Compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders
The present invention discloses compounds according to Formula I: wherein Cy, R 1 , L 1 , R 3 , R 4 , R 5 , L a , and R a are as defined herein. Novel benzimidazoles according to Formula I, able to inhibit JAK are disclosed, these compounds may be prepared as a pharmaceutical composition, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, allergic diseases, inflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 or hypersecretion of interferons.
1. A compound according to Formula I:
wherein
R 1 is H, or Me;
L 1 is —NR 2 —; —O—, or —CH 2 —;
Cy is phenyl;
R 2 is H, or C 1-4 alkyl;
R 3 is H, halo, C 1-4 alkyl optionally substituted with one or more halo, or C 1-4 alkoxy optionally substituted with one or more halo;
R 4 is H, or halo;
R 5 is —CN, halo, or is -L 2 -R 6 ;
-L 2 is absent, or is —C(═O)—, —C(═O)NR 7 —, —NR 7 C(═O)—, —SO 2 NR 7 —, or —NR 7 SO 2 —;
R 6 is H, or C 1-6 alkyl optionally substituted with one or more independently selected R 8 groups;
R 7 is H, or C 1-4 alkyl;
R 8 is OH, CN, halo, or C 1-4 alkoxy,
L a is absent, or is —C(═O)—, —C(═O)O—, or —C(═O)NH—;
R a is:
H,
C 1-4 alkyl optionally substituted with one or more independently selected R b , or
C 3-7 monocyclic cycloalkyl optionally substituted with one or more independently selected R c ,
R b is
halo,
CN,
OH,
C 1-4 alkoxy,
C 3-7 cycloalkyl,
—SO 2 —C 1-4 alkyl, or
—C(═O)NR b1 R b2
R c is
halo,
CN,
OH,
C 1-4 alkyl,
—C(═O)OH, or
—C(═O)NR c1 R c2 ; and
each R b1 , R b2 , R c1 and R c2 is independently selected from H, and C 1-4 alkyl, or a pharmaceutically acceptable salt thereof.
2. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is Me.
3. A compound or pharmaceutically acceptable salt according to claim 1 , wherein the compound is according to Formula IIa:
wherein L 1 , R 3 , R 4 , L a , R a and R 5 are as described in claim 1 .
4. A compound or pharmaceutically acceptable salt according to claim 1 , wherein the compound is according to Formula IVa or IVd:
wherein R 3 , R 4 , R 5 , L a , and R a are as described in claim 1 .
5. A compound or pharmaceutically acceptable salt according to claim 1 , wherein the compound is according to Formula Va or Vd:
wherein R 3 , R 4 , R 5 , L a , and R a are as described in claim 1 .
6. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 4 is H, F, or Cl.
7. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is H, Me, or Et.
8. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 5 is CN, F, Cl, —SO 2 Me or —SO 2 Et.
9. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R a is:
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to claim 1 .
11. A compound, or pharmaceutically acceptable salt thereof, according to claim 1 wherein the compound is:
N-(6-((4-cyano-2-ethyl-6-fluorophenyl)(methyl)amino)-1-methyl-1H-benzo[d]imidazol-4-yl)cyclopropanecarboxamide,
Methyl 6-((4-cyano-2-ethyl-6-fluorophenyl)(methyl)amino)-1-methyl-1H-benzo[d]imidazol-4-ylcarbamate,
N-(6-((4-cyano-2-ethyl-6-fluorophenyl)(methyl)amino)-1-methyl-1H-benzo[d]imidazol-4-yl)-2-fluorocyclopropanecarboxamide,
(1R,2R)-N-[6-(4-cyano-2-ethyl-phenoxy)-1-methyl-benzimidazol-4-yl]-2-fluoro-cyclopropanecarboxamide,
(1R,2R)-N-[6-(2-chloro-4-cyano-6-fluoro-N-methyl-anilino)-1-methyl-benzimidazol-4-yl]-2-fluoro-cyclopropanecarboxamide,
(1R,2R)-N-[6-(4-cyano-2-fluoro-N-methyl-anilino)-1-methyl-benzimidazol-4-yl]-2-fluoro-cyclopropanecarboxamide,
(1R,2R)-2-fluoro-N-[6-(2-fluoro-N,6-dimethyl-4-methyl sulfonyl-anilino)-1-methyl-benzimidazol-4-yl]cyclopropanecarboxamide,
(1R,2R)-2-fluoro-N-[6-(2-fluoro-N-methyl-4-methylsulfonyl-anilino)-1-methyl-benzimidazol-4-yl]cyclopropanecarboxamide,
N-[6-(2-fluoro-N,6-dimethyl-4-methylsulfonyl-anilino)-1-methyl-benzimidazol-4-yl]cyclopropanecarboxamide,
(1R,2R)-N-[6-(N,2-dimethyl-4-methylsulfonyl-anilino)-1-methyl-benzimidazol-4-yl]-2-fluoro-cyclopropanecarboxamide,
(1R,2R)-N-[6-(4-ethylsulfonyl-N,2-dimethyl-anilino)-1-methyl-benzimidazol-4-yl]-2-fluoro-cyclopropanecarboxamide, or
N-[6-[4-(cyanomethyl)anilino]-1-methyl-benzimidazol-4-yl]cyclopropanecarboxamide.