US2022259182A1PendingUtilityA1
Benzethers and anilines of pyrazolyl-amino-pyrimidinyl derivatives, and compositions and methods thereof
Est. expiryApr 8, 2039(~12.7 yrs left)· nominal 20-yr term from priority
A61P 1/16A61P 7/04A61P 25/24A61P 25/16A61P 13/12A61P 9/10A61P 37/08A61P 1/04A61P 5/14A61P 21/04A61P 19/02A61P 19/08A61P 7/00A61P 35/02A61P 3/10A61P 11/06A61P 37/06A61P 17/14A61P 17/00A61P 17/06A61P 1/00A61P 37/02A61P 29/00A61P 35/00C07D 401/14C07D 405/14C07D 403/12A61P 37/00A61K 31/506
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Claims
Abstract
Provided is a novel class of orally and/or topically available, selective and potent JAK inhibitors as safe and effective therapeutics against various diseases and disorders. Also provided is pharmaceutical composition of these compounds and methods of their preparation and use thereof.
Claims
exact text as granted — not AI-modified1 . A compound having the structural formula (I):
wherein
L is O or NR 4′ ;
X is N or CR x , wherein R x is R′, halogen, CN or OR′;
Y is N or CR Y , wherein R Y is R′, halogen, CN or OR′;
each of Z 1 and Z 2 is independently selected from N and CR′, provided that one of Z 1 and Z 2 is N and the other is CR′;
R 1 is hydrogen, halogen, CN, C 1 -C 6 unsubstituted or substituted alkyl or OR′;
R 2 is a C 1 -C 16 aliphatic group optionally comprising one or more heteroatoms selected from N, O, S and P, wherein the aliphatic group is optionally substituted with one or more of halogen, OR′, NRR′, CN, CONRR′, NRCOR′ and C 1 -C 6 alkyl, which is in turn optionally substituted with F, OR′ or NRR′;
R 3 is R′ or halogen;
each of R 4 and R 4′ , when L is NR 4′ , is selected from hydrogen and C 1 -C 16 aliphatic groups optionally comprising one or more heteroatoms selected from N, O, S and P, and R 4 and R 4′ together may form a 3- to 7-membered ring, having 0 to 3 heteroatoms selected from O, N and S, and wherein each of R 4 and R 4′ is optionally substituted with CN, CF 3 or OR′; provided that if one of R 4 and R 4′ is hydrogen, the other is not hydrogen; and
each R and R′ is independently hydrogen or a C 1 -C 12 unsubstituted or substituted alkyl group,
or a pharmaceutically acceptable form or an isotope derivative thereof.
2 . The compound of claim 1 , wherein L is O, having the structural formula (I-A):
3 . The compound of claim 1 , wherein L is NR 4′ , having the structural formula (I-B):
4 . The compound of claim 1 , wherein X is CR x , wherein R x is H, halogen, C 1 -C 6 unsubstituted or substituted alkyl or alkoxy.
5 . The compound of claim 1 , wherein X is CH.
6 . The compound of claim 1 , wherein X is N.
7 . The compound of claim 1 , wherein Y is CR Y , wherein R Y is H, halogen, C 1 -C 6 unsubstituted or substituted alkyl or alkoxy.
8 . The compound of claim 1 , wherein Y is CH.
9 . The compound of claim 1 , wherein Y is N.
10 . The compound of claim 1 , wherein Z 1 is CH and Z 2 is N.
11 . The compound of claim 1 , wherein R 4 comprises a linear, branched or cyclic C 1 -C 12 unsubstituted or substituted alkyl group.
12 . The compound of claim 1 , wherein R 4 comprises a 3- to 7-membered ring having 0 to 3 heteroatoms selected from O, N and S.
13 - 21 . (canceled)
22 . The compound of claim 1 , wherein R 4 is a C 3 , C 4 or C 5 alkyl group substituted with CN.
23 - 27 . (canceled)
28 . The compound of claim 1 , wherein L is O, X is CR x , Y is CH, Z 1 is CH and Z 2 is N, having the structural formula (II):
29 . The compound of claim 1 , wherein L is NR 4′ , X is CR x , Y is CH, Z 1 is CH and Z 2 is N, having the structural formula (III):
30 . The compound of claim 1 , wherein R 1 is F, Cl or a C 1 -C 3 alkyl.
31 - 33 . (canceled)
34 . The compound of claim 1 , wherein R 2 is a C 1 -C 6 aliphatic group with 0 to 2 carbon atoms replaced by one or more heteroatoms selected from N, O, S and P, wherein the aliphatic group is optionally substituted with a CN or CF 3 group.
35 . The compound of claim 1 , wherein R 2 is a C 7 -C 16 aliphatic group with 0 to 3 carbon atoms replaced by one or more heteroatoms selected from N, O, S and P, wherein the aliphatic group is optionally substituted with a CN or CF 3 group.
36 . The compound of claim 1 , wherein R 2 comprises a C 3 -C 16 cyclic alkyl with 0 to 8 carbon atoms replaced by one or more heteroatoms selected from N, O, S and P, optionally substituted with a CN or CF 3 group.
37 - 42 . (canceled)
43 . The compound of claim 1 , wherein R 2 is:
wherein
Z 3 is N, CH or O, wherein when Z 3 is O, R 5 is absent;
each of m and n is independently 0, 1, 2, 3 or 4; provided that m and n are not both 0 at the same time, and
R 5 is a C 1 -C 6 alkyl, CN, halogen or C(O)R 6 , wherein R 6 is a C 1 -C 6 alkyl; provided that when Z 3 is N, R 5 is not CN or halo.
44 . The compound of claim 43 , wherein each of m and n is 2.
45 . The compound of claim 43 , wherein Z 3 is N.
46 - 49 . (canceled)
50 . The compound of claim 43 , wherein Z 3 is O.
51 . (canceled)
52 . A compound selected from:
Example
Structure
IUPAC name
1
3-(4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4- yl)phenoxy)-2,2-dimethylpropanenitrile
2
3-(4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4- yl)phenoxy)cyclobutanecarbonitrile
3
1-((4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4- yl)phenoxy)methyl)cyclobutanecarbonitrile
4
3-(4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4-yl)-2- fluorophenoxy)-2,2-dimethylpropanenitrile
5
1-((4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4-yl)-2- fluorophenoxy)methyl)cyclopropane- carbonitrile
6
1-((2-fluoro-4-(5-methyl-2-((1- (tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)phenoxy)methyl)cyclopropanecarbonitrile
7
3-(2-fluoro-4-(5-methyl-2-((1-(tetrahydro- 2H-pyran-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenoxy)-2,2- dimethylpropanenitrile
8
1-((4-(2-((1-(1- (cyclopropanecarbonyl)piperidin-4-yl)- 1H-pyrazol-4-yl)amino)-5- methylpyrimidin-4-yl)-2- fluorophenoxy)methyl)cyclopropane- carbonitrile
9
1-((2-fluoro-4-(5-methyl-2-((1-(1-(1- methylcyclopropanecarbonyl)piperidin-4- yl)-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenoxy)methyl)cyclopropanecarbonitrile
10
1-((4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4-yl)-2,6- difluorophenoxy)methyl)cyclopropane carbonitrile
11
1-(((5-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4- yl)pyridin-2- yl)oxy)methyl)cyclopropanecarbonitrile
12
3-(2-fluoro-4-(5-methyl-2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)phenoxy)propanenitrile
13
1-((4-(2-((1-(1-acetylpiperidin-4-yl)-1H- pyrazol-4-yl)amino)-5-methylpyrimidin-4- yl)-2- fluorophenoxy)methyl)cyclopropane- carbonitrile
14
1-(((5-(5-methyl-2-((1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)pyridin-2- yl)oxy)methyl)cyclopropanecarbonitrile
15
2,2-dimethyl-3-(4-(5-methyl-2-((1- (tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)phenoxy)propanenitrile
16
2,2-dimethyl-3-(4-(5-methyl-2-((1- (tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)phenoxy)butanenitrile
17
2,2-dimethyl-3-(4-(5-methyl-2-((1-(1- methylpiperidin-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)phenoxy)propanenitrile
18
3-(2-fluoro-4-(5-methyl-2-((1-(1- methylpiperidin-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenoxy)-2,2- dimethylpropanenitrile
19
3-(2-fluoro-4-(2-((1-(2-methoxyethyl)-1H- pyrazol-4-yl)amino)-5-methylpyrimidin-4- yl)phenoxy)-2,2-dimethylpropanenitrile
20
1-((2-fluoro-4-(5-methyl-2-((1-(1- methylpiperidin-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)phenoxy)methyl)cyclopropanecarbonitrile
21
1-((2-fluoro-4-(2-((1-(2-methoxyethyl)- 1H-pyrazol-4-yl)amino)-5- methylpyrimidin-4- yl)phenoxy)methyl)cyclopropanecarbonitrile
22
1-((2-fluoro-4-(5-fluoro-2-((1-(tetrahydro- 2H-pyran-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)phenoxy)methyl)cyclopropanecarbonitrile
23
1-((4-(5-chloro-2-((1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2- fluorophenoxy)methyl)cyclopropane- carbonitrile
24
1-((4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-fluoropyrimidin-4-yl)-2- fluorophenoxy)methyl)cyclopropane- carbonitrile
25
3-(2-fluoro-4-(5-fluoro-2-((1-(tetrahydro- 2H-pyran-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenoxy)-2,2- dimethylpropanenitrile
26
3-(4-(5-chloro-2-((1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2- fluorophenoxy)-2,2-dimethylpropanenitrile
27
1-((4-(5-chloro-2-((1-cyclopropyl-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)-2- fluorophenoxy)methyl)cyclopropane- carbonitrile
28
3-(4-(2-((1-(1-acetylpiperidin-4-yl)-1H- pyrazol-4-yl)amino)-5-methylpyrimidin-4- yl)-2-fluorophenoxy)-2,2- dimethylpropanenitrile
29
3-(4-(5-chloro-2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenoxy)-2,2- dimethylpropanenitrile
30
3-(4-(2-((1-(cyanomethyl)-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4-yl)-2- fluorophenoxy)-2,2-dimethylpropanenitrile
31
1-((4-(2-((1-(cyanomethyl)-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4-yl)-2- fluorophenoxy)methyl)cyclopropane- carbonitrile
32
3-(4-(5-chloro-2-((1-cyclopropyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)phenoxy)-2,2-dimethylpropanenitrile
33
1-(((4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4-yl)-2- fluorophenyl)(methyl)amino)methyl) cyclopropanecarbonitrile
34
6-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4- yl)chroman-3-carbonitrile
35
3-((4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4-yl)-2- fluorophenyl)(methypamino)-2,2- dimethylpropanenitrile
36
3-((4-(5-chloro-2-((1-cyclopropyl-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)-2- fluorophenyl)(methyl)amino)-2,2- dimethylpropanenitrile
37
3-((4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4-yl)-2- fluorophenyl)amino)-2,2- dimethylpropanenitrile
38
2,2-dimethyl-3-(4-(5-methyl-2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenoxy)propanenitrile
39
3-(2-fluoro-4-(5-methyl-2-((1-(piperidin-4- yl)-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenoxy)-2,2-dimethylpropanenitrile
40
3-(2-fluoro-4-(5-methyl-2-((1-(1,1,1- trifluoropropan-2-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenoxy)-2,2- dimethylpropanenitrile
41
3-(4-(5-methyl-2-((1-methyl-1H-pyrazol- 4-yl)amino)pyrimidin-4- yl)phenoxy)propanenitrile
42
1-(((4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4- yl)phenyl)amino)methyl)cyclopropane- carbonitrile
43
1-(((4-(5-methyl-2-((1-(1-methylpiperidin- 4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)amino)methyl)cyclopropane- carbonitrile
44
1-(((4-(5-chloro-2-((1-(piperidin-4-yl)-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)amino)methyl)cyclopropane- carbonitrile
Example
Structure
IUPAC name
1
3-(4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4- yl)phenoxy)-2,2-dimethylpropanenitrile
3
1-((4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4- yl)phenoxy)methyl)cyclobutanecarbonitrile
12
3-(2-fluoro-4-(5-methyl-2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4- yl)phenoxy)propanenitrile
29
3-(4-(5-chloro-2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenoxy)-2,2- dimethylpropanenitrile
38
2,2-dimethyl-3-(4-(5-methyl-2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenoxy)propanenitrile
41
3-(4-(5-methyl-2-((1-methyl-1H-pyrazol- 4-yl)amino)pyrimidin-4- yl)phenoxy)propanenitrile
42
1-(((4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4- yl)phenyl)amino)methyl)cyclopropane- carbonitrile
Example
Structure
IUPAC name
4
3-(4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4-yl)-2- fluorophenoxy)-2,2-dimethylpropanenitrile
5
1-((4-(2-((1-cyclopropyl-1H-pyrazol-4- yl)amino)-5-methylpyrimidin-4-yl)-2- fluorophenoxy)methyl)cyclopropane- carbonitrile
6
1-((2-fluoro-4-(5-methyl-2-((1- (tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)phenoxy)methyl)cyclopropanecarbonitrile
7
3-(2-fluoro-4-(5-methyl-2-((1-(tetrahydro- 2H-pyran-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenoxy)-2,2- dimethylpropanenitrile
13
1-((4-(2-((1-(1-acetylpiperidin-4-yl)-1H- pyrazol-4-yl)amino)-5-methylpyrimidin-4- yl)-2- fluorophenoxy)methyl)cyclopropane- carbonitrile
17
2,2-dimethyl-3-(4-(5-methyl-2-((1-(1- methylpiperidin-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)phenoxy)propanenitrile
19
3-(2-fluoro-4-(2-((1-(2-methoxyethyl)-1H- pyrazol-4-yl)amino)-5-methylpyrimidin-4- yl)phenoxy)-2,2-dimethylpropanenitrile
20
1-((2-fluoro-4-(5-methyl-2-((1-(1- methylpiperidin-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)phenoxy)methyl)cyclopropanecarbonitrile
40
3-(2-fluoro-4-(5-methyl-2-((1-(1,1,1- trifluoropropan-2-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenoxy)-2,2- dimethylpropanenitrile
53 - 56 . (canceled)
57 . A pharmaceutical composition comprising a compound according to claim 1 , effective to treat or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
58 - 62 . (canceled)
63 . The pharmaceutical composition of any one of claims 57 - 62 , being suitable for oral administration, topical administration or GI-restricted administration.
64 - 70 . (canceled)
71 . A unit dosage form comprising a pharmaceutical composition according to claim 57 .
72 . (canceled)
73 . A method for treating or reducing a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound having the structural formula (I):
wherein
L is O or NR 4′ ;
X is N or CR x , wherein R x is R′, halogen, CN or OR′;
Y is N or CR Y , wherein R Y is R′, halogen, CN or OR′;
each of Z 1 and Z 2 is independently selected from N and CR′, provided that one of Z 1 and Z 2 is N and the other is CR′;
R 1 is hydrogen, halogen, CN, C 1 -C 6 unsubstituted or substituted alkyl or OR′;
R 2 is a C 1 -C 16 aliphatic group optionally comprising one or more heteroatoms selected from N, O, S and P, wherein the aliphatic group is optionally substituted with one or more of halogen, OR′, NRR′, CN, CONRR′, NRCOR′ and C 1 -C 6 alkyl, which is in turn optionally substituted with F, OR′ or NRR′;
R 3 is R′ or halogen;
each of R 4 and R 4′ , when L is NR 4′ , is selected from hydrogen and C 1 -C 16 aliphatic groups optionally comprising one or more heteroatoms selected from N, O, S and P, and R 4 and R 4′ together may form a 3- to 7-membered ring, having 0 to 3 heteroatoms selected from O, N and S, and wherein each of R 4 and R 4′ is optionally substituted with CN, CF 3 or OR′; provided that if one of R 4 and R 4′ is hydrogen, the other is not hydrogen; and
each R and R′ is independently hydrogen or a C 1 -C 12 unsubstituted or substituted alkyl group,
or a pharmaceutically acceptable form or an isotope derivative thereof, effective to treat, prevent, or reduce one or more of inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
74 - 93 . (canceled)Join the waitlist — get patent alerts
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