Imidazopyrimidines as modulators of IL-17
The present application discloses compounds of Formula I or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5 are defined in the specification, as well as methods of making and using the compounds disclosed herein for treating or ameliorating an IL-17 mediated syndrome, disorder and/or disease.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —C (1-6) alkyl or —C (0-3) alkylC (3-6) cycloalkyl;
wherein the —C (1-6) alkyl and the —C (0-3) alkylC (3-6) cycloalkyl are unsubstituted or substituted with one to six fluorine atoms;
R 2 is —C (3-5) cycloalkyl;
R 3 is-C (0-1) alkylC (3-6) cycloalkyl, wherein the —C (0-1) alkylC (3-6) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms;
R 4 is-C (3-4) cycloalkyl or a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S;
wherein the C (3-4) cycloalkyl is unsubstituted or substituted with one to three R 4a groups; and
wherein the 5- to 6-membered heteroaryl is unsubstituted or substituted with one or two R 4b groups;
each R 4a group is independently selected from-C (1-4) alkyl that is unsubstituted or substituted with one to six fluorine atoms; and
each R 4b group is independently selected from-C (0-2) alkylC (3-4) cycloalkyl or —C (1-5) alkyl, wherein the —C (0-2) alkylC (3-4) cycloalkyl and —C (1-5) alkyl are unsubstituted or substituted with one to six fluorine atoms;
R 5 is H or F;
wherein
when R 4 is —C (3-4) cycloalkyl then the compound of Formula I is a compound of Formula Ia:
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —C (1-6) alkyl or —C (0-3) alkylC (3-6) cycloalkyl;
wherein the —C (1-6) alkyl and the —C (0-3) alkylC (3-6) cycloalkyl are unsubstituted or substituted with one to six fluorine atoms;
R 2 is —C (3-5) cycloalkyl;
R 3 is —C (0-1) alkylC (3-6) cycloalkyl, wherein the —C (0-1) alkylC (3-6) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms;
R 4 is a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S;
wherein the 5- to 6-membered heteroaryl is unsubstituted or substituted with one or two R 4b groups;
each R 4b group is independently selected from —C (0-2) alkylC (3-4) cycloalkyl or —C (1-5) alkyl, wherein the —C (0-2) alkylC (3-4) cycloalkyl and —C (1-5) alkyl are unsubstituted or substituted with one to six fluorine atoms; and
R 5 is H or F.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 5 is H.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is-C (1-4) alkyl, wherein the —C (1-4) alkyl is unsubstituted or substituted with one to six fluorine atoms.
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C (1-2) alkylC (3-5) cycloalkyl, wherein the —C (1-2) alkylC (3-5) cycloalkyl is unsubstituted or substituted with one to three fluorine atoms.
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:
is:
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is cyclopropyl.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 3 is
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 4 is pyridinyl that is unsubstituted or substituted with C (1-2) alkyl that is unsubstituted or substituted with one to three fluorine atoms.
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 4 is pyrazolyl, triazolyl, isoxazolyl, or oxadiazolyl that is unsubstituted or substituted with one or two R 4b groups,
each R 4b group is independently selected from-C (0-1) alkylC (3) cycloalkyl or —C (1-3) alkyl, wherein the —C (0-1) alkylC (3) cycloalkyl and —C (1-3) alkyl are unsubstituted or substituted with one to four fluorine atoms.
11 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is 1H-pyrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, isoxazole-4-yl, or 1,2,5-oxadiazolyl that is unsubstituted or substituted with one or two R 4b groups.
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is:
13 . The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 4 is:
14 . The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 4 is:
15 . The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 4 is:
16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 4 is —C (3) cycloalkyl;
wherein the C (3) cycloalkyl is unsubstituted or substituted with one to three R 4a groups; and
each R 4a group is independently selected from —C (1-2) alkyl that is unsubstituted or substituted with one to three fluorine atoms; and
wherein the compound of Formula I is a compound of Formula Ia:
17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
18 . The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
19 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is
20 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is
21 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is
22 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is
23 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is
24 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is
25 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is
26 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is
27 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is
28 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is
29 . A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
30 . A method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
31 . The method of claim 30 , wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.
32 . The method of claim 31 , wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is psoriasis.
33 . The method of claim 31 , wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis or rheumatoid arthritis.
34 . The method of claim 31 , wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.
35 . The method of claim 31 , wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.
36 . The method of claim 30 , wherein the compound, or a pharmaceutically acceptable salt thereof, is administered orally.
37 . The method of claim 36 , wherein the compound, or a pharmaceutically acceptable salt thereof, is administered as a tablet or a capsule.