• 专利附录
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    • 专利摘要:
    The present invention provides a new class of aminobenzophenone derivatives, pharmaceutical preparations containing such compounds, dosage units of such preparations, methods of treating patients, including the administration of such compounds, and methods of treating such compounds in the manufacture of pharmaceutical preparations. It is about a use.
    公开号:KR20040029455A
    申请号:KR10-2004-7003014
    申请日:2002-08-26
    公开日:2004-04-06
    发明作者:오토젠에릭리터；호르네만안네마리；량시푸
    申请人:레오 파마 에이/에스；
    IPC主号:
    专利说明:

    Novel aminobenzoephenones
    [2] Already a series of closely related aminobenzophenones (eg 4- (2-amino-4-nitrophenylamino) benzophenones) have been published (Hussein, FA et al, Iraqi J. Sci., 22,54). -66 (1981)). However, its use is not described. WO 98/32730, WO 01/05744, WO 01/05746, WO 01/05749, WO 01/05751, WO 01/05745 and W0 01/42189 are tested Aminobenzophenone inhibitors of the secretion of intraluminal interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) secretion are described, which compounds include inflammatory diseases associated with pathogenic cytokine production, for example asthma, rheumatoid Potentially useful for the treatment of arthritis, psoriasis, contact dermatitis and atopic dermatitis. In addition, the compounds of the aforementioned patent applications were subjected to in vivo testing for anti-inflammatory properties in chronic dermatitis models of 12-O-tetradecanoylpobol-13-acetate (TPA) -induced rats (De Young, LM et al., Agents Actions, 26, 335-341 (1989); Carlson, RP et al., Agents Actions, 17, 197-204 (1985); Alford, JG et al., Agents Action, 37, (1992); Stanley, PL et al., Skin Pharmacol, 4,262-271 (1991)). In a chronic dermatitis model, the compound has similar potency as the reference compound hydrocortisone.
    [3] The preparation of structurally related aminobenzophenones useful as textile dyes is described in Man-Made Text. India (1987), 30 (6), 275-6, Man-Made Text. India (1986), 29 ( 5), 224-30; Man-Made Text.India (1985), 28 (11), 425,427-9, 431), aminobenzophenones structurally related as reactants in the preparation of fluorane dye precursors are described in Japanese patents. No. 81-61259.
    [4] It is an object of the present invention to further provide pharmaceutically active benzophenone derivatives having excellent physicochemical properties, in particular improved bioavailability.
    [5] Summary of the Invention
    [6] Surprisingly, it has now been found that the novel aminobenzophenone derivatives of formula (I) are potent inhibitors of in vitro secretion of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), resulting in cytokine or More specifically, the secretion and regulation of in vitro interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) has potentially been made available for the treatment of inflammatory diseases implicated in pathogenesis. Inhibition or low level regulation of cytokines may be due to inhibition of MAP kinases.
    [7] Accordingly, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts, solvates thereof (such as hydrates thereof).
    [8]
    [9] In the above formula,
    [10] X is oxygen, sulfur or N-ORc,
    [11] R 1 is halogen, hydroxy, mercapto, trifluoromethyl, amino, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin group, (C 1 -C 3 ) alkoxy, (C 1- C 3 ) alkylthio, (C 1 -C 6 ) alkylamino, (C 1 -C 3 ) alkoxycarbonyl, cyano, -CONH 2 , phenyl and nitro, a substituent selected from the group consisting of:
    [12] R 2 is hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin group, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) at least one same or different selected from the group consisting of alkylthio, (C 1 -C 6 ) alkylamino, (C 1 -C 3 ) alkoxycarbonyl, cyano, -CONH 2 , phenyl and nitro Substituents,
    [13] R 3 is hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, cyano, carboxy, carbamoyl, nitro, (C 1 -C 10 ) alkyl, (C 2 -C 10 ) olefin group, (C 3 -C 12 ) at least one identical or selected from the group consisting of cyclic hydrocarbon groups, (C 1 -C 10 ) alkoxy, (C 1 -C 10 ) alkylthio, (C 1 -C 10 ) alkoxycarbonyl and phenyl Different substituents,
    [14] R 4 is hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group, (C 3 -C 6 ) cyclic hydrocarbon group or -C (O) OC (R d ) (R e ) (-OC (O) -R 14 ), wherein the R 14 group is optionally substituted with one or more identical or different substituents of R 8 ,
    [15] R 5 is one or more identical or different substituents selected from the group consisting of hydrogen and R 1 ,
    [16] R 6 is (C 1 -C 1O ) alkyl-heterocyclyl, (C 1 -C 10 ) alkyl- (C 3 -C 12 ) cyclic hydrocarbon group, (C 1 -C 10 ) alkyl, (C 2- C 10 ) olefin group, (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 10 ) alkynyl, Y 1 R 21 , Y 2 R 22 or Y 4 R 24 , wherein (( C 1 -C 10 ) alkyl, (C 2 -C 10 ) olefin group and (C 3 -C 12 ) cyclic hydrocarbon group are substituted with one or more identical or different substituents of R 7 , and (C 1 -C 10 ) Alkyl-heterocyclyl, (C 1 -C 10 ) alkyl- (C 3 -C 12 ) cyclic hydrocarbon groups, heterocyclyl and (C 2 -C 10 ) alkynyl are one or more identical or different substituents of R 7 Is optionally substituted with
    [17] R 7 is R 12 , YH or YR 14 , wherein the R 12 and YR 14 groups are optionally substituted with one or more identical or different substituents of R 8 ,
    [18] R 8 is R 12 , YH, YR 14 or R 14 , wherein the R 12 , YR 14 and R 14 groups are optionally substituted with one or more identical or different substituents of R 9 ,
    [19] R 9 is R 12 , YH, YR 14 or R 14 , wherein the R 12 , YR 14 and R 14 groups are optionally substituted with one or more identical or different substituents of R 10 ,
    [20] R 10 is R 12 , YH, YR 14 or R 14 , wherein the R 12 , YR 14 and R 14 groups are optionally substituted with one or more identical or different substituents of R 11 ,
    [21] R 11 is R 12 or R 14 , wherein the R 12 and R 14 groups are optionally substituted with one or more identical or different substituents of R 12 ,
    [22] R 12 is halogen, hydroxy, mercapto, trifluoromethyl, amino, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) alkylthio, (C 1 -C 6 ) alkylamino, (C 1 -C 3 ) alkoxycarbonyl, (C 1 -C 9 ) trialkylammonium associated with anion, (C 2 -C 10 ) dialkylphosphinoyl, (C 1 -C 5 ) alkyl (hydroxy) phosphinoyl , (C 2 -C 10 ) dialkylphosphinoyloxy, (C 1 -C 5 ) alkyl (hydroxy) phosphinoyloxy, dihydroxyphosphinoyl, dihydroxyphosphinoyloxy, cyano, Azido, nitro, -CHO, -COOH, -CONH 2 , -CONHR 'or -CONRR', where R and R 'are (C 1 -C 3 ) alkyl,
    [23] Y is -O-, -S-, -S (O) -, -S (0) 2 -, -NR a -, -NR a C (Z) NR b -, -NR a C (Z) -, -C (Z) NR a -, - C (O) -, -C (S) -, -C (Z) O-, -C (O) Z-, -C (S) S- -OC (Z ) -, -NR a C (Z ) O-, -OC (Z) NR a -, -S (0) 2 O-, -OS (0) 2 -, -S (0) 2 NR a -, - NR a S (O) 2- , -OC (Z) O-, -OC (Z) Z-, -OP (O) (OR a ) 0-, -P (O) (OR a ) 0-,- C (NR a )-, -C (NOR a )-, -N = C (R a )-, -N = C (OR a )-, -N (OR a )-, -ON (R a )- , -N (R a ) O-, -N (R a ) C (= NR b ) NR c- , -C (= NR a ) NR b -or -N (R a ) C (= NR b )- ego,
    [24] Z is oxygen or sulfur,
    [25] R 14 is (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group, (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl or (C 2 -C 6 ) alkynyl,
    [26] Y 1 is -NR a C (S) NR b- , -C (O)-, -C (S)-, -C (S) O-, -C (O) S-, -C (S) S -, -OC (S) -, -OC (O) -, -NR a C (S) O-, -OC (Z) NR a -, -S (0) 2 O-, -OS (0) 2 -, -S (0) 2 NR a -, -NR a S (O) 2 -, -OC (Z) O-, -OC (Z) Z-, -OP (O) (OR a) O-, -P (O) (OR a ) 0-, -C (NR a )-, -C (NOR a )-, -N = C (R a )-, -N = C (OR a )-, -N (OR a )-, -ON (R a )-, -N (R a ) O-, -N (R a ) C (= NR b ) NR c- , -C (= NR a ) NR b -or -N (R a ) C (= NR b )-,
    [27] R 21 is a (C 1 -C 10 ) alkyl-heterocyclyl, (C 1 -C 10 ) alkyl- (C 3 -C 12 ) cyclic hydrocarbon group, optionally substituted with one or more identical or different substituents of R 7 , (C 1 -C 10 ) alkyl, (C 2 -C 1 O ) olefin group, (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl or (C 2 -C 10 ) alkynyl,
    [28] Y 2 is -0-, -S-, -C (0) O- or -C (O) NR a -, and
    [29] R 22 is (C 1 -C 10 ) alkyl-heterocyclyl, (C 1 -C 10 ) alkyl- (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 10 ) alkynyl , (C 1 -C 1O ) alkyl, (C 2 -C 10 ) olefin group or (C 3 -C 12 ) monocyclic hydrocarbon group, wherein (C 1 -C 10 ) alkyl is one or more of the same as R 7 Or substituted with a different substituent, and (C 1 -C 10 ) alkyl-heterocyclyl, (C 1 -C 10 ) alkyl- (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 10 ) alkynyl, (C 2 -C 10 ) olefin group and (C 3 -C 12 ) monocyclic hydrocarbon group are optionally substituted with one or more identical or different substituents of R 7 ),
    [30] Y 4 is -NR a C (O) NR b CH (R c) -, -NR a C (O) NR b S (O) 2 -, -NR a -, NR a C (Z) -, -NR a C (O) OCH (R c )-, -NR a C (O) NR b C (R d ) (R e ) -OC (O)-or -NR a C (O) OC (R d ) ( R e ) -OC (0)-,
    [31] R 24 represents (C 1 -C 1O ) alkyl-heterocyclyl, (C 1 -C 10 ) alkyl- (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 10 ) alkynyl , (C 1 -C 10 ) alkyl, (C 2 -C 1O ) olefin group or (C 3 -C 12 ) cyclic hydrocarbon group, wherein (C 1 -C 10 ) alkyl, (C 2 -C 10 ) The olefin group and the (C 3 -C 12 ) cyclic hydrocarbon group are substituted with one or more identical or different substituents of R 15 , and are (C 1 -C 1O ) alkyl, (C 2 -C 10 ) olefin groups, (C 3 -C 12 ) cyclic hydrocarbon group, (C 1 -C 10 ) alkyl-heterocyclyl, (C 1 -C 10 ) alkyl- (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl and (C 2 -C 10 ) alkynyl is optionally substituted with one or more identical or different substituents of R 7 ),
    [32] R 15 is R 12a , R 12b or R 12C , wherein R 12a , R 12b or R 12C is optionally substituted with one or more identical or different substituents of R 7 ,
    [33] R 12a is (C 1 -C 3) substituted with one or more identical or different substituents of R 42 alkoxy, (C 1 -C 3) alkylthio, (C 1 -C 6) alkylamino, (C 1 -C 3 ) Alkoxycarbonyl, -CONHR 'or -CONRR' where R and R 'are (C 1 -C 3 ) alkyl, provided that when further substituted with R 42 , R 12a or R 15 is- ( QO) n -Q or -CH 2 (QO) n -Q (where Q is (C 1 -C 3 ) alkyl and n is an integer of at least 1) so that the group is a continuous linear sequence of atoms having at least 16 elements Including,
    [34] R 12b is (C 4 -C 10 ) alkoxy, (C 4 -C 10 ) alkylthio, (C 7 -C 12 ) alkylamino, (C 4 -C optionally substituted with one or more identical or different substituents of R 7 10 ) alkoxycarbonyl, -CONHR 'or -CONRR', wherein R and R 'are (C 4 -C 10 ) alkyl,
    [35] R 12c is —Y 5 (C 1 -C 10 ) alkyl, -Y-aryl, -Y-heterocyclyl, -Y- (C 3 -C 12 ) optionally substituted with one or more identical or different substituents of R 7 Cyclic hydrocarbon group and -Y- (C 2 -C 10 ) olefin group,
    [36] Y 5 is -S (O) -, -S ( O) 2 -, -NR a C (Z) -, -NR a C (Z) NR b -, -C (S) NR a -, -C ( O)-, -C (S)-, -C (S) O-, -C (O) S-, -C (S) S-, -OC (Z)-, -NR a C (Z) O -, -OC (Z) NR a -, -S (0) 2 0-, -OS (O) 2 -, -S (O) 2 NR a -, -NR a S (O) 2 -, -OC (Z) O-, -OC (Z) Z-, -OP (O) (OR a ) 0-, -P (O) (OR a ) O-, -C (NR a )-, -C (NOR a )-, -N = C (R a )-, -N = C (OR a )-, -N (OR a )-, -ON (R a )-, -N (R a ) O-,- N (R a ) C (= NR b ) NR c- , -C (= NR a ) NR b -or -N (R a ) C (= NR b )-,
    [37] R 42 is -YH, YR 14 , R 52 , halogen, trifluoromethyl, cyano, azido or nitro, wherein R 52 and -YR 14 are optionally substituted with one or more identical or different substituents of R 8 ego,
    [38] R 52 represents (C 6 -C 1O ) alkyl, (C 2 -C 6 ) olefin group, (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 6 ) alkynyl or heteroaryl ego,
    [39] R a , R b and R c are independently hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin groups, (C 3 -C) optionally substituted with one or more identical or different substituents of R 12 12 ) a cyclic hydrocarbon group, aryl, heterocyclyl or (C 2 -C 6 ) alkynyl,
    [40] R d and R e are hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group and (C 3 -C 12 ) cyclic hydrocarbon optionally substituted with one or more identical or different substituents of R 12 Group.
    [41] In a further aspect, the present invention relates to a pharmaceutical formulation containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable excipient or vehicle.
    [42] In another aspect the invention relates to a method of treating inflammation in a patient, comprising administering to the patient an effective amount of a compound of formula (I).
    [43] In another aspect, the invention relates to the use of a compound of formula (I) in combination with a pharmaceutically acceptable excipient or vehicle, optionally in the manufacture of a medicament for the treatment of inflammation.
    [1] The present invention relates to a novel class of compounds, aminobenzophenone derivatives, pharmaceutical preparations containing such compounds, dosage units of such preparations, methods of treating patients, including the administration of such compounds, and in the preparation of pharmaceutical preparations. It relates to the use of the compound.
    [44] In many but not many drug development processes, in vivo testing of candidates that appear promising during the in vitro selection phase generally results in no therapeutic effect, which is also well known. These observations can be explained by rapid drug metabolism or insufficient plasma stability. The most frequent factor is insufficient bioavailability. The bioavailability of the drug is controlled by several factors, referred to collectively as physicochemical properties. Physicochemical properties that are key to bioavailability are, for example, Solubility and log P are defined as. Log P values between 1 and 5 give optimal bioavailability for most drugs. Thus, it would be beneficial for any drug development program if it would be possible to identify one or more groups of molecular structures that could be manipulated physicochemical properties and eventually regulate bioavailability by replacing them without altering their biological activity. Surprisingly, it has now been found that substituent R 6 can be engineered to modulate the physicochemical properties of the compound of formula (I) while maintaining almost no biological activity.
    [45] Thus, preferred compounds of the invention are those in which R 1 is halogen, hydroxy, trifluoromethyl, amino, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin group, (C 1 -C 3 ) alkoxy And cyano.
    [46] In another preferred embodiment, R 2 is a group consisting of hydrogen, halogen, hydroxy, trifluoromethyl, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin groups and (C 1 -C 3 ) alkoxy One or more substituents independently selected from.
    [47] In another preferred embodiment, R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, cyano, nitro, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group, (C 3 -C 6 ) one or more identical or different substituents independently selected from the group consisting of monocyclic hydrocarbon groups, (C 1 -C 6 ) alkoxy and (C 1 -C 6 ) alkoxycarbonyl.
    [48] In another preferred embodiment, R 4 is hydrogen, (C 1 -C 6 ) alkyl or (C 2 -C 6 ) olefin group.
    [49] In another preferred embodiment, R 5 is hydrogen and halogen, hydroxy, trifluoromethyl, amino, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin group, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) one or more substituents independently selected from the group consisting of alkoxycarbonyl and cyano.
    [50] In another preferred embodiment, X is O or N-OR c .
    [51] In another preferred embodiment, R 6 is (C 1 -C 6 ) alkyl-heterocyclyl, (C 1 -C 6 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon group, (C 1 -C 6 ) Alkyl, (C 2 -C 6 ) olefin group, (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 6 ) alkynyl, Y 1 R 21 , Y 2 R 22 or Y 4 R 24 , wherein (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group and (C 3 -C 6 ) cyclic hydrocarbon group are substituted with one or more identical or different substituents of R 7 , and C 1 -C 6 ) alkyl-heterocyclyl, (C 1 -C 6 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon groups, heterocyclyl and (C 2 -C 6 ) alkynyl is selected from R 7 Optionally substituted with one or more identical or different substituents),
    [52] R 7 is R 12 , YH or YR 14 , wherein the R 12 and YR 14 groups are optionally substituted with one or more identical or different substituents of R 8 ,
    [53] R 8 is R 12 , YH, YR 14 or R 14 , wherein the R 12 , YR 14 and R 14 groups are optionally substituted with one or more identical or different substituents of R 9 ,
    [54] R 9 is R 12 , YH, YR 14 or R 14 , wherein the R 12 , YR 14 and R 14 groups are optionally substituted with one or more identical or different substituents of R 10 ,
    [55] R 10 is R 12 or R 14 , wherein the R 12 , YR 14 and R 14 groups are optionally substituted with one or more identical or different substituents of R 11 ,
    [56] R 12 is halogen, hydroxy, mercapto, trifluoromethyl, amino, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) alkylthio, (C 1 -C 6 ) alkylamino, (C 1 -C 3 ) alkoxycarbonyl, (C 1 -C 6 ) trialkylammonium associated with anion, (C 2 -C 6 ) dialkylphosphinoyl, (C 1 -C 3 ) alkyl (hydroxy) phosphinoyl , (C 2 -C 6 ) dialkylphosphinoyloxy, (C 1 -C 3 ) alkyl (hydroxy) phosphinoyloxy, dihydroxyphosphinoyl, dihydroxyphosphinoyloxy, cyano, Azido, nitro, -CHO, -COOH, -CONH 2 , -CONHR 'or -CONRR', where R and R 'are (C 1 -C 3 ) alkyl,
    [57] Y is -O-, -S-, -S (O) -, -S (0) 2 -, -NR a -, -NR a C (Z) NR b -, -NR a C (Z) -, -C (Z) NR a -, -C (O) -, -C (Z) O-, -OC (Z) -, -NR a C (Z) O-, -OC (Z) NR a -, -S (0) 2 O-, -OS (0) 2 -, -S (0) 2 NR a -, -NR a S (O) 2 -, -OC (Z) Z-, -OP (O) (OR a ) 0-, -P (O) (OR a ) 0-, -C (NOR a )-, -N (OR a )-, -ON (R a )-, -N (R a ) O -, -N (R a ) C (= NR b ) NR c- , -C (= NR a ) NR b -or -N (R a ) C (= NR b )-,
    [58] Z is oxygen,
    [59] R 14 is (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group, (C 3 -C 9 ) cyclic hydrocarbon group, heterocyclyl or (C 2 -C 6 ) alkynyl,
    [60] Y 1 is -NR a C (S) NR b -, -C (O) -, -OC (O) -, -NR a C (S) O-, -OC (Z) NR a -, -S ( 0) 2 NR a -, -NR a S (O) 2 -, -OC (Z) O-, -C (NR a) -, -C (NOR a) -, -N (OR a) -, - ON (R a )-, -N (R a ) O-, -N (R a ) C (= NR b ) NR c- , -C (= NR a ) NR b -or -N (R a ) C (= NR b )-,
    [61] R 21 is a (C 1 -C 6 ) alkyl-heterocyclyl, (C 1 -C 6 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon group, optionally substituted with one or more identical or different substituents of R 7 , (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group, (C 3 -C 9 ) cyclic hydrocarbon group, heterocyclyl or (C 2 -C 6 ) alkynyl,
    [62] Y 2 is -0-, -S-, -C (0) O- or -C (O) NR a -, and
    [63] R 22 is (C 1 -C 6 ) alkyl-heterocyclyl, (C 1 -C 6 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 6 ) alkynyl , (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group or (C 3 -C 9 ) monocyclic hydrocarbon group, wherein (C 1 -C 6 ) alkyl is one or more of the same as R 7 Or substituted with a different substituent, and (C 1 -C 6 ) alkyl-heterocyclyl, (C 1 -C 6 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 6 ) alkynyl, (C 2 -C 6 ) olefin groups and (C 3 -C 9 ) monocyclic hydrocarbon groups are optionally substituted with one or more identical or different substituents of R 7 ),
    [64] Y 4 is -NR a C (O) NR b CH (R c) -, -NR a C (O) NR b S (O) 2 -, -NR a -, NR a C (Z) -, -NR a C (O) OCH (R c )-, -NR a C (O) NR b C (R d ) (R e ) -OC (O)-or -NR a C (O) OC (R d ) ( R e ) -OC (0)-,
    [65] R 24 is (C 1 -C 6 ) alkyl-heterocyclyl, (C 1 -C 6 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 6 ) alkynyl , (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group or (C 3 -C 9 ) cyclic hydrocarbon group, wherein (C 1 -C 6 ) alkyl, (C 2 -C 6 ) The olefin group and the (C 3 -C 9 ) cyclic hydrocarbon group are substituted with one or more identical or different substituents of R 15 , and are (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin groups, (C 3 -C 9 ) cyclic hydrocarbon group, (C 1 -C 6 ) alkyl-heterocyclyl, (C 1 -C 6 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon group, heterocyclyl and (C 2 -C 6 ) alkynyl is optionally substituted with one or more identical or different substituents of R 7 ),
    [66] R 15 is R 12a , R 12b or R 12C , wherein R 12a , R 12b or R 12C is optionally substituted with one or more identical or different substituents of R 7 ,
    [67] R 12a is (C 1 -C 3) substituted with one or more identical or different substituents of R 42 alkoxy, (C 1 -C 3) alkylthio, (C 1 -C 6) alkylamino, (C 1 -C 3 ) Alkoxycarbonyl, -CONHR 'or -CONRR' where R and R 'are (C 1 -C 3 ) alkyl, provided that when further substituted with R 42 , R 12a or R 15 is- ( QO) n -Q or -CH 2 (QO) n -Q (where Q is (C 1 -C 3 ) alkyl and n is an integer of at least 1) so that the group is a continuous linear sequence of atoms having at least 16 elements Including,
    [68] R 12b is (C 4 -C 6 ) alkoxy, (C 4 -C 6 ) alkylthio, (C 7 -C 12 ) alkylamino, (C 4 -C) optionally substituted with one or more identical or different substituents of R 7 8 ) alkoxycarbonyl, -CONHR 'or -CONRR', wherein R and R 'are (C 4 -C 8 ) alkyl,
    [69] R 12c is —Y 5 (C 1 -C 10 ) alkyl, -Y-aryl, -Y-heterocyclyl, -Y- (C 3 -C 9 ) optionally substituted with one or more identical or different substituents of R 7 Cyclic hydrocarbon group and -Y- (C 2 -C 6 ) olefin group,
    [70] Y 5 is -S (O)-, -S (O) 2- , -NR a C (Z)-, -NR a C (Z) NR b- , -C (O)-, -OC (Z) -, -NR a C (Z) O-, -OC (Z) NR a -, -S (O) 2 NR a -, -NR a S (O) 2 -, -OC (Z) O-, - OP (O) (OR a ) 0-, -P (O) (OR a ) O-, -C (NR a )-, -C (NOR a )-, -N (OR a )-, -ON ( R a )-, -N (R a ) O-, -N (R a ) C (= NR b ) NR c- , -C (= NR a ) NR b -or -N (R a ) C (= NR b )-,
    [71] R 42 is -YH, -YR 14 , R 52 , halogen, trifluoromethyl, cyano, azido or nitro, wherein R 52 and -YR 14 are optionally substituted with one or more identical or different substituents of R 8 )ego,
    [72] R 52 represents a (C 6 -C 8 ) alkyl, (C 2 -C 4 ) olefin group, (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 4 ) alkynyl or heteroaryl ego,
    [73] R a , R b and R c are independently hydrogen, (C 1 -C 4 ) alkyl, (C 2 -C 4 ) olefin groups, (C 3 -C) optionally substituted with one or more identical or different substituents of R 12 9 ) a cyclic hydrocarbon group, aryl, heterocyclyl or (C 2 -C 4 ) alkynyl,
    [74] R d and R e are independently between hydrogen, (C 1 -C 4 ) alkyl, (C 2 -C 4 ) olefin group and (C 3 -C 9 ) optionally substituted with one or more identical or different substituents of R 12 Click hydrocarbon group.
    [75] In another preferred embodiment, R 1 is halogen, hydroxy, trifluoromethyl, amino, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin group, (C 1 -C 3 ) alkoxy and cya Selected from the group of furnaces,
    [76] R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, trifluoromethyl, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin groups and (C 1 -C 3 ) alkoxy One or more substituents,
    [77] R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, cyano, nitro, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group, (C 3 -C 6 ) monocyclic hydrocarbon One or more substituents independently selected from the group consisting of a group, (C 1 -C 6 ) alkoxy and (C 1 -C 6 ) alkoxycarbonyl,
    [78] R 4 is hydrogen, (C 1 -C 6 ) alkyl or (C 2 -C 6 ) olefin group,
    [79] R 5 is hydrogen, halogen, hydroxy, trifluoromethyl, amino, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin group, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) one or more substituents independently selected from the group consisting of alkoxycarbonyl and cyano.
    [80] In a more preferred embodiment, R 1 is a substituent selected from the group consisting of halogen, cyano, methyl and methoxy.
    [81] In a more preferred embodiment, R 2 is one or more substituents independently selected from the group consisting of hydrogen, halogen, cyano, methyl and methoxy.
    [82] In a more preferred embodiment, R 3 is one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, methyl, methoxy and cyano.
    [83] In a more preferred embodiment, R 4 is hydrogen, methyl or ethyl.
    [84] In a more preferred embodiment, R 5 is one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, trifluoromethyl, methyl, ethyl and methoxy.
    [85] In a more preferred embodiment, X is O.
    [86] In a more preferred embodiment, R 6 is (C 1 -C 4 ) alkyl-heterocyclyl, (C 1 -C 4 ) alkyl- (C 3 -C 6 ) cyclic hydrocarbon group, (C 1 -C 6 ) alkyl , (C 2 -C 4 ) olefin group, heterocyclyl, (C 2 -C 4 ) alkynyl, Y 1 R 21 , Y 2 R 22 or Y 4 R 24 , wherein (C 1 -C 6 ) alkyl And (C 2 -C 4 ) olefin groups are substituted with one or more identical or different substituents of R 7 , and (C 1 -C 4 ) alkyl-heterocyclyl, (C 1 -C 4 ) alkyl- (C 3- C 6 ) cyclic hydrocarbon group, heterocyclyl and (C 2 -C 4 ) alkynyl are optionally substituted with one or more identical or different substituents of R 7 ),
    [87] R 7 is R 12 , YH or YR 14 , wherein the R 12 and YR 14 groups are optionally further substituted with one or more identical or different substituents of R 8 ,
    [88] R 8 is R 12 , YH, YR 14 or R 14 , wherein the R 12 , YR 14 and R 14 groups are optionally further substituted with one or more identical or different substituents of R 9 ,
    [89] R 9 is R 12 , YH, YR 14 or R 14 , wherein the R 12 , YR 14 and R 14 groups are optionally substituted with one or more identical or different substituents of R 10 ,
    [90] R 12 is halogen, hydroxy, trifluoromethyl, amino, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) alkylthio, (C 1 -C 6 ) alkylamino, (C 1 -C 3 ) Alkoxycarbonyl, (C 1 -C 6 ) trialkylammonium associated with anion, (C 2 -C 6 ) dialkylphosphinoyl, (C 2 -C 6 ) dialkylphosphinoyloxy, dihydroxyforce Pinoyl, dihydroxyphosphinoyloxy, cyano, -COOH, -CONH 2 , -CONHR 'or -CONRR', where R and R 'are (C 1 -C 3 ) alkyl,
    [91] Y is -O-, -S-, -S (O) -, -S (0) 2 -, -NR a -, -NR a C (Z) NR b -, -NR a C (Z) -, -C (Z) NR a -, - C (O) -, -C (Z) O-, -OC (Z) -, -NR a C (Z) O-, -OC (Z) NR a -, -S (0) 2 O-, -OS (0) 2 -, -S (0) 2 NR a -, -NR a S (O) 2 -, -OC (Z) Z-, -N (R a ) C (= NR b ) NR c- , -C (= NR a ) NR b -or -N (R a ) C (= NR b )-,
    [92] Z is oxygen,
    [93] R 14 is (C 1 -C 4 ) alkyl, (C 2 -C 4 ) olefin group, (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl or (C 2 -C 3 ) alkynyl,
    [94] Y 1 is -NR a C (S) NR b -, -C (O) -, -OC (O) -, -NR a C (S) O-, -OC (Z) NR a -, -S ( or a -OC (Z) O-, - 0 ) 2 NR a -, -NR a S (O) 2
    [95] R 21 is a (C 1 -C 4 ) alkyl-heterocyclyl, (C 1 -C 4 ) alkyl- (C 3 -C 6 ) cyclic hydrocarbon group, optionally substituted with one or more identical or different substituents of R 7 , (C 1 -C 6 ) alkyl, (C 2 -C 4 ) olefin group, (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl or (C 2 -C 6 ) alkynyl,
    [96] Y 2 is -0-, -S-, -C (0) O- or -C (O) NR a -, and
    [97] R 22 is (C 1 -C 4 ) alkyl-heterocyclyl, (C 1 -C 4 ) alkyl- (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 4 ) alkynyl , (C 1 -C 6 ) alkyl, (C 2 -C 4 ) olefin group or (C 3 -C 6 ) monocyclic hydrocarbon group, wherein (C 1 -C 6 ) alkyl is one or more of the same as R 7 Or substituted with a different substituent, and (C 1 -C 4 ) alkyl-heterocyclyl, (C 1 -C 4 ) alkyl- (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 4 ) alkynyl, (C 2 -C 4 ) olefin groups and (C 3 -C 6 ) monocyclic hydrocarbon groups are optionally substituted with one or more identical or different substituents of R 7 ),
    [98] Y 4 is -NR a C (O) NR b CH (R c) -, -NR a C (O) NR b S (O) 2 -, -NR a -, NR a C (Z) -, -NR a C (O) OCH (R c )-, -NR a C (O) NR b C (R d ) (R e ) -OC (O)-or -NR a C (O) OC (R d ) ( R e ) -OC (0)-,
    [99] R 24 is (C 1 -C 4 ) alkyl-heterocyclyl, (C 1 -C 4 ) alkyl- (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 4 ) alkynyl , (C 1 -C 6 ) alkyl, (C 2 -C 4 ) olefin group or (C 3 -C 9 ) cyclic hydrocarbon group, wherein (C 1 -C 6 ) alkyl, (C 2 -C 4 ) The olefin group and the (C 3 -C 9 ) cyclic hydrocarbon group are substituted with one or more identical or different substituents of R 15 , (C 1 -C 6 ) alkyl, (C 2 -C 4 ) olefin group, (C 3 -C 9 ) cyclic hydrocarbon group, (C 1 -C 4 ) alkyl-heterocyclyl, (C 1 -C 4 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon group, heterocyclyl and (C 2 -C 4 ) alkynyl is optionally substituted with one or more identical or different substituents of R 7 ),
    [100] R 15 is R 12a , R 12b or R 12C , wherein R 12a , R 12b or R 12C is optionally substituted with one or more identical or different substituents of R 7 ,
    [101] R 12a is (C 1 -C 3) substituted with one or more identical or different substituents of R 42 alkoxy, (C 1 -C 3) alkylthio, (C 1 -C 6) alkylamino, (C 1 -C 3 ) Alkoxycarbonyl, -CONHR 'or -CONRR' where R and R 'are (C 1 -C 3 ) alkyl, provided that when further substituted with R 42 , R 12a or R 15 is- ( QO) n -Q or -CH 2 (QO) n -Q (where Q is (C 1 -C 3 ) alkyl and n is an integer of at least 1) so that the group is a continuous linear sequence of atoms having at least 16 elements Including,
    [102] R 12b is (C 4 -C 6 ) alkoxy, (C 4 -C 6 ) alkylthio, (C 7 -C 12 ) alkylamino, (C 4 -C) optionally substituted with one or more identical or different substituents of R 7 8 ) alkoxycarbonyl, -CONHR 'or -CONRR', wherein R and R 'are (C 4 -C 8 ) alkyl,
    [103] R 12c is —Y 5 (C 1 -C 6 ) alkyl, -Y-aryl, -Y-heterocyclyl, -Y- (C 3 -C 9 ) optionally substituted with one or more identical or different substituents of R 7 Cyclic hydrocarbon group and -Y- (C 2 -C 6 ) olefin group,
    [104] Y 5 is -S (O)-, -S (O) 2- , -NR a C (Z)-, -NR a C (Z) NR b- , -C (O)-, -OC (Z) -, -NR a C (Z) O-, -OC (Z) NR a - or a -OC (Z) O-, -, -S (O) 2 NR a -, -NR a S (O) 2
    [105] R 42 is -YH, YR 14 , R 52 , halogen, trifluoromethyl, cyano, azido or nitro, wherein R 52 and -YR 14 are optionally substituted with one or more identical or different substituents of R 8 ego,
    [106] R 52 represents a (C 6 -C 8 ) alkyl, (C 2 -C 4 ) olefin group, (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 4 ) alkynyl or heteroaryl ego,
    [107] R a , R b and R c are independently hydrogen, (C 1 -C 2 ) alkyl, (C 2 -C 3 ) olefin groups or (C 2 -C) optionally substituted with one or more identical or different substituents of R 12 3 ) alkynyl,
    [108] R d and R e are hydrogen or (C 1 -C 2 ) alkyl.
    [109] In a more preferred embodiment, R 1 is a substituent selected from the group consisting of halogen, cyano, methyl and methoxy,
    [110] R 2 is one or more substituents independently selected from the group consisting of hydrogen, halogen, cyano, methyl and methoxy,
    [111] R 3 is one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, methyl, methoxy and cyano,
    [112] R 4 is hydrogen, methyl or ethyl,
    [113] R 5 is one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, trifluoromethyl, methyl, ethyl and methoxy,
    [114] X is O.
    [115] In a particularly preferred embodiment, X is O, R 1 is methyl, R 2 is 2-Cl, R 3 is hydrogen or 4-Br and R 4 and R 5 are hydrogen.
    [116] Bioavailability of a drug is generally inversely proportional to the molecular weight of the drug. In other words, any biologically active structure has an upper limit of molecular weight size at which activity is stopped due to a number of factors, such as insufficient solubility, transmembrane inability, steric hindrance of drug-receptor interactions, and the like. Thus, in a more preferred embodiment, the present invention relates to compounds of formula (I), having a molecular weight of at most 1500 Da or about 1500 Da, more preferably at most 1200 Da or about 1200 Da, even more preferably at most 800 Da or about 800 Da.
    [117] In a more preferred embodiment, the compound of formula (I)
    [118] [2-chloro-4-({2- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    [119] (2-chloro-4-{[Z- (2-hydroxyethyl) phenyl] amino} phenyl) (Z-methylphenyl) methanone;
    [120] 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl acetate;
    [121] 4- (2- {2-[(3-chloro-4- (2-methylbenzoyl) phenyl) amino] phenyl} ethoxy) -4-oxobutanoic acid;
    [122] 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl hexanoate;
    [123] 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -1-methylethyl acetate;
    [124] (2-chloro-4-{[2- (2-hydroxypropyl) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    [125] [2-chloro-4-({2-[(1E) -3-hydroxyprop-1-enyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    [126] (2-chloro-4-{[2- (3-hydroxypropyl) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    [127] [2-chloro-4-({2-[(1E) -4-hydroxybut-1-enyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    [128] [4-({2-[(1E) -3-aminoprop-1-enyl] phenyl} amino) -2-chlorophenyl] (2-methylphenyl) methanone;
    [129] Diethyl (2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enylphosphonate;
    [130] [2-chloro-4-({2-[(1E) -3-hydroxy-3-methylbut-1-enyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    [131] Ethyl (2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) acrylate;
    [132] (2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) acrylic acid;
    [133] {2-chloro-4-[(2-{(1E) -3-[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] prop-1-enyl} phenyl) amino ] Phenyl} (2-methylphenyl) methanone;
    [134] [2-chloro-4-({2-[(1E) -3- (2,3-dihydroxypropoxy) prop-1-enyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    [135] Tert-butyl (1R) -3-{[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] amino} -1- (hydroxymethyl) -2-oxoethylylcarbamate;
    [136] Methyl O- (tert-butyl) -N-({[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl ] Aminocarbonyl) -L-serinate;
    [137] N- (tert-butyl) -N '-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] thio Urea;
    [138] N-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-Z-enyl] -4-oxopentanamide;
    [139] N-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -N'-ethylurea;
    [140] Ethyl 4-{[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] amino} -4-oxobutanoate ;
    [141] N-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -N'-cyclohexylurea;
    [142] N '-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -N, N-dimethylsuccinamide;
    [143] Dimethyl [(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] malonate;
    [144] [2-chloro-4-({2-[(1E) -3-morpholin-4-ylprop-1-enyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    [145] 6-O-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -1,2: 3,4- Di-0- (1-methylethylidene) -α-D-galactopyranose;
    [146] Methyl 5-0-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -2,3-O- ( 1-methylethylidene) -β-D-ribofuranoside;
    [147] Methyl 5-O-[(2E) -3- (2- [3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -β-D-riboplanoside ;
    [148] Methyl (4E) -5- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -2- (methylsulfonyl) pent-4-enoate;
    [149] Ethyl {[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] thio} acetate;
    [150] [2-chloro-4-{[2-((1E) -3- {bis [2- (acetyloxy) ethyl] amino} prop-1-enyl) phenyl] amino} phenyl] (2-methylphenyl) methane On;
    [151] [2-chloro-4-{[2-((1E) -3- {bs [2- (hydroxy) ethyl] amino} prop-1-enyl) phenyl] amino} phenyl] (2-methylphenyl) methane On;
    [152] (2-chloro-4-{[2-((1E) -3- {4- [2- (acetyloxy) ethyl] piperidin-1-yl} prop-1-enyl) phenyl] amino} phenyl ) (2-methylphenyl) methanone;
    [153] {2-chloro-4-[(2-{(1E) -3- [4- (2-hydroxyethyl) piperidin-1-yl] prop-1-enyl} phenyl) amino] phenyl} ( 2-methylphenyl) methanone;
    [154] {2-chloro-4-[(2- {2-[(tetrahydrofuran-2-ylmethyl) amino] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    [155] [2-chloro-4-({2- [2- (4-methylpiperazin-1-yl) ethyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    [156] {2-chloro-4-[(2- {2-[(3-morpholin-4-ylpropyl) amino] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    [157] (2-chloro-4-{[2- (2-{[2- (dimethylamino) ethyl] amino} ethyl) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    [158] {2-chloro-4-[(2- {2-[(2-methoxyethyl) amino] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    [159] 1- [3-({2- [2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethyl} amino) propyl] pyrrolidin-2-one;
    [160] {2-chloro-4-[(2- {2- [methyl (tetrahydrofuran-2-ylmethyl) amino] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    [161] (2-chloro-4-{[2- (2-{[(2,2-dimethyl-1,3-dioxolan-4-yl) methyl] amino} ethyl) phenyl] amino} phenyl) (2-methylphenyl Methanone;
    [162] {2-chloro-4-[(2- {2- [4- (2-methoxyethyl) piperazin-1-yl] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    [163] (2-chloro-4-{[2- (2-morpholin-4-ylethyl) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    [164] {2-chloro-4-[(2- {2-[(2,3-dihydroxypropyl) amino] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    [165] (4-{[2- (aminomethyl) phenyl] amino} -2-chlorophenyl) (2-methylphenyl) methanone;
    [166] (2-chloro-4-{[2-({2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethoxy} methyl) phenyl] amino} phenyl) (2-methylphenyl) Methanone;
    [167] {2-chloro-4-[(2-{[(tetrahydro-2H-pyran-2-yloxy) ethoxy] methyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    [168] [2-chloro-4-({2-[(2- {2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethoxy} ethoxy) methyl] phenyl} amino) phenyl ] (2-methylphenyl) methanone;
    [169] [2-chloro-4-({2-[(3,3,3-trifluoropropoxy) methyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    [170] Diethyl 2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzylphosphonate;
    [171] 2- [2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] -1H-isoindole-1,3 (2H) -dione;
    [172] {2-chloro-4-[(2-{[2- (2-hydroxyethoxy) ethoxy] methyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    [173] [2-chloro-4-({2-[(hydroxyethoxy) methyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    [174] (2-chloro-4-{[2-({2- [2- (2-hydroxyethoxy) ethoxy] ethoxy} methyl) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    [175] [4-({4-bromo-2-[(2-hydroxyethoxy) methyl] phenyl} amino) -2-chlorophenyl] (2-methylphenyl) methanone;
    [176] (4-{[4-bromo-2-({2- [2- (2-hydroxyethoxy) ethoxy] ethoxy} methyl) phenyl] amino} -2-chlorophenyl) (2-methylphenyl) Methanone;
    [177] {4-[(4-bromo-2-{[2- (2-hydroxyethoxy) ethoxy] methyl} phenyl) amino] -2-chlorophenyl} (2-methylphenyl) methanone;
    [178] Diethyl 5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzylphosphonate;
    [179] [4-({4-bromo-2-[(3,3,3-trifluoropropoxy) methyl] phenyl} amino) -2-chlorophenyl] (2-methylphenyl) methanone;
    [180] 2-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl 4-methylbenzenesulfonate;
    [181] 2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl 4-methylbenzenesulfonate;
    [182] 2- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethoxy) ethyl 4-methylbenzenesulfonate;
    [183] 2- [2- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethoxy) ethoxy] ethyl 4 Methylbenzenesulfonate;
    [184] [4-({4-bromo-2-[(2-iodoethoxy) methyl] phenyl] phenyl} amino) -2-chlorophenyl] (2-methylphenyl) methanone;
    [185] {4-[(4-bromo-2-{[2- (2-iodoethoxy) ethoxy] methyl} phenyl) amino] -2-chlorophenyl} (2-methylphenyl) methanone;
    [186] (4-{[4-bromo-2-({2- [2- (2-iodoethoxy) ethoxy] ethoxy} methyl) phenyl] amino} -2-chlorophenyl) (2-methylphenyl) Methanone;
    [187] [2-chloro-4-({2-[(2-iodoethoxy) methyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    [188] Diethyl 2-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethylphosphonate;
    [189] Diethyl 2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl phosphonate;
    [190] Diethyl 2-({[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethoxy) ethylphosphonate;
    [191] Diethyl 2- [2- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethoxy) ethoxy] Ethylphosphonate;
    [192] Diethyl 2-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] amino} -2-oxoethylphosphonate;
    [193] Diethyl 2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] amino} -2-oxoethylphosphonate;
    [194] {[2-({5-bromo-3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl (diethoxyphosphoryl) acetate;
    [195] 2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzylphosphonic acid;
    [196] N- [2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] -2,2,2-trifluoroethanesulfonamide;
    [197] N- [5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] -2,2,2-trifluoroethanesulfonamide;
    [198] {2-chloro-4-[(2-{[(tetrahydro-2H-pyran-2-yloxy) propoxy] methyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    [199] [2-chloro-4-({2-[(hydroxypropoxy) methyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    [200] Diethyl 3-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} propylphosphonate;
    [201] Diethyl 2- [2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethylphosphonate;
    [202] Diethyl 2- [5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethylphosphonate;
    [203] 2-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] amino} -2-oxoethylphosphonic acid;
    [204] (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -carbamic acid phenethyl ester;
    [205] N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -2-phenoxy-acetamide;
    [206] N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -3-phenoxy-propionamide;
    [207] N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) Acetamide;
    [208] N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -succinic acid 2- (2-methoxy-ethoxy) ethyl ester;
    [209] N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -benzenesulfonamide;
    [210] Acetic acid (2-{[2-chloro-4- (2-methylbenzoyl) phenyl] amino} phenylcarbamoyl) -methyl ester;
    [211] 1- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) pyrrolidine-2,5-dione;
    [212] 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl propionate;
    [213] 2,2-dimethyl-propionic acid 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl ester;
    [214] [2-chloro-4-({2- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    [215] (2-chloro-4-{[2- (3-hydroxypropoxy) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    [216] Tert-butyl 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl carbonate;
    [217] 2-({[(5-bromo-2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) amino] carbonyl} amino) ethyl 2-methylacrylate;
    [218] (4-{[4-bromo-2- (2-hydroxyethyl) phenyl] amino} -2-chloro-phenyl) (2-methylphenyl) methanone;
    [219] 3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenoxy) propyl acetate;
    [220] [2-chloro-4-({2- [3- (morpholin-4-yl) propoxy] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    [221] N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -N '-(4-phenoxybutyl) succinamide;
    [222] N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -N '-(6-hydroxyhexyl) succinamide;
    [223] N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -N '-(2,3-dihydroxypropyl) succinamide;
    [224] Tert-butyl (1R) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -1- (hydroxymethyl) propylcarbamate;
    [225] Diethyl 6- [3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenylcarbamoyl) propionylamino] -hexyl phosphate;
    [226] Ethyl N-({[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] amino} carbonyl) glycinate ;
    [227] Tert-butyl 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl (methyl) carbamate;
    [228] N- (5-bromo-2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -N '-(6-hydroxyhexyl) succinamide;
    [229] N- (5-bromo-2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -N '-(2,3-dihydroxypropyl) succinamide;
    [230] (2Z) -N-[(2E) -3- (2- [3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -2- (2,5- Dioxoimidazolidine-4-ylidene) acetamide;
    [231] (2-chloro-4-{[2- (difluoromethyl) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    [232] 3-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethyl} -1-methylimidazolidine-2,4-dione;
    [233] 3-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethyl} -5,5-dimethyloxazoline-2,4-dione;
    [234] 4-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethyl} morpholine-3,5-dione;
    [235] 1-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethyl} piperidine-2,6-dione;
    [236] 4- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) morpholine-3,5-dione;
    [237] 1- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) pyrrolidine-2,5-dione ;
    [238] Ethyl 2- [3- (2- {5-bromo- [2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyloxy} ethyl) -2,4,5 -Trioximidazolidin-1-yl] acetate;
    [239] 3- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) imidazolidine-2,4- Diones;
    [240] 1- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) -3,4-cis-diacetoc Cypyrrolidin-2,5-dione;
    [241] 3- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) thiazoline-2,4-dione;
    [242] 3- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) -1-methylimidazolidine- 2,4-dione;
    [243] 1- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) imidazolidine-2,4, 5-trione;
    [244] (2-chloro-4-{[(2-hydroxymethyl) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    [245] 2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} benzyl acetate and pharmaceutically acceptable salts and solvates thereof, for example hydrates.
    [246] Compounds of formula (I) include asymmetric carbon atoms that allow for double bonds, ring systems, and isoforms. It will be understood that the present invention includes all isomeric forms of the compounds of formula (I) as pure forms or mixtures thereof.
    [247] The term "pharmaceutically acceptable salts" refers to compounds of formula I suitable for inorganic or organic acids, such as hydrochloric acid, bromic acid, iodic acid, sulfuric acid, nitric acid, acetic acid, phosphoric acid, lactic acid, maleic acid, phthalic acid, citric acid, propionic acid, Salts prepared by reacting with benzoic acid, glutaric acid, gluconic acid, methanesulfonic acid, salicylic acid, succinic acid, tartaric acid, toluenesulfonic acid, sulfamic acid or fumaric acid. Pharmaceutically acceptable salts of compounds of formula I may also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, ammonia and the like.
    [248] The term “solvate” means a solid phase formed by the interaction of a compound, such as a compound of formula (I), with a solvent such as alcohol, glycerol and water. When water is a solvent, this kind is called hydrate.
    [249] The term "continuous linear sequence of atoms" means a group of atoms excluding hydrogen atoms. Thus, diethyl ether and di-1-propyl ketone are continuous linear sequences of atoms having 5 and 7 atoms, respectively.
    [250] The term "halogen" means a group 7 element of the periodic table, for example fluorine, chlorine, bromine and iodine.
    [251] The term "alkyl" means a monovalent group derived from straight or branched alkane by removing a hydrogen atom from any carbon atom, for example (C 1 -C 3 ) alkyl, (C 1 -C 10 ) alkyl, methyl Subclasses of primary, secondary and tertiary alkyl groups including ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, t-butyl, pentyl, hexyl, heptyl, decanyl and the like It includes.
    [252] The term "olefin group" means a straight or branched chain bicyclic hydrocarbon having one or more carbon-carbon double bonds of appropriate E or Z stereochemistry. This term refers to, for example, (C 2 -C 10 ) olefin groups, (C 2 -C 3 ) olefin groups, vinyl, allyl, 1-butenyl, 2-butenyl and 2-methyl-2-propenyl, 2,4-pentenedienyl and the like.
    [253] The term "alkoxy" refers to a radical of the formula -OR wherein R is alkyl as described above, for example (C 1 -C 10 ) alkoxy, (C 1 -C 3 ) alkoxy, methoxy, ethoxy, n- Propoxy, t-butoxy and the like).
    [254] The term "alkylthio" refers to a radical of the formula -SR wherein R is alkyl as described above, for example (C 1 -C 10 ) alkylthio, (C 1 -C 3 ) alkylthio, methylthio, ethylthio , n-propylthio, 2-propylthio, and the like).
    [255] The term "alkylamino" is a radical of the formula -NHR or -NR 2 , wherein R is alkyl as described above, for example methylamino, dimethylamino, di- (n-propyl) amino, n-butyl (ethyl ) Amino and the like).
    [256] The term "alkoxycarbonyl" refers to a radical of the formula -COOR wherein R is alkyl as described above, for example methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl And the like).
    [257] The term "cyclic hydrocarbon group" refers to any saturated and unsaturated fused bicyclic hydrocarbon ring, such as (C 3 -C 12 ) cycloalkyl (eg cyclopropyl, cyclopentyl, cyclohexyl and cyclooctyl), ( C 3 -C 12 ) cycloalkene groups (eg cycloprop-2-enyl, cyclobut-2-ethyl, cyclopent-2-enyl, cyclohex-3-enyl, cycloocta-4-enyl, cyclohex -3,5-dienyl, indanyl, indenyl, 1,4-dihydronaphthyl, phenyl and naphthyl). The term “cyclohydrocarbon group” also refers to the aforementioned compounds, eg oxocyclohexyl, in which one or more ring —CH 2 fragments are replaced by —C (O) — fragments and / or exo-cyclic carbon-carbon double bonds; Oxocyclopentyl, 4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl, 1-oxo-1,2,3,4-tetrahydronaphthalen-1-yl, 2-oxocyclohex- 3-en-1-yl and 2-oxocyclohex-1-en-1-yl and , , It includes.
    [258] The term "alkynyl" refers to a monovalent group derived from a straight or branched chain alkyne from which hydrogen has been removed from any carbon atom and includes subclasses of each of the primary, secondary and tertiary alkyl groups having carbon numbers specified, e.g. ( C 1 -C 10 ) alkynyl, ethynyl, propynyl, 1,1-dimethyl-3-butynyl and the like.
    [259] The term "heterocyclyl" means any saturated or unsaturated fused carbocyclic ring comprising one or more heteroatoms selected from the group consisting of O, N and S, for example pyrrole, furanyl, thiophenyl , Imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, putinyl, quinolinyl , Isoquinolinyl, 1,2-dihydroquinolinyl and the like. The term "heterocyclyl" also refers to the above-mentioned compounds, for example dioxopiperidi, in which one or more ring -CH 2 fragments are replaced by -C (O)-fragments and / or exo-cyclic carbon-carbon double bonds. Nil, 1-oxo-3,4-dihydroisoquinolin-2 (1H) -yl and It includes.
    [260] The compounds of the present invention are useful in the medical and veterinary arts as systemic or topical therapies for the prevention, treatment and / or alleviation of the recurrence of disease associated with disease exacerbation, disease symptoms and / or anti-inflammatory or dysfunction of cytokine regulatory systems. These diseases or conditions include arthritis, including acne, asthma, allergies, rheumatoid arthritis, and spondyloarthritis, gout, atherosclerosis, chronic inflammatory bowel disease (Crohn's disease), proliferative and inflammatory dermatitis (eg psoriasis, atopic dermatitis, uveitis) , Sepsis shock, AIDS and osteoporosis).
    [261] In another embodiment, the present invention relates to pharmaceutical formulations of the compound of formula (I). For veterinary and medical use the formulations of the present invention contain the active ingredient associated with any pharmaceutically acceptable carrier and any other pharmaceutical ingredient. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient.
    [262] Conveniently, the formulation contains 0.1 to 100% by weight of active ingredient. Conveniently, the dosage unit of the formulation contains 0.07 mg to 1 g of the compound of formula (I).
    [263] The term “dose unit” means a single dose, ie, a single dose that can be administered to a patient, is easy to handle, and can be packaged. Diluents or mixtures of carriers and actives.
    [264] The formulation may be, for example, in a form suitable for oral (eg, sustained release or release at specific times), rectal, parenteral (eg, subcutaneous, abdominal, muscle, joint and vein), transdermal, ophthalmic, topical, nasal or oral administration. Included.
    [265] The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy, such as, for example, Remington, The Science and Practice of Pharmacy, 20 th ed., 2000). All methods include the step of bringing into association the active ingredient in a carrier consisting of one or more accessory ingredients. Generally, formulations are prepared by uniformly and directly associating the active ingredient in a liquid carrier or finely divided solid carrier, or both, and optionally molding the product into the desired formulation.
    [266] Formulations of the present invention suitable for oral administration may be presented in discrete unit forms, eg, capsules, circuits, tablets or lozenges containing a predetermined amount of active ingredient; Powder or granules; In the form of a solution or suspension in an aqueous or non-aqueous liquid (e. G. Or oil-in-water emulsion or water-in-oil emulsion type. The oils mentioned above are edible oils, for example cottonseed oil, sesame oil, coconut oil or peanut oil. Dispersants or suspending agents suitable for aqueous suspensions include synthetic or natural rubbers such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose , Carbomer and polyvinylpyrrolidone. The active ingredient may also be in the form of pills, softeners or pastes.
    [267] Tablets may be prepared by pressing or shaping the active ingredient with any one or more accessory ingredients. Compressed tablets may be, in suitable machines, binders (e.g., lactose, glucose, starch, gelatin, acacia rubber, tragacanth gum, sodium alginate, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, wax, etc.), Lubricants (e.g. sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc.), disintegrants (e.g. starch, methylcellulose, agar, bentonite, croscarmellose sodium, sodium starch glycolate, cross Or free flowing active ingredients such as powders or granules optionally mixed with povidone or the like or a dispersant such as polysorbate 80. Molded tablets can be prepared by molding on a suitable machine a mixture of a suitable carrier and a powdered active ingredient moistened with an inert liquid diluent.
    [268] Rectal formulations may be in the form of suppositories in which the compounds of the present invention are mixed with low melting water soluble or water insoluble solids such as coconut butter, hydrogenated vegetable oils, polyethylene glycols or fatty acid esters of polyethylene glycol, and elixirs may be used in combination with myristyl palmitate. Can be prepared.
    [269] Formulations conveniently suited for parenteral administration preferably contain water-soluble or sterile oily preparations of the active ingredient isotonic with the recipient's blood, such as isotonic saline, isotonic glucose solutions or buffers. The formulation can be conveniently sterilized, for example, by filtration through a filter to filter out bacteria, adding a sterilant to the formulation, and irradiating or heating the formulation. Liposomal formulations, for example as described in the following documents, are also suitable for parenteral administration (Encyclopedia of Pharmaceutical Technology, vol. 9, 1994).
    [270] In addition, the compounds of formula (I) may be present as sterile solid preparations, for example lyophilized powders, which are readily dissolved in sterile solvents immediately before use.
    [271] Transdermal formulations may be in the form of pasters or patches.
    [272] Formulations suitable for ophthalmic administration may be in sterile, water-soluble formulations of the active ingredient, which may be in microcrystalline form, for example in the form of a water soluble microcrystalline suspension. For example, liposome formulations or biodegradable polymer systems described in the following documents can be used to prepare active ingredient formulations for ophthalmic administration (Encyclopedia of Pharmaceutical Technology, vol. 2, 1989).
    [273] Formulations suitable for topical or ophthalmic administration include liquid or semi-liquid preparations, such as stains, lotions, gels, topical agents, oil-in-water or water-in-oil emulsions (such as creams, studies or pastes) or aqueous solutions or suspensions (such as Drop) is included.
    [274] Formulations suitable for nasal or oral administration include powders, self-propelled and nebulized formulations such as aerosols and atomisers.
    [275] Prodrugs of the invention can also be delivered using monoclonal antibodies as individual carriers to which compound molecules are coupled.
    [276] In addition to the aforementioned ingredients, the compound formulation of formula (I) may contain one or more additional ingredients such as diluents, buffers, flavoring agents, colorants, surfactants, thickeners, preservatives (e.g. methyl hydroxybenzoate with antioxidants), emulsifiers And the like.
    [277] In the systemic treatment using the present invention, a daily dose of 0.001 to 500 mg, preferably 0.002 to 100 mg / kg body weight, for example 0.003 to 20 mg / kg body weight, of the compound of formula I per kg body weight is administered, For adults, the daily dose typically corresponds to 0.01 to 37000 mg. In topical treatment of skin diseases, ointments, creams or lotions containing 0.1 to 750 mg / g, preferably 0.1 to 500 mg / g, for example 0.1 to 200 mg / g, of the compound of formula (I) are applied. In topical use of ophthalmic ointments, drops containing 0.1 to 750 mg / g, preferably 0.1 to 500 mg / g, for example 0.1 to 200 mg / g, of the compound of formula (I) are administered. Oral compositions are preferably formulated as tablets, capsules or drops containing 0.07 to 1000 mg, preferably 0.1 to 500 mg of the compound of formula I per dosage unit.
    [278] The present invention also includes incorporating other pharmaceutically active ingredients commonly used in the treatment of the above mentioned disease states in the formulations of the present invention. Other pharmaceutically active ingredients described above include, but are not limited to, glucocorticoids, vitamin D analogues, antihistamines, platelet activator (PAF) antagonists, anticolergenic agents, methyl xanthines, β-adrenergic agents, COX-2 inhibitors , Salicylate, indomethacin, flufenamate, naproxen, thimegadine, gold salt, penicillamine, serum cholesterol reducing agents, retinoids, zinc salts and salicylazosulpypyridine.
    [279] The present invention also found that certain sets of compounds are particularly suitable for the preparation of compounds of formula (I).
    [280] Thus, the present invention also
    [281] 2- (2-bromophenyl) -1-methylethyl acetate (compound 402);
    [282] (3E) -2-methyl-4- (tributylstannyl) but-3-en-2-ol (Compound 403);
    [283] Tributyl {(1E) -3-[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] prop-1-enyl} stanan (Compound 404);
    [284] Dimethyl [(2E) -3- (tributylstannyl) prop-1-enyl] malonate (Compound 405);
    [285] 4-[(2E) -3- (tributylstannyl) prop-2-enyl] morpholine (Compound 406);
    [286] 1,2: 3,4-di-O- (1-methylethylidene) -6-O-[(2E) -3- (tributylstannyl) prop-2-enyl] -α-D- Galactopyranose (Compound 407);
    [287] Methyl 2,3-O- (1-methylethylidene) -5-0-[(2E) -3- (tributylstannyl) prop-2-enyl] -β-D-ribofuranoside ( Compound 408);
    [288] Methyl (4E) -2- (methylsulfonyl) -5- (tributylstannyl) pent-4-enoate (Compound 409);
    [289] Ethyl [(2E) -3- (tributylstannyl) prop-2-enyl] thio} acetate (Compound 410);
    [290] Tributyl {{(1E) -3- [bis (2-hydroxyethyl) amino] prop-1-enyl} stanan (Compound 411);
    [291] Tributyl ((1E) -3- {bis [2- (acetyloxy) ethyl] aminoprop-1-enyl) stannan (Compound 412);
    [292] Tributyl {(1E) -3- [4- (2-hydroxyethyl) piperidin-1-yl] prop-1-enyl] stannan (Compound 413);
    [293] Tributyl ((1E) -3- {4- [2- (acetyloxy) ethyl] piperidin-1-yl} prop-1-enyl) stannan (Compound 414);
    [294] 2- (2-{(2-bromobenzyl) oxy} ethoxy) ethanol (Compound 415);
    [295] 2- (2- {2-[(2-bromobenzyl) oxy] ethoxy} ethoxy) ethanol (Compound 416);
    [296] 2-bromobenzyl 3,3,3-trifluoropropyl ether (Compound 419);
    [297] 2- (2- {2-[(2-bromobenzyl) oxy] ethoxy} ethoxy) tetrahydro-2H-pyran (Compound 420);
    [298] 2- [2- (2- {2-[(2-bromobenzyl) oxy] ethoxy} ethoxy) ethoxy] tetrahydro-2H-pyran (Compound 421);
    [299] 2- {2-[(2-bromobenzyl) oxy] ethoxy} tetrahydro-2H-pyran (Compound 422);
    [300] 2- {3-[(2-bromobenzyl) oxy] propoxy} tetrahydro-2H-pyran (Compound 425);
    [301] 3-[(2-bromobenzyl) oxy] propyl 4-methylbenzenesulfonate (Compound 426);
    [302] 1-bromo-2- (3-iodo-propoxymethyl) benzene (Compound 427);
    [303] Diethyl 3-[(2-bromobenzyl) oxy] propylphosphonate (Compound 428);
    [304] Diethyl 2- (2-bromophenyl) ethylphosphonate (Compound 431);
    [305] (2-chloro-4-iodophenyl) (2-methylphenyl) methanone (Compound 432);
    [306] Tert-butyl (4R) -4- [2- (2-aminophenyl) ethyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylate (Compound 433);
    [307] Tert-butyl (4R) -4- [2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl] -2,2-dimethyl-oxazolidine-3 Carboxylate (compound 434);
    [308] Tert-butyl [2- (2-bromophenyl) ethyl] (methyl) carbamate (Compound 435);
    [309] 3- [2- (2-bromophenyl) ethyl] -1-methylimidazolidine-2,4-dione (Compound 436);
    [310] 3- [2- (2-bromophenyl) ethyl] -5,5-dimethyloxazolidine-2,4-dione (Compound 437);
    [311] 4- [2- (2-bromophenyl) ethyl] morpholine-3,5-dione (Compound 438);
    [312] 1- [2- (2-bromophenyl) ethyl] piperidine-2,6-dione (Compound 439);
    [313] 2-bromobenzyl (triisopropyl) silyl ether (Compound 440) and
    [314] A compound selected from the group consisting of {2-chloro-4-[(2-{[(triisopropyl) siloxy] methyl} phenyl) amino] phenyl} (2-methylphenyl) methanone (Compound 441) is provided.
    [315] Manufacturing method
    [316] The compounds of the present invention can be prepared according to various methods well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using methods known in the field of synthetic organic chemistry or modifications thereof that would be appreciated by those skilled in the art. Preferred methods include, but are not limited to the following.
    [317] Compounds of formula (I) can be prepared using the reactions and techniques described in this section. The reaction is carried out in a solvent suitable for the reagents and materials used and suitable for the variant to be carried out. In addition, in the synthesis method described below, all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, duration of experiment, and post-treatment, are selected in accordance with standard reaction conditions that can be easily recognized by those skilled in the art. Those skilled in the art will appreciate that the functional groups present in the various parts of the vitreous molecules must be compatible with the reagents and reactants to be proposed. Not all of the compounds of formula I included in this class are compatible with some of the reaction conditions required by some of the methods described above. Those skilled in the art will readily appreciate the limitations on the substituents that are compatible with the reaction conditions, and other methods may be used.
    [318] The compounds according to the invention comprise a process comprising coupling an amine of formula (III) with a bromide, iodide, fluoride, chloride or triflate of formula (II) as shown in Scheme 1, or as shown in Scheme 1 An amine of IIa can be prepared by a process comprising coupling with an iodide of formula IIIa.
    [319]
    [320] In the above formula,
    [321] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and X, except that any substituents or potential reactive functional groups in the coupling reaction are protected before carrying out the coupling reaction and then subsequently removed Is as described above.
    [322] The coupling reaction is carried out using any diphenylamine formation method known to those skilled in the art of organic synthesis. Preferred methods are palladium catalyzed amination processes comprising coupling an amine with an arylhalogenide (or aryltriplate) in an inert solvent in the presence of a base, a suitable Pd source and a suitable phosphine ligand. Various palladium compounds can be used in the process, examples of which include palladium (II) acetate, palladium (II) chloride, palladium (II) bromide, dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenyl) Phosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), including but not limited to. Preferred phosphine ligands include racemic or non-racemic 2,2'-bis (diphenylphosphino) -1,1'-binafthyl (hereinafter referred to as BINAP), tri-O-tolylphosphine, tri- Tert-butylphosphine, 1,1'-bis (diphenylphosphino) -ferrocene, bis [(2-diphenylphosphino) phenyl] ether (DPEphos), 2-dicyclohexylphosphanyl-2'- Dimethylaminobiphenyl, 2- (di-tert-butylphosphino) biphenyl and 9,9-dimethyl-4,6-bis (diphenylphosphino) xanthene (Xantphos) are included but are not limited thereto. Palladium and ligands used in the process are typically in the range of 0.1 to 10 mole percent, relative to the amount of aromatic halide (or triflate) used.
    [323] In particular sodium-tert-butoxide (NaOt-Bu) and cesium carbonate (Cs 2 CO 3 ) have proven to be preferred bases in the process, but other bases may also be used.
    [324] The reaction is typically carried out at elevated temperature (80-120 ° C.) in an inert solvent such as 1,4-dioxane, toluene, benzene and tetrahydrofuran under an inert atmosphere such as argon or nitrogen.
    [325] Compounds according to the invention wherein R 4 is not hydrogen are amines of formula I as shown in Scheme 1 wherein R 4 is H and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and X are , As described above, except that any substituents or potential reactive functional groups in the coupling reaction are protected before carrying out the coupling reaction and then subsequently removed). have. Typically the alkylating agents of formula R 4 -W are iodide (W = I), bromide (W = Br), chloride (W = Cl) and sulfonate [L = OSO 2 R ′ wherein R ′ is methyl, Trifluoromethyl or 4-methylphenyl), but is not limited thereto.
    [326] In special cases, the compounds according to the invention can be prepared by simple functional group transformation (FGI), which means standard methods well known to those skilled in the art of organic synthesis, wherein the functional groups of the compounds of formula (I) Modification with other functional groups yields novel compounds of formula (I). Examples of such methods include hydrolysis of esters which produce acids under basic conditions, for example dehydrogenation of methyl ethers to produce phenols by treatment with boronitribromide (BBr 3 ) and catalytic hydrogenation of olefins to produce saturated hydrocarbons. Including but not limited to. Compounds according to the invention of formula (I), wherein X is S, can be prepared from ketones (formula (I), wherein X is O) by one of a number of thiocarbonylation reagents known to those skilled in the art of organic synthesis. . Examples of such thiocarbonylation reagents include phosphorus pentasulfide, Lawesson's reagent (2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiaphosphane-2,4-disulfide ), But are not limited to such.
    [327] Compounds according to the invention of formula (I), wherein X is N-OR c , are prepared by treating ketones (formula (I), wherein X is O) with H 2 N-ORc, or a protected derivative thereof in a suitable solvent such as pyridine or methanol It can be prepared by deprotection.
    [328] The compounds according to the invention of formula III can be prepared by several methods known to those skilled in the art of organic synthesis. One useful sequence is shown in Scheme 2. The benzophenol of formula IV can be obtained by an important step comprising coupling the bromide (or iodide) of formula VI with the acid chloride of formula V. The compound of formula IV can then be reduced to the corresponding amine of formula III by treatment with a standard reducing agent. Examples of such reducing agents include, but are not limited to, tin chloride dihydrate, hydrogen, ammonium formate or hydrazine hydrate, and catalytic amounts of palladium on carbon. Coupling reactions are carried out by, for example, modifying bromide (VI) to reactive organometallic intermediates by treatment with butyllithium to obtain lithium derivatives or by treatment with magnesium to obtain magnesium derivatives.
    [329]
    [330] The reactivity of the intermediates described above is then controlled by a metal exchange reaction exchanged with zinc by treatment with ZnCl 2 , ZnBr 2 or ZnI 2 . This organozinc compound is then coupled with the acid chloride of formula V under the influence of a catalytic amount of palladium (0) complex. Examples of such catalysts include tetrakis (triphenylphosphine) palladium (0), tetrakis (triphenylarcin) palladium (0), dichlorobis (triphenylphosphine) palladium (II) or benzylchlorobis (tri) Phenylphosphine) palladium (II), including but not limited to.
    [331] As shown in Scheme 2, the compound of formula IV wherein X is O is modified by the FGI method as described above to give formula IV wherein X is S or N-OR c . This is merely to illustrate the flexibility of the synthesis method and in general the order of the above described methods is only one of several possible methods for synthesizing the compounds of the present invention. That is, in some cases, it may be more advantageous to change the order of the methods described above. The order of the above processes should not be considered to be limited to the process for the preparation of the compounds of the present invention, and those skilled in the art of organic synthesis will obviously be able to change the order of reaction. This aspect of the invention may be particularly advantageous when synthesizing compounds having different substituents on the R 6 group. Easily available intermediates can serve as a starting point for the synthesis of a series of different compounds included in Formula (I). Examples of such compounds are shown in Schemes 3 and 4, which are examples of the synthesis of the compounds included in Formula I (Formulas Ia through Ie).
    [332]
    [333] Compounds with free hydroxyl groups (formulas VIIa and VIIb) can be used to couple carboxylic acids (R-COOH) or activated derivatives thereof by methods well known to those skilled in the art of organic synthesis to obtain esters of formulas (Ia) and (Ib). Can be.
    [334] Compounds with free amino groups (Formulas VIIc and VIId) can be coupled to carboxylic acids (R-COOH) or activated derivatives thereof to obtain amides of Formulas Ic and Id by methods well known to those skilled in the art of organic synthesis. have.
    [335]
    [336] Compounds with free carboxylic acid groups (Formula VIIe) can be coupled to amines (R-NH 2 ) or activated derivatives thereof by methods well known to those skilled in the art of organic synthesis to obtain the amides of formula (Ie).
    [337] Suitable reactive carboxylic acid derivatives are, for example, acyl chlorides, mixed anhydrides or active esters. The reaction is typically carried out under a suitable base such as triethylamine, potassium carbonate or pyridine in an inert solvent such as diethyl ether, tetrahydrofuran or dichloromethane. Essential starting materials, such as compounds of formula (II), (IIa), R-NH 2 and R-COOH, can be prepared by methods described in the literature or by standard methods of organic chemistry. Such starting materials are described in the accompanying preparation method.
    [338] General Methods, Preparation Methods and Examples
    [339] Exemplary compounds are listed in Table 1. Not all melting points are accurate. Unless otherwise specified, for 1 H nuclear magnetic resonance (NMR) spectra (300 MHz) and 13 C NMR (75.6 MHz), internal tetramethylsilane (δ = 0.00) or chloroform (δ = 7.25) or double chloroform ( 13 For C NMR, the chemical shift value (δ) (ppm) of the double chloroform solution relative to δ = 76.81) standard. If no range is specified, a multiple term is given, defined as the double term (d), triplet (t), quadruple (q) or (m) at the approximate center point. The organic solvent used is anhydride. Chromatography was performed on silica gel using flash technology.
    [340] The following abbreviations were used throughout:
    [341] BOC tert-butyloxycarbonyl
    [342] dba dibenzylidene acetone
    [343] DCM dichloromethane
    [344] DMF N, N-dimethylformamide
    [345] DMTMM 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride
    [346] MS mass spectrometer
    [347] NMM N-methylmorpholine
    [348] NMR nuclear magnetic resonance
    [349] rac-BINAP racemic 2,2'-bis (diphenylphosphino) -1,1'-binaftil
    [350] RT room temperature
    [351] TFA trifluoroacetic acid
    [352] THF tetrahydrofuran
    [353] THP tetrahydropyran
    [354] Numbers in Table 1 are as shown in Formula (I).
    [355] Formula I
    [356]
    [357]
    [358]
    [359]
    [360]
    [361]
    [362]
    [363]
    [364]
    [365]
    [366]
    [367] Preparation Method 1: 2- [2- (2-bromophenyl) ethoxy] tetrahydro-2H-pyran (Compound 401)
    [368] A solution of 2-bromophenethyl alcohol (9.88 g), 3,4-dihydro-2H-pyran (4.45 mL) and 4-toluenesulfonic acid (0.20 g) in THF (20 mL) was stirred at 50 ° C. for 2 hours. Stir and then stir overnight at room temperature. The reaction mixture is poured into a mixture of cold water and EtOAc. The aqueous solution is extracted with EtOAc (x2). The combined organic phases are washed with saturated NaHCO 3 and brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by chromatography eluting with petroleum ether / EtO 2 4: 1 to afford the title compound as a colorless oil.
    [369] Preparation Method 2: 2- (2-Bromophenyl) -1-methylethyl acetate (Compound 402)
    [370] Acetic anhydride (1.2 mL) in pyridine (1.0 mL) is added to 1- (2-bromophenyl) -2-propanol solution (529 mg) with stirring at 20 ° C. The reaction mixture is stirred overnight and then poured into a mixture of water and EtOAc. The aqueous phase is extracted with more EtOAc (x2). The combined organic phases are washed with water (x3), dried (MgSO 4 ) filtered and concentrated in vacuo to afford the title compound as a syrup.
    [371] Preparation Method 3: (3E) -2-Methyl-4- (tributylstannyl) but-3-en-2-ol (Compound 403)
    [372] While stirring, a mixture of 2-methylbut-3-yn-2-ol (2.00 g), tributyl tin hydride (10.5 g) and [alpha] '-azobisisobutyronitrile (190 mg) is heated to 80 < 0 > C. . After 4 hours, the reaction mixture is cooled to room temperature. The crude product is purified by chromatography eluting with petroleum ether / EtO 2 7: 1 to afford the title compound as a liquid.
    [373] Preparation Method 4: Tributyl {(1E) -3-[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] prop-1-enyl} stanan (Compound 404)
    [374] At 0 ° C. sodium hydroxide (215 mg) is added to a (2,2-dimethyl-1,3-dioxolan-4-yl) methanol solution (644 mg) in anhydrous DMF (25 mL). After 10 minutes, [(1E) -3-bromoprop-1-enyl] (tributyl) stanan (1.00 g) is added to the reaction mixture. The reaction mixture is stirred at 20 ° C. for 20 hours and then quenched with saturated NH 4 Cl (aq). Extract with EtOAc, dry the organic phase (Na 2 SO 4 ) and concentrate in vacuo to afford the crude product. Purification by chromatography eluting with petroleum ether / EtOAc 10: 1 affords the title compound as a liquid.
    [375] Preparation Method 5: Dimethyl [(2E) -3- (tributylstannyl) prop-1-enyl] malonate (Compound 405)
    [376] Sodium hydroxide (75 mg) is added to a dimethyl malonate solution (387 mg) in anhydrous DMF (5 mL) at 0 ° C. After 10 minutes, [(1E) -3-bromoprop-1-enyl] (tributyl) stanan (600 mg) is added to the reaction mixture. The reaction mixture is stirred at 20 ° C. for 3 hours and then quenched with saturated NH 4 Cl (aq). Extract with EtOAc, dry the organic phase (Na 2 SO 4 ) and concentrate in vacuo to afford the crude product. Purification by chromatography eluting with petroleum ether / Et 2 O 12: 1 affords the title compound as a liquid.
    [377] Preparation Method 6: 4-[(2E) -3- (tributylstannyl) prop-2-enyl] morpholine (Compound 406)
    [378] A solution of [(1E) -3-bromoprop-1-enyl] (tributyl) stanan (1.00 g) and morpholine (637 mg) in anhydrous DMF (8.0 mL) is stirred at 20 ° C. for 24 h. . The reaction mixture is quenched with saturated NH 4 Cl (aq). Extract with Et 2 O, dry the organic phase (Na 2 SO 4 ) and concentrate in vacuo to afford the crude product. Purification by chromatography eluting with petroleum ether / EtOAc 10: 1 affords the title compound as a liquid.
    [379] Preparation Method 7: 1,2: 3,4-Di-O-[(1-methylethylidene) -6-O-[(2E) -3- (tributylstannyl) prop-2-enyl] -α-D-galactopyranose (Compound 407)
    [380] Sodium hydroxide (62 mg) was added 1,2: 3,4-di-O- (1-methylethylidene) -α-D-galapyranosan solution (635 mg) in anhydrous DMF (8 mL) at 0 ° C. Add to After 10 minutes, [(1E) -3-bromoprop-1-enyl] (tributyl) stanan (500 mg) is added to the reaction mixture. The reaction mixture is stirred at 20 ° C. for 20 hours and then quenched with saturated NH 4 Cl (aq). Extract with Et 2 O, dry the organic phase (Na 2 SO 4 ) and concentrate in vacuo to afford the crude product. Purification by chromatography eluting with petroleum ether / Et 2 O 9: 1 affords the title compound as a liquid.
    [381] Preparation Method 8: Methyl 2,3-O- (1-methylethylidene) -5-O-[(2E) -3- (tributylstannyl) prop-2-enyl] -β-D-ribo Furanoside (Compound 408)
    [382] The reaction is carried out as described in the process for the preparation of compound 407 using 2,3-O- (1-methylethylidene) -β-D-ribofuranose (598 mg) as the alcohol. Purification by flash chromatography eluting with a mixture of petroleum ether / EtOAc 30: 1 affords the title compound as a liquid.
    [383] Preparation Method 9: Methyl (4E) -2- (methylsulfonyl) -5- (tributylstannyl) pent-4-enoate (Compound 409)
    [384] The reaction is carried out as described in the method for the preparation of compound 407 using methyl (methylsulfonyl) acetate (446 mg) as the nucleophilic component. Purification by flash chromatography eluting with a mixture of petroleum ether / Et 2 O 5: 1 affords the title compound as a liquid.
    [385] Preparation Method 10: Ethyl {[(2E) -3- (tributylstannyl) prop-2-enyl] thio} acetate (Compound 410)
    [386] The reaction is carried out as described in the method for the preparation of compound 407 using ethyl mercaptoacetate (550 mg) as the nucleophilic component. Purification by flash chromatography eluting with a mixture of petroleum ether / Et 2 O 100: 1 affords the title compound as a liquid.
    [387] Preparation Method 11: Tributyl {[(1E) -3- [bis (2-hydroxyethyl) amino] prop-1-enyl} stanan (Compound 411)
    [388] N-ethyl-N, N-diisopropylamine (315 mg) is added to a diethanolamine solution (256 mg) in anhydrous DMF (5 mL) at 0 ° C. After 10 minutes, [(1E) -3-bromoprop-1-enyl] (tributyl) stanan (600 mg) is added to the reaction mixture. The reaction mixture is stirred at 20 ° C. for 15 h and then quenched with saturated NH 4 Cl (aq). Extract with Et 2 O, dry the organic phase (Na 2 SO 4 ) and concentrate in vacuo to afford the crude product. Purification by chromatography eluting with Et 2 O / MeOH 100: 4 affords the title compound as a liquid.
    [389] Preparation 12: Tributyl ((1E) -3- {bis [2- (acetyloxy) ethyl] amino} prop-1-enyl) stanan (Compound 412)
    [390] The reaction is carried out as described in the process for the preparation of compound 402 using compound 411 (575 mg) as the alcohol. Purification by flash chromatography eluting with a mixture of petroleum ether / Et 2 O 4: 1 affords the title compound.
    [391] Preparation Method 13: Tributyl {(1E) -3- [4- (2-hydroxyethyl) piperidin-1-yl] prop-1-enyl} stanan (Compound 4123)
    [392] The reaction is carried out as described in the process for the preparation of compound 411 using compound 2-piperidin-4-ylethanol (504 mg) as the amine. Purification by flash chromatography eluting with a mixture of Et 2 O / MeOH 92: 8 affords the title compound.
    [393] Preparation 14: Tributyl ((1E) -3- {4- [2- (acetyloxy) ethyl] piperidin-1-yl} prop-1-enyl) stanan (Compound 414)
    [394] The reaction is carried out as described in the process for the preparation of compound 402 using compound 413 (510 mg) as the alcohol. Purification by flash chromatography eluting with a mixture of petroleum ether / Et 2 O 1: 2 affords the title compound.
    [395]
    [396] Preparation 15: 2- (2-{(2-bromobenzyl) oxy} ethoxy) ethanol (Compound 415)
    [397] NaH (60% in 0.53 g oil, 13 mmol) is suspended in dry THF (80 mL) in anhydrous Schlenk tube under argon atmosphere. Diethylene glycol (11.4 mL, 120 mmol) was added slowly while stirring. The suspension is stirred for 30 minutes at room temperature. 2-bromo-benzylbromide (5.0 g, 20 mmol) dissolved in 5 mL of dry THF was added, followed by tetrabutylammonium iodide (74 mg, 0.2 mmol). 50 ml of H 2 O is added and the reaction mixture is refluxed for 18 hours. The aqueous phase is extracted twice with EtOAc and the combined organic phases are washed with water and brine, dried (MgSO 4 ), filtered and evaporated in vacuo. The crude product is purified by flash chromatography eluting with DCM / acetone 3: 1. This gives the title compound as a yellow day of the week.
    [398] Preparation method 16: 2- (2- {2-[(2-bromobenzyl) oxy] ethoxy} ethoxy) ethanol (Compound 416)
    [399] Triethylene glycol (16.0 mL, 120 mmol) instead of diethylene glycol was used to prepare and work up the title compound as described in the preparation of compound 415. The crude product is purified by flash chromatography using DCM / acetone 6: 1 to 3: 1 as eluent to afford the title compound as a pale yellow oil.
    [400] Preparation 17: 2-((2-bromobenzyl) oxy) ethanol (Compound 417)
    [401] The reaction and workup are carried out as described for the preparation of compound 415. Starting materials were NaH (60% in oil, 1.8 g, 44 mmol) in THF (160 mL), ethylene glycol (13.4 mL, 240 mmol), 2-bromo-benzyl bromide (10 g, 40 mmol) dissolved in 5 mL of dry THF and Tetrabutylammonium iodide (0.15 g, 0.4 mmol). The crude product is purified by flash chromatography using DCM / acetone 30: 1 as eluent to afford the title compound as a pale yellow oil.
    [402] Preparation Method 18: Diethyl 2-bromobenzylphosphonate (Compound 418)
    [403] Diethyl phosphite (0.77 mL, 6.0 mmol) is dissolved in dry THF (10 mL) in anhydrous Schlenk tube under argon atmosphere. The solution is cooled in an ice bath, NaH (0.24 g, 60% in oil, 6.0 mmol) is added and stirred for 5 minutes. 2-bromo-benzylbromide (1.0 g, 4.0 mmol) dissolved in 2 mL of dry THF is added and the reaction mixture is refluxed overnight. H 2 O (20 mL) is added and the aqueous phase is extracted with EtOAc (3 × 10 mL). The combined organic phases are washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using EtOAc as eluent to afford the title compound as a colorless oil.
    [404] Preparation 19: 2-bromobenzyl 3,3,3-trifluoropropyl ether (Compound 419)
    [405] The reaction and workup are carried out as described in the preparation of compound 415. The starting material is NaH (60% in oil, 0.08 g, 2 mmol) in THF (10 mL), 3,3,3-trifluoropropane- 1-ol (0.23 g, 2 mmol), 2-bromo-benzyl bromide (0.50 g, 2 mmol) and tetrabutylammonium iodide (0.74 g, 0.2 mmol). The crude product is purified by flash chromatography using EtOAc / petroleum ether 1:35 as eluent to afford the title compound as a pale yellow oil.
    [406]
    [407] Preparation Method 20: 2- (2- {2-[(2-bromobenzyl) oxy] ethoxy} ethoxy) tetrahydro-2H-pyran (Compound 420)
    [408] Compound 415 (2.78 g, 10.0 mmol) was dissolved in anhydrous THF (6 mL) under argon atmosphere. 3,4-Dihydro-2H-pyran (1.03 mL, 11.3 mmol) is added followed by p-toluenesulfonic acid (43 mg, 0.23 mmol). Aqueous NaHC0 3 (5%, 30 mL) is added and the reaction mixture is stirred at 50 ° C. for 2 h. The aqueous phase is extracted with EtOAc (3 × 15 mL) and the combined organic phases are washed with water, dried (Na 2 SO 4 ) filtered and evaporated in vacuo. The crude product is purified by flash chromatography eluting with EtOAc / petroleum ether 1: 3. This gives the title compound as a yellow oil.
    [409] Preparation Method 21: 2- [2- (2- {2-[(2-bromobenzyl) oxy] ethoxy} ethoxy) ethoxy) ethoxy] tetrahydro-2H-pyran (Compound 421)
    [410] The reaction and workup are carried out as described for the preparation of compound 420. Starting materials are compound 416 (2.82 g, 8.9 mmol), 3,4-dihydro-2H-pyran (0.89 mL, 9.8 mmol) and p-toluenesulfonic acid (37 mg, 0.19 mmol) in 6 mL of anhydrous THF. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 3 as eluent to afford the title compound as a pale yellow oil.
    [411] Preparation 22: 2- {2-[(2-bromobenzyl) oxy] ethoxy} tetrahydro-2H-pyran (Compound 422)
    [412] The reaction and workup are carried out as described for the preparation of compound 420. Starting materials were compound 417 (8.0 g, 34.9 mmol), 3,4-dihydro-2H-pyran (3.2 mL, 34.9 mmol) and p-toluenesulfonic acid (0.14 g, 0.76 mmol) in 20 mL of anhydrous THF. The time is four hours. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 2 as eluent to afford the title compound as a colorless oil.
    [413] Preparation 23: 2- (2-Bromobenzyl) -1H-isoindole-1,3 (2H) -dione (Compound 423)
    [414] 2-bromobenzyl bromide (5.25 g, 21.0 mmol) is dissolved in anhydrous DMF (200 mL) and potassium phthalimide (3.89 g, 21.0 mmol) is added. The suspension is stirred at 70 ° C. for 5 hours. The mixture is cooled to room temperature and poured into ice water (200 mL). After 30 minutes, the mixture is filtered and the crystalline compound is dried overnight. Recrystallization from DCM / petroleum ether affords the title compound as colorless crystals.
    [415] Preparation 24: 3-[(2-bromobenzyl) oxy] propanol (Compound 424)
    [416] The reaction and workup are carried out as described for the preparation of compound 415. Starting material was 2-bromobenzylbromide (5.0 g) dissolved in NaH (60% in oil, 0.86 g, 22 mmol) in THF (80 mL), 1,3-propanediol (8.67 mL, 120 mmol) and 4 mL of dry THF. 20 mmol) and tetrabutylammonium iodide (0.07 g, 0.2 mmol). The crude product is purified by flash chromatography using EtOAc / Petroleum ether 1: 1 to 2: 1 as eluent to afford the title compound as a pale yellow oil.
    [417] Preparation Method 25: 2- {3-[(2-bromobenzyl) oxy] propoxy} tetrahydro-2H-pyran (Compound 425)
    [418] The reaction and workup are carried out as described for the preparation of compound 420. Starting materials are compound 424 (2.41 g, 9.8 mmol), 3,4-dihydro-2H-pyran (0.99 mL, 10.8 mmol) and p-toluenesulfonic acid (37 mg. 0.19 mmol) in 7 mL of anhydrous THF. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 4 as eluent to afford the title compound as a pale yellow oil.
    [419] Preparation 26: 3-[(2-bromobenzyl) oxy] propyl 4-methylbenzenesulfonate (Compound 426)
    [420] The reaction and workup are carried out as described in the preparation of compound 420 using compound 424 (2.50 g, 10.2 mmol) and p-toluenesulfonyl chloride (2.14 g, 11.2 mmol) in pyridine (3 mL). The crude product is purified by flash chromatography eluting with EtOAc / petroleum ether 1: 3. This gives the title compound as a colorless crystalline compound.
    [421] Preparation 27: 1-Bromo-2- (3-iodo-propoxymethyl) benzene (Compound 427)
    [422] The reaction and workup are carried out as described in the preparation of compound 420 using 8 ml of acetone and compound 426 (3.04 g, 7.6 mmol) in NaI (2.28 g, 15.2 mmol). The crude product is purified by flash chromatography eluting with EtOAc / petroleum ether 1: 2. This gives the title compound as a colorless oil.
    [423] Preparation 28: Diethyl 3-[(2-bromobenzyl) oxy] propylphosphonate (Compound 428)
    [424] Reaction and workup were carried out as described in the preparation of compound 171 using NaH (0.036 g, 60% in oil, 0.9 mmol) and diethylphosphite (0.12 mL, 0.9 mmol) in dry THF (2 mL). do. Compound 427 (0.20 g, 0.6 mmol) dissolved in anhydrous THF (1 mL) was added, followed by stirring at room temperature for 48 hours and post-treatment as described for the preparation of compound 171. The crude product is purified by flash chromatography using EtOAc as eluent to afford the title compound as a colorless oil.
    [425] Preparation method 29: 2- (2-bromophenyl) ethyl 4-methylbenzenesulfonate (Compound 428)
    [426] Reaction and workup were carried out as described in the preparation of compound 163 using 2-bromophenethyl alcohol (5 g, 25 mmol) and p-toluenesulfonyl chloride (5.2 g, 27.5 mmol) in pyridine (12 mL). do. The crude product is purified by flash chromatography eluting with EtOAc / petroleum ether 1: 4. This gives the title compound as a colorless crystalline compound.
    [427] Preparation 30: 1-Bromo-2- (2-iodoethyl) benzene (Compound 430)
    [428] The reaction and workup were carried out as described in the preparation of compound 167 using compound 429 (7.98 g, 22.5 mmol) and NaI (6.7 g, 44.9 mmol) in 22 ml of acetone. The crude product is purified by flash chromatography using petroleum ether as eluent to afford the title compound as a colorless oil.
    [429] Preparation 31: Diethyl 2- (2-Bromophenyl) ethylphosphonate (Compound 431)
    [430] The reaction is carried out as described in the preparation of compound 171 using NaH (0.19 g, 60% in oil, 4.8 mmol) and diethylphosphite (0.62 mL, 4.8 mmol) in dry THF (10 mL). Compound 430 (1.Og, 3.2mmol) was added and stirred at room temperature for 18 hours. Post-treatment is carried out as described for the preparation of compound 171. The crude product is purified by flash chromatography using EtOAc / petroleum ether 0: 1 to 1: 0 as eluent to afford the title compound as a colorless oil.
    [431] Preparation Method 32: (2-Chloro-4-iodophenyl) (2-methylphenyl) methanone (Compound 432)
    [432] Stirred suspension of 4- (amino-2-chlorophenyl) (2-methylphenyl) methanone (9.83 g, 40 mmol) in HCl (37%, 150 mL) at 0 ° C. (WO 01/42189 Al) ) Was added a solution of NaNO 2 (5.52 g, 80 mmol) in water (40 mL) over 20 minutes. The reaction mixture is stirred for 15 minutes and KI solution (36 g, 240 mmol) in water (100 mL) is added with stirring. After 2 hours at room temperature the aqueous phase is extracted twice with diethyl ether. The combined organic phases are washed with Na 2 CO 3 (10%) and NaHSO 3 (40%), dried over Na 2 SO 4 and concentrated in vacuo. The residue is purified by flash chromatography using petroleum ether / EtOAc 40: 1 as eluent to afford the title compound as a solid.
    [433] Preparation 33: Tert-butyl (4R) -4- [2- (2-aminophenyl) ethyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylate (Compound 433)
    [434] Potassium tert-butoxide (498 mg, 4.44 mmol) was added to a solution of (2-nitrobenzyl) triphenylphosphonium chloride (2.04 g, 4.89 mmol) in 1,4-dioxane (10 mL) under argon atmosphere. do. The mixture is stirred at room temperature for 30 minutes and then at 80 ° C. for 40 minutes. Tert-butyl (4S) -4-formyl-2,2-dimethyl-oxazolidine-3-carboxylate (510 mg, 2.22 mmol) in 1,4-dioxane (3.0 mL) was added by syringe. The resulting mixture was refluxed for 4 hours and then left at room temperature overnight. The reaction mixture is poured into water and extracted with EtOAc (x3). The organic phases are combined, washed with brine and dried over MgSO 4 . The crude product was purified by flash chromatography eluting with petroleum ether / EtOAc 9: 1 to give tert-butyl (4R) -2,2-dimethyl-4- [2- (2-nitrophenyl) vinyl]-as a yellow oil. Obtain 1,3-oxazolidine-3-carboxylate. 288 mg of the obtained product was dissolved in EtOAc (10 mL), Pd / C (40 mg, 10%) was added, followed by stirring under hydrogen atmosphere (1 atm) for 4 hours. The reaction mixture is filtered through a decalite pad and concentrated in vacuo. The crude product is purified by flash chromatography eluting with petroleum ether / EtOAc 2: 1 to afford the title compound as a white solid.
    [435] Preparation 34: tert-butyl (4R) -4- [2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl] -2,2-dimethyl-oxa Zolidine-3-carboxylate (Compound 434)
    [436] Using 432 (378 mg, 1.06 mmol) and 433 (340 mg, 1.06 mmol), the reaction and workup were carried out as described in the preparation of compound 101. Purification by flash chromatography eluting with petroleum ether / EtOAc 9: 1 affords the title compound as a foam.
    [437] Preparation 35: tert-butyl [2- (2-bromophenyl) ethyl] (methyl) carbamate (compound 435)
    [438] A tert-butyl [2- (2-bromophenyl) ethyl] carbamate solution (810 mg, 2.7 mmol) in anhydrous THF (2.0 mL) was dissolved in anhydrous THF (2.0 mL) sodium hydride suspension (65 mg) under an argon atmosphere. 2.7 mmol) into a flask. The mixture is stirred at room temperature for 15 minutes and at 60 ° C. for 10 minutes. Iodomethane (0.19 mL, 2.97 mmol) is added by syringe. After 4 hours, the reaction mixture is poured into water and extracted with EtOAc (x3). The organic phases are combined, washed with brine and dried over MgSO 4 . The crude product is purified by chromatography eluting with petroleum ether / EtOAc 10: 1 to afford the title compound as a colorless oil.
    [439]
    [440] Preparation 36: 3- [2- (2-bromophenyl) ethyl] -1-methylimidazolidine-2,4-dione (Compound 436)
    [441] To a solution of triphenylphosphine (734 mg, 2.8 mmol), 2-bromophenethyl alcohol (402 mg, 2.0 mmol) and 1-methylhydantoin (320 mg, 2.8 mmol) in THF (20 mL) at room temperature Diethyl azodicarboxylate solution (40% in toluene, 1.22 mL, 2.8 mmol) is added. The reaction solution is stirred at the same temperature for 3 hours and concentrated in vacuo. The residue is purified by chromatography (petroleum ether / ethyl acetate 1: 1) to afford the title compound as a colorless oil.
    [442] 13 C NMR (CDCl 3 ): δ 169.6, 156.7, 137.6, 132.9, 130.9, 128.5, 127.6, 124.6, 51.6, 38.6, 34.4, 29.6
    [443] Preparation 37: [3- [2- (2-bromophenyl) ethyl] -5,5-dimethyloxazolidine-2,4-dione (Compound 437)
    [444] 2-Bromophenethyl alcohol (402 mg, 2 mmol) and 5,5-dimethyl-oxazolidine-2,4-dione (361 mg, 2.8 mmol) were treated as described for the preparation of compound 436. Purification by flash chromatography (petroleum ether / ethyl acetate 4: 1) affords the title compound as a colorless solid.
    [445] 13 C NMR (CDCl 3 ): δ 175.7, 154.4, 136.6, 133.1, 131.1, 128.8, 127.5, 124.7, 83.6, 39.2, 33.7, 23.5
    [446] Preparation 38: 4- [2- (2-bromophenyl) ethyl] morpholine-3,5-dione (Compound 438)
    [447] 2-bromophenethyl alcohol (402 mg, 2 mmol) and morpholine-3,5-dione (322 mg, 2.8 mmol) were treated as described for the preparation of compound 436. Purification by flash chromatography (petroleum ether / ethyl acetate 4: 1) affords the title compound as a colorless solid.
    [448] 13 C NMR (CDCl 3 ): δ 168.9, 137.7, 132.9, 131.0, 128.5, 127.5, 124.7,67.7, 38.2, 34.0
    [449] Preparation method 39: 1- [2- (2-bromophenyl) ethyl] piperidine-2,6-dione (Compound 439)
    [450] 2-bromophenethyl alcohol (402 mg, 2 mmol) and glutarimide (317 mg, 2.8 mmol) were treated as described for the preparation of compound 436. Purification by flash chromatography (petroleum ether / ethyl acetate 2: 1) affords the title compound as a colorless solid.
    [451] 13 C NMR (CDCl 3 ): δ 172.3, 138.3, 132.7, 131.0, 128.2, 127.4, 124.7, 39.0, 34.1, 32.8, 17.1
    [452] Preparation 40: 2-Bromobenzyl (triisopropyl) silyl ether (Compound 440)
    [453] To a solution of imidazole (1.36 g, 20 mmol) and 0-bromobenzyl alcohol (2.55 g, 13.6 mmol) in H 2 C1 2 (20 mL) was added triisopropylsilyl chloride (2.6 mL, 12 mmol) at room temperature. . The resulting mixture is stirred for 11 hours at the same temperature and captured in H 2 O. After phase separation, the aqueous phase is extracted twice with petroleum ether. The combined organic phases are dried over MgSO 4 and concentrated in vacuo. The residue is purified by filtration through a short silica gel column to give the title compound as a colorless liquid.
    [454] 13 C NMR (CDCl 3 ): δ 140.3, 131.7, 127.8, 127.2, 127.1, 120.6, 64.6,17.9, 11.8
    [455] Preparation method 41: {2-Chloro-4-[(2-{[(triisopropyl) siloxy] methyl} phenyl) amino] phenyl} (2-methylphenyl) methanone (Compound 441)
    [456] A mixture of 4-amino-2-chlorophenyl) (2-methylphenyl) methanone (2.15 g. 8.74 mmol) (WO 01/42189 Al) and compound 440 (3.0 g, 8.74 mmol) was prepared using compound 215. Treatment is as described in the preparation method. Purification by flash chromatography (petroleum ether / ethyl acetate 20: 1) affords the title compound as a red oil.
    [457] 13 C NMR (CDCl 3 ): δ 196.2, 147.3, 140.3, 139.1, 137.6, 134.9, 133.4, 131.0, 130.6, 129.4, 128.9, 128.7, 128.5, 125.2, 122.4, 119.1, 116.5, 113.2, 65.2, 20.2, 17.8 , 17.5
    [458]
    [459] Example 1: [2-Chloro-4-({2- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] phenyl} amino) phenyl] (2-methylphenyl) methanone (Compound 101)
    [460] (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (9.42 g) in 1,4-dioxane (60 mL) in a Schlenk tube (reference: WO 01/42189 Al), compound 401 (12.0 g), Cs 2 CO 3 (17.5 g), Pd 2 (dba) 3 (440 mg) and rac-BINAP (900 mg) are charged. The tube is sealed with a rubber diaphragm and argon flows for 5 minutes and then stirred at 100 ° C. for 72 hours. The reaction mixture is left to cool to room temperature and then poured into a mixture of water and EtOAc. The aqueous phase is extracted with more EtOAc (x2). The combined organic phases are washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by chromatography eluting with petroleum ether / ether 2: 1 to give the title compound as an orange semisolid.
    [461] 13 C NMR (CDCl 3 ): δ 196.3, 149.0, 139.6, 139.5, 137.6, 135.3, 133.9, 133.5, 131.1, 130.6, 129.4, 127.8, 127.4, 125.3, 124.4, 122.3, 115.8, 112.1, 99.3, 70.2, 62.3 , 32.8, 30.6, 25.2, 20.3, 19.6
    [462] Example 2: (2-chloro-4-({2- [2- (hydroxyethyl) phenyl] amino} phenyl) (2-methylphenyl) methanone (Compound 102)
    [463] A solution of 4-toluenesulfonic acid (2.54 g) and compound 101 (4.00 g) in methanol (25 mL) is stirred at room temperature for 2 hours. The reaction mixture is poured into a mixture of 1N NaOH and EtOAc. The aqueous phase is extracted with more EtOAc (x2). The combined organic phases are washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by chromatography eluting with petroleum ether / ether 2: 1 to afford the title compound as a yellow syrup.
    [464] 13 C NMR (CDCl 3 ): δ 196.6, 149.0, 139.5, 137.6, 135.3, 133.8, 133.4, 131.2, 131.2, 130.6, 129.5, 127.8, 127.5, 125.3, 124.6, 122.7, 115.9, 112.2, 65.0, 34.6, 20.3
    [465]
    [466] Example 3: 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl acetate (Compound 103)
    [467] Acetic anhydride (0.12 mL) is added to compound 102 (306 mg) in pyridine (3.0 mL) with stirring at 0 ° C. The reaction mixture is left overnight at room temperature and then poured into a mixture of water and EtOAc. The aqueous phase is extracted with more EtOAc (x2). The combined organic phases are washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by chromatography eluting with petroleum ether / Et 2 O 1: 1 to afford the title compound as a syrup.
    [468] 13 C NMR (CDCl 3 ): δ 196.4, 171.4, 148.8, 139.3, 138.9, 137.8, 135.1, 133.6, 131.2, 131.1, 130.7, 129.6, 128.7, 128.1, 125.3, 124.8, 123.1, 116.1, 112.7, 64.6, 31.2 , 21.0, 20.4
    [469] Example 4: 4- (2- {2-[(3-chloro-4- (2-methylbenzoyl) phenyl) amino] phenyl} ethoxy) -4-oxobutanoic acid (Compound 104)
    [470] The reaction is carried out as described for the preparation of compound 103 using compound 102 (1.37 g) and succinic anhydride (0.56 g) as alcohol. Purification by flash chromatography eluting with a mixture of petroleum ether / EtOAc 4: 1 and 5% acetic acid affords the title compound as a yellow syrup.
    [471] 13 C NMR (CDCl 3 ): δ 196.6, 176.3, 172.7, 149.0, 148.6, 139.3, 138.8, 137.8, 135.1, 133.6, 131.2, 131.0, 129.6, 128.4, 128.1, 125.3, 125.1, 123.8, 115.9, 112.5, 64.8 , 31.0, 29.0, 28.8, 20.4
    [472] Example 5: 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl hexanoate (Compound 105)
    [473] The reaction is carried out as described for the preparation of compound 103 using compound 102 (0.42 g) and hexane anhydride (0.40 mL) as alcohol. The combined organic phases are also washed with 0.5N NaOH. Purification by flash chromatography eluting successively with petroleum ether / EtOAc 9: 1 and petroleum ether / EtOAc 4: 1 affords the title compound as a yellow syrup.
    [474] 13 C NMR (CDCl 3 ): δ 196.4, 174.3, 148.8, 139.3, 138.9, 137.8, 135.2, 133.6, 131.2, 133.1, 130.8, 130.7, 129.6, 128.6, 128.0, 125.3, 124.8, 123.2, 116.1, 112.6, 64.4 , 34.3, 31.3, 24.6, 24.4, 22.3, 20.4, 13.9.
    [475] Example 6: 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -1-methylethyl acetate (compound 106)
    [476] The reaction is carried out as described in the preparation of compound 101 using compound 402 (304 mg) as bromide. Purification by flash chromatography eluting with a mixture of petroleum ether / EtOAc 4: 1 affords the title compound as an orange syrup.
    [477] 13 C NMR (CDCl 3 ): δ 196.5, 171.7, 148.5, 139.4, 139.3, 137.8, 135.1, 133.6, 131.7, 131.2, 130.7, 129.6, 129.0, 128.8, 127.9, 125.3, 123.7, 121.5, 116.4, 113.2, 71.6 , 39.0, 21.4, 20.4, 19.1
    [478] Example 7: (2-chloro-4-{[2- (2-hydroxypropyl) phenyl] amino} phenyl) (2-methylphenyl) methanone (Compound 107)
    [479] A solution of compound 106 (49 mg) in THF (1.0 mL) is added to a solution of sodium methoxide in methanol (3.0 mL, 0.33 M) and then stirred at 20 ° C. for 45 min. The reaction mixture is poured into a mixture of water and EtOAc. The aqueous phase is extracted with more EtOAc (x2). The combined organic phases are washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo to afford the title compound as a yellow syrup.
    [480] 13 C NMR (CDCl 3 ): δ 196.5, 148.9, 139.7, 139.6, 137.6, 135.3, 133.9, 132.0, 132.0, 131.1, 130.6, 129.4, 127.7, 127.5, 125.3, 124.1, 122.3, 116.0, 112.3, 70.6, 40.6 , 23.8, 20.3
    [481]
    [482] Example 8: [2-Chloro-4-({2-[(1E) -3-hydroxyprop-1-enyl] phenyl} amino) phenyl] (2-methylphenyl) methanone (Compound 108)
    [483] Under argon atmosphere, {2-chloro-4-[(2-bromophenyl) amino] phenyl} (2-methylphenyl) methanone (300 mg) in dioxane (1.5 mL) (reference WO 01/42189) ) And Pt-Bu 3 solution (18 mg) in dioxane (1.0 mL) were added sequentially to a Schlenk tube filled with Pd 2 (dba) 3 (21 mg) and CsF (152 mg). (2E) -3- (tributylstannyl) prop-2-en-1-ol (273 mg) was added by syringe, then the Schlenk tube was sealed and placed in an oil bath at 35 to 50 ° C., followed by 48 Stir for hours. The reaction mixture is cooled to room temperature, then diluted with acetonitrile and filtered through a pad of celite. The celite is washed with acetonitrile and the combined organic phases are washed thoroughly with petroleum ether and concentrated in vacuo. The product is purified by flash chromatography eluting with a mixture of petroleum ether / EtOAc 4: 1 to afford the title compound as a yellow syrup.
    [484] 13 C NMR (CDCl 3 ): δ 196.8, 149.0, 139.2, 137.7, 137.2, 135.1, 133.6, 133.9, 131.5, 131.2, 130.8, 129.6, 128.6, 128.4, 127.4, 126.0, 125.4, 125.4, 124.0, 116.1, 112.5 , 63.4, 20.4
    [485] Example 9: (2-chloro-4-{[2- (3-hydroxypropyl) phenyl] amino} phenyl) (2-methylphenyl) methanone (Compound 109)
    [486] A mixture of compound 108 (50 mg) and 10% Pd / C (7 mg) in ethanol (1.0 mL) is stirred at room temperature under hydrogen atmosphere for 8 hours. The reaction mixture is concentrated in vacuo and purified by flash chromatography eluting with a mixture of DCM / MeOH 97: 3 to afford the title compound as a yellow syrup.
    [487] 13 C NMR (CDCl 3 ): δ 196.5, 149.4, 139.5, 138.7, 137.7, 135.2, 134.7, 133.8, 131.2, 130.7, 130.6, 129.5, 128.0, 127.1, 125.3, 124.9, 123.1, 115.8, 112.2, 60.9, 32.8 , 26.6, 20.4
    [488] Example 10: [2-Chloro-4-({2-[(1E) -4-hydroxybut-1-enyl] phenyl} amino) phenyl] (2-methylphenyl) methanone (Compound 110)
    [489] The reaction is carried out as described in the preparation of compound 108 using (2E) -4- (tributylstannyl) but-3-en-1-ol (304 mg) as stanan. Elution with an 8: 1 mixture of petroleum ether / EtOAc, then purification by flash chromatography eluting with a 1: 1 mixture, affords the title compound as a yellow syrup.
    [490] 13 C NMR (CDCl 3 ): δ 196.5, 149.0, 139.3, 137.8, 136.8, 135.1, 133.6, 131.2, 130.8, 129.8, 129.6, 128.3, 127.9, 127.3, 125.5, 125.3, 124.2, 116.0, 112.4, 61.9, 36.6 , 20.4
    [491] Example 11: [4-({2-[(1E) -3-aminoprop-1-enyl] phenyl} amino) -2-chlorophenyl] (2-methylphenyl) methanone (Compound 111)
    [492] The reaction is carried out as described in the method for the preparation of compound 108 using (2E) -4- (tributylstannyl) but-2-en-1-amine (273 mg) as stanan. Purification by flash chromatography eluting with a 90: 5: 5 mixture of DCM / MeOH / Et 3 N affords the title compound as a yellow foam.
    [493] 13 C NMR (CDCl 3 ): δ 196.5, 149.0, 139.3, 137.8, 137.1, 135.1, 133.6, 132.2, 131.2, 130.8, 129.6, 128.5, 128.4, 127.4, 125.4, 125.3, 125.2, 123.9, 116.2, 112.5, 44.2 , 20.4
    [494] Example 12: Diethyl (2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enylphosphonate (Compound 112)
    [495] The reaction is carried out as described in the preparation of compound 108 using (2E) -3- (tributylstannyl) prop-2-enylphosphonate (219 mg) as stanan. Purification by flash chromatography eluting with a 1: 1 mixture of petroleum ether / EtOAc affords the title compound.
    [496] 13 C NMR (CDCl 3 ): δ 196.4, 148.9, 139.3, 137.8, 137.1, 135.1, 133.6, 132.0, 131.2, 130.8, 130.3, 13.1, 129.6, 128.7, 127.4, 125.3, 123.9, 122.2, 122.0, 116.1, 112.5 , 62.1, 31.3, 20.4, 16.5
    [497] Example 13: [2-Chloro-4-({2-[(1E) -3-hydroxy-3-methylbut-1-enyl] phenyl} amino) phenyl] (2-methylphenyl) methanone (Compound 113 )
    [498] The reaction is carried out as described in the process for the preparation of compound 108 using compound 403 as stanan. Purification by flash chromatography eluting with a 2: 1 mixture of petroleum ether / EtOAc affords the title compound as a syrup.
    [499] 13 C NMR (CDCl 3 ): δ 196.5, 148.8, 140.5, 139.3, 137.8, 137.2, 135.0, 133.5, 132.1, 131.2, 130.8, 129.6, 128.7, 128.5, 127.4, 125.5, 125.3, 124.1, 121.8, 116.2, 112.7 , 71.2, 30.0, 20.4
    [500] Example 14: Ethyl (2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) acrylate (Compound 114)
    [501] The reaction is carried out as described in the preparation of compound 108 using diethyl (2E) -3- (tributylstannyl) acrylate (295 mg) as stanan. Elution with a 6: 1 mixture of petroleum ether / EtOAc, followed by flash chromatography eluting with a 1: 1 mixture to afford the title compound as a yellow syrup.
    [502] 13 C NMR (CDCl 3 ): δ 196.5, 167.2, 148.2, 139.7, 139.3, 139.0, 138.0, 135.0, 133.4, 131.3, 130.9, 129.8 129.6, 129.0, 128.0, 125.4, 125.3, 123.9, 119.9, 116.8, 113.3, 51.8, 20.5
    [503] Example 15: (2E) -3 (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) acrylic acid (Compound 115)
    [504] Compound 114 (190 mg) in THF (2.0 mL) was added to a lithium hydroxide solution (22 mg) in a mixture of MeOH / H20 (3: 4; 3.5 mL) and then stirred at 20 ° C. for 72 hours. The reaction mixture is poured into a mixture of 1N HCl (aq.) And DCM. The aqueous phase is extracted with more DCM (x3). The combined organic phases are washed with brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo to afford the crude product as a solid. Crystallization from EtOAc affords the target compound as yellow crystals.
    [505] 13 C NMR (DMSO-d 6 ): δ 195.2, 167.5, 149.8, 139.3, 139.2, 139.1, 136.5, 133.5, 131.2, 131.0, 130.7, 128.9, 128.9, 127.7, 126.7, 125.6, 125.2, 124.8, 120.0, 115.1 , 112.1, 19.7
    [506] Example 16: {2-Chloro-4-[(2-{(1E) -3-[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] prop-1-enyl } Phenyl) amino] phenyl} (2-methylphenyl) methanone (Compound 116)
    [507] The reaction is carried out as described in the process for the preparation of compound 108 using compound 404 (351 mg) as stanan. Purification by flash chromatography eluting with a mixture of petroleum ether / EtOAc 2: 1 affords the title compound as a yellow syrup.
    [508] 13 C NMR (CDCl 3 ): δ 196.4, 148.8, 139.3, 137.9, 137.2, 135.1, 133.5, 131.9, 131.3, 130.8, 129.6, 129.9, 128.8, 127.5, 125.5, 125.4, 124.1, 116.2, 112.6, 109.5, 74.8 , 72.1, 71.4, 66.7, 26.8, 25.4, 20.4
    [509] Example 17: [2-Chloro-4-({2-[(1E) -3- (2,3-dihydroxypropoxy) prop-1-enyl] phenyl} amino) phenyl] (2-methylphenyl Methanone (Compound 117)
    [510] A solution of compound 116 (70 mg) in a mixture of THF (1.0 mL) and aqueous HCl (1.0 mL, 1N) is stirred at 20 ° C. for 24 h. The reaction mixture is poured into a mixture of water and EtOAc. The organic phase is dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by chromatography eluting with a mixture of DCM / MeOH 95: 5 to give the title compound as a yellow syrup.
    [511] 13 C NMR (CDCl 3 ): δ 196.9, 149.2, 139.1, 137.9, 137.3, 135.0, 133.5, 131.9, 131.3, 130.9, 129.7, 128.8, 128.4, 128.1, 127.9, 127.3, 125.6, 125.4, 124.5, 116.0, 112.4 , 71.8, 71.7, 70.7, 63.9, 20.4
    [512]
    [513] Example 18 tert-butyl (1R) -2-{[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2- Enyl] amino} -1- (hydroxymethyl) -2-oxoethylcarbamate (compound 118)
    [514] A mixture of N- (t-butoxycarbonyl) -L-serine (30 mg) and Compound 111 (50 mg) in THF (1.0 mL) is stirred at 20 ° C. for 10 minutes. DMTMM (40 mg) is added to the mixture and stirred at 20 ° C. for 20 hours. The reaction mixture is poured into water and extracted with EtOAc (x3). The organic phases are combined, washed with brine and dried over MgSO 4 . The crude product is purified by chromatography eluting with EtOAc / trifluoroacetic acid 99: 1 to give the title compound as a yellow foam.
    [515] 13 C NMR (CDCl 3 ): δ 196.8, 171.4, 156.2, 149.0, 139.2, 137.9, 137.3, 135.0, 133.5, 131.3, 131.2, 130.9, 129.7, 128.7, 128.4, 127.6, 127.2, 126.8, 125.4, 125.1, 123.7 , 116.2, 112.6, 80.7, 62.8, 55.5, 41.5, 28.3, 20.4
    [516] Example 19: Methyl O- (t-butyl) -N-({[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop- 2-enyl] amino} carbonyl) -L-serinate (compound 119)
    [517] Compound 111 (50 mg) and O- (t-butyl) -N- (oxomethylene) -L-serinate (40 mg) in DCM (3.0 mL) are stirred at 20 ° C. for 1 hour. Ethylamine (20 mg) is added and the reaction mixture is stirred for 2 hours. It was concentrated in vacuo and then chromatographed with eluting with petroleum ether / EtOAc 2: 1 to afford the title compound as a yellow foam.
    [518] 13 C NMR (CDCl 3 ): δ 196.5, 172.9, 158.1, 149.3, 139.5, 137.7, 137.6, 134.9, 133.6, 131.2, 131.1, 130.6, 129.5, 129.0, 128.3, 127.9, 127.2, 126.3, 125.3, 124.5, 123.0 , 116.6, 127.7, 73.5, 62.4, 54.0, 46.1, 27.3, 20.4
    [519] Example 20 N- (t-butyl) -N '-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2- Enyl] thiourea (compound 120)
    [520] A mixture of t-butyl isothiocyanate (19 mg) and compound 111 (50 mg) in DCM (3.0 mL) is stirred at 20 ° C. for 1.5 h. Ethylamine (20 mg) is added and the reaction mixture is stirred for 24 hours. It was concentrated in vacuo and then chromatographed with eluting with petroleum ether / EtOAc 3: 1 to afford the title compound.
    [521] 13 C NMR (CDCl 3 ): δ 196.6, 181.4, 149.0, 139.2, 137.8, 137.2, 135.0, 133.6, 131.9, 131.3, 130.8, 129.6, 128.8, 128.5, 127.9, 127.8, 127.4, 125.5, 125.4, 124.0, 116.1 , 112.5, 53.0, 47.5, 29.5, 20.4
    [522] Example 21 N-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -4-oxopentanamide ( Compound 121)
    [523] The reaction is carried out using 4-oxopentanoic acid (25 mg) as described for the preparation of compound 118. Purification by flash chromatography eluting with a mixture of petroleum ether / EtOAc 2: 3 affords the title compound.
    [524] 13 C NMR (CDCl 3 ): δ 208.5, 196.5, 172.0, 149.1, 139.4, 137.8, 137.3, 135.0, 133.6, 131.2, 131.0, 130.7, 129.6, 128.4, 128.4, 128.2, 127.1, 125.7, 125.3, 124.9, 123.4 , 116.5, 112.6, 41.3, 38.6, 29.9, 20.4
    [525]
    [526] Example 22 N-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -N'-ethylurea ( Compound 122)
    [527] A mixture of ethyl isocyanate (28 mg) and compound 111 (100 mg) in DCM (1.0 mL) is stirred at 20 ° C. for 2.5 h. The reaction mixture is poured into water and extracted with DCM (x3). The organic phases are combined, washed with brine and dried over MgSO 4 . The crude product is purified by chromatography eluting with petroleum ether / EtOAc 2: 3 to afford the title compound as a yellow syrup.
    [528] 13 C NMR (CDCl 3 ): δ 197.0, 158.7, 149.5, 139.2, 137.7, 137.1, 134.9, 133.6, 132.1, 131.3, 130.9, 129.9, 129.6, 128.4, 127.8, 127.3, 126.5, 125.4, 125.4, 124.2, 116.2 , 112.3, 42.5, 35.2, 20.4, 15.5
    [529] Example 23: ethyl 4-{[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] amino} -4- Oxobutanoate (compound 123)
    [530] The reaction is carried out as described for the preparation of compound 118 using ethyl hydrogen succinate (32 mg) as the carboxylic acid. Purification by flash chromatography eluting with a mixture of DCM / MeOH 95: 5 affords the title compound as a syrup.
    [531] 13 C NMR (CDCl 3 ): δ 196.6, 173.3, 171.7, 149.2, 139.3, 137.7, 137.3, 135.0, 133.6, 131.4, 131.2, 130.8, 129.6, 128.5, 128.3, 128.2, 127.2, 126.5, 125.4, 125.2, 123.8 , 116.2, 112.5, 60.9, 41.6, 30.9, 29.5, 20.4, 14.1
    [532] Example 24 N-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -N'-cyclohexylurea (Compound 124)
    [533] The reaction is carried out as described in the process for the preparation of compound 122 using cyclohexyl isocyanate (40 mg). Purification by flash chromatography eluting with a mixture of petroleum ether / EtOAc 1: 1 yields the title compound as a syrup.
    [534] 13 C NMR (CDCl 3 ): δ 196.8, 157.8, 149.2, 139.2, 137.8, 137.1, 134.9, 133.5, 132.0, 131.3, 130.9, 130.0, 129.7, 128.5, 128.1, 127.4, 126.7, 125.4, 125.3, 124.0, 116.3 , 112.5, 49.1, 42.6, 33.9, 25.6, 25.0, 20.4
    [535] Example 25 N '-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -N, N-dimethyl Succiamide (Compound 125)
    [536] The reaction is carried out as described in the preparation method of compound 118 using N, N-dimethylsuccinic acid (32 mg) as the carboxylic acid. Purification by flash chromatography eluting with a mixture of EtOAc / MeOH 95: 5 affords the title compound as a syrup.
    [537] 13 C NMR (CDCl 3 ): δ 196.5, 172.7, 172.1, 149.6, 139.6, 137.6, 137.5, 135.1, 133.7, 131.1, 130.6, 129.4, 128.2, 127.8, 126.9, 125.6, 125.3, 124.7, 123.5, 116.1, 112.3 , 41.4, 37.1, 35.7, 31.2, 28.6, 20.3
    [538] Example 26: Dimethyl [(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] malonate (Compound 126)
    [539] The reaction is carried out as described in the method for the preparation of compound 108 using compound 405 (300 mg) as stanan. Purification by flash chromatography eluting with a mixture of petroleum ether / EtOAc 6: 1 affords the title compound as a yellow syrup.
    [540] 13 C NMR (CDCl 3 ): δ 196.4, 169.2, 148.6, 139.3, 137.8, 137.1, 135.1, 133.6, 131.8, 131.2, 130.8, 129.6, 129.0, 128.7, 128.5, 127.7, 125.3, 125.0, 123.1, 116.2, 112.6 , 52.6, 51.6, 32.4, 20.4
    [541] Example 27: [2-Chloro-4- (2-[(1E) -3-morpholin-4-ylprop-1-enyl] phenyl} amino) phenyl] (2-methylphenyl) methanone (Compound 127 )
    [542] The reaction is carried out as described in the process for the preparation of compound 108 using compound 406 (466 mg) as stanan. Purification by flash chromatography eluting with EtOAc affords the title compound as a yellow foam.
    [543] 13 C NMR (CDCl 3 ): δ 196.4, 149.0, 139.3, 137.8, 136.9, 135.1, 133.5, 132.4, 131.3, 130.8, 129.6, 128.9, 128.7, 128.7, 127.3, 125.8, 125.4, 124.6, 115.9, 112.5, 66.9 , 61.5, 53.7, 20.4
    [544] Example 28: 6-O-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -1,2: 3,4-di-O- (1-methylethylidene) -α-D-galactopyranose (compound 128)
    [545] The reaction is carried out as described in the method for the preparation of compound 108 using compound 407 (400 mg) as stanan. Purification by flash chromatography eluting with a mixture of petroleum ether / EtOAc 5: 1 affords the title compound as a yellow syrup.
    [546] 13 C NMR (CDCl 3 ): δ 196.4, 148.7, 139.3, 137.8, 137.3, 135.1, 133.6, 131.6, 131.2, 130.7, 129.6, 129.3, 128.7, 128.6, 127.6, 127.3, 125.3, 125.1, 123.5, 116.3, 112.6 , 109.4, 108.6, 96.4, 71.8, 71.3, 70.7, 70.5, 69.4, 67.1, 26.1, 26.0, 24.9, 24.5, 20.4
    [547] Example 29: Methyl 5-O-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -2,3 -O- (1-methylethylidene) -β-D-ribofuranoside (Compound 129)
    [548] The reaction is carried out as described in the process for the preparation of compound 108 using compound 408 (427 mg) as stanan. Purification by flash chromatography eluting with a mixture of petroleum ether / EtOAc 6: 1 affords the title compound as a yellow syrup.
    [549] 13 C NMR (CDCl 3 ): δ 196.4, 148.8, 139.3, 137.8, 137.2, 135.1, 133.6,131.7, 131.2, 130.8, 129.6, 129.0, 128.8, 127.5, 127.4, 125.4, 125.3, 123.9, 116.2, 112.6, 112.5 , 109.4, 85.2, 82.1, 71.8, 71.5, 54.9, 26.5, 25.0, 20.4
    [550] Example 30 Methyl 5-O-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -β-D Ribofuranoside (Compound 130)
    [551] Compound 129 (50 mg) is dissolved in 80% aqueous acetic acid (1.0 mL) and the mixture is stirred at 50 ° C. for 7 days. The reaction mixture is poured into saturated aqueous Na 2 CO 3 (10 mL) and the aqueous phase is extracted with EtOAc (3 × 10 mL). The combined organic phases are dried (Na 2 SO 4 ), filtered and evaporated in vacuo. Purification by flash chromatography eluting with a mixture of petroleum ether / EtOAc 1: 4 affords the title compound as a yellow foam.
    [552] 13 C NMR (CDCl 3 ): δ 197.4, 149.2, 138.8, 138.2, 137.0, 134.9, 133.3, 132.4, 131.4, 131.1, 130.1, 128.8, 128.7, 127.4, 127.3, 125.9, 125.4, 124.8, 116.0, 112.4, 108.4 , 81.7, 75.1, 72.4, 71.9, 71.7, 55.3, 20.6
    [553] Example 31 Methyl (4E) -5- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -2- (methylsulfonyl) pent-4-enoate (compound 131)
    [554] The reaction is carried out as described in the process for the preparation of compound 108 using compound 409 (250 mg) as stanan. Purification by flash chromatography eluting with a mixture of petroleum ether / EtOAc 3: 1 affords the title compound as a syrup.
    [555] 13 C NMR (CDCl 3 ): δ 196.4, 166.5, 148.6, 139.2, 137.9, 137.3, 135.0, 133.5, 131.5, 131.3, 130.8, 130.2, 129.7, 128.9, 128.9, 127.6, 126.1, 125.4, 125.3, 123.8, 116.1 , 112.6, 68.8, 53.5, 39.4, 30.4, 20.4
    [556] Example 32: Ethyl {[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] thio} acetate (Compound 132)
    [557] The reaction is carried out as described in the process for the preparation of compound 108 using compound 410 (300 mg) as stanan. Purification by flash chromatography eluting with a mixture of petroleum ether / EtOAc 10: 1 affords the title compound as a syrup.
    [558] 13 C NMR (CDCl 3 ): δ 196.4, 171.0, 148.6, 139.3, 137.8, 137.5, 135.1, 133.6, 131.2, 131.0, 130.7, 129.6, 129.3, 128.7, 127.5, 127.0, 125.3, 124.8, 122.9, 116.4, 112.6 , 61.6, 35.2, 32.4, 20.4, 14.1
    [559] Example 33: [2-Chloro-4-{[2-((1E) -3- {bis [2- (acetyloxy) ethyl] amino} prop-1-enyl) phenyl] amino) phenyl] (2 -Methylphenyl) methanone (compound 133)
    [560] The reaction is carried out as described in the process for the preparation of compound 108 using compound 412 (454 mg) as stanan. Purification by flash chromatography eluting with a mixture of petroleum ether / EtOAc 1: 2 affords the title compound as a foam.
    [561] 13 C NMR (CDCl 3 ): δ 196.4, 171.2, 149.0, 139.4, 137.8, 137.4, 135.1, 133.6, 131.9, 131.2, 130.7, 129.7, 129.6, 128.5, 128.3, 127.5, 125.3, 125.1, 123.5, 116.4, 112.6 , 62.4, 57.6, 52.8, 21.0, 20.4
    [562] Example 34: [2-Chloro-4-{[2-((1E) -3- {bis [2- (hydroxy) ethyl] amino} prop-1-enyl) phenyl] amino} phenyl] (2 -Methylphenyl) methanone (compound 134)
    [563] The reaction is carried out as described in the process for the preparation of compound 107 using compound 133 (172 mg) as the ester. Purification by flash chromatography eluting with a mixture of DCM / MeOH 10: 1 affords the title compound as a yellow syrup.
    [564] 13 C NMR (CDCl 3 ): δ 196.6, 149.1, 139.2, 137.9, 137.1, 135.0, 133.5, 132.0, 131.3, 130.8, 129.7, 129.2, 128.6, 128.6, 128.5, 127.4, 125.4, 125.3, 124.0, 116.1, 112.6 , 59.6, 57.0, 56.0, 20.4
    [565] Example 35: (2-Chloro-4-{[2-((1E) -3- {4- [2- (acetyloxy) ethyl] piperidin-1-yl} prop-1-enyl) phenyl ] Amino} phenyl) (2-methylphenyl) methanone (Compound 135)
    [566] The reaction is carried out as described in the process for the preparation of compound 108 using compound 413 (280 mg) as stanan. Purification by flash chromatography eluting with EtOAc affords the title compound as a foam.
    [567] 13 C NMR (CDCl 3 ): δ 196.5, 171.1, 149.0, 139.3, 137.8, 1370.0, 135.1, 133.5, 132.3, 131.2, 130.8, 129.6, 129.1, 128.7, 128.6, 127.3, 125.6, 125.3, 124.4, 116.0, 112.5 , 62.4, 61.3, 53.8, 35.1, 32.5, 31.9, 21.0, 20.4
    [568] Example 36 {2-chloro-4-[(2-{(1E) -3- [4- (2-hydroxyethyl) piperidin-1-yl] prop-1-enyl} phenyl) amino ] Phenyl} (2-methylphenyl) methanone (Compound 136)
    [569] The reaction is carried out as described in the process for the preparation of compound 107 using compound 135 (170 mg) as an ester. Purification by flash chromatography eluting with a mixture of DCM / MeOH 17: 3 affords the title compound as a yellow solid.
    [570] 13 C NMR (CDCl 3 ): δ 196.6, 149.0, 139.3, 137.8, 137.5, 135.0, 133.5, 131.4, 131.2, 130.8, 129.6, 128.9, 128.5, 127.3, 125.3, 125.2, 123.9, 116.1, 112.7, 60.6, 60.1 , 53.5, 38.8, 31.7, 31.1, 20.4
    [571]
    [572] Example 37: {2-chloro-4-[(2- {2-[(tetrahydrofuran-2-ylmethyl) amino] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone (Compound 137)
    [573] Compound 102 (0.15 g, 0.41 mmol) was dissolved in pyridine (0.2 mL) at 0 ° C. and p-toluenesulfonyl chloride (0.086 g, 0.45 mmol) was added. The suspension is stirred at 0 ° C. for 45 minutes and then amine (tetrahydro-furfuryl amine, 0.127 mL, 1.23 mmol) is added. The reaction mixture is stirred for 18 hours at room temperature. H 2 0 (10 mL) is added and the aqueous phase is extracted with EtOAc (5 × 10 mL). The combined organic phases are washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using EtOAc / MeOH / Et 3 N 10: 1: 0.1 as eluent to afford the title compound as a yellow oil.
    [574] 13 C NMR (CDCl 3 ): δ 196.4, 149.3, 139.9, 137.5, 135.3, 134.4, 134.0, 131.2, 131.1, 130.4, 129.3, 127.3, 127.2, 125.3, 123.8, 121.8, 116.2, 112.1, 78.0, 68.0, 54.6 , 51.7, 33.5, 29.4, 25.7, 20.3
    [575] Example 38: [2-Chloro-4-({2- [2- (4-methylpiperazin-1-yl) ethyl] phenyl} amino) phenyl] (2-methylphenyl) methanone (Compound 138)
    [576] The reaction is carried out as described for the preparation of compound 137 using 1-methylpiperazine (0.137 mL, 1.23 mmol) as the amine. The workup is carried out as described in the preparation of compound 137 and the crude product is purified by flash chromatography eluting with EtOAc / EtOH / Et 3 N 7: 1: 0.5 to afford the title compound as a yellow oil.
    [577] 13 C NMR (CDCl 3 ): δ 196.3, 149.1, 139.8, 139.6, 137.7, 135.3, 134.7, 133.8, 131.2, 130.6, 129.4, 128.0, 127.2, 125.3, 123.8, 121.4, 116.8, 112.8, 60.8, 55.2, 54.0 , 46.1, 30.9, 20.4
    [578] Example 39: {2-chloro-4-[(2- {2-[(3-morpholin-4-ylpropyl) amino] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone (Compound 139 )
    [579] The reaction is carried out as described for the preparation of compound 137 using 1-morpholino-3-aminopropane (0.18 mL, 1.23 mmol) as the amine. The workup is carried out as described in the preparation of compound 137 and the crude product is purified by flash chromatography eluting with EtOAc / EtOH / Et 3 N 5: 1: 0.5 to afford the title compound as an orange oil.
    [580] 13 C NMR (CDCl 3 ): δ 196.7, 149.6, 140.2, 140.0, 137.9, 135.7, 134.3, 133.9, 131.5, 131.4, 130.9, 129.8, 127.9, 127.8, 125.7, 124.4, 122.6, 116.4, 112.6, 67.2, 57.9 , 54.2, 51.4, 49.5, 33.0, 26.1, 20.7
    [581] Example 40: (2-Chloro-4-{[2- (2-{[2- (dimethylamino) ethyl] amino} ethyl) phenyl] amino} phenyl) (2-methylphenyl) methanone (Compound 140)
    [582] The reaction is carried out as described in the preparation method of compound 137 using 2-dimethylamino-ethylamine (0.13 mL, 1.23 mmol) as the amine. The workup is carried out as described in the preparation of compound 137 and the crude product is purified by flash chromatography eluting with EtOAc / EtOH / Et 3 N 4: 1: 0.5. This gives the title compound as a yellow oil.
    [583] 13 C NMR (CDCl 3 ): δ 196.4, 149.4, 139.8, 139.8, 137.5, 135.3, 133.9, 131.1, 131.1, 130.5, 129.4, 127.4, 125.3, 123.9, 121.9, 116.2, 112.1, 58.2, 51.2, 47.0, 45.3 , 33.0, 20.3
    [584] Example 41: {2-chloro-4-[(2- {2-[(2-methoxyethyl) amino] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone (Compound 141)
    [585] The reaction is carried out as described for the preparation of compound 137 using 2-methoxy-ethylamine (0.11 mL, 1.23 mmol) as the amine. The workup is carried out as described in the preparation of compound 137 and the crude product is purified by flash chromatography eluting with EtOAc / MeOH / Et 3 N 4: 1: 0.5. This gives the title compound as a yellow oil.
    [586] 13 C NMR (CDCl 3 ): δ 196.4, 149.2, 13.8, 139.8, 137.5, 135.3, 134.2, 133.9, 131.2, 131.1, 130.5, 129.4, 127.4, 127.3, 125.3, 123.8, 121.7, 116.2, 112.1, 71.5, 58.9 , 51.4, 49.4, 33.3, 20.3
    [587] Example 42 1- [3-({2- [2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethyl} amino) propyl] pyrrolidine-2 -On (Compound 142)
    [588] Compound 102 (0.15 g, 0.41 mmol) was dissolved in pyridine (0.2 mL) at 3 ° C. and p-toluenesulfonyl chloride (0.086 g, 0.45 mmol) was added. The suspension is stirred at 3 ° C. for 45 minutes and then amine (1- (2-aminopropyl) -2-pyrrolidinone, 0.18 mL, 1.23 mmol) is added. The reaction mixture is stirred at 3 ° C. for 3 days. Work up as described in the preparation of compound 137 and the crude product is purified by flash chromatography eluting with EtOAc / EtOH / Et 3 N 4: 1: 0.5. This gives the title compound as a yellow oil.
    [589] 13 C NMR (CDCl 3 ): δ 196.4, 175.5, 149.3, 139.7, 139.6, 137.5, 135.2, 134.0, 134.0, 131.2, 131.1, 130.5, 129.4, 127.4, 127.3, 125.3, 124.0, 122.0, 116.0, 112.2, 51.0 , 47.2, 46.6, 39.9, 33.0, 30.9, 27.0, 20.3, 17.9
    [590] Example 43: {2-Chloro-4-[(2- {2- [methyl (tetrahydrofuran-2-ylmethyl) amino] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone (Compound 143 )
    [591] The reaction is carried out as described for the preparation of compound 142 using N-methyl-tetrahydrofurfurylamine (0.14 g, 1.23 mmol) as the amine. The workup is carried out as described in the preparation of compound 137 and the crude product is purified by flash chromatography eluting with EtOAc / MeOH / Et 3 N 20: 1: 0.1. This gives the title compound as a yellow oil.
    [592] 13 C NMR (CDCl 3 ): δ 196.4, 155.8, 149.5, 140.0, 139.9, 137.5, 135.3, 134.7, 134.0, 131.2, 131.1, 130.4, 129.3, 127.1, 125.3, 123.6, 121.4, 116.4, 112.3, 76.8, 67.9 , 63.2, 60.9, 42.9, 31.5, 30.2, 25.3, 20.3
    [593] Example 44: (2-Chloro-4-{[2- (2-{[2,2-dimethyl-1,3-dioxolan-4-yl) methyl] amino} ethyl) phenyl] amino} phenyl) ( 2-methylphenyl) methanone (Compound 144)
    [594] The reaction is carried out as described for the preparation of compound 142 using 2,2-dimethyl-1,3-dioxolane-4-methanamine (0.16 mL, 1.23 mmol) as the amine. The workup is carried out as described in the preparation of compound 137 and the crude product is purified by flash chromatography eluting with EtOAc / MeOH / Et 3 N 15: 1: 0.1. This gives the title compound as a yellow oil.
    [595] 13 C NMR (CDCl 3 ): δ 196.4, 149.2, 139.7, 137.6, 135.3, 134.4, 133.9, 131.2, 131.1, 130.5, 129.4, 127.5, 127.3, 125.3, 124.1, 122.1, 116.1, 112.1, 109.5, 75.0, 67.3 , 53.1, 51.8, 33.6, 26.9, 25.2, 20.3
    [596] Example 45: {2-chloro-4-[(2- {2- [4- (2-methoxyethyl) piperazin-1-yl] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone (Compound 145)
    [597] The reaction is carried out as described for the preparation of compound 142 using 1- (2-methoxyethyl) -piperazine (0.18 mL, 1.23 mmol) as the amine. The workup is carried out as described for the preparation of compound 137 and the crude product is purified by flash chromatography eluting with EtOAc / EtOH / Et 3 N 15: 1: 0.1. This gives the title compound as a yellow oil.
    [598] 13 C NMR (CDCl 3 ): δ 196.3, 149.1, 139.8, 139.6, 137.6, 135.3, 134.7, 133.8, 131.2, 130.6, 129.4, 127.9, 127.2, 125.3, 123.7, 121.3, 116.8, 112.8, 70.0, 60.9, 58.9 , 57.9, 54.0, 53.6, 30.9, 20.3
    [599] Example 46: (2-chloro-4-{[(2- (2-morpholin-4-ylethyl) phenyl] amino} phenyl) (2-methylphenyl) methanone (Compound 146)
    [600] The reaction is carried out as described for the preparation of compound 142. Starting materials are compound 102 (2.0 g) 5.45 mmol) in pyridine (2.7 mL), p-toluenesulfonyl chloride (1.15 g, 6.0 mmol), and morpholine (1.43 mL, 16.4 mmol) as an amine. The workup is carried out as described in the preparation of compound 137 and the crude product is purified by flash chromatography eluting with EtOAc / petroleum ether 1: 2 and 1: 0. This gives the title compound as a yellow crystalline compound.
    [601] 13 C NMR (CDCl 3 ): δ 196.3, 149.1, 139.5, 139.5, 137.7, 135.3, 134.7, 133.8, 131.2, 131.1, 130.6, 129.5, 128.1, 127.4, 125.3, 124.1, 122.0, 116.3, 112.7, 67.1, 61.3 , 54.4, 30.4, 20.4
    [602] Example 47: {2-Chloro-4-[(2- {2-[(2,3-dihydroxypropyl) amino] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone (Compound 147)
    [603] Compound 144 is dissolved in 1M HCl / THF 1: 1 (1.2 mL) and the mixture is stirred for 18 hours at room temperature. The reaction mixture is poured into 10% aqueous NaHCO 3 (10 mL) and the aqueous phase is extracted with EtOAc (3 × 10 mL). The combined organic phases are dried (MgSO 4 ), filtered and concentrated in vacuo. This gives the title compound as a yellow oil.
    [604] 13 C NMR (CDCl 3 ): δ 196.7, 149.6, 139.4, 139.0, 137.7, 135.2, 134.2, 133.8, 131.2, 131.0, 130.7, 129.5, 127.8, 127.6, 125.3, 125.1, 123.8, 115.8, 112.1, 70.1, 65.3 , 52.1, 50.7, 32.3, 20.4
    [605] Example 48: (4-{[2- (aminomethyl) phenyl] amino} -2-chlorophenyl) (2-methylphenyl) methanone (Compound 148)
    [606] Compound 154 (2.17 g, 4.51 mmol) was dissolved in DCM (50 mL) and EtOH (10 mL). Hydrazine hydrate (0.44 mL, 9.0 mmol) is added and the reaction mixture is stirred for 4 days at room temperature. The suspension is filtered and the filtrate is concentrated in vacuo. The crude product is purified by flash chromatography using EtOAc / MeOH / Et 3 N 10: 1: 0.1 as eluent. This gives the title compound as a yellow oil.
    [607] 13 C NMR (CDCl 3 ): δ 196.4, 147.8, 141.1, 139.5, 137.7, 135.1, 133.7, 131.2, 130.7, 130.0, 129.5, 128.4, 128.4, 125.3, 122.4, 119.2, 116.8, 113.1, 45.4, 20.4
    [608]
    [609] Example 49: (2-chloro-4-{[2-({2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethoxy} methyl) phenyl] amino} phenyl) ( 2-methylphenyl) methanone (Compound 149)
    [610] Compound 420 (3.39 g, 10.3 mmol) was dissolved in 5 ml of anhydrous 1,4-dioxane in a Schlenk tube under an argon atmosphere. (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (reference: WO 01/42189) is added and dissolved in a solvent. Rac-BINAP (0.26 g, 0.42 mmol), Pd 2 (dba) 3 (0.19 g, 0.20 mmol) and Cs 2 CO 3 (4.7 g, 14.4 mmol) were added and the reaction mixture was 18 h at 100 ° C. under an argon atmosphere. Stir while. The reaction mixture is diluted with H 2 0 and EtOAc and the aqueous phase is extracted twice with EtOAc. The combined organic phases are washed with brine, dried (MgSO 4 ) and evaporated in vacuo. The crude product is purified by flash chromatography using DCM / acetone 100: 1 as eluent to afford the title compound as an oil.
    [611] 13 C NMR (CDCl 3 ): δ 196.4, 147.9, 140.9, 139.4, 137.8, 135.0, 133.6, 131.2, 130.7, 130.4, 129.6, 129.3, 128.7, 128.5, 125.3, 122.8, 120.1, 116.9, 113.3, 99.1, 72.3 , 70.6, 70.3, 69.4, 66.6, 62.3, 30.6, 25.4, 20.4, 19.5
    [612] Example 50: {2-Chloro-4-[(2-{[(tetrahydro-2H-pyran-2-yloxy) ethoxy] methyl} phenyl) amino] phenyl} (2-methylphenyl) methanone (compound 150)
    [613] The reaction and workup are carried out as described for the preparation of compound 149. Starting materials were compound 422 (8.3 g, 26.3 mmol), (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (6.47 g, 26.3 mmol) in 38 mL of dioxane anhydride (reference WO 01 / 42189), rac-BINAP (0.67 g, 1.07 mmol), Pd 2 (dba) 3 (0.48 g, 0.52 mmol) and Cs 2 CO 3 (11.98 g, 36.8 mmol). The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 2 as eluent to afford the title compound as an oil.
    [614] 13 C NMR (CDCl 3 ): δ 196.4, 147.7, 140.9, 139.3, 137.8, 135.0, 133.5, 131.2, 130.7, 130.5, 129.6, 129.2, 128.9, 128.3, 125.3, 122.7, 119.8, 117.1, 113.2, 99.4, 72.3 , 69.4, 66.6, 62.7, 30.7, 25.3, 20.4, 19.8
    [615] Example 51: [2-Chloro-4-({2-[(2- {2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethoxy} ethoxy) methyl] phenyl } Amino) phenyl] (2-methylphenyl) methanone (Compound 151)
    [616] The reaction and workup are carried out as described for the preparation of compound 149. Starting materials were compound 421 (3.12 g, 7.74 mmol), (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (2.06 g, 8.37 mmol) in 15 mL of anhydrous dioxane (Reference WO 01 / 42189), rac-BINAP (0.21 g, 0.34 mmol), Pd 2 (dba) 3 (0.15 g, 0.17 mmol) and Cs 2 CO 3 (3.8 g, 11.7 mmol). The crude product is purified by flash chromatography using EtOAc / petroleum ethers 1: 2, 1: 1 and 1: 0 as eluent to afford the title compound as an oil.
    [617] 13 C NMR (CDCl 3 ): δ 196.4, 147.9, 140.8, 139.4, 137.8, 135.0, 133.6, 131.2, 130.7, 130.5, 129.6, 129.3, 128.7, 128.5, 125.3, 122.8, 120.1, 117.0, 113.2, 99.0, 72.2 , 70.6, 70.4, 69.4, 66.6, 62.2, 30.6, 25.4, 20.4, 19.5
    [618] Example 52: [2-Chloro-4-({2-[(3,3,3-trifluoropropoxy) methyl] phenyl} amino) phenyl] (2-methylphenyl) methanone (Compound 152)
    [619] The reaction and workup are carried out as described for the preparation of compound 149. The starting material was (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (0.19 g, 0.79 mmol) in 4 mL of 1,4-dioxane anhydrous (reference WO 01/42189 A1) and compound 419 (0.22 g, 0.97 mmol), rac-BINAP (20.0 mg, 0.03 mmol), Pd 2 (dba) 3 (14 mg, 0.016 mmol) and Cs 2 CO 3 (0.36 g, 1.1 mmol). The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 2 as eluent to afford the title compound as an oil.
    [620] 13 C NMR (CDCl 3 ): δ 196.4, 147.3, 140.6, 139.2, 137.9, 135.0, 133.5, 131.3, 130.8, 130.6, 129.7, 29.6, 129.4, 127.6, 126.3, 125.4, 122.9, 120.0, 117.0, 113.6, 72.3 , 63.0, 34.4, 20.5
    [621] Example 53: Diethyl 2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzylphosphonate (Compound 153)
    [622] The reaction and workup are carried out as described for the preparation of compound 149. The starting material was (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (0.44 g, 1.79 mmol) in 15 mL of 1,4-dioxane anhydride (reference WO 01/42189 A1) and compounds 418 (0.55 g, 1.97 mmol), rac-BINAP (44 mg, 0.07 mmol), Pd 2 (dba) 3 (33 mg, 0.04 mmol) and Cs 2 CO 3 (0.82 g, 2.51 mmol). After 16 hours at about 100 ° C., rac-BINAP (44 mg, 0.07 mmol) and Pd 2 (dba) 3 (33 mg, 0.04 mmol) are added and stirred at 100 ° C. for 7 hours. Post-treatment is carried out as described for the preparation of compound 149. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 1 as eluent to afford the title compound as a brown oil.
    [623] 13 C NMR (CDCl 3 ): δ 195.7, 148.0, 139.4, 138.8, 137.0, 134.5, 133.0, 131.4, 130.5, 129.9, 128.8, 127.4, 124.6, 124.0, 123.7, 122.3, 115.6, 112.1, 62.1, 30.4, 19.7 , 15.7
    [624] Example 54: 2- [2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] -1H-isoindole-1,3 (2H) -dione (Compound 154)
    [625] The reaction and workup are carried out as described for the preparation of compound 149. Starting materials were (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (3.1 g, 12.7 mmol) in 125 mL of anhydrous toluene (reference WO 01/42189 A1) and compound 423 (4.0 g, 12.65 mmol), rac-BINAP (0.47 g, 0.76 mmol), Pd 2 (dba) 3 (0.35 g, 0.38 mmol) and Cs 2 CO 3 (5.77 g, 17.7 mmol). After 18 hours of stirring at 100 ° C., rac-BINAP (0.24 g, 0.38 mmol) and Pd 2 (dba) 3 (0.17 g, 0.19 mmol) are added and the reaction mixture is further stirred at 100 ° C. for 8 hours. Post-treatment is carried out as described for the preparation of compound 149. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 3 as eluent to afford the title compound as a yellow crystalline compound.
    [626] 13 C NMR (CDCl 3 ): δ 196.4, 168.9, 148.4, 139.4, 137.8, 135.2, 134.4, 133.6, 132.7, 131.9, 131.2, 130.7, 129.6, 129.5, 128.7, 128.2, 125.3, 124.2, 123.6, 122.2, 116.5 , 112.9, 37.9, 20.4
    [627]
    [628] Example 55: {2-chloro-4-[(2-{[2- (2-hydroxyethoxy) ethoxy] methyl} phenyl) amino] phenyl} (2-methylphenyl) methanone (Compound 155)
    [629] Compound 149 (5.68 g, 10.8 mmol) was added to MeOH (100 mL) and p-toluenesulfonic acid (3.09 g, 16.3 mmol) was added. The solution is stirred at room temperature for 2 hours. Aqueous NaHCO 3 (5%, 100 mL) is added and the aqueous phase is extracted with EtOAc (3 × 50 mL). The combined organic phases are washed with brine (50 mL), dried (MgSO 4 ) and evaporated in vacuo. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 1 to 3: 2 as eluent to afford the title compound as an orange oil.
    [630] 13 C NMR (CDCl 3 ): δ 196.4, 147.7, 140.7, 139.3, 137.9, 135.0, 133.5, 131.2, 130.8, 130.5, 129.7, 129.4, 129.0, 128.3, 125.4, 122.9, 120.1, 117.0, 113.3, 72.5, 72.2 , 70.3, 69.2, 61.8, 20.4
    [631] Example 56: [2-Chloro-4-({2-[(hydroxyethoxy) methyl] phenyl} amino) phenyl] (2-methylphenyl) methanone (Compound 156)
    [632] The reaction and workup are carried out as described for the preparation of compound 155. Starting materials are compound 150 (13 g, 27 mmol) and p-toluenesulfonic acid (7.6 g, 40.4 mmol) in 290 mL methanol. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 2 to 1: 1 as eluent to afford the title compound as a yellow oil.
    [633] 13 C NMR (CDCl 3 ): δ 196.6, 147.7, 140.7, 139.3, 137.8, 135.0, 133.5, 131.2, 130.8, 130.5, 129.6, 129.4, 128.9, 128.3, 125.4, 122.9, 120.0, 117.0, 113.4, 72.1, 71.3 , 61.7, 20.4
    [634] Example 57: (2-Chloro-4-{[2-({2- [2- (2-hydroxyethoxy) ethoxy] ethoxy} methyl) phenyl] amino} phenyl) (2-methylphenyl) methane On (Compound 157)
    [635] The reaction and workup are carried out as described for the preparation of compound 155. Starting materials are compound 151 (4.4 g, 7.75 mmol) and p-toluenesulfonic acid (2.2 g, 11.6 mmol) in 100 mL of MeOH. The crude product is purified by flash chromatography using EtOAc / petroleum ether 3: 1 as eluent to afford the title compound as an orange oil.
    [636] 13 C NMR (CDCl 3 ): δ 196.4, 148.1, 140.7, 139.4, 137.8, 135.0, 133.6, 131.2, 130.7, 130.7, 129.6, 129.4, 128.8, 128.6, 125.3, 123.1, 120.7, 116.9, 113.0, 72.5, 72.1 , 70.5, 70.3, 70.3, 69.3, 61.7, 20.4
    [637]
    [638] Example 58: [4-({4-bromo-2-[(2-hydroxyethoxy) methyl] phenyl} amino) -2-chlorophenyl] (2-methylphenyl) methanone (Compound 158)
    [639] Compound 156 (3.8 g, 9.6 mmol) was dissolved in DMSO (115 mL). The solution is cooled in an ice bath and slowly added 48% aqueous HBr (32 mL, 285 mmol). The solution is stirred for 5 days in a closed vessel at room temperature. The reaction mixture was cooled in an ice bath and 27% aqueous NaOH (30 mL) was added to give a solution for base. The aqueous phase is extracted three times with EtOAc and the combined organic phases are washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 1 as eluent to afford the title compound as a slightly colored crystalline compound.
    [640] 13 C NMR (CDCl 3 ): δ 196.5, 147.0, 140.0, 139.0, 138.0, 134.9, 133.3, 133.1, 132.1, 131.3, 130.9, 130.1, 129.8, 129.6, 125.4, 121.1, 117.4, 114.8, 113.8, 71.5, 71.4 , 61.7, 20.5
    [641] Example 59: (4-{[4-bromo-2-({2- [2- (2-hydroxyethoxy) ethoxy] ethoxy} methyl) phenyl] amino} -2-chlorophenyl) ( 2-methylphenyl) methanone (Compound 159)
    [642] The reaction and workup are carried out as described for the preparation of compound 158. Starting materials are compound 157 (2.14 g, 2.56 mmol) and 48% water soluble HBr (8.6 mL, 76.8 mmol) in 36 mL DMSO. The reaction time is 8 days. The crude product is purified by flash chromatography eluting with EtOAc / petroleum ether 3: 1 to afford the title compound as a yellow oil.
    [643] 1 H NMR (CDCl 3 ): δ 7.48 (1H, bs), 7.24-7.45 (7H, m), 7.20 (1H, t), 7.04 (1H, d), 6.90 (1H, dd), 4.51 (2H, s), 3.55-3.75 (12H, m), 2.45 (3H, s)
    [644] Example 60: {4-[(4-bromo-2-{[2- (2-hydroxyethoxy) ethoxy] methyl} phenyl) amino] -2-chlorophenyl} (2-methylphenyl) methanone (Compound 160)
    [645] The reaction and workup are carried out as described for the preparation of compound 158. Starting materials are compound 155 (1.19 g, 2.70 mmol) and 48% water soluble HBr (9.1 mL, 81.1 mmol) in 36 mL DMSO. The reaction time is 8 days. The crude product is purified by flash chromatography eluting with EtOAc / petroleum ether 3: 1 to afford the title compound as an orange oil.
    [646] 13 C NMR (CDCl 3 ): δ 196.4, 147.0, 140.0, 139.0, 138.0, 134.9, 133.4, 133.2, 132.2, 131.3, 130.9, 130.1, 129.8, 129.7, 125.4, 121.2, 117.4, 114.8, 113.6, 72.5, 71.6 , 70.2, 69.3, 61.8, 20.5
    [647] Example 61 diethyl 5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzylphosphonate (Compound 161)
    [648] The reaction is carried out as described in the preparation of Compound 158 using Compound 153 (0.11 g, 0.23 mmol) and 48% water soluble HBr (0.77 mL, 6.9 mmol) in DMSO (3 mL). The reaction time is 11 days. The reaction is quenched with water soluble NaHC0 3 (10%, 10 mL). The aqueous phase is extracted with EtOAc and the combined organic phases are washed with H 2 O and brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography eluting with EtOAc / petroleum ether 1: 1 to afford the title compound as a slightly colored oil.
    [649] 13 C NMR (CDCl 3 ): δ 196.4, 148.0, 139.4, 139.3, 137.8, 135.1, 134.6, 133.5, 131.2, 130.8, 129.6, 128.8, 126.7, 125.3, 124.0, 124.0, 116.6, 116.4, 113.1, 63.0, 30.9 , 20.4, 16.4
    [650] Example 62: [4-({4-bromo-2-[(3,3,3-trifluoropropoxy) methyl] phenyl} amino) -2-chlorophenyl] (2-methylphenyl) fetanone ( Compound 162)
    [651] The reaction is carried out as described in the preparation of Compound 158 using Compound 152 (0.10 g, 0.22 mmol) and 48% water soluble HBr (0.75 mL, 6.70 mmol) in DMSO (2.65 mL). The reaction time is 6 days. The crude product is purified by flash chromatography eluting with EtOAc / petroleum ether 1: 4 as eluent. This gives the title compound as a yellow oil.
    [652] 1 H NMR (CDCl 3 ): δ 7.5-7.25 (7H, m), 7.20 (1h, t), 7.00 (1H, d), 6.92 (1H, bs), 6.84 (1H, dd), 4.51 (2H, s), 3.71 (2H, t), 2.55-2.35 (2H, m), 2.46 (3H, s)
    [653]
    [654] Example 63: 2-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl 4-methylbenzenesulfonate (Compound 163)
    [655] Compound 156 (1.0 g, 2.55 mmol) was dissolved in pyridine (1.3 mL) under argon atmosphere. The solution is cooled in an ice bath and p-toluenesulfonyl chloride (0.56 g, 2.9 mmol) is added. The suspension is stirred for 3 days at room temperature. The reaction is quenched with water and the aqueous phase is washed twice with EtOAc. The combined organic phases are washed with brine, dried (Na 2 SO 4 ), filtered and evaporated in vacuo. The crude product is purified by flash chromatography eluting with EtOAc / petroleum ether 1: 2. This gives the title compound as a yellow oil.
    [656] 13 C NMR (CDCl 3 ): δ 196.5, 147.4, 145.1, 140.7, 139.2, 137.9, 134.9, 133.5, 132.9, 131.3, 130.8, 130.6, 129.9, 129.7, 129.6, 129.2, 127.9, 127.6, 125.4, 122.8, 120.0 , 117.0, 113.8, 72.2, 68.9, 67.5, 21.6, 20.5
    [657] Example 64 2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl 4-methylbenzenesulfonate (Compound 164 )
    [658] The reaction is carried out as described in the preparation of compound 158 using compound 158 (1.99 g, 4.19 mmol) and p-toluenesulfonyl chloride (0.92 g, 4.19 mmol) in pyridine (4 mL). The crude product is purified by flash chromatography eluting with EtOAc / petroleum ether 1: 2 to afford the title compound as a yellow oil.
    [659] 13 C NMR (CDCl 3 ): δ 196.5, 146.7, 145.2, 140.0, 139.0, 138.1, 134.8, 133.3, 133.2, 132.8, 132.3, 131.3, 131.0, 130.0, 129.8, 129.5, 127.9, 125.4, 121.3, 117.4, 114.8 , 114.2, 71.5, 68.8, 67.6, 21.7, 20.5
    [660] Example 65: 2- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethoxy) ethyl 4-methyl Benzenesulfonate (Compound 165)
    [661] The reaction is carried out as described for the preparation of compound 163 using compound 160 (1.10 g, 2.12 mmol) and p-toluenesulfonyl chloride (0.47 g, 2.44 mmol) in pyridine (2 mL). The crude product is purified by flash chromatography eluting with EtOAc / petroleum ether 1: 2. This gives the title compound as a yellow oil.
    [662] 13 C NMR (CDCl 3 ): δ 196.4, 146.9, 144.9, 140.0, 139.0, 138.0, 134.8, 133.4, 133.1, 132.9, 132.1, 131.3, 130.9, 130.1, 129.9, 129.8, 129.6, 127.9, 125.4, 121.0, 117.3 , 114.7, 113.7, 71.5, 70.5, 69.2, 69.0, 68.8, 21.6, 20.5
    [663] Example 66: 2- [2- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethoxy) ethyl 4-methylbenzenesulfonate (Compound 166)
    [664] The reaction is carried out as described for the preparation of compound 163 using compound 159 (1.15 g, 2.04 mmol) and p-toluenesulfonyl chloride (0.45 g, 2.35 mmol) in pyridine (2 mL). The crude product is purified by flash chromatography eluting with EtOAc / petroleum ether 2: 3. This gives the title compound as a yellow oil.
    [665] 13 C NMR (CDCl 3 ): δ 196.4, 149.5, 147.1, 144.8, 140.0, 139.1, 138.0, 134.8, 133.4, 133.1, 132.0, 131.3, 130.9, 130.3, 129.8, 129.7, 129.5, 127.9, 125.4, 121.2, 117.4 , 114.8, 113.4, 71.5, 70.8, 70.4, 70.4, 69.4, 69.2, 68.7, 21.6, 20.5
    [666]
    [667] Example 67: [4-({4-bromo-2-[(2-iodoethoxy) methyl] phenyl} amino) -2-chlorophenyl] (2-methylphenyl) methanone (Compound 167)
    [668] Compound 164 (1.72 g, 2.73 mmol) was added to anhydrous acetone (2.7 mL) and anhydrous NaI (0.82 g, 5.47 mmol). The suspension is stirred for 20 h in a light shield flask at room temperature, then diluted with water with the reaction mixture and the aqueous phase is extracted three times with EtOAc. The combined organic phases are washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. This gives the title compound as a yellow oil.
    [669] 13 C NMR (CDCl 3 ): δ 196.8, 147.1, 140.4, 139.3, 138.5, 135.2, 133.7, 132.8, 131.7, 131.4, 130.4, 130.2, 130.0, 125.8, 121.6, 118.0, 115.2, 114.6,71.6, 70.8, 20.9 , 4.1
    [670] Example 68: {4-[(4-bromo-2-{[2- (2-iodoethoxy) ethoxy] methyl} phenyl) amino] -2-chlorophenyl} (2-methylphenyl) methanone (Compound 168)
    [671] The reaction and workup were carried out as described in the preparation of compound 167 using compound 165 (0.87 g, 1.29 mmol) and NaI (0.39 g, 2.59 mmol) in 1.3 mL of acetone. Workup affords the title compound as a yellow oil.
    [672] 13 C NMR (CDCl 3 ): δ 196.4, 146.9, 140.1, 139.0, 138.0, 134.9, 133.4, 133.1, 132.1, 131.3, 130.9, 130.0, 129.8, 129.7, 125.4, 121.0, 117.5, 114.7, 113.7, 72.0, 71.7 , 69.9, 69.3, 20.5, 2.4
    [673] Example 69: (4-{[4-bromo-2-({2- [2- (2-iodoethoxy) ethoxy] ethoxy} methyl) phenyl] amino} -2-chlorophenyl} ( 2-methylphenyl) methanone (Compound 169)
    [674] The reaction and workup are carried out as described in the preparation of compound 167 using compound 166 (1.07 g, 1.49 mmol) and NaI (0.45 g, 2.98 mmol) in 1.5 ml of acetone. Workup affords the title compound as a yellow oil.
    [675] 13 C NMR (CDCl 3 ): δ 196.4, 147.1, 140.1, 139.1, 138.0, 134.9, 133.4, 133.1, 132.0, 131.3, 130.9, 130.2, 129.7, 129.5, 125.4, 121.1, 117.4, 114.7,113.5, 71.9, 71.6 , 70.5, 70.4, 70.2, 69.4, 20.5, 2.7
    [676] Example 70: [2-Chloro-4-({2-[(2-iodoethoxy) methyl] phenyl} amino) phenyl] (2-methylphenyl) methanone (Compound 170)
    [677] The reaction and workup were carried out as described in the preparation of compound 167 using compound 163 (0.26 g, 0.48 mmol) and NaI (0.14 g, 0.96 mmol) in 1.5 ml of acetone. The crude product is purified by flash chromatography eluting with EtOAc / petroleum ether 1: 2 to afford the title compound as a pale yellow oil.
    [678] 13 C NMR (CDCl 3 ): δ 196.4, 147.4, 140.7, 139.2, 137.9, 135.0, 133.4, 131.3, 130.8, 130.7, 129.7, 129.6, 129.3, 127.8, 125.4, 122.9, 120.0, 117.2, 113.8, 71.9, 70.3 , 20.5, 3.9
    [679]
    [680] Example 71 Diethyl 2-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethylphosphonate (Compound 171)
    [681] NaH (0.01 g, 60% in oil, 0.24 mmol) is suspended in anhydrous THF (0.2 mL) in anhydrous Schlenk tube under argon atmosphere and diethylphosphite (0.031 mL, 0.24 mmol) is added. After 10 minutes, Compound 170 (0.10 g, 0.20 mmol) dissolved in anhydrous THF (0.3 mL) is added and the reaction mixture is heated at reflux for 15 hours. The reaction mixture is diluted with H 2 O and the aqueous phase is extracted twice with EtOAc. The combined organic phases are washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 2 as eluent to afford the title compound as a slightly colored oil.
    [682] 13 C NMR (CDCl 3 ): δ 196.3, 148.7, 140.7, 139.4, 137.4, 134.8, 133.4, 130.9, 130.7, 130.3, 129.3, 129.2, 129.1, 127.9, 125.1, 123.1, 121.6, 116.5, 112.8, 71.6, 63.9 , 61.6, 26.5, 20.1, 16.1
    [683] Example 72: Diethyl 2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethylphosphonate (Compound 172)
    [684] The reaction is carried out as described in the preparation of compound 171 using NaH (0.036 g, 60% in oil, 0.9 mmol) and diethyl phosphite (0.13 mL, 1.0 mmol) in dry THF (0.5 mL). Compound 167 (0.48 g, 0.82 mmol) dissolved in anhydrous THF (0.8 mL) was added and refluxed for 18 hours. Post-treatment is carried out as described for the preparation of compound 171. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 2 to 4: 1 as eluent to afford the title compound as a yellow oil.
    [685] 13 C NMR (CDCl 3 ): δ 196.5, 148.4, 140.2, 139.4, 137.8, 134.9, 133.6, 133.5, 132.2, 131.3, 131.2, 130.7, 129.6, 128.7, 125.3, 123.2, 117.1, 115.3, 113.3, 71.1, 64.3 , 61.8, 26.6, 20.4, 16.4
    [686] Example 73: diethyl 2-({[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethoxy) ethylphosphonate (Compound 173)
    [687] The reaction is carried out as described in the preparation of compound 171 using NaH (0.023 g, 60% in oil, 0.6 mmol) and diethyl phosphite (0.078 mL, 0.6 mmol) in dry THF (0.3 mL). Compound 168 (0.34 g, 0.55 mmol) dissolved in anhydrous THF (1.0 mL) was added and refluxed for 18 hours. Post-treatment is carried out as described for the preparation of compound 171. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 2 to 1: 0 as eluent to afford the title compound as a yellow oil.
    [688] 13 C NMR (CDCl 3 ): δ 196.3, 147.2, 139.8, 139.1, 137.9, 134.9, 133.4, 132.9, 131.9, 131.3, 130.9, 130.4, 129.7, 129.5, 125.4, 121.2, 117.4, 114.9, 113.4, 71.4, 70.0 , 69.3, 65.3, 61.7, 27.0, 20.5, 16.4
    [689] Example 74: diethyl 2- [2- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethoxy ) Ethoxy] ethylphosphonate (Compound 174)
    [690] The reaction is carried out as described in the preparation of compound 171 using NaH (0.03 g, 60% in oil, 0.76 mmol) and diethylphosphite (0.098 mL, 0.76 mmol) in dry THF (0.3 mL). Compound 169 (0.47 g, 0.69 mmol) dissolved in anhydrous THF (1.0 mL) was added and refluxed for 18 hours. Post-treatment is carried out as described for the preparation of compound 171. The crude product is purified by flash chromatography using EtOAc / Petroleum ether 1: 1 to EtOAc / MeOH 20: 1 as eluent to afford the title compound as a yellow oil.
    [691] 13 C NMR (CDCl 3 ): δ 196.3, 147.3, 139.9, 139.1, 137.9, 134.9, 133.4, 133.0, 132.0, 131.3, 130.9, 130.6, 129.7, 129.3, 125.4, 121.5, 117.3, 114.9, 113.4, 71.4, 70.4 , 70.3, 70.1, 69.4, 65.1, 61.6, 27.0, 20.4, 16.4
    [692]
    [693] Example 75: diethyl 2-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] amino} -2-oxoethylphosphonate (Compound 175)
    [694] Compound 148 (0.20 g, 0.56 mmol) is dissolved in anhydrous DCM (1 mL) in an oven dried glass vessel under an argon atmosphere. Diethylphosphonoacetic acid (0.09 mL, 0.56 mmol) was added, followed by the dropwise addition of dicyclohexylcarbodiimide (0.13 g, 0.61 mmol) dissolved in 1 mL of dry DCM. The suspension is stirred for 7 hours at room temperature and then filtered. The filtrate is diluted with 5 ml of DCM and washed with 10% water soluble NaHC0 3 , H 2 O and brine. The organic phase is dried (MgSO 4 ) filtered and concentrated in vacuo. The crude product is purified by flash chromatography using EtOAc as eluent to afford the title compound as a slightly colored oil.
    [695] 13 C NMR (DMSO-d 6 ): δ 195.1, 164.5, 149.8, 139.3, 137.8, 136.4, 133.6, 132.8, 131.0, 130.6, 129.0, 128.7, 128.0, 126.3, 125.5, 124.6, 123.5, 114.9, 111.7, 61.6 , 54.8, 34.5, 19.7, 16.1
    [696] Example 76: diethyl 2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] amino} -2-oxoethylphosphonate (Compound 176)
    [697] The reaction is carried out in an oven dried glass vessel under argon atmosphere. Diethylphosphonoacetic acid (0.085 mL, 0.53 mmol) was dissolved in anhydrous toluene (1 mL) and thionyl chloride (0.044 mL, 0.61 mmol) was added. The reaction mixture is refluxed for 1 hour and then concentrated in vacuo. {4-[(2-amino-4-bromophenyl) amino] -2-chlorophenyl} (2-methylphenyl) methanone (0.28 g, 0.48 mmol) (reference: WO 01/05744) Dissolve in DCM (1 mL) and add N, N-diisopropylethyl amine (0.16 mL, 0.96 mmol), then add the acid chloride described above dissolved in anhydrous DCM (2.5 mL) dropwise. The reaction mixture is stirred at rt for 22 h and then diluted with DCM. The organic phase is washed with 10% aqueous NaHCO 3 , H 2 O and brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using EtOAc / petroleum ether 3: 1 as eluent to afford the title compound as an oil.
    [698] 13 C NMR (CDCl 3 ): δ 196.5, 163.2, 148.0, 139.0, 138.0, 134.9, 133.3, 131.9, 131.8, 131.3, 130.9, 129.7, 129.4, 129.2, 126.9, 125.4, 124.5, 117.2, 116.6, 113.0, 63.4 , 36.1, 20.5, 16.3
    [699] Example 77: {[5-Bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl (diethoxyphosphoryl) acetate (Compound 177)
    [700] The reaction is carried out in an oven dried glass vessel under argon atmosphere. Diethylphosphonoacetic acid (0.053 mL, 0.33 mmol) was dissolved in anhydrous toluene (2 mL) and thionyl chloride (0.065 mL, 0.9 mmol) was added. The reaction mixture is refluxed for 2 hours and then concentrated in vacuo. Compound 158 (0.14 g, 0.3 mmol) is dissolved in anhydrous THF (1.5 mL). 4-N, N-dimethylaminopyridine (0.073 g, 0.6 mmol) is added, followed by the acid chloride described above dissolved in THF (1.5 mL). The reaction mixture is heated at complete temperature for 20 hours. The reaction mixture is diluted with EtOAc and water soluble NaHC0 3 , the organic phase is washed with H 2 O and brine and the combined aqueous phases are extracted with EtOAc. The combined organic phases are dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using EtOAc / petroleum ether 2: 1 as eluent to afford the title compound as a slightly colored oil.
    [701] 13 C NMR (CDCl 3 ): δ 196.4, 165.7, 147.5, 139.4, 139.1, 138.0, 134.9, 133.4, 133.0, 132.0, 131.3, 130.9, 129.7, 129.5, 125.4, 122.1, 117.3, 115.5, 113.4, 70.9, 68.1 , 64.8, 62.9, 34.4, 20.5, 16.3
    [702]
    [703] Example 78: 2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzylphosphonic acid (Compound 178)
    [704] Compound 153 (0.27 g, 0.56 mmol) in argon atmosphere is dissolved in anhydrous DCM (5 mL). Trimethylsilyl bromide (0.37 mL, 2.8 mmol) is added and the solution is stirred at room temperature for 20 hours. The solution is concentrated in vacuo and then concentrated three times with MeOH. The crude product is dissolved in MeOH, treated with activated charcoal, filtered and concentrated in vacuo to afford the title compound as an orange oil.
    [705] 13 C NMR (DMSO-D 6 ): δ 195.0, 149.2, 139.3, 138.9, 136.3, 133.8, 133.7, 132.0, 130.9, 130.6, 128.7, 127.8, 127.2, 126.2, 125.5, 124.3, 122.6, 114.7, 111.9, 32.3 , 19.7
    [706]
    [707] Example 79 N- [2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] -2,2,2-trifluoroethanesulfonamide (Compound 179)
    [708] Compound 178 (0.18 g, 0.71 mmol) was dissolved in anhydrous pyridine (0.9 mL) and 2,2,2-trifluoroethanesulfonyl chloride (0.12 mL, 1.1 mmol) was added. The solution is stirred at rt for 1 h and then concentrated in vacuo. The oil is diluted with H 2 O and the aqueous phase is extracted three times with EtOAc. The combined organic phases are washed with 10% aqueous NaHCO 3 , dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 2 as eluent to afford the title compound as a yellow oil.
    [709] 13 C NMR (CDCl 3 ): δ 196.8, 148.1, 139.3, 139.0, 137.9, 135.0, 133.5, 131.3, 131.0, 130.1, 129.8, 129.3, 128.5, 125.4, 124.8, 123.2, 121.5, 116.5, 113.2, 54.6, 44.5 , 20.4
    [710] Example 80 N- [5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] -2,2,2-trifluoroethanesulfonamide (Compound 180)
    [711] {4-[(2-amino-4-bromophenyl) amino] -2-chlorophenyl} (2-methylphenyl) methanone (0.15 g, 0.35 mmol) in pyridine (0.47 mL) (reference: WO 01 / 05744) and trifluoroethanesulfonyl chloride (0.059 mL, 0.53 mmol) were used to carry out the reaction as described for the preparation of compound 179. The reaction time is 4 hours. Post-treatment as described for the preparation of compound 179 gives the title compound as brown crystals.
    [712] 13 C NMR (CDCl 3 ): δ 196.8, 149.2, 147.3, 138.5, 138.3, 134.9, 134.0, 133.2, 131.5, 131.3, 131.0, 130.2, 130.0, 127.1, 125.7, 125.5, 121.3, 118.0, 117.1, 113.7, 53.1 , 20.6.
    [713] Example 81: {2-Chloro-4-[(2-{[(tetrahydro-2H-pyran-2-yloxy) propoxy] methyl} phenyl) amino] phenyl} (2-methylphenyl) methanone (Compound 181)
    [714] The reaction and workup are carried out as described for the preparation of compound 149. Starting materials were compound 425 (2.6 g, 7.9 mmol), (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (2.14 g, 8.7 mmol) in 15 mL of 1,4-dioxane anhydride (reference) WO 01/42189 A1), rac-BINAP (0.22 g, 0.35 mmol), Pd 2 (dba) 3 (0.16 g, 0.17 mmol) and CS 2 CO 3 (3.9 g, 12.0 mmol). The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 3 as eluent to afford the title compound as a yellow oil.
    [715] 13 C NMR (CDCl 3 ): δ 196.4, 147.5, 140.6, 139.3, 137.9, 135.0, 133.5, 131.3, 130.8, 130.5, 129.7, 129.2, 129.1, 128.5, 125.4, 122.8, 119.7, 117.0, 113.4, 99.1, 72.0 , 67.4, 64.3, 62.6, 30.7, 30.0, 25.4, 20.4, 19.8
    [716] Example 82: [2-Chloro-4-({2-[(hydroxypropoxy) methyl] phenyl} amino) phenyl] (2-methylphenyl) methanone compound 182)
    [717] The reaction and workup are carried out as described for the preparation of compound 155. Starting materials are compound 181 (3.89 g, 7.9 mmol) and p-toluenesulfonic acid (2.25 g, 11.82 mmol) in 100 mL of MeOH. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 1 as eluent to afford the title compound as a yellow oil.
    [718] 13 C NMR (CDCl 3 ): δ 196.5, 147.6, 140.5, 139.2, 137.9, 135.0, 133.5, 131.3, 130.8, 130.6, 129.7, 129.3, 129.1, 128.4, 125.4, 123.0, 120.1, 116.9, 113.4, 72.0, 68.5 , 61.1, 32.2, 20.4
    [719] Example 83 diethyl 3-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} propylphosphonate (Compound 183)
    [720] The reaction and workup are carried out as described for the preparation of compound 149. Starting materials were compound 428 (0.14 g, 0.4 mmol), (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (0.098 g, 0.4 mmol) in 3 ml of anhydrous 1,4-dioxane (reference) WO 01/42189 A1), rac-BINAP (0.01 g, 0.016 mmol), Pd 2 (dba) 3 (0.008 g, 0.009 mmol) and CS 2 CO 3 (0.18 g, 0.56 mmol). The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 2 to 4: 1 as eluent to afford the title compound as a pale yellow oil.
    [721] 13 C NMR (CDCl 3 ): δ 196.4, 147.6, 140.5, 139.3, 137.9, 135.0, 133.5, 131.3, 130.8, 130.7, 129.7, 129.3, 129.1, 128.4, 125.4, 122.9, 120.0, 117.1, 113.5, 71.8, 69.6 , 61.6, 23.4, 23.0, 20.4, 16.5
    [722] Example 84 Diethyl 2- [2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethylphosphonate (Compound 183)
    [723] The reaction and workup are carried out as described for the preparation of compound 149. Starting materials were compound 431 (0.73 g, 2.3 mmol), (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (0.55 g, 2.3 mmol) in 19 mL of 1,4-dioxane anhydride (reference) WO 01/42189 A1), rac-BINAP (0.06 g, 0.08 mmol), Pd 2 (dba) 3 (0.046 g, 0.05 mmol) and CS 2 CO 3 (1.04 g, 3.18 mmol). The crude product is purified by flash chromatography using EtOAc as eluent to afford the title compound as a yellow oil.
    [724] 13 C NMR (CDCl 3 ): δ 196.4, 149.7, 139.7, 138.5, 137.6, 135.3, 134.9, 134.7, 133.8, 131.1, 130.6, 130.5, 129.4, 127.6, 125.3, 125.2, 124.4, 115.6, 112.2, 61.7, 26.6 , 23.9, 20.3, 16.3
    [725] Example 85 diethyl 2- [5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethylphosphonate (Compound 185)
    [726] The reaction and workup are carried out as described for the preparation of compound 158. Starting materials are compound 184 (0.37 g, 0.8 mmol) and 48% water soluble HBr (2.6 mL, 23 mmol) in 11 mL DMSO. The reaction time is 5 days. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 2 to 1: 0 as eluent to afford the title compound as a colorless crystalline compound.
    [727] 13 C NMR (CDCl 3 ): δ 196.4, 149.0, 139.4, 138.0, 137.8, 136.7, 136.6, 135.2, 133.7, 133.4, 131.2, 130.7, 129.5, 128.3, 125.5, 125.3, 117.4, 115.9, 112.5, 61.9, 26.4 , 23.7, 20.4, 16.3
    [728] Example 86: 2-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] amino} -2-oxoethylphosphonic acid (Compound 186)
    [729] Compound 175 (0.04 g, 0.075 mmol) is dissolved in anhydrous CH 2 Cl 2 (0.5 mL) under argon atmosphere. Trimethylsilyl bromide (0.1 ml, 0.75 mmol) is added and the solution is held at room temperature for 45 minutes. The solution is concentrated in vacuo and then concentrated three times with MeOH. This gives the title compound as an orange oil.
    [730] 13 C NMR (DMSO-d 6 ): δ 195.6, 166.3, 150.3, 139.7, 138.2, 136.7, 134.1, 133.9, 133.6, 131.4, 131.0, 129.6, 129.1, 128.3, 126.5, 126.0, 125.1, 124.0, 115.2, 112.1 , 37.5, 20.1
    [731] Example 87: (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -carbamic acid phenethyl ester (Compound 187)
    [732] The reaction is carried out under argon atmosphere. The 2-phenylethanol solution (0.108 mL) in DCM (2.5 mL, 0.90 mmol) is cooled to 0 ° C. A mixture of bis (trichloromethyl) carbonate (0.097 g, 0.33 mmol) and pyridine (0.07 mL, 0.90 mmol) in DCM (2.5 mL) is added slowly with stirring. The reaction mixture is stirred at rt for 2 h, then filtered and concentrated in vacuo. The residue was dissolved in DCM (2.5 mL) and {2-chloro-4-[(2-aminophenyl) amino] phenyl} (2-methylphenyl) methanone (0.150 g, 0.45 mmol) (reference: WO 98 / 32730) and potassium carbonate (0.25 g) 1.78 mmol). The reaction mixture is heated at room temperature for 48 hours and then poured into a mixture of water and Et 2 O. The aqueous phase is extracted with more EtO 2 . The combined organic phases are washed with water and brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 3 as eluent to afford the title compound.
    [733] 13 C NMR (CDCl 3 ): δ 196.6, 154.0, 149.1, 139.1, 137.9, 137.5, 135.0, 133.5, 133.1, 131.3, 130.9, 130.6, 129.7, 129.0, 128.9, 128.6, 126.8, 126.7, 125.8, 125.4, 125.0 , 121.9, 116.1, 112.4, 66.1, 35.3, 20.4
    [734] Example 88: N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -2-phenoxy-acetamide (Compound 188)
    [735] A solution of 2-phenoxyacetic acid (75 mg, 0.49 mmol), thionyl chloride (72 μL, 1.0 mmol) and a drop of DMF in toluene (2.0 mL) was refluxed for 30 minutes. The reaction mixture is concentrated in vacuo and the crude acid chloride obtained is dissolved in anhydrous DCM (2.0 mL). The solution was triethylamine (135 mg, 1.33 mmol) and {2-chloro-4-[(2-aminophenyl) amino] phenyl} (2-methylphenyl) methanone (0.150 g, 0.45 mmol in DCM (5.0 mL). Is slowly added to a cooled (0 ° C.) solution of (reference: WO 98/32730). The solution is left to reach room temperature. The reaction mixture is stirred for 3 hours and then poured into NaHC0 3 (aq.) And EtOAc. The aqueous phase is extracted with more EtOAc (x2). The combined organic phases are washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using DCM as eluent to afford the title compound as a yellow oil.
    [736] 13 C NMR (CDCl 3 ): δ 196.5, 166.9, 156.7, 148.8, 139.0, 137.8, 135.1, 133.6, 131.8, 131.4, 131.2, 130.8, 129.9, 129.6, 128.9, 126.6, 126.3, 125.7, 125.3, 122.9, 122.4 , 116.0, 114.5, 112.1, 67.3, 20.4
    [737] Example 89 N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -3-phenoxy-propionamide (Compound 189)
    [738] The reaction and workup are carried out as described in the preparation of compound 188 using 3-phenoxypropionic acid (81 mg, 0.49 mmol) as carboxylic acid. Purification by flash chromatography eluting with petroleum ether / EtOAc 1: 1 affords the title compound as a yellow oil.
    [739] 13 C NMR (CDCl 3 ): δ 196.7, 170.0, 157.9, 148.8, 139.2, 137.7, 134.9, 133.5, 132.4, 132.0, 131.2, 130.8, 129.6, 129.5, 128.5, 126.1, 125.9, 125.4, 124.9, 123.8, 121.5 , 116.2, 114.5, 112.4, 63.9, 37.2, 20.4
    [740] Example 90: N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -2- (1,3-dioxo-1,3-dihydro-isoindole- 2-yl) -acetamide (Compound 190)
    [741] Reaction and after using (1,3-dioxo-1,3-dihydro-isoindol-2-yl) acetyl chloride (219 mg, 0.98 mmol) as acid chloride as described in the preparation of compound 188 Perform the process. Purification by flash chromatography eluting with petroleum ether / EtOAc 10: 1 affords the title compound as a yellow oil.
    [742] 13 C NMR (CDCl 3 ): δ 196.5, 167.8, 165.2, 148.9, 139.1, 137.9, 134.9, 134.6, 133.5, 132.1, 131.7, 131.3, 130.9, 129.7, 128.9, 126.4, 126.2, 125.4, 123.8, 123.0, 116.1 , 112.3, 41.6, 20.5
    [743] Example 91 N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -succinic acid acid 2- (2-methoxy-ethoxy) ethyl ester (Compound 191)
    [744] Diethylazodicarboxylate solution (40% in toluene, 229 μl, 0.5 mmol) was diluted with N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} in anhydrous toluene (2.5 mL). Phenyl) -succinic acid (200 mg, 0.46 mmol) (reference: WO 01/05746), triphenylphosphine (132 mg, 0.50 mmol) and 2- (2-methoxyethoxy) ethanol (55 Mg, 0.46 mmol) is added slowly. The reaction mixture is stirred for 48 hours and then poured into a mixture of water and EtOAc. The aqueous phase is extracted with more EtOAc (x2). The combined organic phases are washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using EtOAc as eluent to afford the title compound as a yellow oil.
    [745] 13 C NMR (CDCl 3 ): δ 196.6, 173.0, 171.1, 148.7, 139.3, 137.7, 135.0, 133.6, 133.4, 131.2, 130.9, 130.8, 129.5, 128.4, 126.4, 125.4, 125.1, 124.7, 123.7, 116.4, 112.5 , 71.8, 70.4, 68.9, 63.9, 59.0, 31.7, 29.7, 20.4
    [746] Example 92: N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -benzenesulfonamide (Compound 192)
    [747] Of {2-chloro-4-[(2-aminophenyl) amino] phenyl} (2-methylphenyl) methanone (0.67 g, 2.0 mmol) in pyridine (10 mL) (reference: WO 98/32730) To a cold (ice / water) solution is added benzenesulfonyl chloride (0.32 mL, 2.5 mmol). The reaction mixture is warmed to room temperature. After stirring for 48 hours, the reaction mixture is poured into ice water. The precipitate is filtered off and washed with water and diethyl ether to afford the crude product. Crystallization from acetic acid affords the title compound as a solid.
    [748] Melting point: 211-215 ° C.
    [749] 13 C NMR (DMSO-d 6 ): δ 195.2, 148.6, 139.4, 139.2, 136.4, 134.0, 133.2, 133.2, 132.3, 131.0, 130.6, 129.7, 128.7, 126.7, 126.6, 126.4, 126.2, 125.6, 124.6, 123.8 , 114.6, 112.1, 19.7
    [750] Example 93 Acetic acid (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenylcarbamoyl) -methyl ester (Compound 193)
    [751] The reaction and workup are carried out as described in the preparation of compound 188 using acetoxyacetyl chloride (62 μl, 0.58 mmol) as the acid chloride. Purification by flash chromatography eluting with petroleum ether / EtOAc 1: 1 affords the title compound as a yellow oil.
    [752] 13 C NMR (CDCl 3 ): δ 196.5, 169.3, 165.8, 148.6, 138.9, 138.0, 135.0, 133.5, 131.7, 131.6, 131.4, 131.0, 129.7, 129.3, 126.6, 125.6, 125.4, 123.2,116.0, 112.4, 63.2 , 20.5
    [753] Example 94: 1- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) pyrrolidine-2,5-dione (Compound 194)
    [754] Isobutylchloroformate (60 μl, 0.46 mmol) was treated with N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -seat in THF (5.0 mL) at −15 ° C. To a stirred solution of cinnamic acid (200 mg, 0.46 mmol) (WO 01/05746) and 4-methylmorpholine (51 μl, 0.46 mmol). After 5 minutes at 0 ° C., the reaction mixture is cooled to −15 ° C. and a solution of ethyl diisopropyl amine (65 μl, 0.46 mmol) in THF (5.0 mL) is added. The reaction mixture obtained is kept at 0 ° C. for 1 hour. The reaction mixture is stirred at rt for 16 h and then poured into a mixture of 1M HCl (aq.) And EtOAc. The organic phase is washed with more HCl (aq.) (X2). The organic phase is washed with brine, dried (MgSO 4 ) filtered and concentrated in vacuo. The crude product is purified by flash chromatography using petroleum ether / EtOAc 1: 2 as eluent to afford the title compound as an oil.
    [755] 13 C NMR (CDCl 3 ): δ 196.5, 176.2, 147.8, 138.9, 138.0, 137.0, 134.8, 133.3, 131.3, 131.0, 130.3, 129.7, 129.5, 129.1, 126.3, 125.6, 125.4, 125.2, 116.9, 113.1, 28.6 , 20.5
    [756] Example 95: 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl propionate (Compound 195)
    [757] The reaction and workup are carried out as described in the preparation of compound 188 using propionyl chloride (63 mg, 0.68 mmol) as the acid chloride. Purification by flash chromatography eluting with DCM affords the title compound as a yellow oil.
    [758] 13 C NMR (CDCl 3 ): δ 196.4, 174.8, 148.8, 139.3, 138.9, 137.8, 135.1, 133.7, 131.2, 131.1, 130.9, 130.7, 129.6, 128.6, 128.0, 125.3, 124.8, 123.2, 116.0, 112.7, 64.5 , 31.2, 27.6, 20.4, 9.0
    [759] Example 96: 2,2-Dimethyl-propionic acid 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl ester (Compound 196)
    [760] The reaction and workup are carried out as described in the preparation of compound 188 using pivaloyl chloride (32 mg, 0.27 mmol) as the acid chloride. Purification by flash chromatography eluting with petroleum ether / EtOAc 10: 1 affords the title compound as a yellow oil.
    [761] 13 C NMR (CDCl 3 ): δ 196.5, 179.2, 148.9, 139.4, 138.8, 137.8, 135.2, 133.6, 131.2, 131.1, 130.8, 130.7, 129.6, 128.6, 128.0, 125.3, 124.8, 123.3, 116.0, 112.6, 64.1 , 38.8, 31.2, 27.2, 20.4
    [762] Example 97: [2-Chloro-4-({2- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] phenyl} amino) phenyl] (2-methylphenyl) methanone (Compound 197 )
    [763] The reaction and workup are carried out as described in the process for the preparation of compound 101 using 2- [3- (2-bromophenoxy) propoxy] tetrahydro-2H-pyran (4.10 g) as bromide. Purification by flash chromatography eluting with petroleum ether / EtOAc 4: 1 affords the title compound as a yellow oil.
    [764] 13 C NMR (CDCl 3 ): δ 196.4, 149.2, 147.4, 139.2, 137.9, 134.9, 133.4, 131.3, 130.8, 130.1, 129.7, 129.3, 125.4, 123.0, 120.9, 118.6, 117.1, 113.5, 112.4, 99.1, 65.8 , 64.0, 62.6, 30.7, 29.6, 25.4, 20.4, 19.7
    [765] Example 98: (2-Chloro-4-({2- (3-hydroxypropoxy) phenyl] amino} phenyl) (2-methylphenyl) methanone (Compound 198)
    [766] The reaction and workup are carried out as described for the preparation of compound 102. Starting materials are compound 197 (2.56 g) and 4-toluenesulfonic acid (1.52 g) in MeOH (5.0 mL). Purification by flash chromatography eluting with petroleum ether / EtOAc 4: 1 affords the title compound as a yellow oil.
    [767] 13 C NMR (CDCl 3 ): δ 196.5, 149.5, 147.4, 139.2, 137.9, 134.9, 133.4, 131.3, 130.8, 130.1, 129.7, 129.3, 125.4, 123.3, 121.2, 119.1, 117.0, 113.5,112.8, 66.4, 60.1 , 32.0, 20.5
    [768] Example 99 tert-butyl 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl carbonate (Compound 199)
    [769] Compound 102 (200 mg) was added to anhydrous triethylamine (3.0 mL) and {[(tert-butoxycarbonyl) oxy] amino} (phenyl) acetonitrile (148 mg). The solution is stirred at 70 ° C. for 5 hours. The reaction mixture is cooled to room temperature and then poured into a mixture of water and EtOAc. The aqueous phase is extracted with more EtOAc (x2). The combined organic phases are washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using petroleum ether / diethyl ether 8: 1 to afford the title compound.
    [770] 13 C NMR (CDCl 3 ): δ 196.5, 153.5, 148.8, 139.4, 139.2, 137.8, 135.2, 133.7, 131.3, 131.2, 130.8, 129.6, 128.5, 128.0, 125.3, 124.6, 122.6, 116.4, 112.6, 82.9, 67.5 , 31.7, 27.8, 20.4
    [771] Example 100: 2-({[(5-bromo-2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) amino] carbonyl} amino) ethyl 2-methylacrylate (Compound 200)
    [772] 2-Isocyanatoethyl 2-methylacrylate (0.31 g, 2.2 mmol) was obtained from {4-[(2-amino-4-bromophenyl) amino] -2-chlorophenyl} in anhydrous pyridine (3.00 mL). To (2-methylphenyl) methanone solution (0.60 g, 1.44 mmol) (WO 01/05744). The solution is stirred at rt for 6 h and then poured into a mixture of water and EtOAc. The aqueous phase is extracted with more EtOAc (x2). The combined organic phases are washed with brine, dried (MgSO 4), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using petroleum ether / EtOAc 4: 1 as eluent to afford the title compound as a light brown solid.
    [773] 13 C NMR (CDCl 3 ): δ 197.4, 167.6, 155.7, 149.0, 138.8, 137.8, 135.8, 135.0, 134.8, 133.6, 131.4, 131.2, 130.1, 129.8, 128.5, 127.3, 126.3, 126.1, 125.5, 125.4, 118.7 , 116.3, 112.5, 63.7, 39.6, 20.5, 18.3
    [774] Example 101: (4-{[4-bromo-2- (2-hydroxyethyl) phenyl] amino} -2-chloro-phenyl) (2-methylphenyl) methanone (Compound 201)
    [775] The reaction and workup are carried out as described in the preparation of compound 158 using compound 102 (0.10 g, 0.2 mmol) and 48% water soluble HBr (0.4 mL, 6.70 mmol) in DMSO (3 mL). The reaction time is 2 days. The crude product is purified by flash chromatography using EtOAc / petroleum ether 1: 4 as eluent to afford the title compound as a yellow compound.
    [776] 13 C NMR (CDCl 3 ): δ 196.6, 148.3, 139.3, 139.0, 137.8, 135.5, 135.2, 133.9, 133.7, 131.2, 130.8, 130.4, 129.6, 128.4, 125.3, 123.7, 116.7, 116.2,112.5, 64.9, 34.4 , 20.4
    [777] Example 102: 3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenoxy) propyl acetate (Compound 202)
    [778] At 20 ° C. acetic anhydride (72 μl, 0.77 mmol) is added to a solution of compound 198 (121 mg, 0.31 mmol) in 100% acetic acid (1.0 mL) with stirring. The reaction mixture is stirred at 80 ° C. overnight and then poured into a mixture of water and EtOAc. The aqueous phase is extracted with more EtOAc (x2). The combined organic phases are washed with water, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using petroleum ether / EtOAc 4: 1 as eluent to afford the title compound.
    [779] 13 C NMR (CDCl 3 ): δ 196.8, 171.5, 149.5, 147.8, 139.6, 138.3, 135.3, 133.8, 131.7, 131.2, 130.5, 130.1, 129.6, 125.8, 123.5, 121.5, 119.3, 117.5, 114.0, 112.8, 65.4 , 61.4, 29.0, 21.4, 20.8
    [780] Example 103: [2-Chloro-4-({2- [3- (morpholin-4-yl) propoxy] phenyl} amino) phenyl] (2-methylphenyl) methanone (Compound 203)
    [781] Compound 198 (100 mg, 0.25 mmol) is dissolved in anhydrous pyridine (130 μl) under argon atmosphere. The solution is cooled in an ice bath and 4-toluenesulfonyl chloride (48 mg, 0.25 mmol) is added. After 45 minutes at room temperature, the reaction mixture is quenched with water. The aqueous phase is extracted twice with EtOAc. The combined organic phases are washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude product is purified by flash chromatography using petroleum ether / EtOAc 4: 1 as eluent to afford the title compound as a yellow oil.
    [782] 13 C NMR (CDCl 3 ): δ 196.4, 149.4, 147.4, 139.2, 137.9, 134.9, 133.4, 131.3, 130.8, 129.9, 129.7, 129.3, 125.4, 123.2, 120.9, 119.0, 117.1, 113.6, 112.3, 66.9, 66.9 , 55.5, 53.8, 26.4, 20.5
    [783] Example 104 N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -N '-(4-phenoxybutyl) succinamide (Compound 204)
    [784] 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholin-4-ium chloride (DMTMM) (69 mg, 0.25 mmol) was methanol (2.0 mL) N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -succinic acid solution (100 mg, 0.23 mmol) in WO 01/05746 and To a solution of 4-phenoxybutylamine (30 mg, 0.25 mmol). The reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is poured into 1N HCl (aq.) And extracted with EtOAc (x2). The combined organic phases are washed with water, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using DCM / MeOH / NH 3 (aq.) 95: 5: 0.5 as eluent to afford the title compound as a yellow solid.
    [785] 13 C NMR (CDCl 3 ): δ 196.6, 172.4, 171.8, 158.8, 148.6, 139.2, 137.8,134.9, 133.5, 133.4, 131.2, 130.8, 130.6, 129.7, 129.5, 128.6, 126.3, 125.4, 124.9, 124.7, 123.2 , 120.8, 116.6, 114.5, 112.4, 67.2, 39.5, 32.4, 31.5, 26.7, 26.3, 20.4
    [786] Example 105: N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -N '-(6-hydroxyhexyl) succinamide (Compound 205)
    [787] 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholin-4-ium chloride (DMTMM) (138 mg, 0.50 mmol) was THF (4.0 mL) N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -succinic acid solution (200 mg, 0.46 mmol) in WO 01/05746 and To a solution of 6-aminohexanol (60 mg, 0.51 mmol). The reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is poured into 1N HCl (aq.) And extracted with EtOAc (x2). The combined organic phases are washed with water, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using DCM / MeOH / NH 3 (aq.) 95: 5: 0.5 as eluent to afford the title compound as a yellow solid.
    [788] 13 C NMR (CDCl 3 ): δ 196.7, 172.5, 171.8, 148.6, 139.2, 137.8, 134.9, 133.5, 133.4, 131.3, 130.8, 130.5, 129.7, 128.6, 126.2, 125.4, 124.9, 124.7, 123.0, 116.6, 112.5 , 62.4, 39.6, 32.5, 32.3, 31.5, 29.4, 26.2, 25.1, 20.4
    [789] Example 106 N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -N '-(2,3-dihydroxypropyl) succinamide (Compound 206)
    [790] The reaction and workup are carried out as described for the preparation of compound 204. Starting material was N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -succinic acid (100 mg, 0.46 mmol) (WO 01/05746). And 3-aminopropane-1,2-diol (23 mg, 0.25 mmol). The crude product is purified by flash chromatography using DCM / MeOH / NH 3 (aq.) 90: 10: 0.5 as eluent to afford the title compound as a yellow solid.
    [791] 13 C NMR (CDCl 3 ): δ 197.1, 173.8, 172.2, 148.8, 138.9, 137.9, 134.7, 133.4, 133.3, 131.3, 131.1, 130.7, 129.8, 128.4, 126.4, 125.4, 124.9, 123.5, 70.9, 63.9, 42.3 , 32.0, 31.0, 20.5
    [792] Example 107 tert-butyl (1R) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -1- (hydroxymethyl) propylcarbamate (compound 207)
    [793] Trifluoroacetic acid (78 μl, 0.78 mmol) is added to a solution of compound 434 (213 mg, 0.39 mmol) in MeOH (2.50 mL). The reaction mixture is refluxed for 10 hours and then poured into a mixture of saturated NaHC0 3 and EtOAc. The organic phase is washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using petroleum ether / EtOAc 2: 1 as eluent to afford the title compound as a yellow oil.
    [794] 13 C NMR (CDCl 3 ): δ 196.5, 156.7, 149.8, 139.5, 138.2, 137.7, 136.0, 135.2, 133.8, 131.2, 130.6, 130.5, 129.5, 127.9, 127.3, 125.5, 125.3, 124.6, 115.9, 112.1, 80.1 , 65.4, 52.2, 32.6, 28.4, 27.5, 20.4
    [795] Example 108 Diethyl 6- [3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenylcarbamoyl) propionylamino] -hexylphosphate (Compound 208)
    [796] At 0 ° C., quantitative iodine (53 mg, 0.21 [mmol)) is added to a solution of triethylphosphite (36 [mu] l, 0.21 mmol) in dry DCM (0.50 mL). After stirring for 15 minutes at 0 ° C. and 5 minutes at room temperature, this solution is added via cannula to a solution of compound 205 (101 mg, 0.19 mmol) in anhydrous pyridine (61 μl, 0.75 mmol). Stir for 90 minutes at 0 ° C. and another 90 minutes at room temperature, then pour the reaction mixture into water and DCM. The organic phase is washed with water, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using DCM / MeOH 97: 3 as eluent to afford the title compound as a yellow oil.
    [797] 13 C NMR (CDCl 3 ): δ 196.6, 172.5, 171.9, 148.7, 139.3, 137.8, 134.9, 133.5, 133.4, 131.2, 130.8, 129.6, 128.5, 126.1, 125.4, 124.9, 124.6, 123.1, 116.6, 112.4, 67.3 , 63.8, 39.3, 32.7, 31.6, 29.9, 29.2, 25.9, 24.7, 20.4, 16.1
    [798] Example 109: ethyl N-({[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] amino} carbonyl Glycinate (Compound 209)
    [799] Ethyl isocyanatoacetate (45 mg, 0.35 mmol) is added to a solution of compound 111 (100 mg, 0.27 mmol) in dry DCM (1.0 mL). The solution is stirred at room temperature for 5 hours and then poured into a mixture of water and DCM. The aqueous phase is extracted with more DCM (x2). The combined organic phases are washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography using petroleum ether / EtOAc 4: 1 as eluent to afford the title compound.
    [800] 13 C NMR (CDCl 3 ): δ 196.8, 172.0, 158.6, 149.4, 139.4, 137.6, 137.5, 135.0, 133.6, 131.3, 131.2, 130.8, 129.5, 129.2, 128.4, 127.8, 127.2, 126.1, 125.4, 124.9, 123.4 , 116.5, 112.5, 61.5, 42.6, 42.2, 20.4, 14.1
    [801] Example 110 tert-butyl 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl (methyl) carbamate (compound 210)
    [802] The reaction and workup are carried out as described for the preparation of compound 101. Starting materials are (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (211 mg, 0.86 mmol) (WO 01/42189 A1) and compound 435 (324 mg, 1.03 mmol). . The crude product is purified by flash chromatography using petroleum ether / EtOAc 6: 1 as eluent to afford the title compound as a yellow oil.
    [803] 13 C NMR (CDCl 3 ): δ 196.5, 149.3, 139.7, 139.4, 137.7, 135.2, 133.7, 131.1, 130.5, 129.5, 127.5, 125.3, 123.5, 122.0, 116.4, 112.2, 80.4, 50.0, 35.1, 31.1, 28.5 , 20.3
    [804] Example 111 N- (5-bromo-2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -N '-(6-hydroxyhexyl) succinamide (Compound 211 )
    [805] The reaction and workup are carried out as described for the preparation of compound 205. Starting material was N- (5-bromo-2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -succinic acid (600 mg, 1.16 mmol) (WO 01/05746). And 6-aminohexanol (151 mg, 1.28 mmol). The crude product is purified by flash chromatography using EtOAc as eluent to afford the title compound as a yellow solid.
    [806] 13 C NMR (CDCl 3 ): δ 196.7, 172.6, 171.8, 148.2, 139.0, 138.0, 134.9, 133.3, 132.1, 131.4, 131.0, 129.8, 129.2, 128.9, 127.2, 125.4, 124.3, 117.0, 116.8, 112.7, 62.4 , 39.7, 32.5, 32.3, 31.4, 29.4, 26.3, 25.1, 20.5
    [807] Example 112 N- (5-bromo-2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -N '-(2,3-dihydroxypropyl) succinamide (Compound 212)
    [808] The reaction and workup are carried out as described for the preparation of compound 211. Starting material was N- (5-bromo-2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -succinic acid (600 mg, 1.16 mmol) (WO 01/05746). Prepared in a similar manner to that described in the US.) And 3-amino-1,2-propane-diol (117 mg, 1.28 mmol). The crude product is purified by flash chromatography using EtOAc as eluent followed by EtOAc / MeOH to afford the title compound as a solid.
    [809] 13 C NMR (CDCl 3 ): δ 197.2, 173.9, 172.2, 148.4, 138.7, 138.1, 134.6, 133.3, 132.3, 132.0, 131.4, 131.3, 130.0, 129.0, 127.2, 125.5, 124.9, 117.3, 116.8, 112.7, 70.9 , 64.0, 42.4, 32.1, 31.6, 20.6
    [810] Example 113: (2Z) -N-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -2- (2,5-dioxoimidazolidine-4-ylidene) acetamide (Compound 213)
    [811] A mixture of (2Z)-(2,5-dioxoimidazolidine-4-ylidene) acetic acid (35 mg, 0.22 mmol) and compound 111 (75 mg, 0.20) in THF (1.5 mL) was added at 20 ° C. Stir for 10 minutes. DMTMM (40 mg) is added to the mixture and stirred at 20 ° C. for 20 hours. The reaction mixture is poured into water and extracted with EtOAc (x3). The organic phases are combined, washed with brine and dried (MgS0 4 ). The crude product is purified by chromatography eluting with petroleum ether / EtOAc 2: 3 and then eluting with EtOAc to afford the title compound as a yellow foam.
    [812] 13 C NMR (DMSO-d 6 ): δ 195.1, 164.7, 164.4, 154.6, 150.4, 139.3, 137.3, 137.1, 136.3, 133.6, 131.8, 130.9, 130.5, 128.7, 128.5, 127.9, 126.5, 126.2, 125.9, 125.5 , 125.4, 125.1, 114.7, 111.5, 97.6, 40.8, 19.7
    [813] Example 114: (2-Chloro-4-{[2- (difluoromethyl) phenyl] amino} phenyl) (2-methylphenyl) methanone (Compound 214)
    [814] The reaction and workup are carried out as described for the preparation of compound 101. Starting materials were (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (270 mg, 1.10 mmol) (WO 01/42189 A1) and compound 1-bromo-2- (di Fluoromethoxy) benzene (324 mg, 1.03 mmol). The crude product is purified by flash chromatography using petroleum ether / EtOAc 9: 1 as eluent to afford the title compound as a yellow oil.
    [815] 13 C NMR (CDCl 3 ): δ 196.4, 146.2, 141.6, 138.8, 138.2, 134.8, 133.1, 132.9, 131.4, 131.1, 130.7, 130.0, 126.3, 125.4, 123.1, 120.3, 119.7, 117.8, 116.3, 114.4, 20.6
    [816]
    [817] Example 115: 3-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethyl} -1-methylimidazolidine-2,4-dione ( Compound 215)
    [818] (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (61 mg. 0.25 mmol) in 1,4-dioxane (5 mL) (reference: 01/42189 A1), Compound 436 ( 89 mg, 0.30 mmol), BINAP (5 mg), Pd 2 (dba) 3 (5 mg) and CS 2 CO 3 (114 mg, 0.35 mmol) were heated to 120 ° C. with stirring for 3 days. The reaction mixture is then filtered. The resulting solution is concentrated in vacuo. The residue is purified by chromatography (petroleum ether / ethyl acetate 1: 1) to afford the desired product. The impure product is further purified by preparative TLC (petroleum ether / ethyl acetate 2: 1) to afford the title compound as a brown oil.
    [819] 13 C NMR (CDCl 3 ): δ 7.53 (d, 1H), 7.4-7.0 (m, 9H), 6.95 (bs, 1H), 6.89 (dd, 1H), 3.80 (s, 2H), 3.79 (m, 2H), 3.08 (m, 2H), 2.91 (s, 3H), 2.44 (s, 3H)
    [820] Example 116: 3-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethyl} -5,5-dimethyloxazoline-2,4-dione ( Compound 215)
    [821] A mixture of (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (31 mg. 0.13 mmol) (01/42189 A1) and compound 437 (47 mg, 0.15 mmol) was obtained by compound 215. Treatment is as described in the preparation method. Purification by flash chromatography (petroleum ether / ethyl acetate 4: 1) affords the title compound as a brown oil.
    [822] 13 C NMR (CDCl 3 ): δ 196.5, 176.1, 154.6, 149.0, 139.3, 139.0, 137.9, 135.1, 133.6, 131.4, 131.2, 131.0, 130.7, 129.6, 128.8, 128.6, 125.4, 125.3, 124.7, 116.0, 112.6 , 84.0, 39.0, 29.8, 23.4, 20.4
    [823] Example 117: 4-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethyl} morpholine-3,5-dione (Compound 217)
    [824] A mixture of (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (61 mg. 0.25 mmol) (01/42189 A1) and compound 438 (89 mg, 0.30 mmol) was obtained by compound 215. Treatment is as described in the preparation method. Purification by flash chromatography (petroleum ether / ethyl acetate 4: 1) affords the title compound as a brown oil.
    [825] 13 C NMR (CDCl 3 ): δ 196.5, 169.5, 148.5, 139.3, 139.0, 137.8, 135.1, 133.6, 131.2, 131.2, 130.7, 129.8, 129.6, 128.8, 128.2, 125.3, 124.1, 122.2, 116.3, 113.0, 77.2 , 67.6, 38.6, 30.3, 20.4
    [826] Example 118: 1-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethyl} piperidine-2,6-dione (Compound 218)
    [827] A mixture of (4-amino-2-chlorophenyl) (2-methylphenyl) methanone (61 mg. 0.25 mmol) (01/42189 A1) and compound 439 (89 mg, 0.30 mmol) was obtained by compound 215. Treatment is as described in the preparation method. Purification by flash chromatography (petroleum ether / ethyl acetate 2: 1) affords the title compound as a brown oil.
    [828] 13 C NMR (CDCl 3 ): δ 196.5, 172.9, 148.6, 139.4, 139.1, 137.8, 135.0, 133.6, 131.2, 130.7, 130.2, 129.7, 129.6, 128.5, 127.9, 125.3, 123.6, 121.4, 116.4, 113.1, 39.6 , 32.7, 30.6, 20.4, 17.1
    [829]
    [830] Example 119: 4- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) morpholine-3, 5-dione (Compound 219)
    [831] Diethyl at room temperature in a solution of compound 158 (47 mg, 0.1 mmol), morpholine-3,5-dione (16 mg, 0.14 mmol) and triphenylphosphine (37 mg, 0.14 mmol) in THF (5 mL). Azodicarboxylate solution (40% in toluene, 0.1 mL, 0.23 mmol) is added. At the same temperature, the reaction solution is stirred for 18 hours and concentrated in vacuo. The residue is purified by chromatography (petroleum ether / ethyl acetate 1: 1) to afford the title compound which is impure. The product is further purified by preparative TLC (petroleum ether / ethyl acetate 1: 1) to afford the title compound as a yellow oil.
    [832] 13 C NMR (CDCl 3 ): δ 196.5, 169.4, 147.0, 140.0, 139.1, 138.0, 134.9, 133.4, 132.2, 131.3, 130.9, 129.9, 129.8, 125.4, 121.4, 117.4, 114.8, 113.9, 71.1, 67.7, 66.8 , 38.1, 20.5
    [833] Example 120 1- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) pyrrolidine-2 , 5-dione (compound 220)
    [834] Compound 158 (47 mg, 0.1 mmol) and succinimide (14 mg, 0.14 mmol) were treated as described for the preparation of compound 219. Purification by flash chromatography (petroleum ether / ethyl acetate 1: 1) affords the title compound as a yellow oil.
    [835] 13 C NMR (CDCl 3 ): δ 196.5, 177.4, 147.2, 139.9, 139.0, 138.0, 134.9, 133.5, 133.4, 132.2, 131.3, 130.9, 130.0, 129.8, 129.6, 125.4, 121.7, 117.3, 114.9, 113.8, 70.8 , 66.6, 38.5, 28.2, 20.5
    [836] Example 121: ethyl 2- [3- (2- {5-bromo- [2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzoyloxy} ethyl) -2 , 4,5-trioxoimidazolidin-1-yl] acetate (Compound 221)
    [837] Compound 158 (47 mg, 0.1 mmol) and ethyl 2,4,5-trioximidazolidine-1-acetate (28 mg, 0.14 mmol) were treated as described for the preparation of compound 219. Purification by flash chromatography (petroleum ether / ethyl acetate 1: 1) affords the title compound as impure. The product is further purified by chromatography (CH 2 Cl / ethyl acetate 15: 1) to afford the title compound as a yellow foam.
    [838] 13 C NMR (CDCl 3 ): δ 165.8, 153.1, 146.9, 139.9, 139.0, 138.1, 134.8, 133.4, 133.3, 132.4, 131.4, 131.0, 130.0, 129.8, 129.7, 125.4, 121.7, 117.4, 115.0, 114.0, 71.1 , 66.1, 62.6, 39.8, 39.3, 20.5, 14.0
    [839] Example 122: 3- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) imidazolidine- 2,4-dione (Compound 222)
    [840] Compound 158 (47 mg, 0.1 mmol) and hydantoin (14 mg, 0.14 mmol) were treated as described for the preparation of compound 219. Purification by flash chromatography (petroleum ether / ethyl acetate 1: 1) affords the title compound as impure. The product is further purified by preparative TLC (petroleum ether / ethyl acetate 1: 1) to afford the title compound as a yellow oil.
    [841] 13 C NMR (CDCl 3 ): δ 196.5, 171.3, 157.8, 147.4, 139.9, 139.1, 138.0, 134.9, 133.5, 133.4, 132.2, 131.3, 130.9, 130.2, 129.8, 129.5, 125.4, 121.9, 117.3, 115.0, 113.7 , 70.9, 66.9, 46.4, 38.5, 20.5
    [842] Example 123: 1- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) -3,4- Cis-diacetoxypyrrolidine-2,5-dione (compound 223)
    [843] Compound 158 (67 mg, 0.1 mmol) and 2,3-cis-diacetoxysuccinimide (30 mg, 0.14 mmol) were treated as described for the preparation of compound 219. Purification by flash chromatography (CH 2 Cl / ethyl acetate 1:20) affords the title compound as a yellow oil.
    [844] 13 C NMR (CDCl 3 ): δ 196.5, 169.9, 169.5, 147.1, 139.9, 139.0, 138.0, 134.8, 133.5, 133.3, 132.3, 131.3, 130.9, 130.0, 129.8, 125.4, 121.7, 117.5, 115.0, 113.9, 72.7 , 71.0, 66.1, 39.2, 20.5, 20.3
    [845] Example 124 3- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) thiazoline-2, 4-dione (Compound 224)
    [846] Compound 158 (47 mg, 0.1 mmol) and 2,4-thiazolidione (16 mg, 0.14 mmol) were treated as described for the preparation of compound 219. Purification by flash chromatography (petroleum ether / ethyl acetate 3: 1) affords the title compound as impure. The product is further purified by preparative TLC (petroleum ether / ethyl acetate 3: 1) to afford the title compound as a yellow oil.
    [847] 13 C NMR (CDCl 3 ): δ 196.5, 172.0, 171.6, 147.0, 139.9, 139.0, 138.0, 134.9, 133.4, 133.4, 132.3, 131.3, 130.9, 129.8, 125.4, 121.6, 117.4, 114.9, 114.0, 71.0, 66.3 , 41.5, 33.8, 20.5
    [848] Example 125: 3- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) -1-methyl Midazolidine-2,4-dione (Compound 225)
    [849] Compound 158 (47 mg, 0.1 mmol) and methylhydantoin (16 mg, 0.14 mmol) were treated as described for the preparation of compound 219. Purification by flash chromatography (petroleum ether / ethyl acetate 1: 1) affords the title compound as impure. The product is further purified by preparative TLC (petroleum ether / ethyl acetate 1: 1) to afford the title compound as a yellow oil.
    [850] 13 C NMR (CDCl 3 ): δ 196.5, 170.0, 156.7, 147.4, 140.0, 139.1, 137.9, 134.9, 133.6, 133.4, 132.2, 131.3, 130., 130.3, 129.7, 129.5, 125.4, 121.9, 117.4, 115.0, 113.7, 70.8, 67.2, 51.7, 38.7, 29.7, 20.5
    [851] Example 126: 1- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) imidazolidine- 2,4,5-trione (compound 226)
    [852] Compound 158 (47 mg, 0.1 mmol) and parabanic acid (16 mg, 0.14 mmol) were treated as described for the preparation of compound 219. Purification by flash chromatography (CH 2 Cl 2 / ethyl acetate 4: 1) affords the title compound as impure. The product is further purified by preparative TLC (CH 2 Cl 2 / ethyl acetate 20: 1) to afford the title compound as a yellow oil.
    [853] 13 C NMR (CDCl 3 ): δ 196.4, 156.4, 153.8, 146.8, 139.7, 138.9, 138.1, 134.8, 133.3, 132.4, 131.4, 131.0, 130.0, 129.9, 129.8, 125.4, 121.8, 117.4, 115.1, 113.9, 70.9 , 66.1, 39.2, 20.5
    [854]
    [855] Example 127: (2-Chloro-4-{[2- (hydroxymethyl) phenyl] amino} phenyl) (2-methylphenyl) methanone (Compound 227)
    [856] Compound 441 (3.21 g, 6.32 mmol) and TBAF.3H 2 O (2.99 g, 6.32 mmol) were dissolved in THF (20 mL). The obtained reaction solution is stirred at room temperature for 0.5 hours. After the reaction, the solution is concentrated in vacuo. The residue is redissolved in CH 2 Cl 2 and washed with H 2 O. The aqueous phase is extracted twice with CH 2 Cl 2 . The combined organic phases are dried over MgSO 4 and concentrated in vacuo. The crude product is purified by chromatography (petroleum ether / ethyl acetate 2: 1) to afford the title compound as a red foam.
    [857] 13 C NMR (CDCl 3 ): δ 196.7, 147.5, 140.4, 139.1, 137.9, 135.0, 133.5, 131.3, 130.9, 130.8, 129.7, 129.7, 129.2, 129.0, 125.4, 123.1, 120.1, 117.0, 113.4, 64.3, 20.4
    [858] Example 128: 2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} benzyl acetate (Compound 228)
    [859] Ac 2 O (0.05 mL) is added to a solution of compound 227, Et 3 N (0.1 mL) and DMAP (3 mg) (50 mg, 0.14 mmol) at room temperature. The reaction solution is stirred at the same temperature for 1 hour. After the reaction, the solution is concentrated in vacuo. The residue is redissolved in CH 2 Cl 2 and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase is extracted twice with CH 2 Cl 2 . The combined organic phases are dried over MgSO 4 and concentrated in vacuo. The residue is filtered through a short silica gel column (ethyl acetate / petroleum ether 1: 2) to afford the title compound as a yellow oil.
    [860] 13 C NMR (CDCl 3 ): δ 196.4, 171.8, 148.1, 139.7, 139.2, 137.8, 135.1, 133.5, 132.3, 131.2, 130.8, 130.1, 129.6, 128.9, 128.0, 125.3, 124.2, 122.1, 116.5, 113.0, 63.6 , 21.0, 20.4
    权利要求:
    Claims (28)
    [1" claim-type="Currently amended] A compound of formula (I) and pharmaceutically acceptable salts, solvates and hydrates thereof.
    Formula I

    In the above formula,
    X is oxygen, sulfur or N-ORc,
    R 1 is halogen, hydroxy, mercapto, trifluoromethyl, amino, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin group, (C 1 -C 3 ) alkoxy, (C 1- C 3 ) alkylthio, (C 1 -C 6 ) alkylamino, (C 1 -C 3 ) alkoxycarbonyl, cyano, -CONH 2 , phenyl and nitro, a substituent selected from the group consisting of:
    R 2 is hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin group, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) at least one same or different selected from the group consisting of alkylthio, (C 1 -C 6 ) alkylamino, (C 1 -C 3 ) alkoxycarbonyl, cyano, -CONH 2 , phenyl and nitro Substituents,
    R 3 is hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, cyano, carboxy, carbamoyl, nitro, (C 1 -C 10 ) alkyl, (C 2 -C 10 ) olefin group, (C 3 -C 12 ) at least one identical or selected from the group consisting of cyclic hydrocarbon groups, (C 1 -C 10 ) alkoxy, (C 1 -C 10 ) alkylthio, (C 1 -C 10 ) alkoxycarbonyl and phenyl Different substituents,
    R 4 is hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group, (C 3 -C 6 ) cyclic hydrocarbon group or -C (O) OC (R d ) (R e ) (-OC (O) -R 14 ), wherein the R 14 group is optionally substituted with one or more identical or different substituents of R 8 ,
    R 5 is one or more identical or different substituents selected from the group consisting of hydrogen and R 1 ,
    R 6 is (C 1 -C 1O ) alkyl-heterocyclyl, (C 1 -C 10 ) alkyl- (C 3 -C 12 ) cyclic hydrocarbon group, (C 1 -C 10 ) alkyl, (C 2- C 10 ) olefin group, (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 10 ) alkynyl, Y 1 R 21 , Y 2 R 22 or Y 4 R 24 , wherein (( C 1 -C 10 ) alkyl, (C 2 -C 10 ) olefin group and (C 3 -C 12 ) cyclic hydrocarbon group are substituted with one or more identical or different substituents of R 7 , and (C 1 -C 10 ) Alkyl-heterocyclyl, (C 1 -C 10 ) alkyl- (C 3 -C 12 ) cyclic hydrocarbon groups, heterocyclyl and (C 2 -C 10 ) alkynyl are one or more identical or different substituents of R 7 Is optionally substituted with
    R 7 is R 12 , YH or YR 14 , wherein the R 12 and YR 14 groups are optionally substituted with one or more identical or different substituents of R 8 ,
    R 8 is R 12 , YH, YR 14 or R 14 , wherein the R 12 , YR 14 and R 14 groups are optionally substituted with one or more identical or different substituents of R 9 ,
    R 9 is R 12 , YH, YR 14 or R 14 , wherein the R 12 , YR 14 and R 14 groups are optionally substituted with one or more identical or different substituents of R 10 ,
    R 10 is R 12 , YH, YR 14 or R 14 , wherein the R 12 , YR 14 and R 14 groups are optionally substituted with one or more identical or different substituents of R 11 ,
    R 11 is R 12 or R 14 , wherein the R 12 and R 14 groups are optionally substituted with one or more identical or different substituents of R 12 ,
    R 12 is halogen, hydroxy, mercapto, trifluoromethyl, amino, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) alkylthio, (C 1 -C 6 ) alkylamino, (C 1 -C 3 ) alkoxycarbonyl, (C 1 -C 9 ) trialkylammonium associated with anion, (C 2 -C 10 ) dialkylphosphinoyl, (C 1 -C 5 ) alkyl (hydroxy) phosphinoyl , (C 2 -C 10 ) dialkylphosphinoyloxy, (C 1 -C 5 ) alkyl (hydroxy) phosphinoyloxy, dihydroxyphosphinoyl, dihydroxyphosphinoyloxy, cyano, Azido, nitro, -CHO, -COOH, -CONH 2 , -CONHR 'or -CONRR', where R and R 'are (C 1 -C 3 ) alkyl,
    Y is -O-, -S-, -S (O) -, -S (0) 2 -, -NR a -, -NR a C (Z) -, -NR a C (Z) NR b -, -NR a C (Z) -, -C (Z) a NR -, -C (O) -, -C (S) -, -C (Z) O-, -C (O) Z-, -C (S) S- -OC (Z) -, -NR a C (Z) O-, -OC (Z) NR a -, -S (0) 2 O-, -OS (0) 2 -, -S (0) 2 NR a -, -NR a S (O) 2 -, -OC (Z) O-, -OC (Z) Z-, -OP (O) (OR a) 0-, -P (O ) (OR a ) 0-, -C (NR a )-, -C (NOR a )-, -N = C (R a )-, -N = C (OR a )-, -N (OR a ) -, -ON (R a )-, -N (R a ) O-, -N (R a ) C (= NR b ) NR c- , -C (= NR a ) NR b -or -N (R a ) C (= NR b )-,
    Z is oxygen or sulfur,
    R 14 is (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group, (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl or (C 2 -C 6 ) alkynyl,
    Y 1 is -NR a C (S) NR b- , -C (O)-, -C (S)-, -C (S) O-, -C (O) S-, -C (S) S -, -OC (S) -, -OC (O) -, -NR a C (S) O-, -OC (Z) NR a -, -S (0) 2 O-, -OS (0) 2 -, -S (0) 2 NR a -, -NR a S (O) 2 -, -OC (Z) O-, -OC (Z) Z-, -OP (O) (OR a) O-, -P (O) (OR a ) 0-, -C (NR a )-, -C (NOR a )-, -N = C (R a )-, -N = C (OR a )-, -N (OR a )-, -ON (R a )-, -N (R a ) O-, -N (R a ) C (= NR b ) NR c- , -C (= NR a ) NR b -or -N (R a ) C (= NR b )-,
    R 21 is a (C 1 -C 10 ) alkyl-heterocyclyl, (C 1 -C 10 ) alkyl- (C 3 -C 12 ) cyclic hydrocarbon group, optionally substituted with one or more identical or different substituents of R 7 , (C 1 -C 10 ) alkyl, (C 2 -C 1 O ) olefin group, (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl or (C 2 -C 10 ) alkynyl,
    Y 2 is -0-, -S-, -C (0) O- or -C (O) NR a -, and
    R 22 is (C 1 -C 10 ) alkyl-heterocyclyl, (C 1 -C 10 ) alkyl- (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 10 ) alkynyl , (C 1 -C 1O ) alkyl, (C 2 -C 10 ) olefin group or (C 3 -C 8 ) monocyclic hydrocarbon group, wherein (C 1 -C 10 ) alkyl is one or more of the same as R 7 Or substituted with a different substituent, and (C 1 -C 10 ) alkyl-heterocyclyl, (C 1 -C 10 ) alkyl- (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 10 ) alkynyl, (C 2 -C 10 ) olefin group and (C 3 -C 12 ) monocyclic hydrocarbon group are optionally substituted with one or more identical or different substituents of R 7 ),
    Y 4 is -NR a C (O) NR b CH (R c) -, -NR a C (O) NR b S (O) 2 -, -NR a -, -NR a C (Z) -, - NR a C (O) OCH (R c )-, -NR a C (O) NR b C (R d ) (R e ) -OC (O)-or -NR a C (O) OC (R d ) (R e ) -OC (0)-,
    R 24 represents (C 1 -C 1O ) alkyl-heterocyclyl, (C 1 -C 10 ) alkyl- (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 10 ) alkynyl , (C 1 -C 10 ) alkyl, (C 2 -C 1O ) olefin group or (C 3 -C 12 ) cyclic hydrocarbon group, wherein (C 1 -C 10 ) alkyl, (C 2 -C 10 ) The olefin group and the (C 3 -C 12 ) cyclic hydrocarbon group are substituted with one or more identical or different substituents of R 15 , and are (C 1 -C 1O ) alkyl, (C 2 -C 10 ) olefin groups, (C 3 -C 12 ) cyclic hydrocarbon group, (C 1 -C 10 ) alkyl-heterocyclyl, (C 1 -C 10 ) alkyl- (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl and (C 2 -C 10 ) alkynyl is optionally substituted with one or more identical or different substituents of R 7 ),
    R 15 is R 12a , R 12b or R 12C , wherein R 12a , R 12b or R 12C is optionally substituted with one or more identical or different substituents of R 7 ,
    R 12a is (C 1 -C 3) substituted with one or more identical or different substituents of R 42 alkoxy, (C 1 -C 3) alkylthio, (C 1 -C 6) alkylamino, (C 1 -C 3 ) Alkoxycarbonyl, -CONHR 'or -CONRR' where R and R 'are (C 1 -C 3 ) alkyl, provided that when further substituted with R 42 , R 12a or R 15 is- ( QO) n -Q or -CH 2 (QO) n -Q, wherein Q is (C 1 -C 3 ) alkyl and n is an integer of at least 1 so that the group is a continuous linear sequence of atoms having at least 16 atoms Including,
    R 12b is (C 4 -C 10 ) alkoxy, (C 4 -C 10 ) alkylthio, (C 7 -C 12 ) alkylamino, (C 4 -C optionally substituted with one or more identical or different substituents of R 7 10 ) alkoxycarbonyl, -CONHR 'or -CONRR', wherein R and R 'are (C 4 -C 10 ) alkyl,
    R 12c is —Y 5 (C 1 -C 10 ) alkyl, -Y-aryl, -Y-heterocyclyl, -Y- (C 3 -C 12 ) optionally substituted with one or more identical or different substituents of R 7 Cyclic hydrocarbon group and -Y- (C 2 -C 10 ) olefin group,
    Y 5 is -S (O) -, -S ( O) 2 -, -NR a C (Z) -, -NR a C (Z) NR b -, -C (S) NR a -, -C ( O)-, -C (S)-, -C (S) O-, -C (O) S-, -C (S) S-, -OC (Z)-, -NR a C (Z) O -, -OC (Z) NR a -, -S (0) 2 0-, -OS (O) 2 -, -S (O) 2 NR a -, -NR a S (O) 2 -, -OC (Z) O-, -OC (Z) Z-, -OP (O) (OR a ) 0-, -P (O) (OR a ) O-, -C (NR a )-, -C (NOR a )-, -N = C (R a )-, -N = C (OR a )-, -N (OR a )-, -ON (R a )-, -N (R a ) O-,- N (R a ) C (= NR b ) NR c- , -C (= NR a ) NR b -or -N (R a ) C (= NR b )-,
    R 42 is -YH, YR 14 , R 52 , halogen, trifluoromethyl, cyano, azido or nitro, wherein R 52 and -YR 14 are optionally substituted with one or more identical or different substituents of R 7 ego,
    R 52 represents (C 6 -C 1O ) alkyl, (C 2 -C 6 ) olefin group, (C 3 -C 12 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 6 ) alkynyl or heteroaryl ego,
    R a , R b and R c are independently hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin groups, (C 3 -C) optionally substituted with one or more identical or different substituents of R 12 12 ) a cyclic hydrocarbon group, aryl, heterocyclyl or (C 2 -C 6 ) alkynyl,
    R d and R e are hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group and (C 3 -C 12 ) cyclic hydrocarbon optionally substituted with one or more identical or different substituents of R 12 Group.
    [2" claim-type="Currently amended] The compound of claim 1, wherein R 1 is halogen, hydroxy, trifluoromethyl, amino, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin group, (C 1 -C 3 ) alkoxy and cyan A compound which is a substituent selected from the group consisting of a furnace.
    [3" claim-type="Currently amended] The compound of claim 1, wherein R 2 consists of hydrogen, halogen, hydroxy, trifluoromethyl, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin group and (C 1 -C 3 ) alkoxy At least one substituent independently selected from the group.
    [4" claim-type="Currently amended] The compound of claim 1, wherein R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, cyano, nitro, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group, (C 3 -C 6 ) A compound which is one or more substituents independently selected from the group consisting of monocyclic hydrocarbon groups, (C 1 -C 6 ) alkoxy and (C 1 -C 6 ) alkoxycarbonyl.
    [5" claim-type="Currently amended] The compound of claim 1, wherein R 4 is hydrogen, (C 1 -C 6 ) alkyl, or (C 2 -C 6 ) olefin group.
    [6" claim-type="Currently amended] The compound of claim 1, wherein R 5 is hydrogen and halogen, hydroxy, trifluoromethyl, amino, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin group, (C 1 -C 3 ) alkoxy , (C 1 -C 3 ) at least one substituent independently selected from the group consisting of alkoxycarbonyl and cyano.
    [7" claim-type="Currently amended] The method of claim 1,
    R 6 is (C 1 -C 6 ) alkyl-heterocyclyl, (C 1 -C 6 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon group, (C 1 -C 6 ) alkyl, (C 2- C 6 ) olefin group, (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 6 ) alkynyl, Y 1 R 21 , Y 2 R 22 or Y 4 R 24 , wherein (( C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group and (C 3 -C 6 ) cyclic hydrocarbon group are substituted with one or more identical or different substituents of R 7 , and (C 1 -C 6 ) Alkyl-heterocyclyl, (C 1 -C 6 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon groups, heterocyclyl and (C 2 -C 6 ) alkynyl are one or more identical or different substituents of R 7 Is optionally substituted with
    R 7 is R 12 , YH or YR 14 , wherein the R 12 and YR 14 groups are optionally substituted with one or more identical or different substituents of R 8 ,
    R 8 is R 12 , YH, YR 14 or R 14 , wherein the R 12 , YR 14 and R 14 groups are optionally substituted with one or more identical or different substituents of R 9 ,
    R 9 is R 12 , YH, YR 14 or R 14 , wherein the R 12 , YR 14 and R 14 groups are optionally substituted with one or more identical or different substituents of R 10 ,
    R 10 is R 12 or R 14 , wherein the R 12 and R 14 groups are optionally substituted with one or more identical or different substituents of R 12 ,
    R 12 is halogen, hydroxy, mercapto, trifluoromethyl, amino, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) alkylthio, (C 1 -C 6 ) alkylamino, (C 1 -C 3 ) alkoxycarbonyl, (C 1 -C 6 ) trialkylammonium associated with anion, (C 2 -C 6 ) dialkylphosphinoyl, (C 1 -C 3 ) alkyl (hydroxy) phosphinoyl , (C 2 -C 6 ) dialkylphosphinoyloxy, (C 1 -C 3 ) alkyl (hydroxy) phosphinoyloxy, dihydroxyphosphinoyl, dihydroxyphosphinoyloxy, cyano, Azido, nitro, -CHO, -COOH, -CONH 2 , -CONHR 'or -CONRR', where R and R 'are (C 1 -C 3 ) alkyl,
    Y is -O-, -S-, -S (O) -, -S (0) 2 -, -NR a -, -NR a C (Z) NR b -, -NR a C (Z) -, -C (Z) NR a -, -C (O) -, -C (Z) O-, -OC (Z) -, -NR a C (Z) O-, -OC (Z) NR a -, -S (0) 2 O-, -OS (0) 2 -, -S (0) 2 NR a -, -NR a S (O) 2 -, -OC (Z) Z-, -OP (O) (OR a ) 0-, -P (O) (OR a ) 0-, -C (NOR a )-, -N (OR a )-, -ON (R a )-, -N (R a ) O -, -N (R a ) C (= NR b ) NR c- , -C (= NR a ) NR b -or -N (R a ) C (= NR b )-,
    Z is oxygen,
    R 14 is (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group, (C 3 -C 9 ) cyclic hydrocarbon group, heterocyclyl or (C 2 -C 6 ) alkynyl,
    Y 1 is -NR a C (S) NR b -, -C (O) -, -OC (O) -, -NR a C (S) O-, -OC (Z) NR a -, -S ( 0) 2 NR a -, -NR a S (O) 2 -, -OC (Z) O-, -C (NR a) -, -C (NOR a) -, -N (OR a) -, - ON (R a )-, -N (R a ) O-, -N (R a ) C (= NR b ) NR c- , -C (= NR a ) NR b -or -N (R a ) C (= NR b )-,
    (C 1 -C 6 ) alkyl-heterocyclyl, (C 1 -C 6 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon groups, wherein R 21 is optionally substituted with one or more identical or different substituents of R 7 , (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group, (C 3 -C 9 ) cyclic hydrocarbon group, heterocyclyl or (C 2 -C 6 ) alkynyl,
    Y 2 is -0-, -S-, -C (0) O- or -C (O) NR a -, and
    R 22 is (C 1 -C 6 ) alkyl-heterocyclyl, (C 1 -C 6 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 6 ) alkynyl , (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group or (C 3 -C 9 ) monocyclic hydrocarbon group, wherein (C 1 -C 6 ) alkyl is one or more of the same as R 7 Or substituted with a different substituent, and (C 1 -C 6 ) alkyl-heterocyclyl, (C 1 -C 6 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 6 ) alkynyl, (C 2 -C 6 ) olefin groups and (C 3 -C 9 ) monocyclic hydrocarbon groups are optionally substituted with one or more identical or different substituents of R 7 ),
    Y 4 is -NR a C (O) NR b CH (R c) -, -NR a C (O) NR b S (O) 2 -, -NR a -, -NR a C (Z) -, - NR a C (O) OCH (R c )-, -NR a C (O) NR b C (R d ) (R e ) -OC (O)-or -NR a C (O) OC (R d ) (R e ) -OC (0)-,
    R 24 is (C 1 -C 6 ) alkyl-heterocyclyl, (C 1 -C 6 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 6 ) alkynyl , (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group or (C 3 -C 9 ) cyclic hydrocarbon group, wherein (C 1 -C 6 ) alkyl, (C 2 -C 6 ) The olefin group and the (C 3 -C 9 ) cyclic hydrocarbon group are substituted with one or more identical or different substituents of R 15 , and are (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin groups, (C 3 -C 9 ) cyclic hydrocarbon group, (C 1 -C 6 ) alkyl-heterocyclyl, (C 1 -C 6 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon group, heterocyclyl and (C 2 -C 6 ) alkynyl is optionally substituted with one or more identical or different substituents of R 7 ),
    R 15 is R 12a , R 12b or R 12C , wherein R 12a , R 12b or R 12C is optionally substituted with one or more identical or different substituents of R 7 ,
    R 12a is (C 1 -C 3) substituted with one or more identical or different substituents of R 42 alkoxy, (C 1 -C 3) alkylthio, (C 1 -C 6) alkylamino, (C 1 -C 3 ) Alkoxycarbonyl, -CONHR 'or -CONRR' where R and R 'are (C 1 -C 3 ) alkyl, provided that when further substituted with R 42 , R 12a or R 15 is- ( QO) n -Q or -CH 2 (QO) n -Q, wherein Q is (C 1 -C 3 ) alkyl and n is an integer of at least 1 so that the group is a continuous linear sequence of atoms having at least 16 atoms Including,
    (C 4 -C 6 ) alkoxy, (C 4 -C 6 ) alkylthio, (C 7 -C 12 ) alkylamino, (C 4 -C), wherein R 12b is optionally substituted with one or more identical or different substituents of R 7 8 ) alkoxycarbonyl, -CONHR 'or -CONRR', wherein R and R 'are (C 4 -C 8 ) alkyl,
    -Y 5 (C 1 -C 10 ) alkyl, -Y-aryl, -Y-heterocyclyl, -Y- (C 3 -C 9 ), wherein R 12c is optionally substituted with one or more identical or different substituents of R 7 Cyclic hydrocarbon group and -Y- (C 2 -C 6 ) olefin group,
    Y 5 is -S (O)-, -S (O) 2- , -NR a C (Z)-, -NR a C (Z) NR b- , -C (O)-, -OC (Z) -, -NR a C (Z) O-, -OC (Z) NR a -, -S (O) 2 NR a -, -NR a S (O) 2 -, -OC (Z) O-, - OP (O) (OR a ) 0-, -P (O) (OR a ) O-, -C (NR a )-, -C (NOR a )-, -N (OR a )-, -ON ( R a )-, -N (R a ) O-, -N (R a ) C (= NR b ) NR c- , -C (= NR a ) NR b -or -N (R a ) C (= NR b )-,
    R 42 is -YH, YR 14 , R 52 , halogen, trifluoromethyl, cyano, azido or nitro, wherein R 52 and -YR 14 are optionally substituted with one or more identical or different substituents of R 8 ego,
    R 52 is (C 6 -C 8 ) alkyl, (C 2 -C 4 ) olefin group, (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 4 ) alkynyl or heteroaryl ego,
    Hydrogen, (C 1 -C 4 ) alkyl, (C 2 -C 4 ) olefin group, (C 3 -C), wherein R a , R b and R c are independently substituted with one or more identical or different substituents of R 12 ; 9 ) a cyclic hydrocarbon group, aryl, heterocyclyl or (C 2 -C 4 ) alkynyl,
    R d and R e are independently between hydrogen, (C 1 -C 4 ) alkyl, (C 2 -C 4 ) olefin group and (C 3 -C 9 ), optionally substituted with one or more identical or different substituents of R 12 Compounds that are click hydrocarbon groups.
    [8" claim-type="Currently amended] The method of claim 1,
    R 1 is selected from the group consisting of halogen, hydroxy, trifluoromethyl, amino, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin groups, (C 1 -C 3 ) alkoxy and cyano Substituents,
    R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, trifluoromethyl, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin groups and (C 1 -C 3 ) alkoxy One or more substituents,
    R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, cyano, nitro, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) olefin group, (C 3 -C 6 ) monocyclic hydrocarbon One or more substituents independently selected from the group consisting of a group, (C 1 -C 6 ) alkoxy and (C 1 -C 6 ) alkoxycarbonyl,
    R 4 is hydrogen, (C 1 -C 6 ) alkyl or (C 2 -C 6 ) olefin group,
    R 5 is hydrogen and halogen, hydroxy, trifluoromethyl, amino, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) olefin group, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) at least one substituent independently selected from the group consisting of alkoxycarbonyl and cyano.
    [9" claim-type="Currently amended] The compound of claim 1, wherein X is O or N-OR c , wherein N-OR c is as defined in claim 1.
    [10" claim-type="Currently amended] The compound of claim 1, wherein R 1 is a substituent selected from the group consisting of halogen, cyano, methyl and methoxy.
    [11" claim-type="Currently amended] The compound of claim 1, wherein R 2 is one or more substituents independently selected from the group consisting of hydrogen, halogen, cyano, methyl and methoxy.
    [12" claim-type="Currently amended] The compound of claim 1, wherein R 3 is one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, methyl, methoxy and cyano.
    [13" claim-type="Currently amended] The compound of claim 1, wherein R 4 is hydrogen, methyl or ethyl.
    [14" claim-type="Currently amended] The compound of claim 1, wherein R 5 is one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, trifluoromethyl, methyl, ethyl and methoxy.
    [15" claim-type="Currently amended] The compound of claim 1, wherein X is O.
    [16" claim-type="Currently amended] The compound of claim 1, wherein R 6 is (C 1 -C 4 ) alkyl-heterocyclyl, (C 1 -C 4 ) alkyl- (C 3 -C 6 ) cyclic hydrocarbon group, (C 1 -C 6 ) Alkyl, (C 2 -C 4 ) olefin group, heterocyclyl, (C 2 -C 4 ) alkynyl, Y 1 R 21 , Y 2 R 22 or Y 4 R 24 , wherein (C 1 -C 6 ) Alkyl and (C 2 -C 4 ) olefin groups are substituted with one or more identical or different substituents of R 7 , and (C 1 -C 4 ) alkyl-heterocyclyl, (C 1 -C 4 ) alkyl- (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl and (C 2 -C 4 ) alkynyl are optionally substituted with one or more identical or different substituents of R 7 ),
    R 7 is R 12 , YH or YR 14 , wherein the R 12 and YR 14 groups are optionally further substituted with one or more identical or different substituents of R 8 ,
    R 8 is R 12 , YH, YR 14 or R 14 , wherein the R 12 , YR 14 and R 14 groups are optionally substituted with one or more identical or different substituents of R 9 ,
    R 9 is R 12 , YR 14 or R 14 , wherein the R 12 , YR 14 and R 14 groups are optionally substituted with one or more identical or different substituents of R 12 ,
    R 12 is halogen, hydroxy, trifluoromethyl, amino, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) alkylthio, (C 1 -C 6 ) alkylamino, (C 1 -C 3 ) Alkoxycarbonyl, (C 1 -C 6 ) trialkylammonium associated with anion, (C 2 -C 6 ) dialkylphosphinoyl, (C 2 -C 6 ) dialkylphosphinoyloxy, dihydroxyforce Pinoyl, dihydroxyphosphinoyloxy, cyano, -COOH, -CONH 2 , -CONHR 'or -CONRR', where R and R 'are (C 1 -C 3 ) alkyl,
    Y is -O-, -S-, -S (O) -, -S (0) 2 -, -NR a -, -NR a C (Z) NR b -, -NR a C (Z) -, -C (Z) NR a -, -C (O) -, -C (Z) O-, -OC (Z) -, -NR a C (Z) O-, -OC (Z) NR a -, -S (0) 2 O-, -OS (0) 2 -, -S (0) 2 NR a -, -NR a S (O) 2 -, -OC (Z) Z-, -N (R a ) C (= NR b ) NR c- , -C (= NR a ) NR b -or -N (R a ) C (= NR b )-,
    Z is oxygen,
    R 14 is (C 1 -C 4 ) alkyl, (C 2 -C 4 ) olefin group, (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl or (C 2 -C 3 ) alkynyl,
    Y 1 is -NR a C (S) NR b -, -C (O) -, -OC (O) -, -NR a C (S) O-, -OC (Z) NR a -, -S ( or a -OC (Z) O-, - 0 ) 2 NR a -, -NR a S (O) 2
    (C 1 -C 4 ) alkyl-heterocyclyl, (C 1 -C 4 ) alkyl- (C 3 -C 6 ) cyclic hydrocarbon group, wherein R 21 is substituted with one or more identical or different substituents of R 7 , ( C 1 -C 6 ) alkyl, (C 2 -C 4 ) olefin group, (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl or (C 2 -C 6 ) alkynyl,
    Y 2 is -0-, -S-, -C (0) O- or -C (O) NR a -, and
    R 22 is (C 1 -C 4 ) alkyl-heterocyclyl, (C 1 -C 4 ) alkyl- (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 4 ) alkynyl , (C 1 -C 6 ) alkyl, (C 2 -C 4 ) olefin group or (C 3 -C 6 ) monocyclic hydrocarbon group, wherein (C 1 -C 6 ) alkyl is one or more of the same as R 7 Or substituted with a different substituent, and (C 1 -C 4 ) alkyl-heterocyclyl, (C 1 -C 4 ) alkyl- (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 4 ) alkynyl, (C 2 -C 4 ) olefin groups and (C 3 -C 6 ) monocyclic hydrocarbon groups are optionally substituted with one or more identical or different substituents of R 7 ),
    Y 4 is -NR a C (O) NR b CH (R c) -, -NR a C (O) NR b S (O) 2 -, -NR a -, -NR a C (Z) -, - NR a C (O) OCH (R c )-, -NR a C (O) NR b C (R d ) (R e ) -OC (O)-or -NR a C (O) OC (R d ) (R e ) -OC (0)-,
    R 24 is (C 1 -C 4 ) alkyl-heterocyclyl, (C 1 -C 4 ) alkyl- (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 4 ) alkynyl , (C 1 -C 6 ) alkyl, (C 2 -C 4 ) olefin group or (C 3 -C 9 ) cyclic hydrocarbon group, wherein (C 1 -C 6 ) alkyl, (C 2 -C 4 ) The olefin group and the (C 3 -C 9 ) cyclic hydrocarbon group are substituted with one or more identical or different substituents of R 15 , (C 1 -C 6 ) alkyl, (C 2 -C 4 ) olefin group, (C 3 -C 9 ) cyclic hydrocarbon group, (C 1 -C 4 ) alkyl-heterocyclyl, (C 1 -C 4 ) alkyl- (C 3 -C 9 ) cyclic hydrocarbon group, heterocyclyl and (C 2 -C 4 ) alkynyl is optionally substituted with one or more identical or different substituents of R 7 ),
    R 15 is R 12a , R 12b or R 12C , wherein R 12a , R 12b or R 12C is optionally substituted with one or more identical or different substituents of R 7 ,
    R 12a is (C 1 -C 3) substituted with one or more identical or different substituents of R 42 alkoxy, (C 1 -C 3) alkylthio, (C 1 -C 6) alkylamino, (C 1 -C 3 ) Alkoxycarbonyl, -CONHR 'or -CONRR' where R and R 'are (C 1 -C 3 ) alkyl, provided that when further substituted with R 42 , R 12a or R 15 is- ( QO) n -Q or -CH 2 (QO) n -Q, wherein Q is (C 1 -C 3 ) alkyl and n is an integer of at least 1 so that the group is a continuous linear sequence of atoms having at least 16 atoms Including,
    (C 4 -C 6 ) alkoxy, (C 4 -C 6 ) alkylthio, (C 7 -C 12 ) alkylamino, (C 4 -C), wherein R 12b is optionally substituted with one or more identical or different substituents of R 7 8 ) alkoxycarbonyl, -CONHR 'or -CONRR', wherein R and R 'are (C 4 -C 8 ) alkyl,
    -Y 5 (C 1 -C 6 ) alkyl, -Y-aryl, -Y-heterocyclyl, -Y- (C 3 -C 9 ), wherein R 12c is optionally substituted with one or more identical or different substituents of R 7 Cyclic hydrocarbon group and -Y- (C 2 -C 6 ) olefin group,
    Y 5 is -S (O)-, -S (O) 2- , -NR a C (Z)-, -NR a C (Z) NR b- , -C (O)-, -OC (Z) -, -NR a C (Z) O-, -OC (Z) NR a - or a -OC (Z) O-, -, -S (O) 2 NR a -, -NR a S (O) 2
    R 42 is -YH, YR 14 , R 52 , halogen, trifluoromethyl, cyano, azido or nitro, wherein R 52 and -YR 14 are optionally substituted with one or more identical or different substituents of R 8 ego,
    R 52 is (C 6 -C 6 ) alkyl, (C 2 -C 4 ) olefin group, (C 3 -C 6 ) cyclic hydrocarbon group, heterocyclyl, (C 2 -C 4 ) alkynyl or heteroaryl ego,
    R a , R b and R c are independently hydrogen, (C 1 -C 2 ) alkyl, (C 2 -C 3 ) olefin groups or (C 2 -C) optionally substituted with one or more identical or different substituents of R 12 3 ) alkynyl,
    R d and R e are hydrogen or (C 1 -C 2 ) alkyl.
    [17" claim-type="Currently amended] The method of claim 1,
    R 1 is a substituent selected from the group consisting of halogen, cyano, methyl and methoxy,
    R 2 is one or more substituents independently selected from the group consisting of hydrogen, halogen, cyano, methyl and methoxy,
    R 3 is one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, methyl, methoxy and cyano,
    R 4 is hydrogen, methyl or ethyl,
    R 5 is one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, trifluoromethyl, methyl, ethyl and methoxy,
    X is O.
    [18" claim-type="Currently amended] The compound of claim 1, wherein the compound has a molecular weight of about 1500 Da or less.
    [19" claim-type="Currently amended] The compound of claim 1, wherein the compound has a molecular weight of about 1200 Da or less.
    [20" claim-type="Currently amended] The compound of claim 1, wherein the compound has a molecular weight of about 800 Da or less.
    [21" claim-type="Currently amended] The method of claim 1,
    [2-chloro-4-({2- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    (2-chloro-4-{[2- (2- (hydroxyethyl) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl acetate;
    4- (2- {2-[(3-chloro-4- (2-methylbenzoyl) phenyl) amino] phenyl} ethoxy) -4-oxobutanoic acid;
    2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl hexanoate;
    2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -1-methylethyl acetate;
    (2-chloro-4-{[2- (2-hydroxypropyl) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    [2-chloro-4-({2-[(1E) -3-hydroxyprop-1-enyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    (2-chloro-4-{[2- (3-hydroxypropyl) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    [2-chloro-4-({2-[(1E) -4-hydroxybut-1-enyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    [4-({2-[(1E) -3-aminoprop-1-enyl] phenyl} amino) -2-chlorophenyl] (2-methylphenyl) methanone;
    Diethyl (2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enylphosphonate;
    [2-chloro-4-({2-[(1E) -3-hydroxy-3-methylbut-1-enyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    Ethyl (2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) acrylate;
    (2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) acrylic acid;
    {2-chloro-4-[(2-{(1E) -3-[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] prop-1-enyl} phenyl) amino ] Phenyl} (2-methylphenyl) methanone;
    [2-chloro-4-({2-[(1E) -3- (2,3-dihydroxypropoxy) prop-1-enyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    Tert-butyl (1R) -3-{[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] amino} -1- (hydroxymethyl) -2-oxoethylylcarbamate;
    Methyl O- (tert-butyl) -N-({[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl ] Amino} carbonyl) -L-serinate;
    N- (tert-butyl) -N '-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] thio Urea;
    N-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl} prop-2-enyl] -4-oxopentanamide;
    N-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl} prop-2-enyl] -N'-ethylurea;
    Ethyl 4-{[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] amino} -4-oxobutanoate ;
    N-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -N'-cyclohexylurea;
    N '-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -N, N-dimethylsuccinamide;
    Dimethyl [(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] malonate;
    [2-chloro-4-({2-[(1E) -3-morpholin-4-ylprop-1-enyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    6-0-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -1,2: 3,4- Di-0- (1-methylethylidene) -α-D-galactopyranose;
    Methyl 5-O-[(2) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -2,3-O- ( 1-methylethylidene) -β-D-ribofuranoside;
    Methyl 5-0-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -β-D-ribofurano side;
    Methyl (4E) -5- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -2- (methylsulfonyl) pent-4-enoate;
    Ethyl {[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] thio} acetate;
    [2-chloro-4-{[2-((1E) -3- {bis [2- (acetyloxy) ethyl] amino} prop-1-enyl) phenyl] amino} phenyl] (2-methylphenyl) methane On;
    [2-chloro-4-{[2-((1E) -3- {bis [2- (hydroxy) ethyl] amino} prop-1-enyl) phenyl] amino} phenyl] (2-methylphenyl) methane On;
    (2-chloro-4-{[2-((1E) -3- {4- [2- (acetyloxy) ethyl] piperidin-1-yl} prop-1-enyl) phenyl] amino} phenyl ) (2-methylphenyl) methanone;
    {2-chloro-4-[(2-{(1E) -3- [4- (2-hydroxyethyl) piperidin-1-yl] prop-1-enyl} phenyl) amino] phenyl} ( 2-methylphenyl) methanone;
    {2-chloro-4-[(2- {2-[(tetrahydrofuran-2-ylmethyl) amino] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    [2-chloro-4-({2- [2- (4-methylpiperazin-1-yl) ethyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    {2-chloro-4-[(2- {2-[(3-morpholin-4-ylpropyl) amino] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    (2-chloro-4-{[2- (2-{[2- (dimethylamino) ethyl] amino} ethyl) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    {2-chloro-4-[(2- {2-[(2-methoxyethyl) amino] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    1- [3-({2- [2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethyl} amino) propyl] pyrrolidin-2-one;
    {2-chloro-4-[(2- {2- [methyl (tetrahydrofuran-2-ylmethyl) amino] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    (2-chloro-4-{[2- (2-{[(2,2-dimethyl-1,3-dioxolan-4-yl) methyl] amino} ethyl) phenyl] amino} phenyl) (2-methylphenyl Methanone;
    {2-chloro-4-[(2- {2- [4- (2-methoxyethyl) piperazin-1-yl] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    (2-chloro-4-{[2- (2-morpholin-4-ylethyl) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    {2-chloro-4-[(2- {2-[(2,3-dihydroxypropyl) amino] ethyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    (4-{[2- (aminomethyl) phenyl] amino} -2-chlorophenyl) (2-methylphenyl) methanone;
    (2-chloro-4-{[2-({2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethoxy} methyl) phenyl] amino} phenyl) (2-methylphenyl) Methanone;
    {2-chloro-4-[(2-{[(tetrahydro-2H-pyran-2-yloxy) ethoxy] methyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    [2-chloro-4-({2-[(2- {2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethoxy} ethoxy) methyl] phenyl} amino) phenyl ] (2-methylphenyl) methanone;
    [2-chloro-4-({2-[(3,3,3-trifluoropropoxy) methyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    Diethyl 2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzylphosphonate;
    2- [2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] -1H-isoindole-1,3 (2H) -dione;
    {2-chloro-4-[(2-{[2- (2-hydroxyethoxy) ethoxy] methyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    [2-chloro-4-({2-[(hydroxyethoxy) methyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    (2-chloro-4-{[2-({2- [2- (2-hydroxyethoxy) ethoxy] ethoxy} methyl) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    [4-({4-bromo-2-[(2-hydroxyethoxy) methyl] phenyl} amino) -2-chlorophenyl] (2-methylphenyl) methanone;
    (4-{[4-bromo-2-({2- [2- (2-hydroxyethoxy) ethoxy] ethoxy} methyl) phenyl] amino} -2-chlorophenyl) (2-methylphenyl) Methanone;
    {4-[(4-bromo-2-{[2- (2-hydroxyethoxy) ethoxy] methyl} phenyl) amino] -2-chlorophenyl} (2-methylphenyl) methanone;
    Diethyl 5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzylphosphonate;
    [4-({4-bromo-2-[(3,3,3-trifluoropropoxy) methyl] phenyl} amino) -2-chlorophenyl] (2-methylphenyl) methanone;
    2-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl 4-methylbenzenesulfonate;
    2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl 4-methylbenzenesulfonate;
    2- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethoxy) ethyl 4-methylbenzenesulfonate;
    2- [2- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethoxy) ethoxy] ethyl 4 Methylbenzenesulfonate;
    [4-({4-bromo-2-[(2-iodoethoxy) methyl] phenyl} amino) -2-chlorophenyl] (2-methylphenyl) methanone;
    {4-[(4-bromo-2-{[(2- (2-iodoethoxy) ethoxy] methyl} phenyl) amino] -2-chlorophenyl} (2-methylphenyl) methanone;
    (4-{[4-bromo-2-({2- [2- (2-iodoethoxy) ethoxy] ethoxy} methyl) phenyl] amino} -2-chlorophenyl) (2-methylphenyl) Methanone;
    [2-chloro-4-({2-[(2-iodoethoxy) methyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    Diethyl 2-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethylphosphonate;
    Diethyl 2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethylphosphonate;
    Diethyl 2-{{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethoxy) ethylphosphonate;
    Diethyl 2- [2- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethoxy) ethoxy] Ethylphosphonate;
    Diethyl 2-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] amino} -2-oxoethylphosphonate;
    Diethyl 2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] amino} -2-oxoethylphosphonate;
    {[2-({5-bromo-3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl (diethoxyphosphoryl) acetate;
    2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzylphosphonic acid;
    N- [2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] -2,2,2-trifluoroethanesulfonamide;
    N- [5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] -2,2,2-trifluoroethanesulfonamide;
    {2-chloro-4-[(2-{[(tetrahydro-2H-pyran-2-yloxy) propoxy] methyl} phenyl) amino] phenyl} (2-methylphenyl) methanone;
    [2-chloro-4-({2-[(hydroxypropoxy) methyl] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    Diethyl 3-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} propylphosphonate;
    Diethyl 2- [2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethylphosphonate;
    Diethyl 2- [5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethylphosphonate;
    2-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] amino} -2-oxoethylphosphonic acid;
    (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -carbamic acid phenethyl ester;
    N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -2-phenoxy-acetamide;
    N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -3-phenoxy-propionamide;
    N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) Acetamide;
    N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -succinic acid 2- (2-methoxy-ethoxy) ethyl ester;
    N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -benzenesulfonamide;
    Acetic acid (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenylcarbamoyl) -methyl ester;
    1- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) pyrrolidine-2,5-dione;
    2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl propionate;
    2,2-dimethyl-propionic acid 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl ester;
    [2-chloro-4-({2- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    (2-chloro-4-{[2- (3-hydroxypropoxy) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    Tert-butyl 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl carbonate;
    2-({[(5-bromo-2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) amino] carbonyl} amino) ethyl 2-methylacrylate;
    (4-{[4-bromo-2- (2-hydroxyethyl) phenyl] amino} -2-chloro-phenyl) (2-methylphenyl) methanone;
    3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenoxy) propyl acetate;
    [2-chloro-4-({2- [3- (morpholin-4-yl) propoxy] phenyl} amino) phenyl] (2-methylphenyl) methanone;
    N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -N '-(4-phenoxybutyl) succinamide;
    N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -N '-(6-hydroxyhexyl) succinamide;
    N- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -N '-(2,3-dihydroxypropyl) succinamide;
    Tert-butyl (1R) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -1- (hydroxymethyl) propylcarbamate;
    Diethyl 6- [3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenylcarbamoyl) propionylamino] -hexyl phosphate;
    Ethyl N-({[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] amino} carbonyl) glycinate ;
    Tert-butyl 2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl (methyl) carbamate;
    N- (5-bromo-2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -N '-(6-hydroxyhexyl) succinamide;
    N- (5-bromo-2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) -N '-(2,3-dihydroxypropyl) succinamide;
    (2Z) -N-[(2E) -3- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) prop-2-enyl] -2- (2,5 -Dioxoimidazolidine-4-ylidene) acetamide;
    (2-chloro-4-{[2- (difluoromethyl) phenyl] amino} phenyl) (2-methylphenyl) methanone;
    3-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethyl} -1-methylimidazolidine-2,4-dione;
    3-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethyl} -5,5-dimethyloxazoline-2,4-dione;
    4-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethyl} morpholine-3,5-dione;
    1-{[2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) phenyl] ethyl} piperidine-2,6-dione;
    4- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) morpholine-3,5-dione;
    1- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) pyrrolidine-2,5-dione ;
    Ethyl 2- [3- (2- {5-bromo- [2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyloxy} ethyl) -2,4,5 -Trioximidazolidin-1-yl] acetate;
    3- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) imidazolidine-2,4- Diones;
    1- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) -3,4-cis-diacetoc Cypyrrolidin-2,5-dione;
    3- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) thiazoline-2,4-dione;
    3- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) -1-methylimidazolidine- 2,4-dione;
    1- (2-{[5-bromo-2-({3-chloro-4-[(2-methylphenyl) carbonyl] phenyl} amino) benzyl] oxy} ethyl) imidazolidine-2,4, 5-trione;
    (2-chloro-4-{[(2-hydroxymethyl) phenyl] amino} phenyl) (2-methylphenyl) methanone and
    A compound selected from the group consisting of 2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} benzyl acetate and pharmaceutically acceptable salts, solvates and hydrates thereof.
    [22" claim-type="Currently amended] 22. A compound according to any one of claims 1 to 21 and any pharmaceutically acceptable excipients, and glucocorticoids, vitamin D analogues, antihistamines, platelet activating factor (PAF) antagonists, anticolergenic agents, Methyl Xanthine, β-Adrenergic Agent, COX-2 Inhibitor, Salicylate, Indomethacin, Flufenamate, Naproxen, Thimegadine, Gold Salt, Penicillamine, Serum Cholesterol Reducing Agent, Retinoid, Zinc Salt and Salicylic A pharmaceutical composition containing any other pharmaceutically active ingredient selected from the group consisting of azosulfapiridine.
    [23" claim-type="Currently amended] The pharmaceutical composition of claim 22 containing from 0.1 to 100% of a compound of formula (I).
    [24" claim-type="Currently amended] The pharmaceutical composition of claim 22 in the form of a dosage unit containing from 0.07 mg to 1 g of the compound of formula (I).
    [25" claim-type="Currently amended] An effective amount of the compound according to claim 1 and any pharmaceutically acceptable excipients and glucocorticoids, vitamin D analogues, antihistamines, platelet activating factor (PAF) antagonists, anticollagens, methyl xanthines, β-adrenergic agents, COX- 2 inhibitors, salicylate, indomethacin, flufenamate, naproxen, thimegadine, gold salt, penicillamine, serum cholesterol reducing agents, retinoids, zinc salts and salicylazosulpypyridine Other pharmaceutically active ingredients include asthma, allergies, arthritis, rheumatoid arthritis, gout, atherosclerosis, chronic inflammatory bowel disease (Crohn's disease), proliferative and inflammatory dermatitis, psoriasis, atopic dermatitis, uveitis, sepsis shock, AIDS And administering to a patient in need thereof for the treatment or prevention of osteoporosis and acne.
    [26" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 21 in the manufacture of a medicament.
    [27" claim-type="Currently amended] Treatment of asthma, allergies, arthritis, rheumatoid arthritis, gout, atherosclerosis, chronic inflammatory bowel disease (Crohn's disease), proliferative and inflammatory skin disease, psoriasis, atopic dermatitis, uveitis, septic shock, AIDS, osteoporosis and acne or Use of a compound according to any one of claims 1 to 21 in the manufacture of a medicament for prophylaxis.
    [28" claim-type="Currently amended] 2- (2-bromophenyl) -1-methylethyl acetate;
    (3E) -2-methyl-4- (tributylstannyl) but-3-en-2-ol;
    Tributyl {(1E) -3-[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] prop-1-enyl} stanan;
    Dimethyl [(2E) -3- (tributylstannyl) prop-1-enyl] malonate;
    4-[(2E) -3- (tributylstannyl) prop-2-enyl] morpholine;
    1,2: 3,4-di-O- (1-methylethylidene) -6-O-[(2E) -3- (tributylstannyl) prop-2-enyl] -α-D- Galactopyranose;
    Methyl 2,3-0- (1-methylethylidene) -5-0-[(2E) -3- (tributylstannyl) prop-2-enyl] -β-D-ribofuranoside;
    Methyl (4E) -2- (methylsulfonyl) -5- (tributylstannyl) pent-4-enoate;
    Ethyl {[(2E) -3- (tributylstannyl) prop-2-enyl] thio} acetate;
    Tributyl {(1E) -3- [bis (2-hydroxyethyl) amino] prop-1-enyl} stannan;
    Tributyl ((1E) -3- {bis [2- (acetyloxy) ethyl] amino] prop-1-enyl) stannan;
    Tributyl {(1E) -3- [4- (2-hydroxyethyl) piperidin-1-yl] prop-1-enyl} stannan;
    Tributyl ((1E) -3- {4- [2- (acetyloxy) ethyl] piperidin-1-yl} prop-1-enyl) stannan;
    2- (2-{(2-bromobenzyl) oxy} ethoxy) ethanol;
    2- (2- {2-[(2-bromobenzyl) oxy] ethoxy} ethoxy) ethanol;
    2-bromobenzyl 3,3,3-trifluoropropyl ether;
    2- (2- {2-[(2-bromobenzyl) oxy] ethoxy} ethoxy) tetrahydro-2H-pyran;
    2- [2- (2- {2-[(2-bromobenzyl) oxy] ethoxy} ethoxy) ethoxy] tetrahydro-2H-pyran;
    2- {2-[(2-bromobenzyl) oxy] ethoxy} tetrahydro-2H-pyran;
    2- {3-[(2-bromobenzyl) oxy] propoxy} tetrahydro-2H-pyran;
    3-[(2-bromobenzyl) oxy] propyl 4-methylbenzenesulfonate;
    1-bromo-2- (3-iodo-propoxymethyl) benzene;
    Diethyl 3-[(2-bromobenzyl) oxy] propylphosphonate;
    Diethyl 2- (2-bromophenyl) ethylphosphonate;
    (2-chloro-4-iodophenyl) (2-methylphenyl) methanone;
    Tert-butyl (4R) -4- [2- (2-aminophenyl) ethyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylate;
    Tert-butyl (4R) -4- [2- (2-{[3-chloro-4- (2-methylbenzoyl) phenyl] amino} phenyl) ethyl] -2,2-dimethyl-oxazolidine-3 Carboxylates;
    Tert-butyl [2- (2-bromophenyl) ethyl] (methyl) carbamate;
    3- [2- (2-bromophenyl) ethyl] -1-methylimidazolidine-2,4-dione;
    3- [2- (2-bromophenyl) ethyl] -5,5-dimethyloxyazolidine-2,4-dione;
    4- [2- (2-bromophenyl) ethyl] morpholine-3,5-dione;
    1- [2- (2-bromophenyl) ethyl] piperidine-2,6-dione;
    2-bromobenzyl (triisopropyl) silyl ether and
    {2-chloro-4-[(2-{[(triisopropyl) siloxy] methyl} phenyl) amino] phenyl} (2-methylphenyl) methanone.
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    IL160442D0|2004-07-25|
    BR0212249A|2004-10-05|
    HK1068606A1|2008-06-06|
    JP2010189410A|2010-09-02|
    US20030119902A1|2003-06-26|
    KR100896667B1|2009-05-14|
    HU0401644A2|2004-11-29|
    CN100347151C|2007-11-07|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-08-28|Priority to US31502501P
    2001-08-28|Priority to US60/315,025
    2002-02-08|Priority to DKPA200200189
    2002-02-08|Priority to DKPA200200189
    2002-08-26|Application filed by 레오 파마 에이/에스
    2002-08-26|Priority to PCT/DK2002/000557
    2004-04-06|Publication of KR20040029455A
    2009-05-14|Application granted
    2009-05-14|Publication of KR100896667B1
    优先权:
    申请号 | 申请日 | 专利标题
    US31502501P| true| 2001-08-28|2001-08-28|
    US60/315,025|2001-08-28|
    DKPA200200189|2002-02-08|
    DKPA200200189|2002-02-08|
    PCT/DK2002/000557|WO2003018535A2|2001-08-28|2002-08-26|Novel aminobenzoephenones|
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