JPWO2020025517A5

JPWO2020025517A5 -

Info

Publication number: JPWO2020025517A5
Application number: JP2021505638A
Authority: JP
Publication date: 2022-08-08
Anticipated expiration: 2039-07-29

Claims

Formula I,

A compound represented by the formula:
Ring A is aryl or heteroaryl having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of which is optionally substituted ;
Ring B is aryl or heteroaryl having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of which is optionally substituted ;
R ¹ is -Me, -CF ₃ , -OMe, -OEt, or -CN;
Each R ² is independently —H, —R, halogen, —haloalkyl, —OR, —SR, —CN, —NO ₂ , —SO ₂ R, —SOR, —C(O)R, —CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R, or -N(R) ₂ ;
Each R ³ is independently —H, —R, halogen, —haloalkyl, —OR, —SR, —CN, —NO ₂ , —SO ₂ R, —SOR, —C(O)R, —CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R, or -N(R) ₂ ;
X is C( ^R4 ) ₂ , O, NR4, S, S( ^R4 ), or S ₍ ^R4 ) ² ;
Each R ⁴ is independently —H, —R, halogen, —haloalkyl, —OR, —SR, —CN, —NO ₂ , —SO ₂ R, —SOR, —C(O)R, —CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R, or -N(R) ₂ ;
Each R ⁵ is independently —H, —R, halogen, —haloalkyl, —OR, —SR, —CN, —NO ₂ , —SO ₂ R, —SOR, —C(O)R, —CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R, or -N(R) ₂ ;
Each R is independently hydrogen, C _1-6 aliphatic, C _3-10 aryl, 3-8 membered saturated or partially unsaturated carbocyclic ring, 1-4 heteroatoms (independently , nitrogen, oxygen, or sulfur), or 5- having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur). is a 6-membered monocyclic heteroaryl ring; each of which is optionally substituted; or two R groups on the same atom together with the atom to which they are attached are , C _3-10 aryl, 3-8 membered saturated or partially unsaturated carbocyclic ring, 3- having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur) forming a 7-membered heterocycle or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of which is optionally substituted;
k is 0 or 1;
n is 0, 1, or 2;
p is 0, 1, or 2;
r is 0, 1, or 2; and t is 0, 1, or 2;
or derivatives, solvates, hydrates, tautomers or stereoisomers thereof, and/or pharmaceutically acceptable salts of each of the above, and mixtures thereof in all proportions.

2. The compound of Claim 1, or a derivative, solvate, water thereof, wherein Ring A is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; each of which may be optionally substituted; hydrates, tautomers or stereoisomers, and/or pharmaceutically acceptable salts of each of the above, and mixtures thereof in all proportions.

2. The claim 1, wherein ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrole, imidazole, isoxazole, oxazole, or thiazole; each of which is optionally substituted. compounds, or derivatives, solvates, hydrates, tautomers or stereoisomers thereof, and/or pharmaceutically acceptable salts of each of the above, and mixtures thereof in all proportions.

Ring A and ring B are

A compound according to any one of claims 1 to 3, or a derivative, solvate, hydrate, tautomer or stereoisomer thereof, and/or a pharmaceutically acceptable salts, and mixtures thereof in all proportions.

a compound according to any one of claims 1 to 4, or a derivative, solvate, hydrate, tautomer or stereoisomer thereof, wherein X is C(R ⁴ ) ₂ or O; and/or pharmaceutically acceptable salts of each of the above, and mixtures thereof in any proportion.

Each ^R4 independently

A compound according to any one of claims 1 to 5, or a derivative, solvate, hydrate, tautomer or stereoisomer thereof, and/or a pharmaceutically acceptable salts, and mixtures thereof in all proportions.

7. The compound of any one of claims 1 to ⁶ , or a derivative, solvate, hydrate thereof, wherein each R5 is independently methyl, cyclopropyl, -F, or _-CF3 , tautomers or stereoisomers, and/or pharmaceutically acceptable salts of each of the above, and mixtures thereof in all ratios.

Formula Ia,

or a pharmaceutically acceptable salt thereof, according to claim 1.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R ¹ is -CF ₃ or -OMe.

Formula Ib,

or a pharmaceutically acceptable salt thereof, according to claim 1.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R ¹ is -OMe.

Formula Ic,

or a pharmaceutically acceptable salt thereof, according to claim 1.

13. The compound of claim 12 , wherein each ^R4 is independently -NRC(O)R, or -N(R) ₂ ; each of which is optionally substituted; or pharmaceutically acceptable salts.

Formula Id,

or a pharmaceutically acceptable salt thereof, according to claim 1.

15. The compound of claim 12 or 14 , or a pharmaceutically acceptable salt thereof, wherein R ¹ is -CN.

each R ⁴ is independently —H, C _1-6 aliphatic, —C(O)N(R) ₂ , —NRC(O)R, or —N(R) ₂ ; each of which 15. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 8, 10 and 14 , wherein is optionally substituted.

15. The compound of any one of claims 8, 10, 12 and 14 ^, or a pharmaceutically acceptable salt thereof, wherein each R5 is independently methyl, -F, or _-CF3 .

18. A compound according to any one of claims 1-17 , selected from Examples 1-388, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1-18 and a pharmaceutically acceptable adjuvant, carrier or vehicle.

A compound for use in a method of therapy, wherein said compound is selected from a compound according to any one of claims 1-18, or a pharmaceutically acceptable salt thereof.

21. The compound of claim 20, wherein said method of treatment is for treating a TLR7/8 mediated disorder or cancer.

said TLR7/8-mediated disorder is rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes, II type diabetes, inflammatory bowel disease, Crohn's disease, ulcerative colitis, hyper-IgDemia, periodic fever syndrome, cryopyrin-associated periodic syndrome, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, sham 21. Selected from gout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease, and cancer. The compound described in .