CDK inhibitor compounds

Abstract

Provided herein are CDK inhibitor compounds having a fused 6-6 bicyclic heteroaryl core, such as naphthyridine, quinazoline, pyridopyrimidine or a further substituted associated electron isosteric core structure. The core structure may be substituted with an amino group, wherein the amino group is further substituted with a cyclic group having an additional hydrophilic group. Also provided herein are compositions comprising the subject CDK inhibitor compounds. In some embodiments, the CDK inhibitor compound is a CDK2 inhibitor or a CDK4 inhibitor. Methods of using the compositions of the present disclosure in research or as therapeutic agents are also provided.

Description

1. Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 502,371, filed May 15, 2023, which is incorporated herein by reference in its entirety.

[0002] 2. Introduction Cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases. When heterodimerized with regulatory subunits called cyclins, CDKs are fully activated and regulate key cellular processes, including cell cycle progression and cell division. Uncontrolled proliferation is a hallmark of cancer cells. Dysregulation of CDK activity is associated with abnormal regulation of the cell cycle and has been detected in almost all forms of human cancer.

[0003] CDK2 is a cyclin-dependent kinase that plays a crucial role in regulating the cell cycle transition from G1 to S phase. It is involved in numerous other cellular processes, including DNA replication and repair, transcription, RNA processing, and cytoskeleton organization, making it an attractive target for cancer therapy. CDK2 has attracted significant attention because dysregulation of its activity occurs frequently in various human cancers. Although CDK2 is largely non-essential in the cell cycle of normally functioning cells, it is essential for the abnormal growth processes of cancer cells. The CCNE1 gene produces cyclin E, one of the two main protein-binding partners of CDK2. Overexpression of CCNE1 occurs in many tumor cells, leading to cells becoming dependent on both CDK2 and cyclin E. Aberrant cyclin E activity has also been observed in breast cancer, lung cancer, colorectal cancer, gastric cancer, bone cancer, as well as leukemia and lymphoma. Similarly, aberrant expression of cyclin A2 is associated with chromosomal instability and tumor proliferation, while inhibition leads to a slowing of tumor growth.

[0004] Therefore, CDK2 and its cyclin-binding partner represent potential therapeutic targets for novel cancer therapies. CDK2 inhibitors are a class of small molecule drugs that block CDK2 activity, leading to cell cycle arrest and potentially inducing cell death. However, identifying selective CDK2 inhibitors is challenging due to the extreme similarity of CDK2's active sites to those of other CDKs, such as CDK1. CDK1 is the only essential cyclin-dependent kinase in the cell cycle, so inhibiting it could lead to unintended side effects. 3. Summary of the Invention This document provides CDK inhibitor compounds. CDK inhibitor compounds may have a fused 6-6 bicyclic core, such as naphthidine, quinazoline, pyridopyrimidine, or further substituted isostatic core structures with associated electrons. The core structure may be substituted with an amino group, wherein the amino group is further substituted with a cyclic group having an additional hydrophilic group. The CDK inhibitor compound may be a CDK2 inhibitor. The CDK inhibitor compound may be a CDK4 inhibitor. This document also provides pharmaceutical compositions comprising the subject CDK inhibitor compound. Methods for using the compositions of this disclosure in investigations and as therapeutic agents are also provided.

[0006] Therefore, this disclosure includes CDK inhibitor compounds of formula I: (I) Or its pharmaceutically acceptable salt, wherein: Y 1 Is it N or CR? 1 ; Y 2 Is it N or CR? 2 ; Y 3 Is it N or CR? 3 ; Y 5 Is it N or CR? 5 ; R 6 Having a style ,in: A is a cyclic group selected from carbocyclic, heterocyclic, aryl, heteroaryl and their substituted forms; Z is an optional hydrophilic group; L 1 and L 2 It is an optional linker; and R represents 6 Connection point with adjacent nitrogen atoms; R 4 Selected from optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted heteroaryl and optionally substituted aryl; R 1 -R 3 R 5 and R 7 Independently selected from H, optionally substituted (C) 1-6 )alkyl, halogenated (C 1-6 )alkyl, -COR 30 -OR 30 halogens and CN; and R30 It is H or optionally substituted (C) 1-6 )alkyl.

[0007] In some embodiments of formula (I), the compound has formula (IA): (IA), Or it could be a pharmaceutically acceptable salt. 4. Detailed Implementation The CDK inhibitor compounds, compositions, and methods of this disclosure are described in more detail below. A specific class of CDK2 inhibitor compounds is described. Pharmaceutical compositions comprising the subject CDK inhibitor compounds are also described. Methods for using the CDK inhibitor compounds and compositions are also described.

[0009] 4.1 CDK inhibitor compounds As summarized above, this disclosure provides CDK inhibitor compounds having a fused 6-6 bicyclic heteroaryl core structure. In some embodiments, the compound has a 2,6-naphthidine core or an associated isosteric core. In some embodiments, the compound has a pyrido[3,4-d]pyrimidine core. In some embodiments, the compound has a quinazoline core. The naphthidine core may be substituted with an amino group, wherein the amino group is further substituted with a cyclic group having an additional hydrophilic group connected by an optional linker. In some embodiments, the hydrophilic group is an electrophilic group. In some embodiments, the CDK inhibitor is a classical inhibitor, wherein the inhibitory compound binds to a CDK and prevents other molecules from binding to the kinase. Classical inhibitors may not permanently bind to the receptor, i.e., they bind to the receptor and reversibly dissociate from the receptor, for example, through hydrogen bonds or van der Waals interactions.

[0010] In some embodiments, the hydrophilic group is an electrophilic reactive moiety. Generally, an electrophilic reactive moiety is a chemical group capable of covalently conjugating a biological target. In some embodiments, CDK inhibitors including an electrophilic reactive moiety are referred to as covalent inhibitors, wherein the covalent inhibitor binds to the CDK target at the desired binding site and forms a covalent chemical bond with the receptor. In some embodiments, the formed covalent chemical bond is irreversible. In some embodiments, the CDK inhibitor is a covalently reversible inhibitor. Such inhibitors can form a covalent bond with the receptor, but this chemical conjugation reaction is reversible. In some embodiments, the CDK is CDK2. In some embodiments, the CDK is CDK4.

[0011] This disclosure includes CDK inhibitor compounds of formula I: (I) Or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: Y 1 Is it N or CR? 1 ; Y 2 Is it N or CR? 2 ; Y 3 Is it N or CR? 3 ; Y 5 Is it N or CR? 5 ; R 6 Having a style ,in A is a cyclic group selected from carbocyclic, heterocyclic, aryl, heteroaryl and their substituted forms; Z is an optional hydrophilic group; L 1 and L 2 It is an optional linker; and R represents 6 The junction with the nitrogen atom; R 4 Selected from optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted heteroaryl and optionally substituted aryl; R 1 -R 3 R 5 and R 7 Independently selected from H, optionally substituted (C) 1-6 )alkyl, halogenated (C 1-6 )alkyl, -COR 30 -OR 30 halogens and CN; and R 30 It is H or optionally substituted (C) 1-6 )alkyl.

[0012] In some embodiments of the compound of formula I, Y 1 -Y 3 One or more of them are N. In some implementations, Y 3 It is N. In some implementations, Y 2 It is N. In some implementations, Y 1 It is N. In some implementations, Y 1 and Y 3 It is N. In some implementations, Y 2 and Y 3 It is N. In some implementations, Y1 and Y 2 It is N.

[0013] In some embodiments of the compounds of Formula I, ring A is an optionally substituted aryl group or an optionally substituted heteroaryl group. In some embodiments of Formula I, A is an optionally substituted aryl group. In some embodiments of Formula I, A is an optionally substituted heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is pyridyl, pyridazine, pyrimidine, or triazine.

[0014] In some embodiments of the compound of formula I, R 6 Includes structure 6A: (6A) in: Y 6 -Y 10 The groups are independently selected from CZ, CR 12 Or N, where Y 6 -Y 10 One of them is CZ; Each R 12 Independently selected from H, optionally substituted alkyl, optionally substituted alkoxy, hydroxyl, halogen, and CN; and Z is a group as described in this article.

[0015] In some implementations of 6A, Y 8 It is CZ. In some implementations of 6A, Y 6 Or Y 10 It is CZ. In some implementations of 6A, Y 7 Or Y 9 It's CZ.

[0016] In some implementations of 6A, Y 6 -Y 10 At least one of them is N. In some cases of 6A, Y 6 Or Y 10 It is N. In some cases of 6A, Y 6 and Y 10 Both are N. In some cases of 6A, Y 7 Or Y 9 It is N. In some cases of 6A, Y 7 and Y 9 Both are N. In some cases of 6A, Y 8 It is N.

[0017] In some implementations of 6A, Y 6 -Y 10One and only one of them is N. In some cases of 6A, Y 6 It is N. In some cases of 6A, Y 7 It is N.

[0018] In some implementations of 6A, Z is connected to Y. 8 And Y 6 Y 7 Y 9 and Y 10 Each is CR 12 In some implementation schemes, each R 12 It is H. In some implementations, at least one R 12 Not H. In some implementations, at least one R 12 Selected from (C) 1-3 )alkyl, (C 1-3 Alkyl groups, halogens, and nitriles. In some embodiments, R... 12 It is methyl. In some embodiments, R 12 It is Cl or F. In some implementations, R 12 It is a nitrile.

[0019] In some embodiments of the compound of formula I, R 6 It has structure 6A1: (6A1) Where m is 0, 1, 2, 3 or 4, and Z and R 12 As described in this article.

[0020] In some embodiments of 6A1, m is 0. It should be understood that when m is 0, each of the 2, 3, 5, and 6 positions of the aryl ring will not have a non-hydrogen substituent.

[0021] In some implementations of 6A1, m is greater than 0, such as 1, 2, 3, or 4, and each R 12 It is a non-hydrogen substituent. In some embodiments, each R 12 Independently selected from optional substitutions (C) 1-3 )alkyl, optionally substituted (C 1-3 Alkyl, hydroxyl, halogen, and CN. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 1 and R 12 It is an optional substitution (C) 1-3 )alkyl, optionally substituted (C 1-3 Alkyl, hydroxyl, halogen, or CN. In some embodiments, m is 2 and each R 12 Independently selected from optional substitutions (C) 1-3)alkyl, optionally substituted (C 1-3 Alkoxy, hydroxy, halogen, and CN.

[0022] In some implementations of 6A1, R 6 It has structure 6A2: (6A2) Where R 12 Selected from hydrogen, halogens (e.g., F), and optionally substituted (C) 1-6 )alkyl and optionally substituted (C 1-6 )alkoxy.

[0023] In some implementations of 6A2, R 12 It is hydrogen. In some implementations of 6A2, R 12 It is a halogen. In some embodiments, the halogen is F or Cl. In some embodiments of 6A2, R 12 It is an optional substitution (C) 1-3 )alkyl. In some embodiments, R 12 It is methyl. In some embodiments, R 12 It is trifluoromethyl. In some implementations, R 12 Yes (C) 1-3 )alkoxy. In some embodiments, R 12 It is a methoxy group.

[0024] In some embodiments of the compounds of Formula I, A is selected from optionally substituted cycloalkyl groups and optionally substituted heterocyclic groups. In some embodiments of Formula I, A is an optionally substituted cycloalkyl group. In some embodiments, the cycloalkyl group is cyclohexyl. In some embodiments, the cycloalkyl group is cyclopentyl. In some embodiments of Formula I, A is an optionally substituted heterocyclic group. In some embodiments, the heterocyclic group includes one or more nitrogen atoms. In some embodiments, the heterocyclic group includes one or more oxygen atoms. In some embodiments, the heterocyclic group includes one or more sulfur atoms. In some embodiments, the heterocyclic group is a 6-membered heterocyclic group. In some embodiments, the 6-membered heterocyclic group is selected from piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiazide, dithiazide, morpholine, and thiomorpholine. In some embodiments, the 6-membered heterocyclic group is piperidine. In some embodiments, the heterocyclic group is tetrahydropyran.

[0025] In some implementations of Formula I, R 6 Includes structure 6B: (6B) in: Y 11 Selected from O, S, CH2, C(R) 11 )2 and NR 9 ; R 9 It is hydrogen, optionally substituted alkyl, -L 2 -Z or Z; Each R 11 Independently selected from -L 2 -Z, Z, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl carbonyloxy, hydroxyl, halogen and CN; L 2 As described in this article; k is 0 or 1; and n is an integer from 0 to 9.

[0026] In some implementations of 6B, Y 11 It is O. In some implementations of 6B, Y 11 It is S. In some implementations of 6B, Y 11 It is C(R) 11 2. In some implementation schemes, Y 11 It is CH2. In some implementations, an R 11 It is H and the other is selected from -L 2 -Z, Z, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl carbonyloxy, hydroxyl, halogen, and CN. In some embodiments of 6B, Y 11 It is NR 9 In some implementation schemes, Y 11 It is NH. In some implementations, Y 11 It is NR 9 And R 9 It is an substituted alkyl group, -L 2 -Z or Z. In some implementations, R 9 It is an optionally substituted (C1-C3) alkyl group. In some embodiments, R 9 Yes -L 2 -Z. In some implementations, R 9 It's Z.

[0027] In some implementations of 6B, k is 0. In some implementations of 6B, k is 1.

[0028] In some embodiments of the compound of formula I, R 6 Includes structure 6B1: (6B1).

[0029] In some implementations of 6B1, n is 0, such that R does not exist. 11 Substituents. In some embodiments of 6B1, n is 1, 2, 3, or 4, and each R 11Independently selected from (C) 1-3 )alkyl, optionally substituted (C 1-3 Alkyl, hydroxyl, halogen, and CN. In some embodiments, R 11 Independently selected from methyl, methoxy, CF3, OCF3, hydroxy, and fluorine. In some embodiments, n is 1 and R 11 Selected from (C) 1-3 )alkyl, optionally substituted (C 1-3 Alkyl, hydroxyl, halogen, and CN. In some embodiments, n is 1 and R 11 Selected from methyl, methoxy, CF3, OCF3, hydroxyl and fluorine.

[0030] In some implementations of 6B1, R 6 Includes structure 6B2: (6B2).

[0031] In some embodiments of the compound of formula I, R 6 Includes 6B3: (6B3).

[0032] In some implementations of 6B3, n is 0, such that R does not exist. 11 Substituents. In some embodiments of 6B3, n is 1, 2, 3, or 4, and each R 11 Independently selected from (C) 1-3 )alkyl, optionally substituted (C 1-3 Alkyl, hydroxyl, halogen, and CN. In some embodiments, R 11 Independently selected from methyl, methoxy, CF3, OCF3, hydroxy, and fluorine. In some embodiments, n is 1 and R 11 Selected from (C) 1-3 )alkyl, optionally substituted (C 1-3 Alkyl, hydroxyl, halogen, and CN. In some embodiments, n is 1 and R 11 Selected from methyl, methoxy, CF3, OCF3, hydroxyl and fluorine.

[0033] In some implementations of 6B3, R 6 Includes structure 6B4: (6B4).

[0034] In some implementations of Formula I, R 4 It is selected from substituted amines, optionally substituted alkyl groups, optionally substituted alkynyl groups, optionally substituted cycloalkyl groups, optionally substituted cycloolefins, optionally substituted heterocyclic groups, optionally substituted heteroaryl groups, and optionally substituted aryl groups.

[0035] In some implementations of Formula I, R 4 It is an acetylinyl group that is optionally substituted.

[0036] In some implementations of Formula I, R 4 It is an optional substituted cycloalkyl group.

[0037] In some implementations of Formula I, R 4 It is an optional substituted cyclic olefin.

[0038] In some implementations of Formula I, R 4 It is an optional substituted heterocyclic group.

[0039] In some implementations of Formula I, R 4 It is an aryl group that is optionally substituted.

[0040] In some implementations of Formula I, R 4 It is an optional substituted heteroaryl group.

[0041] In some implementations of Formula I, R 4 It is a monocyclic group.

[0042] In some implementations of Formula I, R 4 It is a bicyclic group. In R... 4 In some embodiments, the bicyclic group is a spirocyclic group. In R 4 In some implementations, the bicyclic group is a fused bicyclic group.

[0043] In some implementations of Formula I, R 4 Selected from substituted amines, (C2-C6) alkynyl groups, cyclobutane, cyclopentane, cyclohexane, cyclohexene, piperidinyl, pyrrolidine, pyrrole, pyrrole, pyrazole, azacyclobutane, azacycloheptane, pyridinyl, phenyl, pyrimidine, benzisoxazole, indazole, thiazole, dihydropyran, tetrahydropyran, azaindole, indoline, hydroxyindole, triazole, oxadiazole, cyclohexanone, wherein R 4 Any of the groups may be substituted.

[0044] In some implementations of Formula I, R 4 The amine is selected from substituted amines. In some embodiments, the amine is substituted with two C1-C6 alkyl groups.

[0045] In some implementations of Formula I, R 4 It is an optionally substituted C2-C3 alkynyl group. In some embodiments, the alkynyl group is substituted with a cycloalkyl, aryl, heteroaryl, heterocyclic, or substituted alkyl group.

[0046] In some implementations of Formula I, R 4 It is an optionally substituted cyclobutane. In some embodiments, R4 It is an optionally substituted cyclopentane. In some embodiments, R 4 It is an optionally substituted cyclohexane. In some embodiments, R 4 It is an substituted cyclohexene.

[0047] In some implementations of Formula I, R 4 It is an optionally substituted piperidinyl group. In some embodiments, R 4 It is an optionally substituted pyrrolidine. In some embodiments, R 4 It is an optional substituted pyrrole. In some embodiments, R 4 It is an optionally substituted pyrazole. In some embodiments, R 4 It is an optionally substituted nitrogen-containing heterocyclic butane. In some embodiments, R 4 It is an optionally substituted azaheptane. In some embodiments, R 4 It is an optionally substituted pyridyl group. In some embodiments, R 4 It is an optionally substituted phenyl group. In some embodiments, R 4 It is an optionally substituted pyrimidine. In some embodiments, R 4 It is an optionally substituted benzoxazole. In some embodiments, R 4 It is an optionally substituted indazole. In some embodiments, R 4 It is an optionally substituted thiazole. In some embodiments, R 4 It is an optionally substituted dihydropyran. In some embodiments, R 4 It is an optionally substituted tetrahydropyran. In some embodiments, R 4 It is an optionally substituted aza-indole. In some embodiments, R 4 It is an optionally substituted indoline. In some embodiments, R 4 It is an optionally substituted hydroxyindole. In some embodiments, R 4 It is an optionally substituted triazole. In some embodiments, R 4 It is an optionally substituted oxadiazole. In some embodiments, R 4 It is an optional substituted cyclohexanone.

[0048] In some implementations of Formula I, R 4 It has formula 4A: (4A), in: X 12 It is CH2, C(R) 15 2. O or NR 25 ; R 15It is selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and optional substituents of nitriles; R 25 It is H, optionally substituted (C1-6) alkyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloolefin, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; and r is 0 or 1.

[0049] In some implementations of Equation 4A, q is 0, such that R does not exist. 15 Substituents. In some embodiments, q is 1 to 11, and each R 15 The substituents are independently selected from (C1-C3) alkyl, hydroxyl, halogen, and nitrile groups. In some embodiments, q is 1 and R 15 It is a nitrile. In some embodiments, q is 1 and R 15 It is a hydroxyl group.

[0050] In some embodiments of Equation 4A, r is 0. In some embodiments of Equation 4A, r is 1.

[0051] In some implementations of 4A, R 4 It has formula 4A1: (4A1), Where R 15 q and r are as described in this article.

[0052] In some implementations of 4A1, r is 0. In some implementations of 4A1, r is 1.

[0053] In some implementations of 4A1, q is 0, such that R does not exist. 15 Substituents. In some embodiments, q is 1 to 11, and each R 15 The substituents are independently selected from (C1-C3) alkyl, hydroxyl, halogen, and nitrile groups. In some embodiments, q is 1 and R 15 It is a nitrile. In some embodiments, q is 1 and R 15 It is a hydroxyl group.

[0054] In some implementations of 4A, R 4 It has formula 4A2: (4A2), in: R 25It is H or an optionally substituted (C1-6) alkyl group; and R 15 And q as described in this article.

[0055] In some implementations of 4A2, R 25 It is H. In some implementations of 4A2, R 25 It is an optional substituted (C1-3) alkyl group.

[0056] In some implementations of 4A2, q is 0, such that R does not exist. 15 Substituents. In some embodiments, q is 1 to 11, and each R 15 The substituents are independently selected from (C1-C3) alkyl, hydroxyl, halogen, and nitrile groups. In some embodiments, q is 1 and R 15 It is a nitrile. In some embodiments, q is 1 and R 15 It is a hydroxyl group.

[0057] In some implementations of Formula I, R 4 Formula 4B: (4B), in: X 1 Is it O or C(R)? 26 )2; R 16 It is selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and optional substituents of nitriles; Each R 26 Selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; and s is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9.

[0058] In some implementations of Formula 4B, X 1 It is C(R) 26 )2. In some implementation schemes, each R 26 It is H (i.e., X) 1 It is CH2). In some embodiments of formula 4B, X 1 It is O.

[0059] In some implementations of Equation 4B, s is 0, such that R does not exist. 16 Substituents. In some embodiments, s is 1 to 9, and each R 16The substituents are independently selected from (C1-C3) alkyl, hydroxyl, halogen, and nitrile groups. In some embodiments, q is 1 and R 16 It is a nitrile. In some embodiments, q is 1 and R 16 It is a hydroxyl group.

[0060] In some implementations of Formula I, R 4 It has formula 4C: (4C), in: R 17 It is selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and optional substituents of nitriles; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and u is 0, 1, or 2.

[0061] In some implementations of Equation 4C, t is 0, such that R does not exist. 17 Substituents. In some embodiments, t is 1 to 10, and each R 17 The substituents are independently selected from (C1-C3) alkyl, hydroxyl, halogen, and nitrile groups. In some embodiments, t is 1 and R 17 It is a nitrile. In some embodiments, t is 1 and R 17 It is a hydroxyl group.

[0062] In some embodiments of Formula 4C, u is 0. In some embodiments of Formula 4C, u is 1. In some embodiments of Formula 4C, u is 2.

[0063] In some implementations of Formula I, R 4 Having 4D: (4D), in: X 14 Is it O or NR? 25 ; R 17 It is selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and optional substituents of nitriles; Each R 25 Selected from H, (C1-6)alkyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloolefin, optionally substituted heterocyclic, optionally substituted heteroaryl, or optionally substituted aryl; and k can be 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0064] In some implementations of Formula I, R 4 It has formula 4E: (4E), in: X 2 Selected from NR 25 C(R) 26 2. C = O, O, and S; X 3 and X 4 Each is independently selected from N and CR 26 ; R 18 It is selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and optional substituents of nitriles; R 25 Selected from H, optionally substituted C1-6 alkyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloolefin, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl; Each R 26 Selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; and v can be 0, 1, 2, or 3.

[0065] In some implementations of Formula 4E, X 2 It is C(R) 26 )2. In some implementation schemes, each R 26 It is H. In some implementations, at least one R 26 The group is an optionally substituted alkyl group. In some embodiments of formula 4E, X 2 It is O. In some implementations of Formula 4E, X 2 It is NR 25 In some implementations, R 25 It is H. In some implementations, R 25 It is a (C1-3) alkyl group. In some embodiments of formula 4E, X 2 It is S. In some implementations of Formula 4E, X 2 It is C=O.

[0066] In some implementations of Formula 4E, X 3 It is N. In some implementations of Equation 4E, X3 It is CR 26 In some implementations, R 26 It is H. In some implementations, R 26 It is an alkyl group that is optionally substituted.

[0067] In some implementations of Formula 4E, X 4 It is N. In some implementations of Equation 4E, X 4 It is CR 26 In some implementations, R 26 It is H. In some implementations, R 26 It is an alkyl group that is optionally substituted.

[0068] In some implementations of Formula 4E, X 2 It is NR 25 X 3 It is CR 26 And X 4 It is CR 26 In some implementations of Formula 4E, X 2 It is NR 25 X 3 It is N and X 4 It is CR 26 In some implementations of Formula 4E, X 2 It is O, X 3 It is CR 26 And X 4 It is N.

[0069] In some implementations of Equation 4E, v is 0, such that R does not exist. 18 Substituents. In some embodiments, v is 1 to 3, and each R 18 The substituents are independently selected from (C1-3) alkyl, hydroxyl, halogen, and nitrile groups. In some embodiments, v is 1 and R 18 It is a (C1-3) alkyl group. In some embodiments, the (C1-3) alkyl group is methyl. In some embodiments, v is 1 and R is 1. 18 It is a halogen. In some implementations, the halogen is Cl or F.

[0070] In some implementations of Formula 4E, R 4 Choose from one of the following structures: , , , , , and .

[0071] In some implementations of Formula 4E, R 4 Selected from: or Where R 25 R 18 And v as defined in this article.

[0072] In some implementations of Formula 4E, R 4 Selected from: or Where R 25 R 18 And v as defined in this article.

[0073] In some implementations of Formula 4E, R 4 Selected from: or Where R 25 R 18 And v as defined in this article.

[0074] In some implementations of Formula 4E, R 25 It has the following structure: Where R 33 -R 37 Independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3 and halogens, and / or R 33 -R 37 Any two (e.g., R) 33 and R 34 and / or R 36 and R 37 These can be cyclically linked and, together with the carbon atoms to which they are linked, provide C3-C7 carbon rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, R 33 and R 34 Together with the carbon atoms they are attached to, they form C3-C7 carbon rings (e.g., cyclopropyl or cyclobutyl). In some embodiments, R 36 and R 37 Together with the carbon atoms they are attached to, they form C3-C7 carbon rings (e.g., cyclopropyl or cyclobutyl). In some embodiments, R 33 -R 37 At least one of them is a halogen. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl. In some embodiments, R 33 -R 35One or both of them are CF3. In some implementations, R 33 -R 35 One of them is CF3. In some implementations, R 33 -R 35 Both of them are CF3. In some implementations, R 33 -R 35 One or both of them are OH. In some embodiments, R 33 -R 35 One of them is OH. In some implementations, R 33 -R 35 Both of them are OH. In some implementations, R 36 -R 37 One or both of them are H. In some implementations, R 36 It is H, and R 37 Selected from CF3, CHF2, CH2F, CH3, OH, OCH3, and halogens. In some embodiments, R 36 and R 37 Both are H.

[0075] In some implementations of Formula 4E, R 25 It has the following structure: or in: R 33 -R 37 (If present) independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogens; and g and h are independently 1, 2, 3, 4 or 5 (e.g., 1 or 2).

[0076] In some implementations, g is 1. In some implementations, g is 2. In some implementations, h is 2. In some implementations, h is 1.

[0077] In some implementations of Formula 4E, R 25 yes or And R 33 -R 37 (If present) Independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3 and halogens.

[0078] In some implementations of Formula 4E, R 25 It has the following structure: . In some implementations of Formula 4E, R 25 It has the following structure: . In some embodiments of Formula 4E, the compound is: Where R 18 And v as defined in this article.

[0079] In some embodiments of Formula 4E, the compound is: Where R 18 And v as defined in this article.

[0080] In some embodiments of Formula 4E, the compound is: Where R 18 And v as defined in this article.

[0081] In some embodiments of Formula 4E, the compound is: Where R 18 And v as defined in this article.

[0082] In some implementations of Formula I, R 4 It has formula 4F: (4F), in: X 9 and X 10 Each independently selected from NR 25 C(R) 26 2. C = O, O, and S; X 3 and X 4 Each is independently selected from N and CR 26 ; R 24 It is selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and optional substituents of nitriles; R 29 and R 30 Each is independently H or an optionally substituted C1-6 alkyl group, or R 29 and R 30 Together with the carbon atoms to which they are attached, they form optionally substituted spirocyclic groups; and y is 0, 1, 2 or 3.

[0083] In some implementations of Formula 4F, X 9 It is C(R) 26 )2. In some implementation schemes, each R 26 It is H. In some implementations, at least one R 26 The group is an optionally substituted alkyl group. In some embodiments of formula 4F, X 9 It is O. In some implementations of Formula 4F, X 9 It is NR 25 In some implementations, R 25 It is H. In some implementations, R 25 It is a (C1-C3) alkyl group. In some embodiments of formula 4F, X 2 It is S. In some implementations of Formula 4F, X 2 It is C=O.

[0084] In some implementations of Formula 4F, X 10 It is C(R) 26 )2. In some implementation schemes, each R 26 It is H. In some implementations, at least one R 26 The group is an optionally substituted alkyl group. In some embodiments of formula 4F, X 10 It is O. In some implementations of Formula 4F, X 10 It is NR 25 In some implementations, R 25 It is H. In some implementations, R 25 It is a (C1-C3) alkyl group. In some embodiments of formula 4F, X 10 It is S. In some implementations of Formula 4F, X 10 It is C=O.

[0085] In some implementations of Formula 4F, X 9 It is NR 25 And X 10 It is C(R) 26 )2. In some implementations of Formula 4F, X 2 It is NR 25 And X 4 It is C=O. In some implementations of Equation 4F, X 9 It is C(R) 26 )2, and X 10 It is NR 25 In some implementations of Formula 4F, X 9 It is C=O, and X 10 It is NR 25 .

[0086] In some implementations of Equation 4F, y is 0, such that R does not exist. 24 Substituents. In some implementations, y is 1-3, and each R 24 The substituents are independently selected from (C1-C3) alkyl, hydroxyl, halogen, and nitrile groups. In some embodiments, y is 1 and R 24 It is a (C1-C3) alkyl group. In some embodiments, y is 1 and R 24 It is a halogen. In some implementations, the halogen is Cl or F.

[0087] In some embodiments of formula 4F, the compound is selected from: or Where R 24 R 25 R 29 R 30 And y are as defined in this article.

[0088] In some implementations of Formula 4F, R 29 and R 30 Each is independently H or an optionally substituted (C1-3) alkyl group. In some embodiments, R 29 and R 30 One of them is H, and the other is an optionally substituted (C1-3) alkyl group. In some embodiments, R 29 and R 30 Both are H. In some implementations, R 29 and R 30 All are optional substituted (C1-3) alkyl groups.

[0089] In some implementations of Formula 4F, R 29 and R 30 Together with the carbon atoms to which they are attached, they form optionally substituted spirocyclic groups. In some embodiments, the spirocyclic group is an optionally substituted spiropropyl group. In some embodiments, the spirocyclic group is an optionally substituted spirobutyl group.

[0090] In some embodiments of formula 4F, the compound is selected from: and Where R 24 R 25 And y are as defined in this article.

[0091] In some implementations of Formula I, R 4 Features 4G: (4G) in: X 8 Is it N or CR? 26 ; R 21 and R 22 Each is independently an optionally substituted (C1-C6) alkyl group; and R 26 The group is selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitriles.

[0092] In some implementations of 4G, X 8 It is N. In some implementations of 4G, X 8 It is CR 26 In some implementations, R 26 It is H. In some implementations, R 26 It is an alkyl group that is optionally substituted.

[0093] In some implementations of 4G, R 21 and R 22 Each is a (C1-C6) alkyl group selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl. In some embodiments of formula 4G, R 21 and R 22 They are the same. In some implementations of Type 4G, R 21 and R 22 They are different.

[0094] In some implementations of 4G, X 8 It is N and R 21 and R 22 Each is a different C1-C6 alkyl group. In some embodiments, R 21 It is methyl and R 22 It is isopropyl. In some implementations, R 21 It is methyl and R 22 It is ethyl. In some embodiments, R 21 It is methyl and R 22 It is propyl. In some implementations, R 21 It is methyl and R 21 It is butyl. In some implementations, R 21 It is methyl and R 22 It is tert-butyl.

[0095] In some implementations of 4G, X 8 It is CR 26 And R 21 and R22 They are the same. In some implementations, R 21 and R 22 Both are methyl groups. In some implementations, R 21 and R 22 Both are ethyl. In some embodiments, R 21 and R 22 They are all propyl.

[0096] In some implementations of any of Equation I, R 4 Having formula 4H: (4H), in: R 27 and R 28 Each is independently H or an optionally substituted (C1-C6) alkyl group; or R 27 and R 28 Together with the nitrogen atoms they are attached to, they form optionally substituted cyclic groups.

[0097] In some implementations of formula 4H, R 27 It is H. In some implementations, R 27 It is an optionally substituted (C1-C6) alkyl group. In some embodiments of formula 4H, R 28 It is H. In some implementations, R 28 It is an optionally substituted (C1-C6) alkyl group. In some embodiments, R 27 and R 28 They are different. In some implementations, R 27 and R 28 They are the same.

[0098] In some implementations of formula 4H, R 27 and R 28 Together with the nitrogen atoms to which they are attached, they form optionally substituted cyclic groups. In some embodiments, the cyclic groups are selected from 5-, 6-, or 7-membered heterocyclic groups. In some cases, the heterocyclic group is an optionally substituted piperidinyl group. In some cases, the heterocyclic group is an optionally substituted piperazine group.

[0099] In some implementations of Formula I, R 4 Having Equation 4I: (4I), in: R 23 It is H, optionally substituted (C1-C6) alkyl, optionally substituted cycloalkyl, optionally substituted cycloolefin, optionally substituted heterocyclic, optionally substituted heteroaryl, and optionally substituted aryl.

[0100] In some implementations of Formula 4I, R 23 It is H. In some implementations of Equation 4I, R 23 It is an optionally substituted (C1-C6) alkyl group. In some embodiments, R 23 It is methyl, ethyl, or propyl. In some embodiments, R 23 It is an optionally substituted cycloalkyl group. In some embodiments, the cycloalkyl group is selected from cyclobutene, cyclopentane, or cyclohexane. In some embodiments, R... 23 It is an optionally substituted cyclic olefin. In some embodiments, R 23 It is an optionally substituted heterocyclic group. In some embodiments, R 23 It is an optionally substituted heteroaryl group. In some embodiments, R 23 It is an aryl group that is optionally substituted.

[0101] In some implementations of Formula 4I, R 23 Selected from: (4E) (4F) (4J) (4K) (4L) and (4M), in: X 2 X 6 X 9 and X 10 Each independently selected from NR 25 C(R) 26 2. C = O, O, and S; X 3 X 4 X 5 and X 7 Each is independently selected from N and CR 26 ; Each R 18 -R 20 and R 24 It is independently selected from optional substituted alkyl, optional substituted amino, optional substituted alkoxy, hydroxy, carboxyl, halogen, optional substituted heterocyclic, optional substituted heteroaryl, optional substituted aryl, optional substituted cycloalkyl and optional substituents of CN; R 25 It is H or an optional substituted (C1-6) alkyl group; Each R 26Independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and nitriles; R 29 and R 30 Each is independently H or an optionally substituted (C1-6) alkyl group, or R 29 and R 30 Together with the carbon atoms they are attached to, they form spirocyclic groups with optional substitutions; v and y are each independently 0, 1, 2 or 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2.

[0102] In some implementations of Formula 4I, R 23 Having 4F (4F).

[0103] In some implementations of Formula 4I, R 23 Choose from one of the following structures: , , and Where R 24 R 25 R 29 R 30 And y are as defined in this article.

[0104] In some implementations of Formula I, R 4 It has any one of Equation 4J-Equation 4L: (4J) (4K) (4L), in: X 5 Is it N or CR? 26 ; R 19 It is selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and optional substituents of nitriles; R 26 Selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; and w ranges from 0 to 4.

[0105] In some implementations of Formula 4J, X 5 It is N. In some implementations of Equation 4J, X 5 It is CR 26 In some implementations, R 26 It is H. In some implementations, R 26 It can be an optionally substituted alkyl, amino, hydroxyl, halogen, or nitrile. In some embodiments, R 26 It is a nitrile. In some implementations, R 26 It is an amino group. In some embodiments, R 26 It is a hydroxyl group.

[0106] In some implementations of Equation 4J, w is 0, such that R does not exist. 19 Substituents. In some embodiments, w is 1 to 4, and each R 19 The substituents are independently selected from optionally substituted (C1-C3) alkyl, optionally substituted (C1-C3) alkoxy, amino, hydroxyl, halogen, and nitrile groups. In some embodiments, w is 1 and R 19 It is a C1-C3 alkyl group. In some embodiments, w is 1 and R 19 It is a C1-C3 alkyl group substituted with a hydroxyl or alkoxy group. In some embodiments, w is 1 and R is 1. 19 It is a C1-C3 alkoxy group. In some embodiments, R 19 It is -OCF3. In some implementations, w is 1 and R 19 It is a nitrile. In some embodiments, w is 1 and R 19 It is a nitrile. In some embodiments, w is 1 and R 19 It is a hydroxyl group.

[0107] In some implementations of Type 4K, X 5 It is N. In some implementations of Equation 4K, X 5 It is CR 26 In some implementations, R 26 It is H. In some implementations, R 26 It can be an optionally substituted alkyl, amino, hydroxyl, halogen, or nitrile. In some embodiments, R 26 It is a nitrile. In some implementations, R 26 It is an amino group. In some embodiments, R 26 It is a hydroxyl group.

[0108] In some implementations of Equation 4K, w is 0, such that R does not exist. 19 Substituents. In some embodiments, w is 1 to 4, and each R 19The substituents are independently selected from optionally substituted (C1-C3) alkyl, optionally substituted (C1-C3) alkoxy, amino, hydroxyl, halogen, and nitrile groups. In some embodiments, w is 1 and R 19 It is a C1-C3 alkyl group. In some embodiments, w is 1 and R 19 It is a C1-C3 alkyl group substituted with a hydroxyl or alkoxy group. In some embodiments, w is 1 and R is 1. 19 It is a C1-C3 alkoxy group. In some embodiments, R 19 It is -OCF3. In some implementations, w is 1 and R 19 It is a nitrile. In some embodiments, w is 1 and R 19 It is a nitrile. In some embodiments, w is 1 and R 19 It is a hydroxyl group.

[0109] In some implementations of Formula 4L, X 5 It is N. In some implementations of Equation 4L, X 5 It is CR 26 In some implementations, R 26 It is H. In some implementations, R 26 It can be an optionally substituted alkyl, amino, hydroxyl, halogen, or nitrile. In some embodiments, R 26 It is a nitrile. In some implementations, R 26 It is an amino group. In some embodiments, R 26 It is a hydroxyl group.

[0110] In some implementations of Equation 4L, w is 0, such that R does not exist. 19 Substituents. In some embodiments, w is 1 to 4, and each R 19 The substituents are independently selected from optionally substituted (C1-C3) alkyl, optionally substituted (C1-C3) alkoxy, amino, hydroxyl, halogen, and nitrile groups. In some embodiments, w is 1 and R 19 It is a C1-C3 alkyl group. In some embodiments, w is 1 and R 19 It is a C1-C3 alkyl group substituted with a hydroxyl or alkoxy group. In some embodiments, w is 1 and R is 1. 19 It is a C1-C3 alkoxy group. In some embodiments, R 19 It is -OCF3. In some implementations, w is 1 and R 19 It is a nitrile. In some embodiments, w is 1 and R 19 It is a nitrile. In some embodiments, w is 1 and R 19 It is a hydroxyl group.

[0111] In some implementations of Formula I, R 4 It has a 4M designation: (4M), in: X 6 Selected from NR 25 C(R) 26 2. C = O, O, and S; X 7 Is it N or CR? 26 ; R 20 It is selected from optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and optional substituents of nitriles; R 25 Selected from H or optionally substituted C1-C6 alkyl groups; Each R 26 Selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, and nitrile; and x is 0, 1, or 2.

[0112] In some implementations of Formula 4M, X 6 It is C(R) 26 )2. In some implementation schemes, each R 26 It is H. In some implementations, at least one R 26 The group is an optionally substituted alkyl group. In some embodiments of formula 4M, X 6 It is O. In some implementations of Formula 4M, X 6 It is NR 25 In some implementations, R 25 It is H. In some implementations, R 25 It is a C1-C3 alkyl group. In some embodiments of formula 4M, X 2 It is S.

[0113] In some implementations of Formula 4M, X 7 It is N. In some implementations of Formula 4M, X 7 It is CR 26 In some implementations, R 26 It is H. In some implementations, R 26 It is an alkyl group that is optionally substituted.

[0114] In some implementations of Formula 4M, X 6 It is NR 25 And X 7 It is CR 26In some implementations of Formula 4M, X 2 It is S and X 7 It is N.

[0115] In some implementations of Equation 4M, x is 0, such that R does not exist. 20 Substituents. In some embodiments, x is 1 or 2, and each R 20 The substituents are independently selected from C1-C3 alkyl, hydroxyl, halogen, and nitrile groups. In some embodiments, x is 1 and R 20 It is a C1-C3 alkyl group.

[0116] In some embodiments of formula 4M, the compound is: . In some embodiments of formula 4M, the compound is: Where R 25 As defined in this article.

[0117] Where R 24 R 25 And y are as defined in this article.

[0118] In some implementations of Formula I, R 6 It contains a hydrophilic group (Z). In some embodiments, Z contains a substantially bioinert hydrophilic portion. In some embodiments, Z contains an electrophilic reactive portion capable of covalently binding to a biological target.

[0119] In some embodiments of Formula I, Z comprises a group selected from sulfonyl, sulfone, sulfonamide, sulfonylimide, sulfinylimide, sulfonylimideamide, sulfonate, formamide, carboxyl, hydroxyl, hydroxyalkyl, aldehyde, ester, thioester, alkoxy, nitrile, halogen, thiolactone, and any combination thereof. In some embodiments, Z comprises a sulfonyl group. In some embodiments, Z comprises a sulfone. In some embodiments, Z comprises a thioimide. In some embodiments, Z comprises a sulfinylimide. In some embodiments, Z comprises a sulfonylimideamide. In some embodiments, Z comprises a sulfonate. In some embodiments, Z comprises a formamide. In some embodiments, Z comprises a carboxyl group. In some embodiments, Z comprises a hydroxyl or hydroxyalkyl group. In some embodiments, Z comprises an aldehyde. In some embodiments, Z comprises an ester. In some embodiments, Z comprises a thioester. In some embodiments, Z comprises an alkoxy group. In some embodiments, Z comprises a nitrile. In some embodiments, Z comprises a halogen. In some embodiments, Z comprises a thiolactone. In some embodiments, Z comprises both formamide and thiolactone.

[0120] In some embodiments of Formula I, Z is an alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, or heterocyclic sulfonyl. In some embodiments, Z is an alkylsulfonyl. In some embodiments, Z is a cycloalkylsulfonyl. In some embodiments, Z is an alkenylsulfonyl. In some embodiments, Z is a heterocyclic sulfonyl.

[0121] In some embodiments of Formula I, Z is an alkylsulfinimide, a cycloalkylsulfinimide, a heterocyclic sulfinimide, a sulfonamide, or an alkylsulfonamide. In some embodiments, Z is an alkylsulfinimide. In some embodiments, Z is a cycloalkylsulfinimide. In some embodiments, Z is a heterocyclic sulfinimide. In some embodiments, Z is a sulfonamide. In some embodiments, Z is an alkylsulfonamide.

[0122] In some implementations of Formula I, R 6 Contains one or more linker bases (L 1 and / or L 2 In some implementations, one or more linker bases are optionally replaced (C). 1-6 Alkylene. In some embodiments, one or more linking groups are independently -CH2-, -(CH2)2-, or -(CH2)3-. In some embodiments of Formula I, L 1 and L 2 It does not exist. In some implementations, L 1 It does not exist and L 2 It is an optional substitution (C) 1-6 )alkylene. In some embodiments, L 2 It does not exist and L 1 It is an optional substitution (C) 1-6 )alkylene. In some embodiments, L 1 and L 2 All are optional substitutions (C) 1-6 )alkylene.

[0123] In some implementations of Formula I, R 6 Having a style .

[0124] In some embodiments of Formula I, Z is selected from sulfones, sulfonates, carboxyl groups, esters, hydroxyl groups, hydroxyalkyl groups, aldehydes, optionally substituted thiolactones, and optionally substituted formamides. In some embodiments, Z is a sulfone. In some embodiments, Z is a sulfonate. In some embodiments, Z is an optionally substituted formamide. In some embodiments, Z is a formamide substituted with a thiolactone group. In some embodiments, the thiolactone is a γ-thiolactone. In some embodiments, Z is a carboxyl group. In some embodiments, Z is a hydroxyl or hydroxyalkyl group. In some embodiments, Z is an aldehyde. In some embodiments, Z is an ester. In some embodiments, Z is an ester. In some embodiments, Z is a thioester (e.g., -COSR). 12 , where R 12 It is an optional substitution (C) 1-6 (alkyl group). In some embodiments, Z comprises an optionally substituted thiolactone. In some embodiments, the thiolactone is a γ-thiolactone.

[0125] In some implementations of Formula I, -L 2 -Z or Z is one of Z1-Z6: (Z1) (Z2) (Z3) (Z4) (Z5) and (Z6), in: Y 9 It does not exist; it is -O- or -NR. 9 -、-(C 1-6 )alkylene-O-, -(C 1-6 )alkylene-NR 9 -; X 11 It is O or NH; R 51 Selected from halogens, R 8 -NR 9 R 10 (C) 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 ) alkynyl, cycloalkyl, heterocyclic groups and their substituted forms; R 8 Yes (C) 1-6 )alkyl (e.g., (C 3-6 )cycloalkyl), (C 2-6 )alkenyl, (C 2-6 ) alkynyl, cycloalkyl, heterocyclic or their substituted forms; R 9It is H or optionally substituted (C) 1-6 )alkyl; R 10 It is H, or optional substitution (C) 1-6 )alkyl, optionally substituted (C 3-8 )cycloalkyl, optionally substituted heterocyclic, sulfone (e.g., formula Z1), or thiolactone (e.g., formula Z2); and R 52 It is H, or optional substitution (C) 1-6 Alkyl, optionally substituted aryl, or optionally substituted heterocyclic groups; m is 0, 1, or 2; and p, q, s, and t are independently 0, 1, 2, 3, 4, 5, or 6.

[0126] In some implementations of Z1, -L 2 -Z or Z has the formula Z1A: (Z1A), in: R 51 It is halogen, -NR 9 R 10 Optional substitution (C) 1-6 )alkyl or optionally substituted (C 2-6 )alkenyl.

[0127] In some implementations of Z1A, R 51 It is a halogen. In some implementations of Z1A, R 51 It is F. In some implementations of Z1A, R 51 Yes (C) 1-6 )alkyl. In some embodiments of Z1A, R 51 Yes -NR 9 R 10 In some implementations of Z1A, R 51 Yes (C) 2-6 )alkenyl.

[0128] In some implementations of Z1, -L 2 -Z or Z has the formula Z1B: (Z1B), in: X 11 It is O or NH; and R 8 Yes (C) 1-6 )alkyl (e.g. (C 3-6 )cycloalkyl), (C 2-6 )alkenyl, (C 2-6) alkynyl, cycloalkyl, heterocyclic or their substituted forms.

[0129] In some implementations of Z1B, X 11 It is O. In some implementations of Z1B, X 11 It is NH. In some implementations of Z1B, R 8 Yes (C) 1-6 )alkyl. In some embodiments of Z1B, R 8 It is methyl. In some embodiments of Z1B, R 8 Yes (C) 2-6 )alkenyl. In some embodiments of Z1B, R 8 It is -CH=CH2 or -C(CH3)=CH2. In some implementations of Z1B, R 8 Yes (C) 2-6 ) alkynyl group. In some embodiments of Z1B, R 8 It is -CCH or -CC-CH3. In some implementations of Z1B, R 8 It is an optional substitution (C) 3-7 )cycloalkyl. In some embodiments of Z1B, R 8 It is an optional substitution (C) 3-7 Heterocyclic group. In some embodiments of Z1B, R 8 It is R 8 Yes (C) 3-4 )cycloalkyl. In some embodiments of Z1B, R 8 Yes (C) 2-4 Heterocyclic group.

[0130] In some implementations of Z1B, X 11 It is NH, R 8 Yes (C) 1-6 )alkyl. In some embodiments of Z1B, X 11 It is NH, and R 8 It is a cycloalkyl group. In some embodiments of Z1B, X 11 It is NH, and R 8 It is a heterocyclic group.

[0131] In some implementations of Z1B, X 11 It is O, R 8 Yes (C) 1-6 )alkyl. In some embodiments of Z1B, X 11 It is O, and R 8 It is a cycloalkyl group. In some embodiments of Z1B, X 11 It is O, and R 8 It is a heterocyclic group.

[0132] In some implementations of Z1, -L 2 -Z or Z has the formula Z1C: (Z1C), in: X 11 It is O or NH; R 9 It is H or optionally substituted (C) 1-6 )alkyl; and R 10 It is H, or optional substitution (C) 1-6 )alkyl, optionally substituted (C 3-8 )Cycloalkyl, optionally substituted heterocyclic groups.

[0133] In some implementations of Z1C, X 11 It is O. In some implementations of Z1C, X 11 It is NH. In some implementations of Z1C, R 9 It is H. In some implementations of Z1C, R 9 Yes (C) 1-6 )alkyl. In some embodiments of Z1C, R 10 It is H. In some implementations of Z1C, R 10 Yes (C) 1-6 )alkyl. In some embodiments of Z1C, R 10 It is an optionally substituted cycloalkyl group. In some embodiments of Z1C, R 10 It is an optionally substituted heterocyclic group. In some embodiments of Z1C, R 9 It is H, and R 10 Yes (C) 1-6 )alkyl. In some embodiments of Z1C, R 9 It is H, and R 10 It is H.

[0134] In some implementations of Z1C, X 11 It is NH, R 9 It is H and R 10 Yes (C) 1-6 )alkyl. In some embodiments of Z1C, X 11 It is NH, R 9 It is H and R 10 It is methyl. In some embodiments of Z1C, X 11 It is NH, R 9 It is H and R 10 It is an ethyl group.

[0135] In some implementations of Z1C, X 11 It is O, R9 It is H and R 10 Yes (C) 1-6 )alkyl. In some embodiments of Z1C, X 11 It is O, R 9 It is H and R 10 It is methyl. In some embodiments of Z1C, X 11 It is O, R 9 It is H and R 10 It is an ethyl group.

[0136] In some implementations of Z4, -L 2 -Z or Z has the formula Z4A: (Z4A), in: R 9 It is H; and R 10 Yes - SO2R 38 ;and R 38 It can be an alkyl or amino group that is optionally substituted.

[0137] In some implementations of Z4A, R 38 Yes (C) 1-6 )alkyl. In some embodiments of Z4A, R 18 It is methyl. In some embodiments of Z4A, R 38 It is an ethyl group.

[0138] In some implementations of Formula I, -L 2 -Z or Z has the formula Z4B: (Z4B), in: R 9 It is H; and R 10 Yes - SO2R 38 , where R 38 It is an optionally substituted alkenyl group, or R 10 It is an optional substituted thiolactone.

[0139] In some implementations of formula Z4B, R 10 It is an optionally substituted alkenyl group. In some cases, R 10 It is -CH=CH2. In some implementations of Z4B, R 10 It is a thiolactone. In some embodiments, R 10 It is a γ-thiolactone.

[0140] In some implementations, Z4B has the formula Z4C: (Z4C), Where m is 0, 1, or 2. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2.

[0141] In some implementations of Formula I, -L 2 -Z or Z has the formula Z2: (Z2), Where m is 0, 1, or 2. In some implementations, m is 1. In some implementations, m is 0. In some implementations, m is 2.

[0142] In some implementations of Formula I, -L 2 -Z or Z has the formula Z3: (Z3) in: R 52 It is an optionally substituted alkyl, optionally substituted aryl, or optionally substituted heterocyclic group; and t is 0, 1, or 2.

[0143] In some implementations of Z3, R 52 Yes (C) 1-6 )alkyl. In some embodiments of Z3, R 52 It is an optionally substituted aryl group. In some embodiments of Z3, R 52 It is an optionally substituted heterocyclic group. In some embodiments, -OR 12 It is a leaving group, which allows Z3 to be characterized as an active ester. In some embodiments, R 52 yes: . In some embodiments of Z3, t is 1. In some embodiments of Z3, t is 2. In some embodiments of Z3, t is 0.

[0144] In some implementations, Z3 has the formula Z3A: (Z3A), Where R 52 It is H.

[0145] In some implementations of Formula I, -L 2 -Z or Z has the formula Z5: (Z5), Where q is 0, 1 or 2.

[0146] In some implementations of Z5, q is 0. In some implementations of Z5, q is 1. In some implementations of Z5, q is 2.

[0147] In some implementations of Formula I, -L 2 -Z or Z has equation Z6: (Z6), Where p is 0, 1, 2, 3, 4, or 5. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0148] In some implementations of Formula I, -L 2 -Z or Z is a non-electrophilic hydrophilic group.

[0149] In some embodiments of Formula I, Z is a non-electrophilic hydrophilic group of Formula Z1, wherein R 51 It is an optionally substituted alkyl or amino group. In some embodiments, Z is Z1, and R... 51 It is an amino group. In some embodiments, Z is Z1 and R 51 Z is an alkyl group that is optionally substituted. Therefore, in some embodiments of Formula I, Z is an alkyl sulfone. In some embodiments, Z is an alkyl sulfone of Formula Z1D: (Z1D) Where R 53 It is H or an optionally substituted C1-C6 alkyl group. In some embodiments of Z1D, R 53 It is H. In some implementations of Z1D, R 13 It is a C1-C3 alkyl group.

[0150] In some embodiments of Formula I, Z is a non-electrophilic hydrophilic group of Formula Z4, wherein; R 9 It is H; and R 10 With formula -SO2R 38 ;and R 38 It can be an alkyl or amino group that is optionally substituted.

[0151] In some embodiments of Formula I, Z is formamide of Formula Z4, R 10 Yes - SO2R 38 And R 38 It is methyl. In some embodiments, Z is formamide of formula Z4, and R 10 It is a formula - SO2R38 And R 38 It is an amino group.

[0152] In some embodiments of Formula I, Z is a non-electrophilic hydrophilic group of Formula Z6, where p is 0, 1, or 2. In some embodiments, p is 0, such that Z6 is -OH. In some embodiments, p is 1, such that Z6 is -CH2OH. In some embodiments, p is 2, such that Z6 is CH2CH2OH.

[0153] In some embodiments of Formula I, Z is a non-electrophilic hydrophilic group of Formula Z3, wherein R 52 It is H (i.e., Z is -CO2H).

[0154] In some embodiments of Formula I, Z is an electrophilic and hydrophilic group.

[0155] In some embodiments of Formula I, Z is an electrophilic reactive hydrophilic group of Formula Z1, wherein R 51 It is an optional substitution (C) 2-6 Alkenyl. Therefore, in some embodiments of Formula I, Z is an alkenyl sulfone (e.g., vinyl sulfone). In some embodiments, Z is an alkenyl sulfone of Formula Z1E: (Z1E) Where R 14 It is H or optionally substituted (C) 1-6 )alkyl. In some embodiments of Z1E, R 14 It is H. In some implementations of Z1E, R 14 It is an optional substituted C1-C3 alkyl group.

[0156] In some embodiments of Formula I, Z is formamide of Formula Z4, R 10 Yes - SO2R 38 Or thiolactone, where R 38 It is an optionally substituted alkenyl group. In some embodiments, Z is a formamide of formula Z4, and R... 10 Yes - SO2R 38 And R 38 It is a substituted alkenyl group. In some cases, R 38 It is -CH=CH2. In some embodiments, Z is formamide of formula Z4, R 10 It is a thiolactone. In some embodiments, Z has the formula Z4C.

[0157] In some embodiments of Formula I, Z is a thiolactone of Formula Z2. In some embodiments, Z has Formula Z2 and m is 0. In some embodiments, Z has Formula Z2 and m is 1. In some embodiments, Z has Formula Z2 and m is 2.

[0158] In some embodiments of Equation I, Z has Equation Z1A, where R 51 It is a halogen. In some implementations, R 51 It is F.

[0159] In some embodiments of Equation I, Z has Equation Z3, where R 52 It is an optional substitution (C) 1-6 )Alkyl or heterocyclic group. In some embodiments, Z has the formula Z3, wherein R 52 It is a heterocyclic ring. In some implementations, R 52 yes: . In some embodiments of the compound of formula I, Y 1 -Y 3 The two or more of them are CR 1 CR 2 and CR 3 In some embodiments of the compound of formula I, Y 1 -Y 3 CR 1 CR 2 and CR 3 In some implementations, R 1 -R 3 Each of them is H. In some implementations, R 1 -R 3 At least one of them is not H. In some implementations, Y 2 It is CR 2 And R 2 Not H. In some implementations, R 2 Selected from substituted alkyl, alkyl halide or -COR 30 , where R 30 Is it H or C? 1-6 alkyl.

[0160] In some embodiments of the compound of formula I, Y 3 It is N and Y 1 and Y 2 Each is a CR 1 and CR 2 In some embodiments of the compound of formula I, Y 1 It is N and Y 2 and Y 3 Each is a CR 2 and CR 3 In some embodiments of the compound of formula I, Y 2 It is N and Y 1and Y 3 Each is a CR 1 and CR 3 .

[0161] In some implementations of Formula I, Y 5 It is CR 5 In some implementations, R 5 Selected from H, CH3, CF3, and halogens. In some embodiments, R 5 It is CH3. In some implementations, R 5 It is CF3. In some implementations, R 5 It is a halogen. In some implementations, R 5 It is F or Cl. In some implementations, R 5 It is H.

[0162] In some implementations of Formula I, Y 5 It is N.

[0163] In some implementations of Formula I, R 7 Selected from H, CH3, CF3, and halogens. In some embodiments, R 7 It is CH3. In some implementations, R 7 It is CF3. In some implementations, R 7 It is a halogen. In some implementations, R 7 It is F or Cl. In some implementations, R 7 It is H.

[0164] In some implementations of Formula I, Y 1 It is CR 1 In some implementations, R 1 Selected from H, CH3, CF3, and halogens. In some embodiments, R 1 It is CH3. In some implementations, R 1 It is CF3. In some implementations, R 1 It is a halogen. In some implementations, R 1 It is F or Cl. In some implementations, R 1 It is H.

[0165] In some implementations of Formula I, Y 1 It is N.

[0166] In some implementations of Formula I, Y 2 It is CR 2 In some implementations, R 2 Selected from H, CH3, CF3, -CHF2, -CH2Cl, halogens, -C(=O)H and -(CH2).z OH, where z is 1, 2, or 3. In some implementations, R 2 It is CH3. In some implementations, R 2 It is CF3. In some implementations, R 2 It is -CHF2. In some implementations, R 2 It is -CH2Cl. In some implementations, R 2 It is a halogen. In some implementations, R 2 It is F or Cl. In some implementations, R 2 It is -C(=O)H. In some implementations, R 2 It is -(CH2) z OH, where z is 1. In some implementations, R 2 It is -(CH2) z OH, where z is 2. In some implementations, R 2 It is -(CH2) z OH, where z is 3. In some implementations, R 2 It is H.

[0167] In some implementations of Formula I, Y 2 It is N.

[0168] In some embodiments of Formula I, the compound has Formula IA: (IA) Or its pharmaceutically acceptable salt, of which R 1 R 2 R 4 R 5 R 6 and R 7 As defined in this article.

[0169] In some embodiments of Formula I, the compound has Formula IB: (IB) Or its pharmaceutically acceptable salt, of which R 1 R 2 R 4 R 6 and R 7 As defined in this article.

[0170] In some embodiments of Formula I, the compound has Formula I: (IC) Or its pharmaceutically acceptable salt, of which R 1 -R 7 As defined in this article.

[0171] In some embodiments of Formula I, the compound has Formula ID: (ID) Or its pharmaceutically acceptable salt, of which R 1 -R 4 R 6 and R 7 As defined in this article.

[0172] In some embodiments of Formula I, the compound has Formula IE: (IE) Or its pharmaceutically acceptable salt, of which R 2 -R 7 As defined in this article.

[0173] In some embodiments of Formula I, the compound has Formula IF: (IF) Or its pharmaceutically acceptable salt, of which R 2 -R 4 R 6 and R 7 As defined in this article.

[0174] In some embodiments of Formula I, the compound has Formula IG: (IG) Or its pharmaceutically acceptable salt, of which R 2 R 4 R 5 R 6 and R 7 As defined in this article.

[0175] In some embodiments of Formula I, the compound has Formula IH: (IH) Or its pharmaceutically acceptable salt, of which R 2 R 4 R 6 and R 7 As defined in this article.

[0176] In some embodiments of Formula I, the compound has Formula IJ: (IJ) Or its pharmaceutically acceptable salt, of which R 1 R 4 R 5 R 6 and R7 As defined in this article.

[0177] In some embodiments of Formula I, the compound has Formula IK: (IK) Or its pharmaceutically acceptable salt, of which R 1 R 4 R 6 and R 7 As defined in this article.

[0178] In some embodiments of Formula I, the compound has Formula IL: (IL) Or its pharmaceutically acceptable salt, of which R 1 R 3 R 4 R 5 R 6 and R 7 As defined in this article.

[0179] In some embodiments of Formula I, the compound has Formula IM: (IM) Or its pharmaceutically acceptable salt, of which R 1 R 3 R 4 R 6 and R 7 As defined in this article.

[0180] In some embodiments of Formula I, the compound has Formula IA.

[0181] In some embodiments of Formula I, the compound has Formula IB.

[0182] In some implementations of Formula I or Formula IA-IM, ring A is as defined herein.

[0183] In some embodiments of any of Formula I or Formula IC-Form IF or Formula IL-Form IM, R 3 It is CN. In any of the embodiments of Formula I or Formula IC-Formula IF or Formula IL-Formula IM, R 3 It is H.

[0184] In some implementations of Formula I, Formula IA, or Formula IC, R 1 R 2 R 5 and R 7 Each is H.

[0185] In some embodiments of Formula I or Formula IA-IM, R 6 Selected from: (6C) (6D) (6E) (6F) (6G) (6H) and (6I), in: R 8 It is an optional substitution (C) 1-6 )alkyl, optionally substituted (C 2-6 Alkenyl, optionally substituted cycloalkyl, or optionally substituted heterocyclic groups; R 9 It is H or optionally substituted (C) 1-6 )alkyl; R 10 It is a sulfone or a thiolactone; R 52 It is H, or optional substitution (C) 1-6 )alkyl or optionally substituted heterocyclic groups; R 55 It is H, which can be arbitrarily substituted (C) 1-6 )alkyl; and m is an integer between 0 and 2.

[0186] In some embodiments of Formula I or Formula IA-IM, R 6 It has formula 6C. In some implementations of 6C, R 8 It is an optional substitution (C) 1-6 )alkyl. In some embodiments, R 8 It is -CH3 or -CH2-R 13 And R 13 It is an optionally substituted (C1-6) alkyl group. In some embodiments at 6C, R 8 It is an optional substitution (C) 2-6 )alkenyl. In some embodiments of 6C, R 8 It is -CH=CH2 or -CH=CH-R 14 And R 14 It is an optionally substituted (C1-6) alkyl group. In some embodiments at 6C, R 8 It is an optional substitution (C) 3-7 )cycloalkyl. In some embodiments of 6C, R 8 Yes (C) 3-4 )cycloalkyl. In some embodiments of 6D, R 8It is an optional substitution (C) 2-6 Heterocyclic group. In some implementations of 6C, R 8 Yes (C) 2-4 Heterocyclic group.

[0187] In some embodiments of Formula I or Formula IA-IM, R 6 It has the formula 6D. In some implementations of 6D, R 8 It is an optional substitution (C) 1-6 )alkyl. In some embodiments, R 8 It is -CH3 or -CH2-R 13 And R 13 It is an optionally substituted (C1-6) alkyl group. In some embodiments of 6D, R 8 It is an optional substitution (C) 2-6 )alkenyl. In some embodiments of 6D, R 8 It is -CH=CH2 or -CH=CH-R 14 And R 14 It is an optionally substituted (C1-6) alkyl group. In some embodiments of 6D, R 8 It is an optional substitution (C) 3-7 )cycloalkyl. In some embodiments of 6D, R 8 Yes (C) 3-4 )cycloalkyl. In some embodiments of 6D, R 8 It is an optional substitution (C) 2-6 Heterocyclic groups. In some implementations of 6D, R 8 Yes (C) 2-4 Heterocyclic group.

[0188] In some embodiments of Formula I or Formula IA-IM, R 6 It has formula 6E. In some implementations of 6E, R 9 It is H, and R 55 It is H or optionally substituted (C) 1-6 )alkyl.

[0189] In some embodiments of Formula I or Formula IA-IM, R 6 It has formula 6F. In some implementations of 6F, R 9 It is H, and R 55 It is H or optionally substituted (C) 1-6 )alkyl.

[0190] In some embodiments of Formula I or Formula IA-IM, R 6 It features 6G. In some implementations of 6G, R... 9 It is H, and R10 It is a sulfone or a thiolactone.

[0191] In some embodiments of Formula I or Formula IA-IM, R 6 It has formula 6H. In some embodiments of 6H, m is 1. In some embodiments of 6H, m is 0. In some embodiments of 6H, m is 2.

[0192] In some embodiments of Formula I or Formula IA-IM, R 6 It has formula 6I. In some implementations of 6I, R 52 It is H. In some implementations of 6I, R 52 It is an optional substitution (C) 1-6 )alkyl. In some embodiments, R 52 It is -CH3 or -CH2-R 13 And R 13 It is an optionally substituted (C1-6) alkyl group. In some embodiments of 6I, R 52 It is an optional substitution (C) 2-6 Heterocyclic groups. In some embodiments of 6I, R 52 Yes (C) 2-4 Heterocyclic group.

[0193] In some embodiments of any of 6C-6I, ring A is selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted 4-piperidinyl, and optionally substituted cyclohexyl. In some embodiments of any of 6C-6I, ring A is phenyl. In some embodiments of 6C-6I, ring A is pyridyl. In some embodiments of 6C-6I, ring A is 4-piperidinyl. In some embodiments of 6C-6I, ring A is cyclohexyl.

[0194] In some embodiments of Formula I or Formula IA-IM, R 4 Choose from any one of Equations 4A to 4M: (4A) (4B) (4C) (4D) (4E) (4F) (4G) (4H) (4I) (4J) (4K) (4L) and (4M), in, X 1 Is it O or C(R)? 26 )2; X 12 It is C(R) 15 2. O or NR 25 ; X 14 Is it O or NR? 43 ; X 2 X 6 X 9 and X 10 Each independently selected from NR 25 C(R) 26 2. C = O, O, and S; X 3 X 4 X 5 X 7 and X 8 Each is independently selected from N and CR 26 ; Each R 15 -R 20 and R 24 It is independently selected from optional substituted alkyl, optional substituted amino, optional substituted alkoxy, hydroxy, carboxyl, halogen, optional substituted heterocyclic, optional substituted heteroaryl, optional substituted aryl, optional substituted cycloalkyl and optional substituents of CN; R 21 and R 22 Each is independently a C1-6 alkyl group with optional substitution; R 23 It is H, optionally substituted C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted cycloolefin, optionally substituted heterocyclic, optionally substituted heteroaryl, or optionally substituted aryl; R 25 It is H or an optional substituted C1-6 alkyl group; Each R 26 Independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and nitriles; R 27 and R 28 Each is independently H or an optionally substituted (C1-6) alkyl group, or R 27 and R 28 Together with the nitrogen atoms they are attached to, they form optionally substituted cyclic groups; R29 and R 30 Each is independently H or an optionally substituted C1-6 alkyl group, or R 29 and R 30 Together with the carbon atoms to which they are attached, they form optionally substituted spirocyclic groups (e.g., optionally substituted spiropropyl or spirobutyl). k is 0, 1, 2, 3, 4, 5, 6, 7 or 8; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; r is 0 or 1; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; u is 0, 1, or 2; v and y are each independent integers from 0 to 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2; and R 6 Selected from: (6A) and (6B), in: Y 11 Selected from O, S, CH2, C(R) 11 )2 and NR 9 ; R 9 It is H, or optional substitution (C) 1-6 )alkyl, -L 2 -Z or Z; Each R 11 Independently selected from -L 2 -Z, Z, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl carbonyloxy, hydroxyl, halogen and CN; k is 0 or 1; n is an integer from 0 to 9.

[0195] Y 6 -Y 10 The groups are independently selected from CZ, CR 12 Or N, where Y 6 -Y 10 One of them is CZ; and Each R 12 Independently selected from H, optionally substituted alkyl groups, halogens, and CN.

[0196] In some embodiments of Formula I or Formula IA-IM, R 4It has Equation 4A, and R 6 It has Formula 6A. In some embodiments of Formula I or Formula IA-IM, R 4 It has Equation 4B, and R 6 It has Formula 6A. In some embodiments of Formula I or Formula IA-IM, R 4 It has formula 4C, and R 6 It has Formula 6A. In some embodiments of Formula I or Formula IA-IM, R 4 It has 4D, and R 6 It has Formula 6A. In some embodiments of Formula I or Formula IA-IM, R 4 It has Equation 4E, and R 6 It has Formula 6A. In some embodiments of Formula I or Formula IA-IM, R 4 It has Equation 4F, and R 6 It has Formula 6A. In some embodiments of Formula I or Formula IA-IM, R 4 It has 4G and R 6 It has Formula 6A. In some embodiments of Formula I or Formula IA-IM, R 4 It has the formula 4H, and R 6 It has Formula 6A. In some embodiments of Formula I or Formula IA-IM, R 4 It has Equation 4I, and R 6 It has Formula 6A. In some embodiments of Formula I or Formula IA-IM, R 4 It has Equation 4J, and R 6 It has Formula 6A. In some embodiments of Formula I or Formula IA-IM, R 4 It has 4K and R 6 It has Formula 6A. In some embodiments of Formula I or Formula IA-IM, R 4 It has formula 4L, and R 6 It has Formula 6A. In some embodiments of Formula I or Formula IA-IM, R 4 It has formula 4M, and R 6 It has formula 6A.

[0197] In some embodiments of Formula I or Formula IA-IM, R 4 It has Equation 4A, and R 6 It has Formula 6B. In some embodiments of Formula I or Formula IA-IM, R 4 It has formula 4B, and R 6It has Formula 6B. In some embodiments of Formula I or Formula IA-IM, R 4 It has formula 4C, and R 6 It has Formula 6B. In some embodiments of Formula I or Formula IA-IM, R 4 It has 4D, and R 6 It has Formula 6B. In some embodiments of Formula I or Formula IA-IM, R 4 It has Equation 4E, and R 6 It has Formula 6B. In some embodiments of Formula I or Formula IA-IM, R 4 It has Equation 4F, and R 6 It has Formula 6B. In some embodiments of Formula I or Formula IA-IM, R 4 It has 4G and R 6 It has Formula 6B. In some embodiments of Formula I or Formula IA-IM, R 4 It has the formula 4H, and R 6 It has Formula 6B. In some embodiments of Formula I or Formula IA-IM, R 4 It has Equation 4I, and R 6 It has Formula 6B. In some embodiments of Formula I or Formula IA-IM, R 4 It has Equation 4J, and R 6 It has Formula 6B. In some embodiments of Formula I or Formula IA-IM, R 4 It has 4K and R 6 It has Formula 6B. In some embodiments of Formula I or Formula IA-IM, R 4 It has formula 4L, and R 6 It has Formula 6B. In some embodiments of Formula I or Formula IA-IM, R 4 It has formula 4M, and R 6 It has formula 6B.

[0198] In some embodiments of Formula I or Formula IA-IM, R 4 Selected from Table 1 In some embodiments of Formula I or Formula IA-IM, R 6 Selected from Table 2 In some embodiments of formula I or any of formulas IA-IM, the compound has formula IIA: (IIA), in, Y 1 -Y 3 Y 5 R 4 Z is as defined in this paper; Each R 11 The substituents are selected from optionally substituted alkyl groups, halogens, and nitriles; and n is between 0 and 9.

[0199] In some implementations of Formula IIA, Y 1 -Y 3 One or more of them are N. In some implementations, Y 3 It is N. In some implementations, Y 2 It is N. In some implementations, Y 1 It is N. In some implementations, Y 1 and Y 3 It is N. In some implementations, Y 2 and Y 3 It is N. In some implementations, Y 1 and Y 2 It is N.

[0200] In some embodiments of the compound of formula IIA, Y 1 -Y 3 The two or more of them are CR 1 CR 2 and CR 3 In some embodiments of the compound of formula IIA, Y 1 -Y 3 CR 1 CR 2 and CR 3 In some implementations, R 1 -R 3 Each of them is H. In some implementations, R 1 -R 3 At least one of them is not H. In some implementations, Y2 It is CR 2 And R 2 Not H. In some implementations, R 2 Selected from substituted alkyl, alkyl halide or -COR 30 , where R 30 Is it H or C? 1-6 alkyl.

[0201] In some embodiments of the compound of formula IIA, Y 3 It is N and Y 1 and Y 2 Each is a CR 1 and CR 2 In some embodiments of the compound of formula IIA, Y 1 It is N and Y 2 and Y 3 Each is a CR 2 and CR 3 In some embodiments of the compound of formula IIA, Y 2 It is N and Y 1 and Y 3 Each is a CR 1 and CR 3 .

[0202] In some implementations of Formula IIA, Y 5 It is CR 5 In some implementations, R 5 It is H.

[0203] In some implementations of Formula IIA, Y 5 It is N.

[0204] In some embodiments of formula IIA, n is 1-9, such that the piperidine ring includes one or more R... 11 Substituents. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, R 11 Selected from C 1-3 Alkyl groups, halogens, and nitriles. In some embodiments, R... 11 It is methyl. In some embodiments, R 11 It is Cl or F. In some implementations, R 11 It is a nitrile.

[0205] In some embodiments of formula IIA, n is 0, such that the piperidine ring does not contain any R. 11 Substituents.

[0206] In some embodiments of formula IIA, the compound has formula IIIA: (IIIA) Where R 1 R 2 Y 5 R 4 Z is as defined in this article.

[0207] In some implementations of Formula IIIA, Y 5 It is CR 5 In some implementations, R 5 It is H. In some implementations of Formula IIIA, Y 5 It is N.

[0208] In some implementations of Formula IIA-IIIA, R 4 It has any one of Formula 4A-4M. In some embodiments, R 4 Selected from Table 1.

[0209] In some embodiments of formulas IIA-IIIA, Z has any one of formulas Z1-Z6.

[0210] In some embodiments of formula I or any of formulas IA-IM, the compound has formula IIB: (IIB), in: Z connects to Y 6 -Y 10 One of them, and the remaining Y 6 -Y 10 The groups are independently selected from CR 12 Or N, Among them, each R 12 Independently selected from H, optionally substituted alkyl groups, halogens, and nitriles.

[0211] In some implementations of Formula IIB, Z is connected to Y. 8 In some implementations, Z is connected to Y. 6 Or Y 10 In some implementations, Z is connected to Y. 7 Or Y 9 .

[0212] In some implementations of Formula IIB, Z is connected to Y. 8 And Y 6 Y 7 Y 9 and Y 10 Each is CR12 In some implementation schemes, each R 12 It is H. In some implementations, at least one R 12 Not H. In some implementations, at least one R 12 Selected from C 1-3 Alkyl groups, halogens, and nitriles. In some embodiments, R... 12 It is methyl. In some embodiments, R 12 It is Cl or F. In some implementations, R 12 It is a nitrile.

[0213] In some implementations of Formula IIB, Y 6 -Y 10 At least one of them is N. In some cases, Y 6 Or Y 10 It is N. In some cases, Y 6 and Y 10 All are N. In some cases, Y 7 Or Y 9 It is N. In some cases, Y 7 and Y 9 All are N. In some cases, Y 8 It is N.

[0214] In some implementations of Formula IIB, Y 1 -Y 3 One or more of them are N. In some implementations, Y 3 It is N. In some implementations, Y 2 It is N. In some implementations, Y 1 It is N. In some implementations, Y 1 and Y 3 It is N. In some implementations, Y 2 and Y 3 It is N. In some implementations, Y 1 and Y 2 It is N.

[0215] In some embodiments of the compound of formula IIB, Y 1 -Y 3 The two or more of them are CR 1 CR 2 and CR 3 In some embodiments of the compound of formula IIB, Y 1 -Y 3 CR 1 CR 2 and CR 3 In some implementations, R 1 -R3 Each of them is H. In some implementations, R 1 -R 3 At least one of them is not H. In some implementations, Y 2 It is CR 2 And R 2 Not H. In some implementations, R 2 Selected from substituted alkyl, alkyl halide or -COR 30 , where R 30 Is it H or C? 1-6 alkyl.

[0216] In some embodiments of the compound of formula IIB, Y 3 It is N and Y 1 and Y 2 Each is a CR 1 and CR 2 In some embodiments of the compound of formula IIB, Y 1 It is N and Y 2 and Y 3 Each is a CR 2 and CR 3 In some embodiments of the compound of formula IIB, Y 2 It is N and Y 1 and Y 3 Each is a CR 1 and CR 3 .

[0217] In some implementations of Formula IIB, Y 5 It is CR 5 In some implementations, R 5 It is H.

[0218] In some implementations of Formula IIB, Y 5 It is N.

[0219] In some embodiments of formula IIB, the compound has formula IIIB: (IIIB), Where R 1 R 2 Y 5 R 4 Z is as defined in this article.

[0220] In some implementations of Formula IIIB, Y 5 It is CR 5 In some implementations, R 5 It is H. In some implementations of formula IIIB, Y5 It is N.

[0221] In some implementations of formulas IIB-IIIB, R 4 It has any one of Formula 4A-4M. In some embodiments, R 4 Selected from Table 1.

[0222] In some embodiments of formulas IIB-IIIB, Z has any one of formulas Z1-Z6.

[0223] In some embodiments of Formula I, the compound has Formula IA or its pharmaceutically acceptable salt.

[0224] In some embodiments of formula IA, the compound has formula IV: (IV), Or its pharmaceutically acceptable salts, of which: Y 6 Y 7 Y 9 and Y 10 Independently selected from CR 12 and N, where Y 6 Y 7 Y 9 and Y 10 At least two of them are CR 12 ; Each R 12 Independently selected from H, optionally substituted (C) 1-6 Alkyl, hydroxyl, halogen, and CN; and R 1 R 2 R 4 R 5 R 7 Z is as defined in this article.

[0225] In some implementations of Formula IV, Y 6 Y 7 Y 9 and Y 10 Each is CR 12 In some implementation schemes, each R 12 It is H. In some implementations, at least one R 12 Not H. In some implementations, at least one R 12 Selected from C 1-3 Alkyl groups, halogens, and nitriles. In some embodiments, at least one R 12 It is methyl. In some embodiments, at least one R 12 It is Cl or F. In some implementations, at least one R12 It is a nitrile.

[0226] In some implementations of Formula IV, Y 6 Y 7 Y 9 Or Y 10 At least one of them is N. In some cases, Y 6 Or Y 10 It is N. In some cases, Y 6 and Y 10 All are N. In some cases, Y 7 Or Y 9 It is N. In some cases, Y 7 and Y 9 All are N.

[0227] In some implementations of Formula IV, Y 6 Y 7 Y 9 and Y 10 Each is independently CH or CR 12 And the compound has formula V: (V), Or it could be a pharmaceutically acceptable salt. Where m is 0, 1, 2, 3 or 4.

[0228] In some implementations of formula IV-V, R 4 It has any one of Formula 4A-4M. In some embodiments, R 4 Selected from Table 1.

[0229] In some embodiments, the compound of formula V has formula VIA: (VIA) Or it could be a pharmaceutically acceptable salt. Where R 1 R 2 R 5 R 7 R 12 R 18 X 2 X 3 X 4 Z, m, and v are as defined in this paper.

[0230] In some implementations of VIA, X 2 It is C(R) 26 )2. In some implementation schemes, each R 26 It is H. In some implementations, at least one R 26The group is an optionally substituted alkyl group. In some embodiments of formula VIA, X 2 It is O. In some implementations of VIA, X 2 It is NR 25 In some implementations, R 25 It is H. In some implementations, R 25 It is a (C1-C3) alkyl group. In some embodiments of formula VIA, X 2 It is S. In some implementations of VIA, X 2 It is C=O.

[0231] In some implementations of VIA, X 3 It is N. In some implementations of formula VIA, X 3 It is CR 26 In some implementations, R 26 It is H. In some implementations, R 26 It is an alkyl group that is optionally substituted.

[0232] In some implementations of VIA, X 4 It is N. In some implementations of formula VIA, X 4 It is CR 26 In some implementations, R 26 It is H. In some implementations, R 26 It is an alkyl group that is optionally substituted.

[0233] In some implementations of VIA, X 2 It is NR 25 X 3 It is CR 26 And X 4 It is CR 26 In some implementations of VIA, X 2 It is NR 25 X 3 It is N and X 4 It is CR 26 In some implementations of VIA, X 2 It is O, X 3 It is CR 26 And X 4 It is N.

[0234] In some implementations of VIA, R 4 Choose from one of the following structures: , , , , , and .

[0235] In some implementations of VIA, R 4 Selected from: or Where R 25 R 18 And v as defined in this article.

[0236] In some implementations of VIA, R 4 Selected from: or Where R 25 R 18 And v as defined in this article.

[0237] In some implementations of VIA, R 4 Selected from: or Where R 25 R 18 And v as defined in this article.

[0238] In some embodiments of any of Formula IV-Formula VIA, Z has any of Formula Z1-Formula Z6.

[0239] In some embodiments of any of Formula IV-Form VIA, Z has Formula ZIB or Formula Z1C. (Z1B) or (Z1C), Where X 11 R 8 R 9 and R 10 As defined in this article.

[0240] R 8 Yes (C) 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 ) alkynyl, cycloalkyl, heterocyclic or their substituted forms; R 9 It is H or optionally substituted (C) 1-6 )alkyl; R 10 It is H, or optional substitution (C) 1-6 )alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclic groups; and X 11It is O or NH.

[0241] In some implementations of formula VIA, Z is Z1C, and X 11 It is O. In some implementations of formula VIA, Z is Z1C, and X 11 It is NH. In some embodiments of formula VIA, Z is Z1C, and R 9 It is H. In some implementations of formula VIA, Z is Z1C, and R 9 Yes (C) 1-6 )alkyl. In some embodiments of formula VIA, Z is Z1C, and R 10 It is H. In some implementations of formula VIA, Z is Z1C, and R 10 Yes (C) 1-6 )alkyl. In some embodiments of formula VIA, Z is Z1C, and R 10 It is an optionally substituted cycloalkyl group. In some embodiments of formula VIA, Z is Z1C, and R is... 10 It is an optionally substituted heterocyclic group. In some embodiments of formula VIA, Z is Z1C, R 9 It is H, and R 10 Yes (C) 1-6 )alkyl. In some embodiments of formula VIA, Z is Z1C, R 9 It is H, and R 10 It is H.

[0242] In some implementations of formula VIA, Z is Z1C, X 11 It is NH, R 9 It is H and R 10 Yes (C) 1-6 )alkyl. In some embodiments of formula VIA, Z is Z1C, X 11 It is NH, R 9 It is H and R 10 It is methyl. In some embodiments of formula VIA, Z is Z1C, X 11 It is NH, R 9 It is H and R 10 It is an ethyl group.

[0243] In some implementations of formula VIA, Z is Z1C, X 11 It is O, R 9 It is H and R 10 Yes (C) 1-6 )alkyl. In some embodiments of formula VIA, Z is Z1C, X 11 It is O, R 9 It is H and R 10 It is methyl. In some embodiments of formula VIA, Z is Z1C, X11 It is O, R 9 It is H and R 10 It is an ethyl group.

[0244] In some embodiments of formula VIA, Z has formula Z1B, and X 11 It is O. In some implementations of formula VIA, Z is Z1B, and X 11 It is NH. In some embodiments of formula VIA, Z is Z1B, and R 8 Yes (C) 1-6 )alkyl. In some embodiments of formula VIA, Z is Z1B, and R 8 It is methyl. In some embodiments of formula VIA, Z is Z1B, and R 8 Yes (C) 2-6 Alkenyl. In some embodiments of formula VIA, Z is Z1B, and R 8 It is -CH=CH2 or -C(CH3)=CH2. In some embodiments of formula VIA, Z is Z1B, and R 8 Yes (C) 2-6 ) yyn group. In some embodiments of formula VIA, Z is Z1B, and R 8 It is -CCH or -CC-CH3. In some embodiments of formula VIA, Z is Z1B, and R 8 It is an optional substitution (C) 3-7 ) cycloalkyl. In some embodiments of formula VIA, Z is Z1B, and R 8 It is an optional substitution (C) 3-7 Heterocyclic group. In some embodiments of formula VIA, Z is Z1B, and R 8 Yes (C) 3-4 ) cycloalkyl. In some embodiments of formula VIA, Z is Z1B, and R 8 Yes (C) 2-4 Heterocyclic group.

[0245] In some implementations of formula VIA, Z is Z1B, X 11 It is NH, and R 8 Yes (C) 1-6 )alkyl. In some embodiments of formula VIA, Z is Z1B, X 11 It is NH, and R 8 It is a cycloalkyl group. In some embodiments of formula VIA, Z is Z1B, X 11 It is NH, and R 8 It is a heterocyclic group.

[0246] In some implementations of formula VIA, Z is Z1B, X 11 It is O, and R8 Yes (C) 1-6 )alkyl. In some embodiments of formula VIA, Z is Z1B, X 11 It is O, and R 8 It is a cycloalkyl group. In some embodiments of formula VIA, Z is Z1B, X 11 It is O, and R 8 It is a heterocyclic group.

[0247] In some embodiments, compounds of formula VIA have formula VIIA: (VIIA) Or its pharmaceutically acceptable salts, of which: R 25 It is an optionally substituted (C1-6) alkyl or an optionally substituted -C(=O)C1-6 alkyl; X 11 It is O or NH; R 41 It is R 8 or N(R) 9 )R 10 ; R 8 Yes (C) 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 ) alkynyl, cycloalkyl, heterocyclic or their substituted forms; R 9 It is H or optionally substituted (C) 1-6 )alkyl; and R 10 It is H, or optional substitution (C) 1-6 )alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclic groups; and Where R 1 R 2 R 5 R 7 R 12 R 18 m and v are as defined in this article.

[0248] In some embodiments of any of formulas V, VIA, or VIIA, each R 12 It is H (or m is 0). In some implementations, m is 1, 2, 3, or 4, and at least one R 12 Not H. In some implementations, at least one R 12 Selected from C 1-3 Alkyl groups, halogens, and nitriles. In some embodiments, at least one R 12 It is methyl. In some embodiments, at least one R 12It is Cl or F. In some implementations, at least one R 12 It is a nitrile.

[0249] In some implementations of formula VIA or VIIA, v is 0, such that R does not exist. 18 Substituents. In some embodiments, v is 1 to 3, and each R 18 The substituents are independently selected from (C1-3) alkyl, hydroxyl, halogen, and nitrile groups. In some embodiments, v is 1 and R 18 It is a (C1-3) alkyl group. In some embodiments, v is 1 and R 18 It is a halogen. In some implementations, the halogen is Cl or F.

[0250] In some embodiments, compounds of formula VIIA have formula VIIIA: (VIIIA) Or its pharmaceutically acceptable salts, of which: R 25 It is an optional substituted (C1-6) alkyl group; R 18 It is H, halogen, optionally substituted (C1-6) alkyl, or optionally substituted (C1-6) alkoxy; and R 12 It is H, halogen, optionally substituted (C1-6) alkyl or optionally substituted (C1-6) alkoxy; Where X 11 and R 41 As defined in this article.

[0251] In some embodiments of either Formula VIIA or Formula VIIIA, R 25 It has the following structure: Where R 33 -R 37 Independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3 and halogens, and / or R 33 -R 37 Any two (e.g., R) 33 and R 34 and / or R 36 and R 37 These can be cyclically linked and, together with the carbon atoms to which they are linked, provide C3-C7 carbon rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, R 33 and R 34 Together with the carbon atoms they are attached to, they form C3-C7 carbon rings (e.g., cyclopropyl or cyclobutyl). In some embodiments, R36 and R 37 Together with the carbon atoms they are attached to, they form C3-C7 carbon rings (e.g., cyclopropyl or cyclobutyl). In some embodiments, R 33 -R 37 At least one of them is a halogen. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl. In some embodiments, R 33 -R 35 One or both of them are CF3. In some implementations, R 33 -R 35 One of them is CF3. In some implementations, R 33 -R 35 Both of them are CF3. In some implementations, R 33 -R 35 One or both of them are OH. In some embodiments, R 33 -R 35 One of them is OH. In some implementations, R 33 -R 35 Both of them are OH. In some implementations, R 36 -R 37 One or both of them are H. In some implementations, R 36 It is H, and R 37 Selected from CF3, CHF2, CH2F, OH, OCH3, and halogens. In some embodiments, R 36 and R 37 Both are H.

[0252] In some embodiments of either Formula VIIA or Formula VIIIA, R 25 It has the following structure: . In some embodiments of either Formula VIIA or Formula VIIIA, R 25 It has the following structure: . In some embodiments of any of formulas V, VIA, VIIA, or VIIIA, R 12 It is H. In some implementations, R 12 It is a (C1-6) alkyl group. In some embodiments, R 12 It is methyl. In some embodiments, R 12 It is ethyl. In some embodiments, R 12 It is propyl. In some implementations, R 12 It is a halogen. In some implementations, R 12It is F. In some implementations, R 12 It is Cl. In some implementations, R 12 It is a (C1-6)alkoxy group. In some embodiments, R 12 It is a methoxy group.

[0253] In some embodiments of any of Formula VIA, Formula VIIA, or Formula VIIIA, R 18 It is H. In some implementations, R 18 It is a (C1-6) alkyl group. In some embodiments, R 18 It is methyl. In some embodiments, R 18 It is ethyl. In some embodiments, R 18 It is propyl. In some implementations, R 18 It is a halogen. In some implementations, R 18 It is F. In some implementations, R 18 It is Cl. In some implementations, R 18 It is a (C1-6)alkoxy group. In some embodiments, R 18 It is a methoxy group.

[0254] In some embodiments of formula VIIA or VIIIA, R 41 It is R 8 (As defined herein). In some implementations, R 41 Yes (C) 1-6 )alkyl. In some embodiments, R 41 Selected from methyl, ethyl, or propyl. In some embodiments, R 41 It is methyl. In some embodiments, R 41 It is an optional substitution (C) 3-7 )cycloalkyl or optionally substituted (C 2-6 Heterocyclic groups. In some implementations, R 41 Yes (C) 3-4 )cycloalkyl or (C 2-4 Heterocyclic groups. In some implementations, R 41 It is N(R) 9 )R 10 In some implementations, R 41 It is NH2. In some implementations, R 41 It is an -NH(C1-6) alkyl group. In some embodiments of formula VIIA or VIIIA, X 11 It is NH. In some implementations, X 11 It is O.

[0255] In some embodiments of Formula VIIA or VIIIA, X 11It is NH, and R 41 Yes (C) 1-6 )alkyl. In some embodiments of formula VIIA or VIIIA, X 11 It is NH, and R 41 It is a cycloalkyl group. In some embodiments of formula VIIA or VIIIA, X 11 It is NH, and R 41 It is a heterocyclic group.

[0256] In some embodiments of Formula VIIA or VIIIA, X 11 It is O, R 41 Yes (C) 1-6 )alkyl. In some embodiments of formula VIIA or VIIIA, X 11 It is O, and R 41 It is a cycloalkyl group. In some embodiments of formula VIIA or VIIIA, X 11 It is O, and R 41 It is a heterocyclic group.

[0257] In some embodiments, the compound of formula V has formula VIB: (VIB) Or its pharmaceutically acceptable salts, of which: R 1 R 2 R 5 R 7 R 12 R 23 Z and m are as defined in this paper.

[0258] In some implementations of VIB, R 23 It is H. In some implementations of formula VIB, R 23 It is an optionally substituted (C1-6) alkyl group. In some embodiments, R 23 It is methyl, ethyl, or propyl. In some embodiments, R 23 It is an optionally substituted cycloalkyl group. In some embodiments, the cycloalkyl group is selected from cyclobutene, cyclopentane, or cyclohexane. In some embodiments, R... 23 It is an optionally substituted cyclic olefin. In some embodiments, R 23 It is an optionally substituted heterocyclic group. In some embodiments, R 23 It is an optionally substituted heteroaryl group. In some embodiments, R 23 It is an aryl group that is optionally substituted.

[0259] In some implementations of VIB, R 23 Selected from: (4E) (4F) (4J) (4K) (4L) and (4M), in: X 2 X 6 X 9 and X 10 Each independently selected from NR 25 C(R) 26 2. C = O, O, and S; X 3 X 4 X 5 and X 7 Each is independently selected from N and CR 26 ; Each R 18 -R 20 and R 24 It is independently selected from optional substituted alkyl, optional substituted amino, optional substituted alkoxy, hydroxy, carboxyl, halogen, optional substituted heterocyclic, optional substituted heteroaryl, optional substituted aryl, optional substituted cycloalkyl and optional substituents of CN; R 25 It is H or an optional substituted (C1-6) alkyl group; Each R 26 Independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and nitriles; R 29 and R 30 Each is independently H or an optionally substituted (C1-6) alkyl group, or R 29 and R 30 Together with the carbon atoms they are attached to, they form spirocyclic groups with optional substitutions; v and y are each independently 0, 1, 2 or 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2.

[0260] In some implementations of VIB, R 23 Having 4F (4F).

[0261] In some implementations of VIB, R 23 Choose from one of the following structures: , , and Where R 24 R 25 R 29 R 30 And y are as defined in this article.

[0262] In some implementations of formula VIB, Z has formula ZIB or formula Z1C. (Z1B) or (Z1C), Where X 11 R 8 R 9 and R 10 As defined in this article.

[0263] R 8 Yes (C) 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 ) alkynyl, cycloalkyl, heterocyclic or their substituted forms; R 9 It is H or optionally substituted (C) 1-6 )alkyl; R 10 It is H, or optional substitution (C) 1-6 )alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclic groups; and X 11 It is O or NH.

[0264] In some implementations of formula VIB, Z is Z1C, and X 11 It is O. In some implementations of formula VIB, Z is Z1C, and X 11 It is NH. In some embodiments of formula VIB, Z is Z1C, and R 9 It is H. In some implementations of formula VIB, Z is Z1C, and R 9 Yes (C) 1-6 Alkyl group. In some embodiments of formula VIB, Z is Z1C, and R... 10 It is H. In some implementations of formula VIB, Z is Z1C, and R 10 Yes (C) 1-6 Alkyl group. In some embodiments of formula VIB, Z is Z1C, and R... 10 It is an optionally substituted cycloalkyl group. In some embodiments of formula VIB, Z is Z1C, and R 10It is an optionally substituted heterocyclic group. In some embodiments of formula VIB, Z is Z1C, R 9 It is H, and R 10 Yes (C) 1-6 )alkyl. In some embodiments of formula VIB, Z is Z1C, R 9 It is H, and R 10 It is H.

[0265] In some implementations of formula VIB, Z is Z1C, X 11 It is NH, R 9 It is H and R 10 Yes (C) 1-6 )alkyl. In some embodiments of formula VIB, Z is Z1C, X 11 It is NH, R 9 It is H and R 10 It is methyl. In some embodiments of formula VIB, Z is Z1C, X 11 It is NH, R 9 It is H and R 10 It is an ethyl group.

[0266] In some implementations of formula VIB, Z is Z1C, X 11 It is O, R 9 It is H and R 10 Yes (C) 1-6 )alkyl. In some embodiments of formula VIB, Z is Z1C, X 11 It is O, R 9 It is H and R 10 It is methyl. In some embodiments of formula VIB, Z is Z1C, X 11 It is O, R 9 It is H and R 10 It is an ethyl group.

[0267] In some embodiments of formula VIB, Z has formula Z1B, and X 11 It is O. In some implementations of formula VIB, Z is Z1B, and X 11 It is NH. In some embodiments of formula VIB, Z is Z1B, and R 8 Yes (C) 1-6 )alkyl. In some embodiments of formula VIB, Z is Z1B, and R 8 It is methyl. In some embodiments of formula VIB, Z is Z1B, and R 8 Yes (C) 2-6 Alkenyl. In some embodiments of formula VIB, Z is Z1B, and R 8It is -CH=CH2 or -C(CH3)=CH2. In some embodiments of formula VIB, Z is Z1B, and R 8 Yes (C) 2-6 ) yne group. In some embodiments of formula VIB, Z is Z1B, and R 8 It is -CCH or -CC-CH3. In some embodiments of formula VIB, Z is Z1B, and R 8 It is an optional substitution (C) 3-7 ) cycloalkyl. In some embodiments of formula VIB, Z is Z1B, and R 8 It is an optional substitution (C) 3-7 Heterocyclic group. In some embodiments of formula VIB, Z is Z1B, and R 8 Yes (C) 3-4 ) cycloalkyl. In some embodiments of formula VIB, Z is Z1B, and R 8 Yes (C) 2-4 Heterocyclic group.

[0268] In some implementations of formula VIB, Z is Z1B, X 11 It is NH, and R 8 Yes (C) 1-6 )alkyl. In some embodiments of formula VIB, Z is Z1B, X 11 It is NH, and R 8 It is a cycloalkyl group. In some embodiments of formula VIB, Z is Z1B, X 11 It is NH, and R 8 It is a heterocyclic group.

[0269] In some implementations of formula VIB, Z is Z1B, X 11 It is O, and R 8 Yes (C) 1-6 )alkyl. In some embodiments of formula VIB, Z is Z1B, X 11 It is O, and R 8 It is a cycloalkyl group. In some embodiments of formula VIB, Z is Z1B, X 11 It is O, and R 8 It is a heterocyclic group.

[0270] In some embodiments, compounds of formula VIB have formula VIIB: (VIIB) Or its pharmaceutically acceptable salts, of which: R 1 R 2 R 5 R 7 R 12 R24 R 25 R 29 R 30 X 11 R 41 y and m are as defined in this article.

[0271] In some embodiments, compounds of formula VIIB have formula VIIIB: (VIIIB) Or its pharmaceutically acceptable salts, of which: R 1 R 2 R 5 R 7 R 12 R 24 R 25 R 29 R 30 X 11 R 41 y and m are as defined in this article.

[0272] In some embodiments, compounds of formula VIIIB have formula IX: (IX) Or its pharmaceutically acceptable salts, of which: R 12 R 29 R 30 X 11 and R 41 As defined in this article.

[0273] In some embodiments of any of Formula VIB, Formula VIIB, Formula VIIIB, or Formula IX, R 12 It is H. In some implementations, R 12 It is a (C1-6) alkyl group. In some embodiments, R 12 It is methyl. In some embodiments, R 12 It is ethyl. In some embodiments, R 12 It is propyl. In some implementations, R 12 It is a halogen. In some implementations, R 12 It is F. In some implementations, R 12 It is Cl. In some implementations, R 12 It is a (C1-6)alkoxy group. In some embodiments, R 12 It is a methoxy group.

[0274] In some embodiments of any of Formula VIIB, Formula VIIIB, or Formula IX, R29 and R 30 Each is independently an optionally substituted (C1-6) alkyl group. In some embodiments, R 29 and R 30 Each is independently (C1-3) alkyl. In some embodiments, R 29 and R 30 Each is a methyl group. In some embodiments, R 29 and R 30 Each is an ethyl group.

[0275] In some embodiments of any of Formula VIIB, Formula VIIIB, or Formula IX, R 29 and R 30 Together with the carbon atoms to which they are attached, they form optionally substituted spirocyclic groups. In some embodiments, the spirocyclic group is spiropropyl or spirobutyl.

[0276] In some embodiments of any of Formula VIIB, Formula VIIIB, or Formula IX, R 41 It is R 8 (As defined herein). In some implementations, R 41 Yes (C) 1-6 )alkyl. In some embodiments, R 41 Selected from methyl, ethyl, or propyl. In some embodiments, R 41 It is methyl. In some embodiments, R 41 It is an optional substitution (C) 3-7 )cycloalkyl or optionally substituted (C 2-6 Heterocyclic groups. In some implementations, R 41 Yes (C) 3-4 )cycloalkyl or (C 2-4 Heterocyclic groups. In some implementations, R 41 It is N(R) 9 )R 10 In some implementations, R 41 It is NH2. In some implementations, R 41 It is an -NH(C1-6) alkyl group. In some embodiments of formula VIIB, VIIIB, or IX, X 11 It is NH. In some implementations, X 11 It is O.

[0277] In some embodiments of any of Formula VIIB, Formula VIIIB, or Formula IX, X 11 It is NH, and R 41 Yes (C) 1-6 )alkyl. In some embodiments of any of formula VIIB, VIIIB, or IX, X 11It is NH, and R 41 It is a cycloalkyl group. In some embodiments of formula VIIB, VIIIB, or IX, X 11 It is NH, and R 41 It is a heterocyclic group.

[0278] In some embodiments of any of Formula VIIB, Formula VIIIB, or Formula IX, X 11 It is O, R 41 Yes (C) 1-6 )alkyl. In some embodiments of any of formula VIIB, VIIIB, or IX, X 11 It is O, and R 41 It is a cycloalkyl group. In some embodiments of any of formula VIIB, VIIIB, or IX, X 11 It is O, and R 41 It is a heterocyclic group.

[0279] In some embodiments of formula IA, the compound has formula X: (X) Or its pharmaceutically acceptable salts, of which: Each R 11 Independently selected from optionally substituted alkyl groups, optionally substituted alkoxy groups, halogens, OH, and CN; and n is an integer from 0 to 9; where: R 1 R 2 R 4 R 5 R 7 Z is as defined in this article.

[0280] In some implementations of formula X, R 4 It has any one of Formula 4A-4M. In some embodiments, R 4 Selected from Table 1.

[0281] In some implementations of formula X, R 4 It has formula 4A, formula 4E, formula 4F or formula 4I: (4A) (4E) (4F) and (4I), in: X 2 X 9 and X 10 Each independently selected from NR 25 C(R) 26 2. C = O, O, and S; X 3 and X 4 Each is independently selected from N and CR 26 ; X 12 It is C(R) 42 )2 or NR 43 ; Each R 15 R 18 and R 24 It is independently selected from optional alkyl, optional amino, optional alkoxy, hydroxy, carboxyl, halogen, optional heterocyclic, optional heteroaryl, optional aryl, optional cycloalkyl and optional substituents of nitriles; R 23 It is H, optionally substituted (C1-6) alkyl, optionally substituted cycloalkyl, optionally substituted cycloolefin, optionally substituted heterocyclic, optionally substituted heteroaryl or optionally substituted aryl; Each R 26 Independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and nitriles; R 29 and R 30 Each is independently H or an optionally substituted (C1-6) alkyl group, or R 29 and R 30 Together with the carbon atoms to which they are attached, they form optionally substituted spirocyclic groups (e.g., optionally substituted spiropropyl or spirobutyl). R 42 It is H, optionally substituted (C1-6) alkyl, optionally substituted acyl, optionally substituted formamide, optionally substituted cycloalkyl, optionally substituted cycloolefin, optionally substituted heterocyclic, optionally substituted heteroaryl or optionally substituted aryl; R 43 It is H, optionally substituted (C1-6) alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloolefin, optionally substituted heterocyclic, optionally substituted heteroaryl or optionally substituted aryl; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. r is 0 or 1; and v and y are each an independent integer from 0 to 3.

[0282] In some implementations of formula X, R 4 It has Equation 4E, and X 2 X 3 X 4 R18 And v as defined in this article.

[0283] In some implementations of formula X, R 4 It has Equation 4F, and X 9 X 10 R 24 R 29 R 30 And y are as defined in this article.

[0284] In some implementations of formula X, R 4 It has Equation 4I, and R 23 As defined in this article.

[0285] In some implementations of formula X, R 4 Having formula 4A, and the compound having formula XI: (XI) Or its pharmaceutically acceptable salts, of which: R 1 R 2 R 5 R 7 R 11 R 15 X 12 Z, n, and q are as defined in this paper.

[0286] In some embodiments of the compound of formula XI: X 12 It is CHR 42 ;and R 42 It is selected from H, optionally substituted (C1-6) alkyl, acyl, optionally substituted formamide, optionally substituted cycloalkyl, optionally substituted cycloolefin, optionally substituted heterocyclic, optionally substituted heteroaryl and optionally substituted aryl.

[0287] In some embodiments of the compound of formula XI, X 12 It is CHR 42 ;and R 42 It is -C(=O)R 42a -C(=O)NHR 42a -NHC(=O)R 42a , where R 42a It is H, an optionally substituted (C1-6) alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclic, an optionally substituted heteroaryl, or an optionally substituted aryl. In some embodiments, X 12 It is CHR 42 And R 42It is an optionally substituted (C1-6) alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted heteroaryl, or optionally substituted aryl. In some embodiments, X 12 It is CHR 42 And R 42 It is an optional substitution of -(CH2). z Cycloalkyl, optionally substituted -(CH2) z Heterocyclic, optionally substituted -(CH2) z Heteroaryl or optionally substituted -(CH2) z Aryl, where z is 1, 2, 3, 4 or 5.

[0288] In some embodiments of the compound of formula XI: X 12 It is NR 43 ;and R 43 It is selected from H, optionally substituted (C1-6) alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloolefin, optionally substituted heterocyclic, optionally substituted heteroaryl and optionally substituted aryl.

[0289] In some embodiments of the compound of formula XI, X 12 It is NR 43 ;and R 43 It is an optionally substituted -C(=O)C1-6 alkyl, an optionally substituted -C(=O)cycloalkyl, an optionally substituted -C(=O) heterocyclic, an optionally substituted -C(=O) heteroaryl, or an optionally substituted -C(=O) aryl. In some embodiments, X 12 It is NR 43 And R 43 It is an optionally substituted (C1-6) alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted heteroaryl, or optionally substituted aryl. In some embodiments, X 12 It is NR 43 And R 43 It is an optional substitution of -(CH2). z Cycloalkyl, optionally substituted -(CH2) z Heterocyclic, optionally substituted -(CH2) z Heteroaryl or optionally substituted -(CH2) z Aryl, where z is 1, 2, 3, 4 or 5.

[0290] In some embodiments of formula X or formula XI, Z has formula ZIB or formula Z1C. (Z1B) or (Z1C), Where X11 R 8 R 9 and R 10 As defined in this article.

[0291] In some embodiments of formula X or formula XI, Z is Z1C, and X 11 It is O. In some embodiments of formula X or formula XI, Z is Z1C, and X 11 It is NH. In some embodiments of formula X or XI, Z is Z1C, and R 9 It is H. In some embodiments of formula X or XI, Z is Z1C, and R 9 Yes (C) 1-6 )alkyl. In some embodiments of formula X or XI, Z is Z1C, and R 10 It is H. In some embodiments of formula X or XI, Z is Z1C, and R 10 Yes (C) 1-6 )alkyl. In some embodiments of formula X or XI, Z is Z1C, and R 10 It is an optionally substituted cycloalkyl group. In some embodiments of formula X or XI, Z is Z1C, and R is... 10 It is an optionally substituted heterocyclic group. In some embodiments of formula X or XI, Z is Z1C,R 9 It is H, and R 10 Yes (C) 1-6 )alkyl. In some embodiments of formula X or XI, Z is Z1C, R 9 It is H, and R 10 It is H.

[0292] In some implementations of formula X or formula XI, Z is Z1C, X 11 It is NH, R 9 It is H and R 10 Yes (C) 1-6 )alkyl. In some embodiments of formula X or XI, Z is Z1C, X 11 It is NH, R 9 It is H and R 10 It is methyl. In some embodiments of formula X or XI, Z is Z1C, X is... 11 It is NH, R 9 It is H and R 10 It is an ethyl group.

[0293] In some implementations of formula X or formula XI, Z is Z1C, X 11 It is O, R 9 It is H and R 10 Yes (C) 1-6)alkyl. In some embodiments of formula X or XI, Z is Z1C, X 11 It is O, R 9 It is H and R 10 It is methyl. In some embodiments of formula X or XI, Z is Z1C, X is... 11 It is O, R 9 It is H and R 10 It is an ethyl group.

[0294] In some embodiments of formula X or formula XI, Z has formula Z1B, and X 11 It is O. In some embodiments of formula X or formula XI, Z is Z1B, and X 11 It is NH. In some embodiments of formula X or XI, Z is Z1B, and R 8 Yes (C) 1-6 Alkyl group. In some embodiments of formula X or XI, Z is Z1B, and R 8 It is methyl. In some embodiments of formula X or XI, Z is Z1B, and R 8 Yes (C) 2-6 Alkenyl. In some embodiments of formula X or XI, Z is Z1B, and R 8 It is -CH=CH2 or -C(CH3)=CH2. In some embodiments of formula X or XI, Z is Z1B, and R 8 Yes (C) 2-6 ) yynyl group. In some embodiments of formula X or XI, Z is Z1B, and R 8 It is -CCH or -CC-CH3. In some embodiments of formula X or XI, Z is Z1B, and R 8 It is an optional substitution (C) 3-7 ) cycloalkyl. In some embodiments of formula X or XI, Z is Z1B, and R 8 It is an optional substitution (C) 3-7 Heterocyclic group. In some embodiments of formula X or XI, Z is Z1B, and R 8 Yes (C) 3-4 ) cycloalkyl. In some embodiments of formula X or XI, Z is Z1B, and R 8 Yes (C) 2-4 Heterocyclic group.

[0295] In some implementations of formula X or formula XI, Z is Z1B, X 11 It is NH, and R 8 Yes (C) 1-6 )alkyl. In some embodiments of formula X or XI, Z is Z1B, X 11 It is NH, and R 8It is a cycloalkyl group. In some embodiments of formula X or XI, Z is Z1B, X is Z1B. 11 It is NH, and R 8 It is a heterocyclic group.

[0296] In some implementations of formula X or formula XI, Z is Z1B, X 11 It is O, and R 8 Yes (C) 1-6 )alkyl. In some embodiments of formula X or XI, Z is Z1B, X 11 It is O, and R 8 It is a cycloalkyl group. In some embodiments of formula X or XI, Z is Z1B, X is Z1B. 11 It is O, and R 8 It is a heterocyclic group.

[0297] In some embodiments of Formula I or Formula IA-IM, Formula IIA-IIB, Formula IIIA-IIIB, Formula IV, Formula V, Formula VIA-VIB, Formula VIIA-VIIB, Formula VIIIA-VIIIB, Formula IX, Formula X or Formula XI, the compound is selected from one of Tables 3 to 15, or any of Compound 1 to Compound 965, or a pharmaceutically acceptable salt thereof.

[0298] In some implementations of any of Equation I, Y 5 It is CR 5 In some implementations, R 5 Selected from H, CH3, CF3, and halogens. In some cases, R... 5 It is H. In some cases, R 5 It is CH3. In some cases, R 5 It's CF3. In some cases, R... 5 It is a halogen. In some cases, the halogen is F or Cl.

[0299] In any of Formula I or in some embodiments of Formula IA-IM, Formula IIA-IIB, Formula IIIA-IIIB, Formula IV, Formula V, Formula VIA-VIB, Formula VIIA-VIIB, Formula VIIIA-VIIIB, Formula IX, Formula X or Formula XI, R 7 Selected from H, CH3, CF3, and halogens. In some embodiments of formula I or formula IA-IM, formula IIA-IIB, formula IIIA-IIIB, formula IV, formula V, formula VIA-VIB, formula VIIA-VIIB, formula VIIIA-VIIIB, formula IX, formula X, or formula XI, R 7 It is H.

[0300] In some implementations of Formula I, Y 1 It is CR 1 In some implementations, R 1 Selected from H, CH3, CF3, and halogens. In some cases, R... 1 It is H. In some cases, R 1 It is CH3. In some cases, R 1 It's CF3. In some cases, R... 1 It is a halogen. In some cases, the halogen is F or Cl.

[0301] In some implementations of Formula I, Y 2 It is CR 2 In some implementations, R 2 Selected from H, CH3, CF3, -CH(F)2, -CH2Cl, halogens, -C(O)H, and -(CH2). z OH, where z is 1 to 3. In some embodiments, R 2 It is H. In some implementations, R 2 It is CH3. In some implementations, R 2 It is CF3. In some implementations, R 2 It is -CH(F)2. In some implementations, R 2 It is -CH2Cl. In some implementations, R 2 It is a halogen. In some implementations, R 2 It is -C(O)H. In some implementations, R 2 It is -(CH2) z OH, where z is 1 to 3. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3.

[0302] In some embodiments, the compound has formula XII: (XII) in: R 4 Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;and R 6 Selected from: , , , , , , , , , , , , , , and .

[0303] Exemplary CDK inhibitor compounds of this disclosure are shown in the “Preparation Methods” section of the Examples chapter and in Tables 5-6.

[0304] In some embodiments, the compound of formula I is a compound listed or described in any of Tables 3-15. In some embodiments, the compound of formula I is a compound listed in Table 3. In some embodiments, the compound of formula I is a compound listed in Table 4. In some embodiments, the compound of formula I is a compound numbered 1-965. In some embodiments, the compound of formula I is a compound numbered 1-188, 193-217, or 220-946. In some embodiments, the compound of formula I is a compound numbered 189-192, 218-219, or 947-965.

[0305] In some implementations of Formula I, R 6 It is a (methylsulfonyl)piperidine group, and the compounds are numbered 1-2, 4-8, 11-12, 17-19, 21-22, 25-98, 102, 111, 115-119, 212, 251 or 260-262.

[0306] In some implementations of Formula I, R 6 It is a (vinylsulfonyl)piperidine group, and the compounds are numbered 3, 10, 15, 20, 24 or 103-109.

[0307] In some implementations of Formula I, R 4 It is a cyclohexene group, and the compounds are numbered 20, 99-102, 113-114, 127, 253 or 254.

[0308] In some implementations of Formula I, R 6It is (methylsulfonyl)phenyl, and the compounds are numbered 23, 120-121, 124-127, 129-130, 135, 138-139, 142, 144, 146, 147-148, 150-155, 158-159, 163-184, 186, 189, 193-204, 206-208, 213-216, 220, 223-240, 242-244, 246-248, 250, 252, 259, 267.

[0309] In some implementations of Formula I, R 6 It is (vinylsulfonyl)phenyl, and the compounds are numbered 122-123, 131, 136-137, 141, 145, 149, 156-157, 160-162, 185, 205, 209, 188, 211, 217, 241 or 245.

[0310] In some implementations of Formula I, R 6 This includes electrophilic reactive hydrophilic Z groups, such as compounds 9, 13-14, 16, 110, 112-114, 128, 140, 249, 253-254, or 258.

[0311] In some implementations of Formula I, R 6 This includes non-electrophilic hydrophilic Z groups, such as compounds 23, 99-101, 16, 110, 132-134, 143, 187, 210, 221, or 222.

[0312] In some embodiments of Formula I, the compound is 16 or 110-114. In some implementations of Formula I, R 6 It is aryl, and the compound is one of the compounds listed in Table 12.

[0313] In some implementations of Formula I, R 4 It contains indazole, and the compounds are those listed in Table 13.

[0314] In some implementations of Formula I, R 4 It contains substituted alkynes, and the compounds are those listed in Table 14.

[0315] In some embodiments of Formula I, the compound has Formula IA, such as compounds 1-188, 193-217, or 220-946.

[0316] In some embodiments of Formula I, the compound contains an alternative core of Formula IA (e.g., the core of any of Formulas IB-IM), such as the compounds in Table 15 or Table 4.

[0317] In some embodiments of Formula I, the compound has Formula IB, such as compounds 219, 956, 958, 963 or 965.

[0318] In some embodiments of Formula I, the compound has Formula I, such as compound 190 or 192.

[0319] In some embodiments of Formula I, the compound has Formula ID, such as compound 189, 191, 955, 957, 961, 962 or 964.

[0320] In some embodiments of Formula I, the compound has Formula IE, such as compound 959.

[0321] In some embodiments of Formula I, the compound has Formula IG, such as compound 218 or 960.

[0322] In some embodiments, the compounds are described by the structure of one of the compounds shown in the heading "Preparation Methods" in the Examples section or in Tables 5-6. It should be understood that any compound shown herein may exist in salt form. In some cases, the salt form of the compound is a pharmaceutically acceptable salt.

[0323] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Pharmaceutically acceptable salts include acid addition salts (e.g., formed from the free amino group of a compound) and salts formed from inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, etc.). Salts formed from free carboxyl groups can also be derived from inorganic bases, such as sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Salts derived from organic bases include, but are not limited to, salts containing primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and salts from basic ion exchange resins.

[0324] The term "prodrug" refers to a drug produced through some physiological or chemical process. In the body The agent is converted into a drug (e.g., a prodrug is converted into the desired drug form upon reaching physiological pH). It should be understood that any of the compounds shown in the heading "Preparation Methods" in the Examples section or in Tables 5-6 may be in prodrug form.

[0325] This disclosure includes compounds having at least one desired isotope substitution (e.g., as described herein) in amounts higher than the natural abundance of the isotope, i.e., enriched. An isotope is an atom with the same atomic number but different mass numbers, i.e., the same number of protons but different numbers of neutrons.

[0326] Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 F 31 P, 32 P, 35 S, 36 Cl and 125 I. In one non-limiting embodiment, the isotope-labeled compound can be used for metabolic studies (using, for example...) 14 C) Reaction kinetic studies (using, for example) 2 H or 3 H) Detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)), including drug or substrate tissue distribution assays, or for the treatment of patients. Specifically, 18 F-labeled compounds are particularly desirable for 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 by performing the schemes or examples and preparation procedures disclosed below.

[0327] Isotopic substitution (e.g., deuterium substitution) can be partial or complete. Partial deuterium substitution means that at least one hydrogen atom is substituted with deuterium. In some embodiments, the isotope is enriched by 90%, 95%, or 99% or more at any site of interest. In a non-limiting embodiment, deuterium is enriched by 90%, 95%, or 99% at the desired site.

[0328] In some embodiments, the hydrogen atom substitution for the deuterium atom may be provided in any compound of formula I, formula IA-IM, formula IIA-IIB, formula IIIA-IIIB, formula IV, formula V, formula VIA-VIB, formula VIIA-VIIB, formula VIIIA-VIIIB, formula IX, formula X, formula XI, or formula XII, or exemplary compound 1-compound 965. In a non-limiting embodiment, the hydrogen atom substitution for the deuterium atom occurs within one or more groups selected from: R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 11 R12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R, R', and R'', etc. For example, when any of the groups is or, for example, contains methyl, ethyl, or methoxy, alkyl residues may be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In some other embodiments, when two substituents combine to form a ring or ring system, the unsubstituted carbon may be deuterated.

[0329] 4.2 Pharmaceutical Composition This article also provides a pharmaceutical composition comprising a subject CDK2 inhibitor compound and a pharmaceutically acceptable carrier or excipient.

[0330] "Pharmaceutical composition" means a composition suitable for administration to subjects (such as mammals, especially humans). Generally, a "pharmaceutical composition" is sterile and preferably free of contaminants that could cause adverse reactions in a subject (e.g., the compounds in the pharmaceutical composition are pharmaceutical grade). Pharmaceutical compositions can be designed to be administered to subjects or patients in need via a variety of different routes of administration, including oral, sublingual, rectal, parenteral, intraperitoneal, intradermal, intratracheal, intramuscular, and subcutaneous.

[0331] Typically, the compositions of this disclosure will comprise a therapeutically effective amount and be administered via a desired mode of administration. Appropriate dosage ranges depend on numerous factors, such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication for which administration is intended, and the preferences and experience of the medical practitioner involved. Those skilled in the art of treating such diseases will be able to determine the therapeutically effective amount of the compositions of this disclosure for a specific disease without excessive experimentation and reliance on personal knowledge and the disclosure of this application.

[0332] As used herein, the terms "effective amount," "pharmaceutical effective amount," or "therapeutic effective amount" refer to an amount of composition sufficient to provide the desired efficacy when administered to a subject suffering from a particular condition. Therefore, the term "therapeutic effective amount" refers to an amount of therapeutic cells or a composition containing therapeutic cells sufficient to promote a specific effect when administered to a subject requiring treatment. Effective amounts will also include amounts sufficient to prevent or delay the development of disease symptoms, alter the course of disease symptoms (e.g., but not limited to slowing the progression of disease symptoms), or reverse disease symptoms. It should be understood that, for any given situation, an appropriate "effective amount" can be determined by a person skilled in the art using routine experiments.

[0333] The term "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that, to a reasonable extent of medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit / risk ratio. "Pharmaceutically acceptable carriers or excipients" may encompass substances referred to as pharmaceutically acceptable diluents, pharmaceutically acceptable additives, and pharmaceutically acceptable carriers.

[0334] Pharmaceutically acceptable carriers, diluents, or excipients for therapeutic use are well known in the pharmaceutical field and described, for example, in Remington's Pharmaceutical Sciences, 18th edition (Easton, Pa.: Mack Publishing Company, 1990), and include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, surfactants, or emulsifiers approved by the U.S. Food and Drug Administration for use in humans or livestock. Carriers (including excipients) must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to patients receiving treatment. Carriers may be inert or may have their own pharmaceutical benefits. As described in more detail herein, the amount of carrier used in conjunction with the disclosed compound is sufficient to provide the actual amount of material for administration per unit dose of the compound.

[0335] 4.3 Usage Method This article also provides methods for using the subject CDK inhibitor compounds and pharmaceutical compositions in research and as therapeutic agents.

[0336] 4.4.1 Methods to suppress CDK As illustrated in the working examples, the subject compound inhibits cyclin-dependent kinases (such as CDK2 or CDK4). Inhibition of CDKs means, for example, in a sample or biological system, that the enzyme activity is reduced relative to any suitable enzyme. in vitro Inhibition of a control in an assay is defined as a reduction of 10% or more, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more. In some cases, CDK inhibition means a reduction in enzyme activity to 1 / 2 or less, such as 1 / 3 or less, 1 / 5 or less, 1 / 10 or less, 1 / 100 or less, or 1 / 1000 or less, relative to the enzyme's normal activity (e.g., relative to a control as measured by any suitable assay).

[0337] In some cases, this method is a method for suppressing CDK in a sample. As used herein, the term "sample" refers to a material or mixture of materials, typically but not necessarily in fluid form, containing one or more components of interest.

[0338] Therefore, in some embodiments, a method for inhibiting cyclin-dependent kinases (e.g., CDK2 or CDK4) is provided, the method comprising contacting a biological sample containing CDK with an effective amount of the subject compound or pharmaceutical composition as described herein to inhibit CDK.

[0339] In some embodiments, a method for inhibiting CDK2 is provided, which includes contacting a sample with a CDK2 inhibitor to inhibit CDK2 activity. In some embodiments, a method for inhibiting CDK4 is provided, which includes contacting a sample with a CDK2 inhibitor to inhibit CDK4 activity. In some cases, the sample is a cell sample.

[0340] In some embodiments, a CDK (e.g., CDK2 or CDK4) inhibitor is a compound as defined herein. In some embodiments, a CDK (e.g., CDK2 or CDK4) inhibitor is an inhibitor of any of Formula I, IA-IM, IIA-IIB, IIIA-IIIB, IV, V, VIA-VIB, VIIA-VIIB, VIIIA-VIIIB, IX, X, XI, or XII, or exemplary compounds 1-965, or pharmaceutically acceptable salts thereof. In some cases, a CDK inhibitor is any compound shown in Tables 3-15 or a pharmaceutically acceptable salt thereof. In some cases, a CDK2 inhibitor is any of compounds 1-965.

[0341] In some embodiments, the CDK inhibitor is a covalent inhibitor. In some embodiments, a method for inhibiting CDK is provided, the method comprising contacting a sample with a CDK inhibitor that covalently binds to CDK to inhibit CDK. In some embodiments, the CDK inhibitor covalently binds to a lysine residue of CDK to inhibit CDK.

[0342] In some embodiments, the CDK inhibitor is a classic inhibitor. In some embodiments, a method for inhibiting CDK is provided, which includes contacting a sample with a CDK inhibitor that binds to CDK to inhibit CDK.

[0343] In some embodiments, the CDK inhibitor is a covalently reversible inhibitor. In some embodiments, a method for inhibiting CDK is provided, the method comprising contacting a sample with a CDK inhibitor that reversibly covalently binds to CDK to inhibit CDK.

[0344] In some embodiments, the subject compound has a CDK inhibition profile reflecting the activity against other enzymes. In some embodiments, the subject compound selectively inhibits CDK2 without significantly inhibiting one or more other enzymes. In some embodiments, the subject compound specifically inhibits CDK2 without producing undesirable inhibition of CDK1. In some embodiments, the subject compound exhibits superior selective inhibition of CDK2 compared to CDK4 and / or CDK6. In some embodiments, the subject compound exhibits superior selective inhibition of CDK4 compared to CDK1. In some embodiments, the subject compound exhibits superior selective inhibition of CDK4 compared to CDK2 and / or CDK6.

[0345] In some embodiments, the subject compound inhibits CDKs (e.g., CDK2 or CDK4), as determined by an inhibition assay, such as by measuring the IC50 after treatment with the subject compound relative to a control. 50 or EC 50The IC50 value is used to determine the activity level of enzymes in cell-free systems or cells. In some embodiments, the IC50 value of the subject compound is used. 50 Value (or EC) 50 The value is 10 μM or lower, such as 3 μM or lower, 1 μM or lower, 500 nM or lower, 300 nM or lower, 200 nM or lower, 100 nM or lower, 50 nM or lower, 30 nM or lower, 10 nM or lower, 5 nM or lower, 3 nM or lower, 1 nM or lower or even lower.

[0346] As summarized above, aspects of this disclosure include methods for inhibiting CDKs (e.g., CDK2 or CDK4). The subject compound (e.g., as described herein) can inhibit the activity of CDKs (e.g., CDK2 or CDK4) in the range of 10% to 100%, such as 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more. In some assays, the subject compound can be 1 × 10⁻⁶. "6 M or lower (e.g., 1×10) "6 M or lower, 1×10 "7 M or lower, 1×10 "8 M or lower, 1×10 -9 M or lower, 1×10 10 M or lower or 1×10 11 IC (M or lower) 50 Inhibit its target.

[0347] Numerous methods can be used to determine CDK activity, including but not limited to: cell-free assays, such as binding assays; assays using purified enzymes; cell assays measuring cell phenotypes, such as gene expression assays; and in vivo assays involving specific animals (in some embodiments, which may be animal models of diseases associated with the target pathogen).

[0348] In some implementation schemes, the subject approach is... in vitro The method includes contacting a sample with a subject compound that specifically inhibits CDK. In some embodiments, the sample is suspected of containing CDK, and the subject method further includes assessing whether the compound inhibits CDK.

[0349] In some embodiments, the subject compound is a modified compound that includes a label (e.g., a fluorescent label), and the subject method also includes, for example, using optical detection to detect the label in the sample (if present).

[0350] In some embodiments, the compound is modified with a carrier or with an affinity group (e.g., biotin) that binds to the carrier, such that any sample not bound to the compound can be removed (e.g., by washing). The specifically bound CDK (if present) can then be detected using any suitable means, such as binding with a labeled target-specific probe or using a fluorescent protein reactive reagent.

[0351] In another embodiment of the method of the present invention, the sample is known to contain the target CDK.

[0352] In some embodiments, this method is a method for reducing cancer cell proliferation, wherein the method includes contacting cells with an effective amount of a subject CDK (e.g., CDK2 or CDK4) inhibitor compound (e.g., as described herein) to reduce cancer cell proliferation. This method may be performed in combination with chemotherapeutic agents (e.g., as described herein). Cancer cells can... in vitro or in vivo In some cases, the method involves contacting cells with CDK (e.g., CDK2 or CDK4) inhibitor compounds (e.g., as described herein) and with chemotherapeutic agents. This can target any suitable cancer cells.

[0353] In some embodiments, a method for inhibiting a subject's CDKs (e.g., CDK2 or CDK4) is provided, the method comprising administering to the subject a compound or pharmaceutical composition as described herein to inhibit the subject's CDKs (e.g., CDK2 or CDK4).

[0354] 4.4.2 Treatment methods The compounds disclosed herein can inhibit CDKs (e.g., CDK2 or CDK4) and are therefore useful for treating diseases in which the underlying pathology is wholly or partially mediated by CDKs. Therefore, this document provides a method for treating a subject with a CDK-related disease or condition, comprising administering to a subject suffering from a CDK-related disease or condition a therapeutically effective amount of a compound or pharmaceutical composition as described herein.

[0355] Such diseases or conditions associated with CDKs (e.g., CDK2 or CDK4) include cancer and other diseases involving proliferative abnormalities. In some embodiments, this disclosure provides for the use of the subject compound (e.g., a compound of formula (I) or its salts or stereoisomers). In the body Treating an individual or patient to suppress the growth of cancerous tumors. Subject CDK (e.g., CDK2 or CDK4) inhibitor compounds can be used to inhibit the growth of cancerous tumors with abnormal CDK kinase activity. These include, but are not limited to, diseases (e.g., cancer) characterized by the amplification or overexpression of CCNE1 or cyclin D (CCND).

[0356] In some embodiments, the CDK (e.g., CDK2 or CDK4) inhibitor is an inhibitor as defined herein. In some embodiments, the CDK inhibitor is an inhibitor of any of Formula I, Formula IA-IM, Formula IIA-IIB, Formula IIIA-IIIB, Formula IV, Formula V, Formula VIA-VIB, Formula VIIA-VIIB, Formula VIIIA-VIIIB, Formula IX, Formula X, Formula XI, or Formula XII. In some cases, the CDK inhibitor is a compound shown in any of Tables 3-15 or a pharmaceutically acceptable salt thereof. In some cases, the CDK inhibitor is any of Compound 1-Compound 965 or a pharmaceutically acceptable salt thereof.

[0357] Therefore, in some embodiments of this method, the patient has been previously identified as having cyclin E1 (CCNE1) gene amplification, and / or the CCNE1 expression level in a biological sample obtained from a human subject is higher than the control expression level of CCNE1. Alternatively, the subject CDK2 inhibitor compound may be used in combination with other agents or standard cancer treatments.

[0358] In one embodiment, this disclosure provides In vitro Methods to inhibit tumor cell growth. These methods include... In vitro The tumor cells are brought into contact with the subject compound. In another embodiment, this disclosure provides a method for inhibiting the growth of tumor cells in an individual or patient that exhibit CCNE1 amplification and overexpression. The method includes administering a therapeutically effective amount of the subject compound to the individual or patient in need.

[0359] In some embodiments, this document provides a method for inhibiting CDKs, the method comprising contacting the CDKs with a subject CDK inhibitor compound. In some embodiments, this document provides a method for inhibiting CDKs in a patient, the method comprising administering to the patient a compound of formula (I) or any of the formulas described herein, a compound listed in any of the claims and described herein, or a salt thereof.

[0360] In some embodiments, this document provides a method for treating cancer. The method includes administering a therapeutically effective amount of a subject CDK inhibitor compound to a patient (in need). In another embodiment, the cancer is characterized by amplification or overexpression of CCNE1.

[0361] In some implementations, the disease or condition is associated with CDK4. In some implementations, CDK4-associated diseases or conditions are associated with the amplification and / or overexpression of the cyclin D (CCND) axis.

[0362] In some embodiments, this document provides a method for treating a patient with a CDK2-related disease or condition, the method comprising administering to the patient a therapeutically effective amount of a subject CDK2 inhibitor compound. In some embodiments, the CDK2-related disease or condition is associated with amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1. In some embodiments, the CDK2-related disease or condition is N-myc-amplified neuroblastoma cells, K-Ras-mutant lung cancer, and cancers with FBXW7 mutations and CCNE1 overexpression.

[0363] 4.4 Utility The methods and compositions described above can be used in any application requiring CDK inhibition. Applications of interest include both research and therapeutic applications. These applications include, but are not limited to, research, diagnostic, and therapeutic applications.

[0364] In some cases, the application of interest is therapeutic, such as for the treatment of diseases. For example, the compositions and methods of this application can be used to deliver a subject CDK inhibitor to cells to treat diseases or conditions in which the underlying pathology is wholly or partially mediated by CDKs. As a non-limiting example, the compositions of this application can be used to treat CDK-related diseases or conditions, such as cancer and other diseases with proliferative abnormalities.

[0365] 4.5 Definition When describing embodiments of this disclosure (which may include compounds and their pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions), unless otherwise stated, the following terms (if present) shall have the following meanings. Those skilled in the art will understand that, in general, the terms used herein, and especially in the appended claims (e.g., the body of the appended claims), are typically intended to be “open-ended” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “at least having,” the term “includes” should be interpreted as “including but not limited to,” etc.). Those skilled in the art will also understand that if a specific numerical value is intended in the introductory claim, that intention will be explicitly stated in the claim, and the absence of such a statement will not imply this intention. For example, to aid understanding, the appended claims may contain the use of the introductory phrases “at least one” and “one or more” to introduce the claim statement. However, the use of such phrases should not be construed as implying that introducing a claim record with the indefinite article "a (or an)" limits any particular claim containing that introduced claim record to containing only one embodiment of that record, even if the same claim includes the introductory phrase "one or more" or "at least one" and indefinite articles such as "a (or an)" (e.g., "a (a and / or an)" should be interpreted as "at least one" or "one or more"); the same applies to the use of definite articles to introduce a claim record. Furthermore, even if a specific numerical value is explicitly recited in the introduced claim record, those skilled in the art will recognize that such a recitation should be interpreted as meaning at least the recited numerical value (e.g., "two recitations" without other modifiers means at least two recitations or two or more recitations). Furthermore, when using expressions such as "at least one of A, B, and C," this construction intent is generally interpreted in accordance with the meaning that a person skilled in the art would understand from the expression (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, systems having only A, only B, only C, both A and B, both A and C, both B and C, and / or both A, B, and C). When using expressions such as "at least one of A, B, or C," this construction intent is generally interpreted in accordance with the meaning that a person skilled in the art would understand from the expression (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, systems having only A, only B, only C, both A and B, both A and C, both B and C, and / or both A, B, and C). A person skilled in the art will also understand that virtually any extractive word and / or phrase presenting two or more optional terms, whether in the specification, claims, or drawings, should be understood to cover the possibility of including one of the terms, any one of the terms, or both of the terms. For example, the phrase “A or B” would be understood to include the possibility of “A” or “B” or “A and B”.

[0366] Furthermore, where features or aspects of this disclosure are described in the form of a Markush group, those skilled in the art will recognize that this disclosure is also described in the manner of any individual member or subgroup of members within that Markush group.

[0367] As those skilled in the art will understand, for all purposes, such as providing a written description, all scopes disclosed herein also encompass all possible subscopes and combinations thereof. Any listed scope can be readily considered sufficiently descriptive and decomposed into at least two, three, four, five, ten, etc., equal parts. As a non-limiting example, the scopes discussed herein can be readily decomposed into a lower third, a middle third, and an upper third, etc. Similarly, as those skilled in the art will understand, all terms such as “at most,” “at least,” “greater than,” “less than,” etc., include the listed numerical values ​​and refer to a scope that can subsequently be decomposed into subscopes as described above. Finally, as those skilled in the art will understand, a scope includes each individual member. Thus, for example, a group having 1-3 items means a group having 1, 2, or 3 items. Similarly, a group having 1-5 items means a group having 1, 2, 3, 4, or 5 items, and so on.

[0368] Compounds are described using standard nomenclature. Any compound in any of the formulas described herein may be in the form of a racemic mixture, enantiomer, mixture of enantiomers, diastereomers, mixture of diastereomers, tautomer, N-oxide, or isomer, such as a rotational isomer; each is specifically described unless the context explicitly excludes it.

[0369] The compounds disclosed herein include those generally described above, and are further illustrated by the categories, subclasses, and species disclosed herein. Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this disclosure, chemical elements are identified according to the periodic table, CAS version, Handbook of Chemistry and Physics, 75th edition. Furthermore, the general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0370] The abbreviations used in this article have their conventional meanings, even for those outside the chemical and biological fields. The chemical structures and formulas shown in this article are constructed according to the standard rules of valence known in the field of chemistry.

[0371] As used herein, the phrases “having a formula” or “having a structure” are not intended to be restrictive and are used in the same manner as the commonly used term “comprising”. The term “independently selected” is used herein to indicate that the listed elements, such as the R group, may be the same or different.

[0372] As used herein, the term "aliphatic" or "aliphatic group" refers to a fully saturated or branched, substituted or unsubstituted hydrocarbon chain that is straight-chain (i.e., unbranched) or branched, containing one or more unsaturated units; or a fully saturated or non-aromatic monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic," "cycloaliphatic," or "cycloalkyl") having a single connection point to the remainder of the molecule. Unless otherwise stated, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocyclic" or "cycloalkyl") refers to a fully saturated or non-aromatic monocyclic C3-C7 hydrocarbon containing one or more unsaturated units, having a single connection point to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and their complex groups, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0373] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen; or substituted nitrogen in a heterocycle, such as N (e.g., in 3,4-dihydro-2H-pyrrole), NH (e.g., in pyrrolealkyl), or NR). + (e.g., in N-substituted pyrroleyl groups).

[0374] As used in this article, the term "unsaturated" means that a part has one or more unsaturated units.

[0375] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2). n - where n is a positive integer, such as 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below with respect to substituted aliphatic groups.

[0376] As used herein, the term "cyclopropylidene" refers to a divalent cyclopropyl group having the following structure: .

[0377] As used herein, the term "bridged bicyclic" refers to any bicyclic system having at least one bridging bond, i.e., a carbocyclic or heterocyclic system, saturated or partially unsaturated. As defined by IUPAC, a "bridging bond" is an unbranched chain of atoms or a single atom or valence bond connecting two bridgehead atoms, wherein a "bridgehead atom" is any skeletal atom of a ring system bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups listed below, wherein each group is attached to the remainder of the molecule at any substituted carbon or nitrogen atom. Unless otherwise stated, the bridged bicyclic group is optionally substituted with one or more substituents as described with respect to aliphatic groups. Additionally or alternatively, any substituted nitrogen atom in the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic compounds include: . A hyphen ("-") that is not between two letters or symbols is used to indicate the connection point of a substituent. For example, -CN is connected by a carbon atom.

[0378] When listing a range of values, it is intended to cover every value and subrange within that range. For example, "C1-C6 alkyl" is intended to cover C1, C2, C3, C4, C5, C6 ... 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0379] As used herein, the term "acyl" refers to an RC(O)- group, such as, but not limited to, (alkyl)-C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)-C(O)-, and (heterocyclic)-C(O)-, wherein the group is linked to the parent molecule structure via a carbonyl functional group. In some embodiments, it is a C1-10 acyl group, which refers to, for example, the total number of chain or ring atoms of an alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl moiety plus the carbonyl carbon of the acyl group. For example, a C4-acyl group has three other ring or chain atoms plus a carbonyl group.

[0380] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight-chain or branched group with 2-8 carbon atoms, referred to herein as (C2-C8)alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-buten)-pentenyl.

[0381] As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon, such as a straight-chain or branched group with 1 to 8 carbon atoms, referred to herein as C14. 1-8 Alkyl groups. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. In some embodiments, "alkyl" is a straight-chain hydrocarbon. In some embodiments, "alkyl" is a branched-chain hydrocarbon.

[0382] The term "alkoxy" refers to a straight-chain or branched saturated hydrocarbon containing 1 to 12 carbon atoms, such as -O (alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy.

[0383] As used herein, the term "alkylene" refers to a divalent alkyl group. Representative examples of C1-10 alkylene groups include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, secondary butylene, isobutylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, and n-decylene.

[0384] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight-chain or branched group with 2-8 carbon atoms, referred to herein as (C2-C8) alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentyynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

[0385] The term "aryl" in this document refers to all carbon monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent carbon atom pairs) groups having a fully conjugated π-electron system. Aryl groups may be selected from: monocyclic carbocyclic aromatic rings, such as phenyl; bicyclic systems, such as 7-12 membered, for example 9-10 membered bicyclic systems, wherein at least one ring is a carbocyclic and aromatic, such as those selected from naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and tricyclic systems, such as 10-15 membered tricyclic systems, wherein at least one ring is a carbocyclic and aromatic, such as fluorene.

[0386] For example, an aryl group can be a 6-membered carbocyclic aromatic ring fused with a 5- to 7-membered cycloalkyl or heterocyclic ring, wherein the heterocyclic ring optionally contains at least one heteroatom selected from N, O, and S, provided that: when the carbocyclic aromatic ring is fused with a heterocyclic ring, the connection point is located at the carbocyclic aromatic ring; and when the carbocyclic aromatic ring is fused with a cycloalkyl group, the connection point can be located at the carbocyclic aromatic ring or the cycloalkyl group. A divalent group formed from a substituted benzene derivative and having a free valence at a ring atom is named a substituted phenylene. A divalent group derived from a monovalent polycyclic hydrocarbon group whose name ends in "-yl" and obtained by removing a hydrogen atom from a carbon atom with a free valence is named by adding "-idene" to the name of the corresponding monovalent group; for example, a naphthyl group with two connection points is called a naphthylidene.

[0387] The term "heteroaryl" refers to a group having 5 to 10 ring atoms, or 5, 6, or 9 ring atoms; having 6, 10, or 14 shared π electrons in a cyclic array; and having one to five heteroatoms in addition to a carbon atom. Heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrazinyl, mesoazinyl, purine, naphridinyl, and pteridinyl. As used herein, the term "heteroaryl" also includes groups in which a heteroaryl ring is fused with one or more aryl, cycloaliphatic, or heterocyclic rings, wherein the group or linking point is located on the heteroaryl ring (or, in the case of a divalent fused heteroaryl subcyclic ring system, at least one group or linking point is located on the heteroaryl ring). Non-limiting examples include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cenolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolinyl, carbazoleyl, acridineyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroarylene," any of which includes optionally substituted rings.

[0388] As used in this article, the term "cyano" refers to CN.

[0389] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group derived from cycloalkanes with 3-16 carbons or 3-8 carbons (referred to herein as "(C3-C8)cycloalkyl"). Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, and cyclopentene. A cycloalkyl group may be substituted with the following groups: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, aralkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic, hydroxyl, ketone, nitro, phosphate, thioether, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thion. A cycloalkyl group may be fused with other cycloalkyl (saturated or partially unsaturated), aryl, or heterocyclic groups to form bicyclic, tetracyclic, etc. The term "cycloalkyl" also includes bridged and spirocyclic cyclic structures that may or may not contain heteroatoms.

[0390] As used herein, the term “halogenated” or “halogen” refers to -F, -Cl, -Br and / or -I.

[0391] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens. Examples of halogenated alkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0392] A "heterocyclic group" or "heterocyclic group" is a ring structure having 3 to 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S, wherein the ring N atom can be oxidized to NO, and the ring S atom can be oxidized to SO or SO2, and the remaining ring atoms are carbon. Heterocyclic groups can be monocyclic, bicyclic, spirocyclic, or bridged ring systems. The heterocyclic group can optionally be substituted independently at the ring nitrogen atom by an alkyl, aralkyl, or alkyl carbonyl group, or at the sulfur atom by a lower alkyl group. Examples of heterocyclic groups include, but are not limited to, epoxy groups, aziridine, aziridine propane, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrrolidone, piperidinyl, piperazinyl, imidazoalkyl, imidazopyridinyl, thiazoalkyl, dithiazoalkyl, trithiazoalkyl, dioxolanecycloalkyl, oxazolidinone, decahydroquinolinyl, piperidinone, 4-piperidinone, quininecycloyl, thiomorpholinyl, morpholinyl, aziridine heptyl, oxaziridine heptyl, aziridine bicyclohexyl, aziridine bicycloheptyl, aziridine bicyclooctyl, aziridine bicyclononyl (e.g., octahydroinyl), and aziridine bicyclononyl (e.g., octahydroinyl). The term includes compounds with adjacent rings of O and / or S atoms. The scope of this term explicitly excludes compounds with adjacent rings of O and / or S atoms.

[0393] "Spirocyclic," "spirocyclic group," or "spirocyclic subcyclic group" means a chemical entity having two heterocyclic groups or two cycloalkyl moieties as defined herein, or a combination of one or more heterocyclic groups and one or more cycloalkyl moieties having a common ring atom, i.e., two rings connected by a common ring atom. Some exemplary spirocyclic systems, but non-limiting examples of spirocyclic systems include... , , , , , , , , , , , , or .

[0394] As used herein, the term "partially unsaturated" refers to a ring moiety comprising at least one double or triple bond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but is not intended to include aryl or heteroaryl moiety as defined herein.

[0395] As used herein, unless otherwise stated, the suffix "-ene (subunit)" is used to describe divalent groups. Therefore, any of the above terms may be modified with the suffix "-ene" to describe the divalent form of that part. For example, a divalent carbocyclic ring is "carbocyclic subunit," a divalent aryl ring is "arylene," a divalent benzene ring is "phenylene," a divalent heterocyclic ring is "heterocyclic subunit," a divalent heteroaryl ring is "heteroaryl subunit," a divalent alkyl chain is "alkylene," a divalent alkenyl chain is "alkylene," a divalent alkynyl chain is "alkynyl," and so on.

[0396] As described herein, when specified, compounds of this disclosure may contain an "optionally substituted" moiety. Generally, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens in the specified moiety are replaced by suitable substituents. "Substituent" applies to one or more hydrogens explicitly or implicitly present in the structure (e.g., It means at least ;and It means at least , , or Furthermore, in polycyclic systems, unless otherwise stated, substituents may replace hydrogen on any single ring (e.g., It means at least , , or Unless otherwise stated, an "optionally substituted" group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure may be substituted by more than one substituent selected from a particular group. For example, when the term "substituted" appears before or after a list of potentially substituted groups, the term is intended to apply to each member of that group. For example, the phrase "substituted alkyl and aryl" should be interpreted as "substituted alkyl and substituted aryl".

[0397] The combinations of substituents contemplated in this disclosure are those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" means a compound that remains substantially unchanged when subjected to conditions that allow it to be purified, tested, and, in some embodiments, recovered, purified, and used for the purposes disclosed herein.

[0398] On the substituted carbon atom of the "optionally substituted" group, suitable monovalent substituents are independently: halogen; -(CH2). 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R°;-O(CH2) 0-4 C(O)OR°;-O(CH2) 0-4 OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°;-(CH2) 0-4 Ph, which can be replaced by R°; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be substituted by R°; -CH=CHPh, which can be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 -Pyridyl group, which can be substituted with R°; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)N(R°)2;-N(R°)C(S)N(R°)2;-(CH2) 0-4 N(R°)C(S)N(R°)2;-(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)N(R°)2; -N(R°)N(R°)C(O)OR°; -(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSi(R°)3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°;-SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)N(R°)2;-C(S)N(R°)2;-C(S)SR°;-SC(S)SR°;-(CH2) 0- 4OC(O)N(R°)2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0-4SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)₂OR°;-(CH₂) 0-4 OS(O)2R°;-S(O)2NR°;-(CH2) 0-4 S(O)R°; -N(R°)S(O)2N(R°)2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)N(R°)2; -P(OR°)2; -P(O)(R°)2; -OP(O)(R°)2; -OP(O)(OR°)2; -SiR°3; -(C 1-4 (linear or branched alkylene)ON(R°)2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R°)2, wherein each R° can be substituted as defined below, and is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, despite the above definition, two independently occurring R° together with the atoms between them to form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring containing 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and which may be substituted as defined below.

[0399] Suitable monovalent substituents on R° (or a ring formed by two independently occurring R°s together with the atoms in between) are, independently: halogen; -(CH2) 0-2 R ● ;-(halogenated R) ● -(CH2) 0-2 OH; -(CH2) 0-2 OR ● ;-(CH2) 0-2 CH(OR ● )2;-O(halogenated R ● -CN; -N3; ​​-(CH2) 0-2 C(O)R ● ;-(CH2) 0-2 C(O)OH;-(CH2) 0-2 C(O)OR ● ;-(CH2) 0-2 SR ● ;-(CH2) 0-2 SH; -(CH2) 0-2 NH2;-(CH2) 0-2 NHR ● ;-(CH2)0-2 NR ● 2; -NO2, -SiR ● 3; -OSiR ● 3;-C(O)SR ● ;-(C 1-4 (straight-chain or branched alkylene)C(O)OR ● or -SSR ● ; where each R ● It is either unsubstituted or, in the case of "halogenated" preceding it, substituted by only one or more halogens, and independently selected from C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on the saturated carbon atom at R° include =O and =S.

[0400] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include: =O; =S; =NNR # 2;=NNHC(O)R # 2; =NNHC(O)OR # 2;=NNHS(O)2R # 2; =NR # =NOR # ;-O(C(R) # 2)) 2-3 O-; or -S(C(R) # 2)) 2-3 S-; where each R appears independently # Selected from hydrogen, C 1-6 An aliphatic group (which may be substituted as defined below), or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents attached to the ortho-substituted carbon of the "optionally substituted" group include: -O(CR # 2) 2-3 O-, where each R appears independently # Selected from hydrogen, C 1-6 Aliphatic groups (which may be substituted as defined below), or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0 to 4 independent heteroatoms selected from nitrogen, oxygen, and sulfur.

[0401] In R # Suitable substituents on the aliphatic group include halogens and -R. ● 、-(halogenated) ● -OH, -OR ● -O (halogenated) ●-CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2, or -NO2, where each R ● It is either unsubstituted or, in the case of a preceding "halogen," substituted by only one or more halogens, and independently C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0402] Suitable substituents for the substituted nitrogen atom of the "optionally substituted" group include -R. † -NR † 2. -C(O)R † -C(O)OR † -C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R) † )S(O)2R † 2, where each R † Independently, it is hydrogen, C1-6 aliphatic (which may be substituted as defined below), unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, despite the above definition, two independently occurring R... † Together with the atoms therein, they form 3 to 12 saturated, partially unsaturated, or aryl monocyclic or bicyclic rings, which contain 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0403] In R † On the aliphatic group, suitable substituents are independently halogens, -R ● 、-(halogenated) ● -OH, -OR ● -O (halogenated) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, in the case of a preceding "halogen," substituted by only one or more halogens, and independently C. 1-4Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0404] Those skilled in the art will understand that, as used herein, the designation of a small molecule structure as... A bond is a bond that is a single bond (e.g., saturated) in some embodiments and a double bond (e.g., unsaturated) in others. For example, the following structure: Intent to cover and Both.

[0405] As used in this article, the term "oxo" refers to oxygen that bonds to a carbon atom in a double bond to form a carbonyl group.

[0406] As used in this article, the terms “hydroxyl” and “hydroxyl group” refer to -OH.

[0407] Some compounds can exist at different hydrogen bonding sites, a phenomenon known as "tautomerism." For example, compounds containing a carbonyl group (CH2C(O)-) (ketone form) can undergo tautomerism to form a hydroxyl group (CH=C(OH)-) (enol form). Where applicable, ketone and enol forms (alone and mixtures thereof) are also intended to be included.

[0408] The compounds, tautomers, solvates, or pharmaceutically acceptable salts disclosed herein may contain asymmetric centers and thus exist as enantiomers. For example, when a compound has two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to the broader class of stereoisomers. All such possible stereoisomers, such as substantially pure separated enantiomers, racemic mixtures thereof, and mixtures of diastereomers, are intended to be included in this disclosure. All stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts of the compounds are intended to be included. Unless otherwise specifically mentioned, reference to one isomer applies to any of the possible isomers. Whenever the isomer composition is not specified, all possible isomers are included.

[0409] In some embodiments, the compounds, tautomers, solvates, or pharmaceutically acceptable salts disclosed herein may contain a meso moiety, be meso compounds, or exhibit meso isomerism.

[0410] A mixture of diastereomers can be separated into their respective diastereomers based on their physicochemical differences using methods well known to those skilled in the art, such as chromatography and / or stepwise crystallization. Enantiomers can be separated by the following steps: reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary agent, such as a chiral alcohol or Mosher acyl chloride) to convert the enantiomer mixture into a diastereomer mixture; separating the diastereomers and converting (e.g., hydrolyzing) individual diastereomers into their respective pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column.

[0411] "Stereoisomer" or "optical isomer" means a stable isomer having at least one chiral atom or restricted rotation (resulting in a plane perpendicular to the asymmetry plane, such as certain biphenyls, propylenes, and spirocyclic compounds) and capable of rotating plane-polarized light. Because the compounds of this disclosure contain asymmetric centers and other chemical structures that can cause stereoisomerism, this disclosure covers stereoisomers and mixtures thereof. The compounds of this disclosure and their salts include asymmetric carbon atoms and can therefore exist as single stereoisomers, racemates, and mixtures of enantiomers and diastereomers. Typically, such compounds are prepared as racemic mixtures. However, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures rich in stereoisomers. As discussed in more detail below, individual stereoisomers of the compound are prepared by synthesis from optically active raw materials containing the desired chiral center, or by preparing a mixture of enantiomers followed by separation or resolution, such as by converting to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, using chiral resolving agents, or by direct separation of the enantiomers on a chiral column. Starting compounds with specific stereochemistry are commercially available or prepared by the methods described below and resolved using techniques well known in the art.

[0412] It is well known in the art that the biological and pharmacological activities of a compound are sensitive to its stereochemistry. Therefore, enantiomers often exhibit significantly different biological activities, including differences in pharmacokinetic properties (including metabolism, protein binding, etc.) and pharmacological properties (including the type, degree, and toxicity of the activity exhibited). Therefore, those skilled in the art will understand that when one enantiomer is enriched relative to another, or when separated from another enantiomer, that enantiomer may be more active or exhibit beneficial effects. Furthermore, those skilled in the art will know how to separate, enrich, or selectively prepare enantiomers of the compounds disclosed herein, and will possess prior art knowledge.

[0413] Therefore, although racemic forms of drugs can be used, they are often less effective than administering an equal amount of the enantiomer; in fact, in some cases, an enantiomer may be pharmacologically inactive and used only as a simple diluent. For example, although ibuprofen was previously administered as a racemic compound, only the S-isomer of ibuprofen has been shown to be effective as an anti-inflammatory agent (however, in the case of ibuprofen, although the R-isomer is inactive, it is converted to the S-isomer in vivo, thus the racemic form of the drug acts at a slower rate than the pure S-isomer). Furthermore, enantiomers can have different biological activities. For example, S-penicillamine is a treatment for chronic arthritis, while R-penicillamine is toxic. In fact, some purified enantiomers have advantages over racemic compounds because purified single isomers have been reported to have faster transdermal penetration rates compared to racemic mixtures. See U.S. Patent Nos. 5,114,946 and 4,818,541.

[0414] In some embodiments, the compound is a racemic mixture of (S)- and (R)- isomers. In other embodiments, mixtures of compounds are provided herein, wherein individual compounds in the mixture are present primarily in (S)- or (R)- isomer configurations. For example, the compound mixture has an excess of more than 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% or higher of the (S)-enantiomer. In other embodiments, the compound mixture has an excess of (S)-enantiomers of more than 55% to 99.5%, more than 60% to 99.5%, more than 65% to 99.5%, more than 70% to 99.5%, more than 75% to 99.5%, more than 80% to 99.5%, more than 85% to 99.5%, more than 90% to 99.5%, more than 95% to 99.5%, more than 96% to 99.5%, more than 97% to 99.5%, more than 98% to 99.5%, more than 99% to 99.5%, or higher. In other embodiments, the compound mixture has an (R)-enantiomer purity of more than 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or higher. In some other embodiments, the compound mixture has an excess of (R)-enantiomers of more than 55% to 99.5%, more than 60% to 99.5%, more than 65% to 99.5%, more than 70% to 99.5%, more than 75% to 99.5%, more than 80% to 99.5%, more than 85% to 99.5%, more than 90% to 99.5%, more than 95% to 99.5%, more than 96% to 99.5%, more than 97% to 99.5%, more than 98% to 99.5%, more than 99% to 99.5%, or higher.

[0415] Individual stereoisomers of the compounds disclosed herein can be prepared from commercially available raw materials containing asymmetric or stereo / chiral centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by: (1) linking an enantiomer mixture to a chiral auxiliary agent, separating the resulting diastereomeric mixture by recrystallization or chromatography, and releasing an optically pure product from the auxiliary agent; (2) forming a salt using an optically active resolving agent; or (3) directly separating an optically enantiomer mixture on a chiral chromatographic column. The stereoisomer mixture can also be resolved into its component stereoisomers by well-known methods such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallizing the compound into a chiral salt complex, or crystallizing the compound in a chiral solvent. The stereoisomers can also be obtained from stereoisomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0416] Therefore, if one enantiomer is pharmacologically more active, less toxic, or has a preferred distribution in vivo than another enantiomer, then preferential administration of that enantiomer is more beneficial for treatment.

[0417] As used herein, the term "pharmaceutically acceptable carrier" refers to all solvents, dispersion media, coatings, isotonic agents, and absorption delayers compatible with drug administration. The use of such media and agents for the active pharmaceutical ingredient is well known in the art. The composition may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic function.

[0418] Additionally, as used herein, refers to pharmaceutical excipients, such as pharmaceutically and physiologically acceptable organic or inorganic carriers suitable for enteral or parenteral administration that do not react adversely with the active agent. Suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, and carbohydrates (such as lactose, amylose, or starch), fatty acid esters, hydroxymethyl cellulose, and polyvinylpyrrolidone. Such formulations can be sterilized and, if necessary, mixed with adjuvants (such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants, and / or aromatic substances, etc.) that do not react adversely with the compounds disclosed herein.

[0419] As used herein, the term "pharmaceuticalally acceptable composition" refers to a composition comprising at least one compound as disclosed herein, formulated together with one or more pharmaceutically acceptable carriers.

[0420] The term "pharmaceutically acceptable salt" refers to a salt containing acidic or basic groups that may be present in the compounds used in the compositions of the present invention. Compounds contained in the compositions of the present invention that are basic in nature can form a variety of salts with various inorganic and organic acids. The pharmaceutically acceptable acid addition salts that can be used to prepare such basic compounds are those acids that form non-toxic acid addition salts (i.e., salts containing pharmaceutically acceptable anions), including but not limited to: sulfates, citrates, malates, acetates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, sucroseates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ates (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthylcarbamate)). Compounds comprising the amino moiety included in the compositions of the present invention can form pharmaceutically acceptable salts with various amino acids other than those mentioned above. The acidic compounds contained in the compositions of this invention are capable of forming basic salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.

[0421] The compounds disclosed herein can form solvates with solvents, including water. Therefore, in a non-limiting embodiment, this disclosure includes solvated forms of the compounds. The term "solvate" refers to a molecular complex of a compound (including its salts) and one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex comprising the compound and water. Pharmaceutically acceptable solvates according to the invention include those in which the solvent can be isotopically substituted, for example, D₂O, d₆-acetone, d₆-DMSO. Solvates may be in liquid or solid form.

[0422] Salt, solvate, hydrate, and prodrug forms of the compound are of interest. This disclosure covers all such forms. Therefore, the compounds described herein include their salt, solvate, hydrate, prodrug, and isomer forms, including their pharmaceutically acceptable salt, solvate, hydrate, prodrug, and isomer forms. In some embodiments, the compound can be metabolized into a pharmaceutically active derivative.

[0423] Generate chemical names using PerkinElmer ChemDraw® Professional version 17.

[0424] The compounds disclosed herein may contain one or more chiral centers and / or double bonds, and thus exist as stereoisomers (such as geometric isomers, enantiomers, or diastereomers). When used herein, the term "stereoisomer" encompasses all geometric isomers, enantiomers, or diastereomers. These compounds may be designated by the symbols "R" or "S," depending on the configuration of the substituents surrounding the stereocarbon atom. This disclosure covers a wide variety of stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated in nomenclature as "(±)", but those skilled in the art will recognize that a structure may implicitly represent a chiral center. In some embodiments, enantiomers or stereoisomers substantially free of the corresponding enantiomers may be provided.

[0425] As used herein, “cancer” refers to a disease, condition, or symptom involving abnormal cell growth that has the potential to invade or spread to other parts of the body. Exemplary cancers include, but are not limited to, breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.

[0426] As used herein, the term "subject" refers to an animal. Generally, an animal is a mammal. "Subject" also refers to, for example, primates (e.g., human, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the subject is a primate. In some embodiments, the subject is a human.

[0427] As used herein, the term “inhibit (inhibition or inhibiting)” refers to the reduction or suppression of a given symptom, condition, or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0428] As used herein, the term "dosing regimen" (or "treatment regimen") is a set of unit doses (usually more than once) administered individually to a subject, typically with a time interval between each dose. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, the dosing regimen includes multiple doses spaced at equal intervals between each dose; in some embodiments, the dosing regimen includes multiple doses and at least two distinct time intervals separating the individual doses.

[0429] As will be understood from the context, a "reference" compound is a compound that is sufficiently similar to a particular target compound to allow for relevant comparisons. In some embodiments, information about the reference compound is obtained simultaneously with information about the particular compound. In some embodiments, a comparison of the particular target compound with the reference compound establishes the identity, similarity, or difference of the particular target compound relative to the compound.

[0430] As used herein, the phrase “therapeutic agent” means any agent that, when administered to a subject, has a therapeutic effect and / or elicits the desired biological and / or pharmacological effect.

[0431] As used herein, in one embodiment, the term "treat, treating, or treatment" for any disease or condition means improving the disease or condition (i.e., slowing or halting or reducing the development of the disease or alleviating at least one of its clinical symptoms). In another embodiment, "treatment" means relieving or improving at least one physical parameter, including those that the patient may not be able to discern. In yet another embodiment, "treatment" means regulating the disease or condition physically (e.g., by stabilizing discernible symptoms), physiologically (e.g., by stabilizing physical parameters), or both. In yet another embodiment, "treatment" means preventing or delaying the onset, development, or progression of the disease or condition.

[0432] As used in this article, a subject “needs” the treatment if the subject will benefit from it biologically, medically, or in terms of quality of life.

[0433] Definitions of other terms and concepts appear throughout the detailed description.

[0434] The following examples are provided by way of illustration rather than limitation.

[0435] Other implementation plans This disclosure is further described by the following non-restrictive provisions: Clause 1. A compound of Formula I: (I) Or its pharmaceutically acceptable salt. in: Y 1 Is it N or CR? 1 ; Y 2 Is it N or CR? 2 ; Y 3 Is it N or CR? 3 ; Y 5 Is it N or CR? 5 ; R 6 Having a style ,in: A is a cyclic group selected from carbocyclic, heterocyclic, aryl, heteroaryl and their substituted forms; Z is an optional hydrophilic group; L 1 and L2 It is an optional linker; and R represents 6 Connection point with adjacent nitrogen atoms; R 4 Selected from optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted heteroaryl and optionally substituted aryl; R 1 -R 3 R 5 and R 7 Independently selected from H, optionally substituted (C) 1-6 )alkyl, halogenated (C 1-6 )alkyl, -COR 30 -OR 30 halogens and CN; and R 30 It is H or optionally substituted (C) 1-6 )alkyl.

[0436] Clause 2. A compound as described in Clause 1, wherein A is an optionally substituted aryl or optionally substituted heteroaryl.

[0437] Clause 3. The compound as described in Clause 2, wherein R 6 Includes structure 6A: (6A) in: Y 6 -Y 10 Independently selected from CZ and CR 12 Or N, where Y 6 -Y 10 One of them is CZ; and Each R 12 Independently selected from H, optionally substituted alkyl, optionally substituted alkoxy, hydroxyl, halogen and CN.

[0438] Clause 4. The compound as described in Clause 3, wherein Y 8 It's CZ.

[0439] Clause 5. The compound as described in Clause 3 or 4, wherein Y 6 -Y 10 At least one of them is N.

[0440] Clause 6. The compound as described in Clause 5, wherein Y 6 -Y 10 One and only one of them is N.

[0441] Clause 7. The compound as described in Clause 5 or 6, wherein Y 6 It is N.

[0442] Clause 8. The compound as described in Clause 5 or 6, wherein Y 7 It is N.

[0443] Clause 9. The compound as described in Clause 4, wherein R 6 It has structure 6A1: (6A1) Where m is 0, 1, 2, 3 or 4.

[0444] Clause 10. The compound as described in Clause 9, wherein R 6 It has structure 6A2: (6A2) Where R 12 Selected from hydrogen, halogen, or optionally substituted (C) 1-6 )alkyl and optionally substituted (C 1-6 )alkoxy.

[0445] Clause 11. A compound as described in Clause 1, wherein A is an optionally substituted cycloalkyl or optionally substituted heterocyclic group (e.g., piperidinyl).

[0446] Clause 12. The compound as described in Clause 11, wherein R 6 Includes structure 6B: (6B) in: Y 11 Selected from O, S, CH2, CHR 11 C(R) 11 )2 and NR 9 ; R 9 It is H, optionally substituted alkyl, -L 2 -Z or Z; Each R 11 Independently selected from -L 2 -Z, Z, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl carbonyloxy, hydroxyl, halogen and CN; k is 0 or 1; and n is an integer from 0 to 9.

[0447] Clause 13. The compound as described in Clause 12, wherein R 6 Includes structure 6B1 or 6B3: (6B1) or (6B3).

[0448] Clause 14. The compound as described in Clause 13, wherein: n is 0, 1, 2, 3, or 4; and Each R 11 Independently selected from optional substitutions (C) 1-3 )alkyl, optionally substituted (C 1-3 Alkoxy, hydroxy, halogen, and CN.

[0449] Clause 15. The compound as described in Clause 14, wherein each R 11 It is independently selected from methyl, methoxy, CF3, OCF3, hydroxy and fluorine.

[0450] Clause 16. The compound as described in Clause 13, wherein R 6 It has structure 6B2: (6B2).

[0451] Clause 17. The compound as described in Clause 4, wherein R 6 It has structure 6B4: (6B4).

[0452] Clause 18. The compound as described in any one of Clauses 1 to 17, wherein R 4 It is selected from substituted amines, optionally substituted alkyl groups, optionally substituted alkynyl groups, optionally substituted cycloalkyl groups, optionally substituted cycloolefins, optionally substituted heterocyclic groups, optionally substituted heteroaryl groups, and optionally substituted aryl groups.

[0453] Clause 19. The compound as described in any one of Clauses 1 to 18, wherein R 4 It is an acetylinyl group that is optionally substituted.

[0454] Clause 20. The compound as described in any one of Clauses 1 to 18, wherein R 4 It is an optional substituted cycloalkyl group.

[0455] Clause 21. The compound as described in any one of Clauses 1 to 18, wherein R 4 It is an optional substituted cyclic olefin.

[0456] Clause 22. The compound as described in any one of Clauses 1 to 18, wherein R 4 It is an optional substituted heterocyclic group.

[0457] Clause 23. The compound as described in any one of Clauses 1 to 18, wherein R 4 It is an aryl group that is optionally substituted.

[0458] Clause 24. The compound as described in any one of Clauses 1 to 18, wherein R 4 It is an optional substituted heteroaryl group.

[0459] Clause 25. The compound as described in any one of Clauses 20 to 24, wherein R 4 It is an optional substituted monocyclic group.

[0460] Clause 26. The compound as described in any one of Clauses 20 to 24, wherein R 4 It is an optional substituted bicyclic group.

[0461] Clause 27. The compound as described in Clause 26, wherein R 4 It is an optional substituted spirocyclic group.

[0462] Clause 28. The compound as described in Clause 26, wherein R 4 It is an optionally substituted fused bicyclic group.

[0463] Clause 29. The compound as described in any one of Clauses 18 to 28, wherein R 4 Selected from substituted amines, (C 2-6 Alkyne, cyclobutane, cyclopentane, cyclohexane, cyclohexene, piperidinyl, pyrrolidine, pyrrole, pyrazole, aziridine, azircycloheptane, pyridinyl, phenyl, pyrimidine, benzisoxazole, indazole, thiazole, dihydropyran, tetrahydropyran, azirindole, indoline, hydroxyindole, triazole, oxadiazole, cyclohexanone, and their optionally substituted forms.

[0464] Clause 30. The compound as described in any one of Clauses 18 to 29, wherein R 4 Choose any one of Equations 4A-4M: (4A) (4B) (4C) (4D) (4E) (4F) (4G) (4H) (4I) (4J) (4K) (4L) and (4M), in, X 1 It is O, CH2 or C(R) 26 )2; X 12 It is CH2, C(R) 15 )2, O, NCOR 25 or NR 25 ; X 14 It is O, NCOR 25 or NR 25 ; X 2 X 6 X 9 and X 10 Each independently selected from NR 25 C(R) 26 2. C = O, O, and S; X 3 X 4 X 5 X 7 and X 8 Each is independently selected from N and CR 26 ; Each R 15 -R 20 and R 24 It is independently selected from optional substituted alkyl, optional substituted amino, optional substituted alkoxy, hydroxy, carboxyl, halogen, optional substituted heterocyclic, optional substituted heteroaryl, optional substituted aryl, optional substituted cycloalkyl and optional substituents of CN; R 21 and R 22 Each is independently an optional substituted (C1-6) alkyl group; R 23 It is H, optionally substituted (C1-6) alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted heteroaryl or optionally substituted aryl; R 25 It is H, optionally substituted (C1-6) alkyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted heteroaryl or optionally substituted aryl; Each R 26 Independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and nitriles; R 27 and R 28 Each is independently H or an optionally substituted (C1-6) alkyl group, or R 27 and R 28 Together with the nitrogen atoms they are attached to, they form optionally substituted cyclic groups; R29 and R 30 Each is independently H or an optionally substituted (C1-6) alkyl group, or R 29 and R 30 Together with the carbon atoms they are attached to, they form spirocyclic groups with optional substitutions; k is 0, 1, 2, 3, 4, 5, 6, 7 or 8; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; r is 0 or 1; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; u is 0, 1, or 2; v and y are each independently 0, 1, 2 or 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2.

[0465] Clause 31. The compound as described in Clause 30, wherein R 4 It has formula 4A.

[0466] Clause 32. The compound as described in Clause 31, wherein R 4 It has formula 4A1 or formula 4A2: (4A1) or (4A2), in: r is 0, 1, or 2; and R 25 It is H or an optional substituted (C1-6) alkyl group.

[0467] Clause 33. The compound as described in Clause 30, wherein R 4 It has formula 4B.

[0468] Clause 34. The compound as described in Clause 33, wherein X 1 It is CH2.

[0469] Clause 35. The compound as described in Clause 30, wherein R 4 It has formula 4C or formula 4D.

[0470] Clause 36. The compound as described in Clause 35, wherein R 4 It has equation 4C, where u is 2.

[0471] Clause 37. The compound as described in Clause 30, wherein R 4 It has formula 4E: (4E).

[0472] Clause 38. The compound as described in Clause 37, wherein R 4 Choose from one of the following structures: , , , , , and .

[0473] Clause 39. The compound as described in Clause 38, wherein R 4 Choose from one of the following structures: , , , , and .

[0474] Clause 40. The compound as described in Clause 38 or 39, wherein R 25 It has the following structure: Where R 33 -R 37 Independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3 and halogens, and / or R 33 -R 37 Any two (e.g., R) 33 and R 34 and / or R 36 and R 37 They can be cyclically linked and together with the carbon atoms to which they are linked, provide C3-C7 carbon rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0475] Clause 41. The compound as described in Clause 30, wherein R 4 It has one of the following: Formula 4J-Formula 4L (4J) (4K) or (4L).

[0476] Clause 42. The compound as described in Clause 41, wherein X 5 It is CR 26 .

[0477] Clause 43. The compound as described in Clause 41, wherein X 5 It is N.

[0478] Clause 44. The compound as described in Clause 30, wherein R 4 It has a 4M designation: (4M).

[0479] Clause 45. The compound as described in Clause 44, wherein R 4 yes: or .

[0480] Clause 46. The compound as described in Clause 30, wherein R 4 Features 4G: (4G)

[0481] Clause 47. The compound as described in Clause 46, wherein X 8 It is N Clause 48. The compound as described in Clause 46, wherein X 8 It is CH.

[0482] Clause 49. The compound as described in Clause 30, wherein R 4 Having Equation 4I: . Clause 50. The compound as described in Clause 49, wherein R 23 Selected from optionally substituted heterocyclic groups, optionally substituted heteroaryl groups, and optionally substituted aryl groups.

[0483] Clause 51. The compound as described in Clause 50, wherein R 23 Selected from: (4E) (4F) (4J) (4K) (4L) and (4M), in: X 2 X 6 X 9 and X 10 Each independently selected from NR 25 C(R) 26 2. C = O, O, and S; X 3 X 4 X 5 and X 7 Each is independently selected from N and CR 26 ; Each R 18 -R 20 and R 24 It is independently selected from optional substituted alkyl, optional substituted amino, optional substituted alkoxy, hydroxy, carboxyl, halogen, optional substituted heterocyclic, optional substituted heteroaryl, optional substituted aryl, optional substituted cycloalkyl and optional substituents of CN; R 25 It is H or an optional substituted C1-6 alkyl group; Each R 26 Independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and CN; R 29 and R 30 Each is independently H or an optionally substituted (C1-6) alkyl group, or R 29 and R 30 Together with the carbon atoms they are attached to, they form spirocyclic groups with optional substitutions; v and y are each independently 0, 1, 2 or 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2.

[0484] Clause 52. The compound as described in Clause 51, wherein R 23 Having 4F (4F).

[0485] Clause 53. The compound as described in Clause 52, wherein R 23 Choose from one of the following structures: , , and .

[0486] Clause 54. The compound as described in Clause 30, wherein R 4 It has formula 4F: (4F).

[0487] Clause 55. The compound as described in Clause 54, wherein R 4 Choose from one of the following structures: , , and .

[0488] Clause 56. The compound as described in Clause 30, wherein R 4 It has the formula 4H: (4H).

[0489] Clause 57. The compound as described in Clause 56, wherein R 27 and R 28 Together with the nitrogen atoms to which they are linked, they are cyclically linked to provide optionally substituted piperidinyl groups.

[0490] Clause 58. The compound of any one of Clauses 1 to 57, wherein Z comprises a substantially biologically inert hydrophilic portion.

[0491] Clause 59. The compound of any one of Clauses 1 to 57, wherein Z comprises an electrophilic reactive moiety capable of covalently binding a biological target.

[0492] Clause 60. The compound of any one of Clauses 1 to 59, wherein Z comprises a group selected from sulfonyl, sulfone, sulfonamide, sulfonimide, sulfinimide, sulfonamide, sulfonate, formamide, carboxyl, hydroxyl, hydroxyalkyl, aldehyde, ester, alkoxy, nitrile, halogen, thiolactone and any combination thereof.

[0493] Clause 61. A compound as described in Clause 60, wherein Z is an alkylsulfonyl group, a cycloalkylsulfonyl group, an alkenylsulfonyl group, an alkynylsulfonyl group, or a heterocyclic sulfonyl group.

[0494] Clause 62. The compound as described in Clause 60, wherein Z is an alkyl sulfinimide, a cycloalkyl sulfinimide, a heterocyclic sulfinimide, a sulfonamide, or an alkyl sulfonamide.

[0495] Clause 63. The compound as described in any one of Clauses 1 to 62, wherein L 1 and L 2 Independently absent or arbitrarily substituted (C) 1-6 Alkylene (e.g., CH2, (CH2)2 or (CH2)3).

[0496] Clause 64. The compound as described in any one of Clauses 1 to 63, wherein -L 2 -Z or Z is one of Z1-Z6: (Z1) (Z2) (Z3) (Z4) (Z5) or (Z6), in: Y 9 It does not exist; it is -O- or -NR. 9 -、-(C 1-6 )alkylene-O-, -(C 1-6 )alkylene-NR 9 -; X 11 It is O or NH; R 51 Selected from halogens, R 8 -NR 9 R 10 ; R 9 It is H or optionally substituted (C) 1-6 )alkyl; R 10 It is H, or optional substitution (C) 1-6 )alkyl, optionally substituted (C 3-8 )cycloalkyl, optionally substituted heterocyclic, sulfone (e.g., SO2alkyl or SO2NHalkyl), or thiolactone; and R 52 It is H, or optional substitution (C) 1-6 Alkyl, optionally substituted aryl, or optionally substituted heterocyclic groups; R 8 Yes (C) 1-6 )alkyl (e.g., (C 3-6 )cycloalkyl), (C 2-6 )alkenyl, (C 2-6 ) alkynyl, cycloalkyl, heterocyclic or their substituted forms; m is 0, 1, or 2; and p, q, s, and t are independently 0, 1, 2, 3, 4, 5, or 6.

[0497] Clause 65. The compound as described in Clause 64, wherein -L 2 -Z or Z has the formula Z1 and has one of the following structures: (Z1A) (Z1B) or (Z1C), in: R 51 It is halogen; R 8 Yes (C) 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 ) alkynyl, cycloalkyl, heterocyclic or their substituted forms; R9 It is H or optionally substituted (C) 1-6 )alkyl; and R 10 It is H, or optional substitution (C) 1-6 )alkyl, optionally substituted (C 3-8 ) cycloalkyl or optionally substituted heterocyclic groups.

[0498] Clause 66. The compound as described in Clause 65, wherein -L 2 -Z or Z is And R 8 It is a (C1-C6) alkyl group.

[0499] Clause 67. The compound as described in Clause 66, wherein R 8 It is a methyl group.

[0500] Clause 68. The compound as described in Clause 65, wherein -L 2 -Z or Z is And R 8 It is a C2-C6 alkenyl group.

[0501] Clause 69. The compound as described in Clause 68, wherein R 8 It is -CH=CH2 or -C(CH3)=CH2.

[0502] Clause 70. The compound as described in Clause 65, wherein -L 2 -Z or Z is And R 8 It is a C2-C6 acetylene group.

[0503] Clause 71. The compound as described in Clause 70, wherein R 8 It is -CCH or -CC-CH3.

[0504] Clause 72. The compound as described in Clause 65, wherein -L 2 -Z or Z is And R 8 It is an optional substitution (C) 3-7 )cycloalkyl or optionally substituted (C 2-6 Heterocyclic group.

[0505] Clause 73. The compound as described in Clause 72, wherein R 8 Yes (C) 3-4 )cycloalkyl or (C 2-4 Heterocyclic group.

[0506] Clause 74. The compound as described in Clause 65, wherein -L 2 -Z or Z is R 9It is H, and R 10 It is H or optionally substituted (C) 1-6 )alkyl.

[0507] Clause 75. The compound as described in any one of Clauses 65-74, wherein X 11 It is O.

[0508] Clause 76. The compound as described in any one of Clauses 65-74, wherein X 11 It is NH.

[0509] Clause 77. The compound as described in Clause 65, wherein -L 2 -Z or Z has the following formula: , Where R 51 It is halogen.

[0510] Clause 78. The compound as described in Clause 64, wherein -L 2 -Z or Z has the formula Z4, where s is 0: (Z4A) in; R 9 It is H; and R 10 Yes - SO2R 38 ;and R 38 It can be an alkyl or amino group that is optionally substituted.

[0511] Clause 79. The compound as described in Clause 64, wherein -L 2 -Z or Z has the formula Z4, where s is 0: , in; R 9 It is H; and R 10 Yes - SO2R 38 , where R 38 It is an optionally substituted alkenyl group, or R 10 It is an optional substituted thiolactone.

[0512] Clause 80. The compound as described in Clause 79, wherein -L 2 -Z has the formula Z4C: (Z4C) Where m is 0, 1 or 2.

[0513] Clause 81. The compound as described in Clause 64, wherein -L 2 -Z or Z has the formula Z2: (Z2) Where m is 0, 1 or 2.

[0514] Clause 82. The compound as described in Clause 64, wherein -L 2 -Z or Z has the formula Z3: (Z3) in: R 52 It is an optionally substituted alkyl, optionally substituted aryl, or optionally substituted heterocyclic group; and t is 0, 1, or 2.

[0515] Clause 83. The compound as described in Clause 82, wherein R 52 yes: . Clause 84. The compound as described in Clause 64, wherein -L 2 -Z or Z has the formula Z3A, where t is 0. (Z3A) Where R 52 It is H.

[0516] Clause 85. The compound as described in Clause 64, wherein -L 2 -Z or Z has the formula Z5.

[0517] (Z5) Where q is 0, 1 or 2.

[0518] Clause 86. The compound as described in Clause 64, wherein -L 2 -Z or Z has the formula Z6, (Z6) Where p is 0, 1 or 2.

[0519] Clause 87. The compound as described in any one of Clauses 1 to 86, wherein R 5 Selected from H, CH3, CF3 and halogens.

[0520] Clause 88. The compound as described in Clause 87, wherein R 5 It is H.

[0521] Clause 89. The compound as described in any one of Clauses 1 to 88, wherein R 7 Selected from H, CH3, CF3 and halogens.

[0522] Clause 90. The compound as described in Clause 89, wherein R 7 It is H.

[0523] Clause 91. The compound as described in any one of Clauses 1 to 90, wherein R 1 Selected from H, CH3, CF3 and halogens.

[0524] Clause 92. The compound as described in Clause 91, wherein R 1 It is H.

[0525] Clause 93. The compound as described in any one of Clauses 1 to 92, wherein R 2 Selected from H, CH3, CF3, -CHF2, -CH2Cl, halogens, -C(=O)H and -(CH2). z OH, where z is 1, 2 or 3.

[0526] Clause 94. The compound as described in Clause 93, wherein R 2 It is H.

[0527] Clause 95. A compound as described in any one of Clauses 1 to 94, wherein the compound has any one of Formula 1A to Formula 1M: (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL) and (IM), Or it could be a pharmaceutically acceptable salt.

[0528] Clause 96. The compound as described in Clause 95, wherein R 3 It's CN.

[0529] Clause 97. The compound as described in Clause 95, wherein R 3 It is H.

[0530] Clause 98. The compound as described in any one of Clauses 95 to 97, wherein R 1 R 2 R 5 and R 7 Each is H.

[0531] Clause 99. The compound as described in any one of Clauses 95 to 98, wherein R 6 Selected from: (6C) (6D) (6E) (6F) 6G) (6H) and (6I), in: A is a cyclic group selected from carbocyclic, heterocyclic, aryl, heteroaryl and their substituted forms; R 8 It is an optional substitution (C) 1-6 )alkyl, optionally substituted (C 2-6 Alkenyl, optionally substituted cycloalkyl, or optionally substituted heterocyclic groups; R 9 It is H or optionally substituted (C) 1-6 )alkyl; R 10 It is a sulfone or a thiolactone; R 52 It is H, or optional substitution (C) 1-6 )alkyl or optionally substituted heterocyclic groups; R 55 It is H or optionally substituted (C) 1-6 )alkyl; and m is an integer between 0 and 2.

[0532] Clause 100. The compound as described in Clause 99, wherein R 6 It has the following formula: . Clause 101. The compound as described in Clause 99, wherein R 6 It has the following formula: . Clause 102. The compound as described in any one of Clauses 100 to 101, wherein: R 8 It is -CH3 or -CH2-R 13 ,and R 13 It is an optional substituted (C1-6) alkyl group.

[0533] Clause 103. The compound as described in any one of Clauses 100 to 101, wherein: R 8 It is -CH=CH2 or -CH=CH-R 14 ,and R 14 It is an optional substituted (C1-6) alkyl group.

[0534] Clause 104. The compound as described in any one of Clauses 100 to 101, wherein R 8 It is an optional substitution (C) 3-7 )cycloalkyl or optionally substituted (C 2-6 Heterocyclic group.

[0535] Clause 105. The compound as described in any one of Clauses 100 to 101, wherein R 8 Yes (C) 3-4 )cycloalkyl or (C 2-4 Heterocyclic group.

[0536] Clause 106. The compound as described in Clause 99, wherein R 6 It has the following formula: . Clause 107. The compound as described in Clause 99, wherein R 6 It has the following formula: . Clause 108. The compound as described in any one of Clauses 106 to 107, wherein R 9 It is H, and R 10 It is H or optionally substituted (C) 1-6 )alkyl.

[0537] Clause 109. The compound of any one of Clauses 99 to 108, wherein ring A is selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted 4-piperidinyl and optionally substituted cyclohexyl.

[0538] Clause 110. The compound as described in any one of Clauses 95 to 109, wherein: R 4 Choose any one of Equations 4A-4M: (4A) (4B) (4C) (4D) (4E) (4F) (4G) (4H) (4I) (4J) (4K) (4L) and (4M), in, X 1 It is O, CH2 or C(R) 26 )2; X 12 It is CH2, C(R) 15 )2, O, NCOR 25 or NR 25 ; X 14 It is O, NCOR 43 or NR 43 ; X 2 X 6 X 9 and X 10 Each independently selected from NR 25 C(R) 26 2. C = O, O, and S; X 3 X 4 X 5 X 7 and X 8 Each is independently selected from N and CR 26 ; Each R 15 -R 20 and R 24 It is independently selected from optional substituted alkyl, optional substituted amino, optional substituted alkoxy, hydroxy, carboxyl, halogen, optional substituted heterocyclic, optional substituted heteroaryl, optional substituted aryl, optional substituted cycloalkyl and optional substituents of CN; R 21 and R 22 Each is independently a C1-6 alkyl group with optional substitution; R 23 It is H, optionally substituted (C1-6) alkyl, optionally substituted cycloalkyl, optionally substituted cycloolefin, optionally substituted heterocyclic, optionally substituted heteroaryl or optionally substituted aryl; R 25 It is H or an optional substituted (C1-6) alkyl group; Each R 26Independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and nitriles; R 27 and R 28 Each is independently H or an optionally substituted (C1-6) alkyl group, or R 27 and R 28 Together with the nitrogen atoms they are attached to, they form optionally substituted cyclic groups; R 29 and R 30 Each is independently H or an optionally substituted (C1-6) alkyl group, or R 29 and R 30 Together with the carbon atoms they are attached to, they form spirocyclic groups with optional substitutions; k is 0, 1, 2, 3, 4, 5, 6, 7 or 8; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; r is 0 or 1; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; u is 0, 1, or 2; v and y are each independent integers from 0 to 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2; and R 6 Selected from: and , in: Y 11 Selected from O, S, CH2, CHR 11 C(R) 11 )2 and NR 9 ; R 9 It is H, or optional substitution (C) 1-6 )alkyl, -L 2 -Z or Z; Each R 11 Independently selected from -L 2 -Z, Z, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl carbonyloxy, hydroxyl, halogen and CN; k is 0 or 1; n is an integer from 0 to 9.

[0539] Y 6-Y 10 The groups are independently selected from CZ, CR 12 Or N, where Y 6 -Y 10 One of them is CZ; and Each R 12 Independently selected from H, optionally substituted alkyl groups, halogens, and CN.

[0540] Clause 111. The compound as described in Clause 110, wherein R 4 Selected from Table 1.

[0541] Clause 112. The compound as described in Clause 110, wherein R 6 Selected from Table 2.

[0542] Clause 113. The compound of any one of Clauses 95 to 112, wherein the compound has the formula (IA): (IA), Or it could be a pharmaceutically acceptable salt.

[0543] Clause 114. The compound as described in Clause 113, wherein the compound has Formula IV: (IV) Or its pharmaceutically acceptable salts, of which: Y 6 Y 7 Y 9 and Y 10 Independently selected from CR 12 and N, where Y 6 Y 7 Y 9 and Y 10 At least two of them are CR 12 ;and Each R 12 Independently selected from H, optionally substituted (C) 1-6 )alkyl, optionally substituted (C 1-6 Alkoxy, hydroxy, halogen, and CN.

[0544] Clause 115. The compound as described in Clause 114, wherein Y 6 Y 7 Y 9 and Y 10 Each is independently CH or CR 12 And the compound has formula V: (V) Or it could be a pharmaceutically acceptable salt. Where m is an integer from 0 to 4.

[0545] Clause 116. The compound as described in Clause 115, wherein the compound has the formula VIA: (VIA) Or it could be a pharmaceutically acceptable salt.

[0546] Clause 117. The compound as described in any one of Clauses 113 to 115, wherein Z is (Z1B) or (Z1C), in: R 8 Yes (C) 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 ) alkynyl, cycloalkyl, heterocyclic or their substituted forms; R 9 It is H or optionally substituted (C) 1-6 )alkyl; R 10 It is H, or optional substitution (C) 1-6 )alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclic groups; and X 11 It is O or NH.

[0547] Clause 118. A compound as described in Clause 116 or 117, wherein said compound has the formula (VIIA): (VIIA) Or its pharmaceutically acceptable salts, of which: R 25 It is an optionally substituted (C1-6) alkyl or an optionally substituted -C(=O)C1-6 alkyl; X 11 It is O or NH; R 41 It is R 8 or N(R) 9 )R 10 ; R 8 Yes (C) 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 ) alkynyl, cycloalkyl, heterocyclic or their substituted forms; R 9 It is H or optionally substituted (C) 1-6 )alkyl; and R 10It is H, or optional substitution (C) 1-6 Alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclic groups.

[0548] Clause 119. The compound as described in Clause 118, wherein the compound has the formula VIIIA: (VIIIA) Or its pharmaceutically acceptable salts, of which: R 25 It is an optional substituted (C1-6) alkyl group; R 18 It is H, halogen, optionally substituted (C1-6) alkyl, or optionally substituted (C1-6) alkoxy; and R 12 It is H, halogen, optionally substituted (C1-6) alkyl or optionally substituted (C1-6) alkoxy.

[0549] Clause 120. The compound as described in any one of Clauses 118 to 119, wherein R 25 Selected from methyl, ethyl, propyl, isopropyl, isobutyl, isopentyl and their substituted forms.

[0550] Clause 121. The compound as described in any one of Clauses 118 to 120, wherein R 25 It has the following structure: Where R 33 -R 37 Independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3 and halogens, and / or R 33 -R 37 Any two (e.g., R) 33 and R 34 and / or R 36 and R 37 They can be cyclically linked and together with the carbon atoms to which they are linked, provide C3-C7 carbon rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0551] Clause 122. The compound as described in Clause 121, wherein R 35 It is OH.

[0552] Clause 123. The compound as described in Clause 122, wherein R 25 yes: or .

[0553] Clause 124. The compound as described in any one of Clauses 118 to 123, wherein R41 It is R 8 .

[0554] Clause 125. The compound as described in Clause 124, wherein R 8 Yes (C) 1-6 )alkyl.

[0555] Clause 126. The compound as described in Clause 124, wherein R 8 It is an optional substitution (C) 3-7 )cycloalkyl or optionally substituted (C 2-6 Heterocyclic group.

[0556] Clause 127. The compound as described in Clause 126, wherein R 8 Yes (C) 3-4 )cycloalkyl or (C 2-4 Heterocyclic group.

[0557] Clause 128. The compound as described in any one of Clauses 118 to 123, wherein R 41 It is N(R) 9 )R 10 .

[0558] Clause 129. The compound as described in Clause 128, wherein R 41 It is an NH2 or -NH(C1-6) alkyl group. Clause 130. The compound as described in any one of Clauses 117 to 129, wherein X 11 It is O.

[0559] Clause 131. The compound as described in any one of Clauses 117 to 129, wherein X 11 It is NH.

[0560] Clause 132. The compound as described in Clause 115, wherein said compound has the formula VIB: (VIB) Or its pharmaceutically acceptable salt, where m is an integer from 0 to 4.

[0561] Clause 133. The compound as described in Clause 132, wherein the compound has the formula VIIB: (VIIB) Or its pharmaceutically acceptable salts, of which: Each R 24 It is independently selected from optional alkyl, optional amino, optional alkoxy, hydroxy, carboxyl, halogen, optional heterocyclic, optional heteroaryl, optional aryl, optional cycloalkyl and optional substituents of nitriles; R 25 It is H or an optional substituted (C1-6) alkyl group; R 29 and R 30 Each is independently H or an optionally substituted (C1-6) alkyl group, or R 29 and R 30 Together with the carbon atoms to which they are attached, they form optionally substituted spirocyclic groups; and y is 0, 1, 2 or 3.

[0562] Clause 134. The compound as described in Clause 133, wherein the compound has the formula VIIIB: (VIIIB) Or it could be a pharmaceutically acceptable salt.

[0563] Clause 135. The compound as described in Clause 133 or 134, wherein the compound has the formula IX: (IX) Or it could be a pharmaceutically acceptable salt.

[0564] Clause 136. The compound as described in any one of Clauses 133 to 135, wherein R 12 It is H, halogen, optionally substituted (C1-6) alkyl or optionally substituted (C1-6) alkoxy.

[0565] Clause 137. The compound as described in Clause 136, wherein R 12 It is H.

[0566] Clause 138. The compound as described in Clause 136, wherein R 12 It is a (C1-6) alkyl group.

[0567] Clause 139. The compound as described in Clause 138, wherein R 12 It is a methyl group.

[0568] Clause 140. The compound as described in Clause 136, wherein R 12 It is halogen.

[0569] Clause 141. The compound as described in Clause 136, wherein R 12 It is a (C1-6)alkoxy group.

[0570] Clause 142. The compound as described in Clause 141, wherein R 12 It is a methoxy group.

[0571] Clause 143. The compound as described in any one of Clauses 133 to 142, wherein R29 and R 30 Each is independently an optional substituted (C1-6) alkyl group.

[0572] Clause 144. The compound as described in Clause 143, wherein R 29 and R 30 Each is independently an (C1-3) alkyl group.

[0573] Clause 145. The compound as described in Clause 144, wherein R 29 and R 30 Each is a methyl group.

[0574] Clause 146. The compound as described in Clause 144, wherein R 29 and R 30 Each is an ethyl group.

[0575] Clause 147. The compound as described in any one of Clauses 133 to 142, wherein R 29 and R 30 Together with the carbon atoms they are attached to, they form spirocyclic groups with optional substitutions.

[0576] Clause 148. The compound as described in Clause 147, wherein the optionally substituted spirocyclic group is spiropropyl or spirobutyl.

[0577] Clause 149. The compound as described in any one of Clauses 133 to 148, wherein R 41 It is R 8 .

[0578] Clause 150. The compound as described in Clause 149, wherein R 8 Yes (C) 1-6 )alkyl.

[0579] Clause 151. The compound as described in Clause 149, wherein R 8 It is an optional substitution (C) 3-7 )cycloalkyl or optionally substituted (C 2-6 Heterocyclic group.

[0580] Clause 152. The compound as described in Clause 151, wherein R 8 Yes (C) 3-4 )cycloalkyl or (C 2-4 Heterocyclic group.

[0581] Clause 153. The compound as described in any one of Clauses 133 to 148, wherein R 41 It is N(R) 9 )R 10 .

[0582] Clause 154. The compound as described in Clause 153, wherein R 41 It is an NH2 or NH-(C1-6) alkyl group.

[0583] Clause 155. The compound as described in any one of Clauses 133 to 154, wherein X 11 It is O.

[0584] Clause 156. The compound as described in any one of Clauses 133 to 154, wherein X 11 It is NH.

[0585] Clause 157. A compound as described in Clause 113, wherein said compound has the formula X: (X) Or its pharmaceutically acceptable salts, of which: Each R 11 Independently selected from optionally substituted alkyl groups, optionally substituted alkoxy groups, halogens, OH, and CN; and n is an integer from 0 to 9.

[0586] Clause 158. The compound as described in Clause 157, wherein R 4 Selected from: (4I) (4D) (4I) and (4H), in: X 2 X 9 and X 10 Each independently selected from NR 25 C(R) 26 2. C = O, O, and S; X 3 and X 4 Each is independently selected from N and CR 26 ; X 12 It is CH2, CHR 42 C(R) 42 2. NCOR 43 or NR 43 ; Each R 15 R 18 and R 24 It is independently selected from optional alkyl, optional amino, optional alkoxy, hydroxy, carboxyl, halogen, optional heterocyclic, optional heteroaryl, optional aryl, optional cycloalkyl and optional substituents of nitriles; R23 It is H, optionally substituted (C1-6) alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted heteroaryl or optionally substituted aryl; Each R 26 Independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and nitriles; R 29 and R 30 Each is independently H or an optionally substituted (C1-6) alkyl group, or R 29 and R 30 Together with the carbon atoms to which they are attached, they form optionally substituted spirocyclic groups (e.g., optionally substituted spiropropyl or spirobutyl). R 42 It is H, optionally substituted (C1-6) alkyl, optionally substituted acyl, optionally substituted formamide, optionally substituted cycloalkyl, optionally substituted cycloolefin, optionally substituted heterocyclic, optionally substituted heteroaryl or optionally substituted aryl; R 43 It is H, optionally substituted (C1-6) alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloolefin, optionally substituted heterocyclic, optionally substituted heteroaryl or optionally substituted aryl; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. r is 0 or 1; and v and y are each an independent integer from 0 to 3.

[0587] Clause 159. A compound as described in Clause 157 or 158, wherein said compound has the formula XI: (XI) Or it could be a pharmaceutically acceptable salt.

[0588] Clause 160. The compound as described in Clause 159, wherein: X 12 It is CHR 42 ;and R 42 It is selected from H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted formamide, optionally substituted cycloalkyl, optionally substituted cycloolefin, optionally substituted heterocyclic, optionally substituted heteroaryl, and optionally substituted aryl.

[0589] Clause 161. The compound as described in Clause 160, wherein: R 42It is -C(=O)R 42a -C(=O)NHR 42a -NHC(=O)R 42a , where R 42a It is H, optionally substituted (C1-6) alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted heteroaryl or optionally substituted aryl; R 42 It is an optionally substituted (C1-6) alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted heteroaryl, or optionally substituted aryl; or R 42 It is an optional substitution of -(CH2). z Cycloalkyl, optionally substituted -(CH2) z Heterocyclic, optionally substituted -(CH2) z Heteroaryl or optionally substituted -(CH2) z Aryl, where z is 1, 2, 3, 4 or 5.

[0590] Clause 162. The compound as described in Clause 159, wherein: X 12 It is NR 43 ;and R 43 It is selected from H, optionally substituted (C1-6) alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloolefin, optionally substituted heterocyclic, optionally substituted heteroaryl and optionally substituted aryl.

[0591] Clause 163. The compound as described in Clause 161, wherein: R 43 It is an optional substituted -C(=O)C1-6 alkyl, an optional substituted -C(=O)cycloalkyl, an optional substituted -C(=O) heterocyclic, an optional substituted -C(=O) heteroaryl or an optional substituted -C(=O) aryl; R 43 It is an optionally substituted (C1-6) alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted heteroaryl, or optionally substituted aryl; or R 43 It is an optional substitution of -(CH2). z Cycloalkyl, optionally substituted -(CH2) z Heterocyclic, optionally substituted -(CH2) z Heteroaryl or optionally substituted -(CH2) z Aryl, where z is 1, 2, 3, 4 or 5.

[0592] Clause 164. The compound of any one of Clauses 157 to 163, wherein Z has the following formula: (Z1B) or (Z1C), Where: R 8 Yes (C) 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 ) alkynyl, cycloalkyl, heterocyclic, or their substituted forms; R 9 It is H or optionally substituted (C) 1-6 )alkyl; R 10 It is H, or optional substitution (C) 1-6 ) alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclic group; and X 11 It is O or NH.

[0593] Clause 165. A compound as described in any one of Clauses 1-164, wherein the compound is selected from any one of Compound 1-965 and the compounds in Tables 3-15 (e.g., as described in the Experimental Section) or pharmaceutically acceptable salts thereof.

[0594] Clause 166. A pharmaceutical composition comprising a compound as described in any one of Clauses 1 to 165 and a pharmaceutically acceptable excipient.

[0595] Clause 167. A method for inhibiting cyclin-dependent kinase (CDK), the method comprising contacting a biological sample containing CDK with an amount of a compound as described in any one of Clauses 1 to 165 that effectively inhibits said CDK.

[0596] Clause 168. A method of inhibiting CDK in a subject, the method comprising administering to the subject a compound as described in any one of Clauses 1 to 165 or a pharmaceutical composition as described in Clause 166 to inhibit CDK in the subject.

[0597] Clause 169. The method described in Clause 167 or 168, wherein the CDK is CDK2.

[0598] Clause 170. The method as described in Clause 167 or 168, wherein the CDK is CDK4.

[0599] Clause 171. A method of treating a subject for a CDK2-related disease or condition, the method comprising administering to the subject in need a dose of a compound as described in any one of Clauses 1 to 165 or a pharmaceutical composition as described in Clause 166.

[0600] Clause 172. As described in Clause 171, the disease or condition associated with CDK2 is cancer.

[0601] 5. Examples The following embodiments are provided to provide those skilled in the art with a complete disclosure and description of how to prepare and use this disclosure, and are not intended to limit the scope of the disclosure as the inventors believe it to be, nor are they intended to represent all or only experiments conducted. Efforts have been made to ensure the accuracy of figures used (e.g., amounts, temperatures, etc.), but some experimental errors and biases should be taken into account. Unless otherwise stated, parts are parts by weight, molecular weight is weight-average molecular weight, temperature is degrees Celsius, and pressure is atmospheric pressure or close to atmospheric pressure.

[0602] General methods in molecular and cellular biochemistry can be found in standard textbooks such as: Molecular Cloning: A Laboratory Manual, 3rd edition (Sambrook et al., HaRBor Laboratory Press 2001); Short Protocols in Molecular Biology, 4th edition (Ausubel et al., John Wiley & Sons 1999); Protein Methods (Bollag et al., John Wiley & Sons 1996); Nonviral Vectors for Gene Therapy (Wagner et al., Academic Press 1999); Viral Vectors (Kaplift and Loewy, Academic Press 1995); Immunology Methods Manual (I. Lefkovits, Academic Press 1997); and Cell and Tissue Culture: Laboratory Procedures in Biotechnology (Doyle and Griffiths, John Wiley & Sons 1998), the contents of which are incorporated herein by reference. Reagents, cloning vectors, cells, and kits used in the methods mentioned or related to this disclosure are available from commercial suppliers such as BioRad, Agilent Technologies, ThermoFisher Scientific, Sigma-Aldrich, New England Biolabs (NEB), Takara Bio USA, Inc., and repositories such as Addgene, Inc., and the American Type Culture Collection (ATCC).

[0603] CDK2 assay The potency of the compounds described herein was evaluated using CDK homogeneous time-resolved fluorescence (HTRF) assay.

[0604] Add 100 nL of 100x DMSO solution of the test compound and 5 μL of 2x CDK enzyme in assay buffer (50 mM HEPES, 1 mM EGTA, 10 mM MgCl2, 0.01% Tween 20, 2 mM DTT) to an untreated 384-well ProxiPlate. Centrifuge the plate at 800 RPM for 1 min and incubate at 23 °C for 20 min. Add 2.5 μL / well 4x ATP and 2.5 μL / well 4x ULight™-eIF4E binding protein 1 (Thr37 / 46) peptide substrate to all wells. After addition, centrifuge the plate at 800 RPM for 1 min. Incubate the plate at 23 °C for 60 min. Add 5 μL / well 4x EDTA solution to each well to terminate the reaction. Add 5 μL of 4x LANCE Ultra europium-antiphosphorylated eIF4E-binding protein 1 (Thr37 / 46) antibody to each well, and centrifuge the plate at 800 RPM for 1 min. Incubate the plate at 23 °C for 60 min. Read the fluorescence at 340 nm excitation and 665 nm emission using an EnVision 2105 fluorescence reader. The final concentrations of reagents for the activity assay were 3 nM CDK2 / CCNE1, 1 mM ATP, 50 nM ULight™-eIF4E-binding protein 1 (Thr37 / 46) peptide substrate, 1% DMSO, 10 mM EDTA, and 2 nM LANCE Ultra europium-antiphosphorylated eIF4E-binding protein 1 (Thr37 / 46).

[0605] Dosage-response titrations were performed using an 11-point, semi-logarithmic serial dilution protocol, typically starting at 10 μM. The signal was reported as fluorescence units at 665 nm or the ratio of fluorescence units at 665 nm to fluorescence units at 615 nm. This signal is referred to below as the "Lance signal". Compound potency was determined first by calculating the percentage of inhibition at each compound concentration using the following formula: Inhibition % = (Lance signal - Lance signal value of DMSO control - Lance signal value of sample) 100 / (Lance DMSO control - background Lance signal value), where the Lance signal of the DMSO control represents the average of 8-16 replicates, the Lance signal value of the sample represents the average of 2 replicates, and the Lance signal of the background represents the average of 8-16 replicates.

[0606] CDK1 assay The potency of the compounds described herein was evaluated using CDK homogeneous time-resolved fluorescence (HTRF) assay.

[0607] Add 100 nL of 100x DMSO solution of the test compound and 5 μL of 2x CDK enzyme in assay buffer (50 mM HEPES, 1 mM EGTA, 10 mM MgCl2, 0.01% Tween 20, 2 mM DTT) to an untreated 384-well ProxiPlate. Centrifuge the plate at 800 RPM for 1 min and incubate at 23 °C for 20 min. Add 2.5 μL / well 4x ATP and 2.5 μL / well 4x ULight™-eIF4E binding protein 1 (Thr37 / 46) peptide substrate to all wells. After addition, centrifuge the plate at 800 RPM for 1 min. Incubate the plate at 23 °C for 60 min. Add 5 μL / well 4x EDTA solution to each well to terminate the reaction. Add 5 μL of 4x LANCE Ultra europium-antiphosphorylated eIF4E-binding protein 1 (Thr37 / 46) antibody to each well, and centrifuge the plate at 800 RPM for 1 min. Incubate the plate at 23 °C for 60 min. Read the fluorescence at 340 nm excitation and 665 nm emission using an EnVision 2105 fluorescence reader. The final concentrations of reagents for the activity assay were 0.5 nM CDK1 / CCNB1, 1 mM ATP, 50 nM Light™-eIF4E-binding protein 1 (Thr37 / 46) peptide substrate, 1% DMSO, 10 mM EDTA, and 2 nM LANCE Ultra europium-antiphosphorylated eIF4E-binding protein 1 (Thr37 / 46).

[0608] Dosage-response titrations were performed using an 11-point, semi-logarithmic serial dilution protocol, typically starting at 10 μM. The signal was reported as fluorescence units at 665 nm or the ratio of fluorescence units at 665 nm to fluorescence units at 615 nm. This signal is referred to below as the "Lance signal". Compound potency was determined first by calculating the percentage of inhibition at each compound concentration using the following formula: Inhibition % = (Lance signal - Lance signal value of DMSO control - Lance signal value of sample) 100 / (Lance DMSO control - background Lance signal value), where the Lance signal of the DMSO control represents the average of 8-16 replicates, the Lance signal value of the sample represents the average of 2 replicates, and the Lance signal of the background represents the average of 8-16 replicates.

[0609] CDK4 assay The potency of the compounds described herein was evaluated using CDK homogeneous time-resolved fluorescence (HTRF) assay.

[0610] Add 100 nL of 100x DMSO solution of the test compound and 5 μL of 2x CDK enzyme in assay buffer (50 mM HEPES, 1 mM EGTA, 10 mM MgCl2, 0.01% Tween 20, 2 mM DTT) to an untreated 384-well ProxiPlate. Centrifuge the plate at 800 RPM for 1 min and incubate at 23 °C for 20 min. Add 2.5 μL / well 4x ATP and 2.5 μL / well 4x ULight™-eIF4E binding protein 1 (Thr37 / 46) peptide substrate to all wells. After addition, centrifuge the plate at 800 RPM for 1 min. Incubate the plate at 23 °C for 60 min. Add 5 μL / well 4x EDTA solution to each well to terminate the reaction. Add 5 μL of 4x LANCE Ultra europium-antiphosphorylated eIF4E-binding protein 1 (Thr37 / 46) antibody to each well, and centrifuge the plate at 800 RPM for 1 min. Incubate the plate at 23 °C for 60 min. Read the fluorescence at 340 nm excitation and 665 nm emission on an EnVision 2105 fluorescence reader. The final concentrations of reagents for the activity assay were 1.5 nM CDK4 / CCND3, 1 mM ATP, 50 nM Light™-eIF4E-binding protein 1 (Thr37 / 46) peptide substrate, 1% DMSO, 10 mM EDTA, and 2 nM LANCE Ultra europium-antiphosphorylated eIF4E-binding protein 1 (Thr37 / 46).

[0611] Dosage-response titrations were performed using an 11-point, semi-logarithmic serial dilution protocol, typically starting at 10 μM. The signal was reported as fluorescence units at 665 nm or the ratio of fluorescence units at 665 nm to fluorescence units at 615 nm. This signal is referred to below as the "Lance signal". Compound potency was determined first by calculating the percentage of inhibition at each compound concentration using the following formula: Inhibition % = (Lance signal - Lance signal value of DMSO control - Lance signal value of sample) 100 / (Lance DMSO control - background Lance signal value), where the Lance signal of the DMSO control represents the average of 8-16 replicates, the Lance signal value of the sample represents the average of 2 replicates, and the Lance signal of the background represents the average of 8-16 replicates.

[0612] CDK6 assay The potency of the compounds described herein was evaluated using CDK homogeneous time-resolved fluorescence (HTRF) assay.

[0613] Add 100 nL of 100x DMSO solution of the test compound and 5 μL of 2x CDK enzyme in assay buffer (50 mM HEPES, 1 mM EGTA, 10 mM MgCl2, 0.01% Tween 20, 2 mM DTT) to an untreated 384-well ProxiPlate. Centrifuge the plate at 800 RPM for 1 min and incubate at 23 °C for 20 min. Add 2.5 μL / well 4x ATP and 2.5 μL / well 4x ULight™-eIF4E binding protein 1 (Thr37 / 46) peptide substrate to all wells. After addition, centrifuge the plate at 800 RPM for 1 min. Incubate the plate at 23 °C for 60 min. Add 5 μL / well 4x EDTA solution to each well to terminate the reaction. Add 5 μL of 4x LANCE Ultra europium-antiphosphorylated eIF4E-binding protein 1 (Thr37 / 46) antibody to each well, and centrifuge the plate at 800 RPM for 1 min. Incubate the plate at 23 °C for 60 min. Read the fluorescence at 340 nm excitation and 665 nm emission using an EnVision 2105 fluorescence reader. The final concentrations of reagents for the activity assay were 1 nM CDK6 / CCND1, 1 mM ATP, 50 nM ULight™-eIF4E-binding protein 1 (Thr37 / 46) peptide substrate, 1% DMSO, 10 mM EDTA, and 2 nM LANCE Ultra europium-antiphosphorylated eIF4E-binding protein 1 (Thr37 / 46).

[0614] Dosage-response titrations were performed using an 11-point, semi-logarithmic serial dilution protocol, typically starting at 10 μM. The signal was reported as fluorescence units at 665 nm or the ratio of fluorescence units at 665 nm to fluorescence units at 615 nm. This signal is referred to below as the "Lance signal". Compound potency was determined first by calculating the percentage of inhibition at each compound concentration using the following formula: Inhibition % = (Lance signal - Lance signal value of DMSO control - Lance signal value of sample) 100 / (Lance DMSO control - background Lance signal value), where the Lance signal of the DMSO control represents the average of 8-16 replicates, the Lance signal value of the sample represents the average of 2 replicates, and the Lance signal of the background represents the average of 8-16 replicates.

[0615] Using this assay, the IC50 of the example compounds was determined. 50 Values. Table 3 shows the IC values ​​of various formula IA example compounds. 50 Table 4 shows the IC values ​​of various other Formula I example compounds. 50 ND = Not determined.

[0616] Table 3: IC50 of the compounds in the examples of Formula IA 50 .

[0617] Table 4: IC50 values ​​of other Formula I compounds 50 .

[0618] Preparation method Synthetic schemes for preparing the intermediates and compounds of this disclosure are described below. The illustrative schemes described are not intended to limit the methods that can be used to prepare the compounds or to imply a specific order of steps required, nor are any of the R groups intended to limit any of the claims described herein. Unless otherwise stated, the compounds are prepared as racemic mixtures. Chiral pure substances can be obtained by chiral preparative HPLC separation of the racemic mixture, chiral SFC separation, or by using chiral pure starting materials.

[0619] Scheme 1 illustrates a method for obtaining compounds of the type exemplified by 1-8. The formation of the naphthidine core (1-5) can be obtained from carboxylic acid 1-1 via four steps. Methyl ester 1-2 can be treated with a suitable boric acid or borate ester to generate 1-3. Following the esterification to an amide (1-4), acid-mediated cyclization provides compounds similar to 1-5. Activation of 1-5 can be carried out using PyBOP, followed by coupling with a suitable amine to generate compounds characterized as 1-7. This two-step sequence can be carried out by other methods known to those skilled in the art. Additional Pd-mediated coupling reactions can provide compounds similar to 1-8. Further modification of the R group can be performed using methods known to those skilled in the art to generate additional 1-8 analogs.

[0620] Option 1 Scheme 2 provides an alternative sequence for introducing peripheral groups. Pd-mediated coupling at 1-5 provides intermediates similar to 2-9. Conversion to trifluoromethanesulfonate 2-10 offers the opportunity to generate compounds similar to 2-11. Those skilled in the art will recognize alternatives to trifluoromethanesulfonate esters as coupling partners. Using R... 4 -X is a potential coupling partner. Using amine coupling partners would represent an alternative method for obtaining the compounds illustrated by 1-8.

[0621] Option 2 Scheme 3 illustrates a method for alkylating 1-5 to produce intermediates 3-12. Pd-mediated coupling reactions with amines can produce compounds similar to 3-13.

[0622] Option 3 Scheme 4 illustrates another synthesis capable of obtaining a core with additional substitution sites. Starting from 1-2, coupling of Sonogashira followed by conversion to an amide yields intermediates such as 4-15. Base-mediated cyclization produces compounds similar to 4-16, which can be further modified using methods described in other schemes.

[0623] Option 4 Scheme 5 illustrates a potential synthetic route for introducing an alkyne moiety onto a naphthidine core. Starting with 4-16, an aryl or heteroaryl amine can be introduced using Buchwald-Hartwig coupling. This reaction can also be carried out on non-aromatic amines. After conversion to trifluoromethanesulfonate 5-18, a shaving reaction with an alkyne can be performed under standard conditions to produce 5-19. Besides trifluoromethanesulfonate, this reaction can also be carried out with appropriately substituted halogens. A second shaving reaction can be performed to produce an adduct similar to 5-20. Although the listed conditions involve in-situ deprotection of the alkyne, this can also be accomplished in two steps. Alternative metals to palladium, such as nickel, can also be used.

[0624] Option 5 Scheme 6 details an alternative route to obtain a final compound similar to 5-20. In this scheme, 4-16 can be initially converted to trifluoromethanesulfonate 6-21, followed by splinter coupling to obtain 6-22. The trifluoromethanesulfonate can also be halogenated. In-situ deprotection followed by a second splinter reaction yields a compound similar to 6-23. Similar to Scheme 5, deprotection can occur in situ or as a separate synthetic step. To obtain compounds like 5-20, aryl amines as shown can be introduced using Buchwald-Hartwig coupling. Heteroaryl, alkyl, and cycloalkylamines can also be coupled in this manner or via relevant reactions known to those skilled in the art. Further substitution of the aryl group can occur after isolating compounds like 5-20.

[0625] Option 6 While schemes 5 and 6 detail methods for introducing alkynes through several steps, scheme 7 provides a convergent method for obtaining compounds similar to 7-25. Compounds similar to 5-18 and 7-24 can undergo stalk coupling to introduce a more fully functionalized alkyne in a single step. In some cases, the synthesis of alkynes may require several steps, and additional deprotection steps may be necessary after stalk coupling to obtain the final product.

[0626] Option 7 Indazole-containing analogs similar to 8-29 and 8-30 can be prepared by several different methods described in the following schemes. In Scheme 8, the ring-opening of the epoxy in 8-26 results in two isomers of 8-27. Although the illustration uses epoxides as electrophiles, alkyl halides are also suitable coupling partners in this transformation. The halogen in 8-27, after conversion to a borate ester or boric acid, can be coupled with 5-18 via Suzuki coupling to produce compounds similar to 8-29 and 8-30. The regioisomers can be separated individually using chiral separation methods such as chiral SFC or chiral HPLC.

[0627] Option 8 Alternative methods for introducing indazole are shown in Scheme 9. Indazole borate esters can be coupled with 7-24 under Suzuki conditions to produce 9-31. Ring-opening of the epoxide under basic conditions yields 8-29 and 8-30. Chiral purification is required to obtain the various regioisomers. Although the illustration uses the epoxide as the electrophile, any alkyl halide can be used as the electrophile in this scheme.

[0628] Option 9 Following the route outlined in Scheme 10 avoids the separation of indazole regioisomers. The substituted hydrazine is then reacted with a mixture similar to 10⁻³². adjacent Fluorobenzaldehyde undergoes an addition reaction to produce regioisomeric indazoles, such as 10-33. Although the example shows a tertiary alcohol, any alkyl hydrazine is applicable. Reduction of the nitro group leads to 10-34, which can be further converted to produce the borate ester exemplified by 10-35. Coupling with the naphthidine core shown or with the suzu core of 7-24 produces the penultimate compound in the sequence. Buchwald-Hartwig coupling with aniline produces the final compound exemplified by 8-29. Besides arylamines, heteroaryl, alkyl, cycloalkyl, and heterocyclic amines all play a role in the coupling reaction.

[0629] Option 10 Schemes 11 through 16 detail the synthesis of alternative cores for naphthidine. Heck coupling of 1-2, followed by base treatment to initiate cyclization, provides cores 11-38. For compounds exemplified by 11-39, amines can be introduced using Buchwald-Hartwig coupling. This is first converted to a trifluoromethanesulfonate, followed by another palladium-mediated coupling to introduce a group such as an alkyne, indazole, or other group, yielding compounds exemplified by 11-41. Initial hydrolysis of methyl esters 11-41, followed by conversion to amides 11-43, results in the conversion to cyano compounds exemplified by 11-44. Dehydration with a reagent such as Burgess reagent forms cyano compounds 11-44.

[0630] Option 11 Scheme 12 can be initiated by substituting the chlorine of 12-45 with an amine to produce 12-46. Palladium-mediated cyanation followed by trifluoromethanesulfonation yields 12-48. Various palladium couplings can introduce R1 to produce analogs similar to 12-49.

[0631] Option 12 Scheme 13 can begin with the oxidation of thioethers to sulfones 13-51. Amine coupling can occur under basic conditions to produce compounds represented by 13-52. Various palladium-mediated reactions can be used to introduce additional functional groups and produce compounds such as those exemplified by 13-53.

[0632] Option 13 The synthesis of the compounds exemplified by 14-57 is highlighted in Scheme 14. After conversion to chlorides 14-55, various functional groups can be introduced into R1 via palladium-mediated coupling. Subsequent Buchwald-Hartwig coupling can introduce amines and complete the synthesis.

[0633] Option 14 The core exemplified in Scheme 15 can be obtained using the following steps: First, Buchwald-Hartwig coupling is performed to produce a compound such as 15-59. After conversion to trifluoromethanesulfonate 15-60, palladium-mediated coupling can introduce other functional groups to produce a compound similar to 15-61.

[0634] Option 15 Scheme 16 describes a two-step method for obtaining the compounds exemplified by 16-63. The introduction of an amine can occur via acid-mediated substitution to produce 16-62. Various functional groups can be introduced via palladium-mediated reactions to produce the final compounds.

[0635] Option 16 In the examples listed herein, analytical LCMS injection is used to assist in the characterization of intermediates. The instruments used and the methods employed are as follows: Instrument names: Shimadzu LC2020 Nexera series; Shimadzu MS2020 N series; Agilent 1290; Agilent 1260 and 6125B.

[0636] Method A Mobile phase: A: 0.1% HCOOH aqueous solution, B: ACN; Column: ZORBAX ECLIPSE PLUS C18 (50mm × 2.1mm), 1.8mm.

[0637] Method B Mobile phase: A: 10mM NH4HCO3 aqueous solution, B: ACN; Column: Phenomenex Kinetex EVO C18 (50mm×3.0mm), 2.5mm.

[0638] Method C Mobile phase: A: 0.1% TFA aqueous solution, B: ACN; Column: XBRIGDE C8 (4.6mm × 50mm), 3.5μm.

[0639] Method D Mobile phase: A: 10mM NH4HCO3 aqueous solution, B: ACN; Column: Phenomenex Kinetex EVOC18 (3.0mm×50mm), 2.6μm.

[0640] Method E Mobile phase: A: 10mM NH4HCO3 aqueous solution, B: ACN; Column: Xbridge C18 (2.1mm×50mm), 5μm.

[0641] Method F Mobile phase: A: 0.04% TFA aqueous solution, B: 0.02% TFA in ACN solution; Column: Luna-C18(2) (2.0mm×50mm), 5μm.

[0642] Purification of intermediates and final compounds can be accomplished using normal-phase or reversed-phase chromatography. Conditions for normal-phase chromatography are listed in the experimental section. The methods and instruments used for preparative HPLC purification are shown below: Instrument Name: Shimadzu LC; Prominence-I series instruments, such as those used for monitoring with % and UV detection (Maxplot).

[0643] Method A Mobile phase: A-0.1% formic acid aqueous solution, B: ACN; Flow rate: 2.0 mL / min; Column: X-Select CSHC18 (4.6 mm × 150 mm, 5 μm).

[0644] Method B Mobile phase: A-10mM ammonium bicarbonate aqueous solution, B: ACN; Flow rate: 2.0mL / min; Column: X-Bridge C8 (4.6mm×150mm, 5μm).

[0645] Method C Mobile phase: A - 0.1% TFA aqueous solution, B - ACN; Column: Phenomenex Luna C18 (75mm × 30mm, 3μm; flow rate: 25.0mL / min) (100mm × 40mm, 3μm; flow rate: 25.0mL / min) (150mm × 25mm, 10μm; flow rate: 60.0mL / min) (250mm × 150mm, 15μm; flow rate: 60.0mL / min).

[0646] Method D Mobile phase: A - 10mM ammonium bicarbonate aqueous solution, B - ACN; Flow rate: 60mL / min; Column: Welch Ultimate C18 (180mm×70mm, 10μm) Method E Mobile phase: A - 10mM ammonium bicarbonate aqueous solution, B - ACN; Column: Waters Xbridge BEH C18 (100mm×25mm, 10μm; flow rate: 25.0mL / min) (100mm×30mm, 10μm; flow rate: 25.0mL / min) (250mm×50mm, 10μm; flow rate: 60.0mL / min) (250mm×70mm, 10μm; flow rate: 60.0mL / min).

[0647] NMR data were acquired using a Bruker Avance Neo Nano Bay 400MHz NMR spectrometer. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (DMSO). δ 2.50), methanol ( δ3.31), chloroform ( δ 7.26) or other solvents indicated in the NMR spectral data. Dissolve a small amount (1 mg-5 mg) of the sample in a suitable deuterated solvent (0.6 mL).

[0648] The final compound characterization and purity were evaluated and determined using orthogonal HPLC analysis, LCMS, and NMR.

[0649] Example 1: 1-(7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthidin-1-yl)piperidin-4-ol (1) 1A: Methyl 5-bromo-2-chloroisonicotinic acid: SOCl2 (30.9 mL, 423 mmol) was added to a solution of 5-bromo-2-chloroisonicotinic acid (100 g, 423 mmol) in MeOH (400 mL) at 0 °C under a nitrogen atmosphere, and the reaction mixture was stirred at 60 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was... In a vacuum Concentrate to obtain a crude substance that is a colorless liquid. Dilute the crude product with water, alkalize with a 10% NaHCO3 aqueous solution, and extract with EtOAc (3 × 500 mL). Wash the combined organic layers with water (300 mL), dry with Na2SO4, filter, and... In a vacuum Concentration. The crude product (130 g) was purified by Biotage Isolera (60-120 silica gel, using a 10% EtOAc hexane solution as the eluent) to obtain the desired product, methyl 5-bromo-2-chloroisonicotinic acid (100 g, 94% yield), as a colorless liquid.

[0650] 1 H-NMR (400 MHz, CDCl3): δ 8.65 (s, 1H), 7.69 (s, 1H), 4.00 (s, 3H). LCMS: RT: 2.30min, m / z: 250.0 (M+H) + 1B: ( E 2-Chloro-5-(2-ethoxyvinyl)isonicotinic acid methyl ester: methyl 5-bromo-2-chloroisonicotinic acid (100g, 399mmol) was loaded into a 5-liter pressure reactor. E2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (95 g, 479 mmol) and Cs₂CO₃ (390 g, 120 mmol) were added, followed by the addition of 1,4-dioxane (1800 mL) and water (200 mL). The reaction mixture was degassed for 10 min, after which PdCl₂ (dppf) (14.6 g, 20.0 mmol) was added. The reaction mixture was then heated at 80 °C for 24 h. The reaction progress was monitored by TLC. After the reaction was complete, the reactants were... In a vacuum Evaporation. The resulting crude product was treated with water (500 mL) and extracted with EtOAc (2 × 500 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was collected. In a vacuum The crude product was concentrated and purified by passing it through a Biotage Isolera (60-120 silica gel, eluted in a 10% EtOAc hexane solution) to provide the desired product as a yellow solid. E 2-chloro-5-(2-ethoxyvinyl)isonicotinic acid methyl ester (58g, yield 59%).

[0651] 1 H-NMR (400 MHz, DMSO- d 6): δ 8.71 (s, 1H), 7.69 (s, 1H), 7.40 (d, J = 12.8Hz, 1H), 6.29 (d, J = 13.2 Hz, 1H), 3.96 (q, J = 6.8 Hz, 2H), 3.88 (s, 3H), 1.28(t, J = 6.8 Hz, 3H). LCMS: RT: 2.53min, m / z: 242.0 (M+H) + 1C: ( E 2-Chloro-5-(2-ethoxyvinyl)isonicotinamide: In a 2-liter pressure reactor, ( E Methyl 2-chloro-5-(2-ethoxyvinyl)isonicotinic acid (58 g, 240 mmol) was dissolved in 1.0 L of 7 M NH3 MeOH solution and stirred at 60 °C for 20 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was... In a vacuum Evaporation yields the desired product, which is a yellow solid. E 2-Chloro-5-(2-ethoxyvinyl)nicotinamide (52.0 g, 230 mmol, 96% yield).

[0652] 1 H-NMR (400 MHz, DMSO- d 6): δ 8.58 (s, 1H), 8.05 (s, 1H), 7.76 (s, 1H),7.39 (s, 1H), 7.35 (d, J = 12.8 Hz, 1H), 5.95 (d, J = 13.2 Hz, 1H), 3.91 (q, J =6.8 Hz, 2H), 1.26 (t, J = 6.8 Hz, 3H). LCMS: RT: 1.73min, m / z: 227.1 (M+H) + 1D: 7-Chloro-2,6-Naphthyl-1-ol: In rt direction ( E A suspension of 2-chloro-5-(2-ethoxyvinyl)isonicotinamide (52 g, 229 mmol) in toluene (550 mL) was supplemented with PTSA monohydrate (21.8 g, 115 mmol). The resulting reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h. The reaction progress was monitored by TLC. The reaction mixture was then... In a vacuum Evaporation. Add 10% NaHCO3 aqueous solution to the obtained crude product, and filter, wash with water and dry the precipitated solid to obtain the desired product 7-chloro-2,6-naphthidine-1-ol (40 g, yield 95%) as a brown solid.

[0653] 1 H-NMR (400 MHz, DMSO- d 6): δ 11.77 (s, 1H), 8.96 (s,1H), 7.99 (s,1H),7.35 (d, J = 7.2 Hz, 1H), 6.71 (d, J = 7.2 Hz, 1H). LCMS: RT: 1.12min, m / z: 181.1 (M+H) + 1E:1-((1 H -Benz[d][1,2,3]triazol-1-yl)oxy)-7-chloro-2,6-naphthidine:PyBOP (14.4 g, 27.7 mmol) and DBU (12.7 g, 83 mmol) were added to a solution of 7-chloro-2,6-naphthid-1-ol (5.0 g, 27.7 mmol) in DMF (50 mL), and the mixture was stirred at rt under a nitrogen atmosphere for 4 h. The reaction progress was monitored by TLC. The reaction mixture was diluted with ice-cold water (100 mL), and the solid precipitate was filtered through a Buchner funnel, washed with water, and dried to give the desired product 1-((1) as a brown solid. H -Benzo[d][1,2,3]triazol-1-yl)oxy)-7-chloro-2,6-naphthidine (7.0 g crude). It was used in the next reaction without purification.

[0654] 1 H-NMR (400 MHz, DMSO- d 6): δ 9.49 (s, 1H), 8.57 (s, 1H), 8.21 (d, J = 8.4Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 6.4 Hz, 2H), 7.84-7.81 (m, 1H), 7.67 -7.63 (m, 1H), 7.58-7.54 (m, 1H). LCMS: RT: 2.49min, m / z: 298.1 (M+H) + 1F: 1-(7-chloro-2,6-naphthid-1-yl)piperidin-4-ol: At rt direction 1-((1 H A solution of benzo[d][1,2,3]triazol-1-yl)oxy)-7-chloro-2,6-naphthidine (3.0 g, 10.08 mmol) in 100 mL of ACN was supplemented with DIPEA (6.51 g, 50.4 mmol) and piperidine-4-ol (2.55 g, 25.2 mmol). The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was... In a vacuum The crude product was concentrated and purified by passing it through a Biotage Isolera (100-200 silica gel, using a 35% EtOAc hexane solution as the eluent) to obtain the desired product 1-(7-chloro-2,6-naphthid-1-yl)piperidin-4-ol (1.70 g, 6.46 mmol, yield 64%) as a yellow solid.

[0655] 1 H-NMR (400 MHz, DMSO- d 6): δ 9.20 (s, 1H), 8.25 (d, J = 6.0 Hz, 1H), 7.82(s, 1H), 7.50 (d, J = 5.6 Hz, 1H), 4.77 (d, J = 4.0 Hz, 1H), 3.78-3.65 (m, 3H), 3.16-3.09 (m, 2H), 1.99-1.92 (m, 2H), 1.69-1.62 (m, 2H). LCMS: RT: 1.60min, m / z: 264.2 (M+H) + 1： Cs₂CO₃ (1.85 g, 5.69 mmol) was added to a solution of 1-(7-chloro-2,6-naphthid-1-yl)piperidin-4-ol (500 mg, 1.90 mmol) and 1-(methanesulfonyl)piperidin-4-amine (676 mg, 3.79 mmol) in NMP (10 mL), and the reaction mixture was degassed with nitrogen for 5 min. Pd-PEPPSI-iHeptCl (184 mg, 0.190 mmol) was added to the reaction mixture, and the mixture was stirred at 120 °C under a nitrogen atmosphere for 16 h. After the reaction was complete, the reaction mixture was... In a vacuum The crude product was concentrated and purified by reversed-phase chromatography using Biotage Isolera (C18 mesh, 30% ammonium bicarbonate aqueous solution and ACN as elution solvent). The fraction was then lyophilized to give the desired compound 1-(7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthidin-1-yl)piperidin-4-ol (345 mg, 45% yield) as a pale yellow solid.

[0656] 1 H-NMR (400 MHz, DMSO- d 6): δ 8.84 (s, 1H), 7.76 (d, J = 5.6 Hz, 1H), 7.19(d, J = 5.6 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.76 (s, 1H), 4.75 (d, J = 4.0 Hz, 1H), 3.89 (t, J= 7.2 Hz, 1H), 3.74-3.68 (m, 1H), 3.58-3.55 (m, 4H), 2.97-2.91(m, 4H), 2.90 (s, 3H), 2.06-2.04 (m, 2H), 1.94-1.92 (m, 2H), 1.70-1.61 (m,2H), 1.58-1.48 (m, 2H). LCMS: RT: 1.84min, m / z: 406.4 (M+H) + Example 2: N -(1-(methylsulfonyl)piperidin-4-yl)-5-(pyrrolidin-1-yl)-2,6-naphthidin-3-amine (2) 2A: 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthidin-1-ol: Under a nitrogen atmosphere, 1-(methanesulfonyl)piperidin-4-amine (987 mg, 5.54 mmol) and Cs₂CO₃ (2.71 g, 8.31 mmol) were added to a solution of 7-chloro-2,6-naphthyl-1-ol (1D) (500 mg, 2.77 mmol) in NMP (5 mL), and the mixture was degassed with argon for 5 min. Pd-PEPPSI-iHeptCl (269 mg, 0.277 mmol) was added to the reaction mixture, and the mixture was stirred at 120 °C for 16 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over sodium sulfate and concentrated to obtain a crude product, which was then purified by Biotage Isolera (100-200 silica gel, using 10% MeOH in DCM solution as eluent) to obtain the desired product 7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthid-1-ol (80 mg, 0.244 mmol, 9% yield) as a pale yellow solid.

[0657] LCMS: RT: 1.48min, m / z: 323.2 (M+H) + 2B: 7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthidium-1-yl trifluoromethanesulfonate:Pyridine (172 mg, 2.171 mmol) and trifluoromethanesulfonic anhydride (184 mg, 0.651 mmol) were added to a solution of 7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthyl-1-ol (70 mg, 0.217 mmol) in DCM (5 mL) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at rt for 6 h. The reaction mixture was quenched with water (20 mL), extracted with DCM (3 × 20 mL), and the combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by Biotage Isolera (using 100-200 silica gel and 60% petroleum ether solution of EtOAc as eluent) to obtain the desired product 7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthidin-1-yltrifluoromethanesulfonate (76 mg, 0.134 mmol, yield 62%) as a light green gel-like solid.

[0658] LCMS: RT: 2.66min, m / z: 455.0 (M+H) + 2： Pyrrolidine (0.03 mL, 0.308 mmol) and Cs₂CO₃ (151 mg, 0.462 mmol) were added to a solution of 7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthid-1-yl trifluoromethanesulfonate (70 mg, 0.154 mmol) in 1,4-dioxane (5 mL). The reaction mixture was degassed with nitrogen, and then Xantphos (8.91 mg, 0.015 mmol) and Pd₂(dba)₃ (14.1 mg, 0.015 mmol) were added at 25 °C under a nitrogen atmosphere. The reaction mixture was stirred at 120 °C under a nitrogen atmosphere for 16 h, and the reaction progress was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was quenched with water and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over sodium sulfate and concentrated to give the crude product. The crude product was purified by prep-HPLC using formic acid as a buffer, and the purified fractions were lyophilized to obtain the desired compound as a yellow solid. N -(1-(methylsulfonyl)piperidin-4-yl)-5-(pyrrolidine-1-yl)-2,6-naphthyl-3-aminocarbamate (4.3 mg, 0.011 mmol, yield 7.3%).

[0659] 1 H NMR (400 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.34 (s, 1H), 7.63 (d, J= 5.7Hz, 1H), 7.08 (s, 1H), 6.89 (d, J = 5.7 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 3.87(d, J = 10.9 Hz, 1H), 3.74 – 3.69 (m, 4H), 2.98 – 2.92 (m, 1H), 2.89 (s, 3H),2.04 (d, J = 12.6 Hz, 2H), 1.97 – 1.90 (m, 4H), 1.56 – 1.45 (m, 2H). LCMS: RT: 1.50min, m / z: 376.4 (M+H) + Example 3: Synthesis of 5-(piperidin-1-yl)- N -(1-(vinylsulfonyl)piperidin-4-yl)-2,6-naphthyl-3-amine (3) 3A: 7-Chloro-1-(piperidin-1-yl)-2,6-naphthidine : at rt direction 1-((1 H A solution of benzo[d][1,2,3]triazol-1-yl)oxy)-7-chloro-2,6-naphthidine (1E) (350 mg, 1.18 mmol) in ACN (10 mL) was supplemented with DIPEA (0.61 mL, 3.53 mmol) and piperidine (0.23 mL, 2.35 mmol). The reaction mixture was stirred at 80 °C for 16 h, and the reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and In a vacuum The crude product was concentrated to obtain a crude product. The crude product was purified by passing it through a Biotage Isolera (60-120 silica gel, using a 15% EtOAc hexane solution as the eluent) to obtain the desired product 7-chloro-1-(piperidin-1-yl)-2,6-naphthidine (110 mg, 0.443 mmol, yield 38%) as a yellow solid.

[0660] LCMS: RT: 2.45min, m / z: 248.2 (M+H) + 3B: 4-((5-(piperidin-1-yl)-2,6-naphthidin-3-yl)amino)piperidin-1-carboxylic acid Uncle Butyl acetate Cs₂CO₃ (434 mg, 1.33 mmol) and 4-aminopiperidin-1-carboxylic acid were added to a solution of 7-chloro-1-(piperidin-1-yl)-2,6-naphthylidine (110 mg, 0.444 mmol) in NMP (5 mL). UncleButyl ester (178 mg, 0.888 mmol). The reaction mixture was degassed with nitrogen for 5 min, followed by the addition of Pd-PEPPSI-iHeptCl (43.2 mg, 0.044 mmol), and the reaction mixture was stirred at 120 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and... In a vacuum Concentration. The crude product was purified by passing it through a Biotage Isolera (60-120 silica gel, using a 30% EtOAc hexane solution as the eluent) to obtain the desired product, 4-((5-(piperidin-1-yl)-2,6-naphthidin-3-yl)amino)piperidin-1-carboxylic acid, as a yellow solid. Uncle Butyl ester (110 mg, 0.258 mmol, yield 58%).

[0661] LCMS:RT:2.09min,m / z:412.2 (M+H) + 3C: 5-(piperidin-1-yl)- N -(piperidin-4-yl)-2,6-naphthyl-3-amine: 4-((5-(piperidin-1-yl)-2,6-naphthidin-3-yl)amino)piperidin-1-carboxylic acid Uncle A solution of butyl ester (100 mg, 0.243 mmol) in 1,4-dioxane (2 mL) was added to a solution of 4 M HCl in 1,4-dioxane (1 mL, 0.243 mmol). The reaction mixture was stirred at 25 °C for 2 h. In truth In the air Concentrate, dilute with water (20 mL), and wash with EtOAc (2 × 20 mL). Alkalinize the aqueous phase with a 10% sodium hydroxide solution (pH approximately 10), then extract with DCM (2 × 20 mL). Wash the organic layer with brine (20 mL), dry to anhydrous sodium sulfate, filter, and... In a vacuum Concentrate to obtain the desired product, 5-(piperidin-1-yl)-, as a yellow solid. N -(piperidin-4-yl)-2,6-naphthyl-3-amine (60 mg, 0.153 mmol, yield 63%).

[0662] LCMS:RT:1.15min,m / z:312.2 (M+H) + 3： At 0°C under a nitrogen atmosphere, 5-(piperidin-1-yl)- NA solution of 30 mg (30 mg, 0.096 mmol) of 3-(piperidin-4-yl)-2,6-naphthyl-3-amine in DCM (2 mL) was added with vinylsulfonyl chloride (12 mg, 0.096 mmol) and TEA (97 mg, 0.963 mmol). The reaction mixture was stirred at 0 °C for 30 min. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and... In a vacuum Concentration. The crude product was purified by prep-HPLC, and the fractions were lyophilized to obtain the desired product 5-(piperidin-1-yl)- , which was a pale yellow solid. N -(1-(vinylsulfonyl)piperidin-4-yl)-2,6-naphthyl-3-amine (5.6 mg, 0.013 mmol, yield 14%).

[0663] 1 H NMR (400 MHz, DMSO-d6): δ 8.83 (s, 1H), 7.77 (d, J = 5.7 Hz, 1H), 7.19(dd, J = 5.8, 0.8 Hz, 1H), 6.90 – 6.70 (m, 3H), 6.23 – 6.08 (m, 2H), 3.91 –3.80 (m, 1H), 3.53 (d, J = 12.5 Hz, 2H), 3.21 (t, J = 5.1 Hz, 4H), 2.92 – 2.77(m, 2H), 2.04 (dd, J = 13.3, 3.7 Hz, 2H), 1.75 (m, 4H), 1.65 (d, J = 5.5 Hz, 2H),1.58 – 1.48 (m, 2H). LCMS: RT: 1.93min, m / z: 402.1 (M+H) + Example 4: 5-(1-methyl-1 H -pyrazole-4-yl)- N -(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyl- 3-amine (4) Cs₂CO₃ (25 mg, 0.077 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-trifluoromethanesulfonate (2B) (25 mg, 0.055 mmol) were added to a solution of 7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthidin-1-yltrifluoromethanesulfonate (2B) (25 mg, 0.055 mmol) in 1,4-dioxane (1.8 mL) and water (0.2 mL). H -Pyrazole (12.6 mg, 0.061 mmol) was added, and the mixture was degassed with nitrogen for 5 min. Pd(PPh3)4 (25 mg, 0.022 mmol) was added to the resulting solution, and the reaction mixture was stirred at 85 °C under nitrogen atmosphere for 16 h. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was... In a vacuum The crude product was concentrated and purified by Prep-HPLC. The collected fraction was concentrated and then lyophilized to give the desired product, 5-(1-methyl-1-ethylhexyl)-1-ethylhexylene, as a yellow solid. H -pyrazole-4-yl)- N -(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyl-3-amine (5 mg, 0.013 mmol, yield 23%).

[0664] 1 H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.31 (s, 1H), 8.17 (d, J = 5.6Hz, 1H), 8.01 (s, 1H), 7.54 (d, J = 5.7 Hz, 1H), 7.14 (s, 1H), 6.86 (d, J = 7.7Hz, 1H), 3.97 – 3.94 (m, 4H), 3.55 (d, J = 11.7 Hz, 2H), 2.97 (d, J = 11.1 Hz,2H), 2.90 (s, 3H), 2.06 (d, J = 13.5 Hz, 2H), 1.54 (d, J = 11.5 Hz, 2H). LCMS: RT: 1.59min, m / z: 387.4 (M+H) + Example 5: 5-Methoxy- N -(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyl-3-amine (5) TEA (3.7 mL, 26.4 mmol) was added to a solution of 7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthid-1-yltrifluoromethanesulfonate (2B) (4 g, 8.80 mmol) in DMF (35 mL) and MeOH (35 mL) at 25 °C. The reaction mixture was degassed for 10 min, followed by the addition of palladium(II) acetate (790 mg, 3.52 mmol) and dppf (2 mg, 3.52 mmol) at rt. The reaction mixture was stirred at 80 °C under a CO atmosphere for 16 h, and the reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and In a vacuum Concentrate to obtain a crude product (liquid). Purify the crude product (50 mg) using a Biotage Isolera (100-200 silica, 20% EtOAc-hexane as eluent) to obtain the byproduct methyl 7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthyl-1-carboxylate (250 mg, 0.686 mmol, yield 7.8%) and the main product 5-methoxy- N -(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyl-3-amine (1.2 g, 3.57 mmol, yield 41%).

[0665] 1 H NMR (400 MHz, DMSO-d6): δ 8.86 (s, 1H), 7.67 (d, J = 5.9 Hz, 1H), 7.24(dd, J = 5.9, 0.9 Hz, 1H), 6.85 (d, J = 14.1 Hz, 2H), 4.01 (s, 3H), 3.95 – 3.77(m, 1H), 3.54 (d, J = 12.2 Hz, 2H), 3.01 – 2.83 (m, 5H), 2.07 – 1.91 (m, 2H), 1.64 – 1.43 (m, 2H). LCMS: RT: 1.95min, m / z 337.2 (M+H) + Example 6: 5-Isopropyl- N -(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyl-3-amine (6) 6A: N -(1-(methylsulfonyl)piperidin-4-yl)-5-(prop-1-en-2-yl)-2,6-naphthidin-3-amine:Using a procedure similar to that disclosed in Example 4, starting with 7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthidium-1-yltrifluoromethanesulfonate (2B) (300 mg, 0.660 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborhecyclopentane (111 mg, 0.660 mmol), tetra(triphenylphosphine)palladium(0) (153 mg, 0.132 mmol), and Cs₂CO₃ (645 mg, 1.98 mmol), a product was generated. N -(1-(methylsulfonyl)piperidin-4-yl)-5-(prop-1-en-2-yl)-2,6-naphthidin-3-amine (62 mg, 0.178 mmol, yield 27%).

[0666] LCMS: RT: 1.66min, m / z 347.2 (M+H) + 6： Towards N A solution of 1-(1-(methanesulfonyl)piperidin-4-yl)-5-(prop-1-en-2-yl)-2,6-naphthidin-3-amine (61 mg, 0.176 mmol) in methanol (6 mL) was added to Pd / C (19 mg, 0.176 mmol). The resulting reaction mixture was stirred in a hydrogen gas chamber for 1 h. The reaction progress was monitored by LCMS. After completion, the reaction mixture was diluted with methanol (20 mL) and filtered. The filtrate was... In a vacuum The crude product was concentrated and purified by Prep-HPLC. The resulting fraction was then lyophilized to obtain the desired product, 5-isopropyl- N -(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyl-3-amine (11 mg, 0.030 mmol, yield 17%).

[0667] 1 H-NMR (400 MHz, DMSO- d 6): δ 8.95 (s, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7.50 (dd, J = 5.7, 0.9 Hz, 1H), 6.90 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 3.98 – 3.87(m, 1H), 3.69 (h, J = 6.8 Hz, 1H), 3.56 (dd, J= 12.0, 4.5 Hz, 2H), 3.00 – 2.88(m, 5H), 2.05 (dt, J = 13.3, 3.9 Hz, 2H), 1.55 (dtd, J = 14.3, 10.7, 4.0 Hz, 2H),1.30 (d, J = 6.7 Hz, 6H). LCMS: RT: 1.86min, m / z 349.2 (M+H) + Example 7: N -(4-(methylsulfonyl)phenyl)-5-(prop-1-yn-1-yl)-2,6-naphthidium-3-amine (7) 7A: 7-((4-(methanesulfonyl)phenyl)amino)-2,6-naphthidium-1-yltrifluoromethanesulfonate Using a procedure similar to that disclosed in Example 2B, 7-((4-(methanesulfonyl)phenyl)amino)-2,6-naphthid-1-ol (1.20 g, 3.81 mmol), trifluoromethanesulfonic anhydride (3.22 g, 11.4 mmol), and pyridine (3.01 g, 38.1 mmol) were used to obtain 7-((4-(methanesulfonyl)phenyl)amino)-2,6-naphthid-1-yl trifluoromethanesulfonate (1.01 g, 2.24 mmol, 59% yield).

[0668] 7: TEA (1.2 mL, 8.94 mmol) was added to a solution of 7-((4-(methanesulfonyl)phenyl)amino)-2,6-naphthid-1-yltrifluoromethanesulfonate (400 mg, 0.894 mmol) in 1,4-dioxane (2 mL), and the mixture was purged with N2 for 10 min. Copper(I) iodide (17.0 mg, 0.089 mmol) and PdCl2(PPh3)2 (31.5 mg, 0.045 mmol) were added to the resulting solution at rest, and the mixture was purged with N2 again for 5 min. Propylene (860 mg, 1.07 mmol, 5% THF solution) was added to the reaction mixture, and the mixture was stirred at rest for 16 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with EtOAc (50 mL), filtered through a diatomaceous earth mat, and washed with EtOAc (50 mL). The filtrate was... In a vacuum Concentrate the residue, then purify it using a Biotage Isolera (60-120 silica gel, using a 5% EtOAc hexane solution as the eluent) to obtain the desired product. N -(4-(methylsulfonyl)phenyl)-5-(prop-1-yn-1-yl)-2,6-naphthidine-3-amine (190 mg, 0.552 mmol, yield 62%).

[0669] 1 H-NMR (400 MHz, DMSO- d 6): δ 10.10 (s, 1H), 9.28 (d, J = 1.0 Hz, 1H), 8.37(d, J = 5.6 Hz, 1H), 7.92 – 7.76 (m, 5H), 7.59 (s, 1H), 3.16 (s, 3H), 2.29 (s, 3H). LCMS: RT: 1.60min, m / z: 338.2 (M+H) + Example 8: N -(1-(methylsulfonyl)piperidin-4-yl)-5-(pyridin-2-yl)-2,6-naphthyl-3-amine (8) A solution of 7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthidin-1-yltrifluoromethanesulfonate (2B) (150 mg, 0.33 mmol) and 2-(tributyltinyl)pyridine (243 mg, 0.660 mmol) in 1,4-dioxane (4.0 mL) was degassed for 10 min. Pd(dppf)Cl2 (48.3 mg, 0.066 mmol) was added to the reaction mixture under a nitrogen atmosphere, and the reaction mixture was stirred at 100 °C for 16 h. After completion, the reaction mixture was filtered through a diatomaceous earth bed and washed with EtOAc (100 mL). The filtrate was... In a vacuum The product was concentrated to obtain a crude product as a yellow solid, which was then purified by Prep-HPLC. The product fractions were lyophilized to obtain the desired compound as a light yellow solid. N -(1-(methylsulfonyl)piperidin-4-yl)-5-(pyridin-2-yl)-2,6-naphthyl-3-amine (12.5 mg, 0.031 mmol, yield 9.4%).

[0670] 1 H-NMR (400 MHz, DMSO- d 6): δ 9.07 (s, 1H), 8.77 (dt, J = 4.8, 1.5 Hz, 1H), 8.31 (d, J = 5.5 Hz, 1H), 8.07 – 7.96 (m, 2H), 7.77 (d, J = 5.4 Hz, 1H), 7.63 (s,1H), 7.54 (ddd, J= 6.8, 4.9, 2.0 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 3.89 (s,1H), 3.55 (d, J = 12.2 Hz, 2H), 2.89 (s, 5H), 2.03 (d, J = 12.9 Hz, 2H), 1.54 (q, J = 10.1 Hz, 2H). LCMS: RT: 1.87min, m / z: 384.3 (M+H) + Example 9: 5-(piperidin-1-yl)- N -(1-(vinylsulfonyl)pyrrolid-3-yl)-2,6-naphthidium-3-amine (9) 9A: 3-((5-(piperidin-1-yl)-2,6-naphthidin-3-yl)amino)pyrrolidine-1-carboxylic acid Uncle Butyl ester: Under continuous nitrogen bubbling, 7-chloro-1-(piperidin-1-yl)-2,6-naphthyl (3A) (400 mg, 1.62 mmol) and 3-aminopyrrolidine-1-carboxylic acid were reacted. Uncle A solution of butyl ester (601 mg, 3.23 mmol) in 1,4-dioxane (10 mL) was supplemented with Cs₂CO₃ (1.58 g, 4.84 mmol). Pd-PEPPSI-iHeptCl (157 mg, 0.161 mmol) was added to the resulting solution, and the reaction mixture was stirred at 110 °C for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was... In a vacuum The crude product was concentrated and purified by passing it through a Biotage Isolera (100-200 mesh silica gel, using a 35% EtOAc hexane solution as the eluent) to obtain the desired product, 3-((5-(piperidin-1-yl)-2,6-naphthidin-3-yl)amino)pyrrolidine-1-carboxylic acid, as a brown solid. Uncle Butyl ester (500 mg, 1.22 mmol, yield 76%).

[0671] LCMS: RT: 2.01min, m / z: 398.2 (M+H) + 9B: 5-(piperidin-1-yl)- N -(pyrrolidine-3-yl)-2,6-naphthidium-3-amine HCl: At 0°C under a nitrogen atmosphere, 3-((5-(piperidin-1-yl)-2,6-naphthidium-3-yl)amino)pyrrolidine-1-carboxylic acid UncleA solution of butyl ester (500 mg, 1.26 mmol) in 1,4-dioxane (5 mL) was added to a solution of 4N HCl in 1,4-dioxane (4.7 mL, 18.9 mmol). The reaction mixture was stirred at 25 °C for 1 h, and the reaction progress was monitored by TLC. The reaction mixture was then... In a vacuum Concentrate to obtain a crude product that is a light brown gel. Pulverize the crude product with MTBE (20 mL) and dry the resulting solid precipitate to obtain the desired product, 5-(piperidin-1-yl)-, a light yellow solid. N -(pyrrolidone-3-yl)-2,6-naphthidine-3-amine HCl (500 mg, 1.29 mmol, yield 103%).

[0672] LCMS: RT: 1.37min, m / z: 298.3 (M+H) + 9: At 0°C under a nitrogen atmosphere, 5-(piperidin-1-yl)- N A solution of 150 mg (0.504 mmol) of pyrrolidine-3-yl)-2,6-naphthyl-3-amine in 10 mL of DCM was supplemented with TEA (0.7 mL, 5.04 mmol) and 2-chloroethane-1-sulfonyl chloride (82 mg, 0.504 mmol). The reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 1 h. The reaction progress was monitored by LCMS. After completion, the reaction mixture was... In a vacuum The product was concentrated to obtain a crude product as a brown solid. The crude compound was purified by Prep-HPLC, and the fractions were lyophilized to obtain the desired product, 5-(piperidin-1-yl)-, as a brown solid. N -(1-(vinylsulfonyl)pyrrolidine-3-yl)-2,6-naphthidine-3-amine (8.7 mg, 0.022 mmol, yield 4.3%).

[0673] 1 H-NMR (400 MHz, DMSO- d 6): δ 8.87 (s, 1H), 7.80 (d, J = 5.7 Hz, 1H), 7.21(dd, J = 5.8, 0.8 Hz, 1H), 7.05 (d, J = 6.1 Hz, 1H), 6.88 (dd, J = 16.5, 10.0 Hz, 1H), 6.77 (t, J = 1.0 Hz, 1H), 6.10 (dd, J= 13.3, 3.3 Hz, 2H), 4.40 (p, J = 5.8Hz, 1H), 3.55 (dd, J = 10.2, 6.1 Hz, 1H), 3.44 (dt, J = 10.1, 7.2 Hz, 1H), 3.36 –3.33 (m, 1H), 3.22 (t, J = 5.3 Hz, 4H), 3.12 (dd, J = 10.2, 4.6 Hz, 1H), 2.22(ddd, J = 14.3, 12.8, 6.9 Hz, 1H), 1.92 (dq, J = 12.9, 6.2 Hz, 1H), 1.75 (d, J =7.1 Hz, 4H), 1.65 (d, J = 5.6 Hz, 2H). LCMS: RT: 1.68min, m / z: 388.3 (M+H) + Example 10: 5-(4,4-difluoropiperidin-1-yl)- N -(1-(vinylsulfonyl)piperidin-4-yl)-2,6-naphthalene pyridine-3-amine (10) 10A: 7-Chloro-1-(4,4-difluoropiperidin-1-yl)-2,6-naphthidine Using a procedure similar to that disclosed in Example 1F, 1-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-7-chloro-2,6-naphthidine (1E) (600 mg, 2.02 mmol) and 4,4-difluoropiperidine (488 mg, 4.03 mmol) were started to produce 7-chloro-1-(4,4-difluoropiperidine-1-yl)-2,6-naphthidine (300 mg, 1.06 mmol, 52% yield).

[0674] LCMS: RT: 2.62min, m / z: 284.2 (M+H) + 10B: 4-((5-(4,4-difluoropiperidin-1-yl)-2,6-naphthidin-3-yl)amino)piperidin-1-carboxylic acid Uncle Butyl ester: Under continuous nitrogen bubbling, 7-chloro-1-(4,4-difluoropiperidin-1-yl)-2,6-naphthylidine (300 mg, 1.06 mmol) and 4-aminopiperidin-1-carboxylic acid were reacted. UncleA solution of butyl ester (424 mg, 2.12 mmol) in NMP (5 mL) was supplemented with Cs₂CO₃ (1.03 g, 3.17 mmol). Pd-PEPPSI-iHeptCl (103 mg, 0.106 mmol) was added to the resulting solution under a nitrogen atmosphere, and the reaction mixture was stirred at 110 °C for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was... In a vacuum The crude product, a brown liquid, was concentrated and purified by passing it through a Biotage Isolera (100-200 mesh silica gel, using 15% EtOAc-hexane as eluent) to obtain 4-((5-(4,4-difluoropiperidin-1-yl)-2,6-naphthidin-3-yl)amino)piperidin-1-carboxylic acid, a green solid. Uncle Butyl ester (450 mg, 0.941 mmol, yield 89%).

[0675] LCMS: RT: 2.58min, m / z: 448.4 (M+H) + 10C: 5-(4,4-difluoropiperidin-1-yl)- N -(piperidin-4-yl)-2,6-naphthyl-3-amine: At 0°C under a nitrogen atmosphere, 4-((5-(4,4-difluoropiperidin-1-yl)-2,6-naphthidin-3-yl)amino)piperidin-1-carboxylic acid Uncle A solution of butyl ester (450 mg, 1.01 mmol) in 1,4-dioxane (5 mL) was added to a solution of 4N HCl in 1,4-dioxane (3.8 mL, 15.1 mmol). The reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 1 h, and the reaction progress was monitored by TLC. After completion, the reaction mixture was... In a vacuum Concentrate to obtain a crude product that is a green gel-like substance. Dilute the reaction mixture with 10% NaHCO3 solution (20 mL) and extract with 10% MeOH in DCM solution (3 × 40 mL). Wash the combined organic extracts with brine (50 mL), dry to anhydrous sodium sulfate, filter, and... In a vacuum Concentration yields the desired product, 5-(4,4-difluoropiperidin-1-yl)-, as a green solid. N -(piperidin-4-yl)-2,6-naphthyl-3-amine (250 mg, 0.703 mmol, 70% yield).

[0676] LCMS: RT: 1.37min, m / z: 348.3 (M+H) + 10： At 0°C under a nitrogen atmosphere, 5-(4,4-difluoropiperidin-1-yl)- NA solution of (piperidin-4-yl)-2,6-naphthyl-3-amine (250 mg, 0.720 mmol) was added with TEA (1 mL, 7.20 mmol) and 2-chloroethane-1-sulfonyl chloride (82 mg, 0.504 mmol). The reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 4 h. The reaction progress was monitored by LCMS. After completion, the reaction mixture was... In a vacuum The product was concentrated to obtain a crude product that was a grayish-white solid. The crude product was purified by Prep-HPLC. The fractions were lyophilized to obtain the desired product, 5-(4,4-difluoropiperidin-1-yl)-, as a yellow solid. N -(1-(vinylsulfonyl)piperidin-4-yl)-2,6-naphthyl-3-amine (35.2 mg, 0.079 mmol, yield 11%).

[0677] 1 H-NMR (400 MHz, DMSO- d 6): δ 8.88 (s, 1H), 7.80 (d, J = 5.7 Hz, 1H), 7.27(d, J = 5.7 Hz, 1H), 6.89 – 6.72 (m, 3H), 6.24 – 6.07 (m, 2H), 3.90 (d, J = 10.1Hz, 1H), 3.53 (d, J = 12.4 Hz, 2H), 3.40 (t, J = 5.7 Hz, 4H), 2.88 (t, J = 10.9 Hz, 2H), 2.24 (d, J = 14.7 Hz, 4H), 2.09 – 1.99 (m, 2H), 1.53 (q, J = 9.8 Hz, 2H). MSI ESI: RT: 2.25min, m / z: 438.2 (M+H) + Example 11: 5-(benzyloxy)- N -(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyl-3-amine (11) 11A: 1-(benzyloxy)-7-chloro-2,6-naphthidine:Silver carbonate (3.05 g, 11.1 mmol) was added (10 mL) to a solution of 7-chloro-2,6-naphthid-1-ol (1D) (1.00 g, 5.54 mmol) in toluene. Benzyl bromide (0.8 mL, 7.20 mmol) was added to the reaction mixture, and the resulting mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was poured into ice-cold water and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (10 mL) and brine (3 mL), dried over anhydrous Na₂SO₄, and... In a vacuum Concentration. The crude compound was purified by passing it through Biotage Isolera (100-200 mesh silica gel, using a 4% EtOAc hexane solution as the eluent) to give the desired product, 1-(benzyloxy)-7-chloro-2,6-naphthidine (370 mg, 1.23 mmol, 22% yield), as a pale yellow solid.

[0678] LCMS: RT: 2.27min, m / z: 270.1 (M+H) + 11： Under continuous nitrogen bubbling, Cs₂CO₃ (108 mg, 0.332 mmol) was added to a solution of 1-(benzyloxy)-7-chloro-2,6-naphthidine (30 mg, 0.111 mmol) and 1-(methanesulfonyl)piperidin-4-amine (19.8 mg, 0.111 mmol) in 3 mL of 1,4-dioxane. Pd-PEPPSI-iHeptCl (8.77 mg, 0.011 mmol) was added to the resulting solution, and the reaction mixture was stirred at 120 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was... In a vacuum The product was concentrated to obtain a crude product. The crude product was purified by Prep-HPLC. The fractions were lyophilized to obtain the desired product, 5-(benzyloxy)-, as a pale yellow solid. N -(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyl-3-amine (35 mg, 0.083 mmol, 75% yield).

[0679] 1 H-NMR (400 MHz, DMSO- d 6): δ 8.87 (s, 1H), 7.67 (d, J = 5.8 Hz, 1H), 7.58– 7.50 (m, 2H), 7.48 – 7.39 (m, 2H), 7.39 – 7.33 (m, 1H), 7.26 (dd, J= 5.9, 0.9 Hz, 1H), 6.95 (t, J = 1.0 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 5.50 (s, 2H), 3.93 (s, 1H), 3.58 – 3.46 (m, 2H), 3.02 – 2.90 (m, 2H), 2.88 (s, 3H), 2.01(dd, J = 13.3, 3.9 Hz, 2H), 1.60 – 1.42 (m, 2H). LCMS: RT: 2.05min, m / z: 413.2 (M+H) + Example 12: (4-hydroxypiperidin-1-yl)(7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthalene (Pyridin-1-yl)methyl ketone (12) 12A: Synthesis of methyl 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyl-1-carboxylate: TEA (3.7 mL, 26.4 mmol) was added to a solution of 7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthid-1-yltrifluoromethanesulfonate (2B) (4.0 g, 8.80 mmol) in DMF (35 mL) and MeOH (35.0 mL) at 25 °C. The reaction mixture was degassed for 10 min, followed by the addition of palladium(II) acetate (790 mg, 3.52 mmol) and dppf (1.95 g, 3.52 mmol) at rt. The reaction mixture was stirred at 80 °C under a CO atmosphere for 16 h, and the reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and In a vacuum Concentrate to obtain a crude product (liquid). Purify the crude product using a Biotage Isolera (100-200 silica, using 20% ​​EtOAc-hexane as eluent) to obtain the desired compound 5-methoxy- in the form of a white solid. N -(1-(methylsulfonyl)piperidin-4-yl)-2,6-naphthyl-3-amine (1.20 g, 3.57 mmol, yield 41%).

[0680] LCMS: RT: 1.90min, m / z: 365.2 (M+H) + .

[0681] 12B: 7-((1-(methylsulfonyl)piperidin-4-yl)amino)-2,6-naphthyl-1-carboxylic acid:LiOH (59.1 mg, 2.47 mmol) was added to a solution of methyl 7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthyl-1-carboxylate (300 mg, 0.823 mmol) in water (0.6 mL) and THF (3 mL) at 0 °C, and the reaction mixture was stirred at rt for 30 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was then... In a vacuum Concentrate the extract and dissolve the residue in water (50 mL), acidify with citric acid, and extract with DCM (2 × 50 mL). Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and... In a vacuum Concentrate to obtain the desired product 7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthyl-1-carboxylic acid (250 mg, 0.700 mmol, yield 85%), which is a yellow solid.

[0682] LCMS: RT: 1.48min, m / z: 351.1 (M+H) + 12： HATU (40.7 mg, 0.107 mmol), DIPEA (23 mg, 0.178 mmol), and piperidine-4-ol (7.2 mg, 0.071 mmol) were added to a solution of 7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthyl-1-carboxylic acid (25 mg, 0.071 mmol) in DMF (1.5 mL) under nitrogen atmosphere. The reaction mixture was stirred under nitrogen atmosphere for 16 h. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over sodium sulfate and... In a vacuum The crude product was concentrated to obtain a crude product. The crude product was purified by Prep-HPLC and the fractions were lyophilized to obtain the desired product (4-hydroxypiperidin-1-yl)(7-((1-(methanesulfonyl)piperidin-4-yl)amino)-2,6-naphthidin-1-yl) methyl ketone (16 mg, 0.037 mmol, yield 51%), which was a light yellow solid.

[0683] 1 H-NMR (400 MHz, DMSO- d 6): δ 9.06 (s, 1H), 8.16 (d, J = 5.6 Hz, 1H), 7.73(d, J = 5.7 Hz, 1H), 7.05 (d, J= 7.7 Hz, 1H), 6.58 (s, 1H), 4.84 (d, J = 3.9 Hz, 1H), 4.15 (d, J = 12.3 Hz, 1H), 3.92 (s, 1H), 3.77 (s, 1H), 3.54 (d, J = 12.5 Hz,1H), 2.92-2.84 (m, 6H), 2.08 – 1.77 (m, 4H), 1.74 – 1.31 (m, 5H), 1.26 (d, J =14.4 Hz, 2H). LCMS: RT: 1.64min, m / z: 434.2 (M+H) + Example 13: 3-((5-(4-cyanopiperidin-1-yl)-2,6-naphthidin-3-yl)amino)phenylthiofluoride (13) 13A: 1-(7-chloro-2,6-naphthid-1-yl)piperidine-4-carboxynitrile: Under a nitrogen atmosphere, rt is directed towards 1-((1) H A solution of benzo[d][1,2,3]triazol-1-yl)oxy)-7-chloro-2,6-naphthyl (1E) (2.000 g, 6.72 mmol) in NMP (10 mL) was supplemented with DIPEA (3.51 mL, 20.2 mmol) and piperidine-4-carboxynitrile (1.11 g, 10.08 mmol). The reaction mixture was stirred at 100 °C for 16 h and monitored by TLC. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and... In a vacuum Concentration. The crude product (2.5 g) was purified by Biotage Isolera (using 100-200 silica gel and a 25% EtOAc hexane solution as eluent) to provide the desired compound 1-(7-chloro-2,6-naphthid-1-yl)piperidin-4-carboxynitrile (1.03 g, 3.70 mmol, 55% yield) as a yellow solid.

[0684] LCMS: RT: 2.25min, m / z: 273.2 (M+H) + 13B: 1-(7-((3-hydroxyphenyl)amino)-2,6-naphthid-1-yl)piperidin-4-carboxynitrile:3-Aminophenol (90 mg, 0.825 mmol) and Cs₂CO₃ (538 mg, 1.65 mmol) were added to a solution of 1-(7-chloro-2,6-naphthid-1-yl)piperidin-4-carboxynitrile (150 mg, 0.550 mmol) in NMP (10 mL), and the reaction mixture was degassed with nitrogen for 10 min. Pd-PEPPSI-iHeptCl (53.5 mg, 0.055 mmol) was added to the resulting solution under nitrogen atmosphere, and the mixture was stirred at 120 °C for 16 h under nitrogen atmosphere. The reaction progress was monitored by LCMS. After completion, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and… In a vacuum The crude product was concentrated to obtain a crude product. The crude product was purified by passing it through a Biotage Isolera (60-120 silica gel, using a 60% EtOAc hexane solution as the eluent) to obtain the desired compound 1-(7-((3-hydroxyphenyl)amino)-2,6-naphthid-1-yl)piperidin-4-carboxynitrile (190 mg, 0.546 mmol, 99% yield) as a yellow solid.

[0685] LCMS: RT: 2.25min, m / z: 346.2 (M+H) + 13： A solution of 1-(7-((3-hydroxyphenyl)amino)-2,6-naphthid-1-yl)piperidin-4-carboxynitrile (190 mg, 0.550 mmol) in THF (25 mL) was added to the reaction mixture at 25 °C under a nitrogen atmosphere. AISF (182 mg, 0.578 mmol) and DBU (0.18 mL, 1.210 mmol) were added. The reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 1 h. The reaction progress was monitored by LCMS. After completion, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and... In a vacuum The product was concentrated to obtain a crude product. The crude product was purified by Prep-HPLC to obtain the desired product, 3-((5-(4-cyanopiperidin-1-yl)-2,6-naphthidin-3-yl)amino)phenyl thiofluoride (55 mg, 0.129 mmol, yield 23%), which was a light yellow solid.

[0686] 1 H-NMR (400 MHz, DMSO- d 6): δ 9.73 (s, 1H), 9.11 (d, J= 0.9 Hz, 1H), 8.08– 7.91 (m, 2H), 7.61 (ddd, J = 8.4, 2.0, 0.9 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.41 (dd, J = 5.8, 0.9 Hz, 1H), 7.30 (t, J = 1.1 Hz, 1H), 7.08 (dd, J = 8.1, 2.5Hz, 1H), 3.57 – 3.39 (m, 2H), 3.21 (ddd, J = 12.8, 8.6, 3.6 Hz, 3H), 2.14 (ddd, J = 13.4, 7.3, 2.7 Hz, 2H), 2.01 (ddt, J = 13.5, 9.0, 4.2 Hz, 2H). LCMS: RT: 2.58min, m / z: 428.2 (M+H) + Example 14: 4-((5-(4-cyanopiperidin-1-yl)-2,6-naphthidin-3-yl)amino)phenyl thiofluoride (14) 14A: 1-(7-((4-hydroxyphenyl)amino)-2,6-naphthidium-1-yl)piperidine-4-carboxynitrile: 4-Aminophenol (90 mg, 0.825 mmol) and Cs₂CO₃ (538 mg, 1.65 mmol) were added to a solution of 1-(7-chloro-2,6-naphthid-1-yl)piperidin-4-carboxynitrile (13A) (150 mg, 0.550 mmol) in NMP (10 mL), and the reaction mixture was degassed with nitrogen for 10 min. Pd-PEPPSI-iHeptCl (53.5 mg, 0.055 mmol) was added to the resulting solution at 25 °C under nitrogen atmosphere, and the reaction mixture was stirred at 120 °C under nitrogen atmosphere for 16 h. The reaction progress was monitored by LCMS. After completion, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and… In a vacuum The crude product was concentrated to obtain the crude product. The crude product was purified by passing it through a Biotage Isolera (60-120 silica gel, using a 60% EtOAc hexane solution as the eluent) to obtain the desired product 1-(7-((4-hydroxyphenyl)amino)-2,6-naphthid-1-yl)piperidin-4-carboxynitrile (190 mg, 0.528 mmol, yield 96%).

[0687] LCMS: RT: 1.68min, m / z: 346.2 (M+H) + 14： AISF (182 mg, 0.578 mmol) and DBU (0.18 mL, 1.21 mmol) were added to a solution of 1-(7-((4-hydroxyphenyl)amino)-2,6-naphthid-1-yl)piperidin-4-carboxynitrile (190 mg, 0.550 mmol) in THF (25 mL) under a nitrogen atmosphere at 25 °C. The reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 1 h. The reaction progress was monitored by LCMS. After completion, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and... In a vacuum The crude product was concentrated to obtain a crude product. The crude product was purified by Prep-HPLC and the fractions were lyophilized to obtain the desired compound 4-((5-(4-cyanopiperidin-1-yl)-2,6-naphthidin-3-yl)amino)phenyl thiofluoride (32 mg, 0.075 mmol, yield 14%) as a light yellow solid.

[0688] 1 H NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 9.07 (d, J = 0.8 Hz, 1H), 7.97 (d, J = 5.8 Hz, 1H), 7.83 – 7.74 (m, 2H), 7.56 – 7.47 (m, 2H), 7.43 – 7.37(m, 1H), 7.27 (s, 1H), 3.56 – 3.43 (m, 2H), 3.19 (dt, J = 13.1, 4.8 Hz, 3H),2.20 – 2.06 (m, 2H), 2.00 (dtd, J = 12.2, 8.4, 3.2 Hz, 2H). LCMS: RT: 2.59min, m / z: 428.2 (M+H) + Example 15: 1-(7-((4-(vinylsulfonyl)phenyl)amino)-2,6-naphthidium-1-yl)piperidin-4-carboxynitrile (15) 15A: 1-(7-((4-((2-hydroxyethyl)sulfonyl)phenyl)amino)-2,6-naphthidium-1-yl)piperidine-4-carboxynitrile:Under continuous nitrogen bubbling, Cs₂CO₃ (956 mg, 2.93 mmol) and 2-((4-aminophenyl)sulfonyl)ethane-1-ol (443 mg, 2.20 mmol) were added to a solution of 1-(7-chloro-2,6-naphthid-1-yl)piperidin-4-carboxynitrile (13A) (400 mg, 1.47 mmol) in 1,4-dioxane (20 mL). Pd-PEPPSI-iHeptCl (143 mg, 0.147 mmol) was added to the resulting solution at 25 °C, and the reaction mixture was stirred at 100 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through a diatomaceous earth bed and washed with EtOAc. The organic layer was evaporated to dryness to obtain the crude product. The crude product was purified by Prep-HPLC, and the obtained fractions were lyophilized to obtain the desired product 1-(7-((4-((2-hydroxyethyl)sulfonyl)phenyl)amino)-2,6-naphthid-1-yl)piperidin-4-carboxynitrile (70 mg, 0.157 mmol, yield 11%).

[0689] LCMS: RT: 1.82min, m / z: 438.2 (M+H) + 15： TEA (0.16 mL, 1.14 mmol) and SOCl2 (20.4 mg, 0.171 mmol) were added to a solution of 1-(7-((4-((2-hydroxyethyl)sulfonyl)phenyl)amino)-2,6-naphthid-1-yl)piperidin-4-carboxynitrile (50 mg, 0.114 mmol) in ACN (5 mL) under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 6 h, and the reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and... In a vacuum The product was concentrated to obtain a crude product that was a black liquid. The crude product (100 mg) was purified by Prep-HPLC and the fraction was lyophilized to obtain the desired product 1-(7-((4-(vinylsulfonyl)phenyl)amino)-2,6-naphthid-1-yl)piperidin-4-carboxynitrile (4.38 mg, 10.3 µmol, yield 9.0%), which was a light yellow solid.

[0690] 1 H-NMR (400 MHz, DMSO- d 6):) δ 9.92 (s, 1H), 9.13 (d, J = 0.8 Hz, 1H), 8.02(d, J= 5.7 Hz, 1H), 7.90 – 7.81 (m, 2H), 7.81 – 7.68 (m, 2H), 7.49 – 7.32 (m,2H), 7.05 (dd, J = 16.4, 9.8 Hz, 1H), 6.25 (d, J = 16.4 Hz, 1H), 6.11 (d, J = 9.9Hz, 1H), 3.57 – 3.45 (m, 2H), 3.22 (ddt, J = 12.9, 8.1, 3.5 Hz, 3H), 2.14 (ddt, J = 9.8, 7.0, 3.5 Hz, 2H), 2.01 (dtd, J = 12.2, 8.5, 3.3 Hz, 2H). LCMS: RT: 2.15min, m / z: 420.2 (M+H) + Example 16: 4-((5-(4-cyanopiperidin-1-yl)-2,6-naphthidin-3-yl)amino)- N -(2-oxotetrahydrothiazolyl) phen-3-yl)benzamide (16) 16A: 4-Aminobenzoic acid (189 mg, 1.38 mmol) and Cs₂CO₃ (1.49 g, 4.58 mmol) were added to a solution of 1-(7-chloro-2,6-naphthid-1-yl)piperidin-4-carboxynitrile (13A) (250 mg, 0.917 mmol) in NMP (5 mL). The reaction mixture was degassed with nitrogen for 10 min, and Pd-PEPPSI-iHeptCl (89 mg, 0.092 mmol) was added at rt under nitrogen atmosphere. The reaction mixture was stirred at 120 °C under nitrogen atmosphere for 16 h. The reaction was monitored by TLC, and the reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase Biotage Isolera (using 50% ACN and formic acid as eluent). The fractions were freeze-dried to obtain the desired product, 4-((5-(4-cyanopiperidin-1-yl)-2,6-naphthidin-3-yl)amino)benzoic acid (201 mg, 0.499 mmol, yield 54%), as a light yellow solid.

[0691] LCMS: RT: 1.92min, m / z: 372.2 (M+H) + 16: Under a nitrogen atmosphere, at 25 °C, EDC (154 mg, 0.803 mmol), 3-aminodihydrothiophene-2(3H)-one, HCl (82 mg, 0.536 mmol), HOBt (123 mg, 0.803 mmol), and DMAP (7 mg, 0.054 mmol) were added to a stirred solution of 4-((5-(4-cyanopiperidin-1-yl)-2,6-naphthyl-3-yl)amino)benzoic acid (200 mg, 0.536 mmol) in DMF (3 mL). The reaction mixture was stirred at rt for 15 min, followed by the addition of DIPEA (0.47 mL, 2.68 mmol). The resulting mixture was stirred at 25 °C under a nitrogen atmosphere for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with cold water (10 mL), extracted with EtOAc (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and... In a vacuum The crude product was concentrated to obtain a crude compound. The crude compound was purified by Prep-HPLC and lyophilized to give the desired compound, 4-((5-(4-cyanopiperidin-1-yl)-2,6-naphthidin-3-yl)amino), as a pale yellow solid. N -(2-oxotetrahydrothiophene-3-yl)benzamide (86.8 mg, 0.181 mmol, yield 34%).

[0692] 1 H-NMR (400 MHz, DMSO- d 6):) δ 9.62 (s, 1H), 9.10 (d, J = 0.8 Hz, 1H), 8.55(d, J = 8.4 Hz, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.88 – 7.78 (m, 2H), 7.75 – 7.60(m, 2H), 7.41 (dd, J = 5.9, 0.9 Hz, 1H), 7.33 (t, J = 1.0 Hz, 1H), 4.85 (ddd, J =12.7, 8.4, 7.0 Hz, 1H), 3.5...

Claims

1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, (I) wherein: A is a cyclic group selected from carbocyclyl, heterocyclyl, aryl, heteroaryl, and substituted forms thereof; Y 1 is N or CR 1 ; Y 2 is N or CR 2 ; Y 3 is N or CR 3 ; Y 5 is N or CR 5 ; R 6 of formula (I) wherein: Z is an optional hydrophilic group; 2. The compound of claim 1, wherein A is optionally substituted aryl or optionally substituted heteroaryl. L 1 and L 2 is an optional linker; and represents R 6 point of attachment to the adjacent nitrogen atom; R 4 selected from the group consisting of optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl; R 1 -R 3 R 5 and R 7 Independently selected from H, optionally substituted (C) 1-6 )alkyl, halogenated (C 1-6 )alkyl, -COR 30 -OR 30 halogens and CN; and R 30 is H or optionally substituted (C 1-6 )alkyl. wherein:

3. The compound of claim 2, wherein R 6 comprising structure 6A: (6A) wherein m is 0, 1, 2, 3, or 4. Y 6 -Y 10 independently selected from C-Z, CR 12 or N, wherein Y 6 -Y 10 one of R1, R2, R3, and R4is C-Z; and Each R 12 Independently selected from H, optionally substituted alkyl, optionally substituted alkoxy, hydroxyl, halogen and CN.

4. The compound of claim 3, wherein Y is C-Z. 8 is C-Z.

5. The compound of claim 3 or 4, wherein at least one of Y 6 -Y 10 is N.

6. The compound of claim 5, wherein Y 6 - Y 10 one and only one of R1, R2, R3, and R4is N.

7. The compound of claim 5 or 6, wherein Y is N. 6 is N.

8. The compound of claim 5 or 6, wherein Y 7 It is N.

9. The compound of claim 4, wherein R 6 having structure 6A1 : (6A1) 11. The compound of claim 1, wherein A is optionally substituted cycloalkyl or optionally substituted heterocyclyl.

10. The compound of claim 9, wherein R 6 having structure 6A2: (6A2) wherein R 12 is selected from hydrogen, halogen, optionally substituted (C 1-6 )alkyl and optionally substituted (C 1-6 )alkoxy. wherein:

12. The compound of claim 11, wherein R 6 comprising structure 6B: (6B) k is 0 or 1; and Y 11 is selected from O, S, CH2, CHR 11 , C(R 11 )2 and NR 9 ; R 9 is H, optionally substituted alkyl, -L 2 -Z or Z; Each R 11 Independently selected from -L 2 -Z, Z, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl carbonyloxy, hydroxyl, halogen and CN; n is an integer from 0 to 9.

14. The compound of claim 13, wherein:

13. The compound of claim 12, wherein R 6 comprising structure 6B1 or 6B3: (6B1) or (6B3). n is 0, 1, 2, 3, or 4; and k is 0, 1, 2, 3, 4, 5, 6, 7, or 8; Each R 11 Independently selected from optional substitutions (C) 1-3 )alkyl, optionally substituted (C 1-3 Alkoxy, hydroxy, halogen and CN.

15. The compound of claim 14, wherein each R 11 is independently selected from the group consisting of methyl, methoxy, CF3, OCF3, hydroxyl, and fluoro.

16. The compound of claim 13, wherein R 6 having structure 6B2: (6B2)。 17. The compound of claim 4, wherein R 6 having structure 6B4: (6B4)。 18. The compound of any one of claims 1 to 17, wherein R 4 is selected from substituted amines, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl.

19. The compound of any one of claims 1 to 18, wherein R 4 is optionally substituted alkynyl.

20. The compound of any one of claims 1 to 18, wherein R 4 is optionally substituted cycloalkyl.

21. The compound of any one of claims 1 to 18, wherein R 4 is optionally substituted cycloalkenyl.

22. The compound of any one of claims 1 to 18, wherein R 4 is optionally substituted heterocyclyl.

23. The compound of any one of claims 1 to 18, wherein R 4 is optionally substituted aryl.

24. The compound of any one of claims 1 to 18, wherein R 4 is optionally substituted heteroaryl.

25. The compound of any one of claims 20 to 24, wherein R 4 is an optionally substituted monocyclic group.

26. The compound of any one of claims 20 to 24, wherein R 4 is an optionally substituted bicyclic group.

27. The compound of claim 26, wherein R 4 is an optionally substituted spirocyclic group.

28. The compound of claim 26, wherein R 4 is an optionally substituted fused bicyclic group.

29. The compound of any one of claims 18 to 28, wherein R 4 is selected from substituted amines, (C 2-6 )alkynyl, cyclobutane, cyclopentane, cyclohexane, cyclohexene, piperidinyl, pyrrolidine, pyrrole, pyrazole, azetidine, azepine, pyridinyl, phenyl, pyrimidine, benzisoxazole, indazole, thiazole, dihydropyran, tetrahydropyran, azaindole, indoline, oxindole, triazole, oxadiazole, cyclohexanone, and optionally substituted versions thereof.

30. The compound of any one of claims 18 to 29, wherein R 4 is selected from any one of formula 4A - formula 4M: (4A), (4B), (4C), (4D), (4E), (4F), (4G), (4H), (4I), (4J)、 (4K)、 (4L) and (4M), wherein, X 1 is O, CH2or C(R 26 )2; X 12 is CH2, C(R 15 )2, O, NCOR 25 or NR 25 ; X 14 is O, NCOR 25 or NR 25 ; X 2 , X 6 , X 9 and X 10 are each independently selected from NR 25 , C(R 26 )2, C=0, O and S; X 3 , X 4 , X 5 , X 7 and X 8 are each independently selected from N and CR 26 ; Each R 15 -R 20 and R 24 It is independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and optional substituents of CN; R 21 and R 22 each independently is optionally substituted (Ci_6)alkyl; R 23 is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl; R 25 is H, optionally substituted (C1-6)alkyl, acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted heteroaryl, or optionally substituted aryl; Each R 26 Independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and CN; R 27 and R 28 each independently is H or optionally substituted (Ci_6)alkyl, or R 27 and R 28 together with the nitrogen atom to which they are attached form an optionally substituted cyclic group; R 29 and R 30 each independently is H or optionally substituted (Ci_6)alkyl, or R 29 and R 30 together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; r is 0 or 1; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; u is 0, 1, or 2; v and y are each independently 0, 1, 2, or 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2. wherein:

31. The compound of claim 30, wherein R 4 has formula 4A.

32. The compound of claim 31, wherein R 4 of Formula 4A1 or Formula 4A2: (4A1) or (4A2), r is 0, 1, or 2; and wherein: R 25 is H or optionally substituted (Ci_6)alkyl.

33. The compound of claim 30, wherein R 4 has formula 4B.

34. The compound of claim 33, wherein X 1 is CH2.​ 35. The compound of claim 30, wherein R 4 is of Formula 4C or Formula 4D.

36. The compound of claim 35, wherein R 4 having formula 4C, wherein u is 2.

37. The compound of claim 30, wherein R 4 having formula 4E: (4E)。 38. The compound of claim 37, wherein R 4 is selected from one of the following structures: , , , 、 、 and .

39. The compound of claim 38, wherein R 4 is selected from one of the following structures: , , , , and .

40. The compound of claim 38 or 39, wherein R 25 having the structure: , , or wherein R 33 -R 37 are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen; and g and h are independently 1, 2, 3, 4, or 5 (e.g., 1 or 2).

41. The compound of claim 30, wherein R 4 is one of Formula 4J-Formula 4L: (4J)、 (4K) or (4L).

42. The compound of claim 41, wherein X 5 is CR 26 .

43. The compound of claim 41, wherein X 5 is N.​ 44. The compound of claim 30, wherein R 4 having Formula 4M: (4M)。 45. The compound of claim 44, wherein R 4 is: or .

46. The compound of claim 30, wherein R 4 of Formula 4G: (4G)。 47. The compound of claim 46, wherein X 8 is N.​ 48. The compound of claim 46, wherein X 8 is CH.​ 49. The compound of claim 30, wherein R 4 of Formula 4I: 。 50. The compound of claim 49, wherein R 23 is selected from the group consisting of optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl.

51. The compound of claim 50, wherein R 23 is selected from: (4E), (4F), (4J)、 (4K)、 (4L) and (4M), v and y are each independently 0, 1, 2, or 3; X 2 , X 6 , X 9 and X 10 are each independently selected from NR 25 , C(R 26 )2, C=0, O and S; X 3 , X 4 , X 5 and X 7 are each independently selected from N and CR 26 ; Each R 18 -R 20 and R 24 It is independently selected from optional alkyl, optional amino, optional alkoxy, hydroxy, carboxyl, halogen, optional heterocyclic, optional heteroaryl, optional aryl, optional cycloalkyl and optional substituent of CN; R 25 is H or optionally substituted C1-6alkyl; Each R 26 Independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and CN; R 29 and R 30 each independently is H or optionally substituted (Ci_6)alkyl, or R 29 and R 30 together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2.

58. The compound of any one of claims 1 to 57, wherein Z comprises a substantially biologically inert hydrophilic moiety.

52. The compound of claim 51, wherein R 23 of Formula 4F (4F)。 53. The compound of claim 52, wherein R 23 is selected from one of the following structures: , , and .

54. The compound of claim 30, wherein R 4 having Formula 4F: (4F)。 55. The compound of claim 54, wherein R 4 is selected from one of the following structures: , , and .

56. The compound of claim 30, wherein R 4 having Formula 4H: (4H)。 57. The compound of claim 56, wherein R 27 and R 28 are cyclically linked with the nitrogen atom to which they are attached to provide an optionally substituted piperidinyl group.

59. The compound of any one of claims 1 to 57, wherein Z comprises an electrophilic reactive moiety capable of covalently conjugating a biological target.

60. The compound of any one of claims 1 to 59, wherein Z comprises a group selected from sulfonyl, sulfone, sulfonamide, sulfoximine, sulfilimine, sulfilimine amide, sulfonate, carboxamide, carboxyl, hydroxyl, hydroxyalkyl, aldehyde, ester, alkoxy, nitrile, halogen, thiolactone, and any combination thereof.

61. The compound of claim 60, wherein Z is alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, or heterocyclylsulfonyl.

62. The compound of claim 60, wherein Z is alkylsulfilimine, cycloalkylsulfilimine, heterocyclylsulfilimine, sulfonamide, or alkylsulfonamide. wherein:

63. The compound of any one of claims 1 to 62, wherein L 1 and L 2 is independently absent or an optionally substituted (C 1-6 )alkylene (e.g., CH2, (CH2)2, or (CH2)3).

64. The compound of any one of claims 1-63, wherein -L 2 -Z or Z is one of Z1-Z6: (Z1)、 (Z2), (Z3), (Z4) (Z5) or (Z6), m is 0, 1, or 2; and Y 9 absent, -O-, -NR 9 -, -(C 1-6 )alkylene-O-, -(C 1-6 )alkylene-NR 9 -; X 11 is O or NH; R 51 selected from halogen, R 8 , -NR 9 R 10 ; R 9 is H or optionally substituted (C 1-6 )alkyl; R 10 is H, optionally substituted (C 1-6 )alkyl, optionally substituted (C 3-8 )cycloalkyl, optionally substituted heterocyclyl, sulfone, or thiolactone; and R 52 is H, optionally substituted (C 1-6 )alkyl, optionally substituted aryl, or optionally substituted heterocyclyl; R 8 is (C 1-6 )alkyl (e.g., (C 3-6 ) cycloalkyl), (C 2-6 ) alkenyl, (C 2-6 ) alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; p, q, s, and t are independently 0, 1, 2, 3, 4, 5, or 6. wherein:

65. The compound of claim 64, wherein -L 2 -Z or Z has the formula Z1 and has one of the following structures: (Z1A), (Z1B), (Z1C), ( (Z1B) or (Z1C), wherein; R 51 is halogen; R 8 is (C 1-6 )alkyl (e.g., (C 3-6 ) cycloalkyl), (C 2-6 ) alkenyl, (C 2-6 ) alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R 9 is H or optionally substituted (C 1-6 )alkyl; and R 10 is H, optionally substituted (C 1-6 )alkyl, optionally substituted (C 3-8 )cycloalkyl, or optionally substituted heterocyclyl.

66. The compound of claim 65, wherein -L 2 -Z or Z is and R 8 is (Ci-C6)alkyl.

67. The compound of claim 66, wherein R 8 is methyl.

68. The compound of claim 65, wherein -L 2 -Z or Z is and R 8 is C2-C6 alkenyl.

69. The compound of claim 68, wherein R 8 is -CH=CH2 or -C(CH3)=CH2.

70. The compound of claim 65, wherein -L 2 -Z or Z is and R 8 is C2-C6alkynyl.

71. The compound of claim 70, wherein R 8 is -CCH or -CC-CH3.

72. The compound of claim 65, wherein -L 2 -Z or Z is and R 8 is optionally substituted (C 3-7 )cycloalkyl or optionally substituted (C 2-6 )heterocyclyl.

73. The compound of claim 72, wherein R 8 is (C 3-4 ) cycloalkyl or (C 2-4 ) heterocyclyl.

74. The compound of claim 65, wherein -L 2 -Z or Z is , R 9 is H, and R 10 is H or optionally substituted (C 1-6 )alkyl.

75. The compound of any one of claims 65-74, wherein X 11 is O.

76. The compound of any one of claims 65-74, wherein X 11 is NH.

77. The compound of claim 65, wherein -L 2 -Z or Z has the formula: , wherein R 51 is halogen.

78. The compound of claim 64, wherein -L 2 -Z or Z is of formula Z4, wherein s is 0: (Z4A) wherein; R 9 is H; and R 10 is -SO2R 38 ; and R 38 is optionally substituted alkyl or amino.

79. The compound of claim 64, wherein -L 2 -Z or Z is of formula Z4, wherein s is 0: , (Z4C) R 9 is H; and R 10 is -SO2R 38 wherein R 38 is optionally substituted alkenyl, or R 10 is an optionally substituted thiolactone.

80. The compound of claim 79, wherein -L 2 -Z is of formula Z4C: wherein m is 0, 1, or 2. wherein m is 0, 1, or 2.

81. The compound of claim 64, wherein -L 2 -Z or Z is of formula Z2: (Z2) wherein:

82. The compound of claim 64, wherein -L 2 -Z or Z is of formula Z3: (Z3) t is 0, 1, or 2. R 52 is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heterocyclyl; and (Z3A) 83. The compound of claim 82, wherein R 52 is: 。 84. The compound of claim 64, wherein -L 2 -Z or Z is of formula Z3A, wherein t is 0, wherein q is 0, 1, or 2. wherein R 52 is H.

85. The compound of claim 64, wherein -L 2 -Z or Z is of formula Z5. (Z5) wherein p is 0, 1, or 2.

86. The compound of claim 64, wherein -L 2 -Z or Z is of formula Z6, (Z6) 95. The compound of any one of claims 1 to 94, wherein the compound is of any one of Formulae IA-IM:

87. The compound of any one of claims 1 to 86, wherein R 5 is selected from H, CH3, CF3, and halo.

88. The compound of claim 87, wherein R 5 is H.

89. The compound of any one of claims 1 to 88, wherein R 7 is selected from H, CH3, CF3, and halo.

90. The compound of claim 89, wherein R 7 is H.

91. The compound of any one of claims 1 to 90, wherein R 1 is selected from H, CH3, CF3, and halo.

92. The compound of claim 91, wherein R 1 is H.

93. The compound of any one of claims 1 to 92, wherein R 2 is selected from H, CH3, CF3, -CHF2, -CH2C1, halogen, -C(=0)H, and -(CH2) z OH, wherein z is 1, 2, or 3.

94. The compound of claim 93, wherein R 2 is H. (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), and (IM), or a pharmaceutically acceptable salt thereof. wherein:

96. The compound of claim 95, wherein R 3 is CN.

97. The compound of claim 95, wherein R 3 is H.

98. The compound of any one of claims 95 to 97, wherein R 1 , R 2 , R 5 , and R 7 are each H.

99. The compound of any one of claims 95 to 98, wherein R 6 is selected from: (6C), (6D), (6E), (6F), 6G)、 (6H) and (6I), A is a cyclic group selected from carbocyclyl, heterocyclyl, aryl, heteroaryl, and substituted forms thereof; m is an integer from 0 to 2. R 8 is optionally substituted (C 1-6 )alkyl, optionally substituted (C 2-6 )alkenyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; R 9 is H or optionally substituted (C 1-6 )alkyl; R 10 is a sulfone or a thiolactone; R 52 is H, optionally substituted (C 1-6 )alkyl or optionally substituted heterocyclyl; R 55 is H or optionally substituted (C 1-6 )alkyl; and ​ 100. The compound of claim 99, wherein R 6 of the following formula: 。 101. The compound of claim 99, wherein R 6 of the following formula: 。 102. The compound of any one of claims 100-101, wherein: R 8 is -CH3or -CH2-R 13 and R 13 is optionally substituted (Ci_6)alkyl.

103. The compound of any one of claims 100-101, wherein: R 8 is -CH=CH2or -CH=CH-R 14 and R 14 is optionally substituted (Ci_6)alkyl.

104. The compound of any one of claims 100 to 101, wherein R 8 is optionally substituted (C 3-7 )cycloalkyl or optionally substituted (C 2-6 )heterocyclyl.

105. The compound of any one of claims 100 to 101, wherein R 8 is (C 3-4 ) cycloalkyl or (C 2-4 ) heterocyclyl.

106. The compound of claim 99, wherein R 6 of the following formula: 。 107. The compound of claim 99, wherein R 6 of the following formula: 。 108. The compound of any one of claims 106-107, wherein R 9 is H, and R 10 is H or optionally substituted (C 1-6 )alkyl.

109. The compound of any one of claims 99-108, wherein the A ring is selected from the group consisting of optionally substituted phenyl, optionally substituted pyridyl, optionally substituted 4-piperidinyl, and optionally substituted cyclohexyl.

110. The compound of any one of claims 95-109, wherein: R 4 selected from any one of Formula 4A-Formula 4M: (4A), (4B), (4C), (4D), (4E), (4F), (4G), (4H), (4I), (4J)、 (4K)、 (4L) and (4M), wherein, X 1 is O, CH2or C(R 26 )2; X 12 is CH2, C(R 15 )2, O, NCOR 25 or NR 25 ; X 14 is O, NCOR 43 or NR 43 ; X 2 , X 6 , X 9 and X 10 are each independently selected from NR 25 , C(R 26 )2, C=0, O and S; X 3 , X 4 , X 5 , X 7 and X 8 are each independently selected from N and CR 26 ; Each R 15 -R 20 and R 24 It is independently selected from optional alkyl, optional amino, optional alkoxy, hydroxy, carboxyl, halogen, optional heterocyclic, optional heteroaryl, optional aryl, optional cycloalkyl and optional substituent of CN; R 21 and R 22 each independently is optionally substituted C1-6alkyl; R 23 is H, optionally substituted (Ci_6)alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl; R 25 is H or optionally substituted (Ci_6)alkyl; Each R 26 Independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and CN; R 27 and R 28 each independently is H or optionally substituted (Ci_6)alkyl, or R 27 and R 28 together with the nitrogen atom to which they are attached form an optionally substituted cyclic group; R 29 and R 30 each independently is H or optionally substituted (Ci_6)alkyl, or R 29 and R 30 together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; k is 0, 1, 2, 3, 4, 5, 6, 7, or 8; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; r is 0 or 1; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; u is 0, 1, or 2; v and y are each independently an integer from 0 to 3; w is 0, 1, 2, 3, or 4; and x is 0, 1, or 2; and R 6 selected from the group consisting of: and , wherein: Y 11 selected from O, S, CH2, CHR 11 , C(R 11 )2 and NR 9 ; R 9 is H, optionally substituted (C 1-6 )alkyl, -L 2 -Z or Z; Each R 11 Independently selected from -L 2 -Z, Z, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl carbonyloxy, hydroxyl, halogen and CN; k is 0 or 1; n is an integer from 0 to 9. Y 6 -Y 10 groups are independently selected from C-Z, CR 12 or N, wherein Y 6 -Y 10 one of R and R Each R 12 Independently selected from H, optionally substituted alkyl groups, halogens, and CN.

111. The compound of claim 110, wherein R 4 is selected from Table 1.

112. The compound of claim 110, wherein R 6 is selected from Table 2.

113. The compound of any one of claims 95-112, wherein the compound is of Formula (IA): (IA), or a pharmaceutically acceptable salt thereof.

114. The compound of claim 113, wherein the compound is of Formula IV: (IV) or a pharmaceutically acceptable salt thereof, wherein: Y 6 , Y 7 , Y 9 , and Y 10 are independently selected from CR 12 and N, wherein at least two of Y 6 , Y 7 , Y 9 , and Y 10 are CR 12 ; and Each R 12 Independently selected from H, optionally substituted (C) 1-6 )alkyl, optionally substituted (C 1-6 Alkoxy, hydroxy, halogen and CN.

115. The compound of claim 114, wherein Y 6 , Y 7 , Y 9 , and Y 10 are each independently CH or CR 12 , and the compound is of Formula V: (V) or a pharmaceutically acceptable salt thereof, wherein m is an integer from 0 to 4.

116. The compound of claim 115, wherein the compound is of Formula VIA: (VIA) or a pharmaceutically acceptable salt thereof.

117. The compound of any one of claims 113-115, wherein Z is (Z1B) or (Z1C), wherein: R 8 is (C 1-6 )alkyl (e.g., (C 3-6 ) cycloalkyl), (C 2-6 ) alkenyl, (C 2-6 ) alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R 9 is H or optionally substituted (C 1-6 )alkyl; R 10 is H, optionally substituted (C 1-6 )alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; and X 11 is O or NH.

118. The compound of claim 116 or 117, wherein the compound is of Formula VIIA: (VIIA) or a pharmaceutically acceptable salt thereof, wherein: R 25 is optionally substituted (Ci_6)alkyl or optionally substituted -C(=0)Ci_6alkyl; X 11 is O or NH; R 41 is R 8 or N(R 9 )R 10 ; R 8 is (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R 9 is H or optionally substituted (C 1-6 )alkyl; and R 10 is H, optionally substituted (C 1-6 )alkyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl.

119. The compound of claim 118, wherein the compound is of Formula VIIIA: (VIIIA) or a pharmaceutically acceptable salt thereof, wherein: R 25 is optionally substituted (Ci_6)alkyl; R 18 is H, halogen, optionally substituted (Ci_6)alkyl or optionally substituted (Ci_6)alkoxy; and R 12 is H, halogen, optionally substituted (Ci_6)alkyl or optionally substituted (Ci_6)alkoxy.

120. The compound of any one of claims 118-119, wherein R 25 is selected from methyl, ethyl, propyl, isopropyl, isobutyl, isopentyl, and substituted versions thereof.

121. The compound of any one of claims 118-120, wherein R 25 has the structure: , , or wherein R 33 -R 37 are independently selected from H, CF3, CHF2, CH2F, CH3, OH, OCH3, and halogen; and g and h are independently 1, 2, 3, 4, or 5 (e.g., 1 or 2).

122. The compound of claim 121, wherein R 35 is OH.

123. The compound of claim 122, wherein R 25 is: or .

124. The compound of any one of claims 118 to 123, wherein R 41 is R 8 .

125. The compound of claim 124, wherein R 8 is (C 1-6 )alkyl.

126. The compound of claim 124, wherein R 8 is optionally substituted (C 3-7 )cycloalkyl or optionally substituted (C 2-6 )heterocyclyl.

127. The compound of claim 126, wherein R 8 is (C 3-4 ) cycloalkyl or (C 2-4 ) heterocyclyl.

128. The compound of any one of claims 118 to 123, wherein R 41 is N(R 9 )R 10 .

129. The compound of claim 128, wherein R 41 is NH2 or -NH(Ci-6)alkyl.

130. The compound of any one of claims 117 to 129, wherein X 11 is O.

131. The compound of any one of claims 117 to 129, wherein X 11 is NH.

132. The compound of claim 115, wherein the compound is of Formula VIB: (VIB) or a pharmaceutically acceptable salt thereof, wherein m is an integer from 0 to 4.

133. The compound of claim 132, wherein the compound is of Formula VIIB: (VIIB). or a pharmaceutically acceptable salt thereof, wherein: Each R 24 It is independently selected from optional alkyl, optional amino, optional alkoxy, hydroxy, carboxyl, halogen, optional heterocyclic, optional heteroaryl, optional aryl, optional cycloalkyl and optional substituent of CN; R 25 is H or optionally substituted (Ci_6)alkyl; R 29 and R 30 each independently is H or optionally substituted (Ci_6)alkyl, or R 29 and R 30 together with the carbon atom to which they are attached form an optionally substituted spirocyclic group; and y is 0, 1, 2, or 3.

134. The compound of claim 133, wherein the compound is of Formula VIIIB: (VIIIB) or a pharmaceutically acceptable salt thereof.

135. The compound of claim 133 or 134, wherein the compound is of Formula IX: (IX) or a pharmaceutically acceptable salt thereof.

136. The compound of any one of claims 133 to 135, wherein R 12 is H, halogen, optionally substituted (Ci_6)alkyl, or optionally substituted (Ci_6)alkoxy.

137. The compound of claim 136, wherein R 12 is H.

138. The compound of claim 136, wherein R 12 is (Ci-6)alkyl.

139. The compound of claim 138, wherein R 12 is methyl.

140. The compound of claim 136, wherein R 12 is halogen.

141. The compound of claim 136, wherein R 12 is (Ci-6)alkoxy.

142. The compound of claim 141, wherein R 12 is methoxy.

143. The compound of any one of claims 133 to 142, wherein R 29 and R 30 each independently is optionally substituted (Ci_6)alkyl.

144. The compound of claim 143, wherein R 29 and R 30 are each independently (Ci-3)alkyl.

145. The compound of claim 144, wherein R 29 and R 30 are each methyl.

146. The compound of claim 144, wherein R 29 and R 30 are each ethyl.

147. The compound of any one of claims 133 to 142, wherein R 29 and R 30 together with the carbon atom to which they are attached form an optionally substituted spirocyclic group.

148. The compound of claim 147, wherein the optionally substituted spirocyclic group is spirocyclopropyl or spirocyclobutyl.

149. The compound of any one of claims 133 to 148, wherein R 41 is R 8 .

150. The compound of claim 149, wherein R 8 is (C 1-6 )alkyl.

151. The compound of claim 149, wherein R 8 is optionally substituted (C 3-7 )cycloalkyl or optionally substituted (C 2-6 )heterocyclyl.

152. The compound of claim 151, wherein R 8 is (C 3-4 )cycloalkyl or (C 2-4 )heterocyclyl.

153. The compound of any one of claims 133 to 148, wherein R 41 is N(R 9 )R 10 .

154. The compound of claim 153, wherein R 41 is NH2 or NH-(Ci-6)alkyl.

155. The compound of any one of claims 133 to 154, wherein X 11 is O.

156. The compound of any one of claims 133 to 154, wherein X 11 is NH.

157. The compound of claim 113, wherein the compound is of Formula X: (X) or a pharmaceutically acceptable salt thereof, wherein: Each R 11 Independently selected from optionally substituted alkyl groups, optionally substituted alkoxy groups, halogens, OH, and CN; and n is an integer from 0 to 9.

158. The compound of claim 157, wherein R 4 is selected from: (4I), (4D), (4I) and (4H), wherein: X 2 , X 9 , and X 10 are each independently selected from NR 25 , C(R 26 )2, C=0, O, and S; X 3 and X 4 are each independently selected from N and CR 26 ; X 12 is CH2, CHR 42 , C(R 42 )2, NCOR 43 or NR 43 ; Each R 15 R 18 and R 24 It is independently selected from optional alkyl, optional amino, optional alkoxy, hydroxy, carboxyl, halogen, optional heterocyclic, optional heteroaryl, optional aryl, optional cycloalkyl and optional substituent of CN; R 23 is H, optionally substituted (Ci_6)alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl; Each R 26 Independently selected from H, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, hydroxyl, carboxyl, halogen, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl and CN; R 29 and R 30 each independently is H or optionally substituted (C1-6)alkyl, or R 29 and R 30 together with the carbon atom to which they are attached form an optionally substituted spirocyclic group (e.g., an optionally substituted spirocyclopropyl or spirocyclobutyl); R 42 is H, optionally substituted (Ci_6)alkyl, optionally substituted acyl, optionally substituted carboxamide, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl; R 43 is H, optionally substituted (C1-6)alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 r is 0 or 1; and each v and y is independently an integer from 0 to 3.

159. The compound of claim 157 or 158, wherein the compound is of Formula XI: (XI) or a pharmaceutically acceptable salt thereof.

160. The compound of claim 159, wherein: X 12 is CHR 42 ; and R 42 is selected from H, optionally substituted (Ci_6)alkyl, optionally substituted acyl, optionally substituted carboxamide, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl.

161. The compound of claim 160, wherein: R 42 is -C(=O)R 42a , -C(=O)NHR 42a , -NHC(=O)R 42a , wherein R 42a is H, optionally substituted (C1-6)alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl or optionally substituted aryl; R 42 is optionally substituted (Ci_6)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl; or R 42 is optionally substituted -(CH2) z cycloalkyl, optionally substituted -(CH2) z heterocycle, optionally substituted -(CH2) z heteroaryl or optionally substituted -(CH2) z aryl, wherein z is 1, 2, 3, 4 or 5.

162. The compound of claim 159, wherein: X 12 is NR 43 ; and R 43 is selected from H, optionally substituted (Ci_6)alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl.

163. The compound of claim 161, wherein: R 43 is optionally substituted -C(=O)C1-6alkyl, optionally substituted -C(=O)cycloalkyl, optionally substituted -C(=O)heterocycle, optionally substituted -C(=O)heteroaryl, or optionally substituted -C(=O)aryl; R 43 is optionally substituted (Ci_6)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl; or R 43 is optionally substituted -(CH2) z cycloalkyl, optionally substituted -(CH2) z heterocycle, optionally substituted -(CH2) z heteroaryl or optionally substituted -(CH2) z aryl, wherein z is 1, 2, 3, 4 or 5.

164. The compound of any one of claims 157 to 163, wherein Z is of the formula: (Z1B) or (Z1C), wherein: R 8 is (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, cycloalkyl, heterocyclyl, or a substituted version thereof; R 9 is H or optionally substituted (C 1-6 )alkyl; R 10 is H, optionally substituted (C 1-6 )alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; and X 11 is O or NH.

165. The compound of any one of claims 1-164, wherein the compound is selected from any one of Compounds 1-Compounds 965 and the compounds of Tables 3-15, or a pharmaceutically acceptable salt thereof.

166. A pharmaceutical composition comprising a compound of any one of claims 1 to 165 and a pharmaceutically acceptable excipient.

167. A method of inhibiting a cyclin-dependent kinase (CDK), the method comprising contacting a biological sample containing a CDK with a compound of any one of claims 1 to 165 in an amount effective to inhibit the CDK.

168. A method of inhibiting a CDK in a subject, comprising administering to the subject a compound of any one of claims 1 to 165 or a pharmaceutical composition of claim 166 to inhibit the CDK in the subject.

169. The method of claim 167 or 168, wherein the CDK is CDK2.

170. The method of claim 167 or 168, wherein the CDK is CDK4.

171. A method of treating a disease or disorder associated with CDK2 in a subject, the method comprising administering to a subject in need thereof a dose of a compound of any one of claims 1 to 165 or a pharmaceutical composition of claim 166.

172. The method of claim 171, wherein the disease or disorder associated with CDK2 is cancer.

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