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US 9,802,958 B2Granted
Tetrahydro[1,8]naphthyridine sulfonamide and related compounds for use as agonists of RORy and the treatment of disease
AssigneeLycera Corporation
InventorsThomas D. Aicher, Peter L. Toogood, Xiao Hu
Life of this patent
Estimating the term…
Abstract
The invention provides tetrahydro[1,8]naphthyridine and related compounds, pharmaceutical compositions, methods of promoting RORγ activity, increasing the amount of IL-17 in a subject, and treating cancer using such tetrahydro[1,8]naphthyridine and related compounds.
Claims25
A compound represented by Formula I:
- or a pharmaceutically acceptable salt or solvate thereof;
- wherein:
- A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl;
- each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, C1-6haloalkoxy, —N(R4)(R5), —CO2R6, —C(O)R6, —CN, —C1-4alkylene-C1-4alkoxy, —C1-4alkylene-N(R4)(R5), —C1-4alkylene-CO2R6, —O—C1-6alkylene-N(R4)(R5), —N(R4)C(O)—C1-6alkylene-N(R4)(R5), —S(O)pC1-6alkyl, —SO2N(R4)(R5), —N(R4)SO2(C1-6alkyl), —C(O)N(R4)(R5), and —N(R4)C(O)N(R4)(R5);
- X is —C(R6)2—[C(R6)(R7)]—[C(R6)2]m-ψ or —C(O)—[C(R6)(R7)]—[C(R6)2]m-ψ, wherein ψ is a bond to the sulfonamide ring nitrogen atom in Formula I;
- Y is —N(R2)(R3) or —O-aralkyl, wherein said aralkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6alkoxy, C1-6haloalkoxy, C1-6alkyl, C1-6haloalkyl, —N(R4)(R5), —CN, —CO2—C1-6alkyl, —C(O)—C1-6alkyl, —C(O)N(R4)(R5), —S(O)pC1-6alkyl, —SO2N(R4)(R5), and —N(R4)SO2(C1-6alkyl);
- R1 represents independently for each occurrence hydrogen, halogen, or C1-6alkyl;
- R2 is —C(O)-aryl, —C(O)-aralkyl, —C(O)—[C(R6)2]m-cycloalkyl, —C(O)—[C(R6)2]m-heterocyclyl, —C(O)—C1-8alkyl, —C(O)—C1-6alkylene-C1-6alkoxyl, —C(O)—C1-6alkylene-cycloalkyl, or —C(O)—C1-6alkylene-heterocycloalkyl;
- each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6alkoxy, C1-6haloalkoxy, C1-6alkyl, C1-6haloalkyl, —N(R4)(R5), —CN, —CO2—C1-6alkyl, —C(O)—C1-6alkyl, —C(O)N(R4)(R5), —S(O)pC1-6alkyl, —SO2N(R4)(R5), and —N(R4)SO2(C1-6alkyl);
- R3 is hydrogen or C1-6alkyl;
- R4 and R5 each represent independently for each occurrence hydrogen or C1-6alkyl;
- or R4 and R5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;
- R6 represents independently for each occurrence hydrogen or C1-6alkyl;
- R7 is hydrogen, hydroxyl, C1-6hydroxyalkyl, C1-6alkyl, C1-6haloalkyl, —CO2R6, C1-6alkylene-CO2R6, C1-4hydroxyalkylene-CO2R6, —N(R4)(R5), C1-6alkylene-N(R4)(R5), C1-6hydroxyalkylene-N(R4)(R5), —N(R4)C(O)R9, C1-6alkylene-N(R4)C(O)R9, C1-6alkylene-C(O)N(R4)(R5), —N(4)CO2—C1-6alkyl, or C1-6alkylene-N(R4)(C(O)N(R4)(R5);
- or R7 is heterocycloalkyl or C1-4alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halogen, hydroxyl, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, and C1-6haloalkoxy;
- R9 is hydrogen, C1-6alkyl, C1-6hydroxyalkyl, C1-6alkylene-N(R4)(R5), or C1-6alkylene-N(R4)C(O)—C1-6alkyl;
- n is 1 or 2;
- and
- m and p each represent independently for each occurrence 0, 1, or 2.
16 more elements
A compound in Table 1A, 2A, or 3A below or a pharmaceutically acceptable salt thereof:
- TABLE 1A
- No.
- Y
- Z
- I-1
- I-2
- I-3
- I-4
- I-5
- I-6
- I-7
- I-8
- I-9
- I-10
- I-11
- I-12
- I-13
- I-14
- I-15
- I-16
- I-17
- I-18
- I-19
- I-20
- I-21
- I-22
- I-23
- I-24
- I-25
- I-26
- I-27
- I-28
- I-29
- I-30
- I-31
- I-32
- I-33
- I-34
- I-35
- I-36
- I-37
- I-38
- I-39
- I-40
- I-41
- I-42
- I-43
- I-44
- I-45
- TABLE 2A
- No.
- Y
- Z
- II-1
- II-2
- II-3
- II-4
- II-5
- II-6
- II-7
- II-8
- II-9
- II-10
- II-26
- II-27
- II-28
- II-29
- II-30
- II-31
- TABLE 3A
- No.
- Compound
- III-27
- III-28
- III-33
- III-34
- III-35
- III-36
- III-37
- III-38
- III-39
- III-41
- III-42
- III-43
- III-44
- III-45
- III-40
- III-47
- III-46
- III-50
87 more elements
Dependencies are inferred from the claim text.