Capsid inhibitors for the treatment of HIV

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 disclosed herein are useful for treating or preventing a Retroviridae virus infection, including an infection caused by an HIV virus.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application 63 / 044,086, filed June 25, 2020, the full text of which is incorporated herein by reference for all purposes. Technical Field

[0003] This disclosure relates in its entirety to novel compounds, pharmaceutical compositions comprising said compounds, and methods for preparing and using said compounds and pharmaceutical compositions. In some embodiments, the novel compounds provided herein can be used to treat infections caused by Retroviridae viruses, including infections caused by HIV. Background Technology

[0004] Single-stranded RNA viruses belonging to the family Retroviridae include those from the subfamily Orthoretrovirinae, which causes many human and animal diseases, and the genera Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus, and Spumavirus. Among lentiviruses, HIV-1 infection in humans leads to T helper cell depletion and immune dysfunction, resulting in immunodeficiency and susceptibility to opportunistic infections. Highly active antiretroviral therapy (HAART) for HIV-1 infection has been shown to be effective in reducing viral load and significantly delaying disease progression (Hammer, SM et al.; JAMA 2008, 300:555-570). However, these treatments may lead to the emergence of HIV strains resistant to current therapies (Taiwo, B., International Journal of Infectious Diseases 2009, 13:552-559; Smith, RJ et al., Science 2010, 327:697-701). Therefore, there is an urgent need to discover new antiretroviral agents active against emerging drug-resistant HIV variants. There is a need for effective and stable compounds exhibiting improved pharmacokinetic and / or pharmacodynamic properties for the treatment of retroviral infections, including those caused by HIV. Summary of the Invention

[0005] In one respect, this article provides a compound of formula I,

[0006]

[0007] Or its pharmaceutically acceptable salt.

[0008] in

[0009] R 2 and R 3 Each independently is H or C 1-3 alkyl;

[0010] Each R 5 These can be the same or different halogens;

[0011] R 1 H, -CN, halogen, C 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl, -C(O)NR 6 R 6 -NR 6 R 6 -NR 7 C(O)R 8 or -C(O)R 8 , of which C 1-8 Alkyl and C 3-7 Each of the monocyclic cycloalkyl groups is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution;

[0012] Ring B, together with the two carbons it is attached to, forms ring C. 3-7 Monocyclic cycloalkyl, 5- to 9-membered fused or bridged bicyclic cycloalkyl, 3- to 4-membered monocyclic heterocyclic, 5- to 7-membered monocyclic heterocyclic, or 5- to 9-membered fused or bridged bicyclic heterocyclic.

[0013] Among them, C 3-7 Monocyclic cycloalkyl, 5- to 9-membered fused or bridged bicyclic cycloalkyl, 3- to 7-membered monocyclic heterocyclic and 5- to 9-membered fused or bridged bicyclic heterocyclic, each optionally surrounded by 1 to 5 R 16 Group substitution

[0014] The 3- to 4-membered monocyclic heterocyclic group has 1 to 2 independent cyclic heteroatoms selected from N, O, and S, and

[0015] The 5- to 7-membered monocyclic heterocyclic group and the 5- to 9-membered fused or bridged bicyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S;

[0016] Each R 16 Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-8 Alkyl, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl, -C(O)NR6 R 6 -NR 6 R 6 -NR 6 C(O)R 8 or -C(O)R 8 , of which C 1-8 Alkyl and C 3-7 Each of the monocyclic cycloalkyl groups is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution;

[0017] R 4 It is a phenyl group, a 5- to 6-membered monocyclic heterocyclic group, a 5- to 6-membered monocyclic heteroaryl group, an 8- to 10-membered fused or bridged bicyclic heterocyclic group, an 8- to 10-membered fused bicyclic heteroaryl group, a 9- to 12-membered fused or bridged tricyclic heterocyclic group, or a 9- to 12-membered fused tricyclic heteroaryl group.

[0018] The phenyl group, the 5- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, the 9- to 12-membered fused or bridged tricyclic heterocyclic group, and the 9- to 12-membered fused tricyclic heteroaryl group are each optionally surrounded by 1 to 3 R groups. 4a Group substitution, and

[0019] Each of the 5- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, the 9- to 12-membered fused or bridged tricyclic heterocyclic group and the 9- to 12-membered fused tricyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms from N, O and S;

[0020] Each R 4a Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-8 Alkyl, C 1-8 Alkoxy, -NR 6 R 6 -NR 7 S(O)2R 9 -NR 7 S(O)2NR 6 R 6 -NR 7 C(O)R 8 -NR 7 C(O)R 10 NR 6 R 6 -NR 7 C(O)NR 6 R 6 or -C(O)NR 6 R 6 , of which C1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution, or

[0021] The 1 to 3 Rs 4a The two Rs in the group 4a Connected to the same carbon and both R 4a Together with the carbon they are attached to, they form C 3-7 Monocyclic cycloalkyl;

[0022] Each R 6 H and C independently 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl groups, or 4- to 6-membered monocyclic heterocyclic groups having 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S.

[0023] Among them, C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 The alkoxy group is substituted, and

[0024] Among them, C 3-7 The monocyclic cycloalkyl group and the 4- to 6-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S are each optionally surrounded by 1 to 3 independently selected cyclic heteroatoms chosen from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkoxy group substitution; or

[0025] Two Rs 6 Together with the nitrogen atoms to which they are attached, they form 4- to 6-membered monocyclic heterocyclic groups having 1 to 3 independent cyclic heteroatoms selected from N, O, and S;

[0026] Each R 7 H can be independent or can be the same or different from C. 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution;

[0027] Each R 8 Independently -OH, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic or 4- to 6-membered monocyclic heteroaryl

[0028] Among them, C 1-8 Alkyl and C 1-8 Each alkoxy group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4Alkoxy group substitution,

[0029] Among them, C 3-7 The monocyclic cycloalkyl group, the 4- to 6-membered monocyclic heterocyclic group, and the 4- to 6-membered monocyclic heteroaryl group are each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0030] Each of the 4- to 6-membered monocyclic heterocyclic groups and the 4- to 6-membered monocyclic heteroaryl groups has 1 to 3 independent cyclic heteroatoms selected from N, O and S;

[0031] Each R 9 Independently for C 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered monocyclic heteroaryl

[0032] Among them, C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution,

[0033] Among them, C 3-7 The monocyclic cycloalkyl group, the 4- to 6-membered monocyclic heterocyclic group, and the 5- to 6-membered monocyclic heteroaryl group are each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0034] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S;

[0035] Each R 10 For C, which can be the same or different 1-4 Alkylene;

[0036] Ring A together with the two carbons attached thereto forms a 5- to 6-membered monocyclic heterocyclic group or a 5- to 6-membered monocyclic heteroaryl group, wherein each of the 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group is substituted by a Z group and each has 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0037] Z is

[0038] i) Oxide group.

[0039] ii)-OH,

[0040] iii)-CN,

[0041] iv)C 1-5 Alkyl, wherein the C 1-5The alkyl group is formed by a group selected from -OH and C. 1-4 The alkoxy group is substituted, and wherein the C 1-5 The alkyl group may optionally be further substituted with one or two independently selected groups chosen from -OH, halogen, and -CN.

[0042] v)C 6-8 Alkyl, wherein the C 6-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution,

[0043] vi)-Z 1 -Z 2 -Z 3 -Z 4 ,

[0044] Z 1 Optionally selected by one to three independently chosen from -OH, halogen, -CN, and C 1-4 The C group substituted with the alkoxy group 2-6 Imyethynyl,

[0045] Z 2 and Z 3 Each independently is C 3-7 Monocyclic cycloalkylene, C 6-10 Monocyclic or fused bicyclic aryl groups, 4- to 6-membered monocyclic heterocyclic aryl groups, 5- to 6-membered monocyclic heterocyclic aryl groups, 8- to 10-membered fused or bridged bicyclic heterocyclic aryl groups, 8- to 10-membered fused bicyclic heterocyclic aryl groups, or 7- to 10-membered spirocyclic heterocyclic aryl groups, wherein the C 3-7 Monocyclic cycloalkylene, C 6-10 The monocyclic or fused bicyclic aryl group, the 4- to 6-membered monocyclic heterocyclic aryl group, the 5- to 6-membered monocyclic heterocyclic aryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic aryl group, the 8- to 10-membered fused bicyclic heterocyclic aryl group, and the 7- to 10-membered spirocyclic heterocyclic aryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The groups are substituted, and wherein the 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroarylene group, the 8- to 10-membered fused or bridged bicyclic heterocyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroarylene group, and the 7- to 10-membered spirocyclic heterocyclic heterocyclic group each have 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S, and

[0046] Z 4 C 3-7 Monocyclic cycloalkyl, C 6-10Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic, or 7- to 10-membered spirocyclic heterocyclic, wherein the C 3-7 Monocyclic cycloalkyl, C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic and 7- to 10-membered spirocyclic heterocyclic, each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The groups are substituted, and each of the 4- to 6-membered monocyclic heterocyclic group, 5- to 6-membered monocyclic heteroaryl group, 8- to 10-membered fused or bridged bicyclic heterocyclic group, 8- to 10-membered fused bicyclic heteroaryl group and 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S.

[0047] vii) optionally selected by 1 to 3 independently chosen from -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The C group substituted with the alkoxy group 3-7 Monocyclic cycloalkyl,

[0048] viii)-S(C 1-8 alkyl), wherein the C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution,

[0049] ix)-NR 11 R 12 , where R 11 and R 12 One of them is H or C 1-8 Alkyl and R 11 and R 12 The other one is C. 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heteroaryl, or 7- to 10-membered spirocyclic heterocyclic.

[0050] Each C 1-8 Alkyl groups are 1 to 3 R 17 Group substitution,

[0051] Among them, C 3-7Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heteroaryl, and 7- to 10-membered spirocyclic heterocyclic are each optionally composed of 1 to 3 independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0052] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0053] x) optionally selected by 1 to 3 independently chosen from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 -NR 6 R 6 C groups substituted with 4- to 6-membered monocyclic heterocyclic groups and 5- to 6-membered monocyclic heteroaryl groups 6-10 Monocyclic or fused bicyclic aryl groups

[0054] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 and -NR 6 R 6 The group is substituted, and

[0055] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0056] xi) has 1 to 3 cyclic heteroatoms independently selected from N, O and S and optionally surrounded by 1 to 3 R atoms. 13 4- to 6-membered monocyclic heterocyclic groups with substituent groups,

[0057] xii) having 1 to 3 independent cyclic heteroatoms selected from N, O, and S and optionally surrounded by 1 to 3 R atoms 13 8- to 10-membered fused or bridged bicyclic heterocyclic groups with substituent groups

[0058] xiii) having 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 R atoms13 5- to 6-membered monocyclic heteroaryl groups substituted with functional groups

[0059] xiv) having 1 to 3 independent cyclic heteroatoms selected from N, O, and S and optionally bounded by 1 to 3 R 13 8- to 10-membered fused bicyclic heteroaryl groups with substituted groups, or

[0060] xv) has 1 to 3 independent cyclic heteroatoms selected from N, O and S and optionally surrounded by 1 to 3 R 13 7- to 10-membered spirocyclic heterocyclic groups with substituent groups;

[0061] Each R 17 Independently -OH, halogen, -CN, C 1-4 Alkoxy, -NR 6 R 6 C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic groups, 5- to 6-membered monocyclic heteroaryl groups, 8- to 10-membered fused or bridged bicyclic heterocyclic groups, 8- to 10-membered fused bicyclic heteroaryl groups, and 7- to 10-membered spirocyclic heterocyclic groups.

[0062] Among them, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heteroaryl, and 7- to 10-membered spirocyclic heterocyclic are each optionally composed of 1 to 3 independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0063] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0064] Each R 13 Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-4 Alkyl, C 1-4 Alkoxy, -NR 6 R 6 -C(O)R 10 NR 6 R 6 -C(O)NR 6 R 6 -C(O)R 8 C 6-10Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic, or 7- to 10-membered spirocyclic heterocyclic.

[0065] Among them, C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic and 7- to 10-membered spirocyclic heterocyclic, each optionally surrounded by 1 to 3 R 14 Group substitution, and

[0066] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0067] Each R 14 Independent of halogen, C 1-4 Alkyl, -C(O)R 8 4- to 6-membered monocyclic heterocyclic groups, 5- to 6-membered monocyclic heteroaryl groups, 8- to 10-membered fused or bridged bicyclic heterocyclic groups, 8- to 10-membered fused bicyclic heteroaryl groups, or 7- to 10-membered spirocyclic heterocyclic groups.

[0068] Among them, C 1-4 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, CN and C. 1-4 The alkoxy group is substituted, and

[0069] Among them, the 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group are each optionally C 1-3 Alkyl substitution, wherein the C 1-3 Alkyl optional -OR 10 Si(R 15 )3 Replacement;

[0070] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0071] Each R 15 Independently, C can be the same or different. 1-3 Alkyl; and

[0072] n can be 0, 1, 2, or 3.

[0073] In one aspect, this document provides pharmaceutical compositions comprising a compound provided herein 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.

[0074] 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 compositions further comprise a therapeutically effective amount of one or more (i.e., one, two, three, or four; one or two; one to three; or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.

[0075] In one aspect, this disclosure provides a method for treating or preventing human immunodeficiency virus (HIV) infection in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula I, Ia, II or IIa) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein. Detailed Implementation

[0076] I. Definition

[0077] It should be understood in the following description that this disclosure is considered illustrative of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and should not be construed as limiting the claims in any way. Embodiments exemplified under any heading may be combined with embodiments exemplified under any other heading.

[0078] Unless otherwise defined, 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 “an,” “a,” and “the” include plural references unless the context clearly specifies otherwise. Thus, for example, reference to “compound” includes a plurality of such compounds, and reference to “determination” includes reference to one or more determinations known to those skilled in the art and their equivalents, and so on.

[0079] 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.

[0080] A dash ("-") not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -CONH2 is attached via a carbon atom. A dash at the beginning or end of a chemical group is for convenience; a chemical group can be depicted without one or more dashes without losing its general meaning. A wavy line drawn through a line in the structure indicates the attachment point of a group. The order in which chemical groups are written or named does not indicate or imply directionality unless required by chemistry or structure. A solid line extending from the center of the ring indicates that the attachment point of a substituent on the ring can be at any ring atom. For example, R in the following structure... a It can be attached to any one of the five carbon ring atoms, or R a Hydrogen atoms that can be replaced by nitrogen ring atoms:

[0081]

[0082] 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. Similarly, the term "xy-membered" ring (where x and y are numerical ranges, such as "3 to 12-membered heterocyclic group") refers to a ring containing xy atoms (i.e., 3 to 12), of which up to 80% can be heteroatoms such as N, O, S, P, and the remaining atoms are carbon.

[0083] Furthermore, certain commonly used alternative chemical names may or may not be used. For example, divalent groups (such as divalent "alkyl" groups, divalent "aryl" groups, etc.) may also be referred to as "alkylene" groups ("alkylene" group or "alkylenyl" group or "alkylyl group") and "arylene" groups ("arylene" group or "arylenyl" group or "arylyl group"), respectively.

[0084] "Compounds disclosed herein" or "compounds provided herein" or "compounds described herein" refers to compounds of formulas I, II, IIa, III, IV and / or V. Specific compounds from Examples 1 to 195 are also included.

[0085] The term "about" as used herein includes (and describes) embodiments relating to the value or parameter itself. In some embodiments, the term "about" includes an indicated amount ±10%. In other embodiments, the term "about" includes an indicated amount ±5%. In some still embodiments, the term "about" includes an indicated amount ±1%. Furthermore, the term "about X" includes a description of "X".

[0086] "Alkyl" refers to a saturated hydrocarbon chain that is unbranched or branched. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, 1 to 12 carbon atoms (i.e., C464) 1-12 Alkyl groups, 1 to 8 carbon atoms (i.e., C464) 1-8 Alkyl groups, 1 to 6 carbon atoms (i.e., C646) 1-6 Alkyl groups, 1 to 4 carbon atoms (i.e., C464) 1-4 Alkyl groups, 1 to 3 carbon atoms (i.e., C464) 1-3 Alkyl group or 1 to 2 carbon atoms (i.e., C46) 1-2 Alkyl groups. 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 with a specific number of carbons is named by a chemical name or identified by a molecular formula, it can encompass all positional isomers having that number of carbons; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., (CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0087] "Alkenyl" refers to a group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C20 ... 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 groups are aliphatic groups. Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0088] "Alkyne" refers to a group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C360, C460, C560, C6 ... 2-20 acetylsyl), 2 to 8 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 2-8 acetylsyl), 2 to 6 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C7 ... 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C46) 2-4 The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0089] "Alkylene" refers to a divalent, unbranched saturated hydrocarbon chain. As used herein, alkylene chains have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkylene), 1 to 12 carbon atoms (i.e., C 1-12 Alkylene), 1 to 8 carbon atoms (i.e., C1-8 Alkylene), 1 to 6 carbon atoms (i.e., C 1-6 Alkylene), 1 to 4 carbon atoms (i.e., C42-C ... 1-4 Alkylene), 1 to 3 carbon atoms (i.e., C 1-3 Alkylene or 1 to 2 carbon atoms (i.e., C46) 1-2 Alkylenes. Examples of alkylene groups include methylene, ethylene, propylene, butylene, pentylene, and hexylene. In some embodiments, the alkylene group is optionally substituted with an alkyl group. Examples of substituted alkylene groups include -CH(CH3)CH2-, -CH2CH(CH3)-, -CH2CH(CH2CH3)-, -CH2C(CH3)2-, -C(CH3)2CH2-, -CH(CH3)CH(CH3)-, -CH2C(CH2CH3)(CH3)-, and -CH2C(CH2CH3)2.

[0090] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy. "Haloalkoxy" refers to an alkoxy group as defined above, in which one or more hydrogen atoms are replaced by a halogen.

[0091] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of these can be optionally substituted, as defined herein. Examples of acyl groups include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0092] "Acylamino" refers to the "C-acylamino" group (which refers to the group -C(=O)NR). y R z ) and "N-amide" group (which refers to the -NR group) y C(=O)R z ), where R y and R z It is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, heteroaryl, cycloalkyl, or heterocyclic groups; each of them can be optionally substituted.

[0093] "Amino" refers to the -NR group. y R z , where R y and R z Independently selected from the group consisting of: hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; each of which may optionally be substituted.

[0094] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) comprising a fused system. As used herein, aryl groups have 6 to 20 ring carbon atoms (i.e., C64 ... 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl group) or 6 to 10 carbon ring atoms (i.e., C46, ​​C56, C6 ... 6-10 Aryl groups. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracene. However, aryl does not encompass heteroaryl groups as defined below or overlap with them in any way. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is a heteroaryl ring.

[0095] "Cyano" or "formonitrile" refers to the -CN group.

[0096] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or comprising multiple rings in fused, bridged, and spirocyclic 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 cyclic carbon atoms (i.e., C4, C5, C6, C7, C8, C9 ... 3-20 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12+ ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C14 and C24). 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-6 (Cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0097] "Bridged" refers to ring fusion in which non-adjacent atoms on the ring are linked by a divalent substituent (such as an alkylene group, an alkylene group containing one or two heteroatoms) or a single heteroatom. Quinine cycloyl and adamantyl are examples of bridged ring systems.

[0098] The term "fusion" refers to a ring that is bonded to an adjacent ring.

[0099] "Spiro" refers to a cyclic substituent linked by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are spiro substituents, respectively.

[0100] "Halogen" or "halogen group" includes fluorine, chlorine, bromine, and iodine. "Halogenated alkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by a halogen. For example, in cases where residues are substituted by more than one halogen, it can be referred to by using a prefix corresponding to the number of attached halogen moieties. Dihalogenated alkyl and trihalogenated alkyl refer to alkyl groups substituted by two ("di") or three ("tri") halogen groups, which may be, but are not necessarily, the same halogen. Examples of halogenated alkyl groups include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0101] "Heteroalkylene" refers to a divalent, unbranched saturated hydrocarbon chain having one, two, or three heteroatoms selected from NH, O, or S. As used herein, heteroalkylene has 1 to 20 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C2O2 ... 1-20 Heteroalkylene); 1 to 8 carbon atoms and one, two or three heteroatoms selected from NH, O and S (i.e., C 1-8 Heteroalkylene); 1 to 6 carbon atoms and one, two or three heteroatoms selected from NH, O and S (i.e., C 1-6 Heteroalkylene); 1 to 4 carbon atoms and one, two or three heteroatoms selected from NH, O and S (i.e., C 1-4 Heteroalkylene); 1 to 3 carbon atoms and one, two or three heteroatoms selected from NH, O and S (i.e., C 1-3 Heteroalkylene); or one to two carbon atoms and one, two or three heteroatoms selected from NH, O and S (i.e., C 1-3 (Heteroalkylene). For example, CH2O- is a C1 heteroalkylene and -CH2SCH2- is a C2 heteroalkylene. Examples of heteroalkylene include -CH2CH2OCH2-, -CH2SCH2OCH2-, -CH2O-, and -CH2NHCH2-. In some embodiments, the heteroalkylene is optionally substituted with an alkyl group. Examples of substituted heteroalkylene groups include -CH(CH3)N(CH3)CH2-, -CH2OCH(CH3)-, -CH2CH(CH2CH3)S-, -CH2NHC(CH3)2-, -C(CH3)2SCH2-, -CH(CH3)N(CH3)CH(CH3)O-, -CH2SC(CH2CH3)(CH3)-, and -CH2C(CH2CH3)2NH-.

[0102] "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 groups comprise 1 to 20 carbon ring atoms (i.e., C1646-C264 ... 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); and one to five, one to four, one to three, one to two, or one cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purine, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl groups as defined above.

[0103] The term "heterocyclic group" or "heterocycle" refers to a non-aromatic cyclic alkyl group in which one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, unless otherwise indicated, "heterocyclic group" or "heterocycle" refers to a saturated or partially saturated ring; for example, in some embodiments, "heterocyclic group" or "heterocycle" refers to a partially saturated ring under specified conditions. The term "heterocyclic group" or "heterocycle" includes a heterocyclic alkenyl group (i.e., a heterocyclic group having at least one double bond). A heterocyclic group can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged, or spirocyclic. As used herein, a heterocyclic group has 2 to 20 carbon ring atoms (i.e., C64 ... 2-20 Heterocyclic group), 2 to 12 carbon ring atoms (i.e., C 2-12 Heterocyclic group), 2 to 10 carbon ring atoms (i.e., C 2-10 Heterocyclic group), 2 to 8 carbon ring atoms (i.e., C 2-8 Heterocyclic group), 3 to 12 carbon ring atoms (i.e., C 3-12 Heterocyclic group), 3 to 8 carbon ring atoms (i.e., C 3-8 Heterocyclic group) or 3 to 6 carbon ring atoms (i.e., C 3-6Heterocyclic groups; having 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclic groups include pyrrolidinyl, piperidinyl, piperazineyl, oxobutyranyl, dioxopentyl, azirrobutyranyl, and morpholinyl. As used herein, the term “bridged-heterocyclic group” refers to a four- to ten-membered ring moiety having one or more (e.g., 1 or 2) four- to ten-membered ring moiety having at least one heteroatom attached to two non-adjacent atoms of the heterocyclic group, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein, “bridged-heterocyclic group” includes bicyclic and tricyclic ring systems. As used herein, the term "spiro-heterocyclic" refers to a cyclic system in which a ternary to ten-membered heterocyclic group has one or more additional rings, wherein the one or more additional rings are ternary to ten-membered cycloalkyl groups or ternary to ten-membered heterocyclic groups, and wherein individual atoms of the one or more additional rings are also atoms of the ternary to ten-membered heterocyclic group. Examples of spiro-heterocyclic groups include bicyclic and tricyclic cyclic systems, such as 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. As used herein, the terms "heterocyclic," "heterocyclic group," and "heterocyclic" are used interchangeably. In some embodiments, the heterocyclic group is substituted with an oxo group.

[0104] A hydroxyl group ("Hydroxy" or "hydroxyl") refers to the -OH group.

[0105] "Oxide group" refers to a group (=O) or (O).

[0106] "Sulfonyl" refers to the group -S(O)2R. c , where R c It can be alkyl, haloalkyl, heterocyclic, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl groups are methanesulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0107] As used herein, “2-oxa-6-azaspiro[3.3]heptane” has the following structure:

[0108]

[0109] As used herein, “2,5-diazabicyclo[2.2.1]heptane” has the following structure:

[0110]

[0111] As used herein, “2,6-diazaspiro[3.3]heptane” has the following structure:

[0112]

[0113] As used herein, “1,6-diazaspiro[3.3]heptane” has the following structure:

[0114]

[0115] As used herein, “2,7-diazaspiro[3.5]nonane” has the following structure:

[0116]

[0117] As used herein, “1-oxa-3,8-diazaspiro[4.5]decane” has the following structure:

[0118]

[0119] As used herein, “5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine” has the following structure:

[0120]

[0121] As used in this article, “2,3-dihydrobenzo[b][1,4]dioxin” has the following structure:

[0122]

[0123] As used herein, “1H-benzis[d]imidazole” has the following structure:

[0124]

[0125] Unless otherwise indicated, whenever the graphical representation of a group terminates at a single-bonded nitrogen atom, the group represents an -NH group. Similarly, unless otherwise expressed, hydrogen atoms are implied and assumed to be present where necessary, based on knowledge of valence or stability acquired by those skilled in the art.

[0126] The terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes instances where said event or situation occurs and instances where said event or situation does not occur. Furthermore, the term “optionally substituted” means that any one or more hydrogen atoms on the designated atom or group may or may not be substituted by portions other than hydrogen.

[0127] The term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, provided that the substitution does not exceed the normal valence of the specified atom. Such one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidine, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidinyl, haloyl, haloalkyl, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazine, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar indeterminate structures obtained by defining substituents with an unlimited number of further substituents (e.g., substituted aryl groups with substituted alkyl groups, which themselves are substituted by substituted aryl groups, which are further substituted by substituted heteroalkyl groups, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, the successive substitution of a substituted aryl group having two other substituted aryl groups is limited to ((substituted aryl)-substituted aryl)-substituted aryl. Similarly, the above definition is not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl". Unless otherwise stated, groups described as optionally substituted are those whose substituents are themselves unsubstituted.

[0128] In some embodiments, the substituted cycloalkyl, substituted heterocyclic, substituted aryl, and / or substituted heteroaryl groups comprise cycloalkyl, heterocyclic, aryl, and / or heteroaryl groups having substituents on the ring atom, which are linked to the remainder of the compound. For example, in the following moiety, the cyclopropyl group is substituted with a methyl group:

[0129]

[0130] 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 stereoisomers that may be defined by absolute stereochemistry as (R)- or (S)- or for amino acids as (D)- or (L)-. This disclosure is intended to include all such possible isomers as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain an alkene double bond or other geometrically asymmetric centers, and unless otherwise stated, the compounds are intended to include E and Z geometric isomers. Similarly, all tautomers are also intended to be included. When a compound is represented in its chiral form, it should be understood that the embodiments cover, but are not limited to, specific diastereomeric or enantiomerically enriched forms. When chirality is not specified but is present, it should be understood that the embodiments relate to specific diastereomeric or enantiomerically enriched forms; or racemic or non-racemic mixtures of such compounds. As used herein, a “non-racemic mixture” is a mixture of stereoisomers in a ratio not equal to 1:1.

[0131] "Stereoisomers" are compounds composed of identical atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This disclosure envisions various stereoisomers and mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0132] An enantiomer is a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture. A mixture of enantiomers in a different 1:1 ratio is a non-racemic mixture.

[0133] A "diastereomer" is a stereoisomer that has at least two asymmetric atoms but is not a mirror image of each other.

[0134] "Tautomerism" refers to the migration of a proton from one atom of a molecule to another atom of the same molecule. This disclosure includes tautomerisms of any compounds provided herein.

[0135] Some of the compounds described herein exist as tautomers. These tautomers are in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with their imine tautomers. Regardless of which tautomer is exhibited, and regardless of the nature of the equilibrium between the tautomers, those skilled in the art will understand that the compounds include both amide and imine tautomers. Therefore, amide-containing compounds are understood to include their imine tautomers. Similarly, imine-containing compounds are understood to include their amide tautomers.

[0136] "Solvates" are formed through the interaction of a solvent and a compound. Solvates of salts of the compounds provided herein are also provided. Hydrates of the compounds provided herein are also provided.

[0137] Any formula or structure provided herein is intended to represent both the unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures described by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, isotopes of these elements. 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 125 I. This document also provides various isotope-labeled compounds of this disclosure, such as those incorporating radioactive isotopes such as 2 H, 3 H, 13 C and 14 Those containing C. These isotope-labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including tissue distribution assays of drugs or substrates, or for radiation therapy of patients.

[0138] This disclosure also includes compounds of formula I, II, or IIa, wherein one to n hydrogen atoms bonded to a carbon atom are replaced by deuterium, where n is the number of hydrogen atoms in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore used to prolong the half-life of any compound of formula I, II, or IIa when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci., Vol. 5 (No. 12): pp. 524-527 (1984). Such compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0139] The deuterium-labeled or substituted therapeutic compounds disclosed herein may have improved DMPK (drug metabolism and pharmacokinetics) properties, which involve absorption, distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirements, and / or improved therapeutic index. 18 F-labeled compounds can be used in PET or SPECT studies. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents, or by following the procedures disclosed in the examples and formulations described below. It should be understood that, in this context, deuterium is considered a substituent in compounds of formula I, II, or IIa.

[0140] The concentration of such heavier isotopes (particularly deuterium) can be defined by the isotope enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope means that atom represents any stable isotope. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to be hydrogen having its naturally occurring isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) means that deuterium is represented.

[0141] In many cases, the compounds disclosed herein are capable of forming acid salts and / or base salts by means of amino groups and / or carboxyl groups or similar groups.

[0142] The term "pharmaceutically acceptable salt" for a given compound refers to a salt that retains the biological efficacy 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, dienylamines, trienylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, monocyclic alkylamines, dicyclic alkylamines or tricyclic alkylamines, monoarylamines, diarylamines or triarylamines or mixed amines, etc. Specific examples of suitable amines, by way of example only, include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0143] 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, and phosphoric acid. 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, and salicylic acid.

[0144] As used herein, "pharmaceutically acceptable carrier" or "pharmaceuticalally acceptable excipient" includes any and all solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents, and absorption delay agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in a therapeutic composition should be considered. Additional active ingredients may also be incorporated into the composition.

[0145] "Treatment" (or "treating") is a method used to achieve a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes include one or more of the following: a) suppressing a disease or condition (i.e., reducing one or more symptoms caused by the disease or condition, and / or reducing the severity of the disease or condition); b) slowing or halting the development of one or more clinical symptoms associated with the disease or condition (i.e., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying its spread (i.e., metastasis of the disease or condition); and / or c) alleviating the disease, i.e. leading to the resolution of clinical symptoms (i.e., improving the disease state, providing partial or overall relief from the disease or condition, enhancing the effects of another medication, delaying the progression of the disease, increasing quality of life, and / or prolonging survival).

[0146] "Prevention" or "preventing" means any treatment that prevents the development of clinical symptoms of a disease or condition. In some implementations, the compound may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0147] "Subject" refers to an animal, such as a mammal (including a human), which has been or will be the subject of treatment, observation, or experimentation. The methods described herein can be used for human therapeutics and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0148] The term "therapeutic effective amount" or "effective amount" as used with respect to compounds or their pharmaceutically acceptable salts, isomers, or mixtures described herein means an amount sufficient, when administered to a subject, to achieve therapeutic effects and provide therapeutic benefits such as improvement of symptoms or slowing of disease progression. For example, a therapeutic effective amount may be an amount sufficient to alleviate symptoms of a disease or condition that responds to activation of protein kinase C (PKC). Therapeutic effective amounts can vary depending on the subject, the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the route of administration, which can be readily determined by those skilled in the art.

[0149] II.Compounds

[0150] In one respect, this article provides a compound of formula I,

[0151]

[0152] Or its pharmaceutically acceptable salt.

[0153] in

[0154] R 2 and R 3 Each independently is H or C 1-3 alkyl;

[0155] Each R 5 These can be the same or different halogens;

[0156] R 1 H, -CN, halogen, C 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl, -C(O)NR 6 R 6 -NR 6 R 6 -NR 7 C(O)R 8 or -C(O)R 8 , of which C 1-8 Alkyl and C3-7 Each of the monocyclic cycloalkyl groups is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution;

[0157] Ring B, together with the two carbons it is attached to, forms ring C. 3-7 Monocyclic cycloalkyl, 5- to 9-membered fused or bridged bicyclic cycloalkyl, 3- to 4-membered monocyclic heterocyclic, 5- to 7-membered monocyclic heterocyclic, or 5- to 9-membered fused or bridged bicyclic heterocyclic.

[0158] Among them, C 3-7 Monocyclic cycloalkyl, 5- to 9-membered fused or bridged bicyclic cycloalkyl, 3- to 7-membered monocyclic heterocyclic and 5- to 9-membered fused or bridged bicyclic heterocyclic, each optionally surrounded by 1 to 5 R 16 Group substitution,

[0159] The 3- to 4-membered monocyclic heterocyclic group has 1 to 2 independent cyclic heteroatoms selected from N, O, and S, and

[0160] The 5- to 7-membered monocyclic heterocyclic group and the 5- to 9-membered fused or bridged bicyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S;

[0161] Each R 16 Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-8 Alkyl, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl, -C(O)NR 6 R 6 -NR 6 R 6 -NR 6 C(O)R 8 or -C(O)R 8 , of which C 1-8 Alkyl and C 3-7 Each of the monocyclic cycloalkyl groups is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution;

[0162] R 4 It is a phenyl group, a 5- to 6-membered monocyclic heterocyclic group, a 5- to 6-membered monocyclic heteroaryl group, an 8- to 10-membered fused or bridged bicyclic heterocyclic group, an 8- to 10-membered fused bicyclic heteroaryl group, a 9- to 12-membered fused or bridged tricyclic heterocyclic group, or a 9- to 12-membered fused tricyclic heteroaryl group.

[0163] The phenyl group, the 5- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, the 9- to 12-membered fused or bridged tricyclic heterocyclic group, and the 9- to 12-membered fused tricyclic heteroaryl group are each optionally surrounded by 1 to 3 R groups.4a Group substitution, and

[0164] Each of the 5- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, the 9- to 12-membered fused or bridged tricyclic heterocyclic group and the 9- to 12-membered fused tricyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms from N, O and S;

[0165] Each R 4a Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-8 Alkyl, C 1-8 Alkoxy, -NR 6 R 6 -NR 7 S(O)2R 9 -NR 7 S(O)2NR 6 R 6 -NR 7 C(O)R 8 -NR 7 C(O)R 10 NR 6 R 6 -NR 7 C(O)NR 6 R 6 or -C(O)NR 6 R 6 , of which C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution, or

[0166] The 1 to 3 Rs 4a The two Rs in the group 4a Connected to the same carbon and both R 4a Together with the carbon they are attached to, they form C 3-7 Monocyclic cycloalkyl;

[0167] Each R 6 Independently for H and C 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl groups, or 4- to 6-membered monocyclic heterocyclic groups having 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S.

[0168] Among them, C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 The alkoxy group is substituted, and

[0169] Among them, C 3-7The monocyclic cycloalkyl group and the 4- to 6-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S are each optionally surrounded by 1 to 3 independently selected cyclic heteroatoms chosen from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkoxy group substitution; or

[0170] Two Rs 6 Together with the nitrogen atoms to which they are attached, they form 4- to 6-membered monocyclic heterocyclic groups having 1 to 3 independent cyclic heteroatoms selected from N, O, and S;

[0171] Each R 7 H can be independent or can be the same or different from C. 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution;

[0172] Each R 8 Independently -OH, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic or 4- to 6-membered monocyclic heteroaryl

[0173] Among them, C 1-8 Alkyl and C 1-8 Each alkoxy group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution,

[0174] Among them, C 3-7 The monocyclic cycloalkyl group, the 4- to 6-membered monocyclic heterocyclic group, and the 4- to 6-membered monocyclic heteroaryl group are each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0175] Each of the 4- to 6-membered monocyclic heterocyclic groups and the 4- to 6-membered monocyclic heteroaryl groups has 1 to 3 independent cyclic heteroatoms selected from N, O and S;

[0176] Each R 9 Independently for C 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered monocyclic heteroaryl

[0177] Among them, C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution,

[0178] Among them, C3-7 The monocyclic cycloalkyl group, the 4- to 6-membered monocyclic heterocyclic group, and the 5- to 6-membered monocyclic heteroaryl group are each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0179] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S;

[0180] Each R 10 For C, which can be the same or different 1-4 Alkylene;

[0181] Ring A together with the two carbons attached thereto forms a 5- to 6-membered monocyclic heterocyclic group or a 5- to 6-membered monocyclic heteroaryl group, wherein each of the 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group is substituted by a Z group and each has 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0182] Z is

[0183] i) Oxide group.

[0184] ii)-OH,

[0185] iii)-CN,

[0186] iv)C 1-5 Alkyl, wherein the C 1-5 The alkyl group is formed by a group selected from -OH and C. 1-4 The alkoxy group is substituted, and wherein the C 1-5 The alkyl group may optionally be further substituted with one or two independently selected groups chosen from -OH, halogen, and -CN.

[0187] v)C 6-8 Alkyl, wherein the C 6-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution,

[0188] vi)-Z 1 -Z 2 -Z 3 -Z 4 ,

[0189] Z 1 Optionally selected by one to three independently chosen from -OH, halogen, -CN, and C 1-4 The C group substituted with the alkoxy group 2-6 Imyethynyl,

[0190] Z 2 and Z3 Each independently is C 3-7 Monocyclic cycloalkylene, C 6-10 Monocyclic or fused bicyclic aryl groups, 4- to 6-membered monocyclic heterocyclic aryl groups, 5- to 6-membered monocyclic heterocyclic aryl groups, 8- to 10-membered fused or bridged bicyclic heterocyclic aryl groups, 8- to 10-membered fused bicyclic heterocyclic aryl groups, or 7- to 10-membered spirocyclic heterocyclic aryl groups, wherein the C 3-7 Monocyclic cycloalkylene, C 6-10 The monocyclic or fused bicyclic aryl group, the 4- to 6-membered monocyclic heterocyclic aryl group, the 5- to 6-membered monocyclic heterocyclic aryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic aryl group, the 8- to 10-membered fused bicyclic heterocyclic aryl group, and the 7- to 10-membered spirocyclic heterocyclic aryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The groups are substituted, and wherein the 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroarylene group, the 8- to 10-membered fused or bridged bicyclic heterocyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroarylene group, and the 7- to 10-membered spirocyclic heterocyclic heterocyclic group each have 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S, and

[0191] Z 4 C 3-7 Monocyclic cycloalkyl, C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic, or 7- to 10-membered spirocyclic heterocyclic, wherein the C 3-7 Monocyclic cycloalkyl, C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic and 7- to 10-membered spirocyclic heterocyclic, each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The groups are substituted, and each of the 4- to 6-membered monocyclic heterocyclic group, 5- to 6-membered monocyclic heteroaryl group, 8- to 10-membered fused or bridged bicyclic heterocyclic group, 8- to 10-membered fused bicyclic heteroaryl group and 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S.

[0192] vii) optionally selected by 1 to 3 independently chosen from -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The C group substituted with the alkoxy group 3-7 Monocyclic cycloalkyl,

[0193] viii)-S(C1-8 alkyl), wherein the C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution,

[0194] ix)-NR 11 R 12 , where R 11 and R 12 One of them is H or C 1-8 Alkyl and R 11 and R 12 The other one is C. 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heteroaryl, or 7- to 10-membered spirocyclic heterocyclic.

[0195] Each C 1-8 Alkyl groups are 1 to 3 R 17 Group substitution,

[0196] Among them, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heteroaryl, and 7- to 10-membered spirocyclic heterocyclic are each optionally composed of 1 to 3 independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0197] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0198] x) optionally selected by 1 to 3 independently chosen from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 -NR 6 R 6 C groups substituted with 4- to 6-membered monocyclic heterocyclic groups and 5- to 6-membered monocyclic heteroaryl groups 6-10 Monocyclic or fused bicyclic aryl groups

[0199] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 and -NR 6 R 6 The group is substituted, and

[0200] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0201] xi) has 1 to 3 cyclic heteroatoms independently selected from N, O and S and optionally surrounded by 1 to 3 R atoms. 13 4- to 6-membered monocyclic heterocyclic groups with substituent groups,

[0202] xii) having 1 to 3 independent cyclic heteroatoms selected from N, O, and S and optionally surrounded by 1 to 3 R atoms 13 8- to 10-membered fused or bridged bicyclic heterocyclic groups with substituent groups

[0203] xiii) having 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 R atoms 13 5- to 6-membered monocyclic heteroaryl groups substituted with functional groups

[0204] xiv) having 1 to 3 independent cyclic heteroatoms selected from N, O, and S and optionally bounded by 1 to 3 R 13 8- to 10-membered fused bicyclic heteroaryl groups with substituted groups, or

[0205] xv) has 1 to 3 independent cyclic heteroatoms selected from N, O and S and optionally surrounded by 1 to 3 R 13 7- to 10-membered spirocyclic heterocyclic groups with substituent groups;

[0206] Each R 17 Independently -OH, halogen, -CN, C 1-4 Alkoxy, -NR 6 R 6 C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic groups, 5- to 6-membered monocyclic heteroaryl groups, 8- to 10-membered fused or bridged bicyclic heterocyclic groups, 8- to 10-membered fused bicyclic heteroaryl groups, and 7- to 10-membered spirocyclic heterocyclic groups.

[0207] Among them, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heteroaryl, and 7- to 10-membered spirocyclic heterocyclic are each optionally composed of 1 to 3 independently selected from oxo, -OH, halogen, -CN, C 1-4Alkyl and C 1-4 The alkoxy group is substituted, and

[0208] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0209] Each R 13 Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-4 Alkyl, C 1-4 Alkoxy, -NR 6 R 6 -C(O)R 10 NR 6 R 6 -C(O)NR 6 R 6 -C(O)R 8 C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic, or 7- to 10-membered spirocyclic heterocyclic.

[0210] Among them, C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic and 7- to 10-membered spirocyclic heterocyclic, each optionally surrounded by 1 to 3 R 14 Group substitution, and

[0211] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0212] Each R 14 Independent of halogen, C 1-4 Alkyl, -C(O)R 8 4- to 6-membered monocyclic heterocyclic groups, 5- to 6-membered monocyclic heteroaryl groups, 8- to 10-membered fused or bridged bicyclic heterocyclic groups, 8- to 10-membered fused bicyclic heteroaryl groups, or 7- to 10-membered spirocyclic heterocyclic groups.

[0213] Among them, C 1-4 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, CN and C. 1-4 The alkoxy group is substituted, and

[0214] Among them, the 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group are each optionally C 1-3 Alkyl substitution, wherein the C 1-3 Alkyl optional -OR 10 Si(R 15 )3 Replacement;

[0215] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0216] Each R 15 Independently for C, which can be the same or different 1-3 Alkyl; and

[0217] n can be 0, 1, 2, or 3.

[0218] In some embodiments, the compound of formula I has formula Ia:

[0219]

[0220] Or its pharmaceutically acceptable salt.

[0221] In some embodiments of the compound of formula I or Ia or its pharmaceutically acceptable salt,

[0222] R 2 and R 3 Each independently is H or C 1-3 alkyl;

[0223] Each R 5 These can be the same or different halogens;

[0224] R 1 H, -CN, halogen, C 1-8 Alkyl or C 3-7 Monocyclic cycloalkyl, wherein the C 1-8 Alkyl and C 3-7 Each of the monocyclic cycloalkyl groups is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution;

[0225] Ring B, together with the two carbons it is attached to, forms ring C. 3-7 Monocyclic cycloalkyl or 5- to 9-membered fused or bridged bicyclic cycloalkyl groups,

[0226] Among them, C 3-7Monocyclic cycloalkyl groups and 5 to 9 fused or bridged bicyclic cycloalkyl groups are each optionally surrounded by 1 to 5 R groups. 16a Group substitution;

[0227] Each R 16a Independently -OH, halogen, -CN, C 1-8 Alkyl, C 1-4 Alkoxy and C 3-7 Monocyclic cycloalkyl, wherein the C 1-8 Alkyl and C 3-7 Each of the monocyclic cycloalkyl groups is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution;

[0228] R 4 It is a phenyl group, an 8- to 10-membered fused or bridged bicyclic heterocyclic group, an 8- to 10-membered fused bicyclic heteroaryl group, or a 9- to 12-membered fused or bridged tricyclic heterocyclic group.

[0229] The phenyl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 9- to 12-membered fused or bridged tricyclic heterocyclic group are each optionally surrounded by 1 to 3 R groups. 4a Group substitution, and

[0230] The 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 9- to 12-membered fused or bridged tricyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0231] Each R 4a Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-8 Alkyl, C 1-8 Alkoxy, -NR 6 R 6 -NR 7 S(O)2R 9 or -C(O)NR 6 R 6 , of which C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution, or

[0232] The 1 to 3 Rs 4a The two Rs in the group 4a Connected to the same carbon and both R 4a Together with the carbon they are attached to, they form C 3-7 Monocyclic cycloalkyl;

[0233] Each R 6 Independently for H and C 1-8 Alkyl or C3-7 Monocyclic cycloalkyl,

[0234] Among them, C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 The alkoxy group is substituted, and

[0235] Among them, C 3-7 The monocyclic cycloalkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkoxy group substitution;

[0236] Each R 7 H can be independent or can be the same or different from C. 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution;

[0237] Each R 8 Independently -OH, C 1-8 Alkyl or C 1-8 Alkoxy;

[0238] Each R 9 Independently for C 1-8 Alkyl or C 3-7 Monocyclic cycloalkyl,

[0239] Among them, C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 The alkoxy group is substituted, and

[0240] Among them, C 3-7 The monocyclic cycloalkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkoxy group substitution;

[0241] Each R 10 For C, which can be the same or different 1-4 Alkylene;

[0242] Ring A together with the two carbons attached thereto forms a 5- to 6-membered monocyclic heterocyclic group or a 5- to 6-membered monocyclic heteroaryl group, wherein each of the 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group is substituted by a Z group and each has 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0243] Z is

[0244] i) Oxide group.

[0245] ii)-OH,

[0246] iii)-CN,

[0247] iv)C 1-5 Alkyl, wherein the C 1-5 The alkyl group is formed by a group selected from -OH and C. 1-4 The alkoxy group is substituted, and wherein the C 1-5 The alkyl group may optionally be further substituted with one or two independently selected groups chosen from -OH, halogen, and -CN.

[0248] v)C 6-8 Alkyl, wherein the C 6-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution,

[0249] vi)-Z 1 -Z 2 -Z 3 -Z 4 ,

[0250] Z 1 Optionally selected by 1 to 3 independently chosen from -OH, halogen, -CN and C 1-4 The C group substituted with the alkoxy group 2-6 Imyethynyl,

[0251] Z 2 C 6-10 Monocyclic or fused bicyclic arylene, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered monocyclic heterocyclic arylene, wherein the C 6-10 The monocyclic or fused bicyclic arylene, the 4- to 6-membered monocyclic heterocyclic arylene, and the 5- to 6-membered monocyclic heterocyclic arylene are each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The groups are substituted, and each of the 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroarylene group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S.

[0252] Z 3 It is a 5- to 6-membered monocyclic heterocyclic group or a 5- to 6-membered monocyclic heteroarylene group.

[0253] The 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heterocyclic aryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted, and

[0254] The 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroarylene group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S, and

[0255] Z 4 It is a 5- to 6-membered monocyclic heterocyclic group or a 5- to 6-membered monocyclic heteroaryl group.

[0256] The 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted, and

[0257] The 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0258] vii) optionally selected by 1 to 3 independently chosen from -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The C group substituted with the alkoxy group 3-7 Monocyclic cycloalkyl,

[0259] viii)-S(C 1-4 alkyl), wherein the C 1-4 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution,

[0260] ix)-NR 11 R 12 , where R 11 and R 12 One of them is H or C 1-8 Alkyl and R 11 and R 12 The other one is C 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered monocyclic heteroaryl, wherein each C 1-8 Alkyl groups are 1 to 3 R 17a Group substitution;

[0261] Among them, C 3-7 The monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic and 5- to 6-membered monocyclic heteroaryl groups are each optionally composed of 1 to 3 independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0262] The 4- to 6-membered monocyclic heterocyclic groups and the 5- to 6-membered monocyclic heteroaryl groups each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0263] x) optionally selected by 1 to 3 independently chosen from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 -NR 6 R 6 C groups substituted with 4- to 6-membered monocyclic heterocyclic groups and 5- to 6-membered monocyclic heteroaryl groups 6-10 Monocyclic or fused bicyclic aryl groups

[0264] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 and -NR 6 R 6 The group is substituted, and

[0265] The 4- to 6-membered monocyclic heterocyclic groups and the 5- to 6-membered monocyclic heteroaryl groups each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0266] xi) has 1 to 3 independent cyclic heteroatoms selected from N, O and S and optionally surrounded by 1 to 3 R atoms. 13 4- to 6-membered monocyclic heterocyclic groups with substituent groups,

[0267] xii) having 1 to 3 independent cyclic heteroatoms selected from N, O, and S and optionally surrounded by 1 to 3 R atoms 13 8- to 10-membered fused or bridged bicyclic heterocyclic groups with substituent groups

[0268] xiii) having 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 R atoms 13 5- to 6-membered monocyclic heteroaryl groups with substituted groups

[0269] xiv) optionally by 1 to 3 R 13 8- to 10-membered fused bicyclic heteroaryl groups with substituted groups, or

[0270] xv) has 1 to 3 independent cyclic heteroatoms selected from N, O and S and optionally surrounded by 1 to 3 R 13 7- to 10-membered spirocyclic heterocyclic groups substituted with functional groups;

[0271] Each R 17a Independently -OH, halogen, -CN, C 1-4 Alkoxy, -NR 6 R 6 C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic groups, and 5- to 6-membered monocyclic heteroaryl groups

[0272] Among them, C 1-4 Alkoxy, C 3-7 The monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic and 5- to 6-membered monocyclic heteroaryl groups are each optionally composed of 1 to 3 independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0273] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S;

[0274] Each R 13 Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-4 Alkyl, C 1-4 Alkoxy, -NR 6 R 6 -C(O)R 10 NR 6 R 6 -C(O)NR 6 R 6 -C(O)R 8 C 6-10 Monocyclic or fused bicyclic aryl groups, 4- to 6-membered monocyclic heterocyclic groups, 5- to 6-membered monocyclic heterocyclic groups, 8- to 10-membered fused or bridged bicyclic heterocyclic groups, or 8- to 10-membered fused bicyclic heterocyclic groups.

[0275] Among them, C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic and 8- to 10-membered fused bicyclic heterocyclic are each optionally surrounded by 1 to 3 R 14 Group substitution, and

[0276] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group and the 8- to 10-membered fused bicyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0277] Each R 14 Independent of halogen, C 1-4 Alkyl, -C(O)R 8Or a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S.

[0278] Among them, C 1-4 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, CN and C. 1-4 The alkoxy group is substituted, and

[0279] The 5- to 6-membered monocyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O, and S is optionally surrounded by C. 1-3 Alkyl substitution, wherein the C 1-3 Alkyl optional -OR 10 Si(R 15 )3 Replacement;

[0280] Each R 15 Independently for C, which can be the same or different 1-3 Alkyl; and

[0281] n can be 0, 1, 2, or 3.

[0282] In some embodiments of the compounds of formula I or Ia or their pharmaceutically acceptable salts, n is 0, 1, 2, or 3. In some embodiments of the compounds of formula I or Ia or their pharmaceutically acceptable salts, n is 0. In some embodiments of the compounds of formula I or Ia or their pharmaceutically acceptable salts, n is 1. In some embodiments of the compounds of formula I or Ia or their pharmaceutically acceptable salts, n is 2. In some embodiments of the compounds of formula I or Ia or their pharmaceutically acceptable salts, n is 3.

[0283] In some embodiments, the compound of formula I has formula II:

[0284]

[0285] Or its pharmaceutically acceptable salt.

[0286] In some embodiments, the compounds of formula I, Ia, or II have formula IIa:

[0287]

[0288] Or its pharmaceutically acceptable salt.

[0289] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 2 and R 3 Each independently is H or C 1-3 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 2 and R3 One of them is H and R 2 and R 3 The other one is C 1-3 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 2 and R 3 One of them is H and R 2 and R 3 The other is methyl. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 2 and R 3 One of them is H and R 2 and R 3 The other is ethyl. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 2 and R 3 One of them is H and R 2 and R 3 The other is propyl. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 2 and R 3 One of them is H and R 2 and R 3 The other is isopropyl. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 2 and R 3 All are H. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, R 2 and R 3 Each can be methyl, ethyl, propyl, or isopropyl.

[0290] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 5 The halogens may be the same or different. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, each R 5 Independently chlorine, fluorine, bromine, or iodine. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 5 Independently chlorine, fluorine, or bromine. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 5 Fluorine. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, the two R... 5Fluorine. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R... 5 It is fluorine.

[0291] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms C. 3-7 Monocyclic cycloalkyl, 5- to 9-membered fused or bridged bicyclic cycloalkyl, 3- to 4-membered monocyclic heterocyclic, 5- to 7-membered monocyclic heterocyclic, or 5- to 9-membered fused or bridged bicyclic heterocyclic.

[0292] Among them, C 3-7 Monocyclic cycloalkyl, 5- to 9-membered fused or bridged bicyclic cycloalkyl, 3- to 7-membered monocyclic heterocyclic and 5- to 9-membered fused or bridged bicyclic heterocyclic, each optionally surrounded by 1 to 5 R 16 Group substitution

[0293] The 3- to 4-membered monocyclic heterocyclic group has 1 to 2 independent cyclic heteroatoms selected from N, O, and S, and

[0294] The 5- to 7-membered monocyclic heterocyclic group and the 5- to 9-membered fused or bridged bicyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0295] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms C. 3-7 Monocyclic cycloalkyl or 5- to 9-membered fused or bridged bicyclic cycloalkyl groups,

[0296] Among them, C 3-7 The monocyclic cycloalkyl group and the 5- to 9-membered fused or bridged bicyclic cycloalkyl group are each optionally surrounded by 1 to 5 R groups. 16a Group substitution.

[0297] In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, ring B together with the two carbons to which it is attached forms a cyclohexyl group or a 6- or 7-membered fused or bridged bicyclic cycloalkyl group, wherein the cyclohexyl group and the 6- or 7-membered fused or bridged bicyclic cycloalkyl group are each optionally substituted with 1 to 5 halogens.

[0298] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms C. 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is optionally surrounded by 1 to 5 R groups. 16 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms C.3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is optionally surrounded by 1 to 5 R groups. 16a Group substitution.

[0299] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms C. 3-7 Monocyclic cycloalkyl, wherein the C 3-7 Monocyclic cycloalkyl groups are marked with 1 to 5 R groups. 16 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms C. 3-7 Monocyclic cycloalkyl, wherein the C 3-7 Monocyclic cycloalkyl groups are marked with 1 to 5 R groups. 16a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms C. 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is independently selected from 1 to 5 -OH, halogen, -CN and C. 1-8 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms C. 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is substituted with 1 to 5 halogens. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms C. 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is substituted with 1 to 5 fluorine atoms. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, ring B together with the two carbons to which it is attached forms a cyclopentyl group, wherein the cyclopentyl group is substituted with 1 to 5 fluorine atoms.

[0300] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms C. 3-7 Monocyclic cycloalkyl. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, ring B together with the two carbons to which it is attached forms cyclopentyl or cyclohexyl.

[0301] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a cyclohexyl group, wherein the cyclohexyl group is optionally substituted with 1 to 5 halogens. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a cyclohexyl group, wherein the cyclohexyl group is substituted with 1 to 4 halogens. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a cyclohexyl group, wherein the cyclohexyl group is substituted with 1 to 5 fluorine atoms.

[0302] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 5- to 9-membered fused or bridged bicyclic cycloalkyl group, wherein the 5- to 9-membered fused or bridged bicyclic cycloalkyl group is optionally surrounded by 1 to 5 R groups. 16 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 5- to 9-membered fused or bridged bicyclic cycloalkyl group, wherein the 5- to 9-membered fused or bridged bicyclic cycloalkyl group is optionally replaced by 1 to 5 R groups. 16a Group substitution.

[0303] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 5- to 9-membered fused or bridged bicyclic cycloalkyl group, wherein the 5- to 9-membered fused or bridged bicyclic cycloalkyl group is formed by 1 to 5 independently selected from -OH, halogen, -CN, and C. 1-8Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 5- to 9-membered fused or bridged bicyclic cycloalkyl group, wherein the 5- to 9-membered fused or bridged bicyclic cycloalkyl group is substituted with 1 to 5 halogens. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 5- to 9-membered fused or bridged bicyclic cycloalkyl group, wherein the 5- to 9-membered fused or bridged bicyclic cycloalkyl group is substituted with 1 to 4 halogens. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 5- to 9-membered fused or bridged bicyclic cycloalkyl group, wherein the 5- to 9-membered fused or bridged bicyclic cycloalkyl group is substituted with 1 to 5 fluorine groups. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 6-8 fused or bridged bicyclic cycloalkyl group, wherein the 6-8 fused or bridged bicyclic cycloalkyl group is substituted with 1 to 5 fluorine atoms. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 6-fused or bridged bicyclic cycloalkyl group, wherein the 6-fused or bridged bicyclic cycloalkyl group is substituted with 1 to 5 fluorine atoms. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 7-fused or bridged bicyclic cycloalkyl group, wherein the 7-fused or bridged bicyclic cycloalkyl group is substituted with 1 to 5 fluorine atoms.

[0304] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 6- or 7-membered fused or bridged bicyclic cycloalkyl group, wherein the 6- or 7-membered fused or bridged bicyclic cycloalkyl group is optionally substituted with 1 to 5 halogens. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 6- or 7-membered fused or bridged bicyclic cycloalkyl group, wherein the 6- or 7-membered fused or bridged bicyclic cycloalkyl group is substituted with 1 to 4 halogens. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 6- or 7-membered fused or bridged bicyclic cycloalkyl group, wherein the 6- or 7-membered fused or bridged bicyclic cycloalkyl group is substituted with 1 to 3 halogens. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 6- or 7-membered fused or bridged bicyclic cycloalkyl group, wherein the 6- or 7-membered fused or bridged bicyclic cycloalkyl group is substituted with 1 to 3 fluorines.

[0305] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 3- to 4-membered monocyclic heterocyclic group, wherein the 3- to 4-membered monocyclic heterocyclic group has 1 to 2 independently selected cyclic heteroatoms chosen from N, O, and S and optionally surrounded by 1 to 5 R atoms. 16 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 3- to 4-membered monocyclic heterocyclic group, wherein the 3- to 4-membered monocyclic heterocyclic group has 1 to 2 independently selected cyclic heteroatoms chosen from N, O, and S and optionally is replaced by 1 to 5 R groups. 16a Group substitution.

[0306] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 3- to 4-membered monocyclic heterocyclic group, wherein the 3- to 4-membered monocyclic heterocyclic group has 1 to 2 independently selected cyclic heteroatoms chosen from N, O, and S and is surrounded by 1 to 5 R atoms. 16 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 3- to 4-membered monocyclic heterocyclic group, wherein the 3- to 4-membered monocyclic heterocyclic group has 1 to 2 independently selected cyclic heteroatoms chosen from N, O, and S and is substituted by 1 to 5 R groups. 16aGroup substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, ring B together with the two carbons to which it is attached forms a 3- to 4-membered monocyclic heterocyclic group having 1 to 2 independent cyclic heteroatoms selected from N, O and S.

[0307] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 5- to 7-membered monocyclic heterocyclic group, wherein the 5- to 7-membered monocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and optionally surrounded by 1 to 5 R atoms. 16 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 5- to 7-membered monocyclic heterocyclic group, wherein the 5- to 7-membered monocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and optionally is replaced by 1 to 5 R groups. 16a Group substitution.

[0308] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 5- to 7-membered monocyclic heterocyclic group, wherein the 5- to 7-membered monocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and is surrounded by 1 to 5 R atoms. 16 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 5- to 7-membered monocyclic heterocyclic group, wherein the 5- to 7-membered monocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and is substituted by 1 to 5 R groups. 16a Group substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 5- to 7-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S.

[0309] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 5- to 9-membered fused or bridged bicyclic heterocyclic group, wherein the 5- to 9-membered fused or bridged bicyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and optionally bounded by 1 to 5 R atoms. 16 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 5- to 9-membered fused or bridged bicyclic heterocyclic group, wherein the 5- to 9-membered fused or bridged bicyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and optionally is surrounded by 1 to 5 R groups. 16a Group substitution.

[0310] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 5- to 9-membered fused or bridged bicyclic heterocyclic group, wherein the 5- to 9-membered fused or bridged bicyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and is bounded by 1 to 5 R atoms. 16 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B, together with the two carbons to which it is attached, forms a 5- to 9-membered fused or bridged bicyclic heterocyclic group, wherein the 5- to 9-membered fused or bridged bicyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and is substituted by 1 to 5 R groups. 16a Group substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, ring B together with the two carbons to which it is attached forms a 5- to 9-membered fused or bridged bicyclic heterocyclic group having 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0311] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B is cyclohexyl or tetrahydropyranyl.

[0312]

[0313] Each of them is optionally selected independently from 1 to 5 groups: oxo group, -OH, halogen, -CN, C. 1-8 Alkyl, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl, -C(O)NR 6 R 6 -NR 6 R 6 -NR 6 C(O)R 8 and -C(O)R 8 Substitution of groups.

[0314] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B is cyclohexyl or tetrahydropyranyl.

[0315]

[0316] Each of them is optionally selected independently from 1 to 4 oxo groups, -OH, halogens, -CN, C 1-8 Alkyl, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl, -C(O)NR 6 R 6 -NR6 R 6 -NR 6 C(O)R 8 and -C(O)R 8 Substitution of groups.

[0317] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B is cyclohexyl.

[0318]

[0319] Each of them is optionally substituted with 1 to 5 halogens. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring B is cyclohexyl.

[0320]

[0321] Each of them may be optionally replaced by 1 to 5 fluorine molecules.

[0322] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 16 Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-8 Alkyl, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl, -C(O)NR 6 R 6 -NR 6 R 6 -NR 6 C(O)R 8 or -C(O)R 8 , of which C 1-8 Alkyl and C 3-7 Each of the monocyclic cycloalkyl groups is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution.

[0323] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 16a Independently -OH, halogen, -CN, C 1-8 Alkyl, C 1-4 Alkoxy and C 3-7 Monocyclic cycloalkyl, wherein the C 1-8 Alkyl and C 3-7 Each of the monocyclic cycloalkyl groups is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution.

[0324] In some embodiments of compounds of formula I, Ia, II or IIa, or pharmaceutically acceptable salts thereof,

[0325]

[0326] for:

[0327]

[0328] In some embodiments of compounds of formula I, Ia, II or IIa, or pharmaceutically acceptable salts thereof,

[0329]

[0330] for:

[0331]

[0332] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 H, -CN, halogen, C 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl, -C(O)NR 6 R 6 -NR 6 R 6 -NR 7 C(O)R 8 or -C(O)R 8 , of which C 1-8 Alkyl and C 3-7 Each of the monocyclic cycloalkyl groups is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 1 H, -CN, halogen, C 1-8 Alkyl or C 3-7 Monocyclic cycloalkyl, wherein the C 1-8 Alkyl and C 3-7 Each of the monocyclic cycloalkyl groups is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution.

[0333] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 For H. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, R 1 For -CN.

[0334] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 It is a halogen. In some embodiments of compounds of formula I, Ia, II or IIa, or pharmaceutically acceptable salts thereof, R 1 It is chlorine, fluorine, bromine, or iodine. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 It is chlorine, fluorine, or bromine.

[0335] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 C 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 1 C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 1 C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 1 C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally replaced by one to three halogens.

[0336] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 C 1-8 Alkyl, wherein the C 1-8 The alkyl group is selected independently by one to three elements from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 1 C 1-6 Alkyl, wherein the C 1-6 The alkyl group is selected independently by one to three elements from -OH, halogen, -CN, and C. 1-4Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 1 C 1-4 Alkyl, wherein the C 1-4 The alkyl group is selected independently by one to three elements from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 1 C 1-4 Alkyl, wherein the C 1-4 The alkyl group is substituted with one to three halogens. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 1 C 1-3 Alkyl, wherein the C 1-3 The alkyl group is substituted with one to three halogens. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 1 C 1-3 Alkyl, wherein the C 1-3 The alkyl group is substituted with one to three fluorine atoms. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 The methyl group is substituted with one to three fluorine atoms. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 Ethyl groups substituted with 1 to 3 fluorine atoms. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 It can be either -CHF2 or -CF3.

[0337] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 C 1-8 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 C 1-6 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 C 1-4 alkyl.

[0338] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 C 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN and C.1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 1 C 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is independently selected from 1 to 3 -OH, halogen, -CN and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 1 C 3-7 Monocyclic cycloalkyl.

[0339] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 -C(O)NR 6 R 6 In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 For -NR 6 R 6 In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 For -NR 7 C(O)R 8 In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 1 -C(O)R 8 .

[0340] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a phenyl group, a 5- to 6-membered monocyclic heterocyclic group, a 5- to 6-membered monocyclic heteroaryl group, an 8- to 10-membered fused or bridged bicyclic heterocyclic group, an 8- to 10-membered fused bicyclic heteroaryl group, a 9- to 12-membered fused or bridged tricyclic heterocyclic group, or a 9- to 12-membered fused tricyclic heteroaryl group.

[0341] The phenyl group, the 5- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, the 9- to 12-membered fused or bridged tricyclic heterocyclic group, and the 9- to 12-membered fused tricyclic heteroaryl group are each optionally surrounded by 1 to 3 R groups. 4a Group substitution, and

[0342] Each of the 5- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, the 9- to 12-membered fused or bridged tricyclic heterocyclic group, and the 9- to 12-membered fused tricyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S.

[0343] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a phenyl group, an 8- to 10-membered fused or bridged bicyclic heterocyclic group, an 8- to 10-membered fused bicyclic heteroaryl group, or a 9- to 12-membered fused or bridged tricyclic heterocyclic group.

[0344] The phenyl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 9- to 12-membered fused or bridged tricyclic heterocyclic group are each optionally surrounded by 1 to 3 R groups. 4a Group substitution, and

[0345] The 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 9- to 12-membered fused or bridged tricyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0346] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a phenyl group or a 9- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the phenyl group and the 9- to 10-membered fused or bridged bicyclic heterocyclic group are each optionally surrounded by 1 to 3 R groups. 4a The group is substituted, and wherein the 9- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S.

[0347] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a phenyl group, wherein the phenyl group is optionally surrounded by 1 to 3 R groups. 4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a phenyl group, wherein the phenyl group is formed by 1 to 3 R groups. 4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a phenyl group.

[0348] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a 5- to 6-membered monocyclic heterocyclic group, wherein the 5- to 6-membered monocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and optionally surrounded by 1 to 3 R atoms.4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a 5- to 6-membered monocyclic heterocyclic group, wherein the 5- to 6-membered monocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and is surrounded by 1 to 3 R atoms. 4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a 5- to 6-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0349] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and optionally surrounded by 1 to 3 R atoms. 4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and is surrounded by 1 to 3 R atoms. 4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O, and S.

[0350] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and optionally bounded by 1 to 3 R atoms. 4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and is bounded by 1 to 3 R atoms. 4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is an 8- to 10-membered fused or bridged bicyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0351] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a 9- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 9- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and optionally bounded by 1 to 3 R atoms. 4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a 9- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 9- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and is bounded by 1 to 3 R atoms. 4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a 9- to 10-membered fused or bridged bicyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0352] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is an 8- to 10-membered fused bicyclic heteroaryl group, wherein the 8- to 10-membered fused bicyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and optionally surrounded by 1 to 3 R atoms. 4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is an 8- to 10-membered fused bicyclic heteroaryl group, wherein the 8- to 10-membered fused bicyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and is surrounded by 1 to 3 R atoms. 4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is an 8- to 10-membered fused bicyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0353] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a 9- to 12-membered fused or bridged tricyclic heterocyclic group, wherein the 9- to 12-membered fused or bridged tricyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and optionally surrounded by 1 to 3 R atoms. 4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a 9- to 12-membered fused or bridged tricyclic heterocyclic group, wherein the 9- to 12-membered fused or bridged tricyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and is bounded by 1 to 3 R atoms.4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a 9- to 12-membered fused or bridged tricyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0354] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a 9- to 12-membered fused tricyclic heteroaryl group, wherein the 9- to 12-membered fused tricyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and optionally surrounded by 1 to 3 R atoms. 4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a 9- to 12-membered fused tricyclic heteroaryl group, wherein the 9- to 12-membered fused tricyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and is surrounded by 1 to 3 R atoms. 4a Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 It is a 9- to 12-membered fused tricyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0355] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 for

[0356]

[0357] Each of them is optionally divided by 1 to 3 R 4a Group substitution.

[0358] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 for

[0359]

[0360]

[0361] Each of them is subject to 1 to 3 Rs 4a Group substitution.

[0362] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 for

[0363]

[0364] Each of them is optionally divided by 1 to 3 R 4a Group substitution.

[0365] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 for

[0366]

[0367] Each of them is subject to 1 to 3 Rs 4a Group substitution.

[0368] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 for

[0369]

[0370] It is optionally divided by 1 to 3 R 4a Group substitution.

[0371] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 4 for

[0372]

[0373] It is composed of 1 to 3 Rs 4a Group substitution.

[0374] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 4a Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-8 Alkyl, C 1-8 Alkoxy, -NR 6 R 6 -NR 7 S(O)2R 9 -NR 7 S(O)2NR 6 R 6 -NR 7 C(O)R 8 -NR 7 C(O)R 10 NR 6 R 6 -NR 7 C(O)NR 6 R 6 or -C(O)NR 6 R 6 , of which C 1-8The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution; or the 1 to 3 R groups 4a The two Rs in the group 4a Connected to the same carbon and both R 4a Together with the carbon they are attached to, they form C 3-7 Monocyclic cycloalkyl. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, each R 4a Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-8 Alkyl, C 1-8 Alkoxy, -NR 6 R 6 -NR 7 S(O)2R 9 or -C(O)NR 6 R 6 , of which C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution; or the 1 to 3 R groups 4a The two Rs in the group 4a Connected to the same carbon and both R 4a Together with the carbon they are attached to, they form C 3-7 Monocyclic cycloalkyl.

[0375] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 4a Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-8 Alkyl, C 1-8 Alkoxy, -NR 6 R 6 -NR 7 S(O)2R 9 -NR 7 S(O)2NR 6 R 6 -NR 7 C(O)R 8 -NR 7 C(O)R 10 NR 6 R 6 -NR 7 C(O)NR 6 R 6 or -C(O)NR 6 R 6 , of which C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C.1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 4a Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-8 Alkyl, C 1-8 Alkoxy, -NR 6 R 6 -NR 7 S(O)2R 9 or -C(O)NR 6 R 6 , of which C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution.

[0376] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 4a Independently oxidized, halogenated, -CN, C 1-8 Alkyl, -NR 6 R 6 -NR 7 S(O)2R 9 or -C(O)NR 6 R 6 .

[0377] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a It is an oxo group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, an R 4a It is an oxo group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a It is -OH.

[0378] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a It is a halogen. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, one or more R 4a It is fluorine or chlorine. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, an R 4a Fluorine. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, an R 4a It is chlorine.

[0379] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a -CN. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, an R 4a For -CN.

[0380] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a C 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a C 1-8 Alkyl, wherein the C 1-8 The alkyl group is selected independently by one to three elements from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a C 1-8 alkyl.

[0381] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a C 1-4 Alkyl, wherein the C 1-4 The alkyl group is selected independently by one to three elements from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a C 1-4 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R... 4a It is methyl, ethyl, propyl, or isopropyl. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a It is a methyl group.

[0382] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a C 1-8 Alkyl group.

[0383] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a For -NR 6 R 6 In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a -NH2. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, an R 4a It is -NH2.

[0384] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a For -NR 7 S(O)2R 9 In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a -NHS(O)2R 9 In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, an R 4a -NHS(O)2R 9 In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, an R 4a -NHS(O)2(C 1-4 Alkyl). In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, an R 4a -NHS(O)2CH3. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, an R 4a -NHS(O)2CH2CH3. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, an R 4a -NHS(O)2(C 3-5 (Cycloalkyl). In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, an R 4a It is -NHS(O)2 (cyclopropyl).

[0385] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a For -NR 7 S(O)2NR 6 R 6 In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a For -NR 7 C(O)R 8 In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a For -NR 7 C(O)R 10 NR 6 R 6 In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a For -NR 7 C(O)NR 6 R 6 .

[0386] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a -C(O)NR 6 R 6 In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 4a For -C(O)NH2. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, an R 4a It is -C(O)NH2.

[0387] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, the 1 to 3 R 4a The two Rs in the group 4a Connected to the same carbon and both R 4a Together with the carbon they are attached to, they form C 3-7 Monocyclic cycloalkyl. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, the 1 to 3 R... 4a The two Rs in the group 4a Connected to the same carbon and both R 4a Together with the carbon they are attached to, they form C 3-5Monocyclic cycloalkyl. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, the 1 to 3 R... 4a The two Rs in the group 4a Connected to the same carbon and both R 4a Together with the carbon atoms they are attached to, they form cyclopropyl, cyclobutyl, or cyclopentyl groups. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, the 1 to 3 R groups... 4a The two Rs in the group 4a Connected to the same carbon and both R 4a Together with the carbon atoms they are attached to, they form cyclopropyl groups.

[0388] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, optionally, one to three R... 4a R with substituent group 4 for:

[0389]

[0390]

[0391]

[0392] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, optionally, one to three R... 4a R with substituent group 4 for:

[0393]

[0394] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, optionally, one to three R... 4a R with substituent group 4 for:

[0395]

[0396] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 6 Independently for H and C 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl groups, or 4- to 6-membered monocyclic heterocyclic groups having 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S.

[0397] Among them, C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4The alkoxy group is substituted, and

[0398] Among them, C 3-7 The monocyclic cycloalkyl group and the 4- to 6-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S are each optionally surrounded by 1 to 3 independently selected cyclic heteroatoms chosen from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkoxy group substitution; or

[0399] Two Rs 6 Together with the nitrogen atoms to which they are attached, they form 4- to 6-membered monocyclic heterocyclic groups having 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0400] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 6 H and C independently 1-8 Alkyl or C 3-7 Monocyclic cycloalkyl,

[0401] Among them, C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 The alkoxy group is substituted, and

[0402] Among them, C 3-7 The monocyclic cycloalkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkoxy group substitution.

[0403] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 6 Independently H or C 1-4 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 6 It can be H or methyl on its own.

[0404] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 6 For H.

[0405] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 6 C 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 6 C 1-8 Alkyl, wherein the C 1-8 The alkyl group is selected independently by one to three elements from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 6 C 1-8 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R... 6 C 1-4 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R... 6 It is a methyl group.

[0406] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 6 C 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 6 C 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is independently selected from 1 to 3 groups of -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 6 C 3-7 Monocyclic cycloalkyl.

[0407] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 6 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 6 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 6 It is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0408] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, the two R... 6 Together with the nitrogen atoms to which they are attached, they form 4- to 6-membered monocyclic heterocyclic groups having 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0409] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 7 H can be independent or can be the same or different from C. 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 7 H can be independent or can be the same or different from C. 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 7 H can be independent or can be the same or different from C. 1-3 alkyl.

[0410] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 7 For H. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, one or more R 7 For C, which can be the same or different 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C.1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 7 For C, which can be the same or different 1-8 Alkyl, wherein the C 1-8 The alkyl group is selected independently by one to three elements from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 7 For C, which can be the same or different 1-8 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R... 7 For C, which can be the same or different 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 7 For C, which can be the same or different 1-4 Alkyl, wherein the C 1-4 The alkyl group is selected independently by one to three elements from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 7 For C, which can be the same or different 1-4 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R... 7 For C, which can be the same or different 1-3 alkyl.

[0411] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 8 Independently -OH, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic or 4- to 6-membered monocyclic heteroaryl

[0412] Among them, C 1-8 Alkyl and C 1-8 Each alkoxy group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution,

[0413] Among them, C3-7 The monocyclic cycloalkyl group, the 4- to 6-membered monocyclic heterocyclic group, and the 4- to 6-membered monocyclic heteroaryl group are each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0414] Each of the 4- to 6-membered monocyclic heterocyclic groups and the 4- to 6-membered monocyclic heteroaryl groups has 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0415] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 8 Independently -OH, C 1-8 Alkyl or C 1-8 Alkyl group.

[0416] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 It is -OH.

[0417] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 C 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 C 1-8 Alkyl, wherein the C 1-8 The alkyl group is selected independently by one to three elements from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 C 1-8 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R... 8 C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 C 1-4 Alkyl, wherein the C 1-4The alkyl group is selected independently by one to three elements from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 C 1-4 alkyl.

[0418] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 C 1-8 alkoxy group, wherein the C 1-8 The alkoxy group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 C 1-8 alkoxy group, wherein the C 1-8 The alkoxy group is independently selected from 1 to 3 groups, including -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 C 1-8 Alkyl group.

[0419] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 C 1-5 alkoxy group, wherein the C 1-5 The alkoxy group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 C 1-5 alkoxy group, wherein the C 1-5 The alkoxy group is independently selected from 1 to 3 groups, including -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 C 1-5 Alkyl group.

[0420] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 C 3-7 Monocyclic cycloalkyl, wherein the C 3-7The monocyclic cycloalkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 C 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is independently selected from 1 to 3 groups of -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 C 3-7 Monocyclic cycloalkyl.

[0421] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 It is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0422] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 It is a 4- to 6-membered monocyclic heteroaryl group, wherein the 4- to 6-membered monocyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8It is a 4- to 6-membered monocyclic heteroaryl group, wherein the 4- to 6-membered monocyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 8 It is a 4- to 6-membered monocyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0423] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 9 Independently for C 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered monocyclic heteroaryl

[0424] Among them, C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution,

[0425] Among them, C 3-7 The monocyclic cycloalkyl group, the 4- to 6-membered monocyclic heterocyclic group, and the 5- to 6-membered monocyclic heteroaryl group are each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0426] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0427] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 9 Independently for C 1-8 Alkyl or C 3-7 Monocyclic cycloalkyl,

[0428] Among them, C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 The alkoxy group is substituted, and

[0429] Among them, C 3-7 The monocyclic cycloalkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkoxy group substitution.

[0430] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 9 Independently for C 1-3 Alkyl or C 3-5 Monocyclic cycloalkyl.

[0431] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 C 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 C 1-8 Alkyl, wherein the C 1-8 The alkyl group is selected independently by one to three elements from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 C 1-8 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R... 9 C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 C 1-4 Alkyl, wherein the C 1-4 The alkyl group is selected independently by one to three elements from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 C 1-4 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R... 9 C 1-3 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R... 9 It is methyl, ethyl, propyl, or isopropyl. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, an R9 Methyl. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, an R 9 Ethyl. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, an R 9 For propyl. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, an R 9 It is isopropyl.

[0432] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 C 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 C 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is independently selected from 1 to 3 groups of -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 C 3-7 Monocyclic cycloalkyl. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, one or more R 9 C 3-5 Monocyclic cycloalkyl, wherein the C 3-5 The monocyclic cycloalkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 C 3-5 Monocyclic cycloalkyl, wherein the C 3-5 The monocyclic cycloalkyl group is independently selected from 1 to 3 groups of -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 C 3-5Monocyclic cycloalkyl. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, an R 9 It is cyclopropyl.

[0433] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 It is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0434] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 It is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 It is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 9 It is a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O, and S.

[0435] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 10 For C, which can be the same or different 1-4 Alkylene. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, each R 10 Independently, it is methylene, ethylene, propylene, isopropylene, butylene, or isobutylene. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 10 It is -CH(CH3)2-.

[0436] In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, ring A together with the two carbons to which it is attached forms a 5- to 6-membered monocyclic heterocyclic group or a 5- to 6-membered monocyclic heteroaryl group, wherein each of the 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group is substituted by a Z group and each has 1 to 3 independently selected cyclic heteroatoms selected from N, O and S.

[0437] In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, ring A together with the two carbons to which it is attached forms a 5- to 6-membered monocyclic heterocyclic group or a 5- to 6-membered monocyclic heteroaryl group, wherein each of the 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group is substituted by a Z group and each has 1 to 3 independently selected cyclic heteroatoms selected from N, O and S, one or two of which are nitrogen.

[0438] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring A, together with the two carbons to which it is attached, forms a 5- to 6-membered monocyclic heterocyclic group, wherein the 5- to 6-membered monocyclic heterocyclic group is substituted with a Z group and has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring A, together with the two carbons to which it is attached, forms a 5- to 6-membered monocyclic heterocyclic group, wherein the 5- to 6-membered monocyclic heterocyclic group is substituted with a Z group and has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S, one or two of which are nitrogen.

[0439] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring A, together with the two carbons to which it is attached, forms a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group is substituted with a Z group and has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, ring A, together with the two carbons to which it is attached, forms a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group is substituted with a Z group and has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S, one or two of which are nitrogen.

[0440] In some embodiments of compounds of formula I, Ia, II or IIa, or pharmaceutically acceptable salts thereof,

[0441]

[0442] for:

[0443]

[0444] In some embodiments of compounds of formula I, Ia, II or IIa, or pharmaceutically acceptable salts thereof,

[0445]

[0446] for:

[0447]

[0448] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is...

[0449] i) Oxide group.

[0450] ii)-OH,

[0451] iii)-CN,

[0452] iv)C 1-5 Alkyl, wherein the C 1-5 The alkyl group is formed by a group selected from -OH and C. 1-4 The alkoxy group is substituted, and wherein the C 1-5 The alkyl group may optionally be further substituted with one or two independently selected groups chosen from -OH, halogen, and -CN.

[0453] v)C 6-8 Alkyl, wherein the C 6-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution,

[0454] vi)-Z 1 -Z 2 -Z 3 -Z 4 ,

[0455] Z 1 Optionally selected by 1 to 3 independently chosen from -OH, halogen, -CN and C 1-4 The C group substituted with the alkoxy group 2-6 Imyethynyl,

[0456] Z 2 and Z 3 Each independently is C 3-7 Monocyclic cycloalkylene, C 6-10 Monocyclic or fused bicyclic aryl groups, 4- to 6-membered monocyclic heterocyclic aryl groups, 5- to 6-membered monocyclic heterocyclic aryl groups, 8- to 10-membered fused or bridged bicyclic heterocyclic aryl groups, 8- to 10-membered fused bicyclic heterocyclic aryl groups, or 7- to 10-membered spirocyclic heterocyclic aryl groups, wherein the C 3-7 Monocyclic cycloalkylene, C 6-10 The monocyclic or fused bicyclic aryl group, the 4- to 6-membered monocyclic heterocyclic aryl group, the 5- to 6-membered monocyclic heterocyclic aryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic aryl group, the 8- to 10-membered fused bicyclic heterocyclic aryl group, and the 7- to 10-membered spirocyclic heterocyclic aryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The groups are substituted, and wherein the 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroarylene group, the 8- to 10-membered fused or bridged bicyclic heterocyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroarylene group, and the 7- to 10-membered spirocyclic heterocyclic heterocyclic group each have 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S, and

[0457] Z 4 C 3-7 Monocyclic cycloalkyl, C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic, or 7- to 10-membered spirocyclic heterocyclic, wherein the C 3-7 Monocyclic cycloalkyl, C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic and 7- to 10-membered spirocyclic heterocyclic, each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8The groups are substituted, and each of the 4- to 6-membered monocyclic heterocyclic group, 5- to 6-membered monocyclic heteroaryl group, 8- to 10-membered fused or bridged bicyclic heterocyclic group, 8- to 10-membered fused bicyclic heteroaryl group and 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S.

[0458] vii) optionally selected by 1 to 3 independently chosen from -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The C group substituted with the alkoxy group 3-7 Monocyclic cycloalkyl,

[0459] viii)-S(C 1-8 alkyl), wherein the C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution,

[0460] ix)-NR 11 R 12 , where R 11 and R 12 One of them is H or C 1-8 Alkyl and R 11 and R 12 The other one is C 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heteroaryl, or 7- to 10-membered spirocyclic heterocyclic.

[0461] Each C 1-8 Alkyl groups are 1 to 3 R 17 Group substitution,

[0462] Among them, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heteroaryl, and 7- to 10-membered spirocyclic heterocyclic are each optionally composed of 1 to 3 independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0463] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0464] x) optionally selected by 1 to 3 independently chosen from -OH, halogen, -CN, C 1-4Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 -NR 6 R 6 C groups substituted with 4- to 6-membered monocyclic heterocyclic groups and 5- to 6-membered monocyclic heteroaryl groups 6-10 Monocyclic or fused bicyclic aryl groups

[0465] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 and -NR 6 R 6 The group is substituted, and

[0466] The 4- to 6-membered monocyclic heterocyclic groups and the 5- to 6-membered monocyclic heteroaryl groups each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0467] xi) has 1 to 3 independent cyclic heteroatoms selected from N, O and S and optionally surrounded by 1 to 3 R atoms. 13 4- to 6-membered monocyclic heterocyclic groups with substituent groups,

[0468] xii) having 1 to 3 independent cyclic heteroatoms selected from N, O, and S and optionally surrounded by 1 to 3 R atoms 13 8- to 10-membered fused or bridged bicyclic heterocyclic groups with substituent groups

[0469] xiii) having 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 R atoms 13 5- to 6-membered monocyclic heteroaryl groups substituted with functional groups

[0470] xiv) having 1 to 3 independent cyclic heteroatoms selected from N, O, and S and optionally bounded by 1 to 3 R 13 8- to 10-membered fused bicyclic heteroaryl groups with substituted groups, or

[0471] xv) has 1 to 3 independent cyclic heteroatoms selected from N, O and S and optionally surrounded by 1 to 3 R 13 7- to 10-membered spirocyclic heterocyclic groups substituted with functional groups.

[0472] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is...

[0473] i) Oxide group.

[0474] ii)-OH,

[0475] iii)-CN,

[0476] iv)C 1-5 Alkyl, wherein the C 1-5 The alkyl group is formed by a group selected from -OH and C. 1-4 The alkoxy group is substituted, and wherein the C 1-5 The alkyl group may optionally be further substituted with one or two independently selected groups chosen from -OH, halogen, and -CN.

[0477] v)C 6-8 Alkyl, wherein the C 6-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution,

[0478] vi)-Z 1 -Z 2 -Z 3 -Z 4 ,

[0479] Z 1 Optionally selected by 1 to 3 independently chosen from -OH, halogen, -CN and C 1-4 The C group substituted with the alkoxy group 2-6 Imyethynyl,

[0480] Z 2 C 6-10 Monocyclic or fused bicyclic arylene, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered monocyclic heterocyclic arylene, wherein the C 6-10 The monocyclic or fused bicyclic arylene, the 4- to 6-membered monocyclic heterocyclic arylene, and the 5- to 6-membered monocyclic heterocyclic arylene are each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The groups are substituted, and each of the 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroarylene group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S.

[0481] Z 3 It is a 5- to 6-membered monocyclic heterocyclic group or a 5- to 6-membered monocyclic heteroarylene group.

[0482] The 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted, and

[0483] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroarylene group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S, and

[0484] Z 4 It is a 5- to 6-membered monocyclic heterocyclic group or a 5- to 6-membered monocyclic heteroaryl group.

[0485] The 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted, and

[0486] The 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0487] vii) optionally selected by 1 to 3 independently chosen from -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The C group substituted with the alkoxy group 3-7 Monocyclic cycloalkyl,

[0488] viii)-S(C 1-4 alkyl), wherein the C 1-4 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkoxy group substitution,

[0489] ix)-NR 11 R 12 , where R 11 and R 12 One of them is H or C 1-8 Alkyl and R 11 and R 12 The other one is C 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered monocyclic heteroaryl

[0490] Each C 1-8 Alkyl groups are 1 to 3 R 17a Group substitution,

[0491] Among them, C 3-7 The monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic and 5- to 6-membered monocyclic heteroaryl groups are each optionally composed of 1 to 3 independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0492] The 4- to 6-membered monocyclic heterocyclic groups and the 5- to 6-membered monocyclic heteroaryl groups each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0493] x) optionally selected by 1 to 3 independently chosen from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 -NR 6 R 6 C groups substituted with 4- to 6-membered monocyclic heterocyclic groups and 5- to 6-membered monocyclic heteroaryl groups 6-10 Monocyclic or fused bicyclic aryl groups

[0494] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 and -NR 6 R 6 The group is substituted, and

[0495] The 4- to 6-membered monocyclic heterocyclic groups and the 5- to 6-membered monocyclic heteroaryl groups each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0496] xi) has 1 to 3 independent cyclic heteroatoms selected from N, O and S and optionally surrounded by 1 to 3 R atoms. 13 4- to 6-membered monocyclic heterocyclic groups with substituent groups,

[0497] xii) having 1 to 3 independent cyclic heteroatoms selected from N, O, and S and optionally surrounded by 1 to 3 R atoms 13 8- to 10-membered fused or bridged bicyclic heterocyclic groups with substituent groups

[0498] xiii) having 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 R atoms 13 5- to 6-membered monocyclic heteroaryl groups with substituted groups

[0499] xiv) optionally by 1 to 3 R 13 8- to 10-membered fused bicyclic heteroaryl groups with substituted groups, or

[0500] xv) has 1 to 3 independent cyclic heteroatoms selected from N, O and S and optionally surrounded by 1 to 3 R 13 7- to 10-membered spirocyclic heterocyclic groups substituted with functional groups.

[0501] In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is an oxo group.

[0502] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -OH or -CN.

[0503] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is C. 1-5 Alkyl, wherein the C 1-5 The alkyl group is formed by a group selected from -OH and C. 1-4 The alkoxy group is substituted, and wherein the C 1-5 The alkyl group is optionally further substituted with one or two groups independently selected from -OH, halogen, and -CN. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is C. 1-5 Alkyl, wherein the C 1-5 The alkyl group is formed by a group selected from -OH and C. 1-4 The alkoxy group is substituted, and wherein the C 1-5 The alkyl group is further substituted with one or two groups independently selected from -OH, halogen, and -CN. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is C. 1-5 Alkyl, wherein the C 1-5 The alkyl group is independently selected from -OH and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is C. 1-5 Alkyl, wherein the C 1-5 The alkyl group is substituted with a -OH group. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is -C(CH3)2OH.

[0504] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is C. 6-8 Alkyl, wherein the C 6-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is C. 6-8Alkyl, wherein the C 6-8 The alkyl group is selected independently by one to three elements from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is C. 6-8 alkyl.

[0505] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -Z. 1 -Z 2 -Z 3 -Z 4 ,

[0506] Z 1 Optionally selected by 1 to 3 independently chosen from -OH, halogen, -CN and C 1-4 The C group substituted with the alkoxy group 2-6 Imyethynyl,

[0507] Z 2 and Z 3 Each independently is C 3-7 Monocyclic cycloalkylene, C 6-10 Monocyclic or fused bicyclic aryl groups, 4- to 6-membered monocyclic heterocyclic aryl groups, 5- to 6-membered monocyclic heterocyclic aryl groups, 8- to 10-membered fused or bridged bicyclic heterocyclic aryl groups, 8- to 10-membered fused bicyclic heterocyclic aryl groups, or 7- to 10-membered spirocyclic heterocyclic aryl groups, wherein the C 3-7 Monocyclic cycloalkylene, C 6-10 The monocyclic or fused bicyclic aryl group, the 4- to 6-membered monocyclic heterocyclic aryl group, the 5- to 6-membered monocyclic heterocyclic aryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic aryl group, the 8- to 10-membered fused bicyclic heterocyclic aryl group, and the 7- to 10-membered spirocyclic heterocyclic aryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The groups are substituted, and wherein the 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroarylene group, the 8- to 10-membered fused or bridged bicyclic heterocyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroarylene group, and the 7- to 10-membered spirocyclic heterocyclic heterocyclic group each have 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S, and

[0508] Z 4 C 3-7 Monocyclic cycloalkyl, C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic, or 7- to 10-membered spirocyclic heterocyclic, wherein the C 3-7 Monocyclic cycloalkyl, C6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic and 7- to 10-membered spirocyclic heterocyclic, each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The groups are substituted, and each of the 4- to 6-membered monocyclic heterocyclic group, 5- to 6-membered monocyclic heteroaryl group, 8- to 10-membered fused or bridged bicyclic heterocyclic group, 8- to 10-membered fused bicyclic heteroaryl group and 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0509] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -Z. 1 -Z 2 -Z 3 -Z 4 ,

[0510] Z 1 Optionally selected by 1 to 3 independently chosen from -OH, halogen, -CN and C 1-4 The C group substituted with the alkoxy group 2-6 Imyethynyl,

[0511] Z 2 C 6-10 Monocyclic or fused bicyclic arylene, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered monocyclic heterocyclic arylene, wherein the C 6-10 The monocyclic or fused bicyclic arylene, the 4- to 6-membered monocyclic heterocyclic arylene, and the 5- to 6-membered monocyclic heterocyclic arylene are each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The groups are substituted, and each of the 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroarylene group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S.

[0512] Z 3 It is a 5- to 6-membered monocyclic heterocyclic group or a 5- to 6-membered monocyclic heteroarylene group.

[0513] The 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heterocyclic aryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted, and

[0514] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroarylene group each have 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S, and Z 4 It is a 5- to 6-membered monocyclic heterocyclic group or a 5- to 6-membered monocyclic heteroaryl group.

[0515] The 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted, and

[0516] Each of the 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0517] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 1 Optionally selected by one to three independently chosen from -OH, halogen, -CN, and C 1-4 The C-aryl group substituted with the alkoxy group 2-6 Alynyl group. In some embodiments of compounds of formula I, Ia, II or IIa, or pharmaceutically acceptable salts thereof, Z 1 It is selected independently by 1 to 3 elements from -OH, halogen, -CN, and C. 1-4 The C-aryl group substituted with the alkoxy group 2-6 Alynyl group. In some embodiments of compounds of formula I, Ia, II or IIa, or pharmaceutically acceptable salts thereof, Z 1 C 2-6 Alynyl group. In some embodiments of compounds of formula I, Ia, II or IIa, or pharmaceutically acceptable salts thereof, Z 1 Optionally selected by one to three independently chosen from -OH, halogen, -CN, and C 1-4 The C-aryl group substituted with the alkoxy group 2-4 Alynyl group. In some embodiments of compounds of formula I, Ia, II or IIa, or pharmaceutically acceptable salts thereof, Z 1 It is selected independently by 1 to 3 elements from -OH, halogen, -CN, and C. 1-4 The C-aryl group substituted with the alkoxy group 2-4 Alynyl group. In some embodiments of compounds of formula I, Ia, II or IIa, or pharmaceutically acceptable salts thereof, Z 1 C 2-4 Alynyl group. In some embodiments of compounds of formula I, Ia, II or IIa, or pharmaceutically acceptable salts thereof, Z 1 It is a C2-acetylinyl group.

[0518] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 2 C 3-7 Monocyclic cycloalkylene, C 6-10 Monocyclic or fused bicyclic aryl groups, 4- to 6-membered monocyclic heterocyclic aryl groups, 5- to 6-membered monocyclic heterocyclic aryl groups, 8- to 10-membered fused or bridged bicyclic heterocyclic aryl groups, 8- to 10-membered fused bicyclic heterocyclic aryl groups, or 7- to 10-membered spirocyclic heterocyclic aryl groups, wherein the C 3-7 Monocyclic cycloalkylene, C 6-10 The monocyclic or fused bicyclic aryl group, the 4- to 6-membered monocyclic heterocyclic aryl group, the 5- to 6-membered monocyclic heterocyclic aryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic aryl group, the 8- to 10-membered fused bicyclic heterocyclic aryl group, and the 7- to 10-membered spirocyclic heterocyclic aryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The groups are substituted, and the 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroarylene group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroarylene group and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independently selected cyclic heteroatoms selected from N, O and S.

[0519] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 2 C 6-10 Monocyclic or fused bicyclic arylene, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered monocyclic heterocyclic arylene, wherein the C 6-10 The monocyclic or fused bicyclic arylene, the 4- to 6-membered monocyclic heterocyclic arylene, and the 5- to 6-membered monocyclic heterocyclic arylene are each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The groups are substituted, and each of the 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroarylene group has 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0520] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 2 C 3-7 Monocyclic cycloalkylene, wherein the C 3-7 The monocyclic cycloalkylene group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 2 C 3-7 Monocyclic cycloalkylene, wherein the C 3-7 The monocyclic cycloalkylene group is independently selected from 1 to 3 groups: -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 2 C 3-7 Monocyclic cycloalkylene.

[0521] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 2 C 6-10 Monocyclic or fused bicyclic arylene, wherein the C 6-10 The monocyclic or fused bicyclic arylene group is optionally surrounded by 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 2 C 6-10 Monocyclic or fused bicyclic arylene, wherein the C 6-10 The monocyclic or fused bicyclic arylene group is independently selected from 1 to 3 groups of -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 2 C 6-10 Monocyclic or fused bicyclic aryl group. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 2 It is a phenylene oxide.

[0522] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 2 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 2 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 2 It is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0523] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 2 It is a 5- to 6-membered monocyclic heteroarylene, wherein the 5- to 6-membered monocyclic heteroarylene has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 2 It is a 5- to 6-membered monocyclic heteroarylene, wherein the 5- to 6-membered monocyclic heteroarylene has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 2 It is a 5- to 6-membered monocyclic heteroarylene with 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0524] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 2 It is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z2 It is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 2 It is an 8- to 10-membered fused or bridged bicyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0525] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 2 It is an 8- to 10-membered fused bicyclic heteroarylene, wherein the 8- to 10-membered fused bicyclic heteroarylene has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 2 It is an 8- to 10-membered fused bicyclic heteroarylene, wherein the 8- to 10-membered fused bicyclic heteroarylene has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 2 It is an 8- to 10-membered fused bicyclic heteroarylene group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0526] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 2 It is a 7- to 10-membered spirocyclic heterocyclic group, wherein the 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 2It is a 7- to 10-membered spirocyclic heterocyclic group, wherein the 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 2 It is a 7- to 10-membered spirocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0527] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 1 It is C2-alkynyl and Z 2 It is a phenylene oxide.

[0528] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 3 C 3-7 Monocyclic cycloalkylene, C 6-10 Monocyclic or fused bicyclic aryl groups, 4- to 6-membered monocyclic heterocyclic aryl groups, 5- to 6-membered monocyclic heterocyclic aryl groups, 8- to 10-membered fused or bridged bicyclic heterocyclic aryl groups, 8- to 10-membered fused bicyclic heterocyclic aryl groups, or 7- to 10-membered spirocyclic heterocyclic aryl groups, wherein the C 3-7 Monocyclic cycloalkylene, C 6-10 The monocyclic or fused bicyclic aryl group, the 4- to 6-membered monocyclic heterocyclic aryl group, the 5- to 6-membered monocyclic heterocyclic aryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic aryl group, the 8- to 10-membered fused bicyclic heterocyclic aryl group, and the 7- to 10-membered spirocyclic heterocyclic aryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The groups are substituted, and the 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroarylene group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroarylene group and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independently selected cyclic heteroatoms selected from N, O and S.

[0529] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 3 It is a 5- to 6-membered monocyclic heterocyclic group or a 5- to 6-membered monocyclic heterocyclic aryl group, wherein each of the 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heterocyclic aryl group is optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8The group is substituted, and the 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroarylene group each have 1 to 3 independently selected cyclic heteroatoms selected from N, O and S.

[0530] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 3 C 3-7 Monocyclic cycloalkylene, wherein the C 3-7 The monocyclic cycloalkylene group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 3 C 3-7 Monocyclic cycloalkylene, wherein the C 3-7 The monocyclic cycloalkylene group is independently selected from 1 to 3 groups: -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 3 C 3-7 Monocyclic cycloalkylene.

[0531] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 3 C 6-10 Monocyclic or fused bicyclic arylene, wherein the C 6-10 The monocyclic or fused bicyclic arylene group is optionally surrounded by 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 3 C 6-10 Monocyclic or fused bicyclic arylene, wherein the C 6-10 The monocyclic or fused bicyclic arylene group is independently selected from 1 to 3 groups of -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 3 C 6-10 Monocyclic or fused bicyclic aryl groups.

[0532] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 3 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 3 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 3 It is a 4- to 6-membered monocyclic heterocyclic group with 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0533] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 3 It is a 5- to 6-membered monocyclic heteroarylene, wherein the 5- to 6-membered monocyclic heteroarylene has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 3 It is a 5- to 6-membered monocyclic heteroarylene, wherein the 5- to 6-membered monocyclic heteroarylene has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 3 It is a 5- to 6-membered monocyclic heteroarylene group having 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, Z 3 It is an imidazole group.

[0534] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 3 It is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 3 It is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 3 It is an 8- to 10-membered fused or bridged bicyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0535] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 3 It is an 8- to 10-membered fused bicyclic heteroarylene, wherein the 8- to 10-membered fused bicyclic heteroarylene has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 3 It is an 8- to 10-membered fused bicyclic heteroarylene, wherein the 8- to 10-membered fused bicyclic heteroarylene has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 3 It is an 8- to 10-membered fused bicyclic heteroarylene group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0536] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 3 It is a 7- to 10-membered spirocyclic heterocyclic group, wherein the 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 3 It is a 7- to 10-membered spirocyclic heterocyclic group, wherein the 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 3 It is a 7- to 10-membered spirocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0537] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 4 C 3-7 Monocyclic cycloalkyl, C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic, or 7- to 10-membered spirocyclic heterocyclic, wherein the C 3-7 Monocyclic cycloalkyl, C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic and 7- to 10-membered spirocyclic heterocyclic, each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The groups are substituted, and each of the 4- to 6-membered monocyclic heterocyclic group, 5- to 6-membered monocyclic heteroaryl group, 8- to 10-membered fused or bridged bicyclic heterocyclic group, 8- to 10-membered fused bicyclic heteroaryl group and 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0538] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 4It is a 5- to 6-membered monocyclic heterocyclic group or a 5- to 6-membered monocyclic heterocyclic group, wherein each of the 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heterocyclic group is optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted, and the 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independently selected cyclic heteroatoms selected from N, O and S.

[0539] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 4 C 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 C 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is independently selected from 1 to 3 groups: -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 C 3-7 Monocyclic cycloalkyl.

[0540] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 4 C 6-10 Monocyclic or fused bicyclic aryl, wherein the C 6-10 The monocyclic or fused bicyclic aryl group is optionally surrounded by 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 C 6-10 Monocyclic or fused bicyclic aryl, wherein the C 6-10 The monocyclic or fused bicyclic aryl group is independently selected from 1 to 3 groups of -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 C 6-10 Monocyclic or fused bicyclic aryl groups.

[0541] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 4 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 It is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0542] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 4 It is a 5- to 6-membered monocyclic heterocyclic group, wherein the 5- to 6-membered monocyclic heterocyclic group has 1 to 3 independent cyclic heteroatoms selected from N, O and S and optionally surrounded by a ring heteroatom selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 It is a 5- to 6-membered monocyclic heterocyclic group, wherein the 5- to 6-membered monocyclic heterocyclic group has 1 to 3 independent cyclic heteroatoms selected from N, O and S and is surrounded by a ring heteroatom selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4It is a 5- to 6-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0543] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 4 It is selected independently by 1 to 3 elements from -OH, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The pyrroleyl group is substituted with a pyrroleyl group. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 For a -C(O)R 8 Substituted pyrroloalkyl. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 4 It is a pyrroleyl group.

[0544] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 4 It is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 It is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 It is a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O, and S.

[0545] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 4 It is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 It is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 It is an 8- to 10-membered fused or bridged bicyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0546] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 4 It is an 8- to 10-membered fused bicyclic heteroaryl group, wherein the 8- to 10-membered fused bicyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 It is an 8- to 10-membered fused bicyclic heteroaryl group, wherein the 8- to 10-membered fused bicyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 It is an 8- to 10-membered fused bicyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0547] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z 4 It is a 7- to 10-membered spirocyclic heterocyclic group, wherein the 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 It is a 7- to 10-membered spirocyclic heterocyclic group, wherein the 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, Z 4 It is a 7- to 10-membered spirocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0548] In some embodiments of compounds of formula I, Ia, II or IIa, or pharmaceutically acceptable salts thereof,

[0549] Z 2 C 6-10 Monocyclic or fused bicyclic arylene, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered monocyclic heterocyclic arylene, wherein the C 6-10 The monocyclic or fused bicyclic arylene, the 4- to 6-membered monocyclic heterocyclic arylene, and the 5- to 6-membered monocyclic heterocyclic arylene are each optionally composed of 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The groups are substituted, and the 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroarylene group each have 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S.

[0550] Z 3 It is a 5- to 6-membered monocyclic heterocyclic group or a 5- to 6-membered monocyclic heteroarylene group.

[0551] The 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy and -C(O)R 8 The group is substituted, and

[0552] Each of the 5- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0553] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is C. 3-7 Monocyclic cycloalkyl or -S(C 1-4 alkyl), wherein the C 3-7Monocyclic cycloalkyl and the C 1-4 Each alkyl group is optionally surrounded by one or two independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is C. 3-7 Monocyclic cycloalkyl or -S(C 1-4 alkyl), wherein the C 3-7 Monocyclic cycloalkyl and the C 1-4 Each alkyl group is independently selected from one or two -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is C. 3-7 Monocyclic cycloalkyl or -S(C 1-4 alkyl).

[0554] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is C. 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is C. 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is independently selected from 1 to 3 groups of -OH, halogen, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is C. 3-7 Monocyclic cycloalkyl. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is cyclopropyl.

[0555] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -S(C 1-8 alkyl), wherein the C 1-8 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -S(C 1-8 alkyl), wherein the C1-8 The alkyl group is selected independently by one to three elements from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -S(C 1-8 alkyl).

[0556] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -S(C 1-4 alkyl), wherein the C 1-4 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -S(C 1-4 alkyl), wherein the C 1-4 The alkyl group is selected independently by one to three elements from -OH, halogen, -CN, and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -S(C 1-4 Alkyl group). In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is -S(methyl), -S(ethyl), -S(propyl) or -S(isopropyl). In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is -S(CH3).

[0557] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H or C 1-8 Alkyl and R 11 and R 12 The other one is C 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heteroaryl, or 7- to 10-membered spirocyclic heterocyclic.

[0558] Each C 1-8 Alkyl groups are 1 to 3 R 17 Group substitution,

[0559] Among them, C 3-7Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heteroaryl, and 7- to 10-membered spirocyclic heterocyclic are each optionally composed of 1 to 3 independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0560] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0561] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H or C 1-8 Alkyl and R 11 and R 12 The other one is C 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered monocyclic heteroaryl

[0562] Each C 1-8 Alkyl groups are 1 to 3 R 17a Group substitution,

[0563] Among them, C 3-7 The monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic and 5- to 6-membered monocyclic heteroaryl groups are each optionally composed of 1 to 3 independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0564] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0565] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other one is C 1-8 Alkyl, C 3-7Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heteroaryl, or 7- to 10-membered spirocyclic heterocyclic.

[0566] Each C 1-8 Alkyl groups are 1 to 3 R 17 Group substitution,

[0567] Among them, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heteroaryl, and 7- to 10-membered spirocyclic heterocyclic are each optionally composed of 1 to 3 independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0568] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0569] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other one is C 1-8 Alkyl, wherein the C 1-8 Alkyl groups are 1 to 3 R 17 Group substitution.

[0570] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other one is C 1-6 Alkyl, wherein the C 1-6 Alkyl groups are 1 to 3 R 17 Group substitution.

[0571] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R12 One of them is H and R 11 and R 12 The other one is C. 1-8 Alkyl, wherein the C 1-8 Alkyl groups are 1 to 3 R 17a Group substitution.

[0572] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other one is C. 1-6 Alkyl, wherein the C 1-6 Alkyl groups are 1 to 3 R 17a Group substitution.

[0573] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other one is C. 1-6 Alkyl, wherein the C 1-6 The alkyl group is substituted by one to three independent groups selected from -OH, halogen and -CN.

[0574] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other one is C. 1-6 Alkyl, wherein the C 1-6 The alkyl group is selected independently from C1 to C3. 1-4 Alkoxy and -NR 6 R 6 The group is substituted, and wherein the C 1-4 Alkyl groups are optionally surrounded by a C 1-4 Alkyl substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other one is C.1-6 Alkyl, wherein the C 1-6 The alkyl group is surrounded by a group selected from -OH, methoxy, -OCH2CH2OCH3 or -N(C 1-3 Alkyl group substitution, wherein each C 1-3 Alkyl groups can be the same or different.

[0575] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other one is C 1-6 Alkyl, wherein the C 1-6 Alkyl groups are 1 to 3 R 17a Group substitution.

[0576] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other one is C 1-6 Alkyl, wherein the C 1-6 The alkyl group is substituted with a group selected from cyclopropyl, morpholino, and imidazolyl, wherein the cyclopropyl, morpholino, and imidazolyl groups are each optionally substituted with a group selected from -OH, halogen, and C. 1-4 Alkoxy group substitution.

[0577] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where -NR 11 R 12 for

[0578]

[0579] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other one is C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered monocyclic heteroaryl

[0580] Among them, C 3-7 The monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic and 5- to 6-membered monocyclic heteroaryl groups are each optionally composed of 1 to 3 independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0581] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0582] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other is cyclopropyl, oxetyl, tetrahydrofuranyl, or pyrrolidinyl, each of which is optionally composed of one to three independently selected from an oxo group, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkoxy group substitution.

[0583] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other one is C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered monocyclic heteroaryl

[0584] Among them, C 3-7 The monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic and 5- to 6-membered monocyclic heteroaryl groups are each composed of 1 to 3 independently selected oxo groups, -OH, halogens, -CN, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0585] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0586] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R11 and R 12 One of them is H and R 11 and R 12 The other is cyclopropyl, oxetyl, tetrahydrofuranyl, or pyrrolidinyl, each of which is independently selected from 1 to 3 oxo groups, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkoxy group substitution.

[0587] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other one is C. 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered monocyclic heteroaryl

[0588] Among them, C 3-7 The monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic and 5- to 6-membered monocyclic heteroaryl groups are each optionally composed of 1 to 3 independently selected from oxo and C groups. 1-4 Alkyl groups are substituted, and

[0589] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0590] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other one is C. 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered monocyclic heteroaryl

[0591] Among them, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic and 5- to 6-membered monocyclic heteroaryl groups are each composed of 1 to 3 independently selected oxo and C groups. 1-4 Alkyl groups are substituted, and

[0592] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0593] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other one is C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, or 5- to 6-membered monocyclic heteroaryl. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, R 11 and R 12 One of them is H and R 11 and R 12 The other one is cyclopropyl, oxetyl, tetrahydrofuranyl, or pyrrolidinyl.

[0594] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other one is C 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is optionally surrounded by one to three independently selected oxo groups, -OH, halogens, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other one is C 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is independently selected from 1 to 3 oxo groups, -OH, halogens, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other one is C 3-7 Monocyclic cycloalkyl.

[0595] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other component is a cyclopropyl group, wherein the cyclopropyl group is optionally surrounded by one to three independently selected oxo groups, -OH, halogens, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other component is a cyclopropyl group, wherein the cyclopropyl group is composed of 1 to 3 independently selected oxo groups, -OH, halogens, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other one is cyclopropyl.

[0596] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other one is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O, and S.

[0597] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other is an oxetyl, tetrahydrofuranyl, or pyrrolidinyl group, wherein the oxetyl, tetrahydrofuranyl, and pyrrolidinyl group are each optionally selected independently from one to three oxo groups, -OH, halogens, -CN, C... 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other is an oxetyl, tetrahydrofuranyl, or pyrrolidinyl group, wherein each of the oxetyl, tetrahydrofuranyl, and pyrrolidinyl groups is independently selected from one to three oxo groups, -OH, halogens, -CN, and C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other one is an oxetane, tetrahydrofuranyl, or pyrrolidinyl.

[0598] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12The other is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other one is a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O, and S.

[0599] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other component is a pyrazolyl group, wherein the pyrazolyl group is optionally surrounded by one to three independently selected oxo groups, -OH, halogens, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other component is a pyrazolyl group, wherein the pyrazolyl group is composed of 1 to 3 independently selected oxo groups, -OH, halogens, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R12 The other one is a pyrazol group.

[0600] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is surrounded by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other is an 8- to 10-membered fused or bridged bicyclic heterocyclic group having 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0601] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other is an 8- to 10-membered fused bicyclic heteroaryl group, wherein the 8- to 10-membered fused bicyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other is an 8- to 10-membered fused bicyclic heteroaryl group, wherein the 8- to 10-membered fused bicyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other one is an 8- to 10-membered fused bicyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O, and S.

[0602] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is H and R 11 and R 12 The other is a 7- to 10-membered spirocyclic heterocyclic group, wherein the 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12 The other is a 7- to 10-membered spirocyclic heterocyclic group, wherein the 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is H and R 11 and R 12The other one is a 7- to 10-membered spirocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O, and S.

[0603] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where -NR 11 R 12 for

[0604]

[0605] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other one is C 1-8 Alkyl, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heteroaryl, or 7- to 10-membered spirocyclic heterocyclic.

[0606] Each C 1-8 Alkyl groups are 1 to 3 R 17 Group substitution,

[0607] Among them, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heteroaryl, and 7- to 10-membered spirocyclic heterocyclic are each optionally composed of 1 to 3 independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0608] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0609] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is C 1-8 Alkyl and R11 and R 12 The other one is C 1-8 alkyl,

[0610] Each C 1-8 Alkyl groups are 1 to 3 R 17 Group substitution.

[0611] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is C 1-6 Alkyl and R 11 and R 12 The other one is C 1-6 alkyl,

[0612] Each C 1-6 Alkyl groups are 1 to 3 R 17 Group substitution.

[0613] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other one is C 1-8 alkyl,

[0614] Each C 1-8 Alkyl groups are 1 to 3 R 17a Group substitution.

[0615] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is C 1-6 Alkyl and R 11 and R 12 The other one is C 1-6 alkyl,

[0616] Each C 1-6 Alkyl groups are 1 to 3 R 17a Group substitution.

[0617] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R17 Independently -OH, halogen, -CN, C 1-4 Alkoxy, -NR 6 R 6 C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic groups, 5- to 6-membered monocyclic heteroaryl groups, 8- to 10-membered fused or bridged bicyclic heterocyclic groups, 8- to 10-membered fused bicyclic heteroaryl groups, and 7- to 10-membered spirocyclic heterocyclic groups.

[0618] Among them, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heteroaryl, and 7- to 10-membered spirocyclic heterocyclic are each optionally composed of 1 to 3 independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0619] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0620] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 17a Independently -OH, halogen, -CN, C 1-4 Alkoxy, -NR 6 R 6 C 3-7 Monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic groups, and 5- to 6-membered monocyclic heteroaryl groups

[0621] Among them, C 1-4 Alkoxy, C 3-7 The monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic and 5- to 6-membered monocyclic heteroaryl groups are each optionally composed of 1 to 3 independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted, and

[0622] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0623] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12One of them is C 1-8 Alkyl and R 11 and R 12 The other one is C. 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is optionally surrounded by one to three independently selected oxo groups, -OH, halogens, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other one is C. 3-7 Monocyclic cycloalkyl, wherein the C 3-7 The monocyclic cycloalkyl group is independently selected from 1 to 3 oxo groups, -OH, halogens, -CN, C. 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other one is C. 3-7 Monocyclic cycloalkyl.

[0624] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12The other is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other one is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O, and S.

[0625] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other one is a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O, and S.

[0626] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is surrounded by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other is an 8- to 10-membered fused or bridged bicyclic heterocyclic group having 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0627] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other is an 8- to 10-membered fused bicyclic heteroaryl group, wherein the 8- to 10-membered fused bicyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other is an 8- to 10-membered fused bicyclic heteroaryl group, wherein the 8- to 10-membered fused bicyclic heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other one is an 8- to 10-membered fused bicyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O, and S.

[0628] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is -NR. 11 R 12 , where R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other is a 7- to 10-membered spirocyclic heterocyclic group, wherein the 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and optionally surrounded by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R 12 One of them is C 1-8 Alkyl and R 11 and R 12 The other is a 7- to 10-membered spirocyclic heterocyclic group, wherein the 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 cyclic heteroatoms independently selected from N, O, and S and is further divided by 1 to 3 cyclic heteroatoms independently selected from oxo, -OH, halogen, -CN, C 1-4 Alkyl and C 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or their pharmaceutically acceptable salts, R 11 and R12 One of them is C 1-8 Alkyl and R 11 and R 12 The other one is a 7- to 10-membered spirocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O, and S.

[0629] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is optionally composed of one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 -NR 6 R 6 C groups substituted with 4- to 6-membered monocyclic heterocyclic groups and 5- to 6-membered monocyclic heteroaryl groups 6-10 Monocyclic or fused bicyclic aryl groups

[0630] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 and -NR 6 R 6 The group is substituted, and

[0631] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0632] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is composed of one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 -NR 6 R 6 C groups substituted with 4- to 6-membered monocyclic heterocyclic groups and 5- to 6-membered monocyclic heteroaryl groups 6-10 Monocyclic or fused bicyclic aryl groups

[0633] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 and -NR 6 R 6 The group is substituted, and

[0634] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0635] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is C. 6-10 Monocyclic or fused bicyclic aryl groups.

[0636] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is optionally composed of one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 -NR 6 R 6 phenyl groups substituted with 4- to 6-membered monocyclic heterocyclic groups and 5- to 6-membered monocyclic heteroaryl groups,

[0637] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 and -NR 6 R 6 The group is substituted, and

[0638] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0639] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is composed of one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 -NR 6 R 6phenyl groups substituted with 4- to 6-membered monocyclic heterocyclic groups and 5- to 6-membered monocyclic heteroaryl groups,

[0640] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group are each optionally selected from 1 to 3 independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 and -NR 6 R 6 The group is substituted, and

[0641] The 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0642] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is a phenyl group, wherein the phenyl group is optionally composed of one to three independently selected from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 The groups are substituted with 4- to 6-membered monocyclic heterocyclic groups and 5- to 6-membered monocyclic heteroaryl groups, wherein each of the 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group is optionally replaced by a -C(O)R group. 8 Each of the following is substituted and has one to three independently selected cyclic heteroatoms chosen from N, O, and S. In some embodiments of compounds of formula I, Ia, II, or IIa or pharmaceutically acceptable salts thereof, Z is a phenyl group, wherein the phenyl group is substituted with one to three independently selected cyclic heteroatoms chosen from -OH, halogen, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy, -C(O)NR 6 R 6 -C(O)R 8 The groups are substituted with 4- to 6-membered monocyclic heterocyclic groups and 5- to 6-membered monocyclic heteroaryl groups, wherein each of the 4- to 6-membered monocyclic heterocyclic group and the 5- to 6-membered monocyclic heteroaryl group is optionally replaced by a -C(O)R group. 8 Each of the substituted atoms has one to three independent cyclic heteroatoms selected from N, O, and S.

[0643] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is a phenyl group, wherein the phenyl group is optionally composed of one to three independently selected halogens, -C(O)NR 6 R 6The morpholino or piperazine group is substituted, wherein the morpholino and piperazine groups are each optionally replaced by a -C(O)R group. 8 Substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is a phenyl group, wherein the phenyl group is independently selected from 1 to 3 halogens, -C(O)NR 6 R 6 The morpholino or piperazine group is substituted, wherein the morpholino and piperazine groups are each optionally replaced by a -C(O)R group. 8 replace.

[0644] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is...

[0645]

[0646] In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is phenyl.

[0647] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is a 4- to 6-membered monocyclic heterocyclic group, an 8- to 10-membered fused or bridged bicyclic heterocyclic group, a 5- to 6-membered monocyclic heteroaryl group, an 8- to 10-membered fused bicyclic heteroaryl group, or a 7- to 10-membered spirocyclic heterocyclic group, wherein each of the 4- to 6-membered monocyclic heterocyclic group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group is optionally surrounded by 1 to 3 R groups. 13 The groups are substituted and each has 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0648] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is a 4- to 6-membered monocyclic heterocyclic group, an 8- to 10-membered fused or bridged bicyclic heterocyclic group, a 5- to 6-membered monocyclic heteroaryl group, an 8- to 10-membered fused bicyclic heteroaryl group, or a 7- to 10-membered spirocyclic heterocyclic group, wherein each of the 4- to 6-membered monocyclic heterocyclic group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group is optionally surrounded by 1 to 3 R groups. 13 The groups are substituted and each has 1 to 3 independent cyclic heteroatoms selected from N, O and S, wherein at least one cyclic heteroatom is nitrogen.

[0649] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is a 4- to 6-membered monocyclic heterocyclic group, an 8- to 10-membered fused or bridged bicyclic heterocyclic group, a 5- to 6-membered monocyclic heteroaryl group, an 8- to 10-membered fused bicyclic heteroaryl group, or a 7- to 10-membered spirocyclic heterocyclic group, wherein each of the 4- to 6-membered monocyclic heterocyclic group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group is optionally surrounded by 1 to 2 R groups. 13 The groups are substituted and each has 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0650] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is a 4- to 6-membered monocyclic heterocyclic group, an 8- to 10-membered fused or bridged bicyclic heterocyclic group, a 5- to 6-membered monocyclic heteroaryl group, an 8- to 10-membered fused bicyclic heteroaryl group, or a 7- to 10-membered spirocyclic heterocyclic group, wherein each of the 4- to 6-membered monocyclic heterocyclic group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group is optionally surrounded by 1 to 2 R groups. 13 The groups are substituted and each has 1 to 3 independent cyclic heteroatoms selected from N, O and S, wherein at least one cyclic heteroatom is nitrogen.

[0651] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is an azirrobutyl, pyrrolyl, morpholinyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 1-oxa-3,8-diazaspiro[4.5]decyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, each of which is optionally surrounded by 1 to 3 R 13 Group substitution.

[0652] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is an azirrobutyl, pyrrolyl, morpholinyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 1-oxa-3,8-diazaspiro[4.5]decyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, each of which is optionally surrounded by 1 to 2 R 13 Group substitution.

[0653] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is an azirrobutyl, pyrrolyl, morpholinyl, piperazine, piperidinyl, pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 1-oxa-3,8-diazaspiro[4.5]decyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine, each of which is bound by 1 to 3 R 13 Group substitution.

[0654] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is an azirrobutyl, pyrrolyl, morpholinyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 1-oxa-3,8-diazaspiro[4.5]decyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, each of which is bound by 1 to 2 R 13 Group substitution.

[0655] In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is azacyclobutane, pyrrolyl, morpholinyl, piperazine, piperidinyl, pyrazolyl, imidazolyl, pyrimidinyl, isoindolinyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 1-oxa-3,8-diazaspiro[4.5]decyl or 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine.

[0656] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and optionally surrounded by 1 to 3 R atoms. 13 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and is substituted by 1 to 3 R groups. 13 Group substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0657] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is an azacyclic butyl, pyrrolidinyl, morpholinyl, piperazineyl, or piperidinyl group, wherein the azacyclic butyl, pyrrolidinyl, morpholinyl, piperazineyl, and piperidinyl group are each optionally surrounded by 1 to 3 R groups. 13 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is an aziridine, pyrrolidinyl, morpholinyl, piperazineyl, or piperidinyl group, wherein the aziridine, pyrrolidinyl, morpholinyl, piperazineyl, and piperidinyl group are each substituted with one to three R groups. 13 Group substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is azacyclic butyl, pyrrolidinyl, morpholinyl, piperazineyl or piperidinyl.

[0658] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and optionally surrounded by 1 to 3 R atoms. 13Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and is substituted by 1 to 3 R groups. 13 Group substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is an 8- to 10-membered fused or bridged bicyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0659] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is 2,5-diazabicyclo[2.2.1]heptyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 2,3-dihydrobenzo[b][1,4]dioxinyl, wherein the 2,5-diazabicyclo[2.2.1]heptyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, and 2,3-dihydrobenzo[b][1,4]dioxinyl are each optionally surrounded by 1 to 3 R 13 Substitution of a group. In some embodiments of compounds of formula I, Ia, II, or IIa or pharmaceutically acceptable salts thereof, Z is 2,5-diazabicyclo[2.2.1]heptyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 2,3-dihydrobenzo[b][1,4]dioxinyl, wherein the 2,5-diazabicyclo[2.2.1]heptyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, and 2,3-dihydrobenzo[b][1,4]dioxinyl are each substituted with one to three R groups. 13 Group substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is 2,5-diazabicyclo[2.2.1]heptyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 2,3-dihydrobenzo[b][1,4]dioxinyl.

[0660] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and optionally surrounded by 1 to 3 R atoms. 13 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and is substituted by 1 to 3 R groups. 13Group substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0661] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is pyrazolyl, imidazolyl, pyrimidinolyl, isoindololinyl, pyrazolyl, imidazolyl, or pyrimidinolyl, wherein each of the pyrazolyl, imidazolyl, pyrimidinolyl, isoindololinyl, pyrazolyl, imidazolyl, and pyrimidinolyl groups is optionally surrounded by 1 to 3 R groups. 13 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is pyrazolyl, imidazoleyl, pyrimidindolinyl, isoyindolinyl, pyrazolyl, imidazoleyl, or pyrimidinyl, wherein the pyrazolyl, imidazoleyl, pyrimidinyl, isoyindolinyl, pyrazolyl, imidazoleyl, and pyrimidinyl groups are each substituted with one to three R groups. 13 Group substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is pyrazolyl, imidazolyl, pyrimidinolyl, isoindolineyl, pyrazolyl, imidazolyl or pyrimidinyl.

[0662] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is an 8- to 10-membered fused bicyclic heteroaryl group, wherein the 8- to 10-membered fused bicyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and optionally surrounded by 1 to 3 R atoms. 13 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is an 8- to 10-membered fused bicyclic heteroaryl group, wherein the 8- to 10-membered fused bicyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and is substituted by 1 to 3 R groups. 13 Group substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is an 8- to 10-membered fused bicyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0663] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is isoindolinyl or 1H-benzo[d]imidazolyl, wherein the isoindolinyl and 1H-benzo[d]imidazolyl are each optionally surrounded by 1 to 3 R... 13 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is isoindolinyl or 1H-benzo[d]imidazolyl, wherein the isoindolinyl and 1H-benzo[d]imidazolyl are each substituted with 1 to 3 R groups. 13Group substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is isoindoline or 1H-benzo[d]imidazolium.

[0664] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is a 7- to 10-membered spirocyclic heterocyclic group, wherein the 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and optionally surrounded by 1 to 3 R atoms. 13 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is a 7- to 10-membered spirocyclic heterocyclic group, wherein the 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and is substituted by 1 to 3 R groups. 13 Group substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is a 7- to 10-membered spirocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0665] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, or 1-oxa-3,8-diazaspiro[4.5]decyl, wherein the 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, and 1-oxa-3,8-diazaspiro[4.5]decyl are each optionally surrounded by 1 to 3 R 13 Substitution of a group. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl or 1-oxa-3,8-diazaspiro[4.5]decyl, wherein the 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl and 1-oxa-3,8-diazaspiro[4.5]decyl are each substituted with 1 to 3 R groups. 13Group substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, Z is 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl or 1-oxa-3,8-diazaspiro[4.5]decyl.

[0666] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is...

[0667]

[0668] in

[0669] Ring Z a The heterocyclic group is a 4- to 6-membered monocyclic heterocyclic group, an 8- to 10-membered fused or bridged bicyclic heterocyclic group, a 5- to 6-membered monocyclic heteroaryl group, an 8- to 10-membered fused bicyclic heteroaryl group, or a 7- to 10-membered spirocyclic heterocyclic group, wherein each of the 4- to 6-membered monocyclic heterocyclic group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group has one nitrogen-containing ring heteroatom and each optionally has one or two additional ring heteroatoms independently selected from N, O, and S.

[0670] Ring Z a Optionally by 1 to 3 R 13 Group substitution.

[0671] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, Z is...

[0672]

[0673] in

[0674] Ring Z a The heterocyclic group is a 4- to 6-membered monocyclic heterocyclic group, an 8- to 10-membered fused or bridged bicyclic heterocyclic group, a 5- to 6-membered monocyclic heteroaryl group, an 8- to 10-membered fused bicyclic heteroaryl group, or a 7- to 10-membered spirocyclic heterocyclic group, wherein each of the 4- to 6-membered monocyclic heterocyclic group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group has one nitrogen-containing ring heteroatom and each optionally has one or two ring heteroatoms independently selected from N, O, and S.

[0675] Ring Z a Optionally by 1 to 2 R 13 Group substitution.

[0676] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, cyclo-Z a for

[0677]

[0678] Each of them is optionally divided by 1 to 3 Rs 13 Group substitution.

[0679] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, cyclo-Z a for

[0680]

[0681] Each of them is optionally divided by 1 to 2 Rs 13 Group substitution.

[0682] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 13 Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-4 Alkyl, C 1-4 Alkoxy, -NR 6 R 6 -C(O)R 10 NR 6 R 6 -C(O)NR 6 R 6 -C(O)R 8 C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic, or 7- to 10-membered spirocyclic heterocyclic.

[0683] Among them, C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, 8- to 10-membered fused bicyclic heterocyclic and 7- to 10-membered spirocyclic heterocyclic, each optionally surrounded by 1 to 3 R 14 Group substitution, and

[0684] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0685] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R13 Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-4 Alkyl, C 1-4 Alkoxy, -NR 6 R 6 -C(O)R 10 NR 6 R 6 -C(O)NR 6 R 6 -C(O)R 8 C 6-10 Monocyclic or fused bicyclic aryl groups, 4- to 6-membered monocyclic heterocyclic groups, 5- to 6-membered monocyclic heterocyclic groups, 8- to 10-membered fused or bridged bicyclic heterocyclic groups, or 8- to 10-membered fused bicyclic heterocyclic groups.

[0686] Among them, C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic and 8- to 10-membered fused bicyclic heterocyclic are each optionally surrounded by 1 to 3 R 14 Group substitution, and

[0687] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, and the 8- to 10-membered fused bicyclic heteroaryl group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0688] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 13 Independently, it can be an oxo group, -OH, halogen, -CN, or C. 1-4 Alkyl, C 1-4 Alkoxy, -NR 6 R 6 -C(O)R 10 NR 6 R 6 -C(O)NR 6 R 6 -C(O)R 8 C 6-10 Monocyclic or fused bicyclic aryl, 4- to 6-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heterocyclic, 8- to 10-membered fused or bridged bicyclic heterocyclic, or 8- to 10-membered fused bicyclic heterocyclic, wherein the C 6-10 Monocyclic or fused bicyclic aryl groups are optionally surrounded by 1 to 3 R groups. 14 The group is substituted, and wherein the 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group and the 8- to 10-membered fused bicyclic heteroaryl group each have 1 to 3 independently selected cyclic heteroatoms selected from N, O and S.

[0689] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 13 Independently, it can be an oxo group, -OH, halogen, methyl, ethyl, isopropyl, or -NR. 6 R 6 -C(O)R 10 NR 6 R 6 -C(O)NR 6 R 6 -C(O)R 8 phenyl, oxetyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, pyridyl, pyrimidinyl, or 1H-benzo[d]imidazolyl, wherein the phenyl group is optionally marked with an R 14 Group substitution.

[0690] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 13 It is an oxo group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 13 -OH. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, one or more R 13 It is a halogen. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, one or more R 13 -CN. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, one or more R 13 C 1-4 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R... 13 C 1-4 Alkyl group. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R... 13 For -NR 6 R 6 In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 13 -C(O)R 10 NR 6 R 6 In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 13 -C(O)NR 6 R 6In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 13 -C(O)R 8 .

[0691] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 13 C 6-10 Monocyclic or fused bicyclic aryl, wherein the C 6-10 Monocyclic or fused bicyclic aryl groups are optionally surrounded by 1 to 3 R groups. 14 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R groups are substituted. 13 C 6-10 Monocyclic or fused bicyclic aryl, wherein the C 6-10 Monocyclic or fused bicyclic aryl groups are surrounded by 1 to 3 R groups. 14 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R groups are substituted. 13 C 6-10 Monocyclic or fused bicyclic aryl groups.

[0692] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 13 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and optionally surrounded by 1 to 3 R atoms. 14 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R groups are substituted. 13 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and is surrounded by 1 to 3 R atoms. 14 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R groups are substituted. 13 It is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0693] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 13 It is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and optionally surrounded by 1 to 3 R atoms. 14Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R groups are substituted. 13 It is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and is surrounded by 1 to 3 R atoms. 14 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R groups are substituted. 13 It is a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O, and S.

[0694] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 13 It is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and optionally bounded by 1 to 3 R atoms. 14 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R groups are substituted. 13 It is an 8- to 10-membered fused or bridged bicyclic heterocyclic group, wherein the 8- to 10-membered fused or bridged bicyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and is bounded by 1 to 3 R atoms. 14 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R groups are substituted. 13 It is an 8- to 10-membered fused or bridged bicyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0695] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 13 It is an 8- to 10-membered fused bicyclic heteroaryl group, wherein the 8- to 10-membered fused bicyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and optionally surrounded by 1 to 3 R atoms. 14 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R groups are substituted. 13 It is an 8- to 10-membered fused bicyclic heteroaryl group, wherein the 8- to 10-membered fused bicyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S and is surrounded by 1 to 3 R atoms. 14 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R groups are substituted. 13 It is an 8- to 10-membered fused bicyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0696] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 13 It is a 7- to 10-membered spirocyclic heterocyclic group, wherein the 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and optionally surrounded by 1 to 3 R atoms. 14 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R groups are substituted. 13 It is a 7- to 10-membered spirocyclic heterocyclic group, wherein the 7- to 10-membered spirocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and is surrounded by 1 to 3 R atoms. 14 Group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R groups are substituted. 13 It is a 7- to 10-membered spirocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0697] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 14 Independent of halogen, C 1-4 Alkyl, -C(O)R 8 4- to 6-membered monocyclic heterocyclic groups, 5- to 6-membered monocyclic heteroaryl groups, 8- to 10-membered fused or bridged bicyclic heterocyclic groups, 8- to 10-membered fused bicyclic heteroaryl groups, or 7- to 10-membered spirocyclic heterocyclic groups.

[0698] Among them, C 1-4 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, CN and C. 1-4 The alkoxy group is substituted, and

[0699] Among them, the 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group are each optionally C 1-3 Alkyl substitution, wherein the C 1-3 Alkyl optional -OR 10 Si(R 15 )3 Replacement;

[0700] The 4- to 6-membered monocyclic heterocyclic group, the 5- to 6-membered monocyclic heteroaryl group, the 8- to 10-membered fused or bridged bicyclic heterocyclic group, the 8- to 10-membered fused bicyclic heteroaryl group, and the 7- to 10-membered spirocyclic heterocyclic group each have 1 to 3 independent cyclic heteroatoms selected from N, O, and S.

[0701] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R14 Independent of halogen, C 1-4 Alkyl, -C(O)R 8 Or a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S.

[0702] Among them, C 1-4 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, CN and C. 1-4 The alkoxy group is substituted, and

[0703] The 5- to 6-membered monocyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O, and S is optionally surrounded by C. 1-3 Alkyl substitution, wherein the C 1-3 Alkyl optional -OR 10 Si(R 15 )3 Replacement.

[0704] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 14 Independent of halogen, C 1-4 Alkyl or 5- to 6-membered monocyclic heteroaryl,

[0705] Among them, C 1-4 The alkyl group is optionally substituted with one to three halogens, and

[0706] The 5- to 6-membered heteroaryl group is optionally substituted with -CH2OCH2CH2Si(CH3)3 and has 1 to 3 independent cyclic heteroatoms selected from N, O and S.

[0707] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, each R 14 Independent of halogen, C 1-4 alkyl or imidazole group, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 halogens, and wherein the imidazole group is optionally substituted with -CH2OCH2CH2Si(CH3)3.

[0708] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 14 It is a halogen. In some embodiments of compounds of formula I, Ia, II or IIa or their pharmaceutically acceptable salts, one or more R 14 -C(O)R 8 .

[0709] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 14 C1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally surrounded by one to three independently selected from -OH, halogen, CN and C. 1-4 Alkyl group substitution. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 14 C 1-4 Alkyl, wherein the C 1-4 The alkyl group is selected independently by one to three elements from -OH, halogen, CN, and C. 1-4 Alkoxy group substitution.

[0710] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 14 C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with one to three halogens. In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 14 C 1-4 Alkyl, wherein the C 1-4 The alkyl group is replaced by 1 to 3 halogens.

[0711] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 14 C 1-4 alkyl.

[0712] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 14 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and optionally bonded by C. 1-3 Alkyl substitution, wherein the C 1-3 Alkyl optional -OR 10 Si(R 15 )3 substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, one or more R 14 It is a 4- to 6-membered monocyclic heterocyclic group, wherein the 4- to 6-membered monocyclic heterocyclic group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and is constituting a C 1-3 Alkyl substitution, wherein the C 1-3 Alkyl optional -OR 10 Si(R 15 )3 substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, one or more R 14It is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 independently selected cyclic heteroatoms from N, O and S.

[0713] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 14 It is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and optionally bonded by C. 1-3 Alkyl substitution, wherein the C 1-3 Alkyl optional -OR 10 Si(R 15 )3 substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, one or more R 14 It is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group has 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S and is bonded by C. 1-3 Alkyl substitution, wherein the C 1-3 Alkyl optional -OR 10 Si(R 15 )3 substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, one or more R 14 It is a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 independently selected cyclic heteroatoms from N, O, and S.

[0714] In some embodiments of compounds of formula I, Ia, II, or IIa, or pharmaceutically acceptable salts thereof, one or more R 14 It is an imidazole group, wherein the imidazole group is optionally C 1-3 Alkyl substitution, wherein the C 1-3 Alkyl optional -OR 10 Si(R 15 )3 substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, one or more R 14 It is an imidazole group, wherein the imidazole group is C 1-3 Alkyl substitution, wherein the C 1-3 Alkyl optional -OR 10 Si(R 15 )3 substitution. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, one or more R 14 The group is an imidazole group, wherein the imidazole group is optionally substituted with -CH2OCH2CH2Si(CH3)3. In some embodiments of compounds of formula I, Ia, II or IIa or pharmaceutically acceptable salts thereof, one or more R 14 It is an imidazole group.

[0715] In some embodiments of compounds of formula I, Ia, II, or IIa, or p...

Claims

1. A compound, wherein the structure of said compound is any one of the following: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and , Or its pharmaceutically acceptable salt.

2. A compound having the structure of any one of the following: , , , , , , , , , , ,and , Or its pharmaceutically acceptable salt.

3. A compound having the structure of any one of the following: , , , , , , , , , , , , , , , and ; Or its pharmaceutically acceptable salt.

4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition further comprises one or more additional therapeutic agents or pharmaceutically acceptable salts thereof.

6. Use of the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 4 or 5, in the preparation of a medicament for treating or preventing human immunodeficiency virus (HIV) infection in a subject.

7. The use according to claim 6, wherein the medicament comprises a therapeutically effective amount of one or more additional therapeutic agents or a pharmaceutically acceptable salt thereof, or is administered therewith.

8. The use according to claim 7, wherein the one or more adjunctive therapeutic agents are selected from the group consisting of: HIV protease inhibitors, HIV reverse transcriptase non-nucleoside or non-nucleotide inhibitors, HIV reverse transcriptase nucleoside or nucleotide inhibitors, HIV integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, defensin modulators, dendritic ICAM-3 grasping non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors and pharmacokinetic enhancers, or pharmaceutically acceptable salts of any of the foregoing substances or any combination thereof.

9. The use according to any one of claims 7 to 8, wherein the one or more additional therapeutic agents are selected from the group consisting of: HIV protease inhibitors, HIV reverse transcriptase non-nucleoside inhibitors, HIV reverse transcriptase non-nucleotide inhibitors, HIV reverse transcriptase nucleoside inhibitors, HIV reverse transcriptase nucleotide inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, or pharmaceutically acceptable salts of any of the foregoing substances or any combination thereof.

10. The use according to any one of claims 7 to 8, wherein the one or more additional therapeutic agents are selected from the group consisting of: iseltamivir, bicitiravir, abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide fumarate, or a pharmaceutically acceptable salt of any of the foregoing substances or any combination thereof.

11. The use according to any one of claims 7 to 8, wherein the one or more additional therapeutic agents are selected from the group consisting of: 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bicretiravir, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing substances or any combination thereof.

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