CN117120450A - Thienopyrrole compounds - Google Patents

Thienopyrrole compounds Download PDF

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Publication number
CN117120450A
CN117120450A CN202280027627.9A CN202280027627A CN117120450A CN 117120450 A CN117120450 A CN 117120450A CN 202280027627 A CN202280027627 A CN 202280027627A CN 117120450 A CN117120450 A CN 117120450A
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membered
heterocyclyl
pharmaceutically acceptable
groups
alkyl
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CN202280027627.9A
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Inventor
S·E·阿曼
E·Y·卡纳莱斯
W·K·常
H·H·金菲
S·E·拉泽威瑟
M·L·米切尔
Y·莫阿扎米
S·D·施罗德
D·G·肖尔
C·J·斯万克
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Gilead Sciences Inc
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Gilead Sciences Inc
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Priority claimed from PCT/US2022/024984 external-priority patent/WO2022221642A1/en
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Abstract

The present disclosure relates generally to certain compounds, pharmaceutical compositions comprising the compounds, and methods of making and using the compounds and pharmaceutical compositions. The compounds and compositions provided herein can be used to treat or prevent autoimmune diseases and/or inflammatory disorders, including systemic lupus erythematosus and cutaneous lupus erythematosus.

Description

Thienopyrrole compounds
Cross Reference to Related Applications
The present application claims priority from U.S. provisional application 63/176,109 filed on month 4 of 2021, U.S. provisional application 63/216,418 filed on month 29 of 2021, and U.S. provisional application 63/305,610 filed on month 2 of 2022, each of these provisional applications being incorporated herein in their entirety for all purposes.
Technical Field
The present disclosure relates generally to novel thienopyrrole compounds, pharmaceutical compositions comprising the compounds, and methods of making and using the compounds and pharmaceutical compositions. In some embodiments, the novel thienopyrrole compounds provided herein are useful for treating certain diseases and disorders, including but not limited to inflammatory conditions, systemic lupus erythematosus, cutaneous lupus erythematosus, or lupus nephritis.
Background
Toll-like receptors (TLRs) are a family of transmembrane immune receptors that sense pathogens, trigger innate immune responses, and elicit adaptive immunity. TLR7/8/9 is an endosomal localized TLR that responds to single stranded RNA (TLR 7/8) or unmethylated DNA (TLR 9) containing cytosine-phosphate-guanine (CpG) motifs. TLR7/8/9 activation leads to inflammatory responses including type I interferon and pro-inflammatory cytokine production, B cell activation and antibody production, and neutrophil arrest death (netois). Aberrant activation of TLR7/8/9 helps to raise type I interferon responses, increase pro-inflammatory cytokines, and sustain autoantibody production, which can promote chronic progression of a variety of autoimmune diseases and inflammatory conditions, leading to extensive inflammation and tissue damage. (Kawai et al, 2010,Nat Immunol 11, 373; joosten et al, 2016,Nat Rev Rheomatol 12, 344; crown et al, 2019,Lupus Sci Med 6, e000336; garcia-Romo et al, 2011,Sci Transl Med 3, 73ra20; kono et al, 2009, PNA 106, 12061; koh et al, 2013,J Immunol 190, 4982). Thus, there is a need for compounds that are potent TLR7 and/or TLR8 and/or TLR9 antagonists that are stable and exhibit potent pharmacokinetic and/or pharmacodynamic profiles.
Disclosure of Invention
In one embodiment, provided herein are compounds of formula I,
or a pharmaceutically acceptable salt thereof,
wherein the method comprises the steps of
R 1 Is an 8-to 10-membered fused bicyclic heterocyclyl or an 8-to 10-membered fused bicyclic heteroaryl, wherein 8-to 10-membered fused bicyclic heterocyclyl and 8-to 10-membered fused bicyclic heteroaryl are each independently optionally substituted with 1 to 4R a Group substitution;
R 2 is H, C 1-6 Alkyl or C 3-7 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-7 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 The group of the alkoxy group is substituted,
wherein C is 1-6 Alkoxy is optionally substituted with 1 to 3 halo groups;
R 3 is H, halogen, -CN, C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl or 4-to 7-membered monocyclic heterocyclyl,
wherein C is 1-6 Alkyl, C 3-7 Monocyclic cycloalkylAnd 4 to 7 membered monocyclic heterocyclyl groups each independently optionally being selected from the group consisting of-OH, halogen, -CN, C, and 1 to 3 independently 1-4 Alkoxy, -C (O) C 1-6 Alkyl, -C (O) N (R) 4 ) 2 4-to 7-membered monocyclic heterocyclyl, C 3-7 A monocyclic cycloalkoxy group and a 4-to 7-membered monocyclic hetero-epoxy group,
wherein C is 1-4 Alkoxy is optionally substituted with 1 to 3 halo groups;
each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached, form a 4 to 7 membered monocyclic heterocyclyl;
Z is C 1-6 Alkyl, C 2-6 Alkenyl, -C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 、C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 1-6 Alkyl and C 2-6 Alkenyl groups are each independently optionally substituted with 1 to 4R b Group substitution;
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally being substituted with 1-2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a Group substitution;
R 6 is C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7Up to 10 membered spirocyclic heterocyclyl groups,
Wherein C is 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5 - 10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally substituted with 1-4R a Group substitution;
R 13 is C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally substituted with 1-4R a Group substitution;
R 7 is H, C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl or 4-to 6-membered monocyclic heterocyclyl, wherein C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl and 4-to 6-membered monocyclic heterocyclyl are each independently optionally selected from the group consisting of-OH, halogen, -CN, and C, optionally by 1 to 4 1-6 Substitution of the alkoxy group;
each R 8 Independently halogen, -C (O) R 9 、-NR 10 R 10 、C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bisCyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spirocyclic heterocyclyl, -OR 5 、-C(O)OR 5 、-C(O)N(R 5 )(R 5 )、-N(R 5 ) 2 (R 5 ) + 、-N(R 5 )C(O)R 5 、-N(R 5 )C(O)OR 5 、-N(R 5 )C(O)N(R 5 )(R 5 )、-N(R 5 )S(O) 2 (R 5a )、-NR 5 S(O) 2 N(R 5 )(R 5 )、-NR 5 S(O) 2 O(R 5a )、-OC(O)R 5 、-OC(O)OR 5 、-OC(O)N(R 5 )(R 5 )、-SR 5 、-S(O)R 5a 、-S(O)(NH)R 5 、-S(O) 2 R 5a 、-S(O) 2 N(R 5 )(R 5 ) Or-n=s (R 5a )(R 5a )＝O，
Wherein C is 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally substituted with 1-4R a Group substitution;
each R 9 Independently C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
Wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, said 8-to 10-membered fused bicyclic heteroaryl and 7-to 10-membered spiroheterocyclyl being each independentlyOptionally at the ground by 1 to 4R a Group substitution;
each R 5 And R is 10 H, C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl groups are each independently optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally substituted with 1-4R a Group substitution;
each R 5a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7 - 10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl groups are each independently optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroarylThe radicals and 7-to 10-membered spirocyclic heterocyclic radicals are each independently optionally substituted by 1 to 4R a Group substitution;
each R a Independently oxo, imino, halogen, -NO 2 、-N 3 、-CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-NR 11 R 11 、-N(R 11 ) 2 (R 11 ) + 、-N(R 11 )C(O)R 11 、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)N(R 11 )(R 11 )、-N(R 11 )S(O) 2 (R 11a )、-NR 11 S(O) 2 N(R 11 )(R 11 )、-NR 11 S(O) 2 O(R 11a )、-OC(O)R 11 、-OC(O)OR 11 、-OC(O)N(R 11 )(R 11 )、-SR 11 、-S(O)R 11a 、-S(O)(NH)R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 ) Or-n=s (R 11a )(R 11a )＝O，
Wherein C is 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl groups are each independently optionally substituted with 1 to 3R c The substitution of the groups is carried out,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl each independently optionally being substituted with 1-3R d The substitution of the groups is carried out,
each R b Independently oxo, imino, halogen, -NO 2 、-N 3 、-CN、C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spirocyclic heterocyclyl, -OR 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-NR 11 R 11 、-N(R 11 ) 2 (R 11 ) + 、-N(R 11 )C(O)R 11 、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)N(R 11 )(R 11 )、-N(R 11 )S(O) 2 (R 11a )、-NR 11 S(O) 2 N(R 11 )(R 11 )、-NR 11 S(O) 2 O(R 11a )、-OC(O)R 11 、-OC(O)OR 11 、-OC(O)N(R 11 )(R 11 )、-SR 11 、-S(O)R 11a 、-S(O)(NH)R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 ) Or-n=s (R 11a )(R 11a )＝O，
Wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl each independently optionally being substituted with 1-3R d Group substitution;
each R c Independently halogen, -CN, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 12 、-C(O)R 12 、-C(O)OR 12 、-C(O)N(R 12 )(R 12 )、-NR 12 R 12 、-N(R 12 ) 2 (R 12 ) + 、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 12 )、-N(R 12 )S(O) 2 (R 12a )、-NR 12 S(O) 2 N(R 12 )(R 12 )、-NR 12 S(O) 2 O(R 12a )、-OC(O)R 12 、-OC(O)OR 12 、-OC(O)N(R 12 )(R 12 )、-SR 12 、-S(O)R 12a 、-S(O)(NH)R 12 、-S(O) 2 R 12a 、-S(O) 2 N(R 12 )(R 12 ) Or-n=s (R 12a )(R 12a )＝O；
Each R d Independently oxo, halogen, -CN, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 12 、-C(O)R 12 、-C(O)OR 12 、-C(O)N(R 12 )(R 12 )、-NR 12 R 12 、-N(R 12 ) 2 (R 12 ) + 、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 12 )、-N(R 12 )S(O) 2 (R 12a )、-NR 12 S(O) 2 N(R 12 )(R 12 )、-NR 12 S(O) 2 O(R 12a )、-OC(O)R 12 、-OC(O)OR 12 、-OC(O)N(R 12 )(R 12 )、-SR 12 、-S(O)R 12a 、-S(O)(NH)R 12 、-S(O) 2 R 12a 、-S(O) 2 N(R 12 )(R 12 ) Or-n=s (R 12a )(R 12a )＝O；
Each R 11 H, C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, the naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl each independently are optionally substituted with 1 to 3R c Group substitution;
each R 11a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl each independently optionally being substituted with 1-3R c Group substitution;
each R 12 H, C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl,A 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl, 6 to 10 membered bridged bicyclic heterocyclyl, 8 to 10 membered fused bicyclic heteroaryl, or 7 to 10 membered spiro heterocyclyl;
each R 12a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, or 7-to 10-membered spiro heterocyclyl;
wherein each 4-membered monocyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 5-to 7-membered monocyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S;
wherein each 6-membered bridged bicyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 7-membered bridged bicyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S; and is also provided with
Wherein each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.
In one embodiment, provided herein are pharmaceutical compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
In one embodiment, provided herein is a method of inhibiting toll-like receptor 7 and/or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, provided herein is a method of inhibiting toll-like receptor 7 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, provided herein is a method of inhibiting toll-like receptor 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, provided herein is a method of treating a disease or disorder associated with increased toll-like receptor 7 and/or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, provided herein is a method of treating a disease or disorder associated with increased toll-like receptor 7 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, provided herein is a method of treating a disease or disorder associated with increased toll-like receptor 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, provided herein is a method of treating an inflammatory disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, provided herein is a method of treating systemic lupus erythematosus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, provided herein is a method of treating cutaneous lupus erythematosus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, provided herein is a method of treating lupus nephritis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, provided herein is the use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in therapy.
In one embodiment, provided herein is a use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of inhibiting toll-like receptor 7 and/or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
In one embodiment, provided herein is a use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of inhibiting toll-like receptor 7 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
In one embodiment, provided herein is a use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of inhibiting toll-like receptor 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
In one embodiment, provided herein is a use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of treating a disease or disorder associated with increased toll-like receptor 7 and/or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
In one embodiment, provided herein is a use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of treating a disease or disorder associated with increased toll-like receptor 7 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
In one embodiment, provided herein is a use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of treating a disease or disorder associated with increased toll-like receptor 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
In one embodiment, provided herein is a use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of treating an inflammatory disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
In one embodiment, provided herein is a use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of treating systemic lupus erythematosus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
In one embodiment, provided herein is a use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of treating cutaneous lupus erythematosus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
In one embodiment, provided herein is a use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of treating lupus nephritis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
Detailed Description
I. Definition of the definition
It should be understood, upon making the following description, that the present disclosure is considered an exemplification of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are provided for convenience and should not be construed as limiting the claims in any way. The embodiments illustrated under any heading may be combined with the embodiments illustrated under any other heading.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It must be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays known to those skilled in the art and equivalents thereof, and so forth.
As used in this disclosure, the following words, phrases and symbols are generally intended to have the meanings described below, unless the context in which they are used indicates otherwise.
A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH 2 By means of carbon atomsSub-connections. Dashes at the front or end of the chemical group are for convenience; chemical groups can be depicted without one or more dashes without losing their ordinary meaning. Wavy lines drawn through lines in the structure indicate attachment points of the groups. No directionality is indicated or implied by the order in which chemical groups are written or named unless chemical or structural requirements. Solid lines drawn from the center of a ring (including fused, bridged or spiro ring systems) indicate that the point of attachment of substituents on the ring can be at any ring atom. For example, R in the following structure aa Can be attached to any one of five carbon ring atoms, or R aa Hydrogen, which may be substituted for the nitrogen ring atom:
as another example, R in the following structure aa ：
R aa Can be connected to any of the numbered positions shown below:
solid lines drawn from the center of a ring (including fused, bridged or spiro ring systems) indicate that the point of attachment of the ring system to the remainder of the compound may be at any ring atom of the fused, bridged or spiro ring system. For example, in the following structure:
the monocyclic heterocyclyl may be attached to the remainder of the compound at any of the numbered positions shown below:
As another example, in the following fused bicyclic heterocyclic ring structure,
the fused bicyclic heterocyclic group may be at any of the eight numbered positions shown below
Attached to the remainder of the compound:
prefix "C u-v "indicates that the following groups have u to v carbon atoms. For example, "C 1-6 Alkyl "indicates that the alkyl group has 1 to 6 carbon atoms. Likewise, the term "x-y membered" ring (where x and y are a range of values such as "3 to 12 membered heterocyclyl") refers to a ring containing x-y atoms (i.e., 3-12), up to 80% of which may be heteroatoms such as N, O, S, P, and the remaining atoms being carbon.
Moreover, some common alternative chemical names may or may not be used. For example, a divalent group (such as a divalent "alkyl" group, a divalent "aryl" group, etc.) may also be referred to as an "alkylene" group ("alkyl" group or "alkenyl group), an" arylene "group (" aryl "group or" alkenyl "group or" aryl group), respectively.
"Compounds disclosed herein" or "compounds of the present disclosure" or "compounds provided herein" or "compounds described herein" refer to compounds of formula I. Specific compounds of examples 1 to 68 are also included.
Reference herein to "about" a value or parameter includes (and describes) embodiments that relate to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In certain other embodiments, the term "about" includes the indicated amount ± 1%. Furthermore, the term "about X" includes descriptions of "X".
"alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C 1-20 Alkyl), 1 to 12 carbon atoms (i.e., C 1-12 Alkyl), 1 to 8 carbon atoms (i.e., C 1-8 Alkyl), 1 to 6 carbon atoms (i.e., C 1-6 Alkyl), 1 to 4 carbon atoms (i.e., C 1-4 Alkyl), 1 to 3 carbon atoms (i.e., C 1-3 Alkyl) or 1 to 2 carbon atoms (i.e., C 1-2 Alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl residue having a particular carbon number is named by chemical name or identified by molecular formula, all positional isomers having that carbon number are contemplated; thus, for example, a "butyl" includes n-butyl (i.e., - (CH) 2 ) 3 CH 3 ) Sec-butyl (i.e. -CH (CH) 3 )CH 2 CH 3 ) Isobutyl (i.e. -CH) 2 CH(CH 3 ) 2 ) And tert-butyl (i.e. -C (CH) 3 ) 3 ) The method comprises the steps of carrying out a first treatment on the surface of the And "propyl" includes n-propyl (i.e. (CH) 2 ) 2 CH 3 ) And isopropyl (i.e. -CH (CH) 3 ) 2 )。
"alkenyl" means a compound containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2-20 Alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl) or 2 to 4 carbon atoms (i.e., C 2-4 Alkenyl) aliphatic groups. Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1, 2-butadienyl and 1, 3-butadienyl).
"alkynyl" means a compound containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 Alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl) or 2 to 4 carbon atoms (i.e., C 2-4 Alkynyl) aliphatic groupA bolus. The term "alkynyl" also includes those groups having one triple bond and one double bond.
"alkylene" refers to a divalent and unbranched saturated hydrocarbon chain. As used herein, alkylene groups have 1 to 20 carbon atoms (i.e., C 1-20 Alkylene), 1 to 12 carbon atoms (i.e., C 1-12 Alkylene), 1 to 8 carbon atoms (i.e., C 1-8 Alkylene), 1 to 6 carbon atoms (i.e., C 1-6 Alkylene), 1 to 4 carbon atoms (i.e., C 1-4 Alkylene), 1 to 3 carbon atoms (i.e., C 1-3 Alkylene) or 1 to 2 carbon atoms (i.e., C 1-2 An alkylene group). Examples of alkylene groups include methylene, ethylene, propylene, butylene, pentylene, and hexylene. In some embodiments, the alkylene is optionally substituted with an alkyl group. Examples of substituted alkylene groups include-CH (CH 3 )CH 2 -、-CH 2 CH(CH 3 )-、-CH 2 CH(CH 2 CH 3 )-、-CH 2 C(CH 3 ) 2 -、-C(CH 3 ) 2 CH 2 -、-CH(CH 3 )CH(CH 3 )-、-CH 2 C(CH 2 CH 3 )(CH 3 ) -and-CH 2 C(CH 2 CH 3 ) 2 。
"alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1, 2-dimethylbutoxy. "haloalkoxy" refers to an alkoxy group, as defined above, wherein one or more hydrogen atoms are replaced with halogen.
"acyl" refers to the group-C (O) R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted as defined herein. Examples of acyl groups include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and benzoyl.
"Acylamido" means a "C-acylamino" group (which refers to the group-C (=O) NR y R z ) And an "N-amido" group (which means group-NR y C(＝O)R z ) Wherein R is y And R is z Independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, heteroaryl, cycloalkyl, or heterocyclyl; each of which can be optionally substituted.
"amino" means a group-NR y R z Wherein R is y And R is z Independently selected from the group consisting of: hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; each of which can be optionally substituted.
"aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) containing fused systems. As used herein, aryl groups have 6 to 20 ring carbon atoms (i.e., C 6-20 Aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 Aryl) or 6 to 10 carbon ring atoms (i.e., C 6-10 Aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracyl. However, aryl does not encompass or overlap in any way with heteroaryl as defined below. If one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is heteroaryl.
"cyano" or "carbonitrile" refers to the group-CN.
"cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl groups have 3 to 20 ring carbon atoms (i.e., C 3-20 Cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 Cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 Cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 Cycloalkyl) or 3 to 6 ring carbon atoms (i.e., C 3-6 Cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
"Cycloalkoxy" refers to the group "cycloalkyl-O-". Examples of cycloalkyloxy groups include, but are not limited to:
"bridging" refers to ring fusion in which the different atoms on the ring are connected by a divalent substituent (such as an alkylene group, an alkylene group containing one or two heteroatoms) or a single heteroatom. Quinuclidinyl and adamantyl are examples of bridging ring systems.
The term "fused" refers to a ring that binds to an adjacent ring.
"spiro" refers to a ring substituent attached at the same carbon atom through two bonds. Examples of spiro groups include 1, 1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, wherein cyclopentane and piperidine are each spiro substituents.
"halogen" or "halo" includes fluorine, chlorine, bromine and iodine.
"haloalkyl" refers to an unbranched or branched alkyl group as defined above wherein one or more hydrogen atoms are replaced by halogen. For example, in the case where the residue is substituted with more than one halogen, it may be mentioned by using a prefix corresponding to the number of attached halogen moieties. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl groups include difluoromethyl (-CHF) 2 ) And trifluoromethyl (-CF) 3 )。
"heteroalkylene" refers to a divalent and unbranched saturated hydrocarbon chain having one, two, or three heteroatoms selected from NH, O, or S. As used herein, a heteroalkylene has 1 to 20 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C 1-20 A heteroalkylene group); 1 to 8 carbon atoms and one, two or three heteroatoms selected from NH, O and S (i.e., C 1-8 A heteroalkylene group); 1 to 6 carbon atoms and one, two or three heteroatoms selected from NH, O and S (i.e., C 1-6 A heteroalkylene group); 1 to 4 carbon atoms and one, two or three heteroatoms selected from NH, O and S (i.e., C 1-4 A heteroalkylene group); 1 to 3 carbon atoms and one, two or three selected from NH,Hetero atoms of O and S (i.e. C 1-3 A heteroalkylene group); or 1 to 2 carbon atoms and one, two or three heteroatoms selected from NH, O and S (i.e., C 1-3 Heteroalkylene groups). For example, CH 2 O-is C 1 Heteroalkylene and-CH 2 SCH 2 -is C 2 A heteroalkylene group. Examples of heteroalkylene groups include-CH 2 CH 2 OCH 2 -、-CH 2 SCH 2 OCH 2 -、-CH 2 O-and-CH 2 NHCH 2 -. In some embodiments, the heteroalkylene is optionally substituted with an alkyl group. Examples of substituted heteroalkylene groups include-CH (CH 3 )N(CH 3 )CH 2 -、-CH 2 OCH(CH 3 )-、-CH 2 CH(CH 2 CH 3 )S-、-CH 2 NHC(CH 3 ) 2 -、-C(CH 3 ) 2 SCH 2 -、-CH(CH 3 )N(CH 3 )CH(CH 3 )O-、-CH 2 SC(CH 2 CH 3 )(CH 3 ) -and-CH 2 C(CH 2 CH 3 ) 2 NH-。
"heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 carbon ring atoms (i.e., C 1-20 Heteroaryl), 3 to 12 carbon ring atoms (i.e., C 3-12 Heteroaryl) or 3 to 8 carbon ring atoms (i.e., C 3-8 Heteroaryl group); and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.
"heterocyclyl" or "heterocycle" refers to a non-aromatic cyclic alkyl group in which one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, unless otherwise indicated, "heterocyclyl" or "heterocycle" refers to saturated or partially saturatedFor example, in some embodiments, "heterocyclyl" or "heterocycle" refers to a ring that is partially saturated under the circumstances specified. The term "heterocyclyl" or "heterocycle" includes heterocyclyl groups (i.e., heterocyclyl groups having at least one double bond). The heterocyclyl may be a single ring or multiple rings, wherein the multiple rings may be fused, bridged or spiro. As used herein, heterocyclyl has 2 to 20 carbon ring atoms (i.e., C 2-20 Heterocyclyl), 2 to 12 carbon ring atoms (i.e., C 2-12 Heterocyclyl), 2 to 10 carbon ring atoms (i.e., C 2-10 Heterocyclyl), 2 to 8 carbon ring atoms (i.e., C 2-8 Heterocyclyl), 3 to 12 carbon ring atoms (i.e., C 3-12 Heterocyclyl), 3 to 8 carbon ring atoms (i.e., C 3 - 8 Heterocyclyl) or 3 to 6 carbon ring atoms (i.e., C 3-6 A heterocyclic group); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term "bridged-heterocyclyl" refers to a four to ten membered ring moiety having one or more (e.g., 1 or 2) four to ten membered ring moieties having at least one heteroatom attached to two non-adjacent atoms of the heterocyclyl, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. As used herein, "bridged-heterocyclyl" includes both bicyclic and tricyclic ring systems. Also as used herein, the term "spiro-heterocyclyl" refers to a ring system in which a tri-to decanyl heterocyclyl has one or more additional rings, wherein the one or more additional rings are tri-to decanyl or tri-to decanyl, wherein a single atom of the one or more additional rings is also an atom of a tri-to decanyl. Examples of spiro-heterocyclyl groups include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro [3.5 ] ]Nonyl, 2-oxa-6-azaspiro [3.4 ]]Octyl and 6-oxa-1-azaspiro [3.3 ]]A heptyl group. As used herein, the terms "heterocycle", "heterocyclyl" and "heterocycle" are used interchangeably. In some embodiments, the heterocyclyl is substituted with an oxo group.
"Heterocyclyloxy" refers to the group "-O (heterocyclyl)". Examples of hetero-epoxy groups include, but are not limited to, -O (pyrrolidinyl), -O (tetrahydrofuranyl), -O (piperidinyl), -O (morpholinyl), -O (oxetanyl), and-O (2-oxa-7-azaspiro [3.5] nonyl).
"Hydroxy" or "hydroxyl" refers to the group-OH.
"oxo" refers to a group (=o) or (O).
"sulfonyl" refers to the group-S (O) 2 R bb Wherein R is bb Is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl or aryl. Examples of sulfonyl groups are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and tosyl.
Each time a graphic representation of a group terminates in a singly-bound nitrogen atom, the group represents an-NH group, unless otherwise indicated. Similarly, unless otherwise indicated, hydrogen atoms are implied and deemed to be present as necessary, based on knowledge of the skilled artisan to accomplish valences or to provide stability.
The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. Moreover, the term "optionally substituted" means that any one or more hydrogen atoms on a given atom or group may or may not be replaced by a moiety other than hydrogen.
The term "substituted" means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the normal valency of the designated atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures obtained by defining substituents with infinitely additional further substituents (e.g., substituted aryl groups with substituted alkyl groups themselves substituted with substituted aryl groups further substituted with substituted heteroalkyl groups, etc.) are not intended to be included herein. The maximum number of consecutive substitutions in the compounds described herein is three, unless otherwise indicated. For example, the sequential substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl) -substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorine or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. The term "substituted" when used in reference to modifying a chemical group may describe other chemical groups as defined herein. For example, the term "substituted aryl" includes, but is not limited to "alkylaryl". Unless otherwise indicated, where groups are described as optionally substituted, any substituents of these groups are themselves unsubstituted.
In some embodiments, substituted cycloalkyl, substituted heterocyclyl, substituted aryl, and/or substituted heteroaryl includes cycloalkyl, heterocyclyl, aryl, and/or heteroaryl groups having substituents on the ring atoms, which cycloalkyl, heterocyclyl, aryl, and/or heteroaryl groups are attached to the remainder of the compound. For example, in the following moieties, the cyclopropyl group is substituted with a methyl group:
the compounds of the embodiments disclosed herein or their pharmaceutically acceptable salts may include one or more asymmetric centers and thus may produce enantiomers, diastereomers and other stereoisomeric forms which may be defined as (R) -or (S) -or (D) -or (L) -for amino acids, depending on the absolute stereochemistry. The present disclosure is intended to include all such possible isomers and their racemic and optically pure forms. Optically active (+) and (-), (R) -and (S) -or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing/separating the individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC). When a compound described herein contains an olefinic double bond or other geometric asymmetric center, and unless specified otherwise, it is intended that the compound include both E and Z geometric isomers. Also, all tautomeric forms are intended to be included. Where a compound is represented in its chiral form, it is to be understood that this embodiment encompasses, but is not limited to, a particular diastereomeric or enantiomerically enriched form. When chirality is not specified but is present, it is understood that this embodiment relates to a particular diastereomeric or enantiomerically enriched form; or a racemic or non-racemic mixture of such compounds. As used herein, a "non-racemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.
"stereoisomers" refers to compounds that consist of the same atoms bonded by the same bonds but have different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other.
"enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. The 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Mixtures of enantiomers in ratios other than 1:1 are "non-racemic" mixtures.
"diastereomers" are stereoisomers that have at least two asymmetric atoms but which are not mirror images of each other.
"tautomer" refers to proton transfer from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any of the compounds provided herein.
Some of the compounds provided herein exist in tautomeric forms. Tautomers are balanced with each other. For example, amide-containing compounds may exist in equilibrium with imido tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium between the tautomers, one of ordinary skill in the art will understand that compounds include amide and imide tautomers. Thus, amide-containing compounds are understood to include the imido acid tautomers thereof. Also, the imide acid containing compounds are understood to include amide tautomers thereof.
"solvates" are formed by the interaction of a solvent and a compound. Solvates of salts of the compounds provided herein are also provided. Also provided are hydrates of the compounds provided herein.
Any formula or structure provided herein is also intended to represent an unlabeled form of a compound and an isotopically labeled form. Isotopically-labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C、 13 C、 14 C、 15 N、 18 F、 31 P、 32 p、 35 S、 36 Cl and Cl 125 I. Also provided herein are various isotopically-labeled compounds of the present disclosure, for example, into which a radioisotope such as 2 H、 3 H、 13 C and C 14 Those of C. Such isotopically-labeled compounds are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as Positron Emission Tomography (PET) or single photon emission electron computed tomography (SPECT), tissue distribution assays including drugs or substrates, or in radiation therapy of patients.
The present disclosure also includes compounds of formula I or II wherein 1 to n hydrogens attached to a carbon atom are replaced with deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound of formula I or II when administered to a mammal, especially a human. See, for example, foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", trends pharmacol. Sci. Volume 5 (stage 12): pages 524-527 (1984). Such compounds are synthesized by methods well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced with deuterium.
Deuterium labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, which involve absorption, distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or improved therapeutic index. 18 F-labeled compounds can be used in PET or SPECT studies. Isotopically-labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the examples and formulations described below by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent. It is to be understood that deuterium in this context is considered a substituent in the compounds of formula I or II.
The concentration of such heavier isotopes, particularly deuterium, may be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," that position is understood to be hydrogen having its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.
In many cases, the compounds of the present disclosure are capable of forming acid and/or base salts with the aid of amino groups and/or carboxyl groups or groups similar thereto.
The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. By way of example only, salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di (substituted alkyl) amines, tri (substituted alkyl) amines, alkenylamines, dienylamine, trialkenylamine, substituted alkenylamines, di (substituted alkenylamines, tri (substituted alkenylamines), monocycloalkylamines, dicycloalkylamines or tricycloalkylamines, monoarylamines, diarylamines or triarylamines or mixed amines, and the like. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri (isopropyl) amine, tri (N-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional medium or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the composition.
"treatment" is a method for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include one or more of the following: a) Inhibiting the disease or disorder (i.e., reducing one or more symptoms caused by the disease or disorder, and/or reducing the extent of the disease or disorder); b) Slowing or arresting the development of one or more clinical symptoms associated with the disease or disorder (i.e., stabilizing the disease or disorder, preventing or delaying the progression or worsening of the disease or disorder, and/or preventing or delaying the spread (i.e., metastasis of the disease or disorder); and/or c) alleviating the disease, i.e., causing regression of the clinical symptoms (i.e., improving the disease state, providing partial or total relief of the disease or condition, enhancing the effect of another drug, delaying the progression of the disease, increasing the quality of life, and/or extending survival).
"preventing" means any treatment of any disease or disorder that results in the clinical symptoms of the disease or disorder not developing. In some embodiments, the compounds may be administered to a subject (including a human) at risk or having a family history of the disease or disorder.
"subject" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation or experiment. The methods described herein may be used for human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.
The term "therapeutically effective amount" or "effective amount" of a compound, or pharmaceutically acceptable salt, isomer, or mixture thereof, as described herein, refers to an amount sufficient to effect treatment to provide a therapeutic benefit such as ameliorating symptoms or slowing the progression of a disease when administered to a subject. For example, a therapeutically effective amount may be an amount sufficient to ameliorate a symptom of a disease or disorder responsive to inhibition of toll-like receptor 7, 8, and/or 9. The therapeutically effective amount may vary depending on the subject, the disease or disorder being treated, the weight and age of the subject, the severity of the disease or disorder, and the mode of administration, as can be readily determined by one skilled in the art.
II compounds
In one embodiment, provided herein are compounds of formula I,
or a pharmaceutically acceptable salt thereof,
wherein the method comprises the steps of
R 1 Is an 8-to 10-membered fused bicyclic heterocyclic group or an 8-to 10-membered fused bicyclic heteroaryl group,
wherein 8 to 10 membered fused bicyclic heterocyclyl and 8 to 10 membered fused bicyclic heteroaryl are each independently optionally substituted with 1 to 4R a Group substitution;
R 2 is H, C 1-6 Alkyl or C 3-7 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-7 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 The group of the alkoxy group is substituted,
wherein C is 1-6 Alkoxy is optionally substituted with 1 to 3 halo groups;
R 3 is H, halogen, -CN, C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl or 4-to 7-membered monocyclic heterocyclyl,
wherein C is 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl and 4-to 7-membered monocyclic heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl, -C (O) N (R) 4 ) 2 4-to 7-membered monocyclic heterocyclyl, C 3-7 A monocyclic cycloalkoxy group and a 4-to 7-membered monocyclic hetero-epoxy group,
wherein C is 1-4 Alkoxy is optionally substituted with 1 to 3 halo groups;
each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached, form a 4 to 7 membered monocyclic heterocyclyl;
Z is C 1-6 Alkyl, C 2-6 Alkenyl, -C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 、C 3-7 Monocyclic cycloalkyl, c 7-10 Condensed bicyclocycloalkyl, c 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 1-6 Alkyl and C 2-6 Alkenyl groups are each independently optionallyIs 1 to 4R b Group substitution, wherein C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally being substituted with 1-2R 8 The substitution of the groups is carried out,
and each independently is optionally substituted with 1 to 3R a Group substitution;
R 6 is C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
Wherein C is 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally substituted with 1-4R a Group substitution;
R 13 is C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridgeThe bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl are each independently optionally substituted with 1 to 4R a Group substitution;
R 7 is H, C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl or 4-to 6-membered monocyclic heterocyclyl, wherein C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl and 4-to 6-membered monocyclic heterocyclyl are each independently optionally selected from the group consisting of-OH, halogen, -CN, and C, optionally by 1 to 4 1-6 Substitution of the alkoxy group;
each R 8 Independently halogen, -C (O) R 9 、-NR 10 R 10 、C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 5 、-C(O)OR 5 、-C(O)N(R 5 )(R 5 )、-N(R 5 ) 2 (R 5 ) + 、-N(R 5 )C(O)R 5 、-N(R 5 )C(O)OR 5 、-N(R 5 )C(O)N(R 5 )(R 5 )、-N(R 5 )S(O) 2 (R 5a )、-NR 5 S(O) 2 N(R 5 )(R 5 )、-NR 5 S(O) 2 O(R 5a )、-OC(O)R 5 、-OC(O)OR 5 、-OC(O)N(R 5 )(R 5 )、-SR 5 、-S(O)R 5a 、-S(O)(NH)R 5 、-S(O) 2 R 5a 、-S(O) 2 N(R 5 )(R 5 ) Or-n=s (R 5a )(R 5a )＝O，
Wherein C is 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclylThe radicals, 8-to 10-membered fused bicyclic heteroaryl and 7-to 10-membered spirocyclic heterocyclyl are each independently optionally substituted with 1 to 4R a Group substitution;
each R 9 Independently C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spiro heterocyclyl, wherein C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally substituted with 1-4R a Group substitution;
each R 5 And R is 10 H, C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl groups are each independently optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally substituted with 1-4R a Group substitution;
each R 5a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl groups are each independently optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally substituted with 1-4R a Group substitution;
each R a Independently oxo, imino, halogen, -NO 2 、-N 3 、-CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-NR 11 R 11 、-N(R 11 ) 2 (R 11 ) + 、-N(R 11 )C(O)R 11 、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)N(R 11 )(R 11 )、-N(R 11 )S(O) 2 (R 11a )、-NR 11 S(O) 2 N(R 11 )(R 11 )、-NR 11 S(O) 2 O(R 11a )、-OC(O)R 11 、-OC(O)OR 11 、-OC(O)N(R 11 )(R 11 )、-SR 11 、-S(O)R 11a 、-S(O)(NH)R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 ) Or-n=s (R 11a )(R 11a )＝O，
Wherein C is 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl groups are each independently optionally substituted with 1 to 3R c The substitution of the groups is carried out,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl each independently optionally being substituted with 1-3R d The substitution of the groups is carried out,
each R b Independently oxo, imino, halogen, -NO 2 、-N 3 、-CN、C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spirocyclic heterocyclyl, -OR 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-NR 11 R 11 、-N(R 11 ) 2 (R 11 ) + 、-N(R 11 )C(O)R 11 、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)N(R 11 )(R 11 )、-N(R 11 )S(O) 2 (R 11a )、-NR 11 S(O) 2 N(R 11 )(R 11 )、-NR 11 S(O) 2 O(R 11a )、-OC(O)R 11 、-OC(O)OR 11 、-OC(O)N(R 11 )(R 11 )、-SR 11 、-S(O)R 11a 、-S(O)(NH)R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 ) Or-n=s (R 11a )(R 11a )＝O，
Wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl each independently optionally being substituted with 1-3R d Group substitution;
each R c Independently halogen, -CN, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 12 、-C(O)R 12 、-C(O)OR 12 、-C(O)N(R 12 )(R 12 )、-NR 12 R 12 、-N(R 12 ) 2 (R 12 ) + 、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 12 )、-N(R 12 )S(O) 2 (R 12a )、-NR 12 S(O) 2 N(R 12 )(R 12 )、-NR 12 S(O) 2 O(R 12a )、-OC(O)R 12 、-OC(O)OR 12 、-OC(O)N(R 12 )(R 12 )、-SR 12 、-S(O)R 12a 、-S(O)(NH)R 12 、-S(O) 2 R 12a 、-S(O) 2 N(R 12 )(R 12 ) Or-n=s (R 12a )(R 12a )＝O；
Each R d Independently oxo, halogen, -CN, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 12 、-C(O)R 12 、-C(O)OR 12 、-C(O)N(R 12 )(R 12 )、-NR 12 R 12 、-N(R 12 ) 2 (R 12 ) + 、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 12 )、-N(R 12 )S(O) 2 (R 12a )、-NR 12 S(O) 2 N(R 12 )(R 12 )、-NR 12 S(O) 2 O(R 12a )、-OC(O)R 12 、-OC(O)OR 12 、-OC(O)N(R 12 )(R 12 )、-SR 12 、-S(O)R 12a 、-S(O)(NH)R 12 、-S(O) 2 R 12a 、-S(O) 2 N(R 12 )(R 12 ) Or-n=s (R 12a )(R 12a )＝O；
Each R 11 H, C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl each independently optionally being substituted with 1-3R c Group substitution;
each R 11a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 7-membered monocyclic heteroarylA 10-membered spiro heterocyclic group,
wherein C is 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3 - 7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl each independently optionally being substituted with 1-3R c Group substitution;
each R 12 H, C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, or 7-to 10-membered spiro heterocyclyl;
each R 12a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, or 7-to 10-membered spiro heterocyclyl;
wherein each 4-membered monocyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 5-to 7-membered monocyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S;
wherein each 6-membered bridged bicyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 7-membered bridged bicyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S; and is also provided with
Wherein each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.
In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof,
R 1 is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 4R a Group substitution;
R 2 is C 1-6 Alkyl or C 3-7 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-7 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of the alkoxy group;
R 3 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl and-C (O) N (R) 4 ) 2 Is substituted by a group of (2);
each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached, form a 4 to 7 membered monocyclic heterocyclyl;
z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 、C 3-7 Monocyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 3-7 Monocyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally being substituted with 1-2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a Group substitution;
R 6 is 4 to 7 yuanMonocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
R 13 is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
R 7 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 Substitution of the alkoxy group;
each R 8 independently-C (O) R 9 、-NR 10 R 10 、-S(O) 2 R 5a 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 6-to 10-membered bridged bicyclic heterocyclyl or 7-to 10-membered spiroheterocyclyl,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein 4 to 7 membered monocyclic heterocyclyl, 5 to 6 membered monocyclic heteroaryl, 6 to 10 membered bridged bicyclic heterocyclyl and 7 to 10 membered spiro heterocyclyl are each independently optionally substituted with 1 to 4R a Group substitution;
each R 9 Independently C 3-7 Monocyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl or 7-to 10-membered spiroheterocyclyl, wherein C 3-7 Monocyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, and 7-to 10-membered spiro heterocyclyl each independently are optionally substituted with 1 to 4R a Group substitution;
each R 10 Independently H or 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
each R 5a Independently 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
wherein each 4-membered monocyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 5-to 7-membered monocyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S;
wherein each 6-membered bridged bicyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 7-membered bridged bicyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S; and is also provided with
Wherein each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, and 8-to 10-membered fused bicyclic heteroaryl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.
In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof,
R 1 is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 4R a Group substitution;
R 2 is C 1-6 Alkyl or C 3-7 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-7 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of the alkoxy group;
R 3 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl and-C (O) N (R) 4 ) 2 Is substituted by a group of (2);
each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached, form a 4 to 7 membered monocyclic heterocyclyl;
z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 A 4-to 7-membered monocyclic heterocyclic group, a phenyl group, a naphthyl group, a 5-to 6-membered monocyclic heteroaryl group, a 8-to 10-membered fused bicyclic heterocyclic group, a 6-to 10-membered bridged bicyclic heterocyclic group, a 8-to 10-membered fused bicyclic heteroaryl group or a 7-to 10-membered spiro heterocyclic group,
wherein 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl, 6 to 10 membered bridged bisThe cyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl are each independently optionally substituted with 1 to 2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a Group substitution;
R 6 is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
R 13 is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
R 7 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 Substitution of the alkoxy group;
each R 8 independently-C (O) R 9 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclic group or 6-to 10-membered bridged bicyclic heterocyclic group,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein 4 to 7 membered monocyclic heterocyclyl and 6 to 10 membered bridged bicyclic heterocyclyl are each independently optionally substituted with 1 to 4R a Group substitution;
each R 9 Independently is a 4 to 7 membered monocyclic heterocyclyl, a 6 to 10 membered bridged bicyclic heterocyclyl, or a 7 to 10 membered spiro heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl, 6 to 10 membered bridged bicyclic heterocyclyl, and 7 to 10 membered spiro heterocyclyl are each independently optionally substituted with 1 to 4R a Group substitution;
wherein each 4-membered monocyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 5-to 7-membered monocyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S;
wherein each 6-membered bridged bicyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 7-membered bridged bicyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S; and is also provided with
Wherein each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, and 8-to 10-membered fused bicyclic heteroaryl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.
In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof,
R 1 is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-6 Alkyl and C 3-7 Group substitution of monocyclic cycloalkyl;
wherein C is 1-6 Alkyl and C 1-4 Alkoxy groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted by a group of (2);
R 2 is C 1-6 Alkyl or C 3-5 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-5 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of the alkoxy group;
R 3 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl and-C (O) N (R) 4 ) 2 Is substituted by a group of (2);
each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached, form a 4 to 7 membered monocyclic heterocyclyl;
z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 、C 3-7 Monocyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
Wherein C is 3-7 Monocyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4 to 7 membered monoA cyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to l 0-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally substituted with 1 to 2R 8 Groups are substituted and each independently is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
R 6 is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-4 Alkoxy and C 1-5 Alkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted by a group of (2);
R 13 is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
R 7 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 Substitution of the alkoxy group;
each R 8 independently-C (O) R 9 、-NR 10 R 10 、-S(O) 2 R 5a 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 6-to 10-membered bridged bicyclic heterocyclyl or 7-to 10-membered spiroheterocyclyl,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)NR 11 R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Alkoxy and R 8a Is substituted by a group of (a) or (b),
wherein 4 to 7 membered monocyclic heterocyclyl, 5 to 6 membered monocyclic heteroaryl, 6 to 10 membered bridged bicyclic heterocyclyl, and 7 to 10 membered spiro heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 8b Is substituted by a group of (2);
each R 8a Independently 4 to 7 membered monocyclic heterocyclyl or 5 to 6 membered monocyclic heteroaryl;
each R 8b Independently 4 to 7 membered monocyclic heterocyclyl;
each R 9 Independently C 3-7 Monocyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl or 7-to 10-membered spiroheterocyclyl, wherein C 3-7 Monocyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, and 7-to 10-membered spiro heterocyclyl each independently are optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted by a group of (2);
Each R 9a Independently 4 to 7 membered monocyclic heterocyclyl;
each R 10 Independently H or 4 to 7 membered monocyclic heterocyclyl;
each R 5a Independently 4 to 7 membered monocyclic heterocyclyl;
each R 11 H, C independently 1-6 Alkyl, C 3-7 A monocyclic cycloalkyl or 4-to 7-membered monocyclic heterocyclyl;
each R 11a Independently C 1-4 An alkyl group;
each R 12 Independently H or C 1-4 An alkyl group;
wherein each 4-membered monocyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 5-to 7-membered monocyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S;
wherein each 6-membered bridged bicyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 7-membered bridged bicyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S; and is also provided with
Wherein each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, and 8-to 10-membered fused bicyclic heteroaryl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.
In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof,
R 1 is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-6 Alkyl and C 3-7 Group substitution of monocyclic cycloalkyl;
wherein C is 1-6 Alkyl and C 1-4 Alkoxy groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted by a group of (2);
R 2 is C 1-6 Alkyl or C 3-5 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-5 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of the alkoxy group;
R 3 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl and-C (O) N (R) 4 ) 2 Is substituted by a group of (2);
each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached, form a 4 to 7 membered monocyclic heterocyclyl;
z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 4-to 7-membered monocyclic heterocyclic group, phenyl group, naphthyl group, 5-to 6-membered monocyclic heteroaryl group, 8-to 10-membered condensed bicyclic heterocyclic group, and,A 6-to 10-membered bridged bicyclic heterocyclic group, an 8-to 10-membered fused bicyclic heteroaryl group, or a 7-to 10-membered spiro heterocyclic group,
wherein 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl, 6 to 10 membered bridged bicyclic heterocyclyl, 8 to 10 membered fused bicyclic heteroaryl, and 7 to 10 membered spiro heterocyclyl are each independently optionally substituted with 1 to 2R 8 Groups are substituted and each independently is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
R 6 is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-4 Alkoxy and C 1-5 Alkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted by a group of (2);
R 13 is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
R 7 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 Substitution of the alkoxy group;
each R 8 independently-C (O) R 9 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclic group or 6-to 10-membered bridged bicyclic heterocyclic group,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)NR 11 R 11 、-S(O) 2 R 11a 、C 1-4 Alkoxy and R 8a Is substituted by a group of (a) or (b),
wherein 4 to 7 membered monocyclic heterocyclyl and 6 to 10 membered bridged bisThe cyclic heterocyclic groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
R 8a is a 4 to 7 membered monocyclic heterocyclyl;
each R 9 Independently 4 to 7 membered monocyclic heterocyclyl, 6 to 10 membered bridged bicyclic heterocyclyl, or 7 to 10 membered spiro heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl, 6 to 10 membered bridged bicyclic heterocyclyl, and 7 to 10 membered spiro heterocyclyl are each optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
each R 11 H, C independently 1-6 Alkyl, C 3-7 A monocyclic cycloalkyl or 4-to 7-membered monocyclic heterocyclyl;
each R 11a Independently C 1-4 An alkyl group;
each R 12 Independently H or C 1-4 An alkyl group;
wherein each 4-membered monocyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 5-to 7-membered monocyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S;
wherein each 6-membered bridged bicyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 7-membered bridged bicyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S; and is also provided with
Wherein each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, and 8-to 10-membered fused bicyclic heteroaryl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.
In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof,
R 1 is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 4R a Group substitution;
R 2 is C 1-6 Alkyl or C 3-7 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-7 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of the alkoxy group;
R 3 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl and-C (O) N (R) 4 ) 2 Is substituted by a group of (2);
each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached, form a 4 to 7 membered monocyclic heterocyclyl;
z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 A 4-to 7-membered monocyclic heterocyclic group, a phenyl group, a naphthyl group, a 5-to 6-membered monocyclic heteroaryl group, a 8-to 10-membered fused bicyclic heterocyclic group, a 6-to 10-membered bridged bicyclic heterocyclic group, a 8-to 10-membered fused bicyclic heteroaryl group or a 7-to 10-membered spiro heterocyclic group,
wherein 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl, 6 to 10 membered bridged bicyclic heterocyclyl, 8 to 10 membered fused bicyclic heteroaryl, and 7 to 10 membered spiro heterocyclyl are each independently optionally substituted with 1 to 2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a Group substitution;
R 6 is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
R 13 is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
R 7 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 Substitution of the alkoxy group;
each R 8 independently-C (O) R 9 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclic group or 6-to 10-membered bridged bicyclic heterocyclic group,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein 4 to 7 membered monocyclic heterocyclyl and 6 to 10 membered bridged bicyclic heterocyclyl are each independently
Optionally by 1 to 4R a Group substitution;
R 9 is a 4 to 7 membered monocyclic heterocyclyl or a 6 to 10 membered bridged bicyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl and 6 to 10 membered bridged bicyclic heterocyclyl are each independently optionally substituted with 1 to 4R a Group substitution;
wherein each 4-membered monocyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 5-to 7-membered monocyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S;
wherein each 6-membered bridged bicyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
Wherein each 7-membered bridged bicyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S; and is also provided with
Wherein each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, and 8-to 10-membered fused bicyclic heteroaryl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.
In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof,
R 1 is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-6 Alkyl and C 3-7 Group substitution of monocyclic cycloalkyl;
wherein C is 1-6 Alkyl and C 1-4 Alkoxy groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted by a group of (2);
R 2 is C 1-6 Alkyl or C 3-5 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-5 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of the alkoxy group;
R 3 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl and-C (O) N (R) 4 ) 2 Is substituted by a group of (2);
each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached, form a 4 to 7 membered monocyclic heterocyclyl;
z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 A 4-to 7-membered monocyclic heterocyclic group, a phenyl group, a naphthyl group, a 5-to 6-membered monocyclic heteroaryl group, a 8-to 10-membered fused bicyclic heterocyclic group, a 6-to 10-membered bridged bicyclic heterocyclic group, a 8-to 10-membered fused bicyclic heteroaryl group or a 7-to 10-membered spiro heterocyclic group,
wherein 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl, 6 to 10 membered bridged bicyclic heterocyclyl, 8 to 10 membered fused bicyclic heteroaryl, and 7 to 10 membered spiro heterocyclyl are each independently optionally substituted with 1 to 2R 8 Groups are substituted and each independently is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxygen
Substituted, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
R 6 is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-4 Alkoxy and C 1-5 Alkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted by a group of (2);
R 13 is a 4-to 7-membered monocyclic heterocyclic group, wherein 4-to 7-membered isThe 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
R 7 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 Substitution of the alkoxy group;
each R 8 independently-C (O) R 9 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclic group or 6-to 10-membered bridged bicyclic heterocyclic group,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)NR 11 R 11 、C 1-4 Alkoxy and R 8a Is substituted by a group of (a) or (b),
wherein 4 to 7 membered monocyclic heterocyclyl and 6 to 10 membered bridged bicyclic heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
R 8a is a 4 to 7 membered monocyclic heterocyclyl;
R 9 is a 4 to 7 membered monocyclic heterocyclyl or a 6 to 10 membered bridged bicyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl and 6 to 10 membered bridged bicyclic heterocyclyl are each optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
each R 11 H, C independently 1-6 Alkyl, C 3-7 A monocyclic cycloalkyl or 4-to 7-membered monocyclic heterocyclyl;
each R 12 Independently H or C 1-4 An alkyl group;
wherein each 4-membered monocyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
Wherein each 5-to 7-membered monocyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S;
wherein each 6-membered bridged bicyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 7-membered bridged bicyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S; and is also provided with
Wherein each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, and 8-to 10-membered fused bicyclic heteroaryl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.
In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof,
R 1 is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 4R a Group substitution;
R 2 is C 1-6 Alkyl or C 3-7 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-7 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of the alkoxy group;
R 3 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl and-C (O) N (R) 4 ) 2 Is substituted by a group of (2);
each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached, form a 4 to 7 membered monocyclic heterocyclyl;
z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl or 8-to 10-membered fused bicyclic heteroaryl,
wherein 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl and 8 to 10 membered fused bicyclic heteroaryl are each independently optionally substituted with 1 to 2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a Group substitution；
R 6 Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
R 13 is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
R 7 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 Substitution of the alkoxy group;
each R 8 independently-C (O) R 9 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclic group or 6-to 10-membered bridged bicyclic heterocyclic group,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein 4 to 7 membered monocyclic heterocyclyl and 6 to 10 membered bridged bicyclic heterocyclyl are each independently optionally substituted with 1 to 4R a Group substitution;
R 9 Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
wherein each 4-membered monocyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 5-to 7-membered monocyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S;
wherein each 6-membered bridged bicyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 7-membered bridged bicyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S; and is also provided with
Wherein each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, and 8-to 10-membered fused bicyclic heteroaryl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.
In some embodiments of the compounds of formula I or II or pharmaceutically acceptable salts thereof,
R 1 is 8 to 10A membered fused bicyclic heteroaryl wherein the 8 to 10 membered fused bicyclic heteroaryl is optionally substituted with 1 to 3 groups independently selected from-OH, -CN, oxo, halogen, C 1-6 Alkyl, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl and-NR 11 R 11 Is substituted by a group of (a) or (b),
wherein C is 1-6 Alkyl and C 1-4 Alkoxy groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted by a group of (2);
R 2 is C 1-6 Alkyl or C 3-5 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-5 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of the alkoxy group;
R 3 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl and-C (O) N (R) 4 ) 2 Is substituted by a group of (2);
each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached, form a 4 to 7 membered monocyclic heterocyclyl;
z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl or 8-to 10-membered fused bicyclic heteroaryl,
wherein 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl and 8 to 10 membered fused bicyclic heteroaryl are each independently optionally substituted with 1 to 2R 8 Groups are substituted and each independently is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
R 6 is a 4 to 7 membered monocyclic heterocyclyl wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The group of the alkyl group is substituted,
wherein C is 1-4 Alkoxy and C 1-5 Alkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted by a group of (2);
R 13 is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
R 7 is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 Substitution of the alkoxy group;
each R 8 independently-C (O) R 9 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclic group or 6-to 10-membered bridged bicyclic heterocyclic group,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)NR 11 R 11 、C 1-4 Alkoxy and R 8a Is substituted by a group of (a) or (b),
wherein 4 to 7 membered monocyclic heterocyclyl and 6 to 10 membered bridged bicyclic heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
each R 8a Independently 4 to 7 membered monocyclic heterocyclyl;
R 9 is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
each R 11 H, C independently 1-6 Alkyl, C 3-7 A monocyclic cycloalkyl or 4-to 7-membered monocyclic heterocyclyl;
each R 12 Independently H or C 1-4 An alkyl group;
wherein each 4-membered monocyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 5-to 7-membered monocyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S;
wherein each 6-membered bridged bicyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 7-membered bridged bicyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S; and is also provided with
Wherein each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, and 8-to 10-membered fused bicyclic heteroaryl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.
As used herein, each 4-membered monocyclic heterocyclyl has 1 ring heteroatom selected from N, O and S, unless otherwise specified. As used herein, each 5-to 7-membered monocyclic heterocyclyl has 1 to 2 ring heteroatoms independently selected from N, O and S, unless otherwise specified. As used herein, each 6-membered bridged bicyclic heterocyclyl has 1 ring heteroatom selected from N, O and S, unless otherwise specified. As used herein, each 7-membered bridged bicyclic heterocyclyl has 1 to 2 ring heteroatoms independently selected from N, O and S, unless otherwise specified. As used herein, each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl independently has 1 to 4 ring heteroatoms independently selected from N, O and S, unless otherwise specified.
In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 Is an 8-to 10-membered fused bicyclic heterocyclyl or an 8-to 10-membered fused bicyclic heteroaryl, wherein 8-to 10-membered fused bicyclic heterocyclyl and 8-to 10-membered fused bicyclic heteroaryl are each independently optionally substituted with 1 to 4R a And (3) group substitution.
In some embodiments of the compounds of formula I or pharmaceutically acceptable salts thereof，R 1 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-6 The groups of the alkyl groups are substituted.
In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 Is an 8-to 10-membered fused bicyclic heterocyclic group in which the 8-to 10-membered fused bicyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 Is an 8-to 10-membered fused bicyclic heterocyclic group in which the 8-to 10-membered fused bicyclic heterocyclic group is substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、C 1-4 Alkoxy and C 1-6 The groups of the alkyl groups are substituted.
In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 Is an 8-to 10-membered fused bicyclic heterocyclic group.
In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 Is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 Is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 3R a And (3) group substitution. In the formulaIn some embodiments of the compound of I or a pharmaceutically acceptable salt thereof, R 1 Is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-6 Alkyl and C 3-7 Radical substitution of monocyclic cycloalkyl, wherein C 1-6 Alkyl and C 1-4 Alkoxy groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted with a group of (a).
In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 Is an 8-to 10-membered fused bicyclic heteroaryl group, wherein the 8-to 10-membered fused bicyclic heteroaryl group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 Is an 8-to 10-membered fused bicyclic heteroaryl group, wherein the 8-to 10-membered fused bicyclic heteroaryl group is substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 Is an 8-to 10-membered fused bicyclic heteroaryl group, wherein the 8-to 10-membered fused bicyclic heteroaryl group is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、C 1-4 Alkoxy, C 1-6 Alkyl and C 3-7 Radical substitution of monocyclic cycloalkyl, wherein C 1-6 Alkyl and C 1-4 Alkoxy groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted with a group of (a).
In some embodiments of the compounds of formula I, the compounds are compounds of formula II,
or a pharmaceutically acceptable salt thereof,
Wherein the method comprises the steps of
X 1 And X 2 Each independently is CR 1a Or N;
R 1a 、R 1b and R is 1c Each independently is H, halogen, C 1-6 Alkyl, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl or-N (R) 14 )(R 14 ) Wherein C 1-6 Alkyl and C 1-4 Alkoxy groups are each independently optionally substituted with 1 to 3 halo groups; and is also provided with
Each R 14 H, C independently 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl or 4-to 7-membered monocyclic heterocyclyl.
In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, X 1 Is CR (CR) 1a Or N. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, X 1 Is CR (CR) 1a . In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, X 1 Is CR (CR) 1a And R is 1a Is H. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, X 1 Is N.
In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, X 2 Is CR (CR) 1a Or N. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, X 2 Is CR (CR) 1a . In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, X 2 Is CR (CR) 1a And R is 1a Is H. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, X 2 Is N.
In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1a 、R 1b And R is 1c Each independently is H, halogen, C 1-6 Alkyl, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl or-N (R) 14 )(R 14 ) Wherein C 1-6 Alkyl and C 1-4 The alkoxy groups are each independently optionally substituted with 1 to 3 halo groups. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1a 、R 1b And R is 1c Each independently H, halogen, methyl, methoxy-CF 3 Or CHF 2 。
In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, each R 1a Independently H, halogen, C 1-6 Alkyl, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl or-N (R) 14 )(R 14 ) Wherein C 1-6 Alkyl and C 1-4 The alkoxy groups are each independently optionally substituted with 1 to 3 halo groups. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, each R 1a Independently H, halogen, methyl, methoxy, -CF 3 Or CHF 2 . In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, one or two R 1a Is H. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, one or two R 1a Is halogen. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, one or two R 1a Is C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally substituted with 1 to 3 halogen groups. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, one or two R 1a Is methyl. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, one or two R 1a is-CF 3 . In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, one or two R 1a Is CHF 2 . In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, one or two R 1a Is C 1-4 Alkoxy group, wherein C 1-4 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, one or two R 1a Is methoxy. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, one or two R 1a Is C 3-7 A monocyclic cycloalkyl group. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, one or two R 1a is-N (R) 14 )(R 14 )。
In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1b Is H, halogen, C 1-6 Alkyl, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl or-N (R) 14 )(R 14 ) Wherein C 1-6 Alkyl and C 1-4 The alkoxy groups are each independently optionally substituted with 1 to 3 halo groups. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1b Is H, halogen, methyl, methoxy, -CF 3 Or CHF 2 . In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1b Is H. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1b Is halogen. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1b Is C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally substituted with 1 to 3 halogen groups. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1b Is methyl. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1b is-CF 3 . In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1b Is CHF 2 . In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1b Is C 1-4 Alkoxy group, wherein C 1-4 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1b Is methoxy. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1b Is C 3-7 A monocyclic cycloalkyl group. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1b is-N (R) 14 )(R 14 )。
In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1c Is H, halogen, C 1-6 Alkyl, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl or-N (R) 14 )(R 14 ) WhereinC 1-6 Alkyl and C 1-4 The alkoxy groups are each independently optionally substituted with 1 to 3 halo groups. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1c Is H, halogen, methyl, methoxy, -CF 3 Or CHF 2 . In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1c Is H. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1c Is halogen. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1c Is C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally substituted with 1 to 3 halogen groups. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1c Is methyl. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1c is-CF 3 . In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1c Is CHF 2 . In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1c Is C 1-4 Alkoxy group, wherein C 1-4 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1c Is methoxy. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1c Is C 3-7 A monocyclic cycloalkyl group. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, R 1c is-N (R) 14 )(R 14 )。
In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, each R 14 H, C independently 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl or 4-to 7-membered monocyclic heterocyclyl. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, one or two R 14 Is H. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, one or two R 14 Is C 1-6 An alkyl group. In the form of a compound of formula II or a pharmaceutically acceptable salt thereofIn some embodiments of the acceptable salts, one or both R 14 Is C 3-7 A monocyclic cycloalkyl group. In some embodiments of the compound of formula II, or a pharmaceutically acceptable salt thereof, one or two R 14 Is a 4 to 7 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 1 Is that
Each of them is optionally selected from the group consisting of halogen, C, and 1 to 3 1-3 Alkyl and C 1-3 Substitution of alkoxy groups, where C 1-3 The alkyl group is optionally substituted with 1 to 3 halogen groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 1 Is that
Optionally from 1 to 3 of which are independently selected from halogen, C 1-3 Alkyl and C 1-3 Substitution of alkoxy groups, where C 1-3 The alkyl group is optionally substituted with 1 to 3 halogen groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 1 Is that
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 1 Is that
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In a compound of formula I or IIIn some embodiments of pharmaceutically acceptable salts thereof, R 1 Is that
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 1 Is that
Each of them is optionally substituted with 1 to 3 groups independently selected from halogen, -CN, C 1-3 Alkyl and C 1-3 The groups of the alkoxy groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 1 Is that
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is H, C 1-6 Alkyl or C 3-7 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-7 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is H, C 1-6 Alkyl or C 3-7 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-7 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from halogen and C 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is H, C 1-6 Alkyl or C 3-7 Monocyclic cycloalkyl, which isMiddle C 1-6 Alkyl and C 3-7 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from halogen and C 1-3 Substitution of alkoxy groups, where C 1-3 The alkoxy groups are optionally substituted with 1 to 3 halogen groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl or C 3-5 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-5 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl or C 3-5 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-5 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from halogen and C 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl or C 3-5 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-5 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from halogen and C 1-3 Substitution of alkoxy groups, where C 1-3 The alkoxy groups are optionally substituted with 1 to 3 halogen groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl or C 3-5 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-5 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl or C 3-5 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-5 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from halogen and C 1-6 Alkoxy radicalAnd (3) group substitution of the groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl or C 3-5 Monocyclic cycloalkyl wherein C 1-6 Alkyl and C 3-5 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from halogen and C 1-3 The groups of the alkoxy groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and C 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and C 1-3 Substitution of alkoxy groups, where C 1-3 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl, wherein C 1-6 Alkyl groups are independently selected from halogen and C by 1 to 4 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl, wherein C 1-6 Alkyl groups are independently selected from halogen and C by 1 to 3 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl, wherein C 1-6 Alkyl groups are independently selected from 1 to 3Halogen and C 1-3 Substitution of alkoxy groups, where C 1-3 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and C 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and C 1-3 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl, wherein C 1-6 Alkyl groups are independently selected from halogen and C by 1 to 4 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl, wherein C 1-6 Alkyl groups are independently selected from halogen and C by 1 to 3 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 Alkyl, wherein C 1-6 Alkyl groups are independently selected from halogen and C by 1 to 3 1-3 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-6 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-4 Alkyl, wherein C 1-4 Alkyl is optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 The groups of the alkoxy groups are substituted. At the position ofIn some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-4 Alkyl, wherein C 1-4 Alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and C 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-4 Alkyl, wherein C 1-4 Alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and C 1-3 The groups of the alkoxy groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-4 Alkyl, wherein C 1-4 Alkyl groups are independently selected from halogen and C by 1 to 4 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-4 Alkyl, wherein C 1-4 Alkyl groups are independently selected from halogen and C by 1 to 3 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-4 Alkyl, wherein C 1-4 Alkyl groups are independently selected from halogen and C by 1 to 3 1-3 The groups of the alkoxy groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-4 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 1-3 An alkyl group. In some embodiments of the compounds of formula I or II or pharmaceutically acceptable salts thereof, R 2 Is ethyl or isopropyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is methyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is ethyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is propyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is isopropyl.
In formula I orIn some embodiments of the compound of II or a pharmaceutically acceptable salt thereof, R 2 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 3 groups independently selected from halogen and C 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 3 groups independently selected from halogen and C 1-3 Substitution of alkoxy groups, where C 1-3 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl groups are independently selected from halogen and C by 1 to 4 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl groups are independently selected from halogen and C by 1 to 3 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl groups are independently selected from halogen and C by 1 to 3 1-3 Substitution of alkoxy groups, where C 1-3 The alkoxy groups are optionally substituted with 1 to 3 halogen groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 3 groups independently selected from halogen and C 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 3 groups independently selected from halogen and C 1-3 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl groups are independently selected from halogen and C by 1 to 4 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl groups are independently selected from halogen and C by 1 to 3 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl groups are independently selected from halogen and C by 1 to 3 1-3 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-7 A monocyclic cycloalkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-5 Monocyclic cycloalkyl wherein C 3-5 Monocyclic cycloalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-5 Monocyclic cycloalkyl wherein C 3-5 Monocyclic cycloalkyl groups are optionally substituted with 1 to 3Independently selected from halogen and C 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-5 Monocyclic cycloalkyl wherein C 3-5 Monocyclic cycloalkyl is optionally substituted with 1 to 3 groups independently selected from halogen and C 1-3 Substitution of alkoxy groups, where C 1-3 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-5 Monocyclic cycloalkyl wherein C 3-5 Monocyclic cycloalkyl groups are independently selected from halogen and C by 1 to 4 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-5 Monocyclic cycloalkyl wherein C 3-5 Monocyclic cycloalkyl groups are independently selected from halogen and C by 1 to 3 1-6 Substitution of alkoxy groups, where C 1-6 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-5 Monocyclic cycloalkyl wherein C 3-5 Monocyclic cycloalkyl groups are independently selected from halogen and C by 1 to 3 1-3 Substitution of alkoxy groups, where C 1-3 The alkoxy groups are optionally substituted with 1 to 3 halogen groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-5 Monocyclic cycloalkyl wherein C 3-5 Monocyclic cycloalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-5 Monocyclic cycloalkyl wherein C 3-5 Monocyclic cycloalkyl is optionally substituted with 1 to 3 groups independently selected from halogen and C 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-5 Monocyclic cycloalkyl wherein C 3-5 Monocyclic cycloalkyl is optionally substituted with 1 to 3 groups independently selected from halogen and C 1-3 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-5 Monocyclic cycloalkyl wherein C 3-5 Monocyclic cycloalkyl groups are independently selected from halogen and C by 1 to 4 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-5 Monocyclic cycloalkyl wherein C 3-5 Monocyclic cycloalkyl groups are independently selected from halogen and C by 1 to 3 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-5 Monocyclic cycloalkyl wherein C 3-5 Monocyclic cycloalkyl groups are independently selected from halogen and C by 1 to 3 1-3 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is C 3-5 A monocyclic cycloalkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is cyclopropyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 2 Is isopropyl or cyclopropyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is H, hydrogen, -CN, C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl or 4-to 7-membered monocyclic heterocyclyl,
wherein C is 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl and 4-to 7-membered monocyclic heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl, -C (O) N (R) 4 ) 2 4-to 7-membered monocyclic heterocyclyl, C 3-7 A monocyclic cycloalkoxy group and a 4-to 7-membered monocyclic hetero-epoxy group,
wherein C is 1-4 The alkoxy groups are optionally substituted with 1 to 3 halogen groups.
In formula I or IIIn some embodiments of the compound or pharmaceutically acceptable salt thereof, R 3 Is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl and-C (O) N (R) 4 ) 2 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is H or C 1-6 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is H or methyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is H. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is halogen. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 is-CN.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl, -C (O) N (R) 4 ) 2 4-to 7-membered monocyclic heterocyclyl, C 3-7 Group substitution of monocyclic cycloalkoxy and 4 to 7 membered monocyclic hetero-epoxy, wherein C 1-4 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl groups are independently selected from-OH, halogen, -CN, C by 1 to 3 1-4 Alkoxy, -C (O) C 1-6 Alkyl, -C (O) N (R) 4 ) 2 4-to 7-membered monocyclic heterocyclyl, C 3-7 Group substitution of monocyclic cycloalkoxy and 4 to 7 membered monocyclic hetero-epoxy, wherein C 1-4 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is C 3-7 A monocyclic cycloalkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is a 4 to 7 membered monocyclic heterocyclyl wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl, -C (O) N (R) 4 ) 2 4-to 7-membered monocyclic heterocyclyl, C 3-7 Group substitution of monocyclic cycloalkoxy and 4 to 7 membered monocyclic hetero-epoxy, wherein C 1-4 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl, -C (O) N (R) 4 ) 2 4-to 7-membered monocyclic heterocyclyl, C 3-7 Group substitution of monocyclic cycloalkoxy and 4 to 7 membered monocyclic hetero-epoxy, wherein C 1-4 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is a 4 to 7 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl, -C (O) N (R) 4 ) 2 4-to 7-membered monocyclic heterocyclyl, C 3-7 Group substitution of monocyclic cycloalkoxy and 4 to 7 membered monocyclic hetero-epoxy, wherein C 1-4 The alkoxy groups are optionally substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, halogen, -CN, C by 1 to 3 1-4 Alkoxy, -C (O) C 1-6 Alkyl, -C (O) N (R) 4 ) 2 4-to 7-membered monocyclic heterocyclyl, C 3-7 Group substitution of monocyclic cycloalkoxy and 4 to 7 membered monocyclic hetero-epoxy, wherein C 1-4 Alkoxy groups optionally substituted with 1 to 3 halogen groups。
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl and-C (O) N (R) 4 ) 2 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, halogen, -CN, C by 1 to 3 1-4 Alkoxy, -C (O) C 1-6 Alkyl and-C (O) N (R) 4 ) 2 Is substituted with a group of (a).
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is optionally selected from-OH, halogen, -CN and C by 1 to 3 groups independently 1-3 C substituted by groups of alkoxy groups 1-4 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is methyl substituted with 1 to 3 halogen groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 is-CHF 2 。
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is C 1-6 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is C 1-4 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is C 1-3 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is methyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 3 Is H, methyl, -CHF 2 、-CH 2 OH、-CH 2 OCH 3 Or ethyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached form a 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 4 Is H. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 4 Is C 1-6 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, two R 4 Together with the nitrogen to which they are attached form a 4 to 7 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 1-6 Alkyl, C 2-6 Alkenyl, -C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 、C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 1-6 Alkyl and C 2-6 Alkenyl groups are each independently optionally substituted with 1 to 4R b Group substitution, wherein C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally being substituted with 1-2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 、C 3-7 Monocyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bisA cyclic heterocyclyl, a 6-to 10-membered bridged bicyclic heterocyclyl, an 8-to 10-membered fused bicyclic heteroaryl, or a 7-to 10-membered spiro heterocyclyl,
wherein C is 3-7 Monocyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally being substituted with 1-2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 A 4-to 7-membered monocyclic heterocyclic group, a phenyl group, a naphthyl group, a 5-to 6-membered monocyclic heteroaryl group, a 8-to 10-membered fused bicyclic heterocyclic group, a 6-to 10-membered bridged bicyclic heterocyclic group, a 8-to 10-membered fused bicyclic heteroaryl group or a 7-to 10-membered spiro heterocyclic group,
Wherein 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl, 6 to 10 membered bridged bicyclic heterocyclyl, 8 to 10 membered fused bicyclic heteroaryl, and 7 to 10 membered spiro heterocyclyl are each independently optionally substituted with 1 to 2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 A 4-to 7-membered monocyclic heterocyclic group, a phenyl group, a naphthyl group, a 5-to 6-membered monocyclic heteroaryl group, a 8-to 10-membered fused bicyclic heterocyclic group, a 6-to 10-membered bridged bicyclic heterocyclic group, a 8-to 10-membered fused bicyclic heteroaryl group or a 7-to 10-membered spiro heterocyclic group,
wherein 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl, 6 to 10 membered bridged bicyclic heterocyclyl, 8 to 10 membered fused bicyclic heteroaryl, and 7 to 10 membered spiro heterocyclyl are each independently optionally substituted with 1 to 2R 8 Substituted with groups and each independently optionally substituted with 1 to 3 groupsIndependently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 、C 3-7 Monocyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 3-7 Monocyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally being substituted with 1-2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 、C 3-7 A monocyclic cycloalkyl group, a 4-to 7-membered monocyclic heterocyclic group, a phenyl group, a naphthyl group, a 5-to 6-membered monocyclic heteroaryl group, a 8-to 10-membered fused bicyclic heterocyclic group, a 6-to 10-membered bridged bicyclic heterocyclic group, a 8-to 10-membered fused bicyclic heteroaryl group or a 7-to 10-membered spiro heterocyclic group,
wherein C is 3-7 Monocyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl each independently optionally being substituted with 1-2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl or 8-to 10-membered fused bicyclic heteroaryl,
wherein 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl and 8 to 10 membered fused bicyclic heteroaryl are each independently optionally substituted with 1 to 2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 、C 3-7 Monocyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 3-7 Monocyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally being substituted with 1-2R 8 Groups are substituted and each independently is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl or 8-to 10-membered fused bicyclic heteroaryl,
wherein 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl and 8 to 10 membered fused bicyclic heteroarylEach radical independently is optionally substituted with 1 to 2R 8 Groups are substituted and each independently is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl or 8-to 10-membered fused bicyclic heteroaryl,
wherein C is 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, and 8-to 10-membered fused bicyclic heteroaryl, each independently, are optionally substituted with 1-2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 7-10 Fused bicyclic cycloalkyl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl or 8-to 10-membered fused bicyclic heteroaryl,
wherein C is 7-10 Fused bicyclic cycloalkyl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, and 8-to 10-membered fused bicyclic heteroaryl, each independently, are optionally substituted with 1-2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 1-6 Alkyl, wherein C 1-6 Alkyl is substituted with 1 to 4R b And (3) group substitution. In formula I or IIIn some embodiments of the compound or pharmaceutically acceptable salt thereof, Z is C 1-6 Alkyl, wherein C 1-10 Alkyl is substituted with 1 to 3R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 1-6 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 2-6 Alkenyl group, wherein C 2-6 Alkenyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 2-6 Alkenyl group, wherein C 2-6 Alkenyl is optionally substituted with 1 to 3R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 2-6 Alkenyl group, wherein C 2-6 Alkenyl is substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 2-6 Alkenyl group, wherein C 2-6 Alkenyl is substituted with 1 to 3R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 2-6 Alkenyl groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is substituted with 1 to 2R 8 Substituted with groups, and optionally with 1Up to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is substituted with 1 to 2R 8 Substituted by 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is substituted with 1 to 2R 8 And (3) group substitution. In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, Z is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 3-7 A monocyclic cycloalkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is cyclobutyl, cyclopentyl, orA cyclohexenyl group, each of which is optionally substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1 to 2R 8 And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 The fused bicyclic cycloalkyl is optionally substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 Fused bicyclic cycloalkyl is substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 Fused bicyclic cycloalkyl is substituted with 1 to 2R 8 Substituted by 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 Fused bicyclic cycloalkyl is substituted with 1 to 2R 8 And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 The fused bicyclic cycloalkyl is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 7-10 Fused bicyclic cycloalkyl groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl groups are substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl groups are substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl groups are substituted with 1 to 2R 8 Substituted by 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl groups are substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl groups are substituted with 1 to 2R 8 And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl groups are optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 5-10 Bridged bicyclic cycloalkyl groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is
Which is optionally substituted with one R 8 And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is
Which is optionally substituted with one R 8 And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is substituted with 1 to 2R 8 Substituted by 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is substituted with 1 to 2R 8 And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 4 to 7 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 5 to 6 membered monocyclic heterocyclyl, wherein 5 to 6 membered monocyclic heterocyclyl is optionally substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In a compound of formula I or IIIn some embodiments of pharmaceutically acceptable salts thereof, Z is a 5-to 6-membered monocyclic heterocyclyl, wherein the 5-to 6-membered monocyclic heterocyclyl is optionally substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 5 to 6 membered monocyclic heterocyclyl, wherein 5 to 6 membered monocyclic heterocyclyl is substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 5 to 6 membered monocyclic heterocyclyl, wherein 5 to 6 membered monocyclic heterocyclyl is substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 5 to 6 membered monocyclic heterocyclyl, wherein 5 to 6 membered monocyclic heterocyclyl is substituted with 1 to 2R 8 Substituted by 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 5 to 6 membered monocyclic heterocyclyl, wherein 5 to 6 membered monocyclic heterocyclyl is substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 5 to 6 membered monocyclic heterocyclyl, wherein 5 to 6 membered monocyclic heterocyclyl is substituted with 1 to 2R 8 And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is a 5-to 6-membered monocyclic heterocyclyl, wherein 5-to 6-membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 5 to 6 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is phenyl, wherein phenyl is optionally substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is phenyl, wherein phenyl is optionally substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is phenyl, wherein phenyl is substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is phenyl, wherein phenyl is substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is phenyl, wherein phenyl is substituted with 1 to 2R 8 Substituted by 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is phenyl, wherein phenyl is substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is phenyl, wherein phenyl is substituted with 1 to 2R 8 And (3) group substitution. In some embodiments of the compounds of formula I or pharmaceutically acceptable salts thereofIn embodiments, Z is phenyl, wherein phenyl is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is phenyl, wherein phenyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is phenyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is naphthyl, wherein naphthyl is optionally substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is naphthyl, wherein naphthyl is optionally substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is naphthyl, wherein naphthyl is substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is naphthyl, wherein naphthyl is substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is naphthyl, wherein naphthyl is substituted with 1 to 2R 8 Substituted by 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is naphthyl, wherein naphthyl is substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is naphthyl, wherein naphthyl is substituted with 1 to 2R 8 And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is naphthyl, wherein naphthyl is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is naphthyl, wherein naphthyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is naphthyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is substituted with 1 to 2R 8 Substituted by 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is substituted with 1 to 2R 8 And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 5 to 6 membered monocyclic heteroaryl.
Compounds of formula I or II or medicaments thereofIn some embodiments of the pharmaceutically acceptable salts, Z is 6 membered monocyclic heteroaryl, wherein 6 membered monocyclic heteroaryl is optionally substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 6 membered monocyclic heteroaryl, wherein 6 membered monocyclic heteroaryl is optionally substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 6 membered monocyclic heteroaryl, wherein the 6 membered monocyclic heteroaryl is substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 6 membered monocyclic heteroaryl, wherein the 6 membered monocyclic heteroaryl is substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 6 membered monocyclic heteroaryl, wherein the 6 membered monocyclic heteroaryl is substituted with 1 to 2R 8 Substituted by 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 6 membered monocyclic heteroaryl, wherein the 6 membered monocyclic heteroaryl is substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 6 membered monocyclic heteroaryl, wherein the 6 membered monocyclic heteroaryl is substituted with 1 to 2R 8 And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is a 6 membered monocyclic ring Heteroaryl, wherein a 6 membered monocyclic heteroaryl is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 6 membered monocyclic heteroaryl, wherein the 6 membered monocyclic heteroaryl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 6 membered monocyclic heteroaryl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heterocyclyl, wherein 8-to 10-membered fused bicyclic heterocyclyl is optionally substituted with 1-2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heterocyclyl, wherein 8-to 10-membered fused bicyclic heterocyclyl is optionally substituted with 1-2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heterocyclyl, wherein 8-to 10-membered fused bicyclic heterocyclyl is substituted with 1-2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heterocyclyl, wherein 8-to 10-membered fused bicyclic heterocyclyl is substituted with 1-2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heterocyclyl, wherein 8-to 10-membered fused bicyclic heterocyclyl is substituted with 1-2R 8 Substituted by radicals and from 1 to3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heterocyclyl, wherein 8-to 10-membered fused bicyclic heterocyclyl is substituted with 1-2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heterocyclyl, wherein 8-to 10-membered fused bicyclic heterocyclyl is substituted with 1-2R 8 And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heterocyclyl, wherein 8-to 10-membered fused bicyclic heterocyclyl is optionally substituted with 1-3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heterocyclyl, wherein 8-to 10-membered fused bicyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is a 6-to 10-membered bridged bicyclic heterocyclyl, wherein the 6-to 10-membered bridged bicyclic heterocyclyl is optionally substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is a 6-to 10-membered bridged bicyclic heterocyclyl, wherein the 6-to 10-membered bridged bicyclic heterocyclyl is optionally substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 6A bridged bicyclic heterocyclic group of up to 10 members, wherein the bridged bicyclic heterocyclic group of up to 6 to 10 members is substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is a 6-to 10-membered bridged bicyclic heterocyclyl, wherein the 6-to 10-membered bridged bicyclic heterocyclyl is substituted with 1-2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is a 6-to 10-membered bridged bicyclic heterocyclyl, wherein the 6-to 10-membered bridged bicyclic heterocyclyl is substituted with 1-2R 8 Substituted by 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is a 6-to 10-membered bridged bicyclic heterocyclyl, wherein the 6-to 10-membered bridged bicyclic heterocyclyl is substituted with 1-2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is a 6-to 10-membered bridged bicyclic heterocyclyl, wherein the 6-to 10-membered bridged bicyclic heterocyclyl is substituted with 1-2R 8 And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is a 6-to 10-membered bridged bicyclic heterocyclyl, wherein the 6-to 10-membered bridged bicyclic heterocyclyl is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is a 6-to 10-membered bridged bicyclic heterocyclyl, wherein the 6-to 10-membered bridged bicyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is a 6-to 10-membered bridged bicyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7-to 8-membered bridged bicyclic heterocyclyl, wherein 7-to 8-membered bridged bicyclic heterocyclyl is optionally substituted with 1-2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7-to 8-membered bridged bicyclic heterocyclyl, wherein 7-to 8-membered bridged bicyclic heterocyclyl is optionally substituted with 1-2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7-to 8-membered bridged bicyclic heterocyclyl, wherein 7-to 8-membered bridged bicyclic heterocyclyl is substituted with 1-2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7-to 8-membered bridged bicyclic heterocyclyl, wherein 7-to 8-membered bridged bicyclic heterocyclyl is substituted with 1-2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7-to 8-membered bridged bicyclic heterocyclyl, wherein 7-to 8-membered bridged bicyclic heterocyclyl is substituted with 1-2R 8 Substituted by 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7-to 8-membered bridged bicyclic heterocyclyl, wherein 7-to 8-membered bridged bicyclic heterocyclyl is substituted with 1-2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7-to 8-membered bridgedBicyclic heterocyclyl wherein 7 to 8 membered bridged bicyclic heterocyclyl is substituted with 1 to 2R 8 And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7-to 8-membered bridged bicyclic heterocyclyl, wherein 7-to 8-membered bridged bicyclic heterocyclyl is optionally substituted with 1-3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7-to 8-membered bridged bicyclic heterocyclyl, wherein 7-to 8-membered bridged bicyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7-to 8-membered bridged bicyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heteroaryl, wherein 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1-2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heteroaryl, wherein 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1-2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is substituted with 1-2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is substituted with 1-2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is substituted with 1-2R 8 Substituted by 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is substituted with 1-2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is substituted with 1-2R 8 And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heteroaryl, wherein 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1-3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 8-to 10-membered fused bicyclic heteroaryl, wherein 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1-3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, Z is 8-to 10-membered fused bicyclic heteroaryl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7-to 10-membered spirocyclic heterocyclyl, wherein 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1-2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7-to 10-membered spirocyclic heterocyclyl, wherein 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1-2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7 to 10 membered spirocyclic heterocyclyl, wherein 7 to 10 membered spirocyclic heterocyclyl is substituted with 1 to 2R 8 Substituted with groups and optionally with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7 to 10 membered spirocyclic heterocyclyl, wherein 7 to 10 membered spirocyclic heterocyclyl is substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7 to 10 membered spirocyclic heterocyclyl, wherein 7 to 10 membered spirocyclic heterocyclyl is substituted with 1 to 2R 8 Substituted by 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7 to 10 membered spirocyclic heterocyclyl, wherein 7 to 10 membered spirocyclic heterocyclyl is substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7 to 10 membered spirocyclic heterocyclyl, wherein 7 to 10 membered spirocyclic heterocyclyl is substituted with 1 to 2R 8 And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7 to 10 membered spirocyclic heterocyclyl, wherein 7 to 10 membered spirocyclic heterocyclyl is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 7-to 10-membered spirocyclic heterocyclyl, wherein 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In the formulaIn some embodiments of the compounds of I or II, or pharmaceutically acceptable salts thereof, Z is 7 to 10 membered spirocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl, or 8 to 10 membered fused bicyclic heteroaryl,
wherein 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl and 8 to 10 membered fused bicyclic heteroaryl are each independently optionally substituted with 1 to 2R 8 Groups are substituted and each independently is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl, or 8 to 10 membered fused bicyclic heteroaryl,
wherein 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl and 8 to 10 membered fused bicyclic heteroaryl are each independently optionally substituted with 1 to 2R 8 Groups are substituted and each independently is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substituted by alkyl radicals, and
wherein 4 to 7 membered monocyclic heterocyclyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl and 8 to 10 membered fused bicyclic heteroaryl each independently have one or two ring heteroatoms which are N.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is a 5 to 6 membered monocyclic heterocyclyl,
wherein 5 to 6 membered monocyclic heterocyclyl is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substituted by alkyl radicals, and
wherein the 5-to 6-membered monocyclic heterocyclic group has one or two ring heteroatoms which are N.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is pyrrolidinyl or piperidinyl, each of which is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is piperidinyl, wherein piperidinyl is optionally substituted with one R 8 And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is optionally substituted with one R 8 Azetidinyl substituted with a group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is azepanyl, wherein azepanyl is optionally substituted with one R 8 And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is phenyl, naphthyl, or 6-membered monocyclic heteroaryl, each of which is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is phenyl, pyridinyl or pyrimidinyl, each of which is optionally substituted with one R 8 And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is phenyl or pyridinyl, each of which is optionally substituted with one R 8 And (3) group substitution.
In formula I or IIIn some embodiments of the compound or pharmaceutically acceptable salt thereof, Z is 8-to 10-membered fused bicyclic heterocyclyl or 8-to 10-membered fused bicyclic heteroaryl, each of which is optionally substituted with 1-2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is
Each of them is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is optionally substituted with 1 to 2R 8 Groups are substituted and optionally with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The group of the alkyl group is substituted with a 6-to 10-membered bridged bicyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is optionally substituted with 1 to 2R 8 Groups are substituted and optionally with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 A 7-to 8-membered bridged bicyclic heterocyclic group substituted with a group of an alkyl group, wherein the 7-to 8-membered bridged bicyclic heterocyclic group has one or two ring heteroatoms which are N.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is optionally substituted with 1 to 2R 8 Groups are substituted and optionally with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 A 7-to 10-membered spirocyclic heterocyclic group substituted with a group of alkyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is optionally substituted with 1 to 2R 8 Groups are substituted and optionally with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 A 7-to 10-membered spirocyclic heterocyclyl substituted with an alkyl group, wherein the 7-to 10-membered spirocyclic heterocyclyl has one or two ring heteroatoms independently selected from N and O.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is
Each of them is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is
Each of them is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is
Each of them is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is
Each of them is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is
Each of them is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is
Each of them is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Alkyl group And (3) substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is
Each of them is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is
Each of them is optionally substituted with one R 8 And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is
Each of them is optionally substituted with one R 8 And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is
Each of them is optionally substituted with one R 8 And (3) group substitution.
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compounds of formula I or II or pharmaceutically acceptable salts thereof Is covered by one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
Compounds of formula I or II or pharmaceutical compositions thereofIn some embodiments of the above acceptable salts, are substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is substituted with one R 8 Z substituted by radicals is
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Independently halogen, -C (O) R 9 、-NR 10 R 10 、C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 5 、-C(O)OR 5 、-C(O)N(R 5 )(R 5 )、-N(R 5 ) 2 (R 5 ) + 、-N(R 5 )C(O)R 5 、-N(R 5 )C(O)OR 5 、-N(R 5 )C(O)N(R 5 )(R 5 )、-N(R 5 )S(O) 2 ( R5a )、-NR 5 S(O) 2 N(R 5 )(R 5 )、-NR 5 S(O) 2 O(R 5a )、-OC(O)R 5 、-OC(O)OR 5 、-OC(O)N(R 5 )(R 5 )、-SR 5 、-S(O)R 5a 、-S(O)(NH)R 5 、-S(O) 2 R 5a 、-S(O) 2 N(R 5 )(R 5 ) Or-n=s (R 5a )(R 5a )＝O，
Wherein C is 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered
Each independently of the other, a membered fused bicyclic heterocyclic group, a 6-to 10-membered bridged bicyclic heterocyclic group, a 8-to 10-membered fused bicyclic heteroaryl group and a 7-to 10-membered spiro heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 independently-C (O) R 9 、-NR 10 R 10 、-S(O) 2 R 5a 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 6-to 10-membered bridged bicyclic heterocyclyl or 7-to 10-membered spiroheterocyclyl,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein 4 to 7 membered monocyclic heterocyclyl, 5 to 6 membered monocyclic heteroaryl, 6 to 10 membered bridged bicyclic heterocyclyl and 7 to 10 membered spiro heterocyclyl are each independently optionally substituted with 1 to 4R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 independently-C (O) R 9 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclic group or 6-to 10-membered bridged bicyclic heterocyclic group,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein 4 to 7 membered monocyclic heterocyclyl and 6 to 10 membered bridged bicyclic heterocyclyl are each independently optionally substituted with 1 to 4R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 independently-C (O) R 9 、-NR 10 R 10 、-S(O) 2 R 5a 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 6-to 10-membered bridged bicyclic heterocyclyl or 7-to 10-membered spiroheterocyclyl,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)NR 11 R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Alkoxy and R 8a Is substituted by a group of (a) or (b),
wherein 4 to 7 membered monocyclic heterocyclyl, 5 to 6 membered monocyclic heteroaryl, 6 to 10 membered bridged bicyclic heterocyclyl, and 7 to 10 membered spiro heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 8b Is substituted with a group of (a).
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 independently-C (O) R 9 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclic group or 6-to 10-membered bridged bicyclic heterocyclic group,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)NR 11 R 11 、-S(O) 2 R 11a 、C 1-4 Alkoxy and R 8a Is substituted by a group of (a) or (b),
wherein 4 to 7 membered monocyclic heterocyclyl and 6 to 10 membered bridged bicyclic heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 independently-C (O) R 9 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclic group or 6-to 10-membered bridged bicyclic heterocyclic group,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)NR 11 R 11 、C 1-4 Alkoxy and R 8a Is substituted by a group of (a) or (b),
wherein 4 to 7 membered monocyclic heterocyclyl and 6 to 10 membered bridged bicyclic heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8a Independently 4 to 7 membered monocyclic heterocyclyl or 5 to 6 membered monocyclic heteroaryl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8a Is a 4 to 7 membered monocyclic heterocyclyl. In formula I or IIIn some embodiments of the substance or pharmaceutically acceptable salt thereof, R 8a Is a 5 to 6 membered monocyclic heteroaryl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8b Independently 4 to 7 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8b Is a 4 to 7 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is halogen. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 is-OR 5 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 is-C (O) OR 5 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 is-C (O) N (R) 5 )(R 5 ). In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or two R 8 is-N (R) 5 ) 2 (R 5 ) + . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 is-N (R) 5 )C(O)R 5 . In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or two R 8 is-N (R) 5 )C(O)OR 5 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 is-N (R) 5 )C(O)N(R 5 )(R 5 ). In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or two R 8 is-N (R) 5 )S(O) 2 (R 5a ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 is-NR 5 S(O) 2 N(R 5 )(R 5 ). In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof,one or two R 8 is-NR 5 S(O) 2 O(R 5a ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 is-OC (O) R 5 . In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or two R 8 is-OC (O) OR 5 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 is-OC (O) N (R) 5 )(R 5 ). In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or two R 8 is-SR 5 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 is-S (O) R 5a . In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or two R 8 is-S (O) (NH) R 5 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 is-S (O) 2 R 5a . In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or two R 8 is-S (O) 2 N(R 5 )(R 5 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is-n=s (R 5a )(R 5a )＝O。
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Alkoxy and R 8a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Groups substituted with alkoxy, 4 to 7 membered monocyclic heterocyclyl and 5 to 6 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Groups substituted with alkoxy, 4 to 5 membered monocyclic heterocyclyl and 5 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、C 1-4 Alkoxy and 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)N(R 11 )(R 11 )、C 1-4 Alkoxy and 4 to 7 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Alkoxy and R 8a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Groups substituted with alkoxy, 4 to 7 membered monocyclic heterocyclyl and 5 to 6 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Groups substituted with alkoxy, 4 to 5 membered monocyclic heterocyclyl and 5 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、-C(O)NR 11 R 11 、-S(O) 2 R 11a 、C 1-4 Alkoxy and 4 to 5 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 1l R 11 、-C(O)NR 11 R 11 、C 1-4 Alkoxy and 4 to 5 membered monocyclic heterocyclyl. A compound of formula I or II or a pharmaceutically acceptable salt thereofIn some embodiments of (2), R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, -CN, oxo, -N by 1 to 2 R11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)NR 11 R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 ) Group substitution of 4 to 5 membered monocyclic heterocyclyl and 5 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, oxo, -NR by 1 to 2 11 R 11 、-C(O)NR 11 R 11 、-S(O) 2 R 11a And 4 to 5 membered monocyclic heterocyclyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from the group consisting of-OH, -CN, oxo, -NH by 1 to 3 2 、-N(CH 3 ) 2 -C (O) (azetidinyl), -C (O) OH, -C (O) OCH (CH) 3 ) 3 、-C(O)NH 2 、-C(O)NH 2 、-C(O)NH(CH 3 )、-C(O)NH(CH 2 CH 3 )、-C(O)NH(CH(CH 3 ) 2 ) -C (O) NH (cyclopropyl), -C (O) NH (oxetanyl), -C (O) N (CH) 3 ) 2 、-S(O) 2 CH 3 、-S(O) 2 NH 2 、-S(O) 2 NH(CH 3 )、-S(O) 2 N(CH 3 ) 2 Group substitution of 4 to 5 membered monocyclic heterocyclyl and 5 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, oxo, -NH by 1 to 3 2 、-N(CH 3 ) 2 、-C(O)NH 2 、-C(O)N(CH 3 ) 2 、-S(O) 2 CH 3 And 4-membered monocyclic heterocyclyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, oxo, -NH by 1 to 3 2 、-N(CH 3 ) 2 、-C(O)NH 2 、-C(O)N(CH 3 ) 2 And 4-membered monocyclic heterocyclyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, oxo, -N (CH) 3 ) 2 、-C(O)NH 2 、-S(O) 2 CH 3 And oxetanyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, oxo, -N (CH) 3 ) 2 、-C(O)NH 2 And oxetanyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is independently selected from-C (O) NH 2 and-C (O) NHCH 3 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is covered by a-C (O) NH group 2 Methyl substituted by a group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, oxo, -N (CH) 3 ) 2 、-C(O)NH 2 、-C(O)NHCH 3 、-S(O) 2 CH 3 Group substitutions of oxetanyl and pyrrolidinyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, oxo, -N (CH) 3 ) 2 、-C(O)NH 2 、-C(O)NHCH 3 Group substitutions of oxetanyl and pyrrolidinyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Alkoxy and R 8a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C1- 6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Groups substituted with alkoxy, 4 to 7 membered monocyclic heterocyclyl and 5 to 6 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C1- 6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Groups substituted with alkoxy, 4 to 5 membered monocyclic heterocyclyl and 5 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl groups optionally being 1 to 3 independentlySelected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、C 1-4 Alkoxy and 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)N(R 11 )(R 11 )、C 1-4 Alkoxy and 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, oxo, -NH 2 、-N(CH 3 ) 2 、-C(O)NH 2 、-C(O)N(CH 3 ) 2 、-S(O) 2 CH 3 And 4-membered monocyclic heterocyclyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, oxo, -NH 2 、-N(CH 3 ) 2 、-C(O)NH 2 、-C(O)N(CH 3 ) 2 And 4-membered monocyclic heterocyclyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, oxo, -NH 2 、-N(CH 3 ) 2 、-C(O)NH 2 、-C(O)N(CH 3 ) 2 、-S(O) 2 CH 3 And 4-membered monocyclic heterocyclyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, oxo, -NH 2 、-N(CH 3 ) 2 、-C(O)NH 2 、-C(O)N(CH 3 ) 2 And 4-membered monocyclic heterocyclyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, oxo, -N (CH) 3 ) 2 、-C(O)NH 2 、-S(O) 2 CH 3 And oxetanyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, oxo, -N (CH) 3 ) 2 、-C(O)NH 2 And oxetanyl groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Alkoxy and R 8a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Groups substituted with alkoxy, 4 to 7 membered monocyclic heterocyclyl and 5 to 6 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Groups substituted with alkoxy, 4 to 5 membered monocyclic heterocyclyl and 5 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、C 1-4 Alkoxy and 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)N(R 11 )(R 11 )、C 1-4 Alkoxy and 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is optionally substituted with 1 to 2 groups independently selected from oxo, -NR 11 R 11 、-C(O)N(R 11 )(R 11 ) And 4 to 7 membered monocyclic heterocyclyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is optionally substituted with one independently selected from-C (O) NH 2 and-C (O) NHCH 3 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is optionally substituted with a-C (O) NH group 2 Methyl substituted by a group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is substituted with 1 to 4R b And (3) group substitution. In the formula I or IIIn some embodiments of the compound or pharmaceutically acceptable salt thereof, one or both R 8 Is c 1-6 Alkyl, wherein C 1-6 Alkyl is substituted with 1 to 3R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Alkoxy and R 8 a is substituted by a group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Groups substituted with alkoxy, 4 to 7 membered monocyclic heterocyclyl and 5 to 6 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Groups substituted with alkoxy, 4 to 5 membered monocyclic heterocyclyl and 5 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、C 1-4 Alkoxy and 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、-C(O)N(R 11 )(R 11 )、C 1-4 Alkoxy and 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, -CN, oxo, -NR by 1 to 2 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)NR 11 R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 ) Group substitution of 4 to 5 membered monocyclic heterocyclyl and 5 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, oxo, -NR by 1 to 2 11 R 11 、-C(O)NR 11 R 11 、-S(O) 2 R 11a And 4 to 5 membered monocyclic heterocyclyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from the group consisting of-OH, -CN, oxo, -NH by 1 to 3 2 、-N(CH 3 ) 2 -C (O) (azetidinyl), -C (O) OH, -C (O) OCH (CH) 3 ) 3 、-C(O)NH 2 、-C(O)NH 2 、-C(O)NH(CH 3 )、-C(O)NH(CH 2 CH 3 )、-C(O)NH(CH(CH 3 ) 2 ) -C (O) NH (cyclopropyl, yl), -C (O) NH (oxetanyl), -C (O) N (CH) 3 ) 2 、-S(O) 2 CH 3 、-S(O) 2 NH 2 、-S(O) 2 NH(CH 3 )、-S(O) 2 N(CH 3 ) 2 4 to 5 membered monocyclic heterocyclyl and 5 membered monocyclic heteroarylAnd (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, oxo, -NH by 1 to 3 2 、-N(CH 3 ) 2 、-C(O)NH 2 、-C(O)N(CH 3 ) 2 、-S(O) 2 CH 3 And 4-membered monocyclic heterocyclyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, oxo, -NH by 1 to 3 2 、-N(CH 3 ) 2 、-C(O)NH 2 、-C(O)N(CH 3 ) 2 And 4-membered monocyclic heterocyclyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, oxo, -N (CH) 3 ) 2 、-C(O)NH 2 、-S(O) 2 CH 3 And oxetanyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, oxo, -N (CH) 3 ) 2 、-C(O)NH 2 And oxetanyl groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Alkoxy and R 8a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl group, itMiddle C 1-3 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Groups substituted with alkoxy, 4 to 7 membered monocyclic heterocyclyl and 5 to 6 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、-S(O)2N(R 11 )(R 11 )、C 1-4 Groups substituted with alkoxy, 4 to 5 membered monocyclic heterocyclyl and 5 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、-C(O)N(R 11 )(R 11 )、-S(O) 2 R 11a 、C 1-4 Alkoxy and 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、-C(O)N(R 11 )(R 11 )、C 1-4 Alkoxy and 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is independently selected from-OH, -CN, oxo, -NR by 1 to 2 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)NR 11 R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 ) Group substitution of 4 to 5 membered monocyclic heterocyclyl and 5 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, oxo, -NR by 1 to 2 11 R 11 、-C(O)NR 11 R 11 、-S(O) 2 R 11a And 4 to 5 membered monocyclic heterocyclyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is independently selected from oxo, -NR by 1 to 2 11 R 11 、-C(O)N(R 11 )(R 11 ) And 4 to 7 membered monocyclic heterocyclyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is independently selected from the group consisting of-OH, -CN, oxo, -NH by 1 to 3 2 、-N(CH 3 ) 2 -C (O) (azetidinyl), -C (O) OH, -C (O) OCH (CH) 3 ) 3 、-C(O)NH 2 、-C(O)NH 2 、-C(O)NH(CH 3 )、-C(O)NH(CH 2 CH 3 )、-C(O)NH(CH(CH 3 ) 2 ) -C (O) NH (cyclopropyl), -C (O) NH (oxetanyl), -C (O) N (CH) 3 ) 2 、-S(O) 2 CH 3 、-S(O) 2 NH 2 、-S(O) 2 NH(CH 3 )、-S(O) 2 N(CH 3 ) 2 Group substitution of 4 to 5 membered monocyclic heterocyclyl and 5 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl groups are independently selected from the group consisting of-OH, -CN, oxo, pyrrolidinyl, 1 to 3,
And->Is substituted with a group of (a).
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is independently selected from-C (O) NH 2 and-C (O) NHCH 3 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is covered by a-C (O) NH group 2 Methyl substituted by a group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-3 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, oxo, -N (CH) 3 ) 2 、-C(O)NH 2 、-C(O)NHCH 3 、-S(O) 2 CH 3 Group substitutions of oxetanyl and pyrrolidinyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, oxo, -N (CH) 3 ) 2 、-C(O)NH 2 、-C(O)NHCH 3 Group substitutions of oxetanyl and pyrrolidinyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is substituted with 1 to 4R a And (3) group substitution. In a compound of formula I or IIIn some embodiments of pharmaceutically acceptable salts thereof, one or both R 8 Is C 3-7 A monocyclic cycloalkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 The fused bicyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 Fused bicyclic cycloalkyl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 7-10 Fused bicyclic cycloalkyl groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl groups are substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is C 5-10 Bridged bicyclic cycloalkyl groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 4-to 7-membered monocyclic heterocyclic groupWherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 8b Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 4-to 7-membered monocyclic heterocyclic group, wherein the 4-to 7-membered monocyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 4-to 7-membered monocyclic heterocyclic group, wherein the 4-to 7-membered monocyclic heterocyclic group is substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 8b Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 4 to 7 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 5-to 6-membered monocyclic heterocyclic group, wherein the 5-to 6-membered monocyclic heterocyclic group is optionallyGround cover 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 5-to 6-membered monocyclic heterocyclic group, wherein the 5-to 6-membered monocyclic heterocyclic group is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 5-to 6-membered monocyclic heterocyclyl, wherein 5-to 6-membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 5-to 6-membered monocyclic heterocyclic group, wherein the 5-to 6-membered monocyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 5-to 6-membered monocyclic heterocyclic group, wherein the 5-to 6-membered monocyclic heterocyclic group is substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 5-to 6-membered monocyclic heterocyclyl wherein the 5-to 6-membered monocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 5-to 6-membered monocyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is phenyl, wherein phenyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is phenyl, wherein phenyl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is phenyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is naphthyl, wherein naphthyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is naphthyl, wherein the naphthyl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a naphthyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 8b Is substituted with a group of (a).
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 5 to 6 membered monocyclic heteroaryl, wherein the 5 to 6 membered monocyclic heteroaryl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R8 Is a 5 to 6 membered monocyclic heteroaryl, wherein the 5 to 6 membered monocyclic heteroaryl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 8b Is substituted with a group of (a).
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 5 to 6 membered monocyclic heteroaryl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 8-to 10-membered fused bicyclic heterocyclic groupWherein the 8-to 10-membered fused bicyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is an 8-to 10-membered fused bicyclic heterocyclic group in which the 8-to 10-membered fused bicyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is an 8-to 10-membered fused bicyclic heterocyclic group in which the 8-to 10-membered fused bicyclic heterocyclic group is substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is an 8-to 10-membered fused bicyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 6 to 10 membered bridgeA bridged bicyclic heterocyclic group wherein the 6 to 10 membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 8b Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 groups 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 8b Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 groups 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In the formula I or IIOr a pharmaceutically acceptable salt thereof, one or both R 8 Is a 6-to 10-membered bridged bicyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 7-to 8-membered bridged bicyclic heterocyclic group, wherein the 7-to 8-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 7-to 8-membered bridged bicyclic heterocyclic group, wherein the 7-to 8-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 7-to 8-membered bridged bicyclic heterocyclic group, wherein the 7-to 8-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 7-to 8-membered bridged bicyclic heterocyclic group, wherein the 7-to 8-membered bridged bicyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 7-to 8-membered bridged bicyclic heterocyclic group, wherein the 7-to 8-membered bridged bicyclic heterocyclic group is substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 7-to 8-membered bridged bicyclic heterocyclic group, wherein the 7-to 8-membered bridged bicyclic heterocyclic group is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 groups 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 7-to 8-membered bridged bicyclic heterocyclic group.
Some embodiments of the compounds of formula I or II or pharmaceutically acceptable salts thereofIn embodiments, one or two R 8 Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 8b Is substituted with a group of (a).
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 7-to 10-membered spirocyclic heterocyclic group in which the 7-to 10-membered spirocyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 7-to 10-membered spirocyclic heterocyclyl wherein the 7-to 10-membered spirocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 8b Is substituted with a group of (a).
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 Is a 7-to 10-membered spirocyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Independently is a 4 to 7 membered monocyclic heterocyclyl or a 6 to 10 membered bridged bicyclic heterocyclyl,
wherein 4 to 7 membered monocyclic heterocyclyl and 6 to 10 membered bridged bicyclic heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Independently is a 4 to 7 membered monocyclic heterocyclyl or a 6 to 10 membered bridged bicyclic heterocyclyl,
wherein 4 to 7 membered monocyclic heterocyclyl and 6 to 10 membered bridged bicyclic heterocyciylThe cyclic groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substituted by alkyl radicals, and
wherein the 4-to 7-membered monocyclic heterocyclyl and the 6-to 10-membered bridged bicyclic heterocyclyl each independently have one or two ring heteroatoms independently selected from N and S.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each
R 8 Independently is a 5-to 6-membered monocyclic heterocyclic group or a 7-to 8-membered bridged bicyclic heterocyclic group,
wherein 5-to 6-membered monocyclic heterocyclyl and 7-to 8-membered bridged bicyclic heterocyclyl are each independently optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Is oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
Each of them is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Is oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
Each of which is optionally substituted with 1 to 3 groups independently selected from halogen and oxo.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Independently of the above, is a piperazinyl group,
each of them is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Independently is
Each of them is substituted with 1 to 2 oxo groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Independently is
Each of them is substituted with 1 to 2 oxo groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Independently is
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Independently is
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Independently 7 to 10 membered spirocyclic heterocyclyl wherein 7 to 10 membered spirocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Independently is a 7 to 10 membered spirocyclic heterocyclyl, wherein the 7 to 10 membered spirocyclic heterocyclyl is optionally substituted with 1 to 3 oxo groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Independently is
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Independently is
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Independently is a 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 8b Is substituted with a group of (a).
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Independently is a 5 to 6 membered monocyclic heteroaryl, wherein the 5 to 6 membered monocyclic heteroaryl is optionally substituted with one R 8b And (3) substitution.
Compounds of formula I or II or medicaments thereofIn some embodiments of the pharmaceutically acceptable salts, each R 8 Independently is
Each of them is optionally substituted with one R 8b And (3) substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8b Independently a 6 to 7 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8b Independently a 6 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8b Independently morpholinyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 8 is-C (O) R 9 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 is-C (O) R 9 。
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 9 Independently C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally substituted with 1-4R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 9 Independently C 3-7 Monocyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl or 7-to 10-membered spiroheterocyclyl, wherein C 3-7 Monocyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, and 7-to 10-membered spiro heterocyclyl each independently are optionally substituted with 1 to 4R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 9 Independently is a 4 to 7 membered monocyclic heterocyclyl, a 6 to 10 membered bridged bicyclic heterocyclyl, or a 7 to 10 membered spiro heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl, 6 to 10 membered bridged bicyclic heterocyclyl, or 7 to 10 membered spiro heterocyclyl are each optionally substituted with 1 to 4R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 9 Independently is a 4 to 7 membered monocyclic heterocyclyl or a 6 to 10 membered bridged bicyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl and 6 to 10 membered bridged bicyclic heterocyclyl are each optionally substituted with 1 to 4R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 9 Independently c 3-7 Monocyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl or 7-to 10-membered spiroheterocyclyl, wherein C 3-7 Monocyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, and 7-to 10-membered spiro heterocyclyl each independently are optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted with a group of (a).
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 9a Independently 4 to 7 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 9 Independently 4 to 7 membered monocyclic heterocyclyl, 6 to 10 membered bridged bicyclic heterocyclyl, or 7 to 10 membered spiro heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl, 6 to 10 membered bridged bicyclic heterocyclyl, and 7 to 10 membered spiro heterocyclyl are each optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 9 Independently 4 to 7 membered monocyclic heterocyclyl or 6 to 10 membered bridged bicyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl and 6 to 10 membered bridged bicyclic heterocyclyl are each optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is C 3-7 A monocyclic cycloalkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 The fused bicyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 Fused bicyclic cycloalkyl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is C 7-10 Fused bicyclic cycloalkyl groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl groups are substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is C 5-10 Bridged bicyclic cycloalkyl groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is phenyl, wherein phenyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is phenyl, wherein phenyl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is phenyl group。
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is naphthyl, wherein naphthyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is naphthyl, wherein the naphthyl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a naphthyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 5 to 6 membered monocyclic heteroaryl, wherein the 5 to 6 membered monocyclic heteroaryl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 5 to 6 membered monocyclic heteroaryl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is an 8-to 10-membered fused bicyclic heterocyclic group in which the 8-to 10-membered fused bicyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one orTwo R 9 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is an 8-to 10-membered fused bicyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is an 8-to 10-membered fused bicyclic heteroaryl group, wherein the 8-to 10-membered fused bicyclic heteroaryl group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is an 8-to 10-membered fused bicyclic heteroaryl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. Some embodiments of the compounds of formula I or II or pharmaceutically acceptable salts thereofIn embodiments, one or two R 9 Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, -NR 11 R 11 、C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 7-to 10-membered spirocyclic heterocyclic group in which the 7-to 10-membered spirocyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 7-to 10-membered spirocyclic heterocyclyl wherein the 7-to 10-membered spirocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 7-to 10-membered spirocyclic heterocyclyl wherein the 7-to 10-membered spirocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 7-to 10-membered spirocyclic heterocyclyl wherein the 7-to 10-membered spirocyclic heterocyclyl is independently selected from the group consisting of-OH, halogen, -CN, -NR by 1 to 3 11 R 11 、C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 7-to 10-membered spirocyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 4 to 7 membered monocyclic heterocyclyl wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH,Halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R i1 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 4-to 7-membered monocyclic heterocyclic group, wherein the 4-to 7-membered monocyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 4 to 7 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 5-to 7-membered monocyclic heterocyclyl, wherein 5-to 7-membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 5-to 7-membered monocyclic heterocyclyl, wherein 5-to 7-membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 5-to 7-membered monocyclic heterocycle, wherein 5-to 7-membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, -NR 11 R 11 、C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 5-to 7-membered monocyclic heterocyclic group, wherein the 5-to 7-membered monocyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 5-to 7-membered monocyclic heterocyclyl wherein the 5-to 7-membered monocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 5-to 7-membered monocyclic heterocycle wherein 5-to 7-membered monocyclic heterocyclyl is independently selected from-OH, halogen, -CN, -NR by 1 to 3 11 R 1l 、C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 5-to 7-membered monocyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 4 to 6 membered monocyclic heterocyclyl, wherein 4 to 6 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 4 to 6 membered monocyclic heterocyclyl wherein 4 to 6 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one orTwo R 9 Is a 4 to 6 membered monocyclic heterocycle wherein 4 to 6 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, -NR 11 R 11 、C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 4 to 6 membered monocyclic heterocycle wherein the 4 to 6 membered monocyclic heterocyclyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 4-to 6-membered monocyclic heterocyclic group, wherein the 4-to 6-membered monocyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 4 to 6 membered monocyclic heterocyclyl wherein the 4 to 6 membered monocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 4 to 6 membered monocyclic heterocycle wherein the 4 to 6 membered monocyclic heterocyclyl is independently selected from-OH, halogen, -CN, -NR by 1 to 3 11 R 11 、C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 4-to 6-membered monocyclic heterocycle wherein the 4-to 6-membered monocyclic heterocyclyl is substituted with 1 to 2 groups independently selected from-OH, halogen, C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 4-to 6-membered monocyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution. In formula IOr a compound of II or a pharmaceutically acceptable salt thereof, one or both R 9 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 6-to 10-membered bridged bicyclic heterocycle wherein the 6-to 10-membered bridged bicyclic heterocycle is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, -NR 11 R 11 、C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 groups 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 groups 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 6-to 10-membered bridged bicyclic heterocycle wherein the 6-to 10-membered bridged bicyclic heterocycle is independently selected from the group consisting of-OH, halogen, -CN, -NR by 1 to 3 11 R 11 、C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 9 Is a 6-to 10-membered bridged bicyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 9 Is C 3-5 Monocyclic cycloalkyl wherein C 3-5 Monocyclic cycloalkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and 4 to 7 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 9 Is cyclopropyl, wherein cyclopropyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, C 1-3 Alkoxy, C 1-3 Alkyl and 5 to 6 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 9 Is cyclopropyl, wherein the cyclopropyl is substituted with morpholinyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 9 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 9 Is a 4-to 7-membered monocyclic heterocyclic group,
wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group; and is also provided with
Wherein the 4-to 7-membered monocyclic heterocyclyl has one or two ring heteroatoms which are N.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 9 Is a 4 to 6 membered monocyclic heterocyclyl wherein the 4 to 6 membered monocyclic heterocyclyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -NH 2 、C 1-3 Alkoxy and C 1-3 The alkyl group is substituted and wherein the 4 to 6 membered monocyclic heterocyclic group has one ring heteroatom which is N.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 9 Is a 4 to 6 membered monocyclic heterocyclyl wherein 4 to 6 membered monocyclic heterocyclyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, C 1-3 Alkoxy and C 1-3 The alkyl group is substituted and wherein the 4 to 6 membered monocyclic heterocyclic group has one ring heteroatom which is N.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 9 Independently azetidinyl or pyrrolidinyl, each of which is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 9 Independently is
Each of which is optionally substituted with one methyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 9 Independently oxetanyl, pyrrolidinyl, piperazinyl, or morpholinyl, each of which is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II or pharmaceutically acceptable salts thereofIn the scheme, each R 9 Independently pyrrolidinyl, piperazinyl, or morpholinyl, each of which is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 9 Independently is an 8-to 10-membered fused bicyclic heterocyclyl, wherein the 8-to 10-membered fused bicyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 9 Independently is an 8-to 10-membered fused bicyclic heterocyclic group,
wherein the 8-to 10-membered fused bicyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substituted by alkyl radicals, and
wherein the 8-to 10-membered fused bicyclic heterocyclic group has 1 to 3 ring heteroatoms independently selected from N and O.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 9 Independently is
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 9 Is optionally 1 to 2 independently selected from-OH, halogen, C 1-3 Alkoxy and C 1-3 A 6 to 10 membered bridged bicyclic heterocyclic group substituted with a group of an alkyl group, and wherein the 6 to 10 membered bridged bicyclic heterocyclic group has one ring heteroatom which is N.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 9 Is that
Each of which is optionally substituted with 1 to 3 groups independently selected from fluoro, methoxy and methyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 9 Is optionally 1 to 2 independently selected from-OH, halogen, C 1-3 Alkoxy and C 1-3 A 7-to 10-membered spirocyclic heterocyclic group substituted with a group of alkyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 9 Is a 9 membered monocyclic heterocyclyl having 1 to 2 ring heteroatoms independently selected from N and O.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 9 Is that
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 8 Is independently-NR 10 R 10 or-S (O) 2 R 5a 。
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 is-NR 10 R 10 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 8 is-S (O) 2 R 5a 。
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is-C (O) NR 6 R 7 or-S (O) 2 R 6 。
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is-S (O) 2 R 6 。
Some embodiments of the compounds of formula I or II or pharmaceutically acceptable salts thereofIn embodiments, Z is-C (O) NR 6 R 7 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is-C (O) N (H) R 6 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is-C (O) N (CH 3 )R 6 。
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally substituted with 1-4R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-6 Alkyl or 4 to 7 membered monocyclic heterocyclyl,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 3R b The substitution of the groups is carried out,
wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-6 Alkyl or 4 to 7 membered monocyclic heterocyclyl,
wherein C is 1-6 Alkyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -NR 11 R 11 And C 1-3 The group of the alkoxy group is substituted,
wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, -NR 11 R 11 、C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substituted by alkyl radicals, and wherein C 1-4 Alkoxy and C 1-5 Alkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted with a group of (a).
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 And C 1-4 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 And C 1-3 The groups of the alkoxy groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is substituted with 1 to 4R b And (3) group substitution. Some embodiments of the compounds of formula I or II or pharmaceutically acceptable salts thereofIn embodiments, R 6 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is substituted with 1 to 3R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 And C 1-4 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 2 11 R 11 And C 1-3 The groups of the alkoxy groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-6 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-4 Alkyl, wherein C 1-4 Alkyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-4 Alkyl, wherein C 1-4 Alkyl is optionally substituted with 1 to 3R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-4 Alkyl, wherein C 1-4 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 And C 1-4 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-4 Alkyl, wherein C 1-4 Alkyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 And C 1-3 The groups of the alkoxy groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-4 Alkyl, wherein C 1-4 Alkyl is substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-4 Alkyl, wherein C 1-4 Alkyl is substituted with 1 to 3R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-4 Alkyl, wherein C 1-4 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 And C 1-4 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-4 Alkyl, wherein C 1-4 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 2 11 R 11 And C 1-3 The groups of the alkoxy groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is optionally covered with a-NR 11 R 11 Substituted C 1-4 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is independently selected from-NH 2 、NH(CH 3 ) And N (CH) 3 ) 2 C substituted by a group of (C) 1-4 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 1-4 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 3-7 A monocyclic cycloalkyl group.
A compound of formula I or II or a pharmaceutically acceptable thereofIn some embodiments of the salts of R 6 Is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 The fused bicyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 Fused bicyclic cycloalkyl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 7-10 Fused bicyclic cycloalkyl groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl groups are substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is C 5-10 Bridged bicyclic cycloalkyl groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-4 Alkoxy and C 1-5 Alkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 4 to 7 membered monocyclic heterocyclyl wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, -NR 11 R 11 、C1- 3 Alkoxy and C 1 - 3 Radical substitution of alkyl radicals, where C 1-3 Alkoxy and C 1-3 Alkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 5-to 6-membered monocyclic heterocyclyl, wherein 5-to 6-membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, -NR 11 R 11 、C 1-3 Alkoxy and C 1-3 Radical substitution of alkyl radicals, where C 1-3 Alkoxy and C 1-3 Alkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted with a group of (a).
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 4-to 7-membered monocyclic heterocyclic group, wherein the 4-to 7-membered monocyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 4-to 7-membered monocyclic heterocyclic group, wherein the 4-to 7-membered monocyclic heterocyclic group is substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-4 Alkoxy and C 1 - 5 Alkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 4-to 7-membered monocyclic heterocyclic group, wherein 4-to 7-membered monocyclic ring isHeterocyclyl is independently selected from-OH, halogen, -CN, -NR by 1 to 3 11 R 11 、C 1-3 Alkoxy and C 1-3 Radical substitution of alkyl radicals, where C 1-3 Alkoxy and C 1-3 Alkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 5-to 6-membered monocyclic heterocyclic group, wherein the 5-to 6-membered monocyclic heterocyclic group is independently selected from-OH, halogen, -CN, -NR by 1 to 3 groups 11 R 11 、C 1-3 Alkoxy and C 1-3 Radical substitution of alkyl radicals, where C 1-3 Alkoxy and C 1-3 Alkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted with a group of (a).
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 5-to 6-membered monocyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 4-to 7-membered monocyclic heterocyclic group,
wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-4 Alkoxy and C 1-5 Alkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted by a group of (2); and is also provided with
Wherein the 4-to 7-membered monocyclic heterocyclyl has one or two ring heteroatoms which are N.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 5-to 6-membered monocyclic heterocyclic group,
wherein the 5-to 6-membered heterocyclyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN and C 1-5 Alkoxy groupIs substituted by a group of (C) and
wherein C is 1-5 The alkyl group is optionally substituted with 1 to 2 groups independently selected from-OH and halogen.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN and C 1-5 Radical substitution of alkyl radicals, where C 1-5 The alkyl group is optionally substituted with 1 to 2 groups independently selected from-OH and halogen.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted with one C 1-3 Alkyl group substitution wherein C 1-3 The alkyl group is optionally substituted with 1 to 2 groups independently selected from-OH and halogen.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is that
Each of them is optionally C 1-3 Alkyl substitution, wherein C 1-3 The alkyl group is substituted with one-OH group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is phenyl, wherein phenyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is phenyl, wherein phenyl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is phenyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is naphthyl, wherein naphthyl is optionally substituted with 1 to 4R a And (3) group substitution. Compounds of formula I or II or pharmaceutical compositions thereof In some embodiments of the above acceptable salts, R 6 Is naphthyl, wherein the naphthyl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a naphthyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 5 to 6 membered monocyclic heteroaryl, wherein the 5 to 6 membered monocyclic heteroaryl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 5 to 6 membered monocyclic heteroaryl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is an 8-to 10-membered fused bicyclic heterocyclic group in which the 8-to 10-membered fused bicyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is an 8-to 10-membered fused bicyclic heterocyclic group in which the 8-to 10-membered fused bicyclic heterocyclic group is substituted with 1 to 3R a And (3) group substitution. In the formula I or II or in the formula IIIn some embodiments of the pharmaceutically acceptable salts, R 6 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is an 8-to 10-membered fused bicyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 groups 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 6-to 10-membered bridged bicyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 7-to 10-membered spirocyclic heterocyclic group in which the 7-to 10-membered spirocyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 6 Is a 7-to 10-membered spirocyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is H, C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl or 4-to 6-membered monocyclic heterocyclyl, wherein C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl and 4-to 6-membered monocyclic heterocyclyl are each independently optionally selected from the group consisting of-OH, halogen, -CN, and C, optionally by 1 to 4 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is H or C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 The groups of the alkoxy groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is H or C 1-3 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is H or methyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is H.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 The groups of alkoxy groups being takenAnd (3) replacing. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is independently selected from-OH, halogen, -CN and C by 1 to 4 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is C 1-6 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is C 1-3 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is methyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is independently selected from-OH, halogen, -CN and C by 1 to 4 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is C 3-7 A monocyclic cycloalkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is a 4 to 6 membered monocyclic heterocyclyl wherein 4 to 6 membered monocyclic heterocyclyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is a 4 to 6 membered monocyclic heterocyclyl wherein the 4 to 6 membered monocyclic heterocyclyl is substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 The groups of the alkoxy groups are substituted. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is a 4-to 6-membered monocyclic heterocyclic group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 7 Is oxetanyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, Z is-C (O) R 13 。
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally substituted with 1-4R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 4-to 7-membered monocyclic heterocyclic group, a 8-to 10-membered fused bicyclic heterocyclic group, a 6-to 10-membered bridged bicyclic heterocyclic group or a 7-to 10-membered spiro heterocyclic group,
Wherein 4 to 7 membered monocyclic heterocyclyl, 8 to 10 membered fused bicyclic heterocyclyl, 6 to 10 membered bridged bicyclic heterocyclyl and 7 to 10 membered spiro heterocyclyl are each independently optionally substituted with 1 to 3R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 4-to 7-membered monocyclic heterocyclic group, a 8-to 10-membered fused bicyclic heterocyclic group, a 6-to 10-membered bridged bicyclic heterocyclic group or a 7-to 10-membered spiro heterocyclic group,
wherein 4 to 7 membered monocyclic heterocyclyl, 8 to 10 membered fused bicyclic heterocyclyl, 6 to 10 membered bridged bicyclic heterocyclyl, and 7 to 10 membered spiro heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals，
Wherein C is 1-5 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 Is substituted with a group of (a).
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 4-to 7-membered monocyclic heterocyclic group, a 8-to 10-membered fused bicyclic heterocyclic group, a 6-to 10-membered bridged bicyclic heterocyclic group or a 7-to 10-membered spiro heterocyclic group,
wherein 4 to 7 membered monocyclic heterocyclyl, 8 to 10 membered fused bicyclic heterocyclyl, 6 to 10 membered bridged bicyclic heterocyclyl, and 7 to 10 membered spiro heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The group of the alkyl group is substituted,
wherein C is 1-5 Alkyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted by a group of (C) and
wherein each R is 12 Independently H or C 1-3 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is C 3-7 A monocyclic cycloalkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 The fused bicyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 Fused bicyclic cycloalkyl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is C 7-10 Fused bicyclic cycloalkyl groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl groups are substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is C 5-10 Bridged bicyclic cycloalkyl groups.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-5 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The radicals of alkyl radicals being takenGeneration of C 1-5 Alkyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 And wherein each R is substituted with a group 12 Independently H or C 1-3 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 4-to 7-membered monocyclic heterocyclic group, wherein the 4-to 7-membered monocyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 4-to 7-membered monocyclic heterocyclic group, wherein the 4-to 7-membered monocyclic heterocyclic group is substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-5 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-5 Alkyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 And wherein each R is substituted with a group 12 Independently H or C 1-3 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted. In some embodiments of the compounds of formula I or II or pharmaceutically acceptable salts thereofIn the scheme, R 13 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 4-to 7-membered monocyclic heterocyclic group,
wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group; and is also provided with
Wherein the 4-to 7-membered monocyclic heterocyclyl has one or two ring heteroatoms which are N.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 5-to 6-membered monocyclic heterocyclyl, wherein 5-to 6-membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 5-to 6-membered monocyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is piperazinyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is phenyl, wherein phenyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is phenyl, wherein phenyl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is phenyl.
In formula I or IIIn some embodiments of the compound or pharmaceutically acceptable salt thereof, R 13 Is naphthyl, wherein naphthyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is naphthyl, wherein the naphthyl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a naphthyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 5 to 6 membered monocyclic heteroaryl, wherein the 5 to 6 membered monocyclic heteroaryl is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 5 to 6 membered monocyclic heteroaryl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-5 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is an 8-to 10-membered fused bicyclic heterocyclic group in whichThe 8-to 10-membered fused bicyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-5 Alkyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 And wherein each R is substituted with a group 12 Independently H or C 1-3 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is an 8-to 10-membered fused bicyclic heterocyclic group in which the 8-to 10-membered fused bicyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is an 8-to 10-membered fused bicyclic heterocyclic group in which the 8-to 10-membered fused bicyclic heterocyclic group is substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-5 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-5 Alkyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 And wherein each R is substituted with a group 12 Independently H or C 1-3 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is an 8-to 10-membered fused bicyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-5 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-5 Alkyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 And wherein each R is substituted with a group 12 Independently H or C 1-3 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 6-to 10-membered bridged bicyclic heteroA cyclic group wherein the 6-to 10-membered bridged bicyclic heterocyclic group is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-5 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 groups 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-5 Alkyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 And wherein each R is substituted with a group 12 Independently H or C 1-3 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 6-to 10-membered bridged bicyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-5 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-5 Alkyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 And wherein each R is substituted with a group 12 Independently H or C 1-3 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 7-to 10-membered spirocyclic heterocyclic group in which the 7-to 10-membered spirocyclic heterocyclic group is substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 7-to 10-membered spirocyclic heterocyclic group in which the 7-to 10-membered spirocyclic heterocyclic group is substituted with 1 to 3R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 7-to 10-membered spirocyclic heterocyclyl wherein the 7-to 10-membered spirocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-5 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 7-to 10-membered spirocyclic heterocyclyl wherein the 7-to 10-membered spirocyclic heterocyclyl is substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of alkyl radicals, where C 1-5 Alkyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo and-NR 12 R 12 And wherein each R is substituted with a group 12 Independently H or C 1-3 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 13 Is a 7-to 10-membered spirocyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 5 H, C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
Wherein C is 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl groups are each independently optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally substituted with 1-4R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5 Is H. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5 Is C 2-6 Alkenyl group, wherein C 2-6 Alkenyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5 Is C 2-6 Alkynyl group, wherein C 2-6 Alkynyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkylOptionally by 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5 Is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 The fused bicyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5 Is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5 Is phenyl, wherein phenyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5 Is naphthyl, wherein naphthyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5 Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5 Is a 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5 Is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 4R a And (3) group substitution. Compounds of formula I or II or pharmaceutical compositions thereofIn some embodiments of the above acceptable salts, one or more R 5 Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 10 H, C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl groups are each independently optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein c 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally substituted with 1-4R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 10 Independently H or 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 10 Is H. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 10 Is a 4 to 7 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 10 Independently H or C 1-6 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 10 Independently H or C 1-3 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is H. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is C 1-3 Alkyl, wherein C 1-3 Alkyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is C 1-3 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is C 2-6 Alkenyl group, wherein C 2-6 Alkenyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is C 2 - 6 Alkynyl group, wherein C 2-6 Alkynyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 The fused bicyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is phenyl, wherein phenyl is optionally substituted with 1 to 4R a And (3) group substitution. In the formula I or II or in the formula IIIn some embodiments of the pharmaceutically acceptable salts, one or both R 10 Is naphthyl, wherein naphthyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is a 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or both R 10 Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 10 Independently H or 4-to 6-membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 10 Independently H or oxetanyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 5a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl groups are each independently optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl, each independently, optionally substituted with 1-4R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 5a Independently 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 5a Independently 4 to 7 membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5a Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5a Is C 2-6 Alkenyl group, wherein C 2-6 Alkenyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5a Is C 2-6 Alkynyl group, wherein C 2-6 Alkynyl is optionally substituted with 1 to 4R b And (3) group substitution. In some embodiments of the compounds of formula I or II or pharmaceutically acceptable salts thereof,one or more R 5a Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5a Is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 The fused bicyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5a Is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5a Is phenyl, wherein phenyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5a Is naphthyl, wherein naphthyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5a Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5a Is a 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5a Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5a Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5a Is an 8 to 10 membered fused bicyclic heteroaryl group, wherein 8 toThe 10 membered fused bicyclic heteroaryl is optionally substituted with 1 to 4R a And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 5a Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 4R a And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 5a Is a 4-to 6-membered monocyclic heterocyclic group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 5a Is piperazinyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R a Independently oxo, imino, halogen, -NO 2 、-N 3 、-CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-NR 11 R 11 、-N(R 11 ) 2 (R 11 ) + 、-N(R 11 )C(O)R 11 、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)N(R 11 )(R 11 )、-N(R 11 )S(O) 2 (R 11a )、-NR 11 S(O) 2 N(R 11 )(R 11 )、-NR 11 S(O) 2 O(R 11a )、-OC(O)R 11 、-OC(O)OR 11 、-OC(O)N(R 11 )(R 11 )、-SR 11 、-S(O)R 11a 、-S(O)(NH)R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 ) Or-n=s (R 11a )(R 11a )＝O，
Wherein C is 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl groups are each independently optionally substituted with 1 to 3R c Substituted with radicals, and
wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl each independently optionally being substituted with 1-3R d And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R a independently-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy or C 1-5 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R a independently-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-3 Alkoxy or C 1-3 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is oxo. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is an imino group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is halogen. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-NO 2 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-N 3 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-CN. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-OR 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-C (O) R 11 . At the position ofIn some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-C (O) OR 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-C (O) N (R) 11 )(R 11 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-NR 11 R 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-N (R) 11 ) 2 (R 11 ) + . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-N (R) 11 )C(O)R 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-N (R) 11 )C(O)OR 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-N (R) 11 )C(O)N(R 11 )(R 11 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-N (R) 11 )S(O) 2 (R 11a ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-NR 11 S(O) 2 N(R 11 )(R 11 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-NR 11 S(O) 2 O(R 11a ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-OC (O) R 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-OC (O) OR 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-OC (O) N (R) 11 )(R 11 ). Compounds of formula I or II or pharmaceutical compositions thereofIn some embodiments of the above acceptable salts, one or more R a is-SR 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-S (O) R 11a . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-S (O) (NH) R 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-S (O) 2 R 11a . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a is-S (O) 2 N(R 11 )(R 11 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is-n=s (R 11a )(R 11a )＝O。
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is C 2-6 Alkenyl group, wherein C 2-6 Alkenyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is C 2-6 Alkynyl group, wherein C 2-6 Alkynyl is optionally substituted with 1 to 3R c And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 The fused bicyclic cycloalkyl is optionally substituted with 1 to 3R d And (3) group substitution. Compounds of formula I or II or medicaments thereofIn some embodiments of the pharmaceutically acceptable salts, one or more R a Is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is phenyl, wherein phenyl is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is naphthyl, wherein naphthyl is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is a 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R a Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 3R d And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R b Independent and independentIs oxo, imino, halogen, -NO 2 、-N 3 、-CN、C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-NR 11 R 11 、-N(R 11 ) 2 (R 11 ) + 、-N(R 11 )C(O)R 11 、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)N(R 11 )(R 11 )、-N(R 11 )S(O) 2 (R 11a )、-NR 11 S(O) 2 N(R 11 )(R 11 )、-NR 11 S(O) 2 O(R 11a )、-OC(O)R 11 、-OC(O)OR 11 、-OC(O)N(R 11 )(R 11 )、-SR 11 、-S(O)R 11a 、-S(O)(NH)R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 ) Or-n=s (R 11a )(R 11a )＝O，
Wherein C is 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl each independently optionally being substituted with 1-3R d And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R b independently-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heteroarylA cyclic group, an 8-to 10-membered bridged bicyclic heterocyclic group, a 6-to 10-membered bridged bicyclic heterocyclic group, an 8-to 10-membered fused bicyclic heteroaryl group, or a 7-to 10-membered spiro heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R a independently-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)N(R 11 )(R 11 )、C 1-4 Alkoxy or 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R b independently-OH, halogen, -CN, oxo, -NR 11 R 11 Or C 1-4 An alkoxy group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R b independently-OH, halogen, -CN, oxo, -NR 11 R 11 Or C 1-3 An alkoxy group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R b Independently halogen or C 1-3 An alkoxy group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R b Independently is a 4 to 7 membered monocyclic heterocyclyl, an 8 to 10 membered fused bicyclic heterocyclyl, or a 6 to 10 membered bridged bicyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is a 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is a 5-to 7-membered monocyclic heterocyclic group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is an 8-to 10-membered fused bicyclic heterocyclic group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is a 6-to 10-membered bridged bicyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is oxo. In some embodiments of the compounds of formula I or II or pharmaceutically acceptable salts thereof,one or more R b Is an imino group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is halogen. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-NO 2 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-N 3 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-CN. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-OR 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-C (O) R 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-C (O) OR 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-C (O) N (R) 11 )(R 11 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-NR 11 R 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-N (R) 11 ) 2 (R 11 ) + . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-N (R) 11 )C(O)R 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-N (R) 11 )C(O)OR 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-N (R) 11 )C(O)N(R 11 )(R 11 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-N (R) 11 )S(O) 2 (R 11a ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-NR 11 S(O) 2 N(R 11 )(R 11 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-NR 11 S(O) 2 O(R 11a ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-OC (O) R 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-OC (O) OR 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-OC (O) N (R) 11 )(R 11 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-SR 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-S (O) R 11a . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-S (O) (NH) R 11 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-S (O) 2 R 11a . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b is-S (O) 2 N(R 11 )(R 11 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is-n=s (R 11a )(R 11a )＝O。
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is C 7-10 Condensed withBicyclic cycloalkyl wherein C 7-10 The fused bicyclic cycloalkyl is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is phenyl, wherein phenyl is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is naphthyl, wherein naphthyl is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is a 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 3R d And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R b Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 3R d And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R b Independently halogen, -CN, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 12 、-C(O)R 12 、-C(O)OR 12 、-C(O)N(R 12 )(R 12 )、-NR 12 R 12 、-N(R 12 ) 2 (R 12 ) + 、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 12 )、-N(R 12 )S(O) 2 (R 12a )、-NR 12 S(O) 2 N(R 12 )(R 12 )、-NR 12 S(O) 2 O(R 12a )、-OC(O)R 12 、-OC(O)OR 12 、-OC(O)N(R 12 )(R 12 )、-SR 12 、-S(O)R 12a 、-S(O)(NH)R 12 、-S(O) 2 R 12a 、-S(O) 2 N(R 12 )(R 12 ) Or-n=s (R 12a )(R 12a )＝O。
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c Is halogen. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-CN. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c Is C 7-10 Fused bicyclic cycloalkyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c Is C 5-10 Bridged bicyclic cycloalkyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c Is phenyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c Is a naphthyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c Is a 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c Is a 5 to 6 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c Is an 8-to 10-membered fused bicyclic heterocyclic group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c Is a 6-to 10-membered bridged bicyclic heterocyclic group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c Is an 8-to 10-membered fused bicyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c Is a 7-to 10-membered spirocyclic heterocyclic group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-OR 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-C (O) R 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-C (O) OR 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-C (O) N (R) 12 )(R 12 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-NR 12 R 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-N (R) 12 ) 2 (R 12 ) + . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-N (R) 12 )C(O)R 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-N (R) 12 )C(O)OR 12 . In formula I orIn some embodiments of the compound of II or a pharmaceutically acceptable salt thereof, one or more R c is-N (R) 12 )C(O)N(R 12 )(R 12 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-N (R) 12 )S(O) 2 (R 12a ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-NR 12 S(O) 2 N(R 12 )(R 12 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-NR 12 S(O) 2 O(R 12a ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-OC (O) R 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-OC (O) OR 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-OC (O) N (R) 12 )(R 12 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-SR 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-S (O) R 12a . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-S (O) (NH) R 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-S (O) 2 R 12a . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-S (O) 2 N(R 12 )(R 12 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c Is-n=s (R 12a )(R 12a )＝O。
In the form of compounds of formula I or II or pharmaceutically acceptable salts thereofIn some embodiments of the accepted salts, each R c independently-OH, halogen, -CN, oxo or-NR 12 R 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R c independently-OH, halogen, -CN or-NR 12 R 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c is-OH. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R c Is halogen.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R c Independently oxo, halogen, -CN, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 12 、-C(O)R 12 、-C(O)OR 12 、-C(O)N(R 12 )(R 12 )、-NR 12 R 12 、-N(R 12 ) 2 (R 12 ) + 、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 12 )、-N(R 12 )S(O) 2 (R 12a )、-NR 12 S(O) 2 N(R 12 )(R 12 )、-NR 12 S(O) 2 O(R 12a )、-OC(O)R 12 、-OC(O)OR 12 、-OC(O)N(R 12 )(R 12 )、-SR 12 、-S(O)R 12a 、-S(O)(NH)R 12 、-S(O) 2 R 12a 、-S(O) 2 N(R 12 )(R 12 ) Or-n=s (R 12a )(R 12a )＝O。
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d Is oxo. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R is a number of d Is halogen. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-CN. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d Is C 7-10 Fused bicyclic cycloalkyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d Is C 5-10 Bridged bicyclic cycloalkyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d Is phenyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d Is a naphthyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d Is a 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d Is a 5 to 6 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d Is an 8-to 10-membered fused bicyclic heterocyclic group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d Is a 6-to 10-membered bridged bicyclic heterocyclic group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d Is an 8-to 10-membered fused bicyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d Is a 7-to 10-membered spirocyclic heterocyclic group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-OR 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-C (O) R 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-C (O) OR 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-C (O) N (R) 12 )(R 12 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-NR i2 R 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-N (R) 12 ) 2 (R 12 ) +. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-N (R) 12 )C(O)R 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-N (R) 12 )C(O)OR 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-N (R) 12 )c(O)N(R 12 )(R 12 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-N (R) 12 )S(O) 2 (R 12a ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-NR 12 S(O)2N(R 12 )(R 12 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-NR 12 S(O) 2 O(R 12a ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-OC (O) R 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-OC (O) OR 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-OC (O) N (R) 12 )(R 12 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-SR 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-S (O) R 12a . Compounds of formula I or II or medicaments thereofIn some embodiments of the pharmaceutically acceptable salts, one or more R d is-S (O) (NH) R 12 . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-S (O) 2 R 12a . In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d is-S (O) 2 N(R 12 )(R 12 ). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R d Is-n=s (R 12a )(R 12a )＝O。
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 11 H, C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein C is 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl each independently optionally being substituted with 1-3R c And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 11 H, C independently 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl or 4-to 7-membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 11 Independently H or C 1-4 Alkyl, wherein C 1-4 Alkyl is optionally substituted with one member selected from the group consisting of-OH and-NR 12 R 12 Is substituted with a group of (a). In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 11 Independently H or C 1-4 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 11 Independently H or C 1-3 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 11 Independently H or methyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 11 H, C independently 1-4 Alkyl, C 3-5 Monocyclic cycloalkyl or 4-to 6-membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, -NR 11 R 11 and-C (O) NR 11 R 11 Each R of (2) 11 Independently H or C 1-3 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is C 1-4 Alkyl, wherein C 1-4 Alkyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is methyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is H. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is C 2-6 Alkenyl group, wherein C 2-6 Alkenyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is C 2-6 Alkynyl group, wherein C 2-6 Alkynyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 The fused bicyclic cycloalkyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is phenyl, wherein phenyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is naphthyl, wherein naphthyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is a 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3R c And (3) group substitution. A compound of formula I or II or a pharmaceutically acceptable thereofIn some embodiments of the salts of (2) one or more R 11 Is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11 Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 3R c And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 11a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
Wherein C is 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl each independently optionally being substituted with 1-3R c And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11a Is C 1-6 Alkyl, wherein C 1-6 Alkyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 11a Independently C 1-4 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, R 11a Is C 1-3 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11a Is C 2-6 Alkenyl group, wherein C 2-6 Alkenyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11a Is C 2-6 Alkynyl group, wherein C 2-6 Alkynyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11a Is C 3-7 Monocyclic cycloalkyl wherein C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11a Is C 7-10 Fused bicyclic cycloalkyl wherein C 7-10 The fused bicyclic cycloalkyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11a Is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11a Is phenyl, wherein phenyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11a Is naphthyl, wherein naphthyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11a Is a 4 to 7 membered monocyclic heterocyclyl, wherein 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11a Is a 5 to 6 membered monocyclic heteroaryl, wherein 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11a Is an 8-to 10-membered fused bicyclic heterocyclic group, wherein the 8-to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 3R c Group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11a Is a 6-to 10-membered bridged bicyclic heterocyclic group, wherein the 6-to 10-membered bridged bicyclic heterocyclic group is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11a Is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 3R c And (3) group substitution. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 11a Is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 3R c And (3) group substitution.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 12 H, C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, or 7-to 10-membered spiro heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 12 Independently H or C 1-4 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 12 Independently H or C 1-3 An alkyl group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is H. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is C 1-6 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is C 1-4 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one Or a plurality of R 12 Is C 1-3 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is C 2-6 Alkenyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is C 2-6 Alkynyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is C 3-7 A monocyclic cycloalkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is C 7-10 Fused bicyclic cycloalkyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is C 5-10 Bridged bicyclic cycloalkyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is phenyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is a naphthyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is a 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is a 5 to 6 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is an 8-to 10-membered fused bicyclic heterocyclic group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is a 6-to 10-membered bridged bicyclic heterocyclic group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is an 8-to 10-membered fused bicyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12 Is a 7-to 10-membered spirocyclic heterocyclic group.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, each R 12a Independently C 1-6 Alkyl group,C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, or 7-to 10-membered spiro heterocyclyl.
In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12a Is C 1-6 An alkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12a Is C 2-6 Alkenyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12a Is C 2-6 Alkynyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12a Is C 3-7 A monocyclic cycloalkyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12a Is C 7-10 Fused bicyclic cycloalkyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12a Is C 5-10 Bridged bicyclic cycloalkyl groups. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12a Is phenyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12a Is a naphthyl group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12a Is a 4 to 7 membered monocyclic heterocyclyl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12a Is a 5 to 6 membered monocyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12a Is an 8-to 10-membered fused bicyclic heterocyclic group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12a Is a 6-to 10-membered bridged bicyclic heterocyclic group. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12a Is an 8-to 10-membered fused bicyclic heteroaryl. In some embodiments of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, one or more R 12a Is a 7-to 10-membered spirocyclic heterocyclic group.
In one embodiment, provided herein is a compound selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
In one embodiment, provided herein is a compound selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
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or a pharmaceutically acceptable salt thereof.
In one embodiment, provided herein is a compound selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
In one embodiment, provided herein is a compound selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
In one embodiment, provided herein is a compound selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
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or a pharmaceutically acceptable salt thereof.
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or a pharmaceutically acceptable salt thereof.
In one embodiment, provided herein is a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
In one embodiment, provided herein is a compound that is:
or a pharmaceutically acceptable salt thereof.
In one embodiment, provided herein is a compound that is:
or a pharmaceutically acceptable salt thereof.
In one embodiment, provided herein is a compound that is:
or a pharmaceutically acceptable salt thereof.
In one embodiment, provided herein is a compound that is:
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In one embodiment, provided herein is a compound that is:
or a pharmaceutically acceptable salt thereof.
In one embodiment, provided herein is a compound that is:
or a pharmaceutically acceptable salt thereof.
In one embodiment, provided herein is a compound that is:
or a pharmaceutically acceptable salt thereof.
In one embodiment, provided herein is a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
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III compositions and kits
The compounds provided herein, or pharmaceutically acceptable salts thereof, are generally administered in the form of a pharmaceutical composition. Accordingly, also provided herein are pharmaceutical compositions comprising one or more compounds provided herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. The compounds provided herein, or pharmaceutically acceptable salts thereof, may be the only active ingredient or one of the active ingredients of the pharmaceutical composition. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical arts. See, e.g., remington's Pharmaceutical Sciences, mace Publishing co., philiadelphia, pa., 17 th edition, (1985); and Modern Pharmaceutics, marcel Dekker, inc. 3 rd edition (edited by g.s. Banker and c.t. Rhodes).
In one embodiment, provided herein are pharmaceutical compositions comprising a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.
In some embodiments, the one or more additional therapeutic agents comprise an antimalarial agent. In some embodiments, the antimalarial agent is selected from chloroquine and hydroxychloroquine or pharmaceutically acceptable salts thereof.
In some embodiments, the one or more additional therapeutic agents include agents that treat an inflammatory disorder, in some embodiments, the one or more additional therapeutic agents are selected from the group consisting of: vitozumab, PF-06835375, exkulizumab, mi Latuo bead mab, SM-06, SM-03, BT-063, QX-006-N, BOS-161721, AK-101, TNX-1500, cilarizumab, dasardiod Li Shan, TAK-079, fevertuzumab, illimumab, anilauzumab, iskarituxab, PEGylated dapirobenzolimumab, ranafuzumab, LY-3361237, JNJ-55920839, UBP-1213, DS-7011, PFI-102, BIIB-059, obtuzumab, tatuzumab Wo Bali bead mab, TE-2324, PRV-3279, chloroquine, hydroxychloroquine sulfate, COV-08-4; GNKS-356, AVO-101, lobifupα (rozibafusplfa), VRN-02, annexuzlimab, ALPN-101, bendamustine hydrochloride, BMS-986256, NKTR-35, asenaproxen, taitazipran, BMS-986256, M-5049, KZR-616, KPG-818, vandicable (verdineor), ALPN-303, valoxepin, LA-1, west Nemod, prednisone corticotropin, deuterocortinib, CPL-409116, CS-12192, tofacitinib citrate, ISB-830, DV-1079, juliemic acid, illicit, TAM-01, BML-258, bupacitinib, SDC-1801, SDC-1802, ICP-330, NTR-441, darapatinib, GSK-2646264, SKI-O-703, and pharmaceutical compositions containing them Lannaptinib (GS-9876), GNS-1653, HMPL-523, RSLV-132, interleukin-2 subsequent biological preparation, interleukin-2 Anteluke, interking recombinant human interleukin-2, ILT-101, CUG-252, DZ-2002, PEGylated HLA-X (SLE), AC-0058, non-nilotinib, XNW-1011, tiralutinib hydrochloride, brinbutinib, albuttinib, obutinib, DWP-213388, INV-103, R-salbutamol sulfate, dockerin, NIK-SMI1, X-6, INV-17, O Sha Di D (Oshadi D), barittinib, wu Pati, non-golitinib, tatinib, INCB-54707, dighatinib, DWP-212525, CKD-971, as mometasone, betamethasone, formoterol, arachidonylethanolamine, DCB-SLE1, arsenic trioxide, tai ruimide, TV-4710 (per Qu Tai), allogenic human umbilical cord-derived mesenchymal stem cell therapy (hUC-MSC), LC-200, BI-705564, SM-934, GX-101, TXR-712, TXR-711, CIT-013, MHV-370,TPX-6001, TPX-7001, dihydroartemisinin and AMG-592, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.
The pharmaceutical composition may be administered in single or multiple doses. The pharmaceutical compositions may be administered by a variety of methods including, for example, rectal, buccal, intranasal, and transdermal routes. In some embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.
One mode of administration is parenteral, for example by injection. The pharmaceutical compositions described herein may be incorporated therein for administration by injection in forms such as aqueous or oil suspensions or emulsions, with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical vehicles. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions are administered by subcutaneous injection.
The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents which have been mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1, 3-butanediol, or as a lyophilized powder. Acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
In some embodiments, the sterile injectable formulations disclosed herein may also be sterile injectable solutions or suspensions (such as solutions in 1, 3-butanediol) prepared from reconstituted lyophilized powders in a non-toxic parenterally acceptable diluent or solvent. Acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. In certain embodiments, the suspension is a microsuspension. In certain embodiments, the suspension is a nanosuspension.
In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and Subcutaneous (SC) administration) will comprise one or more excipients. The excipient should be compatible with the other ingredients of the formulation and physiologically harmless to its recipient. Examples of suitable excipients are well known to those skilled in the art of parenteral formulations and can be found, for example, in Handbook of Pharmaceutical Excipients (Rowe, sheskey and Quinn editions), 6 th edition 2009. Examples of solubilizing excipients in parenteral formulations (e.g., SC or IM formulations) include, but are not limited to, polysorbates (e.g., polysorbate 20 or 80) and poloxamers (e.g., poloxamer 338, 188 or 207).
In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts and pharmaceutical compositions thereof, are administered with an implant.
Oral administration may be another route for administering a compound provided herein or a pharmaceutically acceptable salt thereof. Administration may be via, for example, a capsule or an enteric coated tablet. In preparing pharmaceutical compositions comprising at least one compound provided herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, an active ingredient (such as a compound provided herein) is typically diluted and/or encapsulated with an excipient within such a carrier, which may be in the form of a capsule, pouch, paper, or other container. When the excipient serves as a diluent, it may be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier, or medium for the active ingredient. Thus, pharmaceutical compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose or any combination thereof. The pharmaceutical composition may additionally include lubricants such as talc, magnesium stearate and mineral oil; a wetting agent; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; a sweetener; and a flavoring agent; or any combination thereof.
Pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, may be formulated so as to provide rapid, sustained, or delayed release of the active ingredient (such as the compounds provided herein) upon administration to a subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems that include polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. nos. 3,845,770, 4,326, 525, 4,902,514 and 5,616,345. Another formulation for use in the methods of the present disclosure employs a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous infusion of controlled amounts of the compounds provided herein. The construction and use of transdermal patches for delivering pharmaceutical agents is well known in the art. See, for example, U.S. Pat. nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be configured for continuous, pulsatile, or on-demand delivery of the medicament.
To prepare a solid composition (such as a tablet), the primary active ingredient may be admixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein, or a pharmaceutically acceptable salt, isomer or mixture thereof. When these preformulated compositions are referred to as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equivalent unit dosage forms such as tablets, pills and capsules.
Tablets or pills of the compounds provided herein or pharmaceutically acceptable salts thereof may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, a tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.
Pharmaceutical compositions for inhalation or insufflation may comprise solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. The liquid or solid composition may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by the oral or nasal respiratory route to achieve a local or systemic effect. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized by use of an inert gas. The aerosolized solution may be inhaled directly from the aerosolization device, or the aerosolization device may be attached to a mask tent or intermittent positive pressure ventilator. The solution, suspension or powder composition may be administered from a device that delivers the formulation in a suitable manner, preferably orally or nasally.
In one embodiment, provided herein is a kit comprising a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a suitable package. In some embodiments, the kit further comprises instructions for use. In some embodiments, the kit includes a label and/or instructions for using a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, to treat an indication (including a disease or disorder) described herein.
In some embodiments, the kit further comprises one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.
In one embodiment, provided herein are articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, in a suitable container. In some embodiments, the container may be a vial, a jar, an ampoule, a prefilled syringe, or an intravenous bag.
IV method
The methods provided herein can be applied to cell populations in vivo or ex vivo. By "in vivo" is meant within a living individual, such as within an animal or human. In this context, the methods provided herein may be used for the treatment of an individual. By "ex vivo" is meant outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the present disclosure may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the present disclosure may be used ex vivo to determine an optimal schedule and/or dosage of administration of TLR 7, 8 and/or 9 inhibitors as disclosed herein for a given cell type, individual and other parameters. The information collected from such use may be used for experimental purposes or clinically in formulating an in vivo treatment regimen. Other ex vivo uses to which the present disclosure may be suitable are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized as dosages that check the safety or tolerability of a human or non-human subject. Such properties can be checked using methods generally known to those skilled in the art.
In one embodiment, the present disclosure provides a method of inhibiting toll-like receptor 7, 8 and/or 9 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, the present disclosure provides methods of inhibiting toll-like receptor 7, 8, and 9 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, the present disclosure provides a method of inhibiting toll-like receptor 7, 8, or 9 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides a method of inhibiting toll-like receptor 7 and/or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, the present disclosure provides methods of inhibiting toll-like receptor 7 and 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, the present disclosure provides a method of inhibiting toll-like receptor 7 or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides a method of inhibiting toll-like receptor 7 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, the present disclosure provides a method of inhibiting toll-like receptor 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides a method of treating a disease or disorder associated with elevated toll-like receptor 7, 8 and/or 9 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, the present disclosure provides methods of treating a disease or disorder associated with increased toll-like receptor 7, 8, and 9 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, the present disclosure provides a method of treating a disease or disorder associated with increased toll-like receptor 7, 8 or 9 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides a method of treating a disease or disorder associated with increased toll-like receptor 7 and/or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, the present disclosure provides methods of treating a disease or disorder associated with increased toll-like receptor 7 and 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, the present disclosure provides a method of treating a disease or disorder associated with increased toll-like receptor 7 or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides a method of treating a disease or disorder associated with increased toll-like receptor 7 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, the present disclosure provides a method of treating a disease or disorder associated with increased toll-like receptor 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides a method of treating an inflammatory disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
Non-limiting examples of inflammatory conditions include, but are not limited to, acne, acid-induced lung injury, addison's disease, adrenal hyperplasia, adrenocortical insufficiency, adult-onset still disease, adult Respiratory Distress Syndrome (ARDS), age-related macular degeneration, aging, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary, allergic conjunctivitis, allergic contact dermatitis, allergy, allergic encephalomyelitis, allergic neuritis, allograft rejection, hair loss, alopecia areata, alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, angina, angioedema, vascular fibroma, antiperspirant ectodermal dysplasia, anti-glomerular basement membrane disease, antigen-antibody complex mediated disease, ankylosing spondylitis, antiphospholipid syndrome aphthous stomatitis, appendicitis, arthritis, ascites, aspergillosis, asthma, atherosclerosis, atherosclerotic plaques, atopic dermatitis, atrophic thyroiditis, autoimmune diseases, autoimmune hemolytic anemia (immune whole blood cytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune polycystic endocrine diseases, autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune mediated thrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorders, autoimmune inflammatory diseases, back pain, bacillus anthracis infection, behcet's disease, inflammation caused by bee stings, behcet's syndrome, bell palsy, beryllium poisoning, blau syndrome, bone pain, bronchiolitis, bullous Pemphigoid (BP) asthma, burns, bursitis, cardiac hypertrophy, carpal tunnel syndrome, kalman's disease, catabolic disorders, cataracts, celiac disease, cerebral aneurysms, chemical stimulus-induced inflammation, chorioretinitis, chronic atypical neutrophil skin diseases with lipodystrophy and elevated body temperature (CANDLE) syndrome, chronic heart failure, chronic pulmonary disease in premature infants, chronic Obstructive Pulmonary Disease (COPD), chronic pancreatitis, chronic prostatitis, chronic recurrent multifocal osteomyelitis, cicatricial alopecia, colitis, complex regional pain syndrome, organ transplant complications, conjunctivitis, connective tissue disease, contact dermatitis, corneal graft neovascularization, corneal ulceration, crohn's disease, cryptothermal protein-related periodic syndrome, cutaneous Lupus Erythematosus (CLE), cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist Deficiency (DIRA) dermatitis, dermatitis endotoxemia, dermatomyositis, diabetic macular edema, diverticulitis, eczema, encephalitis, endometriosis, endotoxemia, eosinophilic pneumonia, epicondylitis, epidermolysis bullosa, erythema multiforme, juvenile erythropenia, esophagitis, familial amyloid polyneuropathy, familial cold urticaria, familial mediterranean fever, fetal growth retardation, fibromyalgia, fistula type Crohn's disease, food allergies, giant cell arteritis, glaucoma, glioblastoma, glomerular disease, glomerulonephritis (glomerular nephritis), glomerulonephritis (glomerulonephritis), gluten sensitive enteropathy, gout, gouty arthritis, graft Versus Host Disease (GVHD), granulomatosis hepatitis, graves disease, growth plate injury, guillain-Barre syndrome, intestinal tract disease, alopecia, hashimoto thyroiditis, head injury, headache, hearing loss, heart disease, hemangioma, hemolytic anemia, hemophilia joint, henno-Schonlein purpura, hepatitis, hereditary periodic fever syndrome, connective tissue hereditary disease, shingles and herpes simplex, suppurative sweat gland (HS), hip joint replacement, hodgkin's disease, huntington's disease, hyalopathy, hyperreactivity, hypercoammonemia, hypercalcemia, hypercholesteremia, hypereosinophilic syndrome (HES), hyperimmunoglobulin syndrome D with recurrent fever (HIDS), allergic pneumonia, hypertrophic bone formation, dysplasia and other anemias, dysplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy, idiopathic inflammatory myopathy (dermatomyositis, polymyositis), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, immunoglobulin, immune complex hematophagic disease, immune deficiency, immunonephritic purpura, idiopathic thrombocytopenic purpura (P-P), HIV infection, inflammatory disease (ITP-Schonlein syndrome), including viral diseases such as AIDS (HIV infection), hepatitis a, hepatitis b, hepatitis c, hepatitis D and hepatitis e, herpes; inflammation, CNS inflammation, inflammatory Bowel Disease (IBD), inflammatory diseases of the lower respiratory tract (including bronchitis or chronic obstructive pulmonary disease), inflammatory diseases of the upper respiratory tract (including nasal and nasal sinuses) such as rhinitis or sinusitis, inflammatory diseases of the respiratory tract, inflammatory ischemic events such as stroke or sudden cardiac arrest, inflammatory lung disease, inflammatory myopathies such as myocarditis, inflammatory liver disease, inflammatory neuropathy, inflammatory pain, inflammation caused by insect bites, interstitial cystitis, interstitial lung disease, iritis, inflammation caused by irritants, ischemia/reperfusion, joint replacement, juvenile arthritis, juvenile rheumatoid arthritis, keratitis, kidney injury caused by parasitic infection, renal transplant rejection, leptospirosis, leukocyte adhesion deficiency, lichen Sclerosus (LS), lambert-eaton myasthenia syndrome luffler's syndrome, lupus nephritis, lyme disease, ma Fanzeng Syndrome (MFS), mast cell activation syndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixed connective tissue disease, mu Keer-wils syndrome (urticaria, deafness, amyloidosis), mucositis, multiple organ injury syndrome, multiple sclerosis, muscle atrophy, muscular dystrophy, and Myasthenia Gravis (MG), myelodysplastic syndrome, myocarditis, myositis, sinusitis, necrotizing enterocolitis, neonatal Onset Multisystem Inflammatory Disease (NOMID) neovascular glaucoma, nephrotic syndrome, neuritis, neuropathic disease, non-allergen induced asthma, obesity, ocular allergy, optic neuritis, organ transplant rejection, osler-Weber syndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis, osteoporosis, osteoarthritis, otitis, congenital panonycis, paget's disease, pancreatitis, parkinson's disease, pediatric rheumatism, pelvic inflammatory disease, pemphigus Vulgaris (PV), bullous Pemphigoid (BP), pericarditis, periodic fever, periodontitis, endometriosis, pernicious anemia (Addison's disease), pertussis, PFAPA (periodic fever aphtha pharyngitis and cervical adenosis), pharyngitis and adenosis (PFAPA syndrome), inflammation caused by plant irritants, infection by pneumosporosis, pneumonia, localized pneumonia, inflammation caused by Pugegen/urushiol oil, nodular polyarthritis, polychondritis, polycystic kidney disease, polymyalgia rheumatica, giant cell arteritis, polymyositis pouch inflammation, reperfusion injury and graft rejection, primary biliary cirrhosis, primary pulmonary hypertension, primary Sclerosing Cholangitis (PSC), proctitis, psoriasis vulgaris, psoriatic arthritis, psoriatic epidermis, psychosocial stress disease, pulmonary fibrosis, pulmonary hypertension, pyoderma gangrenosum, post-suppurative granulomatous fibrohyperplasia s, suppurative aseptic arthritis, raynaud's syndrome, leider's disease, reactive arthritis, kidney disease, renal transplant rejection, reperfusion injury, respiratory distress syndrome, retinal disease, post-lens fibrosis, raynaud's syndrome, rheumatic heart disease, rheumatic arthritis, rhinitis, psoriasis, rosacea, rhinitis, sarcoidosis, schnitzeler syndrome, scleritis, scleroderma, scoliosis, seborrhea, sepsis, septic shock, severe pain, szechuan syndrome, sickle cell anemia, silica-induced disease (silicosis), sjogren's syndrome, dermatological disorders, skin irritation, rash, skin allergies (contact dermatitis or allergic contact dermatitis), sleep apnea, spinal cord injury, spinal stenosis, spondyloarthropathies, sports injury, sprains and strains, stevens-johnson syndrome (SJS), stroke, subarachnoid hemorrhage, sunburn, synovial inflammation, systemic Inflammatory Response Syndrome (SIRS), systemic Lupus Erythematosus (SLE) Systemic Mastocytosis (SMCD) systemic vasculitis, idiopathic systemic vasculitis, temporal arteritis, tendinitis, tenosynovitis, thrombocytopenia, thyroiditis (thyroditis), thyroiditis (thyroiditis), tissue transplantation, toxoplasmosis, trachoma, transplant rejection, traumatic brain injury, tuberculosis, tubular interstitial nephritis, tumor Necrosis Factor (TNF) receptor-associated periodic syndrome (trap), type 1 diabetes, type 2 diabetes, type 1 or type 2 diabetic complications, ulcerative colitis, urticaria, uterine fibroids, uveitis, vascular restenosis, vasculitis (NHLBI), vitiligo, wegener granulomatosis, and whipple's disease.
In some embodiments, the inflammatory disorder is selected from the group consisting of inflammatory bowel disease, psoriasis, psoriatic arthritis, rheumatoid arthritis, glomerulonephritis, mixed Connective Tissue Disease (MCTD), dermatomyositis, polymyositis, systemic sclerosis, anti-neutrophil cytoplasmic antibody-associated vasculitis, anti-phospholipid syndrome, autoimmune hemolytic anemia, macrophage activation syndrome-driven inflammatory anemia, igA nephropathy, type I diabetes, non-alcoholic steatohepatitis, and sjogren syndrome. In some embodiments, the inflammatory disorder is inflammatory bowel disease. In some embodiments, the inflammatory disorder is psoriasis. In some embodiments, the inflammatory disorder is psoriatic arthritis. In some embodiments, the inflammatory disorder is rheumatoid arthritis. In some embodiments, the inflammatory disorder is glomerulonephritis. In some embodiments, the inflammatory disorder is Mixed Connective Tissue Disease (MCTD). In some embodiments, the inflammatory disorder is dermatomyositis. In some embodiments, the inflammatory disorder is polymyositis. In some embodiments, the inflammatory disorder is systemic sclerosis. In some embodiments, the inflammatory disorder is anti-neutrophil cytoplasmic antibody associated vasculitis. In some embodiments, the inflammatory disorder is antiphospholipid syndrome. In some embodiments, the inflammatory disorder is autoimmune hemolytic anemia. In some embodiments, the inflammatory disorder is macrophage activation syndrome-driven inflammatory anemia. In some embodiments, the inflammatory disorder is IgA nephropathy. In some embodiments, the inflammatory disorder is type I diabetes. In some embodiments, the inflammatory condition is non-alcoholic steatohepatitis. In some embodiments, the inflammatory disorder is sjogren's syndrome.
The compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions provided herein, can treat or ameliorate Systemic Lupus Erythematosus (SLE), cutaneous Lupus Erythematosus (CLE), lupus nephritis, lupus-associated SLE symptoms, CLE symptoms, or other autoimmune disorders. Symptoms of systemic lupus erythematosus include joint pain, joint swelling, arthritis, fatigue, hair loss, canker sores, lymphadenectasis, sun sensitivity, rash, headache, tingling, stinging, epilepsy, vision problems, personality changes, abdominal pain, nausea, vomiting, heart rhythm abnormalities, hemoptysis and dyspnea, patchy skin color, and Raynaud's phenomenon.
In one embodiment, the present disclosure provides a method of treating systemic lupus erythematosus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides a method of treating cutaneous lupus erythematosus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides a method of treating lupus nephritis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In some embodiments, the methods provided herein further comprise administering a therapeutically effective amount of one or more additional therapeutic agents or pharmaceutically acceptable salts thereof.
In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of: vitozumab, PF-06835375, exkulizumab, mi Latuo bead mab, SM-06, SM-03, BT-063, QX-006-N, BOS-161721, AK-101, TNX-1500, cilarizumab, dasardiod Li Shan, TAK-079, fevertuzumab, illimumab, anilauzumab, iskarituxab, PEGylated dapirobenzolimumab, ranafuzumab, LY-3361237, JNJ-55920839, UBP-1213, DS-7011, PFI-102, BIIB-059, obtuzumab, tatuzumab Wo Bali bead mab, TE-2324, PRV-3279, chloroquine, hydroxychloroquine sulfate, COV-08-4; GNKS-356, AVO-101, lobifupα, VRN-02, annexuzlimab, ALPN-101, bendamustine hydrochloride, BMS-986256 (afimepran)), NKTR-35, asenapine, tiazepine, M-5049, KZR-616, KPG-818, vandixol, ALPN-303, valoxepin, LA-1, cilnemmod, prednisone, corticotropin, deuterium-celecoxib, CPL-409116, CS-12192, tofacitinib citrate, ISB-830, DV-1079, juliemic acid, il Bei Du amine, TAM-01, BML-258, bupropion, SDC-1801, SDC-1802, ICP-330, NTR-441, darapamide, GSK-2646264, SKI-O-703, lansopanib (GS-9876), GS-1653, HMPL-523, RSK-132, interleukin-2, and the like, and the following biological preparation Interleukin-2 Anteluke, interking recombinant human interleukin-2, ILT-101, CUG-252, DZ-2002, PEGylated HLA-X (SLE), AC-0058, non-Nibutinib, XNW-1011, tiramitinib hydrochloride, brinbinib, albutinib, obutinib, DWP-213388, INV-103, R-salbutamol sulfate, ankyrin, NIK-SMI1, X-6, INV-17, O Sha Di D, baritinib, wu Pati, non-Gotinib, itatinib, INCB-54707, DIGatinib, DWP-212525, CKD-971, as mometasone, betamethasone, furitol, arachidonic acid ethanolamine, DCB-SLE1, arsenic trioxide, tairuimide, TV-4710 (E Qu Tai), allogenic human umbilical cord derived mesenchymal stem cell therapy (hUC-MSC), LC-200, BI-705564, SM-934, GX-101, TXR-712, TXR-711, CIT-013, MHV-370, TPX-6001, TPX-7001, dihydroartemisinin, corticosteroids, azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab, non-steroidal anti-inflammatory drugs, belimumab, fuciclosporin and AMG-592, or pharmaceutically acceptable salts thereof.
In some embodiments, corticosteroids include, but are not limited to, prednisone and other drugs that inhibit the immune system. In some embodiments, the non-steroidal anti-inflammatory drugs include, but are not limited to, ibuprofen and naproxen.
In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of: wituzumab, PF-06835375, exkuzhuMonoclonal antibodies, mi Latuo bead monoclonal antibodies, SM-06, SM-03, BT-063, QX-006-N, BOS-161721, AK-101, TNX-1500, sirolimus, damady Li Shan antibody, TAK-079, fevertuzumab, illi-group monoclonal antibodies, anilumab, iskurituximab, pegylated dapirobuzumab, ranolast, LY-3361237, JNJ-55920839, UBP-1213, DS-7011, PFI-102, BIIB-059, obezilimab, trastuzumab, wo Bali bead monoclonal antibodies, TE-2324, PRV-3279, chloroquine, hydroxychloroquine sulfate, COV-08-0064; GNKS-356, AVO-101, lobifuα, VRN-02, annexuzlimab, ALPN-101, bendamustine hydrochloride, BMS-986256, NKTR-35, asenapine, tiazepine, BMS-986256, M-5049, KZR-616, KPG-818, vandicable, ALPN-303, valoxepin, LA-1, cinamomod, prednisone, corticotropin, deuterostatinib, CPL-409116, CS-12192, tofacitinib citrate, ISB-830, DV-1079, juliemic acid, I Bei Du amine, TAM-01, BML-258, bupacitinib, SDC-1801, SDC-1802, ICP-330, NTR-441, datazapeptide, GSK-2646264, SKI-O-703, lanprinib (GS-9876), GNS-1653, HMPL-523; RSLV-132, interleukin-2 subsequent biological preparation, interleukin-2 Anteluke, interking recombinant human interleukin-2, ILT-101, CUG-252, DZ-2002, PEGylated HLA-X (SLE), AC-0058, non-Nibutinib, XNW-1011, tiralutinib hydrochloride, brinbutinib, albutinib, obutinib, DWP-213388, INV-103, R-salbutamol sulfate, ankyrin, NIK-SMI1, X-6, INV-17, O Sha Di D, barittinib, wu Pati, non-golitinib, itatinib, INCB-54707, dighatinib, DWP-212525, CKD-971, as mometasone, betamethasone, furitol, arachidonylethanolamine, DCB-SLE1, arsenic trioxide, tairuimide, TV-4710 (Qu Tai), allogenic human umbilical cord derived mesenchymal stem cell therapy (hUC-MSC), LC-200, BI-705564, SM-934, GX-101, TXR-712, TXR-711, CIT-013, MHV-370, TPX-6001, TPX-7001, dihydroartemisinin and AMG-592, or any of the foregoingPharmaceutically acceptable salts of the substances or any combination thereof. />
In some embodiments, the one or more additional therapeutic agents are selected from chloroquine and hydroxychloroquine or pharmaceutically acceptable salts thereof. In some embodiments, the one or more additional therapeutic agents is chloroquine. In some embodiments, the one or more additional therapeutic agents is hydroxychloroquine. In some embodiments, the one or more additional therapeutic agents is a pharmaceutically acceptable salt of hydroxychloroquine. In some embodiments, the one or more additional therapeutic agents is hydroxychloroquine sulfate.
In some embodiments of the methods provided herein, the subject is a human.
In some embodiments, the methods provided herein comprise administering a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II) or a pharmaceutically acceptable salt thereof. In some embodiments, the methods provided herein comprise administering a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides the use of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein in therapy.
In one embodiment, the present disclosure provides the use of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of inhibiting toll-like receptor 7, 8 and/or 9 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, is used in a method of inhibiting the activity of toll-like receptors 7, 8, and 9 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, is used in a method of inhibiting toll-like receptor 7, 8, or 9 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides the use of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of inhibiting toll-like receptor 7 and/or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, a compound provided herein (i.e., a compound of formula I or II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, is used in a method of inhibiting toll-like receptor 7 and 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II) or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, a compound provided herein (i.e., a compound of formula I or II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, is used in a method of inhibiting toll-like receptor 7 or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II) or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides the use of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of inhibiting toll-like receptor 7 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, a compound provided herein (i.e., a compound of formula I or II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, is used in a method of inhibiting toll-like receptor 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II) or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides the use of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of treating a disease or disorder associated with increased toll-like receptor 7, 8 and/or 9 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, is used in a method of treating a disease or disorder associated with increased toll-like receptor 7, 8, and 9 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, is used in a method of treating a disease or disorder associated with increased toll-like receptor 7, 8, or 9 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides the use of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of treating a disease or disorder associated with increased toll-like receptor 7 and/or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, is used in a method of treating a disease or disorder associated with increased toll-like receptor 7 and 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, is used in a method of treating a disease or disorder associated with increased toll-like receptor 7 or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides the use of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of treating a disease or disorder associated with increased toll-like receptor 7 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein. In some embodiments, a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, is used in a method of treating a disease or disorder associated with increased toll-like receptor 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, for use in a method of treating an inflammatory disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
Non-limiting examples of inflammatory conditions include, but are not limited to, acne, acid-induced lung injury, addison's disease, adrenal hyperplasia, adrenocortical insufficiency, adult-onset still disease, adult Respiratory Distress Syndrome (ARDS), age-related macular degeneration, aging, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary, allergic conjunctivitis, allergic contact dermatitis, allergy, allergic encephalomyelitis, allergic neuritis, allograft rejection, hair loss, alopecia areata, alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, angina, angioedema, vascular fibroma, antiperspirant ectodermal dysplasia, anti-glomerular basement membrane disease, antigen-antibody complex mediated disease, ankylosing spondylitis, antiphospholipid syndrome aphthous stomatitis, appendicitis, arthritis, ascites, aspergillosis, asthma, atherosclerosis, atherosclerotic plaques, atopic dermatitis, atrophic thyroiditis, autoimmune diseases, autoimmune hemolytic anemia (immune whole blood cytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune polycystic endocrine diseases, autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune mediated thrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorders, autoimmune inflammatory diseases, back pain, bacillus anthracis infection, behcet's disease, inflammation caused by bee stings, behcet's syndrome, bell palsy, beryllium poisoning, blau syndrome, bone pain, bronchiolitis, bullous Pemphigoid (BP) asthma, burns, bursitis, cardiac hypertrophy, carpal tunnel syndrome, kalman's disease, catabolic disorders, cataracts, celiac disease, cerebral aneurysms, chemical stimulus-induced inflammation, chorioretinitis, chronic atypical neutrophil skin diseases with lipodystrophy and elevated body temperature (CANDLE) syndrome, chronic heart failure, chronic pulmonary disease in premature infants, chronic Obstructive Pulmonary Disease (COPD), chronic pancreatitis, chronic prostatitis, chronic recurrent multifocal osteomyelitis, cicatricial alopecia, colitis, complex regional pain syndrome, organ transplant complications, conjunctivitis, connective tissue disease, contact dermatitis, corneal graft neovascularization, corneal ulceration, crohn's disease, cryptothermal protein-related periodic syndrome, cutaneous Lupus Erythematosus (CLE), cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist Deficiency (DIRA) dermatitis, dermatitis endotoxemia, dermatomyositis, diabetic macular edema, diverticulitis, eczema, encephalitis, endometriosis, endotoxemia, eosinophilic pneumonia, epicondylitis, epidermolysis bullosa, erythema multiforme, juvenile erythropenia, esophagitis, familial amyloid polyneuropathy, familial cold urticaria, familial mediterranean fever, fetal growth retardation, fibromyalgia, fistula type Crohn's disease, food allergies, giant cell arteritis, glaucoma, glioblastoma, glomerular disease, glomerulonephritis (glomerular nephritis), glomerulonephritis (glomerulonephritis), gluten sensitive enteropathy, gout, gouty arthritis, graft Versus Host Disease (GVHD), granulomatosis hepatitis, graves disease, growth plate injury, guillain-Barre syndrome, intestinal tract disease, alopecia, hashimoto thyroiditis, head injury, headache, hearing loss, heart disease, hemangioma, hemolytic anemia, hemophilia joint, henno-Schonlein purpura, hepatitis, hereditary periodic fever syndrome, connective tissue hereditary disease, shingles and herpes simplex, suppurative sweat gland (HS), hip joint replacement, hodgkin's disease, huntington's disease, hyalopathy, hyperreactivity, hypercoammonemia, hypercalcemia, hypercholesteremia, hypereosinophilic syndrome (HES), hyperimmunoglobulin syndrome D with recurrent fever (HIDS), allergic pneumonia, hypertrophic bone formation, dysplasia and other anemias, dysplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy, idiopathic inflammatory myopathy (dermatomyositis, polymyositis), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, immunoglobulin, immune complex hematophagic disease, immune deficiency, immunonephritic purpura, idiopathic thrombocytopenic purpura (P-P), HIV infection, inflammatory disease (ITP-Schonlein syndrome), including viral diseases such as AIDS (HIV infection), hepatitis a, hepatitis b, hepatitis c, hepatitis D and hepatitis e, herpes; inflammation, CNS inflammation, inflammatory Bowel Disease (IBD), inflammatory diseases of the lower respiratory tract (including bronchitis or chronic obstructive pulmonary disease), inflammatory diseases of the upper respiratory tract (including nasal and nasal sinuses) such as rhinitis or sinusitis, inflammatory diseases of the respiratory tract, inflammatory ischemic events such as stroke or sudden cardiac arrest, inflammatory lung disease, inflammatory myopathies such as myocarditis, inflammatory liver disease, inflammatory neuropathy, inflammatory pain, inflammation caused by insect bites, interstitial cystitis, interstitial lung disease, iritis, inflammation caused by irritants, ischemia/reperfusion, joint replacement, juvenile arthritis, juvenile rheumatoid arthritis, keratitis, kidney injury caused by parasitic infection, renal transplant rejection, leptospirosis, leukocyte adhesion deficiency, lichen Sclerosus (LS), lambert-eaton myasthenia syndrome luffler's syndrome, lupus nephritis, lyme disease, ma Fanzeng Syndrome (MFS), mast cell activation syndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixed connective tissue disease, mu Keer-wils syndrome (urticaria, deafness, amyloidosis), mucositis, multiple organ injury syndrome, multiple sclerosis, muscle atrophy, muscular dystrophy, and Myasthenia Gravis (MG), myelodysplastic syndrome, myocarditis, myositis, sinusitis, necrotizing enterocolitis, neonatal Onset Multisystem Inflammatory Disease (NOMID) neovascular glaucoma, nephrotic syndrome, neuritis, neuropathic disease, non-allergen induced asthma, obesity, ocular allergy, optic neuritis, organ transplant rejection, osler-Weber syndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis, osteoporosis, osteoarthritis, otitis, congenital panonycis, paget's disease, pancreatitis, parkinson's disease, pediatric rheumatism, pelvic inflammatory disease, pemphigus Vulgaris (PV), bullous Pemphigoid (BP), pericarditis, periodic fever, periodontitis, endometriosis, pernicious anemia (Addison's disease), pertussis, PFAPA (periodic fever aphtha pharyngitis and cervical adenosis), pharyngitis and adenosis (PFAPA syndrome), inflammation caused by plant irritants, infection by pneumosporosis, pneumonia, localized pneumonia, inflammation caused by Pugegen/urushiol oil, nodular polyarthritis, polychondritis, polycystic kidney disease, polymyalgia rheumatica, giant cell arteritis, polymyositis pouch inflammation, reperfusion injury and graft rejection, primary biliary cirrhosis, primary pulmonary hypertension, primary Sclerosing Cholangitis (PSC), proctitis, psoriasis vulgaris, psoriatic arthritis, psoriatic epidermis, psychosocial stress disease, pulmonary fibrosis, pulmonary hypertension, pyoderma gangrenosum, post-suppurative granulomatous fibrohyperplasia s, suppurative aseptic arthritis, raynaud's syndrome, leider's disease, reactive arthritis, kidney disease, renal transplant rejection, reperfusion injury, respiratory distress syndrome, retinal disease, post-lens fibrosis, raynaud's syndrome, rheumatic heart disease, rheumatic arthritis, rhinitis, psoriasis, rosacea, rhinitis, sarcoidosis, schnitzeler syndrome, scleritis, scleroderma, scoliosis, seborrhea, sepsis, septic shock, severe pain, szechuan syndrome, sickle cell anemia, silica-induced disease (silicosis), sjogren's syndrome, dermatological disorders, skin irritation, rash, skin allergies (contact dermatitis or allergic contact dermatitis), sleep apnea, spinal cord injury, spinal stenosis, spondyloarthropathies, sports injury, sprains and strains, stevens-johnson syndrome (SJS), stroke, subarachnoid hemorrhage, sunburn, synovial inflammation, systemic Inflammatory Response Syndrome (SIRS), systemic Lupus Erythematosus (SLE) Systemic Mastocytosis (SMCD) systemic vasculitis, idiopathic systemic vasculitis, temporal arteritis, tendinitis, tenosynovitis, thrombocytopenia, thyroiditis (thyroditis), thyroiditis (thyroiditis), tissue transplantation, toxoplasmosis, trachoma, transplant rejection, traumatic brain injury, tuberculosis, tubular interstitial nephritis, tumor Necrosis Factor (TNF) receptor-associated periodic syndrome (trap), type 1 diabetes, type 2 diabetes, type 1 or type 2 diabetic complications, ulcerative colitis, urticaria, uterine fibroids, uveitis, vascular restenosis, vasculitis (NHLBI), vitiligo, wegener granulomatosis, and whipple's disease.
In some embodiments, the inflammatory disorder is selected from the group consisting of inflammatory bowel disease, psoriasis, psoriatic arthritis, rheumatoid arthritis, glomerulonephritis, mixed Connective Tissue Disease (MCTD), dermatomyositis, polymyositis, systemic sclerosis, anti-neutrophil cytoplasmic antibody-associated vasculitis, anti-phospholipid syndrome, autoimmune hemolytic anemia, macrophage activation syndrome-driven inflammatory anemia, igA nephropathy, type I diabetes, non-alcoholic steatohepatitis, and sjogren syndrome. In some embodiments, the inflammatory disorder is inflammatory bowel disease. In some embodiments, the inflammatory disorder is psoriasis. In some embodiments, the inflammatory disorder is psoriatic arthritis. In some embodiments, the inflammatory disorder is rheumatoid arthritis. In some embodiments, the inflammatory disorder is glomerulonephritis. In some embodiments, the inflammatory disorder is Mixed Connective Tissue Disease (MCTD). In some embodiments, the inflammatory disorder is dermatomyositis. In some embodiments, the inflammatory disorder is polymyositis. In some embodiments, the inflammatory disorder is systemic sclerosis. In some embodiments, the inflammatory disorder is anti-neutrophil cytoplasmic antibody associated vasculitis. In some embodiments, the inflammatory disorder is antiphospholipid syndrome. In some embodiments, the inflammatory disorder is autoimmune hemolytic anemia. In some embodiments, the inflammatory disorder is macrophage activation syndrome-driven inflammatory anemia. In some embodiments, the inflammatory disorder is IgA nephropathy. In some embodiments, the inflammatory disorder is type I diabetes. In some embodiments, the inflammatory condition is non-alcoholic steatohepatitis. In some embodiments, the inflammatory disorder is sjogren's syndrome.
The compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions provided herein, can treat or ameliorate Systemic Lupus Erythematosus (SLE), cutaneous Lupus Erythematosus (CLE), lupus nephritis, lupus-associated SLE symptoms, CLE symptoms, or other autoimmune disorders. Symptoms of systemic lupus erythematosus include joint pain, joint swelling, arthritis, fatigue, hair loss, canker sores, lymphadenectasis, sun sensitivity, rash, headache, tingling, stinging, epilepsy, vision problems, personality changes, abdominal pain, nausea, vomiting, heart rhythm abnormalities, hemoptysis and dyspnea, patchy skin color, and Raynaud's phenomenon.
In one embodiment, the present disclosure provides the use of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in a method of treating systemic lupus erythematosus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In one embodiment, the present disclosure provides a method of treating cutaneous lupus erythematosus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition provided herein.
In some embodiments, the uses provided herein further comprise administering a therapeutically effective amount of one or more additional therapeutic agents or pharmaceutically acceptable salts thereof.
In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of:vitozumab, PF-06835375, exkulizumab, mi Latuo bead mab, SM-06, SM-03, BT-063, QX-006-N, BOS-161721, AK-101, TNX-1500, cilarizumab, dasardiod Li Shan, TAK-079, fevertuzumab, illimumab, anilauzumab, iskarituxab, PEGylated dapirobenzolimumab, ranafuzumab, LY-3361237, JNJ-55920839, UBP-1213, DS-7011, PFI-102, BIIB-059, obtuzumab, tatuzumab Wo Bali bead mab, TE-2324, PRV-3279, chloroquine, hydroxychloroquine sulfate, COV-08-4; GNKS-356, AVO-101, lobifuα, VRN-02, annexuzlimab, ALPN-101, bendamustine hydrochloride, BMS-986256 (almitoram), NKTR-35, asenapine, tiazepine, M-5049, KZR-616, KPG-818, vandicable, ALPN-303, valoxipn, LA-1, cinamode, prednisone, corticotropin, deuterostazetinib, CPL-409116, CS-12192, tofacitinib citrate, ISB-830, DV-1079, juliemic acid, idamin, TAM-01, BML-258, bupacitinib, SDC-1801, SDC-1802, 1802-330, NTR-441, darapazapeptide, GSK-2646264, SKI-O-703, lanprib (GS-9876), GNS-1653 HMPL-523, RSLV-132, interleukin-2 subsequent biological preparation, interleukin-2 Anteluke, interking recombinant human interleukin-2, ILT-101, CUG-252, DZ-2002, pegylated HLA-X (SLE), AC-0058, non-nilotinib, XNW-1011, tiralutinib hydrochloride, brinbutinib, albuttinib, oxybutytinib, DWP-213388, INV-103, R-salbutamol sulfate, ankyrin, NIK-SMI1, X-6, INV-17, olan Sha Di D, baritinib, wu Pati, non-goltinib, itatinib, INCB-54707, dihigh-tinib, DWP-212525, CKD-971, as mometasone, betamethasone, formoterol, arachidonylethanolamine, DCB-SLE1, arsenic trioxide, tairuimide, TV-4710 (Qu Tai), allogenic human umbilical cord-derived mesenchymal stem cell therapy (hUC-MSC), LC-200, BI-705564, SM-934, GX-101, TXR-712, TXR-711, CIT-013, MHV-370, TPX-6001, TPX-7001, doubleHydroartemisinin, corticosteroids, azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab, non-steroidal anti-inflammatory drugs, belimumab, fusarium and AMG-592, or pharmaceutically acceptable salts thereof.
In some embodiments, corticosteroids include, but are not limited to, prednisone and other drugs that inhibit the immune system. In some embodiments, the non-steroidal anti-inflammatory drugs include, but are not limited to, ibuprofen and naproxen.
In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of: vitozumab, PF-06835375, exkulizumab, mi Latuo bead mab, SM-06, SM-03, BT-063, QX-006-N, BOS-161721, AK-101, TNX-1500, cilarizumab, dasardiod Li Shan, TAK-079, fevertuzumab, illimumab, anilauzumab, iskarituxab, PEGylated dapirobenzolimumab, ranafuzumab, LY-3361237, JNJ-55920839, UBP-1213, DS-7011, PFI-102, BIIB-059, obtuzumab, tatuzumab Wo Bali bead mab, TE-2324, PRV-3279, chloroquine, hydroxychloroquine sulfate, COV-08-4; GNKS-356, AVO-101, lobifuα, VRN-02, annexuzlimab, ALPN-101, bendamustine hydrochloride, BMS-986256, NKTR-35, asenapine, tiazepine, BMS-986256, M-5049, KZR-616, KPG-818, vandicable, ALPN-303, valoxepin, LA-1, cinnimod, prednisone, corticotropin, deuterium-celecoxib, CPL-409116, CS-12192, tofacitinib citrate, ISB-830, DV-1079, juliemic acid, I Bei Du amine, TAM-01, BML-258, bupacitinib, SDC-1801, SDC-1802 ICP-330, NTR-441, darapatide, GSK-2646264, SKI-O-703, lanaptanib (GS-9876), GNS-1653, HMPL-523, RSLV-132, interleukin-2 subsequent biologicals, interleukin-2 Anteluke, interking recombinant human interleukin-2, ILT-101, CUG-252, DZ-2002, pegylated HLA-X (SLE), AC-0058, non-nilotinib, XNW-1011, tiralutinib hydrochloride, brinbutinib, ai-butentinib, obutinib, DWP-213388, INV-103, R-salbutamol sulfate, dockerin, NIK-SMI1, X -6, INV-17, O Sha Di D, barittinib, wu Pati, fagotinib, italtinib, INCB-54707, degatinib, DWP-212525, CKD-971, as mometasone, betamethasone, furimmod, arachidonylethanolamine, DCB-SLE1, arsenic trioxide, tairuimide, TV-4710 (E Qu Tai), allogeneic human umbilical cord-derived mesenchymal Stem cell therapy (hUC-MSC), LC-200, BI-705564, SM-934, GX-101, TXR-712, TXR-711, CIT-013, MHV-370,TPX-6001, TPX-7001, dihydroartemisinin and AMG-592, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.
In some embodiments, the one or more additional therapeutic agents are selected from chloroquine and hydroxychloroquine or pharmaceutically acceptable salts thereof. In some embodiments, the one or more additional therapeutic agents is chloroquine. In some embodiments, the one or more additional therapeutic agents is hydroxychloroquine. In some embodiments, the one or more additional therapeutic agents is a pharmaceutically acceptable salt of hydroxychloroquine. In some embodiments, the one or more additional therapeutic agents is hydroxychloroquine sulfate.
In some embodiments of the uses provided herein, the subject is a human.
In some embodiments, the uses provided herein include administering a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I or II) or a pharmaceutically acceptable salt thereof. In some embodiments, the methods provided herein comprise administering a therapeutically effective amount of a pharmaceutical composition provided herein.
V. application of
The compounds of the present disclosure, or pharmaceutically acceptable salts thereof (also referred to herein as active ingredients), may be administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary depending on, for example, the recipient's conditions. An advantage of certain compounds disclosed herein, or pharmaceutically acceptable salts thereof, is that they are orally bioavailable and can be administered orally.
The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered to an individual for a desired period or duration of time, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more, according to an effective dosing regimen. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered on a daily or intermittent schedule during the life of the individual.
The specific dosage level of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for any particular subject will depend on a variety of factors including the activity of the particular compound employed, the age, weight, general health, sex, diet, time of administration, route of administration and rate of excretion, drug combination and the severity of the particular disease of the subject undergoing therapy. For example, the dosage may be expressed as milligrams of a compound provided herein or a pharmaceutically acceptable salt thereof per kilogram of subject body weight (mg/kg). Dosages between about 0.1mg/kg and 150mg/kg may be appropriate. In some embodiments, a dosage of between about 0.1mg/kg and 100mg/kg may be appropriate. In other embodiments, a dosage of between 0.5mg/kg and 60mg/kg may be appropriate. Normalization to the weight of a subject is particularly useful in adjusting the dose between subjects of widely varying sizes, such as when using drugs in children and adults, or when converting an effective dose in a non-human subject such as a dog to a dose suitable for a human subject.
Daily doses may also be described as the total amount of a compound described herein or a pharmaceutically acceptable salt thereof per dose or administered daily. The daily dose of a compound of formula I or II, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, may be between about 1mg and 4,000mg, between about 2,000 mg/day and 4,000 mg/day, between about 1 mg/day and 2,000 mg/day, between about 1 mg/day and 1,000 mg/day, between about 10 mg/day and 500 mg/day, between about 20 mg/day and 500 mg/day, between about 50 mg/day and 300 mg/day, between about 75 mg/day and 200 mg/day, or between about 15 mg/day and 150 mg/day.
The dosage or frequency of administration of a compound of the present disclosure or a pharmaceutically acceptable salt thereof can be adjusted during treatment based on the judgment of the administering physician.
The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be administered to a subject (e.g., a human) in a therapeutically effective amount. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered once daily.
The compounds provided herein, or pharmaceutically acceptable salts thereof, may be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof may include from about 0.00001mg/kg body weight/day to about 10mg/kg body weight/day, such as from about 0.0001mg/kg body weight/day to about 10mg/kg body weight/day, or such as from about 0.001mg/kg body weight/day to about 1mg/kg body weight/day, or such as from about 0.01mg/kg body weight/day to about 1mg/kg body weight/day, or such as from about 0.05mg/kg body weight/day to about 0.5mg/kg body weight/day. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, comprises from about 0.3 mg/day to about 30 mg/day, or from about 30 mg/day to about 300 mg/day, or from about 0.3 μg/day to about 30 mg/day, or from about 30 μg/day to about 300 μg/day.
The compounds of the present disclosure or pharmaceutically acceptable salts thereof may be combined with one or more additional therapeutic agents at any dose (e.g., 1mg to 1000mg of the compound) of the compounds of the present disclosure or pharmaceutically acceptable salts thereof. A therapeutically effective amount may comprise from about 0.1 mg/dose to about 1000 mg/dose, such as from about 50 mg/dose to about 500 mg/dose, or such as from about 100 mg/dose to about 400 mg/dose, or such as from about 150 mg/dose to about 350 mg/dose, or such as from about 200 mg/dose to about 300 mg/dose, or such as from about 0.01 mg/dose to about 1000 mg/dose, or such as from about 0.01 mg/dose to about 100 mg/dose, or such as from about 0.1 mg/dose to about 100 mg/dose, or such as from about 1 mg/dose to about 10 mg/dose, or such as from about 1 mg/dose to about 1000 mg/dose. Other therapeutically effective amounts of the compounds of formula I or II, or pharmaceutically acceptable salts thereof, are about 1 mg/dose, or about 2 mg/dose, 3 mg/dose, 4 mg/dose, 5 mg/dose, 6 mg/dose, 7 mg/dose, 8 mg/dose, 9 mg/dose, 10 mg/dose, 15 mg/dose, 20 mg/dose, 25 mg/dose, 30 mg/dose, 35 mg/dose, 40 mg/dose, 45 mg/dose, 50 mg/dose, 55 mg/dose, 60 mg/dose, 65 mg/dose, 70 mg/dose, 75 mg/dose, 80 mg/dose, 85 mg/dose, 90 mg/dose, 95 mg/dose, or about 100 mg/dose. Other therapeutically effective amounts of the compounds of the present disclosure or pharmaceutically acceptable salts thereof are about 100 mg/dose, 125 mg/dose, 150 mg/dose, 175 mg/dose, 200 mg/dose, 225 mg/dose, 250 mg/dose, 275 mg/dose, 300 mg/dose, 325 mg/dose, 350 mg/dose, 375 mg/dose, 400 mg/dose, 425 mg/dose, 450 mg/dose, 475 mg/dose, 500 mg/dose, 525 mg/dose, 550 mg/dose, 575 mg/dose, 600 mg/dose, 625 mg/dose, 650 mg/dose, 675 mg/dose, 700 mg/dose, 725 mg/dose, 750 mg/dose, 775 mg/dose, 800 mg/dose, 825 mg/dose, 850 mg/dose, 875 mg/dose, 900 mg/dose, 925 mg/dose, 950 mg/dose, 975 mg/dose, or about 1000 mg/dose.
In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is from about 1mg to about 600mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is from about 1mg to about 500mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is from about 1mg to about 400mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is from about 1mg to about 300mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is from about 1mg to about 200mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is from about 1mg to about 100mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is from about 1mg to about 75mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is from about 1mg to about 50mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is from about 1mg to about 25mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is from about 1mg to about 20mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is from about 1mg to about 15mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is from about 1mg to about 10mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is from about 1mg to about 5mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 21mg, about 22mg, about 23mg, about 24mg, or about 25mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is about 5mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is about 10mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is about 15mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is about 20mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is about 25mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is about 30mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is about 35mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is about 40mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is about 45mg. In some embodiments, the therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is about 50mg.
In some embodiments, the methods described herein comprise administering to a subject an initial daily dose of about 1mg to 500mg of a compound provided herein, or a pharmaceutically acceptable salt thereof, and gradually increasing the dose until clinical efficacy is achieved. Increments of about 5mg, 10mg, 25mg, 50mg or 100mg may be used to increase the dose. The dosage may be increased daily, every other day, twice weekly, biweekly, tricyclically or monthly.
When administered orally, the total daily dose of a human subject may be between about 1mg and 1,000mg, between about 10 mg/day and 500 mg/day, between about 50 mg/day and 300 mg/day, between about 75 mg/day and 200 mg/day, or between about 100 mg/day and 150 mg/day. In some embodiments, the total daily dose of a human subject may be about 100 mg/day, 200 mg/day, 300 mg/day, 400 mg/day, 500 mg/day, 600 mg/day, 700 mg/day, 800 mg/day, 900 mg/day, or 1000 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 200 mg/day, 300 mg/day, 400 mg/day, 500 mg/day, 600 mg/day, 700 mg/day, or 800 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 300 mg/day, 400 mg/day, 500 mg/day, or 600 mg/day administered in a single dose.
In some embodiments, the total daily dose of a human subject may be about 100 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 150 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 200 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 250 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 300 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 350 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 400 mg/day administered in a single dose. In some embodiments, the total daily dose of the human subject may be about 450 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 500 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 550 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 600 mg/day administered in a single dose. In some embodiments, the total daily dose of the human subject may be about 650 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 700 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 750 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 800 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 850 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 900 mg/day administered in a single dose. In some embodiments, the total daily dose of the human subject may be about 950 mg/day administered in a single dose. In some embodiments, the total daily dose of a human subject may be about 1000 mg/day administered in a single dose.
A single dose may be administered hourly, daily, weekly or monthly. For example, a single dose may be administered every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or every 24 hours. A single dose may also be administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or once every 7 days. A single dose may also be administered once every 1 week, 2 weeks, 3 weeks, or once every 4 weeks. In certain embodiments, a single dose may be administered once a week. A single dose may also be administered once a month. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered once daily in a method disclosed herein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered twice daily in a method disclosed herein.
The frequency of the dosage of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, will be determined by the needs of the individual patient and may be, for example, once a day or two or more times a day. Administration of the compound or pharmaceutically acceptable salt thereof continues for a period of time necessary to treat the inflammatory disorder or any other indication described herein. For example, the compound or pharmaceutically acceptable salt thereof may be administered to a human afflicted with an inflammatory disorder for a period of 20 to 180 days, or for a period of, for example, 20 to 90 days, or for a period of, for example, 30 to 60 days.
Administration may be intermittent, with the patient receiving a daily dose of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, over a period of days or more, followed by a period of days or more, with the patient not receiving a daily dose of the compound, or a pharmaceutically acceptable salt thereof. For example, the patient may receive a dose of the compound or a pharmaceutically acceptable salt thereof every other day or three times a week. Again by way of example, a patient may receive a dose of a compound or a pharmaceutically acceptable salt thereof daily for a period of 1 day to 14 days, then the patient does not receive a dose of the compound or a pharmaceutically acceptable salt thereof for a period of 7 days to 21 days, then the patient receives a dose of the compound or a pharmaceutically acceptable salt thereof again for a subsequent period of time (e.g., 1 day to 14 days). The alternating periods of administration of the compound or pharmaceutically acceptable salt thereof followed by the absence of administration of the compound or pharmaceutically acceptable salt thereof may be repeated depending on the clinical needs of the patient being treated.
The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present disclosure, may be administered once, twice, three times, or four times a day using any suitable pattern described above. Moreover, administration or treatment with the compound or pharmaceutically acceptable salt thereof may continue for a number of days; for example, for one treatment cycle, typically treatment will continue for at least 7 days, 14 days, or 28 days. The therapeutic cycle is well known for inflammatory conditions and other indications described herein. In some embodiments, the treatment cycle typically alternates with a rest period of about 1 to 28 days, typically about 7 days or about 14 days between cycles. In other embodiments, the treatment cycle may also be continuous.
VI combination therapy
Patients treated by administration of the compounds provided herein, or pharmaceutically acceptable salts thereof, generally exhibit diseases or disorders that benefit from treatment with other therapeutic agents. These diseases or conditions may be of an inflammatory nature, or may be associated with cancer, metabolic disorders, gastrointestinal disorders, and the like. Thus, one embodiment of the present disclosure is a method of treating an inflammatory-related disease or condition or metabolic disorder, gastrointestinal disorder, or cancer, or the like, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to a subject, particularly a human subject, in need thereof in combination with one or more compounds useful in treating such diseases.
In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and/or they may be selected from different classes of therapeutic agents.
In some embodiments, when a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one or more additional therapeutic agents as described herein, the components of the composition are administered in a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, e.g., as a solid dosage form for oral administration.
In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with one or more additional therapeutic agents.
Co-administration includes administering a unit dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, before or after administering a unit dose of one or more additional therapeutic agents. The compounds provided herein, or pharmaceutically acceptable salts thereof, can be administered within seconds, minutes, or hours of administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered first, followed by administration of the unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, within seconds or minutes. In some embodiments, a unit dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered first, followed by administration of the unit dose of one or more additional therapeutic agents after a period of several hours (i.e., 1 to 12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of the unit dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, after a period of several hours (i.e., 1 to 12 hours).
In some embodiments, the compound of formula I or II, or a pharmaceutically acceptable salt thereof, is formulated as a tablet, which may optionally contain one or more other compounds useful in the treatment of the disease being treated. In certain embodiments, the tablet may contain another active ingredient for use in treating an inflammatory disorder or other indications described herein. In some embodiments, such tablets are suitable for once daily administration.
Also provided herein are methods of treatment, wherein a compound of formula I or II, or a tautomer or pharmaceutically acceptable salt thereof, is administered to a patient in combination with one or more additional therapeutic agents or therapies. In some embodiments, the total daily dose of a compound of formula I or II, or a tautomer or pharmaceutically acceptable salt thereof, may be from about 1 mg/day to about 500 mg/day, administered to a human subject in a single dose.
Combination therapy for inflammatory disorders or diseases
In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, may be combined with one or more additional therapeutic agents to treat or ameliorate an inflammatory disorder. Non-limiting examples of inflammatory conditions include, but are not limited to, acne, acid-induced lung injury, addison's disease, adrenal hyperplasia, adrenocortical insufficiency, adult-onset still disease, adult Respiratory Distress Syndrome (ARDS), age-related macular degeneration, aging, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary, allergic conjunctivitis, allergic contact dermatitis, allergy, allergic encephalomyelitis, allergic neuritis, allograft rejection, hair loss, alopecia areata, alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, angina, angioedema, vascular fibroma, antiperspirant ectodermal dysplasia, anti-glomerular basement membrane disease, antigen-antibody complex mediated disease, ankylosing spondylitis, antiphospholipid syndrome aphthous stomatitis, appendicitis, arthritis, ascites, aspergillosis, asthma, atherosclerosis, atherosclerotic plaques, atopic dermatitis, atrophic thyroiditis, autoimmune diseases, autoimmune hemolytic anemia (immune whole blood cytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune polycystic endocrine diseases, autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune mediated thrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorders, autoimmune inflammatory diseases, back pain, bacillus anthracis infection, behcet's disease, inflammation caused by bee stings, behcet's syndrome, bell palsy, beryllium poisoning, blau syndrome, bone pain, bronchiolitis, bullous Pemphigoid (BP) asthma, burns, bursitis, cardiac hypertrophy, carpal tunnel syndrome, kalman's disease, catabolic disorders, cataracts, celiac disease, cerebral aneurysms, chemical stimulus-induced inflammation, chorioretinitis, chronic atypical neutrophil skin diseases with lipodystrophy and elevated body temperature (CANDLE) syndrome, chronic heart failure, chronic pulmonary disease in premature infants, chronic Obstructive Pulmonary Disease (COPD), chronic pancreatitis, chronic prostatitis, chronic recurrent multifocal osteomyelitis, cicatricial alopecia, colitis, complex regional pain syndrome, organ transplant complications, conjunctivitis, connective tissue disease, contact dermatitis, corneal graft neovascularization, corneal ulceration, crohn's disease, cryptothermal protein-related periodic syndrome, cutaneous Lupus Erythematosus (CLE), cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist Deficiency (DIRA) dermatitis, dermatitis endotoxemia, dermatomyositis, diabetic macular edema, diverticulitis, eczema, encephalitis, endometriosis, endotoxemia, eosinophilic pneumonia, epicondylitis, epidermolysis bullosa, erythema multiforme, juvenile erythropenia, esophagitis, familial amyloid polyneuropathy, familial cold urticaria, familial mediterranean fever, fetal growth retardation, fibromyalgia, fistula type Crohn's disease, food allergies, giant cell arteritis, glaucoma, glioblastoma, glomerular disease, glomerulonephritis (glomerular nephritis), glomerulonephritis (glomerulonephritis), gluten sensitive enteropathy, gout, gouty arthritis, graft Versus Host Disease (GVHD), granulomatosis hepatitis, graves disease, growth plate injury, guillain-Barre syndrome, intestinal tract disease, alopecia, hashimoto thyroiditis, head injury, headache, hearing loss, heart disease, hemangioma, hemolytic anemia, hemophilia joint, henno-Schonlein purpura, hepatitis, hereditary periodic fever syndrome, connective tissue hereditary disease, shingles and herpes simplex, suppurative sweat gland (HS), hip joint replacement, hodgkin's disease, huntington's disease, hyalopathy, hyperreactivity, hypercoammonemia, hypercalcemia, hypercholesteremia, hypereosinophilic syndrome (HES), hyperimmunoglobulin syndrome D with recurrent fever (HIDS), allergic pneumonia, hypertrophic bone formation, dysplasia and other anemias, dysplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy, idiopathic inflammatory myopathy (dermatomyositis, polymyositis), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, immunoglobulin, immune complex hematophagic disease, immune deficiency, immunonephritic purpura, idiopathic thrombocytopenic purpura (P-P), HIV infection, inflammatory disease (ITP-Schonlein syndrome), including viral diseases such as AIDS (HIV infection), hepatitis a, hepatitis b, hepatitis c, hepatitis D and hepatitis e, herpes; inflammation, CNS inflammation, inflammatory Bowel Disease (IBD), inflammatory diseases of the lower respiratory tract (including bronchitis or chronic obstructive pulmonary disease), inflammatory diseases of the upper respiratory tract (including nasal and nasal sinuses) such as rhinitis or sinusitis, inflammatory diseases of the respiratory tract, inflammatory ischemic events such as stroke or sudden cardiac arrest, inflammatory lung disease, inflammatory myopathies such as myocarditis, inflammatory liver disease, inflammatory neuropathy, inflammatory pain, inflammation caused by insect bites, interstitial cystitis, interstitial lung disease, iritis, inflammation caused by irritants, ischemia/reperfusion, joint replacement, juvenile arthritis, juvenile rheumatoid arthritis, keratitis, kidney injury caused by parasitic infection, renal transplant rejection, leptospirosis, leukocyte adhesion deficiency, lichen Sclerosus (LS), lambert-eaton myasthenia syndrome luffler's syndrome, lupus nephritis, lyme disease, ma Fanzeng Syndrome (MFS), mast cell activation syndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixed connective tissue disease, mu Keer-wils syndrome (urticaria, deafness, amyloidosis), mucositis, multiple organ injury syndrome, multiple sclerosis, muscle atrophy, muscular dystrophy, and Myasthenia Gravis (MG), myelodysplastic syndrome, myocarditis, myositis, sinusitis, necrotizing enterocolitis, neonatal Onset Multisystem Inflammatory Disease (NOMID) neovascular glaucoma, nephrotic syndrome, neuritis, neuropathic disease, non-allergen induced asthma, obesity, ocular allergy, optic neuritis, organ transplant rejection, osler-Weber syndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis, osteoporosis, osteoarthritis, otitis, congenital panonycis, paget's disease, pancreatitis, parkinson's disease, pediatric rheumatism, pelvic inflammatory disease, pemphigus Vulgaris (PV), bullous Pemphigoid (BP), pericarditis, periodic fever, periodontitis, endometriosis, pernicious anemia (Addison's disease), pertussis, PFAPA (periodic fever aphtha pharyngitis and cervical adenosis), pharyngitis and adenosis (PFAPA syndrome), inflammation caused by plant irritants, infection by pneumosporosis, pneumonia, localized pneumonia, inflammation caused by Pugegen/urushiol oil, nodular polyarthritis, polychondritis, polycystic kidney disease, polymyalgia rheumatica, giant cell arteritis, polymyositis pouch inflammation, reperfusion injury and graft rejection, primary biliary cirrhosis, primary pulmonary hypertension, primary Sclerosing Cholangitis (PSC), proctitis, psoriasis vulgaris, psoriatic arthritis, psoriatic epidermis, psychosocial stress disease, pulmonary fibrosis, pulmonary hypertension, pyoderma gangrenosum, post-suppurative granulomatous fibrohyperplasia s, suppurative aseptic arthritis, raynaud's syndrome, leider's disease, reactive arthritis, kidney disease, renal transplant rejection, reperfusion injury, respiratory distress syndrome, retinal disease, post-lens fibrosis, raynaud's syndrome, rheumatic heart disease, rheumatic arthritis, rhinitis, psoriasis, rosacea, rhinitis, sarcoidosis, schnitzeler syndrome, scleritis, scleroderma, scoliosis, seborrhea, sepsis, septic shock, severe pain, szechuan syndrome, sickle cell anemia, silica-induced disease (silicosis), sjogren's syndrome, dermatological disorders, skin irritation, rash, skin allergies (contact dermatitis or allergic contact dermatitis), sleep apnea, spinal cord injury, spinal stenosis, spondyloarthropathies, sports injury, sprains and strains, stevens-johnson syndrome (SJS), stroke, subarachnoid hemorrhage, sunburn, synovial inflammation, systemic Inflammatory Response Syndrome (SIRS), systemic Lupus Erythematosus (SLE) Systemic Mastocytosis (SMCD) systemic vasculitis, idiopathic systemic vasculitis, temporal arteritis, tendinitis, tenosynovitis, thrombocytopenia, thyroiditis (thyroditis), thyroiditis (thyroiditis), tissue transplantation, toxoplasmosis, trachoma, transplant rejection, traumatic brain injury, tuberculosis, tubular interstitial nephritis, tumor Necrosis Factor (TNF) receptor-associated periodic syndrome (trap), type 1 diabetes, type 2 diabetes, type 1 or type 2 diabetic complications, ulcerative colitis, urticaria, uterine fibroids, uveitis, vascular restenosis, vasculitis (NHLBI), vitiligo, wegener granulomatosis, and whipple's disease.
Non-limiting examples of therapeutic agents that may be used in combination with the compounds provided herein or pharmaceutically acceptable salts thereof for the treatment of inflammatory diseases or conditions include alpha fetoprotein modulators; adenosine A3 receptor antagonists; adrenomedullin ligand; AKT1 gene inhibitors; an antibiotic; an antifungal agent; ASK1 inhibitors; atpase inhibitors; beta adrenergic receptor antagonists; BTK inhibitors; calcineurin inhibitors; a carbohydrate metabolism modulator; cathepsin S inhibitors; CCR9 chemokine antagonists; CD233 modulators; CD29 modulators; CD3 antagonists; a CD40 ligand inhibitor; CD40 ligand receptor antagonists; chemokine CXC ligand inhibitors; CHST15 gene inhibitors; collagen modulators; COT protein kinase inhibitors; CSF-1 agonists; CSF-1 antagonists; CX3CR1 chemokine modulator DYRK-1 alpha protein kinase inhibitor, eosinophil chemokine ligand inhibitor; EP4 prostaglandin receptor agonists; f1f0 ATP synthase modulators; a farnesyl ester X receptor (FXR, NR1H 4) agonist or modulator; fecal Microorganism Transplantation (FMT), actin ligand inhibitor; free fatty acid receptor 2 antagonists; GATA 3 transcription factor inhibitors; glucagon-like peptide 2 agonists; glucocorticoid agonists; glucocorticoid receptor modulators; guanylate cyclase receptor agonists; HIF prolyl hydroxylase inhibitors; histone deacetylase inhibitors; HLA class II antigen modulators; hypoxia inducible factor-1 stimulators; ICAM1 gene inhibitors; IL-1 beta ligand modulators; an IL-12 antagonist; IL-13 antagonists; IL-18 antagonists; IL-18 receptor accessory protein antagonists and IL-22 agonists; an IL-23 antagonist; inhibitors of IL-23A; IL-6 antagonists; IL-7 receptor antagonists; IL-8 receptor antagonists; IL-36 inhibitors, integrin alpha-4/beta-1 antagonists; integrin alpha-4/beta-7 antagonists; integrin antagonists; an interleukin ligand inhibitor; an interleukin receptor 17A antagonist; an interleukin-1 beta ligand; an interleukin 1-like receptor 2 inhibitor; IL-6 receptor modulators; JAK tyrosine kinase inhibitors; jak1 tyrosine kinase inhibitors; jak3 tyrosine kinase inhibitors; lactoferrin stimulators; lanC-like protein 2 modulators; leukocyte elastase inhibitors; an inhibitor of leukocyte protease-3; MAdCAM inhibitors; melanin-concentrating hormone (MCH-1) antagonists; melanocortin agonists; metalloproteinase-9 inhibitors; therapies targeting microbiome; a natriuretic peptide receptor C agonist; a neuregulin-4 ligand; NLRP3 inhibitors; NKG 2D activates NK receptor antagonists; NR1H4 receptor (FXR) agonists or modulators (deleted); nuclear factor κb inhibitors; opioid receptor antagonists; an OX40 ligand inhibitor; an oxidoreductase inhibitor; P2X7 purinergic receptor modulators; PDE 4 inhibitors; pellino homolog 1 inhibitors; PPAR alpha/beta agonists; pparγ agonists; protein arginine deiminase IV inhibitors, protein fimH inhibitors; p-selectin glycoprotein ligand-1 inhibitors; ret tyrosine kinase receptor inhibitors; inhibitors of RIP-1 kinase; inhibitors of RIP-2 kinase; an RNA polymerase inhibitor; sphingosine 1 phosphatase 1 stimulators; sphingosine-1 phosphate receptor-1 agonists; sphingosine-1 phosphate receptor-5 agonists; sphingosine-1 phosphate receptor-1 antagonists; sphingosine-1 phosphate receptor-1 modulators; stem cell antigen-1 inhibitors; superoxide dismutase modulators; SYK inhibitors; tissue transglutaminase inhibitors; TLR-3 antagonists; TLR-4 antagonists; toll-like receptor 8 (TLR 8) inhibitors; a tnfα ligand inhibitor; TNF ligand inhibitors; tnfα ligand modulators; TNF antagonists; TPL-2 inhibitors; tumor necrosis factor 14 ligand modulators; tumor necrosis factor 15 ligand inhibitors; tyk2 tyrosine kinase inhibitors; type I IL-1 receptor antagonists; capsaicin VR1 agonist; and a desmin inhibitor; or any combination thereof.
Adenosine A3 receptor antagonists include, but are not limited to, PBF-677.
Adrenomedullin ligands include, but are not limited to, adrenomedullin.
Antibiotics include, but are not limited to, ciprofloxacin, clarithromycin, metronidazole, vancomycin, rifamycin, rifaximin, and tosufloxacin.
ASK1 inhibitors include, but are not limited to GS-4997.
Alpha fetoprotein modulators include, but are not limited to ACT-101.
anti-CD 28 inhibitors include, but are not limited to JNJ-3133 and abacavir.
Beta adrenergic receptor antagonists include, but are not limited to NM-001.
BTK inhibitors include, but are not limited to GS-4059.
Calcineurin inhibitors include, but are not limited to, tacrolimus and cyclosporine.
Modulators of carbohydrate metabolism include, but are not limited to ASD-003.
Cathepsin S inhibitors include, but are not limited to VBY-129.
CCR9 chemokine antagonists include, but are not limited to CCX-507.
CD233 modulators include, but are not limited to GSK-2831781.
CD29 modulators include, but are not limited to, PF-06687234.
CD3 antagonists include, but are not limited to, NI-0401, moromiab-CD 3, and ti Li Zhushan.
CD4 antagonists include, but are not limited to IT-1208.
CD40 ligand inhibitors include, but are not limited to SAR-441344 and Leuconostoc.
CD40 gene inhibitors include, but are not limited to, NJA-730.
CD40 ligand receptor antagonists include, but are not limited to, FFP-104, BI-655064, ABBV-323, and VIB-4920.
Chaperonin-binding immunoglobulins include, but are not limited to IRL-201805.
Chemokine CXC ligand inhibitors include, but are not limited to LY-3041658.
CHST15 gene inhibitors include, but are not limited to STNM-01.
Collagen modulators include, but are not limited to ECCS-50 (DCCT-10).
COT protein kinase inhibitors include, but are not limited to GS-4875.
CSF-1 antagonists include, but are not limited to, JNJ-40346527 (PRV-6527) and SNDX-6352.
CX3CR1 chemokine modulators include, but are not limited to E-6130.
DYRK-1 alpha protein kinase inhibitors include, but are not limited to VRN-02.
Therapies targeting microbiome include, but are not limited to, SER-287, SER-301 and SER-155.
Eosinophil chemokine ligand inhibitors include, but are not limited to, bai Ti xylanase.
EP4 prostaglandin receptor agonists include, but are not limited to KAG-308.
Modulators of F1F0 ATP synthase include, but are not limited to LYC-30937EC.
Inhibitors of the actin ligand include, but are not limited to, quinine Mo Lishan anti (E-6011).
Free fatty acid receptor 2 antagonists include, but are not limited to, GLPG-0974.
GATA 3 transcription factor inhibitors include, but are not limited to SB-012.
Glucagon-like peptide 2 agonists include, but are not limited to, tiltutin and apltutin.
Glucocorticoid receptor agonists include, but are not limited to, budesonide, beclomethasone dipropionate, and dexamethasone sodium phosphate.
Glucocorticoid receptor modulators/TNF ligand inhibitors include, but are not limited to ABBV-3373.
Guanylate cyclase receptor agonists include, but are not limited to, dulcamide (dolcanatide).
HIF prolyl hydroxylase inhibitors include, but are not limited to, DS-1093 and AKB-4924.
HIF prolyl hydroxylase-2 inhibitors/hypoxia inducible factor-1 stimulators include, but are not limited to, GB-004.
Histone deacetylase inhibitors include, but are not limited to, ji Weisi he and NIPEP-CARE.
Inhibitors of histone deacetylase-6 include, but are not limited to, CKD-506.
HLA class II antigen modulators include, but are not limited to, HLA class II protein modulators.
ICAM1 gene inhibitors include, but are not limited to, A Li Kafu sen (Alicaforsen).
IL-12 antagonists include, but are not limited to, utility model antibody (IL 12/IL 23).
IL-13 antagonists include, but are not limited to, qu Luolu monoclonal antibodies.
IL-18 antagonists include, but are not limited to GSK-1070806.
IL-18 receptor accessory protein antagonists include, but are not limited to, anti-IL-1R 7 canonical antibodies.
IL-22 agonists include, but are not limited to, AMT-126 and RG-7880.
IL-23 antagonists include, but are not limited to, teridazumab, rasagilawood monoclonal antibody (BI-655066), mi Jizhu monoclonal antibody (LY-3074828), cloth Lei Kushan antibody (AMG-139), IBI-112, and PTG-200.
IL-23A inhibitors include, but are not limited to, antilinukab.
IL-6 antagonists include, but are not limited to, olorimab.
IL-7 receptor antagonists include, but are not limited to OSE-127.
IL-8 receptor antagonists include, but are not limited to, clotrimazole.
Integrin alpha-4/beta-1 antagonists include, but are not limited to natalizumab.
Integrin alpha-4/beta-7 antagonists include, but are not limited to, itraconazole (a 4b7/aEb 7), vedolizumab, methylcalicheat (carotegrast methyl), TRK-170 (a 4b7/a4b 1), PTG-100 and PN-10943.
Integrin antagonists include, but are not limited to, E-6007.
Interleukin ligand inhibitors include, but are not limited to, bicizumab (IL-17A/IL-17F).
Interleukin receptor 17A antagonists include, but are not limited to, bai Dalu monoclonal antibodies.
Interleukin-1 beta ligands include, but are not limited to, K (D) PT.
Interleukin 1-like receptor 2 inhibitors include, but are not limited to, BI-655130.
IL-6 receptor modulators include, but are not limited to, amilo-5MER and Oxizepine.
JAK tyrosine kinase inhibitors include, but are not limited to, tofacitinib (1/3), pefacitinib (1/3), TD-3504, and TD-1473.
Jak1 tyrosine kinase inhibitors include, but are not limited to, the compounds disclosed in U.S. patent No. 9238628.
Jak3 tyrosine kinase inhibitors include, but are not limited to OST-122 and PF-06651600.
Jak3 tyrosine kinase inhibitors/TrkA receptor antagonists include, but are not limited to SNA-125.
Examples of other JAK inhibitors include, but are not limited to, AT9283, AZD1480, baratinib, BMS-911543, phenanthrene Zhuo Tini, non-golitinib (GLPG 0634), gan Duo tinib (LY 278444), INCB039110, letatinib, molotinib (CYT 0387), NS-018, panatinib (SB 1518), pefitinib (ASP 015K), lu Suoti, tofacitinib (previously known as tasatinib), XL019, wu Pati ni (ABT-494), LPG-0555, SHR-0302, and bupatinib (PF-06700841) (JAK 1/Tyk 2).
Lactoferrin stimulators include, but are not limited to, recombinant human lactoferrin (VEN-100).
LanC-like protein 2 modulators include, but are not limited to, BT-11 and BT-104.
Leukocyte elastase inhibitors/leukocyte protease-3 inhibitors include, but are not limited to, tiprenostat (tiprelestat).
MAdCAM inhibitors include, but are not limited to, SHP-647 (PF-547659).
Melanin concentrating hormone (MCH-1) antagonists include, but are not limited to, CSTI-100.
Melanocortin MC1 receptor agonists include, but are not limited to, ASP-3291 and PL-8177.
Metalloproteinase-9 inhibitors include, but are not limited to GS-5745.
Microbiome modulators include, but are not limited to, ABI-M201.
Natriuretic peptide receptor C agonists include, but are not limited to, procalcitonin.
Neuregulin-4 ligands include, but are not limited to, NRG-4.
NKG 2D-activating NK receptor antagonists include, but are not limited to JNJ-4500.
NLRP3 inhibitors include, but are not limited to, dapam Shu Jing, BMS-986299, SB-414, MCC-950, IFM-514, JT-194, PELA-167 and NBC-6.
The farnesyl ester X receptor (FXR, NR1H 4) agonists or modulators include, but are not limited to, AGN-242266, cilofaxadiol (cilofexor tromethamine) (GS-9674), EDP-305, EYP-001, GNF-5120, MET-409, MET-642, nidufexol (nidofor) (LMB-763), obeticholic acid, TERN-101, and topifexol (tropifexor).
Nuclear factor kappa B inhibitors include, but are not limited to, setannix (Thetanix).
Opioid receptor antagonists include, but are not limited to, naltrexone and IRT-103.
OX40 ligand inhibitors include, but are not limited to, KHK-4083.
Oxidoreductase inhibitors include, but are not limited to, olsalazine.
Pellino homolog 1 inhibitors include, but are not limited to, BBT-401.
P2X7 purinergic receptor modulators include, but are not limited to SGM-1019.
PDE 4 inhibitors include, but are not limited to, apremilast.
PPARα/δ agonists include, but are not limited to, eiafeno (elafiltrano) (GFT-1007).
PPARgamma agonists include, but are not limited to, GED-0507-34-Levo.
Protein fimH inhibitors include, but are not limited to, sibofimoc (EB-8018).
P-selectin glycoprotein ligand-1 inhibitors include, but are not limited to, SEL-K2, abGn-168H, and Ne Hu Zhushan antibodies.
Ret tyrosine kinase receptor inhibitors include, but are not limited to, GSK-3179106.
RIP-1 kinase inhibitors include, but are not limited to, GSK-2982772 and VRN-04.
RIP-2 kinase inhibitors include, but are not limited to GSK-2983559.
Sphingosine 1 phosphate phosphatase 1 stimulators include, but are not limited to, itramod.
Sphingosine-1-phosphate receptor-1 agonists include, but are not limited to, mo Kewei molds (mocravidmod) (KRP-203) and BMS-986166.
Sphingosine-1-phosphate receptor-1 agonists/sphingosine-1-phosphate receptor-5 agonists include, but are not limited to, ozanimod (ozanimod).
Sphingosine-1-phosphate receptor-1 antagonists include, but are not limited to, amixomod (MT-1303).
Sphingosine-1-phosphate receptor-1 modulators include, but are not limited to OPL-002, SK1-I.
Stem cell antigen-1 inhibitors include, but are not limited to, amountin (Ampion) (DMI-9523).
Superoxide dismutase modulators include, but are not limited to, medium dismutase (missmase).
Syk inhibitors include, but are not limited to GS-9876.
Tissue transglutaminase inhibitors include, but are not limited to, zanpipimumab
TLR-3 antagonists include, but are not limited to PRV-300.
TLR-4 antagonists include, but are not limited to JKB-122.
Toll-like receptor 8 (TLR 8) inhibitors include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, mo Tuo molde (motolimod), raschimod (resiquimod), VTX-1463, and VTX-763.
TNFα ligand inhibitors include, but are not limited to, adalimumab, pegylated cetuximab, infliximab, golimumab, DLX-105, debio-0512, HMPL-004, CYT-020-TNFQb, hemay-007, and V-565.
TNFα ligand modulators/IL-1β ligand modulators include, but are not limited to, PUR-0110.
TNF antagonists include, but are not limited to, AVX-470, tolengept (tulingercept), and etanercept.
Tumor necrosis factor 14 ligand modulators include, but are not limited to AEVI-002.
Tumor necrosis factor 15 ligand inhibitors include, but are not limited to PF-06480605.
Tyk2 tyrosine kinase inhibitors include, but are not limited to PF-06826647 and BMS-986165.
Type I IL-1 receptor antagonists include, but are not limited to, anakinra.
The catenin inhibitors include, but are not limited to, lanreozole acetate.
In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one or more anti-inflammatory agents. Anti-inflammatory agents include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs), non-specific and COX-2 specific cyclooxygenase inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, and immunosuppressants.
Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxenAnd naproxen sodium, diclofenac, a combination of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac (etodolac), fenoprofen calcium, ketoprofen, nabumetone sodium, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Additional examples of NSAIDs also include, but are not limited to, COX-2 specific inhibitors (i.e., IC in a specific ratio to COX-1 50 At least 50 times lower IC 50 COX-2 inhibiting compounds) such as celecoxib, valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib.
In some embodiments, the anti-inflammatory agent is salicylate. Salicylates include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate, choline, and magnesium salicylate.
In some embodiments, the anti-inflammatory agent is a corticosteroid. Non-limiting examples of corticosteroids include cortisone, dexamethasone, methylprednisolone, prednisolone sodium phosphate, and prednisone.
In some embodiments, the anti-inflammatory agent is a gold compound, such as gold sodium thiomalate or gold nofin.
In some embodiments, the anti-inflammatory agent is a metabolic inhibitor. Non-limiting examples of metabolic inhibitors include dihydrofolate reductase inhibitors such as methotrexate, or dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide.
In some embodiments, the anti-inflammatory agent is an anti-C5 monoclonal antibody (such as eculizumab or pegzhuzumab), a TNF antagonist (such as etanercept), or infliximab, which is an anti-tnfα monoclonal antibody.
In some embodiments, the anti-inflammatory agent is an immunosuppressant. Non-limiting examples of immunosuppressants include methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, sodium mycophenolate, mercaptopurine, and mycophenolate mofetil.
In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with one or more agents useful in the treatment and/or prevention of Osteoarthritis (OA). Non-limiting examples of such agents include non-steroidal anti-inflammatory drugs (NSAIDs), topical capsaicin, intra-articular glucocorticoid injections, acetaminophen, duloxetine, tramadol, and injectable corticosteroids such as methylprednisolone acetate, triamcinolone acetonide acetate, betamethasone acetate and betamethasone sodium phosphate, hexamcinolone acetonide (triamcinolone hexacetonide) and dexamethasone.
In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with one or more agents useful in the treatment and/or prevention of pulmonary diseases, such as Idiopathic Pulmonary Fibrosis (IPF) or Interstitial Lung Disease (ILD). Non-limiting examples of such agents include nintedanib, pirfenidone, corticosteroids such as prednisone, other rheumatological drugs, including mycophenolate esters (e.g.,) Azathioprine (e.g.)>) Leflunomide (e.g., a->) Rituximab (e.g.)>) Cyclophosphamide (e.g.)>) Tacrolimus (e.g.)>) Gastric acid reducing agents such as H-2-receptor antagonists or proton pump inhibitors, such as lansoprazole (e.g.)>) Omeprazole (e.g. Prilosec OTC) andpantoprazole (e.g., a>)。
In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with one or more agents useful in the treatment and/or prevention of liver disease or kidney disease, such as NAFLD, NASH, DKD or CKD. Non-limiting examples of such agents include metformin, sodium-glucose cotransporter-2 inhibitors (SGLT 2 i), drug therapies for glycemic control, DPP-4 inhibitors, insulin, sulfonylurea, TZD (thiazolidinedione), alpha-glucosidase inhibitors, SGLT2 inhibitors (e.g., engagliflozin (empagliflozin), canaglizin (canaglizin), dapagliflozin (dapagliflozin)), glucagon-like peptide-1 receptor agonists (GLP-1 RA) (e.g., lixisenatide), liraglutide (liraglutide), plug Ma Gelu peptide (semaglutinide), exenatide (exenatide), abiratide (albiglutide), dulcitide (dulaglutin), DPP-4 inhibitors (e.g., saxagliptin), alogliptin (alogliptin), sitagliptin (alexin), sitagliptin (35 b), drugs such as for the treatment of obesity, vascular disorders (e.g., diabetes), vascular drugs (e.g., vascular drugs), vascular drugs (e.g., vascular drugs), and glucose-lowering drugs (e.g., glucose-2).
In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with one or more agents useful in the treatment and/or prevention of skin disorders such as Atopic Dermatitis (AD). Non-limiting examples of such agents include Topical Corticosteroids (TCS) (e.g., budesonide, hydrocortisone, fluocinolone, triamcinolone, betamethasone dipropionate), topical Calcineurin Inhibitors (TCI) (e.g., tacrolimus, pimecrolimus), topical antimicrobials and preservatives, cyclosporine, methotrexate, mycophenolate mofetil, interferon gamma, phosphodiesterase 4 (PDE 4) inhibitors such as crizoole (crisabole), JAK inhibitors such as ruxotinib, wu Pati ni (upadacrinib), abaxitinib (abrocitib)), systemic glucocorticoids (e.g., prednisone), dipyridamole Li Youshan anti (dupilumab) and anti-IL-13 antibodies (e.g., qu Luolu monoclonal antibodies).
Combination therapy for lupus
In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is combined with one or more additional therapeutic agents, the one or more additional therapeutic agents target adenosine homocysteine, ADP ribosyl cyclase-1 (CD 38), corticotropin ligand, AIMP multisynthetase complex protein 1, annexin A1 modulator, B and T lymphocyte attenuation factor (BTLA), BDCA2, beta 2 adrenergic receptor, B lymphocyte antigen CD19, B lymphocyte antigen CD20, B lymphocyte adhesion molecule (CD 22), B lymphocyte stimulatory factor ligand (BAFF), btk tyrosine kinase, cannabinoid CB2 receptor, CD11B agonist, CD38 activation-inducible TNF receptor, CD40 (CD 154) ligand, CD74, CD79B modulator, CDw123, collagen VII (ColVII), complement C5 factor type C lectin domain protein 4C, CXCR5 chemokine modulators, deoxyribonuclease modulators, DNA binding proteins Ikaros, DYRK-1 alpha protein kinase, dndoplasmin, exporter 1, FK506 binding proteins, glucocorticoid receptor, HLA antigen, IL-10, IL-23 mIL-12 receptor, IL-2 receptor alpha subunit, IL-21 modulator, IL-6R, immunoglobulin gamma Fc receptor II modulator, immunoglobulin gamma Fc receptor IIB, inducible T cell costimulatory molecules, interferon alpha ligand (INF-alpha), interferon omega ligand (INFomega), interferon type I receptor, interleukin-2 ligand, itk tyrosine kinase, JAK tyrosine kinase, jak1 tyrosine kinase, jak2 tyrosine kinase, jak3 tyrosine kinase, KCNA voltage-gated potassium channel-3, leukocyte Ig-like receptor A4 modulator, mitochondrial 10kDa heat shock protein, mTOR, non-receptor tyrosine kinase TYK2, nuclear export, nuclear factor κb-induced kinase, nuclease stimulator, OX-40 receptor, PARP modulator, proteasome modulator, protein arginine deiminase IV (PAD 4), cerebellar protein modulator, protein MB21D1, retinoid Z receptor gamma reversal, rho-associated protein kinase 1, rho-associated protein kinase 2, serine threonine protein kinase TBK1 (TBK 1), sphingosine kinase 1, sphingosine-1-phosphate receptor-1 modulator, interferon gene stimulator protein, syk tyrosine kinase, T cell surface glycoprotein CD28, T cell differentiation antigen CD6, tyrosine-7 modulator, TLR-8 modulator, TLR-9 modulator, transcription factor modulator, tumor necrosis factor ligand 13 (apl), TYK2 kinase, ubiquitin ligase modulator and/or zinc finger binding protein.
In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one, two, three, or four additional therapeutic agents selected from the group consisting of:
activation-induced TNF receptor agonists including, but not limited to BMS-986256;
adenosine homocysteine inhibitors including, but not limited to, DZ-2002;
corticotropin ligands including, but not limited to, corticotropin;
AIMP multiple synthase complex protein 1 stimulators/Endoplasmin inhibitors, including but not limited to, dockerin;
anti-CDw 123 antibodies, including but not limited to tuzumab-b;
annexin A1 modulators, including but not limited to annexuzlimab;
anti-IL-12/IL 23 antibodies, including but not limited to AK-101;
anti-BAFF-R antibodies, including but not limited to ranagliptin;
anti-BDCA 2 antibodies, including but not limited to BIIB-059;
anti-BLys antibodies, including but not limited to belgium and UBP-1213;
anti-BTLA modulator antibodies, including but not limited to LY-3361237;
anti-C5 antibodies, including but not limited to eculizumab;
anti-CD 154 antibodies, including but not limited to TNX-1500;
anti-CD 19/CD32b antibodies, including but not limited to obeticlopidine;
anti-CD 20 antibodies, including but not limited to veltuzumab;
anti-CD 22 antibodies, including but not limited to SM-06, SM-03;
anti-CD 28 antibodies, including but not limited to sirolimus;
anti-CD 38 antibodies, including but not limited to TAK-079 and fezetuzumab;
anti-CD 40 antibodies, including but not limited to, iscalicheamicin and pegylated dapiromant;
anti-CD 6 antibodies, including but not limited to illicit mab;
anti-CD 74 antibodies, including but not limited to Mi Latuo bead mab;
anti-CXCR 5 antibodies including but not limited to PF-06835375;
anti-IFN- α antibodies, including but not limited to QX-006-N;
anti-IFN-alpha/omega antibodies, including but not limited to JNJ-55920839;
anti-IL-10 antibodies, including but not limited to BT-063;
anti-IL-21 antibodies, including but not limited to BOS-161721;
anti-IL-6R nanobodies, including but not limited to Wo Bali bead mab;
anti-ILT 7 antibodies, including but not limited to dasdipy Li Shan antibodies;
an anti-interferon alpha vaccine, including but not limited to CKD-971;
anti-interferon receptor type I antibodies, including but not limited to anilurumab;
anti-PAD 4 antibodies, including but not limited to PFI-102;
anti-TLR-7 antibodies, including but not limited to DS-7011;
BAFF/APRIL inhibitors, including but not limited to ALPN-303;
β2 adrenergic receptor agonists including, but not limited to, salbutamol R-sulfate;
bispecific antibodies targeting BAFF/ICOSL, including but not limited to lobifuα;
bispecific antibodies targeting CD32B/CD79B, including but not limited to PRV-3279;
bispecific antibodies targeting Col VII/BAFF, including but not limited to TE-2324;
b lymphocyte stimulating factor ligand inhibitors including, but not limited to, asenapine and taitaziprap;
btk tyrosine kinase inhibitors including, but not limited to, AC-0058, non-nilotinib, XNW-1011, tiramitinib hydrochloride, brinbutinib, albuttinib, and obutinib;
btk/itk tyrosine kinase inhibitors, including but not limited to DWP-213388;
Btk/Jak3 tyrosine kinase inhibitors including, but not limited to DWP-212525;
cannabinoid CB2 receptor agonists, including but not limited to juliemic acid;
CD11b agonists, including but not limited to LA-1;
deoxyribonuclease gamma stimulators, including but not limited to NTR-441;
deoxyribonuclease modulators, including but not limited to ao Sha Di D;
DYRK-1 alpha protein kinase inhibitors, including but not limited to VRN-02;
Output protein 1 inhibitors, including but not limited to SINE compounds;
glucocorticoid receptor agonists including, but not limited to, prednisone;
HLA antigen modulators, including but not limited to pegylated HLA-x (SLE);
IL-2 receptor alpha subunit stimulators including, but not limited to, NKTR-35;
immunoglobulin gamma Fc receptor IIB modulators, including but not limited to valoxepin;
inducible T cell costimulatory molecule Inhibitors (ICOS)/T cell surface glycoprotein CD28 inhibitors including, but not limited to ALPN-101;
interferon alpha ligand modulators/TLR-7/TLR-9 modulators, including but not limited to DV-1079;
interleukin-2 ligands including, but not limited to, interleukin-2 Anteluke, interking recombinant human interleukin-2, ILT-101 and CUG-252;
interleukin-2 ligand/IL-2 receptor agonist including but not limited to interleukin-2 subsequent biologic;
JAK 1/2/3 and ROCK 1/2 inhibitors, including but not limited to CPL-409116;
JAK tyrosine kinase inhibitors including, but not limited to, diltiatinib;
jak1/Jak2 tyrosine kinase inhibitors, including but not limited to baratinib;
jak1 tyrosine kinase inhibitors including, but not limited to Wu Pati Ni, fingolitinib, itatinib and INCB-54707;
Jak1/Tyk2 tyrosine kinase inhibitors including, but not limited to, bupacitinib, SDC-1801, and SDC-1802;
JAK3/1 and TBK1 kinase inhibitors including, but not limited to CS-12192;
JAK3/JAK1 tyrosine kinase inhibitors including, but not limited to, tofacitinib citrate;
KCNA voltage-gated potassium channel-3 inhibitors, including but not limited to dalapatin;
mitochondrial 10kDa heat shock protein stimulators including, but not limited to, INV-103;
mTOR inhibitors, including but not limited to TAM-01;
non-receptor tyrosine kinase TYK2 antagonists including, but not limited to ICP-330;
nuclear output inhibitors, including but not limited to, vandinisole;
nuclear factor κb-induced kinase inhibitors including, but not limited to NIK-SMI1;
nuclease-stimulating agents, including but not limited to RSLV-132;
OX-40 receptor antagonists including, but not limited to ISB-830;
PARP modulators, including but not limited to bendamustine hydrochloride;
NK-92 cell therapy expressing PD-L1 CAR;
proteasome inhibitors, including but not limited to KZR-616;
cerebellar protein modulators, including but not limited to, ifenprodil Bei Du;
protein MB21D1 inhibitors, including but not limited to X-6;
retinoid Z receptor gamma inverse agonists, including but not limited to INV-17;
Sphingosine kinase 1 inhibitors, including but not limited to BML-258;
sphingosine-1-phosphate receptor-1 modulators, including but not limited to, cinnemod;
syk tyrosine kinase inhibitors, including but not limited to GSK-2646264, SKI-O-703, lanrapini (GS-9876), GNS-1653, and HMPL-523;
TLR-9 antagonists including, but not limited to, chloroquine, hydroxychloroquine sulfate, COV-08-0064; GNKS-356 and AVO-101;
TLR7/8 antagonists including, but not limited to, M-5049, E-6887, and BMS-986256;
TLR-8 antagonists including, but not limited to ZG-170607;
TLR7/8/9 antagonists including, but not limited to IMO-8400 and IMO-9200;
tyk2 tyrosine kinase inhibitors including, but not limited to, deuterated celecoxib;
ubiquitin ligase modulators including, but not limited to, KPG-818; and
other agents for treating lupus, including but not limited to, mometasone, betamethasone, formoterol, arachidonylethanolamine, DCB-SLE1, arsenic trioxide, tairuimide, TV-4710 (Qu Tai), allogenic human umbilical cord-derived mesenchymal stem cell therapy (hUC-MSC), LC-200, BI-705564, SM-934, GX-101, TXR-712, TXR-711, CIT-013, MHV-370,TPX-6001, TPX-7001, dihydroartemisinin, AMG-592, phosphatidylserine-liposome based immunotherapy and CD4+CD317lo/-CD25+ polyclonal regulatory T cells.
In some casesIn embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, may be combined with one, two, three, or four additional therapeutic agents selected from the group consisting of: vitozumab, PF-06835375, exkulizumab, mi Latuo bead mab, SM-06, SM-03, BT-063, QX-006-N, BOS-161721, AK-101, TNX-1500, cilarizumab, dasardiod Li Shan, TAK-079, fevertuzumab, illimumab, anilauzumab, iskarituxab, PEGylated dapirobenzolimumab, ranafuzumab, LY-3361237, JNJ-55920839, UBP-1213, DS-7011, PFI-102, BIIB-059, obtuzumab, tatuzumab Wo Bali bead mab, TE-2324, PRV-3279, chloroquine, hydroxychloroquine sulfate, COV-08-4; GNKS-356, AVO-101, lobifuα, VRN-02, annexuzlimab, ALPN-101, bendamustine hydrochloride, BMS-986256, NKTR-35, asenapine, tiazepine, BMS-986256, M-5049, KZR-616, KPG-818, vandicable, ALPN-303, valoxepin, LA-1, cinamomod, prednisone, corticotropin, deuterostatinib, CPL-409116, CS-12192, tofacitinib citrate, ISB-830, DV-1079, juliemic acid, I Bei Du amine, TAM-01, BML-258, bupacitinib, SDC-1801, SDC-1802, ICP-330, NTR-441, datazapeptide, GSK-2646264, SKI-O-703, lanprinib (GS-9876), GNS-1653, HMPL-523; RSLV-132, interleukin-2 subsequent biological preparation, interleukin-2 Anteluke, interking recombinant human interleukin-2, ILT-101, CUG-252, DZ-2002, PEGylated HLA-X (SLE), AC-0058, non-Nibutinib, XNW-1011, tiralutinib hydrochloride, brinbutinib, albutinib, obutinib, DWP-213388, INV-103, R-salbutamol sulfate, ankyrin, NIK-SMI1, X-6, INV-17, O Sha Di D, barittinib, wu Pati, non-golitinib, itatinib, INCB-54707, dighatinib, DWP-212525, CKD-971, as mometasone, betamethasone, furitol, arachidonylethanolamine, DCB-SLE1, arsenic trioxide, tairuimide, TV-4710 (Qu Tai), allogenic human umbilical cord-derived mesenchymal stem cell therapy (hUC-MSC), LC-200, BI-705564, SM-934, GX-101, TXR-712, TXR-711, CIT-013, MHV-370, TPX-6001, TPX-7001, dihydroartemisinin and AMG-592, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.
In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with one or more agents useful for treating and/or preventing Systemic Lupus Erythematosus (SLE) or Lupus Nephritis (LN). Non-limiting examples of such agents include immunosuppressive drugs that inhibit immune system activity and agents approved for the treatment of SLE, such as hydroxychloroquine, steroids and corticosteroids (e.g., prednisone, methylprednisolone), beluzumab, azathioprine, methotrexate, cyclophosphamide, meclofenoxate and mycophenolate mofetil, cyclosporine, leflunomide, cyclosporine, abacavine, anilamab, rituximab, NSAIDS such as naproxen sodium and ibuprofen, antimalarials such as hydroxychloroquine, calcineurin inhibitors and tacrolimus.
In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with two or more agents useful in treating LN, such as prednisone+mycophenolic acid analog, prednisone+mycophenolate sodium prednisone+cyclophosphamide, prednisone+tacrolimus, prednisone+cyclosporine, prednisone+ Bei Liyou mab+mycophenolic acid analog, prednisone+ Bei Liyou mab+cyclophosphamide, prednisone+rituximab.
In further embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with two or more agents useful in treating LN, such as prednisone+mycophenolic acid analog, prednisone+mycophenolate sodium, prednisone+azathioprine, prednisone+tacrolimus, prednisone+cyclosporine, prednisone+mizoribine.
Combination therapy for psoriasis
In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, may be combined with one, two, three, or four additional therapeutic agents useful in treating or ameliorating psoriasis. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one, two, three, or four additional therapeutic agents selected from the group consisting of: acetaldehyde dehydrogenase inhibitors, adenosine A1 receptor antagonists, adenosine A3 receptor agonists, ADPribosyl cyclase-1 inhibitors, alpha 2 adrenergic receptor modulators, apolipoprotein A antagonists, arene receptor agonists, bcl-xL Bcl-2 related death promoter modulators, beta amyloid antagonists, beta-catenin inhibitors, bromodomain-containing protein inhibitors, ca2+ release-activating Ca2+ channel 1 inhibitors, calcineurin inhibitors, calcium channel inhibitors, cannabinoid CB1 receptor antagonists, cathepsin S inhibitors, CCR3 chemokine antagonists, CXCR2 chemokine antagonists, CXCR1/2 chemokines, CCR6 chemokine antagonists, CD223 modulators, CD40 ligand receptor antagonists, cell adhesion molecule inhibitors, cell surface glycoprotein MUC18 inhibitors, CREB binding protein inhibitors, CXCR4 chemokine modulators, cytokine receptor antagonists, cytoplasmic phospholipase A2 inhibitors, DHFR inhibitors, DYRK-1 alpha protein kinase inhibitors, EGFR family tyrosine kinase receptor inhibitors, enolase 1 inhibitors, eosinophil chemokine ligand inhibitors, F1F0 ATP synthase modulators, free fatty acid receptor 2 agonists, free fatty acid receptor 3 agonists, galectin-3 inhibitors, glucocorticoid agonists, GM-CSF ligand inhibitors, GNRH receptor modulators, 5-HT1a receptor antagonists, FGF receptor antagonists, groEL protein 2 inhibitors, histamine H1 receptor antagonists, histamine H4 receptor antagonists, histone deacetylase-1 inhibitors, histone deacetylase-2 inhibitors, histone deacetylase-3 inhibitors, histone deacetylase-6 inhibitors, hsp90 inhibitors, IL-1 receptor antagonists, interleukin 1-like receptor 2 inhibitors, IL-2 receptor alpha subunit stimulators, IL-2 modulators, IL-10 antagonists, IL-12 antagonists, IL-17 agonists, IL17RA gene inhibitors, IL-17 antagonists, IL-23 antagonists, IL-8 antagonists, immunoglobulin-like domain receptor 2 antagonists, insulin receptor substrate-1 inhibitors, interferon gamma receptor antagonists, interleukin 17 ligand inhibitors, interleukin 17A ligand modulators, interleukin 17F ligand inhibitors, interleukin 23A inhibitors, interleukin receptor 17A antagonists, interleukin receptor 17A modulators, interleukin-1 alpha ligand inhibitors, interleukin-1 beta ligand modulators, IRAK-4 protein kinase inhibitors, itk tyrosine kinase inhibitors, JAK tyrosine kinase inhibitors, jak1 tyrosine kinase inhibitors, jak2 tyrosine kinase inhibitors, jak3 tyrosine kinase inhibitors, KCNA voltage-gated potassium channel-3 inhibitors, lck tyrosine kinase inhibitors, lysophosphatidic acid-1 receptor antagonists, MALT protein 1 inhibitors, MAP kinase inhibitors, membrane copper amine oxidase inhibitors, metalloprotease-1 inhibitors, mitochondrial 10kDa heat shock protein stimulators, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, non-receptor tyrosine kinase TYK2 antagonists, nuclear factor erythroid 2-related factor 2 stimulators, nuclear factor kappa B inhibitors, nucleotide reverse transcriptase inhibitors, oncostatin M receptor subunit beta inhibitors, opioid receptor delta antagonists, OX40 ligand inhibitors, parathyroid hormone ligand inhibitors, PDE 4b inhibitors, P2Y6 purinergic receptor modulators; p-glycoprotein inhibitors, phosphoinositide-3 kinase delta inhibitors, phosphoinositide-3 kinase gamma inhibitors, phospholipase A2 inhibitors, apoptosis ligand 1 modulators, apoptosis protein 1 stimulators, P-selectin glycoprotein ligand-1 stimulators, retinoic acid receptor agonists, retinoic acid receptor gamma antagonists, retinoic acid receptor gamma inverse agonists, retinoid receptor agonists, retinoid X receptor modulators, retinoid Z receptor gamma agonists, retinoid Z receptor gamma inverse agonists, retinoid Z receptor gamma antagonists, rho-related protein kinase 2 inhibitors, ribonuclease P inhibitors, RIP-1 kinase inhibitors, sphingosine-1-phosphate receptor-1 antagonists sphingosine-1-phosphate receptor-1 modulators, src tyrosine kinase inhibitors, STAT-3 inhibitors, syk tyrosine kinase inhibitors, T-box transcription factor TBX21 modulators, T cell differentiation antigen CD6 inhibitors, T cell surface glycoprotein CD8 inhibitors, T cell surface glycoprotein CD28 stimulators, TGF beta agonists, TLR-7 antagonists, TLR-8 antagonists, TLR-9 antagonists, TNF alpha ligand inhibitors, TNF alpha ligand modulators, TNF antagonists, TNF binding agents, TNF gene inhibitors, topoisomerase II inhibitors, trkA receptor antagonists, tubulin binding agents, tyk2 tyrosine kinase inhibitors, type II TNF receptor modulators, unspecified cytokine receptor antagonists, vitamin D3 receptor agonists, vitamin D3 receptor modulators, wnt ligand inhibitors and Wnt 5A ligand inhibitors.
In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one, two, three, or four additional therapeutic agents selected from the group consisting of: AP-005, 18C3 (anti-IL-1α fully human antibody), ABX-464, averment, adalimumab, adipocell, AFB-035, alganison (aganirsen), AKP-11, alfasin, aliskiren acid, amilo-5mer, aminopterin, amiximod, apremilast, ASKP-1240, AST-005, ATI-2138, AVX-001, balatinib, beraprost (belapectin) (GR-MD-02), bai Ti Mumab, betamethasone, BI-655066, BI-730357, BI-730460, BI-730460, bimeigzhuzumab, BMS-986165, BMX-010, bruuzumab, bai Dalu mab, BTT-1023, C-82, calciposide, triol, calcitriol, CC-90005, CCL-20LD, CD-10367' Pegylated cetuximab, CF-101, cyclosporin, CJM-112, CKBA, clobetasol propionate+retinoic acid, CM-2489, CPL-409116, clenbuterol, CS-12192, CT-327, CTX-101, darapatide, DFD-06, dimethyl fumarate, dithranol, DLX-105, DSXS-1411, DSXS-1535, DUR-928, EDP-1815, etanercept, fluocinolone acetonide, FPP-003, GK-664-S, GLG-801, GLPG-3121, GLPG-3667, GLPG-3970, GLY-2028, GMDP, GSK-2800528, GSK-2831781, GSK-2981278A, guzekuzumab, halometasone, HAT-1, IMO-3100, IMO-8400, inecalcitol, infliximab, INV-103 IR-444, IR-502, illicimumab, EQizumab, JN-2528, KBL-697, KD-025, LAS-41004, LEO-124249, LEO-29102, LEO-32731, LEO-35299, lithium succinate, LNP-1955, LP-0200, M-1095, maxacalcitol, MDX-018, methotrexate, MOL-4249, mometasone, MP-1032, MSB-03, myristyl nicotinate, nalmeflozumab, ne Hu Zhushan antibody, niclosamide, NLP-91, NP-000888, NVN-1000, olopatadine, oreotid (orilmod), P-3072, P-3073, PAT-7, 4, pentafluorostol (pefcall), PF-06700841 Prurisol, PRX-003, PRX-167700, PUR-0110, recombinant human LFA-3/antibody fusion protein, RON-2315, RTU-1096, S-414114, stuzumab, SHP-141, SMET-D1, SNK-01, SP-14019, SSS-07, tacalcitol, tazarotene, teridakamab, ter Ban Bulin (KX-01), tofacitinib, tolireline, trorimab, TU-2100, UCB-5857, UHE-105, ubetasol, ubeclomab, VBY-891, fuciclosporin, VTP-43742, WBI-1001 and ZPL-389 or a pharmaceutically acceptable salt of any of the foregoing or any combination thereof.
In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one, two, three, or four additional therapeutic agents selected from the group consisting of:
acetaldehyde dehydrogenase inhibitors including, but not limited to ADX-629;
adenosine A3 receptor agonists including, but not limited to, piridenoson (CF-101);
adenosine A3 receptor antagonists including, but not limited to PBF-1650;
ADP ribosyl cyclase-1 inhibitors, including but not limited to IMO-3100;
5-HT1a receptor antagonists, including, but not limited to AX-1602;
apolipoprotein a antagonists including, but not limited to, octreotide Su Shan antibodies;
cytokine receptor antagonists, including but not limited to, ben-rimod (tapinaof);
aromatic hydrocarbon receptor modulators including, but not limited to, NTI-528 and RLV-102;
Bcl-xL Bcl-2 related death promoting factor modulators, including but not limited to Pc4;
beta-catenin inhibitors, including but not limited to C-82;
bromodomain-containing protein inhibitors including, but not limited to BOS-475;
ca2+ release activates ca2+ channel 1 inhibitors, including but not limited to CM-2489 and PRCL-02;
calcineurin inhibitors including, but not limited to Fu Huan sporon, pimecrolimus, tacrolimus
Sesamycin, cyclosporine, HS-378, oxycyclosporine, OLO-400, ADV-P3 and CTX-006;
calcium channel inhibitors, including but not limited to RP-3128;
cathepsin S inhibitors including, but not limited to VBY-129, VBY-891, RWJ-445380 and CRA-028129;
CCR3 chemokine antagonists including, but not limited to Bai Ti mab;
CXCR2 chemokine antagonists including, but not limited to CCX-624;
CD223 modulators, including but not limited to GSK-2831781;
CD40 ligand receptor antagonists including, but not limited to ASKP-1240, lu Kamu monoclonal antibodies and tolaguemab;
cell adhesion molecule inhibitors including, but not limited to BIRT-2584, PC-114, A Li Kafu Sen, IC-747, ICM-3 and ISIS-2302;
cell surface glycoprotein MUC18 inhibitors including, but not limited to, PRX-003 and ipu Li Shan antibodies;
CREB binding protein inhibitors including, but not limited to, C-82;
CXCR1/2 chemokines including, but not limited to LY-3041658;
CXCR4 chemokine modulators, including but not limited to CD184-FK506 ADC;
cytosolic phospholipase A2 inhibitors including, but not limited to AVX-001;
DHFR inhibitors, including but not limited to methotrexate, CH-4051, cePep, CH-1504, MQX-5902, and MPI-2505;
DYRK-1 alpha protein kinase inhibitors, including but not limited to VRN-02;
EGFR family tyrosine kinase receptor inhibitors including, but not limited to erlotinib, icotinib hydrochloride and SGT-210;
enolase 1 inhibitors, including but not limited to HuL-001;
eosinophil chemokine ligand inhibitors, including but not limited to Bai Ti xylanase;
F1F0 ATP synthase modulators, including but not limited to LYC-30937;
FGF receptor antagonists including, but not limited to, potassium oxybenzene sulfonate;
free fatty acid receptor 2, 3 agonists, including but not limited to SFA-002;
galectin-3 inhibitors including, but not limited to, beraprost (GR-MD-02);
glucocorticoid agonists including, but not limited to, betamethasone, clobetasol, auranofin, NM-135, DSXS-1538b and SEGRA;
GM-CSF ligand inhibitors including, but not limited to, nalmefene;
GNRH receptor modulators, including but not limited to NL-001;
GroEL protein 2 inhibitors, including but not limited to prozumab;
histamine H1 receptor antagonists including, but not limited to olopatadine and loratadine + nortriptyline;
histamine H4 receptor antagonists including, but not limited to, tolterodine and ZPL-389;
Inhibitors of histone deacetylase-2, including but not limited to KAR-1880;
inhibitors of histone deacetylases 1, 6, 2, 3, including but not limited to remimetinostat (SHP-141);
hsp 90 inhibitors, including but not limited to CTXT-102;
IL-2 receptor alpha subunit stimulators including, but not limited to, NKTR-358;
IL-2 modulators; including but not limited to CC-92252;
IL-10 antagonists, including but not limited to pimecrolimus;
IL-12 antagonists, including but not limited to BOW-090, bryumab, FM-202, and apilimod;
IL-17 antagonists, including but not limited to, evodiumab, stuzumab, AFB-035, KD-025, DLX-3003, EBI-028, M-1095, IMO-3100, GR-1501, 608, funadir monoclonal antibody, solodizumab, AK-111, HB-0017 and SIM-335;
IL-17 agonists, including but not limited to ZL-1102;
IL17RA gene inhibitors, including but not limited to XCUR-17;
IL-23 antagonists, including but not limited to, teridazumab, BI-655066, AMG-139, brauzumab, mi Jizhu mab (LY-3074828), FM-202, apilimod, LY-2525623, ruixabebian, and IBI-112;
IL-23 antagonists, including but not limited to Utility mab and AK-101;
IL-8 antagonists, including but not limited to BMS-986253 (MDX-018), AS-101, ABX-IL8, LI-312, SB-332235, and LF-216;
immunoglobulin-like domain receptor 2 antagonists, including but not limited to CGEN-15001;
insulin receptor substrate-1 inhibitors including, but not limited to, alganison;
interferon gamma receptor antagonists including, but not limited to, pimecrolimus, AMG-811, OA-1, AGT-1, mometasone + nortriptyline and rituximab;
interleukin 17 ligand inhibitors including, but not limited to, CJM-1l2, nitazomycin and AFB-035;
interleukin 17A ligand inhibitors including, but not limited to, COVA-322, JS-005, and ABY-035/AFO2;
interleukin 17A ligand modulators, including but not limited to QX-002-N;
interleukin 17A/17F ligand inhibitors including, but not limited to, bimagrumab;
interleukin 23A inhibitors including, but not limited to, antique pessary mab and QX-004-N; interleukin receptor 17A antagonists including, but not limited to, bai Dalu mab and LZM-012;
interleukin 1-like receptor 2 inhibitors including, but not limited to, ste Bai Suoli mab (spisolimab) and ismidolimab (imsidolimab);
interleukin-1 alpha ligand inhibitors including, but not limited to, bei Maiji mab (bermekimab) (CA-18C 3);
Interleukin-1 beta ligand modulators, including but not limited to PUR-0110 and AR-100; IRAK-4 protein kinase inhibitors including, but not limited to BAY-1834845;
itk tyrosine kinase inhibitors, including but not limited to JTE-051;
JAK tyrosine kinase inhibitors including, but not limited to CS-17380;
jak1 tyrosine kinase inhibitors including, but not limited to, itatinib, abxitinib (PF-04965842), soritinib, SHR-0302 and non-gotinib;
JAK1,2,3 tyrosine kinase inhibitors including, but not limited to, jacktinib;
JAk1,2 tyrosine kinase inhibitors including, but not limited to, barytinib and ruxotinib;
TYk2 tyrosine kinase inhibitors including, but not limited to, bupacitinib;
jak1 tyrosine kinase inhibitors, including but not limited to PF-06263276;
JAk1, 3 tyrosine kinase inhibitors including, but not limited to, CS-944X, tofacitinib, and pefacitinib;
KCNA voltage-gated potassium channel-3 inhibitors including, but not limited to KPI-150, dalazalide, BNC-164, and SPS-4251;
lck tyrosine kinase inhibitors, including but not limited to BMS-350751 and NTRC-0625-0;
lysophosphatidic acid-1 receptor antagonists including, but not limited to BMS-986202;
MAP kinase inhibitors, including but not limited to AIK-33 and KIN-3032;
membrane copper amine oxidase inhibitors including, but not limited to, vipamomab, BTT-1023, RTU-1096, and PRX-167700;
inhibitors of metalloprotease-1, including but not limited to KIN-3032 and HMR-1571;
mitochondrial 10kDa heat shock protein stimulators including, but not limited to, INV-103;
non-receptor tyrosine kinase TYK2 antagonists including, but not limited to SAR-20347, ICP-332 and SDC-1801;
nuclear factor Red 2-associated factor 2 stimulators, including but not limited to dimethyl fumarate and XP-23829;
nuclear factor κb inhibitors including but not limited to S-414114, VGX-1027, AKBA, SP-100030 and YP-008;
nucleotide reverse transcriptase inhibitors, including but not limited to Prurisol;
inhibitors of oncostatin M receptor subunit β including, but not limited to, vitamin Sha Ruili mab (vixarelimab);
opioid receptor delta antagonists including, but not limited to, HS-378;
OX40 ligand inhibitors, including but not limited to KY-1005;
p38 MAP kinase inhibitors, including but not limited to AMG-101, AIK-3, VGX-1027, AIK-a1, BMS-582949, da Ma Mode, plug Ma Mode, TA-5493, HEP-689, and RWJ-68354;
parathyroid hormone ligand inhibitors including, but not limited to, inecalcitol;
PDE 4 inhibitors including, but not limited to, apremilast, roflumilast, orelset, MK-0873, ro-20-1724, HMR-1571, RPR-122818, HPP-737, clenbuterol and DC-591042;
PDE 4b inhibitors, including but not limited to GRT-6015;
tnfα ligand inhibitors, including but not limited to Hemay-005;
p-glycoprotein inhibitors including, but not limited to, boningmycin;
beta amyloid antagonists including, but not limited to GC-021109;
phosphoinositide-3 kinase delta inhibitors including, but not limited to, celecoxib Li Xibu (UCB-5857);
mTOR complex 2 inhibitors, including but not limited to, sibutra (bimiralisib) at ratio Mi Lali;
phosphoinositide-3 kinase gamma inhibitors including, but not limited to TAT-N25 peptide;
phospholipase A2 inhibitors including, but not limited to ZPL-521, items P-0229, BMS-181162 and BMS-188184;
apoptosis ligand 1 modulators, including but not limited to GX-P2;
apoptosis protein 1 stimulators, including but not limited to LY-3462817 and CC-90006;
p-selectin glycoprotein ligand-1 stimulators, including but not limited to, ne Hu Zhushan antibodies;
p-selectin glycoprotein ligand-1, including but not limited to AbGn-168H;
Retinoic acid receptor agonists including, but not limited to, abamectin, tazarotene, tretinoin, tazarotene Luo Tingfang tretinoin tromethamine, CD-1599, AM-580, BMS-181163 and CPR-2005;
retinoic acid receptor gamma antagonists, including but not limited to VTP-43742 and BBI-6000;
retinoic acid receptor gamma inverse agonists including, but not limited to, GSK-2981278A and JNJ-3534;
retinoid receptor agonists, including but not limited to RASP;
retinoid X receptor agonists, including but not limited to LGD-1550;
retinoid X receptor modulators including, but not limited to, bexarotene, alisretinate, ALRT-1069, LGD-1069 and Net-4IB;
retinoid Z receptor gamma agonists, including but not limited to NCE-407;
retinoid Z receptor gamma inverse agonists, including but not limited to ARN-6039, IMU-935, BOS-172767, SAR-441169 and INV-17;
retinoid Z receptor gamma antagonists including, but not limited to, AUR-101, JTE-451, ESR-114, ABBV-157 and AZD-0284;
rho-associated protein kinase 2 inhibitors, including but not limited to KD-025;
RIP-1 kinase inhibitors, including but not limited to GSK-2982772, DNL-758, and VRN-04;
ribonuclease P inhibitors, including but not limited to RASP;
Sphingosine-1-phosphate receptor-1 modulators, including but not limited to amixomod, AKP-11, FP-253, and CS-0777;
sphingosine-1-phosphate receptor-1 agonists, including but not limited to AK-119, SCD-044 and SYL-927;
sphingosine-1-phosphate receptor-5 modulators, including but not limited to CBP-307;
src tyrosine kinase inhibitors including, but not limited to, japanese patent Ban Bulin (KX-01);
STAT-3 inhibitors, including but not limited to TAK-114, GLG-801, and MOL-4249;
syk tyrosine kinase inhibitors, including but not limited to HMPL-523;
t-box transcription factor TBX21 modulators, including but not limited to SB-020;
t cell differentiation antigen CD6 inhibitors including, but not limited to, illicit mab;
t cell surface glycoprotein CD8 inhibitors including, but not limited to, trestuzumab;
t cell surface glycoprotein CD28 stimulators including, but not limited to, sirolimus;
tgfβ agonists, including but not limited to trestuzumab;
TLR-7 antagonists, including but not limited to IMO-3100;
TLR-9 antagonists including, but not limited to IMO-3100 and GNKS-356;
TLR 7,8,9 antagonists, including but not limited to IMO-8400;
TNFα ligand inhibitors including, but not limited to, adalimumab, CHS-1420, BAX-2923, MSB-11022, ABP-501, MYL-1401A, infliximab, pegylated cetuximab, AST-005, etanercept, openkempt, ISIS-104838, DLX-105, SSS-07, DLX-2751, DLX-105, debio-0512, TAQ-588, adalimumab, praguemab, PMI-001, CYT-020-TNFQb, AN-0128, CYT-007-TNFQb, SYI-2074, YP-008, SCT-640A, SBT-104, and T-1649;
TNFα ligand modulators, including but not limited to PUR-0110, CDP-571, and ACU-D2;
TNF antagonists, including but not limited to, PEGylated cetuximab, SCB-808, BAX-2200, CT-P05, SCB-131, GSK-2800528, onacemide, and ALS-00T2-0501;
TNF binding agents including, but not limited to, adalimumab, pegylated cetuximab SCB-131, onacemide, CT-P17, SBC-808, ABP-501, MYL-1401A, MSB-11022, BAX-2923, CHS-1420, and BCD-057;
TNF gene inhibitors, including but not limited to AST-005;
topoisomerase II inhibitors including, but not limited to GPX-150;
TrkA receptor antagonists including, but not limited to, VM-902A, CT-327, K-252a, and letatinib;
tubulin binding agents including, but not limited to, KX-01 and paclitaxel;
tyk2 tyrosine kinase inhibitors including, but not limited to, deuterated celecoxib, PF-06826647, ABBV-712, and CS-43001;
type II TNF receptor modulators, including but not limited to TNR-001, BAX-2200, and SCB-131;
unspecified cytokine receptor antagonists including, but not limited to, tetrathiomolybdate, JD-4000, X-083-NAB, SPHD-400, pimecrolimus, and HMPL-010;
vitamin D3 receptor agonists including, but not limited to, inecalcitol, maxacalcitol, calcipotriol, fluoxetol, maxacalcitol, calcitriol NS-78, tacalcitol, calcithiozol, ecalcitrane, linacalcitol, atocalcitol, and Ro-65-2299;
Vitamin D, D3 receptor modulators, including but not limited to VS-320 and VS-105;
wnt ligand inhibitors including, but not limited to SM-04755; and
wnt 5A ligand inhibitors including, but not limited to Box-5.
Combination therapy for rheumatoid arthritis
In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, may be combined with one, two, three, or four additional therapeutic agents useful in treating or ameliorating rheumatoid arthritis. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one, two, three, or four additional therapeutic agents selected from the group consisting of: 14-3-3 protein eta inhibitors, 5-lipoxygenase inhibitors, abl tyrosine kinase inhibitors, ACTH receptor agonists, adenosine A3 receptor agonists, adenosine deaminase inhibitors, ADP-ribosyl cyclase-1 modulators, ADP-ribosylating factor 6 inhibitors, corticotropin ligands, polyproteinase-2 inhibitors, albumin modulators, anti-TNF steroid conjugates, adenosine A1 receptor antagonists, annexin A1 modulators, AP1 transcription factor inhibitors, apolipoprotein B modulators, arene receptor agonists plus autoantigens, basic immunoglobulin inhibitors, bcr protein inhibitors, B lymphocyte antigen CD19 inhibitors, B lymphocyte antigen CD20 modulators, B lymphocyte adhesion molecule inhibitors, B lymphocyte stimulating factor ligand inhibitors bradykinin receptor modulators, BRAF gene inhibitors, branched amino acid transaminase 1 inhibitors, bromodomain-containing protein inhibitors, btk tyrosine kinase inhibitors, cadherin-11 antagonists, calcineurin inhibitors, calcium channel inhibitors, calreticulin inhibitors, carbonic anhydrase inhibitors, cathepsin K inhibitors, cathepsin S inhibitors, CCR1 chemokine antagonists, CCR2 chemokine antagonists, CCR3 gene modulators, CCR5 chemokine antagonists, CD126 antagonists, CD29 modulators, CD3 modulators, CD39 agonists, CD4 antagonists, CD40 ligand inhibitors, CD40 ligand receptor antagonists, CD40 ligand receptor modulators, CD52 antagonists, CD73 agonists, CD79B modulators, CD80 antagonists, CD86 antagonists, CD95 antagonists, cell adhesion molecule inhibitor, chaperonin modulator, choline kinase inhibitor, aggregative stimulator, complement C5 factor inhibitor, complement factor stimulator, C-reactive protein inhibitor, CSF-1 antagonist, CXC10 chemokine ligand inhibitor, CXCR4 chemokine antagonist, cyclin-dependent kinase inhibitor 1 inhibitor, cyclin-dependent kinase-2 inhibitor, cyclin-dependent kinase-4 inhibitor, cyclin-dependent kinase-5 inhibitor, cyclin-dependent kinase-6 inhibitor, cyclin-dependent kinase-7 inhibitor, cyclin-dependent kinase-9 inhibitor, cyclooxygenase 2 modulator, cyclooxygenase inhibitor, cytoplasmic phospholipase A2 inhibitor, cytotoxic T lymphocyte protein-4 modulator, cytotoxic T lymphocyte protein-4 stimulator deoxyribonuclease gamma stimulator, DHFR inhibitor, diamine acetyltransferase inhibitor, dihydroorotate dehydrogenase inhibitor, DYRK-1 alpha protein kinase inhibitor, elongation factor 2 inhibitor, enolase 1 inhibitor, eosinophil chemokine 2 ligand inhibitor, EP4 prostaglandin receptor antagonist, erythropoietin receptor agonist, factor XIIa antagonist, fas ligand, FGF-2 ligand inhibitor, FK506 binding protein-12 modulator, folic acid antagonist, folic acid receptor agonist, folic acid receptor beta antagonist, folic acid receptor modulator, actin ligand inhibitor, fyn tyrosine kinase inhibitor, G protein coupled receptor 15 antagonist, GABA A receptor modulator, glucocorticoid agonist, glucocorticoid antagonist, glucocorticoid-induced leucine zipper protein stimulator, GM-CSF ligand inhibitors, GM-CSF receptor antagonists, GM-CSF receptor modulators, growth regulator alpha ligand inhibitors, H+K+ ATPase inhibitors, histamine H4 receptor antagonists, histone deacetylase inhibitors, histone deacetylase-6 inhibitors, HIV-1 gp120 protein inhibitors, HLA class II antigen DQ-2 alpha modulators, HLA class II antigen inhibitors, HLA class II antigen modulators, hsp 70 family inhibitors, hypoxia inducible factor-1 inhibitors, IFNB gene stimulators, I-kappa B kinase beta inhibitors, I-kappa B kinase inhibitors, IL-1 antagonists, IL-10 agonists, IL-11 agonists, IL-12 antagonists, IL-15 antagonists, IL-17 receptor modulators, IL-18 receptor accessory protein antagonists IL-8 ligand inhibitors, IL-2 agonists, IL-2 antagonists, IL-21 antagonists, IL-23 antagonists, IL-3 antagonists, IL-4 agonists, IL-6 antagonists, IL-6 receptor modulators, IL-6 neutralizing human antibodies, anti-IL 6 antibodies, immunoglobulin antagonists, immunoglobulin G1 agonists, immunoglobulin G1 antagonists, immunoglobulin G1 modulators, immunoglobulin G2 antagonists, immunoglobulin G2 modulators, immunoglobulin gamma Fc receptor II modulators, immunoglobulin gamma Fc receptor IIB antagonists, immunoglobulin kappa modulators, immunoglobulin M antagonists, inducible nitric oxide synthase inhibitors (iNOS inhibitors), inosine monophosphate dehydrogenase inhibitors, insulin sensitizers, integrin alpha-1/beta-1 antagonists, integrin alpha-4/beta-1 antagonists, integrin alpha-9 antagonists, integrin antagonists, interferon beta ligands, interferon gamma ligands, interleukin 17A ligand inhibitors, interleukin 17F ligand inhibitors, interleukin 23A inhibitors, interleukin ligand, interleukin receptor 17A antagonists, interleukin-1 beta ligand inhibitors, interleukin-10 ligand, interleukin-2 ligand, interleukin-4 ligand, interleukin-6 ligand inhibitors, itk tyrosine kinase inhibitors, JAK tyrosine kinase inhibitors, jak1 tyrosine kinase inhibitors, jak2 tyrosine kinase inhibitors, JAK3 gene inhibitors, jak3 tyrosine kinase inhibitors Jun N-terminal kinase inhibitor, KCNA voltage-gated potassium channel-3 modulator, kelch-like ECH-related protein 1 modulator, kit tyrosine kinase inhibitor, lanC-like protein 2 modulator, leukotriene BLT receptor antagonist, LITAF gene inhibitor, lymphocyte function antigen-3 receptor antagonist, lyn tyrosine kinase inhibitor, macrophage-drug conjugate (MDC), macrophage mannose receptor 1 modulator, MAdCAM inhibitor, MAP kinase modulator, MAP3K2 gene inhibitor, MAPKAPK5 inhibitor, matrix metalloproteinase inhibitor, MCL1 gene inhibitor, MEK protein kinase inhibitor, MEK-1 protein kinase inhibitor, MEK-2 protein kinase inhibitor, membrane copper amine oxidase inhibitor, metalloproteinase-2 inhibitor, metalloproteinase-9 inhibitor, methylprednisolone, midkine ligand inhibitor, mitochondrial 10kDa heat shock protein stimulator, mTOR complex 1 inhibitor, mTOR inhibitor, NADADP ribosyl transferase stimulator, NAMPT gene inhibitor, NF kappa B inhibitor stimulator, NFAT gene inhibitor, NFE2L2 gene stimulator, nicotinic acetylcholine receptor antagonist, NK cell receptor modulator, NKG 2A B-activated NK receptor antagonist, NKG 2D-activated NK receptor antagonist, nuclear factor erythroid 2-associated factor 2 stimulator, nuclear factor kappa B inhibitor, nuclear factor kappa B modulator, nuclear factor kappa B P inhibitor, opioid growth factor receptor agonist, opioid receptor delta antagonist, osteoclast differentiation factor ligand inhibitor, oxidoreductase inhibitor, P2X7 purine receptor agonist, P38 MAP kinase alpha inhibitor P38 MAP kinase inhibitors, PDE 4 inhibitors, PDE 5 inhibitors, PDGF receptor agonists, PDGF receptor antagonists, PDGF-B ligand inhibitors, PERK gene inhibitors, phosphoinositide-3 kinase delta inhibitors, phosphoinositide-3 kinase gamma inhibitors, phospholipase A2 inhibitors, platelet activating factor receptor antagonists, PPARgamma agonists, modulators of apoptosis protein 1, prostaglandin D synthase stimulators, protein arginine deiminase inhibitors, protein tyrosine kinase inhibitors, protease activating receptor-2 antagonists, purH purine biosynthesis protein inhibitors, rho-associated protein kinase 2 inhibitors, separation enzyme (seprase) inhibitors, signal transduction protein CD24 modulators, signal transduction inhibitors, sodium glucose transporter-2 inhibitors, sphingosine 1 phosphophosphatase modulators, STAT3 gene inhibitors, serum amyloid A modulators, superoxide dismutase stimulators, SYK family tyrosine kinase inhibitors, syk tyrosine kinase inhibitors, multi-ligand proteoglycan-1 inhibitors, T cell receptor antagonists, T cell receptor modulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD28 stimulators, TAK1 binding protein modulators, ankyrin modulators, T cell differentiation antigen CD6 inhibitors, T cell surface glycoprotein CD8 inhibitors, tenascin modulators, TGF beta agonists, thymosin agonists, TLR-2 antagonists, TLR-4 antagonists, TLR-9 antagonists, TNF alpha ligand inhibitors, TNF alpha ligand modulators, TNF antagonists TNF gene inhibitors, TNF receptor modulators, TNFSF11 gene inhibitors, transcription factor p65 inhibitors, transcription factor RelB inhibitors, transferrin modulators, transthyretin modulators, tumor necrosis factor 13C receptor antagonists, tumor necrosis factor 15 ligand inhibitors, tumor necrosis factor ligand 13 inhibitors, tumor necrosis factor ligand inhibitors, IL-1 receptor antagonists type I, TNF receptor modulators type II, unspecified GPCR agonists, VEGF receptor antagonists, VEGF-2 receptor modulators, VEGF-B ligand inhibitors, X-linked apoptosis inhibitor proteins and zap70 tyrosine kinase inhibitors.
In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one, two, three, or four additional therapeutic agents selected from the group consisting of: 99mTc labeled annexin V-128, abapyrip, abapyric biological analog, ABBV-257, ABT-122, ABT-494, acartinib, aceclofenac, axolitide, adMSCs, MS-392, adalimumab biological analog, adalimumab subsequent biological preparation, AK-106, ALX-0061, amilo-5MER, aminopterin, AMT-101, anakinout biological preparation, annexuzlimab, ARG-301, ARQ-250, ASLAN-003, ASP-5094, AT-132, AZD-9567, barittinib, BI-655064, biMegambirab, biP (rheumatoid arthritis), BLHP-006, BS-986104, BMS-986142, ABBV-105, BTT-1023, cardamascen Cortili (Cartistem), CCX-354, CD24-IgFc, celecoxib, ceritinib, PEGylated cetuximab, CF-101, CFZ-533, CHR-5154, silbivalide, cyclosporine, cladazazumab, CNTO-6785, corticotropin, CR-6086, creaVax-RA, CWG-92, CWG-940, cx-611, DE-098, DEN-181, defucort, rheumavax, denomab, diacerein, diclofenac, DWJ-1421, E-6011, eicosapentaenoic acid glycerol monoester, etanercept subsequent biologicals, etodolac, etoricoxib, non-gotinib, fodacobate (fosdagrosat), GLPG-3970, gilimab (glimezumab), ginsenoside C-K, ji Weisi He, GLPG-4399, goat polyclonal antibody, golimumab, GS-5745, GS-9876, GSK-3196165, HHT-109, HM-71224, HMPL-523, HST-003, sodium hyaluronate, (S) -hydroxychloroquine, IB-RA (injectable, rheumatoid arthritis), IB-RA (oral, rheumatoid arthritis), icanoMAB, ICP-022, iguratimod, IMD-2560, imidazole salicylate, infliximab antibiotic bioaugmente, infliximab antibiotic analogue, CT-P13, INSIX RA, interferon gamma subsequent biologic, interleukin-2 (injectable), interleukin-2 subsequent biologic, INV-103, IR-501, illimumab, JNJ-40346527, casutinin, KB-312, KD-025, ketoprofen + omeprazole, KINE-101, LB-600, leflunomide, renz lumab LLDT-8, LNK-01001, LNP-1955, lumiracoxib, LY-3090106, marfolimumab, MBS-2320, MEDI-5117, meloxicam, methotrexate, MGD-010, misoprostol+diclofenac, MM-A01-01, mo Nali bead mab, MORAB-022, MPC-300-IV, MRC-375, nabumetone, nalmeflozumab, naproxen+esomeprazole strontium, NIP-046, oxcarbatozumab, ofatumumab, OHR-118, oxford monoclonal antibody, OM-89, naproxen (oral controlled release, pain), ONO-4059, oralgam, olanimumab, PAR-2 inhibitor, pefetinib, pebiprofen, PF-06687234, piperidone hydrochloride, piroxicam, prednisolone, prednisone, procell, prosorba, PRT-2607, PRTX-100, PRX-167700, QBSAU, rabeximod (rabeximod), RCT-18, recombinant human CD22 monoclonal antibody (intravenous infusion), lonn Ryonn Pharma/SinoMab Bioscience (deep zhen), RA-curcumin liposome, recombinant human interleukin-1 receptor antagonist (rheumatoid arthritis), recombinant human interleukin-2 recombinant TNF receptor 2-Fc fusion protein mutant, RG-6125, rhuDex, rifabutin+clarithromycin+clofazimine, rituximab rituximab anti-biological analogues, torriz, rituximab follow-up biological preparation, RPI-78, SAN-300, sha Lilu mab, SBI-087, ce Li Xili, SHR-0302, ce Lu Kushan mab, capetinib, SR-047, SSS-07, KDF-201110-06, syn-1002, T-5224, TAB-08, tacrolimus, TAK-020, TAK-079, tarenflurbiprate (transdermal insufflation gel, dermatological/rheumatoid arthritis), technetium Tc99 m-Ma Nuosai, technetium [99Tc ] methylenediphosphate, tenoxicam, debio-0512, tozumab, tofacitinib citrate, TQG-2813, pig flagellin, umbilical cord-derived mesenchymal stem cells (veins, RA/liver disease), utekey monoclonal antibody, VAY-736, VB-201, WF-10, xmAb-5871, YH-1713, YHB-1411-2, YRA-1909 and ZM-008 or pharmaceutically acceptable salts of any of the foregoing or any combination thereof.
In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one, two, three, or four additional therapeutic agents selected from the group consisting of:
14-3-3 protein eta inhibitors including, but not limited to, anti-AGX-020 mab (rheumatoid arthritis) and Augurex;
5-lipoxygenase inhibitors including, but not limited to, debuflounder, japanese Ding Feilong, ZD-2138, etalloxib, PGV-20229, L-708780, T-0757, T-0799, ZM-216800, L-699333, BU-4601A and SKF-104351;
5-lipoxygenase/cyclooxygenase inhibitors including, but not limited to, tenoxicam, li Kefei Dragon, tenidap, teposaline, fluo Luo Bufen, SKF-86002, WY-28342, and CI-986;
5-lipoxygenase/PPARgamma agonists, including but not limited to etaloxy;
abl tyrosine kinase inhibitor/Bcr protein inhibitor/Kit tyrosine kinase inhibitor/PDGF receptor antagonist/signal transduction inhibitor, including but not limited to imatinib;
ACTH receptor agonists/corticotropin ligands/opioid growth factor receptor agonists including, but not limited to FAR-404 and methionine enkephalin acetate + Qu Kake peptide acetate;
adenosine A1 receptor antagonists, including but not limited to CP-25;
Adenosine A3 receptor agonists including, but not limited to CF-101 (piridesone);
adenosine deaminase inhibitors, cladribine, pravastatin and FR-221647;
ADP ribosyl cyclase-1 inhibitors including, but not limited to, darimumab;
ADP ribosyl cyclase-1 modulators/multi-ligand proteoglycan-1 inhibitors, including but not limited to infliximab;
ADP ribosylating factor 6 inhibitors including, but not limited to NAV-2729;
corticotropin ligands including, but not limited to, corticotropin and Mallinckrodt;
inhibitors of the polyproteinase-2/TNF gene including, but not limited to, GIBH-R-001-2;
albumin modulators, including but not limited to ONS-1210;
albumin modulators/IL-6 antagonists including, but not limited to ALX-0061 (Wo Bali bead mab);
albumin modulators/tnfα ligand inhibitors, including but not limited to HOT-3010;
AP1 transcription factor/nuclear factor kb inhibitors including, but not limited to, talent fluroxypyr and SP-100030;
anti-TNF steroid antibody-drug conjugates (anti-TNF-GRM), including but not limited to ABBV-3373 and ABBV-154;
basic immunoglobulin inhibitors/branched chain amino acid transaminase 1/metalloprotease 9 inhibitors/metalloprotease 2 inhibitors, including but not limited to ERG-240;
BET inhibitors including, but not limited to GSK-3358699;
bispecific anti-CD 86/IL-10, including but not limited to APVO-210;
bispecific humanized monoclonal antibodies targeting BAFF and IL-17A, including but not limited to tibrizumab;
bispecific antibody-peptide conjugates (BAFF/ICOSL), including but not limited to AMG-570;
b lymphocyte antigen CD19 inhibitors including, but not limited to MDX-1342;
b lymphocyte antigen CD19 inhibitors/immunoglobulin gamma Fc receptor IIB antagonists, including but not limited to XmAb-5871;
b lymphocyte antigen CD20 inhibitors, including but not limited to, oregano mab, ofatuzumab, rituximab, ABP-798, maball, mabtas, reditux, zytux, veltuzumab, oxcarbatuzumab, BLX-301, IDEC-102, ABP-798, GP-2013, MK-8808, HLX-01, CT-P10, TL-011, PF-05280586, IBPM-001RX, IBI-301, AME-133v, BCD-020, BT-D004, SAIT-101, and JHL-1101;
b lymphocyte antigen CD20 modulators, including but not limited to SBI-087, TRU-015, DXL-625 and MabionCD20;
b lymphocyte cell adhesion molecule inhibitors including, but not limited to SM-06;
b lymphocyte stimulating factor ligand inhibitors including, but not limited to, belimumab, RCT-18, cloth Li Mode, he Bei Lushan antibody, and bupropion;
B lymphocyte stimulating factor ligand/tumor necrosis factor ligand 13 inhibitors including, but not limited to, asenapine;
bradykinin receptor modulators/histone deacetylase inhibitors/P2X 7 purinergic agonists including but not limited to Ji Weisi he;
BRAF gene/MEK protein kinase/PERK gene inhibitors, including but not limited to bemetinib;
bromodomain-containing protein inhibitors including, but not limited to RVX-297, ZEN-003694
Btk tyrosine kinase inhibitors including, but not limited to, AC-0058, acartinib, HM-71224, capetinib, BMS-986142, TAK-020, tiramitinib (ONO-4059), TAS-5315, ABBV-105, GDC-0834, EBI-1459, BMS-986195, ibrutinib, febutinib, SIMM-016 and YZJ-3058;
btk tyrosine kinase inhibitor/Syk tyrosine kinase inhibitor/VEGF-2 receptor antagonists, including but not limited to CG-026806;
btk tyrosine kinase inhibitors/IL-6 antagonists including, but not limited to RN-486;
btk tyrosine kinase/Jak 1 tyrosine kinase inhibitors, including but not limited to Wu Pati Ni+ABBV-105;
btk tyrosine kinase/Jak 3 tyrosine kinase inhibitors, including but not limited to AC-0025;
cadherin-11 antagonists, including but not limited to RG-6125;
Calcineurin inhibitors including, but not limited to, cyclosporine;
calcineurin inhibitors/opioid receptor delta antagonists including, but not limited to HS-378;
calcium channel inhibitors, including but not limited to RP-3128;
calreticulin inhibitors including, but not limited to ALB-001 and ZYBK-2;
carbonic anhydrase/cyclooxygenase 2 inhibitors including, but not limited to, pam Ma Kao shake;
cathepsin K inhibitors including, but not limited to CRA-013783 and VEL-0230; cathepsin K/cathepsin S inhibitors including, but not limited to AM-3876 and NPI-2019;
cathepsin S inhibitors including, but not limited to MIV-247 and RWJ-445380;
CCR1 chemokine antagonists including, but not limited to, BX-471, BMS-817399, BI-638683, CCX-354, MLN-3701, MLN-3897, CP-481715 and PS-375179;
CCR2 chemokine antagonists including, but not limited to MK-0812 and AZD-6942;
CCR3 gene modulators/eosinophil chemokine 2 ligand inhibitors, including but not limited to CM-102;
CCR5 chemokine antagonists including, but not limited to, OHR-118, NIBR-6465, AZD-5672 and AZD-8566;
CD29 modulators/interleukin-10 ligands, including but not limited to PF-06687234;
CD3 modulators, including but not limited to oxybutynin;
CD39/CD73 agonists, including but not limited to AAV5-CD39/CD73 (rheumatoid arthritis) and Arthrogen;
CCR5 chemokine antagonists/CD 4 agonists/HIV-1 gp120 protein inhibitors, including but not limited to maraviroc;
CD4 antagonists including, but not limited to, zazalomab, MTRX-1011A, BW-4162W94, EP-1645, cleiximab and DerG-PG275Cit;
CD40 ligand inhibitors including, but not limited to, pegylated dapiromab and TNX-1500;
CD40 ligand receptor antagonists including, but not limited to, BI-655064, anti-CD 40-XTEN, tenectimab, VIB-4920 and Iskarituximab;
CD40 ligand receptor modulators/immunoglobulin G1 modulators, including but not limited to CFZ-533;
CD52 antagonists/collectin stimulators, including but not limited to alemtuzumab;
bispecific CD32B/CD79B antibodies, including but not limited to PRV-3279 (MGD-010);
CD80 antagonists, including but not limited to abamectin improvers;
CD80 antagonists/T cell surface glycoprotein CD28 inhibitors including, but not limited to RhuDex;
CD80 antagonists/CD 86 antagonists including, but not limited to XENP-9523 and ASP-2408;
CD86 antagonists including, but not limited to, abamectin biological winners (biosuperior);
CD86 antagonists/cytotoxic T lymphocyte protein-4 modulators, including but not limited to ES-210;
CD95 antagonists, including but not limited to DE-098 and CS-9507;
cell adhesion molecule inhibitors including, but not limited to, aj Li Kafu sen, NPC-17923, TK-280 and PD-144795;
chemokine receptor antagonists including, but not limited to, PF-06835375;
complement C5 factor inhibitors including, but not limited to, eculizumab,
complement C5 factor inhibitors/IL-1 antagonists including, but not limited to, antisense oligonucleotides (rheumatoid arthritis), and the university of leyton medical center (Leiden UniversityMedical Center) complement factor stimulators including, but not limited to CM-101;
inhibitors of C-reactive protein including, but not limited to ISIS-353512;
c-reactive protein inhibitor/cyclooxygenase 2 inhibitor/nuclear factor κb inhibitor/immunoglobulin M antagonist/IL-2 receptor antagonist/PGE 2 antagonist: IB-RACCF-1 antagonists including, but not limited to, marseitinib, FPA-008, JNJ-27301937, JNJ-40346527, PLX-5622, CT-1578, PD-360324, and JNJ-28312141;
CSF-1 antagonists/Fyn tyrosine kinase inhibitors/Kit tyrosine kinase inhibitors/Lyn tyrosine kinase inhibitors/NK cell receptor modulators/PDGF receptor antagonists, including but not limited to masitinib;
CXC10 chemokine ligand inhibitors including, but not limited to 946414-98-8 and BMS-936557;
CXCR4 chemokine antagonists, including but not limited to plexafu;
CDK-2/7/9 inhibitor/MCL 1 gene inhibitor, including but not limited to plug Li Xili;
inhibitors of CDK-1/2/5/7/9, including but not limited to BP-14;
chaperonin modulators, including but not limited to IRL-201805;
cyclooxygenase 2 inhibitors including, but not limited to, celecoxib, etoricoxib, meloxicam and lumiracoxib;
cyclooxygenase 2/oxidoreductase inhibitors including, but not limited to, etodolac;
cyclooxygenase 2 modulators, including but not limited to DRGT-46;
cyclooxygenase inhibitors including, but not limited to, aceclofenac, diclofenac, naproxen etemesil, nabumetone, naproxen, pebiprofen, LY-210073, NS-398, bromfenac, L-746483, LY-255283, ibuprofen, flurbiprofen, SC-57666, and bermoprofen;
cyclooxygenase inhibitors/H+K+ATPase inhibitors including, but not limited to, naproxen+esomeprazole strontium;
cyclooxygenase inhibitors/PGE 1 agonists including, but not limited to misoprostol + diclofenac;
cyclooxygenase inhibitors/oxidoreductase inhibitors including, but not limited to, imidazole salicylate;
Cytosolic phospholipase A2 inhibitors/phospholipase A2 inhibitors, including but not limited to AVX-002;
cytotoxic T lymphocyte protein-4 stimulators/T cell surface glycoprotein CD28 inhibitors including, but not limited to, abamectin, BMS-188667 and beracetirizine;
deoxyribonuclease gamma stimulators, including but not limited to NTR-441;
DHFR inhibitors including, but not limited to MPI-2505, jylamvo and ZeNEO-methotrexate;
DHFR inhibitors/folic acid antagonists/transferrin modulators, including but not limited to methotrexate;
diamine acetyltransferase inhibitors, including but not limited to diacetyl amide;
dihydroorotate dehydrogenase inhibitors including, but not limited to, ASLAN-003, HWA-486, and ABR-224050;
dihydroorotate dehydrogenase/protein tyrosine kinase inhibitors including, but not limited to, leflunomide;
DYRK-1 alpha protein kinase inhibitors, including but not limited to VRN-02;
elongation factor 2 inhibitors/interleukin-2 ligand/NAD ADP ribosyl transferase stimulators, including but not limited to dini interleukin-toxin linker (denileukin diftitox);
enolase 1 inhibitors, including but not limited to HuL-001;
EP4 prostaglandin receptor antagonists including, but not limited to CR-6086;
Erythropoietin receptor agonists including, but not limited to, sibiricin;
fas ligands, including but not limited to AP-300;
FGF-2 ligand inhibitors, including but not limited to RBM-007;
FK506 binding protein-12 modulator/mTOR inhibitors, including but not limited to temsirolimus;
folic acid antagonists/transferrin modulators/DHFR inhibitors, including but not limited to MBP-Y003;
folate receptor modulators, including but not limited to technetium (99 mTc) etaforatide (etarfatide);
inhibitors of the actin ligand, including but not limited to E-6011;
fyn tyrosine kinase inhibitors/GABA a receptor modulators/cyclooxygenase 2 inhibitors/dihydroorotate dehydrogenase inhibitors, including but not limited to raffinolimus;
glucocorticoid agonists including, but not limited to, prednisone Long Hefu s-dakola;
glucocorticoid antagonists, including but not limited to REC-200;
glucocorticoid-induced leucine zipper protein stimulators including, but not limited to ART-G01;
GM-CSF ligand inhibitors including, but not limited to, nalmefene, gemmizumab (MORAB-022), and TJM-2;
GM-CSF receptor antagonists including, but not limited to, mafrerimab;
Modulators of GM-CSF receptors including, but not limited to GSK-3196165 and octreotide Li Shan antibodies;
growth regulator protein alpha ligand inhibitor/AP 1 transcription factor inhibitor/IL-6 antagonist/interleukin-1 beta ligand inhibitor/cathepsin K inhibitor/NFAT gene inhibitor, including but not limited to T-5224;
h+k+atpase inhibitors including, but not limited to, naproxen+esomeprazole, ketoprofen+omeprazole, KEO-25001, HC-1004 and PN-40020;
histamine H4 receptor antagonists including, but not limited to, tolterodine and GD-48;
histone deacetylase inhibitors, including but not limited to CHR-5154 (GSK-3117391) and NIPEP-CARE;
histone deacetylase-6 inhibitors, including but not limited to CKD-506;
HLA class II antigens DQ-2 alpha modulators, including but not limited to NexVax2;
HLA class II antigen inhibitors, including but not limited to HLA-DR1/DR4 inhibitors (rheumatoid arthritis) and Provid;
HLA class II antigen modulators, including but not limited to recombinant T-cell receptor ligands (rheumatoid arthritis) and artielles;
hsp 70 family inhibitors including, but not limited to, guanrolimus dihydrochloride;
hypoxia inducible factor-1 inhibitors/VEGF receptor antagonists including, but not limited to, 2-methoxyestradiol;
IFNB gene stimulators including but not limited to ART-102;
i- κB kinase β inhibitors including, but not limited to, IMD-2560;
i- κB kinase β inhibitors/nuclear factor K B inhibitors including, but not limited to, IMD-0560;
i- κB kinase inhibitor/NFE 2L2 gene stimulator/nuclear factor κB inhibitor/STAT 3 gene inhibitor, including but not limited to methyl bardoxolone;
IL-1 antagonists, including but not limited to recombinant human interleukin-1 receptor antagonists (rheumatoid arthritis), shanghai's Kangdan Zhang biological medicine Co., ltd;
IL-1 antagonists/interleukin-1 beta ligand inhibitors, including but not limited to, cilomimetic;
IL-10 agonists, including but not limited to polyethylene glycol-ilointerleukin;
IL-11 agonists/PDGF receptor agonists, including but not limited to, epleril;
IL-12 antagonists/IL-23 antagonists, including but not limited to, utility mab and branchizumab;
IL-15 antagonists, including but not limited to AMG-714;
IL-17 antagonists, including but not limited to, evizumab and Stuzumab;
IL-17 receptor modulators, including but not limited to CNTO-6785;
IL-2 receptor agonists, including but not limited to interleukin-2 subsequent biological agents (IL-2), anteluke, and interning;
IL-2/IL-21/IL-15 antagonists, including but not limited to BNZ-132-2;
IL-21 antagonists, including but not limited to NN-8828;
IL-4 agonists, including but not limited to SER-130-AMI;
IL-6 antagonists, including but not limited to BCD-089, olomoumab, cladagumab, cetuximab Lu Kushan, SA-237, FB-704A, OP-R003, peptide IL-6 antagonists, MEDI-5117, AMG-220, FM-101, BLX-1025, ai Na molars, TA-383, and Sha Lilu monoclonal antibodies;
IL-6 antagonists/interleukin-1 beta ligand inhibitors/TNFα ligand inhibitors, including but not limited to K-832;
IL-6 antagonists/insulin sensitizers/interleukin-1 beta ligand inhibitors, including but not limited to BLX-1002;
IL-6 receptor antagonists/modulators, including but not limited to Touzumab, HS-628 and LusiNEX;
IL-6 receptor modulators, including but not limited to BAT-1806 and RO-4877533;
immunoglobulin antagonists including, but not limited to, iguratimod;
immunoglobulin G1 agonists, including but not limited to BX-2922 and HF-1020;
immunoglobulin G1 agonists/interleukin-1 beta ligand inhibitors, including but not limited to cinacalcet;
immunoglobulin G1 agonists/tnfα ligand inhibitors, including but not limited to STI-002;
Immunoglobulin G1 antagonists/TNFα ligand inhibitors, including but not limited to YHB-1411-2;
immunoglobulin G1 modulators/GM-CSF ligand inhibitors/immunoglobulin kappa modulators, including but not limited to, lorentzumab;
immunoglobulin G2 antagonists/nfkb inhibitor stimulators/osteoclast differentiation factor antagonists/osteoclast differentiation factor ligand inhibitors/TNFSF 11 gene inhibitors, including but not limited to denomab;
immunoglobulin gamma Fc receptor II modulators, including but not limited to MGD-010;
inducible nitric oxide synthase inhibitors/cyclooxygenase 2 inhibitors/MAP kinase modulators/nuclear factor κB inhibitors, including but not limited to SKLB-023;
inosine monophosphate dehydrogenase inhibitors including, but not limited to, mizoribine;
insulin sensitizers/nuclear factor κb inhibitors/interleukin ligand inhibitors, including but not limited to HE-3286;
integrin alpha-1/beta-1 antagonists including, but not limited to SAN-300;
integrin alpha-4/beta-1 antagonists/cell adhesion molecule inhibitors including, but not limited to natalizumab;
integrin alpha-9 antagonists including, but not limited to, ASP-5094;
integrin antagonists including, but not limited to, PEG-HM-3 and CY-9652;
Interferon beta ligands, including but not limited to recombinant interferon beta-1 a;
interferon beta ligand/IL-6 antagonists including, but not limited to, TA-383;
interferon gamma ligands including, but not limited to, li Zhu Yin De Fu and cloned gamma;
interleukin 17A ligand inhibitor/tumor necrosis factor ligand inhibitor including, but not limited to ABT-122 and ABBV-257;
interleukin 17F ligand inhibitors including, but not limited to, bimagrumab;
interleukin 18 ligand inhibitors including, but not limited to, tad interleukin alpha (tadekinig alfa);
interleukin 23A inhibitors including, but not limited to, antique pessary;
interleukin ligand/IL-1 antagonists including, but not limited to IBPB-007-IL;
interleukin receptor 17A antagonists, including but not limited to Bai Dalu mab;
interleukin-1 beta ligand inhibitors including, but not limited to, gemini mab, LY-2189102, CDP-484, and AR-100;
interleukin-1 beta ligand inhibitor/tnfα ligand inhibitor, including but not limited to PMI-001;
interleukin-1 beta ligand/tnfα ligand modulators, including but not limited to PUR-0110;
interleukin-2 ligands including, but not limited to, recombinant interleukin-2 and CUG-252;
IL-2 modulators, including but not limited to AMG-592;
interleukin-4 ligand/tenascin-modulating agents including, but not limited to, tetravil;
interleukin-6 ligand inhibitors including, but not limited to, gemtuzumab (gerilimzumab) and PF-4236921;
IRAK-4 protein kinase inhibitors including, but not limited to, BAY-1830839, BAY-1834845, PF-06650833 and KT-474;
itk tyrosine kinase inhibitors, including but not limited to JTE-051;
itk tyrosine kinase inhibitors/Jak 3 tyrosine kinase inhibitors, including but not limited to ARN-4079;
JAK tyrosine kinase inhibitors including, but not limited to, deuterated tofacitinib analogs, SD-900, and WXSH-0150;
JAK tyrosine kinase inhibitors/Syk tyrosine kinase inhibitors including, but not limited to, ceritinib and CVXL-0074;
jak1 tyrosine kinase inhibitors including, but not limited to, ABT-494 (Wu Pati Ni), lu Suoti Ni, fingolitinib, itatinib, NIP-585, YJC-50018, GLPG-0555, MRK-12 and SHR-0302;
jak1/3 tyrosine kinase inhibitors including, but not limited to, tofacitinib citrate, pefacitinib, CKD-374 and CS-944X;
JAK1/3 inhibitor/ROCK 1/2 inhibitor: CPL-409116
Jak1/2 tyrosine kinase inhibitors including, but not limited to, baritinib, lu Suoti ni, LW-104 and TLL-018;
jak2 tyrosine kinase inhibitors/CSF-1 antagonists, including but not limited to CT-1578;
JAK3 gene inhibitors, including but not limited to PF-06651600;
jak3 tyrosine kinase inhibitors including, but not limited to, dixitinib, DNX-04042, MTF-003, and PS-020613;
jun N-terminal kinase inhibitors, including but not limited to IQ-1S;
KCNA voltage-gated potassium channel-3 modulators, including but not limited to MRAD-P1;
kelch-like ECH-related protein 1 modulators/nuclear factor erythroid 2-related factor 2 stimulators, including but not limited to dimethyl fumarate;
LanC-like protein 2 modulators, including but not limited to BT-11 and BT-104;
LDL receptor-associated protein-1 stimulators including but not limited to SP-16;
leukotriene BLT receptor antagonists/complement C5 factor inhibitors, including but not limited to nor Ma Kepan;
LITAF gene inhibitor/JAK 3 gene inhibitor/MAP 3K2 gene inhibitor/TNF antagonist, including but not limited to GBL-5b;
lymphocyte function antigen-3 receptor antagonists, including but not limited to alfasin;
macrophage mannose receptor 1 modulators, including but not limited to technetium Tc 99m instead Ma Nuosai;
MAdCAM inhibitors/immunoglobulin G2 modulators, including but not limited to PF-547659;
MAPKAPK5 inhibitors/matrix metalloproteinase inhibitors, including, but not limited to GLPG-0259;
MEK protein kinase inhibitors, including but not limited to AD-GL0001;
membrane copper amine oxidase inhibitors including, but not limited to, BTT-1023, PRX-167700, and vipamomab;
metalloproteinase-9 inhibitors, including but not limited to GS-5745;
microbiome modulators, including but not limited to EDP-1815;
midkine ligand inhibitors, including but not limited to CAB-102;
mitochondrial 10kDa heat shock protein stimulators including, but not limited to, INV-103;
mTOR inhibitors including, but not limited to, everolimus;
NAMPT gene inhibitors, including but not limited to ART-DO1;
nicotinic acetylcholine receptor antagonists, including but not limited to RPI-78 and RPI-MN;
NKG 2A B activates NK receptor antagonists including, but not limited to Mo Nali bead mab;
NKG 2D-activated NK receptor antagonists including, but not limited to NNC-0142-002;
nuclear factor kappa B inhibitors including, but not limited to, dehydroepoxymethylquinone mycin, MP-42, VGX-1027, SP-650003, MG-132, SIM-916, VGX-350, VGX-300, GIT-027, MLN-1145, and NVP-IKK-005;
Nuclear factor κb modulator/nuclear factor κ B p105 inhibitor/transcription factor RelB inhibitor/transcription factor p65 inhibitor, including but not limited to REM-1086;
osteoclast differentiation factor antagonists, including but not limited to cyclic peptide mimics (rheumatoid arthritis/osteoporosis), michigan university;
p38 MAP kinase alpha inhibitors, including but not limited to VX-745, BMS-582949 and BMS-751324;
p38 MAP kinase inhibitors, including but not limited to BCT-197, lomod and ARRY-797;
PDE 4 inhibitors including, but not limited to, apremilast;
PDE5 inhibitors, including but not limited to PDE5 inhibitors (rheumatoid arthritis), university of rochester;
PDGF-B ligand inhibitors/VEGF receptor antagonists including, but not limited to SL-1026;
phosphoinositide-3 kinase delta inhibitors including but not limited to CT-732, INK-007 and GNE-293;
phosphoinositide-3 kinase delta/gamma inhibitors including, but not limited to, dimelli and RP-6503;
phospholipase A2 inhibitors including, but not limited to AK-106, methyl varesplady, ro-31-4493, BM-162353, ro-23-9358 and YM-26734;
platelet activating factor receptor antagonists including, but not limited to, piperidone hydrochloride;
Pparγ agonists, including but not limited to rosiglitazone XR;
pparγ agonists/insulin sensitizers, including but not limited to rosiglitazone;
apoptosis protein 1 modulators, including but not limited to INSIX RA;
prostaglandin D synthase stimulators including, but not limited to HF-0220;
protein tyrosine kinase inhibitors including, but not limited to, tameimide;
PurH purine biosynthesis protein inhibitors/inosine monophosphate dehydrogenase inhibitors including, but not limited to mycophenolate mofetil;
rev protein modulators, including but not limited to ABX-464;
RIP-1 kinase inhibitors, including but not limited to GSK-2982772 and VRN-04;
IL-17 antagonists/rho-associated protein kinase 2 inhibitors, including but not limited to KD-025;
signal transduction protein CD24 modulators, including but not limited to CD24-IgFc;
sodium glucose transporter-2 inhibitors/ppary agonists/insulin sensitizers, including but not limited to THR-0921;
STAT3 gene inhibitors including, but not limited to, vidoflradium (vidof1 udimus);
STAT-3 inhibitors, including but not limited to HL-237;
superoxide dismutase stimulators including, but not limited to, i Mi Pameng;
SYK family tyrosine kinase inhibitors/Zap 70 tyrosine kinase inhibitors, including but not limited to MK-8457;
Syk tyrosine kinase inhibitors including, but not limited to, futaminib, entoltinib, KDF-201110-06, HMPL-523, AB-8779, GS-9876, PRT-2607, CG-103065 and SKI-O-703;
t cell receptor antagonists, including but not limited to TCR-inhibitory SCHOOL peptides (systemic/local, rheumatoid arthritis/dermatitis/scleroderma), singibook and CII-modified peptides (rheumatoid arthritis);
t cell receptor modulators/HLA class II antigen modulators, including but not limited to ARG-301;
t cell surface glycoprotein CD28 stimulators including, but not limited to, TAB-08 and sirolimus;
TAK1 binding protein modulators, including but not limited to epigallocatechin 3-gallate;
tamarin modulators, including but not limited to short-form Tamarin modulators (rheumatoid arthritis), kayteeBio;
t cell differentiation antigen CD6 inhibitors including, but not limited to, illicit mab;
t cell surface glycoprotein CD8 inhibitors/tgfβ agonists/CD 4 antagonists, including but not limited to treglimumab;
thymosin agonists, including but not limited to Syn-1002;
TLR-2/TLR-4 antagonists, including but not limited to VB-201;
TLR-4 antagonists, including but not limited to NI-0101;
TLR-2/4/9 antagonists, including but not limited to P-13;
TNF agonists/TNF antagonists/type II TNF receptor modulators, including but not limited to lifmix;
a tnfα ligand inhibitor and a therapeutic agent, including but not limited to Adfrar, FKB-327, ximale, cinnora, mabura, adalimumab, infliximab, flixabi, PF-06438179, hadlima, recombinant humanized anti-TNF-alpha monoclonal antibodies, CMAB-008, CT-P13, GB-242, golimumab (CNTO-148), olimumab, AT-132, ISIS-104838, ISU-202, CT-P17, MB-612, debio-0512, anti-TNF-alpha human monoclonal antibodies, UB-721, KN-002, DA-3113, BX-2922, R-TPR-015, BOW-050, PF-06410293, CKD-760, CHS-1420, GS-071, ABP-710 BOW-015, HLX-03, BI-695501, MYL-1401A, ABP-501, BAX-2923, SCH-215596, ABT-D2E7, BAT-1406, XPro-1595, atsttrin, SSS-07, golimu single antibiotic analog, TA-101, BLX-1002, ABX-0401, TAQ-588, teHL-1, praguemab, CYT-007-TNFQb, SSR-150106, passTNF, verigen, DOM-0200, DOM-0215, AME-527, anti-TNF-alpha mab, GENZ-38167, BLX-1028, CYT-020-TNFQb, CC-1080, CC-1069, LBAL, GP-2017, idacio, IBI-303, HS-016, TNF-2 and IA-14069;
Tnfα ligand inhibitors/TNF antagonists/type II TNF receptor modulators, including but not limited to BAX-2200;
tnfα ligand inhibitors/type II TNF receptor modulators, including but not limited to Eucept, tnfα ligand modulators: MM-A01-01, CDP-571, card Mo Bu, and JNJ-63823539;
TNF antagonists, including but not limited to DNX-114, TNF antagonists+IL-12 antagonists (rheumatoid arthritis), oxford university, BN-006, perindopril, ACE-772, onazepine, DE-096, PN-0615, lenacil, ITF-1779, MDL-201112, HD-203, jiang Ke (Qiangke) and TNF a Fc;
TNF antagonists/type II TNF receptor modulators, including but not limited to Altebrel, intacept, QL-0902, etanercept, erelzi, etanercept, ecosystem, annuo, benepali, YLB-113, SCB-808, DA-3853, and SCB-131;
TNF antagonists/tnfα ligand inhibitors including, but not limited to, pegylated cetuximab;
TNF receptor modulators, including but not limited to recombinant TNF receptor 2-Fc fusion protein mutants, T-0001;
TNF receptor modulators/tnfα ligand inhibitors including, but not limited to tgAAV-TNFR: an Fc;
tumor necrosis factor 13 C receptor antagonists including, but not limited to, VAY-736;
Tumor necrosis factor 15 ligand inhibitors including, but not limited to, anti-TL 1A antibodies (rheumatoid arthritis/inflammatory bowel disease), NIAMS;
tumor necrosis factor ligand inhibitors including, but not limited to, etanercept biosimilar;
type I IL-1 receptor antagonists, including but not limited to anakinra, IL-1 Ra, anakinra-subsequent biologicals, and AXXO;
type I TNF receptor antagonists, including but not limited to NM-940 and EN-2001;
type II TNF receptor modulators, including but not limited to LBEC-0101, DMB-3853, DWP-422, and BT-D001;
unspecified GPCR agonists, including but not limited to NCP-70X;
VEGF receptor antagonists, including but not limited to NSC-650853;
VEGF-2 receptor modulators, including but not limited to VEGFR2 neutralizing antibodies (rheumatoid arthritis), university of Rochester;
VEGF-B ligand inhibitors, including but not limited to CSL-346;
x-linked apoptosis inhibitor proteins including, but not limited to IAP inhibitors (oral), pharmascience; and
zap70 tyrosine kinase inhibitors including, but not limited to CT-5332.
In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with one or more agents useful in the treatment and/or prevention of a rheumatic disorder.
In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with one or more agents useful in the treatment and/or prevention of rheumatoid arthritis. Non-limiting examples of such agents include disease modifying antirheumatic drugs (DMARDS) such as hydroxychloroquine, sulfasalazine, methotrexate and leflunomide; TNF inhibitors (e.g., etanercept, adalimumab, infliximab, golimumab, pegylated cetuximab), T cell costimulatory inhibitors (e.g., abamectin), IL-6 receptor inhibitors (e.g., tolizumab, sha Lilu mab), anti-CD 20 antibodies (e.g., rituximab); and JAK inhibitors (e.g., tofacitinib, barytanib, wu Pati ni); NSAIDs such as ibuprofen, naproxen and diclofenac; COX-2 inhibitors such as celecoxib and etoricoxib; steroids and corticosteroids such as prednisolone and cortisone; and biological agents known for the treatment and/or prevention of such disorders, including, for example, etanercept (e.g., ENBREL), infliximab (e.g., REMICADE), adalimumab (e.g., HUMIRA), anakinra (e.g., KINARET), abarupr (ORENCIA), rituximab (e.g., RITUXAN), cetuximab (e.g., CIMZIA), golimumab (e.g., SIMPONI), and tolizumab (e.g., actemira). In some embodiments, the compounds of the present disclosure are administered with two additional therapeutic agents useful in the treatment and/or prevention of rheumatic disorders. In some embodiments, agents useful in the treatment and/or prevention of rheumatic disorders include the compounds of the present disclosure and two additional therapeutic agents, such as methotrexate + leflunomide, methotrexate + sulfasalazine, methotrexate + cyclosporine, methotrexate + hydroxychloroquine and triple therapy for the treatment of hydroxychloroquine + sulfasalazine + methotrexate, hydroxychloroquine + sulfasalazine + leflunomide.
Combination therapy for inflammatory bowel disease
In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, may be combined with one or more additional therapeutic agents to treat or ameliorate Inflammatory Bowel Disease (IBD).
As used herein, the term "inflammatory bowel disease" or "IBD" is a collective term describing inflammatory lesions of the gastrointestinal tract, the most common forms of which are ulcerative colitis and crohn's disease. Other forms of IBD that may be treated with the compounds provided herein or pharmaceutically acceptable salts thereof or the pharmaceutical compositions provided herein include, but are not limited to, diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autism enterocolitis, non-established colitis, behcet's disease, gastroduodenal CD, jejunum ileitis, ileal colitis, crohn's (granulomatous) colitis, irritable bowel syndrome, mucositis, radiation enteritis, short bowel syndrome, celiac disease, gastric ulcers, diverticulitis, chu Daiyan, proctitis, and chronic diarrhea.
Treating or preventing IBD also includes ameliorating or reducing one or more symptoms of IBD. As used herein, the term "symptoms of IBD" refers to detected symptoms such as abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite, and other more serious complications such as dehydration, anemia, and malnutrition. Many such symptoms require quantitative analysis (e.g., weight loss, fever, anemia, etc.). Some symptoms are readily determined from blood tests (e.g., anemia) or tests that detect the presence of blood (e.g., rectal bleeding). The term "wherein the symptom is reduced" refers to a qualitative or quantitative reduction in a detectable symptom, including but not limited to a detectable effect on recovery from a disease (e.g., weight gain rate). Diagnosis is typically determined by endoscopic observation of the mucosa and pathological examination of endoscopic biopsy specimens.
The course of IBD varies and is often associated with intermittent periods of disease remission and disease progression. Various methods for characterizing the disease activity and severity of IBD and the response to treatment of a subject with IBD have been described. The treatment according to the methods and uses of the invention is generally applicable to subjects suffering from any level or extent of disease activity in IBD.
The methods and uses provided herein are also applicable to any point in the disease process. In some embodiments, these methods and uses are applied to a subject suffering from IBD during periods of remission (i.e., inactive disease). In some embodiments, the methods and uses of the invention provided herein provide benefits by extending the period of remission (e.g., extending the period of inactivity disease) or by preventing, reducing, or delaying the onset of activity disease. In some embodiments, the methods and uses provided herein may be applied to a subject suffering from IBD during active disease. In some embodiments, the methods and uses provided herein provide benefits by reducing the duration of active disease, reducing or ameliorating one or more symptoms of IBD, or treating IBD.
Measures for determining the efficacy of treatment of IBD in clinical practice have been described and include, for example, the following: symptom control; fistula closure; the extent of corticosteroid therapy required; and improvement of quality of life. Quality of Life (HRQL) associated with health can be assessed using an Inflammatory Bowel Disease Questionnaire (IBDQ), which is widely used in clinical practice to assess quality of life in IBD subjects. ( See Guyatt et al (1989) Gastroenterology 96:804-810. )
In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, may be combined with one or more additional therapeutic agents to treat or ameliorate IBD. Non-limiting examples of therapeutic agents for treating or ameliorating IBC include allogeneic bone marrow derived MSC therapy, AMP-activated protein kinase stimulators, aromatic hydrocarbon receptor agonists and T-cell receptor modulators, ASK1 inhibitors, beta adrenergic receptor antagonists, BTK inhibitors, beta-catenin stimulators, beta-glucuronidase inhibitors, bradykinin receptor modulators, calcineurin inhibitors, calcium channel inhibitors, cathepsin S inhibitors, CCR3 chemokine antagonists, CD40 ligand receptor antagonists, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen modulators, CXCR3 chemokine antagonists, CSF-1 antagonists, cyclooxygenase inhibitors, cytochrome P4503A4 inhibitors, DYRK-1 alpha protein kinase inhibitors, endothelial dysfunction and vascular leakage blockers enolase 1 inhibitors, eosinophil ligand inhibitors, EP4 prostaglandin receptor agonists, erythropoietin receptor agonists, exporter 1 inhibitors, actin ligand inhibitors, free fatty acid receptor 2 antagonists, GATA 3 transcription factor inhibitors, glucagon-like peptide 2 agonists, glucocorticoid agonists, guanylate cyclase receptor agonists, histone deacetylase inhibitors, HLA class II antigen modulators, IL-12 antagonists, IL-13 antagonists, interleukin-2 ligands, IL-23 antagonists, IL-6 receptor modulators, interleukin-7 receptor modulators, IL-7 antagonists, IL-8 antagonists, integrin alpha-4/beta-1 antagonists, integrin alpha-4/beta-7 antagonists, integrin alpha-E antagonists, integrin beta-7 antagonists, interleukin ligand inhibitors, interleukin-10 ligands, interleukin receptor 17A antagonists, interleukin 23A inhibitors, interleukin-1 beta ligands, interleukin-1 beta ligand modulators, IRAK4 inhibitors, JAK tyrosine kinase inhibitors, jak1 tyrosine kinase inhibitors, jak3 tyrosine kinase inhibitors, lanC-like protein 2 modulators, lipoxygenase modulators, macrophage mannose receptor 1 modulators, MAdCAM inhibitors, matrix metalloproteinase inhibitors, melanocortin agonists, metalloproteinase-9 inhibitors, NADPH oxidase inhibitors, natriuretic peptide receptor C agonists, NC-301, next generation intestinal flora therapy, and methods of treating or preventing a disease neuregulin-4 ligand, NKG 2D-activating NK receptor antagonist, non-receptor tyrosine kinase TYK2 antagonist, opioid receptor delta antagonist, oxidoreductase inhibitor, P2X7 purinergic agonist, PDE 4 inhibitor, phagocytosis stimulating peptide modulator, potassium channel inhibitor, PPARα agonist, PPARδ agonist, PPARγ agonist, protein fimH inhibitor, P-selectin glycoprotein ligand-1 inhibitor, RNA polymerase inhibitor, sphingosine 1 phosphophosphatase 1 stimulator, sphingosine 1 phosphophosphatase modulator, sphingosine 1-phosphate receptor-1 agonist, sphingosine 1-phosphate receptor-1 antagonist, sphingosine 1-phosphate receptor-1 modulator, sphingosine 1-phosphate receptor-5 modulator, STAT3 gene inhibitor, stem cell antigen-1 inhibitors, superoxide dismutase modulators, superoxide dismutase stimulators, SYK inhibitors, TGF beta 1 ligand inhibitors, thymosin agonists, TLR antagonists, TNF alpha ligand inhibitors, TNF antagonists, tumor necrosis factor 14 ligand modulators, type II TNF receptor modulators, tpl 2 inhibitors, X-box binding protein 1 stimulators, and even inhibitors.
In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, may be combined with one or more additional therapeutic agents selected from the group consisting of: ABX-464, adalimumab; ALLO-ASC-CD, AMG-966, AMT-101, anakinra, apremilast; alequesl; ALV-304, AMG-139; amicetmod, anti-CXCR 3 mab, ASD-003, ASP-3291, AX-1505, balsalazide; beclomethasone dipropionate; BI-655130, BMC-321, BMC-322, BMS-986184; BT-051, budesonide; CBX-111, CEQ-508; cetuximab; xibonnide, clostridium butyricum; chAdOx2-HAV, CU-06, CUG-252 dexamethasone sodium phosphate, DNVX-078, EB-7020, EM-101, etanercept; ENERGI-F704, ETX-201, golimumab; GS-4997, GS-5718, GS-9876, GS-4875, GS-4059, infliximab; IMS-001, mesalamine, HLD-400, IBI-112, IMM-H013, KB-295, LFS-829, LYC-30937EC; IONIS-JBI1-2.5Rx, JNJ-64304500, JNJ-66525433, JNJ-4447, aspargonic acid, MET-642, MVA-HAV, naltrexone; natalizumab; inner Hu Lizhu mab, oxalazine; ext> NOSext> -ext> 1244ext>,ext> NTGext> -ext> Aext> -ext> 009ext>,ext> PHext> -ext> 46ext> -ext> Aext>,ext> propionylext> -ext> Lext> -ext> carnitineext>;ext> PTG-100; remstemcel-L; tacrolimus; tidollutide; tofacitinib; ASP-1002; utekey monoclonal antibody; vedolizumab; AVX-470; INN-108; SGM-1019; PF-06480605; PF-06651600; PR-600; RBX-8225, R-2187, RG-6287, SER-287; TOP-1288; VBY-129;99 mTc-annexin V-128; bai Ti wood monoclonal antibody; DLX-105; a dulcina peptide; quinuclidine Mo Lishan antibody (E-6011); FFP-104; non-gotinib; resistance to Fu Lei Lushan; GED-0507-34-Levo; ji Weisi he; GLPG-0974; i Bei Jiate (iberogast); ICP-330, JNJ-40346527; k (D) PT; KAG-308; KHK-4083; KRP-203; larezodone acetate; LY-3074828, missmase; oloside monoclonal antibody; ovaSave; P-28-GST; PF-547659; prednisolone; qbcco; RG-7835; RBX-2660, RO7049665, JKB-122; SYGN-313, SB-012; STNM-01; SZN-1326, TJC-0434, debio-0512; TRK-170; ABT-494; an ame; BI-655066; methyl calicheat; comparable tolmod; elaflibanor; itrarinab; GS-5745; HMPL-004; LP-02, ozanimod; pefeitinib; QX-004-N, RHB-104; SEFA-1024, teridamab; TOP-1890, qu Luolu monoclonal antibodies; bromobudadizumab; laquinimod; and procalcitonin; or a pharmaceutically acceptable salt of any of the foregoing; or any combination thereof.
In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with one or more agents useful in the treatment and/or prevention of gastrointestinal disorders such as Ulcerative Colitis (UC) or Crohn's Disease (CD). Non-limiting examples of such agents include infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, you-terumab, natalizumab, asparatic acid, azo-bonded 5-ASA, sulfasalazine, balsalazide, olsalazine, corticosteroids such as budesonide, hydrocortisone, methylprednisolone, and prednisone; immunosuppressants or immunomodulators such as azathioprine and 6-mercaptopurine, cyclosporine and methotrexate.
VII preparation of the Compounds
Some embodiments of the present disclosure relate to methods and intermediates useful for preparing compounds provided herein or pharmaceutically acceptable salts thereof.
The compounds described herein may be purified by any method known in the art, including chromatographic methods, such as High Performance Liquid Chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase may be used, including normal and reverse phases, as well as ion resins. Most typically, the disclosed compounds are purified by silica gel and/or alumina chromatography.
During any of the methods for preparing the compounds provided herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any molecule of interest. This can be achieved by conventional protecting groups as described in standard works such as T.W.Greene and P.G.M.Wuts, "Protective Groups in Organic Synthesis", 4 th edition, wiley, new York 2006. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.
Exemplary chemical entities useful in the methods of embodiments will now be described by reference to the general preparations herein and the specific examples of illustrative synthetic schemes below. The skilled artisan will recognize that in order to obtain the various compounds herein, the starting materials may be appropriately selected such that the final desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to replace the final desired substituent with a suitable group that can be subjected to the reaction scheme and optionally substituted with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order compatible with the functionality of the particular pendant group. Each reaction depicted in the general scheme is preferably run at a temperature of about 0 ℃ to the reflux temperature of the organic solvent used.
The methods of the present disclosure generally provide a particular enantiomer or diastereomer as a desired product, although stereochemistry of the enantiomer or diastereomer is not established in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is depicted without the particular stereocenter exhibiting any stereochemistry, even though the compound may be substantially enantiomerically or diastereomerically pure.
Representative syntheses of the compounds of the present disclosure are described in the following schemes and in the specific examples that follow.
Certain abbreviations and acronyms are used to describe experimental details. While most abbreviations and abbreviations will be readily recognized and understood by those of ordinary skill in the art, the following list provides many meanings of the abbreviations and abbreviations.
Abbreviations and abbreviation list
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General synthetic procedure
General reaction schemes 1-13 are provided as additional embodiments of the present disclosure and illustrate general methods for preparing certain compounds of the present disclosure and additional compounds useful for preparing the present disclosure. Each variable (e.g., R) of the compounds disclosed in general schemes 1-13 1 、R 2 、R 3 、R 4 ) As defined herein.
The compounds of the present disclosure may be prepared using the methods disclosed herein and conventional modifications thereof, as will be apparent to those skilled in the art in view of the disclosure herein and methods well known in the art. Conventional and well known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein can be accomplished as described in the examples below. Reagents, if available, are commercially available, for example from Sigma Aldrich or other chemical suppliers. In general, the compounds described herein are generally stable and separable at moderate temperatures and pressures.
Typical embodiments of the compounds disclosed herein can be synthesized using the general reaction schemes described below. It will be apparent to those skilled in the art in view of the description herein that the general scheme may be altered by substituting starting materials with other materials having similar structures to produce correspondingly different products. A description of the synthesis then provides many examples of how the starting materials may be varied to provide the corresponding products. In view of the desired product defining the substituent groups, the necessary starting materials can generally be determined by examination. The starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing the compounds of the embodiments disclosed in this disclosure, an examination of the structure of the compound to be synthesized will provide an identification of each of the substituent groups. In view of the examples herein, the identification of the end product will typically render the identification of the starting material apparent through a simple inspection process.
The term "solvent", "inert organic solvent" or "inert solvent" refers to a solvent that is inert under the reaction conditions described in connection therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, and the like). Unless specified to the contrary, the solvents used in the reactions of the present disclosure are all inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen or argon.
General reaction scheme 1：
Intermediate 1.1 (where M is-B, -Sn, -Zn, -Si, or-Mg) can be reacted with intermediate 2 in the presence of a suitable palladium catalyst to produce intermediate 1.3. Intermediate 1.4 can be reacted in the presence of a metallization reagent (e.g., iPrMgBr, n-BuLi) and di-tert-butyl azodicarboxylate to give intermediate 1.6. Intermediate 1.3 and intermediate 1.6 can be reacted in the presence of an acid (e.g., PTSA) at an elevated temperature to afford intermediate 1.7.
General reaction scheme 2：
Intermediate 1.7 can be prepared in the presence of a suitable base (e.g., liOH, me 3 SnOH) and heat to produce intermediate 2.1. Intermediate 2.1 can then be reacted in the presence of a suitable base (e.g., DBU) and heat to produce intermediate 2.2. Alternatively, intermediate 2.2 may be provided by reacting intermediate 1.7 in the presence of a suitable base (e.g., liOH) and prolonged heating. Intermediate 2.2 can be reacted in the presence of a suitable halogenating reagent (e.g., NBS, NIS, NCS) to yield intermediate 2.3, where x= I, br or Cl.
General reaction scheme 3：
The compounds of formula (i.a) can be assembled by combining intermediate 2.1 with a suitable primary or secondary amine 3.1 in the presence of a suitable peptide coupling reagent (e.g., HATU, TCFH, EDC) and a suitable base (e.g., N-diisopropylethylamine, triethylamine). If the compound of formula (i.a) contains a tert-butyl carbamate functionality, this can then be removed by treatment with an acid (e.g. trifluoroacetic acid or hydrochloric acid) to reveal a compound of formula (i.a) containing a primary or secondary amine. If the compound of formula (I.a) contains a benzylamine function, this can then be removed (e.g. using a metal catalyst and H) 2 Gas) to show a compound of formula (i.a) containing a primary or secondary amine.
General reaction scheme 4：
The compound of formula (I.b) can be assembled by combining intermediate 2.1 with a suitable cyclic secondary amine 4.1 in the presence of a suitable peptide coupling reagent (e.g., HATU, TCFH, EDC) and a suitable base (e.g., N-diisopropylethylamine, triethylamine). If a compound of formula (I.b)Containing a tert-butyl carbamate functional group, this can then be removed by treatment with an acid (e.g., trifluoroacetic acid or hydrochloric acid) to reveal a compound of formula (I.b) containing a primary or secondary amine. If the compound of formula (I.b) contains a benzylamine functionality, this can then be removed (e.g., using a metal catalyst and H 2 Gas) to show a compound of formula (I.b) containing a primary or secondary amine.
General reaction scheme 5:
compounds of formula (I.c) containing a (1, 3, 4) -oxadiazole moiety can be assembled by first reacting intermediate 2.1 with intermediate 5.1 in the presence of a suitable peptide coupling reagent (e.g., HATU, TCFH, EDC, CDI) and a suitable base (e.g., N-diisopropylethylamine, triethylamine) followed by the presence of an oxidizing agent (e.g., a bergius reagent). Alternatively, intermediate 2.1 and intermediate 5.1 may be prepared by first in the presence of a suitable peptide coupling reagent (e.g., HATU, TCFH, EDC, CDI) and a suitable base (e.g., N-diisopropylethylamine, triethylamine), followed by the presence of a sulfur reagent (e.g., lawsen reagent, P) 2 S 5 ) Is reacted to assemble a compound of formula (i.d) containing a (1, 3, 4) -thiadiazole moiety. If the compound of formula (I.c) or (i.d) contains a tert-butyl carbamate functionality, this can then be removed by treatment with an acid (e.g., trifluoroacetic acid or hydrochloric acid) to reveal a compound of formula (I.c) or (i.d) containing a primary or secondary amine. If the compound of formula (I.c) or (I.d) contains a benzylamine functionality, this can then be removed (e.g., using a metal catalyst and H) 2 Gas) to show a compound of formula (I.c) or (i.d) containing a primary or secondary amine.
General reaction scheme 6：
The compound of formula (I.e) containing a (1, 2, 4) -oxadiazole moiety can be assembled by first reacting intermediate 2.1 with intermediate 6.1 in the presence of a coupling reagent (e.g., CDI) and heat. If the compound of formula (I.e) contains a tert-butyl carbamate functionality, this can then be removed by treatment with an acid (e.g., trifluoroacetic acid or hydrochloric acid) to reveal a compound of formula (I.e) containing a primary or secondary amine. If the compound of formula (I.e) contains a benzylamine functionality, this can then be removed (e.g., using a metal catalyst and H 2 Gas) to show a compound of formula (I.e) containing a primary or secondary amine.
General reaction scheme 7：
The oxazoline moiety-containing compound of formula (I.f) may be assembled by first reacting intermediate 2.1 with intermediate 7.1 in the presence of a suitable peptide coupling reagent (e.g., HATU, TCFH, EDC, CDI) and a suitable base (e.g., N-diisopropylethylamine, triethylamine), followed by the presence of an oxidizing agent (e.g., a bergius reagent). Alternatively, compounds of formula (I.g) containing an oxazoline moiety may be assembled by first reacting intermediate 2.1 with intermediate 7.2 in the presence of a suitable peptide coupling reagent (e.g., HATU, TCFH, EDC, CDI) and a suitable base (e.g., N-diisopropylethylamine, triethylamine), followed by the presence of an oxidizing agent (e.g., a bergiut reagent). If the compound of formula (I.f) or (I.g) contains a tert-butyl carbamate functionality, this can then be removed by treatment with an acid (e.g., trifluoroacetic acid or hydrochloric acid) to reveal a compound of formula (I.f) or (I.g) containing a primary or secondary amine. If the compound of formula (I.f) or (I.g) contains a benzylamine functionality, this can then be removed (e.g., using a metal catalyst and H) 2 Gas) to show a compound of formula (I.f) or (I.g) containing a primary or secondary amine.
General reaction scheme 8：
The compound of formula (I.h) can be assembled by combining intermediate 2.3 with a suitable metallized coupling partner M-Z (where Z is aryl, heteroaryl, alkenyl, and M is-B, -Sn, -Zn, -Si, or-Mg) using a suitable palladium catalyst and a base (e.g., cesium carbonate, tripotassium phosphate, sodium carbonate) to produce the compound of formula (I.h). If the compound of formula (I.h) contains an olefin, this can then be removed (e.g., using a metal catalyst and H 2 Gas). If the compound of formula (I.h) contains a tert-butyl carbamate functionality, this can then be removed by treatment with an acid (e.g., trifluoroacetic acid or hydrochloric acid) to reveal a compound of formula (I.h) containing a primary or secondary amine. If the compound of formula (I.h) contains a benzylamine functionality, this can then be removed (e.g., using a metal catalyst and H 2 Gas) to show a compound of formula (I.h) containing a primary or secondary amine.
General reaction scheme 9：
The compound of formula (I.j) can be assembled by combining a compound of formula (I.i) (produced via one of the methods set forth above, such as scheme 3) with the appropriate formic acid 9.1 in the presence of an appropriate peptide coupling reagent (e.g., HATU, TCFH, EDC) and an appropriate base (e.g., N-diisopropylethylamine, triethylamine). Alternatively, a compound of formula (I.i) can be combined with a suitable aldehyde 9.2 in the presence of a suitable reducing agent (e.g., naBH 4 、Na(OAc) 3 BH、Na(CN) 3 BH) are combined to assemble the compounds of formula (I.k). Alternatively, a base (e.g., N, N-diisopropylethylamine, triethylamine, K) can be present by reacting a compound of formula (I.i) with intermediate 9.3, wherein X is a leaving group (e.g., -Cl, -Br, -I, OTs, -OMs) 2 CO 3 、csCO 3 ) In combination to assemble the compound of formula (i.1). If formula (i.j.), the term (I).k) Or (i.1) contains a tert-butyl carbamate functionality, then this can be subsequently removed by treatment with an acid (e.g., trifluoroacetic acid or hydrochloric acid) to reveal compounds of formula (i.j.), I.k) or (i.1) containing a primary or secondary amine. If the compound of formula (i.j.), (I.k) or (i.1) contains a benzylamine functionality, this can be subsequently removed (e.g., using a metal catalyst and H) 2 Gas) to show a compound of formula (i.j.), or (I.k), or (i.1) containing a primary or secondary amine.
General reaction scheme 10：
Intermediate 2.3 can be coupled with intermediate 10.1 (where-M is-B, -Sn, or-Zn, and Pg is Boc or Bn) in the presence of a palladium catalyst and a base (e.g., cesium carbonate, tripotassium phosphate, sodium carbonate) to produce intermediate 10.2. Intermediate 10.2 may be prepared in the presence of a metal catalyst (e.g., palladium) and H 2 The reaction under gas conditions to produce intermediate 10.3. Alternatively, intermediate 2.3 can be coupled with intermediate 10.4 (where-M is-B or-Zn and Pg is Boc or Bn) in the presence of a palladium catalyst to yield intermediate 10.3. Alternatively, intermediate 2.3 can be coupled with intermediate 10.5 (where-X is-C1, -Br, -I, OMs, -OTs, -OTf, and Pg is Boc or Bn) in the presence of a palladium or nickel catalyst to yield intermediate 10.3. If pg=boc, intermediate 10.3 can be reacted in the presence of an acid (e.g., TFA, HCl) to produce a compound of formula (I.m). Alternatively, if pg=bn, intermediate 10.3 may be made in the presence of a metal catalyst (e.g., palladium) and H 2 Reacted under gas conditions to produce the compound of formula (I.m).
General reaction scheme 11：
Can be prepared by a compound of formula (I.n) (via one of the methods set forth above, such as scheme 10)Produced) is combined with a suitable methyl 11.1 in the presence of a suitable peptide coupling reagent (e.g., HATU, TCFH, EDC) and a suitable base (e.g., N-diisopropylethylamine, triethylamine) to assemble a compound of formula (I.n). Alternatively, a compound of formula (I.m) can be combined with a suitable aldehyde or ketone 11.2 in the presence of a suitable reducing agent (e.g., naBH 4 、Na(OAc) 3 BH、Na(CN) 3 BH) are combined to assemble the compounds of formula (I.o). Alternatively, a base (e.g., N, N-diisopropylethylamine, triethylamine, K) can be present by reacting a compound of formula (I.m) with intermediate 10.3, wherein X is a leaving group (e.g., -C1, 0Br, -I, OTs, -OMs) 2 CO 3 、CsCO 3 ) In combination to assemble the compound of formula (I.p). If the compound of formula (I.n), (I.o) or (I.p) contains a tert-butyl carbamate functionality, this can then be removed by treatment with an acid (e.g., trifluoroacetic acid or hydrochloric acid) to reveal a compound of formula (I.n), (I.o) or (I.p) containing a primary or secondary amine. If the compound of formula (I.n), (I.o) or (I.p) contains a benzylamine functionality, this can be subsequently removed (e.g., using a metal catalyst and H) 2 Gas) to show a compound of formula (I.n), (I.o) or (I.p) containing a primary or secondary amine.
General reaction scheme 12：
Intermediate 2.3 can be coupled with intermediate 12.1 (where-M is-B, -Sn, or-Zn, and the ketal moiety may or may not cyclize to form a ring) in the presence of a palladium catalyst and a base (e.g., cesium carbonate, tripotassium phosphate, sodium carbonate) to yield intermediate 12.2. Intermediate 12.2 can be prepared in the presence of a metal catalyst (e.g., palladium) and H 2 The reaction under gas conditions to produce intermediate 12.3. Alternatively, intermediate 2.3 may be coupled with intermediate 12.4 (where-M is-B or-Zn, and the ketal moiety may or may not be cyclized to form a ring) in the presence of a palladium catalyst to yield intermediate 12.3. Alternatively, intermediate 2.3 and intermediate 12.5 (wherein-X is-Cl, -B)r, -I, OMs, -OTs, -OTf, and the ketal moiety may or may not cyclize to form a ring) in the presence of a palladium or nickel catalyst to yield intermediate 12.3. Intermediate 10.3 can be reacted in the presence of an acid (e.g., TFA, HCl) to produce a compound of formula (I.q).
General reaction scheme 13：
Can be prepared by reacting a compound of formula (I.q) with a suitable primary or secondary amine 13.1 in the presence of a suitable reducing agent (e.g., naBH 4 、Na(OAc) 3 BH、Na(CN) 3 BH) are combined to assemble the compounds of formula (I.r). Can be prepared by reacting a compound of formula (I.q) with a suitable cyclic amine 4.1 in the presence of a suitable reducing agent (e.g., naBH 4 、Na(OAc) 3 BH、Na(CN) 3 BH) are combined to assemble the compounds of formula (I.s). If the compound of formula (I.r) or (I.s) contains a tert-butyl carbamate functionality, this can then be removed by treatment with an acid (e.g., trifluoroacetic acid or hydrochloric acid) to reveal a compound of formula (I.r) or (I.s) containing a primary or secondary amine. If the compound of formula (I.r) or (I.s) contains a benzylamine functionality, this can then be removed (e.g., using a metal catalyst and H) 2 Gas) to show a compound of formula (I.r) or (I.s) containing a primary or secondary amine.
VIII. Examples
Exemplary chemical entities of the present disclosure are provided in the following specific examples. Those skilled in the art will recognize that in order to obtain the various compounds herein, the starting materials may be appropriately selected such that the final desired substituents will be reacted, optionally with or without protection, to yield the desired product. Alternatively, it may be necessary or desirable to replace the final desired substituent with a suitable group that can be subjected to the reaction scheme and optionally substituted with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order compatible with the functionality of the particular pendant group.
The examples provided herein describe the synthesis of the compounds disclosed herein and intermediates useful in the preparation of these compounds. It should be understood that the various steps described herein may be combined. It will also be appreciated that individual batches of the compounds may be combined and then continued in the next synthesis step.
In the following example description, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the disclosure. Other embodiments may be utilized, and logical and other changes may be made without departing from the scope of the present disclosure. Accordingly, the following description is not intended to limit the scope of the present disclosure.
Intermediate products
Preparation of intermediate 1：
3-methyl-1- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) butan-1-one (I-1): addition of 8-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) - [1,2,4 to the vial]Triazolo [1,5-a ]]Pyridine (7.77 g,30.0 mmol), palladium acetate (0.337 g,1.50 mmol) and tris (4-methoxyphenyl) phosphine (0.611 g,1.75 mmol) were then added THF (100 mL), water (1.13 mL,62.5 mmol) and isovaleryl anhydride (5.00 mL,25.0 mmol). Argon was bubbled through the mixture for 4 minutes and the reaction mixture was heated to 60 ℃ for 16 hours. The reaction mixture was filtered through celite, eluted with DCM, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (0% -50% etoac/hexanes) to give the title compound. ES/MS:218.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d) 4 )δ9.39(s，1H)，8.52(s，1H)，7.98(s，1H)，2.97(d，J＝6.8Hz，2H)，2.66(s，3H)，2.37-2.23(m，1H)，1.04(dd，J＝6.7，0.8Hz，6H)。
Intermediate partPreparation of body I-2：
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Di-tert-butyl 1- (5- (methoxycarbonyl) -4-methylthiophene-2-yl) hydrazine-1, 2-dicarboxylate (I-2): to a solution of 5-bromo-3-methyl-thiophene-2-carboxylic acid methyl ester (3.90 g,16.6 mmol) in THF (50 mL) cooled to-40 ℃ was added dropwise a solution of isopropyl magnesium bromide in 2-MeTHF (2.90 mol/L,8.01mL,23.2 mmol) and the solution was stirred at-40 ℃ for 30 minutes. A solution of di-tert-butyl azodicarbonate (4.58 g,19.9 mmol) in THF (50 mL) was then added dropwise and the reaction stirred at-40℃for 15 min. The reaction was quenched by addition of saturated aqueous ammonium chloride and the mixture was extracted with DCM (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (0% -50% etoac/hexanes) to give the title compound. ES/MS:387.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 6.62 (s, 1H), 3.82 (s, 3H), 2.46 (s, 3H), 1.60-1.51 (m, 18H).
Preparation of intermediate I-3:
4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-2-carboxylic acid methyl ester (I-3): to a solution of di-tert-butyl 1- (5- (methoxycarbonyl) -4-methylthiophene-2-yl) hydrazine-1, 2-di-carboxylate (I-2) (4.63 g,12.0 mmol) and p-toluenesulfonic acid monohydrate (12.4 g,71.9 mmol) in 2-MeTHF (140 mL) in a 500mL round bottom flask was added 3-methyl-1- (8-methyl- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-6-yl) butan-1-one (I-1) (2.86 g,13.2 mmol) and the reaction mixture was heated to 90℃for 16 hours using a reflux condenser. The reaction mixture was concentrated in vacuo, dissolved in EtOAc and washed with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with EtOAc (2X)The combined organic layers were taken and washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (0% -100% etoac/hexanes) to give the title compound. ES/MS:369.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d) 4 )δ8.66(s，1H)，8.46(s，1H)，7.58(t，J＝1.4Hz，1H)，3.85(s，3H)，3.41-3.34(m，1H)，2.88(s，3H)，2.69(s，3H)，1.40(d，J＝7.1Hz，6H)。
Preparation of intermediate I-4：
4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-2-carboxylic acid (I-4): to 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]To a solution of pyrrole-2-carboxylic acid methyl ester (I-3) (52.3 mg,0.14 mmol) in DCE (1.00 mL) was added trimethyltin hydroxide (0.257 g,0.00142 mol) and the reaction mixture was heated to 120℃for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (0% -100% etoac/hexanes) to give the title compound. ES/MS:355.1 (M+H) + )。
Preparation of intermediate I-5：
4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole (I-5): to 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]To a solution of pyrrole-2-carboxylic acid methyl ester (I-3) (2.62 g,7.11 mmol) in methanol (75 mL) and water (7.5 mL) was added potassium hydroxide (1.60 g,28.4 mmol) and the reaction mixture was heated to 100deg.C for 24 hours. The reaction mixture was concentrated under reduced pressure, then diluted with hydrochloric acid (1.00 mol/L,42.7mL,42.7 mmol) and waterThe precipitate was collected by filtration and air dried for 1 hour to give the crude title product. ES/MS:311.2 (M+H) + )。
Preparation of intermediate I-6：
2-bromo-4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole (I-6): to 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]A solution of pyrrole (I-5) (2.21 g,7.12 mmol) in THF (57 mL) cooled to 0deg.C was slowly added N-bromosuccinimide (1.27 g,7.12 mmol) and the reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction was diluted with DCM and quenched by addition of 10% aqueous thiosulfate solution and the layers separated. The aqueous layer was extracted with DCM (2×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (0% -100% etoac/hexanes) to give the title compound. ES/MS:391.1 (M+H) + )。 1 H NMR (400 MHz, methanol-d) 4 )δ8.63(s，1H)，8.47(s，1H)，7.59(s，1H)，3.31-3.23(m，2H)，2.69(s，3H)，2.48(s，3H)，1.40(dd，J＝7.1，1.0Hz，6H)。
Preparation of intermediate I-7：
4- (4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester: to a mixture containing 2-bromo-4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]To a solution of pyrrole (I-6) (92.7 mg,0.24 mmol) in acetonitrile (2.0 mL) was added 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2)-methyl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.103 g,0.33 mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (o.0253 g,0.036 mmol) and 1.0M potassium acetate/1.5M sodium carbonate in water (0.60 ml,0.60mmol/0.89 mmol) and the reaction mixture was heated to 120 ℃ in a microwave oven for 30 min. The reaction mixture was dried over sodium sulfate, filtered through celite, eluted with DCM and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (0% -100% etoac/hexanes) to give the title compound. ES/MS:492.2 (M+H) + )。
4- (4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b ]Pyrrol-2-yl) piperidine-1-carboxylic acid tert-butyl ester: to 4- [ 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrol-2-yl]To a solution of tert-butyl 3, 6-dihydro-2H-pyridine-1-carboxylate (37.4 mg,0.0761 mmol) in ethanol (2 mL) and ethyl acetate (1 mL) was added acetic acid (O.1 mL). Nitrogen was bubbled through the solution for 4 minutes, then 10 wt% palladium on carbon (10.o%, 16.2mg,0.0152 mmol) was added and the reaction mixture stirred for 48 hours. The reaction mixture was degassed with argon, diluted with EtOAc, and filtered through celite, eluting with EtOAc and the filtrate concentrated under reduced pressure to give the crude product, which was used directly in the next step. ES/MS:494.2 (M+H) + )。
4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (piperidin-4-yl) -6H-thieno [2,3-b]Pyrrole hydrochloride (I-7): to 4- [ 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrol-2-yl]To a solution of tert-butyl piperidine-1-carboxylate (37.0 mg,0.0749 mmol) in DCM (2.0 mL) was added a 4.0N HCl solution in dioxane (4.O0 mol/L,0.187mL,0.749 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound as HCl salt, which was used directly in the subsequent reaction. ES/MS:394.2 (M+H) + )。
Preparation of intermediate I-8：
Di-tert-butyl 1- (5- (methoxycarbonyl) thiophen-2-yl) hydrazine-1, 2-dicarboxylate (I-8): the reaction was carried out in a similar manner to I-2, starting with methyl 5-bromothiophene-2-carboxylate to give the title compound. ES/MS:373.2 (M+H) + )。
Preparation of intermediate I-9：
4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-2-carboxylic acid methyl ester (I-9): the reaction was carried out in a similar manner to I-3, starting with I-8 to give the title compound. ES/MS:355.1 (M+H) + )
Preparation of intermediate I-10：
4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-2-carboxylic acid (I-10): to 4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]To a solution of pyrrole-2-carboxylic acid methyl ester (I-9) in acetonitrile (1.00 mL) and water (0.10 mL) was added lithium hydroxide monohydrate (0.0152 g,0.362 mmol) and the reaction mixture was stirred at 100deg.C for 16 h. The reaction mixture was concentrated in vacuo, then diluted with hydrochloric acid (1.00 mol/L,1.18ml,1.18 mmol) and water, and the precipitate was collected by filtration to give the title compound which was used directly in the next step. ES/MS:341.2 (M+H) + )。
Preparation of intermediate I-12：
4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole (I-11): to 4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]To a solution of pyrrole-2-carboxylic acid (I-10) (181 mg,0.611 mmol) in DMA (7 mL) was added DBU (0.263 mL,1.76 mmol) and the resulting reaction mixture was stirred at 150deg.C for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 mL) and extracted with brine (2×20 mL). The aqueous layers were combined and extracted with EtOAc (30 mL). The combined organic layers were taken up over Na 2 SO 4 Dried, concentrated under reduced pressure, and purified by flash column chromatography. ES/MS:297.1 (M+H) + )。
2-bromo-4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole (I-12): to an ice-cooled stirred solution of I-11 (121 mg,0.41 mmol) in acetonitrile (24 mL) and methanol (40 mL) was added drop-wise NBS (73 mg,0.41 mmol) dissolved in acetonitrile (10 mL) until LCMS showed the reaction was complete. The reaction mixture was diluted with EtOAc (50 mL) and the resulting mixture was extracted with saturated sodium thiosulfate solution (30 mL). The organic layer was then washed successively with water (2X 30 mL) and brine (30 mL), over Na 2 SO 4 Drying, filtration and evaporation under reduced pressure gave I-12.ES/MS:375.1 (M) + )
Preparation of intermediate I-13：
7, 8-dimethyl-6- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) - [1,2,4 ]]Triazolo [1,5-a ]]Pyridine (I-13): 6-bromo-7, 8-methyl- [1,2,4 ] was added to 500mL RBF]Triazolo [1,5-a ]]Pyridine (10 g,44.2 mmol), bis (pinacolato) diboron (14.6 g,57.5 mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (2.62 g,3.54 mmol) and potassium propionate (14.9 g,133 mmol). The mixture was dissolved in 1, 4-dioxane (140 mL) and nitrogen was bubbled throughInto the reaction mixture for 5 minutes. The mixture was heated at 100 ℃ under nitrogen for 1 hour. The mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: etOAc/hexane) to give product I-13.ES/MS:274.2 (M+H) + )。
Preparation of intermediate I-14：
3-methyl-1- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) butan-1-one (I-14): addition of 7, 8-dimethyl-6- (4, 5-tetramethyl-1, 3, 2-di-oxacyclopentaborane-2-yl) - [1,2,4 ] to the vial]Triazolo [1,5-a ]]Pyridine (I-13) (1 g,3.66 mmol), palladium acetate (0.043 g,0.193 mmol) and 1,1' -bis (diphenylphosphino) ferrocene (dppf) (0.142 g,0.26 mmol) were then added THF (15 mL), water (0.5 mL,27.8 mmol), sodium carbonate (0.194 g,1.83 mmol) and isovaleric anhydride (1.00 mL,5.0 mmol). Argon was bubbled through the mixture for 4 minutes and the reaction mixture was heated to 60 ℃ for 16 hours. The reaction mixture was filtered through celite, eluted with DCM, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (0% -50% etoac/hexanes) to give the title compound. ES/MS:232.3 (M+H) + )。
Preparation of intermediate I-15：
2-bromo-4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-15): to 2-bromo-4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]To a solution of pyrrole (I-6) (1.0 g,2.57 mmol) in THF (15 mL) was added N, N-dimethylpyridine-4-amine (DMAP) (0.408 g,3.34 mmol) and tert-butyl t-butoxycarbonyl carbonate (673 mg,3.08 mmol).The mixture was stirred at room temperature for 60 minutes. The mixture was concentrated under reduced pressure. The crude residue was purified by flash chromatography (eluent: etOAc/hexane) to give the product. ES/MS:489.1 (M) + )。
Preparation of intermediate I-16：
2-bromo-5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-16): prepared in a similar manner to I-25, I-6, I-5 and I-3, but with 3-methyl-1- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) butan-1-one (I-1) is replaced by 3-methyl-1- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) butan-1-one (I-14). ES/MS:503.2 (M) + )。
Preparation of intermediate I-16 ：
2-bromo-5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-16): to 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]To a solution of pyrrole-6-carboxylic acid tert-butyl ester (I-34) (10.2 g,24 mmol) in ACN (250 mL) and methanol (100) cooled to 0deg.C was added dropwise N-bromosuccinimide (4.28 g,24 mmol) dissolved in ACN (50 mL) and the reaction mixture monitored by LCMS for reaction completion (I-34 prepared as disclosed herein). The reaction mixture was concentrated under reduced pressure, then diluted with EtOAc (300 mL), and washed with 50% aqueous sodium thiosulfate (100 mL), water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (0% -100% etoac/hexanes) to give the title compound I-16.ES/MS:503.2 (M) + )。 1 H NMR (400 MHz, chloroform-d) δ8.37 (s, 1H), 8.34 (s, 1H), 2.89 (hept, j=7.1 hz, 1H), 2.67 (s, 3H), 2.48 (s, 3H), 2.15 (s, 3H), 1.33 (s, 9H), 1.24 (d, j=7.2 hz, 3H), 1.18 (d, j=7.1 hz, 3H).
Preparation of intermediate I-17 ：
Di-tert-butyl 1- (4- (difluoromethyl) thiophen-2-yl) hydrazine-1, 2-dicarboxylate (I-17): prepared in a similar manner to I-2, but replacing 5-bromo-3-methyl-thiophene-2-carboxylic acid methyl ester with 2-bromo-4- (difluoromethyl) thiophene. ES/MS:387.1 (M+23)
Preparation of intermediate I-18：
2-bromo-3- (difluoromethyl) -4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole (I-18): prepared in a similar manner to I-6, I-5 and I-3, but substituting di-tert-butyl 1- (5- (methoxycarbonyl) -4-methylthiophene-2-yl) hydrazine-1, 2-dicarboxylate (I-2) with di-tert-butyl 1- (4- (difluoromethyl) thiophen-2-yl) hydrazine-1, 2-dicarboxylate (I-17). ES/MS:425.1 (M) + )。
Preparation of intermediate I-19：
2-bromo-3- (difluoromethyl) -4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-19): prepared in a similar manner to I-15, but with 2-bromo-4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole (I-6) is replaced by 2-bromo-3- (difluoromethyl) -4-isopropyl-5- (8-methyl- [1,2, 4)]Triazole compoundsAnd [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b ]Pyrrole (I-18). ES/MS:525.1 (M) + )。
Preparation of intermediate I-20：
6-iodo-2-azaspiro [3.3 ]]Heptane-2-carboxylic acid tert-butyl ester (I-20): to 6-hydroxy-2-azaspiro [3.3 ]]To a solution of tert-butyl heptane-2-carboxylate (1.5 g,7.03 mmol) in toluene (50 mL) was added triphenylphosphine (2.61 g,10.5 mmol), molecular iodine (1.79 g,7.03 mmol) and imidazole (958 mg,14.1 mmol). The mixture was stirred at reflux for 2 to 16 hours. The mixture was concentrated under reduced pressure. The crude residue was purified by flash chromatography (eluent: etOAc/hexane) to give the product. ES/MS:268.0 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-21：
Exo-3-iodo-8-azabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (I-20): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3 ]]Substitution of heptane-2-carboxylic acid tert-butyl ester with internal-3-hydroxy-8-azabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester. ES/MS:282.0 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-22：
Internal-8-iodo-3-azabicyclo [3.2.1]Octane-3-carboxylic acid tert-butyl ester (I-22): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3 ]]Substitution of heptane-2-carboxylic acid tert-butyl ester with exo-8-hydroxy-3-azabicyclo [3.2.1 ]Octane-3-carboxylic acid tert-butyl ester. ES/MS:282.1 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-23：
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6-iodo-3-azabicyclo [3.1.1]Heptane-3-carboxylic acid tert-butyl ester (I-23): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3]]Substitution of heptane-2-carboxylic acid tert-butyl ester with 6-hydroxy-3-azabicyclo [3.1.1]Heptane-3-carboxylic acid tert-butyl ester. ES/MS:268.0 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-24：
(1S, 4S, 5S) -5-iodo-2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (I-24): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3]]Substitution of heptane-2-carboxylic acid tert-butyl ester with (1S, 4S, 5R) -5-hydroxy-2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester. ES/MS:268.0 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-25：
(3 aR,6 aS) -5-iodohexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (I-25): prepared in a similar manner to I-20, but replacing tert-butyl 6-hydroxy-2-azaspiro [3.3] heptane-2-carboxylate with tert-butyl (3 ar,6 as) -5-hydroxycyclopenta [ c ] pyrrole-2 (1H) -carboxylate.
Preparation of intermediate I-26：
7-iodo-3-oxa-9-azabicyclo [3.3.1]Nonane-9-carboxylic acid tert-butyl esterButyl ester (I-26): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3] ]Substitution of heptane-2-carboxylic acid tert-butyl ester with 7-hydroxy-3-oxa-9-azabicyclo [3.3.1]Nonane-9-carboxylic acid tert-butyl ester. ES/MS:353.6 (M+H) + )。
Preparation of intermediate I-27：
(1R, 4R) -5-iodo-2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (I-27): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3 ]]Substitution of heptane-2-carboxylic acid tert-butyl ester with (1R, 4R) -5-hydroxy-2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester. ES/MS:268.0 (M+H) + ) (mass minus t-butyl)
Preparation of intermediate I-28：
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2-iodo-6-azaspiro [3.4 ]]Octane-6-carboxylic acid tert-butyl ester (I-28): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3 ]]Substitution of heptane-2-carboxylic acid tert-butyl ester with 2-hydroxy-6-azaspiro [3.4 ]]Octane-6-carboxylic acid tert-butyl ester. ES/MS:282.1 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-29：
(1S, 4S, 5R) -5-iodo-2-azabicyclo [2.2.2]Octane-2-carboxylic acid tert-butyl ester (I-29): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3 ]]Substitution of heptane-2-carboxylic acid tert-butyl ester with (1S, 4S, 5S) -5-hydroxy-2-azabicyclo [2.2.2]Octane-2-carboxylic acid tert-butyl ester. ES/MS:282.0 (M+H) + ) (mass minus t-butyl)
Preparation of intermediate I-30 ：
2-iodo-5-oxa-8-azaspiro [3.5] nonane-8-carboxylic acid tert-butyl ester (I-30): prepared in a similar manner to I-20, but replacing the 6-hydroxy-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester with 2-hydroxy-5-oxa-8-azaspiro [3.5] nonane-8-carboxylic acid tert-butyl ester. ES/MS:298.0 (M+H+) (mass minus t-butyl).
Preparation of intermediate I-31：
(1S, 4S, 5R) -5-iodo-2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (I-31): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3]]Substitution of heptane-2-carboxylic acid tert-butyl ester with (1S, 4S, 5S) -5-hydroxy-2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester. ES/MS:268.0 (M+H+) (mass minus t-butyl). 1 H NMR (400 MHz, chloroform-d) δ4.20 (s, 1H), 4.08 (ddd, 1H), 3.29 (dd, 1H), 3.06 (d, 1H), 2.90-2.84 (m, 1H), 2.59-2.47 (m, 1H), 2.26 (dt, 1H), 2.10 (d, 1H), 1.78 (dd, 1H), 1.46 (d, 9H).
Preparation of intermediates I-31 and I-24：
(1S, 4S) -5-hydroxy-2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester: (1S, 4S) -5-oxo-2-azabicyclo [2.2.1]A solution of tert-butyl heptane-2-carboxylate (10 g,47.3 mmol) in methanol (100 mL) was cooled to 0deg.C. Sodium borohydride (1.8 g,47.3 mmol) was slowly added to the reaction, which was then stirred for 30 minutes and checked for completion. The reaction was quenched with saturated ammonium chloride and further diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium chloride, Drying over magnesium sulfate, filtration and concentration gave the product as a mixture of diastereomers, which was used in the next step without further purification. ES/MS:213.8 (M+H) + )。
(1S, 4S, 5R) -5-iodo-2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (I-31) and (1S, 4S, 5S) -5-iodo-2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (I-24): to a solution of tert-butyl (1S, 4S) -5-hydroxy-2-azabicyclo [2.2.1] heptane-2-carboxylate (mixture of diastereomers) (10 g,46.9mmol, mixture of isomers) in toluene (250 mL) was added triphenylphosphine (14 g,56.3 mmol), molecular iodine (14 g,56.3 mmol) and imidazole (6.4 g,93.8 mmol). The mixture was concentrated under reduced pressure and the crude residue was purified by flash chromatography on silica gel (eluent: etOAc/hexane) to give two products, I-31 (major product) eluting first and I-24 (minor product) eluting second.
(1S, 4S, 5R) -5-iodo-2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (I-31): ES/MS:268.0 (M+H+) (mass minus t-butyl). 1 H NMR (400 MHz, chloroform-d) δ4.20 (s, 1H), 4.08 (ddd, 1H), 3.29 (dd, 1H), 3.06 (d, 1H), 2.90-2.84 (m, 1H), 2.59-2.47 (m, 1H), 2.26 (dt, 1H), 2.10 (d, 1H), 1.78 (dd, 1H), 1.46 (d, 9H).
(1S, 4S, 5S) -5-iodo-2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (I-21): ES/MS:268.0 (M+H+) (mass minus t-butyl). 1 H NMR (400 MHz, chloroform-d) delta 4.32 (dd, 1H), 4.04 (s, 1H), 3.66 (d, 1H), 3.41 (d, 1H), 2.71 (s, 1H), 2.45 (ddd, 1H), 2.07 (s, 1H), 1.74 (d, 1H), 1.57 (d, 1H), 1.49 (s, 9H).
Preparation of intermediate I-32：
5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole-2-carboxylic acid methyl ester (I-32): to 1- (5- (methoxycarbonyl) -4-methylthiophene-2-yl) hydrazine-1, 2-dicarboxylic acid di-tert-butyl ester (I-2) (5.69g,14.7 mmol) and p-toluenesulfonic acid monohydrate (20.1 g,51.9 mmol) in a 500mL round bottom flask was added 1- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) 3-methylbutan-1-one (I-14) (10 g,43.2 mmol) and 2-butanol (220 mL). The reaction mixture was heated to 100 ℃ and stirred with a reflux condenser for 24 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and water (200 mL) was added. The mixture was left to stand at 0 ℃ for 30 min and filtered, then the filter cake was washed with water (4×25 mL) and further dried overnight in a lyophilizer to give product I-32 as PTSA salt. ES/MS:383.1 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) δ9.16 (s, 1H), 9.01 (s, 1H), 7.77-7.69 (m, 2H), 7.24 (d, j=7.9 hz, 2H), 3.86 (s, 3H), 3.12 (dt, j=14.2, 7.0hz, 1H), 2.88 (s, 3H), 2.70 (s, 3H), 2.41 (s, 3H), 2.39 (s, 3H), 1.32 (d, j=7.1 hz, 3H), 1.26 (d, j=7.1 hz, 3H).
Preparation of intermediate I-33：
5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole (I-33): to 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]To a solution of pyrrole-2-carboxylic acid methyl ester (PTSA salt) (I-32) (10.7 g,19.3 mmol) in ethanol (200 mL) and water (50 mL) was added potassium hydroxide (6.5 g,116 mmol) and the reaction mixture was heated to 90 ℃ for 24 hours. The reaction mixture was concentrated under reduced pressure, diluted with hydrochloric acid (1.00 mol/L,154mL,154 mmol), and then cooled to 0deg.C for 30 min. The reaction mixture was then filtered and the filter cake was collected by filtration, washed with water (2×40 mL) and air dried for 1 hour to give the title product. The material was further dried overnight in a lyophilizer to complete the drying process. ES/MS:325.2 (M+H+). 1 H NMR (400 MHz, chloroform-d) delta 8.43-8.39 (m, 1H), 8.36 (s, 1H), 6.50 (d, J=1.5 Hz, 1H), 3.03-2.91 (m, 1H), 2.64 (s, 3H), 2.54 (s, 3H),2.22(s，3H)，1.27(d，J＝7.5Hz，6H)。
preparation of intermediate I-34：
5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-34): to 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]To a solution of pyrrole (I-33) (11.8 g,36.5 mmol) in THF (180 mL) was added N, N-dimethylpyridine-4-amine (DMAP) (6.24 g,51.1 mmol) and di-tert-butyl dicarbonate (Boc anhydride) (10.4 g,47.4 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The crude residue was purified by flash chromatography (eluent: etOAc/hexane) to give the product. ES/MS:425.2 (M+H) + )。 1 H NMR (400 MHz, chloroform-d) δ8.37 (s, 1H), 8.33 (s, 1H), 6.69 (d, j=1.2 hz, 1H), 2.86 (hept, j=7.1 hz, 1H), 2.67 (s, 3H), 2.53 (s, 3H), 2.17 (s, 3H), 1.31 (s, 9H), 1.25 (d, j=7.1 hz, 3H), 1.21 (d, j=7.1 hz, 3H).
Preparation of intermediate I-35：
5- (7, 8-dimethyl- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-6H-thieno [2,3-b]Pyrrole-2-carboxylic acid methyl ester (I-35): prepared in a similar manner to I-3, but substituting di-tert-butyl 1- (5- (methoxycarbonyl) -4-methylthiophene-2-yl) hydrazine-1, 2-dicarboxylate (I-2) with di-tert-butyl 1- (5- (methoxycarbonyl) thiophen-2-yl) hydrazine-1, 2-dicarboxylate (I-8) and substituting 3-methyl-1- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) butan-1-one (I-1) is replaced by 3-methyl-1- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) butan-1-one (I-14). ES/MS:369.2 (M+H) + )。
Preparation of intermediate I-36：
5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-6H-thieno [2,3-b]Pyrrole-2-carboxylic acid (I-36): to 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-6H-thieno [2,3-b]To a solution of pyrrole-2-carboxylic acid methyl ester (5 g,13.6 mmol) (I-35) in ethanol (80 mL) was added potassium hydroxide (1M aqueous solution, 67.9mL,67.9 mmol) and the reaction mixture was stirred at 60℃for 16 h. The reaction mixture was concentrated in vacuo, then diluted with hydrochloric acid (1.00 mol/L,82mL,82 mmol) and cooled to 0deg.C. The reaction mixture was then filtered and the filter cake provided the title compound which was used directly in the next step. ES/MS:355.1 (M+H) + )。
Preparation of intermediate I-37：
5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-6H-thieno [2,3-b]Pyrrole (I-37): prepared in a similar manner to I-11, but with 4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-2-carboxylic acid (I-10) is replaced by 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-6H-thieno [2,3-b]Pyrrole-2-carboxylic acid (I-36). ES/MS:311.1 (M+H) + )。
Preparation of intermediate I-38：
5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-3)8): prepared in a similar manner to I-34, but with 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole (I-33) is replaced by 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-6H-thieno [2,3-b]Pyrrole (I-37). ES/MS:411.2 (M+H) + )。
Preparation of intermediate I-39：
2-bromo-5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-39): prepared in a similar manner to I-16, but with 5- (7, 8-dimethyl- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Substitution of solution of tert-butyl pyrrole-6-carboxylate (I-34) with 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-38). ES/MS:489.1 (M) + )。
Preparation of intermediate I-40：
5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-2- (3- (methoxycarbonyl) cyclobutyl) -3-methyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester: 2-bromo-5- (7, 8-dimethyl- [1,2, 4) was added to the dried vial]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-16) (120 mg,0.238 mmol), 3-iodocyclobutane-1-carboxylic acid methyl ester (143 mg,0.596 mmol), tetrabutylammonium iodide (TBAI) (105 mg,1.43 mmol), ni (dtbbpy) (H 2 O) 4 Cl 2 (11.2 mg,0.024 mmol) and zinc powder (93 mg,1.43 mmol). Anhydrous DMA (1 mL) was added and the mixture was degassed with argon for 1 minute. The vial was sealed and the reaction was allowed to proceedThe mixture was stirred at 70℃for 16 hours. The reaction was then cooled and the crude mixture was purified directly by silica gel chromatography (eluent: etOAc/hexane) to give the product. ES/MS:537.2 (M+H) + )。
3- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) cyclobutane-1-carboxylic acid (I-40): addition of 5- (7, 8-dimethyl- [1,2, 4) to the vial]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-2- (3- (methoxycarbonyl) cyclobutyl) -3-methyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (128 mg,0.23 mmol) and this material was dissolved in MeOH (1 mL) and potassium carbonate (saturated aqueous solution, 0.25 mL) was added. The mixture was stirred at 50 ℃ overnight. The mixture was concentrated under reduced pressure, and the mixture was acidified with 2N HCl. The mixture was filtered and the precipitate was washed with water and dried in a lyophilizer to give the product as a mixture of cis/trans isomers. ES/MS:423.2 (M+H) + )。
Preparation of intermediate I-41：
(R) -morpholine-3, 4-dicarboxylic acid 4- (tert-butyl) 3-methyl ester: to 50mL of RBF were added (3R) -4-tert-butoxycarbonylmorpholine-3-carboxylic acid (250 mg,1.08 mmol), potassium carbonate (447 mg,3.24 mmol) and DMF (10 mL). Methyl iodide (0.68 ml,2.7 mmol) was added and the reaction stirred at room temperature overnight. The mixture was diluted with water (20 mL) and EtOAc (100 mL), and the layers were separated. The organic layer was washed once with water (20 mL) and the organic layer was dried over MgSO 4 Dried, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: etOAc/hexane) to give the product. ES/MS:268.2 (M+23).
(R) -3- (hydrazinocarbonyl) morpholine-4-carboxylic acid tert-butyl ester (I-41): to a 10mL vial was added 4- (tert-butyl) 3-methyl (R) -morpholine-3, 4-dicarboxylic acid (260 mg,1.08 mmol) and isopropanol (2 mL). Hydrazine hydrate (0.16 ml,3.18 mmol) was added and the reaction stirred at 50 ℃ for 16 hours. The mixture is mixedDilute with EtOAc (50 mL) and wash the organic layer with water (2×15 mL). The organic layer was dried over MgSO 4 Drying, filtering and concentrating under reduced pressure to obtain the product. ES/MS:268.1 (M+23).
Preparation of intermediate I-42：
(S) -3- (hydrazinocarbonyl) morpholine-4-carboxylic acid tert-butyl ester (I-42): prepared in a similar manner to I-41, but replacing (3R) -4-tert-butoxycarbonylmorpholine-3-carboxylic acid with (3S) -4-tert-butoxycarbonylmorpholine-3-carboxylic acid.
Preparation of intermediate I-43：
3-ethynyl morpholine-4-carboxylic acid tert-butyl ester (I-43): to 50mL of RBF were added 3-formylmorpholine-4-carboxylic acid tert-butyl ester (400 mg,1.86 mmol), potassium carbonate (1.03 mg,7.43 mmol), dimethyl (1-diazo-2-oxopropyl) phosphonate (500 mg,2.6 mmol) and MeOH (15 mL). The reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, the crude residue was diluted with EtOAc (50 mL) and water (10 mL), and the layers were separated. The organic layer was washed once with water (10 mL) and the organic layer was dried over MgSO 4 Dried, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: etOAc/hexane) to give the product. ES/MS:156.1 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-44：
2- (3-iodocyclobutyl) isoindoline-1, 3-dione (I-44): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3 ]]Substitution of tert-butyl heptane-2-carboxylate with 2- (3-hydroxycyclobutyl) isoindoline-1, 3-di-Ketones. ES/MS:327.98 (M+H) + )。
Preparation of intermediate I-45：
5- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) quinoline-8-carbonitrile (I-45): prepared in a similar manner to I-13, but with 6-bromo-7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridine is replaced by 5-bromoquinoline-8-carbonitrile. ES/MS:281.2 (M+H) + )。
Preparation of intermediate I-46：
8- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) quinoxaline-5-carbonitrile (I-46): prepared in a similar manner to I-13, but with 6-bromo-7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridine is replaced by 8-bromoquinoxaline-5-carbonitrile. ES/MS:200.1 (M+H) + ) (mass of borate).
Preparation of intermediate I-47：
8-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazo [1,2-a ]Pyridine (I-47): prepared in a similar manner to I-13, but with 6-bromo-7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Substitution of pyridine for 6-bromo-8-methylimidazo [1,2-a ]]Pyridine. ES/MS:259.2 (M+H) + )。
Preparation of intermediate I-48：
7-methyl-6- (4, 5-tetramethyl-1, 3-dioxolan-2-yl) - [1,2,4 ]]Triazolo [1,5-a ]]Pyridine (I-48): prepared in a similar manner to I-13, but with 6-bromo-7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Substitution of pyridine with 6-bromo-7-methyl- [1,2,4]Triazolo [1,5-a ]]Pyridine. ES/MS:260.2 (M+H) + )。
Preparation of intermediate I-49：
5-bromo-2-hydrazino-3-methyl-1, 2-dihydropyridine: to a stirred solution of 2, 5-dibromo-3-methylpyridine (10 g,40 mmol) in ethanol (100 mL) was added hydrazine hydrate (20 mL,400 mmol) at room temperature. After the addition was complete, the reaction mixture was heated to 110 ℃ and stirred for 48 hours. After 48 hours, the reaction mixture was cooled to room temperature and the suspension was filtered. The precipitate was washed with ethanol (20 mL) and dried under reduced pressure to give the product.
6-bromo-8-methyltetrazolo [1,5-a ]]Pyridine (I-49): to 5-bromo-2-hydrazino-3-methyl-1, 2-dihydropyridine (4 g,19.8 mmol) in AcOH: H at 0deg.C over a period of 30 minutes 2 NaNO was added dropwise to a stirred solution of O (3:1) (100 mL) 2 Aqueous solution (4.0 g in 10mL water). The reaction mixture was stirred at 0 ℃ for 2 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, etOAc and water were added to the reaction mixture and stirred for an additional 20 minutes. The layers were separated and the aqueous layer was extracted with EtOAc (3X 100 mL). The combined organic layers were first treated with saturated Na 2 CO 3 Aqueous (500 mL) and brine (300 mL). The organic layer was treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The crude residue obtained was triturated with diethyl ether followed by n-pentane to give the product. ES/MS:213.1 (M) + )。
Preparation of intermediates 1-50：
8-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) tetrazolo [1,5-a ]]Pyridine (I-50): prepared in a similar manner to I-13, but with 6-bromo-7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Substitution of pyridine for 6-bromo-8-methyltetrazolo [1,5-a ]]Pyridine (I-49). ES/MS:276.2 (M+H) + )。
Preparation of intermediate I-51：
8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) - [1,2,4 ]]Triazolo [1,5-a ]]Pyridine (I-51): prepared in a similar manner to I-13, but with 6-bromo-7, 8-dimethyl- [1,2,4 ]Triazolo [1,5-a ]]Substitution of pyridine with 6-bromo-8-methoxy- [1,2,4]Triazolo [1,5-a ]]Pyridine. ES/MS:276.2 (M+H) + )。
Preparation of intermediate I-52：
5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (3- (1, 3-dioxoisoindolin-2-yl) cyclobutyl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ]]Pyrrole-6-carboxylic acid tert-butyl ester: 2-bromo-5- (7, 8-dimethyl- [1,2, 4) was added to the dried vial]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-16) (300 mg,0.596 mmol), 2- (3-iodocyclobutyl) isoindoline-1, 3-dione (I-44) (390 mg,1.19 mmol), tetrabutylammonium iodide (TBAI) (264 mg,3.58 mmol), ni (dtbbpy) (H) 2 O) 4 Cl 2 (28 mg,0.06 mmol) and zinc dust (232 mg,3.58 mmol). Anhydrous DMA (3 mL) was added and the mixture was degassed with argon for 1 minute. The vial was sealed and the reaction was stirred at 70 ℃ for 16 hours. The reaction was then cooled and straightenedThe crude mixture was then purified by silica gel chromatography (eluent: etOAc/hexane) to give the product.
2- ((3- (5- (7, 8-dimethyl- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ]Pyrrol-2-yl) cyclobutyl) carbamoyl) benzoic acid: addition of 5- (7, 8-dimethyl- [1,2, 4) to the vial]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (3- (1, 3-dioxoisoindolin-2-yl) cyclobutyl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ]]Pyrrole-6-carboxylic acid tert-butyl ester (300 mg,0.48 mmol) and this material was dissolved in MeOH (2 mL) and potassium carbonate (saturated aqueous solution, 1 mL) was added. The mixture was stirred at 55 ℃ overnight. Solid LiOH (100 mg) was added and the mixture was stirred at 70 ℃ for 24 hours. The mixture was carefully acidified with concentrated HCl and the mixture was diluted with EtOAc (100 mL) and water (15 mL). The layers were separated and the organic layer was washed with brine (5 mL). The organic layer was dried over MgSO 4 Drying, filtering and concentrating under reduced pressure to obtain the product. ES/MS:542.2 (M+H) + )。
3- (5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl) cyclobut-1-amine (I-52): to a 10mL vial was added 2- ((3- (5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl) cyclobutyl) carbamoyl) benzoic acid (200 mg,0.369 mmol) and ethanol (3 mL). Hydrazine hydrate (0.22 ml,4.43 mmol) was added and the reaction stirred at 80 ℃ for 36 hours. TFA (1 mL) was slowly added and the crude mixture was concentrated under reduced pressure. The crude residue was dissolved in acetonitrile and water and filtered through acrodisc and purified directly by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18 angstrom, 250X 21.2 mm) to give the product as a mixture of cis/trans isomers. ES/MS:394.2 (M+23).
Preparation of intermediate I-53：
4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole-2, 5-dicarboxylic acid 5-ethyl ester 2-methyl ester: to a solution of di-tert-butyl 1- (5- (methoxycarbonyl) -4-methylthiophene-2-yl) hydrazine-1, 2-dicarboxylate (I-2) (32.2 g,83 mmol) and p-toluenesulfonic acid monohydrate (66.1 g,348 mmol) in 2-butanol (140 mL) in a 500mL round bottom flask was added ethyl 4-methyl-2-oxo-pentanoate (prepared as described in org. Preparations and Procedures International, volume 21, 4, page 501, 1989) (11 g,69.5 mmol) and the reaction mixture was heated to 90℃with a reflux condenser for 16 hours. The reaction mixture was concentrated under reduced pressure, then dissolved in EtOAc and water. The layers were separated, the aqueous layer was extracted with EtOAc (2×), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude oil was used in the next step without further purification. ES/MS:310.0 (M+H) + )。
4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrole-2, 5-dicarboxylic acid: to a solution of 5-ethyl-2-methyl-4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrole-2, 5-dicarboxylic acid (21 g,67.9 mmol) in ethanol (150 mL) was added potassium hydroxide (339 mL,1m aqueous solution), and the reaction mixture was heated to 100 ℃ for 24 hours. The reaction mixture was concentrated under reduced pressure, then diluted with hydrochloric acid (399 ml,1m aqueous solution), and poured into brine solution. The product was extracted with EtOAc (2×) from the aqueous phase and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude oil was used in the next step without further purification. ES/MS:268.0 (M+H+).
4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole: to 4-isopropyl-3-methyl-6H-thieno [2,3-b]To a solution of pyrrole-2, 5-dicarboxylic acid (18.1 g,67.7 mmol) in DMA (120 mL) was added DBU (30.3 mL,203 mmol) and the resulting reaction mixture was stirred at 150℃for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 mL) and extracted with brine (2×20 mL). The aqueous layers were combined and extracted with EtOAc (30 mL). The combined organic layers were taken up over Na 2 SO 4 Dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography (eluent: etOAc/hexane) to giveThe product is obtained. ES/MS:180.1 (M+H) + )。
4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester: to 4-isopropyl-3-methyl-6H-thieno [2,3-b]To a solution of pyrrole (12.1 g,67.5 mmol) in THF (150 mL) was added N, N-dimethylpyridin-4-amine (DMAP) (2.0 g,16.9 mmol), triethylamine (9.41 mL,67.5 mmol) and tert-butyl t-butoxycarbonyl carbonate (15.5 g,70.9 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. The crude residue was purified by flash chromatography (eluent: etOAc/hexane) to give the product. 1 H NMR (400 MHz, chloroform-d) delta 7.00 (s, 1H), 6.57 (s, 1H), 3.14 (pd, j=6.8, 1.0hz, 1H), 2.43 (s, 3H), 1.67 (s, 9H), 1.32 (d, j=6.8 hz, 6H).
2-bromo-4-isopropyl-3-methyl-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-53): at 0 ℃, 4-isopropyl-3-methyl-6H-thieno [2,3-b ]]To a solution of tert-butyl pyrrole-6-carboxylate (7.02 g,25.1 mmol) in acetonitrile (70.1 mL) was added NBS (4.47 g,25.1 mmol) dissolved in acetonitrile (10 mL) dropwise until LCMS showed completion of the reaction. The reaction mixture was diluted with EtOAc (150 mL) and the resulting mixture was extracted with saturated sodium thiosulfate solution (30 mL). The organic layer was then washed with water (2X 30 mL) followed by brine (30 mL) over Na 2 SO 4 Dried, filtered and evaporated under reduced pressure, and the crude residue was purified by column chromatography (eluent: etOAc/hexanes) to give the product. ES/MS:302.0 (M) + ) (mass minus t-butyl).
1 H NMR(400MHz，DMSO-d 6 )δ7.18(s，1H)，3.21-2.97(m，1H)，2.32(s，3H)，1.59(s，9H)，1.24(d，J＝6.8Hz，6H)。
Preparation of intermediate I-54：
2- (1-tert-Butoxycarbonyl-3, 6-dihydro-2H-pyridin-4-yl) -4-isopropyl-3-methyl-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester: to 2-bromo-4-isopropyl-3-methyl-thieno [2,3-b ]]To a solution of tert-butyl pyrrole-6-carboxylate (I-53) (4.1G, 11.4 mmol) in 10:1 dioxane (100 mL) and water (10 mL) was added tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylate (4.6G, 14.8 mmol), XPhos Pd G3 (859 mg,1.1 mmol) and cesium carbonate (11.1G, 34.2 mmol). The reaction mixture was degassed with argon and heated to 110 ℃ for 2 hours. The reaction mixture was diluted with EtOAc (150 mL) and the resulting mixture was extracted with saturated sodium thiosulfate solution (30 mL). The organic layer was then washed with water (2X 30 mL) and brine (30 mL), and dried over Na 2 SO 4 Dried, filtered and evaporated under reduced pressure. The crude residue was purified by column chromatography (eluent: etOAc/hexane) to give the product. ES/MS:461.2 (M+H) + )。
2- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester: to 2- (1-tert-butoxycarbonyl-3, 6-dihydro-2H-pyridin-4-yl) -4-isopropyl-3-methyl-thieno [2,3-b]To a solution of tert-butyl pyrrole-6-carboxylate (4.2 g,9.12 mmol) in ethyl acetate (25 mL) was added 10 wt% palladium on carbon (10.o%, 970mg,9.12 mmol) and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 24 hours. The reaction mixture was then degassed with argon, diluted with EtOAc, and filtered through celite, and rinsed with EtOAc. The filtrate was concentrated under reduced pressure to give the product, which was used in the next step without further purification. ES/MS:463.3 (M+H) + )。
4- (4-isopropyl-3-methyl-6H-thieno [2, 3-b)]Pyrrole-2-yl) piperidine-1-carboxylic acid tert-butyl ester (I-54): to 2- (1-tert-butoxycarbonyl-4-piperidinyl) -4-isopropyl-3-methyl-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (4.2 g,9.1 mmol) to a 1:1:1 mixture of EtOH/THF/water (50 mL) was added LiOH (1.4 g,54.7 mmol) and the reaction mixture was stirred at 80℃for 16 h. The reaction mixture was diluted with EtOAc (150 mL), and then the organic layer was washed with water (2×50 mL) and brine (50 mL) in this order, over Na 2 SO 4 Drying, filtration and evaporation under reduced pressure gave the product. ES/MS:363.3 (M+H) + )。
Preparation of intermediate I-55：
2- ((1S, 4R, 5R) -2- (tert-Butoxycarbonyl) -2-azabicyclo [ 2.2.1)]Hept-5-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester: addition of 4- (4-isopropyl-3-methyl-6H-thieno [2, 3-b) to a dry vial]Pyrrole-2-yl) piperidine-1-carboxylic acid tert-butyl ester (I-53) (250 mg,0.7 mmol), (1S, 4S, 5R) -5-iodo-2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (I-31) (457mg, 1.4 mmol), tetrabutylammonium iodide (TBAI) (309 mg,0.837 mmol), ni (dtbbpy) (H 2 O) 4 Cl 2 (32.8 mg,0.07 mmol) and zinc powder (272 mg,4.19 mmol). Anhydrous DMA (2.5 mL) was added and the mixture was degassed with argon for 1 minute. The vial was sealed and the reaction was stirred at 70 ℃ for 16 hours. The reaction was then cooled and the crude mixture was purified directly by silica gel chromatography (eluent: etOAc/hexane) to give the product.
(1S, 4R, 5R) -5- (4-isopropyl-3-methyl-6H-thieno [2, 3-b)]Pyrrol-2-yl) -2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (I-55): to 2- ((1S, 4R, 5R) -2- (tert-butoxycarbonyl) -2-azabicyclo [ 2.2.1)]Hept-5-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ]To a solution of tert-butyl pyrrole-6-carboxylate (320 mg,0.67 mmol) in THF (1 mL) and MeOH (2 mL) was added LiOH monohydrate (100 mg,2.38 mmol) (dissolved in 1mL water) and the reaction mixture was stirred at 90 ℃ for 6 hours. The reaction mixture was diluted with EtOAc (50 mL), and then the organic layer was washed with water (15 mL) followed by brine (5 mL) over MgSO 4 Drying, filtration and evaporation under reduced pressure gave the product. ES/MS:375.2 (M+H) + )。
Preparation of intermediate I-56：
(1S, 4S) -spiro [ bicyclo [2.2.1]]Heptane-2, 2′-[1，3]Dioxolane]-5-alcohol: to (1S, 4S) -spiro [ bicyclo [2.2.1]]Heptane-2, 2' - [1,3]]Dioxolane]To a solution of 5-ketone (1.0 g,5.95 mmol) in methanol (20 mL) cooled to 0deg.C was added sodium borohydride (0.22 g,5.95 mmol). The mixture was warmed slowly to room temperature over 2 hours. The mixture was quenched with saturated ammonium chloride and the reaction was diluted in ethyl acetate. The layers were separated and the organic phase was washed with water over MgSO 4 Dried, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography (eluent: etOAc/hexane) to give the product.
(1S, 4S) -5-iodospiro [ bicyclo [2.2.1] heptane-2, 2' - [1,3] dioxolane ] (I-56): to a solution of (1S, 4S) -spiro [ bicyclo [2.2.1] heptane-2, 2' - [1,3] dioxolan ] -5-ol (0.9 g,5.3 mmol) in toluene (50 mL) was added triphenylphosphine (1.57 g,6.35 mmol), molecular iodine (1.61 g,6.35 mmol) and imidazole (720 mg,10.6 mmol). The mixture was stirred at reflux for 16 hours. The mixture was concentrated under reduced pressure. The crude residue was purified by flash chromatography (eluent: etOAc/hexane) to give the product.
Preparation of intermediate I-57：
5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-2- ((1S, 4S) -5-oxobicyclo [2.2.1]Hept-2-yl) -6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-57): 2-bromo-5- (7, 8-methyl- [1,2, 4) was added to the dried vial]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-16) (700 mg,1.39 mmol), (1S, 4S) -5-iodospiro [ bicyclo [2.2.1 ]]Heptane-2, 2' - [1,3 ]]Dioxolane](I-56) (545 mg,1.95 mmol), tetrabutylammonium iodide (TBAI) (514 mg,1.39 mmol), ni (dtbbpy) (H) 2 O) 4 Cl 2 (53.6 mg,0.114 mmol) and zinc powder (452 mg,6.95 mmol). Anhydrous DMA (6 mL) was added and the mixture was degassed with argon for 1 minute. The vial was sealed and the reaction was stirred at 70 ℃ for 16 hours. ThenThe reaction was cooled and the crude mixture was purified directly by silica gel chromatography (eluent: etOAc/hexane). The purified material was dissolved in DCM (5 mL), cooled to 0 ℃, and TFA (1.0 mL) was then added dropwise. The mixture was stirred at 0 ℃ for 3 hours. LCMS showed removal of intermediate I-56 and dilution of the mixture with EtOAc (60 mL) and saturated sodium bicarbonate (6 mL). The layers were separated and the organic layer was washed with brine (5 mL). The organic layer was dried over MgSO 4 Drying, filtering and concentrating under reduced pressure to obtain the product. ES/MS:533.3 (M+H) + )。
Preparation of intermediate I-58：
5- [ tert-Butoxycarbonyl- (tert-Butoxycarbonylamino) amino group]Thiophene-3-carboxylic acid methyl ester (I-58): prepared in a similar manner to I-2, but replacing 5-bromo-3-methyl-thiophene-2-carboxylic acid methyl ester with 5-bromothiophene-3-carboxylic acid methyl ester. ES/MS:373.1 (M) + H + )。
Preparation of intermediate I-59：
4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-3-carboxylic acid methyl ester (I-59): prepared in a similar manner to I-3, but substituting di-tert-butyl 1- (5- (methoxycarbonyl) -4-methylthiophene-2-yl) hydrazine-1, 2-dicarboxylate (I-2) with 5- [ tert-butoxycarbonyl- (tert-butoxycarbonylamino) amino group]Thiophene-3-carboxylic acid methyl ester (I-58). ES/MS:355.2 (M+H) + )。
Preparation of intermediate I-60：
4-isopropyl-5- (8-methyl- [1,2, 4)]Triazole compoundsAnd [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-3, 6-dicarboxylic acid 6- (tert-butyl) 3-methyl ester (I-60): prepared in a similar manner to I-15, but with 2-bromo-4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole (I-6) is replaced by 4-isopropyl-5- (8-methyl- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-3-carboxylic acid methyl ester (I-59). ES/MS:455.3 (M+H) + )。
Preparation of intermediate I-61：
3- (hydroxymethyl) -4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-61): to 4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]To a solution of pyrrole-3, 6-dicarboxylic acid 6- (tert-butyl) 3-methyl ester (I-60) (5.3 g,11.7 mmol) in THF (50 mL) cooled to 0deg.C was added lithium aluminum hydride (1M in THF) (11.7 mL,11.7 mmol) and the reaction mixture was stirred. Then 3ml LiAlH was added 4 Three times. The reaction mixture was treated with saturated NH 4 Quench Cl and dilute with EtOAc. The layers were separated, the aqueous layer was extracted with EtOAc (2×), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The material was carried forward without further purification. ES/MS:427.4 (M+H) + )。
Preparation of intermediate I-62：
4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -3- (((triisopropylsilyl) oxy) methyl) -6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-62): to 3- (hydroxymethyl) -4-isopropyl-5- (8-methyl- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thiophenesAnd [2,3-b ]]To a solution of tert-butyl pyrrole-6-carboxylate (I-61) (5.0 g,11.7 mmol) in DMF (40 mL) was added imidazole (1.6 g,23.3 mmol), DMAP (1.4 g,11.7 mmol) and triisopropylchlorosilane (3.7 mL,17.5 mmol). The reaction mixture was stirred overnight. The reaction mixture was quenched with water and diluted with EtOAc. The layers were separated, the aqueous layer was extracted with EtOAc (2×), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (0-100% etoac/hexanes) to give the product. ES/MS:583.9 (M+H) + )。
Preparation of intermediate I-63：
2-bromo-4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -3- (((triisopropylsilyl) oxy) methyl) -6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-63): prepared in a similar manner to I-16, but with 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Solution of pyrrole-6-carboxylic acid tert-butyl ester (I-34) is replaced by 4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -3- (((triisopropylsilyl) oxy) methyl) -6H-thieno [2,3-b ]Pyrrole-6-carboxylic acid tert-butyl ester (I-62). ES/MS:662.2 (M) + )。
Preparation of intermediate I-64：
(1S, 4R) -6-hydroxy-2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (I-64): (1S, 4R) -6-oxo-2-azabicyclo [2.2.1 ] in a 250mL round bottom flask at 0deg.C]To a solution of tert-butyl heptane-2-carboxylate (1.00 g,4.73 mmol) in methanol (20.0 mL) was added sodium borohydride (0.18 g,4.73 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was then chlorinated with saturationAqueous ammonium solution (5 mL) was quenched, diluted with water (10 mL) and EtOAc (10 mL), and extracted with EtOAc (2X 20 mL). The combined organic layers were dried over MgSO 4 Drying, vacuum filtration, and concentration under reduced pressure gave the crude product. The crude material was used directly in the subsequent reaction without further purification. ES/MS:158.2 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-65：
(1S, 4R) -6-iodo-2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (I-65): prepared in a similar manner to I-20 but with 6-hydroxy-2-azabicyclo [3.3]The tert-butyl heptane-2-carboxylate is replaced by I-64.ES/MS:268.0 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-66：
2- [4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) phenyl ] morpholine-4-carboxylic acid tert-butyl ester (I-66): prepared in a similar manner to I-13, but replacing 6-bromo-7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridine with tert-butyl 2- (4-bromophenyl) morpholine-4-carboxylate. ES/MS:334.2 (M+H+) (mass minus t-butyl).
Preparation of intermediate I-67：
4- [5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidin-2-yl]Piperidine-1-carboxylic acid tert-butyl ester (I-67): prepared in a similar manner to I-13, but with 6-bromo-7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridine is replaced by 4- (5-bromopyrimidin-2-yl) piperidine-1-carboxylic acid tert-butyl ester. ES/MS:334.2 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-68：
(1S, 4R) -2-hydroxy-7-azabicyclo [2.2.1]Heptane-7-carboxylic acid tert-butyl ester (I-68): prepared in a similar manner to I-CJS3 but with (1S, 4R) -6-oxo-2-azabicyclo [2.2.1]Substitution of heptane-2-carboxylic acid tert-butyl ester with (1S, 4R) -2-oxo-7-azabicyclo [2.2.1]Heptane-7-carboxylic acid tert-butyl ester. ES/MS:158.2 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-69：
(1S, 4R) -2-iodo-7-azabicyclo [2.2.1]Heptane-7-carboxylic acid tert-butyl ester (I-69): prepared in a similar manner to I-20 but with 6-hydroxy-2-azabicyclo [3.3]The tert-butyl heptane-2-carboxylate is replaced by I-68.ES/MS:268.1 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-70：
(1R, 4R, 5R) -5-iodo-2-azabicyclo [2.2.2]Octane-2-carboxylic acid tert-butyl ester (I-70): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3 ] ]Substitution of heptane-2-carboxylic acid tert-butyl ester with (1R, 4R, 5S) -5-hydroxy-2-azabicyclo [2.2.2]Octane-2-carboxylic acid tert-butyl ester. ES/MS:268.0 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-71：
Di-tert-butyl 1- (4-ethyl-5- (methoxycarbonyl) thiophen-2-yl) hydrazine-1, 2-dicarboxylate (I-71): prepared in a similar manner to I-2, but replacing 5-bromo-3-methyl-thiophene-2-carboxylic acid methyl ester with 5-bromo-3-ethyl thiophene-2-carboxylic acid methyl ester.
Preparation of intermediate I-72：
2-bromo-3-ethyl-4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole (I-72): prepared in a similar manner to I-6, I-5 and I-3, but substituting di-tert-butyl 1- (5- (methoxycarbonyl) -4-methylthiophene-2-yl) hydrazine-1, 2-dicarboxylate (I-2) with di-tert-butyl 1- (4-ethyl-5- (methoxycarbonyl) thiophen-2-yl) hydrazine-1, 2-dicarboxylate (I-71). ES/MS:402.1 (M) + )。
Preparation of intermediate I-73：
2-bromo-3-ethyl-4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-73): prepared in a similar manner to I-15, but with 2-bromo-4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ] ]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole (I-6) is replaced by 2-bromo-3-ethyl-4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole (I-72). ES/MS:503.2 (M) + )。
Preparation of intermediate I-74：
2- (2-ethoxycarbonylcyclopropyl) -4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazole compoundsAnd [1,5-a ]]Pyridin-6-yl) thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester: to 2-bromo-4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) thieno [2,3-b]To a solution of tert-butyl pyrrole-6-carboxylate (I-15) (350 mg,0.72 mmol) in 10:1 toluene and water (4 mL) was added ethyl 2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopropanecarboxylate (275 mg,1.2 mmol),APd G3 (52.1 mg,0.072 mmol) and cesium carbonate (699 mg,2 mmol). The reaction mixture was taken up in N 2 Heat to 100 ℃ for 16 hours. The reaction mixture was dried over sodium sulfate, filtered through celite, eluted with DCM, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (0-100% etoac/hexanes) to give the product. ES/MS:523.3 (M+H) + )。/>
2- [ 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrol-2-yl]Cyclopropanecarboxylic acid (I-74): to 2- (2-ethoxycarbonylcyclopropyl) -4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) thieno [2,3-b]To a solution of tert-butyl pyrrole-6-carboxylate (350 mg,0.67 mmol) in 1:1:1 THF/EtOH/water (6 mL) was added lithium hydroxide monohydrate (80.2 mg,0.52 mmol) and the reaction mixture was stirred at 90℃for 4 hours. The reaction mixture was concentrated in vacuo, then diluted with hydrochloric acid (1.00 mol/L,1.18ml,1.18 mmol) and water, and then the precipitate was collected by filtration to give the product. ES/MS:395.2 (M+H) + )。
Preparation of intermediate I-75：
2- (1-benzyloxycarbonyl-3, 6-dihydro-2H-pyridin-4-yl) -5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester: to 2-bromo-5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-thieno [2,3-b]To a solution of tert-butyl pyrrole-6-carboxylate (I-16) (800 mg,1.60 mmol) in 10:1 dioxane and water (13 mL) was added 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylate (09 mg,2.07 mmol), xphos Pd G3 (125 mg,0.16 mmol) and cesium carbonate (1553 mg,4.77 mmol). The reaction mixture was taken up in N 2 Heat to 110 ℃ for 3 hours. The reaction mixture was dried over sodium sulfate, filtered through celite, eluted with DCM, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (0-100% etoac/hexanes) to give the product. ES/MS:640.4 (M+H) + )。
5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-2- (4-piperidinyl) thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-75): to 2- (1-benzyloxycarbonyl-3, 6-dihydro-2H-pyridin-4-yl) -5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-thieno [2,3-b]To a solution of tert-butyl pyrrole-6-carboxylate (1 g,1.56 mmol) was added ethanol (20 mL). Nitrogen was bubbled through the solution for 4 minutes, then palladium on carbon (10 wt%, 166mg,1.56 mmol) was added and the reaction mixture was stirred under a hydrogen atmosphere for 24 hours. The reaction mixture was degassed with argon, diluted with EtOAc, and filtered through celite, eluting with EtOAc, and the filtrate concentrated under reduced pressure to give the crude product, which was used in the next step without further purification. ES/MS:508.3 (M+H) + )。
Preparation of intermediate I-76：
9-iodo-1-oxa-4-azaspiro [5.5 ] ]Undecane-4-carboxylic acid tert-butyl ester (I-76): at 0 ℃, to 9-oxo-1-oxa-4-azaspiro [5.5 ]]To a solution of tert-butyl undecane-4-carboxylate (0.5 g,1.86 mmol) in MeOH (10 mL) was added NaBH 4 (70.2 mg,1.86 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was then saturated with 5mLAnd NH 4 The aqueous Cl solution was quenched slowly and diluted with water (20 mL) and EtOAc (20 mL). The aqueous layer was then extracted with EtOAc (2X 20 mL). The organic layers were combined, over MgSO 4 Drying, filtering, concentrating, and then drying under high vacuum. The crude oil was then dissolved in toluene (25 mL) and triphenylphosphine (0.55 g,2.21 mmol), molecular iodine (0.56 g,2.21 mmol) and imidazole (0.25 g,3.69 mmol) were added to the mixture. The mixture was stirred at reflux overnight. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (eluent: hexane/EtOAc) to give the product. ES/MS:326.0 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-77：
6-bromo-7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridin-2-amine: to a solution of 5-bromo-3, 4-dimethyl-pyridin-2-amine (2.0 g,9.95 mmol) in 1, 4-dioxane (69 mL) was added dropwise ethoxycarbonyl isothiocyanate (1.30 g,1.17mL,9.95 mmol) at room temperature. After stirring for 19 hours, the solvent was evaporated under reduced pressure. The residue was dissolved in a 1:1 mixture of MeOH and EtOH (IMS grade) (128 mL) and hydroxylamine hydrochloride (3.46 g,49.7 mmol) was added, and the reaction mixture was heated to 60℃followed by DIPEA (5.2 mL,29.8 mmol). The reaction was then heated at 60 ℃ for 4 hours, and the reaction mixture was then cooled to room temperature. The resulting precipitate was collected by filtration, washed with MeOH and dried to give the product. ES/MS:241.0 (M) + )。
6-bromo-2-chloro-7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridine: to a suspension of copper (II) chloride (1.25 g,9.33 mmol) and tert-butyl nitrite (1.11 mL,9.33 mmol) in anhydrous MeCN (30 mL) was added 6-bromo-7, 8-dimethyl- [1,2,4 at 70 ℃]Triazolo [1,5-a ]]Pyridin-2-amine (1.50, 6.22 mmol). After stirring at 70℃for 4 hours, the reaction mixture was poured into 5N HCl aqueous solution (20 mL) and extracted with EtOAc (4X 20 mL). The combined organic phases were taken up in Na 2 SO 4 Drying, filtering and concentrating under reduced pressureTo dryness. The crude product was purified by flash chromatography (eluent: etOAc/hexane) to give the product. ES/MS:262.0 (M) + )。 1 H NMR(400MHz，CDCl 3 )δ8.56(s，1H)，2.62(s，3H)，2.49(s，3H)。
2-chloro-7, 8-dimethyl-6- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) - [1,2,4 ]]Triazolo [1,5-a ]]Pyridine (I-77): 6-bromo-2-chloro-7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridine (0.76 g,2.9 mmol) and 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1,3, 2-dioxapentaborane (1.11 g,4.35 mmol), pd (dppf) Cl 2 A solution of (215 mg,0.29 mmol) and potassium propionate (1.14 g,10.2 mmol) in 1, 4-dioxane (5 mL) was degassed with argon for 3 min and stirred at 90℃for 2 h. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated to dryness. The residual product was purified by flash chromatography (eluent: etOAc: hexanes) to give the product. ES/MS:308.1 (M+H) + )。 1 H NMR(400MHz，CDCl 3 )δ8.68(s，1H)，2.56(d，J＝12.8Hz，6H)，1.38(d，J＝1.5Hz，12H)。
Preparation of intermediate I-78：
4- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]Cyclohexanone (I-78): 2-bromo-5- (7, 8-dimethyl- [1,2, 4) was added to the dried vial]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-16) (160 mg,0.32 mmol), 8-iodo-1, 4-dioxaspiro [4.5 ]]Decane (170 mg,0.64 mmol), tetrabutylammonium iodide (TBAI) (141 mg,0.38 mmol), ni (dtbbpy) (H 2 O) 4 Cl 2 (18 mg,0.038 mmol) and zinc powder (124 mg,1.91 mmol). Anhydrous DMA (1 mL) was added and the mixture was degassed with argon for 1 minute. The vial was sealed and the reaction was stirred at 70 ℃ for 16 hours. Then, the process is carried out,the reaction was cooled and the crude mixture was purified directly by silica gel chromatography (eluent: etOAc/hexane). (ES/MS: 565.2[ M+H ]]). To a solution of the purified ketal intermediate in THF (1 mL) and MeOH (1 mL) was added LiOH (excess) and the resulting reaction mixture was stirred at 80 ℃ for 3 hours. The reaction mixture was diluted with EtOAc (10 mL) and water (5 mL). The organic layer was washed with brine (5 mL), and dried over MgSO 4 Dried, filtered and concentrated. The resulting material was dissolved in DCM (1 mL) and treated with 4M HCl in dioxane (2 mL) and 3 drops of water. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (10 mL) and saturated NaHCO 3 Aqueous (10 mL), brine (5 mL) and washed with Na 2 SO 4 Dried, filtered and concentrated. The crude product was purified to give the product. ES/MS:421.0 (M+H) + )。
Preparation of intermediate I-79：
6-bromo-2, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridine (I-79): to a stirred solution of 2-amino-5-bromopyridine (10 g,53.5 mmol) in N, N-dimethylformamide (24 mL) was added 1, 1-dimethoxy-N, N-dimethylethan-1-amine (23.4 mL,0.16 mol). The reaction mixture was heated to 130 ℃ overnight. After cooling to room temperature, volatiles were removed under reduced pressure to give the intermediate imine product. To an ice-cold stirred solution of the intermediate imine product in methanol (80 mL) and pyridine (8.7 mL) was added hydroxylamine-O-sulfonic acid (9.07 g,80.2 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The volatiles were removed under reduced pressure and the residue was partitioned between aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The aqueous layer was further extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with water (100 mL) followed by brine (100 mL), dried over magnesium sulfate and concentrated in vacuo to give the product. ES/MS:226.2 (M) + )。
Preparation of intermediate I-80：
2, 8-dimethyl-6- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) - [1,2,4 ] ]Triazolo [1,5-a ]]Pyridine (I-80): prepared in a similar manner to I-13, but with 6-bromo-7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Substitution of pyridine with 6-bromo-2, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridine (I-79). ES/MS:192.1 (M+H) + ) (mass of boric acid). 1 H NMR(400MHz，CDCl 3 )δ8.72(t，J＝0.9Hz，1H)，7.55(p，J＝1.1Hz，1H)，2.66-2.57(m，6H)，1.38(s，12H)。
Preparation of intermediate I-81：
1- (2, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -3-methyl-butan-1-one (I-81): prepared in a similar manner to I-14, but with 7, 8-dimethyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) - [1,2,4 ]]Triazolo [1,5-a ]]Substitution of pyridine with 2, 8-dimethyl-6- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) - [1,2,4 ]]Triazolo [1,5-a ]]Pyridine (I-80). ES/MS:232.2 (M+H) + )。 1 H NMR(400MHz，CDCl 3 )δ8.99(d，J＝1.7Hz，1H)，2.82(d，J＝6.9Hz，2H)，2.66(d，J＝3.3Hz，6H)，2.33(dh，J＝13.3，6.7Hz，1H)，1.04(d，J＝6.7Hz，6H)。
Preparation of intermediate I-82：
5- (2, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole-2-carboxylic acid methyl ester (I-82): prepared in a similar manner to I-3, but by reacting 3-methyl-1- (8-methyl- [ 1),2，4]triazolo [1,5-a ]]Pyridin-6-yl) butan-1-one replacement with 1- (2, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -3-methyl-butan-1-one (I-81). ES/MS:383.2 (M+H) + )。
Preparation of intermediate I-83：
5- (2, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole (I-83): prepared in a similar manner to I-5, but with 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-2-carboxylic acid methyl ester is replaced by 5- (2, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole-2-carboxylic acid methyl ester (I-82). ES/MS:325.2 (M+H) + )。
Preparation of intermediate I-84：
2-bromo-5- (2, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole (I-84): prepared in a similar manner to I-6, but with 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Substitution of pyrrole (I-5) with 5- (2, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole (I-83). ES/MS:405.1 (M+2H) + )。
Preparation of intermediate I-85：
2-bromo-5- (2, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-thieno [2,3-b ] ]Pyrrole-6-carboxylic acid tert-butyl ester (I-85): prepared in a similar manner to I-15, but with 2-bromo-4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole substitution with 2-bromo-5- (2, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole (I-84). ES/MS:504.2 (M) + )。 1 H NMR(400MHz，CDCl 3 )δ8.31(d，J＝1.6Hz，1H)，7.25-7.19(m，1H)，2.96(hept，J＝7.1Hz，1H)，2.66(d，J＝3.5Hz，6H)，2.47(s，3H)，1.36(s，9H)，1.24(d，J＝7.1Hz，6H)。
Preparation of intermediate I-86：
Methyl 4-iodocyclohexane carboxylate (I-86): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3 ]]The tert-butyl heptane-2-carboxylate is replaced by methyl 4-hydroxycyclohexane carboxylate. 1 H NMR(400MHz，CDCl3)δ4.64(t，J＝4.5Hz，1H)，3.68(s，3H)，2.41(tt，J＝9.9，4.0Hz，1H)，2.16-2.05(m，2H)，2.05-1.86(m，2H)，1.86-1.61(m，4H)。
Preparation of intermediate I-87：
3-iodo-8-azaspiro [4.5 ]]Decane-8-carboxylic acid tert-butyl ester (I-87): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3 ]]Substitution of heptane-2-carboxylic acid tert-butyl ester with 3-hydroxy-8-azaspiro [4.5 ]]Decane-8-carboxylic acid tert-butyl ester. ES/MS:310.0 (M+H) + ) (mass minus t-butyl).
Intermediate I-88 pyridine preparation：
2-iodo-6-azaspiro [3.5 ]]Nonane-6-carboxylic acid tert-butyl ester (I-88): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3 ]]Substitution of heptane-2-carboxylic acid tert-butyl ester with 2-hydroxy-6-azaspiro [3.5 ]]Nonane-6-carboxylic acid tert-butyl ester. ES/MS:296.1 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-89：
2-iodo-5-azaspiro [3.4 ]]Octane-5-carboxylic acid tert-butyl ester (I-89): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3]]Substitution of heptane-2-carboxylic acid tert-butyl ester with 2-hydroxy-5-azaspiro [3.4 ]]Octane-5-carboxylic acid tert-butyl ester. ES/MS:282.1 (M+H) + ) (mass minus t-butyl).
Preparation of intermediate I-90：
5-iodo-2-azaspiro [3.3]]Heptane-2-carboxylic acid tert-butyl ester (I-90): prepared in a similar manner to I-20, but with 6-hydroxy-2-azaspiro [3.3]]Substitution of heptane-2-carboxylic acid tert-butyl ester with 7-hydroxy-2-azaspiro [3.3]]Heptane-2-carboxylic acid tert-butyl ester. ES/MS:268.0 (M+H) + ) (mass minus t-butyl). 1 H NMR(400MHz，CDCl3)δ4.59-4.48(m，1H)，4.22(dd，J＝9.0，1.0Hz，1H)，3.96(dd，J＝9.1，1.0Hz，1H)，3.78(dd，J＝9.2，1.0Hz，1H)，3.72(dd，J＝9.2，1.0Hz，1H)，2.59-2.37(m，2H)，2.32-2.17(m，2H)，1.46(s，9H)。
Preparation of intermediate I-91：
(1R, 4R, 5R) -5-iodo-2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester (I-91): prepared in a similar manner to I-20, but replacing tert-butyl 6-hydroxy-2-azaspiro [3.3] heptane-2-carboxylate with tert-butyl (1 r,4r,5 s) -5-hydroxy-2-azabicyclo [2.2.2] octane-2-carboxylate.
Preparation of intermediate I-92：
(6-iodospiro [ 3.3)]Tert-butyl hept-2-yl) carbamate (I-92): prepared in a similar manner to I-76, but 9-oxo-1-oxa-4-azaspiro [5.5]Undecane-4-carboxylic acid tert-butyl ester is replaced by (6-oxo spiro [3.3] ]Hept-2-yl) carbamic acid tert-butyl ester. ES/MS:282.0 (M+H) + ) (mass minus t-butyl).
Final program
Procedure 1, example 1
4-isopropyl-N-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -N- (piperidin-4-yl) -6H-thieno [2,3-b]Pyrrole-2-carboxamide (example 1): to 4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]To a solution of pyrrole-2-carboxylic acid (I-10) (20.0 mg,0.0588 mmol) in DCM (0.75 mL) was added tert-butyl 4- (methylamino) piperidine-1-carboxylate (0.0439 mL,0.206 mmol), HATU (26.8 mg,0.0705 mmol) and N, N-diisopropylethylamine (0.0512 mL, 0.254 mmol) and the reaction mixture was heated to 60℃and stirred for 30 min. Trifluoroacetic acid (0.250 ml,3.27 mmol) was added and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure and the crude residue was purified directly by RP-HPLC (0.1% TFA-ACN/0.1% TFA-water, column: gemini 5. Mu.M, NX-C18 Angstrom, 250X 21.2 mm) to give the title compound, example 1.ES/MS:437.3 (M+H) + )。 1 H NMR(400MHz，DMSO-d6)δ11.74(s，1H)，8.81-8.74(m，1H)，8.53(s，1H)，8.25-8.02(m，2H)，7.65-7.52(m，2H)，4.59-4.46(m，2H)，3.14(s，3H)，3.21-2.97(m，4H)，2.62(s，3H)，2.06-1.82(m，4H)，1.37(d，J＝6.9Hz，6H)。
The following examples were prepared in a similar manner according to procedure 1 and are shown in table 1 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 1 were used, and these reagents/starting materials are noted in the last column of table 1- "procedure 1 variation: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 1 are replaced with different reagents/starting materials described below.
Procedure 2, example 6
4- ((5-bromothiophen-2-yl) sulfonyl) piperazine-1-carboxylic acid tert-butyl ester: to a solution of 5-bromothiophene-2-sulfonyl chloride (1.00 g,3.82 mmol) in THF (15.0 mL) cooled to 0 ℃ was added a solution of tert-butyl piperazine-1-carboxylate (0.783 g,4.21 mmol) in THF (5 mL), and the reaction was stirred at 0 ℃ for 30 min. The reaction was quenched by the addition of water and the mixture was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (0% -50% etoac/hexanes) to give the title compound. ES/MS:435.0 (M+Na) + )。
1- (5- ((4- (tert-butoxycarbonyl) piperazin-1-yl) sulfonyl) thiophen-2-yl) hydrazine-1, 2-dicarboxylic acid di-tert-butyl ester: to 4- [ (5-bromo-2-thienyl) sulfonyl]Tert-butyl piperazine-1-carboxylate (0.823 g,2.00 mmol) was added dropwise to a solution of THF (6 mL) cooled to-40℃with a solution of isopropyl magnesium bromide in 2-MeTHF (2.90 mol/L,0.841mL,2.44 mmol), and the solution was taken upThe solution was stirred at-40℃for 30 min. A solution of di-tert-butyl azodicarbonate (0.507 g,2.20 mmol) in THF (6 mL) was then added dropwise and the reaction stirred at-40℃for 30 min. The reaction was quenched by addition of saturated aqueous ammonium chloride and the mixture was extracted with DCM (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and the filtrate concentrated in vacuo. The crude residue was purified by column chromatography (0% -50% etoac/hexanes) to give the title compound. ES/MS:585.3 (M+Na) + )。
1 H NMR (400 MHz, chloroform-d) delta 7.34-7.30 (m, 1H), 6.80-6.76 (m, 1H), 3.61-3.49 (m, 4H), 3.11-3.00 (m, 4H), 1.61-1.42 (m, 27H).
4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (piperazin-1-ylsulfonyl) -6H-thieno [2,3-b]Pyrrole (example 6): to 5- [ tert-butoxycarbonyl- (tert-butoxycarbonylamino) amino group]To a solution of thiophene-2-carboxylic acid methyl ester (200 mg,0.537 mmol) and p-toluenesulfonic acid monohydrate (0.555 g,3.22 mmol) in ethanol (12 mL) was added 3-methyl-1- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) butan-1-one (I-1) (0.175 g,0.806 mmol) and the reaction mixture was heated to 130℃for 30 minutes in a microwave oven. The reaction mixture was concentrated in vacuo, dissolved in EtOAc and washed with saturated aqueous sodium bicarbonate. The layers were separated, the organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified directly by RP-HPLC (0.1% TFA-ACN/0.1% TFA-water, column: gemini 5. Mu.M, NX-C18110 angstroms, 250X 21.2 mm) to give the title compound, example 6.ES/MS:445.2 (M+H) + )。 1 H NMR(400MHz，DMSO-d6)δ12.03(s，1H)，8.87-8.81(m，1H)，8.55(s，1H)，8.54-8.47(m，2H)，7.89(s，1H)，7.61-7.54(m，1H)，3.42-3.12(m，9H)，2.63(s，3H)，1.38(d，J＝6.9Hz，6H)。
Procedure 3, example 7
N- (1- (2-hydroxyethyl) piperidin-4-yl) -4-isopropyl-N, 3-dimethyl-5- (8-methyl- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-2-carboxamide (example 7): to 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]To a solution of pyrrole-2-carboxylic acid (44.0 mg,0.124 mmol) in DCM (0.75 mL) was added 2- [4- (methylamino) -1-piperidinyl]Ethanol (21.6 mg,0.137 mmol), HATU (56.6 mg,0.149 mmol) and N, N-diisopropylethylamine (0.108 ml, 0.6271 mmol) and the reaction mixture was stirred for 30 min. Trifluoroacetic acid (0.250 ml,3.27 mmol) was added and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure and the crude residue was purified directly by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18110 angstroms, 250X 21.2 mm) to give the title compound, example 7.ES/MS:495.3 (M+H) + )。 1 H NMR(400MHz，DMSO-d6)δ11.62(s，1H)，9.06(s，1H)，8.77(s，1H)，8.53(s，1H)，7.52(t，J＝1.5Hz，1H)，5.46-5.30(m，1H)，4.43-4.28(m，1H)，3.77-3.69(m，2H)，3.62-3.52(m，2H)，3.26-3.04(m，5H)，2.89(s，3H)，2.62(s，3H)，2.43(s，3H)，2.24-2.07(m，2H)，1.94-1.81(m，2H)，1.33(d，J＝7.1Hz，6H)。
Procedure 4, example 8
4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (piperidin-4-yl) -6H-thieno [2,3-b]Pyrrole (example 8): to 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (piperidin-4-yl) -6H-thieno [2,3-b]To a solution of pyrrole hydrochloride (I-7) (32.0 mg,0.075 mmol) in DCM (0.5 mL) was added trifluoroacetic acid (O.1 mL), and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure and the crude residue was directly passed through RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18110 angstroms, 250X 21). 2 mm) to give the title compound example 8.ES/MS:394.3 (M+H) + )。 1 H NMR(400MHz，DMSO-d6)δ11.40(s，1H)，8.68(s，1H)，8.60-8.52(m，1H)，8.52(s，1H)，8.30-8.13(m，1H)，7.49(s，1H)，3.28-3.14(m，3H)，3.14-3.00(m，2H)，2.63-2.60(m，4H)，2.41(s，3H)，2.00(d，J＝13.6Hz，2H)，1.82-1.65(m，2H)，1_32(d，J＝7.1Hz，6H)。
Procedure 5, example 9
2- (4- (4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrol-2-yl) piperidin-1-yl) acetamide (example 9): to 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (piperidin-4-yl) -6H-thieno [2,3-b]To a solution of pyrrole hydrochloride (I-7) (70 mg,0.163 mmol) in 1, 2-dichloroethane (2 mL) was added 2-bromoacetamide (27 mg,0.195 mmol) and 1, 8-diazabicyclo [5.4.0]Undec-7-ene (0.097 mL, O.65 mmol). The mixture was stirred at room temperature overnight. To the mixture was added 0.5mL of DMSO and O.1mL of TFA, followed by removal of DCE under reduced pressure. Acetonitrile (O.5 mL) and water (O.1 mL) were added and the mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18 110 Angstrom, 250X 21.2 mm) to give the title compound, example 9.ES/MS:451.3 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 10.95 (s, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 7.58 (s, 1H), 3.99 (s, 2H), 3.74 (d, j=12.1 hz, 2H), 3.52-3.35 (m, 1H), 3.31-3.10 (m, 3H), 2.69 (s, 3H), 2.50 (s, 3H), 2.23 (d, j=14.4 hz, 2H), 2.08 (q, j=12.8, 12.4hz, 2H), 1.40 (d, j=7.1 hz, 6H).
Procedure 6, example 10
2- (dimethylamino) -1- (4- (4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrol-2-yl) piperidin-1-yl) ethan-1-one (example 10): to 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (piperidin-4-yl) -6H-thieno [2,3-b]To a solution of pyrrole hydrochloride (I-7) (15 mg,0.035 mmol) in 1, 2-dichloroethane (1 mL) was added 2- (dimethylamino) acetyl chloride (6 mg,0.042 mmol) and triethylamine (O.02 mL,0.14 mmol). The mixture was stirred at room temperature for 2 hours. To the mixture was added 0.1mL TFA followed by removal of DCE under reduced pressure. Acetonitrile (0.5 mL) and water (0.1 mL) were added and the mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18 110 Angstrom, 250X 21.2 mm) to give the title compound, example 10.ES/MS:479.3 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.58 (s, 1H), 8.45 (s, 1H), 7.57 (s, 1H), 4.68 (d, j=13.5 hz, 2H), 4.42-4.17 (m, 3H), 3.79 (d, j=13.5 hz, 2H), 3.31-3.26 (m, 1H), 3.00 (s, 3H), 2.97 (s, 3H), 2.91 (t, j=13.8 hz, 1H), 2.68 (s, 3H), 2.49 (s, 3H), 2.12-1.97 (m, 2H), 1.80-1.52 (m, 2H), 1.41 (d, j=7.3 hz, 6H).
Procedure 7, example 11
2- (dimethylamino) -1- (4- (4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrol-2-yl) piperidin-1-yl) ethan-1-one (example 11): to a catalyst containing 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (piperidin-4-yl) -6H-thieno [2,3-b]To a flange vial (dram device) of a solution of pyrrole hydrochloride (I-7) (12 mg,0.028 mmol) in 1, 2-dichloroethane (1 mL) was added 3-methyl oxetane-3-carbaldehyde (6 mg,0.056 mmol), N-diisopropylethylamine (0.01 mL,0.056 mmol) and acetic acid (1 drop). The mixture was allowed to stand at room temperatureStirred for 2 hours. Sodium Triacetoxyborohydride (STAB) (18 mg,0.084 mmol) was then added to the mixture, and the mixture was stirred at room temperature overnight. To the mixture was added 0.1mL TFA followed by removal of DCE under reduced pressure. Acetonitrile (0.5 mL) and water (0.1 mL) were added and the mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18 110 Angstrom, 250X 21.2 mm) to give the title compound, example 11.ES/MS:478.3 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.60 (s, 1H), 8.46 (s, 1H), 7.57 (s, 1H), 4.65 (d, j=6.2 hz, 2H), 4.44 (d, j=6.2 hz, 2H), 3.58-3.38 (m, 7H), 3.30-3.24 (m, 1H), 2.68 (s, 3H), 2.50 (s, 3H), 2.23 (d, j=14.6 hz, 2H), 2.09-1.95 (m, 2H), 1.61 (s, 3H), 1.40 (d, j=7.1 hz, 6H).
The following examples were prepared in a similar manner according to procedure 7 and are shown in table 2 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 7 were used, and these reagents/starting materials are noted in the last column of table 2- "procedure 7 variation: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 7 are replaced with different reagents/starting materials described below.
Table 2.
Procedure 8, example 13
2- (4- (4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrol-2-yl) piperidin-1-yl) ethan-1-ol (example 13): to a catalyst containing 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (piperidine-4-yl) -6H-thieno [2,3-b]A Vial of pyrrole hydrochloride (I-7) (20 mg,0.047 mmol) in 1, 2-dichloroethane (0.5 mL) was added 2- [ tert-butyl (dimethyl) silyl]Oxyacetaldehyde (18 mg,0.093 mmol), N-diisopropylethylamine (0.02 mL,0.093 mmol) and acetic acid (1 drop). The mixture was stirred at room temperature for 2 hours. Sodium Triacetoxyborohydride (STAB) (30 mg, O.14 mmol) was then added to the mixture, and the mixture was stirred at room temperature overnight. The crude mixture was purified directly by silica gel chromatography (eluent EtOAc/hexanes). The product was then dissolved in acetonitrile (1 mL) and TFA (0.25 mL) was added. The reaction was heated at 40 ℃ for 3 hours. Water (0.15 mL) was added and the mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18. Ang. 110, 250X 21.2 mm) to give the title compound, example 13.ES/MS:438.3 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.60 (s, 1H), 8.46 (s, 1H), 7.58 (s, 1H), 3.94 (t, j=5.3 hz, 2H), 3.76 (d, j=12.3 hz, 2H), 3.62-3.37 (m, 4H), 3.29-3.18 (m, 2H), 2.69 (s, 3H), 2.50 (s, 3H), 2.24 (d, j=14.2 hz, 2H), 2.14-1.95 (m, 2H), 1.41 (d, j=7.1 hz, 6H).
Procedure 9, example 14
(S) -4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (1-prolylpiperidin-4-yl) -6H-thieno [2,3-b]Pyrrole (example 14): to a catalyst containing 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (piperidin-4-yl) -6H-thieno [2,3-b]To a Violet vial of pyrrole hydrochloride (I-7) (15 mg,0.035 mmol) in 1, 2-dichloroethane (1 mL) was added (2S) -1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (10 mg,0.045 mmol), 2- (7-aza-1H-benzotriazol-1-yl) -1, 3-tetramethylurea Hexafluorophosphate (HATU) (17 mg,0.45 mmol), N-diisopropylethylamine (0.03 mL,0.14 mmol). The mixture was stirred at room temperature for 5 hours.TFA (0.25 mL) was added to the mixture, and the mixture was stirred at room temperature for 2 hours. The crude mixture was concentrated under reduced pressure, and acetonitrile (0.7 mL) and water (0.15 mL) were added. The mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18A, 250X 21.2 mm) to give the title compound, example 14.ES/MS:491.3 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.59 (s, 1H), 8.46 (s, 1H), 7.58 (s, 1H), 4.79-4.55 (m, 2H), 3.99 (d, j=13.3 hz, 1H), 3.47-3.36 (m, 2H), 2.94 (t, j=13.1 hz, 1H), 2.68 (s, 3H), 2.65-2.51 (m, 1H), 2.49 (s, 3H), 2.20-1.88 (m, 5H), 1.76-1.51 (m, 2H), 1.41 (d, j=7.1 hz, 6H).
The following examples were prepared in a similar manner according to procedure 9 and are shown in table 3 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 9 were used, and these reagents/starting materials are noted in the last column of table 3— "change in procedure 9: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 9 are replaced with different reagents/starting materials described below.
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Procedure 10, example 20
4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (6- (piperazin-1-yl) pyridin-3-yl) -6H-thieno [2,3-b]Pyrrole (example 20): 2-bromo-4-isopropyl-3-methyl-5- (8-methyl- [ 1) was added to the vial,2，4]triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole (I-6) (40 mg,0.10 mmol), 4- [5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyridinyl ]Piperazine-1-carboxylic acid tert-butyl ester (80 mg,0.21 mmol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium (II) dichloride (11 mg,0.015 mmol). Dimethoxyethane (0.5 mL) and sodium carbonate (2M aqueous solution, 0.1mL,0.21 mmol) were added and the mixture was degassed with argon for 30 seconds. The vial was sealed and the mixture was heated in a microwave oven at 120 ℃ for 20 minutes. The crude mixture was purified directly by silica gel chromatography (eluent EtOAc/hexanes). The product was then dissolved in acetonitrile (1 mL) and TFA (o.25 mL) was added. The reaction was heated at 40 ℃ for 3 hours. Water (0.15 mL) was added and the mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18. Ang. 110, 250X 21.2 mm) to give the title compound example 20.ES/MS:472.3 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.64 (s, 1H), 8.48 (s, 1H), 8.29 (d, j=2.4 hz, 1H), 7.77 (dd, j=8.8, 2.5hz, 1H), 7.62 (s, 1H), 7.04 (d, j=8.8 hz, 1H), 3.96-3.84 (m, 4H), 3.41-3.37 (m, 4H), 3.27 (s, 1H), 2.70 (s, 3H), 2.51 (s, 3H), 1.44 (d, j=7.1 hz, 6H).
The following examples were prepared in a similar manner according to procedure 10 and are shown in table 4 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 10 were used, and these reagents/starting materials are noted in the last column of table 4- "change in procedure 10: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 10 are replaced with different reagents/starting materials described below.
The following examples were prepared in a similar manner according to the reference procedure and are shown in table 5a below. To prepare the following examples, reagents/starting materials different from some of those described in the reference procedure were used, and these reagents/starting materials are noted in the last column of table 5 a- "change in reference procedure: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of the reference procedure are replaced with different reagents/starting materials described below.
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Procedure 11, example 58：
6- (4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrol-2-yl) -2-azaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester: 2-bromo-4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4) addition to the dry vial]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-15) (200 mg,0.409 mmol), 6-iodo-2-azaspiro [3.3 ]]Heptane-2-carboxylic acid tert-butyl ester (I-20) (198mg, 0.313 mmol), tetrabutylammonium iodide (TBAI) (37.7 mg,0.102 mmol), ni (dtbbpy) (H) 2 O) 4 Cl 2 (23.2 mg,0.049 mmol), zinc powder (133 mg,2.04 mmol) and 4 angstrom molecular sieve (100 mg). Anhydrous DMA (1.5 mL) and the mixture were degassed with argon for 1 minute. The vial was sealed and the reaction was stirred at 70 ℃ for 16 hours. The reaction was then cooled and the crude mixture was purified directly by silica gel chromatography (eluent: etOAc/hexane). The purified material was dissolved in MeOH (1.5 mL) and potassium carbonate (saturated aqueous solution, 0.25 mL) was added. The mixture was stirred at 40 ℃ overnight. LCMS showed removal of the Boc group and the mixture was diluted with EtOAc (30 mL) and water (5 mL). The layers were separated and the organic layer was washed with brine (5 mL). The organic layer was dried over MgSO 4 Drying, filtering and concentrating under reduced pressure to obtain the product. ES/MS:506.3 (M+H) + )
4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (2-azaspiro [3.3]Hept-6-yl) -6H-thieno [2,3-b]Pyrrole (example 58): to a composition containing 6- (4-isopropyl-3-methyl-5-(8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrol-2-yl) -2-azaspiro [3.3]To a vial of tert-butyl heptane-2-carboxylate (90 mg,0.178 mmol) was added 1, 4-dioxane (0.25 mL) and methanol (0.25 mL). HCl (4M in dioxane, 0.55ml,2.22 mmol) was added and the mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was complete and the volatiles were evaporated under reduced pressure. The mixture was dissolved in acetonitrile (1 mL), water (0.5 mL) and trifluoroacetic acid (0.1 mL), and the crude material was purified directly by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18. ANG., 250X 21.2 mm) to give the title compound example 58.ES/MS:406.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.59 (s, 1H), 8.47 (s, 1H), 7.63-7.39 (m, 1H), 4.27 (s, 2H), 4.07 (s, 2H), 3.89-3.76 (m, 1H), 3.32-3.21 (m, 1H), 2.86-2.76 (m, 2H), 2.69 (s, 3H), 2.48-2.34 (m, 5H), 1.39 (d, J=7.1 Hz, 6H).
The following examples were prepared in a similar manner according to procedure 11 and are shown in table 6 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 11 were used, and these reagents/starting materials are noted in the last column of table 6- "procedure 11 variation: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 11 are replaced with different reagents/starting materials described below.
Procedure 12, example 62：
3- (4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrol-2-yl) -8-azabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester: addition of 2-bromo-4-isopropyl-3-methyl to a dry vial1,2, 4-methyl-5- (8-methyl-)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-15) (95 mg,0.194 mmol), 6-iodo-2-azaspiro [3.3 ]]Heptane-2-carboxylic acid tert-butyl ester (I-21) (98 mg, 0.2918 mmol), tetrabutylammonium iodide (TBAI) (18 mg,0.0485 mmol), ni (dtbbpy) (H) 2 O) 4 Cl 2 (11 mg,0.023 mmol), zinc powder (63 mg,0.97 mmol) and 4 angstrom molecular sieves (100 mg). Anhydrous DMA (1.0 mL) and the mixture were degassed with argon for 1 minute. The vial was sealed and the reaction was stirred at 70 ℃ for 16 hours. The reaction was then cooled and the crude mixture was purified directly by silica gel chromatography (eluent: etOAc/hexane). The purified material was dissolved in MeOH (1.5 mL) and potassium carbonate (saturated aqueous solution, 0.25 mL) was added. The mixture was stirred at 40 ℃ overnight. LCMS showed removal of the Boc group and the mixture was diluted with EtOAc (30 mL) and water (5 mL). The layers were separated and the organic layer was washed with brine (5 mL). The organic layer was dried over MgSO 4 Drying, filtering and concentrating under reduced pressure to obtain the product. ES/MS:520.3 (M+H) + )。
2- (8-azabicyclo [3.2.1] oct-3-yl) -4-isopropyl-3-methyl-5- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -6H-thieno [2,3-b ] pyrrole: to a vial containing 3- (4-isopropyl-3-methyl-5- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -6H-thieno [2,3-b ] pyrrol-2-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (50 mg,0.096 mmol) was added 1, 4-dioxane (0.25 mL) and methanol (0.25 mL). HCl (4M in dioxane, 0.55ml,2.22 mmol) was added and the mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was complete and the volatiles were evaporated under reduced pressure. The material was further treated as HCl salt. ES/MS:420.3 (M+H+).
2- (3- (4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrol-2-yl) -8-azabicyclo [3.2.1]Octane-8-yl) acetamide (example 62): to 2- (8-azabicyclo [ 3.2.1)]Octane-3-yl) -4-isopropyl-3-methyl-5- (8-methyl- [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]To a solution of pyrrole hydrochloride (50 mg,0.132 mmol) in 1, 2-dichloroethane (1 mL) was added 2- Bromoacetamide (18 mg,0.132 mmol) and 1, 8-diazabicyclo [5.4.0]Undec-7-ene (O.066 mL,0.44 mmol). The mixture was stirred at room temperature overnight. To the mixture was added 0.2mL TFA followed by removal of DCE under reduced pressure. Acetonitrile (0.5 mL) and water (0.2 mL) were added and the mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18 110 Angstrom, 250X 21.2 mm) to give the title compound example 62.ES/MS:477.3 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.60 (d, j=1.4 hz, 1H), 8.46 (s, 1H), 7.58 (t, j=1.4 hz, 1H), 4.15 (s, 2H), 3.89 (s, 2H), 3.83-3.66 (m, 1H), 3.30-3.25 (m, 1H), 2.69 (s, 3H), 2.51 (s, 3H), 2.45-2.09 (m, 8H), 1.40 (d, j=7.1 hz, 6H).
The following examples were prepared in a similar manner according to procedure 12 and are shown in table 7 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 12 were used, and these reagents/starting materials are noted in the last column of table 7— "change in procedure 12: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 12 are replaced with different reagents/starting materials described below.
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Procedure 13, example 68：
2- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -3- (difluoromethyl) -4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester: small to dry2-bromo-3- (difluoromethyl) -4-isopropyl-5- (8-methyl- [1,2, 4) was added to the flask]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-19) (54 mg,0.103 mmol), 4- (p-toluenesulfonyloxy) piperidine-1-carboxylic acid tert-butyl ester (73 mg,0.205 mmol), potassium iodide (26 mg,0.154 mmol), niBr 2 DME (5 mg,0.015 mmol), manganese powder (28 mg,0.51 mmol), 4-tert-butyl-2- (4-tert-butyl-2-pyridinyl) pyridine (dtbbpy) (4.1 mg,0.015 mmol) and 4-ethylpyridine (11 mg,0.103 mmol). Anhydrous DMA (O.5 mL) was added and the mixture was degassed with argon for 1 minute. The vial was sealed and the reaction was stirred at 80 ℃ for 16 hours. The reaction was then cooled and the crude mixture was purified directly by silica gel chromatography (eluent: etOAc/hexane).
3- (difluoromethyl) -4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (piperidin-4-yl) -6H-thieno [2,3-b]Pyrrole (example 68): the purified material was dissolved in 1, 4-dioxane (0.1 mL) and methanol (0.2 mL). HCl (4M in dioxane, 0.2ml,0.8 mmol) was added and the mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was complete and the volatiles were evaporated under reduced pressure. The mixture was dissolved in acetonitrile (1 mL), water (0.5 mL) and trifluoroacetic acid (0.1 mL), and the crude material was purified directly by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18110 angstroms, 250X 21.2 mm) to give the title compound example 68.ES/MS:430.2 (M+H) + )。 1 NMR (400 MHz, methanol-d 4) delta 8.67 (s, 1H), 8.48 (s, 1H), 7.59 (s, 1H), 7.21 (t, j=54.4 hz, 1H), 3.79-3.64 (m, 1H), 3.57-3.37 (m, 3H), 3.30-3.11 (m, 2H), 2.69 (s, 3H), 2.28 (d, j=14.2 hz, 2H), 2.02-1.80 (m, 2H), 1.29 (d, j=7.2 hz, 6H).
Procedure 14, example 69 and example 69a：
(3 aR,6 aS) -5- (4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3 ]b]Pyrrol-2-yl) hexahydrocyclopenta [ c ]]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester: 2-bromo-4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4) addition to the dry vial]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-15) (150 mg,0.306 mmol), (3 aR,6 aS) -5-iodohexahydrocyclopenta [ c ]]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (I-25) (155 mg,0.46 mmol), tetrabutylammonium iodide (TBAI) (28.3 mg,0.077 mmol), ni (dtbbpy) (H 2 O) 4 Cl 2 (17.3 mg,0.037 mmol) and zinc powder (100 mg,1.53 mmol). Anhydrous DMA (1.5 mL) was added and the mixture was degassed with argon for 1 minute. The vial was sealed and the reaction was stirred at 70 ℃ for 16 hours. The reaction was then cooled and the crude mixture was purified directly by silica gel chromatography (eluent: etOAc/hexane). The purified material was dissolved in MeOH (1 mL) and potassium carbonate (saturated aqueous solution, 0.5 mL) was added. The mixture was stirred at 40 ℃ overnight. LCMS showed removal of the Boc group and the mixture was diluted with EtOAc (30 mL) and water (5 mL). The layers were separated and the organic layer was washed with brine (5 mL). The organic layer was dried over MgSO 4 Drying, filtration and concentration under reduced pressure gives the product as a mixture of diastereomers (any designated stereochemistry), which is continued.
Tert-butyl (3 aR,6 aS) -5- (4-isopropyl-3-methyl-5- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -2- ((3 aR,6 aS) -octahydrocyclopenta [ C ] pyrrol-5-yl) -6H-thieno [2,3-b ] pyrrole (example 69 and example 69 a) to a small bottle containing (3 aR,6 aS) -5- (4-isopropyl-3-methyl-5- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -6H-thieno [2,3-b ] pyrrol-2-yl) hexahydrocyclopenta [ C ] pyrrol-2 (1H) -carboxylic acid tert-butyl ester (70 mg, O.135 mmol) and trifluoroacetic acid (1 mL) were added to a small bottle of dichloromethane (1 mL) and a mixture of (1.35 mL of tri-fluoroacetic acid, TFS) and the mixture was directly evaporated in a small vacuum flask at room temperature in 1.35% water (1.35 mL of TFA, 110% water and vacuum, and stirred at 0.20% water, 250 x 21.2 mm) to give two isomers (any given stereochemistry), first eluted product example 69 and second eluted product example 69a.
Example 69：
ES/MS：420.2(M+H + )。 1 H NMR(400MHz，MeOD)δ10.88(s，1H)，8.59(d，J＝1.7Hz，1H)，8.45(s，1H)，7.58(t，J＝1.4Hz，1H)，3.73(td，J＝11.6，5.9Hz，2H)，3.66(dd，J＝11.1，7.4Hz，2H)，3.15-2.97(m，5H)，2.68(t，J＝0.9Hz，3H)，2.49(s，3H)，2.07(dd，J＝13.3，6.4Hz，2H)，1.94(td，J＝12.8，7.0Hz，2H)，1.41(d，J＝7.1Hz，6H)。
Procedure 15, example 70：
2- ((3 aR,6 aS) -5- (4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrol-2-yl) hexahydrocyclopenta [ c ]]Pyrrole-2 (1H) -yl) acetamide (example 70): to 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- ((3 ar,6 as) -octahydrocyclopentyl [ c]Pyrrol-5-yl) -6H-thieno [2,3-b]To a solution of pyrrole trifluoroacetic acid (example 69) (20 mg,0.0386 mmol) in 1, 2-dichloroethane (6 mL) was added 2-bromoacetamide (8 mg,0.058 mmol) and 1, 8-diazabicyclo [5.4.0]Undec-7-ene (0.023 mL,0.16 mmol). The mixture was stirred at room temperature overnight. To the mixture was added 0.2mL TFA followed by removal of DCE under reduced pressure. Acetonitrile (0.5 mL) and water (0.2 mL) were added and the mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18 110 Angstrom, 250X 21.2 mm) to give the title compound example 70. ES/MS:477.3 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.59(dd，J＝1.6，0.8Hz，1H)，8.47(s，1H)，7.59(t，J＝1.4Hz，1H)，4.15(s，2H)，4.02(s，2H)，3.10(s，2H)，2.93(t，J＝9.9Hz，2H)，2.68(t，J＝0.9Hz，3H)，2.51(s，3H)，2.05(dd，J＝13.2，6.0Hz，2H)，1.41(d，J＝7.1Hz，6H)。
Program 16Example 71：
2- ((3 aR,6 aS) -5- (4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b ]Pyrrol-2-yl) hexahydrocyclopenta [ c ]]Pyrrole-2 (1H) -yl) acetamide (example 71): to 4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- ((3 ar,6 as) -octahydrocyclopentyl [ c]Pyrrol-5-yl) -6H-thieno [2,3-b]To a solution of pyrrole trifluoroacetic acid (example 69 a) (10 mg,0.019 mmol) in 1, 2-dichloroethane (3 mL) was added 2-bromoacetamide (4 mg,0.029 mmol) and 1, 8-diazabicyclo [5.4.0]Undec-7-ene (0.012 mL,0.08 mmol). The mixture was stirred at room temperature overnight. To the mixture was added 0.1mL TFA followed by removal of DCE under reduced pressure. Acetonitrile (0.5 mL) and water (0.2 mL) were added and the mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18 110 Angstrom, 250X 21.2 mm) to give the title compound example 71.ES/MS:477.3 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.60(dd，J＝1.7，0.8Hz，1H)，8.49(s，1H)，7.63-7.57(m，1H)，4.05(t，J＝22.5Hz，3H)，3.73(d，J＝11.6Hz，2H)，3.32-3.24(m，3H)，3.13(s，1H)，3.06(s，1H)，2.69(t，J＝0.9Hz，3H)，2.46(s，5H)，1.63(q，J＝12.1Hz，2H)，1.40(d，J＝7.1Hz，6H)。
Procedure 17, example 72：
(1S, 4R, 5R) -5- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester: 2-bromo-5- (7, 8-dimethyl- [1,2, 4) was added to the dry vial]Triazolo [1,5-a ] ]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3 ]b]Pyrrole-6-carboxylic acid tert-butyl ester (I-16) (500 mg,0.993 mmol), (1S, 4S, 5R) -5-iodo-2-azabicyclo [2.2.1 ]]Heptane-2-carboxylic acid tert-butyl ester (I-31) (481mg, 1.49 mmol), tetrabutylammonium iodide (TBAI) (440 mg,1.19 mmol), ni (dtbbpy) (H 2 O) 4 Cl 2 (46.7 mg,0.099 mmol) and zinc powder (387 mg,5.96 mmol). Anhydrous DMA (5 mL) was added and the mixture was degassed with argon for 1 minute. The vial was sealed and the reaction was stirred at 70 ℃ for 16 hours. The reaction was then cooled and the crude mixture was purified directly by silica gel chromatography (eluent: etOAc/hexane). The purified material was dissolved in MeOH (3 mL) and potassium carbonate (saturated aqueous solution, 1.5 mL) was added. The mixture was stirred at 50 ℃ overnight. The mixture was diluted with EtOAc (60 mL) and water (6 mL). The layers were separated and the organic layer was washed with brine (5 mL). The organic layer was dried over MgSO 4 Dried, filtered, and concentrated under reduced pressure to give the title product. ES/MS:520.3 (M+H) + )。
2- ((1S, 4R, 5R) -2-azabicyclo [ 2.2.1)]Hept-5-yl) -5- (7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole (example 72): to (1S, 4R, 5R) -5- (5- (7, 8-dimethyl- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -2-azabicyclo [2.2.1]To a vial of tert-butyl heptane-2-carboxylate (350 mg,0.673 mmol) was added methanol (3 mL). HCl (4M in dioxane, 2.02ml,8.08 mmol) was added and the mixture was stirred at room temperature for 16 hours. The volatiles were then evaporated under reduced pressure and the residue was triturated with acetonitrile (2 mL) and dried under reduced pressure to give the desired compound as the HCl salt. The mixture was dissolved in acetonitrile (2 mL), water (1.5 mL) and trifluoroacetic acid (0.5 mL), and the crude material was filtered through acrodisc and purified directly by RP-HPLC (0.1% tfA-ACN/0.1% tfa water, column: gemini 5 μm, NX-C18 a, 250 x 21.2 mm) to give the title compound example 72 as trifluoroacetate salt. ES/MS:420.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.57 (s, 1H), 8.44 (s, 1H), 4.22 (s, 1H), 3.61-3.44 (m, 1H), 3.28-3.25 (m, 2H), 3.06 (p, j=7.1 hz, 1H), 2.79 (s, 1H), 2.64 (s,3H)，2.53-2.39(m，4H)，2.31-2.25(m，4H)，2.02-1.91(m，1H)，1.82(d，J＝11.8Hz，1H)，1.30(d，J＝7.5Hz，3H)，1.23(d，J＝7.0Hz，3H)。
the following examples were prepared in a similar manner according to procedure 17 and are shown in table 8 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 17 were used, and these reagents/starting materials are noted in the last column of table 8- "change in procedure 17: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 17 are replaced with different reagents/starting materials described below.
Procedure 18, example 77：
2- (3- (tert-Butoxycarbonyl) -3-azabicyclo [ 4.1.0)]Hept-6-yl) -5- (7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester: to a mixture containing 2-bromo-5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-thieno [2,3-b]To 10:1 toluene of pyrrole-6-carboxylic acid tert-butyl ester (I-16) (200 mg,0.40 mmol) and aqueous solution (13 mL) was added 6- (trifluoromethylboryl) -3-azabicyclo [4.1.0]Tert-butyl heptane-3-carboxylate, potassium salt (193 mg,0.64 mmol),APd G3 (28.9 mg,0.040 mmol) and cesium carbonate (3838 mg,1.2 mmol). The reaction mixture was taken up in N 2 Heat to 100 ℃ for 16 hours. The reaction mixture was dried over sodium sulfate, filtered through celite, eluted with DCM, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (0% -100% etoac/hexanes) to giveTo the title product. ES/MS:620.4 (M+H) + )。
2- (3-azabicyclo [ 4.1.0)]Hept-6-yl) -5- (7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole (example 77): 2- (3-tert-Butoxycarbonyl-3-azabicyclo [ 4.1.0) ]Hept-6-yl) -5- (7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (230 mg,0.37 mmol) was added to a vial containing acetonitrile and trifluoroacetic acid (1:1 mixture, 5 mL) and the reaction mixture was stirred at 80 ℃ until the reaction was complete. The reaction mixture was concentrated under reduced pressure and the crude material was dissolved in acetonitrile (1 mL), water (0.5 mL) and trifluoroacetic acid (0.1 mL) and the crude material was purified directly by RP-HPLC (0.1% tfA-ACN/0.1% tfa water, column: gemini 5 μm, NX-C18 a, 250 x 21.2 mm) to give the title compound example 77 as trifluoroacetate salt. ES/MS:420.3 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.59(s，1H)，8.47(s，1H)，3.83(dd，J＝13.5，7.4Hz，1H)，3.24(dd，J＝12.9，5.5Hz，1H)，3.11-2.91(m，3H)，2.65(s，3H)，2.54(s，3H)，2.39(tp，J＝15.0，5.2Hz，3H)，2.27(s，3H)，1.71(d，J＝7.5Hz，1H)，1.44-1.36(m，1H)，1.32-1.20(m，7H)。
Procedure 19, example 78：
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3- (((trifluoromethyl) sulfonyl) oxy) -1-oxa-8-azaspiro [4.5 ]]Dec-3-ene-8-carboxylic acid tert-butyl ester: to 3-oxo-1-oxa-8-azaspiro [4.5 ] under nitrogen at-78deg.C]To a solution of tert-butyl decane-8-carboxylate (1.00 g,3.92 mmol) in dry THF (26 mL) was added LiHMDS (983 mg,5.88 mmol) dropwise. After 20 minutes, a solution of N-phenyltrifluoromethanesulfonyl imide (1.82 g,5.09 mmol) in THF (5 mL) was added and the reaction was gradually warmed to 0deg.C and stirred for 3 hours. The reaction was taken up with saturated NaHCO 3 The aqueous solution (10 mL) was quenched and the resulting mixture was concentrated under reduced pressure. Passing the residue throughFlash chromatography was purified using EtOAc/hexanes as the eluent to give the title product. 1 H NMR(400MHz，CDCl3)δ5.76(t，J＝2.2Hz，1H)，4.66(d，J＝2.1Hz，2H)，3.77(dt，J＝9.1，4.4Hz，2H)，3.27(ddd，J＝13.9，8.5，5.6Hz，2H)，1.76-1.63(m，4H)，1.48(s，9H)。
3- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1-oxa-8-azaspiro [4.5 ]]Dec-3-ene-8-carboxylic acid tert-butyl ester: 3- (((trifluoromethyl) sulfonyl) oxy) -1-oxa-8-azaspiro [4.5 ] was added to 50mL RBF]Tert-butyl dec-3-ene-8-carboxylate (0.78 g,2.02 mmol), bis (pinacolato) diboron (0.62 g,2.42 mmol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium (II) dichloride (0.15 g,0.20 mmol) and potassium propionate (0.68 g,6.06 mmol). The mixture was dissolved in 1, 4-dioxane (10 mL) and nitrogen was bubbled into the reaction mixture for 3 minutes. The mixture was heated at 80 ℃ under nitrogen for 3 hours. The mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: etOAc/hexane) to give the title product. ES/MS:388.3[ M+23 ]]。 1 H NMR(400MHz，CDCl3)δ6.40(t，J＝2.4Hz，1H)，4.77(d，J＝2.4Hz，2H)，3.73(m，2H)，3.31(ddd，J＝13.6，10.0，3.7Hz，2H)，1.72-1.55(m，4H)，1.48(s，9H)，1.29(d，J＝10.1Hz，12H)。
3- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -1-oxa-8-azaspiro [4.5 ]Decane (example 78): 2-bromo-5- (7, 8-dimethyl- [1,2, 4) was added to MW vial]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-16) (0.100 g,0.20 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1-oxa-8-azaspiro [4.5 ]]Tert-butyl dec-3-ene-8-carboxylate (0.87 g,0.24 mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (0.014 g,0.02 mmol) and 1.0M potassium acetate/1.5M sodium carbonate (0.5 mL). The mixture was dissolved in acetonitrile (3 mL) and nitrogen was bubbled into the reaction mixture for 3 minutes. The mixture was heated in MW at 140℃for 45 min. The mixture was cooled to room temperature, diluted with EtOAc, filtered through celite, washed with excess EtOAc, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: etOAc/hexanes) to give the olefin intermediate: 3- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -1-oxa-8-azaspiro [4.5]Dec-3-ene-8-carboxylic acid tert-butyl ester. The material was dissolved in EtOH (4 mL) and a spoon of palladium on carbon (10%) was added and the resulting mixture was stirred under a hydrogen atmosphere for two days. The reaction mixture was filtered through celite and the filtrate was concentrated to dryness. The residue was then dissolved in DCM (2 mL) and treated with TFA (0.3 mL). The mixture was stirred at room temperature for 1 hour and the volatiles were evaporated under reduced pressure. Acetonitrile (0.5 mL) and water (0.2 mL) were added and the mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18110 angstroms, 250X 21.2 mm) to give product example 78 as trifluoroacetate salt. ES/MS:464.2[ M+H ] + ]。 1 H NMR(400MHz，MeOD)δ8.61(s，1H)，8.49(s，1H)，4.26(t，J＝7.9Hz，1H)，4.07(p，J＝8.5Hz，1H)，3.79(t，J＝8.8Hz，1H)，3.33-3.26(m，4H)，3.05(hept，J＝7.1Hz，1H)，2.65(s，3H)，2.48-2.38(m，4H)，2.28(s，3H)，2.13-1.84(m，5H)，1.40-1.12(m，6H)。
Procedure 20, example 79
2- ((1S, 4R, 5R) -5- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -2-azabicyclo [2.2.1]Hept-2-yl) acetamide (example 79): to 2- ((1S, 4R, 5R) -2-azabicyclo [ 2.2.1)]Hept-5-yl) -5- (7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]To a solution of pyrrole (HCl salt) (example 72) (460 mg,1.01 mmol) in 1, 2-dichloroethane (18 mL) was added 2-bromoacetamide (67 mg, 1)21 mmol) and 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU) (0.6 mL,4 mmol). The mixture was stirred at room temperature overnight. To the mixture was added 1mL TFA followed by removal of DCE under reduced pressure. Acetonitrile (5 mL) and water (5 mL) were added and the mixture was gently heated. The mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18A, 250X 21.2 mm) to give the title compound example 79 as trifluoroacetate salt. ES/MS:477.3 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 10.76 (s, 1H), 8.58 (s, 1H), 8.46 (s, 1H), 4.34-3.96 (m, 3H), 3.76 (dd, j=25.5, 11.6hz, 1H), 3.67-3.48 (m, 1H), 3.22-2.97 (m, 2H), 2.84-2.71 (m, 1H), 2.64 (s, 3H), 2.48 (s, 3H), 2.41-2.20 (m, 4H), 2.12 (d, j=12.1 hz, 1H), 2.09-1.91 (m, 2H), 1.30 (d, j=7.0 hz, 3H), 1.23 (d, j=7.2 hz, 3H).
The following examples were prepared in a similar manner according to procedure 20 and are shown in table 9 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 20 were used, and these reagents/starting materials are noted in the last column of table 9- "change in procedure 20: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 20 are replaced with different reagents/starting materials described below.
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Program 21: example 85 and example 86：
2- (2- (5- (7, 8-dimethyl- [1,2, 4))]The amino acid is a triazolo [1 ],5-a]pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -6-azaspiro [3.4]Oct-6-yl) acetamide (example 85 and example 86): 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-2- (6-azaspiro [3.4 ]]Oct-2-yl) -6H-thieno [2,3-b]Pyrrole (example 75) was purified by chiral SFC (AD-H4.6X100 mm with 35% EtOH-NH) 3 Cosolvents) to give two different stereoisomers. These isomers were reacted separately according to the conditions in procedure 20 to give two diastereomers, arbitrarily designated isomer 1 (example 85) and isomer 2 (example 86):
Isomer 1:2- (2- (5- (7, 8-dimethyl- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -6-azaspiro [3.4]Oct-6-yl) acetamide (example 85). ES/MS:491.3[ M+H ] + ]。 1 H NMR(400MHz，MeOD)δ8.60(s，1H)，8.50(s，1H)，4.18-3.69(m，5H)，3.32-3.09(m，2H)，3.03(hept，J＝7.1Hz，1H)，2.78-2.19(m，15H)，1.31-1.15(m，6H)。
Isomer 2:2- (2- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -6-azaspiro [3.4]Oct-6-yl) acetamide (example 86). ES/MS:491.3[ M+H ] + ]。 1 H NMR(400MHz，MeOD)δ8.60(s，1H)，8.50(s，1H)，4.18-3.69(m，5H)，3.32-3.09(m，2H)，3.03(hept，J＝7.1Hz，1H)，2.78-2.19(m，15H)，1.31-1.15(m，6H)。
Program 22: examples 87 and 88：
2- (3- (5- (7, 8-dimethyl- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -1-oxa-8-azaspiro [4.5]Dec-8-yl) acetamide (example 87 and example 88): 3- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno[2，3-b]Pyrrol-2-yl) -1-oxa-8-azaspiro [4.5]Decane (example 78) was prepared by chiral SFC (IG 4.6X100mm 5mic with 40% IPA-NH) 3 Cosolvents) to give two different stereoisomers. These isomers were reacted separately according to the conditions in procedure 20 to give two enantiomers, arbitrarily designated isomer 1 (example 87) and isomer 2 (example 88):
Isomer 1:2- (3- (5- (7, 8-dimethyl- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -1-oxa-8-azaspiro [4.5]Dec-8-yl) acetamide (example 87). ES/MS:521.2[ M+H ] + ]。 1 H NMR(400MHz，MeOD)δ8.61(s，1H)，8.49(d，J＝7.1Hz，1H)，4.26(t，J＝8.0Hz，1H)，4.15-3.93(m，3H)，3.82(dt，J＝17.5，8.7Hz，1H)，3.57(d，J＝11.8Hz，2H)，3.38(d，J＝11.6Hz，2H)，3.05(hept，J＝7.1Hz，1H)，2.65(s，3H)，2.46(s，4H)，2.28(s，3H)，2.21-1.87(m，5H)，1.38-1.15(m，6H)。
Isomer 2:2- (3- (5- (7, 8-dimethyl- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -1-oxa-8-azaspiro [4.5]Dec-8-yl) acetamide (example 88). ES/MS:521.3[ M+H ] + ]。 1 H NMR(400MHz，MeOD)δ8.61(s，1H)，8.49(d，J＝7.1Hz，1H)，4.26(t，J＝8.0Hz，1H)，4.15-3.93(m，3H)，3.82(dt，J＝17.5，8.7Hz，1H)，3.57(d，J＝11.8Hz，2H)，3.38(d，J＝11.6Hz，2H)，3.05(hept，J＝7.1Hz，1H)，2.65(s，3H)，2.46(s，4H)，2.28(s，3H)，2.21-1.87(m，5H)，1.38-1.15(m，6H)。
Program 23: example 89 and example 90：
2- (5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl) -5-oxa-8-azaspiro [3.5] nonane (example 88 and example 90): 2- (5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl) -5-oxa-8-azaspiro [3.5] nonane (example 76) was separated as a mixture of 2 stereoisomers by chiral SFC (IG 4.6x100mm 5mic with 35% ipa-NH3 co-solvent) to give two different diastereomers, which were arbitrarily designated as isomer 1 (example 89) and isomer 2 (example 90).
Isomer 1:2- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -5-oxa-8-azaspiro [3.5]Nonane (example 89). ES/MS:450.3[ M+H ] + ]。 1 H NMR(400MHz，MeOD)δ8.60(s，1H)，8.48(d，J＝1.1Hz，1H)，3.88(dd，J＝6.0，4.0Hz，2H)，3.64(p，J＝9.0Hz，1H)，3.43(s，2H)，3.26-3.15(m，2H)，3.03(hept，J＝7.2Hz，1H)，2.88-2.71(m，2H)，2.65(s，3H)，2.40(s，3H)，2.26(d，J＝17.1Hz，5H)，1.35-1.14(m，6H)。
Isomer 2:2- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -5-oxa-8-azaspiro [3.5]Nonane (example 90). ES/MS:450.3[ M+H ] + ]。 1 H NMR(400MHz，MeOD)δ8.57(s，1H)，8.43(s，1H)，4.08(p，J＝8.6Hz，1H)，4.00-3.90(m，2H)，3.29-3.12(m，4H)，3.03(hept，J＝7.0Hz，1H)，2.84-2.70(m，2H)，2.64(s，3H)，2.44-2.20(m，8H)，1.35-1.18(m，6H)。
The following examples were prepared in a similar manner according to the reference procedure and are shown in table 10 below. To prepare the following examples, reagents/starting materials different from some of those described in the reference procedure were used, and these reagents/starting materials are noted in the last column of table 10- "change in reference procedure: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of the reference procedure are replaced with different reagents/starting materials described below.
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Program 24: example 100 and example 101：
2- ((1 s,4r,5 r) -5- (5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl) -2-azabicyclo [2.2.1] hept-2-yl) propanamide (example 100 and example 101): 2- ((1S, 4R, 5R) -5- (5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl) -2-azabicyclo [2.2.1] hept-2-yl) propionamide (example 95) was separated as a mixture of 2 stereoisomers by chiral SFC (AD-H4.6X100 mm column with 35% MeOH-DEA co-solvent) to give two different diastereomers, which were arbitrarily designated as isomer 1 (example 100) and isomer 2 (example 101).
Isomer 1:2- ((1S, 4R, 5R) -5- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -2-azabicyclo [2.2.1]Hept-2-yl) propanamide (example 100). ES/MS:491.9 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 10.76 (s, 1H), 8.57 (s, 1H), 8.43 (s, 1H), 4.31 (s, 1H), 4.13 (d, 1H), 4.04 (s, 1H), 3.89 (q, 1H), 3.74 (dd, 1H), 3.58 (dt, 1H), 3.47 (d, 1H), 3.06 (p, 1H), 2.95 (d, 1H), 2.78 (d, 1H), 2.64 (s, 3H), 2.48 (d, 3H), 2.38 (d, 1H), 2.26 (s, 3H), 2.04 (d, 2H), 1.60 (dd, 3H), 1.26 (dd, 6H).
Isomer 2:2- ((1S,4R, 5R) -5- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -2-azabicyclo [2.2.1]Hept-2-yl) propanamide (example 101). ES/MS:491.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 10.76 (s, 1H), 8.57 (s, 1H), 8.42 (s, 1H), 4.41 (d, 1H), 4.10-3.87 (m, 1H), 3.72 (d, 1H), 3.64-3.52 (m, 1H), 3.20-2.98 (m, 2H), 2.79 (s, 1H), 2.64 (s, 3H), 2.49 (d, 3H), 2.34 (d, 1H), 2.26 (s, 3H), 2.11-1.94 (m, 2H), 1.68 (dd, 3H), 1.26 (dd, 6H).
Program 25: example 102 and example 103：
2- [6- [5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl ] -3-azabicyclo [4.1.0] hept-3-yl ] acetamide (examples 102 and 103): 2- [6- [5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl ] -3-azabicyclo [4.1.O ] hept-3-yl ] acetamide (example 89) was isolated as a mixture of 2 stereoisomers by chiral SFC (AD-H column with 35% IPA-NH3 co-solvent) to give the two enantiomers, which were arbitrarily designated as isomer 1 (example 102) and isomer 2 (example 103).
Isomer 1:2- [6- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]-3-azabicyclo [4.1.0]Hept-3-yl]Acetamide (example 102) ES/MS:477.2 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.60(s，1H)，8.50(s，1H)，4.00(d，J＝60.9Hz，4H)，3.03(p，J＝7.1Hz，2H)，2.65(s，3H)，2.55(s，6H)，2.27(s，3H)，1.77(s，1H)，1.50-1.10(m，10H)。
Isomer 2:2- [6- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]-3-azabicyclo [4.1.0]Hept-3-yl]Acetamide (example 103). ES/MS:477.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.46-8.41 (m, 1H), 8.12 (dd, j=8.6, 1.5hz, 1H), 7.82 (t, j=7.8 hz, 1H), 7.74-7.67 (m, 2H), 7.62 (dd, j=8.0, 1.5hz, 1H), 7.57 (d, j=9.0 hz, 2H), 7.23 (dd, j=7.6, 1.7hz, 1H), 7.06-6.97 (m, 2H), 4.76 (t, j=5.0 hz, 2H), 4.69 (s, 2H), 3.84 (t, j=4.9 hz, 2H), 3.32 (s, 3H), 2.17 (d, j=1.0 hz, 3H).
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Program 26: example 238 and example 239：
(3- (5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl) cyclobutyl) (piperazin-1-yl) methanone (example 238 and example 240): (3- (5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl) cyclobutyl) (piperazin-1-yl) methanone (example 151) was isolated as a mixture of 2 stereoisomers by chiral SFC (CCO-F2 column with 25% meoh co-solvent) to give two isomers, the cis/trans stereochemistry of which was arbitrarily designated as isomer 1 and isomer 2.
Isomer 1: (3- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ]Pyrrol-2-yl) cyclobutyl) (piperazin-1-yl) methanone (example 238): ES/MS:491.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.62 (s, 1H), 8.53 (s, 1H), 4.00 (t, j=8.4 hz, 1H), 3.94-3.83 (m, 2H), 3.76-3.66 (m, 2H), 3.49 (dq, j=9.3, 4.7hz, 1H), 3.31-3.22 (m, 4H), 3.02 (dq, j=14.6, 7.3hz, 1H), 2.79 (ddd, j=13.0, 6.8,3.4hz, 2H), 2.65 (s, 3H), 2.57-2.44 (m, 2H), 2.36 (s, 3H), 2.30 (s, 3H), 1.34-1.21 (m, 6H).
Isomer 2: (3- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) cyclobutyl) (piperazin-1-yl) methanone (example 239): ES/MS:491.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.59 (s, 1H), 8.47 (s, 1H), 3.97-3.72 (m, 5H), 3.42 (p, j=9.0 hz, 1H), 3.29-3.22 (m, 4H), 3.03 (p, j=7.1 hz, 1H), 2.70 (qd, j=8.1, 2.5hz, 2H), 2.65 (s, 3H), 2.45-2.33 (m, 4H), 2.28 (s, 3H), 1.32-1.17 (m, 6H).
Program 27: examples 240 and 241：
(R) -3- (5- (3- (5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl) cyclobutyl) -1,3, 4-oxadiazol-2-yl) morpholine: to a solution of 3- (5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl) cyclobutane-1-carboxylic acid (I-40) (75 mg,0.177 mmol) in THF (1.0 mL) was added tert-butyl (R) -3- (hydrazinocarbonyl) morpholine-4-carboxylate (I-41) (56.6 mg,0.231 mmol), 2- (7-aza-1H-benzotriazol-1-yl) -1, 3-tetramethylurea Hexafluorophosphate (HATU) (80.9 mg,0.213 mmol) and N, N-diisopropylethylamine (0.06 mL,0.36 mmol), and the reaction mixture was stirred overnight at room temperature. Subsequently, a berg reagent (127 mg,0.532 mmol) was added to the reaction mixture. The mixture was stirred at 60℃for 2 hours. TFA (1 mL) was added and the reaction was heated at 45 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure, and acetonitrile and water were added. The mixture was filtered through acrodisc and purified by RP-HPLC (eluent: water/MeCN 0.1% tfa) to give the product as two separable trans and cis isomers, the stereochemistry of which was arbitrarily designated as isomer 1 and isomer 2.
Isomer 1: example 240.ES/MS:532.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.59 (s, 1H), 8.45 (s, 1H), 5.05 (dd, j=8.8, 3.7hz, 1H), 4.43 (dd, j=12.8, 3.7hz, 1H), 4.28 (p, j=8.6 hz, 1H), 4.18-4.00 (m, 2H), 3.99-3.76 (m, 2H), 3.65-3.54 (m, 1H), 3.53-3.40 (m, 1H), 3.04 (p, j=7.0 hz, 1H), 2.92 (tt, j=8.6, 4.0hz, 2H), 2.76 (q, j=10.3, 9.7hz, 2H), 2.65 (s, 3H), 2.39 (s, 3H), 2.29 (s, 3H), 1.29 (d, j=7.40 (m, 1H), 3.04 (p, j=7.0 hz, 1H).
Isomer 2: example 241.ES/MS:532.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.57 (s, 1H), 8.43 (s, 1H), 5.02 (dd, J=8.8, 3.7Hz, 1H), 4.40 (dd, J=12.8, 3.7Hz, 1H), 4.17-3.98 (m, 3H), 3.96-3.72 (m, 2H), 3.61-3.38(m，2H)，3.09-2.88(m，3H)，2.64(s，3H)，2.57(d，J＝10.5Hz，2H)，2.43(s，3H)，2.28(s，3H)，1.29(d，J＝7.2Hz，3H)，1.22(d，J＝7.0Hz，3H)。
The following examples were prepared in a similar manner according to procedure 27 and are shown in table 12 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 27 were used, and these reagents/starting materials are noted in the last column of table 12— "change in procedure 27: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 27 are replaced with different reagents/starting materials described below.
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Program 28: example 244 and example 245：
3- (1- (3- (5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl) cyclobutyl) -1H-1,2, 3-triazol-4-yl) morpholine: to 3- (5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl) cyclobutan-1-amine; to a solution of trifluoroacetate (I-52) (65 mg, O.165 mmol) in MeOH (2.0 mL) was added potassium carbonate (70 mg,0.50 mmol), 1H-imidazole-1-sulfonyl azide; sulfate (68 mg,0.25 mmol), copper sulfate; pentahydrate (7 mg,0.025 mmol) and the reaction mixture was stirred at room temperature for 2 hours. Subsequently, acetic acid (0.05 mL,0.8 mmol) was added to the reaction mixture. To the reaction was added THF (1 mL), 3-ethynyl morpholine-4-carboxylic acid tert-butyl ester (I-43) (53 mg, O.25 mmol) and copper (26.5 mg, O.417 mmol). The mixture was stirred at room temperature for 1 hour. The crude mixture was purified directly by silica gel chromatography (eluent: etOAc/hexane). The purified material was dissolved in ACN (1 mL) and TFA (o.5 mL) and the reaction was heated at 35 ℃ for 1 hour. Water (0.5 mL) was added and the mixture was filtered through acrodisc and purified by RP-HPLC (eluent: water/MeCN. 1% TFA) to give the product as two separable trans and cis isomers, the stereochemistry of which was arbitrarily designated as isomer 1 and isomer 2.
Isomer 1: example 244.ES/MS:531.3 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.59 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 5.39 (p, j=7.1 hz, 1H), 4.76 (dd, j=9.8, 3.7hz, 1H), 4.38-4.19 (m, 2H), 4.13 (d, j=13.0 hz, 1H), 4.01 (dd, j=12.8, 9.9hz, 1H), 3.90 (dt, j=13.1, 6.7hz, 1H), 3.43 (dd, j=6.8, 3.1hz, 2H), 3.21-2.96 (m, 3H), 2.88 (dt, j=13.5, 7.7hz, 2H), 2.65 (s, 3H), 2.40 (s, 3H), 2.29 (s, 3H), 1.30 (j=13.1, 6.7hz, 1H), 3.21-2.96 (m, 3H).
Isomer 2: example 245.ES/MS:531.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.58 (s, 1H), 8.43 (s, 1H), 8.23 (s, 1H), 5.17 (q, j=8.2 hz, 1H), 4.74 (dd, j=9.9, 3.6hz, 1H), 4.25 (dd, j=12.7, 3.7hz, 1H), 4.12 (d, j=12.9 hz, 1H), 3.99 (dd, j=12.8, 10.0hz, 1H), 3.89 (p, j=6.3 hz, 2H), 3.46-3.39 (m, 2H), 3.14 (d, j=10.2 hz, 2H), 3.05 (p, j=7.1 hz, 1H), 2.73 (q, j=10.2 hz, 2H), 2.65 (s, 3H), 2.45 (s, 3H), 2.28 (d, 3.0hz, 3.3H), 3.46-3.39 (m, 2H), 3.14 (d, j=10.2 hz, 2H).
Program 29: example 246：
4- (4-isopropyl-5- (8-methoxy- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-6-yl) -3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) piperidine-1-carboxylic acid tert-butyl ester: 4- (4-isopropyl-3-methyl-6H-thieno [2, 3-b)]A solution of tert-butyl pyrrol-2-yl) piperidine-1-carboxylate (I-54) (75 mg, O.207 mmol) in ACN (4 mL) was cooled to 0deg.C and N-bromoamber was added dropwiseImide (35 mg, 0.197mmol) (dissolved in 1mL ACN). After the addition was complete, LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure. The crude residue was dissolved in DME (1 mL) and the solution was added to a solution containing 8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) - [1,2,4]Triazolo [1,5-a ]]Pyridine (I-51) (114 mg,0.414 mmol), XPhos Pd G3 (26 mg,0.031 mmol) and cesium carbonate (202 mg,0.621 mmol). Water (0.2 mL) was added and the mixture was degassed with argon for 30 seconds. The vial was sealed and the mixture was heated in a microwave oven at 120 ℃ for 15 minutes. The crude mixture was purified directly by silica gel chromatography (eluent EtOAc/hexanes). ES/MS:510.2 (M+H) + )。
4-isopropyl-5- (8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -3-methyl-2- (piperidin-4-yl) -6H-thieno [2,3-b ]Pyrrole (example 246): to a catalyst containing 4- (4-isopropyl-5- (8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -3-methyl-6H-thieno [2,3-b]To a vial of tert-butyl pyrrol-2-yl) piperidine-1-carboxylate (60 mg,0.118 mmol) was added acetonitrile (0.5 mL) and TFA (0.5 mL). The reaction was stirred at room temperature for 2 hours. Water (0.5 mL) was added and the mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18. Ang. 110, 250X 21.2 mm) to give the title compound, example 246.ES/MS:410.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.41 (s, 1H), 8.36 (d, j=1.3 hz, 1H), 7.13 (d, j=1.4 hz, 1H), 4.12 (s, 3H), 3.57-3.48 (m, 2H), 3.48-3.35 (m, 2H), 3.27-3.12 (m, 2H), 2.50 (s, 3H), 2.20 (d, j=14.2 hz, 2H), 1.90 (qd, j=13.2, 3.9hz, 2H), 1.42 (d, j=7.1 hz, 6H).
The following examples were prepared in a similar manner according to procedure 29 and are shown in table 13 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 29 were used, and these reagents/starting materials are noted in the last column of table 13— "change in procedure 29: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 29 are replaced with different reagents/starting materials described below.
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Program 30: example 253
N- ((1S, 4S) -5- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) bicyclo [2.2.1]Hept-2-yl) oxetan-3-amine (example 253): to 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-2- ((1S, 4S) -5-oxobicyclo [2.2.1]Hept-2-yl) -6H-thieno [2,3-b]To a solution of tert-butyl pyrrole-6-carboxylate (I-57) (100 mg,0.23 mmol) in THF (1 mL) and DMF (1 mL) was added acetic acid (0.02 mL), and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in anhydrous MeOH (4 mL). The mixture was cooled to-78 ℃ and sodium cyanoborohydride (73 mg,1.16 mmol) was added in one portion, stirred at that temperature for 3 hours, then allowed to come to room temperature. The reaction was quenched with water (1 mL) and the reaction was diluted with ethyl acetate. The layers were separated and the organic phase was washed with water over MgSO 4 Dried, filtered and concentrated under reduced pressure. The crude material was dissolved in MeOH (1.5 mL) and lithium hydroxide (20 mg,8 mmol) was added. The mixture was stirred at 70℃for 3 hours. The mixture was diluted with EtOAc (30 mL) and water (5 mL) in sequence. The organic phase was separated and concentrated. Acetonitrile (0.5 mL) and water (0.2 mL) were added and the mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18 110 Angstrom, 250X 21.2 mm) to give the trifluoroacetate salt as a solution The title compound of formula example 253.ES/MS:490.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 8.60 (s, 1H), 8.49 (s, 1H), 5.06-4.92 (m, 2H), 4.75 (dt, j=8.1, 4.9hz, 2H), 4.55 (tt, j=7.0, 5.4hz, 1H), 3.67-3.46 (m, 1H), 3.18-2.97 (m, 1H), 2.65 (s, 4H), 2.55-2.37 (m, 4H), 2.33-2.18 (m, 5H), 2.04 (d, j=10.9 hz, 1H), 1.84 (dt, j=14.7, 4.9hz, 1H), 1.57 (d, j=11.1 hz, 1H), 1.45-1.08 (m, 8H).
The following examples were prepared in a similar manner according to procedure 30 and are shown in table 14 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 30 were used, and these reagents/starting materials are noted in the last column of table 14— "change in procedure 30: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 30 are replaced with different reagents/starting materials described below.
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Procedure 31, examples 258 and 259：
4- (4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -3- (((triisopropylsilyl) oxy) methyl) -6H-thieno [2,3-b]Pyrrol-2-yl) piperidine-1-carboxylic acid tert-butyl ester: 2-bromo-4-isopropyl-5- (8-methyl- [1,2, 4) addition to the dry vial ]Triazolo [1,5-a ]]Pyridin-6-yl) -3- (((triisopropylsilyl) oxy) methyl) -6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-63) (170 mg,0.257 mmol), 4-iodopiperidine-1-carboxylic acid tert-butyl ester (95.9 mg,0.308 mmol),Tetrabutylammonium iodide (TBAI) (23.7 mg,0.064 mmol), ni (dtbbpy) (H 2 O) 4 Cl 2 (7.3 mg,0.015 mmol) and zinc powder (83.5 mg,1.28 mmol). Anhydrous DMA (3 mL) was added and the mixture was degassed with argon for 1 minute. The vial was sealed and the reaction was stirred at 70 ℃ for 16 hours. The reaction was then cooled and the crude mixture was purified directly by silica gel chromatography (eluent: etOAc/hexane). The purified material was dissolved in MeOH (1 mL) and potassium carbonate (saturated aqueous solution, 0.25 mL) was added. The mixture was stirred at 40 ℃ overnight. The mixture was diluted with EtOAc (60 mL) and water (6 mL). The layers were separated and the organic layer was washed with brine (5 mL). The organic layer was dried over MgSO 4 Drying, filtering and concentrating under reduced pressure to obtain the product. ES/MS:766.9 (M+H) + )。
(4-isopropyl-5- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -2- (piperidin-4-yl) -6H-thieno [2,3-b ] pyrrol-3-yl) methanol (example 258) and 4-isopropyl-3- (methoxymethyl) -5- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -2- (piperidin-4-yl) -6H-thieno [2,3-b ] pyrrole (example 259): to a vial containing tert-butyl 4- (4-isopropyl-5- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3- (((triisopropylsilyl) oxy) methyl) -6H-thieno [2,3-b ] pyrrol-2-yl) piperidine-1-carboxylate (87 mg,0.131 mmol) was added methanol (0.25 mL). HCl (4M in dioxane, 0.41ml,1.63 mmol) was added and the mixture was stirred at room temperature for 16 hours. The volatiles were evaporated under reduced pressure. The crude residue was dissolved in acetonitrile (2 mL), water (1.5 mL) and trifluoroacetic acid (0.5 mL), and the crude material was filtered through acrodisc and purified directly by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18A, 250X 21.2 mm) to give the title compounds example 258 and example 259 as trifluoroacetate salts.
Example 258: ES/MS:410.1 (M+H+). 1 H NMR (400 MHz, acetonitrile-d 3) δ9.40 (s, 1H), 8.57 (d, 1H), 8.34 (s, 1H), 7.64 (s, 2H), 7.49 (t, 1H), 4.80 (s, 2H), 3.52 (t, 3H), 3.35 (p, 1H), 3.13 (d, 2H), 2.65 (t, 3H), 1.35 (d, 6H).
Example 259: ES-MS：424.1(M+H + )。 1 H NMR (400 MHz, acetonitrile-d 3) δ9.44 (s, 1H), 8.57 (dd, 1H), 8.36 (s, 1H), 7.63 (s, 2H), 7.50 (q, 1H), 4.61 (s, 2H), 3.54-3.46 (m, 3H), 3.41 (s, 3H), 3.31 (p, 1H), 3.13 (d, 2H), 2.65 (d, 3H), 2.19-2.10 (m, 2H), 1.33 (d, 6H).
Procedure 32, example 260：
(R) - (4- (3- (hydroxymethyl) -4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrol-2-yl) piperidin-1-yl) (morpholin-3-yl) methanone (example 260): to a composition containing 3- (difluoromethyl) -4-isopropyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -2- (piperidin-4-yl) -6H-thieno [2,3-b]Pyrrole (HCl salt) (example 68) (15 mg,0.032 mmol) in 1, 2-dichloroethane (1 mL) was added ((R) -4- (tert-butoxycarbonyl) morpholine-3-carboxylic acid (9.7 mg,0.042 mmol), 2- (7-aza-1H-benzotriazol-1-yl) -1, 3-tetramethylurea Hexafluorophosphate (HATU) (12 mg,0.32 mmol) and N, N-diisopropylethylamine (0.02 mL,0.13 mmol) to a vial of ((R) -4- (tert-butoxycarbonyl) morpholine-3-carboxylic acid (9.7 mg,0.042 mmol), the mixture was stirred at room temperature for 16 hours TFA (0.25 mL) and the crude mixture was concentrated under reduced pressure and methanol (1 mL) and NaBH were added 4 (5 mg,0.13 mmol). The mixture was stirred for 1 hour and then quenched with water. The crude mixture was concentrated under reduced pressure, and acetonitrile (0.7 mL) and water (0.15 mL) were added. The mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18A, 250X 21.2 mm) to give the title compound example 260 as trifluoroacetate salt. ES/MS:523.1 (M+H) + )。
1 H NMR (400 MHz, methanol-d 4) delta 8.61 (dd, 1H), 8.46 (s, 1H), 7.58 (d, 1H), 4.72 (dd, 1H), 4.66 (d, 1H), 4.28 (dd, 1H), 4.06 (t, 2H), 3.88-3.75 (m, 1H), 3.75-3.63 (m, 1H), 3.61-3.47 (m, 1H), 3.43-3.35 (m, 3H), 2.90 (t, 1)H)，2.68(d，3H)，2.18(dd，2H)，1.81-1.55(m，2H)，1.41(d，6H)。
The following examples were prepared in a similar manner according to procedure 32 and are shown in table 15 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 32 were used, and these reagents/starting materials are noted in the last column of table 15— "change in procedure 32: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 32 are replaced with different reagents/starting materials described below.
TABLE 15
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Program 33: example 262 and example 263：
2- (4- (4-isopropyl-3-methyl-5- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -6H-thieno [2,3-b ] pyrrol-2-yl) azepan-1-yl) acetamide (examples 262 and 263): 2- (4- (4-isopropyl-3-methyl-5- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -6H-thieno [2,3-b ] pyrrol-2-yl) azepan-1-yl) acetamide (example 161) in the form of a mixture of 2 stereoisomers was separated by chiral SFC (ia4.6x100mm column with 40% meoh-DEA co-solvent) to give two enantiomers whose stereochemistry was arbitrarily partitioned into isomer 1 and isomer 2.
Isomer 1:2- (4- (4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrol-2-yl) azepan-1-yl) acetamide (example 262): ES/MS:465.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d) 4 )δ8.58(s，1H)，8.43(s，1H)，7.57(s，1H)，3.43-3.37(m，1H)，3.31-3.24(m，3H)，2.99-2.85(m，5H)，2.68(d，3H)，2.45(s，3H)，2.17-2.04(m，1H)，2.03-1.90(m，1H)，1.90-1.77(m，2H)，1.40(d，6H)。
Isomer 2:2- (4- (4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -6H-thieno [2,3-b]Pyrrol-2-yl) azepan-1-yl) acetamide (example 263): ES/MS:465.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d) 4 )δ8.58(s，1H)，8.44(s，1H)，7.57(s，1H)，3.44-3.36(m，1H)，3.31-3.23(m，3H)，3.13-3.00(m，5H)，2.68(s，3H)，2.45(s，3H)，2.22-2.08(m，1H)，2.08-1.95(m，1H)，1.96-1.76(m，2H)，1.40(d，6H)。
Procedure 34, example 264：
2- ((1S, 4R, 5R) -5- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -2-azabicyclo [2.2.1]Hept-2-yl) acetic acid (example 264): to a mixture containing 2- ((1S, 4R, 5R) -5- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -2-azabicyclo [2.2.1]To a vial of tert-butyl hept-2-yl) acetate (example 179) (25.5 mg,0.048 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 16 hours. The crude mixture was concentrated under reduced pressure, and acetonitrile (0.7 mL) and water (0.15 mL) were added. The mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18A, 250X 21.2 mm) to give the title compound example 264.ES/MS:478.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 10.76 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 4.37-4.09 (m, 3H), 3.76 (d, 1H), 3.59 (d, 1H), 3.22 (d, 1H), 3.06 (p, 1H), 2.79 (s, 1H), 2.65 (s, 3H), 2.48 (s, 3H), 2.27 (s, 3H), 2.15 (d, 1H), 2.09-1.94 (m, 1H), 1.36-1.15 (m, 7H).
Procedure 35, example 265：
2- ((1S, 4R, 5R) -5- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -2-azabicyclo [2.2.1]Hept-2-yl) -1- (3-hydroxyazetidin-1-yl) ethan-1-one (example 265): to 2- ((1S, 4R, 5R) -5- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -2-azabicyclo [2.2.1]To a solution of hept-2-yl) acetic acid (example 264) (13 mg,0.026 mmol) in DCM (2 mL) was added azetidin-3-ol hydrochloride (5.7 mg, O.052 mmol), HATU (20 mg,0.052 mmol) and N, N-diisopropylethylamine (0.019 mL,0.10 mmol) and the reaction mixture was stirred for 4 h. The crude mixture was concentrated under reduced pressure, and acetonitrile (0.7 mL) and water (0.15 mL) were added. The mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA water, column: gemini 5. Mu.M, NX-C18A, 250X 21.2 mm) to give the title compound example 265 as trifluoroacetate salt. ES/MS:533.3 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 10.75 (s, 1H), 8.57 (s, 1H), 8.43 (s, 1H), 4.73-4.65 (m, 1H), 4.50-4.38 (m, 1H), 4.31 (dd, 1H), 4.17 (s, 1H), 4.12 (d, 1H), 4.04 (d, 1H), 3.88 (d, 1H), 3.82-3.69 (m, 1H), 3.55 (t, 1H), 3.21-3.11 (m, 1H), 3.06 (p, 1H), 2.64 (s, 3H), 2.48 (d, 3H), 2.26 (s, 3H), 2.15 (d, 1H), 2.08-1.94 (m, 1H), 1.26 (dd, 6H).
The following examples were prepared in a similar manner according to procedure 35 and are shown in table 16 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 35 were used, and these reagents/starting materials are noted in the last column of table 16— "change in procedure 35: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 35 are replaced with different reagents/starting materials described below.
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Procedure 36, example 275：
2- ((1S, 4R, 5S) -2-azabicyclo [ 2.2.1)]Hept-5-yl) -5- (7, 8-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole (example 275): 2-bromo-5- (7, 8-dimethyl- [1,2, 4) was added to a dry round bottom flask]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-16) (5 g,9.9 mmol), (1S, 4S, 5R) -5-iodo-2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (I-31) (4.5 g,13.9 mmol), tetrabutylammonium iodide (TBAI) (3.7 g,9.9 mmol), ni (dtbbpy) (H 2 O) 4 Cl 2 (280 mg,0.60 mmol) and zinc powder (3.2 g,49.7 mmol). Anhydrous DMA (33 mL) was added and the mixture was degassed with argon for 1 minute. The vial was sealed and the reaction was stirred at room temperature for 16 hours. The reaction was then filtered and diluted with EtOAc, water and 5% licl (aq). The layers were separated and the organic layer was washed with water, followed by brine. The organic layer was dried over sodium sulfate and concentrated. The d.r. > 20:1 of the product was observed to favor the exo isomer. The crude mixture was purified by silica gel chromatography (eluent: etOAc/hexane). The purified material was dissolved in MeOH (3.7 mL) and HCl (3M in methanol, 19 mL). The mixture was stirred at 70 ℃ overnight. The mixture was concentrated to near dryness. ACN (33 mL) was added to the mixture and the mixture was stirred for 30 minutes, then filtered. The residue collected was identified as example 72 (major product; exo isomer); the mother liquor contained a mixture of example 72 and example 275 (minor product; endo isomer) which was purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA-water, column: gemini 5. Mu.M, NX-C18. ANG. 110. ANG., 250X 21.2 mm) to afford example 275 as a TFA salt. ES/MS:420.2 (M+H) + )。 1 H NMR (400 MHz, methanol-d 4) delta 10.79 (s, 1H), 8.56 (d, 1H), 8.42 (s, 1H), 4.16 (s, 1H), 3.99-3.85 (m, 1H), 3.47-3.36 (m, 1H), 3.07 (d, 2H), 2.99 (s, 1H), 2.65 (s, 3H), 2.48 (s, 3H), 2.48-2.40 (m, 1H), 2.27 (s, 3H), 2.16 (d, 1H), 1.95 (d, 1H), 1.86 (ddd, 1H), 1.27 (dd, 6H).
Procedure 37, example 276：
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2- [ (Z) -2- (1-tert-Butoxycarbonyl-4-piperidinyl) vinyl]-4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester: to 2-bromo-4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ] ]Pyridin-6-yl) thieno [2,3-b]To a 10:1 dioxane/water solution (5 mL) of tert-butyl pyrrole-6-carboxylate (I-15) (200 mg,0.41 mmol) was added 4- [2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) vinyl]Tert-butyl piperidine-1-carboxylate (165 mg,0.49 mmol), XPhos PdG3 (30.7 mg,0.041 mmol) and cesium carbonate (399 mg,1.2 mmol). The reaction mixture was taken up in N 2 Heat to 110 ℃ for 3 hours. Sodium sulfate was added to the reaction, and the mixture was filtered through celite, rinsed with DCM, and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (eluent: etOAc/hexane) to give the product. ES/MS:620.4 (M+H) + )。
2- (3-azabicyclo [ 4.1.0)]Hept-6-yl) -5- (7, 8-dimethyl- [1,2,4]triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrole (example 276): to a vinyl group containing 2- [2- (1-tert-butoxycarbonyl-4-piperidinyl)]-4-isopropyl-3-methyl-5- (8-methyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) thieno [2,3-b]To a vial of tert-butyl pyrrole-6-carboxylate (80 mg,0.129 mmol) was added EtOH (4 mL) and a catalytic amount of palladium on carbon (10% wt) and the resulting mixture was stirred under a hydrogen atmosphere for two days. Upon completion of the reaction as judged by LCMS, the reaction mixture was degassed with argon, filtered through celite, and the filtrate was concentrated to dryness. The crude residue was added to a vial containing acetonitrile and trifluoroacetic acid (1:1 mixture, 5 mL) and the reaction mixture was stirred at 80 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude material was dissolved in acetonitrile (1 mL), water (0.5 mL) and trifluoroacetic acid (0.1 mL) and the crude material was purified directly by RP-HPLC (0.1% tfA-ACN/0.1% tfa water, column: gemini 5 μm, NX-C18 a, 250 x 21.2 mm) to give the title compound example 276 as trifluoroacetate salt. ES/MS:422.4 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.58(s，1H)，8.46(s，1H)，7.58(t，J＝1.4Hz，1H)，3.41(d，J＝12.7Hz，2H)，3.32-3.26(m，2H)，3.03-2.95(m，2H)，2.86(t，J＝7.5Hz，2H)，2.69(s，3H)，2.43(s，3H)，2.05(d，J＝14.2Hz，2H)，1.68(q，J＝7.0Hz，4H)，1.46(s，1H)，1.40(d，J＝7.1Hz，6H)。
The following examples were prepared in a similar manner according to procedure 37 and are shown in table 17 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 37 were used, and these reagents/starting materials are noted in the last column of table 17- "procedure 37 variation: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 37 are replaced with different reagents/starting materials described below.
The program 38 is executed in accordance with the program code,example 279：
[4- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]-1-piperidinyl group]- [ (3R, 6R) -6-methylmorpholin-3-yl]Methanone (example XX): to 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-2- (4-piperidinyl) thieno [2,3-b]To a Violet vial of tert-butyl pyrrole-6-carboxylate (I-75) (50 mg,0.099 mmol) in 1, 2-dichloroethane (1 mL) was added (3R, 6R) -4-tert-butoxycarbonyl-6-methyl-morpholine-3-carboxylic acid (29.0 mg,0.12 mmol), 2- (7-aza-1H-benzotriazol-1-yl) -1, 3-tetramethylurea Hexafluorophosphate (HATU) (27.8 mg,0.12 mmol) and N, N-diisopropylethylamine (0.05 mL,0.3 mmol). The mixture was stirred at room temperature for 1 hour. The crude mixture was added to a vial containing acetonitrile and trifluoroacetic acid (1:1 mixture, 5 mL) and the reaction mixture was stirred at 80 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure, and the crude material was dissolved in acetonitrile (1 mL), water (0.5 mL) and trifluoroacetic acid (0.1 mL), and the crude material was purified directly by RP-HPLC (0.1% tfA-ACN/0.1% tfa water, column: gemini 5 μm, NX-C18 a, 250 x 21.2 mm) to give the title compound example 279 as trifluoroacetate salt. ES/MS:535.2 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.59(s，1H)，8.48(s，1H)，4.64(t，J＝16.6Hz，2H)，4.29(d，J＝13.4Hz，1H)，4.05(d，J＝14.1Hz，1H)，3.87(s，1H)，3.64(t，J＝11.6Hz，1H)，3.40(d，J＝13.6Hz，2H)，3.23(dd，J＝12.6，2.9Hz，1H)，3.07(h，J＝7.2Hz，1H)，2.91(s，1H)，2.65(s，3H)，2.47(s，3H)，2.28(s，3H)，2.06(d，J＝9.1Hz，2H)，1.67(s，2H)，1.26(dt，J＝20.3，7.2Hz，10H)。
The following examples were prepared in a similar manner according to procedure 38 and are shown in table 18 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 38 were used, and these reagents/starting materials are noted in the last column of table 18— "change in procedure 38: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 38 are replaced with different reagents/starting materials described below.
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Procedure 39, example 286：
3- [4- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]-1-piperidinyl group]Piperidin-2-one (example 286): to 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-2- (4-piperidinyl) thieno [2,3-b]To a solution of tert-butyl pyrrole-6-carboxylate (I-75) (20 mg,0.0386 mmol) in ACN (6 mL) was added 3-bromopiperidin-2-one (22.2 mg,0.13 mmol) and 1, 8-diazabicyclo [5.4.0]Undec-7-ene (0.023 mL,0.16 mmol). The mixture was stirred at 80 ℃ overnight. The crude mixture was added to a vial containing acetonitrile and trifluoroacetic acid (1:1 mixture, 5 mL) and the reaction mixture was stirred at 80 ℃ for 3 hours. The mixture was concentrated under reduced pressure and the crude residue was dissolved in acetonitrile (1 mL), water (0.5 mL) and trifluoroacetic acid (0.1 mL) and the crude material was purified directly by RP-HPLC (0.1% tfA-ACN/0.1% tfa water, column: gemini 5 μm, NX-C18 a, 250 x 21.2 mm) to give the title compound example 286 as trifluoroacetate salt. ES/MS:505.2 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.65(s，1H)，8.58(s，1H)，4.18(dd，J＝11.9，5.7Hz，1H)，3.58-3.34(m，7H)，3.23(q，J＝7.2Hz，1H)，3.06(hept，J＝7.2Hz，1H)，2.67(d，J＝7.7Hz，3H)，2.48(s，3H)，2.40(t，J＝8.4Hz，1H)，2.30(s，3H)，2.27-2.22(m，2H)，2.12-1.94(m，3H)，1.30(ddt，J＝26.3，20.7，6.4Hz，7H)。
The following examples were prepared in a similar manner according to procedure 39 and are shown in table 19 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 39 were used, and these reagents/starting materials are noted in the last column of table 19— "change in procedure 39: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 39 are replaced with different reagents/starting materials described below.
Procedure 40, example 290 and example 291：
3- [4- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]-1-piperidinyl group]Pyrrolidin-2-one (example 290 and example 291): 3- [4- [5- (7, 8-dimethyl- [1,2, 4) in the form of a mixture of 2 stereoisomers]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]-1-piperidinyl group]Pyrrolidin-2-one (example 287) was passed over chiral SFC (AD-H column with 45% EtOH-NH) 3 Cosolvents) to give two enantiomers, the absolute stereochemistry of which is arbitrarily designated as isomer 1 and isomer 2.
Isomer 1:3- [4- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]-1-piperidinyl group]Pyrrolidin-2-one (example 290): ES/MS:491.3 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.58(s，1H)，8.43(s，1H)，4.30(t，J＝9.7Hz，1H)，4.01(d，J＝12.2Hz，1H)，3.59-3.39(m，5H)，3.07(p，J＝7.1Hz，1H)，2.65(s，2H)，2.48(s，3H)，2.43(d，J＝11.6Hz，1H)，2.27(s，4H)，2.13-1.99(m，2H)，1.26(dd，J＝29.3，7.4Hz，6H)。
Isomer 2:3- [4- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]-1-piperidinyl group]Pyrrolidin-2-one (example 291): ES/MS:491.3 (M+H) + )。 1 H NMR (400 mhz, meod) delta 8.58 (s, 1H), 8.44 (s, 1H), 4.30 (t, j=9.7 hz, 1H), 4.01 (d, j=12.3 hz, 1H), 3.48 (dq, j=28.5, 8.7,8.2hz, 5H), 3.07 (p, j=7.1 hz, 1H), 2.65 (s, 3H), 2.58 (t, j=7.1 hz, 1H), 2.48 (s, 4H), 2.27 (s, 4H), 2.14-1.99 (m, 2H), 1.26 (dd, j=28.8, 7.1hz, 6H).
Procedure 41, example 292 and example 293：
9- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -1-oxa-4-azaspiro [5.5]Undecane (example 292 and example 293): 9- (5- (7, 8-dimethyl- [1,2, 4) in the form of a mixture of 2 stereoisomers]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ]Pyrrol-2-yl) -1-oxa-4-azaspiro [5.5]Undecane (example 144) was prepared by chiral SFC (AD-H4.6X100 mm; etOH-NH) 3 (30%) to give two diastereomers, the stereochemistry of which is arbitrarily designated as isomer 1 and isomer 2.
Isomer 1:9- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -1-oxa-4-azaspiro [5.5]Undecane (example 292): ES/MS:478.2 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.64(s，1H)，8.58(s，1H)，4.00-3.91(m，2H)，3.24-3.17(m，2H)，3.15-2.99(m，4H)，2.67-2.63(m，3H)，2.43(s，3H)，2_30(s，3H)，2.24-2.15(m，2H)，1.86-1.73(m，4H)，1.56(td，J＝13.4，6.2Hz，2H)，1.35-1.18(m，6H)。
Isomer 2:9- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -1-oxa-4-azaspiro [5.5]Undecane (example 293): ES/MS:478.2 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.58(s，1H)，8.44(s，1H)，3.97(dd，J＝6.2，4.1Hz，2H)，3.35(s，2H)，3.27-2.94(m，4H)，2.64(s，3H)，2.44(s，3H)，2.27(s，5H)，2.05(d，J＝13.2Hz，2H)，1.72(td，J＝13.3，3.7Hz，2H)，1.65-1.50(m，2H)，1.34-1.18(m，6H)。
Procedure 42, example 294：
3- [ (1S, 4R) -5- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]-2-azabicyclo [2.2.1]Hept-2-yl]Thiacyclopentane 1, 1-dioxide (example 294): a mixture of example 72 (HCl salt) (26.0 mg,0.057 mmol), DBU (34. Mu.L, 0.23 mmol), 2, 3-dihydrothiophene 1, 1-dioxide (13.5 mg,0.114 mmol) in MeOH (2 mL) was stirred at 90℃for two weeks. Volatiles were removed under reduced pressure and the crude product was dissolved in acetonitrile/water/trifluoroacetic acid (2 ml;5/1/0.2 ratio) and the crude material was filtered through acrodisc and purified directly by RP-HPLC (0.1% tfA-ACN/0.1% tfa water) to give the product as trifluoroacetate salt. ES/MS:538.2 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.59(s，1H)，8.46(s，1H)，4.49-3.40(m，7H)，3.04(dp，J＝15.7，7.6Hz，1H)，2.83(s，2H)，2.65(s，3H)，2.49(s，4H)，2.34(s，2H)，2.27(s，3H)，2.11-1.93(m，2H)，1.86-1.59(m，2H)，1.36-1.18(m，6H)。
Procedure 43, example 295：
[4- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]-1-piperidinyl group]- [8- (2-hydroxyethyl) -5-oxa-8-azaspiro [3.5 ]]Non-2-yl]Methanone (example 295): 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-2- [1- (5-oxa-8-azaspiro [3.5 ]]Nonane-2-carbonyl) -4-piperidinyl]Thieno [2,3-b ]]Pyrrole-6-carboxylic acid tert-butyl ester (HCl salt) (prepared in a similar manner to example 94 using I-75 as starting material) (25 mg,0.036 mmol), 2-bromoethanol (30.5. Mu.L, 0.043 mmol) and DBU (21.4. Mu.L, 0.14 mmol) in CH 3 The solution in CN (1 mL) was stirred at 80℃for 1 week. After LCMS showed the reaction was complete, the reaction mixture was cooled to room temperature. TFA (0.2 mL) was added and the reaction stirred overnight. The crude mixture was concentrated under reduced pressure, and acetonitrile (0.7 mL) and water (0.15 mL) were added. The mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% tfA-ACN/0.1% tfa-water) to give the product as trifluoroacetate salt. ES/MS:605.2 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.59(s，1H)，8.47(s，1H)，4.66(d，J＝13.2Hz，1H)，4.09-3.77(m，6H)，3.73-3.13(m，7H)，3.05(p，J＝7.1Hz，2H)，2.83(dd，J＝14.0，11.4Hz，1H)，2.64(s，4H)，2.46(s，6H)，2.28(s，3H)，2.08-1.93(m，2H)，1.58(dq，J＝12.3，6.5Hz，2H)，1.40-1.09(m，6H)。
Procedure 44, example 296：
[4- [5- (7, 8-dimethyl- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]-1-piperidinyl group]- (8-methyl-5-oxa-8-azaspiro [3.5 ]]Non-2-yl) methanone (example 296): to a catalyst containing [4- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5 ]-a]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]-1-piperidinyl group]- (5-oxa-8-azaspiro [3.5 ]]To a Violet vial of 1, 2-dichloroethane solution (1 mL) of non-2-yl) methanone (example 94) (20 mg,0.036 mmol) was added formaldehyde (3.2 mg,0.11 mmol) and acetic acid (1 drop). The mixture was stirred at room temperature for 2 hours. Sodium Triacetoxyborohydride (STAB) (23 mg,0.11 mmol) was then added to the mixture, and the mixture was stirred at room temperature overnight. To the mixture was added 0.1mL TFA followed by removal of DCE under reduced pressure. Acetonitrile (0.5 mL) and water (0.1 mL) were added and the mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% tfA-ACN/0.1% tfa-water) to give the product as trifluoroacetate salt. ES/MS:575.3 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.59(s，1H)，8.47(s，1H)，4.66(d，J＝13.1Hz，1H)，3.95(d，J＝13.5Hz，2H)，3.79(d，J＝12.0Hz，2H)，3.44-3.36(m，1H)，3.28-3.01(m，6H)，2.97(s，3H)，2.83(dd，J＝13.9，11.3Hz，1H)，2.64(s，4H)，2.46(s，4H)，2.37(s，2H)，2.28(s，3H)，2.03(t，J＝11.1Hz，2H)，1.56(qd，J＝15.2，6.6Hz，2H)，1.36-1.20(m，6H)。
The following examples were prepared in a similar manner according to procedure 44 and are shown in table 20 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 44 were used, and these reagents/starting materials are noted in the last column of table 20— "change in procedure 44: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 44 are replaced with different reagents/starting materials described below.
Procedure 45, example 298：
[8- (2, 2-difluoroethyl) -5-oxa-8-azaspiro [3.5 ]]Non-2-yl]- [4- [5- (7, 8-dimethyl- [1,2, 4)]Triazolyl [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]-1-piperidinyl group]Methanone (example 298): will [4- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]-1-piperidinyl group]- (5-oxa-8-azaspiro [3.5 ]]A solution of non-2-yl) methanone (example 94) (TFA salt) (15 mg,0.022 mmol), 2-bromo-1, 1-difluoro-ethane (2.5. Mu.L, 0.029 mmol) and DBU (13.3. Mu.L, 0.089 mmol) in 1, 2-dichloroethane (1 mL) was stirred at room temperature overnight. The crude mixture was concentrated under reduced pressure, and acetonitrile (0.7 mL), water (0.15 mL) and TFA (0.1 mL) were added. The mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% tfA-ACN/0.1% tfa-water) to give the product as trifluoroacetate salt. ES/MS:624.3 (M) + )。 1 H NMR(400MHz，MeOD)δ8.61(s，1H)，8.52(s，1H)，4.66(d，J＝13.1Hz，1H)，4.16-3.84(m，5H)，3.64(t，J＝6.3Hz，2H)，3.51-3.40(m，2H)，3.33-3.17(m，2H)，3.05(hept，J＝7.1Hz，1H)，2.83(dd，J＝14.0，11.4Hz，1H)，2.65(s，3H)，2.59-2.37(m，7H)，2.29(s，3H)，2.01(q，J＝14.7Hz，2H)，1.80(p，J＝7.1Hz，1H)，1.69(p，J＝5.3Hz，1H)，1.64-1.50(m，2H)，1.35-1.09(m，6H)。
Procedure 46, example 299：
2- [4- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]Cyclohexyl group]-2, 6-diazaspiro [3.4 ]]Octan-5-one (example 299): to a composition comprising 4- [5- (7, 8-dimethyl- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]A Violet vial of 1, 2-dichloroethane solution (1 mL) of cyclohexanone (I-78) (47 mg,0.11 mmol) was charged with 2, 6-diazaspiro [3.4 ]]Octan-5-one (42 mg,0.34 mmol) and acetic acid (1 drop). The mixture was stirred at room temperature for 2 hoursWhen (1). Sodium Triacetoxyborohydride (STAB) (71 mg,0.34 mmol) was then added to the mixture, and the mixture was stirred at room temperature overnight. To the mixture was added 0.1mL TFA followed by removal of DCE under reduced pressure. Acetonitrile (0.5 mL) and water (0.1 mL) were added and the mixture was filtered through acrodisc and then purified by RP-HPLC (o.1% TFA-ACN/0.1% tfa-water) to give the product as trifluoroacetate salt. ES/MS:531.2 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.60(s，1H)，8.49(s，1H)，4.27(d，J＝11.5Hz，3H)，3.69-3.49(m，1H)，3.44-3.33(m，3H)，3.29-3.14(m，1H)，3.06(dtd，J＝14.4，7.4，4.7Hz，1H)，2.64(s，4H)，2.44(s，3H)，2.28(s，3H)，2.16(d，J＝14.4Hz，1H)，2.10-1.86(m，5H)，1.84-1.37(m，3H)，1.35-1.17(m，6H)。
The following examples were prepared in a similar manner according to procedure 46 and are shown in table 21 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 46 were used, and these reagents/starting materials are noted in the last column of table 21— "change in procedure 46: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 46 are replaced with different reagents/starting materials described below.
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Program 47, example 305 and example 306：
2- [4- [5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl ] cyclohexyl ] -2, 6-diazaspiro [3.4] oct-5-one (example 305 and example 306): 2- [4- [5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl ] cyclohexyl ] -2, 6-diazaspiro [3.4] oct-5-one (example 299) in the form of a mixture of 2 stereoisomers was separated by chiral SFC (OD-H4.6X100 mm; MEOH-DEA (30%)) to give two diastereomers, the stereochemistry of which was arbitrarily designated as isomer 1 and isomer 2.
Isomer 1:2- [4- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]Cyclohexyl group]-2, 6-diazaspiro [3.4]]Octan-5-one (example 305): ES/MS:531.2 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.59(s，1H)，8.47(s，1H)，4.44-4.31(m，2H)，4.28-4.15(m，2H)，3.33(p，J＝1.7Hz，3H)，3.12-2.98(m，2H)，2.61(d，J＝7.0Hz，4H)，2.44(s，4H)，2.33-2.10(m，7H)，1.69-1.36(m，4H)，1.34-1.15(m，6H)。
Isomer 2:2- [4- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]Cyclohexyl group]-2, 6-diazaspiro [3.4]]Octan-5-one (example 306): ES/MS:531.2 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.63(s，1H)，8.56(s，1H)，4.53(d，J＝l1.0Hz，1H)，4.34-4.20(m，3H)，3.66-3.60(m，1H)，3.39(q，J＝8.5Hz，2H)，3.29-3.18(m，1H)，3.05(hept，J＝7.2Hz，1H)，2.64(d，J＝9.2Hz，4H)，2.54(t，J＝6.8Hz，1H)，2.44(s，3H)，2.30(s，3H)，2.07-1.90(m，6H)，1.73(t，J＝13.1Hz，2H)，1.38-1.14(m，6H)。
Procedure 48, example 307：
2- ((2- ((1S, 4R, 5R) -5- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -2-azabicyclo [2.2.1]Hept-2-yl) Ethyl) sulfonyl) ethan-1-ol (example 307): a solution of example 72 (HCl salt) (15 mg,0.033 mmol), 2- (2-bromoethylsulfonyl) ethanol (9.3 mg,0.043 mmol) and DBU (19.6. Mu.L, 0.13 mmol) in acetonitrile (1 mL) was stirred overnight at 80 ℃. The crude mixture was concentrated under reduced pressure, and acetonitrile (0.7 mL), water (0.15 mL) and TFA (0.1 mL) were added. The mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% tfA-ACN/0.1% tfa-water) to give the product. ES/MS:556.2 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.59(s，1H)，8.46(s，1H)，4.33(s，1H)，4.05(t，J＝5.3Hz，2H)，3.94-3.59(m，5H)，3.57-3.38(m，3H)，3.25(d，J＝10.5Hz，1H)，3.06(hept，J＝7.3Hz，1H)，2.81(d，J＝17.5Hz，1H)，2.65(s，3H)，2.58-2.14(m，9H)，2.06-1.94(m，2H)，1.38-1.14(m，6H)。
Procedure 49, example 308：
2- ((1S, 4R, 5R) -5- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -2-azabicyclo [2.2.1]Hept-2-yl) propane-1, 3-diol (example 308): to a flange vial containing 1, 2-dichloroethane r solution (1 mL) of example 72 (HCl salt) (20 mg,0.044 mmol) was added 2, 2-dimethyl-1, 3-dioxan-5-one (17 mg,0.13 mmol) and acetic acid (1 drop). The mixture was stirred at room temperature for 2 hours. Sodium Triacetoxyborohydride (STAB) (28 mg,0.13 mmol) was then added to the mixture, and the mixture was stirred at room temperature overnight. To the mixture was added a 4N HCl dioxane solution (5 mL) and stirred at room temperature overnight. The volatiles were then removed under reduced pressure. Acetonitrile (0.5 mL) and water (0.1 mL) were added and the mixture was filtered through acrodisc and then purified by RP-HPLC (0.1% tfA-ACN/0.1% tfa-water) to give the product. ES/MS:534.3 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.59(s，1H)，8.47(s，1H)，4.68-4.16(m，2H)，4.07-3.84(m，3H)，3.71-3.41(m，3H)，3.33-3.23(m，1H)，3.06(hept，J＝7.0Hz，1H)，2.83-2.73(m，2H)，2.65(s，3H)，2.48(d，J＝5.2Hz，3H)，2.39-2.19(m，4H)，2.15-1.73(m，2H)，1.45-1.15(m，6H)。
Procedure 50, example 309：
4- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]Cyclohexane carboxylic acid: 2-bromo-5- (7, 8-dimethyl- [1,2, 4) was added to the dried vial]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-thieno [2,3-b]Pyrrole-6-carboxylic acid tert-butyl ester (I-16) (150 mg,0.30 mmol), methyl 4-iodocyclohexanecarboxylate (I-86) (160 mg,0.60 mmol), tetrabutylammonium iodide (TBAI) (132 mg,0.36 mmol), ni (dtbbpy) (H) 2 O) 4 Cl 2 (17 mg,0.036 mmol) and zinc powder (116 mg,1.79 mmol). Anhydrous DMA (1 mL) was added and the mixture was degassed with argon for 1 minute. The vial was sealed and the reaction was stirred at 70 ℃ for 16 hours. The reaction was then cooled and the crude mixture was purified directly by silica gel chromatography (eluent: etOAc/hexane). (ES/MS: 565.2[ M+H ]]). To a solution of the purified product in THF (1 mL) and MeOH (1 mL) was added LiOH (excess) and the resulting reaction mixture was stirred at 80 ℃ for 1 hour. Volatiles were removed in vacuo, and the reaction was diluted with water (5 mL) and neutralized with aqueous 1NHCI (2 mL). The aqueous layer was extracted with EtOAc (3X 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the product. ES/MS:451.2 (M+H) + )。
(4- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) cyclohexyl) (piperazin-1-yl) methanone (example 309): to a composition comprising 4- [5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl]Vial of cyclohexane carboxylic acid (35 mg,0.077 mmol) in DMF (1 mL) was added piperazine-1-carboxylic acid tert-butyl ester (19 mg,0.10 mmol), 2- (7-aza) as a solution-1H-benzotriazol-1-yl) -1, 3-tetramethyluronium Hexafluorophosphate (HATU) (35.4 mg,0.093 mmol) and N, N-diisopropylethylamine (20.3 μl,0.12 mmol). The mixture was stirred at 60℃for 1 hour. After cooling to room temperature, a 4N HCl dioxane solution (5 mL) was added, and the resulting reaction mixture was stirred at 70 ℃ for 1 hour. The crude mixture was concentrated under reduced pressure, and acetonitrile (0.7 mL), water (0.15 mL) and TFA (0.1 mL) were added. The mixture was filtered through aCrodisc and then purified by RP-HPLC (0.1% TFA-ACN/0.1% TFA-water) to give the product. ES/MS:519.3 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.58(s，1H)，8.45(s，1H)，4.04-3.79(m，4H)，3.28(d，J＝15.7Hz，4H)，3.13-2.98(m，2H)，2.86-2.70(m，1H)，2.64(s，3H)，2.43(s，3H)，2.28(s，3H)，2.13-2.05(m，2H)，1.92(d，J＝12.8Hz，2H)，1.79-1.54(m，4H)，1.41-1.10(m，6H)。
The following examples were prepared in a similar manner according to procedure 50 and are shown in table 22 below. To prepare the following examples, reagents/starting materials different from some of those described in procedure 50 were used, and these reagents/starting materials are noted in the last column of table 22— "change in procedure 50: different reagents/starting materials). One of ordinary skill in the art will readily recognize which reagents/starting materials of procedure 50 are replaced with different reagents/starting materials described below.
Table 22
Program 51：Example 311 and example 312：
2- (3- (5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl) pyrrolidin-1-yl) acetamide (example 311 and example 312): 2- (3- (5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b ] pyrrol-2-yl) pyrrolidin-1-yl) acetamide (example 128) in the form of a mixture of 2 stereoisomers was separated by chiral SFC (IA 4.6X100mm 5mic column; etOH (30%)) to give two enantiomers, the stereochemistry of which was arbitrarily designated as isomer 1 and isomer 2.
Isomer 1:2- (3- (5- (7, 8-dimethyl- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrolidin-2-yl) pyrrolidin-1-yl) acetamide (example 311): ES/MS:437.3 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.63-8.55(m，1H)，8.47(s，1H)，7.58(t，J＝1.3Hz，1H)，4.20(s，2H)，4.12-3.39(m，4H)，3.31-3.24(m，1H)，3.23-3.06(m，1H)，2.78-2.44(m，7H)，2.40-2.04(m，1H)，1.40(d，J＝7.1Hz，6H)。
Isomer 2:2- (3- (5- (7, 8-dimethyl- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrolidin-2-yl) pyrrolidin-1-yl) acetamide (example 312): ES/MS:437.3 (M+H) + )。 1 H NMR(400MHz，MeOD)δ8.63-8.55(m，1H)，8.47(s，1H)，7.58(t，J＝1.3Hz，1H)，4.20(s，2H)，4.12-3.39(m，4H)，3.31-3.24(m，1H)，3.23-3.06(m，1H)，2.78-2.44(m，7H)，2.40-2.04(m，1H)，1.40(d，J＝7.1Hz，6H)。
Program 52：Example 313 and example 314：
5- (7, 8-dimethyl- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-2- (6- (2- (methylsulfonyl) ethyl) -6-azaspiro [3.4]Oct-2-yl) -6H-thieno [2,3-b]Pyrrole (example 313 and example 314): 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-2- (6-azaspiro [3.4 ]]Oct-2-yl) -6H-thieno [2,3-b]Pyrrole (example 75) was purified by chiral SFC (AD-H4.6X100 mm column; E)TOH-NH 3 (35%) separation to give two different stereoisomers. These isomers react separately according to the conditions in procedure 20 to give two diastereomers, the absolute stereochemistry of which is arbitrarily designated as isomer 1 and isomer 2.
Isomer 1:5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-2- (6- (2- (methylsulfonyl) ethyl) -6-azaspiro [3.4]Oct-2-yl) -6H-thieno [2,3-b]Pyrrole (example 313): ES/MS:540.3[ M+H ] + ]。 1 H NMR(400MHz，MeOD)δ8.61(s，1H)，8.51(s，1H)，4.25-3.37(m，9H)，3.15(s，3H)，3.03(p，J＝7.1Hz，1H)，2.75-2.62(m，5H)，2.51-2.14(m，10H)，1.38-1.13(m，6H)。
Isomer 2:5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-2- (6- (2- (methylsulfonyl) ethyl) -6-azaspiro [3.4]Oct-2-yl) -6H-thieno [2,3-b]Pyrrole (example 314): ES/MS:540.3[ M+H ] + ]。 1 H NMR(400MHz，MeOD)δ8.59(s，1H)，8.48(s，1H)，4.09-3.60(m，9H)，3.13(s，3H)，3.03(p，J＝7.1Hz，1H)，2.71-2.23(m，15H)，1.31-1.14(m，6H)。
Program 53: examples 315 and 316 ：
2- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -2-azaspiro [3.3]Hept-2-yl) acetamide (example 315 and example 316): 5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-2- (2-azaspiro [3.3 ]]Hept-5-yl) -6H-thieno [2,3-b]Pyrrole (example 228) was purified by chiral SFC (AD-H4.6X100 mm column; etOH-NH) 3 (35%) separation to give two different stereoisomers. These isomers react separately according to the conditions in procedure 20 to give two enantiomers, the absolute stereochemistry of which is arbitrarily designated as isomer 1 and isomer 2.
Isomer 1:2- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -2-azaspiro [3.3]Hept-2-yl) acetamide (example 315): ES/MS:477.3[ M+H ] + ]。 1 H NMR(400MHz，MeOD)δ8.69-8.52(m，1H)，8.46(s，1H)，4.63-3.71(m，7H)，3.16-3.08(m，1H)，2.79-1.97(m，13H)，1.45-1.12(m，6H)。
Isomer 2:2- (5- (7, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) -4-isopropyl-3-methyl-6H-thieno [2,3-b]Pyrrol-2-yl) -2-azaspiro [3.3]Hept-2-yl) acetamide (example 316): ES/MS:477.2[ M+H ] + ]。 1 H NMR(400MHz，MeOD)δ8.75-8.50(m，1H)，8.46(s，1H)，4.60-3.75(m，7H)，3.16-3.08(m，1H)，2.77-1.98(m，13H)，1.41-1.07(m，6H)。
Biological examples
In the following examples (examples A-1, B-1), example A-1 as disclosed in example 15 of WO2018/005586 has the following structure:
and embodiment B-1 as disclosed in embodiment 413 of WO2021/067326 has the following structure:
example A
Cell-based assays for TLR7/9 human Peripheral Blood Mononuclear Cells (PBMCs)
Human Peripheral Blood Mononuclear Cells (PBMCs) consist of lymphocytes, monocytes and dendritic cells expressing TLR7, TLR8 and TLR 9. These cells respond to TLR7, TLR8 and TLR9 ligand stimulation and produce cytokines and chemokines in vitro and in vivo. Thus, human PBMCs are suitable for use in cell-based assays to assess the in vitro efficacy of TLR7, 8 and/or 9 antagonists. The results are expected to be more convertible into in vivo pharmacodynamic responses than cell line-based assays.
Frozen human PBMCs from healthy donors were thawed and resuspended in RPMI-1640 medium containing L-glutamine (Corning) and supplemented with 10% fetal bovine serum (Hyclone) and 1X penicillin-streptomycin (Corning). After counting, the cell density was adjusted to 2 million cells/ml and at 37℃5% CO 2 Incubate for 1 hour to allow recovery. After recovery, cells were plated by adding 50 μl/well (100,000 cells) to 384 well cell culture plates (Greiner) (100% dmso solution containing 250nl of test antagonist per well) in a 10-point dose response and quadruplicate manner. PBMCs were tested in the presence of test antagonists at 37 ℃ with 5% co 2 Incubate for one hour and then stimulate with TLR7 or TLR9 agonists. GS-986 (GileadSciences) was used as a TLR7 agonist at a final concentration of 400 nM. ODN-2216 (InvivoGen) was used as a TLR9 agonist at a final concentration of 3. Mu.M. PBMCs were tested for antagonists and TLR7 (or TLR 9) agonists at 37 ℃, 5% co 2 Incubate for another 6 hours. At the end of the incubation, the cell culture plates were centrifuged at 500g for 5 minutes and the cell culture supernatant was collected. The levels of cytokines (IL-6 and IFNα) in the supernatant were measured by electrochemiluminescence immunoassay (Mesoscale Discovery) according to the manufacturer's recommended protocol. The measured cytokine levels were plotted against the test antagonist concentration and fitted to a sigmoid function to determine EC 50 The results are shown in table 11 below.
Cell-based assays for TLR8 human Peripheral Blood Mononuclear Cells (PBMCs)
Frozen human PBMCs from healthy donors were thawed and resuspended in RPMI-1640 medium containing L-glutamine (Corning) and supplemented with 10% fetal bovine serum (Hyclone) and 1X penicillin-streptomycin (Corning). After counting, the cell density was adjusted to 2 million cells/ml and at 37℃5% CO 2 Incubate for 1 hour to allow recovery. After recovery, 50. Mu.l/well was measured by following a 10-point dose response and in quadruplicates 100,000 cells) were added to 384 well cell culture plates (Greiner) (100% dmso solution containing 250nl of test antagonist per well) and the cells plated. PBMC were exposed to 5% CO at 37deg.C in the presence of an antagonist 2 Incubate for one hour and then stimulate with TLR8 agonist. Compound a (Gilead Sciences, U.S. patent No. 10,285,990) was used as a TLR8 agonist at a final concentration of 800 nM. PBMCs were incubated in the presence of antagonists and TLR8 agonists at 37 ℃, 5% co 2 Incubate for another 6 hours. At the end of the incubation, the cell culture plates were centrifuged at 500g for 5 minutes and the cell culture supernatant was collected. The levels of cytokines (TNFa and IL12p 40) in the supernatants were measured by electrochemiluminescence immunoassay (Mesoscale Discovery) according to the manufacturer's recommended protocol. The measured cytokine levels were plotted against antagonist concentration and fitted to a sigmoid function to determine EC 50 The results are shown in table 11 below. Compound a has the following structure:
TABLE 5.
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Example B
Human liver stability
Each test compound was incubated in a suspension of cryopreserved hepatocytes at a final concentration of 1 μm. The vials containing the cryopreserved hepatocytes were removed from the liquid nitrogen and immediately immersed in a 37 ℃ water bath. The vial was gently rotated until the contents thawed. They were then immediately poured into 48mL of pre-warmed HT medium in 50mL conical tubes. Cells remaining in the vials were resuspended in 1.0mL of pre-warmed HT medium and added to the conical tube. The tube was capped and then gently flipped several times to resuspend the hepatocytes. The cell suspension was centrifuged at 500 Xg for 10 min at room temperature and the supernatant was discarded. The pellet was loosened by gently swirling the centrifuge tube. Non-supplemented KHB medium was added to obtain the appropriate target cell density.
For incubation, aliquots of hepatocyte suspension (250 mL, concentration 2X 10) 6 Individual cells/mL) was added to 250mL of 2mm of each test compound in the double wells of a 24-well plate. The final concentration at incubation was 1X 10 6 Each cell/mL and 1mM of each test compound. Propranolol, a compound known to be efficiently metabolized by hepatocytes by oxidation and binding, was used as a positive control (1 mM final concentration) in parallel incubations. Cell-free controls were also tested at the same time as incubation. Incubation was performed under a humid atmosphere of 95% air/5% CO2 (v/v) with gentle shaking in an incubator at 37 ℃. At 0 hours, 1Aliquots (100 mL) were removed after hours, 3 hours and 6 hours and added to 200mL IS/Q. The sample was then placed on a shaker for 10 minutes followed by centrifugation at 3000 Xg for 20 minutes. The supernatant was transferred to a new plate and diluted with 100 μl of water to reduce the organic solvent content, then placed on a shaker for 10 minutes. Samples were injected and analyzed using LC-MS/MS. The results are recorded in table 23 below.
Table 23
Examples Predictive clearance rate (L/hr/kg)
A-1 0.27
B-1 0.26
56 0.25
67 0.14
79 0.26
84 0.53
91 0.24
97 0.81
98 0.11
175 0.26
183 0.64
221 0.16
229 0.22
Example C
Kinetic solubility at pH 7.4
In a Millipore solubility filter plate with a 0.45 μm polycarbonate filter membrane, a 100-fold dilution of a 10mM DMSO stock solution of each compound to be tested was prepared separately by mixing 3. Mu.L of DMSO stock solution with 297. Mu.L of the appropriate medium (0.1N HCL (Alfa Aesar part number 35644-K2) and 1 XPBS buffer (pH 7.4)) using a Hamilton Starlet liquid treatment. The final DMSO concentration was 1.0% and the maximum theoretical compound concentration was 100 μm. The filter plate is sealed. After 24 hours incubation at ambient temperature (21.7 ℃ -23.8 ℃) the samples were vacuum filtered and the filtrate was collected in 96-well polypropylene plates for analysis. The collection plate was sealed for analysis.
The filtrate was injected into a nitrogen detector to perform quantification on an Analiza auto discovery workstation. Results were recorded in μg/ml.
The equimolar nitrogen response of the detector was calibrated using a standard spanning the dynamic range of 0.08 μg/ml to 4500 μg/ml nitrogen of the instrument. The filtrate was quantified relative to the calibration curve. The calculated solubility values were corrected for background nitrogen present in DMSO and the medium used to prepare the samples. The solubility results presented in table 24 below assume that the sample is free of nitrogen-containing impurities and stable under the assay conditions.
PBS (Fisher Bioreagent part number BP 399-500) was added to about 450mL HPLC grade H by adding 50mL of phosphate buffered saline solution 10X 2 O was used to prepare 1 XPBS buffer (pH 7.4). The volume of the solution was then adjusted to 500mL, the total dilution was 1:10, and the final PBS concentration was 1X. The pH of the final solution was measured and found to be 7.4.
Each test compound was analyzed as trifluoroacetate salt.
Table 24
Examples pH 7.4 solubility (μg/mL)
A-1 ＜1
B-1 22
56 26.5
67 16.8
79 21.5
91 2.2
97 22.8
98 24.9
100 23.5
175 21.1
221 1
229 27.7
Example D
50 MATE2-K IC assay
MATE2-K (multi-drug and toxin extrusion protein 2) is expressed in the kidney's apical membrane and mediates elimination of compounds into urine. MDCK-II cells were maintained in DMEM with low glucose and 10% FBS. Cells passaged up to 40 passages were seeded at 60 K.+ -.10K cells/well on 96-well transwell plates about 24 hours prior to transfection. Transport assays were performed about 48 hours after transfection. On the day of assay DMEM was removed and cells were washed with HBSS. After washing, the cells in each well were washed with a solution containing 30mM NH 4 HBSS of Cl was pre-incubated with either vehicle (compound tested at 6 concentrations of 0.127 μm to 40 μm) or 100 μm cimetidine Ding Yiqi as a reference inhibitor. The assay plate was then placed in a 37 ℃ incubator with orbital shaking at about 60RPM for a pre-incubation time of 15 minutes. The pre-incubation solution was then removed and the cells were washed once with HBSS. 100. Mu.L of incubation buffer was added to each well containing HBSS containing 10. Mu.M 14 [C]-metformin asFor probe substrates, vehicle controls, compounds to be tested (6 concentrations in the range of 0.127 μm to 40 μm) or reference inhibitors. The assay plates were incubated at 37℃with orbital shaking at about 60RPM for an incubation time of 5 minutes. At the end of the 5 minute incubation, 15 μl of dosing solution was removed from each well containing the compound to be tested and measured using LC/MS for dose recovery assessment. The assay Kong Sici was then washed with ice-cold PBS. mu.L of cell extract was added to each well and the plate incubated at 37℃and orbital shaking was performed at about 60RPM for 15 minutes. After incubation, 30 μl was removed from each well, added to 200 μl scintillation fluid, and counted on 1450Microbeta (Perkin-Elmer) to measure probe substrate uptake. Determining IC by dividing the rate of transporter-mediated uptake in the presence of the test compound or reference inhibitor by the rate of transporter-mediated uptake in the presence of a vehicle control and fitting an sigmoid function 50 Values are used to calculate the inhibition potential of the compounds to be tested. The results are recorded in table 25 below.
Table 25
Examples MATE2-KIC 50 (μM)
A-1 0.3
B-1 1.1
56 7.7
67 6.2
79 8.1
82 ＞14.5
91 7.8
100 9.7
All references, including publications, patents, and patent documents, are incorporated by reference herein as if individually incorporated by reference. The present disclosure provides references to various embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the disclosure. It should be understood that this description is deemed to be an exemplification of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated.

Claims (175)

1. A compound of the formula I,
or a pharmaceutically acceptable salt thereof,
wherein the method comprises the steps of
R 1 Is an 8-to 10-membered fused bicyclic heterocyclyl or an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heterocyclyl and the 8-to 10-membered fused bicyclic heteroaryl are each independently optionally substituted with 1 to 4R a Group substitution;
R 2 is H, C 1-6 Alkyl or C 3-7 Monocyclic cycloalkyl wherein said C 1-6 Alkyl and said C 3-7 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 The group of the alkoxy group is substituted,
wherein said C 1-6 Alkoxy is optionally substituted with 1 to 3 halo groups;
R 3 Is H, halogen, -CN, C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl or 4-to 7-membered monocyclic heterocyclyl,
wherein said C 1-6 Alkyl, the C 3-7 Monocyclic cycloalkyl and said 4-to 7-membered monocyclic heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl, -C (O) N (R) 4 ) 2 4-to 7-membered monocyclic heterocyclyl, C 3-7 A monocyclic cycloalkoxy group and a 4-to 7-membered monocyclic hetero-epoxy group,
wherein said C 1-4 Alkoxy is optionally substituted with 1 to 3 halo groups;
each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached, form a 4 to 7 membered monocyclic heterocyclyl;
z is C 1-6 Alkyl, C 2-6 Alkenyl, -C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 、C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein said C 1-6 Alkyl and said C 2-6 Alkenyl groups are each independently optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein said C 3-7 Monocyclic cycloalkyl, the C 7-10 Fused bicyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, the 4-to 7-membered monocyclic heterocyclyl, the phenyl, the naphthyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl The 6-to 10-membered bridged bicyclic heterocyclyl, the 8-to 10-membered fused bicyclic heteroaryl, and the 7-to 10-membered spiro heterocyclyl are each independently optionally substituted with 1 to 2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a Group substitution;
R 6 is C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein said C 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein said C 3-7 Monocyclic cycloalkyl, the C 7-10 Fused bicyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, the 4-to 7-membered monocyclic heterocyclyl, the phenyl, the naphthyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, the 6-to 10-membered bridged bicyclic heterocyclyl, the 8-to 10-membered fused bicyclic heteroaryl, and the 7-to 10-membered spiroheterocyclyl are each independently optionally substituted with 1 to 4R' s a Group substitution;
R 13 is C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
Wherein said C 3-7 Monocyclic cycloalkyl, the C 7-10 Fused bicyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, the 4-to 7-membered monocyclic heterocyclyl, the phenyl, the naphthyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, the 6-to 10-membered bridged bicyclic heterocyclyl, the 8-to 10-membered fused bicyclic heteroaryl, and the 7-to 10-membered spiroheterocyclyl are each independently optionally substituted with 1 to 4R' s a Group substitution;
R 7 is H, C 1-6 Alkyl, C 3-7 A monocyclic cycloalkyl group or a 4-to 6-membered monocyclic heterocyclic group, wherein the C 1-6 Alkyl, the C 3-7 Monocyclic cycloalkyl and said 4-to 6-membered monocyclic heterocyclyl are each independently optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 Substitution of the alkoxy group;
each R 8 Independently halogen, -C (O) R 9 、-NR 10 R 10 、C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 5 、-C(O)OR 5 、-C(O)N(R 5 )(R 5 )、-N(R 5 ) 2 (R 5 ) + 、-N(R 5 )C(O)R 5 、-N(R 5 )C(O)OR 5 、-N(R 5 )C(O)N(R 5 )(R 5 )、-N(R 5 )S(O) 2 (R 5a )、-NR 5 S(O) 2 N(R 5 )(R 5 )、-NR 5 S(O) 2 O(R 5a )、-OC(O)R 5 、-OC(O)OR 5 、-OC(O)N(R 5 )(R 5 )、-SR 5 、-S(O)R 5a 、-S(O)(NH)R 5 、-S(O) 2 R 5a 、-S(O) 2 N(R 5 )(R 5 ) Or-n=s (R 5a )(R 5a )＝O，
Wherein said C 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein said C 3-7 Monocyclic cycloalkyl, the C 7-10 Fused bicyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, the 4-to 7-membered monocyclic heterocyclyl, the phenyl, the naphthyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, the 6-to 10-membered bridged bicyclic heterocyclyl, the 8-to 10-membered fused bicyclic heteroaryl, and the 7-to 10-membered spirocyclic heterocyclylEach radical independently is optionally substituted with 1 to 4R a Group substitution;
each R 9 Independently C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein said C 3-7 Monocyclic cycloalkyl, the C 7-10 Fused bicyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, the phenyl, the naphthyl, the 4-to 7-membered monocyclic heterocyclyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, the 6-to 10-membered bridged bicyclic heterocyclyl, the 8-to 10-membered fused bicyclic heteroaryl, and the 7-to 10-membered spiroheterocyclyl are each independently optionally substituted with 1 to 4R a Group substitution;
each R 5 And R is 10 H, C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein said C 1-6 Alkyl, the C 2-6 Alkenyl and said C 2-6 Alkynyl groups are each independently optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein said C 3-7 Monocyclic cycloalkyl, the C 7-10 Fused bicyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, the phenyl, the naphthyl, the 4-to 7-membered monocyclic heterocyclyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, the 6-to 10-membered bridged bicyclic heterocyclyl, the 8-to 10-membered fused bicyclic heteroaryl, and the 7-to 10-membered spiroheterocyclyl are each independently optionally substituted with 1 to 4R a Group substitution;
each R 5a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
Wherein said C 1-6 Alkyl, the C 2-6 Alkenyl and said C 2-6 Alkynyl groups are each independently optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein said C 3-7 Monocyclic cycloalkyl, the C 7-10 Fused bicyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, the phenyl, the naphthyl, the 4-to 7-membered monocyclic heterocyclyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, the 6-to 10-membered bridged bicyclic heterocyclyl, the 8-to 10-membered fused bicyclic heteroaryl, and the 7-to 10-membered spiroheterocyclyl are each independently optionally substituted with 1 to 4R a Group substitution;
each R a Independently oxo, imino, halogen, -NO 2 、-N 3 、-CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-NR 11 R 11 、-N(R 11 ) 2 (R 11 ) + 、-N(R 11 )C(O)R 11 、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)N(R 11 )(R 11 )、-N(R 11 )S(O) 2 (R 11a )、-NR 11 S(O) 2 N(R 11 )(R 11 )、-NR 11 S(O) 2 O(R 11a )、-OC(O)R 11 、-OC(O)OR 11 、-OC(O)N(R 11 )(R 11 )、-SR 11 、-S(O)R 11a 、-S(O)(NH)R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 ) Or-n=s (R 11a )(R 11a )＝O，
Wherein said C 1-6 Alkyl, the C 2-6 Alkenyl and said C 2-6 Alkynyl groups are each independently optionally substituted with 1 to 3R c The substitution of the groups is carried out,
wherein said C 3-7 Monocyclic cycloalkyl, the C 7-10 Fused bicyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, the phenyl, the naphthyl, the 4-to 7-membered monocyclic heterocyclyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, the 6-to 10-membered bridged bicyclic heterocyclyl, the 8-to 10-membered fused bicyclic heteroaryl, and the 7-to 10-membered spiroheterocyclyl are each independently optionally substituted with 1 to 3R d The substitution of the groups is carried out,
each R b Independently oxo, imino, halogen, -NO 2 、-N 3 、-CN、C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spirocyclic heterocyclyl, -OR 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)N(R 11 )(R 11 )、-NR 11 R 11 、-N(R 11 ) 2 (R 11 ) + 、-N(R 11 )C(O)R 11 、-N(R 11 )C(O)OR 11 、-N(R 11 )C(O)N(R 11 )(R 11 )、-N(R 11 )S(O) 2 (R 11a )、-NR 11 S(O) 2 N(R 11 )(R 11 )、-NR 11 S(O) 2 O(R 11a )、-OC(O)R 11 、-OC(O)OR 11 、-OC(O)N(R 11 )(R 11 )、-SR 11 、-S(O)R 11a 、-S(O)(NH)R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 ) Or-n=s (R 11a )(R 11a )＝O，
Wherein said C 3-7 Monocyclic cycloalkyl, the C 7-10 Fused bicyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, the phenyl, the naphthyl, the 4-to 7-membered monocyclic heterocyclyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, the 6-to 10-membered bridged bicyclic heterocyclyl, the 8-to 10-membered fused bicyclic heteroaryl, and the 7-to 10-membered spiroheterocyclyl are each independently optionally substituted with 1 to 3R d Group substitution;
each R c Independently halogen, -CN, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 12 、-C(O)R 12 、-C(O)OR 12 、-C(O)N(R 12 )(R 12 )、-NR 12 R 12 、-N(R 12 ) 2 (R 12 ) + 、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 12 )、-N(R 12 )S(O) 2 (R 12a )、-NR 12 S(O) 2 N(R 12 )(R 12 )、-NR 12 S(O) 2 O(R 12a )、-OC(O)R 12 、-OC(O)OR 12 、-OC(O)N(R 12 )(R 12 )、-SR 12 、-S(O)R 12a 、-S(O)(NH)R 12 、-S(O) 2 R 12a 、-S(O) 2 N(R 12 )(R 12 ) Or-n=s (R 12a )(R 12a )＝O；
Each R d Independently oxo, halogen, -CN, C 7-10 Condensed bicyclocycloalkyl, C 5-10 BridgingBicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, 7-to 10-membered spiroheterocyclyl, -OR 12 、-C(O)R 12 、-C(O)OR 12 、-C(O)N(R 12 )(R 12 )、-NR 12 R 12 、-N(R 12 ) 2 (R 12 ) + 、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 12 )、-N(R 12 )S(O) 2 (R 12a )、-NR 12 S(O) 2 N(R 12 )(R 12 )、-NR 12 S(O) 2 O(R 12a )、-OC(O)R 12 、-OC(O)OR 12 、-OC(O)N(R 12 )(R 12 )、-SR 12 、-S(O)R 12a 、-S(O)(NH)R 12 、-S(O) 2 R 12a 、-S(O) 2 N(R 12 )(R 12 ) Or-n=s (R 12a )(R 12a )＝O；
Each R 11 H, C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein said C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-7 Monocyclic cycloalkyl, the C 7-10 Fused bicyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, the phenyl, the naphthyl, the 4-to 7-membered monocyclic heterocyclyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, the 6-to 10-membered bridged bicyclic heterocyclyl, the 8-to 10-membered fused bicyclic heteroaryl, and the 7-to 10-membered spiroheterocyclyl are each independently optionally substituted with 1 to 3R c Group substitution;
each R 11a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein said C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-7 Monocyclic cycloalkyl, the C 7-10 Fused bicyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, the phenyl, the naphthyl, the 4-to 7-membered monocyclic heterocyclyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, the 6-to 10-membered bridged bicyclic heterocyclyl, the 8-to 10-membered fused bicyclic heteroaryl, and the 7-to 10-membered spiroheterocyclyl are each independently optionally substituted with 1 to 3R c Group substitution;
each R 12 H, C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, or 7-to 10-membered spiro heterocyclyl;
each R 12a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Monocyclic cycloalkyl, C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, phenyl, naphthyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, or 7-to 10-membered spiro heterocyclyl;
wherein each 4-membered monocyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 5-to 7-membered monocyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S;
wherein each 6-membered bridged bicyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 7-membered bridged bicyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S; and is also provided with
Wherein each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, and 7-to 10-membered spiro heterocyclyl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 4R a And (3) group substitution.
3. The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein Z is C 7-10 Condensed bicyclocycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl or 8-to 10-membered fused bicyclic heteroaryl,
wherein said C 7-10 Fused bicyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, the 8-to 10-membered fused bicyclic heterocyclyl, the 6-to 10-membered bridged bicyclic heterocyclyl, and the 8-to 10-membered fused bicyclic heteroaryl are each independently optionally substituted with 1 to 2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a And (3) group substitution.
4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 、C 3-7 Monocyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic ringHeteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl, or 7-to 10-membered spiro heterocyclyl,
wherein said C 3-7 Monocyclic cycloalkyl, the C 5-10 Bridged bicyclic cycloalkyl, the 4-to 7-membered monocyclic heterocyclyl, the phenyl, the naphthyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, the 6-to 10-membered bridged bicyclic heterocyclyl, the 8-to 10-membered fused bicyclic heteroaryl, and the 7-to 10-membered spiroheterocyclyl are each independently optionally substituted with 1 to 2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a And (3) group substitution.
5. The compound according to any one of claims 1 to 2 and 4, or a pharmaceutically acceptable salt thereof, wherein
R 1 Is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 4R a Group substitution;
R 2 is C 1-6 Alkyl or C 3-7 Monocyclic cycloalkyl wherein said C 1-6 Alkyl and said C 3-7 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of the alkoxy group;
R 3 Is H or C 1-6 Alkyl, wherein the C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl and-C (O) N (R) 4 ) 2 Is substituted by a group of (2);
each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached, form a 4 to 7 membered monocyclic heterocyclyl;
z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 、C 3-7 Monocyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclicHeterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein said C 3-7 Monocyclic cycloalkyl, the C 5-10 Bridged bicyclic cycloalkyl, the 4-to 7-membered monocyclic heterocyclyl, the phenyl, the naphthyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, the 6-to 10-membered bridged bicyclic heterocyclyl, the 8-to 10-membered fused bicyclic heteroaryl, and the 7-to 10-membered spiroheterocyclyl are each independently optionally substituted with 1 to 2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a Group substitution;
R 6 is a 4 to 7 membered monocyclic heterocyclyl, wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
R 13 Is a 4 to 7 membered monocyclic heterocyclyl, wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
R 7 is H or C 1-6 Alkyl, wherein the C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 Substitution of the alkoxy group;
each R 8 independently-C (O) R 9 、-NR 10 R 10 、-S(O) 2 R 5a 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 6-to 10-membered bridged bicyclic heterocyclyl or 7-to 10-membered spiroheterocyclyl,
wherein said C 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein each of the 4-to 7-membered monocyclic heterocyclyl, the 5-to 6-membered monocyclic heteroaryl, the 6-to 10-membered bridged bicyclic heterocyclyl, and the 7-to 10-membered spiro heterocyclyl is independently optionally substituted with 1 to 4R a Group substitution;
each R 9 Independently C 3-7 A monocyclic cycloalkyl group, a 4-to 7-membered monocyclic heterocyclic group, a 8-to 10-membered fused bicyclic heterocyclic group, a 6-to 10-membered bridged bicyclic heterocyclic group, or a 7-to 10-membered spiro heterocyclic group, wherein the C 3-7 Monocyclic cycloalkyl, said 4-to 7-membered monocyclic heterocyclyl, said 8-to 10-membered fused bicyclic ringHeterocyclyl, the 6-to 10-membered bridged bicyclic heterocyclyl and the 7-to 10-membered spiro heterocyclyl are each independently optionally substituted with 1 to 4R a Group substitution;
each R 10 Independently H or 4 to 7 membered monocyclic heterocyclyl, wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
each R 5a Independently is a 4 to 7 membered monocyclic heterocyclyl, wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
wherein each 4-membered monocyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 5-to 7-membered monocyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S;
wherein each 6-membered bridged bicyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 7-membered bridged bicyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S; and is also provided with
Wherein each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, and 8-to 10-membered fused bicyclic heteroaryl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.
6. The compound according to any one of claims 1 to 2 and 4 to 5, or a pharmaceutically acceptable salt thereof, wherein
R 1 Is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-6 Alkyl and C 3-7 Group substitution of monocyclic cycloalkyl;
Wherein said C 1-6 Alkyl and said C 1-4 Alkoxy groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted by a group of (2);
R 2 is C 1-6 Alkyl or C 3-5 Monocyclic cycloalkyl wherein said C 1-6 Alkyl and said C 3-5 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of the alkoxy group;
R 3 is H or C 1-6 Alkyl, wherein the C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl and-C (O) N (R) 4 ) 2 Is substituted by a group of (2);
each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached, form a 4 to 7 membered monocyclic heterocyclyl;
z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 、C 3-7 Monocyclic cycloalkyl, C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl, 8-to 10-membered fused bicyclic heteroaryl or 7-to 10-membered spirocyclic heterocyclyl,
wherein said C 3-7 Monocyclic cycloalkyl, the C 5-10 Bridged bicyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, said phenyl, said naphthyl, said 5-to 6-membered monocyclic heteroaryl, said 8-to 10-membered fused bicyclic heterocyclyl, said 6-to 10-membered bridged bicyclic heterocyclyl, said 8-to 10-membered fused bicyclic heteroaryl and said 7-to 10-membered spirocyclic heterocyclyl are each independently optionally substituted with 1-2R 8 Groups are substituted and each independently is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
R 6 is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of an alkyl radical, wherein said C 1-4 Alkoxy and said C 1-5 Alkyl groups are each independently optionally substituted with 1 to 3 groupsSelected from-OH, halogen, -CN and-NR 12 R 12 Is substituted by a group of (2);
R 13 is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
R 7 is H or C 1-6 Alkyl, wherein the C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 Substitution of the alkoxy group;
each R 8 independently-C (O) R 9 、-NR 10 R 10 、-S(O) 2 R 5a 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclyl, 5-to 6-membered monocyclic heteroaryl, 6-to 10-membered bridged bicyclic heterocyclyl or 7-to 10-membered spiroheterocyclyl,
wherein said C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)NR 11 R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Alkoxy and R 8a Is substituted by a group of (a) or (b),
wherein each of said 4-to 7-membered monocyclic heterocyclyl, said 5-to 6-membered monocyclic heteroaryl, said 6-to 10-membered bridged bicyclic heterocyclyl, and said 7-to 10-membered spiro heterocyclyl is independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 8b Is substituted by a group of (2);
each R 8a Independently 4 to 7 membered monocyclic heterocyclyl or 5 to 6 membered monocyclic heteroaryl;
each R 8b Independently 4 to 7 membered monocyclic heterocyclyl;
each R 9 Independently C 3-7 Monocyclic cycloalkyl, 4-to 7-membered monocyclic heterocyclyl, 8-to 10-membered fused bicyclic heterocyclyl, 6-to 10-membered bridged bicyclic heterocyclyl or 7-to 10-membered spiroheterocyclyl, which areThe C of 3-7 Monocyclic cycloalkyl, the 4-to 7-membered monocyclic heterocyclyl, the 8-to 10-membered fused bicyclic heterocyclyl, the 6-to 10-membered bridged bicyclic heterocyclyl, and the 7-to 10-membered spiro heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 9a Is substituted by a group of (2);
each R 9a Independently 4 to 7 membered monocyclic heterocyclyl;
each R 10 Independently H or 4 to 7 membered monocyclic heterocyclyl;
each R 5a Independently 4 to 7 membered monocyclic heterocyclyl;
each R 11 H, C independently 1-6 Alkyl, C 3-7 A monocyclic cycloalkyl or 4-to 7-membered monocyclic heterocyclyl;
each R 11a Independently C 1-4 An alkyl group;
each R 12 Independently H or C 1-4 An alkyl group;
wherein each 4-membered monocyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 5-to 7-membered monocyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S;
Wherein each 6-membered bridged bicyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 7-membered bridged bicyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S; and is also provided with
Wherein each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, and 8-to 10-membered fused bicyclic heteroaryl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.
7. The compound according to any one of claims 1 to 2 and 4 to 6, or a pharmaceutically acceptable salt thereof, wherein
R 1 Is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic ringHeteroaryl is optionally substituted with 1 to 4R a Group substitution;
R 2 is C 1-6 Alkyl or C 3-7 Monocyclic cycloalkyl wherein said C 1-6 Alkyl and said C 3-7 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of the alkoxy group;
R 3 is H or C 1-6 Alkyl, wherein the C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl and-C (O) N (R) 4 ) 2 Is substituted by a group of (2);
each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached, form a 4 to 7 membered monocyclic heterocyclyl;
Z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl or 8-to 10-membered fused bicyclic heteroaryl,
wherein each of the 4-to 7-membered monocyclic heterocyclyl, the phenyl, the naphthyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, and the 8-to 10-membered fused bicyclic heteroaryl is independently optionally substituted with 1 to 2R 8 Substituted with groups and each independently optionally substituted with 1 to 3R a Group substitution;
R 6 is a 4 to 7 membered monocyclic heterocyclyl, wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
R 13 is a 4 to 7 membered monocyclic heterocyclyl, wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
R 7 is H or C 1-6 Alkyl, wherein the C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 Substitution of the alkoxy group;
each R 8 independently-C (O) R 9 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterogeniesA cyclic group or a 6-to 10-membered bridged bicyclic heterocyclic group,
wherein said C 1-6 Alkyl is optionally substituted with 1 to 4R b The substitution of the groups is carried out,
wherein the 4-to 7-membered monocyclic heterocyclyl and the 6-to 10-membered bridged bicyclic heterocyclyl are each independently optionally substituted with 1 to 4R a Group substitution;
R 9 Is a 4 to 7 membered monocyclic heterocyclyl, wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 4R a Group substitution;
wherein each 4-membered monocyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 5-to 7-membered monocyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S;
wherein each 6-membered bridged bicyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 7-membered bridged bicyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S; and is also provided with
Wherein each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, and 8-to 10-membered fused bicyclic heteroaryl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.
8. The compound according to any one of claims 1 to 2 and 4 to 7, or a pharmaceutically acceptable salt thereof, wherein
R 1 Is an 8-to 10-membered fused bicyclic heteroaryl, wherein the 8-to 10-membered fused bicyclic heteroaryl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-6 Alkyl and C 3-7 Group substitution of monocyclic cycloalkyl;
wherein said C 1-6 Alkyl and said C 1-4 Alkoxy groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted by a group of (2);
R 2 is C 1-6 Alkyl or C 3-5 Monocyclic cycloalkyl wherein said C 1-6 Alkyl and said C 3-5 Monocyclic cycloalkyl groups are each independently optionally substituted with 1 to 4 groups independently selected from halogen and C 1-6 Substitution of the alkoxy group;
R 3 is H or C 1-6 Alkyl, wherein the C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, C 1-4 Alkoxy, -C (O) C 1-6 Alkyl and-C (O) N (R) 4 ) 2 Is substituted by a group of (2);
each R 4 Independently H or C 1-6 Alkyl, or two R 4 Together with the nitrogen to which they are attached, form a 4 to 7 membered monocyclic heterocyclyl;
z is-C (O) R 13 、-C(O)NR 6 R 7 、-S(O) 2 R 6 4-to 7-membered monocyclic heterocyclyl, phenyl, naphthyl, 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl or 8-to 10-membered fused bicyclic heteroaryl,
wherein each of the 4-to 7-membered monocyclic heterocyclyl, the phenyl, the naphthyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, and the 8-to 10-membered fused bicyclic heteroaryl is independently optionally substituted with 1 to 2R 8 Groups are substituted and each independently is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
R 6 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of an alkyl radical, wherein said C 1-4 Alkoxy and said C 1-5 Alkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted by a group of (2);
R 13 is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
R 7 is H or C 1-6 Alkyl, wherein the C 1-6 Alkyl is optionally substituted with 1 to 4 groups independently selected from-OH, halogen, -CN and C 1-6 Substitution of the alkoxy group;
each R 8 independently-C (O) R 9 、C 1-6 Alkyl, 4-to 7-membered monocyclic heterocyclic group or 6-to 10-membered bridged bicyclic heterocyclic group,
wherein said C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)NR 11 R 11 、C 1-4 Alkoxy and R 8a Is substituted by a group of (a) or (b),
wherein the 4-to 7-membered monocyclic heterocyclyl and the 6-to 10-membered bridged bicyclic heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
R 8a is a 4 to 7 membered monocyclic heterocyclyl;
R 9 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group;
each R 11 H, C independently 1-6 Alkyl, C 3-7 A monocyclic cycloalkyl or 4-to 7-membered monocyclic heterocyclyl;
each R 12 Independently H or C 1-4 An alkyl group;
wherein each 4-membered monocyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 5-to 7-membered monocyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S;
wherein each 6-membered bridged bicyclic heterocyclyl independently has 1 ring heteroatom selected from N, O and S;
wherein each 7-membered bridged bicyclic heterocyclyl independently has 1 to 2 ring heteroatoms independently selected from N, O and S; and is also provided with
Wherein each of the 5-to 6-membered monocyclic heteroaryl, 8-to 10-membered fused bicyclic heterocyclyl, 8-to 10-membered bridged bicyclic heterocyclyl, and 8-to 10-membered fused bicyclic heteroaryl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.
9. The compound according to any one of claim 1 to 8, wherein the compound has formula II,
or a pharmaceutically acceptable salt thereof,
wherein the method comprises the steps of
X 1 And X 2 Each independently is CR 1a Or N;
R 1a 、R 1b and R is 1c Each independently is H, halogen, C 1-6 Alkyl, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl or-N (R) 14 )(R 14 ) Wherein said C 1-6 Alkyl and said C 1-4 Alkoxy groups are each independently optionally substituted with 1 to 3 halo groups; and is also provided with
Each R 14 H, C independently 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl or 4-to 7-membered monocyclic heterocyclyl.
10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b And R is 1c Each independently is H, halogen, methyl, methoxy, -CF 3 Or CHF 2 。
11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 1 The method comprises the following steps:
each of them is optionally selected from the group consisting of halogen, C, and 1 to 3 1-3 Alkyl and C 1-3 Substitution of the alkoxy group, wherein said C 1-3 The alkyl group is optionally substituted with 1 to 3 halogen groups.
12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 1 The method comprises the following steps:
optionally from 1 to 3 of which are independently selected from halogen, C 1-3 Alkyl and C 1-3 Substitution of the alkoxy group, wherein said C 1-3 The alkyl group is optionally substituted with 1 to 3 halogen groups.
13. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 1 The method comprises the following steps:
14. the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 1 The method comprises the following steps:
15. the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 1 The method comprises the following steps:
16. the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 1 Is that
Each of them is optionally substituted with 1 to 3 groups independently selected from halogen, -CN, C 1-3 Alkyl and C 1-3 The groups of the alkoxy groups are substituted.
17. The compound according to any one of claims 1 to 8 and 16, or a pharmaceutically acceptable salt thereof, wherein R 1 Is that
18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 2 Is C 1-6 An alkyl group.
19. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 2 Is isopropyl or cyclopropyl.
20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R 2 Is isopropyl.
21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 3 Is H or C 1-6 An alkyl group.
22. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 3 Is optionally selected from-OH, halogen, -CN and C by 1 to 3 groups independently 1-3 C substituted by groups of alkoxy groups 1-4 An alkyl group.
23. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R 3 Is H or methyl.
24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 3 Is methyl.
25. The compound according to any one of claims 1 to 20 and 22, or a pharmaceutically acceptable salt thereof, wherein R 3 Is methyl substituted with 1 to 3 halogen groups.
26. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 3 Is H, methyl, -CHF 2 、-CH 2 OH、-CH 2 OCH 3 Or ethyl.
27. The compound according to any one of claims 1 to 2, 4 to 6 and 9 to 26, or a pharmaceutically acceptable salt thereof, wherein Z is C 3-7 Monocyclic cycloalkyl wherein said C 3-7 Monocyclic cycloalkyl is optionally substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
28. The compound according to any one of claims 1 to 2, 4 to 6 and 9 to 27, or a pharmaceutically acceptable salt thereof, wherein Z is cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with 1 to 2R 8 Substituted with groups, and optionally with 1 to 3 unitsThe site is selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
29. The compound according to any one of claims 1 to 6 and 9 to 26, or a pharmaceutically acceptable salt thereof, wherein Z is C 5-10 Bridged bicyclic cycloalkyl wherein C 5-10 Bridged bicyclic cycloalkyl is optionally substituted with 1 to 2R 8 Substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
30. The compound according to any one of claims 1 to 6, 9 to 26 and 29, or a pharmaceutically acceptable salt thereof, wherein Z is
Which is optionally substituted with one R 8 And (3) group substitution.
31. The compound according to any one of claims 1 to 6, 9 to 26 and 29 to 30, or a pharmaceutically acceptable salt thereof, wherein Z is
Which is optionally substituted with one R 8 And (3) group substitution.
32. The compound of any one of claims 1 to 2 and 4 to 26, or a pharmaceutically acceptable salt thereof, wherein Z is 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl, or 8 to 10 membered fused bicyclic heteroaryl,
wherein the 4-to 7-membered monocyclic heterocyclic group, the phenyl group, The naphthyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, and the 8-to 10-membered fused bicyclic heteroaryl are each independently optionally substituted with 1 to 2R 8 Groups are substituted and each independently is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
33. The compound of any one of claim 1 to 2, 4 to 26 and 32, or a pharmaceutically acceptable salt thereof, wherein Z is 4 to 7 membered monocyclic heterocyclyl, phenyl, naphthyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered fused bicyclic heterocyclyl or 8 to 10 membered fused bicyclic heteroaryl,
wherein each of the 4-to 7-membered monocyclic heterocyclyl, the phenyl, the naphthyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, and the 8-to 10-membered fused bicyclic heteroaryl is independently optionally substituted with 1 to 2R 8 Groups are substituted and each independently is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substituted by alkyl radicals, and
wherein the 4-to 7-membered monocyclic heterocyclyl, the 5-to 6-membered monocyclic heteroaryl, the 8-to 10-membered fused bicyclic heterocyclyl, and the 8-to 10-membered fused bicyclic heteroaryl each independently have one or two ring heteroatoms that are N.
34. The compound of any one of claim 1 to 2, 4 to 26 and 32 to 33, or a pharmaceutically acceptable salt thereof, wherein Z is a 5 to 6 membered monocyclic heterocyclyl,
wherein the 5-to 6-membered monocyclic heterocyclyl is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substituted by alkyl radicals, and
wherein the 5-to 6-membered monocyclic heterocyclyl has one or two ring heteroatoms which are N.
35. The compound of any one of claims 1 to 2, 4 to 26 and 32 to 34, or a pharmaceutically acceptable salt thereof, wherein Z is pyrrolidinyl or piperidinyl, each of which is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
36. The compound according to any one of claims 1 to 2, 4 to 26 and 32 to 35, or a pharmaceutically acceptable salt thereof, wherein Z is piperidinyl, wherein said piperidinyl is optionally substituted with one R 8 And (3) group substitution.
37. The compound according to any one of claims 1 to 2, 4 to 26 and 32 to 33, or a pharmaceutically acceptable salt thereof, wherein Z is azetidinyl, wherein said azetidinyl is optionally substituted with one R 8 And (3) group substitution.
38. The compound according to any one of claims 1 to 2, 4 to 26 and 32 to 33, or a pharmaceutically acceptable salt thereof, wherein Z is azepanyl, wherein said azepanyl is optionally substituted with one R 8 And (3) group substitution.
39. The compound of any one of claims 1-2, 4-26, and 32-33, or a pharmaceutically acceptable salt thereof, wherein Z is phenyl, naphthyl, or 6-membered monocyclic heteroaryl, each of which is optionally substituted with 1-2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
40. The compound according to any one of claims 1 to 2, 4 to 26, 32 to 33, and 39, or a pharmaceutically acceptable salt thereof, wherein ZIs phenyl, pyridinyl or pyrimidinyl, each of which is optionally substituted with one R 8 And (3) group substitution.
41. The compound of any one of claims 1 to 26 and 32 to 33, or a pharmaceutically acceptable salt thereof, wherein Z is 8-to 10-membered fused bicyclic heterocyclyl or 8-to 10-membered fused bicyclic heteroaryl, each of which is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
42. The compound according to any one of claims 1 to 26, 32 to 33 and 41, or a pharmaceutically acceptable salt thereof, wherein Z is
Each of them is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
43. The compound of any one of claims 1 to 6 and 9 to 26, or a pharmaceutically acceptable salt thereof, wherein Z is optionally substituted with 1 to 2R 8 Groups are substituted and optionally with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The group of the alkyl group is substituted with a 6-to 10-membered bridged bicyclic heterocyclic group.
44. The compound according to any one of claims 1 to 6, 9 to 26 and 43, or a pharmaceutically acceptable salt thereof, wherein Z is optionally substituted with 1 to 2R 8 Groups are substituted and optionally with 1 to 2 groups independently selected from-OH, halogen, -CN, oxoRadical, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 A 7-to 8-membered bridged bicyclic heterocyclic group substituted with a group of an alkyl group, wherein the 7-to 8-membered bridged bicyclic heterocyclic group has one or two ring heteroatoms that are N.
45. The compound of any one of claims 1 to 6 and 9 to 26, or a pharmaceutically acceptable salt thereof, wherein Z is optionally substituted with 1 to 2R 8 Groups are substituted and optionally with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 A 7-to 10-membered spirocyclic heterocyclic group substituted with a group of alkyl.
46. The compound of any one of claims 1 to 6, 9 to 26 and 45, or a pharmaceutically acceptable salt thereof, wherein Z is optionally substituted with 1 to 2R 8 Groups are substituted and optionally with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 A 7-to 10-membered spirocyclic heterocyclyl substituted with a group of alkyl, wherein the 7-to 10-membered spirocyclic heterocyclyl has one or two ring heteroatoms independently selected from N and O.
47. The compound according to any one of claims 1 to 6 and 9 to 26, or a pharmaceutically acceptable salt thereof, wherein Z is
Each of them is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
48. The compound according to any one of claims 1 to 6, 9 to 26 and 47, or a pharmaceutically acceptable salt thereof, wherein Z is
/>
Each of them is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
49. The compound according to any one of claims 1 to 6, 9 to 26 and 47 to 48, or a pharmaceutically acceptable salt thereof, wherein Z is
Each of them is optionally substituted with 1 to 2R 8 Substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
50. The compound according to any one of claims 1 to 2 and 4 to 26, or a pharmaceutically acceptable salt thereof, wherein Z is
Each of them is optionally substituted with one R 8 And (3) group substitution.
51. Any one of claims 1 to 2, 4 to 26 and 32 to 33The compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R is 8 Z substituted by radicals is
52. The compound according to any one of claims 1 to 2, 4 to 26, 32 to 33 and 50 to 51, or a pharmaceutically acceptable salt thereof, wherein one R 8 Z substituted by radicals is
53. The compound according to any one of claims 1 to 2, 4 to 6 and 9 to 26, or a pharmaceutically acceptable salt thereof, wherein one R 8 Z substituted by radicals is
54. The compound according to any one of claims 1 to 2, 4 to 6 and 9 to 26, or a pharmaceutically acceptable salt thereof, wherein one R 8 Z substituted by radicals is
/>
55. A compound according to any one of claims 1 to 2, 4 to 6, 9 to 26 and 54, or a pharmaceutically acceptable thereofAn acceptable salt, wherein R is 8 Z substituted by radicals is
56. The compound according to any one of claims 1 to 6, 9 to 26, 43 to 44 and 54 to 55, or a pharmaceutically acceptable salt thereof, wherein one R 8 Z substituted by radicals is
57. The compound according to any one of claims 1 to 6, 9 to 26, 43 to 44, 47 to 48, 50 and 54 to 55, or a pharmaceutically acceptable salt thereof, wherein one R 8 Z substituted by radicals is
58. The compound according to any one of claims 1 to 6, 9 to 26, 43 to 44, 47 to 48, 50 and 54 to 55, or a pharmaceutically acceptable salt thereof, wherein one R 8 Z substituted by radicals is
59. The compound according to any one of claims 1 to 6, 9 to 26, 43 to 44, 47 to 48, 50 and 54 to 55, or a pharmaceutically acceptable salt thereof, wherein one R 8 Z substituted by radicals is
60. The compound according to any one of claims 1 to 2, 4 to 6, 9 to 26, 46 to 47, 50 and 54 to 55, or a pharmaceutically acceptable salt thereof, wherein one R 8 Z substituted by radicals is
61. The compound according to any one of claims 1 to 2, 4 to 6, 9 to 26, 46 to 47, 49 to 50 and 54 to 55, or a pharmaceutically acceptable salt thereof, wherein one R 8 Z substituted by radicals is
62. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein each R 8 Independently is a 4 to 7 membered monocyclic heterocyclyl or a 6 to 10 membered bridged bicyclic heterocyclyl,
wherein the 4-to 7-membered monocyclic heterocyclyl and the 6-to 10-membered bridged bicyclic heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
63. The compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, wherein each R 8 Independently is a 4 to 7 membered monocyclic heterocyclyl or a 6 to 10 membered bridged bicyclic heterocyclyl,
wherein the 4-to 7-membered monocyclic heterocyclyl and the 6-to 10-membered bridged bicyclic heterocyclyl are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen-CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substituted by alkyl radicals, and
wherein the 4-to 7-membered monocyclic heterocyclyl and the 6-to 10-membered bridged bicyclic heterocyclyl each independently have one or two ring heteroatoms independently selected from N and S.
64. The compound of any one of claims 1 to 63, or a pharmaceutically acceptable salt thereof, wherein each R 8 Independently is a 5-to 6-membered monocyclic heterocyclic group or a 7-to 8-membered bridged bicyclic heterocyclic group,
wherein said 5-to 6-membered monocyclic heterocyclyl and said 7-to 8-membered bridged bicyclic heterocyclyl are each independently optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
65. The compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein each R 8 Independently oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
Each of them is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
66. The compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt thereof, wherein each R 8 Independently oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
Each of which is optionally substituted with 1 to 3 groups independently selected from halogen and oxo.
67. The compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, wherein each R 8 Independently is
Each of them is substituted with 1 to 2 oxo groups.
68. The compound of any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, wherein each R 8 Independently is
69. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein each R 8 Independently is a 7-to 10-membered spirocyclic heterocyclyl, wherein the 7-to 10-membered spirocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
70. The compound of any one of claims 1 to 61 and 69, or a pharmaceutically acceptable salt thereof, wherein each R 8 Independently is a 7 to 10 membered spirocyclic heterocyclyl, wherein said 7 to 10 membered spirocyclic heterocyclyl is optionally substituted with 1 to 3 oxo groups.
71. The compound of any one of claims 1 to 61 and 69 to 70, or a pharmaceutically acceptable salt thereof, wherein each R 8 Independently is
72. The compound of any one of claims 1 to 61 and 67 to 71, or a pharmaceutically acceptable salt thereof, wherein each R 8 Independently is
73. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein each R 8 Independently is a 5 to 6 membered monocyclic heteroaryl, wherein the 5 to 6 membered monocyclic heteroaryl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and R 8b Is substituted with a group of (a).
74. The compound of any one of claims 1 to 61 and 73, or a pharmaceutically acceptable salt thereof, wherein each R 8 Independently a 5 to 6 membered monocyclic heteroaryl, wherein said 5 to 6 membered monocyclic heteroaryl is optionally substituted with one R 8b And (3) substitution.
75. The compound of any one of claims 1 to 61 and 73 to 74, or a pharmaceutically acceptable salt thereof, wherein each R 8 Independently is
Each of them is optionally substituted with one R 8b And (3) substitution.
76. The compound of any one of claims 1 to 61 and 73 to 75, or a pharmaceutically acceptable salt thereof, wherein each R 8b Independently a 6 to 7 membered monocyclic heterocyclyl.
77. The compound according to any one of claims 1 to 61 and 73 to 76, or a pharmaceutically acceptable salt thereof, wherein R 8b Is a 6-membered monocyclic heterocyclic group.
78. The compound according to any one of claims 1 to 61 and 73 to 77, or a pharmaceutically acceptable salt thereof, wherein R 8b Is morpholinyl.
79. The compound according to any one of claims 1 to 7 and 9 to 61, or a pharmaceutically acceptable salt thereof, wherein R 8 Is C 1-6 Alkyl, wherein the C 1-6 Alkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)NR 11 R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Groups substituted with alkoxy, 4 to 7 membered monocyclic heterocyclyl and 5 to 6 membered monocyclic heteroaryl.
80. The compound according to any one of claims 1 to 7, 9 to 61 and 79, or a pharmaceutically acceptable salt thereof, wherein R 8 Is C 1-6 Alkyl, wherein the C 1-6 Alkyl is independently selected from-OH, halogen, -CN, oxo, -NR by 1 to 3 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)NR 11 R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 )、C 1-4 Groups substituted with alkoxy, 4 to 5 membered monocyclic heterocyclyl and 5 membered monocyclic heteroaryl.
81. A compound according to any one of claims 1 to 7, 9 to 61 and 79 to 80, or a pharmaceutical thereofSalts of the above acceptable, wherein R 8 Is C 1-6 Alkyl, wherein the C 1-6 Alkyl is independently selected from-OH, -CN, oxo, -NR by 1 to 2 11 R 11 、-C(O)R 11 、-C(O)OR 11 、-C(O)NR 11 R 11 、-S(O) 2 R 11a 、-S(O) 2 N(R 11 )(R 11 ) Group substitution of 4 to 5 membered monocyclic heterocyclyl and 5 membered monocyclic heteroaryl.
82. The compound according to any one of claims 1 to 7, 9 to 61 and 79 to 81, or a pharmaceutically acceptable salt thereof, wherein R 11a Is C 1-3 An alkyl group.
83. The compound of any one of claims 1 to 7, 9 to 61, and 79 to 81, or a pharmaceutically acceptable salt thereof, wherein each R 11 H, C independently 1-4 Alkyl, C 3-5 Monocyclic cycloalkyl or 4-to 6-membered monocyclic heterocyclyl.
84. The compound according to any one of claims 1 to 7, 9 to 61 and 79 to 81, or a pharmaceutically acceptable salt thereof, wherein R 8 Is C 1-6 Alkyl, wherein the C 1-6 Alkyl is independently selected from the group consisting of-OH, -CN, oxo, -NH by 1 to 3 2 、-N(CH 3 ) 2 -C (O) (azetidinyl), -C (O) OH, -C (O) OCH (CH) 3 ) 3 、-C(O)NH 2 、-C(O)NH 2 、-C(O)NH(CH 3 )、-C(O)NH(CH 2 CH 3 )、-C(O)NH(CH(CH 3 ) 2 ) -C (O) NH (cyclopropyl), -C (O) NH (oxetanyl), -C (O) N (CH) 3 ) 2 、-S(O) 2 CH 3 、-S(O) 2 NH 2 、-S(O) 2 NH(CH 3 )、-S(O) 2 N(CH 3 ) 2 Group substitution of 4 to 5 membered monocyclic heterocyclyl and 5 membered monocyclic heteroaryl.
85. The compound according to any one of claims 1 to 7, 9 to 61, 79 to 81 and 84An agent or a pharmaceutically acceptable salt thereof, wherein R 8 Is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are independently selected from the group consisting of-OH, -CN, oxo, pyrrolidinyl, 1 to 3,
Is substituted with a group of (a).
86. The compound according to any one of claims 1 to 7, 9 to 61 and 79 to 84, or a pharmaceutically acceptable salt thereof, wherein R 8 Is C 1-6 Alkyl, wherein the C 1-6 Alkyl is independently selected from-OH, oxo, -N (CH) 3 ) 2 、-C(O)NH 2 、-S(O) 2 CH 3 And oxetanyl groups.
87. The compound according to any one of claims 1 to 7, 9 to 64 and 79 to 84, or a pharmaceutically acceptable salt thereof, wherein R 8 Is C 1-6 Alkyl, wherein the C 1-6 Alkyl is independently selected from-OH, oxo, -N (CH) 3 ) 2 、-C(O)NH 2 、-C(O)NHCH 3 、-S(O) 2 CH 3 Group substitutions of oxetanyl and pyrrolidinyl.
88. The compound of any one of claims 1 to 61, 79 to 84 and 86 to 87, or a pharmaceutically acceptable salt thereof, wherein R 8 Is C 1-3 Alkyl, wherein the C 1-3 Alkyl is independently selected from-C (O) NH 2 and-C (O) NHCH 3 Is substituted with a group of (a).
89. The compound of any one of claims 1 to 61, 79 to 84 and 86 to 88, or a pharmaceutically acceptable salt thereof, wherein R 8 Is covered by a-C (O) NH group 2 Methyl substituted by a group.
90. According to claim1 to 6 and 9 to 61, or a pharmaceutically acceptable salt thereof, wherein each R 8 Is independently-NR 10 R 10 or-S (O) 2 R 5a 。
91. The compound of any one of claims 1 to 6, 9 to 61 and 90, or a pharmaceutically acceptable salt thereof, wherein each R 10 Independently H or 4-to 6-membered monocyclic heterocyclyl.
92. The compound of any one of claims 1 to 6, 9 to 61, and 90 to 91, or a pharmaceutically acceptable salt thereof, wherein each R 10 Independently H or oxetanyl.
93. The compound of any one of claims 1 to 6, 9 to 61 and 90, or a pharmaceutically acceptable salt thereof, wherein R 5a Is a 4-to 6-membered monocyclic heterocyclic group.
94. The compound of any one of claims 1 to 6, 9 to 61, 90 and 93, or a pharmaceutically acceptable salt thereof, wherein R 5a Is piperazinyl.
95. A compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R 8 is-C (O) R 9 。
96. The compound according to any one of claims 1 to 6, 9 to 61 and 95, or a pharmaceutically acceptable salt thereof, wherein R 9 Is C 3-5 Monocyclic cycloalkyl wherein said C 3-5 Monocyclic cycloalkyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy, C 1-5 Alkyl and 4 to 7 membered monocyclic heterocyclyl.
97. A compound according to any one of claims 1 to 6, 9 to 61 and 95 to 96, or a pharmaceutically acceptable thereofSalts, wherein R is 9 Is cyclopropyl, wherein said cyclopropyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, C 1-3 Alkoxy, C 1-3 Alkyl and 5 to 6 membered monocyclic heterocyclyl.
98. The compound according to any one of claims 1 to 6, 9 to 61 and 95 to 97, or a pharmaceutically acceptable salt thereof, wherein R 9 Is cyclopropyl, wherein said cyclopropyl is substituted with morpholinyl.
99. The compound of any one of claims 1 to 61 and 95, or a pharmaceutically acceptable salt thereof, wherein R 9 Is a 4 to 7 membered monocyclic heterocyclyl wherein the 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
100. The compound of any one of claims 1 to 61, 95 and 99, or a pharmaceutically acceptable salt thereof, wherein R 9 Is a 4-to 7-membered monocyclic heterocyclic group,
wherein the 4-to 7-membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group; and is also provided with
Wherein the 4-to 7-membered monocyclic heterocyclyl has one or two ring heteroatoms which are N.
101. The compound according to any one of claims 1 to 61, 95 and 99 to 100, or a pharmaceutically acceptable salt thereof, wherein R 9 Is a 4 to 6 membered monocyclic heterocyclyl wherein the 4 to 6 membered monocyclic heterocyclyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -NH 2 、C 1-3 Alkoxy and C 1-3 The group of the alkyl group is substituted, and wherein the 4-to 6-membered monocyclic heterocyclic group has one ring heteroatom which is N.
102. The compound of any one of claims 1 to 61, 95 and 99 to 101, or a pharmaceutically acceptable salt thereof, wherein each R 9 Independently azetidinyl or pyrrolidinyl, each of which is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted.
103. The compound of any one of claims 1 to 61, 95 and 99 to 101, or a pharmaceutically acceptable salt thereof, wherein each R 9 Independently is
Each of which is optionally substituted with one methyl group.
104. The compound of any one of claims 1 to 61, 95 and 99 to 101, or a pharmaceutically acceptable salt thereof, wherein each R 9 Independently oxetanyl, pyrrolidinyl, piperazinyl, or morpholinyl, each of which is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, C 1-3 Alkoxy and C 1-3 The groups of the alkyl groups are substituted.
105. The compound of any one of claims 1 to 6, 9 to 61 and 95, or a pharmaceutically acceptable salt thereof, wherein each R 9 Independently is an 8-to 10-membered fused bicyclic heterocyclyl, wherein the 8-to 10-membered fused bicyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
106. The compound of any one of claims 1 to 6, 9 to 61, 95 and 105, or a pharmaceutically acceptable salt thereof, wherein each R 9 Independently is an 8-to 10-membered fused bicyclic heterocyclic group, whereinThe 8-to 10-membered fused bicyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substituted by alkyl radicals, and
wherein the 8-to 10-membered fused bicyclic heterocyclyl has 1 to 3 ring heteroatoms independently selected from N and O.
107. The compound of any one of claims 1 to 6, 9 to 61, 95 and 105 to 106, or a pharmaceutically acceptable salt thereof, wherein each R 9 Independently is
108. The compound according to any one of claims 1 to 6, 9 to 61 and 95, or a pharmaceutically acceptable salt thereof, wherein R 9 Is optionally 1 to 2 independently selected from-OH, halogen, C 1-3 Alkoxy and C 1-3 A 6-to 10-membered bridged bicyclic heterocyclic group substituted with a group of an alkyl group, and wherein the 6-to 10-membered bridged bicyclic heterocyclic group has one ring heteroatom which is N.
109. The compound according to any one of claims 1 to 6, 9 to 61, 95 and 108, or a pharmaceutically acceptable salt thereof, wherein R 9 Is that
Each of which is optionally substituted with 1 to 3 groups independently selected from fluoro, methoxy and methyl.
110. The compound according to any one of claims 1 to 6, 9 to 61 and 95, or a pharmaceutically acceptable salt thereof, wherein R 9 Is optionally 1 to 2 independently selected from-OH, halogen, C 1-3 Alkoxy and C 1-3 A 7-to 10-membered spirocyclic heterocyclic group substituted with a group of alkyl.
111. The compound according to any one of claims 1 to 6, 9 to 61, 95 and 110, or a pharmaceutically acceptable salt thereof, wherein R 9 Is a 9 membered spirocyclic heterocyclyl having 1 to 2 ring heteroatoms independently selected from N and O.
112. The compound according to any one of claims 1 to 6, 9 to 61, 95 and 110 to 111, or a pharmaceutically acceptable salt thereof, wherein R 9 Is that
113. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Z is-C (O) NR 6 R 7 or-S (O) 2 R 6 。
114. The compound according to any one of claims 1 to 26 and 113, or a pharmaceutically acceptable salt thereof, wherein R 6 Is a 4-to 7-membered monocyclic heterocyclic group,
wherein the 4-to 7-membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Radical substitution of an alkyl radical, wherein said C 1-4 Alkoxy and said C 1-5 Alkyl groups are each independently optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN and-NR 12 R 12 Is substituted by a group of (2); and is also provided with
Wherein the 4-to 7-membered monocyclic heterocyclyl has one or two ring heteroatoms which are N.
115. The compound of any one of claims 1 to 26 and 113-114, or a pharmaceutically acceptable salt thereof, wherein R 6 Is 5 to 5A 6-membered monocyclic heterocyclic group,
wherein the 5-to 6-membered heterocyclyl is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN and C 1-5 Substituted by groups of alkoxy groups, and
wherein said C 1-5 The alkyl group is optionally substituted with 1 to 2 groups independently selected from-OH and halogen.
116. The compound according to any one of claims 1 to 26 and 113 to 115, or a pharmaceutically acceptable salt thereof, wherein R 6 Is pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted with 1 to 2 groups independently selected from-OH, halogen, -CN and C 1-5 Radical substitution of an alkyl radical, wherein said C 1-5 The alkyl group is optionally substituted with 1 to 2 groups independently selected from-OH and halogen.
117. The compound according to any one of claims 1 to 26 and 113 to 116, or a pharmaceutically acceptable salt thereof, wherein R 6 Is pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted with one C 1-3 Alkyl group substitution wherein the C 1-3 The alkyl group is optionally substituted with 1 to 2 groups independently selected from-OH and halogen.
118. The compound according to any one of claims 1 to 26 and 113 to 117, or a pharmaceutically acceptable salt thereof, wherein R 6 Is that
Each of them is optionally C 1-3 Alkyl substitution wherein said C 1-3 The alkyl group is substituted with one-OH group.
119. The compound according to any one of claims 1 to 26 and 113 to 118, or a pharmaceutically acceptable salt thereof, wherein R 7 Is H or methyl.
120. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Z is-C (O) R 13 。
121. The compound of any one of claims 1 to 26 and 120, or a pharmaceutically acceptable salt thereof, wherein R 13 Is a 4-to 7-membered monocyclic heterocyclic group,
wherein the 4-to 7-membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 Substitution of the alkyl group; and is also provided with
Wherein the 4-to 7-membered monocyclic heterocyclyl has one or two ring heteroatoms which are N.
122. The compound of any one of claims 1 to 26 and 120-121, or a pharmaceutically acceptable salt thereof, wherein R 13 Is a 5-to 6-membered monocyclic heterocyclic group,
wherein the 5-to 6-membered monocyclic heterocyclyl is optionally substituted with 1 to 3 groups independently selected from-OH, halogen, -CN, oxo, -NR 11 R 11 、C 1-4 Alkoxy and C 1-5 The groups of the alkyl groups are substituted.
123. The compound of any one of claims 1 to 26 and 120-122, or a pharmaceutically acceptable salt thereof, wherein R 13 Is a 5-to 6-membered monocyclic heterocyclic group.
124. The compound according to any one of claims 1 to 26 and 120-123, or a pharmaceutically acceptable salt thereof, wherein R 13 Is piperazinyl.
125. The compound of any one of claims 1 to 124, or a pharmaceutically acceptable salt thereof, wherein R 11 Is H or C 1-3 An alkyl group.
126. A compound selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
127. A compound selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
128. A compound selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
129. A compound selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
130. A compound selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
131. A compound selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
132. A compound selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
133. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
134. A compound which is
Or a pharmaceutically acceptable salt thereof.
135. A compound which is
Or a pharmaceutically acceptable salt thereof.
136. A compound which is
Or a pharmaceutically acceptable salt thereof.
137. A compound which is
Or a pharmaceutically acceptable salt thereof.
138. A compound which is
Or a pharmaceutically acceptable salt thereof.
139. A compound which is
Or a pharmaceutically acceptable salt thereof.
140. A compound which is
Or a pharmaceutically acceptable salt thereof.
141. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
142. A compound selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
143. A pharmaceutical composition comprising a compound according to any one of claims 1 to 142, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
144. The pharmaceutical composition of claim 143, further comprising one or more additional therapeutic agents or pharmaceutically acceptable salts thereof.
145. The pharmaceutical composition of claim 144, wherein the one or more additional therapeutic agents comprise an antimalarial agent.
146. The pharmaceutical composition of claim 145, wherein the antimalarial agent is selected from chloroquine and hydroxychloroquine or their respective pharmaceutically acceptable salts.
147. A method of inhibiting toll-like receptor 7 and/or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-142, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition of any one of claims 143-146.
148. A method of inhibiting toll-like receptor 7 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-142, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition of any one of claims 143-146.
149. A method of inhibiting toll-like receptor 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-142, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition of any one of claims 143-146.
150. A method of treating a disease or disorder associated with increased toll-like receptor 7 and/or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 142, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition according to any one of claims 143 to 146.
151. A method of treating a disease or disorder associated with increased toll-like receptor 7 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 142, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition according to any one of claims 143 to 146.
152. A method of treating a disease or disorder associated with increased toll-like receptor 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 142, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition according to any one of claims 143 to 146.
153. A method of treating an inflammatory disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 142, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition according to any one of claims 143 to 146.
154. The method of claim 153, wherein the inflammatory disorder is selected from the group consisting of inflammatory bowel disease, psoriasis, psoriatic arthritis, rheumatoid arthritis, glomerulonephritis, mixed Connective Tissue Disease (MCTD), dermatomyositis, polymyositis, systemic sclerosis, anti-neutrophil cytoplasmic antibody associated vasculitis, anti-phospholipid syndrome, autoimmune hemolytic anemia, macrophage activation syndrome driven inflammatory anemia, igA nephropathy, type I diabetes, non-alcoholic steatohepatitis, and sjogren syndrome.
155. A method of treating systemic lupus erythematosus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-142, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition of any one of claims 143-146.
156. A method of treating cutaneous lupus erythematosus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-142, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition of any one of claims 143-146.
157. A method of treating lupus nephritis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-142, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition of any one of claims 143-146.
158. The method of any one of claims 147 to 157, further comprising administering a therapeutically effective amount of one or more additional therapeutic agents or pharmaceutically acceptable salts thereof.
159. The method of claim 158, wherein the one or more additional therapeutic agents are selected from the group consisting of: wituzumab, PF-06835375, ekuizumab, mi Latuo, SM-06, SM-03, BT-063, QX-006-N, BOS-161721, AK-101, TNX-1500, cilazalizumab, damady Li Shan, TAK-079, fezeitumumab, illimumab, anilumab, iskarituximab, polyethylene glycol The preparation method comprises the following steps of (1) enabling the preparation of the drug composition by using the drugs of (1) dapiromalizumab, ranolaouab, LY-3361237, JNJ-55920839, UBP-1213, DS-7011, PFI-102, BIIB-059, obelimumab, tatuzumab, wo Bali bead mab, TE-2324, PRV-3279, chloroquine, hydroxychloroquine sulfate, COV-08-0064, GNKS-356, AVO-101, lobifuα, VRN-02, annexuzlimab, ALPN-101, bendamustine hydrochloride, BMS-986256 (almitoram), NKTR-35, asenaproxide, tyliprovalicide, M-5049, KZR-616, KPG-818, vandicable, ALPN-303, valuzepine, LA-1, cinnolide, prednisone, corticotropine, deuterium, celecoxib, CPL-409116, and the preparation of the drug composition CS-12192, tofacitinib citrate, ISB-830, DV-1079, juliemic acid, itufenamine, TAM-01, BML-258, bupacitinib, SDC-1801, SDC-1802, ICP-330, NTR-441, darapamide, GSK-2646264, SKI-O-703, lanraptinib (GS-9876), GNS-1653, HMPL-523, RSLV-132, interleukin-2 subsequent biologic, interleukin-2 Anteluke, interking recombinant human interleukin-2, ILT-101, CUG-252, DZ-2002, pegylated HLA-x (SLE), AC-0058, non-nilotinib, XNW-1011, tirapatinib hydrochloride, brinbutinib, albuminib, oxybutytinib, INV-213388, INV-103, DZ-2002, R-salbutamol sulfate, dockerin, NIK-SMI1, X-6, INV-17, O Sha Di D, barittinib, wu Pati, fagolitinib, italtinib, INCB-54707, degatinib, DWP-212525, CKD-971, as mometasone, betamethasone, furitmod, arachidonylethanolamine, DCB-SLE1, arsenic trioxide, tairuimide, TV-4710 (E Qu Tai), allogeneic human umbilical cord-derived mesenchymal stem cell therapy (hUC-MSC), LC-200, BI-705564, SM-934, GX-101, TXR-712, TXR-711, CIT-013, MHV-370, TPX-6001, TPX-7001, dihydroartemisinin, corticosteroids, azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab, non-steroidal anti-inflammatory drugs, belimumab, fuciclosporin and AMG-592, or pharmaceutically acceptable salts of any of the foregoing or any combination thereof.
160. The method of any one of claims 147 to 159, wherein the subject is a human.
161. A compound according to any one of claims 1 to 142 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 143 to 146 for use in therapy.
162. Use of a compound according to any one of claims 1 to 142, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 143 to 146, in a method of inhibiting toll-like receptor 7 and/or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
163. Use of a compound according to any one of claims 1 to 142, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 143 to 146, in a method of inhibiting toll-like receptor 7 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
164. Use of a compound according to any one of claims 1 to 142, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 143 to 146, in a method of inhibiting toll-like receptor 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
165. Use of a compound according to any one of claims 1 to 142, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 143 to 146, in a method of treating a disease or disorder associated with increased toll-like receptor 7 and/or 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
166. Use of a compound according to any one of claims 1 to 142, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 143 to 146, in a method of treating a disease or disorder associated with increased toll-like receptor 7 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
167. Use of a compound according to any one of claims 1 to 142, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 143 to 146, in a method of treating a disease or disorder associated with increased toll-like receptor 8 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
168. Use of a compound according to any one of claims 1 to 142, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 143 to 146, in a method of treating an inflammatory disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
169. The use of claim 168, wherein the inflammatory disorder is selected from inflammatory bowel disease, psoriasis, psoriatic arthritis, rheumatoid arthritis, glomerulonephritis, mixed Connective Tissue Disease (MCTD), dermatomyositis, polymyositis, systemic sclerosis, anti-neutrophil cytoplasmic antibody-associated vasculitis, anti-phospholipid syndrome, autoimmune hemolytic anemia, macrophage activation syndrome-driven inflammatory anemia, igA nephropathy, type I diabetes, non-alcoholic steatohepatitis, and sjogren syndrome.
170. Use of a compound according to any one of claims 1 to 142, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 143 to 146, in a method of treating systemic lupus erythematosus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
171. Use of a compound according to any one of claims 1 to 142, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 143 to 146, in a method of treating cutaneous lupus erythematosus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
172. Use of a compound according to any one of claims 1 to 142, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 143 to 146, in a method of treating lupus nephritis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition.
173. The use of any one of claims 161-172, further comprising administering one or more additional therapeutic agents.
174. The method of claim 173The use, wherein the one or more additional therapeutic agents are selected from the group consisting of: vitozumab, PF-06835375, ekuizumab, mi Latuo, SM-06, SM-03, BT-063, QX-006-N, BOS-161721, AK-101, TNX-1500, cilarizumab, darudi Li Shan, TAK-079, fevertuzumab, illimumab, anilauzumab, iscalimumab, pegylated dapirobenzab, ranafuzumab, LY-3361237, JNJ-55920839, UBP-1213, DS-7011, PFI-102, BIIB-059, obtuzumab, tatuzumab Wo Bali, TE-2324, PRV-3279, chloroquine, hydroxychloroquine sulfate, COV-08-4, GNKS-356, AVO-101, lobifuzumab, VRN-02, annexuzlimab, ALPN-101' bendamustine hydrochloride, BMS-986256 (almitoram), NKTR-35, asenapine, tiazepine, M-5049, KZR-616, KPG-818, vandixol, ALPN-303, valoxepin, LA-1, tenebrio molmod, prednisone, corticotropin, deuterocortib, CPL-409116, CS-12192, tofacitinib citrate, ISB-830, DV-1079, juliemic acid, ib Bei Du amine, TAM-01, BML-258, bupatinib, SDC-1801, SDC-1802, ICP-330, NTR-441, darapazapeptide, GSK-2646264, SKI-O-703, lansopanib (GS-9876), GS-1653, HMPL-830, rsk-132, interleukin-2, and the like, interleukin-2 Anteluke, interking recombinant human interleukin-2, ILT-101, CUG-252, DZ-2002, PEGylated HLA-X (SLE), AC-0058, non-Nibutinib, XNW-1011, tiralutinib hydrochloride, brinbinib, albutinib, obutinib, DWP-213388, INV-103, R-salbutamol sulfate, dockerin, NIK-SMI1, X-6, INV-17, O Sha Di D, baritinib, wu Pati, non-Gotinib, itratinib, INCB-54707, dighatinib, DWP-212525, CKD-971, as mometasone, betamethasone, furitol, arachidonic acid ethanolamine, DCB-SLE1, arsenic trioxide, tairuimide, TV-4710 (E Qu Tai), allogeneic human mesenchymal stem cell therapy (hUC-MSC), UC-200, BI-705564, SM, X-101, GT-934, MHz-711, MHV-934, TXV-711, and YL-013, TPX-6001, TPX-7001, dihydroartemisinin, corticosteroids, azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab, non-steroidal anti-inflammatory drugs, belimumab, fuciclosporin and AMG-592, or pharmaceutically acceptable salts thereof.
175. The use of any one of claims 161-174, wherein the subject is a human.
CN202280027627.9A 2021-04-16 2022-04-15 Thienopyrrole compounds Pending CN117120450A (en)

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US202263305610P 2022-02-01 2022-02-01
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