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US 12,729,195 B2Granted
Immunomodulator
AssigneeHitgen Inc.
InventorsJin Li, Dengyou Zhang, Xiaoguang Bai, Yi Gong, Xiansi Zhou, Lichuan Liu, Qingran Li, Xin Chen, Yan Lan
Life of this patent
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Abstract
Disclosed is a compound capable of inhibiting interleukin 17A (IL-17A), which is represented by formula (I). An application of the compound or a stereoisomer thereof in the preparation of drugs for inhibiting IL-17A is also provided.
Claims24
A compound of formula (I), or a deuterated compound, a stereoisomer or a pharmacologically acceptable salt thereof:
- wherein:
- R1 is selected from the group consisting of:
- R2 and R3 are independently selected from the group consisting of hydrogen, —C1-6 alkyl and —C0-2 alkylidene-(3 to 10-membered cycloalkyl);
- A ring is selected from the group consisting of 5 to 10-membered aromatic ring and 5 to 10-membered heteroaromatic ring, wherein aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two or three RA1;
- and
- each RA1 is independently selected from the group consisting of hydrogen, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, halogen, cyano group, ═O, ═S, nitro, —OH, —O(C1-6 alkyl), —NH2, —NH(C1-6 alkyl) and —N(C1-6 alkyl)(C1-6 alkyl);
- X is O, S, NRx1 or CRx2Rx3;
- Rx1 is selected from the group consisting of hydrogen, —C1-6 alkyl and —C0-2 alkylidene-(3 to 10-membered cycloalkyl);
- and
- Rx2 and Rx3 are independently selected from the group consisting of hydrogen, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, halogen, cyano group, nitro, —OH, —O(C1-6 alkyl), —NH2, —NH(C1-6 alkyl) and —N(C1-6 alkyl)(C1-6 alkyl);
- n is 0, 1, 2 or 3;
- B ring is selected from the group consisting of 3 to 6-membered cycloalkane and 3 to 6-membered heterocyclic alkylidene, wherein cycloalkane and heterocyclic alkylidene are independently unsubstituted or substituted with one, two or three RB1;
- and
- each RB1 is independently selected from the group consisting of hydrogen, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, halogen, cyano group, ═O, ═S, nitro, —OH, —O(C1-6 alkyl), —NH2, —NH(C1-6 alkyl) and —N(C1-6 alkyl)(C1-6 alkyl);
- C ring is selected from the group consisting of 3 to 10-membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 5 to 10-membered aromatic ring, 5 to 10-membered heteroaromatic ring, 5 to 12-membered spiro ring, 5 to 12-membered spiro heterocycle, 5 to 12-membered bridged ring and 5 to 12-membered bridged heterocycle, wherein cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, spiro ring, spiro heterocycle, bridged ring and bridged heterocycle are independently unsubstituted or substituted with one, two or three RC1;
- each RC1 is independently selected from the group consisting of hydrogen, halogen, cyano group, ═O, ═S, nitro, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, —C0-2 alkylidene-ORC2, —C0-2 alkylidene-C(O)RC2, —C0-2 alkylidene-C(O)NRC2RC3, —C0-2 alkylidene-NRC2RC3, —C0-2 alkylidene-NRC2C(O)RC32, 3 to 10-membered cycloalkyl and 3 to 10-membered heterocycloalkyl, wherein alkyl and alkylidene are independently unsubstituted or substituted with one, two or three RC4;
- RC2 and RC3 are independently selected from the group consisting of hydrogen, —C1-6 alkyl, —C0-2 alkylidene-(3 to 10-membered cycloalkyl) and —C0-2 alkylidene-(3 to 10-membered heterocycloalkyl), wherein alkyl and alkylidene are independently unsubstituted or substituted with one, two or three RC4;
- and
- each RC4 is independently selected from the group consisting of hydrogen, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, halogen, cyano group, ═O, ═S, nitro, —OH, —O(C1-6 alkyl), —NH2, —NH(C1-6 alkyl) and —N(C1-6 alkyl)(C1-6 alkyl);
- or
- if two RC1 are linked to the same atom, the two RC1 are linked to form 3 to 10-membered cycloalkyl or 3 to 10-membered heterocycloalkyl;
- L is O, S, CRD1RD1, NRL, NRLC(O), NRLS(O), NRLS(O)2, C(O)NRL, C(O), S(O)NRL or S(O)2NRL, or absent;
- RL is hydrogen, —C1-6 alkyl or —C0-2 alkylidene-(3 to 10-membered cycloalkyl);
- D ring is 3 to 10-membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 5 to 10-membered aromatic ring, 5 to 10-membered heteroaromatic ring, 5 to 12-membered spiro ring, 5 to 12-membered spiro heterocycle, 5 to 12-membered bridged ring, or 5 to 12-membered bridged heterocycle, or absent, wherein cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, spiro ring, spiro heterocycle, bridged ring and bridged heterocycle are independently unsubstituted or substituted by one, two or three RD1;
- when L is absent and the D ring is not absent, the C ring is directly linked to the D ring;
- each RD1 is independently selected from the group consisting of hydrogen, halogen, cyano group, ═O, ═S, nitro, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, —C0-2 alkylidene-C(O)RD2, —C0-2 alkylidene-OC(O)RD2, —C0-2 alkylidene-C(O)NRD2RD3, —C0-2 alkylidene-NRD2RD3, —C0-2 alkylidene-NRD2C(O)RD3, —C0-4 alkylidene-OP(O)(OH)2, —C0-2 alkylidene-(3 to 10-membered cycloalkyl), —C0-2 alkylidene-(3 to 10-membered heterocycloalkyl), —C0-2 alkylidene-(5 to 10-membered aromatic ring) and —C0-2 alkylidene-(5 to 10-membered heteroaromatic ring), wherein alkyl, alkylidene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two or three RD4;
- RD2 and RD3 are independently selected from the group consisting of hydrogen, —C1-6 alkyl, —C0-2 alkylidene-(3 to 10-membered cycloalkyl), —C0-2 alkylidene-(3 to 10-membered heterocycloalkyl), —C0-2 alkylidene-(5 to 10-membered aromatic ring) and —C0-2 alkylidene-(5 to 10-membered heteroaromatic ring), wherein alkyl, alkylidene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two or three RD4;
- and
- each RD4 is independently selected from the group consisting of hydrogen, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, halogen, cyano group, ═O, ═S, nitro, —OH, —O(C1-6 alkyl), —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), —C0-2 alkylidene-(3 to 10-membered cycloalkyl), —C0-2 alkylidene-(3 to 10-membered heterocycloalkyl), —C0-2 alkylidene-(5 to 10-membered aromatic ring) and —C0-2 alkylidene-(5 to 10-membered heteroaromatic ring).
26 more elements
A compound represented by formula (II), or a deuterated compound, a stereoisomer or a pharmacologically acceptable salt thereof:
- wherein R11 is selected from the group consisting of hydrogen, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, —C0-2 alkylidene-(3 to 10-membered cycloalkyl), —C0-2 alkylidene-(3 to 10-membered heterocycloalkyl), —C0-2 alkylidene-(5 to 10-membered aromatic ring) and —C0-2 alkylidene-(5 to 10-membered heteroaromatic ring), wherein alkyl, alkylidene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two or three R1a;
- each R1a is independently selected from the group consisting of hydrogen, halogen, cyano group, ═O, ═S, nitro, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, —C0-2 alkylidene-OR1b, —C0-2 alkylidene-C(O)R1b, —C0-2 alkylidene-C(O)NR1bR1c, —C0-2 alkylidene-NR1bRc1, —C0-2 alkylidene-NR1bC(O)R1c, —C0-4 alkylidene-S(O)2R1bR1c, —C0-2 alkylidene-(3 to 10-membered cycloalkyl), —C0-2 alkylidene-(3 to 10-membered heterocycloalkyl), —C0-2 alkylidene-(5 to 10-membered aromatic ring) and —C0-2 alkylidene-(5 to 10-membered heteroaromatic ring), wherein alkyl, alkylidene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two or three R1b;
- R1b and R1c are independently selected from the group consisting of hydrogen, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, halogen, cyano group, ═O, ═S, nitro, —OH, —O(C1-6 alkyl), —NH2, —NH(C1-6 alkyl) and —N(C1-6 alkyl)(C1-6 alkyl);
- the A ring is selected from the group consisting of 5 to 10-membered aromatic ring and 5 to 10-membered heteroaromatic ring, wherein aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two or three RA1;
- and
- each RA1 is independently selected from the group consisting of hydrogen, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, halogen, cyano group, ═O, ═S, nitro, —OH, —O(C1-6 alkyl), —NH2, —NH(C1-6 alkyl) and —N(C1-6 alkyl)(C1-6 alkyl);
- X is O, S or —CH2—;
- n is 0 or 1;
- the B ring is selected from the group consisting of 3-membered cycloalkane, 4-membered cycloalkane, 5-membered cycloalkane and 6-membered cycloalkane, wherein cycloalkane is unsubstituted or substituted with one, two or three RB1;
- each RB1 is independently selected from the group consisting of hydrogen, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, halogen, cyano group, ═O, ═S, nitro, —OH, —O(C1-6 alkyl), —NH2, —NH(C1-6 alkyl) and —N(C1-6 alkyl)(C1-6 alkyl);
- the C ring is selected from the group consisting of 5 to 10-membered heterocycloalkyl, 5 to 10-membered aromatic ring and 5 to 10-membered heteroaromatic ring, wherein heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two or three RC1;
- and
- each RC1 is independently selected from the group consisting of hydrogen, halogen, cyano group, ═O, ═S, nitro, —C1-6 alkyl and halogen-substituted —C1-6 alkyl;
- the D ring is selected from the group consisting of 3 to 10-membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 5 to 10-membered aromatic ring and 5 to 10-membered heteroaromatic ring, wherein cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two or three RD1;
- each RD1 is independently selected from the group consisting of hydrogen, halogen, cyano group, ═O, ═S, nitro, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, —C0-2 alkylidene-ORD2, —C0-2 alkylidene-C(O)RD2, —C0-2 alkylidene-C(O)NRD2RD3, —C0-2 alkylidene-NRD2RD3, —C0-2 alkylidene-NRD2C(O)RD3 and —C0-4 alkylidene-OP(O)(OH)2;
- and
- RD2 and RD3 are independently selected from the group consisting of hydrogen, —C1-6 alkyl, —C0-2 alkylidene-(3 to 10-membered cycloalkyl), —C0-2 alkylidene-(3 to 10-membered heterocycloalkyl), —C0-2 alkylidene-(5 to 10-membered aromatic ring) and —C0-2 alkylidene-(5 to 10-membered heteroaromatic ring).
14 more elements
A compound represented by formula (III), or a deuterated compound, a stereoisomer or a pharmacologically acceptable salt thereof:
- wherein R11 is selected from the group consisting of —C1-6 alkyl, halogen-substituted —C1-6 alkyl, —C0-2 alkylidene-(3 to 10-membered cycloalkyl), —C0-2 alkylidene-(3 to 10-membered heterocycloalkyl), —C0-2 alkylidene-(5 to 10-membered aromatic ring) and —C0-2 alkylidene-(5 to 10-membered heteroaromatic ring), wherein alkyl, alkylidene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two or three R1a;
- each R1a is independently selected from the group consisting of hydrogen, halogen, cyano group, ═O, ═S, nitro, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, —C0-2 alkylidene-OR1b, —C0-2 alkylidene-C(O)R1b, —C0-2 alkylidene-C(O)NR1bR1c, —C0-2 alkylidene-NR1bR1c, —C0-2 alkylidene-NR1bC(O)R1c, —C0-4 alkylidene-S(O)2R1bR1c, —C0-2 alkylidene-(3 to 10-membered cycloalkyl), —C0-2 alkylidene-(3 to 10-membered heterocycloalkyl), —C0-2 alkylidene-(5 to 10-membered aromatic ring) and —C0-2 alkylidene-(5 to 10-membered heteroaromatic ring), wherein alkyl, alkylidene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two or three R1b;
- R1b and R1c are independently selected from the group consisting of hydrogen, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, halogen, cyano group, ═O, ═S, nitro, —OH, —O(C1-6 alkyl), —NH2, —NH(C1-6 alkyl) and —N(C1-6 alkyl)(C1-6 alkyl);
- the A ring is selected from the group consisting of 5 to 10-membered aromatic ring and 5 to 10-membered heteroaromatic ring, wherein aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two or three RA1;
- each RA1 is independently selected from the group consisting of hydrogen, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, halogen, cyano group, ═O, ═S, nitro, —OH, —O(C1-6 alkyl), —NH2, —NH(C1-6 alkyl) and —N(C1-6 alkyl)(C1-6 alkyl);
- X is O, S or —CH2—;
- n is 0 or 1;
- the B ring is selected from the group consisting of 3-membered cycloalkane, 4-membered cycloalkane, 5-membered cycloalkane and 6-membered cycloalkane, wherein cycloalkane is unsubstituted or substituted with one, two or three RB1;
- and
- each RB1 is independently selected from the group consisting of hydrogen, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, halogen, cyano group, ═O, ═S, nitro, —OH, —O(C1-6 alkyl), —NH2, —NH(C1-6 alkyl) and —N(C1-6 alkyl)(C1-6 alkyl);
- the C ring is selected from the group consisting of 5 to 10-membered heterocycloalkyl, 5 to 10-membered aromatic ring and 5 to 10-membered heteroaromatic ring, wherein aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two or three RC1;
- each RC1 is independently selected from the group consisting of hydrogen, halogen, cyano group, ═O, ═S, nitro, —C1-6 alkyl and halogen-substituted —C1-6 alkyl;
- the D ring is selected from the group consisting of 3 to 10-membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 5 to 10-membered aromatic ring and 5 to 10-membered heteroaromatic ring, wherein cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two or three RD1;
- each RD1 is independently selected from the group consisting of hydrogen, halogen, cyano group, ═O, ═S, nitro, —C1-6 alkyl, halogen-substituted —C1-6 alkyl, —C0-2 alkylidene-ORD2, —C0-2 alkylidene-C(O)RD2, —C0-2 alkylidene-C(O)NRD2RD3, —C0-2 alkylidene-NRD2RD3, —C0-2 alkylidene-NRD2C(O)RD3 and —C0-4 alkylidene-OP(O)(OH)2;
- and
- RD2 and RD3 are independently selected from the group consisting of hydrogen, —C1-6 alkyl, —C0-2 alkylidene-(3 to 10-membered cycloalkyl), —C0-2 alkylidene-(3 to 10-membered heterocycloalkyl), —C0-2 alkylidene-(5 to 10-membered aromatic ring) and —C0-2 alkylidene-(5 to 10-membered heteroaromatic ring).
13 more elements
Dependencies are inferred from the claim text.