US2022402866A1PendingUtilityA1
3,4-disubstituted 3-cyclobutene-1,2-diones and use thereof
Est. expiryAug 14, 2037(~11 yrs left)· nominal 20-yr term from priority
Inventors:Christopher D. HeinTien T. DuongSantosh SinhaLing LiJeremiah H. NguyenDavid W. OldRobert M. BurkVeena ViswanathSandhya RaoJohn E. Donello
C07C 2601/14C07C 311/43C07C 2601/04C07C 2601/08C07B 59/00C07D 215/42C07B 2200/05C07C 2603/97A61P 29/00C07D 307/79C07D 307/36C07C 2603/70C07C 2602/12C07C 237/44C07D 333/54C07C 2602/10C07C 2601/02A61P 17/06C07C 211/52C07C 2601/18C07C 311/39A61P 27/02
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Claims
Abstract
Described herein are compounds, or pharmaceutically acceptable salts thereof, of the following formula: The compounds are useful for treating inflammatory and autoimmune diseases.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula I or a pharmaceutically acceptable salt thereof, including an enantiomer, a diastereoisomer, a tautomer thereof:
wherein
R 1 is selected from
i) 6 to 12 membered aryl optionally substituted with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
ii) 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
iii) 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
iv) 5 to 12 membered heteroaryl optionally with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
v) tri-C 1-5 alkylsilyl, and
vi) C 1-10 alkyl optionally substituted with at least one group selected from OR 6 , 6 to 12 membered aryl, 3 to 11 membered cycloalkyl, —CO 2 R 6 , —C(O)NR 6 R 7 , halo, 5 to 12 membered heteroaryl, 4 to 12 membered heterocyclyl, C 2-5 alkenyl, and C 2-5 alkynyl;
R 2 is selected from hydrogen, C 1-5 alkyl, C 2-5 alkenyl, and C 2-5 alkynyl;
or R 1 and R 2 together with the carbon to which they are attached form
i) a 6 to 12 membered aryl optionally with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
ii) a 3 to 11 membered cycloalkyl optionally with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
iii) a 5 to 12 membered heteroaryl optionally with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , CD 3 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W, or
iv) a 4 to 12 membered heterocyclyl optionally with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
provided that R 3 is absent when the carbon to which R 1 and R 2 are attached is part of an aromatic or double bond;
R 3 is selected from
i) hydrogen, deuterium, —CO 2 R 6 , —NR 6 R 7 , —C(O)NR 6 R 7 , —OR 6 , CD 2 CD 3 , halo, C 2-5 alkenyl, C 2-5 alkynyl, sulfonate, phosphonate,
ii) 6 to 12 membered aryl optionally substituted with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
iii) 3 to 11 membered cycloalkyl optionally with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
iv) 4 to 12 membered heterocyclyl optionally with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
v) 5 to 12 membered heteroaryl optionally substituted with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W, and
vi) C 1-5 alkyl optionally substituted with at least one group selected from OR 6 , 6 to 12 membered aryl, 3 to 11 membered cycloalkyl, —CO 2 R 6 , —C(O)NR 6 R 7 , halo, 5 to 12 membered heteroaryl, 4 to 12 membered heterocyclyl, —Si(C 1-6 alkyl), C 2-5 alkenyl, and C 2-5 alkynyl;
R 4 is selected from —CO 2 R 6 , —C(O)NR 6 R 7 , —NR 6 C(O)R 7 , —NR 6 CO 2 R 7 , —NR 6 C(O)NR 6 R 7 , —NR 7 SO 2 R 6 , —NR 7 SO 2 NR 6 R 7 , C 1-6 hydroxyalkyl, C 1-6 haloalkyl, halo, CN, —SO 2 NR 6 R 7 , and —SO 2 R 6 ;
R 5 is selected from hydrogen, C 1-6 alkyl, —OR 6 , halo, —NR 6 R 7 , CN, C 1-6 haloalkyl, and —NO 2 ;
R 6 and R 7 are independently selected from
i) hydrogen,
ii) C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkoxyalkyl, aralkyl, CD 3 ,
iii) C 2-5 alkenyl, C 2-5 alkynyl,
iv) 6 to 12 membered aryl optionally substituted with at least one group selected from W,
v) 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W,
vi) 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and
vii) 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
or R 6 and R 7 together with the nitrogen to which they are attached form a 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W;
W is selected from C 1-6 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, halo, C 1-6 alkoxy, and hydroxyl; with the provisos:
a) that when R 1 is 6 to 12 membered aryl optionally substituted as described above or 5 to 12 membered heteroaryl optionally substituted as described above, R 3 is not a 4 or 5 membered heterocyclyl optionally substituted as described above, and that when R 3 is 6 to 12 membered aryl optionally substituted as described above or 5 to 12 membered heteroaryl optionally substituted as described above, R 1 is not a 4 or 5 membered heterocyclyl optionally substituted as described above;
b) that when any of R 1 , R 2 , or R 3 are C 1-5 alkyl or C 1-10 alkyl, and R 4 is —SO 2 NR 6 R 7 , R 5 is not hydrogen;
c) that when either R 1 or R 3 is 4 or 5 membered heterocyclyl optionally substituted as described above, R 2 is not C 1-10 alkyl;
d) that when either R 1 or R 3 is 5 to 12 membered heteroaryl optionally substituted as described above, and R 4 is —SO 2 NR 6 R 7 , then neither R 6 or R 7 in the —SO 2 NR 6 R 7 is hydrogen or 5 to 12 membered heteroaryl optionally substituted as described above;
e) that when R 1 and R 2 together with the carbon to which they are attached form a 6 to 12 membered aryl optionally substituted as described above, and R 4 is —SO 2 NR 6 R 7 , R 5 is not C 1-6 alkyl or CN and both R 6 and R 7 in the —SO 2 NR 6 R 7 are C 1-6 alkyl; and
f) that when R 1 and R 2 together with the carbon to which they are attached form a 4 to 12 membered heterocyclyl optionally substituted as described above, R 3 is not hydrogen.
2 . The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein
R 1 is selected from
i) 6 to 12 membered aryl optionally substituted with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
ii) 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
iii) 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
iv) 5 to 12 membered heteroaryl optionally with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
v) tri-C 1-5 alkylsilyl, and
vi) C 1-10 alkyl optionally substituted with at least one group selected from OR 6 , 6 to 12 membered aryl, 3 to 11 membered cycloalkyl, —CO 2 R 6 , —C(O)NR 6 R 7 , halo, 5 to 12 membered heteroaryl, 4 to 12 membered heterocyclyl, C 2-5 alkenyl, and C 2-5 alkynyl;
R 2 is selected from hydrogen, C 1-5 alkyl, C 2-5 alkenyl, and C 2-5 alkynyl; R 3 , R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 1 ;
with the provisos:
a) that when R 1 is 6 to 12 membered aryl optionally substituted as described above or 5 to 12 membered heteroaryl optionally substituted as described above, R 3 is not a 4 or 5 membered heterocyclyl optionally substituted as described above, and that when R 3 is 6 to 12 membered aryl optionally substituted as described above or 5 to 12 membered heteroaryl optionally substituted as described above, R 1 is not a 4 or 5 membered heterocyclyl optionally substituted as described above;
b) that when any of R 1 , R 2 , or R 3 are C 1-5 alkyl or C 1-10 alkyl, and R 4 is —SO 2 NR 6 R 7 , R 5 is not hydrogen;
c) that when either R 1 or R 3 is 4 or 5 membered heterocyclyl optionally substituted as described above, R 2 is not C 1-10 alkyl;
d) that when either R 1 or R 3 is 5 to 12 membered heteroaryl optionally substituted as described above, and R 4 is —SO 2 NR 6 R 7 , then neither R 6 or R 7 in the —SO 2 NR 6 R 7 is hydrogen or 5 to 12 membered heteroaryl optionally substituted as described above.
3 . The compound or a pharmaceutically acceptable salt thereof of claim 2 , wherein R 1 is C 1-10 alkyl substituted with at least one group selected from OR 6 halo, —CO 2 R 6 , and 3 to 11 membered cycloalkyl, and wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 2 .
4 . The compound or a pharmaceutically acceptable salt thereof of claim 2 , wherein R 2 is hydrogen, and wherein R 3 , R 4 , R 5 , R 6 , and R 7 , and W are as defined in claim 2 .
5 . The compound or a pharmaceutically acceptable salt thereof of claim 2 , wherein R 3 is 6 to 12 membered aryl or C 1-5 alkyl, and wherein R 4 , R 5 , R 6 , and R 7 , and W are as defined in claim 2 .
6 . The compound or a pharmaceutically acceptable salt thereof of claim 2 , wherein R 6 is hydrogen or C 1-6 alkyl.
7 . The compound or a pharmaceutically acceptable salt thereof of claim 6 , wherein R 6 is hydrogen.
8 . The compound or a pharmaceutically acceptable salt thereof of claim 2 , wherein R 1 is C 1-10 alkyl, and wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 2 .
9 . The compound or a pharmaceutically acceptable salt thereof of claim 8 , wherein R 2 is hydrogen, and wherein R 3 , R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 2 .
10 . The compound or a pharmaceutically acceptable salt thereof of claim 8 , wherein R 3 is 6 to 12 membered aryl.
11 . The compound or a pharmaceutically acceptable salt thereof of claim 8 , wherein R 3 is 5 to 12 membered heteroaryl optionally substituted with at least one C 1-6 alkyl group.
12 . The compound or a pharmaceutically acceptable salt thereof of claim 8 , wherein R 3 is —C(O)NR 6 R 7 , and wherein R 6 and R 7 are independently selected from hydrogen, C 1-6 alkyl, and 3 to 11 membered cycloalkyl.
13 . The compound or a pharmaceutically acceptable salt thereof of claim 8 , wherein R 2 is C 1-5 alkyl, and wherein R 3 , R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 2 .
14 . The compound or a pharmaceutically acceptable salt thereof of claim 8 , wherein R 3 is hydrogen, and wherein R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 2 .
15 . The compound or a pharmaceutically acceptable salt thereof of claim 8 , wherein R 3 is C 1-5 alkyl, and wherein R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 2 .
16 . The compound or a pharmaceutically acceptable salt thereof of claim 8 , wherein R 3 is 6 to 12 membered aryl, and wherein R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 2 .
17 . The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein
R 1 and R 2 together with the carbon to which they are attached form
i) a 6 to 12 membered aryl optionally with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
ii) a 3 to 11 membered cycloalkyl optionally with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
iii) a 5 to 12 membered heteroaryl optionally with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , CD 3 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W, or
iv) a 4 to 12 membered heterocyclyl optionally with at least one group selected from C 1-6 alkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, —NR 6 R 7 , C 1-6 alkyl-C(O)O—, —C(O)O—C 1-6 alkyl, C(O)NR 6 R 7 , —NR 6 C(O)R 7 , halo, OR 6 , R 6 S(O) 2 O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
provided that R 3 is absent when the carbon to which R 1 and R 2 are attached is part of an aromatic or double bond; and R 3 , R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 1 ; and
with the provisos:
a) that when R 1 and R 2 together with the carbon to which they are attached form a 6 to 12 membered aryl optionally substituted as described above, and R 4 is —SO 2 NR 6 R 7 , R 5 is not C 1-6 alkyl or CN and both R 6 and R 7 in the —SO 2 NR 6 R 7 are C 1-6 alkyl; and
b) that when R 1 and R 2 together with the carbon to which they are attached form a 4 to 12 membered heterocyclyl optionally substituted as described above, R 3 is not hydrogen.
18 . The compound or a pharmaceutically acceptable salt thereof of claim 17 , wherein R 1 and R 2 together with the carbon to which they are attached form a 6 to 12 membered aryl optionally substituted with at least one C 1-6 alkyl group, and wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 17 .
19 . The compound or a pharmaceutically acceptable salt thereof of claim 17 , wherein R 1 and R 2 together with the carbon to which they are attached form a 5 to 12 membered heteroaryl optionally substituted with at least one C 1-6 alkyl group, and wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 17 .
20 . The compound or a pharmaceutically acceptable salt thereof of claim 17 , wherein R 1 and R 2 together with the carbon to which they are attached form a 3 to 11 membered cycloalkyl optionally with at least one group selected from C 1-6 alkyl, and wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 17 .
21 . The compound or a pharmaceutically acceptable salt thereof of claim 17 , wherein R 3 is hydrogen, and wherein R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 17 .
22 . The compound or a pharmaceutically acceptable salt thereof of claim 17 , wherein R 3 is selected from
i) C 1-5 alkyl, optionally substituted with at least one group selected from OR 6 , C 2-5 alkenyl, and 6 to 12 membered aryl; ii) 5 to 12 membered heteroaryl; iii) 6 to 12 membered aryl optionally substituted with at least one group selected from C 1-6 alkyl, and halo; iv) 3 to 11 membered cycloalkyl; v) C 2-5 alkynyl;
and wherein R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 17 .
23 . The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is selected from methyl, ethyl, isopropyl, tert-butyl, methoxymethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
24 . The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 and R 2 together with the carbon to which they are attached form a ring selected from
wherein indicates the point of attachment to NH, and wherein R 3 , R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 1 .
25 . The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is selected from hydrogen, methyl, ethyl, propyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynl, phenyl,
and wherein R 4 , R 5 , R 6 , R 7 , and W are as defined in claim 1 .
26 . The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R 4 is —C(O)NR 6 R 7 or —SO 2 NR 6 R 7 .
27 . The compound or a pharmaceutically acceptable salt thereof of claim 26 , wherein R 6 and R 7 are independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, aralkyl, or R 6 and R 7 together with the nitrogen to which they are attached form a 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W.
28 . The compound or a pharmaceutically acceptable salt thereof of claim 27 , wherein R 6 and R 7 are independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, or aralkyl.
29 . The compound or a pharmaceutically acceptable salt thereof of claim 27 , wherein both R 6 and R 7 are C 1-6 alkyl.
30 . The compound or a pharmaceutically acceptable salt thereof of claim 27 , wherein R 6 is C 1-6 alkyl and R 7 is C 1-6 hydroxyalkyl.
31 . The compound or a pharmaceutically acceptable salt thereof of claim 27 , wherein R 6 is C 1-6 alkyl and R 7 is aralkyl.
32 . The compound or a pharmaceutically acceptable salt thereof of claim 27 , wherein R 6 and R 7 together with the nitrogen to which they are attached form a 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W.
33 . The compound or a pharmaceutically acceptable salt thereof of claim 26 , wherein R 4 is —C(O)NR 6 R 7 .
34 . The compound or a pharmaceutically acceptable salt thereof of claim 26 , wherein R 4 is —SO 2 NR 6 R 7 .
35 . The compound or a pharmaceutically acceptable salt thereof of claim 26 , wherein R 4 is halo.
36 . The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein the moiety:
is of the form:
37 . The compound or a pharmaceutically acceptable salt thereof of any one of claim 1 , wherein the moiety:
is of the form:
38 . The compound or a pharmaceutically acceptable salt thereof of claim 1 , which is selected from
or a pharmaceutically acceptable salt thereof.
39 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
40 . A method of treating an inflammatory or autoimmune disease in a mammal in need thereof which method comprises administering to the mammal in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of claim 1 , and a pharmaceutically acceptable carrier.
41 . The method of claim 40 , wherein the inflammatory or autoimmune disease is selected from the group consisting of psoriasis, rheumatoid arthritis, multiple sclerosis, Sjogren's disease, GvHD, alopecia areata, uveitis, dry eye, diabetic retinopathy and allergic diseases.
42 . The method of claim 41 , wherein the inflammatory or autoimmune disease is selected from the group consisting of psoriasis and dry eye.
43 . The method of claim 42 , wherein the inflammatory or autoimmune disease is psoriasis.
44 . The method of claim 42 , wherein the inflammatory or autoimmune disease is dry eye.Join the waitlist — get patent alerts
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