VIIIb is reacted with a suitable reagent, such as 1, 1, 1-tris (acetoxy) -1, 1-dihydro-1, 2-benziodoxol-3(1H) -one (1, 1, 1-tris (acetoxy) -1, 1-dihydro-1, 2-benziodoxol-3(1H) -one), bis (trifluoroacetoxy) iodobenzene, N-bromosuccinimide or a mixture of trifluoroacetic acid with sodium nitrite or formaldehyde in a suitable solvent, such as dichloromethane, acetonitrile, chloroform, acetone or water or mixtures thereof, at a temperature of-5 ℃ to 40 ℃. The presence of an alcohol (e.g., t-butanol) may aid in the reaction; or

b) Hydrolyzing a compound of formula VIIIa or VIIIb by: treatment of a compound of formula VIIIa or VIIIb with a suitable reagent or combination of reagents (e.g. N-chlorosuccinimide and silver nitrate, N-iodosuccinimide, 3-chloroperoxybenzoic acid, cerium (IV) ammonium nitrate, thallium (III) nitrate, mercury (II) chloride and calcium carbonate or mercury (II) acetate) in a suitable solvent (e.g. water, acetonitrile, methanol, acetone or diethyl ether or mixtures thereof) at from-50 ℃ to 50 ℃ followed or preceded by treatment with a reagent (e.g. 1, 1, 1-tris (acetoxy) -1, 1-dihydro-1, 2-benziodoxy-3 (1H) -one, manganese dioxide, hydrogen peroxide, potassium permanganate, pyridinium chlorochromate, hydrogen chloride, ammonium nitrate, thallium (III) nitrate, mercury (II) chloride and calcium carbonate or mercury (II) acetate in a suitable solvent (e.g. dichloromethane, water, acetonitrile, chloroform or dimethylformamide) at from 0 ℃ to reflux temperature, Copper sulfate or bromine).

(vi) Oxidation of a compound of formula X to give a compound of formula IX, wherein R¹⁷And R¹⁸As defined above in (iii),

the oxidation may be carried out by: the compound of formula X is reacted with a suitable reagent or mixture of reagents (e.g. sodium periodate and ruthenium dioxide, iodine and dimethyl sulfoxide, palladium dichloride and dimethyl sulfoxide, ozone, hydrogen peroxide, oxygen, potassium permanganate, ruthenium tetroxide or selenium dioxide) in a suitable solvent (e.g. dimethyl sulfoxide, dichloromethane, acetonitrile, water, acetone, chloroform or carbon tetrachloride) at-78 ℃ to 150 ℃. The presence of a catalyst (e.g., ruthenium trichloride or iron trichloride) aids in the reaction.

(vii) Converting the compound of formula IX to provide a compound of formula XI, wherein R¹⁷And R¹⁸As defined above in (iii), and R¹⁹Exactly as above for R¹As defined, or in a protected variation thereof,

the transformation can be carried out by the following method: a compound of formula IX is reacted with a suitable N-substituted thiourea, for example N-methylthiourea, in a suitable solvent, for example water, dimethyl sulphoxide, ethanol or methanol or mixtures thereof, in the presence of a suitable base, for example potassium hydroxide or sodium hydroxide, at a temperature of from 20 ℃ to reflux temperature.

(viii) Converting the compound of formula XI to give a compound of formula XII, wherein R¹⁷、R¹⁸And R¹⁹As defined above in (iii) and (vii),with the proviso that XII is not the final compound,

the transformation can be carried out by the following method: the compound of formula XI is reacted with ammonia or an ammonia equivalent and an alkyl hydroperoxide, e.g. tert-butyl hydroperoxide, in a solvent, e.g. ethanol, methanol or water or mixtures thereof, at 0 to 50 ℃.

(ix) Boronation of a compound of formula XIII to give a compound of formula XIV, wherein "halogen" represents halogen (e.g., iodine, bromine, or chlorine), and R²⁰May be the groups outlined in FIG. I, wherein R is²¹And R²²Are, for example, the following groups: OH or C fused together to form a 5-or 6-membered boron-containing heterocyclic ring_1-6Alkyl O or C_2-3Alkyl O, and the alkyl, cycloalkyl or aryl may be optionally substituted; r²³Including hydrogen or R as above⁷Those groups as defined, provided that the substituents are compatible with the cross-coupling chemistry. In addition to phenyl, alternative optionally substituted aromatic and heteroaromatic ring systems are also included in the process.

The boronation can be carried out by the following method:

a) a compound of formula XIII is reacted with an alkyl lithium (e.g. butyl lithium) or magnesium and a suitable boron compound (e.g. trimethyl borate or triisopropyl borate). The reaction can be carried out under the following conditions: the reaction is carried out in a suitable solvent (e.g. tetrahydrofuran, hexane or dichloromethane) at-78 ℃ to +20 ℃; or

b) Reacting a compound of formula XIII with a suitable boron species, such as biscatecholdiboronic acid ester (biscatecholdiboron), bisphenodiboron (bispinacolatodiboron) or pinacolborane (pinacolborane), under the following conditions: the reaction is carried out in the presence of a suitable palladium catalyst, such as tetrakis (triphenylphosphine) palladium, diphenylphosphinoferrocene palladium dichloride (palladium diphenyl phosphinothricinocene dichloride) or palladium diacetate, with or without a suitable ligand, such as 2- (dicyclohexylphosphinothricin) biphenyl, and a suitable base such as a tertiary amine, such as triethylamine or diisopropylethylamine, or potassium acetate may be used. The reaction can be carried out under the following conditions: the reaction is carried out in a solvent (e.g. dioxane, toluene, acetonitrile, water, ethanol or 1, 2-dimethoxyethane or mixtures thereof) at 20 ℃ to +160 ℃.

(x) Converting a compound of formula XV to a compound of formula XVI wherein "halo" represents halo (e.g. chloro, bromo or iodo), R¹⁹R is as defined above in (vii)²⁴Exactly as for R²Or R³Described, or a protected variant thereof, and R²⁵As defined above for the compound of formula XIV in (ix), except that R²⁵Is instead of R ²⁰With the proviso that the compound of the formula XVI obtained is not the final compound,

the transformation can be carried out by the following method: dehalogenation of a compound of formula XV with a suitable compound of formula XIV. The reaction can be carried out by the following method: coupling a compound of formula XV with a suitable aryl boronic acid of formula XIV or a boronic ester thereof. The reaction can be carried out under the following conditions: the reaction is carried out with or without a suitable ligand (e.g., tri-tert-butylphosphine or 2- (dicyclohexylphosphino) biphenyl) using a suitable palladium catalyst (e.g., tetrakis (triphenylphosphine) palladium, diphenylphosphino ferrocene dichloropalladium, or palladium diacetate); or by using a nickel catalyst (e.g., nickel/carbon or 1, 2-bis (diphenylphosphino) ethane nickel dichloride) and zinc and triphenylphosphine sodium trimetaphosphate. A suitable base such as cesium fluoride, an alkylamine (e.g. triethylamine) or an alkali or alkaline earth metal carbonate or hydroxide (e.g. potassium carbonate, sodium carbonate, cesium carbonate or sodium hydroxide) may be used in the reaction, which may be carried out under the following conditions: the reaction is carried out in a suitable solvent (e.g. toluene, tetrahydrofuran, dioxane, dimethoxyethane, water, ethanol or N, N-dimethylformamide or mixtures thereof) at +20 ℃ to +160 ℃.

(xi) Conversion of a compound of formula XVII to give a compound of formula XVIII, wherein R¹⁹And R²⁴As defined above, and R²⁶By R⁸Or R¹²The method is used for covering the part to be covered,

the transformation can be carried out by the following method: the compound of formula XVII is reacted with a suitable reagent such as an alkyl sulfonyl chloride (e.g. methanesulfonyl chloride), an alkyl sulfonic anhydride (e.g. trifluoromethanesulfonic anhydride) or a sulfonamide (e.g. N-phenyl-bis (trifluoromethanesulfonyl) imide) in a suitable solvent (e.g. dichloromethane, tetrahydrofuran, chloroform, toluene, dimethylformamide or pyridine) at-78 ℃ to 120 ℃ in the presence of a suitable base such as an organic amine (e.g. pyridine, 2, 6-dimethylpyridine, mesitylidine, triethylamine, diisopropylethylamine, morpholine, N-methylmorpholine, diazabicyclo [5.4.0] undec-7-ene or tetramethylguanidine) or an alkali or alkaline earth metal carbonate (e.g. sodium carbonate, potassium carbonate or calcium carbonate) or potassium phosphate. 4-dimethylaminopyridine may assist in the reaction.

Process for the preparation of the end product

It is a further object of the present invention to provide processes a, b or c for the preparation of compounds of formula I and salts thereof, wherein R, unless otherwise specified, is¹、R²And R³As defined above. When an acid addition salt is desired, the free base may be treated with an acid such as a hydrogen halide (e.g. hydrogen chloride), sulphuric acid, a sulphonic acid (e.g. methanesulphonic acid) or a carboxylic acid (e.g. acetic acid or citric acid) in a suitable solvent (e.g. tetrahydrofuran, diethyl ether, methanol, ethanol, chloroform or dichloromethane or mixtures thereof), which reaction may be carried out at-30 ℃ to +50 ℃.

These methods include:

(a) converting the compound of formula XIX to obtain the compound of formula I,

the reaction of the process (a) can be carried out by the following process: the compound of formula XIX is reacted with ammonia or an ammonia equivalent and an alkyl hydroperoxide (e.g. tert-butyl hydroperoxide) in a solvent (e.g. ethanol, methanol or water or mixtures thereof) at 0 ℃ to 50 ℃.

(b) Conversion of a compound of formula XX to give a compound of formula I '(wherein I' is included in the general definition of compounds of formula I) wherein "halogen" represents halogen (e.g. chlorine, bromine or iodine), defines ring B as once halogen is replaced by R⁷Substituted, the end product I' obtained is then covered by the compounds of the formula I,

the reaction of the process (b) can be carried out by the following process: the compound of formula XX is subjected to a dehalogenation coupling reaction with a suitable compound of formula XIV. The reaction can be carried out by the following method: coupling of a compound of formula XX with a suitable aryl boronic acid of formula XIV or a boronic ester of formula XIV. The reaction can be carried out under the following conditions: the reaction is carried out with or without a suitable ligand (e.g., tri-tert-butylphosphine or 2- (dicyclohexylphosphino) biphenyl) using a suitable palladium catalyst (e.g., tetrakis (triphenylphosphine) palladium, diphenylphosphino ferrocene dichloropalladium, or palladium diacetate); or by using a nickel catalyst (such as nickel/carbon or 1, 2-bis (diphenylphosphino) ethane nickel dichloride) and zinc and sodium triphenylphosphine tri-m-sulfonate. A suitable base such as cesium fluoride, an alkylamine (e.g. triethylamine) or an alkali or alkaline earth metal carbonate or hydroxide (e.g. potassium carbonate, sodium carbonate, cesium carbonate or sodium hydroxide) may be used in the reaction, which may be carried out under the following conditions: the reaction is carried out in a suitable solvent (e.g. toluene, tetrahydrofuran, dioxane, dimethoxyethane, water, ethanol or N, N-dimethylformamide or mixtures thereof) at +20 ℃ to +160 ℃.

(c) Conversion of a compound of formula XXI to give a compound of formula I '(wherein I' is included in the general definition of compounds of formula I), wherein ring C is defined as when-OH is replaced by-OSO₂R⁸or-OSO₂R¹²Instead, the resulting end product I' is covered by a compound of the formula I,

the reaction of the process (c) can be carried out by the following process: a compound of formula XXI is reacted with a suitable reagent such as an alkyl sulfonyl chloride (e.g.methanesulfonyl chloride) in a suitable solvent (e.g.dichloromethane, tetrahydrofuran, chloroform, toluene, dimethylformamide or pyridine) at-78 ℃ to 120 ℃ in the presence of a suitable base such as an organic amine (e.g.pyridine, 2, 6-lutidine, mesitylidine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, morpholine, N-methylmorpholine, diazabicyclo [5.4.0] undec-7-ene or tetramethylguanidine) or an alkali or alkaline earth metal carbonate or hydroxide (e.g.sodium hydroxide, sodium carbonate, potassium carbonate or calcium carbonate) or potassium phosphate, alkyl sulfonic anhydrides (e.g., trifluoromethanesulfonic anhydride) or sulfonimides (e.g., N-phenyl-bis (trifluoromethanesulfonyl) imide). 4-dimethylaminopyridine may assist in the reaction.

Examples

The following are several non-limiting examples of compounds of the present invention.

General procedure

The starting materials used are either commercially available or prepared according to literature methods.

Microwave heating was carried out in a Creator, Initiator or Smith Synthesizer single mode microwave cavity (microwave cavity) to produce continuous irradiation at 2450 MHz.

Recording in the indicated deuterated solvents at 400MHz using the following instrument¹H NMR Spectroscopy, unless otherwise stated, the instrument is equipped with a 3mm flow injection SEI¹H/D-¹³A Bruker av400 NMR spectrometer with C-probe (with Z-gradient), BEST 215 liquid handler for sample injection or Bruker DPX400 NMR spectrometer equipped with 4-nuclear probe (with Z-gradient). 600MHz recording using a Bruker DRX600 NMR spectrometer equipped with a 5mm TXI probe (with Z-gradient)¹H NMR. Chemical shifts are given in ppm low and ppm high fields relative to TMS. The resonance diversity is expressed as s, d, t, q, m and br for singlet, doublet, triplet, quartet, multiplet and broad, respectively.

LC-MS analysis was recorded on a Waters LCMS equipped with a Waters X-Terra MS, C8 column (3.5 μm, 100 mm. times.3.0 mm i.d.). The mobile phase system is composed of A: 10mM ammonium acetate in water/acetonitrile (95: 5) and B: and acetonitrile. A linear gradient was applied, which changed from 0% B to 100% B in 4-5 minutes, at a flow rate of 1.0 mL/min. The mass spectrometer was equipped with an electrospray ion source (ESI) operating in positive or negative ion mode. The capillary voltage was 3kV and the mass spectrometer typically scanned m/z 100-700.

GC-MS analysis was performed on an Agilent 6890N GC equipped with a Chrompack CP-Sil 5CB chromatography column (25m × 0.25mm i.d. df ═ 0.25), which Agilent 6890N GC was connected to an Agilent 5973 mass selective detector operating in Chemical Ionization (CI) mode, and MS scanned m/z 50-500.

HPLC measurements were performed using an Agilent HP1100 Series system equipped with a Waters X-Terra MS, C8 column (3.0X 100mm, 3.5 μm). The column temperature was set to 40 ℃ and the flow rate was set to 1.0 mL/min. The diode array detector scans 200-300 nm. A linear gradient was applied, which changed from 0% B to 100% B within 4 min. Mobile phase a was a 10mM ammonium acetate in water/acetonitrile (95: 5) solution, while mobile phase B was acetonitrile.

Preparative HPLC was performed on a Waters autopurification HPLC-UV system with a diode array detector using a Waters XTerra MS C8 chromatography column (19 × 300mm, 7 μm) and applying a linear gradient of mobile phase B. Mobile phase a was a 0.1M solution of ammonium acetate in water/acetonitrile (95: 5) and mobile phase B was acetonitrile. The flow rate was 20 mL/min.

Alternatively, preparative chromatography was performed on a Waters FractionLynx system with autosampler and autosampler collector (Waters 2767), gradient pump (Waters 2525), regeneration pump (Waters 600), offset pump (Waters 515), Waters ActiveSplitter, Column Switch (Waters CFO), PDA (Waters 2996) and Waters ZQ mass spectrometer. The chromatographic column is Xbridge ^TM Prep C8 5μm OBD^TM19X 100mm (with guard column) or XTerraPrep MS C810 μm 19X 10mm Cartidge. For LC separation, 100% A (95% 0.1M NH) was applied at a flow rate of 25ml/min₄MilliQ of OAcAqueous solution and 5% MeCN) to 100% B (100% MeCN). The PDA scans 210 and 350 nm. The ZQ mass spectrometer was operated in positive mode ESI. The capillary voltage was 3kV and the cone voltage was 30V. The mixability trigger signals, i.e., UV and MS signals, determine fraction collection.

On Merch TLC plates (silica gel 60F)₂₅₄) Thin Layer Chromatography (TLC) was performed and spots were visualized using UV. Merck silica gel 60(0.040-0.063mm) or Combi Flash is utilizedCompanion^TMSystem (using RediSep)^TMNormal phase flash chromatography column).

Compounds were named using ACD/Name (version 8.08) (Advanced Chemistry Development, Inc. (ACD/Labs), Toronto ON, Canada, www.acdlabs.com, 2004).

Example 1

2-acetyl-7-bromo-1, 2, 3, 4-tetrahydroisoquinoline

7-bromo-1, 2, 3, 4-tetrahydroisoquinoline (550mg, 2.21mmol), triethylamine (0.68mL, 4.87mmol) and N, N-dimethylpyridin-4-amine (27mg, 0.22mmol) were dissolved in anhydrous dichloromethane (10mL) and then cooled to 0 ℃ under argon. Acetic anhydride (0.22mL, 2.32mmol) was added dropwise and the resulting mixture was stirred under argon at ambient temperature for 15 h. The mixture was then poured into aqueous hydrochloric acid (1M, 10mL), and the organic phase was separated, washed with aqueous hydrochloric acid (1M, 10mL) and saturated aqueous sodium bicarbonate (10mL), dried over magnesium sulfate, and concentrated in vacuo to give the title compound (556mg, 99% yield). ¹H-NMR(DMSO-d₆)：δ7.44-7.41(m，1H)，7.37-7.33(m，1H)，7.14(d，J＝8.0Hz，1H)，4.64(s，1H)，4.58(s，1H)，3.63(t, J ═ 6.0Hz, 2H), 2.81(t, J ═ 5.9Hz, 1H), 2.70(t, J ═ 5.9Hz, 1H), 2.07(s, 3H); MS (ESI) M/z 254 and 256[ M +1 ]]⁺。

Example 2

2-acetyl-7- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline

2-acetyl-7-bromo-1, 2, 3, 4-tetrahydroisoquinoline (150mg, 0.59mmol), 4, 4, 4 ', 4', 5, 5, 5 ', 5' -octamethyl-2, 2 '-di-1, 3, 2-dioxaborolane (180mg, 0.71mmol), and [1, 1' -di (diphenylphosphino) ferrocene were irradiated with microwaves]Palladium dichloride dichloromethane adduct (15mg, 0.018mmol), potassium acetate (174mg, 1.77mmol) and 1, 2-dimethoxyethane (4mL) were kept at 150 ℃ for 15 min. When cooled to ambient temperature, the mixture was diluted with water (4mL) and then extracted with ether (3X 5 mL). The combined organic extracts were passed through a silica gel pad. The product fractions were collected and then concentrated to give the title compound (125mg, 70% yield).¹H-NMR(DMSO-d₆)：δ7.53-7.44(m，2H)，7.21-7.16(m，1H)，4.65(s，1H)，4.58(s，1H)，3.64(t，J＝5.8Hz，2H)，2.87(t，J＝5.8Hz，1H)，2.77(t，J＝5.9Hz，1H)，2.07(s，3H)，1.28(s，6H)，1.16(s，6H)；MS(ESI)m/z 302[M+1]⁺。

Example 3

5- (3-bromo-phenyl) -3-methyl-5-phenyl-2-thioxo-imidazolidin-4-one

M-Bromobenzoyl (10.99g, 38mmol, described in C)hristy, m.e.et al.j.med.chem.1977, 20, 421.) was dissolved in dimethyl sulfoxide (65 mL). N-methylthiourea (6.85g, 76mmol) was added and the solution was then heated to 100 ℃. An aqueous solution of potassium hydroxide (1.5M, 26mL, 38mmol) was added, and the resulting solution was stirred at this temperature for 3min, cooled, and then poured into water (300 mL). The resulting slurry was stirred vigorously and the pH was adjusted to below 7 with aqueous hydrochloric acid (12M, about 4 mL). Stirring was continued for 20min, and then the precipitate was collected by filtration. The filter cake was washed with water (150mL) and then dried under vacuum to give 13.98g (100% yield) of the title compound. ¹H-NMR(DMSO-d₆): δ 11.61(s, 1H), 7.57(d, J ═ 8Hz, 1H), 7.48(s, 1H), 7.35-7.40(m, 5H), 7.26(d, J ═ 8Hz, 2H), 3.14(s, 3H); MS (ESI) M/z 359 and 361[ M +1 ]]⁺。

Example 4

2-amino-5- (3-bromophenyl) -3-methyl-5-phenyl-3, 5-dihydro-imidazol-4-one

5- (3-bromo-phenyl) -3-methyl-5-phenyl-2-thioxo-imidazolidin-4-one (2.53g, 7mmol) was added to a mixture of methanol (30mL) and aqueous ammonia (25%, 10 mL). Aqueous tert-butyl hydroperoxide (70%, 12.5mL, 105mmol) was added and the resulting mixture was stirred at 35 ℃ for 2 h. The mixture was then poured into water (300mL) and extracted with dichloromethane (3X 30 mL). The combined organic phases were washed with water (200mL), dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane: methanol 90: 10(20mL), filtered through a pad of silica gel with suction and then concentrated in vacuo. Recrystallization from chloroform gave 1.48g (68% yield) of the title compound.¹H-NMR(DMSO-d₆): δ 7.61(s, 1H), 7.40-7.50(m, 4H), 7.22-7.32(m, 4H), 6.72(s, 2H), 2.98(s, 3H); MS (ESI) M/z 344 and 346[ M +1 ]]⁺。

Example 5

5- [3- (2-acetyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one

2-acetyl-7- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline (125mg, 0.42mmol), 2-amino-5- (3-bromo-phenyl) -3-methyl-5-phenyl-3, 5-dihydro-imidazol-4-one (143mg, 0.42mmol), and [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane adduct (17mg, 0.021mmol), cesium carbonate (406mg, 1.25mmol) and solvent (4mL of 1, 2-dimethoxyethane: water: ethanol 6: 3: 1) were kept at 150 ℃ for 15 min. When cooled to ambient temperature, the mixture was diluted with water (5mL) and then extracted with ether (3X 5 mL). The combined organic extracts were concentrated and then purified by preparative HPLC to give 14mg (8% yield) of the title compound. MS (ESI) M/z 439[ M +1 ]]⁺。

Example 6

5- [3- (2-acetyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride

Reacting 5- [3- (2-acetyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) phenyl]-2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one (14mg, 0.032mmol) was dissolved in dichloromethane (1mL) and hydrochloric acid (1.0M in ether, 33. mu.L, 0.033mmol) was added. The resulting mixture was concentrated to dryness in vacuo to give the title compound (12mg, 79% yield). ¹H-NMR(DMSO-d₆)：δ9.60(s，2H)，7.73-7.63(m，2H)，7.58-7.50(m，1H)，7.49-7.36(m，8H)，7.30-7.26(m，1H)，4.70(s，1H)，4.65(s，1H)，3.67(t，J＝5.9Hz，2H)，3.21(s，3H)，2.89(t，J＝5.9Hz，1H)，2.78(t，J＝5.9Hz，1H)，2.09(s，3H)；MS(ESI)m/z 439[M+1]⁺。

Example 7

1-acetyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline

The title compound was synthesized from 1-acetyl-5-bromoindoline in 85% yield as described in example 2.¹H-NMR(DMSO-d₆)：δ8.04-8.00(m，1H)，7.51-7.45(m，2H)，4.09(t，J＝8.5Hz，2H)，3.12(t，J＝8.5Hz，2H)，2.16(s，3H)，1.27(s，6H)，1.16(s，6H)；MS(CI)m/z 288[M+1]⁺。

Example 8

5- [3- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized as described in example 5 from 2-amino-5- (3-bromo-phenyl) -3-methyl-5-phenyl-3, 5-dihydro-imidazol-4-one and 1-acetyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline in 15% yield. MS (ESI) M/z 425[ M +1 ]]⁺。

Example 9

5- [3- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride

From 5- [3- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) phenyl as described in example 6]-2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one to synthesize the title compound in 93% yield.¹H-NMR(DMSO-d₆): δ 11.66(s, 1H), 9.62(s, 2H), 8.11-8.07(m, 1H), 7.75-7.63(m, 2H), 7.46-7.37(m, 9H), 4.13(t, J ═ 8.5Hz, 2H), 3.42-3.30(m, 2H, blurred due to water signals), 3.21(s, 3H), 2.17(s, 3H); MS (ESI) M/z 425[ M +1 ] ]⁺。

Example 10

6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1-benzofuran

The title compound was synthesized as described in example 2 from 6-bromo-2, 3-dihydro-1-benzofuran (described in Song, z.et al. The crude product was subjected to flash chromatography using a gradient of dichloromethane and methanol (containing 1% ammonia) to give the title compound (97% yield).¹H NMR(DMSO-d₆)δ7.24(m，1H)，7.16(dd，J＝7.3，0.8Hz，1H)，6.95(s，1H)，4.49(t，J＝8.8Hz，2H)，3.18(t，J＝8.7Hz，2H)，1.27(s，12H)；MS(CI)m/z 247[M+1]⁺。

Example 11

2-amino-5- [3- (2, 3-dihydro-1-benzofuran-6-yl) phenyl ] -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized as described in example 5 from 2-amino-5- (3-bromophenyl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one and 6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1-benzofuran. The crude product was subjected to flash chromatography using a gradient of dichloromethane and methanol (containing 1% ammonia) followed by preparative HPLC to give the title compound (61% yield).¹H NMR(DMSO-d₆)δ7.68(s，1H)，7.51-7.42(m，4H)，7.38-7.27(m，4H)，7.24-7.18(m，1H)，6.98(dd，J＝7.7，1.6Hz，1H)，6.89(d，J＝1.3Hz，1H)，6.68(br s，2H)，4.56(t，J＝8.7Hz，2H)，3.19(t，J＝8.6Hz，2H)，2.99(s，3H)；MS(ESI)m/z 384[M+1]⁺。

Example 12

2-amino-5- [3- (2, 3-dihydro-1-benzofuran-6-yl) phenyl ] -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride

From 2-amino-5- [3- (2, 3-dihydro-1-benzofuran-6-yl) phenyl as described in example 6 ]-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one to synthesize the title compound in 96% yield. The crude product was subjected to flash chromatography using a gradient of dichloromethane and methanol (containing 1% ammonia) followed by preparative HPLC to give the title compound (61% yield).¹H NMR(DMSO-d₆)δ7.68(s，1H)，7.51-7.42(m，4H)，7.38-7.27(m，4H)，7.24-7.18(m，1H)，6.98(dd，J＝7.7，1.6Hz，1H)，6.89(d，J＝1.3Hz，1H)，6.68(br s，2H)，4.56(t，J＝8.7Hz，2H)，3.19(t，J＝8.6Hz，2H)，2.99(s，3H)；MS(ESI)m/z 384[M+1]⁺。

Example 13

(4- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) [2- (3' -methoxybiphenyl-3-yl) -1, 3-dithiane-2-yl ] methanol

2- (3' -Methoxybiphenyl-3-yl) -1, 3-dithiane (799mg, 2.64mmol) was dissolved in anhydrous tetrahydrofuran (10mL) and the resulting mixture was cooled to-78 ℃. N-butyllithium (1.6M in hexane, 1.82mL, 2.91mmol) was added, the resulting solution was stirred for 2h, and then 4- { [ tert-butyl (diphenyl) silyl was added]Oxy } benzaldehyde (1.00g, 2.77mmol, described in Mullen, D.G.; Barany, G., J.org. chem.53, 1988, 5240.) in tetrahydrofuran (1.5 mL). The resulting mixture was brought to ambient temperature over 4 h. Saturated aqueous ammonium chloride (10mL) was added and the organic phase was separated. The aqueous layer was extracted 3 times with dichloromethane and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give 1.80g (72% yield) of the title product, which was used without further purification. MS (ESI) M/z 645M-Water ]⁺。

Example 14

1- (4- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) -2- (3' -methoxybiphenyl-3-yl) ethane-1, 2-dione

Reacting (4- { [ tert-butyl (diphenyl) silyl group]Oxy [ phenyl ], [2- (3' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl]Methanol (1.60g, 2.41mmol) and tert-butanol (630mg, 8.44mmol) were dissolved in dichloromethane (20 mL). Adding 1, 1, 1-tri (acetoxyl) -1 lambda⁵2-Benzoiodoxy-3 (1H) -one (2.56g, 6.03mmol) and the resulting mixture was stirred for 18H. Sodium thiosulfate (2.50g) in saturated aqueous sodium bicarbonate (40mL) was added, followed by dichloromethane (20mL), and the organic phase was separated. The aqueous layer was extracted 3 times with dichloromethane, and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography (heptane: ethyl acetate gradient) afforded 1.27g (74% yield) of the title compound.¹H NMR(CDCl₃)δ8.16(t，J＝1.8Hz，1H)，7.92-7.87(m，1H)，7.87-7.83(m，1H)，7.80-7.76(m，2H)，7.72-7.67(m，4H)，7.55(t，J＝7.7Hz，1H)，7.48-7.42(m，2H)，7.42-7.36(m，5H)，7.19-7.14(m，1H)，7.12-7.09(m，1H)，6.96-6.92(m，1H)，6.86-6.82(m，2H)，3.87(s，3H)，1.11(s，9H)；MS(ESI)m/z 571[M+1]⁺。

Example 15

5- (4-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one

1- (4- { [ tert-butyl (diphenyl) silyl group]Oxy } phenyl) -2- (3' -methoxybiphenyl-3-yl) ethane-1, 2-dione (1.21g, 2.12mmol) and N-methylthiourea (382mg, 4.24mmol) were dissolved in dimethyl sulfoxide (6 mL). Aqueous potassium hydroxide (1.2M, 3.53mL, 4.24mmol) was added, and the resulting mixture was heated to 100 ℃ by microwave irradiation for 2 min. After cooling, the mixture was diluted with chloroform and water, and the pH of the aqueous phase was then adjusted to about 4 by careful addition of aqueous hydrochloric acid (2M). The two phases were separated and the aqueous layer was extracted 3 times with chloroform. The combined organic extracts were washed 3 times with water, 1 time with brine, Dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography (heptane: ethyl acetate gradient elution) afforded 525mg (55% yield) of the title compound.¹H NMR(CDCl₃)δ8.11(s，1H)，7.60-7.52(m，2H)，7.44(t，J＝7.8Hz，1H)，7.36-7.31(m，2H)，7.20-7.15(m，2H)，7.12-7.08(m，1H)，7.07-7.04(m，1H)，6.92-6.88(m，1H)，6.82-6.77(m，2H)，3.84(s，3H)，3.34(s，3H)；MS(ESI)m/z405[M+1]⁺。

Example 16

Methanesulfonic acid 4- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester

5- (4-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one (150mg, 0.37mmol) was dissolved in dichloromethane (3mL) and then cooled to 0 ℃. Triethylamine (52. mu.L, 0.37mmol) was added followed by methanesulfonyl chloride (32. mu.L, 0.41mmol), and after 5min the mixture was allowed to reach ambient temperature. After 2.5h, the mixture was cooled to 0 ℃ and then additional triethylamine (10 μ L, 0.07mmol) was added, followed by methanesulfonyl chloride (7 μ L, 0.09 mmol). The mixture was warmed to ambient temperature and stirred for 2.5 h. Then, it was diluted with dichloromethane and washed with aqueous hydrochloric acid (1.2M). The aqueous layer was extracted again with dichloromethane and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (heptane: ethyl acetate gradient elution) afforded 141mg (79% yield) of the title compound. ¹H NMR(CDCl₃)δ8.23(s，1H)，7.62-7.58(m，1H)，7.51(t，J＝1.77Hz，1H)，7.49-7.43(m，3H)，7.37-7.28(m，4H)，7.12-7.08(m，1H)，7.06-7.03(m，1H)，6.93-6.88(m，1H)，3.84(s，3H)，3.34(m，3H)，3.17(s，3H)；MS(ESI)m/z 483[M+1]⁺。

Example 17

Methanesulfonic acid 4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester

From methanesulfonic acid 4- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl as described in example 4]Phenyl ester, except purified by flash chromatography (heptane: ethyl acetate gradient elution) to afford 87mg (64% yield) of the title compound.¹H NMR(CDCl₃)δ7.70(t，J＝1.8Hz，1H)，7.61-7.55(m，2H)，7.51-7.47(m，1H)，7.46-7.42(m，1H)，7.39-7.29(m，2H)，7.22-7.16(m，2H)，7.15-7.11(m，1H)，7.10-7.06(m，1H)，6.90-6.85(m，1H)，5.56(br s，2H)，3.82(s，3H)，3.08(s，3H)，3.06(s，3H)；MS(ESI)m/z 466[M+1]⁺。

Example 18

Methanesulfonic acid 4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride

From methanesulfonic acid 4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl as described in example 6]The title compound was synthesized in 88% yield from phenyl ester. MS (ESI) M/z 466[ M +1 ]]⁺。

Example 19

4- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl trifluoromethanesulfonate

5- (4-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one (150mg, 0.37mmol) was dissolved in dichloromethane (3mL) and then cooled to 0 ℃. Triethylamine (57. mu.L, 0.41mmol) was added, followed by trifluoromethanesulfonic anhydride (69. mu.L, 0.41mmol), and after 5 minutes the mixture was allowed to reach ambient temperature. After 2.5h, the mixture was diluted with dichloromethane and washed with aqueous hydrochloric acid (1.2M). The aqueous layer was extracted again with dichloromethane and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (heptane: ethyl acetate gradient elution) afforded 101mg (51% yield) of the title compound. ¹H NMR(CDCl₃)δ8.25(s，1H)，7.63-7.58(m，1H)，7.54-7.45(m，4H)，7.38-7.27(m，4H)，7.12-7.06(m，1H)，7.05-7.02(m，1H)，6.93-6.88(m，1H)，3.84(s，3H)，3.35(s，3H)；MS(ESI)m/z 537[M+1]⁺。

Example 20

4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate

From trifluoromethanesulfonic acid 4- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl radical as described in example 4]Phenyl ester, except purified by flash chromatography (heptane: ethyl acetate gradient elution) to afford 23mg (24% yield) of the title compound.¹HNMR(CDCl₃)δ7.70-7.64(m，3H)，7.53-7.48(m，1H)，7.46-7.41(m，1H)，7.41-7.30(m，2H)，7.23-7.18(m，2H)，7.15-7.10(m，1H)，7.09-7.06(m，1H)，6.91-6.86(m，1H)，5.08(br s，2H)，3.83(s，3H)，3.11(s，3H)；MS(ESI)m/z520[M+1]⁺。

Example 21

4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate hydrochloride

From trifluoromethanesulfonic acid 4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl as described in example 6]The title compound was synthesized in 86% yield from phenyl ester. MS (ESI) M/z 520[ M +1 ]]⁺。

Example 22

2-amino-5- (3' -hydroxybiphenyl-3-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized as described in example 5 from 2-amino-5- (3-bromo-phenyl) -3-methyl-5-phenyl-3, 5-dihydro-imidazol-4-one and 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol. After completion of the reaction, the solvent was evaporated and the residue was purified by flash chromatography (using a gradient of dichloromethane/methanol as eluent) to give the title compound in 19% yield. MS (ESI) M/z357[ M +1 ] ]⁺。

Example 23

Trifluoromethanesulfonic acid 3' - (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) biphenyl-3-yl ester hydrochloride

2-amino-5- (3' -hydroxybiphenyl-3-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one (76mg, 0.21mmol), N-phenyl-bis (trifluoromethanesulfonyl) imide (76mg, 0.21mmol), anhydrous potassium carbonate (178mg, 1.29mmol), and tetrahydrofuran (1mL) were mixed, followed by microwave irradiation to 120 ℃ for 6 min. The mixture was filtered, the solvent evaporated and the residue purified by flash chromatography (using a gradient of dichloromethane/methanol as eluent) to give 80mg of base. The base was dissolved in dichloromethane (3mL) and hydrochloric acid (1M in ether, 0.36 mL). The mixture was stirred at room temperature for 5min, then the solvent was evaporated to give 86mg (77% yield) of the title compound.¹H NMR(DMSO-d₆)δ11.62(br s，1H)，9.59(br s，2H)，7.78(m，2H)，7.74-7.67(m，3H)，7.59(t，J＝7.8Hz，1H)，7.53(m，1H)，7.48-7.41(m，3H)，7.41-7.37(m，3H)，3.21(s，3H)；MS(ESI)m/z 490[M+1]⁺。

Example 24

4-methoxy-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol

The title compound was synthesized as described in example 2, using 2-bromo-4-methoxyphenol as starting material. The product was used in the next step without purification.

Example 25

2-amino-5- (2 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized as described in example 5 using 4-methoxy-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol as the starting material to give the title compound in 43% yield. MS (ES) M/z 388[ M +1 ]]⁺。

Example 26

Trifluoromethanesulfonic acid 3' - (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-2-ol hydrochloride

The title compound was synthesized as described in example 23 using 2-amino-5- (2 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one as starting material to give the title compound in 47% yield.¹H NMR(DMSO-d₆)δ11.44(br s，1H)，9.55(br s，2H)，7.63-7.54(m，2H)，7.51-7.46(m，3H)，7.46-7.40(m，3H)，7.38-7.32(m，2H)，7.12(dd，J＝9.3，3.0Hz，1H)，7.05(d，J＝3.3Hz，1H)，3.84(s，3H)，3.18(s，3H)；MS(ESI)m/z 520[M+1]⁺。

Example 27

1- (3-hydroxyphenyl) -2-phenylethane-1, 2-dione

3- (Phenylethynyl) phenol (1.80g, 9.27mmol, described in Mohamed Ahmed, M.S.; Mori)Tetrahedron 2004, 60, 9977. meso) and palladium dichloride (0.176g, 0.992mmol) in dimethylsulfoxide (25mL) were heated at 140 ℃ for 5 h. The solvent was evaporated and the residue was purified by flash chromatography using a gradient of heptane/ethyl acetate as eluent to yield 1.057g (50% yield) of the title compound.¹H NMR(DMSO-d₆)δ10.08(br s，1H)，7.90(d，J＝7.3Hz，2H)，7.80(m，1H)，7.63(m，2H)，7.43(m，1H)，7.30(m，2H)，7.17(m，1H)；MS(ESI)m/z 225[M-1]^-。

Example 28

5- (3-hydroxyphenyl) -3-methyl-5-phenyl-2-thioimidazolidin-4-one

The title compound was synthesized as described in example 3 using 1- (3-hydroxyphenyl) -2-phenylethane-1, 2-dione as starting material to give the title compound in 99% yield.¹H NMR(DMSO-d₆)δ11.56(br s，1H)，9.60(br s，1H)，7.45-7.36(m，3H)，7.34(m，2H)，7.20(m，1H)，6.73(m，3H)，3.17(s，3H)；MS(ESI)m/z 297[M-1]^-。

Example 29

Methanesulfonic acid 3- (1-methyl-5-oxo-4-phenyl-2-thioimidazolidin-4-yl) phenyl ester

Triethylamine (0.38mL, 2.73mmol) was added to a cooled (0 ℃ C.) solution of 5- (3-hydroxyphenyl) -3-methyl-5-phenyl-2-thioimidazolidin-4-one (0.165g, 0.55mmol) in dichloromethane (4mL), followed by methanesulfonyl chloride (0.050mL, 0.65 mmol). The resulting mixture was stirred at 0 ℃ for 1.5h, thenWarm to ambient temperature. Dichloromethane was added and the organic phase was washed with aqueous hydrochloric acid (2M) and water, dried over magnesium sulfate and concentrated in vacuo to give the title compound which was used in the next step without purification. MS (ESI) M/z 375[ M-1 ]]^-。

Example 30

Methanesulfonic acid 3- (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) phenyl ester hydrochloride

The title compound was synthesized as described in example 4 using 3- (1-methyl-5-oxo-4-phenyl-2-thioimidazolidin-4-yl) phenyl methanesulfonate as starting material to give 79mg (40% yield) of base. The base was dissolved in dichloromethane, hydrochloric acid (1M in ether, 0.44mL) was added, and the resulting mixture was stirred at ambient temperature for 10 min. Evaporation of the solvent gave 87mg (100% yield) of the title compound. ¹H NMR(DMSO-d₆)δ11.73(br s，1H)，9.69(br s，2H)，7.59(t，J＝8.0Hz，1H)，7.50-7.40(m，5H)，7.39-7.32(m，3H)，3.41(s，3H)，3.20(s，3H)；MS(ESI)m/z 360.0[M+1]⁺。

Example 31

2-amino-5- (3-hydroxyphenyl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized as described in example 4 using 5- (3-hydroxyphenyl) -3-methyl-5-phenyl-2-thioimidazolidin-4-one as starting material to give the title compound in 80% yield.¹H NMR(DMSO-d₆)δ10.73(br s，1H)，9.29(br s，2H)，7.42(m，2H)，7.28(m，2H)，7.22(m，1H)，7.06(m，1H)，6.85(m，2H)，6.59(m，1H)，2.97(s，3H)；MS(ESI)m/z 282[M+1]⁺。

Example 32

Trifluoromethanesulfonic acid 3- (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) phenyl ester hydrochloride

The title compound was synthesized as described in example 23 using 2-amino-5- (3-hydroxyphenyl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one as the starting material to give the title compound in 35% yield.¹H NMR(DMSO-d₆)δ11.70(br s，1H)，9.72(br s，2H)，7.69(t，J＝8.0Hz，1H)，7.61(m，1H)，7.56(m，1H)，7.50-7.42(m，4H)，7.34(m，2H)，3.20(s，3H)；MS(ESI)m/z 414[M+1]⁺。

Example 33

3-bromo-4- { [ tert-butyl (diphenyl) silyl ] oxy } benzaldehyde

3-bromo-4-hydroxybenzaldehyde (505mg, 2.51mmol) and imidazole (342mg, 5.02mmol) were dissolved in dimethylformamide (15mL) under a nitrogen atmosphere. Tert-butyldiphenylchlorosilane (898mg, 3.27mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 3 h. Dichloromethane and water were added and then the two phases were separated. The organic phase was dried over sodium sulfate and then concentrated in vacuo. The crude product was purified by flash chromatography (heptane: ethyl acetate gradient elution) to yield 501mg (45% yield) of the title compound. ¹H NMR(CDCl₃) δ ppm 9.76(s, 1H), 8.11(d, J ═ 2.0Hz, 1H), 7.73(m, 4H), 7.51-7.37(m, 7H), 6.54(d, J ═ 8.3Hz, 1H), 1.17(s, 9H); MS (ESI) M/z 439 and 441[ M +1 ]]⁺。

Example 34

3-bromo-4- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) (2-phenyl-1, 3-dithian-2-yl) methanol

From 2-phenyl-1, 3-dithiane (213mg, 1.08mmol) and 3-bromo-4- { [ tert-butyl (diphenyl) silyl as described in example 13]Oxy } benzaldehyde (500mg, 1.14mmol) to synthesize the title compound. The crude product was purified by flash chromatography (heptane: ethyl acetate gradient elution) to yield 633mg (92% yield) of the title compound.¹H NMR(DMSO-d₆) δ ppm 7.65(m, 4H), 7.54-7.42(m, 8H), 7.25-7.21(m, 3H), 6.84(d, J ═ 2.0Hz, 1H), 6.40(dd, J ═ 8.4, 2.1Hz, 1H), 6.15(d, J ═ 8.3Hz, 1H), 5.94(br s, 1H), 4.77(s, 1H), 2.70(m, 2H), 2.47-2.31(m, 2H), 1.82(m, 1H), 1.67(m, 1H), 1.06(s, 9H); MS (ESI) M/z617 and 619[ M + 1-Water]⁺。

Example 35

1- (3-bromo-4- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) -2-phenylethane-1, 2-dione

From 3-bromo-4- { [ tert-butyl (diphenyl) silyl as described in example 14]Oxy } phenyl) (2-phenyl-1, 3-dithian-2-yl) methanol to synthesize the title compound. The crude product was purified by flash chromatography (heptane: ethyl acetate) Elution) to afford the title compound in 80% yield.¹H NMR(DMSO-d₆) δ 8.19(d, J ═ 2.3Hz, 1H), 7.92-7.86(m, 2H), 7.80-7.73(m, 1H), 7.71-7.66(m, 4H), 7.64-7.56(m, 3H), 7.55-7.44(m, 5H), 7.41-7.36(m, 1H), 6.55(d, J ═ 8.5Hz, 1H), 1.09(s, 9H); MS (ESI) M/z 543 and 545[ M +1 ]]⁺。

Example 36

5- (3-bromo-4-hydroxyphenyl) -3-methyl-5-phenyl-2-thioimidazolidin-4-one

From 1- (3-bromo-4- { [ tert-butyl (diphenyl) silyl as described in example 3]Oxy } phenyl) -2-phenylethane-1, 2-dione to synthesize the title compound, except that the product was extracted from the acidified aqueous phase with dichloromethane, dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography (heptane: ethyl acetate gradient) to afford the title compound in 67% yield.¹H NMR(DMSO-d₆) δ 11.54(s, 1H), 10.58(br s, 1H), 7.44-7.35(m, 4H), 7.29(m, 2H), 7.16(dd, J ═ 8.5, 2.3Hz, 1H), 6.98(d, J ═ 8.8Hz, 1H), 3.17(s, 3H); MS (ESI) M/z 377 and 379[ M +1 ]]⁺。

Example 37

2-amino-5- (3-bromo-4-hydroxyphenyl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized from 5- (3-bromo-4-hydroxyphenyl) -3-methyl-5-phenyl-2-thioimidazolidin-4-one as described in example 4, except that the reaction mixture was stirred at 35 deg.C Stir until reaction is complete as judged by HPLC. The crude product was purified by flash chromatography (dichloromethane: methanol (containing 1% ammonia) gradient elution) to afford the title compound in 80% yield.¹H NMR(DMSO-d₆) δ 7.50(d, J ═ 1.5Hz, 1H), 7.38(d, J ═ 7.5Hz, 2H), 7.31-7.19(m, 4H), 6.87(d, J ═ 8.5Hz, 1H), 2.97(s, 3H); MS (ESI) M/z 360 and 362[ M +1 ]]⁺。

Example 38

2-amino-5- (6-hydroxy-3' -methoxybiphenyl-3-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized from 2-amino-5- (3-bromo-4-hydroxyphenyl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one and (3-methoxyphenyl) boronic acid as described in example 5. The crude product was purified by flash chromatography (dichloromethane: methanol (containing 1% ammonia) gradient elution) to afford the title compound in 27% yield. MS (ESI) M/z 388[ M +1 ]]⁺。

Example 39

Trifluoromethanesulfonic acid 5- (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) -3' -methoxybiphenyl-2-ester

2-amino-5- (6-hydroxy-3' -methoxybiphenyl-3-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one (14mg, 0.036mmol), N-phenyl-bis (trifluoromethanesulfonyl) imide (20mg, 0.054mmol), anhydrous potassium carbonate (30mg, 0.216mmol), and tetrahydrofuran (1.5mL) were mixed and then irradiated to 120 ℃ with microwave for 18 min. Adding another part of N-phenyl-di (trifluoromethanesulfonyl) imide (40mg, 0.018mmol) and then the reaction mixture was irradiated with microwaves to 120 ℃ for 18min to ensure complete conversion. Dichloromethane was added and the mixture was filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography (dichloromethane: methanol (containing 1% ammonia) gradient) followed by preparative HPLC to give 4mg (21% yield) of the title compound.¹HNMR(CDCl₃)δ7.66(d，J＝2.3Hz，1H)，7.58(dd，J＝8.7，2.4Hz，1H)，7.50-7.45(m，2H)，7.37-7.29(m，5H)，7.03(m，1H)，6.99(m，1H)，6.94(ddd，J＝8.3，2.6，1.0Hz，1H)，3.84(s，3H)，3.13(s，3H)；MS(ESI)m/z 520[M+1]⁺。

Example 40

2- (3' -methoxybiphenyl-3-yl) -1, 3-dithiane

Boron trifluoride-diethyl ether complex (14mL, 110mmol) was added dropwise to a cooled (0 ℃ C.) solution of 3' -methoxybiphenyl-3-carbaldehyde (5.95g, 28.0mmol, described in Mor, M.et al.J. Med.chem.2004, 47, 4998.) and 1, 3-propanedithiol (2.8mL, 28mmol) in dichloromethane (80 mL). The resulting mixture was stirred at 0 ℃ for 1 h. Saturated aqueous sodium bicarbonate was added and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, aqueous potassium hydroxide (10%) and water, dried over magnesium sulfate and concentrated in vacuo to give 8.36g (99% yield) of the title compound.¹H NMR(DMSO-d₆)δ7.68(s，1H)，7.62(m，1H)，7.49-7.35(m，3H)，7.19(t，J＝7.8Hz，1H)，7.15(m，1H)，6.96(m，1H)，5.47(s，1H)，3.83(s，3H)，3.10(m，2H)，2.91(m，2H)，2.14(m，1H)，1.75(m，1H)；MS(ESI)m/z 303[M+1]⁺。

EXAMPLE 41

(3- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) [2- (3' -methoxybiphenyl-3-yl) -1, 3-dithiane-2-yl ] methanol

From 2- (3' -methoxybiphenyl-3-yl) -1, 3-dithiane and 3- { [ tert-butyl (diphenyl) silyl as described in example 13]Oxy benzaldehyde (described inT.et al tetrahedron 2000, 56, 1873) to synthesize the title compound. The crude product was purified by flash chromatography using cyclohexane/ethyl acetate (20: 1) as eluent to give the title compound in 39% yield.¹H NMR(DMSO-d₆)δ7.73(br s，1H)，7.68(d，J＝7.8Hz，1H)，7.62-7.56(m，4H)，7.51(d，J＝7.8Hz，1H)，7.47-7.29(m，8H)，7.02(d，J＝7.8Hz，1H)，6.95-6.90(m，2H)，6.81(t，J＝7.8Hz，1H)，6.45-6.39(m，2H)，6.34(d，J＝7.8Hz，1H)，5.93(d，J＝4.3Hz，1H)，4.78(d，J＝3.8Hz，1H)，3.75(s，3H)，2.76-2.62(m，2H)，2.49-2.35(m，2H)，1.88-1.79(m，1H)，1.73-1.60(m，1H)，0.96(s，9H)。

Example 42

1- (3- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) -2- (3' -methoxybiphenyl-3-yl) ethane-1, 2-dione

From (3- { [ tert-butyl (diphenyl) silyl as described in example 14]Oxy } phenyl) [2- (3' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl]Methanol to synthesize the title compound. The crude product was purified by flash chromatography (using isopropyl ether)As eluent) to yield 1g (73% yield) of the title compound.¹HNMR(DMSO-d₆)δ8.11-8.06(m，1H)，7.98-7.94(m，1H)，7.73-7.64(m，2H)，7.60(dd，J＝7.8，1.5Hz，4H)，7.50-7.33(m，9H)，7.25-7.18(m，3H)，7.17-7.15(m，1H)，7.02(dd，J＝8.0，2.3Hz，1H)，3.84(s，3H)，1.04(s，9H)。

Example 43

5- (3-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one

From 1- (3- { [ tert-butyl (diphenyl) silyl as described in example 15]Oxy } phenyl) -2- (3' -methoxybiphenyl-3-yl) ethane-1, 2-dione, except that the product was used without purification. The product was dried in a vacuum oven at 35 ℃ overnight to give the title compound in 77% yield. ¹H NMR(DMSO-d₆)δ11.63(s，1H)，9.61(s，1H)，7.71-7.66(m，1H)，7.64-7.61(m，1H)，7.52(t，J＝7.8Hz，1H)，7.43-7.36(m，2H)，7.24-7.12(m，3H)，6.97(dd，J＝7.9，2.1Hz，1H)，6.77-6.72(m，3H)，3.81(s，3H)，3.19(s，3H)；MS(ESI)m/z 403[M-1]^-。

Example 44

Trifluoromethanesulfonic acid 3- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester

Mixing 5- (3-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one (0.1g, 0.24mmol), 1, 1, 1-trifluoro-N-phenyl-N- [ (trifluoromethyl) sulfonyl group]A mixture of methanesulfonamide (0.088g, 0.24mmol) and aqueous potassium carbonate (0.21g, 1.50mmol) in anhydrous tetrahydrofuran (3mL) was heated in a microwave reactor at 120 ℃ for 6 minutes. The mixture was evaporated, ethyl acetate was added, and then insoluble materials were removed by filtration. Evaporation of the solution gave 125mg (97% yield) of the title compound.¹H NMR(CDCl₃，600MHz)δ8.07(s，1H)，7.61(d，J＝7.7Hz，1H)，7.53-7.44(m，4H)，7.37-7.30(m，3H)，7.28-7.25(m，1H)，7.09(d，J＝7.7Hz，1H)，7.05-7.02(m，1H)，6.91(dd，J＝8.3，2.6Hz，1H)，3.85(s，3H)，3.36(s，3H)；MS(ESI)m/z 535.0[M-1]^-。

Example 45

3- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate hydrochloride

Tert-butyl hydroperoxide (70% in water, 0.40mL) was added to trifluoromethanesulfonic acid 3- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl]A solution of phenyl ester (160mg, 0.30mmol) in ethanol (5mL) and aqueous ammonia (25%, 2.5 mL). The resulting mixture was stirred at 35 ℃ overnight, then poured into water (5mL) and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash chromatography (using acetonitrile/triethylamine (90: 10) as eluent) to give 35mg of base. The base was dissolved in dichloromethane and then treated with a solution of hydrochloric acid (4M) in ether. The mixture was concentrated in vacuo and the residue was dried in a vacuum oven at 45 ℃ overnight to yield 45mg (27% yield) of the title compound. ¹H NMR(DMSO-d₆)δ11.79(br s，1H)，9.73(br s，2H)，7.74(d，J＝8.0Hz，1H)，7.68(d，J＝8.3Hz，1H)，7.63-7.58(m，3H)，7.56-7.52(m，2H)，7.42-7.34(m，2H)，7.19-7.13(m，2H)，6.97(dd，J＝8.2，1.9Hz，1H)，3.81(s，3H)，3.20(s，3H)；MS(ESI)m/z 518[M-1]^-。

Example 46

Methanesulfonic acid 3- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester

The title compound was synthesized in 95% yield from 5- (3-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one as described in example 29.¹H NMR(CDCl₃，600MHz)δ7.96(br s，1H)，7.60(d，J＝7.7Hz，1H)，7.49-7.45(m，3H)，7.40(d，J＝8.3Hz，1H)，7.37-7.33(m，2H)，7.32-7.30(m，1H)，7.30-7.27(m，1H)，7.10(d，J＝7.7Hz，1H)，7.06-7.03(m，1H)，6.91(dd，J＝8.0，2.0Hz，1H)，3.85(s，3H)，3.36(s，3H)，3.15(s，3H)；MS(ESI)m/z 481[M-1]^-。

Example 47

Methanesulfonic acid 3- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride

3- [4- (3' -Methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] methanesulfonate as described in example 45]Phenyl ester was used to synthesize the title compound except that the hydrochloride salt formed was precipitated by the addition of diethyl ether and the product was collected by filtration in 35% yield.¹H NMR(DMSO-d₆)δ11.71(br s，1H)，9.67(br s，2H)，7.73(d，J＝7.8Hz，1H)，7.65-7.57(m，2H)，7.54(t，J＝7.9Hz，1H)，7.48-7.42(m，2H)，7.42-7.35(m，3H)，7.20-7.14(m，2H)，6.97(dd，J＝8.0，2.3Hz，1H)，3.81(s，3H)，3.41(s，3H)，3.20(s，3H)；MS(ESI)m/z 464.0[M-1]^-。

Example 48

5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1-benzofuran

The title compound was synthesized as described in example 2 from 5-bromo-2, 3-dihydro-1-benzofuran in 99% yield.¹H-NMR(DMSO-d₆)：δ7.52(s，1H)，7.40-7.45(m，1H)，6.75(d，J＝7.8Hz，1H)，4.53(t，J＝8.8Hz，2H)，3.16(t，J＝8.8Hz，2H)，1.26(s，6H)，1.16(s，6H)；MS(CI)m/z 247[M+1]⁺。

Example 49

2-amino-5- [3- (2, 3-dihydro-1-benzofuran-5-yl) phenyl ] -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized as described in example 5 from 2-amino-5- (3-bromo-phenyl) -3-methyl-5-phenyl-3, 5-dihydro-imidazol-4-one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1-benzofuran in 20% yield. MS (ESI) M/z 384[ M +1 ] ]⁺。

Example 50

2-amino-5- [3- (2, 3-dihydro-1-benzofuran-5-yl) phenyl ] -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride

From 2-amino-5- [3- (2, 3-dihydro-1-benzofuran-5-yl) phenyl as described in example 6]-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one to synthesize the title compound in 99% yield.¹HNMR(DMSO-d₆) δ 11.61(s, 1H), 9.61(s, 2H), 7.27-7.66(m, 11H), 6.85(d, J ═ 8.3Hz, 1H), 4.56(t, J ═ 8.8Hz, 2H), 3.23(t, J ═ 8.8Hz, 2H, blurred due to the signal at 3.21), 3.21(s, 3H); MS (ESI) M/z 384[ M +1 ]]⁺。

Example 51

2, 3-dihydro-1-benzofuran-5-yl (2-phenyl-1, 3-dithian-2-yl) methanol

From 2-phenyl- [1, 3 ] as described in example 13]Dithiane and 2, 3-dihydro-benzofuran-5-carbaldehyde. The product was purified by flash chromatography (n-heptane/ethyl acetate) to yield the title compound in 82% yield.¹H NMR(CDCl₃)δ7.73(ddd，J＝6.38，1.71，1.52Hz，2H)，7.28-7.36(m，3H)，6.71(s，1H)，6.51-6.60(m，2H)，4.94(s，1H)，4.53(t，J＝8.84Hz，2H)，3.08(t，J＝8.72Hz，2H)，2.65-2.77(m，4H)，1.89-2.00(m，2H)。

Example 52

1- (2, 3-dihydro-1-benzofuran-5-yl) -2-phenylethane-1, 2-dione

From (2, 3-dihydro-benzofuran-5-yl) - (2-phenyl- [1, 3) as described in example 14]Dithiane-2-yl) -methanol the title compound was synthesized in 65% yield. ¹H NMR(CDCl₃)δ7.96-8.02(m，2H)，7.87(d，J＝1.52Hz，1H)，7.81(dd，J＝8.46，1.89Hz，1H)，7.62-7.69(m，1H)，7.48-7.55(m，2H)，6.86(d，J＝8.34Hz，1H)，4.70(t，J＝8.84Hz，2H)，3.27(t，J＝8.72Hz，2H)；MS(CI)m/z 253[M+1]⁺。

Example 53

5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-5-phenyl-2-thioimidazolidin-4-one

The title compound was synthesized as described in example 3 from 1- (2, 3-dihydro-1-benzofuran-5-yl) -2-phenylethane-1, 2-dione, but with the different steps: water (30mL) was added and the pH was adjusted to 5 with concentrated HCl. The product was extracted with dichloromethane (3X 30 mL). The combined organic phases were concentrated in vacuo and the product was purified by flash chromatography (n-heptane/ethyl acetate) to yield the title compound in 71% yield.¹H NMR(CDCl₃)δ7.46(s，1H)，7.33-7.42(m，5H)，7.11(s，1H)，7.02(dd，J＝8.34，2.27Hz，1H)，6.76(d，J＝8.59Hz，1H)，4.60(t，J＝8.72Hz，2H)，3.34(s，3H)，3.19(t，J＝8.72Hz，2H)；MS(ESI)m/z 323[M-1]^-。

Example 54

2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized from 5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-5-phenyl-2-thioimidazolidin-4-one as described in example 4, except that the reaction was carried out for 3 h. The product was purified by flash chromatography (n-heptane/ethyl acetate) to yield the title compound in 84% yield.¹H NMR(CDCl₃)δppm 7.43-7.49(m，2H)，7.28-7.36(m，3H)，7.24(s，1H)，7.18(dd，J＝8.34，2.02Hz，1H)，6.72(d，J＝8.59Hz，1H)，4.55(t，J＝8.72Hz，2H)，3.16(t，2H)，3.14(s，3H)；MS(ESI)m/z 308[M+1]⁺。

Example 55

2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride

The title compound was synthesized from 2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one as described in example 6.

Examples 56 and 57

(R) -4- [ 2-amino-4- (3 '-methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate hydrochloride and (S) -4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate hydrochloride

Chromatographic separation of the enantiomers of 4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate hydrochloride

4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate hydrochloride (50mg) was dissolved in ethanol (7mL), and the resulting solution was divided into two equal parts. Chiral HPLC separation (using heptane: ethanol (70: 30) as eluent at a flow rate of 12mL/min) was performed on a Chiralpak AD chromatography column (21.2X 250 mm). Detection was performed at 254nm, and both isomers were collected and then concentrated in vacuo.

Isomer 1, example 56

The eluted previous enantiomer (23mg, 50. mu. mol) was dissolved in chloroform (1mL) and then treated with hydrochloric acid (1.0M in ether, 50. mu.L, 50. mu. mol) to give the hydrochloride salt. The resulting mixture was concentrated to dryness to give 23mg of (S) -4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl methanesulfonate ]Phenyl ester hydrochloride.¹H NMR(CDCl₃)δ7.71(t，J＝1.8Hz，1H)，7.64-7.61(m，2H)，7.53-7.45(m，2H)，7.42-7.32(m，2H)，7.27-7.23(m，2H)，7.16-7.13(m，1H)，7.10-7.08(m，1H)，6.91-6.88(m，1H)，3.86(s，3H)，3.15(s，3H)，3.12(s，3H)；MS(ESI)m/z 466[M+1]⁺。

Isomer 2, example 57

The eluted latter enantiomer (25mg, 55. mu. mol) was treated in the same manner as isomer 1 to give 25mg of (R) -4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl methanesulfonate]Phenyl ester hydrochloride.¹H NMR(CDCl₃)δ7.72(t，J＝1.6Hz，1H)，7.65-7.60(m，2H)，7.54-7.45(m，2H)，7.42-7.31(m，2H)，7.27-7.23(m，2H)，7.17-7.13(m，1H)，7.10-7.08(m，1H)，6.92-6.87(m，1H)，3.86(s，3H)，3.14(s，3H)，3.12(s，3H)；MS(ESI)m/z 466[M+1]⁺。

Example 58

2-amino-3-methyl-5- [3- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) phenyl ] -5-phenyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized as described in example 5 from 2-amino-5- (3-bromophenyl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one and 4-methyl-7- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydro-2H-1, 4-benzoxazine. Flash chromatography of the crude product (using a gradient of dichloromethane and methanol (containing 1% ammonia)) afforded the title compound (19% yield).¹H NMR(DMSO-d₆)δ7.62(s，1H)，7.48-7.19(m，8H)，7.00-6.95(m，1H)，6.85-6.83(m，1H)，6.75(d，J＝8.28Hz，1H)，4.28-4.22(m，2H)，3.27-3.23(m，2H)，2.99(s，3H)，2.85(s，3H)；MS(ESI)m/z 413[M+1]⁺。

Example 59

2-amino-3-methyl-5- [3- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) phenyl ] -5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride

From 2-amino-3-methyl-5- [3- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) phenyl as described in example 6]-5-phenyl-3, 5-dihydro-4H-imidazol-4-one to synthesize the title compound in 99% yield. ¹H NMR(DMSO-d₆)δppm 11.64(s，1H)，9.63(s，2H)，7.60(d，J＝7.78Hz，1H)，7.55-7.51(m，1H)，7.48-7.36(m，6H)，7.25(d，J＝8.78Hz，1H)，7.06(dd，J＝8.28，2.26Hz，1H)，6.95(d，J＝2.26Hz，1H)，6.76(d，J＝8.28Hz，1H)，4.27-4.20(m，2H)，3.29-3.24(m，2H)，3.21(s，3H)，2.86(s，3H)；MS(ESI)m/z413[M+1]⁺。

Example 60

2-acetyl-5-chloro-1, 2, 3, 4-tetrahydroisoquinoline

The title compound was synthesized as described in example 1 from 5-chloro-1, 2, 3, 4-tetrahydroisoquinoline in 100% yield.¹H NMR(DMSO-d₆)δppm 7.32(d，J＝7.03Hz，1H)，7.26-7.17(m，2H)，4.67-4.61(m，2H)，3.70(td，J＝6.02，2.51Hz，2H)，2.86(t，J＝6.02Hz，1H)，2.74(t，J＝6.02Hz，1H)，2.10-2.07(m，3H)；MS(ESI)m/z 210[M+1]⁺。

Example 61

2-acetyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline

Mixing tris [ di (benzylidene) acetone]The dipalladium chloroform adduct (21mg, 0.02mmol) and tricyclohexylphosphine (26mg, 0.09mmol) were dissolved in 1, 2-dimethoxyethane (4mL) and stirred at ambient temperature for 30 min. 2-acetyl-5-chloro-1, 2, 3, 4-tetrahydroisoquinoline (140mg, 0.67mmol), 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -di-1, 3, 2-dioxaborolane (188mg, 0.74mmol) and potassium acetate (99mg, 1.01mmol) were added, and then the resulting mixture was irradiated with microwaves and maintained at 150 ℃ for 2 hours. When cooled to ambient temperature, the mixture was diluted with water (4mL) and then with diethyl ether (3X 5)mL) was extracted. The combined organic extracts were passed through a silica gel pad. The product fractions were collected and then concentrated to give the title compound (96mg, 32% yield). MS (ESI) M/z 302[ M +1 ]]⁺。

Example 62

5- [3- (2-acetyl-1, 2, 3, 4-tetrahydroisoquinolin-5-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized as described in example 5 from 2-amino-5- (3-bromophenyl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one and 2-acetyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline in 23% yield.¹H NMR(CDCl₃)δppm 7.54-7.07(m，12H)，4.77-4.59(m，2H)，3.76-3.43(m，2H)，3.16-3.06(m，3H)，2.82-2.60(m，2H)，2.22-2.08(m，3H)；MS(ESI)m/z 439[M+1]⁺。

Example 63

5- [3- (2-acetyl-1, 2, 3, 4-tetrahydroisoquinolin-5-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride

From 5- [3- (2-acetyl-1, 2, 3, 4-tetrahydroisoquinolin-5-yl) phenyl as described in example 6]-2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one to synthesize the title compound in 89% yield. MS (ESI) M/z 439[ M +1 ]]⁺。

Examples 64 and 65

(R) -4- [ 2-amino-4- (3 '-methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate hydrochloride and (S) -4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate hydrochloride

Chromatographic separation of the enantiomers of 4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate hydrochloride

4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate hydrochloride (16mg) was dissolved in a mixture of isopropanol (2mL) and heptane (2 mL). Chiral HPLC separation (flow rate 12mL/min using heptane: isopropanol (90: 10) as eluent) was performed on a Chiralpak AD column (21.2X 250 mm). Detection was performed at 254nm, and both isomers were collected and then concentrated in vacuo.

Isomer 1, example 64

The former enantiomer was eluted at 4.4 mg.¹H NMR(CDCl₃)δ7.70-7.64(m，3H)，7.53-7.49(m，1H)，7.46-7.36(m，2H)，7.36-7.31(m，1H)，7.25-7.20(m，2H)，7.15-7.10(m，1H)，7.09-7.06(m，1H)，6.91-6.86(m，1H)，3.84(s，3H)，3.15(s，3H)；MS(ESI)m/z 520[M+1]⁺。

Isomer 2, example 65

The latter enantiomer was eluted at 4.5 mg.¹H NMR(CDCl₃)δ7.71-7.64(m，3H)，7.53-7.48(m，1H)，7.45-7.38(m，2H)，7.37-7.31(m，1H)，7.25-7.19(m，2H)，7.15-7.10(m，1H)，7.09-7.05(m，1H)，6.92-6.86(m，1H)，3.84(s，3H)，3.13(s，3H)；MS(ESI)m/z 520[M+1]⁺。

Example 66

(4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) (2-phenyl-1, 3-dithian-2-yl) methanol

2-phenyl- [1, 3]Dithiane (527mg, 2,69mmol) was dissolved under nitrogen in 15mL anhydrous tetrahydrofuran and then cooled to-78 ℃. N-butyllithium (1,18mL, 2,5M) was added dropwise via syringe. The solution was stirred at-78 ℃ for 20min and then treated with 4-methyl-3, 4-dihydro-2H-1, 4-benzoxazine-7-carbaldehyde (500mg, 2,82mmol) by syringe. The reaction mixture was stirred for a further 20min and then allowed to reach room temperature. After 1 hour, 20mL of ammonium chloride (saturated) was added to the reaction mixture, which was then extracted with dichloromethane (2X 20 mL). The combined organic phases were concentrated in vacuo and the product was isolated by flash chromatography (ethyl acetate/n-heptane) to yield 290mg (14% yield) of the title compound which was used in the next step without further purification. Ms (esi): m/z 374[ M +1 ] ]⁺。

Example 67

1- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) -2-phenylethane-1, 2-dione

(4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) (2-phenyl-1, 3-dithian-2-yl) methanol (590mg, 0,79mmol) from the above step was dissolved in 20mL of dichloromethane (containing t-butanol (204mg, 2,76mmol)) under nitrogen. 1, 1, 1-tri (acetoxyl) -1 lambda⁵2-Benzoiodoxy-3 (1H) -one (755mg, 1,78mmol) was added to the above solution, and then the reaction was performedThe mixture was stirred overnight. The reaction was quenched with 10mL aqueous sodium thiosulfate (1M) and 10mL sodium bicarbonate (saturated), then diluted with dichloromethane. The two layers were separated and the organic phase was then concentrated in vacuo. Purification by flash chromatography (ethyl acetate/n-heptane) afforded 150mg (34% yield) of the title compound. Ms (ci): m/z 282[ M +1 ]]⁺。

Example 68

3-methyl-5- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) -5-phenyl-2-thioimidazolidin-4-one

1- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) -2-phenylethane-1, 2-dione (150mg, 0,267mmol) and N-methylthiourea (48,1mg, 0,533mmol) were dissolved in 7mL of dimethyl sulfoxide and then heated to 100 ℃. An aqueous solution of potassium hydroxide (455. mu.L, 1,2M) was slowly added to the above solution via syringe. The reaction mixture was stirred at 100 ℃ for 5 minutes and then cooled to ambient temperature. The solution was diluted with 30mL of water, carefully acidified to pH 5 with concentrated HCl, and extracted with dichloromethane (3X 30 mL). The combined organic phases were concentrated in vacuo and the product was isolated by preparative HPLC. The collected fraction was made basic using 10mL of 2M sodium hydroxide and then extracted with 20mL of dichloromethane to yield 33mg (24% yield) of the title compound. Ms (esi): m/z 354[ M +1 ] ]⁺。

Example 69

2-amino-3-methyl-5- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) -5-phenyl-3, 5-dihydro-4H-imidazol-4-one acetate

3-methyl-5- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) -5-phenyl-2-thioimidazolidin-4-one (22.1mg, 0,0623mmol) was diluted in 40mL of 3: 1 methanol/ammonium hydroxide and treated with t-butyl hydroperoxide (84,7mg, 0,94 mmol). The mixture was stirred at room temperature overnight, then placed in vacuo and concentrated until about 50% of the volume remained. The mixture was diluted with 30mL of water and 40mL of dichloromethane. The two layers were separated and the organic phase was concentrated in vacuo, then the product was isolated using preparative HPLC to give 4mg (16% yield) of the title product as the acetate salt. Ms (esi): m/z 337[ M +1 ]]⁺；¹H NMR(CDCl₃)δppm 7.54-7.45(m，2H)，7.36-7.28(m，3H)，6.86-6.80(m，2H)，6.59(d，J＝8.34Hz，1H)，4.27-4.17(m，2H)，3.28-3.19(m，2H)，3.15(s，3H)，2.85(s，3H)。

Example 70

6-iodo-1, 2, 3, 4-tetrahydronaphthalene

1, 2, 3, 4-tetrahydronaphthalene (500mg, 3,79mmol) and iodine (961mg, 3,79mmol) were dissolved in 50mL of dichloromethane and then cooled to 0 ℃. Silver nitrate (644mg, 3,79mmol) was added to the above solution in portions while stirring. The reaction mixture was allowed to reach room temperature and stirred for 3 days. The yellow precipitate was filtered off, and the filtrate was washed with 3X 30mL of sodium bicarbonate (saturated). The organic phase was concentrated in vacuo and the remaining liquid was purified by Kugelrohr distillation to give 538mg (33% yield) of the title compound. Ms (ci): m/z 258[ M +1 ] ]⁺；¹H NMR(CDCl₃)δppm 7.41(s，1H)，7.39-7.37(d，1H)，6.81-6.78(d，1H)，2.76-2.64(m，4H)，1.78-1.72(m，4H)。

Example 71

6- (Phenylethynyl) -1, 2,3, 4-tetrahydronaphthalene

6-iodo-1, 2,3, 4-tetrahydronaphthalene (1,2g, 2,79mmol), ethynylbenzene (475mg, 4,65mg), bis (triphenylphosphine) palladium dichloride (16mg, 0,023mmol) and cuprous iodide (4,4mg, 0.023mmol) were dissolved in 15mL of anhydrous tetrahydrofuran and 15mL of anhydrous triethylamine and purged with nitrogen. The reaction mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was quenched by the addition of 30mL of 2M hydrochloric acid and 30mL of dichloromethane, and the two layers were separated. The organic phase was concentrated in vacuo, diluted with dimethyl sulfoxide and then divided into 7 portions (1750 μ L each) which were purified by preparative HPLC to give 540mg (68% yield) of the title compound. Ms (ci): m/z 233[ M +1 ]]⁺。

Example 72

1-phenyl-2- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) ethane-1, 2-dione

6- (Phenylethynyl) -1, 2,3, 4-tetrahydronaphthalene (540mg, 2,32mmol) and palladium dichloride (41mg, 0,23mmol) were dissolved in 20mL of dimethyl sulfoxide, heated to 140 ℃ and stirred overnight. The reaction mixture was cooled to room temperature and then quenched with 50mL of water and 30mL of dichloromethane. The two layers were separated and the organic phase was washed with 2X 50mL of water and then concentrated in vacuo. The product was isolated by flash chromatography (ethyl acetate/n-heptane) to yield 337mg (55% yield) of the title compound. Ms (ci): m/z 263[ M-1 ] ]^-；¹H NMR(CDCl₃)δppm 8.03-7.95(d，2H)，7.72-7.63(m，3H)，7.51(t，J＝7.83Hz，2H)，7.20(d，J＝7.83Hz，1H)，2.88-2.78(m，4H)，1.82(dt，J＝6.57，3.28Hz，4H)。

Example 73

3-methyl-5-phenyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -2-thioimidazolidin-4-one

1-phenyl-2- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) ethane-1, 2-dione (337mg, 1,27mmol) and N-methylthiourea (230mg, 2,55mmol) were dissolved in 10mL of dimethyl sulfoxide and then heated to 100 ℃. Aqueous potassium hydroxide (2.18mL, 1.2M) was slowly added dropwise to the above solution via syringe. The reaction mixture was stirred at 100 ℃ for 5min and then cooled to room temperature. The solution was diluted with 30mL of water, carefully acidified with concentrated HCl to pH 5, then extracted with 3X 30mL of dichloromethane and washed with 2X 20mL of water. The organic phase was concentrated in vacuo to give 496mg of the title compound. Ms (esi): m/z337[ M +1 ]]⁺；¹H NMR(CDCl₃)δppm 7.40-7.32(m，5H)，7.07-7.05(d，1H)，7.01-6.97(m，2H)，3.33(s，4H)，2.74(dd，J＝6.44，3.66Hz，4H)，1.79(ddd，J＝6.44，3.41，3.28Hz，4H)。

Example 74

2-amino-3-methyl-5-phenyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3, 5-dihydro-4H-imidazol-4-one hydrochloride

3-methyl-5-phenyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -2-thioimidazolidin-4-one (250mg, 0,743mmol) was diluted in 40mL of 3: 1 methanol/ammonium hydroxide and treated with t-butyl hydroperoxide (1g, 11.15 mmol). The mixture was stirred at room temperature overnight, then placed in vacuo and concentrated until about 50% of the volume remained. The mixture was washed with 30mL of water and 40mL of dichloromethane And (6) diluting. The layers were separated and the organic phase was concentrated in vacuo and the product was purified by flash chromatography (1: 933% ammonium hydroxide in methanol) to give 208mg of a solid. The product was further purified by preparative HPLC to give 90mg of product, which was dissolved in 263. mu.L of 1M HCl in ether to give 93mg (35% yield) of the hydrochloride salt. Ms (esi): m/z 320[ M +1 ]]⁺；¹H NMR(DMSO-d₆)δppm 7.46-7.35(d，2H)，7.28(t，J＝7.45Hz，2H)，7.21(d，J＝7.07Hz，1H)，7.16-7.09(m，2H)，6.95(d，J＝8.59Hz，1H)，2.96(s，3H)，2.64(m，4H)，1.75-1.65(m，4H)。

Example 75

1-acetyl-5-iodoindoline

1-acetyl-5-bromoindoline (250mg, 1,04mmol), sodium iodide (624mg, 4,16mmol) and cuprous iodide (40mg, 0,208mmol) were dissolved in 30mL anhydrous dioxane and 500. mu.L triethylamine. N, N' -dimethylethylene-1, 2-diamine (37mg, 0.416mmol) was added, and then the reaction mixture was refluxed for 3 days. The solution was filtered through a short plug of silica gel and then concentrated. The crude material was diluted with 30mL of dichloromethane and 30mL of water, and the two layers were separated. The organic phase was concentrated in vacuo to yield 247mg (62% yield) of product. Ms (ci): m/z 288[ M +1 ]]⁺。

Example 76

1-acetyl-5- (phenylethynyl) indoline

The title compound was synthesized from 1-acetyl-5-iodoindoline as described in example 71,except that the product was purified by flash chromatography (ethyl acetate/n-heptane) instead of preparative HPLC (70% yield). Ms (esi): m/z 262[ M +1 ] ]⁺。

Example 77

1- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) -2-phenylethane-1, 2-dione

The title compound was synthesized from 1-acetyl-5- (phenylethynyl) indoline as described in example 72 to give the product, which was used in the next step without further purification. Ms (esi): m/z 293[ M +1 ]]⁺。

Example 78

5- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) -3-methyl-5-phenyl-2-thioimidazolidin-4-one

The title compound was synthesized as described in example 73 from 1- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) -2-phenylethane-1, 2-dione to yield 80mg (55% yield). Ms (esi): m/z 366[ M +1]⁺。

Example 79

5- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride

The title compound was synthesized as described in example 74 from 5- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) -3-methyl-5-phenyl-2-thioimidazolidin-4-one to give 23mg (29% yield) of the product as the hydrochloride salt. Ms (esi): m/z 349[ M +1 ]]⁺；¹H NMR(CDCl₃)δppm 8.11(d，1H)，7.46-7.40(d，2H)，7.33-7.22(m，5H)，4.02(t，J＝8.59Hz，2H)，3.14-3.09(m，5H)，2.20(s，3H)。

Example 80

1-acetyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline

The title compound was synthesized as described in example 2 from 1-acetyl-4-bromoindoline (described in Berrier, C.et al. New Journal of Chemistry 1987, 11(8-9), 605-9) in 70% yield. Purification was performed on a silica gel chromatography column using acetonitrile as eluent. ¹H-NMR(DMSO-d₆)：δ8.16(d，J＝7.8Hz，1H)，7.27(dd，J＝7.5，1.0Hz，1H)，7.14(t，J＝7.6Hz，1H)，4.05(t，J＝8.5Hz，2H)，3.25(t，J＝8.5Hz，2H)，2.15(s，3H)，1.29(s，12H)；MS(ESI)m/z 288[M+1]⁺。

Example 81

5- [3- (1-acetyl-2, 3-dihydro-1H-indol-4-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride

From 2-amino-5- (3-bromo-phenyl) -3-methyl-5-phenyl-3, 5-dihydro-imidazole as described in example 5-4-keto and 1-acetyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline to synthesize the base of the title compound, which is then prepared as described in example 6 as a salt of the base, in 40% yield. The crude product was purified by flash chromatography using acetonitrile/triethylamine (95/5) as eluent. After addition of diethyl ether, the hydrochloride salt formed precipitated out.¹H-NMR(DMSO-d₆)：δ11.62(br s，1H)，9.58(br s，2H)，8.10(d，J＝8.0Hz，1H)，7.56-7.52(m，2H)，7.50-7.36(M，7H)，7.26(t，J＝7.9Hz，1H)，7.00(d，J＝7.5Hz，1H)，4.06(t，J＝8.3Hz，2H)，3.20(s，3H)，3.14-3.06(m，2H)，2.17(s，3H)；MS(ESI)m/z 425[M+1]⁺。

Example 82

8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) chroman

The title compound was synthesized as described in example 2 from 8-bromochroman (described in Gerard H.Thomas et al tetrahedron Letters, 1998, 39, 2219-. Purification was performed on a silica gel chromatography column using dichloromethane/methanol (95/5) as eluent.¹H-NMR(DMSO-d₆)：δ7.32(dd，J＝7.3，1.5Hz，1H)，7.12(dd，J＝7.4，1.6Hz，1H)，6.76(t，J＝7.4Hz，1H)，4.12(t，J＝5.0Hz，2H)，2.71(t，J＝6.5Hz，2H)，1.92-1.84(m，2H)，1.25(s，12H)。

Example 83

2-amino-5- [3- (3, 4-dihydro-2H-chromen-8-yl) phenyl ] -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one acetate

The title compound was synthesized as described in example 5 from 2-amino-5- (3-bromo-phenyl) -3-methyl-5-phenyl-3, 5-dihydro-imidazol-4-one and 8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) chromane. The crude product was subjected to acid/base extraction followed by flash chromatography using acetonitrile/triethylamine (95/5) as eluent followed by preparative HPLC separation to afford the title compound after lyophilization (8% yield). ¹H-NMR(600MHz，DMSO-d₆)：δ7.54(s，1H)，7.49(d，J＝7.4Hz，2H)，7.37(d，J＝7.7Hz，1H)，7.33-7.26(m，4H)，7.24-7.20(m，1H)，7.03(d，J＝7.4Hz，1H)，6.96(d，J＝6.6Hz，1H)，6.86(t，J＝7.5Hz，1H)，4.06(t，J＝5.0Hz，2H)，2.98(s，3H)，2.78(t，J＝6.4Hz，2H)，1.93-1.88(m，4H)；MS(ESI)m/z398[M+1]⁺。

Example 84

3-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol

Microwave irradiation of 3-chloro-5-methoxyphenol (1.59g, 10.0mmol), bis (pinacolato) diboron (2.79g, 11.0mmol), tris [ bis (benzylidene) propanone]Dipalladium (0.28g, 0.30mmol), potassium acetate (1.47g, 15.0mmol), tricyclohexylphosphine (0.33g, 1.2mmol) and 1, 2-dimethoxyethane (12mL) were maintained at 150 ℃ for 2 h. The reaction was carried out 3 times, the combined reaction mixture was poured into water and then extracted with ether, and the organic phase was dried over magnesium sulfate and then concentrated. Purification by column chromatography (using a gradient of methanol in chloroform (0-3%)) gave 6.61g (88% yield) of the title compound.¹H NMR(CDCl₃)δ6.85(d，J＝2.02Hz，1H)，6.78(d，J＝2.27Hz，1H)，6.45(t，J＝2.40Hz，1H)，4.59(br s，1H)，3.73(s，3H)，1.27(s，12H)；MS(ES)m/z 251[M+1]⁺。

Example 85

3 '-hydroxy-5' -methoxybiphenyl-3-carbaldehyde

Microwave irradiation of 3-bromobenzaldehyde (1.22g, 6.6mmol), 3-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (1.50g, 6.0mmol), [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane adduct (0.25g, 0.30mmol), cesium carbonate (3.91g, 12.0mmol), 1, 2-dimethoxyethane (9mL), water (4.5mL) and ethanol (1.5mL) were maintained at 150 ℃ for 40 min. The reaction was carried out 3 times and a saturated ammonium chloride solution and water were added to the combined reaction mixture. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulfate and then concentrated. Purification by column chromatography (using heptane/ethyl acetate 3/1) gave 2.47g (60% yield) of the title compound. ¹H NMR(CDCl₃)δ10.01(s，1H)，8.00(t，J＝1.64Hz，1H)，7.72-7.83(m，2H)，7.53(t，J＝7.58Hz，1H)，6.66-6.69(m，1H)，6.61-6.64(m，1H)，6.38(t，J＝2.27Hz，1H)，4.81(br s，1H)，3.78(s，3H)；MS(ES)m/z 227[M-1]^-。

Example 86

3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-carbaldehyde

3 '-hydroxy-5' -methoxybiphenyl-3-carbaldehyde (2.46g, 10.8mmol), triethylamine (1.7mL, 11.9mmol), 4-dimethylaminopyridine (0.066g, 0.54mmol) and tert-butylA solution of diphenylchlorosilane (3.1mL, 11.9mmol) in dichloromethane (50mL) was stirred overnight. Dichloromethane was added, and then the organic phase was washed with water, dried over magnesium sulfate, and then concentrated. The residue was purified by column chromatography (using a gradient of heptane/ethyl acetate 9/1-6/1) to yield 4.44g (88% yield) of the title compound.¹H NMR(CDCl₃)δ10.02(s，1H)，7.73-7.84(m，6H)，7.58-7.63(m，1H)，7.39-7.54(m，7H)，6.69-6.72(m，1H)，6.57-6.60(m，1H)，6.39(t，J＝2.15Hz，1H)，3.68(s，3H)，1.17(s，9H)；MS(ES)m/z 467[M+1]⁺。

Example 87

Tert-butyl { [ 3' - (1, 3-dithian-2-yl) -5-methoxybiphenyl-3-yl ] oxy } diphenylsilane

Boron trifluoride-diethyl ether complex (4.8mL, 38.0mmol) was added dropwise to 3' - { [ tert-butyl (diphenyl) silyl at 0 deg.C]Oxy } -5' -methoxybiphenyl-3-carbaldehyde (4.44g, 9.5mmol), 1, 3-propanedithiol (0.91mL, 9.0mmol) anda mixture of molecular sieves (8g) in dichloromethane (50 mL). After stirring the reaction mixture at 0 ℃ for 1.5h, saturated sodium bicarbonate solution was added and the mixture was extracted with dichloromethane, then the organic phase was washed successively with water, 10% potassium hydroxide solution and water, dried over magnesium sulfate and then concentrated. Purification by column chromatography (using heptane/ethyl acetate 6/1) gave 4.52g (85% yield) of the title compound. ¹H NMR(CDCl₃)δ7.64-7.71(m，4H)，7.28-7.41(m，8H)，7.23(t，J＝7.58Hz，1H)，7.14-7.19(m，1H)，6.56-6.60(m，1H)，6.51-6.54(m，1H)，6.20(t，J＝2.27Hz，1H)，5.09(s，1H)，3.54(s，3H)，2.95-3.06(m，2H)，2.83-2.89(m，2H)，2.08-2.16(m，1H)，1.82-1.95(m，1H)，1.06(s，9H)；MS(ES)m/z 557[M+1]⁺。

Example 88

[2- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl ] (pyridin-4-yl) methanol

N-butyllithium (1.6M in hexane, 3.3mL, 5.3mmol) was added to-78 deg.C t-butyl { [ 3' - (1, 3-dithian-2-yl) -5-methoxybiphenyl-3-yl]A solution of oxy diphenylsilane (2.68g, 4.8mmol) in tetrahydrofuran. After 40min, a solution of 4-pyridinecarboxaldehyde (0.51mL, 5.3mmol) in tetrahydrofuran (5mL) was added and the reaction mixture was stirred at-78 ℃ for 40min and then at room temperature for 1 h. The reaction mixture was partitioned between water and dichloromethane and the organic phase was dried over magnesium sulfate and then concentrated. Purification by column chromatography (using chloroform) gave 1.09g (34% yield) of the title compound.¹H NMR(CDCl₃)δ8.11-8.18(m，J＝6.57Hz，2H)，7.58-7.63(m，1H)，7.50-7.58(m，J＝6.57Hz，5H)，7.11-7.28(m，9H)，6.97-7.02(m，1H)，6.36-6.41(m，1H)，6.28-6.32(m，1H)，6.19(t，J＝2.15Hz，1H)，4.86(s，1H)，3.46(s，3H)，2.39-2.65(m，4H)，1.68-1.78(m，2H)，0.92(s，9H)；MS(ES)m/z 664[M+1]⁺。

Example 89

1- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -2-pyridin-4-ylethyl-1, 2-dione

Reacting [2- (3' - { [ tert-butyl (diphenyl) silyl)]Oxy } -5' -methylOxybiphenyl-3-yl) -1, 3-dithian-2-yl]A mixture of (pyridin-4-yl) methanol (1.09g, 1.6mmol), tert-butanol (0.39mL, 4.1mmol) and Dess-Martin iodophor (Dess-Martin periodinane) (1.73g, 4.1mmol) was stirred overnight and a saturated solution of sodium bicarbonate and sodium thiosulfate was added. After 0.5h, the mixture was extracted with chloroform and the organic phase was dried over magnesium sulfate and then concentrated. Purification by column chromatography (using chloroform/methanol 99/1) gave 0.27g (29% yield) of the title compound. ¹H NMR(CDCl₃)δ8.86-8.94(m，2H)，7.36-8.05(m，16H)，6.64-6.68(m，1H)，6.56-6.59(m，1H)，6.37(t，J＝2.27Hz，1H)，3.65(s，3H)，1.16(s，9H)；MS(ES)m/z 572[M+1]⁺。

Example 90

5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5-pyridin-4-yl-2-thioimidazolidin-4-one

1- (3' - { [ tert-butyl (diphenyl) silyl)]Oxy } -5' -methoxybiphenyl-3-yl) -2-pyridin-4-ylethyl-1, 2-dione (0.27g, 0.47mmol), N-methylthiourea (0.085g, 0.94mmol) and dimethyl sulfoxide (2mL) were kept at 100 ℃ for 5min, a solution of potassium hydroxide (1M, 0.99mL) was added, and the mixture was kept at 100 ℃ for a further 5 min. Water was added, followed by neutralization with hydrochloric acid (1M). The mixture was extracted with dichloromethane, the organic phase was dried over magnesium sulfate and the solvent was evaporated. Purification by column chromatography (using chloroform/methanol 98/2) gave 0.16g (85% yield) of the title compound.¹H NMR(CDCl₃)δ8.81(br s，1H)，8.50-8.55(m，2H)，7.44-7.49(m，1H)，7.33-7.37(m，2H)，7.28-7.31(m，2H)，7.20-7.24(m，1H)，6.48-6.52(m，1H)，6.45-6.47(m，1H)，6.32(t，J＝2.15Hz，1H)，3.70(s，3H)，3.24(s，3H)；MS(ES)m/z 406[M+1]⁺。

Example 91

Methanesulfonic acid 5-methoxy-3' - (1-methyl-5-oxo-4-pyridin-4-yl-2-thioimidazolidin-4-yl) biphenyl-3-yl ester

Methanesulfonyl chloride (0.034mL, 0.44mmol) was added to a 0 deg.C solution of 5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5-pyridin-4-yl-2-thioimidazolidin-4-one (0.16g, 0.40mmol) and triethylamine (0.073mL, 0.52mmol) in dichloromethane (3 mL). After 2h at 0 ℃, water was added, then the mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulfate and then concentrated to give the title compound which was used without further purification. MS (ES) M/z 484[ M +1 ] ]⁺。

Example 92

Methanesulfonic acid 3' - (2-amino-1-methyl-5-oxo-4-pyridin-4-yl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-3-yl ester

A mixture of methanesulfonic acid 5-methoxy-3' - (1-methyl-5-oxo-4-pyridin-4-yl-2-thioimidazolidin-4-yl) biphenyl-3-yl ester, methanol (3mL), ammonium hydroxide (25%, 0.4mL), and tert-butyl hydroperoxide (70% in water, 0.58mL, 6.0mmol) was stirred overnight, water (5mL) was added, and the mixture was extracted with dichloromethane, dried over magnesium sulfate, and evaporated. Purification by column chromatography (using a gradient of chloroform/methanol 95/5-85/15) gave 0.069g (37% yield) of the title compound.¹H NMR(CDCl₃)δ8.50-8.54(m，2H)，7.70(t，J＝1.64Hz，1H)，7.53-7.59(m，1H)，7.45-7.51(m，3H)，7.39(t，J＝7.71Hz，1H)，7.01-7.07(m，2H)，6.78(t，J＝2.15Hz，1H)，5.43(br s，2H)，3.82(s，3H)，3.13(s，3H)，3.12(s，3H)；MS(ES)m/z467[M+1]⁺。

Example 93

[2- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl ] (pyridin-2-yl) methanol

The title compound was synthesized in 27% yield using pyridine-2-carbaldehyde as the starting material as described in example 88.¹H NMR(CDCl₃)δ8.37-8.44(m，1H)，7.70-7.81(m，5H)，7.58-7.63(m，1H)，7.36-7.51(m，7H)，7.27-7.35(m，1H)，7.20-7.25(m，1H)，7.11-7.17(m，1H)，6.76-6.83(m，1H)，6.49-6.52(m，1H)，6.42-6.47(m，1H)，6.31(t，J＝2.15Hz，1H)，5.15(br s，1H)，3.63(s，3H)，2.55-2.89(m，4H)，1.85-2.04(m，2H)，1.15(s，9H)；MS(ES) m/z 664[M+1]⁺。

Example 94

1- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -2-pyridin-2-ylethyl-1, 2-dione

From [2- (3' - { [ tert-butyl (diphenyl) silyl ] as described in example 89]Oxy } -5' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl ](pyridin-2-yl) methanol was used to synthesize the title compound in a yield of 57%. MS (ES) M/z 572[ M +1]⁺。

Example 95

5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5-pyridin-2-yl-2-thioimidazolidin-4-one

From 1- (3' - { [ tert-butyl (diphenyl) silyl) as described in example 90]The title compound was synthesized from oxy } -5' -methoxybiphenyl-3-yl) -2-pyridin-2-ylethyl-1, 2-dione in a yield of 76%. MS (ES) M/z 406[ M +1 ]]⁺。

Example 96

Methanesulfonic acid 5-methoxy-3' - (1-methyl-5-oxo-4-pyridin-2-yl-2-thioimidazolidin-4-yl) biphenyl-3-yl ester

The title compound was synthesized from 5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5-pyridin-2-yl-2-thioimidazolidin-4-one as described in example 91. MS (ES) M/z 484[ M +1 ]]⁺。

Example 97

Methanesulfonic acid 3' - (2-amino-1-methyl-5-oxo-4-pyridin-2-yl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-3-yl ester

The title compound was synthesized as described in example 92 from methanesulfonic acid 5-methoxy-3' - (1-methyl-5-oxo-4-pyridin-2-yl-2-thioimidazolidin-4-yl) biphenyl-3-yl ester in 6% yield.¹H NMR(CDCl₃)δ8.44-8.51(m，1H)，7.69-7.76(m，1H)，7.49-7.65(m，3H)，7.37-7.43(m，1H)，7.33(t，J＝7.71Hz，1H)，7.11-7.17(m，1H)，6.92-6.98(m，2H)，6.74(t，J＝2.15Hz，1H)，3.77(s，3H)，3.08(s，3H)，3.07(s，3H)；MS(ES)m/z 467[M+1]⁺。

Example 98

[2- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl ] (3-furyl) methanol

The title compound was synthesized in 84% yield using 3-furaldehyde as the starting material as described in example 88.¹H NMR(CDCl₃)δ7.64-7.74(m，6H)，7.28-7.40(m，6H)，7.24(t，J＝7.71Hz，1H)，7.14-7.19(m，1H)，7.04(t，J＝1.64Hz，1H)，6.98-7.01(m，1H)，6.49-6.52(m，1H)，6.44-6.46(m，1H)，6.24(t，J＝2.15Hz，1H)，5.72-5.75(m，1H)，4.85(d，J＝3.79Hz，1H)，3.56(s，3H)，2.53-2.71(m，4H)，1.80-1.88(m，2H)，1.06(s，9H)；MS(ES)m/z 653[M+1]⁺。

Example 99

1- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -2- (3-furyl) ethane-1, 2-dione

From [2- (3' - { [ tert-butyl (diphenyl) silyl ] as described in example 89]Oxy } -5' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl]The title compound was synthesized in 67% yield from (3-furyl) methanol.¹H NMR(CDCl₃)δ8.21-8.24(m，1H)，8.07(t，J＝1.52Hz，1H)，7.93-7.98(m，1H)，7.73-7.80(m，4H)，7.53-7.63(m，2H)，7.37-7.52(m，7H)，6.96-6.99(m，1H)，6.66-6.70(m，1H)，6.58-6.62(m，1H)，6.35(t，J＝2.15Hz，1H)，3.65(s，3H)，1.16(s，9H)；MS(ES)m/z 561[M+1]⁺。

Example 100

5- (3-furyl) -5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one

From 1- (3' - { [ tert-butyl (diphenyl) silyl) as described in example 90]The title compound was synthesized from oxy } -5' -methoxybiphenyl-3-yl) -2- (3-furyl) ethane-1, 2-dione in 84% yield.¹HNMR(CDCl₃)δ7.55-7.61(m，2H)，7.44-7.52(m，3H)，7.39-7.43(m，1H)，6.65-6.69(m，1H)，6.58-6.61(m，1H)，6.44(t，J＝2.15Hz，1H)，6.36(dd，J＝1.89，0.88Hz，1H)，4.81(s，1H)，3.85(s，3H)，3.36(s，3H)；MS(ES)m/z393[M-1]^-。

Example 101

Methanesulfonic acid 3' - [4- (3-furyl) -1-methyl-5-oxo-2-thioxoimidazolidin-4-yl ] -5-methoxybiphenyl-3-yl ester

The title compound was synthesized from 5- (3-furyl) -5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one as described in example 91. MS (ES) M/z 471[ M-1]^-。

Example 102

Methanesulfonic acid 3' - [ 2-amino-4- (3-furyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester

From methanesulfonic acid 3' - [4- (3-furyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl as described in example 92]-5-Methoxybiphenyl-3-yl ester to give the title compound in 59% yield.¹H NMR(CDCl₃)δ7.76(t，J＝1.64Hz，1H)，7.58-7.64(m，1H)，7.44-7.52(m，2H)，7.34-7.42(m，2H)，7.04(d，J＝2.02Hz，2H)，6.78(t，J＝2.15Hz，1H)，6.41(dd，J＝1.77，0.76Hz，1H)，5.83(br s，2H)，3.82(s，3H)，3.12(s，3H)，3.09(s，3H)；MS(ES)m/z 456[M+1]⁺。

Example 103

[2- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl ] (1, 3-thiazol-5-yl) methanol

The title compound was synthesized in 54% yield using thiazole-5-carbaldehyde as the starting material as described in example 88.¹H NMR(CDCl₃)δ9.05(s，1H)，7.71-7.82(m，5H)，7.30-7.55(m，10H)，6.62-6.65(m，1H)，6.48-6.51(m，1H)，6.41(t，J＝2.15Hz，1H)，5.36(s，1H)，3.70(s，3H)，2.66-2.95(m，4H)，1.94-2.06(m，2H)，1.15(s，9H)；MS(ES)m/z 670[M+1]⁺。

Example 104

1- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -2- (1, 3-thiazol-5-yl) ethane-1, 2-dione

From [2- (3' - { [ tert-butyl (diphenyl) silyl ] as described in example 89]Oxy } -5' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl]The title compound was synthesized in 58% yield from (1, 3-thiazol-5-yl) methanol.¹H NMR(CDCl₃)δ9.17(s，1H)，8.64(s，1H)，8.09(t，J＝1.77Hz，1H)，7.96-8.02(m，1H)，7.74-7.80(m，4H)，7.60-7.66(m，1H)，7.38-7.54(m，7H)，6.66-6.70(m，1H)，6.58-6.62(m，1H)，6.36(t，J＝2.15Hz，1H)，3.65(s，3H)，1.16(s，9H)；MS(ES)m/z 578[M+1]⁺。

Example 105

5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5- (1, 3-thiazol-5-yl) -2-thioimidazolidin-4-one

From 1- (3' - { [ tert-butyl (diphenyl) silyl) as described in example 90]Oxy } -5' -methoxybiphenyl-3-yl) -2- (1, 3-thiazol-5-yl) ethane-1, 2-dione was synthesized in 65% yield. MS (ES) M/z 412[ M +1 ] ]⁺。

Example 106

Methanesulfonic acid 5-methoxy-3' - [ 1-methyl-5-oxo-4- (1, 3-thiazol-5-yl) -2-thioimidazolidin-4-yl ] biphenyl-3-yl ester

The title compound was synthesized from 5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5- (1, 3-thiazol-5-yl) -2-thioimidazolidin-4-one as described in example 91. MS (ES) M/z 490[ M +1 ]]⁺。

Example 107

Methanesulfonic acid 3' - [ 2-amino-1-methyl-5-oxo-4- (1, 3-thiazol-5-yl) -4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester

From methanesulfonic acid 5-methoxy-3' - [ 1-methyl-5-oxo-4- (1, 3-thiazol-5-yl) -2-thioimidazolidin-4-yl as described in example 92]The title compound was synthesized in 22% yield from biphenyl-3-yl ester.¹HNMR(DMSO-d₆)δ8.98(s，1H)，7.89(s，1H)，7.75-7.81(m，1H)，7.57-7.65(m，2H)，7.46(t，J＝7.71Hz，1H)，7.05-7.13(m，2H)，6.98(t，J＝2.15Hz，1H)，6.94(s，2H)，3.86(s，3H)，3.44(s，3H)，3.00(s，3H)；MS(ES)m/z 473[M+1]⁺。

Example 108

[2- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl ] (1, 3-thiazol-4-yl) methanol

The title compound was synthesized in 66% yield using thiazole-4-carbaldehyde as the starting material as described in example 88. MS (ES) M/z 670[ M +1 ]]⁺。

Example 109

1- (3 '- { [ tert-butyl (diphenyl) silyl ] oxy } -5' -methoxybiphenyl-3-yl) -2- (1, 3-thiazol-4-yl) ethane-1, 2-dione

From [2- (3' - { [ tert-butyl (diphenyl) silyl ] as described in example 89 ]Oxy } -5' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl]The title compound was synthesized in 63% yield from (1, 3-thiazol-4-yl) methanol. MS (ES) M/z 578[ M +1 ]]⁺。

Example 110

5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5- (1, 3-thiazol-4-yl) -2-thioimidazolidin-4-one

From 1- (3' - { [ tert-butyl (diphenyl) silyl) as described in example 90]Oxy } -5' -methoxybiphenyl-3-yl) -2- (1, 3-thiazol-4-yl) ethane-1, 2-dione was synthesized in 93% yield.¹H NMR(CDCl₃)δ8.92(d，J＝2.02Hz，1H)，8.32(s，1H)，7.69(d，J＝2.02Hz，1H)，7.62-7.59(m，1H)，7.57-7.53(m，1H)，7.47-7.43(m，1H)，6.68-6.65(m，1H)，6.61-6.58(m，1H)，6.43(t，J＝2.27Hz，1H)，3.84(s，3H)，3.35(s，3H)；MS(ES)m/z 412[M+1]⁺。

Example 111

Methanesulfonic acid 5-methoxy-3' - [ 1-methyl-5-oxo-4- (1, 3-thiazol-4-yl) -2-thioimidazolidin-4-yl ] biphenyl-3-yl ester

The title compound was synthesized from 5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5- (1, 3-thiazol-4-yl) -2-thioimidazolidin-4-one as described in example 91. MS (ES) M/z 490[ M +1 ]]⁺。

Example 112

Methanesulfonic acid 3' - [ 2-amino-1-methyl-5-oxo-4- (1, 3-thiazol-4-yl) -4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester

From methanesulfonic acid 5-methoxy-3' - [ 1-methyl-5-oxo-4- (1, 3-thiazol-4-yl) -2-thioimidazolidin-4-yl ] as described in example 92]The title compound was synthesized in 49% yield from biphenyl-3-yl ester. ¹HNMR(CDCl₃)δ8.75(d，J＝2.02Hz，1H)，7.93-7.86(m，1H)，7.72-7.64(m，1H)，7.51-7.45(m，1H)，7.41-7.31(m，2H)，7.04-7.00(m，2H)，6.76(t，J＝2.15Hz，1H)，6.10(br s，2H)，3.79(s，3H)，3.11(s，3H)，3.10(s，3H)；MS(ES)m/z473[M+1]⁺。

Example 113

4-bromo-1-fluoro-2-methoxybenzene

Aqueous hydrobromic acid (48%, 2.41mL) was added to a solution of 4-fluoro-3-methoxyaniline (1.0g, 7.1mmol) in water (10mL) and the resulting mixture was cooled to 0 ℃ in an ice bath. A solution of sodium nitrite (538mg, 7.8mmol) in water (5mL) was added dropwise over 15min while maintaining the temperature at 0-5 ℃. The resulting solution of the diazonium salt (diazoniumsalt) is added to the bromidesA suspension of copper (1.12g, 7.8mmol) in water (5mL) which had been preheated to 75 deg.C. The mixture was shaken well, aqueous hydrobromic acid (48%, 12.07mL) was added and the solution was stirred at ambient temperature for 16 h. Excess water was added, the product extracted with ether, and the combined organic extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and the solvent evaporated in vacuo to give 1.02g (70% yield) of the title compound.¹H-NMR(DMSO-d₆)：δ7.36(dd，J＝7.78，2.26Hz，1H)，7.23-7.17(m，1H)，7.14-7.09(m，1H)，3.86(s，3H)；MS(EI)(m/z，％)204，206(100)，189，191(23)，161，163(45)。

Example 114

2- (4-fluoro-3-methoxyphenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane

Anhydrous 1, 2-dimethoxyethane (12mL) was added to 4-bromo-1-fluoro-2-methoxybenzene (1.02g, 5.0mmol), tris [ bis (benzylidene) acetone ] dipalladium (228mg, 0.25mmol), tricyclohexylphosphine (209mg, 0.75mmol), potassium acetate (732mg, 7.5mmol), and 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -di-1, 3, 2-dioxaborolane (1.14g, 4.5mmol), and the mixture was then irradiated with microwaves under an argon atmosphere and maintained at 150 ℃ for 1 h. Upon cooling to ambient temperature, the mixture was filtered and the solvent was evaporated in vacuo to give the title compound as an oil. MS (EI) (m/z,%) 252(81), 237(44), 166(78), 152 (100).

Example 115

4- [ (3-bromophenyl) ethynyl ] phenol

A solution of 1-bromo-3-ethynylbenzene (14.85g, 82mmol) in anhydrous tetrahydrofuran (34mL) was added dropwise to a solution of 4-iodophenol (14.43g, 65.6mmol), cuprous iodide (94mg, 0.49mmol) and bis (triphenylphosphine) palladium dichloride (345mg, 0.49mmol) in a 2: 1 mixture of tetrahydrofuran/triethylamine (230 mL). The reaction mixture was stirred at ambient temperature under an argon atmosphere for 16 h. More 4-iodophenol (541mg, 2.5mmol) was added and the mixture was stirred for a further 3h to complete the reaction. The reaction mixture was filtered and the solvent was evaporated in vacuo. The crude product was slurried in water (400mL) and the product was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. Purification was by column chromatography (using 25-50% ethyl acetate in heptane as eluent). The final product was dried in a vacuum oven at 40 ℃ overnight to yield 15.25g (68% yield) of the title compound. MS (ES) M/z 271, 273[ M-H]^-。

Example 116

1- (3-bromophenyl) -2- (4-hydroxyphenyl) ethane-1, 2-dione

Reacting 4- [ (3-bromophenyl) ethynyl group]A solution of phenol (972mg, 3.6mmol) and palladium dichloride (68mg, 0.38mmol) in anhydrous dimethylsulfoxide (10mL) was heated in an oil bath at 140 ℃ for 3 h. The warm reaction mixture was poured into water/diethyl ether and the aqueous phase was extracted with diethyl ether. The combined organic extracts were washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The solid was purified by column chromatography using 5-40% ethyl acetate in heptane as eluent to give 469mg (43% yield) of the title compound. ¹H-NMR(DMSO-d₆)：δ10.93(br s，1H)，8.02(t，J＝1.63Hz，1H)，8.00-7.97(m，1H)，7.88-7.84(m，1H)，7.83-7.79(m，2H)，7.57(t，J＝7.91Hz，1H)，6.97-6.92(m，2H)；MS(ES)m/z 303，305[M-H]^-。

Example 117

5- (3-bromophenyl) -5- (4-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one

1- (3-bromophenyl) -2- (4-hydroxyphenyl) ethane-1, 2-dione (10.20g, 33.4mmol) and N-methylthiourea (6.03g, 66.9mmol) were aliquoted into 11 microwave vials (microwave virtual). Dimethyl sulfoxide (10mL) and an aqueous solution of potassium hydroxide (5.2mL, 1,2M) were added to each vial. The vial was capped and then irradiated with microwaves and maintained at 100 ℃ for 9 min. Upon cooling to ambient temperature, the reaction mixture was pooled, water (50mL) and chloroform (60mL) were added, and the pH was then adjusted to 5 with 2M aqueous hydrochloric acid. The aqueous phase was extracted with chloroform and the combined organic extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and the solvent was then reduced in vacuo. Water was added, and then the extraction step was repeated using ether instead of chloroform. The resulting crude product was purified by column chromatography using 35% ethyl acetate in heptane as eluent. Methanol was added and the solution was then heated until the product started to recrystallize. The slurry was filtered and the crystalline product was washed with methanol and finally dried in a vacuum oven at ambient temperature overnight to yield 10.95g (87% yield) of the title compound. ¹H-NMR(CDCl₃)：δ7.78(brs，1H)，7.55-7.50(m，2H)，7.32-7.28(m，2H)，7.17-7.12(m，2H)，6.86-6.82(m，2H)，5.31(br s，1H)，3.35(s，3H)；MS(ES)m/z 375，377[M-H]^-。

Example 118

Methanesulfonic acid 4- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester

A solution of 5- (3-bromophenyl) -5- (4-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one (88mg, 0.23mmol) and triethylamine (71mg, 0.70mmol) purged with argon was cooled to 0 ℃. Methanesulfonyl chloride (27mg, 0.23mmol) was added and the reaction mixture was stirred at 0 ℃ for 30min, then at ambient temperature overnight. The next day more methanesulfonyl chloride (13mg, 0.12mmol) and triethylamine (35mg, 0.35mmol) were added. The mixture was stirred for 30min to allow sufficient conversion to product. The solvent was evaporated in vacuo and the resulting crude product was purified by column chromatography using 2-80% ethyl acetate in heptane as eluent to yield 74mg (70% yield) of the title compound.¹H-NMR(DMSO-d₆)：δ11.71(s，1H)，7.65-7.61(m，1H)，7.54(t，J＝1.77Hz，1H)，7.46-7.37(m，6H)，3.41(s，3H)，3.18(s，3H)；MS(ES)m/z 453，455[M-H]^-。

Example 119

Methanesulfonic acid 4- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester

From methanesulfonic acid 4- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl as described in example 4]The title compound was synthesized in 63% yield from phenyl ester. Purification was performed by column chromatography using a mixture of ethyl acetate: aqueous ammonium hydroxide (33%): methanol (94%, 1% and 5%, respectively) as eluent. ¹H-NMR(DMSO-d₆): δ 7.64(t, J ═ 1.76Hz, 1H), 7.56-7.51(m, 2H) overlapping 7.51-7.43(m, 2H), 7.33-7.26(m, 3H), 6.78(br s, 2H), 3.35(s, 3H), 3.00(s, 3H); MS (ES) m/z 436, 438[ ]M-H]^-。

Example 120

Methanesulfonic acid 4- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester 0.25 acetate

Methanesulfonic acid 4- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxoimidazolidin-4-yl]Phenyl ester (64mg, 0.15mmol), pyridin-3-ylboronic acid (23mg, 0.19mmol), [1, 1' -bis (diphenylphosphino) ferrocene]A mixture of palladium dichloride dichloromethane adduct (12mg, 0.015mmol) and potassium carbonate (121mg, 0.88mmol) in anhydrous tetrahydrofuran (3mL) was irradiated with microwaves under an argon atmosphere and maintained at 150 ℃ for 2 h. When cooled to ambient temperature, the mixture was filtered and then dimethyl sulfoxide (500 μ L) was added. The solution was concentrated in vacuo to remove tetrahydrofuran and then purified by preparative HPLC to give 10mg (12% yield) of the title compound.¹H-NMR(DMSO-d₆)：δ8.77(d，J＝2.26Hz，1H)，8.57(dd，J＝4.77，1.51Hz，1H)，7.97-7.93(m，1H)，7.79-7.77(m，1H)，7.63-7.57(m，3H)，7.54(d，J＝8.28Hz，1H)，7.51-7.41(m，2H)，7.29(d，J＝8.53Hz，2H)，3.35(s，3H)，3.00(s，3H)，1.90(s，0.67H)；MS(ES)m/z 435[M-H]^-。

Example 121

2-Methoxyethanesulfonic acid 4- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester

From 5- (3-bromophenyl) -5- (4-hydroxyphenyl) -3-methyl-2-thioimidazolidine as described in example 118 The title compound was synthesized in 71% yield from (E) -4-one and 2-methoxyethanesulfonyl chloride (described in Matlack A.S.J.org.chem.1958, 23, 729-731). Purification was performed by column chromatography (using 40% ethyl acetate in heptane as eluent).¹H-NMR(DMSO-d₆)：δ11.69(s，1H)，7.65-7.61(m，1H)，7.56-7.52(m，1H)，7.45-7.37(m，6H)，3.85-3.76(m，4H)，3.28(s，3H)，3.18(s，3H)；MS(ES)m/z 497，499[M-H]^-。

Example 122

2-Methoxyethanesulfonic acid 4- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester

From 2-methoxyethanesulfonic acid 4- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl group as described in example 4]The title compound was synthesized in 52% yield from phenyl ester. Purification was performed by column chromatography (using a mixture of ethyl acetate: triethylamine: methanol (94%, 1% and 5%, respectively) as eluent).¹H-NMR(DMSO-d₆)：δ7.63(s，1H)，7.55-7.43(m，4H)，7.32-7.24(m，3H)，6.78(br s，2H)，3.77(s，4H)，3.28(s，3H)，2.99(s，3H)；MS(ES)m/z 480，482[M-H]^-。

Example 123

Propane-1-sulfonic acid 4- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester

From 5- (3-bromophenyl) -5- (4-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one and propane-1-sulfonyl chloride as described in example 118The title compound was synthesized in 86% yield. Purification was performed by column chromatography (using 5% acetonitrile in dichloromethane as eluent).¹H-NMR(DMSO-d₆)：δ11.70(s，1H)，7.65-7.60(m，1H)，7.55-7.51(m，1H)，7.46-7.36(m，6H)，3.55-3.48(m，2H)，3.18(s，3H)，1.89-1.77(m，2H)，1.03(t，J＝7.40Hz，3H)；MS(ES)m/z 481，483[M-H]^-。

Example 124

Propane-1-sulfonic acid 4- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester

From propane-1-sulfonic acid 4- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl]The title compound was synthesized in 65% yield from phenyl ester. Purification was performed by column chromatography (using 5% triethylamine in acetonitrile as eluent).¹H-NMR(DMSO-d₆)：δ7.64-7.62(m，1H)，7.55-7.43(m，4H)，7.32-7.24(m，3H)，6.79(br s，2H)，3.50-3.44(s，2H)，2.99(s，3H)，1.88-1.77(m，2H)，1.02(t，J＝7.40Hz，3H)；MS(ES)m/z466，468[M+H]⁺。

Example 125-

Table 1: representative examples of syntheses as described for 4- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate 0.25 acetate

Example 170

Methanesulfonic acid 3-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ester

Stirring 3-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxan) at 0 deg.CTo a solution of borolan-2-yl) phenol (120mg, 0.48mmol) in dichloromethane (3mL) was added triethylamine (58mg, 0.58mmol), followed by methanesulfonyl chloride (71mg, 0.62 mmol). The reaction mixture was allowed to reach ambient temperature, stirred for 18 hours, and the resulting mixture was then concentrated to dryness in vacuo. Purification was performed on a silica gel column using a gradient of dichloromethane/acetonitrile (100/0 to 90/10) as eluent.¹H-NMR(CDCl₃)：δ7.30(d，J＝2.3Hz，1H)，7.28(d，J＝2.0Hz，1H)，6.96(t，J＝2.4Hz，1H)，3.86(s，3H)，3.16(s，3H)，1.35(s，12H)。

Example 171

Propane-1-sulfonic acid 4- (2-amino-4- {3 '-methoxy-5' - [ (methylsulfonyl) oxy ] biphenyl-3-yl } -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl) phenyl ester

Irradiating propane-1-sulfonic acid 4- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl group with microwave under argon atmosphere]Phenyl ester (80mg, 0.17mmol), 3-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl methanesulfonate (73mg, 0.22mmol), [1, 1' -bis (diphenylphosphino) ferrocene]A mixture of palladium dichloride dichloromethane adduct (14mg, 0.017mmol) and potassium carbonate (142mg, 1.03mmol) in anhydrous tetrahydrofuran (3mL) was maintained at 150 ℃ for 2 h. When cooled to ambient temperature, the mixture was filtered and then dimethyl sulfoxide (500 μ L) was added. The solution was concentrated in vacuo to remove tetrahydrofuran and then purified by preparative HPLC to give 32mg (32% yield) of the title compound.¹H-NMR(DMSO-d₆)：δ7.74(s，1H)，7.61-7.51(m，4H)，7.43(t，J＝7.78Hz，1H)，7.26(d，J＝8.78Hz，2H)，7.10-7.04(m，2H)，6.96(t，J＝2.13Hz，1H)，6.75(br s，2H)，3.85(s，3H)，3.49-3.43(m，2H)，3.42(s，3H)，3.00(s，3H)，1.87-1.77(m，2H)，1.01(t，J＝7.40Hz，3H)；MS(ES)m/z 588[M+H]⁺。

Example 172-

Table 2: representative examples of syntheses as described for 4- (2-amino-4- {3 '-methoxy-5' - [ (methylsulfonyl) oxy ] biphenyl-3-yl } -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl) phenyl propane-1-sulfonate

Example 176

2-Methoxyethanesulfonic acid 4- [ 2-amino-1-methyl-5-oxo-4- (3-pyrazin-2-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester 0.25 acetate

Anhydrous tetrahydrofuran (3mL) was added to 2-methoxyethanesulfonic acid 4- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl]Phenyl ester (75mg, 0.16mmol), 2- (tributylstannyl) pyrazine (86mg, 0.23mmol) and bis (triphenylphosphine) palladium dichloride (5.5mg, 0.008mmol), the mixture was then irradiated with microwaves under an argon atmosphere and maintained at 130 ℃ for 1 h. When cooled to ambient temperature, the mixture was filtered and the solvent was evaporated in vacuo. The product was purified by preparative HPLC to give 29mg (31% yield) of the title compound.¹H-NMR(DMSO-d₆)：δ9.16(d，J＝1.51Hz，1H)，8.73-8.70(m，1H)，8.61(d，J＝2.51Hz，1H)，8.32-8.29(m，1H)，8.01-7.97(m，1H)，7.64-7.60(m，1H)，7.57(d，J＝8.78Hz，2H)，7.49(t，J＝7.78Hz，1H)，7.28(d，J＝8.78Hz，2H)，6.76(br s，2H)，3.77(s，4H)，3.27(s，3H)，3.00(s，3H)，1.89(s，0.85H)；MS(ES)m/z 480[M-H]^-。

Example 177

Propane-1-sulfonic acid 4- [ 2-amino-1-methyl-5-oxo-4- (3-pyrazin-2-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester 0.25 acetate

From propane-1-sulfonic acid 4- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl as described in example 176]The title compound was synthesized in 36% yield from phenyl ester. Purification was performed by preparative HPLC.¹H-NMR(DMSO-d₆)：δ9.16(d，J＝1.51Hz，1H)，8.73-8.70(m，1H)，8.61(d，J＝2.51Hz，1H)，8.33-8.30(m，1H)，8.02-7.97(m，1H)，7.64-7.60(m，1H)，7.60-7.55(m，2H)，7.49(t，J＝7.78Hz，1H)，7.29-7.24(m，2H)，6.76(br s，2H)，3.49-3.44(m，2H)，3.00(s，3H)，1.90(s，0.86H)，1.87-1.76(m，2H)，1.01(t.J＝7.40Hz，3H)；MS(ES)m/z 464[M-H]^-。

Examples 178 and 179

(R) -4- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate and (S) -4- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate

Chromatographic separation of the enantiomers of 4- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate

4- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate (7.5mg) was dissolved in isopropanol (2mL), and the resulting solution was loaded on a Chiralpak AD chromatography column (21.2X 250mm) (using isopropanol: heptane (20: 80) as an eluent, at a flow rate of 16 mL/min). Detection was performed at 254nm, and both isomers were collected and then concentrated in vacuo.

Isomer 1, example 178

2.1mg (with unknown absolute configuration) was collected. MS (ESI) M/z 435[ M-H ]]^-。

Isomer 2, example 179

Example 180

Methanesulfonic acid 3' - (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-3-yl ester hydrochloride

The title compound was synthesized as described in example 4 and then the salt of the base was prepared from 2-amino-5- (3-bromo-phenyl) -3-methyl-5-phenyl-3, 5-dihydro-imidazol-4-one and 3-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl methanesulfonate as described in example 171, in 14% yield. The crude product was purified by flash chromatography using acetonitrile/triethylamine (90/10) as eluent. After addition of diethyl ether, the hydrochloride salt formed precipitated out. ¹H-NMR(DMSO-d₆)：δ11.67(s，1H)，9.61(br s，1H)，7.76(d，J＝7.8Hz，1H)，7.69(s，1H)，7.56(t，J＝7.8Hz，1H)，7.49-7.41(m，4H)，7.41-7.35(m，2H)，7.22-7.19(m，1H)，7.17-7.15(m，1H)，6.99(t，J＝2.1Hz，1H)，3.86(s，3H)，3.43(s，3H)，3.20(s，3H)；MS(ESI)m/z466[M+1]⁺。

Example 181

3- [ (3-bromophenyl) ethynyl ] phenol

A solution of 1-bromo-3-ethynylbenzene (16.5g, 90.9mmol, described in Wettergren, J., Minidis, A.B.E. tetrahedron letters.2003, 44, 7611-containing 7612) in anhydrous tetrahydrofuran (25mL) was added to a solution of 3-iodophenol (19g, 86.4mmol), bis (triphenylphosphine) palladium dichloride (383mg, 0.55mmol), cuprous iodide (104mg, 0.55mmol) and triethylamine (75mL, 538mmol) in anhydrous tetrahydrofuran (125mL) at 0 ℃ under an argon atmosphere. The mixture was stirred at 0 ℃ for 10 minutes, then allowed to reach ambient temperature and stirred overnight. The solvent was evaporated in vacuo and the residue was partitioned between dichloromethane (100mL) and water (100 mL). The organic phase was washed with water (2X 150mL) and brine (100mL), dried over magnesium sulfate, and concentrated in vacuo. Purification by column chromatography (using 50% dichloromethane in heptane as eluent) followed by recrystallization in dichloromethane afforded 17.16g (69% yield) of the title compound.¹H NMR(DMSO-d₆)δ9.72(s，1H)，7.77-7.74(m，1H)，7.64-7.60(m，1H)，7.57-7.54(m，1H)，7.41-7.36(m，1H)，7.26-7.20(m，1H)，7.01-6.96(m，1H)，6.94-6.91(m，1H)，6.84(ddd，J＝8.28，2.51，1.00Hz，1H)；MS(ES)m/z 271，273[M-H]^-。

Example 182

1- (3-bromophenyl) -2- (3-hydroxyphenyl) ethane-1, 2-dione

Reacting 3- [ (3-bromophenyl) ethynyl group]A solution of phenol (17.16g, 62.83mmol) and palladium dichloride (1.11g, 6.28mmol) in dimethyl sulfoxide (300mL) was stirred at 140 ℃ for 5 h. When cooled to room temperature, the mixture was diluted with water (900mL) and then extracted with ether (3X 200 mL). The combined organic phases were washed with water (400mL) and brine (400mL), dried over magnesium sulfate, and concentrated to give 19.4g (quantitative yield) of the title compound. MS (ES) M/z 303, 305[ M-H ]^-。

Example 183

5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one

N-Methylthiourea (11.2g, 124mmol) was added to a solution of 1- (3-bromophenyl) -2- (3-hydroxyphenyl) ethane-1, 2-dione (19.4g, 62mmol) in dimethyl sulfoxide (62mL) and then heated to 100 ℃. An aqueous solution of potassium hydroxide (1.5M, 58mL, 86.6mmol) was added slowly and the resulting solution was stirred at 100 ℃ for 10 min. When cooled to room temperature, the mixture was diluted with water (300mL), 6M hydrochloric acid (50mL) was added, and the aqueous phase was extracted with chloroform (3X 150 mL). The combined organic phases were washed with water (250mL) and brine (250mL), dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (using 25% ethyl acetate in heptane as eluent) gave 16.33g (70% yield) of the title compound. MS (ES) M/z 375, 377[ M-H ]]^-。

Example 184

Methanesulfonic acid 3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester

Methanesulfonyl chloride (0.39mL, 4.97mmol) was added under an argon atmosphere to a cooled (0 ℃ C.) solution of 5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one (1.25g, 3.31mmol) and triethylamine (1.4mL, 9.94mmol) in dry dichloromethane (30 mL). The resulting mixture was allowed to reach ambient temperature and stirred for 1.5 h. The solvent was evaporated in vacuo and the residue was then dissolved in ethyl acetate, which resulted in precipitation of the triethylamine salt. The salt was filtered off, and the filtrate was concentrated and purified by column chromatography (using 5-40% ethyl acetate in heptane as eluent) to yield 940mg (62% yield) of the title compound. ¹H NMR(DMSO-d₆)δ11.72(s，1H)，7.65-7.61(m，1H)，7.58(t，J＝8.03Hz，1H)，7.50(m，1H)，7.45-7.39(m，2H)，7.39-7.33(m，2H)，7.30-7.26(m，1H)，3.41(s，3H)，3.18(s，3H)；MS(ES)m/z 453，455[M-H]^-。

Example 185

Methanesulfonic acid 3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester

An aqueous solution (70%) of tert-butyl hydroperoxide (3mL, 31mmol) was added to methanesulfonic acid 3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl]A solution of phenyl ester (940mg, 2.06mmol) in methanol (30mL) and 33% ammonia (6mL) was added, and the resulting mixture was stirred at room temperature for 6 h. The methanol was removed in vacuo and the residue was diluted with water (75mL) and extracted with chloroform (3X 50 mL). The combined organic phases were washed with brine (75mL), dried over sodium sulfate and concentrated in vacuo to give 890mg (99%) of the title compound. MS (ES) M/z 438, 440[ M + H]⁺。

Example 186

2-Methoxyethanesulfonic acid 3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester

The title compound was synthesized from 5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one and 2-methoxyethanesulfonyl chloride (described in Matlack a.s.j.org.chem.1958, 23, 729-propane 731) as described in example 184, except that the reaction mixture was stirred for 1h, yielding 71%. MS (ES) M/z 497, 499[ M-H ]]^-。

Example 187

2-Methoxyethanesulfonic acid 3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester

From 2-methoxyethanesulfonic acid 3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl]The title compound was synthesized in 77% yield from phenyl ester, 33% ammonia and tert-butyl hydroperoxide. MS (ES) M/z 482, 484[ M + H ]]⁺。

Example 188

3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl propane-1-sulfonate

The synthesis was performed as described in example 184 from 5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one and propane-1-sulfonyl chlorideThe title compound was obtained in 94% yield.¹H NMR(DMSO-d₆)δ11.73(s，1H)，7.71(m，1H)，7.66-7.55(m，2H)，7.51-7.31(m，4H)，7.27-7.22(m，1H)，3.56-3.44(m，2H)，3.18(s，3H)，1.89-1.75(m，2H)，1.05-0.95(m，3H)；MS(ES)m/z 481，483[M-H]^-。

Example 189

3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-1-sulfonate

From propane-1-sulfonic acid 3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl as described in example 185]The title compound was synthesized in 94% yield from phenyl ester, 33% ammonia and tert-butyl hydroperoxide. MS (ES) M/z 466, 468[ M + H]⁺。

Example 190

3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl propane-2-sulfonate

The title compound was synthesized from 5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one and propane-2-sulfonyl chloride as described in example 184, except that the reaction mixture was stirred for 3h, yield 55%. MS (ES) M/z 481, 483[ M-H ] ]^-。

Example 191

3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-2-sulfonate

From propane-2-sulfonic acid 3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl as described in example 185]The title compound was synthesized in 84% yield from phenyl ester, 33% ammonia and tert-butyl hydroperoxide. MS (ES) M/z 466, 468[ M + H]⁺。

Example 192

Cyclopropanesulfonic acid 3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester

The title compound was synthesized from 5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one and cyclopropanesulfonyl chloride as described in example 184, except that the reaction mixture was stirred for 23h, yield 60%. MS (ES) M/z 479, 481[ M-H]^-。

Example 193

Cyclopropanesulfonic acid 3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester

3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] cyclopropanesulfonic acid]The title compound was synthesized in 93% yield from phenyl ester, 33% ammonia and tert-butyl hydroperoxide. MS (ES) M/z 462, 464[ M + H ]]⁺。

Example 194

3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl dimethylaminosulfonate

The title compound was synthesized from 5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one and dimethylaminosulfonyl chloride as described in example 184, except that the reaction mixture was stirred over the weekend in 72% yield. MS (ES) M/z 482, 484[ M-H ]]^-。

Example 195

3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl dimethylaminosulfonate

From dimethylaminosulfonic acid 3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl group as described in example 185]The title compound was synthesized in 93% yield from phenyl ester, 33% ammonia and tert-butyl hydroperoxide. MS (ES) M/z 467, 469[ M + H]⁺。

Example 196

Morpholine-4-sulfonic acid 3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester

The title compound was synthesized from 5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one and morpholine-4-sulfonyl chloride as described in example 184, except thatThe reaction mixture was stirred overnight, yielding 34%.¹H NMR(DMSO-d₆)δ11.75(s，1H)，7.65-7.54(m，2H)，7.54-7.47(m，1H)，7.45-7.33(m，4H)，7.32-7.26(m，1H)，3.64-3.57(m，4H)，3.27-3.22(m，4H)，3.18(s，3H)；MS(ES)m/z 524，526[M-H]^-。

Example 197

Morpholine-4-sulfonic acid 3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester

From morpholine-4-sulfonic acid 3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl as described in example 185 ]The title compound was synthesized in 85% yield from phenyl ester, 33% ammonia and tert-butyl hydroperoxide. MS (ES) M/z 509, 511[ M + H]⁺。

Example 198

3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ethanesulfonate

The title compound was synthesized as described in example 184 from 5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one and ethanesulfonyl chloride in 88% yield.¹H NMR(DMSO-d₆)δ11.73(s，1H)，7.64-7.61(m，1H)，7.57(t，J＝8.03Hz，1H)，7.50-7.48(m，1H)，7.48-7.44(m，1H)，7.42-7.32(m，3H)，7.26(t，J＝2.01Hz，1H)，3.58-3.50(m，2H)，3.18(s，3H)，1.37-1.29(m，3H)；MS(ES)m/z 467，469[M-H]^-。

Example 199

3- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ethanesulfonate

From ethanesulfonic acid 3- [4- (3-bromophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl group as described in example 185]The title compound was synthesized in 87% yield from phenyl ester, 33% ammonia and tert-butyl hydroperoxide. Purification was performed by column chromatography (using a mixture of 10% 0.1M ammonia in methanol and 90% dichloromethane as eluent).¹H NMR(DMSO-d₆)δ7.62-7.58(m，1H)，7.50-7.42(m，4H)，7.42-7.38(m，1H)，7.32-7.27(m，1H)，7.25-7.20(m，1H)，6.83(br.s.，2H)，3.50(q，J＝7.28Hz，2H)，2.99(s，3H)，1.37-1.31(m，3H)；MS(ES)m/z 450，452[M-H]^-。

Example 200

2-amino-5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized as described in example 185 from 5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one, 33% ammonia, and tert-butyl hydroperoxide in 57% yield. Purification was performed by column chromatography (using a mixture of 10% 0.1M ammonia in methanol and 90% dichloromethane as eluent). ¹H NMR(DMSO-d₆)δ9.33(br.s.，1H)，7.62-7.59(m，1H)，7.49-7.39(m，2H)，7.28(m，1H)，7.07(m，1H)，6.86-6.81(m，2H)，6.69(br.s.，2H)，6.63-6.58(m，1H)，2.98(s，3H)；MS(ES)m/z 360，362[M+H]⁺。

Example 201

3- { 2-amino-4- [3- (5-methoxypyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ethanesulfonate 0.75 acetate

The title compound was synthesized as described in example 171 from 2-amino-5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one in 14% yield. Purification by preparative HPLC followed by freeze drying.¹H NMR(DMSO-d₆)δ8.34(d，J＝1.76Hz，1H)，8.30(d，J＝2.76Hz，1H)，7.71-7.74(m，1H)，7.61(d，J＝7.53Hz，1H)，7.50-7.56(m，2H)，7.42-7.48(m，4H)，7.19-7.25(m，1H)，6.82(br.s.，2H)，3.89(s，3H)，3.46-3.53(m，2H)，3.01(s，3H)，1.91(s，1H)，1.34(t，J＝7.28Hz，3H)；MS(ES)m/z 479[M-H]^-。

Example 202

Methanesulfonic acid 4- { 2-amino-4- [3- (5-methoxypyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester acetate

From methanesulfonic acid 4- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl as described in example 171]The title compound was synthesized in 16% yield from phenyl ester. Purification by preparative HPLC followed by freeze drying.¹H NMR(DMSO-d₆)δ8.34(d，J＝2.01Hz，1H)，8.30(d，J＝2.76Hz，1H)，7.79-7.76(m，1H)，7.63-7.58(m，3H)，7.56-7.52(m，1H)，7.49-7.42(m，2H)，7.31-7.27(m，2H)，6.77(br.s.，2H)，3.89(s，3H)，3.35(s，3H)，3.00(s，3H)，1.91(s，3H)；MS(ES)m/z 465[M-H]^-。

Example 203

2-amino-5- [3- (2-fluoropyridin-3-yl) phenyl ] -5- (3-hydroxyphenyl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized as described in example 171 from 2-amino-5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one in 67% yield. Purification was performed by column chromatography (using a mixture of 10% 0.1M ammonia in methanol and 90% dichloromethane as eluent). ¹H NMR(DMSO-d₆)δ9.33(s，1H)，8.28-8.23(m，1H)，8.04-7.98(m，1H)，7.70(s，1H)，7.58-7.39(m，4H)，7.13-7.05(m，1H)，6.93-6.82(m，2H)，6.65-6.59(m，1H)，2.99(s，3H)；MS(ES)m/z 377[M+H]⁺。

Example 204

2-amino-5- (3-hydroxyphenyl) -3-methyl-5- (3-pyrimidin-5-ylphenyl) -3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized as described in example 171 from 2-amino-5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one in 39% yield. Purification was performed by column chromatography (using a mixture of 10% 0.1M ammonia in methanol and 90% dichloromethane as eluent). MS (ES) M/z 360[ M + H]⁺。

Example 205

2-amino-5- (3-hydroxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized as described in example 171 from 2-amino-5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one in 38% yield. Purification was performed by column chromatography (using a mixture of 10% 0.1M ammonia in methanol and 90% dichloromethane as eluent). MS (ES) M/z 359[ M + H]⁺。

Example 206

2-amino-5- (3-hydroxyphenyl) -5- [3- (5-methoxypyridin-3-yl) phenyl ] -3-methyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized as described in example 171 from 2-amino-5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one in 19% yield. Purification was performed by column chromatography (using a mixture of 10% 0.1M ammonia in methanol and 90% dichloromethane as eluent). MS (ES) M/z 389[ M + H ] ]⁺。

Example 207

3- { 2-amino-4- [3- (2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl trifluoromethanesulfonate hydrochloride

By micro-mirrorsWave irradiation of 2-amino-5- [3- (2-fluoropyridin-3-yl) phenyl]A mixture of-5- (3-hydroxyphenyl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one (140mg, 0.37mmol), N-phenyl-bis (trifluoromethanesulfonyl) imide (133mg, 0.37mmol) and anhydrous potassium carbonate (310mg, 2.22mmol) in anhydrous tetrahydrofuran (4mL) was maintained at 120 ℃ for 7 min. The mixture was filtered, the solvent evaporated and the residue purified by preparative HPLC to give 32mg of base.¹H NMR(DMSO-d₆)δ8.29-8.19(m，2H)，8.03-7.98(m，1H)，7.70-7.67(m，2H)，7.56-7.45(m，5H)，7.40(dd，J＝8.03，2.01Hz，1H)，6.85(br.s.，2H)，3.01-2.98(m，3H)。

The base was dissolved in anhydrous dichloromethane (3mL) and hydrochloric acid (1M in ether, 0.1mL) was added. The mixture was stirred at room temperature for 5min, then the solvent was evaporated to give 91mg (45% yield) of the title compound. MS (ES) M/z 509[ M + H]⁺。

Example 208

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-5-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate hydrochloride

The title compound was synthesized as described in example 207 from 2-amino-5- (3-hydroxyphenyl) -3-methyl-5- (3-pyrimidin-5-ylphenyl) -3, 5-dihydro-4H-imidazol-4-one in 30% yield. Of the free base ¹HNMR(DMSO-d₆)δ9.19(s，1H)，9.00(s，2H)，7.77-7.75(m，1H)，7.73-7.66(m，2H)，7.60-7.57(m，1H)，7.57-7.48(m，3H)，7.43-7.39(m，1H)，6.86(br.s.，2H)，3.01(s，3H)；MS(ES)m/z 492[M+H]⁺。

Example 209

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl trifluoromethanesulfonate hydrochloride

The title compound was synthesized as described in example 207 from 2-amino-5- (3-hydroxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3, 5-dihydro-4H-imidazol-4-one in 31% yield. Of the free base¹HNMR(DMSO-d₆)δ8.69(d，J＝2.01Hz，1H)，8.51(dd，J＝4.77，1.51Hz，1H)，7.92-7.83(m，1H)，7.69-7.60(m，2H)，7.58-7.32(m，7H)，6.83(br.s.，2H)，2.95(s，3H)；MS(ES)m/z 491[M+H]⁺。

Example 210

3- { 2-amino-4- [3- (5-methoxypyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl trifluoromethanesulfonate hydrochloride

From 2-amino-5- (3-hydroxyphenyl) -5- [3- (5-methoxypyridin-3-yl) phenyl as described in example 207]-3-methyl-3, 5-dihydro-4H-imidazol-4-one to synthesize the title compound in 34% yield. Of the free base¹H NMR(DMSO-d₆)δ8.32(d，J＝15.66Hz，2H)，7.73-7.61(m，3H)，7.61-7.51(m，3H)，7.51-7.41(m，3H)，7.04(br.s.，2H)，3.89(s，3H)，3.03(s，3H)；MS(ES)m/z 521[M+H]⁺。

Examples 211 and 212

Methanesulfonic acid (R) -3 '- (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-3-yl ester hydrochloride and methanesulfonic acid (S) -3' - (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-3-yl ester hydrochloride

Chromatographic separation of enantiomer of methanesulfonic acid 3' - (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-3-yl ester

The free base of methanesulfonic acid 3' - (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-3-yl ester (1.02g) was dissolved in methanol (50mL) and the resulting solution was loaded onto a Chiralcel OJ chromatography column (4.6 x 250mm each, 5 loads) (flow rate 0.8mL/min using methanol as eluent). Detection was performed at 254, 220 and 280nm, and both isomers were collected and then concentrated in vacuo. The residue was dissolved in anhydrous dichloromethane (4mL), then hydrochloric acid (1M in ether, 1mL) was added. The resulting mixture was stirred for 5min, then concentrated by blowing nitrogen, followed by overnight in a vacuum oven.

Isomer 1, example 211

307mg (with unknown absolute configuration) were collected.¹H NMR(DMSO-d₆)δ11.73(br.s.，1H)，9.61(br.s.，2H)，7.76(d，J＝7.78Hz，1H)，7.72-7.69(m，1H)，7.56(t，J＝7.78Hz，1H)，7.48-7.38(m，6H)，7.22-7.20(m，1H)，7.18-7.16(m，1H)，7.00-6.97(m，1H)，3.86(s，3H)，3.43(s，3H)，3.21(s，3H)。

Isomer 2, example 212

404mg (with unknown absolute configuration) was collected.¹H NMR(DMSO-d₆)δ11.75(br.s.，1H)，9.63(br.s.，2H)，7.76(d，J＝7.78Hz，1H)，7.72-7.69(m，1H)，7.56(t，J＝7.78Hz，1H)，7.48-7.38(m，6H)，7.22-7.20(m，1H)，7.18-7.16(m，1H)，6.99(t，J＝2.26Hz，1H)，3.86(s，3H)，3.43(s，3H)，3.21(s，3H)。

Example 213

Methanesulfonic acid 4- [ 2-amino-4- (3 ', 5' -dichlorobiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride

Irradiating methanesulfonic acid 4- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl with microwaves under an argon atmosphere]Phenyl ester (100mg, 0.23mmol), 2- (3, 5-dichlorophenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (81mg, 0.3 mmol; described in Jian-Yang; Tse. et al. science 2002, 295(5553), 305-), [1, 1' -bis (diphenylphosphino) ferrocene ] 308 ]A mixture of palladium dichloride dichloromethane adduct (19mg, 0.02mmol) and potassium carbonate (189mg, 1.37mmol) in anhydrous tetrahydrofuran (3mL) was maintained at 130 ℃ for 2 h. When cooled to ambient temperature, additional 2- (3, 5-dichlorophenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan (50mg, 0.18mmol) was added and the reaction mixture was then irradiated with microwaves under an argon atmosphere and held at 130 ℃ for 3 h. Upon cooling to ambient temperature, the mixture was filtered and then purified by preparative HPLC to give the acetate salt.¹H NMR(DMSO-d₆) δ 7.82-7.76(m, 1H), 7.65-7.55(m, 7H), 7.48-7.41(m, 1H), 7.33-7.26(m, 2H), 6.79(br.s., 2H), 3.35(s, 3H, since H₂O, blurred), 3.00(s, 3H), 1.91(s, 3H).

The acetate was dissolved in anhydrous dichloromethane (1mL) and then hydrochloric acid (1M in ether, 35 μ L) was added. The resulting mixture was concentrated by blowing nitrogen, followed by overnight in a vacuum oven to yield 18mg (14% yield) of the title compound. MS (ES) M/z 504, 506[ M + H]⁺。

Example 214

2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine

2-bromopyrimidine (760mg, 4.78mmol), 4, 4, 4 ', 4', 5, 5, 5 ', 5' -octamethyl-2, 2 '-di-1, 3, 2-dioxaborolane (1.46g, 5.74mmol) and [1, 1' -di (diphenylphosphino) ferrocene were irradiated with microwaves ]A mixture of palladium dichloride dichloromethane adduct (114mg, 0.14mmol) and potassium acetate (1.41g, 14.3mmol) in 1, 2-dimethoxyethane (16mL) and water (1mL) was maintained at 150 ℃ for 15 min. When cooled to ambient temperature, the mixture was evaporated in vacuo, slurried in ethyl acetate, filtered through celite, passed through a pad of silica gel, and then concentrated in vacuo to give 660mg (67% yield) of the title compound. MS (EI) M/z 207[ M +1 ]]⁺。

Example 215-

Table 3: representative examples of syntheses as described for 4- [ 2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate 0.25 acetate

Example 247-

Table 4: representative examples of syntheses as described for 4- (2-amino-4- {3 '-methoxy-5' - [ (methylsulfonyl) oxy ] biphenyl-3-yl } -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl) phenyl propane-1-sulfonate

Due to the short exchange time (5.2s), the aromatic signal shows a lower intensity than expected. (Due to the fast Xtime, 5.2s, aromatic signals with windows low intervals and expected.)

Example 258

1-ethynyl-3- (3-methoxyphenoxy) benzene

A solution of 3-hydroxyphenylacetylene (0.2g, 1.7mmol), 3-methoxy-2- (trimethylsilyl) phenyl trifluoromethanesulfonate (0.54g, 1.65 mmol; described in Pena, D.; Perez, D.; Guitiain, E.; Castedo, L.J.am.Chem.Soc.1999, 121, 5827-Bufonis acid 5828) and cesium fluoride (0.78g, 5.1mmol) in acetonitrile (25mL) was stirred for 48 h. The solvent was removed in vacuo, and the resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium carbonate solution, water and brine. The organic phase is dried over sodium sulfate and then concentrated to yield 0.32g (87% yield) of the title compound. ¹H NMR(DMSO-d₆)δ7.39(t，J＝7.91Hz，1H)，7.31(t，J＝8.16Hz，1H)，7.23-7.25(m，1H)，7.03-7.08(m，2H)，6.75-6.78(m，1H)，6.62(t，J＝2.38Hz，1H)6.56-6.59(m，1H)，4.23(s，1H)，3.74(s，3H)。

Example 259

3- [ (4-methoxyphenyl) ethynyl ] phenol

Triethylamine (10mL) was added to a solution of 3-iodophenol (1.83g, 8.3mmol), 4-ethynylanisole (1.08g, 8.18mmol), bis (triphenylphosphine) palladium dichloride (29mg, 0.04mmol) and cuprous iodide (8mg, 0.04mmol) in anhydrous tetrahydrofuran (30 mL). The mixture was stirred at room temperature overnight and then concentrated. The residue was dissolved in dichloromethane and washed with hydrochloric acid (0.5M) and brine. The organic phase was dried over sodium sulfate and then concentrated. Purification by column chromatography (using 0-15% ethyl acetate in n-heptane as eluent) gave 0.78g (43% yield) of the title compound.¹H NMR(DMSO-d₆)δ9.64(s，1H)，7.46-7.49(m，2H)，7.19(t，J＝7.91Hz，1H)，6.96-6.99(m，2H)，6.92-6.95(m，1H)，6.86-6.88(m，1H)，6.77-6.81(m，J＝8.28，2.51，1.00Hz，1H)，3.79(s，3H)。

Example 260

4- { [3- (3-methoxyphenoxy) phenyl ] ethynyl } phenol

1-ethynyl-3- (3-methoxyphenoxy) benzene (0.32g, 1.44mmol), 4-iodophenol (1.5mmol, 0.33g), cuprous iodide (1.5mg, 0.007mmol) and bis (triphenylphosphine) palladium dichloride (5mg, 0.007mmol) were stirred in anhydrous tetrahydrofuran (10mL) and triethylamine (3mL) for 16h, then concentrated. The residue was dissolved in dichloromethane and washed with hydrochloric acid (0.5M) and brine. The organic phase was dried over sodium sulfate and then concentrated. Purification by column chromatography (using 0-15% ethyl acetate in n-heptane as eluent) gave 0.09g (19% yield) of the title compound. ¹H NMR(DMSO-d₆)δ9.92(s，1H)，7.40-7.43(m，1H)，7.29-7.39(m，3H)，7.23-7.27(m，1H)，7.02-7.06(m，2H)，6.75-6.80(m，3H)，6.63(t，J＝2.38Hz，1H)6.57-6.61(m，1H)，3.75(s，3H)。

Example 261

1- (3-hydroxyphenyl) -2- (4-methoxyphenyl) ethane-1, 2-dione

Reacting 3- [ (4-methoxyphenyl) ethynyl group]A solution of phenol (0.78g, 3.47mmol) and palladium dichloride (61mg, 0.35mmol) in dimethyl sulfoxide (35mL) was heated at 130 ℃ for 5 h. When cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated to give 0.9g (100%Yield) of the title compound.¹H NMR(DMSO-d₆)δ10.54(s，1H)，8.35-8.39(m，2H)，7.92(t，J＝7.65Hz，1H)，7.77-7.81(m，2H)，7.64-7.68(m，3H)，4.39(s，3H)。

Example 262

5- (3-hydroxyphenyl) -5- (4-methoxyphenyl) -3-methyl-2-thioimidazolidin-4-one

A solution of 1- (3-hydroxyphenyl) -2- (4-methoxyphenyl) ethane-1, 2-dione (0.9g, 3.5mmol) and N-methylthiourea (0.63g, 7mmol) in dimethyl sulfoxide (25mL) was heated to 100 ℃. Potassium hydroxide (1.2M in water, 5.8mL, 7mmol) was added and the mixture was held at 100 ℃ for 30 min. Water was added and then the pH was adjusted to about 4 with hydrochloric acid (2M). The mixture was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate and concentrated. Purification by column chromatography (using 20-30% ethyl acetate in n-heptane as eluent) gave 1.04g (90% yield) of the title compound.¹H NMR(DMSO-d₆)δ11.50(s，1H)，9.57(s，1H)，7.22-7.26(m，2H)，7.19(t，J＝7.78Hz，1H)，6.97(d，J＝8.78Hz，2H)，6.68-6.75(m，3H)，3.75(s，3H)，3.16(s，3H)。

Example 263

1- (4-hydroxyphenyl) -2- [3- (3-methoxyphenoxy) phenyl ] ethane-1, 2-dione

4- { [3- (3-methoxyphenoxy) phenyl]A solution of ethynyl } phenol (88mg, 0.27mmol) and palladium dichloride (5mg, 0.03mmol) in dimethyl sulfoxide (3mL) was heated at 130 ℃ for 5 h. After cooling to room temperatureWater was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated to yield 0.07g (76% yield) of the title compound.¹H NMR(DMSO-d₆)δ10.90(s，1H)，7.75-7.79(m，2H)，7.55-7.63(m，2H)，7.41-7.44(m，2H)，7.33(t，J＝8.16Hz，1H)，6.91-6.95(m，2H)，6.80(dd，J＝8.28，2.51Hz，1H)，6.68(t，J＝2.26Hz，1H)，6.62-6.65(m，J＝8.16，2.13Hz，1H)，3.74(s，3H)。

Example 264

5- (4-hydroxyphenyl) -5- [3- (3-methoxyphenoxy) phenyl ] -3-methyl-2-thioimidazolidin-4-one

1- (4-hydroxyphenyl) -2- [3- (3-methoxyphenoxy) phenyl]A solution of ethane-1, 2-dione (71mg, 0.2mmol) and N-methylthiourea (0.04g, 0.4mmol) in dimethyl sulfoxide (5mL) was heated to 100 ℃. Potassium hydroxide (1.2M in water, 0.3mL, 0.4mmol) was added and the mixture was held at 100 ℃ for 1 h. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered and concentrated to give 0.085g (100% yield) of the title compound.¹H NMR(DMSO-d₆)δ7.43(t，J＝8.03Hz，1H)，7.27(t，J＝8.16Hz，1H)，7.12-7.15(m，1H)，7.01-7.08(m，3H)，6.96-7.00(m，1H)，6.74-6.78(m，2H)，6.70-6.73(m，1H)，6.52-6.57(m，2H)，3.71(s，3H)，3.15(s，3H)。

Example 265

1- (4-methoxyphenyl) -2- (3-phenoxyphenyl) ethane-1, 2-dione

1- (3-hydroxyphenyl) -2- (4-methoxyphenyl) ethane-1, 2-dione (0.27g, 1.05mmol) and cesium fluoride (0.48g, 3.15mmol) were dissolved in acetonitrile (15 mL). 2- (trimethylsilyl) phenyl trifluoromethanesulfonate (0.38mL, 1.58mmol) was added, and the mixture was stirred overnight. Ethyl acetate was added, then the organic phase was washed with water and brine, dried over sodium sulfate, and concentrated. Chromatography on silica gel using 0-15% ethyl acetate in n-heptane as eluent gave 0.225g (64% yield) of the title compound.¹H NMR(DMSO-d₆)δ7.86-7.89(m，2H)，7.56-7.64(m，2H)，7.42-7.47(m，4H)，7.21-7.25(m，1H)，7.09-7.16(m，4H)，3.88(s，3H)。

Example 266

5- (4-methoxyphenyl) -3-methyl-5- (3-phenoxyphenyl) -2-thioimidazolidin-4-one

A solution of 1- (4-methoxyphenyl) -2- (3-phenoxyphenyl) ethane-1, 2-dione (0.22g, 0.66mmol) and N-methylthiourea (0.12g, 1.32mmol) in dimethyl sulfoxide (8mL) was heated at 100 ℃. Potassium hydroxide (1.2M in water, 1.1mL, 1.32mmol) was added and the mixture was held at 100 ℃ for 30 min. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered and concentrated to give 0.245g (91% yield) of the title compound.¹H NMR(DMSO-d₆)δ11.57(s，1H)，7.36-7.44(m，3H)，7.19-7.23(m，2H)，7.11-7.17(m，2H)，6.94-7.02(m，6H)，3.74(s，3H)，3.16(s，3H)。

Example 267

5- (4-hydroxyphenyl) -3-methyl-5- (3-phenoxyphenyl) -2-thioimidazolidin-4-one

5- (4-methoxyphenyl) -3-methyl-5- (3-phenoxyphenyl) -2-thioimidazolidin-4-one (0.245g, 0.6mmol) was dissolved in dichloromethane (10mL) and cooled to 0 ℃. Boron tribromide (0.08mL, 0.8mmol) was added and the mixture was allowed to reach room temperature. Additional boron tribromide (0.08mL, 0.8mmol) was added and the mixture was stirred for 6 h. Brine and ethyl acetate were added and the organic phase was collected, dried over sodium sulfate and concentrated to give 0.24g (102% yield) of the title product.¹H NMR(DMSO-d₆)δ11.52(s，1H)，9.67(s，1H)，7.38-7.43(m，2H)，7.11-7.15(m，2H)，7.06-7.08(m，2H)，6.94-7.03(m，5H)，6.75-6.78(m，2H)，3.15(s，3H)。

General Process for preparing sulfonyl chlorides

Example 268

3-methoxypropan-1-sulfonyl chloride

A mixture of 1-bromo-3-methoxypropane (2.5g, 16.34mmol) and sodium sulfite (2.06g, 16.34mmol) in water (25mL) was heated at reflux for 24 h. The solvent was evaporated and the solid formed was washed with a mixture of ether/toluene (8: 2) and dried in vacuo. The solid was added portionwise to phosphoryl chloride (25mL), heated at 80 ℃ for 5h, then at 100 ℃ for 2 h. The mixture was cooled to room temperature, diluted with dichloromethane and filtered. The filtrate was concentrated, ethyl acetate was added, followed by ice. The ice was melted and the organic phase was collected, washed with water and brine, dried over sodium sulfate and concentrated to give 2.8g (100% yield) of the title compound. 3.35(t, J ═ 6.53Hz, 2H), 3.20(s, 3H), 2.44-2.49(m, 2H), 1.74-1.81(m, 2H).

Example 269

3-Methoxypropan-1-sulfonic acid 3- [ 2-amino-4- (4-methoxyphenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride

A solution of 5- (3-hydroxyphenyl) -5- (4-methoxyphenyl) -3-methyl-2-thioimidazolidin-4-one (45mg, 0.14mmol), triethylamine (28. mu.L, 0.2mmol) and 3-methoxypropan-1-sulfonyl chloride (35mg, 0.2mmol) in dichloromethane (5mL) was stirred overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate, and then washed with hydrochloric acid (0.1M), aqueous sodium hydroxide solution (0.1M), and brine. The organic phase was dried over sodium sulfate, concentrated, and the resulting residue was dissolved in methanol (2 mL). Aqueous ammonium hydroxide (concentrated, 1mL) and tert-butyl hydroperoxide (0.15mL, 70% aqueous, 1.5mmol) were added. The mixture was heated at 35 ℃ for 4h, and the product was isolated by preparative HPLC. The fractions were pooled, acetonitrile was evaporated, aqueous sodium carbonate solution was added (saturated), and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and the resulting residue was dissolved in dichloromethane. Hydrochloric acid (0.5mL, 1M in ether) was added, and the solvent was evaporated to give 28mg (41% yield) of the title compound. ¹H NMR(DMSO-d₆)δ7.55-7.61(m，1H)，7.39-7.43(m，2H)，7.30-7.32(m，1H)，7.21-7.25(m，2H)，6.98-7.02(m，2H)，3.76(s，3H)，3.52-3.57(m，2H)，3.41-3.45(m，2H)，3.23(s，3H)，3.18(s，3H)，1.99-2.06(m，2H)。

Example 270-273

Table 5: representative examples of syntheses as described for 3-methoxypropan-1-sulfonic acid 3- [ 2-amino-4- (4-methoxyphenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride

Example 273

Methanesulfonic acid 4- [ 2-amino-1-methyl-5-oxo-4- (3-phenoxyphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride

The title compound was synthesized as described for example 269 from 5- (4-hydroxyphenyl) -3-methyl-5- (3-phenoxyphenyl) -2-thioimidazolidin-4-one in 39% yield.¹H NMR(DMSO-d₆)δ11.79(br.s，1H)，9.75(br.s，2H)，7.48-7.51(m，2H)，7.37-7.46(m，5H)，7.14-7.19(m，2H)，7.10(t，J＝1.89Hz，1H)，6.98-7.03(m，3H)，3.41(s，3H)，3.19(s，3H)；MS(ES)m/z 450[M-1]^-。

Example 274

Propane-1-sulfonic acid 4- [ 2-amino-1-methyl-5-oxo-4- (3-phenoxyphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride

The title compound was synthesized as described for example 269 from 5- (4-hydroxyphenyl) -3-methyl-5- (3-phenoxyphenyl) -2-thioimidazolidin-4-one in 39% yield.¹H NMR(DMSO-d₆)δ7.37-7.49(m，7H)，7.14-7.18(m，2H)，7.09(t，J＝2.02Hz，1H)，6.98-7.03(m，3H)，3.50-3.55(m，2H)，3.17(s，3H)，1.80-1.89(m，2H)，1.03(t，J＝7.45Hz，3H)；MS(ES)m/z 478[M-1]^-。

Example 275

Methanesulfonic acid 4- { 2-amino-4- [3- (3-methoxyphenoxy) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester hydrochloride

From 5- (4-hydroxyphenyl) -5- [3- (3-methoxyphenoxy) phenyl as described in example 269]-3-methyl-2-thioimidazolidin-4-one to synthesize the title compound in a yield of 14%.¹H NMR(DMSO-d₆)δ7.42-7.50(m，5H)，7.28(t，J＝8.16Hz，1H)，7.15-7.18(m，1H)，7.08(t，J＝2.13Hz，1H)，7.02-7.06(m，1H)，6.72-6.75(m，1H)，6.53-6.58(m，2H)，3.72(s，3H)，3.41(s，3H)，3.18(s，3H)；MS(ESI)m/z 480[M-1]^-。

Example 276

3- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioxoimidazolidin-4-yl ] phenyl propane-2-sulfonate

From 5- (3-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazole as described in example 170The title compound was synthesized from alk-4-one and propan-2-sulfonyl chloride in 19% yield. Purification was performed by column chromatography using dichloromethane/acetonitrile (95/5) as eluent.¹H NMR(CDCl₃，400MHz)：δ8.24(s，1H)，7.59(d，J＝8.1Hz，1H)，7.49(t，J＝1.8Hz，1H)，7.48-7.41(m，2H)，7.38-7.27(m，5H)，7.09(d，J＝7.8Hz，1H)，7.06-7.02(m，1H)，6.90(dd，J＝8.0，2.2Hz，1H)，3.84(s，3H)，3.48-3.39(m，1H)，3.35(s，3H)，1.51(dd，J＝6.8，1.3Hz，6H)；MS(ES)m/z 511[M+1]⁺。

Example 277

3- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl propane-2-sulfonate hydrochloride

A70% aqueous solution of tert-butyl hydroperoxide (0.06mL, 0.06mmol) was added to propane-2-sulfonic acid 3- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl]A solution of phenyl ester (0.030g, 0.059mmol) in ethanol/aqueous ammonium hydroxide (33%) (2: 1, 3.8 mL). The resulting mixture was stirred at 35 ℃ overnight. The solvent was evaporated and the residue was poured into water and then extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and the solvent was removed in vacuo to give 30 mg. Purification by column chromatography using a gradient of acetonitrile/triethylamine (100/0 to 90/10) as eluent gave 35mg of base. The base was dissolved in dichloromethane and then treated with hydrochloric acid (4M in ether) and additional ether (30mL) was added. The solvent was evaporated and the residue was dried in a vacuum oven at 45 ℃ overnight to yield 45mg (27% yield) of the title compound. ¹H NMR(DMSO-d₆，400MHz)：δ11.79(br s，1H)，9.73(br s，2H)，7.74(d，J＝8.0Hz，1H)，7.68(d，J＝8.3Hz，1H)，7.63-7.58(m，3H)，7.56-7.52(m，2H)，7.42-7.34(m，2H)，7.19-7.13(m，2H)，6.97(dd，J＝8.2，1.9Hz，1H)，3.81(s，3H)，3.20(s，3H)；MS(ES)m/z 518[M-1]^-。

Example 278

Morpholine-4-sulfonic acid 3- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester

The title compound was synthesized as described in example 170 from 5- (3-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one and morpholine-4-sulfonyl chloride in 47% yield. The crude product was poured into water and then extracted with dichloromethane. The combined extracts were evaporated in vacuo. Purification was performed by column chromatography using dichloromethane/acetonitrile (95/5) as eluent.¹H NMR(CDCl₃，400MHz)：δ8.45(s，1H)，7.59(d，J＝7.8Hz，1H)，7.50(t，J＝1.8Hz，1H)，7.48-7.40(m，2H)，7.38-7.28(m，5H)，7.09(d，J＝7.6Hz，1H)，7.05-7.02(m，1H)，6.89(dd，J＝8.0，2.2Hz，1H)，3.83(s，3H)，3.73-3.68(m，4H)，3.37-3.31(m，7H)；MS(ES)m/z 552[M-1]^-。

Example 279

Morpholine-4-sulfonic acid 3- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride

From morpholine-4-sulfonic acid 3- [4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl as described in example 277]The title compound was synthesized in 41% yield from phenyl ester. By column chromatography (using acetonitrile/triethylamine)(95/5) as eluent) to purify.¹H NMR(DMSO-d₆，400MHz)：δ11.71(s，1H)，9.67(s，2H)，7.72(d，J＝7.5Hz，1H)，7.63-7.51(m，3H)，7.49-7.34(m，5H)，7.20-7.12(m，2H)，6.97(d，J＝7.8Hz，1H)，3.81(s，3H)，3.60-3.55(m，4H)，3.26-3.21(m，4H)，3.20(s，3H)；MS(ES)m/z 537[M+1]⁺。

Example 280

2-amino-5- (3 '-hydroxy-5' -methoxybiphenyl-3-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was synthesized as described in example 5 from 2-amino-5- (3-bromo-phenyl) -3-methyl-5-phenyl-3, 5-dihydro-imidazol-4-one and 3-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol in 33% yield. Purification was performed by column chromatography using ethyl acetate/methanol/aqueous ammonium hydroxide (33%) (94/5/1) as eluent. ¹H-NMR(DMSO-d₆，400MHz)：δ9.56(s，1H)，7.67(s，1H)，7.49-7.42(m，4H)，7.38-7.27(m，3H)，7.25-7.19(m，1H)，6.66(br s，2H)，6.53-6.48(m，2H)，6.33(t，J＝2.1Hz，1H)，3.73(s，3H)，2.99(s，3H)；MS(ES)m/z 388[M+1]⁺。

Example 281

Trifluoromethanesulfonic acid 3' - (2-amino-1-methyl-5-oxo-4-phenyl-4, 5-dihydro-1H-imidazol-4-yl) -5-methoxybiphenyl-3-yl ester hydrochloride

Irradiating with microwave 2-amino-5- (3 '-hydroxy-5'-methoxybiphenyl-3-yl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one (0.050g, 0.13mmol), 1, 1, 1-trifluoro-N-phenyl-N- [ (trifluoromethyl) sulfonyl]A mixture of methanesulfonamide (0.046g, 0.13mmol) and potassium carbonate (0.110g, 0.81mmol) in anhydrous tetrahydrofuran (3mL) was maintained at 120 ℃ for 6 min. Addition of additional 1, 1, 1-trifluoro-N-phenyl-N- [ (trifluoromethyl) sulfonyl group]Methanesulfonamide (0.020g, 0.05mmol) and then the reaction mixture was irradiated with additional microwaves for 6min at 120 ℃. The mixture was filtered and the filtrate was concentrated in vacuo and purified by column chromatography using acetonitrile/triethylamine (95/5) as eluent. The crude product was then poured into water, extracted with dichloromethane, the combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo. The base was dissolved in dichloromethane and then treated with 4M hydrochloric acid in ether, additional ether (20mL) was added. The mixture was evaporated and the residue was dried in a vacuum oven at room temperature overnight to yield 18mg (25% yield) of the title compound. ¹H NMR(DMSO-d₆，400MHz)：δ11.63(br s，1H)，9.59(br s，2H)，7.78(d，J＝7.5Hz，1H)，7.68(s，1H)，7.58(t，J＝7.8Hz，1H)，7.50-7.36(m，6H)，7.32(s，1H)，7.25(s，1H)，7.16-7.12(m，1H)，3.88(s，3H)，3.20(s，3H)；MS(ES)m/z 520[M+1]⁺。

Example 282

Propane-1-sulfonic acid 4- { 2-amino-4- [3- (5-methoxypyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester hydrochloride

From propane-1-sulfonic acid 4- [ 2-amino-4- (3-bromophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl as described in example 5]Phenyl ester and 3-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine to synthesize the title compound in a yield of 12%. By column chromatography (usingEthyl acetate/methanol/aqueous ammonium hydroxide (33%) (94/5/1) as eluent).¹H-NMR(DMSO-d₆400 MHz): δ 11.92(s, 1H), 9.67(s, 2H), 8.59(s, 1H), 8.43(d, J ═ 2.5Hz, 1H), 7.89-7.82(m, 3H), 7.61(t, J ═ 7.8Hz, 1H), 7.56-7.51(m, 2H), 7.47(d, J ═ 8.0, 1H), 7.44-7.39(m, 2H), 3.96(s, 3H), 3.55-3.49(m, 2H) due to H₂O, blurred), 3.20(s, 3H), 1.90-1.78(m, 2H), 1.02(t, J ═ 7.4Hz, 3H); MS (ES) M/z 494[ M +1 ]]⁺。

Example 283

6-iodo-1, 2, 3, 4-tetrahydronaphthalene

1, 2, 3, 4-tetrahydronaphthalene (6.10g, 46.14mmol), silver nitrate (7.84g, 46.14mmol) and iodine (11.71g, 46.14mmol) were added in portions to dichloromethane (500mL) cooled to 0 ℃ and the reaction mixture was stirred at room temperature for 70 h. The resulting precipitate was filtered off, and the filtrate was washed with aqueous sodium thiosulfate (1M) and saturated aqueous sodium bicarbonate. The solvent was evaporated and the product was purified by column chromatography using 0 to 5% ethyl acetate in n-heptane as eluent to yield 5.0g (42% yield) of the title compound. ¹H NMR(CDCl₃)δ7.42-7.36(m，2H)，6.79(d，J＝7.83Hz，1H)，2.68-2.64(m，4H)，1.82-1.72(m，4H)；MS(EI)m/z 258[M]⁺。

Example 284

6- [ (3-bromophenyl) ethynyl ] -1, 2, 3, 4-tetrahydronaphthalene

1-bromo-3Ethynylbenzene (2.11g, 11.63mmol) was added to a solution of 6-iodo-1, 2, 3, 4-tetrahydronaphthalene (3.0g, 11.63mmol), cuprous iodide (41mg, 0.058mmol) and bis (triphenylphosphine) palladium dichloride (11mg, 0.058mmol) in anhydrous tetrahydrofuran (30mL) and triethylamine (15mL) and the reaction mixture was stirred at room temperature overnight. Hydrochloric acid (30mL, 2M) was added and the aqueous phase was extracted with dichloromethane (× 3). The combined organic phases were evaporated and the product was purified by column chromatography (using 0 to 5% ethyl acetate in n-heptane as eluent) to yield 3.0g (83% yield) of the title compound.¹H NMR(CDCl₃)δ7.68(m，1H)，7.50-7.410(m，2H)，7.28-7.19(m，3H)，7.05(d，J＝8.34Hz，1H)，2.78(m，4H)，1.81(m，4H)；MS(EI)m/z 310，312[M]⁺。

Example 285

1- (3-bromophenyl) -2- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) ethane-1, 2-dione

Reacting 6- [ (3-bromophenyl) ethynyl group]A solution of-1, 2, 3, 4-tetrahydronaphthalene (3.0g, 9.60mmol) and palladium dichloride (170mg, 0.96mmol) in anhydrous dimethylsulfoxide (30mL) was heated at 150 ℃ for 4 h. Water was added and the aqueous phase was extracted with dichloromethane (× 3). The combined organic phases were washed with water and then concentrated in vacuo. Purification by column chromatography (using 0-20% ethyl acetate in n-heptane as eluent) gave 2.24g (68% yield) of the title compound. ¹H NMR(CDCl₃)δ7.68(dt，J＝3.28，1.64Hz，1H)，7.50-7.41(m，2H)，7.28-7.19(m，3H)，7.05(d，J＝8.34Hz，1H)，2.78(d，J＝5.81Hz，4H)，1.81(ddd，J＝6.44，3.41，3.28Hz，4H)；MS(ES)m/z 341，343[M-1]^-。

Example 286

5- (3-bromophenyl) -3-methyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -2-thioimidazolidin-4-one

A solution of 1- (3-bromophenyl) -2- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) ethane-1, 2-dione (2.24g, 5.68mmol) and N-methylthiourea (1.02g, 11.36mmol) in dimethyl sulfoxide (40mL) was heated to 100 deg.C, and potassium hydroxide (9.70mL, 1.2M) was added dropwise. After addition, the reaction mixture was stirred at 100 ℃ for 5min and then cooled to room temperature. The solution was diluted with water and then made acidic with concentrated hydrochloric acid, followed by extraction with dichloromethane (× 3). The combined organic phases were washed with water and then concentrated in vacuo to give 2.77g (117% yield) of the title compound. MS (ES) M/z 415, 417[ M +1 ]]⁺。

Example 287

2-amino-5- (3-bromophenyl) -3-methyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) imidazolidin-4-one

Tert-butyl hydroperoxide (9.0g, 100mmol) was added to a solution of 5- (3-bromophenyl) -3-methyl-5- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -2-thioimidazolidin-4-one (2.77g, 6.67mmol) in methanol/ammonium hydroxide (3: 1, 60 mL). The mixture was stirred at room temperature overnight and then concentrated until about 50% of the volume remained. Water was added and the aqueous phase was extracted with dichloromethane (× 3). The combined organic phases were washed with water and then concentrated in vacuo. Purification by column chromatography (using 0-10% ammonium hydroxide/methanol (1: 9) in dichloromethane as eluent) gave 1.16g (44% yield) of the title compound. ¹H NMR(CDCl₃)δ7.69(t，1H)，7.44(d，1H)，7.40(d，1H)，7.18(t，J＝7.96Hz，1H)，7.13-7.10(m，2H)，7.01(d，1H)，3.11(s，3H)，2.76-2.69(m，4H)，1.79-1.74(m，4H)；MS(ES)m/z 398，400[M+1]⁺。

Example 288

6-bromo-1, 2, 3, 4-tetrahydronaphthalen-2-ylmethyl ether

6-bromo-1, 2, 3, 4-tetrahydronaphthalen-2-ol (4.99g, 21.98 mmol; described in Tschaen, D.et al.J.Org.chem.1995, 60(14), 4324-. The mixture was stirred for 5min, then iodomethane (6.24g, 43.96mmol) was added. The reaction mixture was stirred at room temperature overnight, diluted with brine, and then extracted with dichloromethane (× 3). The combined organic phases were washed with water (× 3) and then concentrated in vacuo. Purification by column chromatography (using 0-100% ethyl acetate in n-heptane as eluent) gave 3.79g (72% yield) of the title compound.¹H NMR(CDCl₃)δ7.251-7.21(m，2H)，6.95(d，J＝8.08Hz，1H)，3.73-3.63(m，1H)，3.43(s，3H)，2.99-2.87(m，2H)，2.79-2.70(m，2H)，2.08-1.99(m，1H)，1.90-1.80(m，1H)；MS(EI)m/z 240，242[M]⁺。

Example 289

[ (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) ethynyl ] (trimethyl) silane

Tri-tert-butylphosphine (190mg, 0.94mmol), isopropylamine (1.91g, 18.7mmol) and (trimethylsilyl) acetylene (1.73g, 19.65mmol) were added under an argon atmosphere to a solution of bis (benzonitrile) palladium dichloride (180mg, 0.47mmol) and cuprous iodide (59mg, 0.31mmol) in methanol (40 mL). AddingA solution of 6-bromo-1, 2, 3, 4-tetrahydronaphthalen-2-ylmethyl ether (3.79g, 15.72mmol) in anhydrous dioxane (10mL) was then stirred at room temperature overnight. The reaction mixture was filtered through a short plug of silica gel and then concentrated in vacuo. Purification by column chromatography (using 0-20% ethyl acetate in n-heptane as eluent) gave 3.93g (93% yield) of the title compound. ¹H NMR(CDCl₃)δ7.22(t，J＝7.58Hz，2H)，7.03-6.94(m，1H)，3.66(ddd，J＝10.99，4.67，2.78Hz，1H)，3.42(s，3H)，3.10-2.96(m，1H)，2.96-2.84(m，1H)，2.81-2.70(m，1H)，2.11-1.99(m，1H)，1.90-1.78(m，1H)，0.27-0.18(s，9H)；MS(EI)m/z 258[M]⁺。

Example 290

6-ethynyl-1, 2, 3, 4-tetrahydronaphthalen-2-ylmethyl ether

Mixing [ (6-methoxy-5, 6, 7, 8-tetrahydronaphthalene-2-yl) ethynyl]A solution of (trimethyl) silane (3.93g, 15.2mmol) and potassium carbonate (8.09g, 58.55mmol) in methanol (40mL) was heated at reflux for 2h and then cooled to room temperature. The mixture was filtered and the methanol was evaporated in vacuo. The resulting residue was diluted with chloroform, washed with brine (× 3) and then filtered through a plug of celite. Purification by column chromatography (using 0-100% ethyl acetate in n-heptane as eluent) gave 1.75g (80% yield) of the title compound. MS (EI) M/z 186[ M ]]⁺。

Example 291

6- [ (3-bromophenyl) ethynyl ] -1, 2, 3, 4-tetrahydronaphthalen-2-ylmethyl ether

A solution of 6-ethynyl-1, 2, 3, 4-tetrahydronaphthalen-2-ylmethyl ether (1.75g, 6.95mmol, 74% HPLC purity) in anhydrous tetrahydrofuran (5mL) was added to a solution of 1-bromo-5-iodo-benzene (1.97g, 6.95mmol), bis (triphenylphosphine) palladium dichloride (25mg, 0.035mmol) and cuprous iodide (7mg, 0.035mmol) in anhydrous tetrahydrofuran (30mL) and triethylamine (15 mL). The reaction mixture was stirred at room temperature over the weekend. The mixture was acidified with 2M hydrochloric acid and the aqueous phase was extracted with dichloromethane (× 3). Purification by column chromatography (using 0 to 20% ethyl acetate in n-heptane as eluent) gave 1.68g (71% yield) of the title compound. MS (EI) M/z 340, 342[ M ] ]⁺。

Example 292

1- (3-bromophenyl) -2- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) ethane-1, 2-dione

From 6- [ (3-bromophenyl) ethynyl as described in example 285]-1, 2, 3, 4-tetrahydronaphthalen-2-ylmethyl ether to prepare the title compound in 11% yield. MS (ES) M/z 371, 373[ M-1 ]]^-。

Example 293

5- (3-bromophenyl) -5- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3-methyl-2-thioimidazolidin-4-one

The title compound was prepared from 1- (3-bromophenyl) -2- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) ethane-1, 2-dione as described in example 286 in 104% yield. MS (ES) M/z 443, 445[ M-1 ]]^-。

Example 294

2-amino-5- (3-bromophenyl) -5- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was prepared as described in example 287 from 5- (3-bromophenyl) -5- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3-methyl-2-thioimidazolidin-4-one in 61% yield. MS (ES) M/z428, 430[ M +1 ]]⁺。

Example 295

1-acetyl-6-iodo-1, 2, 3, 4-tetrahydroquinoline

The title compound was prepared in 77% yield from 1-acetyl-1, 2, 3, 4-tetrahydroquinoline (described in Heyde C.et. Eur.J.org.chem.2000, 19, 3273-3278.) as described in example 283. ¹H NMR(CDCl₃)δ7.56-7.47(m，2H)，7.25-6.85(m，1H)，3.82-3.73(m，2H)，2.72(dq，J＝6.69，6.44Hz，2H)，2.23(s，3H)，2.01-1.91(m，2H)；MS(EI)m/z 301[M]⁺。

Example 296

1-acetyl-6- [ (3-bromophenyl) ethynyl ] -1, 2, 3, 4-tetrahydroquinoline

From 1-acetyl-6-iodo-1 as described in example 2842, 3, 4-tetrahydroquinoline to prepare the title compound in 107% yield.¹H NMR(CDCl₃)δ7.68(t，J＝1.77Hz，1H)，7.51-7.40(m，2H)，7.39-7.30(m，2H)，7.23(t，J＝7.83Hz，1H)，7.02-6.91(m，1H)，3.81(t，J＝6.44Hz，2H)，2.75(t，J＝6.57Hz，2H)，2.27(s，3H)，2.05-1.95(m，2H)；MS(ES)m/z 354，356[M+1]⁺。

Example 297

1- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -2- (3-bromophenyl) ethane-1, 2-dione

From 1-acetyl-6- [ (3-bromophenyl) ethynyl as described in example 285]-1, 2, 3, 4-tetrahydroquinoline to prepare the title compound in 95% yield.¹H NMR(CDCl₃)δ8.13(t，J＝1.77Hz，1H)，7.90(dt，J＝7.83，1.26Hz，1H)，7.82-7.75(m，2H)，7.55(d，J＝8.34Hz，1H)，7.41(t，J＝7.83Hz，1H)，7.22-7.08(m，1H)，3.86-3.78(m，2H)，2.81(t，J＝6.57Hz，2H)，2.31(s，3H)，2.05-1.96(m，2H)；MS(ES)m/z 386，388[M+1]⁺。

Example 298

5- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -5- (3-bromophenyl) -3-methyl-2-thioimidazolidin-4-one

The title compound was prepared from 1- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -2- (3-bromophenyl) ethane-1, 2-dione in 83% yield as described in example 286. MS (ES) M/z 458, 460[ M +1 ]]⁺。

Example 299

5- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -2-amino-5- (3-bromophenyl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was prepared from 5- (1-acetyl-1, 2, 3, 4-tetrahydroquinolin-6-yl) -5- (3-bromophenyl) -3-methyl-2-thioimidazolidin-4-one as described in example 287 in 50% yield. MS (ES) M/z441, 443[ M +1 ] ]⁺。

Example 300

5- [ (3-bromophenyl) ethynyl ] indane

The title compound was prepared in 93% yield from 5-iodoindan (described in Walser, A.et al.J.Med.Chem.1991, 34 (4); 1440-1446) as described in example 284.¹H NMR(CDCl₃)δ7.68(t，J＝1.64Hz，1H)，7.45(dt，J＝7.89，1.86Hz，2H)，7.40(s，1H)，7.32(d，J＝7.83Hz，1H)，7.25-7.17(m，2H)，2.92(ddd，J＝11.49，7.71，4.29Hz，4H)，2.15-2.04(m，2H)；MS(EI)m/z 296，298[M]⁺。

Example 301

1- (3-bromophenyl) -2- (2, 3-dihydro-1H-inden-5-yl) ethane-1, 2-dione

From 5- [ (3-bromophenyl) ethynyl as described in example 285]Indane to prepare the title compound in 101% yield.¹H NMR(CDCl₃)δ8.13(t，J＝1.77Hz，1H)，7.89(d，1H)，7.83-7.73(m，3H)，7.42-7.34(m，2H)，3.02-2.92(m，4H)，2.19-2.09(m，2H)；MS(ES)m/z 327，329[M-1]^-。

Example 302

5- (3-bromophenyl) -5- (2, 3-dihydro-1H-inden-5-yl) -3-methyl-2-thioimidazolidin-4-one

The title compound was prepared as described in example 286 from 1- (3-bromophenyl) -2- (2, 3-dihydro-1H-inden-5-yl) ethane-1, 2-dione, in 115% yield. MS (ES) M/z 401, 403[ M +1 ]]⁺。

Example 303

2-amino-5- (3-bromophenyl) -5- (2, 3-dihydro-1H-inden-5-yl) -3-methylimidazolidin-4-one

The title compound was prepared from 5- (3-bromophenyl) -5- (2, 3-dihydro-1H-inden-5-yl) -3-methyl-2-thioimidazolidin-4-one as described in example 287 in 43% yield. MS (ES) M/z 384,386 [ M +1 ]]⁺。

Example 304

2-amino-5- (3' -methoxybiphenyl-3-yl) -5- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate

2-amino-5- (3-bromophenyl) -5- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one (50mg, 0.117mmol), (3-methoxyphenyl) boronic acid (23mg, 0.152mmol), (1, 1' -bis (diphenylphosphino) ferrocene) was irradiated with microwaves]Palladium dichloride dichloromethane adduct (10mg, 0.012mmol), potassium carbonate (102mg, 0.738mmol) and 100. mu.L of water in anhydrous tetrahydrofuran (3mL) were maintained at 150 ℃ for 15 minutes. When cooled to ambient temperature, the mixture was filtered and then dimethyl sulfoxide (500 μ L) was added. The solution was concentrated in vacuo to remove tetrahydrofuran and then purified by preparative HPLC to give 12mg (22% yield) of the title compound.¹H NMR(DMSO-d₆)δ7.72(s，1H)，7.52(d，J＝7.53Hz，1H)，7.44-7.48(m，1H)，7.36-7.42(m，2H)，7.16-7.21(m，2H)，7.11(d，J＝7.78Hz，1H)，7.05-7.08(m，J＝2.26Hz，1H)，6.93-7.02(m，2H)，3.82(s，3H)，3.57-3.65(m，1H)，3.28(s，3h，)，2.90-3.01(m，4H)，2.71-2.80(m，1H)，2.60-2.69(m，2H)，1.89-1.97(m，1H)，1.67-1.76(m，1H)；MS(ES)m/z 456[M+1]⁺。

Example 305-

Table 6: representative examples synthesized as described for 2-amino-5- (3' -methoxybiphenyl-3-yl) -5- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate

Example 326

Methanesulfonic acid 3' - [ 2-amino-4- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester

2-amino-5- (3-bromophenyl) -5- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one (50mg, 0.117mmol), 3-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl methanesulfonate (50mg, 0.152mmol, [1, 1' -bis (diphenylphosphino) ferrocene ]Palladium dichloride dichloromethane adduct (10mg, 0.012mmol) and potassium carbonate (102mg, 0.738mmol) in anhydrous tetrahydrofuran (3mL) was maintained at 130 ℃ for 2 h. When cooled to ambient temperature, the mixture was filtered and then dimethyl sulfoxide (500 μ L) was added. The solution was concentrated in vacuo to remove tetrahydrofuran and then purified by preparative HPLC to give 12mg (22% yield) of the title compound.¹H NMR(DMSO-d₆)δ7.72(s，1H)7.47-7.62(m，2H)7.42(t，J＝7.65Hz，1H)7.16-7.21(m，2H)7.08-7.11(m，1H)7.05-7.07(m，1H)6.95-7.02(m，2H)3.86(s，3H)3.56-3.64(m，1H)3.43(s，3H)3.28(s，3H)2.88-3.04(m，4H)2.58-2.81(m，3H)1.87-1.98(m，1H)1.66-1.76(m，1H)；MS(ES)m/z 550[M+1]⁺。

Example 327-

Table 7: representative examples of syntheses as described for methanesulfonic acid 3' - [ 2-amino-4- (6-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester

Example 330

2, 3-dihydro-1-benzofuran-5-yl [2- (3' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl ] methanol

N-butyllithium (0.94mL, 2.5M) was added dropwise under an argon atmosphere to a cooled (-78 ℃ C.) solution of 2- (3' -methoxybiphenyl-3-yl) -1, 3-dithiane (327.4mg, 2.21mmol) in anhydrous tetrahydrofuran (5 mL). The solution was stirred at-78 ℃ for 20min and then treated with 4-methyl-3, 4-dihydro-2H-1, 4-benzoxazine-7-carbaldehyde (500mg, 2.82 mmol). The reaction mixture was stirred for a further 20min and then allowed to reach room temperature. Silica gel was added, the solvent evaporated and the residue purified by column chromatography (using a gradient of 0 to 30% ethyl acetate in n-heptane as eluent) to give 426mg (43% yield) of the title compound. ¹H NMR(CDCl₃)δ7.88-7.79(m，2H)7.55-7.49(m，1H)7.43(t，J＝7.71Hz，1H)7.34(t，J＝7.96Hz，1H)7.03(d，J＝7.83Hz，1H)6.99-6.93(m，1H)6.89(dd，J＝7.83，2.27Hz，1H)6.70(dd，J＝8.34，1.52Hz，1H)6.64(s，1H)6.59(d，J＝8.34Hz，1H)4.98(d，J ═ 3.54Hz, 1H)4.49(t, J ═ 8.72Hz, 2H)3.86(s, 3H)3.02(t, J ═ 8.59Hz, 2H)2.88(d, J ═ 3.28Hz, 1H)2.77-2.67(m, 4H); MS (ES) M/z 433[ M-Water]⁺。

Example 331

1- (2, 3-dihydro-1-benzofuran-5-yl) -2- (3' -methoxybiphenyl-3-yl) ethane-1, 2-dione

Daiss-Martin iodophors (903mg, 2.13mmol) were added to 2, 3-dihydro-1-benzofuran-5-yl [2- (3' -methoxybiphenyl-3-yl) -1, 3-dithian-2-yl under nitrogen atmosphere]A solution of methanol (460mg, 0.95mmol) and t-butanol (246mg, 3.33mmol) in dichloromethane (20mL) was stirred overnight. Sodium thiosulfate (1M, 10mL) and a saturated solution of sodium bicarbonate (10mL) were added, followed by dichloromethane. The two phases were separated and the organic phase was then concentrated in vacuo. Purification by column chromatography using a gradient of 0 to 100% ethyl acetate in n-heptane as eluent gave 377mg (111% yield) of the title compound.¹H NMR(CDCl₃)δ8.20(t，J＝1.64Hz，1H)8.00-7.81(m，4H)7.58(t，J＝7.71Hz，1H)7.38(t，J＝7.96Hz，1H)7.23-7.16(m，1H)7.15-7.09(m，1H)6.94(dd，J＝6.95，1.39Hz，1H)6.86(d，J＝8.59Hz，1H)4.71(t，J＝8.84Hz，2H)3.88(s，3H)3.27(t，J＝8.84Hz，2H)；MS(ES)m/z 359[M+1]⁺。

Example 332

5- (2, 3-dihydro-1-benzofuran-5-yl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one

A solution of 1- (2, 3-dihydro-1-benzofuran-5-yl) -2- (3' -methoxybiphenyl-3-yl) ethane-1, 2-dione (377mg, 1.05mmol) and N-methylthiourea (189mg, 2.10mmol) in dimethyl sulfoxide (20mL) was heated to 100 ℃. Potassium hydroxide (1.80mL, 1.2M) was added dropwise and the reaction mixture was stirred at 100 ℃ for 5 minutes and then cooled to room temperature. The solution was diluted with 30mL of water and then carefully acidified to pH 5 with concentrated hydrochloric acid and the aqueous phase extracted 3 times with dichloromethane (× 3). The combined organic phases were washed twice with water and then concentrated in vacuo to yield 540mg (100% yield) of the title compound. MS (ES) M/z 431[ M +1 ] ]⁺。

Example 333

2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one hydrochloride

Tert-butyl hydroperoxide (1.43g, 70%, 15.9mmol) was added to a mixture of 5- (2, 3-dihydro-1-benzofuran-5-yl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one (455mg, 1.06mmol) in methanol/ammonium hydroxide (3: 1, 40 mL). The mixture was stirred at room temperature overnight and then concentrated in vacuo until about 50% of the volume remained. The mixture was diluted with water (30mL) and dichloromethane (40 mL). The two phases were separated and the organic phase was then concentrated in vacuo. Purification was by preparative HPLC. The base is treated with hydrochloric acid (1M in ether) to give 110mg (23% yield) of the title compound.¹H NMR(DMSO-d₆)δ7.72(d，J＝7.83Hz，1H)，7.66(d，J＝1.77Hz，1H)，7.54(t，J＝7.83Hz，1H)，7.48-7.36(m，2H)，7.25-7.14(m，3H)，7.07-6.96(m，2H)，6.82(d，J＝8.59Hz，1H)，4.55(t，J＝8.72Hz，2H)，3.82(s，3H)，3.33(s，3H)，3.25-3.14(t，2H)；MS(ES)m/z 414[M+1]⁺。

Example 334

2-acetyl-4-chloroisoindoline

Acetic anhydride (115mg, 1.13mmol) was added to a cooled (0 ℃ C.) solution of 4-chloroisoindoline (136mg, 0.89mmol, described in Clark, R.et al.J.Med.chem.1990, 33(2), 596-152), dimethyl-amino-pyridine (14mg, 0.113mmol) and triethylamine (228mg, 2.26mmol) in dry dichloromethane (20mL) and the reaction mixture was stirred at room temperature overnight. Sodium hydroxide (40mL, 2M) was added and the organic phase was separated. The organic phase is concentrated in vacuo and the residue is purified by column chromatography (using 0 to 30% ammonium hydroxide in methanol (1: 9) in dichloromethane) to yield 126mg (73% yield) of the title compound. MS (ES) M/z 196, 198[ M +1 ] ]⁺。

Example 335

5- [3- (2-acetyl-2, 3-dihydro-1H-isoindol-4-yl) phenyl ] -2-amino-3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one acetate

Under argon atmosphere, tri [ di (benzylidene) acetone]A solution of dipalladium (17mg, 0.019mmol) and tricyclohexylphosphine (25mg, 0.090mmol) in 1, 2-dimethoxyethane (3mL) was stirred at room temperature for 30 min. 2-acetyl-4-chloroisoindoline (126mg, 0.644mmol), 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -di-1, 3, 2-dioxaborolane (180mg, 0.71mmol), and potassium acetate (95mg, 0.966mmol) were added, and the reaction mixture was irradiated with microwaves and maintained at 150 ℃ for 1.5 h. The reaction mixture was diluted with sodium hydroxide (20mL, 0.5M) and extracted with dichloromethane (2X 30 mL). To be combinedThe organic phase was evaporated and the residue was dissolved in 1, 2-dimethoxyethane/water/ethanol (6: 3: 1, 4mL) and 2-amino-5- (3-bromophenyl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one (58mg, 0.17mmol) and [1, 1' -bis (diphenylphosphino) ferrocene were added]Palladium dichloride dichloromethane (83mg, 0.254mmol) and cesium carbonate (5mg, 0.006 mmol). The mixture was irradiated with microwaves and maintained at 150 ℃ for 15 min. The reaction mixture was diluted with water (20mL) and extracted with dichloromethane (3X 30 mL). The combined organic phases were concentrated in vacuo and the product was purified by preparative HPLC to yield 4mg (1% yield) of the title compound. ¹H NMR(CD₃OD)δ7.49-7.33(m，12H)，3.20-3.17(m，4H)，2.18(s，3H)，2.11(s，3H)；MS(ES)m/z 425[M+1]⁺。

Example 336

5- [ (3-bromophenyl) ethynyl ] -2, 3-dihydro-1-benzofuran

To a mixture of bis (triphenylphosphine) palladium dichloride (154mg, 0.219mmol) and cuprous iodide (42mg, 0.219mmol) in anhydrous tetrahydrofuran (50mL) under an argon atmosphere was added triethylamine (15mL), a solution of 5-ethynyl-2, 3-dihydro-1-benzofuran (3.151g, 21.86 mmol; described in walsera.et.al.j.med.chem.1991, 34, 1440-46) in anhydrous tetrahydrofuran (10mL) and 1-bromo-3-iodobenzene (6.18g, 21.86mmol) one after the other. The resulting solution was stirred at room temperature for 20 h. The crude mixture was diluted with ethyl acetate, washed with 1M hydrochloric acid, water and saturated sodium bicarbonate solution, then dried over magnesium sulfate. The solvent was evaporated to give a solid material which was suspended in hexane, the solid was filtered, washed with hexane and then dried in vacuo to give the title product (5.30g, 81% yield).¹H NMR(CDCl₃)δ7.66(m，1H)，7.43(m，2H)，7.37(m，1H)，7.31(m，1H)，7.20(t，J＝7.83Hz，1H)，6.77(d，J＝8.34，1H)，4.62(t，J＝8.72Hz，2H)，3.23(t，J＝8.72Hz，2H)；MS(EI)m/z 298，300[M+H]⁺。

Example 337

1- (3-bromophenyl) -2- (2, 3-dihydro-1-benzofuran-5-yl) ethane-1, 2-dione

Reacting 5- [ (3-bromophenyl) ethynyl group]A solution of-2, 3-dihydro-1-benzofuran (5.30g, 17.71mmol) and palladium dichloride (314mg, 1.77mmol) in dimethylsulfoxide (75mL) was heated at 150 ℃ for 6h under an argon atmosphere. After cooling to room temperature, water was added. The mixture was extracted with dichloromethane (× 3). The combined extracts were washed with 1M hydrochloric acid, water and saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated. Purification by column chromatography (using 0-30% ethyl acetate in hexane as eluent) gave 4.37g (74% yield) of the title compound. ¹H NMR(CDCl₃)8.13(m，1H)，7.89(m，1H)，7.85(m，1H)，7.76-7.81(m，2H)，7.39(t，J＝7.96Hz，1H)，6.87(d，J＝8.59Hz，1H)，4.71(t，J＝8.84Hz，2H)，3.28(t，J＝8.72Hz，2H)；MS(ES)m/z 331.2，333.2[M+H]⁺。

Example 338

5- (3-bromophenyl) -5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-2-thioimidazolidin-4-one

N-Methylthiourea (2.36g, 26.21mmol) was added to a solution of 1- (3-bromophenyl) -2- (2, 3-dihydro-1-benzofuran-5-yl) ethane-1, 2-dione (4.34g, 13.11mmol) in dimethylsulfoxide (50 mL). Heating the solution at 100 deg.C for 5min, and adding 1.2M hydrogen hydroxide dropwise over 6-7minAqueous potassium solution (22.4mL, 26.82 mmol). The mixture was heated for an additional 10min and then cooled to room temperature. Water was added and then the pH was adjusted to 5 by adding 1M hydrochloric acid. The mixture was extracted with dichloromethane (× 3). The combined extracts were washed with water (. times.2), dried over sodium sulfate and evaporated to give 5.48g (100% yield) of the title compound.¹H NMR(CDCl₃)δ7.72(br.s.，1H)，7.49-7.53(m，2H)，7.29-7.33(m，1H)，7.24-7.28(m，1H)，7.07-7.09(m，1H)，6.97-7.01(m，1H)，6.76(d，J＝8.34Hz，1H)，4.60(t，J＝8.72Hz，2H)，3.34(s，3H)，3.20(t，J＝8.72Hz，2H)；MS(ES)m/z 401，403[M+H]^-。

Example 339

2-amino-5- (3-bromophenyl) -5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one

To a solution of 5- (3-bromophenyl) -5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-2-thioimidazolidin-4-one (5.48g, 13.59mmol) in methanol (100mL) was added 70% aqueous tert-butyl hydroperoxide (28mL, 204mmol) and 33% aqueous ammonia (50 mL). The resulting mixture was stirred at room temperature for 16 h. The methanol was evaporated and the aqueous residue was then extracted with 3 aliquots of dichloromethane. The combined extracts were washed with water, dried over sodium sulfate and evaporated. The crude product was purified by column chromatography using 0-10% methanol in dichloromethane and finally 0.1M ammonia in methanol instead of methanol as eluent to yield 2.29g (44% yield) of the title compound. ¹H NMR(CDCl₃)δ7.66(t，J＝1.77Hz，1H)，7.38-7.43(m，2H)，7.21-7.23(m，1H)，7.14-7.20(m，2H)，6.71(d，J＝8.34Hz，1H)，4.55(t，J＝8.72Hz，2H)，3.15(t，J＝8.08Hz，2H)，3.11(s，3H)；MS(ES)m/z 386.2，388.2[M+H]⁺，384.4，386.4[M-H]^-。

Example 340

6- [ (3-bromophenyl) ethynyl ] chromane

The title compound was prepared in 92% yield from 6-iodochroman (described in Togo H.et. al.J.chem.Soc.Perkin Trans.1, 1997, 787-one 793) as described in example 336. Purification was performed by column chromatography (using 0-30% ethyl acetate in n-heptane as eluent).¹H NMR(CDCl₃)δ7.66(t，J＝1.77Hz，1H)7.40-7.45(m，2H)7.23-7.27(m，2H)7.20(t，J＝7.96Hz，1H)6.77(d，J＝8.34Hz，1H)4.20-4.24(m，2H)2.79(t，J＝6.57Hz，2H)1.99-2.06(m，2H)；MS(EI)m/z 312，314[M+H]⁺。

Example 341

1- (3-bromophenyl) -2- (3, 4-dihydro-2H-chromen-6-yl) ethane-1, 2-dione

From 6- [ (3-bromophenyl) ethynyl as described in example 337]The title compound was prepared in 73% yield from chroman.¹H NMR(CDCl₃)δ8.12(t，J＝1.64Hz，1H)，7.89(m，1H)，7.77(m，1H)，7.73(dd，J＝8.59，2.27Hz，1H)，7.69(m，1H)，7.39(t，J＝7.83Hz，1H)，6.88(d，J＝8.59Hz，1H)，4.29(m，2H)，2.83(t，J＝6.44Hz，2H)，2.05(m，2H)；MS(ES)m/z 345.2，347.3[M+H]⁺。

Example 342

5- (3-bromophenyl) -5- (3, 4-dihydro-2H-chromen-6-yl) -3-methyl-2-thioimidazolidin-4-one

The title compound was prepared as described in example 338 from 1- (3-bromophenyl) -2- (3, 4-dihydro-2H-chromen-6-yl) ethane-1, 2-dione, in 100% yield.¹H NMR(CDCl₃)δ7.62(br.s.，1H)，7.49-7.53(m，2H)，7.28-7.32(m，1H)，7.26(t，J＝7.96Hz，1H)，6.91-6.95(m，2H)，6.76-6.80(m，1H)，4.17-4.21(m，2H)，3.33(s，3H)，2.75(t，J＝6.44Hz，2H)，1.97-2.04(m，2H)；MS(ES)m/z 415.3，417.3[M-H]^-。

Example 343

2-amino-5- (3-bromophenyl) -5- (3, 4-dihydro-2H-chromen-6-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was prepared from 5- (3-bromophenyl) -5- (3, 4-dihydro-2H-chromen-6-yl) -3-methyl-2-thioimidazolidin-4-one as described in example 339, 75% yield.¹H NMR(CDCl₃)δ7.66(t，J＝1.89Hz，1H)，7.38-7.44(m，2H)，7.18(t，J＝7.96Hz，1H)，7.06-7.12(m，2H)，6.73(d，J＝8.34Hz，1H)，4.14-4.18(m，2H)，3.11(s，3H)，2.73(t，J＝6.57Hz，2H)，1.94-2.01(m，2H)；MS(ES)m/z 400.2，402.2[M+H]⁺，398.4，400.4[M-H]^-。

Example 344

(3, 4-dihydro-1H-isochromen-7-ylethynyl) (trimethyl) silane

Bis (benzonitrile) palladium dichloride (100mg, 0.260mmol) and cuprous iodide (33mg, 0.174mmol) were added to a dry round bottom flask purged with argon and equipped with a magnetic stirrer and rubber septum. Anhydrous 1, 4-dioxane (20mL), tri-tert-butylphosphine (105mg, 0.521mmol) in 10 wt% hexane, diisopropylamine (1.48mL, 10.42mmol), trimethylsilylacetylene (1.066g, 10.85mmol), and 7-bromo-3, 4-dihydro-1H-isochromene (1.850g, 8.682mmol, described in Unterhalt B.andR., Pharmazie 1996, 51, 641-644). The resulting dark solution was stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate, washed with 1M hydrochloric acid, water and saturated aqueous sodium bicarbonate solution, and then dried over sodium sulfate. After removal of the solvent, the crude material was purified by column chromatography (using 0-15% ethyl acetate in n-heptane as eluent) to isolate 1.67g (84% yield) of the title compound.¹H NMR(CDCl₃)δ7.26(m，1H)7.12(m，1H)7.05(d，J＝7.83Hz，1H)4.73(s，2H)3.97(t，J＝5.68Hz，2H)2.85(t，J＝5.68Hz，2H)；MS(EI)m/z 230[M+H]⁺。

Example 345

7-ethynyl-3, 4-dihydro-1H-isochromene

A mixture of (3, 4-dihydro-1H-isochromen-7-ylethynyl) (trimethyl) silane and powdered potassium carbonate (5.01g, 36.25mmol) in tetrahydrofuran and methanol (1: 2, 60mL) was stirred at room temperature overnight. The mixture was filtered and then concentrated. The residue was dissolved in dichloromethane and then washed with water. After drying over sodium sulfate and removal of the solvent, the crude product is passed through column chromatography (using 0- 10% ethyl acetate in n-heptane as eluent) to yield 0.93g (81% yield) of the title compound.¹H NMR(CDCl₃)δ7.28-7.32(m，1H)，7.14(br.s.，1H)，7.08(d，J＝8.08Hz，1H)，4.74(s，2H)，3.94-4.00(m，2H)，3.03(s，1H)，2.78-2.89(m，2H)；MS(EI)m/z 158[M+H]⁺。

Example 346

7- [ (3-bromophenyl) ethynyl ] -3, 4-dihydro-1H-isochromene

The title compound was prepared as described in example 336 from 7-ethynyl-3, 4-dihydro-1H-isochromene in 65% yield. Purification was performed by column chromatography (using 0-30% ethyl acetate in n-heptane).¹H NMR(CDCl₃)δ7.68(dd，J＝2.02，1.52Hz，1H)，7.42-7.48(m，2H)，7.31-7.35(m，1H)，7.22(t，J＝7.96Hz，1H)，7.17(br.s.，1H)，7.12(d，J＝7.83Hz，1H)，4.77(s，2H)，3.99(t，J＝5.81Hz，2H)，2.88(t，J＝5.68Hz，2H)；MS(EI)m/z 312，314[M+H]⁺。

Example 347

1- (3-bromophenyl) -2- (3, 4-dihydro-1H-isochromen-7-yl) ethane-1, 2-dione

From 7- [ (3-bromophenyl) ethynyl as described in example 337]-3, 4-dihydro-1H-isochromene to prepare the title compound in 100% yield. The product was used in the next reaction without chromatographic purification. MS (ESI) M/z 343.4, 345.5[ M-H ]]^-。

Example 348

5- (3-bromophenyl) -5- (3, 4-dihydro-1H-isochromen-7-yl) -3-methyl-2-thioimidazolidin-4-one

The title compound was prepared from 1- (3-bromophenyl) -2- (3, 4-dihydro-1H-isochromen-7-yl) ethane-1, 2-dione in 95% yield as described in example 338.¹H NMR(CDCl₃)δ7.78(br.s.，1H)，7.48-7.54(m，2H)，7.24-7.30(m，2H)，7.13-7.17(m，1H)，7.04-7.08(m，1H)，6.89-6.91(m，J＝2.02Hz，1H)，4.72(s，2H)，3.98(t，J＝5.81Hz，2H)，3.33(s，3H)，2.86(t，J＝5.56Hz，2H)；MS(ES)m/z 415.4，417.3[M-H]^-。

Example 349

2-amino-5- (3-bromophenyl) -5- (3, 4-dihydro-1H-isochromen-7-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one

The title compound was prepared from 5- (3-bromophenyl) -5- (3, 4-dihydro-1H-isochromen-7-yl) -3-methyl-2-thioimidazolidin-4-one as described in example 339, 17% yield.¹H NMR(CDCl₃)δ7.66(t，J＝1.89Hz，1H)，7.39-7.44(m，2H)，7.22-7.26(m，1H)，7.07-7.10(m，2H)，4.74(br.s.，2H)，3.95(t，J＝5.68Hz，2H)，3.13(s，3H)，2.83(t，J＝5.43Hz，2H)；MS(ES)m/z 400.2，402.2[M+H]⁺，398.4，400[M-H]^-。

Example 350

2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -5- (3' -ethoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate

2-amino-5- (3-bromophenyl) -5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one (60mg, 0.155mmol), (3-ethoxyphenyl) boronic acid (33.5mg, 0.202mmol), (1, 1' -bis (diphenylphosphino) ferrocene) was irradiated with microwaves under an argon atmosphere]Palladium dichloride dichloromethane adduct (13mg, 0.015mmol) and cesium carbonate (151mg, 0.465mmol) in 1, 2-dimethoxyethane, water and ethanol (6: 3: 1, 3mL) were maintained at 130 ℃ for 15 min. When cooled to ambient temperature, the mixture was filtered and then dimethyl sulfoxide (500 μ L) was added. The solution was concentrated in vacuo to remove the reaction solvent and then purified by preparative HPLC to give 20.8mg (31% yield) of the title compound.¹H NMR(DMSO-d₆)δ7.69-7.71(m，1H)，7.48-7.52(m，1H)，7.43-7.46(m，1H)，7.33-7.39(m，2H)，7.27-7.30(m，1H)，7.15-7.19(m，1H)，7.06-7.10(m，1H)，7.02-7.04(m，1H)，6.90-6.94(m，1H)，6.66(d，J＝8.28Hz，1H)，4.47(t，J＝8.66Hz，2H)，4.08(q，J＝7.03Hz，2H)，3.11(t，J＝8.78Hz，2H)，2.98(s，3H)，1.91(s，0.6H)，1.35(t，J＝6.90Hz，3H)；MS(ES)m/z 428.1[M+H]⁺。

Example 351-

Table 8: representative examples of syntheses as described for 2-amino-5- (2, 3-dihydro-1-benzofuran-5-yl) -5- (3' -ethoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one 0.25 acetate

Example 377

Methanesulfonic acid 3' - [ 2-amino-4- (2, 3-dihydro-1-benzofuran-5-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester 0.25 acetate

2-amino-5- (3-bromophenyl) -5- (2, 3-dihydro-1-benzofuran-5-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one (60mg, 0.155mmol), { 3-methoxy-5- [ (methylsulfonyl) oxy- } -n]Phenyl } boronic acid (50mg, 0.202mmol), [1, 1' -bis (diphenylphosphino) ferrocene]A solution of palladium dichloride dichloromethane adduct (13mg, 0.015mmol) and potassium carbonate (107mg, 0.465mmol) in anhydrous tetrahydrofuran (3mL) was maintained at 130 ℃ for 2 h. When cooled to ambient temperature, the mixture was filtered and then dimethyl sulfoxide (500 μ L) was added. The solution was concentrated in vacuo to remove the reaction solvent and then purified by preparative HPLC to give 32mg (41% yield)The title compound.¹H NMR(DMSO-d₆)δ7.69-7.71(m，1H)，7.52-7.56(m，1H)，7.48-7.52(m，1H)，7.40(t，J＝7.78Hz，1H)，7.27-7.29(m，1H)，7.15-7.19(m，1H)，7.06-7.08(m，1H)，7.03-7.05(m，1H)，6.95(t，J＝2.26Hz，1H)，6.66(d，J＝8.53Hz，1H)，4.47(t，J＝8.66Hz，2H)，3.85(s，3H)，3.42(s，3H)，3.11(t，J＝8.66Hz，2H)，2.98(s，3H)，1.91(s，0.4H)；MS(ES)m/z 508[M+H]⁺。

Example 378-

Table 9: representative example synthesized as described for methanesulfonic acid 3' - [ 2-amino-4- (2, 3-dihydro-1-benzofuran-5-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] -5-methoxybiphenyl-3-yl ester 0.25 acetate

Example 380

4- { [ tert-butyl (diphenyl) silyl ] oxy } benzaldehyde

Imidazole (6.1g, 90.0mmol) was added to a solution of 4-hydroxybenzaldehyde (10g, 81.9 mmol; described in George R.Pettit et al, J.Med.Chem, 2002, 45, 2534-. The solution was stirred for 1h, tert-butyldiphenylchlorosilane (23mL, 79.0mmol) was added dropwise, and the resulting mixture was stirred for 48 h. The reaction mixture was poured into water and then diluted with acetic acidExtraction with ethyl ester (. times.3). The combined organic phases were washed with water, dried over magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography using heptane/ethyl acetate (8: 1) to yield 26.8g (94% yield) of the title compound.¹H NMR(CDCl₃)δ9.82(s，1H)，7.72(d，J＝1.52Hz，2H)，7.70(d，J＝1.52Hz，2H)，7.64-7.68(m，2H)，7.44-7.49(m，2H)，7.37-7.42(m，4H)，6.85-6.90(m，2H)，1.13(s，9H)。

Example 381

Tert-butyl [4- (1, 3-dithian-2-yl) phenoxy ] diphenylsilane

Boron trifluoride-diethyl ether complex (25mL, 199mmol) was added dropwise to a cooled (0 ℃ C.) 4- { [ tert-butyl (diphenyl) silyl group]Oxy } benzaldehyde (18.4g, 51.0 mmol; described in Mor, M.et al.J Med. chem.2004, 474998-&Medicine 2002, 2(2), 241-. The resulting mixture was stirred at 0 ℃ for 2 h. Saturated aqueous sodium bicarbonate was added and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, aqueous potassium hydroxide (10%) and water, dried over magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography using heptane/ethyl acetate (8: 1 to 2: 1) as eluent to give 17.0g (74% yield) of the title compound. ¹H NMR(CDCl₃)δ7.71(dd，J＝7.96，1.39Hz，4H)，7.40-7.46(m，2H)，7.35-7.40(m，4H)，7.17-7.23(m，3H)，6.68-6.75(m，2H)，5.07(s，1H)，2.98-3.08(m，2H)，2.84-2.92(m，2H)，2.10-2.20(m，1H)，1.83-1.96(m，1H)，1.09-1.12(m，9H)。

Example 382

(3-bromo-4-fluorophenyl) [2- (4- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) -1, 3-dithiane-2-yl ] methanol

To tert-butyl [4- (1, 3-dithian-2-yl) phenoxy at-78 ℃]A solution of diphenylsilane (2.0g, 4.44 mmol; described in Philip C. Bulman Page et al, Tetrahedron, 199248, 7265-. To the resulting anion at-78 ℃ was added 3-bromo-4-fluorobenzaldehyde (0.95g, 4.66mmol), and the reaction mixture was allowed to reach room temperature overnight. The reaction mixture was poured onto saturated ammonium chloride solution, and then the aqueous layer was extracted with dichloromethane (× 3). The combined organic layers were dried over magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography using heptane/ethyl acetate (7: 1 to 5: 1) as eluent to give 1.95g (67% yield) of the title compound.¹H NMR(CDCl₃)δ7.74(dd，J＝6.82，1.26Hz，4H)，7.43-7.48(m，2H)，7.37-7.43(m，4H)，7.31-7.36(m，2H)，7.10(dd，J＝6.69，2.15Hz，1H)，6.68-6.74(m，3H)，6.54-6.61(m，1H)，4.84(s，1H)，2.61-2.76(m，4H)，1.86-1.95(m，2H)，1.09-1.17(m，9H).HR MS(ES)m/z 635.0881，637.0852[M-18]⁺。

Example 383

1- (3-bromo-4-fluorophenyl) -2- (4- { [ tert-butyl (diphenyl) silyl ] oxy } phenyl) ethane-1, 2-dione

Daiss-Martin iodophor (3.1g, 7.23mmol) was added to (3-bromo-4-fluorophenyl) [2- (4- { [ tert-butyl (diphenyl) under an argon atmosphere ) Silyl radical]Oxy } phenyl) -1, 3-dithian-2-yl]A solution of methanol (1.90g, 2.91mmol) and t-butanol (0.93mL, 10.2mmol) in dichloromethane (40mL) was stirred overnight. Sodium thiosulfate (2.5g) dissolved in saturated aqueous sodium bicarbonate solution (40mL) was added, and the resulting mixture was stirred for 30 minutes. More dichloromethane was added and then the organic phase was separated. The aqueous phase was extracted with dichloromethane (× 3) and the combined organic phases were dried over magnesium sulphate and the solvent was evaporated. The residue was purified by column chromatography using heptane/ethyl acetate (9: 1 to 8: 1) as eluent to give 1.54g (94% yield) of the title compound. HR MS (ES) M/z 561.0924, 563.0913[ M + H ]]⁺。

Example 384

5- (3-bromo-4-fluorophenyl) -5- (4-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one

Aqueous potassium hydroxide (1.2M, 4.45mL, 5.34mmol) was added to 1- (3-bromo-4-fluorophenyl) -2- (4- { [ tert-butyl (diphenyl) silyl) at 100 deg.C]Oxy } phenyl) ethane-1, 2-dione (1.50g, 2.67mmol) and N-methyl-2-thiourea (0.48g, 5.34mmol) in dimethylsulfoxide (10mL) was stirred for 1h and the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water and dichloromethane. The pH was adjusted to 3-4 by addition of aqueous hydrochloric acid (2M). The organic phase was separated and then the aqueous phase was washed with dichloromethane (× 3). The combined organic phases were dried over magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography using heptane/ethyl acetate (3: 1 to 2: 1) as eluent to give 0.73g (69% yield) of the title compound. ¹H NMR(CDCl₃)δ8.75(s，1H)，7.57(dd，J＝6.19，2.15Hz，1H)，7.22-7.39(m，1H)，7.01-7.17(m，3H)，6.78(d，J＝8.59Hz，2H)，3.33(s，3H)：MS(ES)m/z 392.97，394.94[M-H]^-。

Example 385

Methanesulfonic acid 4- [4- (3-bromo-4-fluorophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl ] phenyl ester

Methanesulfonyl chloride (0.96mL, 12.5mmol) was added to a cooled (0 deg.C) solution of 5- (3-bromo-4-fluorophenyl) -5- (4-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one (3.98g, 10.1mmol) and triethylamine (1.74mL, 12.6mmol) in dichloromethane (100mL), and the reaction mixture was maintained at 8 deg.C overnight. The reaction mixture was washed with water and brine. The organic phase is dried over magnesium sulphate and the solvent is evaporated to yield 4.77g (9.7% yield) of the title compound. MS (ES) M/z 470.95, 472.95[ M-H ]]^-。

Example 386

Methanesulfonic acid 4- [ 2-amino-4- (3-bromo-4-fluorophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester

Tert-butyl hydroperoxide (23.4mL, 151.5mmol, 70 wt% aq.) was added to methanesulfonic acid 4- [4- (3-bromo-4-fluorophenyl) -1-methyl-5-oxo-2-thioimidazolidin-4-yl]A solution of phenyl ester (4.77g, 10.1mmol) in a methanol/ammonium hydroxide mixture (25 mL: 75 mL). The reaction mixture was stirred at room temperature for 3h, then at 8 ℃ overnight. The reaction mixture was concentrated, and then the residue was dissolved in chloroform. The organic phase is washed with water, dried over magnesium sulfate and the solvent is evaporated. The residue was purified by column chromatography using ethyl acetate/methanol (20: 1+ 1% triethylamine) as eluent to give 2.6g (60% yield) of the title compound. ¹H NMR(CDCl₃)δ7.72(dd，J＝6.57，2.27Hz，1H)，7.49-7.56(m，2H)，7.38-7.45(m，1H)，7.19-7.25(m，2H)，7.05(t，J＝8.46Hz，1H)，3.11-3.14(m，3H)，3.10(s，3H)：MS(ES)m/z 453.96，455.98[M-H]^-。

Example 387

Methanesulfonic acid 4- [ 2-amino-4- (3' -cyano-6-fluorobiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester

Irradiating methanesulfonic acid 4- [ 2-amino-4- (3-bromo-4-fluorophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl with microwaves under an argon atmosphere]Phenyl ester (80mg, 0.18mmol), (3-cyanophenyl) boronic acid (0.034g, 0.23mol), [1, 1' -bis (diphenylphosphino) ferrocene]A solution of palladium dichloride dichloromethane adduct (0.014g, 0.018mol) and potassium carbonate (0.145mg, 1.05mmol) in anhydrous tetrahydrofuran (3mL) was maintained at 130 ℃ for 2 h. When cooled to ambient temperature, the mixture was filtered and then dimethyl sulfoxide (0.5mL) was added. The solution was concentrated in vacuo to remove tetrahydrofuran and then purified by preparative HPLC to give 0.025g (30% yield) of the title compound.¹H NMR(DMSO-d₆)δ7.94(s，1H)，7.87-7.92(m，1H)，7.78-7.84(m，1H)，7.68-7.73(m，1H)，7.65-7.68(m，1H)，7.55-7.61(m，3H)，7.30-7.36(m，1H)，7.30(s，1H)，7.28(s，1H)，6.77(s，2H)，3.35(s，3H)，2.99(s，3H)；MS(ES)m/z 479.1[M+H]⁺。

Example 388-

Table 10: representative examples of syntheses as described for 4- [ 2-amino-4- (3' -cyano-6-fluorobiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate

Example 406

Methanesulfonic acid 4- { 2-amino-4- [3- (2-chloro-5-methoxypyridin-3-yl) -4-fluorophenyl ] -5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester

Irradiating methanesulfonic acid 4- [ 2-amino-4- (3-bromo-4-fluorophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl with microwaves under an argon atmosphere]Phenyl ester (0.080g, 0.18mmol), 3-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.054g, 0.23mmol), [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane adduct (0.014g, 0.018mmol), potassium carbonate (0.145g, 1.05mmol) and anhydrous tetrahydrofuran (3mL) was maintained at 130 ℃ for 2 h. When cooled to ambient temperature, the mixture was filtered and then dimethyl sulfoxide (0.5mL) was added. The solution was concentrated in vacuo to remove tetrahydrofuran and then purified by preparative HPLC to give 0.009g (10% yield) of the title compound.¹H-NMR(DMSO-d₆)：δ8.34(d，J＝2.76Hz，1H)，8.24(s，1H)，7.65(dd，J＝7.53，2.26Hz，1H)，7.55-7.62(m，3H)，7.42-7.45(m，1H)，7.25-7.36(m，3H)，6.76(br.s.，2H)，3.87(s，3H)，3.35(s，3H)，2.99(s，3H)；MS(ES)m/z 485.0[M+H]⁺。

Example 407-

Table 11: representative examples of syntheses as described for 4- { 2-amino-4- [3- (2-chloro-5-methoxypyridin-3-yl) -4-fluorophenyl ] -5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl methanesulfonate

Practice of

Chemical name

R’

[M+H]⁺m/z

¹H-NMR(DMSO-d₆)δ

Example 410

Methanesulfonic acid 4- [ 2-amino-4- (4-fluoro-3-pyrazin-2-ylphenyl) -5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester

Irradiating methanesulfonic acid 4- [ 2-amino-4- (3-bromo-4-fluorophenyl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl with microwaves under an argon atmosphere ]A solution of phenyl ester (0.080g, 0.18mmol), 2- (tributylstannyl) pyrazine (0.097g, 0.26mmol) and bis (triphenylphosphine) palladium dichloride (0.006g, 0.009mmol) in anhydrous tetrahydrofuran (3mL) was maintained at 130 ℃ for 3 h. When cooled to ambient temperature, the mixture was filtered and then dimethyl sulfoxide (0.5mL) was added. The solution was concentrated in vacuo to remove tetrahydrofuran and then purified by preparative HPLC to give 0.020g (25% yield) of the title compound.¹H NMR(DMSO-d₆)δ9.01(dd，J＝2.91，1.64Hz，1H)，8.79-8.82(m，1H)，8.66(d，J＝2.53Hz，1H)，8.17(dd，J＝7.45，2.40Hz，1H)，7.63-7.70(m，1H)，7.57(s，1H)，7.54(s，1H)，7.37(dd，J＝10.86，8.84Hz，1H)，7.30(s，1H)，7.28(s，1H)，6.80(br.s.，2H)，3.35(s，3H)，2.99(s，3H)；(ES)m/z 454.08[M-H]^-。

Example 411

Table 11: representative examples of syntheses as described for 4- [ 2-amino-4- (4-fluoro-3-pyrazin-2-ylphenyl) -5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl methanesulfonate

Example 412

2-amino-5- (4-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one

Tert-butyl hydroperoxide (6.0mL, 47.4mmol, 70 wt% aq.) was added to a solution of 5- (4-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-2-thioimidazolidin-4-one (1.27g, 3.16mmol) in a methanol/ammonium hydroxide (5 mL: 15mL) mixture. The resulting mixture was heated at 35 ℃ for 2.5h and then allowed to reach room temperature. The reaction mixture was concentrated, and then the residue was dissolved in chloroform. The organic phase is washed with water, dried over magnesium sulfate and the solvent is evaporated. The residue was purified by column chromatography using ethyl acetate/methanol (10: 1+ 1% triethylamine) to give 0.95g (78% yield) of the title compound. ¹H NMR(CDCl₃)δ7.64(s，1H)，7.45(d，J＝7.58Hz，1H)，7.34-7.39(m，1H)，7.30(d，J＝7.83Hz，1H)，7.24(t，J＝7.96Hz，1H)，7.02-7.12(m，4H)，6.82(dd，J＝8.21，2.15Hz，1H)，6.62(d，J＝8.59Hz，2H)，6.02(br.s.，3H)，3.77(s，3H)，3.00(s，3H)；MS(ES)m/z 386.14[M-H]^-。

Example 413

Propane-1-sulfonic acid 4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride

1-Propanesulfonyl chloride (0.012mL, 0.103mmol) was added to a cooled (0 ℃ C.) solution of 2-amino-5- (4-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one (0.040g, 0.103mmol) and triethylamine (0.015mL, 0.103mmol) in dichloromethane (5mL) and stirred for 1.5H. The reaction mixture was concentrated and the residue was purified by column chromatography using ethyl acetate/methanol (20: 1) as eluent to give 0.031g (61% to get)Rate) of the base. The base was dissolved in dichloromethane (0.5mL) and then treated with hydrochloric acid (4.0M in ether). After addition of diethyl ether (2mL), the hydrochloride salt formed precipitated to give 0.013g (39% yield) of the title compound.¹H NMR(CDCl₃)δ11.15(s，1H)，9.94(s，1H)，9.10(s，1H)，7.64(s，1H)，7.58(d，J＝7.33Hz，1H)，7.50-7.56(m，2H)，7.38-7.47(m，2H)，7.25-7.34(m，3H)，7.13(d，J＝7.58Hz，1H)，7.09(d，J＝2.27Hz，1H)，6.87(dd，J＝8.34，2.27Hz，1H)，3.83(s，3H)，3.41(s，3H)，3.18-3.23(m，2H)，1.93-2.05(m，2H)，1.11(t，J＝7.45Hz，3H)；MS(ES)m/z 493.17[M-H]^-。

Example 414

Propane-2-sulfonic acid 4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride

2-Propanesulfonyl chloride (0.012mL, 0.103mmol) was added to a cooled (0 ℃ C.) solution of 2-amino-5- (4-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one (0.040g, 0.103mmol) and triethylamine (0.015mL, 0.103mmol) in dichloromethane (5 mL). After the reaction mixture was stirred at room temperature for 48h, more triethylamine (0.006mL, 0.043mmol) was added. The reaction mixture was stirred for a further 5h and then concentrated. The residue was purified by column chromatography using ethyl acetate/methanol (30: 1) as eluent to give 0.013g (26% yield) of base. The base was dissolved in dichloromethane (0.25mL) and then treated with hydrochloric acid (0.029mL, 1.0M in ether). After addition of diethyl ether (2mL), the hydrochloride salt formed precipitated to give 0.012g (87% yield) of the title compound. ¹H NMR(CDCl₃)δ11.51(s，1H)，9.68(br.s.，1H)，9.56(br.s.，1H)，7.70-7.78(m，1H)，7.63(s，1H)，7.55(t，J＝7.83Hz，1H)，7.47-7.52(m，2H)，7.34-7.45(m，4H)，7.12-7.21(m，2H)，6.98(dd，J＝7.83，2.27Hz，1H)，3.81(s，3H)，3.71-3.78(m，1H)，3.20(s，3H)，1.43(s，3H)，1.42(s，3H)；MS(ES)m/z 493.17[M-H]^-。

Example 415

4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl dimethylaminosulfonate hydrochloride

N, N-dimethylaminosulfonyl chloride (0.017mL, 0.154mmol) was added to a cooled (0 ℃ C.) solution of 2-amino-5- (4-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one (0.040g, 0.103mmol) and triethylamine (0.022mL, 0.0.154mmol) in dichloromethane (5 mL). After the reaction mixture was stirred at room temperature for 20h, more triethylamine (0.017mL, 0.154mmol) and N, N-dimethylaminosulfonyl chloride (0.017mL, 0.154mmol) were added. The reaction mixture was stirred for an additional 3h, then concentrated until 2mL of solvent remained, then stirred for an additional 48 h. The residue was purified by column chromatography using ethyl acetate/methanol (40: 1 to 30: 1) as eluent. The pooled product was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and the solvent was evaporated to give 0.015g (29% yield) of base. The base was dissolved in dichloromethane (0.25mL) and then treated with hydrochloric acid (0.033mL of 1.0M in ether). After addition of diethyl ether (2mL), the hydrochloride salt formed precipitated to give 0.010g (62% yield) of the title compound. ¹H NMR(DMSO-d₆)δ11.54(s，1H)，9.68(br.s.，1H)，9.57(br.s.，1H)，7.74(d，J＝7.83Hz，1H)，7.59-7.62(m，1H)，7.55(t，J＝7.83Hz，1H)，7.34-7.52(m，6H)，7.12-7.20(m，2H)，6.98(dd，J＝8.08，2.02Hz，1H)，3.81(s，3H)，3.17-3.24(m，3H)，2.91(s，6H)；MS(ES)m/z 494.99[M+H]⁺。

Example 416

Morpholine-4-sulfonic acid 4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester

Morpholine-4-sulfonyl chloride (0.029g, 0.154mmol) was added to a cooled (0 ℃) solution of 2-amino-5- (4-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one (0.040g, 0.103mmol) and triethylamine (0.022mL, 0.0.154mmol) in dichloromethane (5 mL). After the reaction mixture was stirred at room temperature for 20h, more triethylamine (0.017mL, 0.154mmol) and morpholine-4-sulfonyl chloride (0.029mL, 0.154mmol) were added. The reaction mixture was stirred for 48h, then concentrated. The residue was purified by column chromatography using ethyl acetate/methanol (50: 1 to 40: 1) as eluent to give 0.011g (20% yield) of the base. The base was dissolved in dichloromethane (0.25mL) and then treated with hydrochloric acid (0.033mL of 1.0M in ether). After addition of diethyl ether (2mL), the hydrochloride salt formed precipitated out to give 0.009g (82% yield) of the title compound.¹H NMR(DMSO-d₆)δ11.46(s，1H)，9.68(br.s.，1H)，9.54(br.s.，1H)，7.74(d，J＝7.58Hz，1H)，7.32-7.66(m，8H)，7.11-7.21(m，2H)，6.98(dd，J＝8.34，2.02Hz，1H)，3.81(s，3H)，3.60-3.70(m，4H)，3.32-3.35(m，4H)，3.20(s，3H)；MS(ES)m/z 537.01[M+H]⁺。

Example 417

2-Methoxyethanesulfonic acid 4- [ 2-amino-4- (3' -methoxybiphenyl-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester hydrochloride

2-methoxy ethyl Sulfonyl chloride (0.036g, 0.227mmol) was added to a cooled (0 ℃) solution of 2-amino-5- (4-hydroxyphenyl) -5- (3' -methoxybiphenyl-3-yl) -3-methyl-3, 5-dihydro-4H-imidazol-4-one (0.080g, 0.206mmol) and triethylamine (0.032mL, 0.227mmol) in dichloromethane (5 mL). After stirring for 1h, the reaction mixture was concentrated. The residue was purified by column chromatography using ethyl acetate/methanol (40: 1 to 30: 1+ 1% triethylamine). The pooled product was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and the solvent was evaporated to give 0.026g (25% yield) of base. The base was dissolved in dichloromethane (0.25mL) and then treated with hydrochloric acid (0.033mL of 1.0M in ether). After addition of diethyl ether (2mL), the hydrochloride salt formed precipitated out to give 0.016g (58% yield) of the title compound.¹H NMR(DMSO-d₆)δ11.69(s，1H)，9.68(br.s.，2H)，7.74(d，J＝7.83Hz，1H)，7.66(s，1H)，7.33-7.60(m，7H)，7.14-7.22(m，2H)，6.98(dd，J＝8.21，1.89Hz，1H)，3.73-3.90(m，7H)，3.28(s，3H)，3.20(s，3H)；MS(ES)m/z 509.97[M+H]⁺。

Measurement of

Compounds were tested in at least one of the following assays:

beta secretase

The enzymes used in the IGEN cleavage assay, fluorescence assay, TR-FRET assay and BiaCore assay are described as follows:

soluble portions of human β -secretase (AA1-AA460) were cloned into the ASP2-Fc10-1-IRES-GFP-neoK mammalian expression vector. The gene was fused to the Fc segment (affinity tag) of IgG1 and then stably cloned into HEK293 cells. Pure sBACE-Fc was stored in Tris buffer (pH 9.2) with a purity of 95%.

IGEN cleavage assay

The enzyme was diluted 1: 30 in 40mM MES pH 5.0. Stock substrate was diluted to 12. mu.M in 40mM MES pH 5.0. Compounds were diluted in dimethyl sulfoxide to the desired concentration (final concentration of dimethyl sulfoxide in the assay was 5%). The assay was performed in 96-well PCR plates (Greiner) (# 650201). A solution of compound in dimethylsulfoxide (3. mu.L) was added to the plate, followed by addition of enzyme (27. mu.L) and preincubation with compound for 10 minutes. The reaction was initiated with substrate (30. mu.L). The final dilution of the enzyme was 1: 60, while the final concentration of the substrate was 6. mu.M. After 20 minutes at room temperature, the reaction was stopped by: mu.L of the reaction mixture was removed and then diluted 1: 25 in 0.2M Trizma-HCl, pH 8.0. Compounds were diluted and added to the plate either by Biomek FX or manually, and then all remaining liquid manipulations were performed on the Biomek 2000 instrument.

All antibodies and streptavidin-coated beads were diluted in PBS (containing 0.5% BSA and 0.5% tween 20). The product was quantified by the following method: mu.L of a neo-epitope antibody (neoepitope antibody) at a dilution of 1: 5000 was added to 50. mu.L of a reaction mixture at a dilution of 1: 25. Then, 100. mu.L of PBS (0.5% BSA, 0.5% Tween 20) containing 0.2mg/mL IGEN beads (Dynabead M-280) and a ruthenium-labeled goat anti-rabbit (Ru-Gar) antibody at a dilution of 1: 5000 was added. The final dilution of the neo-epitope antibody was 1: 20000, the final dilution of Ru-Gar was 1: 10000, and the final concentration of the beads was 0.1 mg/mL. After incubation for 2 hours at room temperature with shaking, the mixture was read on an IGEN instrument (Bio Veris) using the Abbiochemial assay procedure.

Fluorescence measurement

The enzyme was diluted 1: 25 in 40mM MES pH 5.0. Stock substrate (Dabcyl) was diluted to 30. mu.M in 40mM MES pH 5.0. The enzyme and substrate stock solutions were kept on ice until they were placed in the stock plates. All liquid manipulations were performed using a Biomek FX instrument. The enzyme (9. mu.L) was added to the plate with 1. mu.L of compound in dimethyl sulfoxide and preincubated for 10 min. When testing the dose response curve of the compounds, dilutions were made in clean dimethylsulfoxide. Substrate (10. mu.L) was added, and then the reaction was carried out at room temperature for 25 minutes in the absence of light. The assay was performed in a Corning 384 well plate (round bottom, low volume, non-binding surface) (Corning # 3676). The final dilution of the enzyme was 1: 50, while the final concentration of the substrate was 15. mu.M (Km 25. mu.M). The fluorescence of the product was measured on a Victor II plate reader using a protocol directed to labeled Edans peptides, with an excitation wavelength of 360nm and an emission wavelength of 485 nm. The dimethylsulfoxide control defined a 100% activity level, while 0% activity was defined by exclusion of enzyme (replaced with 40mM MES pH 5.0 buffer).

TR-FRET assay

The enzyme (truncated form) was diluted to 6. mu.g/mL (1.3 mg/mL stock) and the substrate (Europium) CEVNLDAEFK (Qsy7) was diluted to 200nM (60. mu.M stock) in reaction buffer (sodium acetate, Chaps, Triton X-100, EDTA pH 4.5). BiomekFX was used for all liquid operations, and the enzyme and substrate solutions were kept on ice until they were placed in Biomek FX. Enzyme (9 μ L) was added to the plate, followed by 1 μ L of compound in DMSO, mixed and pre-incubated for 10 minutes. Then, a substrate (10. mu.L) was added thereto, and mixed, and the reaction was allowed to proceed for 15 minutes at room temperature with exclusion of light. The reaction was stopped by adding a stop solution (7. mu.L, sodium acetate pH 9). The fluorescence of the product was measured on a Victor II plate reader with an excitation wavelength of 340nm and an emission wavelength of 615 nm. The assay was performed in a Corning 384 well plate (round bottom, small volume, non-binding surface) (Corning # 3676). The final concentration of enzyme was 0.3 nM; the final concentration of substrate was 100nM (Km about 250 nM). The dmso control defined a 100% activity level, while 0% activity was defined by addition of peptide substrate alone. Control inhibitors were also used in dose response assays and had an IC of 575nM ₅₀。

Beta-secretase Whole cell assay

Production of HEK-Fc 33-1:

pcDNA3.1 plasmid encoding the cDNA of human full length APP695 was stably transfected into HEK-293 cells using Lipofectamine transfection reagent according to the manual protocol (Invitrogen). Cell populations were selected using 0.1-0.5mg/mL Zeocin. Limited dilution cloning was performed to obtain homogeneous cell lines. Clones were characterized by the level of APP expression and the level of secreted a β in conditioned media using a self-developed ELISA assay.

Cell culture:

HEK293 cells stably expressing human wild type APP (HEK293-APP695) were grown at 37 ℃ in DMEM containing 4500g/L glucose, GlutaMAX and sodium pyruvate, supplemented with 10% FBS, 1% non-essential amino acids and 0.1mg/mL of the selective antibiotic Zeocin.

A β 40 release assay:

when the fusion rate is 80-90%, the cells are collected and then the ratio is 0.2X 10⁶Concentration of individual cells/mL cells were seeded at 100mL cell suspension/well onto black clear-bottom 96-well poly D-lysine coated plates. At 37 ℃ in 5% CO₂After overnight incubation, the cell culture medium was replaced with cell culture medium with penicillin and streptomycin (100U/mL and 100. mu.g/mL, respectively) and containing the test compound (final concentration of dimethyl sulfoxide is 1%). Cells were incubated with test compounds at 37 ℃ in 5% CO ₂And the lower contact is carried out for 24 h. To quantify the amount of released a β, 100 μ L of cell culture medium was transferred to a round bottom polypropylene 96-well plate (assay plate). The cell culture plate was stored and used for ATP measurement in the following ATP measurement. To each well of the assay plate was added 50 μ L of a first detection solution comprising 0.5 μ g/mL rabbit anti-Abeta 40 antibody and 0.5 μ g/mL biotinylated monoclonal mouse 6E10 antibody (in DPBS containing 0.5% BSA and 0.5% Tween 20), followed by overnight incubation at 4 ℃. Then, 50. mu.L of a second detection solution containing 0.5. mu.g/mL ruthenium-labeled goat anti-rabbit antibody and 0.2mg/mL streptavidin-coated Dynabead was added to each well. The plate was shaken vigorously at room temperature for 1-2 h. The plate was then measured for electro-chemiluminescence (electro-chemiluminescence) counts in an igerm 8 analyzer. A β standard curves were obtained using standards containing penicillin and streptomycin (100U/mL and 100 μ g/mL, respectively) at concentrations of 20, 10, 2, and 0.2ngA β/mL in cell culture medium.

ATP determination:

such as byAs noted above, ViaLight, which measures total cellular ATP, was used after transferring 100. mu.L of media from the cell culture plate for A.beta.40 detection^TMThe Plus cell proliferation/cytotoxicity kit (cambrex bioscience) was used to analyze the plates for cytotoxicity. The measurements were performed according to the manual protocol. Briefly, 50. mu.L of cytolytic reagent was added to each well. The plates were incubated at room temperature for 10 minutes. Add 100. mu.L of reconstituted (reconstituted) ViaLight ^TMPlus ATP reagent, 2 min later in Wallac Victor²1420 multiple label counter (multilabel counter) measures the luminescence.

BACE Biacore protocol

Preparing a sensing chip:

BACE was determined on a Biacore 3000 instrument by attaching either a peptide Transition State Isostere (TSI) or a scrambled version of the peptide TSI to the surface of a Biacore CM5 sensor chip. The surface of the CM5 sensor chip had 4 different channels available for coupling peptides. The scrambled peptide KFES-inhibin-ETIAEVENV (KFES-statin-ETIAEVENV) was coupled to channel 1, while the TSI inhibitor KTEEISEVN-inhibin-VAEF (KTEEISEVN-statin-VAEF) was coupled to channel 2 of the same chip. Both peptides were dissolved at 0.2mg/mL in 20mM sodium acetate (pH 4.5) and the solution was centrifuged at 14000rpm to remove all particles. The carboxyl groups on the dextran layer are activated by the following method: a1: 1 mixture of 0.5M N-ethyl-N' - (3-dimethylaminopropyl) -carbodiimide (EDC) and 0.5M N-hydroxysuccinimide (NHS) was injected at a rate of 5 μ L/min for 7 minutes. Then, a stock solution of the control peptide was injected into channel 1 at a rate of 5 μ L/min for 7 minutes, and then the remaining activated carboxyl groups were blocked by the following method: 1M ethanolamine was injected at a rate of 5. mu.L/min for 7 minutes.

Determination protocol:

BACE Biacore assay was performed by diluting BACE to 0.5. mu.M in sodium acetate buffer pH 4.5 (running buffer minus DMSO). The diluted BACE was mixed with DMSO or a DMSO dilution of the compound at a final concentration of 5%. The BACE/inhibitor mixture was incubated at 4 ℃ for 1 hour and then injected into channels 1 and 2 of a CM5Biacore chip at a rate of 20. mu.L/min. When BACE is bound to the chip, the signal is measured in Response Units (RU). BACE binding to TSI inhibitors on channel 2 generates a certain signal. The presence of a BACE inhibitor reduces this signal by binding to BACE thereby inhibiting BACE interaction with the peptide TSI on the chip. Any binding to channel 1 was non-specific and was subtracted from the response value of channel 2. The dimethylsulfoxide control was defined as 100% and the effect of the compound was reported as percent inhibition relative to the dimethylsulfoxide control.

hERG assay

Cell culture:

the reaction mixture (Persson, Carlsson, Duker,&jacobson, 2005) expressing hERG in F-12 Ham Medium at 37 ℃ in a humidified atmosphere (5% CO) ₂) Medium containing L-glutamine, 10% Fetal Calf Serum (FCS) and 0.6mg/ml hygromycin (all from Sigma-Aldrich) to half confluency. Prior to use, the monolayers were washed with a 3ml aliquot of prewarmed (37 ℃) Versene 1: 5000 (Invitrogen). After aspirating this solution, the flask was incubated in an incubator at 37 ℃ for 6 minutes with another 2ml of Versene 1: 5000. Then, the cells were detached from the bottom of the flask by gentle tapping, and 10ml of Dulbecco's phosphate buffered saline (containing calcium (0.9mM) and magnesium (0.5mM)) (PBS; Invitrogen) was added to the flask, which was then pipetted into a 15ml centrifuge tube, followed by centrifugation (50g, 4 minutes). The resulting supernatant was discarded and the pellet was carefully resuspended in 3ml of PBS. A0.5 ml aliquot of the cell suspension was removed and the number of viable cells (based on Trypan blue exclusion) was determined in an automated reader (Cedex; Innovatis) so that the volume of cell resuspension could be adjusted with PBS to obtain the desired final cell concentration. When this parameter is referred to, the cell concentration at that point in the assay is quoted. For use in IonWorks^TMAdjust voltage on HT Offset (voltage offset) CHO-Kv1.5 cells were cultured and prepared for use in the same manner.

Electrophysiology:

the principle and operation of this device is described in (Schroeder, Neagle, Trezise,&worley, 2003). Briefly, the technique is described in 384 well plates (PatchPlates)^TM) A basis in which aspiration is used to position the cells over a small hole separating two independent fluid chambers and to hold the cells thereon, thereby attempting to record in each well. Once the block has been performed, PatchPlate^TMThe solution on the bottom side of (a) becomes a solution comprising amphotericin B. This solution can penetrate the cell patch (patch of cell membrane) covering the hole in each well, thereby allowing the perforated whole-cell patch clamp recording to be actually performed.

Using beta-Test IonWorks^TMHT (essen instrument). This apparatus cannot warm the solution, and therefore operates at room temperature (about 21 ℃ C.) as follows. The container at the "buffer" position contained 4ml of PBS, while the container at the "cell" position contained the CHO-hERG cell suspension described above. Place 96-well plate (V-bottom, Greiner Bio-one) containing the compound to be tested (3 times its final test concentration) in the "plate 1" position, and PatchPlate ^TMClamping to PatchPlate^TMLocation. Each compound plate is designed into 12 columns, so that 10 concentration-action curves formed by connecting 8 points can be constructed; the remaining two columns on the plate were occupied with vehicle (final concentration of DMSO 0.33%) to define the assay baseline, and cisapride (final concentration of 10 μ M) above the maximum blocking concentration to define the 100% inhibition level. Then, IonWorks^TMHT jet head (F head) 3.5. mu.l of PBS was added to PatchPlate^TMAnd its bottom side is perfused with an "internal" solution having the following composition (in mM): potassium Gluconate (K-Gluconate)100, KCl 40, MgCl₂3.2 EGTA 3 and HEPES 5 (all Sigma-Aldrich; using 10M KOH)The pH is adjusted to 7.25-7.30). After start-up and debubbling, the electronic head (E head) surrounds the PatchPlate^TMMoving, a drill hole test method (i.e., applying a voltage pulse to determine if a hole in each well is open) is performed. Then, the F head sends 3.5. mu.l of the above cell suspension to PatchPlate^TMAnd the cells have 200 seconds to reach the hole in each well and seal the hole. Thereafter, the E head around PatchPlate ^TMMoved to determine the resulting closed resistance in each well. Next, PatchPlate^TMBecomes an "inlet" solution having the following composition (in mM): KCl140, EGTA 1, MgCl₂1 and HEPES20 (pH adjusted to 7.25-7.30 using 10M KOH) together with 100. mu.g/ml amphotericin B (Sigma-Aldrich). After a duration of 9 minutes for perforating the membrane, the E heads each wrap around the PatchPlate^TMTo obtain the hERG current measurement before compound addition. Then, F head from the compound plate each hole of 3.5 u l solution to PatchPlate^TM4 wells (final concentration of DMSO in each well is 0.33%). This is achieved by the following method: moving from the most dilute wells of the compound plate to the most concentrated wells of the compound plate to minimize the effect of any compound carryover. After about 3.5 minutes of incubation, the E head surrounds the PatchPlate^TMAll 384 wells are moved to obtain the hERG current measurement after compound addition. In this way, a non-cumulative concentration-effect curve can be obtained, wherein the effect of each concentration of test compound depends on the recording of 1 to 4 cells, provided that acceptance criteria (see below) are met in a sufficient percentage of wells.

The hERG current before and after compound addition was induced by a single voltage pulse consisting of 20 seconds hold at-70 mV, change to-60 mV in 160 millisecond steps (to evaluate leakage), change back to-70 mV in 100 millisecond steps, change to +40mV in 1 second steps, change to-30 mV in 2 second steps, and finally change to-70 mV in 500 millisecond steps. The membrane potential was not clamped any between the voltage pulses before and after the compound addition.The leakage value is subtracted from the current value, which depends on evaluating the current caused at the +10mV step at the beginning of the voltage pulse scheme. One of two ways to IonWorks^TMAny voltage offset in HT is adjusted. When compound potency was determined, a depolarization voltage ramp was applied to CHO-kv1.5 cells, and a voltage was noted at which the current trace (current trace) appeared to be an inflection point (i.e., at which activation of the channel due to the ramping protocol was observed). The voltage at which the above-described phenomenon occurs has been previously determined in conventional electrophysiology using the same voltage command and found to be-15 mV (data not shown), so that an offset potential (offset) can be entered into the IonWorks ^TMIn the HT software, this value is used as a reference point. When determining the basic electrophysiological properties of hERG, any bias is adjusted by: in IonWorks^TMThe hERG tail current reversal potential (reciprocal potential) was determined in HT, compared to values determined in conventional electrophysiology (-82mV), and then at IonWorks^TMThe necessary offset adjustments are made in the HT software. The current signal is collected at a frequency of 2.5 kHz.

By taking the 40 ms average of the current (baseline current) at the-70 mV initial hold period and subtracting the average from the peak of the tail current response, with IonWorks^TMHT software from the deduction of leakage value of the trace automatically measured before and after the scanning hERG current magnitude. The acceptance criteria for the current induced in each well were: the blocking resistance before scanning is larger than 60M omega, the hERG tail current amplitude before scanning is larger than 150pA, and the blocking resistance after scanning is larger than 60M omega. The degree of inhibition of hERG current was evaluated by the following method: for each well, the values of hERG current after scanning are divided by the values of hERG current before the respective scanning.

Results

Typical K of the Compounds of the invention_iValues are from about 1 to about 100000 nM. The biological data for both examples are shown in the table below.

Watch (A)

Example numbering	IC in TR-FRET assays₅₀
Example numbering	IC in TR-FRET assays₅₀	26	743nM
45	258nM	26	743nM

Claims

1. A compound of formula I, in free base form, or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof:

wherein

R¹Selected from hydrogen, C_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, C_3-6Cycloalkyl radical, C_5-7Cycloalkenyl, aryl,Heteroaryl, heterocyclyl-C_1-6Alkyl radical C_3-6Cycloalkyl, -C_1-6Alkylaryl, -C_1-6Alkyl heteroaryl or-C_1-6Alkyl heterocyclic group, wherein said C_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, C_3-6Cycloalkyl radical, C_5-7Cycloalkenyl, aryl, heteroaryl, heterocyclyl, C_1-6Alkyl radical C_3-6Cycloalkyl radical, C_1-6Alkylaryl group, C_1-6Alkyl heteroaryl or C_1-6The alkyl heterocyclyl is optionally substituted with one, two or three a;

R²selected from hydrogen, nitro, cyano, -Q-C_1-6Alkyl, -Q-C_2-6Alkenyl, -Q-C_2-6Alkynyl, -Q-C_3-6Cycloalkyl, -Q-C_5-7Cycloalkenyl radical, -Q-C_1-6Alkyl radical C_3-6Cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C_1-6Alkylaryl, -Q-C_1-6Alkylheteroaryl, -Q-heterocyclyl or-Q-C_1-6Alkylheterocyclyl, wherein said-Q-C_1-6Alkyl, -Q-C_2-6Alkenyl, -Q-C_2-6Alkynyl, -Q-C_3-6Cycloalkyl, -Q-C_5-7Cycloalkenyl radical, -Q-C_1-6Alkyl radical C_3-6Cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C_1-6Alkylaryl, -Q-C_1-6Alkylheteroaryl, -Q-heterocyclyl or-Q-C_1-6The alkyl heterocyclyl is optionally substituted with one, two or three R⁷Substitution;

-Q-is a direct bond, -CONH-, -CO-, -CON (C) _1-6Alkyl) -, -CON (C)_3-6Cycloalkyl) -, -SO₂-、-SO₂NH-、-SO₂N(C_1-6Alkyl) -, -SO₂N(C_3-6Cycloalkyl) -, -NHSO₂-、-N(C_1-6Alkyl) SO₂-、-NHCO-、-N(C_1-6Alkyl) CO-, -N (C)_3-6Cycloalkyl) CO-or-N (C)_3-6Cycloalkyl) SO₂-；

R³Is- (C (R)⁴)(R⁵))_nR⁶、-C_2-4Alkenyl radical R⁶、-C_2-4Alkynyl radical R⁶、-C_5-7Cycloalkenyl radicals R⁶Nitro or cyano, and are asIf n is greater than 1, then each C (R)⁴)(R⁵) Independently of each other;

R⁶selected from methyl and C_3-6Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said methyl, C_3-6Cycloalkyl, heterocyclyl, aryl or heteroaryl each optionally substituted with 1-4R⁷And wherein any of the individual aryl or heteroaryl groups may be optionally fused with a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-4A, with the proviso that the bicyclic ring is not indane, benzo [1, 3 ] or heterocyclyl]Dioxoles or 2, 3-dihydrobenzo [1, 4 ]]-a dioxin ring system;

R⁷selected from halogen, nitro, CHO, -C_0-6Alkyl CN, -OC_1-6Alkyl CN, -C_0-6Alkyl OR⁸、-OC_2-6Alkyl OR⁸Fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -C_0-6Alkyl radical NR⁸R⁹、-OC_2-6Alkyl radical NR⁸R⁹、-OC_2-6Alkyl OC _2-6Alkyl radical NR⁸R⁹、-NR⁸OR⁹、-C_0-6Alkyl group CO₂R⁸、-OC_1-6Alkyl group CO₂R⁸、-C_0-6Alkyl CONR⁸R⁹、-OC_1-6Alkyl CONR⁸R⁹、-OC_2-6Alkyl radical NR⁸(CO)R⁹、-C_0-6Alkyl radical NR⁸(CO)R⁹、-O(CO)NR⁸R⁹、-NR⁸(CO)OR⁹、-NR⁸(CO)NR⁸R⁹、-O(CO)OR⁸、-O(CO)R⁸、-C_0-6Alkyl group COR⁸、-OC_1-6Alkyl group COR⁸、-NR⁸(CO)(CO)R⁸、-NR⁸(CO)(CO)NR⁸R⁹、-C_0-6Alkyl SR⁸、-C_0-6Alkyl (SO)₂)NR⁸R⁹、-OC_1-6Alkyl radical NR⁸(SO₂)R⁹、-OC_0-6Alkyl (SO)₂)NR⁸R⁹、-C_0-6Alkyl (SO) NR⁸R⁹、-OC_1-6Alkyl (SO) NR⁸R⁹、-OSO₂R⁸、-SO₃R⁸、-C_0-6Alkyl radical NR⁸(SO₂)NR⁸R⁹、-C_0-6Alkyl radical NR⁸(SO)R⁹、-OC_2-6Alkyl radical NR⁸(SO)R⁸、-OC_1-6Alkyl SO₂R⁸、-C_1-6Alkyl SO₂R⁸、-C_0-6Alkyl SOR⁸、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6Alkylheterocyclic group and-OC_2-6Alkyl heterocyclic group, wherein any C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_0-6Alkyl radical C_3-6Cycloalkyl radical, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl, C_0-6Alkylheterocyclic group and OC_2-6The alkyl heterocyclic group may be optionally substituted with one or more R¹⁴And wherein any of the individual aryl or heteroaryl groups may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-4A, with the proviso that the bicyclic ring system is not indane, benzo [1, 3 ] or heterocyclyl]Dioxoles or 2, 3-dihydrobenzo [1, 4 ]]-a dioxin ring system;

R¹⁴selected from halogen, nitro, CHO, -C_0-6Alkyl CN, -OC_1-6Alkyl CN, -C_0-6Alkyl OR⁸、-OC_1-6Alkyl OR⁸Fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -C_0-6Alkyl radical NR⁸R⁹、-OC_2-6Alkyl radical NR ⁸R⁹、-OC_2-6Alkyl OC_2-6Alkyl radical NR⁸R⁹、-NR⁸OR⁹、-C_0-6Alkyl group CO₂R⁸、-OC_1-6Alkyl group CO₂R⁸、-C_0-6Alkyl CONR⁸R⁹、-OC_1-6Alkyl CONR⁸R⁹、-OC_2-6Alkyl radical NR⁸(CO)R⁹、-C_0-6Alkyl radical NR⁸(CO)R⁹、-O(CO)NR⁸R⁹、-NR⁸(CO)OR⁹、-NR⁸(CO)NR⁸R⁹、-OR⁸、-O(CO)OR⁸、-O(CO)R⁸、-C_0-6Alkyl group COR⁸、-OC_1-6Alkyl group COR⁸、-NR⁸(CO)(CO)R⁸、-NR⁸(CO)(CO)NR⁸R⁹、-C_0-6Alkyl SR⁸、-C_0-6Alkyl (SO)₂)NR⁸R⁹、-OC_2-6Alkyl radical NR⁸(SO₂)R⁹、-OC_0-6Alkyl (SO)₂)NR⁸R⁹、-C_0-6Alkyl (SO) NR⁸R⁹、-OC_1-6Alkyl (SO) NR⁸R⁹、-OSO₂R⁸、-OSO₂R⁸R⁹、-SO₃R⁸、-C_0-6Alkyl radical NR⁸(SO₂)NR⁸R⁹、-C_0-6Alkyl radical NR⁸(SO)R⁹、-OC_2-6Alkyl radical NR⁸(SO)R⁸、-OC_1-6Alkyl SO₂R⁸、-C_1-6Alkyl SO₂R⁸、-C_0-6Alkyl SOR⁸、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6Alkylheterocyclic group and-OC_2-6Alkyl heterocyclic group, wherein any C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_0-6Alkyl radical C_3-6Cycloalkyl radical, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl, C_0-6Alkylheterocyclic group and OC_2-6The alkyl heterocyclyl may be optionally substituted with 1-4A;

R⁸And R⁹May together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said 4 to 6 membered heterocyclic ring being optionally substituted by a; when two R are ⁸(ii) when present in said structure, then they may optionally together form a 5 or 6 membered heterocyclic ring, said 5 or 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, and being optionally substituted by A;

n is 0, 1, 2 or 3;

a is selected from oxo, halogen, nitro, CN, -OR¹²、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylheterocyclyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -OC_2-6Alkyl radical NR¹²R¹³、-NR¹²R¹³、-CONR¹²R¹³、-NR¹²(CO)R¹³、-O(CO)C_1-6Alkyl, - (CO) OC_1-6Alkyl, -COR¹²、-(SO₂)NR¹²R¹³、-NSO₂R¹²、-SO₂R¹²、-SOR¹²、-(CO)C_1-6Alkyl radical NR¹²R¹³、-(SO₂)C_1-6Alkyl radical NR¹²R¹³、-OSO₂R¹²and-SO₃R¹²Wherein said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl, C_0-6Alkyl heterocyclic radical and C _0-6Alkyl radical C_3-6Cycloalkyl optionally substituted by halogen, -OSO₂R¹²、-SO₃R¹²Nitro, cyano, -OR¹²、C_1-6Alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy and trifluoromethoxy;

R¹²And R¹³May together form a 4-to 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O or S and optionally substituted by hydroxy, C_1-3Alkyloxy, cyano or halogen substitution;

With the proviso that R¹、R²Or R³Any of the individual aryl or heteroaryl groups in (a) are fused with a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-4A, with the proviso that the bicyclic ring is not indane, benzo [1, 3 ] or heterocyclyl]Dioxoles or 2, 3-dihydrobenzo [1, 4 ]]-a dioxin ring system; or

2. The compound of claim 1 in free base form or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, wherein

R²selected from hydrogen, cyano, -Q-C_1-6Alkyl, -Q-C_2-6Alkenyl, -Q-C_2-6Alkynyl, -Q-C_3-6Cycloalkyl, -Q-C_5-7Cycloalkenyl radical, -Q-C_1-6Alkyl radical C_3-6Cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C_1-6Alkylaryl, -Q-C_1-6Alkylheteroaryl, -Q-heterocyclyl or-Q-C _1-6Alkylheterocyclyl, wherein said-Q-C_1-6Alkyl, -Q-C_2-6Alkenyl, -Q-C_2-6Alkynyl, -Q-C_3-6Cycloalkyl, -Q-C_5-7Cycloalkenyl radical, -Q-C_1-6Alkyl radical C_3-6Cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C_1-6Alkylaryl, -Q-C_1-6Alkylheteroaryl, -Q-heterocyclyl or-Q-C_1-6The alkyl heterocyclyl is optionally substituted with one, two or three R⁷Substitution;

R⁶selected from methyl and C_3-6Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said methyl, C_3-6Cycloalkyl, heterocyclyl, aryl or heteroaryl each optionallyGeneration has 1-4R⁷And wherein any of the individual aryl or heteroaryl groups may be optionally fused with a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-3A, with the proviso that the bicyclic ring is not indane, benzo [1, 3 ] or heterocyclyl]Dioxoles or 2, 3-dihydrobenzo [1, 4 ] ]-a dioxin ring system;

R⁷selected from halogen, nitro, -C_0-6Alkyl CN, -OC_1-6Alkyl CN, -C_0-6Alkyl OR⁸、-OC_2-6Alkyl OR⁸Fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -C_0-6Alkyl radical NR⁸R⁹、-OC_2-6Alkyl radical NR⁸R⁹、-OC_2-6Alkyl OC_2-6Alkyl radical NR⁸R⁹、-NR⁸OR⁹、-C_0-6Alkyl group CO₂R⁸、-OC_1-6Alkyl group CO₂R⁸、-C_0-6Alkyl CONR⁸R⁹、-OC_1-6Alkyl CONR⁸R⁹、-OC_2-6Alkyl radical NR⁸(CO)R⁹、-C_0-6Alkyl radical NR⁸(CO)R⁹、-O(CO)NR⁸R⁹、-NR⁸(CO)OR⁹、-NR⁸(CO)NR⁸R⁹、-O(CO)R⁸、-C_0-6Alkyl group COR⁸、-OC_1-6Alkyl group COR⁸、-NR⁸(CO)(CO)R⁸、-NR⁸(CO)(CO)NR⁸R⁹、-C_0-6Alkyl SR⁸、-C_0-6Alkyl (SO)₂)NR⁸R⁹、-OC_1-6Alkyl radical NR⁸(SO₂)R⁹、-OC_0-6Alkyl (SO)₂)NR⁸R⁹、-C_0-6Alkyl (SO) NR⁸R⁹、-OC_1-6Alkyl (SO) NR⁸R⁹、-OSO₂R⁸、-SO₃R⁸、-C_0-6Alkyl radical NR⁸(SO₂)NR⁸R⁹、-C_0-6Alkyl radical NR⁸(SO)R⁹、-OC_2-6Alkyl radical NR⁸(SO)R⁸、-OC_1-6Alkyl SO₂R⁸、-C_1-6Alkyl SO₂R⁸、-C_0-6Alkyl SOR⁸、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6Alkylheterocyclic group and-OC_2-6Alkyl heterocyclic group, wherein any C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_0-6Alkyl radical C_3-6Cycloalkyl radical, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl, C_0-6Alkylheterocyclic group and OC_2-6The alkyl heterocyclic group may be optionally substituted with one or more R¹⁴And wherein any of the individual aryl or heteroaryl groups may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein said bicyclic ring system is optionally substituted with 1-3A, with the proviso that said bicyclic ring system is not indane, benzo [1, 3 ] or heterocyclyl]Dioxoles or 2, 3-dihydrobenzo [1, 4 ] ]-a dioxin ring system;

R⁸and R⁹Independently selected from hydrogen, C_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6alkylheterocyclyl-C_0-6Alkyl radical NR¹⁰R¹¹and-C_1-6Alkyl radical NR¹⁰R¹¹Wherein said C is_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, C_0-6Alkyl radical C_3-6Cycloalkyl radical, C_0-6Alkylaryl group, C _0-6Alkyl heteroaryl or C_0-6Alkyl heterocyclyl is optionally substituted with a; or

n is 0, 1 or 2;

R¹²And R¹³May together form a 4-to 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O or S and optionally substituted by hydroxy, cyano, C_1-3Alkyloxy or halogen.

3. The compound of claim 1 in free base form or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, wherein

R¹Is selected from C_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, C_3-6Cycloalkyl radical, C_5-7Cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C_1-6Alkyl radical C_3-6Cycloalkyl, -C_1-6Alkylaryl, -C_1-6Alkyl heteroaryl or-C _1-6Alkyl heterocyclic group, wherein said C_1-6Alkyl radical, C_3-6Alkenyl radical, C_3-6Alkynyl, C_3-6Cycloalkyl radical, C_5-7Cycloalkenyl, aryl,Heteroaryl, heterocyclyl, C_1-6Alkyl radical C_3-6Cycloalkyl radical, C_1-6Alkylaryl group, C_1-6Alkyl heteroaryl or C_1-6The alkyl heterocyclyl is optionally substituted with one or two a;

R³is- (C (R)⁴)(R⁵))_nR⁶；

R¹⁰and R¹¹Independently selected from hydrogen or C_1-6An alkyl group; or

n is 0;

a is selected from oxo, halogen, nitro, CN, -OR¹²、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, alkynyl,-C_0-6Alkylaryl, -C_0-6Alkyl heteroaryl, -C_0-6Alkyl radical C_3-6Cycloalkyl, -C_0-6Alkylheterocyclyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy and-COR¹²；

R¹²And R¹³Independently selected from hydrogen and C_1-6An alkyl group.

4. A compound according to any one of claims 1 to 3, wherein R¹Is C_1-6An alkyl group.

5. The compound of any one of claims 1 to 4, wherein R²wherein-Q-represents a direct bond.

6. A compound according to any one of claims 1 to 5, wherein R²is-Q-aryl, said aryl being optionally substituted with R⁷。

7. A compound according to any one of claims 1 to 5, wherein R²is-Q-heteroaryl, said heteroaryl being optionally substituted with one, two or three R⁷And (4) substitution.

8. The compound of any one of claims 1 to 7, wherein R ⁷Is selected from-OSO₂R⁸and-C_0-6Alkylaryl, and wherein said C is_0-6The alkylaryl group may optionally be substituted with one or more R¹⁴And wherein any one of the aryl groups may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl, 5, 6 or 7 membered cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-3A.

9. As claimed in claims 1 to 7The compound of any one of the above formulas, wherein R⁷Selected from halogen, nitro, -C_0-6Alkyl CN, -OC_2-6Alkyl OR⁸Trifluoromethyl, fluoromethoxy, trifluoromethoxy, -OSO₂R⁸、-C_0-6Alkylaryl and-C_0-6Alkyl heteroaryl, wherein any C_0-6Alkylaryl or C_0-6The alkylheteroaryl group may be optionally substituted with one or more R¹⁴And wherein any of the individual aryl or heteroaryl groups may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-3A.

10. The compound of claim 8, wherein said C_0-6Alkylaryl represents phenyl.

11. The compound of claim 8 or 10, wherein R is¹⁴represents-C_0-6Alkyl OR⁸or-OSO₂R⁸。

12. The compound of claim 9, wherein R is¹⁴Selected from halogen, nitro, -C_0-6Alkyl CN, -C_0-6Alkyl OR⁸Fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -C _0-6Alkyl group CO₂R⁸、-C_0-6Alkyl radical NR⁸(CO)R⁹、-OR⁸、-O(CO)R⁸、-C_0-6Alkyl group COR⁸、-OSO₂R⁸and-OSO₂R⁸R⁹C_1-6An alkyl group.

13. The compound of any one of claims 8, 10 and 11, wherein R is⁸Is represented by C_1-6Alkyl or trifluoromethyl.

14. The compound of claim 9, wherein R is⁸And R⁹Independently selected from hydrogen, C_1-6Alkyl, trifluoromethyl, -C_0-6Alkylaryl and-C_0-6Alkyl radical NR¹⁰R¹¹Wherein said C is_1-6Alkyl radical, C_0-6Alkylaryl group, C_0-6Alkyl heteroaryl or C_0-6Alkyl heterocyclyl is optionally substituted with a; or

15. The compound of any one of claims 1 to 14, wherein n is 0.

16. The compound of any one of claims 1 to 15, wherein a is selected from-OR¹²、C_1-6Alkyl and-COR¹²(ii) a And R is¹²Is C_1-6An alkyl group.

17. The compound of any one of claims 1 to 16, wherein R⁶Is aryl, wherein said aryl is optionally substituted with 1-4R⁷And wherein said aryl group may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl, 5, 6 or 7 membered cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein said bicyclic ring system is optionally substituted with 1-3A.

18. The compound of claim 17, wherein R⁷Is selected from-OSO₂R⁸and-C_0-6Alkylaryl, and wherein said C is_0-6The alkylaryl group may optionally be substituted with one or more R ¹⁴And (4) substitution.

19. The compound of claim 12, whereinThe R is¹⁴represents-C_0-6Alkyl OR⁸or-OSO₂R⁸。

20. The compound of claim 17, wherein said aryl group is optionally fused to a 5 or 6 membered heterocyclyl to form a bicyclic ring system, wherein said bicyclic ring system is optionally substituted with 1-3 a.

21. The compound of claim 20, wherein a is-COR¹²And R is¹²Is C_1-6An alkyl group.

22. The compound of any one of claims 1 to 16, wherein R⁶Selected from aryl or heteroaryl, wherein said aryl or heteroaryl is each optionally substituted with 1-4R⁷And wherein any of the individual aryl or heteroaryl groups may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-3A.

23. The compound of claim 22, wherein R⁷Selected from halogen, nitro, -C_0-6Alkyl CN, -OC_2-6Alkyl OR⁸Trifluoromethyl, fluoromethoxy, trifluoromethoxy, -OSO₂R⁸、-C_0-6Alkylaryl and-C_0-6Alkyl heteroaryl, wherein any C_0-6Alkylaryl or C_0-6The alkylheteroaryl group may be optionally substituted with one or more R¹⁴And wherein any of the individual aryl or heteroaryl groups may be optionally fused to a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system, wherein the bicyclic ring system is optionally substituted with 1-3A.

24. The compound of claim 23, wherein R¹⁴Selected from halogen, nitro, -C_0-6Alkyl CN, -C_0-6Alkyl OR⁸Fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -C_0-6Alkyl group CO₂R⁸、-C_0-6Alkyl radical NR⁸(CO)R⁹、-OR⁸、-C_0-6Alkyl group COR⁸、-OSO₂R⁸and-OSO₂R⁸R⁹C_1-6An alkyl group.

25. The compound of claim 23 or 24, wherein R⁸And R⁹Independently selected from hydrogen, C_1-6Alkyl, trifluoromethyl, -C_0-6Alkylaryl and-C_0-6Alkyl radical NR¹⁰R¹¹Wherein said C is_1-6Alkyl or C_0-6Alkylaryl optionally substituted with a; or

26. The compound of claim 25, wherein R¹⁰And R¹¹Independently selected from hydrogen or C_1-6An alkyl group; or

27. The compound of claim 23, wherein a is selected from-OR¹²、C_1-6Alkyl and-COR¹²。

28. The compound of claim 27, wherein R¹²Is C_1-6An alkyl group.

29. A compound in free base form or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, which compound is:

2-amino-5- (3-bromophenyl) -3-methyl-5-phenyl-3, 5-dihydro-imidazol-4-one;

2-amino-5- (3-hydroxyphenyl) -3-methyl-5-phenyl-3, 5-dihydro-4H-imidazol-4-one;

5- (4-hydroxyphenyl) -3-methyl-5- (3-phenoxyphenyl) -2-thioimidazolidin-4-one;

2-methoxyethanesulfonic acid 3- { 2-amino-4- [3- (2-fluoropyridin-3-yl) phenyl ] -1-methyl-5-oxo-4, 5-dihydro-1H-imidazol-4-yl } phenyl ester acetate;

2-methoxyethanesulfonic acid 3- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-5-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl ester;

3- [ 2-amino-1-methyl-5-oxo-4- (3-pyrimidin-5-ylphenyl) -4, 5-dihydro-1H-imidazol-4-yl ] phenyl cyclopropanesulfonate;

30. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 29 and a pharmaceutically acceptable excipient, carrier or diluent.

31. The use of a compound according to any one of claims 1 to 29 as a medicament.

32. Use of a compound according to any one of claims 1 to 29 as a medicament for the treatment or prevention of an a β -related pathology.

33. Use of a compound according to any one of claims 1 to 29 as a medicament for the treatment or prevention of an a β -related pathology, wherein said a β -related pathology is down's syndrome, a β -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

34. Use of a compound according to any one of claims 1 to 29 in the manufacture of a medicament for the treatment or prevention of an a β -related pathology.

35. Use of a compound according to any one of claims 1 to 29 in the manufacture of a medicament for the treatment or prevention of an a β -related pathology, wherein said a β -related pathology is down's syndrome, a β -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

36. A method of inhibiting activity of BACE comprising contacting said BACE with a compound of any one of claims 1 to 29.

37. A method of treating or preventing an a β -related pathology in a mammal, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 29.

38. The method of claim 37, wherein said a β -related pathology is downs syndrome, a β -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), alzheimer disease, memory loss, attention deficit symptoms associated with alzheimer disease, neurodegeneration associated with alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

39. The method of claim 37, wherein the mammal is a human.

40. A method of treating or preventing an a β -related pathology in a mammal, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 29 and at least one cognitive enhancing drug, memory enhancing drug, or cholinesterase inhibitor.

41. The method of claim 40, wherein said A β -related pathology is Down's syndrome, β -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("Mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

42. The method of claim 40, wherein the mammal is a human.

43. A compound, which is:

2-acetyl-7-bromo-1, 2, 3, 4-tetrahydroisoquinoline;

5- (3-bromo-phenyl) -3-methyl-5-phenyl-2-thioxo-imidazolidin-4-one;

1-acetyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline;

4-methoxy-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol;

1- (3-hydroxyphenyl) -2-phenylethane-1, 2-dione;

5- (3-hydroxyphenyl) -3-methyl-5-phenyl-2-thioimidazolidin-4-one;

methyl-5-oxo-4-phenyl-2-thioxoimidazolidin-4-yl) phenylmethanesulfonate;

3-bromo-4- { [ tert-butyl (diphenyl) silyl ] oxy } benzaldehyde;

5- (3-bromo-4-hydroxyphenyl) -3-methyl-5-phenyl-2-thioimidazolidin-4-one;

2- (3' -methoxybiphenyl-3-yl) -1, 3-dithiane;

2, 3-dihydro-1-benzofuran-5-yl (2-phenyl-1, 3-dithian-2-yl) methanol;

1- (2, 3-dihydro-1-benzofuran-5-yl) -2-phenylethane-1, 2-dione;

2-acetyl-5-chloro-1, 2, 3, 4-tetrahydroisoquinoline;

1- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) -2-phenylethane-1, 2-dione;

6-iodo-1, 2, 3, 4-tetrahydronaphthalene;

6- (phenylethynyl) -1, 2, 3, 4-tetrahydronaphthalene;

1-phenyl-2- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) ethane-1, 2-dione;

1-acetyl-5-iodoindoline;

1-acetyl-5- (phenylethynyl) indoline;

1- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) -2-phenylethane-1, 2-dione;

1-acetyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline;

8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) chroman;

3-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol;

3 '-hydroxy-5' -methoxybiphenyl-3-carbaldehyde;

4-bromo-1-fluoro-2-methoxybenzene;

2- (4-fluoro-3-methoxyphenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane;

4- [ (3-bromophenyl) ethynyl ] phenol;

1- (3-bromophenyl) -2- (4-hydroxyphenyl) ethane-1, 2-dione;

5- (3-bromophenyl) -5- (4-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one;

3- [ (3-bromophenyl) ethynyl ] phenol;

1- (3-bromophenyl) -2- (3-hydroxyphenyl) ethane-1, 2-dione;

5- (3-bromophenyl) -5- (3-hydroxyphenyl) -3-methyl-2-thioimidazolidin-4-one;

2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine;

1-ethynyl-3- (3-methoxyphenoxy) benzene;

3- [ (4-methoxyphenyl) ethynyl ] phenol;

4- { [3- (3-methoxyphenoxy) phenyl ] ethynyl } phenol;

1- (3-hydroxyphenyl) -2- (4-methoxyphenyl) ethane-1, 2-dione;

5- (3-hydroxyphenyl) -5- (4-methoxyphenyl) -3-methyl-2-thioimidazolidin-4-one;

1- (4-hydroxyphenyl) -2- [3- (3-methoxyphenoxy) phenyl ] ethane-1, 2-dione;

1- (4-methoxyphenyl) -2- (3-phenoxyphenyl) ethane-1, 2-dione;

5- (4-methoxyphenyl) -3-methyl-5- (3-phenoxyphenyl) -2-thioimidazolidin-4-one;

3-methoxypropan-1-sulfonyl chloride;

6-iodo-1, 2, 3, 4-tetrahydronaphthalene;

6- [ (3-bromophenyl) ethynyl ] -1, 2, 3, 4-tetrahydronaphthalene;

6-bromo-1, 2, 3, 4-tetrahydronaphthalen-2-ylmethyl ether;

6-ethynyl-1, 2, 3, 4-tetrahydronaphthalen-2-ylmethyl ether;

1-acetyl-6-iodo-1, 2, 3, 4-tetrahydroquinoline;

1-acetyl-6- [ (3-bromophenyl) ethynyl ] -1, 2, 3, 4-tetrahydroquinoline;

5- [ (3-bromophenyl) ethynyl ] indan;

1- (3-bromophenyl) -2- (2, 3-dihydro-1H-inden-5-yl) ethane-1, 2-dione;

2-acetyl-4-chloroisoindoline;

5- [ (3-bromophenyl) ethynyl ] -2, 3-dihydro-1-benzofuran;

1- (3-bromophenyl) -2- (2, 3-dihydro-1-benzofuran-5-yl) ethane-1, 2-dione;

6- [ (3-bromophenyl) ethynyl ] chromane;

1- (3-bromophenyl) -2- (3, 4-dihydro-2H-chromen-6-yl) ethane-1, 2-dione;

(3, 4-dihydro-1H-isochromen-7-ylethynyl) (trimethyl) silane;

7-ethynyl-3, 4-dihydro-1H-isochromene;

7- [ (3-bromophenyl) ethynyl ] -3, 4-dihydro-1H-isochromene;

1- (3-bromophenyl) -2- (3, 4-dihydro-1H-isochromen-7-yl) ethane-1, 2-dione;

4- { [ tert-butyl (diphenyl) silyl ] oxy } benzaldehyde;

tert-butyl [4- (1, 3-dithian-2-yl) phenoxy ] diphenylsilane;

44. Use of a compound according to claim 43 as an intermediate in the preparation of a compound of formula I according to claim 1.