Abstract
There are described compounds of formula (I): (I) and their use as a medicament in the treatment of diseases associated with the abnormal or elevated catabolism of tryptophan, such as, cancer, immunosuppression, viral infection, depression, a neurodegenerative disorder, trauma, age-related cataracts, organ transplant rejection, or an autoimmune disorder in a patient.
##STR00001##
Claims
1-54. (canceled)
55. A compound of Formula (I): ##STR00390## or a pharmaceutically acceptable salt, or a solvate, or a solvate of the salt thereof, wherein: m is 0 or 1; n is 0, 1 or 2; X is —NR.sup.8; R.sup.1 is H, C.sub.1-6alkyl or a 6-10 membered aryl; R.sup.2 is a 5-6-membered heteroaryl, a fused 9-10 membered bicyclic heteroaryl, a 6-10 membered aryl, a 5-6 membered monocyclic heterocycloalkyl or a 5-11 membered spiroheteroalkyl or a fused 8-10 membered partially unsaturated bicyclic heterocyclyl; each of which may independently be optionally substituted by one or more groups independently selected from C.sub.1-6alkyl, halogen, haloC.sub.1-6alkyl, —OC.sub.1-6alkyl, —CN, —C(═O)C.sub.1-6alkyl, —C(═O)OC.sub.1-6alkyl, —SO.sub.2—C.sub.1-6alkyl, —C(═O)NH.sub.2, haloC.sub.1-6alkyloxy or phenyl; R.sup.3 is H or C.sub.1-6alkyl; or a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 5-6 membered heteroaryl, a fused 9-10 membered bicyclic heteroaryl, a 4-6 membered monocyclic heterocycloalkyl, a —C.sub.1-6alkyl-heteroaryl or a 5-11 membered spiroheteroalkyl; each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl, —OC.sub.1-6alkyl, halogen, —CN or —C(═O)OC.sub.1-6alkyl; A.sup.1 is —N— or —CR.sup.6—; A.sup.2 is —N— or —CR.sup.5—; A.sup.3 is —N— or —CR.sup.7—; A.sup.4 is —N—, —O—, —S—, —CH═N— or —CH═CR.sup.4—; R.sup.4, R.sup.5, R.sup.6 and R.sup.7, which may be the same or different, are each selected from —H, —OH, —C.sub.1-6alkyl, halogen, haloC.sub.1-6alkyl, —CN, —C.sub.1-6alkyl-CN, —OC.sub.1-6alkyl, —C.sub.2-6alkynyl, —C.sub.2-6alkynyl-C.sub.1-6alkyl, —C.sub.2-6alkynyl-aryl, —C.sub.2-6alkynyl-C.sub.1-6alkyl-aryl, —C.sub.2-6alkynyl-C.sub.3-6cycloalkyl, —C.sub.2-6alkynyl-C.sub.1-6alkyl-NR.sup.11R.sup.12, —C.sub.2-6alkynyl-C.sub.1-6alkyl-OR.sup.13, —C(═O)C.sub.1-6alkyl, —C(═O)NH.sub.2, a 3-10 membered cycloalkyl, a 5-11 membered spiroalkyl, a 4-6 membered monocyclic heterocycloalkyl, a 6-10 membered aryl, a 5-6 membered heteroaryl, a 5-6 membered heteroC.sub.3-6cycloalkyl, a fused 9-10 membered bicyclic heteroaryl, each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl, C.sub.1-6alkyl-NR.sup.9R.sup.10, —C.sub.1-6alkyl-OH, —C(═O)OC.sub.1-6alkyl or oxopyrrolidine; or R.sup.5 and R.sup.7 together form a ring —CH═CH—CH═CH—, —OCH.sub.2O— or —CH.sub.2CH.sub.2CH.sub.2—; or the moiety ##STR00391## may be fused with oxopyrrolidine; and R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, and R.sup.13, which may be the same or different, are each selected from H or C.sub.1-6alkyl; provided that the compound of formula I is not 1-(4-chlorobenzyl)-1-cyclopentyl-3-phenylurea; N-(3,5-dimethylphenyl)-3-ethyl-2-methyl-7-phenyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxamide; [194] 1-cyclopentyl-3-phenyl-1-(2-thienylmethyl)urea; [195] 1-(4-chlorophenyl)-3-phenyl-1-(2-thienylmethyl)urea; [196] 1-[1-(4-fluorophenyl)ethyl]-3-phenyl-urea; [197] 1-(4-chlorophenyl)-3-[1-(5-chloro-2-thienyl)ethyl]urea; [199] 3-(3,4-dichlorophenyl)-1-methyl-1-(2-thienylmethyl)urea; [200] 1-[(5-methyl-2-phenyl-oxazol-4-yl)methyl]-3-phenyl-urea; [203] and 1-(3-chlorophenyl)-3-[(3-chloro-2-thienyl)methyl]urea; [204].
56-57. (canceled)
58. The compound according to claim 55, wherein m is 1.
59. The compound according to claim 55, wherein n is 0.
60. The compound according to claim 55, wherein n is 2.
61. The compound according to claim 55, wherein R.sup.1 is H.
62. The compound according to claim 55, wherein X is —NH—.
63. The compound according to claim 55, wherein R.sup.2 is a 5-6-membered heteroaryl or a fused 9-10 membered bicyclic heteroaryl.
64-66. (canceled)
67. The compound according to claim 55, wherein R.sup.3 is a 5-6-membered heteroaryl.
68. (canceled)
69. The compound according to claim 55, wherein R.sup.3 is a 4-6 membered monocyclic heterocycloalkyl.
70. (canceled)
71. The compound according to claim 55, wherein the moiety ##STR00392## is selected from the group consisting of benzothiazole, indane, oxadiazole, phenyl, pyridine, pyrimidine, thiazole and thiophene; each of which may independently be optionally substituted by one or more groups independently selected from OH, —C.sub.1-6alkyl, C.sub.3-6cycloalkyl halogen, haloC.sub.1-6alkyl, —CN, —C.sub.1-6alkyl-CN, —C.sub.1-6alkyl-OH, —OC.sub.1-6alkyl, —C.sub.2-6alkynyl, —C.sub.1-6alkyl-OC.sub.1-6alkyl, haloC.sub.1-6alkyl-O—, —C.sub.1-6alkyl-O—NH.sub.2, C.sub.2-6alkynyl-OC.sub.1-6alkyl; a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 5-6 membered heteroaryl, a 4-6 membered monocyclic heterocycloalkyl, a fused 8-10 membered partially unsaturated bicyclic heterocyclyl or a fused 9-10 membered bicyclic heteroaryl, each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl, C.sub.1-6alkyl-NR.sup.9R.sup.10, —C(═O)C.sub.1-6alkyl, —C(═O)OC.sub.1-6alkyl, —C.sub.1-6alkyl-OH, C.sub.2-6alkynyl-C.sub.1-6alkyl, —C.sub.2-6alkynyl-C.sub.3-6cycloalkyl, —C.sub.2-6alkynyl-C.sub.1-6alkyl-NR.sup.11R.sup.12, —C.sub.2-6alkynyl-C.sub.1-6alkyl-OR.sup.13, C.sub.2-6alkynyl-aryl, C.sub.2-6alkynyl-C.sub.1-6alkyl-aryl, —C(═O)NH.sub.2 or —C(═O)OC.sub.1-6alkyl.
72. The compound according to claim 55, wherein the moiety ##STR00393## is phenyl, which may independently be optionally substituted by one or more groups independently selected from OH, —C.sub.1-6alkyl, C.sub.3-6cycloalkyl halogen, haloC.sub.1-6alkyl, —CN, —C.sub.1-6alkyl-CN, —C.sub.1-6alkyl-OH, —OC.sub.1-6alkyl, —C.sub.2-6alkynyl, —C.sub.1-6alkyl-OC.sub.1-6alkyl, haloC.sub.1-6alkyl-O—, —C.sub.1-6alkyl-O—NH.sub.2, C.sub.2-6alkynyl-OC.sub.1-6alkyl; a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 5-6 membered heteroaryl, a 4-6 membered monocyclic heterocycloalkyl, a fused 8-10 membered partially unsaturated bicyclic heterocyclyl or a fused 9-10 membered bicyclic heteroaryl, each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl, C.sub.1-6alkyl-NR.sup.9R.sup.10, —C(═O)C.sub.1-6alkyl, —C(═O)OC.sub.1-6alkyl, —C.sub.1-6alkyl-OH, C.sub.2-6alkynyl-C.sub.1-6alkyl, —C.sub.2-6alkynyl-C.sub.3-6cycloalkyl, —C.sub.2-6alkynyl-C.sub.1-6alkyl-NR.sup.11R.sup.12, —C.sub.2-6alkynyl-C.sub.1-6alkyl-OR.sup.13, C.sub.2-6alkynyl-aryl, C.sub.2-6alkynyl-C.sub.1-6alkyl-aryl, —C(═O)NH.sub.2 and —C(═O)OC.sub.1-6alkyl.
73. The compound according to claim 55, wherein A.sup.3 is —CR.sup.7—, wherein R.sup.7 is selected from the group consisting of the following ring structures: ##STR00394## ##STR00395##
74. The compound according to claim 55, wherein R.sup.5 is H or halogen.
75. The compound according to claim 55, wherein R.sup.6 is H or —C.sub.1-6alkyl.
76. The compound according to claim 55 wherein the compound is selected from the group consisting of: 1-cyclopentyl-3-(2-phenylethyl)-1-(2-thienylmethyl)urea; [1] 3-(2-chlorophenyl)-1-cyclopentyl-1-(2-thienylmethyl)urea; [2] 1-cyclopentyl-3-(4-ethylphenyl)-1-(2-thienylmethyl)urea; [3] 1-cyclopentyl-3-(3,4-difluorophenyl)-1-(2-thienylmethyl)urea; [4] 1-cyclopentyl-3-(2,4-dimethylphenyl)-1-(2-thienylmethyl)urea; [5] 3-[4-(cyanomethyl)phenyl]-1-cyclopentyl-1-(2-thienylmethyl)urea; [6] 3-(1,3-benzodioxol-5-yl)-1-cyclopentyl-1-(2-thienylmethyl)urea; [7] 1-cyclopentyl-3-[(4-fluorophenyl)methyl]-1-(2-thienylmethyl)urea; [8] 1-cyclopentyl-3-indan-5-yl-1-(2-thienylmethyl)urea; [9] “1-cyclopentyl-3-(2,6-dichloro-4-pyridyl)-1-(2-thienylmethyl)urea; [10]” 1-cyclopentyl-3-(4-pyridyl)-1-(2-thienylmethyl)urea; [11] 1-cyclopentyl-1-(2-thienylmethyl)-3-[4-(trifluoromethyl)phenyl]urea; [13] 1-cyclopentyl-3-(4-methoxyphenyl)-1-(2-thienylmethyl)urea; [14] 3-allyl-1-cyclopentyl-1-(2-thienylmethyl)urea; [15] “1-cyclopentyl-3-(5-ethynyl-2-pyridyl)-1-[(5-methyl-2-furyl)methyl]urea; [16]” “1-cyclopentyl-3-(5-ethynylpyrimidin-2-yl)-1-[(5-methyl-2-furyl)methyl]urea; [17]” 1-cyclopentyl-3-(2,4-dimethoxyphenyl)-1-(2-thienylmethyl)urea; [18] 1-cyclopentyl-3-phenyl-1-(2-thienylmethyl)urea; [19] 1-cyclohexyl-3-(2-phenylethyl)-1-(2-pyridylmethyl)urea; [20] 1-cyclohexyl-3-(4-ethylphenyl)-1-(2-pyridylmethyl)urea; [21] 3-(4-acetylphenyl)-1-cyclopentyl-1-(2-thienylmethyl)urea; [22] 1-cyclopentyl-3-methyl-3-phenyl-1-(2-thienylmethyl)urea; [23] 1-cyclopentyl-1-[(5-methyl-2-thienyl)methyl]-3-phenyl-urea; [24] 1-cyclopentyl-3-(4-ethylphenyl)-1-[(5-methyl-2-thienyl)methyl]urea; [25] 1-cyclopentyl-1-[(5-methyl-2-thienyl)methyl]-3-(2-phenylethyl)urea; [26] “1-cyclopentyl-3-(3,4-difluorophenyl)-1-[(5-methyl-2-thienyl)methyl]urea; [27]” 1-cyclopentyl-1-(2-furylmethyl)-3-phenyl-urea; [28] 1-cyclopentyl-1-(2-furylmethyl)-3-(2-phenylethyl)urea; [29] 1-cyclopentyl-3-(3,4-difluorophenyl)-1-(2-furylmethyl)urea; [30] 1-cyclopentyl-3-(3,4-difluorophenyl)-1-[(5-methyl-2-furyl)methyl]urea; [31] 1-cyclohexyl-3-phenyl-1-(2-pyridylmethyl)urea; [32] 1-cyclohexyl-3-(3,4-difluorophenyl)-1-(2-pyridylmethyl)urea; [33] 1-cyclopentyl-3-(4-fluorophenyl)-1-(2-thienylmethyl)urea; [34] 1-cyclopentyl-3-phenyl-1-(thiazol-2-ylmethyl)urea; [35] 1-cyclopentyl-3-(4-ethylphenyl)-1-(thiazol-2-ylmethyl)urea; [36] 1-cyclopentyl-3-(3,4-difluorophenyl)-1-(thiazol-2-ylmethyl)urea; [37] 1-[(2-chlorophenyl)methyl]-1-cyclopentyl-3-phenyl-urea; [38] 1-[(2-chlorophenyl)methyl]-1-cyclopentyl-3-(4-ethylphenyl)urea; [39] 1-[(2-chlorophenyl)methyl]-1-cyclopentyl-3-(3,4-difluorophenyl)urea; [40] 1-[(5-chloro-1-methyl-pyrazol-4-yl)methyl]-1-cyclopentyl-3-phenyl-urea; [41] 1-[(5-chloro-1-methyl-pyrazol-4-yl)methyl]-1-cyclopentyl-3-(4-ethylphenyl)urea; [42] 1-[(5-chloro-1-methyl-pyrazol-4-yl)methyl]-1-cyclopentyl-3-(3,4-difluorophenyl) urea; [43] 1-[(5-chloro-1-methyl-pyrazol-4-yl)methyl]-1-cyclopentyl-3-(4-fluorophenyl) urea; [44] 1-cyclopentyl-1-[(4-methoxy-3-methyl-phenyl)methyl]-3-phenyl-urea; [45] 1-cyclopentyl-1-[(4-methoxy-3-methyl-phenyl)methyl]-3-(2-phenylethyl)urea; [46] 1-cyclopentyl-3-(3,4-difluorophenyl)-1-[(4-methoxy-3-methyl-phenyl)methyl]urea; [47] 1-cyclopentyl-3-(4-fluorophenyl)-1-[(4-methoxy-3-methyl-phenyl)methyl]urea; [48] 1-cyclopentyl-1-[(2-methoxythiazol-5-yl)methyl]-3-phenyl-urea; [49] 1-[(3-cyano-4-fluoro-phenyl)methyl]-1-cyclopentyl-3-phenyl-urea; [50] 1-[(3-cyano-4-fluoro-phenyl)methyl]-1-cyclopentyl-3-(2-phenylethyl)urea; [51] 1-[(3-cyano-4-fluoro-phenyl)methyl]-1-cyclopentyl-3-(3,4-difluorophenyl)urea; [52] 1-[(3-cyano-4-fluoro-phenyl)methyl]-1-cyclopentyl-3-(4-fluorophenyl)urea; [53] 1-cyclopentyl-3-(2-fluorophenyl)-1-(2-thienylmethyl)urea; [54] 1-cyclopentyl-3-(3-fluorophenyl)-1-(2-thienylmethyl)urea; [55] 3-(4-chlorophenyl)-1-cyclopentyl-1-(2-thienylmethyl)urea; [56] 1-cyclopentyl-3-(3-pyridyl)-1-(2-thienylmethyl)urea; [57] 1-cyclopentyl-1-phenyl-3-(2-thienyl)urea; [58] 1-cyclopentyl-3-(2,4-dichlorophenyl)-1-(2-thienylmethyl)urea; [59] 1-[(5-cyano-2-furyl)methyl]-1-cyclopentyl-3-phenyl-urea; [60] 1-[(5-cyano-2-furyl)methyl]-1-cyclopentyl-3-(4-fluorophenyl)urea; [61] 1-cyclopentyl-3-(4-fluorophenyl)-1-(isoxazol-4-ylmethyl)urea; [62] 3-(4-chlorophenyl)-1-cyclopentyl-1-(isoxazol-4-ylmethyl)urea; [63] 1-cyclopentyl-1-(3-furylmethyl)-3-phenyl-urea; [64] 1-cyclopentyl-3-phenyl-1-(3-pyridylmethyl)urea; [65] 3-(4-chlorophenyl)-1-cyclopentyl-1-(3-pyridylmethyl)urea; [66] 1-cyclopentyl-3-phenyl-1-(2-pyridylmethyl)urea; [67] 1-cyclopentyl-3-(4-fluorophenyl)-1-(2-pyridylmethyl)urea; [68] 3-(4-chlorophenyl)-1-cyclopentyl-1-(2-pyridylmethyl)urea; [69] “1-cyclopentyl-3-(4-fluorophenyl)-1-(pyrazin-2-ylmethyl)urea; [70]” 3-(4-chlorophenyl)-1-cyclopentyl-1-(pyrazin-2-ylmethyl)urea; [71] 1-cyclopentyl-3-(4-fluorophenyl)-1-(pyrimidin-2-ylmethyl)urea; [72] 3-(4-chlorophenyl)-1-cyclopentyl-1-(pyrimidin-2-ylmethyl)urea; [73] 1-cyclopentyl-3-phenyl-1-(4-pyridylmethyl)urea; [74] “1-cyclopentyl-3-(4-fluorophenyl)-1-(4-pyridylmethyl)urea; [75]” 3-(4-chlorophenyl)-1-cyclopentyl-1-(4-pyridylmethyl)urea; [76] tert-butyl 4-[[cyclopentyl(phenylcarbamoyl)amino]methyl]-4-methyl-piperidine-1-carboxylate; [77] “tert-butyl 4-[[cyclopentyl-[(4-fluorophenyl)carbamoyl]amino]methyl]-4-methyl-piperidine-1-carboxylate; [78]” tert-butyl 4-[[(4-chlorophenyl)carbamoyl-cyclopentyl-amino]methyl]-4-methyl-piperidine-1-carboxylate; [79] 3-(4-cyanophenyl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea; [80] 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-(4-pyridyl)urea; [81] 1-cyclobutyl-3-(4-fluorophenyl)-1-[(5-methyl-2-furyl)methyl]urea; [82] 3-(4-chlorophenyl)-1-cyclobutyl-1-[(5-methyl-2-furyl)methyl]urea; [83] 3-(4-cyanophenyl)-1-cyclobutyl-1-[(5-methyl-2-furyl)methyl]urea; [84] 1-cyclopentyl-1-[(4-methyl-4-piperidyl)methyl]-3-phenyl-urea; [85] 1-cyclopentyl-3-(4-fluorophenyl)-1-[(4-methyl-4-piperidyl)methyl]urea; [86] 3-(4-chlorophenyl)-1-cyclopentyl-1-[(4-methyl-4-piperidyl)methyl]urea; [87] “1-cyclopentyl-3-(4-pyridyl)-1-[[3-(trifluoromethyl)phenyl]methyl]urea; [88]” “3-(4-cyanophenyl)-1-cyclopentyl-1-[[3-(trifluoromethyl)phenyl]methyl]urea; [89]” 3-(4-chlorophenyl)-1-cyclobutyl-1-[[3-(trifluoromethyl)phenyl]methyl]urea; [90] 3-(4-cyanophenyl)-1-cyclobutyl-1-[[3-(trifluoromethyl)phenyl]methyl]urea; [91] 3-(6-chloro-3-pyridyl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea; [92] 3-(3-cyanophenyl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea; [93] 3-(4-acetylphenyl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea; [94] 3-(2-cyanophenyl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea; [95] “3-[(4-cyanophenyl)methyl]-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea; [96]” 1-[(1-acetyl-4-methyl-4-piperidyl)methyl]-1-cyclopentyl-3-phenyl-urea; [97] 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-[4-(1-methylpyrazol-4-yl)phenyl] urea; [98] “tert-butyl 4-[4-[[cyclopentyl-[(5-methyl-2-furyl)methyl]carbamoyl]amino]phenyl] pyrazole-1-carboxylate; [99]” 1-cyclopentyl-3-[4-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]phenyl]-1-[(5-methyl-2-furyl)methyl]urea; [100] 1-cyclopentyl-3-[4-[1-(2-hydroxy-1,1-dimethyl-ethyl)pyrazol-4-yl]phenyl]-1-[(5-methyl-2-furyl)methyl]urea; [101] “1-cyclopentyl-3-(4-ethynylphenyl)-1-[(5-methyl-2-furyl)methyl]urea; [102]” “1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-[4-(2-oxopyrrolidin-1-yl)phenyl] urea; [103]” “1-cyclopentyl-3-(4-fluoro-3-hydroxy-phenyl)-1-[(5-methyl-2-furyl)methyl] urea; [104]” “1-cyclopentyl-3-(4-isoxazol-4-ylphenyl)-1-[(5-methyl-2-furyl)methyl]urea; [105]” 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-(4-thiazol-4-ylphenyl)urea; [106] 1-cyclopentyl-3-[4-(2-cyclopropylethynyl)phenyl]-1-[(5-methyl-2-furyl)methyl] urea; [107] 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]urea; [108] 1-cyclopentyl-3-[4-(3-hydroxy-3-methyl-but-1-ynyl)phenyl]-1-[(5-methyl-2-furyl) methyl]urea; [109] 3-[4-(3-aminoprop-1-ynyl)phenyl]-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl] urea; [110] 1-cyclopentyl-3-[4-(3-hydroxyprop-1-ynyl)phenyl]-1-[(5-methyl-2-furyl)methyl] urea; [111] 1-cyclopentyl-3-[4-[3-(dimethylamino)prop-1-ynyl]phenyl]-1-[(5-methyl-2-furyl) methyl]urea; [112] “1-cyclopentyl-3-(4-fluorophenyl)-1-[(4-methyl-1-methylsulfonyl-4-piperidyl)methyl]urea; [113]” 3-(4-chlorophenyl)-1-[(2-cyano-4-pyridyl)methyl]-1-cyclopentyl-urea; [114] 3-(4-chlorophenyl)-1-[(5-cyano-3-pyridyl)methyl]-1-cyclopentyl-urea; [115] 3-(4-chlorophenyl)-1-[(4-cyano-2-pyridyl)methyl]-1-cyclopentyl-urea; [116] 4-[[cyclopentyl-[(5-methyl-2-furyl)methyl]carbamoyl]amino]benzamide; [117] tert-butyl 4-[[cyclopentyl(phenylcarbamoyl)amino]methyl]piperidine-1-carboxylate; [118] tert-butyl 4-[[cyclopentyl-[(4-fluorophenyl)carbamoyl]amino]methyl]piperidine-1-carboxylate; [119] tert-butyl 4-[[(4-chlorophenyl)carbamoyl-cyclopentyl-amino]methyl]piperidine-1-carboxylate; [120] 3-(5-cyano-2-pyridyl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea; [121] 5-[[cyclopentyl-[(4-fluorophenyl)carbamoyl]amino]methyl]-2-fluoro-benzamide; [122] 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-(4-morpholinophenyl)urea; [123] 3-(6-cyano-3-pyridyl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea; [124] 1-[(6-cyano-2-pyridyl)methyl]-1-cyclopentyl-3-phenyl-urea; [125] 1-[(6-cyano-2-pyridyl)methyl]-1-cyclopentyl-3-(4-fluorophenyl)urea; [126] 1-cyclopentyl-3-(4-fluorophenyl)-1-(isoxazol-5-ylmethyl)urea; [127] 3-(4-chlorophenyl)-1-cyclopentyl-1-(isoxazol-5-ylmethyl)urea; [128] 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-(4-phenylthiazol-2-yl)urea; [129] 1-(benzofuran-2-ylmethyl)-3-(4-chlorophenyl)-1-cyclopentyl-urea; [130] 1-(benzofuran-2-ylmethyl)-1-cyclopentyl-3-(4-ethynylphenyl)urea; [131] “1-(benzofuran-2-ylmethyl)-3-(4-cyanophenyl)-1-cyclopentyl-urea; [132]” “1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-[4-(2-pyridyl)thiazol-2-yl]urea; [133]” 3-(1,3-benzothiazol-2-yl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea; [134] “3-(4-cyanothiazol-2-yl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea; [135]” “tert-butyl 4-[(5-methyl-2-furyl)methyl-(phenylcarbamoyl)amino]piperidine-1-carboxylate; [136]” 3-(4-chlorophenyl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea; [137] 1-isopropyl-1-[(5-methyl-2-furyl)methyl]-3-phenyl-urea; [138] 1-cyclopentyl-3-(3,4-difluorophenyl)-1-[[4-fluoro-3-(trifluoromethyl)phenyl]methyl] urea; [139] 1-cyclopentyl-3-(3,4-difluorophenyl)-1-[[3 (trifluoromethyl)phenyl]methyl]urea; [140] 1-cyclopentyl-3-(3,4-difluorophenyl)-1-[[4-fluoro-3 (trifluoromethoxy)phenyl]methyl]urea; [141] 1-cyclopentyl-3-(3,4-difluorophenyl)-1-[[3 (trifluoromethoxy)phenyl]methyl] urea; [142] 1-cyclopentyl-1-[(2-methyloxazol-5-yl)methyl]-3-phenyl-urea; [143] 3-(4-chlorophenyl)-1-cyclopentyl-1-[(2-methyloxazol-5-yl)methyl]urea; [144] 1-cyclopentyl-3-(4-fluorophenyl)-1-[(2-methyloxazol-5-yl)methyl]urea; [145] 3-(4-chlorophenyl)-1-[(3-cyano-4-fluoro-phenyl)methyl]-1-cyclopentyl-urea; [146] 3-(4-chlorophenyl)-1-[(3-cyanophenyl)methyl]-1-cyclopentyl-urea; [147] 3-(4-chlorophenyl)-1-cyclopentyl-1-[[2-(trifluoromethyl)-4-pyridyl]methyl]urea; [148] 3-(4-chlorophenyl)-1-cyclopentyl-1-(isoxazol-3-ylmethyl)urea; [149] 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-(4-phenylphenyl)urea; [150] 3-[5-(benzofuran-2-yl)-1,3,4-oxadiazol-2-yl]-1-cyclopentyl-1-[(5-methyl-2-furyl) methyl]urea; [151] 3-(4-cyanophenyl)-1-cyclobutyl-1-[[2-(trifluoromethyl)-4-pyridyl]methyl]urea; [152] 1-cyclobutyl-3-(4-ethynylphenyl)-1-[[2-(trifluoromethyl)-4-pyridyl]methyl]urea; [153] 1-cyclobutyl-3-(4-prop-1-ynylphenyl)-1-[[2-(trifluoromethyl)-4-pyridyl]methyl] urea; [154] 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-[4-(2-phenylethynyl)phenyl]urea; [155] 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-[4-(3-phenylprop-1-ynyl)phenyl] urea; [156] 3-(4-chlorophenyl)-1-[(6-cyano-2-pyridyl)methyl]-1-cyclopentyl-urea; [157] tert-butyl 3-[4-[[cyclopentyl-[(5-methyl-2-furyl)methyl]carbamoyl]amino]phenyl]-2,5-dihydropyrrole-1-carboxylate; [158] tert-butyl 3-[4-[[cyclopentyl-[(5-methyl-2-furyl)methyl]carbamoyl]amino]phenyl] azetidine-1-carboxylate; [159] 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-[6-(1-methylpyrazol-4-yl)-3-pyridyl] urea; [160] 3-(5-bromothiazol-2-yl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea; [161] 1-cyclopentyl-3-[4-(3-methoxyprop-1-ynyl)phenyl]-1-[(5-methyl-2-furyl)methyl] urea; [162] 1-cyclopentyl-3-(4-ethynylphenyl)-1-(isoxazol-5-ylmethyl)urea; [163] 1-cyclopentyl-3-[4-[4-(hydroxymethyl)triazol-1-yl]phenyl]-1-[(5-methyl-2-furyl) methyl]urea; [164] “1-ethyl-1-[(5-methyl-2-furyl)methyl]-3-phenyl-urea; [165]” “1-[(5-methyl-2-furyl)methyl]-3-phenyl-1-propyl-urea; [166]” “1-cyclopropyl-1-[(5-methyl-2-furyl)methyl]-3-phenyl-urea; [167]” 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-[5-(2-thienyl)-1,3,4-oxadiazol-2-yl] urea; [168] 3-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl] urea; [169] “1-cyclopentyl-1-[(2,4-dimethylthiazol-5-yl)methyl]-3-phenyl-urea; [170]” “1-cyclopentyl-1-[(2,4-dimethylthiazol-5-yl)methyl]-3-(3,4-difluorophenyl)-urea; [171]” 3-(4-chloro-2-fluoro-phenyl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea; [172] 3-(4-chlorophenyl)-1-[1-(3-cyanophenyl)ethyl]-1-cyclopentyl-urea; [173] 3-(4-chlorophenyl)-1-cyclopentyl-1-[1-(2-pyridyl)ethyl]urea; [174] 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-(5-phenyl-1,3,4-oxadiazol-2-yl)urea; [175] “1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-phenyl-urea; [176]” “1-cyclopentyl-3-(4-ethylphenyl)-1-[(5-methyl-2-furyl)methyl]urea; [177]” 1-cyclobutyl-1-[(5-methyl-2-furyl)methyl]-3-phenyl-urea; [178] 1-[(5-methyl-2-furyl)methyl]-1-oxazol-2-yl-3-phenyl-urea; [179] 3-(4-fluorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-oxazol-2-yl-urea; [180] “1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-(2-phenylethyl)urea; [181]” 3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(1-methylimidazol-2-yl) urea; [182] “3-(4-chlorophenyl)-1-(1H-imidazol-5-yl)-1-[(5-methyl-2-furyl)methyl]urea; [183]” 3-(4-cyanophenyl)-1-[1-(3-cyanophenyl)ethyl]-1-cyclobutyl-urea; [184] 3-(4-chlorophenyl)-1-cyclopentyl-1-[1-(5-methyl-2-furyl)ethyl]urea; [185] 1-[1-(3-cyanophenyl)ethyl]-1-cyclopentyl-3-phenyl-urea; [186] 1-[1-(3-cyanophenyl)ethyl]-1-cyclopentyl-3-(4-fluorophenyl)urea; [187] 3-(4-cyanophenyl)-1-[1-(3-cyanophenyl)ethyl]-1-cyclopentyl-urea; [188] 1-[1-(3-cyanophenyl)ethyl]-1-cyclobutyl-3-(4-fluorophenyl)urea; [189] 3-(4-cyanophenyl)-1-cyclopentyl-1-[1-(5-methyl-2-furyl)ethyl]urea; [190] 1-cyclopentyl-3-(4-fluorophenyl)-1-[1-(5-methyl-2-furyl)ethyl]urea; [191] 3-(4-chlorophenyl)-1-[1-(3-cyanopheny)ethy]-1-cyclobutyl-urea; [192] 3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(3-methylimidazol-4-yl)urea; [193] 3-(4-chlorophenyl)-1-[(2-cyano-4-pyridyl)methyl]-1-(3-methylisoxazol-4-yl)urea[198] 3-(4-cyano-3-methoxy-phenyl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea[205]; 3-(4-chlorophenyl)-1-(2,2-difluorocyclopentyl)-1-[(5-methyl-2-furyl)methyl] urea; [206] 3-(4-cyanophenyl)-1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-2-ylmethyl)urea; [207] 3-(4-cyanophenyl)-1-(3-fluorocyclobutyl)-1-[(5-methyl-2-furyl)methyl]urea; [208] 1-(1,3-benzoxazol-6-ylmethyl)-3-(4-cyanophenyl)-1-cyclobutyl-urea; [209] 3-(4-cyanophenyl)-1-cyclobutyl-1-(imidazo[1,2-a]pyridin-2-ylmethyl)urea; [210] 3-(4-cyanophenyl)-1-cyclobutyl-1-(imidazo[1,2-a]pyrazin-2-ylmethyl)urea; [211] 3-(4-chlorophenyl)-1-cyclobutyl-1-(imidazo[1,2-a]pyrazin-2-ylmethyl)urea; [212] 1-(1,3-benzothiazol-6-ylmethyl)-3-(4-cyanophenyl)-1-cyclobutyl-urea; [213] 3-(4-cyanophenyl)-1-(2,2-difluorocyclopentyl)-1-[(5-methyl-2-furyl)methyl] urea; [214] 3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(2-methylpyrazol-3-yl)urea; [215] 3-(4-cyanophenyl)-1-(3-methoxycyclobutyl)-1-[(5-methyl-2-furyl)methyl]urea; [216] 3-(4-cyanophenyl)-1-cyclobutyl-1-[(1-methylindazol-6-yl)methyl]urea; [217] 3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(1-methylpyrazol-4-yl)urea; [218] 1-(2-cyanocyclopentyl)-3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]urea; [219] 3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(2-methylpyrazol-3-yl)urea; [220] 3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(1-methylpyrazol-3-yl)urea; [221] 3-(4-chlorophenyl)-1-(3-fluorocyclobutyl)-1-[(5-methyl-2-furyl)methyl]urea; [222] 1-(1,3-benzoxazol-5-ylmethyl)-3-(4-cyanophenyl)-1-cyclobutyl-urea; [223] 1-(3-cyanocyclopentyl)-3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]urea; [224] 3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(1-methylpyrazol-4-yl)urea; [225] 3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(1-methylpyrazol-3-yl)urea; [226] 3-(4-chlorophenyl)-1-(2-cyanocyclopentyl)-1-[(5-methyl-2-furyl)methyl]urea; [227] 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-[6-(trifluoromethyl)-3-pyridyl] urea; [228] 1-(1,3-benzothiazol-2-ylmethyl)-3-(4-cyanophenyl)-1-cyclobutyl-urea; [229] 3-(4-cyanophenyl)-1-(3,5-dimethylisoxazol-4-yl)-1-[(5-methyl-2-furyl)methyl] urea; [230] 3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(3-methylimidazol-4-yl)urea; [231] 1-(1,3-benzoxazol-5-ylmethyl)-3-(4-chlorophenyl)-1-cyclobutyl-urea; [232] 3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(1-methylimidazol-2-yl)urea; [233] 1-(benzofuran-2-ylmethyl)-3-(4-cyanophenyl)-1-cyclobutyl-urea; [234] 3-(4-chlorophenyl)-1-cyclobutyl-1-[(1-methylindazol-6-yl)methyl]urea; [235] 3-(4-ethynylphenyl)-1-[(5-methyl-2-furyl)methyl]-1-(oxetan-3-yl)urea; [236] 1-(1,3-benzoxazol-6-ylmethyl)-3-(4-chlorophenyl)-1-cyclobutyl-urea; [237] 3-(4-chlorophenyl)-1-(3,5-dimethylisoxazol-4-yl)-1-[(5-methyl-2-furyl)methyl] urea; [238] 3-(4-chlorophenyl)-1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-2-ylmethyl)urea; [239] 1-(2,1,3-benzothiadiazol-5-ylmethyl)-3-(4-chlorophenyl)-1-cyclobutyl-urea; [240] 3-(4-cyanophenyl)-1-(3,3-difluorocyclobutyl)-1-[(5-methyl-2-furyl)methyl]urea; [241] 3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(3-methylimidazol-4-yl) urea; [242] 1-(1,3-benzothiazol-6-ylmethyl)-3-(4-chlorophenyl)-1-cyclobutyl-urea; [243] 3-(4-cyanophenyl)-1-(3,3-difluorocyclopentyl)-1-[(5-methyl-2-furyl)methyl] urea; [244] 3-(4-chlorophenyl)-1-(3,3-difluorocyclopentyl)-1-[(5-methyl-2-furyl)methyl] urea; [245] 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-(6-methyl-3-pyridyl)urea; [246] 3-(4-chlorophenyl)-1-(3,3-difluorocyclobutyl)-1-[(5-methyl-2-furyl)methyl] urea; [247] 1-(1,3-benzothiazol-2-ylmethyl)-3-(4-chlorophenyl)-1-cyclobutyl-urea; [248] 3-(4-cyanophenyl)-1-cyclobutyl-1-(furo[3,2-b]pyridin-2-ylmethyl)urea; [249] 3-(4-chlorophenyl)-1-cyclobutyl-1-(imidazo[1,2-a]pyridin-2-ylmethyl)urea; [250] 3-(4-chlorophenyl)-1-(3-methoxycyclobutyl)-1-[(5-methyl-2-furyl)methyl]urea; [251] 3-(4-chlorophenyl)-1-cyclobutyl-1-(furo[3,2-b]pyridin-2-ylmethyl)urea; [252] 1-cyclopentyl-3-(6-methoxy-3-pyridyl)-1-[(5-methyl-2-furyl)methyl]urea; [253] 3-(4-chlorophenyl)-1-(3-cyanocyclopentyl)-1-[(5-methyl-2-furyl)methyl]urea; [254] 1-(2,1,3-benzothiadiazol-5-ylmethyl)-3-(4-cyanophenyl)-1-cyclobutyl-urea; [255] 3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(5-methylisoxazol-4-yl)urea; [256] 3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(5-methylisoxazol-4-yl)urea; [257] 3-(4-ethynylphenyl)-1-[(5-methyl-2-furyl)methyl]-1-(1-methyl-4-piperidyl)urea; [258] 3-(4-ethynylphenyl)-1-[(5-methyl-2-furyl)methyl]-1-tetrahydropyran-4-yl-urea; [259] 1-(1,3-benzothiazol-5-ylmethyl)-3-(4-chlorophenyl)-1-cyclobutyl-urea; [260] 1-(1,3-benzothiazol-5-ylmethyl)-3-(4-cyanophenyl)-1-cyclobutyl-urea; [261] 1-(1,3-benzothiazol-7-ylmethyl)-3-(4-chlorophenyl)-1-cyclobutyl-urea; [262] 1-(1,3-benzothiazol-7-ylmethyl)-3-(4-cyanophenyl)-1-cyclobutyl-urea; [263] 1-(1,3-benzothiazol-6-ylmethyl)-3-(4-cyanophenyl)-1-(1-methyl-4-piperidyl) urea; [264] 1-(1,3-benzothiazol-6-ylmethyl)-3-(4-cyanophenyl)-1-tetrahydropyran-4-yl-urea; [265] 3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(2-methyl-1,2,4-triazol-3-yl) urea[266]; 3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(3-methyltriazol-4-yl)urea[267]; 3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(3-methyltriazol-4-yl)urea[268]; 3-(4-chlorophenyl)-1-cyclobutyl-1-(imidazo[2,1-b]thiazol-6-ylmethyl)urea[269]; 3-(4-cyanophenyl)-1-cyclobutyl-1-(imidazo[2,1-b]thiazol-6-ylmethyl)urea[270]; 3-(4-chlorophenyl)-1-(3-fluorocyclobutyl)-1-[(5-methyl-2-furyl)methyl]urea[271]; 3-(4-cyanophenyl)-1-(3-fluorocyclobutyl)-1-[(5-methyl-2-furyl)methyl]urea[272]; 3-(4-chlorophenyl)-1-(3-fluorocyclobutyl)-1-[(5-methyl-2-furyl)methyl]urea[273]; 3-(4-cyanophenyl)-1-cyclobutyl-1-(imidazo[1,2-a]pyrimidin-7-ylmethyl)urea[274]; 3-(4-chlorophenyl)-1-cyclobutyl-1-(imidazo[1,2-a]pyrimidin-7-ylmethyl)urea[275]; 1-(1,3-benzothiazol-6-ylmethyl)-3-(4-cyanophenyl)-1-(2-methyl-1H-pyrazol-3-yl) urea[276]; 3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(3-methylisoxazol-4-yl)urea[277]; 3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(3-methylisoxazol-4-yl)urea[278] and 3-[4-(3-methoxyprop-1-ynyl)phenyl]-1-[(5-methyl-2-furyl)methyl]-1-(5-methyl isoxazol-4-yl)urea[279]; 1-(1,3-benzothiazol-6-ylmethyl)-3-[4-(3-hydroxyprop-1-ynyl)phenyl]-1-(2-methylpyrazol-3-yl)urea[280]; 1-(1,3-benzothiazol-5-ylmethyl)-3-(4-cyanophenyl)-1-(5-methylisoxazol-4-yl)urea[281]; 3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(2-pyridyl)urea[282]; 3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(2-pyridyl)urea[283]; 1-(1-bicyclo[1.1.1]pentanyl)-3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]urea[284]; 1-(1-bicyclo[1.1.1]pentanyl)-3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]urea[285]; 3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(2-oxaspiro[3.3]heptan-6-yl)urea[286]; 3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(2-oxaspiro[3.3]heptan-6-yl)urea[287]; 3-(4-cyanophenyl)-1-(5-methylisoxazol-4-yl)-1-[[2-(trifluoromethyl)-4-pyridyl]methyl]urea[288]; 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-[4-(trifluoromethoxy)phenyl]urea[289]; 1-cyclopentyl-3-(4-methoxyphenyl)-1-[(5-methyl-2-furyl)methyl]urea[290]; 3-(4-cyanophenyl)-1-cyclopentyl-1-[(2-methyloxazol-5-yl)methyl]urea[291]; 1-[(5-methyl-2-furyl)methyl]-1-(5-methylisoxazol-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea[292]; 3-(4-cyanophenyl)-1-(5-methylisoxazol-4-yl)-1-[[3-(trifluoromethyl)phenyl]methyl]urea[293]; 1-cyclopentyl-3-[4-(3-hydroxyprop-1-ynyl)phenyl]-1-[(2-methyloxazol-5-yl)methyl]urea[294]; 3-(4-cyanophenyl)-1-cyclopentyl-1-[(5-ethyl-2-furyl)methyl]urea[295]; 1-cyclobutyl-3-[4-(3-hydroxyprop-1-ynyl)phenyl]-1-[[2-(trifluoromethyl)-4-pyridyl]methyl]urea[296]; 1-cyclobutyl-3-[4-(3-hydroxyprop-1-ynyl)phenyl]-1-[(5-methyl-2-furyl)methyl]urea[297]; 3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(4-methyl-1,2,5-oxadiazol-3-yl)urea[298]; 3-(4-cyanophenyl)-1-[(5-ethyl-2-furyl)methyl]-1-(5-methylisoxazol-4-yl)urea[299]; 1-(1,3-benzothiazol-2-yl)-3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]urea[300]; 3-[4-(difluoromethoxy)phenyl]-1-[(5-methyl-2-furyl)methyl]-1-(5-methylisoxazol-4-yl)urea[301]; 3-(4-chlorophenyl)-1-(2-methylpyrazol-3-yl)-1-[[2-(trifluoromethyl)-4-pyridyl]methyl]urea[302]; 1-cyclopentyl-3-(4-hydroxyphenyl)-1-[(5-methyl-2-furyl)methyl]urea[303]; 3-(4-cyanophenyl)-1-isoxazol-4-yl-1-[(5-methyl-2-furyl)methyl]urea[304]; 3-(4-chlorophenyl)-1-isoxazol-4-yl-1-[(5-methyl-2-furyl)methyl]urea[305]; 1-cyclobutyl-3-[4-(3-hydroxyprop-1-ynyl)phenyl]-3-methyl-1-[(5-methyl-2-furyl)methyl]urea[306]; 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-(1-oxoisoindolin-5-yl)urea[307]; 3-[4-[4-(hydroxymethyl)triazol-1-yl]phenyl]-1-(3-methylisoxazol-4-yl)-1-[[3-(trifluoromethyl)phenyl]methyl]urea[308]; 3-[4-(3-hydroxyprop-1-ynyl)phenyl]-1-[(5-methyl-2-furyl)methyl]-1-(1-methylimidazol-2-yl)urea[309]; 3-(4-cyanophenyl)-1-cyclopentyl-1-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-ylmethyl)urea[310]; 3-(4-chlorophenyl)-1-cyclopentyl-1-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-ylmethyl)urea[311]1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-(2-methyl-1-oxo-isoindolin-5-yl)urea[312]; 3-(4-chlorophenyl)-1-[(6-cyano-2-pyridyl)methyl]-1-(3-methylisoxazol-4-yl)urea[313]; 3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(3-methyl-2-pyridyl)urea[314]; 3-[4-(3-hydroxyprop-1-ynyl)phenyl]-1-(3-methylisoxazol-4-yl)-1-[[3-(trifluoromethyl)phenyl]methyl]urea[315]; 3-(4-cyanophenyl)-1-(3-methylisoxazol-4-yl)-1-[(2-methyloxazol-5-yl)methyl]urea[316]; 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-[4-(oxetan-3-yl)phenyl]urea[317]; 3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(3-methyl-2-pyridyl)urea[318]; 1-[(6-cyano-2-pyridyl)methyl]-1-cyclobutyl-3-[4-(3-hydroxyprop-1-ynyl)phenyl]urea[319]; 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-[4-(4-methyltriazol-1-yl)phenyl]urea[320]; 3-[4-(3-hydroxyprop-1-ynyl)phenyl]-1-(3-methylisoxazol-4-yl)-1-[(2-methyloxazol-5-yl)methyl]urea[321]; 3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(4-methyl-1,2,5-oxadiazol-3-yl)urea[322]; 1-cyclopentyl-3-[4-[4-(hydroxymethyl)triazol-1-yl]-3-methoxy-phenyl]-1-[(5-methyl-2-furyl)methyl]urea[323]; 3-(4-cyanophenyl)-1-[(5-methyl-2-furyl)methyl]-1-pyrimidin-2-yl-urea[324]; 3-(4-cyanophenyl)-1-(3-methylisoxazol-4-yl)-1-(2-oxaspiro[3.5]nonan-7-ylmethyl)urea[325]; 3-(4-chlorophenyl)-1-(3-methylisoxazol-4-yl)-1-(2-oxaspiro[3.5]nonan-7-ylmethyl)urea[326]; 3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-pyrimidin-2-yl-urea[327]; and 3-(4-chlorophenyl)-1-[(5-methyl-2-furyl)methyl]-1-(3-methylisothiazol-4-yl)urea[328]; or a pharmaceutically acceptable salt, or a solvate, or a solvate of the salt thereof.
77. The compound according to claim 55 comprising compounds of formula I: ##STR00396## or a pharmaceutically acceptable salt, or a solvate, or a solvate of the salt thereof, wherein: X, n and R.sup.1 are each as herein defined; m is 1; R.sup.2 is a 5-6-membered heteroaryl, a fused 9-10 membered bicyclic heteroaryl, phenyl; each of which may independently be optionally substituted by one or more groups independently selected from C.sub.1-6alkyl, halogen, haloC.sub.1-6alkyl, —CN and haloC.sub.1-6alkyloxy; R.sup.3 is a 4 or 5 membered cycloalkyl, a 5-6-membered heteroaryl or an isoxazole; each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl, —OC.sub.1-6alkyl, halogen and —CN; the moiety ##STR00397## is phenyl or thiazole, each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl, halogen, haloC.sub.1-6alkyl, haloC.sub.1-6alkyl-O—, —CN, —C.sub.1-6alkyl-OH, —C.sub.2-6alkynyl, C.sub.2-6alkynyl-C.sub.1-6alkyl, —C.sub.2-6alkynyl-C.sub.3-6cycloalkyl, —C.sub.2-6alkynyl-C.sub.1-6alkyl-OR.sup.13 and a 5-6 membered heteroaryl; and R.sup.13 is H or C.sub.1-6alkyl.
78. The compound according to claim 55 comprising compounds of formula I: ##STR00398## or a pharmaceutically acceptable salt, or a solvate, or a solvate of the salt thereof, wherein: X and R.sup.1 is as herein defined; m is 1; n is 0; R.sup.2 is a 5-6-membered heteroaryl, a fused 9-10 membered bicyclic heteroaryl, a 6 membered aryl, a 5-6 membered monocyclic heterocycloalkyl or a fused 8-10 membered partially unsaturated bicyclic heterocyclyl; each of which may independently be optionally substituted by one or more groups independently selected from C.sub.1-6alkyl, haloC.sub.1-6alkyl, halogen, —OC.sub.1-6alkyl, —CN and —C(═O)OC.sub.1-6alkyl; R.sup.3 is a 4 or 5 membered cycloalkyl, a 5-6 membered heteroaryl or a 4-6 membered monocyclic heterocycloalkyl each of which may independently be optionally substituted by one or more groups independently selected from C.sub.1-6alkyl, —OC.sub.1-6alkyl, halogen, and —CN; the moiety ##STR00399## is phenyl, pyridine, pyrimidine or thiazole, each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl, halogen, haloC.sub.1-6alkyl, haloC.sub.1-6alkyl-O—, —CN, —OC.sub.1-6alkyl, —C.sub.2-6alkynyl, —C.sub.2-6alkynyl-C.sub.1-6alkyl-NR.sup.11R.sup.12, —C.sub.2-6alkynyl-C.sub.1-6alkyl-OR.sup.13, a 6-10 membered aryl, a 5-6 membered heteroaryl, each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl or —C.sub.1-6alkyl-OH; and R.sup.11, R.sup.12 and R.sup.13, which may be the same or different, are each selected from H and C.sub.1-6alkyl.
79. The compound according to claim 55 comprising compounds of formula I: ##STR00400## or a pharmaceutically acceptable salt, or a solvate, or a solvate of the salt thereof, wherein: X is as herein defined; m is 1; n is 0; R.sup.1 is H or C.sub.1-6alkyl; R.sup.2 is a thiophene, furan, pyrazine, pyridine, isoxazole, benzoxazole, imidazothiazole or phenyl; each of which may independently be optionally substituted by one or more groups independently selected from C.sub.1-6alkyl, halogen, haloC.sub.1-6alkyl, —CN; R.sup.3 is H, 4 or 5 membered cycloalkyl, imidazole, or oxetane; each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl, —OC.sub.1-6alkyl, halogen and —CN; the moiety ##STR00401## is phenyl, pyridine, benzothiazole, benzofuran, each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl, halogen, —CN, —C.sub.2-6alkynyl, —C.sub.2-6alkynyl-aryl, —C.sub.2-6alkynyl-C.sub.1-6alkyl-aryl, —C.sub.2-6alkynyl-C.sub.1-6alkyl-NR.sup.11R.sup.12; or a 5-6 membered heteroaryl, which may be optionally substituted by one or more groups independently selected from —C(═O)OC.sub.1-6alkyl, thiophene, phenyl and —C.sub.1-6alkyl-OH; and R.sup.11 and R.sup.12, which may be the same or different, are each selected from H and C.sub.1-6alkyl.
80. The compound according to claim 55 comprising compounds of formula I: ##STR00402## or a pharmaceutically acceptable salt, or a solvate, or a solvate of the salt thereof, wherein: X is as herein defined; m is 1; n is 0 or 2; R.sup.1 is H or C.sub.1-6alkyl; R.sup.2 is a 5 or 6 membered heteroaryl, a fused 9 or 10 membered bicyclic heteroaryl, a 6 membered aryl or a 5 or 6 membered monocyclic heterocycloalkyl or a fused 8-10 membered partially unsaturated bicyclic heterocyclyl; each of which may independently be optionally substituted by one or more groups independently selected from C.sub.1-6alkyl, halogen, —OC.sub.1-6alkyl, —CN, —C(═O)C.sub.1-6alkyl —C(═O)OC.sub.1-6alkyl, —SO.sub.2—C.sub.1-6alkyl, —C(═O)NH.sub.2, haloC.sub.1-6alkyloxy and phenyl; R.sup.3 is H or C.sub.1-6alkyl; or a 3-6 membered cycloalkyl, a 6 membered aryl, a 5-6 membered heteroaryl, a fused 9-10 membered bicyclic heteroaryl, a 4-6 membered monocyclic heterocycloalkyl or a 5-11 membered spiroheteroalkyl a 5-11 membered spiroheteroalkyl; each of which may independently be optionally substituted by one or more —C.sub.1-6alkyl; the moiety ##STR00403## is phenyl, benzodioxole, indane, pyridine, thiophene or thiazole, each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl, halogen, haloC.sub.1-6alkyl, —CN, —OC.sub.1-6alkyl, —C.sub.1-6alkyl-CN, —C.sub.2-6alkynyl-C.sub.1-6alkyl-OR.sup.13, —C(═O)C.sub.1-6alkyl, —C(═O)NH.sub.2, —C(═O)OC.sub.1-6alkyl and oxopyrrolidine a 5 or 6 membered cycloalkyl, a 4-6 membered monocyclic heterocycloalkyl, a 6 membered aryl, a 5 or 6 membered heteroaryl, a 5 or 6 membered heteroC.sub.3-6cycloalkyl, each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl, —C(═O)OC.sub.1-6alkyl; and R.sup.13 is each selected from H and C.sub.1-6alkyl.
81. The compound according to claim 55 comprising compounds of formula I: ##STR00404## or a pharmaceutically acceptable salt, or a solvate, or a solvate of the salt thereof, wherein: X and n are each as herein defined; m is 1; R.sup.1 is H or C.sub.1-6alkyl; R.sup.2 is a 5-6-membered heteroaryl, a fused 9-10 membered bicyclic heteroaryl, a 6 membered aryl or a 5-6 membered monocyclic heterocycloalkyl or a 5-11 membered spiroheteroalkyl; each of which may independently be optionally substituted by one or more groups independently selected from C.sub.1-6alkyl, halogen, —CN; R.sup.3 is H or a 5 or 6 membered cycloalkyl, a 5 membered heteroaryl, a 6 membered monocyclic heterocycloalkyl, a 5-11 membered spiroheteroalkyl or a —C.sub.1-6alkyl-heteroaryl; each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl, halogen and —C(═O)OC.sub.1-6alkyl; the moiety ##STR00405## is phenyl, pyridine or phenyl fused with oxopyrrolidine, each of which may independently be optionally substituted by one or more groups independently selected from —OH, —C.sub.1-6alkyl, halogen, —CN, —OC.sub.1-6alkyl, —C.sub.2-6alkynyl, —C(═O)C.sub.1-6alkyl, a 5-6 membered heteroaryl, a 5-6 membered heteroC.sub.3-6cycloalkyl, each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl-NR.sup.9R.sup.10 and —C.sub.1-6alkyl-OH; R.sup.9 and R.sup.10, which may be the same or different, are each selected from H and C.sub.1-6alkyl.
82-116. (canceled)
117. A method of treatment of a disease or condition associated with, abnormal or elevated catabolism of tryptophan, reduced levels of tryptophan, or elevated levels of kynurenine, which comprises the administration of a therapeutically effective amount of a compound of Formula (I) to a patient suffering from such a disease or condition: ##STR00406## or a pharmaceutically acceptable salt, or a solvate, or a solvate of the salt thereof, wherein: m is 0 or 1; n is 0, 1 or 2; X is —NR.sup.8; R.sup.1 is H, C.sub.1-6alkyl or a 6-10 membered aryl; R.sup.2 is a 5-6-membered heteroaryl, a fused 9-10 membered bicyclic heteroaryl, a 6-10 membered aryl or a 5-6 membered monocyclic heterocycloalkyl, a 5-11 membered spiroheteroalkyl or a fused 8-10 membered partially unsaturated bicyclic heterocyclyl; each of which may independently be optionally substituted by one or more groups independently selected from C.sub.1-6alkyl, halogen, haloC.sub.1-6alkyl, —OC.sub.1-6alkyl, —CN, —C(═O)C.sub.1-6alkyl, —C(═O)OC.sub.1-6alkyl, —SO.sub.2—C.sub.1-6alkyl, —C(═O)NH.sub.2, haloC.sub.1-6alkyloxy or phenyl; R.sup.3 is H or C.sub.1-6alkyl; or a 3-10 membered cycloalkyl, a 5-11 membered spiroalkyl, a 6-10 membered aryl, a 5-6 membered heteroaryl, a fused 9-10 membered bicyclic heteroaryl, a 4-6 membered monocyclic heterocycloalkyl, a —C.sub.1-6alkyl-heteroaryl or a 5-11 membered spiroheteroalkyl; each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl, —OC.sub.1-6alkyl, halogen, —CN or —C(═O)OC.sub.1-6alkyl; A.sup.1 is —N— or —CR.sup.6—; A.sup.2 is —N— or —CR—; A.sup.3 is —N— or —CR.sup.7—; A.sup.4 is —N—, —O—, —S—, —CH═N— or —CH═CR.sup.4—; R.sup.4, R.sup.5, R.sup.6 and R.sup.7, which may be the same or different, are each selected from —H, —OH, —C.sub.1-6alkyl, halogen, haloC.sub.1-6alkyl, —CN, —C.sub.1-6alkyl-CN, —OC.sub.1-6alkyl, —C.sub.2-6alkynyl, —C.sub.2-6alkynyl-C.sub.1-6alkyl, —C.sub.2-6alkynyl-aryl, —C.sub.2-6alkynyl-C.sub.1-6alkyl-aryl, —C.sub.2-6alkynyl-C.sub.3-6cycloalkyl, —C.sub.2-6alkynyl-C.sub.1-6alkyl-NR.sup.11R.sup.12, —C.sub.2-6alkynyl-C.sub.1-6alkyl-OR.sup.13, —C(═O)C.sub.1-6alkyl, —C(═O)NH.sub.2, a 3-10 membered cycloalkyl, a 5-11 membered spiroalkyl, a 4-6 membered monocyclic heterocycloalkyl, a 6-10 membered aryl, a 5-6 membered heteroaryl, a 5-6 membered heteroC.sub.3-6cycloalkyl, a fused 9-10 membered bicyclic heteroaryl, each of which may independently be optionally substituted by one or more groups independently selected from —C.sub.1-6alkyl, C.sub.1-6alkyl-NR.sup.9R.sup.10, —C.sub.1-6alkyl-OH, —C(═O)OC.sub.1-6alkyl or oxopyrrolidine; or R.sup.5 and R.sup.7 together form a ring —CH═CH—CH═CH—, —OCH.sub.2O— or —CH.sub.2CH.sub.2CH.sub.2—; or the moiety ##STR00407## may be fused with oxopyrrolidine; and R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, and R.sup.13, which may be the same or different, are each selected from H or C.sub.1-6alkyl.
118-135. (canceled)
136. The method according to claim 117, for the treatment of diseases and/or conditions associated with the abnormal or elevated catabolism of tryptophan.
137. The method according to claim 136, wherein the disease or condition associated with the abnormal or elevated catabolism of tryptophan is one or more of cancer, immunosuppression, viral infection, depression, a neurodegenerative disorder, trauma, age-related cataracts, organ transplant rejection, or an autoimmune disorder in a patient.
138-171. (canceled)
Description
[0817] The present invention will now be described by way of example only with reference to the accompanying figures in which:
[0818] FIG. 1a is a graph of dose-dependent reduction in IDO1 protein in SKOV-3 cells after 24 hours exposure to compound 102;
[0819] FIG. 1b is a graph of dose-dependent inhibition of kynurenine production by SKOV-3 after 24 hours exposure to compound 102; and
[0820] FIG. 2 illustrates the activity of Epacadostat and compounds 90 and 102. NucLight™ Red transfected SK-OV-3 ovarian cancer cells seeded in 96-well flat-bottomed plates 24 hours prior to addition of PBMC, rhIL-2, anti-CD3 and anti-CD28 plus Epacadostat, example compound of the invention or DMSO. Cells were incubated in the Incucyte Zoom® and images were taken at 3-hourly intervals. Data are shown as mean number of apoptotic SK-OV-3 cells (n=4 biological replicates), error bars have been removed for clarity.
[0821] The following abbreviations listed in Table 1 are used in the Examples and other parts of the description.
TABLE-US-00001 TABLE 1 List of abbreviations used in experimental section: Abbreviation Definition μL Microliter AcCl Acetyl chloride anhyd. anhydrous aq. aqueous BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphtyl Boc tert-Butyloxycarbonyl Bn Benzyl BPin Boronic acid pinacol ester br. s. broad singlet CDI 1,1′-Carbonyldiimidazole Cpd Compound Cpd# Compound number CPhos 2-(2-dicyclohexylphosphanylphenyl)-N1,N1,N3,N3- tetramethyl-benzene-1,3-diamine CuSO.sub.4x5H.sub.2O Copper (II)sulfate pentahydrate d doublet DBU 1,8-diazabicyclo(5.4.0)undec-7-ene DCM Dichloromethane Deoxo-Fluor Bis(2-methoxyethyl)aminosulfur trifluoride DIPEA N,N-diisopropylethylamine DMAP N,N-Dimethylpyridine-4-amine DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide equiv. Equivalents Et.sub.2O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol ES.sup.+ positive electrospray ionisation mass spectrometry g gram h hour(s) Hal Halogen HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate HPLC High-performance liquid chromatography Int Intermediate iPrOH Isopropyl alcohol LCMS Liquid Chromatography-Mass Spectrometry m multiplet M moldm.sup.−3 MeCN Acetonitrile MeI Methyl iodide MeOH Methanol mg milligram min minute mL millilitre mmol millimoles MsCl Mesyl chloride; methanesulfonyl chloride Mtd Method MW Molecular weight m/z mass divided by charge number Na.sub.2SO.sub.4 sodium sulphate NMR Nuclear Magnetic Resonance Pd(OH).sub.2/C Palladium hydroxide on Carbon, Pearlman's catalyst pH potential of hydrogen (scale of acidity) PhMe Toluene Pd/C Palladium on Carbon 10 wt % Pd(OAc).sub.2 Palladium(II) acetate Pd(PPh.sub.3).sub.4 Tetrakis(triphenylphosphine)palladium(0) Pd(PPh.sub.3).sub.2Cl.sub.2 Bis(triphenylphosphine)palladium(II) dichloride pTsOH xH.sub.2O p-Toluenesulfonic acid monohydrate quint quintet RT Room temperature tBu tert-Butyl s singlet sat. aq. sol. saturated aqueous solution SCX Strong Cation Exchange t triplet TBAFxH.sub.2O tetrabutylammonium fluoride hydrate TBDMSCl tert-Butyldimethylsilyl chloride TEA Triethyl amine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin-layer chromatography UPLC Ultra-performance liquid chromatography XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl XPhos-Pd-G1 (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′- biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride wt. % weight percent
[0822] The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as anillustration only and not limiting the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.
[0823] Where reactions are described as having been carried out in a similar manner to earlier, more completely described reactions, the general reaction conditions used were essentially the same. Work up conditions used were of the types standard in the art, but may have been adapted from one reaction to another. In the procedures that follow, reference to the product of a Description or Example by number is typically provided. This is provided merely for assistance to the skilled chemist to identify the starting material used. The starting material may not necessarily have been prepared from the batch referred to.
[0824] A compound of the invention as well as intermediate of the invention can be produced according to the following procedures.
Synthetic Preparation of the Compound of the Invention
INTERMEDIATES
[0825] ##STR00024##
[0826] Method A: General Procedure for the Preparation of Intermediates of Formula (I) by Reductive Amination
[0827] The reaction is typically performed by combining an appropriate alkyl, cycloalkyl, substituted cycloalkyl or heteroaryl amine of formula R1-NH.sub.2 (1-1.2 equiv.) and a carbonyl compound (aldehyde or methyl-ketone) (0.67-3 equiv.) in the presence of an appropriate base (typically, trimethylamine or sodium acetate), or without a presence of base, and acetic acid (1-3 equiv.) or pTsOH×H.sub.2O or without addition of acetic acid or pTsOH×H.sub.2O in a suitable solvent (typically, methanol or toluene or dichloromethane) in the presence or without molecular sieves or magnesium perchlorate (0.3 equiv.) or sodium sulphate or magnesium sulphate. The resulting mixture is stirred at 0° C. to room temperature to 110° C. for 2 h to 5 days. To the reaction temperature lowered to 0° C. or at room temperature, a reducing agent (1.2-16 equiv.) is added (typically, sodium borohydride or sodium cyanoborohydride or lithium borohydride). The resulting mixture is stirred at room temperature for 1-72 hours. The expected Intermediate of formula (I) may be isolated and, if desired, further purified by methods known to one skilled in the art.
[0828] Alternatively, a mixture of alkyl, cycloalkyl, substituted cycloalkyl or heterocyclic amine (R1-NH.sub.2) (1-1.2 equiv.), a carbonyl compound (0.8-2 equiv.), an appropriate base (typically, trimethylamine), or without a presence of base, and Lewis acid (2.1-2.4 equiv.) (typically, Ti(iPrO).sub.4) in an appropriate solvent, such as dichloromethane, is stirred at room temperature for 12-20 hours or under microwave irradiation at 70° C. for 15 minutes. The reaction mixture is evaporated till dryness, dissolved in an appropriate solvent, such as methanol, and then a reducing agent, such as sodium borohydride, (2-5 equiv.) is added portionwise to give the corresponding intermediate of formula (I), which is isolated and, if desired, may be further purified by methods known to one skilled in the art.
Example A.1
Illustrative Synthesis of N-[(5-methyl-2-furyl)methyl]cyclopentanamine
[0829] ##STR00025##
[0830] To a stirred solution of 5-methylfuran-2-carbaldehyde (2.5 g, 1.1 equiv.) and cyclopentamine (2.01 mL, 1 equiv.) in dry methanol (200 mL) was added glacial acetic acid (3.47 mL, 3 equiv.) and the mixture was stirred at 55° C. for 2 hours. The reaction mixture was cooled to 0° C. before NaBH.sub.3CN (3.31 g, 2.5 equiv.) was added and the mixture was stirred at room temperature for 16 hours. Volatiles were evaporated. The concentrated mixture was transferred to a separatory funnel containing 1N NaOH (150 mL), and extracted with DCM (2×150 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, were filtered, and the solvent was removed in vacuo to yield the crude product, which was dissolved in MeOH (20 mL) and applied to a SCX column and eluted with MeOH followed by 2M ammonia in MeOH. Ammonia/MeOH fractions were combined and evaporated to afford the expected product (3.4 g). LCMS: MW (calcd): 179.26; MS (ES.sup.+, m/z): 180.53 [M+H].sup.+.
Example A.2
Illustrative Synthesis of N-[(5-methyl-2-furyl)methyl]-1H-imidazol-5-amine
[0831] ##STR00026##
[0832] To a stirred solution of 5-methylfuran-2-carbaldehyde (200 mg, 2 equiv.), 2-aminoimidazole hemisulfate (240.1 mg, 1 equiv.) and TEA (281 μL, 2.2 equiv.) in dichloromethane (6 mL) was added Ti(iPrO).sub.4 (619.5 mg, 2.4 equiv.) and the mixture was stirred at room temperature for 16 hours. Volatiles were evaporated. The concentrated mixture was dissolved in MeOH (6 mL) and NaBH.sub.4 (172 mg, 5 equiv.) was added portionwise every 30 minutes until almost complete conversion to the wanted amine. The reaction mixture was transferred to a separatory funnel containing NaHCO.sub.3 (15 mL), and extracted with DCM (2×15 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, were filtered, and the solvent was removed in vacuo to yield the crude product (222 mg). LCMS: MW (calcd): 177.20; MS (ES.sup.+, m/z): 178.08 [M+H].sup.+.
Example A.3
Illustrative Synthesis of 5-methyl-N-[(5-methyl-2-furyl)methyl]isoxazol-4-amine
[0833] ##STR00027##
[0834] To a stirred solution of 5-methylfuran-2-carbaldehyde (199.1 mg, 1.0 equiv.) in methanol (5 mL), molecular sieves 3 Å, 5-methylisoxazol-4-amine hydrochloride (250.0 mg, 1.03 equiv.) and TEA (0.27 mL, 1.07 equiv.) were added. Under the Argon atmosphere, the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C. and diluted with methanol (20 mL) before NaBH.sub.4 (1.03 g, 15.06 equiv.) was added portionwise under Argon atmosphere. The mixture was stirred at 0° C. for 2 hours. To the reaction mixture at 0° C., aqueous solution of iN HCl (40 mL) was added. The resulting solution was extracted with DCM (3×50 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, were filtered, and the solvent was removed in vacuo to yield the crude product (296 mg). LCMS: MW (calcd): 192.09; MS (ES.sup.+, m/z): 192.48 [M+H].sup.+.
##STR00028##
Method B: General Procedure for the Preparation of Intermediates of Formula (I) by Nucleophilic Substitution
[0835] The reaction is typically performed by combining an appropriate alkyl or heteroaryl amine of formula R1-NH.sub.2 (1-1.2 equiv.) and an alkyl halide or aryl halide compound (bromide, chloride, iodide, fluoride) (1 equiv.) in the presence of an appropriate base (typically, N,N-diisopropylethylamine) in a suitable solvent (typically, tetrahydrofuran). The resulting mixture is stirred at room temperature for 17 hours or at 80° C. from 2 to 18 hours. The expected Intermediate of formula (I) may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example B.1
Illustrative Synthesis of 5-methyl-N-[[2-(trifluoromethyl)-4-pyridyl]methyl]isoxazol-4-amine
[0836] ##STR00029##
[0837] To a solution of 4-(chloromethyl)-2-(trifluoromethyl)pyridine (97.8 mg, 1 equiv.), 5-methylisoxazol-4-amine (49.1 mg, 1 equiv.), sodium iodide (225 mg, 3 equiv.) and DIPEA (0.261 mL, 3 equiv.) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and concentrated in vacuo to yield the crude product. The obtained residue was purified by flash chromatography on silica gel (eluting with DCM/2.5% of MeOH in DCM gradient; 0-40% of 2.5% of MeOH in DCM) to afford the expected product (68 mg). LCMS: MW (calcd): 257.21; MS (ES.sup.+, m/z): 258.06 [M+H].sup.+.
Example B.2
Illustrative Synthesis of N-[(5-methyl-2-furyl methy]-1,3-benzothiazol-2-amine
[0838] ##STR00030##
[0839] To a solution of (5-methyl-2-furyl) methanamine (50 mg, 1 equiv.) in DIPEA (0.12 mL, 1.5 equiv.), 2-chloro-1,3-benzothiazole (75 mg, 1 equiv.) was added and stirred at 80° C. overnight. The reaction mixture was diluted with EtOAc (30 mL) and washed with aqueous saturated solution of NaHCO.sub.3 (15 mL) and brine (15 mL). Layers were separated, organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to yield the crude. The obtained residue was purified by flash chromatography on silica gel (eluting with cyclohexane/EtOAc gradient; 0-60% of EtOAc) to afford the expected product (53 mg). LCMS: MW (calcd): 244.31; MS (ES.sup.+, m/z): 245.05 [M+H].sup.+.
##STR00031##
Method C: General Procedure for the Preparation of Intermediates of Formula (I) by Buchwald-Hartwig Amination
[0840] The reaction is typically performed by combining an appropriate aryl or heteroaryl halide of formula R1-Hal (bromide, chloride) (1 equiv.) and an alkyl amine (1-1.2 equiv.) in the presence of a palladium catalyst (0.1 equiv.), such as Pd(OAc).sub.2 or any other suitable catalyst, with or without a suitable ligand (0.1 equiv.), such as BINAP and a base (3-4 equiv.), such as potassium carbonate, in suitable solvent (typically toluene). The resulting mixture is stirred at temperature typically 120-140° C. for 3 hours. The expected Intermediate of formula (I) may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example C.1
Illustrative Synthesis of 3-methyl-N-[(5-methyl-2-furyl)methyl]pyridin-2-amine
[0841] ##STR00032##
[0842] A suspension of 2-chloro-3-methyl-pyridine (120 mg, 1 equiv.), (5-methyl-2-furyl) methanamine (125 mg, 1.2 equiv.), potassium carbonate (545 mg, 3.5 equiv.), BINAP (70 mg, 0.1 equiv.) and Pd (OAc) 2 (30 mg, 0.1 equiv.) in toluene (3 mL) was heated at 130° C. for 3 hours. The reaction mixture was diluted with EtOAc (40 mL) and extracted with aqueous saturated solution of NaHCO.sub.3 (15 mL) and brine (15 mL). Organic phase was separated, dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuo to yield the crude product. The obtained residue was purified by flash chromatography on silica gel (eluting with cyclohexane/EtOAc gradient; 0-30% of EtOAc in cyclohexane) to afford the expected product (125 mg). LCMS: MW (calcd): 202.25; MS (ES.sup.+, m/z): 203.13 [M+H].sup.+.
Compounds
Method D: General Procedures for Preparation of Urea Compounds of Formula (II)
[0843] ##STR00033##
Method D1: Isocyanate
[0844] The reaction is typically performed by adding 1-3 equiv. of isocyanate to a solution of an appropriate compound of formula (I) (0.9-1 equiv.) in a suitable solvent, such as DCM or toluene. The reaction mixture is stirred at room temperature for 30 min to 72 h or at 100-150° C. for 40 min to 3 h using microwave irradiation. The expected product of formula (II) may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example D1.1
Illustrative Synthesis of 3-(4-chlorophenyl)-1-cyclobutyl-1-[[3-(trifluoromethyl)-phenyl]methyl]urea (Compound 90)
[0845] ##STR00034##
[0846] 4-Chlorophenyl isocyanate (120.3 mg, 1 equiv.) and N-[[3-(trifluoromethyl)-phenyl]methyl]cyclobutanamine (crude product, 1 equiv.) were dissolved in DCM (2.5 mL) and stirred at room temperature for 16 h. Solvent was removed in vacuo and the obtained crude product was further purified by preparative LC-MS to afford the expected product (89 mg). LCMS: MW (calcd): 382.81; MS (ES.sup.+, m/z): 383.11 [M+H].sup.+.
Method D2: Triphosgene
[0847] The reaction is typically performed by adding an appropriate amine (1.3 equiv.) and base (4.3-5.6 equiv.) (such as TEA or DIPEA) to a solution of triphosgene (0.5 equiv.) in a suitable solvent, such as THF, at 0° C. to room temperature. The resulting mixture is stirred for 15 min to 1 h at 0° C. to room temperature, then mixed with THF solution (or suspension) of an appropriate compound of formula (I) (1 equiv.) to which, if required, additional amount of base, such as TEA or DIPEA, may be added. The reaction mixture is stirred at room temperature for 1-24 h. The expected product of formula (II) may be isolated and, if desired, further purified by methods known to one skilled in the art.
[0848] Alternatively, to a solution of triphosgene (0.5 equiv.) in a suitable solvent, such as EtOAc with molecular sieves at 0° C., a solution of an appropriate amine (1.0 equiv.) in a suitable solvent, such as EtOAc was added dropwise. The expected isocyanate may be isolated and, if desired, further purified by methods known to one skilled in the art. The reaction of urea formation was typically performed by adding 1-3 equiv. of prepared isocyanate to a solution of an appropriate compound of formula (I) (1 equiv.) in a suitable solvent, such as DCM. The reaction mixture is stirred at room temperature for 30 min to 24 h. The expected product of formula (II) may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example D2.1
Illustrative Synthesis of 1-cyclopentyl-3-(4-ethynylphenyl)-1-[(5-methyl-2-furyl)methyl]urea (Compound 102)
[0849] ##STR00035##
[0850] A solution of 4-ethynylaniline (170 mg, 1.3 equiv.) and TEA (0.68 mL, 4.3 equiv.) in dry THE (4 mL) was added to a solution of triphosgene (167.6 mg, 0.5 equiv.) in dry THE (4 mL) at room temperature. After 30 minutes of stirring, a solution of N-[(5-methyl-2-furyl)methyl] cyclopentanamine (200 mg, 1 equiv.) and TEA (0.2 mL, 1.3 equiv.) in THE (4 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours and then was diluted with DCM, and washed with saturated aqueous solution of NaHCO.sub.3. The organic layer was dried and concentrated under reduced pressure. The obtained residue was purified by flash chromatography on silica gel (eluting with EtOAc/cyclohexane gradient; 0-15% of EtOAc) to afford the expected product (290 mg). LCMS: MW (calcd): 322.40; MS (ES.sup.+, m/z): 323.20 [M+H].sup.+.
Example D2.2
Illustrative Synthesis of 3-[4-(difluoromethoxy)phenyl]-1-[(5-methyl-2-furyl)methyl]-1-(5-methylisoxazol-4-yl)urea (Compound 289)
[0851] ##STR00036##
[0852] To a solution of triphosgene (65 mg, 0.5 equiv.) in EtOAc (11 mL), molecular sieves were added. To the resulting solution previously cooled to 0° C., a solution of 4-(difluoromethoxy) aniline (70 mg, 1.0 equiv.) in EtOAc (11 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 2 hours and washed with saturated aqueous solution of NaHCO.sub.3 and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuo to afford the expected product (49 mg). In order to confirm the structure, 3 mg of product was dissolved in MeOH and evaporated to dryness to obtain Intermediate A. 1H NMR (300 MHz, DMSO-d6) δ=9.70 (s, 1H), 7.46 (d, J=8.7 Hz, 2H), 7.10 (d, J=8.7 Hz, 2H), 7.09 (t, J=74.1 Hz, 1H), 3.65 (s, 3H) ppm.
[0853] Previously prepared 4-(difluoromethoxy) phenyl isocyanate (43 mg, 0.9 equiv.) and 5-methyl-N-[(5-methyl-2-furyl)methyl]isoxazol-4-amine (crude product, 1 equiv.) were dissolved in DCM (2.0 mL) and stirred at room temperature overnight. Solvent was removed in vacuo and the obtained crude product was further purified by flash chromatography on silica gel (eluting with EtOAc/cyclohexane gradient; 0-30% of EtOAc) to afford the expected product (49 mg). LCMS: MW (calcd): 377.34; MS (ES.sup.+, m/z): 378.19 [M+H].sup.+.
Method D3: CDI
[0854] The reaction is typically performed by adding CDI (1-1.1 equiv.) to a solution of the corresponding amine (1 equiv.) in a suitable solvent, such as DMF or DCM, in the presence of a suitable base (typically TEA, 2 equiv.), or without presence of base. The reaction mixture is stirred at room temperature for 1-2 h, then an appropriate compound of formula (I) (1 equiv.) is added and resulting mixture stirred at RT for 16 h. The expected product of formula (II) may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example D3.1
Illustrative Synthesis of 3-(4-chloro-2-fluoro-phenyl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea (Compound 172)
[0855] ##STR00037##
[0856] To a solution of 4-chloro-2-fluoro aniline (0.76 mL, 1 equiv.) in DMF (2.5 mL), TEA (0.19 mL, 2 equiv.) and CDI (110.2 mg, 1 equiv.) were added and the reaction mixture was stirred at room temperature for 1 h. Then N-[(5-methyl-2-furyl)methyl]-cyclopentanamine (162 mg, 1 equiv.) was added and stirring continued at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (20 mL), was transferred to a separatory funnel and washed with sat. aq. sol. NaHCO.sub.3 (3×5 mL). Organic layer was dried over Na.sub.2SO.sub.4 (anhyd.), was filtered and evaporated in vacuo to yield the crude product, which was purified by flash chromatography on silica gel (eluting with DCM:cyclohexane=1:1/cyclohexane gradient; 0-100% of DCM:cyclohexane=1:1) to afford the expected product (84.2 mg). LCMS: MW (calcd): 350.82; MS (ES.sup.+, m/z): 351.80 [M+H].sup.+.
Method D4: Phosgene
[0857] Typically, to a solution of an appropriate amine (1 equiv.) and product of formula (I) (1 equiv.) in THF at RT is added base, typically TEA (4 equiv.), followed by phosgene (15 wt % solution in PhMe, 1 equiv.). Reaction mixture is stirred at room temperature for 16 hours. The expected product of formula (II) may be isolated and, if desired, further purified by methods familiar to one skilled in the art.
Example D4.1
Illustrative Synthesis of 1-(benzofuran-2-ylmethyl)-1-cyclopentyl-3-(4-ethynylphenyl)urea (Compound 131)
[0858] ##STR00038##
[0859] To a stirred solution of N-(benzofuran-2-ylmethyl)cyclopentanamine (50 mg, 1 equiv.), 4-ethynylaniline (32.5 mg, 1 equiv.) and TEA (156 μL, 4 equiv.) in THE (7 mL), a phosgene solution 15 wt % in toluene (199 μL, 1 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. Volatiles were evaporated. The concentrated reaction mixture was transferred to a separatory funnel containing distilled water (50 mL), and was extracted with EtOAc (3×50 mL). Combined organic extracts were evaporated in vacuo to yield the crude product, which was purified by flash chromatography on silica gel (eluting with EtOAc/cyclohexane gradient; 0-50% of EtOAc) to afford the expected product (5.0 mg). LCMS: MW (calcd): 358.43; MS (ES.sup.+, m/z): 359.71 [M+H].sup.+.
Method D5: Phenyl Carbamate
[0860] Typically, an appropriate amine (1 equiv.) and phenyl carbamate (1-2.8 equiv.) are dissolved in a suitable solvent, such as DMSO, with or without a presence of base (1.3 equiv.), such as TEA. The reaction mixture is stirred at room temperature for 16 hours. The expected compound of formula (II) may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example D5.1
Illustrative Synthesis of 1-cyclopentyl-3-(5-ethynyl-2-pyridyl)-1-[(5-methyl-2-furyl)methyl]urea (Compound 16)
[0861] ##STR00039##
[0862] To a stirred solution of phenyl N-(5-ethynyl-2-pyridyl)carbamate (74 mg, 1.1 equiv.) in DMSO (1 mL) was added N-[(5-methyl-2-furyl)methyl]cyclopentanamine (50 mg, 1 equiv.). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was further purified by preparative LC-MS (ES.sup.+ mode, high pH conditions) to afford the expected product (28 mg). LCMS: MW (calcd): 323.39; MS (ES.sup.+, m/z): 324.73 [M+H].sup.+.
Method D6: Isopropenyl Carbamate
[0863] Typically, an appropriate amine (1-2 equiv.) and isopropenyl carbamate (1.1 equiv.) are dissolved in a suitable solvent, such as 1,4-dioxane, with or without a presence of base (0.2-0.3 equiv.), such as DBU. The reaction mixture is stirred at 80° C. for 2 hours. The expected compound of formula (II) may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example D6.1
Illustrative Synthesis of 3-[4-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]phenyl]-1-cyclobutyl-1-[(5-methyl-2-furyl)methyl]urea
[0864] ##STR00040##
[0865] To a stirred solution of isopropenyl N-[4-[2-[tert-butyl(dimethyl)silyl]oxyethynyl]phenyl]carbamate (150 mg, 1.0 equiv.), N-[(5-methyl-2-furyl)methyl]cyclobutanamine (85 mg, 1.09 equiv.) and DBU (15.3 mg, 0.23 equiv) were dissolved in 1,4-dioxane (1.5 mL) and stirred at 80° C. for 2 hours. To the reaction mixture water and brine were added and resulting solution was extracted with DCM (3×15 mL). Combined organic extracts were filtered through phase separator and evaporated in vacuo to yield the crude product, which was purified by flash chromatography on silica gel (eluting with EtOAc/cyclohexane gradient; 0-20% of EtOAc) to afford the expected product (173 mg). LCMS: MW (calcd): 452.66; MS (ES.sup.+, m/z): 453.32 [M+H].sup.+.
Method E: Suzuki Coupling
[0866] The reaction is typically performed by combining an appropriate aryl or heteroaryl halide (1 equiv.) and aryl boronic acid or aryl boronic acid pinacol ester (1-1.5 equiv.) in the presence of a palladium catalyst (0.05-0.2 equiv.), such as Pd(PPh.sub.3).sub.4, XPhos-Pd-G1 or any other suitable catalyst, with or without a suitable ligand (0.1 equiv.), such as XPhos, and a base (2-3 equiv.), such as potassium carbonate, in suitable solvent or mixture of solvents (typically mixture of dioxane and water) under inert atmosphere. The resulting mixture is stirred at temperature of typically 80-100° C. for 30 minutes to 18 h by using conventional heating. The expected compound may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example E.1
Illustrative Synthesis of 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]urea (Compound 108)
[0867] ##STR00041##
[0868] To the solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.84 g, 1.5 equiv.), 3-(4-bromophenyl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea (2.39 g, 1 equiv.), and potassium carbonate (1.75 g, 2 equiv.) in degassed dioxane/water 5:1 (120 mL), Pd(PPh.sub.3).sub.4 (1.46 g, 0.2 equiv.) was added and the solution was further degassed by bubbling argon for 10 minutes. The flask was capped with the septum and heated at 80° C. in a sand bath for 9 hours. Solution was cooled to RT, transferred to a separatory funnel containing distilled water, and extracted with EtOAc (3×300 mL) The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered, and solvent was removed in vacuo to yield the crude product, which was purified by flash chromatography on silica gel (eluting with: 5% MeOH in DCM/DCM gradient; 0-70% of 5% MeOH in DCM) to afford the expected product, which was further recrystallized from DCM. Mother liquor was evaporated till dryness and then triturated with Et.sub.2O to afford the wanted product (171 mg). LCMS: MW (calcd): 364.4; MS (ES.sup.+, m/z): 365.8 [M+H].sup.+.
Example E.2
Illustrative Synthesis of 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-[6-(1-methylpyrazol-4-yl)-3-pyridyl]urea (Compound 160)
[0869] ##STR00042##
[0870] To the solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (59 mg, 1.5 equiv.), 3-(6-chloro-3-pyridyl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea (66 mg, 1 equiv.), and potassium carbonate (82.8 mg, 3 equiv.) in degassed dioxane/water 5:1 (4 mL), XPhos-Pd-G1 (7.4 mg, 0.05 equiv.) and XPhos (9.5 mg, 0.1 equiv.) were added and the reaction mixture was heated at 80° C. for 45 minutes. Solution was cooled to RT, transferred to a separatory funnel containing distilled water (10 mL), and extracted with DCM (3×10 mL). The combined organic extracts were dried, and the solvent was removed in vacuo to yield the crude product, which was purified by flash chromatography on silica gel (eluting with: 10% MeOH in DCM/DCM gradient; 0-10% of 10% MeOH in DCM) to afford the expected product (64 mg). LCMS: MW (calcd): 379.5; MS (ES.sup.+, m/z): 380.8 [M+H].sup.+.
Method F: Sonogashira Coupling
[0871] The reaction is typically performed by combining an appropriate aryl iodide (1 equiv.) and a terminal alkyne (1.3-2 equiv.) in the presence of a palladium catalyst (0.05-0.075 equiv.), such as Pd(PPh.sub.3).sub.2Cl.sub.2, or any other suitable catalyst, and copper catalyst (0.05 equiv.), such as CuI, or any other suitable catalyst, and a base, such as TEA, or any other suitable base, which also acts as a solvent, in a suitable solvent, typically acetonitrile under inert atmosphere. The resulting mixture is stirred at room temperature for 2.5-5 hours. The expected compound may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example F.1
Illustrative Synthesis of 1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]-3-[6-(1-methylpyrazol-4-yl)-3-pyridyl]urea (Compound 110)
[0872] ##STR00043##
[0873] To the solution of 1-cyclopentyl-3-(4-iodophenyl)-1-[(5-methyl-2-furyl)methyl]urea (100 mg, 1 equiv.), Pd(PPh.sub.3).sub.2Cl.sub.2 (8.4 mg, 0.05 equiv.), and CuI (2.4 mg, 0.05 equiv.) in acetonitrile/TEA 1:1 (1.2 mL), prop-2-yn-1-amine (19.2 μL, 1.3 equiv.) was added and the reaction mixture was stirred at room temperature for 3 hours. Second portion of catalysts (2.5% Pd(PPh.sub.3).sub.2Cl.sub.2 and 2.5% CuI) and prop-yn-1-amine (10 μL, 0.7 equiv.) were added and stirring continued at room temperature for 2 h. The reaction mixture was transferred to a separatory funnel containing sat. aq. sol. NaHCO.sub.3 (10 mL) and extracted with DCM (3×10 mL). Organic layers were dried, and solvent was removed in vacuo to yield the crude product, which was purified by preparative LC-MS to afford the expected product (14 mg). LCMS: MW (calcd): 351.4; MS (ES.sup.+, m/z): 352.8 [M+H].sup.+.
Method G: General Procedure for N-Boc Deprotection
[0874] Typically, to a solution of an appropriate compound, in suitable solvent or mixture of solvents, such as DCM, TFA (5 equiv.) is added and the reaction mixture is stirred at 0° C. or room temperature for 30 minutes to give the expected product that may be isolated and, if desired further purified by methods known to one skilled in the art.
Example G.1
Illustrative Synthesis of 1-cyclopentyl-3-(4-fluorophenyl)-1-[(4-methyl-4-piperidyl)methyl]urea (Compound 86)
[0875] ##STR00044##
[0876] To the solution of tert-butyl 4-[[cyclopentyl-[(4-fluorophenyl)carbamoyl]-amino]methyl]-4-methyl-piperidine-1-carboxylate (40 mg, 1 equiv.) in DCM (2.5 mL), TFA (35 μL, 5 equiv.) was added and the reaction mixture was stirred at room temperature for 30 minutes. Volatiles were removed in vacuo to yield the crude product, which was dissolved in MeOH, applied to a SCX column and eluted with MeOH followed by 2M ammonia in MeOH. Ammonia/MeOH fractions were combined and evaporated to afford the expected product (30 mg). LCMS: MW (calcd): 333.4; MS (ES.sup.+, m/z): 334.0 [M+H].sup.+.
Method H: General Procedure for Mesylation
[0877] Typically, to a solution of an appropriate amine (1 equiv.) in DCM (or any other suitable solvent), DIPEA or other suitable base (2.5 equiv.) and mesyl chloride (1.1 equiv.) are added. The reaction mixture is stirred at room temperature for 45 minutes. The expected compound may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example H.1
Illustrative Synthesis of 1-cyclopentyl-3-(4-fluorophenyl)-1-[(4-methyl-1-methylsulfonyl-4-piperidyl)methyl]urea (Compound 113)
[0878] ##STR00045##
[0879] To a solution of 1-cyclopentyl-3-(4-fluorophenyl)-1-[(4-methyl-4-piperidyl)methyl]urea (24 mg, 1 equiv.) and DIPEA (32 μL, 2.5 equiv.) in DCM (1.0 mL) mesyl chloride (6 μL, 1.1 equiv.) was added and the resulting mixture was stirred at RT for 45 minutes. The reaction mixture was transferred to a separatory funnel containing water (5 mL) and extracted with DCM (3×10 mL). Organic layers were combined, then evaporated to dryness to obtain the crude product, which was further purified by preparative LC-MS to afford the expected product (5 mg). LCMS: MW (calcd): 411.5; MS (ES.sup.+, m/z): 412.18 [M+H].sup.+.
Method I: General Procedure for Acetylation
[0880] Typically, to a solution of an appropriate amine (1 equiv.) in THE (or any other suitable solvent) at 0° C., TEA or other suitable base (2.5 equiv.) and acetyl chloride (1.1 equiv.) are added. The reaction mixture is stirred at room temperature for 45 minutes. The expected compound may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example 1.1
Illustrative Synthesis of 1-[(1-acetyl-4-methyl-4-piperidyl)methyl]-1-cyclopentyl-3-phenyl-urea (Compound 97)
[0881] ##STR00046##
[0882] To a solution of 1-cyclopentyl-1-[(4-methyl-4-piperidyl)methyl]-3-phenyl-urea (18 mg, 1 equiv.) and TEA (20 μL, 2.5 equiv.) in THE (1.0 mL) at 0° C. acetyl chloride (4.9 μL, 1.1 equiv.) was added and the resulting mixture was stirred at RT for 45 minutes. The reaction mixture was concentrated, transferred to a separatory funnel containing water (5 mL) and extracted with EtOAc (3×10 mL). Organic layers were evaporated to dryness and the obtained crude product was further purified by flash chromatography on silica gel (eluting with: EtOAc/cyclohexane gradient; 0-50% of EtOAc) to afford the expected product (12 mg). LCMS: MW (calcd): 357.5; MS (ES.sup.+, m/z): 358.24 [M+H].sup.+.
Method J: General Procedure for Methylation
[0883] Typically, to a solution of an appropriate urea (1 equiv.) in DMF (or any other suitable solvent), Cs.sub.2CO.sub.3 or other suitable base (1.5 equiv.) and methyl iodide (1.1 equiv.) are added. The reaction mixture is stirred at room temperature for 24 hours. The expected compound may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example J.1
Illustrative Synthesis of 1-cyclopentyl-3-methyl-3-phenyl-1-(2-thienylmethyl)urea (Compound 23)
[0884] ##STR00047##
[0885] To the suspension of 1-cyclopentyl-3-phenyl-1-(2-thienylmethyl)urea (50 mg, 1 equiv.) and Cs.sub.2CO.sub.3 (81.3 mg, 1.5 equiv.) in DMF (1.0 mL), methyl iodide (12 μL, 1.1 equiv.) was added and the resulting mixture was stirred at RT for 16 hours. The reaction mixture was diluted with EtOAc (5 mL) and washed with brine (3×10 mL). Organic layer was dried over sodium sulphate, filtered and evaporated to dryness. The obtained crude product was further purified by preparative LC-MS to afford the expected product (21 mg). LCMS: MW (calcd): 314.4; MS (ES.sup.+, m/z): 315.70 [M+H].sup.+.
Method K: General Procedure for Negishi Coupling
[0886] Typically, to a suspension of zinc (9.3 equiv.) in THE (or any other suitable solvent) an appropriate alkyl iodide (6.6 equiv.) is added. The reaction mixture is heated at 80° C. for 90 minutes. The reaction temperature is lowered and aryl iodide (1 equiv.), palladium catalyst (0.05 equiv.), such as Pd(OAc).sub.2 or any other suitable catalyst, and ligand (0.1 equiv.), such as CPhos or any other suitable ligand, are added. The reaction mixture is stirred at 60° C. for 2 hours and then at room temperature for 16 hours. The expected compound may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example K.1
Illustrative Synthesis of tert-butyl 3-[4-[[cyclopentyl-[(5-methyl-2-furyl)methyl]-carbamoyl]amino]phenyl]azetidine-1-carboxylate (Compound 159)
[0887] ##STR00048##
[0888] HCl-activated Zn (90.1 mg, 9.3 equiv.) was suspended in THE (0.5 mL) under argon atmosphere. A solution of 1-Boc-3-iodoazetidine (300 mg, 6.6 equiv.) in THE (0.5 mL) was added and the reaction mixture was heated at 80° C. for 90 minutes. The reaction temperature was lowered and 1-cyclopentyl-3-(4-iodophenyl)-1-[(5-methyl-2-furyl)methyl]urea (63 mg, 1 equiv.), Pd(OAc).sub.2 (1.6 mg, 0.05 equiv.) and CPhos (10 mg, 0.1 equiv.) were added. The reaction mixture was heated at 60° C. for 2 hours and then at room temperature for 16 hours. The reaction mixture was diluted with DCM (10 mL) and filtered through a celite pad. Collected organic fraction was transferred to a separatory funnel and washed with sat. aq. sol. NaHCO.sub.3 (10 mL). Organic layer was dried, concentrated and purified by flash chromatography on silica gel (eluting with: EtOAc/cyclohexane gradient; 0-20% of EtOAc) to afford the expected product (36 mg).
Method L: General Procedure for Nitro Reduction
[0889] Typically, to a solution of an appropriate nitro compound (1.0 equiv.), Pd/C 10% (on carbon) (0.01 equiv.) and in a suitable solvent, such as MeOH at room temperature is added. The reaction mixture is stirred under hydrogen atmosphere at room temperature for 4 hours. The expected compound may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example L.1
Illustrative Synthesis of [1-(4-aminophenyl)triazol-4-yl]methanol
[0890] ##STR00049##
[0891] To a solution of [1-(4-nitrophenyl)triazol-4-yl]methanol (500 mg, 1 equiv.) in MeOH (45.0 mL), Pd/C (10% on carbon) (36.0 mg, 0.01 equiv.) at room temperature was added. The resulting mixture was stirred under H.sub.2 atmosphere for 4 hours. The reaction mixture filtered through Celite. Obtained filtrate was concentrated to afford the expected product (422 mg). LCMS: MW (calcd): 190.20; MS (ES.sup.+, m/z): 191.09 [M+H].sup.+.
Example L.2
Illustrative Synthesis of 4-(4-methyltriazol-1-yl)aniline
[0892] ##STR00050##
[0893] To a solution of 4-(fluoromethyl)-1-(4-nitrophenyl)triazole (7 mg, 1 equiv.) in MeOH (2.0 mL), Pd/C (10% on carbon) (5 mg, 0.15 equiv.) at room temperature was added. The resulting mixture was stirred under H.sub.2 atmosphere for 18 hours. The reaction mixture was filtered through syringe filter (PTFE, 0.45 m). Obtained filtrate was concentrated to afford the expected product (3.5 mg). LCMS: MW (calcd): 174.20; MS (ES.sup.+, m/z): 175.06 [M+H].sup.+.
Method M: General Procedure for Silyl Protection
[0894] Typically, to a solution of an appropriate compound (1.0 equiv.), DMAP (0.3 equiv.) and a base (1.5 equiv.), such as TEA in a suitable solvent, such as DCM at 0° C., a solution of tert-butyl-chloro-dimethyl-silane (1.5 equiv.) in a suitable solvent, such as DCM is added. The reaction mixture is stirred at 0° C. for 10 minutes and then at room temperature for 2.5-16 hours. The expected compound may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example M.1
Illustrative Synthesis of 4-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]triazol-1-yl]aniline
[0895] ##STR00051##
[0896] To a solution of [1-(4-aminophenyl)triazol-4-yl]methanol (50 mg, 1 equiv.), DMAP (9.6 mg, 0.3 equiv.) and TEA (54 μL, 1.5 equiv.) in DCM (0.65 mL) at 0° C. TBDMSCl (59 mg, 1.5 equiv.) was added. The resulting mixture was stirred at 0° C. for 10 minutes, and then at room temperature for 16 hours. The reaction mixture was transferred to a separatory funnel containing sat. aq. sol. NaHCO.sub.3 (5 mL) and extracted with DCM (3×5 mL). Organic layers were combined, dried, concentrated and purified by flash chromatography on silica gel (eluting with: EtOAc/cyclohexane gradient; 0-30% of EtOAc) to afford the expected product (72 mg). LCMS: MW (calcd): 304.46; MS (ES.sup.+, m/z): 305.62 [M+H].sup.+.
Method N: General Procedure for Silyl Deprotection
[0897] Typically, to a solution of tert-butyldimethyl silyl protected compound (1.0 equiv.) in an appropriate solvent, such as THE at 0° C., TBAF×H.sub.2O (1 equiv.) is added. The reaction mixture is stirred at 0° C. for 3 hours. The expected compound may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example N.1
Illustrative Synthesis of 1-cyclopentyl-3-[4-[4-(hydroxymethyl)triazol-1-yl]phenyl]-1-[(5-methyl-2-furyl)methyl]urea (Compound 164)
[0898] ##STR00052##
[0899] To a solution of 3-[4-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]triazol-1-yl]phenyl]-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea (8 mg, 1 equiv.) in THF (0.5 mL) at 0° C. TBAF×H.sub.2O (5 mg, 1 equiv.) was added. The resulting mixture was stirred at 0° C. After completion, the reaction mixture was concentrated and purified by a column chromatography (φ 0.5 cm, h-SiO.sub.2 8 cm, eluent: DCM/MeOH=20/1). Collected fractions were combined and evaporated till dryness to afford the expected product (3 mg). LCMS: MW (calcd): 395.45; MS (ES.sup.+, m/z): 396.76 [M+H].sup.+.
Method O: General Procedure for Benzyl Deprotection
[0900] Typically, to a solution of O-benzyl protected compound (1.0 equiv.) in the mixture of solvents ethanol/ethyl-acetate (1:1), Pearlman's catalyst (20% wt. % loading activated) was added. The reaction mixture was hydrogenated in a Parr apparatus at 3 bar at ambient temperature for 17 hours. The expected compound may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example O.1
Illustrative Synthesis of 1-cyclopentyl-3-(4-hydroxyphenyl)-1-[(5-methyl-2-furyl)methyl]urea (Compound 292)
[0901] ##STR00053##
[0902] To a solution of 3-(4-benzyloxyphenyl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea (70 mg, 1 equiv.) in mixture of 96% EtOH/EtOAc (1:1) (30 mL), 20% wt. % Pd(OH).sub.2/C (39 mg, 1.7 equiv) was added. The reaction mixture was hydrogenated in a Parr apparatus at 3 bar at ambient temperature for 17 hours. The resulting suspension was filtered and concentrated in vacuo. Obtained crude product was purified by flash chromatography on silica gel (eluting with: DCM/2.5% MeOH in DCM gradient; 0-10% of 2.5% MeOH in DCM) to afford the expected product (9.6 mg). LCMS: MW (calcd): 314.38; MS (ES.sup.+, m/z): 315.07 [M+H].sup.+.
Method P: General Procedure for the Base-Catalysed Conversion of Nitriles to Amides by Hydrogen Peroxide
[0903] Typically, to a solution of nitrile compound (1.0 equiv.) in DMSO, or any other suitable solvent, a base (30 equiv.), such as potassium carbonate, and hydrogen peroxide (95-115 equiv.) are added. The reaction mixture is stirred at RT for 16 hours. The expected compound may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example P.1
Illustrative Synthesis of 4-[[cyclopentyl-[(5-methyl-2-furyl)methyl]carbamoyl]-amino]benzamide (Compound 117)
[0904] ##STR00054##
[0905] To a suspension of 3-(4-cyanophenyl)-1-cyclopentyl-1-[(5-methyl-2-furyl)methyl]urea (50 mg, 1 equiv.) and K.sub.2CO.sub.3 (639 mg, 30 equiv.) in DMSO (2.5 mL) 30 wt % H.sub.2O.sub.2 in water (1.5 mL, 95 equiv.) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was transferred to a separatory funnel containing water (10 mL) and extracted with DCM (3×10 mL). Organic layers were dried, evaporated in vacuo and crystalized from diethyl ether to afford the expected product (51 mg). LCMS: MW (calcd): 341.40; MS (ES.sup.+, m/z): 342.19 [M+H].sup.+.
Method O: General Procedure for Phenyl Carbamate Synthesis
[0906] Typically, to a solution or a suspension of an appropriate amine (1 equiv.) and a base (1.1 equiv.), such as pyridine in a suitable solvent, such as DCM or CH.sub.3CN, phenyl chloroformate (1-1.05 equiv.) is added at 0° C. The resulting mixture is stirred at 0° C. or at room temperature for 2-16 hours. The expected phenyl carbamate may be isolated and, if desired, further purified by methods known to one skilled in the art or used as a crude product in the following reaction step.
Example Q.1
Illustrative Synthesis of phenyl N-(5-ethynyl-2-pyridyl)carbamate
[0907] ##STR00055##
[0908] To a stirred solution of 5-ethynylpyridine-2-amine (50 mg, 1 equiv.) and pyridine (37 μL, 1.1 equiv.) in dry CH.sub.3CN (1 mL) at 0° C. was added phenyl chloroformate (53 μL, 1 equiv.). A brown precipitate appeared, which was filtered, washed with cold acetonitrile and dried under vacuum overnight to afford the expected product (84 mg). LCMS: MW (calcd): 238.07; MS (ES.sup.+, m/z): 239.63 [M+H].sup.+.
Method R: General Procedure for Isopropenyl Carbamate Synthesis
[0909] Typically, to a solution or a suspension of an appropriate amine (1 equiv.) and a base such as aqueous saturated solution of NaHCO.sub.3 with a suitable solvent, such as EtOAc, isopropenyl chloroformate (1-1.1 equiv.) is added at room temperature. The resulting mixture is stirred at room temperature for 1 hour. The expected phenyl isopropenyl carbamate may be isolated and, if desired, further purified by methods known to one skilled in the art or used as a crude product in the following reaction step.
Example R.1
[0910] Illustrative Synthesis of isopropenyl N-[4-[2-[tert-butyl(dimethyl)silyl]oxyethynyl]phenyl]carbamate
##STR00056##
[0911] To a stirred solution of 4-[2-[tert-butyl(dimethyl)silyl]oxyethynyl]aniline (200 mg, 1.0 equiv.) in EtOAc (6.98 mL), saturated aqueous solution of NaHCO.sub.3 (6.98 mL) and isopropenyl chloroformate (0.092 ml, 1.1 equiv.) were added. The reaction mixture was stirred at room temperature for 1 hour. Organic layer was separated, aqueous layer was extracted with EtOAc (3×15 mL). Combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuo to yield expected product (278 mg). LCMS: MW (calcd): 345.51; MS (ES.sup.−, m/z): 344.14 [M−H]+.
Method S: General Procedure for Copper-Catalysed C-N Coupling of Amides in the Presence of Caesium Fluoride
[0912] Typically, to a solution or a suspension of an appropriate aryl iodide (1.0 equiv.), CsF (2.5 equiv.) and a copper catalyst, such as CuI, in a suitable solvent, such as dioxane, an amide (1.2 equiv.), such as 2-pyrrolidinone, and a ligand (0.1 equiv.), such as 1,2-bis(methylamino)ethane, were added. The resulting mixture is stirred at room temperature for 3 hours. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art or used as a crude product in the following reaction step.
Example S.1
Illustrative Synthesis of 1-(4-aminophenyl)pyrrolidin-2-one
[0913] ##STR00057##
[0914] Into a reaction tube were placed CsF (190 mg, 2.5 equiv.), CuI (4.8 mg, 0.05 equiv.) and 4-iodoaniline (110 mg, 1 equiv.). The tube was evacuated and back-filled with argon (3×). The solids were dissolved in 1,4-dioxane (0.5 mL) and 2-pyrrolidinone (45 μL, 1.2 equiv.) and 1,2-bis(methylamino)ethane (5.4 μL, 0.1 equiv.) were added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (5 mL), transferred to a separatory funnel containing sat. aq. sol. NH.sub.4Cl (5 mL) and was extracted with EtOAc (2×5 mL). The combined organics were dried over Na.sub.2SO.sub.4 (anhyd.), filtered and concentrated. Obtained crude product was pooled with crude product from another reaction that was done in the same way and with the same amount of the starting material and reagents. The combined crude product was purified by flash chromatography on silica gel (eluting with: MeOH/DCM gradient; 0-5% of MeOH) to afford the expected product (62 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): δ=7.32 (d, J=8.9 Hz, 2H), 6.66 (d, J=8.9 Hz, 2H), 3.78 (t, J=7.0 Hz, 2H), 2.55 (t, J=7.8 Hz, 2H), 2.11 (quint, J=7.6 Hz, 2H) ppm.
Method T: General Procedure for Stille Coupling
[0915] Typically, to a solution or a suspension of an appropriate aryl bromide (1.0 equiv.) and a palladium catalyst (0.05 equiv.), such as Pd(PPh.sub.3).sub.4 or any other suitable catalyst, in a suitable solvent, such as toluene, tributyl-propynylstannane (1.2 equiv.) is added. The resulting mixture is heated at 100° C. for 16 hours. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art or used as a crude product in the following reaction step.
Example T.1
Illustrative Synthesis of 4-prop-1-ynylaniline
[0916] ##STR00058##
[0917] To a solution of 4-bromoaniline (150 mg, 1 equiv.) and Pd(PPh.sub.3).sub.4 (50 mg, 0.05 equiv.) in toluene (8.7 mL) under argon atmosphere, tributyl-propynylstannane (344 mg, 1.2 equiv.) was added. The reaction mixture was heated at 100° C. for 16 hours. The reaction was cooled to room temperature, transferred to a separatory funnel containing sat. aq. sol. NaHCO.sub.3 (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 (anhyd.), filtered and concentrated. The crude product was purified by flash chromatography on silica gel (eluting with: EtOAc/cyclohexane gradient; 0-25% of EtOAc) to afford the expected product as a 1:1 mixture with starting 4-bromoaniline (60 mg), and was used in the following reaction without further purification. LCMS: MW (calcd): 131.17; MS (ES.sup.+, m/z): 131.41 [M+H].sup.+.
Method U: General Procedure for Substitution of Hydroxyl Group with Fluorine
[0918] Typically, to a solution or a suspension of an appropriate alkyl hydroxide (1.0 equiv.) in dry DCM, Deoxo-Fluor reagent (13 equiv) is added under argon atmosphere. The resulting mixture was stirred at −40° C. for 72 hours. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art or used as a crude product in the following reaction step.
Example U.1
Illustrative Synthesis of 4-(fluoromethyl)-1-(4-nitrophenyl)triazole
[0919] ##STR00059##
[0920] To a solution of [1-(4-nitrophenyl) triazol-4-yl]methanol (50 mg, 1 equiv.) in dry DCM (2.5 mL), previously cooled to −40° C., under argon atmosphere, Deoxo-Fluor (50% solution in THF) (0.625 mL, 12.94 equiv.) was added. The reaction mixture was stirred at −40° C. for 72 hours under argon atmosphere. To the reaction mixture, water (15 mL) was added and resulting suspension was extracted with EtOAc (3×15 mL). Combined organic layers were filtered through phase separator and evaporated in vacuo to dryness. The obtained crude product was further purified by preparative LC-MS to afford the expected product (9.2 mg). LCMS: MW (calcd): 222.18; MS (ES.sup.+, m/z): 223.06 [M+H].sup.+.
Method V: General Procedure for Azide Formation from Amine
[0921] Typically, to a cooled solution or a suspension of an appropriate amine (1.0 equiv.) in aqueous solution of HCl acid, a solution of sodium nitrite (1.05 equiv.) in water is added dropwise. Reaction mixture was stirred for 10 minutes, followed by addition of sodium azide (1.03 equiv.). The resulting mixture was stirred for 10 minutes, followed by addition of EtOAc. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art or used as a crude product in the following reaction step.
Example V.1
Illustrative Synthesis of 1-azido-2-methoxy-4-nitro-benzene
[0922] ##STR00060##
[0923] To an ice cooled solution of 2-methoxy-4-nitro-aniline (500 mg, 1 equiv.) in 2M aqueous solution of HCl (10 mL), a solution of sodium nitrite (215 mg, 1.05 equiv.) in water (0.9 mL) was added dropwise during 10 minutes. Reaction mixture was continued to stir on ice for additional 10 minutes, followed by addition of sodium azide (200 mg, 1.03 equiv.). The reaction mixture was stirred for 10 minutes, EtOAc (30 mL) was added, and stirring was continued for 10 minutes. Aqueous layer was separated and extracted with EtOAc (2×10 mL). Combined organic layers were filtered through phase separator and evaporated in vacuo to afford the expected product (536 mg). .sup.1H NMR (300 MHz, DMSO-d6): δ=7.91-7.76 (m, 2H), 7.32-7.24 (m, 1H), 3.96 (s, 3H) ppm.
Method W: General Procedure for Synthesis of 1,2,3-triazoles
[0924] In the mixture of suitable solvents (typically DMF/water), an appropriate azide (1.0 equiv), alkyne (1.0 equiv) in the presence of catalyst (typically CuSO.sub.4×5H.sub.2O, 0.8 equiv) and sodium ascorbate (1.35 equiv.) were added. Resulting mixture was exposed to microwave irradiation at 150° C. for 2 minutes. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art or used as a crude product in the following reaction step.
Example W.1 Illustrative Synthesis of [1-(2-methoxy-4-nitro-phenyl)triazol-4-yl]methanol
[0925] ##STR00061##
[0926] To the mixture of DMF (1.95 mL) and water (0.65 mL), 1-azido-2-methoxy-4-nitro-benzene (50 mg, 1.0 equiv), prop-2-yn-1-ol (0.015 mL, 1.0 equiv.), CuSO.sub.4×5H.sub.2O (50 mg, 0.78 equiv.) and sodium ascorbate (69 mg, 1.35 equiv.) were added. To the reaction mixture, water (10 mL) and brine (10 mL) were added. Resulting solution was extracted with DCM (3×15 mL). Combined organic extracts were washed with brine, filtered through phase separator and evaporated in vacuo to afford the expected product (924 mg). LCMS: MW (calcd): 250.21; MS (ES.sup.+, m/z): 251.08 [M+H].sup.+.
Table with Representative Compounds of Formula (I):
TABLE-US-00002 MS MS Cpd (m/z, (m/z, Starting # Structure ES+) ES−) δ NMR Data Int/Cpd# Sequence of Methods Chemical Name 1 [00062]![embedded image]()
329.8 1H NMR (300 MHz, DMSO-d6): δ = 7.32 (dd, J = 1.7, 4.5 Hz, 1H), 7.29-7.21 (m, 2H), 7.19-7.12 (m, 3H), 6.91-6.87 (m, 2H), 6.36 (t, J = 5.3 Hz, 1H), 4.49 (s, 2H), 4.24- 4.12 (m, 1H), 3.27-3.19 (m, 2H), 2.70 (t, J = 7.2 Hz, 2H), 1.72-1.53 (m, 4H), 1.51-1.37 (m, 4H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 2- isocyanatoethyl- benzene 1-cyclopentyl-3- (2-phenylethyl)- 1-(2- thienylmethyl) urea 2 [00063]![embedded image]()
335.7 1H NMR (300 MHz, DMSO-d6): δ = 7.74 (s, 1H), 7.66 (dd, J = 1.5, 8.0 Hz, 1H), 7.41 (d, J = 1.4 Hz, 1H), 7.39 (dd, J = 3.2, 1.2 Hz, 1H) 7.26 (td, J = 7.7, 1.5 Hz, 1H), 7.11- 7.04 (m, 2H), 6.98-6.94 (m, 1H), 4.66 (s, 2H), 4.51-4.41 (m, 1H), 1.88-1.76 (m, 2H), 1.69-1.44 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 1-chloro-2- isocyanato- benzene 3-(2- chlorophenyl)-1- cyclopentyl-1- (2- thienylmethyl) urea 3 [00064]![embedded image]()
329.8 1H NMR (300 MHz, DMSO-d6): δ = 8.24 (s, 1H), 7.36-7.32 (m, 2H), 7.30 (s, 1H), 7.05 (d, J = 8.4 Hz, 2H), 7.00-6.96 (m, 1H), 6.94- 6.98 (m, 1H), 4.65 (s, 2H), 4.46- 4.36 (m, 1H), 2.56 (m, 2H), 1.82- 1.69 (m, 2H), 1.67-1.42 (m, 6H), 1.13 (t, J = 7.4 Hz, 3H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 1-ethyl-4- isocyanato- benzene 1-cyclopentyl-3- (4-ethylphenyl)- 1-(2- thienylmethyl) urea 4 [00065]![embedded image]()
337.7 1H NMR (300 MHz, DMSO-d6): δ = 8.58 (s, 1H), 7.65-7.57 (m, 1H), 7.34 (dd, J = 5.0, 1.2 Hz, 1H), 7.31-7.18 (m, 2H), 7.01-6.97 (m, 1H), 6.94-6.90 (m, 1H), 4.65 (s, 2H), 4.45-4.34 (m, 1H), 1.37-1.85 (m, 8H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 1,2-difluoro-4- isocyanato- benzene 1-cyclopentyl-3- (3,4- difluorophenyl)- 1-(2- thienylmethyl) urea 5 [00066]![embedded image]()
329.7 1H NMR (300 MHz, DMSO-d6): δ = 7.67 (s, 1H), 7.36 (dd, J = 5.0, 1.2 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.02-6.97 (m, 1H), 6.95-6.87 (m, 3H), 4.63 (s, 2H), 4.47-4.36 (m, 1H), 2.22 (s, 3H), 2.01 (s, 3H), 1.84-1.71 (m, 2H), 1.67-1.42 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 1-isocyanato-2,4- dimethylbenzene 1-cyclopentyl-3- (2,4- dimethylphenyl)- 1-(2- thienylmethyl) urea 6 [00067]![embedded image]()
340.7 1H NMR (300 MHz, DMSO-d6): δ = 8.42 (s, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.33 (dd, J = 4.7, 1.7 Hz, 1H), 7.19 (d, J = 8.5 Hz, 2H), 7.00- 6.95 (m, 1H), 6.93-6.89 (m, 1H), 4.66 (s, 2H), 4.48-4.36 (m, 1H), 3.92 (s, 2H), 1.82-1.69 (m, 2H), 1.68-1.43 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 2-(4- isocyanatophenyl) acetonitrile 3-[4- (cyanomethyl) phenyl]-1- cyclopentyl-1- (2- thienylmethyl) urea 7 [00068]![embedded image]()
345.7 1H NMR (300 MHz, DMSO-d6): δ = 8.23 (s, 1H), 7.33 (dd, J = 5.0, 1.3 Hz, 1H), 7.10 (d, J = 1.4 Hz, 1H), 7.02-6.97 (m, 1H), 6.94-6.89 (m, 1H), 6.81-6.75 (m, 2H), 5.93 (s, 2H), 4.63 (s, 2H), 4.44-4.34 (m, 1H), 1.81-1.69 (m, 2H), 1.68- 1.42 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 5-isocyanato-1,3- benzodioxole 3-(1,3- benzodioxol-5- cyclopentyl-1- (2- thienylmethyl) urea 8 [00069]![embedded image]()
333.7 1H NMR (300 MHz, DMSO-d6): δ = 7.36-7.25 (m, 2H), 7.08-6.84 (m, 6H), 4.55 (s, 2H), 4.32-4.21 (m, 3H), 1.78-1.68 (m, 2H), 1.67- 1.55 (m, 2H), 1.54-1.39 (m, 4H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 1-fluoro-4- (isocyanatomethyl) benzene 1-cyclopentyl- [(4- fluorophenyl) methyl]-1-(2- thienylmethyl) urea 9 [00070]![embedded image]()
341.8 1H NMR (300 MHz, DMSO-d6): δ = 8.19 (s, 1H), 7.35-7.30 (m, 2H), 7.14-7.09 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.00-6.96 (m, 1H), 6.94-6.89 (m, 1H), 4.64 (s, 2H), 4.47-4.36 (m, 1H), 2.77 (q, J = 7.3 Hz, 4H), 2.02-1.92 (m, 2H), 1.80- 1.69 (m, 2H), 1.67-1.42 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 5- isocyanatoindane 1-cyclopentyl-3- indan-5-yl-1-(2- thienylmethyl) urea 10 [00071]![embedded image]()
370.7 1H NMR (300 MHz, DMSO-d6): δ = 9.27 (s, 1H), 7.63 (s, 2H), 7.36 (dd, J = 5.1, 1.1 Hz, 1H), 7.01-6.98 (m, 1H), 6.94-6.89 (m, 1H), 4.67 (s, 2H), 4.37 (quin, J = 8.0 Hz, 1H), 1.84-1.71 (m, 2H), 1.70-1.43 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 2,6-dichloro-4- isocyanato-pyridine 1-cyclopentyl-3- (2,6-dichloro-4- pyridyl)-1-(2- thienylmethyl) urea 11 [00072]![embedded image]()
302.6 1H NMR (300 MHz, DMSO-d6): δ = 8.80 (s, 1H), 8.29 (d, J = 6.5 Hz, 2H), 7.46 (d, J = 6.2 Hz, 2H), 7.34 (dd, J = 1.1, 5.0 Hz, 1H), 7.01-6.98 (m, 1H), 6.92 (dd, J = 3.6, 5.0 Hz, 1H), 4.68 (s, 2H), 4.50-4.37 (m, 1H), 1.84-1.70 (m, 2H), 1.70-1.42 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 4- isocyanatopyridine 1-cyclopentyl-3- (4-pyridyl)-1-(2- thienylmethyl) urea 12 [00073]![embedded image]()
307.7 1H NMR (300 MHz, DMSO-d6): δ = 7.32 (dd, J = 4.8, 1.5 Hz, 1H), 6.95-6.88 (m, 2H), 5.82 (d, J = 7.9 Hz, 1H), 4.49 (s, 2H), 4.32-4.21 (m, 1H), 3.49-3.36 (m, 1H), 1.72- 1.36 (m, 13H), 1.27-0.98 (m, 5H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using isocyanatocyclo- hexane 3-cyclohexyl-1- cyclopentyl-1- (2- thienylmethyl) urea 13 [00074]![embedded image]()
369.7 1H NMR (300 MHz, DMSO-d6): δ = 8.76 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.34 (dd, J = 5.0, 1.4 Hz, 1H), 7.02- 6.97 (m, 1H), 6.94-6.90 (m, 1H), 4.69 (s, 2H), 4.52-4.36 (m, 1H), 1.84-1.71 (m, 2H), 1.70-1.44 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 1-isocyanato-4- (trifluoromethyl) benzene 1-cyclopentyl)- (2- thienylmethyl)- 3-[4- (trifluoromethyl) phenyl]urea 14 [00075]![embedded image]()
331.7 1H NMR (500 MHz, DMSO-d6): δ = 8.19 (s, 1H), 7.27-7.38 (m, 3H), 6.96-7.03 (m, 1H), 6.91-6.95 (m, 1H), 6.81 (d, J = 8.85 Hz, 2H), 4.64 (s, 2H), 4.35-4.48 (m, 1H), 3.70 (s, 3H), 1.80-1.70 (m, 2H), 1.70-1.60 (m, 2H), 1.42-1.59 (m, 4H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 1-isocyanato-4- methoxybenzene 1-cyclopentyl-3- (4- methoxyphenyl)- 1-(2- thienylmethyl) urea 15 [00076]![embedded image]()
265.7 1H NMR (500 MHz, DMSO-d6): δ = 7.32 (dd, J = 4.9, 1.2 Hz, 1H), 6.95-6.90 (m, 2H), 6.47 (t, J = 5.8 Hz, 1H), 5.85-5.75 (m, 1H), 5.06- 4.95 (m, 2H), 4.52 (s, 2H), 4.29- 4.21 (m, 1H), 3.68 (t, J = 5.2 Hz, 2H), 1.75-1.65 (m, 2H), 1.64-1.54 (m, 2H), 1.51-1.46 (m, 4H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 3-isocyanato- prop-1-ene 3-allyl-1- cyclopentyl-1- (2- thienylmethyl) urea 16 [00077]![embedded image]()
324.7 1HNMR (300 MHz, DMSO-d6): δ = 8.89 (br.s., 1H), 8.32 (d, J = 1.8 Hz, 1H), 7.83-7.74 (m, 2H), 6.12 (d, J = 3.1 Hz, 1H), 5.96-5.94 (m, 1H), 4.55-4.45 (m, 1H), 4.47 (br.s., 2H), 4.24 (s, 1H), 2.19 (s, 3H), 1.78-1.40 (m, 8H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.3CN; method Q for carbamate synthesis; method D5 using phenyl N-(5-ethynyl-2- pyridyl)carbamate 1-cyclopentyl-3- (5-ethynyl-2- pyridyl)-1-[(5- methyl-2- furyl)methyl] urea 17 [00078]![embedded image]()
325.7 1HNMR (300 MHz, DMSO-d6): δ = 9.59 (s, 1H), 8.63 (s, 2H), 6.07 (d, J = 2.1 Hz, 1H), 5.93 (br.s., 1H), 4.47-4.32 (m, 4H), 2.17 (s, 3H), 1.75-1.44 (m, 8H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.3CN; method Q for carbamate synthesis; method D5 using phenyl N-(5- ethynylpyrimidin-2- yl)carbamate and TEA 1-cyclopentyl-3- (5-ethynyl- pyrimidin- 2-yl)-1-[(5- methyl-2- furyl)methyl] urea 18 [00079]![embedded image]()
361.8 1H NMR (300 MHz, DMSO-d6): δ = 7.59 (d, J = 9.2 Hz, 1H), 7.43 (dd, J = 4.9, 1.4 Hz, 1H), 7.18 (s, 1H), 7.08-7.06 (m, 1H), 7.00 (dd, J = 5.1, 3.5 Hz, 1H), 6.52 (d, J = 2.6 Hz, 1H), 6.42 (dd, J = 8.8, 2.6 Hz, 1H), 4.60 (s, 2H), 4.55-4.42 (m, 1H), 3.70 (s, 3H), 3.67 (s, 3H), 1.88-1.73 (m, 2H), 1.72-1.60 (m, 2H), 1.58-1.44 (m, 4H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 1-isocyanato-2,4- dimethoxybenzene 1-cyclopentyl-3- (2,4- dimethoxy- phenyl)-1-(2- thienylmethyl)- urea 19 [00080]![embedded image]()
301.7 1H NMR (300 MHz, DMSO-d6): δ = 8.33 (s, 1H), 7.42 (d, J = 7.7 Hz, 2H), 7.34 (dd, J = 5.1, 1.2 Hz, 1H), 7.21 (t, J = 7.9 Hz, 2H), 7.01- 6.98 (m, 1H), 6.95-6.89 (m, 2H), 4.66 (s, 2H), 4.50-6.37 (m, 1H), 1.82-1.70 (m, 2H), 1.68-1.41 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using phenyl isocyanate 1-cyclopentyl-3- phenyl-1-(2- thienylmethyl) urea 20 [00081]![embedded image]()
338.8 1H NMR (300 MHz, DMSO-d6): δ = 8.43-8.38 (m, 1H), 7.70 (td, J = 7.6, 1.7 Hz, 1H), 7.29-7.21 (m, 2H), 7.21-7.13 (m, 5H), 6.65 (t, J = 5.6 Hz, 1H), 4.37 (s, 2H), 3.92- 3.80 (bs, 1H), 3.30-3.22 (m, 2H), 2.71 (t, J = 7.3 Hz, 2H), 1.70-1.59 (m, 2H), 1.57-1.42 (m, 3H), 1.34- 1.14 (m, 4H), 1.08-0.92 (m, 1H) ppm N-(2- pyridyl- methyl) cyclohexan amine General method D1 using 2- isocyanatoethyl- benzene 1-cyclohexyl-3- (2-phenylethyl)- 1-(2- pyridylmethyl) urea 21 [00082]![embedded image]()
338.8 1H NMR (300 MHz, DMSO-d6): δ = 9.08 (s, 1H), 8.55 (d, J = 4.2 Hz, 1H), 7.78 (dt, J = 6.8, 1.7 Hz, 1H), 7.41-7.25 (m, 4H), 7.05 (d, J = 8.4 Hz, 2H), 4.54 (s, 2H), 4.12- 3.98 (m, 1H), 2.55-2.48 (m, 2H), 1.74-1.64 (m, 2H), 1.61-1.49 (m, 3H), 1.48-1.19 (m, 4H), 1.18-0.98 (m, 4H) ppm N-(2- pyridyl- methyl) cyclohexan amine General method D1 using 1-ethyl-4- isocyanatobenzene 1-cyclohexyl-3- (4-ethylphenyl)- 1-(2- pyridylmethyl) urea 22 [00083]![embedded image]()
343.8 1H NMR (300 MHz, DMSO-d6): δ = 8.75 (s, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.34 (dd, J = 5.1, 1.2 Hz, 1H), 7.02-6.98 (m, 1H), 6.92 (dd, J = 3.5, 5.1 Hz, 1H), 4.69 (s, 2H), 4.54-4.35 (m, 1H), 1.86-1.71 (m, 2H), 1.70-1.40 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 1-(4- isocyanatophenyl) ethanone 3-(4- acetylphenyl)-1- cyclopentyl-1- (2- thienylmethyl) urea 23 [00084]![embedded image]()
315.7 1H NMR (300 MHz, DMSO-d6): δ = 7.38 (d, J = 4.7 Hz, 1H), 7.32 (t, J = 7.4 Hz, 2H), 7.14-7.01 (m, 3H), 6.98-6.88 (m, 2H), 4.30 (s, 2H), 4.08-3.96 (m, 1H), 3.01 (s, 3H), 1.61-1.46 (m, 2H), 1.45-1.18 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using phenyl isocyanate, method J using MeI and Cs.sub.2CO.sub.3 1-cyclopentyl-3- methyl-3- phenyl-1-(2- thienylmethyl) urea 24 [00085]![embedded image]()
315.7 1H NMR (300 MHz, DMSO-d6): δ = 8.28 (s, 1H), 7.43 (d, J = 7.7 Hz, 2H), 7.21 (t, J = 7.9 Hz, 2H), 6.91 (t, J = 6.4 Hz, 1H), 6.76 (d, J = 3.3 Hz, 1H), 6.58 (dd, J = 3.3, 1.1 Hz, 1H), 4.57 (s, 2H), 4.48- 4.36 (m, 1H), 2.34 (s, 3H), 1.83- 1.69 (m, 2H), 1.68-1.41 (m, 6H) ppm 5- methylthio- phene-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-cyclopentyl-1- [(5-methyl-2- thienyl)methyl]- 3-phenyl-urea 25 [00086]![embedded image]()
343.8 1H NMR (300 MHz, DMSO-d6): δ = 8.19 (s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 3.34 Hz, 1H), 6.58 (dd, J = 3.3, 1.1 Hz, 1H), 4.55 (s, 2H), 4.47-4.34 (m, 1H), 2.56-2.48 (m, 2H), 2.34 (s, 3H), 1.80-1.68 (m, 2H), 1.67-1.41 (m, 6H), 1.13 (t, J = 7.6 Hz, 3H) ppm 5- methylthio- phene-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- ethyl-4- isocyanatobenzene 1-cyclopentyl)- (4-ethylphenyl- 1-[(5-methyl- thienyl)methyl] urea 26 [00087]![embedded image]()
343.8 1H NMR (300 MHz, DMSO-d6): δ = 7.29-7.22 (m, 2H), 7.20-7.12 (m, 3H), 6.65 (d, J = 3.7 Hz, 1H), 6.55 (dd, J = 3.1, 1.1 Hz, 1H), 6.30 (t, J = 5.4 Hz, 1H), 4.39 (s, 2H), 4.23-4.11 (m, 1H), 3.28-3.16 (m, 2H), 2.70 (t, J = 7.2 Hz, 2H), 2.35 (s, 3H), 1.74-1.52 (m, 4H), 1.51- 1.35 (m, 4H) ppm 5- methylthio- phene-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 2- isocyanatoethyl- benzene 1-cyclopentyl-1- [(5-methyl-2- thienyl)methyl]- 3-(2- phenylethyl)urea 27 [00088]![embedded image]()
351.7 1H NMR (300 MHz, DMSO-d6): δ = 8.54 (s, 1H), 7.66-7.56 (m, 1H), 7.34-7.18 (m, 2H), 6.76 (d, J = 3.3 Hz, 1H), 6.58 (dd, J = 3.3, 1.1 Hz, 1H), 4.56 (s, 2H), 4.44- 4.30 (m, 1H), 2.34 (s, 3H), 1.83- 1.69 (m, 2H), 1.68-1.42 (m, 6H) ppm 5- methylthio- phene-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1,2- difluoro-4- isocyanatobenzene 1-cyclopentyl-3- (3,4- difluorophenyl)- 1-[(5-methyl- thienyl)methyl] urea 28 [00089]![embedded image]()
285.7 1H NMR (300 MHz, DMSO-d6): δ = 8.22 (s, 1H), 7.55 (d, J = 0.9 Hz, 1H), 7.43 (d, J = 7.7 Hz, 2H), 7.21 (t, J = 7.7 Hz, 2H), 6.92 (t, J = 7.7 Hz, 1H), 6.39-6.34 (m, 1H), 6.23 (d, J = 3.0 Hz, 1H), 4.49 (s, 2H), 4.47-4.37 (m, 1H), 1.82-1.68 (m, 2H), 1.66-1.39 (m, 6H) ppm furan-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-cyclopentyl-1- (2-furylmethyl)- 3-phenyl-urea 29 [00090]![embedded image]()
313.8 1H NMR (300 MHz, DMSO-d6): δ = 7.51 (m, 1H), 7.31-7.22 (m, 2H), 7.21-7.13 (m, 3H), 6.36-6.28 (m, 2H), 6.11 (d, J = 3.1 Hz, 1H), 4.30 (s, 2H), 4.27-4.16 (m, 1H), 3.27-3.18 (m, 2H), 2.69 (t, J = 7.0 Hz, 2H), 1.72-1.50 (m, 4H), 1.49- 1.32 (m, 4H) ppm furan-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 2- isocyanatoethyl- benzene 1-cyclopentyl-1- (2-furylmethyl)- 3-(2- phenylethyl)urea 30 [00091]![embedded image]()
321.7 1H NMR (300 MHz, DMSO-d6): δ = 8.53 (s, 1H), 7.72-7.49 (m, 2H), 7.38-7.15 (m, 2H), 6.37 (bs, 1H), 6.22 (bs, 1H), 4.48 (bs, 2H), 4.44-4.30 (m, 1H), 1.85-1.38 (m, 8H) ppm furan-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1,2- difluoro-4- isocyanatobenzene 1-cyclopentyl-1- (3,4- difluorophenyl)- 1-(2- furylmethyl)urea 31 [00092]![embedded image]()
335.8 1H NMR (300 MHz, DMSO-d6): δ = 8.48 (s, 1H), 7.70-7.54 (m, 1H), 7.34-7.15 (m, 2H), 6.08 (d, J = 3.1 Hz, 1H), 5.95 (d, J = 2.1 Hz, 1H), 4.50-4.32 (m, 3H), 2.20 (s, 3H), 1.81-1.69 (m, 2H), 1.68-1.41 (m, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1,2- difluoro-4- isocyanatobenzene 1-cyclopentyl-3- (3,4- difluorophenyl)- 1-[(5-methyl-2- furyl)methyl] urea 32 [00093]![embedded image]()
310.7 1H NMR (300 MHz, DMSO-d6): δ = 9.22 (s, 1H), 8.57 (d, J = 4.9 Hz, 1H), 7.79 (dt, J = 7.8, 1.6 Hz, 1H), 7.45-7.36 (m, 3H), 7.32-7.18 (m, 3H), 6.92 (t, J = 7.1 Hz, 1H), 4.55 (s, 2H), 4.13-3.96 (m, 1H), 1.77-1.64 (m, 2H), 1.61-1.50 (m, 3H), 1.49-1.19 (m, 4H), 1.16-0.97 (m, 1H) ppm N-(2- pyridyl- methyl) cyclohexan amine General method D1 using phenyl isocyanate 1-cyclohexyl-3- phenyl-1-(2- pyridylmethyl) urea 33 [00094]![embedded image]()
346.7 1H NMR (300 MHz, DMSO-d6): δ = 9.30 (s, 1H), 8.55 (d, J = 4.2 Hz, 1H), 7.78 (dt, J = 7.7, 1.5 Hz, 1H), 7.67-54 (m, 1H), 7.40-7.33 (m, 1H), 7.32-7.22 (m, 2H), 7.20- 7.12 (m, 1H), 4.56 (s, 2H), 4.13- 3.97 (m, 1H), 1.75-1.62 (m, 2H), 1.61-1.49 (m, 3H), 1.48-1.18 (m, 4H), 1.15-0.96 (m, 1H) ppm N-(2- pyridyl- methyl) cyclohexan amine General method D1 using 1,2-difluoro-4- isocyanatobenzene 1-cyclohexyl-3- (3,4- difluorophenyl)- 1-(2- pyridylmethyl) urea 34 [00095]![embedded image]()
319.7 1H NMR (300 MHz, DMSO-d6): δ = 8.39 (s, 1H), 7.47-7.39 (m, 2H), 7.33 (dd, J = 5.2. 1.2 Hz, 1H), 7.05 (t, J = 8.8 Hz, 2H), 7.00-6.96 (m, 1H), 6.94-6.89 (m, 1H), 4.65 (s, 2H), 4.48-4.32 (m, 1H), 1.83- 1.69 (m, 2H), 1.68-1.41 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 4- fluorophenylisocyanate 1-cyclopentyl-3- (4- fluorophenyl)-1- (2- thienylmethyl) urea 35 [00096]![embedded image]()
302.7 1H NMR (300 MHz, DMSO-d6): δ = 8.65 (s, 1H), 7.71 (d, J = 4.0 Hz, 1H), 7.60 (d, J = 7.60 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.23 (t, J = 8.2 Hz, 2H), 6.98-6.90 (m, 1H), 4.74 (s, 2H), 4.58-4.43 (m, 1H), 1.88-1.72 (m, 2H), 1.71-1.60 (m, 2H), 1.59-1.41 (m, 4H), ppm thiazole-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-cyclopentyl-3- phenyl-1- (thiazol-2- ylmethyl)urea 36 [00097]![embedded image]()
330.7 1H NMR (300 MHz, DMSO-d6): δ = 8.52 (s, 1H), 7.70 (d, J = 3.2 Hz, 1H), 7.59 (d, J = 3.2 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 4.73 (s, 2H), 4.56- 4.40 (m, 1H), 2.58-2.48 (m, 2H), 1.86-1.70 (m, 2H), 1.69-1.85 (m, 2H), 1.57-1.41 (m, 4H), 1.13 (t, J = 7.6 Hz, 3H) ppm thiazole-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- ethyl-4- isocyanatobenzene l-cyclopentyl-3- (4-ethylphenyl)- 1-(thiazol-2- ylmethyl)urea 37 [00098]![embedded image]()
338.7 1H NMR (300 MHz, DMSO-d6): δ = 8.80 (s, 1H), 7.71 (d, J = 3.3 Hz, 1H), 7.66-7.54 (m, 2H), 7.36- 7.18 (m, 2H), 4.74 (s, 2H), 4.56- 4.38 (m, 1H), 1.86-1.72 (m, 2H), 1.71-1.59 (m, 2H), 1.58-1.48 (m, 4H) ppm thiazole-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1,2- difluoro-4- isocyanatobenzene 1-cyclopentyl-3- (3,4- difluorophenyl)- 1-(thiazol-2- ylmethyl)urea 38 [00099]![embedded image]()
329.8 1H NMR (300 MHz, DMSO-d6): δ = 8.44 (s, 1H), 7.47-7.40 (m, 3H), 7.36-7.16 (m, 5H), 6.96-6.89 (m, 1H), 4.65-4.52 (m, 1H), 4.50 (s, 2H), 1.87-1.70 (m, 2H), 1.68- 1.44 (m, 4H), 1.43-1.26 (m, 2H) ppm 2- chlorobenz- aldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-[(2- chlorophenyl) methyl]-1- cyclopentyl-3- phenyl-urea 39 [00100]![embedded image]()
357.8 1H NMR (300 MHz, DMSO-d6): δ = 8.36 (s, 1H), 7.42 (dd, J = 7.8, 1.6 Hz, 1H), 7.36-7.16 (m, 5H), 7.05 (d, J = 8.4 Hz, 2H), 4.65-4.52 (m, 1H), 4.50 (s, 2H), 2.57-2.51 (m, 2H), 1.88-1.69 (m, 2H), 1.67- 1.42 (m, 4H), 1.41-1.26 (m, 2H), 1.13 (t, J = 7.6 Hz, 3H) ppm 2- chlorobenz- aldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- ethyl-4- isocyanatobenzene 1-[(2- chlorophenyl) methyl]-1- cyclopentyl-3- (4- ethylphenyl)urea 40 [00101]![embedded image]()
365.7 1H NMR (300 MHz, DMSO-d6): δ = 8.65 (s, 1H), 7.61 (ddd, J = 13.9, 7.6, 2.0 Hz, 1H), 7.43 (dd, J = 7.6, 1.5 Hz, 1H), 7.36-7.14 (m, 5H), 4.61-4.46 (m, 3H), 1.85-1.71 (m, 2H), 1.67-1.27 (m, 6H) ppm 2- chlorobenz- aldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1,2- difluoro-4- isocyanatobenzene 1-[(2- chlorophenyl) methyl]-1- cyclopentyl-3- (3,4- difluorophenyl) urea 41 [00102]![embedded image]()
333.7 1H NMR (300 MHz, DMSO-d6): δ = 8.33 (s, 1H), 7.21 (t, J = 7.4 Hz, 2H), 7.37 (s, 1H), 7.26-7.16 (m, 2H), 6.92 (t, J = 7.4 Hz, 1H), 4.48- 4.30 (m, 1H), 4.24 (s, 2H), 3.74 (s, 3H), 1.86-1.70 (m, 2H), 1.69- 1.50 (m, 2H), 1.49-1.23 (m, 4H) ppm 5-chloro-1- methyl- pyrazole-4- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-[(5-chloro-1- methyl-pyrazol- 4-yl)methyl]-1- cyclopentyl-3- phenyl-urea 42 [00103]![embedded image]()
361.8 1H NMR (300 MHz, DMSO-d6): δ = 8.25 (s, 1H), 7.26-7.41 (m, 3H), 7.05 (d, J = 8.4 Hz, 3H), 4.47- 4.29 (m, 1H), 4.23 (s, 2H), 3.74 (s, 3H), 2.52-2.48 (m, 2H), 1.82- 1.69 (m, 2H), 1.68-1.50 (m, 2H), 1.67-1.24 (m, 4H), 1.13 (t, J = 7.6 Hz, 3H) ppm 5-chloro-1- methyl- pyrazole-4- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- ethyl-4- isocyanatobenzene 1-[(5-chloro-1- methyl-pyrazol- 4-yl)methyl]-1- cyclopentyl-3- (4- ethylphenyl)urea 43 [00104]![embedded image]()
369.7 1H NMR (300 MHz, DMSO-d6): δ = 8.56 (s, 1H), 7.69-7.50 (m, 1H), 7.37 (s, 1H), 7.35-7.11 (m, 2H), 4.44-4.27 (m, 1H), 4.23 (s, 2H), 3.74 (s, 3H), 1.86-1.70 (m, 2H), 1.69-1.55 (m, 2H), 1.55-1.39 (m, 4H) ppm 5-chloro-1- methyl- pyrazole-4- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1,2- difluoro-4- isocyanatobenzene 1-[(5-chloro-1- methyl-pyrazol- 4-yl)methyl]-1- cyclopentyl-3- (3,4- difluorophenyl) urea 44 [00105]![embedded image]()
351.7 1H NMR (300 MHz, DMSO-d6): δ = 8.39 (s, 1H), 7.49-7.38 (m, 2H), 7.37 (s, 1H), 7.05 (t, J = 9.0 Hz, 2H), 4.40-4.34 (m, 1H), 4.23 (s, 2H), 3.74 (s, 3H), 1.76 (m, 2H), 1.64 (m, 2H), 1.56-1.38 (m, 4H) ppm 5-chloro-1- methyl- pyrazole-4- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- fluorophenyl- isocyanate 1-[(5-chloro-1- methyl-pyrazol- 4-yl)methyl]-1- cyclopentyl-3- (4- fluorophenyl) urea 45 [00106]![embedded image]()
339.8 1H NMR (300 MHz, DMSO-d6): δ = 8.16 (s, 1H), 7.39 (d, J = 7.5 Hz, 2H), 7.19 (t, J = 7.7 Hz, 2H), 6.98-7.05 (m, 2H), 6.77-6.96 (m, 2H), 4.45-4.58 (m, 1H), 4.43 (s, 2H), 3.73 (s, 3H), 2.10 (s, 3H), 1.64-1.80 (m, 2H), 1.53-1.66 (m, 2H), 1.37-1.53 (m, 4H) ppm 4-methoxy- 3-methyl- benzaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-cyclopentyl-1- [(4-methoxy-3- methyl- phenyl)methyl]- 3-phenyl-urea 46 [00107]![embedded image]()
367.8 1H NMR (300 MHz, DMSO-d6): δ = 7.29-7.05 (m, 5H), 6.95-6.88 (m, 2H), 6.85-6.78 (m, 1H), 6.12 (t, J = 5.7 Hz, 1H), 4.40-4.26 (m, 1H), 4.24 (s, 2H), 3.74 (s, 3H), 3.28-3.15 (m, 2H), 2.67 (m, 2H), 2.10 (s, 3H), 1.70-1.47 (m, 4H), 1.49-1.22 (m, 4H) ppm 4-methoxy- 3-methyl- benzaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- ethyl-4- isocyanatobenzene 1-cyclopentyl-1- [(4-methoxy-3- methyl- phenyl)methyl]- 3-(2- phenylethyl)urea 47 [00108]![embedded image]()
375.8 1H NMR (300 MHz, DMSO-d6): δ = 8.44 (s, 1H), 7.71-7.52 (m, 1H), 7.33-7.12 (m, 2H), 7.03-6.94 (m, 2H), 6.88-6.81 (m, 1H), 4.53- 4.37 (m, 3H), 3.73 (s, 3H), 2.10 (s, 3H), 1.79-1.66 (m, 2H), 1.65- 1.54 (m, 2H), 1.54-1.35 (m, 4H) ppm 4-methoxy- 3-methyl- benzaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1,2- difluoro-4- isocyanatobenzene 1-cyclopentyl-3- (3,4- difluorophenyl)- 1-[(4-methoxy- 3-methyl- phenyl)methyl] urea 48 [00109]![embedded image]()
357.8 1H NMR (300 MHz, DMSO-d6): δ = 8.25 (s, 1H), 7.48-7.33 (m, 2H), 7.09-6.93 (m, 4H), 6.91-6.78 (m, 1H), 4.55-4.44 (m, 1H), 4.42 (s, 2H), 3.73 (s, 3H), 2.10 (s, 3H), 1.79-1.66 (m, 2H), 1.64-1.54 (m, 2H), 1.53-1.36 (m, 4H) ppm 4-methoxy- 3-methyl- benzaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- fluorophenyl- isocyanate 1-cyclopentyl-3- (4- fluorophenyl)-1- [(4-methoxy-3- methyl- phenyl)methyl] urea 49 [00110]![embedded image]()
332.7 1H NMR (300 MHz, DMSO-d6): δ = 8.39 (s, 1H), 7.43 (d, J = 7.7 Hz, 2H), 7.29-7.17 (t, J = 7.7 Hz, 2H), 7.09 (s, 1H), 6.99-6.86 (m, 1H), 4.47 (s, 2H), 4.43-4.27 (m, 1H), 3.93 (s, 3H), 1.84-1.41 (m, 8H) ppm 5- methoxy- thiazole-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-cyclopentyl-1- [(2- methoxythiazol- 5-yl)methyl]- phenyl-urea 50 [00111]![embedded image]()
338.7 1H NMR (300 MHz, DMSO-d6): δ = 8.39 (s, 1H), 7.78-7.67 (m, 1H), 7.68-7.54 (m, 1H), 7.54-7.38 (m, 3H), 7.21 (t, J = 7.4 Hz, 2H), 7.01-6.83 (m, 1H), 4.51-4.45 (m, 3H), 1.87-1.69 (m, 2H), 1.69-1.51 (m, 2H), 1.55-1.30 (m, 4H) ppm 2-fluoro-5- formyl- benzonitrile General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-[(3-cyano-4- fluoro- phenyl)methyl]- 1-cyclopentyl-3- phenyl-urea 51 [00112]![embedded image]()
366.8 1H NMR (300 MHz, DMSO-d6): δ = 7.60 (dd, J = 1.9, 6.1 Hz, 1H), 7.55-7.49 (m, 1H), 7.48-7.39 (m, 1H), 7.28-7.21 (m, 2H), 7.21-7.09 (m, 2H), 6.50-6.38 (m, 1H), 4.35 (s, 2H), 4.32-4.17 (m, 1H), 3.30- 3.19 (m, 2H), 2.76-2.64 (m, 2H), 1.71-1.49 (m, 4H), 1.50-1.36 (m, 2H), 1.34-1.17 (m, 2H) ppm 2-fluoro-5- formyl- benzonitrile General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 2- isocyanatoethyl- benzene 1-[(3-cyano-4- fluoro- phenyl)methyl]- 1-cyclopentyl-3- (2- phenylethyl)urea 52 [00113]![embedded image]()
374.7 1H NMR (300 MHz, DMSO-d6): δ = 8.61 (s, 1H), 7.72 (d, J = 6.3 Hz, 1H), 7.68-7.53 (m, 2H), 7.52- 7.43 (m, 1H), 7.36-7.15 (m, 2H), 4.51 (s, 2H), 4.49-4.35 (m, 1H), 1.84-1.69 (m, 2H), 1.69-1.57 (m, 2H), 1.56-1.27 (m, 4H) ppm 2-fluoro-5- formyl- benzonitrile General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1,2- difluoro-4- isocyanatobenzene 1-[(3-cyano-4- fluoro- phenyl)methyl]- 1-cyclopentyl-3- (3,4- difluorophenyl) urea 53 [00114]![embedded image]()
356.7 1H NMR (300 MHz, DMSO-d6): δ = 8.44 (s, 1H), 7.80-7.67 (m, 1H), 7.67-7.55 (m, 1H), 7.54-7.35 (m, 3H), 7.12-6.97 (m, 2H), 4.50 (s, 2H), 4.50-4.36 (m, 1H), 1.87- 1.69 (m, 2H), 1.69-1.56 (m, 2H), 1.56-1.29 (m, 4H) ppm 2-fluoro-5- formyl- benzonitrile General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- fluorophenyl- isocyanate 1-[(3-cyano-4- fluoro- phenyl)methyl]- 1-cyclopentyl-3- (4- fluorophenyl) urea 54 [00115]![embedded image]()
319.7 1H NMR (300 MHz, DMSO-d6): δ = 8.01 (s, 1H), 7.53-7.48 (m, 1H), 7.37 (dd, J = 5.1, 1.2 Hz, 1H), 7.21-7.04 (m, 3H),7.04-6.88 (m, 2H), 4.65 (s, 2H), 4.48-4.34 (m, 1H), 1.83-1.72 (m, 2H), 1.69-1.38 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 2- fluorophenylisocyanate 1-cyclopentyl-3- (2- fluorophenyl)-1- (2- thienylmethyl) urea 55 [00116]![embedded image]()
319.6 1H NMR (300 MHz, DMSO-d6): δ = 8.56 (s, 1H), 7.51-7.37 (m, 1H), 7.34 (dd, J = 5.1, 1.2 Hz, 1H), 7.28-7.16 (m, 2H), 7.01-6.96 (m, 1H), 6.92 (dd, J = 5.1, 3.5 Hz, 1H), 6.81-6.66 (m, 1H), 4.66 (s, 2H), 4.51-4.31 (m, 1H), 1.84-1.70 (m, 2H), 1.69-1.42 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 3- fluorophenylisocyanate 1-cyclopentyl-3- (3- fluorophenyl)-1- (2- thienylmethyl) urea 56 [00117]![embedded image]()
335.6 1H NMR (300 MHz, DMSO-d6): δ = 8.49 (s, 1H), 7.52-7.41 (m, 2H), 7.33 (dd, J = 5.1, 1.2 Hz, 1H), 7.30-7.19 (m, 2H), 6.99-6.96 (m, 1H), 6.92 (dd, J = 5.1, 3.5 Hz, 1H), 4.65 (s, 2H), 4.49-4.43 (m, 1H), 1.82-1.68 (m, 2H), 1.69-1.39 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 2- chlorophenylisocyanate 3-(4- chlorophenyl)-1- cyclopentyl-1- (2- thienylmethyl) urea 57 [00118]![embedded image]()
302.7 1H NMR (300 MHz, DMSO-d6): δ = 8.64-8.57 (m, 1H), 8.14 (dd, J = 4.8, 1.4 Hz, 1H), 7.89-7.83 (m, 1H), 7.34 (dd, J = 5.1, 1.2 Hz, 1H), 7.26-7.21 (m, 1H), 7.02-6.97 (m, 1H), 6.95-6.89 (m, 1H), 4.68 (s, 1H), 4.51-4.35 (m, 1H), 1.84-1.72 (m, 2H), 1.70-1.42 (m, 2H), 1.69- 1.39 (m, 6H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D2 using 3- aminopyridine 1-cyclopentyl-1- (3-pyridyl)-1- thienylmethyl- urea 58 [00119]![embedded image]()
287.6 1H NMR (300 MHz, DMSO-d6): δ = 8.60 (s, 1H), 7.55-7.35 (m, 3H), 7.28-7.12 (m, 2H), 6.74 (dd, J = 5.4, 1.1 Hz, 1H), 6.73-6.62 (m, 1H), 6.51 (dd, J = 3.7, 1.5 Hz, 1H), 4.69-4.54 (m, 1H), 1.88-1.70 (m, 2H), 1.53-1.34 (m, 4H), 1.31-1.14 (m, 2H) ppm N- cyclopentyl- aniline General method D1 using 2-thienyl isocyanate 1-cyclopentyl-1- phenyl-3-(2- thienyl)urea 59 [00120]![embedded image]()
369.6 1H NMR (400 MHz, DMSO-d6): δ = 8.66 (s, 1H), 7.83-7.82 (m, 1H), 7.49-7.44 (m, 2H), 7.34 (dd, J = 3.6, 1.0 Hz, 1H), 7.00-6.96 (m, 1H), 6.92 (dd, J = 5.1, 3.6 Hz, 1H), 4.66 (s, 2H), 4.44-4.34 (m, 1H), 1.83-1.70 (m, 2H), 1.69-1.61 (m, 2H), 1.60-1.45 (m, 4H) ppm N-(2- thienyl- methyl)- cyclopentan- amine General method D1 using 2,4-dichloro-1- isocyanatobenzene 1-cyclopentyl-3- (2,4- dichlorophenyl)- 1-(2- thienylmethyl) urea 60 [00121]![embedded image]()
310.6 1H NMR (400 MHz, DMSO-d6): δ = 8.41 (s, 1H), 7.52 (d, J = 3.6 Hz, 1H), 7.44-7.40 (m, 2H), 7.24- 7.18 (m, 2H), 6.95-6.91 (m, 1H), 6.49 (d, J = 3.7 Hz, 1H), 4.54 (s, 2H), 4.51-4.42 (m, 1H), 1.86-1.73 (m, 2H), 1.71-1.58 (m, 2H), 1.56- 1.41 (m, 4H) ppm 5- formylfuran- 2-carbonitrile General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-[(5-cyano-2- furyl)methyl] cyclopentyl- phenyl-urea 61 [00122]![embedded image]()
328.6 1H NMR (400 MHz, DMSO-d6): δ = 8.46 (s, 1H), 7.51 (d, J = 3.7 Hz, 1H), 7.44-7.39 (m, 2H), 7.05 (t, J = 8.9 Hz, 2H), 6.49 (d, J = 3.7 Hz, 1H), 4.53 (s, 2H), 4.49-4.39 (m, 1H), 1.86-1.73 (m, 2H), 1.71- 1.57 (m, 2H), 1.56-1.40 (m, 4H) ppm 5- formylfuran- 2-carbonitrile General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- fluorophenyl- isocyanate 1-[(5-cyano-2- furyl)methyl]-1- cyclopentyl-3- (4- fluorophenyl) urea 62 [00123]![embedded image]()
304.6 1H NMR (400 MHz, DMSO-d6): δ = 8.79 (d, J = 1.6 Hz, 1H), 8.46 (s, 1H), 7.46-7.41 (m, 2H), 7.09- 7.02 (m, 2H), 6.41 (d, J = 1.6 Hz, 1H), 4.54 (s, 2H), 4.48-4.39 (m, 1H), 1.83-1.71 (m, 2H), 1.68-1.58 (m, 2H), 1.55-1.43 (m, 4H) ppm isoxazole-4- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- fluorophenyl- isocyanate 1-cyclopentyl-3 (4- fluorophenyl)-1- (isoxazol-4- ylmethyl)urea 63 [00124]![embedded image]()
320.6 1H NMR (400 MHz, DMSO-d6): δ = 8.79 (d, J = 1.6 Hz, 1H), 8.54 (s, 1H), 7.48 (d, J = 9.0 Hz, 2H), 7.27 (d, J = 9.0 Hz, 2H), 6.41 (d, J = 1.6 Hz, 1H), 4.55 (s, 2H), 4.49- 4.39 (m, 1H), 1.84-1.71 (m, 2H), 1.69-1.57 (m, 2H), 1.56-1.43 (m, 4H) ppm isoxazole-4- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- chlorophenyl- isocyanate 3-(4- chlorophenyl)-1- cyclopentyl- (isoxazol-4- ylmethyl)urea 64 [00125]![embedded image]()
285.6 1H NMR (400 MHz, DMSO-d6): δ = 8.19 (s, 1H), 7.55 (t, J = 1.4 Hz, 1H), 7.53-7.51 (m, 1H), 7.44-7.40 (m, 2H), 7.23-7.17 (m, 2H), 6.96- 6.88 (m, 1H), 6.39 (dd, J = 1.7, 0.9 Hz, 1H), 4.49-4.38 (m, 1H), 4.31 (s, 2H), 1.81-1.70 (m, 2H), 1.67- 1.59 (m, 2H), 1.57-1.43 (m, 4H) ppm furane-3- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-cyclopentyl-1- (3-furylmethyl)- 3-phenyl-urea 65 [00126]![embedded image]()
296.7 1H NMR (300 MHz, DMSO-d6): δ = 8.46 (d, J = 1.6 Hz, 1H), 8.40 (dd, J = 4.5, 1.8 Hz, 1H), 8.38 (s, 1H), 7.63-7.58 (m, 1H), 7.45-7.39 (m, 2H), 7.35-7.29 (m, 1H), 7.24- 7.16 (m, 2H), 6.95-6.88 (m, 1H), 4.59-4.46 (m, 3H), 1.84-1.70 (m, 2H), 1.69-1.56 (m, 2H), 1.55- 1.36 (m, 4H) ppm pyridine-3- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-cyclopentyl-3- phenyl-1-(3- pyridylmethyl) urea 66 [00127]![embedded image]()
330.6 1H NMR (300 MHz, DMSO-d6): δ = 8.52 (s, 1H), 8.47-8.43 (m, 1H), 8.40 (dd, J = 4.9, 1.6 Hz, 1H), 7.62-7.57 (m, 1H), 7.49-7.42 (m, 2H), 7.37-7.29 (m, 1H), 7.28-7.20 (m, 2H), 4.57-4.43 (m, 3H), 1.84- 1.69 (m, 2H), 1.68-1.55 (m, 2H), 1.54-1.35 (m, 4H) ppm pyridine-3- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- chlorophenyl- isocyanate 3-(4- chlorophenyl)-1- cyclopentyl-1- (3- pyridylmethyl) urea 67 [00128]![embedded image]()
296.7 1H NMR (300 MHz, DMSO-d6): δ = 9.01 (s, 1H), 8.58-8.52 (m, 1H), 7.78 (td, J = 7.6, 2.2 Hz, 1H), 7.46-7.39 (m, 2H), 7.36-7.16 (m, 4H), 6.95-6.87 (m, 1H), 4.60-4.46 (m, 3H), 1.80-1.55 (m, 4H), 1.54- 1.37 (m, 4H) ppm pyridine-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-cyclopentyl-3- phenyl-1-(2- pyridylmethyl) urea 68 [00129]![embedded image]()
314.6 1H NMR (300 MHz, DMSO-d6): δ = 8.96 (s, 1H), 8.57-8.51 (m, 1H), 7.77 (td, J = 7.7, 1.8 Hz, 1H), 7.47-7.37 (m, 2H), 7.35-7.23 (m, 2H), 7.11-6.99 (m, 2H), 4.60-4.44 (m, 3H), 1.79-1.55 (m, 4H), 1.54- 1.37 (m, 4H) ppm pyridine-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- flurophenyl- isocyanate 1-cyclopentyl- (4- fluorophenyl)- (2- pyridylmethyl) urea 69 [00130]![embedded image]()
330.6 1H NMR (300 MHz, DMSO-d6): δ = 9.09 (s, 1H), 8.57-8.51 (m, 1H), 7.77 (td, J = 7.7, 1.8 Hz, 1H), 7.51-7.43 (m, 2H), 7.35-7.22 (m, 4H), 4.58-4.44 (m, 3H), 1.80-1.55 (m, 4H), 1.54-1.37 (m, 4H) ppm pyridine-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- chlorophenyl- isocyanate 3-(4- chlorophenyl)-1- cyclopentyl-1- (2- pyridylmethyl) urea 70 [00131]![embedded image]()
315.6 1H NMR (300 MHz, DMSO-d6): δ = 8.60-8.55 (m, 3H), 8.49 (d, J = 2.4 Hz, 1H), 7.46-7.37 (m, 2H), 7.04 (t, J = 8.8 Hz, 2H), 4.60 (s, 2H), 4.57-4.43 (m, 1H), 1.87-1.70 (m, 2H), 1.69-1.56 (m, 2H), 1.55- 1.37 (m, 4H) ppm pyridine-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- fluorophenyl- isocyanate 1-cyclopentyl-3- (4- fluorophenyl)-1- (pyrazin-2- ylmethyl)urea 71 [00132]![embedded image]()
331.6 1H NMR (300 MHz, DMSO-d6): δ = 8.67 (s, 1H), 8.59-8.55 (m, 2H), 8.50 (d, J = 2.5 Hz, 1H), 7.46 (d, J = 8.9 Hz, 2H), 7.25 (d, J = 8.9 Hz, 2H), 4.60 (s, 2H), 4.59-4.45 (m, 1H), 1.87-1.68 (m, 2H), 1.67- 1.56 (m, 2H), 1.55-1.38 (m, 4H) ppm pyridine-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- chlorophenyl- isocyanate 3-(4- chlorophenyl)-1- cyclopentyl- (pyrazin-2- ylmethyl)urea 72 [00133]![embedded image]()
315.6 1H NMR (300 MHz, DMSO-d6): δ = 8.77 (d, J = 4.9 Hz, 2H), 8.62 (s, 1H), 7.45-7.35 (m, 3H), 7.07-6.98 (m, 2H), 4.64 (s, 2H), 4.61-4.46 (m, 1H), 1.82-1.66 (m, 2H), 1.66- 1.54 (m, 2H), 1.53-1.35 (m, 4H) ppm pyridine-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- fluorophenyl- isocyanate 1-cyclopentyl-3- (4- fluorophenyl)-1- (pyrimidin-2- ylmethyl)urea 73 [00134]![embedded image]()
331.6 1H NMR (300 MHz, DMSO-d6): δ = 8.77 (d, J = 4.9 Hz, 2H), 8.71 (s, 1H), 7.45 (d, J = 8.9 Hz, 2H), 7.38 (t, J = 1.8 Hz, 1H), 7.23 (d, J = 8.9 Hz, 2H), 4.65 (s, 2H), 4.61-4.48 (m, 1H), 1.83-1.67 (m, 2H), 1.65- 1.34 (m, 6H) ppm pyridine-2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- chlorophenyl- isocyanate 3-(4- chlorophenyl)-1- cyclopentyl-1- (pyrimidin-2- ylmethyl)urea 74 [00135]![embedded image]()
296.7 1H NMR (300 MHz, DMSO-d6): δ = 8.49-8.44 (m, 2H), 8.38 (s, 1H), 7.46-7.38 (m, 2H), 7.25-7.15 (m, 4H), 6.96-6.88 (m, 1H), 4.63- 4.49 (m, 3H), 1.84-1.69 (m, 2H), 1.68-1.55 (m, 2H), 1.54-1.27 (m, 4H) ppm pyridine-4- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-cyclopentyl-1- phenyl-1-(4- pyridylmethyl) urea 75 [00136]![embedded image]()
314.6 1H NMR (300 MHz, DMSO-d6): δ = 8.49-8.44 (m, 2H), 8.43 (s, 1H), 7.42 (dd, J = 9.2, 5.1 Hz, 2H), 7.25-7.18 (m, 2H), 7.04 (t, J = 8.9 Hz, 2H), 4.61-4.46 (m, 3H), 1.86- 1.67 (m, 2H), 1.66-1.54 (m, 2H), 1.53-1.25 (m, 4H) ppm pyridine-4- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- fluorophenyl- isocyanate 1-cyclopentyl-1- (4- fluorophenyl)-1- (4- pyridylmethyl) urea 76 [00137]![embedded image]()
330.6 1H NMR (300 MHz, DMSO-d6): δ = 8.52 (s, 1H), 8.49-8.44 (m, 2H), 7.50-7.43 (m, 2H), 7.29-7.18 (m, 4H), 4.62-4.45 (m, 3H), 1.88- 1.68 (m, 2H), 1.56-1.54 (m, 2H), 1.53-1.29 (m, 4H) ppm pyridine-4- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- chlorophenyl- isocyanate 3-(4- chlorophenyl)-1- cyclopentyl-1- (4- pyridylmethyl) urea 77 [00138]![embedded image]()
416.8 1H NMR (500 MHz, DMSO-d6): δ = 8.22 (s, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.21 (t, J = 4.4, 2H), 6.91 (t, J = 4.3 Hz, 1H), 3.90-3.76 (m, 1H), 3.72-3.57 (m, 2H), 3.21 (s, 2H), 3.06-2.58 (m, 2H), 1.84-1.65 (m, 6H), 1.51-1.39 (m, 4H), 1.37 (s, 9H), 1.30-1.19 (m, 2H), 0.95 (s, 3H) ppm tert-butyl 4- formyl-4- methyl- piperidine-1- carboxylate General method A using cyclopentanamine and NaBH.sub.4, method D1 using phenyl isocyanate tert-butyl 4- [[cyclopentyl (phenylcarbamoyl) amino]methyl]-4- methyl- piperidine-1- carboxylate 78 [00139]![embedded image]()
434.8 1H NMR (500 MHz, DMSO-d6): δ = 8.25 (s, 1H), 7.43-7.36 (m, 2H), 7.05 (t, J = 5.6 Hz, 2H), 3.86- 3.76 (m, 1H), 3.69-3.58 (m, 2H), 3.36-3.42 (m, 1H), 3.20 (s, 2H), 3.05-2.86 (bs, 2H), 1.82-1.65 (m, 6H), 1.49-1.39 (m, 4H), 1.37 (s, 9H), 1.28-1.20 (m, 2H), 0.95 (s, 3H) ppm tert-butyl 4- formyl-4- methyl- piperidine-1- carboxylate General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- fluorophenyl- isocyanate tert-butyl 4- [[cyclopentyl- (phenylcarbamoyl) amino]methyl]-4- methyl- piperidine-1- carboxylate 79 [00140]![embedded image]()
450.7 1H NMR (500 MHz, DMSO-d6): δ = 8.35 (s, 1H), 7.44 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H), 3.85-3.76 (m, 1H), 3.70-3.57 (m, 2H), 3.21 (s, 2H), 3.08-2.85 (bs, 1H), 1.83-1.66 (m, 6H), 1.50-1.40 (m, 4H), 1.39 (s, 9H), 1.28-1.19 (m, 2H), 0.94 (s, 3H) ppm tert-butyl 4- formyl-4- methyl- piperidine-1- carboxylate General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- chlorophenyl- isocyanate tert-butyl 4-[[(4- chlorophenyl) carbamoyl- cyclopentyl- amino]methyl]- 4-methyl- piperidine-1- carboxylate 80 [00141]![embedded image]()
324.6 1H NMR (300 MHz, DMSO-d6): δ = 8.76 (s, 1H), 7.65 (s, 4H), 6.08 (d, J = 3.0 Hz, 1H), 5.97-5.93 (m, 1H), 4.50-4.36 (m, 3H), 2.19 (s, 3H), 1.84-1.70 (m, 2H), 1.69-1.40 (m, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- isocyanato- benzonitrile 3-(4- cyanophenyl)- cyclopentyl- [(5-methyl-2- furyl)methyl] urea 81 [00142]![embedded image]()
300.1 1H NMR (300 MHz, DMSO-d6): δ = 8.70 (s, 1H), 8.30-8.25 (m, 2H), 7.48-7.42 (m, 2H), 6.08 (d, J = 3.1 Hz, 1H), 5.96-5.90 (m, 1H), 4.48-4.36 (m, 3H), 2.19 (s, 3H), 1.85-1.71 (m, 2H), 1.70-1.40 (m, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- isocyanato- pyridine 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- (4-pyridyl)urea 82 [00143]![embedded image]()
303 1H NMR (300 MHz, DMSO-d6): δ = 8.27 (s, 1H), 7.57-7.28 (m, 2H), 7.05 (t, J = 8.5 Hz, 2H), 6.06 (s, 1H), 5.96 (s, 1H), 4.51 (s, 2H), 4.46-4.24 (m, 1H), 2.20 (s, 3H), 2.17-1.99 (m, 4H), 1.69-1.37 (m, 2H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclobutanamine, AcOH and NaBH.sub.4, method D1 using 4- fluorophenyl- isocyanate 1-cyclobutyl-3- (4- fluorophenyl)-1- [(5-methyl-2- furyl)methyl]urea 83 [00144]![embedded image]()
319.6 1H NMR (300 MHz, DMSO-d6): δ = 8.37 (s, 1H), 7.47 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H), 6.06 (d, J = 3.0 Hz, 1H), 5.98-5.92 (m, 1H), 4.51 (s,2H), 4.45-4.31 (m, 1H), 2.20 (s, 3H), 2.16-1.99 (m, 4H), 1.68-1.42 (m, 2H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclobutanamine, AcOH and NaBH.sub.4, method D1 using 4- chlorophenyl- isocyanate 3-(4- chlorophenyl)-1- cyclobutyl-1- methyl-2- furyl)methyl]urea 84 [00145]![embedded image]()
310.6 1H NMR (300 MHz, DMSO-d6): δ = 8.74 (s, 1H), 7.70-7.61 (m, 4H), 6.07 (d, J = 3.1 Hz, 1H), 5.97- 5.93 (m, 1H), 4.53 (s, 2H), 4.45- 4.29 (m, 1H), 2.19 (s, 3H), 2.17- 2.01 (m, 4H), 1.68-1.46 (m, 2H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclobutanamine, AcOH and NaBH.sub.4, method D1 using 4- isocyanato- benzonitrile 3-(4- cyanophenyl)-1- cyclobutyl-1-[(5- methyl-2- furyl)methyl]urea 85 [00146]![embedded image]()
316.1 1H NMR (500 MHz, DMSO-d6): δ = 8.16 (s, 1H), 7.40 (d, J = 7.7 Hz, 2H), 7.20 (t, J = 7.7 Hz, 2H), 6.90 (t, J = 4.4 Hz, 1H), 3.86-3.75 (m, 1H), 3.19 (s, 2H), 2.73-2.66 (m, 2H), 2.65-2.56 (m, 2H), 1.88- 1.65 (m, 6H), 1.51-1.35 (m, 4H), 1.27-1.13 (m, 3H), 0.92 (s, 3H) ppm tert-butyl 4- formyl-4- methyl- piperidine-1- carboxylate General method A using cyclopentanamine and NaBH.sub.4, method D1 using phenyl isocyanate, method G using TFA 1-cyclopentyl-1- [(4-methyl-4- piperidyl)methyl]- 3-phenyl-urea 86 [00147]![embedded image]()
334 1H NMR (500 MHz, DMSO-d6): δ = 8.19 (s, 1H), 7.40 (dd, J = 9.0, 4.9 Hz, 2H), 7.04 (t, J = 9.0 Hz, 2H), 3.82-3.72 (m, 1H), 3.17 (s, 2H), 2.73-2.64 (m, 2H), 2.63-2.55 (m, 2H), 1.87-1.64 (m, 6H), 1.50- 1.34 (m, 4H), 1.24-1.14 (m, 2H), 0.92 (s, 3H) ppm tert-butyl 4- formyl-4- methyl- piperidine-1- carboxylate General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- fluorophenyl- isocyanate, method G using TFA 1-cyclopentyl-3- (4- fluorophenyl)- [(4-methyl-4- piperidyl)methyl] urea 87 [00148]![embedded image]()
350 1H NMR (500 MHz, DMSO-d6): δ = 8.30 (s, 1H), 7.44 (d, J = 8.9 Hz, 2H), 7.25 (d, J = 8.9 Hz, 2H), 3.83-3.70 (m, 1H), 3.19 (s, 2H), 2.73-2.65 (m, 2H), 2.64-2.55 (m, 2H), 1.88-1.63 (m, 6H), 1.50-1.34 (m, 4H), 1.26-1.14 (m, 2H), 0.91 (s, 3H) ppm tert-butyl 4- formyl-4- methyl- piperidine-1- carboxylate General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- chlorophenyl- isocyanate, method G using TFA 3-(4- chlorophenyl)-1- cyclopentyl-1- [(4-methyl-4- piperidyl)methyl] urea 88 [00149]![embedded image]()
364.2 1H NMR (300 MHz, DMSO-d6): δ = 8.84 (s, 1H), 8.31-8.26 (m, 2H), 7.62-7.49 (m, 4H), 7.48-43 (m, 2H), 4.63 (s, 2H), 4.59-4.47 (m, 1H), 1.85-1.69 (m, 2H), 1.68- 1.55 (m, 2H), 1.54-1.37 (m, 4H) ppm 3- (trifluoro- methyl) benzaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- isocyanatopyridine 1-cyclopentyl-3- (4-pyridyl)-1- [[3- (trifluoromethyl) phenyl]methyl] urea 89 [00150]![embedded image]()
388.2 1H NMR (300 MHz, DMSO-d6): δ = 8.89 (s, 1H), 7.69-7.7.61 (m, 4H), 7.59-7.48 (m, 4H), 4.63 (s, 2H), 4.59-4.45 (m, 1H), 1.86-1.69 (m, 2H), 1.68-1.55 (m, 2H), 1.54- 1.38 (m, 4H) ppm 3- (trifluoro- methyl) benzaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- isocyanatobenzonitrile 3-(4- cyanophenyl)-1- cyclopentyl-1- [[3- (trifluoromethyl) phenyl]methyl] urea 90 [00151]![embedded image]()
383.1 1H NMR (300 MHz, DMSO-d6): δ = 8.47 (s, 1H), 7.62-7.42 (m, 6H), 7.30-7.23 (m, 2H), 4.73 (s, 2H), 4.65-4.49 (m, 1H), 2.16-1.91 (m, 4H), 1.62-1.40 (m, 2H) ppm 3- (trifluoro- methyl) benzaldehyde General method A using cyclobutanamine, AcOH and NaBH.sub.4, method D1 using 4- chlorophenyl- isocyanate 3-(4- chlorophenyl)- cyclobutyl-1-[[3- (trifluoromethyl) phenyl]methyl] urea 91 [00152]![embedded image]()
374 1H NMR (300 MHz, DMSO-d6): δ = 8.83 (s, 1H), 7.70-7.61 (m, 4H), 7.59-7.46 (m, 4H), 4.75 (s, 2H), 4.66-4.50 (m, 1H), 2.15-1.96 (m, 4H), 1.63-1.45 (m, 2H) ppm 3- (trifluoro- methyl) benzaldehyde General method A using cyclobutanamine, AcOH and NaBH.sub.4, method D1 using 4- isocyanato- benzonitrile 3-(4- cyanophenyl)-1- cyclobutyl-1-[[3- (trifluoromethyl) phenyl]methyl] urea 92 [00153]![embedded image]()
334.1 1H NMR (300 MHz, DMSO-d6): δ = 8.64 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 3.0 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 6.09 (d, J = 3.0 Hz, 1H), 5.97-5.92 (m, 1H), 4.49-4.30 (m, 3H), 2.20 (s, 3H), 1.83-1.70 (m, 2H), 1.69-1.43 (m, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D2 using 6- chloropyridin-3- amine 3-(6-chloro-3- pyridyl)-1- cyclopentyl-1- [(5-methyl-2- furyl)methyl]urea 93 [00154]![embedded image]()
324.1 1H NMR (300 MHz, DMSO-d6): δ = 8.63 (s, 1H), 7.93 (t, J = 1.7 Hz, 1H), 7.77-7.70 (m, 1H), 7.47-7.33 (m, 2H), 6.09 (d, J = 3.1 Hz, 1H), 5.99-5.92 (m, 1H), 4.51-4.32 (m, 3H), 2.21 (s, 3H), 1.86-1.70 (m, 2H), 1.69-1.39 (m, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 3- isocyanato- benzonitrile 3-(3- cyanophenyl)-1- cyclopentyl-1- [(5-methyl-2- furyl)methyl]urea 94 [00155]![embedded image]()
341.2 1H NMR (300 MHz, DMSO-d6): δ = 8.66 (s, 1H), 7.84 (d, J = 8.9 Hz, 2H), 7.59 (d, J = 8.9 Hz, 2H), 6.09 (d, J = 3.1 Hz, 1H), 5.98-5.93 (m, 1H), 4.54-4.34 (m, 3H), 2.20 (m, 3H), 1.83-1.71 (m, 2H), 1.70- 1.43 (m, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1-(4- isocyanatophenyl) ethanone 3-(4- acetylphenyl)-1- cyclopentyl-1- [(5-methyl-2- furyl)methyl]urea 95 [00156]![embedded image]()
324.1 1H NMR (300 MHz, DMSO-d6): δ = 8.57 (s, 1H), 7.71 (dd, J = 7.6, 1.3 Hz, 1H), 7.63-7.56 (m, 1H), 7.48-7.42 (m, 1H), 7.22 (dt, J = 7.6, 1.2 Hz, 1H), 6.16 (d, J = 3.0 Hz, 1H), 5.98-5.94 (m, 1H), 4.44 (s, 2H), 4.42-4.31 (m, 1H), 2.22 (s, 3H), 1.84-1.72 (m, 2H), 1.69-1.42 (m, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 2- isocyanato- benzonitrile 3-(2- cyanophenyl)-1- cyclopentyl- [(5-methyl-2- furyl)methyl]urea 96 [00157]![embedded image]()
338.1 1H NMR (300 MHz, DMSO-d6): δ = 7.80-7.72 (m, 2H), 7.42-7.34 (m, 2H), 6.99 (t, J = 6.0 Hz, 1H), 6.02 (d, J = 3.0 Hz, 1H), 5.97-5.93 (m, 1H), 4.36-4.22 (m, 5H), 2.21 (s, 3H), 1.77-1.54 (m, 4H), 1.53- 1.36 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D2 using 4- (aminomethyl) benzonitrile 3-[(4- cyanophenyl) methyl]-1- cyclopentyl-1- [(5-methyl-2- furyl)methyl]urea 97 [00158]![embedded image]()
358.2 1H NMR (300 MHz, DMSO-d6): δ = 8.24 (s, 1H), 7.42-7.34 (m, 2H), 7.20 (t, J = 8.0 Hz, 2H), 6.94- 6.87 (m, 1H), 3.99-3.77 (m, 2H), 3.64-3.50 (m, 1H), 3.26-3.11 (m, 3H), 2.94-2.78 (m, 1H), 1.94 (s, 3H), 1.84-1.62 (m, 6H), 1.52-1.19 (m, 6H), 0.96 (s, 3H) ppm tert-butyl 4- formyl-4- methyl- piperidine-1- carboxylate General method A using cyclopentanamine and NaBH.sub.4, method D1 using phenyl isocyanate, method G using TFA, method I using AcCl 1-[(1-acetyl-4- methyl-4- piperidyl)methyl]- 1-cyclopentyl- 3-phenyl-urea 98 [00159]![embedded image]()
379.1 1H NMR (500 MHz, CDCl3): δ = 7.69 (s, 1H), 7.54 (s, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 6.97 (bs, 1H), 6.23 (d, J = 2.5 Hz, 1H), 5.96 (d, J = 2.5 Hz, 1H), 4.73-4.66 (m, 1H), 4.34 (s, 2H), 3.93 (s, 3H), 2.33 (s, 3H), 1.97- 1.92 (m, 2H), 1.76-1.69 (m, 2H), 1.67-1.55 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- bromo-4- isocyanatobenzene, method E using 1- methyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)pyrazole, Pd(PPh.sub.3).sub.4 and K.sub.2CO.sub.3 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl] [4-(1- methylpyrazol- 4-yl)phenyl]urea 99 [00160]![embedded image]()
465.3 1H NMR (300 MHz, CDCl3): δ = 8.21 (s, 1H), 7.93 (s, 1H), 7.41 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 8.7 Hz, 2H), 7.01 (s, 1H), 6.18 (d, J = 3.1 Hz, 1H), 5.95 (s, 1H), 4.67 (m, 1H), 4.31 (s, 2H), 2.33 (s, 3H), 2.17-1.85 (m, 2H), 1.79-1.44 (m, 15H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- bromo-4- isocyanatobenzene, method E using tert- butyl 4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)pyrazole-1- carboxylate, Pd(PPh.sub.3).sub.4 and K.sub.2CO.sub.3 tert-butyl 4-[4- [[cyclopentyl- [(5-methyl-2- furyl)methyl] carbamoyl]amino] phenyl]pyrazole- 1-carboxylate 100 [00161]![embedded image]()
436.2 1H NMR (300 MHz, CDCl3): δ = 7.73 (s, 1H), 7.68 (s, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 6.96 (s, 1H), 6.20 (d, J = 2.9 Hz, 1H), 5.97 (d, J = 2.0 Hz, 1H), 4.69 (p, J = 8.4, 8.0 Hz, 1H), 4.34 (s, 2H), 4.30 (t, J = 6.4 Hz, 2H), 2.89 (bs, 2H), 2.31 (s, 3H), 2.30 (s, 3H), 2.92 (s, 3H), 1.96-1.87 (m, 2H), 1.74-1.62 (m, 2H), 1.62- 1.48 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- bromo-4- isocyanatobenzene, method E using N,N- dimethyl-2-[4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)pyrazole-1- yl]ethanamine, Pd(PPh.sub.3).sub.4 and K.sub.2CO.sub.3 1-cyclopentyl-3- [4-[1-[2- (dimethylamino) ethyl]pyrazol- yl]phenyl]-1-[(5- methyl-2- furyl)methyl]urea 101 [00162]![embedded image]()
437.2 1H NMR (400 MHz, CDCl3): δ = 7.70 (s, 1H), 7.67 (s, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 6.95 (s, 1H), 6.18, (d, J = 3.2 Hz, 1H), 5.95-5.92 (m, 1H), 4.71-4.64 (m, 1H), 4.31 (s, 2H), 3.8 (s,2H), 3.82-3.7 (bs, 1H), 2.31 (s, 3H), 1.94-1.88 (m, 2H), 1.76-1.66 (m, 2H), 1.65-1.52 (m, 10H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- bromo-4- isocyanatobenzene, method E using 2- methyl-2-[4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)pyrazole-1-yl]propan- 1-ol, Pd(PPh.sub.3).sub.4 and K.sub.2CO.sub.3 1-cyclopentyl-3- [4-[1-(2- hydroxy-1,1- dimethyl- ethyl)pyrazol-4- yl]phenyl]-1-[(5- methyl-2- furyl)methyl]urea 102 [00163]![embedded image]()
323.2 1H NMR (400 MHz, CDCl3): δ = 7.33 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 7.00 (bs, 1H), 6.11 (d, J = 2.6 Hz, 1H), 5.90 (dd, J = 2.6, 1.2 Hz, 1H), 4.64-4.56 (m, 1H), 4.25 (s, 2H), 2.94 (s, 1H), 2.26 (s, 3H), 1.89-1.83 (m, 2H), 1.66- 1.61 (m, 2H), 1.59-1.46 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D2 using 4- ethynylaniline 1-cyclopentyl-3- (4- ethynylphenyl)- 1-[(5-methyl- furyl)methyl]urea 103 [00164]![embedded image]()
382.2 1H NMR (400 MHz, CDCl3): δ = 7.42 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 6.88 (bs, 1H), 6.10 (d, J = 2.6 Hz, 1H), 5.86 (dd, J = 2.6, 1.2 Hz, 1H), 4.62-4.54 (m, 1H), 4.27 (s, 2H), 3.74 (t, J = 7.6 Hz, 2H), 2.50 (t, J = 7.6 Hz, 2H), 2.22 (s, 3H), 2.09-2.01 (m, 2H), 1.86- 1.80 (m, 2H), 1.63-1.59 (m, 2H), 1.55-1.43 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method S using 4- iodoaniline and 2- pyrrolidinone; method D2 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- [4-(2- oxopyrrolidin-1- yl)phenyl]urea 104 [00165]![embedded image]()
333.7 1H NMR (400 MHz, CDCl3): δ = 7.27-7.23 (m, 1H), 6.91-6.86 (m, 2H), 6.75-6.60 (m, 1H), 6.91- 6.86 (m, 1H), 6.27 (d, J = 3.2 Hz, 1H), 5.96-5.93 (m, 1H), 4.69- 4.60 (m, 1H), 4.29 (s, 2H), 2.30 (s, 3H), 1.96-1.86 (m, 2H), 1.75- 1,64 (m, 2H), 1.63-1.47 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4; method M using tert- butyl-chloro-dimethyl silane; method D2, method N using TBAFxH.sub.2O 1-cyclopentyl-3- (4-fluoro-3- hydroxy- phenyl)-1-[(5- methyl-2- furyl)methyl]urea 105 [00166]![embedded image]()
366.8 1H NMR (500 MHz, CDCl3): δ = 8.50 (s, 1H), 8.40 (s, 1H), 7.43- 7.36 (m, 4H), 6.99 (s, 1H), 6.09 (d, J = 2.0 Hz, 1H), 5.86 (d, J = 2.0 Hz, 1H), 4.61-4.54 (m, 1H) 4.23 (s, 2H), 2.22 (s, 3H), 1.90-1.78 (m, 2H), 1.68-1.56 (m, 2H), 1.55- 1.43 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- bromo-4- isocyanatobenzene, method E using 4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)isoxazole, Pd(PPh.sub.3).sub.4 and K.sub.2CO.sub.3 1-cyclopentyl-3- (4-isoxazol-4- ylphenyl)-1-[(5- methyl-2- furyl)methyl]urea 106 [00167]![embedded image]()
382.7 1H NMR (500 MHz, CDCl3): δ = 8.71 (s, 1H), 8.00 (s, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.10 (s, 1H), 6.23 (d, J = 2.0 Hz, 1H), 5.97 (d, J = 2.0 Hz, 1H), 4.73-4.66 (m, 1H), 4.34 (s, 2H), 2.34 (s, 3H), 1.97-1.89 (m, 2H), 1.79-1.68 (m, 2H), 1.67-1.55 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- bromo-4- isocyanatobenzene, method E using 4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)thiazole, Pd(PPh.sub.3).sub.4 and K.sub.2CO.sub.3 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- (4-thiazol-4- ylphenyl)urea 107 [00168]![embedded image]()
363.8 1H NMR (500 MHz, CDCl3): δ = 7.28 (d, J = 7.2 Hz, 2H), 7.24 (d, J = 7.2 Hz, 2H), 6.99 (s, 1H), 6.18 (d, J = 3.0 Hz, 1H), 5.96 (d, J = 3.0 Hz, 1H), 4.70-4.63 (m, 1H), 4.31 (s, 2H), 2.32 (s, 3H), 1.97-1.90 (m, 2H), 1.74-1.67 (m, 2H), 1.63- 1.53 (m, 4H), 1.46-1.41 (m, 1H), 0.89-0.82 (m, 2H), 0.80-0.77 (m, 2H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- iodo-4- isocyanatobenzene, method F using 4- ethynylcyclopropane, 1,3,2-dioxaborolan-2- Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA 1-cyclopentyl-3- [4-(2- cyclopropyl- ethynyl)phenyl]-1- [(5-methyl-2- furyl)methyl]urea 108 [00169]![embedded image]()
365.8 1H NMR (400 MHz, DMSO-d6): δ = 12.85-12.72 (bs, 1H), 8.23 (s, 1H), 8.02-7.88 (bs, 2H), 7.46- 7.40 (m, 4H), 6.12-6.08 (d, J = 3.6 Hz, 1H), 5.97-5.95 (m, 1H), 4.48-4.40 (m, 3H), 2.21 (s, 3H), 1.82-1.72 (m, 2H), 1.68-1.60 (m, 2H), 1.59-1.44 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- bromo-4- isocyanatobenzene, method E using 4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)-1H-pyrazole, Pd(PPh.sub.3).sub.4 and K.sub.2CO.sub.3 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- [4-(1H-pyrazol- 4-yl)phenyl]urea 109 [00170]![embedded image]()
381.8 1H NMR (500 MHz, CDCl3): δ = 7.32 (d, J = 7.4 Hz, 2H), 7.29 (d, J = 7.4 Hz, 2H), 7.04 (s, 1H), 6.18 (d, J = 3.0 Hz, 1H), 5.97 (d, J = 3.0 Hz, 1H), 4.70-4.63 (m, 1H), 4.32 (s, 2H), 2.33 (s, 3H), 2.11-1.88 (m, 3H), 1.74-1.67 (m, 2H), 1.66- 1.51 (m, 10H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- iodo-4- isocyanatobenzene, method F using 2- methylbut-3-yn-2-ol, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA l-cyclopentyl-3- [4-(3-hydroxy-3- methyl-but-1- ynyl)phenyl]-1- [(5-methyl-2- furyl)methyl]urea 110 [00171]![embedded image]()
352.7 1H NMR (500 MHz, DMSO-d6): δ = 8.40 (s, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 6.11 (d, J = 2.9 Hz, 1H), 5.96 (d, J = 2.9 Hz, 1H), 4.49-4.38 (m, 3H), 3.55-3.42 (bs, 2H), 2.20 (s, 3H), 1.82-1.70 (m, 2H), 1.69-1.60 (m, 2H), 1.58-1.44 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- iodo-4- isocyanatobenzene, method F using prop- 2-yn-1-amine, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA 3-[4-(3- aminoprop-1- ynyl)phenyl]-1- cyclopentyl-1- [(5-methyl-2- furyl)methyl]urea 111 [00172]![embedded image]()
353.7 1H NMR (500 MHz, DMSO-d6): δ = 8.43 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 6.11 (d, J = 2.0 Hz, 1H), 5.96 (d, J = 2.0 Hz, 1H), 5.26 (t, J = 5.7 Hz, 1H), 4.48-4.39 (m, 3H), 4.27 (d, J = 5.7 Hz, 2H), 2.21 (s, 3H), 1.83- 1.71 (m, 2H), 1.70-1.61 (m, 2H), 1.59-1.44 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- iodo-4- isocyanatobenzene, method F using prop- 2-yn-1-ol, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA 1-cyclopentyl-3- [4-(3- hydroxyprop-1- ynyl)phenyl]-1- [(5-methyl-2- furyl)methyl]urea 112 [00173]![embedded image]()
380.8 1H NMR (500 MHz, DMSO-d6): δ = 8.42 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 6.08 (d, J = 2.0 Hz, 1H), 5.96 (d, J = 2.0 Hz, 1H), 4.48-4.40 (m, 3H), 3.42 (s, 2H), 2.24 (s, 6H), 2.21 (s, 3H), 1.84-1.70 (m, 2H), 1.69- 1.61 (m, 2H), 1.59-1.46 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- iodo-4- isocyanatobenzene, method F using N,N- dimethylprop-2-yn-1- amine, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA 1-cyclopentyl-3- [4-[3- (dimethylamino) prop-1- ynyl]phenyl]-1- [(5-methyl-2- furyl)methyl]urea 113 [00174]![embedded image]()
412.2 1H NMR (300 MHz, DMSO-d6): δ = 8.31 (s, 1H), 7.46-7.33 (m, 2H), 7.04 (t, J = 8.9 Hz, 2H), 3.92- 3.77 (m, 1H), 3.21 (s, 2H), 2.99- 2.79 (m, 5H), 1.85-1.62 (m, 7H), 1.61-1.31 (m, 7H), 0.94 (s, 3H) ppm tert-butyl 4- formyl-4- methyl- piperidine-1- carboxylate General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- fluorophenylisocyanate, method F using TFA, method H using MsCl 1-cyclopentyl- (4- fluorophenyl)-1- [(4-methyl-1- methylsulfonyl- 4- piperidyl)methyl] urea 114 [00175]![embedded image]()
355.1 1H NMR (300 MHz, DMSO-d6): δ = 8.66 (d, J = 5.8 Hz, 1H), 8.59 (s, 1H), 7.86 (s, 1H), 7.55 (dd, J = 5.1, 1.4 Hz, 1H), 7.52-7.44 (m, 2H), 7.32-7.22 (m, 2H), 4.61-4.44 (m, 3H), 1.92-1.71 (m, 2H), 1.69- 1.44 (m, 4H), 1.43-1.24 (m, 2H) ppm 4- formyl- pyridine-2- carbonitrile General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(2-cyano-4- pyridyl)methyl]- 1-cyclopentyl- urea 115 [00176]![embedded image]()
355.1 1H NMR (300 MHz, DMSO-d6): δ = 8.87 (d, J = 1.9 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.61 (s, 1H), 8.10-8.06 (m, 1H), 7.48 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H), 4.56 (s, 2H), 4.53-4.42 (m, 1H), 1.89-1.73 (m, 2H), 1.72-1.57 (m, 2H), 1.56-1.31 (m, 4H) ppm 5- formyl- pyridine-2- carbonitrile General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(5-cyano-3- pyridyl)methyl]- 1-cyclopentyl- urea 116 [00177]![embedded image]()
355.1 1H NMR (300 MHz, DMSO-d6): δ = 8.80-8.74 (m, 1H), 8.69 (s, 1H), 7.69 (s, 2H), 7.75-766 (m, 2H), 7.48 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H), 4.59 (s, 2H), 4.57-4.43 (m, 1H), 1.89-1.70 (m, 2H), 1.69-1.56 (m, 2H), 1.55-1.32 (m, 4H) ppm 2-- formyl- pyridine-4- carbonitrile General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(4-cyano-2- pyridyl)methyl]- 1-cyclopentyl- urea 117 [00178]![embedded image]()
342.2 1H NMR (300 MHz, DMSO-d6): δ = 8.49 (s, 1H), 7.74 (d, J = 8.8 Hz, 3H), 7.50 (d, J = 8.8 Hz, 2H), 7.17-7.07 (bs, 1H), 6.09 (d, J = 3.0 Hz, 1H), 5.98- 5.92 (m, 1H), 4.52- 4.36 (m, 3H), 2.20 (s, 3H), 1.86- 1.71 (m, 2H), 1.70-1.41 (m, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- isocyanatobenzonitrile, method P using H.sub.2O.sub.2 and K.sub.2CO.sub.3 4-[[cyclopentyl- [(5-methyl-2- furyl)methyl]car- bamoyl]amino- benzamide 118 [00179]![embedded image]()
402.3 1H NMR (300 MHz, DMSO-d6): δ = 8.18 (s, 1H), 7.42 (dd, J = 8.7, 1.2 Hz, 2H), 7.20 (t, J = 7.9 Hz, 2H), 6.96-6.87 (m, 1H), 4.26-4.10 (m, 1H), 4.00-3.85 (m, 2H), 3.11 (d, J = 7.1 Hz, 2H), 2.69-2.54 (m, 2H), 1.86-1.42 (m, 11H), 1.37 (s, 9H), 1.10-0.92 (m, 2H) ppm tert-butyl 4- formyl- piperidine-1- carboxylate General method A using cyclopentanamine and NaBH.sub.4, method D1 using phenyl isocyanate tert-butyl 4- [[cyclopentyl (phenylcarbamoyl) amino]methyl] piperidine-1- carboxylate 119 [00180]![embedded image]()
420.3 1H NMR (300 MHz, DMSO-d6): δ = 8.22 (s, 1H), 7.47-7.35 (m, 2H), 7.10-6.98 (m, 2H), 4.22-4.06 (m, 1H), 4.00-3.86 (m, 2H), 3.14- 3.08 (m, 2H), 2.70-2.52 (m, 2H), 1.85-1.42 (m, 11H), 1.37 (s, 9H), 1.10-0.91 (m, 2H) ppm tert-butyl 4- formyl- piperidine-1- carboxylate General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- fluorophenylisocyanate tert-butyl 4- [[cyclopentyl- [(4- fluorophenyl) carbamoyl]amino] methyl]piperine- 1-carboxylate 120 [00181]![embedded image]()
436.2 1H NMR (300 MHz, DMSO-d6): δ = 8.35 (s, 1H), 7.44 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H), 4.12-4.07 (m, 1H), 3.99-3.83 (m, 2H), 3.16-3.06 (m, 2H), 2.70-2.53 (m, 2H), 1.84-1.41 (m, 11H), 1.37 (s, 9H), 1.09-0.92 (m, 2H) ppm tert-butyl 4- formyl- piperidine-1- carboxylate General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate tert-butyl 4-[[(4- chlorophenyl) carbamoyl- cyclopentyl- amino]methyl] piperidine-1- carboxylate 121 [00182]![embedded image]()
325.2 1H NMR (300 MHz, DMSO-d6): δ = 9.38 (s, 1H), 8.67 (dd, J = 2.4, 0.8 Hz, 1H), 8.12-8.06 (m, 1H), 7.93-7.88 (m, 1H), 6.11 (d, J = 3.1 Hz, 1H), 5.98-5.94 (m, 1H), 4.56- 4.38 (m, 3H), 2.18 (s, 3H), 1.84- 1.69 (m, 2H), 1.68-1.40 (m, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D2 using 6- aminopyridine-3- carbonitrile 3-(5-cyano-2- pyridyl)-1- cyclopentyl-1- [(5-methyl-2- furyl)methyl]urea 122 [00183]![embedded image]()
374.7 1H NMR (300 MHz, DMSO-d6): δ = 8.39 (s, 1H), 7.62 (bs, 2H), 7.58-7.49 (m, 1H), 7.47-7.38 (m, 2H), 7.37-7.29 (m, 1H), 7.26-7.15 (m, 1H), 7.04 (t, J = 9.0 Hz, 2H), 4.63-4.32 (m, 3H), 1.82-1.67 (m, 2H), 1.66-1.33 (m, 6H) ppm 2-fluoro-5- formyl- benzonitrile General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- fluorophenylisocyanate, method P using H.sub.2O.sub.2 and K.sub.2CO.sub.3 5-[[cyclopentyl- [(4- fluorophenyl) carbamoyl]amino] methyl]-2- fluoro- benzamide 123 [00184]![embedded image]()
384.8 1H NMR (300 MHz, DMSO-d6): δ = 8.03 (s, 1H), 7.26 (d, J = 8.9 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 6.07 (d, J = 3.3 Hz, 1H), 5.97-5.93 (m, 1H), 4.45-4.32 (m, 3H), 3.77- 3.63 (m, 4H), 3.03-2.92 (m, 4H), 2.20 (s, 3H), 1.83-1.67 (m, 2H), 1.66-1.40 (m, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D4 using 4- morpholinoaniline 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- (4- morpholino- phenyl)urea 124 [00185]![embedded image]()
325.7 1H NMR (300 MHz, DMSO-d6): δ = 9.03 (s, 1H), 8.79 (d, J = 2.4 Hz, 1H), 8.11 (dd, J = 8.6, 2.4 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 6.10 (d, J = 3.3 Hz, 1H), 5.96-5.93 (m, 1H), 4.53-4.37 (m, 3H), 2.19 (s, 3H), 1.84-1.71 (m, 2H), 1.70-1.43 (m, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D4 using 5- aminopyridine-2- carbonitrile 3-(6-cyano-3- pyridyl)-1- cyclopentyl- [(5-methyl-2- furyl)methyl]urea 125 [00186]![embedded image]()
321.7 1H NMR (300 MHz, DMSO-d6): δ = 8.52 (s, 1H), 8.01 (t, J = 7.8 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 7.8 Hz, 2H), 7.21 (t, J = 7.6 Hz, 2H), 6.92 (t, J = 7.6 Hz, 1H), 4.70-4.47 (m, 3H), 1.87-1.70 (m, 2H), 1.69- 1.33 (m, 6H) ppm 6- formyl- pyridine-2- carbonitrile General method A using cyclopentanamine and NaBH.sub.4, method D1 using phenyl isocyanate 1-[(6-cyano-2- pyridyl)methyl]- 1-cyclopentyl-3- phenyl-urea 126 [00187]![embedded image]()
339.7 1H NMR (300 MHz, DMSO-d6): δ = 8.55 (s, 1H), 8.01 (t, J = 7.8 Hz, 1H), 7.91 (d, J = 6.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.42 (dd, J = 9.0, 5.1 Hz, 2H), 7.05 (t, J = 8.8 Hz, 2H), 4.59 (s, 2H), 4.65-4.44 (m, 3H), 1.85-1.70 (m, 2H), 1.69-1.56 (m, 2H), 1.55-1.31 (m, 4H) ppm 6- formyl- pyridine-2- carbonitrile General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- fluorophenylisocyanate 1-[(6-cyano-2- pyridyl)methyl]- 1-cyclopentyl-3- (4- fluorophenyl)urea 127 [00188]![embedded image]()
304.7 1H NMR (300 MHz, DMSO-d6): δ = 8.49 (s, 1H), 8.44 (d, J = 1.8 Hz, 1H), 7.48-7.37 (m, 2H), 7.10- 7.00 (m, 2H), 6.28-6.6.24 (m, 1H), 4.62 (s, 2H), 4.52-4.39 (m, 1H), 1.89-1.72 (m, 2H), 1.71-1.57 (m, 2H), 1.56-1.38 (m, 4H) ppm isoxazole-5- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- fluorophenylisocyanate 1-cyclopentyl-2- (4- fluorophenyl)-1- (isoxazol-5- ylmethyl)urea 128 [00189]![embedded image]()
320.7 1H NMR (300 MHz, DMSO-d6): δ = 8.58 (s, 1H), 8.44 (d, J = 1.6 Hz, 1H), 7.47 (d, J = 9.0 Hz, 2H), 7.26 (d, J = 9.0 Hz, 2H), 6.27 (d, J = 1.6 Hz, 1H), 4.63 (s, 2H), 4.53- 4.39 (m, 1H), 1.88-1.72 (m, 2H), 1.71-1.58 (m, 2H), 1.57-1.38 (m, 4H) ppm isoxazole-5- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- cyclopentyl-1- (isoxazol-5- ylmethyl)urea 129 [00190]![embedded image]()
382.7 1H NMR (300 MHz, DMSO-d6): δ = 10.81 (s, 1H), 7.87 (d, J = 7.3 Hz, 2H), 7.45-7.35 (m, 3H), 7.32- 7.24 (m, 1H), 6.11-6.07 (m, 1H), 5.97-5.94 (m, 1H), 4.58-4.40 (m, 3H), 2.21 (s, 3H), 1.82-1.69 (m, 2H), 1.68-1.41 (m, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D4 using 4- phenylthiazol-2 amine 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- (4- phenylthiazol-2- yl)urea 130 [00191]![embedded image]()
369.7 1H NMR (300 MHz, DMSO-d6): δ = 8.55 (s, 1H), 7.59-7.45 (m, 4H), 7.29-7.14 (m, 4H), 6.67 (s, 1H), 4.65 (s, 2H), 4.58-4.43 (m, 1H), 1.91-1.73 (m, 2H), 1.72-1.43 (m, 6H) ppm benzofuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 1-(benzofuran-2- ylmethyl)-3-(4- chlorophenyl)-1- cyclopentyl-urea 131 [00192]![embedded image]()
359.7 1H NMR (300 MHz, DMSO-d6): δ = 8.61 (s, 1H), 7.59-7.44 (m, 4H), 7.32 (d, J = 8.7 Hz, 2H), 7.27- 7.13 (m, 2H), 6.67 (s, 1H), 4.66 (s, 2H), 4.58-4.44 (m, 1H), 4.00 (s, 1H), 1.91-1.73 (m, 2H), 1.72- 1.42 (m, 6H) ppm benzofuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method D4 using 4-ethynylaniline 1-(benzofuran-2- ylmethyl)-1- cyclopentyl-3- (4- ethynylphenyl) urea 132 [00193]![embedded image]()
359.7 1H NMR (300 MHz, DMSO-d6): δ = 8.90 (m, 1H), 7.72-7.63 (m, 4H), 7.57-7.47 (m, 2H), 7.27-7.15 (m, 2H), 6.68 (m, 1H), 4.69 (s, 2H), 4.60-4.42 (m, 1H), 1.90-1.74 (m, 2H), 1.73-1.44 (m, 6H) ppm benzofuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- isocyanato- benzonitrile 1-(benzofuran-2- ylmethyl)-3-(4- cyanophenyl)-1- cyclopentyl-urea 133 [00194]![embedded image]()
383.7 1H NMR. (300 MHz, DMSO-d6): δ = 10.87 (s, 1H), 8.57 (d, J = 4.70 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.85 (dd, J = 7.5, 1.7 Hz, 1H), 7.67 (s, 1H), 7.33-7.25 (m, 1H), 6.10 (d, J = 2.9 Hz, 1H), 5.99-5.93 (m, 1H), 4.63-4.37 (m, 3H), 2.21 (s, 3H), 1.88-1.69 (m, 2H), 1.68-1.42 (m, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D3 using 4-(2- pyridyl)thiazol-2-amine 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]- [4-(2- pyridyl)thiazol- 2-yl]urea 134 [00195]![embedded image]()
356.7 1H NMR (300 MHz, DMSO-d6): δ = 12.15-12.73 (m, 1H), 10.70- 11.37 (m, 1H), 7.47-7.96 (m, 1H), 7.27-7.44 (m, 1H), 7.06-7.26 (m, 1H), 6.01-6.19 (m, 1H), 5.96 (br. s., 1H), 4.54 (m, 3H), 2.20 (s, 3H), 1.33-1.93 (m, 8H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D3 using 1,3- benzothiazol-2-amine 3-(1,3- benzothiazol-2- yl)-1- cyclopentyl-1- [(5-methyl-2- furyl)methyl]urea 135 [00196]![embedded image]()
331.7 1H NMR (300 MHz, DMSO-d6): δ = 11.28 (s, 1H), 8.19 (s, 1H), 6.09 (d, J = 2.9 Hz, 1H), 5.98-5.94 (m, 1H), 4.49 (s, 2H), 4.46-4.34 (m, 1H), 2.20 (s, 3H), 1.82-1.68 (m, 2H), 1.67-1.40 (m, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D3 using 2- aminothiazole-4- carbonitrile 3-(4- cyanothiazol-2- yl)-1- cyclopentyl-1- [(5-methyl-2- furyl)methyl]urea 136 [00197]![embedded image]()
414.8 1H NMR (300 MHz, DMSO-d6): δ = 8.27 (s, 1H), 7.47-7.39 (m, 2H), 7.28-7.17 (m, 2H), 6.98-6.90 (m, 1H), 6.13 (d, J = 2.95 Hz, 1H), 5.99-5.94 (m, 1H), 4.47 (bs, 2H), 4.23-4.10 (m, 1H), 4.00 (d, J = 13.18 Hz, 2H), 2.93-2.61 (m, 2H), 2.21 (d, J = 0.70 Hz, 3H), 1.64- 1.51 (m, 4H), 1.40 (s, 9H) ppm 5- methylfuran- 2- carbaldehyde General method A using tert-butyl 4- aminopiperidine-1- carboxylate, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate tert-butyl 4-[(5- methyl-2- furyl)methyl- (phenylcarba- moyl)amino] piperdine-1- carboxylate 137 [00198]![embedded image]()
333.7 1H NMR (400 MHz, DMSO-d6): δ = 8.39 (s, 1H), 7.47 (d, J = 9.0 Hz, 2H), 7.25 (d, J = 9.0 Hz, 2H), 6.08 (d, J = 3.0 Hz, 1H), 5.96-5.94 (m, 1H), 4.42 (s, 2H), 4.44-4.36 (m, 1H), 2.19 (s, 3H), 1.79-1.69 (m, 2H), 1.67-1.60 (m, 2H), 1.59- 1.43 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- cyclopentyl-1- [(5-methyl-2- furyl)methyl]urea 138 [00199]![embedded image]()
273.7 1H NMR (400 MHz, DMSO-d6): δ = 8.18 (s, 1H), 7.46-7.41 (m, 2H), 7.23-7.17 (m, 2H), 6.93-6.89 (m, 1H), 6.12 (d, J = 3.0 Hz, 1H), 5.97-5.94 (m, 1H), 4.43 (s, 2H), 4.46-4.34 (m, 1H), 2.20 (s, 3H), 1.10 (d, J = 6.8 Hz, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using propan-2-amine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-isopropyl-1- [(5-methyl-2- furyl)methyl]-3- phenyl-urea 139 [00200]![embedded image]()
417.7 1H NMR (400 MHz, DMSO-d6): δ = 8.61 (s, 1H), 7.62-7.54 (m, 3H), 7.49-7.42 (m, 1H), 7.32-7.22 (m, 1H), 7.22-7.18 (m, 1H), 4.55 (s, 2H), 4.50-4.44 (m, 1H), 1.80- 1.70 (m, 2H), 1.68-1.58 (m, 2H), 1.54-1.36 (m, 4H) ppm 4-fluoro-3- trifluoro- methyl- benzaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1,2- difluoro-4- isocyanatobenzene 1-cyclopentyl-3- (3,4- difluorophenyl)- 1-[[4-fluoro- (trifluoromethyl) phenyl]methyl] urea 140 [00201]![embedded image]()
399.7 1H NMR (400 MHz, DMSO- d6):δ = 8.60 (s, 1H), 7.62-7.49 (m, 5H), 7.32-7.22 (m, 1H), 7.22- 7.18 (m, 1H), 4.60 (s, 2H), 4.54- 4.46 (m, 1H), 1.80-1.70 (m, 2H), 1.68-1.58 (m, 2H), 1.54-1.36 (m, 4H) ppm 3- trifluoro- methyl- benzaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1,2- difluoro-4- isocyanatobenzene 1-cyclopentyl-3- (3,4- difluorophenyl)- 1-[[3- (trifluoromethyl) phenyl]methyl] urea 141 [00202]![embedded image]()
433.6 1H NMR (400 MHz, DMSO- d6):δ = 8.60 (s, 1H), 7.63-7.55 (m, 1H), 7.48-7.41 (m, 1H), 7.38- 7.33 (m, 1H), 7.33-7.23 (m, 2H), 7.23-7.17 (m, 1H), 4.52 (s, 2H), 4.50-4.43 (m, 1H), 1.80-1.70 (m, 2H), 1.68-1.56 (m, 2H), 1.54-1.36 (m, 4H) ppm 4-fluoro-3- trifluoro- methyl- benzaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1,2- difluoro-4- isocyanatobenzene 1-cyclopentyl-3- (3,4- difluorophenyl)- 1-[[4-fluoro-3- (trifluoromethoxy) phenyl]methyl] urea 142 [00203]![embedded image]()
415.7 1H NMR (400 MHz, DMSO-d6): δ = 8.59 (s, 1H), 7.62-7.55 (m, 1H), 7.47-7.42 (m, 1H), 7.31-7.23 (m, 2H), 7.22-7.15 (m, 3H), 4.56 (s, 2H), 4.53-4.46 (m, 1H), 1.80- 1.70 (m, 2H), 1.68-1.56 (m, 2H), 1.54-1.36 (m, 4H) ppm 3- trifluoro- methoxy- benzaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1,2- difluoro-4- isocyanatobenzene 1-cyclopentyl-3- (3,4- difluorophenyl)- 1-[[3- (trifluoromethoxy) phenyl]methyl] urea 143 [00204]![embedded image]()
300.6 1H NMR (400 MHz, DMSO-d6): δ = 8.32 (s, 1H), 7.45-7.41 (m, 2H), 7.24-7.18 (m, 2H), 6.95-6.90 (m, 1H), 6.79 (s, 1H), 4.48 (s, 2H), 4.46-4.38 (m, 1H), 2.34 (s, 3H), 1.84-1.74 (m, 2H), 1.70-1.60 (m, 2H), 1.58-1.46 (m, 4H) ppm 2-methyl- oxazole-5- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-cyclopentyl-1- [(2- methyloxazol-5- yl)methyl]-3- phenyl-urea 144 [00205]![embedded image]()
334.6 1H NMR (400 MHz, DMSO-d6): δ = 8.47 (s, 1H), 7.47 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H), 6.79 (s, 1H), 4.48 (s, 2H), 4.46- 4.34 (m, 1H), 2.34 (s, 3H), 1.84- 1.74 (m, 2H), 1.70-1.60 (m, 2H), 1.58-1.46 (m, 4H) ppm 2-methyl- oxazole-5- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- cyclopentyl-1- [(2- methyloxazol-5 yl)methyl]urea 145 [00206]![embedded image]()
318.6 1H NMR (400 MHz, DMSO-d6): δ = 8.37 (s, 1H), 7.46-7.40 (m, 2H), 7.08-7.02 (m, 2H), 6.79 (s, 1H), 4.47 (s, 2H), 4.44-4.36 (m, 1H), 2.34 (s, 3H), 1.84-1.74 (m, 2H), 1.70-1.60 (m, 2H), 1.58-1.44 (m, 4H) ppm 2-methyl- oxazole-5- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- fluorophenylisocyanate 1-cyclopentyl-3- (4- fluorophenyl)-1- [(2- methyloxazol- yl)methyl]urea 146 [00207]![embedded image]()
372.6 1H NMR (300 MHz, DMSO-d6): δ = 8.53 (s, 1H), 7.72 (dd, J = 2.1, 6.3 Hz, 1H), 7.66-7.58 (m, 1H), 7.52-7.43 (m, 3H), 7.30-7.23 (m, 2H), 4.50 (s, 2H), 4.52-4.43 (m, 1H), 1.84-1.70 (m, 2H), 1.68-1.58 (m, 2H), 1.56-1.32 (m, 4H) ppm 2-fluoro-5- formyl- benzonitrile General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)- [(3-cyano-4- fluoro- phenyl)methyl]- 1-cyclopentyl- urea 147 [00208]![embedded image]()
354.6 1H NMR (300 MHz, DMSO- d6):δ = 8.53 (s, 1H), 7.68 (m, 1H), 7.64-7.62 (m, 1H), 7.58-7.50 (m, 2H), 7.47 (d, J = 9.0 Hz, 2H), 7.26 (d, J = 9.0 Hz, 2H), 4.55 (s, 2H), 4.55-4.45 (m, 1H), 1.82-1.72 (m, 2H), 1.66-1.56 (m, 2H), 1.54-1.34 (m, 4H) ppm 3- formylbenzo nitrile General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(3- cyanophenyl) methyl]-1- cyclopentyl-urea 148 [00209]![embedded image]()
398.1 1H NMR (400 MHz, DMSO-d6): δ = 8.67 (d, J = 5.0 Hz, 1H), 8.60 (s, 1H), 7.71 (s, 1H), 7.52 (d, J = 5.0 Hz, 1H), 7.47 (d, J = 9.0 Hz, 2H), 7.26 (d, J = 9.0 Hz, 2H), 4.62 (s, 2H), 4.58-4.50 (m, 1H), 1.84- 1.74 (m, 2H), 1.68-1.58 (m, 2H), 1.56-1.44 (m, 2H), 1.44-1.32 (m, 2H) ppm 2- (trifluoro- methyl) pyridine-4- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- cyclopentyl-1- [[2- (trifluoromethyl)- 4- pyridyl]methyl] urea 149 [00210]![embedded image]()
320.1 1H NMR (400 MHz, DMSO-d6): δ = 8.8 (d, J = 1.7 Hz, 1H), 8.56 (s, 1H), 7.49 (d, J = 9.0 Hz, 2H), 7.27 (d, J = 9.0 Hz, 2H), 6.43 (d, J = 1.7 Hz, 1H), 4.56 (s, 2H), 4.50-4.40 (m, 1H), 1.84-1.74 (m, 2H), 1.72- 1.60 (m, 2H), 1.56-1.44 (m, 4H) ppm isoxazole-3- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- cyclopentyl-1- (isoxazol-3- ylmethyl)urea 150 [00211]![embedded image]()
375.8 1H NMR (300 MHz, DMSO-d6): δ = 8.36 (s, 1H), 7.61 (d, J = 7.4 Hz, 2H), 7.54 (s, 4H), 7.41 (t, J = 7.3 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 6.10 (d, J = 3.0 Hz, 1H), 5.98- 5.94 (m, 1H), 4.45 (s, 2H), 4.50- 4.40 (m, 1H), 2.21 (s, 3H), 1.84- 1.72 (m, 2H), 1.70-1.44 (m, 6H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D3 using 4- phenylaniline 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- (4- phenylphenyl) urea 151 [00212]![embedded image]()
407.8 1H NMR (300 MHz, DMSO-d6): δ = 7.79 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.69 (s, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 6.07-6.11 (m, 1H), 5.95-5.99 (m, 1H), 4.38-4.52 (m, 3H), 2.21 (s, 3H), 1.43-1.80 (m, 8H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 5- (benzofuran-2-yl)- 1,3,4-oxadiazole-2- amine 3-[5- (benzofuran-2- yl)-1,3,4- oxadiazol-2-yl- 1-cyclopentyl- [(5-methyl-2- furyl)methyl]urea 152 [00213]![embedded image]()
375.7 1H NMR (300 MHz, DMSO-d6): δ = 8.88 (s, 1H), 8.68 (d, J = 5.1 Hz, 1H), 7.71-7.63 (m, 5H), 7.50 (d, J = 5.1 Hz, 1H), 4.79 (s, 2H), 4.68- 4.60 (m, 1H), 2.12-1.94 (m, 4H), 1.59-1.51 (m, 2H) ppm 2- (trifluoro- methyl) pyridine-4- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- isocyanatobenzonitrile 3-(4- cyanophenyl)- cyclobutyl-1-[[2- (trifluoromethyl)- 4- pyridyl]methyl] urea 153 [00214]![embedded image]()
374.8 1H NMR (500 MHz, DMSO-d6): δ = 8.69 (d, J = 4.0 Hz, 1H), 8.61 (s, 1H), 7.71 (m, 1H), 7.51 (d, J = 4.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.79 (s, 2H), 4.71-4.58 (m, 1H), 4.02 (s, 1H), 2.18-2.06 (m, 2H), 2.04-1.94 (m, 2H), 1.63-1.47 (m, 2H) ppm 2- (trifluoro- methyl) pyridine-4- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D2 using 4- ethynylaniline 1-cyclobutyl-3- (4- ethynylphenyl)- 1-[[2- (trifluoromethyl)- 4- pyridyl]methyl] urea 154 [00215]![embedded image]()
337.7 1H NMR (500 MHz, DMSO-d6): δ = 8.38 (s, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 6.09 (bs, 1H), 5.96 (bs, 1H), 4.47- 4.38 (m, 3H), 2.21 (s, 3H), 2.00 (s, 3H), 1.82-1.70 (m, 2H), 1.69- 1.60 (m, 2H), 1.59-1.44 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method T using 4- bromoaniline, tributyl- propynylstannane and Pd(PPh.sub.3).sub.4, method D2 using 4-prop-1- ynylaniline 1-cyclobutyl-3- (4-prop-1- ynylphenyl)-1- [[2- (trifluoromethyl)- 4- pyridyl]methyl] urea 155 [00216]![embedded image]()
399.8 1H NMR (500 MHz, DMSO-d6): δ = 8.49 (s, 1H), 7.56-7.48 (m, 4H), 7.43-7.32 (m, 5H), 6.11 (bs, 1H), 5.96 (bs, 1H), 4.48-4.38 (m, 3H), 3.86 (s, 2H), 2.21 (s, 3H), 1.81-1.71 (m, 2H), 1.70-1.60 (m, 2H), 1.58-1.42 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- iodo-4- isocyanatobenzene, method F using ethynylbenzene, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- [4-(2- phenylethynyl) phenyl]urea 156 [00217]![embedded image]()
413.8 1H NMR (500 MHz, DMSO-d6): δ = 8.41 (s, 1H), 7.47-7.24 (m, 9H), 6.12 (bs, 1H), 5.96 (bs, 1H), 4.49-4.39 (m, 3H), 3.86 (s, 2H), 2.21 (s, 3H), 1.81-1.71 (m, 2H), 1.70-1.60 (m, 2H), 1.58-1.42 (m, 4H), ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- iodo-4- isocyanatobenzene, method F using prop-2- ynylbenzene, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- [4-(3- phenylprop-1- ynyl)phenyl]urea 157 [00218]![embedded image]()
355.6 1H NMR (300 MHz, DMSO-d6): δ = 8.64 (s, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 4.61 (s, 2H), 4.61-4.49 (m, 1H), 1.86-1.72 (m, 2H), 1.70- 1.56 (m, 2H), 1.55-1.38 (m, 4H), ppm 6- formyl- pyridine-2- carbonitrile General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)- [(6-cyano-2- pyridyl)methyl- 1-cyclopentyl] urea 158 [00219]![embedded image]()
466.8 1H NMR (500 MHz, DMSO-d6): δ = 8.35 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.35-7.31 (m, 2H), 6.20 (d, J = 18 Hz, 1H), 6.11 (bs, 1H), 5.96 (bs, 1H), 4.48-4.41 (m, 3H), 4.38 - 4.34 (m, 2H), 4.19-4.15 (m, 2H), 2.21 (s, 3H), 1.82-1.71 (m, 2H), 1.70-1.62 (m, 2H), 1.60-1.48 (m, 4H), 1.47-1.40 (m, 9H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- bromo-4- isocyanatobenzene, method E using tert- butyl 3-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-2,5- dihydropyrrole-1- carboxylate, Pd(PPh.sub.3).sub.2 and K.sub.2CO.sub.3 tert-butyl 3-[4- [[cyclopentyl- [(5-methyl-2- furyl)methyl]car- bamoyl]amino] phenyl]-2,5- dihydropyrrole- 1-carboxylate 159 [00220]![embedded image]()
0 1H NMR (500 MHz, DMSO-d6): δ = 8.26 (s, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.09 (d, J = 2.0 Hz, 1H), 5.95 (d, J = 2.0 Hz, 1H), 4.48-4.41 (m, 3H), 4.38-4.34 (m, 2H), 4.27- 4.17 (m, 2H), 3.83-3.76 (m, 2H), 3.73-3.64 (m, 1H), 2.21 (s, 3H), 1.80-“1.71 (m, 2H), 1.70-“1.60 (m, 2H), 1.58-“ 1.48 (m, 4H), 1.40 (s, 9H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- iodo-4- isocyanatobenzene, method K using 1-Boc- 3-iodoazetidine, Zn, Pd(OAc).sub.2 and Cphos tert-butyl 3-[4- [[cyclopentyl- [(5-methyl-2- furyl)methyl]car- bamoyl]amino] phenyl]azetidine- 1-carboxylate 160 [00221]![embedded image]()
380.8 1H NMR (500 MHz, DMSO-d6): δ = 8.54 (d, J = 2.5 Hz, 1H), 8.47 (s, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.84 (dd, J = 8.5, 2.5 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 6.12 (d, J = 2.0 Hz, 1H), 5.96 (d, J = 2.0 Hz, 1H), 4.48-4.41 (m, 3H), 3.86 (s, 3H) 2.22 (s, 3H), 1.84-“1.73 (m, 2H), 1.72-“1.62 (m, 2H), 1.60-“1.40 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D2 using 6- chloropyridin-3-amine, method E using 1- methyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)pyrazole, X-Phos-Pd- G1, XPhos and K.sub.2CO.sub.3 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- [6-(1- methylpyrazol- 4-yl)-3- pyridyl]urea 161 [00222]![embedded image]()
384.6, 386.7 1H NMR (300 MHz, DMSO-d6): δ = 10.75 (bs, 1H), 7.41 (s, 1H), 6.08 (d, J = 3.0 Hz, 1H), 5.95 (d, J = 2.5 Hz, 1H), 4.48 (s, 2H), 4.45- 4.35 (m, 1H), 2.20 (s, 3H), 1.80- 1.43 (m, 8H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method Q for phenyl carbamate synthesis; method D5 using phenyl N-(5- bromothiazol-2- yl)carbamate 3-(5- bromothiazol-2- yl)-1- cyclopentyl-1- [(5-methyl-2- furyl)methyl]urea 162 [00223]![embedded image]()
367.7 1H NMR (400 MHz, DMSO-d6): δ = 8.44 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 6.11 (d, J = 2.7 Hz, 1H), 5.95-5.94 (m, 1H), 4.46-4.38 (m, 3H), 4.28 (s, 2H), 3.30 (s, 3H), 2.20 (s, 3H), 1.80-1.70 (m, 2H), 1.69-1.59 (m, 2H), 1.59-1.45 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- iodo-4- isocyanatobenzene, method F using 3- methoxyprop-1-yne, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA 1-cyclopentyl-3- [4-(3- methoxyprop-1- ynyl)phenyl]-1- [(5-methyl-2- furyl)methyl]urea 163 [00224]![embedded image]()
310.7 1H NMR (400 MHz, DMSO-d6): δ = 8.63 (s, 1H), 8.44 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 6.11 (d, J = 2.0 Hz, 1H), 4.63 (s, 2H), 4.52- 4.45 (m, 1H), 4.03 (s, 1H), 1.86- 1.74 (m, 2H), 1.71-1.61 (m, 2H), 1.57-1.45 (m, 4H) ppm isoxazole-5- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D2 using 4- ethynylaniline 1-cyclopentyl-3- (4- ethynylphenyl)- 1-(isoxazol-5- ylmethyl)urea 164 [00225]![embedded image]()
396.8 1H NMR (500 Hz, CDCl3): δ = 8.55 (s, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 6.08 (d, J = 2.0 Hz, 1H), 5.97 (d, J = 2.0 Hz, 1H), 5.29 (t, J = 5.5 Hz, 1H), 4.59 (d, J = 5.5 Hz, 2H), 4.49- “4.24 (m, 3H), 2.22 (s, 3H), 1.84- “1.73 (m, 2H), 1.72-“1.63 (m, 2H), 1.62-“1.46 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4; method M using tert- butyl-chloro-dimethyl silane; method D2, method N using TBAFxH.sub.2O 1-cyclopentyl-3- [4-[4- (hydroxymethyl) triazol-1- yl]phenyl]-1-[(5- methyl-2- furyl)methyl]urea 165 [00226]![embedded image]()
259.7 1H NMR (300 MHz, DMSO-d6): δ = 8.28 (s, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.22 (t, J = 7.8 Hz, 2H), 6.92 (t, J = 7.3 Hz, 1H), 6.18 (d, J = 2.8 Hz, 1H), 6.00-5.96 (m, 1H), 4.47 (s, 2H), 3.40-3.26 (m, 2H), 2.21 (s, 3H), 1.03 (t, J = 6.9 Hz, 3H) ppm 5- methylfuran- 2- carbaldehyde General method A using ethanaminexHCl, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-ethyl-1-[(5- methyl-2- furyl)methyl]-3- phenyl-urea 166 [00227]![embedded image]()
273.7 1H NMR (300 MHz, DMSO-d6): δ = 8.27 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.22 (t, J = 7.8 Hz, 2H), 6.92 (t, J = 7.4 Hz, 1H), 6.18 (d, J = 2.8 Hz, 1H), 6.00-5.96 (m, 1H), 4.47 (s, 2H), 3.25 (t, J = 7.3 Hz, 2H), 2.21 (s, 3H), 1.55-1.40 (m, 2H), 0.81 (t, J = 7.3 Hz, 3H) ppm 5- methylfuran- 2- carbaldehyde General method A using ethanaminexHCl, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-[(5-methyl-2- furyl)methyl]-3- phenyl-1-propyl- urea 167 [00228]![embedded image]()
271.7 1H NMR (300 MHz, DMSO-d6): δ = 8.25 (s, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.23 (t, J = 7.8 Hz, 2H), 6.95 (t, J = 7.3 Hz, 1H), 6.10 (d, J = 2.8 Hz, 1H), 6.00-5.95 (m, 1H), 4.41 (s, 2H), 2.62-2.52 (m, 1H), 2.21 (s, 3H), 0.94-0.84 (m, 2H), 0.88-0.68 (m, 2H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopropanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-cyclopropyl-1- [(5-methyl-2- furyl)methyl]-3- phenyl-urea 168 [00229]![embedded image]()
373.7 1H NMR (300 MHz, DMSO-d6): δ = 7.89 (d, J = 5.0 Hz, 1H), 7.71 (d, J = 3.5 Hz, 1H), 7.25 (t, J = 4.8 Hz, 1H), 6.10-6.04 (m, 1H), 5.99- 5.92 (m, 1H), 4.60-4.20 (m, 3H), 2.21 (s, 3H), 1.80-1.40 (m, 8H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D3 using 5-(2- thienyl)-1,3,4- oxadiazole-2-amine 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- [5-(2-thienyl)- 1,3,4-oxadiazol- 2-yl]urea 169 [00230]![embedded image]()
373.9 1H NMR (600 MHz, DMSO-d6): δ = 6.10-6.00 (bs, 1H), 5.95 (s, 1H), 4.56-4.26 (m, 3H), 2.90-2.70 (m, 1H), 2.21 (s, 3H), 1.97-1.90 (m, 2H), 1.78-1.66 (m, 3H), 1.66- 1.58 (m, 3H), 1.58-1.40 (m, 6H), 1.40-1.30 (m, 2H), 1.28-1.20 (m, 2H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D3 using 5- cyclohexyl-1,3,4- oxadiazole-2-amine 3-(5-cyclohexyl- 1,3,4-oxadiazol- 2-yl)-1- cyclopentyl-1- [(5-methyl-2- furyl)methyl]urea 170 [00231]![embedded image]()
330.8 1H NMR (500 MHz, CDCl3): δ = 7.30-7.25 (m, 4H), 7.05-7.00 (m, 1H), 6.37 (s, 1H), 4.54-4.45 (m, 1H), 4.49 (s, 2H), 2.64 (s, 3H), 2.43 (s, 3H), 2.04-1.96 (m, 2H), 1.80-1.72 (m, 2H), 1.69-1.62 (m, 2H), 1.62-1.52 (m, 2H) ppm 2,4- dimethyl- thiazole-5- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-cyclopentyl-1- [(2,4- dimethylthiazol- 5-yl)methyl]-3- phenyl-urea 171 [00232]![embedded image]()
366.8 1H NMR (500 MHz, CDCl3): δ = 7.44-7.35 (m, 1H), 7.06-6.99 (m, 1H), 6.82-6.77 (m, 1H), 6.34 (s, 1H), 4.50-4.41 (m, 1H), 4.47 (s, 2H), 2.64 (s, 3H), 2.42 (s, 3H), 2.04-1.96 (m, 2H), 1.80-1.72 (m, 2H), 1.69-1.62 (m, 2H), 1.62-1.52 (m, 2H) ppm 2,4- dimethyl- thiazole-5- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1,2- difluoro-4- isocyanatobenzene 1-cyclopentyl-1- [(2,4- dimethylthiazol- 5-yl)methyl]-3- (3,4- difluorophenyl)- urea 172 [00233]![embedded image]()
351.8 1H NMR (500 MHz, DMSO-d6): δ = 8.05 (s, 1H), 7.58-7.54 (m, 1H), 7.41-7.38 (m, 1H), 7.20-7.18 (m, 1H), 6.14 (d, J = 2.9, 1H), 5.99- 5.98 (m, 1H), 4.44-4.38 (m, 1H), 4.42 (s, 2H) 2.25 (s, 3H), 1.79- 1.73 (m, 2H), 1.67-1.62 (m, 2H), 1.59-1.52 (m, 2H), 1.52-1.45 (m, 2H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D3 using 4- chloro-2-fluoro aniline 3-(4-chloro- fluoro-phenyl)- 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]urea 173 [00234]![embedded image]()
368.8 1H NMR (600 MHz, DMSO-d6): δ = 8.50 (s, 1H), 7.75 (s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 8.9 Hz, 2H), 7.26 (s, J = 8.9 Hz, 2H), 5.03-4.96 (m, 1H), 3.76-3.68 (m, 1H), 1.89-1.82 (m, 1H), 1.82-1.62 (m, 4H), 1.66 (d, J = 6.8 Hz, 3H), 1.49-1.41 (m, 2H), 1.41-1.34 (m, 1H) ppm 3- acetyl- benzonitrile General method A using cyclopentanamine, AcOH and NaCNBH.sub.3, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [1-(3- cyanophenyl) ethyl]-1- cyclopentyl-urea 174 [00235]![embedded image]()
344.8 1H NMR (300 MHz, DMSO-d6): δ = 9.60 (s, 1H), 8.63-8.58 (m, 1H), 7.81 (dt, J = 1.8, 7.8 Hz, 1H), 7.51-7.42 (m, 3H), 7.35-7.29 (m, 1H), 7.26 (d, J = 8.9 Hz, 2H), 4.97-4.86 (m, 1H), 4.10-3.95 (m, 1H), 1.84-1.64 (m, 5H), 1.62 (d, J = 6.9 Hz, 3H), 1.52-1.34 (m, 3H) ppm 2- acetyl- pyridine General method A using cyclopentanamine, AcOH and NaCNBH.sub.3, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- cyclopentyl-1- [1-(2- pyridyl)ethyl]urea 175 [00236]![embedded image]()
367.8 1H NMR (400 MHz, DMSO-d6): δ = 7.89-7.87 (m, 2H), 7.62-7.54 (m, 3H), 6.08-6.06 (m, 1H), 5.96- 5.95 (m, 1H), 4.48-4.42 (m, 1H), 4.46 (s, 2H), 2.20 (s, 3H), 1.79- 1.68 (m, 2H), 1.68-1.60 (m, 2H), 1.60-1.52 (m, 2H), 1.52-1.45 (m, 2H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D3 using 5- phenyl-1,3,4- oxadiazole-2-amine 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- (5-phenyl-1,3,4- oxadiazol-2- yl)urea 176 [00237]![embedded image]()
299.8 1H NMR (300 MHz, DMSO-d6): δ 8.23 (s, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.20 (t, J = 7.9 Hz, 2H), 6.91 (t, J = 7.3 Hz, 1H), 6.09 (d, J = 2.9 Hz, 1H), 5.95 (dd, J = 1.0, 3.0 Hz, 1H), 4.50-4.36 (m, 1H), 4.42 (s, 2H), 2.20 (s, 3H), 1.82-1.68 (m, 2H), 1.68-1.58 (m, 2H), 1.58-1.42 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- phenyl-urea 177 [00238]![embedded image]()
327.8 1H NMR (600 MHz, DMSO-d6): δ = 8.15 (s, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 6.09 (d, J = 3.0 Hz, 1H), 5.96 (dd, J = 1.0, 3.0 Hz, 1H), 4.47-4.40 (m, 1H), 4.42 (s, 2H), 2.55-2.48 (m, 2H), 2.21 (s, 3H), 1.79-1.72 (m, 2H), 1.70-1.60 (m, 2H), 1.58-1.46 (m, 4H), 1.14 (t, J = 7.6 Hz, 3H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 1- ethyl-4- isocyanatobenzene 1-cyclopentyl-3- (4-ethylphenyl)- 1-[(5-methyl-2- furyl)methyl]urea 178 [00239]![embedded image]()
285.8 1H NMR (300 MHz, DMSO-d6): δ = 8.20 (s, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.21 (t, J = 7.8 Hz, 2H), 6.91 (t, J = 7.3 Hz, 1H), 6.06 (d, J = 3.0 Hz, 1H), 5.96 (dd, J = 1.0, 3.0 Hz, 1H), 4.51 (s, 2H), 4.46-4.32 (m, 1H), 2.20 (s, 3H), 2.17-2.01 (m, 4H), 1.66-1.44 (m, 2H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclobutanamine, AcOH and NaBH.sub.4, method D1 using phenyl isocyanate 1-cyclobutyl-1- [(5-methyl-2- furyl)methyl]-3- phenyl-urea 179 [00240]![embedded image]()
298.8 1H NMR (500 MHz, DMSO-d6): δ = 11.32 (s, 1H), 8.00 (s, 1H), 7.52 (d, J = 7.6 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.25 (s, 1H), 7.10 (t, J = 7.3 Hz, 1H), 6.20 (d, J = 3.0 Hz, 1H), 5.99 (dd, J = 3.0, 0.8 Hz, 1H), 5.06 (s, 2H), 2.19 (s, 3H) ppm 5- methylfuran- 2- carbaldehyde General method A using oxazol-2-amine, AcOH and NaCNBH.sub.3, method D1 using phenyl isocyanate 1-[(5-methyl-2- furyl)methyl]-1- oxazol-2-yl-3- phenyl-urea 180 [00241]![embedded image]()
316.8 1H NMR (500 MHz, DMSO-d6): δ = 11.26 (s, 1H), 8.00 (s, 1H), 7.55-7.53 (m, 2H), 7.24 (s, 1H), 7.21-7.17 (m, 2H), 6.20 (d, J = 2.8 Hz, 1H), 5.99-5.98 (m, 1H), 5.05 (s, 2H), 2.19 (s, 3H) ppm 5- methylfuran- 2- carbaldehyde General method A using oxazol-2-amine, AcOH and NaCNBH.sub.3, method D1 using 4- fluorophenylisocyanate 3-(4- fluorophenyl)-1- [(5-methyl-2- furyl)methyl]-1- oxazol-2-yl-urea 181 [00242]![embedded image]()
327.9 1H NMR (500 MHz, DMSO-d6): δ 7.28-7.25 (m, 2H), 7.19-7.16 (m, 3H), 6.25 (t, J = 5.4 Hz, 1H), 5.97-5.96 (m, 1H), 5.94-5.93 (m, 1H), 4.28-4.21 (m. 3H), 3.26-3.21 (m, 2H), 2.70 (t, J = 7.7 Hz, 2H), 2.20 (s, 3H), 1.68-162 (m, 2H), 1.62-1.56 (m, 2H), 1.47-1.40 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine, AcOH and NaBH.sub.4, method D1 using 2- isocyanatoethylbenzene 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- (2- phenylethyl)urea 182 [00243]![embedded image]()
345.7 1H NMR (400 MHz, DMSO-d6): δ = 8.48 (bs, 1H), 7.46 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 1.4 Hz, 1H), 6.84 (d, J = 1.4 Hz, 1H), 4.73 (s, 2H), 3.21 (s, 3H), 2.18 (s, 3H) ppm 5- methylfuran- 2- carbaldehyde General method A using 1-methyl-2- aminoimidazolexHCl, Ti(iPrO).sub.4, TEA and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (1- methylimidazol- 2-yl)urea 183 [00244]![embedded image]()
331.7 1H NMR (400 MHz, DMSO-d6, 353 K): δ = 11.65 (bs, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 9.0 Hz, 2H), 6.88 (bs, 2H), 6.10 (d, J = 2.9 Hz, 1H), 5.94-5.91 (m, 1H), 5.06 (s, 2H), 2.18 (s, 3H) ppm 5- methylfuran- 2- carbaldehyde General method A using 2-aminoimidazole hemisulfate, Ti(iPrO).sub.4, TEA and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- (1H-imidazol-5- yl)-1-[(5-methyl- 2- furyl)methyl]urea 184 [00245]![embedded image]()
345.8 1H NMR (600 MHz, DMSO-d6): δ = 8.74 (s, 1H), 7.73 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.67-7.64 (m, 3H), 7.63-7.60 (m, 2H), 7.55 (t, J = 7.2 Hz, 1H), 5.04-5.00 (m, 1H), 4.27-4.21 (m, 1H), 2.32-2.22 (m, 2H), 2.17-2.08 (m, 2H), 1.68 (d, J = 6.8 Hz, 3H), 1.64-1.59 (m, 1H), 1.56-1.48 (m, 1H) ppm 3- acetyl- benzonitrile General method A using cyclobutanamine, AcOH and NaCNBH.sub.3, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- [1-(3- cyanophenyl) ethyl]-1- cyclobutyl-urea 185 [00246]![embedded image]()
347.7 1H NMR (500 MHz, DMSO-d6): δ = 8.34 (s, 1H), 7.51-7.47 (m, 2H), 7.27-7.24 (m, 2H), 6.22 (d, J = 2.9 Hz, 1H), 6.03-5.99 (m, 1H), 5.09-5.05 (m, 1H), 3.62- 3.57 (m, 1H), 2.22 (s, 3H), 1.94- 1.82 (m, 2H), 1.74-1.60 (m, 3H), 1.47 (d, J = 6.6 Hz, 3H), 1.46- 1.22 (m, 3H) ppm 1-(5-methyl- 2- furyl) ethanone General method A using cyclopentanamine, AcOH and NaCNBH.sub.3, method D1 using 4- cyanophenylisocyanate 3-(4- chlorophenyl)-1- cyclopentyl-1- [1-(5-methyl-2- furyl)ethyl]urea 186 [00247]![embedded image]()
334.8 1H NMR (500 MHz, DMSO-d6): δ = 8.31 (s, 1H), 7.75 (s, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.21 (t, J = 7.5 Hz, 2H), 6.92 (t, J = 7.5 Hz, 1H), 5.02-4.98 (m, 1H), 3.76-3.71 (m, 1H), 1.89-1.84 (m, 1H), 1.82-1.67 (m, 4H), 1.65 (d, J = 7.0 Hz, 3H), 1.49-1.36 (m, 3H) ppm 3- acetyl- benzonitrile General method A using cyclopentanamine, AcOH and NaCNBH.sub.3, method D1 using phenylisocyanate 1-[1-(3- cyanophenyl) ethyl]-1- cyclopentyl-3- phenyl-urea 187 [00248]![embedded image]()
352.8 1H NMR (500 MHz, DMSO-d6): δ = 8.40 (s, 1H), 7.75 (s, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.44-7.40 (m, 2H), 7.07- 7.02 (m, 2H), 5.00-4.96 (m, 1H), 3.78-3.74 (m, 1H), 1.87-1.68 (m, 5H), 1.65 (d, J = 7.0 Hz, 3H), 1.49-1.33 (m, 3H) ppm 3- acetyl- benzonitrile General method A using cyclopentanamine, AcOH and NaCNBH.sub.3, method D1 using 4- fluorophenylisocyanate 1-[1-(3- cyanophenyl) ethyl]-1- cyclopentyl-3- (4- fluorophenyl)urea 188 [00249]![embedded image]()
359.8 1H NMR (500 MHz, DMSO-d6): δ = 8.88 (s, 1H), 7.76 (s, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.67-7.63 (m, 5H), 7.57 (t, J = 8.0 Hz, 1H), 5.06-4.99 (m, 1H), 3.78-3.68 (m, 1H), 1.91-1.69 (m, 5H), 1.66 (d, J = 7.0 Hz, 3H), 1.47-1.33 (m, 3H) ppm 3- acetyl- benzonitrile General method A using cyclopentanamine, AcOH and NaCNBH.sub.3, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- [1-(3- cyanophenyl) ethyl]-1- cyclopentyl-urea 189 [00250]![embedded image]()
338.8 1H NMR (600 MHz, DMSO-d6): δ = 8.26 (s, 1H), 7.72 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.65-7.64 (m, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.43-7.39 (m, 2H), 7.06-7.02 (m, 2H), 5.04-5.00 (m, 1H), 4.23- 4.17 (m, 1H), 2.31-2.21 (m, 2H), 2.16-2.07 (m, 2H), 1.66 (d, J = 7.2 Hz, 3H), 1.63-1.57 (m, 1H), 1.55-1.47 (m, 1H) ppm 3- acetyl- benzonitrile General method A using cyclobutanamine, AcOH and NaCNBH.sub.3, method D1 using fluorophenylisocyanate 1-[1-(3- cyanophenyl) ethyl]-1- cyclobutyl- 3-(4- fluorophenyl)urea 190 [00251]![embedded image]()
338.7 1H NMR (500 MHz, DMSO-d6): δ = 8.75 (s, 1H), 7.66 (s, 4H), 6.25 (d, J = 2.8 Hz, 1H), 6.04-6.00 (m, 1H), 5.13-5.09 (m, 1H), 3.62- 3.54 (m, 1H), 2.21 (s, 3H), 1.93- 1.82 (m, 2H), 1.74-1.63 (m, 3H), 1.48 (d, J = 6.5 Hz, 3H), 1.45- 1.23 (m, 3H) ppm 1-(5-methyl- 2- furyl) ethanone General method A using cyclopentanamine, AcOH and NaCNBH.sub.3, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- cyclopentyl-1- [1-(5-methyl-2- furyl)ethyl]urea 191 [00252]![embedded image]()
331.7 1H NMR (500 MHz, DMSO-d6): δ = 8.23 (s, 1H), 7.45-7.42 (m, 2H), 7.07-7.02 (m, 2H), 6.21 (d, J = 2.8 Hz, 1H), 6.04-6.00 (m, 1H), 5.09-5.05 (m, 1H), 3.63- 3.56 (m, 1H), 2.22 (s, 3H), 1.93- 1.85 (m, 2H), 1.72-1.61 (m, 3H), 1.48 (d, J = 6.8 Hz, 3H), 1.43- 1.28 (m, 3H) ppm 1-(5-methyl- 2- furyl) ethanone General method A using cyclopentaneamine, AcOH and NaCNBH.sub.3, method D1 using 4- fluorophenylisocyanate 1-cyclopentyl-3- (4- fluorophenyl)-1- [1-(5-methyl-2- furyl)ethyl]urea 192 [00253]![embedded image]()
354.8 1H NMR (600 MHz, DMSO-d6): δ = 8.36 (s, 1H), 7.72 (s, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.45-7.44 (m, 2H), 7.32- 7.24 (m, 2H), 5.04-5.00 (m, 1H), 4.24-4.19 (m, 1H), 2.31-2.21 (m, 2H), 2.16-2.07 (m, 2H), 1.66 (d, J = 6.7 Hz, 3H), 1.63-1.58 (m, 1H), 1.55-1.49 (m, 1H) ppm 3- acetyl- benzonitrile General method A using cyclobutanamine, AcOH and NaCNBH.sub.3, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [1-(3- cyanophenyl) ethyl]-1- cyclobutyl-urea 193 [00254]![embedded image]()
345.7 1H NMR (600 MHz, DMSO-d6): δ = 8.25 (s, 1H), 7.61 (s, 1H), 7.48- 7.46 (m, 2H), 7.29-7.27 (m, 2H), 7.73 (d, J = 0.6 Hz, 1H), 6.06 (d, J = 3.2 Hz, 1H), 5.97-5.94 (m, 1H), 4.67 (s, 2H), 3.27 (s, 3H), 2.22 (s, 3H) ppm 5- methylfuran- 2- carbaldehyde General method A using 1-methyl-1H- imidazol-5-amine hydrochloride, Ti(iPrO).sub.4 and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (3- methylimidazol- 4-yl)urea 194 [00255]![embedded image]()
N-(3,5- dimethylphenyl)- 3-ethyl-2- methyl-7- phenyl-5,7- dihydro-4H- thieno[2,3- c]pyridine-6- carboxamide 195 [00256]![embedded image]()
1-cyclopentyl-3- phenyl-1-(2- thienylmethyl) urea 196 [00257]![embedded image]()
1-(4- chlorophenyl)-3- phenyl-1-(2- thienylmethyl) urea 197 [00258]![embedded image]()
1-[1-(4- fluorophenyl) ethyl]-3-phenyl- urea 198 [00259]![embedded image]()
365.99 1H NMR (300 MHz, DMSO-d6) δ: 9.05 (s, 1H), 8.70 (d, J = 4.9 Hz, 1H), 8.63 (s, 1H), 7.93 (br.s., 1H), 7.66-7.61 (m, 1H), 7.52-7.44 (m, 2H), 7.33-7.25 (m, 2H), 4.81 (s, 2H), 2.12 (s, 3H) ppm. 4- formyl- pyridine-2- carbonitrile General method A using 3- methylisooxazol-4- amine hydrochloride, TEA, molecular sieves and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(2-cyano-4- pyridyl)methyl]- 1-(3- methylisoxazol- 4-yl)urea 199 [00260]![embedded image]()
1-(4- chlorophenyl)-3- [1-(5-chloro-2- thienyl)ethyl]urea 200 [00261]![embedded image]()
3-(3,4- dichlorophenyl)- 1-methyl-1-(2- thienylmethyl) urea 201 [00262]![embedded image]()
3-cyclohexyl-1- (p-tolyl)-1-(2- thienylmethyl) urea 202 [00263]![embedded image]()
3-cyclohexyl- (4- methoxyphenyl)- 1-(2- thienylmethyl) urea 203 [00264]![embedded image]()
1-[(5-methyl-2- phenyl-oxazoI-4- yl)methyl]-3- phenyl-urea 204 [00265]![embedded image]()
1-(3- chlorophenyl)- [(3-chloro-2- thienyl)methyl] urea 205 [00266]![embedded image]()
354.25 1H NMR (300 MHz, DMSO-d6) δ: 8.75 (s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.48-7.44 (m, 1H), 7.22 (dd, J = 8.5 Hz, 1.6 Hz, 1H), 6.09 (d, J = 2.9 Hz, 1H), 5.98-5.93 (m, 1H), 4.51-4.36 (m, 1H), 4.46 (s, 2H), 3.83 (s, 3H), 2.20 (s, 3H), 1.85-1.41 (m, 8H). ppm. 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method R using isopropenyl chloroformate, method D6 3-(4-cyano-3- methoxy- phenyl)-1- cyclopentyl-1- [(5-methyl-2- furyl)methyl]urea 206 [00267]![embedded image]()
369.7 1H NMR (300 MHz, DMSO-d6) δ: 8.57 (s, 1H), 7.52-7.41 (m, 2H), 7.33-7.23 (m, 2H), 6.12 (d, J = 2.8 Hz, 1H), 5.99-5.91 (m, 1H), 4.97- 4.75 (m, 2H), 4.31 (d, J = 17.7 Hz, 1H), 2.19 (br.s., 3H), 2.16- 1.88 (m, 4H), 1.87-1.73 (m, 1H), 1.72-1.55 (m, 1H) ppm 5- methylfuran- 2- carbaldehyde General method A using 2,2- difluorocyclopentane-1- amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- (2,2- difluorocyclo- pentyl)-1-[(5- methyl-2- furyl)methyl]urea 207 [00268]![embedded image]()
346.8 1HNMR (300 MHz, CDCl3) δ: 8.90 (br. s, 1H), 8.50-8.43 (m, 1H), 7.60-7.50 (m, 5H), 7.23-7.15 (m, 1H), 6.84 (td, J = 6.8, 1.3 Hz, 1H), 6.47 (s, 1H), 4.78-4.65 (m, 1H), 4.63 (s, 2H), 2.36-2.14 (m, 4H), 1.81-1.65 (m, 2H) ppm pyrazolo(1,5- a)pyridine-2- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- cyclobutyl- (pyrazolo[1,2- a]pyridin-2- ylmethyl)urea 208 [00269]![embedded image]()
328.8 1H NMR (300 MHz, DMSO-d6) δ: 8.90 (s, 1H), 7.76-7.59 (m, 4H), 6.12 (d, J = 2.9 Hz, 1H), 5.99-5.95 (m, 1H), 4.97-4.66 (m, 1H), 4.62- 4.53 (m, 2H), 3.96-3.77 (m, 1H), 2.78-2.59 (m, 2H), 2.42-2.20 (m, 2H), 2.19 (s, 3H) ppm 5- methylfuran- 2- carbaldehyde General method A using 3- fluorocyclobutan-1- amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- cyanophenyl)- (3- fluorocyclobutyl)- 1-[(5-methyl- 2- furyl)methyl]urea 209 [00270]![embedded image]()
347.7 1HNMR (600 MHz, CDCl3) δ: 8.11 (s, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.56-7.50 (m, 3H), 7.43-7.39 (m, 2H), 7.32 (d, J = 8.3 Hz, 1H), 6.57 (br. s, 1H), 4.76 (s, 2H), 4.58-4.50 (m, 1H), 2.32-2.26 (m, 2H), 2.24-2.15 (m, 2H), 1.80-1.69 (m, 2H) ppm 1,3- benzoxazole- 6- carbaldehyde General method A using cyclobutanamine, magnesium perchlorate and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 1-(1,3- benzoxazol-6- ylmethyl)-3-(4- cyanophenyl)-1- cyclobutyl-urea 210 [00271]![embedded image]()
346.7 1HNMR (300 MHz, DMSO-d6) δ: 9.84 (br. s, 1H), 8.52 (d, J = 6.8 Hz, 1H), 7.87 (s, 1H), 7.69 (s, 4H), 7.58 (d, J = 9.0 Hz, 1H), 7.31-7.20 (m, 1H), 6.96-6.85 (m, 1H), 4.67 (s, 2H), 4.63-4.49 (m, 1H), 2.25-2.00 (m, 4H), 1.72-1.46 (m, 2H) ppm imidazo(1,2- a)pyridine-2- carbaldehyde General method A using cyclobutanamine, acetic acid and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- cyclobutyl-1- (imidazo[1,2- a]pyridin-2- ylmethyl)urea 211 [00272]![embedded image]()
347.7 1HNMR (300 MHz, DMSO-d6) δ: 9.16 (br. s, 1H), 9.03 (d, J = 0.8 Hz, 1H), 8.55 (dd, J = 4.5 Hz, 1.4 Hz, 1H), 8.01 (s, 1H), 7.87 (d, J = 4.4 Hz, 1H), 7.68 (s, 4H), 4.78 (s, 2H), 4.56 (m, 1H), 2.22-2.02 (m, 4H), 1.68-1.47 (m, 2H) ppm. imidazo(1,2- a)pyridine-2- carbaldehyde General method A using cyclobutanamine, and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)- cyclobutyl-1- (imidazo[1,2- a]pyrazin-2- ylmethyl)urea 212 [00273]![embedded image]()
356.7 1HNMR (300 MHz, DMSO-d6) δ: 9.02 (d, J = 0.8 Hz, 1H), 8.77 (s, 1H), 8.55 (dd, J = 4.5 Hz, 1.5 Hz, 1H), 7.99 (s, 1H), 7.86 (d, J = 4.4 Hz, 1H), 7.56-7.47 (m, 2H), 7.32-7.23 (m, 2H), 4.76 (s, 2H), 4.56 (m, 1H), 2.21-2.02 (m, 4H), 1.70-1.46 (m, 2H) ppm. imidazo(1,2- a)pyridine-2- carbaldehyde General method A using cyclobutanamine, and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- chlorophenyl)-1- cyclobutyl-1- (imidazo[1,2- a]pyrazin-2- ylmethyl)urea 213 [00274]![embedded image]()
361.5 1HNMR (300 MHz, CDCl3) δ : 9.00 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.90-7.86 (m, 1H), 7.55-7.49 (m, 2H), 7.47-7.39 (m, 3H), 6.49 (br. s, 1H), 4.78 (s, 2H), 4.59-4.44 (m, 1H), 2.36-2.24 (m, 2H), 2.24- 2.13 (m, 2H), 1.81-1.67 (2H) ppm. 1,3- benzothiazole- 6- carbaldehyde General method A cyclobutanamine, magnesium perchlorate and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 1-(1,3- benzothiazol-6- ylmethyl)-3-(4- cyanophenyl)- cyclobutyl-urea 214 [00275]![embedded image]()
360.7 1H NMR (300 MHz, DMSO-d6) δ: 8.93 (s, 1H), 7.78-7.55 (m, 4H), 6.11 (d, J = 2.9 Hz, 1H), 5.91-5.91 (m, 1H), 4.96-4.75 (m, 2H), 4.34 (d, J = 17.8 Hz, 1H), 2.17 (br.s., 3H), 2.23-1.91 (m, 4H), 1.88-1.74 (m, 1H), 1.73-1.58 (m, 1H) ppm 5- methylfuran- 2- carbaldehyde General method A using 2,2- difluorocyclopentane-1- amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)- (2,2- difluorocyclo- pentyl)-1-[(5- methyl-2- furyl)methyl]urea 215 [00276]![embedded image]()
336.8 1H NMR (300 MHz, DMSO-d6): δ = 8.71 (bs, 1H), 7.68 (s, 4H), 7.42 (d, J = 2.0 Hz, 1H), 6.11 (d, J = 2.0 Hz, 1H), 6.08 (d, J = 3.0 Hz, 1H), 5.95 (dd, J = 3.0, 1.0 Hz, 1H), 4.72 (s, 2H), 3.45 (s, 3H), 2.20 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 1-methyl-1H- pyrazol-5-amine, Na.sub.2SO.sub.4 and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (2- methylpyrazol- 3-yl)urea 216 [00277]![embedded image]()
340.7 1H NMR (300 MHz, DMSO-d6) δ: 8.76-8.80 (m, 1H), 7.70-7.60 (m, 4H), 6.10-6.06 (m, 1H), 5.97- 5.93 (m, 1H), 4.65-4.55 (m, 1H), 4.55-4.50 (m, 2H), 3.88-3.48 (m, 1 H), 3.16-3.10 (m, 3H), 2.37- 2.13 (m, 3H), 2.18 (s, 3H), 1.98- 1.82 (m, 1H) ppm 5- methylfuran- 2- carbaldehyde General method A using 3- methoxycyclobutan-1- amine, TEA and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- (3- methoxycyclo- butyl)-1-[(5- methyl-2- furyl)methyl]urea 217 [00278]![embedded image]()
360.8 1HNMR (300 MHz, CDCl3) δ: 7.98 (d, J = 0.9 Hz, 1H), 7.74 (dd, J = 8.3 Hz, 0.6 Hz, 1H), 7.53-7.47 (m, 2H), 7.39-7.33 (m, 2H), 7.27 (br. s, 1H), 7.08 (dd, J = 8.3 Hz, 1.4 Hz, 1H), 6.49 (br. s, 1H), 4.77 (s, 2H), 4.72-4.58 (m, 1H), 4.06 (s, 3H), 2.36-2.24 (m, 2H), 2.24- 2.12 (m, 2H), 1.80-1.65 (m, 2H) ppm 1- methyl- indazole-6- carbaldehyde General method A using molecular sieves, cyclobutanamine and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- cyclobutyl-1-[(1- methylindazol-6- yl)methyl]urea 218 [00279]![embedded image]()
336.7 1HNMR (300 MHz, CDCl3) δ: 7.49-7.43 (m, 2H), 7.43-7.37 (m, 2H), 7.34 (s, 1H), 7.20 (s, 1H), 6.71 (s, 1H), 6.02 (d, J = 3.0 Hz, 1H), 5.84-5.80 (m, 1H), 4.64 (s, 2H), 3.87 (s, 3H), 2.21 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 1-methylpyrazol- 4-amine dihydrochloride, magnesium perchlorate, TEA and NaBH.sub.4, method D1 using 4- cyanophenyl-isocyanate 3-(4- cyanophenyl)-1- [(5-methyl-2- fiiryl)methyl]-1- (1- methylpyrazol- 4-yl)urea 219 [00280]![embedded image]()
349.8 1H NMR (300 MHz, DMSO-d6) δ: 8.99-8.93 (m, 1H), 7.75-7.61 (m, 4H), 6.23-6.16 (m, 1H), 6.01- 5.94 (m, 1H), 4.94-4.62 (m, 1H), 4.62-4.43 (m, 2H), 3.49-3.15 (m, 1H), 2.20 (s, 3H), 2.17-1.87 (m, 2H), 1.85-1.60 (m, 4H) ppm 5- methylfuran- 2- carbaldehyde General method A using 2- aminocyclopentane-1- carbonitrile, TEA and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 1-(2- cyanocyclo- pentyl)-3-(4- cyanophenyl)- [(5-methyl-2- furyl)methyl]urea 220 [00281]![embedded image]()
345.8 1H NMR (300 MHz, DMSO-d6): δ = 8.37 (bs, 1H), 7.47 (d, J = 9.0 Hz, 2H), 7.41 (d, J = 2.0 Hz, 1H), 7.28 (d, J = 8.9 Hz, 2H), 6.09 (d, J = 2.0 Hz, 1H), 6.06 (d, J = 3.0 Hz, 1H), 5.95 (dd, J = 3.0, 1.0 Hz, 1H), 4.70 (s, 2H), 3.45 (s, 3H), 2.20 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 1-methyl-1H- pyrazol-5 amine, Na.sub.2SO.sub.4 and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (2- methylpyrazol- 3-yl)urea 221 [00282]![embedded image]()
336.7 1HNMR (300 MHz, CDCl3) δ: 11.13 (s, 1H), 7.71-7.62 (m, 2H), 7.60-7.52 (m, 2H), 7.31 (d, J = 2.3 Hz, 1H), 6.16 (d, J = 3.1 Hz, 1H), 6.10 (d, J = 2.6 Hz, 1H), 5.89-5.86 (m, 1H), 4.94 (s, 2H), 3.89 (s, 3H), 2.24 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 1-methylpyrazol- 3-amine, magnesium perchlorate and NaBH.sub.4, method D1 using 4- cyanophenyl-isocyanate 3-(4- cyanophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (1- methylpyrazol- 3-yl)urea 222 [00283]![embedded image]()
337.7 1H NMR (300 MHz, DMSO-d6) δ: 8.53 (d, J = 4.7 Hz, 1H), 7.51- 7.42 (m, 2H), 7.30-7.23 (m, 2H), 6.10 (d, J = 3.0 Hz, 1H), 5.99-5.94 (m, 1H), 5.28-4.65 (m, 1H), 4.53 (d, J = 7.0 Hz, 2H), 3.92-3.78 (m, 1H), 2.73-2.51 (m, 2H), 2.44-2.21 (m, 2H), 2.19 (s, 3H) ppm 5- methylfuran- 2- carbaldehyde General method A using 3- fluorocyclobutan-1- amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- chlorophenyl- isocyanate 3-(4- chlorophenyl)-1- (3- fluorocyclobutyl)- 1-[(5-methyl- 2- furyl)methyl]urea 223 [00284]![embedded image]()
347.7 1HNMR (600 MHz, CDCl3) δ: 8.13 (s, 1H), 7.73 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.53-7.50 (m, 2H), 7.42-7.39 (m, 2H), 7.38-7.35 (m, 1H), 6.61 (br. s., 1H), 4.74 (s, 2H), 4.51 (m, 1H), 2.33-2.25 (m, 2H), 2.25-2.15 (m, 2H), 1.82-1.67 (m, 2H) ppm. 1,3- benzoxazole- 6- carbaldehyde General method A using cyclobutanamine, magnesium perchlorate and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 1-(1,3- benzoxazol-5- ylmethyl)-3-(4- cyanophenyl)-1- cyclobutyl-urea 224 [00285]![embedded image]()
349.7 1H NMR (300 MHz, DMSO) δ: 8.83 (br.s., 1H), 7.71-7.61 (m, 4H), 6.14 (d, J = 3.2 Hz, 1H), 5.99-5.96 (m, 1H), 4.55 (br.s., 2H), 4.51-4.37 (m, 1H), 3.05-2.91 (m, 1H), 2.22 (br.s., 3H), 2.20- 2.12 (m, 1H), 2.04-1.72 (m, 5H) ppm 5- methylfuran- 2- carbaldehyde General method A using 3- aminocyclopentane-1- carbonitrile, TEA and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 1-(3- cyanocyclo- pentyl)-3-(4- cyanophenyl)-1- [(5-methyl-2- furyl)methyl]urea 225 [00286]![embedded image]()
345.7 1HNMR (300 MHz, CDCl3) δ: 7.39 (s, 1H), 7.33-7.25 (m, 3H), 7.23-7.16 (m, 2H), 6.53 (s, 1H), 6.08 (d, J = 2.9 Hz, 1H), 5.90-5.85 (m, 1H), 4.70 (s, 2H), 3.92 (s, 3H), 2.27 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 1- methylimidazol-4- amine dihydrochloride, magnesium perchlorate, TEA and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl] (1- methylpyrazol- 4-yl)urea 226 [00287]![embedded image]()
345.7 1HNMR (300 MHz, CDCl3) δ: 10.72 (s, 1H), 7.53-7.45 (m, 2H), 7.30-7.26 (m, 2H), 7.23 (s, 1H), 6.15 (d, J = 3.1 Hz, 1H), 6.07 (d, J = 2.4 Hz, 1H), 5.89-5.83 (m, 1H), 4.94 (s, 2H), 3.86 (s, 3H), 2.24 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 1-methypyrazol- 3-amine, magnesium perchlorate and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (1- methylpyrazol- 3-yl)urea 227 [00288]![embedded image]()
358.7 1H NMR (300 MHz, DMSO) δ: 8.63-8.57 (m, 1H), 7.54-7.44 (m, 2H), 7.32-7.26 (m, 2H), 6.24-6.16 (m, 1H), 6.06-5.95 (m, 1H), 4.92- 4.64 (m, 1H), 4.58-4.40 (m, 2H), 3.48-3.13 (m, 1H), 2.21 (s, 3H), 2.17-1.87 (m, 2H), 1.85-1.60 (m, 4H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 2- aminocyclopentane-1- carbonitrile, TEA and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- (2-cyano- cyclopentyl)- 1-[(5-methyl- 2- furyl)methyl]urea 228 [00289]![embedded image]()
368.7 1HNMR (300 MHz, CDCl3) δ: 8.38 (d, J = 2.5 Hz, 1H), 8.22 (dd, J = 8.5 Hz, 2.4 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.42 (br. s, 1H), 6.21 (d, J = 3.1 Hz, 1H), 6.00-5.96 (m, 1H), 4.74-4.72 (m, 1H), 4.34 (s, 2H), 2.33 (s, 3H), 2.01-1.88 (m, 2H), 1.80-1.54 (m, 6H) ppm. 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method D2 using 6- (trifluoromethyl)pyridin- 3-amine 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]- [6- (trifluoromethyl)- 3-pyridyl]urea 229 [00290]![embedded image]()
363.7 1HNMR (300 MHz, CDCl3) δ: 8.57 (br. s, 1H), 8.10-8.03 (m, 1H), 7.93-7.87 (m, 1H), 7.58 (s, 4H), 7.54 (dd, J = 8.1 Hz, 1.1 Hz, 1H), 7.49-7.41 (m, 1H), 4.89 (s, 2H), 4.67-4.52 (m, 1H), 2.41-2.14 (m, 4H), 1.84-1.64 (m, 2H) ppm. 1,3- benzothiazole- 2- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 1-(1,3- benzothiazol-2- ylmethyl)-3-(4- cyanophenyl)-1- cyclobutyl-urea 230 [00291]![embedded image]()
349.6 1HNMR (300 MHz, CDCl3) δ: 7.60-7.49 (m, 4H), 6.68 (br. s, 1H), 6.09 (s, J = 3.0 Hz, 1H), 5.91-5.81 (m, 1H), 4.91-4.71 (m, 1H), 4.56-4.43 (m, 1H), 2.24 (s, 3H), 2.15 (s, 3H), 2.04 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 3,3-- dimethylisooxazol-4- amine, magnesium perchlorate and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- (3,5- dimethylisoxazol- 4-yl)-1-[(5- methyl-2- furyl)methyl]urea 231 [00292]![embedded image]()
336.7 1HNMR (300 MHz, CDCl3) δ: 7.64 (br. s, 1H), 7.56-7.46 (m, 4H), 7.05 (d, J = 1.5 Hz, 1H), 6.88 (d, J= 1.5 Hz, 1H), 6.11 (d, J = 3.0 Hz, 1H), 5.88-5.83 (m, 1H), 4.88 (s, 2H), 3.36 (s, 3H), 2.22 (s, 3H) ppm 5- methylfuran- 2- carbaldehyde General method A using 3- methylimidazol-4- amine hydrochloride, sodium sulfate, TEA and NaBH.sub.4, method D1 using 4-cyanophenyl- isocyanate 3-(4- cyanophenyl)-1- [(5-methyl-2- furyl)methyl] (3- methylimidazol- 4-yl)urea 232 [00293]![embedded image]()
347.7 1HNMR (600 MHz, CDCl3) δ: 8.11 (s, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.56-7.50 (m, 3H), 7.43-7.39 (m, 2H), 7.32 (d, J = 8.3 Hz, 1H), 6.57 (br. s, 1H), 4.76 (s, 2H), 4.50 (m, 1H), 2.32-2.26 (m, 2H), 2.24- 2.15 (m, 2H), 1.80-1.69 (m, 2H) ppm. 1,3- benzoxazole- 5- carbaldehyde General method A using cyclobutanamine, magnesium perchlorate and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 1-(1,3- benzoxazol-5- ylmethyl)-3-(4- chlorophenyl)-1- cyclobutyl-urea 233 [00294]![embedded image]()
336.9 1H NMR (300 MHz, DMSO-d6): δ = 8.86 (bs, 1H), 7.73-7.64 (m, 4H), 7.09 (d, J = 1.4 Hz, 1H), 6.85 (d, J = 1.4 Hz, 1H), 6.05 (d, J = 3.1 Hz, 1H), 5.93 (dd, J = 3.0, 1.1 Hz, 1H), 4.75 (s, 2H), 3.21 (s, 3H), 2.18 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 1- methylimidazol-2- amine hydrochloride, Na.sub.2SO.sub.4, TEA and NaBH.sub.4, method D1 using 4-cyanophenyl- isocyanate 3-(4- cyanophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (1- methylimidazol- 2-yl)urea 234 [00295]![embedded image]()
346.8 1H NMR (300 MHz, DMSO-d6) δ: 8.86 (s, 1H), 7.68 (br.s., 4H), 7.61-7.48 (m, 2H), 7.29-7.15 (m, 2H), 6.68 (d, J = 0.8 Hz, 1H), 4.80 (s, 2H), 4.63-4.39 (m, 1H), 2.25- 2.07 (m, 4H), 1.73-1.49 (m, 2H) ppm benzofuran- 2- carbaldehyde General method A using cyclobutanamine, magnesium perchlorate and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 1-(benzofuran-2- ylmethyl)-3-(4- cyanophenyl)-1- cyclobutyl-urea 235 [00296]![embedded image]()
369.7 1HNMR (300 MHz, CDCl3) δ: 7.97 (d, J = 0.8 Hz, 1H), 7.72 (dd, J = 8.3 Hz, J = 0.4 Hz, 1H), 7.28 (br. s, 1H), 7.19 (s, 4H), 7.08 (dd, J = 8.3 Hz, 1.2 Hz, 1H), 6.28 (br. s, 1H), 4.76 (s, 2H), 4.71-4.58 (m, 1H), 4.06 (s, 3H), 2.36-2.21 (m, 2H), 2.21-2.10 (m, 2H), 1.79-1.61 (m, 2H) ppm 1- methyl- indazole-6- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- cyclobutyl-1-[(1- methylindazol-6- yl)methyl]urea 236 [00297]![embedded image]()
311.7 1H NMR (300 MHz, DMSO) δ: 8.82 (s, 1H), 7.52-7.41 (m, 2H), 7.39-7.29 (m, 2H), 6.14 (d, J = 3.0 Hz, 1H), 6.00-5.95 (m, 1H), 4.87- 4.73 (m, 1H), 4.61 (br.s, 2H), 4.59 (br.s., 4H), 4.02 (s, 1H), 2.20 (br.s., 3H) ppm 5- methylfuran- 2- carbaldehyde General method A using oxetane-3-amine and NaBH.sub.4, method D2 using 4-ethynylaniline 3-(4- ethynylphenyl)- 1-[(5-methyl-2- furyl)methyl]-1- (oxetan-3- yl)urea 237 [00298]![embedded image]()
356.7 1HNMR (600 MHz, CDCl3) δ: 8.15 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.62 (s, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.31-7.21 (m, 4H), 6.62 (br. s, 1H), 4.78 (s, 2H), 4.52 (m, 1H), 2.35-2.28 (m, 2H), 2.28-2.20 (m, 2H), 1.83-1.72 (m, 2H) ppm. 1,3- benzooxazole- 6- carbaldehyde General method A using cyclobutanamine, magnesium perchlorate and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 1-(1,3- benzoxazol-6- ylmethyl)-3-(4- chlorophenyl)-1- cyclobutyl-urea 238 [00299]![embedded image]()
360.5 1HNMR (300 MHz, CDCl3) δ: 7.34-7.37 (m, 2H), 7.25-7.20 (m, 2H), 6.34 (br. s, 1H), 6.08 (d, J = 2.9 Hz, 1H), 5.90-5.84 (m, 1H), 4.81-4.79 (m, 1H), 4.58-4.44 (m, 1H), 2.24 (s, 3H), 2.14 (s, 3H), 2.05 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 3,3-- dimethylisooxazol-4- amine, magnesium perchlorate and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)- (3,5- dimethylisoxazol- 4-yl)-1-[(5- methyl-2- furyl)methyl]urea 239 [00300]![embedded image]()
355.7 1HNMR (300 MHz, CDCl3) δ: 8.45 (dd, J = 7.1 Hz, 0.9 Hz, 1H), 8.19 (br. s, 1H), 7.51 (dt, J = 7.8 Hz, 1.1 Hz, 1H), 7.41-7.34 (m, 2H), 7.24-7.11 (m, 3H), 6.81 (td, J = 6.9 Hz, 1.3 Hz, 1H), 6.46 (s, 1H), 4.77-4.66 (m, 1H), 4.64 (s, 2H), 2.34-2.16 (m, 4H), 1.80-1.63 (m, 2H) ppm. pyrazolo(1,5- a)pyridine-2- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- cyclobutyl-1- (pyrazolo[1,5- a]pyridin-2- ylmethyl)urea 240 [00301]![embedded image]()
373.7 1HNMR (300 MHz, CDCl3) δ: 8.02-7.95 (m, 1H), 7.88-7.83 (m, 1H), 7.55 (dd, J = 9.0 Hz, 1.7 Hz, 1H), 7.33-7.27 (m, 2H), 7.25-7.19 (m, 2H), 6.33 (br. s, 1H), 4.80 (d, J = 0.9 Hz, 2H), 4.48-4.34 (m, 1H), 2.37-2.11 (m, 4H), 1.83-1.66 (m, 2H) ppm. 2,1,3- benzothia- diazole- 5- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 1-(2,1,3- benzothiadiazol- 5-ylmethyl)- (4- chlorophenyl)-1- cyclobutyl-urea 241 [00302]![embedded image]()
344.7 1HNMR (300 MHz, CDCl3) δ: 7.60-7.53 (m, 2H), 7.45-7.35 (m, 2H), 7.32 (br.s., 1H), 6.24 (d, J = 3.0 Hz, 1H), 6.02-5.97 (m, 1H), 4.53-4.42 (m, 1H), 4.37 (s, 2H), 3.06-2.69 (m, 4H), 2.34 (d, J = 0.5 Hz, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 3,3- difluorocyclobutane-1- amine, TEA and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl) (3,3-difluoro- cyclobutyl)- 1-[(5-methyl- 2- furyl)methyl]urea 242 [00303]![embedded image]()
345.8 1H NMR (500 MHz, DMSO-d6) δ : 8.26 (s, 1H), 7.60 (s, 1H), 7.47 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 6.73 (s, 1H), 6.06 (d, J = 2.8 Hz, 1H), 5.97-5.95 (m, 1H), 4.66 (s, 2H), 3.23 (s, 3H), 2.21 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 1-methyl-1H- imidazol-5-amine hydrochloride, Ti(iPrO).sub.4 and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (3- methylimidazol- 4-yl)urea 243 [00304]![embedded image]()
372.5 1HNMR (300 MHz, CDCl3) δ : 9.02 (br. s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.90 (br. s, 1H), 7.49- 7.40 (m, 1H), 7.26-7.16 (m, 4H), 6.27 (br. s, 1H),4.77(s, 2H), 4.58-4.42 (m, 1H), 2.35-2.22 (m, 2H), 2.22-2.11 (m, 2H), 1.79-1.64 (m, 2H) ppm. 1,3- benzothiazole- 6- carbaldehyde General method A cyclobutanamine, magnesium perchlorate and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 1-(1,3- benzothiazol-2- ylmethyl)-3-(4- chlorophenyl)-1- cyclobutyl-urea 244 [00305]![embedded image]()
360.7 1H NMR (300 MHz, DMSO) δ: 8.88 (s, 1H), 7.72-7.60 (m, 4H), 6.14 (d, J = 3.0 Hz, 1H), 5.99-5.94 (m, 1H), 4.68-4.57 (m, 1H), 4.55 (s, 2H), 2.40-2.20 (m, 3H), 2.19 (br.s., 3H), 2.04-1.85 (m, 3H) ppm 5- methylfuran- 2- carbaldehyde General method A using 3,3- difluorocyclopentane-1- amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- (3,3- difluorocyclo- pentyl)-1-[(5- methyl-2- furyl)methyl]urea 245 [00306]![embedded image]()
369.7 1H NMR (300 MHz, DMSO) δ: 8.53 (s, 1H), 7.53-7.40 (m, 2H), 7.33-7.22 (m, 2H), 6.14 (d, J = 3.10 Hz, 1H), 5.99-5.95 (m, 1H), 4.65- 4.53 (m, 1H), 4.52 (s, 2H), 2.40-2- 20 (m, 3H), 2.20 (br.s., 3H), 2.08- 1.86 (m, 3H) ppm 5- methylfuran- 2- carbaldehyde General method A using 3,3- difluorocyclopentane-1- amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- chlorophenyl)-1- (3,3- difluorocyclo- pentyl)-1-[(5- methyl-2- furyl)methyl]urea 246 [00307]![embedded image]()
314.8 1HNMR (300 MHz, CDCl3) δ: 8.29 (d, J = 2.4 Hz, 1H), 7.95 (dd, J = 8.3 Hz, 2.4 Hz, 1H), 7.18 (br. s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.18 (d, J = 3.0 Hz, 1H), 5.97-5.92 (m, 1H), 4.75-4.60 (m, 1H), 4.34 (s, 2H), 2.51 (s, 3H), 2.30 (s, 3H), 2.02-1.85 (m, 2H), 1.80-1.49 (m, 6H) ppm. 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method D2 using 6-methylpyridin- 3-amine 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-2- (6-methyl-3- pyridyl)urea 247 [00308]![embedded image]()
355.7 1HNMR (300 MHz, CDCl3) δ: 7.24 (s, 4H), 7.00 (br. s, 1H), 6.21 (d, J = 3.1 Hz, 1H), 6.00-5.95 (m, 1H), 4.52-4.42 (m, 1H), 4.36 (s, 2H), 2.98-2.72 (m, 4H), 2.32 (d, J = 0.5 Hz, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 3,3- difluorocyclobutane-1- amine, TEA and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- chlorophenyl)-1- (3,3-difluoro- cyclobutyl)- 1-[(5-methyl- 2- furyl)methyl]urea 248 [00309]![embedded image]()
372.7 1HNMR (300 MHz, CDCl3) δ: 8.04 (s, J = 8.1 Hz, 1H), 7.89 (s, J = 7.8 Hz, 1H), 7.73 (br. s, 1H), 7.56-7.48 (m, 1H), 7.47-7.35 (m, 3H), 7.25-7.20 (m, 2H), 4.91 (s, 2H), 4.59-4.46 (m, 1H), 2.39-2.17 (m, 4H), 1.82-1.65 (m, 2H) ppm. 1,3- benzothiazole- 2- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 1-(1,3- benzothiazol-2- ylmethyl)-3-(4- chlorophenyl)-1- cyclobutyl-urea 249 [00310]![embedded image]()
347.7 1HNMR (300 MHz, CDCl3) δ: 8.52 (dd, J = 5.0 Hz, 1.2 Hz, 1H), 7.87-7.80 (m, 1H), 7.60-7.49 (m, 4H), 7.34-7.26 (m, 1H), 6.95 (d, J = 0.8 Hz, 1H), 6.78 (br. s, 1H), 4.79 (d, J = 0.7 Hz, 2H), 4.42-4.27 (m, 1H), 2.27-2.14 (m, 4H), 1.87- 1.67 (m, 2H) ppm furo(3,2- b)pyridine-2- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- cyclobutyl- (furo[3,2- b]pyridin-2- ylmethyl)urea 250 [00311]![embedded image]()
355.7 1HNMR (300 MHz, DMSO-d6) δ: 9.37 (br. s, 1H), 8.52 (d, J = 6.7 Hz, 1H), 7.85 (s, 1H), 7.61-7.47 (m, 3H), 7.32-7.20 (m, 3H), 6.93- 6.83 (m, 1H), 4.65 (s, 2H), 4.62- 4.50 (m, 1H), 2.23-1.99 (m, 4H), 1.67-1.40 (m, 2H) ppm. imidazo(1,2- a)pyridine-2- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- cyclobutyl-1- (imidazo[1,2- a]pyridin-2- ylmethyl)urea 251 [00312]![embedded image]()
349.7 1H NMR (300 MHz, DMSO) δ: 8.45 (d, J = 5.8 Hz, 1H), 7.53-7.41 (m, 2H), 7.37-7.22 (m, 2H), 6.10- 6.04 (m, 1H), 5.96-5.94 (m, 1H), 4.66-3.89 (m, 1H), 4.52 (d, J = 5.2 Hz, 2H), 4.01-3.47 (m, 1H), 3.13 (d, J = 5.8 Hz, 3H), 2.36-2.21 (m, 2H), 2.24-2.15 (m, 1H), 2.21 (s, 3H), 1.97-1.81 (m, 1H) ppm 5- methylfuran- 2- carbaldehyde General method A using 3- methoxycyclobutan-1- amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- (3-methoxy- cyclobutyl)- 1-[(5- methyl-2- furyl)methyl]urea 252 [00313]![embedded image]()
356.7 1HNMR (300 MHz, CDCl3) δ: 8.51 (dd, J = 4.9 Hz, 1.0 Hz, 1H), 7.75 (dt, J = 7.3 Hz, 1.0 Hz, 1H), 7.36-7.29 (m, 2H), 7.26-7.18 (m, 2H), 6.87 (d, J = 0.8 Hz, 1H), 6.50 (br. s, 1H), 4.77 (d, J = 0.7 Hz, 2H), 4.39-4.25 (m, 1H), 2.41-2.14 (m, 4H), 1.89-1.63 (m, 2H) ppm. furo(3,2- b)pyridine-2- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- cyclobutyl-1- (furo[3,2- b]pyridin-2- ylmethyl)urea 253 [00314]![embedded image]()
330.8 1HNMR (300 MHz, CDCl3) δ : 7.90 (d, J = 2.3 Hz, 1H), 7.80 (dd, J = 8.8 Hz, 2.7 Hz, 1H), 6.84 (br. s, 1H), 6.70 (d, J = 8.7 Hz, 1H), 6.17 (d, J = 3.0 Hz, 1H), 5.97-5.92 (m, 1H), 4.74-4.59 (m, 1H), 4.32 (s, 2H), 3.89 (s, 3H), 2.30 (d, J = 0.5 Hz, 3H), 2.01-1.86 (m, 2H), 1.78-1.48 (m, 6H) ppm. 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method D2 using 6- methoxypyridin-3- amine 1-cyclopentyl- (6-methoxy-3- pyridyl)-1-[(5- methyl-2- furyl)methyl]urea 254 [00315]![embedded image]()
358.7 1H NMR (300 MHz, DMSO) δ: 8.46 (br.s., 1H), 7.52-7.42 (m, 2H), 7.32-7.24 (m, 2H), 6.14 (d, J = 2.9 Hz, 1H), 6.00-5.96 (m, 1H), 4.52 (br.s., 2H), 4.49-4.36 (m, 1H), 3.05-2.91 (m, 1H), 2.22 (br.s, 3H), 2.20-2.11 (m, 1H), 2.04-1.72 (m, 5H) ppm 5- methylfuran- 2- carbaldehyde General method A using 3- aminocyclopentane-1- carbonitrile, TEA and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- (3- cyanocyclo- pentyl)-1-[(5- methyl-2- furyl)methyl]urea 255 [00316]![embedded image]()
364.7 1HNMR (300 MHz, CDCl3) δ/ppm: 8.00 (dd, J = 9.0 Hz, J = 0.3 Hz, 1H), 7.88-7.84 (m, 1H), 7.58-7.51 (m, 3H), 7.50-7.44 (m, 2H), 6.55 (br. s, 1H), 4.80 (s, 2H), 4.50-4.35 (m, 1H), 2.38-2.12 (m, 4H), 1.83-1.66 (m, 2H). 2,1,3- benzothia- diazole- 5- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 1-(2,1,3- benzothiadiazol- 5-ylmethyl)-3- (4- cyanophenyl)- cyclobutyl-urea 256 [00317]![embedded image]()
344.7 1HNMR (300 MHz, CDCl3) δ: 8.08 (s, 1H), 7.33-7.15 (m, 4H), 6.28 (br. s, 1H), 6.13-6.01 (m, 1H), 5.90-5.81 (m, 1H), 4.66 (s, 2H), 2.23 (s, 3H), 2.20 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 5-methylisoxazol- 4-amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (5- methylisoxazol- 4-yl)urea 257 [00318]![embedded image]()
335.6 1HNMR (300 MHz, DMSO-d6) δ: 8.67 (br. s, 1H), 8.50 (d, J = 0.6 Hz, 1H), 7.69 (s, 4H), 6.10 (d, J = 3.0 Hz, 1H), 5.99-5.94 (m, 1H), 4.67 (s, 2H), 2.21 (d, J = 0.4 Hz, 3H), 2.08 (d, J = 0.4 Hz, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 5-methylisoxazol- 4-amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (5- methylisoxazol- 4-yl)urea 258 [00319]![embedded image]()
352.8 1H NMR (300 MHz, DMSO) δ: 8.46 (s, 1H), 7.51-7.43 (m, 2H), 7.38-7.28 (m, 2H), 6.12 (d, J = 3.0 Hz, 1H), 5.98-5.92 (m, 1H), 4.47 (br.s, 2H), 4.00 (s, 1H), 3.99-3.91 (m, 1H), 2.82-2.74 (m, 2H), 2.20 (d, J = 0.7 Hz, 3H), 2.13 (s, 3H), 1.98-1.66 (m, 2H), 1.80-1.64 (m, 2H), 1.58-1.47 (m, 2H) ppm 5- methylfuran- 2- carbaldehyde General method A using 4-amino-1- methylpiperidine and NaBH.sub.4, method D2 using 4-ethynylaniline 3-(4- ethynylphenyl)- 1-[(5-methyl- furyl)methyl]-1- (1-methyl-4- piperidyl)urea 259 [00320]![embedded image]()
339.7 1H NMR (300 MHz, DMSO) δ: 8.48 (s, 1H), 7.51-7.44 (m, 2H), 7.37-7.31 (m, 2H), 6.14 (d, J = 3.2 Hz, 1H), 5.99-5.94 (m, 1H), 4.50 (br.s, 2H), 4.30-4.16 (m, 1H), 4.01 (s, 1H), 3.93-3.83 (m, 2H), 3.42- 3.34 (m, 2H), 2.20 (d, J = 0.7 Hz, 3H) 1.84-1.66 (m, 2H), 1.59-1.49 (m, 2H) ppm 5- methylfuran- 2- carbaldehyde General method A using 4- aminotetrahydropyran and NaBH.sub.4, method D2 using 4-ethynyl aniline 3-(4- ethynylphenyl)- 1-[(5-methyl-2- furyl)methyl]-1- tetrahydropyran- 4-yl-urea 260 [00321]![embedded image]()
372.7 1HNMR (300 MHz, CDCl3) δ: 9.02 (s, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.95 (d, J = 26.1 Hz, 1H), 7.41 (dd, J = 8.3 Hz, 1.4 Hz, 1H), 7.25-7.13 (m, 4H), 6.27 (s, 1H), 4.78 (s, 2H), 4.58-4.44 (m, 1H), 2.34-2.08 (m, 4H), 1.78-1.64 (m, 2H) ppm. 1,3- benzothiazole- 5- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 1-(1,3- benzothiazol-5- ylmethyl)-3-(4- chlorophenyl)-1- cyclobutyl-urea 261 [00322]![embedded image]()
363.7 1HNMR (300 MHz, CDCl3) δ: 9.03 (s, 1H), 8.04 (d, J = 0.3 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.55-7.47 (m, 2H), 7.44-7.36 (m, 3H), 6.50 (s, 1H), 4.79 (s, 2H), 4.61-4.45 (m, 1H), 2.39-2.08 (m, 4H), 1.83-1.65 (m, 2H) ppm. 1,3- benzothiazole- 5- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 1-(1,3- benzothiazol-5- ylmethyl)-3-(4- cyanophenyl)-1- cyclobutyl-urea 262 [00323]![embedded image]()
372.6 1HNMR (300 MHz, CDCl3) δ: 9.03 (s, 1H), 8.09 (dd, J = 8.4 Hz, 0.3 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.39-7.33 (m, 1H), 7.28-7.18 (m, 4H), 6.28 (br. s, 1H), 4.87 (s, 2H), 4.54-4.38 (m, 1H), 2.29-2.06 (m, 4H), 1.77-1.63 (m, 2H) ppm. 1,3- benzothiazole- 7- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 1-(1,3- benzothiazol-7- ylmethyl)-3-(4- chlorophenyl)-1- cyclobutyl-urea 263 [00324]![embedded image]()
363.7 1HNMR (300 MHz, CDCl3) δ: 9.03 (s, 1H), 8.11 (dd, J = 8.1 Hz, 0.7 Hz, 1H), 7.59-7.49 (m, 3H), 7.45-7.39 (m, 2H), 7.38-7.33 (m, 1H), 6.50 (br. s, 1H), 4.88 (s, 2H), 4.54-4.40 (m, 1H), 2.33-2.07 (m, 4H), 1.81-1.60 (m, 2H) ppm. 1,3- benzothiazole- 7- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 1-(1,3- benzothiazol-7- ylmethyl)-3-(4- cyanophenyl)-1- cyclobutyl-urea 264 [00325]![embedded image]()
404.7 1H NMR (300 MHz, DMSO) δ: 9.31 (s, 1H), 8.87 (br.s, 1H), 8.07- 7.96 (m, 2H), 7.65 (s, 4H), 7.44 (dd, J = 8.3 Hz, 1.7 Hz, 1H), 5.75 (s, 1H), 4.74 (br.s, 2H), 4.18-4.02 (m, 2H), 2.77-2.67 (m, 2H), 2.01 (s, 3H), 1.97-1.85 (m, 2H), 1.74- 1.48 (m, 2H) ppm 1,3- benzothiazole- 6- carbaldehyde General method A using 4-amino-1- methylpiperidine and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 1-(1,3- benzothiazol-6- ylmethyl)-3-(4- cyanophenyl)-1- (1-methyl-4- piperidyl)urea 265 [00326]![embedded image]()
391.7 1H NMR (300 MHz, DMSO) δ: 9.32 (s, 1H), 8.89 (br.s, 1H), 8.05- 7.99 (m, 2H), 7.66 (s, 4H), 7.44 (dd, J = 8.4 Hz, 1.5 Hz, 1H), 4.76 (br.s., 2H), 4.43-4.29 (m, 1H), 3.88-3.78 (m, 2H), 3.42-3.33 (m, 2H), 1.77-1.61 (m, 2H), 1.61-1.50 (m, 2H) ppm 1,3- benzothiazole- 6- carbaldehyde General method A using 4- aminotetrahydropyran and NaBH.sub.4, method D1 using 4-cyanophenyl- isocyanate 1-(1,3- benzothiazol-6- ylmethyl)-3-(4- cyanophenyl)-1- tetrahydropyran- 4-yl-urea 266 [00327]![embedded image]()
335.7 1HNMR (300 MHz, DMSO-d6) δ: 9.25 (s, 1H), 7.93 (s, 1H), 7.68- 7.59 (m, 4H), 6.12 (d, J = 2.7 Hz, 1H), 5.99-5.90 (m, 1H), 4.83 (s, 2H), 3.49 (s, 3H), 2.17 (s, 3H) ppm 5- methylfuran- 2- carbaldehyde General method A using 2-methyl-1,2,4- triazol-3-amine, acetic acid and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (2-methyl-1,2,4- triazol-3-yl)urea 267 [00328]![embedded image]()
346.7 1H NMR (300 MHz, DMSO-d6) δ: 8.66 (br.s., 1H), 7.59 (s, 1H), 7.50-7.43 (m, 2H), 7.34-7.28 (m, 2H), 6.11 (d, J = 3.13 Hz, 1H), 5.99-5.95 (m, 1H), 4.76 (br.s., 2H), 3.66 (s, 3H), 2.21 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 3-methyl-triazol- 4-amine, acetic acid and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (3-methyltriazol- 4-yl)urea 268 [00329]![embedded image]()
337.7 1H NMR (300 MHz, DMSO-d6) δ: 8.96 (s, 1H), 7.76-7.64 (m, 4H), 7.60 (s, 1H), 6.13 (d, J = 3.10 Hz, 1H), 5.99-5.95 (m, 1H), 4.78 (br.s., 2H), 3.67 (s, 3H), 2.21 (br.s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 3-methyl-triazol- 4-amine, acetic acid and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (3-methyltriazol- 4-yl)urea 269 [00330]![embedded image]()
361.1 1H NMR (300 MHz, DMSO-d6) δ: 8.98 (s, 1H), 7.86 (d, J = 4.5 Hz, 1H), 7.65 (s, 1H), 7.52 7.45 (m, 2H), 7.31-7.24 (m, 2H), 7.23 (d, J = 4.5 Hz, 1H), 4.58-4.43 (m, 1H), 4.53 (s, 2H), 2.26-2.02 (m, 4H), 1.69-1.45 (m, 2H) ppm. imidazo(2,1- b)thiazole-6- carbaldehyde General method A using cyclobutylamine, molecular sieves and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- cyclobutyl-1- (imidazo[2,1- b]thiazol-6- ylmethyl)urea 270 [00331]![embedded image]()
352.1 1H NMR (300 MHz, DMSO-d6) δ: 9.39 (s, 1H), 7.86 (d, J = 4.4 Hz, 1H), 7.72-7.61 (m, 5H), 7.23 (d, J = 4.5 Hz, 1H), 4.56 (s, 2H), 4.53-4.43 (m, 1H), 2.24-2.03 (m, 4H), 1.70-1.45 (m, 2H) ppm. imidazo(2,1- b)thiazole-6- carbaldehyde General method A using cyclobutylamine, molecular sieves and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- cyclobutyl-1- (imidazo[2,1- b]thiazol-6- ylmethyl)urea 271 [00332]![embedded image]()
337.09 1H NMR (300 MHz, DMSO-d6) δ: 8.53 (s, 1H), 7.47 (m , 2H), 7.28 (m , 2H), 6.11 (d, J = 3.0 Hz, 1H), 5.97 (m, 1H), 4.81 (dp, 2JF- H = 56.7 Hz, 3JH-H = 6.7 Hz, 1H), 4.56 (m, 2H), 3.87 (m, 1H), 2.75 2.61 (m, 2H), 2.37-2.16 (m, 5H) ppm. 5- methylfuran- 2- carbaldehyde General method A using cis-3- fluorocyclobutan-1- amine hydrochloride, TEA, molecular sieves and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- (3- fluorocyclobutyl)- 1-[(5-methyl- 2- furyl)methyl]urea 272 [00333]![embedded image]()
328.09 1H NMR (300 MHz, DMSO-d6) δ: 8.92 (s, 1H), 7.66 (m, 4H), 6.12 (d, J = 3.0 Hz, 1H), 5.97 (m, 1H), 5.16 (dt, J = 57.7, 5.9 Hz, 1H), 4.73 (m, 1H), 4.56 (s, 2H), 2.67- 2.32 (m, 4H), 2.20 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using trans-3- fluorocyclobutan-1- amine hydrochloride, TEA, molecular sieves and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)- (3- fluorocyclobutyl)- 1-[(5-methyl- 2- furyl)methyl]urea 273 [00334]![embedded image]()
337.09 1H NMR (300 MHz, DMSO-d6) δ: 8.55 (s, 1H), 7.47 (m, 2H), 7.28 (m, 2H), 6.11 (d, J = 2.9 Hz, 1H), 5.97 (m, 1H), 5.15 (dt, J = 57.9, 5.8 Hz, 1H), 4.73 (m, 1H), 4.53 (s, 2H), 2.65-2.31 (m, 4H), 2.21 (s, 3H). ppm. 5- methylfuran- 2- carbaldehyde General method A using trans-3- fluorocyclobutan-1- amine hydrochloride, TEA, molecular sieves and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- (3- fluorocyclobutyl)- 1-[(5-methyl- 2- furyl)methyl]urea 274 [00335]![embedded image]()
347.12 1H NMR (500 MHz, DMSO-d6) δ:8.92 (s, 1H), 8.90 (d, J = 7.0 Hz, 1H), 7.86 (d, J = 1.2 Hz, 1H), 7.67 (m , 4H), 7.64 (d, J = 1.1 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H), 4.78 (s, 2H), 4.66 (p, J = 8.5 Hz, 1H), 2.18-2.01 (m, 4H), 1.64 1.48 (m, 2H). ppm. imidazo(1,2- a)pyrimidine- 7- carbaldehyde General method A using cyclobutylamine, TEA, molecular sieves and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- cyclobutyl-1- (imidazo[1,2- a]pyrimidin- ylmethyl)urea 275 [00336]![embedded image]()
356.03 1H NMR (500 MHz, DMSO-d6) δ: 8.89 (d, J = 7.0 Hz, 1H), 8.57 (s, 1H), 7.86 (d, J = 1.2 Hz, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.50 (m, 2H), 7.27 (m, 2H), 6.93 (d, J = 7.0 Hz, 1H), 4.75 (s, 2H), 4.65 (p, J = 8.5 Hz, 1H), 2.20-1.93 (m, 4H), 1.65 1.48 (m, 2H) ppm. imidazo(1,2- a)pyrimidine- 7- carbaldehyde General method A using cyclobutylamine, TEA, molecular sieves and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- cyclobutyl-1- (imidazo[1,2- a]pyrimidin-7- ylmethyl)urea 276 [00337]![embedded image]()
389.18 1H NMR (600 MHz, DMSO-d6) δ: 10.85 (br. s, 1H), 9.34 (s, 1H), 8.05-8.04 (m, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.79-7.74 (m, 4H), 7.68 (dd, J = 2.3 Hz, 0.3 Hz, 1H), 7.46 (dd, J = 8.6 Hz, 1.7 Hz, 1H), 6.08 (d, J = 2.4 Hz, 1H), 5.16 (s, 2H), 3.83 (s, 3H) ppm. 1,3- benzothiazole- 6- carbaldehyde General method A using 2-methylpyrazol- 3-amine, molecular sieves and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 1-(1,3- benzothiazol-6- ylmethyl)-3-(4- cyanophenyl)-1- (2-methyl-1H- pyrazol-3- yl)urea 277 [00338]![embedded image]()
346.05 1H NMR (600 MHz, DMSO-d6) δ: 8.88 (s, 1H), 8.45 (s, 1H), 7.48 (m, 2H), 7.29 (m, 2H), 6.11 (d, J = 3.1 Hz, 1H), 5.97 (m, 1H), 4.67 (s, 2H), 2.21 (s, 3H), 1.92 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 3-methylisoxazol- 4-amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (3- methylisoxazol- 4-yl)urea 278 [00339]![embedded image]()
339.09 1H NMR (600 MHz, DMSO-d6) δ: 8.91 (d, J = 0.5 Hz, 1H), 8.78 (s, 1H), 7.69 (m, 4H), 6.12 (d, J = 3.0 Hz, 1H), 5.97 (m, 1H), 4.69 (s, 2H), 2.21 (d, J = 0.8 Hz, 3H), 1.92 (d, J = 0.5 Hz, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 3-methylisoxazol- 4-amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (3- methylisoxazol- 4-yl)urea 279 [00340]![embedded image]()
380.07 1H NMR (600 MHz, CDCl3) δ: 8.33 (s, 1H), 7.38-7.33 (m, 2H), 7.32-7.28 (m, 2H), 6.35 (br. s, 1H), 6.11 (d, J = 3.0 Hz, 1H), 5.90- 5.87 (m, 1H), 4.70 (s, 2H), 4.29 (s, 2H), 3.43 (s, 3H), 2.29 (s, 3H), 2.10 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 5-methylisoxazol- 4-amine hydrochloride, TEA and NaBH.sub.4, method D1 using 1- iodo-4- isocyanatobenzene, method F using 3- methoxyprop-1-yne, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA 3-[4-(3- methoxyprop-1- ynyl)phenyl]-1- [(5-methyl-2- furyl)methyl]-1- (5- methylisoxazol- 4-yl)urea 280 [00341]![embedded image]()
418.07 1H NMR (600 MHz, CDCl3) δ: 10.95 (s, 1H), 8.93 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 0.9 Hz, 1H), 7.57-7.53 (m, 2H), 7.46 (dd, J = 8.4 Hz, 1.7 Hz, 1H), 7.42-7.38 (m, 2H), 7.22 (d, J = 2.4 Hz, 1H), 5.78 (d, J = 2.3 Hz, 1H), 5.22 (s, 2H), 4.49 (s, 2H), 3.87 (s, 3H) ppm. 1,3- benzothiazole- 6- carbaldehyde General method A using 2-methylpyrazol- 3-amine and NaBH.sub.4, method D1 using 1- iodo-4- isocyanatobenzene, method F using 3- methoxyprop-1-yne, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA 1-(1,3- benzothiazol-6- ylmethyl)-3-[4- (3-hydroxypropyl- 1-ynyl)phenyl- 1-(2- methylpyrazol- 3-yl)urea 281 [00342]![embedded image]()
390.06 1H NMR (600 MHz, DMSO-d6) δ: 9.39 (s, 1H), 8.79 (s, 1H), 8.54 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.93 (s, 1H), 7.73-7.70 (m, 4H), 7.43-7.40 (m, 1H), 4.91 (s, 2H), 2.04 (s, 3H) ppm. 1,3- benzothiazole- 5- carbaldehyde General method A using 5-methylisoxazol- 4-amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 1-(1,3- benzothiazol-1- ylmethyl)-3-(4- cyanophenyl)-1- (5- methylisoxazol- 4-yl)urea 282 [00343]![embedded image]()
342.01 1H NMR (600 MHz, CDCl3) δ: 12.80 (s, 1H), 8.28-8.24 (m, 1H), 7.68-7.64 (m, 1H), 7.50-7.46 (m, 2H), 7.23 (d, J = 8.6 Hz, 1H), 7.22-7.18 (m, 2H), 6.95 (dd, J = 7.2 Hz, 5.0 Hz, 1H), 6.11 (d, J = 2.9 Hz, 1H), 5.81 (d, J = 2.6 Hz, 1H), 5.06 (s, 2H), 2.18 (s, 3H) 5- methylfuran- 2- carbaldehyde General method A using 2-aminopyridine, molecular sieves, p- TsOHxH.sub.2O and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (2-pyridyl)urea 283 [00344]![embedded image]()
333.03 1H NMR (600 MHz, CDCl3) δ: 13.32 (s, 1H), 8.35 (dd, J = 5.1 Hz, 2.1 Hz, 1H), 7.19-7.74 (m, 1H), 7.74-7.70 (m, 2H), 7.61-7.58 (m, 2H), 7.35 (d, J = 8.7 Hz, 1H), 7.06 (dd, J = 7.2 Hz, 5.1 Hz, 1H), 6.20 (d, J = 3.07 Hz, 1H), 5.91- 5.88 (m, 1H), 5.12 (s, 2H), 2.26 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 2-aminopyridine, molecular sieves, p- TsOHxH.sub.2O and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (2-pyridyl)urea 284 [00345]![embedded image]()
331.12 1H NMR (300 MHz, DMSO-d6) δ: 8.23 (s, 1H), 7.52-7.44 (m, 2H), 7.31-7. 24 (m, 2H), 6.12 (d, J = 2.9 Hz, 1H), 5.99-5.95 (m, 1H), 4.49 (s, 2H), 2.41 (s, 1H), 2.21 (s, 3H), 2.08 (s, 6H) ppm. 5- methylfuran- 2- carbaldehyde General method A using bicyclo[1.1.1]pentan-1- amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 1-(1- bicyclo[1.1.1] pentanyl)-3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]urea 285 [00346]![embedded image]()
322.09 1H NMR (300 MHz, DMSO-d6) δ: 8.63 (s, 1H), 7.73-7.60 (m, 4H), 6.13 (d, J = 3.0 Hz, 1H), 6.00-5.95 (m, 1H), 4.52 (s, 2H), 2.43 (s, 1H), 2.20 (s, 3H), 2.09 (s, 6H). ppm. 5- methylfuran- 2- carbaldehyde General method A using bicyclo[1.1.1]pentan-1- amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 1-(1- bicyclo[1.1.1] pentanyl)-3-(4- cyanophenyl)-1- [(5-methyl-2- furyl)methyl]urea 286 [00347]![embedded image]()
361.13 1H NMR (600 MHz, DMSO-d6) δ: 8.39 (s, 1H), 7.46 (m, 2H), 7.27 (m, 2H), 6.06 (d, J = 2.9 Hz, 1H), 5.96 (m, 1H), 4.61 (s, 2H), 4.48 (s, 2H), 4.46 (s, 2H), 4.19 (m, 1H), 2.48 (m, 2H), 2.27 (m, 2H), 2.20 (d, J = 0.7 Hz, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 2- oxaspiro[3.3]heptan-6- amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (2- oxaspiro[3.3] heptan-6-yl)urea 287 [00348]![embedded image]()
352.17 1H NMR (600 MHz, DMSO-d6) δ: 8.76 (s, 1H), 7.68 (m, 2H), 7.63 (m, 2H), 6.08 (d, J = 3.0 Hz, 1H), 5.96 (m, 1H), 4.61 (s, 2H), 4.51 (s, 2H), 4.46 (s, 2H), 4.19 (m, 1H), 2.49 (m, 2H), 2.28 (m, 2H), 2.19 (d, J = 0.7 Hz, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 2- oxaspiro[3.3]heptan-6- amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (2- oxaspiro[3.3] heptan-6-yl)urea 288 [00349]![embedded image]()
402.11 1H NMR (300 MHz, DMSO-d6) δ: 8.87 (br.s., 1H), 8.72 (d, J = 4.8 Hz, 1H), 8.67 (br.s., 1H), 7.78 (br.s., 1H), 7.71 (s, 4H), 7.68-7.64 (m, 1H), 4.89 (br.s., 2H), 2.22 (s, 3H) ppm. 4- (chloro- methyl)-2- (trifluoro- methyl) pyridine General method B.1 using 5- methylisooxazol-4- amine, NaI and DIPEA, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- (5- methylisoxazol- 4-yl)-1-[[2- (trifluoromethyl)- 4- pyridyl]methyl] urea 289 [00350]![embedded image]()
383.15 1H NMR (500 MHz, DMSO-d6) δ: 8.47 (s, 1H), 7.55 (d, J = 9.1 Hz, 2H), 7.22 (d, J = 9.1 Hz, 2H), 6.09 (d, J = 2.8 Hz, 1H), 5.96 (dd, J = 2.8, 0.9 Hz, 1H), 4.47-4.39 (m, 3H), 2.21 (s, 3H), 1.81-1.72 (m, 2H), 1.69-1.61 (m, 2H), 1.59- 1.46 (m, 4H) ppm. 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- (trifluoromethoxy)- phenyl isocyanate 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- [4- (trifluoromethoxy) phenyl]urea 290 [00351]![embedded image]()
329.15 1H NMR (500 MHz, DMSO-d6) δ: 8.09 (s, 1H), 7.31 (d, J = 9.5 Hz, 2H), 6.80 (d, J = 9.5 Hz, 2H), 6.08 (d, J = 3.1 Hz, 1H), 5.97- 5.94 (m, 1H), 4.46-4.38 (m, 3H), 3.70 (s, 3H), 2.21 (s, 3H), 1.80- 1.71 (m, 2H), 1.69-1.60 (m, 2H), 1.58-1.44 (m, 4H) ppm. 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4-methoxyphenyl isocyanate 1-cyclopentyl-1- (4- methoxyphenyl)- 1-[(5-methyl-2- furyl)methyl]urea 291 [00352]![embedded image]()
325.14 1H NMR (500 MHz, DMSO-d6) δ: 8.83 (s, 1H), 7.69-7.64 (m, 4H), 6.81 (s, 1H), 4.52 (s, 2H), 4.47- 4.39 (m, 1H), 2.34 (s, 3H), 1.84- 1.75 (m, 2H), 1.71-1.63 (m, 2H), 1.61-1.47 (m, 4H) ppm. 2- methyl- oxazole-5- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- cyclopentyl-1- [(2- methyloxazol-5- yl)methyl]urea 292 [00353]![embedded image]()
396.08 1H NMR (400 MHz, DMSO-d6) δ: 8.47 (s, 1H), 8.41 (s, 1H), 7.55 (d, J = 8.9 Hz, 2H), 7.23 (d, J = 8.9 Hz, 2H), 6.07 (d, J = 3.0 Hz, 1H), 5.96-5.94 (m, 1H), 4.65 (s, 2H), 2.20 (s, 3H), 2.07 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 5-methylisoxazol- 4-amine hydrochloride, NaOAc and NaCNBH.sub.3, method D1 using 4- cyanophenylisocyanate 1-[(5-methyl-2- furyl)methyl]-1- (5- methylisoxazol- 4-yl)-3-[4- (trifluoromethoxy) phenyl]urea 293 [00354]![embedded image]()
401.22 1H NMR (500 MHz, DMSO-d6) δ: 8.79 (s, 1H), 8.58 (s, 1H), 7.71 (s, 4H), 7.67-7.63 (m, 1H), 7.55- 7.26 (m, 3H), 4.84 (s, 2H), 2.05 (s, 3H) ppm. 3- (trifluoro- methyl) benzaldehyde General method A using 5-methylisoxazol- 4-amine hydrochloride, NaOAc and NaCNBH.sub.3, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- (5- methylisoxazol- 4-yl)-1-[[3- (trifluoromethyl) phenyl]methyl] urea 294 [00355]![embedded image]()
354.13 1H NMR (500 MHz, DMSO-d6) δ: 8.50 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 6.80 (s, 1H), 5.23 (t, J = 5.7 Hz, 1H), 4.40 (s, 2H), 4.45-4.38 (m, 1H), 4.27 (d, J = 5.7 Hz, 2H), 2.34 (s, 3H), 1.84-1.74 (m, 2H), 1.72- 1.62 (m, 2H), 1.60-1.47 (m, 4H) ppm. 2- methyl- oxazole-5- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method F using 4-iodoaniline, prop-2-yn-1-ol, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA, method M using tert-butyl-chloro- dimethyl silane, method R using isopropenyl chloroformate method D6, method N using TBAFxH.sub.2O 1-cyclopentyl-3- [4-(3- hydroxyprop-1- ynyl)phenyl]-1- [(2- methyloxazol-5- yl)methyl]urea 295 [00356]![embedded image]()
338.2 1H NMR (500 MHz, DMSO-d6) δ: 8.78 (s, 1H), 7.69-7.63 (m, 4H), 6.10 (d, J = 3.0 Hz, 1H), 5.96 (d, J = 3.0 Hz, 1H), 4.48 (s, 2H), 4.46- 4.38 (m, 1H), 2.54-2.50 (m, 2H ), 1.82-1.72 (m, 2H), 1.70-1.62 (m, 2H), 1.60-1.45 (m, 4H), 1.11 (t, J = 7.4 Hz, 3H) ppm. 5- ethylfuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- cyclopentyl- [(5-ethyl-2 furyl)methyl]urea 296 [00357]![embedded image]()
404.08 1H NMR (600 MHz, CDCl3) δ: 8.71 (d, J = 8.7 Hz, 1H), 7.61-7.59 (m, 1H), 7.44-7.42 (m, 1H), 7.42- 7.37 (m, 4H), 6.42 (br.s., 1H), 4.73 (s, 2H), 4.51 (d, J = 6.2 Hz, 2H), 4.33-4.27 (m, 1H), 2.35-2.29 (m, 2H), 2.20-2.12 (m, 2H), 1.86- 1.75 (m, 2H), 1.63 (t, J = 6.0 Hz, 1H) ppm. 2- (trifluoro- methyl) pyridine-4- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method F using 4-iodoaniline, prop-2-yn-1-ol, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA, method M using tert-butyl-chloro- dimethyl silane, method R using isopropenyl chloroformate method 1-cyclobutyl-3- [4-(3- hydroxyprop-1- ynyl)phenyl]-1- [[2- (trifluoromethyl)- 4- pyridyl]methyl] urea D6, method N using TBAFxH.sub.2O 297 [00358]![embedded image]()
339.15 1H NMR (500 MHz, DMSO-d6) δ: 8.40 (s, 1H), 7.48-7.43 (m, 2H), 7.30-7.24 (m, 2H), 6.07 (d, J = 2.9 Hz, 1H), 5.97-5.95 (m, 1H), 5.26 (br. s., 1H), 4.52 (s, 2H), 4.38 (m, 1H), 4.26 (s, 2H), 2.20 (s, 3H), 2.16- 2.06 (m, 4H), 1.65-1.49 (m, 2H) ppm. 5- methylfuran- 2- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method F using 4-iodoaniline, prop-2-yn-1-ol, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA, method M using tert-butyl-chloro- dimethyl silane, method R using isopropenyl chloroformate method D6, method N using TBAFxH.sub.2O 1-cyclobutyl-3- [4-(3- hydroxyprop-1- ynyl)phenyl]-1- [(5-methyl-2- furyl)methyl]urea 298 [00359]![embedded image]()
344.9 1H NMR (300 MHz, DMSO-d6) δ: 9.36 (br.s., 1H), 7.53-7.44 (m, 2H), 7.39-7.31 (m, 2H), 6.19 (d, J = 1.6 Hz, 1H), 6.01-5.96 (m, 1H), 4.92 (s, 2H), 2.18 (s, 3H), 2.13 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 4-methyl-1,2-5- oxadiazol-3-amine, toluene, MgSO.sub.4 and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (4-methyl-1,2,5- oxadiazol-3- yl)urea 299 [00360]![embedded image]()
351.14 1H NMR (600 MHz, DMSO-d6) δ: 8.50 (s, 1H), 7.72-7.67 (m, 4H), 6.12 (d, J = 2.8 Hz, 1H), 5.98 (dt, J = 2.8 Hz, 1.0 Hz, 1H), 4.68 (s, 2H), 2.55 (dq, J = 7.5, 1.0 Hz, 2H), 2.07 (d, 3H), 1.11 (t, J = 7.5 Hz, 3H) ppm. 5- ethylfuran- 2- carbaldehyde General method A using 5-methylisoxazol- 4-amine hydrochloride, NaOAc and NaCNBH.sub.3, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- [(5-ethyl-2- furyl)methyl]-1- (5- methylisoxazol- 4-yl)urea 300 [00361]![embedded image]()
398.05 1H NMR (300 MHz, DMSO-d6) δ: 10.0 (s, 1H), 7.93 (d, J = 7.0 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.62-7.57 (m, 2H), 7.45-7.38 (m, 3H), 7.31-7.24 (m, 1H), 6.27 (d, J = 2.8 Hz, 1H), 6.00-5.97 (m, 1H), 5.93 (s, 2H), 2.18 (s, 3H) ppm. 2-chloro-1,3- benzothiazole General method B.2 using (5-methyl-2- furyl)methanamine and DIPEA, method D1 using 4- chlorophenylisocyanate 1-(1,3- benzothiazol-2- yl)-3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]urea 301 [00362]![embedded image]()
378.16 1H NMR (300 MHz, DMSO-d6) δ: 8.47 (s, 1H), 8.30 (s, 1H), 7.50- 7.43 (m, 2H), 7.10 (t, J = 74.4 Hz, 1H), 7.09-7.02 (m, 2H), 6.07 (d, J = 3.0 Hz, 1H), 5.97-5.93 (m, 1H), 4.64 (s, 2H), 2.20 (s, 3H), 2.07 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 5-methylisoxazol- 4-amine hydrochloride, molecular sieves, TEA and NaBH.sub.4, method D2.2 using 4- (difluoromethoxy) aniline 3-[4- (difluoromethoxy) phenyl]-1-[(5- methyl-2- furyl)methyl]-1- (5- methylisoxazol- 4-yl)urea 302 [00363]![embedded image]()
410.11 1H NMR (500 MHz, DMSO-d6) δ: 8.73 (d, J = 8.7 Hz, 1H), 8.59 (s, 1H), 7.75 (s, 1H), 7.65 (d, J = 4.1 Hz, 1H), 7.50-7.46 (m, 2H), 7.42 (d, J = 1.8 Hz, 1H), 7.33-7.28 (m, 2H), 6.12 (d, J = 1.9 Hz, 1H), 4.91 (br.s., 2H), 3.64 (s, 3H) ppm. 4- (chloro- methyl)-2- (trifluoro- methyl) pyridine General method B.1 using 2-methylpyrazol- 3-amine, NaI and DIPEA, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- (2- methylpyrazol- 3-yl)-1-[[2- (trifluoromethyl)- 4- pyridyl]methyl] urea 303 [00364]![embedded image]()
315.07 1H NMR (600 MHz, DMSO-d6) δ: 8.99 (s, 1H), 7.97 (s, 1H), 7.18- 7.15 (m, 2H), 6.65-6.61 (m, 2H), 6.09 (d, J = 3.1, 1H), 5.98-5.96 (m, 1H), 4.39 (br.s., 2H), 2.63- 2.61 (m, 1H), 2.23-2.21 (m, 3H), 1.79-1.72 (m, 2H), 1.68-1.61 (m, 2H), 1.57-1.48 (m, 4H) ppm. 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method D1 using 1-benzyloxy-4- isocyanato benzene and toluene, method O using Pd(OH).sub.2/C 1-cyclopentyl-3- (4- hydroxyphenyl)- 1-[(5-methyl- furyl)methyl]urea 304 [00365]![embedded image]()
323.05 1H NMR (500 MHz, CDCl3) δ: 8.55 (s, 1H), 8.32 (s, 1H), 7.58- 7.43 (m, 4H), 6.77 (br.s., 1H), 6.17 (d, J = 3.1 Hz, 1H), 5.98-5.93 (m, 1H), 4.71 (s, 2H), 2.28 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using isooxazol-4- amine, TEA, toluene, molecular sieves and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- isoxazol-4-yl-1- [(5-methyl-2- furyl)methyl]urea 305 [00366]![embedded image]()
332.07 1H NMR (500 MHz, CDCl3) δ: 8.55 (s, 1H), 8.32 (s, 1H), 7.32- 7.21 (m, 4H), 6.55 (br.s., 1H), 6.19 (d, J = 3.1 Hz, 1H), 5.98-5.93 (m, 1H), 4.71 (s, 2H), 2.28 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using isooxazoll-4- amine, TEA, toluene, molecular sieves and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- isoxazol-4-yl-1- [(5-methyl-2- furyl)methyl]urea 306 [00367]![embedded image]()
353.21 1H NMR (500 MHz, DMSO-d6) δ: 7.35-7.29 (m, 2H), 7.28-7.05 (m, 2H), 6.08 (d, J = 2.9 Hz, 1H), 5.99-5.96 (m, 1H), 5.28 (t, J = 5.9 Hz, 1H), 4.27 (d, J = 6.1 Hz, 2H), 4.23 (s, 2H), 3.72 (m, 1H), 3.07 (s, 3H), 2.24 (s, 3H), 1.98-1.86 (m, 2H), 1.75-1.66 (m, 2H), 1.52- 1.43 (m, 1H), 1.37-1.27 (m, 1H) ppm. 5- methylfuran- 2- carbaldehyde General method A using cyclobutanamine and NaBH.sub.4, method F using 4-iodoaniline, prop-2-yn-1-ol, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA, method M using tert-butyl-chloro- dimethyl silane, method R using isopropenyl chloroformate method 1-cyclobutyl-3- [4-(3- hydroxyprop-1- ynyl)phenyl]-3- methyl-1-[(5- methyl-2- furyl)methyl]urea D6, method J using MeI and Cs.sub.2CO.sub.3, method N using TBAFxH.sub.2O 307 [00368]![embedded image]()
354.18 1H NMR (300 MHz, DMSO-d6) δ: 8.57 (s, 1H), 8.27 (s, 1H), 7.75 (s, 1H), 7.52-7.43 (m, 2H), 6.10 (d, J = 3.0 Hz, 1H), 5.96 (b.s., 1H), 4.46 (s, 2H), 4.46-4.40 (m, 1H), 4.38 (s, 2H), 2.20 (s, 3H), 1.81- 1.72 (m, 2H), 1.71-1.63 (m, 2H), 1.61-1.44 (m, 4H) ppm. 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method R using isopropenyl chloroformate, method D6 1-cyclopentyl) [(5-methyl-2- furyl)methyl]-3- (1- oxoisoindolin-5- yl)urea 308 [00369]![embedded image]()
473.09 1H NMR (300 MHz, DMSO-d6) δ: 8.95 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H) 7.77 (d, J = 8.7 Hz, 2H), 7.70-7.54 (m, 6H), 5.28 (t, J = 5.5 Hz, 1H), 4.85 (s, 2H), 4.58 (d, J = 5.5 Hz, 2H), 1.94 (s, 3H) ppm. 3- (trifluoro- methyl) benzaldehyde General method A using 3-methylisoxazol- 4-amine hydrochloride, NaOAc and NaCNBH.sub.3, method M using tert- butyl-chloro-dimethyl silane, method D2.2 using 4-[4-[[tert- butyl(dimethyl)silyl] oxymethyl]triazol-1- yl]aniline, method D1 using tert-butyl-((4- isocyanatophenyl) triazol-4- yl)methoxy)dimethyl- silane, method N using TBAFxH.sub.2O 3-[4-[4- (hydroxymethyl) triazol-1- yl]phenyl]-1-(3- methylisoxazol- 4-yl)-1-[[3- (trifluoromethyl) phenyl]methyl] urea 309 [00370]![embedded image]()
365.19 1H NMR (500 MHz, DMSO-d6) δ: 8.53 (s, 1H), 7.49-7.42 (m, 2H), 7.33-7.27 (m, 2H), 7.08 (d, J = 1.2 Hz, 1H), 6.84 (d, J = 1.30 Hz, 1H), 6.04 (d, J = 2.9 Hz, 1H), 5.96-5.91 (m, 1H), 5.27 (t, J = 5.9 Hz, 1H), 4.74 (s, 2H), 4.26 (d, J = 5.7 Hz, 2H), 3.22 (s, 3H), 2.19 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 1- methylimidazol-2- amine hydrochloride, Na2SO.sub.4, TEA and NaBH.sub.4, method F using 3-methoxyprop-1-yne, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA, method M using tert-butyl-chloro- dimethyl silane, method D2.2 using 4-[3-[tert- 3-[4-(3- hydroxyprop- ynyl)phenyl]-1- [(5-methyl-2- furyl)methyl]-1- (1- methylimidazol- 2-yl)urea butyl(dimethyl)silyl] oxyprop-1-ynyl]aniline, method N using TBAFxH.sub.2O 310 [00371]![embedded image]()
383.06 1H NMR (500 MHz, DMSO-d6) δ: 9.1 (s, 1H), 7.71-7.65 (m, 4H), 4.71 (m, 4H), 4.55-4.46 (m, 1H), 3.90 (t, J = 3.9 Hz, 2H), 2.78-2.74 (m, 2H), 1.86-1.77 (m, 2H), 1.72- 1.64 (m, 2H), 1.61-1.49 (m, 4H) ppm. 6,7-dihydro- 4H- pyrano[4,3- d]thiazole-2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4 and molecular sieves, method D1 using 4- cyanophenyl isocyanate 3-(4- cyanophenyl)-1- cyclopentyl-1- (6,7-dihydro-4H- pyrano[4,3- d]thiazol-2- ylmethyl)urea 311 [00372]![embedded image]()
392.06 1H NMR (500 MHz, DMSO-d6) δ: 8.74 (s, 1H), 7.51-7.46 (m, 2H), 7.31-7.26 (m, 2H), 4.72-4.66 (m, 4H), 4.52-4.44 (m, 1H), 3.90 (t, J = 5.4 Hz, 2H), 2.78-2.73 (m, 2H), 1.85-1.76 (m, 2H), 1.70-1.63 (m, 2H), 1.58-1.47 (m, 4H) ppm. 6,7-dihydro- 4H- pyrano[4,3- d]thiazole-2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4 and molecular sieves, method D1 using 4- chlorophenyl isocyanate 3-(4- chlorophenyl)-1- cyclopentyl-1- (6,7-dihydro-4H- pyrano[4,3- d]thiazol-2- ylmethyl)urea 312 [00373]![embedded image]()
368.18 1H NMR (500 MHz, DMSO-d6) δ: 8.57 (s, 1H), 7.76 (s, 1H), 7.53- 7.43 (m, 2H), 6.10 (d, J = 3.0 Hz, 1H), 5.98 (b.s., 1H), 4.46 (s, 2H), 4.46-4.40 (m, 1H), 4.38 (s, 2H), 3.03 (s, 3H), 2.20 (s, 3H), 1.82- 1.73 (m, 2H), 1.70-1.62 (m, 2H), 1.62-1.45 (m, 4H) ppm. 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method R using isopropenyl chloroformate, method D6 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- (2-methyl-1- oxo-isoindolin- 5-yl)urea 313 [00374]![embedded image]()
367.98 1H NMR (500 MHz, CDCl3) δ: 8.60 (s, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.58-7.53 (m, 2H), 7.23-7.14 (m, 4H), 6.56 (br. s, 1H), 4.79 (s, 2H), 2.22 (s, 3H) ppm. 6-formyl- pyridine-2- carbonitrile General method A using 3-methylisoxazol- 4-amine hydrochloride, TEA and NaBH.sub.4, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- [(6-cyano-2- pyridyl)methyl]- 1-(3- methylisoxazol- 4-yl)urea 314 [00375]![embedded image]()
345.1 1H NMR (500 MHz, DMSO-d6) δ: 8.81 (s, 1H), 8.38 (d, J = 4.6 Hz, 1H), 7.71-7.60 (m, 5H), 7.27 (dd, J = 7.5, 4.6 Hz, 1H), 5.98 (d, J = 2.6 Hz, 1H), 5.89 (b.s., 1H), 4.89 (s, 2H), 2.14 (s, 3H), 1.97 (s, 3H) ppm. 2-chloro-3- methyl- pyridine General method C.1 using (5-methyl-2- furyl)methanamine, BINAP, Pd(OAc).sub.2 and K.sub.2CO.sub.3, method D1 using 4- cyanophenylisocyanate, TEA in toluene 3-(4- cyanophenyl) [(5-methyl-2- furyl)methyl]-1- (3-methyl-2- pyridyl)urea 315 [00376]![embedded image]()
430.15 1H NMR (300 MHz, DMSO-d6) δ: 8.91 (s, 1H), 8.60 (s, 1H), 7.69- 7.61 (m, 1H), 7.60-7.54 (m, 3H), 7.47 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 5.26 (t, J = 6.2 Hz, 1H), 4.82 (s, 2H), 4.26 (d, J = 6.2 Hz, 2H), 1.91 (s, 3H) ppm. 3- (trifluoro- methyl) benzaldehyde General method A using 3- methylisooxazol-4- amine hydrochloride, NaOAc and NaCNBH.sub.3, method F using 3- methoxyprop-1-yne, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA, method M using tert-butyl-chloro- dimethyl silane, method D2.2 using 4-[3-[tert- 3-[4-(3- hydroxyprop-1- ynyl)phenyl]-1- (3- methylisoxazol- 4-yl)-1-[[3- (trifluoromethyl) phenyl]methyl] urea butyl(dimethyl)silyl] oxyprop-1-ynyl]aniline, method N using TBAFxH.sub.2O 316 [00377]![embedded image]()
338.12 1H NMR (500 MHz, DMSO-d6) δ: 8.99 (s, 1H), 8.81 (s, 1H), 7.74- 7.64 (m, 4H), 6.86 (s, 1H), 4.77 (s, 2H), 2.35 (s, 3H), 1.99 (s, 3H)ppm. 2-methyl- oxazole-5- carbaldehyde General method A using 3-methylisoxazol- 4-amine hydrochloride, NaOAc and NaCNBH.sub.3, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)- (3- methylisoxazol- 4-yl)-1-[(2- methyloxazol-5- yl)methyl]urea 317 [00378]![embedded image]()
355.2 1H NMR (500 MHz, DMSO-d6) δ: 8.25 (s, 1H), 7.46-7.40 (m, 2H), 7.27-7.22 (m, 2H), 6.08 (d, J = 2.8 Hz, 1H), 5.98-5.94 (m, 1H), 4.90 (d, J = 5.80 Hz, 1H), 4.89 (d, J = 5.80 Hz, 1H), 4.57 (t, J = 6.3 Hz, 2H), 4.48-4.38 (m, 1H), 4.43 (s, 2H), 4.16 (m, 1H), 2.21 (s, 3H), 1.81-1.70 (m, 2H), 1.69-1.60 (m, 2H), 1.58-1.44 (m, 4H) ppm. 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method R using isopropenyl chloroformate, method D6 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- [4-(oxetan-3- yl)phenyl]urea 318 [00379]![embedded image]()
356.14 1H NMR (500 MHz, DMSO-d6) δ: 8.43 (s, 1H), 8.36 (dd, J = 4.9, 1.4 Hz, 1H), 7.66 (dd, J = 7.4, 1.1 Hz, 1H), 7.48-7.43 (m, 2H), 7.30- 7.23 (m, 3H), 5.96 (d, J = 2.6 Hz, 1H), 5.90-5.86 (m, 1H), 4.88 (s, 2H), 2.14 (s, 3H), 1.98 (s, 3H)ppm. 2-chloro-3- methyl- pyridine General method C.1 using (5-methyl-2- furyl)methanamine, BINAP, Pd(OAc).sub.2 and K.sub.2CO.sub.3, method D1 using 4- chlorophenylisocyanate, TEA in toluene 3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (3-methyl-2- pyridyl)urea 319 [00380]![embedded image]()
361.16 1H NMR (500 MHz, CDCl3) δ: 7.86 (t, J = 8.2 Hz, 1H), 7.68-7.58 (m, 2H), 7.41-7.36 (m, 4H), 4.66 (s, 2H), 4.48 (d, J = 5.9 Hz, 2H), 4.47-4.41 (m, 1H), 2.32-2.22 (m, 2H), 2.19-2.08 (m, 2H), 1.83-1.68 (m, 2H), 1.65 (t, J = 6.3 Hz, 1H) ppm. 6-formyl- pyridine-2- carbonitrile General method A using cyclobutanamine and NaBH.sub.4, method F using 4-iodoaniline, prop-2-yn-1-ol, Pd(PPh.sub.3).sub.2Cl.sub.2, Cul and TEA, method M using tert-butyl-chloro- dimethyl silane, method R using isopropenyl chloroformate method D6, method N using TBAFxH.sub.2O 1-[(6-cyano-2- pyridyl)methyl- 1-cyclobutyl-3- [4-(3- hydroxyprop-1- ynyl)phenyl]urea 320 [00381]![embedded image]()
380.22 1H NMR (500 MHz, DMSO-d6) δ: 8.53 (s, 1H), 8.41 (s, 1H), 7.72- 7.67 (m, 2H), 7.66-7.62 (m, 2H), 6.11 (s, J = 3.1 Hz, 1H), 5.98-5.96 (m, 1H), 4.48- 4.41 (m, 3H), 2.31 (s, 3H), 2.21 (s, 3H), 1.82-1.74 (m, 2H), 1.71-1.62 (m, 2H), 1.61- 1.46 (m, 4H) ppm. 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method L.2 using 4-(fluoromethyl)- 1-(4- nitrophenyl)triazole, method U using Deoxo- Fluor, method L.2, method R using isopropenyl chloroformate, method D6 1-cyclopentyl-1- [(5-methyl-2- furyl)methyl]-3- [4-(4- methyltriazol-1- yl)phenyl]urea 321 [00382]![embedded image]()
367.15 1H NMR (500 MHz, DMSO-d6) δ: 8.96 (s, 1H), 8.52 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 6.85 (s, 1H), 5.27 (t, J = 4.8 Hz, 1H), 4.75 (s, 2H), 4.27 (d, J = 4.8 Hz, 2H), 2.36 (s, 3H), 1.99 (s, 3H) ppm. 2-methyl- oxazole-5- carbaldehyde General method A using 3- methylisooxazol-4- amine hydrochloride, NaOAc and NaCNBH.sub.3, method F using 3- methoxyprop-1-yne, Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and TEA, method M using tert-butyl-chloro- dimethyl silane, method D2.2 using 4-[3-[tert- butyl(dimethyl)silyl] 3-[4-(3- hydroxyprop-1- ynyl)phenyl]-1- (3- methylisoxazol- 4-yl)-1-[(2- methyloxazol-5- yl)methyl]urea oxyprop-1-ynyl]aniline, method N using TBAFxH.sub.2O 322 [00383]![embedded image]()
336.1 1H NMR (600 MHz, DMSO-d6) δ: 9.65 (br. s, 1H), 7.78-7.74 (m, 2H), 7.67-7.64 (m, 2H), 6.20 (d, J = 3.0 Hz, 1H), 5.99-5.97 (m, 1H), 4.95 (s, 2H), 2.17 (d, J = 0.6 Hz, 3H), 2.13 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 4-methyl-1,2-5- oxadiazol-3-amine, toluene, MgSO.sub.4 and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (4-methyl-1,2,5- oxadiazol-3- yl)urea 323 [00384]![embedded image]()
426.16 1H NMR (600 MHz, DMSO-d6) δ: 8.58 (s, 1H), 8.17 (s, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.6 Hz, 2.1 Hz, 1H), 6.11 (d, J = 2.9 Hz, 1H), 5.99- 5.96 (m, 1H), 5.26 (br. s, 1H), 4.58 (s, 2H), 4.50- 4.44 (m, 1H), 4.47 (s, 2H), 3.79 (s, 3H), 2.22 (d, J = 0.6 Hz, 3H), 1.82-1.75 (m, 2H), 1.70-1.62 (m, 2H), 1.61-1.42 (m, 4H) ppm. 5- methylfuran- 2- carbaldehyde General method A using cyclopentanamine and NaBH.sub.4, method V.1 using sodium nitrite, aq. HCl and sodium azide, method W using CuSO.sub.4x5H.sub.2O, sodium ascorbate and prop-2-yn-1-ol, method L using palladium/C, method M using tert- butyl-chloro-dimethyl silane, method R using isopropenyl chloroformate, method 1-cyclopentyl- [4-[4- (hydroxymethyl) triazol-1-yl]-3- methoxy- phenyl]-1-[(5- methyl-2- furyl)methyl]urea D6, method N using TBAFxH.sub.2O 324 [00385]![embedded image]()
334.15 1H NMR (300 MHz, DMSO-d6) δ: 12.73 (s, 1H), 8.80 (d, J = 4.9 Hz, 2H), 7.87-7.76 (m, 4H), 7.26 (t, J = 4.0 Hz, 1H), 6.07 (d, J = 3.0 Hz, 1H), 5.94-5.89 (m, 1H), 5.32 (s, 2H), 2.17 (s, 3H) ppm. 2-fluoro- pyrimidine General method B.1 using (5-methyl-2- furyl)methanamine and DIPEA, method D1 using 4- cyanophenylisocyanate, TEA in toluene 3-(4- cyanophenyl)-1- [(5-methyl-2- furyl)methyl]-1- pyrimidin-2-yl- urea 325 [00386]![embedded image]()
381.24 1H NMR (500 MHz, DMSO-d6) δ: 9.12 (s, 1H), 8.65 (s, 1H), 7.70- 7.63 (m, 4H), 4.24 (s, 2H), 4.18 (s, 2H), 3.37 (d, J = 6.8 Hz, 2H), 2.11 (s, 3H), 2.00 (d, J = 13.4 Hz, 2H), 1.57 (dd, J = 13.4, 3.0 Hz, 2H), 1.42-1.30 (m, 3H), 0.96-0.86 (m, 2H) ppm. 2- oxaspiro[3.5] nonane-7- carbaldehyde General method A using 3- methylisooxazol-4- amine hydrochloride, NaOAc and NaCNBH.sub.3, method D1 using 4- cyanophenylisocyanate 3-(4- cyanophenyl)- (3- methylisoxazol- 4-yl)-1-(2- oxaspiro[3.5] nonan-7- ylmethyl)urea 326 [00387]![embedded image]()
390.2 1H NMR (500 MHz, DMSO-d6) δ: 9.09 (s, 1H), 8.32 (s, 1H), 7.46- 7.42 (m, 2H), 7.29-7.25 (m, 2H), 4.27 (s, 2H), 4.18 (s, 2H), 2.37- 2.33 (m, 2H, overlapped with H2O), 2.11 (s, 3H), 2.00 (d, J = 13.2 Hz, 2H), 1.57 (dd, J = 13.2, 3.2 Hz, 2H), 1.41-1.31 (m, 3H), 0.96-0.86 (m, 2H) ppm. 2- oxaspiro[3.5] nonane-7- carbaldehyde General method A using 3- methylisooxazol-4- amine hydrochloride, NaOAc and NaCNBH.sub.3, method D1 using 4- chlorophenylisocyanate 3-(4- chlorophenyl)-1- (3- methylisoxazol- 4-yl)-1-(2- oxaspiro[3.5] nonan-7- ylmethyl)urea 327 [00388]![embedded image]()
343.02 1H NMR (600 MHz, DMSO-d6) δ: 12.49 (s, 1H), 8.81 (d, J = 4.9 Hz, 2H), 7.70-7.66 (m, 2H), 7.42- 7.38 (m, 2H), 7.25 (t, J = 4.1 Hz, 1H), 6.07 (d, J = 3.0 Hz, 1H), 5.93 (dd, J = 3.0, 1.1 Hz, 1H), 5.34 (s, 2H), 2.19 (s, 3H) ppm. 2-fluoro- pyrimidine General method B.1 using (5-methyl-2- furyl)methanamine and DIPEA, method D1 using 4- chlorophenylisocyanate, TEA in toluene 3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]-1- pyrimidin-2-yl- urea 328 [00389]![embedded image]()
362.13 1H NMR (500 MHz, DMSO-d6) δ: 8.80 (s, 1H), 8.27 (s, 1H), 7.49- 7.42 (m, 2H), 7.30-7.25 (m, 2H), 6.03 (d, J = 3.0 Hz, 1H), 5.96-5.92 (m, 1H), 4.71 (s, 2H), 2.19 (s, 3H), 2.08 (s, 3H) ppm. 5- methylfuran- 2- carbaldehyde General method A using 3- methylisothiazol-4- amine, molecular sieves and NaBH.sub.4, method D1 using 4- cyanophenylisocyanate 3-(4- chlorophenyl)-1- [(5-methyl-2- furyl)methyl]-1- (3- methylisothiazol- 4-yl)urea
Biological Assays
Example 1—Effect of Compounds on Tryptophan Catabolism in SK-OV-3 Cell Line
[0927] SK-OV-3 cells are seeded in 96-well plates in McCoy's 5A medium supplemented with 10% FBS and incubated overnight at 37° C., 5% CO2, 95% humidity. The next 5 day growth medium is replaced with DMEM F-12 medium supplemented with 6 mg/mL L-tryptophan. Compounds are added to the wells and incubated for 24 h at 37° C., 5% CO2, 95% humidity. Compounds are tested at 8 consecutive 3-fold dilutions starting from 30 μM in duplicate.
[0928] At the end of incubation, concentration of kynurenine in cell supernatants is 10 determined by LC-MS/MS. In parallel, cell viability is assessed by measurement of ATP using CellTiter Glo assay (Promega), according to manufacturer's protocol.
[0929] Inhibition of Kyn production is calculated using the following formula:
[00001]
[0930] IC50 values are determined using GraphPad Prism software 5.04 for Windows by plotting percent of inhibition against log 10 concentrations of compounds using a four-parametric sigmoidal curve with a variable slope.
[0931] Cell viability results are analysed in Microsoft Excel and expressed as fold change over untreated control.
[0932] IC50 ranges for compounds of the invention are presented in Table 2, whereby the IC50 ranges are as follows: [0933] A: IC.sub.50<100 nM [0934] B: IC.sub.50=100-500 [0935] C: IC.sub.50=500-1000 nM [0936] D: IC.sub.50=1000-5000 nM [0937] E: IC.sub.50>5000 nM
TABLE-US-00003 TABLE 2 Effect of compounds on tryptophan catabolism in SK-OV-3 cell line (ic50 values for inhibition of Kynurenine production) Cpd# IC.sub.50 Ranges 1 D 2 D 3 B 4 C 5 D 6 D 7 D 8 E 9 D 10 D 11 D 12 D 13 D 14 E 15 D 16 B 17 B 18 D 19 C 20 E 21 D 22 E 23 E 24 E 25 B 26 A 27 B 28 C 29 E 30 B 31 B 32 E 33 E 34 B 35 D 36 D 37 D 38 C 39 E 40 B 41 D 42 B 43 D 44 C 45 B 46 D 47 B 48 B 49 D 50 B 51 E 52 A 53 B 54 D 55 C 56 A 57 E 58 D 59 C 60 C 61 E 62 E 63 D 64 D 65 D 66 B 67 D 68 D 69 B 70 E 71 C 72 E 73 D 74 E 75 E 76 C 77 B 78 B 79 B 80 A 81 C 82 B 83 A 84 A 85 D 86 D 87 E 88 C 89 A 90 A 91 A 92 A 93 D 94 D 95 D 96 E 97 D 98 B 99 C 100 E 101 E 102 A 103 D 104 E 105 B 106 C 107 A 108 B 109 D 110 B 111 A 112 C 113 D 114 B 115 B 116 B 117 D 118 D 119 C 120 B 121 C 122 D 123 E 124 B 125 D 126 C 127 E 128 C 129 D 130 A 131 A 132 B 133 B 134 C 135 D 136 E 137 A 138 D 139 A 140 A 141 A 142 D 143 D 144 B 145 D 146 A 147 A 148 A 149 C 150 B 151 C 152 B 153 A 154 A 155 C 156 C 157 B 158 C 159 D 160 D 161 A 162 A 163 A 164 A 165 D 166 C 167 D 168 C 169 D 170 D 171 D 172 B 173 A 174 B 175 C 176 B 177 A 178 D 179 E 180 E 181 D 182 B 183 D 184 B 185 A 186 B 187 B 188 B 189 B 190 B 191 C 192 A 193 C 194 B 195 B 196 D 197 D 98 D 199 C 200 D 201 D 202 D 203 D 204 E 205 B 206 A 207 B 208 C 209 C 210 D 211 E 212 D 213 A 214 A 215 E 216 A 217 B 218 C 219 B 220 E 221 C 222 B 223 B 224 B 225 B 226 B 227 A 228 B 229 B 230 B 231 D 232 A 233 D 234 A 235 A 236 C 237 B 238 B 239 B 240 A 241 C 242 B 243 B 244 B 245 B 246 C 247 B 248 B 249 E 250 D 251 C 252 E 253 B 254 C 255 B 256 A 257 A 258 E 259 B 260 A 261 A 262 A 263 B 264 E 265 D 266 D 267 B 268 C 269 B 270 C 271 B 272 C 273 B 274 D 275 D 276 D 277 A 278 A 279 A 280 D 281 D 282 C 283 D 284 B 285 B 286 D 287 E 288 D 289 A 290 B 291 C 292 B 293 B 294 A 295 A 296 B 297 A 298 A 299 B 300 D 301 A 302 D 303 E 304 B 305 A 306 D 307 E 308 C 309 B 310 D 311 B 312 D 313 B 314 B 315 A 316 E 317 D 318 A 319 A 320 B 321 D 322 A 323 B 324 E 325 E 326 E 327 D 328 A
Example 2—IDO1 Enzyme Inhibition Assay
[0938] The effect of compounds on IDO1 enzymatic activity was assessed by use of a hIDO assay kit (Netherlands Translational Research Center B.V., Cat #NTRC-hIDO-1K). IDO1 enzyme and tryptophan substrate are diluted in assay buffer. Compounds are tested at 8 consecutive 3-fold dilutions starting from 30 μM. 267 nL of compound is added per well of a 384-well plate followed by addition of 10 μL of assay buffer. IDO1 enzyme is added at a final concentration of 25 nM and pre-incubated for 30 min at room temperature in the dark. Tryptophan substrate solution is then added at final concentration of 100 μM to all wells and the plate incubated for 60 min at RT in the dark. Finally NFK-green reagent is added at ⅕ of total reaction volume and incubated for 4 h at RT in the dark. After incubation fluorescence is measured at Ex405 nm-Em535 nm using EnVision plate reader.
[0939] IC50 values are determined using GraphPad Prism software 5.04 for Windows by plotting percent of inhibition against log 10 concentrations of compounds using a four-parametric sigmoidal curve with a variable slope.
TABLE-US-00004 TABLE 3 Inhibition of IDO1 activity by a selection of compounds of invention 1 IDO1 Biochemical IDO1 Biochemical Compound assay IC50 (μM) Compound assay IC50 (μM) 3 >30 213 >30 137 >30 215 >30 144 >30 220 >30 80 >30 256 >30 83 >30 257 >30 109 >30 269 >30 111 >30 270 >30 154 >30 276 >30 158 >30 279 >30 162 >30 277 >30
Example 3—TDO2 Enzyme Inhibition Assay
[0940] The effect of compounds on TDO2 enzymatic activity was assess by use of an hTDO2 assay kit (Netherlands Translational Research Center B.V., Cat #NTRC-hTDO-1K). TDO2 enzyme and tryptophan substrate are diluted in assay buffer. Compounds are tested at 8 consecutive 3-fold dilutions starting from 30 μM. 267 nL of compound is added per well of a 384-well plate followed by addition of 10 μL of assay buffer. TDO2 enzyme is added at a final concentration of 50 nM and pre-incubated for 60 min at room temperature in the dark. Tryptophan substrate solution is then added at final concentration of 200 μM to all wells and the plate incubated for 15 min at RT in the dark. Finally NFK-green reagent is added at ⅕ of total reaction volume and incubated for 4 h at RT in the dark. After incubation fluorescence is measured at Ex405 nm-Em535 nm using EnVision plate reader.
[0941] IC50 values are determined using GraphPad Prism software 5.04 for Windows by plotting percent of inhibition against log 10 concentrations of compounds using a four-parametric sigmoidal curve with a variable slope.
TABLE-US-00005 TABLE 4 Inhibition of TDO2 activity by a selection of compounds of invention 1 TDO2 Biochemical TDO2 Biochemical Compound assay IC50 Compound assay IC50 3 >30 130 >30 21 >30 154 >30 137 >30 185 >30 144 >30 74 >30 80 >30 104 >30 83 >30 123 >30 147 >30 105 >30 90 >30 109 6.0 92 >30 110 >30 102 >30 158 6.4 111 4.8/2.2 162 >30
Example 4—Effect of Compounds on IDO1 Expression in SK-OV-3 Cell Line
[0942] SK-OV-3 cells are seeded in 24-well plates in McCoy's 5A medium supplemented with 10% FBS at density of 250000 cells per well and incubated overnight at 37° C., 5% CO2, 95% humidity. The following day growth medium is replaced with DMEM F-12 medium containing 6 mg/mL L-tryptophan. Compounds are added to the wells and the plate is incubated for 24 h at 37° C., 5% CO2, 95% humidity. At the end of incubation medium is removed, cells are washed and then lysed in RIPA buffer. Protein concentrations in the samples are determined using BCA method (Thermo Scientific) and adjusted to 0.5 mg/mL. Western analysis is performed on the Wes system (Protein Simple) using IDO1 (Cell Signalling; Cat #12006S) and GAPDH (Abcam, Cat #ab9485) antibodies. Expression of IDO1 is normalised to GAPDH.
Example 5—Effect of Compounds on Tryptophan Catabolism in Monocyte-Derived Dendritic Cells
[0943] Peripheral blood mononuclear cells are isolated from buffy coats from healthy volunteers by Lymphoprep density gradient centrifugation, followed by lysis of residual erythrocytes with isotonic buffer solution of ammonium chloride. CD14+ cells are isolated by positive selection using MACS® technology and CD14 MicroBeads (Miltenyi Biotec) according to manufacturer's instructions. The isolated monocytes are differentiated into dendritic cells by incubation for 5 days in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), 50 ng/mL GM-CSF and 35 ng/mL IL-4. After 5 days the DCs are seeded in 96-well plates in DMEM supplemented with 10% charcoal stripped FBS, GM-CSF and IL-4. The following day cells are triggered with LPS and IFNγ. After 24 h of incubation medium is replaced with DMEM F-12 medium supplemented with 6 mg/mL L-tryptophan and 10% charcoal stripped FBS. Compounds are added to the cells and incubated for 24 h at 37° C., 5% CO2, 95% humidity. Compounds are tested at 7 consecutive 4-fold dilutions starting from 30 μM in duplicate.
[0944] At the end of incubation concentration of kynurenine in cell supernatants is determined by LC-MS/MS. In parallel, cell viability is assessed by measurement of ATP by use of CellTiter Glo assay (Promega) according to manufacturer's protocol.
[0945] Inhibition of Kyn production is calculated using the following formula:
(1−(Kyn conc. cmpd.−Kyn conc. medium)/(Kyn conc. medium with cells−Kyn conc. medium)).Math.100
[0946] IC50 values are determined using GraphPad Prism software 5.04 for Windows, by plotting percent of inhibition against log 10 concentrations of compounds using a four-parametric sigmoidal curve with a variable slope.
[0947] Cell viability results are analysed in Microsoft Excel and expressed as fold change over untreated control.
TABLE-US-00006 TABLE 5 inhibition of kynurenine production and cytotoxicity of compounds of the invention in dendritic cells Compound Kynurenine IC50 Cytotoxicity at 30 uM 26 0.10 19 56 0.25 94 137 0.040 88 139 0.27 77 140 0.32 92 141 0.47 90 144 0.38 109 146 0.12 103 80 0.026 112 82 0.30 85 83 0.13 89 84 0.18 108 147 0.070 122 148 0.15 103 89 0.065 81 90 0.066 67 91 0.036 71
Example 6—Tumour Cell Killing Assay
[0948] Human PBMCs from healthy donors are prepared from buffy coat and cryopreserved. For the killing assay, on day −1, NucLight™ Red transfected SK-OV-3 ovarian cancer cells are seeded in to a Flat-bottomed 96-well plate at 2×103 cells/well (100 μL per well) and incubated in the Incucyte Zoom® overnight. The following day (day 0) media is aspirated from wells containing SK-OV-3 cells. Caspase 3/7 reagent (1:2000) is prepared and added to wells at 50 μL per well, together with 50 μL test substances. Anti-CD3, (final concentration 0.1 μg/mL), anti-CD28 (final concentration 0.5 μg/mL) and rhIL-2 (final concentration 10 ng/mL) are prepared in complete media and added in a final volume of 50 μL per well. Untouched PBMCs are prepared from cryopreserved stock and added to wells at 1×104 cells per well in a volume of 50 μL per well, such that the final well volume is 200 μL. Cells are incubated/monitored in the Incucyte Zoom® for a period of seven days.
[0949] Wells are imaged at 3-hour intervals in phase, green and red channels. Automated image analysis enables selective quantitation of SK-OV-3 nuclei (Red) per well, apoptotic SK-OV-3 nuclei (Green/Red colocalised) to enable the effect of test substance on apoptosis to be determined and quantified graphically over time.
