Tao Kinase Modulators And Method Of Use
The invention provides compounds and methods for inhibition of kinases, such as those of the TAO family, more specifically KIAA1361, TAO, and JIK kinases. The invention provides compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. Compounds of the invention inhibit, regulate and/or modulate kinase receptor signal transduction pathways related to the changes in cellular activities as mentioned above, and the invention includes compositions which contain these compounds, and methods of using them to treat kinase-dependent diseases and conditions.
1 . A compound according to Formula I,
or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein,
R 1 is selected from optionally substituted C 1-10 alkyl, optionally substituted aryl, optionally substituted aryl-C 1-10 alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl-C 1-10 alkyl;
R 2 is selected from —H and optionally substituted C 1-6 alkyl;
or R 1 and R 2 combine to form an optionally substituted three- to seven-membered heteroalicyclic;
A is a C 1-3 alkylene optionally substituted with one to four of R 6 ;
B is selected from —O—, —N(R 4 )—, —S(O) 0-2 — and —N(CH 2 ) 2 N(CH 2 ) 2 —S(O) 0-2 —;
X is selected from ═O, ═S, and ═NR 7 ;
Y is selected from ═O, ═S, and ═NR 7 ;
Z is C; or
Z=Y is either absent or —CH 2 —;
R 3 is selected from —H, halogen, trihalomethyl, —OR 5 , —N(R 5 )R 5 , —N(R 5 )SO 2 R 5 , —N(R 5 )C(O)R 5 , —NCO 2 R 5 , optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl;
R 4 is selected from —H and optionally substituted C 1-6 alkyl; or
R 4 and one of R 6 , together with the atoms to which they are attached, combine to form an optionally substituted five- to seven-membered non-aromatic ring;
each R 5 is independently selected from —H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
two of R 5 , together with the atom or respective atoms to which they are attached, can combine to form an optionally substituted five- to seven-membered heterocyclic;
each R 6 is independently selected from —H, halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 5 , —NR 5 R 5 , —S(O) 0-2 R 5 , —SO 2 NR 5 R 5 , —CO 2 R 5 , —C(O)NR 5 R 5 , —N(R 5 )SO 2 R 5 . —N(R 5 )C(O)R 5 , —N(R 5 )CO 2 R 5 , —C(O)R 5 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted lower heterocyclylalkyl, and optionally substituted lower arylalkyl;
two of R6, together with the atom or atoms to which they are attached, can combine to form a three to seven-membered non-aromatic ring; and
each R 7 is independently selected from —H, —NO 2 , —NH 2 , —N(R 5 )R 5 , —CN, —OR 5 , optionally substituted lower alkyl, optionally substituted heteroalicyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl and optionally substituted heteroalicyclic;
provided the compound is not one of: 3-benzoylamino-3-phenyl-propionic acid (6-methoxy-benzothiazol-2-ylcarbamoyl)-methyl ester, N-(3,4-dichloro-benzyl)-2-[4-(4-pyridin-2-yl-pyrimidin-2-yl)-phenoxy]-acetamide, 2-(5,6-Dimethyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl)-N-[(6-methoxy-benzothiazol-2-ylcarbamoyl)-methyl]-acetamide, (Naphthalen-1-ylcarbamoylmethylsulfanyl)-acetic acid (5-bromo-pyridin-2-ylcarbamoyl)-methyl ester, (benzooxazol-2-ylsulfanyl)-acetic acid (5-chloro-pyridin-2-ylcarbamoyl)-methyl ester, and 4-[2-(5,6-dimethyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl)-acetylamino]-N-(6-methoxy-benzothiazol-2-yl)-butyramide.
2 . The compound of claim 1 , according to one of the following formulae:
wherein R 2 , R 3 , R 6 , and B are as defined above; Z is a five- to seven-membered ring; each R 8 is independently selected from —H, halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 5 , —NR 5 R 5 , —S(O) 0-2 R 5 , —SO 2 NR 5 R 5 , —CO 2 R 5 , —C(O)NR 5 R 5 , —N(R 5 )SO 2 R 5 , —N(R 5 )C(O)R 5 , —N(R 5 )CO 2 R 5 , —C(O)R 5 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heterocyclylalkyl, and optionally substituted arylalkyl; two of R 8 , together with the atom or atoms to which they are attached, can combine to form a three- to seven-membered ring; and E is selected from —O—, —N(R 9 )—, —CH 2 —, and —S(O) 0-2 —, where R 9 is selected from —H, trihalomethyl, —S(O) 0-2 R 5 , —SO 2 NR 5 R 5 , —CO 2 R 5 , —C(O)NR 5 R 5 , —C(O)R 5 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heterocyclylalkyl, and optionally substituted arylalkyl.
3 . The compound according to claim 2 , wherein B is selected from —O—, —N(R 4 )—, and —S(O) 0-1 —.
4 . The compound according to claim 3 , according to either formula II or III.
5 . The compound according to claim 4 , wherein R 4 is —H or C 1-6 alkyl.
6 . The compound according to claim 5 , wherein R 2 is —H or C 1-6 alkyl.
7 . The compound of claim 6 , according to formula IIa.
8 . The compound according to claim 7 , wherein each R 6 is independently selected from —H, trihalomethyl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, and optionally substituted arylalkyl.
9 . The compound according to claim 8 , wherein one of R 6 is —H, and the other R 6 is selected from trihalomethyl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, and optionally substituted arylalkyl.
10 . The compound according to claim 9 , wherein R 3 is selected from optionally substituted alkoxy, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl.
11 . The compound according to claim 10 , wherein R 3 is selected from lower alkyl substituted with an optionally substituted aryloxy or an optionally substituted heteroaryloxy, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heteroaryl, and optionally substituted lower heteroarylalkyl.
12 . The compound according to claim 11 , wherein R 3 is an aryl, said aryl substituted with at least one of an optionally substituted aryl and an optionally substituted heteroaryl.
13 . The compound according to claim 12 , wherein R 3 is an optionally substituted bis-phenyl.
14 . The compound according to claim 13 , wherein R3 comprises an optionally substituted phenylene, wherein the point of attachment of R3 according to formula IIa, and an optionally substituted phenyl bear a para relationship to one another about said optionally substituted phenylene.
15 . A compound for modulating at least one kinase activity according to formula VI,
or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein, each of R 11 and R 12 is independently selected from —H, halogen, trihalomethyl, —CN, —NO 2 , —NR 14 R 14 , —S(O) 0-2 R 14 , —SO 2 NR 14 R 14 , —CO 2 R 14 , —C(O)NR 14 R 14 , —N(R 14 )SO 2 R 14 , —N(R 14 )C(O)R 14 , —N(R 14 )CO 2 R 14 , —OR 14 , —C(O)R 14 , optionally substituted lower alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, and optionally substituted arylalkyl;
R 14 is selected from —H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
each of X and Y is independently selected from —O—, —N(R 14 )—, and —S(O) 0-2 —;
n is selected from an integer from 0-2;
Ar is an optionally substituted aryl that may be substituted with up to three R 11 , wherein two adjacent R 11 's, together with the annular atoms to which they are attached, can form a five- to seven-membered ring containing up to three heteroatoms and optionally substituted with up to three of R 15 ;
each R 15 is independently selected from —H, halo, trihalomethyl, —CN, —NO 2 , —OR 16 , —N(R 16 )R 16 , —S(O) 0-2 R 16 , —SO 2 N(R 16 )R 16 , —CO 2 R 16 , —C(═O)N(R 16 )R 16 , —C(═NR 17 )N(R 16 )R 16 , —C(═NR 17 )R 16 , —N(R 16 )SO 2 R 16 , —N(R 16 )C(O)R 16 , —NCO 2 R 16 , —C(═O)R 16 , optionally substituted alkoxy, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
R 16 is selected from —H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; and
R 17 is selected from —H, —CN, —NO 2 , —OR 16 , —S(O) 0-2 R 16 , —CO 2 R 16 , optionally substituted lower alkyl, optionally substituted lower alkenyl, and optionally substituted lower alkynyl.
16 . A compound according to claim 15 , wherein X is O.
17 . A compound according to claim 16 , wherein Y is O.
18 . A compound according to claim 17 , wherein R 11 is —H.
19 . A compound according to claim 18 , wherein R 12 is —H.
20 . A compound according to claim 19 , wherein n is 1.
21 . A compound according to claim 20 , wherein Ar is substituted aryl and two adjacent R 11 's, together with the annular atoms to which they are attached, form a substituted six-membered ring containing up to three heteroatoms.
22 . A compound according to claim 20 , wherein Ar is substituted aryl and two adjacent R 11 's, together with the annular atoms to which they are attached, form a substituted seven-membered ring containing up to three heteroatoms.
23 . The compound according to claim 1 or 15 , selected from the following:
TABLE 1
Entry
Name
Structure
1
N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]-4- (pentyloxy)benzamide
2
N˜2˜-[({4- [(phenylmethyl)oxy]phenyl}oxy)acet yl]-N-(1,2,3,4-tetrahydronaphthalen- 1-yl)glycinamide
3
N˜2˜-{[(4-bromophenyl)oxy]acetyl}- N-(1,2,3,4-tetrahydronaphthalen-1- yl)glycinamide
4
4′-ethyl-N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]biphenyl-4- carboxamide
5
4′-ethyl-N-[1-methyl-2-oxo-2- (1,2,3,4-tetrahydronaphthalen-2- ylamino)ethyl]biphenyl-4- carboxamide
6
4-(hexyloxy)-N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]benzamide
7
2-cyclopentyl-N-[2-oxo-1-pyridin-3- yl-2-(1,2,3,4-tetrahydronaphthalen- 1-ylamino)ethyl]-2-phenylacetamide
8
4-(heptyloxy)-N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]benzamide
9
N-[1-methyl-2-oxo-2-(1,2,3,4- tetrahydronaphthalen-2- ylamino)ethyl]-4- (pentyloxy)benzamide
10
4-hexyl-N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]benzamide
11
N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]-4-pentylbenzamide
12
4-heptyl-N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]benzamide
13
Nalpha-{[5,6-bis(methyloxy)-1H- indol-2-yl]carbonyl}-N-(1,2,3,4- tetrahydronaphthalen-1- yl)tryptophanamide
14
Nalpha-{[4- (butyloxy)phenyl]carbonyl}-N-(1,2,3,4-tetrahydronaphthalen-1- yl)tryptophanamide
15
5-{(2E)-3-[3,4- bis(methyloxy)phenyl]prop-2-enoyl}- N-[2-(3-chlorophenyl)ethyl]-4,5,6,7- tetrahydro-3H-imidazol[4,5- c]pyridine-6-carboxamide
16
N-[2-oxo-1-pyridin-3-yl-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]-4-(1H-1,2,4-triazol-1- yl)benzamide
17
Nalpha-{(2E)-3-[3,4- bis(methyloxy)phenyl]prop-2-enoyl}- N-(1,2,3,4-tetrahydronaphthalen-1- yl)tryptophanamide
18
4-(butyloxy)-N-[1-methyl-2-oxo-2- (1,2,3,4-tetrahydronaphthalen-2- ylamino)ethyl]benzamide
19
N-[1-methyl-2-oxo-2-(1,2,3,4- tetrahydronaphthalen-2- ylamino)ethyl]-4- [(phenylmethyl)oxy]benzamide
20
3,5-dimethyl-N-{2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]-4- [(phenylmethyl)oxy]benzamide
21
N˜2˜-({[4- (butyloxy)phenyl]amino}carbonyl)- N-(2-phenylethyl)-O- (phenylmethyl)serinamide
22
(2S)-N˜-1˜-(4-butylphenyl)-N˜2˜- [(3,4- dichlorophenyl)methyl]pyrrolidine- 1,2-dicarboxamide
23
N-[6-(methyloxy)-1,3-benzothiazol- 2-yl]-4-{[(4-oxo-5,6,7,8- tetrahydro[1]benzothieno[2,3- d]pyrimidin-3(4H)- yl)acetyl]amino}butanamide
24
(2S)-N˜2˜-[(3,4- dichlorophenyl)methyl]-N˜1˜-[4-(1- methylethyl)phenyl]pyrrolidine-1,2- dicarboxamide
25
N˜2˜-{[(4-bromophenyl)oxy]acetyl}- N-[(3,4- dichlorophenyl)methyl]glycinamide
26
N-[2-oxo-1-pyridin-3-yl-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]-4-[(E)- phenyldiazenyl]benzamide
27
4-(butyloxy)-N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]benzamide
28
N˜2˜-({[3- (methyloxy)phenyl]oxy}acetyl)-N- (1,2,3,4-tetrahydronaphthalen-1- yl)glycinamide
29
4-butyl-N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]benzamide
30
N˜2˜-{(2E)-3-[3,4- bis(methyloxy)phenyl]prop-2-enoyl}- N-(diphenylmethyl)-O- (phenylmethyl)serinamide
31
N-(1,2,3,4-tetrahydronaphthalen-1- yl)-N˜2˜-[({4- [(trifluoromethyl)oxy]phenyl}oxy)ace tyl]glycinamide
32
N-{3-methyl-1-[(1,2,3,4- tetrahydronaphthalen-1- ylamino)carbonyl]butyl}biphenyl-4- carboxamide
33
N-˜2˜-({[4-(1,1- dimethylethyl)phenyl]oxy}acetyl)-N- (1,2,3,4-tetrahydronaphthalen-1- yl)glycinamide
34
N˜2˜-{[(4-chlorophenyl)oxy]acetyl}- N-(1,2,3,4-tetrahydronaphthalen-1- yl)glycinamide
35
N˜2˜-{[4- (phenyl]carbonyl}-N- (1,2,3,4-tetrahydronaphthalen-1- yl)leucinamide
36
4-(hexyloxy)-N-[1-methyl-2-oxo-2- (1,2,3,4-tetrahydronaphthalen-2- ylamino)ethyl]benzamide
37
2-{[6-(methyloxy)-1,3-benzothiazol- 2-yl]amino}-2-oxoethyl 3-phenyl-3- [(phenylcarbonyl)amino]propanoate
38
N-[(3,4-dichlorophenyl)methyl]-2- {[4-(4-pyridin-2-ylpyrimidin-2- yl)phenyl]oxy]acetamide
39
N-(2,3-dihydro-1,4-benzodioxin-2- ylmethyl)-3-[3-(ethyloxy)propyl]-4- oxo-2-thioxo-1,2,3,4- tetrahydroquinazoline-7- carboxamide
40
N˜2˜-[(5,6-dimethyl-4- oxothieno[2,3-d]pyrimidin-3(4H)- yl)acetyl]-N-[6-(methyloxy)-1,3- benzothiazol-2-yl]glycinamide
41
2-{4-[(2-naphthalen-1- ylethyl)sulfonyl]piperazin-1-yl)-N- pyridin-2-ylacetamide
42
N-(2,3-dihydro-1,4-benzodioxin-2- ylmethyl)-11-oxo-10,11-dihydro-5H- dibenzo[b,e][1,4]diazepine-8- carboxamide
43
N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]biphenyl-4- carboxamide
44
N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]naphthalene-2- carboxamide
45
N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]-4- [(trifluoromethyl)oxy]benzamide
46
N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]quinoline-3- carboxamide
47
N˜2˜-({[3,5- bis(trifluoromethyl)phenyl]amino}car bonyl)-N-(1,2,3,4- tetrahydronaphthalen-1- yl)glycinamide
48
N˜2˜-{[(3- ethylphenyl)amino]carbonyl}-N- (1,2,3,4-tetrahydronaphthalen-1- yl)glycinamide
49
N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]-4- (phenyloxy)benzamide
50
4-cyclohexyl-N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]benzamide
51
N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]-4- [(phenylmethyl)oxy]benzamide
52
4-ethyl-N-{2-oxo-2- [(phenylmethyl)amino]ethyl}biphenyl -4-carboxamide
53
N-[2-(cyclohexylamino)-2-oxoethyl]- 4′-ethylbiphenyl-4-carboxamide
54
N-(2-{[(3,4- dichlorophenyl)methyl]amino}-2- oxoethyl)-4′-ethylbiphenyl-4- carboxamide
55
N˜2˜- [{[cyclopentyl(phenyl)acetyl]amino}(pyridin-3-yl)acetyt]-N-(1,2,3,4- tetrahydronaphthalen-1- yl)glycinamide
56
4-hydroxy-N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]benzamide
57
N-[2-(1,3-dihydro-2H-isoindol-2-yl)- 2-oxoethyl]-4′-ethylbiphenyl-4- carboxamide
58
4-morpholin-4-yl-N-[2-oxo-2- (1,2,3,4-tetrahydronaphthalen-1- ylamino)ethyl]benzamide
59
5,6-bis(methyloxy)-N-(2-oxo-2- (1,2,3,4-tetrahydronaphthalen-1- ylamino)ethyl]-1H-indole-2- carboxamide
60
N-[2-(3,4-dihydroisoquinolin-2(1H)- yl)-2-oxoethyl]-4′-ethylbiphenyl-4- carboxamide
61
4′-ethyl-N-{2-oxo-2-[(1S)-1,2,3,4- tetrahydronaphthalen-1- ylamino]ethyl}biphenyl-4- carboxamide
62
2-amino-N-˜4˜-(2,3-dihydro-1,4- benzodioxin-2-ylmethyl)-N˜1˜-[3- (ethyloxy)propyl]benzene-1,4- dicarboxamide
63
N-{3-[(2-{[6-(methyloxy)-1,3- benzothiazol-2-yl]amino}-2- oxoethyl)amino]-3-oxo-1- phenylpropyl}benzamide
64
4′ethyl-N-(2-{[6-(methyloxy)-1,3- benzothiazol-2-yl]amino}-2- oxoethyl)biphenyl-4-carboxamide
65
N-{2-[(2,3-dihydro-1,4-benzodioxin- 2-ylmethyl)amino]-2-oxoethyl}-4′- ethylbiphenyl-4-carboxamide
66
4′-ethyl-N-methyl-N-[2-oxo-2- (1,2,3,4-tetrahydronaphthalen-1- ylamino)ethyl]biphenyl-4- carboxamide
67
4′-ethyl-N-[2-(naphthalen-1- ylamino)-2-oxoethyl]biphenyl-4- carboxamide
68
4′-ethyl-N-[2-oxo-2-(4- phenylpiperazin-1-yl)ethyl]biphenyl- 4-carboxamide
69
N˜2˜-(biphenyl-4-ylmethyl)-N- (1,2,3,4-tetrahydronaphthalen-1- yl)glycinamide
70
4-(1H-imidazol-1-yl)-N-[2-oxo-2- (1,2,3,4-tetrahydronaphthalen-1- ylamino)ethyl]benzamide
71
4-(1,3-oxazol-5-yl)-N-[2-oxo-2- (1,2,3,4-tetrahydronaphthalen-1- ylamino)ethyl]benzamide
72
N˜2˜-{[(2-biphenyl-4- ylethyl)amino]carbonyl}-N-(1,2,3,4- tetrahydronaphthalen-1- yl)glycinamide
73
N˜2˜-[(biphenyl-4- ylamino)carbonyl]-N-(1,2,3,4- tetrahydronaphthalen-1- yl)glycinamide
74
4′-ethyl-N-(2-{[(2- methylphenyl)methyl]amino}-2- oxoethyl)biphenyl-4-carboxamide
75
4′-ethyl-N-{2-oxo-2-[(2- phenylethyl)amino]ethyl}biphenyl-4- carboxamide
76
4′-ethyl-N-{2-oxo-2-[(1R)-1,2,3,4- tetrahydronaphthalen-1- ylamino]ethyl}biphenyl-4- carboxamide
77
N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]-4-piperidin-1- ylbenzamide
78
4′-ethyl-N-{2-oxo-2-[(1- phenylethyl)amino]ethyl}biphenyl-4- carboxamide
79
4′-ethyl-N-[2-oxo-2-({[2- (trifluoromethyl)phenyl]methyl}amino) ethyl]biphenyl-4-carboxamide
80
N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]quinoline-6- carboxamide
81
N-(3-oxo-3-{[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]amino}-1- phenylpropyl)benzamide
82
N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]-5,6,7,8- tetrahydronaphthalene-2- carboxamide
83
4′-ethyl-N-{2-oxo-2-[(1- phenylpropyl)amino]ethyl}biphenyl- 4-carboxamide
84
3-(acetylamino)-N-(2-{[6- (methyloxy)-1,3-benzothiazol-2- yl]amino}-2-oxoethyl)-3- phenylpropanamide
85
N-(phenylcarbonyl)-beta-alanyl-N- [6-(methyloxy)-1,3-benzothiazol-2- yl]glycinamide
86
N-[2-oxo-2-(5,6,7,8- tetrahydronaphthalen-1- ylamino)ethyl]quinoline-6- carboxamide
87
N-[2-oxo-2-(5,6,7,8- tetrahydronaphthalen-1- ylamino)ethyl]quinoline-3- carboxamide
88
N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]-3-piperidin-1- ylpropanamide
89
N-[2-oxo-2-(5,6,7,8- tetrahydronaphthalen-1- ylamino)ethyl]-4-piperidin-1- ylbenzamide
90
N-(3-{[2-(1,3-benzothiazol-2- ylamino)-2-oxoethyl]amino}-3-oxo- 1-phenylpropyl)benzamide
91
N-[2-oxo-2-(1,2,3,4- tetrahydronaphthalen-1- ylamino)ethyl]-4-phenylpiperazine 1-carboxamide
92
N-(3-oxo-3-{[2-oxo-2-(1,3-thiazol-2- ylamino)ethyl]amino}-1- phenylpropyl)benzamide
93
N-[3-({2-[(4-methyl-1,3-thiazol-2- yl)amino]-2-oxoethyl}amino)-3-oxo- 1-phenylpropyl]benzamide
94
N-{3-[(2-{[5- (methyloxy)[1,3]thiazolo[5,4- b]pyridin-2-yl]amino}-2- oxoethyl)amino]-3-oxo-1- phenylpropyl}benzamide
95
1,1-dimethylethyl 4-({N-[(4′- ethylbiphenyl-4- yl)carbonyl]glycyl}amino)-3,4- dihydroisoquinoline-2(1H)- carboxylate
96
4′-ethyl-N-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin-4- ylamino)ethyl]biphenyl-4- carboxamide
97
N-{3-[(6-hydroxy-1,3-benzothiazol- 2-yl)amino]-3-oxo-1- phenylpropyl)benzamide
98
N-[3-({2-[(6-hydroxy-1,3- benzothiazol-2-yl)amino]-2- oxoethyl}amino)-3-oxo-1- phenylpropyl]benzamide
99
2-[(5-bromopyridin-2-yl)amino]-2- oxoethyl{[2-(naphthalen-1- ylamino)-2-oxoethyl]thio}acetate
100
2-[(5-chloropyridin-2-yl)amino]-2- oxoethyl(1,3-benzoxazol-2- ylthio)acetate
101
4-{[(5,6-dimethyl-4-oxothieno[2,3- d]pyrimidin-3(4H)-yl)acetyl]amino}- N-[6-(methyloxy)-1,3-benzothiazol- 2-yl]butanamide
24 . A pharmaceutical composition comprising a compound according to any one of claims 1 - 23 and a pharmaceutically acceptable carrier.
25 . A metabolite of the compound or the pharmaceutical composition according to any one of claims 1 - 24 .
26 . A method of modulating the ill vivo activity of a kinase, the method comprising administering to a subject an effective amount of either the compound or the pharmaceutical composition according to any of claims 1 - 24 , or a compound, or pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier, selected from the group consisting of 3-benzoylamino-3-phenyl-propionic acid (6-methoxy-benzothiazol-2-ylcarbamoyl)-methyl ester, N-(3,4-dichloro-benzyl)-2-[4-(4-pyridin-2-yl-pyrimidin-2-yl)-phenoxy]-acetamide, 2-(5,6-dimethyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl)-N-[(6-methoxy-benzothiazol-2-ylcarbamoyl)-methyl]-acetamide, (naphthalen-1-ylcarbamoylmethylsulfanyl)-acetic acid (5-bromo-pyridin-2-ylcarbamoyl)-methyl ester, (benzooxazol-2-ylsulfanyl)-acetic acid (5-chloro-pyridin-2-ylcarbamoyl)-methyl ester, and 4-[2-(5,6-dimethyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl)-acetylamino]-N-(6-methoxy-benzothiazol-2-yl)-butyramide.
27 . The method according to claim 26 , wherein the kinase is at least one of KIAA1361, TAO, and JIK.
28 . The method according to claim 27 , wherein modulating the in vivo activity of the kinase comprises inhibition of said kinase.
29 . A method of treating diseases or disorders associated with uncontrolled, abnormal, and/or unwanted cellular activities, the method comprising administering, to a mammal in need thereof, a therapeutically effective amount of either the compound or the pharmaceutical composition as described in any one of claims 1 - 24 , or a compound, or pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier, selected from the group consisting of 3-benzoylamino-3-phenyl-propionic acid (6-methoxy-benzothiazol-2-ylcarbamoyl)-methyl ester, N-(3,4-dichloro-benzyl)-2-[4-(4-pyridin-2-yl-pyrimidin-2-yl)-phenoxy]-acetamide, 2-(5,6-Dimethyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl)-N-[(6-methoxy-benzothiazol-2-ylcarbamoyl)-methyl]-acetamide, (Naphthalen-1-ylcarbamoylmethylsulfanyl)-acetic acid (5-bromo-pyridin-2-ylcarbamoyl)-methyl ester, (benzooxazol-2-ylsulfanyl)-acetic acid (5-chloro-pyridin-2-ylcarbamoyl)-methyl ester, and 4-[2-(5,6-dimethyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl)-acetylamino]-N-(6-methoxy-benzothiazol-2-yl)-butyramide.
30 . A method of screening for a modulator of a kinase, said kinase selected from KIAA1361, TAO, and JIK, the method comprising combining either a compound according to any one of claims 1 - 23 , or a compound selected from the group consisting of 3-benzoylamino-3-phenyl-propionic acid (6-methoxy-benzothiazol-2-ylcarbamoyl)-methyl ester, N-(3,4-dichloro-benzyl)-2-[4-(4-pyridin-2-yl-pyrimidin-2-yl)-phenoxy]-acetamide, 2-(5,6-dimethyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl)-N-[(6-methoxy-benzothiazol-2-ylcarbamoyl)-methyl]-acetamide, (naphthalen-1-ylcarbamoylmethylsulfanyl)-acetic acid (5-bromo-pyridin-2-ylcarbamoyl)-methyl ester, (benzooxazol-2-ylsulfanyl)-acetic acid (5-chloro-pyridin-2-ylcarbamoyl)-methyl ester, and 4-[2-(5,6-dimethyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl)-acetylamino-N-(6-methoxy-benzothiazol-2-yl)-butyramide, and at least one candidate agent and determining the effect of the candidate agent on the activity of said kinase.
31 . A method of inhibiting proliferative activity in a cell, the method comprising administering an effective amount of a composition comprising a compound according any one of claims 1 - 23 , or a compound selected from the group consisting of 3-benzoylamino-3-phenyl-propionic acid (6-methoxy-benzothiazol-2-ylcarbamoyl)-methyl ester, N-(3,4-dichloro-benzyl)-2-[4-(4-pyridin-2-yl-pyrimidin-2-yl)-phenoxy]-acetamide, 2-(5,6-dimethyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl)-N-[(6-methoxy-benzothiazol-2-ylcarbamoyl)-methyl]-acetamide, (naphthalen-1-ylcarbamoylmethylsulfanyl)-acetic acid (5-bromo-pyridin-2-ylcarbamoyl)-methyl ester, (benzooxazol-2-ylsulfanyl)-acetic acid (5-chloro-pyridin-2-ylcarbamoyl)-methyl ester, and 4-[2-(5,6-dimethyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl)-acetylamino]-N-(6-methoxy-benzothiazol-2-yl)-butyramide, to a cell or a plurality of cells.